460 Matching Annotations
  1. Jul 2021
    1. 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 ) .

      S100A8 activates IL1B.

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

      Hypoxia activates S100A8.

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

      Hypoxia activates S100A8.

    4. 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 ) .

      S100A8 activates IL1B.

    1. 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.

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

      PTEN inhibits ARID4B.

    3. 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.

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

      PTEN inhibits ARID4B.

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

      Basophils activates GZMB.

    2. 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 ) .

      Basophils activates GZMB.

    3. 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 ) .

      Basophils activates GZMB.

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

      Basophils activates GZMB.

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

      Basophils activates GZMB.

    6. 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 .
    7. Granzyme B ( GzmB ) promotes neutrophil infiltration , increased macrophage inflammatory protein-2 ( MIP-2 ) / IL-8 levels , and elevated elastase activity .
    8. 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 .

      GZMB activates CASP3.

    9. 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 .
    10. 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 .

      GZMB activates apoptotic process.

  2. May 2021
    1. 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 .

      AR inhibits NGF.

    2. 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 .

      ZBTB46 activates NGF.

    3. 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 .

      ZBTB46 activates NGF.

  3. Apr 2021
    1. 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 .

      PTEN inhibits WNT10B.

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

      GDF2 inhibits PTEN.

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

      GDF2 inhibits PTEN.

    4. 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 .

      PTEN inhibits WNT10B.

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

      GDF2 inhibits PTEN.

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

      GDF2 inhibits PTEN.

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

      MDM2 inhibits TP53.

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

      TP53 inhibits PROM1.

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

      TP53 inhibits PROM1.

    4. With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .
    5. Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

      TP53 activates MIR34A.

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

      TP53 activates MIR34A.

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

      TP53 activates isoxaflutole.

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

      TP53 activates isoxaflutole.

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

      MDM2 inhibits TP53.

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

      TP53 inhibits PROM1.

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

      TP53 inhibits PROM1.

    12. With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .
    13. Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

      TP53 activates MIR34A.

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

      TP53 activates MIR34A.

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

      TP53 activates isoxaflutole.

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

      TP53 activates isoxaflutole.

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

      MDM2 inhibits TP53.

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

      TP53 inhibits PROM1.

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

      TP53 inhibits PROM1.

    20. With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .
    21. Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

      TP53 activates MIR34A.

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

      TP53 activates MIR34A.

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

      TP53 activates isoxaflutole.

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

      TP53 activates isoxaflutole.

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

      MDM2 inhibits TP53.

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

      TP53 inhibits PROM1.

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

      TP53 inhibits PROM1.

    28. With the advent of reprogramming era , it was further highlighted that p53 loss promote dedifferentiation and reprogramming under favorable conditions .
    29. Further , induction of miR-34a by p53 functionally targets the CSC marker CD44 , thereby inhibiting prostate cancer regeneration and metastasis ( Figure 2 ) ( 74 ) .

      TP53 activates MIR34A.

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

      TP53 activates MIR34A.

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

      TP53 activates isoxaflutole.

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

      TP53 activates isoxaflutole.

    1. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy .
    2. 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 .
    3. However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .
    4. Inhibition of PTEN Ameliorates Secondary Hippocampal Injury and Cognitive Deficits after Intracerebral Hemorrhage : Involvement of AKT / FoxO3a / ATG-Mediated Autophagy .
    5. 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 .
    6. However , blockage of PTEN prominently abolished these ATG transcriptions and subsequent autophagy induction .
    1. In the case of high calcium / phosphate treatment , the expression of P53 was decreased , while PLG increased the expression of PTEN .

      PLG activates PTEN.

    2. PLG promotes PTEN expression by increasing P53 signaling .

      PLG activates PTEN.

    3. 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 .

      PLG activates TP53.

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

      PLG activates TP53.

    5. PLG upregulates P53 signaling in vivo and in vitro .

      PLG activates TP53.

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

      PLG activates PTEN.

    7. PLG promotes PTEN expression by increasing P53 signaling .

      PLG activates PTEN.

    8. 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 .

      PLG activates TP53.

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

      PLG activates TP53.

    10. PLG upregulates P53 signaling in vivo and in vitro .

      PLG activates TP53.

    1. 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.

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

      PTEN inhibits ARID4B.

    3. 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.

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

      PTEN inhibits ARID4B.

    1. 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 .
    2. 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 .
    1. Our study showed that hypoxia increased the production of S100A8 in microglia .

      Hypoxia activates S100A8.

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

      Hypoxia activates S100A8.

    3. 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 ) .

      S100A8 activates IL1B.

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

      Hypoxia activates S100A8.

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

      Hypoxia activates S100A8.

    6. 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 ) .

      S100A8 activates IL1B.

    1. 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 CTNNB1.

    2. 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 .

      FBXW7 inhibits VEGF.

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

      FBXW7 inhibits VEGF.

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

      FBXW7 inhibits VEGF.

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

      FBXW7 inhibits VEGF.

    1. 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 .

      limonin inhibits NQO1.

    2. 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 .

      limonin inhibits NQO1.

    1. 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 ) .
    2. 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 ) .
    3. 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 .
    4. 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 .
    5. 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 ) .

      NLRP3 activates Dientamoebiasis.

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

      NLRP3 activates Dientamoebiasis.

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

      NLRP3 activates IL1B.

    8. 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 activates cell migration.

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

      NLRP3 activates NFkappaB.

    10. 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 ) .
    1. 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 .
    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 .
    3. 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 .
    4. 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 .

      SARS-CoV-2 activates TLR4.

    5. 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 ) .

      SARS-CoV-2 activates TLR4.

    6. 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 .

      SARS-CoV-2 activates TLR4.

    7. 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 ) .

      SARS-CoV-2 activates TLR4.

    8. 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 .

      SARS-CoV-2 activates TLR4.

    9. 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 ] ?

      TLR4 activates Myocarditis.

    10. 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 ] ?

      TLR4 activates Myocarditis.

    11. 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 ] ?

      TLR4 activates Fibrosis.

    12. 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 ] ?

      TLR4 activates Fibrosis.

    13. 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 .

      TLR4 activates ACE2.

    14. 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 .

      TLR4 activates ACE2.

    15. 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 .

      TLR4 activates viral process.

    16. 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 .

      TLR4 activates viral process.

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

      ligand activates TLR4.

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

      ligand activates TLR4.

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

      protein activates TLR4.

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

      protein activates TLR4.

    21. 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 .
    22. 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 .
    23. 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 ] .
    24. 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 ] .
    25. TLR4 can be activated by LPS ( classical PAMP ) , DAMPs , or viral PAMPs .
    26. 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 .
    27. 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 .
    28. 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 .
    29. 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 .

      SARS-CoV-2 activates TLR4.

    30. 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 .

      SARS-CoV-2 activates TLR4.

    31. 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 ) .

      SARS-CoV-2 activates TLR4.

    32. 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 ) .

      SARS-CoV-2 activates TLR4.

    33. 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 .

      SARS-CoV-2 activates TLR4.

    34. 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 ] ?

      TLR4 activates Myocarditis.

    35. 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 ] ?

      TLR4 activates Myocarditis.

    36. 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 ] ?

      TLR4 activates Fibrosis.

    37. 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 ] ?

      TLR4 activates Fibrosis.

    38. 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 .

      TLR4 activates ACE2.

    39. 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 .

      TLR4 activates ACE2.

    40. 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 .

      TLR4 activates viral process.

    41. 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 .

      TLR4 activates viral process.

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

      ligand activates TLR4.

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

      ligand activates TLR4.

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

      protein activates TLR4.

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

      protein activates TLR4.

    46. 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 .
    47. 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 .
    48. 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 ] .
    49. 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 ] .
    50. TLR4 can be activated by LPS ( classical PAMP ) , DAMPs , or viral PAMPs .
    1. This is supported by increasing number of studies demonstrating that impaired mitophagy enhances NLRP3 activation , whereas induction of mitophagy reduces NLRP3 activation ( 87-90 ) .

      mitophagy inhibits NLRP3.

    2. 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 activates IL1B.

    3. NLRP3 was shown to modulate autophagy .

      NLRP3 activates autophagy.

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

      NLRP3 activates pyroptosis.

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

      NLRP3 activates pyroptosis.

    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 .

      TLR2 activates TLR4.

    2. TLR4 activation by LPS requires a TLR4-MD2 complex , LPS binding protein , and CD14 which delivers LPS to the TLR4-MD2 complex ( 33 , 34 ) .
    3. TLR4 activation by LPS and LMW-HA require different accessory molecules .
    4. Although both LMW-HA and LPS bind to TLR4 , the results of TLR4 activation by LMW-HA and LPS are not identical .
    5. 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 .
    6. 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 ) .
    7. TLR4 activation by HA also plays a role in wound repair ( 22 ) .

      hyaluronic acid activates TLR4.

    8. 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) .

      hyaluronic acid activates TLR4.

    9. 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 ) .

      hyaluronic acid activates TLR4.

    10. 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 .

      TLR2 activates TLR4.

    11. 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 ) .
    12. TLR4 activation by LPS requires a TLR4-MD2 complex , LPS binding protein , and CD14 which delivers LPS to the TLR4-MD2 complex ( 33 , 34 ) .
    13. TLR4 activation by LPS and LMW-HA require different accessory molecules .
    14. Although both LMW-HA and LPS bind to TLR4 , the results of TLR4 activation by LMW-HA and LPS are not identical .
    15. 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 .
    16. 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) .

      hyaluronic acid activates TLR4.

    17. 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 ) .

      hyaluronic acid activates TLR4.

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

      hyaluronic acid activates TLR4.

    1. 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 ) .

      NAC inhibits NLRP3.

    2. 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 ) .
    3. 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 ) .
    4. 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 .
    1. The expression of TLR4 can be downregulated by TGF-beta and the anti-inflammatory cytokine IL-10 .

      TGFB inhibits TLR4.

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

      TGFB inhibits TLR4.

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

      SOCS1 activates TLR4.

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

      TLR4 activates TLR4.

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

      TGFB inhibits TLR4.

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

      TGFB inhibits TLR4.

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

      SOCS1 activates TLR4.

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

      TLR4 activates TLR4.

    9. 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 ] .
    1. 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 .

      FBXW7 inhibits EZH2.

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

      PJA1 inhibits EZH2.

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

      PJA1 inhibits EZH2.

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

      sorafenib inhibits EZH2.

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

      EZH2 activates Carcinogenesis.

    6. 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 activates Carcinogenesis.

    7. 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 ] .
    8. EZH2 reportedly promotes cancer development and metastasis [ 9 , 17 , 18 ] .
    9. They demonstrated that ZRANB1 can bind , deubiquitinate , and stabilize EZH2 , which enhances breast cancer tumorigenesis and metastasis .
    10. 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 ] .