Optimized therapeutic potential of Yinchenhao decoction for cholestatic hepatitis by combined network meta-analysis and network pharmacology.

BACKGROUND: Cholestatic hepatitis is recognized as a significant contributor to the development of liver fibrosis and cirrhosis. As a well-known classic formula for the treatment of cholestatic hepatitis, Yinchenhao decoction (YCHD) is widely used in countries in Asia, including China, Japan, and Korea. However, in recent years, a risk of liver injury has been reported from Rheum palmatum L. and Gardenia jasmonoides J.Ellis which are the main ingredients of YCHD. Therefore, the question arises whether YCHD is still safe enough for the treatment of cholestatic hepatitis or whether an optimized ratio of ingredients should be applied. These is inevitable questions for the clinical application of YCHD. PURPOSE: To provide a scientific basis for the clinical application of YCHD through a combination of meta-analysis and network pharmacology and to find the best ratio of components to ensure optimal therapeutic efficacy and safety. At the same time, a deeper understanding of the mechanisms of YCHD was explored. METHODS: We retrieved relevant trials from various databases including PubMed, Web of Science, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP and Wanfang databases up to August 2023. After screening for inclusion and exclusion criteria, we assessed efficiency, ALT, AST, and TBIL as outcome parameters. The relevant data underwent a network meta-analysis using STATA 16.0 software. Based on network pharmacology, we screened the disease targets, active ingredients, and targets related to YCHD. The targets were visualized using Cytoscape 3.9.1. Then, potential mechanisms were explored based on bioinformatic techniques. RESULTS: Twenty eligible studies were finally screened and a total of 1,591 patients who fulfilled the inclusion criteria were enrolled in the study. The meta-analysis results indicated that TG-c (treatment group c) [(Artemisia capillaris Thunb. : Gardenia jasminoides J.Ellis : Rheum palmatum L. = 10:5:2-10:5:3) + CT] was the most promising therapeutic approach, demonstrating superior efficacy and notable improvements in both AST and TBIL levels. For ALT, TG-d [(Artemisia capillaris : Gardenia jasminoides : Rheum palmatum = 5:1:1-5:2:1) + CT] exhibited the greatest potential as optimal therapy option. Based on the surface under the cumulative ranking curve (SUCRA) values, TG-c was the best therapy in terms of efficiency and improvement in TBIL levels, while TG-d was the most effective in reducing ALT levels. For AST levels, TG-e [(Artemisia capillaris : Gardenia jasminoides : Rheum palmatum = 5:2:2-5:3:3) + CT] was the most effective therapy. The comprehensive analysis revealed that TG-c exhibited the most pronounced efficacy. Combined network pharmacology, GO enrichment analysis and KEGG pathway enrichment analysis displayed that the key target genes of Artemisia capillaris, Rheum palmatum, and Gardenia jasminoides were closely involved in inflammation response, bile transport, apoptosis, oxidative stress, and regulation of leukocyte migration. Notably, bile secretion dominated the common pathway of the three herbs. On the other hand, Artemisia capillaris exhibited a unique mode of action by regulating the IL-17 signaling pathway, which may play a crucial role in its effectiveness. CONCLUSION: Based on our findings, the optimal TG-C demonstrated the most favorable overall therapeutic efficacy by increasing the dosage of Artemisia capillaris while reducing the dosage of Gardenia jasminoides and Rheum palmatum. This is attributed to the potent ability of Artemisia capillaris. to effectively modulate the IL-17 signaling pathway, thereby exerting a beneficial therapeutic effect. Conversely, Gardenia jasminoides and Rheum palmatum may potentially enhance the activation of the NF-кB signaling pathway, thereby elevating the risk of hepatotoxicity.

Corticosteroid-resistant immune-related adverse events: a systematic review.

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.

Nervonic acid improves liver inflammation in a mouse model of Parkinson's disease by inhibiting proinflammatory signaling pathways and regulating metabolic pathways.

BACKGROUND: Nervonic acid (NA) - a type of bioactive fatty acid that is found in natural sources - can inhibit inflammatory reactions and regulate immune system balance. Therefore, the use of NA for the treatment of neurodegenerative diseases has received considerable attention. Our previous study found that NA inhibited inflammatory responses in the brain of Parkinson's disease (PD) mouse models. In addition to the brain, PD is also associated with visceral organ dysfunction, especially impaired liver function. Thus, studying the role of NA in PD-mediated inflammation of the liver is particularly important. METHODS: A combined transcriptome and metabolomic approach was utilized to investigate the anti-inflammatory effects of NA on the liver of PD mice. Inflammatory signaling molecules and metabolic pathway-related genes were examined in the liver using real-time PCR and western blotting. RESULTS: Liver transcriptome analysis revealed that NA exerted anti-inflammatory effects by controlling several pro-inflammatory signaling pathways, such as the down-regulation of the tumor necrosis factor and nuclear factor kappa B signaling pathways, both of which were essential in the development of inflammatory disease. In addition, liver metabolomic results revealed that metabolites related to steroid hormone biosynthesis, arachidonic acid metabolism, and linoleic acid metabolism were up-regulated and those related to valine, leucine, and isoleucine degradation pathways were down-regulated in NA treatment groups compared with the PD model. The integration of metabolomic and transcriptomic results showed NA significantly exerted its anti-inflammatory function by regulating the transcription and metabolic pathways of multiple genes. Particularly, linoleic acid metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis were the crucial pathways of the anti-inflammatory action of NA. Key genes in these metabolic pathways and key molecules in inflammatory signaling pathways were also verified, which were consistent with transcriptomic results. CONCLUSION: These findings provide novel insights into the liver protective effects of NA against PD mice. This study also showed that NA could be a useful dietary element for improving and treating PD-induced liver inflammation.

A Case Report of Acute Hepatitis Involving the Medicinal Herb Tinospora cordifolia Along with Other Variables.

This is a 54-year-old woman from Germany of central European origin who developed an acute hepatitis while orally taking Ayurvedic herbal remedies, among those was the medicinal herb Tinospora cordifolia. She took the plant powders from July 1, 2021, to October 1, 2021, with the intention of relieving the symptoms of her subjectively irritated gastrointestinal tract. The patient's main symptoms of acute hepatitis were progressively increasing general fatigue, nausea, and exhaustion. During an inpatient hospital admission from November 4, 2021, to November 9, 2021, she was under clinical observation, but no specific therapeutic measures were deemed necessary; however, blood chemistry showed an acute toxic hepatitis. There was no clinical or laboratory evidence of acute liver failure. Aminotransferase values decreased to normal values on December 14, 2021, by themselves. This case report contributes to the ongoing discussion about the potential risks of triggering an acute hepatitis due to the intake of herbal remedies from the Tinospora genus in rare cases, differentiating other involved risk factors. The case also shows that causality assignments are not trivial in the context of multivariate clinical scenarios. In the case of known hepatic metabolism-associated risk factors, T. cordifolia should be used with more caution based on available case reports. At the same time, no hasty and exaggerated prejudgments should be made about this medicinal herb, which has been very successfully used in traditional South Asian systems of medicine for many centuries.

Corydalis saxicola Bunting: A Review of Its Traditional Uses, Phytochemistry, Pharmacology, and Clinical Applications.

Corydalis saxicola Bunting (CSB), whose common name in Chinese is Yanhuanglian, is a herb in the family Papaveraceae. When applied in traditional Chinese medicine, it is used to treat various diseases including hepatitis, abdominal pain, and bleeding haemorrhoids. In addition, Corydalis saxicola Bunting injection (CSBI) is widely used against acute and chronic hepatitis. This review aims to provide up-to-date information on the botanical distribution, description, traditional uses, phytochemistry, pharmacology, and clinical applications of CSB. A comprehensive review was implemented on studies about CSB from several scientific databases, such as SciFinder, Elsevier, Springer, ACS Publications, Baidu Scholar, CNKI, and Wanfang Data. Phytochemical studies showed that 81 chemical constituents have been isolated and identified from CSB, most of which are alkaloids. This situation indicates that these alkaloids would be the main bioactive substances and that they have antitumour, liver protective, antiviral, and antibacterial pharmacological activities. CSBI can not only treat hepatitis and liver cancer but can also be used in combination with other drugs. However, the relationships between the traditional uses and modern pharmacological actions, the action mechanisms, quality standards, and the material basis need to be implemented in the future. Moreover, the pharmacokinetics of CSBI in vivo and the toxicology should be further investigated.

Protective role of Avena fatua against drug-induced liver toxicity.

The study was conducted to examine the protective potential of ethanol seed extract (ESEt) of Avena fatua (wild oats) against antituberculosis drug (ATD)-induced hepatotoxicity in rats. Four groups of rats (n=6) were used. Of which, three groups were given ATD (Rimstar 900mg/15kg) and divided them into hepatotoxic control (distilled water 1mL/kg), positive control (silymarin 200mg/kg) and test group (ESEt 800mg/kg). The fourth was the normal control group treated only with distilled water (1mL/kg). All treatments were orally administered in their respective groups for 26 days. On the 27thday, rats were decapitated. Body and liver weights were measured whereas serum and liver samples were collected for biochemical and histopathological assessments. The rats treated with silymarin and ESEt showed a significant decrease (p<0.05, 0.01& 0.0001) in liver enzymes including alanine & aspartate transaminases, gamma glutamyltranspeptidase and alkaline phosphatase. ESEt also improved total bilirubin (particularly indirect bilirubin), total protein, albumin and low density lipoprotein cholesterol levels in test group. The hepatoprotective ability of extract was also evident by histological study of liver tissues of the test group that showed normal architecture as compared to liver of ATD treated hepatotoxic control group displayed heterogeneous hepatocytes, inflamed central vein, fatty deposits, enlarged sinusoid, Kupffer's cells infiltration, hypertrophy and fibrosis. In conclusion, ESEt of A.fatua is hepatoprotective in nature which may be due to the presence of total phenols and flavonoids already reported from the seeds of this plant.

Promising traditional Chinese medicine for the treatment of cholestatic liver disease process (cholestasis, hepatitis, liver fibrosis, liver cirrhosis).

ETHNOPHARMACOLOGICAL RELEVANCE: Cholestatic liver disease (CLD) is mainly characterized by cholestasis. If not treated, it will deteriorate to cholestatic hepatitis, liver fibrosis, liver cirrhosis, and even liver failure. CLD has a high clinical incidence, and limited treatment with single therapy. In the long-term clinical exploration, traditional Chinese medicine (TCM) has been corroborated with unique therapeutic effects on the CLD process. AIM OF THIS REVIEW: This paper summarizes the effective single and compound TCMs for the treatment of CLD. According to 4 important clinical stages of CLD: cholestasis, hepatitis, liver fibrosis, liver cirrhosis, pharmacological effects and mechanisms of 5 typical TCM examples are reviewed, aims to provide basis for clinical drug selection in different processes of CLD. MATERIALS AND METHODS: Relevant scientific articles regarding therapeutic effects of TCM for the CLD were collected from different databases. We collated three single herbs including Artemisia scoparia Waldst. et Kit. or Artemisia capillaris Thunb. (Artemisiae Scopariae Herba, Yin Chen in Chinese), Paeonia lactiflora Pall. or Paeonia veitchii Lynch. (Paeoniae radix rubra, Chi Shao in Chinese), Poria cocos (Schw.) Wolf (Poria, Fu Ling in Chinese), and two compound herbs of Huang Qi Decoction (HQD) and Yin Chen Hao Decoction (YCHD) to studied and analyzed. RESULTS: We proposed five promising TCMs treatments for the important developmental stages of CLD. Among them, Yin Chen is an essential medicine for protecting liver and gallbladder, and its TCM prescription is also a promising strategy for cholestasis. Based on clinical evidence, high-dose application of Chi Shao is a clinical special treatment of cholestasis hepatitis. Fu Ling can regulate immune cells and increase antibody levels in serum, which is expected to be an emerging therapy to prevent cholestatic liver fibrosis to cirrhosis. HQD can be used as routine clinical medicine for liver fibrosis. In addition, YCHD can exert better comprehensive advantages with multiple components, can treat the whole course of CLD and prevent it from developing to the end-stage. CONCLUSION: Yin Chen, Chi Shao, Fu Ling, HQD and YCHD have shown good clinical efficacy in controlling the development of CLD. Clinically, it is easier to curb the development of CLD by adopting graded diagnosis and treatment measures. We suggest that CLD should be risk stratified in clinical treatment to ensure personalized treatment for patients, so as to slow down the development of the disease.

Therapeutic Effect of Acer tegmentosum Maxim Twig Extract in Bile Duct Ligation-Induced Acute Cholestasis in Mice.

Cholestatic liver disease, or cholestasis, is a condition characterized by liver inflammation and fibrosis following a bile duct obstruction and an intrahepatic accumulation of bile acids. Inhibiting inflammation is a promising therapeutic strategy for cholestatic liver diseases. Acer tegmentosum Maxim extract (ATE) is best known for its anti-inflammatory and antioxidative properties. In this study, we investigated the effects of ATE on liver injury and fibrosis in mice with bile duct ligation (BDL)-induced cholestasis through analysis of gene expression, cytokines, and histological examination. Oral administration of ATE (20 or 50 mg/kg) for 14 days significantly attenuated hepatocellular necrosis compared to vehicle-treated BDL mice, which was accompanied by the reduced level of serum bile acids and bilirubin. We determined that ATE treatment reduced liver inflammation, oxidative stress, and fibrosis. These beneficial effects of ATE were concurrent with the decreased expression of genes involved in the NF-κB pathway, suggesting that the anti-inflammatory effect of ATE could be a possible mechanism against cholestasis-associated liver injury. Our findings substantiate ATE's role as an alternative therapeutic agent for cholestasis-induced liver injury and fibrosis.

Aucubin as a natural potential anti-acute hepatitis candidate: Inhibitory potency and hepatoprotective mechanism.

BACKGROUND: Hepatic inflammation can substantially impact the development of acute hepatitis. It is a pressing need to identify and exploit novel therapeutic targets as well as effective drug therapies against acute hepatitis. Aucubin (AU) is one of the main active components extracted from the leaves of Eucommia ulmoides and possesses significant anti-inflammatory and antioxidant activities. However, the protective effect and mechanism of AU on acute hepatitis have not been reported yet. PURPOSE: This study aims to investigate the protective effect of AU on LPS-induced acute hepatitis and the mechanism of action. METHODS: The limma package was used to analyze differentially expressed genes (DEGs) between LPS-induced acute hepatitis and normal groups based on Gene Expression Omnibus (GEO) microarray data. Network pharmacology predicted targets for AU therapy against acute hepatitis, and Gene Ontology (GO) enrichment analysis of the biological processes involved in these targets. The key pathways were analyzed by protein-protein interaction, KEGG (Kyoto Encyclopedia of Genes and Genomes), and GSEA (Gene Set Enrichment Analysis) enrichment. The important interaction targets between AU and key pathways were evaluated by molecular simulation. The in silico predicted mechanism was verified based on in vitro and in vivo experiments. RESULTS: A total of 116 intersection targets between AU prediction targets and differentially expressed genes were identified. They were functionally involved in the imbalance of "inflammation-anti-inflammation" and "oxidation-antioxidation" systems in the process of LPS-induced cases. In vitro experiments revealed that AU reduced inflammation in LPS-induced HepG2 cells by reducing the inflammatory cytokines TNF-α, IL-6, as well as iNOS enzyme activity levels. In addition, LPS-induced oxidative stress can be alleviated by AU via adjusting the levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), Malone dialdehyde (MDA) and reactive oxygen species (ROS). Protein-protein interaction and GSEA results showed that AU might exert anti-inflammatory effects mainly through the STAT3/NF-κB signal pathway. Molecular dynamics simulation as well as in vivo tests further demonstrated AU restrained nuclear transfer of NF-κB (P65), probably through reducing phosphorylation of STAT3. In addition, AU appears to reduce oxidative stress by upregulating NRF2/HO-1. CONCLUSION: We explored potential targets and signal pathways of AU in inhibiting acute hepatitis. AU exerted anti-inflammatory and antioxidant activities and may be a useful candidate drug for the treatment of acute hepatitis.

Luteolin ameliorates LPS-induced acute liver injury by inhibiting TXNIP-NLRP3 inflammasome in mice.

BACKGROUND: Chemical liver injury is one of the main causes of acute liver failure and death. To date, however, treatment strategies for acute liver injury have been limited. Therefore, there is an urgent need to find new therapeutic targets and effective drugs. NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a complex of multiple proteins that has been shown to induce cell death under inflammatory and stress pathologic conditions and is thought to provide new targets for the treatment of a variety of diseases. PURPOSE: The purpose of this study was to investigate whether luteolin has a protective effect on the liver and further elucidate whether it is realized through the thioredoxin interacting protein (TXNIP)-NLRP3 axis. STUDY DESIGN: Acute hepatic injury in mice caused by intraperitoneal injection of lipopolysaccharide (LPS) was treated with or without luteolin. METHODS: Male C57BL/6 mice and mouse primary hepatocytes were selected. TXNIP protein knockdown was achieved by siRNA, qPCR and Western blot were performed to explore the mechanism of luteolin in alleviating acute liver injury. RESULTS: The results indicated that luteolin had a markedly protective effect on acute liver injury induced by LPS in mice by inhibiting the TXNIP-NLRP3 axis. Luteolin inhibits NLRP3 inflammasome activation by suppressing TXNIP, apoptosis associated speck-like protein containing a CARD domain (ASC), caspase-1, interleukin-1ß (IL-1ß) and IL-18 to reduce liver injury. In addition, luteolin inhibits LPS-induced liver inflammation by inhibiting the production of inflammation-related gene tumor necrosis factor-α (TNF-α), IL-10, and IL-6. What's more, luteolin alleviated LPS-induced hepatocyte injury by inhibiting oxidative stress and regulating MDA, SOD, and GSH levels. However, the protective effect of luteolin on acute LPS-induced liver injury in mice was blocked by si-TXNIP in vitro. CONCLUSIONS: These combined data showed that luteolin may alleviate LPS-induced liver injury through the TXNIP-NLPR3 axis, providing new therapeutic targets and therapeutic drugs for subsequent studies.

Dipterocarpus tuberculatus Roxb. Ethanol Extract Has Anti-Inflammatory and Hepatoprotective Effects In Vitro and In Vivo by Targeting the IRAK1/AP-1 Pathway.

Dipterocarpus tuberculatus Roxb. has been used traditionally as a remedy for many diseases, especially inflammation. Therefore, we analyzed and explored the mechanism of the anti-inflammatory effect of a Dipterocarpus tuberculatus Roxb. ethanol extract (Dt-EE). Dt-EE clearly and dose-dependently inhibited the expression of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1ß in lipopolysaccharide (LPS)-treated RAW264.7 cells. Also, Dt-EE suppressed the activation of the MyD88/TRIF-mediated AP-1 pathway and the AP-1 pathway related proteins JNK2, MKK4/7, and TAK1, which occurred as a result of inhibiting the kinase activity of IRAK1 and IRAK4, the most upstream factors of the AP-1 pathway. Finally, Dt-EE displayed hepatoprotective activity in a mouse model of hepatitis induced with LPS/D-galactosamine (D-GalN) through decreasing the serum levels of alanine aminotransferase and suppressing the activation of JNK and IRAK1. Therefore, our results strongly suggest that Dt-EE could be a candidate anti-inflammatory herbal medicine with IRAK1/AP-1 inhibitory and hepatoprotective properties.

A Network Pharmacology Study of the Molecular Mechanisms of Hypericum japonicum in the Treatment of Cholestatic Hepatitis with Validation in an Alpha-Naphthylisothiocyanate (ANIT) Hepatotoxicity Rat Model.

BACKGROUND This network pharmacology study aimed to identify the active compounds and molecular mechanisms involved in the effects of Hypericum japonicum on cholestatic hepatitis. We validated the findings in an alpha-naphthylisothiocyanate (ANIT) rat model of hepatotoxicity. MATERIAL AND METHODS The chemical constituents and targets of H. japonicum and target genes previously associated with cholestatic hepatitis were retrieved from public databases. A network was constructed using Cytoscape 3.7.2 software and the STRING database and potential protein functions were analyzed based on the public platform of bioinformatics. ANIT was used to induce cholestatic hepatitis in a rat model using 36 Sprague-Dawley rats, and this model was used to investigate intervention with 3 doses of quercetin (low-dose, 50 mg/kg; medium-dose, 100 mg/kg; and high-dose, 200 mg/kg), the main active component of H. japonicum. Levels of serum biochemical indexes were measured by commercial kits, and the messenger RNA (mRNA) levels of markers of liver and mitochondrial function and oxidative stress were detected by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS The main active ingredients of H. japonicum were quercetin, kaempferol, and tetramethoxyluteolin, and their key targets included prostaglandin G/H synthase 2 (PTGS2), B-cell lymphoma-2 (BCL2), cholesterol 7-alpha hydroxylase (CYP7A1), and farnesoid X receptor (FXR). Quercetin intervention promoted recovery from cholestatic hepatitis. CONCLUSIONS The findings from this research provide support for future research on the roles of quercetin, kaempferol, and tetramethoxyluteolin in human liver disease and the roles of the PTGS2, BCL2, CYP7A1, and FXR genes in cholestatic hepatitis.

[A case of early syphilitic hepatitis with jaundice cured by high-dose amoxicillin and probenecid].

A 44-year-old man was admitted because of general malaise, jaundice, and epigastric pain. The patient had no significant medical history. However, the patient visited a brothel 3 months ago and noticed initial induration on his penis 2 months ago. Physical examination revealed swelling surface lymph nodes in the inguinals. Laboratory examination showed moderate hepatic disorder and jaundice. Hepatitis virus markers and various types of autoantibodies were negative, but serological test for syphilis was positive. The symptoms and abnormal data improved immediately after the patient was treated with amoxicillin (3000mg/day) and probenecid (750mg/day). Thus, a diagnosis of early syphilitic hepatitis was established. In addition, syphilis is not just a genital disease. This disease should be thought of in a patient with liver dysfunction, especially among people of high sexual activity.

Network pharmacology assessment of Qingkailing injection treatment of cholestatic hepatitis.

OBJECTIVE: To investigate the targets and mechanisms of action of Qingkailing injection (，QKL) in the treatment of cholestatic hepatitis. METHODS: A network pharmacology method was implemented using drug and disease databases to target QKL and cholestasis hepatitis, respectively. The functional protein association network STRING database was used to construct a protein-protein interaction network using R language and the Bioconductor toolkit. The org.Hs.eg.db and clusterProfiler packages were used for gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, which explored biological functions and pathways of potential targets. Targets were then visualized using Cytoscape 3.6.0 software. RESULTS: We screened 121 compounds in QKL and identified 112 targets for the treatment of cholestatic hepatitis. QKL played a role in the treatment of cholestatic hepatitis through 305 biology process terms, 15 cellular component and 29 molecular function terms. The mechanism of QKL action was mainly related to tumor necrosis factor, mitogen-activated protein kinase, and PI3K-Akt signaling pathways. CONCLUSION: The treatment of cholestatic hepatitis by QKL involved multiple targets, biological functions, and signaling pathways that are closely associated with the disease.

Systemic pharmacology understanding of the key mechanism of Sedum sarmentosum Bunge in treating hepatitis.

Sedum sarmentosum Bunge is a Traditional Chinese Medicine that is widely used in treating hepatitis, whereas the detailed mechanisms have not been fully interpreted. A systemic pharmacology method including absorption, distribution, metabolism and elimination screening, drug targeting, interaction network plotting, and enrichment analysis was applied for exploring the underlying mechanisms of Sedum sarmentosum Bunge in the treatment of hepatitis. A total of 47 ingredients were identified in Sedum sarmentosum Bunge, and 5 active ingredients (DFV, isorhamnetin, beta-sitosterol, luteolin and quercetin) were screened out with the criteria of oral bioavailability (OB) ≥ 30% and drug-likeness (DL) ≥ 0.18. Those 5 ingredients interacted with 170 targets, 163 of which were hepatitis-related. By compound-target-disease network plotting, protein-protein interaction network plotting and enrichment analysis, the pathways that the 5 ingredients engaged in during hepatitis development and progression were investigated, such as threonine-protein kinase signaling. The integrated systemic pharmacology analysis facilitates the in-depth understanding of Sedum sarmentosum Bunge in the hepatitis treatment, which also paves the way for further knowledge of the molecular mechanism of Sedum sarmentosum Bunge in treating hepatitis.

The immunomodulatory activity of Chenopodium ambrosioides reduces the parasite burden and hepatic granulomatous inflammation in Schistosoma mansoni-infection.

ETHNOPHARMACOLOGICAL RELEVANCE: Folk medicine reports have described the use of Chenopodium ambrosioides as an anti-inflammatory, analgesic, and anthelmintic herb. These effects, including its activity against intestinal worms, are already scientifically observed. However, the immunological mechanisms of this species in the treatment of Schistosoma mansoni infection are unknown. AIM OF THE STUDY: To evaluate the immunological and anti-Schistosoma mansoni effects of a crude Chenopodium ambrosioides hydro-alcoholic extract (HCE). MATERIALS AND METHODS: For the in vitro analysis, cercariae and adult worms were exposed to different concentrations (0 to 10,000 µg/mL) of the HCE. For the in vivo evaluation, Swiss mice were infected with 50 cercariae of S. mansoni and separated into groups according to treatment as follows: a negative control (without treatment), a positive control (treated with Praziquantel®), HCE1 Group (treated with HCE during the cutaneous phase), HCE2 Group (treated with HCE during the lung phase), HCE3 Group (treated with HCE during the young worm phase), and HCE4 Group (treated with HCE during the adult worm phase). The animals treated with HCE received daily doses of 50 mg/kg, by gavage, for seven days, corresponding to the different developmental stages of S. mansoni. For comparison, a clean control group (uninfected and untreated) was also included. All animals were euthanized 60 days post-infection to allow the following assessments to be performed: a complete blood cells count, counts of eggs in the feces and liver, the quantification of cytokines and IgE levels, histopathological evaluations of the livers, and the analysis of inflammatory mediators. RESULTS: HCE treatment increased the mortality of cercariae and adult worms in vitro. The HCE treatment in vivo reduced the eggs in feces and liver. The number and area of liver granulomas, independent of the phase of treatment, were also reduced. The treatment with HCE reduced the percentage of circulating eosinophils, IgE, IFN-γ, TNF-α, and IL-4. In contrast, the treatment with the HCE, dependent on the phase, increased IL-10 levels and the number of peritoneal and bone marrow cells, mainly of T lymphocytes, B lymphocytes, and macrophages. This effect could be due to secondary compounds presents in this extract, such as kaempferol, quercetin and derivatives. CONCLUSIONS: This study demonstrates that Chenopodium ambrosioides has antiparasitic and immunomodulatory activity against the different phases of schistosomiasis, reducing the granulomatous inflammatory profile caused by the infection and, consequently, improving the disease prognosis.

Δ9-Tetrahydrocannabinolic Acid markedly alleviates liver fibrosis and inflammation in mice.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, and it is closely associated to obesity, type 2 diabetes mellitus, and dyslipidemia. Medicinal cannabis and some neutral cannabinoids have been suggested as a potential therapy for liver diseases. HYPOTHESIS: Δ9-tetrahydrocannabinolic acid (Δ9-THCA), the non-psychotropic precursor of Δ9-THC, is one of the most abundant cannabinoids presents in Cannabis Sativa. However, its biological activities have been poorly investigated. Herein, we studied the antifibrotic and antiinflammatory activities of Δ9-THCA in two different animal models of liver injury, providing a rationale for additional studies on the medicinal use of this cannabinoid in the treatment of liver fibrosis and the management of NAFLD. STUDY DESIGN: The antifibrotic activity of Δ9-THCA in vitro was investigated in the cell lines LX-2 and NIH-3T3-Col1A2-luc. Non-alcoholic liver fibrosis was induced in mice by CCl4 treatment or, alternatively, by 23-week high fat diet (HFD) feeding. Δ9-THCA was administered daily intraperitoneally during the CCl4 treatment or during the last 3 weeks in HFD-fed mice. METHODS: TGFß-induced profibrotic gene expression was analyzed by luciferase and qPCR assays. Liver fibrosis and inflammation were assessed by immunochemistry and qPCR. Blood glucose, insulin, leptin and triglyceride levels were measured in HFD mice. RESULTS: Δ9-THCA inhibited the expression of Tenascin C (TNC) and Col3A1 induced by TGFß in LX-2 cells and the transcriptional activity of the Col1A2 promoter in fibroblasts. Δ9-THCA significantly attenuated CCl4-induced liver fibrosis and inflammation and reduced T cell and macrophage infiltration. Mice fed HFD for 23 weeks developed severe obesity (DIO), fatty liver and marked liver fibrosis, accompanied by immune cell infiltration. Δ9-THCA, significantly reduced body weight and adiposity, improved glucose tolerance, and drastically attenuated DIO-induced liver fibrosis and immune cell infiltration. CONCLUSIONS: Δ9-THCA prevents TGFß-induced fibrotic markers in vitro and liver inflammation and fibrogenesis in vivo, providing a rationale for additional studies on the medicinal use of this cannabinoid, as well as cannabis preparations containing it, for the treatment of liver fibrosis and the management of NAFLD.

Protective effect of Chushizi (Fructus Broussonetiae) on acetaminophen-induced rat hepatitis by inhibiting the Toll-like receptor 3/c-Jun N-terminal kinase/c-jun/c-fos/janus protein tyrosine kinase/activators of transcription 3 pathway.

OBJECTIVE: To observe the intervention of Chushizi (Fructus Broussonetiae) (CSZ) on drug-induced liver injury (DILI) in rats, as well as indicators of liver function, serum levels of inflammatory cytokines, and expression of proteins and mRNA associated with toll-like receptor 3 (TLR3) and the signal transducer and activator of transcription 3 (STAT3) pathway in the liver [TLR3, janus protein tyrosine kinase 2 (JAK2), c-jun, c-fos, c-Jun N-terminal kinase 2 (JNK2), and STAT3]. METHODS: Forty specified pathogen free grade Sprague-Dawley rats were randomly divided into the control group, the model group, the silybin group and the CSZ group. Rats were given acetaminophen (APAP) to trigger DILI. Histopathology of the liver was observed by hematoxylin-eosin staining. The levels of alanine aminotransferase (ALT), aspartate transaminase (AST), direct bilirubin (DBIL), and total bilirubin (TBIL) in serum were detected by a semi-automatic biochemical instrument. Content of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-13, and IL-22 in serum were detected by the enzyme-linked immunosorbent assay, the expression of TLR3, phosphorylation of JAK2 (p-JAK2), while c-jun and c-fos proteins in the liver were determined by immunohistochemistry; expression of JNK2, and STAT3 in the liver were assayed by Western blot and real-time quantitative polymerase chain reaction. P-JNK2 and p-STAT3 in the liver were assayed by Western blot. RESULTS: After treatment, the activity of ALT, AST, and concentrations of TBIL, DBIL, TNF-α, IL-6, as well as IL-13 in serum, were lower than those in the model group, and expression of p-JAK2, TLR3, c-jun, c-fos, p-STAT3, and p-JNK2 could be downregulated. CONCLUSION: Our findings suggest that CSZ is a valid medicine to alleviate APAP-induced DILI, while its partial mechanism may regulate the TLR3/JNK/ c-jun/c-fos/JAK/STAT3 pathway.

Herbal medicine use among patients with viral and non-viral Hepatitis in Uganda: prevalence, patterns and related factors.

BACKGROUND: There is some evidence that patients with liver diseases commonly use complementary and alternative therapies to address general and liver-disease specific health concerns. The purpose of this study was to assess and describe prevalence, patterns and related factors of herbal medicine use among adults diagnosed with viral and non-viral hepatitis in Kampala, Uganda. METHODS: A cross-sectional study was conducted on 310 adult patients attending the gastrointestinal clinic in Mulago hospital referral hospital in Kampala. Data on prevalence, types and reasons for herbal medicine use was collected using standardized questionnaires and focus group discussions. Modified Poisson regression analyses were used to examine factors related to use. RESULTS: Usage of various herbal remedies within 12 months prior to April 2018 was reported by 46.1% (143/310) of patients with 27.3% (39/143) of these reporting having used conventional and herbal therapies concurrently. Herbal remedies were used to treat various health conditions including hepatitis. Patients with hepatitis C virus infection (PRR = 1.16, p = 0.02) compared to those with hepatitis B virus infection, and those who believed that it was safe to use herbal and conventional therapies concurrently (PRR = 1.23, p = 0.008) had higher prevalence odds of herbal medicine use. Conversely, patients who had been newly diagnosed with hepatitis (PRR = 0.69, p = 0.03) compared to those who had been diagnosed more than one-year prior, had lower prevalence odds of herbal medicine use. Various types of local herbs were reported as most commonly used however most patients did not know the ingredients of commercially prepared herbal therapies. CONCLUSION: A high prevalence of herbal medicine use was found among newly-diagnosed patients and patients with hepatitis C more likely to use herbal remedies after adjusting for other factors. Usage was influenced by the belief that herbal medicine is safe and effective. Health workers need to consistently elicit information about herbal remedy use. Research is needed on benefits, adverse effects and outcomes in patients who use herbal remedies to treat primary liver diseases in order to facilitate evidence of efficacy and product safety.