Exploiting fly models to investigate rare human neurological disorders

Rare neurological diseases,while individually are rare,collectively impact millions globally,leading to diverse and often severe neurological symptoms.Often attributed to genetic mutations that disrupt protein function or structure,understanding their genetic basis is crucial for accurate diagnosis and targeted therapies.To investigate the underlying pathogenesis of these conditions,researchers often use non-mammalian model organisms,such as Drosophila(fruit flies),which is valued for their genetic manipulability,cost-efficiency,and preservation of genes and biological functions across evolutionary time.Genetic tools available in Drosophila,including CRISPR-Cas9,offer a means to manipulate gene expression,allowing for a deep exploration of the genetic underpinnings of rare neurological diseases.Drosophila boasts a versatile genetic toolkit,rapid generation turnover,and ease of large-scale experimentation,making it an invaluable resource for identifying potential drug candidates.Researchers can expose flies carrying disease-associated mutations to various compounds,rapidly pinpointing promising therapeutic agents for further investigation in mammalian models and,ultimately,clinical trials.In this comprehensive review,we explore rare neurological diseases where fly research has significantly contributed to our understanding of their genetic basis,pathophysiology,and potential therapeutic implications.We discuss rare diseases associated with both neuron-expressed and glial-expressed genes.Specific cases include mutations in CDK19 resulting in epilepsy and developmental delay,mutations in TIAM1 leading to a neurodevelopmental disorder with seizures and language delay,and mutations in IRF2BPL causing seizures,a neurodevelopmental disorder with regression,loss of speech,and abnormal movements.And we explore mutations in EMC1 related to cerebellar atrophy,visual impairment,psychomotor retardation,and gain-of-function mutations in ACOX1 causing Mitchell syndrome.Loss-of-function mutations in ACOX1 result in ACOX1 deficiency,characterized by very-long-chain fatty acid accumulation and glial degeneration.Notably,this review highlights how modeling these diseases in Drosophila has provided valuable insights into their pathophysiology,offering a platform for the rapid identification of potential therapeutic interventions.Rare neurological diseases involve a wide range of expression systems,and sometimes common phenotypes can be found among different genes that cause abnormalities in neurons or glia.Furthermore,mutations within the same gene may result in varying functional outcomes,such as complete loss of function,partial loss of function,or gain-of-function mutations.The phenotypes observed in patients can differ significantly,underscoring the complexity of these conditions.In conclusion,Drosophila represents an indispensable and cost-effective tool for investigating rare neurological diseases.By facilitating the modeling of these conditions,Drosophila contributes to a deeper understanding of their genetic basis,pathophysiology,and potential therapies.This approach accelerates the discovery of promising drug candidates,ultimately benefiting patients affected by these complex and understudied diseases.

Secreted Frizzled-Related Protein 5 Mediates Wnt5a Expression in Microcystin-Leucine-Arginine-Induced Liver Lipid Metabolism Disorder in Mice

Objective Microcystin-leucine-arginine(MC-LR)exposure induces lipid metabolism disorders in the liver.Secreted frizzled-related protein 5(SFRP5)is a natural antagonist of winglesstype MMTV integration site family,member 5A(Wnt5a)and an anti-inflammatory adipocytokine.In this study,we aimed to investigate whether MC-LR can induce lipid metabolism disorders in hepatocytes and whether SFRP5,which has anti-inflammatory effects,can alleviate the effects of hepatic lipid metabolism by inhibiting the Wnt5a/Jun N-terminal kinase(JNK)pathway.Methods We exposed mice to MC-LR in vivo to induce liver lipid metabolism disorders.Subsequently,mouse hepatocytes that overexpressed SFRP5 or did not express SFRP5 were exposed to MC-LR,and the effects of SFRP5 overexpression on inflammation and Wnt5a/JNK activation by MC-LR were observed.Results MC-LR exposure induced liver lipid metabolism disorders in mice and significantly decreased SFRP5 mRNA and protein levels in a concentration-dependent manner.SFRP5 overexpression in AML12cells suppressed MC-LR-induced inflammation.Overexpression of SFRP5 also inhibited Wnt5a and phosphorylation of JNK.Conclusion MC-LR can induce lipid metabolism disorders in mice,and SFRP5 can attenuate lipid metabolism disorders in the mouse liver by inhibiting Wnt5a/JNK signaling.

Mechanistic study of lipid metabolism disorders in diabetic kidney disease treated with GLQMP based on network pharmacology,molecular docking and in vitro experiments

Background:In this study,we used network pharmacology and molecular docking combined with vitro experiments to explore the potential mechanism of action of Gualou Qumai pill(GLQMP)against DKD.Methods:We screened effective compounds and drug targets using Chinese medicine systemic pharmacology database and analysis platform and Chinese medicine molecular mechanism bioinformatics analysis tools;and searched for DKD targets using human online Mendelian genetics and gene cards.The potential targets of GLQMP for DKD were obtained through the intersection of drug targets and disease targets.Cytoscape software was applied to build herbal medicine-active compound-target-disease networks and analyze them;protein-protein interaction networks were analyzed using the STRING database platform;gene ontology and Kyoto Encyclopedia of Genes and Genomes were used for gene ontology and gene and genome encyclopedia to enrich potential targets using the DAVID database;and the AutoDock Vina 1.1.2 software for molecular docking of key targets with corresponding key components.In vitro experiments were validated by CCK8,oil red O staining,TC,TG,RT-qPCR,and Western blot.Results:Through network pharmacology analysis,a total of 99 potential therapeutic targets of GLQMP for DKD and the corresponding 38 active compounds were obtained,and 5 core compounds were identified.By constructing the protein-protein interaction network and performing network topology analysis,we found that PPARA and PPARG were the key targets,and then we molecularly docked these two key targets with the 38 active compounds,especially the 5 core compounds,and found that PPARA and PPARG had good binding ability with a variety of compounds.In vitro experiments showed that GLQMP was able to ameliorate HK-2 cell injury under high glucose stress,improve cell viability,reduce TC and TG levels as well as decrease the accumulation of lipid droplets,and RT-qPCR and Western blot confirmed that GLQMP was able to promote the expression levels of PPARA and PPARG.Conclusion:Overall,this study revealed the active compounds,important targets and possible mechanisms of GLQMP treatment for DKD,and conducted preliminary verification experiments on its correctness,provided novel insights into the treatment of DKD by GLQMP.

Huangqin decoction alleviates lipid metabolism disorders and insulin resistance in nonalcoholic fatty liver disease by triggering Sirt1/NF-κB pathway

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is a clinicopathological entity characterized by intrahepatic ectopic steatosis.As a consequence of increased consumption of high-calorie diet and adoption of a sedentary lifestyle,the incidence of NAFLD has surpassed that of viral hepatitis,making it the most common cause of chronic liver disease globally.Huangqin decoction(HQD),a Chinese medicinal formulation that has been used clinically for thousands of years,has beneficial outcomes in patients with liver diseases,including NAFLD.However,the role and mechanism of action of HQD in lipid metabolism disorders and insulin resistance in NAFLD remain poorly understood.AIM To evaluate the ameliorative effects of HQD in NAFLD,with a focus on lipid metabolism and insulin resistance,and to elucidate the underlying mechanism of action.METHODS High-fat diet-induced NAFLD rats and palmitic acid(PA)-stimulated HepG2 cells were used to investigate the effects of HQD and identify its potential mechanism of action.Phytochemicals in HQD were analyzed by highperformance liquid chromatography(HPLC)to identify the key components.RESULTS Ten primary chemical components of HQD were identified by HPLC analysis.In vivo,HQD effectively prevented rats from gaining body and liver weight,improved the liver index,ameliorated hepatic histological aberrations,decreased transaminase and lipid profile disorders,and reduced the levels of pro-inflammatory factors and insulin resistance.In vitro studies revealed that HQD effectively alleviated PA-induced lipid accumulation,inflammation,and insulin resistance in HepG2 cells.In-depth investigation revealed that HQD triggers Sirt1/NF-κB pathwaymodulated lipogenesis and inflammation,contributing to its beneficial actions,which was further corroborated by the addition of the Sirt1 antagonist EX-527 that compromised the favorable effects of HQD.CONCLUSION In summary,our study confirmed that HQD mitigates lipid metabolism disorders and insulin resistance in NAFLD by triggering the Sirt1/NF-κB pathway.

Lipid droplets in the nervous system:involvement in cell metabolic homeostasis

Lipid droplets serve as primary storage organelles for neutral lipids in neurons,glial cells,and other cells in the nervous system.Lipid droplet formation begins with the synthesis of neutral lipids in the endoplasmic reticulum.Previously,lipid droplets were recognized for their role in maintaining lipid metabolism and energy homeostasis;however,recent research has shown that lipid droplets are highly adaptive organelles with diverse functions in the nervous system.In addition to their role in regulating cell metabolism,lipid droplets play a protective role in various cellular stress responses.Furthermore,lipid droplets exhibit specific functions in neurons and glial cells.Dysregulation of lipid droplet formation leads to cellular dysfunction,metabolic abnormalities,and nervous system diseases.This review aims to provide an overview of the role of lipid droplets in the nervous system,covering topics such as biogenesis,cellular specificity,and functions.Additionally,it will explore the association between lipid droplets and neurodegenerative disorders.Understanding the involvement of lipid droplets in cell metabolic homeostasis related to the nervous system is crucial to determine the underlying causes and in exploring potential therapeutic approaches for these diseases.

Study on mechanism and genetic analysis of lipid metabolism disorder in pregnant rats

Objective: To analyze the characteristics and possible mechanism of lipid metabolism in pregnant rats with intestinal flora imbalance. Methods: A total of 129 sexually mature female SD rats were divided into three groups: non-pregnant group (untreated healthy rats), healthy pregnant group (natural insemination pregnant rats), and pregnant microflora disorder group (pregnant rats were given mixed antibiotics by gavage to build the modeling), with 43 rats in each group. The contents of TG, LDL, HDL and TC were detected by automatic biochemical analyzer, and the contents of SCD1, PGC-1 alpha, PEPCK, ApoE and MTTP genes were detected by fluorescence quantitative PCR technology. Regression analysis was used to explore the comprehensive influence of each gene on total cholesterol expression in rats. Principal component analysis was used to explore the internal mechanism of lipid metabolism in pregnant rats with intestinal flora disorder. Results: The contents of TG, TC, LDL and HDL were compared among the three groups of rats and the differences were statistically significant (P<0.05) . The expression levels of related genes (SCD1, PGC-1, PEPCK, ApoE, MTTP) in the three groups were statistically significant (P<0.05) . SCD1 content in the non-pregnant group, healthy pregnancy group, and disordered pregnancy group was (0.92±0.12) μg/mL, (1.20±0.15)μg/mL, and (1.53±0.20) μg/mL, respectively. PGC-1 alpha content in the non-pregnant group, healthy pregnancy group, and disordered pregnancy group was (1.34±0.21) μg/mL, (0.93±0.12) micron /mL, and (0.41±0.08) μg/mL, respectively. PEPCK content in the non-pregnant group, healthy pregnancy group, and disordered pregnancy group was (0.48±0.06) μg/mL, (0.35±0.09)μg/mL, and (0.22±0.05) μg/mL, and the differences were statistically significant (P<0.05) . Multivariate linear regression analysis showed that the influence of gene content on The effect of each gene content on TC content was in order from large to small: SCD1 (OR=4.572) , PGC-1 (OR=3.387) , PEPCK (OR=3.935) , ApoE (OR=3.597) , MTTP (OR=3.096) . The principal component analysis showed that three principal components could be extracted from five related genes of lipid metabolism in pregnant rats with intestinal dysbiosis: SCD1/PEPCK pathway (contribution rate: 36.28%) , PGC-1 /ApoE pathway (contribution rate: 30.42%) , and MTTP pathway (contribution rate: 15.37%) . Conclusion: After pregnancy, blood lipids in rats are significantly increased while the imbalance of intestinal flora will lead to decreased blood lipids. The disorder of lipid metabolism in pregnant rats with intestinal flora imbalance is mainly related to the disorder of gene expression, which further affects the functions of SCD1/PEPCK, PGC-1 /ApoE and MTTP pathways.

Short-chain fatty acids can improve lipid and glucose metabolism independently of the pig gut microbiota

Background:Previous studies have shown that exogenous short-chain fatty acids(SCFAs)introduction attenuated the body fat deposition in conventional mice and pigs.However,limited studies have evaluated the effects of exogenously introduced SCFAs on the lipid and glucose metabolism independently of the gut microbiota.This study was to investigate the effects of exogenous introduction of SCFAs on the lipid and glucose metabolism in a germ-free(GF)pig model.Methods:Twelve hysterectomy-derived newborn pigs were reared in six sterile isolators.All pigs were hand-fed with sterile milk powder for 21 d,then the sterile feed was introduced to pigs for another 21 d.In the second 21-d period,six pigs were orally administrated with 25 mL/kg sterile saline per day and considered as the GF group,while the other six pigs were orally administrated with 25 mL/kg SCFAs mixture(acetic,propionic,and butyric acids,45,15,and 11 mmol/L,respectively)per day and regarded as FA group.Results:Orally administrated with SCFAs tended to increase the adiponectin concentration in serum,enhance the CPT-1 activity in longissimus dorsi,and upregulate the ANGPTL4 mRNA expression level in colon(P<0.10).Meanwhile,the mRNA abundances of ACC,FAS,and SREBP-1C in liver and CD36 in longissimus dorsi of the FA group were decreased(P<0.05)compared with those in the GF group.Besides,the mRNA expression of PGC-1αin liver and LPL in longissimus dorsi tended to(P<0.10)upregulate and downregulate respectively in the FA group.Moreover,oral administration of SCFAs tended to increase the protein level of GPR43(P<0.10)and decrease the protein level of ACC(P<0.10)in liver.Also,oral administration of SCFAs upregulated the p-AMPK/AMPK ratio and the mRNA expressions of GLUT-2 and GYS2 in liver(P<0.05).In addition,the metabolic pathway associated with the biosynthesis of unsaturated fatty acids was most significantly promoted(P<0.05)by oral administration of SCFAs.Conclusions:Exogenous introduction of SCFAs might attenuate the fat deposition and to some extent improve the glucose control in the pig model,which occurred independently of the gut microbiota.

Characteristics of glucose and lipid metabolism and the interaction between gut microbiota and colonic mucosal immunity in pigs during cold exposure

Background Cold regions have long autumn and winter seasons and low ambient temperatures.When pigs are unable to adjust to the cold,oxidative damage and inflammation may develop.However,the differences between cold and non-cold adaptation regarding glucose and lipid metabolism,gut microbiota and colonic mucosal immunological features in pigs are unknown.This study revealed the glucose and lipid metabolic responses and the dual role of gut microbiota in pigs during cold and non-cold adaptation.Moreover,the regulatory effects of dietary glucose supplements on glucose and lipid metabolism and the colonic mucosal barrier were evaluated in cold-exposed pigs.Results Cold and non-cold-adapted models were established by Min and Yorkshire pigs.Our results exhibited that cold exposure induced glucose overconsumption in non-cold-adapted pig models(Yorkshire pigs),decreasing plasma glucose concentrations.In this case,cold exposure enhanced the ATGL and CPT-1αexpression to promote liver lipolysis and fatty acid oxidation.Meanwhile,the two probiotics(Collinsella and Bifidobacterium)depletion and the enrichment of two pathogens(Sutterella and Escherichia-Shigella)in colonic microbiota are not conducive to colonic mucosal immunity.However,glucagon-mediated hepatic glycogenolysis in cold-adapted pig models(Min pigs)maintained the stability of glucose homeostasis during cold exposure.It contributed to the gut microbiota(including the enrichment of the Rikenellaceae RC9 gut group,[Eubacterium]coprostanoligenes group and WCHB1-41)that favored cold-adapted metabolism.Conclusions The results of both models indicate that the gut microbiota during cold adaptation contributes to the protection of the colonic mucosa.During non-cold adaptation,cold-induced glucose overconsumption promotes thermogenesis through lipolysis,but interferes with the gut microbiome and colonic mucosal immunity.Furthermore,glucagon-mediated hepatic glycogenolysis contributes to glucose homeostasis during cold exposure.

Establishment and evaluation of a mouse model of affective disorder combined with atherosclerosis

Objective:To establish a mouse model of affective disorder complicated with atherosclerosis(AS)by high fat feeding and chronic mild unpredictable stimulation(CUMS),and to provide an animal model for the later study of the prevention and treatment of affective disorder complicated with atherosclerosis by traditional Chinese medicine.Methods:10 C57BL/6J mice were used as blank group,and 20 ApoE-/-mice were randomly divided into AS group and AS+CUMS group.After one week of adaptive feeding,except for the blank group,the other two groups were fed with high fat diet.Meanwhile,the AS+CUMS group was given chronic unpredictable mild stress.The model was evaluated after 16 weeks of modeling.During the experiment,the body weight,food intake,excitability,hair color and other general morphology of mice in each group were observed and recorded.Behavioral indexes(Sucrose preference tests and Open Field test)were detected in each group.The levels of 5-hydroxytryptamine(5-HT)and hypothalamic-pituitary-adrenal(HPA)axis hormones,including adrenocorticotropin(ACTH)and corticosterone(CORT),were detected by ELISA.Serum lipid levels,including total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDL-C)and high density lipoprotein cholesterol(HDL-C),were detected by ELISA.HE staining was used to observe the pathological condition of aorta.Results:Compared with blank group,the excitability and food intake of AS+CUMS group were significantly decreased.There were no significant differences in sugar water consumption and activity capacity of mice in AS group,while sugar water consumption and activity capacity of mice in AS+CUMS group were significantly decreased(P<0.01).The serum 5-HT levels in AS group and AS+CUMS group were decreased,and the levels of ACTH and CORT in AS+CUMS group were significantly decreased(P<0.01),and the levels of ACTH and CORT in AS+CUMS group were significantly increased(P<0.01).The serum TC,TG and LDL-C levels of mice in AS group and AS+CUMS group were significantly increased(P<0.01),while the HDL-C level of mice in both groups was significantly decreased(P<0.01).HE staining results showed that the area and degree of plaques in the active vascular lumen of AS group and AS+CUMS group were larger and heavier.Conclusion:High fat feeding combined with CUMS was successful in establishing a mouse model of emotional disorder combined with atherosclerosis.

Gut dysbiosis and systemic inflammation promote cardiomyocyte abnormalities in an experimental model of steatohepatitis

BACKGROUND Cardiovascular disease is the main cause of death in metabolic-associated fatty liver disease,and gut microbiota dysbiosis is associated with both of them.AIM To assess the relationship between gut dysbiosis and cardiovascular risk(CVR)in an experimental model of steatohepatitis.METHODS Adult male Sprague-Dawley rats were randomized to a control group(n=10)fed a standard diet and an intervention group(n=10)fed a high-fat choline-deficient diet for 16 wk.Biochemical,molecular,hepatic,and cardiac histopathology.Gut microbiota variables were evaluated.RESULTS The intervention group had a significantly higher atherogenic coefficient,Castelli’s risk index(CRI)-I and CRI-II,interleukin-1β,tissue inhibitor of metalloproteinase-1(all P<0.001),monocyte chemoattractant protein-1(P=0.005),and plasminogen activator inhibitor-1(P=0.037)than the control group.Gene expression of miR-33a increased(P=0.001)and miR-126(P<0.001)decreased in the intervention group.Steatohepatitis with fibrosis was seen in the intervention group,and heart computerized histological imaging analysis showed a significant decrease in the percentage of cardiomyocytes with a normal morphometric appearance(P=0.007),reduction in the mean area of cardiomyocytes(P=0.037),and an increase of atrophic cardiomyocytes(P=0.007).There were significant correlations between the cardiomyocyte morphometry markers and those of progression and severity of liver disease and CVR.The intervention group had a lower Shannon diversity index and fewer changes in the structural pattern of gut microbiota(both P<0.001)than controls.Nine microbial families that are involved in lipid metabolism were differentially abundant in intervention group and were significantly correlated with markers of liver injury and CVR.CONCLUSION The study found a link between gut dysbiosis and significant cardiomyocyte abnormalities in animals with steatohepatitis.

脂代谢紊乱破坏线粒体功能导致大鼠动脉粥样硬化形成

目的通过大鼠高脂饮食模型了解脂代谢相关基因mRNA表达水平和线粒体功能在主动脉粥样硬化形成中的作用。方法高脂饮食联合维生素D3建立大鼠动脉粥样硬化模型,检测血清中血脂指标以及脂质代谢基因和线粒体合成和分解基因mRNA表达水平。结果模型组主动脉和颈动脉动脉粥样硬化形成明显,并且随着时间的延长病变加重。与对照组比较,模型组Lp(a)、TC、TG和LDL-C水平明显高于对照组(P<0.05),apoB100和HDL-C差异无统计学意义(P>0.05)。另外,模型组主动脉组织脂代谢相关基因SREBF2、LDL、HMGCR、FDFT1、HMGCS 1、LPL和DHCR24基因以及线粒体融合和分解基因MFN2、Drp1 mRNA表达水平明显增高(P<0.05),ABCA和SQLE mRNA表达水平无明显变化(P>0.05)。结论高脂饮食导致血脂增高是动脉粥样硬化形成的关键。主动脉病变组织脂质代谢基因mRNA表达水平明显增高,线粒体融合和分解明显增加。

苦瓜提取物改善柴油尾气颗粒暴露诱导的小鼠糖脂代谢紊乱

目的探讨苦瓜提取物对柴油尾气颗粒(DEP)诱导糖脂代谢异常的影响及作用机制。方法建立小鼠DEP暴露诱导的代谢紊乱动物模型,给予苦瓜提取物500 mg/(kg·d)灌胃处理12周。观察小鼠的体重、空腹血糖水平、胰岛素敏感性等糖代谢指标;小鼠总胆固醇、三酰甘油等脂肪代谢指标;并对胰腺和肝脏进行组织学检测,分析胰岛的面积和数量、肝脏的质地、组织学变化和脂质含量等指标。结果与DEP组相比,苦瓜提取物处理组小鼠体重增长较快,小鼠葡萄糖耐量(IPGTT)和空腹胰岛素水平显著改善,脂肪代谢指标也有改善。组织学分析结果显示,苦瓜提取物可减少DEP引起的胰腺胰岛面积增加,改善胰岛密度,降低肝脏脂质沉积。结论苦瓜提取物能够有效延缓由DEP滴注诱导的小鼠代谢紊乱,降低动物血糖水平,增加胰岛素敏感性,改善脂肪代谢指标。

中药复方干预肥胖型多囊卵巢综合征糖脂代谢异常的Meta分析

目的:通过文献研究阐述中药干预肥胖型多囊卵巢综合征(polycystic ovary syndrome,PCOS)患者代谢异常的有效性及安全性。方法:计算机检索国内外主流医药数据库中关于中医、中西医结合对比单纯西药治疗PCOS的随机对照试验(randomized controlled trial,RCT)。参照Cochrane系统评价手册对全文的设计方案进行质量评价,采用RevMan 5.4软件进行Meta分析。结果:纳入22项RCT进行Meta分析,中药或中西药联合治疗不仅在提升排卵率这一主要研究指标上优于单纯西药治疗(P<0.05),还在改善胰岛素抵抗指数(homeostasis model assessment of insulin resistance,HOMA-IR)、空腹胰岛素(fasting insulin,FINS)、体质量指数(body mass index,BMI)、三酰甘油(triglyceride,TG)、总胆固醇(total cholesterol,TC)、低密度脂蛋白(low density lipoprotein,LDL)、高密度脂蛋白(high density lipoprotein,HDL)等方面优于单纯西药治疗(均P<0.05),但在调节空腹血糖(fasting blood glucose,FBG)和腰臀比(waist-to-hip ratio,WHR)方面与西药治疗差异无统计学意义(均P>0.05)。结论:中药或中西药联合干预肥胖型PCOS糖脂代谢异常,具有多途径、多靶点调控作用,无严重不良反应,优于单纯西药治疗。

血清Kisspeptin、Betatrophin水平与妊娠期糖尿病病人胰岛素抵抗的相关性分析

目的:探讨血清人吻素-1(Kisspeptin)、促代谢因子(Betatrophin)水平与妊娠期糖尿病(GDM)病人胰岛素抵抗的相关性。方法:选择86例GDM病人(GDM组)和60例正常妊娠孕妇(NGT组),均检测血清Kisspeptin、Betatrophin水平,分析其与GDM发生胰岛素抵抗的相关性。结果:GDM组空腹血糖(FPG)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)、糖化血红蛋白(HbAlc)、总胆固醇(TC)、三酰甘油(TG)、Kisspeptin、Betatrophin水平高于NGT组(P<0.01),Pearson相关性分析血清Kisspeptin、Betatrophin水平与TC、TG、PFG、FINS、HOMA-IR呈正相关关系(r=0.367~0.576,P<0.01),Kisspeptin与Betatrophin之间呈正相关关系(r=0.326,P<0.05)。多重线性回归分析Kisspeptin(B=0.671)、Betatrophin(B=0.886)均与GDM病人HOMA-IR独立相关(P<0.05~P<0.01)。结论:GDM病人血清Kisspeptin、Betatrophin水平明显升高,Kisspeptin、Betatrophin水平均与GDM病人胰岛素抵抗存在正线性相关关系。

血脂代谢异常和肥胖患者发生高危前列腺癌的风险可能更高

目的探讨血脂代谢异常和肥胖因素是否影响高危前列腺癌的发生,旨在为前列腺癌的防治提供参考。方法回顾性分析石河子大学第二附属医院(新疆生产建设兵团医院)泌尿外科2016年6月—2022年6月收治的175例前列腺癌患者的临床资料,其中高危前列腺癌组122例,非高危前列腺癌组53例。采用logistic回归分析影响高危前列腺癌发生的独立危险因素,通过受试者工作特征(ROC)曲线评估年龄、胆固醇、身体质量指数(BMI)、前列腺特异性抗原(PSA)等风险因素对高危前列腺癌发生的预测价值及最佳截断值。采用Spearman分析Gleason评分与不同风险因素间的相关性。结果高危前列腺癌组的年龄、BMI、胆固醇水平、PSA水平、肥胖(BIM≥25)及高胆固醇占比均高于非高危前列腺癌组,差异有统计学意义(P<0.05)。多因素logistic回归分析显示年龄(OR=1.097,95%CI:1.005~1.198,P=0.039)、肥胖(OR=4.459,95%CI:1.305~15.239,P=0.017)、PSA(OR=1.170,95%CI:1.069~1.280,P=0.001)、高胆固醇(OR=5.544,95%CI:1.304~23.577,P=0.020)是高危前列腺癌发生的危险因素。ROC曲线显示年龄、胆固醇、BMI、PSA最佳截断值分别为74.50岁(AUC:0.748,95%CI:0.678~0.818)、3.70 mmol/L(AUC:0.800,95%CI:0.731~0.870)、24.97(AUC:0.621,95%CI:0.532~0.711)、18.67 ng/mL(AUC:0.864,95%CI:0.813~0.916),且年龄、胆固醇、BMI、PSA 4项指标联合预测高危前列腺癌的价值最高(AUC:0.931,95%CI:0.895~0.967)。Spearman分析发现前列腺癌患者的年龄(r=0.464,P<0.001)、BMI(r=0.222,P=0.003)、胆固醇(r=0.501,P<0.001)、PSA(r=0.473,P<0.001)与Gleason评分呈正相关。结论肥胖、年龄、PSA及胆固醇水平是高危前列腺癌发生的影响因素,且当患者的年龄≥74.50岁、胆固醇≥3.70 mmol/L、BMI≥24.97、PSA≥18.67 ng/mL时发生高危前列腺癌的可能性更高。

基于孟德尔随机化的肝功能和脂质代谢水平与睡眠障碍的因果关联分析

目的采用孟德尔随机化分析肝功能和脂质代谢水平与睡眠障碍的因果关联。方法对GWAS进行分析,暴露因素为肝功能和脂质代谢水平[ALT、AST、GGT、Alb、血清总蛋白(TP)、TBil、ALP、TG、TG与磷酸甘油酯的比例(TG/G3P)、TC、HDL-C、LDL-C、多不饱和脂肪酸(PUFA)、总脂肪酸(TFA)、PUFA/TFA],结局因素为睡眠障碍(非器质性)。采用逆方差加权法(IVW)、MR-Egger法、Simple Mode法、加权中位数法和Weighted Mode法等回归模型进行孟德尔随机化分析。结果血清Alb(OR=0.728,95%CI:0.535~0.989,P<0.05),HDL-C(OR=0.879,95%CI:0.784~0.986,P<0.05)和PUFA/TFA(OR=0.800,95%CI:0.642~0.998,P<0.05)与睡眠障碍呈负相关。TG/G3P(OR=1.222,95%CI:1.044~1.431,P<0.05)与睡眠障碍呈正相关。孟德尔随机化结果未显示ALT、AST、GGT、TP、TBil、ALP、TG、TC、LDL-C、PUFA、TFA与睡眠障碍有因果关系(P值均>0.05)。MEEgger截距测试结果表明分析结果不存在多效性(P>0.05),孟德尔随机化在本研究中为因果推断的有效方法。结论根据孟德尔随机化分析结果,肝功能和脂质代谢水平与睡眠障碍之间存在显著关联。在预测睡眠障碍的发生风险以及干预方面,可以考虑利用肝功能和脂质代谢水平作为睡眠障碍发生风险以及干预的指标。

清肝降脂汤对体外诱导非酒精性脂肪肝细胞模型脂代谢和过氧化物酶体增殖物激活受体-α的调节作用研究

目的:探讨清肝降脂汤对体外诱导非酒精性脂肪肝(NAFLD)细胞模型脂代谢和过氧化物酶体增殖物激活受体(PPAR)-α的调节作用。方法:取HepG2细胞株,采用油酸构建NAFLD细胞模型。将细胞分为正常对照组(无油酸建模+无药物处理)、模型对照组(有油酸建模+无药物处理)和清肝降脂汤组(有油酸建模+有药物处理)。采用CCK-8实验检测细胞活性。采用油红O染色定性定量检测清肝降脂汤对细胞内脂质的影响,定量计算脂质含量的抑制率。同时,测定细胞内丙二醛(MDA)、超氧化物歧化酶(SOD)、甘油三酯(TG)、总胆固醇(TC)和游离脂肪酸(FFA)含量;并采用聚合酶链反应(PCR)和Western blot检测脂肪代谢标志物PPAR-α和成纤维细胞生长因子-21(FGF21)的表达水平。结果:与正常对照组相比,模型对照组的HepG2细胞活性显著增高,脂质含量显著增高,MDA、SOD、TG、TC和FFA含量显著增高,而PPAR-α和FGF21表达水平显著降低(均P<0.05);而与模型对照组相比,清肝降脂汤组的HepG2细胞活性显著降低,脂质含量显著降低,MDA、SOD、TG、TC和FFA含量显著降低,而PPAR-α和FGF21表达水平显著增高(均P<0.05)。结论:清肝降脂汤有助于降低HepG2细胞活性、脂质含量以及MDA、SOD、TG、TC和FFA含量,并促进PPAR-α和FGF21表达,进而调节脂质代谢,抑制NAFLD发展进程。

高血压及糖尿病合并血脂异常的老年患者5年生存情况分析

背景随着中国人口老年化加剧,老年人慢性病共病发病率逐年上升,高血压及糖尿病或血糖升高、血脂异常是目前中国老年人慢性病共病最常见的模式,但这种慢性病共病最常见模式的生存情况及影响因素目前尚不明确。目的探讨高血压及糖尿病合并血脂异常的老年患者5年生存情况及其常见危险因素。方法采用回顾性队列分析方法,选取2016年在广州医科大学附属第二医院西院区进行健康体检的老年患者(≥60岁)为研究对象,通过患者健康档案信息系统、医保信息网、患者死亡信息网、患者健康管理信息登记平台及电话访视收集研究对象相关信息,主要包括人口学特征、疾病相关情况、就诊记录等基线资料,以及随访情况及死亡信息等。根据研究对象的生存情况分为生存组和死亡组;根据是否患有高血压及糖尿病,分为无高血压及糖尿病组、高血压病组、糖尿病组、高血压合并糖尿病组;根据是否存在血脂异常分为血脂正常组、混合型高脂血症组、高甘油三酯血症组、高胆固醇血症组、单纯脂蛋白紊乱组;根据是否患有高血压及糖尿病及是否合并血脂异常分为正常组、高血压和/或糖尿病组、非单纯脂蛋白紊乱组、非单纯脂蛋白异常+高血压和/或糖尿病组、单纯脂蛋白紊乱组,单纯脂蛋白紊乱+高血压和/或糖尿病组,采用Log-rank检验比较不同组别老年患者5年粗生存率的差异,进一步采用多因素Cox比例风险回归分析探讨高血压及糖尿病合并血脂异常老年体检患者5年生存情况的影响因素。结果共收集资料完整且诊断明确的老年患者3463例,其中,男1486例(42.91%),女1977例(57.09%),至随访截止日期共死亡287例(8.29%);生存组老年体检患者的性别、体育锻炼情况、高血压及糖尿病患病情况、血脂情况、BMI、腰围、空腹血糖水平、红细胞水平、血红蛋白水平、白细胞水平、血小板水平、血清丙氨酸氨基转移酶水平、血清肌酐水平、血尿氮素水平与死亡组比较,差异有统计学意义(P<0.05)。无高血压及糖尿病组、高血压病组、糖尿病组、高血压合并糖尿病组老年体检患者的5年粗生存率比较,差异有统计学意义(χ^(2)=15.730,P=0.001);血脂正常组、混合型高脂血症组、高甘油三酯血症组、高胆固醇血症组、单纯脂蛋白紊乱组老年体检患者的5年粗生存率比较,差异有统计学意义(χ^(2)=29.290,P<0.001);正常组、高血压和/或糖尿病组、非单纯脂蛋白紊乱组、非单纯脂蛋白异常+高血压和/或糖尿病组、单纯脂蛋白紊乱组、单纯脂蛋白紊乱+高血压和/或糖尿病组老年体检患者的5年粗生存率比较,差异有统计学意义(χ^(2)=42.400,P<0.001)。多因素Cox比例风险回归分析结果显示,日常体育锻炼情况、BMI、腰围、空腹血糖水平、红细胞计数、血红蛋白水平、血清天冬氨酸氨基转移酶水平及血清肌酐水平是高血压及糖尿病合并血脂异常老年体检患者5年生存情况的影响因素(P<0.05)。结论相对于普通人群,高血压及糖尿病合并有血脂异常的人群5年的粗生存率更低,特别是存在脂蛋白异常的人群,生活方式、营养状况、肝肾功能也对5年生存情况产生明显影响;在进行高血压、糖尿病及血脂异常等慢性病的管理时,除积极降压、降糖及减低胆固醇、三酰甘油外,还要关注患者的脂蛋白水平、营养状况、肝肾功能及生活方式的改善。

小胶质细胞中的脂滴在中枢神经系统疾病中的研究进展

脂滴曾被简单认为是中性脂质的储存库,但最近的研究表明其在神经胶质细胞的信号转导、代谢和炎症中均发挥重要作用,尤其是在小胶质细胞中。小胶质细胞是中枢神经系统中常驻的单核吞噬细胞,与炎症、吞噬、髓鞘修复,以及衰老过程和神经系统变性疾病密切相关。然而,小胶质细胞内脂滴形成的机制以及对组织病理、相关疾病的影响仍有待阐明。在这篇综述中,我们总结了最近的研究结果,旨在进一步阐明这些问题。

小檗碱调节糖脂代谢作用机制研究进展

随着生活质量的提高,糖脂代谢紊乱导致的疾病如糖尿病、高脂血症、肥胖症、胰岛素抵抗、脂肪肝等的发生率逐年上升。中药黄连在治疗糖脂代谢紊乱相关疾病方面有着显著疗效。小檗碱为黄连中含量最高、代表性最强的活性成分,属异喹啉类生物碱,能通过保护胰岛β细胞,改善胰岛素抵抗、调节胰岛素分泌、促进胰高血糖素样肽1(GLP-1)分泌、调节肠道菌群调节糖代谢,通过减少脂质沉积、促进脂质清除等调节脂代谢,还可通过AMPK通路、肠道菌群等共同调节糖脂代谢。其来源广泛、作用安全,在防治糖脂代谢紊乱导致的相关疾病中有着多通路、多效应的优势。该文归纳总结国内外相关文献,对小檗碱调节糖脂代谢作用机制进行综述,以期为中医药改善糖脂代谢紊乱提供一定的思路和理论依据。