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.

As exhibited in xref , RAC1 overexpression led to the up-regulation of GST-RAC1, RAC1, PAK1, p-PAK1, LIMK1, p-LIMK1, Cofilin, and p-Cofilin in A549 and PC9 cells, while the opposite pattern of these genes was found in the A549 and PC9 cells after Rac1 knockdown.

E.g., RAC1 is activated by IR and the inhibition of RAC1 abrogates G2 checkpoint activation and cell survival following IR in breast cancer cells ( xref , xref ).

Interestingly, CRP-induced MMP9 expression and invasion on RA-FLSs were p38-dependent as addition of a p38 inhibitor (SB202190) but not a NF-κB inhibitor (PDTC) was capable of inhibiting CRP-induced MMP9 expression and cell invasion.

In contrast, blockade of CD16 produced no inhibitory effect on CRP-induced expression of CXCL8, CCL2, MMP9 and IL-6 by RA-FLSs ( xref ), suggesting that CRP may not signal through the CD16 to induce joint inflammation in vitro .

In contrast, blockade of CD16 produced no inhibitory effect on CRP-induced expression of CXCL8, CCL2, MMP9 and IL-6 by RA-FLSs ( xref ), suggesting that CRP may not signal through the CD16 to induce joint inflammation in vitro .

However, CRP- induced expression of CXCL8 was CD32-dependent as it was blunted by the antibody against CD32, whereas CRP-induced MMP9 was blocked by the antibody to CD64, demonstrating that differential signaling mechanisms for CRP in regulating CXCL8 and MMP9 expression in RA-FLSs.

In contrast, blockade of CD16 produced no inhibitory effect on CRP-induced expression of CXCL8, CCL2, MMP9 and IL-6 by RA-FLSs ( xref ), suggesting that CRP may not signal through the CD16 to induce joint inflammation in vitro .

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

In contrast, blockade of CD16 produced no inhibitory effect on CRP-induced expression of CXCL8, CCL2, MMP9 and IL-6 by RA-FLSs ( xref ), suggesting that CRP may not signal through the CD16 to induce joint inflammation in vitro .

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

It has been reported that CRP-induced cytokine expression is also regulated by TWIST transcriptionally in myeloma cells ( xref ).

We thus blocked CD32 or CD64 or both with neutralizing antibodies to differentially determine the signaling mechanisms of CRP-induced cytokine expression.

Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment ( xref C–E).

Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment ( xref C–E).

In this study, we provide evidence that CAPE facilitates NLRP3 ubiquitination by inhibiting ROS in THP-1 cells and inhibits enteritis and tumor burden by inhibiting NLRP3 in an AOM/DSS mouse model.

CAPE Promotes NLRP3 Ubiquitination by Inhibiting ROS.

These findings indicate that CAPE also enhances NLRP3 ubiquitination in vivo .

CAPE Increases NLRP3 Ubiquitination in AOM/DSS Mouse Model.

In conclusion, CAC can be prevented by CAPE-induced NLRP3 inflammasome inhibition, highlighting CAPE as a potential candidate for reducing the risk of CAC in patients with inflammatory bowel disease.

CAPE enhanced the interaction between NLRP3 and Cullin1 and decreased the interaction between NLRP3 and CSN5 in THP-1 cells in a time-dependent manner ( xref ).

CAPE Suppresses Interaction Between NLRP3 and CSN5, and Enhances the Interaction Between NLRP3 and Cullin1.

CAPE enhanced the interaction between NLRP3 and Cullin1 and decreased the interaction between NLRP3 and CSN5 in THP-1 cells in a time-dependent manner ( xref ).

Moreover, CAPE suppressed the interaction between NLRP3 and CSN5 but enhanced that between NLRP3 and Cullin1 both in vivo and in vitro .

CAPE Suppresses Interaction Between NLRP3 and CSN5, and Enhances the Interaction Between NLRP3 and Cullin1.

Moreover, CAPE suppressed the interaction between NLRP3 and CSN5 but enhanced that between NLRP3 and Cullin1 both in vivo and in vitro .

NLRP3 interacts with ASC and pro-caspase-1 to form an inflammasome.

However, CAPE did not affect NLRP3 or IL-1β transcription, but instead enhanced NLRP3 binding to ubiquitin molecules, promoting NLRP3 ubiquitination, and contributing to the anti-tumor effect in the AOM/DSS mouse model.

Moreover, CAPE decreased the mRNA levels of NLRP3, IL-1β, IL-6, and TNF-α ( xref ), increased the binding of NLRP3 to ubiquitin molecules and facilitated NLRP3 ubiquitination ( xref ).

Moreover, CAPE enhanced the binding of NLRP3 to ubiquitin molecules, promoted NLRP3 ubiquitination ( xref ), and significantly blocked the formation of NLRP3 inflammasome, which were again reversed by rotenone ( xref ).

In this study, we provide evidence that CAPE facilitates NLRP3 ubiquitination by inhibiting ROS in THP-1 cells and inhibits enteritis and tumor burden by inhibiting NLRP3 in an AOM/DSS mouse model.

CAPE Promotes NLRP3 Ubiquitination by Inhibiting ROS.

These findings indicate that CAPE also enhances NLRP3 ubiquitination in vivo .

CAPE Increases NLRP3 Ubiquitination in AOM/DSS Mouse Model.

In conclusion, CAC can be prevented by CAPE-induced NLRP3 inflammasome inhibition, highlighting CAPE as a potential candidate for reducing the risk of CAC in patients with inflammatory bowel disease.

CAPE enhanced the interaction between NLRP3 and Cullin1 and decreased the interaction between NLRP3 and CSN5 in THP-1 cells in a time-dependent manner ( xref ).

CAPE Suppresses Interaction Between NLRP3 and CSN5, and Enhances the Interaction Between NLRP3 and Cullin1.

Moreover, CAPE suppressed the interaction between NLRP3 and CSN5 but enhanced that between NLRP3 and Cullin1 both in vivo and in vitro .

CAPE enhanced the interaction between NLRP3 and Cullin1 and decreased the interaction between NLRP3 and CSN5 in THP-1 cells in a time-dependent manner ( xref ).

Moreover, CAPE suppressed the interaction between NLRP3 and CSN5 but enhanced that between NLRP3 and Cullin1 both in vivo and in vitro .

CAPE Suppresses Interaction Between NLRP3 and CSN5, and Enhances the Interaction Between NLRP3 and Cullin1.

NLRP3 interacts with ASC and pro-caspase-1 to form an inflammasome.

However, CAPE did not affect NLRP3 or IL-1β transcription, but instead enhanced NLRP3 binding to ubiquitin molecules, promoting NLRP3 ubiquitination, and contributing to the anti-tumor effect in the AOM/DSS mouse model.

Moreover, CAPE decreased the mRNA levels of NLRP3, IL-1β, IL-6, and TNF-α ( xref ), increased the binding of NLRP3 to ubiquitin molecules and facilitated NLRP3 ubiquitination ( xref ).

Moreover, CAPE enhanced the binding of NLRP3 to ubiquitin molecules, promoted NLRP3 ubiquitination ( xref ), and significantly blocked the formation of NLRP3 inflammasome, which were again reversed by rotenone ( xref ).

Despite the major downstream event of NLRP3 inflammation formation of caspase-1 mediated pyroptosis, NLRP3 seems to mediate the dual-function of apoptosis and survival.

TLR4 uses an accessory protein called MD2 for the recognition of LPS and viral proteins; MD2 initially binds to TLR4 within the cell and is also necessary for the correct trafficking of TLR4 to the cell surface [85].

TLR4 uses an accessory protein called MD2 for the recognition of LPS and viral proteins; MD2 initially binds to TLR4 within the cell and is also necessary for the correct trafficking of TLR4 to the cell surface [85] .

We propose a model in which the SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signalling to increase cell surface expression of ACE2 facilitating entry.

Indeed, we deduce that the spike glycoprotein-TLR4 interaction is stronger than the spike glycoprotein-ACE2 interaction, which is a critical finding that must be exploited.

More relevantly, TLR4 is activated by viral PAMPs to initiate an innate immune and inflammatory response.

TLR4 uses an accessory protein called MD2 for the recognition of LPS and viral proteins; MD2 initially binds to TLR4 within the cell and is also necessary for the correct trafficking of TLR4 to the cell surface [85].

TLR4 uses an accessory protein called MD2 for the recognition of LPS and viral proteins; MD2 initially binds to TLR4 within the cell and is also necessary for the correct trafficking of TLR4 to the cell surface [85] .

We propose a model in which the SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signalling to increase cell surface expression of ACE2 facilitating entry.

Indeed, we deduce that the spike glycoprotein-TLR4 interaction is stronger than the spike glycoprotein-ACE2 interaction, which is a critical finding that must be exploited.

More relevantly, TLR4 is activated by viral PAMPs to initiate an innate immune and inflammatory response.

It was suggested that pyrin interacts with NLRP3 inflammasome component in inhibitory manner and FMF-associated mutations prevent these inhibitory interactions ( xref , xref ).

As mentioned above, pyrin interacts with NLRP3 inflammasome components and leads to their autophagic interaction, thereby acting as anti-inflammatory factor ( xref ).

The first hypothesis involves interaction between thioredoxin-interacting protein (TXNIP) and NLRP3 after an increase in ROS caused by NLRP3 activators, such as MSU.

Upon detecting specific stimuli sensor protein NLRP3 interacts with ASC via homotypic PYD-PYD domain interaction ( xref ) and nucleates ASC into prion-like filaments, thereby forming a single ASC “speck” within activated cell.

The NEK7-NLRP3 interaction was shown to be dependent on potassium efflux ( xref ).

The NLRP3 inflammasome activation triggers the interaction of NLRP3 with NEK7, leading to the inflammasome assembly, the ASC speck formation and caspase 1 activation.

NLRP3 lacking phosphorylation site did not interact with p62 and was not sequestered into phagophore ( xref ).

It was reported that only phosphorylated NLRP3 interacted with p62 in ASC-dependent manner and was sequestered into phagophore.

The molecular mechanism for MSU-induced NLRP3 inflammasome activation is not yet fully elucidated.

Chemotherapy has been the current standard adjuvant treatment for early-stage non-small-cell lung cancer (NSCLC) patients, while recent studies showed benefits of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

Chemotherapy has been the current standard adjuvant treatment for early-stage non-small-cell lung cancer (NSCLC) patients, while recent studies showed benefits of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

Chemotherapy has been the current standard adjuvant treatment for early-stage non-small-cell lung cancer (NSCLC) patients, while recent studies showed benefits of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

For instance, ubiquitination of NLRP3 by FBXL12, TRIM1, ARIH2 or the dopamine-induced E3 ligase MARCH7 promotes the proteasomal degradation of NLRP3 in resting macrophages ( xref ), whereas deubiquitylation of NLRP3 LRR domain on K63 by BRCC3 triggers ASC oligomerization and inflammasome activation ( xref , xref ) ( xref ).

In addition, NLRP3 may also interact with mitochondrial antiviral-signaling protein (MAVS), which is another mitochondrial outer MAM ( xref – xref ).

Indeed, the LBD of VDR is able to physically interact with the NACHT-LRR domain of NLRP3 thus inhibiting the association of NLRP3 with BRCC3 and preventing NLRP3 deubiquitination ( xref ) ( xref ).

In addition, mtROS promotes Thioredoxin-interacting protein (TXNIP)-NLRP3 interaction involved in NLRP3 expression ( xref ) ( xref ).

Upon stimulation, NLRP3 oligomerizes through homotypic interactions between NACHT domains of two NLRP3 proteins and the subsequent recruitment of ASC through PYD-PYD interactions ( xref ).

Regulation of NEK7-NLRP3 assembly is induced by ATP-driven potassium efflux ( xref ) but also in a K + -efflux independent manner ( xref ) and by reactive oxygen species (ROS) production ( xref ).

Then, the ASC adaptor accumulates at Mitochondria-associated ER membranes (MAMs) where the NLRP3-ACS complex is formed ( xref ).

Strikingly, ERβ inhibits TNFα-driven apoptosis and activates NLRP3 in endometriotic tissues ( xref ).

For instance, ubiquitination of NLRP3 by FBXL12, TRIM1, ARIH2 or the dopamine-induced E3 ligase MARCH7 promotes the proteasomal degradation of NLRP3 in resting macrophages ( xref ), whereas deubiquitylation of NLRP3 LRR domain on K63 by BRCC3 triggers ASC oligomerization and inflammasome activation ( xref , xref ) ( xref ).

In addition, NLRP3 may also interact with mitochondrial antiviral-signaling protein (MAVS), which is another mitochondrial outer MAM ( xref – xref ).

Indeed, the LBD of VDR is able to physically interact with the NACHT-LRR domain of NLRP3 thus inhibiting the association of NLRP3 with BRCC3 and preventing NLRP3 deubiquitination ( xref ) ( xref ).

In addition, mtROS promotes Thioredoxin-interacting protein (TXNIP)-NLRP3 interaction involved in NLRP3 expression ( xref ) ( xref ).

Upon stimulation, NLRP3 oligomerizes through homotypic interactions between NACHT domains of two NLRP3 proteins and the subsequent recruitment of ASC through PYD-PYD interactions ( xref ).

Regulation of NEK7-NLRP3 assembly is induced by ATP-driven potassium efflux ( xref ) but also in a K + -efflux independent manner ( xref ) and by reactive oxygen species (ROS) production ( xref ).

Then, the ASC adaptor accumulates at Mitochondria-associated ER membranes (MAMs) where the NLRP3-ACS complex is formed ( xref ).

Strikingly, ERβ inhibits TNFα-driven apoptosis and activates NLRP3 in endometriotic tissues ( xref ).

In addition, the thermal shift and co-immunoprecipitation assays revealed that oleuropein played an essential role in binding to the active sites of TLR4, as well as inhibiting TLR4 dimerization and suppressing the binding of TLR4 to MyD88.

In addition, the thermal shift and co-immunoprecipitation assays revealed that oleuropein played an essential role in binding to the active sites of TLR4, as well as inhibiting TLR4 dimerization and suppressing the binding of TLR4 to MyD88.

In addition, the thermal shift and co-immunoprecipitation assays revealed that oleuropein played an essential role in binding to the active sites of TLR4, as well as inhibiting TLR4 dimerization and suppressing the binding of TLR4 to MyD88.

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE₂ production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

In contrast, TLR4 activation by LMW-HA requires a TLR4-MD2 complex but is independent of CD14 and LPS binding protein.

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

There is evidence that LMW-HA binds both CD44 and TLR4.

This may be the product of endogenous HAs of different molecular weights binding separately to CD44 and TLR4 or it may be the product of HA binding to a CD44-TLR4 complex ( xref , xref ).

This suggests that endogenous HA binding to both CD44 and TLR4 promotes intestinal growth.

TLR2 and TLR4 binding to LMW-HA promotes the production of proinflammatory cytokines including TNFα, MIP, IL-1β, IL-6, and IL-12 ( xref , xref – xref ).

Although most studies suggest that HMW-HA binds CD44 and LMW-HA binds TLR2 and TLR4.

TLR2 and TLR4 preferentially bind to LMW-HA.

This review addresses two novel related intercellular pathways in which a host molecule, HA, binding to TLR2 and TLR4 drives physiologic processes in the intestine and colon.

This suggests that endogenous HA binding to TLR2 and TLR4 blocks bleomycin-induced apoptosis.

PGE₂ binding to EP2 blocks radiation-induced apoptosis by an AKT-EGFR mechanism ( xref ).

EGFR can activate β-catenin via the receptor tyrosine kinase-PI3K-Akt pathway ( xref ).

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 ( xref , xref , xref , xref ).

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 ( xref ).

The presence of CD44 also enhances the effects of HA binding to TLR4 although the presence of CD44 is not required for HA activation of TLR4.

In the first pathway ( xref ), intestinal and colonic growth is regulated by endogenous HA activating TLR4 on pericryptal macrophages resulting in the release of PGE₂ which promotes LGR5+ stem cell proliferation, crypt fission and intestinal elongation.

This suggests that TLR4 activation by endogenous HA promotes healing in DSS colitis.

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

Despite these suggestions there is good evidence that endogenous HA activates TLR4 and promotes growth even though most of the endogenous HA is in the high MW form ( xref , xref , xref ).

In mice deficient in TLR4, PEP-1 does not further reduce LGR5+ stem cell proliferation or crypt fission suggesting that TLR4 activation by endogenous HA drives LGR5+ stem cell proliferation and crypt fission.

TLR4 activation by HA drives LGR5+ epithelial stem cell proliferation and crypt fission in normal growth in the intestine and colon ( xref , xref ).

A study of pulmonary injury induced by intratracheal bleomycin demonstrates the role of HA activation of TLR4 in sterile injury ( xref ).

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE₂ production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

In contrast, TLR4 activation by LMW-HA requires a TLR4-MD2 complex but is independent of CD14 and LPS binding protein.

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

There is evidence that LMW-HA binds both CD44 and TLR4.

This may be the product of endogenous HAs of different molecular weights binding separately to CD44 and TLR4 or it may be the product of HA binding to a CD44-TLR4 complex ( xref , xref ).

This suggests that endogenous HA binding to both CD44 and TLR4 promotes intestinal growth.

Although most studies suggest that HMW-HA binds CD44 and LMW-HA binds TLR2 and TLR4.

TLR2 and TLR4 binding to LMW-HA promotes the production of proinflammatory cytokines including TNFα, MIP, IL-1β, IL-6, and IL-12 ( xref , xref – xref ).

TLR2 and TLR4 preferentially bind to LMW-HA.

This review addresses two novel related intercellular pathways in which a host molecule, HA, binding to TLR2 and TLR4 drives physiologic processes in the intestine and colon.

This suggests that endogenous HA binding to TLR2 and TLR4 blocks bleomycin-induced apoptosis.

PGE₂ binding to EP2 blocks radiation-induced apoptosis by an AKT-EGFR mechanism ( xref ).

EGFR can activate β-catenin via the receptor tyrosine kinase-PI3K-Akt pathway ( xref ).

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 ( xref , xref , xref , xref ).

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 ( xref ).

The presence of CD44 also enhances the effects of HA binding to TLR4 although the presence of CD44 is not required for HA activation of TLR4.

In the first pathway ( xref ), intestinal and colonic growth is regulated by endogenous HA activating TLR4 on pericryptal macrophages resulting in the release of PGE₂ which promotes LGR5+ stem cell proliferation, crypt fission and intestinal elongation.

This suggests that TLR4 activation by endogenous HA promotes healing in DSS colitis.

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

Despite these suggestions there is good evidence that endogenous HA activates TLR4 and promotes growth even though most of the endogenous HA is in the high MW form ( xref , xref , xref ).

In mice deficient in TLR4, PEP-1 does not further reduce LGR5+ stem cell proliferation or crypt fission suggesting that TLR4 activation by endogenous HA drives LGR5+ stem cell proliferation and crypt fission.

TLR4 activation by HA drives LGR5+ epithelial stem cell proliferation and crypt fission in normal growth in the intestine and colon ( xref , xref ).

A study of pulmonary injury induced by intratracheal bleomycin demonstrates the role of HA activation of TLR4 in sterile injury ( xref ).

It was also observed that viral replication was vital for the processing of IL-1β. xref The mitochondrial protein MAVS directly interacts with NLRP3 and also influences IL-1β secretion in response to various NLRP3 activators (eg SeV V protein). xref The molecular interaction of NLRP3 and MAVS in DCs infected with RVFV was observed by confocal microscopy. xref Thus, RVFV brings about the release of IL-1β by activating the NLRP3 inflammasome.

It was also observed that viral replication was vital for the processing of IL-1β. xref The mitochondrial protein MAVS directly interacts with NLRP3 and also influences IL-1β secretion in response to various NLRP3 activators (eg SeV V protein). xref The molecular interaction of NLRP3 and MAVS in DCs infected with RVFV was observed by confocal microscopy. xref Thus, RVFV brings about the release of IL-1β by activating the NLRP3 inflammasome.

The ROS model xref represents a common pathway underlying NLRP3 inflammasome activation. xref Mitochondria are the main intracellular organelles that produce ROS. xref Nigericin, asbestos, silica, and alum induce ROS production, and ROS is generated by NADPH oxidase. xref ROS leads to K + fluxes, activating the NLRP3 inflammasome. xref , xref However, ROS inhibitors manipulate the priming modulation of NLRP3 as used in large concentration. xref Again, mitochondrial DNA release can occur downstream activation of NLRP3. xref Another study reported that mitochondria-associated adaptor MAVS can activatedNLRP3 inflammasome in presence of soluble stimuli such as ATP, nigericin but not particulate matter such as alum or monosodium urate. xref However, some other studies show that mitochondrial MAVS activate NLRP3 inflammasome in presence of RNA viruses but not non-viral stimuli such as ATP or nigericin. xref , xref RNA virus such as murine norovirus (MNV) leads to Gasdermin D (GSDSD) dependent pyroptosis resulting NLRP3 activation in STAT-1 deficient macrophages displayed increased MAVS mediated IL-1β secretion. xref Additionally, Mitofusin-2, an outer membrane protein of mitochondria-responsible for mitochondrial fusion is required for NLRP3 activation after infection with RNA viruses such as influenza, measles or encephalomyocarditis virus (EMCV). xref Still there is a need for deep research to unveil the exact mechanism of mitochondrial effect in NLRP3 activation.

The ROS model xref represents a common pathway underlying NLRP3 inflammasome activation. xref Mitochondria are the main intracellular organelles that produce ROS. xref Nigericin, asbestos, silica, and alum induce ROS production, and ROS is generated by NADPH oxidase. xref ROS leads to K + fluxes, activating the NLRP3 inflammasome. xref , xref However, ROS inhibitors manipulate the priming modulation of NLRP3 as used in large concentration. xref Again, mitochondrial DNA release can occur downstream activation of NLRP3. xref Another study reported that mitochondria-associated adaptor MAVS can activatedNLRP3 inflammasome in presence of soluble stimuli such as ATP, nigericin but not particulate matter such as alum or monosodium urate. xref However, some other studies show that mitochondrial MAVS activate NLRP3 inflammasome in presence of RNA viruses but not non-viral stimuli such as ATP or nigericin. xref , xref RNA virus such as murine norovirus (MNV) leads to Gasdermin D (GSDSD) dependent pyroptosis resulting NLRP3 activation in STAT-1 deficient macrophages displayed increased MAVS mediated IL-1β secretion. xref Additionally, Mitofusin-2, an outer membrane protein of mitochondria-responsible for mitochondrial fusion is required for NLRP3 activation after infection with RNA viruses such as influenza, measles or encephalomyocarditis virus (EMCV). xref Still there is a need for deep research to unveil the exact mechanism of mitochondrial effect in NLRP3 activation.

These results indicate that SeV infection leads to NLRP3-dependent caspase-1 activation. xref SeV infection of THP-1 cells caused caspase-1 activation and IL-1β secretion, while SeV infection of MAVS-knockdown THP-1 cells significantly decreased the formation of active caspase-1 and the mature form of IL-1β (p17).

These results indicate that SeV infection leads to NLRP3-dependent caspase-1 activation. xref SeV infection of THP-1 cells caused caspase-1 activation and IL-1β secretion, while SeV infection of MAVS-knockdown THP-1 cells significantly decreased the formation of active caspase-1 and the mature form of IL-1β (p17).

NLRP3 was activated by ATP or nigericin in lentivirus-M-treated BMDMs of NLRP3 +/+ mice.

NLRP3 was activated by ATP or nigericin in lentivirus-M-treated BMDMs of NLRP3 +/+ mice.

It is worth noting that dopamine has been reported to inhibit NLRP3 inflammasome activation via the dopamine D1 receptor (DRD1), as DRD1 signaling induces the binding of ubiquitin to NLRP3, promoting its degradation ( xref ).

Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity towards MET.

Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity towards MET.

Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity towards MET.

Chronic S15 phosphorylation of mutant p53 has been found in tumors where DNA damage signaling is constitutively activated ( xref , xref ).

Further, NF-kB inhibition by overexpression of IkB also results in S15 phosphorylation of mutant p53 via GADD45α mediated JNK1 activation ( xref ).

It may form a complex with mutant p53 and MDM2 to block their ubiquitination mediated degradation or may form a complex with mutant p53 to prevent aggregation of mutant p53 by inhibiting MDM2 and CHIP in multiple cancer cell lines ( xref , xref ).

A recent study by Capaci et al. showed that mutant p53 can interact with HIF1α to induce miR-30d expression which promotes tubulo-vesiculation of Golgi apparatus leading to enhanced vesicular trafficking and secretion ( xref ) ( xref ).

Binding of mutant p53 to ETS2 can promote expression of Pla2g16 or nucleotide synthesis genes required for invasion depending upon the cancer type ( xref ) ( xref , xref ).

Furthermore, the binding of mutant p53 to EGR1 promotes MYO10 expression which drives breast cancer cell invasion ( xref ) ( xref ).

Further, mutant p53 can interact with PELP1 to promote resistance to platinum-based drugs in triple negative breast cancer ( xref ).

A further study reported that mutant p53 enhance the association of mutant p53 and PARP on the replicating DNA ( xref ) ( xref ).

GOF mutant p53 can bind to TopBP1 and attenuate ATR checkpoint response during replication stress ( xref ) ( xref ).

The compound, RETRA disrupts mutant p53-p73 complex restoring p73-dependent transcription and apoptosis ( xref ) ( xref ).

Short Interfering Mutant p53 Peptides (SIMP) can interact with different mutant p53 proteins and release p73, while peptides aptamers (PA) can inhibit mutant p53 transcription ( xref ) ( xref ).

Zhou et al. showed that mutant p53 binds to novel interacting partner AMPKα in glucose starvation conditions and inhibits its activation by other kinases leading to increased aerobic glycolysis, lipid production, and cell growth ( xref ) ( xref ).

This eliminates mitochondria-associated p53 which would otherwise be activated by PINK1 to mediate suppression of Nanog ( xref ) ( xref ).

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

A recent study by Alam et al. reveals GOF mutant p53 upregulates EFNB2 and activates ephrin B2 reverse signaling to impart enhanced chemoresistance to colorectal cancer cells ( xref ) ( xref ).

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

Chronic S15 phosphorylation of mutant p53 has been found in tumors where DNA damage signaling is constitutively activated ( xref , xref ).

Further, NF-kB inhibition by overexpression of IkB also results in S15 phosphorylation of mutant p53 via GADD45α mediated JNK1 activation ( xref ).

It may form a complex with mutant p53 and MDM2 to block their ubiquitination mediated degradation or may form a complex with mutant p53 to prevent aggregation of mutant p53 by inhibiting MDM2 and CHIP in multiple cancer cell lines ( xref , xref ).

A recent study by Capaci et al. showed that mutant p53 can interact with HIF1α to induce miR-30d expression which promotes tubulo-vesiculation of Golgi apparatus leading to enhanced vesicular trafficking and secretion ( xref ) ( xref ).

Binding of mutant p53 to ETS2 can promote expression of Pla2g16 or nucleotide synthesis genes required for invasion depending upon the cancer type ( xref ) ( xref , xref ).

Furthermore, the binding of mutant p53 to EGR1 promotes MYO10 expression which drives breast cancer cell invasion ( xref ) ( xref ).

Further, mutant p53 can interact with PELP1 to promote resistance to platinum-based drugs in triple negative breast cancer ( xref ).

A further study reported that mutant p53 enhance the association of mutant p53 and PARP on the replicating DNA ( xref ) ( xref ).

GOF mutant p53 can bind to TopBP1 and attenuate ATR checkpoint response during replication stress ( xref ) ( xref ).

The compound, RETRA disrupts mutant p53-p73 complex restoring p73-dependent transcription and apoptosis ( xref ) ( xref ).

Short Interfering Mutant p53 Peptides (SIMP) can interact with different mutant p53 proteins and release p73, while peptides aptamers (PA) can inhibit mutant p53 transcription ( xref ) ( xref ).

Zhou et al. showed that mutant p53 binds to novel interacting partner AMPKα in glucose starvation conditions and inhibits its activation by other kinases leading to increased aerobic glycolysis, lipid production, and cell growth ( xref ) ( xref ).

This eliminates mitochondria-associated p53 which would otherwise be activated by PINK1 to mediate suppression of Nanog ( xref ) ( xref ).

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

A recent study by Alam et al. reveals GOF mutant p53 upregulates EFNB2 and activates ephrin B2 reverse signaling to impart enhanced chemoresistance to colorectal cancer cells ( xref ) ( xref ).

Acetylation of p53 at K373 by CBP/p300 leads to dissociation of HDM2 and TRIM24 and subsequent activation of p53 which in turn transcriptionally activates p21, miR-34a, and miR-145 ( xref ).

Ubiquitination and dephosphorylation of TLR4 or the proteins involved in TLR4 signaling is essential for the modulation of this signaling pathway.

Ubiquitination and dephosphorylation of TLR4 or the proteins involved in TLR4 signaling is essential for the modulation of this signaling pathway.

Therefore, the binding of TLR4 to Stx may have a protective role by sequestering the toxin, or a harmful role by being a direct receptor of Stx, increasing its toxicity.

Another study has reported that histones released from dying renal cells in AKI directly interact with TLR2 and TLR4.

The assembly with sTLR4 prevented the interaction of ligands and coreceptors with transmembrane TLR4, therefore efficiently attenuating TLR4 activation.

Ubiquitination and dephosphorylation of TLR4 or the proteins involved in TLR4 signaling is essential for the modulation of this signaling pathway.

Ubiquitination and dephosphorylation of TLR4 or the proteins involved in TLR4 signaling is essential for the modulation of this signaling pathway.

Therefore, the binding of TLR4 to Stx may have a protective role by sequestering the toxin, or a harmful role by being a direct receptor of Stx, increasing its toxicity.

Another study has reported that histones released from dying renal cells in AKI directly interact with TLR2 and TLR4.

The assembly with sTLR4 prevented the interaction of ligands and coreceptors with transmembrane TLR4, therefore efficiently attenuating TLR4 activation.

Herein, we report an OFMT with unusual morphology and non-specific immunoprofile harboring a novel MEAF6-SUZ12 fusion.

Novel MEAF6-SUZ12 fusion in ossifying fibromyxoid tumor with unusual features.

These results indicated that MICAL2 may promote gastric cancer cell migration through MRTF-A-dependent CDC42 activation and MMP9 expression.

MICAL2 Induces MRTF-A-Dependent CDC42 Activation and MMP9 Expression.

Furthermore, MICAL2 facilitates gastric cancer cell migration by promoting MRTF-A-dependent activation of cell division control protein 42 homolog (CDC42) and expression of MMP9.

As we discussed, the PTM of the EZH2-ubiquitination pathway is an important negative regulator of EZH2.

For instance, CDK1-mediated pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination degradation in breast cancer cell, cervical cancer cell and lung cancer cell [ xref , xref , xref ]; JAK2 phosphorylates Y641-EZH2, leading to E3 ligase β-TrCP-mediated EZH2 degradation in lymphoma cell [ xref ]; and CDK5 phosphorylation of EZH2 at T261 residue results in the E3 ubiquitin ligase FBW7-mediated degradation of EZH2 in pancreatic cancer cell [ xref ].

Mechanistically, YC-1 treatment promotes c-Cbl phosphorylation at T731 and T774, which results in c-Cbl-induced Src and ERK activation, leading to the formation of the c-Cbl-ERK-EZH2 complex and the consequent accumulation of EZH2 ubiquitination and proteasomal degradation.

The first research of EZH2 ubiquitination was from the Aaron lab’s work in 2011 [ xref ].

Ubiquitination, sumoylation, and deubiquitination of EZH2 in tumorigenesis and cancer metastasis.

We showed that R342-EZH2 methylation inhibits TRAF6-mediated EZH2 ubiquitination [ xref ].

Another recent study has reported that CDK5-mediated T261-EZH2 phosphorylation facilitates FBW7-mediated EZH2 ubiquitination and proteasome degradation in pancreatic cancer cells [ xref ].

They found that pT345-EZH2 and pT487-EZH2 facilitate EZH2 ubiquitination and hence its degradation by the proteasome pathway in human cervical cancer cells [ xref ].