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Herbal Extract-Induced DNA Damage, Apoptosis, and Antioxidant Effects of C. elegans: A Comparative Study of Mentha longifolia, Scrophularia orientalis, and Echium biebersteinii
Background: Herbal medicine represents a rich yet complex source of bioactive compounds, offering both therapeutic potential and toxicological risks. Methods: In this study, we systematically evaluated the biological effects of three traditional herbal extracts—Mentha longifolia, Scrophularia orientalis, and Echium biebersteinii—using Caenorhabditis elegans as an in vivo model. Results: All three extracts significantly reduced worm survival, induced larval arrest, and triggered a high incidence of males (HIM) phenotypes, indicative of mitotic failure and meiotic chromosome missegregation. Detailed analysis of germline architecture revealed extract-specific abnormalities, including nuclear disorganization, ectopic crescent-shaped nuclei, altered meiotic progression, and reduced bivalent formation. These defects were accompanied by activation of the DNA damage response, as evidenced by upregulation of checkpoint genes (atm-1, atl-1), increased pCHK-1 foci, and elevated germline apoptosis. LC-MS profiling identified 21 major compounds across the extracts, with four compounds—thymol, carvyl acetate, luteolin-7-O-rutinoside, and menthyl acetate—shared by all three herbs. Among them, thymol and carvyl acetate significantly upregulated DNA damage checkpoint genes and promoted apoptosis, whereas thymol and luteolin-7-O-rutinoside contributed to antioxidant activity. Notably, S. orientalis and E. biebersteinii shared 11 of 14 major constituents (79%), correlating with their similar phenotypic outcomes, while M. longifolia exhibited a more distinct chemical profile, possessing seven unique compounds. Conclusions: These findings highlight the complex biological effects of traditional herbal extracts, demonstrating that both beneficial and harmful outcomes can arise from specific phytochemicals within a mixture. By deconstructing these extracts into their active components, such as thymol, carvyl acetate, and luteolin-7-O-rutinoside, we gain critical insight into the mechanisms driving reproductive toxicity and antioxidant activity. This approach underscores the importance of component-level analysis for accurately assessing the therapeutic value and safety profile of medicinal plants, particularly those used in foods and dietary supplements.
Therapeutic Potential of Lappula patula Extracts on Germline Development and DNA Damage Responses in C. elegans
Qinghao Meng,Anna Hu,Weiyu Xiao,Robert P. Borris and Hyun-Min Kim
13 January 2025 (This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants — In Honour of the 20th Anniversary of Pharmaceuticals)
Background: Lappula patula (L. patula) is a plant with known medicinal properties, and its extracts have shown promise as potential anti-cancer agents. This study aimed to evaluate the nematocidal effects of L. patula extracts and investigate their impact on germline development, DNA damage responses, and apoptosis in Caenorhabditis elegans (C. elegans), a model organism for studying these processes. Methods: C. elegans was exposed to L. patula extracts to assess survival, development, and incidence of male phenotype. Germline abnormalities were examined using microscopy at different developmental stages. The DNA damage response was evaluated through the expression of the atm-1, atl-1 and pCHK-1. Apoptosis was quantified by monitoring cell death during the pachytene stage. LC-MS was used to identify bioactive compounds within the extracts. Results: Exposure to L. patula extracts resulted in a dose-dependent reduction in worm survival and larval developmental progress, with no significant impact on the male incidence. Germline defects were observed, including increased nuclear spacing at premeiotic and pachytene stages, altered number of bivalents during diakinesis. These defects correlated with a significant decrease in brood size. Also, L. patula extracts activated the DNA damage response pathway, marked by increased expression of atm-1 and atl-1. Moreover, the extracts induced apoptosis in the germline in a pCHK-1-independent manner. LC-MS analysis revealed 31 potential anti-tumor compounds, supporting the extract’s cytotoxic properties. Conclusions: Lappula patula extracts exhibit potent nematocidal and cytotoxic properties, suggesting their potential for cancer therapy. The observed DNA damage and apoptosis in C. elegans emphasize the extract’s promising role in anti-cancer drug development. Further studies are needed to explore the therapeutic potential of these compounds in clinical settings.
Keywords: Lappula patula; DNA repair; germline development; medicinal plants; herbs; meiosis
LSD2 Is an Epigenetic Player in Multiple Types of Cancer and Beyond
Hyun-Min Kim* and Zifei Liu
Histone demethylases, enzymes responsible for removing methyl groups from histone proteins, have emerged as critical players in regulating gene expression and chromatin dynamics, thereby influencing various cellular processes. LSD2 and LSD1 have attracted considerable interest among these demethylases because of their associations with cancer. However, while LSD1 has received significant attention, LSD2 has not been recognized to the same extent. In this study, we conduct a comprehensive comparison between LSD2 and LSD1, with a focus on exploring LSD2’s implications. While both share structural similarities, LSD2 possesses unique features as well. Functionally, LSD2 shows diverse roles, particularly in cancer, with tissue-dependent roles. Additionally, LSD2 extends beyond histone demethylation, impacting DNA methylation, cancer cell reprogramming, E3 ubiquitin ligase activity and DNA damage repair pathways. This study underscores the distinct roles of LSD2, providing insights into their contributions to cancer and other cellular processes.
Keywords: AOF1; DNA repair; KDM1A; KDM1B; LSD1; LSD2; cancer; histone demethylase.
Torenia sp. extracts contain multiple potent antitumor compounds with nematocidal activity, triggering an activated DNA damage checkpoint and defective meiotic progression
Qinghao Meng, Robert P. Borris and Hyun-Min Kim*
Pharmaceuticals (impact factor 4.9), 2024, 17(5), 611; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11124231/.
Previously, we analyzed 316 herbal extracts to evaluate their potential nematocidal properties in Caenorhabditis elegans. In this study, our attention was directed towards Torenia sp., resulting in reduced survival and heightened larval arrest/lethality, alongside a noticeable decrease in DAPI-stained bivalent structures and disrupted meiotic progression, thus disrupting develop-mental processes. Notably, Torenia sp. extracts activated a DNA damage checkpoint response via the ATM/ATR and CHK-1 pathways, hindering germline development. LC‒MS analysis revealed 13 compounds in the Torenia sp. extracts, including flavonoids, terpenoids, tanshinones, an analog of resveratrol, iridoids, carotenoids, fatty acids, and alkaloids. Of these, 10 are known for their anti-tumor activity, suggesting the potential of Torenia species beyond traditional gardening, extending into pharmaceutical and therapeutic applications.
Keywords: Torenia species; DNA repair; meiosis; germline development; medicinal plants; herbs
LSD2 Is an Epigenetic Player in Multiple Types of Cancer and Beyond
Hyun-Min Kim* and Zifei Liu
Biomolecules (Impact factor 5.8) 2024, 14(5), 553; https://pubmed.ncbi.nlm.nih.gov/38785960/
Exploring the Impact of Onobrychis cornuta and Veratrum lobelianum Extracts on C. elegans: Implications for MAPK Modulation, Germline Development, and Antitumor Properties
Qinghao Meng, Nishit Pathak, Ren Xiaojing and Robert P. Borris and Hyun-Min Kim*
Nutrients (Impact factor 6.6), 2023 Dec 19. https://pubmed.ncbi.nlm.nih.gov/38201838/
In an era of increasing interest in the potential health benefits of medicinal foods, the need to assess their safety and potential toxicity remains a critical concern. While these natural remedies have garnered substantial attention for their therapeutic potential, a comprehensive understanding of their effects on living organisms is essential. We examined 316 herbal extracts to determine their potential nematocidal attributes in Caenorhabditis elegans. Approximately 16% of these extracts exhibited the capacity to induce diminished survival rates and larval arrest, establishing a correlation between larval arrest and overall worm viability. Certain extracts led to an unexpected increase in male nematodes, accompanied by a discernible reduction in DAPI-stained bivalent structures and perturbed meiotic advancement, thereby disrupting the conventional developmental processes. Notably, Onobrychis cornuta and Veratrum lobelianum extracts activated a DNA damage checkpoint response via the ATM/ATR and CHK-1 pathways, thus hindering germline development. Our LC-MS analysis revealed jervine in V. lobelianum and nine antitumor compounds in O. cornuta. Interestingly, linoleic acid replicated phenotypes induced by O. cornuta exposure, including an increased level of pCHK-1 foci, apoptosis, and the MAPK pathway. Mutants in the MAPK pathway mitigated the decline in worm survival, underscoring its importance in promoting worm viability. This study reveals complex interactions between herbal extracts and C. elegans processes, shedding light on potential antitumor effects and mechanisms. The findings provide insights into the complex landscape of herbal medicine’s impact on a model organism, offering implications for broader applications.
Keywords: DNA repair; O. cornuta; V. lobelianum; germline; linoleic acid; meiosis.
Experimental Insights into the Interplay between Histone Modifiers and p53 in Regulating Gene Expression
Int. J. Mol. Sci.(impact factor 6.2) 3 July 2023. https://pubmed.ncbi.nlm.nih.gov/37446210/
Hyun-Min Kim*, Xiaoyu Zheng and Ethan Lee
Chromatin structure plays a fundamental role in regulating gene expression, with histone modifiers shaping the structure of chromatin by adding or removing chemical changes to histone proteins. The p53 transcription factor controls gene expression, binds target genes, and regulates their activity. While p53 has been extensively studied in cancer research, specifically in relation to fundamental cellular processes, including gene transcription, apoptosis, and cell cycle progression, its association with histone modifiers has received limited attention. This review explores the interplay between histone modifiers and p53 in regulating gene expression. We discuss how histone modifications can influence how p53 binds to target genes and how this interplay can be disrupted in cancer cells. This review provides insights into the complex mechanisms underlying gene regulation and their implications for potential cancer therapy.
A Decade of CRISPR-Cas Gnome Editing in C. elegans
Hyun-Min Kim*, Yebin Hong and Jiani Chen
Int. J. Mol. Sci.(impact factor 6.2), 2022, 23(24), 15863 https://pubmed.ncbi.nlm.nih.gov/36555505/
CRISPR-Cas allows us to introduce desired genome editing, including mutations, epitopes, and deletions, with unprecedented efficiency. The development of CRISPR-Cas has progressed to such an extent that it is now applicable in various fields, with the help of model organisms. C. elegans is one of the pioneering animals in which numerous CRISPR-Cas strategies have been rapidly established over the past decade. Ironically, the emergence of numerous methods makes the choice of the correct method difficult. Choosing an appropriate selection or screening approach is the first step in planning a genome modification. This report summarizes the key features and applications of CRISPR-Cas methods using C. elegans, illustrating key strategies. Our overview of significant advances in CRISPR-Cas will help readers understand the current advances in genome editing and navigate various methods of CRISPR-Cas genome editing.
Keywords: C. elegans; CRISPR; Cas; genome editing; genome engineering.
杜克昆山大学Hyun Min Kim教授实验室招收硕士研究生、博士后、科研专家 Application for the Master of Science Program at Duke Kunshan University
杜克昆山大学Hyun Min Kim教授实验室招收硕士研究生、博士后、科研专家
Kim教授在杜克昆山大学的实验室，主要研究秀丽隐杆线虫 (C. elegans) 遗传和DNA损伤修复机制。
Hyun Min Kim 教授曾在哈佛医学院完成博士后的研究工作，在Nature、Cell等高水平学术期刊上发表数十篇学术论文。成功应聘者能在较短时间内发表高水平学术论文，并有机会到国外高水平学术机构继续深造。
杜克昆山大学为武汉大学和杜克大学联合办学的高等国际学校，学校具有优秀的实验环境，强大的科研背景，汇聚了世界各地高水平教授。
杜克昆山大学自2022年8月起开放招收硕士研究生通道，链接：https://globalhealth.dukekunshan.edu.cn
Kim Lab网站：https://sites.duke.edu/kimlab/
e-mail：hm.k at dukekunshan. edu. cn
由于Professor Kim为外籍全职在华教授，因此非常青睐有英语交流能力的学生，如果你的英语能力不强也不要担心，随着不断的练习你的英语能力也会有非常大的提升，这将对你今后的个人发展有非常大的助益。
英文原版招生信息如下，欢迎大家报名：
Application for the Master of Science Program at Duke Kunshan University
Dear students,
We are recruiting Graduate students for the Master of Science program in my lab.
Advantages
1. This program offers a degree from Duke therefore, you will receive a Duke degree in the USA after graduation. Duke is one of the top-class universities in the world. This is a three-year course for MS degree. Please find more details at the website
https://globalhealth.dukekunshan.edu.cn
2. The program offers the world’s top-class level of faculties and education.
3. Duke Kunshan, located at Kushan Suzhou, provides a very modern and high-tech environment. Kunshan is a beautiful city located in Suzhou.
4. Once you get admitted, you may be eligible for the support of the full tuition fee.
5. You will be appointed to my lab and receive my research guidance. You are expected to work in the lab and to research for publication. Please find more information at Professor Kim lab https://sites.duke.edu/kimlab/
6. Application starts in August 2022. Since the schedule is very tight, you must prepare the application soon. Please see more details at https://globalhealth.dukekunshan.edu.cn
If you want to apply for the my lab for the MS study, e-mail your 1) transcript and 2) Resume/CV to me at hm.k @ dukekunshan. edu. cn
Histone demethylase AMX-1 regulates fertility in a p53/CEP-1 dependent manner, 2022
Xiaojing Ren, Sisi Tian, Qinghao Meng, Hyun-Min Kim*.
Histone methylation shapes the epigenetic configuration and adjusts multiple fundamental nuclear processes, including transcription, cell cycle control and DNA repair. The absence of histone demethylase LSD1/SPR-5 leads to progressive fertility defects as well as a reduction in brood size. Similarly, C. elegans LSD2 homolog AMX-1 has been implicated in regulating H3K4me2 and maintaining interstrand crosslinks (ICL) susceptibility. However, the mechanisms of how lack of AMX-1 induces sterility have not been addressed so far. This study investigated the histone demethylase AMX-1 in C. elegans and uncovered how amx-1 contributes to sterility in a p53/CEP-1 dependent manner. We show that while sterility in spr-5 mutants exhibited progressive over generations, amx-1 mutants displayed non-transgenerational fertility defects. Also, amx-1 mutants exhibited a reduced number of sperms and produced low brood size (LBS) or sterile worms that retain neither sperms nor germline nuclei, suggesting that fertility defects originated from germline development failure. Surprisingly, sterility exhibited in amx-1 was mediated by p53/CEP-1 function. Consistent with this result, upregulation of Piwi expression in amx-1 mutants suggested that AMX-1 is essential for germline development by regulating Piwi gene expressions. We propose that AMX-1 is required for proper Piwi expression and transposon silencing in a p53/CEP-1 dependent manner; thus, the absence of AMX-1 expression leads to defective meiotic development and sterility. This study elucidates how LSD2/AMX-1 contributes to sterility, therefore, expanding the boundaries of histone demethylase function.
Keywords: CEP-1; LSD2; Piwi; fertility; histone methylation; p53; sterility; transposon.
