Archives of medical research · 2025
Semaphorin 7A Induces Liver Inflammation and Promotes Parenteral Nutrition-Associated Cholestasis via ITGβ1/NF-κB Pathway.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Shen Leilei, Sun Xiaodong, Zheng Ruixue, Tao Min, Chen Sheng
Аннотация
OBJECTIVE: To investigate the mechanistic role of semaphorin 7A (Sema7A) in neonatal parenteral nutrition-associated cholestasis (PNAC).
METHODS: First, we measured the expression levels of Sema7A and inflammatory factors in both neonates with PNAC and rat models. Then, to investigate the mechanism underlying the regulatory role of Sema7A in hepatic inflammatory injury, we assessed NF-κB pathway activation and monitored inflammatory factor variations following Sema7A/integrin β1 (ITGβ1) inhibition and overexpression in rat models and isolated primary Kupffer cells. Furthermore, liver pathology and cholestatic changes were systematically examined by Sema7A manipulation (inhibition and overexpression) in animal models.
RESULTS: Neonates and rats with PNAC showed increased levels of TNF-α and IL-1β, and decreased levels of IL-4 and IL-10. Accordingly, Sema7A, ITGβ1, and P65/p-P65 mRNA and protein expression were elevated. In vitro, Sema7A overexpression activated the NF-κB pathway, which was reversible by ITGβ1 inhibition; conversely, Sema7A knockdown attenuated NF-κB activation, which was partially reversible by ITGβ1 overexpression. In vivo, Sema7A overexpression worsened liver injury and cholestasis through activation of the NF-κB pathway, while its inhibition ameliorated these effects.
CONCLUSIONS: Sema7A activates the NF-κB signaling pathway in an ITGβ1-dependent manner and exacerbates PN-induced liver injury and cholestasis. Targeting Sema7A may provide a therapeutic strategy to alleviate neonatal PNAC.
METHODS: First, we measured the expression levels of Sema7A and inflammatory factors in both neonates with PNAC and rat models. Then, to investigate the mechanism underlying the regulatory role of Sema7A in hepatic inflammatory injury, we assessed NF-κB pathway activation and monitored inflammatory factor variations following Sema7A/integrin β1 (ITGβ1) inhibition and overexpression in rat models and isolated primary Kupffer cells. Furthermore, liver pathology and cholestatic changes were systematically examined by Sema7A manipulation (inhibition and overexpression) in animal models.
RESULTS: Neonates and rats with PNAC showed increased levels of TNF-α and IL-1β, and decreased levels of IL-4 and IL-10. Accordingly, Sema7A, ITGβ1, and P65/p-P65 mRNA and protein expression were elevated. In vitro, Sema7A overexpression activated the NF-κB pathway, which was reversible by ITGβ1 inhibition; conversely, Sema7A knockdown attenuated NF-κB activation, which was partially reversible by ITGβ1 overexpression. In vivo, Sema7A overexpression worsened liver injury and cholestasis through activation of the NF-κB pathway, while its inhibition ameliorated these effects.
CONCLUSIONS: Sema7A activates the NF-κB signaling pathway in an ITGβ1-dependent manner and exacerbates PN-induced liver injury and cholestasis. Targeting Sema7A may provide a therapeutic strategy to alleviate neonatal PNAC.