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Drug induced liver injury (DILI) is a kind of liver dysfunction which caused by drugs, and gut microbiota could affect liver injury. However, the relationship between gut microbiota and its metabolites in DILI patients is not clear. The total gut microbiota DNA was extracted from 28 DILI patient and 28 healthy control volunteers (HC) and 16S rDNA gene were amplified. Next, differentially metabolites were screened. Finally, the correlations between the diagnostic strains and differentially metabolites were studied.The richness and uniformity of the bacterial communities decreased in DILI patients, and the structure of gut microbiota changed obviously. Enterococcus and Veillonella which belong to Firmicutes increased in DILI, and Blautia and Ralstonia which belong to Firmicutes, Dialister which belongs to Proteobacteria increased in HC. In addition, these diagnostic OTUs of DILI were associated with the DILI damage mechanism. On the other hands, there were 66 differentially metabolites between DILI and HC samples, and these metabolites were mainly enriched in pyrimidine metabolism and steroid hormone biosynthesis pathways. Furthermore, the collinear network map of the key microbiota-metabolites were constructed and the results indicated that Cortodoxone, Prostaglandin I1, Bioyclo Prostaglandin E2 and Anacardic acid were positively correlated with Blautia and Ralstonia , and negatively correlated with Veillonella .This study analyzed the changes of DILI from the perspective of gut microbiota and metabolites. Key strains and differentially metabolites of DILI were screened and the correlations between them were studied. This study further illustrated the mechanism of DILI.

Background Pancreatic cancer remains one of the most lethal malignancies worldwide, underscoring the urgent need for reliable biomarkers to predict prognosis and guide therapy. This study aimed to identify and characterize such biomarkers using an integrated bioinformatics and experimental approach. Methods The GEO database was used to screen genes differentially expressed in pancreatic cancer. Next, the DAVID database was used for GO functional enrichment and KEGG pathway analyses. STRING database and Cytoscape software were utilized to generate PPI networks and identify key genes. The prognostic value was then evaluated by utilizing the GEPIA database and Cox regression analysis. The relationship between key genes and clinicopathological parameters was analyzed using the UALCAN database. The TISCH2, TIMER, and TISDB databases were used for immune infiltration analysis. The functional role of the key gene was ultimately confirmed through in vitro experiments. Results Through multiple rounds of strict screening, 10 key genes were obtained. After further verification, it was determined that MMP1 was significantly upregulated in pancreatic cancer tissue and correlated with poor prognosis in patients. Immunological analysis revealed correlations between MMP1 expression and the infiltration of specific immune cells (B cells, M1 macrophages, neutrophils, and monocytes) as well as the expression of immune checkpoint genes (VTCN1, LGALS9, TGFBR1, and IL10RB). In vitro functional assays confirmed that MMP1 knockdown in pancreatic cancer cells suppressed proliferation, migration, and invasion, while promoting apoptosis. Furthermore, a co-culture model demonstrated that MMP1 facilitated the recruitment of M1-polarized macrophages. Conclusion MMP1 is an independent prognostic biomarker that drives pancreatic cancer progression through direct oncogenic effects and modulation of the tumor immune microenvironment. Thus, it emerges as an attractive, multifunctional therapeutic target, which calls for future research to confirm its translational potential and delineate the underlying molecular pathways.

Apoptotic bodies (ABs) are extracellular vesicles released during apoptosis and possess diverse biological activities. Initially, ABs were regarded as garbage bags with the main function of apoptotic cell clearance. Recent research has found that ABs carry and deliver various biological agents and are taken by surrounding and distant cells, affecting cell functions and behavior. ABs-mediated intercellular communications are involved in various physiological processes including anti-inflammation and tissue regeneration as well as the pathogenesis of a variety of diseases including cancer, cardiovascular diseases, neurodegeneration, and inflammatory diseases. ABs in biological fluids can be used as a window of altered cellular and tissue states which can be applied in the diagnosis and prognosis of various diseases. The structural and constituent versatility of ABs provides flexibility for tailoring ABs according to disease diagnostic and therapeutic needs. An in-depth understanding of ABs’ constituents and biological functions is mandatory for the effective tailoring of ABs including modification of bio membrane and cargo constituents. ABs’ tailoring approaches including physical, chemical, biological, and genetic have been proposed for bench-to-bed translation in disease diagnosis, prognosis, and therapy. This review summarizes the updates on ABs tailoring approaches, discusses the existing challenges, and speculates the prospects for effective diagnostic and therapeutic applications. Highlights Apoptotic bodies (ABs), a type of cellular waste product discovered as a biomaterial with therapeutic potential ABs mediated intercellular communication, including the transmission of biological signals and biological substances Apoptotic bodies exhibit significant research and application potential in the prevention, diagnosis, and treatment of diseases. The functionality of apoptotic bodies can be enhanced through drug loading, surface modification, and biomimetic preparation.

5‐Methylcytosine modification (m5C) is an important posttranscriptional regulatory mechanism of gene expression. Exhausted CD8+T cells contribute to the development of many major diseases; however, their exact role and relationship to m5C in systemic lupus erythematosus (SLE) remain unknown. In this study, we identified a CD7highCD74high CD8+T subgroup that were robustly expanded in SLE patients through single‐cell transcriptome sequencing (scRNA‐seq). CD7highCD74high CD8+T cells displayed exhausted features and exhibited a superior diagnostic value in SLE. Then, we explored the m5C landscape of SLE patients by performing m5C epitranscriptome sequencing (m5C‐seq). ScRNA‐seq and m5C‐seq were conjointly analyzed to screen m5C‐related therapeutic targets for SLE, and NOP2/Sun RNA methyltransferase 4 (NSUN4) was identified as a key regulator of SLE pathogenesis. Knockdown of NSUN4 downregulated CD74 expression via reduction of m5C and suppressed CD8+T cell exhaustion by declining CD44/mTOR (mechanistic target of rapamycin kinase)‐mediated mitophagy. Finally, we verified that nanoparticle‐delivered siRNA against Nusn4 decreased autoimmune reaction kidney damage in both spontaneous and pristane‐induced SLE mouse models. In conclusion, we identify an exhausted CD7highCD74high CD8+T cell subset and propose the crucial role of NSUN4/CD74‐induced dysregulation of mitophagy in SLE pathogenesis, and targeting NSUN4 is a promising treatment strategy for SLE patients. CD74highCD7high exhausted CD8+T cells were characterized by ScRNA‐seq, and their association with SLE diagnostic indicators was evaluated. NSUN4 was screened as a therapeutic target by integrative analysis of scRNA‐seq and m5C‐seq, and its role in mitochondrial dysfunction was investigated in cultured CD8+T cells in vitro. The therapeutic effect of LPH‐nanoparticle delivered Nsun4–siRNA was confirmed in spontaneous lupus mice and pristane‐induced SLE mice in vivo.

Endoplasmic reticulum stress (ERS) and unfolded protein response are the critical processes of tumour biology. However, the roles of ERS regulatory genes in pancreatic adenocarcinoma (PAAD) remain elusive. A novel ERS‐related risk signature was constructed using the Lasso regression analysis. Its prognostic value, immune effect, metabolic influence, mutational feature and therapeutic correlation were comprehensively analysed through multiple bioinformatic approaches. The biofunctions of KDELR3 and YWHAZ in pancreatic cancer (PC) cells were also investigated through colony formation, Transwell assays, flow cytometric detection and a xenograft model. The upstream miRNA regulatory mechanism of KDELR3 was predicted and validated. ERS risk score was identified as an independent prognostic factor and could improve traditional prognostic model. Meanwhile, it was closely associated with metabolic reprogramming and tumour immune. High ERS risk enhanced glycolysis process and nucleotide metabolism, but was unfavourable for anti‐tumour immune response. Moreover, ERS risk score could act as a potential biomarker for predicting the efficacy of ICBs. Overexpression of KDELR3 and YWHAZ stimulated the proliferation, migration and invasion of SW1990 and BxPC‐3 cells. Silencing KDELR3 suppressed tumour growth in a xenograft model. miR‐137 could weaken the malignant potentials of PC cells through inhibiting KDELR3 (5′‐AGCAAUAA‐3′). ERS risk score greatly contributed to PAAD clinical assessment. KDELR3 and YWHAZ possessed cancer‐promoting capacities, showing promise as a novel treatment target.

目的 探讨药物性肝损伤(DILI)患者的临床特点。 方法 回顾性收集陕西省内20家医院2009—2019年收治的以RUCAM量表为诊断标准的1 376例药物性肝损伤患者的临床资料，分析性别、年龄、基础疾病、可疑肝损伤药物、临床表现、实验室检查、治疗经过及预后。计量资料2组间比较采用成组t检验或Wilcoxon秩和检验；计数资料组间比较采用χ2检验；多分类有序资料比较采用Kruskal-Wallis H秩和检验。 结果 1 376例患者中男577例(41.93%)，女799例(58.07%)，男女比为0.72∶1；各年龄段中40~60岁年龄段高发，占比44.77%；各年龄组中男女性别分布差异有统计学意义(χ2=20.784，P=0.008)，三种临床分型中，男女发病占比差异无统计学意义(χ2=1.409，P=0.494)，各年龄组中临床分型分布差异有统计学意义(χ2=47.025，P＜0.001)。引起肝损伤的药物中，居前三位的依次为：中药(41.13%)、抗结核药(11.70%)、解热镇痛药(7.27%)。临床分型以肝细胞损伤型为主，占比65.77%(905例)；住院时间平均15.31天，以1~4周居多，占比91.86 %；痊愈45例(3.27%)，好转1 322例(96.08%)，整体预后较好。不同临床分型的预后不同，差异具有统计学意义(H=59.300，P=0.011)，进一步比较显示，肝细胞损伤型和混合型预后好于胆汁淤积型(P＜0.05)，肝细胞损伤性和混合型预后差异无统计学意义(P＞0.05)。 结论 DILI在女性及中老年的占比较高，中药是引起DILI的首位原因，不同临床分型的预后不同，整体预后较好。

Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20. Multi-targeting agonists at GIPR, GLP-1R or GCGR are pursued vigorously. Here, the authors report cryo-EM structures of tirzepatide-bound GIPR and GLP-1R, peptide 20-bound GIPR, GLP-1R and GCGR, revealing the molecular basis of their multiplexed pharmacological actions.

Glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that plays an important role in glucose homeostasis and treatment of type 2 diabetes. Structures of full-length class B receptors were determined in complex with their orthosteric agonist peptides, however, little is known about their extracellular domain (ECD) conformations in the absence of orthosteric ligands, which has limited our understanding of their activation mechanism. Here, we report the 3.2 Å resolution, peptide-free crystal structure of the full-length human GLP-1R in an inactive state, which reveals a unique closed conformation of the ECD. Disulfide cross-linking validates the physiological relevance of the closed conformation, while electron microscopy (EM) and molecular dynamic (MD) simulations suggest a large degree of conformational dynamics of ECD that is necessary for binding GLP-1. Our inactive structure represents a snapshot of the peptide-free GLP-1R and provides insights into the activation pathway of this receptor family. Glucagon-like peptide-1 receptor (GLP-1R) plays an important role in glucose homeostasis and treatment of type 2 diabetes. Here authors report the peptide-free crystal structure of human GLP-1R in an inactive state which reveals a unique closed conformation of the extracellular domain.

Background Endoscopy is a critical tool in the management of acute variceal bleeding (AVB). However, the optimal timing for its implementation remains controversial, with varying recommendations across different clinical guidelines. This study aims to evaluating the impact of endoscopy timing on patient outcomes. Methods PubMed, the Cochrane Library, and Embase were searched from the earliest available publication to January 31, 2024. Both fixed-effect and random-effect models were employed to calculate the odds ratio (OR) and 95% confidence intervals (CIs), based on the levels of heterogeneity. Newcastle-Ottawa Scale was used to assess the quality of each included studies. The mortality, incidence of rebleeding and other secondary outcomes were compared between urgent and early endoscopy groups. Subgroup analysis was performed based on the endoscopy time defined in each included studies and the reporting time of primary outcomes. The publication bias was examined through Egger’s test and Begg’s test. Results Our analysis showed no significant difference in overall mortality (OR = 0.99, 95% CI, 0.60–1.62, P  = 0.96) and rebleeding (OR = 1.06, 95% CI, 0.77–1.47, P  = 0.71) as well as secondary outcomes between the two groups. Subgroup analysis indicated that the mortality in the 6–24 h endoscopy group was significantly lower than in the < 6 h endoscopy group (OR = 2.05, 95% CI, 1.29–3.26, P  = 0.002). However, no statistical difference between the other groups. Conclusion Endoscopy performed within 6 h might be associated with higher mortality. Furthermore, urgent and early endoscopy did not significantly affect other outcomes in AVB patients. Therefore, the timing for endoscopy would be more appropriate based on each patient’s condition within 24 h.

Although plenty of drugs are currently available for type 2 diabetes mellitus (T2DM), a subset of patients still failed to restore normoglycemia. Recent studies proved that symptoms of T2DM patients who are unresponsive to conventional medications could be relieved with mesenchymal stem/stromal cell (MSC) therapy. However, the lack of systematic summary and analysis for animal and clinical studies of T2DM has limited the establishment of standard guidelines in anti-T2DM MSC therapy. Besides, the therapeutic mechanisms of MSCs to combat T2DM have not been thoroughly understood. In this review, we present an overview of the current status of MSC therapy in treating T2DM for both animal studies and clinical studies. Potential mechanisms of MSC-based intervention on multiple pathological processes of T2DM, such as β-cell exhaustion, hepatic dysfunction, insulin resistance, and systemic inflammation, are also delineated. Moreover, we highlight the importance of understanding the pharmacokinetics (PK) of transplanted cells and discuss the hurdles in MSC-based T2DM therapy toward future clinical applications.