However, the previous study xref did not test AIM2 activation so perhaps parthenolide only inhibits caspase-1 in response to NLRP3 or NLRC4 activation.

Our results disagree with this assertion as we did not find that parthenolide inhibited caspase-1 in response to AIM2 stimulation.

However, the previous study xref did not test AIM2 activation so perhaps parthenolide only inhibits caspase-1 in response to NLRP3 or NLRC4 activation.

Our results disagree with this assertion as we did not find that parthenolide inhibited caspase-1 in response to AIM2 stimulation.

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 ).

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 ).

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 contrast, we observed the opposite phenotypic and molecular changes in VCaP human prostate cancer cells harboring the recurrent TMPRSS2-ERG fusion (Fig.  xref & Supplementary Fig.  xref ).

RPL5 and RPL11 delay P53 ubiquitination in breast cancer cells by binding MDM2.

In response to nucleolar stress, RPL4, RPL5, RPL11, RPL23, RPS7, and RPS27 translocate from the nucleolus to the nucleoplasm and bind to MDM2, inhibiting its ubiquitin ligase activity toward p53, which leads to p53 accumulation xref – xref .

Additionally, our analysis of the specified ribosomal proteins (RPs), which were demonstrated in theas MDM2-P53 pathway mediators or as interacting with MDM2 xref , revealed that MeCP2 expression was correlated with RP expression, including RPL36A, RPS23, RPL15, RPS11, RPL23A, RPL4, RPL14, RPL11, RPL5, RPS6, RPL26, and RPL23 (Fig. xref ).

Moreover, TFRC activated PTEN induced kinase 1 (PINK1) signaling and induced mitophagy; iron-uptake-induced upregulation of acyl-CoA synthetase long chain family member 4 (ACSL4) was required for mitophagy activation and glutathione peroxidase 4 (GPX4) degradation.

Moreover, TFRC activated PTEN induced kinase 1 (PINK1) signaling and induced mitophagy; iron-uptake-induced upregulation of acyl-CoA synthetase long chain family member 4 (ACSL4) was required for mitophagy activation and glutathione peroxidase 4 (GPX4) degradation.

The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive xref .

In another study, the heat shock-like protein Clusterin was shown to increase AKT2 activity and promote the motility of both normal and malignant prostate cells via an inhibitory activity on PTEN-S380 phosphorylation and consequent inactivation of PTEN xref .

Another study demonstrated that phosphorylation of PTEN on tyrosine 240 by FGFR2 promotes chromatin binding through an interaction with Ki-67, which facilitates the recruitment of RAD51 to promote DNA repair xref . xref summarises these novel functions and signalling axes of nuclear PTEN.

In addition to being a dual specificity phosphatase for lipid and protein substrates, PTEN can also be dephosphorylated at serine/threonine and tyrosine residues.

It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma xref .

Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation xref , thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

CBP–β-catenin signalling regulated the levels of C-terminal PTEN phosphorylation in TICs and promoted stemness via CD133 induction.

We further demonstrated that SPOP promoted the ubiquitination of LATS1 in cells ( xref j).

More importantly, co-overexpression of CKΙδ in cells enhanced the association of LATS1 with SPOP to promote the ubiquitination of LATS1 ( xref d).

Mutagenesis studies demonstrated that the serine 336-to alanine mutation (S336A) in ΔDeg1 rarely attenuated the interaction of LATS1 with SPOP, but mutating Ser334, Ser335, Ser336 to alanine (LATS1-3A) dramatically attenuated the interaction of LATS1 with SPOP in cells ( xref g).

Notably, we observed that LATS1 interacted specifically with SPOP in cells ( xref f and Supplementary Fig. 1g and 1j).

Consistently, deletion of degron 1 or both degrons dramatically attenuated the interaction of LATS1 with SPOP in cells ( xref c).

We found that LATS1 interacted with Cullin3, and depletion of Cullin 3 upregulated the abundance of LATS1 largely via prolonging LATS1 protein half-life.

Mechanistically, SPOP specifically interacted with LATS1, and promoted the poly-ubiquitination and subsequent degradation of LATS1 in a degron-dependent manner.

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.

However, the previous study xref did not test AIM2 activation so perhaps parthenolide only inhibits caspase-1 in response to NLRP3 or NLRC4 activation.

Our results disagree with this assertion as we did not find that parthenolide inhibited caspase-1 in response to AIM2 stimulation.

Knockout of TGF-β receptor 2 in hair follicle melanocyte lineage blocks the Smad2 phosphorylation, resulting in a loss of quiescence state of McSCs.

TGF-β binds TGF-β receptors in melanocytes, leading to the phosphorylation of downstream effector Smad2, which inhibits melanocyte growth and melanogenesis through downregulating PAX3 and MITF transcription xref , xref .

Inhibition of Wnt signaling by a Wnt antagonist secreted frizzled-related protein 4 (sFRP4), which is exclusively expressed in the epithelial cells but not the melanocytes of the hair follicle, results in a decrease of melanocytes differentiation in the regenerating hair follicle xref .

Through interacting with PAX3, FOXD3 prevents binding of PAX3 to MITF promoter to repress melanogenesis in zebrafish, quail and chick neural crest cells xref , xref , suggesting that down-regulation of Foxd3 is a crucial step during the early phase of melanoblast lineage specification from neural crest cells.

In human melanoma cells, MITF also interacts directly with β-catenin and redirects β-catenin transcriptional activity away from target genes regulated by Wnt/β-catenin signaling, toward MITF-specific target promoters to activate transcription xref .

TGF-β binds TGF-β receptors in melanocytes, leading to the phosphorylation of downstream effector Smad2, which inhibits melanocyte growth and melanogenesis through downregulating PAX3 and MITF transcription xref , xref .

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 .

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 .

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.

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

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

We found that p-Y42 RhoA also readily translocated to the nucleus, similarly to β-catenin, upon Wnt3A signaling ( xref A).

However, the mechanism by which p -Tyr42 RhoA translocates to the nucleus remains elusive.

We next tried to identify whether GDP/GTP-bound states of RhoA determine the interaction between RhoA and β-catenin.

Recombinant GST-β-catenin binding to RhoA-GTPγS or RhoA-GDP in vitro was not significantly different, suggesting that GDP or GTP binding to RhoA is not critical for regulating interaction between RhoA with β-catenin ( xref D).

To identify the specific domain of β-catenin associating with RhoA, we expressed and purified GST-fusions of β-catenin domains composed of amino acids (aa) 1–140, 141–390, 391–662 and 663–782 ( xref E and F).

Similarly, GST-RhoA phosphorylated by Src and ATP [ xref ] also readily bound to β-catenin in vitro , irrespective of GDP- or GTPγS-preloaded RhoA, suggesting that phosphorylation of Tyr42, but not GTP/GDP-binding state is critical for interaction between RhoA and β-catenin ( xref D).

The 3D of RhoA revealed Tyr42 residue positioning in extended β2 region did not dramatically alter 3D location, while Tyr34 in switch 1 (aa 28–38) and Tyr66 in switch 2 (aa 61–78) regions revealed significant alteration [ xref ] ( xref E), suggesting that GDP or GTP may not contribute p -Tyr42 RhoA binding to β-catenin.

Interaction of p -Tyr42 RhoA with β-catenin.

Also, RhoA preferentially binds to N -terminal domain (NTD: aa 1–140) of β-catenin ( xref G).

It is remarkable that RhoA Y42F (dephospho-mimetic) did not interfere with β-catenin accumulation ( xref A), but RhoA Y42F could not bind to β-catenin ( xref B and 5C).

Since expression of vimentin can be also induced by β-catenin [ xref ], we speculate p -Tyr42 RhoA binding to β-catenin facilitate vimentin expression.

Meanwhile, p -Tyr42 RhoA bound to β-catenin via the N -terminal domain of β-catenin, thereby leading to the nuclear translocation of p -Tyr42 RhoA/β-catenin complex.

In this study, we found that Wnt3A induces interaction of p -Tyr42 RhoA and β-catenin and p -Tyr42 RhoA delivers β-catenin to the nucleus, where p -Tyr42 RhoA as well as β-catenin regulates expression of specific genes such as Vim by binding to Vim promoter.

In addition, it was demonstrated that p -Tyr42 RhoA directly interact with β-catenin and nuclear localization of p -Tyr42 RhoA is required for nuclear delivery of β-catenin.

Of note, β-catenin binds to Lef1 and activates Lef1 transcription complex, leading to down-regulation of E -cadherin expression [ xref ].

p -Tyr42 Rho binds to promoters of specific genes such as Vim.

In this study, as a novel mechanism, p -Tyr42 RhoA binds to promoter of Vim and regulates vimentin expression, suggesting that p -Tyr42 RhoA regulates EMT ( xref ).

Notably, p -Tyr42 RhoA as well as β-catenin was associated with the promoter of Vim , leading to increased expression of vimentin.

Notably, p -Tyr42 RhoA preferentially bound to ROCK2, which in turn preferentially bound to p47phox, leading Ser345 phosphorylation of p47phox ( xref H and xref ).

It is notable that IKKγ (also known as NEMO) facilitates RhoA activation via IKKγ (NEMO) causing the dissociation of the RhoA-RhoGDI complex [ xref ].

GST-RhoA WT, Y42E and Y42F preloaded with GDP or GTPγS were incubated recombinant purified β-catenin in vitro .

Similarly, GST-RhoA phosphorylated by Src and ATP [ xref ] also readily bound to β-catenin in vitro , irrespective of GDP- or GTPγS-preloaded RhoA, suggesting that phosphorylation of Tyr42, but not GTP/GDP-binding state is critical for interaction between RhoA and β-catenin ( xref D).

Recombinant GST-β-catenin binding to RhoA-GTPγS or RhoA-GDP in vitro was not significantly different, suggesting that GDP or GTP binding to RhoA is not critical for regulating interaction between RhoA with β-catenin ( xref D).

RhoA preloaded with GTPγS readily bound to aa 1–140 NTD of GST-β-catenin domain, conjugated to beads, whereas other domain fusion proteins only marginally bound to RhoA ( xref G).

The results suggest that ROCK2 is a preferential downstream effector protein of p -Tyr42 RhoA while ROCK1 is activated dominantly by RhoA ( xref J).

Of note, β-catenin binds to Lef1 and activates Lef1 transcription complex, leading to down-regulation of E -cadherin expression [ xref ].

Of note, vimentin can activate RhoA through GEF-H1 (also known as ARHGEF2) [ xref ].

Thereby, it is possible that p -Tyr42 RhoA GTPase causes the acetylation of β-catenin through p300 acetyltransferase, remarkably enhancing β-catenin activity as a co-activator of TCF4 in the nucleus.

RhoA GTPase phosphorylated at tyrosine 42 by src kinase binds to β-catenin and contributes transcriptional regulation of vimentin upon Wnt3A.

Meanwhile, p-Tyr42 RhoA bound to β-catenin via the N-terminal domain of β-catenin, thereby leading to the nuclear translocation of p-Tyr42 RhoA/β-catenin complex.

Notably, p-Tyr42 RhoA as well as β-catenin was associated with the promoter of Vim, leading to increased expression of vimentin.

As shown in supplemental xref , treatment of cardiac fibroblasts with Ad-KLK8 induced mRNA expression of the proliferation-related genes Ki67, proliferating cell nuclear antigen (PCNA) and cyclin D1 xref .

The HIF-1α inhibitor echinomycin not only inhibited basal TGF-β1 expression, but also blocked KLK8-induced TGF-β1 mRNA expression and release in HCAECs (Figure xref D).

However, ICG-001 treatment had no significant effect on KLK8-induced TGF-β1 expression ( xref F).

As shown in supplemental xref , treatment of cardiac fibroblasts with Ad-KLK8 induced mRNA expression of the proliferation-related genes Ki67, proliferating cell nuclear antigen (PCNA) and cyclin D1 xref .

The HIF-1α inhibitor echinomycin not only inhibited basal TGF-β1 expression, but also blocked KLK8-induced TGF-β1 mRNA expression and release in HCAECs (Figure xref D).

The present study found that Ad-KLK8 infection resulted in a 2.88 ± 0.35 fold increase in the content of bradykinin in the culture medium of HCAECs.

In HCAECs, it was found that Ad-KLK8 increased the expression levels of α-SMA and vimentin, whereas it decreased the expression levels of CD31 and VE-cadherin, in a dose-dependent manner, suggesting that KLK8 overexpression is able to induce EndMT (Figure xref E-F).

In addition, the permeability of a confluent HCAEC monolayer was measured for 10-kDa FITC-dextran, and it was found that Ad-KLK8 treatment significantly increased endothelial permeability (Figure xref L).

Infection of HCAECs with increasing concentrations of KLK8 adenovirus (Ad-KLK8) led to an increase in KLK8 expression in a dose-dependent manner ( xref ).

As shown in supplemental xref , treatment of cardiac fibroblasts with Ad-KLK8 induced mRNA expression of the proliferation-related genes Ki67, proliferating cell nuclear antigen (PCNA) and cyclin D1 xref .

The present study then examined the composition of the endothelial cell culture medium after cell transfection with Ad-KLK8.

Adenovirus-mediated overexpression of KLK8 (Ad-KLK8) resulted in increases in endothelial cell damage, permeability and transforming growth factor (TGF)-β1 release in HCAECs.

The present study found that KLK8 overexpression significantly increased the association of p53 with Smad3, which was blocked by plakoglobin knockdown (Figure xref F).

KLK8 also induced the binding of p53 with Smad3, subsequently promoting pro-EndMT reprogramming via the TGF-β1/Smad signaling pathway in HCAECs.

Previous study has found that plakoglobin interacts with p53 and increases its transcriptional activity, thereby regulating the expression of various genes involved in tumorigenesis and metastasis xref .

The association of plakoglobin with p53 in diabetic heart tissues was decreased in KLK8 -/- mice (Figure xref F).

As shown in Figure xref A, it was found that high glucose led to a significant increase in the association of plakoglobin with p53, which was blocked by KLK8 knockdown.

Diabetes mellitus increased the association of p53 with both HIF-1α and Smad3 in heart tissues, which was attenuated in KLK8 -/- mice (Figure xref F).

In addition, high glucose induced p53 binding to both HIF-1α and Smad3, which was blocked by siRNA targeting KLK8 and plakoglobin (Figure xref A-B).

The present study found that upregulation of KLK8 leads to plakoglobin-dependent nuclear translocation of p53, which binds to HIF-1α, and further enhances the transactivation effect of HIF-1α on the TGF-β1 promoter and consequently upregulates TGF-β1 expression at the transcriptional level.

Altogether, these data suggest that upregulation of KLK8 leads to plakoglobin-dependent association of p53 with HIF-1α, which further enhances the transactive effect of HIF-1α on the TGF-β1 promoter.

KLK8 overexpression induced the association of p53 with HIF-1α, which was blocked by plakoglobin knockdown (Figure xref F).

Using ChIP analysis, it was found that high glucose treatment led to a significant increase in the binding of HIF-1α to the TGF-β1 promoter, which was largely blocked in the presence of KLK8 siRNA, plakoglobin siRNA (Figure xref C) or the p53 inhibitor pifithrin-α (Figure xref D).

Using ChIP analysis, the present study confirmed the binding of HIF-1α to the TGF-β1 promoter, which was significantly enhanced by KLK8 overexpression (Figure xref E).

KLK8 overexpression led to a significant increase in the association of plakoglobin with both p53 and TCF-4 (Figure xref C).

The present study found that plakoglobin was associated with p53 and TCF-4 in HCAECs (Figure xref C).

Notably, although KLK8 overexpression led to a significant increase in the association of plakoglobin with both p53 and TCF-4, KLK8-induced EndMT was reduced only by a p53 inhibitor, but not by the inhibitor of β-catenin/TCF-mediated transcription.

In addition, KLK8-induced p53 activation promoted the pro-fibrotic reprogramming by TGF-β1 via the cooperation of p53 with Smads in endothelial cells.

In addition, p300-CREB-binding protein (CBP) has been shown to acetylate PTEN at Lys 402 in the PDZ-binding motif.

In addition, p300-CREB-binding protein (CBP) has been shown to acetylate PTEN at Lys 402 in the PDZ-binding motif.

Functionally, our findings confirmed that inhibition of PTEN by PTEN siRNA or specific inhibitor not only ameliorated secondary hippocampal injury but also promoted hippocampal-dependent cognition and memory recovery, suggesting important neuroprotective effects against hemorrhagic insults.

Functionally, our findings confirmed that inhibition of PTEN by PTEN siRNA or specific inhibitor not only ameliorated secondary hippocampal injury but also promoted hippocampal-dependent cognition and memory recovery, suggesting important neuroprotective effects against hemorrhagic insults.

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).

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).

The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive xref .

In another study, the heat shock-like protein Clusterin was shown to increase AKT2 activity and promote the motility of both normal and malignant prostate cells via an inhibitory activity on PTEN-S380 phosphorylation and consequent inactivation of PTEN xref .

Another study demonstrated that phosphorylation of PTEN on tyrosine 240 by FGFR2 promotes chromatin binding through an interaction with Ki-67, which facilitates the recruitment of RAD51 to promote DNA repair xref . xref summarises these novel functions and signalling axes of nuclear PTEN.

It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma xref .

Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation xref , thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

The precise mechanism of how LASP1 promotes PTEN ubiquitination still remains elusive xref .

In another study, the heat shock-like protein Clusterin was shown to increase AKT2 activity and promote the motility of both normal and malignant prostate cells via an inhibitory activity on PTEN-S380 phosphorylation and consequent inactivation of PTEN xref .

Another study demonstrated that phosphorylation of PTEN on tyrosine 240 by FGFR2 promotes chromatin binding through an interaction with Ki-67, which facilitates the recruitment of RAD51 to promote DNA repair xref . xref summarises these novel functions and signalling axes of nuclear PTEN.

It was reported that PTEN could dephosphorylate PGK1, a glycolytic enzyme and protein kinase with a tumorigenic role in glioblastoma xref .

Dephosphorylation of PGK1 by PTEN was found to inhibit its activity, downstream glycolytic functions, and glioblastoma cell proliferation xref , thereby presenting another mechanism in which PTEN functions as a tumour suppressor.

The kinase activity of TAK1 leads to phosphorylation events that activate AP-1 and NF-κB. In parallel to cIAP-induced ubiquitination of RIPK2, XIAP’s enzymatic activity results in the formation of polyubiquitin chains on RIPK2, serving as a platform to engage another E3 ligase complex known as the Linear Ubiquitin Assembly Complex (LUBAC) ( xref , xref ).

K63-linked ubiquitination of RIPK2 has been established as a means to construct protein scaffolds that transduce downstream signaling.

In a step-wise fashion, ubiquitination of RIPK2 leads to activation and recruitment of the TAK1 complex, consisting of TAK1 in association with TAK1-binding protein (TAB)2 and 3.

Despite this focus, much of the nature of the NOD1 and 2 interaction with these structures remains unknown, although recent findings suggest that NOD2 directly binds MDP with high affinity ( xref ), with the N-glycosylated form specific to the mycobacterial cell wall triggering an exceptionally strong immunogenic response compared to N-acetyl MDP ( xref ).

Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome ( xref ).

While this mechanism is still poorly understood, the ability of NLRP10 to interact with NOD1 as well as its signaling targets RIPK2, TAK1, and NEMO, suggests that NLRP10 may be involved in optimizing cytokine release following bacterial infections.

Few ligands have been found for NLRP1 to date, and include bacterial products such as lethal toxin (LT) produced by Bacillus anthracis which activates murine NLRP1b ( xref ), muramyl dipeptide (MDP), a component of bacterial peptidoglycan that activates human NLRP1; and reduced levels of cytosolic ATP ( xref – xref ).

Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome ( xref ).

The kinase activity of TAK1 leads to phosphorylation events that activate AP-1 and NF-κB. In parallel to cIAP-induced ubiquitination of RIPK2, XIAP’s enzymatic activity results in the formation of polyubiquitin chains on RIPK2, serving as a platform to engage another E3 ligase complex known as the Linear Ubiquitin Assembly Complex (LUBAC) ( xref , xref ).

K63-linked ubiquitination of RIPK2 has been established as a means to construct protein scaffolds that transduce downstream signaling.

In a step-wise fashion, ubiquitination of RIPK2 leads to activation and recruitment of the TAK1 complex, consisting of TAK1 in association with TAK1-binding protein (TAB)2 and 3.

Despite this focus, much of the nature of the NOD1 and 2 interaction with these structures remains unknown, although recent findings suggest that NOD2 directly binds MDP with high affinity ( xref ), with the N-glycosylated form specific to the mycobacterial cell wall triggering an exceptionally strong immunogenic response compared to N-acetyl MDP ( xref ).

Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome ( xref ).

While this mechanism is still poorly understood, the ability of NLRP10 to interact with NOD1 as well as its signaling targets RIPK2, TAK1, and NEMO, suggests that NLRP10 may be involved in optimizing cytokine release following bacterial infections.

Few ligands have been found for NLRP1 to date, and include bacterial products such as lethal toxin (LT) produced by Bacillus anthracis which activates murine NLRP1b ( xref ), muramyl dipeptide (MDP), a component of bacterial peptidoglycan that activates human NLRP1; and reduced levels of cytosolic ATP ( xref – xref ).

Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome ( xref ).

Similarly, a clinical case with low baseline PSMA avidity demonstrated increased uptake of 68 Ga-PSMA after enzalutamide on PET/CT and post-therapeutic 177 Lu-PSMA scintigraphy in a patient with mCRPC.

Therefore, enzalutamide pre-treatment might render patients with low PSMA expression eligible for 177 Lu-PSMA RLT.

Positron emission tomography/computed tomography (PET/CT) demonstrated higher tumor uptake of 68 Ga-PSMA after enzalutamide treatment ( p = 0.004).

Similarly, a clinical case with low baseline PSMA avidity demonstrated increased uptake of 68 Ga-PSMA after enzalutamide on PET/CT and post-therapeutic 177 Lu-PSMA scintigraphy in a patient with mCRPC.

Mutations in the TrkA gene cause a related disorder, HSAN IV, which produces a phenotype similar to HSAN V. xref These TrkA gene mutations result in defective binding of NGF to TrkA and, as a result, the inhibition of NGF-induced TrkA phosphorylation and downstream signaling cascades. xref

Upon binding of NGF to the extracellular region of TrkA, the receptor dimerizes, autophosphorylates, and initiates signaling events by docking and phosphorylating downstream targets. xref – xref The NGF-TrkA complex is internalized into endosomes where it can be retrogradely transported, recycled, or degraded. xref Immediate pro-nociceptive effects resulting from NGF/TrkA signaling (such as modulation of ion channel activity) occur in the peripheral nociceptor terminal, while longer-term effects (such as modification of gene expression) occur in the soma following retrograde axonal transport of the NGF/TrkA complex to the DRG. xref , xref Three major signaling cascades initiated by TrkA activation include the phospholipase C-γ (PLCγ) pathway, the mitogen-activated protein kinase (MAPK)/Erk pathway, and the phosphoinositide 3-kinase (PI3K) pathway. xref

NGF null mice have a severe loss of sympathetic and sensory neurons, particularly in the population of peptidergic small- and medium-diameter DRG neurons. xref Animals lacking TrkA receptors show a phenotype similar to NGF null mice, underscoring the importance of NGF-TrkA signaling for the development of the nociceptive system. xref , xref

Mutations in the TrkA gene cause a related disorder, HSAN IV, which produces a phenotype similar to HSAN V. xref These TrkA gene mutations result in defective binding of NGF to TrkA and, as a result, the inhibition of NGF-induced TrkA phosphorylation and downstream signaling cascades. xref

In cultured rodent DRG neurons, for example, Nav1.7 activation is increased via Erk1/2 signaling, and activation of p38 MAPK can directly phosphorylate Nav1.8 leading to an increase in Nav1.8 current density in DRG neurons. xref , xref However, whether these changes to sodium channel activation properties occur downstream of NGF-TrkA signaling, or as part of other signaling pathways, was not explored in these studies.

While numerous studies have demonstrated a role for NGF-TrkA signaling in the modulation of nociceptive ion channel activity, there is also evidence that NGF-p75NTR signaling can contribute to sensory neuron excitability. xref , xref - xref For example, NGF-mediated activation of p75NTR has been shown to increase ceramide levels in a TrkA-independent manner in cell culture, and studies in rodents have shown that ceramide likely mediates NGF-induced sensitization of isolated sensory neurons in vitro and possibly NGF-induced pain-related behaviors in vivo. xref , xref , xref

While numerous studies have demonstrated a role for NGF-TrkA signaling in the modulation of nociceptive ion channel activity, there is also evidence that NGF-p75NTR signaling can contribute to sensory neuron excitability. xref , xref - xref For example, NGF-mediated activation of p75NTR has been shown to increase ceramide levels in a TrkA-independent manner in cell culture, and studies in rodents have shown that ceramide likely mediates NGF-induced sensitization of isolated sensory neurons in vitro and possibly NGF-induced pain-related behaviors in vivo. xref , xref , xref

Mutations in the TrkA gene cause a related disorder, HSAN IV, which produces a phenotype similar to HSAN V. xref These TrkA gene mutations result in defective binding of NGF to TrkA and, as a result, the inhibition of NGF-induced TrkA phosphorylation and downstream signaling cascades. xref

Upon binding of NGF to the extracellular region of TrkA, the receptor dimerizes, autophosphorylates, and initiates signaling events by docking and phosphorylating downstream targets. xref – xref The NGF-TrkA complex is internalized into endosomes where it can be retrogradely transported, recycled, or degraded. xref Immediate pro-nociceptive effects resulting from NGF/TrkA signaling (such as modulation of ion channel activity) occur in the peripheral nociceptor terminal, while longer-term effects (such as modification of gene expression) occur in the soma following retrograde axonal transport of the NGF/TrkA complex to the DRG. xref , xref Three major signaling cascades initiated by TrkA activation include the phospholipase C-γ (PLCγ) pathway, the mitogen-activated protein kinase (MAPK)/Erk pathway, and the phosphoinositide 3-kinase (PI3K) pathway. xref

NGF null mice have a severe loss of sympathetic and sensory neurons, particularly in the population of peptidergic small- and medium-diameter DRG neurons. xref Animals lacking TrkA receptors show a phenotype similar to NGF null mice, underscoring the importance of NGF-TrkA signaling for the development of the nociceptive system. xref , xref

This is associated with higher melanocyte apoptosis and production of pro-inflammatory cytokines IL-6 and TNF-α in vitiligo ( xref ).

Thus, while self-reactive T cells are present in the periphery, their TCR interactions with peptide-MHC Class I complex are insufficient to mediate activation.

Thus, understanding the mechanisms that regulate NKG2DL expression on stressed melanocytes can lead to development of therapeutic approaches targeting the interactions of NKG2D + self-reactive CD8 T cells with melanocytes in vitiligo.

Corroborating this study, a reduction in phosphorylated forms of ERK1/2 and p38 has been reported in an experimental rat model of autoimmune myocarditis study upon treatment with quercetin [ xref ].

An interesting study showed that quercetin and honokiol inhibited cytosolic PLA2 phosphorylation and activation in differentiated SH-SY5Y neuroblastoma cells [ xref ].

Studying various immune cell models (RAW264.7 macrophages and bone marrow-derived macrophages, HMC-1 human mast cells, mouse BV-2 microglia and HUVECs) the inhibitory effects of quercetin on NFκB activation has been reported, including a reduction in nuclear translocation of p50 and p65 subunits, an inhibition of the phosphorylation of IκBα and their consequent degradation, and a blockage of the IKK activation.

For example, quercetin has been shown to interfere with the phosphorylation and activation of JNK on LPS-treated RAW 264.7 macrophages, thus preventing the activator protein 1 (AP-1) from binding to ADN, and inhibiting TNFα transcription [ xref ].

A novel point for cellular control for polyphenols is secondary to their ability to modulate modular epigenetic mechanisms such as DNA methylation, histone modifications and posttranscriptional regulation by microRNAs, modulating the activation and differentiation of immune cells.

SLE represents an AID of epigenetic origin characterized by the deterioration of T-cell DNA methylation.

Epigenetic mechanisms (DNA methylation, histone acetylation, microRNAs), in the influence of environmental factors, affect the prevalence of many AIDs.

Different factors, such as genetic factors (CD25, STAT4), epigenetic factors (DNA methylation, histone modifications) and environmental factors (xenobiotics, drugs, hormones) trigger autoimmunity.

Curcumin has also been reported to reactivate the neprilysin gene (a strong inhibitor of Akt) through CpG demethylation, leading to Akt inhibition and the subsequent inhibition of NFκB in mouse neuroblastoma N2a cells [ xref ].

Considering PLA 2 as the first enzyme in the AA cascade, it has been evidenced the inhibitory capabilities by polyphenols such as quercetin, kaempferol, and galangin, as well as some anthocyanidins (cyanidin, delphinidin malvidin, peonidin and petunidin) [ xref – xref ] Catechol (1,2-dihydroxybenzen) binds to PLA2 preventing the substrate from entering into the active site [ xref ].

Polyphenols activate intracellular pathways such as arachidonic acid dependent pathway, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathway, mitogen-activated protein kinases (MAPKs) pathway, phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway and epigenetic modulation, which regulate the host’s immune response.

In addition, several other polyphenols, such as quercetin, curcumin, myricetin and fisetin also activate SIRT1 [ xref – xref ].

Epigenetic mechanisms (DNA methylation, histone acetylation, microRNAs), in the influence of environmental factors, affect the prevalence of many AIDs.

Knockout of TGF-β receptor 2 in hair follicle melanocyte lineage blocks the Smad2 phosphorylation, resulting in a loss of quiescence state of McSCs.

TGF-β binds TGF-β receptors in melanocytes, leading to the phosphorylation of downstream effector Smad2, which inhibits melanocyte growth and melanogenesis through downregulating PAX3 and MITF transcription xref , xref .

Inhibition of Wnt signaling by a Wnt antagonist secreted frizzled-related protein 4 (sFRP4), which is exclusively expressed in the epithelial cells but not the melanocytes of the hair follicle, results in a decrease of melanocytes differentiation in the regenerating hair follicle xref .

Through interacting with PAX3, FOXD3 prevents binding of PAX3 to MITF promoter to repress melanogenesis in zebrafish, quail and chick neural crest cells xref , xref , suggesting that down-regulation of Foxd3 is a crucial step during the early phase of melanoblast lineage specification from neural crest cells.

In human melanoma cells, MITF also interacts directly with β-catenin and redirects β-catenin transcriptional activity away from target genes regulated by Wnt/β-catenin signaling, toward MITF-specific target promoters to activate transcription xref .

TGF-β binds TGF-β receptors in melanocytes, leading to the phosphorylation of downstream effector Smad2, which inhibits melanocyte growth and melanogenesis through downregulating PAX3 and MITF transcription xref , xref .

TRPA1 proline hydroxylation analogously mediates changes in TRPA1 cold sensitivity in response to intracellular oxygen concentrations [ xref ].

Conversely, factors that suppress TRPV3 activity include oxygen-dependent hydroxylation of TRPV3 by Factor-inhibiting-hypoxia inducible factor [ xref ].

These electrophiles activate TRPA1 by covalent modification of specific cysteine residues located in the channel’s cytoplasmic N-terminus.

At least part of the acute pain component in the former model is attributable to activation of TRPA1 by streptozotocin-generated peroxynitrite [ xref ].

TRPV1 can alternatively be activated by extracellular protons, by certain small lipophilic molecules, including endogenous cannabinoid lipids such as anandamide and N-arachidonoyl dopamine [ xref ], or by a number of other chemical agonists such as 2-aminoethoxydiphenyl borate (2-APB), which had previously been recognized as a dose dependent activator and inhibitor of IP3 receptors and store-operated calcium channels [ xref ].