Search

Hydrogen sulfide (H 2 S) is the third new gas signaling molecule in the human body after the discovery of NO and CO. Similar to NO, it has the functions of vasodilation, anti-inflammatory, antioxidant, and regulation of cell formation. Enzymes that can produce endogenous H 2 S, such as CSE, CSB, and 3-MST, are common in liver tissues and are important regulatory molecules in the liver. In the development of liver fibrosis, H 2 S concentration and expression of related enzymes change significantly, which makes it possible to use exogenous gases to treat liver diseases. This review summarizes the role of H 2 S in liver fibrosis and its complications induced by NAFLD and CCl 4 , and elaborates on the anti-liver fibrosis effect of H 2 S through the mechanism of reducing oxidative stress, inhibiting inflammation, regulating autophagy, regulating glucose and lipid metabolism, providing theoretical reference for further research on the treatment of liver fibrosis with H 2 S. • This article provides an extensive review of the role and mechanism of H 2 S in the development of liver fibrosis. • In mammals, CSE, CBS and 3-MST are the key enzymes to produce endogenous H 2 S. • In liver fibrosis caused by different causes, endogenous H 2 S and the expression of related enzymes were reduced. • NO, CO and H 2 S interact with each other to jointly regulate the development of liver fibrosis. • H 2 S improves liver fibrosis by regulatingoxidative stress, inflammation, autophagy, and glycolipid metabolism. [ABSTRACT FROM AUTHOR]

Bupleurum marginatum Wall.ex DC [Apiaceae] (BM)is widely grown in southwestern China, and the whole plant is used as Traditional Chinese Medicine (TCM). Polysaccharides are main natural products in lots of TCM and have been studied for their effects of reducing oxidative stress, anti-inflammation and immune regulation. Herein, we investigated the extraction techniques of Bupleurum marginatum Wall.ex DC polysaccharides (BMP), the identification of their key components, and their ability to inhibit liver fibrosis in both cellular and animal models. Component identification indicated that monosaccharides in BMP mainly consisted of glucose, galactose, mannose, rhamnose, arabinose, and xylose. In vivo analysis revealed that BMP provided significant protective effects on N-Nitroso dimethylamine (NDMA)-induced liver fibrosis rats through reducing hepatomegaly, reducing tissue inflammation, and reducing collagen deposition. BMP also improved the hepatobiliary system and liver metabolism in accord to reduce the serum levels of ALT, AST, ALP, r-GT, and TBIL. In addition, BMP could reduce the level of inflammation and fibrosis through inhibition of IL-1β and TGF-β1. Cellular studies showed that the BMP could provide therapeutic effects on lipopolysaccharide (LPS)-induced cellular fibrosis model, and could reduce the level of inflammation and fibrosis by decreasing the level of TGF-β1, IL-1β, and TNF-α. Our study demonstrated that BMP may provide a new therapy strategy of liver injury and liver fibrosis. [ABSTRACT FROM AUTHOR]

The core of hepatic fibrosis is the activation of hepatic stellate cells. Through the lipopolysaccharide/TLR4/MyD88/NF-KB signal transduction pathway, the inflammatory response in the liver is directly enhanced, and then returns to promote the activation of hepatic stellate cells. And TLR4/MyD88/NF-κB signaling pathway can directly regulate the activation of NLRP3 inflammasome and is an important pathway for activating hepatic stellate cells. TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway is regulated by upstream microRNAs. These miR-NAs can significantly regulate the inflammatory response of the liver and the activation behavior of hepatic stellate cells, affecting the formation of liver fibrosis. Previous studies have found that the active ingredient of Guangxi specialty ethnic medicine, plumbagin, has a definite anti liver fibrosis effect, but its mechanism of action is not clear. This paper provides a review of the research progress on the above issues, and further research ideas have been derived from this, stating that" the anti liver fibrosis effect of plumbagin is achieved by regulating miRNA/TLR4/MyD88/NF-κB inflammatory pathway and activating downstream NLRP3 inflammasome". [ABSTRACT FROM AUTHOR]

Liver fibrosis is a necessary stage in the progression of chronic liver disease to cirrhosis. So far, no satisfactory drugs have been found to intervene in liver fibrosis. Liver microcirculation disorders are one of the important pathogenesis of chronic liver disease, and hepatic sinusoidal endothelial cells (HSECs) are the main cells that constitute the liver microcirculation barrier. In clinical practice, W-P bodies have been detected in HSECs of most patients with liver fibrosis. W-P bodies serve as a site for the synthesis and storage of vW factors, ET-1 and other cytokines that promote liver fibrosis. They can disrupt the structure and function of HSECs, cause liver microcirculation disorders, and exacerbate the progression of liver fibrosis. Previous studies have found that the Guangxi specialty ethnic medicine, C. kwangsiensis S. G. Lee et C. F. Liang, has definite effects in promoting blood circulation, resolving blood stasis, and resisting liver fibrosis. Based on this, a further research idea has been derived, stating that the blood circulation-promoting, blood stasis-resolving, and anti-liver fibrosis effects of C. kwangsiensis are produced by affecting the formation of W-P bodies, the synthesis and storage of contents in W-P bodies, and intervening in their exocytosis capacity. [ABSTRACT FROM AUTHOR]

Liver fibrosis results from the chronic liver injury and no specific medical therapy is approved so far. Recently, new compound, N-(3,4,5-trichlorophenyl) − 2 (3-nitrobenzenesulfonamido) benzamide, referred to as IMB16–4, was developed to resist liver fibrosis. However, IMB16–4 displays poor aqueous solubility and poor oral bioavailability. To increase the dissolution rate, improve the oral bioavailability and enhance the anti-hepatic fibrosis action of IMB16–4, IMB16–4 self-emulsifying drug delivery systems (SEDDS) with negative charge or positive charge were prepared using simple stirring, respectively. Their stability, oral bioavailability and anti-liver fibrosis effect were evaluated. The results showed IMB16–4 SEDDS in simulated gastric juice were nearly spherical with the diameter of 100～200 nm and possessed good stability in 30 days. The oral bioavailability of IMB16–4 SEDDS with negative charge and positive charge were increased to 33 folds and 58 folds compared with that of pure IMB16–4, respectively. In bile duct ligation (BDL) rats, IMB16–4 SEDDS attenuated the degree of liver damage and decreased collagen accumulation. In addition, IMB16–4 SEDDS with negative charge easily accumulated in the liver and alleviated hepatic fibrosis by TGF-β/Smad signaling. These findings indicate that IMB16- 4 SEDDS may be a potential therapy for the treatment of liver fibrosis.

Four series of imidazoles (15a – g , 20c , and 20d) and thiazoles (18a – g , 22a , and 22b) possessing various amino acids were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) inhibitory activities in an enzymatic assay. Among them, compounds 15g and 18c showed the highest inhibitory activity against ALK5, with IC 50 values of 0.017 and 0.025 μM, respectively. Compounds 15g and 18c efficiently inhibited extracellular matrix (ECM) deposition in TGF-β-induced hepatic stellate cells (HSCs), and eventually suppressed HSC activation. Moreover, compound 15g showed a good pharmacokinetic (PK) profile with a favorable half-life (t 1/2 = 9.14 h). The results indicated that these compounds exhibited activity targeting ALK5 and may have potential in the treatment of liver fibrosis; thus they are worthy of further study. [Display omitted] • Four series of imidazoles and thiazoles possessing amino acids were designed and synthesized. • The most potent compounds 15g and 18c showed more potent activity than the clinical candidate (LY-2157299). • Compounds 15g and 18c markedly suppressed the ECM deposition and HSC activation. [ABSTRACT FROM AUTHOR]

Six undescribed meroterpenoids aspertermeroterpenes A−F and four known analogues were isolated from the marine-derived fungus Aspergillus terreus GZU-31-1. Their structures were elucidated based on spectroscopic methods and electronic circular dichroism calculations. All meroterpenoids possessed the unique acetyl group at C-11, and also aspertermeroterpene A featured the rare C-14 decarboxylated in DMOA meroterpenoids. In the bioassays, aspermeroterpene B exhibited a potent inhibitory effect on the activation of hepatic stellate cells at the concentration of 5 μM via targeting the Nrf2 signaling. This is the first time reported that aspermeroterpene B as a previously undescribed carbon skeleton of meroterpenoid possessed anti-liver fibrosis effect. Six undescribed meroterpenoids from the Marine-derived fungus Aspergillus terreus GZU-31-1 and aspermeroterpene B exerts anti-liver fibrosis effects by targeting Nrf2 signaling pathway in vitro. [Display omitted] • Six undescribed meroterpenoids isolated from the fungus A. terreus GZU-31-1. • The absolute configuration of meroterpenoids were established by ECD calculations. • Aspermeroterpene B possessed anti-liver fibrosis effect at 5 μM. [ABSTRACT FROM AUTHOR]

Objective To observe the effects of white Lingzhi（ganoderma lucidum）extracts（GLE）on the proliferation and activation of rat hepatic stellate cells，and to explore whether it is related to the Wnt/β-catenin signaling pathway. Methods The rat hepatic stellate cells HSC-T6 were divided into the GLE group and control group. The cells in the GLE group were treated with GLE diluted in different multiples，and the control group with the same amount of culture medium. The OD values were measured by CCK-8 at 24，48，and 72 h after the intervention，and we calculated cell proliferation in⁃ hibition rate，and screened GLE action time and action concentration. We divided HSC-T6 cells into the intervention group and control group. The cells in the intervention group were added with the selected concentrations of GLE，and the control group with the same amount of culture medium. During the action time，RT-PCR was used to detect the HSC activation marker protein α-SMA and transforming growth factor β1（TGF-β1）mRNA，and Western blotting was used to detect the key proteins Frizzled-4 and β-catenin in the Wnt/β-catenin signaling pathway. Results With the increased concentrations and the extension of the intervention time，the OD values of HSC-T6 cells gradually decreased in the GLE group； 48 h and 200 times dilution were used as the time and concentration of the follow-up GLE experiment. Compared with the control group，the expression levels of α-SMA，TGF-β1 mRNA，Frizzled-4 and β-catenin proteins in HSC-T6 cells of the interference group decreased（all P<0. 05）. Conclusion GLE may inhibit the proliferation and activation of HSC-T6 cells by inhibiting the activation of the Wnt/β-catenin signaling pathway，and has the potential to develop into a clinical drug for the prevention and treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

Bupleurum marginatum Wall.ex DC [Apiaceae] (BM)is widely grown in southwestern China, and the whole plant is used as Traditional Chinese Medicine (TCM). Polysaccharides are main natural products in lots of TCM and have been studied for their effects of reducing oxidative stress, anti-inflammation and immune regulation. Herein, we investigated the extraction techniques of Bupleurum marginatum Wall.ex DC polysaccharides (BMP), the identification of their key components, and their ability to inhibit liver fibrosis in both cellular and animal models. Component identification indicated that monosaccharides in BMP mainly consisted of glucose, galactose, mannose, rhamnose, arabinose, and xylose. In vivo analysis revealed that BMP provided significant protective effects on N-Nitroso dimethylamine (NDMA)-induced liver fibrosis rats through reducing hepatomegaly, reducing tissue inflammation, and reducing collagen deposition. BMP also improved the hepatobiliary system and liver metabolism in accord to reduce the serum levels of ALT, AST, ALP, r-GT, and TBIL. In addition, BMP could reduce the level of inflammation and fibrosis through inhibition of IL-1β and TGF-β1. Cellular studies showed that the BMP could provide therapeutic effects on lipopolysaccharide (LPS)-induced cellular fibrosis model, and could reduce the level of inflammation and fibrosis by decreasing the level of TGF-β1, IL-1β, and TNF-α. Our study demonstrated that BMP may provide a new therapy strategy of liver injury and liver fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xiao, Sunniya, Li, Kakar, Dai and Li.)

Liver fibrosis is challenging to treat because of the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamido) benzamide referred to as IMB16-4. However, its poor aqueous solubility and poor oral bioavailability obstruct the drug discovery programs. To increase the dissolution, improve the oral bioavailability and enhance the antifibrotic activity of IMB16-4, PVPK30 was selected to establish the IMB16-4 nanoparticles. Drug release behavior, oral bioavailability, and anti-hepatic fibrosis effects of IMB16-4 nanoparticles were evaluated. The results showed that IMB16-4 nanoparticles greatly increased the dissolution rate of IMB16-4. The oral bioavailability of IMB16-4 nanoparticles was improved 26-fold compared with that of pure IMB16-4. In bile duct ligation rats, IMB16-4 nanoparticles significantly repressed hepatic fibrogenesis and improved the liver function. These findings indicate that IMB16-4 nanoparticles will provide information to expand a novel anti-hepatic fibrosis agent.

Liver fibrosis is a major pathological feature of chronic liver diseases, and effective therapies are limited at present. Asiatic acid (AA) is a triterpenoid isolated from Centella asiatica, which exhibits efficient anti-inflammatory and anti-oxidative activities. However, AA shows very low plasma levels after oral administration. In this study, AA loading PEGylated nanostructured lipid carriers (P-AA-NLCs) were prepared. P-AA-NLCs were characterized for particle size distribution, polydispersity index, entrapment efficiency, X-ray powder diffraction (XRD) pattern, differential scanning colorimeter (DSC), and transmission electron microscopy (TEM). The intestinal absorption, in vivo distribution, pharmacokinetics, and anti-fibrosis effects of P-AA-NLC were studied compared with that of AA-NLC. In situ single-pass intestinal perfusion model shows that there are significant differences in absorption between the free and NLCs formulation. The Peff values of P-AA-NLC were significantly enhanced in all four intestinal segments compared to AA-NLC and free AA (p <.05). fa% and Ka showed similar trends, suggesting the PEGylated NLC can improve the gastrointestinal absorption of the drug. The pharmacokinetic studies presented that P-AA-NLC prolonged blood circulation times with a 1.5-fold higher relative bioavailability compared with AA-NLC. In vivo distribution experiments demonstrated that the fluorescence concentration in the liver was higher than that in other organs and the fluorescence intensity in the liver of DIR-P-NLC was about 1.3 times that of DIR-NLC. In addition, oral administration of P-AA-NLC can significantly attenuate CCl4-induced liver fibrosis and functional impairment in a dosage-dependent manner, including an increase in the albumin (ALB) and decrease in aspartate aminotransferase (AST) and alanine transaminase (ALT). Moreover, the MDA and HYP in liver tissue were downregulated, while the SOD activity was upregulated. In conclusion, P-AA-NLC can increase gastrointestinal absorption of AA and enhance anti-liver fibrosis effects in SD rats. [ABSTRACT FROM AUTHOR]

Liver fibrosis remains a significant public health problem. However, few drugs have yet been validated. Costunolide (COS), as a monomeric component of the traditional Chinese medicinal herb Saussurea Lappa, has shown excellent anti-fibrotic efficacy. However, COS displays very poor aqueous solubility and poor stability in gastric juice, which greatly limits its application via an oral administration. To increase the stability, improve the dissolution rate and enhance the anti-liver fibrosis of COS, pH-responsive mesoporous silica nanoparticles (MSNs) were selected as a drug carrier. Methacrylic acid copolymer (MAC) as a pH-sensitive material was used to coat the surface of MSNs. The drug release behavior and anti-liver fibrosis effects of MSNs-COS-MAC were evaluated. The results showed that MSNs-COS-MAC prevented a release in the gastric fluid and enhanced the dissolution rate of COS in the intestinal juice. At half the dose of COS, MSNs-COS-MAC still effectively ameliorated parenchymal necrosis, bile duct proliferation and excessive collagen. MSNs-COS-MAC significantly repressed hepatic fibrogenesis by decreasing the expression of hepatic fibrogenic markers in LX-2 cells and liver tissue. These results suggest that MSNs-COS-MAC shows great promise for anti-liver fibrosis treatment.

Early intervention of liver fibrosis can prevent its further irreversible progression. Both excess reactive oxygen species (ROS) and transforming growth factor beta(TGF-β)/drosophila mothers against decapentaplegic protein (SMADS) pathway balance disorder promote the progression of hepatic stellate cell (HSC) activation, but existing therapeutic strategies failed to focus on those two problems. A new biomimetic mesoporous polydopamine nandrug (MPO) was constructed for liver fibrosis therapy with multiple targets and reliable biosafety. The MPO was formed by mesoporous polydopamine (mPDA) which has the effect of ROS elimination and encapsulated with anti-fibrotic drug -oxymatrine (OMT) which can intervene liver fibrosis targeting TGF-β/SMADSpathway. Particularly, the nanodrug was completed by macrophage-derived exosome covering. The MPO was confirmed to possess a desired size distribution with negative zeta potential and exhibite strong ROS scavenger ability. Besides, in vitro studies, MPO showed efficient endocytosis and superior intracellular ROS scavenging without cytotoxicity; in vivo studies, MPO effectively cleared the excessive ROS in liver tissue and balanced the TGF-β/SMADS pathways, which in turn inhibited HSC activation and showed superior anti-liver fibrosis therapeutic efficiency with good biological safety. Taken together, this work showed highlights the great potential of the MPO for ameliorating liver fibrosis via ROS elimination and TGF-β/SMADS balancing. [Display omitted] • Exosomes coated mesoporous polydopamine loading oxymatrine was developed. • Nanodrug removed reactive oxygen species in liver fibrosis. • Nanodrug regulated TGF-β/SMADS pathway to inhibit hepatic stellate cell activation. [ABSTRACT FROM AUTHOR]

Periplaneta America are the folk traditional medicine derived from southwest area. Until now there have been four related postmarketing drugs on sale-"Kangfuxin Liquid". "Xinmailong Injection", "Ganlong Capsule" and "Xiaozlieng Yigan Tablet". The modern studies show they have obvious effects on inflammation and tumefaction, wound surface, cardio-cerebrovascular diseases. Hepatitis B and liver cancer. But it's very little known about the active ingredients and mechanisms of action, this will significantly limit its usage in future. So. at present, many researchers are engaged in this field and make some progress by extracting secondary metabolites like isoflavones and isocoumarins from the crude materials. Also some of them consider that the mechanism is the result of multiple factors and cytokines. This review outlines recent advances of Periplaneta America in related aspects and is expected to provide a support to the thorough research of Periplaneta America. [ABSTRACT FROM AUTHOR]

Liver fibrosis results from the chronic liver injury and no specific medical therapy is approved so far. Recently, new compound, N-(3,4,5-trichlorophenyl) − 2 (3-nitrobenzenesulfonamido) benzamide, referred to as IMB16–4, was developed to resist liver fibrosis. However, IMB16–4 displays poor aqueous solubility and poor oral bioavailability. To increase the dissolution rate, improve the oral bioavailability and enhance the anti-hepatic fibrosis action of IMB16–4, IMB16–4 self-emulsifying drug delivery systems (SEDDS) with negative charge or positive charge were prepared using simple stirring, respectively. Their stability, oral bioavailability and anti-liver fibrosis effect were evaluated. The results showed IMB16–4 SEDDS in simulated gastric juice were nearly spherical with the diameter of 100～200 nm and possessed good stability in 30 days. The oral bioavailability of IMB16–4 SEDDS with negative charge and positive charge were increased to 33 folds and 58 folds compared with that of pure IMB16–4, respectively. In bile duct ligation (BDL) rats, IMB16–4 SEDDS attenuated the degree of liver damage and decreased collagen accumulation. In addition, IMB16–4 SEDDS with negative charge easily accumulated in the liver and alleviated hepatic fibrosis by TGF-β/Smad signaling. These findings indicate that IMB16- 4 SEDDS may be a potential therapy for the treatment of liver fibrosis. [Display omitted] ● IMB16-4 SEDDS increased dissolution rate. ● IMB16-4 SEDDS drastically improved oral absorption. ● IMB16-4 SEDDS attenuated cholestatic liver injury. ● IMB16-4 SEDDS with negative charge increased liver accumulation and improved liver function. [ABSTRACT FROM AUTHOR]

Background: Amygdalin (Amy) is a cyanoside and is one of the chief active ingredients in Persicae Semen, Armeniacae Semen Amarum, and Pruni Semen. Amy has extensive and remarkable pharmacological activities, including against anti-hepatic fibrosis. However, the pharmacokinetic and anti-liver fibrosis effects of Amy and its enzyme metabolite prunasin (Pru) in vivo have not been studied and compared, and studies on Pru are limited.Purpose: To investigate the pharmacokinetic characteristics and anti-liver fibrosis effect of Amy and its metabolite Pru in vivo and in vitro, and elucidate whether the metabolism of Amy in vivo for Pru is activated.Methods: Pru was prepared from Amy via the enzymatic hydrolysis of β-glucosidase, and isolated by silica gel column chromatography. An efficient and sensitive ultrahigh-performance liquid chromatography-Q exactive hybrid quadrupole orbitrap high-resolution accurate mass spectrometry was developed and validated to determine simultaneously Amy and Pru in rat plasma after dosing intravenously and orally for pharmacokinetic studies. The affinities of Amy and Pru for β-glucosidase were compared by enzyme kinetic experiments to explain the possible reasons for the differences in pharmacokinetic behavior. In vitro, the inhibitory effects of Amy and Pru on hepatic stellate cell activation and macrophage inflammation on JS1 and RAW 264.7 cells were determined. In vivo, the ameliorative effects of Amy and Pru on liver fibrosis effects were comprehensively evaluated by CCl4-induced liver fibrosis model in mice.Results: The standard curves of Amy and Pru in rat plasma showed good linearity within the concentration range of 1.31-5000.00 ng/ml, with acceptable selectivity, carry-over, detection limit and quantification limits, intra- and inter-day precision, accuracy, matrix effect, and stability. The Cmax and AUC(0-∞) of Pru (Cmax = 1835.12 ± 268.09 ng/ml, AUC(0-∞) = 103,913.17 ± 14,202.48 ng•min/ml) were nearly 79.51- and 66.22-fold higher than those of Amy (Cmax = 23.08 ± 5.08 ng/ml, AUC(0-∞) = 1569.22 ± 650.62 ng•min/ml) after the oral administration of Amy. The oral bioavailability of Pru (64.91%) was higher than that of Amy (0.19%). The results of enzyme hydrolysis kinetics assay showed that the Vmax and Km of Pru were lower than those of Amy in commercial β-glucosidase and intestinal bacteria. In vitro cellular assays showed that Amy and Pru were comparable in inhibiting the NO production in the RAW264.7 cell supernatant and the mRNA expression of α-SMA and Col1A1 in JS1 cells. Amy and Pru were also showed comparable activity in ameliorating CCl4-induced liver fibrosis in mice.Conclusion: The pharmacokinetic characteristics of Amy and Pru in rat plasma were significantly different. After the separate gavage of Amy and Pru, Amy was absorbed predominantly as it's metabolite Pru, whereas Pru was absorbed predominantly as a prototype. The anti-liver fibrosis effects of Amy and its deglycosylated metabolite Pru were comparable in vivo and in vitro. The deglycosylated activated metabolite Pru of Amy plays an important role in anti-liver fibrosis. These findings will facilitate the further exploitation of Amy and Pru. [ABSTRACT FROM AUTHOR]

Three new phenolic constituents 1–3 were obtained from the 95% ethanol extract of the roots of Phyllodium pulchellum (Leguminosae). Their structures were elucidated on the basis of spectroscopic analyses, such as NMR, UV, IR, HR-ESI-MS, and CD. Furthermore, in an in vitro bioassay, all compounds were tested for inhibitory effects against the proliferation of acetaldehyde-stimulated HSC-T6 cells, and compound 3 exhibited potent inhibitory activity with the IC50 value of 7.6 μM. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacology: Fuzheng Huayu recipe (FZHY) was formulated on the basis of Chinese medicine theory in treating liver fibrosis. It has a significant efficacy against liver fibrosis caused by chronic hepatitis B, with the action mechanisms of inhibition of hepatic stellate cell activation, protection of hepatocyte oxidative injury and regulations of hepatic matrix remodeling etc. Aim of the study: To identify the absorbed components and metabolites of Danshen in FZHY in rat serum, and find their active components for anti-liver fibrosis. Material and methods: A valid high performance liquid chromatography–electrospray ionization ion trap mass spectrometry (HPLC-ESI/MSn) method was established to investigate the absorbed and metabolized compounds of Danshen in FZHY in rat serum after oral administration. Mass spectra were acquired in both negative and positive modes. Otherwise, to evaluate the anti-hepatic fibrosis efficacies of absorbed and metabolized compounds, the LX-2 cell line of hepatic stellate cell (HSC), which was crucial cellular basis of fibrogenesis, was cultured and incubated with absorbed compounds, the cytotoxicity was determined with the cellomics Multiparameter Cytotoxicity Kit 1 by High Content Screening (HCS), the cell proliferation was assayed with EdU-DNA incorporation, and the cell activation was analyzed through α-smooth muscle actin (α–SMA) expression with high content screening technology. Results: More than 11 compounds and 2 metabolites from Danshen were identified in the serum after oral administration of FZHY by comparing their mass spectra and retention behavior with reference compounds or literature data. Among these compounds, there were no obvious changes in nuclear morphology, membrane permeability with blow 96μM of six polar compounds treatment in comparison with control cells, respectively. And the salvianolic acid B (6μM, 48μM), caffeic acid (6μM, 48μM) and rosmarinic acid (48μM) could obviously inhibit LX-2 cells proliferation, down-regulate α–SMA expression. Conclusion: The results proved that the established method could be applied to analyze the absorbed into blood compounds of Danshen after oral administration FZHY. These absorbed compounds included 11 compounds and 2 metabolites of Danshen. Among them, the salvianolic acid B, caffeic acid and rosmarinic acid were the effective components of FZHY to anti-hepatic fibrosis effects. [Copyright &y& Elsevier]

Liver fibrosis is challenging to treat because of the lack of effective agents worldwide. Recently, we have developed a novel compound, N-(3,4,5-trichlorophenyl)-2(3-nitrobenzenesulfonamido) benzamide referred to as IMB16-4. However, its poor aqueous solubility and poor oral bioavailability obstruct the drug discovery programs. To increase the dissolution, improve the oral bioavailability and enhance the antifibrotic activity of IMB16-4, PVPK30 was selected to establish the IMB16-4 nanoparticles. Drug release behavior, oral bioavailability, and anti-hepatic fibrosis effects of IMB16-4 nanoparticles were evaluated. The results showed that IMB16-4 nanoparticles greatly increased the dissolution rate of IMB16-4. The oral bioavailability of IMB16-4 nanoparticles was improved 26-fold compared with that of pure IMB16-4. In bile duct ligation rats, IMB16-4 nanoparticles significantly repressed hepatic fibrogenesis and improved the liver function. These findings indicate that IMB16-4 nanoparticles will provide information to expand a novel anti-hepatic fibrosis agent. [ABSTRACT FROM AUTHOR]

Liver fibrosis remains a significant public health problem. However, few drugs have yet been validated. Costunolide (COS), as a monomeric component of the traditional Chinese medicinal herb Saussurea Lappa, has shown excellent anti-fibrotic efficacy. However, COS displays very poor aqueous solubility and poor stability in gastric juice, which greatly limits its application via an oral administration. To increase the stability, improve the dissolution rate and enhance the anti-liver fibrosis of COS, pH-responsive mesoporous silica nanoparticles (MSNs) were selected as a drug carrier. Methacrylic acid copolymer (MAC) as a pH-sensitive material was used to coat the surface of MSNs. The drug release behavior and anti-liver fibrosis effects of MSNs-COS-MAC were evaluated. The results showed that MSNs-COS-MAC prevented a release in the gastric fluid and enhanced the dissolution rate of COS in the intestinal juice. At half the dose of COS, MSNs-COS-MAC still effectively ameliorated parenchymal necrosis, bile duct proliferation and excessive collagen. MSNs-COS-MAC significantly repressed hepatic fibrogenesis by decreasing the expression of hepatic fibrogenic markers in LX-2 cells and liver tissue. These results suggest that MSNs-COS-MAC shows great promise for anti-liver fibrosis treatment. [ABSTRACT FROM AUTHOR]

Background: Huangqi decoction (HQD) has been used to treat chronic liver diseases since the 11th century, but the effective components in HQD against liver fibrosis have not been definitively clarified.Purpose: To investigate and identify multiple effective components in HQD against liver fibrosis using a pharmacokinetics-based comprehensive strategy.Methods: The absorbed representative components in HQD and their metabolites were detected in human plasma and urine using high-resolution mass spectrometry combined with a database-directed method, and then pharmacokinetics in multiple HQD components in human plasma was analyzed by ultra-performance liquid chromatography coupled with triple-quadruple mass spectrometry. Furthermore, the anti-fibrotic effect of potential effective HQD components was studied in LX-2 cells and that of a multi-component combination of HQD (MCHD) was verified in a mouse CCl4-induced hepatic fibrosis model.Results: Twenty-four prototype components in HQD and 17 metabolites were identified in humans, and the pharmacokinetic characteristics of 14 components were elucidated. Among these components, astragaloside IV, cycloastragenol, glycyrrhizic acid, glycyrrhetinic acid, liquiritigenin, and isoliquiritigenin downregulated the mRNA expression of α-SMA; cycloastragenol, calycosin-7-O-β-D-glucoside, formononetin, glycyrrhetinic acid, liquiritin, and isoliquiritin downregulated the mRNA expression of Col I; and calycosin, liquiritigenin, isoliquiritigenin, cycloastragenol, and glycyrrhetinic accelerated the apoptosis of LX-2 cells. MCHD reduced serum aminotransferase activity and hepatic collagen fibril deposition in mice with CCl4-induced hepatic fibrosis.Conclusion: Using the pharmacokinetics-based comprehensive strategy, we revealed that multiple effective HQD components act together against liver fibrosis. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a crucial pathological feature which could result in cirrhosis and hepatocarcinoma. But until now, there is no favourable treatment for it. Apigenin (APG) is a flavonoid, which exhibits efficient anti-liver fibrosis activity, but its underlying mechanisms were rarely studied. So this work aims to estimate the potential therapeutic action of APG on liver fibrosis rats and to gain insight into its system-level mechanisms. Hepatic fibrosis was induced by CCl 4 in Wistar rats, and APG was given in the light of the regimen. Biochemical indexes, histopathological change and immunohistochemistry of liver were evaluated. The optimal effect group of APG was selected for further transcriptomic and proteomic analysis. APG ameliorated liver fibrosis via reducing the levels of AST, ALT, ALP, LDH, Hyp, TP, TB, DB, HA, LN, PCIII and IV-C, mitigating fibrosis and inflammation of liver in H&E and Masson staining. Mechanistically, APG elevated the activity of ALB, SOD and GSH-PX with reducing the level of MDA. The results of microarray and TMT revealed that 4919 genes and 4876 proteins were differentially expressed in the APG and model groups. Besides, transcriptomics and proteomics analyses unfolded 120 overlapped proteins, enriched in 111 GO terms containing apoptotic process, angiogenesis, cell migration and proliferation, etc. Meanwhile, KEGG pathway analysis showed that 26 pathways containing HIF-1/MAPK/eNOS/VEGF/PI3K/Akt signaling pathway, regulation of actin cytoskeleton and focal adhesion mostly. APG can ameliorate CCl 4 -induced liver fibrosis via VEGF-mediated FAK phosphorylation through the MAPKs, PI3K/Akt, HIF-1, ROS, and eNOS pathways, which may hopefully become the anti-liver fibrosis activity of natural product. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a common pathological consequence of liver injury, which increases liver failure-related morbidity and mortality. Hence, anti-fibrotic treatment is urgently needed. Oxidative stress plays a pivotal role in the progression of liver fibrosis. Thus, targeting ROS may be an effective strategy for liver fibrosis treatment. In this study, we investigated four benzoquinones derivatives, including 5-isopropyl-2-methyl-1,4-benzoquinone (TQ), 2-tert-butyl-1,4-benzoquinone (tBu-Q) 2,5-dimethyl-p-benzoquinone (Dime-Q) and p-benzoquinone (Ph-Q), as well as the evaluation of their antioxidant activity and anti-fibrotic effects on activated hepatic stellate cells and TAA-induced mice. Electrochemical analysis showed that all compounds possessed antioxidant property. The result was first confirmed by in vitro experiments, which revealed potential anti-fibrotic activity of all four compounds at the cellular level. Benzoquinone derivatives act as ROS-scavenging molecules, which modulated the TLR4-CD14 signaling pathway to inhibit the expression of procaspase-1 and IL-1β in cells, induced apoptosis via a mitochondrial pathway by upregulating the ratio of Bax/Bcl-2 and by activating caspase-3, as well as inhibited the expression of the anti-apoptotic proteins FLIP and XIAP in activated LX-2 cells. In addition, a TAA (Thioacetamide)-induced mouse model was used to further validate the results. Treatment with benzoquinone derivatives significantly decreased the levels of liver injury markers and lipid peroxidation caused by excessive ROS, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA). Moreover, treatment with benzoquinone derivatives significantly inhibited extracellular matrix (ECM) deposition and downregulated the mRNA and protein expression of liver fibrosis markers, such as collagen I, alpha-smooth muscle actin (α-SMA), and TIMP-1. In summary, these results indicate that benzoquinone derivatives may act as potential therapeutic drugs against liver fibrosis. Image 1 • Benzoquinone derivatives exhibit anti-liver fibrosis activity in TAA-induced mice. • Having anti-oxidant properties to regulate the redox balance of cells. • Inhibition of the oxidant stress in LX-2 cells. • Alleviation of the TLR4-mediated inflammatory response. • Showing the ability that inducing the apoptosis of LX-2 cells. [ABSTRACT FROM AUTHOR]

Objective: To investigate the inhibitory effect of Xinhui citrus fermentation liquor on liver fibrosis in mice., Objective: Mouse models of liver fibrosis were established by intraperitoneal injection of CCl 4 in 105 male C57BL/6 mice, followed by gavage of 0.1 mL 40% CCl 4 olive oil 3 times a week (model group, n =49) or daily gavage of citrus liquor at the dose of 0.26 mL (citrus liquor group, n =56) for 8 weeks. Seven mice receiving only olive oil treatment (0.1 mL, 3 times a week) and another 7 treated with citrus liquor served as the control group. Liver tissues and serum samples were collected from 7 mice in the citrus liquor group and model group each week and from the mice in the two control groups at the 8th week for pathological examination of the liver tissues using HE staining and Sirius red staining and for determination of the biochemical indexes of liver function., Objective: The mice in the model group showed progressively worsened liver fibrosis with obvious hepatic steatosis, necrosis and inflammatory cell infiltration. These liver pathologies were much ameliorated in citrus liquor group, which showed significantly reduced vacuolation, inflammatory cell infiltration, collagen deposition and the Ishak score of the liver tissue ( P < 0.05). Serum levels of cholyglycine, alanine aminotransferase, transglutaminase and alanine aminotransferase were all significantly lower in citrus liquor group than in the model group ( P < 0.05)., Objective: Xinhui citrus fermentation liquor has protective effect on the liver and can significantly ameliorate liver fibrosis in mice.