JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Jiabao Lu,Jianchao Li,Peiyi Yin,Nana Huang,Rong Sun
BAP improved glycolipid metabolism, insulin resistance, and hepatic steatosis in MAFLD mice. • Human iPSC-derived liver organoids were used to model MAFLD and evaluate BAP. • Network pharmacology and multi-model validation revealed the mechanism of BAP. Ethnopharmacological relevance Bupleuri Radix (Chaihu) and Aurantii Fructus Immaturus (Zhishi) is a classic herb pair from Si-Ni-San. In traditional Chinese medicine theory, they regulate liver-spleen qi movement through a “one ascending, one descending” dynamic, and are used for syndromes of liver depression and spleen deficiency with phlegm-stasis intermingling. This syndrome pattern closely mirrors the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, the mechanisms underlying the anti-MAFLD effect of this herb pair remain unclear. Aim of the study To determine the effects and molecular mechanisms of the Bupleuri Radix- Aurantii Fructus Immaturus pair (BAP) in alleviating MAFLD. Materials and methods The quality of the BAP preparation used in this study was partially assessed by high-performance liquid chromatography (HPLC). Potential mechanisms were predicted via network pharmacology and functional enrichment analysis, and experimentally explored using high-fat high-sucrose diet mice, FFA-induced AML12 hepatocytes and human induced pluripotent stem cell (iPSC)-derived liver organoids. The PI3K/Akt-GSK3β/FoxO1 signaling pathway was further examined by LY294002 rescue assay. Results BAP ameliorated MAFLD-related hepatic phenotypes both in vivo and in vitro. Four representative quality control markers, namely synephrine, naringin, saikosaponin A, and saikosaponin D, were identified using validated reference standard methods. Network pharmacological analysis predicted that AKT1, GSK3B, and FOXO1 might be central targets, and the PI3K-Akt signalling pathway was identified as a potential pathway associated with the anti-MAFLD effects of BAP. GO and KEGG enrichment analyses revealed that the overlapping targets were significantly enriched in insulin signalling, lipid metabolism, and FoxO signalling pathways. In vivo, BAP treatment significantly reduced body weight gain, improved serum lipid profiles and liver function, alleviated insulin resistance, and attenuated hepatic steatosis and inflammation in HFSW-fed mice. Energy metabolism monitoring indicated that BAP markedly enhanced oxygen consumption and carbon dioxide production throughout the 24-hour light-dark cycle. In human iPSC-derived liver organoids, BAP reduced FFA-induced hepatocyte injury, lipid accumulation, and oxidative stress, and partially normalized the aberrant expression of genes involved in lipogenesis (SREBF1, FASN, SCD1), fatty acid oxidation (PPARA, CPT1A), and gluconeogenesis (G6PC). Western blot analysis demonstrated that BAP significantly upregulated PI3K expression and the phosphorylation levels of Akt (Ser473), GSK-3β (Ser9), and FoxO1 (Ser256), while downregulating p-GS (Ser641) in mouse livers, liver organoids, and AML12 cells. Moreover, co-treatment with the PI3K inhibitor LY294002 partially counteracted the beneficial effects of BAP on these proteins and counteracted the improvements in glycolipid metabolism, suggesting that the anti-MAFLD effects of BAP are associated with modulation of the PI3K/Akt pathway. Conclusions With BAP as the research subject, this study conducts cross-validation across a multi-model system including whole-animal models, hepatocytes and human liver organoids, and suggests that BAP ameliorates glucolipid metabolic disorders and slows MAFLD progression, effects that are closely associated with modulation of the PI3K/Akt-GSK3β/FoxO1 signaling pathway. These findings provide novel compatibility insights and experimental evidence for traditional Chinese medicine-based intervention of MAFLD. Download: Download high-res image (291KB) Download: Download full-size image
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2021
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IF 7.446
Jinxin Che,Xiaoyang Dai,Jian Gao,Haichao Sheng,Wenhu Zhan,Yang Lu,Dan Li,Zizheng Gao,Zegao Jin,Binhui Chen,Peihua Luo,Bo Yang,Yongzhou Hu,Qiaojun He,Qinjie Weng,Xiaowu Dong
Rash is one of the primary dose-limiting toxicities of Akt (protein kinase B) inhibitors in clinical trials. Here, we demonstrate the inhibition of Akt2 isozyme may be a driver for keratinocyte apoptosis, which promotes us to search for new selective Akt inhibitors with an improved cutaneous safety property. According to our previous research, compound 2 is selected for further optimization for overcoming the disadvantages of compound 1, including high Akt2 inhibition and high toxicity against HaCaT keratinocytes. The dihedral angle-based design and molecular dynamics simulation lead to the identification of Hu7691 (B5) that achieves a 24-fold selectivity between Akt1 and Akt2. Hu7691 exhibits low activity in inducing HaCaT apoptosis, promising kinase selectivity, and excellent anticancer cell proliferation potencies. Based on the superior results of safety property, pharmacokinetic profile, and in vivo efficacy, the National Medical Products Administration (NMPA) approved the investigational new drug (IND) application of Hu7691.
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
·
IF 5.4
Xiao-Lu Jie,Zi-Rui Luo,Jin Yu,Zhe-Ren Tong,Qiao-Qiao Li,Jia-Hui Wu,Yi Tao,Pei-Shi Feng,Ji-Ping Lan,Ping Wang
Ethnopharmacological relevance Pi-Pa-Run-Fei-Tang (PPRFT) is an empirical TCM prescription for treating asthma. However, the underlying mechanisms of PPRFT in asthma treatment have yet to be elucidated. Recent advances have revealed that some natural components could ameliorate asthma injury by affecting host metabolism. Untargeted metabolomics can be used to better understand the biological mechanisms underlying asthma development and identify early biomarkers that can help advance treatment. Aim of the study The aim of this study was to verification the efficacy of PPRFT in the treatment of asthma and to preliminarily explore its mechanism. Materials and methods A mouse asthma model was built by OVA induction. Inflammatory cell in BALF was counted. The level of IL-6, IL-1β, and TNF-α in BALF were measured. The levels of IgE in the serum and EPO , NO , SOD , GSH-Px, and MDA in the lung tissue were measured. Furthermore, pathological damage to the lung tissues was detected to evaluate the protective effects of PPRFT. The serum metabolomic profiles of PPRFT in asthmatic mice were determined by GC-MS. The regulatory effects on mechanism pathways of PPRFT in asthmatic mice were explored via immunohistochemical staining and western blotting analysis. Results PPRFT displayed lung-protective effects through decreasing oxidative stress, airway inflammation , and lung tissue damage in OVA-induced mice, which was demonstrated by decreasing inflammatory cell levels, IL-6, IL-1β, and TNF-α levels in BALF, and IgE levels in serum, decreasing EPO, NO, and MDA levels in lung tissue, elevating SOD and GSH-Px levels in lung tissue and lung histopathological changes. In addition, PPRFT could regulate the imbalance in Th17/Treg cell ratios, suppress RORγt, and increase the expression of IL-10 and Foxp3 in the lung. Moreover, PPRFT treatment led to decreased expression of IL-6, p-JAK2/Jak2, p-STAT3/STAT3, IL-17, NF-κB, p-AKT/AKT, and p-PI3K/PI3K. Serum metabolomics analysis revealed that 35 metabolites were significantly different among different groups. Pathway enrichment analysis indicated that 31 pathways were involved. Moreover, correlation analysis and metabolic pathway analysis identified three key metabolic pathways: galactose metabolism; tricarboxylic acid cycle; and glycine, serine , and threonine metabolism. Conclusion This research indicated that PPRFT treatment not only attenuates the clinical symptoms of asthma but is also involved in regulating serum metabolism. The anti-asthmatic activity of PPRFT may be associated with the regulatory effects of IL-6/JAK2/STAT3/IL-17 and PI3K/AKT/NF-κB mechanistic pathways.
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Yassmin Raafat Hassan,Riham A. El-Shiekh,Hala M. El Hefnawy,Osama G. Mohamed,Karema Abu-Elfotuh,Ahmed M. Hamdan,Alshaymaa Darwish,Ayah M.H. Gowifel,Ashootosh Tripathi,Camilia George Michael
Ethnopharmacological relevance Irvingia gabonensis (Aubry-Lecomte ex O'Rorke) Baill., also known as “African mango” or “bush mango”, belonging to family Irvingiaceae, has been mostly used as food and traditional medicine for weight loss and to enhance the health. Aim of the study The overconsumption of high-fat and high-carbohydrate (HFHC) food induces oxidative stress, leading to neurological and cognitive dysfunction . Consequently, there is an immediate need for effective treatment. Hence, this study explored the efficacy of orlistat , metformin , and I. gabonensis seeds' total aqueous extract (IG SAE) in addressing HFHC-induced cognitive impairment by mitigating oxidative stress and their underlying mechanistic pathways. Materials and methods Initially, the secondary metabolite profile of IG SAE is determined using high-performance liquid chromatography coupled with a mass detector (UHPLC/MS). The in vivo study involves two phases: an established model phase with control (10 rats on a standard diet) and HFHC diet group (50 rats) for 3 months. In the study phase, HFHC is divided into 5 groups. The first subgroup receives HFHC diet only, while the remaining groups each receive HFHC diet with either Orlistat, metformin, or IG SAE at doses of 100 mg/kg and 200 mg/kg, respectively, for 28 days. Results More than 150 phytoconstituents were characterized for the first holistic approach onto IG metabolome. Characterization of IG SAE revealed that tannins dominate metabolites in the plant. Total phenolics and flavonoids were estimated to standardize our extract (77.12 ± 7.09 μg Gallic acid equivalent/mg extract and 8.039 ± 0.53 μg Rutin equivalent/mg extract, respectively). Orlistat, metformin, and IG SAE successfully reduced the body weight, blood glucose level, lipid profile, oxidative stress and neurotransmitters levels leading to improved behavioral functions as well as histological alternation. Also, IG SAE halted inflammation, apoptosis, and endoplasmic reticulum stress, together with promoting autophagy, via modulation of PI3K/AKT/GSK-3β/CREB, PERK/CHOP/Bcl-2 and AMPK/SIRT-1/m-TOR pathways. Conclusion Metformin, orlistat, and IG SAE offer a promising multi-target therapy to mitigate HFHC diet-induced oxidative stress, addressing cognitive function. This involves diverse molecular mechanisms, particularly the modulation of inflammation, ER stress, and both PI3K/AKT/GSK-3β/CREB and AMPK/SIRT-1/m-TOR pathways. Furthermore, the higher dose of IG SAE demonstrated effects comparable to orlistat and metformin across most studied parameters.
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DOI
PubMed
高影响因子
Bioengineered
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2022
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IF 6.832
Kun Xiao,Pengfei Liu,Peng Yan,Yanxin Liu,Licheng Song,Yuhong Liu,Lixin Xie
Lung ischemia/reperfusion (I/R) injury (LIRI) is a common complication after lung transplantation, embolism, and trauma. N6-methyladenosine (m6A) methylation modification is implicated in the pathogenesis of I/R injury. However, there are no or few reports of m6A-related regulators in LIRI till now. In this text, dysregulated genes in lung tissues of LIRI rats versus the sham group were identified by RNA sequencing (RNA-seq). RNA-seq outcomes revealed that only YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) were differentially expressed in the LIRI versus sham group among 20 m6A-related regulators. Next, the functions and molecular mechanisms of YTHDF3 and IGF2BP2 in LIRI were investigated in a hypoxia/reoxygenation-induced BEAS-2B cell injury model in vitro. Results showed that YTHDF3 or IGF2BP2 knockdown attenuated hypoxia/reoxygenation-mediated inhibitory effects on cell survival and cell cycle progression and inhibited hypoxia/reoxygenation-induced cell apoptosis and pro-inflammatory cytokine secretion in BEAS-2B cells. Genes that could be directly regulated by YTHDF3 or IGF2BP2 were identified based on prior experimental data and bioinformatics analysis. Moreover, multiple potential downstream pathways of YTHDF3 and IGF2BP2 were identified by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis of the above-mentioned genes. Among these potential pathways, we demonstrated that YTHDF3 or IGF2BP2 knockdown inhibited hypoxia/reoxygenation-activated p38, ERK1/2, AKT, and NF-κB pathways in BEAS-2B cells. In conclusion, YTHDF3 or IGF2BP2 knockdown weakened hypoxia/reoxygenation-induced human lung bronchial epithelial cell injury by inactivating p38, AKT, ERK1/2, and NF-κB pathways.
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PubMed
高影响因子
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