Diabetic kidney disease (DKD) progression is predominantly attributed to podocyte injury. However, the underlying mechanisms remain inadequately understood. DKD patients exhibit elevated lactate concentrations due to impaired glucose metabolism. Lactate serves as a substrate for a post-translational modification known as lactylation, which is integral to numerous cellular processes. The study aimed to explore the potential role of lactylation in DKD podocyte injury and to elucidate its underlying mechanisms. The results showed that lactate concentrations were elevated in the plasma of DKD patients, as well as in the serum and renal tissue of diabetic mice. High glucose (HG) resulted in increased lactate accumulation in podocytes, exacerbated podocyte injury and promoted protein lactylation. Protein modification omics demonstrated that LARS1 lactylation was enhanced, specifically at the K970 site, which further aggravated podocyte injury by inhibiting autophagy and promoting apoptosis. In vivo transfection with LARS1 siRNA significantly improved renal function and mitigated podocyte injury. Our study identified a novel mechanism linking LARS1 lactylation activity to compromised podocyte autophagy, heightened podocyte injury, and the onset of proteinuria within DKD.

Cholesterol is an important part of the human diet. The relationship and molecular mechanisms between intracellular cholesterol and male infertility are unclear. The purpose of this study was to evaluate the role of low-density lipoprotein receptor (LDLR) in male infertility. Both wild-type (WT) and LDLR heterozygous deletion (LDLR+/-) male Golden Syrian hamsters were fed either a high-fat diet (HFD) or a normal diet (ND). Plasma biochemistry, serum hormone, testicular histopathology, mRNA and protein expression of AMPK/Sirt1/PGC-1 alpha in both testicular tissue and isolated Leydig cells (LCs) were measured. Compared with the ND animals, the WT HFD hamsters developed dyslipidemia at three weeks with lipid droplets deposited in LCs, testosterone decreased at four weeks (0.440 +/- 0.264 ng/ml vs. 2.367 +/- 1.236 ng/ml), the number of the Sertoli cells decreased (21.578 +/- 2.934/one tubule vs. 25.733 +/- 3.424/one tubule), the seminiferous epithelium became thinner (0.0813 +/- 0.01729 mm vs. 0.0944 +/- 0.0138 mm), testicular atrophy and AMPK/Sirt1/PGC-1 alpha pathway downregulated at five weeks. All these changes persisted until the end of the study. LDLR+/- alleviated all of the above changes by downregulating the cellular influx of cholesterol induced by HFD except for higher hyperlipidemia. In summary, excessive intracellular cholesterol inactivates AMPK/Sirt1/PGC-1 alpha pathway firstly in LCs and then in both Sertoli and spermatids. Cholesterol toxicity was LDLR dependent.

目的 观察CRISPR/Cas9技术建立的肥胖、代谢综合征和糖尿病前期特征的瘦素受体基因敲除大鼠模型的多种参数,为代谢性疾病的分子机制研究和新药研发提供更为理想的动物模型.方法 1)定期测定Lepr-/-大鼠的体重、摄食量、随机血糖和空腹血糖;葡萄糖耐量试验和胰岛素耐量试验;血清血脂参数;2)观察14周和18周Lepr-/-大鼠主要脏器的病理学改变;3)观察脏器脂质沉积情况.结果 Lepr-/-大鼠表现明显肥胖、高摄食量、葡萄糖耐量受损、胰岛素抵抗和血脂异常;14周和18周出现胰岛增生和心脏肌细胞肥大、脂肪肝、肥胖相关性肾病;肝细胞、肾小管上皮细胞和骨骼肌纤维内脂质沉积.结论 Lepr-/-大鼠是代谢性疾病的病因研究和新药研发的理想动物模型.

目的 探讨国产氧化纤维素可吸收止血纱布对大鼠皮肤伤口愈合的影响机制.方法 8周龄SD大鼠24只(雌雄各半),背侧作3个皮肤全层缺损伤口,分别为空白对照、氧化纤维素纱布和速即纱伤口.观察不同时间点伤口愈合变化、组织病理学变化以及α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)和Ⅰ、Ⅲ型胶原的表达变化.结果 3组伤口愈合时相基本一致:术后第4天伤口呈向心性聚缩,可见痂皮和渗出;术后第7～10天,各组创面面积缩小明显,痂皮基本脱落;术后第14～21天,创面基本愈合.病理组织学观察:3组第7天创面伤口肉芽组织最明显;第14天胶原纤维开始增多;第21天复层鳞状上皮完全覆盖伤口.天狼猩红染色在偏光显微镜下观察发现:3组术后第7天出现纤细的Ⅲ型胶原;第21天Ⅰ、Ⅲ型胶原比例基本相同.α-SMA免疫组化表达及定量分析发现:与空白对照组术后第7天表达量达到峰值相比,氧化纤维素纱布组第7天和第14天表达量基本相同,空白对照组第14天表达量明显降低,但3组第21天表达量基本一致.结论 使用国产氧化纤维素可吸收止血纱布不影响大鼠皮肤伤口的愈合,与国外同类产品(速即纱)无明显差别.

BACKGROUND:The endocannabinoid system is involved in the pathogenesis of liver fibrosis. However, most of the findings in this area have come from experimental studies in animal models or clinical trials on chronic hepatitis C. The roles of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) in hepatofibrosis in patients with chronic hepatitis B (CHB) have not been studied fully. This study aimed to explore the relationship between liver fibrosis and the expression of CB1 and CB2 in patients with CHB.METHODS:Eighty liver biopsy specimens from patients with CHB (52 male, 28 female) were analyzed in this study. Fibrosis was staged on a scale of 1 to 4 (F1 to F4, with F4 defining cirrhosis). There were 20 samples for each fibrosis stage. The expression of hepatic alpha-smooth muscle actin (α-SMA), CB1, and CB2 was detected by immunohistochemistry.RESULTS:Hepatic CB1 and CB2 were expressed in all patients with CHB. The degree of fibrosis was significantly associated with the increased expression of CB1 and CB2 in CHB. Furthermore a significant increase in cells positive for both CB1 and CB2 was detected in stage 3 and stage 4 disease compared to stage 1 and stage 2 disease. There was a strong positive association between CB1 expression and α-SMA expression. Moreover, double immunofluorescence staining for CB1 and α-SMA demonstrated that activated hepatic stellate cells (HSCs) express CB1.CONCLUSIONS:The hepatic expression of CB1 and CB2 plays an important role during the progression of fibrosis induced by CHB. Endogenous activation of CB1 receptors in patients with CHB enhances fibrogenesis by direct effect on activated HSCs.

Alloxan had been recognized as having a direct nephrotoxic effect different from its diabetogenic action. We encountered previously unreported granulomatous tubulointerstitial nephritis with severe luminal and interstitial mineralization in one diabetic rat after one week of alloxan administration. Histopathologically, many dilated and occluded proximal and distal tubules were segmentally observed in the cortex and outer medulla. The tubular lumen contained minerals and cell debris. Tubular epithelial cells were degenerated and piled up, and they protruded into the lumen, where they enveloped minerals. Mineralization was observed mainly in the tubular lumen, and to some extent in the subepithelium and interstitium. The mineralization beneath the tubular epithelium was often continuous from the subepithelium to the interstitium. In these lesions, the tubular basement membrane was disrupted by mineralization, and a granuloma with multinuclear foreign-body giant cells was formed in the interstitial areas.

Objective: To investigate the expression of adipocyte fatty acid binding protein (A-FABP) in OVA-induced asthmatic mice. Methods: Healthy female BALB/c mice were randomly divided into control group and asthma group. A-FABP in lung tissues was located using immunohistochemical staining and quantified by Western blot. A-FABP in serum was quantified by ELISA. Results: A-FABP mainly expressed in the cytoplasm of airway epithelial cells (AECs), macrophages and vessel endothelial cells (VECs). The expression of A-FABP was significantly higher in asthma group than control group (P<0.05). Conclusion: A-FABP might be involved in the pathophysiological process of asthma.

The main function of adipocyte fatty acid-binding protein (A-FABP) is to regulate fatty acid metabolism as its molecular chaperone. The clinical significance of A-FABP in hypoxic-ischemic brain damage (HIBD) neonates is not yet clear. Free fatty acid (FFA) in cerebral cortex increases along with hypoxia ischemia degree. Thus, we aimed to investigate whether FFA can induce A-FABP expression and elevate the serum A-FABP level in HIBD neonates. In the present study, 42 HIBD neonates were selected including 11 cases as mild, 16 cases as moderate and 15 cases as severe. The serum was collected from peripheral vein at 72 h after the first visit (acute stage) and 7 days after birth (recovery stage), and the serum from 10 normal neonates was used as the control. The serum level of A-FABP and FFA in 42 neonates with acute phase and recovery phase HIBD were detected using ELISA and copper colorimetric method. The overall serum A-FABP content in HIBD neonates at the acute stage was significantly higher compared to the normal neonates (P<0.05). The serum A-FABP level in severe HIBD neonates was significantly higher than that in mild HIBD, moderate HIBD and normal neonates (P<0.05). The serum FFA level in HIBD neonates at the acute stage was 1,521.57±605.63 µmol/l, which was significantly higher than that in the normal neonates 838.24±294.22 µmol/l. The serum FFA levels in mild, moderate and severe HIBD neonates were significantly higher than those in the normal neonates. The overall A-FABP level in HIBD neonates at the recovery stage was significantly lower compared to the acute stage, which was significant in severe HIBD neonates. A-FABP levels in mild and moderate HIBD neonates at recovery stage were decreased compared with the acute stage, although there was no statistical difference. There was a positive correlation between serum A-FABP and FFA in HIBD neonates at acute stage (r=0.369, P<0.05). In conclusion, serum A-FABP and FFA levels were signifcantly increased in HIBD neonates at acute stage, and were positively correlated. The serum A-FABP level in HIBD neonates at recovery stage was significantly lower than that in the acute stage. The results suggested that serum A-FABP and FFA levels at acute stage can reflect the severity of HIBD. The detection of serum A-FABP and FFA can be applied as indicators for the early diagnosis of HIBD, but also provides a basis for the clinical evaluation of HIBD treatment.

Context Recently, adenosine triphosphate (ATP) was occasionally found to decrease the triglyceride (TG) levels in several hyperlipidemic patients in our clinical practice.Objective The study investigates the anti-hyperlipidemic effects of ATP in a high-fat fed rabbit model and hyperlipidemic patients.Materials and methods Twenty-four rabbits were randomly divided into three groups of eight animals each as follows: normal diet, high-fat diet and high-fat diet + ATP group. ATP supplementation (40 mg/day) was started at the 20th day and lasted for 10 days. Serum concentrations of total cholesterol (TC), TG, LDL-C, HDL-C were measured on the 20th day and 30th day. Heart, liver and aorta were subjected histopathological examination. Twenty outpatients diagnosed primary hyperlipidemia took ATP at a dose of 60mg twice a day for 1 week.Results Feeding rabbits with a high-fat diet resulted in a significant elevation of lipid parameters including TC, TG, LDL-C, VLDL-C compared to the normal diet group (p<0.01). ATP treatment significantly decreased serum TG level (p<0.01), whilst other parameters remained statistically unaltered. Meanwhile, ATP significantly reduced the thickness of fat layer in cardiac epicardium (p<0.05) and pathological gradation of ballooning degeneration in hepatocytes (p<0.05). After taking ATP for 1 week, hyperlipidemia patients exhibited a significant decrease of TG (p<0.01), but other lipid parameters had no significant change.Discussion and conclusion The study indicates that ATP selectively decreases serum TG levels in high-fat diet rabbits and hyperlipidemic patients. Therefore, ATP supplementation may provide an effective approach to control TG level.

Type 2 diabetes is characterized by hyperglycemia and deregulated lipid metabolism with increased plasma non-esterified fatty acids (NEFA). Apoptosis of glomerular cells is a hallmark in diabetic glomerulosclerosis. Fatty acid-binding protein 4 (FABP4), a carrier protein for fatty acids, has been linked to diabetes and diabetic nephropathy (DN). Here we aimed to investigate the link between FABP4 and apoptosis in diabetic glomerulosclerosis. We first evaluated the presence of FABP4 and ER stress markers as well as apoptosis-related proteins in renal biopsies of patients with DN. Then we used FABP4 inhibitor BMS309403 or siRNA to further investigate the role of FABP4 in ER stress and apoptosis induced by NEFA or high glucose in cultured human mesangial cells (HMCs). We found FABP4 was expressed mainly in glomerular mesangial cells of the human renal biopsies and the glomerular FABP4 was increased in renal biopsies of DN. The up-regulation of FABP4 was accompanied with increased glucose-regulated protein 78 (GRP78) and Caspase-12 as well as down-regulated B-cell CLL/lymphoma 2 (Bcl-2) in glomeruli. Along with the induction of FABP4 and apoptosis, GRP78 and its three sensors as well as C/EBP homologous protein (CHOP) and Caspase-12 were induced in HMCs treated with NEFA or high glucose and these responses were attenuated or even abrogated by treating with FABP4 inhibitor or FABP4 siRNA. Ultrastructure observation confirmed the lipotoxicity of oleic acid by showing the morphological damage in HMCs. Our data suggest that FABP4 in glomerular mesangial cells is up-regulated in DN and FABP4 mediates apoptosis via the ER stress in HMCs.

We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity; These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.

The natural convection heat transfer of a 60% sucrose solution in a vertical converging-diverging tube（CD） with regularly-spaced twisted tapes（RSTT） has been investigated numerically and experimentally. The effects of wall temperature and number of RSTT on the Nusselt number were studied in detail. The distributions of velocity and temperature in the 60% sucrose solution were studied and the simulated results of CD with RSTT were compared with those of the smooth tube. The influence of Rayleigh number and RSTT on the Nusselt number was conducted experimentally. The results indicate that the Nusselt number of the 60% sucrose solution obviously increased with the number of RSTT but increased inconspicuously with 2 and more twisted tapes. The simulation shows that the distance for achieving an optimal heat transfer performance is 46 times the diameter of the tube. The mechanism of the natural convection heat transfer enhancement of the 60% sucrose solution in relationship with the CD and the RSTT was analyzed, and the change of average tangential velocity with the axial distance was presented to demonstrate that the enhancement of heat transfer was realized mainly because of the increase in tangential velocity.

通过实验研究了内插旋流片的缩放管对糖汁蒸发传热的影响,对缩放管和不同个数旋流片对强化传热的影响做了比较分析.与传统蒸发器相比,内插旋流片缩放管的蒸发传热系数提高150％～200％;在此基础上,利用内插不同个数的缩放管对糖厂蒸发器进行改造,对多效蒸发系统进行优化,在相同的总传热温差和总传热面积下,传热系数的提高能够增加系统效数,进而使生蒸汽消耗量减少.优化结果表明,生蒸汽消耗量最减少37％左右,从而达到节能目的.

Objective To investigate the effect of Txnip interference on high glucose( HG)-induced apoptosis in human kidney proximal tubular cell line( HK-2). Methods Cultured HK-2 were divided into normal glucose group(NG),high glucose group( HG),HG + contol plasmid vector( HG + C) and GH + VDUP1 shRNA Plasmid(h)(HG + shRNA). Apoptosis of HK-2 was analyzed by DeadEndTMFluorometric TUNEL System. ROS produc-tion was observed by flow cytometry. The expression level of Txnip,caspase-3,cleaved caspase-3,BAX,BCL-2, P38 MAPK,P-P38 MAPK and cytochrome c protein was observed by Western blot. The expression level of Txnip, BAX,BCL-2 mRNA was observed by RT-PCR. Results Compared with normal glucose group(NG),the production of ROS,the number of cell apoptosis,the expression of cleaved caspase-3 and P-P38 MAPK,ratio of BAX / BCL-2 and the release of cytochrome c from mitochondria to cytoplasm all significantly increased in HK-2 in high glucose group(HG)(P 0. 05). Txnip interference inhibited HG-induced ROS production,cell apoptosis,expression of cleaved caspase-3 and P-P38 MAPK,ratio of BAX / BCL-2 and release of cytochrome c from mitochondria to cytopl-asm in HK-2(P 0. 05). Conclusions Txnip interference can prevent HG-induced HK-2 apoptosis through decrea-sing ROS production,preserving mitochondrial function and inhibiting activation of P38 MAPK.

The natural convection heat transfer of water in a vertical converging-diverging tube (CD) with regularly-spaced twisted tapes was experimentally investigated and numerically simulated, and the natural convection heat transfer coefficient varying with the twisted tape number was explored. Then, the results were compared with those of smooth tubes, and the distributions of velocity and temperature, as well as the variations of heat transfer coefficient and heat flux with axial distance, were simulated with Fluent. It is found that the heat transfer coefficient remarkably increases with the number of twisted tapes and keeps unchanged when 7 twisted tapes are inserted, and that the heat transfer enhancement is independent of the type of twisted tapes. Simulated results indicate that the flow resistance increases with the number of twisted tapes and that the optimal number of regularly-spaced twisted tapes is 7. The authors also primarily analyze the mechanism of the natural convection heat transfer enhancement interrelated by the CD and the regularly-spaced twisted tapes, discuss the change of average tangential velocity with the axial distance and point out that the enhancement of heat transfer is due to the increase of tangential wall velocity.

文章运用CFD软件Fluent分析了三种支撑结构对壳程性能的影响,可为工业用纵流式管壳式换热器优化及强化传热提供依据.文章探讨了水在三种不同支撑结构下的流阻与传热性能,得到不同支撑结构具有不同的传热效果,螺旋片相对其它两种支撑方式更有利于提高传热综合性能,并进一步对这三种换热器的传热强化机理进行了探讨.

Aim To investigate the effect of antioxidant peptide SS-31 on high glucose(HG)-induced apoptosis in mouse mesangial cells(MMCs).Methods Cultured MMCs were divided into normal glucose group(NG),NG plus mannitol group(M),high glucose group(HG) and HG plus SS-31 group(HG + SS31).Apoptosis of MMCs was analyzed by Dead End Fluorometric TUNEL System and flow cytometry.ROS production was observed by flow cytometry.The expression levels of caspase-3,cleaved caspase-3,Bax,Bcl-2,p38 MAPK,p-p38 MAPK and cytochrome c protein were observed by Western blot.Results Compared with normal glucose group(NG),the production of ROS,the number of cell apoptosis,the expression of cleaved caspase-3 and p-p38 MAPK,ratio of Bax / Bcl-2 and the release of cytochrome c from mitochondria to cytoplasm significantly increased in MMCs in high glucose group(HG).Treatment with SS-31 inhibited HG-induced ROS production,cell apoptosis,expression of cleaved caspase-3 and p-p38 MAPK,ratio of Bax / Bcl-2 and release of cytochrome c from mitochondria to cytoplasm in MMCs.Conclusions SS-31 can prevent HG-induced MMC apoptosis through decreasing ROS production,preserving mitochondrial function and inhibiting activation of p38 MAPK.

A retrospective analysis was made on clinical manifestations and autopsy results of 5 sudden deaths from aortic dissecting (AD).Sudden deaths from AD were almost induced by type Ⅰ and Ⅱ of DeBakey Typing.Most patients had a history of hypertension and prodromal symptoms of either chest pain,abdominal pain or back pain.Most common cause of death was cardiac tamponade induced by rupture of the ascending aorta.The clinicians should further recognize of AD so as to achieve the objective of early diagnosis and early treatment.