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NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical bases of NLRP3 activation and regulation and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.The NLRP3 inflammasome mediates pro-inflammatory responses and pyroptotic cell death. Here, the authors describe the complex pathways controlling its activation and regulation and how it is being targeted to treat inflammatory diseases.

Yang Wanli, a renowned poet of the Southern Song Dynasty(1127-1279 AD), has left an indelible mark on the history of Chinese literature with his unique artistic style. He pioneered the Chengzhai Poetic Style, a unique approach characterized by simplicity, naturalness, freshness, and liveliness in poetic creation. This style marked a turning point in the development of Song poetry and exerted a profound influence on the subsequent trends of Song poetry. As such, he was hailed as a \"Leader in Poetry\" by his contemporaries. The Chengzhai Poetic Style was gradually formed during Yang's creation course, under the influence of several important factors, including the Bashu culture and its aesthetic taste represented by Zhang Jun and Zhang Shi, the Zen philosophy that emphasizes liveliness prevailing in the Shu area, and the view that the \"Chinese Yi-ology has its roots in the Shu area.\" Meanwhile, in the Collected Works of Chengzhai(Chengzhai Ji), there are many poems and essays about the Bashu area, which have provided valuable feedback to the Bashu literature and enriched its content.

Recurrence is a challenge to survival after the initial treatment of esophageal squamous cell carcinoma (ESCC). But, its mechanism remains elusive and there are currently no biomarkers to predict postoperative recurrence. Here, the possibility of sterile alpha motif domain‐containing protein 9 (SAMD9) as a predictor of postoperative recurrence of ESCC is evaluated and the molecular mechanisms by which SAMD9 promotes ESCC recurrence are elucidated. The authors found that the high level of SAMD9 is correlated with postoperative recurrence and poor prognosis of ESCC. Overexpression of SAMD9 promotes tumor stemness, angiogenesis, and EMT, while downregulation of SAMD9 reduced these phenotypes. Mechanistically, it is found that SAMD9 stimulated ubiquitination‐mediated glycogen synthase kinase‐3 beta (GSK‐3β) degradation by interaction with myosin‐9 (MYH9) and TNF receptor‐associated factor 6 (TRAF6), which in turn activated Wnt/β‐catenin pathway. Further, the authors demonstrated that silencing SAMD9 inhibited lung metastasis and tumor formation in vivo. Finally, the authors found that silencing MYH9 or β‐catenin, or overexpressing GSK‐3β inhibited SAMD9‐stimulated ESCC cell stemness, EMT, angiogenesis, metastasis, and tumorigenicity. Together, the findings indicate that the SAMD9/MYH9/GSK3β/β‐catenin axis promotes ESCC postoperative recurrence and that SAMD9 is a crucial target for ESCC therapy. Additionally, SAMD9 has the potential as a predictor of postoperative recurrence in ESCC. This work demonstrates the clinical and functional role of SAMD9 in esophageal squamous cell carcinoma (ESCC). SAMD9 promotes MYH9/TRAF6‐regulated ubiquitination and degradation of GSK3β by binding to MYH9, leading to activation of the β‐catenin signaling pathway, which stimulates EMT, angiogenesis, and stemness of ESCC cells, and ultimately promotes ESCC metastasis and recurrence.

There is a significant gap in data regarding the survival time and the factors influencing the survival of people living with HIV (PLWH) undergoing antiretroviral therapy (ART) in Henan Province, a region severely impacted by the AIDS epidemic.Investigating survival and influencing factors after ART can provide valuable insights to enhance patient management strategies and improve the prognosis for PLWH.This retrospective cohort study compiled case data and follow-up records of PLWH receiving ART at the Infectious Disease Hospital of Henan Province between 2004 and 2024. Survival curves were generated using the Kaplan-Meier method, and both univariate and multivariate Cox proportional hazards models were employed to identify factors influencing survival outcomes. Among the 4,307 study participants, a total of 251 (5.83%) patients died. The overall cumulative survival rate to the observation endpoint was 80%. The multifactorial Cox proportional risk regression modeling analysis of the primary outcomes showed that patients aged > 60 years at diagnosis of HIV/AIDS (HR = 4.706, 95% CI: 2.175 ~ 10.180), transmission route of heterosexual (HR = 1.403, 95% CI: 1.021 ~ 1.928) and blood transmission (HR = 1.855, 95% CI:1.206 ~ 2.855), patients with CD4 + T cell count < 200cells/µL (HR = 1.636,95% CI: 1.136 ~ 2.354) had a higher risk of death. Our findings highlight the importance of targeted ART management for high-risk populations, such as older individuals, heterosexual or blood-borne transmission and those with low CD4 + T cell count, to further improve survival outcomes and optimize HIV/AIDS treatment strategies.

Background Ketone β-hydroxybutyrate (BHB) has been reported to prevent tumor cell proliferation and improve drug resistance. However, the effectiveness of BHB in oxaliplatin (Oxa)-resistant colorectal cancer (CRC) and the underlying mechanism still require further proof. Methods CRC-Oxa-resistant strains were established by increasing concentrations of CRC cells to Oxa. CRC-Oxa cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) were checked following BHB intervention in vitro. The subcutaneous and metastasis models were established to assess the effects of BHB on the growth and metastasis of CRC-Oxa in vivo. Eight Oxa responders and seven nonresponders with CRC were enrolled in the study. Then, the serum BHB level and H3K79me, H3K27ac, H3K14ac, and H3K9me levels in tissues were detected. DOT1L (H3K79me methyltransferase) gene knockdown or GNE-049 (H3K27ac inhibitor) use was applied to analyze further whether BHB reversed CRC-Oxa resistance via H3K79 demethylation and/or H3K27 deacetylation in vivo and in vitro. Results Following BHB intervention based on Oxa, the proliferation, migration, invasion, and EMT of CRC-Oxa cells and the growth and metastasis of transplanted tumors in mice were suppressed. Clinical analysis revealed that the differential change in BHB level was associated with drug resistance and was decreased in drug-resistant patient serum. The H3K79me, H3K27ac, and H3K14ac expressions in CRC were negatively correlated with BHB. Furthermore, results indicated that H3K79me inhibition may lead to BHB target deletion, resulting in its inability to function. Conclusions β-hydroxybutyrate resensitized CRC cells to Oxa by suppressing H3K79 methylation in vitro and in vivo.

Blood urea nitrogen (BUN)/creatinine (Cr) ratio was an independent predictor of stroke-in-evolution (SIE) among patients who had suffered an acute ischemic stroke. We investigated the association of changes in BUN/Cr on stroke outcome during hospitalization after acute ischemic stroke (AIS). AIS patients admitted within 3 days from stroke onset (2020–2021) were included in the study. Baseline data, including BUN and Cr levels, were collected. Univariate linear regression and a multivariate regression model were applied to assess the relationship between the change of BUN/Cr and short-term outcomes. One hundred and eighty-one patients were included. The mean increase of BUN/Cr level was − 2.0 ± 1.78. Univariate linear regression suggested that baseline NIHSS, thrombolysis, change of BUN/Cr, and history of atrial fibrillation, statin use, and antiplatelet therapy was associated with the decrease in NIHSS during hospitalization (P < 0.05). After adjusting for potential confounders, multivariate regression analysis revealed the associations between the decrease in BUN/Cr and favorable outcome are significant (β = 0.21, 95% CI = 0.14,−0.28). The decrease in BUN/Cr is positively correlated with a better early neurological improvement in AIS patients. •BUN/Cr change independently predicts short-term outcome after AIS.•BUN/Cr decrease is concerned with better early neurological improvement.•BUN/Cr may serve as an available index of hydration therapy.

The brain is the organ with the highest cholesterol content in the body. Cholesterol in the brain plays a crucial role in maintaining the integrity of synapses and myelin sheaths to ensure normal brain function. Disruptions in cholesterol metabolism are closely associated with various central nervous system (CNS) diseases, including Alzheimer’s disease (AD), Huntington’s disease (HD), and multiple sclerosis (MS). In this review, we explore the synthesis, regulation, transport, and functional roles of cholesterol in the CNS. We discuss in detail the associations between cholesterol homeostasis imbalance and CNS diseases including AD, HD, and MS, highlighting the significant role of cholesterol metabolism abnormalities in the development of these diseases. Sterol regulatory element binding protein-2 (SREBP2) and liver X receptor (LXR) are two critical transcription factors that play central roles in cholesterol synthesis and reverse transport, respectively. Their cooperative interaction finely tunes the balance of brain cholesterol metabolism, presenting potential therapeutic value for preventing and treating CNS diseases. We particularly emphasize the alterations in SREBP2 and LXR under pathological conditions and their impacts on disease progression. This review summarizes current therapeutic agents targeting these two pathways, with the hope of broadening the perspectives of CNS drug developers and encouraging further study into SREBP2 and LXR-related therapies for CNS diseases.

As the latest and most anticipated method of tumor immunotherapy, CAR-NK therapy has received increasing attention in recent years, and its safety and high efficiency have irreplaceable advantages over CAR-T. Current research focuses on the application of CAR-NK in hematological tumors, while there are fewer studies on solid tumor. This article reviews the process of constructing CAR-NK, the effects of hypoxia and metabolic factors, NK cell surface receptors, cytokines, and exosomes on the efficacy of CAR-NK in solid tumor, and the role of CAR-NK in various solid tumor. The mechanism of action and the research status of the potential of CAR-NK in the treatment of solid tumor in clinical practice, and put forward the advantages, limitations and future problems of CAR-NK in the treatment of solid tumor.

Innate immunity to nucleic acids forms the backbone for anti-viral immunity and several inflammatory diseases. Upon sensing cytosolic viral RNA, retinoic acid-inducible gene-I-like receptors (RLRs) interact with the mitochondrial antiviral signaling protein (MAVS) and activate TANK-binding kinase 1 (TBK1) to induce type I interferon (IFN-I). TRAF3-interacting protein 3 (TRAF3IP3, T3JAM) is essential for T and B cell development. It is also well-expressed by myeloid cells, where its role is unknown. Here we report that TRAF3IP3 suppresses cytosolic poly(I:C), 5’ppp-dsRNA, and vesicular stomatitis virus (VSV) triggers IFN-I expression in overexpression systems and Traf3ip3 −/− primary myeloid cells. The mechanism of action is through the interaction of TRAF3IP3 with endogenous TRAF3 and TBK1. This leads to the degradative K48 ubiquitination of TBK1 via its K372 residue in a DTX4-dependent fashion. Mice with myeloid-specific gene deletion of Traf3ip3 have increased RNA virus-triggered IFN-I production and reduced susceptibility to virus. These results identify a function of TRAF3IP3 in the regulation of the host response to cytosolic viral RNA in myeloid cells. RNA viruses can be detected by immune cell pattern recognition receptors, such as RLRs, resulting in MAVS-TBK1-IRF3 signalling and production of antiviral type 1 interferons. Here the authors show that macrophage TRAF3-interacting protein 3 regulates this signalling pathway by interacting with TRAF3 and TBK1 to suppress interferon responses.

Re-emerging pseudorabies (PR) caused by pseudorabies virus (PRV) variant has been prevailing among immunized herds in China since 2011, indicating that commercially available PR vaccine strains couldn’t provide complete protection against novel, epidemic PRV variant. Before this study, a gE/TK-gene-deleted virus (PRV ΔgE/TK) was constructed from PRV QYY2012 variant through homologous recombination and Cre/LoxP system. Here, PRV ΔgE/TK/US3 strain was generated by deleting US3 gene based on PRV ΔgE/TK strain using the same method. The growth characteristics of PRV ΔgE/TK/US3 were analogous to that of PRV ΔgE/TK. Moreover, the deletion of US3 gene could promote apoptosis, upregulate the level of swine leukocyte antigen class I molecule (SLA-I) in vitro, and relieve inflammatory response in inoculated BALB/c mice. Subsequently, the safety and immunogenicity of PRV ΔgE/TK/US3 was evaluated as a vaccine candidate in mice. The results revealed that PRV ΔgE/TK/US3 was safe for mice, and mice vaccinated with PRV ΔgE/TK/US3 could induce a higher level of PRV-specific neutralizing antibodies and cytokines, including IFN-γ, IL-2 and IL-4, also higher level of CD8+ CD69+ Tissue-Resident Memory T cells (TRM). The results show that the deletion of US3 gene of PRV ΔgE/TK strain could induce increased immunogenicity, indicating that the PRV ΔgE/TK/US3 strain is a promising vaccine candidate for preventing and controlling of the epidemic PR in China.