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Background: HBV infection can result in severe liver diseases and is one of the primary causes of liver cell carcinoma-related mortality. Liuwei Wuling tablet (LWWL) is a traditional Chinese medicine formula, with a protecting liver and decreasing enzyme activity, usually used to treat chronic hepatitis B with NAs in clinic. However, its main active ingredients and mechanism of action have not been fully investigated. Hence, we aimed to screen the active ingredient and effective ingredient combinations from Liuwei Wuling tablet to explore the anti-herpatitis B virus activity and mechanism. Methods: Analysis and screening of effective antiviral components in LWWL by network pharmacology, luteolin (Lut) may be a compound with significant antiviral activity. The mechanism of antiviral action of Lut was also found by real-time PCR detection and western blotting. Meanwhile, we established a co-culture model to investigate the antiviral mechanism of Schisandrin C (SC), one of the main active components of Schisandra chinensis fructus (the sovereign drug of LWWL). Next, HBV-infected mice were established by tail vein injection of pAAV-HBV1.2 plasmid and administered continuously for 20 days. And their antiviral capacity was evaluated by checking serum levels of HBsAg, HBeAg, levels of HBV DNA, and liver levels of HBcAg. Results: In this study, we conducted network pharmacology analysis on LWWL, and through in vitro experimental validation and data analysis, we found that luteolin (Lut) possessed obviously anti-HBV activity, inhibiting HBV replication by downregulating hepatocyte nuclear factor 4α (HNF4α) via the ERK pathway. Additionally, we established a co-culture system and proved that SC promoted activation of cGAS-STINIG pathway and IFN-β production in THP-1 cells to inhibit HBV replication in HepG2.2.15 cells. Moreover, we found the combination of SC and Lut shows a greater effect in inhibiting HBV compared to SC or Lut alone in HBV-infected mice. Conclusion: Taken together, our study suggests that combination of SC and Lut may be potential candidate drug for the prevention and treatment of chronic hepatitis B. [ABSTRACT FROM AUTHOR]

Linderae Radix (Lindera aggregata (Sims) Kosterm) is a traditional Chinese medicine known for its capability to regulate qi and relieve pain, particularly in the context of gastrointestinal disorders. While our previous research has demonstrated the efficacy of the Linderae Radix water extract (LRWE) in the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), the precise mechanisms remain elusive. This study aims to provide a comprehensive understanding of the therapeutic effects of LRWE on IBS-D through multi-omics techniques. 16 S rRNA gene sequencing combined with LC-MS metabolomics was employed to investigate the effect of LRWE on the gut microbiota and metabolites of IBS-D rats. Spearman correlation analysis was performed on the gut microbiota and metabolites. LRWE administration significantly ameliorated IBS-D rats' symptoms, including diarrhea, visceral hypersensitivity, and low-grade intestinal inflammation. Gut microbiota analysis revealed that LRWE influenced the diversity of the gut microbiota in IBS-D rats by significantly reducing the relative abundance of Patescibacteria and Candidatus Saccharimonas, while increasing the relative abundance of Jeotgalicoccus. Serum metabolomic analysis identified 16 differential metabolites, associated with LRWE's positive effects on IBS-D symptoms, focusing on glyoxylate and dicarboxylic acid metabolism, and cysteine and methionine metabolism. Spearman analysis demonstrated a strong correlation between cecal microbiota composition and serum metabolite levels. This study elucidates that LRWE plays a crucial role in the comprehensive therapeutic approach to IBS-D by restoring the relative abundance of gut microbiota and addressing the disturbed metabolism of endogenous biomarkers. The identified bacteria and metabolites present potential therapeutic targets for IBS-D. [Display omitted] [ABSTRACT FROM AUTHOR]

Liuweiwuling Tablet (LWWL) is a patented Chinese medicine approved by the Chinese National Medical Products Administration (NMPA). Clinically, it is used to treat a range of liver diseases that precede hepatocellular carcinoma (HCC), including hepatitis, liver fibrosis and cirrhosis. LWWL is hypothesized to inhibit the inflammatory transformation of HCC, which may have a positive impact on the prevention and treatment of HCC. However, its exact mechanism of action remains unknown. To investigate how LWWL is effective in the treatment of HCC and to validate the pathways involved in this process. An in vivo model of HCC induced by diethylnitrosamine (DEN) was established to study the effect of LWWL on the development of HCC. The rat serum was analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (γ-GT). The rat liver tissues were stained with hematoxylin and eosin (HE) and Masson's trichrome for pathological analysis. Rat liver tissue was subjected to transcriptome sequencing. Expression of inflammatory and liver fibrosis-related factors in bone marrow-derived macrophages (BMDMs) and LX-2 cells was detected by QRT-PCR, ELISA and Western blot (WB). The expression of apoptosis and stemness genes in HepG2 and Huh7 cells was assessed through flow cytometry and QRT-PCR. Transcriptomics, network pharmacology, WB, and QRT-PCR were employed to validate the mechanisms associated with the amelioration of HCC development by LWWL. LWWL significantly reduced the severity of hepatitis and liver fibrosis, the expression of tumor stemness genes, and the incidence of HCC. In addition, LWWL inhibited the release of inflammatory substances and nuclear accumulation of P65 protein in BMDMs as well as the conversion of LX-2 cells to fibroblasts. LWWL inhibited the proliferation of HepG2 and Huh7 cells, including the initiation of apoptosis and the reduction of stemness gene expression. Importantly, LWWL regulates the PI3K/AKT/NF-κB pathway, which affects hepatic inflammation and cancer progression. LWWL inhibited the occurrence and development of HCC by modulating the severity of hepatitis and liver fibrosis, indicating the potential clinical relevance of LWWL in preventing and treating HCC. [Display omitted] • Potential efficacy of LWWL in chemically related hepatocellular carcinoma. • LWWL inhibits the development of the hepatitis-fibrosis-HCC axis. • A key mechanism of LWWL is the PI3K/AKT/NF-κB signalling pathway. [ABSTRACT FROM AUTHOR]

Dictamnus dasycarpus Turcz. (Dictamni Cortex, DC), a Chinese herbal medicine, is commonly used for treating chronic dermatosis and rheumatism, but can also cause herb-induced liver injury (HILI). Our study has demonstrated that DC can induce idiosyncratic HILI, but the mechanism remains unknown. The NLRP3 inflammasome has become a major target for addressing many diseases. The activation of NLRP3 inflammasome is responsible for many liver-related inflammatory diseases, including idiosyncratic HILI. The objective of our study was to demonstrate the mechanism underlying the idiosyncratic HILI induced by DC and clarify the susceptible component in DC. Bone marrow-derived macrophages (BMDMs) and THP1 cells were selected to assess the effect of isomaculosidine (IMD) on NLRP3 inflammasome activation in vitro. Western blot, ELISA and Caspase-Glo® 1 Inflammasome Assay, flow cytometry and Immunofluorescence were employed to detect the mechanism of IMD on NLRP3 inflammasome activation. To assess the efficacy of IMD in vivo , mice were intravenously administrated with LPS and then IMD were injected intraperitoneally for 6 h. The results of our in vitro studies demonstrate that IMD, the major constituent of DC, specifically promoted ATP- and nigericin-induced activation of NLRP3 inflammasome, but not NLRC4 and AIM2 inflammasomes. Additionally, IMD promoted nigericin-induced ASC oligomerization. Notably, synergistic induction of mtROS played a key role on the activation of NLRP3 inflammasome. IMD increased the mtROS production in the activation of NLRP3 inflammasome induced by nigericin. In addition, the results of our in vivo study showed that the combination of nonhepatotoxic doses of LPS and IMD can increase the levels of ALT, AST, and DBIL, leading to liver injury. IMD specifically facilitated the activation of NLRP3 inflammasome induced by nigericin and ATP, which is responsible for DC-induced idiosyncratic HILI. [Display omitted] • IMD enhances NLRP3 inflammasome activation triggered by ATP or nigericin. • The production of mtROS was a key element to the promoting effect of IMD on NLRP3 inflammasome activation. • IMD induces idiosyncratic HILI by promoting NLRP3 inflammasome activation. • IMD is responsible for DC-induced idiosyncratic HILI. [ABSTRACT FROM AUTHOR]

Anethum graveolens L. (dill), which has been used as a medicine, spice and aromatic plant since ancient times, is not only a traditional Chinese medicines but also an important medicinal and functional food in Europe and Central and South Asia. In ethnomedicine, dill reportedly exerts a protective effect on the liver and has been widely used as a traditional medicine for the treatment of jaundice in the liver and spleen and inflammatory gout diseases in Saudi Arabia. Furthermore, studies have found that dill can regulate the NAT2 enzyme, and this plant was thus selected to study its alleviating effect on isoniazid liver injury. The purpose of this study was to explore the effect of dill on alleviating liver injury induced by hydrazine compounds represented by isoniazid through the use of network pharmacology combined with in vivo and in vitro experimental verifications. First, we screened the key targets of dill in the treatment of liver injury through the use of network pharmacology; we then performed GO and KEGG pathway enrichment analyses using the DAVID database. We also verified the alleviative and anti-inflammatory effects of dill on isoniazid liver injury in rats by animal experiments. We further investigated the modulating effect of dill on the enzymatic activity of NAT2, a common metabolizing enzyme of hydrazine compounds. A total of 111 key targets were screened through network pharmacology. In vivo experiments showed that dill reduced the amount of inflammatory factors produced by isoniazid, such as IL-10, IL-1β, TNF-α and IL-6, restored the levels of ALT, AST, r-GT, AKP and TBA in vivo, and attenuated isoniazid liver injury. Both in vivo and vitro results indicated that dill could regulate the expression of NAT2 enzymes. The results tentatively demonstrate that dill can alleviate isoniazid liver injury through multiple components, targets and pathways and exerts a regulatory effect on the NAT2 enzyme, and these findings thus provide new ideas for subsequent studies on hydrazide liver injury——reducing the risk of hydrazide-induced liver injury through anti-inflammation and regulation of NAT2 enzymes. [Display omitted] • Predicting potential targets and pathways of dill for the treatment of isoniazid liver injury. • Dill alleviated liver injury in rat. • Dill regulated inflammatory mediators levels in rat. • Dill improves cell survival in isoniazid-treated HepG2. • Dill regulates NAT2. [ABSTRACT FROM AUTHOR]

Schisandra Chinensis (Turcz.) Baill. is a long-term used traditional Chinese medicine with the functions of tonifying the kidney and calming the heart, tonifying qi and engendering fluid. It can be used to treat insomnia and dreaminess, spermatorrhea, coughs, as well as liver and kidney deficiency of Yin or Yang Syndrome. Modern pharmacological studies have shown that Schisandra Chinensis regulates host immunity and exhibits anti-cancer, antiviral and liver-protecting effects. However, the specific mechanism by which Schisandra Chinensis modulates antiviral immunity is unknown. We sought to explore the therapeutic effect of the active components of Schisandra Chinensis on anti-viral immunity and further investigate the underlying mechanism. Immunoblotting, quantitative real-time PCR, enzyme-linked immunosorbent assay, immunofluorescence, and immunoprecipitation were used to investigate the effect of schisandrin C (SC), one of the most abundant and biologically active components of Schisandra Chinensis , on the activation of cGAS-STING signaling pathway and the underlying mechanism. In addition, CMA-mediated STING activation and hydrodynamic injection-mediated HBV-replicating mouse model were used to investigate the effect of SC on the activation of STING signaling pathway and its antiviral effect in vivo. SC promoted cGAS-STING pathway activation, accompanied by increased production of interferon β (IFN β) and downstream gene expression. Moreover, SC also exerted anti-HBV effects, reducing HBeAg, HBcAg, HBsAg, and HBV DNA levels in hydrodynamic injection-mediated HBV-replicating mouse model and elevating the production of IFN β and expression of interferon-stimulated genes (IFIT1, ISG15, and CXCL10). Mechanistically, SC could facilitate the interaction between TANK-binding kinase 1 (TBK1) and STING, which is important for IRF3 phosphorylation and production of IFN β. Our study confirmed that SC enhances cGAS-STING pathway activation and inhibits HBV replication, as well as provides clues for chronic hepatitis B and other infectious diseases treated by SC. [Display omitted] • Schisandrin C (SC) promotes cGAS-STING pathway activation. • SC promotes cGAS-STING pathway activation by facilitating the interaction between TBK1 and STING. • SC markedly attenuates hepatitis B virus replication in vivo and promotes the expression of IFN β and ISGs. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Liuweiwuling (LWWL) tablets contain a six-herb Chinese formula and are commonly prescribed to facilitate nourishment of the liver and kidneys, clear away toxic materials and activate blood circulation. Administration of LWWL is well known for its protective effects on the liver and its capacity to confer long-term stability in patients exhibiting reduced transaminase levels. Clinical studies have reported that LWWL can also be used for the treatment of liver fibrosis with associated treatment regimens resulting in a concomitant reduction in transforming growth factor β1 (TGF-β1) levels in the serum of patients with hepatic fibrosis. TGF-β1 plays a prominent role in stimulating liver fibrogenesis and this effect is mediated by myofibroblasts (MFB) derived from hepatic stellate cells (HSCs). It is likely that this phenomenon underpins the antifibrotic effects associated with LWWL. Aim The purpose of this study was to investigate the antifibrotic effects and mechanisms pertaining to LWWL. Methods Hepatic fibrosis was induced in rats following bile duct ligation (BDL). Rats that underwent BDL received daily gavage administration of colchicine (0.2 mg/kg per day), LWWL (0.4, 1.6, 6.4 g/kg per day) or PBS (for the control group). Pathological changes in hepatic tissue were examined using hematoxylin and eosin (HE) and sirius red staining. Immunohistochemical analysis was performed to monitor α-SMA and type I collagen (Collagen I) protein expression. Real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot analyses were used to monitor the expression of genes and proteins in the TGF-β/Smad signaling pathway, including TGF-β1, bone morphogenic protein and activin membrane-bound inhibitor (Bambi), Smad3, phosphorylated Smad3 (p-Smad3) and Smad7. We also monitored the expression of genes and proteins in the nuclear factor-κB (NF-κB) signaling pathway, including NF-κB p65, IκBα and phosphorylation of IκBα (p-IκBα), tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1β (IL-1β). Results LWWL dose-dependently inhibited BDL-induced liver injury and hepatic fibrosis in rats. Furthermore, LWWL reduced liver tissue collagen deposition, hydroxyproline content, liver dysfunction and α-SMA expression in BDL-induced hepatic fibrosis rats. Moreover, LWWL markedly prevented activation of the TGF-β/Smad signaling pathway by inhibiting expression of Smad2/3 and phosphorylation of Smad3, and upregulating the expression of Bambi and Smad7. In addition, LWWL regulated the expression of the inflammatory cytokines IL-1β, TNF-α and IL-6 by inhibiting the activation of NF-κB p65 and the phosphorylation of IκBα, and increasing the expression of IκBα. Conclusions LWWL can attenuate BDL-induced hepatic fibrosis in rats, and this effect may be due to modulation of the NF-κB-dependent inflammatory response and activation of HSC and TGF-β/Smad-mediated synthesis and degradation of Collagen I. [ABSTRACT FROM AUTHOR]

HIF-1α/mTOR signaling pathway is considered to play a crucial role in genesis and progress of tissue fibrosis. The elevation of HIF-1α and mTOR is relevant to CCl4 induced liver fibrotic rats. Paeoniflorin has been consistently shown to exhibit multiple pharmacological effects in liver disease. However, so far, no research demonstrates the relationship between paeoniflorin and HIF-1α/mTOR fibrogenesis pathway in liver fibrosis. In this study, the liver fibrosis was performed by CCl4 rats and HSC-T6 cell line. The data demonstrated that paeoniflorin treatment could attenuate liver fibrosis and inhibit the activation of HSC. Moreover, paeoniflorin significantly enhanced hepatic function by decreasing serum level of ALT, AST and ALP, and increasing level of ALB, TP. Meanwhile, ECM degradation was modulated by paeoniflorin treated rats with a remarkable reduce of α-SMA and collagen III mRNA expression. Moreover, the alleviation effect of liver fibrosis was relevant to inhibiting HIF-1α and phosphor-mTOR. Our data indicate that paeoniflorin alleviates liver fibrosis by inhibiting HIF-1α expression partly through mTOR pathway and paeoniflorin may be a potential therapeutic agent for liver fibrosis. [ABSTRACT FROM AUTHOR]

Keguan-1, a new traditional Chinese medicine (TCM) prescription contained seven Chinese herbs, is developed to treat coronavirus disease 19 (COVID-19). The first internationally registered COVID-19 randomised clinical trial on integrated therapy demonstrated that Keguan-1 significantly reduced the incidence of ARDS and inhibited the severe progression of COVID-19. To investigate the protective mechanism of Keguan-1 on ARDS, a lipopolysaccharide (LPS)-induced acute lung injury (ALI) model was used to simulate the pathological state of ARDS in patients with COVID-19, focusing on its effect and mechanism on ALI. Mice were challenged with LPS (2 mg/kg) by intratracheal instillation (i.t.) and were orally administered Keguan-1 (low dose, 1.25 g/kg; medium dose, 2.5 g/kg; high dose, 5 g/kg) after 2 h. Bronchoalveolar lavage fluid (BALF) and lung tissue were collected 6 h and 24 h after i.t. administration of LPS. The levels of inflammatory factors tumour necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, keratinocyte-derived chemokine (KC or mCXCL1), macrophage inflammatory protein 2 (MIP2 or mCXCL2), angiotensin II (Ang II), and endothelial cell junction-associated proteins were analysed using ELISA or western blotting. Keguan-1 improved the survival rate, respiratory condition, and pathological lung injury; decreased the production of proinflammatory factors (TNF-α, IL-6, IL-1β, KC, and MIP2) in BALF and the number of neutrophils in the lung tissues; and ameliorated inflammatory injury in the lung tissues of the mice with LPS-induced ALI. Keguan-1 also reduced the expression of Ang II and the adhesion molecule ICAM-1; increased tight junction proteins (JAM-1 and claudin-5) and VE-cadherin expression; and alleviated pulmonary vascular endothelial injury in LPS-induced ALI. These results demonstrate that Keguan-1 can improve LPS-induced ALI by reducing inflammation and pulmonary vascular endothelial injury, providing scientific support for the clinical treatment of patients with COVID-19. Moreover, it also provides a theoretical basis and technical support for the scientific use of TCMs in emerging infectious diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: The crude secondary roots of Aconitum carmichaelii Debeaux (Fuzi), together with its processed products, including Yanfuzi, Heishunpian and Paofupian, are commonly applied in clinic using for thousands of years, such as collapse, syncope, rheumatic fever, painful joints and various tumors. Aim of the study: To explore the different effects of Fuzi and its processed products on energy metabolism, with mitochondria as the model with the aim of guiding the clinical use of Fuzi and its products. fingerprints of Fuzi, Yanfuzi, Heishunpian and Paofupian were established by Ultra-high Performance Liquid Chromatography (UPLC) and effects of Fuzi and its processed products on rat’s liver׳s mitochondrial metabolism were studied by microcalorimetry. Spectrum-effect relationships between UPLC fingerprints and energy metabolism of mitochondria were investigated using canonical correlation analysis (CCA). Results: Because of their inherent differences in chemical compositions, the main activities of energy metabolism of mitochondria were different among Fuzi and its processed products. The potential bioactivity sequence of the tested products was Fuzi>Heishunpian>Paofupian>Yanfuzi. Results of CCA showed that compounds mesaconitine, benzoylaconitine, and benzoylhypacoitine might be the principal active components. Conclusion: Altogether, this work provides a general model of combination of UPLC and microcalorimetry to study the spectrum-effect relationships of Fuzi and its processed products which can offer some references for detecting principal components of traditional Chinese medicine on bioactivity to mitochondrial growth. [Copyright &y& Elsevier]

Abstract: A comparative study was designed and conducted to compare the pharmacokinetic difference of paeoniflorin and albiflorin after oral administration of Radix Paeoniae Rubra to normal rats and the acute cholestasis hepatitis rats induced by alpha-naphthylisothiocyanate (ANIT). UPLC-ESI-MS/MS method was employed to determine the level of paeoniflorin and albiflorin in rat plasma using geniposide as the internal standard (IS). Unpaired Student''s t-test was used for the statistical comparison. The investigation showed that there were significant differences between the normal rats and the acute cholestasis hepatitis rat groups in calculated parameters, such as AUC0− t , AUC0−∞, T max and CLz/F. The results indicated that acute liver injury in rats could alter the pharmacokinetics of drug. Since patients are the final users of the drug, it is essential to investigate the pharmacokinetics of the drug in disease status. Therefore, we used normal rats and the acute cholestasis hepatitis rats to study pharmacokinetics of Radix Paeoniae Rubra with the purpose of examining the influence of disease on the metabolic course. [Copyright &y& Elsevier]

Abstract: Aim of the study: Cornu Saigae Tataricae (antelope horn), Manis Squama (pangolin scale), Cornu Cervi Pantotrichum (velvet antler) and Cornu Bovis grunniens (yak horn) are valuable medicinal animal horns and shells (MAHS). As the major source of biological agents and ethnodrugs, MAHS show pretty good bioactivities. However, with the increased demand for MAHS, some of the medicinal resources are endangered, and there has been a concomitant increase in the prevalence of adulterated or impostor MAHS. It is of great significance to exploit the substitutes for endangered medicinal animal resources. This study is going to provide a new mode for the exploitation of the substitutes of MAHS. Materials and methods: Plasma recalcification time, thrombin time and thrombin consumption were recorded to evaluate the anticoagulation effect of MAHS. Dissolution rate of thrombus in vitro and whole blood–gore were observed to appraise the antithrombotic effect of MAHS. Results: All the MAHS involved in this study except Cornu Procaprae Gutturosae (argali horn), Cornu Saigae Tataricae and Cornu Bovis (cattle horn) could not only prolong recalcification time (P <0.01) and thrombin time (P <0.01), but also dissolve the thrombus in vitro (P <0.01) and whole blood–gore (P <0.01). The bioactivities among MAHS differed greatly from each other. Conclusions: The results indicate that Cornu Caprae Hircus (goat horn), Cornu Bubali (water buffalo horn) and Trionycis Carapax (turtle shell) are rational to be explored as the substitutes of Cornu Saigae Tataricae, Cornu Bovis grunniens and Manis Squama, respectively. On the contrary, velvet antler is not suitable to be substituted by Cornu Cervi (deerhorn). We presume that the bioactive evaluation methods are effective means of seeking substitutive resources of endangered medicinal animals with the advantages of close correlation to drug action, low dosage, and high sensitiveness. [Copyright &y& Elsevier]