Sini San ameliorates CCl4-induced liver fibrosis in mice by inhibiting AKT-mediated hepatocyte apoptosis

Jiang, Meijie; Chun-mei, Huang; Wu, Qiong; Su, Yong; Wang, Xinming; Xuan, Zihua; Wang, Yunlai; Xu, Fan; Ge, Chaoliang

doi:10.1016/j.jep.2022.115965

Cited by 21 publications

(9 citation statements)

References 39 publications

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“…As a second messenger, PIP3 will activate protein kinase B (AKT), which can control cell process through phosphorylation substrate, and finally regulate cell apoptosis, protein synthesis and metabolism [42] . Sini San have been proved to inhibit Akt and PI3K expression to improve hepatocytes apoptosis [43] . Helenalin, a sesquiterpene lactone, could inhibit HSCs activation and promote HSCs apoptosis by blocking the PI3K/Akt/mTOR pathway and regulating the expression of Bcl‐2 and caspase family [44] …”

Section: Resultsmentioning

confidence: 99%

“…[42] Sini San have been proved to inhibit Akt and PI3K expression to improve hepatocytes apoptosis. [43] Helenalin, a sesquiterpene lactone, could inhibit HSCs activation and promote HSCs apoptosis by blocking the PI3K/Akt/mTOR pathway and regulating the expression of Bcl-2 and caspase family. [44] In this research, the crude extract and partly purified compounds from Hovenia genus exhibited the inhibitory ability on the cell viability of HSCs, suggested their application potential in hepatic fibrosis field.…”

Section: Discussionmentioning

confidence: 99%

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Hovenianin A Alleviates Hepatic Fibrosis by Inhibiting the PI3K/AKT Pathway in TGF‐β1‐Induced HSCs Based on Network Pharmacology and Transcriptomic Analysis

Kuang

Cai

et al. 2023

Chemistry & Biodiversity

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Hepatic fibrosis is a global health problem, which currently has no FDA approved antifibrotic therapy yet. This study aimed to explore the mechanism of Hovenia genus in the treatment of hepatic fibrosis by an integrative strategy combining network pharmacology analysis, molecular docking, transcriptomics and experimental validation. The traditional Chinese medicine systems pharmacology (TCMSP) database and literatures were used to collect the components of Hovenia genus. Public databases including GeneCards, TTD, PharmGkb were used to acquire the putative targets. The GO and KEGG analysis were applied to explore the underlying mechanisms. Furthermore, The TGF‐β1 induced hepatic stellate cells (HSCs) model were performed to evaluate the anti‐hepatic fibrosis activity of Hovenia genus. The RT‐qPCR, Western blotting and flow cytometry experiments were used to validate the anti‐hepatic fibrosis mechanisms of Hovenianin A. The KEGG analysis of network pharmacology and transcriptomics revealed that the core targets mainly enriched in PI3K‐Akt signaling pathways. The cell screening results indicated flavonoids were the main active ingredients of Hovenia. Hovenianin A, a bioactive bisflavonol, was validated to promote the apoptosis of HSCs by inhibiting PI3K‐Akt pathway. Molecular docking further corroborated the binding sites between Hovenianin A and AKT1. In summary, Hovenia may have therapeutic effects on liver fibrosis by modulating the PI3K‐Akt apoptosis pathway. Our findings may facilitate the development of Hovenia genus, which could help to treat liver fibrosis in the future.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hovenianin A Alleviates Hepatic Fibrosis by Inhibiting the PI3K/AKT Pathway in TGF‐β1‐Induced HSCs Based on Network Pharmacology and Transcriptomic Analysis

Kuang

Cai

et al. 2023

Chemistry & Biodiversity

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“…Zhao et al reported a relationship between the PI3K/AKT/Raptor/Rictor signaling pathway and apoptosis and observed that Erzhi Pill can ameliorate ALI by inhibiting the pathway to reduce hepatic apoptosis ( Zhao et al, 2018 ). Moreover, AKT phosphorylation can exacerbate ALI, whereas AKT inhibitors can suppress hepatic apoptosis by inhibiting the PI3K/AKT/FXR axis in vitro ( Jiang et al, 2023 ). The PI3K-AKT signaling pathway is also vital in the regulation of inflammation, especially the PI3K/AKT/NF-κB axis ( Zhu et al, 2017 ; Yang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated network analysis and metabolomics reveal the molecular mechanism of Yinchen Sini decoction in CCl4-induced acute liver injury

Zheng,

Shi,

Meng

et al. 2023

Front. Pharmacol.

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Objective: Yinchen Sini decoction (YCSND), a traditional Chinese medicine (TCM) formula, plays a crucial role in the treatment of liver disease. However, the bioactive constituents and pharmacological mechanisms of action remain unclear. The present study aimed to reveal the molecular mechanism of YCSND in the treatment of acute liver injury (ALI) using integrated network analysis and metabolomics.Methods: Ultra-high-performance liquid chromatography coupled with Q-Exactive focus mass spectrum (UHPLC-QE-MS) was utilized to identify metabolites in YCSND, and high-performance liquid chromatography (HPLC) was applied to evaluate the quality of four botanical drugs in YCSND. Cell damage and ALI models in mice were established using CCl4. 1H-NMR metabolomics approach, along with histopathological observation using hematoxylin and eosin (H&E), biochemical measurements, and reverse transcription quantitative real-time PCR (RT-qPCR), was applied to evaluate the effect of YCSND on CCl4- induced ALI. Network analysis was conducted to predict the potential targets of YCSND in ALI.Result: Our results showed that 89 metabolites in YCSND were identified using UHPLC-QE-MS. YCSND protected against ALI by reducing the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and malondialdehyde (MDA) contents and increasing those of superoxide dismutase (SOD), and glutathione (GSH) both in vivo and in vitro. The 1H-NMRmetabolic pattern revealed that YCSND reversed CCl4-induced metabolic abnormalities in the liver. Additionally, the Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis identified five pathways related to liver injury, including the PI3K-AKT, MAPK, HIF-1, apoptosis, and TNF signaling pathways. Moreover, RT-qPCR showed YCSND regulated the inflammatory response (Tlr4, Il6, Tnfα, Nfκb1, Ptgs2, and Mmp9) and apoptosis (Bcl2, Caspase3, Bax, and Mapk3), and inhibited PI3K-AKT signaling pathway (Pi3k and Akt1). Combined network analysis and metabolomics showed a link between the key targets (Tlr4, Ptgs2, and Mmp9) and vital metabolites (choline, xanthine, lactate, and 3-hydroxybutyric acid) of YCSND in ALI.Conclusion: Overall, the results contribute to the understanding of the therapeutic effects of YCSND on ALI, and indicate that the integrated network analysis and metabolomics could be a powerful strategy to reveal the pharmacological effects of TCM.

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“…A recent in vivo and in vitro experimental study ( Lan, et al, 2024 ) found that SNS was able to attenuate lipid accumulation in hepatocytes and mouse liver by modulating the AMPK/p300/SREBP-1c axis, thereby inhibiting the expression of fatty acid synthase. And Jiang, et al (2023) found that SNS can significantly improve the progression of fibrosis and prevent hepatocyte apoptosis in mice with liver fibrosis, and its anti-apoptosis mechanism is closely related to the key component isorhamnin’s inhibition of AKt-mediated downregulation of FXR expression. Shengmai-Yin and Ganmaidazao decoction (SGD) were both TCM prescriptions, which were widely used clinically.…”

Section: Network Pharmacological Study On Non-alcoholic Fatty Liver D...mentioning

confidence: 99%

Chinese medicine in the treatment of non-alcoholic fatty liver disease based on network pharmacology: a review

Zheng,

Xue,

et al. 2024

Front. Pharmacol.

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Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by abnormalities in hepatic fat deposition, the incidence of which has been increasing year by year in recent years. It has become the largest chronic liver disease globally and one of the important causes of cirrhosis and even primary liver cancer formation. The pathogenesis of NAFLD has not yet been fully clarified. Modern medicine lacks targeted clinical treatment protocols for NAFLD, and most drugs lack efficacy and have high side effects. In contrast, Traditional Chinese Medicine (TCM) has significant advantages in the treatment and prevention of NAFLD, which have been widely recognized by scholars around the world. In recent years, through the establishment of a “medicine-disease-target-pathway” network relationship, network pharmacology can explore the molecular basis of the role of medicines in disease prevention and treatment from various perspectives, predicting the pharmacological mechanism of the corresponding medicines. This approach is compatible with the holistic view and treatment based on pattern differentiation of TCM and has been widely used in TCM research. In this paper, by searching relevant databases such as PubMed, Web of Science, and Embase, we reviewed and analyzed the relevant signaling pathways and specific mechanisms of action of single Chinese medicine, Chinese medicine combinations, and Chinese patent medicine for the treatment of NAFLD in recent years. These related studies fully demonstrated the therapeutic characteristics of TCM with multi-components, multi-targets, and multi-pathways, which provided strong support for the exact efficacy of TCM exerted in the clinic. In conclusion, we believe that network pharmacology is more in line with the TCM mindset of treating diseases, but with some limitations. In the future, we should eliminate the potential risks of false positives and false negatives, clarify the interconnectivity between components, targets, and diseases, and conduct deeper clinical or experimental studies.

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Sini San ameliorates CCl4-induced liver fibrosis in mice by inhibiting AKT-mediated hepatocyte apoptosis

Cited by 21 publications

References 39 publications

Hovenianin A Alleviates Hepatic Fibrosis by Inhibiting the PI3K/AKT Pathway in TGF‐β1‐Induced HSCs Based on Network Pharmacology and Transcriptomic Analysis

Hovenianin A Alleviates Hepatic Fibrosis by Inhibiting the PI3K/AKT Pathway in TGF‐β1‐Induced HSCs Based on Network Pharmacology and Transcriptomic Analysis

Integrated network analysis and metabolomics reveal the molecular mechanism of Yinchen Sini decoction in CCl4-induced acute liver injury

Chinese medicine in the treatment of non-alcoholic fatty liver disease based on network pharmacology: a review

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