A dysregulated inflammatory response and inflammation-associated cell death are central features of renal ischemia-reperfusion injury (IRI). PANoptosis, is a recently recognized form of inflammatory programmed cell death characterized by key features of pyroptosis, apoptosis and necroptosis; however, the specific involvement of PANoptosis in renal IRI remains unknown. By using neutrophil extracellular trap (NETs)-depleted Pad4−/− mice, we found that NETs are essential for exacerbating tissue injury in renal IRI. Single-cell RNA sequencing (scRNA-seq) revealed that IRI promoted PANoptosis signalling in proximal tubular epithelial cells (PTs), whereas PAD4 knockout inhibited PANoptosis signalling. PTs expressed mainly RIPK1-PANoptosomes, which executed NET-induced PANoptosis in PTs in renal IRI model mice. Mechanistically, NET-derived double-stranded RNA (dsRNA) promoted PANoptosis in PTs, and PT-expressed TLR3 was responsible for the sensing the extracellular dsRNA. Treating mice with chemical inhibitors of the dsRNA/TLR3 complex suppressed PANoptosis and alleviated tissue injury in renal IRI. Together, the results of this study reveal a mechanism by which the NET-dsRNA-TLR3 axis aggravates PT cell PANoptosis in renal IRI.

Diabetic kidney disease (DKD) features intrarenal inflammation, in which T cells play a part. Hypoxia-inducible factor-1α (HIF-1α), a key transcription factor regulating cellular responses to hypoxia, is reportedly involved in the course of inflammation. The role of HIF-1α in DKD has been investigated, but the conclusions are controversial so far. We report a previously unrecognised high glucose/carbohydrate response element binding protein (ChREBP)/Hif-1α transcription axis in CD4+ T cells. Lck-Cre+Hif1aloxp/loxp (Hif-1α−/−) mice were generated to explore the role of T cell HIF-1α in the pathogenesis of DKD. CD4+ T cells sorted from T cell-specific Hif-1α-ablated mice and wild-type mice were used for functional studies and transcriptional profiling. In this study, we used Lck-Cre transgenic mice to specifically disrupt Hif-1α in T cells and found that ablation of Hif-1α greatly accelerated the progression of DKD in a streptozocin-induced model of diabetes. Adoptive transfer of splenic CD4+ T cells from Hif-1α−/− mice rather than wild-type controls to diabetic mice elicited severe renal damage. Compared with wild-type controls, Hif-1α knockout markedly promoted IFN-γ secretion by CD4+ T cells in response to high glucose. Additional Ifn-γ ablation negated the effect of Hif-1α knockout on DKD progression. Mechanistically, the background Hif-1α mRNA synthesis rate in resting T cells was very low, but culture of T cells under high glucose led to significantly promoted Hif-1α expression, which was dependent on the transcription factor ChREBP. Consistent with results from Hif-1α−/− CD4+ T cells, adoptive transfer of Chrebp−/− CD4+ T cells to wild-type diabetic mice also elicited severe diabetic renal damage. By contrast, Chrebp−/−Ifn-γ−/− CD4+ T cells failed to show nephrotoxic effects. Examination of the Hif-1α promoter identified a ChREBP-binding sequence that mediated transcriptional upregulation of Hif-1α by high glucose. Our study reveals a previously unrecognised high glucose/ChREBP/Hif-1α transcription axis in CD4+ T cells, which serves as a self-protection mechanism against DKD progression via limiting T helper 1 response.

BackgroundImmunometabolic adaptations may induce tumor immune escape and immunotherapeutic resistance, representing crucial mechanisms in cancer progression. Understanding the metabolic rewiring of tumor-infiltrating immune cells as tumors advance could enhance current immune-oncology treatments.MethodsIn this study, we investigated metabolic heterogeneity in immune cells within both tumor and adjacent normal tissue using single-cell transcriptome profiling of colon cancer. We also utilized the MC38 colorectal cancer model, a commonly employed mouse tumor model, to assess the metabolic atlas of major immune cell populations in tumor and normal tissue.ResultsWe examined the immunometabolic features in tumor tissue and adjacent normal tissue using public single-cell transcriptomic datasets of colorectal cancer (CRC) patients, in which myeloid cells showed dominant metabolic activity. Using a mouse tumor model, we demonstrated distinct metabolic reprogramming of major immune cell types in tumor compared to normal tissue. Specifically, we observed increased glucose and lipid uptake, along with abundant lipid accumulation in tumor-infiltrating myeloid cells, particularly macrophages. Additionally, we identified diverse mitochondrial fitness and oxidative stress levels within the tumor immune microenvironment. Macrophages exhibited metabolic fitness, CD8+ T cells displayed mitochondrial depolarization, and neutrophils showed high oxidative stress. Furthermore, we investigated immunometabolic dynamics and observed augmented metabolic activity in immune cells infiltrating progressive and late stages of tumor development. Notably, intratumoral macrophages exhibited metabolic heterogeneity, characterized by robust lipid uptake and synthesis, which correlated with a pro-tumor phenotype and poor clinical outcomes.ConclusionOverall, our study unveils the heterogeneity and dynamics of metabolic properties in immune cells within the tumor microenvironment. These findings provide insights for developing therapeutic strategies that target metabolism to enhance antitumor immunity.

Background: Anti-glomerular basement membrane (anti-GBM) nephritis is mediated by autoantibodies and may progress to end-stage renal disease. Although its pathogenesis is not completely understood, dendritic cells (DCs) have been reported to play an important role in this process. Hypoxia-inducible factor-2α (HIF-2α) has been reported to have a regulatory effect on DCs under hypoxic conditions, while no research has investigated its role in autoimmune nephritis. Methods: Anti-GBM nephritis was induced in CD11c-specific HIF-2α-deficient and WT mice using nephrotoxic serum (NTS). All mice were divided into four groups: (i) WT+PBS, (ii) CD11c-Cre+ Hif2αfl/fl+PBS, (iii) WT+NTS and (iv) CD11c-Cre+ Hif2αfl/fl+NTS. Seven days after induction, renal function, immune cell infiltration and the expression levels of genes in the renal cortex were assessed in each group. Results: On day 7, the levels of serum creatinine and blood urea nitrogen and the urine albumin-to-creatinine ratio were lower for mice with DC-specific deletion of HIF-2α compared with their WT counterparts (p < 0.05). Histopathological analysis showed that there was less crescent formation in the renal cortex with conditional HIF-2α knockout, and the infiltration of DCs and macrophages was also suppressed (p < 0.05). Genes related to antigen processing and presentation were found to be expressed differentially between the two groups, and the activation of the MAPK pathway was affected (p < 0.05). Western blot analysis validated that HIF-2α knockout inhibited the phosphorylation of p38 MAPK (p < 0.05). Conclusions: In this study, we observed a pro-inflammatory effect of HIF-2α in DCs in early anti-GBM nephritis, and the results suggested a regulating effect of HIF-2α on p38 MAPK pathways.

The role of RNA N6-methyladenosine (m6A) modification in immunity is being elucidated. This study aimed to explore the potential association between m6A regulators and the immune microenvironment in IgA nephropathy (IgAN). The expression profiles of 24 m6A regulators in 107 IgAN patients were obtained from the Gene Expression Omnibus (GEO) database. The least absolute shrinkage and selection operator (LASSO) regression and logistic regression analysis were utilized to construct a model for distinguishing IgAN from control samples. Based on the expression levels of m6A regulators, unsupervised clustering was used to identify m6A-induced molecular clusters in IgAN. Gene set enrichment analysis (GSEA) and immunocyte infiltration among different clusters were examined. The gene modules with the highest correlation for each of the three clusters were identified by weighted gene co-expression network analysis (WGCNA). A model containing 10 m6A regulators was developed using LASSO and logistic regression analyses. Three molecular clusters were determined using consensus clustering of 24 m6A regulators. A decrease in the expression level of YTHDF2 in IgAN samples was significantly negatively correlated with an increase in resting natural killer (NK) cell infiltration and was positively correlated with the abundance of M2 macrophage infiltration. The risk scores calculated by the nomogram were significantly higher for cluster-3, and the expression levels of m6A regulators in this cluster were generally low. Immunocyte infiltration and pathway enrichment results for cluster-3 differed significantly from those for the other two clusters. Finally, the expression of YTHDF2 was significantly decreased in IgAN based on immunohistochemical staining. This study demonstrated that m6A methylation regulators play a significant role in the regulation of the immune microenvironment in IgAN. Based on m6A regulator expression patterns, IgAN can be classified into multiple subtypes, which might provide additional insights into novel therapeutic methods for IgAN.

Changes in mechanosensitive ion channels following radiation have seldom been linked to therapeutic sensitivity or specific factors involved in antitumor immunity. Here, in this study, we found that the mechanical force sensor, Piezo2, was significantly upregulated in tumor cells after radiation, and Piezo2 knockout in tumor cells enhanced tumor growth suppression by radiotherapy. Specifically, loss of Piezo2 in tumor cells induced their IL-15 expression via unleashing JAK2/STAT1/IRF-1 axis after radiation. This increase in IL-15 activates IL-15Rα on tumor-infiltrating CD8+ T cells, thereby leading to their augmented effector and stem cell–like properties, along with reduced terminal exhausted feature. Importantly, Piezo2 expression was negatively correlated with CD8 infiltration, as well as with radiosensitivity of patients with rectum adenocarcinoma receiving radiotherapy treatment. Together, our findings reveal that tumor cell–intrinsic Piezo2 induces radioresistance by dampening the IRF-1/IL-15 axis, thus leading to impaired CD8+ T cell–dependent antitumor responses, providing insights into the further development of combination strategies to treat radioresistant cancers.

Background:Renal ischemia-reperfusion injury (IRI) is an inevitable occurrence during kidney transplantation. Mitophagy, ferroptosis, and the associated immune microenvironment (IME) have been shown to play important roles in renal IRI. However, the role of mitophagy-associated IME genes in IRI remains unclear. In this study, we aimed to construct a prediction model of IRI prognosis based on mitophagy-associated IME genes.Method:The specific biological characteristics of the mitophagy-associated IME gene signature were comprehensively analyzed using public databases such as GEO, Pathway Unification, and FerrDb. Correlations between the expression of prognostic genes and immune-related genes and IRI prognosis were determined by Cox regression, LASSO analysis, and Pearson's correlation. Molecular validation was performed using human kidney 2 (HK2) cells and culture supernatant as well as the serum and kidney tissues of mice after renal IRI. Gene expression was measured by PCR, and inflammatory cell infiltration was examined by ELISA and mass cytometry. Renal tissue damage was characterized using renal tissue homogenate and tissue sections.Results:The expression of the mitophagy-associated IME gene signature was significantly correlated with IRI prognosis. Excessive mitophagy and extensive immune infiltration were the primary factors affecting IRI. In particular, FUNDC1, SQSTM1, UBB, UBC, KLF2, CDKN1A, and GDF15 were the key influencing factors. In addition, B cells, neutrophils, T cells, and M1 macrophages were the key immune cells present in the IME after IRI. A prediction model for IRI prognosis was constructed based on the key factors associated with the mitophagy IME. Validation experiments in cells and mice indicated that the prediction model was reliable and applicable.Conclusion:We clarified the relationship between the mitophagy-related IME and IRI. The IRI prognostic prediction model based on the mitophagy-associated IME gene signature provides novel insights on the prognosis and treatment of renal IRI.

Objective·To investigate the role of methyltransferase like 3 (METTL3) acting on N6-methyladenosine (m6A) and regulating pri-miR-21 methylation in the renal fibrosis of diabetic nephropathy (DN).Methods·Eight-week-old male db/db mice were used as DN models, and db/m mice were used as controls. The mice were randomly divided into 4 groups according to whether they received the treatment of 3-deazaadenosine (DAA) by tail vein injection or not (5 mice/group): db/m group, db/db group, db/m+DAA group and db/db+DAA group. From the age of 8 weeks, DAA was injected once per 5 d for a total of 8 times. After the DAA intervention, the mice were kept until they were 19 weeks old. The blood, the urine and the kidney tissue samples of the mice were collected, and blood glucose (BG), serum creatinine (Scr), and urinary albumin-to-creatinine ratio (ACR) were detected. The kidneys were stained with hematoxylin-eosin (H-E), Masson and sirius red to observe the pathological changes. The methylation level of m6A in total RNAs of the kidney was detected with the kit. The expression levels of METTL3 and fibrosis-related proteins in the kidney were detected by Western blotting. The overall pri-miR-21 and the mature miR-21 were detected by real-time quantitative PCR. After enrichment of the m6A-methylated RNAs in the kidney by immunomagnetic beads, the methylated pri-miR-21 at m6A was detected by PCR.Results·Compared with the db/m group, the levels of BG, Scr, and ACR, and METTL3, m6A methylation level, fibrosis-related proteins, overall pri-miR-21, m6A-methylated pri-miR-21 and mature miR-21 in the kidney in the db/db group significantly increased (P<0.05). Furthermore, the mesangial matrix in the kidney increased, glomerular basement membrane thickened, and the accumulation of collagen fibers increased significantly in the db/db group. Compared with the db/db group, the levels of BG, Scr, and ACR, and m6A methylation level, fibrosis-related proteins, m6A-methylated pri-miR-21 and mature miR-21 in the kidney in the db/db+DAA group decreased significantly (P<0.05) and the degree of renal injury and fibrosis was significantly reduced, but the expression level of overall pri-miR-21 significantly increased (P=0.000). The expression level of METTL3 protein did not change significantly.Conclusion·The m6A methylation modification of pri-miR-21 promotes the maturation of miR-21, thereby promoting the occurrence and development of renal fibrosis in DN mice; inhibition of METTL3 can inhibit renal fibrosis in DN mice by regulating m6A methylation of pri-miR-21.

Neutrophils, as the first defenders against external microbes and stimuli, are highly active and finely regulated innate immune cells. Emerging evidence has challenged the conventional dogma that neutrophils are a homogeneous population with a short lifespan that promotes tissue damage. Recent findings on neutrophil diversity and plasticity in homeostatic and disease states have centered on neutrophils in the circulation. In contrast, a comprehensive understanding of tissue-specialized neutrophils in health and disease is still lacking. This article will first discuss how multiomics advances have contributed to our understanding of neutrophil heterogeneity and diversification in resting and pathological settings. This discussion will be followed by a focus on the heterogeneity and role of neutrophils in solid organ transplantation and how neutrophils may contribute to transplant-related complications. The goal of this article is to provide an overview of the research on the involvement of neutrophils in transplantation, with the aim that this may draw attention to an underappreciated area of neutrophil research.

Significance Statement Hypoxia is a hallmark of renal ischemia-reperfusion injury (IRI) and serves as an essential regulator of innate immune responses during this process, although the mechanisms of this regulation remain unclear. Here, we showed in a murine model that HIF-2 α knockout in dendritic cells (DCs) exacerbated renal IRI through activation of natural killer T cells. Mechanistically, HIF-2 α deficiency upregulated CD36 expression of DCs, leading to cellular lipid accumulation. Pharmacologic inhibition of CD36 in DCs resulted in renoprotection by reducing lipid content and suppressing natural killer T cell activation. Our study strongly suggests that targeting the HIF-2 α /CD36 regulatory axis may be a strategy for alleviating renal IRI. Background Hypoxia and hypoxia-inducible factors (HIFs) play essential and multiple roles in renal ischemia-reperfusion injury (IRI). Dendritic cells (DCs) comprise a major subpopulation of the immunocytes in the kidney and are key initiators and effectors of the innate immune responses after IRI. The role of HIF-2 α in DCs remains unclear in the context of renal IRI. Methods To investigate the importance of HIF-2 α in DCs upon renal IRI, we examined the effects of DC-specific HIF-2 α ablation in a murine model. Bone marrow–derived DCs (BMDCs) from DC-specific HIF-2 α –ablated mice and wild-type mice were used for functional studies and transcriptional profiling. Results DC-specific ablation of HIF-2 α led to hyperactivation of natural killer T (NKT) cells, ultimately exacerbating murine renal IRI. HIF-2 α deficiency in DCs triggered IFN- γ and IL-4 production in NKT cells, along with upregulation of type I IFN and chemokine responses that were critical for NKT cell activation. Mechanistically, loss of HIF-2 α in DCs promoted their expression of CD36, a scavenger receptor for lipid uptake, increasing cellular lipid accumulation. Furthermore, HIF-2 α bound directly to a reverse hypoxia-responsive element (rHRE) in the CD36 promoter. Importantly, CD36 blockade by sulfo- N -succinimidyl oleate (SSO) reduced NKT cell activation and abolished the exacerbation of renal IRI elicited by HIF-2 α knockout. Conclusions Our study reveals a previously unrecognized role of the HIF-2 α /CD36 regulatory axis in rewiring DC lipid metabolism under IRI-associated hypoxia. These findings suggest a potential therapeutic target to resolve long-standing obstacles in treatment of this severe complication.

目的 探索供体来源的细胞游离DNA(dd-cfDNA)在肾移植术后移植肾缺血再灌注损伤中的应用价值.方法 前瞻性的纳入2020年3月至5月于上海交通大学医学院附属仁济医院肾移植中心接受同种异体肾移植术的40例受试者,在术后第1、3、7天采集患者外周血,利用二代测序的方法对患者外周血中的dd-cfDNA％进行检测,同时检测患者相应时间点的肌酐.结果 本研究所有患者肾移植术后肾功能恢复顺利,无移植物功能延迟恢复及排斥反应的发生.整体分析发现:肌酐测量值、dd-cfDNA％在3个时间点的整体比较,差异有高度统计学意义(P<0.01).进一步两两比较,组内任意2个时间点的肌酐测量值、dd-cfDNA％浓度比较,差异均有高度统计学意义(P<0.01).术后第3天的肌酐测量值比术后第1天降低245.65μmol/L(95％置信区间:172.70～318.60μmol/L);术后第7天的肌酐测量值较术后第3天进一步降低195.95μmol/L(95％置信区间:153.02～238.88μmol/L).术后第3天的dd-cfDNA％浓度比术后第1天降低8.97％(95％置信区间:7.71％～10.24％);术后第7天的dd-cfDNA％浓度较术后第3天进一步降低1.63％(95％置信区间:1.32％～1.94％).结论 dd-cfDNA在肾移植术后移植肾缺血再灌注的不同时间段有差异性表达,对移植肾缺血再灌注损伤程度的评估具有一定价值.

Exosomes derived from mesenchymal stem cell (MSC) alleviate kidney damage through autophagy. This study determined whether MSCs relieve renal fibrosis and inhibit autophagy by exosome transfer of miRNA-122a. The gene expression involved in the mTOR signaling pathway and autophagy was assessed in TGF-β1-treated human renal tubular epithelial cells (HK-2) and unilateral ureteral obstruction (UUO) mice before and after MSC-derived exosomes and miRNA-122a mimic treatment. Small RNA (sRNA) next-generation sequencing was also performed on TGF-β1-treated HK-2 cells. MSC-derived exosomes relieve fibrosis caused by TGFβ in HK-2 via regulation of the mTOR signaling pathway and downstream autophagy. Furthermore, we found that MSC-derived exosomes mediate miRNA-122a to relieve renal fibrosis in HK-2 cells in response to TGF-β1 through the regulation of mTOR signaling and autophagy. In the UUO mouse model, miRNA-122a mimic-transfected MSC treatment and its combination with 3-MA both recapitulated the same results as the in vitro experiments, along with reduced expansion of renal tubule, interstitial expansion, and preservation of kidney architecture. The antifibrotic activity of MSC-derived exosomes after renal fibrosis occurs partially by autophagy suppression via excreted exosomes containing mainly miRNA-122a. These findings indicate that the export of miRNA-122a via MSC-derived exosomes represents a novel strategy to alleviate renal fibrosis.

OBJECTIVES:To evaluate the efficacy and safety of low-dose trimethoprim (TMP)-sulfamethoxazole (SMX) (TMP-SMX) as the primary prophylaxis for Pneumocystis jirovecii pneumonia (PJP) in adult recipients of kidney transplantation.METHODS:Three kinds of prescriptions in kidney recipients were documented, including 20 mg TMP/100 mg SMX oral daily, 20 mg TMP/100 mg SMX oral every other day, and nonprophylaxis. The primary outcome was the incidence of PJP in the first 180 days of follow-up after kidney transplantation. The secondary outcomes were changes in renal and liver function.RESULTS:Among the 1469 recipients, 1066 (72.56%) received 20 mg TMP/100 mg SMX daily, 127 (8.65%) received 20 mg TMP/100 mg SMX every other day, and 276 (18.79%) did not have prophylaxis prescription. The 276 recipients in the nonprophylaxis group had 124.92 person-years of follow-up, during which PJP occurred in 29 patients, for an incidence rate of 23.21 (95% confidence interval 15.76-32.72) per 100 person-years. The TMP-SMX daily group and the TMP-SMX every other day group had 524.89 and 62.07 person-years of follow-up, respectively, with no occurrence of PJP. There was no significant difference among the three groups in changes in renal and liver function (P >0.05, respectively). A total of 111 recipients in each group were enrolled in the propensity score matching analysis. It was revealed that the 111 nonprophylaxis recipients had 51.27 person-years of follow-up and 10 PJP cases. Prophylaxis was considered effective because there was a significant difference between the three groups (P <0.001).CONCLUSION:Low-dose TMP-SMX prophylaxis significantly reduces the incidence of PJP within 6 months after kidney transplantation and has a favorable safety profile.

Cholangiocarcinoma (CCA) is a type of solid tumor derived from the bile duct epithelium that features universal gemcitabine resistance. Here, we utilized a gene-encoded ROS biosensor probe (HyPer3 probe) to sort subpopulations with different redox statuses from CCA cells. The isolated HyPer-low subpopulation CCA cells, which exhibited relatively lower cellular ROS levels, exhibited higher chemoresistance to gemcitabine than HyPer-high subpopulation CCA cells in vitro and in vivo. Mechanistically, increased expression of MTHFD1 was found in HyPer-low cells. Knocking down MTHFD1 in HyPer-low cells enhanced cellular ROS and restored sensitivity to gemcitabine. Furthermore, the MTHFD1 inhibitor antifolate compound methotrexate (MTX) increased cellular ROS, and combining gemcitabine with MTX effectively suppressed cholangiocarcinoma cell growth. In summary, the MTHFD1 level mediated the heterogeneous cellular redox status in CCA, which resulted in chemoresistance to gemcitabine. Our data suggest a novel strategy for CCA chemotherapy.

Renal ischemia/reperfusion injury (IRI) is the major cause of acute kidney injury. However, mechanisms underlying the sudden loss in kidney function and tissue injury remain to be fully elucidated. Here, we performed RNA sequencing to systematically compare the transcriptome differences between IR injured kidneys and sham kidneys. We observed that mitochondrial dynamics was destructed in renal IRI. Expression of mitochondrial fusion-associated genes was reduced, whereas expression of mitochondrial fission-related genes was increased in renal IRI, and these findings were further confirmed by mitochondrial morphological observations. By screening 19 purinergic receptors, we noticed that P2RX1 expression was markedly upregulated in renal IRI. RNA sequencing and mitochondrial morphological observations revealed that mitochondrial dynamics was preserved in P2RX1 genetic knockout (P2rx1-/-) mice. Neutrophil extracellular traps (NETs) were reported to be essential for tissue injury in renal IRI, but the detailed mechanism remained unclear. In the present study, we found that P2RX1 favored the formation of neutrophil extracellular traps (NETs) in IRI, and NETs was essential for the impairment of mitochondrial dynamics. Mechanistically, P2RX1-involved metabolic interaction between platelets and neutrophils supported NETs formation. Activation of P2RX1 promoted platelets ATP release, which subsequently contributed to neutrophil glycolytic metabolism and NETs generation.

Cholestasis is common in multiple clinical circumstances. The NOD-like receptor protein 3 (NLRP3) inflammasome pathway has been demonstrated to play an important role in liver injury and fibrosis induced by cholestasis. We previously proved that MCC950, a selective NLRP3 inhibitor, alleviates liver fibrosis and injury in experimental liver cholestasis induced by bile-duct ligation (BDL) in mice. Herein, we investigate the role of calcipotriol, a potent vitamin D receptor agonist, in experimental liver cholestasis, test its therapeutic efficacy, and explore its potential protective mechanism. C57BL/6 mice were made to undergo BDL or fed the 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to establish two classic cholestatic models. Calcipotriol was administered intraperitoneally to these mice daily. Serum makers of liver damage and integrity, liver histological changes, levels of liver pro-fibrotic markers, bile acid synthetases and transporters were measured in vivo. The underlying mechanism by which calcipotriol alleviates cholestatic liver injury and fibrosis was further investigated. The results of the current study demonstrated that calcipotriol supplement significantly alleviate cholestatic liver injury and fibrosis. Moreover, calcipotriol supplement markedly inhibited NLRP3 inflammasome pathway activation to alleviate liver injury and fibrosis in vivo and inhibit hepatic stellate cell (HSC) activation in vitro. In addition, VDR agonist calcipotriol exert inhibitory effect on NLRP3 inflammasome activation through activating yes-associated protein 1 (YAP1). In conclusion, our findings proved that calcipotriol suppressed the NLRP3 signal by activating YAP1 to alleviate liver injury and retard fibrogenesis in cholestasis.

BACKGROUND:Endoscopic retrograde biliary drainage (ERBD) is the most frequently performed procedure for treating benign or malignant biliary obstruction. Although duodenal perforations secondary to the biliary plastic stent are quite rare, they can be life-threatening. The treatment strategies for such perforations are diverse and continue to be debated. CASE PRESENTATION:We report three cases of duodenal perforation due to the migration of biliary plastic stents that were successfully managed using an endoscope. The three patients were admitted on complaints of abdominal pain after they underwent ERBD. Abdominal computerized tomography (CT) revealed migration of the biliary plastic stents and perforation of the duodenum. Endoscopy was immediately performed, and perforation was confirmed. All migrated stents were successfully extracted endoscopically by using snares. In two of the three cases, the duodenal defects were successfully closed with haemostatic clips after stent retrieval, and subsequently, endoscopic nasobiliary drainage tubes were inserted. After the endoscopy and medical treatment, all three patients recovered completely. CONCLUSIONS:Duodenal perforations due to the migration of biliary stents are rare, and the treatment strategies remain controversial. Our cases and cases in the literature demonstrate that abdominal CT is the preferred method of examination for such perforations, and endoscopic management is appropriate as a first-line treatment approach.

Objective:To compare the effectiveness of human leukocyte antigen(HLA)matching and different kinds of mismatch score in predicting the risk of neonatal donor-specific antibody mediated acute rejection after kidney transplantation.Methods:Retrospective analysis was performed for the number of HLA high-resolution mismatches, Eplet mismatch scores and EMS mismatch scores in 174 donors and recipients. The study group was composed of 13 recipients with dn DSA-mediated acute rejection while the control group included 161 recipients with negative dn DSA. In conjunctions with clinical data, the effectiveness of three schemes in predicting the risk of dn DSA-mediated acute rejection after kidney transplantation was evaluated.Results:No significant inter-group statistical difference existed in the number of HLA mismatches(6.90 and 6.65, P=0.5824)or total Eplet(45.78 and 36.47, P=0.0876). There were significant inter-group statistical differences in the number of mismatches in Abver Eplet(23.33 and 17.07, P<0.05)and EMS scores for HLA-A (15.06 and 9.73, P=0.0425), HLA-B(16.53 and 8.06, P=0.0468)and HLA-DQ(22.30 and 17.96, P=0.0204). There was no statistical difference in HLA-DR EMS score(23.99 and 13.85, P=0.1356). Conclusions:Abver Eplet and EMS mismatch scoreS for a single HLA site can better predict the risk of dn DSA-mediated acute rejection after kidney transplantation.

目的 探讨内镜下乳头括约肌切开(EST)联合内镜下球囊扩张(EPBD)不同扩张时间对治疗胆总管结石的影响.方法 前瞻性分析上海交通大学医学院附属仁济医院2017年7月至2018年5月胆总管结石患者61例,随机分为三组:A组(22例)、B组(21例)、C组(18例),球囊扩张时间分别为30 s、60 s、180 s,所有患者术后观察48 h以上,根据各组残石率比较不同球囊扩张时间取石的有效性,通过各组术后并发症(胰腺炎、出血、穿孔、高淀粉酶血症等)的发生率比较不同球囊扩张时间的安全性.结果 三组除高淀粉酶血症发生率随球囊扩张时间延长而降低(P<0.05)外,三组手术时间、住院费用、术后住院时间以及术后并发症(残石、胰腺炎、出血、穿孔)发生率均无统计学差异(P>0.05).结论 EST联合EPBD短时间扩张和长时间扩张具有相近的安全性和有效性,建议在操作过程中适当缩短球囊扩张时间.

BACKGROUND:Single-incision laparoscopic surgery has emerged as an alternative to conventional laparoscopic cholecystectomy (LC) in the clinical setting. Limited information is available on the possibility of performing single-incision laparoscopic surgery as an ambulatory procedure. This study aimed to determine the feasibility and safety of single-incision laparoscopic cholecystectomy (SILC) versus conventional LC in an ambulatory setting. METHODS:Ninety-one patients were randomized to SILC (n = 49) or LC (n = 42). The success rate, operative duration, blood loss, hospital stay, gallbladder perforation, drainage, delayed discharge, readmission, total cost, complications, pain score, vomiting, and cosmetic satisfaction of the two groups were then compared. RESULTS:There were significant differences in the operative time (46.89 ± 10.03 min in SILC vs. 37.24 ± 10.23 min in LC; P < 0.001). As compared with LC, SILC was associated with lower total costs (8012.28 ± 752.67 RMB vs. 10258.91 ± 1087.63 RMB; P < 0.001) and better cosmetic satisfaction (4.94 ± 0.24 vs. 4.74 ± 0.54; P = 0.031). There were no significant differences between-group in terms of general data, success rate, blood loss, hospital stay, gallbladder perforation, drainage, delayed discharge, readmission, complications, pain score, and vomiting (P > 0.05). CONCLUSIONS:Ambulatory SILC is safe and feasible for selected patients. The advantages of SILC as compared with LC are improved cosmetic satisfaction and lower total costs.