Paradoxical effects of inhibition of Δ14-reductase and Δ7-reductase on porcine oocyte maturation and subsequent embryo development after parthenogenetic activation

Article

作者: Cha, Dabin ; Lee, Byeong Chun ; Lee, Sanghoon ; Kim, Geon A ; Jin, Jun-Xue

Follicular fluid-derived meiosis-activating sterol (FF-MAS), an intermediate in the cholesterol biosynthesis pathway, plays a crucial role in the meiotic resumption of mammalian oocytes. Maintaining a high concentration of FF-MAS in vitro is challenging; therefore, AY9944 A-7, an inhibitor of Δ14-reductase [which converts FF-MAS to testis meiosis-activating sterol (T-MAS)] and Δ7-reductase (which converts T-MAS to cholesterol), has been used to enhance oocyte maturation. This study examined the effects of various concentrations (0, 10, 20, and 40 μM) of AY9944 A-7 on porcine oocyte maturation and subsequent embryo development. Results indicate that treatment with 10 and 20 μM AY9944 A-7 during in vitro maturation (IVM) enhanced oocyte nuclear maturation, with 10 μM significantly increasing the transcript expression of oocyte maturation-related genes. However, blastocyst formation rates significantly decreased in oocytes treated with AY9944 A-7 concentrations above 10 μM. To explore these unexpected findings, the study evaluated the effects of AY9944 A-7 on lipid content in oocytes and the sonic hedgehog (SHH) signaling pathway in subsequent parthenogenetic embryos. A concentration-dependent decrease in oocyte lipid content was observed following AY9944 A-7 treatment. Additionally, transcripts of SHH signaling pathway genes were detected in preimplantation-stage parthenogenetic embryos, with reduced expression in the 10 μM AY9944 A-7-treated group. Taken together, AY9944 A-7 supplementation during porcine IVM enhanced oocyte maturation by accumulating FF-MAS, but subsequent embryo development was impaired due to cholesterol deficiency, potentially mediated by SHH signaling downregulation.

2024-12-01·JOURNAL OF LIPID RESEARCH

Toxoplasma gondii sustains survival by regulating cholesterol biosynthesis and uptake via SREBP2 activation

Article

作者: Xu, Xiulong ; Zhang, Qing-Qi ; Pan, Ming ; Hou, Zhao-Feng ; Huang, Si-Yang ; Fan, Yi-Min ; Fu, Lizhi

Toxoplasma gondii (T. gondii) is an obligate intracellular parasite that cannot biosynthesize cholesterol via the mevalonate pathway, it sources this lipid from its host. We discovered that T. gondii infection upregulated the expression of host cholesterol synthesis-related genes HMG-CoA reductase(HMGCR), squalene epoxidase (SQLE), and dehydrocholesterol reductase-7 (DHCR7), and increased the uptake pathway gene low-density lipoprotein receptor (LDLR). We found a protein, sterol regulatory element binding protein 2 (SREBP2), which is the key protein regulating the host cholesterol synthesis and uptake during T. gondii infection. T. gondii induced a dose-dependent nuclear translocation of SREBP2. Knockdown SREBP2 reduced T. gondii-induced cholesterol biosynthesis and uptake. Consequently, the parasite's ability to acquire cholesterol was significantly diminished, impairing its invasion, replication, and bradyzoites development. Interfering cholesterol metabolism using AY9944 effectively inhibited T. gondii replication. In summary, SREBP2 played an important role in T. gondii infection in vitro, serving as a potential target for regulating T. gondii-induced cholesterol metabolism, offering insights into the prevention and treatment of toxoplasmosis.

2024-03-01·Veterinary microbiology

Inhibition of pseudorabies virus replication via upregulated interferon response by targeting 7-dehydrocholesterol reductase

Article

作者: Jiang, Chenlong ; Guo, Lei ; Liu, Depeng ; Jiang, Ping ; Ma, Zicheng ; Liu, Xing ; Gao, Yanni ; Pan, Mengjiao ; Bai, Juan

Pseudorabies virus (PRV) is an alpha-herpesvirus capable of infecting a range of animal species, particularly its natural host, pigs, resulting in substantial economic losses for the swine industry. Recent research has shed light on the significant role of cholesterol metabolism in the replication of various viruses. However, the specific role of cholesterol metabolism in PRV infection remains unknown. Here, we demonstrated that the expression of 7-dehydrocholesterol reductase (DHCR7) is upregulated following PRV infection, as evidenced by the proteomic analysis. Subsequently, we showed that DHCR7 plays a crucial role in promoting PRV replication by converting 7-dehydrocholesterol (7-DHC) into cholesterol, leading to increased cellular cholesterol levels. Importantly, DHCR7 inhibits the phosphorylation of interferon regulatory factor 3 (IRF3), resulting in reduced levels of interferon-beta (IFN-β) and interferon-stimulated genes (ISGs). Finally, we revealed that the DHCR7 inhibitor, trans-1,4-bis(2-chlorobenzylaminomethyl) cyclohexane dihydrochloride (AY9944), significantly suppresses PRV replication both in vitro and in vivo. Taken together, the study has established a connection between cholesterol metabolism and PRV replication, offering novel insights that may guide future approaches to the prevention and treatment of PRV infections.

100 项与 AY-9944 相关的药物交易

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