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Ischemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI). The role of N 6- methyladenosine (m6A) modification in AKI remains unclear. Here, we characterize the role of AlkB homolog 5 (ALKBH5) and m6A modification in an I/R-induced renal injury model in male mice. Alkbh5 -knockout mice exhibit milder pathological damage and better renal function than wild-type mice post-IRI, whereas Alkbh5 -knockin mice show contrary results. Also conditional knockout of Alkbh5 in the tubular epithelial cells alleviates I/R-induced AKI and fibrosis. CCL28 is identified as a target of ALKBH5. Furthermore, Ccl28 mRNA stability increases with Alkbh5 deficiency, mediating by the binding of insulin-like growth factor 2 binding protein 2. Treg recruitment is upregulated and inflammatory cells are inhibited by the increased CCL28 level in IRI- Alkbh5 fl/fl Ksp Cre mice. The ALKBH5 inhibitor IOX1 exhibits protective effects against I/R-induced AKI. In summary, inhibition of ALKBH5 promotes the m6A modifications of Ccl 28 mRNA, enhancing its stability, and regulating the Treg/inflammatory cell axis. ALKBH5 and this axis is a potential AKI treatment target. m6A modification has been reported to play roles in many developmental and pathological processes, but its role in AKI remains poorly understood. Here, the authors show the role and the mechanism of the m6A demethylase, ALKBH5 on IRI induced AKI.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a series of pathologic conditions including cancer. MicroRNA (miRNA) has been considered as a regulator in different tumor microenvironments. Recent studies have begun to unravel the crosstalk between miRNAs and MDSCs. The knowledge of the effect of both miRNAs and MDSCs in tumor may improve our understanding of the tumor immune escape and metastasis. The miRNAs target cellular signal pathways to promote or inhibit the function of MDSCs. On the other hand, MDSCs transfer bioinformation through exosomes containing miRNAs. In this review, we summarized and discussed the bidirectional regulation between miRNAs and MDSCs in the tumor microenvironment.

Background Kidney transplantation stands out as the most effective renal replacement therapy for patients grappling with end-stage renal disease. However, post-transplant renal fibrosis is a prevalent and irreversible consequence, imposing a substantial clinical burden. Unfortunately, the clinical landscape remains devoid of reliable biological markers for diagnosing post-transplant renal interstitial fibrosis. Methods We obtained transcriptome and single-cell sequencing datasets of patients with renal fibrosis from NCBI Gene Expression Omnibus (GEO). Subsequently, we employed Weighted Gene Co-Expression Network Analysis (WGCNA) to identify potential genes by integrating core modules and differential genes. Functional enrichment analysis was conducted to unveil the involvement of potential pathways. To identify key biomarkers for renal fibrosis, we utilized logistic analysis, a LASSO-based tenfold cross-validation approach, and gene topological analysis within Cytoscape. Furthermore, histological staining, Western blotting (WB), and quantitative PCR (qPCR) experiments were performed in a murine model of renal fibrosis to verify the identified hub genes. Moreover, molecular docking and molecular dynamics simulations were conducted to explore possible effective drugs. Results Through WGCNA, the intersection of core modules and differential genes yielded a compendium of 92 potential genes. Logistic analysis, LASSO-based tenfold cross-validation, and gene topological analysis within Cytoscape identified four core genes (CD3G, CORO1A, FCGR2A, and GZMH) associated with renal fibrosis. The expression of these core genes was confirmed through single-cell data analysis and validated using various machine learning methods. Wet experiments also verified the upregulation of these core genes in the murine model of renal fibrosis. A positive correlation was observed between the core genes and immune cells, suggesting their potential role in bolstering immune system activity. Moreover, four potentially effective small molecules (ZINC000003830276-Tessalon, ZINC000003944422-Norvir, ZINC000008214629-Nonoxynol-9, and ZINC000085537014-Cobicistat) were identified through molecular docking and molecular dynamics simulations. Conclusion Four potential hub biomarkers most associated with post-transplant renal fibrosis, as well as four potentially effective small molecules, were identified, providing valuable insights for studying the molecular mechanisms underlying post-transplant renal fibrosis and exploring new targets.

Endomyocardial biopsy is the gold standard method for the diagnosis of cardiac allograft rejection. However, it causes damage to the heart. In this study, we developed a noninvasive method for quantification of granzyme B (GzB) by targeted ultrasound imaging, which detects and provides quantitative information for specific molecules, for acute rejection assessment in a murine cardiac transplantation model. Microbubbles bearing anti-GzB antibodies (MB ) or isotype antibodies (MBcon) were prepared. Hearts were transplanted from C57BL/6J (allogeneic) or C3H (syngeneic) donors to C3H recipients. Target ultrasound imaging was performed on Days 2 and 5 post-transplantations. A pathologic assessment was performed. The expression of granzyme B and IL-6 in the heart was detected by Western blotting. After MB injection, we observed and collected data at 3 and 6 min before and after the flash pulse. Quantitative analysis revealed that the reduction in peak intensity was significantly higher in the allogeneic MB group than in the allogeneic MB group and the isogeneic MB group at PODs 2 and 5. In the allogeneic groups, granzyme B and IL-6 expression levels were higher than those in the isogeneic group. In addition, more CD8 T cells and neutrophils were observed in the allogeneic groups. Ultrasound molecular imaging of granzyme B can be used as a noninvasive method for acute rejection detection after cardiac transplantation.

Numerous myofibroblasts are arisen from endothelial cells (ECs) through endothelial to mesenchymal transition (EndMT) triggered by TGF-β. However, the mechanism of ECs transforms to a different subtype, or whether there exists an intermediate state of ECs remains unclear. In present study, we demonstrate Midkine (MDK) mainly expressed by CD31 + ACTA2+ECs going through partial EndMT contribute greatly to myofibroblasts by spatial and single-cell transcriptomics. MDK is induced in TGF-β treated ECs, which upregulates C/EBPβ and increases EndMT genes, and these effects could be reversed by siMDK. Mechanistically, MDK promotes the binding ability of C/EBPβ with ACTA2 promoter by stabilizing the C/EBPβ protein. In vivo, knockout of Mdk or conditional knockout of Mdk in ECs reduces EndMT markers and significantly reverses fibrogenesis. In conclusion, our study provides a mechanistic link between the induction of EndMT by TGF-β and MDK, which suggests that blocking MDK provides potential therapeutic strategies for renal fibrosis. This study focuses on how endothelial cells contribute to ECM accumulation of renal fibrosis and suggests that MDK promotes ACTA2 expression by stabilizing the C/EBPβ protein.

Metal ions play an important role in living organisms and are involved in essential physiological activities. However, the overload state of ions can cause excess free radicals, cell damage, and even cell death. Ferroptosis and cuproptosis are specific forms of cell death that are distinct from apoptosis, necroptosis, and other regulated cell death. These unique modalities of cell death, dependent on iron and copper, are regulated by multiple cellular metabolic pathways, including steady-state metal redox treatment mitochondrial activity of lipid, amino acid and glucose metabolism, and various signaling pathways associated with disease. Although the mechanisms of ferroptosis and cuproptosis are not yet fully understood, there is no doubt that ion overload plays a crucial act in these metal-dependent cell deaths. In this review, we discussed the core roles of ion overload in ferroptosis and cuproptosis, the association between metabolism imbalance and ferroptosis and cuproptosis, the extract the diseases caused by ion overload and current treatment modalities.

IL-37 is an anti-inflammatory cytokine that was only recently identified, and it is highly expressed in tissues from patients with inflammatory and autoimmune diseases. Inflammatory cytokines and inflammatory stimuli can induce the upregulation of IL-37. However, it has not been reported whether anti-inflammatory medications induce the expression of IL-37. In this work, we uncovered, for the first time, that two main bioactive components, triptolide and triptonide, from the herb Tripterygium wilfordii Hook f. （TwHF）, which possess anti-inflammatory activity, upregulate the expression of IL-37, and this expression was suppressed by ERKI/2 and p38 MAPK inhibitors. Overall, our research demonstrated, for the first time, that anti-inflammatory active components （triptolide and triptonide） upregulated the expression of IL-37 most likely via activation of the ERKI/2 and p38 MAPK pathways.

Type 1 interferon （IFN-I） promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by I FN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus （Ad） in IFN-a receptor knockout （IFNAR-/-） and control mice. To disrupt signaling, monoclonal antibodies （mAbs） against IL-7 receptor alpha （IL-7Re） or PD-L1 were i.p. injected. We found that CD8＋ T cells in IFNAR-/- mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-7 production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell （DCs） and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR-/- and control mice. Injection of PD-Ll-specific mAb in IFNAR-/- mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR-/- mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8＋ T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8＋ T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8＋ T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.

Bactrocera dorsalis Hendel （Diptera： Tephritidae） is an invasive pest around the world. The paper summarizes biological and ecological characteristics of B, dorsalis, and reviews its detection methods from the aspects of morphological identification, acoustic detection and molecular detection, in order to provide a reference for further research and development of new detection methods. The hot issues in the study of B. dorsalis, such as ecological adaptation pattern, diffusion pathways and mechanisms, sustainable control measures, are also put forward in the paper.