Protective effect of Tibetan medicine Qiwei Tiexie pills on liver injury induced by acetaminophen overdose: An integrated strategy of network pharmacology, metabolomics and transcriptomics.

BACKGROUND: Drug-induced liver injury, particularly from acetaminophen (APAP), has emerged as a significant public health concern. Unfortunately, there is currently no effective treatment strategy available. Qiwei Tiexie pills (QWTX), a traditional Tibetan medicine, have demonstrated considerable clinical efficacy in treating various liver diseases. Nevertheless, the protective effect of QWTX against drug-induced liver injury and its underlying mechanism remains poorly understood. PURPOSE: This study aimed to assess the therapeutic potential of QWTX, a Tibetan medicine, in an animal model of APAP-induced liver injury. Additionally, we sought to investigate the molecular mechanism through which QWTX exerts its effects. METHODS: We employed LC-MS and network pharmacology to predict the potential targets of QWTX in drug-induced liver injury. Subsequently, we employed HE staining, transcriptomics, metabolomics, and qRT-PCR to analyze the mechanism underlying QWTX treatment in drug-induced liver injury. RESULTS: Network pharmacology analysis revealed that the active components of QWTX are involved in inflammatory and drug metabolism-related pathways. In mouse models, pretreatment with QWTX effectively mitigated the elevated levels of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and inflammatory factors (IL-1ß, IL-6, and TNF-α) induced by APAP overdose. Moreover, APAP inhibited 1459 differentially expressed genes (DEGs) and 874 differential accumulation metabolites (DAMs), while QWTX promoted their expression. Conversely, APAP promoted 874 genes and 119 metabolites, which were inhibited by QWTX. Further analysis demonstrated that QWTX ameliorated the metabolic disorders induced by APAP overdose and potentially exerted a protective effect by inhibiting the expression of critical genes in crucial inflammatory pathways. QWTX also up-regulated antioxidant enzymes, thereby mitigating the oxidative stress resulting from APAP overdose. CONCLUSION: QWTX treatment effectively protects against APAP-induced liver damage in mice. Transcriptomic and metabolomic analyses further revealed that QWTX ameliorated hepatic metabolic disorders induced by APAP overdose while significantly suppressing the inflammatory response and oxidative stress associated with drug-induced liver injury. This study provides a new insight into the treatment of drug-induced liver injury by the TCM system and provides a basis for the development of new therapies for drug-induced liver injury by QWTX and its active ingredients.

The effect of ginsenosides on liver injury in preclinical studies: a systematic review and meta-analysis.

Background: Liver injury is a severe liver lesion caused by various etiologies and is one of the main areas of medical research. Panax ginseng C.A. Meyer has traditionally been used as medicine to treat diseases and regulate body functions. Ginsenosides are the main active components of ginseng, and their effects on liver injury have been extensively reported. Methods: Preclinical studies meeting the inclusion criteria were retrieved from PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wan Fang Data Knowledge Service Platforms. The Stata 17.0 was used to perform the meta-analysis, meta-regression, and subgroup analysis. Results: This meta-analysis included ginsenosides Rb1, Rg1, Rg3, and compound K (CK), in 43 articles. The overall results showed that multiple ginsenosides significantly reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST), affected oxidative stress-related indicators, such as superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GSH-Px), and catalase (CAT), and reduced levels of inflammatory factor, such as factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6). Additionally, there was a large amount of heterogeneity in the meta-analysis results. Our predefined subgroup analysis shows that the animal species, the type of liver injury model, the duration of treatment, and the administration route may be the sources of some of the heterogeneity. Conclusion: In a word, ginsenosides have good efficacy against liver injury, and their potential mechanisms of action target antioxidant, anti-inflammatory and apoptotic-related pathways. However, the overall methodological quality of our current included studies was low, and more high-quality studies are needed to confirm their effects and mechanisms further.

Potential of Medicago sativa and Perilla frutescens for overcoming the soil sickness caused by ginseng cultivation.

There are serious soil sickness in ginseng cultivation. Crop rotation is an effective agricultural management to improve soil sustainability and reduce soil sickness. To explore an appropriate ginseng rotation system, Medicago sativa (alfalfa) and Perilla frutescens (perilla) were planted on ginseng cultivation soil for 1 year to evaluate the improvement effect of both. Through chemical analysis and high-throughput sequencing technology, we found that after alfalfa and perilla cultivation for one-year, various nutrients and enzyme activities in ginseng cultivation soil were significantly improved. In addition, perilla significantly increased the diversity and richness of soil fungal communities. Cultivation of alfalfa and perilla significantly changed the composition of soil bacterial and fungal communities and significantly reduced the abundance of the potentially pathogenic fungi Ilyonectria. Further pot experiments also showed that the improved soil could significantly increase root activity of ginseng plant after two plants were planted. It should be noted that, unlike alfalfa, perilla decreased soil electrical conductivity, increased soil organic matter, soil urease, and may significantly improve the diversity and richness of soil fungal community. Moreover, in the pot experiment, the root fresh weight of ginseng cultured in perilla treated soil increased significantly. This study highlights that perilla may have better soil improvement effect than alfalfa and it has the potential to be used in the soil improvement of ginseng cultivation.

Effects of planting of two common crops, Allium fistulosum and Brassica napus, on soil properties and microbial communities of ginseng cultivation in northeast China.

BACKGROUND: Long-term cultivation of ginseng can cause severe crop disorders and soil sickness. Crop rotation is an effective agricultural management measure to improve soil sustainability and decrease pathogens. However, the suitable ginseng rotation system and the changes in soil microbial community and soil characteristics under the rotation system need to be further explored. METHODS: To explore suitable ginseng crop rotation systems and improve soil utilization, Allium fistulosum and Brassica napus were planted on ginseng cultivation soil for one year. The effects of the two crops on the chemical properties and enzyme activities of the ginseng cultivation soil were evaluated by chemical analysis. In addition, amplicon sequencing targeting 16 s rDNA genes of bacteria and ITS of fungi has been used to characterize the functional and compositional diversity of microbial communities. RESULTS: The results elucidated that the levels of available phosphorus (AP) and available potassium (AK) in the soil increased significantly after one year of cultivation for both crops and Allium fistulosum cultivation may also have reduced soil salinity. In addition, the effects of the two crops on the activities of key soil enzymes were different. Catalase (CAT), urease (URE), and acid phosphatase (A-PHO) activities were significantly reduced and sucrase (SUC), and laccase (LAC) activities were significantly increased after Allium fistulosum planting. While A-PHO activity was significantly increased and LAC activity was significantly decreased after Brassica napus planting. Allium fistulosum significantly reduced the abundance of soil fungal communities. The cultivation of Allium fistulosum and Brassica napus significantly altered the composition of soil bacterial and fungal communities, where changes in the abundance of dominant microorganisms, such as Ascomycota, and Mortierellomycota, etc., were closely related to soil chemistry and enzyme activity. Moreover, both significantly reduced the abundance of the pathogenic fungus Ilyonectria. CONCLUSIONS: Our study clarified the effects of Allium fistulosum and Brassica napus on the microbial community and physicochemical properties of ginseng cultivated soil and provides a basis for the sustainable application of ginseng cultivation soil and the development of ginseng crop rotation systems.

Rhizosphere analysis of field-grown Panax ginseng with different degrees of red skin provides the basis for preventing red skin syndrome.

BACKGROUND: Ginseng red skin root syndrome (GRS) is one of the most common ginseng (Panax ginseng Meyer) diseases. It leads to a severe decline in P. ginseng quality and seriously affects the P. ginseng industry in China. However, as a root disease, the characteristics of the GRS rhizosphere microbiome are still unclear. METHODS: The amplicon bacterial 16 S rRNA genes and fungal ITS (Internal Transcribed Spacer) regions Illumina sequencing technology, combined with microbial diversity and composition analysis based on R software, was used to explore the relationship between soil ecological environment and GRS. RESULTS: There were significant differences in the diversity and richness of soil microorganisms between the rhizosphere with different degrees of disease, especially between healthy P. ginseng (HG) and heavily diseased groups. The variation characteristics of microbial abundance in different taxa levels were analyzed. The interaction network of rhizosphere microorganisms of P. ginseng under GRS background was established. We also found that different P. ginseng rhizosphere microbial communities have multiple changes in stability and complexity through the established interaction network. Microbes closely related to potential pathogenic fungi were also identified according to the interaction network, which provided clues for looking for biological control agents. Finally, the Distance-based redundancy analysis (dbRDA) results indicated that total phosphorus (TP), available potassium (AK), available phosphorus (AP), catalase (CAT), invertase (INV) are the key factors that influence the microbial communities. Moreover, the content of these key factors in the rhizosphere was negatively correlated with disease degrees. CONCLUSIONS: In this study, we comprehensively analyzed the rhizosphere characteristics of P. ginseng with different levels of disease, and explored the interaction relationship among microorganisms. These results provide a basis for soil improvement and biological control of field-grown in the future.

Metabolome and transcriptome analysis reveals the molecular profiles underlying the ginseng response to rusty root symptoms.

BACKGROUND: Ginseng rusty root symptoms (GRS) is one of the primary diseases of ginseng. This disease leads to a severe decline in the quality of ginseng. It has been shown that the occurrence of GRS is associated with soil environmental degradation, which may involve changes in soil microbiology and physicochemical properties. RESULTS: In this study, GRS and healthy ginseng (HG) samples were used as experimental materials for comparative analysis of transcriptome and metabolome. Compared with those in HG samples, 949 metabolites and 9451 genes were significantly changed at the metabolic and transcriptional levels in diseased samples. The diseased tissues' metabolic patterns changed, and the accumulation of various organic acids, alkaloids, alcohols and phenols in diseased tissues increased significantly. There were significant differences in the expression of genes involved in plant hormone signal transduction, phenylpropanoid biosynthesis, the peroxidase pathway, and the plant-pathogen interaction pathway. CONCLUSION: The current study involved a comparative metabolome and transcriptome analysis of GRS and HG samples. Based on the findings at the transcriptional and metabolic levels, a mechanism model of the ginseng response to GRS was established. Our results provide new insights into ginseng's response to GRS, which will reveal the potential molecular mechanisms of this disease in ginseng.

Regulatory role of non-coding RNA in ginseng rusty root symptom tissue.

Ginseng rusty root symptom (GRS) is one of the primary diseases of ginseng. It leads to a severe decline in the quality of ginseng and significantly affects the ginseng industry. The regulatory mechanism of non-coding RNA (ncRNA) remains unclear in the course of disease. This study explored the long ncRNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs) in GRS tissues and healthy ginseng (HG) tissues and performed functional enrichment analysis of the screened differentially expressed ncRNAs. Considering the predictive and regulatory effects of ncRNAs on mRNAs, we integrated ncRNA and mRNA data to analyze and construct relevant regulatory networks. A total of 17,645 lncRNAs, 245 circRNAs, and 299 miRNAs were obtained from HG and GRS samples, and the obtained ncRNAs were characterized, including the classification of lncRNAs, length and distribution of circRNA, and the length and family affiliations of miRNAs. In the analysis of differentially expressed ncRNA target genes, we found that lncRNAs may be involved in the homeostatic process of ginseng tissues and that lncRNAs, circRNAs, and miRNAs are involved in fatty acid-related regulation, suggesting that alterations in fatty acid-related pathways may play a key role in GRS. Besides, differentially expressed ncRNAs play an essential role in regulating transcriptional translation processes, primary metabolism such as starch and sucrose, and secondary metabolism such as alkaloids in ginseng tissues. Finally, we integrated the correlations between ncRNAs and mRNAs, constructed corresponding interaction networks, and identified ncRNAs that may play critical roles in GRS. These results provide a basis for revealing GRS's molecular mechanism and enrich our understanding of ncRNAs in ginseng.

Comparative analysis of rhizosphere soil physiochemical characteristics and microbial communities between rusty and healthy ginseng root.

Ginseng rusty root (GRR) symptom is one of the primary diseases of ginseng. There has been a problem of ginseng rusty root, leading to a severe decline in the quality of ginseng. To clarify the relationship between root symptoms of ginseng rust and soil, the physical and chemical properties, enzyme activity, community structure and microbial diversity of GRR and healthy ginseng (HG) rhizosphere soil were analyzed and compared. The pH and redox potential (Eh) of GRR soil decreased, and the contents of total phosphorus (TP), available phosphorus (AP), and available potassium (AK) decreased. The activity of catalase and phosphatase and invertase was lower than that of HG groups. Besides, the microbial community of GRR rhizosphere soil changes much, and its abundance and diversity are significantly reduced. The community structure of GRR rhizosphere soil also shows apparent differences, and the samples of the HG group gathered together, and the samples of the GRR group were dispersed. In general, GRR was closely associated with decreases in soil pH and Eh; decreases in TP, AP, and AK; decreases in the activity of several enzymes. Additionally, it is strongly associated with an increase in pathogenic microorganisms such as Ilyonectria and a reduction of beneficial microorganisms such as Tremellomycetes Acidobacteria subgroup 6 and Gemmatimonadetes.

The antidepressant effect of 4-hydroxybenzyl alcohol 2-naphthoate through monoaminergic, GABAergic system and BDNF signaling pathway.

Gastrodigenin, also known as 4-hydroxybenzyl alcohol (HBA), is one of the main components of Gastrodia elata, which is a perfect lead compound of natural products. In order to get new active compounds, we modified the structure of HBA through esterification with carboxylic acid, and got a series of derivatives in which 4-hydroxybenzyl alcohol 2-naphthoate (NHBA) showed stronger antidepressant activity than HBA. In this paper, we firstly evaluated the antidepressant activity of NHBA by tail suspension test (TST) and forced swimming test (FST). Then, we carried out the biochemical assay and western blot to determine its mechanism. The results displayed that NHBA could increase the content of serotonin, dopamine, norepinephrine, γ-aminobutyric acid, brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) in mice brain. It suggested that NHBA exhibited an antidepressant-like effect through monoaminergic system, GABAergic system and BDNF/TrkB signaling pathways.

Hepatoprotective effect of chiisanoside against acetaminophen-induced acute liver injury in mice.

This study was designed to investigate the hepatoprotective effect of chiisanoside (CSS) and its possible mechanisms on acetaminophen (APAP)-induced acute liver damage in mice. The serum activities of alanine transaminase (ALT), aspartate transaminase (AST), tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and the hepatic levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA) were determined using the commercially available assay kits. The hepatic mRNA levels were measured by RT-PCR. The hepatic protein expressions of nuclear factor-kappa B (NF-κB), MAPK and their phosphorylated isoforms were evaluated by western blot assays. The results indicated that CSS (240 mg/kg) exhibited the hepatoprotective effects by inhibiting oxidative stress and inflammation on APAP-induced acute liver injury. Furthermore, the anti-inflammatory activity of CSS is largely related to the regulation of the NF-κB and MAPKs signaling pathways. These findings suggested that CSS possessed hepatoprotective effect against APAP-induced hepatotoxicity in mice.

Hepatoprotective effect of chiisanoside from Acanthopanax sessiliflorus against LPS/D-GalN-induced acute liver injury by inhibiting NF-κB and activating Nrf2/HO-1 signaling pathways.

BACKGROUND: In China, Acanthopanax sessiliflorus is a delicious wild vegetable. It is also used to treat inflammation and pain. Chiisanoside (CSS) is the main constituent of the leaf of A. sessiliflorus. Combined use of lipopolysaccharide and d-galactosamine (LPS/D-GalN) can induce acute liver failure in human beings, and there are no reports on the protective effect of CSS against LPS/D-GalN-induced acute liver injury in mice. RESULTS: Chiisanoside pretreatment evidently reduced the activities of alanine transaminase (ALT) and aspartate transaminase (AST) in the changes induced by LPS/D-GalN, and these histopathological changes induced by LPS/GalN were significantly weakened. Catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD) activities increased, and malondialdehyde (MDA) activity decreased after CSS treatment compared with LPS/D-GalN treatment. Pretreatment with CSS also inhibited the expression levels of inflammatory factors. The administration of CSS prevented the phosphorylated expression of inhibitor kappa B (IκB) kinase, and led to a significant increase in heme oxygenase-1 (HO-1) expression and nuclear factor erythroid 2-related factor2 (Nrf2) nuclear translocation. CONCLUSION: The protective effects of CSS are attributed to its antioxidative effect and inflammatory suppression in Nuclear factor kappa beta (NF-κB) and Nrf2/HO-1 signaling pathways. Chiisanoside might therefore be a potential ingredient for drug and food development against acute liver injury in the future. © 2018 Society of Chemical Industry.

Study on antidepressant activity of chiisanoside in mice.

The antidepressant-like effect of chiisanoside from the leaves of Acanthopanax sessiliflorus was evaluated by using mice models of depression, forced swim test (FST) and tail suspension test (TST). The results showed that treatment with chiisanoside at dose of 5.0 mg/kg significantly decreased immobility time in the FST and TST. Pretreatment with haloperidol (a non-selective D2 receptor antagonist), bicuculline (a competitive GABA antagonist) and N-methyl-D-aspartic acid (NMDA, an agonist at the glutamate site) effectively reversed the antidepressant-like effect of chiisanoside (5.0 mg/kg). Moreover, chiisanoside treatment did not change the locomotor activity. And chiisanoside (5.0 mg/kg) also effectively increased the dopamine (DA) and γ-aminobutyric acid (GABA) levels in mice brains exposed to the FST and TST in the co-treatment groups. Then we designed lipopolysaccharide (LPS)-induced antidepressant behavioral experiment, the results showed that LPS significantly increased immobility duration in the TST and FST. Chiisanoside administration could effectively reduce serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels; at the same time, the changes of related indexes of oxidative stress are improved, such as superoxide dismutase (SOD) and malondialdehyde (MDA). Moreover, chiisanoside effectively down-regulated brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and nuclear factor-κB (NF-κB) in hippocampal. In conclusion, chiisanoside displayed significant antidepressant-like effect, which was probably related to the DAergic, GABAergic and glutamatergic systems. And the mechanism of anti-depressant effect of chiisanoside might be via the alterations of animal behaviors, hippocampus inflammation, oxidative stress and neurotrophy, which might be attributed by the BDNF/TrkB/NF-κB pathway.