Biology subjects

Efimova, T.

Publications and source records attributed to Efimova, T..

3 recordsLinked to original sources

bioRxiv2026

p38β/MAPK11 Deficiency Exacerbates Cardiac Structural and Electrophysiological Remodeling and Contributes to Immune Dysregulation in the Aging Heart

Aging is a major risk factor for cardiac diseases, including heart failure, myocardial infarction, and arrhythmias. Activation of p38 MAPKs regulates cardiac remodeling and contributes to age-related cardiac dysfunction. However, the isoform-specific roles of p38 kinases in the aging heart remain poorly understood. Although p38{beta} has been reported to exert cardioprotective effects in models of doxorubicin-induced cardiotoxicity and ischemia-reperfusion, its role in cardiac aging remains unclear. Here, we investigated the role of p38{beta} using p38{beta} germline knockout (p38{beta}-/-) mice. Aged p38{beta}-/- mice exhibited increased LV hypertrophy, QT prolongation, calcium mishandling, heightened susceptibility to arrhythmias, increased myocardial fibrosis, and an altered inflammatory microenvironment, compared with age-matched wild-type controls. Transcriptomic profiling revealed that p38{beta} deletion reprograms the cardiac transcriptome in aged mice, suppressing innate immune and proteostasis-related pathways while promoting adaptive immune activation, developmental, extracellular vesicle-mediated, and ion-transport pathways. Collectively, these findings identify p38{beta} as a critical regulator of structural, electrophysiological, and immune homeostasis in the aging heart and demonstrate that its loss promotes maladaptive remodeling and arrhythmogenic vulnerability. NEW AND NOTEWORTHYWe identify p38{beta} as a previously unrecognized regulator of cardiac aging. Systemic loss of p38{beta} disrupts structural, electrophysiological, and immune homeostasis in the aging heart, revealing its protective role in maintaining cardiac function with age. These findings underscore the importance of isoform-specific p38 signaling and suggest that broadly targeting p38 MAPKs may have unintended consequences in age-related cardiovascular diseases.

physiology↗

bioRxiv2022

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in vitro and in silico screening of a small library of Phenolic compounds

Melanoma and non-melanoma skin cancers are the most-lethal and commonest forms of skin cancers, that affecting one-fifth of the US population. With the aim of identifying new lead compounds as starting point for attaining cost-effective therapies, a small library of about 90 molecules was screened in vitro against A375, SKMEL-28, A431, SCC-12 skin cancer cell lines. About 35 of them, mainly dihydroquinolines, C-C and C-N linked biphenyls, and substituted methylgallate or aniline derivatives, displayed low-micromolar range activities, primarily against the A431 and SCC-12 squamous carcinoma cell lines, with only a handful of these compounds displaying any activity against the A375 and SKMEL-28 melanoma cell lines. Compounds 11 (A431: IC50 = 5.0 {micro}M, SCC-12: IC50 = 2.9 {micro}M, SKMEL-28: IC50 = 4.9 {micro}M, A375: IC50 = 6.7 {micro}M) and 13 (A431: IC50 = 5.0 {micro}M, SCC-12: IC50 = 3.3 {micro}M, SKMEL-28: IC50 = 13.8 {micro}M, A375: IC50 = 17.1 {micro}M) were the most active across all these cell lines. Furthermore, many of the hit compounds showed little to no activity against mammalian nontumorigenic immortalized HaCaT cells, with a far better selectivity index than cisplatin (a well-known anticancer agent used as a positive control). Compounds 11 and 13 significantly and dose-dependently induced apoptosis of SCC-12 and SK-MEL-28 cells as evidenced by the downregulation of Bcl-2 and upregulation of Bax protein expression levels, and by cleaved caspase-3, caspase-9 and PARP levels. Both agents also significantly reduced scratch wound healing, colony formation, and activated expression levels of major cancer molecular targets such as RSK/AKT/ERK1/2 and S6K1. To provide a better attribute profile for each of the hit molecules, in-silico target(s) prediction, pharmacokinetic and ADMET studies are also reported, together with some preliminary structure-activity relationship outlines. The SwissTargetPrediction web-based tool identified CDK8, CLK4, nuclear receptor ROR, tyrosine protein-kinase Fyn/LCK, ROCK1/2, and PARP, all of which are dysregulated in skin cancers, as likely targets for these hit compounds. Furthermore, the SwissADME web_tool predicted these compounds to exhibit high GI tract absorption, good skin permeation, and a viable biodegradability profile. To summarize, these data highlight the promising anticancer potential of these small molecules leads, warranting further investigation and/or optimization towards obtaining clinical candidates for combatting both melanoma and non-melanoma skin cancers.

pharmacology and toxicology↗

bioRxiv2020

p38delta genetic ablation protects female mice from anthracycline cardiotoxicity

BACKGROUNDThe efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38{gamma} and p38{delta}, remain uncharacterized. OBJECTIVESTo determine the potential cardioprotective effects of p38{gamma} and p38{delta} genetic deletion in mice subjected to acute DOX treatment. METHODSMale and female wild-type (WT), p38{gamma}-/-, p38{delta}-/- and p38{gamma}-/-{delta}-/- mice were injected with 30 mg/kg DOX and their survival was tracked for ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining. Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy. RESULTSSignificantly improved survival was observed in p38{delta}-/- female mice post-DOX relative to WT females, but not in p38{gamma}-/- or p38{gamma}-/-{delta}-/- male or female mice. The improved survival in DOX-treated p38{delta}-/- females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38{delta}-/- females. CONCLUSIONSp38{delta} plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38{delta} targeting could be a potential cardioprotective strategy in anthracycline chemotherapy. NEW AND NOTEWORTHYThis study for the first time identifies the roles of the alternative p38{gamma} and p38{delta} MAPK isoforms in promoting DOX-cardiotoxicity in a sex-specific manner. While p38{gamma} systemic deletion did not affect DOX-cardiotoxicity, p38{delta} systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38{delta}-/- females and autophagy was increased.

physiology↗