Resveratrol and Diabetic Cardiomyopathy: Focusing on the Protective Signaling Mechanisms

Diabetic cardiomyopathy (DCM) is a common cardiovascular complication of diabetic mellitus that is characterized by diastolic disorder in the early stage and clinical heart failure in the later stage. Presently, DCM is considered one of the major causes of death in diabetic patients. Resveratrol (RSV), a naturally occurring stilbene, is widely reported as a cardioprotective substance in many heart diseases. Thus far, the specific roles of RSV in DCM prevention and treatment have attracted great attention. Here, we discuss the roles of RSV in DCM by focusing its downstream targets from both in vivo and in vitro studies. Among such targets, Sirtuins 1/3 and AMP-activated kinase have been identified as key mediators that induce cardioprotection during hyperglycemia. In addition, many other signaling molecules (e.g., forkhead box-O3a and extracellular regulated protein kinases) are also regulated in the presence of RSV and exert beneficial effects such as opposing oxidative stress, inflammation, and apoptosis in cardiomyocytes exposed to high-glucose conditions. The beneficial potential of an RSV/stem cell cotherapy is also reviewed as a promising therapeutic strategy for preventing the development of DCM.

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FGF1ΔHBS prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00542-2 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Dezhong Wang ◽

Yuan Yin ◽

Shuyi Wang ◽

Tianyang Zhao ◽

Fanghua Gong ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

Metabolic Regulation ◽

Cardiac Injury ◽

Serum Levels ◽

Ros Generation ◽

Dependent Manner ◽

Cardiac Tissues ◽

Beneficial Effects

AbstractAs a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1∆HBS) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1∆HBS treatment. Both in vivo and in vitro studies indicate that FGF1∆HBS exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5’ AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1∆HBS testify to its promising potential for use in the treatment of DCM and other metabolic disorders.

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GLP-1/GLP-1R Signaling Regulates Ovarian PCOS-Associated Granulosa Cells Proliferation and Antiapoptosis by Modification of Forkhead Box Protein O1 Phosphorylation Sites

International Journal of Endocrinology ◽

10.1155/2020/1484321 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Zhihua Sun ◽

Peiyi Li ◽

Xiao Wang ◽

Shuchang Lai ◽

Hong Qiu ◽

...

Keyword(s):

Granulosa Cells ◽

Polycystic Ovary ◽

Underlying Mechanism ◽

Therapeutic Effects ◽

Childbearing Age ◽

Beneficial Effects ◽

Forkhead Box ◽

Glucagon Like Peptide 1

As the major cause of female anovulatory infertility, polycystic ovary syndrome (PCOS) affects a great proportion of women at childbearing age. Although glucagon-like peptide 1 receptor agonists (GLP-IRAs) show therapeutic effects for PCOS, its target and underlying mechanism remains elusive. In the present study, we identified that, both in vivo and in vitro, GLP-1 functioned as the regulator of proliferation and antiapoptosis of MGCs of follicle in PCOS mouse ovary. Furthermore, forkhead box protein O1 (FoxO1) plays an important role in the courses. Regarding the importance of granulosa cells (GCs) in oocyte development and function, the results from the current study could provide a more detailed illustration on the already known beneficial effects of GLP-1RAs on PCOS and support the future efforts to develop more efficient GLP-1RAs for PCOS treatment.

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The Role of AMPK/mTOR Signaling Pathway in Anticancer Activity of Metformin

Physiological Research ◽

10.33549/physiolres.934618 ◽

2021 ◽

pp. 501-508

Author(s):

Nikola Chomanicova ◽

Andrea Gazova ◽

Adriana Adamickova ◽

Simona Valaskova ◽

Jan Kyselovic

Keyword(s):

Anticancer Activity ◽

Mammalian Target Of Rapamycin ◽

Adenosine Monophosphate ◽

Mtor Pathway ◽

Diabetic Patients ◽

Beneficial Effects ◽

Treatment Of Diabetes

Metformin (MTF) is a widely used drug for the treatment of diabetes mellitus type 2 (DM2) and frequently used as an adjuvant therapy for polycystic ovarian syndrome, metabolic syndrome, and in some cases also tuberculosis. Its protective effect on the cardiovascular system has also been described. Recently, MTF was subjected to various analyzes and studies that showed its beneficial effects in cancer treatment such as reducing cancer cell proliferation, reducing tumor growth, inducing apoptosis, reducing cancer risk in diabetic patients, or reducing likelihood of relapse. One of the MTF’s mechanisms of action is the activation of adenosine-monophosphate-activated protein kinase (AMPK). Several studies have shown that AMPK/mammalian target of rapamycin (mTOR) pathway has anticancer effect in vivo and in vitro. The aim of this review is to present the anticancer activity of MTF highlighting the importance of the AMPK/mTOR pathway in the cancer process.

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Distinct Gut Microbiota Induced by Different Fat-to-Sugar-Ratio High-Energy Diets Share Similar Pro-obesity Genetic and Metabolite Profiles in Prediabetic Mice

mSystems ◽

10.1128/msystems.00219-19 ◽

2019 ◽

Vol 4 (5) ◽

Cited By ~ 3

Author(s):

Kai Shan ◽

Hongyan Qu ◽

Keru Zhou ◽

Liangfang Wang ◽

Congmin Zhu ◽

...

Keyword(s):

Metabolic Syndrome ◽

Gut Microbiota ◽

Early Stage ◽

Amplicon Sequencing ◽

High Energy ◽

Diabetic Patients ◽

Type 2 Diabetic Patients

ABSTRACT Gut microbiota play important roles in host metabolism, especially in diabetes. However, why different diets lead to similar diabetic states despite being associated with different microbiota is not clear. Mice were fed two high-energy diets (HED) with the same energy density but different fat-to-sugar ratios to determine the associations between the microbiota and early-stage metabolic syndrome. The two diets resulted in different microbiota but similar diabetic states. Interestingly, the microbial gene profiles were not significantly different, and many common metabolites were identified, including l-aspartic acid, cholestan-3-ol (5β, 3α), and campesterol, which have been associated with lipogenesis and inflammation. Our study suggests that different metabolic-syndrome-inducing diets may result in different microbiota but similar microbiomes and metabolomes. This suggests that the metagenome and metabolome are crucial for the prognosis and pathogenesis of obesity and metabolic syndrome. IMPORTANCE Various types of diet can lead to type 2 diabetes. The gut microbiota in type 2 diabetic patients are also different. So, two questions arise: whether there are any commonalities between gut microbiota induced by different pro-obese diets and whether these commonalities lead to disease. Here we found that high-energy diets with two different fat-to-sugar ratios can both cause obesity and prediabetes but enrich different gut microbiota. Still, these different gut microbiota have similar genetic and metabolite compositions. The microbial metabolites in common between the diets modulate lipid accumulation and macrophage inflammation in vivo and in vitro. This work suggests that studies that only use 16S rRNA amplicon sequencing to determine how the microbes respond to diet and associate with diabetic state are missing vital information.

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Melatonin alleviates hyperglycemic-induced cardiomyocyte apoptosis via regulation of long non-coding RNA H19/miR-29c/MAPK axis in diabetic cardiomyopathy

10.21203/rs.3.rs-449005/v1 ◽

2021 ◽

Author(s):

Haitao Tang ◽

Hongli Zhong ◽

Wanqing Liu ◽

Tianfeng Hua ◽

Yi Wang ◽

...

Keyword(s):

Diabetic Cardiomyopathy ◽

High Glucose ◽

Diabetic Rats ◽

Cardiomyocyte Apoptosis ◽

Luciferase Assay ◽

Protective Mechanism ◽

Diabetic Patients ◽

Signal Pathways

Abstract BackgroundRecent studies revealed that non-coding RNAs (ncRNAs) play a crucial role in pathophysiological processes involving diabetic cardiomyopathy that contributes to heart failure. The present study was designed to further investigate the anti-apoptotic effect of melatonin on cardiomyocyte in diabetic condition and to elucidate the potential mechanisms associated with ncRNAs. MethodsIn vivo, langendorff-perfusion system and histology staining were used to assess the effect of melatonin on cardiac function. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to measure the expression of ncRNAs. Protein expression levels were assessed by western bolt analysis. In vitro, hoechst 33258 staining and western bolt analysis were used to evaluate the effect of melatonin on apoptosis. We preformed luciferase assay and RNA immunoprecipitation to determine the targets of ncRNAs. RT-qPCR was used to observe the expression of ncRNAs in cardiomyocyte with high glucose treatment.ResultsIn animal models, our results indicated that melatonin notably alleviated cardiac dysfunction and mitigated cardiomyocyte apoptosis in diabetic rats. Interestingly, lncRNA H19 level was increased along with concomitant decrease of miR-29c level in diabetic rats. However, we demonstrated that melatonin significantly downregulated H19 level and upregulated miR-29c level in vivo. In vitro experiments, it has been verified that positive modulation of miR-29c and inhibition of lncRNA H19 as well as mitogen-activated protein kinase (MAPK) pathways distinctly attenuated apoptosis in high glucose-treated H9c2 cells. Luciferase activity assay was conducted to evaluate the potential target sites of miR-29c on lncRNA H19 and MAPK13. LncRNA H19 silencing signiﬁcantly downregulated the expression of the miR-29c target gene MAPK13 via inducing miR-29c expression. Furthermore, MAPK signal pathways were also affected through regulation of H19 and miR-29c. Most importantly, our results showed that melatonin alleviated hyperglycemic-induced cardiomyocyte apoptosis via inhibiting lncRNA H19/MAPK and increasing miR-29c level in vitro.ConclusionsThese results elucidate a novel protective mechanism of melatonin on diabetic cardiomyocyte apoptosis, which associated with the effect of melatonin on lncRNA H19/miR-29c expression and its downstream MAPK signal pathways, providing a promising strategy for preventing DCM in diabetic patients.

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Inhibition of the Long non-coding RNA ZFAS1 attenuates pathogenic ferroptosis by sponging miR-150-5p to activate CCND2 against diabetic cardiomyopathy

10.21203/rs.3.rs-144450/v1 ◽

2021 ◽

Author(s):

Tingjuan Ni ◽

Xiaorong Chen ◽

Xingxiao Huang ◽

Sunlei Pan ◽

Zhongqiu Lu

Keyword(s):

Diabetic Cardiomyopathy ◽

Pathological Process ◽

Left Ventricular ◽

Microarray Data Analysis ◽

Luciferase Reporter ◽

Diabetic Patients ◽

Mice Model ◽

Treatment And Prevention

Abstract Background Diabetic cardiomyopathy (DCM) needs to be responsible for the increasing morbidity and mortality in diabetic patients with heart failure. Unfortunately, the pathogenesis of DCM has yet to be elaborate. Here we investigate the important role of lncRNA-ZFAS1 in the pathological process of DCM associated with ferroptosis. Methods Microarray data analysis of DCM in the patients or mice model from GEO was presented that ZFAS1 was significantly upregulated, miR-150-5p and CCND2 were significantly downregulated. High glucose (HG)-treated cardiomyocytes and db/db mice were simulated DCM in vitro and in vivo. Ad-ZFAS1, Ad-sh-ZFAS1, mimic miR-150-5p, Ad-CCND2, Ad-sh-CCND2 were injected into mice model or transfected into HG-treated Cardiomyocytes to clarify whether ZFAS1 can regulate miR-150-5p and CCND2 on ferroptosis. Effect of ZFAS1 on the left ventricular myocardial tissues in db/db mice and HG-treated cardiomyocytes, ferroptosis and apoptosis was determined by Masson staining, immunohistochemical staining, western blot, MBB staining, immunofluorescence staining and JC-1staining. The relationship among ZFAS1, miR-150-5p, CCND2 was identified by dual luciferase reporter assay and RNA Pull-down assay. Results Inhibition of ZFAS1 led to the reduced collagen deposition, decreased cardiomyocytes apoptosis, ferroptosis and attenuated the DCM progress. ZFAS1 can sponge miR-150-5p to regulate CCND2 expression. Ad-sh-ZFAS1, miR-150-5p mimic and Ad-CCND2 transfection contributed to attenuate ferroptosis and DCM both in vitro and in vivo, while transfection Ad-ZFAS1could reverse the positive effect of miR-150-5p mimic and Ad-CCND2 both in vitro and in vivo. Conclusion lncRNA-ZFAS1 acted as a ceRNA to sponge miR-150-5p can regulate CCND2 to promote cardiomyocytes ferroptosis and developed DCM, and inhibition of ZFAS1 could be a promising therapeutic target for the treatment and prevention of DCM.

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Regenerative Medicine and Angiogenesis; Focused on Cardiovascular Disease

Advanced Pharmaceutical Bulletin ◽

10.34172/apb.2022.072 ◽

2021 ◽

Author(s):

Seyed Zachariah Moradi ◽

Faramarz Jalili ◽

Zohreh Hoseinkhani ◽

Kamran Mansouri

Keyword(s):

Cardiovascular Disease ◽

Early Stage ◽

In Vitro Models ◽

Early Stage Disease ◽

Surgical Interventions ◽

Beneficial Effects ◽

Regeneration Medicine ◽

Affected Tissue

Cardiovascular disease (CVD) is a major concern for health with high mortality rates around the world. CVD is often associated with partial or full occlusion of the blood vessel network. Changes in lifestyle can be useful for management early-stage disease but in the advanced stage, surgical interventions or pharmacological are needed to increase the blood flow through the affected tissue or to reduce the energy requirements. Regeneration medicine is a new science that has provided many different options for treating various diseases, especially in CVD over the years. Stem cell therapy, gene therapy, and tissue engineering are some of the powerful branches of the field that have given patients great hope in improving their condition. In this review, we attempted to examine the beneficial effects, challenges, and contradictory effects of angiogenesis in vivo, and in vitro models’ studies of CVD. We hope that this information will be able to help other researchers to design new effective structures and open new avenues for the treatment of CVD with the help of angiogenesis and regeneration medicine in the future.

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Oleanolic acid derivative HA-20 inhibits adipogenesis in a manner involving PPARγ-FABP4/aP2 pathway

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0075 ◽

2021 ◽

Author(s):

Jie Wang ◽

Yuchao Zhang ◽

Qi Shen ◽

Jing Wu ◽

Jian-Xin Li

Keyword(s):

Oleanolic Acid ◽

Early Stage ◽

Heart Diseases ◽

The Body ◽

In Vivo Studies ◽

Lipid Lowering ◽

In Vitro Assays ◽

Mechanism Study

Obesity is a chronic disease that increases the risk of type II diabetes, heart diseases and nonalcoholic fatty liver disease. Unfortunately, to date, only handful of drugs are approved for clinical use. This study aims at discovery of anti-obesity agents based on naturally sourced oleanolic acid (OA) derivatives. 3T3-L1 preadipocytes were differentiated into mature adipocytes for in vitro assays, and a high fat diet (HFD) induced obesity mice model was established for in vivo studies. The screening of the OA derivatives was performed with 3T3-L1 cell, and resulted in a discovery of a novel compound HA-20 with a potent inhibitory activity on 3T3-L1 adipogenesis. In vitro data demonstrated that HA-20 markedly suppressed the adipogenesis in 3T3-L1 at the early stage without cytotoxicity. In vivo research using HFD mice revealed that HA-20 lowered the body weight, and possessed a lipid-lowering effect. Transcriptome analysis discovered that the mainly adipogenesis/lipogenesis genes regulated by HA-20 were PPARγ, C/EBPα, Fas, ACC, and Fabp4/aP2. Mechanism study revealed that HA-20 played its bioactive roles at least via downregulating PPARγ-FABP4/aP2 pathway in 3T3-L1, which was further confirmed in HFD induced obesity mice. Our findings provided a new insight into fighting fat accumulation based on OA derivatives, and demonstrated that HA-20 may sever as a worthy leading compound for further development of anti-obesity agents.

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Pharmacological Macrophage Attenuation by Imatinib Reverts Hepatic Steatosis and Inflammation in Obese Mice

10.1101/241224 ◽

2017 ◽

Author(s):

Shefaa AlAsfoor ◽

Theresa V. Rohm ◽

Angela J. T. Bosch ◽

Thomas Dervos ◽

Diego Calabrese ◽

...

Keyword(s):

Hepatic Steatosis ◽

Immune Modulation ◽

Diabetic Patients ◽

Human Monocytes ◽

Obese Mice ◽

Alcoholic Fatty Liver ◽

Murine Macrophages ◽

Beneficial Effects

AbstractAimsNon-alcoholic fatty liver disease (NAFLD) has become one of the most common liver diseases worldwide. As macrophages play a key role in NAFLD, therapies targeting macrophages have been postulated. Indeed, strategies depleting macrophages or blocking monocyte recruitment into the liver improve NAFLD, however, are not feasible in clinical practice. Our goal was to assess whether attenuation of macrophages can be achieved by imatinib, an anti-leukemia drug with known anti-inflammatory and anti-diabetic properties, and how this impacts NAFLD.Materials and MethodsMurine macrophages were polarized in vitro to different activation states in the presence or absence of imatinib; mice on high fat diet orally treated with imatinib or vehicle; and human monocytes of diabetic patients and healthy controls treated with or without imatinib for translational application.ResultsImatinib specifically attenuated pro-inflammatory murine macrophages in vitro and in vivo. In livers of obese mice, imatinib caused Kupffer cells to adopt an attenuated phenotype via modulation of the TNFα-pathway. This immune-modulation resulted in markedly improved hepatic steatosis along with beneficial effects on liver function, lipids and systemic inflammation. The immune-dampening effect of imatinib also prevailed in human monocytes, indicating translational applicability.ConclusionsImmune-modulation of myeloid cells as exemplified by imatinib may be a novel therapeutic strategy in patients with NAFLD.

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Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.19.6410 ◽

2009 ◽

Vol 27 (20) ◽

pp. 3297-3302 ◽

Cited By ~ 568

Author(s):

Sao Jiralerspong ◽

Shana L. Palla ◽

Sharon H. Giordano ◽

Funda Meric-Bernstam ◽

Cornelia Liedtke ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Early Stage ◽

Pathologic Complete Response ◽

Complete Response ◽

Multivariate Logistic Regression Model ◽

Diabetic Patients ◽

Incidence And Mortality

Purpose Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this. Our purpose was to determine whether metformin use was associated with a change in pathologic complete response (pCR) rates in diabetic patients with breast cancer receiving neoadjuvant chemotherapy. Patients and Methods We identified 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. Patients were compared by groups: 68 diabetic patients taking metformin, 87 diabetic patients not taking metformin, and 2,374 nondiabetic patients. pCR rates were compared between the three groups using χ2 tests of independence and compared pair- wise using a binomial test of proportions. Factors predictive of pCR were assessed using a multivariate logistic regression model. Results The rate of pCR was 24% in the metformin group, 8.0% in the nonmetformin group, and 16% in the nondiabetic group (P = .02). Pairwise comparisons between the metformin and nonmetformin groups (P = .007) and the nonmetformin and nondiabetic groups (P = .04) were significant. Comparison of the pCR rates between the metformin and nondiabetic groups trended toward but did not meet significance (P = .10). Metformin use was independently predictive of pCR (odds ratio, 2.95; P = .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use. Conclusion Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.

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