Faheem Heba, Alawadhi Rana, Basha Eman H, Abd Ellatif Rasha A, Abdel-Kareem Mona A, Abd El-Azeem Alaa H, Elkordy Alaa, Nasef Nahla Anas, Dawood Lamees Mohamed, El Tabaa Maram Mohammed, El Tabaa Manar Mohammed, Rizk Fatma H
Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt.
Science Department, College of Basic Education, Paaet, Kuwait.
Compr Physiol. 2025 Oct;15(5):e70039. doi: 10.1002/cph4.70039.
Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with liver failure. Nesfatin-1 is a neuropeptide characterized by its antioxidant and anti-inflammatory properties.
This study aimed to evaluate the neuroprotective and hepatoprotective effects of nesfatin-1 in a thioacetamide (TAA)-induced rat model of acute HE. Additionally, the study aimed to examine the underlying mechanisms, particularly the role of the PI3K/Akt/Nrf2/HO-1 signaling pathway.
Male Sprague Dawley rats were divided into five groups: (1) untreated control, (2) nesfatin-1-treated control, (3) thioacetamide-induced hepatic encephalopathy (HE), (4) HE + nesfatin-1, and (5) HE + nesfatin-1 + zinc protoporphyrin IX (ZnPP IX; HO-1 inhibitor). Assessments included behavioral analysis, serum liver function biomarkers, oxidative stress and inflammatory markers, brain water content, mRNA expression of HO-1 (Heme Oxygenase 1) and GFAP (Glial Fibrillary Acidic Protein), PI3K/Akt/Nrf2 protein levels, as well as histological and immunohistochemical evaluations.
Nesfatin-1 significantly improved psychomotor activity, reduced serum ALT, AST, total bilirubin, and ammonia levels, and increased albumin. It also lowered brain MDA, TNF-α, IL-6, and CRP levels, reduced brain water content, and upregulated the expression of HO-1 and GFAP. Furthermore, nesfatin-1 activated the PI3K/Akt/Nrf2 pathway and inhibited the expression of caspase-3 and NF-κB in liver and brain tissues. These protective effects were negated by HO-1 inhibition using ZnppIX. Histological analysis demonstrated the structural integrity of liver and brain tissues in rats treated with nesfatin-1.
Nesfatin-1 exerts potent hepatoprotective and neuroprotective effects in TAA-induced hepatic encephalopathy via antioxidative, anti-inflammatory, and antiapoptotic mechanisms involving the PI3K/Akt/Nrf2/HO-1 pathway.
肝性脑病（HE）是一种与肝功能衰竭相关的神经精神障碍。Nesfatin-1是一种具有抗氧化和抗炎特性的神经肽。
本研究旨在评估Nesfatin-1在硫代乙酰胺（TAA）诱导的急性HE大鼠模型中的神经保护和肝保护作用。此外，该研究旨在探讨潜在机制，特别是PI3K/Akt/Nrf2/HO-1信号通路的作用。
将雄性Sprague Dawley大鼠分为五组：（1）未处理的对照组，（2）Nesfatin-1处理的对照组，（3）硫代乙酰胺诱导的肝性脑病（HE）组，（4）HE + Nesfatin-1组，以及（5）HE + Nesfatin-1 + 锌原卟啉IX（ZnPP IX；HO-1抑制剂）组。评估包括行为分析、血清肝功能生物标志物、氧化应激和炎症标志物、脑含水量、HO-1（血红素加氧酶1）和GFAP（胶质纤维酸性蛋白）的mRNA表达、PI3K/Akt/Nrf2蛋白水平，以及组织学和免疫组织化学评估。
Nesfatin-1显著改善精神运动活动，降低血清ALT、AST、总胆红素和氨水平，并增加白蛋白。它还降低了脑MDA、TNF-α、IL-6和CRP水平，降低了脑含水量，并上调了HO-1和GFAP的表达。此外，Nesfatin-1激活了PI3K/Akt/Nrf2通路，并抑制了肝脏和脑组织中caspase-3和NF-κB的表达。使用ZnppIX抑制HO-1可消除这些保护作用。组织学分析表明，Nesfatin-1处理的大鼠肝脏和脑组织结构完整。
Nesfatin-1通过涉及PI3K/Akt/Nrf2/HO-1通路的抗氧化、抗炎和抗凋亡机制，在TAA诱导的肝性脑病中发挥强大的肝保护和神经保护作用。
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