Targeting histone deacetylases: Emerging applications beyond cancer

Drug Discovery Today, Год журнала: 2024, Номер 29(9), С. 104094 - 104094

Опубликована: Июль 11, 2024

Язык: Английский

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Interplay of the heart, spleen, and bone marrow in heart failure: the role of splenic extramedullary hematopoiesis

Heart Failure Reviews, Год журнала: 2024, Номер 29(5), С. 1049 - 1063

Опубликована: Июль 10, 2024

Improvements in therapies for heart failure with preserved ejection fraction (HFpEF) are crucial improving patient outcomes and quality of life. Although HFpEF is the predominant type among older individuals, its prognosis often poor owing to lack effective therapies. The roles spleen bone marrow overlooked context HFpEF. Recent studies suggest that could play key HFpEF, especially relation inflammation immune responses. can increase production certain cells migrate contribute disease. responses either protect or exacerbate failure. Extramedullary hematopoiesis a role Increased metabolic activity spleen, cell mobilization heart, concomitant cytokine may occur This leads systemic chronic inflammation, along an imbalance (macrophages) resulting progressive fibrosis, potentially leading decreased cardiac function. involved altered iron metabolism anemia, which also review presents concept interplay between setting particular focus on extramedullary spleen. aim this discern whether serve as new therapeutic target

Язык: Английский

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Soy protein β-conglycinin ameliorates pressure overload-induced heart failure by increasing short-chain fatty acid (SCFA)-producing gut microbiota and intestinal SCFAs

Clinical Nutrition, Год журнала: 2024, Номер 43(12), С. 124 - 137

Опубликована: Окт. 1, 2024

Язык: Английский

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Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 2, 2025

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis poorly understood. The ability to assess genetic and pharmacologic interventions hampered by the lack of robust preclinical mouse models HFpEF. We developed a novel "two-hit" model, which combines obesity insulin resistance chronic pressure overload recapitulate clinical features C57Bl6/NJ mice fed high-fat diet (HFD) for > 10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression Renin1d. HFD-Renin (aka "HFpEF") demonstrated resistance, moderate left ventricular hypertrophy, systolic function, diastolic dysfunction indicated echocardiographic measurements; increased atrial mass; elevated natriuretic peptides; exercise intolerance. Transcriptomic metabolomic profiling myocardium upregulation pro-fibrotic pathways downregulation metabolic pathways, particular branched chain amino acid catabolism, similar human Treatment empagliflozin, effective incompletely understood HFpEF therapy, improved multiple endpoints. model recapitulates key will enable studies dissecting contribution individual pathogenic drivers this complex syndrome. Additional allow orthogonal increase validity assessment interventions.

Язык: Английский

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IFN-γ reprograms cardiac microvascular endothelial cells to mediate doxorubicin transport and influences the sensitivity of mice to doxorubicin-induced cardiotoxicity

Experimental & Molecular Medicine, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Abstract Doxorubicin (DOX) is a first-line chemotherapy agent known for its cardiac toxicity. DOX-induced cardiotoxicity (DIC) severely limits the use treating malignant tumors and associated with poor prognosis. The sensitivity to DIC varies among patients, but precise mechanisms remain elusive. Here we constructed mouse model of using DOX investigate potential contributing differential susceptibility DIC. Through surface-enhanced Raman spectroscopy single-cell RNA sequencing, explored underlying phenotypic variations. In vitro in vivo studies small-molecule drugs were conducted. DIC-insensitive mice displayed preserved ejection fractions, lower levels tissues higher serum. Single-cell sequencing revealed differences gene expression endothelial cells between DIC-sensitive groups. IFN-γ pathway-related genes was high mice. administration decreased distribution tissues, whereas PPAR-γ activation increased susceptibility. stimulation upregulated P-glycoprotein expression, leading efflux insensitivity. Our provides insights into preventive strategies.

Язык: Английский

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Antagonizing HFpEF by Targeting Fibrosis

Circulation, Год журнала: 2025, Номер 151(6), С. 396 - 399

Опубликована: Фев. 10, 2025

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Pharmacological manipulation of liver fibrosis progression using novel HDAC6 inhibitors

FEBS Journal, Год журнала: 2025, Номер unknown

Опубликована: Март 14, 2025

Chronic liver injury characterized by unresolved hepatitis leads to fibrosis, potentially progressing cirrhosis and hepatocellular carcinoma. Effective treatments for halting or reversing fibrosis are currently lacking. This study investigates the potential of HDAC6 as a therapeutic target in fibrosis. We synthesized two selective inhibitors, DR‐3 FDR2, assessed their effects on hepatic stellate cell (HSC) activation using human precision cut slices (hPCLS). Molecular docking, deacetylation inhibition assays, various cellular assays were employed evaluate specificity anti‐fibrotic efficacy these inhibitors. FDR2 demonstrated high selectivity over HDAC1, significantly inhibiting HSC markers fibrogenic gene expression. Both inhibitors increased acetylation α‐tubulin suppressed TGF‐β1‐induced SMAD signaling HSCs. In (hPCLS), reduced protein levels collagen deposition. The effectively reduces fibrogenesis models, supporting further investigation therapies.

Язык: Английский

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Preferential HDAC6 inhibitors derived from HPOB exhibit synergistic antileukemia activity in combination with decitabine

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 272, С. 116447 - 116447

Опубликована: Апрель 26, 2024

Histone deacetylase 6 (HDAC6) is an emerging drug target to treat oncological and non-oncological conditions. Since highly selective HDAC6 inhibitors display limited anticancer activity when used as single agent, they usually require combination therapies with other chemotherapeutics. In this work, we synthesized a mini library of analogues the preferential inhibitor HPOB in only two steps via Ugi four-component reaction key step. Biochemical HDAC inhibition cell viability assays led identification 1g (highest antileukemic activity) 2b inhibition) hit compounds. subsequent screens, both especially showed synergy DNA methyltransferase decitabine acute myeloid leukemia (AML). Our findings highlight potential combining strategy improve AML treatment outcomes.

Язык: Английский

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Histone deacetylase 6 controls cardiac fibrosis and remodelling through the modulation of TGF‐β1/Smad2/3 signalling in post‐infarction mice

Journal of Cellular and Molecular Medicine, Год журнала: 2024, Номер 28(17)

Опубликована: Сен. 1, 2024

Abstract Histone deacetylase 6 (HDAC6) belongs to the class IIb group of histone family, which participates in remodelling various tissues. Herein, we sought examine potential regulation HDAC6 cardiac post‐infarction. Experimental myocardial infarction (MI) was created HDAC6‐deficient (HDAC6 −/− ) mice and wild‐type (HADC6 +/+ by left coronary artery ligation. At days 0 14 post‐MI, evaluated function, morphology molecular endpoints repair remodelling. day after surgery, ischemic myocardium had increased levels HADC6 gene protein post‐MI compared non‐ischemic control mice. As with ‐MI mice, deletion markedly improved infarct size fibrosis as well impaired ventricular ejection fraction shortening. levels, resulted a significant reduction transforming growth factor‐beta 1 (TGF‐β1), phosphor‐Smad‐2/3, collagen I III proteins and/or All these beneficial effects were reproduced pharmacological inhibition vivo. In vitro, hypoxic stress expressions gene; alterations significantly prevented silencing TubA loading. These findings indicated that deficiency resists injury TGF‐β1/Smad2/3 signalling activation, leading decreased extracellular matrix production, reduces dysfunction, providing target treatment patients MI.

Язык: Английский

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Inflammaging, a targetable pathway for preventing cardiovascular diseases

Cardiovascular Research, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 12, 2024

Abstract Inflammageing, characterized by persistent chronic inflammation in older adults, has emerged as a critical factor linked to age-related diseases, such cardiovascular diseases (CVDs), metabolic disorders, and cognitive decline, which collectively contribute the leading causes of death globally. Elevated levels cytokines, chemokines, other inflammatory mediators characterize inflammageing serve indicators biological age. Among inflammageing, deterioration immune system, mitochondrial dysfunction, dysbiosis, accumulation DAMPs, together with genetic or epigenetic factors, not only CVD but also conditions. This review examines consequences particularly its implications for atherosclerosis heart failure preserved ejection fraction explores potential strategies mitigate it onset CVD.

Язык: Английский

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