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liraglutide Ameliorates Hyperhomocysteinemia-Induced Alzheimer-Like Pathology and Memory Deficits in Rats via Multi-molecular Targeting

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Neuroscience Bulletin 2019年第4期35卷 724-734页

作者： Yao Zhang Jia-Zhao Xie Xiang-Yang Xu Jun Hu Teng Xu Si Jin Shao-Juan Yang Jian-Zhi Wang Endocrinology Department of Liyuan Hospital and Key Laboratory of the Ministry of Education of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan 430077 China Department of Pathophysiology School of Basic Medicine and the Collaborative Innovation Center for Brain Science Key Laboratory of the Ministry of Education of China for Neurological Disorders Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China Endocrinology Department Liyuan Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430077 China Radiology Department Liyuan Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430077 China

Hyperhomocysteinemia(Hhcy)is an independent risk factor for Alzheimer's disease(AD),and insulinresistance is commonly seen in patients with ***(Lir),a glucagon-like peptide that increases the secretion and sensitivity of insulin,has a neurotrophic or neuroprotective ***,it is not known whether Lir ameliorates the AD-like pathology and memory deficit induced by *** vena caudalis injection of homocysteine to produce the Hhcy model in rats,we found here that simultaneous administration of Lir for 2 weeks ameliorated the Hhcy-induced memory deficit,along with increased density of dendritic spines and up-regulation of synaptic *** also attenuated the Hhcy-induced tau hyperphosphorylation and Aβ overproduction,and the molecular mechanisms involved the restoration of protein phosphatase-2 A activity and inhibition of β-and γ-*** insulin receptor substrate-1 also decreased after treatment with *** data reveal that Lir improves the Hhcy-induced AD-like spatial memory deficit and the mechanisms involve the modulation of insulinresistance and the pathways generating abnormal tau and Aβ.

关键词： liraglutide Hyperhomocysteinemia Glucagon-like peptide-1 receptor Tau β-Amyloid

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liraglutide Suppresses Myocardial Fibrosis Progression by Inhibiting the Smad Signaling Pathway

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Current Medical Science 2023年第5期43卷 955-960页

作者： Wen SUN Hong MI De-ying HE Wen LI Yi-yan SONGYANG Department of Geriatrics Chongqing Hospital of Traditional Chinese MedicineChongqing 400021China Department of Traditional Chinese Medicine Chongqing Hospital of Traditional Chinese MedicineChongqing 400021China Department of Emergency Renmin Hospital of Wuhan UniversityWuhan 430060China Department of Pharmacy Renmin Hospital of Wuhan UniversityWuhan 430060China

Objective liraglutide is a commonly used hypoglycemic agent in clinical practice,and has been demonstrated to have protective effects against the development of cardiovascular ***,its potential role in myocardial fibrosis remains *** present study aims to assess the impact of liraglutide on the activation of cardiac *** Primary rat adult fibroblasts were isolated,cultured,and randomly allocated into 4 groups:control group,transforming growth factor beta1(TGFβ1)stimulation group,liraglutide group,and TGFβ1+liraglutide *** activation was induced by TGFβ*** proliferation activity was assessed using the CKK-8 kit,and cellular activity was determined using the MTT *** transcrition-quantitative polymerase chain reaction(RT-qPCR)was utilized to quantify the level of collagen transcription,immunofluorescence staining was performed to detect the expression level of type III collagen andα-smooth muscle protein(α-SMA),and immunoblotting was conducted to monitor alterations in signal *** The addition of 10,25,50 and 100 nmol/L of liraglutide did not induce any significant impact on the viability of fibroblasts(P>0.05).The rate of cellular proliferation was significantly higher in the TGFβl stimulation group than in the control ***,the treatment with 50 and 100 nmol/L of liraglutide resulted in the reduction of TGFβl-induced cell proliferation(Pliraglutide group(P<0.05).The immunofluorescence staining results revealed a significant increase in the expression levels of type III collagen andα-SMA in the TGFβl stimulation group,when compared to the control group(P<0.05).However,these exp

关键词： liraglutide myocardial fibrosis TGFβl smad

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Neuroprotective effect of liraglutide and memantine in a rat model of Alzheimer’s disease

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Asian Pacific Journal of Tropical Biomedicine 2024年第5期14卷 207-214页

作者： Duaa M.Bakhshwin Foziya W.Alhalabi Mohamad Omar Barasheed Ahmed M.Bakhshwin Maha H.Jamal Mohammed A.Bazuhair Fatemah O.Kamel Rania M.Magadmi Zoheir A Damanhouri Samar M.Alsaggaf Department of Clinical Pharmacology Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia Hera General Hospital MakkahSaudi Arabia Department of Pathology Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia Department of Clinical Anatomy Faculty of MedicineKing Abdulaziz UniversityJeddahSaudi Arabia

Objective:To assess the effect of memantine combined with liraglutide on aluminum chloride(AlCl_(3))and D-galactose(D-GAL)-induced neurotoxicity in ***:Male Wistar rats were divided into 5 groups of 5 animals each:the positive control,the negative control,the memantine-treated group,the liraglutide-treated group,and the combination group treated with memantine and ***_(3)and D-GAL were used to induce *** tests,brain beta-amyloid protein,and oxidative stress biomarkers were ***:The Morris water maze test indicated an enhanced memory in the combination ***,the combination treatment of liraglutide and memantine resulted in a remarkable reduction in the beta-amyloid protein level in the brain *** inflammation and oxidative stress biomarkers were significantly reduced,and the levels of antioxidant parameters were ***:The combination of liraglutide and memantine exerts neuroprotective effects and enhances memory and cognitive functions in rats with Alzheimer’s disease.

关键词： Alzheimer’s disease Cognitive function Glucagonlike peptide-1 liraglutide Memantine

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Successful treatment of hyperglycemia with liraglutide in a hospitalized 27-year-old patient with schizophrenia:A case report

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World Journal of Clinical Cases 2022年第21期10卷 7495-7501页

作者： Lei Zhang Wen-Juan Yu Hui Zhu Hua-Fang Li Jie Qiao Department of Psychiatry Shanghai Mental Health CenterShanghai 200030China School of Medicine Shanghai Jiaotong UniversityShanghai 200025China Department of Endocrinology Shanghai Jiaotong University School of MedicineShanghai 9th HospitalShanghai 200011China

BACKGROUND Antipsychotics are associated with abnormalities in glucose metabolism in patients with schizophrenia. liraglutide, a GLP-1 receptor agonist, is Food and Drug Administration approved for the treatment of type 2 diabetes mellitus. However, ways to maintain the long-term stability of psychotic symptoms and balance the disadvantages of obesity, diabetes, and other metabolic disorders caused by antipsychotic medications remain unclear. In this study, we present a case of weight gain and hyperglycemia in a schizophrenia patient who received antipsychotic polypharmacy for 6 *** SUMMARY A 27-year-old man with olanzapine and sodium valproate-treated disorganized schizophrenia was admitted to a diabetes outpatient clinic. He was diagnosed with type 2 diabetes(fasting blood glucose, 20 mmol/L) and obesity(body mass index, 38.58 kg/m). The patient had been treated with glargine(40 IU/d) and metformin(1.5 g/d) and showed a poor response for 2 mo. Two years of liraglutide treatment resulted in stable blood glucose levels and weight loss in addition to a maintained stable mental status for a long time. The biological activities of GLP-1 significantly improved glucose levels and body weight in the schizophrenia patient treated with antipsychotic *** liraglutide administration can be considered an effective alternative treatment for abnormalities in glucose metabolism in schizophrenia patients receiving antipsychotics.

关键词： Hyperglycemia liraglutide GLP-1 receptor agonist Schizophrenia Antipsychotics Case report

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Mimicking natural cholesterol assimilation to elevate the oral delivery of liraglutide for type Ⅱ diabetes therapy

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Asian Journal of Pharmaceutical Sciences 2022年第5期17卷 653-665页

作者： Ruinan Wu Zhanghan Wu Liyun Xing Xi Liu Lei Wu Zhou Zhou Lian Li Yuan Huang Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡ***,administration of GLP-RA is mainly through repetitive subcutaneous injection,which may seriously decrease the compliance and ***,a bio-inspired oral delivery system was designed to enhance the oral absorption of liraglutide(Lira),a kind of GLP-1 RA,by mimicking the natural cholesterol assimilation.25-hydroxycholesterol(25HC),a cholesterol derivative,was modified on the surfaced of Lira-loaded PLGA nanoparticles(Lira 25HC NPs)and functioned as a“top-down”actuator to facilitate unidirectional transcytosis across the intestinal *** oral delivery,Lira 25HC NPs displayed improved therapeutic effect as compared with oral free Lira on typeⅡdiabetes db/db mice,as evidenced by multiple relieved diabetic symptoms including the enhanced glucose tolerance,repressed weight growth,improved liver glucose metabolism,decreased fasting blood glucose,HbA 1c,serum lipid,and increasedβcells ***,the fasting blood glucose,liver glucose metabolism,and HbA1c of oral Lira-loaded 25HC NPs were comparable to subcutaneous injection of free *** mechanisms revealed that 25HC ligand could mediate the nanoparticles to mimic natural cholesterol absorption by exerting high affinity towards apical Niemann-Pick C1 Like 1(NPC1L1)and then basolateral ATP binding cassette transporter A1(ABCA1)overexpressed on the opposite side of intestinal *** cholesterol assimilation-mimicking strategy achieve the unidirectional transport across the intestinal epithelium,thus improving the oral absorption of *** general,this study established a cholesterol simulated platform and provide promising insight for the oral delivery of GLP-1 RA.

关键词： Glucagon-like peptide-1 Oral delivery Cholesterol assimilation liraglutide TypeⅡdiabetes HbA 1c

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Effects of liraglutide on metabolic syndrome in WBN/Kob diabetic fatty rats supplemented with a high-fat diet

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Animal Models and Experimental Medicine 2020年第1期3卷 62-68页

作者： Noriyuki Kaji Yoshiichi Takagi Satomi Matsuda Anna Takahashi Sakurako Fujio Fumitoshi Asai Laboratory of Veterinary Pharmacology School of Veterinary MedicineAzabu UniversityKanagawaJapan

Background:liraglutide,a GLP-1 receptor agonist,has recently been used to treat metabolic syndrome(MS)because of its anti-diabetic and anti-obesity *** have previously shown that Wistar Bonn Kobori diabetic and fatty(WBN/Kob-Leprfa,WBKDF)rats fed a high-fat diet(HFD)developed MS including marked obesity,hyperglycemia,and *** obtain further information on WBKDF-HFD rats as a severe MS model,we performed a pharmacological investigation into the anti-MS effects of liraglutide in this ***:Seven-week-old male WBKDF-HFD rats were allocated to three groups(n=8 in each group):a vehicle group,a low-dose liraglutide group,and a high-dose liraglutide *** received subcutaneous injections of either saline or liraglutide at doses of 75 or 300μg/kg body weight once daily for 4 ***:Results showed that liraglutide treatment reduced body weight gain and food intake in a dose-dependent *** marked hyperglycemia and the glucose tolerance were also significantly ameliorated in the liraglutide-treated ***,liraglutide also reduced the plasma triglyceride concentration and liver fat ***:The present study demonstrated that liraglutide could significantly alleviate MS in WBKDF-HFD rats,and the reaction to liraglutide is similar to human patients with ***-HFD rats are therefore considered to be a useful model for research on severe human MS.

关键词： diabetes mellitus liraglutide metabolic syndrome models animal obesity

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Protective effect of liraglutide on the myocardium of type 2 diabetic rats by inhibiting polyadenosine diphosphate-ribose polymerase-1

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World Journal of Diabetes 2023年第2期14卷 110-119页

作者： Dong-Dong Xue Xiang Zhang De-Wei Li Yan-Lan Yang Jing-Jin Liu Department of Endocrinology Shanxi Provincial People's HospitalTaiyuan 030000Shanxi ProvinceChina Department of Thyroid Surgery Shanxi Provincial People's HospitalTaiyuan 030000Shanxi ProvinceChina Department of Endocrine Shanxi Provincial People's HospitalTaiyuan 030012Shanxi ProvinceChina

BACKGROUND In recent years,studies have found that the occurrence and development of diabetic cardiomyopathy(DCM)is closely related to an increase in polyadenosine diphosphate-ribose polymerase-1(PARP-1)***-1 activation could be involved in the pathophysiological process of DCM by promoting oxidative stress,the inflammatory response,apoptosis and myocardial *** To investigate the mechanism of liraglutide in improving myocardial injury in type 2 diabetic rats,further clarified the protective effect of liraglutide on the heart,and provided a new option for the treatment of *** Forty healthy male SD rats aged 6 wk were randomly divided into two groups,a normal control group(n=10)and a model group(n=30),which were fed an ordinary diet and a high-sugar and high-fat diet,*** successful modeling,the rats in the model group were fed a high-glucose and high-fat diet for 4 wk and randomly divided into a model group and an intervention group(further divided into a high-dose group and a low-dose group).The rats were fed a high-glucose and high-fat diet for 8 wk and then started drug *** samples were collected from the abdominal aorta to detect fasting blood glucose and lipid *** heart tissue was dissected,and its weight was used to calculate the heart weight *** and eosin staining was used to observe the pathological changes in the myocardium and the expression of PARP-1 in the heart by *** The body weight and heart weight index of rats in the model group were significantly increased compared with those in the normal control group,and those in the intervention group were decreased compared with those in the model group,with a more obvious decrease observed in the high-dose group(P<0.05).In the model group,myocardial fibers were disordered,and inflammatory cells and interstitial fibrosis were *** cardiomyopathy of rats in the intervention group was improved to di

关键词： liraglutide animal models Type 2 diabetic rats Polyadenosine diphosphate-ribose polymerase-1 Haematoxylin and eosin staining Immunohistochemistry

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Effect of liraglutide on endoplasmic reticulum stress in the renal tissue of type 2 diabetic rats

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World Journal of Diabetes 2020年第12期11卷 611-621页

作者： Xuan-Ye Zhao Ting-Ting Yu Sheng Liu Yao-Ji Liu Jing-Jin Liu Jie Qin Department of Endocrinology Shanxi Provincial People's HospitalTaiyuan 030012Shanxi ProvinceChina

BACKGROUND liraglutide is a glucagon-like peptide 1 receptor agonist analog that has been found to have a therapeutic effect in *** addition to its ability to treat diabetes,liraglutide has beneficial effects on the cardiovascular system and kidney as well as other beneficial effects,but its specific mechanism is not *** this study,a rat model of type 2 diabetes was established by administration of a high-sugar,high-fat diet combined with low-dose streptozotocin(STZ)to observe the effect of liraglutide on the kidneys of type 2 diabetes rats and the possible underlying *** To explore whether liraglutide has a protective effect on type 2 diabetic rat kidneys and the underlying *** Eight-week-old male Sprague-Dawley rats were randomly divided into a control group,model group,low-dose liraglutide group,and high-dose liraglutide *** rats were fed a standard diet,while model group and intervention group rats were fed high-sugar,high-fat feed for 1 mo and then intraperitoneally injected with 40 mg/kg STZ to induce type 2 *** low-dose and highdose intervention groups received 100μg/kg and 200μg/kg liraglutide,respectively,once daily by subcutaneous *** control and model groups were given an equivalent volume of physiological saline for 8 *** changes in renal tissues were observed by hematoxylin and eosin staining and periodic acid-Schiff staining,and GRP78 and caspase-12 expression was detected by Western blot and reverse transcription-polymerase chain reaction(RT-PCR).RESULTS Western blot analysis showed that GRP78 and caspase-12 protein expression in kidney tissue was significantly higher in model rats than in normal rats and lowerin the liraglutide-treated groups than in the model group,with a more significant decrease being observed in the high-dose group than in the low-dose *** showed that the mRNA expression of GRP78 and caspase-12 was higher in model rats than in control rats and

关键词： liraglutide Diabetes Diabetic nephropathy Endoplasmic reticulum stress Rat Nephropathy

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liraglutide reduces oxidized LDL-induced oxidative stress and fatty degen- eration in Raw 264.7 cells involving the AMPK/SREBP1 pathway

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Journal of Geriatric Cardiology 2015年第4期12卷 410-416页

作者： Yan-Gui WANG Tian-Lun YANG Department of Cardiology Xiangya Hospital Central South University No. 8 7 Xiangya Road Changsha Hunan China Deparment of Geriatrics Hunan Provincial People's Hospital No.61 Jiefang West Road Changsha Hunan China

Baekgound Recent studies have suggested a potential role for liraglutide in the prevention and stabilization ofatherosclerotic vascular disease. However, the molecular mechanisms underlying the effect of liraglutide on atherosclerosis have not been well elucidated. The pur- pose of this study was to examine whether liraglutide protects against oxidative stress and fatty degeneration via modulation of AMP-activated protein kinase （AMPK）/sterol regulatory element binding transcription factor 1 （SREBP1） signaling pathway in foam ceils. Methods Mouse macrophages Raw264.7 cells were exposed to oxidized low density lipoprotein （oxLDL） to induce the formation of foam cells. The cells were incubated with oxLDL （50 μg/mL）, liraglutide （0.1, 0.5, 1 and 2 nmol/L） or exendin-3 （9-39）（1, 10 and 100 nmol/L） alone, or in combination. Oil Red O staining was used to detect intracellular lipid droplets. The levels of TG and cholesterol were measured using the commercial kits. Oxidative stress was determined by measuring intracellular reactive oxygen species （ROS）, malondialdehyde （MDA） and superoxide dismutase 1 （SOD）. Western blot analysis was used to examine the expression of AMPKal, SREBP1, phosphory- lated AMPKal, phosphorylated SREBP1, glucagon-like peptide-1 （GLP-1） and GLP-1 receptor （GLP-1R）. Results Oil Red O staining showed that the cytoplasmic lipid droplet accumulation was visibly decreased in foam cells by treatment with liraglutide. The TG and cholesterol content in the liraglutide-treated foam cells was significantly decreased. In addition, foam ceils manifested an impaired oxidative stress following liraglutide treatment, as evidenced by increased SOD, and decreased ROS and MDA. However, these effects of liraglutide on foam cells were attenuated by the use of GLP-IR antagonist exendin-3 （9-39）. Furthermore, we found that the expression level of AMPKa 1 and phosphorylated AMPKct 1 was significantly increased while the expression level of SREBP 1 and phosphorylated SRE

关键词： AMPK/SREBP1 pathway Fatty degeneration Foam cell liraglutide Oxidative stress

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liraglutide prevents high glucose level induced insulinoma cells apoptosis by targeting autophagy

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Chinese Medical Journal 2013年第5期126卷 937-941页

作者： CHEN Ze-fang LI Yan-bo HAN Jun-yong YIN Jia-jing WANG Yang ZHU Li-bo XIE Guang-ying Department of Endocrinology First Affiliated Hospital of HarbinMedical University Harbin Heilongjiang 150001 China Department of Cardiology Fifth Affiliated Hospital Sun Yat-senUniversity Zhuhai Guangdong 519000 China

Background The pathophysiology of type 2 diabetes is progressive pancreatic beta cell failure with consequential reduced insulin secretion. Glucotoxicity results in the reduction of beta cell mass in type 2 diabetes by inducing apoptosis. Autophagy is essential for the maintenance of normal islet architecture and plays a crucial role in maintaining the intracellular insulin content by accelerating the insulin degradation rate in beta cells. Recently more attention has been paid to the effect of autophagy in type 2 diabetes. The regulatory pathway of autophagy in controlling pancreatic beta cells is still not clear. The aim of our study was to evaluate whether liraglutide can inhibit apoptosis and modulate autophagy in vitro in insulinoma cells （INS-1 cells）. Methods INS-1 cells were incubated for 24 hours in the presence or absence of high levels of glucose, liraglutide （a long-acting human glucagon-like peptide-1 analogue）, or 3-methyadenine （3-MA）. Cell viability was measured using the Cell Counting Kit-8 （CCK8） viability assay. Autophagy of INS-1 cells was tested by monodansylcadaverine （MDC） staining, an autophagy fluorescent compound used for the labeling of autophagic vacuoles, and by Western blotting of microtubule-associated protein I light chain 3 （LC3）, a biochemical markers of autophagic initiation. Results The viability of INS-1 cells was reduced after treatment with high levels of glucose. The viability of INS-1 cells was reduced and apoptosis was increased when autophagy was inhibited. The viability of INS-1 cells was significantly increased by adding liraglutide to supplement high glucose level medium compared with the cells treated with high glucose levels alone. Conclusions Apoptosis and autophagy were increased in rat INS-1 cells when treated with high level of glucose, and the viability of INS-1 cells was significantly reduced by inhibiting autophagy. liraglutide protected INS-1 cells from high glucose level-induced apoptosis that is accompanied b

关键词： autophagy pancreatic beta-cell type 2 diabetes liraglutide apoptosis

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