Antidepressant effects of Peiyuan Jieyu formula in a mouse model of chronic stress in conjunction with lipopolysaccharide-induced depression

Objective:To explore the mechanism of the Peiyuan Jieyu formula in treating depression by assessing its impact on a lipopolysaccharide-induced(LPS-induced)depression mouse model.Methods:We created a mouse model of depression by exposing mice that had previously received chronic stress to intraperitoneal LPS injections.The mice were divided into the following groups:control,model,fluoxetine,Tiansi Yin,Sini powder,and low-,medium-,and high-dose Peiyuan Jieyu formula groups.Forced swim and tail suspension tests were used to assess the efficacy of the depression(despair)model,and weight gain rates were also measured.Furthermore,serum levels of various depression and inflammation-associated molecules,including tumor necrosis factor-a(TNF-a),interferon-γ(IFN-γ),tryptophan,5-hydroxytryptamine,kynurenine(KYN),and kynurenic acid(KA)were assessed.Furthermore,the expression levels of ionic calcium-binding adaptor molecule-1(IBA-1)and indoleamine 2,3-dioxygenase(IDO)mRNA in hippocampal microglia were measured.Results:The model group displayed greater despair-associated immobility,which was shortened in response to various doses of Peiyuan Jieyu formula.Furthermore,formula administration significantly reduced serum TNF-a levels and hippocampal IDO mRNA expression.The high formula dose also reduced IFN-γand IBA-1 levels,the latter was also decreased in response to the medium formula dose.However,the low formula dose reduced serum KYN level and KYN/tryptophan(TRP)and KYN/KA ratios.Conclusion:The Peiyuan Jieyu formula holds immense potential in treating depression in a mouse model,potentially inhibiting inflammation and improving TRP-KYN metabolic disorders.

Glutaredoxin-1 alleviates acetaminophen-induced liver injury by decreasing its toxic metabolites

Excessive N-acetyl-p-benzoquinone imine(NAPQI)formation is a starting event that triggers oxidative stress and subsequent hepatocyte necrosis in acetaminophen(APAP)overdose caused acute liver failure(ALF).S-glutathionylation is a reversible redox post-translational modification and a prospective mechanism of APAP hepatotoxicity.Glutaredoxin-1(Glrx1),a glutathione-specific thioltransferase,is a primary enzyme to catalyze deglutathionylation.The objective of this study was to explored whether and how Glrx1 is associated with the development of ALF induced by APAP.The Glrx1 knockout mice(Glrx1^(-/-))and liver-specific overexpression of Glrx1(AAV8-Glrx1)mice were produced and underwent APAPinduced ALF.Pirfenidone(PFD),a potential inducer of Glrx1,was administrated preceding APAP to assess its protective effects.Our results revealed that the hepatic total protein S-glutathionylation(PSSG)increased and the Glrx1 level reduced in mice after APAP toxicity.Glrx1^(-/-)mice were more sensitive to APAP overdose,with higher oxidative stress and more toxic metabolites of APAP.This was attributed to Glrx1 deficiency increasing the total hepatic PSSG and the S-glutathionylation of cytochrome p4503a11(Cyp3a11),which likely increased the activity of Cyp3a11.Conversely,AAV8-Glrx1 mice were defended against liver damage caused by APAP overdose by inhibiting the S-glutathionylation and activity of Cyp3a11,which reduced the toxic metabolites of APAP and oxidative stress.PFD precede administration upregulated Glrx1 expression and alleviated APAP-induced ALF by decreasing oxidative stress.We have identified the function of Glrx1 mediated PSSG in liver injury caused by APAP overdose.Increasing Glrx1 expression may be investigated for the medical treatment of APAP-caused hepatic injury.

Advances in ATM,ATR,WEE1,and CHK1/2 inhibitors in the treatment of PARP inhibitor-resistant ovarian cancer

Ovarian cancer(OC)poses a significant challenge in modern gynecologic oncology,both diagnostically and therapeutically.According to the American Cancer Society,an estimated 21,000 new cases of OC were reported in the United States alone in 20211.The most prevalent subtype of OC87,highgrade serous(HGS),is characterized by heightened genomic instability and defects in DNA damage response(DDR)pathways,which contribute to disease development and progression2.Notably,approximately 50%of HGS ovarian cancer(HGSOC)patients exhibit homologous recombination repair(HRR)defects(HRDs)3.

基于有限元方法的轴肩应力集中处网格划分尺度及类型研究

为了研究不同网格划分尺度及类型的线弹性材料对轴肩应力集中处最大应力的影响,采用有限元方法进行数值模拟,研究了弯曲和扭转载荷下倒角大小、单元网格类型、倒角分段数、单元梯度以及周向分段数等多种影响因素对轴肩应力集中处最大应力的影响规律,并与参考文献中的光弹性试验结果做对比,得出了不同倒角下最优的网格划分组合方式。本文得到的轴肩网格划分方法对其他类似结构的仿真计算网格划分具有一定的指导意义。

Effects of aging treatment and heat input on the microstructures and mechanical properties of TIG-welded 6061-T6 alloy joints

Aging treatment and various heat input conditions and mechanical properties of TIG welded 606I-T6 alloy joints were adopted to investigate the microstructural evolution by microstructural observations, microhardness tests, and tensile tests. With an increase in heat input, the width of the heat-affected zone （HAZ） increases and grains in the fusion zone （FZ） coarsen. Moreover, the hardness of the HAZ decreases, whereas that of the FZ decreases initially and then increases with an increase in heat input. Low heat input results in the low ultimate tensile strength of the welded joints due to the presence of partial penetrations and pores in the welded joints. After a simple artificial aging treatment at 175℃ for 8 h, the microstructure of the welded joints changes slightly. The mechanical properties of the welded joints enhance significantly after the aging process as few precipitates distribute in the welded seam.

The Effect of Home-Based Cardiac Rehabilitation on Functional Capacity,Behavior,and Risk Factors in Patients with Acute Coronary Syndrome in China

Aim:To investigate the effect of home-based cardiac rehabilitation on functional capacity,health behavior,and risk factors in patients with acute coronary syndrome in China.Methods:Eighty patients with acute coronary syndrome were enrolled in this prospective randomized controlled study.Patients in the cardiac rehabilitation group(n=52)received home-based cardiac rehabilitation with a heart manual and a home exercise video for 3 months and patients in the control group(n=28)received only routine secondary prevention.The 6-min walk distance,laboratory test results,healthy behavior(questionnaire),quality of life(12-item Short Form Health Survey),anxiety(7-item Generalized Anxiety Disorder Questionnaire),and depression(9-item Patient Health Questionnaire)were evaluated at the beginning and after treatment for 3 months.Results:Compared with baseline data,52 patients who participated in cardiac rehabilitation had longer 6-min walk distance(515.26±113.74 m vs 0.445.30±97.92 m,P<0.0002),higher proportions of“always exercise”(78.26% vs.28%,P<0.05),“always limit food with sugar”(65.22% vs 12%,P<0.05),“always eat fruits 200–400 g every day”(82.61% vs.4%,P<0.05).and“always eat vegetables 300–500 g every day”(21.74%vs.12%,P<0.06)after treatment for 3 months.The low-density lipoprotein cholesterol control rate(52.17% vs.28%,P<0.05)and the systolic blood pressure control rate(100%vs.68%,P<0.05)were also signifi cantly increased after treatment for 3 months in the cardiac rehabilitation group.No signifi cant increase was found in the control group after treatment for 3 months.No cardiac-event related to home exercise was reported in both groups.Conclusion:Home-based cardiac rehabilitation is a feasible and available cardiac rehabilitation mode in China.

舒芬太尼联合右美托咪定对Ⅱ型呼吸衰竭机械通气患者镇痛镇静效果研究

目的研究舒芬太尼联合右美托咪定用于Ⅱ型呼吸衰竭机械通气患者早期目标导向性镇痛镇静的临床方法。方法选取2015年7月-2017年6月四川绵阳四O四医院Ⅱ型呼吸衰竭患者90例,采用随机数字表法分为对照组(芬太尼联合咪达唑仑方案)和观察组(舒芬太尼联合右美托咪定镇痛镇静方案),每组各45例。镇痛目标CPOT≤2,镇静目标RASS在-2~1范围。比较两组患者带机时间、血压减低、呼吸抑制、谵妄发生、唤醒时间、ICU住院时间、炎症因子水平方面的指标。结果两组在达到镇静目标所需时间差异无统计学意义(P>0.05);两组在达到镇痛目标所需时间差异有统计学意义(P<0.05);唤醒时间方面,观察组与对照组比较,差异有统计学意义(P<0.05);前者更容易唤醒;观察组机械通气时间与对照组比较,差异有统计学意义(P<0.05),观察组机械通气时间短于对照组;观察组谵妄和呼吸抑制发生率低于对照组(P <0.05);观察组血压减低发生率低于对照组(P <0.05);两组患者镇静24 h时血浆TNF-α水平比较差异无统计学意义(P>0.05)。观察组患者镇静24 h时血浆IL-1水平较对照组低(P<0.05)。结论Ⅱ型呼吸衰竭患者施行早期目标导向镇静是可行的,镇静效果满意,可缩短ICU住院及机械通气时间,呼吸循环影响较小,谵妄发生较少。

Clinical literature review of 1858 Crohn's disease cases requiring surgery in China

AIM: To summarize the clinical characteristics of Crohn's disease(CD) patients who underwent surgery in China.METHODS: We searched four main Chinese electronic databases: CBM, VIP, CNKI, and Wanfang(from January1990 to October 2013). Then, we selected and carefully read 97 studies and extracted the surgical data for CD. We found that 1858 patients with CD underwent surgery between 1961 and 2012. The patients were stratified into two groups according to the year of surgery: 1961-2000 and 2000-2012. The clinical characteristics of these CD cases were compared between the two groups.RESULTS: The mean age at the time of surgery was 38.13 years. The most common locations of disease were the small intestine(40.84%), the colon(33.60%) and the ileocolon(23.09%). The primary indications for surgery were intestinal obstruction or stricture(23.84%), failure of drug therapy(14.80%), acute abdominal disease(13.46%), abdominal mass(10.93%), intestinal fistulae(9.90%), intestinal perforation(8.45%), perianal disease(6.73%), gastrointestinal bleeding(4.79%), and abdominal abscess(4.04%). The rate of diagnosis of CD before surgery was low(34.78%), and the misdiagnosis rate was 20.49%. The predominant surgical procedure for CD was bowel resection(69.54%). The rate of surgical complications was 20.34%, and the primary complications of surgery were infection(39.44%) and intestinal fistulae(26.09%). The relapse rate after surgery was 27.71%. For the periods of 1961-2000 and 2000-2013, the rates of both misdiagnosis before surgery and surgery related-death decreased(34.90% vs 12.10%, P < 0.001, and 23.53% vs 5.26%, P < 0.001, respectively). CONCLUSION: The rates of surgical complications and misdiagnosis were higher, whereas the rate of CDassociated tumor and the relapse rate were lower in China than in West countries.

Time serial transcriptome reveals Cyp2c29 as a key gene in hepatocellular carcinoma development

Objective:Hepatocellular carcinoma(HCC)is a severely lethal cancer that usually originates from chronic liver injury and inflammation.Although progress on diagnosis and treatment is obvious,the cause of HCC remains unclear.In this study,we sought to determine key genes in HCC development.Methods:To identify key regulators during HCC progression,we performed transcriptome sequencing to obtain time series gene expression data from a mouse model with diethylnitrosamine-induced liver tumors and further verified gene expression and function in vitro and in vivo.Results:Among the differentially expressed genes,Cyp2c29 was continuously downregulated during HCC progression.Overexpression of Cyp2c29 suppressed N F-kB activation and proinflammatory cytokine production by increasing the production o f 14,15-epoxyeicosatrienoic acid in vitro.Furthermore,overexpression of Cyp2c29 in vivo protected against liver inflammation in mouse models of liver injury induced by both acetaminophen and CC14.Two human homologs of mouse Cyp2c29,CYP2C8 and CYP2C9,were found to be downregulated in human HCC progression,and their expression was positively correlated with overall survival in patients with HCC(significance:P=0.046 and 0.0097,respectively).Conclusions:Collectively,through systematic analysis and verification,we determined that C yp2c29 is a novel gene involved in liver injury and inflammation,which may be a potential biomarker for HCC prevention and prognosis determination.

Ag+/TiO2/SiO2纳米复合材料的制备及抗变色性能、抑菌性能研究

以TiO2为前驱体,采用液相沉淀法成功制备了Ag+/TiO2/SiO2纳米复合材料。考察了正硅酸四乙酯(TEOS)加入量对复合材料粒径和白度的影响,并对复合材料的抗变色性和抗菌性能进行了研究。通过改变TEOS加入量,优化了SiO2外壳的厚度,使Ag+/TiO2/SiO2纳米复合材料具有较小的粒径,同时增加了复合材料的抗变色性能和抑菌性能。抑菌性能测试表明,Ag+/TiO2/SiO2纳米复合材料对大肠杆菌(E.coli)、金黄色葡萄球菌(S.aureus)和白色念珠菌(C.albicans)具有较强的抑菌作用,达到99%抗菌率的最小浓度分别是55mg/L、75mg/L和65mg/L。

基于金纳米棒纳米载体的智能释药体系的制备

合成了7-(双十二烷基胺)-4-羟甲基香豆素,通过光敏性的酯键将其引入到纳米载体GNR@SiO2-DOX@CouC12-HA(GSDCH)中,实现了药物释放的智能控制,制备了具有良好生物相容性与对Hela细胞的靶向性的纳米载体.结果表明:单独的阿霉素与癌细胞共孵育后,Hela细胞的存活率在50%以上;将DOX先载入纳米载体后,细胞存活率低于20%.与仅使用DOX相比,GSDCH结合了热疗和化疗,对Hela肿瘤细胞的治疗效果显著提高,在肿瘤治疗中具有很大的潜力.

The Influences of the Nozzle Throat Length and the Orifice Grooving Degree on Internal Flow Field for a Multi-Entry Fan Nozzle Based on FLUENT

Spray nozzle is a key component in equipment for plant protection and water-saving irrigation. The fan nozzle is a kind of spray nozzle, which is widely used in agriculture and forestry for irrigation and control of diseases, insects, and weeds. In consideration of the increasing velocity of the flow field, when the hydraulic pressure remains unchanged and the flow path becomes narrow, and because the increase of the velocity of spray drops can increase the penetrability of spray drops into the plant canopy, a kind of new fan nozzle with multi entries and simple inner structure was designed and the influences of its structure parameters on the inner flow field were analyzed using FLUENT software. The experimental results showed that the influence of the throat length on the inner flow field of the nozzle was insignificant, while the orifice grooving degree had a significant effect on inner flow field of the nozzle. The larger the grooving degree was, the smaller the pressure and velocity of internal flow field of the nozzle. The nozzle throat length had little influence on the velocity change of internal flow field. Positive correlation was shown between throat length and flow field velocity.

Withaferin A exerts anti-tumor effects in glioblastoma cells by arresting cell cycle at G_2/M phase

Glioblastoma(GBM) is the most common,malignant,and lethal primary brain tumor in adults.Up to now,there is no effective drug for GBM.Withaferin A(WFA) is mainly derived from Indian Winter cherry.It has been traditionally used in ayurvedic medicine.WFA has wide range of pharmaco.logical activities including cardioprotective,anti-inflammatory,immuno-modulatory properties.Recently,WFA was reported to inhibit the growth of many cancer cells;however,the precise molecular mecha.nisms of its anti-cancer activities in GBM remain unclear.Here,we found that treatment of WFA in U251 and U87-MG glioma cells inhibited the cell proliferation,released the cellular LDH,decreased the DNA synthesis,and inhibited the migration,invasion,and colony formation of cells.WFA also in.creased the apoptotic rate of cells,decreased the mitochondrial membrane potential,arrested cell cy.cle at G_2/M,inhibited the activity of caspase 3/7,and increased the protein expression of cleaved-cas.pase 3,cleaved PARP in U251 and U87-MG cells.In addition,cell apoptosis induced by WFA was as.sociated with increasing level of Bim,Bad,P21,P53 and decreasing the level of p-CDK1,cyclin A and B.It was also shown that cell apoptosis induced by WFA was associated with P38 signal pathway.These results demonstrated that WFA induced mitochondrial dependent apoptosis in glioblastoma cells which was associated with arresting the cell cycle at G_2/M phase by P38 pathway.Taken together,our findings suggest that WFA might be a promising chemotherapy drug in the treatment of GBM.

Correction: MELK is an oncogenic kinase essential for metastasis, mitotic progression, and programmed death in lung carcinoma

After online publication of the article[1]the authors noticed inadvertent errors in the panel of 95-D cells(+MELK and-siSlug)invasion in Fig.2J which is partly overlapped with the panel of the 95-D cells(+MELK and+siSlug)migration in Fig.2J,and the panel of H1299 cells(siMMP7-1)invasion in Supplementary Fig.

FBXW7βloss-of-function enhances FASN-mediated lipogenesis and promotes colorectal cancer growth

Continuous de novo fatty acid synthesis is required for the biosynthetic demands of tumor.FBXW7 is a highly mutated gene in CRC,but its biological functions in cancer are not fully characterized.Here,we report that FBXW7β,a FBXW7 isoform located in the cytoplasm and frequently mutated in CRC,is an E3 ligase of fatty acid synthase(FASN).Cancer-specific FBXW7βmutations that could not degrade FASN can lead to sustained lipogenesis in CRC.COP9 signalosome subunit 6(CSN6),an oncogenic marker of CRC,increases lipogenesis via interacting with and stabilizing FASN.Mechanistic studies show that CSN6 associates with both FBXW7βand FASN,and antagonizes FBXW7β’s activity by enhancing FBXW7βautoubiquitination and degradation,which in turn prevents FBXW7β-mediated FASN ubiquitination and degradation,thereby regulating lipogenesis positively.Both CSN6 and FASN are positively correlated in CRC,and CSN6-FASN axis,regulated by EGF,is responsible for poor prognosis of CRC.The EGF-CSN6-FASN axis promotes tumor growth and implies a treatment strategy of combination of orlistat and cetuximab.Patient-derived xenograft experiments prove the effectiveness of employing orlistat and cetuximab combination in suppressing tumor growth for CSN6/FASN-high CRC.Thus,CSN6-FASN axis reprograms lipogenesis to promote tumor growth and is a target for cancer intervening strategy in CRC.

Discovery of Novel Androgen Receptor Ligands by Structure-based Virtual Screening and Bioassays

Androgen receptor(AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway.Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening(VS) on the basis of the crystal structure of the AR ligand binding domain(LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them(HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 m M and 4.92 m M, respectively, which are even lower than that of enzalutamide(Enz, IC50= 13.87 m M), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics(MD) simulations and principal components analysis(PCA) were carried out to reveal the binding principle of the newlyidentified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary,the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.

MELK is an oncogenic kinase essential for metastasis,mitotic progression,and programmed death in lung carcinoma

Lung cancer is the fastest growth rate of morbidity and mortality in nearly a decade,and remains difficult to treat.Furthermore,the molecular mechanisms underlying its development are still unclear.In this study,bioinformatics analysis showed that MELK was highly expressed in lung cancer and negatively correlated to the survival of lung adenocarcinoma(LUAD).Immunohistochemistry analysis of LUAD patient tissues revealed there were a high level of MELK expression in LUAD.Knockdown of MELK expression inhibits the migration and invasion of LUAD cells,which may be mediated by Twist1,Slug,MMP7,and N-catenin.Overexpression of MELK promoted the growth of LUAD cells in medium,3D Matrigel,and nude mice.Inhibition of MELK by OTSSP167 arrested cycle of LUAD cells at G2/M phase via PLK1-CDC25C-CDK1 pathway,and triggered apoptosis-mediated pyroptosis.Together,these data indicate that MELK is critical for metastasis,mitotic progression,and programmed death of LUAD and may be a promising therapeutic target for LUAD.

Self‐assembled fullerene(C60)‐pentacene superstructures for photodetectors

Fullerene assembling with specific donor molecules would yield multi-functional metamaterials via the collective behavior,wherein linear acenes are widely used as donor molecules to construct the charge‐transfer heterojunction structure with fullerene.However,they are generally prepared by vacuum deposition due to the insoluble property of high‐performance linear acenes molecules in common solvents,which makes the construction of fullerene with insoluble donor molecules still be a big challenge in the solution‐processed method.To this end,chemical modification provides an effective solution‐processed strategy to construct donor and acceptor systems.Here,the C60‐pentacene is assembled into controllable flower‐like superstructures by the surface grafting method.It is found that the nanofeatures of the microflowers could be regulated by temperature,resulting in dense‐flakes morphology at room temperature and loose flakes at high temperatures.Furthermore,the dense‐flakes microflowers structures with less mass but better crystalline structure exhibit better optoelectronic properties.Our results reveal an effective control on the nanofeatures of the self‐assembled fullerenes complex super-structures and their role for the optoelectronic performance,which may promote the exploring of fullerene superstructures as photodetectors.

Synthesis of N-alkyl substituted iminosugars from D-ribose

An effective and facile method for the synthesis of N-alkylated hydroxylpyrrolidine and hydroxylpiper- idine is described, A number of N-alkyl substituted iminosugars were prepared using iodine-induced intramolecular cyclization of acyclic alkenylamines as key step.

MELK is an oncogenic kinase essential for metastasis,mitotic progression,and programmed death in lung carcinoma

Lung cancer is the fastest growth rate of morbidity and mortality in nearly a decade,and remains difficult to treat.Furthermore,the molecular mechanisms underlying its development are still unclear.In this study,bioinformatics analysis showed that MELK was highly expressed in lung cancer and negatively correlated to the survival of lung adenocarcinoma(LUAD).Immunohistochemistry analysis of LUAD patient tissues revealed there were a high level of MELK expression in LUAD.Knockdown of MELK expression inhibits the migration and invasion of LUAD cells,which may be mediated by Twist1,Slug,MMP7,and N-catenin.Overexpression of MELK promoted the growth of LUAD cells in medium,3D Matrigel,and nude mice.Inhibition of MELK by OTSSP167 arrested cycle of LUAD cells at G2/M phase via PLK1-CDC25C-CDK1 pathway,and triggered apoptosis-mediated pyroptosis.Together,these data indicate that MELK is critical for metastasis,mitotic progression,and programmed death of LUAD and may be a promising therapeutic target for LUAD.