المؤلفون: Alessio Mazzieri, Francesca Porcellati, Francesca Timio, Gianpaolo Reboldi

المصدر: International Journal of Molecular Sciences, Vol 25, Iss 7, p 3969 (2024)

مصطلحات موضوعية: diabetic kidney disease, pathogenetic mechanisms, RAAS blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Diabetic kidney disease (DKD) is a chronic microvascular complication in patients with diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD). Although glomerulosclerosis, tubular injury and interstitial fibrosis are typical damages of DKD, the interplay of different processes (metabolic factors, oxidative stress, inflammatory pathway, fibrotic signaling, and hemodynamic mechanisms) appears to drive the onset and progression of DKD. A growing understanding of the pathogenetic mechanisms, and the development of new therapeutics, is opening the way for a new era of nephroprotection based on precision-medicine approaches. This review summarizes the therapeutic options linked to specific molecular mechanisms of DKD, including renin-angiotensin-aldosterone system blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, endothelin receptor antagonists, and aldosterone synthase inhibitors. In a new era of nephroprotection, these drugs, as pillars of personalized medicine, can improve renal outcomes and enhance the quality of life for individuals with DKD.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/25/7/3969Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/68d0adfe5f924586b7afb03696e2b094Test

المؤلفون: Chao-Shun Chan, Fong-Jhih Lin, Yao-Chang Chen, Yung-Kuo Lin, Satoshi Higa, Shih-Ann Chen, Yi-Jen Chen

المصدر: International Journal of Molecular Sciences, Vol 24, Iss 17, p 13100 (2023)

مصطلحات موضوعية: glucagon-like peptide-1 receptor agonist, atrial fibrillation, pulmonary vein, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Glucagon-like peptide-1 (GLP-1) receptor agonists are associated with reduced atrial fibrillation risk, but the mechanisms underlying this association remain unclear. The GLP-1 receptor agonist directly impacts cardiac Ca2+ homeostasis, which is crucial in pulmonary vein (PV, the initiator of atrial fibrillation) arrhythmogenesis. This study investigated the effects of the GLP-1 receptor agonist on PV electrophysiology and Ca2+ homeostasis and elucidated the potential underlying mechanisms. Conventional microelectrodes and whole-cell patch clamp techniques were employed in rabbit PV tissues and single PV cardiomyocytes before and after GLP-1 (7-36) amide, a GLP-1 receptor agonist. Evaluations were conducted both with and without pretreatment with H89 (10 μM, an inhibitor of protein kinase A, PKA), KN93 (1 μM, an inhibitor of Ca2+/calmodulin-dependent protein kinase II, CaMKII), and KB-R7943 (10 μM, an inhibitor of Na+/Ca2+ exchanger, NCX). Results showed that GLP-1 (7-36) amide (at concentrations of 1, 10, and 100 nM) reduced PV spontaneous activity in a concentration-dependent manner without affecting sinoatrial node electrical activity. In single-cell experiments, GLP-1 (7-36) amide (at 10 nM) reduced L-type Ca2+ current, NCX current, and late Na+ current in PV cardiomyocytes without altering Na+ current. Additionally, GLP-1 (7-36) amide (at 10 nM) increased sarcoplasmic reticulum Ca2+ content in PV cardiomyocytes. Furthermore, the antiarrhythmic effects of GLP-1 (7-36) amide on PV automaticity were diminished when pretreated with H89, KN93, or KB-R7943. This suggests that the GLP-1 receptor agonist may exert its antiarrhythmic potential by regulating PKA, CaMKII, and NCX activity, as well as modulating intracellular Ca2+ homeostasis, thereby reducing PV arrhythmogenesis.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/24/17/13100Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/04979443ccc84522b539be8040f19f38Test

المؤلفون: Tim Hropot, Rok Herman, Andrej Janez, Luka Lezaic, Mojca Jensterle

المصدر: International Journal of Molecular Sciences, Vol 24, Iss 10, p 8592 (2023)

مصطلحات موضوعية: obesity, weight loss, brown adipose tissue, glucagon-like peptide-1 receptor agonists, energy expenditure, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Adipose tissue can be divided into white adipose tissue (WAT), brown adipose tissue (BAT), and beige adipose tissue, according to the differences in morphology. WAT acts as a buffer for increased energy intake and decreased energy expenditure during the development of obesity, resulting in visceral and ectopic WAT accumulation. These WAT depots are strongly associated with chronic systemic inflammation, insulin resistance, and cardiometabolic risk related to obesity. They represent a primary weight loss target in anti-obesity management. Second-generation anti-obesity medications glucagon-like peptide-1 receptor agonists (GLP-1RAs) cause weight loss and improve body composition by reducing visceral and ectopic fat depots of WAT, resulting in improved cardiometabolic health. Recently, the understanding of the physiological significance of BAT beyond its primary function in generating heat through non-shivering thermogenesis has been expanded. This has raised scientific and pharmaceutical interest in the manipulation of BAT to further enhance weight reduction and body weight maintenance. This narrative review focuses on the potential impact of GLP-1 receptor agonism on BAT, particularly in human clinical studies. It provides an overview of the role of BAT in weight management and highlights the need for further research to elucidate the mechanisms by which GLP-1RAs affect energy metabolism and weight loss. Despite encouraging preclinical data, limited clinical evidence supports the notion that GLP-1RAs contribute to BAT activation.

العلاقة: https://www.mdpi.com/1422-0067/24/10/8592Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test; https://doaj.org/article/a6143e5fcdab40b287390104a95af263Test

الإتاحة: https://doi.org/10.3390/ijms24108592Test
https://doaj.org/article/a6143e5fcdab40b287390104a95af263Test

المؤلفون: More, Vijay R.¹ vijay.more@merck.com, Lao, Julie¹, McLaren, David G.², Cumiskey, Anne-Marie³, Murphy, Beth Ann³, Chen, Ying¹, Previs, Stephen¹, Stout, Steven², Patel, Rajesh¹, Satapati, Santhosh¹, Li, Wenyu¹, Kowalik, Edward², Szeto, Daphne³, Nawrocki, Andrea³, Pocai, Alessandro¹, Wang, Liangsu¹, Carrington, Paul¹

المصدر: PLoS ONE. 10/24/2017, Vol. 12 Issue 10, p1-18. 18p.

مصطلحات موضوعية: *GLUCAGON-like peptide-1 receptor, *LIPID synthesis, *CHOLESTEROL, *DEUTERIUM, *ESTERIFICATION

مستخلص: Lipid lowering properties of glucagon have been reported. Blocking glucagon signaling leads to rise in plasma LDL levels. Here, we demonstrate the lipid lowering effects of acute dosing with Glp1r/Gcgr dual agonist (DualAG). All the experiments were performed in 25 week-old male diet-induced (60% kCal fat) obese mice. After 2 hrs of fasting, mice were injected subcutaneously with vehicle, liraglutide (25nmol/kg) and DualAG (25nmol/kg). De novo cholesterol and palmitate synthesis was measured by deuterium incorporation method using D2O. 13C18-oleate infusion was used for measuring fatty acid esterification. Simultaneous activation of Glp1r and Gcgr resulted in decrease in plasma triglyceride and cholesterol levels. DualAG enhanced hepatic LDLr protein levels, along with causing decrease in content of plasma ApoB48 and ApoB100. VLDL secretion, de novo palmitate synthesis and fatty acid esterification decreased with acute DualAG treatment. On the other hand, ketone levels were elevated with DualAG treatment, indicating increased fatty acid oxidation. Lipid relevant changes were absent in liraglutide treated group. In an acute treatment, DualAG demonstrated significant impact on lipid homeostasis, specifically on hepatic uptake, VLDL secretion and de novo synthesis. These effects collectively reveal that lipid lowering abilities of DualAG are primarily through glucagon signaling and are liver centric. [ABSTRACT FROM AUTHOR]

المؤلفون: Krzysztof Bednarz, Karolina Kowalczyk, Marlena Cwynar, Dominika Czapla, Wiktor Czarkowski, Dominika Kmita, Artur Nowak, Paweł Madej

المصدر: International Journal of Molecular Sciences, Vol 23, Iss 4334, p 4334 (2022)

مصطلحات موضوعية: polycystic ovary syndrome (PCOS), insulin resistance (IR), glucagon-like peptide-1 receptor agonists (GLP-1RAs), obesity, inflammation, oxidative stress, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Insulin resistance is documented in clamp studies in 75% of women with polycystic ovary syndrome (PCOS). Although it is not included in the diagnostic criteria of PCOS, there is a crucial role of this metabolic impairment, which along with hormonal abnormalities, increase each other in a vicious circle of PCOS pathogenesis. Insulin resistance in this group of patients results from defects at the molecular level, including impaired insulin receptor-related signaling pathways enhanced by obesity and its features: Excess visceral fat, chronic inflammation, and reactive oxygen species. While lifestyle intervention has a first-line role in the prevention and management of excess weight in PCOS, the role of anti-obesity pharmacological agents in achieving and maintaining weight loss is being increasingly recognized. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) not only act by reducing body weight but also can affect the mechanisms involved in insulin resistance, like an increasing expression of glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism. They also tend to improve fertility either by increasing LH surge in hypothalamus-pituitary inhibition due to estrogen excess connected with obesity or decreasing too high LH levels accompanying hyperinsulinemia. GLP1-RAs seem promising for effective treatment of obese PCOS patients, acting on one of the primary causes of PCOS at the molecular level.

العلاقة: https://www.mdpi.com/1422-0067/23/8/4334Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test; https://doaj.org/article/2de9623f834948b48a847d4f25770381Test

الإتاحة: https://doi.org/10.3390/ijms23084334Test
https://doaj.org/article/2de9623f834948b48a847d4f25770381Test

المؤلفون: Agata Winiarska, Monika Knysak, Katarzyna Nabrdalik, Janusz Gumprecht, Tomasz Stompór

المصدر: International Journal of Molecular Sciences, Vol 22, Iss 10822, p 10822 (2021)

مصطلحات موضوعية: type 2 diabetes, sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor antagonists, diabetic kidney disease, oxidative stress, inflammation, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: The incidence of type 2 diabetes (T2D) has been increasing worldwide, and diabetic kidney disease (DKD) remains one of the leading long-term complications of T2D. Several lines of evidence indicate that glucose-lowering agents prevent the onset and progression of DKD in its early stages but are of limited efficacy in later stages of DKD. However, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor (GLP-1R) antagonists were shown to exert nephroprotective effects in patients with established DKD, i.e., those who had a reduced glomerular filtration rate. These effects cannot be solely attributed to the improved metabolic control of diabetes. In our review, we attempted to discuss the interactions of both groups of agents with inflammation and oxidative stress—the key pathways contributing to organ damage in the course of diabetes. SGLT2i and GLP-1R antagonists attenuate inflammation and oxidative stress in experimental in vitro and in vivo models of DKD in several ways. In addition, we have described experiments showing the same protective mechanisms as found in DKD in non-diabetic kidney injury models as well as in some tissues and organs other than the kidney. The interaction between both drug groups, inflammation and oxidative stress appears to have a universal mechanism of organ protection in diabetes and other diseases.

العلاقة: https://www.mdpi.com/1422-0067/22/19/10822Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test; https://doaj.org/article/92e00e02cf5d411da35b9cb0c24ebab7Test

الإتاحة: https://doi.org/10.3390/ijms221910822Test
https://doaj.org/article/92e00e02cf5d411da35b9cb0c24ebab7Test

المؤلفون: Jelena Vekic, Aleksandra Zeljkovic, Aleksandra Stefanovic, Rosaria Vincenza Giglio, Marcello Ciaccio, Manfredi Rizzo

المصدر: International Journal of Molecular Sciences, Vol 22, Iss 12409, p 12409 (2021)

مصطلحات موضوعية: insulin resistance, hyperglycemia, oxidative stress, inflammation, small dense LDL, glucagon-like peptide-1 receptor agonists, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Epidemiological data have demonstrated a significant association between the presence of type 2 diabetes mellitus (T2DM) and the development of colorectal cancer (CRC). Chronic hyperglycemia, insulin resistance, oxidative stress, and inflammation, the processes inherent to T2DM, also play active roles in the onset and progression of CRC. Recently, small dense low-density lipoprotein (LDL) particles, a typical characteristic of diabetic dyslipidemia, emerged as another possible underlying link between T2DM and CRC. Growing evidence suggests that antidiabetic medications may have beneficial effects in CRC prevention. According to findings from a limited number of preclinical and clinical studies, glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be a promising strategy in reducing the incidence of CRC in patients with diabetes. However, available findings are inconclusive, and further studies are required. In this review, novel evidence on molecular mechanisms linking T2DM with CRC development, progression, and survival will be discussed. In addition, the potential role of GLP-1RAs therapies in CRC prevention will also be evaluated.

العلاقة: https://www.mdpi.com/1422-0067/22/22/12409Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test; https://doaj.org/article/d789fe012af54893836fdd938c2a60f2Test

الإتاحة: https://doi.org/10.3390/ijms222212409Test
https://doaj.org/article/d789fe012af54893836fdd938c2a60f2Test

المؤلفون: Juliana de Freitas Germano, Ankush Sharma, Miroslava Stastna, Chengqun Huang, Marianne Aniag, Angie Aceves, Jennifer E. Van Eyk, Robert M. Mentzer, Honit Piplani, Allen M. Andres, Roberta A. Gottlieb

المصدر: International Journal of Molecular Sciences, Vol 22, Iss 8711, p 8711 (2021)

مصطلحات موضوعية: proteomics, glucagon-like peptide-1 receptor agonists, DMB, early cardiac remodeling, mitochondrion, cellular respiration, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Cardiovascular disease is the main cause of death worldwide, making it crucial to search for new therapies to mitigate major adverse cardiac events (MACEs) after a cardiac ischemic episode. Drugs in the class of the glucagon-like peptide-1 receptor agonists (GLP1Ra) have demonstrated benefits for heart function and reduced the incidence of MACE in patients with diabetes. Previously, we demonstrated that a short-acting GLP1Ra known as DMB (2-quinoxalinamine, 6,7-dichloro-N-[1,1-dimethylethyl]-3-[methylsulfonyl]-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline or compound 2, Sigma) also mitigates adverse postinfarction left ventricular remodeling and cardiac dysfunction in lean mice through activation of parkin-mediated mitophagy following infarction. Here, we combined proteomics with in silico analysis to characterize the range of effects of DMB in vivo throughout the course of early postinfarction remodeling. We demonstrate that the mitochondrion is a key target of DMB and mitochondrial respiration, oxidative phosphorylation and metabolic processes such as glycolysis and fatty acid beta-oxidation are the main biological processes being regulated by this compound in the heart. Moreover, the overexpression of proteins with hub properties identified by protein–protein interaction networks, such as Atp2a2, may also be important to the mechanism of action of DMB. Data are available via ProteomeXchange with identifier PXD027867.

العلاقة: https://www.mdpi.com/1422-0067/22/16/8711Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test; https://doaj.org/article/d9d6cd8eb7cf4fd190ec9d99d13fd8d3Test

الإتاحة: https://doi.org/10.3390/ijms22168711Test
https://doaj.org/article/d9d6cd8eb7cf4fd190ec9d99d13fd8d3Test

المؤلفون: Shizuka Takaku, Masami Tsukamoto, Naoko Niimi, Hideji Yako, Kazunori Sango

المصدر: International Journal of Molecular Sciences, Vol 22, Iss 2971, p 2971 (2021)

مصطلحات موضوعية: glucagon-like peptide-1 receptor, exendin-4, IFRS1 Schwann cells, survival, migration, dorsal root ganglion neurons, Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Besides its insulinotropic actions on pancreatic β cells, neuroprotective activities of glucagon-like peptide-1 (GLP-1) have attracted attention. The efficacy of a GLP-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) for functional repair after sciatic nerve injury and amelioration of diabetic peripheral neuropathy (DPN) has been reported; however, the underlying mechanisms remain unclear. In this study, the bioactivities of Ex-4 on immortalized adult rat Schwann cells IFRS1 and adult rat dorsal root ganglion (DRG) neuron–IFRS1 co-culture system were investigated. Localization of GLP-1R in both DRG neurons and IFRS1 cells were confirmed using knockout-validated monoclonal Mab7F38 antibody. Treatment with 100 nM Ex-4 significantly enhanced survival/proliferation and migration of IFRS1 cells, as well as stimulated the movement of IFRS1 cells toward neurites emerging from DRG neuron cell bodies in the co-culture with the upregulation of myelin protein 22 and myelin protein zero. Because Ex-4 induced phosphorylation of serine/threonine-specific protein kinase AKT in these cells and its effects on DRG neurons and IFRS1 cells were attenuated by phosphatidyl inositol-3′-phosphate-kinase (PI3K) inhibitor LY294002, Ex-4 might act on both cells to activate PI3K/AKT signaling pathway, thereby promoting myelination in the co-culture. These findings imply the potential efficacy of Ex-4 toward DPN and other peripheral nerve lesions.

العلاقة: https://www.mdpi.com/1422-0067/22/6/2971Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test; https://doaj.org/article/70f411c16de04480a23f15f2b229c7dbTest

الإتاحة: https://doi.org/10.3390/ijms22062971Test
https://doaj.org/article/70f411c16de04480a23f15f2b229c7dbTest

المؤلفون: Yang, Yi^1,2, Chen, Fang², Wan, Deyou², Liu, Yunhui², Yang, Li², Feng, Hongru², Cui, Xinling², Gao, Xin² gaox_amms@126.com, Song, Haifeng^1,2

المصدر: PLoS ONE. 5/27/2016, Vol. 11 Issue 5, p1-14. 14p.

مصطلحات موضوعية: *GLUCAGON-like peptide-1 receptor, *GENE expression, *GLYCEMIC control, *CHIMERIC proteins, *CD26 antigen, *WESTERN immunoblotting

مستخلص: Human GLP-1 (glucagon-like peptide-1) can produce a remarkable improvement in glycemic control in patients with type 2 diabetes. However, its clinical benefits are limited by its short half-life, which is less than 2 min because of its small size and rapid enzymatic inactivation by dipeptidyl peptidase IV. We engineered GLP-1-IgG2σ-Fc, a 68-kDa fusion protein linking a variant human GLP-1 (A8G/G26E/R36G) to a human IgG2σ constant heavy-chain. A stably transfected Chinese hamster ovary cell line was obtained using electroporation. Western blotting showed that the expressed protein was immunoreactive to both GLP-1 and IgG antibodies. GLP-1-IgG2σ-Fc stimulated insulin secretion from INS-1 cells in a dose- and glucose-dependent manner and increased insulin mRNA expression. The half-life of GLP-1-IgG2σ-Fc in cynomolgus monkeys was approximately 57.1 ± 4.5 h. In the KKAy mouse model of diabetes, one intraperitoneal injection of GLP-1-IgG2σ-Fc (1 mg/kg) reduced blood glucose levels for 5 days. A 4-week repeat-administration study identified sustained effects on blood glucose levels. Oral glucose tolerance tests conducted at the beginning and end of this 4-week period showed that GLP-1-IgG2σ-Fc produced a stable glucose lowering effect. In addition, KKAy mice treated with GLP-1-IgG2σ-Fc showed statistically significant weight loss from day 23. In conclusion, these properties of GLP-1-IgG2σ-Fc demonstrated that it represented a potential long-acting GLP-1 receptor agonist for the treatment of type 2 diabetes. [ABSTRACT FROM AUTHOR]