USP19 Stabilizes TAK1 to Regulate High Glucose/Free Fatty Acid-induced Dysfunction in HK-2 Cells

Objective Obesity-induced kidney injury contributes to the development of diabetic nephropathy(DN).Here,we identified the functions of ubiquitin-specific peptidase 19(USP19)in HK-2 cells exposed to a combination of high glucose(HG)and free fatty acid(FFA)and determined its association with TGF-beta-activated kinase 1(TAK1).Methods HK-2 cells were exposed to a combination of HG and FFA.USP19 mRNA expression was detected by quantitative RT-PCR(qRT-PCR),and protein analysis was performed by immunoblotting(IB).Cell growth was assessed by Cell Counting Kit-8(CCK-8)viability and 5-ethynyl-2′-deoxyuridine(EdU)proliferation assays.Cell cycle distribution and apoptosis were detected by flow cytometry.The USP19/TAK1 interaction and ubiquitinated TAK1 levels were assayed by coimmunoprecipitation(Co-IP)assays and IB.Results In HG+FFA-challenged HK-2 cells,USP19 was highly expressed.USP19 knockdown attenuated HG+FFA-triggered growth inhibition and apoptosis promotion in HK-2 cells.Moreover,USP19 knockdown alleviated HG+FFA-mediated PTEN-induced putative kinase 1(PINK1)/Parkin pathway inactivation and increased mitochondrial reactive oxygen species(ROS)generation in HK-2 cells.Mechanistically,USP19 stabilized the TAK1 protein through deubiquitination.Importantly,increased TAK1 expression reversed the USP19 knockdown-mediated phenotypic changes and PINK1/Parkin pathway activation in HG+FFA-challenged HK-2 cells.Conclusion The findings revealed that USP19 plays a crucial role in promoting HK-2 cell dysfunction induced by combined stimulation with HG and FFAs by stabilizing TAK1,providing a potential therapeutic strategy for combating DN.

Serum bile acid and unsaturated fatty acid profiles of non-alcoholic fatty liver disease in type 2 diabetic patients

BACKGROUND The understanding of bile acid(BA)and unsaturated fatty acid(UFA)profiles,as well as their dysregulation,remains elusive in individuals with type 2 diabetes mellitus(T2DM)coexisting with non-alcoholic fatty liver disease(NAFLD).Investigating these metabolites could offer valuable insights into the pathophy-siology of NAFLD in T2DM.AIM To identify potential metabolite biomarkers capable of distinguishing between NAFLD and T2DM.METHODS A training model was developed involving 399 participants,comprising 113 healthy controls(HCs),134 individuals with T2DM without NAFLD,and 152 individuals with T2DM and NAFLD.External validation encompassed 172 participants.NAFLD patients were divided based on liver fibrosis scores.The analytical approach employed univariate testing,orthogonal partial least squares-discriminant analysis,logistic regression,receiver operating characteristic curve analysis,and decision curve analysis to pinpoint and assess the diagnostic value of serum biomarkers.RESULTS Compared to HCs,both T2DM and NAFLD groups exhibited diminished levels of specific BAs.In UFAs,particular acids exhibited a positive correlation with NAFLD risk in T2DM,while theω-6:ω-3 UFA ratio demonstrated a negative correlation.Levels ofα-linolenic acid andγ-linolenic acid were linked to significant liver fibrosis in NAFLD.The validation cohort substantiated the predictive efficacy of these biomarkers for assessing NAFLD risk in T2DM patients.CONCLUSION This study underscores the connection between altered BA and UFA profiles and the presence of NAFLD in individuals with T2DM,proposing their potential as biomarkers in the pathogenesis of NAFLD.

High-starchy carbohydrate diet aggravates NAFLD by increasing fatty acids influx mediated by NOX2

Nonalcoholic fatty liver disease(NAFLD)is a high-incidence lipid disorder that affects more than a quarter of the population worldwide,and dietary intervention is the recognized treatment.Starch is the main component of staple foods that are consumed daily,and the effects,metabolic pathway,and molecular mechanism of starch in the context of NAFLD remain unclear.Our study showed that a high-starch carbohydrate diet(HCD)led to the occurrence and exacerbation of NAFLD in mice.Transcriptomics and metabonomic analyses showed that the increased fatty acid influx mediated by NADPH oxidase 2(NOX2)exacerbated NAFLD.Knocking down NOX2 specifically alleviated HCD-induced NAFLD in vivo and in vitro.Moreover,the large amounts of ROS produced by NOX2 further exacerbated insulin resistance and increased lipolysis in perirenal white adipose tissue(periWAT),thereby providing fatty acids for hepatic lipid synthesis.In addition,the interaction between AMPKα1 and p47phox was the pathway that mediated the high expression of NOX2 induced by a HCD.Our study systematically demonstrated the effect of a HCD on NAFLD.Elevated fatty acid influx is a unique molecular regulatory pathway that mediates HCD-induced NAFLD exacerbation,which is different from the effect of simple sugars.Additionally,NOX2 was suggested to be a specific and effective drug target for NAFLD.

2型糖尿病伴干眼症病人血清和泪液分泌型卷曲相关蛋白5、脂肪酸结合蛋白4水平与病情严重程度的相关性

目的分析分泌型卷曲相关蛋白5(SFRP-5)、脂肪酸结合蛋白4(FABP4)在2型糖尿病(T2DM)伴干眼症病人血清和泪液中的表达及其与病情严重程度的相关性。方法选取2020年12月至2021年12月唐山市眼科医院收治的T2DM病人145例,其中单纯T2DM病人84例168眼(T2DM组),伴干眼症病人61例122眼(T2DM伴干眼症组),另选取同期该院体检健康者50例100眼作为对照组。T2DM伴干眼症病人又分为轻度组(29例)、中度组(17例)、重度组(15例)。利用酶联免疫吸附法测定所有受试者血清和泪液中SFRP-5、FABP4水平;相关性分析采用Pearson法或Spearman法;logistic回归分析影响T2DM病人干眼症发生的因素。结果T2DM伴干眼症组、T2DM组血清和泪液SFRP-5水平均低于对照组(106.09±8.37、135.72±9.26比158.34±9.45,28.85±5.13、58.27±6.14比45.18±5.92),T2DM伴干眼症组低于T2DM组(P<0.05);T2DM伴干眼症组、T2DM组血清和泪液FABP4水平均高于对照组(70.63±6.59、58.27±6.14比45.18±5.92,15.91±3.76、10.28±3.58比7.72±3.29),T2DM伴干眼症组高于T2DM组(P<0.05)。重度组、中度组血清和泪液SFRP-5水平(68.29±7.15、95.54±8.34比131.82±9.02,12.83±4.62、24.72±5.49比39.56±5.18)、泪膜破裂时间(BUT)、泪液分泌试验(SIT)低于轻度组,重度组低于中度组(P<0.05);重度组、中度组血清和泪液FABP4水平(84.56±6.83、73.18±6.94比61.93±6.27,25.64±4.19、17.15±3.86比10.16±3.47)及眼表疾病指数量表(OSDI)积分高于轻度组,重度组高于中度组(P<0.05)。T2DM伴干眼症病人血清与泪液SFRP-5水平呈正相关,血清与泪液FABP4水平也呈正相关(P<0.05)。T2DM伴干眼症病人血清和泪液SFRP-5水平与OSDI积分均呈负相关,与BUT、SIT均呈正相关(P<0.05);血清和泪液FABP4水平与OSDI积分均呈正相关,与BUT、SIT均呈负相关(P<0.05)。血清和泪液SFRP-5水平是影响T2DM病人干眼症发生的独立保护因素,而血清和泪液FABP4水平是独立危险因素(P<0.05)。结论SFRP-5在T2DM伴干眼症病人血清和泪液中均低表达,FABP4均高表达,二者与病情严重程度密切相关。

视网膜静脉阻塞患者血清FABP4,VWF和LCN-2水平表达与继发黄斑水肿程度及预后的关系研究

目的 探究视网膜静脉阻塞(retinal vein obstruction,RVO)患者血清脂肪细胞型脂肪酸结合蛋白(fatty acid-binding protein 4,FABP4)、血管性假血友病因子(von willebrand factor,VWF)、脂质运载蛋白2(lipocalin-2,LCN-2)水平表达与继发黄斑水肿(macular edema,ME)程度及预后的关系研究。方法 选取2021年1月~2023年8月来西北大学附属第一医院治疗的98例确诊的RVO继发ME患者为观察组,根据黄斑水肿程度分为重度组(n=46)、中度组(n=32)和轻度组(n=20),根据预后情况分为预后不良组(n=36)和预后良好组(n=62);另选取98例单纯RVO患者为对照组。比较各组血清FABP4,VWF,LCN-2水平;多因素Logistic回归分析RVO继发ME患者发生预后不良的影响因素;ROC曲线分析血清FABP4,VWF和LCN-2水平对RVO继发ME患者发生预后不良的预测价值。结果 与对照组相比,观察组血清FABP4(35.24±4.43 ng/ml vs 23.19±3.69 ng/ml),VWF(2.67±0.67 ng/ml vs1.48±0.38 ng/ml),LCN-2(112.53±12.74 mg/L vs 85.49±9.86 mg/L)水平明显升高,差异具有统计学意义(t=20.690,15.294,16.616,均P<0.05);随病情逐渐发展,轻、中、重度组血清FABP4(33.38±4.29 ng/ml,35.79±4.49 ng/ml,38.64±4.65 ng/ml),VWF(2.36±0.59 ng/ml,2.72±0.66 ng/ml,3.29±0.87 ng/ml),LCN-2(105.84±12.24 mg/L,114.61±12.88 mg/L,124.59±13.69 mg/L)水平逐渐升高,差异具有统计学意义(F=10.194,13.294,15.703,均P<0.05);与预后良好组相比,预后不良组血清FABP4(39.64±4.59 ng/ml vs 32.69±4.34 ng/ml),VWF(3.26±0.87ng/ml vs 2.33±0.55 ng/ml),LCN-2(124.56±13.42 mg/L vs 105.54±12.34 mg/L)水平明显升高,差异具有统计学意义(t=7.482,6.487,7.122,均P<0.05));血清FABP4(OR=2.236,95%CI:1.109~4.510),VWF(OR=2.069,95%CI:1.044~4.100),LCN-2(OR=1.875,95%CI:1.015~3.463)为RVO继发ME患者发生预后不良的独立危险因素(均P<0.05);血清FABP4,VWF,LCN-2水平预测患者发生预后不良的AUC(95%CI)分别为0.817(0.726~0.888),0.791(0.697~0.867)和0.798(0.705~0.872),三者联合预测的AUC为0.932(0.863~0.973),三者联合预测优于各因子单独预测(Z=2.034,2.375,2.385,P=0.042,0.018,0.017)。结论 RVO继发ME患者血清FABP4,VWF和LCN-2水平均上调,且均为患者发生预后不良的独立危险因素,三者联合检测对RVO继发ME患者发生预后不良具有更高的预测价值。

2型糖尿病合并代谢综合征患者血清CTRP9、A-FABP水平变化及临床意义

目的研究2型糖尿病(T2DM)合并代谢综合征(MS)(T2DM~MS)患者血清补体C1q肿瘤坏死因子相关蛋白(CTRP9)、脂肪型脂肪酸结合蛋白(A-FABP)水平变化及临床意义。方法前瞻性选择2021年1月至2023年12月于广西医科大学第二附属医院治疗的90例T2DM患者纳入研究组,根据是否合并MS将其分为T2DM~MS组(n=71)、T2DM未合并MS组(n=19)。将同期于广西医科大学第二附属医院进行体检的90名健康者纳入对照组。检测并比较研究组与对照组、T2DM~MS组与T2DM未合并MS组的糖脂代谢指标[空腹血糖、高密度脂蛋白(HDL-C)、总胆固醇、低密度脂蛋白(LDL-C)、甘油三酯]及血清CTRP9、A-FABP水平。采用Pearson相关性分析CTRP9、A-FABP与各糖脂代谢指标的相关性;采用受试者操作特征(ROC)曲线评价CTRP9、A-FABP对T2DM~MS的诊断效能。结果研究组的空腹血糖、总胆固醇、LDL-C、甘油三酯及血清A-FABP水平分别为(9.37±0.95)mmol/L、(4.38±0.45)mmol/L、(2.83±0.29)mmol/L、(1.58±0.17)mmol/L、(15.48±1.72)ng/mL,均高于对照组,研究组HDL-C及血清CTRP9水平分别为(1.23±0.14)mmol/L、(8.38±0.85)ng/mL,均低于对照组,差异均有统计学意义(P<0.05)。T2DM~MS组空腹血糖、总胆固醇、LDL-C、甘油三酯及血清A-FABP水平分别为(10.26±1.32)mmol/L、(4.51±0.47)mmol/L、(3.15±0.33)mmol/L、(1.74±0.20)mmol/L、(18.21±2.06)ng/mL,均高于T2DM未合并MS组,T2DM~MS组HDL-C及血清CTRP9水平分别为(1.12±0.13)mmol/L、(7.26±0.75)ng/mL,均低于T2DM未合并MS组,差异均有统计学意义(P<0.05)。经Pearson相关分析,血清CTRP9水平与空腹血糖、总胆固醇、LDL-C、甘油三酯均呈负相关(r=-0.902、-0.780、-0.745、-0.753;均P<0.05),与HDL-C呈正相关(r=0.827,P<0.05);血清A-FABP水平与空腹血糖、总胆固醇、LDL-C、甘油三酯均呈正相关(r=0.843、0.812、0.839、0.722;均P<0.05),与HDL-C呈负相关(r=-0.768,P<0.05)。经ROC曲线分析,血清CTRP9联合A-FABP对T2DM~MS的诊断效能高于两者单独诊断。结论T2DM~MS患者血清CTRP9水平低表达,A-FABP水平高表达,血清CTRP9、A-FABP水平与糖脂代谢指标密切相关。血清CTRP9联合A-FABP可提高T2DM~MS的诊断效能,监测血清CTRP9、A-FABP水平有助于预测T2DM~MS的发生。

脂肪酸结合蛋白4在2型糖尿病肾病中的诊断价值

目的:探讨2型糖尿病(type 2 diabetes mellitus,T2DM)患者血清脂肪酸结合蛋白4(fatty acid-binding protein 4,FABP4)与糖尿病肾病(diabetic nephropathy,DN)的相关性及其作为DN早期诊断的应用价值。方法:纳入T2DM患者218例及健康体检者(对照组)20名,收集受试者的一般临床资料如身高、体质量、腰围、糖尿病病程等,计算BMI;收集血糖、糖化血红蛋白、空腹胰岛素、空腹C肽、肝肾功能、血脂等指标,计算稳态模型胰岛素抵抗指数(homeostasis model assessment-insulin resistance index,HOMA-IR)。采用ELISA测定血清FABP4水平;采用联合血肌酐(serum creatinine,Scr)和胱抑素C(cystatin C,Cys C)的慢性肾脏病流行病学协作方程式计算肾小球滤过率;测定尿白蛋白和肌酐水平,计算尿微量蛋白与肌酐比值(urinary albumin to creatinine ratio,UACR)。根据估算的肾小球滤过率(estimated glomerular filtration rate,eGFR)水平将T2DM患者分为肾功能正常组(eGFR≥90 mL/min/1.73 m^(2))、轻度肾功能不全组(eGFR 60~<90 mL/min/1.73 m^(2))和中度肾功能不全组(eGFR 30~<60 mL/min/1.73 m^(2));根据UACR水平分为正常蛋白尿组(UACR<30 mg/g)、微量蛋白尿组(UACR 30~<300 mg/g)和大量蛋白尿组(UACR≥300 mg/g)。采用回归分析评估FABP4与eGFR、UACR严重程度的相关性。结果:(1)与对照组相比,T2DM患者的血清FABP4显著升高。(2)在根据eGFR分层的3个亚组中,随着eGFR的下降,血清FABP4水平显著增加(P<0.001)。但在UACR亚组中差异无统计学意义(P=0.382)。(3)Spearman相关分析显示FABP4与eGFR呈负相关(r=-0.203,P=0.001),与UACR无相关性(r=0.130,P=0.055)。(4)多元线性回归表明,FABP4与eGFR呈独立负相关(r=-0.211,P<0.001),与UACR无相关性(r=-0.047,P=0.534)。(5)ROC曲线显示FABP4诊断DN的最佳截断值为103.9μg/L,AUC为0.745(灵敏度51.2%,特异度92.7%)。结论:T2DM患者血清FABP4水平升高与DN发生发展相关,有可能作为DN早期诊断的生物标志物。

苍柴调中方辅助改善肝郁脾虚型肥胖2型糖尿病的疗效及对胰岛素抵抗、FFA、LDL-C水平的影响

目的:探讨苍柴调中方辅助改善肝郁脾虚型肥胖2型糖尿病(T2DM)的疗效,并分析其对胰岛素抵抗、游离脂肪酸(FFA)、低密度脂蛋白胆固醇(LDL-C)水平的影响。方法:选取2020年4月至2023年4月该院收治的肝郁脾虚型肥胖T2DM患者100例,根据随机数字表法分为两组,各50例。对照组患者使用二甲双胍治疗,观察组患者在对照组基础上联合苍柴调中方辅助治疗。观察两组患者的治疗效果,比较两组患者治疗前后中医症状积分、糖代谢指标[空腹血糖(FBG)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)]、血清FFA、LDL-C、肿瘤坏死因子α(TNF-α)水平的差异,并对不良反应发生率进行统计。结果:观察组患者的治疗总有效率高于对照组,不良反应发生率低于对照组,差异均有统计学意义(P<0.05)。治疗后,观察组患者倦怠乏力、精神抑郁、脘腹闷胀及大便黏滞等中医症状积分均低于对照组,差异均有统计学意义(P<0.05)。与治疗前比较,两组患者治疗后的FBG、HOMA-IR、FINS水平均明显降低,其中观察组患者治疗后的FINS、FBG及HOMA-IR水平低于对照组,差异均有统计学意义(P<0.05)。观察组患者治疗后的血清LDL-C、FFA、TNF-α水平均低于对照组,差异均有统计学意义(P<0.05)。结论:苍柴调中方辅助治疗可明显提高肝郁脾虚型肥胖T2DM患者的治疗效果,改善胰岛素抵抗,下调血清FFA、LDL-C水平。

盐碱水对鲌鲂“先锋2号”营养品质的影响

[目的]探究水体盐碱度对鲌鲂“先锋2号”肌肉营养品质的影响,为淡水鱼在盐碱水环境中养殖提供科学依据。[方法]通过在盐碱水(5‰NaCl、1‰NaHCO_(3))中暂养鲌鲂“先锋2号”0 d(对照组)、8、16、30 d,分别对其肌肉中常规营养成分、氨基酸和脂肪酸含量和组成以及肌肉质构特性进行测定。[结果]试验组8 d、16 d和30 d的鱼肉蛋白质、脂肪含量均显著高于对照组0 d(P<0.05)。肌肉中氨基酸总量、必需氨基酸总量和非必需氨基酸总量随暂养时间延长呈先升后降的趋势,在16 d时含量达到最高值。在检测到的19种脂肪酸中,16种脂肪酸含量随着暂养时间延长而显著上升(P<0.05)。盐碱水暂养30 d时,肌肉硬度和弹性显著高于对照组0 d(P<0.05),8 d时回复性显著高于对照组(P<0.05)。[结论]鲌鲂“先锋2号”可以适应盐碱环境,且盐碱水可有效提高其肌肉营养品质,改善肌肉质地,具有较高的食用价值和经济价值。根据本研究结果与实际养殖情况综合考虑,建议鲌鲂“先锋2号”在盐碱水中暂养16 d。

短链脂肪酸在2型糖尿病中的发病机制与中医药应用展望

糖尿病是一种严重的糖代谢性疾病,近年来,其发病率逐渐增高。其中2型糖尿病以多种原因引起胰岛素分泌相对缺乏、胰岛素抵抗为主要发病机制,以血糖升高及蛋白质、脂质代谢异常为主要表现。肠道菌群是人体中最大微生态系统,对机体健康至关重要。现代药理研究表明,肠道微生态环境失调可通过多种通路影响糖脂正常代谢,导致肥胖甚至是胰岛素抵抗,因此,2型糖尿病的发生发展与肠道菌群有着密切联系。短链脂肪酸作为肠道菌群重要代谢产物,能够通过与FFAR2/3等受体结合从而促进肠道激素分泌,减少机体炎症反应,调节糖异生,改善血脂紊乱,抑制脂肪积累,改善2型糖尿病的高血糖状态。且这种机制与中医学“脾为后天之本”“阴阳平衡”理论相契合,因此有望通过调节短链脂肪酸及其受体FFAR2/3保持平衡状态,为2型糖尿病患者提供更有效的治疗靶点,开发更有效的治疗药物。

基于肠道菌群及其代谢产物SCFA探讨左归降糖通脉方对2型糖尿病大鼠糖脂代谢的影响

目的基于肠道菌群及代谢产物短链脂肪酸(short-chain fatty acid,SCFA)探讨左归降糖通脉方(Zuogui Jiangtang Tongmai formula,ZJTF)干预2型糖尿病(type 2 diabetes mellitus,T2DM)的可能机制。方法取12只SD大鼠为空白(Control)组,喂食普通饲料;48只大鼠为造模组,以高脂饲料联合链脲佐菌素(streptozocin,STZ)制备T2DM模型。造模成功后随机分为模型(DM)组、ZJTF低剂量(ZJTF.L,12 g·kg^(-1))组、ZJTF高剂量(ZJTF.H,24 g·kg^(-1))组、二甲双胍150 mg·kg^(-1)+阿托伐他汀10 mg·kg^(-1)(M.A)组,药物干预4周。监测大鼠精神状态、体质量与随机血糖;ELISA检测血清胰岛素(insulin,INS)、糖化血红蛋白(glycosylated hemoglobin,HbA1c)、炎症因子的水平;生化分析法检测血脂常规含量;HE染色观察结肠病理改变;16SrRNA观察肠道菌群结构;GC-MS检测血清SCFA水平。结果与Control组比较,DM组出现多饮、多食、多尿、体质量减轻等症状;血糖、INS、HbA1c明显上升(P<0.01);总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)水平升高,高密度脂蛋白胆固醇(high density lipoprotein cholesterol,HDL-C)明显降低(P<0.01);白细胞介素-1β(interleukin-1β,IL-1β)、白细胞介素-6(interleukin-6,IL-6)及肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)水平均明显升高(P<0.01);结肠固有层出现部分中断和消失,细胞肿胀、绒毛紊乱。DM组厚壁菌门和变形菌门、肠杆菌科、埃希菌-志贺菌属的相对丰度增加;血清乙酸、丁酸含量下降(P<0.05,P<0.01)。与DM组比较,ZJTF组血糖、INS、HbAlc均明显降低(P<0.05,P<0.01);TC、TG、LDL-C明显降低,HDL-C明显升高(P<0.01);IL-1β、IL-6及TNF-α水平明显降低(P<0.01);结肠细胞肿胀及炎性浸润缓解;拟杆菌门和疣微菌门、乳酸菌科、阿克曼菌属丰度增加;血清丁酸、乙酸含量升高(P<0.05,P<0.01)。结论左归降糖通脉方可能通过调节肠道菌群和SCFAs水平起到降血糖、稳血脂、减轻炎症反应的作用。

短链脂肪酸在2型糖尿病中的作用研究进展

短链脂肪酸(SCFAs)在肠道微生物群调控宿主代谢中起到了主要介导作用,且与2型糖尿病(T2DM)密切相关,可改善T2DM患者的血糖、体质量和血脂指标。尽管有学者认为SCFAs有望成为T2DM的新型治疗靶点,但目前尚未有相关综述。本文总结了短链脂肪酸的生物学特性,讨论了SCFAs调节食欲、炎症、胰岛β细胞、脂质代谢与肝脏糖原代谢的证据,进一步明确调控SCFAs在T2DM中的作用及其研究进展,探讨了调控SCFAs治疗T2DM的潜力。

Short-chain fatty acids act as antiinflammatory mediators by regulating prostaglandin E_2 and cytokines

AIM： To investigate the effect of short-chain fatty acids （SCFAs） on production of prostaglandin E2 （PGE2）, cytokines and chemokines in human monocytes. METHODS： Human neutrophils and monocytes were isolated from human whole blood by using 1-Step Polymorph and RosetteSep Human Monocyte Enrichment Cocktail, respectively. Human GPR41 and GPR43 mRNA expression was examined by quantitative realtime polymerase chain reaction, The calcium flux assay was used to examine the biological activities of SCFAs in human neutrophils and monocytes. The effect of SCFAs on human monocytes and peripheral blood mononuclear cells （PBMC） was studied by measuring PGE2, cytokines and chemokines in the supernatant. The effect of SCFAs in vivo was examined by intraplantar injection into rat paws. RESULTS： Human GPR43 is highly expressed in human neutrophils and monocytes. SCFAs induce robust calcium flux in human neutrophils, but not in human monocytes. In this study, we show that SCFAs can induce human monocyte release of PGE2 and that this effect can be enhanced in the presence of lipopolysaccharide （LPS）. In addition, we demonstrate that PGE2 production induced by SCFA was inhibited by pertussis toxin, suggesting the involvement of a receptor-mediated mechanism. Furthermore, SCFAs can specifically inhibit constitutive monocyte chemotactic protein-1 （MCP-1） production and LPS-induced interleukin-10 （IL-10） production in human monocytes without affecting the secretion of other cytokines and chemokines examined. Similar activities were observed in human PBMC for the release of PGE2, MCP-1 and IL-10 after 5CFA treatment. In addition, SCFAs inhibit LPS-induced production of tumor necrosis factor-α and interferon-7 in human PBIVlC. Finally, we show that SCFAs and LPS can induce PGE2 production in vivo by intraplantar injection into rat paws （P 〈 0.01）. CONCLUSION： SCFAs can have distinct antiinflammatory activities due to their regulation of PGE2, cytokine and chemokine release from human immune cells.

Fatty Acid Synthase and Hormone-sensitive Lipase Expression in Liver Are Involved in Zinc-α2-glycoprotein-induced Body Fat Loss in Obese Mice

Objective To explore the effects of zinc-0t2-glycoprotein （ZAG） on body weight and body fat in high-fat-diet （HF1））-induced obesity in mice and the possible mechanism. Methods Thirty-six male mice were fed with standard food （SF） （n=9） and HFD （n=27）, respectively. Five weeks later, 9 mice fed with HFD were subjected to ZAG expression plasmid DNA transfection by liposome transfection method, and another 9 mice to negative control plasmid transfection. Two weeks later, serum ZAG level in the mice was assayed by Western blot, and the effects of ZAG over-expression on body weight, body fat, serum biochemical indexes, and adipose tissue of obese mice were evaluated. The mRNA expressions of fatty acid synthase （FAS） and hormone sensitive lipase （HSL） in liver tissue were deterlnined by reverse transcription-polymerase chain reaction. Results Serum ZAG level significantly lowered in simple HFD-fed mice in comparison to SF-fed mice （0.51±0.10 AU vs. 0.75±0.07 AU, P〈0.01）. Further statistical analysis demonstrated that ZAG level was negatively correlated with body weight （r =-0.56, P〈0.001）, epididymal fat mass （r=-0.67, P〈O. 001）, percentage of epididymal fat （r= 0.65, P〈0.001）, and increased weight （r= 0.57, P〈0.001） in simple SF- and HFD fed mice. ZAG over-expression in obese mice reduced body weight and the percentage of epididyreal fat. Furthermore, FAS mRNA expression decreased （P〈0.01） and HSL mRNA expression increased （P〈0.001） in the liver in ZAG over-expressing mice. Conclusions ZAG is closely related to obesity. Serum ZAG level is inversely correlated with body weight and percentage of body fat. The action of ZAG is associated with reduced FAS expression and increased HSL expression in the liver of obese mice.

High Sn-2 Docosahexaenoic Acid Lipids for Brain Benefits, and Their Enzymatic Syntheses: A Review

The normal development and maintenance of central neural functions are highly correlated with the amount of docosahexaenoic acid(DHA;ω-3 fatty acid)accumulated in the brain.DHA incorporated at the sn-2 position of lipids is well absorbed by intestinal mucosa and utilized efficiently in vivo.However,modern consumers have a reduced direct intake of DHA and increased intake of saturated fats or ω-6 fatty acid oils,resulting in behavioral and neurophysiological deficits.To provide an understanding of the integrated beneficial effects of DHA on the human brain,this review introduces the positional difference(sn-2 and sn-1,3 positions)of DHA on a glycerol skeleton in natural fats and oils,and further discusses the possible functional mechanism regarding DHA supplementation and the gut-brain axis.The multiple bidirectional routes in this axis offer a novel insight into the interaction between DHA supplementation,the gut microbiota,and brain health.To achieve high sn-2 DHA in diets,it is suggested that sn-2 DHA lipids be enzymatically produced in more efficient and economical ways by improving the specific activities of lipases and optimizing the purification procedures.These types of diets will benefit individuals with strong needs for sn-2 ω-3 lipids such as infants,children,and pregnant and lactating women.

基于酪蛋白寡肽的W_(1)/O/W_(2)双重乳液体系构建及体外模拟消化特性研究

酪蛋白寡肽的生理活性取决于其活性物质在胃肠道消化过程中的稳定性。实验以酪蛋白寡肽为芯材,营养较丰富的亲脂性乳化剂磷脂作为外水相(W_(1)/O),亲水性乳化剂磷酸酯双淀粉作为外水相W_(2),制备W_(1)/O/W_(2)双重乳液体系,探究乳化条件(高压均质和高压微射流)对双重乳液体系稳定性的影响。并通过体外模拟消化实验探究其在胃肠中的变化,分析消化过程寡肽缓释特性。结果表明,25 MPa压力下乳液的稳定性较好,包封率为95.5%。双重乳液体系能够抵抗胃酶及较低的pH环境,酪蛋白寡肽的包封率>70%。在胰酶作用下随消化时间增加,该体系游离脂肪酸的释放量增加,酪蛋白寡肽的包封率降低,达到酪蛋白寡肽的缓释。

T2DM患者丘脑微观结构改变与轻度认知功能障碍及肠道短链脂肪酸的相关性

目的 利用扩散峰度成像(diffusion kurtosis imaging, DKI)评估2型糖尿病(type 2 diabetes mellitus, T2DM)患者背侧丘脑的微观结构改变,探讨DKI的参数变化与认知功能评分及肠道短链脂肪酸改变的相关性。材料与方法 对57例T2DM患者[其中T2DM伴轻度认知障碍(mild cognitive impairment,MCI)患者(T2DM-MCI组) 29例、 T2DM不伴MCI患者(T2DM-nonMCI组)28例]和30例健康对照(healthy control, HC)(HC组)双侧丘脑进行DKI数据采集,测量其各向异性分数(fractional anisotropy, FA)值、平均峰度(mean kurtosis, MK)值、径向峰度(radial kurtosis, RK)值及峰度分数各向异性(fractional anisotropy of kurtosis, FAK)值;同时行肠道代谢物短链脂肪酸检测;将3组间差异脑区的平均DKI参数值与认知功能评分及短链脂肪酸行相关性分析。结果 T2DM-MCI组左侧丘脑MK值均低于T2DM-nonMCI及HC组,且T2DM-MCI与T2DM-nonMCI组间差异具有统计学意义(P<0.05);与HC组比较,T2DM-MCI组左侧丘脑RK、右侧丘脑FA、KFA值均减低(P<0.05),两两比较显示左侧丘脑RK值在HC与T2DM-nonMCI组间差异有统计学意义(P<0.05),右侧丘脑FA、KFA值在T2DM-nonMCI与T2DM-MCI组间差异有统计学意义(P<0.05)。此外,T2DM患者右侧丘脑FA、FAK值与MoCA评分呈正相关(r=0.328,P=0.015;r=0.435,P=0.001);左侧丘脑RK值与己酸浓度呈正相关(r=0.431,P=0.001);左侧丘脑MK值与MoCA评分及己酸浓度呈正相关(r=0.294,P=0.030;r=0.287,P=0.033);右侧丘脑FAK值与TMT-A评分之间呈负相关(r=-0.318,P=0.018)。结论 T2DM患者丘脑微观结构改变可能是引起认知障碍的重要生理机制,且肠道己酸含量或可在一定程度上影响左侧丘脑微观结构完整性。

Free fatty acids receptors 2 and 3 control cell proliferation by regulating cellular glucose uptake

BACKGROUND Colorectal cancer(CRC)is a worldwide problem,which has been associated with changes in diet and lifestyle pattern.As a result of colonic fermentation of dietary fibres,short chain free fatty acids are generated which activate free fatty acid receptors(FFAR)2 and 3.FFAR2 and FFAR3 genes are abundantly expressed in colonic epithelium and play an important role in the metabolic homeostasis of colonic epithelial cells.Earlier studies point to the involvement of FFAR2 in colorectal carcinogenesis.AIM To understand the role of short chain FFARs in CRC.METHODS Transcriptome analysis console software was used to analyse microarray data from CRC patients and cell lines.We employed short-hairpin RNA mediated down regulation of FFAR2 and FFAR3 genes,which was validated using quantitative real time polymerase chain reaction.Assays for glucose uptake and cyclic adenosine monophosphate(cAMP)generation was done along with immunofluorescence studies to study the effects of FFAR2/FFAR3 knockdown.For measuring cell proliferation,we employed real time electrical impedancebased assay available from xCELLigence.RESULTS Microarray data analysis of CRC patient samples showed a significant down regulation of FFAR2 gene expression.This prompted us to study the FFAR2 in CRC.Since,FFAR3 shares significant structural and functional homology with FFAR2,we knocked down both these receptors in CRC cell line HCT 116.These modified cell lines exhibited higher proliferation rate and were found to have increased glucose uptake as well as increased level of glucose transporter 1.Since,FFAR2 and FFAR3 signal through G protein subunit(Gαi),knockdown of these receptors was associated with increased cAMP.Inhibition of protein kinase A(PKA)did not alter the growth and proliferation of these cells indicating a mechanism independent of cAMP/PKA pathway.CONCLUSION Our results suggest role of FFAR2/FFAR3 genes in increased proliferation of colon cancer cells via enhanced glucose uptake and exclude the role of PKA mediated cAMP signalling.Alternate pathways could be involved that would ultimately result in increased cell proliferation as a result of down regulated FFAR2/FFAR3 genes.This study paves the way to understand the mechanism of action of short chain FFARs in CRC.

尿脂肪酸结合蛋白1与老年2型糖尿病患者肾功能快速下降的相关性

目的探讨尿脂肪酸结合蛋白1(urinary fatty acid-binding protein 1,u-FABP1)与老年2型糖尿病(diabetes mellitus type 2,T2DM)患者肾功能快速下降的相关性。方法本研究为前瞻性观察性研究,纳入2017年1月至12月在西安市第一医院内分泌门诊就诊的430例T2DM且保留肾功能的老年患者,至少随访5年,进行一系列估算肾小球滤过率(estimating the glomerular filtration rate,e GFR)测量。肾功能快速下降定义为年度eGFR下降值>3 mL·min^(-1)·(1.73m^(2))^(-1)。研究基线血清u-FABP1水平与年度eGFR下降率之间的关系。结果在5年的随访中,70例患者(16.28%)肾功能迅速下降。与非快速下降组患者相比,肾功能快速下降组患者基线u-FABP1水平[用尿肌酐(urine creatinine,uCr)校正]明显更高[27.29(21.20,34.03)μg/g uCr比39.61(34.06,50.00)μg/g uCr,Z=-12.240,P<0.001]。调整年龄、性别、体重指数、糖化血红蛋白和基线eGFR等临床风险因素后,年度e GFR下降率与基线u-FABP1呈负相关(rs=-0.150,P=0.005)。此外,经单因素和多因素Logistic回归分析,年龄>75岁和基线u-FABP1水平≥16.76μg/g uCr是肾功能快速下降的独立预测因子(P<0.05)。当基线u-FABP1水平≥22.45μg/g uCr时可良好的预测老年T2DM患者随访5年内肾功能快速下降的风险,受试者工作特征曲线下面积为0.962(95%CI:0.943~0.981),特异度和灵敏度分别为97.10%和77.70%。结论较高的基线u-FABP1水平与肾功能保留的老年T2DM患者肾功能快速下降高风险有关,表明u-FABP1可能在早期糖尿病肾脏疾病的进展中发挥作用。

Genetic Variants in the ELOVL5 but not ELOVL2 Gene Associated with Polyunsaturated Fatty Acids in Han Chinese Breast Milk

The present study was designed to examine the contributions of the fatty acid elongase （ELOVL） gene polymorphisms to the levels of polyunsaturated fatty acids （PUFAs） in breast milk. Two hundred and nine healthy Han Chinese mothers were included in the study. Carriers of minor alleles of SNPs （rs2397142 and rs9357760） in ELOVL5 were associated with higher levels of linoleic acid （LA）, dihomo-γ-linolenic acid （DGLA）, arachidonic acid （AA）, docosatetraenoic acid （DTA）, docosahexenoic acid （DHA）, while in rs209512 of ELOVL5 the carriers of minor alleles had lower levels of DTA compared to major homozygote alleles （P ranged from 0.004-0.046）, and genetically explained variability ranged from 3.2% for eicosapentaenoic acid （EPA） to 6.0% for LA. Our findings demonstrated that common variation in ELOVL5 gene encoding rate-limiting enzymes in the metabolism of PUFAs contribute to the PUFAs in breast milk.