目的:研究低氧状态下自噬对2型糖尿病(Diabetes mellitus type 2, T2DM)合并股骨骨折大鼠模型不同时间点的骨折愈合程度及低氧诱导因子-1α (HIF-1α)、碱性磷酸酶(alkaline phosphatase, ALP)、Runt-相关转录因子-2 (Runx2)、微管相关...目的:研究低氧状态下自噬对2型糖尿病(Diabetes mellitus type 2, T2DM)合并股骨骨折大鼠模型不同时间点的骨折愈合程度及低氧诱导因子-1α (HIF-1α)、碱性磷酸酶(alkaline phosphatase, ALP)、Runt-相关转录因子-2 (Runx2)、微管相关蛋白1A/1B-轻链3 (LC3II/I)表达情况。方法:大鼠随机分为高糖高脂饲养前(Control)组、高糖高脂饲养8周后(HFD)组及T2DM模型(T2DM)组,采用高糖髙脂饲料联合链脲佐菌素制备T2DM模型,在T2DM模型基础上制作股骨骨折模型。实验大鼠分为对照组(T2DM合并股骨骨折模型组,Model)及治疗组(氯化钴(CoCl2)治疗的T2DM合并股骨骨折模型组,Treatment),根据检测时间点每组继续分为造模后7 d、28 d、42 d的三个亚组。X线评估股骨愈合情况,WB检测HIF-1α、ALP、Runx2、LC3II/I表达。结果:T2DM合并股骨骨折模型随时间的增长,治疗组在第28 d相比于对照组已有较好的恢复,骨组织中ALP、Runx2表达增加,自噬蛋白LC3II/I的检测结果显示随时间增长自噬水平有所减弱。结论:低氧可以诱导自噬来促进T2DM大鼠骨折愈合。Objective: To investigate fracture healing and hypoxia-inducible factor-1α (HIF-1α), alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and microtubule associated protein-II/I (LC3II/I) expression at different time points in T2DM rats with femoral fracture under hypoxic conditions. Methods: The rats were randomly divided into high-sugar and high-fat pre-feeding groups, high-sugar and high-fat feeding groups after 8 weeks of feeding and a T2DM model group, T2DM was prepared with high-glucose and high-fat diet combined with streptavidin. Femoral fractures were modeled on the basis of T2DM. Experimental rats were divided into a control group (T2DM with femoral fracture model group, Model) and a treatment group (CoCl2 treatment group, Treatment) and continued to be divided into three subgroups on days 7, 28, and 42 post-molecularization for each group at the time of measurement. Femoral healing was assessed by X-ray. HIF-1α, ALP, Runx2, and LC3II/I expression was measured by Western blotting. Result: In the T2DM combined femoral fracture model, as time progresses, the treatment group shows better recovery compared to the control group at day 28. The expression of ALP and Runx2 in bone tissue increases, and the detection results of autophagy protein LC3II/I indicate that autophagy levels weaken over time. Conclusion: Hypoxia can induce autophagy to promote fracture healing in T2DM rats.展开更多
目的分析基于TLR4/MyD88/NF-κB信号通路探讨梓醇对T2DM大鼠肾损伤的保护作用。方法选择SPF级雄性SD大鼠50只,造模过程中有10只大鼠造模失败,采用随机数表法将大鼠分为正常组(control,10只)和模型组、西药组、梓醇组四组,每组各10只。...目的分析基于TLR4/MyD88/NF-κB信号通路探讨梓醇对T2DM大鼠肾损伤的保护作用。方法选择SPF级雄性SD大鼠50只,造模过程中有10只大鼠造模失败,采用随机数表法将大鼠分为正常组(control,10只)和模型组、西药组、梓醇组四组,每组各10只。比较各组大鼠干预前后空腹血糖、肾功能指标以及TLR4、MyD88、NF-κB蛋白表达量。结果干预4周后,模型组和西药组、梓醇组FPG、FINS、HOMA-IR水平比较,差异均具有统计学意义(P<0.05);模型组、西药组和梓醇组FPG、FINS、HOMAIR均高于正常组,差异均具有统计学意义(P<0.05);西药组和梓醇组FPG、FINS、HOMAIR低于模型组,差异具有统计学意义(P<0.05);且梓醇组FPG、FINS、HOMAIR低于西药组,差异均具有统计学意义(P<0.05);干预4周后,模型组和西药组、梓醇组BUN、Scr及24 h mALB水平比较,差异均具有统计学意义(P<0.05);模型组、西药组和梓醇组BUN、Scr及24 h mALB均高于正常组,差异均具有统计学意义(P<0.05);西药组和梓醇组BUN、Scr及24 h mALB低于模型组,差异具有统计学意义(P<0.05);且梓醇组BUN、Scr及24 h mALB低于西药组,差异均具有统计学意义(P<0.05);模型组与正常组相比,大鼠肾组织TLR4、MyD88、NF-κB的表达明显上调;与模型组相比,西药组、梓醇组的肾组织TLR4、MyD88、NF-κB的表达明显下调。模型组、西药组、梓醇组TLR4、MyD88、NF-κB的mRNA相对表达量均明显高于正常组,且西药组、梓醇组TLR4、MyD88、NF-κB的mRNA相对表达量明显低于模型组,差异具有统计学意义(P<0.05);梓醇组TLR4、MyD88、NF-κB的mRNA相对表达量低于西药组,差异具有统计学意义(P<0.05)。结论梓醇对2型糖尿病大鼠肾损伤有一定保护作用,可能与抑制TLR4/MyD88/NF-κB信号通路异常激活有关。展开更多
Background:The type 2 diabetes mellitus(T2DM)pharmacodynamic study of various parts of Schisandra sphenanthera was conducted in the previous stage,and it was found that dichloromethane extracted part(SDP)had a signifi...Background:The type 2 diabetes mellitus(T2DM)pharmacodynamic study of various parts of Schisandra sphenanthera was conducted in the previous stage,and it was found that dichloromethane extracted part(SDP)had a significant hypoglycemic effect.Therefore,the components of SDP were analyzed,and the specific mechanism of its anti-T2DM was explored.Methods:We used a high-fat,high-sugar diet in combination with streptozotocin to induce a T2DM rat model,and the model rats were divided into two groups according to body weight and blood glucose.Triglyceride,oral glucose tolerance test,fasting blood glucose,low density lipoprotein cholesterol,superoxide dismutase,insulin,glycated hemoglobin,total cholesterol,nonesterified free fatty acids,alanine aminotransferase,high-density lipoprotein cholesterol,aspartate aminotransferase,malondialdehyde,and glutathione peroxidase were measured,organ indices were calculated,and pathological sections of pancreas and liver were observed.The 16S rRNA V3–V4 region of intestinal flora was sequenced to explore the effect of SDP on biochemical indicators and intestinal flora.Based on the above indicators,the anti-T2DM mechanism of SDP in Schisandra sphenanthera was analyzed.Results:After six weeks of administration,the biochemical indices of diabetic rats were diminished compared to the control group.And SDP could significantly increase the gut microbialα-diversity index,resulting in significant changes in the flora of T2DM rats,with increased richness and diversity,reduced harmful flora,and significantly back-regulated the levels of acetic acid,propionic acid,and butyric acid.Conclusion:SDP can improve the symptoms associated with elevated blood glucose,dyslipidemia,elevated fasting insulin levels,and damaged glucose tolerance in rats.SDP against T2DM may be through the control of intestinal flora to normalize and exert anti-diabetic effect;its main active components may be lignans and terpenoids.展开更多
T2DM与骨代谢失衡之间的关系引起了广泛关注,尤其是在绝经后女性中,骨质疏松和骨折风险显著增加。多项研究已表明,炎症因子在T2DM患者骨代谢失衡中发挥着核心作用。炎症因子(如TNF-α、IL-1β、IL-6等)通过增强破骨细胞活性和抑制成骨...T2DM与骨代谢失衡之间的关系引起了广泛关注,尤其是在绝经后女性中,骨质疏松和骨折风险显著增加。多项研究已表明,炎症因子在T2DM患者骨代谢失衡中发挥着核心作用。炎症因子(如TNF-α、IL-1β、IL-6等)通过增强破骨细胞活性和抑制成骨细胞功能,导致骨吸收和骨生成失衡,加剧骨质丧失。此外,慢性低度炎症、胰岛素抵抗和高血糖状态共同作用,进一步扰乱骨代谢平衡。本文综述了炎症因子在T2DM骨代谢中的作用机制,重点分析了炎症因子通过Wnt/β-Catenin、RANK/RANKL/OPG、PI3K/Akt以及MAPK等信号通路在骨代谢调控中的作用。特别是在绝经后女性群体中,随着雌激素水平下降和脂肪代谢改变,炎症因子的作用显著增强,从而加剧骨代谢失衡。通过探讨这些分子机制,以期为临床个性化治疗提供理论依据,进而有效降低骨折风险,推动精准治疗策略的实施。The relationship between T2DM and bone metabolism imbalance has garnered considerable attention, particularly in postmenopausal women, in whom the risk of osteoporosis and fractures is significantly elevated. Numerous studies have shown that inflammatory cytokines play a pivotal role in the bone metabolic imbalance observed in T2DM patients. Inflammatory cytokines (such as TNF-α, IL-1β, IL-6, etc.) enhance osteoclast activity and inhibit osteoblast function, thereby leading to an imbalance between bone resorption and formation and accelerating bone loss. Furthermore, chronic low-grade inflammation, insulin resistance, and hyperglycemia collectively disrupt bone metabolism. This review summarizes the mechanisms through which inflammatory cytokines affect bone metabolism in T2DM, with a focus on their roles in bone metabolism regulation via signaling pathways such as Wnt/β-Catenin, RANK/RANKL/OPG, PI3K/Akt, and MAPK. Particularly in postmenopausal women, the decline in estrogen levels and changes in lipid metabolism significantly amplify the effects of inflammatory cytokines, thereby exacerbating the imbalance in bone metabolism. By exploring these molecular mechanisms, we aim to provide a theoretical foundation for clinical personalized treatments, thereby effectively reducing fracture risk and promoting the implementation of precision therapeutic strategies.展开更多
Dysregulation of microRNA(miRNA)expression following the development of obesity is closely linked to the onset of type 2 diabetes mellitus(T2DM).Identifying differentially expressed miRNAs and their roles in regulatin...Dysregulation of microRNA(miRNA)expression following the development of obesity is closely linked to the onset of type 2 diabetes mellitus(T2DM).Identifying differentially expressed miRNAs and their roles in regulating glucose metabolism will provide a theoretical foundation for the molecular mechanisms underlying obesity-induced T2DM.Here,we perform a genome-wide association study involving 5 glycolipid metabolism traits in 1783 Kazakh and 1198 Uyghur individuals to identify miRNAs associated with fasting plasma glucose(FPG)levels.A miR-548ab mimic and inhibitor are administered to hepatocytes and adipocytes,as well as obese and diabetic mice,to determine miR-548ab-related downstream signalling pathways.The effects of miR-548ab on glucose metabolism are validated using the glucose tolerance test and insulin tolerance test.Collectively,these results indicate that miR-548ab is significantly associated with FPG levels and obesity-related T2DM in both Kazakh and Uyghur populations.The miR-548ab-GULP1/SLC25A21-GLUT4 network exerts regulatory effects on glucose metabolism,obesity,and T2DM,positioning it as a candidate risk factor,potential diagnostic marker,and therapeutic target for obesity-induced T2DM.Additionally,through evolutionary analysis,the authentic variants or haplotypes of GULP1 and SLC25A21 are categorized according to their genetic susceptibility to T2DM.The miR-548ab inhibitor shows beneficial effects in obese and diabetic mice.展开更多
文摘目的:研究低氧状态下自噬对2型糖尿病(Diabetes mellitus type 2, T2DM)合并股骨骨折大鼠模型不同时间点的骨折愈合程度及低氧诱导因子-1α (HIF-1α)、碱性磷酸酶(alkaline phosphatase, ALP)、Runt-相关转录因子-2 (Runx2)、微管相关蛋白1A/1B-轻链3 (LC3II/I)表达情况。方法:大鼠随机分为高糖高脂饲养前(Control)组、高糖高脂饲养8周后(HFD)组及T2DM模型(T2DM)组,采用高糖髙脂饲料联合链脲佐菌素制备T2DM模型,在T2DM模型基础上制作股骨骨折模型。实验大鼠分为对照组(T2DM合并股骨骨折模型组,Model)及治疗组(氯化钴(CoCl2)治疗的T2DM合并股骨骨折模型组,Treatment),根据检测时间点每组继续分为造模后7 d、28 d、42 d的三个亚组。X线评估股骨愈合情况,WB检测HIF-1α、ALP、Runx2、LC3II/I表达。结果:T2DM合并股骨骨折模型随时间的增长,治疗组在第28 d相比于对照组已有较好的恢复,骨组织中ALP、Runx2表达增加,自噬蛋白LC3II/I的检测结果显示随时间增长自噬水平有所减弱。结论:低氧可以诱导自噬来促进T2DM大鼠骨折愈合。Objective: To investigate fracture healing and hypoxia-inducible factor-1α (HIF-1α), alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), and microtubule associated protein-II/I (LC3II/I) expression at different time points in T2DM rats with femoral fracture under hypoxic conditions. Methods: The rats were randomly divided into high-sugar and high-fat pre-feeding groups, high-sugar and high-fat feeding groups after 8 weeks of feeding and a T2DM model group, T2DM was prepared with high-glucose and high-fat diet combined with streptavidin. Femoral fractures were modeled on the basis of T2DM. Experimental rats were divided into a control group (T2DM with femoral fracture model group, Model) and a treatment group (CoCl2 treatment group, Treatment) and continued to be divided into three subgroups on days 7, 28, and 42 post-molecularization for each group at the time of measurement. Femoral healing was assessed by X-ray. HIF-1α, ALP, Runx2, and LC3II/I expression was measured by Western blotting. Result: In the T2DM combined femoral fracture model, as time progresses, the treatment group shows better recovery compared to the control group at day 28. The expression of ALP and Runx2 in bone tissue increases, and the detection results of autophagy protein LC3II/I indicate that autophagy levels weaken over time. Conclusion: Hypoxia can induce autophagy to promote fracture healing in T2DM rats.
文摘目的分析基于TLR4/MyD88/NF-κB信号通路探讨梓醇对T2DM大鼠肾损伤的保护作用。方法选择SPF级雄性SD大鼠50只,造模过程中有10只大鼠造模失败,采用随机数表法将大鼠分为正常组(control,10只)和模型组、西药组、梓醇组四组,每组各10只。比较各组大鼠干预前后空腹血糖、肾功能指标以及TLR4、MyD88、NF-κB蛋白表达量。结果干预4周后,模型组和西药组、梓醇组FPG、FINS、HOMA-IR水平比较,差异均具有统计学意义(P<0.05);模型组、西药组和梓醇组FPG、FINS、HOMAIR均高于正常组,差异均具有统计学意义(P<0.05);西药组和梓醇组FPG、FINS、HOMAIR低于模型组,差异具有统计学意义(P<0.05);且梓醇组FPG、FINS、HOMAIR低于西药组,差异均具有统计学意义(P<0.05);干预4周后,模型组和西药组、梓醇组BUN、Scr及24 h mALB水平比较,差异均具有统计学意义(P<0.05);模型组、西药组和梓醇组BUN、Scr及24 h mALB均高于正常组,差异均具有统计学意义(P<0.05);西药组和梓醇组BUN、Scr及24 h mALB低于模型组,差异具有统计学意义(P<0.05);且梓醇组BUN、Scr及24 h mALB低于西药组,差异均具有统计学意义(P<0.05);模型组与正常组相比,大鼠肾组织TLR4、MyD88、NF-κB的表达明显上调;与模型组相比,西药组、梓醇组的肾组织TLR4、MyD88、NF-κB的表达明显下调。模型组、西药组、梓醇组TLR4、MyD88、NF-κB的mRNA相对表达量均明显高于正常组,且西药组、梓醇组TLR4、MyD88、NF-κB的mRNA相对表达量明显低于模型组,差异具有统计学意义(P<0.05);梓醇组TLR4、MyD88、NF-κB的mRNA相对表达量低于西药组,差异具有统计学意义(P<0.05)。结论梓醇对2型糖尿病大鼠肾损伤有一定保护作用,可能与抑制TLR4/MyD88/NF-κB信号通路异常激活有关。
基金supported by the Fundamental Research Foundation of the National Natural Science Foundation of China(No.82174111)the State Administration of Traditional Chinese Medicine and the Sci-Tech Innovation Talent System Construction Program of Shaanxi University of Chinese Medicine(No.2023-CXTD-05).
文摘Background:The type 2 diabetes mellitus(T2DM)pharmacodynamic study of various parts of Schisandra sphenanthera was conducted in the previous stage,and it was found that dichloromethane extracted part(SDP)had a significant hypoglycemic effect.Therefore,the components of SDP were analyzed,and the specific mechanism of its anti-T2DM was explored.Methods:We used a high-fat,high-sugar diet in combination with streptozotocin to induce a T2DM rat model,and the model rats were divided into two groups according to body weight and blood glucose.Triglyceride,oral glucose tolerance test,fasting blood glucose,low density lipoprotein cholesterol,superoxide dismutase,insulin,glycated hemoglobin,total cholesterol,nonesterified free fatty acids,alanine aminotransferase,high-density lipoprotein cholesterol,aspartate aminotransferase,malondialdehyde,and glutathione peroxidase were measured,organ indices were calculated,and pathological sections of pancreas and liver were observed.The 16S rRNA V3–V4 region of intestinal flora was sequenced to explore the effect of SDP on biochemical indicators and intestinal flora.Based on the above indicators,the anti-T2DM mechanism of SDP in Schisandra sphenanthera was analyzed.Results:After six weeks of administration,the biochemical indices of diabetic rats were diminished compared to the control group.And SDP could significantly increase the gut microbialα-diversity index,resulting in significant changes in the flora of T2DM rats,with increased richness and diversity,reduced harmful flora,and significantly back-regulated the levels of acetic acid,propionic acid,and butyric acid.Conclusion:SDP can improve the symptoms associated with elevated blood glucose,dyslipidemia,elevated fasting insulin levels,and damaged glucose tolerance in rats.SDP against T2DM may be through the control of intestinal flora to normalize and exert anti-diabetic effect;its main active components may be lignans and terpenoids.
文摘T2DM与骨代谢失衡之间的关系引起了广泛关注,尤其是在绝经后女性中,骨质疏松和骨折风险显著增加。多项研究已表明,炎症因子在T2DM患者骨代谢失衡中发挥着核心作用。炎症因子(如TNF-α、IL-1β、IL-6等)通过增强破骨细胞活性和抑制成骨细胞功能,导致骨吸收和骨生成失衡,加剧骨质丧失。此外,慢性低度炎症、胰岛素抵抗和高血糖状态共同作用,进一步扰乱骨代谢平衡。本文综述了炎症因子在T2DM骨代谢中的作用机制,重点分析了炎症因子通过Wnt/β-Catenin、RANK/RANKL/OPG、PI3K/Akt以及MAPK等信号通路在骨代谢调控中的作用。特别是在绝经后女性群体中,随着雌激素水平下降和脂肪代谢改变,炎症因子的作用显著增强,从而加剧骨代谢失衡。通过探讨这些分子机制,以期为临床个性化治疗提供理论依据,进而有效降低骨折风险,推动精准治疗策略的实施。The relationship between T2DM and bone metabolism imbalance has garnered considerable attention, particularly in postmenopausal women, in whom the risk of osteoporosis and fractures is significantly elevated. Numerous studies have shown that inflammatory cytokines play a pivotal role in the bone metabolic imbalance observed in T2DM patients. Inflammatory cytokines (such as TNF-α, IL-1β, IL-6, etc.) enhance osteoclast activity and inhibit osteoblast function, thereby leading to an imbalance between bone resorption and formation and accelerating bone loss. Furthermore, chronic low-grade inflammation, insulin resistance, and hyperglycemia collectively disrupt bone metabolism. This review summarizes the mechanisms through which inflammatory cytokines affect bone metabolism in T2DM, with a focus on their roles in bone metabolism regulation via signaling pathways such as Wnt/β-Catenin, RANK/RANKL/OPG, PI3K/Akt, and MAPK. Particularly in postmenopausal women, the decline in estrogen levels and changes in lipid metabolism significantly amplify the effects of inflammatory cytokines, thereby exacerbating the imbalance in bone metabolism. By exploring these molecular mechanisms, we aim to provide a theoretical foundation for clinical personalized treatments, thereby effectively reducing fracture risk and promoting the implementation of precision therapeutic strategies.
基金supported by the Natural Science Foundation of China(82160156,82260162,and 32370669)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB38040200)+1 种基金the Tianshan Talent Project in Xinjiang Autonomous Region(2023TSYCCX0116 and 2023TSYCQNTJ0032)the Scientific and Technological Research Project of Xinjiang Production and Construction Corps(2022ZD001,2021AB028,2022AB022,2023AB057,and 2023ZD037).
文摘Dysregulation of microRNA(miRNA)expression following the development of obesity is closely linked to the onset of type 2 diabetes mellitus(T2DM).Identifying differentially expressed miRNAs and their roles in regulating glucose metabolism will provide a theoretical foundation for the molecular mechanisms underlying obesity-induced T2DM.Here,we perform a genome-wide association study involving 5 glycolipid metabolism traits in 1783 Kazakh and 1198 Uyghur individuals to identify miRNAs associated with fasting plasma glucose(FPG)levels.A miR-548ab mimic and inhibitor are administered to hepatocytes and adipocytes,as well as obese and diabetic mice,to determine miR-548ab-related downstream signalling pathways.The effects of miR-548ab on glucose metabolism are validated using the glucose tolerance test and insulin tolerance test.Collectively,these results indicate that miR-548ab is significantly associated with FPG levels and obesity-related T2DM in both Kazakh and Uyghur populations.The miR-548ab-GULP1/SLC25A21-GLUT4 network exerts regulatory effects on glucose metabolism,obesity,and T2DM,positioning it as a candidate risk factor,potential diagnostic marker,and therapeutic target for obesity-induced T2DM.Additionally,through evolutionary analysis,the authentic variants or haplotypes of GULP1 and SLC25A21 are categorized according to their genetic susceptibility to T2DM.The miR-548ab inhibitor shows beneficial effects in obese and diabetic mice.
