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).

The data suggest that in hepatocytes merlin is functionally linked to the hippo pathway and acts upstream Mst1/2 by recruiting LATS to the membrane comparable to what has been shown in FH912 Schwann cell line.

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

Translocation of merlin to the nucleus allows merlin to bind and inhibit the E3 ubiquitin ligase CRL4 DCAF1 ( D DB1- and C ul4- A ssociated F actor 1) ( xref , xref ).

For example, in confluent human umbilical vein endothelial cells, merlin suppressed recruitment of Rac to the plasma membrane, and its silencing promoted recruitment of Rac1 to sites of extracellular matrix adhesion, and promoted cell growth ( xref ).

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

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 ( xref , xref ).

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 ( xref , xref ).

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 ( xref , xref ).

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.

In sub-confluent primary Schwann cells, we found that merlin binds to paxillin and mediates merlin localization at the plasma membrane and association with β1-integrin and ErbB2, modifying the organization of the actin cytoskeleton in a cell density-dependent manner ( xref ).

Merlin-Amot interaction was required for merlin regulation of mitogenic MAPK signaling.

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

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

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

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

Studies in human meningioma tumors and in paired cell lines—KY21MG1 or MENII-1 meningioma cell lines and AC1 arachnoidal cells—demonstrated that merlin loss was associated with increased YAP expression and nuclear localization.

Amot-p130 isoform bound to the WW domains of YAP and blocked LATS1 access to YAP.

The activation of Rac1 through CD44 was identified via the interaction of CD44 with Tiam-1, a Rac1 guanine nucleotide exchange factor (GEF) that catalyzes the replacement of the tightly-bound GDP with GTP.

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 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 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.

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 ( xref , xref , xref ).

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

Hyaluronan-CD44 interaction in astrocytes and an immortalized mouse mammary epithelial cell line, EpH4, leads to Rac1 signaling activation and actin cytoskeleton rearrangement ( xref , xref ).

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.

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.

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.

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.

Silencing DCAF1 in Meso-33, merlin deficient mesothelioma cells reduced their proliferation by arresting the cell cycle in G1 phase.

Significantly, silencing of DCAF1 in schwannoma cells isolated from NF2 patients also reduced their proliferation.

Silencing DCAF1 in Meso-33, merlin deficient mesothelioma cells reduced their proliferation by arresting the cell cycle in G1 phase.

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

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.

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

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

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.

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.

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

Finally, a recent meningioma study of 73 patients found a high incidence of TERT promoter activating mutations in meningiomas undergoing malignant transformation in both NF2-related and sporadic meningiomas, whereas no TERT mutations were found in benign tumors.

We recently showed that PI3K inhibition in merlin deficient mouse Schwann cells selectively decreased their proliferation.

In primary rat Schwann cells, CD44 was shown to constitutively associate with the heterodimer receptor tyrosine kinase ErbB2 and ErbB3 and CD44 enhanced neuregulin induced ErbB2 activating phosphorylation.

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.

In the canonical hippo pathway, mammalian Ste20 like kinases (Mst1/2; hippo homolog) phosphorylate large tumor suppressor kinases (LATS 1/2), which in turn phosphorylate and inactivate YAP and TAZ, blocking their role as TEAD and MEAD transcription factor co-activators.

SOS is a GEF that activates Ras by catalyzing the nucleotide exchange.

The data suggest that in hepatocytes merlin is functionally linked to the hippo pathway and acts upstream Mst1/2 by recruiting LATS to the membrane comparable to what has been shown in FH912 Schwann cell line.

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

Translocation of merlin to the nucleus allows merlin to bind and inhibit the E3 ubiquitin ligase CRL4 DCAF1 ( D DB1- and C ul4- A ssociated F actor 1) ( xref , xref ).

For example, in confluent human umbilical vein endothelial cells, merlin suppressed recruitment of Rac to the plasma membrane, and its silencing promoted recruitment of Rac1 to sites of extracellular matrix adhesion, and promoted cell growth ( xref ).

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

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 ( xref , xref ).

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 ( xref , xref ).

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 ( xref , xref ).

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.

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.

Several excellent studies have focused on the interactions between heparin/HS and the SARS-CoV-2 S protein, especially structure specificity of the carbohydrate chains.

Further elucidation of the heparin/HS–S protein interaction will facilitate the construction of structurally defined oligosaccharide sequences that can be prepared through several methods reported (Roy et al., xref ; Hansen et al., xref ; Baytas and Linhardt, xref ; Zhang et al., xref ).

To obtain insights into heparin/HS–S protein binding and virus infection in a safer circumstance, Tandon et al. pseudotyped SARS-CoV-2 S protein on a third-generation lentiviral (pLV) vector for testing the impact of various sulfated polysaccharides on transduction efficiency in mammalian cells (Tandon et al., xref ).

Interactions Between Heparin/HS and Cytokines.

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.

Interactions Between Heparin/HS and the S Protein.

The polyproteins can be further cleaved into 15–16 non-structural proteins (nsp2-nsp16 or nsp1-nsp16).

Meanwhile, interactions of selectins and cytokines (e.g., IL-6 and TNF-α) with HS expressed on endothelial cells are crucial in controlling the recruitment of immune cells during inflammation.

In a recent study, interactions between heparin/HS and various cytokines were characterized by coupling surface plasmon resonance imaging for thermodynamic analysis method and Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS) for structural determination (Przybylski et al., xref ).

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.

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

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.

The previously determined octasaccharide composed of IdoA2S-GlcNS6S repeating subunits could inhibit heparin–S protein interaction with an IC 50 of 38 nM.

Consistent with Liu et al. ( xref ), the authors claimed that the interaction between heparin and the S protein was independent of the anti-coagulant activity.

A ternary complex of heparin, ACE2, and the S protein was demonstrated by binding of S protein to immobilized heparin-BSA and titrating with biotinylated ACE2, in which case the binding of ACE2 increased in proportion to the amount of S protein bound to the heparin-BSA.

A ternary complex of heparin, ACE2, and the S protein was demonstrated by binding of S protein to immobilized heparin-BSA and titrating with biotinylated ACE2, in which case the binding of ACE2 increased in proportion to the amount of S protein bound to the heparin-BSA.

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

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

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

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 (Gao et al., xref ).

A ternary complex of heparin, ACE2, and the S protein was demonstrated by binding of S protein to immobilized heparin-BSA and titrating with biotinylated ACE2, in which case the binding of ACE2 increased in proportion to the amount of S protein bound to the heparin-BSA.

Captured carbohydrates were carried out directly on the biochip surface using MALDI-TOF-MS, while MS identification was enhanced by on-chip digestion of the cytokine-bound GAGs by heparinase treatment.

During viral infection, a two-step sequential protease cleavage process triggers the activation of S proteins, which is modulated by host range and cell tropism.

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.