A therapeutic strategy of parthenolide in improving imiquimod-induced psoriasis-like skin inflammation targeting IL-36/NETs through skin transdermal therapeutic system.

BACKGROUND: Psoriasis is an inflammatory skin disease that occurs repeatedly over time. The natural product of sesquiterpene lactones, Parthenolide (Par), is isolated from Tanacetum parthenium L. (feverfew) which has significant effects on anti-inflammatory. The therapeutic effect of the medication itself is crucial, but different routes of administration of the same drug can also produce different effects. PURPOSE: The aim of our research sought to investigate the ameliorating effects of Par in psoriasis-like skin inflammation and its related mechanism of action. RESULTS: In the IMQ-induced model, intragastric administration of Par reduced the Psoriasis Area and Severity Index (PASI) score, improved skin erythema, scaling, and other symptoms. And Par decreased the expression of Ki67, keratin14, keratin16 and keratin17, and increased the expression of keratin1. Par could reduce IL-36 protein expressions, meanwhile the expression of Il1b, Cxcl1 and Cxcl2 mRNA were also decreased. Par regulated the expression levels of F4/80, MPO and NE. However, skin transdermal administration of Par was more effective. Similarly, Par attenuated IL-36γ, IL-1ß and caspase-1 activated by Poly(I:C) in in vitro and ex vivo. In addition, Par also reduced NE, PR3, and Cathepsin G levels in explant skin tissues. CONCLUSION: Par ameliorated psoriasis-like skin inflammation in both in vivo and in vitro, especially after treatment with transdermal drug delivery, possibly by inhibiting neutrophil extracellular traps and thus by interfering IL-36 signaling pathway. It indicated that Par provides a new research strategy for the treatment of psoriasis-like skin inflammation and is expected to be a promising drug.

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.

Potential skin health promoting benefits of costunolide: a therapeutic strategy to improve skin inflammation in imiquimod-induced psoriasis.

Psoriasis is a recurrent inflammatory skin disease. IL-36-related cytokines are overexpressed in psoriasis, but the mechanism is not yet clear. Costunolide (Cos) is a sesquiterpenoid compound derived from the root of the traditional Chinese medicine Aucklandia lappa Decne. This study aimed to explore the mechanism of Cos on improving psoriasis-like skin inflammation. An in vivo model was established by applying imiquimod treatment to the back skin of mice, and an in vitro model was established by using polyinosinic-polycytidylic acid (Poly(I:C)) stimulated-mouse primary dermal fibroblasts to induce inflammation. The results showed that Cos improved the pathological changes of psoriasis-like skin inflammation. In addition, Cos could inhibit epidermal damage and inflammation-related expression and improve the occurrence of skin-related inflammation in both in vivo and in vitro experiments. The improvement of psoriasis-like skin inflammatory response might be through the P2X7R/IL-36 signaling pathway. Collectively, Cos has an inhibitory effect on the expression of psoriasis-like skin inflammation. This showed that Cos has potential skin health promoting benefits by preventing psoriasis-like skin inflammation.

Carnosic acid suppressed the formation of NETs in alcoholic hepatosteatosis based on P2X7R-NLRP3 axis.

BACKGROUND: Alcoholic liver disease (ALD) is accompanied by a disruption of lipid metabolism and an inflammatory response in the liver during the process of disease. Carnosic acid (CA), a natural diterpene extracted from Rosmarinus officinalis (rosemary) and Salvia officinalis (sage), has more pharmacological activities, which is known to be useful in the treatment of obesity and acts by regulating energy metabolism. However, the role and regulation mechanism of CA against ALD remain unclear. HYPOTHESIS: We hypothesized that CA might improve alcoholic-induced hepatosteatosis. STUDY DESIGN AND METHODS: The alcoholic liver disease model was established a mouse chronic ethanol feeding by Lieber-DeCarli control liquid feed (10 d) plus a single binge with or without CA administration. AML12 cells were exposed to ethanol for 24 h. Murine peritoneal macrophages (MPM) were stimulated with LPS and ATP. RESULTS: CA ameliorated lipid accumulation in the liver of mice in the NIAAA model, acting by inhibiting the expression of genes related to lipid synthesis. CA reduced alcohol-induced immune cell infiltration in the liver, and inhibited the activation of P2X7R-NLRP3 inflammasome, meanwhile blocked the formation of NETs in mouse livers tissue. In AML12 cells, CA attenuated the lipid accumulation triggered by ethanol stimulation, which was achieved by inhibiting the expression of SREBP1 and CA reduced the release of inflammatory factor IL-1ß by inhibiting the activation of P2X7R-NLRP3. In MPM, IL-1ß and HMGB1 were reduced after LPS/ATP stimulation in CA-treated cells and supernatant. CONCLUSIONS: CA attenuated alcohol-induced fat accumulation, suppressed the formation of NETs based on P2X7R-NLRP3 axis in mouse livers. Our data indicated that CA exerted hepatoprotective effects, which might be a promising candidate.

Systematic Evaluation of Randomized Clinical Trials of Huangqin Tang in Combination with Mesalazine for Ulcerative Colitis.

Objective: To systematically evaluate the efficacy and safety of Huangqin Tang (HQT) combined with mesalazine for the treatment of ulcerative colitis (UC). Methods: The China Knowledge Network, Wanfang Data, VIP, PubMed, SinoMed, Embase, and Cochrane Library databases were searched for randomized controlled trials (RCTs) of UC with HQT in Chinese and English. The search time was from the establishment of the database to October 2021. The included literature was evaluated for data extraction and risk of bias, efficacy and safety were evaluated using the RevMan5.3 software, and the quality of evidence was evaluated using GRADE. Results: Six studies with a total of 565 subjects were included, and a meta-analysis showed that HQT combined with mesalazine for UC significantly improved the cure rate (RR = 1.56, 95% CI [1.23, 1.98), P=0.0003) and overall efficacy rate (RR = 1.24, 95% CI [1.14, 1.35], P=0.00001), which significantly reduced the clinical symptom scores; however, all had high heterogeneity. HQT combined with mesalazine modulated the patients' serum IL-6, IL-10, IgA, and IgG levels. HQT combined with mesalazine for UC tended to reduce adverse effects; however, the difference was not statistically significant. All GRADE ratings of the quality of evidence were of low quality. Conclusions: HQT combined with mesalazine in the treatment of UC significantly improved the cure rate and overall treatment efficiency and regulated the expression levels of serum IL-6, IL-10, IgA, and IgG.

Traditional Chinese Medicine and Natural Products: Potential Approaches for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a rare, recurrent, and intractable inflammation obstruction of the stomach tract, usually accompanied by inflammation of cell proliferation and inflammation of the colon and carries a particular cause of inflammation. The clinical use of drugs in western countries affects IBD treatment, but various adverse effects and high prices limit their application. For these reasons, Traditional Chinese Medicine (TCM) is more advantageous in treating IBD. This paper reviews the mechanism and research status of TCM and natural products in IBD treatment by analyzing the relevant literature to provide a scientific and theoretical basis for IBD treatment.

Taxifolin blocks monosodium urate crystal-induced gouty inflammation by regulating phagocytosis and autophagy.

Gout is a chronic disease caused by monosodium urate (MSU) crystal deposition in the joints and surrounding tissues. We examined the effects of Taxifolin, a natural flavonoid mainly existing in vegetables and fruits, on MSU-induced gout. Pretreatment with Taxifolin significantly reduced IL-1ß, Caspase-1 and HMGB1 levels, upregulation of autophagy-related protein, LC3, as well as improved phagocytosis of macrophages. This study indicated that Taxifolin-attenuated inflammatory response in MSU-induced acute gout model by decreasing pro-inflammatory cytokine production and promoting the autophagy and phagocytic capacity of macrophages. Dietary supplementation with Taxifolin induces the autophagy and attenuated inflammatory response, which in consequence modulates acute gout. A preventive strategy combining dietary interventions with Taxifolin may offer a potential therapeutic alternative to pharmacological treatment to reduce inflammatory response to gout.

Inflammatory bowel disease: an overview of Chinese herbal medicine formula-based treatment.

Inflammatory bowel disease (IBD) is a chronic recurrent inflammatory disease of the intestine, including Crohn's disease (CD) and ulcerative colitis (UC), whose etiology and pathogenesis have not been fully understood. Due to its prolonged course and chronic recurrence, IBD imposes a heavy economic burden and psychological stress on patients. Traditional Chinese Herbal Medicine has unique advantages in IBD treatment because of its symptomatic treatment. However, the advantages of the Chinese Herbal Medicine Formula (CHMF) have rarely been discussed. In recent years, many scholars have conducted fundamental studies on CHMF to delay IBD from different perspectives and found that CHMF may help maintain intestinal integrity, reduce inflammation, and decrease oxidative stress, thus playing a positive role in the treatment of IBD. Therefore, this review focuses on the mechanisms associated with CHMF in IBD treatment. CHMF has apparent advantages. In addition to the exact composition and controlled quality of modern drugs, it also has multi-component and multi-target synergistic effects. CHMF has good prospects in the treatment of IBD, but its multi-agent composition and wide range of targets exacerbate the difficulty of studying its treatment of IBD. Future research on CHMF-related mechanisms is needed to achieve better efficacy.

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.

Correlation analysis between characteristics under gastroscope and image information of tongue in patients with chronic gastriti.

OBJECTIVE: To explore the correlation between diagnostic information of tongue and gastroscopy results of patients with chronic gastritis. METHODS: Frequent pattern growth (FP-Growth), SPSS Modeler was used to analyze the correlation rules between the image information of tongue parameters and the characteristics of the stomach and duodenum seen under gastroscopy. RESULTS: Ranking in order of confidence: cyanotic tongue, slippery fur, yellow fur and spotted tongue were sequently associated with both gastric antrum mucosal hyperemia or edema and gastric antrum mucosal erythema/macula. L, one value of tongue coating color, which counted among (30, 60), tooth-marked tongue and b, one value of tongue coating color, which counted in the range of (5, 20) were sequently associated with gastric antrum mucosal erythema /macula. A, one value of tongue body color, which counted in the range of (0, 20), was related to both gastric antrum mucosal hyperemia or edema and gastric antrum mucosal erythema /macula. a, one value of tongue coating color, which counted in the range of (15, 35), was associated with gastric antrum mucosal erythema / macula. There are a total of 9 strong correlation rules. CONCLUSIONS: Cyanotic tongue, slippery fur, yellow fur, the CIE Lab value of tongue coating, a, the value of tongue body color, spotted tongue, and tooth-marked tongue are all related to the gastric antrum mucosal hyperemia or edema and gastric antrum mucosal erythema / macula. The conditions of gastric mucosa could be predicted by the examination of the above related image information of tongue.

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.

Development of a new atmospheric pressure plasmaspray ionization for ambient mass spectrometry.

A new atmospheric pressure ionization method, plasmaspray ionization, termed as PSI, was developed to be an alternative ambient ion source for mass spectrometry. It comprises a plasma jet device and a sample spray part. While the nonthermal plasma jet strikes the surface of stainless steel tube out of the spray capillary, the sprayed sample will be ionized with the assistant of auxiliary gas. Although PSI is a little bit more complex than electrospray ionization (ESI) in instrument, it shows both better linearity and higher sensitivity for organic compounds. For protein samples, it presents wider distributions of multiply charged ions and higher mass resolution without sacrificing any sensitivity. For the mechanism of PSI, the charge build-up process on the tip of capillary should play a key role for the ion formation, and the stimulated pulsed voltage on the flow tube will promote the ion aggregation speed until the charge density is high enough. PSI source contains the features of plasma ionization and ESI and can be considered as a novel combo bridging these techniques. These results reflect that this method of PSI can be applied and further developed as a versatile new ion source for a wild range of organic and biological samples.

Genus Gentiana: A review on phytochemistry, pharmacology and molecular mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: As the largest genus of Gentianaceae family, the Gentiana genus harbors over 400 species, widely distributed in the alpine areas of temperate regions worldwide. Plants from Gentiana genus are traditionally used to treat a wide variety of diseases including easing pain dispelling rheumatism, and treating liver jaundice, chronic pharyngitis and arthritis in China since ancient times. In this review, a systematic and constructive overview of the traditional uses, phytochemistry, molecular mechanisms, toxicology and pharmacological activities of the researched species of genus Gentiana is provided. MATERIALS AND METHODS: The used information in this review is based on various databases (PubMed, Science Direct, Wiley online library, Wanfang Data, Web of Science) through a search using the keyword "Gentiana" in the period of 1981-2019. Besides, other ethnopharmacological information was acquired from Chinese herbal classic books and Chinese pharmacopoeia 2015 edition. RESULTS: The plants from Gentiana genus have a long tradition of various medicinal uses in Europe and Asia. Phytochemical studies showed that the main bioactive components isolated from this genus includes iridoids xanthones and flavonoids. These compounds and extracts isolated from this genus show a wide range of protective activities including hepatic protection, gastrointestinal protection, cardiovascular protection, immunomodulation, joint protection, pulmonary protection, bone protection and reproductive protection. Molecular mechanism studies also indicated several potential therapeutic targets in the treatment of certain diseases by plants from this genus. Besides, natural products from this plant show no significant animal toxicity, cytotoxicity or genotoxicity. CONCLUSION: This review summarized the traditional medicinal uses, phytochemistry, pharmacology, toxicology and molecular mechanism of genus Gentiana, providing references and research tendency for plant-based drug development and further clinical studies.

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.

Agriophyllum oligosaccharides ameliorate hepatic injury in type 2 diabetic db/db mice targeting INS-R/IRS-2/PI3K/AKT/PPAR-γ/Glut4 signal pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Agriophyllum squarrosum (L.) Moq. is a traditional Mongol medicine generally used to treat diabetes. OBJECTIVE: To investigate the protective effects and potential mechanisms of Agriophyllum oligosaccharides (AOS) on liver injury in type 2 diabetic db/db mice. MATERIALS AND METHODS: The db/db mice were divided into the model group (Model), metformin group (MET), high-dose AOS group (HAOS), and low-dose AOS group (LAOS). Nondiabetic littermate control db/m mice were used as the normal control group (Control). Mice in AOS groups were treated with AOS (380 or 750 mg/kg) daily, for 8 weeks. At 8 weeks, blood samples were collected to detect lipid and enzyme parameters concerning hepatic function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein (TP), albumin (ALB), globulin (GLB), triglyceride (TG), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C). Random blood glucose (RBG) test, oral glucose tolerance test (OGTT), and oral maltose tolerance test (OMTT) were also conducted. Microscopy was used to observe morphological changes in the liver of AOS-treated groups. Real-time PCR was used to detect the mRNA expression, including insulin receptor substrate 2 (IRS-2), phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), peroxisome proliferator-activated receptor (PPAR)-γ, insulin receptor (INS-R), and Glut4. Furthermore, western blotting was performed to identify proteins, including phosphorylation of IRS-2 (p-IRS-2), PI3K, p-AKT, PPAR-γ, INS-R, and Glut4. Hepatic protein expression of p-IRS-2, PI3K, p-AKT, PPAR-γ, INS-R, and Glut4 was observed using immunohistochemical staining. RESULTS: AOS treatment significantly decreased RBG, OGTT, and OMTT in mice, as well as serum ALT and AST activities. AOS groups demonstrated significantly higher expressions of p-IRS-2, PI3K, PPAR-γ, p-AKT, INS-R, and Glut4 protein and IRS-2, PI3K, AKT, PPAR-γ, INS-R, and Glut4 mRNA in the liver tissue of db/db mice; the degeneration and necrosis of hepatocytes and formation of collagen fibres markedly reduced, improving the structural disorder in the liver. CONCLUSION: The results suggest that AOS could protect the liver in type 2 diabetes, in part by activating insulin in the INS-R/IRS2/PI3K/AKT/Glut4/PPAR-γ signal pathway, facilitating hepatocyte proliferation, and further reducing the blood glucose levels.

Signaling pathways involved in p38-ERK and inflammatory factors mediated the anti-fibrosis effect of AD-2 on thioacetamide-induced liver injury in mice.

Ginseng is a type of medicinal and edible homologous plant that is very common in medicine, food and even cosmetics. Ginsenosides are the main active constituents of ginseng, which has many pharmacological activities. AD-2 is a type of ginsenoside extracted from ginseng and prepared in large quantities in our laboratory. However, the anti-fibrosis effects and mechanism of ginsenosides are rarely reported. In this study, the anti-fibrosis pharmacodynamics of AD-2 were evaluated. The results revealed that AD-2 could reduce the expression of collagen I, TIMP-1 and MMP-13, inhibit the deposition of extracellular matrix, and play an role in anti-hepatic fibrosis. The mechanism and related pathways of AD-2 against liver fibrosis have also been studied. Inflammatory factors (including TNF-α, IL-1ß, caspase-1 and IL-6) associated with hepatic fibrosis, and the p-JNK and the p38-ERK pathways, have been shown to be associated with the anti-fibrotic effect of AD-2. In conclusion, our study reveals that AD-2, as a small-molecule, targeted drug for improving liver function, needs further study.

Thymoquinone Attenuates Acetaminophen Overdose-Induced Acute Liver Injury and Inflammation Via Regulation of JNK and AMPK Signaling Pathway.

Thymoquinone (TQ) is a main aromatic component of Nigella sativa L. seeds or Agastache rugosa (Fisch. & C.A.Mey.) Kuntze. The protective mechanism of TQ against acute liver injury induced by acetaminophen (APAP), however, remains unclear. We aimed to investigated the hepato-protective mechanism of TQ on the development of APAP-induced acute liver injury. Male kunming mice were pretreated with TQ or N-acetylcysteine (NAC) before a single APAP injection. Human Chang liver cells were incubated with TQ, SP600125 or AICAR in presence of APAP for 24 h. TQ pretreatment reduced levels of serum aminotransferases and increased hepatic glutathione and glutathione peroxidase activities via inhibiting CYP2E1 expression. TQ inhibited JNK, ERK and P38 phosphorylation induced by APAP. Meanwhile, TQ inhibited PI3K/mTOR signaling activation and activated AMPK phosphorylation. Moreover, TQ prevented APAP-induced hepatocytes apoptosis regulated by Bcl-2 and Bax. Furthermore, TQ inhibited STAT3 phosphorylation on APAP-induced acute liver injury. In addition, TQ significantly inhibited P2X7R protein expression and IL-1 ß release. APAP-enhanced JNK phosphorylation and APAP-suppressed AMPK phosphorylation were also observed in Chang liver cells, and these changes were recovered by pretreatment with TQ, SP600125 and AICAR. Our findings suggest that TQ may actively prevent APAP-induced acute liver injury, and the effect may be mediated by JNK and AMPK signaling pathways.

Potential Pharmacokinetic Herb-Drug Interactions: Have we Overlooked the Importance of Human Carboxylesterases 1 and 2?

BACKGROUND: Herbal products have grown steadily across the globe and have increasingly been incorporated into western medicine for healthcare aims, thereby causing potential pharmacokinetic Herb-drug Interactions (HDIs) through the inhibition or induction of drug-metabolizing enzymes and transporters. Human Carboxylesterases 1 (CES1) and 2 (CES2) metabolize endogenous and exogenous chemicals including many important therapeutic medications. The growing number of CES substrate drugs also underscores the importance of the enzymes. Herein, we summarized those potential inhibitors and inducers coming from herbal constituents toward CES1 and CES2. We also reviewed the reported HDI studies focusing on herbal products and therapeutic agents metabolized by CES1 or CES2. METHODS: We searched in PubMed for manuscript published in English after Jan 1, 2000 combining terms "carboxylesterase 1", "carboxylesterase 2", "inhibitor", "inducer", "herb-drug interaction", "inhibitory", and "herbal supplement". We also searched specific websites including FDA and EMA. The data of screened papers were analyzed and summarized. RESULTS: The results showed that more than 50 natural inhibitors of CES1 or CES2, including phenolic chemicals, triterpenoids, and tanshinones were found from herbs, whereas only few inducers of CES1 and CES2 were reported. Systemic exposure to some commonly used drugs including oseltamivir, irinotecan, and clopidogrel were changed when they were co-administered with herb products such as goldenseal, black cohosh, ginger, St. John's Wort, curcumin, and some Chinese compound formula in animals. CONCLUSION: Nonclinical and clinical studies on HDIs are warranted in the future to provide safety information toward better clinical outcomes for the combination of herbal products and conventional drugs.