Abstract Background & aims Abnormal cholesterol metabolism is involved in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). We investigated the role and mechanisms of lanosterol synthase (LSS) loss of function in the pathological process of MASLD. Methods MASLD models were induced by methionine-and choline-deficient diet (MCD) feeding in LSS+/− mice or wild type mice given LSS inhibitor RO48-8071. Transcriptomics analysis was performed to analyze differentially expressed genes in mice model. Lipidomic Profiling revealed the overall composition of lipid classes in MCD induced MASLD model. In vitro experiments using a MCDE (identical medium completely deficient of methionine and choline) induced cell model assessed the effect of LSS knockdown on MASLD development. Quantitative real-time PCR (qRT-PCR) and Western blot were employed to evaluate the differential expression of interested genes. Results In MCD induced MASLD models, obviously reduced steatotic phenotype, hepatic inflammatory injury and hepatocyte ballooning were found in LSS+/− mice. LSS loss of function alleviates liver injury and hepatic steatosis via reducing fatty deposition and triglyceride accumulation in hepatocytes. Mechanistically, LSS dysfunction promotes fatty acid β-oxidation and ketogenesis in liver cells to mediate attenuating effect on MASLD development. Conclusions Targeting LSS alleviates MASLD development by promoting fatty acid β-oxidation and ketogenesis.

BACKGROUND:Bronchopulmonary dysplasia (BPD) is a chronic lung disease characterized by inflammation, often caused by prolonged hyperoxia exposure in preterm infants. Platelet-activating factor (PAF) is a potent inflammatory mediator, but its role in BPD is unclear. This study explores the therapeutic potential of the PAF receptor antagonist Ginkgolide B (GB) in hyperoxia-induced lung injury. METHODS:We observed the activation status of platelets and neutrophils in BALF（bronchoalveolar lavage fluid) of patients with BPD. The supernatant of BALF from patients was sent for protein chip detection and validated by ELISA. We also measured the levels of PAF in peripheral blood and BALF. In vitro experiments, we stimulated neutrophils with PAF to detect the expression of inflammatory cytokine genes. Finally, we established a neonatal rat model of hyperoxia-induced lung injury mimicking BPD and intervened with GB. RESULTS:We observed early activation of platelets and neutrophils in the peripheral blood of BPD patients, with elevated plasma levels of PAF and myeloperoxidase-DNA (MPO-DNA). In BALF, neutrophils showed increased CD66b and MPO expression. In vitro, PAF stimulation decreased CD62L expression on neutrophils and upregulated IL-6 mRNA. Elevated levels of PAF, IL-6, IL-8, and GM-CSF were found in BPD infants' BALF supernatant. Using animal models of BPD, we found that GB significantly reduced lung damage in hyperoxia-exposed rats. GB decreased neutrophil-derived IL-6 and downregulated key proteins in the IL-6 signaling pathway (pJak2 and pStat3). CONCLUSION:Our study demonstrates that PAF activates neutrophils and promotes their lung residence. GB effectively inhibits neutrophil-derived IL-6 and alleviates hyperoxia-induced lung damage. Targeting the PAF pathway with GB may be a promising strategy for BPD and other hyperoxia-related lung diseases.

BDE-209 exposure induced male reproductive toxicity with sperm quality decline. However, the role of autophagy in this was unclear. The purpose was to evaluate the protective effect and its potential mechanism of trehalose (Tre, autophagy inducer) on reproductive damage during spermiogenesis induced by BDE-209. We used 2% w/v Tre and 75 mg/kg/d BDE-209 cotreated mice for 42 days. GC-2 spd cells were cotreated with Tre, chloroquine (CQ, inhibition of autophagic flux), compound C (CC, AMPK inhibitor), and BDE-209. Tre intake significantly recovered decrease in sexual organ ratio and poor sperm quality in BDE-209-exposed mice. Supplementation with Tre rescued sperm head malformation by improving aberrant histone-protamine exchange in BDE-209-exposed mice. However, Tre intake couldn't restore the acrosome biogenesis. In addition, Tre supplementation improved testicular damage induced by BDE-209. BDE-209 blocked autophagic flux with increased P62 and LC3BII/I levels. Mechanistically, CQ treatment aggravated elevation of P62 and LC3BII/I levels induced by BDE-209, otherwise, CC and Tre treatments inhibited the rise in p-AMPK, p-ULK1, P62 and LC3BII/I levels induced by BDE-209. Tre supplementation improved reproductive injury in BDE-209-exposed mice by regulating autophagic flow via AMPK-ULK1 signaling pathways, which providing a new theoretical basis and possible therapeutic targets for male reproductive toxicity.

Most studies of enviromental toxic chemicals focused on the meiosis stage during spermatogenesis, however, the research on the spermiogenesis damage phenotype of BDE-209 is limited. This study aimed to evaluate the processes by which BDE-209 regulates the formation of acrosomes and mitochondrial sheath (MS), key structures during spermiogenesis and fertilization. ICR mice were divided into control, low, medium, and high-dose BDE-209 groups and treated for 42 days. A comprehensive method combining ultrastructural analysis, transcriptomics, molecular biology, and fertility experiments was adopted. In mice exposed to BDE-209, testicular dysplasia, altered sex hormone concentrations, decreased semen quality, and head and tail deformities occurred. Chromatin condensation failure was present in BDE-209-exposed spermatozoa with decreased mRNA and protein levels of PRM1 and TNP1. BDE-209 disrupts the acrosome biogenesis process by disrupting the Golgi structure and the apical ectoplasmic specialization (ES) structure. BDE-209 exposure caused multiple damage to the MS and down-regulated the mRNA levels of Akap3, Akap4, Cfap44, Ccdc40, Dhah1, etc. These injuries resulted in subfertility in BDE-209 male mice, and the male offspring also exhibited gonadal dysplasia, sex hormonal changes, and decreased semen quality. Conclusively, BDE-209 exposure induced spermiogenesis defects and subfertility. F0 and F1 males showed a similar injury phenotype. This study advanced the understanding of the damage phenotype of spermiogenesis and complemented the reproductive toxicity of F1 male mice. These findings might be important for the study of related molecular mechanisms and the mitigation of BDE-209 exposure on offspring development.

Given resveratrol's (RES) potential as an anti-aging agent, this study explored its ability to inhibit the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome through the miR-217/SIRT1 axis in senescent endothelial cells. Male C57BL/6 mice were administered a customized regular diet supplemented with 0.04 % RES for 64 consecutive weeks. Subsequently, the effects of RES on senescent human umbilical vein endothelial cells (HUVECs) induced by H2O2 were evaluated. Gene expression analyses were conducted following SIRT1 knockdown in HUVECs treated with H2O2 and RES, or transfected with miR-217 mimics and inhibitors. The study found that RES reduced body weight, improved endothelial function, enhanced SIRT1 expression, and suppressed the expression of miR-217, NADPH oxidase 4 (NOX4), and NLRP3 in the senescent thoracic aorta. Additionally, RES significantly reduced the expression of NOX4, X-box binding protein 1 spliced (XBP1s), and reactive oxygen species (ROS) production in a dose-dependent manner in senescent HUVECs. SIRT1 knockdown resulted in the activation of the NLRP3 inflammasome by upregulating NOX4 and XBP1s expression, an effect that was partially attenuated by RES pretreatment. RES also suppressed the expression of miR-217 induced by H2O2. The miR-217 mimic facilitated cellular senescence; however, RES mitigated this effect, which was further amplified by the miR-217 inhibitor.

BackgroundGallbladder cancer (GBC) poses a significant risk to human health. Its development is influenced by numerous factors, particularly the homeostasis of reactive oxygen species (ROS) within cells. This homeostasis is crucial for tumor cell survival, and abnormal regulation of ROS is associated with the occurrence and progression of many cancers. Dihydrotanshinone I (DHT I), a biologically effective ingredient isolated from salvia miltiorrhiza, has exhibited cytotoxic properties against various tumor cells by inducing apoptosis. However, the precise molecular mechanisms by which dht I exerts its cytotoxic effects remain unclear.PurposeTo explore the anti-tumor impact of dht I on GBC and elucidate the potential molecular mechanisms.MethodsThe proliferation of GBC cells, NOZ and SGC-996, was assessed using various assays, including CCK-8 assay, colony formation assay and EdU staining. We also examined cell apoptosis, cell cycle progression, ROS levels, and alterations in mitochondrial membrane potential to delve into the intricate molecular mechanism. Quantitative PCR (qPCR), immunofluorescence staining, and Western blotting were performed to evaluate target gene expression at both the mRNA and protein levels. The correlation between nuclear factor erythroid 2-related factor 2 (Nrf2) and kelch-like ECH-associated protein 1 (Keap1) were examined using co-immunoprecipitation. Finally, the in vivo effect of dht I was investigated using a xenograft model of gallbladder cancer in mice.ResultsOur research findings indicated that dht I exerted cytotoxic effects on GBC cells, including inhibiting proliferation, disrupting mitochondrial membrane potential, inducing oxidative stress and apoptosis. Our in vivo studies substantiated the inhibition of dht I on tumor growth in xenograft nude mice. Mechanistically, dht I primarily targeted Nrf2 by promoting Keap1 mediated Nrf2 degradation and inhibiting protein kinase C (PKC) induced Nrf2 phosphorylation. This leads to the suppression of Nrf2 nuclear translocation and reduction of its target gene expression. Moreover, Nrf2 overexpression effectively counteracted the anti-tumor effects of dht I, while Nrf2 knockdown significantly enhanced the inhibitory effect of dht I on GBC. Meanwhile, PKC inhibitors and nuclear import inhibitors increased the sensitivity of GBC cells to dht I treatment. Conversely, Nrf2 activators, proteasome inhibitors, antioxidants and PKC activators all antagonized dht I induced apoptosis and ROS generation in NOZ and SGC-996 cells.ConclusionOur findings indicated that dht I inhibited the growth of GBC cells by regulating the Keap1-Nrf2 signaling pathway and Nrf2 phosphorylation. These insights provide a strong rationale for further investigation of dht I as a potential therapeutic agent for GBC treatment.

Acyl-CoA thioesterase 4 (ACOT4) has been reported to be related to acetyl-CoA carboxylase activity regulation; However, its exact functions in liver lipid and glucose metabolism are still unclear. Here, we discovered explored the regulatory roles of ACOT4 in hepatic lipid and glucose metabolism in vitro. We found that the expression level of ACOT4 was significantly increased in the hepatic of db/db and ob/ob mice as well as obese mice fed a high fat diet. Adenovirus-mediated overexpression of ACOT4 promoted gluconeogenesis and high-glucose/high-insulin-induced lipid accumulation and impaired insulin sensitivity in primary mouse hepatocytes, whereas ACOT4 knockdown notably suppressed gluconeogenesis and decreased the triglycerides accumulation in hepatocytes. Furthermore, ACOT4 knockdown increased insulin-induced phosphorylation of AKT and GSK-3β in primary mouse hepatocytes. Mechanistically, we found that upregulation of ACOT4 expression inhibited AMP-activated protein kinase (AMPK) activity, and its knockdown had the opposite effect. However, activator A769662 and inhibitor compound C of AMPK suppressed the impact of the change in ACOT4 expression on AMPK activity. Our data indicated that ACOT4 is related to hepatic glucose and lipid metabolism, primarily via the regulation of AMPK activity. In conclusion, ACOT4 is a potential target for the therapy of non-alcoholic fatty liver (NAFLD) and type 2 diabetes.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-induced protein, and it has been reported that ER stress and unfolded protein response (UPR) are closely related to the immune system. The spleen is an important immune organ and we have shown in our previous research that MANF is expressed in human spleen tissues. However, there have been limited studies about the effect of MANF on spleen development. In this study, we detected MANF expression in spleen tissues and found that MANF was expressed in the red pulp and marginal zone. Additionally, MANF was localized in the CD68+ and CD138+ cells of adult rat spleen tissues, but not in the CD3+ cells. We performed immunohistochemical staining to detect MANF expression in the spleen tissues of rats that were different ages, and we found that MANF+ cells were localized together in the spleen tissues of rats that were 1-4 weeks old. MANF was also expressed in CD68+ cells in the spleen tissues of rats and mice. Furthermore, we found that MANF deficiency inhibited white pulp development in MANF knockout mice, thus indicating that MANF played an important role in the white pulp development of rodent spleen tissues.

Non-alcoholic fatty liver disease (NAFLD) is a major health concern worldwide, and the incidence of metabolic disorders associated with NAFLD is rapidly increasing because of the obesity epidemic. There are currently no approved drugs that prevent or treat NAFLD. Recent evidence shows that bavachin, a flavonoid isolated from the seeds and fruits of Psoralea corylifolia L., increases the transcriptional activity of PPARγ and insulin sensitivity during preadipocyte differentiation, but the effect of bavachin on glucose and lipid metabolism remains unclear. In the current study we investigated the effects of bavachin on obesity-associated NAFLD in vivo and in vitro. In mouse primary hepatocytes and Huh7 cells, treatment with bavachin (20 μM) significantly suppressed PA/OA or high glucose/high insulin-induced increases in the expression of fatty acid synthesis-related genes and the number and size of lipid droplets. Furthermore, bavachin treatment markedly elevated the phosphorylation levels of AKT and GSK-3β, improving the insulin signaling activity in the cells. In HFD-induced obese mice, administration of bavachin (30 mg/kg, i.p. every other day for 8 weeks) efficiently attenuated the increases in body weight, liver weight, blood glucose, and liver and serum triglyceride contents. Moreover, bavachin administration significantly alleviated hepatic inflammation and ameliorated HFD-induced glucose intolerance and insulin resistance. We demonstrated that bavachin protected against HFD-induced obesity by inducing fat thermogenesis and browning subcutaneous white adipose tissue (subWAT). We revealed that bavachin repressed the expression of lipid synthesis genes in the liver of obese mice, while promoting the expression of thermogenesis, browning, and mitochondrial respiration-related genes in subWAT and brown adipose tissue (BAT) in the mice. In conclusion, bavachin attenuates hepatic steatosis and obesity by repressing de novo lipogenesis, inducing fat thermogenesis and browning subWAT, suggesting that bavachin is a potential drug for NAFLD therapy.

Most nonalcoholic steatohepatitis (NASH) patients develop severe fibrosis through extracellular matrix (ECM) accumulation, which can lead to hepatocellular carcinoma (HCC). Fibroblast growth factor 9 (FGF9) is involved in serial types of cancer; however, the specific role of FGF9 in NASH-driven HCC is not fully understood. This study finds that FGF9 is increased in patients with NASH-associated HCC. Furthermore, NASH-driven HCC mice models by feeding wildtype mice with high-fat/high-cholesterol (HFHC) diet and low dose carbon tetrachloride (CCl4 ) treatment is established; and identified that hepatic FGF9 is increased; with severe fibrosis. Additionally, AAV-mediated knockdown of FGF9 reduced the hepatic tumor burden of NASH-driven HCC mice models. Hepatocyte-specific FGF9 transgenic mice (FGF9Alb ) fed with a HFHC diet without CCl4 treatment exhibited an increased hepatic ECM and tumor burden. However, XAV-939 treatment blocked ECM accumulation and NASH-driven HCC in FGF9Alb mice fed with HFHC diet. Molecular mechanism studies show that FGF9 stimulated the expression of ECM related genes in a β-catenin dependent manner; and FGF9 exerts its effect on β-catenin stability via the ERK1/2-GSK-3β signaling pathway. In summary, the data provides evidence for the critical role of FGF9 in NASH-driven HCC pathogenesis; wherein it promotes the tumors formation through the ECM pathway.

BACKGROUND Long term peritoneal dialysis leads to peritoneal epithelial-mesenchymal transformation (EMT), angiogenesis, and ultrafiltration failure. Although recent evidence suggests that inhibiting STAT3 (signal transducer and activator of transcription 3) can prevent kidney fibrosis, and that STAT3 can enhance glucose metabolism, the effect of STAT3 in peritoneal fibrosis (PF) has not been clarified. METHODS Our study determined the effects of STAT3 on EMT and key glycolysis enzymes in mesothelial HMrSV5 cells by knockdown and overexpression of STAT3. In addition, we established a rat PF model to examine the role of pharmacologic inhibition of STAT3 or 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3) in this process. RESULTS High glucose (HG) caused the upregulation of α-smooth muscle actin and transforming growth factor beta 1 and the downregulation of E-cadherin, and induced STAT3 activation in HMrSV5 cells. In addition, HMrSV5 cells cultured in high glucose showed high expression of key glycolysis enzymes, which could be inhibited by STAT3 siRNA. Furthermore, treating mesothelial cells with 3PO, the PFKFB3 inhibitor, could attenuate high glucose-induced EMT. Moreover, daily administration of dialysis fluid could induce peritoneal fibrosis. The peritoneal fibrosis was accompanied by enhanced phosphorylation of STAT3 and the upregulation of PFKFB3. The administration of BP-1-102 or 3PO prevented fibrosis and inhibited angiogenesis in PF rats. CONCLUSIONS si-STAT3 attenuated the HG-induced EMT and hyperglycolysis, and the overexpression of STAT3 could induce EMT in HMrSV5 cells. 3PO could markedly attenuate HG-induced EMT by decreasing PFKEB3 in HMrSV5 cells. In addition, we demonstrated that inhibiting STAT3 signaling or peritoneal hyperglycolysis could attenuate peritoneal fibrosis and angiogenesis in vivo. Our findings linked the STAT3/PFKFB3 signaling to the development of PF. HG/STAT3/PFKFB3 might promote the progression of PF through regulating profibrosis and angiogenesis.

The morbidity and mortality of pancreatic cancer have been continuously increasing, causing seven deaths per 100,000 individuals/year. At present, effective therapies are severely lacking, thus, highlighting the importance of developing novel therapeutic approaches. The present study aimed to investigate the inhibitory roles of the 2,3-oxidosqualene cyclase inhibitor, RO 48-8071 (RO), on pancreatic ductal adenocarcinoma. RO was used to treat the pancreatic cancer cell line (PANC-1) in vitro to examine the effects of RO on cell viability, as well as to determine its potential molecular mechanism. Moreover, experiments in a xenograft model of subcutaneous tumors generated by injecting PANC-1 cells hypodermically into nude mice were performed to observe the inhibition of RO on tumor growth. It was found that RO inhibited PANC-1 cell viability when treatment was given for 24, 48 and 72 h. The in vivo study demonstrated that RO markedly inhibited subcutaneous tumor growth in nude mice. Further studies revealed that RO could induce cell cycle arrest in the G(1) phase by regulating p27, cyclin B1 and cyclin E expression to inhibit PANC-1 cell viability. Moreover, RO inactivated the JNK and ERK MAPK signaling pathway by decreasing the phosphorylation levels of JNK and ERK. Collectively, the present study demonstrated that RO served anti-pancreatic cancer roles in vitro and in vivo, which may provide new ideas and facilitate the development of novel treatment options for pancreatic cancer.

Chronic cerebral hypoperfusion (CCH), as a critical factor of chronic cerebrovascular diseases, has greatly influenced the health of patients with vascular dementia. Vitexin, a flavone C-glycoside (apigenin-8-C-β-D-glucopyranoside) that belongs to the flavone subclass of flavonoids, has been shown to possess antioxidant and anti-ischemic properties; however, the putative protective effects of vitexin on the CCH need further investigation. In the current study, the role of vitexin and its underlying mechanism were investigated with permanent bilateral common carotid artery occlusion (2VO) in rats as well as mouse hippocampal neuronal (HT22) cells with oxygen and glucose deprivation/reoxygenation (OGD/R) injury model. The results demonstrated that vitexin improved cognitive dysfunction as well as alleviated pathological neuronal damage in hematoxylin plus eosin (HE) and TUNEL results. The decreased levels of exchange protein directly activated by cAMP 1 (Epac1), Epac2, Ras-associated protein 1 (Rap1), and phospho-extracellular signal-regulated kinase (p-ERK) were reversed by vitexin in rats with CCH. Furthermore, this study indicated that vitexin alleviated CCH-induced inflammation injuries by reducing the expression of NOD-like receptor 3 (NLRP3), caspase-1, interleukin 1β (IL-1β), IL-6, and cleaved caspase-3. In vitro, vitexin increased the expression of Epac1 and Epac2, decreased the activation of the NLRP3-mediated inflammation, and improved cell viability. Taken together, our findings suggest that vitexin can reduce the degree of the progressing pathological damage in the cortex and hippocampus and inhibit further deterioration of cognitive function in rats with CCH. Epac and NLRP3 can be regulated by vitexin in vivo and in vitro, which provides enlightenment for the protection of CCH injury.

OBJECTIVEThis study aimed to explore the relationship between diabetic xerostomia and changes in aquaporin-1 (AQP1), aquaporin-5 (AQP5), and aquaporin-8 (AQP8) expression in the submandibular glands (SMGs), to further study the pathogenesis of diabetic xerostomia and to observe the therapeutic effect of insulin (INS).METHODSThirty SD rats were randomized equally into 3 groups: control group, diabetic model (DM) group and insulin (INS) group (n=10, respectively). The control group received no treatment. DM group and INS group were induced by a high-fat diet and streptozotocin intraperitoneal injection. After establishment of a diabetic rat model, the rats in INS group were treated with insulin. Then all rats were fed continuously with ordinary diet for 2 months. H&E staining was used to describe morphologic changes in the SMGs of rats. Immunohistochemistry was used to analyze the expressions and localization of AQP1, AQP5, and AQP8 in the SMGs. Computer image analysis was used to detect the mean optical density (MOD) values of AQP1, AQP5, and AQP8 expression, and changes in the diameters of acini and ducts.RESULTSThe acini were mildly atrophied and the acinar cells were rearranged in an irregular way. The morphology of insulin-administered diabetic SMGs was similar to that of the control group. The acinar average circumference and GCT average diameter in DM group were significantly reduced (P<0.05). The acinar average circumference and GCT average diameter of INS group were significantly increased (P<0.05). The expressions of AQP1, AQP5, and AQP8 were significantly reduced in DM group (P<0.05). The expressions of AQP1, AQP5, and AQP8 in INS group were significantly increased (P<0.05).CONCLUSIONThe decreased expressions of AQP1, AQP5, and AQP8 led to decreased salivary secretion of SMGs in diabetic rats, which may be involved in the pathogenesis of diabetic xerostomia. Insulin could up-regulate the expressions of AQP1, AQP5 and AQP8, and play a protective role in the secretory function of diabetic SMGs.

Pancreatic cancer ranks seventh in terms of cancer‑related mortality in men and women worldwide, where the most common subtype is pancreatic ductal adenocarcinoma (PDAC). To date, the pathogenesis of PDAC remains incompletely understood and the prognosis of PDAC is poor. In the present study, the expression of interleukin‑28 receptor α subunit (IL‑28RA) in PDAC tissues was detected using immunofluorescence staining and western blotting. IL‑28RA recombinant plasmids and control pCMV6‑entrymammalian expression plasmid, short hairpin (sh)IL‑28RA plasmids and control pRS scrambled shRNA vector purchased were used to produce stably transfected PANC‑1 cells overexpressing IL‑28RA or with IL‑28RA expression knocked down. MTS assays were used to measure cell viability and wound healing assay was used to assess the cell migratory ability in vitro. Flow cytometry analysis was performed to determine the proportion of cells in each phase of the cell cycle whereas total protein and phosphorylated protein levels were assessed using western blotting. Xenograft models of subcutaneous tumors were established by injecting PANC‑1 cells hypodermically into nude mice to investigate the effect of IL‑28RA on tumorigenesis and tumor growth. The results showed that the expression of IL‑28RA in PDAC tissues was lower compared with that in normal tissues. IL‑28RA overexpression in vitro resulted in the activation of the IL‑28RA pathway, which reduced cell viability and decreased the proportion of cells in the G2/M phase by reducing cyclin B1 expression. In addition, IL‑28RA overexpression inhibited migration of PDAC cells. By contrast, an increased proportion of cells in G2/M phase, upregulated cyclin B1 expression and enhanced cell viability and migratory ability along with inhibition of the IL‑28RA pathway were observed in PANC‑1 cells following IL‑28RA knockdown. The inhibitory effect of IL‑28RA was observed by tumor size in a nude mouse model induced by PANC‑1 cells with stable IL‑28RA overexpression or knockdown. The tumor size induced by PANC‑1 cells with stable IL‑28RA overexpression were smaller, whilst larger tumors induced by PANC‑1 cells were observed following stable IL‑28RA knockdown, when compared to control. Further studies showed that the effect of IL‑28RA on PDAC cells was exerted by regulating the phosphorylation levels of STAT1 and AKT. In conclusion, lower IL‑28RA expression may contribute to the pathogenesis of PDAC, where results from the present may provide further insights into the progression of PDAC, in addition to highlighting potentially novel therapeutic targets for this disease.

第二课堂是提升大学生综合素质与实践能力的重要渠道,是高校科技创新人才培养不可缺少的育人课堂,也是全面落实素质教育的基本途径.本实验室为开展大学生第二课堂途径进行了多方位的积极探索,总结了第二课堂在大学生综合素质提升、能力培养和教学相长中的独特作用.

目的 探讨磷酸化tau蛋白(P-tau)及其与总tau蛋白(P-tau/T-tau)比对预测创伤性脑损伤(traumatic brain injury,TBI)病人6个月内死亡和预后情况的诊断效能.方法 2017年6月～2019年6月收治的TBI病人90例.采用格拉斯哥预后评分(GOS)记录病人随访6个月后死亡和预后情况,由此将病人分为死亡组、存活组、预后良好组、预后不良组,采用Logistic回归分析死亡相关因素,分析伤后6小时内P-tau、P-tau/T-tau与GOS评分相关性,绘制ROC曲线评估前二者对死亡和预后的预测效能.结果 最终纳入86例,死亡组发病至入院时间、P-tau、P-tau/T-tau均高于存活组,格拉斯哥昏迷评分(GCS)低于存活组,差异有统计学意义(P<0.05);P-tau和P-tau/T-tau为死亡危险因素(P<0.05);预后良好组GOS评分高于预后不良组,P-tau和P-tau/T-tau低于预后不良组,差异有统计学意义(P<0.05);P-tau和P-tau/T-tau均与GOS评分呈负相关(r=-0.773、-0.745,均P=0.000);P-tau和P-tau/T-tau预测病人死亡的AUC分别为0.767与0.873、0.968与0.961,两者预测死亡(91.30％和91.34％)和预后(94.11％和91.24％)的敏感性无明显差异(P>0.05).结论 P-tau水平和P-tau/T-tau值可有效预测TBI病人6个月内死亡和预后情况.

Vitexin (VT) is a main bioactive flavonoid compound derived from the dried leaf of hawthorn (Crataegus pinnatifida), a widely used Chinese traditional folk medicine. Recent studies have shown that vitexin presents cardioprotective effects in vivo and in vitro. Mitochondrial dysfunction is a salient feature of myocardial ischemia/reperfusion (I/R) injury (MIRI), but the potential mechanism is still unclear. This study investigated the cardioprotective effect of vitexin against MIRI and its possible mechanism. Isolated SD rat hearts were subjected to MIRI in a Langendorff perfusion system, and H9c2 cells were subjected to hypoxia/reoxygenation (H/R) in vitro. Ex vivo experiments showed improved left ventricular function and reduced infarct size in the vitexin group. Transmission electron microscopy showed that I/R caused outer mitochondrial membrane rupture, cristae disappearance and vacuolation, while vitexin reduced mitochondrial damage and ultimately reduced cardiomyocyte apoptosis. In vitro, vitexin protected H9c2 cells from H/R-induced mitochondrial dysfunction, significantly reducing ROS levels; improving mitochondrial activity, mitochondrial membrane potential and ATP content; markedly increasing MFN2 expression and reducing the recruitment of Drp1 in mitochondria. These results suggest a new protective mechanism of vitexin for ischemic heart disease treatment.

目的 探讨白藜芦醇(resveratrol,Res)对H2O2处理的佐剂性关节炎(adjuvant arthritis,AA)大鼠软骨细胞增生的影响及其与自噬的关系.方法 采取弗氏完全佐剂注射SD大鼠左侧足趾皮下制作AA动物模型.第15天时,动物处死,取股动脉血,检测AA大鼠氧化应激状态.酶消化法体外培养和鉴定AA大鼠原代软骨细胞,给予低浓度H2O2(5μmol/L)处理原代软骨细胞,模拟体内氧化应激状态.给予不同浓度Res处理,MTT法检测软骨细胞增生活性,激光共聚焦检测软骨细胞中自噬相关基因5(Atg5)的表达,Western blot法检测软骨细胞中p62、Beclin-1自噬相关蛋白的表达.结果 组织染色结果显示:AA大鼠踝关节滑膜组织增生,滑膜中炎细胞明显浸润,软骨膜的连续性被破坏,排列紊乱.AA模型中血清丙二醛含量(11.65±1.06)μmol/L增加,谷胱甘肽过氧化物酶含量(140.18±8.65)μmol/L、超氧化物歧化酶活性(133.72±8.36) U/mL均显著下降,差异有统计学意义(P＜0.05).细胞组织化学染色示原代软骨细胞胞质Ⅱ型胶原表达阳性.不同浓度Res(1、3、5、10、20、40、80、160 mg/L)可抑制H2O2处理的软骨细胞增生,抑制率分别为(2.2±0.4)％、(5.3±0.6)％、(12.1±1.3)％、(26.6±2.4)％、(40.3±3.1)％、(52.7±4.2)％、(69.2±4.5)％、(72.5±5.1)％,呈剂量依赖性(P＜0.05);半数致死量值为37.2 mg/L.软骨细胞质中Atg5绿色荧光呈剂量依赖性增加;软骨细胞中p62蛋白表达呈剂量依赖性降低,Beclin-1蛋白表达呈剂量依赖性升高,差异有统计学意义(P＜0.05).结论 Res可抑制氧化应激状态下AA大鼠软骨细胞增生,其作用机制可能与Res诱导的软骨细胞自噬改变有关.