Repurposing levomilnacipran to attenuate premature ovarian insufficiency induced by cyclophosphamide in female Wistar albino rats through modulation of TLR4/p38-MAPK/NF-κB p65, caspase-3-driven apoptosis, and Klotho protein expression

IF 3.9 3区医学 Q2 FOOD SCIENCE & TECHNOLOGY

Food and Chemical Toxicology Pub Date : 2025-03-26 DOI:10.1016/j.fct.2025.115406

Remon Roshdy Rofaeil , Ehab E. Sharata , Mina Ezzat Attya , Amira M. Abo-Youssef , Ramadan AM. Hemeida , Marwa M. Khalaf

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引用次数: 0

Abstract

Aim

This study aims to explore the mitigative impact of levomilnacipran (LVM) against cyclophosphamide (CPA)-induced premature ovarian insufficiency by targeting TLR4/p38 MAPK/NF-κB p65, and klotho expression.

Methods

Rats were allocated into five groups as follows: control, LVM, CPA, CPA + LVM, and CPA + TRI. Serum hormones and histopathological examination were performed. To assess oxidative stress, ovarian MDA, GSH, and SOD were evaluated. The ovarian contents of caspase-3 and inflammatory markers were assessed using the ELISA method. The expression of ovarian NF-κB p65 was examined using an immunohistochemical technique. RT-qPCR was used to measure Bax and Bcl-2 mRNA expression. Utilizing a Western blot, the TLR4, p38 MAPK, α-Klotho, and cleaved caspase-3 levels were estimated. The estrous cycle was also monitored.

Findings

LVM attenuated CPA-induced ovarian toxicity by regulating hormones and alleviating histopathological aberrations. It also raised SOD and GSH levels and lowered MDA's ovarian content. Moreover, Bcl-2 levels were raised, Bax and caspase-3 expression levels were reduced, and IL-18, IL-1β, and TNF-α levels were all reduced. LVM-induced ovarian protection by diminishing TLR4/p38 MAPK/NF-κB p65 expression and boosting the protein levels of α-Klotho.

Significance

LVM mitigated POI caused by CPA by downregulating TLR4/p38 MAPK/NF-κB p65, enhancing the α-Klotho level and attenuating caspase-3 derived apoptosis.

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来源期刊

Food and Chemical Toxicology 工程技术-毒理学

CiteScore

10.90

自引率

4.70%

发文量

651

审稿时长

31 days

期刊介绍： Food and Chemical Toxicology (FCT), an internationally renowned journal, that publishes original research articles and reviews on toxic effects, in animals and humans, of natural or synthetic chemicals occurring in the human environment with particular emphasis on food, drugs, and chemicals, including agricultural and industrial safety, and consumer product safety. Areas such as safety evaluation of novel foods and ingredients, biotechnologically-derived products, and nanomaterials are included in the scope of the journal. FCT also encourages submission of papers on inter-relationships between nutrition and toxicology and on in vitro techniques, particularly those fostering the 3 Rs. The principal aim of the journal is to publish high impact, scholarly work and to serve as a multidisciplinary forum for research in toxicology. Papers submitted will be judged on the basis of scientific originality and contribution to the field, quality and subject matter. Studies should address at least one of the following: -Adverse physiological/biochemical, or pathological changes induced by specific defined substances -New techniques for assessing potential toxicity, including molecular biology -Mechanisms underlying toxic phenomena -Toxicological examinations of specific chemicals or consumer products, both those showing adverse effects and those demonstrating safety, that meet current standards of scientific acceptability. Authors must clearly and briefly identify what novel toxic effect (s) or toxic mechanism (s) of the chemical are being reported and what their significance is in the abstract. Furthermore, sufficient doses should be included in order to provide information on NOAEL/LOAEL values.