Abstract Non‐alcoholic steatohepatitis (NASH) is a severe inflammatory phase of the non‐alcoholic fatty liver disease (NAFLD) spectrum and can progress to advanced stages of NAFLD if left untreated. This study uses multi‐omics data to elucidate the underlying mechanism of naringenin's reported benefit in alleviating (NASH). Male mice were fed a NASH‐inducing (methionine‐choline‐deficient) MCD diet with or without naringenin supplementation for 6 weeks. Naringenin prevented NASH‐induced histopathological liver damage and reversed the abnormal levels of hepatic triglyceride (TG)/total cholesterol (TC), serum TG/TC, serum alanine aminotransferase/aspartate transaminase, and hepatic malondialdehyde and glutathione. Importantly, naringenin intervention significantly modulated the relative abundance of gut microbiota and the host metabolomic profile. We detected more than 700 metabolites in the serum and found that the gut genus levels of Anaeroplasma and the [Eubacterium] nodatum group were closely associated with xanthine, 2‐picoline, and securinine, respectively. Tuzzerella alterations showed the highest number of associations with host endogenous metabolites such as FAHFA (8:0/10:0), FFA (20:2), carnitine C8:1, tridecanedioic acid, securinine, acetylvaline, DL‐O‐tyrosine, and Phe‐Asn. This study indicates that the interplay between host serum metabolites and gut microbiota may contribute to the therapeutic effect of naringenin against NASH.

Naringenin prevents non‐alcoholic steatohepatitis by modulating the host metabolome and intestinal microbiome in MCD diet‐fed mice

Ginsenoside, the principal active constituent of ginseng, exhibits enhanced bioavailability and medicinal efficacy in rare ginsenosides compared to major ginsenosides. Current research is focused on efficiently and selectively removing sugar groups attached to the major ginsenoside sugar chains to convert them into rare ginsenosides that meet the demands of medical industry and functional foods. The methods for preparing rare ginsenosides encompass chemical, microbial, and enzymatic approaches. Among these, the enzyme conversion method is highly favored by researchers due to its exceptional specificity and robust efficiency. This review summarizes the biological activities of different rare ginsenosides, explores the various glycosidases used in the biotransformation of different major ginsenosides as substrates, and elucidates their respective corresponding biotransformation pathways. These findings will provide valuable references for the development, utilization, and industrial production of ginsenosides.

Advancements in enzymatic biotransformation and bioactivities of rare ginsenosides：A Review

Ginsenosides, the primary pharmacologically active constituents of the Panax genus, have demonstrated a variety of medicinal properties, including anticardiovascular disease, cytotoxic, antiaging, and antidiabetes effects. However, the low concentration of ginsenosides in plants and the challenges associated with their extraction impede the advancement and application of ginsenosides. Heterologous biosynthesis represents a promising strategy for the targeted production of these natural active compounds. As representative triterpenoids, the biosynthetic pathway of the aglycone skeletons of ginsenosides has been successfully decoded. While the sugar moiety is vital for the structural diversity and pharmacological activity of ginsenosides, the mining of uridine diphosphate-dependent glycosyltransferases (UGTs) involved in ginsenoside biosynthesis has attracted a lot of attention and made great progress in recent years. In this paper, we summarize the identification and functional study of UGTs responsible for ginsenoside synthesis in both plants, such as Panax ginseng and Gynostemma pentaphyllum, and microorganisms including Bacillus subtilis and Saccharomyces cerevisiae. The UGT-related microbial cell factories for large-scale ginsenoside production are also mentioned. Additionally, we delve into strategies for UGT mining, particularly potential rapid screening or identification methods, providing insights and prospects. This review provides insights into the study of other unknown glycosyltransferases as candidate genetic elements for the heterologous biosynthesis of rare ginsenosides.

Progress in Identification of UDP-Glycosyltransferases for Ginsenoside Biosynthesis.

Stroke is a medical condition characterized by a sudden, localized neurological impairment caused by damage to the central nervous system due to either a blockage or bleeding in the blood vessels. This process leads to increased oxidation, which can exacerbate brain damage. Flavonoids are compounds that are widely found in nature and are considered to have numerous health benefits. 7,8‑dihydroxyflavone (7,8‑DHF) is a flavonoid that has tropomyosin receptor kinase B agonist activity. However, the other beneficial activities of 7,8‑DHF remain to be explored, particularly in neuron‑related diseases. The present study aimed to explore 7,8‑DHF as an antioxidant agent using in vivo and in silico analyses. An in vivo experiment was conducted using Rattus novergicus, in which ischemia‑reperfusion brain injury was induced. A total of 30 rats were divided into the sham‑operated, control and treatment groups. The treatment groups were administered doses of 10, 20 and 50 mg/kg body weight of 7,8‑DHF orally, once daily for a duration of 14 days following the induction of ischemia‑reperfusion brain injury. Subsequently, blood and brain tissues were collected for the examination of nuclear factor E2‑related factor 2 (Nrf2) expression, glutathione peroxidase‑1 (GPX‑1) expression and the malondialdehyde (MDA) level. Molecular docking analysis and dynamic simulations of 7,8‑DHF and Kelch like ECH‑associated protein 1 (Keap1) protein interactions were performed using AutoDock Vina and AMBER. The visualization of the interaction was performed using ChimeraX and Discovery Studio. The drug‑like properties of 7,8‑DHF were predicted using the SwissADME web server, and the bioactivity of the compounds was evaluated using the PASS online server. The results revealed that 7,8‑DHF exhibits antioxidant activity through the inhibition of Keap1, thereby increasing Nrf2 and GPX‑1 expression and decreasing the levels of MDA. In silico analysis revealed that 7,8‑DHF can bind Keap1 protein, thereby disrupting the interaction between Nrf2 and Keap1. Molecular dynamics also demonstrated that 7,8‑DHF has good stability compared to the control. On the whole, as demonstrated in the present study 7,8‑DHF has promising biological activity as an antioxidant agent in the rat model of ischemia‑reperfusion brain injury. Further studies on the effects of 7,8‑DHF are required to clarify its potential as a novel therapeutic agent for cerebral infarction.

7,8‑Dihydroxyflavone functions as an antioxidant through the inhibition of Kelch‑like ECH‑associated protein 1: Molecular docking and an in vivo approach in a rat model of ischemia‑reperfusion brain injury

Organoids are three-dimensional cell accusations generated from pluripotent stem cells or adult stem cells in vitro. With many advantages over cell and animal models, organoids have been increasingly used in drug and clinical medical research in recent years. Chinese herbal medicine (CHM) is characterized by multi-target and multi-pathway treatment methods; however, there is no commonly accepted study method regarding efficacy and underlying mechanisms. In this review we summarized the important applications of organoid models in pharmacodynamic mechanism studies, efficacy and safety evaluations, and CHM personalized medicine, thus providing the theoretical basis for its development and innovation.

https://www.scienceopen.com/document_file/5d95ac2d-16f0-4dbe-9b04-ff7015ca008f/ScienceOpen/amm20220047.pdf

Organoid models for Chinese herbal medicine studies

Atherosclerosis (AS) is a global disease that causes a heavy economic burden and can significantly impact human health. Pinolenic acid (PLA) has antioxidant, anti-inflammatory, and lipid-lowering effects. However, it is unclear whether PLA holds a therapeutic promise for AS treatment or prevention. This study aims to investigate whether PLA can effectively treat AS and elucidate its therapeutic mechanism. To this end, potential PLA targets in AS treatment were identified by using network pharmacology. Additionally, an in vitro AS cell model was established by H2O2-induced damaging of human coronary artery endothelial cells (HCAECs). Subsequently, endothelial cell function was evaluated by evaluating cell proliferation, oxidative markers, reactive oxygen species (ROS), and nitric oxide (NO) levels. Cellular metabolomics was further employed to assess differential intracellular metabolites following H2O2 injury. In total, 87 overlapping target genes for PLA and AS were detected. PPI network analysis identified 38 hub genes closely associated with oxidative stress and fatty acid metabolism. Moreover, PLA improved cell survival and reduced oxidative stress injury by activating the NRF2/ARE signaling pathway in vitro. Cellular metabolomics confirmed that PLA might help maintain redox homeostasis and reduce endothelial cell injury by upregulating fatty acid β-oxidation. Taken together, our findings suggest that PLA prevents H2O2-induced HCAEC injury by maintaining redox homeostasis and may, therefore, represent a therapeutic potential for AS.

Integrating Network Pharmacology and Metabolomics to Explore the Potential Mechanism of Pinolenic Acid against Atherosclerosis

Mammalian Reovirus Μ1 Protein Attenuates RIG-I and MDA5-Mediated Signaling Transduction by Blocking IRF3 Phosphorylation and Nuclear Translocation

Oxidative stress is an important pathogenic mechanism in degenerative diseases such as Alzheimer’s disease. Although ginsenoside compound K (CK) is protective against neuronal oxidative damage, the underlying mechanism remains to be understood. In this study, the protective effects of ginsenoside CK against oxidative stress damage induced by hydrogen peroxide in HT22 cells were investigated with 1H nuclear magnetic resonance (1H-NMR)-based metabolomics. The optimal CK concentration for decreasing oxidative stress damage in nerves was determined with MTT assays. CK (8 μM) significantly increased the HT22 cell survival rate after the model was established. Cell lysates were subjected to 1H-NMR metabolomics, western blotting, and ATP assays for verification. Metabolic perturbation occurred in HT22 cells in the model group but not the control group. Twenty biomarkers were identified and used to analyze metabolic pathways. CK reversed metabolic changes in HT22 cells by altering taurine, glutamate, glycine, and glutathione metabolism. Subsequently, CK increased ATP content and the expression of components of the PI3K/AKT signaling pathway in HT22 cells. These findings demonstrated that CK prevents oxidative stress damage and protects nerves by regulating energy-metabolism pathways, such as those of taurine, glutamate, and other amino acids, thus providing a rationale for the use of CK in Alzheimer’s disease treatment.

/pdf/protective-effects-of-ginsenoside-ck-against-oxidative-3s2u4fji.pdf

Protective effects of ginsenoside CK against oxidative stress-induced neuronal damage, assessed with 1H-NMR-based metabolomics

Background: Alzheimer’s disease (AD) is the most common neurodegenerative condition worldwide, with amyloid ß (Aβ) fibrils presenting as its main pathological feature. This study investigated whether Ginsenoside Compound K (CK) has activity against Aβ and its mechanism in reducing synaptic damage and cognitive impairment. Methods: The binding capacity of CK to Aβ42 and Nrf2/Keap1 was determined using molecular docking. Transmission electron microscopy was used to monitor CK-mediated degradation of Aβ fibrils. The effect of CK on the survival of Aβ42-damaged HT22 cells was determined using a CCK-8 assay. The therapeutic efficacy of CK in a scopoletin hydrobromide (SCOP) induced cognitive dysfunction mouse model was measured using a step-down passive avoidance test. GO enrichment analysis of mouse brain tissue was peformed using Genechip. Hydroxyl radical scavenging and reactive oxygen species assays were performed to verify the antioxidant activity of CK. The effects of CK on the expression of Aβ42, the Nrf2/Keap1 signaling pathway, and other proteins were determined by western blotting, immunofluorescence, and immunohistochemistry. Results: Molecular docking results showed that CK interacts with Lys16 and Glu3 of Aβ42. CK reduced the aggregation of Aβ42 as observed using transmission electron microscopy. CK increased the level of insulin-degrading enzyme and decreased the levels ß-secretase and γ-secretase; therefore, it can potentially inhibit the accumulation of Aβ in neuronal extracellular space in vivo. CK improved cognitive impairment and increased postsynaptic density protein 95 and synaptophysin expression levels in mice with SCOP-induced cognitive dysfunction. Further, CK inhibited the expression of cytochrome C, Caspase-3, and cleaved Caspase-3. Based on Genechip data, CK was found to regulate molecular functions such as oxygen binding, peroxidase activity, hemoglobin binding, and oxidoreductase activity, thus affecting the production of oxidative free radicals in neurons. Further, CK regulated the expression of the Nrf2/Keap1 signaling pathway through its interaction with the Nrf2/Keap1 complex. Conclusion: Our findings show that CK regulates the balance between Aβ monomers production and clearance, CK binds to Aβ monomer to inhibits the accumulation of Aβ, increases the level of Nrf2 in neuronal nuclei, reduces oxidative damage of neurons, improves synaptic function, thus ultimately protecting neurons.

https://www.frontiersin.org/articles/10.3389/fphar.2023.1103012/pdf

Ginsenoside ompound K reduces neuronal damage and improves neuronal synaptic dysfunction by targeting Aβ

A candidate multi-epitopes vaccine against encephalomyocarditis virus confers protection in mice.

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