硫化氢对自发性高血压大鼠心肌重构的作用及机制研究

目的探讨硫化氢H2S对自发性高血压大鼠(SHR)间隙连接蛋白40(Cx40)、43(Cx43)表达的调控作用,以及与心肌重构的关系。方法取8周龄雄性SHR16只,随机分为SHR对照组(n=8)、SHR+硫氢化钠NaHS组(n=8);取同周龄的正常Wistar京都(WKY)雄性大鼠8只,设为WKY组。SHR+NaHS组腹腔注射NaHS56μmol/(kg·d),SHR对照组和WKY组每日腹腔注射等量生理盐水,持续8周。用分光光度计检测各组大鼠外周血和心肌组织中H2S含量;通过HE染色及Masson三色染色观察H2S对心肌的病理学改变;通过免疫组织化学检测3组大鼠心脏组织中Cx40、Cx43表达位置的变化;运用Westernblotting检测3组大鼠心脏组织中Cx40、Cx43及α-平滑肌肌动蛋白(α-SMA)、骨桥蛋白(OPN)表达量的变化。结果与WKY组大鼠比较,SHR组大鼠外周血及心肌组织中H2S含量减少(P<0.05),NaHS干预后SHR外周血及心肌组织中H2S含量增加(P<0.05);与WKY组大鼠比较,SHR组大鼠心肌纤维结构排列较为紊乱,NaHS干预后SHR心肌纤维排列较为整齐;SHR组大鼠心肌中的Cx40、Cx43表达增加且分布紊乱,SHR+NaHS组大鼠心肌中的Cx40、Cx43分布较规整;且SHR组大鼠心肌中Cx40、Cx43、α-SMA、OPN表达升高(P<0.05),SHR+NaHS组大鼠心肌中Cx40、Cx43、α-SMA、OPN表达降低(P<0.05)。结论H2S可能通过调控Cx40、Cx43的表达来改善SHR心肌重构。

Chemotherapy and resection for gastric cancer with synchronous liver metastases

AIM: To investigate the effect of surgery and chemotherapy for gastric cancer with multiple synchronous liver metastases (GCLM). METHODS: A total of 114 patients were entered in this study, and 20 patients with multiple synchronous liver metastases were eligible. After screening with preoperative chemotherapy, 20 patients underwent curative gastrectomy and hepatectomy for GCLM; 14 underwent major hepatectomy, and the remaining six underwent minor hepatectomy. There were 94 patients without aggressive treatment, and they were in the non-operative group. Two regimens of perioperative chemotherapy were used: S-1 and cisplatin (SP) in 12 patients, and docetaxel, cisplatin and 5-fluorouracil (DCF) in eight patients. These GCLM patients were given preoperative chemotherapy consisting of two courses chemotherapy of SP or DCF regimens. After chemotherapy, gastrectomy and hepatectomy were preformed. Evaluation of patient survival was by follow-up contact using telephone and outpatient records. All patients were assessed every 3 mo during the first year and every 6 mo thereafter. RESULTS: Twenty patients underwent gastrectomy and hepatectomy and completed their perioperative chemotherapy and hepatic arterial infusion before and after surgery. Ninety-four patients had no aggressive treatment of liver metastases because of technical difficulties with resection and severe cardiopulmonary dysfunction. In the surgery group, there was no toxicity greater than grade 3 during the course of chemotherapy. The response rate was 100% according to the Response Evaluation Criteria in Solid Tumors Criteria. For all 114 patients, the overall survival rate was 8.0%, 4.0%, 4.0% and 4.0% at 1, 2, 3 and 4 years, respectively, with a median survival time (MST) of 8.5 mo (range: 0.5-48 mo). For the 20 patients in the surgery group, MST was 22.3 mo (range: 4-48 mo). In the 94 patients without aggressive treatment, MST was 5.5 mo (range: 0.5-21 mo). There was a significant difference between the surgery and unresectable patients (P = 0.000). Three patients in surgery group were still alive at the end of the cut-off date. CONCLUSION: Perioperative weekly DCF and SP achieved a good response, and combined with surgery, they could improve prognosis of GCLM.

Advances in Drug Therapy for Alzheimer’s Disease

Alzheimer’s disease(AD)is a chronic neurodegenerative disease that mainly causes dementia.It is a serious threat to the health of the global elderly population.Considerable money and effort has been invested in the development of drug therapy for AD worldwide.Many drug therapies are currently under development or in clinical trials,based on two known mechanisms of AD,namely,Aβtoxicity and the abnormal Tau hyperphosphorylation.Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation,neurotransmitter imbalance,oxidative damage and mitochondrial dysfunction,neuron loss and degeneration.Even so,the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited.However,multi-drug combinations may provide a new avenue for drug therapy for AD.In addition,early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.

Clinical significance of nerve growth factor and tropomyosin-receptor-kinase signaling pathway in intrahepatic cholangiocarcinoma

AIM: To investigate the correlation between nerve growth factor-tropomyosin-receptor-kinase (NGF-TrkA) signaling pathway and prognosis in intrahepatic cholangiocarcinoma (IHCC).

RNA结合蛋白ELAVL1与肿瘤进展的关系研究

胚胎致死性异常视觉样蛋白1(ELAVL1/HuR)是一种RNA结合蛋白,通过与特定的mRNA结合参与转录后调控,从而影响细胞增殖、凋亡、分化等生物学行为。近年来研究表明,ELAVL1与肿瘤细胞的增殖、血管生成、侵袭、转移及耐药性明显相关。本文就ELAVL1蛋白与肿瘤进展关系展开综述。

Application of air insufflation to prevent clinical pancreatic fistula after pancreaticoduodenectomy

AIM:To introduce an air insufflation procedure and to investigate the effectiveness of air insufflation in preventing pancreatic fistula(PF).of 185 patients underwent pancreaticoduodenectomy(PD)at our institution,and 74 patients were not involved in this study for various reasons.The clinical outcomes of 111 patients were retrospectively analyzed.The air insufflation test was performed in 46 patients to investigate the efficacy of the pancreaticojejunal anastomosis during surgery,and 65 patients who did not receive the air insufflation test served as controls.Preoperative assessments and intraoperative outcomes were compared between the 2 groups.Univariate and multivariate analyses were performed to identify the risk factors for PF.RESULTS:The two patient groups had similar baseline demographics,preoperative assessments,operative factors,pancreatic factors and pathological results.The overall mortality,morbidity,and PF rates were1.8%,48.6%,and 26.1%,respectively.No significant differences were observed in either morbidity or mortality between the two groups.The rate of clinical PF(grade B and grade C PF)was significantly lower in the air insufflation test group,compared with the nonair insufflation test group(6.5%vs 23.1%,P=0.02).Univariate analysis identified the following parameters as risk factors related to clinical PF:estimated blood loss;pancreatic duct diameter≤3 mm;invagination anastomosis technique;and not undergoing air insufflation test.By further analyzing these variables with multivariate logistic regression,estimated blood loss,pancreatic duct diameter≤3 mm and not undergoing air insufflation test were demonstrated to be independent risk factors.CONCLUSION:Performing an air insufflation test could significantly reduce the occurrence of clinical PF after PD.Not performing an air insufflation test was an independent risk factor for clinical PF.

Regulation of PPAR-γactivity in lipid-laden hepatocytes affects macrophage polarization and inflammation in nonalcoholic fatty liver disease

BACKGROUND Lipid metabolism disorder and inflammatory-immune activation are vital triggers in the pathogenesis of nonalcoholic fatty liver disease(NAFLD).Various studies have shown that PPAR-γexerts potent anti-inflammatory and immunomodulatory properties.However,little is known about the regulation of PPAR-γactivity in modulating cell crosstalk in NAFLD.AIM To investigate whether the regulation of PPAR-γactivity in lipid-laden hepatocytes affects macrophage polarization and inflammation.METHODS Primary hepatocytes were isolated from wild-type C57BL6/J mice or hepatocytespecific PPAR-γknockout mice and incubated with free fatty acids(FFAs).Macrophages were incubated with conditioned medium(CM)from lipid-laden hepatocytes with or without a PPAR-γagonist.Wild-type C57BL/6J mice were fed a high-fat(HF)diet and administered rosiglitazone.RESULTS Primary hepatocytes exhibited significant lipid deposition and increased ROS production after incubation with FFAs.CM from lipid-laden hepatocytes promoted macrophage polarization to the M1 type and activation of the TLR4/NF-κB pathway.A PPAR-γagonist ameliorated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes and subsequently prevented M1 macrophage polarization.Hepatocyte-specific PPAR-γdeficiency aggravated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes,which further promoted M1 macrophage polarization.Rosiglitazone administration improved oxidative stress and NLRP3 inflammasome activation in HF diet-induced NAFLD mice in vivo.CONCLUSION Upregulation of PPAR-γactivity in hepatocytes alleviated NAFLD by modulating the crosstalk between hepatocytes and macrophages via the reactive oxygen species-NLRP3-IL-1βpathway.

In situ subtotal spleen resection combined with selective pericardial devascularization for the treatment of portal hypertension

BACKGROUND Hypersplenism and esophageal varices bleeding are the major complications of portal hypertension(PHT).In recent years,increasing attention has been given to spleen preservation operations.The mode and long-term effects of subtotal splenectomy and selective pericardial devascularization for PHT remain controversial.AIM To investigate the clinical efficacy and safety of subtotal splenectomy combined with selective pericardial devascularization for the treatment of PHT.METHODS This was a retrospective study of 15 patients with PHT who underwent subtotal splenectomy not preserving the splenic artery or vein combined with selective pericardial devascularization in the Department of Hepatobiliary Surgery,Qilu Hospital of Shandong University from February 2011 to April 2022.Fifteen propensity score-matched patients with PHT who underwent total splenectomy at the same time served as the control group.The patients were followed for up to 11 years after surgery.We compared the postoperative platelet levels,perioperative splenic vein thrombosis,and serum immunoglobulin levels between the two groups.Abdominal enhanced computed tomography was used to evaluate the blood supply and function of the residual spleen.The operation time,intraoperative blood loss,evacuation time,and hospital stay were compared between the two groups.RESULTS The postoperative platelet level of patients in the subtotal splenectomy group was significantly lower than that in the total splenectomy group(P<0.05),and the postoperative portal system thrombosis rate in the subtotal splenectomy group was also much lower than that in the total splenectomy group.The levels of serum immunoglobulins(IgG,IgA,and IgM)showed no significant differences after surgery compared with before surgery in the subtotal splenectomy group(P>0.05),but serum immunoglobulin IgG and IgM levels decreased dramatically after total splenectomy(P<0.05).The operation time in the subtotal splenectomy group was longer than that in the total splenectomy group(P<0.05),but there were no significant differences in the amount of intraoperative blood loss,evacuation time,or hospital stay between the two groups.CONCLUSION Subtotal splenectomy not preserving the splenic artery or vein combined with selective pericardial devascularization is a safe and effective surgical treatment for patients with PHT,not only correcting hypersplenism but also preserving splenic function,especially immunological function.

Highly expression of MYBL2 is correlated with a poor prognosis and immune infiltration in clear cell renal carcinoma

Background:Clear cell renal carcinoma(ccRCC)is notorious for its highly unfavorable prognosis,closely related to immune cell infiltration(ICI).MYB Proto-Oncogene Like 2(MYBL2)is elevated in multiple types of human cancer and is recognized as a crucial role in tumorigenesis.In the present study,we aimed to determine the roles of MYBL2 in the prognostic outcomes of ccRCC.Methods:We analyzed the GSE100666 dataset from the Gene Expression Omnibus(GEO)database and found that the expression of MYBL2 was significantly higher in ccRCC subjects than in normal controls.Next,RNA sequencing data related to ccRCC were retrieved from The Cancer Genome Atlas(TCGA)database and the levels of MYBL2 were compared between tumor and peri-tumor tissues.The correlation between MYBL2 and clinicopathological parameters was assessed by logistic analysis.The Kaplan-Meier method,Cox-regression analysis,and nomograms,were applied to investigate the potential clinical benefits of MYBL2 in ccRCC.We also evaluated the correlation between MYBL2 and immune cell infiltration with a single-sample gene set enrichment analysis(ssGSEA).The association between MYBL2 and immune checkpoints was determined via the TIMER and TISIDB databases.Finally,correlation analysis was conducted to predict upstream non-coding RNAs(ncRNAs)regulating MYBL2,and a completing endogenous RNA(ceRNA)network was constructed to visualize the long non-coding RNAs(lncRNAs)-microRNAs(miRNAs)-MYBL2 axis in ccRCC.Finally,further analysis of upstream lncRNAs was carried out to validate the accuracy of the network.Results:MYBL2 was significantly over-expressed in ccRCC(P<0.001).High levels of MYBL2 expression in ccRCC correlated with a worse T stage,a more advanced N stage,a higher M stage,a more deleterious pathological stage,and higher histological grades.MYBL2 was identified as a risk factor for disease-specific survival(hazard ratio(HR)=2.73,P<0.001),overall survival(HR=1.91,P<0.001),and progression-free interval(HR=2.03,P<0.001).MYBL2 also positively associated with multiple types of immune cells and checkpoints.Finally,two ceRNA axes,PVT1-miR-30e-5p-MYBL2 and LINC00511-miR-29c-3p-MYBL2 were detected as the most promising upstream ncRNAs regulating MYBL2 in ccRCC,and we also validated the expression of MYBL2 and PVT1 by launching qRT-PCR.We found that the expression of MYBL2 was significantly higher in 786-O than in human kidney-2 cell line HK-2(P<0.001)and the expression of PVT1 was significantly higher in Caki-1 than in HK-2(P<0.001).Conclusion:Our study revealed that ncRNAs might upregulated the expression of MYBL2 in ccRCC and that this was associated with an unfavorable prognosis and immune infiltration.

Effects of the ABCB1 genetic polymorphism on vancomycin blood concentration in critically ill patients of Chinese

To investigate the clinical application of vancomycin blood concentration monitoring in critically ill patients and the influence of the ABCB1 gene polymorphism on vancomycin dnug concentrations to guide clinically rational usage of vancomycin.The vancomycin blood concentration monitoring data on 141 critically ill patients in our hospital from November 2016 to March 2017 were analyzed and 68 patients who received the same dosages of vancomycin were subjected to ABCB1 genotyping.The results showed that among the 141 critically ill patients,68(48.22%)showed sub-target concentrations of vancomycin,averaging 5.58±2.54μg/mL;29 patients(20.56%)had higher than target concentrations,with an average value of 33.01±9.38μg/mL;and 44 cases(31.21%)were in the normal concentration range,with an average of 14.72±2.75μg/mL.The vancomycin concentrations in 1236TT-genotype patients were significantly higher than those of the 1236CC and 1236CT-genotype patients.The concentrations in the 2677AA-genotype patients were significantly higher than those in the 2677AT,2677GA,2677GG and 2677GT patients.Vancomycin concentrations in 3435CT patients were significantly higher than those in 3435CC,but slightly lower than those in 3435TT patients.The ABCB11236C>T,2677G>T/A and 3435C>T gene mutations may affect vancomycin blood concentrations.At the same time,other factors such as gender,age,co-morbidities and other transporters possiblely play the roles in influencing the concentration of vancomycin in patients.All these factors finally cause individual differences.

Analysis and measurement of vibration characteristics of a hollowing defect based on a laser self-mixing interferometer

To solve the problems with the existing methods for detecting hollowing defects,such as inconvenient operation,low efficiency and intense subjectivity,and to improve the efficiency of the acoustic-optic fusion method for detecting hollowing defects,in this paper the vibration characteristics of hollowing defects are measured and analyzed using a laser self-mixing interferometer.The ceramic tile above the hollowing defect is equivalent to a thin circular plate with peripheral fixed support.According to Kirchhoff's classical circular plate theory and the circular plate displacement function based on the improved Fourier series,a theoretical model of a circular plate is established.By solving the characteristic equation,the theoretical modal parameters of hollowing defects are obtained.Subsequently,an experimental system based on a laser self-mixing interferometer is built,and modal experiments are carried out using the hammering method.The experimental modal parameters are obtained with a professional modal analysis software.Through comparative analysis between the theoretical and experimental modal parameters,the error of the natural frequency results is found to be tiny and the mode shapes are consistent.These results provide theoretical guidance for a practical non-destructive acoustic-optic fusion method for detecting hollowing defects.

基于枝化多肽的多功能药物递送系统用于肿瘤细胞核的精准靶向治疗

为了改善在肿瘤治疗过程中,药物载体靶向性差和药物靶点定位效率低等不足,设计了一种能精准靶向肿瘤细胞核,将药物高效递送至作用靶点的多功能纳米载药体系.利用具有细胞核定位能力的两亲性枝化多肽包载化疗药物阿霉素(DOX)形成载药纳米胶束DD,并通过静电作用将具有肿瘤靶向功能的透明质酸(HA)包覆在DD表面,得到具有靶向肿瘤细胞核能力的纳米药物HDD.HA的存在赋予了HDD对肿瘤的靶向功能和电荷屏蔽能力,可增加体系的稳定性,延长其血液循环时间,降低正常组织和细胞对HDD的非特异性摄取,实现其在肿瘤部位的特异性富集和肿瘤细胞的高效摄取.进入肿瘤细胞后,HA层的降解有利于纳米胶束DD在多肽的核定位作用下精准、快速地将DOX递送至细胞核,最终实现高效的肿瘤抑制效果.

Homocysteine-Induced Disturbances in DNA Methylation Contribute to Development of Stress-Associated Cognitive Decline in Rats

Chronic stress is generally accepted as the main risk factor in the development of cognitive decline;however,the underlying mechanisms remain unclear.Previous data have demonstrated that the levels of homocysteine(Hcy)are significantly elevated in the plasma of stressed animals,which suggests that Hcy is associated with stress and cognitive decline.To test this hypothesis,we analyzed the cognitive function,plasma concentrations of Hcy,and brain-derived neurotropic factor(BDNF)levels in rats undergoing chronic unpredicted mild stress(CUMS).The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia(HHcy)levels in stressed rats.Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS,while Hcy reduction(by means of vitamin B complex supplements)alleviated the cognitive deficits and BDNF reduction in CUMS rats.Furthermore,we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter.In contrast,control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain.These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline.We also used ten-eleven translocation(TET1),an enzyme that induces DNA demethylation,to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline.The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats.Taken together,novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits.In addition,the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter.The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.

Highly Efficient Base Editing in Viral Genome Based on Bacterial Artificial Chromosome Using a Cas9-Cytidine Deaminase Fused Protein

Viruses evolve rapidly and continuously threaten animal health and economy,posing a great demand for rapid and efficient genome editing technologies to study virulence mechanism and develop effective vaccine.We present a highly efficient viral genome manipulation method using CRISPR-guided cytidine deaminase.We cloned pseudorabies virus genome into bacterial artificial chromosome,and used CRISPR-guided cytidine deaminase to directly convert cytidine(C)to uridine(U)to induce premature stop mutagenesis in viral genes.The editing efficiencies were 100%.Comprehensive bioinformatic analysis revealed that a large number of editable sites exist in pseudorabies virus(PRV)genomes.Notably,in our study viral genome exists as a plasmid in E.coli,suggesting that this method is virus species-independent.This application of base-editing provided an alternative approach to generate mutant virus and might accelerate study on virulence and vaccine development.

神经调控技术的进展与挑战:跨学科机遇与合作

Neurological diseases,such as intractable pain,Parkinson’s disease,and depression,have imposed significant health and economic burden globally.According to the World Health Organization(WHO),approximately one billion people,one-sixth of the global population,are afflicted with neurological diseases.These disorders have become the primary contributors to disability-adjusted life-years(DALYs)and are ranked as the second leading cause of death[1].The economic losses caused by brain diseases can exceed trillions of dollars every year in major countries.Thus,developing and applying innovative neuroscience technology for the treatment of brain diseases has been a central goal in large-scale brain research projects with a budget of billions of dollars,like the China Brain Project[2],the EU’s Human Brain Project,Japan’s Brain/MINDS Project,the US’s BRAIN Initiative[3].