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

Taken together these studies addressing the cellular location of the TLR4 signaling that drives growth and wound repair and the nature of the relevant TLR4 ligand suggest that HA activation of myeloid TLR4 mediates intestinal and colonic growth and wound repair.

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

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

There are suggestions that TLR4 is preferentially activated by the low MW form of HA.

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

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.

TLR2 and TLR4 activation by HA mediates wound repair in the bleomycin model of lung injury.

Wound repair mediated by HA activation of TLR2 and TLR4 is also seen in the lung.

In this pathway, TLR4, which is usually associated with innate immunity, is activated not by the microbial product LPS, but by HA, a host molecule.

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 ) .

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.

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.

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 ).

In the first pathway (XREF_FIG), 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.

Based on the growth studies, it is likely that EGFR activation by PGE2 is also the mechanism of the increased epithelial proliferation in the repair phase of DSS colitis.

In growth EGFR activation by PGE2 accounts for about 30% of LGR5+ cell proliferation.

Although the evidence suggests that EGFR activation in response to TLR4 signaling is mediated by PGE2, it is also possible that TLR4 signaling promotes EGFR activation through the production of amphiregulin, epiregulin or other EGFR ligands.

Mechanistically, LCZ696 prevents LPS induced activation of the TLR4 and Myd88 pathway and nuclear translocation of nuclear factor kappa-B (NF-kappaB) p65 factor.

The TLR4 signaling inhibitor, TAK-242, inhibited HUVEC IL-8 secretion in response to SS plasma by 85%.

Free heme released by hemolyzed red blood cells can bind to myeloid differentiation factor-2 (MD-2) and activate TLR4 pro inflammatory signaling on endothelium to promote vaso-occlusion and acute chest syndrome in murine models of SCD.

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.

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

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

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

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

Thus, CAPE suppresses the interaction between NLRP3 and deubiquitinating enzymes, and enhances its interaction with a ubiquitin conjugating enzyme in vivo and in vitro, promoting NLRP3 ubiquitination.

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

CAPE Promotes NLRP3 Ubiquitination by Inhibiting ROS.

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.

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

We found that CAPE decreased NLRP3 inflammasome activation in BMDMs and THP-1 cells and protected mice from colorectal cancer induced by AOM and DSS.

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.

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.

Overall, the results indicate that activated NLRP3 in AOM and DSS mouse model is suppressed by CAPE.

To determine whether CAPE inhibits NLRP3 inflammasome in vivo, we assessed NLRP3 expression in the AOM and DSS mouse model by immunohistochemistry and western blotting.

Moreover, CAPE significantly inhibited the formation of ASC dimers and reduced the abundance of NLRP3 inflammasome complexes in a dose dependent manner (XREF_FIG).

We first investigated whether CAPE inhibits the activation of NLRP3 inflammasome induced by ATP and LPS in macrophages in vitro.

CAPE Decreases NLRP3 Inflammasome Activation in BMDMs and THP-1 Cells.

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

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

As shown in XREF_FIG, LPS + ATP promoted the expression of NLRP3 and pro-IL-1beta in THP-1 cells; however, real-time PCR revealed that after treatment with CAPE for 12 h, mRNA levels of NLRP3 and IL-1beta in THP-1 cells were similar to control (XREF_FIG), indicating that CAPE does not affect the transcription of NLRP3 and IL-1beta.

As shown in XREF_FIG, LPS + ATP promoted the expression of NLRP3 and pro-IL-1beta in THP-1 cells; however, real-time PCR revealed that after treatment with CAPE for 12 h, mRNA levels of NLRP3 and IL-1beta in THP-1 cells were similar to control (XREF_FIG), indicating that CAPE does not affect the transcription of NLRP3 and IL-1beta.

Western blotting showed that CAPE significantly inhibited the increased protein levels of NLRP3, caspase-1, and IL-1beta in BMDMs and THP-1 cells after LPS and ATP stimulation (XREF_FIG).

Furthermore, CAPE significantly reduced the expression of NLRP3, cleaved caspase-1, and cleaved IL-1beta, which was restored by rotenone (XREF_FIG).

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

We then examined whether CAPE also reduces NLRP3 mRNA levels.

Altogether, these results indicate that CAPE reduces NLRP3 protein levels and suppresses NLRP3 activation in macrophages.

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_FIG).

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_FIG).

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

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.

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 ).

Altogether, these results indicate that CAPE reduces NLRP3 protein levels and suppresses NLRP3 activation in macrophages.

Activated NLRP3 promotes pro-caspase-1 proteolysis into its active form, caspase-1 (p20), and then cleaves pro-IL-1beta and pro-IL-18 into their mature forms (IL-1beta and IL-18).

NLRP3 triggers innate immunity by activating caspase-1 and then cleaves immune and metabolic substrates, especially the pro inflammatory cytokine interleukin-1beta (IL-1beta), which induces inflammation and promotes tumor growth.

Moreover, NLRP3 inhibition was found to prevent CAC.

Altogether, our findings indicate that inhibition of NLRP3 inflammasome by CAPE prevents CAC.

NLRP3 triggers innate immunity by activating caspase-1 and then cleaves immune and metabolic substrates, especially the pro inflammatory cytokine interleukin-1beta (IL-1beta), which induces inflammation and promotes tumor growth.

Altogether, our findings demonstrate that CAPE prevents CAC by post-transcriptionally inhibiting NLRP3 inflammasome.

Caffeic Acid Phenethyl Ester Prevents Colitis Associated Cancer by Inhibiting NLRP3 Inflammasome.

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 and DSS mouse model.

We first investigated whether CAPE inhibits the activation of NLRP3 inflammasome induced by ATP and LPS in macrophages in vitro.

We first investigated whether CAPE inhibits the activation of NLRP3 inflammasome induced by ATP and LPS in macrophages in vitro.

Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and B-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic KRAS and mutant p53 to mitigate metastasis.

Specifically, mutant p53 and CREB1 upregulate the pro metastatic, pioneer transcription factor, FOXA1, activating its transcriptional network while promoting Wnt and B-catenin signaling, together driving PDAC metastasis.

Furthermore, it blocked HMGB1 mediated TLR4 dependent signalling in vitro and circulating HMGB1 in vivo [XREF_BIBR].

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 .

We also briefly review the proposed use of TLR4 antagonists as antiviral treatments, including Eritoran, Resatorvid (CLI-095 and TAK242), and glycyrrhizin, as well as another compound, nifuroxazide, that interrupts TLR4 signalling.

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 [XREF_BIBR].

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] .

COVID-19 and Toll Like Receptor 4 (TLR4) : SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation.

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.

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).

This can be extrapolated to SARS-CoV-2, where intracellularly, its M protein may be inducing TLR4 dependent TRAF3 independent IFN-beta production.

Hence, a possible model for the interaction of SARS-CoV-2 and TLR4 is outlined in Section 11 and the graphical abstract (XREF_FIG) 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 and 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 .

Specifically, the disulphide form of HMGB1 stimulates TLR4, while extracellular HMGB1 can form complexes with DNA, RNA, other DAMP or PAMP molecules; the complexes are endocytosed via RAGE and transported to the endolysosomal system.

A review by Andersson et al. suggests that HMGB1 released as a DAMP or secreted by activated immune cells could activate both TLR4 and the receptor for advanced glycation end-products (RAGE) to generate proinflammatory cytokines [XREF_BIBR].

Moreover, HMGB1 and other DAMPS released from necrotic and lytic cells, as well as ambient LPS levels entering the lungs or released from opportunistic gram negative bacteria, can also activate TLR4, amplifying the already severe inflammation.

IL-18 is also induced by the NLRP3 inflammasome in the lungs and heart.

Inhibition of the NLRP3 inflammasome signalling pathway downstream of TLR4 attenuates LPS induced acute lung injury [XREF_BIBR, XREF_BIBR].

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

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 .

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 [XREF_BIBR - XREF_BIBR]?

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

Inhibition of the NLRP3 inflammasome signalling pathway downstream of TLR4 attenuates LPS induced acute lung injury [XREF_BIBR, XREF_BIBR].

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 .

DAMP Mediated TLR4 Activation.

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 [XREF_BIBR, XREF_BIBR], 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 [XREF_BIBR, XREF_BIBR].

Furthermore, while LPS increased TLR4 content in the lungs and heart by at least twofold, nifuroxazide was shown to significantly reduce TLR4 content by 45.7% in the lungs and 31.2% in the heart in the curative regimen and more so in the prophylactic regimen, compared to the LPS control [XREF_BIBR].

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 .

Additionally, it inhibited RSVF-, DENV-NS1-, and EBOV glycoprotein mediated TLR4 activation.

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 ).

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 .

Loss or gain-of-function mutations in TP53 induce dedifferentiation and proliferation of SCs with damaged DNA leading to the generation of CSCs.

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

Furthermore, p53 loss was found to trigger dedifferentiation of mature hepatocytes to pluripotent cells by the activation of SC marker Nestin, which remains suppressed in wild-type p53 bearing cells (XREF_FIG).

TP53 maintains homeostasis between self-renewal and differentiation depending on the cellular and developmental state and prevents the dedifferentiation and reprogramming of somatic cells to stem cells.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

Mutant p53 can itself disrupt the balance between stem cell proliferation and differentiation as well as sequester p63 or p73 thereby hindering apoptosis, augmenting proliferation, and driving chemoresistance and metastasis typical of cancer stem cells.

Mutant p53 mediated repression of p63 function can also modulate the expression of certain miRNAs involved in invasion and metastasis such as let-7i, miR-155, miR-205, miR-130b, and miR-27a (XREF_FIG).

Hence, loss of NUMB in breast cancer cells leads to decreased p53 levels and increased activity of NOTCH receptor which confers increased chemoresistance.

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 ).

Mutant p53 and p63 complex can increase RAB coupling protein (RCP)-mediated recycling of cell surface growth promoting receptors.

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_FIG).

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

Further, the human p53 isoform Delta133p53beta lacking the transactivation domain was observed to promote CSC features in breast cancer cell lines by expression of Sox2, Oct3/4, and Nanog in a Delta133p53beta dependent manner.

Acetylation of p53 at K373 by CBP and 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_FIG).

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 ) .

Acetylation of p53 at K373 by CBP and 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_FIG).

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 ).

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 .

Mutant p53 implicate various context and tissue dependent mechanisms to promote cancer cell invasion and metastasis.

Various transcription factors such as NF-Y, SREBPs, ETS, and EGFR1 play crucial role in mutant p53 driven invasion and metastasis.

Mutant p53 implicate various context and tissue dependent mechanisms to promote cancer cell invasion and metastasis.

Various transcription factors such as NF-Y, SREBPs, ETS, and EGFR1 play crucial role in mutant p53 driven invasion and metastasis.

This suggests that acetylation at K320 and K373 can alter the structure of mutant p53 and restore wild type p53 functions.

Mutant p53 can also induce YAP and TAZ nuclear localization by interacting with SREBP and activating the mevalonate pathway.

Mutant p53 can also promote proliferation by inducing the REG-gamma proteosome pathway in association with p300 (XREF_FIG).

GOF mutant p53 can modify the tumor microenvironment and has been found to support chronic inflammation.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

This underscores the significance of PARP1 inhibitors (PARPi) to augment synthetic lethality in the context of mutant p53 mediated incapacitation of DNA repair (XREF_FIG).

In absence of AMPK, mitochondrial stress augments aerobic glycolysis, also called " Warburg effect " in tumor cells, which is promoted by mutant p53.

Several evidence demonstrate that mutant p53 promotes glycolysis and reprograms the cellular metabolism of cancer cells.

However, whether mutant p53 induced EMT trigger stemness properties in cancer cells, is still quite unexplored.

Gain-of function mutant p53 further promotes EMT and stemness phenotypes by activating genes regulating them.

Although these studies highlight that mutant p53 mediated EMT phenotype confer stemness in cancer cells, however, there is still a lot to explore in context of molecular mechanisms of mutant p53 driven stemness through activation of EMT genes.

While wild type p53 suppresses inflammatory response by inhibiting the production of cytokines and antagonizing NF-kB activity, mutant p53 on the other hand enhances NF-kB activity in response to TNF-alpha and promotes inflammation (XREF_FIG).

The sustained activation of NF-kB signaling by mutant p53 not only elevate inflammatory response but also protects the cancer cells from cytotoxic effects of tumor microenvironment by activating pro survival pathways.

Mutant p53 can also induce YAP and TAZ nuclear localization by interacting with SREBP and activating the mevalonate pathway.

Interaction of mutant p53 to SREBPs activates mevalonate pathway that promotes invasion in breast cancer cells (XREF_FIG).

Similarly, p53 activation by nutlin leads to transcriptional activation of p21 that cause cell cycle arrest and induces differentiation in human ESCs.

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 ).

Growth Hormone Modulation of Hepatic Epidermal Growth Factor Receptor Signaling.

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).

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

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, whereas deubiquitylation of NLRP3 LRR domain on K63 by BRCC3 triggers ASC oligomerization and inflammasome activation (XREF_FIG).