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Cardiovascular Research Mar 2020Coronary microvascular dysfunction (CMD) is commonly present in patients with metabolic derangements and is increasingly recognized as an important contributor to... (Review)
Review
Coronary microvascular dysfunction (CMD) is commonly present in patients with metabolic derangements and is increasingly recognized as an important contributor to myocardial ischaemia, both in the presence and absence of epicardial coronary atherosclerosis. The latter condition is termed 'ischaemia and no obstructive coronary artery disease' (INOCA). Notwithstanding the high prevalence of INOCA, effective treatment remains elusive. Although to date there is no animal model for INOCA, animal models of CMD, one of the hallmarks of INOCA, offer excellent test models for enhancing our understanding of the pathophysiology of CMD and for investigating novel therapies. This article presents an overview of currently available experimental models of CMD-with an emphasis on metabolic derangements as risk factors-in dogs, swine, rabbits, rats, and mice. In all available animal models, metabolic derangements are most often induced by a high-fat diet (HFD) and/or diabetes mellitus via injection of alloxan or streptozotocin, but there is also a wide variety of spontaneous as well as transgenic animal models which develop metabolic derangements. Depending on the number, severity, and duration of exposure to risk factors-all these animal models show perturbations in coronary microvascular (endothelial) function and structure, similar to what has been observed in patients with INOCA and comorbid conditions. The use of these animal models will be instrumental in identifying novel therapeutic targets and for the subsequent development and testing of novel therapeutic interventions to combat ischaemic heart disease, the number one cause of death worldwide.
Topics: Animals; Cardiology; Coronary Circulation; Coronary Vessels; Disease Models, Animal; Energy Metabolism; Heart Diseases; Humans; Microcirculation; Microvessels; Nitrosative Stress; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species; Translational Research, Biomedical
PubMed: 31926020
DOI: 10.1093/cvr/cvaa002 -
International Journal of Molecular... Jun 2023Preclinical biomedical models are a fundamental tool to improve the knowledge and management of diseases, particularly in diabetes mellitus (DM) since, currently, the... (Review)
Review
Preclinical biomedical models are a fundamental tool to improve the knowledge and management of diseases, particularly in diabetes mellitus (DM) since, currently, the pathophysiological and molecular mechanisms involved in its development are not fully clarified, and there is no treatment to cure DM. This review will focus on the features, advantages and limitations of some of the most used DM models in rats, such as the spontaneous models: Bio-Breeding Diabetes-Prone (BB-DP) and LEW.1AR1-, as representative models of type 1 DM (DM-1); the Zucker diabetic fatty (ZDF) and Goto-kakizaki (GK) rats, as representative models of type 2 DM (DM-2); and other models induced by surgical, dietary and pharmacological-alloxan and streptozotocin-procedures. Given the variety of DM models in rats, as well as the non-uniformity in the protocols and the absence of all the manifestation of the long-term multifactorial complications of DM in humans, the researchers must choose the one that best suits the final objectives of the study. These circumstances, added to the fact that most of the experimental research in the literature is focused on the study of the early phase of DM, makes it necessary to develop long-term studies closer to DM in humans. In this review, a recently published rat DM model induced by streptozotocin injection with chronic exogenous administration of insulin to reduce hyperglycaemia has also been included in an attempt to mimic the chronic phase of DM in humans.
Topics: Humans; Rats; Animals; Disease Models, Animal; Streptozocin; Rats, Zucker; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2
PubMed: 37373455
DOI: 10.3390/ijms241210309 -
Laboratory Animal Research Aug 2021Diabetes mellitus, a very common and multifaceted metabolic disorder is considered as one of the fastest growing public health problems in the world. It is characterized... (Review)
Review
Diabetes mellitus, a very common and multifaceted metabolic disorder is considered as one of the fastest growing public health problems in the world. It is characterized by hyperglycemia, a condition with high glucose level in the blood plasma resulting from defects in insulin secretion or its action and in some cases both the impairment in secretion and also action of insulin coexist. Historically, animal models have played a critical role in exploring and describing malady pathophysiology and recognizable proof of targets and surveying new remedial specialists and in vivo medicines. In the present study, we reviewed the experimental models employed for diabetes and for its related complications. This paper reviews briefly the broad chemical induction of alloxan and streptozotocin and its mechanisms associated with type 1 and type 2 diabetes. Also we highlighted the different models in other species and other animals.
PubMed: 34429169
DOI: 10.1186/s42826-021-00101-4 -
Frontiers in Endocrinology 2023Various animal and cell culture models of diabetes mellitus (DM) have been established and utilized to study diabetic peripheral neuropathy (DPN). The divergence of... (Review)
Review
Various animal and cell culture models of diabetes mellitus (DM) have been established and utilized to study diabetic peripheral neuropathy (DPN). The divergence of metabolic abnormalities among these models makes their etiology complicated despite some similarities regarding the pathological and neurological features of DPN. Thus, this study aimed to review the omics approaches toward DPN, especially on the metabolic states in diabetic rats and mice induced by chemicals (streptozotocin and alloxan) as type 1 DM models and by genetic mutations (MKR, db/db and ob/ob) and high-fat diet as type 2 DM models. Omics approaches revealed that the pathways associated with lipid metabolism and inflammation in dorsal root ganglia and sciatic nerves were enriched and controlled in the levels of gene expression among these animal models. Additionally, these pathways were conserved in human DPN, indicating the pivotal pathogeneses of DPN. Omics approaches are beneficial tools to better understand the association of metabolic changes with morphological and functional abnormalities in DPN.
Topics: Humans; Mice; Rats; Animals; Diabetic Neuropathies; Diabetes Mellitus, Experimental; Sciatic Nerve; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 1
PubMed: 38089620
DOI: 10.3389/fendo.2023.1208441 -
Journal of Medicine and Life Mar 2022This study aimed to evaluate metformin as a widely used oral hypoglycemic agent and identify the effects on biochemical and antioxidant body systems of rabbits. Four...
This study aimed to evaluate metformin as a widely used oral hypoglycemic agent and identify the effects on biochemical and antioxidant body systems of rabbits. Four groups of rabbits were randomly allocated as the control, the alloxan-induced diabetic, metformin-treated, and alloxan treated with metformin. The results revealed that alloxan leads to significant elevation in glucose (Glc) levels, malondialdehyde (MDA), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), triglycerides (TGs), and total cholesterol (TCH), and a significant decline in high-density lipoprotein (HDL) and glutathione (GSH) as compared with the control group. Metformin alone caused a significant decline in Glc and HDL with significant elevation in LDL and MDA without significant changes in TCH, TGs, VLDL, and GSH. When metformin was offered as a treatment for alloxan-induced diabetic animals, it caused a significant decline in Glc, TCH, TGs, LDL, and VLDL levels with significant elevation in GSH and without a significant change in HDL and MDA. Metformin causes a decline in glucose levels due to its ability to decrease the use of substances hepatic cells use to create glucose and its ability to induce the enzymes participating in glucose oxidation.
Topics: Animals; Rabbits; Alloxan; Diabetes Mellitus, Experimental; Glutathione; Hypoglycemic Agents; Metformin
PubMed: 35450001
DOI: 10.25122/jml-2021-0417 -
BMC Medicine Sep 2022Recent studies have reported improved diastolic function in patients administered sodium-glucose cotransporter 2 inhibitors (SGLT2i). We aimed to investigate the effect...
BACKGROUND
Recent studies have reported improved diastolic function in patients administered sodium-glucose cotransporter 2 inhibitors (SGLT2i). We aimed to investigate the effect of dapagliflozin on left ventricular (LV) diastolic function in a diabetic animal model and to determine the molecular and cellular mechanisms underlying its function.
METHODS
A total of 30 male New Zealand white rabbits were randomized into control, diabetes, or diabetes+dapagliflozin groups (n = 10/per each group). Diabetes was induced by intravenous alloxan. Cardiac function was evaluated using echocardiography. Myocardial samples were obtained for histologic and molecular evaluation. For cellular evaluation, fibrosis-induced cardiomyoblast (H9C2) cells were obtained, and transfection was performed for mechanism analysis (serum and glucocorticoid-regulated kinase 1 (SGK1) signaling analysis).
RESULTS
The diabetes+dapagliflozin group showed attenuation of diastolic dysfunction compared with the diabetes group. Dapagliflozin inhibited myocardial fibrosis via inhibition of SGK1 and epithelial sodium channel (ENaC) protein, which was observed both in myocardial tissue and H9C2 cells. In addition, dapagliflozin showed an anti-inflammatory effect and ameliorated mitochondrial disruption. Inhibition of SGK1 expression by siRNA decreased and ENaC and Na+/H+ exchanger isoform 1 (NHE1) expression was confirmed as significantly reduced as siSGK1 in the diabetes+dapagliflozin group.
CONCLUSIONS
Dapagliflozin attenuated left ventricular diastolic dysfunction and cardiac fibrosis via regulation of SGK1 signaling. Dapagliflozin also reduced macrophages and inflammatory proteins and ameliorated mitochondrial disruption.
Topics: Animals; Male; Rabbits; Benzhydryl Compounds; Diabetes Mellitus; Fibrosis; Glucosides; Sodium-Glucose Transporter 2 Inhibitors
PubMed: 36068525
DOI: 10.1186/s12916-022-02485-z -
Frontiers in Immunology 2023Macrophages are central cells in mediating the inflammatory response.
INTRODUCTION
Macrophages are central cells in mediating the inflammatory response.
OBJECTIVE AND METHODS
We evaluated the effect of high glucose conditions on the inflammatory profile and the autophagy pathway in Bone-Marrow Derived Macrophages (BMDM) from diabetic (D-BMDM) (alloxan: 60mg/kg, i.v.) and non-diabetic (ND-BMDM) C57BL/6 mice. BMDM were cultured in medium with normal glucose (5.5 mM), or high glucose (25 mM) concentration and were primed with Nigericin (20µM) stimulated with LPS (100 ng/mL) at times of 30 minutes; 2; 4; 6 and 24 hours, with the measurement of IL-6, IL-1β and TNF-α cytokines.
RESULTS
We have further identified changes in the secretion of pro-inflammatory cytokines IL-6, IL-1β and TNF-α, where BMDM showed increased secretion of these cytokines after LPS + Nigericin stimulation. In addition, changes were observed in the autophagy pathway, where the increase in the autophagic protein LC3b and Beclin-1 occurred by macrophages of non-diabetic animals in hyperglycemic medium, without LPS stimulation. D-BMDM showed a reduction on the expression of LC3b and Beclin-1, suggesting an impaired autophagic process in these cells.
CONCLUSION
The results suggest that hyperglycemia alters the inflammatory pathways in macrophages stimulated by LPS, playing an important role in the inflammatory response of diabetic individuals.
Topics: Mice; Animals; Tumor Necrosis Factor-alpha; Interleukin-6; Lipopolysaccharides; Beclin-1; Nigericin; Mice, Inbred C57BL; Macrophages; Cytokines; Autophagy; Glucose
PubMed: 37122742
DOI: 10.3389/fimmu.2023.1130662 -
Cells Feb 2022Oxidative stress caused by the exposure of pancreatic ß-cells to high levels of fatty acids impairs insulin secretion. This lipotoxicity is thought to play an important...
Oxidative stress caused by the exposure of pancreatic ß-cells to high levels of fatty acids impairs insulin secretion. This lipotoxicity is thought to play an important role in ß-cell failure in type 2 diabetes and can be prevented by antioxidants. Gamma-hydroxybutyrate (GHB), an endogenous antioxidant and energy source, has previously been shown to protect mice from streptozotocin and alloxan-induced diabetes; both compounds are generators of oxidative stress and yield models of type-1 diabetes. We sought to determine whether GHB could protect mouse islets from lipotoxicity caused by palmitate, a model relevant to type 2 diabetes. We found that GHB prevented the generation of palmitate-induced reactive oxygen species and the associated lipotoxic inhibition of glucose-stimulated insulin secretion while increasing the NADPH/NADP+ ratio. GHB may owe its antioxidant and insulin secretory effects to the formation of NADPH.
Topics: Animals; Antioxidants; Diabetes Mellitus, Type 2; Islets of Langerhans; Mice; NADP; Palmitates; Sodium Oxybate
PubMed: 35159354
DOI: 10.3390/cells11030545 -
Molecules (Basel, Switzerland) May 2021Diabetic dyslipidemia and hyperglycemia contribute to excessive reactive oxygen species (ROS) production, leading to deleterious complications, such as nephropathy,...
Diabetic dyslipidemia and hyperglycemia contribute to excessive reactive oxygen species (ROS) production, leading to deleterious complications, such as nephropathy, atherosclerosis and cardiac dysfunction, and target major organs in the body. The aim of this study was to investigate the effect of caffeic acid (CA) on mouse weight and survival, serum level of fasting blood glucose (FBG), serum lipid parameters and atherogenic indices, oxidative damage in blood, liver and kidney tissue, pathophysiological changes and their function markers in healthy and alloxan-induced type 1 diabetic mice. Diabetes was induced in mice with a single intravenous injection of alloxan (75 mg kg). Two days later, CA (50 mg kg) was given intraperitoneally for seven days in diabetic mice. Diabetes affected glucose level, lipid profile, hematological and biochemical parameters, induced DNA damage and apoptotic/necrotic death in whole blood cells, liver and kidney, leading to weight loss and a decreased lifespan. CA treatment of diabetic mice revealed a protective effect on the liver and kidney, hypoglycemic and hypolipidemic properties and high protection against atherogenic outcomes. The obtained results suggest that CA is a safe and potent agent against diabetes that acts as an effective antioxidant in reducing serum glucose, lipid profile and atherogenic indices, leading to increased lifespan in mice.
Topics: Alloxan; Animals; Antioxidants; Apoptosis; Atherosclerosis; Blood Glucose; Caffeic Acids; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Erythrocytes; Hemolysis; Hyperglycemia; Hypoglycemia; Lipid Peroxidation; Lipids; Liver; Male; Mice; Necrosis; Oxidative Stress; Reactive Oxygen Species; Risk Assessment
PubMed: 34071554
DOI: 10.3390/molecules26113262 -
Lipids in Health and Disease Aug 2022Syntaxin regulates pancreatic β cell mass and participates in insulin secretion by regulating insulin exocytosis. In addition, syntaxin 4 reduces IFNγ and TNF-α...
Syntaxin regulates pancreatic β cell mass and participates in insulin secretion by regulating insulin exocytosis. In addition, syntaxin 4 reduces IFNγ and TNF-α signaling via NF-ĸB in islet β-cells that facilitates plasma glucose sensing and appropriate insulin secretion. Arachidonic acid (AA) has potent anti-inflammatory actions and prevents the cytotoxic actions of alloxan and streptozotocin (STZ) against pancreatic β cells and thus, prevents the development of type 1 diabetes mellitus (induced by alloxan and STZ) and by virtue of its anti-inflammatory actions protects against the development of type 2 diabetes mellitus (DM) induced by STZ in experimental animals that are models of type 1 and type 2 DM in humans. AA has been shown to interact with syntaxin and thus, potentiate exocytosis. AA enhances cell membrane fluidity, increases the expression of GLUT and insulin receptors, and brings about its anti-inflammatory actions at least in part by enhancing the formation of its metabolite lipoxin A4 (LXA4). Prostaglandin E2 (PGE2), the pro-inflammatory metabolite of AA, activates ventromedial hypothalamus (VMH) neurons of the hypothalamus and inhibits insulin secretion leading to reduced glucose tolerance and decreases insulin sensitivity in the skeletal muscle and liver. This adverse action of PGE2 on insulin release and action can be attributed to its (PGE2) pro-inflammatory action and inhibitory action on vagal tone (vagus nerve and its principal neurotransmitter acetylcholine has potent anti-inflammatory actions). High fat diet fed animals have hypothalamic inflammation due to chronic elevation of PGE2. Patients with type 2 DM show low plasma concentrations of AA and LXA4 and elevated levels of PGE2. Administration of AA enhances LXA4 formation without altering or reducing PGE2 levels and thus, tilts the balance more towards anti-inflammatory events. These results suggest that administration of AA is useful in the prevention and management of DM by enhancing the action of syntaxin, increasing cell membrane fluidity, and reducing VMH inflammation. Docosahexaenoic acid (DHA) has actions like AA: it increases cell membrane fluidity; has anti-inflammatory actions by enhancing the formation of its anti-inflammatory metabolites resolvins, protectins and maresins; interacts with syntaxin and enhance exocytosis in general and of insulin. But the DHA content of cell membrane is lower compared to AA and its content in brain is significant. Hence, it is likely DHA is important in neurotransmitters secretion and regulating hypothalamic inflammation. It is likely that a combination of AA and DHA can prevent DM.
Topics: Alloxan; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Diabetes Mellitus, Type 2; Dinoprostone; Docosahexaenoic Acids; Humans; Inflammation; Insulins; Qa-SNARE Proteins; Streptozocin
PubMed: 35982452
DOI: 10.1186/s12944-022-01681-3