Angelica dahurica extract and its effective component bergapten alleviated hepatic fibrosis by activating FXR signaling pathway.

Angelica dahurica (A. dahurica) has a wide range of pharmacological effects, including analgesic, anti-inflammatory and hepatoprotective effects. In this study, we investigated the effect of A. dahurica extract (AD) and its effective component bergapten (BG) on hepatic fibrosis and potential mechanisms. Hepatic fibrosis was induced by intraperitoneal injection with carbon tetrachloride (CCl4) for 1 week, and mice were administrated with AD or BG by gavage for 1 week before CCl4 injection. Hepatic stellate cells (HSCs) were stimulated by transforming growth factor-ß (TGF-ß) and cultured with AD, BG, GW4064 (FXR agonist) or Guggulsterone (FXR inhibitor). In CCl4-induced mice, AD significantly decreased serum aminotransferase, reduced excess accumulation of extracellular matrix (ECM), inhibited caspase-1 and IL-1ß, and increased FXR expressions. In activated HSCs, AD suppressed the expressions of α-SMA, collagen I, and TIMP-1/MMP-13 ratio and inflammatory factors, functioning as FXR agonist. In CCl4-induced mice, BG significantly improved serum transaminase and histopathological changes, reduced ECM excessive deposition, inflammatory response, and activated FXR expression. BG increased FXR expression and inhibited α-SMA and IL-1ß expressions in activated HSCs, functioning as GW4064. FXR deficiency significantly attenuated the decreasing effect of BG on α-SMA and IL-1ß expressions in LX-2 cells. In conclusion, AD could regulate hepatic fibrosis by regulating ECM excessive deposition and inflammation. Activating FXR signaling by BG might be the potential mechanism of AD against hepatic fibrosis.

Can vitamin B6 alleviate the adverse reactions of quadruple anti-Helicobacter pylori regimen? : randomized controlled trial.

BACKGROUND: Vitamin B6 is an essential water-soluble vitamin for humans. It is often used to prevent a variety of neuropathies, relieve vomiting, and relieve symptoms such as hand and foot neuritis. AIM: To evaluate whether vitamin B6 can alleviate the adverse reactions caused by the quadruple anti-Helicobacter pylori treatment regimen containing minocycline and metronidazole. METHODS: In this randomized controlled trial, 280 patients with H. pylori infection were randomly placed into one of two treatment groups-the conventional treatment group and the vitamin B6 supplement treatment group-for 2 weeks. The primary endpoint was the total incidence of adverse reactions up to 2 weeks after treatment initiation. The study was designed according to CONSORT Medicinal Interventions. And it was registered with Chinese Clinical Trial Registry under the number ChiCTR2100053833. RESULTS: In terms of efficacy, vitamin B6 does not affect the efficacy of conventional regimen. In the vitamin B6 supplement treatment group, the incidence of adverse reactions was 56.92%, which was significantly lower than the 74.62% observed in the conventional treatment group. In addition, the severity of adverse reactions was also significantly reduced. The proportion of moderate to severe central nervous system symptoms decreased from 58.7 to 14.63%. And, the proportion of moderate to severe gastrointestinal reactions decreased from 33.33 to 0%. We speculate that the mechanism of vitamin B6 of reducing adverse reaction may be related to the production of GABA in the brain. CONCLUSIONS: Vitamin B6 can alleviate adverse reactions of the quadruple anti-H. pylori regimen containing minocycline and metronidazole.

Protective role of Siberian onions against toxin-induced liver dysfunction: an insight into health-promoting effects.

Siberian onions (SOs) are delicious wild vegetables. Their taste is most unique, not only like scallions but also like leeks or garlic. They also have a traditional medicinal value for anti-inflammation, anti-oxidation, and anti-pyretic analgesia, particularly facilitating hepatoprotective effects. The current study investigates the potential mechanism of SOs against toxin-induced liver dysfunction. BALB/c mice were administrated with SO or silymarin by oral gavage for one week, followed by injecting carbon tetrachloride (CCl4) to induce hepatic fibrosis. The effect of SO against hepatic fibrosis was evaluated by examining the liver tissue for serum transaminase, oxidative stress, extracellular matrix, histological alterations, cytokine levels, and apoptosis. In vitro, HSC-T6 cells were cultured with the supernatant from Raw 264.7 cells stimulated with lipopolysaccharides, followed by SO extracts or Niclosamide (Signal Transducer and Activator of Transcription 3 (STAT3) inhibitor) at indicated time periods and doses. SO decreased serum transaminase levels and oxidative stress, and regulated the balance of ECM in CCl4-induced mice, including α-SMA, collagen-I and TIMP-1. SO reduced the release of inflammatory factors and regulated apoptosis-associated proteins, which is related to the inhibition of STAT3 phosphorylation. Moreover, SO reduced the positive expressions of α-SMA and NLRP3 by inhibiting STAT3 phosphorylation in activated HSCs. SO could show health-promoting effects for liver dysfunction by alleviating hepatic fibrogenesis, apoptosis and inflammation in the development of hepatic fibrosis potential depending on the STAT3 signaling pathway.

Inhibition of HMGB1/TLR4 Signaling Pathway by Digitoflavone: A Potential Therapeutic Role in Alcohol-Associated Liver Disease.

Digitoflavone (DG) is a natural flavonoid abundant in many fruits, vegetables, and medicinal plants. We investigated whether DG inhibits lipid accumulation and inflammatory responses in alcoholic liver disease (ALD) in vivo and in vitro. The mouse ALD model was established by chronically feeding male C57BL/6 mice an ethanol-containing Lieber-DeCarli liquid diet. In vitro, mouse peritoneal macrophages (MPMs) and mouse bone marrow-derived macrophages (BMDMs) were stimulated with LPS/ATP, whereas HepG2 cells and mouse primary hepatocytes were treated with ethanol. DG reduced the serum levels of transaminase and serum and hepatic levels of triglycerides and malondialdehyde in ALD mice. DG downregulated SREBP1 and its target genes and upregulated PPARα and its target genes in the liver of mice with ALD. DG inhibited TLR4-mediated NLRP3 inflammasome activation, consequently reversing the inflammatory response, including the production of HMGB1, IL-1ß, and IL-36γ, as well as the infiltration of macrophages and neutrophils. DG blocked NLRP3/ASC/caspase-1 inflammasome activation and HMGB1 release in LPS/ATP-stimulated MPMs. When Tlr4 was knocked in LPS/ATP-stimulated BMDMs, HMGB1 production and release were blocked, and NLRP3-mediated cleavage and release of IL-1ß was suppressed in Hmgb1-silenced BMDMs. DG amplified these inhibitory effects in Tlr4 or Hmgb1 knockdown BMDMs. In ethanol-exposed hepatocytes, DG reduced lipogenesis and promoted lipid oxidation by inhibiting the HMGB1-TLR4 signaling pathway while suppressing the inflammatory response induced by ethanol exposure. Our data demonstrated that DG inhibited the occurrence of lipid accumulation and the inflammatory response via the HMGB1-TLR4 axis, underscoring a promising approach and utility of DG for the treatment of ALD.

Allium victorialis L. Extracts Promote Activity of FXR to Ameliorate Alcoholic Liver Disease: Targeting Liver Lipid Deposition and Inflammation.

Allium victorialis L. (AVL) is a traditional medicinal plant recorded in the Compendium of Materia Medica (the Ming Dynasty). In general, it is used for hemostasis, analgesia, anti-inflammation, antioxidation, and to especially facilitate hepatoprotective effect. In recent years, it has received more and more attention due to its special nutritional and medicinal value. The present study investigates the effect and potential mechanism of AVL against alcoholic liver disease (ALD). C57BL/6 mice were fed Lieber-DeCarli liquid diet containing 5% ethanol plus a single ethanol gavage (5 g/kg), and followed up with the administration of AVL or silymarin. AML12 cells were stimulated with ethanol and incubated with AVL. AVL significantly reduced serum transaminase and triglycerides in the liver and attenuated histopathological changes caused by ethanol. AVL significantly inhibited SREBP1 and its target genes, regulated lipin 1/2, increased PPARα and its target genes, and decreased PPARγ expression caused by ethanol. In addition, AVL significantly enhanced FXR, LXRs, Sirt1, and AMPK expressions compared with the EtOH group. AVL also inhibited inflammatory factors, NLRP3, and F4/80 and MPO, macrophage and neutrophil markers. In vitro, AVL significantly reduced lipid droplets, lipid metabolism enzymes, and inflammatory factors depending on FXR activation. AVL could ameliorate alcoholic steatohepatitis, lipid deposition and inflammation in ALD by targeting FXR activation.

Parthenolide, bioactive compound of Chrysanthemum parthenium L., ameliorates fibrogenesis and inflammation in hepatic fibrosis via regulating the crosstalk of TLR4 and STAT3 signaling pathway.

The current study focused on the regulatory effects of parthenolide (PNL), a bioactive component derived from Chrysanthemum parthenium L., against hepatic fibrosis via regulating the crosstalk of toll-like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) in activated hepatic stellate cells (HSCs). HSCs or Raw 264.7 macrophages were activated by TGF-ß or LPS for 1 hr, respectively, and then treated with PNL, CLI-095 (TLR4 inhibitor), or Niclosamide (STAT3 inhibitor) for the indicated time to detect the crosstalk of TLR4 and STAT3. PNL significantly decreased the expressions of α-SMA, collagen I, and the ratio of TIMP1 and MMP13 in TGF-ß-activated HSCs. PNL significantly reduced the releases of pro-inflammatory cytokines, including IL-6, IL-1ß, IL-1α, IL-18, and regulated signaling P2X7r/NLRP3 axis activation. PNL obviously induced the apoptosis of activated HSCs by regulating bcl-2 and caspases family. PNL significantly inhibited the expressions of TLR4 and STAT3, including their downstream signaling. PNL could regulate the crosstalk of TLR4 and STAT3, which were verified by their inhibitors in activated HSCs or Raw 264.7 cell macrophages. Thus, PNL could decrease the expressions of fibrosis markers, reduce the releases of inflammatory cytokines, and also induce the apoptosis of activated HSCs. In conclusion, PNL could bi-directionally inhibit TLR4 and STAT3 signaling pathway, suggesting that blocking the crosstalk of TLR4 and STAT3 might be the potential mechanism of PNL against hepatic fibrosis.

20S-Protopanaxatriol Ameliorates Hepatic Fibrosis, Potentially Involving FXR-Mediated Inflammatory Signaling Cascades.

Ginseng has been used as a functional food and tonic for enhancing immune power. Here, the potential protective effect of 20S-protopanaxatriol (M4), the metabolite of protopanaxatriol, against hepatic fibrosis is investigated, which could provide nutritional interventions for disease treatment. M4 could inhibit extracellular matrix (ECM) deposition and reduce the levels of proinflammatory cytokines such as caspase 1, interleukin 1 ß (IL-1ß), interleukin 1 receptor type 1 (IL1R1), and interleukin 6 (IL-6). M4 also significantly increased the expression of farnesoid X receptor (FXR), suppressed the purinergic ligand-gated ion channel 7 receptor (P2X7r) signaling pathway, and works as an FXR agonist, GW4064. In thioacetamide (TAA)-induced mice, M4 could attenuate the histopathological changes and significantly regulate the expression levels of FXR and P2X7r. M4 ameliorated TAA-induced hepatic fibrosis due to the reduction of P2X7r secretion, inhibition of hepatic stellate cell (HSCs) activation, and inflammation, which were all associated with FXR activation. Hence, M4 might be useful a nutritional preventive approach in antihepatic fibrosis and antihepatic inflammation.