Baicalin enhances proliferation and reduces inflammatory-oxidative stress effect in H <sub>2</sub>O <sub>2</sub>-induced granulosa cells apoptosis via USP48 protein regulation

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Abstract

Background

Oxidative stress and inflammation can lead to apoptosis of ovarian granulosa cells (GCs), resulting in ovulation disorders and infertility. Baicalin (BAI) promotes cell proliferation and reduces inflammation and oxidative stress. However, the mechanisms by which BAI treatment affects oxidative stress and inflammation in GCs remain incompletely understood.

Methods

KGN cells were treated with hydrogen peroxide (H ₂O ₂) to analyze the effect of oxidative stress on GCs in vitro. Subsequently, H ₂O ₂-stimulated KGN cells were treated with BAI. The levels of GSH-Px, CAT, and SOD were measured using an activity assay kit. The levels of MDA, IL-1β, IL-6, IL-8, and TNF-α were measured by ELISA. Proliferation, apoptosis, and mRNA and protein levels were measured using the CCK8, flow cytometry, qRT-PCR, and western blotting.

Results

H ₂O ₂ treatment inhibited KGN cell proliferation and promoted apoptosis, accompanied by increased oxidative stress and inflammation. BAI promoted proliferation, inhibited apoptosis, and reduced oxidative stress and inflammation in H ₂O ₂-stimulated KGN cells. BAI treatment promoted USP48 protein expression, and USP48 knockdown abrogated the protective effects of BAI, indicating that USP48 is a downstream mediator of BAI.

Conclusion

BAI treatment enhanced cell proliferation and ameliorated oxidative stress and inflammation by enhancing USP48 protein expression. BAI, which is used clinically and as a dietary supplement, may alleviate oxidative stress-induced GC injury and ovarian disorders.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12906-024-04346-z.

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Most cited references 47

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We established a steroidogenic human ovarian granulosa-like tumor cell line, designated KGN, from a patient with invasive ovarian granulosa cell carcinoma. KGN had a relatively long population doubling time of about 46.4 h and had an abnormal karyotype of 45,XX, 7q-, -22. A steroid analysis of the cultured medium by RIA performed 5 yr after the initiation of culture showed that KGN was able to secrete pregnenolone and progesterone, and both dramatically increased after stimulation with (Bu)(2)cAMP. However, little or no secretion of 17alpha-hydroxylated steroids, dehydroepiandrosterone, androstenedione, or estradiol was observed. The aromatase activity of KGN was relatively high and was further stimulated by (Bu)(2)cAMP or FSH. These findings showed a pattern similar to that of steroidogenesis in human granulosa cells, thus allowing analysis of naturally occurring steroidogenesis in human granulosa cells. Fas-mediated apoptosis of KGN was also observed, which mimicked the physiological regulation of apoptosis in normal human granulosa cells. Based on these findings, this cell line is considered to be a very useful model for understanding the regulation of steroidogenesis, cell growth, and apoptosis in human granulosa cells.

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Proper functioning of the ovary is critical to maintain fertility and overall health, and ovarian function depends on the maintenance and normal development of ovarian follicles. This review presents evidence about the potential impact of oxidative stress on the well-being of primordial, growing and preovulatory follicles, as well as oocytes and early embryos, examining cell types and molecular targets. Limited data from genetically modified mouse models suggest that several antioxidant enzymes that protect cells from reactive oxygen species (ROS) may play important roles in follicular development and/or survival. Exposures to agents known to cause oxidative stress, such as gamma irradiation, chemotherapeutic drugs, or polycyclic aromatic hydrocarbons, induce rapid primordial follicle loss; however, the mechanistic role of ROS has received limited attention. In contrast, ROS may play an important role in the initiation of apoptosis in antral follicles. Depletion of glutathione leads to atresia of antral follicles in vivo and apoptosis of granulosa cells in cultured antral follicles. Chemicals, such as cyclophosphamide, dimethylbenzanthracene, and methoxychlor, increase proapoptotic signals, preceded by increased ROS and signs of oxidative stress, and cotreatment with antioxidants is protective. In oocytes, glutathione levels change rapidly during progression of meiosis and early embryonic development, and high oocyte glutathione at the time of fertilization is required for male pronucleus formation and for embryonic development to the blastocyst stage. Because current evidence suggests that oxidative stress can have significant negative impacts on female fertility and gamete health, dietary or pharmacological intervention may prove to be effective strategies to protect female fertility.

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Author and article information

Contributors

Wei Bian: xiaowanzi1719@sina.com

Journal

Journal ID (nlm-ta): BMC Complement Med Ther

Journal ID (iso-abbrev): BMC Complement Med Ther

Title: BMC Complementary Medicine and Therapies

Publisher: BioMed Central (London )

ISSN (Electronic): 2662-7671

Publication date (Electronic): 20 January 2024

Publication date PMC-release: 20 January 2024

Publication date Collection: 2024

Volume: 24

Electronic Location Identifier: 42

Affiliations

[1 ]GRID grid.440218.b, ISNI 0000 0004 1759 7210, Department of Traditional Chinese Medicine, , Shenzhen People’s Hospital (The Second Clinical Medical College of Jinan University; The First Affiliated Hospital of Southern University of Science and Technology), ; No. 1017, Dongmen North Road, Luohu District, Shenzhen, 518020 China

[2 ]GRID grid.440218.b, ISNI 0000 0004 1759 7210, Department of Rehabilitation Medicine, , Shenzhen People’s Hospital (The Second Clinical Medical College of Jinan University; The First Affiliated Hospital of Southern University of Science and Technology), ; Shenzhen, 518020 China

Article

Publisher ID: 4346

DOI: 10.1186/s12906-024-04346-z

PMC ID: 10799411

PubMed ID: 38245760

SO-VID: 8f932b78-f3b5-4971-a8b8-14229a6bcf26

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 13 October 2023

Date accepted : 11 January 2024

Custom metadata

Keywords: usp48,baicalin,oxidative stress,inflammation,ovarian granulosa cell

Data availability:

Keywords: usp48, baicalin, oxidative stress, inflammation, ovarian granulosa cell