Article
Cell Biology
Jana Petrusova, Jasper Manning, Dominik Filipp
Summary: This article discusses the potential role of the autoimmune regulator AIRE in male infertility. The authors found that Aire is exclusively expressed in Sertoli cells in the testes and propose an unknown mechanism by which testicular Aire regulates fertility. This challenges the current perception of Aire's function in the testes.
Article
Developmental Biology
Yi Jacky Peng, Xinyu Thomas Tang, Hui Sophie Shu, Wenjie Dong, Hongfang Shao, Bo O. Zhou
Summary: The study found that testicular stromal cells, including Sertoli, endothelial, Leydig, smooth muscle, and Tcf21-CreER+ stromal cells, express stem cell factor (SCF), an essential growth factor for spermatogenesis. Undifferentiated and differentiating spermatogonia were associated with SCF-expressing Sertoli cells. Conditional deletion of SCF from Sertoli cells blocked the differentiation of spermatogonia, leading to male infertility. Conditional overexpression of SCF in Sertoli cells significantly increased spermatogenesis.
Article
Environmental Sciences
Weiqi Sun, Fang Tian, Hongjie Pan, Xiuli Chang, Minjie Xia, Jingying Hu, Yuzhu Wang, Runsheng Li, Weihua Li, Mingjun Yang, Zhijun Zhou
Summary: This study systematically explored the male reproductive toxicity of FLC and found that it caused testicular dysfunction and damage in mice, leading to abnormal spermatogenesis and decreased sperm quality. The potential mechanisms include interference with spermatogonial proliferation and meiosis, as well as apoptosis and mitochondrial damage in testicular Sertoli cells.
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
(2022)
Review
Obstetrics & Gynecology
Indrashis Bhattacharya, Souvik Sen Sharma, Subeer S. Majumdar
Summary: Spermatogenesis is a complex process involving interactions between germ cells and testicular cells. Male infertility can be caused by congenital abnormalities, genetic mutations, endocrine/metabolic dysfunction, environmental toxicant exposure, and lifestyle-related disorders. Despite extensive research, a significant number of infertility cases remain idiopathic, highlighting the need for a better understanding of the regulation of spermatogenesis. Dysfunction of testicular Sertoli cells has emerged as a potential underlying cause of male infertility.
REPRODUCTIVE SCIENCES
(2023)
Review
Cell Biology
Liza O'Donnell, Lee B. Smith, Diane Rebourcet
Summary: Sertoli cells play essential roles in spermatogenesis, supporting germ cell development and regulating other testis somatic cells. They are crucial for maintaining the stem cell niche, facilitating meiosis and spermiogenesis, and regulating androgen production.
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
(2022)
Review
Endocrinology & Metabolism
Sheng Gao, Xiaolong Wu, Lingling Wang, Tiao Bu, Adolfo Perrotta, Giuseppe Guaglianone, Bruno Silvestrini, Fei Sun, C. Yan Cheng
Summary: Emerging evidence suggests that environmental toxicants like cadmium and PFOS may disrupt Sertoli cell and testis function through signaling proteins and cascades similar to pharmaceuticals. This indicates that toxicants may be interfering with physiological mechanisms that support spermatogenesis. Manipulating the expression of these signaling proteins could potentially manage toxicant-induced male reproductive dysfunction.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Review
Endocrinology & Metabolism
Juho-Antti Makela, Jorma Toppari
Summary: The RB protein family members play crucial roles in cell cycle progression, apoptosis, and stem cell self-renewal and differentiation. RB proteins exert their effects through interaction with E2F transcription factors. RB and E2F family members are widely and dynamically expressed in the testis and have versatile roles during spermatogenesis. RB-E2F interaction is critical for male fertility and proper germline maintenance and lifelong sperm production.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Cell Biology
Yoshifumi Mori, Seiji Takashima, Mito Kanatsu-Shinohara, Zheng Yi, Takashi Shinohara
Summary: The study found that Cdc42 is essential for the development of the germline niche, as its deficiency results in a significant reduction in the number of spermatogonial stem cells in the testes, affecting GDNF expression and Sertoli cell development.
Article
Cell Biology
Junjie Xu, Mengmeng Sang, Jinmei Cheng, Chunhai Luo, Jie Shi, Fei Sun
Summary: In this study, the role of DAAM2 in cytoskeleton and phagocytosis of rat Sertoli cells was investigated through siRNA transfection and intratesticular injection. Knockdown of DAAM2 attenuated marker expression related to cytoskeleton and tight junction, as well as the integrity of Sertoli cell monolayer. Loss of DAAM2 in rats resulted in disarrangement and deformation of sperms, accumulation of apoptotic sperms, and abnormalities in the blood-testis barrier, indicating its involvement in spermatogenesis.
MOLECULAR AND CELLULAR ENDOCRINOLOGY
(2023)
Article
Obstetrics & Gynecology
Arthi Thirumalai, John K. Amory
Summary: There have been promising advances in male contraception research, including novel hormonal and nonhormonal approaches. These research efforts aim to provide a wider range of contraceptive options for couples to choose from.
FERTILITY AND STERILITY
(2021)
Article
Agriculture, Dairy & Animal Science
Yi Zheng, Qiang Gao, Tianjiao Li, Ruifang Liu, Zechao Cheng, Ming Guo, Jinhong Xiao, De Wu, Wenxian Zeng
Summary: The study systematically investigated the development patterns of Sertoli cells and spermatogonia in pigs from neonate to sexual maturity, shedding light on previously unknown details. The findings not only expand knowledge about spermatogenesis and testicular development in pigs, but also provide a theoretical basis for porcine breeding and rearing.
JOURNAL OF ANIMAL SCIENCE AND BIOTECHNOLOGY
(2022)
Review
Endocrinology & Metabolism
Wasim Shah, Ranjha Khan, Basit Shah, Asad Khan, Sobia Dil, Wei Liu, Jie Wen, Xiaohua Jiang
Summary: The process of spermatogenesis relies on hormones and growth factors acting through endocrine and paracrine pathways. Sertoli cells are major regulators, while sex hormones play a significant role in determining their proliferation.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Article
Endocrinology & Metabolism
Lingling Wang, Ming Yan, Huitao Li, Siwen Wu, Renshan Ge, Chris K. C. Wong, Bruno Silvestrini, Fei Sun, C. Yan Cheng
Summary: Adjudin is a nonhormonal male contraceptive that induces reversible male infertility without perturbing hormone levels. It works by disrupting specific junctions in the testis to induce spermatid exfoliation, without affecting germ cell development. Studies suggest that its contraceptive effects are mediated through changes in microtubule associated proteins and signaling proteins.
Article
Multidisciplinary Sciences
Wei Yang, Li-Bo Liu, Feng-Liang Liu, Yan-Hua Wu, Zi-Da Zhen, Dong-Ying Fan, Zi-Yang Sheng, Zheng-Ran Song, Jia-Tong Chang, Yong-Tang Zheng, Jing An, Pei-Gang Wang
Summary: Through single-cell RNA sequencing of ZIKV-infected mouse testes, it is found that spermatogenic cells, especially spermatogonia, are vulnerable to ZIKV infection. The complement system genes are significantly upregulated in infiltrated S100A4 + monocytes/macrophages. Complement activation and testicular damage are verified in ZIKV-infected macaques and the complement inhibitor C1INH and S100A4 inhibitors sulindac and niclosamide are tested. C1INH alleviates testicular pathology but worsens ZIKV infection, while niclosamide effectively reduces infiltration, inhibits complement activation, alleviates testicular damage, and improves fertility. This discovery highlights the importance of male reproductive health protection during future ZIKV epidemics.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Fengling Lai, Haoyu Wang, Xinyue Zhao, Kangning Yang, Le Cai, Mengxin Hu, Lan Lin, Xizhong Xia, Wei Li, Hanhua Cheng, Rongjia Zhou
Summary: In this study, a mouse model with Sertoli cells-specific knockout of Rnf20 was generated using conditional knockout technology. The Amh-Rnf20(-/-) male mice exhibited infertility due to spermatogenic failure, resembling the Sertoli cell-only syndrome in humans. Knockout of Rnf20 resulted in loss of H2BK120ub in the Sertoli cells, impairing the transcription elongation of Cldn11, a gene encoding a component of tight junction. Importantly, RNF20 deficiency disrupted cell adhesion, caused disorganization of seminiferous tubules, and induced apoptotic cell death in spermatogonia and spermatocytes.
CELL AND BIOSCIENCE
(2023)
Article
Chemistry, Medicinal
Jiewei Jiang, Logan H. Sigua, Alice Chan, Prakriti Kalra, William C. K. Pomerantz, Ernst Schonbrunn, Jun Qi, Gunda Georg
Summary: The study focused on structural modifications of a previously reported compound to improve affinity for BRDT by altering linker length and type. The analogs were found to be highly selective for BET bromodomains, with a preference for the BD1 and BD2 bromodomains of BRD4 over BRDT.
Article
Pharmacology & Pharmacy
Erick J. Carlson, Gunda Georg, Jon E. Hawkinson
Summary: In this study, it was found that medroxyprogesterone acetate, levonorgestrel, and aldosterone selectively antagonize the calcium influx induced by progesterone and prostaglandin E1 through the CatSper cation channel in human sperm. Unlike T-type calcium channel blockers, these steroid antagonists preferentially reduce hyperactivated sperm motility, which is essential for fertilization. The discovery of these competitive antagonists provides a starting point for the development of male contraceptive agents acting through this unique mechanism.
MOLECULAR PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Erick J. Carlson, Rawle Francis, Yutong Liu, Ping Li, Maximilian Lyon, Celia M. Santi, Derek J. Hook, Jon E. Hawkinson, Gunda Georg
Summary: This study identified novel inhibitors targeting the cation channel of sperm and investigated one promising compound in depth. These inhibitors showed high selectivity for CatSper channel and inhibited hyperactivated sperm motility.
Article
Chemistry, Medicinal
Jiewei Jiang, Pei-Liang Zhao, Logan H. Sigua, Alice Chan, Ernst Schonbrunn, Jun Qi, Gunda Georg
Summary: Nine lactone ring-opened ester and seven amide analogs were synthesized based on a previously reported virtual screening hit. However, there was no significant improvement in the affinity and selectivity for BET bromodomains. X-ray analysis showed that the ester side chain was located near the ZA loop and exposed to solvent.
ARCHIV DER PHARMAZIE
(2022)
Article
Chemistry, Medicinal
Xianghong Guan, Narsihmulu Cheryala, Rezaul Md. Karim, Alice Chan, Norbert Berndt, Jun Qi, Gunda I. Georg, Ernst Schonbrunn
Summary: Bromodomain and extraterminal domain (BET) proteins, including BRD4 and BRDT, play crucial roles in gene transcription and chromatin remodeling. Novel bivalent inhibitors show increased activity and selectivity for BRDT, due to differential plasticity of BET bromodomains upon inhibitor-induced dimerization. X-ray crystallographic and solution studies reveal unique structural states of BET proteins upon interaction with bivalent inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Raymond K. Hau, Joseph S. Tash, Gunda I. Georg, Stephen H. Wright, Nathan J. Cherrington
Summary: This study characterizes the carrier-mediated processes that allow H2-GMZ and other drugs to enter Sertoli cells, and explores the impact of the blood-testis barrier on the pharmacokinetics and pharmacodynamics of drugs.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2022)
Correction
Chemistry, Medicinal
Erick J. Carlson, Rawle Francis, Yutong Liu, Ping Li, Maximilian Lyon, Celia M. Santi, Derek J. Hook, Jon E. Hawkinson, Gunda I. Georg
Article
Chemistry, Medicinal
Jillian L. Kyzer, Md Abdullah Al Noman, Rebecca A. D. Cuellar, Sanny S. W. Chung, Soma Maitra, Tahmina Naqvi, Jon E. Hawkinson, Debra J. Wolgemuth, Gunda I. Georg
Summary: Retinoic acid receptor alpha (RAR alpha) antagonist ER-50891 and its 15 analogs were studied for their potency and selectivity at RAR alpha, RAR beta, and RAR gamma in vitro. Minor modifications to the parent molecule, such as introducing a C4 tolyl group instead of the C4 phenyl group on the quinoline moiety, slightly increased the selectivity for RAR alpha, while larger substituents significantly decreased potency. Replacement of the pyrrole moiety of ER-50891 with triazole, amides, or a double bond resulted in inactive compounds. ER-50891 was stable in male mouse liver microsomes and its effects on spermatogenesis were observed in male mice, showing characteristic albeit modest and transient effects.
ARCHIV DER PHARMAZIE
(2023)
Editorial Material
Chemistry, Medicinal
Jane Aldrich, Shelley Allen, Erika Araujo, Joanne Bronson, Amanda Bryant-Friedrich, Shana K. Cyr, Erin F. DiMauro, Carolyn Dzierba, Amanda L. Garner, Gunda I. Georg, Nicole C. Goodwin, Krupanandan Haranahalli, Rong Huang, Katerina Leftheris, Tricia L. May-Dracka, Margaret E. Olson, Maria-Jesus Blanco
Summary: On March 8, 2023, the International Women's Day, we want to celebrate and highlight the contributions of many women volunteers in the American Chemical Society Division of Medicinal Chemistry (ACS MEDI).
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Editorial Material
Chemistry, Medicinal
Maria-Jesus Blanco, Amanda Bryant-Friedrich, Gunda Georg, Amjad Ali, Paul L. L. Ornstein, Lori Ferrins, Paul C. C. Trippier
Summary: The American Chemical Society Division of Medicinal Chemistry (MEDI) awards achievements in medicinal chemistry through a variety of awards, fellowships, and honors. In celebration of the Gertrude Elion Medical Chemistry Award, the ACS MEDI Division wishes to inform the community about the numerous awards, fellowships, and travel grants available to members.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Editorial Material
Chemistry, Medicinal
Jane Aldrich, Shelley Allen, Erika Araujo, Joanne Bronson, Amanda Bryant-Friedrich, Shana K. Cyr, Erin F. DiMauro, Carolyn Dzierba, Amanda L. Garner, Gunda I. Georg, Nicole C. Goodwin, Krupanandan Haranahalli, Rong Huang, Katerina Leftheris, Tricia L. May-Dracka, Margaret E. Olson, Maria-Jesus Blanco
Summary: On the occasion of the 2023 International Women's Day on March 8, 2023, we want to celebrate and highlight the contributions of many women volunteers in the American Chemical Society Division of Medicinal Chemistry (ACS MEDI).
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Editorial Material
Chemistry, Medicinal
Maria-Jesus Blanco, Amanda Bryant-Friedrich, Gunda Georg, Amjad Ali, Paul L. Ornstein, Lori Ferrins, Paul C. Trippier
Summary: The American Chemical Society Division of Medicinal Chemistry (MEDI) bestows a range of awards, fellowships, and honors to acknowledge outstanding contributions in medicinal chemistry. In celebration of the creation of the Gertrude Elion Medical Chemistry Award, the ACS MEDI Division aims to inform the community about the various available awards, fellowships, and travel grants for members.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Biographical-Item
Chemistry, Medicinal
David P. Rotella, Gunda Georg
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Md Abdullah Al Noman, Rebecca A. D. Cuellar, Jillian L. Kyzer, Sanny S. W. Chung, Narsihmulu Cheryala, Trinh A. D. Holth, Soma Maitra, Tahmina Naqvi, Henry L. Wong, Ernst Schonbrunn, Jon E. Hawkinson, Debra J. Wolgemuth, Gunda I. Georg
Summary: A series of retinoic acid analogs based on dihydronaphthalene and chromene scaffolds were synthesized and evaluated in vitro. Compound 21, a chromene amide analog, was identified as the most potent retinoic acid receptor alpha antagonist with favorable physicochemical properties and pharmacokinetic profile. In a mouse model, compound 21 showed modest effects on spermatogenesis at low doses, but did not impact fertility. Further investigation on its effects on male fertility may not be warranted.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Physiology
Shirin V. Sundar, Julie Xia Zhou, Brenda S. Magenheimer, Gail A. Reif, Darren P. Wallace, Gunda I. Georg, Sudhakar R. Jakkaraj, Joseph S. Tash, Alan S. L. Yu, Xiaogang Li, James P. Calvet
Summary: Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder characterized by the formation of large fluid-filled cysts. A study found that the lonidamine derivative H2-GMZ inhibits Cl- secretion, cell proliferation, and cyst growth, suggesting its potential therapeutic value for ADPKD treatment.
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
(2022)