Our study showed that hypoxia increased the production of S100A8 in microglia .

FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

Our study showed that hypoxia increased the production of S100A8 in microglia .

FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

BP patient samples and the murine models of PDs indicate that GzmB is produced in PDs by TBO-positive mast cells and / or basophils .

Double immunostaining of GzmB and a mouse basophil-specific marker , mouse mast cell protease-8 ( mMCP-8 ) 22 , in WT mice with EBA , showed a subset of GzmB-positive cells was also mMCP-8 positive , which supported our findings with TBO staining that not only mast cells but also basophils were major sources of GzmB ( Fig. 1e ) .

Double immunostaining of GzmB and mMCP-8 in mast cell-deficient mice ( diphtheria toxin ( DT ) - treated Mcpt5-Cre iDTR mice ) with EBA further confirmed that basophils were a source of GzmB ( Supplementary Fig. 1b ) .

These findings suggested that mast cells but not basophils were a significant source of GzmB in this neonatal BP model .

Mast cells and / or basophils produce GzmB to degrade hemidesmosomal proteins .

GzmB deficiency hinders neutrophil infiltration through impeded secretion of chemoattractant macrophage inflammatory protein-2 / IL-8 Next , the effects of GzmB on the inflammatory response in the EBA murine model were assessed .

Granzyme B ( GzmB ) promotes neutrophil infiltration , increased macrophage inflammatory protein-2 ( MIP-2 ) / IL-8 levels , and elevated elastase activity .

Indeed , a recent work revealed that GzmB activates caspase 3 in secretory lysosomes of mast cells , a mechanism which possibly contributes to enhanced caspase 3-dependent proteolytic cleavage in the extracellular space39 .

As proteolytic degradation of alpha6 integrin by other proteases has been reported31 , we hypothesized that GzmB augments inflammation to increase the activity of other proteases to degrade alpha6 integrin .

In this traditional dogma , GzmB was considered to be exclusively released from the granules of cytotoxic T and natural killer cells and internalized into target cells through perforin-mediated pores to initiate apoptosis .

The loss of AR increased NGF expression in our study , suggesting that the AR may act as an upstream regulator that downregulates the NGF in the absence of ADT .

ZBTB46 directly binds to the regulatory sequence of the NGF and upregulates NGF expression We hypothesized that ZBTB46 upregulates NGF expression in prostate cancer cells by acting as a transcriptional activator and binding to a ZBTB46-binding element ( ZBE ) in the NGF regulatory sequence .

Moreover , ZBTB46-binding signals were enriched in C4-2 and LNCaP cells in response to CSS-containing medium or MDV3100 ( Fig. 2e , f ) , supporting the hypothesis that ADT-increased ZBTB46 upregulates NGF expression .

In this study , we demonstrate that the inhibitory effect of PTEN on BMP9-induced osteogenic differentiation can be partially reversed by Wnt10b , and the expression of Wnt10b can be inhibited by PTEN through disturbing the interaction between CREB and BMP / Smad signaling at least .

Our previous study shows that PTEN is downregulated by BMP9 during the osteogenic process in MSCs ( Huang et al ., 2014 ) .

In this study , we confirmed that BMP9 inhibits PTEN and increases Wnt10b simultaneously in MSCs .

In this study , we demonstrate that the inhibitory effect of PTEN on BMP9-induced osteogenic differentiation can be partially reversed by Wnt10b , and the expression of Wnt10b can be inhibited by PTEN through disturbing the interaction between CREB and BMP / Smad signaling at least .

Our previous study shows that PTEN is downregulated by BMP9 during the osteogenic process in MSCs ( Huang et al ., 2014 ) .

In this study , we confirmed that BMP9 inhibits PTEN and increases Wnt10b simultaneously in MSCs .

On the contrary , Nanog suppresses p53 activity while Gli activated by Nanog inhibits p53 by activating Mdm2 to promote pluripotency .

p53 loss upregulates CD133 which subsequently promotes CSC marker expression and confers stemness .

For example , p53 repress CD133 by directly binding to its promoter and recruiting HDAC1 ( Figure 2 ) .

With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .

Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

Additionally , p53 upregulates miR-34a that represses Notch ( Figure 2 ) and anti-apoptotic Bcl2 thereby promoting differentiation and apoptosis ( 82 ) .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

On the contrary , Nanog suppresses p53 activity while Gli activated by Nanog inhibits p53 by activating Mdm2 to promote pluripotency .

p53 loss upregulates CD133 which subsequently promotes CSC marker expression and confers stemness .

For example , p53 repress CD133 by directly binding to its promoter and recruiting HDAC1 ( Figure 2 ) .

With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .

Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

Additionally , p53 upregulates miR-34a that represses Notch ( Figure 2 ) and anti-apoptotic Bcl2 thereby promoting differentiation and apoptosis ( 82 ) .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

On the contrary , Nanog suppresses p53 activity while Gli activated by Nanog inhibits p53 by activating Mdm2 to promote pluripotency .

p53 loss upregulates CD133 which subsequently promotes CSC marker expression and confers stemness .

For example , p53 repress CD133 by directly binding to its promoter and recruiting HDAC1 ( Figure 2 ) .

With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .

Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

Additionally , p53 upregulates miR-34a that represses Notch ( Figure 2 ) and anti-apoptotic Bcl2 thereby promoting differentiation and apoptosis ( 82 ) .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

On the contrary , Nanog suppresses p53 activity while Gli activated by Nanog inhibits p53 by activating Mdm2 to promote pluripotency .

p53 loss upregulates CD133 which subsequently promotes CSC marker expression and confers stemness .

For example , p53 repress CD133 by directly binding to its promoter and recruiting HDAC1 ( Figure 2 ) .

With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .

Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

Additionally , p53 upregulates miR-34a that represses Notch ( Figure 2 ) and anti-apoptotic Bcl2 thereby promoting differentiation and apoptosis ( 82 ) .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Inactivation of p53 disrupts this balance and promotes pluripotency and somatic cell reprogramming .

Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy .

Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy Spontaneous intracerebral hemorrhage ( ICH ) commonly causes secondary hippocampal damage and delayed cognitive impairments , but the mechanisms remain elusive .

However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .

Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy .

Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy Spontaneous intracerebral hemorrhage ( ICH ) commonly causes secondary hippocampal damage and delayed cognitive impairments , but the mechanisms remain elusive .

However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .

In the case of high calcium / phosphate treatment , the expression of P53 was decreased , while PLG increased the expression of PTEN .

PLG promotes PTEN expression by increasing P53 signaling .

Western blotting and qRT-PCR analyses showed that high calcium / phosphate treatment reduced the P53 expression level in VSMCs and that PLG significantly increased the P53 expression level compared to the control group .

These results showed that PLG upregulated the expression of P53 during vascular calcification by reducing STAT3 phosphorylation .

PLG upregulates P53 signaling in vivo and in vitro .

In the case of high calcium / phosphate treatment , the expression of P53 was decreased , while PLG increased the expression of PTEN .

PLG promotes PTEN expression by increasing P53 signaling .

Western blotting and qRT-PCR analyses showed that high calcium / phosphate treatment reduced the P53 expression level in VSMCs and that PLG significantly increased the P53 expression level compared to the control group .

These results showed that PLG upregulated the expression of P53 during vascular calcification by reducing STAT3 phosphorylation .

PLG upregulates P53 signaling in vivo and in vitro .

Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

Newer studies add to this small body of data , including an intriguing study where a novel PTEN / ARID4B / PI3K pathway in which PTEN inhibits the expression of ARID4B was characterised .

PTEN inhibits ARID4B expression and thus prevents the transcriptional activation of ARID4B transcriptional targets PIK3CA and PIK3R2 ( PI3K subunits ) 79 .

Furthermore , IR induced RAC1 expression and activity via the activation of PI3K / AKT signaling pathway , and then enhancing cell proliferation , survival , migration and metastasis and increasing levels of epithelial-to-mesenchymal transition ( EMT ) markers , which facilitated the cell survival and invasive phenotypes .

Furthermore , IR induced RAC1 expression and activity via the activation of PI3K / AKT signaling pathway , and then enhancing cell proliferation , survival , migration and metastasis and increasing levels of epithelial-to-mesenchymal transition ( EMT ) markers , which facilitated the cell survival and invasive phenotypes .

Our study showed that hypoxia increased the production of S100A8 in microglia .

FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

Our study showed that hypoxia increased the production of S100A8 in microglia .

FACS analysis showed that the increase of S100A8 levels in microglia by hypoxia promoted neuronal apoptosis , which was confirmed by immunofluorescence .

In our study , the increase of IL-1beta expression by S100A8 indicated that S100A8 was involved in the priming signal for NLRP3 inflammasome assembly in microglia ( Figure 2B ) .

Previous studies have demonstrated that beta-catenin signaling helps VEGF regulate angiogenesis , and that FBXW7 promotes the degradation of beta-catenin ( 42,43 ) .

FBXW7 inhibits VEGF expression through inactivation of beta-catenin signaling To further elucidate the potential molecular mechanism by which FBXW7 mediates its antitumor effects in OC , western blot analysis was performed to detect the expression levels of key proteins in beta-catenin signaling .

Collectively , these results suggested that FBXW7 may inhibit VEGF expression through inactivation of beta-catenin signaling in SKOV3 cells .

Mechanistically , FBXW7 suppressed VEGF expression by inactivating beta-catenin signaling .

Overall , the current results suggested that FBXW7 may inhibit VEGF expression through inactivation of beta-catenin signaling in SKOV3 cells .

At the same time , limonin down-regulated the expression of NQO1 , indicating that limonin may indirectly act on the apoptosis pathway by regulating the expression activity of antioxidant enzymes in vivo , thus exerting its inhibitory effect on tumor cells , which provides an idea for the molecular mechanism that natural products can indirectly exert their anticancer effect by regulating the activity of antioxidant enzymes .

At the same time , limonin down-regulated the expression of NQO1 , indicating that limonin may indirectly act on the apoptosis pathway by regulating the expression activity of antioxidant enzymes in vivo , thus exerting its inhibitory effect on tumor cells , which provides an idea for the molecular mechanism that natural products can indirectly exert their anticancer effect by regulating the activity of antioxidant enzymes .

Dong et al. found that NLRP3 inhibits senescence and enables replicative immortality through regulating the Wnt / beta-catenin pathway via the thioredoxin-interacting protein ( TXNIP ) / NLRP3 axis ( 74 ) .

Inhibition of NLRP3 suppresses the proliferation , migration and invasion , and promotes apoptosis in glioma cells , while in contrast , increased expression of NLRP3 significantly enhances the proliferation , migration and invasion as well as attenuating apoptosis in glioma cells ( 56 ) ( Table 2 ) .

The role of NLRP3 in promoting invasion has been demonstrated with human endometrial cancer cell lines such as Ishikawa and HEC-1A cells , where knockdown of NLRP3 significantly reduces proliferation , clonogenicity , invasion and migration .

The knockdown of NLRP3 significantly reduces the proliferation , clonogenicity , invasion and migration in both Ishikawa and HEC-1A cells , while in contrast , NLRP3 overexpression enhances the proliferation , migration and invasion in both Ishikawa and HEC-1A cells and furthermore , increases caspase-1 activation and the release of IL-1beta in endometrial cancer cells .

Liu et al. concluded that the upregulation of NLRP3 expression promotes the progression of endometrial cancer ; therefore , NLPR3 inflammasome might be a new therapeutic target for endometrial cancer ( 55 ) .

Collectively , these results indicate that upregulated NLRP3 expression promotes the progression of endometrial cancer ( 55 ) .

NLRP3 enhances IL-1beta , subsequently activating NF-kappaB , and initiates JNK signaling to cause proliferation and invasion in gastric cancer ( 21 ) .

Consistently , knockdown of NLRP3 induces cell apoptosis in MCF-7 cells and decreases cell migration ( 54 ) ; nevertheless , in other cell-types , NLRP3 inflammasome may pharmacologically repress proliferation and metastasis of hepatic cell carcinoma ( HCC ) ( 21 ) ( Table 4 ) .

NLRP3 enhances IL-1beta , subsequently activating NF-kappaB , and initiates JNK signaling to cause proliferation and invasion in gastric cancer ( 21 ) .

Moreover , NLRP3 downstream , IL-1beta , also stimulates the production of ROS that , in turn , induces DNA damage and cancer development in CRC ( 42 ) ( Table 2 ) .

TLR4 - / - mice are more susceptible to SARS-CoV-1 than wild-type mice with higher viral titers [ 113 ] , which means that there was impairment in the innate immune response due to the lack of TLR4 , and hence difficulty in fighting the virus .

TLR4 - / - mice are more susceptible to SARS-CoV-1 than wild-type mice with higher viral titers [ 113 ] , which means that there was impairment in the innate immune response due to the lack of TLR4 , and hence difficulty in fighting the virus .

In addition , SARS-CoV-2 may activate TLR4 to increase PI3K / Akt signalling in infected cells , preventing apoptosis and thus increasing time for viral replication .

Hence , a possible model for the interaction of SARS-CoV-2 and TLR4 is outlined in Section 11 and the graphical abstract ( Figure 1 ) in which SARS-CoV-2 may activate TLR4 in the heart and lungs to cause aberrant TLR4 signalling in favour of the proinflammatory MyD88-dependent ( canonical ) pathway rather than the alternative TRIF / TRAM-dependent anti-inflammatory and interferon pathway .

We can confidently extrapolate the above findings in Sections 8.1 and 8.2 from SARS-CoV-1 to SARS-CoV-2 ; hence , we propose that SARS-CoV-2 would activate TLR4 directly , probably via its spike protein binding to TLR4 ( and / or MD2 ) .

Hence , a possible model for the interaction of SARS-CoV-2 and TLR4 is outlined in Section 11 and the graphical abstract ( Figure 1 ) in which SARS-CoV-2 may activate TLR4 in the heart and lungs to cause aberrant TLR4 signalling in favour of the proinflammatory MyD88-dependent ( canonical ) pathway rather than the alternative TRIF / TRAM-dependent anti-inflammatory and interferon pathway .

We can confidently extrapolate the above findings in Sections 8.1 and 8.2 from SARS-CoV-1 to SARS-CoV-2 ; hence , we propose that SARS-CoV-2 would activate TLR4 directly , probably via its spike protein binding to TLR4 ( and / or MD2 ) .

In addition , SARS-CoV-2 may activate TLR4 to increase PI3K / Akt signalling in infected cells , preventing apoptosis and thus increasing time for viral replication .

This raises the question , is it only ACE2 that the spike protein of SARS-CoV-2 binds to or is there also another receptor involved , such as TLR4 which is known to promote cardiac hypertrophy , myocardial inflammation , and fibrosis [ 58-60 ] ?

This raises the question , is it only ACE2 that the spike protein of SARS-CoV-2 binds to or is there also another receptor involved , such as TLR4 which is known to promote cardiac hypertrophy , myocardial inflammation , and fibrosis [ 58-60 ] ?

This raises the question , is it only ACE2 that the spike protein of SARS-CoV-2 binds to or is there also another receptor involved , such as TLR4 which is known to promote cardiac hypertrophy , myocardial inflammation , and fibrosis [ 58-60 ] ?

This raises the question , is it only ACE2 that the spike protein of SARS-CoV-2 binds to or is there also another receptor involved , such as TLR4 which is known to promote cardiac hypertrophy , myocardial inflammation , and fibrosis [ 58-60 ] ?

This would potentially serve 3 simultaneous benefits : ( a ) it would increase the compliance of the lung alveoli and prevent their collapse ; ( b ) confer antiviral actions by shielding and preventing infection of naive cells , especially if TLR4 is proven to be an entry receptor or contributes to ACE2 upregulation ; and ( c ) block TLR4 to reduce inflammation and excessive cytokine production .

This would potentially serve 3 simultaneous benefits : ( a ) it would increase the compliance of the lung alveoli and prevent their collapse ; ( b ) confer antiviral actions by shielding and preventing infection of naive cells , especially if TLR4 is proven to be an entry receptor or contributes to ACE2 upregulation ; and ( c ) block TLR4 to reduce inflammation and excessive cytokine production .

For instance , ( 1 ) evidence that TLR4 has the strongest protein-protein interaction with the spike glycoprotein of SARS-CoV-2 compared to other TLRs [ 30 ] , together with ( 2 ) evidence that SARS-COV-2 strongly induces interferon-stimulated gene ( ISG ) expression in an immunopathogenic context in the respiratory tract [ 31 ] ; ( 3 ) evidence that ISG activation results in increased expression of ACE2 [ 32 ] and ( 4 ) evidence that pulmonary surfactants in the lung prevent viral infection by blocking TLR4 [ 33 ] suggest a possible mechanism in which the virus may be binding to and activating TLR4 to increase expression of ACE2 which promotes viral entry .

For instance , ( 1 ) evidence that TLR4 has the strongest protein-protein interaction with the spike glycoprotein of SARS-CoV-2 compared to other TLRs [ 30 ] , together with ( 2 ) evidence that SARS-COV-2 strongly induces interferon-stimulated gene ( ISG ) expression in an immunopathogenic context in the respiratory tract [ 31 ] ; ( 3 ) evidence that ISG activation results in increased expression of ACE2 [ 32 ] and ( 4 ) evidence that pulmonary surfactants in the lung prevent viral infection by blocking TLR4 [ 33 ] suggest a possible mechanism in which the virus may be binding to and activating TLR4 to increase expression of ACE2 which promotes viral entry .

As mentioned previously , TLR4 is activated by its typical ligand , LPS .

As mentioned previously , TLR4 is activated by its typical ligand , LPS .

These proteins cause TLR4 activation , to induce an inflammatory response during acute viral infection .

These proteins cause TLR4 activation , to induce an inflammatory response during acute viral infection .

Even if the virus infects cardiomyocytes via ACE2 only , the subsequent immune-mediated myocardial injury and inflammation is likely mediated via TLR4 due to the DAMPs released from the lysed cardiomyocytes .

Even if the virus infects cardiomyocytes via ACE2 only , the subsequent immune-mediated myocardial injury and inflammation is likely mediated via TLR4 due to the DAMPs released from the lysed cardiomyocytes .

TLR4 activation by LPS on cardiomyocytes leads to subsequent reduction in myocardial contractility [ 77 , 81 ] , and the predominant view in the literature is that TLR4 activation on cardiac structural fibroblasts and cardiac macrophages leads to a profibrotic and proinflammatory response , respectively [ 78 , 82 ] .

TLR4 activation by LPS on cardiomyocytes leads to subsequent reduction in myocardial contractility [ 77 , 81 ] , and the predominant view in the literature is that TLR4 activation on cardiac structural fibroblasts and cardiac macrophages leads to a profibrotic and proinflammatory response , respectively [ 78 , 82 ] .

TLR4 can be activated by LPS ( classical PAMP ) , DAMPs , or viral PAMPs .

TLR4 - / - mice are more susceptible to SARS-CoV-1 than wild-type mice with higher viral titers [ 113 ] , which means that there was impairment in the innate immune response due to the lack of TLR4 , and hence difficulty in fighting the virus .

TLR4 - / - mice are more susceptible to SARS-CoV-1 than wild-type mice with higher viral titers [ 113 ] , which means that there was impairment in the innate immune response due to the lack of TLR4 , and hence difficulty in fighting the virus .

In addition , SARS-CoV-2 may activate TLR4 to increase PI3K / Akt signalling in infected cells , preventing apoptosis and thus increasing time for viral replication .

Hence , a possible model for the interaction of SARS-CoV-2 and TLR4 is outlined in Section 11 and the graphical abstract ( Figure 1 ) in which SARS-CoV-2 may activate TLR4 in the heart and lungs to cause aberrant TLR4 signalling in favour of the proinflammatory MyD88-dependent ( canonical ) pathway rather than the alternative TRIF / TRAM-dependent anti-inflammatory and interferon pathway .

Hence , a possible model for the interaction of SARS-CoV-2 and TLR4 is outlined in Section 11 and the graphical abstract ( Figure 1 ) in which SARS-CoV-2 may activate TLR4 in the heart and lungs to cause aberrant TLR4 signalling in favour of the proinflammatory MyD88-dependent ( canonical ) pathway rather than the alternative TRIF / TRAM-dependent anti-inflammatory and interferon pathway .

We can confidently extrapolate the above findings in Sections 8.1 and 8.2 from SARS-CoV-1 to SARS-CoV-2 ; hence , we propose that SARS-CoV-2 would activate TLR4 directly , probably via its spike protein binding to TLR4 ( and / or MD2 ) .

We can confidently extrapolate the above findings in Sections 8.1 and 8.2 from SARS-CoV-1 to SARS-CoV-2 ; hence , we propose that SARS-CoV-2 would activate TLR4 directly , probably via its spike protein binding to TLR4 ( and / or MD2 ) .

In addition , SARS-CoV-2 may activate TLR4 to increase PI3K / Akt signalling in infected cells , preventing apoptosis and thus increasing time for viral replication .

This raises the question , is it only ACE2 that the spike protein of SARS-CoV-2 binds to or is there also another receptor involved , such as TLR4 which is known to promote cardiac hypertrophy , myocardial inflammation , and fibrosis [ 58-60 ] ?

This raises the question , is it only ACE2 that the spike protein of SARS-CoV-2 binds to or is there also another receptor involved , such as TLR4 which is known to promote cardiac hypertrophy , myocardial inflammation , and fibrosis [ 58-60 ] ?

This raises the question , is it only ACE2 that the spike protein of SARS-CoV-2 binds to or is there also another receptor involved , such as TLR4 which is known to promote cardiac hypertrophy , myocardial inflammation , and fibrosis [ 58-60 ] ?

This raises the question , is it only ACE2 that the spike protein of SARS-CoV-2 binds to or is there also another receptor involved , such as TLR4 which is known to promote cardiac hypertrophy , myocardial inflammation , and fibrosis [ 58-60 ] ?

This would potentially serve 3 simultaneous benefits : ( a ) it would increase the compliance of the lung alveoli and prevent their collapse ; ( b ) confer antiviral actions by shielding and preventing infection of naive cells , especially if TLR4 is proven to be an entry receptor or contributes to ACE2 upregulation ; and ( c ) block TLR4 to reduce inflammation and excessive cytokine production .

This would potentially serve 3 simultaneous benefits : ( a ) it would increase the compliance of the lung alveoli and prevent their collapse ; ( b ) confer antiviral actions by shielding and preventing infection of naive cells , especially if TLR4 is proven to be an entry receptor or contributes to ACE2 upregulation ; and ( c ) block TLR4 to reduce inflammation and excessive cytokine production .

For instance , ( 1 ) evidence that TLR4 has the strongest protein-protein interaction with the spike glycoprotein of SARS-CoV-2 compared to other TLRs [ 30 ] , together with ( 2 ) evidence that SARS-COV-2 strongly induces interferon-stimulated gene ( ISG ) expression in an immunopathogenic context in the respiratory tract [ 31 ] ; ( 3 ) evidence that ISG activation results in increased expression of ACE2 [ 32 ] and ( 4 ) evidence that pulmonary surfactants in the lung prevent viral infection by blocking TLR4 [ 33 ] suggest a possible mechanism in which the virus may be binding to and activating TLR4 to increase expression of ACE2 which promotes viral entry .

For instance , ( 1 ) evidence that TLR4 has the strongest protein-protein interaction with the spike glycoprotein of SARS-CoV-2 compared to other TLRs [ 30 ] , together with ( 2 ) evidence that SARS-COV-2 strongly induces interferon-stimulated gene ( ISG ) expression in an immunopathogenic context in the respiratory tract [ 31 ] ; ( 3 ) evidence that ISG activation results in increased expression of ACE2 [ 32 ] and ( 4 ) evidence that pulmonary surfactants in the lung prevent viral infection by blocking TLR4 [ 33 ] suggest a possible mechanism in which the virus may be binding to and activating TLR4 to increase expression of ACE2 which promotes viral entry .

As mentioned previously , TLR4 is activated by its typical ligand , LPS .

As mentioned previously , TLR4 is activated by its typical ligand , LPS .

These proteins cause TLR4 activation , to induce an inflammatory response during acute viral infection .

These proteins cause TLR4 activation , to induce an inflammatory response during acute viral infection .

Even if the virus infects cardiomyocytes via ACE2 only , the subsequent immune-mediated myocardial injury and inflammation is likely mediated via TLR4 due to the DAMPs released from the lysed cardiomyocytes .

Even if the virus infects cardiomyocytes via ACE2 only , the subsequent immune-mediated myocardial injury and inflammation is likely mediated via TLR4 due to the DAMPs released from the lysed cardiomyocytes .

TLR4 activation by LPS on cardiomyocytes leads to subsequent reduction in myocardial contractility [ 77 , 81 ] , and the predominant view in the literature is that TLR4 activation on cardiac structural fibroblasts and cardiac macrophages leads to a profibrotic and proinflammatory response , respectively [ 78 , 82 ] .

TLR4 activation by LPS on cardiomyocytes leads to subsequent reduction in myocardial contractility [ 77 , 81 ] , and the predominant view in the literature is that TLR4 activation on cardiac structural fibroblasts and cardiac macrophages leads to a profibrotic and proinflammatory response , respectively [ 78 , 82 ] .

TLR4 can be activated by LPS ( classical PAMP ) , DAMPs , or viral PAMPs .

This is supported by increasing number of studies demonstrating that impaired mitophagy enhances NLRP3 activation , whereas induction of mitophagy reduces NLRP3 activation ( 87-90 ) .

The NLPR3 inflammasome assembly was disrupted due to reduced NLRP3 protein levels , which resulted in decreased caspase-1 activation and IL-1beta production upon the NLRP3 inflammasome activation after Ka treatment ( 101 ) .

NLRP3 was shown to modulate autophagy .

Meanwhile , GAS inhibited pyroptosis by downregulating NLRP3 , inflammatory factors ( IL-1beta , IL-18 ) and cleaved caspase-1 .

Meanwhile , GAS inhibited pyroptosis by downregulating NLRP3 , inflammatory factors ( IL-1beta , IL-18 ) and cleaved caspase-1 .

In contrast , in adult mice TLR2 / TLR4 activation on pericryptal macrophages by exogenous HA or other TLR2 / TLR4 agonists results in CXCL12 production resulting in the migration of COX-2 expressing MSCs .

TLR4 activation by LPS requires a TLR4-MD2 complex , LPS binding protein , and CD14 which delivers LPS to the TLR4-MD2 complex ( 33 , 34 ) .

TLR4 activation by LPS and LMW-HA require different accessory molecules .

Although both LMW-HA and LPS bind to TLR4 , the results of TLR4 activation by LMW-HA and LPS are not identical .

Activation of TLR2 by LTA or activation of TLR4 by LPS or HA results in the release of the chemokine CXCL12 , which binds to CXCR4 on COX-2 expressing MSCs .

Although there are differences in the accessory molecules involved in TLR4 activation by LPS and LMW - HA , TLR4 activation by either one promotes wound healing ( 12 , 27 , 28 , 33 ) .

TLR4 activation by HA also plays a role in wound repair ( 22 ) .

TLR4 activation by HA also affects the immune response in ischemia - reperfusion injury in the kidney and in acute allograft rejection in a skin transplant model ( 8) .

Moreover , in contrast to wound repair where activation of TLRs by both microbial PAMPs and non-microbial agents , such as HA , play a role ( 11 , 12 ) , intestinal growth is driven only by TLR4 activation by the nonmicrobial agent , HA ( 17 ) .

In contrast , in adult mice TLR2 / TLR4 activation on pericryptal macrophages by exogenous HA or other TLR2 / TLR4 agonists results in CXCL12 production resulting in the migration of COX-2 expressing MSCs .

Although there are differences in the accessory molecules involved in TLR4 activation by LPS and LMW - HA , TLR4 activation by either one promotes wound healing ( 12 , 27 , 28 , 33 ) .

TLR4 activation by LPS requires a TLR4-MD2 complex , LPS binding protein , and CD14 which delivers LPS to the TLR4-MD2 complex ( 33 , 34 ) .

TLR4 activation by LPS and LMW-HA require different accessory molecules .

Although both LMW-HA and LPS bind to TLR4 , the results of TLR4 activation by LMW-HA and LPS are not identical .

Activation of TLR2 by LTA or activation of TLR4 by LPS or HA results in the release of the chemokine CXCL12 , which binds to CXCR4 on COX-2 expressing MSCs .

TLR4 activation by HA also affects the immune response in ischemia - reperfusion injury in the kidney and in acute allograft rejection in a skin transplant model ( 8) .

Moreover , in contrast to wound repair where activation of TLRs by both microbial PAMPs and non-microbial agents , such as HA , play a role ( 11 , 12 ) , intestinal growth is driven only by TLR4 activation by the nonmicrobial agent , HA ( 17 ) .

TLR4 activation by HA also plays a role in wound repair ( 22 ) .

The ROS inhibitor , N-acetyl-l-cysteine ( NAC ) , significantly reduced IL-1beta production , and blocked NLRP3 and ASC upregulation after exposure to PrP106-126 in murine microglia ( Shi et al ., 2012 ) .

The ROS inhibitor , N-acetyl-l-cysteine ( NAC ) , significantly reduced IL-1beta production , and blocked NLRP3 and ASC upregulation after exposure to PrP106-126 in murine microglia ( Shi et al ., 2012 ) .

The ROS inhibitor , N-acetyl-l-cysteine ( NAC ) , significantly reduced IL-1beta production , and blocked NLRP3 and ASC upregulation after exposure to PrP106-126 in murine microglia ( Shi et al ., 2012 ) .

The NLRP3 inflammasome assembles in response to two signals ; toll-like receptor 4 ( TLR4 ) stimulation by LPS induces the NF-kappabeta-mediated transcription of pro-IL-1beta and pro-IL-18 , and stimuli such as P2X7 receptor-facilitated potassium ( K + ) efflux trigger NLRP3 inflammasome activation .

The expression of TLR4 can be downregulated by TGF-beta and the anti-inflammatory cytokine IL-10 .

Specifically , TGF-beta inhibits TLR4 gene expression and promotes MyD88 degradation , thus decreasing downstream signaling [ 106,107 ] .

SOCS1 is induced upon receptor activation and modulates TLR4 through two mechanisms .

TLR4 Mediated Effects TLR4 is a key molecule involved in the pathogenesis of inflammatory diseases [ 63,64 ] .

The expression of TLR4 can be downregulated by TGF-beta and the anti-inflammatory cytokine IL-10 .

Specifically , TGF-beta inhibits TLR4 gene expression and promotes MyD88 degradation , thus decreasing downstream signaling [ 106,107 ] .

SOCS1 is induced upon receptor activation and modulates TLR4 through two mechanisms .

TLR4 Mediated Effects TLR4 is a key molecule involved in the pathogenesis of inflammatory diseases [ 63,64 ] .

Some of these TLR4 inhibitors have strong anti-inflammatory effects and prevent cytokine production in these diseases , such as Eritoran , NI-0101 , CX-01 and JKB-121 [ 242 ] .

Moreover , Jin et al. [ 50 ] revealed that FBW7 decreases EZH2 activity and attenuates the motility of pancreatic cancer cells by mediating the degradation of the EZH2 ubiquitin proteasome pathway .

Recently , a report has confirmed that Praja1 degrades EZH2 during skeletal myogenesis [ 38 ] .

Aaron and his colleagues illustrated that Praja1 promotes EZH2 degradation through K48-linkage polyubiquitination and suppresses cells growth and migration in breast cancer [ 87 ] .

A recent research has disclosed that sorafenib can prevent EZH2 expression by accelerating its ubiquitination-proteasome degradation in hepatoma cells [ 117 ] .

It means that EZH2 can activate gene expression and oncogenesis without being dependent on its methyltransferase activity .

For instance , EZH2 can promote the invasion and metastasis by suppressing E-cadherin transcriptional expression [ 28 , 29 ] ; EZH2 can also increase tumorigenesis by silencing tumor suppressors [ 9 , 20 , 25 ] .

For instance , EZH2 can promote the invasion and metastasis by suppressing E-cadherin transcriptional expression [ 28 , 29 ] ; EZH2 can also increase tumorigenesis by silencing tumor suppressors [ 9 , 20 , 25 ] .

EZH2 reportedly promotes cancer development and metastasis [ 9 , 17 , 18 ] .