AIM To study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease(NAFLD) in db/db mice. METHODS Male diabetic db /db mice(BKS.Cg-Dock7m+/+Leprdb/J) aged 10 wk received the dipeptidyl...AIM To study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease(NAFLD) in db/db mice. METHODS Male diabetic db /db mice(BKS.Cg-Dock7m+/+Leprdb/J) aged 10 wk received the dipeptidyl peptidase 4(DPP4) inhibitor linagliptin(10 mg/kg) or saline as a placebo once per day by gavage for 8 wk. Intact db/db mice served as controls. Structural changes in the liver were analyzed from light and electron microscopic images of sections from intact, placebo-treated and linagliptin-treated animals. We estimated the changes in hepatocytes, sinusoidal cells, liver microvasculature and lymphatic roots. Hepatic staining for lymphatic vessel endothelial hyaluronan receptor-1(LYVE-1) was assessed by immunohistochemistry. RESULTS In 18-wk-old diabetic mice, liver steatosis(predominantly microvesicular and mediovesicular steatosis) was accompanied by dilation of the roots of the lymphatic system, interlobular blood vessels and bile canaliculi. Compared to saline-treated mice, linagliptin-treated mice exhibited a reduction in the mean numeral densities of hepatocytes with lipid droplets(92.4% ± 1.7% vs 64.9% ± 5.8% per field of view, P = 0.0002) and a lower proportion of hepatocytes with a high density of lipid droplets(20.7% ± 3.6% vs 50.4% ± 3.1%, P = 0.0007). We observed heterogeneous hepatocytes and relatively preserved cell structures in the linagliptin group. Dilation of blood and lymphatic vessels, as well as ultrastructural changes in the hepatocyte endoplasmic reticulum and mitochondria, were alleviated by linagliptin treatment. In intact and placebo-treated mice, immunohistochemical staining for LYVE-1 was observed in the endothelial cells of interlobular lymphatic vessels and on the membranes of some endothelial sinusoidal cells. We observed an enlarged LYVE-1 reaction area in linagliptin-treated mice compared to intact and placebo-treated mice. The improvement in the structural parameters of the liver in linagliptin-treated mice was independent to changes in the plasma glucose levels. CONCLUSION The DPP4 inhibitor linagliptin alleviates liver steatosis and structural changes in the hepatic microvasculature and lymphatic roots in a model of NAFLD in diabetic db/db mice.展开更多
Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatme...Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatments may help treat Parkinson's disease.To further investigate the mechanisms of action of these two compounds,we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin.We found that both exendin-4 and linagliptin reversed motor dysfunction,glial activation,and dopaminergic neuronal death in this model.In addition,both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion.Moreover,in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain-and leucine-rich-repeat-and pyrin-domaincontaining 3/caspase-1/interleukin-1βpathway and subsequent pyroptosis by decreasing the production of reactive oxygen species.These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotidebinding oligomerization domain-and leucine-rich-repeat-and pyrin-domain-containing 3/caspase-1/interleukin-1βpathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Therefore,these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.展开更多
Dipeptidyl peptidase 4 (DPP-4) inhibitors have been shown to have neuroprotective effects in diabetic patients suffering from stroke, but less research has focused on patients with mild hyperglycemia below the thresho...Dipeptidyl peptidase 4 (DPP-4) inhibitors have been shown to have neuroprotective effects in diabetic patients suffering from stroke, but less research has focused on patients with mild hyperglycemia below the threshold for a diagnosis of diabetes. In this investigation, a hyperglycemic mouse model was generated by intraperitoneal injection of streptozotocin and then subjected to focal cerebral ischemia. We demonstrated that the DPP-4 inhibitor linagliptin significantly decreased the infarct volume, reduced neuronal cell death, decreased inflammation, and improved neurological deficit compared with control mice. Linagliptin up-regulated the expression of p-Akt and p-m TOR and regulated the apoptosis factors Bcl-2, Bax, and caspase 9. Taken together, these results suggest that linagliptin exerts a neuroprotective action likely through activation of the Akt/m TOR pathway along with anti-apoptotic and anti-inflammatory mechanisms.Therefore, linagliptin may be considered as a therapeutic treatment for stroke patients with mild hyperglycemia.展开更多
Diabetic cardiomyopathy(DCM)is an important cardiovascular complication of diabetes mellitus,while the pathogenesis of DCM has not been fully elucidated.In the present study,we aimed to investigate the effect of Linag...Diabetic cardiomyopathy(DCM)is an important cardiovascular complication of diabetes mellitus,while the pathogenesis of DCM has not been fully elucidated.In the present study,we aimed to investigate the effect of Linagliptin on cardiomyocytes of diabetic rats and its mechanism.Cardiac function was evaluated by two-dimensional ultrasound at different time points for each group.HE staining was used to evaluate myocardial injury and inflammatory condition.Sirius-red staining was used to observe the degree of myocardial fibrosis under optical microscope.TUNEL staining was used to investigate the degree of cardiomyocyte apoptosis in four groups.The expressions of m RNAs in relevant cells,including Bcl-2,Bax,TNF-α,PAI-1,CTGF and TGF-β1,were measured by reverse transcription polymerase chain reaction(RT-PCR)and Western blotting analysis in different groups.The expression and transcriptional function of Nrf2 in myocardium activated by Lingliptin were determined using RT-PCR,Western blotting analysis and immunofluorescence.The results showed that the left ventricular volume(LV),left ventricular thickness(LT),fasting blood glucose(FBG)and heart weight/body weight(HW/BW)in diabetes and Linagliptin CO treatment group were significantly lower compared with diabetic group(P<0.05),while the ejection fraction(EF)was higher compared with diabetic group(P<0.05).From HE staining,the treatment of Linagliptin made the arrangement of myocardial fibers more regular,and the striation of myocardial cells became clearer.The Sirus-red staining showed that there was significant accumulation of collagen in the diabetic group rats,indicating that the rats in diabetic group had cardiac fibrosis.The phenomenon in diabetes and Linagliptin CO treatment group was alleviated.TUNEL staining showed that at time point of 4 weeks,the degree of cardiomyocyte apoptosis in diabetes and Linagliptin CO treatment group was lower compared with diabetic group(P<0.01).The expressions of cleaved-caspase-3,TNF-α,PAI-1,CTGF and TGF-β1 proteins in diabetic rats were significantly decreased by Linagliptin,and the difference was statistically significant(cleaved-caspase-3:P<0.01;TNF-α:P<0.01;PAI-1:P<0.05;CTGF:P<0.05;TGF-β1:P<0.05).Compared with the diabetic group,the ratio of Bcl-2/Bax was inecreased in diabetes and Linagliptin CO treatment group,and the difference was statistically significant(P<0.05).From Nrf2 expression in the nucleus and cytosol by RT-PCR,Western blotting analysis and immunofluorescence test,the results showed that Linagliptin promoted the Nrf2 nuclear translocation in myocardial tissue cells.The expression of Nrf2 was significantly down-regulated in the heart of diabetic rats(P<0.01),while this phenomenon in diabetes and Linagliptin CO treatment group was greatly ameliorated.This paper studied the effect of Linagliptin on diabetic myocardial injur and found that the protective mechanism might be related to Nrf2 signaling pathway of antioxidant stress.Collectively,our finding provided new ideas and therapeutic targets for the prevention and treatment of DCM.展开更多
In the present study,we aimed to investigate the effects of linagliptin on inflammatory factors and carotid intima-media thickness(CIMT)in newly diagnosed type 2 diabetes mellitus(T2 DM)patients with carotid atheroscl...In the present study,we aimed to investigate the effects of linagliptin on inflammatory factors and carotid intima-media thickness(CIMT)in newly diagnosed type 2 diabetes mellitus(T2 DM)patients with carotid atherosclerotic disease(CAD).A total of 326 patients with newly diagnosed T2 DM complicated with CAD were randomly divided into two groups.There were 163 patients in the control group,who were treated with metformin monotherapy.There were 163 patients in the experimental group,who were treated with metformin in combination with linagliptin.The CIMT before and after treatment was measured by color Doppler ultrasound,and the contents of IL-6 and IL-1βbefore and after treatment were detected by ELISA.The levels of inflammatory factors and CIMT before and after treatment were compared between the two groups,and the correlation between IL-6,IL-1βand CIMT was studied.After 24 weeks of treatment,the levels of inflammatory factors and CIMT in the experimental group were significantly lower compared with the control group(P<0.01),and the serum levels of IL-6 and IL-1βwere positively correlated with CIMT.In the present study,we concluded that linagliptin could improve the levels of inflammatory factors and CIMT in newly diagnosed T2 DM patients with CAD,and IL-6 and IL-1βmight participate in the occurrence and development of CAD by influencing CIMT.展开更多
Impaired insulin signaling in Alzheimer’s disease（AD）brains：The insulin signaling pathway is a fundamental physiological mechanism that presents in nearly all vertebrate cells.However,sometimes cells stop respondi...Impaired insulin signaling in Alzheimer’s disease（AD）brains：The insulin signaling pathway is a fundamental physiological mechanism that presents in nearly all vertebrate cells.However,sometimes cells stop responding properly to insulin stimulation.This condition is known as insulin resistance,which is a hallmark of two very common conditions,metabolic syndrome and type 2 diabetes（T2D）.展开更多
BACKGROUND Cardiovascular outcome trials have demonstrated cardiovascular safety of glimepiride(a sulfonylureas) against dipeptidyl peptidase-4 inhibitor linagliptin.Gliclazide(another newer sulfonylureas) has shown s...BACKGROUND Cardiovascular outcome trials have demonstrated cardiovascular safety of glimepiride(a sulfonylureas) against dipeptidyl peptidase-4 inhibitor linagliptin.Gliclazide(another newer sulfonylureas) has shown similar glycemic efficacy and 50% decreased risk of hypoglycemia compared to glimepiride.AIM Considering the absence of cardiovascular outcome trials for gliclazide, we decided to conduct a systematic review of the literature to assess the cardiovascular(CV) safety by assessing the risk for major adverse CV events and hypoglycemia risk of gliclazide vs linagliptin in patients with type 2 diabetes(T2D).METHODS This systematic review followed the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to analyze all the clinical studies published from 2008 that compared the two drugs in patients with T2D with no risk of CV disease(CVD). We included only evidence designated high quality by the Oxford Center for Evidence-based Medicine-Levels of Evidence.RESULTS Eight clinical studies were included in the narrative descriptive analysis(gliclazide: 5 and linagliptin: 3). The CV safety of gliclazide in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial and of linagliptin in the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin(CARMELINA) and CARdiovascular Outcome study of LINAgliptin vs glimepiride in patients with T2D(CAROLINA)trials were excluded from the comparative analysis as these trials demonstrated CV and hypoglycemia benefits in patients at high risk of CVD. However, since these are landmark trials,they were discussed in brief to show the CV benefits and low hypoglycemia risk of gliclazide and linagliptin. We did not find any study comparing gliclazide with linagliptin. Hence, direct comparison of their major adverse CV events and hypoglycemia risk could not be carried out.However, the literature meeting the inclusion criteria showed that both drugs were effective in achieving the desired glycemic control and had low major adverse CV events and hypoglycemia risk in adult patients with no history of CVD.CONCLUSION Gliclazide can be considered an effective and safe glucose-lowering drug in T2D patients with no established CVD but at high risk of CVD due to their T2D status. Future randomized controlled trials comparing gliclazide with linagliptin or dipeptidyl peptidase-4 inhibitors can confirm these findings.展开更多
AIM To evaluate the comparative effectiveness of anagliptin and linagliptin on the clinical parameters in patients with type 2 diabetes mellitus(T2 DM). METHODS A 2-year retrospective cohort study was conducted in pat...AIM To evaluate the comparative effectiveness of anagliptin and linagliptin on the clinical parameters in patients with type 2 diabetes mellitus(T2 DM). METHODS A 2-year retrospective cohort study was conducted in patients with T2 DM who received anagliptin and linagliptin. We enrolled 234 patients(anagliptin group, 117 patients; linagliptin group, 117 patients). RESULTS The glycemic control considerably improved 3, 6, 12, and 24 mo after the administration of both dipeptidyl peptidase-4(DPP-4) inhibitors. Following the administration of anagliptin, the diastolic blood pressure and serum total cholesterol levels decreased. However, serum high-density lipoprotein cholesterol levels increased and urinary albumin-creatinine ratio decreased following linagliptin administration. Furthermore, the liver function improved after the administration of linagliptin.CONCLUSION These findings suggest that that the efficacy of DPP-4 inhibitors on the blood pressure, lipid profile, and liver function differs between anagliptin and linagliptin.展开更多
Objective:To explore the effect of Linagliptin on tumor necrosis factor receptor and monocyte chemoattractant protein-1 in patients with diabetic nephropathy.Methods: A total of 98 patients with diabetic nephropathy a...Objective:To explore the effect of Linagliptin on tumor necrosis factor receptor and monocyte chemoattractant protein-1 in patients with diabetic nephropathy.Methods: A total of 98 patients with diabetic nephropathy admitted to the Hospital from January 2017 to September 2018 were enrolled. The patients were divided into two groups according to the random double-blind method, with 49 cases in each group. The control group was treated with Metformin, whereas the experimental group was treated with Linagliptin plus Metformin. After 3 months of continuous treatment, the renal function [urinary albumin excretion rate, 24 h urine protein quantitation and serum creatinine], glycolipids metabolic levels [glycated hemoglobin, fasting blood glucose, total cholesterol and triglycerides], monocyte chemoattractant protein-1, tumor necrosis factor receptor, high-sensitivity C-reactive protein, and adverse reactions were compared between the two groups.Results:After 3 months of treatment, the levels of UAER, 24 h Upor and Scr in the experimental group were shown to be lower than those in the control group, and the difference was statistically significant. After 3 months of treatment, the levels of HbA1c, FPG, TC and TG in the experimental group were shown to be lower than the control group, and the difference was statistically significant. After 3 months of treatment, the levels of MCP-1, sTNFR1 and hs-CRP in the experimental group were lower than those in the control group, and the difference was statistically significant. There was no significant difference in incidence of adverse reactions between the two groups.Conclusion: For patients with diabetic nephropathy, Linagliptin is with higher safety, which can help improve their glycolipids metabolic levels and renal function, reduce the inflammatory response and the levels of MCP-1 and sTNFR1, and yet incur fewer adverse reactions.展开更多
The polymerase 1 and transcript release factor(PTRF)–cytoplasmic phospholipase A2(cPLA2)phospholipid remodeling pathway facilitates tumor proliferation in glioma.Nevertheless,blockade of this pathway leads to the exc...The polymerase 1 and transcript release factor(PTRF)–cytoplasmic phospholipase A2(cPLA2)phospholipid remodeling pathway facilitates tumor proliferation in glioma.Nevertheless,blockade of this pathway leads to the excessive activation of oncogenic receptors on the plasma membrane and subsequent drug resistance.Here,CD26/dipeptidyl peptidase 4(DPP4)was identified through screening of CRISPR/Cas9 libraries.Suppressing PTRF–cPLA2 signaling resulted in the activation of the epidermal growth factor receptor(EGFR)pathway through phosphatidylcholine and lysophosphatidylcholine remodeling,which ultimately increased DPP4 transcription.In turn,DPP4 interacted with EGFR and prevented its ubiquitination.Linagliptin,a DPP4 inhibitor,facilitated the degradation of EGFR by blocking its interaction with DPP4.When combined with the cPLA2 inhibitor AACOCF3,it exhibited synergistic effects and led to a decrease in energy metabolism in glioblastoma cells.Subsequent in vivo investigations provided further evidence of a synergistic impact of linagliptin by augmenting the sensitivity of AACOCF3 and strengthening the efficacy of temozolomide.DPP4 serves as a novel target and establishes a constructive feedback loop with EGFR.Linagliptin is a potent inhibitor that promotes EGFR degradation by blocking the DPP4–EGFR interaction.This study presents innovative approaches for treating glioma by combining linagliptin with AACOCF3 and temozolomide.展开更多
目的 研制与原研制剂体外溶出一致、体内生物等效的利格列汀片仿制药。方法 制备利格列汀片,通过建立利格列汀片体外溶出高效液相色谱法检测方法,分别在p H 1.0盐酸溶液、p H 4.5醋酸钠盐缓冲溶液、p H 6.8磷酸二氢钾盐缓冲溶液、水介质...目的 研制与原研制剂体外溶出一致、体内生物等效的利格列汀片仿制药。方法 制备利格列汀片,通过建立利格列汀片体外溶出高效液相色谱法检测方法,分别在p H 1.0盐酸溶液、p H 4.5醋酸钠盐缓冲溶液、p H 6.8磷酸二氢钾盐缓冲溶液、水介质中,测定利格列汀片自制制剂与原研制剂的累积溶出情况,采用非模型依赖方法(f_(2)相似因子)计算自制制剂与原研制剂的溶出相似性;同时在健康成年受试者中进行单剂量、两制剂、两序列、两周期交叉试验设计的药代动力学研究,检测空腹及高脂餐后两种状态下受试者的血药浓度,计算药代动力学参数。结果 在4种溶出介质中,自制制剂与原研制剂的累积溶出曲线相似;药代动力学研究显示,空腹及餐后状态下,自制制剂与原研制剂的药代参数C_(max)、AUC_(0-t)的几何均值比值及其90%置信区间均在80.00%~125.00%范围内。结论 自制制剂与原研制剂体外溶出相似,且在药代动力学上生物等效。展开更多
基金Supported by Grants from the Russian Ministry of Education and Science,Nos.14.621.21.0010,RFMEFI62114X0010 and14.619.21.0005,RFMEFI61914X0005
文摘AIM To study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease(NAFLD) in db/db mice. METHODS Male diabetic db /db mice(BKS.Cg-Dock7m+/+Leprdb/J) aged 10 wk received the dipeptidyl peptidase 4(DPP4) inhibitor linagliptin(10 mg/kg) or saline as a placebo once per day by gavage for 8 wk. Intact db/db mice served as controls. Structural changes in the liver were analyzed from light and electron microscopic images of sections from intact, placebo-treated and linagliptin-treated animals. We estimated the changes in hepatocytes, sinusoidal cells, liver microvasculature and lymphatic roots. Hepatic staining for lymphatic vessel endothelial hyaluronan receptor-1(LYVE-1) was assessed by immunohistochemistry. RESULTS In 18-wk-old diabetic mice, liver steatosis(predominantly microvesicular and mediovesicular steatosis) was accompanied by dilation of the roots of the lymphatic system, interlobular blood vessels and bile canaliculi. Compared to saline-treated mice, linagliptin-treated mice exhibited a reduction in the mean numeral densities of hepatocytes with lipid droplets(92.4% ± 1.7% vs 64.9% ± 5.8% per field of view, P = 0.0002) and a lower proportion of hepatocytes with a high density of lipid droplets(20.7% ± 3.6% vs 50.4% ± 3.1%, P = 0.0007). We observed heterogeneous hepatocytes and relatively preserved cell structures in the linagliptin group. Dilation of blood and lymphatic vessels, as well as ultrastructural changes in the hepatocyte endoplasmic reticulum and mitochondria, were alleviated by linagliptin treatment. In intact and placebo-treated mice, immunohistochemical staining for LYVE-1 was observed in the endothelial cells of interlobular lymphatic vessels and on the membranes of some endothelial sinusoidal cells. We observed an enlarged LYVE-1 reaction area in linagliptin-treated mice compared to intact and placebo-treated mice. The improvement in the structural parameters of the liver in linagliptin-treated mice was independent to changes in the plasma glucose levels. CONCLUSION The DPP4 inhibitor linagliptin alleviates liver steatosis and structural changes in the hepatic microvasculature and lymphatic roots in a model of NAFLD in diabetic db/db mice.
基金supported by the National Natural Science Foundation of China,Nos.81771271(to JF),31800898(to WL),81430025(to JYL),and U1801681(to JYL)Key Research and Development Program of Liaoning Province,No.2020JH2/10300047(to JF)+1 种基金the Key Field Research Development Program of Guangdong Province,No.2018B030337001(to JYL)the Outstanding Scientific Fund of Shengjing Hospital,No.M0475(to JF)。
文摘Use of glucagon-like peptide-1 receptor agonist or dipeptidyl peptidase 4 inhibitor has been shown to lower the incidence of Parkinson's disease in patients with diabetes mellitus.Therefore,using these two treatments may help treat Parkinson's disease.To further investigate the mechanisms of action of these two compounds,we established a model of Parkinson's disease by treating mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and then subcutaneously injected them with the glucagon-like peptide-1 receptor agonist exendin-4 or the dipeptidyl peptidase 4 inhibitor linagliptin.We found that both exendin-4 and linagliptin reversed motor dysfunction,glial activation,and dopaminergic neuronal death in this model.In addition,both exendin-4 and linagliptin induced microglial polarization to the anti-inflammatory M2 phenotype and reduced pro-inflammatory cytokine secretion.Moreover,in vitro experiments showed that treatment with exendin-4 and linagliptin inhibited activation of the nucleotide-binding oligomerization domain-and leucine-rich-repeat-and pyrin-domaincontaining 3/caspase-1/interleukin-1βpathway and subsequent pyroptosis by decreasing the production of reactive oxygen species.These findings suggest that exendin-4 and linagliptin exert neuroprotective effects by attenuating neuroinflammation through regulation of microglial polarization and the nucleotidebinding oligomerization domain-and leucine-rich-repeat-and pyrin-domain-containing 3/caspase-1/interleukin-1βpathway in a mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Therefore,these two drugs may serve as novel anti-inflammatory treatments for Parkinson's disease.
基金supported by the John E. Steinhaus Endowment fund.
文摘Dipeptidyl peptidase 4 (DPP-4) inhibitors have been shown to have neuroprotective effects in diabetic patients suffering from stroke, but less research has focused on patients with mild hyperglycemia below the threshold for a diagnosis of diabetes. In this investigation, a hyperglycemic mouse model was generated by intraperitoneal injection of streptozotocin and then subjected to focal cerebral ischemia. We demonstrated that the DPP-4 inhibitor linagliptin significantly decreased the infarct volume, reduced neuronal cell death, decreased inflammation, and improved neurological deficit compared with control mice. Linagliptin up-regulated the expression of p-Akt and p-m TOR and regulated the apoptosis factors Bcl-2, Bax, and caspase 9. Taken together, these results suggest that linagliptin exerts a neuroprotective action likely through activation of the Akt/m TOR pathway along with anti-apoptotic and anti-inflammatory mechanisms.Therefore, linagliptin may be considered as a therapeutic treatment for stroke patients with mild hyperglycemia.
文摘Diabetic cardiomyopathy(DCM)is an important cardiovascular complication of diabetes mellitus,while the pathogenesis of DCM has not been fully elucidated.In the present study,we aimed to investigate the effect of Linagliptin on cardiomyocytes of diabetic rats and its mechanism.Cardiac function was evaluated by two-dimensional ultrasound at different time points for each group.HE staining was used to evaluate myocardial injury and inflammatory condition.Sirius-red staining was used to observe the degree of myocardial fibrosis under optical microscope.TUNEL staining was used to investigate the degree of cardiomyocyte apoptosis in four groups.The expressions of m RNAs in relevant cells,including Bcl-2,Bax,TNF-α,PAI-1,CTGF and TGF-β1,were measured by reverse transcription polymerase chain reaction(RT-PCR)and Western blotting analysis in different groups.The expression and transcriptional function of Nrf2 in myocardium activated by Lingliptin were determined using RT-PCR,Western blotting analysis and immunofluorescence.The results showed that the left ventricular volume(LV),left ventricular thickness(LT),fasting blood glucose(FBG)and heart weight/body weight(HW/BW)in diabetes and Linagliptin CO treatment group were significantly lower compared with diabetic group(P<0.05),while the ejection fraction(EF)was higher compared with diabetic group(P<0.05).From HE staining,the treatment of Linagliptin made the arrangement of myocardial fibers more regular,and the striation of myocardial cells became clearer.The Sirus-red staining showed that there was significant accumulation of collagen in the diabetic group rats,indicating that the rats in diabetic group had cardiac fibrosis.The phenomenon in diabetes and Linagliptin CO treatment group was alleviated.TUNEL staining showed that at time point of 4 weeks,the degree of cardiomyocyte apoptosis in diabetes and Linagliptin CO treatment group was lower compared with diabetic group(P<0.01).The expressions of cleaved-caspase-3,TNF-α,PAI-1,CTGF and TGF-β1 proteins in diabetic rats were significantly decreased by Linagliptin,and the difference was statistically significant(cleaved-caspase-3:P<0.01;TNF-α:P<0.01;PAI-1:P<0.05;CTGF:P<0.05;TGF-β1:P<0.05).Compared with the diabetic group,the ratio of Bcl-2/Bax was inecreased in diabetes and Linagliptin CO treatment group,and the difference was statistically significant(P<0.05).From Nrf2 expression in the nucleus and cytosol by RT-PCR,Western blotting analysis and immunofluorescence test,the results showed that Linagliptin promoted the Nrf2 nuclear translocation in myocardial tissue cells.The expression of Nrf2 was significantly down-regulated in the heart of diabetic rats(P<0.01),while this phenomenon in diabetes and Linagliptin CO treatment group was greatly ameliorated.This paper studied the effect of Linagliptin on diabetic myocardial injur and found that the protective mechanism might be related to Nrf2 signaling pathway of antioxidant stress.Collectively,our finding provided new ideas and therapeutic targets for the prevention and treatment of DCM.
文摘In the present study,we aimed to investigate the effects of linagliptin on inflammatory factors and carotid intima-media thickness(CIMT)in newly diagnosed type 2 diabetes mellitus(T2 DM)patients with carotid atherosclerotic disease(CAD).A total of 326 patients with newly diagnosed T2 DM complicated with CAD were randomly divided into two groups.There were 163 patients in the control group,who were treated with metformin monotherapy.There were 163 patients in the experimental group,who were treated with metformin in combination with linagliptin.The CIMT before and after treatment was measured by color Doppler ultrasound,and the contents of IL-6 and IL-1βbefore and after treatment were detected by ELISA.The levels of inflammatory factors and CIMT before and after treatment were compared between the two groups,and the correlation between IL-6,IL-1βand CIMT was studied.After 24 weeks of treatment,the levels of inflammatory factors and CIMT in the experimental group were significantly lower compared with the control group(P<0.01),and the serum levels of IL-6 and IL-1βwere positively correlated with CIMT.In the present study,we concluded that linagliptin could improve the levels of inflammatory factors and CIMT in newly diagnosed T2 DM patients with CAD,and IL-6 and IL-1βmight participate in the occurrence and development of CAD by influencing CIMT.
文摘Impaired insulin signaling in Alzheimer’s disease（AD）brains：The insulin signaling pathway is a fundamental physiological mechanism that presents in nearly all vertebrate cells.However,sometimes cells stop responding properly to insulin stimulation.This condition is known as insulin resistance,which is a hallmark of two very common conditions,metabolic syndrome and type 2 diabetes（T2D）.
文摘BACKGROUND Cardiovascular outcome trials have demonstrated cardiovascular safety of glimepiride(a sulfonylureas) against dipeptidyl peptidase-4 inhibitor linagliptin.Gliclazide(another newer sulfonylureas) has shown similar glycemic efficacy and 50% decreased risk of hypoglycemia compared to glimepiride.AIM Considering the absence of cardiovascular outcome trials for gliclazide, we decided to conduct a systematic review of the literature to assess the cardiovascular(CV) safety by assessing the risk for major adverse CV events and hypoglycemia risk of gliclazide vs linagliptin in patients with type 2 diabetes(T2D).METHODS This systematic review followed the current Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to analyze all the clinical studies published from 2008 that compared the two drugs in patients with T2D with no risk of CV disease(CVD). We included only evidence designated high quality by the Oxford Center for Evidence-based Medicine-Levels of Evidence.RESULTS Eight clinical studies were included in the narrative descriptive analysis(gliclazide: 5 and linagliptin: 3). The CV safety of gliclazide in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial and of linagliptin in the Cardiovascular and Renal Microvascular Outcome Study With Linagliptin(CARMELINA) and CARdiovascular Outcome study of LINAgliptin vs glimepiride in patients with T2D(CAROLINA)trials were excluded from the comparative analysis as these trials demonstrated CV and hypoglycemia benefits in patients at high risk of CVD. However, since these are landmark trials,they were discussed in brief to show the CV benefits and low hypoglycemia risk of gliclazide and linagliptin. We did not find any study comparing gliclazide with linagliptin. Hence, direct comparison of their major adverse CV events and hypoglycemia risk could not be carried out.However, the literature meeting the inclusion criteria showed that both drugs were effective in achieving the desired glycemic control and had low major adverse CV events and hypoglycemia risk in adult patients with no history of CVD.CONCLUSION Gliclazide can be considered an effective and safe glucose-lowering drug in T2D patients with no established CVD but at high risk of CVD due to their T2D status. Future randomized controlled trials comparing gliclazide with linagliptin or dipeptidyl peptidase-4 inhibitors can confirm these findings.
文摘AIM To evaluate the comparative effectiveness of anagliptin and linagliptin on the clinical parameters in patients with type 2 diabetes mellitus(T2 DM). METHODS A 2-year retrospective cohort study was conducted in patients with T2 DM who received anagliptin and linagliptin. We enrolled 234 patients(anagliptin group, 117 patients; linagliptin group, 117 patients). RESULTS The glycemic control considerably improved 3, 6, 12, and 24 mo after the administration of both dipeptidyl peptidase-4(DPP-4) inhibitors. Following the administration of anagliptin, the diastolic blood pressure and serum total cholesterol levels decreased. However, serum high-density lipoprotein cholesterol levels increased and urinary albumin-creatinine ratio decreased following linagliptin administration. Furthermore, the liver function improved after the administration of linagliptin.CONCLUSION These findings suggest that that the efficacy of DPP-4 inhibitors on the blood pressure, lipid profile, and liver function differs between anagliptin and linagliptin.
文摘Objective:To explore the effect of Linagliptin on tumor necrosis factor receptor and monocyte chemoattractant protein-1 in patients with diabetic nephropathy.Methods: A total of 98 patients with diabetic nephropathy admitted to the Hospital from January 2017 to September 2018 were enrolled. The patients were divided into two groups according to the random double-blind method, with 49 cases in each group. The control group was treated with Metformin, whereas the experimental group was treated with Linagliptin plus Metformin. After 3 months of continuous treatment, the renal function [urinary albumin excretion rate, 24 h urine protein quantitation and serum creatinine], glycolipids metabolic levels [glycated hemoglobin, fasting blood glucose, total cholesterol and triglycerides], monocyte chemoattractant protein-1, tumor necrosis factor receptor, high-sensitivity C-reactive protein, and adverse reactions were compared between the two groups.Results:After 3 months of treatment, the levels of UAER, 24 h Upor and Scr in the experimental group were shown to be lower than those in the control group, and the difference was statistically significant. After 3 months of treatment, the levels of HbA1c, FPG, TC and TG in the experimental group were shown to be lower than the control group, and the difference was statistically significant. After 3 months of treatment, the levels of MCP-1, sTNFR1 and hs-CRP in the experimental group were lower than those in the control group, and the difference was statistically significant. There was no significant difference in incidence of adverse reactions between the two groups.Conclusion: For patients with diabetic nephropathy, Linagliptin is with higher safety, which can help improve their glycolipids metabolic levels and renal function, reduce the inflammatory response and the levels of MCP-1 and sTNFR1, and yet incur fewer adverse reactions.
基金supported by the National Key R&D Program of China,MOST(2023YFC2510000)the Key-Area Research and Development Program of Guangdong Province(2023B1111020008)the National Natural Science Foundation of China(82373147 and 82473379).
文摘The polymerase 1 and transcript release factor(PTRF)–cytoplasmic phospholipase A2(cPLA2)phospholipid remodeling pathway facilitates tumor proliferation in glioma.Nevertheless,blockade of this pathway leads to the excessive activation of oncogenic receptors on the plasma membrane and subsequent drug resistance.Here,CD26/dipeptidyl peptidase 4(DPP4)was identified through screening of CRISPR/Cas9 libraries.Suppressing PTRF–cPLA2 signaling resulted in the activation of the epidermal growth factor receptor(EGFR)pathway through phosphatidylcholine and lysophosphatidylcholine remodeling,which ultimately increased DPP4 transcription.In turn,DPP4 interacted with EGFR and prevented its ubiquitination.Linagliptin,a DPP4 inhibitor,facilitated the degradation of EGFR by blocking its interaction with DPP4.When combined with the cPLA2 inhibitor AACOCF3,it exhibited synergistic effects and led to a decrease in energy metabolism in glioblastoma cells.Subsequent in vivo investigations provided further evidence of a synergistic impact of linagliptin by augmenting the sensitivity of AACOCF3 and strengthening the efficacy of temozolomide.DPP4 serves as a novel target and establishes a constructive feedback loop with EGFR.Linagliptin is a potent inhibitor that promotes EGFR degradation by blocking the DPP4–EGFR interaction.This study presents innovative approaches for treating glioma by combining linagliptin with AACOCF3 and temozolomide.
文摘目的 研制与原研制剂体外溶出一致、体内生物等效的利格列汀片仿制药。方法 制备利格列汀片,通过建立利格列汀片体外溶出高效液相色谱法检测方法,分别在p H 1.0盐酸溶液、p H 4.5醋酸钠盐缓冲溶液、p H 6.8磷酸二氢钾盐缓冲溶液、水介质中,测定利格列汀片自制制剂与原研制剂的累积溶出情况,采用非模型依赖方法(f_(2)相似因子)计算自制制剂与原研制剂的溶出相似性;同时在健康成年受试者中进行单剂量、两制剂、两序列、两周期交叉试验设计的药代动力学研究,检测空腹及高脂餐后两种状态下受试者的血药浓度,计算药代动力学参数。结果 在4种溶出介质中,自制制剂与原研制剂的累积溶出曲线相似;药代动力学研究显示,空腹及餐后状态下,自制制剂与原研制剂的药代参数C_(max)、AUC_(0-t)的几何均值比值及其90%置信区间均在80.00%~125.00%范围内。结论 自制制剂与原研制剂体外溶出相似,且在药代动力学上生物等效。
