Bile Acids and Farnesoid X Receptor: Novel Target for the Treatment of Diabetic Cardiomyopathy

Diabetes mellitus (DM) has become an increasingly common disease with high disability and mortality rates. Diabetes complications are the main cause of diabetes death and about 50% of diabetic patients died from heart disease in developed countries reported by World Health Organization. Diabetic cardiomyopathy (DCM) has been considered as a high incidence and serious complication of DM and plays a key role in the incidence and development of diabetes related heart failure. Metabolism dysregulation is regarded as an important and earlier factor occurred in the pathogenesis of DCM. Insulin resistance, oxidative stress, inflammation and mitochondrial dysfunction also contribute to the development of DCM. Farnesoid X Receptor (FXR) is a member of nuclear receptor superfamily, and plays a critical role in regulating lipid and glucose metabolism, oxidative stress and inflammation. FXR is activated by primary bile acids (BAs) such as chenodeoxycholic acid, cholic acid and synthetic agonists such as obeticholic acid. BAs are the main active ingredients of many natural products and traditional medicines, especially bile or gallstones in animals, such as calculus bovis. Due to the regulatory effect of FXR on glucose and lipid metabolism, oxidative stress and inflammation, the treatment of BAs and FXR agonists for metabolic syndrome and DCM have gained more attention. This review will focus on the pathogenesis of diabetic cardiomyopathy and the regulatory effect of BAs and FXR on DCM.

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Susceptibility to oxidative stress, insulin resistance, and insulin secretory response in the development of diabetes from obesity

Vojnosanitetski pregled ◽

10.2298/vsp0706391k ◽

2007 ◽

Vol 64 (6) ◽

pp. 391-397 ◽

Cited By ~ 9

Author(s):

Radivoj Kocic ◽

Dusica Pavlovic ◽

Gordana Kocic ◽

Milica Pesic

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Lipid Peroxidation ◽

Insulin Sensitivity ◽

Healthy Subjects ◽

Critical Role ◽

Secretory Response ◽

Diabetic Patients ◽

Apparent Difference ◽

Insulin Secretory Response

Background/Aim. Oxidative stress plays a critical role in the pathogenesis of various diseases. Recent reports indicate that obesity may induce systemic oxidative stress. The aim of the study was to potentiate oxidative stress as a factor which may aggravate peripheral insulin sensitivity and insulinsecretory response in obesity in this way to potentiate development of diabetes. The aim of the study was also to establish whether insulin-secretory response after glucagonstimulated insulin secretion is susceptible to prooxidant/ antioxidant homeostasis status, as well as to determine the extent of these changes. Methods. A mathematical model of glucose/insulin interactions and C-peptide was used to indicate the degree of insulin resistance and to assess their possible relationship with altered antioxidant/prooxidant homeostasis. The study included 24 obese healthy and 16 obese newly diagnozed non-insulin dependent diabetic patients (NIDDM) as well as 20 control healthy subjects, matched in age. Results. Total plasma antioxidative capacity, erythrocyte and plasma reduced glutathione level were significantly decreased in obese diabetic patients, but also in obese healthy subjects, compared to the values in controls. The plasma lipid peroxidation products and protein carbonyl groups were significantly higher in obese diabetics, more than in obese healthy subjects, compared to the control healthy subjects. The increase of erythrocyte lipid peroxidation at basal state was shown to be more pronounced in obese daibetics, but the apparent difference was obtained in both the obese healthy subjects and obese diabetics, compared to the control values, after exposing of erythrocytes to oxidative stress induced by H2O2. Positive correlation was found between the malondialdehyde (MDA) level and index of insulin sensitivity (FIRI). Conclusion. Increased oxidative stress together with the decreased antioxidative defence seems to contribute to decreased insulin sensitivity and impaired insulin secretory response in obese diabetics, and may be hypothesized to favour the development of diabetes during obesity.

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Evaluation of the Therapeutic Effectiveness of Combined Action Antiallergic Drugs in Monotherapy of Allergic Conjunctivitis

Ophthalmology in Russia ◽

10.18008/1816-5095-2020-1-117-123 ◽

2020 ◽

Vol 17 (1) ◽

pp. 117-123

Author(s):

N. G. Zumbulidze ◽

V. M. Khokkanen ◽

I. B. Litvin

Keyword(s):

Allergic Conjunctivitis ◽

Systemic Exposure ◽

Local Therapy ◽

Allergic Diseases ◽

Developed Countries ◽

World Health ◽

Common Disease ◽

Ophthalmic Manifestations ◽

The World ◽

Health Organization

According to statistical studies in recent decades, there has been an increase of allergic diseases in most countries of the world. Predisposing factors are the deterioration of the environmental situation, the total “chemicalization” of life and the forced use of drugs. Twenty years ago, the World Health Organization called the new century “the century of allergies” and the disease itself as an “epidemic”. As time has shown, these forecasts have come true: from 2001 to 2010, the number of allergic people in the world increased by 20 % and many of these patients suffer from ophthalmic manifestations of the pathology: the eyes are involved in the process in almost every second case. This is due to the fact that the eyes are directly exposed to the environment and a variety of external allergens. The most common disease of an eye-allergic nature is allergic conjunctivitis: approximately 15 % of the total population of economically developed countries suffer from it. Allergic blepharitis, eyelid dermatitis, keratitis, iritis, uveitis, retinitis and optic neuritis are much less common. The following manifestations are typical for allergic conjunctivitis: burning, lacrimation, pruritus, hyperemia of the eyelids and conjunctiva, photophobia. In the case of a transition to a chronic form, pronounced tissue changes are observed. Therefore, timely diagnosis and effective treatment certainly have a positive effect on the quality of life of the patient and the course of the disease. The treatment of patients with allergic conjunctivitis, first of all, consists in the maximum possible restriction of contact with the allergen. During desensitizing therapy, local and general drugs are used. Numerous studies have proven the advantage of targeted and effective antiallergic local therapy compared with systemic exposure. Currently used local ophthalmic antiallergic drugs belonging to various groups. The tactics of their use is determined by the acuity, severity and etiology of the process. When choosing a drug, in some cases, you should focus on the presence of substances that provide a double mechanism of action: a pronounced antihistamine activity in combination with the stabilization properties of mast cells, which has a quick and long therapeutic effect. This study evaluated efficacy of Vizallergol (olopatadin 0.2 %) application in cases of allergic conjunctivitis in 239 patients was evaluated. The medication arrested the symptoms of allergic conjunctivitis in 89 % of patients, at that the mean period of treatment made 10.7 ± 0.3 days. In the treatment of allergic conjunctivitis, the therapeutic efficacy of Vizallergol 0.2 % was comparable to opatanol 0.1 % and was found to be more comfortable for most patients due to the convenience of a single use.

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Oral Health Problems of Diabetic Patients

Bangladesh Journal of Dental Research & Education ◽

10.3329/bjdre.v3i2.16610 ◽

2013 ◽

Vol 3 (2) ◽

pp. 29-35

Author(s):

S Mahbub ◽

S Ferdouse ◽

MH Zaman

Keyword(s):

Health Status ◽

Oral Health ◽

Family Income ◽

Dental Health ◽

Developed Countries ◽

Health Problems ◽

Oral Health Status ◽

World Health ◽

Diabetic Patients ◽

Cross Sectional

The worldwide estimated prevalence of Diabetes Mellitus is 4.6% in 20-79 year aged population. In 1985, an estimated 30 million people worldwide had diabetes. The World Health Organization warns diabetes will reach epidemic with 300 million by 2025.The prevalence of diabetes is the highest in developed countries but developing countries are expected to have the largest increase in next decade.1 Uncontrolled diabetes leads to soreness, ulcers, infections and tooth decay and decrease oral health status.3 Objective: To assess oral health status among the diabetic patients in dental department of BIRDEM. Methods: It was a cross sectional type of descriptive study conducted among 110 patients for 6 months period. Data were collected using questionnaire and oral examination checklist. SPSS software was used for data analysis. Results: Males were 61.8% and 32.7% were in 40-50 years age group, post-graduate educated were 47.3%, 40.9% were employed in job and monthly family income was taka >20000. The highest 31.8% were diabetic for 3-10 years and 47.3% were under control. Regularly 85.5% patients checked blood sugar and followed the advice. Oral hypoglycemic was taken by 60.9% patients and followed diabetic diet 76.4%. Dental health problems developed in 44.5% diabetes patients, 41.8% developed Gum Swelling, 22.7% Bleeding during brushing teeth, 16.4% Bad breath, 16.4% had Pain and 2.7% having loosening their teeth. Both grade 3 gingivitis and grade 2 periodontitis were found in 34.5%. Maximum 48.2% visited dental surgeon. Conclusion: Regular dental care is particularly important for people with diabetes. DOI: http://dx.doi.org/10.3329/bjdre.v3i2.16610 Bangladesh Journal of Dental Research & Education Vol.3(2) 2013: 29-35

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Oxidative Stress and Diabetic Retinopathy

Experimental Diabetes Research ◽

10.1155/2007/43603 ◽

2007 ◽

Vol 2007 ◽

pp. 1-12 ◽

Cited By ~ 227

Author(s):

Renu A. Kowluru ◽

Pooi-See Chan

Keyword(s):

Oxidative Stress ◽

Clinical Trials ◽

Animal Studies ◽

Antioxidant Defense System ◽

Oxygen Metabolism ◽

Developed Countries ◽

Causal Link ◽

Diabetic Patients ◽

Metabolic Abnormalities ◽

Beneficial Effects

Oxygen metabolism is essential for sustaining aerobic life, and normal cellular homeostasis works on a fine balance between the formation and elimination of reactive oxygen species (ROS). Oxidative stress, a cytopathic consequence of excessive production of ROS and the suppression of ROS removal by antioxidant defense system, is implicated in the development of many diseases, including Alzheimer's disease, and diabetes and its complications. Retinopathy, a debilitating microvascular complication of diabetes, is the leading cause of acquired blindness in developed countries. Many diabetes-induced metabolic abnormalities are implicated in its development, and appear to be influenced by elevated oxidative stress; however the exact mechanism of its development remains elusive. Increased superoxide concentration is considered as a causal link between elevated glucose and the other metabolic abnormalities important in the pathogenesis of diabetic complications. Animal studies have shown that antioxidants have beneficial effects on the development of retinopathy, but the results from very limited clinical trials are somewhat ambiguous. Although antioxidants are being used for other chronic diseases, controlled clinical trials are warranted to investigate potential beneficial effects of antioxidants in the development of retinopathy in diabetic patients.

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The Potential Role of Flavonoids in Ameliorating Diabetic Cardiomyopathy via Alleviation of Cardiac Oxidative Stress, Inflammation and Apoptosis

International Journal of Molecular Sciences ◽

10.3390/ijms22105094 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5094

Author(s):

Fatin Farhana Jubaidi ◽

Satirah Zainalabidin ◽

Izatus Shima Taib ◽

Zariyantey Abd Hamid ◽

Siti Balkis Budin

Keyword(s):

Oxidative Stress ◽

Risk Factors ◽

Diabetic Cardiomyopathy ◽

Mortality Risk ◽

Potential Role ◽

Therapeutic Potential ◽

Biological Activities ◽

Diabetic Patients ◽

Remedial Actions

Diabetic cardiomyopathy is one of the major mortality risk factors among diabetic patients worldwide. It has been established that most of the cardiac structural and functional alterations in the diabetic cardiomyopathy condition resulted from the hyperglycemia-induced persistent oxidative stress in the heart, resulting in the maladaptive responses of inflammation and apoptosis. Flavonoids, the most abundant phytochemical in plants, have been reported to exhibit diverse therapeutic potential in medicine and other biological activities. Flavonoids have been widely studied for their effects in protecting the heart against diabetes-induced cardiomyopathy. The potential of flavonoids in alleviating diabetic cardiomyopathy is mainly related with their remedial actions as anti-hyperglycemic, antioxidant, anti-inflammatory, and anti-apoptotic agents. In this review, we summarize the latest findings of flavonoid treatments on diabetic cardiomyopathy as well as elucidating the mechanisms involved.

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Abstract 16563: FOXO1 Induces Cardiomyocyte-KLF5, Which Drives Oxidative Stress and Diabetic Cardiomyopathy

Circulation ◽

10.1161/circ.142.suppl_3.16563 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Ioannis D Kyriazis ◽

Matthew K Hoffman ◽

Lea Gaignebet ◽

Anna Maria Lucchese ◽

Chao Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Constitutive Expression ◽

Diabetic Patients ◽

Mrna Levels ◽

Dependent Manner ◽

Lipid Species ◽

Ceramide Accumulation ◽

Klf5 Expression

Introduction: Cardiomyopathy in type 1 diabetes (T1D) is accompanied by impaired mitochondrial function, oxidative stress and lipotoxicity. We showed that cardiomyocyte (CM) Krüppel-like factor 5 (KLF5) is increased in streptozotocin-induced T1D and induces Peroxisome Proliferator Activated Receptor (PPAR)α in mice. Hypothesis: KLF5 upregulation by FOXO1 induces diabetic cardiomyopathy (DbCM). Methods and Results: Analyses in CM from diabetic patients showed higher KLF5 mRNA levels compared to non-diabetic individuals. In vitro mechanistic and in vivo analyses in αMHC- Foxo1 -/- mice revealed that FOXO1 stimulates KLF5 expression via direct promoter binding. Genetic inhibition of CM FOXO1 alleviated DbCM. Additionally, AAV-mediated CM-specific KLF5 overexpression in C57Bl/6 (WT) mice induced cardiac dysfunction. Mice with CM-specific KLF5 constitutive expression (αMHC-rtTA- Klf5 ), which we generated, recapitulated cardiomyopathy without T1D. Moreover, Pparα -/- mice with T1D, had higher CM-KLF5 levels and developed DbCM, suggesting that KLF5-driven DbCM is PPARα-independent. Additionally, CM-KLF5 induced oxidative stress through increased NADPH oxidase (NOX)4 expression and lower mitochondria abundance. Conversely, KLF5 inhibition prevented NOX4 upregulation and superoxide formation. Furthermore, CM-KLF5 promoted NOX4 expression via direct promoter binding. Antioxidant treatment in diabetic WT and αMHC-rtTA- Klf5 mice alleviated cardiac dysfunction partially, suggesting other pathways that contribute in KLF5-induced DbCM. For that, we performed cardiac lipidome analysis where we found clustering of αMHC-rtTA- Klf5 with diabetic WT mice. Of note, KLF5 inhibition in diabetic mice resulted in similar lipidome with non-diabetic WT mice. Individual lipid species analysis showed increased ceramide accumulation in diabetic WT and αMHC-rtTA- Klf5 mice that was reversed upon KLF5 inhibition. Thus, CM-KLF5 activation correlates with cardiac ceramide accumulation, that has been associated with cardiac lipotoxicity. Conclusions: In conclusion, T1D stimulates FOXO1, which induces CM-KLF5 expression that leads to oxidative stress and DbCM in a non-PPARα-dependent manner, as well as to cardiac ceramide accumulation.

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Role of Oxidative Stress in Metabolic and Subcellular Abnormalities in Diabetic Cardiomyopathy

International Journal of Molecular Sciences ◽

10.3390/ijms21072413 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2413 ◽

Cited By ~ 2

Author(s):

Naranjan S. Dhalla ◽

Anureet K. Shah ◽

Paramjit S. Tappia

Keyword(s):

Oxidative Stress ◽

Diabetic Cardiomyopathy ◽

Cardiac Dysfunction ◽

Critical Role ◽

Renin Angiotensin System ◽

High Energy ◽

Diabetic Heart ◽

Therapeutic Approaches ◽

Angiotensin System

Although the presence of cardiac dysfunction and cardiomyopathy in chronic diabetes has been recognized, the pathophysiology of diabetes-induced metabolic and subcellular changes as well as the therapeutic approaches for the prevention of diabetic cardiomyopathy are not fully understood. Cardiac dysfunction in chronic diabetes has been shown to be associated with Ca2+-handling abnormalities, increase in the availability of intracellular free Ca2+ and impaired sensitivity of myofibrils to Ca2+. Metabolic derangements, including depressed high-energy phosphate stores due to insulin deficiency or insulin resistance, as well as hormone imbalance and ultrastructural alterations, are also known to occur in the diabetic heart. It is pointed out that the activation of the sympathetic nervous system and renin–angiotensin system generates oxidative stress, which produces defects in subcellular organelles including sarcolemma, sarcoplasmic reticulum and myofibrils. Such subcellular remodeling plays a critical role in the pathogenesis of diabetic cardiomyopathy. In fact, blockade of the effects of neurohormonal systems has been observed to attenuate oxidative stress and occurrence of subcellular remodeling as well as metabolic abnormalities in the diabetic heart. This review is intended to describe some of the subcellular and metabolic changes that result in cardiac dysfunction in chronic diabetes. In addition, the therapeutic values of some pharmacological, metabolic and antioxidant interventions will be discussed. It is proposed that a combination therapy employing some metabolic agents or antioxidants with insulin may constitute an efficacious approach for the prevention of diabetic cardiomyopathy.

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Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation

Physiological Reviews ◽

10.1152/physrev.00010.2008 ◽

2009 ◽

Vol 89 (1) ◽

pp. 147-191 ◽

Cited By ~ 898

Author(s):

Philippe Lefebvre ◽

Bertrand Cariou ◽

Fleur Lien ◽

Folkert Kuipers ◽

Bart Staels

Keyword(s):

Cardiovascular Disease ◽

Metabolic Syndrome ◽

Bile Acids ◽

Disease Risk ◽

Critical Role ◽

Elevated Serum ◽

Farnesoid X Receptor ◽

The Metabolic Syndrome ◽

Increased Risk

The incidence of the metabolic syndrome has taken epidemic proportions in the past decades, contributing to an increased risk of cardiovascular disease and diabetes. The metabolic syndrome can be defined as a cluster of cardiovascular disease risk factors including visceral obesity, insulin resistance, dyslipidemia, increased blood pressure, and hypercoagulability. The farnesoid X receptor (FXR) belongs to the superfamily of ligand-activated nuclear receptor transcription factors. FXR is activated by bile acids, and FXR-deficient ( FXR−/−) mice display elevated serum levels of triglycerides and high-density lipoprotein cholesterol, demonstrating a critical role of FXR in lipid metabolism. In an opposite manner, activation of FXR by bile acids (BAs) or nonsteroidal synthetic FXR agonists lowers plasma triglycerides by a mechanism that may involve the repression of hepatic SREBP-1c expression and/or the modulation of glucose-induced lipogenic genes. A cross-talk between BA and glucose metabolism was recently identified, implicating both FXR-dependent and FXR-independent pathways. The first indication for a potential role of FXR in diabetes came from the observation that hepatic FXR expression is reduced in animal models of diabetes. While FXR−/−mice display both impaired glucose tolerance and decreased insulin sensitivity, activation of FXR improves hyperglycemia and dyslipidemia in vivo in diabetic mice. Finally, a recent report also indicates that BA may regulate energy expenditure in a FXR-independent manner in mice, via activation of the G protein-coupled receptor TGR5. Taken together, these findings suggest that modulation of FXR activity and BA metabolism may open new attractive pharmacological approaches for the treatment of the metabolic syndrome and type 2 diabetes.

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The farnesoid X receptor modulates renal lipid metabolism and diet-induced renal inflammation, fibrosis, and proteinuria

AJP Renal Physiology ◽

10.1152/ajprenal.00404.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. F1587-F1596 ◽

Cited By ~ 90

Author(s):

Xiaoxin X. Wang ◽

Tao Jiang ◽

Yan Shen ◽

Luciano Adorini ◽

Mark Pruzanski ◽

...

Keyword(s):

Oxidative Stress ◽

Growth Factors ◽

Lipid Metabolism ◽

Lipid Accumulation ◽

Regulatory Element ◽

Critical Role ◽

Farnesoid X Receptor ◽

Mesangial Expansion ◽

Triglyceride Accumulation ◽

Podocyte Loss

Diet-induced obesity is associated with proteinuria and glomerular disease in humans and rodents. We have shown that in mice fed a high-fat diet, increased renal expression of the transcriptional factor sterol-regulatory element binding protein-1 (SREBP-1) plays a critical role in renal lipid accumulation and increases the activity of proinflammatory cytokines and profibrotic growth factors. In the current study, we have determined a key role of the farnesoid X receptor (FXR) in modulating renal SREBP-1 activity, glomerular lesions, and proteinuria. We found that feeding a Western-style diet to DBA/2J mice results in proteinuria, podocyte loss, mesangial expansion, renal lipid accumulation, and increased expression of proinflammatory factors, oxidative stress, and profibrotic growth factors. Treatment of these mice with the highly selective and potent FXR-activating ligand 6-α-ethyl-chenodeoxycholic acid (INT-747) ameliorates triglyceride accumulation by modulating fatty acid synthesis and oxidation, improves proteinuria, prevents podocyte loss, mesangial expansion, accumulation of extracellular matrix proteins, and increased expression of profibrotic growth factors and fibrosis markers, and modulates inflammation and oxidative stress. Our results therefore indicate that FXR activation could represent an effective therapy for treatment of abnormal renal lipid metabolism with associated inflammation, oxidative stress, and kidney pathology in patients affected by obesity.

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Ultrasound-targeted Microbubble Destruction Promotes Myocardial Angiogenesis and Functional Improventments in Rat Model of Diabetic Cardiomyopathy

10.21203/rs.3.rs-33215/v1 ◽

2020 ◽

Author(s):

Xijun Zhang ◽

Haohui Zhu ◽

Nanqian Zhou ◽

Zhixin Fang ◽

Yuping Yang ◽

...

Keyword(s):

Protective Effect ◽

Diabetic Cardiomyopathy ◽

Rat Model ◽

Critical Role ◽

Therapeutic Angiogenesis ◽

Diabetic Patients ◽

Therapeutic Effects ◽

Novel Approach ◽

Cardiac Functions ◽

Cycle Group

Abstract Objective: Microvascular insufficiency takes a critical role in the development of diabetic cardiomyopathy (DCM), therapeutic angiogenesis has been mainly used for the treatment of ischemic diseases. The present study sought to investigate the preclinical performance of SonoVue microbubbles(MBs) combined ultrasound(US) treatment on myocardial angiogenesis in a rat model of DCM and investigate the optimal ultrasonic parameters.Methods and Results: After the DCM model was established, the cardio protective effect of SonoVue MBs using US techniques was examined by histology, morphometry, and echocardiography evaluations. From morphologic observation and echocardiography, the DCM rats had a set of structural abnormalities in the heart compared to the normal rats. The US-MB groups exerted cardio protective effect in DCM rats, improved reparative neovascularization and increased cardiac perfusion, while the 26 cycle group showed significantly therapeutic effects on the cardiac functions in DCM rats.Conclusion: This strategy using SonoVue MB and US can significantly improve or even reverse cardiac dysfunction and pathological abnormalities, especially using the 26 cycle parameters. Under further study, this combined strategy might provide a novel approach for early intervention of DCM in diabetic patients.

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