Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress

IF 4.2 2区 医学 Q1 INTEGRATIVE & COMPLEMENTARY MEDICINE Journal of Integrative Medicine-Jim Pub Date : 2024-07-01 DOI:10.1016/j.joim.2024.05.003
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Abstract

Objective

Hepatolenticular degeneration (HLD) is an autosomal recessive disorder that manifests as multiorgan damage due to impaired copper (Cu) metabolism. Female patients with HLD often experience reproductive impairments. This study investigated the protective effect of berberine against ovarian damage in toxic-milk (TX) mice, a murine model for HLD.

Methods

Mice were categorized into control group, HLD TX group (HLD group), penicillamine (Cu chelator)-treated TX group and berberine-treated TX group. Body weight, ovary weight and the number of ovulated eggs were recorded. Follicular morphology and cellular ultrastructure were examined. Total iron, ferrous iron (Fe2+) and trivalent iron (Fe3+) levels, as well as malondialdehyde (MDA), glutathione (GSH) and oxidized glutathione (GSSG), were measured in the ovaries. Western blot analysis was used to analyze the expression of proteins related to ferroptosis and endoplasmic reticulum (ER) stress.

Results

Ovarian tissue damage was evident in the HLD group, with a significant increase in ferroptosis and ER stress compared to the control group. This damage was inhibited by treatment with penicillamine, a Cu chelator. Compared with the HLD group, berberine increased the number of ovulations, and improved ovarian morphology and ultrastructure. Further, we found that berberine reduced total iron, Fe2+, MDA and GSSG levels, elevated GSH levels, decreased the expression of the ferroptosis marker protein prostaglandin-endoperoxide synthase 2 (PTGS2), and increased glutathione peroxidase 4 (GPX4) expression. Furthermore, berberine inhibited the expression of ER stress-associated proteins mediated by the protein kinase RNA-like ER kinase (PERK) pathway.

Conclusion

Ferroptosis and ER stress are involved in Cu-induced ovarian damage in TX mice. Berberine ameliorates ovarian damage in HLD TX mice by inhibiting ferroptosis and ER stress.

Please cite this article as: Liu QZ, Han H, Fang XR, Wang LY, Zhao D, Yin MZ, Zhang N, Jiang PY, Ji ZH, Wu LM. Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress. J Integr Med. 2024; 22(4): 494–503.

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小檗碱通过抑制铁突变和内质网应激减轻肝细胞变性小鼠的卵巢组织损伤
目的肝曲霉变性(HLD)是一种常染色体隐性遗传疾病,表现为铜(Cu)代谢障碍导致的多器官损害。HLD女性患者通常会出现生殖障碍。方法将小鼠分为对照组、HLD TX 组(HLD 组)、青霉胺(铜螯合剂)处理 TX 组和小檗碱处理 TX 组。记录体重、卵巢重量和排卵数量。检查卵泡形态和细胞超微结构。测量卵巢中的总铁、亚铁(Fe2+)和三价铁(Fe3+)水平,以及丙二醛(MDA)、谷胱甘肽(GSH)和氧化谷胱甘肽(GSSG)。结果HLD组卵巢组织损伤明显,与对照组相比,铁变态反应和内质网(ER)应激显著增加。使用铜螯合剂青霉胺治疗可抑制这种损伤。与 HLD 组相比,小檗碱增加了排卵数量,并改善了卵巢的形态和超微结构。此外,我们还发现小檗碱降低了总铁、Fe2+、MDA和GSSG水平,提高了GSH水平,减少了铁变态反应标志蛋白前列腺素内过氧化物合成酶2(PTGS2)的表达,并增加了谷胱甘肽过氧化物酶4(GPX4)的表达。此外,小檗碱还能抑制由蛋白激酶 RNA 样 ER 激酶(PERK)通路介导的 ER 应激相关蛋白的表达。小檗碱通过抑制铁变态反应和ER应激改善了HLD TX小鼠的卵巢损伤:Liu QZ, Han H, Fang XR, Wang LY, Zhao D, Yin MZ, Zhang N, Jiang PY, Ji ZH, Wu LM.小檗碱通过抑制铁突变和内质网应激减轻肝细胞变性小鼠的卵巢组织损伤J Integr Med.2024; 22(4):494-503.
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来源期刊
Journal of Integrative Medicine-Jim
Journal of Integrative Medicine-Jim Medicine-Complementary and Alternative Medicine
CiteScore
9.20
自引率
4.20%
发文量
3319
期刊介绍: The predecessor of JIM is the Journal of Chinese Integrative Medicine (Zhong Xi Yi Jie He Xue Bao). With this new, English-language publication, we are committed to make JIM an international platform for publishing high-quality papers on complementary and alternative medicine (CAM) and an open forum in which the different professions and international scholarly communities can exchange views, share research and their clinical experience, discuss CAM education, and confer about issues and problems in our various disciplines and in CAM as a whole in order to promote integrative medicine. JIM is indexed/abstracted in: MEDLINE/PubMed, ScienceDirect, Emerging Sources Citation Index (ESCI), Scopus, Embase, Chemical Abstracts (CA), CAB Abstracts, EBSCO, WPRIM, JST China, Chinese Science Citation Database (CSCD), and China National Knowledge Infrastructure (CNKI). JIM Editorial Office uses ThomsonReuters ScholarOne Manuscripts as submitting and review system (submission link: http://mc03.manuscriptcentral.com/jcim-en). JIM is published bimonthly. Manuscripts submitted to JIM should be written in English. Article types include but are not limited to randomized controlled and pragmatic trials, translational and patient-centered effectiveness outcome studies, case series and reports, clinical trial protocols, preclinical and basic science studies, systematic reviews and meta-analyses, papers on methodology and CAM history or education, conference proceedings, editorials, commentaries, short communications, book reviews, and letters to the editor. Our purpose is to publish a prestigious international journal for studies in integrative medicine. To achieve this aim, we seek to publish high-quality papers on any aspects of integrative medicine, such as acupuncture and traditional Chinese medicine, Ayurveda medicine, herbal medicine, homeopathy, nutrition, chiropractic, mind-body medicine, taichi, qigong, meditation, and any other modalities of CAM; our commitment to international scope ensures that research and progress from all regions of the world are widely covered. These ensure that articles published in JIM have the maximum exposure to the international scholarly community. JIM can help its authors let their papers reach the widest possible range of readers, and let all those who share an interest in their research field be concerned with their study.
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