The protective effect of forsythiaside A on 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholestatic liver injury in mice: Based on targeted metabolomics and molecular biology technology.

Cholestasis is a disorder of bile secretion and excretion caused by a variety of etiologies. At present, there is a lack of functional foods or drugs that can be used for intervention. Forsythiaside A (FTA) is a natural phytochemical component isolated from the medicinal plant Forsythia suspensa (Thunb.) Vahl, which has a significant hepatoprotective effect. In this study, we investigated whether FTA could alleviate liver injury induced by cholestasis. In vitro, FTA reversed the decrease in viability of human intrahepatic bile duct epithelial cells, the decrease in antioxidant enzymes (SOD1, CAT and GSH-Px), and cell apoptosis induced by lithocholic acid. In vivo, FTA protected mice from 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury, abnormal serum biochemical indexes, abnormal bile duct hyperplasia, and inflammatory infiltration. Furthermore, FTA treatment alleviated liver fibrosis by inhibiting collagen deposition and HSC activation. The metabonomic results showed that DDC-induced bile acid disorders in the liver and serum were reversed after FTA treatment, which may benefit from the activation of the FXR/BSEP axis. In addition, FTA treatment increased the levels of antioxidant enzymes in the serum and liver. Meanwhile, FTA treatment inhibited ROS and MDA levels and cleaved caspase 3 protein expression, thereby reducing DDC-induced hepatic oxidative stress and apoptosis. Further studies showed that the antioxidant effects of FTA were dependent on the activation of the BRG1/NRF2/HO-1 axis. In a word, FTA has a significant hepatoprotective effect on cholestatic liver injury, and can be further developed as a functional food or drug to prevent and treat cholestatic liver injury.

Protective effects of dietary quercetin on cerebral ischemic injury: pharmacology, pharmacokinetics and bioavailability-enhancing nanoformulations.

Cerebral ischemia, as an ischemic stroke-like disease, has become a health problem of global concern. Studies have found that oxidative stress, inflammation, apoptosis, and impaired blood-brain barrier (BBB) and ion channel regulation are the basis for the development of cerebral ischemia pathology. Quercetin, a flavonoid compound, commonly found in the daily diet and in some Chinese herbal medicines, including vegetables, fruits, and tea, is one of the most prominent dietary antioxidants. Modern pharmacological studies have shown that quercetin can effectively protect against cerebral ischemic injury, and its mechanisms may involve antioxidant, anti-inflammatory, anti-apoptotic, BBB protection, ion channel regulation, cell excitatory glutamate toxicity alleviation and cognitive impairment recovery activities. However, the low bioavailability of quercetin and the presence of the BBB structure limit the therapeutic efficacy. There have been studies targeting the delivery of quercetin to the injury site through nanotechnology to enhance the therapeutic effect of quercetin. This review discusses and reviews the pharmacological activity, pharmacokinetic characteristics, and targeted delivery nanosystems of quercetin in protecting against cerebral ischemic injury, and provides information on various downstream signaling pathways regulated by quercetin, such as PI3k/Akt, MAPK, and Sirt1. We hope to provide a scientific basis for the development and application of quercetin in the field of cerebral ischemia.

CD44-Targeting Drug Delivery System of Exosomes Loading Forsythiaside A Combats Liver Fibrosis via Regulating NLRP3-Mediated Pyroptosis.

Liver fibrosis is a progressive pathological process induced by various stimuli and may progress to liver cirrhosis and cancer. Forsythiaside A (FA) is an active ingredient extracted from traditional Chinese medicine Forsythiae Fructus and has prominent hepatoprotective activities. However, the unsatisfactory pharmacokinetic properties restrict its clinical application. In this study, the nanocarrier of CD44-specific ligand Hyaluronic acid (HA)-modified milk-derived exosomes (mExo) encapsulated with FA (HA-mExo-FA) is developed. As a result, HA modification could deliver drug-loaded exosomes to the target cells and form a specific ligand-receptor interaction with CD44, thus improving the anti-liver fibrosis effect of FA. In vitro findings indicate that HA-mExo-FA could inhibit TGF-ß1-induced LX2 cell proliferation, reduce α-SMA and collagen gene and protein levels, and promote the apoptosis of activated LX2 cells. In vivo results demonstrate that HA-mExo-FA could improve liver morphology and function changes in zebrafish larvae. The anti-liver fibrosis mechanism of HA-mExo-FA may be attributed to the inhibition of NLRP3-mediated pyroptosis. In addition, the effect of HA-mExo-FA on TAA-induced increase in NLRP3 production is attenuated by NLRP3 inhibitor MCC950. Collectively, this study demonstrates the promising application of HA-mExo-FA in drug delivery with high specificity and provides a powerful and novel delivery platform for liver fibrosis therapy.

Phillygenin inhibited M1 macrophage polarization and reduced hepatic stellate cell activation by inhibiting macrophage exosomal miR-125b-5p.

Liver fibrosis (LF) is an important stage in chronic liver disease development, characterized by hepatic stellate cell (HSC) activation and excessive extracellular matrix deposition. Phillygenin (PHI), an active component in the traditional Chinese medicine Forsythiae Fructus with a significant anti-inflammatory effect, has been proved to inhibit HSC activation. Macrophages can polarize to pro-inflammatory M1 phenotype and anti-inflammatory M2 phenotype, participating in LF development. Currently, Forsythiae Fructus and its many components have been proved to inhibit the inflammatory activation of macrophages. However, there is no direct evidence that PHI can regulate macrophage polarization, and the relationship between macrophage polarization and the anti-LF effect of PHI has not been studied. In this study, we found that PHI inhibited the co-expression of CD80 and CD86, and inhibited the mRNA expression and protein secretion of related inflammatory cytokines in RAW264.7 cells. For mechanism, PHI was found to inhibit the JAK1/JAK2-STAT1 and Notch1 signaling pathways. Subsequently, mHSCs were co-cultured with the conditioned media or exosomes from macrophages with different treatments. It was found that the conditioned media and exosomes from PHI-treated macrophages inhibited the expression of MMP2, TIMP1, TGF-ß, α-SMA, COL1 and NF-κB in mHSCs. Moreover, through bioinformatic analysis and cell transfection, we confirmed that PHI reduced HSC activation by inhibiting the overexpression of miR-125b-5p in M1 macrophage-derived exosomes and restoring Stard13 expression in mHSCs. On the whole, PHI could inhibit M1 macrophage polarization by suppressing the JAK1/JAK2-STAT1 and Notch1 signaling pathways, and reduce HSC activation by inhibiting macrophage exosomal miR-125b-5p targeting Stard13. DATA AVAILABILITY: The raw data supporting the conclusions of this study are available in the article/Supplementary figures, and can be obtained from the first or corresponding author.

Forsythiaside A alleviated carbon tetrachloride-induced liver fibrosis by modulating gut microbiota composition to increase short-chain fatty acids and restoring bile acids metabolism disorder.

Liver fibrosis is a chronic and progressive disease with complex pathogenesis related to bile acids (BAs) and gut microbiota. Forsythiaside A (FTA), isolated from the traditional Chinese medicine Forsythiae Fructus (Lian Qiao), is a natural hepatoprotective agent. The purpose of this study was to investigate the protective effect of FTA on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Liver fibrosis was induced in mice by intraperitoneal injection of 2 mL/kg CCl4 three times a week for 4 weeks. FTA attenuated CCl4-induced liver fibrosis in mice, which was proved by the results of Masson and Sirius red staining, liver hydroxyproline, hyaluronic acid, laminin, type III procollagen, and type IV collagen assays. FTA inhibited hepatic stellate cell activation, and reduced hepatic inflammation and oxidative stress in mice treated with CCl4. What's more, FTA ameliorated CCl4-induced gut dysbiosis, maintained intestinal barrier function, increased the production of short-chain fatty acids (SCFAs), and improved endotoxemia, as manifested by decreased serum lipopolysaccharide levels and increased expression of ileal tight junction proteins. Besides, FTA can modulate the genes related to bile acid metabolism to alter the distribution of fecal BAs in fibrotic mice. In a word, FTA can improve liver fibrosis by inhibiting inflammation and oxidative stress, regulating gut microbiota and BA metabolism, and increasing the content of SCFAs. The results of this study provided an important reference for the study on the mechanisms by which natural products prevent liver fibrosis.

A review: Pharmacology and pharmacokinetics of Schisandrin A.

Schisandrin A (SA) is a bioactive lignan isolated from the traditional Chinese medicine Fructus schisandrae chinensis. In recent years, it has attracted extensive attention because of its multiple pharmacological activities. This review is the first to provide an overview of SA-related pharmacological effects and pharmacokinetic characteristics. The results showed that SA had many pharmacological effects, such as antiinflammation, anticancer, hepatoprotection, antioxidation, neuroprotection, antidiabetes mellitus, and musculoskeletal protection. Among them, NF-κB, Nrf2, MAPK, NLRP3, PI3K/AKT, Wnt, miRNA, P-gp, CYP450, PXR, and other signal transduction pathways are involved. Pharmacokinetic studies showed that SA had good pharmacokinetic characteristics, but these were affected by other factors, such as drugs or hepatic fibrosis. Thus, SA has a variety of pharmacological effects and good pharmacokinetic characteristics, which is worthy of further research and development in the future.

Potential Natural Compounds for the Prevention and Treatment of Nonalcoholic Fatty Liver Disease: A Review on Molecular Mechanisms.

Nonalcoholic fatty liver disease (NAFLD) is a kind of metabolic stress-induced liver injury closely related to insulin resistance and genetic susceptibility, and there is no specific drug for its clinical treatment currently. In recent years, a large amount of literature has reported that many natural compounds extracted from traditional Chinese medicine (TCM) can improve NAFLD through various mechanisms. According to the latest reports, some emerging natural compounds have shown great potential to improve NAFLD but are seldom used clinically due to the lacking special research. This paper aims to summarize the molecular mechanisms of the potential natural compounds on improving NAFLD, thus providing a direction and basis for further research on the pathogenesis of NAFLD and the development of effective drugs for the prevention and treatment of NAFLD. By searching various online databases, such as Web of Science, SciFinder, PubMed, and CNKI, NAFLD and these natural compounds were used as the keywords for detailed literature retrieval. The pathogenesis of NAFLD and the molecular mechanisms of the potential natural compounds on improving NAFLD have been reviewed. Many natural compounds from traditional Chinese medicine have a good prospect in the treatment of NAFLD, which can serve as a direction for the development of anti-NAFLD drugs in the future.

A review of pharmacological and pharmacokinetic properties of Forsythiaside A.

Traditional Chinese medicine plays a significant role in the treatment of various diseases and has attracted increasing attention for clinical applications. Forsythiae Fructus, the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a widely used Chinese medicinal herb in clinic for its extensive pharmacological activities. Forsythiaside A is the main active index component isolated from Forsythiae Fructus and possesses prominent bioactivities. Modern pharmacological studies have confirmed that Forsythiaside A exhibits significant activities in treating various diseases, including inflammation, virus infection, neurodegeneration, oxidative stress, liver injury, and bacterial infection. In this review, the pharmacological activities of Forsythiaside A have been comprehensively reviewed and summarized. According to the data, Forsythiaside A shows remarkable anti-inflammation, antivirus, neuroprotection, antioxidant, hepatoprotection, and antibacterial activities through regulating multiple signaling transduction pathways such as NF-κB, MAPK, JAK/STAT, Nrf2, RLRs, TRAF, TLR7, and ER stress. In addition, the toxicity and pharmacokinetic properties of Forsythiaside A are also discussed in this review, thus providing a solid foundation and evidence for further studies to explore novel effective drugs from Chinese medicine monomers.

Research progress in use of traditional Chinese medicine monomer for treatment of non-alcoholic fatty liver disease.

With the improvement of people's living standards and the change of eating habits, non-alcoholic fatty liver disease (NAFLD) has gradually become one of the most common chronic liver diseases in the world. However, there are no effective drugs for the treatment of NAFLD. Therefore, it is urgent to find safe, efficient, and economical anti-NAFLD drugs. Compared with western medicines that possess fast lipid-lowering effect, traditional Chinese medicines (TCM) have attracted increasing attention for the treatment of NAFLD due to their unique advantages such as multi-targets and multi-channel mechanisms of action. TCM monomers have been proved to treat NAFLD through regulating various pathways, including inflammation, lipid production, insulin sensitivity, mitochondrial dysfunction, autophagy, and intestinal microbiota. In particular, peroxisome proliferator-activated receptor α (PPAR-α), sterol regulatory element-binding protein 1c (SREBP-1c), nuclear transcription factor kappa (NF-κB), phosphoinositide 3-kinase (PI3K), sirtuin1 (SIRT1), AMP-activated protein kinase (AMPK), p53 and nuclear factor erythroid 2-related factor 2 (Nrf2) are considered as important molecular targets for ameliorating NAFLD by TCM monomers. Therefore, by searching PubMed, Web of Science and SciFinder databases, this paper updates and summarizes the experimental and clinical evidence of TCM monomers for the treatment of NAFLD in the past six years (2015-2020), thus providing thoughts and prospects for further exploring the pathogenesis of NAFLD and TCM monomer therapies.

Hepatoprotective effect of forsythiaside a against acetaminophen-induced liver injury in zebrafish: Coupling network pharmacology with biochemical pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Forsythiae Fructus, the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a commonly used traditional Chinese medicine and possesses various pharmacological activities, including anti-inflammation, anti-oxidant and liver protection. AIM OF THE STUDY: Although acetaminophen (APAP) has been frequently used for its antipyretic and analgesic effects, it leads to liver injury at an overdose or long-term medication. Forsythiaside A (FA), the principal active component of Forsythiae Fructus, exerts prominent antioxidant, anti-inflammatory and hepatoprotective effects. However, the protective property and underlying mechanism of FA against APAP challenge have not yet been elucidated. Therefore, we aimed to explore the hepatoprotective effect and action mechanism of FA against APAP-induced liver injury in zebrafish. MATERIALS AND METHODS: In this study, liver-specific transgenic zebrafish larvae (lfabp: EGFP) were used to investigate the protective effect of FA against overdose APAP exposure. The liver phenotype, morphological and biochemical assessments were carried out to evaluate the hepatoprotective effect of FA. Network pharmacology and molecular docking study were conducted to analyze the potential targets of FA in the treatment of APAP-induced liver injury. Finally, the mechanism of action was verified by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). RESULTS: The liver phenotype, morphological and biochemical assessments indicated that FA could mitigate APAP-triggered liver injury. Network pharmacology and molecular docking analysis indicated that the protective effect of FA might be related to the regulation of targets tumor necrosis factor (TNF), matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 2 (MMP2), and phosphatidylinositol 3-kinase (PI3K). PCR results confirmed that FA could reverse the progressive alterations of genes involving in extracellular matrix remolding and PI3K/AKT-mediated apoptosis signaling pathway. CONCLUSIONS: Our results indicated that FA could mitigate APAP-induced liver injury through modulating the remolding of extracellular matrix and PI3K/AKT-mediated apoptosis.

Effect of Shexiang Tongxin Dropping Pills () on the Immediate Blood Flow of Patients with Coronary Slow Flow.

OBJECTIVE: To observe the immediate effect and safety of Shexiang Tongxin dropping pills (, STDP) on patients with coronary slow flow (CSF), and furthermore, to explore new evidence for the use of Chinese medicine in treating ischemic chest pain. METHODS: Coronary angiography (CAG) with corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) was applied (collected at 30 frames/s). The treatment group included 22 CSF patients, while the control group included 22 individuals with normal coronary flow. CSF patients were given 4 STDP through sublingual administration, and CAG was performed 5 min after the medication. The immediate blood flow frame count, blood pressure, and heart rate of patients before and after the use of STDP were compared. The liver and kidney functions of patients were examined before and after treatments. RESULTS: There was a significant difference in CTFC between groups (P<0.05). The average CTFC values of the vessels with slow blood flow in CSF patients were, respectively, 49.98 ± 10.01 and 40.42 ± 11.33 before and after the treatment with STDP, a 19.13% improvement. The CTFC values (frame/s) measured before and after treatment at the left anterior descending coronary artery, left circumflex artery, and right coronary artery were, respectively, 48.00 ± 13.32 and 41.80 ± 15.38, 59.00 ± 4.69 and 50.00 ± 9.04, and 51.90 ± 8.40 and 40.09 ± 10.46, giving 12.92%, 15.25%, and 22.76% improvements, respectively. The CTFC values of vessels with slow flow before treatment were significantly decreased after treatment (P<0.05). There were no apparent changes in the heart rate, blood pressure, or liver or kidney function of CSF patients after treatment with STDP (all P>0.05). CONCLUSIONS: The immediate effect of STDP in treating CSF patients was apparent. This medication could significantly improve coronary flow without affecting blood pressure or heart rate. Our findings support the potential of Chinese medicine to treat ischemic chest pain.