Phenylpropanoids of Eleutherococcus senticosus (Rupr. & maxim.) maxim. Alleviate oxidative stress in Alzheimer's disease in vitro and in vivo models by regulating Mst1 and affecting the Nrf2/Sirt3 pathway

Article

Author: Kuang, Hai-Xue ; Li, Meng-Meng ; Zhang, Li-Li ; Liu, Yan ; Xu, Shi-Qi ; Li, Hua ; Guan, Wei ; Meng, Xin ; Yang, Bing-You ; Wang, Si-Yi ; Chen, Qing-Shan ; Zhao, Wei ; Yang, Rui

Alzheimer's disease (AD) is a common neurodegenerative disorder, and oxidative stress plays a significant role in its progression. Owing to its nourishing effects, Eleutherococcus senticosus (Rupr. & maxim.) maxim. (ES) has gained widespread popularity globally as a functional food and long-term consumption has been shown to enhance memory. The phenylpropanoid components extracted from Eleutherococcus senticosus (Rupr. & maxim.) maxim. (ESP) exhibit a diverse array of bioactivities and are commonly employed in the treatment of central nervous system (CNS) disorders. Nonetheless, the exact mechanisms by which ESP alleviates oxidative stress in AD models require further investigation. Therefore, this study utilized SAMP8 mice as models for AD and employed L-glutamate (L-Glu)-induced HT22 cells to establish an in vitro AD model. The effects of ESP on cognitive function were evaluated using the Morris water maze (MWM) test. Additionally, various techniques such as pathology, immunofluorescence staining (IF), ROS staining, cellular thermal shift assay (CETSA), Mst1 inhibitor analysis, and western blotting (WB) were conducted to further investigate the pharmacological efficacy and potential molecular mechanisms of ESP. In vivo, ESP was found to improve cognitive function in SAMP8 mice and alleviate AD-like pathological features. In vitro, ESP reduced intracellular ROS levels. Mechanistically, CETSA analysis confirmed the binding affinity between ESP and Mst1, demonstrated that ESP modulated the Mst1 signaling pathway to mitigate oxidative stress and decrease ROS levels. These findings suggested that ESP holded significant potential for developing therapeutic strategies for AD.

10 Sep 2024·JCI Insight

Inhibiting endothelial cell Mst1 attenuates acute lung injury in mice

Article

Author: Zhang, Chen ; Li, Chao ; Tongmuang, Nopprarat ; Zuo, Mei-Xing ; Hu, Louis ; Summer, Ross ; Guo, Zhi-Fu ; Sun, Jianxin ; Capreri, Daniel

Lung endothelium plays a pivotal role in the orchestration of inflammatory responses to acute pulmonary insults. Mammalian sterile 20-like kinase 1 (Mst1) is a serine/threonine kinase that has been shown to play an important role in the regulation of apoptosis, stress responses, and organ growth. This study investigated the role of Mst1 in lung endothelial activation and acute lung injury (ALI). We found that Mst1 was significantly activated in inflamed lung endothelial cells (ECs) and mouse lung tissues. Overexpression of Mst1 promoted nuclear factor κ-B (NF-κB) activation through promoting JNK and p38 activation in lung ECs. Inhibition of Mst1 by either its dominant negative form (DN-Mst1) or its pharmacological inhibitor markedly attenuated cytokine-induced expression of cytokines, chemokines, and adhesion molecules in lung ECs. Importantly, in a mouse model of lipopolysaccharide-induced (LPS-induced) ALI, both deletion of Mst1 in lung endothelium and treatment of WT mice with a pharmacological Mst1 inhibitor significantly protected mice from LPS-induced ALI. Together, our findings identified Mst1 kinase as a key regulator in controlling lung EC activation and suggest that therapeutic strategies aimed at inhibiting Mst1 activation might be effective in the prevention and treatment of inflammatory lung diseases.

29 Feb 2024·PNAS Nexus

A small molecule MST1/2 inhibitor accelerates murine liver regeneration with improved survival in models of steatohepatitis

Article

Author: Chatterjee, Arnab ; Surakattula, Murali ; Choi, Seung Hyuk ; Smoot, Rory ; Zhu, Siying ; Joseph, Sean ; Pereya, David ; Gores, Gregory ; Maedler, Kathrin ; Kumar, Manoj ; Tremblay, Matthew ; Wang, Chen ; Starlinger, Patrick ; Geravandi, Shirin ; Gamo, Ana ; Tomlinson, Jennifer ; Shen, Weijun ; Roland, Jason ; Li, Sijia ; McCabe, Chantal ; Yu, Shan ; Petrassi, Mike ; Rogers, Nikki ; Baguley, Tyler ; Buckarma, EeeLN ; Lupse, Blaz ; Watkins, Ryan ; Werneburg, Nathan W ; Ardestani, Amin ; Nguyen-Tran, Van

AbstractDysfunctional liver regeneration following surgical resection remains a major cause of postoperative mortality and has no therapeutic options. Without targeted therapies, the current treatment paradigm relies on supportive therapy until homeostasis can be achieved. Pharmacologic acceleration of regeneration represents an alternative therapeutic avenue. Therefore, we aimed to generate a small molecule inhibitor that could accelerate liver regeneration with an emphasis on diseased models, which represent a significant portion of patients who require surgical resection and are often not studied. Utilizing a clinically approved small molecule inhibitor as a parent compound, standard medicinal chemistry approaches were utilized to generate a small molecule inhibitor targeting serine/threonine kinase 4/3 (MST1/2) with reduced off-target effects. This compound, mCLC846, was then applied to preclinical models of murine partial hepatectomy, which included models of diet-induced metabolic dysfunction-associated steatohepatitis (MASH). mCLC846 demonstrated on target inhibition of MST1/2 and reduced epidermal growth factor receptor inhibition. The inhibitory effects resulted in restored pancreatic beta-cell function and survival under diabetogenic conditions. Liver-specific cell-line exposure resulted in Yes-associated protein activation. Oral delivery of mCLC846 perioperatively resulted in accelerated murine liver regeneration and improved survival in diet-induced MASH models. Bulk transcriptional analysis of regenerating liver remnants suggested that mCLC846 enhanced the normal regenerative pathways and induced them following liver resection. Overall, pharmacological acceleration of liver regeneration with mCLC846 was feasible, had an acceptable therapeutic index, and provided a survival benefit in models of diet-induced MASH.

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Preclinical	United States	Mayo Clinic	-
Nonalcoholic Steatohepatitis	Preclinical	Austria	Medical University of Vienna	-

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