Nuclear receptor coactivator 6 is a critical regulator of NLRP3 inflammasome activation and gouty arthritis

Transcriptional coactivators regulate the rate of gene expression in the nucleus.Nuclear receptor coactivator 6(NCOA6),a coactivator,has been implicated in embryonic development,metabolism,and cancer pathogenesis,but its role in innate immunity and inflammatory diseases remains unclear.Here,we demonstrated that NCOA6 was expressed in monocytes and macrophages and that its level was increased under proinflammatory conditions.Unexpectedly,nuclear NCOA6 was found to translocate to the cytoplasm in activated monocytes and then become incorporated into the inflammasome with NLRP3 and ASC,forming cytoplasmic specks.Mechanistically,NCOA6 associated with the ATP hydrolysis motifs in the NACHT domain of NLRP3,promoting the oligomerization of NLRP3 and ASC and thereby instigating the production of IL-1βand active caspase-1.Of note,Ncoa6 deficiency markedly inhibited NLRP3 hyperactivation caused by the Nlrp3^(R258W) gain-of-function mutation in macrophages.Genetic ablation of Ncoa6 substantially attenuated the severity of two NLRP3-dependent diseases,folic-induced acute tubular necrosis and crystal-induced arthritis,in mice.Consistent with these findings,NCOA6 was highly expressed in macrophages derived from gout patients,and NCOA6-positive macrophages were significantly enriched in gout macrophages according to the transcriptome profiling results.Conclusively,NCOA6 is a critical regulator of NLRP3 inflammasome activation and is therefore a promising target for NLRP3-dependent diseases,including gout.

Differential risk of 23 site-specific incident cancers and cancer-related mortality among patients withmetabolic dysfunction-associated fatty liver disease:a population-based cohort study with 9.7 million Korean subjects

Introduction:Although an association between metabolic dysfunctionassociated fatty liver disease(MAFLD)and cardiovascular disease or overall mortality has been reported,it is unclearwhether there is an association between MAFLD and cancer incidence or mortality.We aimed to investigate the differential risk of all-and site-specific cancer incidence and mortality according to MAFLD subgroups categorized by additional etiologies of liver disease.Methods:Using the Korean National Health Insurance Service database,we stratified the participants into three groups:(1)single-etiology MAFLD(SMAFLD)or MAFLD of pure metabolic origin;(2)mixed-etiology MAFLD(M-MAFLD)or MAFLD with additional etiological factor(s)(i.e.,concomitant liver diseases and/or heavy alcohol consumption);and(3)non-MAFLD.Hepatic steatosis and fibrosiswere defined using the fatty liver index and the BARDscore,respectively.Cox proportional hazards regression was performed to estimate the risk of cancer events.Results:Among the 9,718,182 participants,the prevalence of S-MAFLD and M-MAFLD was 29.2%and 6.7%,respectively.During the median 8.3 years of follow-up,510,330(5.3%)individuals were newly diagnosed with cancer,and 122,774(1.3%)cancer-related deaths occurred among the entire cohort.Compared with the non-MAFLD group,the risk of all-cancer incidence and mortality was slightly higher among patients in the S-MAFLD group(incidence,adjusted hazard ratio[aHR]=1.03;95%confidence interval[CI]:1.02−1.04;mortality,aHR=1.06;95%CI:1.04−1.08)and highest among patients with M-MAFLD group(incidence,aHR=1.31;95%CI:1.29−1.32;mortality,aHR=1.45;95%CI:1.42−1.48,respectively).The M-MAFLD with fibrosis group(BARD score≥2)showed the highest relative risk of all-cancer incidence(aHR=1.38,95%CI=1.36–1.39),followed by the M-MAFLD without fibrosis group(aHR=1.09,95%CI=1.06–1.11).Similar trends were observed for cancer-related mortality.Conclusions:MAFLD classification,by applying additional etiologies other than pure metabolic origin,can be used to identify a subgroup of patients with poor cancer-related outcomes.

Overcoming the obstacles of current photodynamic therapy in tumors using nanoparticles

Photodynamic therapy(PDT)has been applied in clinical treatment of tumors for a long time.However,insufficient supply of pivotal factors including photosensitizer(PS),light,and oxygen in tumor tissue dramatically reduces the therapeutic efficacy of PDT.Nanoparticles have received an influx of attention as drug carriers,and recent studies have demonstrated their promising potential to overcome the obstacles of PDT in tumor tissue.Physicochemical optimization for passive targeting,ligand modification for active targeting,and stimuli-responsive release achieved efficient delivery of PS to tumor tissue.Various trials using upconversion NPs,two-photon lasers,X-rays,and bioluminescence have provided clues for efficient methods of light delivery to deep tissue.Attempts have been made to overcome unfavorable tumor microenvironments via artificial oxygen generation,Fenton reaction,and combination with other chemical drugs.In this review,we introduce these creative approaches to addressing the hurdles facing PDT in tumors.In particular,the studies that have been validated in animal experiments are preferred in this review over proof-of-concept studies that were only performed in cells.

A novel cytokine consisting of the p40 and EBI3 subunits suppresses experimental autoimmune arthritis via reciprocal regulation of Th17 and Treg cells

OBJECTIVE:The interleukin(IL)-12 cytokine family is closely related to the development of T helper cells,which are responsible for autoimmune disease enhancement or suppression.IL-12 family members are generally heterodimers and share threeα-subunits(p35,p19,and p28)and twoβ-subunits(p40 and EBI3).However,aβ-sheet p40 homodimer has been shown to exist and antagonize IL-12 and IL-23 signaling 1.Therefore,we assumed the existence of a p40-EBI3 heterodimer in nature and sought to investigate its role in immune regulation.METHODS:The presence of the p40-EBI3 heterodimer was confirmed by ELISA,immunoprecipitation,and western blotting.A p40-EBI3 vector and p40-EBI3-Fc protein were synthesized to confirm the immunological role of this protein in mice with collageninduced arthritis(CIA).The anti-inflammatory effects of p40-EBI3 were analyzed with regard to clinical,histological,and immune cell-regulating features in mice with CIA.RESULTS:Clinical arthritis scores and the expression levels of proinflammatory cytokines(e.g.,IL-17,IL-1β,IL-6,and TNF-α)were significantly attenuated in p40-EBI3-overexpressing and p40-EBI3-Fc-treated mice with CIA compared to vehicle-treated mice with CIA.Structural joint damage and vessel formation-related gene expression were also reduced by p40-EBI3 heterodimer treatment.In vitro,the p40-EBI3-Fc protein significantly suppressed the differentiation of Th17 cells and reciprocally induced CD4+CD25+Foxp3+(regulatory T)cells.p40-EBI3 also inhibited osteoclast formation in a concentrationdependent manner.CONCLUSION:In this study,p40-EBI3 ameliorated proinflammatory conditions both in vivo and in vitro.We propose that p40-EBI3 is a novel anti-inflammatory cytokine involved in suppressing the immune response through the expansion of Treg cells and suppression of Th17 cells and osteoclastogenesis.

Lichen Planus Pigmentosus Inversus:Two Case Reports

Introduction:Lichen planus pigmentosus inversus(LPPI)is a rare a rare variant of lichen planus characterized by hyperpigmented patches with predominating localization in intertriginous areas.Due to its rarity,only a few LPPI cases are reported.We herein describe two rare cases of LPPI.Case presentation:The two patients were all with a brownish macular lesion on the intertriginous area.A diagnosis of LPPI was made based on their clinical manifestations,dermoscopic features,and histopathologic features,which revealed an interface change,lichenoid infiltration,and pigmentary incontinence.Discussion:LPPI is pruritic or asymptomatic,hyperpigmented macules and patches on the flexural folds.The axillae and flanks were the most commonly affected areas,followed by the groin and genitalia.About half of the female patients had inframammary fold lesions.LPPI shows higher female predominance than Lichen planus pigmentosus.There were fewer cases that lasted more than 3 years compared to LPP.Conclusion:LPPI is a rare variant of lichen planus,with a locational characteristic and female predominance.Therefore,in the case of a pigmented disease occurring in the flexural folds,it should be placed in the differential diagnosis.

Intracellular zinc signaling via Kruppel-like transcription factor 6 promotes HuD expression in pancreaticβcell

Dysfunction of pancreaticβcells caused by zinc deficiency is related to the pathogenesis of diabetes.1 Impaired zinc homeostasis in diabetes is associated with reduced zinc transporters.2 Down-regulation of HuD,an essential factor for normalβcell function,has been shown in diabetes.