Triploid Pacific oyster Crassostrea gigas exhibits notable differences in fecundity, with the majority being sterile individuals, referred to as female β, which produce few oocytes, while a minority are fertile individuals, referred to as female α, which produce abundant oocytes. However, the molecular mechanisms underlying these differences in triploid fecundity remain poorly understood. CDC42 has been implicated in processes related to increased DNA damage and genomic instability. Here, we investigate the crucial role of CDC42 in DNA damage repair during oogenesis in triploid C. gigas. Immunofluorescence analysis of γH2AX, a marker for DNA double-stranded breaks, showed significantly higher levels of DNA damage in gonadal cells of triploids compared to diploids, particularly in female β. Histological and ultrastructural analyses revealed abnormal germ cells, termed β gonia, characterized by giant nuclei condensed into irregular chromosome-like chromatin, present in triploid gonadal follicles. RNAseq and proteomic analyses revealed significantly elevated CDC42 expression in triploid gonads compared to the diploids. Inhibition of CDC42 activity in triploids using ZCL278, a CDC42-specific inhibitor, resulted in a significant reduction in DNA damage, increased oocyte numbers, and a decrease in β gonia count. Transcriptome profiling revealed that CDC42 inhibition upregulated the PI3K-AKT signaling pathway along with DNA repair activation. Overall, our findings suggest that overexpression of CDC42 during oogenesis in triploid C. gigas impedes DNA repair, leading to the accumulation of DNA damage, and consequently, oogenesis blockade and abnormal germ cell differentiation. Conversely, inhibition of CDC42 activity activates the PI3K-AKT signaling pathway and promotes DNA repair, thereby mitigating DNA damage and facilitating oogenesis in triploids. This study provides new insights into the molecular mechanisms of sterility in female triploid C. gigas.

2024-10-01·Biomedicine & Pharmacotherapy

Pharmacokinetic profiling of ZCL-278, a cdc42 inhibitor, and its effectiveness against chronic kidney disease

Article

作者: Lu, Liqian ; Liu, Zhangsuo ; Zhou, Chunyu ; Wang, Pei ; Qin, Zhiying ; Liu, Dongwei ; Wang, Jiao ; Lu, Manman ; Zhang, Qing ; Wang, Qiang

ZCL-278 is a selective small molecule specifically inhibiting the Cdc42-intersectin interaction, yet its in-vivo pharmacokinetic and pharmacodynamic properties against renal diseases had not been determined. Thus, our study explored the absorption, distribution and excretion of ZCL-278 as well as its pharmacological efficacy against chronic kidney disease (CKD). With the optimized detection method, absolute oral bioavailability of ZCL-278 was determined as 10.99 % in male and 17.34 % in female rats. ZCL-278 was rapidly and abundantly distributed in various tissues, especially the kidney and heart, while few excreted through urine and feces. In the adenine-induced CKD mice, the increased plasma creatinine and urea, the decreased body weight as well as the renal pathological alterations, including vacuolization of renal tubular epithelial cells, granular degeneration, cell flattening, luminal dilation, and cylindruria, were significantly ameliorated after ZCL-278 administration. Moreover, ZCL-278 could also reverse the increased intensities of renal inflammation and fibrosis in the CKD mice. These results clarified the pharmacokinetics of ZCL-278 in rats and preliminarily indicated that ZCL-278 has favorable pharmacodynamic properties for CKD primed for lead development and optimization, warranting further drug development.

2019-06-03·Cancer Biology & Therapy

Inhibition of Cdc42–intersectin interaction by small molecule ZCL367 impedes cancer cell cycle progression, proliferation, migration, and tumor growth

Article

作者: Chen, Yan-Hua ; Aguilar, Byron J. ; Zhao, Yaxue ; Huo, Shouquan ; Zhou, Huchen ; Lu, Qun

Cdc42 is a member of the Rho family of small GTPases that are at the crossroads of major oncogenic signaling pathways involved in both lung and prostate cancers. However, the therapeutic potential of Cdc42 regulation is still unclear due to the lack of pharmacological tools. Herein, we report that ZCL367 is a bona fide Cdc42 inhibitor that suppressed cancer development and ZCL278 can act as a partial Cdc42 agonist. In lung cancer cell lines with varying EGFR and Ras mutations as well as both androgen-independent and androgen-dependent prostate cancer cell lines, ZCL367 impeded cell cycle progression, reduced proliferation, and suppressed migration. ZCL367 decreased Cdc42-intersectin interactions and reduced Cdc42-mediated filopodia formation. ZCL367 showed increased potency and selectivity for Cdc42 when compared to Rac1 and RhoA. ZCL367 reduced A549 tumorigenesis in a xenograft mouse model. Altogether, ZCL367 is a selective Cdc42 inhibitor and an excellent candidate for lead compound optimization for further anticancer studies.

100 项与 ZCL278 相关的药物交易

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