Frontiers in Bioscience-Landmark
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2025
·Vol. 30
·期 7
·39311
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IF 3.1
Zhao Pan,Li Jiang,Jiacheng Chen,Sicong Xu,Ping Zhang,Yili Yi,Yangzhi Xie,Yongjun Chen
Background:The metabolites derived from judicious dietary choices play a crucial role in the management and treatment of depression. Hydroxy-carboxylic acid receptor 2 (HCAR2) functions as a receptor for various diet-derived metabolites. Although a growing body of evidence indicates these metabolites exert beneficial effects on depression, the precise mechanisms underlying these benefits require further investigation.Methods:We established a mouse model of corticosterone (Cor)-induced depression to evaluate the therapeutic potential of HCAR2 activation on depression. A series of behavioral experiments were conducted to investigate whether HCAR2 activation could alleviate depressive-like behaviors in mice. The neuroprotective effects of HCAR2 in the hippocampus were examined using Nissl and hematoxylin-eosin (HE) staining. The levels of monoamine neurotransmitters in mouse serum were quantified, as well as the cell viability and lactate dehydrogenase (LDH) activity of hippocampal neurons co-cultured with primary microglia. Microglia-associated neuroinflammation was evaluated by quantifying pro-inflammatory cytokines using ELISA, and by assessing the polarization state of M1 microglia, including the mRNA expression levels of M1 markers and double fluorescence staining for inducible nitric oxide synthase/ionized calcium-binding adapter molecule 1 (iNOS/Iba1). The expression level of proteins in the protein kinase B-inhibitor of nuclear factor kappa-B kinase subunits alpha and beta-nuclear factor kappa-light-chain-enhancer of activated B cells (AKT-IKKαβ-NFκB) pathway in primary microglia was analyzed using western blot. Transcriptomic changes in microglia induced by HCAR2 activation were examined through RNA sequencing. Mice were fed PLX5622 chow to deplete microglia in vivo.Results:Activation of HCAR2 by its agonist MK-6892 in a Cor-induced model of depression significantly alleviated depressive-like behaviors, attenuated hippocampal neuronal injury, increased serum monoamine levels, reduced microglia-associated neuroinflammation, and inhibited the expression of proteins in the AKT-IKKαβ-NFκB pathway in primary microglia. Additionally, HCAR2 activation markedly enhanced hippocampal neuronal viability and decreased LDH activity in this co-culture system. Importantly, these protective effects were abolished in HCAR2 knockout mice. RNA sequencing revealed that HCAR2 activation induced changes in multiple signaling pathways. Moreover, the depletion of microglia also eliminated the protective effects of MK-6892.Conclusion:Activation of HCAR2 can reduce depressive-like behaviors, neuronal injury, and neuroinflammation. Our findings suggest these neuroprotective effects are, at least in part, mediated through modulation of microglial activity by HCAR2.
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高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 8
·e70510
·
IF 4.2
Songlun Jiang,Xu Zhang,Fanfan Chen,Zifan Zhao,Chenglong Zhang,Yuchun Sun
Bone organoids offer potential for bone regeneration and in vitro organ models. Current limitations in bone organoid culture systems include low efficiency in construction and functionality, as well as increased apoptosis in prolonged cultures of larger sizes. The ketone body 3-hydroxybutyrate (3HB), synthesized in the liver, addresses these challenges effectively. Our findings suggest that 3HB increases intracellular calcium ion (Ca 2+ ) levels in human bone marrow-derived mesenchymal stem cells (hBMSCs) by activating the hydroxycarboxylic acid receptor 2 (HCAR2). This activation initiates the cAMP/PKA/CREB pathway, which elevates the expression of anti-apoptotic genes such as myeloid cell leukemia 1 (MCL1) and B cell lymphoma 2-related protein A1 (BCL2A1), thereby reducing apoptosis. Furthermore, this pathway boosts the expression of osteogenic proteins, including Runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP2), facilitating osteogenesis in bone organoids. Consequently, 3HB may enhance the construction of bone organoids that are more mature, larger, and have longer viability. Graphical Our study demonstrates that 3-Hydroxybutyrate (3HB) activates the HCAR2 receptor in hBMSCs, leading to an increase in intracellular calcium levels and subsequent activation of the cAMP/PKA/CREB signaling pathway. This pathway upregulates the expression of the anti-apoptotic molecule MCL1 and early osteogenic factors RUNX2 and BMP2. These dual effects of 3HB, promoting osteogenesis and inhibiting apoptosis, provide a promising strategy for constructing more viable and mature bone organoids with higher efficiency.
研究领域:
再生医学
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细胞生物学
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分子生物学
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高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Zihao He,Siyuan Deng,Zhijing Wu,Zheng Cui,Hao Mei,Jinglin Wang,Kaiping Wang,Yu Zhang
Ethnopharmacological relevance Dysfunction of the intestinal barrier was an important trigger for alcoholic liver damage and alcohol had brought about intestinal damage before causing liver damage. The root of Angelica sinensis (Oliv.) Diels, crucial traditional medicinal material, was widely utilized for its blood-invigorating, intestinal-lubricating and gynecological benefits. Angelica sinensis polysaccharide (ASP) was an essential natural active ingredient of Angelica sinensis and exhibited considerable potential for gastrointestinal protection. Nevertheless, the systematic research of ASP on the gastrointestinal tract remained insufficient. Aim of this study To systematically explore the protective effect and underlying mechanisms of ASP against alcohol-induced gastrointestinal injury, including the stomach, ileum and colon. Materials and methods The AFLD mice model was established via the intragastric administration of alcohol twice a day for one week. The protective effect of ASP on the representative segments of the gastrointestinal tract (stomach, ileum and colon) was subsequently studied after confirming its hepatoprotective activity. The impact of ASP on gastrointestinal alcohol metabolism was examined to explain its antioxidant and antiapoptotic activities. Furthermore, the effect of ASP on short-chain fatty acids (SCFA) in the colon and colonic contents was investigated to further enhance the understanding of the underlying mechanisms. Results ASP could reduce oxidative stress and apoptosis in the gastrointestinal tract via regulating CYP2E1-mediated alcohol metabolism. Additionally, ASP could significantly increase the levels of FFAR2, FFAR3 and HCAR2 in colon, thereby promoting the utilization of SCFA. Conclusion ASP was proven for the first time to improve gastrointestinal damage caused by alcohol, indicating its enormous potential as a candidate medicine for the treatment of alcohol related gastrointestinal injury.
研究领域:
药理学
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胃肠病学
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肝病学
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营养保健品
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民族药理学
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高影响因子
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