Indole‐3‐Lactic Acid Inhibits Doxorubicin‐Induced Ferroptosis Through Activating Aryl Hydrocarbon Receptor/Nrf2 Signalling Pathway

Journal of Cellular and Molecular Medicine, Journal Year: 2025, Volume and Issue: 29(2)

Published: Jan. 1, 2025

ABSTRACT The clinical application of doxorubicin (DOX) is limited due to its cardiotoxicity, which primarily attributed interaction with iron in mitochondria, leading lipid peroxidation and myocardial ferroptosis. This study aimed investigate the role gut microbiota‐derived metabolite, indole‐3‐lactic acid (ILA), mitigating DOX‐induced cardiotoxicity (DIC). Cardiac function, pathological changes, ferroptosis were assessed vivo. cardioprotective effects mechanisms ILA explored using multi‐omics approaches, including single‐nucleus RNA sequencing (snRNA‐seq) bulk RNA‐seq, further validated Nrf2 knockout mice. findings revealed that DOX treatment disrupted microbiota, significantly reducing levels tryptophan metabolite ILA. In DIC models, supplementation markedly improved cardiac reduced collagen deposition, mitigated atrophy. snRNA‐seq analyses indicated played a crucial Experimental data demonstrated decreased both mice DOX‐treated H9C2 cells, evidenced by restoration GPX4 SLC7A11 reduction ACSL4. Mechanistically, functions as ligand for aryl hydrocarbon receptor (AhR), upregulation expression. protective against abolished silencing AhR. Moreover, beneficial on eliminated Nrf2‐deficient conclusion, exerts therapeutic inhibiting through activation AhR/Nrf2 signalling pathway. Identifying microbial could offer viable strategies DIC.

Language: Английский

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Activation of Sirt6 by icariside Ⅱ alleviates depressive behaviors in mice with poststroke depression by modulating microbiota-gut-brain axis

Journal of Advanced Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Sirt6-mediated gut microbiota plays a vital role in poststroke depression (PSD). Icariside Ⅱ (ICS Ⅱ) is naturally-occurring neuroprotectant with Sirt6 induction potency. However, it unknown whether ICS protects against PSD through modulation of microbiota. This study aimed to reveal the effect and potential mechanisms on PSD, microbiota-gut-brain axis was investigated. Using middle cerebral artery occlusion (MCAO) chronic unpredictable mild stress (CUMS) establish post-stroke (PSD) mice, we assessed anti-depressant effects via behavioral tests, immunohistochemistry, western blot. Transcriptome profiling, molecular docking, surface plasmon resonance were used identify key targets. 16S rDNA genomic-derived taxonomic profiling fecal transplantation (FMT) conducted figure out mechanistic short-chain fatty acids (SCFAs). ameliorated depressive-like behaviors mice as evidenced by sucrose preference test, forced swimming test tail suspension test. restored mitochondrial function, reduced oxidative damage pro-inflammatory cytokines both brain intestine regulation Sirt6/NF-κB pathway. significantly increased abundance (such asAkkermansia Ligilactobacillus), enhanced SCFAs concentrations, repaired intestinal barrier integrity upreglated tight junction protein expression. FMT from II-treated replicated these benefits, confirming microbiota's role. Mechanistically, directly bound its activity. Ⅱ-mediated neuroprotection neutralized or hydrogen peroxide-induced enteric glial cells when absent. Our findings expand pharmacological properties II demonstrating ability ameliorate axis. Ⅱ, novel activator, could be translated into an alternative microbiota-targeted avenue for coping PSD.

Language: Английский

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The mechanism and therapeutic strategies in Doxorubicin induced cardiotoxicity: Role of programmed cell death

Cell Stress and Chaperones, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

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Role of Gut Microbial Metabolites in Ischemic and Non-Ischemic Heart Failure

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2242 - 2242

Published: March 2, 2025

The effect of the gut microbiota extends beyond their habitant place from gastrointestinal tract to distant organs, including cardiovascular system. Research interest in relationship between heart and has recently been emerging. secretes metabolites, Trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), bile (BAs), indole propionic acid (IPA), hydrogen sulfide (H2S), phenylacetylglutamine (PAGln). In this review, we explore accumulating evidence on role these secreted metabolites pathophysiology ischemic non-ischemic failure (HF) by summarizing current knowledge clinical studies experimental models. Elevated TMAO contributes HF through TGF-ß/Smad signaling-mediated myocardial hypertrophy fibrosis, impairments mitochondrial energy production, DNA methylation pattern change, intracellular calcium transport. Also, high-level can promote via inflammation, histone methylation-mediated vascular platelet hyperactivity, thrombosis, as well cholesterol accumulation activation MAPK signaling. Reduced SCFAs upregulate Egr-1 protein, T-cell infiltration, HDAC 5 6 activities, leading HF, while reactive oxygen species production hyperactivation caveolin-ACE axis result HF. An altered BAs level worsens contractility, opens permeability transition pores inducing apoptosis, enhances accumulation, eventually exacerbating IPA, inhibition nicotinamide N-methyl transferase expression increased nicotinamide, NAD+/NADH, SIRT3 levels, ameliorate HF; meanwhile, H2S suppressing Nox4 ROS stimulating PI3K/AKT pathway also protect against Furthermore, PAGln affect sarcomere shortening ability myocyte contraction. This emerging field research new avenues for therapies restoring dietary interventions, prebiotics, probiotics, or fecal transplantation such normalizing circulating levels TMAO, SCFA, BAs, H2S, PAGln.

Language: Английский

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Microbiota-indole-3-propionic acid-heart axis mediates the protection of leflunomide against αPD1-induced cardiotoxicity in mice

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 19, 2025

Anti-programmed death 1 (αPD1) immune checkpoint blockade is used in combination for cancer treatment but associated with cardiovascular toxicity. Leflunomide (Lef) can suppress the growth of several tumor and mitigate cardiac remodeling mice. However, role Lef αPD1-induced cardiotoxicity remains unclear. Here, we report that inhibits αPD1-related without compromising efficacy αPD1-mediated immunotherapy. changes community structure gut microbiota αPD1-treated melanoma-bearing Moreover, mice receiving transplants from Lef+αPD1-treated have better function compared to Mechanistically, analyze metabolomics identify indole-3-propionic acid (IPA), which protects dysfunction IPA directly bind aryl hydrocarbon receptor promote phosphoinositide 3-kinase expression, thus curtailing cardiomyocyte response injury. Our findings reveal mitigates toxicity through modulation microbiota-IPA-heart axis. The authors show leflunomide microbiota-indole-3-propionic acid-heart

Language: Английский

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The Gut–Heart Axis and Its Role in Doxorubicin-Induced Cardiotoxicity: A Narrative Review

Microorganisms, Journal Year: 2025, Volume and Issue: 13(4), P. 855 - 855

Published: April 9, 2025

Doxorubicin is a widely used chemotherapy for the treatment of several types cancer. However, its application restricted due to adverse effects, particularly cardiotoxicity, which can progress heart failure—a chronic and debilitating condition. Several mechanisms have been identified in pathophysiology doxorubicin-induced including oxidative stress, mitochondrial dysfunction, inflammation, disruption collagen homeostasis. More recently, dysbiosis gut microbiota has implicated development perpetuation cardiac injury. Studies reported alterations composition abundance during doxorubicin treatment. Therefore, as recent, there new field research order develop strategies involving prevent or attenuate cardiotoxicity since no effective therapy at moment. This narrative review aims provide an update on role intestinal permeability cardiovascular diseases, more specifically cardiotoxicity. Additionally, it seeks establish foundation future targeting alleviate

Language: Английский

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CARD11-BCL10-MALT1 complex-dependent MALT1 activation facilitates myocardial oxidative stress in doxorubicin-treated mice via enhancing k48-linked ubiquitination of Nrf2

Antioxidants and Redox Signaling, Journal Year: 2024, Volume and Issue: unknown

Published: May 30, 2024

Downregulation of nuclear factor erythroid 2-related 2 (Nrf2) contributes to doxorubicin (DOX)-induced myocardial oxidative stress, and inhibition mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) increased Nrf2 level in rat heart suffering ischemia/reperfusion, indicating a connection between MALT1 Nrf2. This study aims explore the role DOX-induced stress underlying mechanisms.

Language: Английский

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Salidroside Alleviates Myocardial Ischemia Reperfusion by Balancing Mitochondrial Homeostasis via Nrf2

Journal of Food Biochemistry, Journal Year: 2024, Volume and Issue: 2024, P. 1 - 15

Published: Feb. 14, 2024

Salidroside (SAL), a phenylpropanoid glycoside compound mainly from Rhodiola rosea, showed potential effects on myocardial ischemia reperfusion (MIRI) in our previous studies. The primary objective of this investigation was to study the mechanism by which SAL preserves mitochondrial homeostasis order provide protection against MIRI. impact hypoxia/reoxygenation (H/R)-induced H9c2 cells detected using CCK-8, LDH, and AST. number, function, morphology mitochondria were examined TEM, RT-qPCR, western blot. binding ability between Nrf2 explored through molecular docking cell thermal shift assay. Combined with inhibitor ML385, results demonstrated that promotes activating Nrf2, decreasing oxidative stress, altering AMPK/PGC-1α/PPARα pathway. In addition, elevates ATP levels improves dynamics imbalance inducing both autophagy mitophagy. These findings highlight therapeutic benefits for cardiac health mitigation

Language: Английский

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Fecal Microbiota Transplantation: A Systematic Review of Therapeutic Potential, Preparation Techniques, and Delivery Methods Across Medical Conditions

Kurdistan Journal of Applied Research, Journal Year: 2024, Volume and Issue: 9(2), P. 65 - 85

Published: Nov. 2, 2024

Fecal microbiota transplantation (FMT) is revolutionizing the treatment of gastrointestinal disorders by leveraging gut microbiome in innovative ways. This systematic review evaluates clinical effectiveness and safety FMT across various medical conditions, offering insights into its therapeutic potential limitations. A comprehensive search PubMed, Web Science, Scopus, Embase, ClinicalTrials.gov from January 2000 to December 2023 identified 97 relevant studies on FMT's efficacy, safety, changes after eliminating duplicates. has demonstrated high success rates, particularly treating recurrent refractory Clostridium difficile infections (CDI), with up 90% effectiveness, establishing it as a primary for antibiotic-resistant cases. FMT’s applications are expanding inflammatory bowel diseases (IBD), including ulcerative colitis Crohn's disease, well metabolic neuropsychiatric conditions. Remission rates IBD range 37-45%, outcomes influenced donor characteristics, stool preparation, disease subtype. mild, self-limiting side effects such transient diarrhea abdominal cramping. However, rare serious adverse events underscore need rigorous screening standardized preparation protocols mitigate risks. ability restore healthy flora highlights promise both systemic management. further research essential establish optimized procedures, guidelines, long-term data facilitate integration mainstream practice.

Language: Английский

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