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 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.

scholarly journals The SGLT-2 Inhibitor Empagliflozin Improves Myocardial Strain, Reduces Cardiac Fibrosis and Pro-Inflammatory Cytokines in Non-Diabetic Mice Treated With Doxorubicin

2020 ◽  
Author(s):  
Vincenzo Quagliariello ◽  
Michelino De Laurentiis ◽  
Domenica Rea ◽  
Antonio Barbieri ◽  
Maria Gaia Monti ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Inflammatory Cytokines ◽  
Longitudinal Strain ◽  
Cardiac Fibrosis ◽  
Myocardial Strain ◽  
Diabetic Patients ◽  
Diabetic Mice ◽  
Type 2 Diabetic Patients ◽  
Human Cardiomyocytes ◽  
Pro Inflammatory Cytokines

Abstract BackgroundEmpagliflozin (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. Other clinical trials evaluated beneficial effects of empagliflozin in non-diabetic patients. We aimed to evaluate the effects of empagliflozin on myocardial strain of non-diabetic mice treated with doxorubicin evaluating changes in cardiac cytokine profile, fibrosis and apoptosis. Methods Preliminary cellular studies were performed on HL-1 human cardiomyocytes exposed to doxorubicin alone or combined to empagliflozin. Reactive oxygen species, intracellular calcium homeostasis, expression of leukotrienes, NF-kB and interleukin-1β, 8 and 6 were analysed. C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin (DOXO, n=6), empagliflozin (EMPA, n=6) or doxorubicin and empagliflozin (DOXO-EMPA, n=6). Radial and longitudinal strain were analysed through transthoracic echocardiography (Vevo 2100). Cardiac fibrosis and apoptosis were studied through Picrosirius red and TdT-mediated dUTP nick-end labelling (TUNEL) assay, respectively; interleukins were quantified in tissues through ELISA.ResultsA significant increase in intracellular calcium and pro-inflammatory markers associated to pro-oxidant mediators were seen after cell exposure to doxorubicin; co-incubation with empagliflozin reduced significantly the magnitude of the effects. Oral administration of empagliflozin in mice prevented the reduction of radial and longitudinal strain during treatment with doxorubicin, reduced significantly both cardiac fibrosis and apoptosis. A reduced expression of pro-inflammatory cytokines, NLRP3 and NF-kB in heart, liver and kidney was also seen in DOXO-EMPA group (p<0.001).ConclusionEmpagliflozin reduced fibrosis, apoptosis and inflammation in doxorubicin-treated mice, enhancing significantly the 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 Silica nanoparticles induce NLRP3 inflammasome activation in human primary immune cells

2017 ◽  
Vol 23 (8) ◽  
pp. 697-708 ◽  
Author(s):  
Diana M Gómez ◽  
Silvio Urcuqui-Inchima ◽  
Juan C Hernandez
Keyword(s):  
Physicochemical Properties ◽  
Silica Nanoparticles ◽  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Deep Understanding ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Dose Dependent ◽  
Pro Inflammatory Cytokines

In recent years, the potential use of silica nanoparticles (SiNPs) among different biomedical fields has grown. A deep understanding of the physicochemical properties of nanoparticles (NPs) and their regulation of specific biological responses is crucial for the successful application of NPs. Exposure to NP physicochemical properties (size, shape, porosity, etc.) could result in deleterious effects on cellular functions, including a pro-inflammatory response mediated via activation of the NLRP3 inflammasome. The aim of this study was to evaluate the potential in vitro immunomodulatory effect of 12-nm and 200-nm SiNPs on the expression of pro-inflammatory cytokines and NLRP3 inflammasome components in human primary neutrophils and PBMCs. This study demonstrates that regardless of the size of the nanoparticles, SiNPs induce the production of pro-inflammatory cytokines in a dose-dependent manner. Induced IL-1β production after exposure to SiNPs suggests the involvement of NLRP3 inflammasome components participation in this process. In conclusion, SiNPs induce the production of pro-inflammatory cytokines in a dose-dependent manner. Furthermore, our data suggest that the production and release of IL-1β possibly occurs through the formation of the NLRP3 inflammasome.

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 Intravitreal pro-inflammatory cytokines in non-obese diabetic mice: Modelling signs of diabetic retinopathy

PLoS ONE ◽  
2018 ◽  
Vol 13 (8) ◽  
pp. e0202156 ◽  
Author(s):  
Odunayo O. Mugisho ◽  
Ilva D. Rupenthal ◽  
David M. Squirrell ◽  
Sarah J. Bould ◽  
Helen V. Danesh-Meyer ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Inflammatory Cytokines ◽  
Diabetic Mice ◽  
Pro Inflammatory Cytokines

scholarly journals Ultrastructural and cellular basis for the development of abnormal myocardial mechanics during the transition from hypertension to heart failure

2014 ◽  
Vol 306 (1) ◽  
pp. H88-H100 ◽  
Author(s):  
Sanjiv J. Shah ◽  
Gary L. Aistrup ◽  
Deepak K. Gupta ◽  
Matthew J. O'Toole ◽  
Amanda F. Nahhas ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Fibrosis ◽  
Systolic Dysfunction ◽  
Radial Strain ◽  
Hypertensive Heart Disease ◽  
Tissue Doppler ◽  
Chronic Hypertension ◽  
Myocardial Mechanics ◽  
Cellular Basis ◽  
Intracellular Ca

Although the development of abnormal myocardial mechanics represents a key step during the transition from hypertension to overt heart failure (HF), the underlying ultrastructural and cellular basis of abnormal myocardial mechanics remains unclear. We therefore investigated how changes in transverse (T)-tubule organization and the resulting altered intracellular Ca2+ cycling in large cell populations underlie the development of abnormal myocardial mechanics in a model of chronic hypertension. Hearts from spontaneously hypertensive rats (SHRs; n = 72) were studied at different ages and stages of hypertensive heart disease and early HF and were compared with age-matched control (Wistar-Kyoto) rats ( n = 34). Echocardiography, including tissue Doppler and speckle-tracking analysis, was performed just before euthanization, after which T-tubule organization and Ca2+ transients were studied using confocal microscopy. In SHRs, abnormalities in myocardial mechanics occurred early in response to hypertension, before the development of overt systolic dysfunction and HF. Reduced longitudinal, circumferential, and radial strain as well as reduced tissue Doppler early diastolic tissue velocities occurred in concert with T-tubule disorganization and impaired Ca2+ cycling, all of which preceded the development of cardiac fibrosis. The time to peak of intracellular Ca2+ transients was slowed due to T-tubule disruption, providing a link between declining cell ultrastructure and abnormal myocardial mechanics. In conclusion, subclinical abnormalities in myocardial mechanics occur early in response to hypertension and coincide with the development of T-tubule disorganization and impaired intracellular Ca2+ cycling. These changes occur before the development of significant cardiac fibrosis and precede the development of overt cardiac dysfunction and HF.

Polydatin reduces cardiotoxicity of tyrosine kinase inhibitor sunitinib by decreasing pro-oxidative stress, pro-inflammatory cytokines and NLRP3 inflammasome expression.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15065-e15065
Author(s):  
Massimiliano Berretta ◽  
Vincenzo Quagliariello ◽  
Simona Buccolo ◽  
Martina Iovine ◽  
Michelino De Laurentiis ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Growth Factors ◽  
Inflammatory Cytokines ◽  
Transcriptional Activation ◽  
Nlrp3 Inflammasome ◽  
Fetal Cardiomyocytes ◽  
Cardioprotective Effects ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

e15065 Background: : Polydatin has anticancer and anti-inflammatory properties, however no studies investigated on its putative cardioprotective effects against anticancer therapies. Sunitinib, a recently-approved, multi-targeted tyrosine kinases inhibitor, prolongs survival in patients with metastatic renal cell carcinoma and gastrointestinal stromal tumors, however a dose related cardiotoxicity was well described. We investigated on the reduction of cytokines and growth factors of polydatin resulting in putative cardioprotective effects. Methods: Human fetal cardiomyocytes were untreated (control) or treated for 48 h with polydatin (50,100,200 and 400 µM) or sunitinib (5,10,25 and 50 µM) alone or combined to polydatin. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Exposure of adult cardiomyocytes to polydatin combined to plasma-relevant concentrations of sunitinib reduces significantly intracellular reactive oxygen species, lipid peroxidation and cytochrome c release from mitochondria leading to a reduction in cell death compared to cells exposed to sunitinib alone. Polydatin reduces expression of pro-inflammatory cytokines and growth factors involved in myocardial damages and down-regulates the signaling pathway of NLRP3 inflammasome and NF-κB, increasing cellular resistance to sunitinib-mediated damages. Conclusions: Data of the present study, although in vitro, indicate that polydatin, besides reducing oxidative stress, has cardioprotective and anti-inflammatory properties, thus indicating one the mechanism(s) by which this metabolite of resveratrol might decrease sunitinib-mediated cardiotoxicity.

scholarly journals Selective inhibition of the K+ efflux sensitive NLRP3 pathway by Cl− channel modulation

2020 ◽  
Vol 11 (43) ◽  
pp. 11720-11728 ◽  
Author(s):  
Tessa Swanton ◽  
James A. Beswick ◽  
Halah Hammadi ◽  
Lucy Morris ◽  
Daniel Williams ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Selective Inhibition ◽  
Interleukin 1Β ◽  
Channel Modulation ◽  
Cl Channel ◽  
Pro Inflammatory Cytokines

The NLRP3 inflammasome regulates production of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and contributes to inflammation exacerbating disease.

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