From 1554f6d77fc254219b2085239fcf5172ebe0bbeb Mon Sep 17 00:00:00 2001 From: Charles Tapley Hoyt Date: Fri, 15 Feb 2019 15:57:01 +0100 Subject: [PATCH] Add curation sheet with 500 BEL statements @ddomingof there's definitely room for more. Also, looks like there are quite a few miRNAs that get missed by INDRA. See sorgerlab/indra#255 at https://github.com/sorgerlab/indra/issues/255 --- curation/README.rst | 13 +- curation/curation.tsv | 502 ++++++++++++++++++++++++++++++++++++ curation/generate.sh | 7 + curation/generation-log.txt | 71 +++++ curation/pubmeds.txt | 3 - curation/statements.pkl | Bin 0 -> 578728 bytes 6 files changed, 581 insertions(+), 15 deletions(-) create mode 100644 curation/curation.tsv create mode 100755 curation/generate.sh create mode 100644 curation/generation-log.txt create mode 100644 curation/statements.pkl diff --git a/curation/README.rst b/curation/README.rst index d9aabc4..dde1b9d 100644 --- a/curation/README.rst +++ b/curation/README.rst @@ -1,14 +1,3 @@ Curation ======== -1. Generate a PubMed identifier list: - -.. code-block:: sh - - $ cat pubmeds.tsv | cut -f 1 | grep -e "^\d\+$" > pubmeds.txt - - -2. Generate curation sheet and pickles: - -.. code-block:: sh - - $ bel-enrichment from-pmids --pmids pubmeds.txt --output curation.tsv --pickle-file statements.pkl +The ``generate.sh`` script was used to create ``pmids.txt``, ``statements.pkl``, and ``curation.tsv``. It is logged with ``generation-log.txt``. diff --git a/curation/curation.tsv b/curation/curation.tsv new file mode 100644 index 0000000..2a20d73 --- /dev/null +++ b/curation/curation.tsv @@ -0,0 +1,502 @@ +INDRA UUID Belief PMID Evidence API Subject Predicate Object +d58da677-6b7d-40bc-a7ba-083b03da81a7 0.99 10360949 Insulin and IGF-1 receptors activate Akt to a similar extent, whereas GSK-3 inactivation in response to IGF-1 is considerably lower in both -/- and WT cells, compared to the effect of insulin in WT cells. reach p(HGNC:INS) directlyIncreases act(p(FPLX:AKT)) +a260ff4f-5ab3-4b69-9708-a635f62f528d 0.95 10366600 Some clusters of VCAM-1 were present on the surface of TNF-α–activated HUVECs treated with anti–VCAM-1 antibody (Fig. xref g), but addition of secondary antibodies caused a marked increase in VCAM-1 clustering (Fig. xref h). sparser p(HGNC:TNF) directlyIncreases act(p(HGNC:SLC7A6)) +eb01c4cc-e251-4217-a9f6-6ce86cf2993e 0.99 10759890 IKK-i significantly induced NF-kappaB activation upon over-expression, as did IKK-alpha and IKK-beta. reach p(HGNC:IKBKE) directlyIncreases act(p(FPLX:NFkappaB)) +eb01c4cc-e251-4217-a9f6-6ce86cf2993e 0.99 10759890 Unlike IKK-alpha and IKK-beta, IKK-i phosphorylated Ser36 but not Ser32 in vitro, suggesting that IKK-i activates NF-kappaB by distinct mechanisms from the conventional IKKs. sparser p(HGNC:IKBKE) directlyIncreases act(p(FPLX:NFkappaB)) +920a4f0a-c035-4346-96ce-2d79dab40db5 1.0 11007948 Instead, TLR4 is probably activated by the complex of CD14 and LPS binding protein (LBP) with LPS, and induces transmembrane signaling . sparser p(HGNC:CD14) directlyIncreases act(p(HGNC:TLR4)) +46ccb254-c30d-42d1-891d-17303d643d21 1.0 11059778 Overall, the data indicate that O6MeG induces apoptosis via secondary lesions that trigger Bcl-2 decline, cytochrome c release, and caspase-9 and caspase-3 activation independently of Fas and Fas ligand and p53, for which the cells are mutated. reach p(HGNC:CASP3) directlyIncreases act(p(HGNC:TP53)) +018c50fb-d378-418b-b20c-0301870c00ab 0.95 11152283 EGF is clearly able to activate gene transcription, suggesting that the differences in the biological activities of EGF and NGF can not be explained by the inability of EGF to stimulate gene transcription. reach p(HGNC:NGF) directlyIncreases bp(GO:"GO:0006351") +cf39b25c-ca63-4355-924a-043483d3d5af 0.95 11278362 Caspase mediated proteolytic activation parallels cell death and appears to be a pro apoptotic factor in stress induced cell death. reach p(FPLX:Caspase) directlyIncreases bp(GO:"GO:0008219") +0991ea45-f706-4dc8-bb41-b161314148c3 0.95 11356694 Addition of the specific PI 3-K inhibitor LY294002 to the granulosa cell cultures decreased Akt phosphorylation and induced apoptosis in a dose dependent manner. reach p(FPLX:AKT) directlyIncreases bp(GO:"GO:0006915") +12fc128d-91e3-4acd-985a-ebb192b3a6e2 0.99 11521063 MD-2 enables TLR4 to respond to a wide variety of endotoxic LPS partial structures, Gram negative bacteria, and Gram positive lipoteichoic acid, but not to Gram positive bacteria, peptidoglycan, and lipopeptide. reach p(HGNC:LY96) directlyIncreases act(p(HGNC:TLR4)) +0755e65a-7681-44e8-a0af-ce15e55fe046 0.99 11571288 Our results suggest that NGF utilizes both the Ras and ERK and phosphatidylinositol 3-kinase pathways to up-regulate NR1 promoter activity and that Sp1 is a novel substrate of NGF activated ERKs. reach p(HGNC:NGF) directlyIncreases act(p(FPLX:ERK)) +c97a3b8b-eddb-4255-8abf-e28ef34d4cf0 0.99 11911828 All these responses required functional PI3Kγ, were toxin sensitive (data not shown), and correlated with a PI3Kγ-dependent activation of PKB . sparser p(HGNC:PIK3CG) directlyIncreases act(p(FPLX:AKT)) +adb6555d-fc3d-46de-a8da-8c557580958a 0.95 11960013 In addition, IRAK-4 is able to phosphorylate IRAK-1, and overexpression of dominant negative IRAK-4 is blocking the IL-1-induced activation and modification of IRAK-1, suggesting a role of IRAK-4 as a central element in the early signal transduction of Toll/IL -1 receptors, upstream of IRAK-1. reach p(HGNC:IRAK4) directlyDecreases act(p(HGNC:IRAK1)) +73461c97-a89b-40ad-be13-3d7f30e4ea6f 0.98 12138165 The substitution of Thr-66 with alanine or glutamate prevented spontaneous activation of NF-kappaB by overexpressed IRAK but enhanced IL-1-induced activation of the factor. sparser p(HGNC:IRAK1) directlyIncreases act(p(FPLX:NFkappaB)) +92e92d63-67d0-44fc-8cf2-8c751ef82a11 1.0 12401334 Using immunocytochemistry and immunoblotting, we have also demonstrated that Abeta treatment can significantly increase the phosphorylation of tau protein in septal cultures. reach p(HGNC:APP) directlyIncreases p(HGNC:MAPT, pmod(Ph)) +cf39b25c-ca63-4355-924a-043483d3d5af 0.95 12415117 Mutant brains showed caspase specific poly (ADP-ribose) polymerase cleavage product (85-kDa fragment) in vivo and in vitro, suggesting redundant mechanisms and persistence of caspase mediated cell death. reach p(FPLX:Caspase) directlyIncreases bp(GO:"GO:0008219") +3f9b72b1-85a2-4895-97fd-f3ee843f4860 0.95 12512601 The minimal doses of leptin that decreased IGF-I- and fetal bovine serum stimulated cell proliferation were 64 and 1 ng/ml, respectively. reach p(HGNC:IGF1) directlyIncreases bp(GO:"GO:0008283") +623eaef0-1c13-478b-9d18-bb5aecb85570 1.0 12647306 By comparison, IGF-I increased the levels of the phosphorylated forms of ERK-1 and -2, and Akt and PKB. reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:AKT)) +3f9b72b1-85a2-4895-97fd-f3ee843f4860 0.95 12810174 Furthermore, IGF-I administration (10 ng/ml) in vitro significantly increased cell proliferation of the BMOp cells isolated from normally loaded bone, but not that of cells from unloaded bone. reach p(HGNC:IGF1) directlyIncreases bp(GO:"GO:0008283") +adb6555d-fc3d-46de-a8da-8c557580958a 0.95 12925671 XREF_FIG C demonstrates that, unlike WT IRAK-4, this more truncated form of IRAK-4 also failed to augment endogenous IRAK-1 kinase activity and inhibited endogenous basal and IL-1-induced IRAK-1 activity, although less than observed upon overexpression of pRK7-IRAK4 (M # 1). reach p(HGNC:IRAK4) directlyDecreases act(p(HGNC:IRAK1)) +775f864e-0093-4adc-87f9-d77148273465 1.0 14697248 Reduction of ErbB2 expression in ErbB2 overexpressing SKBR3/IGF-IR cells by using ErbB2 antisense did not have any effect on IGF-I-induced activation of IGF-IR, IRS-1, and AKT (data not shown). sparser p(HGNC:IGF1) directlyIncreases act(p(HGNC:IRS1)) +a260ff4f-5ab3-4b69-9708-a635f62f528d 0.95 14742243 Coverslips of control and TNF-α-activated HUVECs were used as the bottom plates of a parallel flow chamber as described with minor modifications. sparser p(HGNC:TNF) directlyIncreases act(p(HGNC:SLC7A6)) +0c71874f-464d-4378-8f68-7d4af12d3414 0.95 15322075 Together, our findings suggest that CHOP regulates ER stress induced apoptosis, at least in part, through enhancing DR5 expression in some types of human cancer cells. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0006915") +775f864e-0093-4adc-87f9-d77148273465 1.0 15576984 This seminar summarize the involvements of a key molecule of adipocytic differentiation PPAR-gamma, essential IGF-I signaling molecules IRS-1 and IRS-2, and an anti-aging gene klotho in the pathophysiology of age related osteoporosis. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:IRS1)) +7a204913-3db0-486e-bf55-7cc3a7fcc489 0.98 15578154 However, the mechanisms underlying SOCS-3 inhibition of IL-1beta signalling and prevention against apoptosis remain unknown. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL1B)) +78d8d903-7ff1-4f78-8807-c9688954a60b 0.95 15630138 Biochemical assays indicate that Spred-1 suppresses IL-5-dependent cell proliferation and ERK activation. reach p(HGNC:SPRED1) directlyDecreases act(p(FPLX:ERK)) +78d8d903-7ff1-4f78-8807-c9688954a60b 0.95 15630138 Like Sproutys, Spred-1, Spred-2, and Spred-3 also down-regulate Ras and ERK signaling. reach p(HGNC:SPRED1) directlyDecreases act(p(FPLX:ERK)) +efc0f64c-a37a-4cf4-9c89-049ff1b9d7ad 0.95 15642743 An interesting problem arises from the fact that p38 MAPK activation is a frequent stress response, which normally does not lead to cell death. reach bp(GO:"GO:0006950") directlyIncreases bp(GO:"GO:0008219") +018c50fb-d378-418b-b20c-0301870c00ab 0.95 15813958 Nerve growth factor inducible B (NGFIB) (also known as Nur77) is a transcription factor that is rapidly induced by NGF [XREF_BIBR]. reach p(HGNC:NGF) directlyIncreases bp(GO:"GO:0006351") +775f864e-0093-4adc-87f9-d77148273465 1.0 16166225 Immunoblotting revealed that methyl-cyclodextrin had no effect on IGF-I-induced activation of the IGF-IR or insulin receptor substrate 1 but increased and decreased the phosphorylation of MAPK and protein kinase B, respectively. sparser p(HGNC:IGF1) directlyIncreases act(p(HGNC:IRS1)) +623eaef0-1c13-478b-9d18-bb5aecb85570 1.0 16373405 These results suggest that IGF-I may activate Akt via PI3K in human endometrium and decidua. sparser p(HGNC:IGF1) directlyIncreases act(p(FPLX:AKT)) +51dd5a26-38f6-4ed6-816a-35ab60dc1fd3 1.0 16507160 Tollip inhibits Irak signaling by targeting it for ubiquitination [XREF_BIBR]. reach p(HGNC:TOLLIP) directlyDecreases act(p(HGNC:IRAK1)) +623eaef0-1c13-478b-9d18-bb5aecb85570 1.0 16684509 To further examine the utility of IGF-F1-1 as an IGF-1 antagonist we tested its ability to inhibit IGFBP-2 and IGFBP-3 binding to IGF-1, (125)I-IGF-1 binding to IGF-1Rs and to block IGF-1 induced Akt activation, cell cycle changes and [(3)H]thymidine incorporation in MCF-7 cells. sparser p(HGNC:IGF1) directlyIncreases act(p(FPLX:AKT)) +4d0054ac-5799-4ccf-9361-26f88691d77a 0.95 17200689 In summary, we have demonstrated that IGF-1 stimulates Akt and GSK-3beta pathway leading to CREB phsophorylation and CRE binding activity in glomerular mesangial cells. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:GSK3B)) +716cc167-a897-4a68-acd0-4134b89a2790 0.95 17217928 Compared with control subjects, thapsigargin- and tunicamycin induced increases in XBP1 and CHOP but not GRP78 messenger RNA levels were significantly lower in BD-I patients. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:DDIT3)) +72000a1a-331a-4cd0-b932-fc0dac5bb4d9 0.95 17255561 NF-kappaB activation in the neonatal lung is antiinflammatory, protecting against LPS mediated lung inflammation by repressing similar inflammatory genes induced in the adult. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006954") +a260ff4f-5ab3-4b69-9708-a635f62f528d 0.95 17541274 On the other hand, the levels of eosinophils accumulating on TNF-alpha-activated HUVECs were the same at all time points (1, 3, 6, 18 and 24 h). sparser p(HGNC:TNF) directlyIncreases act(p(HGNC:SLC7A6)) +fd8191a7-4762-4760-82ee-85b1429564a8 0.95 17804721 Indeed, suppression of CHOP protein levels with small hairpin RNA reduced cell death. reach p(HGNC:DDIT3) directlyIncreases bp(GO:"GO:0008219") +775f864e-0093-4adc-87f9-d77148273465 1.0 17823215 In intestinal epithelial cells, IRS-1 was expressed at higher levels than IRS-2 and was preferentially activated by IGF-I. In contrast, IGF-I activated both IRS-1 and IRS-2 in intestinal myofibroblasts and IRS-2 activation was upregulated in IRS-1-null myofibroblasts. sparser p(HGNC:IGF1) directlyIncreases act(p(HGNC:IRS1)) +efc0f64c-a37a-4cf4-9c89-049ff1b9d7ad 0.95 17875675 In these studies, we only provide evidence for the effect of XBP-1 deficiency on cell death induced by the ER stress response; future studies will aim to examine other forms of DC survival and death. reach bp(GO:"GO:0006950") directlyIncreases bp(GO:"GO:0008219") +716cc167-a897-4a68-acd0-4134b89a2790 0.95 17942911 Knockdown of GRP78 in glioblastoma cell lines induces CHOP and activates caspase-7 in temozolomide treated cells. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:DDIT3)) +0755e65a-7681-44e8-a0af-ce15e55fe046 0.99 17999938 NGF stimulation also resulted in detectable activation of FAK, Akt and MAPK by 10 min. reach p(HGNC:NGF) directlyIncreases act(p(FPLX:ERK)) +1f42ee8f-af93-46eb-a92b-4ababffef749 1.0 18076874 When the cardiomyocytes were incubated in the presence of 10 microM tanshinone VI, IGF-1- and endothelin-1-induced increases in pERK, but not pAkt, were partially attenuated. reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:ERK, pmod(Ph))) +adb6555d-fc3d-46de-a8da-8c557580958a 0.95 18079163 These results suggested that the expression of IRAK-4 alone is sufficient to cause the degradation of IRAK-1; the autophosphorylation of IRAK-1 is not necessary to terminate the TLR induced activation of NF-kappaB. reach p(HGNC:IRAK4) directlyDecreases act(p(HGNC:IRAK1)) +ee10d13e-6b36-4b84-9925-ef650bd004dd 0.95 18174271 In WT livers, BDL induced overexpression of CHOP and Bax, a downstream target in the CHOP mediated ER stress pathway. reach p(HGNC:DDIT3) directlyIncreases act(p(HGNC:ESR1)) +69c67fc7-405a-40da-a682-44605602a364 0.95 18458112 Accordingly, forced expression of ATF4 was sufficient to promote cell death and loss of glutathione. reach p(HGNC:ATF4) directlyIncreases bp(GO:"GO:0008219") +0755e65a-7681-44e8-a0af-ce15e55fe046 0.99 18469341 U0126 is known to block NGF-induced activation of ERK1/2 in PC12 cells ( xref ). sparser p(HGNC:NGF) directlyIncreases act(p(FPLX:ERK)) +697a8013-0350-4626-a5db-6228b907506c 0.99 18575606 This suggests that the major effect of X11L overexpression is the γ-secretase independent inhibition of AICD. sparser p(HGNC:APP) directlyDecreases act(p(HGNC:APP)) +840e5f0e-ec8e-4eb9-81cb-b619edb48caf 0.95 18761401 Using stable alpha-syn-expressing N27 cell lines, we first developed a PI mediated neurotoxic model of PD and tested it in terms of cell viability and GSH metabolism. reach p(FPLX:PI3K) directlyIncreases bp(MESH:D010300) +cd9dc75f-8113-49b7-aa3f-3b9d97c729dc 0.98 18789402 Furthermore, Akt and NF-kappaB inhibitors also reverses the apoptosis resistance, accordingly, Akt constitutive activation rescues NF-kappaB activation and Bcl-xL expression in rapamycin pretreated colon cancer cells, suggesting Akt disruption is critical to the process. reach p(FPLX:AKT) directlyIncreases act(p(FPLX:NFkappaB)) +efc0f64c-a37a-4cf4-9c89-049ff1b9d7ad 0.95 18852129 These data suggest that abrogation of stress response induction by MEL may cause added cell death when it is combined with GA.. reach bp(GO:"GO:0006950") directlyIncreases bp(GO:"GO:0008219") +92e92d63-67d0-44fc-8cf2-8c751ef82a11 1.0 18854169 AICD-mediated transcriptional activation may be a positive feedback mechanism to increase Aβ generation and hyperphosphorylated tau generation, since BACE and GSK-3β are capable of generating Aβ from [MISSING/INVALID API KEY: limited to 200 char for Elsevier] sparser p(HGNC:APP) directlyIncreases p(HGNC:MAPT, pmod(Ph)) +fa2d0182-7d30-4f39-864f-7cd17a0eb20b 0.98 18948188 For example, a possible pathogenic pathway of Alzheimer 's disease may be ROS mediated down-regulation of BiP, since BiP can prevent the buildup of amyloid-beta plaques. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:HSPA5)) +cd9dc75f-8113-49b7-aa3f-3b9d97c729dc 0.98 19049803 These results indicated that insulin regulated P-glycoprotein function and expression through signal transduction pathways involving activation of PKC and NF-kappaB but not PI3K and Akt pathway. reach p(FPLX:AKT) directlyIncreases act(p(FPLX:NFkappaB)) +3f9b72b1-85a2-4895-97fd-f3ee843f4860 0.95 19105244 Following treatment of INS-1 cells for 24 hrs with 50 ng/ml IGF-I or 20 ng/ml betacellulin, IGF-I and betacellulin enhanced INS-1 cell proliferation as reflected by a greater than 2-fold increase in the percentage of BrdU + cells in IGF-I- and betacellulin treated vs. control cells. reach p(HGNC:IGF1) directlyIncreases bp(GO:"GO:0008283") +51e70dc9-716d-467e-962f-eaf8aaa06ff0 0.95 19183502 High constitutive NF-kappaB activity mediates resistance to oxidative stress in neuronal cells [XREF_BIBR] and, agents that inhibit NF-kappaB activation induced apoptosis in response to several neurotoxins [XREF_BIBR - XREF_BIBR]. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006915") +c071ed43-4f92-4778-ada7-ec6542768122 0.95 19241442 In ER stress induced apoptosis, GADD153 is activated by ROS and dimerizes with other C/EBP family members to exercise its function. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:DDIT3)) +fd8191a7-4762-4760-82ee-85b1429564a8 0.95 19243235 In particular, while short term induction of CHOP is an important element of the protective UPR, prolonged expression of CHOP can lead to cell death. reach p(HGNC:DDIT3) directlyIncreases bp(GO:"GO:0008219") +ee10d13e-6b36-4b84-9925-ef650bd004dd 0.95 19329340 The presence of CHOP and subsequently GADD34 lead to dephosphorylation of eIF2alpha, increased protein synthesis and greater ER stress in these neurons. reach p(HGNC:DDIT3) directlyIncreases act(p(HGNC:ESR1)) +623eaef0-1c13-478b-9d18-bb5aecb85570 1.0 19382214 Moreover, we show that activation of Akt by IGF-I occurs in CEMs, providing support for the hypothesis that these molecules associate functionally in these domains. reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:AKT)) +c97a3b8b-eddb-4255-8abf-e28ef34d4cf0 0.99 19384426 The p110delta isoform constitutively activated the Akt signaling pathway, but p110gamma activated Akt only in the presence of serum [XREF_BIBR]. reach p(HGNC:PIK3CG) directlyIncreases act(p(FPLX:AKT)) +c97a3b8b-eddb-4255-8abf-e28ef34d4cf0 0.99 19384426 The p110δ isoform constitutively activated the Akt signaling pathway, but p110γ activated Akt only in the presence of serum [ xref ]. sparser p(HGNC:PIK3CG) directlyIncreases act(p(FPLX:AKT)) +cf39b25c-ca63-4355-924a-043483d3d5af 0.95 19490089 Growth hormone releasing peptide 6 partially reversed glutamate induced cell death but not the activation of caspases, suggesting blockage of the caspase independent cell death pathway, which included interference with the translocation of apoptosis inducing factor to the nucleus associated with the induction of Bcl-2. reach p(FPLX:Caspase) directlyIncreases bp(GO:"GO:0008219") +06bd0dfa-24ce-4570-91f4-feea991b6ca4 0.95 19643666 SOCS3 might partially mediate this effect by suppressing STAT3 activation and blocking IL-6 and IL-23 induction [XREF_BIBR]. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL6)) +a6f8e61d-9758-4de0-ad6e-9ae0e93491f0 0.95 19645497 There is in fact, another side to macrophage functioning : suppression of inflammation and wound repair. reach p(PFAM:PF12252) directlyDecreases bp(GO:"GO:0006954") +eee57673-9e37-4cd5-8c8c-6989f2ab5af5 0.95 19736567 Furthermore, p28 (GANK) upregulates glucose regulated protein 78 (GRP78), a key ER chaperone protein, which subsequently enhances the ER folding capacity and promotes recovery from ER stress. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:ESR1)) +775f864e-0093-4adc-87f9-d77148273465 1.0 19744489 In this case, IGF-1 selectively activates IRS-2 and the PI3K pathway but not the IRS-1 and ERK pathway. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:IRS1)) +e097dc81-706a-4ccd-9e57-d535f600f989 0.95 19752148 However, there was little change in insulin induced P-Akt (S473) in triceps following trauma and hemorrhage from 3-week old rats (XREF_FIG). reach p(HGNC:INS) directlyIncreases act(p(UP:P54644)) +d58da677-6b7d-40bc-a7ba-083b03da81a7 0.99 19780047 These FFA also decreased Akt activation by insulin. sparser p(HGNC:INS) directlyIncreases act(p(FPLX:AKT)) +1f42ee8f-af93-46eb-a92b-4ababffef749 1.0 19815064 As a positive control, IGF-1 at 10 ng/ml strongly enhanced the green staining of the phosphorylated MAPK (i and l). reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:ERK, pmod(Ph))) +0221e1d5-71ae-4d51-851d-85133aab51d9 0.95 19846873 TRIF -/- mice infected with Kp showed impaired survival and reduced bacterial clearance, neutrophil influx, histopathologic evidence of inflammation, and TNF-alpha, IL-6, KC, MIP-2, but not LIX, expression in the lungs. reach p(HGNC:TICAM1) directlyDecreases bp(GO:"GO:0006954") +d58da677-6b7d-40bc-a7ba-083b03da81a7 0.99 19933999 Therefore, we investigated whether exposing L6 myotubes to SR141716 would abrogate the effects of CB1 activation on insulin stimulated PKB and ERK1/2 activation. reach p(HGNC:INS) directlyIncreases act(p(FPLX:AKT)) +78d8d903-7ff1-4f78-8807-c9688954a60b 0.95 19956540 A novel gene Spred-1 (Sproutyrelated Ena and VASP homology 1-domain-containing protein-1) is involved in the inhibition of the Ras/Raf-1/ERK pathway impairing the growth-factor-mediated activation of ERK1/2 kinases XREF_BIBR. reach p(HGNC:SPRED1) directlyDecreases act(p(FPLX:ERK)) +78d8d903-7ff1-4f78-8807-c9688954a60b 0.95 20014119 SPRED1 negatively regulates the Ras and MAPK signaling pathway at the Ras-Raf interface. reach p(HGNC:SPRED1) directlyDecreases act(p(FPLX:ERK)) +12fc128d-91e3-4acd-985a-ebb192b3a6e2 0.99 20046508 XREF_BIBR Otherwise, MD-2 is essential for signaling of TLR4. reach p(HGNC:LY96) directlyIncreases act(p(HGNC:TLR4)) +46ccb254-c30d-42d1-891d-17303d643d21 1.0 20050848 FLX-induced increase in mitochondrial Bax levels, decrease in cytosolic Bid and Bcl-2 levels, loss of the mitochondrial transmembrane potential, cytochrome c release, caspase-3 activation and up-regulation of p53. sparser p(HGNC:CASP3) directlyIncreases act(p(HGNC:TP53)) +716cc167-a897-4a68-acd0-4134b89a2790 0.95 20070977 The expression of macrophage glucose response protein 78 (GRP78), X-box binding protein 1 (XBP1), activating transcription factor 6 (ATF6), and C-EBP homologous protein (CHOP) in macrophages was determined. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:DDIT3)) +12fc128d-91e3-4acd-985a-ebb192b3a6e2 0.99 20083193 MD2 mediates TLR4 recognition of PAMPs, but CD14 mediates TLR4 recognition of DAMPs released by necrotic cells [XREF_BIBR]. reach p(HGNC:LY96) directlyIncreases act(p(HGNC:TLR4)) +e097dc81-706a-4ccd-9e57-d535f600f989 0.95 20093624 eNos-/- mice exhibited increased aortic phospho-IkappaBalpha and ICAM protein levels when fed a LF diet whereas WT mice exhibited increased aortic phospho-IkappaBalpha protein levels and reduced insulin mediated activation of pAkt only when fed the HF diet (XREF_FIG). reach p(HGNC:INS) directlyIncreases act(p(UP:P54644)) +73461c97-a89b-40ad-be13-3d7f30e4ea6f 0.98 20124483 It has been reported that NF-kappaB could be activated by IRAK-1, which is a target of miR-146a. reach p(HGNC:IRAK1) directlyIncreases act(p(FPLX:NFkappaB)) +d58da677-6b7d-40bc-a7ba-083b03da81a7 0.99 20153328 However, mitochondrial displacement of HK II induced cell death also after insulin-dependent Akt activation or in cells lacking VDAC1 and 3 (and without detectable binding between HK II and residual VDAC2) [ xref ], and even in the absence of Bax and Bak [ xref ] (also discussed in [ xref ]). sparser p(HGNC:INS) directlyIncreases act(p(FPLX:AKT)) +40d279b2-9c40-483b-8e4e-106c763ded54 0.99 20179151 NMD targeted transcripts include ATF-4 and the ATF-4 targets CHOP (gadd153) and ATF-3. reach p(HGNC:ATF4) directlyIncreases act(p(HGNC:DDIT3)) +c97a3b8b-eddb-4255-8abf-e28ef34d4cf0 0.99 20179753 Thus, PI3Kgamma -/- mice fail to activate AKT and ERK1/2 immediately following M I/R injury, and this lack of activation can be localized to the area at risk. reach p(HGNC:PIK3CG) directlyIncreases act(p(FPLX:AKT)) +fd8191a7-4762-4760-82ee-85b1429564a8 0.95 20209087 Persistent ER stress induces the expression of the C/EBP homologous protein (CHOP), which initiates the cell death machinery XREF_BIBR. reach p(HGNC:DDIT3) directlyIncreases bp(GO:"GO:0008219") +1f42ee8f-af93-46eb-a92b-4ababffef749 1.0 20371701 IGF-I caused dissociation of pERK from PSF. reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:ERK, pmod(Ph))) +6549fbd1-6832-4252-9130-823a07ab1a87 0.95 20380815 (2) miR-7, which was shown to suppress alpha-Synuclein in mouse and human neuroblastoma cells. reach p(HGNC:"MIR7-1") directlyDecreases act(p(HGNC:SNCA)) +cf39b25c-ca63-4355-924a-043483d3d5af 0.95 20409278 The N-terminus of some NLR proteins contains a caspase activating and recruitment domain (CARD), which potentially links them to processes of caspase mediated cell death. reach p(FPLX:Caspase) directlyIncreases bp(GO:"GO:0008219") +16bef0c1-9d04-464f-8639-6c1bf6028f87 1.0 20414356 Pref-1 activates ERK/MAPK and upregulates Sox9 expression to inhibit adipocyte differentiation. sparser p(HGNC:DLK1) directlyIncreases act(p(FPLX:ERK)) +16bef0c1-9d04-464f-8639-6c1bf6028f87 1.0 20414356 Pref-1 activates ERK/MAPK and upregulates Sox9 expression to inhibit adipocyte differentiation. sparser p(HGNC:DLK1) directlyIncreases act(p(FPLX:ERK)) +bdb1c9f1-3aae-4131-9397-3eeaec2e52fc 0.98 20414356 Prevention of this second ERK phosphorylation by use of the MAPK/ERK kinase (MEK) inhibitor PD98059 or siRNA-mediated knockdown of ERK enhances adipocyte differentiation, indicating that Pref-1 activation of MEK–ERK is required for Pref-1 inhibition of adipogenesis. sparser p(HGNC:DLK1) directlyIncreases act(p(FPLX:MEK)) +840e5f0e-ec8e-4eb9-81cb-b619edb48caf 0.95 20471698 In contrast, PI3K activation enhances the neuroprotective effects of GDNF against H 2 O 2 -induced neuronal death in PD cybrids. reach p(FPLX:PI3K) directlyIncreases bp(MESH:D010300) +840e5f0e-ec8e-4eb9-81cb-b619edb48caf 0.95 20471698 On the other hand, the inhibition of phosphoinositide 3-kinase (PI3K) blocked GDNF mediated neuronal protection in the 6-OHDA-induced PD model. reach p(FPLX:PI3K) directlyIncreases bp(MESH:D010300) +eee57673-9e37-4cd5-8c8c-6989f2ab5af5 0.95 20501829 Under conditions of ER stress, BiP and GRP78 increases the load of ER client proteins, whereas loss of BiP and GRP78 binding correlates with oligomerization, trans-autophosphorylation, and activation of downstream signaling by PERK. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:ESR1)) +c6d4aeed-e612-44c2-a648-40d5c509b402 0.95 20514433 Many of these mechanisms, and, in particular, NAD + / NADH redox imbalances, accumulation of intracellular Ca 2+, activation of PARP and cyclooxygenase-2 (COX-2), and activation of NF-kappaB and resultant increase in cytokine production and pro inflammatory response, have also been implicated in IR injury. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0001816") +c071ed43-4f92-4778-ada7-ec6542768122 0.95 20559423 Moreover, inhibition of ROS and p38 MAPK reduced the level of GADD153 activation and caspase-3 activity of the cell. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:DDIT3)) +eee57673-9e37-4cd5-8c8c-6989f2ab5af5 0.95 20561923 Cleavage of BiP by SubA induces ER stress, which was demonstrated by activation of double stranded RNA activated protein kinase like ER kinase (PERK) and eukaryotic initiation factor-2alpha (eIF2alpha), leading to transient inhibition of protein synthesis, and induction of CHOP, with cell cycle arrest in G 1 phase as a result of downregulation of cyclin D1 [XREF_BIBR]. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:ESR1)) +716cc167-a897-4a68-acd0-4134b89a2790 0.95 20561923 We further report that signaling from CHOP, Ire1alpha, or JNK, which were activated by SubAB induced BiP cleavage, did not suppress cytochrome c release by Bax activation, although those mediators were involved in ER stress induced apoptosis in other cell types using different death stimuli [XREF_BIBR, XREF_BIBR]. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:DDIT3)) +fd8191a7-4762-4760-82ee-85b1429564a8 0.95 20647473 However, persistent proteotoxic stress with unresolved UPR and ER stress results in protracted PERK signaling and CHOP mediated cell death. reach p(HGNC:DDIT3) directlyIncreases bp(GO:"GO:0008219") +c071ed43-4f92-4778-ada7-ec6542768122 0.95 20660016 CHOP expression increases in diabetic mouse kidneys and in podocytes treated with ROS and FFA. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:DDIT3)) +73461c97-a89b-40ad-be13-3d7f30e4ea6f 0.98 20671252 IRAK1 along with other molecules activate NF-kappaB XREF_BIBR. reach p(HGNC:IRAK1) directlyIncreases act(p(FPLX:NFkappaB)) +c6d4aeed-e612-44c2-a648-40d5c509b402 0.95 20672047 In addition, inhibition of NF-kappaB and AP-1 activation in influenza virus infected cells leads to suppressed proinflammatory cytokine production, for example, IL-8 and TNF-alpha. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0001816") +4d0054ac-5799-4ccf-9361-26f88691d77a 0.95 20694829 In agreement with this, Wnt-3a did not induce GSK-3beta phosphorylation in differentiating myoblasts, nor did it affect NFATc3 transcriptional activity, as opposed to IGF-I mediated GSK-3beta inactivation. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:GSK3B)) +78d8d903-7ff1-4f78-8807-c9688954a60b 0.95 20736167 The best described, SPRED1, has been shown to inhibit the Ras and ERK pathway downstream of Ras. reach p(HGNC:SPRED1) directlyDecreases act(p(FPLX:ERK)) +fbad71e6-c835-48ec-95f7-c7291379ea64 0.95 20808843 MicroRNA miR-7 has been shown to target epidermal growth factor receptor protein (EGFR, also known as HER1 or ErbB-1) and reduce activation of Akt and extracellular signal regulated kinase 1/2 using cell-lines. reach p(HGNC:"MIR7-1") directlyDecreases act(p(FPLX:AKT)) +0c71874f-464d-4378-8f68-7d4af12d3414 0.95 20856677 ER stress enhances Mycobacterium bovis bacillus Calmette-Guerin (BCG)-induced apoptosis in cultured macrophages. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0006915") +eb01c4cc-e251-4217-a9f6-6ce86cf2993e 0.99 20863366 This is in agreement with the finding that IKKepsilon activates the NF-kappaB pathway in breast cancer, although the mechanism is not fully elucidated [XREF_BIBR, XREF_BIBR]. reach p(HGNC:IKBKE) directlyIncreases act(p(FPLX:NFkappaB)) +72000a1a-331a-4cd0-b932-fc0dac5bb4d9 0.95 20922166 The compatibility between the level of clinical periodontal scores and NF-kappaB and IkappaB expression provides evidence of the effectiveness of NF-kappaB activation in chronic periodontal inflammation. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006954") +40d279b2-9c40-483b-8e4e-106c763ded54 0.99 20926331 It has been documented that eIF2alpha phosphorylation activates the transcription factor ATF4, which activates GADD153. reach p(HGNC:ATF4) directlyIncreases act(p(HGNC:DDIT3)) +fbad71e6-c835-48ec-95f7-c7291379ea64 0.95 20931396 As a consequence, miR-7 and miR-331-3p reduce Akt activity and thus have the capacity to regulate a signaling pathway critical to the development and progression of glioblastoma and prostate cancer. reach p(HGNC:"MIR7-1") directlyDecreases act(p(FPLX:AKT)) +51e70dc9-716d-467e-962f-eaf8aaa06ff0 0.95 20965417 In contrast, RelA (p65), a subunit of NF-kB, is targeted to the nucleolus in a stress dependent manner and triggers apoptosis. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006915") +46ccb254-c30d-42d1-891d-17303d643d21 1.0 21035514 7-Ketocholesterol induced a decrease in cytosolic Bid and Bcl-2 levels, increase in cytosolic Bax levels, cytochrome c release, caspase-3 activation and upregulation of p53. sparser p(HGNC:CASP3) directlyIncreases act(p(HGNC:TP53)) +cd9dc75f-8113-49b7-aa3f-3b9d97c729dc 0.98 21035514 Results from this study suggest that 7-ketocholesterol may exert an apoptotic effect against PC12 cells by inducing activation of the caspase-8-dependent pathway as well as activation of the mitochondria mediated cell death pathway, leading to activation of caspases, via the reactive oxygen species dependent activation of NF-kappaB, which is mediated by the Akt pathway. reach p(FPLX:AKT) directlyIncreases act(p(FPLX:NFkappaB)) +539653f4-019f-40a2-b351-4ca8a006a593 0.98 21076081 This study compared the temporal effect of VCD on protein distribution of KIT and its downstream PIK3 activated proteins, AKT and FOXO3. reach p(UP:P54675) directlyIncreases act(p(FPLX:AKT)) +539653f4-019f-40a2-b351-4ca8a006a593 0.98 21076081 This study compared the temporal effect of VCD on protein distribution of KIT and its downstream PIK3-activated proteins, AKT and FOXO3. sparser p(UP:P54675) directlyIncreases act(p(FPLX:AKT)) +c071ed43-4f92-4778-ada7-ec6542768122 0.95 21127198 Overall, our results demonstrate that DBA potentiates TRAIL induced apoptosis through downregulation of cell survival proteins and upregulation of death receptors via ROS mediated CHOP activation. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:DDIT3)) +623eaef0-1c13-478b-9d18-bb5aecb85570 1.0 21127754 Our results show that IGF-1 is a potent activator of Erk and Akt in rhabdomyosarcoma RMS cells which can be effectively blocked by sorafenib. reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:AKT)) +73461c97-a89b-40ad-be13-3d7f30e4ea6f 0.98 21179087 This signature was also inhibited after IRAK1 knockdown (XREF_SUPPLEMENTARY), indicating that IRAK1 mediates NF-kappaB activation by MYD88 L265P. reach p(HGNC:IRAK1) directlyIncreases act(p(FPLX:NFkappaB)) +623eaef0-1c13-478b-9d18-bb5aecb85570 1.0 21197386 IGF1-induced Akt activation is inhibited by myostatin in skeletal muscle cells [ xref , xref ], but a role for myostatin in the inhibition of insulin-induced activation of Akt has not yet been demonstrated. sparser p(HGNC:IGF1) directlyIncreases act(p(FPLX:AKT)) +3f9b72b1-85a2-4895-97fd-f3ee843f4860 0.95 21203386 IGF-I promoted cell proliferation in the AVG neuroblast population, as witnessed by the increased number of Islet-1 positive cells and the 160% increase of the AVG area (XREF_FIG, compare a with b; XREF_FIG, bars on the right). reach p(HGNC:IGF1) directlyIncreases bp(GO:"GO:0008283") +e097dc81-706a-4ccd-9e57-d535f600f989 0.95 21241723 In the LF animals, insulin increased pAKT, consistent with insulin-induction of insulin signaling. reach p(HGNC:INS) directlyIncreases act(p(UP:P54644)) +c97a3b8b-eddb-4255-8abf-e28ef34d4cf0 0.99 21256851 PI3Kgamma and Akt activation following GCPR stimulation typically leads to pathological (maladaptive) hypertrophy [XREF_BIBR, XREF_BIBR - XREF_BIBR], whereas loss of PI3Kgamma prevents activation of Akt and PKB and ERK1/2 pathways in response to beta-AR stimulation, resulting in a marked reduction in hypertrophy [XREF_BIBR]. reach p(HGNC:PIK3CG) directlyIncreases act(p(FPLX:AKT)) +cd9dc75f-8113-49b7-aa3f-3b9d97c729dc 0.98 21279667 In the absence of PTEN, AKT is constitutively active and can activate NF-κB [ xref ]. sparser p(FPLX:AKT) directlyIncreases act(p(FPLX:NFkappaB)) +92e92d63-67d0-44fc-8cf2-8c751ef82a11 1.0 21289177 Moreover, we show that Aβ increases tau phosphorylation and that a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks the increased tau phosphorylation induced by Aβ and prevents Aβ-induced impairment of LTP in wild-type mice. sparser p(HGNC:APP) directlyIncreases p(HGNC:MAPT, pmod(Ph)) +78d8d903-7ff1-4f78-8807-c9688954a60b 0.95 21364986 We found that hSpred1 and hSpred2 also inhibited PGA 1 -triggered ERK activation (XREF_FIG), and both hSpred proteins abolished EGF, FGF, or PGA 1 -induced Elk1 activation (XREF_FIG). reach p(HGNC:SPRED1) directlyDecreases act(p(FPLX:ERK)) +efc0f64c-a37a-4cf4-9c89-049ff1b9d7ad 0.95 21384408 When the activation of the UPR fails to promote cell survival, the cell is taken down the pro apoptotic ER stress response pathway which can ultimately lead to apoptotic cell death, inflammation and/or fat accumulation. reach bp(GO:"GO:0006950") directlyIncreases bp(GO:"GO:0008219") +dfd819b2-1f47-4fa7-b0e6-9fa85181aa95 0.65 21387008 The gene expression data indicated a significant up-regulation of several genes involved in Cer and SM synthesis (SPTLC2, FVT1, DEGS1, SGMS1) in the PD VC (XREF_FIG). reach p(HGNC:CBLN1) directlyIncreases bp(MESH:D010300) +840e5f0e-ec8e-4eb9-81cb-b619edb48caf 0.95 21403858 Consequently, NQO1 is a novel therapeutic target for PD, which can be upregulated by PI3K and Nrf2 activation [XREF_BIBR]. reach p(FPLX:PI3K) directlyIncreases bp(MESH:D010300) +4d0054ac-5799-4ccf-9361-26f88691d77a 0.95 21418519 To explore the possible mechanism involved in AAC and IGF-1 deficiency induced myocardial morphological and functional responses, the impact of AAC and IGF-1 deficiency on expression of the cardiac hypertrophy markers ANF and GATA4, the cardiac proliferation factor Akt, and its downstream targets mTOR and GSK-3beta, which govern protein synthesis and glycogen synthesis, respectively. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:GSK3B)) +623eaef0-1c13-478b-9d18-bb5aecb85570 1.0 21480565 Radiation-induced DNA damage activates p53, which transactivates genes involved in cell death, cell cycle arrest and DNA repair. xref We have previously shown that IGF1 activates endogenous Akt in vivo and suppresses radiation-induced apoptosis; this correlates with preservation of salivary gland function. xref Studies in vitro have indicated that radiation can lead to accumulation of cells in G2/M, thereby reducing the S-phase population. xref To examine this, single cell suspensions from treated parotid glands were stained with propidium iodide and analyzed by flow cytometry. sparser p(HGNC:IGF1) directlyIncreases act(p(FPLX:AKT)) +cf39b25c-ca63-4355-924a-043483d3d5af 0.95 21493032 The in vitro data indicate that FasL mediated atrophy gene induction is independent of caspase induced cell death (XREF_TABLE), suggesting the possibility that a signaling cascade observed in glioblastoma cells that consists of a src kinase, PI3K, and PKB may be involved XREF_BIBR. reach p(FPLX:Caspase) directlyIncreases bp(GO:"GO:0008219") +06bd0dfa-24ce-4570-91f4-feea991b6ca4 0.95 21520181 As mentioned above, TNFalpha and IL-6 were down-regulated by the expression of SOCS3 through hepcidin and Fpn STAT3 mediated pathway. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL6)) +78d8d903-7ff1-4f78-8807-c9688954a60b 0.95 21531714 Finally, we found two tyrosine residues on SPRED1 that are required, when phosphorylated, to inhibit Ras and ERK activation and identified Tyr 420 as a specific dephosphorylation target of SHP2. reach p(HGNC:SPRED1) directlyDecreases act(p(FPLX:ERK)) +e097dc81-706a-4ccd-9e57-d535f600f989 0.95 21554521 Infusion of insulin detemir into the head, but not into the portal or peripheral circulation, significantly increased both pAkt and Akt and pSTAT3 and STAT3 in the liver, compared with glargine infusion. reach p(HGNC:INS) directlyIncreases act(p(UP:P54644)) +efc0f64c-a37a-4cf4-9c89-049ff1b9d7ad 0.95 21605076 This situation leads to stress ER, involving the transcriptional and translational machinery to induce the expression and post-transcriptional modifications of many factors involved in ER stress response mediated cell death. reach bp(GO:"GO:0006950") directlyIncreases bp(GO:"GO:0008219") +06bd0dfa-24ce-4570-91f4-feea991b6ca4 0.95 21620768 IL-10 also induces SOCS3 expression that suppresses IL-6 signaling pathways and is important for maintaining a regulatory phenotype. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL6)) +c6d4aeed-e612-44c2-a648-40d5c509b402 0.95 21637390 We next investigated the role of NF-kappaB in HBHA induced proinflammatory cytokine production by BMDMs. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0001816") +018c50fb-d378-418b-b20c-0301870c00ab 0.95 21645329 It is plausible that such NGF dependent pathways could drive both acute (receptor sensitization) and chronic (increased transcription and translation) changes in nociceptor phenotype. reach p(HGNC:NGF) directlyIncreases bp(GO:"GO:0006351") +78d8d903-7ff1-4f78-8807-c9688954a60b 0.95 21668589 Overexpression of miR126 suppressed Spred1 expression and enhanced ERK activity in primary bone marrow cells and MC9 mast cells, which were associated with elevated FcepsilonRI mediated cytokine production. reach p(HGNC:SPRED1) directlyDecreases act(p(FPLX:ERK)) +018c50fb-d378-418b-b20c-0301870c00ab 0.95 21677785 XREF_TABLE describes the analysis of the main functional categories of genes whose expression levels correlate with those of the transcription factors modulated by the NGF or proNGF. reach p(HGNC:NGF) directlyIncreases bp(GO:"GO:0006351") +0c71874f-464d-4378-8f68-7d4af12d3414 0.95 21681220 Because caspase 4 is an ER-resident caspase known to be implicated in ER stress induced apoptosis, we decided to investigate whether or not caspase 4 is activated following the Ad-INFalpha treatment. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0006915") +51e70dc9-716d-467e-962f-eaf8aaa06ff0 0.95 21689746 The NF-kappaB transcription factor mediates resistance to apoptosis by promoting the gene transcription of a variety of antiapoptotic proteins [XREF_BIBR]. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006915") +6651b919-e95e-4e34-b29a-c55dc6677fb6 0.95 21726895 IGF-1 activates the pAKT pathway in low-grade SOC and is inhibited by the AKT inhibitor MK-2206 and IGF-1R knockdown. reach p(HGNC:IGF1) directlyIncreases act(p(UP:P54644)) +6651b919-e95e-4e34-b29a-c55dc6677fb6 0.95 21726895 In order to confirm that IGF-1 activates the pAKT pathway in ovarian cancer, we performed Western blot analysis of pAKT activation in ovarian cancer cell lines treated with exogenous IGF-1. reach p(HGNC:IGF1) directlyIncreases act(p(UP:P54644)) +51e70dc9-716d-467e-962f-eaf8aaa06ff0 0.95 21776018 10 Activation of NF-kappaB and activator protein-1 (AP-1) increased cytokine expression and apoptosis in the cochlea and in immortalized cochlear cells derived from the organ of Corti. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006915") +40d279b2-9c40-483b-8e4e-106c763ded54 0.99 21801305 We demonstrate that salermide induces expression of ATF4, and ATF4 up-regulates ATF3 and subsequently modulates CHOP. reach p(HGNC:ATF4) directlyIncreases act(p(HGNC:DDIT3)) +69c67fc7-405a-40da-a682-44605602a364 0.95 21821103 Interestingly, phosphorylation of eIF2a favors translation of activating transcription factor 4 (ATF4) which has been shown to promote apoptotic cell death via transactivation of C/EBP-homologous protein (CHOP). reach p(HGNC:ATF4) directlyIncreases bp(GO:"GO:0008219") +eee57673-9e37-4cd5-8c8c-6989f2ab5af5 0.95 21908404 For example, GRP78 expression was induced by ER stress to release the ER stress. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:ESR1)) +59e4b84b-c1c9-494b-8c48-9ab41d78affd 1.0 21911421 We found that knockdown of Src and PKCzeta could inhibit CHIP mediated increase in the phosphorylated levels of IRAK1 and TBK1 (XREF_FIG), indicating that CHIP may promote the activation of Src and PKCzeta, which, in turn, phosphorylated and activated IRAK1 and TBK1. reach p(HGNC:IRAK1) directlyIncreases act(p(HGNC:IRAK1)) +51e70dc9-716d-467e-962f-eaf8aaa06ff0 0.95 21935918 NF-kappaB promotes pancreatic cancer growth in part by opposing apoptosis XREF_BIBR, XREF_BIBR and mediates the induction of mitogenic gene products 8. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006915") +0991ea45-f706-4dc8-bb41-b161314148c3 0.95 21949832 These data suggest that Akt mediates IL-10 regulation of TNF-alpha induced cardiomyocyte apoptosis. reach p(FPLX:AKT) directlyIncreases bp(GO:"GO:0006915") +40d279b2-9c40-483b-8e4e-106c763ded54 0.99 21966512 If, however this adaptation process fails, then the pro-apoptotic process will be initiated by ATF6 and ATF4 dependent transcriptional activation of CHOP. sparser p(HGNC:ATF4) directlyIncreases act(p(HGNC:DDIT3)) +78d8d903-7ff1-4f78-8807-c9688954a60b 0.95 21986312 XREF_BIBR) Spred-1 could suppress IL-5-dependent cell proliferation and ERK activation. reach p(HGNC:SPRED1) directlyDecreases act(p(FPLX:ERK)) +cd9dc75f-8113-49b7-aa3f-3b9d97c729dc 0.98 22110694 In particular, PKB and Akt dependent activation of NFkappaB induces expression of anti-apoptotic and/or neurotrophic factors XREF_BIBR, XREF_BIBR. reach p(FPLX:AKT) directlyIncreases act(p(FPLX:NFkappaB)) +920a4f0a-c035-4346-96ce-2d79dab40db5 1.0 22133269 When attached to LPS binding protein (LBP), an acute phase protein, this complex binds to CD14, which further activates TLR4. reach p(HGNC:CD14) directlyIncreases act(p(HGNC:TLR4)) +0755e65a-7681-44e8-a0af-ce15e55fe046 0.99 22140566 It has been reported that NGF mediated ERK activation induces phosphorylation of cAMP response element binding protein (CREB), which further recruits the CREB binding protein (CBP) to the promoter regions of cAMP responsive genes associated with dendritic spine growth, morphology change, synaptic plasticity, and long-term memory XREF_BIBR, XREF_BIBR. reach p(HGNC:NGF) directlyIncreases act(p(FPLX:ERK)) +920a4f0a-c035-4346-96ce-2d79dab40db5 1.0 22194732 Although unable to trigger cellular signaling, CD14 promotes loading of TLR4 and MD2 and TLR2 with their ligands, a mechanism that contributes to detection of these soluble molecules in small amounts. reach p(HGNC:CD14) directlyIncreases act(p(HGNC:TLR4)) +775f864e-0093-4adc-87f9-d77148273465 1.0 22362362 In control rat fibroblasts, 50 ng/ml IGF1 induced rapid and strong activation of IRS1, as evidenced by the phosphorylation of Tyr612, which is essential for IRS1 activation and to generate a docking site for the downstream PI3K (XREF_FIG). reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:IRS1)) +72000a1a-331a-4cd0-b932-fc0dac5bb4d9 0.95 22393127 Published data show that NF-kappaB signaling in astrocytes promotes neurotoxicity and CNS inflammation. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006954") +0755e65a-7681-44e8-a0af-ce15e55fe046 0.99 22404972 In contrast, NGF induced ERK activation in the same cells is sustained and accompanied by a nuclear translocation causing cell cycle arrest and neuronal differentiation. reach p(HGNC:NGF) directlyIncreases act(p(FPLX:ERK)) +06bd0dfa-24ce-4570-91f4-feea991b6ca4 0.95 22476871 Since SOCS3 is one of the inhibitors of the IL-6 and STAT3 signaling, here we aim at investigating whether SOCS3 can antagonize the IL-6 and STAT3 pathway, thus improving muscle wasting in cancer- and burn associated cachexia. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL6)) +697a8013-0350-4626-a5db-6228b907506c 0.99 22491325 sAPP-alpha decreases Abeta species and beta-CTF in vitro. reach p(HGNC:APP) directlyDecreases act(p(HGNC:APP)) +6549fbd1-6832-4252-9130-823a07ab1a87 0.95 22494990 The repression of alpha-synuclein by miR-7 has been shown to be protective against oxidative stress and apoptosis of DA neurons in the striatum [XREF_BIBR]. reach p(HGNC:"MIR7-1") directlyDecreases act(p(HGNC:SNCA)) +fa2d0182-7d30-4f39-864f-7cd17a0eb20b 0.98 22530004 In addition, it has been shown that mutant Htt caused increased levels of reactive oxygen species (ROS) in neuronal and non neuronal cells XREF_BIBR and ER stress caused by ROS activated HSPA5 expression XREF_BIBR. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:HSPA5)) +fa2d0182-7d30-4f39-864f-7cd17a0eb20b 0.98 22530004 In addition, it has been shown that mutant Htt caused increased levels of reactive oxygen species (ROS) in neuronal and non neuronal cells XREF_BIBR and ER stress caused by ROS activated HSPA5 expression XREF_BIBR. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:HSPA5)) +e097dc81-706a-4ccd-9e57-d535f600f989 0.95 22590537 Chronic hyperinsulinemia has been shown to reduce acute insulin induced Akt-p in hepatocytes XREF_BIBR. reach p(HGNC:INS) directlyIncreases act(p(UP:P54644)) +d58da677-6b7d-40bc-a7ba-083b03da81a7 0.99 22596190 Students will be fascinated to learn that the same kinase (Akt) that is activated by insulin to enhance cellular glucose uptake is also activated in most cancers. reach p(HGNC:INS) directlyIncreases act(p(FPLX:AKT)) +cd9dc75f-8113-49b7-aa3f-3b9d97c729dc 0.98 22683727 Inhibiting any one of these 3 pathways, Akt, p38 or JNK, is sufficient to block NFkappaB activation. reach p(FPLX:AKT) directlyIncreases act(p(FPLX:NFkappaB)) +f5fc46a8-a98a-4bd1-9930-0f3564842809 0.95 22781655 Apart from ER specific apoptotic pathway, the capacity of ER stress to induce cell death through a series of events at the mitochondrial level has been suggested [XREF_BIBR]. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0008219") +72000a1a-331a-4cd0-b932-fc0dac5bb4d9 0.95 22940906 Recent research revealed that proinflammatory pathway of IkappaB kinase (IKKbeta) and downstream nuclear factor-kappaB (NF-kappaB) mediates HFD induced hypothalamic inflammation to cause metabolic syndrome XREF_BIBR - XREF_BIBR. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006954") +46ccb254-c30d-42d1-891d-17303d643d21 1.0 22949823 Later, these authors [XREF_BIBR] investigated the mechanism of antiproliferative activity of these compounds and concluded that they induced apoptosis, provoked changes in cell cycle distribution, caspase-3 activation and activation of the p53 tumor suppressor gene family p73. reach p(HGNC:CASP3) directlyIncreases act(p(HGNC:TP53)) +697a8013-0350-4626-a5db-6228b907506c 0.99 22950863 Consequently, we suggest that γ-secretase inhibitors that preferentially inhibit PS1-containing γ-secretase complexes (e.g., sulfonamides [ xref , xref ]) represent a promising avenue for reducing Aβ production while leaving the generation of the physiologically critical AICD and NICD products relatively unaffected. sparser p(HGNC:APP) directlyDecreases act(p(HGNC:APP)) +12fc128d-91e3-4acd-985a-ebb192b3a6e2 0.99 22982462 Since CD14, MD2 and lipid rafts play a role in the recycling phenomenon, it is possible that the 4F mediated decrease in CD14 and MD2 (XREF_FIG) may prevent the reassembly of the TLR4 ligand complex. reach p(HGNC:LY96) directlyIncreases act(p(HGNC:TLR4)) +51e70dc9-716d-467e-962f-eaf8aaa06ff0 0.95 23028889 The NLR activation in cardiomyocytes was associated with NF-kappaB activation and induction of apoptosis. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006915") +697a8013-0350-4626-a5db-6228b907506c 0.99 23049854 In intracerebral injection group, the levels of Abeta and APP-CT in Tg-hASC were significantly reduced (Abeta, from 1.0 +/-0.039 to 0.55 +/-0.018, P < 0.05, XREF_FIG; APP-CT, from 1.0 +/-0.033 to 0.63 +/-0.029, P < 0.05, XREF_FIG). reach p(HGNC:APP) directlyDecreases act(p(HGNC:APP)) +f5fc46a8-a98a-4bd1-9930-0f3564842809 0.95 23066505 When unmitigated, ER stress is toxic to cells and triggers cell death. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0008219") +72000a1a-331a-4cd0-b932-fc0dac5bb4d9 0.95 23088768 It also suggest that p38alpha MAP kinase and p65 (NF-kappaB) inhibition in vascular endothelium may limit excessive tissue inflammation induced by radiation therapy, and thereby limit the associated acute and late tissue damage. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006954") +efc0f64c-a37a-4cf4-9c89-049ff1b9d7ad 0.95 23091802 Importantly, cell death induced by ATR or CHK1 inhibitors occurs independent of p53, suggesting that reactivation of p53 and inhibition of the replication stress response might trigger distinct cell death pathways in Myc driven tumors. reach bp(GO:"GO:0006950") directlyIncreases bp(GO:"GO:0008219") +6651b919-e95e-4e34-b29a-c55dc6677fb6 0.95 23119004 Among these four growth factors, IGF-I induced the highest activation of pAKT in MCF7 and T47D cells (XREF_FIG). reach p(HGNC:IGF1) directlyIncreases act(p(UP:P54644)) +73461c97-a89b-40ad-be13-3d7f30e4ea6f 0.98 23160924 Interleukin-1 receptor associated kinase 1 (IRAK1) is the upstream gene that stimulates the NF-kappaB pathway [XREF_BIBR]. reach p(HGNC:IRAK1) directlyIncreases act(p(FPLX:NFkappaB)) +51e70dc9-716d-467e-962f-eaf8aaa06ff0 0.95 23164372 Sequestered RACK1 is unable to activate apoptosis mediated by MTK1, and TRAF2 is unable to activate apoptosis mediated by TNFalpha and NFkappaB. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006915") +92e92d63-67d0-44fc-8cf2-8c751ef82a11 1.0 23175838 Using the antibody 6D11 to prevent oligomeric Aβ from binding to PrP c , we abolished Fyn activation and Fyn-dependent tau hyperphosphorylation induced by endogenous oligomeric Aβ in vitro . sparser p(HGNC:APP) directlyIncreases p(HGNC:MAPT, pmod(Ph)) +06bd0dfa-24ce-4570-91f4-feea991b6ca4 0.95 23185530 SOCS3 has a differential effect on IL-6 and IL-10 receptor signaling : the IL-6 receptor signaling is down-regulated by SOCS3, whereas that by IL-10 receptor is not XREF_BIBR. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL6)) +623eaef0-1c13-478b-9d18-bb5aecb85570 1.0 23236487 It has previously been demonstrated that IGF-1 activates Akt leading to suppression of apoptosis in irradiated salivary acinar cells XREF_BIBR, XREF_BIBR. reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:AKT)) +51dd5a26-38f6-4ed6-816a-35ab60dc1fd3 1.0 23244239 In fact, Tollip overexpression dramatically inhibits IRAK1 kinase activity [XREF_BIBR] and suppresses NF-kappaB activation [XREF_BIBR, XREF_BIBR, XREF_BIBR]. reach p(HGNC:TOLLIP) directlyDecreases act(p(HGNC:IRAK1)) +cd9dc75f-8113-49b7-aa3f-3b9d97c729dc 0.98 23251686 The PI3K and Akt pathway, acting in conjunction with other factors, is known to increase the activation of the NF-kappaB pathway by phosphorylation of IKK XREF_BIBR, XREF_BIBR. reach p(FPLX:AKT) directlyIncreases act(p(FPLX:NFkappaB)) +cf39b25c-ca63-4355-924a-043483d3d5af 0.95 23265941 The depletion of glutathione in mitochondria favors the accumulation of ROS and induces the release of cytochrome c which triggers caspase induced cell death. reach p(FPLX:Caspase) directlyIncreases bp(GO:"GO:0008219") +0991ea45-f706-4dc8-bb41-b161314148c3 0.95 23306701 Our findings that inactivated PI3K or Akt induces apoptosis and that dominant negative Akt has the ability to enhance apoptosis highlight the importance of PI3K and Akt signaling in promoting survival. reach p(FPLX:AKT) directlyIncreases bp(GO:"GO:0006915") +4d0054ac-5799-4ccf-9361-26f88691d77a 0.95 23388061 IGF-I increases pGSK3beta signaling in the OSE. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:GSK3B)) +21f34343-4d1f-4f2a-97f2-dcbe4704a698 0.86 23396211 However, IKKepsilon and TBK1 may attenuate, without eliminating, the inflammatory response. reach p(HGNC:IKBKE) directlyDecreases bp(GO:"GO:0006954") +775f864e-0093-4adc-87f9-d77148273465 1.0 23403580 IGF-1 and IGF-1R induces differentiation rather than proliferation when the cells do not express or underexpress insulin receptor substrate-1 (IRS-1), a docking protein for both IGF-1R and the insulin receptor that is known to send a mitogenic, anti-apoptotic and anti-differentiation signal XREF_BIBR XREF_BIBR. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:IRS1)) +a6f8e61d-9758-4de0-ad6e-9ae0e93491f0 0.95 23514404 Second, it is important to realise that the contribution of higher prevalence CRFs in RA is one side of the coin, but the other side is effective suppression of the inflammation. reach p(PFAM:PF12252) directlyDecreases bp(GO:"GO:0006954") +51e70dc9-716d-467e-962f-eaf8aaa06ff0 0.95 23559016 3 Conversely, loss of cardiomyocytes during MI has been mainly attributed to necrosis, 9 although involvement of reactive oxygen species, 10 P38-mitogen-activated protein kinase (MAPK) 11 and NF-kappaB activation in cardiomyocyte apoptosis during MI has been reported. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006915") +eee57673-9e37-4cd5-8c8c-6989f2ab5af5 0.95 23559016 Though mitochondrial VDAC1 and endoplasmic reticulum (ER) stress marker GRP78 were upregulated during hypertrophy and MI, whether this upregulation resulted in dysfunction of mitochondria or ER leading to myocyte apoptosis was not clear. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:ESR1)) +69c67fc7-405a-40da-a682-44605602a364 0.95 23624402 To determine whether ATF4 and CHOP can initiate cell death, we examined cell survival after adenovirus mediated delivery of ATF4 and/or CHOP (XREF_SUPPLEMENTARY). reach p(HGNC:ATF4) directlyIncreases bp(GO:"GO:0008219") +e097dc81-706a-4ccd-9e57-d535f600f989 0.95 23675368 Moreover NLRP3 -/- mice were protected from the adverse metabolic effects elicited by HFD; demonstrated by improved glucose homeostasis, greater insulin induced pAKT activity in VAT, subcutaneous adipose tissue (SAT), liver and muscle. reach p(HGNC:INS) directlyIncreases act(p(UP:P54644)) +ee10d13e-6b36-4b84-9925-ef650bd004dd 0.95 23720337 Recent work has linked the CHOP target ER oxidase 1alpha (ERO1alpha)-induced oxidative stress, the calcium sensing kinase CaMKII, and the ER calcium channel inositol 1,2,5-triphosphate receptor activity to ER stress induced apoptosis. reach p(HGNC:DDIT3) directlyIncreases act(p(HGNC:ESR1)) +fbad71e6-c835-48ec-95f7-c7291379ea64 0.95 23724959 In addition, miR-7 down-regulates EGFR mRNA and protein expression in cancer cell lines (lung, breast, and glioblastoma) and the AKT pathway [XREF_BIBR, XREF_BIBR] inhibiting schwannoma cell growth [XREF_BIBR] and inducing cell cycle arrest and cell death, which suggests a negative regulatory mechanism acting on the MAPK pathway [XREF_BIBR]. reach p(HGNC:"MIR7-1") directlyDecreases act(p(FPLX:AKT)) +0755e65a-7681-44e8-a0af-ce15e55fe046 0.99 23772401 In this study, we have demonstrated that LPC specifically promotes NGF induced MAPK and Akt signaling pathways in PC12 cells. reach p(HGNC:NGF) directlyIncreases act(p(FPLX:ERK)) +bdb1c9f1-3aae-4131-9397-3eeaec2e52fc 0.98 23840193 Pref-1 interacts with fibronectin and activates MEK/ERK to induce Sox9 expression, which blocks adipocyte differentiation by binding to the promoter regions of C/EBPβ and C/EBPδ and preventing activation of C/EBPα and PPARγ. sparser p(HGNC:DLK1) directlyIncreases act(p(FPLX:MEK)) +06bd0dfa-24ce-4570-91f4-feea991b6ca4 0.95 23853585 In conclusion, although IL-6 levels are increased in lungs of infected Socs3 fl/fl LysM cre mice, SOCS3 does not impair IL-6 secretion by mycobacteria infected BMM. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL6)) +46ccb254-c30d-42d1-891d-17303d643d21 1.0 23907460 29 In contrast, induction of the apoptotic pathway by QUE specifically via intrinsic caspase-3 activation in p53 wild-type and mutant cells has been reported. reach p(HGNC:CASP3) directlyIncreases act(p(HGNC:TP53)) +51dd5a26-38f6-4ed6-816a-35ab60dc1fd3 1.0 23937116 Toll interacting protein (TOLLIP) interacts with many types of TLR signaling downstream pathways and potently inhibits the activity of IRAK after TLR activation. reach p(HGNC:TOLLIP) directlyDecreases act(p(HGNC:IRAK1)) +fd8191a7-4762-4760-82ee-85b1429564a8 0.95 23940416 The inhibition of CHOP or JNK alone by either siRNA or inhibitors partially abolished the antiproliferative activity of SF-LY NPs, whereas combinational inhibition of CHOP and JNK significantly rescued the cell death induced by SF-LY NPs (XREF_FIG and C). reach p(HGNC:DDIT3) directlyIncreases bp(GO:"GO:0008219") +fa2d0182-7d30-4f39-864f-7cd17a0eb20b 0.98 24051401 In order to identify the different ROS involved in GA induced GRP78 induction, several ROS scavengers, such as mannitol (a hydroxyl radical scavenger), superoxide dismutase (SOD, catalyzing the degradation of O 2 -), catalase (catalyzing auto-oxidoreduction of H 2 O 2) and N-acetylcysteine (NAC, the precursor of glutathione), were employed to examine the individual inhibitory effect. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:HSPA5)) +018c50fb-d378-418b-b20c-0301870c00ab 0.95 24054150 It is well established that NGF deprivation causes apoptosis by activating the transcription factor c-JUN. reach p(HGNC:NGF) directlyIncreases bp(GO:"GO:0006351") +6549fbd1-6832-4252-9130-823a07ab1a87 0.95 24058335 miR-7 and miR-153 have been found to downregulate synthesis of alpha-synuclein; suppression of the expression of these miRNA in midbrain of PD patients is expected but has not been demonstrated yet. reach p(HGNC:"MIR7-1") directlyDecreases act(p(HGNC:SNCA)) +7a204913-3db0-486e-bf55-7cc3a7fcc489 0.98 24076584 Simultaneously, SOCS3 suppresses Stat dependent signaling of inflammatory cytokines IL-6, [XREF_BIBR] TNF-alpha, and IL-1beta [XREF_BIBR]. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL1B)) +0991ea45-f706-4dc8-bb41-b161314148c3 0.95 24086481 We investigated the role of PI3K and AKT pathway in miR-27a induced apoptosis by targeting PIK3CD and found that specific transient miR-27a expression reduced expression of PIK3CD, p-AKT, Bcl-2 and NF-kappaB in accordance with the results in damaged cells. reach p(FPLX:AKT) directlyIncreases bp(GO:"GO:0006915") +6549fbd1-6832-4252-9130-823a07ab1a87 0.95 24133413 In addition, miR-7 suppresses SNCA mediated cytotoxicity in neuronal cell models. reach p(HGNC:"MIR7-1") directlyDecreases act(p(HGNC:SNCA)) +40d279b2-9c40-483b-8e4e-106c763ded54 0.99 24142645 The pro apoptotic transcription factor C/EBP homologous protein (CHOP)/GADD153, which suppresses the transcription of Bcl-2, can also be induced by a combination of the PERK and ATF4 and ATF6 pathways. reach p(HGNC:ATF4) directlyIncreases act(p(HGNC:DDIT3)) +ee10d13e-6b36-4b84-9925-ef650bd004dd 0.95 24142645 XREF_BIBR study, cleaved caspase 12 activates caspase 3 to trigger apoptosis, and CHOP can directly induce ER stress associated apoptosis. reach p(HGNC:DDIT3) directlyIncreases act(p(HGNC:ESR1)) +d58da677-6b7d-40bc-a7ba-083b03da81a7 0.99 24150286 We therefore hypothesized that PP2A inhibition would enhance insulin stimulated Akt activity and decrease glucose production. reach p(HGNC:INS) directlyIncreases act(p(FPLX:AKT)) +7a204913-3db0-486e-bf55-7cc3a7fcc489 0.98 24176948 13 SOCS-3 can inhibit not only IL-1beta- and IFN-gamma-induced apoptosis but also NO production through a direct interaction with JAK in INS-1 cells and primary beta cells. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL1B)) +7a204913-3db0-486e-bf55-7cc3a7fcc489 0.98 24176948 XREF_BIBR, XREF_BIBR Moreover, SOCS-3 also inhibits IL-1beta signaling and gene regulation, at least in part, through inhibition of NF-kappaB signaling. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL1B)) +46ccb254-c30d-42d1-891d-17303d643d21 1.0 24236158 In contrast, SAHA increased expression of Caspase-3, p21 and p53 mRNA, and upregulated acetyl-Histones H3 and H4, Caspase-8, and p53 proteins. reach p(HGNC:CASP3) directlyIncreases act(p(HGNC:TP53)) +7a204913-3db0-486e-bf55-7cc3a7fcc489 0.98 24238405 Although SOCS3 was reported to reduce the anabolic action of insulin like growth factor 1, SOCS3 overexpression in bovine chondrocytes decreased the production of IL-1beta or lipopolysaccharide (LPS)-induced nitric oxide [XREF_BIBR, XREF_BIBR]. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL1B)) +72000a1a-331a-4cd0-b932-fc0dac5bb4d9 0.95 24265774 As NF-kappaB is a major contributor of inflammation following an insult to brain, understanding the factors responsible for its induction helps in controlling its activity XREF_BIBR. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006954") +920a4f0a-c035-4346-96ce-2d79dab40db5 1.0 24275652 We conclude that CD14 has a critical role in mediating TLR4 signaling through IRF3 in resident corneal epithelial cells and macrophages and thereby modulates TLR4 cell surface activation of the MyD88/NF-kappaB/AP -1 pathway and production of CXC chemokines and neutrophil infiltration to infected tissues. reach p(HGNC:CD14) directlyIncreases act(p(HGNC:TLR4)) +12fc128d-91e3-4acd-985a-ebb192b3a6e2 0.99 24303065 Importantly, Rallabhandi and colleagues did not show MD2 dependent TLR4 activation with intact RSV. sparser p(HGNC:LY96) directlyIncreases act(p(HGNC:TLR4)) +0991ea45-f706-4dc8-bb41-b161314148c3 0.95 24304591 PEITC also can depress pro survival signaling pathways of NF-kappaB and PI3K and Akt [XREF_BIBR], as PEITC inhibits IKK, IkappaB and Akt phosphorylation leading to inhibit cell proliferation and apoptosis. reach p(FPLX:AKT) directlyIncreases bp(GO:"GO:0006915") +e097dc81-706a-4ccd-9e57-d535f600f989 0.95 24319696 Pyruvate oxidation went up (XREF_FIG) and so did insulin stimulated pAkt and GLUT4 (XREF_FIG). reach p(HGNC:INS) directlyIncreases act(p(UP:P54644)) +01b609ef-49a5-45f8-99a1-a5d20665488c 0.86 24331705 Using results from the chimeric mouse studies, we also evaluated the effect of macrophages on inflammation over a three-week experiment for chimeric mice treated with buffer (Ch) or diphtheria toxin (Ch + DT), as well as normal C57BL/6 mice treated with buffer (C57BL/6) or diphtheria toxin (C57BL/6 + DT). reach p(PFAM:PF00307) directlyIncreases bp(GO:"GO:0006954") +c57d5a35-956b-4820-8e96-11b924736350 0.86 24412542 Replicating RNA viruses generate small amounts of dsRNA that are detected by cytoplasmic helicases which signal TBK1 and IKKepsilon complexes to activate NF-kappaB and cellular IFN response factors (IRFs3/5/7). reach complex(p(HGNC:IKBKE), p(HGNC:TBK1)) directlyIncreases act(p(FPLX:NFkappaB)) +c6d4aeed-e612-44c2-a648-40d5c509b402 0.95 24416274 These results further confirmed that MMP3 interacts with NFkappaB via its C-terminal hinge and hemopexin like domain and activates NFkappaB upon DENV infection, thereby exerts an antiviral effect by promoting the NFkappaB directed cytokine production. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0001816") +623eaef0-1c13-478b-9d18-bb5aecb85570 1.0 24428908 As shown in Figure XREF_FIG C, BENC-511 suppressed AKT activation raised by both IGF-1 and IL-6 within 2 or 4 hours. reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:AKT)) +6651b919-e95e-4e34-b29a-c55dc6677fb6 0.95 24438088 Moreover, activation of both pIGF-1R and pAkt by IGF-1 was downregulated by glucosamine. reach p(HGNC:IGF1) directlyIncreases act(p(UP:P54644)) +ee10d13e-6b36-4b84-9925-ef650bd004dd 0.95 24525736 CHOP may induce cell death by promoting protein synthesis and oxidation in the stressed ER. reach p(HGNC:DDIT3) directlyIncreases act(p(HGNC:ESR1)) +716cc167-a897-4a68-acd0-4134b89a2790 0.95 24527073 Downregulation of GRP78 upregulates CHOP and the proapoptotic factor Bax, inhibiting the expression of the antiapoptotic factor Bcl-2, thus, resulting in the inhibition of cell growth and proliferation. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:DDIT3)) +018c50fb-d378-418b-b20c-0301870c00ab 0.95 24559646 Cell differentiation was induced with nerve growth factor (NGF) in an early transient stimulation that induced an extracellular signal regulated kinase (ERK) - and transcription dependent latent process, and a second sustained NGF stimulation driving the fast neurite extension process by ERK- and PI3K dependent activities (XREF_SUPPLEMENTARY). reach p(HGNC:NGF) directlyIncreases bp(GO:"GO:0006351") +6549fbd1-6832-4252-9130-823a07ab1a87 0.95 24559646 In cell culture or in mice, miR-7 and miR-153 downregulated alpha-Synuclein, a protein associated with PD, miR-433 inhibited translation of the DA neuron associated mitogen FGF20 in vitro, miR-133b was a regulator of midbrain DA cell development in mice by targeting the transcriptional activator Pitx3, and miR-34b/c might affect mitochondrial function through an indirect mechanism that could include Parkin and DJ1. reach p(HGNC:"MIR7-1") directlyDecreases act(p(HGNC:SNCA)) +1cbb5c6a-9977-4e0b-8258-3d2456ae81ba 0.65 24559646 Other examples include miR-470, -669 b, and -681, which were recently identified as potential suppressors of IGF-1R and AKT in the hippocampus of aged Ames dwarf and growth hormone receptor knock out mice, and miR-7 and miR-98, which inhibit IGF-1 and AKT signaling by targeting IRS-1 in glioblastoma or N2A cells, respectively. reach p(HGNC:"MIR7-1") directlyDecreases act(p(HGNC:IGF1)) +4ef018d6-f006-4812-807a-f45765c51ae4 0.86 24559646 miR-126 is upregulated and can be associated with dysregulated IGF-1 and PI3K signaling in PD DA neurons. reach p(HGNC:IGF1) directlyIncreases bp(MESH:D010300) +840e5f0e-ec8e-4eb9-81cb-b619edb48caf 0.95 24559646 miR-126 is upregulated and can be associated with dysregulated IGF-1 and PI3K signaling in PD DA neurons. reach p(FPLX:PI3K) directlyIncreases bp(MESH:D010300) +a6f8e61d-9758-4de0-ad6e-9ae0e93491f0 0.95 24580770 Moreover, topical RV-D1 may be more beneficial than other current anti-inflammatory agents for ocular surface inflammation, which are limited by their undesired long term side effects. reach p(PFAM:PF12252) directlyDecreases bp(GO:"GO:0006954") +775f864e-0093-4adc-87f9-d77148273465 1.0 24648009 Here we show that IGF-1 promotes interaction of IRS-1 with ADAM10 and prevents the destabilizing impact of TNF-alpha on neuronal processes. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:IRS1)) +efc0f64c-a37a-4cf4-9c89-049ff1b9d7ad 0.95 24649299 The aim of this review was to summarize our current understanding regarding the mechanisms of ER stress response by which cisplatin induces cell death and the basis for cisplatin resistance. reach bp(GO:"GO:0006950") directlyIncreases bp(GO:"GO:0008219") +72000a1a-331a-4cd0-b932-fc0dac5bb4d9 0.95 24658543 They bind their ligands, then cause activation of the transcription factors, NF-kappaB and activator protein-1 (AP-1), stimulating the expression of inflammation related genes XREF_BIBR, XREF_BIBR, thus leading to bulk release of harmful cytokines and hippocampal injury. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006954") +0755e65a-7681-44e8-a0af-ce15e55fe046 0.99 24667984 Furthermore, lovastatin, an inhibitor of Ras, blocked the NGF-induced activation of ERK1/2 and neurite outgrowth xref , xref . sparser p(HGNC:NGF) directlyIncreases act(p(FPLX:ERK)) +c97a3b8b-eddb-4255-8abf-e28ef34d4cf0 0.99 24703913 PI3Kgamma activates Akt and PKB after GPCR activation, leading to pathological hypertrophy. reach p(HGNC:PIK3CG) directlyIncreases act(p(FPLX:AKT)) +40d279b2-9c40-483b-8e4e-106c763ded54 0.99 24718591 Activated ATF4 and ATF6 can activate CHOP, a specially pro-apoptosis molecular of ER stress, which is also a downstream target of XBP-1 xref . sparser p(HGNC:ATF4) directlyIncreases act(p(HGNC:DDIT3)) +d58da677-6b7d-40bc-a7ba-083b03da81a7 0.99 24735980 In parallel, the activation of PI3K/Akt/mTOR is reported to cause insulin receptor substrate 1 (IRS1) inhibition, disabling normal activation of PI3K and Akt by insulin, IGF-1 and other growth factors. reach p(HGNC:INS) directlyIncreases act(p(FPLX:AKT)) +716cc167-a897-4a68-acd0-4134b89a2790 0.95 24795528 The observed up-regulation of CHOP, TRB3 and GRP78, the main ER stress markers, in MG63 cells supported the involvement of ER stress in WIN induced vacuolization which was also confirmed by the loss of vacuolar structures observed both in CHOP silenced WIN treated cells and in cells co-treated with WIN and BAPTA-AM, a chelator of intracellular calcium. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:DDIT3)) +3f9b72b1-85a2-4895-97fd-f3ee843f4860 0.95 24808494 IGF-I stimulated glucose transport and cell proliferation via the cell surface IGF-I receptor (IGFIR) and, downstream of the receptor, by the phosphatidylinositol 3-kinase signal transduction pathway. reach p(HGNC:IGF1) directlyIncreases bp(GO:"GO:0008283") +51e70dc9-716d-467e-962f-eaf8aaa06ff0 0.95 24823879 IMD-0354, an inhibitor of NF-kappaB, inhibits phosphorylation of IkappaBalpha and release of NF-kappaB proteins, and thus induces breast CSC apoptosis [XREF_BIBR]. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006915") +73461c97-a89b-40ad-be13-3d7f30e4ea6f 0.98 24831346 MiR-146a also targets IL-1 receptor associated kinase 1 (IRAK1) and TNF receptor associated factor 6 (TRAF6), and derepression of IRAK1 and TRAF6 increase activation of NFkappaB. reach p(HGNC:IRAK1) directlyIncreases act(p(FPLX:NFkappaB)) +cf39b25c-ca63-4355-924a-043483d3d5af 0.95 24837502 This was observed due to the high caspase mediated cell death as a control mechanism of antigen independent expansion by cord blood RTEs [XREF_BIBR]. reach p(FPLX:Caspase) directlyIncreases bp(GO:"GO:0008219") +6549fbd1-6832-4252-9130-823a07ab1a87 0.95 24868395 XREF_BIBR The down-regulation of alpha-synuclein by miR-7 protects cells from oxidative damage, and 1-methyl-4-phenyl-1,2,3,6 tetrahydropyri-dinium (MPTP)-induced Parkinson mice have reduced miR-7 levels. reach p(HGNC:"MIR7-1") directlyDecreases act(p(HGNC:SNCA)) +6651b919-e95e-4e34-b29a-c55dc6677fb6 0.95 24882635 17b-estradiol treatment in vivo results in a dose dependent activation of ERK and Akt and has a synergistic effect on IGF-1 mediated activation of the pAkt and PKB pathway. reach p(HGNC:IGF1) directlyIncreases act(p(UP:P54644)) +cf39b25c-ca63-4355-924a-043483d3d5af 0.95 24995293 Liposomal curcumin initiated the caspase cascade that led to apoptotic cell death in vitro. reach p(FPLX:Caspase) directlyIncreases bp(GO:"GO:0008219") +c071ed43-4f92-4778-ada7-ec6542768122 0.95 25023940 Overall, our data suggest a new mechanism for the PL induced cell death in which ROS mediates CHOP activation, and combination treatment with PL and TRAIL could be a potential strategy for breast cancer therapy. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:DDIT3)) +4d0054ac-5799-4ccf-9361-26f88691d77a 0.95 25035811 Insulin and IGF -1 resistance typically reduces Akt [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR], and increases GSK-3beta [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] activity. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:GSK3B)) +4d0054ac-5799-4ccf-9361-26f88691d77a 0.95 25035811 Since insulin and IGF -1 networks cross-talk with Wnt via GSK-3beta [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR], increased GSK-3beta activity caused by insulin and IGF -1 resistance could have further impaired Wnt signaling in juvenile cerebella. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:GSK3B)) +12fc128d-91e3-4acd-985a-ebb192b3a6e2 0.99 25036103 ARPE19 cells lack expression of MD-2 and CD14, two key components needed for LPS to activate TLR4 (data not shown). reach p(HGNC:LY96) directlyIncreases act(p(HGNC:TLR4)) +9264c3da-0592-425a-80b8-039b4e8e272b 0.86 25036103 ATF4 which is known to be also activated by TLR4 XREF_BIBR and is known to mediate CHOP expression XREF_BIBR, may be a possible mediator the 7KCh induced cell death pathway. reach p(HGNC:TLR4) directlyIncreases act(p(HGNC:ATF4)) +21f34343-4d1f-4f2a-97f2-dcbe4704a698 0.86 25036103 Amlexanox, a IKKepsilon and TBK1 inhibitor XREF_BIBR did not attenuate the inflammatory response but potentiated it instead. reach p(HGNC:IKBKE) directlyDecreases bp(GO:"GO:0006954") +be78fa82-eacd-4572-bb3f-ea75d398e447 0.65 25036103 However, overexpression of TRAF1 (a TRIF inhibitor) decreased the induction of IL-1beta, IL-6, IL-8 and CHOP (XREF_TABLE, XREF_FIG). reach p(HGNC:TRAF1) directlyDecreases act(p(HGNC:CXCL8)) +834e4d9e-35c7-4b48-91f9-36289efce4b5 0.65 25036103 However, overexpression of TRAF1 (a TRIF inhibitor) decreased the induction of IL-1beta, IL-6, IL-8 and CHOP (XREF_TABLE, XREF_FIG). reach p(HGNC:TRAF1) directlyDecreases act(p(HGNC:DDIT3)) +46cae2a7-4c9d-4c5a-b6fd-8440f2809b69 0.65 25036103 However, overexpression of TRAF1 (a TRIF inhibitor) decreased the induction of IL-1beta, IL-6, IL-8 and CHOP (XREF_TABLE, XREF_FIG). reach p(HGNC:TRAF1) directlyDecreases act(p(HGNC:IL1B)) +23ccecb1-9f1a-4d74-aa4b-2ecd9e817448 0.65 25036103 However, overexpression of TRAF1 (a TRIF inhibitor) decreased the induction of IL-1beta, IL-6, IL-8 and CHOP (XREF_TABLE, XREF_FIG). reach p(HGNC:TRAF1) directlyDecreases act(p(HGNC:IL6)) +0221e1d5-71ae-4d51-851d-85133aab51d9 0.95 25036103 Inhibition TRIF and TRAM side by targeting the RIP1 kinase and IKKepsilon and TBK1 complex enhanced the 7KCh induced inflammation (XREF_FIG a, b). reach p(HGNC:TICAM1) directlyDecreases bp(GO:"GO:0006954") +d6caf1c0-1d9a-4b43-8054-b4523a3c99e4 0.65 25036103 Inhibition TRIF and TRAM side by targeting the RIP1 kinase and IKKepsilon and TBK1 complex enhanced the 7KCh induced inflammation (XREF_FIG a, b). reach p(HGNC:TRAM1) directlyDecreases bp(GO:"GO:0006954") +a6f8e61d-9758-4de0-ad6e-9ae0e93491f0 0.95 25036103 Inhibition TRIF and TRAM side by targeting the RIP1 kinase and IKKepsilon and TBK1 complex enhanced the 7KCh induced inflammation (XREF_FIG a, b). reach p(PFAM:PF12252) directlyDecreases bp(GO:"GO:0006954") +50bf56c8-9dd0-4cfe-b0fb-66e96c3b8b91 0.86 25036103 Inhibition of CK2 with the specific inhibitor 4, 5, 6, 7-tetrabromobenzotriazole (TBB) XREF_BIBR did not suppress the 7KCh induced inflammation (XREF_FIG). reach p(FPLX:CK2) directlyIncreases bp(GO:"GO:0006954") +825ba291-52d1-4acb-8ae1-1ffd4e751dbd 0.65 25036103 MKP2 is known to dephosphorylate various activated kinases downstream of multiple inflammatory pathways XREF_BIBR, XREF_BIBR and thus attenuating the inflammatory response. reach p(HGNC:DUSP4) directlyDecreases bp(GO:"GO:0006954") +7a204913-3db0-486e-bf55-7cc3a7fcc489 0.98 25036103 Overexpression of SOCS3 also causes significant suppression of IL-1beta and IL-6 (XREF_FIG). reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL1B)) +59e4b84b-c1c9-494b-8c48-9ab41d78affd 1.0 25036103 TOLLIP inhibits the activation of IRAK1 by IRAK 4. sparser p(HGNC:IRAK1) directlyIncreases act(p(HGNC:IRAK1)) +adb6555d-fc3d-46de-a8da-8c557580958a 0.95 25036103 TOLLIP inhibits the activation of IRAK1 by IRAK 4. reach p(HGNC:IRAK4) directlyDecreases act(p(HGNC:IRAK1)) +51dd5a26-38f6-4ed6-816a-35ab60dc1fd3 1.0 25036103 TOLLIP inhibits the activation of IRAK1 by IRAK 4. reach p(HGNC:TOLLIP) directlyDecreases act(p(HGNC:IRAK1)) +1c182227-a6dc-4107-a2b9-7cba9bd62c32 0.65 25036103 The SOCS1 induction was minor as compared with SOCS2 and 3 (XREF_FIG, see Y-axis).7 KCh treatment did not cause an increase in SOCS2 levels, but the SOCS2 overexpressing virus increased the SOCS2 mRNA by 6000-fold (XREF_FIG). reach p(PFAM:PF16944) directlyIncreases p(HGNC:SOCS2) +7a204913-3db0-486e-bf55-7cc3a7fcc489 0.98 25036103 The SOCS2 overexpression caused a statistically significant decrease in all of the inflammatory markers (XREF_FIG) while overexpression of SOCS3 only decreased IL-1beta and IL-6 (XREF_FIG). reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL1B)) +c57d5a35-956b-4820-8e96-11b924736350 0.86 25036103 The TRIF and TRAM signaling activates the receptor interacting protein 1 kinase (RIP1) which phosphorylates the IKKepsilon and TBK1 complex which then phosphorylates ikappaB and activates the NFkappaB complex XREF_BIBR. reach complex(p(HGNC:IKBKE), p(HGNC:TBK1)) directlyIncreases act(p(FPLX:NFkappaB)) +c795df0e-885c-42b3-8378-8fe55efc0c70 0.88 25036103 The TRIF and TRAM signaling activates the receptor interacting protein 1 kinase (RIP1) which phosphorylates the IKKepsilon and TBK1 complex which then phosphorylates ikappaB and activates the NFkappaB complex XREF_BIBR. reach p(HGNC:RIPK1) directlyIncreases p(HGNC:IKBKE, pmod(Ph)) +a3611322-6782-4e22-b691-3fdef632d842 0.88 25036103 The TRIF and TRAM signaling activates the receptor interacting protein 1 kinase (RIP1) which phosphorylates the IKKepsilon and TBK1 complex which then phosphorylates ikappaB and activates the NFkappaB complex XREF_BIBR. reach p(HGNC:RIPK1) directlyIncreases p(HGNC:TBK1, pmod(Ph)) +ccdfbb5d-57c9-4937-aa30-869df19bf087 0.65 25036103 The TRIF/TRAM signaling activates the receptor interacting protein 1 kinase (RIP1) which phosphorylates the IKKε/TBK1 complex which then phosphorylates iκB and activates the NFκB complex xref . sparser p(HGNC:IKBKE) directlyIncreases p(HGNC:BPIFA4P, pmod(Ph)) +c795df0e-885c-42b3-8378-8fe55efc0c70 0.88 25036103 The TRIF/TRAM signaling activates the receptor interacting protein 1 kinase (RIP1) which phosphorylates the IKKε/TBK1 complex which then phosphorylates iκB and activates the NFκB complex xref . sparser p(HGNC:RIPK1) directlyIncreases p(HGNC:IKBKE, pmod(Ph)) +a3611322-6782-4e22-b691-3fdef632d842 0.88 25036103 The TRIF/TRAM signaling activates the receptor interacting protein 1 kinase (RIP1) which phosphorylates the IKKε/TBK1 complex which then phosphorylates iκB and activates the NFκB complex xref . sparser p(HGNC:RIPK1) directlyIncreases p(HGNC:TBK1, pmod(Ph)) +fad90a50-0b3a-4321-aacf-d188ef6b889f 0.65 25036103 The TRIF/TRAM signaling activates the receptor interacting protein 1 kinase (RIP1) which phosphorylates the IKKε/TBK1 complex which then phosphorylates iκB and activates the NFκB complex xref . sparser p(HGNC:TBK1) directlyIncreases p(HGNC:BPIFA4P, pmod(Ph)) +c343ab9c-c029-46b1-b954-02295b40cf6d 0.65 25036103 The siRNA knockdown of CHOP did cause a 60% decrease IL-6 induction (XREF_FIG). reach p(HGNC:DDIT3) directlyDecreases act(p(HGNC:IL6)) +12f5f48b-9f0e-4905-a6ba-5800bde4b7b1 0.86 25036103 We have also previously shown that Ch causes no inflammation or angiogenesis in vivo using our anterior chamber rat model (9). reach p(PFAM:PF00307) directlyIncreases bp(GO:"GO:0001525") +01b609ef-49a5-45f8-99a1-a5d20665488c 0.86 25036103 We have also previously shown that Ch causes no inflammation or angiogenesis in vivo using our anterior chamber rat model (9). reach p(PFAM:PF00307) directlyIncreases bp(GO:"GO:0006954") +d58da677-6b7d-40bc-a7ba-083b03da81a7 0.99 25043058 Consistent with the hepatic and peripheral insulin sensitizing effects of rFGF1, insulin stimulated AKT signaling was enhanced in both the liver and muscle of chronic rFGF1 treated DIO mice (XREF_FIG). reach p(HGNC:INS) directlyIncreases act(p(FPLX:AKT)) +697a8013-0350-4626-a5db-6228b907506c 0.99 25056803 Furthermore, NLRP3 deficiency in APP transgenic mice decreased Abeta plaque load, suggesting a prominent role of NLRP3 in the pathogenesis of AD and a potential target for therapeutic intervention [XREF_BIBR]. reach p(HGNC:APP) directlyDecreases act(p(HGNC:APP)) +f5fc46a8-a98a-4bd1-9930-0f3564842809 0.95 25061609 Since ER stress and ER induced cell death play a nonredundant role in the pathogenesis of atherosclerosis and diabetic macrovascular complications, pharmaceutical targeting of ER stress components and pathways may be beneficial in the treatment and prevention of cardiovascular pathology. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0008219") +6651b919-e95e-4e34-b29a-c55dc6677fb6 0.95 25062088 Our earlier studies demonstrated that IGF-1 increases the risk for breast cancer and contributes to poor outcome in cancer patients XREF_BIBR and pAkt is associated with poor clinical outcome in breast cancer patients XREF_BIBR. reach p(HGNC:IGF1) directlyIncreases act(p(UP:P54644)) +16bef0c1-9d04-464f-8639-6c1bf6028f87 1.0 25072597 Others like TCF7L2, WNT1, WNT3A and LRP5 have a role in Wnt and beta-catenin pathway XREF_BIBR, XREF_BIBR whereas DLK1 activates MAPK kinase and ERK pathway XREF_BIBR and ADRB2 regulate adipogenesis via cAMP and PKA pathway XREF_BIBR. reach p(HGNC:DLK1) directlyIncreases act(p(FPLX:ERK)) +59e4b84b-c1c9-494b-8c48-9ab41d78affd 1.0 25076949 Upon IRAK recruitment, IRAK4 phosphorylates IRAK1 at key serine and threonine residues, and enables IRAK1 to eventually activate tumor necrosis factor receptor associated factor 6 (TRAF6) that subsequently activates transforming growth factor-beta-activated protein kinase 1 (TAK1), a member of the mitogen activated protein (MAP) kinase kinase kinase (MAP3K) family. reach p(HGNC:IRAK1) directlyIncreases act(p(HGNC:IRAK1)) +c6d4aeed-e612-44c2-a648-40d5c509b402 0.95 25101851 Activation of NF-kappaB and MAPKs, particularly the stimulation of ERK subgroup, has been demonstrated as the critical signals to trigger the cytokine production from immune responsive cells. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0001816") +78d8d903-7ff1-4f78-8807-c9688954a60b 0.95 25143442 These genes encode proteins involved in inhibiting production of type-I IFN (i.e., PCBP2) and inflammatory cytokines and chemokines (i.e., COMMD1, COMMD10, PPM1B, SPRED1, RORA, IKBA, ELOB) via distinct intracellular mechanisms : e.g., SPRED1 (sprouty related, EVH1 domain containing 1) negatively regulates the RAS and MAPK pathway; COMMD1 and COMMD10 (copper metabolism MURR1 domain containing 1) disrupt NF-kappaB binding of target genes in the nucleus; and RORA (RAR related orphan receptor A) sequesters NF-kappaB in the cytoplasm. reach p(HGNC:SPRED1) directlyDecreases act(p(FPLX:ERK)) +0c71874f-464d-4378-8f68-7d4af12d3414 0.95 25161878 These results demonstrate that ER stressors can initiate apoptosis or autophagy, which depends on the chemical nature of the stressor, the extent and the duration of the stress. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0006915") +fd8191a7-4762-4760-82ee-85b1429564a8 0.95 25171414 Prolonged CHOP expression leads to cell death, and therefore, we asked if Abeta 1-42 -dependent neurodegeneration was mediated by axonally synthesized ATF4. reach p(HGNC:DDIT3) directlyIncreases bp(GO:"GO:0008219") +72000a1a-331a-4cd0-b932-fc0dac5bb4d9 0.95 25187272 NF-kappaB activation in myeloid cells typically enhances inflammation in the tumor microenvironment by increasing the secretion of pro inflammatory cytokines such as TNF-alpha and IL-6, which eventually leads to rapid proliferation of tumor cells. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006954") +c071ed43-4f92-4778-ada7-ec6542768122 0.95 25238096 Because MDSCs were a major source of PNT in tumors (XREF_FIG), we aimed to determine if the endogenous production of ROS or PNT in MDSCs modulated Chop. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:DDIT3)) +51e70dc9-716d-467e-962f-eaf8aaa06ff0 0.95 25249281 Transcription factor NF-kappaB activates many host antiapoptotic and proinflammatory genes and is activated by NS1 and NS2 genes rapidly during RSV infection to delay apoptosis. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006915") +697a8013-0350-4626-a5db-6228b907506c 0.99 25253696 Taken together, our findings demonstrate that A673T, a protective allele of APP, reproducibly reduces amyloidogenic processing of APP and also mildly decreases Abeta aggregation. reach p(HGNC:APP) directlyDecreases act(p(HGNC:APP)) +69c67fc7-405a-40da-a682-44605602a364 0.95 25279668 Several reports have shown that ER stress induced activation of the transcription factor ATF4 and CHOP increases protein synthesis, which in turn causes ATP depletion, oxidative stress, and cell death. reach p(HGNC:ATF4) directlyIncreases bp(GO:"GO:0008219") +3f9b72b1-85a2-4895-97fd-f3ee843f4860 0.95 25286675 So the activated IGF-I level in local microebvironnment increased, which may cause the descend of cell proliferation and the increasing of apoptosis. reach p(HGNC:IGF1) directlyIncreases bp(GO:"GO:0008283") +a260ff4f-5ab3-4b69-9708-a635f62f528d 0.95 25301142 To assess endocytosis of ICAM-1 in the +absence of ligands, TNF-α-activated HUVECs were incubated continuously +for 30 min, 1, 3, or 5 h at 37 °C with 20 μg/mL TxR-labeled +tomato lectin to stain the cell surface. sparser p(HGNC:TNF) directlyIncreases act(p(HGNC:SLC7A6)) +a260ff4f-5ab3-4b69-9708-a635f62f528d 0.95 25330306 Similarly, 100 nM U0126, RDEA119, AZD6244 or trametinib also decreased SSRBC adhesion to TNFα-activated HUVECs to levels below baseline adhesion of sham-treated SSRBCs to non-activated HUVECs ( p <0.0001 for each of the MEK inhibitors) ( xref ). sparser p(HGNC:TNF) directlyIncreases act(p(HGNC:SLC7A6)) +920a4f0a-c035-4346-96ce-2d79dab40db5 1.0 25332099 Although both groups interpreted their data differently, both sets of results in fact seem to indicate that CD14 participation ameliorates the differences between the ability of rLPS and sLPS to activate TLR4. reach p(HGNC:CD14) directlyIncreases act(p(HGNC:TLR4)) +ee10d13e-6b36-4b84-9925-ef650bd004dd 0.95 25332179 In ERp44 -/- 6 months old hearts there was a significant increase in gene expression for nearly all the ER stress response members, including PDI, glucose regulated protein 78 kDa (GRP78), CHOP, ERp72, activating transcription factor 6 (ATF6), ER membrane oxidoreductase 1 (ERO1), heat shock protein 70 (HSP70), and X-box-binding protein 1 (XBP-1), when compared to WT mice (XREF_FIG A; n = 3/genotype; P < 0.05). reach p(HGNC:DDIT3) directlyIncreases act(p(HGNC:ESR1)) +eee57673-9e37-4cd5-8c8c-6989f2ab5af5 0.95 25332179 In ERp44 -/- 6 months old hearts there was a significant increase in gene expression for nearly all the ER stress response members, including PDI, glucose regulated protein 78 kDa (GRP78), CHOP, ERp72, activating transcription factor 6 (ATF6), ER membrane oxidoreductase 1 (ERO1), heat shock protein 70 (HSP70), and X-box-binding protein 1 (XBP-1), when compared to WT mice (XREF_FIG A; n = 3/genotype; P < 0.05). reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:ESR1)) +0221e1d5-71ae-4d51-851d-85133aab51d9 0.95 25360076 However, TRIF deficiency reduces IL-17 associated with neutrophilic asthma in an OVA induced model of allergic airway inflammation. reach p(HGNC:TICAM1) directlyDecreases bp(GO:"GO:0006954") +12fc128d-91e3-4acd-985a-ebb192b3a6e2 0.99 25360749 When MD2, a protein associated with the extracellular domain of TLR4, was transfected with TLR4 in HEK293 cells, MD2 enhanced TLR4 mediated production of IL-8 by LPS or EV71 VLPs. reach p(HGNC:LY96) directlyIncreases act(p(HGNC:TLR4)) +c071ed43-4f92-4778-ada7-ec6542768122 0.95 25387669 ROS activate transcription factors to induce the growth arrest and DNA damage 153 (GADD153) gene, which in turn causes the cell to undergo apoptosis through the upregulation of caspase-3. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:DDIT3)) +1f42ee8f-af93-46eb-a92b-4ababffef749 1.0 25407931 Addition of IGF-1 increased AKT, pAKT, pERK, and pGSK-3beta, but not ERK and GSK-3beta. reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:ERK, pmod(Ph))) +4d0054ac-5799-4ccf-9361-26f88691d77a 0.95 25407931 Addition of IGF-1 increased AKT, pAKT, pERK, and pGSK-3beta, but not ERK and GSK-3beta. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:GSK3B)) +6651b919-e95e-4e34-b29a-c55dc6677fb6 0.95 25407931 Addition of IGF-1 increased AKT, pAKT, pERK, and pGSK-3beta, but not ERK and GSK-3beta. reach p(HGNC:IGF1) directlyIncreases act(p(UP:P54644)) +7c47e975-614c-436e-85fe-ca81fc557f83 0.86 25407931 Also, intracellular Abeta appears to directly interfere with PIK3 activation of AKT and subsequent GSK-3beta phosphorylation which is partly responsible for Tau hyperphosphorylation and the regulation of Tau gene expression [XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR]. reach p(UP:P54675) directlyIncreases p(FPLX:AKT, pmod(Ph)) +4b21044a-2857-4766-bd0d-011858a272c7 0.65 25407931 Also, intracellular Abeta appears to directly interfere with PIK3 activation of AKT and subsequent GSK-3beta phosphorylation which is partly responsible for Tau hyperphosphorylation and the regulation of Tau gene expression [XREF_BIBR - XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR]. reach p(UP:P54675) directlyIncreases p(HGNC:GSK3B, pmod(Ph)) +539653f4-019f-40a2-b351-4ca8a006a593 0.98 25407931 Also, intracellular Aβ appears to directly interfere with PIK3 activation of AKT and subsequent GSK-3β phosphorylation which is partly responsible for Tau hyperphosphorylation and the regulation of Tau gene expression [ xref – xref , xref , xref , xref , xref ]. sparser p(UP:P54675) directlyIncreases act(p(FPLX:AKT)) +16bef0c1-9d04-464f-8639-6c1bf6028f87 1.0 25407931 Dlk1 activates the MEK and ERK pathway [XREF_BIBR], plays a functional role in motor neurons [XREF_BIBR], and has been identified as a novel target of the orphan nuclear receptor Nurr1 in meso-diencephalon DA neurons [XREF_BIBR]. reach p(HGNC:DLK1) directlyIncreases act(p(FPLX:ERK)) +bdb1c9f1-3aae-4131-9397-3eeaec2e52fc 0.98 25407931 Dlk1 activates the MEK and ERK pathway [XREF_BIBR], plays a functional role in motor neurons [XREF_BIBR], and has been identified as a novel target of the orphan nuclear receptor Nurr1 in meso-diencephalon DA neurons [XREF_BIBR]. reach p(HGNC:DLK1) directlyIncreases act(p(FPLX:MEK)) +1636852e-f1a2-4f10-8f3b-03cc48564851 0.65 25407931 In Abeta 1-42 toxicity, IGF-1, NGF, and sAPPalpha caused upregulation of IRS-1 in control neurons, but downregulation when miR-126 was overexpressed (XREF_FIG, XREF_SUPPLEMENTARY). reach p(HGNC:APP) directlyIncreases act(p(HGNC:IRS1)) +212b9c9b-51f4-4c97-b2c8-f0a2a43df64e 0.65 25407931 In Abeta 1-42 toxicity, IGF-1, NGF, and sAPPalpha caused upregulation of IRS-1 in control neurons, but downregulation when miR-126 was overexpressed (XREF_FIG, XREF_SUPPLEMENTARY). reach p(HGNC:NGF) directlyIncreases act(p(HGNC:IRS1)) +33e09888-6ad0-442d-9d33-4ed87966095d 0.65 25407931 When we examined miR-126 expression levels, we found that the endogenous miRNA was increased (1.5-2 fold) in STS and IGF-1-treated cells (XREF_FIG), while in the Syn.miR-126 transduced cells, STS caused a decrease and IGF-1 a slight increase in miRNA levels, which could have been associated with different Synapsin promoter regulation as a consequence of cell treatment. reach p(HGNC:STS) directlyIncreases act(p(HGNC:IGF1)) +1f42ee8f-af93-46eb-a92b-4ababffef749 1.0 25424625 According to the cell signaling assays shown in Figure  xref F, LMAb1 could block the IGF-1 induced activation of pERK, pAKT and pIGF-1R along with the increase concentration of LMAb1, indicating that inhibition of PI3K-AKT as well as MAPK cascade might be one of the anti-tumor mechanisms of anti-IGF-1R antibody LMAb1. sparser p(HGNC:IGF1) directlyIncreases act(p(FPLX:ERK, pmod(Ph))) +59e4b84b-c1c9-494b-8c48-9ab41d78affd 1.0 25452754 IRAK-4 is thought to phosphorylate IRAK-1, which allows IRAK-1 to initiate an auto-phosphorylation cascade occurring in three sequential steps. reach p(HGNC:IRAK1) directlyIncreases act(p(HGNC:IRAK1)) +4d0054ac-5799-4ccf-9361-26f88691d77a 0.95 25520943 As shown in Figure XREF_FIG A, increased levels of P-Akt, P-GSK3alpha, and P-GSK3beta were observed in mouse prostate tissues treated with insulin alone, IGF1 alone, a combination of insulin and IL-17, and a combination of IGF1 and IL-17, compared to the control group. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:GSK3B)) +f5fc46a8-a98a-4bd1-9930-0f3564842809 0.95 25569104 In addition, the fact that ER stress can trigger an inflammatory type of cell death, which contrasts with apoptosis that is in many conditions immunosilent, opens doors for future studies on the role of ER stress in inflammation driven pathologies. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0008219") +fbad71e6-c835-48ec-95f7-c7291379ea64 0.95 25593996 This study confirmed that miR-7 negatively regulates also AKT, and ERK 1/2 [XREF_BIBR], whereas Rai et al. also confirmed these results finding that miR-7 ectopic expression allowed EGFR TKIs to overcome resistance in lung cancer cell lines [XREF_BIBR]. reach p(HGNC:"MIR7-1") directlyDecreases act(p(FPLX:AKT)) +c6d4aeed-e612-44c2-a648-40d5c509b402 0.95 25683963 Inhibition of NFkappaB successfully diminishes cytokine production, but the effects of inhibition are broad, considering the relative importance of NFkappaB signaling in essential innate immune responses and the initiation of inflammation XREF_BIBR - XREF_BIBR. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0001816") +eb01c4cc-e251-4217-a9f6-6ce86cf2993e 0.99 25753787 IKKalpha/beta/gamma and TBK1 and IKKepsilon then activate the transcription factors NF-kappaB and IFN-regulatory factors 3 and 7 (IRF3/7), respectively. reach p(HGNC:IKBKE) directlyIncreases act(p(FPLX:NFkappaB)) +16bef0c1-9d04-464f-8639-6c1bf6028f87 1.0 25790378 A recent study reported that adipogenic inhibitor Pref-1 activated ERK and inhibited adipogenesis [ xref ]. sparser p(HGNC:DLK1) directlyIncreases act(p(FPLX:ERK)) +f5fc46a8-a98a-4bd1-9930-0f3564842809 0.95 25793496 Also needed is further information identifying the interacting partners of these phosphorylated proteins, their upstream cognate kinases and their mutants that could provide further insights into the mechanisms underlying ER stress induced INS-1 cell death and anti-apoptotic effect of exenatide. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0008219") +0221e1d5-71ae-4d51-851d-85133aab51d9 0.95 25819428 This cleavage of TRIF by NS3/4A could prevent TLR3 activation and the resulting inflammation observed during HCV infection or it could alleviate TLR3 independent TRIF signaling of innate immunity. reach p(HGNC:TICAM1) directlyDecreases bp(GO:"GO:0006954") +0755e65a-7681-44e8-a0af-ce15e55fe046 0.99 25846612 In sensory neurons, nerve growth factor (NGF) and interleukin 6 (IL6), two factors known to induce priming, induce an increase in ERK and mTORC1 signaling leading to a local, axonal increase in protein synthesis. reach p(HGNC:NGF) directlyIncreases act(p(FPLX:ERK)) +920a4f0a-c035-4346-96ce-2d79dab40db5 1.0 25869127 Equally, the suppressed LPS-response in Hpa-tg microglia indicated a loss of CD14-dependent TLR4 activation, suggesting that microglial HSPGs facilitate this process. sparser p(HGNC:CD14) directlyIncreases act(p(HGNC:TLR4)) +12f5f48b-9f0e-4905-a6ba-5800bde4b7b1 0.86 25884955 Ch ' ng et al. proposed that tumor stromal TAMs influence tubular architecture and, eventually, tumor grade, whereas tumor nest TAMs have a closer relationship with hypoxia induced angiogenesis, indicating that the TAMs have different effects on tumor progression according to their histologic location [XREF_BIBR]. reach p(PFAM:PF00307) directlyIncreases bp(GO:"GO:0001525") +fd8191a7-4762-4760-82ee-85b1429564a8 0.95 25886386 Studies have shown that apoptosis of podocytes induced by ER stress plays an important role in the process of glomerulosclerosis, and that CHOP (C/EBP homologous protein) is a key mediator of cell death in response to ER stress [XREF_BIBR - XREF_BIBR]. reach p(HGNC:DDIT3) directlyIncreases bp(GO:"GO:0008219") +9264c3da-0592-425a-80b8-039b4e8e272b 0.86 25914608 In line with these findings, we show that activation of TLR4 by LPS induces ER stress and upregulates ATF4 in brain and retinal microvascular endothelial cells. reach p(HGNC:TLR4) directlyIncreases act(p(HGNC:ATF4)) +6651b919-e95e-4e34-b29a-c55dc6677fb6 0.95 25921925 As shown in XREF_FIG, IGF-1 augments pAKT S473 but not pAKT T308 in HPASMC. reach p(HGNC:IGF1) directlyIncreases act(p(UP:P54644)) +4d0054ac-5799-4ccf-9361-26f88691d77a 0.95 25981038 Indeed, IGF-1 treatment is sufficient to cause muscle hypertrophy via Akt activation of mTOR and inhibition of GSK3beta. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:GSK3B)) +697a8013-0350-4626-a5db-6228b907506c 0.99 26002056 Alternatively sorting of APP to ILVs could prevent intracellular Abeta accumulation by targeting APP and/or its processing products for lysosomal degradation. reach p(HGNC:APP) directlyDecreases act(p(HGNC:APP)) +cd9dc75f-8113-49b7-aa3f-3b9d97c729dc 0.98 26028029 We sought to discover whether augmented AKT activity from Pten deletion would further increase NF-kappaB activity in PSGR over-expressing conditions and facilitate prostate cancer progression. reach p(FPLX:AKT) directlyIncreases act(p(FPLX:NFkappaB)) +72000a1a-331a-4cd0-b932-fc0dac5bb4d9 0.95 26055622 It is known that NF-kappaB is the vital signaling of oxidative stress and inflammation on AT 1 R expression, we checked NF-kappaB related pathway, it showed that there was a marked increase in phosphorylation of IKK and IkappaBalpha in ZDF rats, which was accompanied by decreased protein expression of IkappaBalpha. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006954") +a260ff4f-5ab3-4b69-9708-a635f62f528d 0.95 26064179 Here, we show that natural product, S. indicus extract along with one of its active constituent, 7-HF mediate anti-inflammatory effects by effectively modulating the expression of cell adhesion molecules via suppression of NF-κB/IκBα signaling in TNF-α activated HUVECs. sparser p(HGNC:TNF) directlyIncreases act(p(HGNC:SLC7A6)) +a260ff4f-5ab3-4b69-9708-a635f62f528d 0.95 26077188 Hence, shear stress adaptation reduces the uptake of unmodified AuNPs and increases the association between anti-ICAM-1 AuNPs and TNF-activated HUVECs. sparser p(HGNC:TNF) directlyIncreases act(p(HGNC:SLC7A6)) +46ccb254-c30d-42d1-891d-17303d643d21 1.0 26090071 It is demonstrated that ceramides decrease phosphorylation of extracellular signal regulated kinases (ERKs) and their upstream activators MAPKs kinases (MEKs) and trigger JNK and p38 MAPK cascades inducing neuronal death through caspase-3 activation and upregulation of c-jun, c-fos, and p53 [XREF_BIBR, XREF_BIBR]. reach p(HGNC:CASP3) directlyIncreases act(p(HGNC:TP53)) +fd8191a7-4762-4760-82ee-85b1429564a8 0.95 26090483 CHOP induced cell death has been associated with downregulation of BCL-2 levels [XREF_BIBR]. reach p(HGNC:DDIT3) directlyIncreases bp(GO:"GO:0008219") +fbad71e6-c835-48ec-95f7-c7291379ea64 0.95 26172296 These findings indicated that PI3K and Akt pathway was indeed suppressed by miR-7 in PCa and in turn caused an overall inhibition of prostatic tumor growth. reach p(HGNC:"MIR7-1") directlyDecreases act(p(FPLX:AKT)) +efc0f64c-a37a-4cf4-9c89-049ff1b9d7ad 0.95 26186544 In any case, the present study clearly shows conclusive evidence that GGA is one of the natural lipids that induce a lipid induced ER stress response and UPR at sub-ten muM, which is potentially responsible for lipotoxicity or lipid induced cell death, while canonical lipid induced ER stress response occurs with some hundreds muM saturated fatty acids such as palmitate. reach bp(GO:"GO:0006950") directlyIncreases bp(GO:"GO:0008219") +716cc167-a897-4a68-acd0-4134b89a2790 0.95 26239352 BiP inducer X (1-(3,4-dihydroxyohenyl)-2-thiocyanate-ethanone, BIX) is a small molecule GRP78 and BiP inducer that also increases GRP94, calreticulin, and CHOP [XREF_BIBR]. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:DDIT3)) +840e5f0e-ec8e-4eb9-81cb-b619edb48caf 0.95 26261796 Out of the several factors contributing to PD prognosis, the role of p38 MAPK (Mitogen activated protein-kinase) and PI3K and AKT signalling module in PD brains is crucial because the impaired balance between the pro- apoptotic and anti-apoptotic pathways trigger unwanted phenotypes such as microglia activation, neuroinflammation, oxidative stress and apoptosis. reach p(FPLX:PI3K) directlyIncreases bp(MESH:D010300) +92e92d63-67d0-44fc-8cf2-8c751ef82a11 1.0 26300842 In neural cell cultures, Abeta induced the phosphorylation of PKR, glycogen synthase kinase-3beta (GSK-3beta), and tau. reach p(HGNC:APP) directlyIncreases p(HGNC:MAPT, pmod(Ph)) +cd9dc75f-8113-49b7-aa3f-3b9d97c729dc 0.98 26310859 Moreover, inhibition of Akt phosphorylation by apocynin26 could partly inhibit NF-kappaB transcriptional activity through IKK activation. reach p(FPLX:AKT) directlyIncreases act(p(FPLX:NFkappaB)) +fa2d0182-7d30-4f39-864f-7cd17a0eb20b 0.98 26327128 Second, our findings link FD induced ROS to redox adaptation mediated upregulation of GRP78 and Survivin. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:HSPA5)) +eee57673-9e37-4cd5-8c8c-6989f2ab5af5 0.95 26353013 The upregulation in BiP is crucial to initiate the ER stress response via ER membrane located proteins such as IRE1alpha, PERK and ATF6 which in turn activates XBP1, ATF4 and ATF6 itself as transcription factors to induce ER stress. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:ESR1)) +eb01c4cc-e251-4217-a9f6-6ce86cf2993e 0.99 26380323 Our results are in agreement with these studies in suggesting that IKKepsilon mediated NF-kappaB signaling may relate to pathogenesis of pSS. reach p(HGNC:IKBKE) directlyIncreases act(p(FPLX:NFkappaB)) +12fc128d-91e3-4acd-985a-ebb192b3a6e2 0.99 26385043 Of these pathways, the iNOS pathway ( xref ), which is activated via toll-like receptor 4 (TLR-4)-LY96 receptor complex activation, has been previously identified as a relevant pathway to AF. xref Therefore, we analyzed the potential gene-gene interaction between LY96 SNP and each of the 4 functionally relevant candidate genes in the iNOS-related signaling pathway ( xref and xref ) in terms of their association with postoperative AF. sparser p(HGNC:LY96) directlyIncreases act(p(HGNC:TLR4)) +eb01c4cc-e251-4217-a9f6-6ce86cf2993e 0.99 26385424 IKKalpha and beta, IKKepsilon and TAK1 are targeted by viral proteins to stimulate NF-kappaB activation. reach p(HGNC:IKBKE) directlyIncreases act(p(FPLX:NFkappaB)) +73461c97-a89b-40ad-be13-3d7f30e4ea6f 0.98 26458447 Approximately 90% of WM patients carry MYD88L265P, which activates IRAK and BTK, which in turn activate NFkappaB. reach p(HGNC:IRAK1) directlyIncreases act(p(FPLX:NFkappaB)) +539653f4-019f-40a2-b351-4ca8a006a593 0.98 26465359 Expression of dominant active PIK3 and AKT in prostate cancer cell line DU145 in which PIK3, AKT, and PTEN are wild type caused the cells to be reflectory to the inhibition of delta-T, supporting that delta-T inhibits the PIK3 mediated activation of AKT. reach p(UP:P54675) directlyIncreases act(p(FPLX:AKT)) +06bd0dfa-24ce-4570-91f4-feea991b6ca4 0.95 26514620 Since p70 S6K1 is one of the downstream targets of the TORC1 signaling pathway, it was also possible that p70 S6K1 may negatively regulate SOCS3 expression to block IL-6 signaling. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL6)) +fbad71e6-c835-48ec-95f7-c7291379ea64 0.95 26516313 Fang et al. showed that miR-7 arrests hepatocellular carcinoma cells in the G0/G1 phase and negatively regulates the PI3K and AKT pathway by targeting AKT, mammalian target of rapamycin, and ribosomal protein S6 kinase, which are key signaling molecules involved in the promotion of liver cancer cell growth and metastasis [XREF_BIBR]. reach p(HGNC:"MIR7-1") directlyDecreases act(p(FPLX:AKT)) +a260ff4f-5ab3-4b69-9708-a635f62f528d 0.95 26544976 We suggest that the decreased secretion of IL-6 in TNF-α-activated HUVECs after adenine treatment contributes to the lower expression of adhesion molecules in the present study. sparser p(HGNC:TNF) directlyIncreases act(p(HGNC:SLC7A6)) +1f42ee8f-af93-46eb-a92b-4ababffef749 1.0 26554308 Furthermore, activation of IGF1R by IGF-1 induced activation of pERK, but not of pAKT in PC9 and H460 cells (Figure xref ). sparser p(HGNC:IGF1) directlyIncreases act(p(FPLX:ERK, pmod(Ph))) +1f42ee8f-af93-46eb-a92b-4ababffef749 1.0 26554308 Furthermore, activation of IGF1R by IGF-1 induced activation of pERK, but not of pAKT in PC9 and H460 cells. reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:ERK, pmod(Ph))) +1f42ee8f-af93-46eb-a92b-4ababffef749 1.0 26554308 We herein showed that activation of IGF1R by IGF-1 induced activation of the pERK, but not of pAKT in both PC-9 and H460 cells, whereas pERK decreased dramatically when IGF1R was silenced. reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:ERK, pmod(Ph))) +1f42ee8f-af93-46eb-a92b-4ababffef749 1.0 26554308 We herein showed that activation of IGF1R by IGF-1 induced activation of the pERK, but not of pAKT in both PC-9 and H460 cells, whereas pERK decreased dramatically when IGF1R was silenced. sparser p(HGNC:IGF1) directlyIncreases act(p(FPLX:ERK, pmod(Ph))) +73461c97-a89b-40ad-be13-3d7f30e4ea6f 0.98 26569329 TRAF6 and UBC13 catalyse the formation of K63 linked polyubiquitin chains on both TRAF6 and IRAK1, which subsequently induce MAPK and NF-kappaB pathways by activating the TAK1/TAB1/TAB2/TAB2, and IKK complex, respectively [XREF_BIBR] (XREF_FIG). reach p(HGNC:IRAK1) directlyIncreases act(p(FPLX:NFkappaB)) +6549fbd1-6832-4252-9130-823a07ab1a87 0.95 26633009 In terms of PD, miR-7 and miR-153 and miR-205-5p have been shown to down-regulate SNCA and LRRK2, respectively whilst DJ-1 and Parkin are regulated by miR-34b/c [XREF_BIBR, XREF_BIBR, XREF_BIBR]. reach p(HGNC:"MIR7-1") directlyDecreases act(p(HGNC:SNCA)) +40d279b2-9c40-483b-8e4e-106c763ded54 0.99 26634309 One of the known target genes activated by ATF4, Chop or Ddit3, also codes for a TF with unique target genes XREF_BIBR. reach p(HGNC:ATF4) directlyIncreases act(p(HGNC:DDIT3)) +920a4f0a-c035-4346-96ce-2d79dab40db5 1.0 26668716 In contrast to this it has been reported that lung epithelial cells do express TLR 1-6, including adaptor molecules like CD14 and MD-2, with bronchial epithelial cells showing CD14 dependent activation of TLR4 and alveolar epithelial cells showing LPS binding protein (LBP)-dependent inhibition of TLR4 signalling [XREF_BIBR, XREF_BIBR], confirming the relevance of co-factors for a proper TLR signalling. reach p(HGNC:CD14) directlyIncreases act(p(HGNC:TLR4)) +920a4f0a-c035-4346-96ce-2d79dab40db5 1.0 26668716 In contrast to this it has been reported that lung epithelial cells do express TLR 1–6, including adaptor molecules like CD14 and MD-2, with bronchial epithelial cells showing CD14-dependent activation of TLR4 and alveolar epithelial cells showing LPS-binding protein (LBP)-dependent inhibition of TLR4 signalling [ xref , xref ], confirming the relevance of co-factors for a proper TLR signalling. sparser p(HGNC:CD14) directlyIncreases act(p(HGNC:TLR4)) +eee57673-9e37-4cd5-8c8c-6989f2ab5af5 0.95 26673894 We report that deletion of FICD, a gene encoding an ER localized AMPylating enzyme, abolished detectable modification of endogenous BiP enhancing ER buffering of unfolded protein stress in mammalian cells, whilst deregulated FICD activity had the opposite effect. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:ESR1)) +0755e65a-7681-44e8-a0af-ce15e55fe046 0.99 26691724 Altogether, these results suggest that the proximal part of the DUSP5 promoter is sufficient to enable activation of transcription by serum and growth factors, such as NGF, known to activate the MAPK pathway. reach p(HGNC:NGF) directlyIncreases act(p(FPLX:ERK)) +3f9b72b1-85a2-4895-97fd-f3ee843f4860 0.95 26701791 Our data indicate that IGF1 pro forms can induce breast cancer cell proliferation via the IGF1R, independent from the mature IGF1 form. reach p(HGNC:IGF1) directlyIncreases bp(GO:"GO:0008283") +92e92d63-67d0-44fc-8cf2-8c751ef82a11 1.0 26711827 The phosphorylation of tau was induced by Aβ(25-35) in primary cortical neuron. sparser p(HGNC:APP) directlyIncreases p(HGNC:MAPT, pmod(Ph)) +eb01c4cc-e251-4217-a9f6-6ce86cf2993e 0.99 26712804 Finally, Lys500 was reported as a single site of IFN-I–activating polyubiquitination by an unknown E3, inhibiting NF-κB activation by sequestering IKKε ( xref ). sparser p(HGNC:IKBKE) directlyIncreases act(p(FPLX:NFkappaB)) +f5fc46a8-a98a-4bd1-9930-0f3564842809 0.95 26713093 Exposure of BRAF mutated melanoma cells to clinically relevant doses of BRAFi leads to apoptotic cell death mediated by ER stress [XREF_BIBR]. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0008219") +3f9b72b1-85a2-4895-97fd-f3ee843f4860 0.95 26732039 Previous studies have shown that GH and IGF-I may enhance tumorigenesis, metastasis, and cell proliferation in humans and animals. reach p(HGNC:IGF1) directlyIncreases bp(GO:"GO:0008283") +775f864e-0093-4adc-87f9-d77148273465 1.0 26868487 IGF-1 induces activation of two different pathways downstream of IRS-1; the PI3K and the MAP-kinase (MAPK) MEK and ERK pathways. reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:IRS1)) +c97a3b8b-eddb-4255-8abf-e28ef34d4cf0 0.99 26884348 Likewise, Akt activated by PI3Kgamma contributes to pathological hypertrophy during pressure overload or beta-adrenergic receptor activation, but is dispensable for physiological growth [XREF_BIBR - XREF_BIBR]. reach p(HGNC:PIK3CG) directlyIncreases act(p(FPLX:AKT)) +69c67fc7-405a-40da-a682-44605602a364 0.95 26884599 ATF4 can cause cell death in certain conditions, especially when stress exposure is prolonged, usually because of transcriptional induction of CHOP. reach p(HGNC:ATF4) directlyIncreases bp(GO:"GO:0008219") +a260ff4f-5ab3-4b69-9708-a635f62f528d 0.95 26888313 Indeed, we report that Rhus coriari a inhibited the migration and invasion of MDA-MB-231 cells, blocked their adhesion to fibronectin, to HUVECs and to lung microvascular endothelial (HMVEC-L) and inhibited their transendothelial migration through TNF-α-activated HUVECs. sparser p(HGNC:TNF) directlyIncreases act(p(HGNC:SLC7A6)) +0991ea45-f706-4dc8-bb41-b161314148c3 0.95 26918349 Both Hoechst 33342 staining and TUNEL assay consistently demonstrated that combination of aspirin and inhibitor of Akt, MEK or AMPK synergistically induced HepG2 cells apoptosis. reach p(FPLX:AKT) directlyIncreases bp(GO:"GO:0006915") +fd8191a7-4762-4760-82ee-85b1429564a8 0.95 26943907 When cells are experiencing ER stress GADD153 is induced and hence initiating the cell death process. reach p(HGNC:DDIT3) directlyIncreases bp(GO:"GO:0008219") +920a4f0a-c035-4346-96ce-2d79dab40db5 1.0 26960718 By interacting with LPS binding protein (LBP), lipid A is extracted from LPS micelles and transferred to membrane CD14 XREF_BIBR, which initiates the Toll like receptor 4 (TLR4) signalling pathway and activates the transcription factor NF-kappaB, leading to the production of TNF-alpha, IL-6, and other inflammatory mediators XREF_BIBR. reach p(HGNC:CD14) directlyIncreases act(p(HGNC:TLR4)) +eee57673-9e37-4cd5-8c8c-6989f2ab5af5 0.95 27004760 The investigation of the effect of GRP78 and BiP redistribution on viral protein expression and viral particle production indicates that permanent ER stress caused by the redistribution of GRP78 and BiP is beneficial to EV71 (XREF_FIG), which is consistent with our previous study. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:ESR1)) +6651b919-e95e-4e34-b29a-c55dc6677fb6 0.95 27039345 In 17beta-estradiol treatment in vivo results in a dose dependent activation of ERK and Akt and has a synergistic effect on IGF-1 mediated activation of the pAkt and PKB pathway. reach p(HGNC:IGF1) directlyIncreases act(p(UP:P54644)) +16bef0c1-9d04-464f-8639-6c1bf6028f87 1.0 27044861 These results indicate that Pref-1 activates ERK1/2 and Akt independently, and that ERK1/2 signaling precedes FOXO1 phosphorylation. sparser p(HGNC:DLK1) directlyIncreases act(p(FPLX:ERK)) +0755e65a-7681-44e8-a0af-ce15e55fe046 0.99 27081296 The ELISA results revealed that NGF significantly promoted the production and secretion of VEGF in Muller cells after 12 or 24 h of stimulation, with more elevation after 24 h. Furthermore, NGF activated ERK1/2 and PI3K and AKT signaling, which was shown by the marked upregulation of phosphorylation in the western blot. reach p(HGNC:NGF) directlyIncreases act(p(FPLX:ERK)) +697a8013-0350-4626-a5db-6228b907506c 0.99 27084356 Interestingly, although they have not found evidence for a direct alpha-secretase stimulation neither in vivo nor in vitro, De Strooper and collaborators explained their findings by stating that activation of 5-HT 4 receptors had probably stimulated alpha-secretase activity, which in turn increased non amyloidogenic proteolysis of APP responsible for the observed decreased soluble and insoluble Abeta concentrations measured (both in cultured human neuroblastoma cells and in the hippocampus of the hAPP and PS1 mouse model of AD). reach p(HGNC:APP) directlyDecreases act(p(HGNC:APP)) +69c67fc7-405a-40da-a682-44605602a364 0.95 27148687 Surprisingly, AQ still protected ATF4 silenced cells against glutamate induced cell death. reach p(HGNC:ATF4) directlyIncreases bp(GO:"GO:0008219") +0991ea45-f706-4dc8-bb41-b161314148c3 0.95 27151366 This finding is explained, in part, by Akt gene modifications, which enhanced the viability of stem cells and resistance to apoptosis. reach p(FPLX:AKT) directlyIncreases bp(GO:"GO:0006915") +40d279b2-9c40-483b-8e4e-106c763ded54 0.99 27211800 Generally, ATF4 is a transcription factor that regulates a wide range of genes, which play a crucial role in cell adaptation to stress conditions, but paradoxically, during long-term ER stress, ATF4 may also stimulate genes of CCAAT-enhancer-binding protein homologous protein (CHOP), which is responsible for initiation of the apoptotic cascade [XREF_BIBR] (XREF_FIG). reach p(HGNC:ATF4) directlyIncreases act(p(HGNC:DDIT3)) +0c71874f-464d-4378-8f68-7d4af12d3414 0.95 27211800 The group of BH3 domain- only proteins is also engaged in ER induced apoptosis. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0006915") +46ccb254-c30d-42d1-891d-17303d643d21 1.0 27222705 This pro-apoptotic effect of AMPK has been attributed to inhibition of cell cycle progression, activation of the JNK pathway and caspase-3 activation, and up-regulation of the pro-apoptotic p53 protein [ xref ]. sparser p(HGNC:CASP3) directlyIncreases act(p(HGNC:TP53)) +efc0f64c-a37a-4cf4-9c89-049ff1b9d7ad 0.95 27230858 JNK1 is also a key mediator of the oxidative stress response, which can promote cell death or survival, depending on the magnitude and context of its activation. reach bp(GO:"GO:0006950") directlyIncreases bp(GO:"GO:0008219") +ee10d13e-6b36-4b84-9925-ef650bd004dd 0.95 27277680 14 However, whether CHOP mediated ER stress is involved in Ang II induced cardiac injury is unknown and the role of ER stress in this process remains unclear. reach p(HGNC:DDIT3) directlyIncreases act(p(HGNC:ESR1)) +fbad71e6-c835-48ec-95f7-c7291379ea64 0.95 27282910 miR-7, which acts as a tumor suppressor, directly targets EGFR and can independently repress the Akt pathway through targeting of its upstream regulators. reach p(HGNC:"MIR7-1") directlyDecreases act(p(FPLX:AKT)) +69c67fc7-405a-40da-a682-44605602a364 0.95 27286262 As neurosphere assays may not evaluate the effect drug treatment has on viability, we determined if ATF4 knockdown decreased cell death in our U87NS sh control and shATF4 C1 and E7 lines by carrying out a time course of trypan blue counts. reach p(HGNC:ATF4) directlyIncreases bp(GO:"GO:0008219") +7a204913-3db0-486e-bf55-7cc3a7fcc489 0.98 27318131 STAT3 induces suppressor of cytokine signaling 3 (SOCS3), which inhibits IL-1beta, IL-6, and TNFalpha. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL1B)) +7a204913-3db0-486e-bf55-7cc3a7fcc489 0.98 27318131 STAT3 induces suppressor of cytokine signaling 3 (SOCS3), which inhibits IL-1β, IL-6, and TNFα. sparser p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL1B)) +69c67fc7-405a-40da-a682-44605602a364 0.95 27409837 Furthermore, ATF4 KO MEFs were substantially resistant to death to H 2 O 2 compared to ATF4 WT MEFs supporting the notion that ATF4 and LATS1 act in the same pathway to induce cell death under oxidative stress. reach p(HGNC:ATF4) directlyIncreases bp(GO:"GO:0008219") +16bef0c1-9d04-464f-8639-6c1bf6028f87 1.0 27420916 Interestingly, while this MAPK cascade is also initiated by DLK-1 (MAP3K), it utilizes the MAP2K MKK-4, instead of SEK-3 which we found to be required for Ptbb-6 : : GFP induction. reach p(HGNC:DLK1) directlyIncreases act(p(FPLX:ERK)) +efc0f64c-a37a-4cf4-9c89-049ff1b9d7ad 0.95 27447570 If the DNA damage was too severe to repair, it was transmitted by cellular stress response to mediate cell death [XREF_BIBR, XREF_BIBR, XREF_BIBR]. reach bp(GO:"GO:0006950") directlyIncreases bp(GO:"GO:0008219") +fbad71e6-c835-48ec-95f7-c7291379ea64 0.95 27448964 Some miR-7 associated cancer research have also shown that miR-7 could attenuate the activation of PI3K and AKT and MAPK signaling pathways [XREF_BIBR - XREF_BIBR], leading to suppression of tumor cell proliferation and survival and inhibition of tumor invasion and metastasis. reach p(HGNC:"MIR7-1") directlyDecreases act(p(FPLX:AKT)) +6651b919-e95e-4e34-b29a-c55dc6677fb6 0.95 27532210 There was clear and consistent induction of pAKT by IGF1 in all 4 cell lines, but little if any evidence of pERK response to IGF1 (XREF_SUPPLEMENTARY). reach p(HGNC:IGF1) directlyIncreases act(p(UP:P54644)) +12fc128d-91e3-4acd-985a-ebb192b3a6e2 0.99 27534656 However, the Der p 2 allergen within HDM, a structural homologue of MD-2, can mimic its function and induce TLR4 signaling in epithelial cells in the absence of MD-2 [XREF_BIBR]. reach p(HGNC:LY96) directlyIncreases act(p(HGNC:TLR4)) +eee57673-9e37-4cd5-8c8c-6989f2ab5af5 0.95 27570969 ER Ca 2+ depletion and accumulation of unfolded proteins activate the molecular chaperone GRP78 (glucose regulated protein 78) which in turn triggers the ER stress response (ERSR) pathway aimed to restore ER homeostasis. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:ESR1)) +06bd0dfa-24ce-4570-91f4-feea991b6ca4 0.95 27581515 SOCS3 inhibits the signaling of IL-6, granulocyte colony stimulating factor, and leptin by binding to their respective receptors. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL6)) +1f42ee8f-af93-46eb-a92b-4ababffef749 1.0 27586516 Similarly, pre-treatment of CXCR4-Ab was sufficient to inhibit both SDF-1alpha and/or IGF1 induced p-ERK1/2 and p-Akt enhancement in hDSCs (XREF_FIG). reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:ERK, pmod(Ph))) +920a4f0a-c035-4346-96ce-2d79dab40db5 1.0 27648302 37 One mechanism by which it activates monocytes requires its binding to lipopolysaccharide (LPS) with subsequent transfer of the LPS to CD14 to enhance toll like receptor 4 (TLR4)-mediated tumor necrosis factor-alpha (TNF-alpha) production. reach p(HGNC:CD14) directlyIncreases act(p(HGNC:TLR4)) +92e92d63-67d0-44fc-8cf2-8c751ef82a11 1.0 27650389 In primary neuronal culture, Aβ is capable of inducing tau phosphorylation( xref ). sparser p(HGNC:APP) directlyIncreases p(HGNC:MAPT, pmod(Ph)) +59e4b84b-c1c9-494b-8c48-9ab41d78affd 1.0 27658294 IRAK4 then phosphorylates IRAK1, allowing IRAK1 to interact with TNF receptor associated factor 6 (TRAF6) to assemble into a signaling complex. reach p(HGNC:IRAK1) directlyIncreases act(p(HGNC:IRAK1)) +46ccb254-c30d-42d1-891d-17303d643d21 1.0 27706063 Furthermore, pretreatment with koumine suppressed LPS mediated p53 activation, loss of mitochondrial membrane potential, caspase-3 activation, decrease of Bcl-2 expression, and elevation of Bax and caspase-3 expressions, suggesting that koumine might act directly on RAW 264.7 cells to inhibit LPS induced apoptosis. reach p(HGNC:CASP3) directlyIncreases act(p(HGNC:TP53)) +12fc128d-91e3-4acd-985a-ebb192b3a6e2 0.99 27731905 Thus, MD-2 activates TLR4 signaling by mediating receptor dimerization XREF_BIBR, XREF_BIBR. reach p(HGNC:LY96) directlyIncreases act(p(HGNC:TLR4)) +a260ff4f-5ab3-4b69-9708-a635f62f528d 0.95 27738004 Neutrophils were adhered to TNF-activated HUVECs, TNF-activated C166 mouse endothelial cells, or ICAM-1–coated surfaces in the presence of f MLP. sparser p(HGNC:TNF) directlyIncreases act(p(HGNC:SLC7A6)) +ee10d13e-6b36-4b84-9925-ef650bd004dd 0.95 27783653 We had shown earlier that with over-expression of the cytoprotective heat shock protein alphaB-crystallin, CHOP elevation in ER stress can be suppressed leading to an anti-apoptotic response [XREF_BIBR]. reach p(HGNC:DDIT3) directlyIncreases act(p(HGNC:ESR1)) +c97a3b8b-eddb-4255-8abf-e28ef34d4cf0 0.99 27821807 Inhibition of PI3Kgamma prevents Akt activation and blunts the HG induced increase in HMGB1 expression by the cardiomyocytes. reach p(HGNC:PIK3CG) directlyIncreases act(p(FPLX:AKT)) +92e92d63-67d0-44fc-8cf2-8c751ef82a11 1.0 27834631 Unlike enhanced tau phosphorylation by Aβ 1-42 in control cells, knockdown of SHIP2 expression in SH-SY5Y cells abrogated tau phosphorylation by Aβ 1-42 ( xref ). sparser p(HGNC:APP) directlyIncreases p(HGNC:MAPT, pmod(Ph)) +6549fbd1-6832-4252-9130-823a07ab1a87 0.95 27866512 miR-7 and miR-153 are highly expressed in the brain, and can synergistically repress the SNCA translation. reach p(HGNC:"MIR7-1") directlyDecreases act(p(HGNC:SNCA)) +06bd0dfa-24ce-4570-91f4-feea991b6ca4 0.95 27888331 IL-6 inhibits the suppression induced by Treg cells [XREF_BIBR], thus highlighting that SOCS3 which negatively regulate IL-6 prolongs Treg function. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL6)) +716cc167-a897-4a68-acd0-4134b89a2790 0.95 27958308 In contrast, the combination treatment of thapsigargin and BiP interference extensively elevated the level of CHOP protein, and the proportion of up-regulated CHOP in the bystander cells treated with hypoxic conditioned medium was much more notable than that of normoxic treatment group. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:DDIT3)) +3f9b72b1-85a2-4895-97fd-f3ee843f4860 0.95 2808386 Insulin like growth factor (IGF-I) stimulates thyroid cell proliferation. reach p(HGNC:IGF1) directlyIncreases bp(GO:"GO:0008283") +c071ed43-4f92-4778-ada7-ec6542768122 0.95 28116245 These results suggest that 7KCHO induces apoptosis of MC3T3-E1 cells through ROS dependent activation of CHOP, and GRP78 may increase to counteract excessive induction of CHOP. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:DDIT3)) +fa2d0182-7d30-4f39-864f-7cd17a0eb20b 0.98 28116245 These results suggest that 7KCHO induces apoptosis of MC3T3-E1 cells through ROS-dependent activation of CHOP, and GRP78 may increase to counteract excessive induction of CHOP. sparser p(HGNC:ROS1) directlyIncreases act(p(HGNC:HSPA5)) +ee10d13e-6b36-4b84-9925-ef650bd004dd 0.95 28125634 Here we show that under ketamine exposure, ER stress is activated by the increase of CHOP and GADD153 mRNA levels in NSCs. reach p(HGNC:DDIT3) directlyIncreases act(p(HGNC:ESR1)) +eb01c4cc-e251-4217-a9f6-6ce86cf2993e 0.99 28133539 TBK1 and IKKepsilon inhibition accelerated cellular senescence by suppressing the p65 subunit of NF-kappaB and inducing p16 Ink4a. reach p(HGNC:IKBKE) directlyIncreases act(p(FPLX:NFkappaB)) +c071ed43-4f92-4778-ada7-ec6542768122 0.95 28209994 It appeared that CHOP upregulation was triggered by ROS generation and Ca 2+ increase, because antioxidants (NAC and catalase) and BAPTA-AM were able to block TSN induced CHOP expression. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:DDIT3)) +4ef018d6-f006-4812-807a-f45765c51ae4 0.86 28221705 Serum IGF1 levels were significantly increased in de novo, drug-naive PD patients compared to controls (p = 0.036), although they were not correlated with motor dysfunction in PD patients (p = 0.220). reach p(HGNC:IGF1) directlyIncreases bp(MESH:D010300) +69c67fc7-405a-40da-a682-44605602a364 0.95 28242652 The role of these responses and the subsequent translational arrest is to restore homeostasis; however, eIF2alpha phosphorylation and ATF4 induction also induce cell death if damage is not repaired. reach p(HGNC:ATF4) directlyIncreases bp(GO:"GO:0008219") +c97a3b8b-eddb-4255-8abf-e28ef34d4cf0 0.99 28282033 As PI3Kdelta and PI3Kgamma are known to activate AKT, we analysed the phosphorylation status of s473 in response to idelalisib, CZC24832 and duvelisib. reach p(HGNC:PIK3CG) directlyIncreases act(p(FPLX:AKT)) +51dd5a26-38f6-4ed6-816a-35ab60dc1fd3 1.0 28295231 IRAK-M acts by preventing dissociation of IRAK-1 from MyD88 or inducing other negative regulators A20, SHIP-1, inhibitor of NF-kappaB-alpha [XREF_BIBR, XREF_BIBR], whereas Tollip suppresses IRAK1 activation [XREF_BIBR]. reach p(HGNC:TOLLIP) directlyDecreases act(p(HGNC:IRAK1)) +fbad71e6-c835-48ec-95f7-c7291379ea64 0.95 28325285 These results suggested that TTF-1-promoter-operating miR-7 expression attenuated the growth of human lung cells invitro and invivo by altering the transduction of the Akt and Erk pathway, which was consistent with our previous findings. reach p(HGNC:"MIR7-1") directlyDecreases act(p(FPLX:AKT)) +69c67fc7-405a-40da-a682-44605602a364 0.95 28358364 Moreover, we found that functional inhibition of acid sphingomyelinase leads to overactivation of hypoxia stress response pathways and that hypoxia specific cell death is mediated by the stress responsive transcription factor ATF4. reach p(HGNC:ATF4) directlyIncreases bp(GO:"GO:0008219") +018c50fb-d378-418b-b20c-0301870c00ab 0.95 2837417 In these characteristics, SCG10 induction appears to constitute a reliable molecular index of the transcription dependent neuronal differentiation induced by NGF. reach p(HGNC:NGF) directlyIncreases bp(GO:"GO:0006351") +623eaef0-1c13-478b-9d18-bb5aecb85570 1.0 28402933 Western blotting analysis showed that IGF-1 treatment resulted in activation of AKT, as evidenced by increased level of phosphorylated AKT at Thr308. reach p(HGNC:IGF1) directlyIncreases act(p(FPLX:AKT)) +a6f8e61d-9758-4de0-ad6e-9ae0e93491f0 0.95 28422570 Furthermore, the IACS wrapped side of the graft showed less cell infiltration compared with the other side, which may have reduced inflammation in the area. reach p(PFAM:PF12252) directlyDecreases bp(GO:"GO:0006954") +0221e1d5-71ae-4d51-851d-85133aab51d9 0.95 28462384 These results indicate that the TRIF pathway contributes to hepatic steatosis, but negatively regulates hepatic injury, inflammation, and fibrosis. reach p(HGNC:TICAM1) directlyDecreases bp(GO:"GO:0006954") +59e4b84b-c1c9-494b-8c48-9ab41d78affd 1.0 28512203 However, the phosphorylation of one or more threonine residues in IRAK1 enables IRAK1 to interact with the Forkhead associated domains of Pellino isoforms [XREF_BIBR], which is likely to facilitate the IRAK1 catalyzed phosphorylation of these proteins and their conversion into active E3 ligases. reach p(HGNC:IRAK1) directlyIncreases act(p(HGNC:IRAK1)) +59e4b84b-c1c9-494b-8c48-9ab41d78affd 1.0 28512203 They also do not support the conclusion that the phosphorylation of IRAK1 by IRAK4 or autophosphorylation enhances the intrinsic catalytic activity of IRAK1 [XREF_BIBR]. reach p(HGNC:IRAK1) directlyIncreases act(p(HGNC:IRAK1)) +51dd5a26-38f6-4ed6-816a-35ab60dc1fd3 1.0 28529512 Tollip also negatively regulates IRAK-1 and IRAK-2 by directly binding to these proteins via the CUE domain and inhibiting auto-phosphorylation. reach p(HGNC:TOLLIP) directlyDecreases act(p(HGNC:IRAK1)) +0c71874f-464d-4378-8f68-7d4af12d3414 0.95 28545479 While chronic ER stress in neurons largely triggers signals to initiate apoptosis, extensive ER stress in glial cells has the potential to promote an inflammatory microenvironment characteristic in neurodegenerative diseases. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0006915") +0c71874f-464d-4378-8f68-7d4af12d3414 0.95 28555054 In addition, our previous work has shown that expression of Grp78 and CHOP was increased in the granulosa cells of atretic follicles and cells treated with tunicamycin in vitro, suggesting that apoptosis in goat granulosa cells was triggered by ER stress [XREF_BIBR]. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0006915") +e097dc81-706a-4ccd-9e57-d535f600f989 0.95 28594573 Phosphorylated eIF2alpha : total eIF2alpha, ATF4, XBP1 expression, and insulin induced pAKT and AKT expression changes were examined in vWATs. reach p(HGNC:INS) directlyIncreases act(p(UP:P54644)) +c6d4aeed-e612-44c2-a648-40d5c509b402 0.95 28652573 Furthermore, LTF-ICs utilized both membrane anchored CD14 and CD32a (FcgammaRIIa) to trigger monocyte activation in an internalization-, Toll like receptor (TLR) 4- and TLR9 dependent manner, and also that LTF-IC-induced cytokine production was blocked by specific inhibitors of caspase-1, NF-kappaB and MAPK. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0001816") +40d279b2-9c40-483b-8e4e-106c763ded54 0.99 28681594 The next phase of ATF4 mediated C/EBP homologous protein (CHOP) activation can also induce apoptosis via a transcriptional route. reach p(HGNC:ATF4) directlyIncreases act(p(HGNC:DDIT3)) +e097dc81-706a-4ccd-9e57-d535f600f989 0.95 28710921 An intravenous injection of insulin significantly elevated the contents of pAkt and p-S6 in the skeletal muscle (P < 0.01). reach p(HGNC:INS) directlyIncreases act(p(UP:P54644)) +f5fc46a8-a98a-4bd1-9930-0f3564842809 0.95 28717166 It has been previously shown that calpain-2 is involved in ER stress mediated cell death XREF_BIBR, XREF_BIBR. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0008219") +72000a1a-331a-4cd0-b932-fc0dac5bb4d9 0.95 28782089 An in vivo study showed that n-3 PUFA has several mechanisms that contribute to its anti-inflammatory effects through inhibition of nuclear factor kappa B (NF-kappabeta) activation in an animal inflammation model as well as through regulation of eicosanoid metabolism [XREF_BIBR]. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0006954") +73461c97-a89b-40ad-be13-3d7f30e4ea6f 0.98 28783736 TLR4 can transfer signal to MyD88 and IRAK1, which then stimulate NF-kappaB to produce pro inflammatory cytokines, such as TNF-alpha. reach p(HGNC:IRAK1) directlyIncreases act(p(FPLX:NFkappaB)) +d58da677-6b7d-40bc-a7ba-083b03da81a7 0.99 28832322 These observations led us to formulate a model in which FGF modulates Akt activation through a mechanism distinct from insulin stimulated Akt activation and sensitive to CAPE activity (XREF_FIG). reach p(HGNC:INS) directlyIncreases act(p(FPLX:AKT)) +c6d4aeed-e612-44c2-a648-40d5c509b402 0.95 28836571 In summary, this study indicates that CLI-095 and PDTC exhibit renoprotective effects in the development of rhabdomyolysis induced AKI, and importantly, pharmacological inhibition of TLR4 and NF-kappaB suppresses macrophage infiltration and proinflammatory cytokine production. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0001816") +fbad71e6-c835-48ec-95f7-c7291379ea64 0.95 28901375 Fang et al proposed that miR-7 inhibits the growth and metabolism of hepatocellular carcinoma by regulating the PI3K and Akt signalling pathway. reach p(HGNC:"MIR7-1") directlyDecreases act(p(FPLX:AKT)) +cd9dc75f-8113-49b7-aa3f-3b9d97c729dc 0.98 28903400 Akt subsequently activated NF-kappaB and up-regulated Bcl-2 and YAP leading to attenuation of the adipogenic differentiation of 3T3-L1 cells. reach p(FPLX:AKT) directlyIncreases act(p(FPLX:NFkappaB)) +ee10d13e-6b36-4b84-9925-ef650bd004dd 0.95 28944924 However, during IRI, intensive ER stress is initiated by C/EBP homologous protein (CHOP) accumulation, inositol requiring enzyme 1 (IRE1) phosphorylation and c-Jun N-terminal kinase (JNK) activation, leading to the apoptotic UPR phase. reach p(HGNC:DDIT3) directlyIncreases act(p(HGNC:ESR1)) +92e92d63-67d0-44fc-8cf2-8c751ef82a11 1.0 28973985 Specifically, SAM supplementation contrasts PSEN1 and BACE1 overexpression induced by B-vitamin deprivation, reduces beta- and gamma-secretase activities, Abeta production and plaques burden, restores PP2A activity and normal levels of Tau phosphorylation. reach p(HGNC:APP) directlyIncreases p(HGNC:MAPT, pmod(Ph)) +92e92d63-67d0-44fc-8cf2-8c751ef82a11 1.0 28990726 It is known that increment in Aβ‐induced tau phosphorylation is a key aspect of AD xref ; to evaluate whether the neuroprotective effect of DMF is also related to tau phosphorylation, we examined the expression of phosphor‐tau (p‐tau) in SHSY5Y cells. sparser p(HGNC:APP) directlyIncreases p(HGNC:MAPT, pmod(Ph)) +eb01c4cc-e251-4217-a9f6-6ce86cf2993e 0.99 29048430 IKBKE has been reported to activate the NF-kappaB pathway by interacting with several cellular proteins, XREF_BIBR, XREF_BIBR, XREF_BIBR that induce expression of the pro tumorigenic cytokines IL-6 and CCL5 and subsequent activation of the JAK and STAT pathway. reach p(HGNC:IKBKE) directlyIncreases act(p(FPLX:NFkappaB)) +fa2d0182-7d30-4f39-864f-7cd17a0eb20b 0.98 29066868 TUNEL analysis revealed that apoptosis in testicular tissue by ROS mediated activation of GRP-78, p-IRE1, p-JNK, procaspase-3 and cleaved caspase-3 path-ways was recovered by administration of DA-9401. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:HSPA5)) +f5fc46a8-a98a-4bd1-9930-0f3564842809 0.95 29082311 However, prolonged ER stress when UPR fails to restore the normal function of the ER causes aberrant neuronal differentiation, retardation in neurite outgrowth, or even cell death. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0008219") +16bef0c1-9d04-464f-8639-6c1bf6028f87 1.0 29104457 The phosphorylation of ERK is significantly observed when B16F10 cells are treated with PG2. reach p(HGNC:DLK1) directlyIncreases act(p(FPLX:ERK)) +16bef0c1-9d04-464f-8639-6c1bf6028f87 1.0 29104457 These results suggest that PG2 increases ERK signaling to inhibit melanogenesis. reach p(HGNC:DLK1) directlyIncreases act(p(FPLX:ERK)) +697a8013-0350-4626-a5db-6228b907506c 0.99 29114205 A pulse-chase study showed that cadmium chloride increased APP levels but dramatically reduced APP proteolysis, while APP mRNA levels remained unchanged in cultured cells following cadmium chloride treatment. reach p(HGNC:APP) directlyDecreases act(p(HGNC:APP)) +fd8191a7-4762-4760-82ee-85b1429564a8 0.95 29137221 Although CHOP is known to trigger cell death following ER stress [XREF_BIBR], PANC-1 cells survived probably due to the increased levels of the ER chaperone BIP, which was sufficient for survival. reach p(HGNC:DDIT3) directlyIncreases bp(GO:"GO:0008219") +0991ea45-f706-4dc8-bb41-b161314148c3 0.95 29138545 Role of Notch and Akt in CSE induced MSC apoptosis. reach p(FPLX:AKT) directlyIncreases bp(GO:"GO:0006915") +0c71874f-464d-4378-8f68-7d4af12d3414 0.95 29142472 ER stress is known to induce hepatocyte apoptosis under various pathological conditions [XREF_BIBR]. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0006915") +adb6555d-fc3d-46de-a8da-8c557580958a 0.95 29147012 On the other hand, PMOC affected neither the IRAK-4 auto-phosphorylation in LPS- or CpG ODN activated whole liver cells and RAW 264.7 cells, in which N-(2-morpholinylethyl)-2-(3-nitrobenzoylamindo)-benzimidazole (IS409, IRAK-1/4 inhibitor) was used as a positive control agent (XREF_SUPPLEMENTARY), nor the IRAK-1 degradation in LPS activated cells (XREF_SUPPLEMENTARY). reach p(HGNC:IRAK4) directlyDecreases act(p(HGNC:IRAK1)) +716cc167-a897-4a68-acd0-4134b89a2790 0.95 29149522 Similarly, the protein level of Bip and Grp78 did not differ, but activated P50ATF6, ATF4, and CHOP protein expression decreased in TUDCA (200mumol/L) and/or melatonin (0.1 mumol/L)-treated COCs. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:DDIT3)) +40d279b2-9c40-483b-8e4e-106c763ded54 0.99 29163138 Moreover, ATF4, ATF6, and XBP-1 stimulate C/EBP homologous protein (CHOP) and its target growth arrest and DNA damage inducible 34 (GADD34), as well as pro apoptotic components of the B cell lymphoma-2 (BCL2) family of proteins. reach p(HGNC:ATF4) directlyIncreases act(p(HGNC:DDIT3)) +d58da677-6b7d-40bc-a7ba-083b03da81a7 0.99 29180716 The activation of insulin and insulin like growth factor signaling stimulates two major kinase cascades : the PI3K and AKT pathway and MAPK and ERK pathways 5. reach p(HGNC:INS) directlyIncreases act(p(FPLX:AKT)) +06bd0dfa-24ce-4570-91f4-feea991b6ca4 0.95 29186034 SOCS3 serves to functionally inhibit IL-6 signaling by binding to gp130 and Jak by targeting the complex for ubiquitination and degradation [XREF_BIBR]. reach p(HGNC:SOCS3) directlyDecreases act(p(HGNC:IL6)) +0221e1d5-71ae-4d51-851d-85133aab51d9 0.95 29209174 Another, complex TIR, domain, and containing adaptor protein called Sterile alpha and HEAT (Armadillo motif; SARM) inhibits the TRIF mediated (MyD88 independent) pathway, and attenuates LPS mediated signaling to dampen inflammation and abrogate septic shock and multiple organ dysfunction syndrome. reach p(HGNC:TICAM1) directlyDecreases bp(GO:"GO:0006954") +7c47e975-614c-436e-85fe-ca81fc557f83 0.86 29228667 PIK3 activation leads to Akt phosphorylation, which is further involved in diverse molecular cascade reaction. reach p(UP:P54675) directlyIncreases p(FPLX:AKT, pmod(Ph)) +c071ed43-4f92-4778-ada7-ec6542768122 0.95 29230213 There are a number of studies establishing the signaling axis of ROS induced CHOP upregulation via MAPKs signaling pathways in different cells. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:DDIT3)) +0991ea45-f706-4dc8-bb41-b161314148c3 0.95 29247644 Thus, ATRAP regulates carotid intimal hyperplasia through controlling the PI3K-Akt signal mediated VSMCs apoptosis. reach p(FPLX:AKT) directlyIncreases bp(GO:"GO:0006915") +840e5f0e-ec8e-4eb9-81cb-b619edb48caf 0.95 29257079 Defective PI3K and Akt pathway signaling leads to PD like neurodegeneration, and the activation of Akt may provide protection against neurodegenerative diseases [XREF_BIBR]. reach p(FPLX:PI3K) directlyIncreases bp(MESH:D010300) +16bef0c1-9d04-464f-8639-6c1bf6028f87 1.0 29257328 DLK1 additionally activates the mitogen activated protein kinase (MAPK) and MAPK kinase (MEK)/extracellular signal regulated kinase (ERK) pathways to inhibit adipogenesis and chondrogenesis. reach p(HGNC:DLK1) directlyIncreases act(p(FPLX:ERK)) +bdb1c9f1-3aae-4131-9397-3eeaec2e52fc 0.98 29257328 DLK1 additionally activates the mitogen activated protein kinase (MAPK) and MAPK kinase (MEK)/extracellular signal regulated kinase (ERK) pathways to inhibit adipogenesis and chondrogenesis. reach p(HGNC:DLK1) directlyIncreases act(p(FPLX:MEK)) +cf39b25c-ca63-4355-924a-043483d3d5af 0.95 29263441 After the CFU-E stage, IL-6 induced potent upregulation of reactive oxygen species and caspase mediated cell death whereas TNFalpha mainly affects GATA1 protein levels. reach p(FPLX:Caspase) directlyIncreases bp(GO:"GO:0008219") +0c71874f-464d-4378-8f68-7d4af12d3414 0.95 29317830 XREF_BIBR - XREF_BIBR Prolonged ER stress can also lead to apoptosis via activation of eIF2alpha or proapoptotic genes such as Bax via the p53 pathway. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0006915") +eb01c4cc-e251-4217-a9f6-6ce86cf2993e 0.99 29333957 XREF_BIBR, XREF_BIBR Previous studies indicated that IKBKE is an activator of NF-kappaB in breast cancer 13 and suppresses the apoptosis of glioma cells through NF-kappaB, 14 while miR-98 can downregulate the activation of NF-kappaB. reach p(HGNC:IKBKE) directlyIncreases act(p(FPLX:NFkappaB)) +f5fc46a8-a98a-4bd1-9930-0f3564842809 0.95 29403459 Thus, ER stress induced cell death in the mucosa after H. pylori infection may favor the progression from precancerous lesions into GC. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0008219") +c6d4aeed-e612-44c2-a648-40d5c509b402 0.95 29423064 Furthermore, in terms of downstream signal transduction, proinflammatory cytokine protein levels exhibited an identical pattern to NF-kappaB expression (an upstream signal of cytokine production). reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0001816") +f5fc46a8-a98a-4bd1-9930-0f3564842809 0.95 29430279 On the contrary, ER stress also triggers immunogenic cell death (ICD) and antitumor immunity [XREF_BIBR]. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0008219") +cf39b25c-ca63-4355-924a-043483d3d5af 0.95 29434943 Caspase-8 represents initiator caspases of the extrinsic apoptotic pathway and its activation results in the processing of the downstream effector caspases (caspase-3, -6, -7), which induce cell death. reach p(FPLX:Caspase) directlyIncreases bp(GO:"GO:0008219") +0991ea45-f706-4dc8-bb41-b161314148c3 0.95 29435141 Next, we determined the role of the MAPK and AKT pathways on NCTD induced apoptosis. reach p(FPLX:AKT) directlyIncreases bp(GO:"GO:0006915") +0c71874f-464d-4378-8f68-7d4af12d3414 0.95 29502045 It is also well-known that ER stress contributes to cellular apoptosis in response to cardiac IR injury. reach p(HGNC:ESR1) directlyIncreases bp(GO:"GO:0006915") +adb6555d-fc3d-46de-a8da-8c557580958a 0.95 29502358 MyD88 recruits IL-1R-associated kinase-4 (IRAK4), which subsequently recruits, activates and degrades IRAK1. reach p(HGNC:IRAK4) directlyDecreases act(p(HGNC:IRAK1)) +c6d4aeed-e612-44c2-a648-40d5c509b402 0.95 29636837 The inflammatory processes are mainly activated by NF-kappaB, which modulate cytokine production and therefore increased the production of inflammatory cytokines [XREF_BIBR]. reach p(FPLX:NFkappaB) directlyIncreases bp(GO:"GO:0001816") +697a8013-0350-4626-a5db-6228b907506c 0.99 29642616 After nine months of treatment in APP and PS1 double-transgenic mice, scutellarin significantly improves behavior, reduces soluble and insoluble Abeta levels in the brain and plasma, decreases Abeta plaque associated gliosis and levels of proinflammatory cytokines TNF-alpha and IL-6, attenuates neuroinflammation, displays anti-amyloidogenic effects, and highlights the beneficial effects of intervention on development or progression of AD like neuropathology. reach p(HGNC:APP) directlyDecreases act(p(HGNC:APP)) +775f864e-0093-4adc-87f9-d77148273465 1.0 29661273 In contrast to GFP-IRS-1 wild-type (WT)-expressing cells, surface phospho-IGF-IR was reduced by prolonged IGF-I stimulation in GFP-IRS-1 3YA expressing cells (XREF_FIG). reach p(HGNC:IGF1) directlyIncreases act(p(HGNC:IRS1)) +adb6555d-fc3d-46de-a8da-8c557580958a 0.95 29749650 Bacterial infection of IRAK4 KI macrophages led to attenuated activation of IRAK1, MAPKs and NF-kappaB, impaired induction of inducible NO synthase mRNA and secretion of NO, but resulted in elevated microbial burdens. reach p(HGNC:IRAK4) directlyDecreases act(p(HGNC:IRAK1)) +adb6555d-fc3d-46de-a8da-8c557580958a 0.95 29749650 Bacterial infection of IRAK4 KI macrophages led to attenuated activation of IRAK1, MAPKs and NF-kappaB, impaired induction of inducible NO synthase mRNA and secretion of NO, but resulted in elevated microbial burdens. reach p(HGNC:IRAK4) directlyDecreases act(p(HGNC:IRAK1)) +e097dc81-706a-4ccd-9e57-d535f600f989 0.95 29892042 Equivalent exosome amounts were added to differentiated adipocytes in culture, after which insulin sensitivity was assessed using 0nM and 5nM insulin induced pAKT and AKT expression changes by western blotting. reach p(HGNC:INS) directlyIncreases act(p(UP:P54644)) +46ccb254-c30d-42d1-891d-17303d643d21 1.0 29904383 p53 Regulated IAV Susceptibility Is Not Mediated by Caspase 3 Activity. reach p(HGNC:CASP3) directlyIncreases act(p(HGNC:TP53)) +0221e1d5-71ae-4d51-851d-85133aab51d9 0.95 29977930 Lundberg and colleagues reported that TRIF deficiency in hematopoietic cells reduced atherogenic diet induced vascular inflammation and protected against atherosclerosis, as shown in Ldlr -/- mice after receiving a bone marrow transfer from TRIF deficient mice [XREF_BIBR]. reach p(HGNC:TICAM1) directlyDecreases bp(GO:"GO:0006954") +fa2d0182-7d30-4f39-864f-7cd17a0eb20b 0.98 29990757 In line with the ultrastructure alterations, SiNPs triggered mitochondrial ROS generation, DeltaPsim collapse, cytosolic Ca 2+ overload, as well as ER stress confirmed by enhanced ER staining, up-regulated GRP78 and BiP and XBP1 splicing. reach p(HGNC:ROS1) directlyIncreases act(p(HGNC:HSPA5)) +c97a3b8b-eddb-4255-8abf-e28ef34d4cf0 0.99 30030497 Collectively, these results suggest that PI3Kgamma induced activation of Akt may be at least in part responsible for cell survival and proliferation in fibroblasts. reach p(HGNC:PIK3CG) directlyIncreases act(p(FPLX:AKT)) +716cc167-a897-4a68-acd0-4134b89a2790 0.95 30111318 To determine whether the loss in progesterone production depends on PRDX1, we attempted to identify a functional link between PRDX1 and UPR signaling (GRP78 and BIP, p-eIF2alpha, p50ATF6, and p-IRE1) and ER-stress mediated apoptotic factors (p-JNK, CHOP, and cleaved caspase-3) in the functional stage using WT and Prdx1 K/O mice. reach p(HGNC:HSPA5) directlyIncreases act(p(HGNC:DDIT3)) +50bf56c8-9dd0-4cfe-b0fb-66e96c3b8b91 0.86 30271323 Consistent with our results, renal ischemia and reperfusion injury results in increased CK2alpha expression, and CK2 inhibition attenuated inflammation and oxidative stress which results in reduced apoptosis and concomitant renal dysfunction. reach p(FPLX:CK2) directlyIncreases bp(GO:"GO:0006954") +73461c97-a89b-40ad-be13-3d7f30e4ea6f 0.98 30279971 Inhibiting IRAK1 using IRAK1/4 inhibitor I blocks NF-kappaB activation, interferes with MDS progenitor cell function and growth, and ameliorates disease in an MDS xenograft model. reach p(HGNC:IRAK1) directlyIncreases act(p(FPLX:NFkappaB)) +018c50fb-d378-418b-b20c-0301870c00ab 0.95 7624117 Finally, in the RET and PTC transfected PC12 cells, NGF is unable to induce further their transcription. reach p(HGNC:NGF) directlyIncreases bp(GO:"GO:0006351") +018c50fb-d378-418b-b20c-0301870c00ab 0.95 9447994 A-CREB completely inhibited cAMP mediated, but only partially inhibited Ca2+ - and NGF mediated, transcription of a reporter gene containing 750 bp of the native c-fos promoter. reach p(HGNC:NGF) directlyIncreases bp(GO:"GO:0006351") +018c50fb-d378-418b-b20c-0301870c00ab 0.95 9572272 As determined by transient expression, two NGF response elements (REs) were required for transcription induced by NGF in SH-SY5Y cells with stable expression of an exogenous NGF receptor TRK-A gene (SH-SY5Y and trk). reach p(HGNC:NGF) directlyIncreases bp(GO:"GO:0006351") +3f9b72b1-85a2-4895-97fd-f3ee843f4860 0.95 9950785 Proinsulin and insulin like growth factor I (IGF-I) stimulated cell proliferation up to threefold above controls, with half-maximal action already in the picomolar range and with additive effects. reach p(HGNC:IGF1) directlyIncreases bp(GO:"GO:0008283") diff --git a/curation/generate.sh b/curation/generate.sh new file mode 100755 index 0000000..085daec --- /dev/null +++ b/curation/generate.sh @@ -0,0 +1,7 @@ +#!/usr/bin/env bash + +# Slice out just the identifiers column and skip the missing entries +cat pubmeds.tsv | cut -f 1 | grep -e "^\d\+$" > pubmeds.txt + +# Generate INDRA statements and BEL from those PubMed identifiers +bel-enrichment from_pmids --pmids pubmeds.txt --output curation.tsv --pickle-file statements.pkl 2> generation-log.txt diff --git a/curation/generation-log.txt b/curation/generation-log.txt new file mode 100644 index 0000000..0d81d2a --- /dev/null +++ b/curation/generation-log.txt @@ -0,0 +1,71 @@ +WARNING: [2019-02-15 15:54:58] indra.sources.reach.api - Could not import jnius, offline reading option will not be available. +WARNING: [2019-02-15 15:54:58] indra.config - Key SITEMAPPER_CACHE_PATH not in environment or config file. +INFO: [2019-02-15 15:54:58] indra.sources.indra_db_rest.util - url and query string: https://db.indra.bio/statements/from_papers +INFO: [2019-02-15 15:54:58] indra.sources.indra_db_rest.util - headers: {'content-type': 'application/json'} +INFO: [2019-02-15 15:54:58] indra.sources.indra_db_rest.util - data: {'ids': [{'id': '19969070', 'type': 'pmid'}, {'id': '21387008', 'type': 'pmid'}, {'id': '25036103', 'type': 'pmid'}, {'id': '30063760', 'type': 'pmid'}, {'id': '21035514', 'type': 'pmid'}, {'id': '28116245', 'type': 'pmid'}, {'id': '28124620', 'type': 'pmid'}, {'id': '29417334', 'type': 'pmid'}, {'id': '26205378', 'type': 'pmid'}, {'id': '25407931', 'type': 'pmid'}, {'id': '24559646', 'type': 'pmid'}, {'id': '25534921', 'type': 'pmid'}]} +INFO: [2019-02-15 15:54:58] indra.sources.indra_db_rest.util - params: {'ev_limit': 10, 'best_first': True, 'max_stmts': None, 'api_key': '[api-key]'} +INFO: [2019-02-15 15:54:59] indra.tools.assemble_corpus - Combining duplicates on 161 statements... +INFO: [2019-02-15 15:54:59] indra.tools.assemble_corpus - 161 unique statements +INFO: [2019-02-15 15:54:59] indra.tools.assemble_corpus - Combining related on 161 statements... +INFO: [2019-02-15 15:55:00] indra.preassembler - Grouping Activation (89) +INFO: [2019-02-15 15:55:03] indra.preassembler - Grouping Complex (5) +INFO: [2019-02-15 15:55:03] indra.preassembler - Grouping DecreaseAmount (1) +INFO: [2019-02-15 15:55:03] indra.preassembler - Grouping IncreaseAmount (6) +INFO: [2019-02-15 15:55:03] indra.preassembler - Grouping Inhibition (43) +INFO: [2019-02-15 15:55:03] indra.preassembler - Grouping Phosphorylation (17) +INFO: [2019-02-15 15:55:03] indra.tools.assemble_corpus - Filtering 161 statements for top-level... +INFO: [2019-02-15 15:55:03] indra.tools.assemble_corpus - 154 statements after filter... +INFO: [2019-02-15 15:55:03] indra.tools.assemble_corpus - 154 top-level statements +INFO: [2019-02-15 15:55:03] indra.tools.assemble_corpus - Filtering 154 statements to above 0.300000 belief +INFO: [2019-02-15 15:55:03] indra.tools.assemble_corpus - 154 statements after filter... +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent 7KCHO() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent Insulin/IGF-1/PI3K() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent Phosphoinositides 3-kinases() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent RSK1/2 activator() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent RSK1/2() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent RSKs() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent RSKs() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent ST2825 inhibitor() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent ST2825 inhibitor() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent TBK1 inhibitor() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent TLR4 receptor() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent beta-interferon(activity) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent beta-interferon(activity) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent ikappaB() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent Abeta 1-42 toxicity(activity) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent Abeta 1-42(activity) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent GSK-3beta ratios(activity) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent IGF-1/PI3K/AKT(activity) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent Tg6799 mutant(activity) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent IGF-1 receptor() has no grounding. +INFO: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Skipping modification of type modification on agent VC(mods: (modification)) +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent alpha-syn() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent double-stranded RNA-activated protein kinase(activity) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent beta-interferon(activity) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent Necrostatin() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent SL0101() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent SL0101() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent SOCS1-3() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent YVAD-CMK() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-126() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-433() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-433() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-98() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-98() has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent ikappaB(mods: (phosphorylation)) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent ikappaB(mods: (phosphorylation)) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-98(mods: (modification)) has no grounding. +WARNING: [2019-02-15 15:55:03] indra.assemblers.pybel.assembler - Agent miR-98(mods: (modification)) has no grounding. diff --git a/curation/pubmeds.txt b/curation/pubmeds.txt index 41ed8c0..662b49b 100644 --- a/curation/pubmeds.txt +++ b/curation/pubmeds.txt @@ -1,4 +1,3 @@ -PubMedID 19969070 21387008 25036103 @@ -11,5 +10,3 @@ PubMedID 25407931 24559646 25534921 -X -X diff --git a/curation/statements.pkl b/curation/statements.pkl new file mode 100644 index 0000000000000000000000000000000000000000..b616976685a0fb569425b06114d63728b54e7cf4 GIT binary patch literal 578728 zcmb51349!7{r}4)P(UCYfp9H|l0rAx`v4WvG;OnO)0hS*Vkxt`vrQn$W}hT21tTIT zC@SIwh=L#d;;kqu-U=cja(MpVpJ!%vXQ%n`2VOKY`~5!8?Cd#S!dRrbf;!#LZ^#|$LcfFV|BA_!kHbfPc3fju;hZqj`NM3 zx;N~$Xwf2f%XrnDs<@4vH#T-z;7S31@qpiOapQShVAuJ^ZrvLebAg%qoT<2*oayn# z?i+R$VcIb>u4ydZuzQO=UTy3#v|(om)03R#_%;$@lM6R)yZ940oGrP&SwVB5A z=No%>+t$Nt2bVYYX>Yx+<&2KN=_viP*0sZiUAXS>+I|T8*?ZzVolNJlscd8a4LiYH 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