Abstract 371: Cardiac Fibrosis is Associated With Increased Gut Barrier Leakage and Circulating Peptidoglycan in Type 2 Diabetic Mice With Ace2 Deficiency

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Ram Prasad ◽  
Prabhat Ranjan ◽  
Suresh K Verma ◽  
Maria Grant
Keyword(s):  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Fold Increase ◽  
Cardiovascular Complications ◽  
Diabetic Mice ◽  
Gut Barrier ◽  
Barrier Permeability ◽  
Junction Molecules

Purpose: Cardiac fibrosis is linked with hyperglycemia and increases the risk of cardiovascular complications and heart failure. Despite several advancements, the molecular mechanisms responsible for cardiac fibrosis in diabetes remain unclear. The renin-angiotensin system (RAS) is activated and plays an essential role in diabetes-induced cardiac dysfunctions through activation of Ang II. However, angiotensin converting enzyme 2 (ACE2), the protective arm of RAS, opposes the classical RAS functions mediated by ACE. Previously, we have reported that ACE2 deficient exacerbates hyperglycemia-induced gut dysbiosis, increased gut barrier permeability, and facilities translocation of gut microbial peptides (GMPs) into system circulation in type 1 diabetic mice. Here, we sought to determine whether dysbiosis induced by type 2 diabetes and ACE2 deficiency contributes to cardiac fibrosis. Methods: Toll-like receptor- (TLR-2) associated inflammatory signaling and cardiac fibrosis were studied in WT, db/db, and ACE2 -/y -db/db mice with 4-months of diabetes. The levels of peptidoglycan (PGN), a TLR-2 ligand, were measured by ELISA assay. The markers of gut barriers and inflammatory cytokines were assessed by immunohistochemistry and qRT-PCR. To measure cardiac fibrosis, Masson’s trichrome staining was used to stain collagen fibers. Results: ACE2 -/y -db/db mice exhibited increased myocardial fibrosis as compared with db/db and WT mice. In the myocardium, TLR-2 expression (4 folds, p<0.005) and pro-inflammatory cytokines IL-1β (p<0.001), IL-6 (p<0.0001), and TNF-α (p<0.01 were significantly up-regulated in ACE2 -/y -db/db mice compared with db/db and WT mice. Increased gut barrier permeability as detected by a reduction in expression of tight junction molecules (ZO-1, p120-catenin, and VE-cadherin) and a 2- fold increase in circulating PGN was observed in ACE2 -/y -db/db mice when compared to db/db. Conclusions: These data suggest that PGN and other circulating gut microbial particles may have a deleterious impact on cardiac health by promoting inflammation-mediated fibrosis. In addition to controlling hyperglycemia, strategies aimed at restoring gut barrier integrity may prevent diabetic cardiovascular complications.

scholarly journals Author Correction: BCG and BCGΔBCG1419c protect type 2 diabetic mice against tuberculosis via different participation of T and B lymphocytes, dendritic cells and pro-inflammatory cytokines

npj Vaccines ◽  
2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Cristian Alfredo Segura-Cerda ◽  
Brenda Marquina-Castillo ◽  
Vasti Lozano-Ordaz ◽  
Dulce Mata-Espinosa ◽  
Jorge Alberto Barrios-Payán ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Lymphocytes ◽  
Inflammatory Cytokines ◽  
T And B Lymphocytes ◽  
Diabetic Mice ◽  
Type 2 Diabetic ◽  
Pro Inflammatory Cytokines

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

scholarly journals Beneficial Effects of Potentilla discolor Bunge Water Extract on Inflammatory Cytokines Release and Gut Microbiota in High-Fat Diet and Streptozotocin-Induced Type 2 Diabetic Mice

Nutrients ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 670 ◽  
Author(s):  
Lihua Han ◽  
Tiange Li ◽  
Min Du ◽  
Rui Chang ◽  
Biyuan Zhan ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Inflammatory Cytokines ◽  
High Fat Diet ◽  
Intestinal Inflammation ◽  
Water Extract ◽  
Perennial Herb ◽  
Diabetic Mice ◽  
High Fat ◽  
Type 2 Diabetic

Potentilla discolor Bunge (PDB), a perennial herb, has been used as a traditional Chinese medicine in the therapy of many diseases. The aim of the current study was to investigate the effect of PDB water extract on systemic inflammation and gut microbiota in type 2 diabetic (T2D) mice induced by high-fat diet (HFD) and streptozotocin (STZ) injection. C57BL/6J mice were randomly divided into a normal diet (ND) group, T2D group, and PDB group (diabetic mice treated with PDB water extract at a dose of 400 mg/kg body weight). Results showed that PDB significantly decreased the levels of lipopolysaccharide (LPS) and pro-inflammatory cytokines in serum. Further investigation showed that PDB significantly reduced the ratio of Firmicutes/Bacteroidetes and the relative abundance of Proteobacteria in fecal samples of diabetic mice. In addition, PDB notably alleviated intestinal inflammation as evidenced by decreased expression of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor-κB (NF-κB), and inflammatory cytokines. PDB also reversed the decreased expression of intestinal mucosal tight junction proteins including Claudin3, ZO-1, and Occludin. Meanwhile, the levels of fecal acetic acid and butyric acid and their specific receptors including G-protein-coupled receptor (GPR) 41 and 43 expression in the colon were also increased after PDB treatment. Our results indicated that PDB might serve as a potential functional ingredient against diabetes and related inflammation.

scholarly journals Obesity and Insulin Resistance: An Abridged Molecular Correlation

2013 ◽  
Vol 6 ◽  
pp. LPI.S10805 ◽  
Author(s):  
Biswajit Mukherjee ◽  
Chowdhury M. Hossain ◽  
Laboni Mondal ◽  
Paramita Paul ◽  
Miltu K. Ghosh
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Physiological Role ◽  
Cardiovascular Complications ◽  
Vital Role ◽  
Diabetic Patients ◽  
Predisposing Factor ◽  
Main Culprit

A relationship between obesity and type 2 diabetes is now generally well accepted. This relationship represents several major health hazards including morbid obesity and cardiovascular complications worldwide. Diabetes mellitus is a complex metabolic disorder characterized by impaired insulin release and insulin resistance. Lipids play an important physiological role in skeletal muscle, heart, liver and pancreas. Deregulation of fatty acid metabolism is the main culprit for developing insulin resistance and type 2 diabetes. A predominant predisposing factor to developing obesity, insulin resistance and type 2 diabetes is the permanent elevation of free fatty acids in plasma followed by impaired utilization of lipids by muscle. Diabetes-induced inflammation and oxidative stress have also vital role for development of insulin resistance in diabetic patients. The present review is intended to describe the correlation between lipids, obesity and insulin resistance based on current literature, in order to elucidate involved molecular mechanisms in depth.

scholarly journals GW25-e3223 Urotensin II blockade with urantide attenuates cardiac fibrosis in spontaneous type 2 diabetic mice

2014 ◽  
Vol 64 (16) ◽  
pp. C22
Author(s):  
Xiao-Bo Xu ◽  
Yu-Qiang Cui ◽  
Xiao-Ying Li ◽  
Bo-Zhi Cai ◽  
Zi-Han Chen ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Diabetic Mice ◽  
Urotensin Ii ◽  
Type 2 Diabetic

scholarly journals Effects of Lespedeza Bicolor Extract on Regulation of AMPK Associated Hepatic Lipid Metabolism in Type 2 Diabetic Mice

Antioxidants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 599 ◽  
Author(s):  
Younmi Kim ◽  
Heaji Lee ◽  
Sun Yeou Kim ◽  
Yunsook Lim
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Smooth Muscle Actin ◽  
Lipid Synthesis ◽  
Hepatic Damage ◽  
Related Factor ◽  
Nuclear Factor ◽  
Diabetic Mice ◽  
Lespedeza Bicolor

Lespedeza bicolor (LB) is one of the ornamental plants used for the treatment of inflammation caused by oxidative damage. However, its beneficial effects on hyperglycemia-induced hepatic damage and the related molecular mechanisms remain unclear. We hypothesized that Lespedeza bicolor extract (LBE) would attenuate hyperglycemia-induced liver injury in type 2 diabetes mellitus (T2DM). Diabetes was induced by a low dosage of streptozotocin (STZ) injection (30 mg/kg) with a high fat diet in male C57BL/6J mice. LBE was administered orally at 100 mg/kg or 250 mg/kg for 12 weeks. LBE supplementation regardless of dosage ameliorated plasma levels of hemoglobin A1c (HbA1c) in diabetic mice. Moreover, both LBE supplementations upregulated AMP-activation kinase (AMPK), which may activate sirtuin1 (SIRT) associated pathway accompanied by decreased lipid synthesis at low dose of LBE supplementation. These changes were in part explained by reduced protein levels of oxidative stress (nuclear factor erythroid 2-related factor 2 (Nrf2) and catalase), inflammation (nuclear factor kappa B (NF-κB), interleukin-1β (IL-1β), interleukin-6 (IL-6), and nitric oxide synthases (iNOS)), and fibrosis (α-smooth muscle actin (α-SMA) and protein kinase C (PKC)) in diabetic liver. Taken together, LBE might be a potential nutraceutical to ameliorate hepatic damage by regulation of AMPK associated pathway via oxidative stress, inflammation, and fibrosis in T2DM.

scholarly journals The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin

2021 ◽  
Author(s):  
Vincenzo Quagliariello ◽  
Michelino De Laurentiis ◽  
Domenica Rea ◽  
Antonio Barbieri ◽  
Maria Gaia Monti ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Longitudinal Strain ◽  
Cardiac Fibrosis ◽  
Myocardial Strain ◽  
Radial Strain ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Intracellular Ca ◽  
Pro Inflammatory Cytokines

Abstract BackgroundEmpagliflozin, a selective inhibitor of the sodium glucose co-transporter 2, reduced the risk of hospitalization for heart failure and cardiovascular death in type 2 diabetic patients in the EMPA‐REG OUTCOME trial. Recent trials evidenced several cardio-renal benefits of empagliflozin in non-diabetic patients through the involvement of biochemical pathways that are still to be deeply analyzed . We aimed to evaluate the effects of empagliflozin on myocardial strain of non-diabetic mice treated with doxorubicin (DOXO) through the analysis of NLRP3 inflammasome and Myd88-related pathways resulting in anti-apoptotic and anti-fibrotic effects.Methods Preliminary cellular studies were performed on mouse cardiomyocytes (HL-1 cell line) exposed to doxorubicin alone or combined to empagliflozin. The following analysis were performed: determination of cell viability (through a modified MTT assay), study of intracellular ROS production, lipid peroxidation (quantifying intracellular malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed: expression of NLRP3 inflammasome, MyD88 myddosome and p65/NF-κB associated to secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin (DOXO, n=6), empagliflozin (EMPA, n=6) or doxorubicin combined to empagliflozin (DOXO-EMPA, n=6). DOXO was injected intraperitoneally. Radial and longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100). Cardiac fibrosis and apoptosis were histologically studied through Picrosirius red and TdT-mediated dUTP nick-end labelling (TUNEL) assay, respectively. Tissue NLRP3, Myd88 and cytokines were quantified after treatments.ResultsCardiomyocytes exposed to doxorubicin increased the intracellular Ca2+ content and expression of several pro-inflammatory markers associated to cell death; co-incubation with empagliflozin reduced significantly the magnitude of the effects. In preclinical study, empagliflozin prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin (radial strain (RS) 30.3 % in EMPA-DOXO vs 15.7% in DOXO mice ; longitudinal strain (LS) -17% in EMPA-DOXO vs -11,7% in DOXO mice (p<0.001 for both). A significant reduction of cardiac fibrosis and apoptosis were also seen. A reduced expression of pro-inflammatory cytokines, NLRP3, MyD88 and NF-kB in heart, liver and kidneys was also seen in DOXO-EMPA group compared to DOXO mice (p<0.001)ConclusionEmpagliflozin reduced fibrosis, apoptosis and inflammation in doxorubicin-treated mice through the involvement of NLRP3 and MyD88-related pathways, resulting in a significant improvement of myocardial strain. These findings provides the proof of concept for translational studies designed to reduce adverse cardiovascular outcomes in non-diabetic cancer patients treated with doxorubicin.

scholarly journals Targeting Inflammatory Cytokines to Improve Type 2 Diabetes Control

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Tsvetelina V. Velikova ◽  
Plamena P. Kabakchieva ◽  
Yavor S. Assyov ◽  
Tsvetoslav А. Georgiev
Keyword(s):  
Type 2 Diabetes ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Therapeutic Option ◽  
Model Studies ◽  
Abnormal Immune Response ◽  
Islet Inflammation ◽  
Cytokine Dysregulation

Type 2 diabetes (T2D) is one of the most common chronic metabolic disorders in adulthood worldwide, whose pathophysiology includes an abnormal immune response accompanied by cytokine dysregulation and inflammation. As the T2D-related inflammation and its progression were associated with the balance between pro and anti-inflammatory cytokines, anticytokine treatments might represent an additional therapeutic option for T2D patients. This review focuses on existing evidence for antihyperglycemic properties of disease-modifying antirheumatic drugs (DMARDs) and anticytokine agents (anti-TNF-α, anti-interleukin-(IL-) 6, -IL-1, -IL-17, -IL-23, etc.). Emphasis is placed on their molecular mechanisms and on the biological rationale for clinical use. Finally, we briefly summarize the results from experimental model studies and promising clinical trials about the potential of anticytokine therapies in T2D, discussing the effects of these drugs on systemic and islet inflammation, beta-cell function, insulin secretion, and insulin sensitivity.

scholarly journals Blackcurrant Improves Diabetic Cardiovascular Dysfunction by Reducing Inflammatory Cytokines in Type 2 Diabetes Mellitus Mice

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 4177
Author(s):  
Hye-Yoom Kim ◽  
Jung-Joo Yoon ◽  
Hyeon-Kyoung Lee ◽  
Ai-Lin Tai ◽  
Yun-Jung Lee ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Inflammatory Cytokines ◽  
Cardiovascular Complications ◽  
Extracellular Matrix Protein ◽  
Protein Accumulation ◽  
Cardiovascular Dysfunction ◽  
Cardiovascular Fibrosis

Diabetic cardiovascular dysfunction is a representative complication of diabetes. Inflammation associated with the onset and exacerbation of type 2 diabetes mellitus (T2DM) is an essential factor in the pathogenesis of diabetic cardiovascular complications. Diabetes-induced myocardial dysfunction is characterized by myocardial fibrosis, which includes structural heart changes, myocardial cell death, and extracellular matrix protein accumulation. The mice groups in this study were divided as follows: Cont, control (db/m mice); T2DM, type 2 diabetes mellitus mice (db/db mice); Vil.G, db/db + vildagliptin 50 mg/kg/day, positive control, dipeptidyl peptidase-4 (DPP-4) inhibitor; Bla.C, db/db + blackcurrant 200 mg/kg/day. In this study, Bla.C treatment significantly improved the homeostatic model evaluation of glucose, insulin, and insulin resistance (HOMA-IR) indices and diabetic blood markers such as HbA1c in T2DM mice. In addition, Bla.C improved cardiac function markers and cardiac thickening through echocardiography. Bla.C reduced the expression of fibrosis biomarkers, elastin and type IV collagen, in the left ventricle of a diabetic cardiopathy model. Bla.C also inhibited TD2M-induced elevated levels of inflammatory cytokines in cardiac tissue (IL-6, IL-1β, TNF-α, and TGF-β). Thus, Bla.C significantly improved cardiac inflammation and cardiovascular fibrosis and dysfunction by blocking inflammatory cytokine activation signals. This showed that Bla.C treatment could ameliorate diabetes-induced cardiovascular complications in T2DM mice. These results provide evidence that Bla.C extract has a significant effect on the prevention of cardiovascular fibrosis, inflammation, and consequent diabetes-induced cardiovascular complications, directly or indirectly, by improving blood glucose profile.

scholarly journals The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Vincenzo Quagliariello ◽  
Michelino De Laurentiis ◽  
Domenica Rea ◽  
Antonio Barbieri ◽  
Maria Gaia Monti ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Longitudinal Strain ◽  
Cardiac Fibrosis ◽  
Myocardial Strain ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Before And After ◽  
Intracellular Ca ◽  
Pro Inflammatory Cytokines

Abstract Background Empagliflozin (EMPA), a selective inhibitor of the sodium glucose co-transporter 2, reduced the risk of hospitalization for heart failure and cardiovascular death in type 2 diabetic patients in the EMPA‐REG OUTCOME trial. Recent trials evidenced several cardio-renal benefits of EMPA in non-diabetic patients through the involvement of biochemical pathways that are still to be deeply analysed. We aimed to evaluate the effects of EMPA on myocardial strain of non-diabetic mice treated with doxorubicin (DOXO) through the analysis of NLRP3 inflammasome and MyD88-related pathways resulting in anti-apoptotic and anti-fibrotic effects. Methods Preliminary cellular studies were performed on mouse cardiomyocytes (HL-1 cell line) exposed to doxorubicin alone or combined to EMPA. The following analysis were performed: determination of cell viability (through a modified MTT assay), study of intracellular ROS production, lipid peroxidation (quantifying intracellular malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studies were also performed: expression of NLRP3 inflammasome, MyD88 myddosome and p65/NF-κB associated to secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). C57Bl/6 mice were untreated (Sham, n = 6) or treated for 10 days with doxorubicin (DOXO, n = 6), EMPA (EMPA, n = 6) or doxorubicin combined to EMPA (DOXO-EMPA, n = 6). DOXO was injected intraperitoneally. Ferroptosis and xanthine oxidase were studied before and after treatments. Cardiac function studies, including EF, FS and radial/longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100). Cardiac fibrosis and apoptosis were histologically studied through Picrosirius red and TUNEL assay, respectively and quantified through pro-collagen-1α1, MMP-9 and Caspase-3 expression. Tissue NLRP3, MyD88 and cytokines were also quantified before and after treatments through ELISA methods. Results Cardiomyocytes exposed to doxorubicin increased the intracellular Ca2+ content and expression of several pro-inflammatory markers associated to cell death; co-incubation with EMPA reduced significantly the magnitude of the effects. In preclinical study, EMPA increased EF and FS compared to DOXO groups (p < 0.05), prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin (RS) 30.3% in EMPA-DOXO vs 15.7% in DOXO mice; LS − 17% in EMPA-DOXO vs – 11.7% in DOXO mice (p < 0.001 for both). Significant reductions in ferroptosis, xanthine oxidase expression, cardiac fibrosis and apoptosis in EMPA associated to DOXO were also seen. A reduced expression of pro-inflammatory cytokines, NLRP3, MyD88 and NF-kB in heart, liver and kidneys was also seen in DOXO-EMPA group compared to DOXO (p < 0.001). Conclusion EMPA reduced ferroptosis, fibrosis, apoptosis and inflammation in doxorubicin-treated mice through the involvement of NLRP3 and MyD88-related pathways, resulting in significant improvements in cardiac functions. These findings provides the proof of concept for translational studies designed to reduce adverse cardiovascular outcomes in non-diabetic cancer patients treated with doxorubicin.

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