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    1. 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.

      CRP increases the amount of MMP9.

    2. 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.

      CRP increases the amount of IL6.

    3. 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.

      CRP increases the amount of CCL2.

    4. 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.

      CD32 binds CRP.

    5. 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.
    6. 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.
    7. 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.

      CRP activates MMP9.

    8. 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).

      CRP activates MMP9.

    9. 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.

      CRP activates MMP2.

    10. 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).

      CRP activates MMP2.

    11. 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.

      CRP activates CXCL8.

    12. 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).

      CRP activates CXCL8.

    13. 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.

      CRP activates IL6.

    14. 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).

      CRP activates IL6.

    15. 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.

      CRP activates CCL2.

    16. 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).

      CRP activates CCL2.

    17. 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.
    18. 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.
    19. Here we tested the hypothesis that CRP may be produced locally by FLSs and functions to induce the synovial inflammation in patients with RA.
    20. CRP may promote synovial inflammation via mechanism associated with activation of CD32/64- p38 and NF-kappaB signaling.
    21. In the present study, we found that CRP signaled primarily through CD32, to a less extent of CD64, to differentially regulate joint inflammation.
    22. CRP Promotes RA-FLS Pro inflammatory Response Differentially via the CD32/64-p 38 and NF-kappaB-Dependent Mechanisms in vitro.
    23. CRP can induce synovial inflammation via mechanisms associated with activation of CD32/64-p 38 and NF-kappaB signaling.
    24. 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.

      CRP activates p38.

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

      CRP activates NFkappaB.

    1. 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 inhibits TNF.

    2. 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).

      nitric oxide inhibits IL6.

    3. 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).

      nitric oxide inhibits TNF.

    4. 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).

      quercetin inhibits PTGS2.

    5. 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).

      quercetin inhibits NOS2.

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

      quercetin inhibits HMOX1.

    1. 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 inhibits BCL2.

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

      quercetin inhibits PTGS2.

    3. 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 inhibits BAX.

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

      quercetin inhibits NOS2.

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

      quercetin inhibits FAS.

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

      quercetin inhibits TNF.

    1. 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].
    2. 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.
    3. In contrast, resveratrol, EGCG, luteolin and structural analogs of luteolin, specifically inhibit TLR3 and TLR4 signaling by targeting TBK1 and RIP1 in TRIF complex.
    4. 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.
    5. In contrast, resveratrol, EGCG, luteolin and structural analogs of luteolin, specifically inhibit TLR3 and TLR4 signaling by targeting TBK1 and RIP1 in TRIF complex.
    6. 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.

      sulforaphane inhibits TLR4.

    7. 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.

      sulforaphane inhibits TLR4.

    8. 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].

      curcumin inhibits IRF3.

    9. 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 inhibits TLR4.

    10. 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 inhibits TLR4.

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

      curcumin inhibits TLR4.

    12. 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.

      curcumin inhibits TLR4.

    13. 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.

      resveratrol inhibits MYD88.

    14. 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.

      resveratrol inhibits TICAM1.

    15. 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.

      resveratrol inhibits TLR4.

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

      resveratrol inhibits TLR4.

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

      resveratrol inhibits TLR4.

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

      resveratrol inhibits TLR3.

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

      resveratrol inhibits TLR3.

    20. 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.

      resveratrol inhibits TLR3.

    21. 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).

      resveratrol inhibits TBK1.

    22. 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.
    23. 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.
    24. 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].

      luteolin inhibits TICAM1.

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

      luteolin inhibits TLR3.

    26. 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.

      luteolin inhibits TLR3.

    1. 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 inhibits ATF4.

    2. Melatonin Attenuates the Activation of ASK1 under IR Condition.

      melatonin inhibits MAP3K5.

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

      melatonin inhibits INS.

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

      melatonin inhibits ERN1.

    5. 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 inhibits ERN1.

    6. 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 inhibits EIF2S1.

    7. 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 inhibits DDIT3.

    1. 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].
    2. Curcumin is a potent inhibitor of COX-2.

      curcumin inhibits PTGS2.

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

      curcumin inhibits STAT3.

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

      resveratrol inhibits PTGS2.

    5. 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].

      resveratrol inhibits PTGS2.

    6. 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].

      quercetin inhibits BCL2L1.

    7. 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].

      quercetin inhibits BCL2.

    1. 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).

      prednisolone inhibits TMPRSS2.

    2. 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).

      ribavirin inhibits TMPRSS2.

    3. 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).
    4. 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).
    5. 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).

      darunavir inhibits TMPRSS2.

    6. 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).

      chloroquine inhibits TMPRSS2.

    7. 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).

      chloroquine inhibits TMPRSS2.

    8. 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.

      chloroquine inhibits TMPRSS2.

    9. 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).

      lopinavir inhibits TMPRSS2.

    10. 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).

      lopinavir inhibits TMPRSS2.

    11. 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).

      camostat inhibits TMPRSS2.

    12. 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.

      camostat inhibits TMPRSS2.

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

      curcumin inhibits PTGS2.

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

      curcumin inhibits IL1B.

    3. 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.

      curcumin inhibits IL1B.

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

      curcumin inhibits IL18.

    5. 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].

      curcumin inhibits AKT.

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

      resveratrol inhibits IL1B.

    7. 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].

      resveratrol inhibits CASP3.

    1. 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.

      sulforaphane inhibits NFE2L2.

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

      sulforaphane inhibits IL1B.

    3. 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.

      sulforaphane inhibits IL1B.

    4. 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.

      sulforaphane inhibits NLRP3.

    5. 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.

      sulforaphane inhibits CASP1.

    6. 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].

      curcumin inhibits IL1B.

    7. 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.

      curcumin inhibits NLRP3.

    8. 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.

      resveratrol inhibits IL1B.

    9. 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.

      resveratrol inhibits CASP1.

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

      quercetin inhibits IL1B.

    11. 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].

      quercetin inhibits NLRP3.

    1. 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 inhibits IL1B.

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

      curcumin inhibits IL1B.

    3. 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.

      curcumin inhibits IL1B.

    4. 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.

      curcumin inhibits IL1B.

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

      curcumin inhibits ERN1.

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

      curcumin inhibits EIF2AK3.

    7. 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 inhibits TXNIP.

    8. 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.

      curcumin inhibits NLRP3.

    9. 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 inhibits NLRP3.

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

      curcumin inhibits NLRP3.

    11. 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 inhibits NLRP3.

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

      curcumin inhibits NLRP3.

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

      curcumin inhibits NLRP3.

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

      curcumin inhibits CASP3.

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

      curcumin inhibits CASP3.

    16. 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 inhibits CASP1.

    17. 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).

      curcumin inhibits TLR4.

  2. Apr 2021
    1. Translocation of merlin to the nucleus allows merlin to bind and inhibit the E3 ubiquitin ligase CRL4 DCAF1 (DDB1- and Cul4 Associated Factor 1).

      NF2 translocates to the nucleus.

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

      NF2 leads to the phosphorylation of YAP1 on S127.

    3. 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.

      ERBB3 leads to the phosphorylation of NF2 on S518.

    4. 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.

      ERBB3 leads to the phosphorylation of NF2 on S518.

    5. 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.

      ERBB2 leads to the phosphorylation of NF2 on S518.

    6. 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.

      Integrins leads to the phosphorylation of NF2 on S518.

    7. 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.

      AKT phosphorylates NF2 on T230.

    8. 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.

      AKT phosphorylates NF2 on S315.

    9. 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.

      AKT phosphorylates NF2 on S10.

    10. 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.

      PAK1 inhibits cell cycle.

    11. Adenoviral transduction of NF2 in Meso-17 and Meso-25 cell lines decreased invasion through Matrigel membranes compared to cells transduced with empty vector.
    12. Loss of merlin in mesotheliomas has been linked not only to increased proliferation, but also increased invasiveness, spreading and migration.
    13. 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.

      NF2 inhibits PAK1.

    14. 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.

      NF2 inhibits RHOA.

    15. 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).

      NF2 inhibits ERBB3.

    16. 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).

      NF2 inhibits ERBB2.

    17. 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).

      NF2 inhibits CDC42.

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

      NF2 inhibits CD44.

    19. 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.

      NF2 inhibits SRC.

    20. 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.

      NF2 inhibits TEAD.

    21. 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.

      NF2 inhibits Integrins.

    22. 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.

      NF2 inhibits ERK.

    23. 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.

      NF2 inhibits AKT.

    24. 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.

      NF2 inhibits fluorescein.

    25. 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.

      Mutated NF2 inhibits transport.

    26. In a similar fashion, NF2 mutations increased the resistance to dihydrofolate reductase inhibitors methotrexalate and pyremethamine as well as the JNK inhibitor JNK-9L.
    27. 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.
    28. Binding of merlin unphosphorylated at Ser518 with the cytoplasmic tail of CD44 mediates contact inhibition at high cell density.
    29. 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.

      mTORC1 inhibits ERK.

    30. 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.

      PKC inhibits NF2.

    31. 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.

      PKC inhibits Phosphatase.

    32. 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.

      Integrins inhibits mTORC1.

    33. 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.
    34. 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.

      sirolimus inhibits NF2.

    35. 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.

      Modified NF2 leads to the dephosphorylation of PTK2 on Y397.

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

      NF2 decreases the amount of ERBB3.

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

      NF2 decreases the amount of ERBB3.

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

      NF2 decreases the amount of ERBB2.

    39. 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.

      NF2 binds PXN.

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

      AMOT binds NF2.

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

      YAP1 binds NF2.

    42. 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.

      SRC binds ERBB2.

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

      Tubulin binds NF2.

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

      GTPase binds PI3K.

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

      RAC1 activates cell migration.

    47. 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.

      RAC1 activates Wnt.

    48. 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.

      PXN bound to NF2 activates NF2.

    49. 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.

      PXN bound to NF2 activates localization.

    50. FAK silencing decreased schwannoma cell proliferation and was associated with increased levels of total and nuclear p53.
    51. In a similar fashion, NF2 mutations increased the resistance to dihydrofolate reductase inhibitors methotrexalate and pyremethamine as well as the JNK inhibitor JNK-9L.
    52. Furthermore, it was shown that overactive PAK and LIMK pathway activity contributed to cell proliferation through cofilin phosphorylation and auroraA activation.
    53. 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.

      IGFBP1 activates PTK2.

    54. 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.

      IGFBP1 activates SRC.

    55. Moreover, neuregulin survival signaling through the ErbB2 and ErbB3 receptor activates PI3K in rat Schwann cells through the activation of Akt and inhibition of Bad, a pro apoptotic Blc-2 family protein.

      ERBB3 activates PI3K.

    56. ErbB2 activation in mouse Nf2 deficient spinal cord neural progenitor cells was shown to be caused by Rac mediated retention of the receptor at the plasma membrane.

      ERBB2 activates NF2.

    57. Silencing DCAF1 in Meso-33, merlin deficient mesothelioma cells reduced their proliferation by arresting the cell cycle in G1 phase.
    58. Significantly, silencing of DCAF1 in schwannoma cells isolated from NF2 patients also reduced their proliferation.
    59. Silencing DCAF1 in Meso-33, merlin deficient mesothelioma cells reduced their proliferation by arresting the cell cycle in G1 phase.

      DCAF1 activates cell cycle.

    60. Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

      AMOT activates RAC1.

    61. Silencing of Amot in Nf2 -/- Schwann cells (SC4) selectively reduced cell proliferation because it did not change the proliferation rate of SC4 with merlin re-expression.
    62. Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

      AMOT activates RAS.

    63. Furthermore, Amot silencing attenuated Rac1 and Ras and MAPK signaling pathway.

      AMOT activates MAPK.

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

      CD44 bound to hyaluronic acid activates RAC1.

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

      CD44 bound to hyaluronic acid activates TIAM1.

    1. This is an indication that RO-heparin could attenuate L- and P-selectin-mediated acute inflammation.
    2. 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.

      sunitinib inhibits Actin.

    3. 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%.
    4. 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%.

      heparin inhibits SARS-CoV-2.

    5. 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.
    6. 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.

      Latrunculin inhibits Actin.

    7. The most prominent example is the binding of antithrombin with the unique pentasaccharide sequence, -GlcNS and Ac6S-GlcA-GlcNS 3S6S-IdoA2S-GlcNS6S- in heparin, where the 3-O-sulfation is critical.

      Antithrombins binds Ac6S-GlcA-GlcNS3S6S-IdoA2S-GlcNS6S-.

    8. For instance, the interaction between HS and FGF2, a member of the fibroblast growth factor family, prefers the disaccharide unit of IdoA2S and GlcNS on heparin/HS.

      His-Ser binds FGF2.

    9. , the authors claimed that the interaction between heparin and the S protein was independent of the anti-coagulant activity.

      heparin binds S.

    10. In support of the microarray data, SPR experiments showed that the SARS-CoV-2 S protein bound with higher affinity to heparin (K D = 55 nM) compared to the RBD (K D = 1 muM) alone.

      heparin binds S.

    11. The analysis revealed a conformational selection mechanism of GAGs binding and determined the structural specificity in the FGF1 and heparin complex.

      heparin binds FGF1.