Inhibition of EZH2 decreased the activity of mTORC1 and mTORC2.

These data indicated that HuR is situated between the mTOR complexes and Bcl-2 and that EZH2 inhibition might inactivate mTORC1 and mTORC2 in some manner, thus downregulating HuR and Bcl-2 expression and leading to cell apoptosis.

Many previous studies have shown that the canonical function of EZH2 is mediating trimethylation of histone H3 lysine 27 and inhibiting downstream target genes XREF_BIBR, XREF_BIBR, XREF_BIBR.

Many previous studies have shown that the canonical function of EZH2 is mediating trimethylation of histone H3 lysine 27 and inhibiting downstream target genes XREF_BIBR, XREF_BIBR, XREF_BIBR.

Additionally, EZH2 specific microRNA-98 could effectively inhibit cell proliferation in vitro and regulate the pRb-E2F pathway in human epithelial ovarian cancer stem cells (EOCSCs) XREF_BIBR.

The results showed that EZH2 inhibition significantly increased cisplatin induced cell apoptosis and necrosis and reduced the number of colonies formed by SK-3rd cells compared with control groups.

In addition, ChIP assays showed that EZH2 bound directly to region 1 and region 2 within the CHK1 promoter region in both SKOV3 and A2780 cells, indicating that EZH2 upregulated CHK1 expression by targeting the CHK1 promoter.

However, EZH2 DeltaSET mutant increased CHK1 level as efficiently as wild-type EZH2 (XREF_SUPPLEMENTARY G), suggesting that the histone methyltransferase activity may not be required for CHK1 activation.

EZH2 transcriptionally upregulates CHK1 expression by directly binding to the CHK1 promoter, and inhibition of CHK1abrogates G2/M checkpoints and promotes DNA damaging agent induced cell death in EOCSC.

Similarly, a previous study revealed that EZH2 promotes breast CSC expansion and leads to tumor initiation XREF_BIBR.

EZH2 promotes CSC properties and chemoresistance by upregulating CHK1.

By providing previously unidentified evidence that EZH2 promotes the platinum resistance of ovarian CSCs by directly activating CHK1 signaling, our work paves the way for targeting EZH2 to reverse recurrence and platinum resistance in ovarian cancer.

EZH2 activates CHK1 signaling to promote ovarian cancer chemoresistance by maintaining the properties of cancer stem cells.

EZH2 promotes CSC properties and chemoresistance by upregulating CHK1.

A luciferase reporter assay and chromatin immunoprecipitation assay were performed to identify activation of CHK1 by EZH2.

Upregulation of CHK1 partially relieved these effects on the cell cycle and apoptosis caused by EZH2 depletion.

Upregulation of CHK1 partially relieved these effects on the cell cycle and apoptosis caused by EZH2 depletion.

However, blocking CD32 but not CD64 to inhibit CRP induced FLS proliferation, invasiveness, and proinflammatory cytokine CXCL8 production revealed a major role for CD32 signaling in synovial inflammation, although CRP via CD64, not CD32, to induce MMP9 expression was noticed.

As shown in XREF_FIG, CRP induced expression of CCL2 and IL-6 was blocked by either neutralizing antibody to CD32 or CD64 or both, suggesting that CRP signals through both CD32 and CD64 to induce expression of CCL2 and IL-6.

As shown in XREF_FIG, CRP induced expression of CCL2 and IL-6 was blocked by either neutralizing antibody to CD32 or CD64 or both, suggesting that CRP signals through both CD32 and CD64 to induce expression of CCL2 and IL-6.

Thus, it is highly possible that high concentration of CRP in synovial fluid in patients with RA may directly bind primarily CD32 to activate p38 MAP kinase and NF-kappaB signaling in RA-FLSs to differentially regulate synovial inflammation.

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

RA-FLS was a major cell type responsible for CRP production in RA patients, accounting for more than 65% of CRP producing cells as identified by co-expressing CRP and vimentin in the inflamed synovial tissues in patients with RA.

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

As shown in XREF_FIG, multiplex cytokine assay kits assays showed that addition of CRP dose-dependently upregulated CCL2, CXCL8, IL-6, MMP2, MMP9 in RA-FLS but not in HFLS, although expression of IL-1beta and TNFalpha was not significantly changed (XREF_FIG).

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

As shown in XREF_FIG, multiplex cytokine assay kits assays showed that addition of CRP dose-dependently upregulated CCL2, CXCL8, IL-6, MMP2, MMP9 in RA-FLS but not in HFLS, although expression of IL-1beta and TNFalpha was not significantly changed (XREF_FIG).

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

As shown in XREF_FIG, multiplex cytokine assay kits assays showed that addition of CRP dose-dependently upregulated CCL2, CXCL8, IL-6, MMP2, MMP9 in RA-FLS but not in HFLS, although expression of IL-1beta and TNFalpha was not significantly changed (XREF_FIG).

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

As shown in XREF_FIG, multiplex cytokine assay kits assays showed that addition of CRP dose-dependently upregulated CCL2, CXCL8, IL-6, MMP2, MMP9 in RA-FLS but not in HFLS, although expression of IL-1beta and TNFalpha was not significantly changed (XREF_FIG).

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

As shown in XREF_FIG, multiplex cytokine assay kits assays showed that addition of CRP dose-dependently upregulated CCL2, CXCL8, IL-6, MMP2, MMP9 in RA-FLS but not in HFLS, although expression of IL-1beta and TNFalpha was not significantly changed (XREF_FIG).

In vitro studies confirmed this notion and found that CRP was able to upregulate both CD32 and CD64 and induced FLS proliferation, invasion, and pro inflammatory expression by increasing production of CCL2, CXCL8, IL-6, MMP2, MMP9 while suppressing an anti-inflammatory cytokine IL-10 expression.

This was further confirmed by the ability of pre-treating RA-FLS with a NF-kappaB inhibitor, PDTC (100 mumol/L) to inhibit CRP induced proliferation (XREF_FIG) and upregulation of CXCL8, CCL2.

Here we tested the hypothesis that CRP may be produced locally by FLSs and functions to induce the synovial inflammation in patients with RA.

CRP may promote synovial inflammation via mechanism associated with activation of CD32/64- p38 and NF-kappaB signaling.

In the present study, we found that CRP signaled primarily through CD32, to a less extent of CD64, to differentially regulate joint inflammation.

CRP Promotes RA-FLS Pro inflammatory Response Differentially via the CD32/64-p 38 and NF-kappaB-Dependent Mechanisms in vitro.

CRP can induce synovial inflammation via mechanisms associated with activation of CD32/64-p 38 and NF-kappaB signaling.

This was supported by the findings that CRP induced activation of p38 MAP kinase and NF-kappaB signaling was blunted by neutralizing antibodies against CD32 but not CD64.

To examine whether CRP induces NF-kappaB nuclear translation, immunofluorescence and subcellular fractionation were performed.

Resveratrol significantly suppresses the secretion of TNF-alpha and nitric oxide in LPS stimulated rat cortical microglia and N9 microglial cells (Bi et al., 2005) and also inhibits the production of TNF-alpha, IL-1, IL-6, IL-12 and IFN-gamma by splenic lymphocytes and macrophages (Gao et al., 2001; Kowalski et al., 2005).

Resveratrol significantly suppresses the secretion of TNF-alpha and nitric oxide in LPS stimulated rat cortical microglia and N9 microglial cells (Bi et al., 2005) and also inhibits the production of TNF-alpha, IL-1, IL-6, IL-12 and IFN-gamma by splenic lymphocytes and macrophages (Gao et al., 2001; Kowalski et al., 2005).

Resveratrol significantly suppresses the secretion of TNF-alpha and nitric oxide in LPS stimulated rat cortical microglia and N9 microglial cells (Bi et al., 2005) and also inhibits the production of TNF-alpha, IL-1, IL-6, IL-12 and IFN-gamma by splenic lymphocytes and macrophages (Gao et al., 2001; Kowalski et al., 2005).

Kaempferol and quercetin reduce the activity of iNOS and COX-2 by suppressing the signalling of STAT-1, NF-kappa B and AP-1 in LPS- or cytokine stimulated macrophages and HUVECs (Crespo et al., 2008; Hamalainen et al., 2007).

Kaempferol and quercetin reduce the activity of iNOS and COX-2 by suppressing the signalling of STAT-1, NF-kappa B and AP-1 in LPS- or cytokine stimulated macrophages and HUVECs (Crespo et al., 2008; Hamalainen et al., 2007).

Kaempferol, quercetin, and luteolin also afford protection against oxidative stress by inducing the expression of HO-1, however, apigenin inhibits HO-1 induction.

Our in vitro experiments show that quercetin inhibits the intrinsic apoptotic pathway by increasing the ratio of BCL-2 and BAX, thus preventing apoptosis and DNA damage in RPE cells under oxidative stress.

Quercetin could not effectively downregulate the increased transcripts of the ocular inflammatory mediators Tnf-alpha, Cox-2 and Inos.

Our in vitro experiments show that quercetin inhibits the intrinsic apoptotic pathway by increasing the ratio of BCL-2 and BAX, thus preventing apoptosis and DNA damage in RPE cells under oxidative stress.

Quercetin could not effectively downregulate the increased transcripts of the ocular inflammatory mediators Tnf-alpha, Cox-2 and Inos.

Additionally, quercetin could not effectively suppress ocular transcripts of the pro apoptotic factors Fas, FasL and Caspase-3.

Quercetin could not effectively downregulate the increased transcripts of the ocular inflammatory mediators Tnf-alpha, Cox-2 and Inos.

Additional studies showed that EGCG, luteolin and structural analogs of luteolin such as quercetin, chrysin, and eriodictyol, also inhibited TRIF signaling pathway by targeting TBK1 kinase [XREF_BIBR, XREF_BIBR].

In contrast, resveratrol, EGCG, luteolin, and structural analogs of luteolin specifically inhibit TLR3 and TLR4 signaling by targeting TANK binding kinase 1 (TBK1) and receptor interacting protein 1 (RIP1) in Toll/IL -1 receptor domain containing adaptor inducing IFN-beta (TRIF) complex.

In contrast, resveratrol, EGCG, luteolin and structural analogs of luteolin, specifically inhibit TLR3 and TLR4 signaling by targeting TBK1 and RIP1 in TRIF complex.

In contrast, resveratrol, EGCG, luteolin, and structural analogs of luteolin specifically inhibit TLR3 and TLR4 signaling by targeting TANK binding kinase 1 (TBK1) and receptor interacting protein 1 (RIP1) in Toll/IL -1 receptor domain containing adaptor inducing IFN-beta (TRIF) complex.

In contrast, resveratrol, EGCG, luteolin and structural analogs of luteolin, specifically inhibit TLR3 and TLR4 signaling by targeting TBK1 and RIP1 in TRIF complex.

Curcumin, helenalin, and cinnamaldehyde with alpha, beta unsaturated carbonyl groups, or sulforaphane with an isothiocyanate group, inhibit TLR4 activation by interfering with cysteine residue mediated receptor dimerization, while resveratrol, with no unsaturated carbonyl group, did not.

Curcumin, helenalin, cinnamaldehyde and sulforaphane, containing alpha, beta unsaturated carbonyl or isothiocyanate group, respectively, that are known to interact with free SH groups in cysteine residues, but not resveratrol (with no unsaturated carbonyl group), inhibit TLR4 activation by interfering with TLR4 receptor dimerization.

However, curcumin did not inhibit interferon regulatory factor 3 (IRF3) activation induced by another immediate TLR4 downstream component TIR-domain-containing adaptor inducing interferon-beta (TRIF), suggesting that the target of curcumin is the receptor itself, but not the downstream components of TRIF pathway [XREF_BIBR].

Further studies indicate that curcumin and helenalin, which contain alpha, beta unsaturated carbonyl group, but not resveratrol (with no unsaturated carbonyl group, XREF_FIG), inhibit TLR4 activation by interfering with receptor dimerization [XREF_BIBR] (XREF_FIG).

Curcumin, helenalin, and cinnamaldehyde with alpha, beta unsaturated carbonyl groups, or sulforaphane with an isothiocyanate group, inhibit TLR4 activation by interfering with cysteine residue mediated receptor dimerization, while resveratrol, with no unsaturated carbonyl group, did not.

Such conclusion was further supported by the result that curcumin inhibits ligand independent dimerization of constitutively active TLR4.

Curcumin, helenalin, cinnamaldehyde and sulforaphane, containing alpha, beta unsaturated carbonyl or isothiocyanate group, respectively, that are known to interact with free SH groups in cysteine residues, but not resveratrol (with no unsaturated carbonyl group), inhibit TLR4 activation by interfering with TLR4 receptor dimerization.

Furthermore, the suppressive effect of resveratrol on LPS induced NF-kappaB activation was abolished in TRIF deficient mouse embryonic fibroblasts, but not in MyD88 deficient macrophages (XREF_FIG), suggesting that resveratrol specifically inhibits MyD88 independent signaling pathways downstream of TLR3 and TLR4.

Furthermore, the suppressive effect of resveratrol on LPS induced NF-kappaB activation was abolished in TRIF deficient mouse embryonic fibroblasts, but not in MyD88 deficient macrophages (XREF_FIG), suggesting that resveratrol specifically inhibits MyD88 independent signaling pathways downstream of TLR3 and TLR4.

In contrast, resveratrol, EGCG, luteolin, and structural analogs of luteolin specifically inhibit TLR3 and TLR4 signaling by targeting TANK binding kinase 1 (TBK1) and receptor interacting protein 1 (RIP1) in Toll/IL -1 receptor domain containing adaptor inducing IFN-beta (TRIF) complex.

Together, these results demonstrate that resveratrol specifically inhibits TLR3 and TLR4 signaling pathway by targeting TBK1 and RIP1 in TRIF complex.

In contrast, resveratrol, EGCG, luteolin and structural analogs of luteolin, specifically inhibit TLR3 and TLR4 signaling by targeting TBK1 and RIP1 in TRIF complex.

Together, these results demonstrate that resveratrol specifically inhibits TLR3 and TLR4 signaling pathway by targeting TBK1 and RIP1 in TRIF complex.

In contrast, resveratrol, EGCG, luteolin and structural analogs of luteolin, specifically inhibit TLR3 and TLR4 signaling by targeting TBK1 and RIP1 in TRIF complex.

In contrast, resveratrol, EGCG, luteolin, and structural analogs of luteolin specifically inhibit TLR3 and TLR4 signaling by targeting TANK binding kinase 1 (TBK1) and receptor interacting protein 1 (RIP1) in Toll/IL -1 receptor domain containing adaptor inducing IFN-beta (TRIF) complex.

In further delineating the target of resveratrol, it was found that resveratrol inhibited the kinase activity of TBK1 and the NF-kappaB activation induced by RIP1 [XREF_BIBR] (XREF_FIG).

Curcumin, helenalin, and cinnamaldehyde with alpha, beta unsaturated carbonyl groups, or sulforaphane with an isothiocyanate group, inhibit TLR4 activation by interfering with cysteine residue mediated receptor dimerization, while resveratrol, with no unsaturated carbonyl group, did not.

Curcumin, helenalin, cinnamaldehyde and sulforaphane, containing alpha, beta unsaturated carbonyl or isothiocyanate group, respectively, that are known to interact with free SH groups in cysteine residues, but not resveratrol (with no unsaturated carbonyl group), inhibit TLR4 activation by interfering with TLR4 receptor dimerization.

Additional studies showed that EGCG, luteolin and structural analogs of luteolin such as quercetin, chrysin, and eriodictyol, also inhibited TRIF signaling pathway by targeting TBK1 kinase [XREF_BIBR, XREF_BIBR].

In contrast, resveratrol, EGCG, luteolin and structural analogs of luteolin, specifically inhibit TLR3 and TLR4 signaling by targeting TBK1 and RIP1 in TRIF complex.

In contrast, resveratrol, EGCG, luteolin, and structural analogs of luteolin specifically inhibit TLR3 and TLR4 signaling by targeting TANK binding kinase 1 (TBK1) and receptor interacting protein 1 (RIP1) in Toll/IL -1 receptor domain containing adaptor inducing IFN-beta (TRIF) complex.

Insulin induced mRNA or protein expressions of cell death signaling markers such as cleaved PARP, p53, and Bax, as well as the ER stress markers such as p-eIF2alpha, ATF4, CHOP, sXBP1, and p-IRE1 were significantly attenuated by melatonin treatment.

Melatonin Attenuates the Activation of ASK1 under IR Condition.

On the other hand, the decreased cell viability by insulin stimulation was recovered when treated with melatonin.

In addition, immunofluorescence analysis confirmed that p-IRE1 induced by insulin stimulation was significantly suppressed by melatonin treatment (XREF_FIG C).

Insulin induced mRNA or protein expressions of cell death signaling markers such as cleaved PARP, p53, and Bax, as well as the ER stress markers such as p-eIF2alpha, ATF4, CHOP, sXBP1, and p-IRE1 were significantly attenuated by melatonin treatment.

Insulin induced mRNA or protein expressions of cell death signaling markers such as cleaved PARP, p53, and Bax, as well as the ER stress markers such as p-eIF2alpha, ATF4, CHOP, sXBP1, and p-IRE1 were significantly attenuated by melatonin treatment.

Insulin induced mRNA or protein expressions of cell death signaling markers such as cleaved PARP, p53, and Bax, as well as the ER stress markers such as p-eIF2alpha, ATF4, CHOP, sXBP1, and p-IRE1 were significantly attenuated by melatonin treatment.

EGCG also markedly inhibited the activation of Stat3 in YCU-H891 (carcinoma of the hypopharynx) cells [XREF_BIBR] and BT-474 (human breast cancer cell) cells [XREF_BIBR].

Curcumin is a potent inhibitor of COX-2.

Curcumin was shown to inhibit constitutive and IL-6-induced Stat3 activation in human multiple myeloma cells [XREF_BIBR].

Resveratrol dose-dependently prevented both COX-2 induction and PGE (2) production in bFGF stimulated fibroblasts [XREF_BIBR].

Resveratrol suppressed NF-kappaB-regulated gene products (COX-2, MMP-3, MMP-9, and VEGF), inhibited anti-apoptosis (Bcl-2, and Bcl-xL) [XREF_BIBR].

Treatment of quercetin down-regulated the antiapoptotic proteins Bcl-2 and Bcl-xL and also up-regulated the proapoptotic proteins Bax and caspase-3 in prostatic PC-3 carcinoma cells [XREF_BIBR].

Treatment of quercetin down-regulated the antiapoptotic proteins Bcl-2 and Bcl-xL and also up-regulated the proapoptotic proteins Bax and caspase-3 in prostatic PC-3 carcinoma cells [XREF_BIBR].

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine and hydroxychloroquine (inhibitor of endocytosis), lopinavir and darunavir (inhibitor of 3-chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO cosponsored Solidarity Trial (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments).

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine and hydroxychloroquine (inhibitor of endocytosis), lopinavir and darunavir (inhibitor of 3-chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO cosponsored Solidarity Trial (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments).

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine/hydroxychloroquine (inhibitor of endocytosis), lopinavir/darunavir (inhibitor of 3‑chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA-dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO-cosponsored Solidarity Trial (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments).

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine and hydroxychloroquine (inhibitor of endocytosis), lopinavir and darunavir (inhibitor of 3-chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO cosponsored Solidarity Trial (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments).

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine and hydroxychloroquine (inhibitor of endocytosis), lopinavir and darunavir (inhibitor of 3-chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO cosponsored Solidarity Trial (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments).

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine/hydroxychloroquine (inhibitor of endocytosis), lopinavir/darunavir (inhibitor of 3‑chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA-dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO-cosponsored Solidarity Trial (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments).

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine and hydroxychloroquine (inhibitor of endocytosis), lopinavir and darunavir (inhibitor of 3-chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO cosponsored Solidarity Trial (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments).

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine/ hydroxychloroquine (inhibitor of endocytosis), lopinavir/darunavir (inhibitor of 3-chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA-dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO-cosponsored Solidarity Trial (https://www.

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine and hydroxychloroquine (inhibitor of endocytosis), lopinavir and darunavir (inhibitor of 3-chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO cosponsored Solidarity Trial (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments).

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine/hydroxychloroquine (inhibitor of endocytosis), lopinavir/darunavir (inhibitor of 3‑chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA-dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO-cosponsored Solidarity Trial (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments).

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine/hydroxychloroquine (inhibitor of endocytosis), lopinavir/darunavir (inhibitor of 3‑chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA-dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO-cosponsored Solidarity Trial (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments).

Antivirals such as camostat mesylate (inhibitor of TMPRSS2), chloroquine/ hydroxychloroquine (inhibitor of endocytosis), lopinavir/darunavir (inhibitor of 3-chymotrypsin-like protease) or ribavirin, remdesivir, favipiravir (inhibitor of RNA-dependent RNA polymerase), or prednisolone should be restricted to controlled or randomized trials such as the worldwide WHO-cosponsored Solidarity Trial (https://www.

Curcumin is also able to antagonize the IL-1beta and TNF-alpha-dependent up-regulation of MMPs and COX-2.

Curcumin is also able to antagonize the IL-1beta and TNF-alpha-dependent up-regulation of MMPs and COX-2.

Curcumin has been shown to inhibit the inflammatory and apoptotic effects of IL-1beta on chondrocytes and this correlates with down-regulation of NF-kappaB-specific gene products that are known to mediate inflammation, degradation and apoptosis of chondrocytes in OA.

Studies on RA derived synovial fibroblasts have shown that curcumin dose-dependently abrogates the effect of IL-18 on VEGF production [XREF_BIBR].

Curcumin also inhibits the IL-1beta-induced stimulation of up-stream protein kinase B Akt, molecular events that correlate with down-regulation of NF-kappaB targets including COX-2 and MMP-9 [XREF_BIBR].

Resveratrol inhibits membrane bound IL-1beta and mature IL-1beta protein production in chondrocytes.

Furthermore, we have demonstrated that resveratrol inhibits the cysteine protease caspase-3 and the subsequent cleavage of the DNA repair enzyme PARP and the IL-1beta-induced up-regulation of reactive oxygen species (ROS) in chondrocytes [XREF_BIBR].

It was also demonstrated that SFN inhibits the inflammasome in an Nrf2 independent manner, as SFN mediated inhibition of NLRP3- and NLRC4 dependent IL-1beta processing and secretion was not reversed in Nrf2-knockout BMDMs.

It was shown that SFN inhibited IL-1beta processing by NLRP1-, NLRP3-, NLRC4-, and AIM2- inflammasome complexes in mouse BMDMs [XREF_BIBR].

In a peritonitis model of acute gout, SFN treatment significantly reduced MSU crystal induced IL-1beta production, demonstrating that SFN inhibits the NLRP3 inflammasome function in vivo.

In a peritonitis model of acute gout, SFN treatment significantly reduced MSU crystal induced IL-1beta production, demonstrating that SFN inhibits the NLRP3 inflammasome function in vivo.

When SFN was added directly to the cell lysates, it did not inhibit IL-1beta processing, demonstrating that SFN does not directly inhibit the protease activity of caspase-1.

In another study performed on mouse macrophage cell line J774A.1 and peritoneal macrophages, curcumin was shown to strongly inhibit IL-1beta secretion triggered by LPS plus nigericin, aluminum, ATP, or MSU [XREF_BIBR].

As a possible molecular mechanism, they found that, in mice hippocampus, glutamate stimulation increased NLRP3 expression and the cleaved form of caspase-1 enzyme, while curcumin attenuated NLRP3 and cleaved caspase-1 expression.

In a recent study [XREF_BIBR], it was found that resveratrol treatment successfully suppressed the maturation of both IL-1beta and caspase-1 in response to Pam3CSK4; a TLR1/2 agonist, plus various inducers (like nigericin, ATP, MSU, and silica) of the NLRP3-inflammasome.

In a recent study [XREF_BIBR], it was found that resveratrol treatment successfully suppressed the maturation of both IL-1beta and caspase-1 in response to Pam3CSK4; a TLR1/2 agonist, plus various inducers (like nigericin, ATP, MSU, and silica) of the NLRP3-inflammasome.

It was shown that the STZ induced expression of inflammasome components was restrained, and IL-1beta secretion was reduced by quercetin treatment.

In a study, using streptozotocin- (STZ-) induced diabetic nephropathy rat model leading to hyperuricemia and dyslipidemia, quercetin was found to block NLRP3 inflammasome activation [XREF_BIBR].

As a result from suppression of ER stress associated TXNIP induction, curcumin inhibited NLRP3 and caspase-1 activation, and thereby reduced IL-1beta secretion.

Curcumin treatment inhibited IL-1beta secretion, but no influence was observed on increased glutamate release.

These results indicated that curcumin as well as TUDCA inhibited IL-1beta secretion without affecting glutamate release.We observed ROS generation in cells with specific fluorescent probe dye DCFH-DA.

Similar to the regulation by curcumin, ER stress inhibitor TUDCA inhibited IL-1beta secretion without affection of glutamate release, suggesting that ER stress was an event after glutamate release in response to ischemic insult.Because oxidative stress is proposed to be involved in glutamate neurotoxicity (Lai et al., 2014), and ROS is manifested in ER stress (Zhang and Kaufman, 2008), we observed the effect of curcumin on ROS production in SH-SY5Y cells.

Therefore we observed PERK and IRE1alpha phosphorylation for ER stress and found that curcumin inhibited PERK and IRE1alpha activation.

Therefore we observed PERK and IRE1alpha phosphorylation for ER stress and found that curcumin inhibited PERK and IRE1alpha activation.

Our work showed that curcumin inhibited TXNIP and NLRP3 inflammasome activation by suppressing ER stress, and thereby protected neuronal cell survival from glutamate neurotoxicity.Brain ischemia induces extrasynaptic glutamate release (Soria et al., 2014).

These results indicated that curcumin suppressed NLRP3 inflammasome activation and thus inhibited inflammatory response.In addition to evoked inflammation, NLRP3 inflammasome activation is responsible for apoptosis, in which mitochondrial malfunction plays a critical role.

As a result from suppression of ER stress associated TXNIP induction, curcumin inhibited NLRP3 and caspase-1 activation, and thereby reduced IL-1beta secretion.

These results demonstrated that curcumin inhibited NLRP3 inflammasome activation under ER stress conditions.

Our work showed that curcumin inhibited TXNIP and NLRP3 inflammasome activation by suppressing ER stress, and thereby protected neuronal cell survival from glutamate neurotoxicity.Brain ischemia induces extrasynaptic glutamate release (Soria et al., 2014).

Curcumin, as well as TUDCA, attenuated NLRP3 and cleaved caspase-1 expression (Figs. 6 A & B), and as expected, reduced IL-1beta secretion.

Curcumin treatment prevented ER stress and NLRP3 inflammasome activation in the hippocampus, indicating the potential molecular target for its action.

Curcumin prevented the collapse of mitochondrial membrane potential and inhibited caspase-3 activity, and this action should contribute to the prevention of cell apoptosis.

These results showed that curcumin protected mitochondrial function and prevented caspase-3 activation.

As a result from suppression of ER stress associated TXNIP induction, curcumin inhibited NLRP3 and caspase-1 activation, and thereby reduced IL-1beta secretion.

Consistent with the recently published study which shows that curcumin inhibits TLR4 and NF-kappaB-dependent inflammation in brain injury (Zhou et al., 2010), our finding further provided a potential mechanism through which curcumin inhibits inflammatory and oxidative response in the brain (Ahmad et al., 2013; Wang et al., 2014; Zhou et al., 2010).

Translocation of merlin to the nucleus allows merlin to bind and inhibit the E3 ubiquitin ligase CRL4 DCAF1 (DDB1- and Cul4 Associated Factor 1).

Notably, NF2 transfection into these cells induced YAP1 phosphorylation at Ser127, YAP1 retention in the cytoplasm and consequent reduction of YAP1 nuclear localization.

Previously, we showed that activation of ErbB2 and ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA.

Previously, we showed that activation of ErbB2 and ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA.

Previously, we showed that activation of ErbB2 and ErbB3 receptors in primary rat Schwann cells by neuregulin-1 induced merlin phosphorylation at Ser518 via PKA.

We reported that merlin associates with beta 1 -integrin in primary Schwann cells and undifferentiated Schwann cell and neuron co-cultures, and in primary Schwann cell cultures, laminin-1 stimulated integrin signaled though PAK1 and caused merlin Ser518 phosphorylation and inactivation of its tumor suppressor function.

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin 's proteasome mediated degradation by ubiquitination to prevent its interaction with binding partners.

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin 's proteasome mediated degradation by ubiquitination to prevent its interaction with binding partners.

Merlin is phosphorylated at Ser10, Thr230 and Ser315 by Akt (also known as protein kinase B, PKB) and controls merlin 's proteasome mediated degradation by ubiquitination to prevent its interaction with binding partners.

Loss of merlin results in integrin mediated activation of mTORC1 through PAK1, which promotes cell cycle progression by inducing translation of cyclin-D1 mRNA and cyclin-D1 expression.

Adenoviral transduction of NF2 in Meso-17 and Meso-25 cell lines decreased invasion through Matrigel membranes compared to cells transduced with empty vector.

Loss of merlin in mesotheliomas has been linked not only to increased proliferation, but also increased invasiveness, spreading and migration.

Second, similar to NF2 schwannomas, mesothelioma cells with NF2 inactivation, exhibit activated PAK1 and AKT, and re-expression of merlin in merlin-null human mesothelioma cells (Meso-17) decreases PAK1 activity.

Soon after merlin was cloned, evidence that merlin inhibits another important member of the Rho GTPases family, Ras, was reported in v-Ha-Ras-transformed NIH3T3cells in which merlin overexpression counteracted the oncogenic role of Ras.

Merlin re-expression in Nf2 -/- Schwann cells similarly reduced the transport of growth factor receptors ErbB2 and ErbB3, insulin like growth factor 1 receptor (IGF1R) and platelet derived growth factor receptor (PDGFR).

Merlin re-expression in Nf2 -/- Schwann cells similarly reduced the transport of growth factor receptors ErbB2 and ErbB3, insulin like growth factor 1 receptor (IGF1R) and platelet derived growth factor receptor (PDGFR).

In sum, multiple lines of evidence have established a feedback regulation loop with merlin being phosphorylated at Ser518 (growth permissive form) via activated Rho small GTPases Rac1 and Cdc42 through PAK, and in turn, merlin associating with PAK to inhibit Rac1 and Cdc42 signaling (XREF_FIG).

Collectively, these results indicate that merlin inhibits cell growth by contact inhibition in part by binding CD44 and negatively regulating CD44 function (XREF_FIG).

Merlin inactivation of Src signaling was also shown in CNS glial cells, where merlin competitively inhibits Src binding to ErbB2 thereby preventing ErbB2 mediated Src phosphorylation and downstream mitogenic signaling.

In the NF2 -/- breast cancer MDA-MB-231 cell line, merlin re-expression inhibited YAP and TEAD activity that was eliminated by LATS1/2 silencing.

Loss of merlin results in integrin mediated activation of mTORC1 through PAK1, which promotes cell cycle progression by inducing translation of cyclin-D1 mRNA and cyclin-D1 expression.

Loss of merlin activated mTORC1 signaling independently of Akt or ERK in these tumor cells; however, the molecular mechanism connecting merlin loss to mTORC1 activation remains to be elucidated.

Loss of merlin activated mTORC1 signaling independently of Akt or ERK in these tumor cells; however, the molecular mechanism connecting merlin loss to mTORC1 activation remains to be elucidated.

Furthermore, merlin overexpression in Tr6BC1 mouse schwannoma cells inhibited the binding of fluorescein labeled hyaluronan to CD44 and inhibited subcutaneous tumor growth in immunocompromised mice, and overexpression of a merlin mutant lacking the CD44 binding domain was unable to inhibit schwannoma growth.

Further studies showed that wild-type merlin is transported throughout the cell by microtubule motors and merlin mutants or depletion of the microtubule motor kinesin-1 suppressed merlin transport and was associated with accumulation of yorkie, a Drosophila homolog of the hippo pathway transcriptional co-activator Yes associated protein (YAP), in the nucleus.

In a similar fashion, NF2 mutations increased the resistance to dihydrofolate reductase inhibitors methotrexalate and pyremethamine as well as the JNK inhibitor JNK-9L.

The disrupted cell-contact inhibition signaling and merlin phosphorylation correlated with increased expression of NOTCH1 and its downstream target gene, HES1, which represses the transcription factor E2F in cell-contact growth arrest.

Binding of merlin unphosphorylated at Ser518 with the cytoplasmic tail of CD44 mediates contact inhibition at high cell density.

Loss of merlin activated mTORC1 signaling independently of Akt or ERK in these tumor cells; however, the molecular mechanism connecting merlin loss to mTORC1 activation remains to be elucidated.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

First, protein kinase C potentiated phosphatase inhibitor (CPI-17), which is frequently overexpressed in mesothelioma tumors, inhibits merlin phosphatase MYPT1-PP1delta, providing one potential pathway by which merlin 's tumor suppressor function might be inactivated through maintenance of phosphorylation at Ser518.

Loss of merlin results in integrin mediated activation of mTORC1 through PAK1, which promotes cell cycle progression by inducing translation of cyclin-D1 mRNA and cyclin-D1 expression.

HDAC inhibitors disrupt the PP1-HDAC interaction facilitating Akt dephosphorylation and decrease human meningioma and schwannoma cell proliferation and schwannoma growth in an allograft model and meningioma growth in an intracranial xenograft model.

The mTORC1 inhibitor rapamycin selectively inhibited proliferation of seven merlin-null mesothelioma cell lines, but not merlin positive cell lines, suggesting a potential pharmacological target for merlin deficient mesotheliomas.

Merlin expression in Meso-17 and Meso-25 cells decreased FAK Tyr397 phosphorylation and consequently disrupted FAK-Src and PI3K interaction, providing a mechanism for the observed enhancement of invasion and spreading caused by merlin inactivation.

Accordingly, merlin was shown to reduce the levels of ErbB2 and ErbB3 receptor levels at the plasma membrane.

Accordingly, merlin was shown to reduce the levels of ErbB2 and ErbB3 receptor levels at the plasma membrane.

Accordingly, merlin was shown to reduce the levels of ErbB2 and ErbB3 receptor levels at the plasma membrane.

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with beta1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density dependent manner.

Moreover, in cultured Schwann cells, merlin interaction with Amot was demonstrated by co-immunoprecipitation of the endogenous proteins.

Moreover, co-immunoprecipitation experiments revealed that merlin interacts with YAP1, although the interaction is not direct.

Merlin inactivation of Src signaling was also shown in CNS glial cells, where merlin competitively inhibits Src binding to ErbB2 thereby preventing ErbB2 mediated Src phosphorylation and downstream mitogenic signaling.

Merlin interacts with tubulin and acetylated-tubulin and stabilizes the microtubules by attenuating tubulin turnover -- lowering the rates of microtubule polymerization and depolymerization.

Merlin inhibits PI3K activity by binding phosphatidylinositol 3-kinase enhancer-L (PIKE-L), the GTPase that binds and activates PI3K.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

In various cell types, the binding of hyaluronan to CD44 stimulates Tiam1 dependent Rac1 signaling and cytoskeleton mediated tumor cell migration.

Pharmacological or genetic inhibition of Rac1 in Nf2 -/- MEFs reduced the Wnt signaling activation to basal levels as assessed by reporter assay of transactivation of the nuclear beta-catenin-dependent T-cell factor 4 transcription factor.

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with beta1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density dependent manner.

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with beta1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density dependent manner.

FAK silencing decreased schwannoma cell proliferation and was associated with increased levels of total and nuclear p53.

In a similar fashion, NF2 mutations increased the resistance to dihydrofolate reductase inhibitors methotrexalate and pyremethamine as well as the JNK inhibitor JNK-9L.

Furthermore, it was shown that overactive PAK and LIMK pathway activity contributed to cell proliferation through cofilin phosphorylation and auroraA activation.

Interestingly, it was shown that schwannoma cells release insulin like growth factor binding protein 1 which in beta1-integrin dependent manner activates Src and FAK signaling.

This is an indication that RO-heparin could attenuate L- and P-selectin-mediated acute inflammation.

Several other drugs, Sunitinib BNTX and Latrunculin, which disrupt actin dynamics on the cell surface, were also proven to inhibit SARS-CoV-2 cell entry.

In a subsequent study, the authors found that the addition of heparin to Vero cells between 6.25 and 200 mug ml -1 inhibited invasion of SARS-CoV-2 by 44-80%.

In a subsequent study, the authors found that the addition of heparin to Vero cells between 6.25 and 200 mug ml -1 inhibited invasion of SARS-CoV-2 by 44-80%.

Gao et al. reported that periodate oxidized, borohydride reduced heparin (RO-heparin) could inhibit thioglycollate induced peritoneal inflammation by preventing neutrophil recruitment dependent on the release of L- and P-selectin.

Several other drugs, Sunitinib BNTX and Latrunculin, which disrupt actin dynamics on the cell surface, were also proven to inhibit SARS-CoV-2 cell entry.