peoniflorin and Liver-Cirrhosis

To delve into the influence of paeoniflorin (PA) on abating primary biliary cholangitis (PBC)-induced liver fibrosis and its causative role.. Our team allocated the mice to control group, PA group, PBC group and PBC+PA group. We recorded the weight change of mice in each group. We used Masson staining for determining liver fibrosis, immunofluorescence staining for measuring tumor necrosis factor-α (TNF-α) expression, quantitative real-time polymerase chain reaction (qRT-PCR) for assaying related gene expression, as well as Western blot for testing related protein expression.. The weight of PBC model mice declined. Twenty-four weeks after modeling, the positive rate of anti-mitochondrial antibody-M2 (AMA-M2) in PBC mice reached 100%. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), hydroxyproline (HYP), laminin (LN), procollagen type III (PC III), and malondialdehyde (MDA) contents saliently waxed (p<0.01). Meanwhile, superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activity patently waned (p<0.01). Liver fibrosis levels were flagrantly higher (p<0.01), and TNF-α, NOD-like receptor protein 3 (NLRP3), caspase-1, interleukin-18 (IL-18), and interleukin-1β (IL-1β) protein or gene expression were manifestly up-regulated (p<0.01). PA could restore the weight of PBC mice, strikingly restrain the positive expression of AMA-M2, and down-regulate serum ALP, ALT, AST, HYP, LN, PC III, MDA in PBC mice (p<0.01). PA could also significantly up-regulate SOD and GSH-px levels (p<0.01), down-regulate IL-1β, IL-18, caspase-1, NLRP3, and TNF-α protein or gene expression in PBC mice (p<0.01) and inhibit liver fibrosis levels (p<0.01).. PA can reduce PBC-induced liver fibrosis in mice and may function by curbing the formation of NLRP3.

Topics: Animals; Aspartate Aminotransferases; Glucosides; Liver; Liver Cirrhosis; Mice; Monoterpenes; NLR Family, Pyrin Domain-Containing 3 Protein

Hepatic fibrosis is a major consequence of liver disease. Radix Paeoniae Rubra (RPR), the dry root of Paeonia lactiflora Pall., has a long history of clinical application in traditional Chinese medicine (TCM) for the treatment of liver diseases. The researches of RPR active ingredients are mainly focused on paeoniflorin. However, the functional roles of other ingredients have not been clarified sufficiently in the treatment of hepatic fibrosis with RPR.. This study was to figure out the anti-hepatic fibrosis potential and mechanisms of CS-4, one of the paeoniflorin-free subfraction of RPR.. With the guide of bioassay, CS-4, a subfraction of RPR showed in vitro inhibition of hepatic stellate cell activation, was obtained using multiple chromatographic techniques. Its ingredients were determined by UPLC-Q-TOF-MS/MS. Then, the target profiles of ingredients were obtained from the HERB database, and the disease targets were collected from the DisGeNET database. Through the network pharmacology method, a protein-protein interaction network of CS-4 against hepatic fibrosis was established to analyze and excavate the potential therapeutic targets. Combined with the KEGG analysis, a series of signaling pathways were obtained, thereby validated by western blot analysis.. The paeoniflorin-free subfraction of RPR, CS-4, was obtained and showed the most potential anti-fibrotic effect in vitro. A total of 20 main ingredients were identified from CS-4 and considered as its active ingredients. From HERB and DisGeNET databases, 1460 potential targets of CS-4 and 1180 disease targets were obtained, respectively. The overlapped 79 targets were considered to exert the potential anti-fibrosis effect of CS-4, such as JAK2, MYC, SMAD3, and IFNG. The gene enrichment analysis revealed that classical TGF-β/Smad signaling pathway and nonclassical TGF-β/PI3K-AKT signaling pathway may be two of the main mechanisms of CS-4 against hepatic fibrosis, which supported by western blot analysis.. In this study, a paeoniflorin-free subfraction with potential anti-hepatic fibrosis activity in vitro, CS-4, was obtained from RPR. Its multiple ingredients, multiple targets, and multiple mechanisms against hepatic fibrosis were explained by network pharmacology and verified by western blot analysis to further support the clinical applications of RPR.

Topics: Drugs, Chinese Herbal; Glucosides; Humans; Liver Cirrhosis; Monoterpenes; Network Pharmacology; Paeonia; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Tandem Mass Spectrometry; Transforming Growth Factor beta

The role of Paeoniflorin on hepatic fibrosis and the specific mechanisms has not yet been elucidated. Therefore, we explored whether Paeoniflorin exerted protective effects on carbon tetrachloride (CCl4)-induced hepatic fibrosis and the underlying mechanisms.. A model of hepatic fibrosis was induced by intraperitoneally injecting with CCl4 (10% 5 μl/g) twice a week for 7 weeks. To explore the effects of Paeoniflorin, mice were treated with Paeoniflorin (100 mg/kg) by gavage once a day at 1 week after modeling until they were sacrificed.. Paeoniflorin remarkably improved liver function and histopathological changes of hepatic tissues in CCl4-induced liver injury. Besides, the serum MAO enzyme activity and hydroxyproline contents were notably decreased following the intervention of Paeoniflorin. The decreased expression of Vimentin, α-SMA, Col1a and Desmin manifested the inhibition of the hepatic stellate cells (HSCs) activation. Interestingly, Paeoniflorin intervention significantly upregulated the expression of heme oxygenase-1, and attenuated the inflammatory cytokines production as well as the CCl4-induced oxidative stress imbalance.. Paeoniflorin could effectively alleviate CCl4-induced hepatic fibrosis by upregulation of heme oxygenase-1, and it might be a new effective option for the comprehensive treatment of hepatic fibrosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbon Tetrachloride; Cytokines; Disease Models, Animal; Glucosides; Heme Oxygenase-1; Hepatic Stellate Cells; Inflammation; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Monoterpenes; Oxidative Stress; Up-Regulation

Schistosomiasis is a chronic helminthic disease causing hepatic fibrosis. Some studies demonstrated direct effect of targeting apoptosis on fibrosis regression. This study is a novel trial of Paeoniflorin (PAE) on S. mansoni induced hepatic fibrosis in murine model compared to Praziquantel (PZQ) evaluating their anti-parasitic and anti-fibrotic properties aiming to discover a new therapy that decrease schistosomiasis morbidity. Thirty two laboratory bred Swiss albino male CD-1 mice were used in this study. The mice were classified into four groups (8 mice each), control healthy, control infected, PZQ treated (300 mg/kg/12 h), PAE treated (50 mg/kg/d) groups. All mice groups were sacrificed 15 weeks post infection for assessment of drugs efficacy by parasitological, histopathological, immunohistochemical and serological studies. Our results showed that PAE improved the parasitological parameters including decrease worm burden, immature, mature eggs and increase dead ones yet, still PZQ had the upper hand in this aspect. However, PAE exceeded PZQ as an anti-fibrotic therapy seemed in marked decrease in hepatic mean granuloma diameter and fibrosis area, besides, marked increase in serum tumor necrosis factor-alpha; TNF-α level, caspase-3 and P53 apoptotic expressions. There was marked decrease in serum IL-13 level, nuclear factor-kappa B; NF-kB, Transforming Growth Factor-Beta1; TGF-β1, Alpha-Smooth Muscle Actin; α-SMA fibrotic expressions. Conclusively, PAE could be an anti schistosomiasis mansoni therapy exceeding PZQ in targeting apoptosis and ameliorating fibrosis. This study provides a perspective for a novel therapeutic approach to prevent liver fibrosis following liver injury due to schistosomiasis mansoni.

Topics: Actins; Animals; Anthelmintics; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Biomphalaria; Female; Glucosides; Hepatic Stellate Cells; Image Processing, Computer-Assisted; Immunohistochemistry; Interleukin-13; Liver; Liver Cirrhosis; Male; Mice; Monoterpenes; NF-kappa B; Praziquantel; Schistosomiasis mansoni; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

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.

Topics: Animals; Cell Line; Glucosides; Hepatic Stellate Cells; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Liver Cirrhosis; Male; Monoterpenes; Rats, Sprague-Dawley; Signal Transduction; TOR Serine-Threonine Kinases

To observe in vitro the effect of rat drug serum on the proliferation of HSC-T6 hepatic stellate cells in the pharmacokinetic model for determining peoniflorin in Fufang Biejia Ruangan tablet, in order to discover the rational daily administration frequency of Fufang Biejia Ruangan tablet. Fufang Biejia Ruangan tablet was orally administered to rats with different daily administration frequency. Their blood was collected from veins behind eye sockets at different time points before the administration and after the first administration, in order to determine the concentration of peoniflorin in blood plasma and the effect of rat drug serums on the proliferation of HSC-T6. A comprehensive analysis was made on the relationship between pharmacodynamics and pharmacokinetics to determine the rational daily administration frequency of Fufang Biejia Ruangan tablet. The results showed a good correlation between the inhibitory effect of Fufang Biejia Ruangan tablet-contained serum on HSC-T6 and the concentration of peoniflorin in blood. The two-time administration group showed higher pharmacologic and pharmacokinetic AUCs than one-time administration and three-time administration groups. In conclusion, Fufang Biejia Ruangan table is recommended to be taken twice a day for treating liver fibrosis in chronic hepatitis.

Topics: Administration, Oral; Animals; Area Under Curve; Benzoates; Bridged-Ring Compounds; Cell Proliferation; Cells, Cultured; Drugs, Chinese Herbal; Glucosides; Hepatic Stellate Cells; Liver Cirrhosis; Male; Monoterpenes; Rats; Rats, Sprague-Dawley; Tablets

Macrophages in other organs (e.g. kidneys, lungs, and spleen, et. al) have rarely been reported in the development of liver fibrosis. Therefore, it is important to investigate macrophage activation in the main organs in liver fibrosis. We investigated the potential antifibrogenic effects of paeoniflorin (PF) in a dimethylnitrosamine (DMN)-induced rat model with special focus on inhibiting macrophage activation in the main organs.. Rat hepatic fibrosis was induced by treatment with DMN three times weekly over a 4-week period. DMN rats were treated with water, PF, or gadolinium chloride (GdCl3) from the beginning of the 3rd week. The expression of CD68, marker of macrophage, was investigated using immunohistochemical, real-time PCR, and western blot analysis.. Hepatic hydroxyproline content markedly decreased and histopathology improved in the DMN-PF rats. Expression of desmin and collagen 1 decreased notably in DMN-PF liver. CD68 expression in the liver, spleen and kidney increased markedly after 2 weeks but decreased in DMN-water rats. PF and GdCl3 decreased CD68 expression in the liver and spleen and there was no effect on kidney. CD68 expression in the lung increased gradually during the course of DMN-induced liver fibrosis, and PF inhibited CD68 expression in the lung significantly while GdCl3 increased CD68 markedly. Expression of tumor necrosis factor (TNF-α) was decreased significantly by GdCl3 in the liver, as revealed by real-time PCR analysis. However, GdCl3 could not decrease TNF-α level in the serum by enzyme linked immunosorbent assay (ELISA).. Macrophage activation was disrupted in the liver, spleen, lung and kidney during development of DMN-induced liver fibrosis. PF administration attenuated DMN-induced liver fibrosis at least in part by regulating macrophage disruption in the main organs.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Benzoates; Bridged-Ring Compounds; Chemical and Drug Induced Liver Injury; Collagen Type I; Desmin; Dimethylnitrosamine; Disease Models, Animal; Glucosides; Hydroxyproline; Kidney; Liver; Liver Cirrhosis; Lung; Macrophages; Male; Monoterpenes; Paeonia; Phytotherapy; Plant Extracts; Rats; Rats, Wistar; Spleen; Tumor Necrosis Factor-alpha

Interleukin (IL)-13 and alternatively activated macrophages (AAMs) play an important role in liver granuloma and fibrosis of schistosomiasis. Paeoniflorin (PAE, C23H28O11) has been reported to have an anti-hepatic fibrosis effect in schistosomiasis; however, the mechanism has not been fully elucidated. In this study, we measured serum hyaluronic acid (HA) concentrations, liver granuloma diameter and volume density, fibrosis degree and expressions of IL-13, arginase-1 (ARG-1), nitric oxide synthase-2 (NOS-2), and phosphorylated signal transducer and activator of transcription 6 (p-STAT6) in mice liver of schistosomiasis. Then we detected expressions of specific biomarkers of AAMs and activity of Arg-1 in Kupffer cells (KCs) from infected and PAE-treated mice, or in KCs from uninfected mice, but exposed to rIL-13 in vitro. Finally, we observed expression of IL-13 signalling molecules in KCs and secretion of IL-13 from lymphocytes of infected and PAE-treated mice. Our results showed that during schistosomiasis, IL-13 expression and secretion increased with liver macrophages activated alternatively. PAE not only directly inhibited alternative activation of macrophages via reducing the phosphorylations of janus-activated kinase 2 (JAK2) and/or STAT6, leading to reduction of AAMs-related markers and Arg-1 activity, but also indirectly suppressed alternative activation of macrophages through decreasing secretion of IL-13. PAE might be a promising prophylactic agent for hepatic granuloma and fibrosis of schistosomiasis japonica.

Topics: Animals; Arginase; Benzoates; Bridged-Ring Compounds; Female; Gene Expression; Glucosides; Granuloma; Humans; Hyaluronic Acid; Interleukin-13; Janus Kinase 2; Kupffer Cells; Liver; Liver Cirrhosis; Macrophage Activation; Macrophages; Mice; Mice, Inbred BALB C; Monoterpenes; Nitric Oxide Synthase Type II; Phosphorylation; Schistosoma japonicum; Schistosomiasis japonica; STAT6 Transcription Factor

To observe the effects of paeoniflorin on the expressions of CTGF and PDGF in liver tissue of fibrosis and the serum level of TNF-alpha in mice infected with Schistosoma japonicum, and to explore the protective effect and its mechanisms of paeoniflorin on liver fibrosis.. Kunming mice were divided randomly into 5 groups, namely normal control group (Group A), paeoniflorin groups (Group B, C, D) and infected control group (Group E). The mice in Group B-E were infected with cercariae of Schistosoma japonicum, and then they were treated with praziquantel (400 mg/kg per day) for 2 days after 6 weeks. After that, the mice in Group B, C, D were given paeoniflorin with a dose of 30, 60, 120 mg/(kg x d), respectively. After 8 weeks of paeoniflorin treatment, all the mice were killed, and their livers and serum were obtained. Hematoxylin and eosin stain and Masson stain were used to observe the degree of hepatic fibrosis. Immunohistochemical staining was performed to detect the expressions of CTGF and PDGF in liver tissue. The serum level of TNF-alpha was detected by ELISA.. The expression levels of CTGF and PDGF proteins in liver tissue and the serum level of TNF-alpha of the mice in the high dosage paeoniflorin treatment group (Group D) were significantly lower than those in the infected control group (P < 0.05).. The effects of paeoniflorin on hepatic fibrosis induced by Schistosoma japonicum infection depends on its dosage. Paeoniflorin may exert its effects by inhibiting the serum level of TNF-alpha and down regulating the expression of CTGF and PDGF proteins.

Topics: Animals; Benzoates; Bridged-Ring Compounds; Connective Tissue Growth Factor; Gene Expression Regulation; Glucosides; Humans; Liver; Liver Cirrhosis; Male; Mice; Monoterpenes; Platelet-Derived Growth Factor; Random Allocation; Schistosoma japonicum; Schistosomiasis japonica; Tumor Necrosis Factor-alpha

Treatment of liver fibrosis associated with Schistosoma japonicum ova-induced granulomas remains a challenging proposition. Paeoniflorin (PAE, C23H28O11) has anti-inflammatory, anti-allergic, and immunoregulatory effects and it is commonly used in Chinese Herbal prescriptions to treat hepatic disorders. The present study was carried out to investigate the effects of PAE on hepatic fibrosis of mice infected with S. japonicum and to explore its possible mechanism. Upon pathological examination of PAE-treated mice, the size of egg granuloma, fibrosis scores, the concentration of IL-13 and hydroxyproline in liver were significantly reduced compared with the model mice. In the primary culture of hepatic stellate cells (HSCs), PAE inhibited IL-13-induced collagen synthesis. These results suggested that PAE might alleviate the hepatic granulomas and fibrosis caused by S. japonicum and the inhibitory effect of PAE on hepatic fibrosis might be associated with its ability to decrease the level of IL-13 and to interfere with the IL-13 signalling molecule in HSCs.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Bridged-Ring Compounds; Cells, Cultured; Collagen; Female; Gene Expression Regulation; Glucosides; Granuloma; Hepatic Stellate Cells; Interleukin-13; Liver Cirrhosis; Mice; Mice, Inbred BALB C; Monoterpenes; Paeonia; Schistosoma japonicum; Schistosomiasis japonica; Signal Transduction

Treatment of liver fibrosis associated with Schistosoma japonicum ova-induced granulomas remains a challenging proposition. There is a close relationship between high levels of interleukin-13 (IL-13) and the development of severe schistosome fibrosis. In contrast, IL-13 receptor (R) α2 has an effective role in attenuation of profibrosis. Several Chinese herbs have significant beneficial effects in liver disease. Accordingly, the purpose of the present study was to investigate the therapeutic effect of Paeoniflorin (PAE) on liver fibrosis. A mouse model for liver fibrosis was established, using infection with S. japonicum cercariae via the skin. Liver tissue was used to examine the effect of PAE on hydroxyproline, collagen I and III, and IL-13 and IL-13Rα2. The results showed that PAE has significant suppressive effect on the increase of both hepatic hydroxyproline and collagen I and III, which are the main components of extracellular matrix (ECM). Meanwhile, PAE not only inhibits IL-13 production, it also elevates IL-13Rα2 in PAE-pretreated groups compared with controls. These results suggested that PAE can improve liver fibrosis due to S. japonicum infection. The effect of PAE appears to depend on a decrease of IL-13 and an increase of IL-13Rα2.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Bridged-Ring Compounds; Collagen Type I; Collagen Type III; Disease Models, Animal; Drugs, Chinese Herbal; Female; Glucosides; Hydroxyproline; Interleukin-13; Interleukin-13 Receptor alpha2 Subunit; Liver; Liver Cirrhosis; Mice; Mice, Inbred BALB C; Monoterpenes; Paeonia; Plant Roots; Random Allocation; Schistosomiasis japonica