Sodium-glucose cotransporter 2 inhibitor Dapagliflozin prevents ejection fraction reduction, reduces myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity DOI Creative Commons
Vincenzo Quagliariello,

Maria Laura Canale,

Irma Bisceglia

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: July 18, 2023

Abstract Background Anthracycline-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in cancer patients. Cardioprotective strategies primary secondary prevention still needed clinical practice to improve patient survival avoid drug therapy discontinuation. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exerts multiple cardiometabolic benefits patients with/without type diabetes, chronic kidney disease heart failure with reduced preserved ejection fraction. We hypothesized that Dapagliflozin, an SGLT2i. administered before during doxorubicin therapy, could cardiac function reduce pro-inflammatory pathways preclinical models. Methods Female C57Bl/6 mice were treated a saline solution (Saline, n = 6) or for 10 days i.p at 2.17 mg/kg (DOXO, 6), DAPA (DAPA, combined (DOXO-DAPA, 6). Ejection fraction, radial longitudinal strain analysed through transthoracic echocardiography (Vevo 2100). Cardiac troponin, BNP NT-pro-BNP quantified. Myocardial expression NLRP-3 inflammasome MyD-88 quantified selective ELISA methods. Systemic levels ferroptosis-related biomarkers (MDA 4-HNA), Galectin-3, hs-CRP chemokines/growth factors (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, GM-CSF) After treatments, immunohistochemical (IHC) staining myocardial renal p65/NF-kB was performed. Results prevented reduction fraction after treatment doxorubicin. A seen DOXO-DAPA group compared DOXO (p < 0.001). G-CSF GM-CSF significantly DAPA, indicating anti-inflammatory properties. Serum galectine-3 strongly enhanced group; contrary, their DAPA-DOXO 0.005). Biomarkers cardiotoxicity, troponin-T, group, revealing cardioprotective properties SGLT2-i. The Saline distinctly different, associated larger reductions tissue than DOXO. Conclusion is able systemic involved inflammation. IHC analysis clearly indicates tissues therapy. overall picture study encourages use cardiomyopathies induced by anthracyclines

Language: Английский

Diabetes mellitus: Classification, mediators, and complications; A gate to identify potential targets for the development of new effective treatments DOI Open Access
Samar A. Antar,

Nada A. Ashour,

Marwa Sharaky

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115734 - 115734

Published: Oct. 17, 2023

Nowadays, diabetes mellitus has emerged as a significant global public health concern with remarkable increase in its prevalence. This review article focuses on the definition of and classification into different types, including type 1 (idiopathic fulminant), 2 diabetes, gestational hybrid forms, slowly evolving immune-mediated ketosis-prone other special types. Diagnostic criteria for are also discussed. The role inflammation both is explored, along mediators potential anti-inflammatory treatments. Furthermore, involvement various organs highlighted, such adipose tissue obesity, gut microbiota, pancreatic β-cells. manifestation Langerhans β-cell islet inflammation, oxidative stress, impaired insulin production secretion addressed. Additionally, impact liver cirrhosis, acute kidney injury, immune system complications, diabetic complications like retinopathy neuropathy examined. Therefore, further research required to enhance diagnosis, prevent chronic identify therapeutic targets management associated dysfunctions.

Language: Английский

Citations

140
Neutrophil extracellular traps mediate cardiomyocyte ferroptosis via the Hippo–Yap pathway to exacerbate doxorubicin-induced cardiotoxicity DOI Creative Commons
Peng Zhao, You Li,

Xiangli Xu

et al.

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: March 8, 2024

Abstract Doxorubicin-induced cardiotoxicity (DIC), which is a cardiovascular complication, has become the foremost determinant of decreased quality life and mortality among survivors malignant tumors, in addition to recurrence metastasis. The limited ability accurately predict occurrence severity doxorubicin-induced injury greatly hindered prevention DIC, but reducing dose mitigate side effects may compromise effective treatment primary malignancies. This posed longstanding clinical challenge for oncologists cardiologists. Ferroptosis cardiomyocytes been shown be pivotal mechanism underlying cardiac dysfunction DIC. influenced by multiple factors. innate immune response, as exemplified neutrophil extracellular traps (NETs), play significant role regulation ferroptosis. Therefore, objective this study was investigate involvement NETs cardiomyocyte ferroptosis elucidate their regulatory role. confirmed presence DIC vivo. Furthermore, we demonstrated that depleting neutrophils effectively reduced myocardial Additionally, our findings showed high mobility group box 1 (HMGB1) critical molecule implicated emphasized its modulation subsequent inhibition. Mechanistically, obtained preliminary evidence suggesting could modulate yes-associated protein (YAP) activity releasing HMGB1, subsequently bound toll like receptor 4 (TLR4) on membrane, thereby influencing vitro. Our suggest via HMGB1/TLR4/YAP axis, contributing injury. offers novel approach preventing alleviating targeting alterations microenvironment.

Language: Английский

Citations

14
Protective effects of esculetin against doxorubicin‐induced toxicity correlated with oxidative stress in rat liver: In vivo and in silico studies DOI

Zeynep Özdemir Köroğlu,

Duygu Kizir, Melike Karaman

et al.

Journal of Biochemical and Molecular Toxicology, Journal Year: 2024, Volume and Issue: 38(4)

Published: April 1, 2024

Abstract Doxorubicin (DOX) is widely used in cancer treatment but the dose‐related toxicity of DOX on organs including liver limit its use. Therefore, there great interest combining with natural compounds antioxidant properties to reduce and increase drug efficacy. Esculetin a coumarin derivative biological encompassing anti‐inflammatory activities. In light these properties, this study was meticulously crafted investigate potential esculetin preventing doxorubicin (DOX)‐induced hepatotoxicity Sprague‐Dawley rats. The rats were divided into total six groups: control group, group (administered at cumulative dose 5 mg/kg intraperitoneally every other day for 2 weeks), E50 50 day), E100 100 day) combined groups (DOX + E100) which administered together DOX. treatments, both alone combination E50, manifested reduction catalase (CAT mRNA) levels comparison group. Notably, enzymatic activities superoxide dismutase (SOD), CAT, glutathione peroxidase (GPx) witnessed significant decreases treated Moreover, induced statistically elevation malondialdehyde (MDA) levels, coupled concurrent decrease (GSH) levels. Additionally, molecular docking studies conducted. However, further are needed confirm hepatoprotective precisely elucidate mechanisms action.

Language: Английский

Citations

12
The anti‐inflammatory effect of metformin: The molecular targets DOI Creative Commons
Natsumi Sakata

Genes to Cells, Journal Year: 2024, Volume and Issue: 29(3), P. 183 - 191

Published: Feb. 4, 2024

Metformin is an anti-diabetic drug. mainly inhibits gluconeogenesis in the liver and reduces blood sugar. In addition to effects, many studies have revealed that metformin has anti-inflammatory effects. Various molecules were suggested be target of metformin's However, conclusion not clear. related a number identification main effects leads understanding inflammation metformin. this article, I discuss each molecule, involved mechanisms, their relationship with various diseases.

Language: Английский

Citations

10
Sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents ejection fraction reduction, reduces myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity DOI Creative Commons

Vincenzo Quagliariello,

Maria Laura Canale,

Isabella Bisceglia

et al.

Frontiers in Cardiovascular Medicine, Journal Year: 2024, Volume and Issue: 11

Published: May 16, 2024

Background Anthracycline-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in patients with cancer. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exert multiple cardiometabolic benefits with/without type diabetes, chronic kidney disease, heart failure reduced preserved ejection fraction. We hypothesized that SGLT2i dapagliflozin administered before during doxorubicin (DOXO) therapy could prevent cardiac dysfunction reduce pro-inflammatory pathways preclinical models. Methods Cardiomyocytes were exposed to DOXO alone or combined (DAPA) at 10 100 nM for 24 h; cell viability, iATP, Ca ++ quantified; lipid peroxidation products (malondialdehyde 4-hydroxy 2-hexenal), NLRP3, MyD88, cytokines also analyzed through selective colorimetric enzyme-linked immunosorbent assay (ELISA) methods. Female C57Bl/6 mice treated days a saline solution (2.17 mg/kg), DAPA (10 DAPA. Systemic levels ferroptosis-related biomarkers, galectin-3, high-sensitivity C-reactive protein (hs-CRP), chemokines (IL-1 α , IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, GM-CSF) quantified. After treatments, immunohistochemical staining myocardial renal p65/NF-kB was performed. Results exerts cytoprotective, antioxidant, anti-inflammatory properties human cardiomyocytes by reducing iATP iCa levels, peroxidation, NLRP-3, MyD88 expression. Pro-inflammatory intracellular reduced. In models, prevented reduction radial longitudinal strain fraction after treatment DOXO. A expression NLRP-3 MyD-88 seen DOXO-DAPA group compared mice. GM-CSF significantly Serum galectine-3 hs-CRP strongly enhanced group; on other hand, their DAPA-DOXO group. Troponin-T, B-type natriuretic peptide (BNP), N-Terminal Pro-BNP (NT-pro-BNP) group, revealing cardioprotective SGLT2i. Mice exhibited NF-kB Conclusion The overall picture study encourages use primary prevention cardiomyopathies induced anthracyclines

Language: Английский

Citations

8
HMGB1 as an extracellular pro-inflammatory cytokine: Implications for drug-induced organic damage DOI Creative Commons
Jianye Yuan,

Lin Guo,

JiaTing Ma

et al.

Cell Biology and Toxicology, Journal Year: 2024, Volume and Issue: 40(1)

Published: July 15, 2024

Drug-induced organic damage encompasses various intricate mechanisms, wherein HMGB1, a non-histone chromosome-binding protein, assumes significant role as pivotal hub gene. The regulatory functions of HMGB1 within the nucleus and extracellular milieu are interlinked. exerts crucial influence on key biological processes including cell survival, inflammatory regulation, immune response. can be released extracellularly from during these processes, where it pro-inflammation cytokine. interacts with multiple membrane receptors, primarily Toll-like receptors (TLRs) receptor for advanced glycation end products (RAGE), to stimulate cells trigger excessive or uncontrolled release leads heightened responses cellular demise, instigating exacerbating inflammation demise in different diseases. Therefore, thorough review significance drug-induced is highly important advancement pharmaceuticals, ensuring their effectiveness safety treating well immune-related In this review, we initially outline characteristics emphasizing relevance disease pathology. Then, comprehensively summarize prospect promising therapeutic target toxicity. Lastly, discuss major challenges propose potential avenues advancing development HMGB1-based therapeutics.

Language: Английский

Citations

6
Review on the role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome pathway in diabetes: mechanistic insights and therapeutic implications DOI
Abhishek Satheesan, Janardanan Kumar,

K.V. Leela

et al.

Inflammopharmacology, Journal Year: 2024, Volume and Issue: 32(5), P. 2753 - 2779

Published: Aug. 19, 2024

Language: Английский

Citations

6
Leucine zipper protein 1 prevents doxorubicin-induced cardiotoxicity in mice DOI Creative Commons
Di Fan,

Zhili Jin,

Jianlei Cao

et al.

Redox Biology, Journal Year: 2023, Volume and Issue: 64, P. 102780 - 102780

Published: June 18, 2023

Doxorubicin (DOX) is commonly used for chemotherapy; however, its clinical value extremely dampened because of the fatal cardiotoxicity. Leucine zipper protein 1 (LUZP1) plays critical roles in cardiovascular development, and this study designed determining function mechanism DOX-induced cardiotoxicity.Cardiac-specific Luzp1 knockout (cKO) transgenic (cTG) mice received a single or repeated DOX injections to establish acute chronic Biomarkers inflammation, oxidative damage cell apoptosis were evaluated. Transcriptome co-immunoprecipitation analysis screen underlying molecular pathways. Meanwhile, primary cardiomyocytes applied confirm beneficial effects LUZP1 depth.LUZP1 was upregulated DOX-injured hearts cardiomyocytes. Cardiac-specific deficiency aggravated, while cardiac-specific overexpression attenuated DOX-associated damage, cardiac injury. Mechanistic studies revealed that ameliorated cardiotoxicity through activating 5'-AMP-activated kinase (AMPK) pathway, AMPK abolished cardioprotection LUZP1. Further findings suggested interacted with phosphatase activate pathway. Moreover, we determined could also attenuate injury mice.LUZP1 attenuates ventricular impairment regulating gene therapy targeting may provide novel therapeutic approached treat

Language: Английский

Citations

13
Reliability of Metformin’s protective effects against doxorubicin-induced cardiotoxicity: a meta-analysis of animal studies DOI Creative Commons
Ming‐Li Sun, Wei Chen, Xinghe Wang

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 8, 2024

Background The protective effects of metformin (Met) against doxorubicin (Dox)-induced cardiotoxicity via potential hypotheses mechanisms action with unknown reliability and credibility. Objectives This study aimed to investigate the Met Dox-induced underlying action, as well examine their Methods A comprehensive search was conducted within PubMed, Embase, Web Science, Science Direct, Scopus, CNKI databases from inception 31 December 2023. Animal experiments evaluating efficacy were included in this study. primary outcomes markers myocardial injury. Effect size measured using standardized mean difference for continuous variables. Data pooled a random-effects model Stata 18 statistical software package. Results Twenty-one studies involving 203–208 animals treated Dox 271–276 analysis. Quality assessment revealed high-quality scores. Pooled results favored treatment based on serum lactate dehydrogenase (LDH), creatine kinase-myocardial band (CK-MB), cardiac troponin I (cTnI), aspartate aminotransferase levels. Sensitivity analysis leave-one-out method demonstrated stable results. Funnel plots, Egger’s test, Begg’s test confirmed publication bias. oxidative stress hypothesis has been investigated extensively abundant evidence. Conclusion is effective safe protecting cardiotoxicity, thus making it an appropriate drug clinical investigation. mechanism established highest

Language: Английский

Citations

4
Small Molecules Targeting Mitochondria: A Mechanistic Approach to Combating Doxorubicin-Induced Cardiotoxicity DOI

Chinmay Pal

Cardiovascular Toxicology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 4, 2024

Language: Английский

Citations

4