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Epigenetic regulation, which is characterized by reversible and heritable genetic alterations without changing DNA sequences, has recently been increasingly studied in diseases. Histone variant regulation is an essential component of epigenetic regulation. The substitution of canonical histones by histone variants profoundly alters the local chromatin structure and modulates DNA accessibility to regulatory factors, thereby exerting a pivotal influence on gene regulation and DNA damage repair. Histone H2A variants, mainly including H2A.Z, H2A.B, macroH2A, and H2A.X, are the most abundant identified variants among all histone variants with the greatest sequence diversity. Harboring varied chromatin occupancy and structures, histone H2A variants perform distinct functions in gene transcription and DNA damage repair. They are implicated in multiple pathophysiological mechanisms and the emergence of different illnesses. Cancer, embryonic development abnormalities, neurological diseases, metabolic diseases, and heart diseases have all been linked to histone H2A variant alterations. This review focuses on the functions of H2A histone variants in mammals, including H2A.Z, H2A.B, macroH2A, and H2A.X, and their current roles in various diseases. [ABSTRACT FROM AUTHOR]

Renal interstitial fibrosis (RIF) is a classic pathophysiological process of chronic kidney disease (CKD). However, the mechanisms underlying RIF remain unclear. The present study found that a novel circular RNA, cirInpp5b, might be involved in RIF by high-throughput sequencing. Subsequent experiments revealed that circInpp5b was reduced in UUO mouse kidney tissues and TGF-β1-treated proximal tubular cells. The overexpression of circInpp5b inhibited RIF in UUO mice and prevented extracellular matrix (ECM) deposition in TGF-β1-treated proximal tubular cells. Furthermore, overexpression of circInpp5b down-regulated the protein level of DDX1. Mechanistically, circInpp5b bound to the DDX1 protein and promoted its lysosomal degradation. Collectively, the findings of our study demonstrate that circInpp5b ameliorates RIF by binding to the DDX1 protein and promoting its lysosomal degradation. [ABSTRACT FROM AUTHOR]

Achieving excellent optical properties and stability is crucial for the practical utilization of perovskite emitters. Herein, ultra-stable CsPbBr3-DPSI/MS composites with a high photoluminescence quantum yield (PLQY) of 93.2% are obtained through passivation of the surface of CsPbBr3 quantum dots (QDs) by 3-(decyldimethylammonio)-propane-sulfonate inner salt (DPSI) and encapsulating these QDs using silica molecular sieve (MS) templates. After aging for 1000 hours under harsh synergistic conditions (i.e., temperature of 60 °C, relative humidity of 90%, and blue light irradiation with a power density of 3500 W m−2), these composites still retain 90% of their initial photoluminescence (PL) intensity. To the best of our knowledge, these CsPbBr3-DPSI/MS composites represent the most stable CsPbBr3 emitters in an accelerated aging test under these synergistic humidity–heat–light conditions. The liquid crystal display (LCD) backlight module utilizing these stable composites shows a wide color gamut of 111.7% NTSC. Furthermore, these CsPbBr3-DPSI/MS composites exhibit exceptional X-ray scintillator performance and impressive radiation hardness, delivering a high X-ray imaging spatial resolution of up to ≈16 lp mm−1 and a low detection limit of 339 nGyair s−1. [ABSTRACT FROM AUTHOR]

Severe renal impairment is a common complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and is associated with poor prognosis and shorter survival. It is urgent to find effective treatments to improve the prognosis of AAV patients. This study was designed to assess the efficacy and safety of protein A immunoadsorption (PAIA) and therapeutic plasma exchange (TPE) for AAV with severe renal involvement. A total of 48 AAV patients with renal involvement admitted to the Second Xiangya Hospital from January 2018 to February 2021 were selected. Clinical data, myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), remission at 6 months, and outcomes were evaluated. The primary outcomes of interest were death and renal survival as defined by the occurrence of end-stage renal disease (ESRD). PAIA was effective in the removal of MPO-ANCA and IgG, and showed superior over TPE in the clearance of MPO-ANCA within 1 month after treatment. After a median follow-up of 14.5 months, PAIA therapy showed an advantage in reducing mortality over TPE. There was no difference in the development of ESRD between the two groups. Multivariate Cox regression analysis indicated that higher serum creatinine (SCr) and lower haemoglobin level were independent risks of ESRD. Age > 60, lower serum albumin (ALB), and failure to achieve remission at 6 months were independent risks of death. PAIA treatment reduces MPO-ANCA and IgG as well as mortality in AAV patients, and may be beneficial for severe AAV in clinical practice. Higher SCr, lower serum ALB or haemoglobin levels, age > 60, and failure to achieve remission at 6 months independently predict the ESRD or death of AAV patients with severe renal involvement. Compared with therapeutic plasma exchange, protein A immunoadsorption treatment eliminates myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) and IgG better and reduces mortality in ANCA-associated vasculitis (AAV) patients with severe renal involvement. Higher serum creatinine, lower serum albumin or haemoglobin levels, age > 60, and failure to achieve remission at 6 months independently predict the end-stage renal disease (ESRD) or death of AAV patients with severe renal involvement. [ABSTRACT FROM AUTHOR]

Bowman's capsule rupture (BCR) is a glomerular pathological change, but it is still not well recognized in immunoglobulin A vasculitis nephritis (IgAV-N). The Oxford MEST-C score is a classification for IgA nephropathy; however, its clinical correlation and prognostic value in adult patients with IgAV-N are unclear. A retrospective study of 145 adult patients with IgAV-N diagnosed by renal biopsy was conducted. Clinical manifestations, pathological changes and the prognosis of IgAV-N patients were compared depending on the presence or absence of BCR, International Study of Kidney Disease in Children (ISKDC) classification and MEST-C score. The primary endpoint events were end-stage renal disease, renal replacement therapy and all-cause death. In total, 51 of 145 (35.17%) patients with IgAV-N presented with BCR. Patients with BCR had more proteinuria, lower serum albumin, and more crescents. Compared with IgAV-N patients with crescents only, 51/100 patients with crescents combined with BCR had a higher proportion of crescents in all glomeruli (15.79% vs. 9.09%; p = 0.003). Patients with higher ISKDC grades had more severe clinical presentation, but it did not reflect the prognosis. However, the MEST-C score not only reflected clinical manifestations but also predicted prognosis (p < 0.05). BCR contributed to the effectiveness of the MEST-C score in predicting the prognosis of IgAV-N (C-index: 0.845 to 0.855). BCR is associated with clinical manifestations and pathological changes in patients with IgAV-N. The ISKDC classification and MEST-C score are related to the patient's condition, but only the MEST-C score is correlated with the prognosis of patients with IgAV-N, while BCR can improve its predictive ability. BCR was associated with clinical manifestations and pathological changes in patients with IgAV-N, particularly crescents. The ISKDC classification was related to clinical manifestations of patients with IgAV-N, but it wasn't associated with prognosis. The Oxford MEST-C score was correlated to clinical presentations and prognosis of patients with IgAV-N, while BCR can improve its predictive ability. [ABSTRACT FROM AUTHOR]

Objectives: Conventional glucocorticoid (GC) treatment poses significant risks for opportunistic infections due to its suppressive impact on CD4+ T cells. This study aimed to explore the mechanisms by which GCs modulate the functionality of CD4+ T cells during infection. Methods: We consistently measured FOXP3, inflammatory cytokines and phospho‐S6 ribosomal protein levels in CD4+ T cells from patients undergoing conventional GC treatment. Using Foxp3EGFP animals, we investigated the dynamic activation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and its correlation with the immunoregulatory function of CD4+ T cells under the influence of GCs. Results: GCs dynamically altered the expression pattern of FOXP3 in CD4+ T cells, promoting their acquisition of an active T regulatory (Treg) cell phenotype upon stimulation. Mechanistically, GCs undermined the kinetics of the mTORC1 pathway, which was closely correlated with phenotype conversion and functional properties of CD4+ T cells. Dynamic activation of the mTORC1 signaling modified the GC‐dampened immunoregulatory capacity of CD4+ T cells by phenotypically and functionally bolstering the FOXP3+ Treg cells. Interventions targeting the mTORC1 pathway effectively modulated the GC‐dampened immunoregulatory capacity of CD4+ T cells. Conclusion: These findings highlight a novel mTORC1‐mediated mechanism underlying CD4+ T cell immunity in the context of conventional GC treatment. [ABSTRACT FROM AUTHOR]

Background: Gentamicin-induced nephrotoxicity is one of the most common causes of acute kidney injury (AKI). The phenotypic alterations that contribute to acute kidney injury include inflammatory response and oxidative stress. Curcumin has a wide range biological functions, especially as an antioxidant. This study was designed to evaluate the renoprotective effects of curcumin treatment in gentamicin-induced AKI. Methods: Gentamicin-induced AKI was established in female Sprague-Dawley rats. Rats were treated with curcumin (100 mg/kg body mass) by intragastric administration, once daily, followed with an intraperitoneal injection of gentamicin sulfate solution at a dose of 80 mg/kg body mass for 8 consecutive days. At days 3 and 8, the rats were sacrificed, and the kidneys and blood samples were collected for further analysis. Results: The animals treated with gentamicin showed marked deterioration of renal function, together with higher levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) in the plasma as compared with the controls. Animals that underwent intermittent treatment with curcumin exhibited significant improvements in renal functional parameters. We also observed that treatment with curcumin significantly attenuated renal tubular damage, apoptosis, and oxidative stress. Curcumin treatment exerted anti-apoptosis and anti-oxidative effects by up-regulating Nrf2/HO-1 and Sirtl expression. Conclusions: Our data clearly demonstrate that curcumin protects kidney from gentamicin-induced AKI via the amelioration of oxidative stress and apoptosis of renal tubular cells, thus providing hope for the amelioration of gentamicin-induced nephrotoxicity. Key words: oxidative stress, apoptosis, Nrf2, HO-1, Sirtl. Contexte: la nephrotoxicite induite par la gentamycine est l'une des causes les plus frequentes d'insuffisance renale aigue (IRA). Les modifications phenotypiques qui contribuent a l'insuffisance renale aigue incluent la reponse inflammatoire et le stress oxydant. La curcumine possede un large spectre de fonctions biologiques, particulierement des fonctions antioxydantes. Cette etude a ete concue afin d'evaluer les effets protecteurs d'un traitement a la curcumine dans l'IRA induite par la gentamycine. Methodes : l'IRA induite par la gentamycine a ete provoquee chez des rats Sprague-Dawley femelles. Les rats ont ete traites quotidiennement a la curcumine, 100 mg/kg de poids corporel, par voie intra-gastrique, et au sulfate de gentamycine, 80 mg/kg de poids corporel, par voie intra-peritoneale, pendant 8 jours consecutifs. Aux jours 3 et 8, des rats ont ete sacrifies, et les reins et des echantillons sanguins ont ete preleves pour analyse subsequente. Resultats : les animaux ayant recu de la gentamycine presentaient une deterioration marquee de la fonction renale, accompagnee de niveaux plus eleves de NGAL (' neutrophil gelatinase-associated lipocalin ') et de KIM-1 (' kidney injury molecule-1 ') dans le plasma, comparativement aux controles. Les animaux exposes de facon intermittente a la curcumine presentaient des ameliorations significatives sur le plan des parametres de la fonction renale. Les auteurs ont aussi observe que le traitement a la curcumine attenuait significativement le dommage tubulaire renal, l'apoptose et le stress oxydant. Le traitement a la curcumine exercait des effets anti-apoptose et antioxydants en regulant a la hausse l'expression de Nrf2/HO-1 et Sirt1. Conclusions : ces donnees demontrent clairement que la curcumine protege le rein de l'IRA induite par la gentamycine en attenuant le stress oxydant et l'apoptose dans les cellules tubulaires renales, suscitant ainsi un espoir d'amelioration de la nephro-toxicite induite par la gentamycine. [Traduit par la Redaction] Mots-cles : stress oxydant, apoptose, Nrf2, HO-1, Sirt1., Introduction Over the past 2 decades there have been rapidly increasing numbers of reports of incidences of acute kidney injury (AKI), highlighting advanced kidney disease as a growing contribution to [...]

The structure of CsPbI3 nanocrystals (NCs) with excellent photoelectric properties easily collapses, which hinders their application in light-emitting diodes (LEDs). Herein, we accomplished the synthesis of efficient and stable CsPbI3 NCs by regulating structural rigidity under the synergistic effect of Mg2+ and AcO− ions. The introduced AcO− and Mg2+ ions increase surface steric hindrance and defect formation energy, which enhances the structural rigidity of the perovskite. As a result, the CsPbI3 NCs display an outstanding photoluminescence quantum yield of 95.7%, in conjunction with reduced defect state density, balanced carrier injection, and distinguished conductivity. Remarkably, the modified CsPbI3 NCs exhibit excellent stability under ambient conditions for 180 days and can even survive when the temperature reaches 150 °C. Given their enhanced structural rigidity, LEDs made from these modified CsPbI3 NCs exhibit a maximum luminance and an EQE of 3281 cd m−2 and 13.2%, respectively, which are significantly improved compared with those of unmodified CsPbI3 NC LEDs. [ABSTRACT FROM AUTHOR]

Background Acute kidney injury (AKI) is a public health problem with no specific therapies in the clinic and the underlying pathogenesis of AKI remains obscure. Bombesin receptor-activated protein (BRAP, C6ORF89 protein) was initially discovered as a ligand for a previously orphan G-protein-coupled receptor bombesin-like receptor-3. At present, accepted biological effects of BRAP include cell cycle progression, wound repair and the activation of histone deacetylases. However, its role in kidney disease is unknown. In this study we have investigated the role of BRAP and underlying mechanisms involved in cisplatin (CP)-induced AKI. Methods Here we used Bc004004 (homologous of C6ORF89 in mice) knockout mice and HK2 cells to investigate the effect of BRAP on AKI in vitro and in vivo. We analyzed ChIP-Seq and RNA-Seq data to search for the upstream regulators of BRAP and downstream mediators of BRAP action in AKI. Immunostaining, real-time polymerase chain reaction (PCR), co-immunoprecipitation, a dual-luciferase reporter assay and ChIP-PCR assay were applied to reveal the upstream and downstream regulation mechanism of BRAP during cisplatin-induced AKI. Results BRAP was downregulated in mice and human kidneys with AKI. Global Bc004004 deletion alleviated tubular cell apoptosis and necroptosis in CP-induced AKI mice, whereas local overexpression of BRAP in kidneys aggravated them. Pan-caspase inhibitor Z-VAD pretreatment attenuated CP-induced blood creatinine increase and kidney injury in wild-type mice but not in BRAP -/- mice. The activation of mixed lineage kinase like-domain was magnified by Z-VAD in CP-treated mice, especially in BRAP -/- mice. The cytoprotective effect of Z-VAD was more substantial than necrostatin-1 (Nec-1, an inhibitor of necroptosis) in CP-treated human kidney proximal tubular epithelial (HK2) cells. Furthermore, Nec-1 pretreatment reduced the CP-induced cell death in BRAP overexpression HK2 cells but did not work in cells with normal BRAP levels. We determined that CP treatment activated the nuclear factor-κB subunit P65 and inhibition of P65 increased the messenger RNA (mRNA) levels of BRAP in HK2 cells. The chromatin immunoprecipitation assay and dual-luciferase reporter gene assay verified P65 binding to the C6ORF89 promoter and reduced its mRNA expression upon CP treatment. Next we found that sirtuin 2 (SIRT2) was downregulated in CP-induced AKI and BRAP levels directly impacted the protein levels of SIRT2. Our findings further confirmed that BRAP regulates the SIRT2 protein levels by affecting SIRT2's interactions with E3 ubiquitin ligase HRD1 and subsequent proteasomal degradation. Conclusions Our results demonstrated that BRAP played an important role in tubular cell apoptosis and necroptosis during CP-induced AKI. Safe and efficient BRAP inhibitors might be effective therapeutic options for AKI. [ABSTRACT FROM AUTHOR]

Mutations in PARKIN, pten-induced putative kinase 1 (PINK1), and DJ-1 are individually linked to autosomal recessive early-onset familial forms of Parkinson disease (PD). Although mutations in these genes lead to the same disease state, the functional relationships between them and how their respective disease-associated mutations cause PD are largely unknown. Here, we show that Parkin, PINK1, and DJ-1 formed a complex (termed PPD complex) to promote ubiquitination and degradation of Parkin substrates, including Parkin itself and Synphilin-1 in neuroblastoma cells and human brain lysates. Genetic ablation of either Pink1 or Dj-1 resulted in reduced ubiquitination of endogenous Parkin as well as decreased degradation and increased accumulation of aberrantly expressed Parkin substrates. Expression of PINK1 enhanced Parkin-mediated degradation of heat shock--induced misfolded protein. In contrast, PD-pathogenic Parkin and PINK1 mutations showed reduced ability to promote degradation of Parkin substrates. This study identified a functional ubiquitin E3 ligase complex consisting of PD-associated Parkin, PINK1, and DJ-1 to promote degradation of un-/misfolded proteins and suggests that their PD-pathogenic mutations impair E3 ligase activity of the complex, which may constitute a mechanism underlying PD pathogenesis., Introduction Parkinson disease (PD) is a progressive neurodegenerative movement disorder affecting approximately 2% of the population over 65 years of age. It is pathologically characterized by pronounced loss of dopaminergic [...]

Background: Mesangial cell proliferation is the most basic pathological feature of immunoglobulin A nephropathy (IgAN); however, the specific underlying mechanism and an appropriate therapeutic strategy are yet to be unearthed. This study aimed to investigate the therapeutic effect of triptolide (TP) on IgAN and the mechanism by which TP regulates autophagy and proliferation of mesangial cells through the CARD9/p38 MAPK pathway. Methods: We established a TP‐treated IgAN mouse model and produced IgA1‐induced human mesangial cells (HMC) and divided them into control, TP, IgAN, and IgAN+TP groups. The levels of mesangial cell proliferation (PCNA, cyclin D1, cell viability, and cell cycle) and autophagy (P62, LC3 II, and autophagy flux rate) were measured, with the autophagy inhibitor 3‐Methyladenine used to explore the relationship between autophagy and proliferation. We observed CARD9 expression in renal biopsies from patients and analyzed its clinical significance. CARD9 siRNA and overexpression plasmids were constructed to investigate the changes in mesangial cell proliferation and autophagy as well as the expression of CARD9 and p‐p38 MAPK/p38 MAPK following TP treatment. Results: Administering TP was safe and effectively alleviated mesangial cell proliferation in IgAN mice. Moreover, TP inhibited IgA1‐induced HMC proliferation by promoting autophagy. The high expression of CARD9 in IgAN patients was positively correlated with the severity of HMC proliferation. CARD9/p38 MAPK was involved in the regulation of HMC autophagy and proliferation, and TP promoted autophagy to inhibit HMC proliferation by downregulating the CARD9/p38 MAPK pathway in IgAN. Conclusion: TP promotes autophagy to inhibit mesangial cell proliferation in IgAN via the CARD9/p38 MAPK pathway. [ABSTRACT FROM AUTHOR]

Flexible perovskite light‐emitting diodes (LEDs) have been highly expected to realize advanced wearable optoelectronic applications due to the excellent optoelectronic properties of perovskites. However, the poor water and oxygen stability and limited flexibility of perovskites prevent their commercialization and applications in flexible LEDs. Herein, the low‐cost and green biomass materials‐ethyl cellulose (EC) is added in the CsPbI3 nanocrystals (NCs), acting as a cross‐linker between neighboring halide octahedra through hydrogen bonds and PbO coordination bonds. It reduces the defect densities of NCs, leading to improved photoluminescence quantum yield. Simultaneously, the synergistic effect of efficient defect passivation and hydrophobic ether groups of EC significantly improve the environment stability of NCs. Additionally, the favorable flexibility of EC and cross‐linking between EC and perovskite NCs improve the deformation resistance of the perovskite layer with stable photoluminescence and negligible cracks after repeated bending. Consequently, flexible LEDs based on the EC‐passivated CsPbI3 NCs achieved a record external quantum efficiency of 12.1% and significantly enhanced operational stability. Moreover, the flexible LEDs show small luminance degradation after bending for 1000 cycles at a radius of 3 mm, and still retain high performance even after repeatedly bending at an ultrasmall bending radius of 1 mm. [ABSTRACT FROM AUTHOR]