Celastrol as an emerging anticancer agent: Current status, challenges and therapeutic strategies.

Celastrol is a pentacyclic triterpenoid extracted from the traditional Chinese medicine Tripterygium wilfordii Hook F., which has multiple pharmacological activities. In particular, modern pharmacological studies have demonstrated that celastrol exhibits significant broad-spectrum anticancer activities in the treatment of a variety of cancers, including lung cancer, liver cancer, colorectal cancer, hematological malignancies, gastric cancer, prostate cancer, renal carcinoma, breast cancer, bone tumor, brain tumor, cervical cancer, and ovarian cancer. Therefore, by searching the databases of PubMed, Web of Science, ScienceDirect and CNKI, this review comprehensively summarizes the molecular mechanisms of the anticancer effects of celastrol. According to the data, the anticancer effects of celastrol can be mediated by inhibiting tumor cell proliferation, migration and invasion, inducing cell apoptosis, suppressing autophagy, hindering angiogenesis and inhibiting tumor metastasis. More importantly, PI3K/Akt/mTOR, Bcl-2/Bax-caspase 9/3, EGFR, ROS/JNK, NF-κB, STAT3, JNK/Nrf2/HO-1, VEGF, AR/miR-101, HSF1-LKB1-AMPKα-YAP, Wnt/ß-catenin and CIP2A/c-MYC signaling pathways are considered as important molecular targets for the anticancer effects of celastrol. Subsequently, studies of its toxicity and pharmacokinetic properties showed that celastrol has some adverse effects, low oral bioavailability and a narrow therapeutic window. In addition, the current challenges of celastrol and the corresponding therapeutic strategies are also discussed, thus providing a theoretical basis for the development and application of celastrol in the clinic.

Quercetin alleviates ethanol-induced hepatic steatosis in L02 cells by activating TFEB translocation to compensate for inadequate autophagy.

This study aimed to investigate the therapeutic effect of quercetin on ethanol-induced hepatic steatosis in L02 cells and elucidate the potential mechanism. In brief, L02 cells were pretreated with or without ethanol (3%) for 24 h, then treated quercetin (80, 40, 20 µM) for 24 h. The transfection procedure was performed with transcription factor EB (TFEB) small interfering RNA (siRNA TFEB) for 24 h. Our results showed that quercetin autophagic flux in the L02 cells, via upregulating of microtubule associated protein light chain 3B (LC3-II) and lysosome-associated membrane protein 1 (LAMP1), then downregulating of protein sequestosome 1 (SQSTM1/p62). Mechanistically, quercetin activated TFEB nuclear translocation, contributing to lysosomal biogenesis and autophagic activation. Accordingly, the genetic inhibition of TFEB-dependent autophagy decreased ethanol-induced fat accumulation in L02 cells via regulating fatty acid ß oxidation and lipid synthesis. Subsequently, quercetin-induced TFEB-dependent autophagic activation was also linked to inhibit oxidative stress via suppressing reactive oxygen species (ROS), enhancing activities of antioxidant enzymes, and promoting nuclear transfer of the nuclear factor E2-related factor 2 (Nrf2) translocation. Thus, we uncovered a novel protective mechanism against ethanol-induced hepatic steatosis and oxidative stress through TFEB-mediated lysosomal biogenesis and discovered insufficient autophagy as a novel previously unappreciated autophagic flux.

Carthami flos extract against carbon tetrachloride-induced liver fibrosis via alleviating angiogenesis in mice.

BACKGROUND: Angiogenesis is a pathological phenomenon contribute to the development of chronic liver diseases, and anti-angiogenic therapy is an effective strategy to alleviate liver fibrosis. Carthami flos, a medicinal and edible herb, has the effects of improving blood circulation and regulating angiogenesis. However, the anti-angiogenic effect of Carthami flos in liver fibrosis remains unknown. METHODS: We investigated the protective effect and therapeutic mechanism of Carthami flos extract (CFE) on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. The liver injury and collagen deposition were observed and evaluated by conducting HE, Masson, and Sirius red staining, testing the serum biochemical indexes (ALT, AST, ALP, γ-GT), and measuring the contents of HYP and four indexes of liver fiber (Col-IV, LN, HA, PC-III). Simultaneously, the expressions of α-SMA and Collagen-I were detected to determine the activation of hepatic stellate cells (HSCs). Subsequently, we measured the expressions of angiogenesis-related proteins such as PDGFRB, ERK1/2, p-ERK1/2, MEK, p-MEK, HIF-1α, VEGFA, VEGFR2, AKT and eNOS, and the mRNA levels of PDGFRB and VEGFA. Additionally, immunofluorescence staining and RT-qPCR assays were carried out to ascertain the expressions of continuous endothelial markers CD31, CD34 and vWF, and scanning electron microscope analysis was performed to observe the number of sinusoidal endothelial fenestrations. RESULTS: Herein, we found that CFE could significantly reduce liver injury and collagen deposition, like the same effect of colchicine. CFE significantly alleviated CCl4-induced liver injury and fibrosis, mainly manifested by reducing the levels of ALT, AST, ALP and γ-GT and decreasing the contents of HYP, Col-IV, LN, HA and PC-III. Additionally, CCl4 promoted the activation of HSCs by increasing the expressions of α-SMA and Collagen-I, while CFE could rectify the condition. Moreover, CFE treatment prevented the CCl4-induced the up-regulation of PDGFRB, p-MEK, p-ERK1/2, HIF-1α, VEGFA, VEGFR2, AKT and eNOS, suggesting that CFE might provide the protection against abnormal angiogenesis. In the meantime, the gradual disappearance of sinusoidal capillarization after CFE treatment was supported by the decreased the contents of CD31, CD34 and vWF, as well as the increased number of sinusoidal endothelial fenestrae. CONCLUSION: In this study, the reduction of collagen deposition, the obstruction of HSCs activation, the inactivation of angiogenic signaling pathways and the weakening of hepatic sinusoidal capillarization jointly confirmed that CFE might be promising to resist angiogenesis in liver fibrosis via the PDGFRB/ERK/HIF-1α and VEGFA/AKT/eNOS signaling pathways. Nevertheless, as a potential therapeutic drug, the deeper mechanism of Carthami flos still needs to be further elucidated.

Forsythiae Fructuse extracts alleviates LPS-induced acute lung injury in mice by regulating PPAR-γ/RXR-α in lungs and colons.

ETHNOPHARMACOLOGICAL RELEVANCE: Forsythiae Fructuse (FF), the dried fruit of Forsythia suspensa (Thunb.) Vahl, is used as a traditional Chinese medicine that has been reported to exert good anti-inflammatory effects in the treatment of many lung diseases. AIM OF THE STUDY: The purpose of this study was to investigate the anti-inflammatory mechanism of FF in the treatment of acute lung injury (ALI) based on gut-lung axis. MATERIALS AND METHODS: ALI model was established by the intratracheal instillation of 5 mg/kg LPS in ICR mice. Mice were administered intragastrically with dexamethasone (DEX), and low-dose, medium-dose and high-dose of FF extracts (LFF, MFF and HFF) in addition to the mice of control (CON) and model (MOD) groups. Pathological observation and inflammation scoring of lung tissues were based on HE staining. Limulus lysate assay was used to detect endotoxin levels in serum. Western blot and Real-time quantitative PCR were respectively applied to detect the protein and mRNA expressions in both lung and colon tissues. RESULTS: Lung pathological injury, inflammatory score and inflammatory genes (IL-6, IL-1ß, TNF-α) could be effectively suppressed by FF in LPS-induced ALI mice. FF also increased the proteins of epithelial markers (E-cadherin, ZO-1 and Claudin-1) in lung and colon tissues, and decreased colonic inflammatory genes for protecting the epithelial barriers of lung and colon. The protein expression of TLR4/MAPK/NF-κB inflammatory signaling pathway in lung and colon was significantly inhibited by FF via the regulation of PPAR-γ, a nuclear hormone receptor that forms the heterodimer with RXR-α to inhibit inflammatory gene transcription. More specifically, FF promoted the upregulation of protein, phosphorylated proteins and genes of PPAR-γ/RXR-α in lungs, while inhibited the protein overexpression and phosphorylation of PPAR-γ/RXR-α in colons. CONCLUSIONS: FF exhibited anti-inflammatory effects and protected the epithelial barriers in lungs and colons by regulating PPAR-γ/RXR-α in the treatment of LPS-induced ALI.

Aconiti Lateralis Radix Praeparata lipid-soluble alkaloids alleviates IL-1ß-induced inflammation of human fibroblast-like synoviocytes in rheumatoid arthritis by inhibiting NF-κB and MAPKs signaling pathways and inducing apoptosis.

BACKGROUND: Fuzi lipid-soluble alkaloids (FLA) is the main bioactive components extracted from the traditional Chinese medicine Aconiti Lateralis Radix Praeparata ("Fuzi" in Chinese), which has promising analgesic and anti-inflammatory effects. However, the effects and the underlying mechanisms of FLA on rheumatoid arthritis (RA) have not been studied. The present study aimed to explore the anti-arthritic effects of FLA and its underlying mechanisms. METHODS: To standardize the FLA, UPLC-HR-MS was used for quantitative and qualitative analysis of the representative alkaloids. Cell viability was measured by MTT. The anti-inflammatory activity of FLA was examined by analyzing the expression levels of inflammatory mediators such as TNF-α, IL-6, MMP-1, MMP-3, PGE2, and COX-2 using ELISA and RT-PCR analysis. The Annexin V-FITC/PI double staining method was used to detect the apoptosis of HFLS-RA and analyzed by flow cytometry. Western blot analysis was used to analyze the expression of NF-κB, MAPKs and mitochondrial apoptosis pathway related proteins. RESULTS: FLA had a significant inhibitory effect on the proliferation of HFLS-RA induced by IL-1ß, which was accompanied by decreased expression levels of TNF-α, IL-6, MMP-1, MMP-3, COX-2 and PGE2. Remarkably, FLA inhibited the activation of NF-κB and MAPKs signaling pathways in IL-1ß-induced HFLS-RA, as well as inducing HFLS-RA apoptosis through the mitochondrial apoptosis pathway. CONCLUSIONS: FLA inhibited the expression and synthesis of inflammatory mediators by inhibiting the activation of NF-κB and MAPKs signaling pathways in HFLS-RA, and induced apoptosis of HFLS-RA via the mitochondrial apoptosis pathway.

Forsythiaside A Regulates Activation of Hepatic Stellate Cells by Inhibiting NOX4-Dependent ROS.

Hepatic stellate cells (HSCs) activation is an important step in the process of hepatic fibrosis. NOX4 and reactive oxygen species expressed in HSCs play an important role in liver fibrosis. Forsythiaside A (FA), a phenylethanoid glycoside extracted and isolated from Forsythiae Fructus, has significant antioxidant activities. However, it is not clear whether FA can play a role in inhibiting the HSCs activation through regulating NOX4/ROS pathway. Therefore, our purpose is to explore the effect and mechanism of FA on HSCs activation to alleviate liver fibrosis. LX2 cells were activated by TGF-ß1 in vitro. MTT assay and Wound Healing assay were used to investigate the effect of FA on TGF-ß1-induced LX2 cell proliferation and migration. Elisa kit was used to measure the expression of MMP-1 and TIMP-1. Western blot and RT-qPCR were used to investigate the expression of fibrosis-related COLI, α-SMA, MMP-1 and TIMP-1, and inflammation-related TNF-α, IL-6 and IL-1ß. The hydroxyproline content was characterized using a biochemical kit. The mechanism of FA to inhibit HSCs activation and apoptosis was detected by DCF-DA probe, RT-qPCR, western blot and flow cytometry. NOX4 siRNA was used to futher verify the effect of FA on NOX4/ROS pathway. The results showed that FA inhibited the proliferation and migration of LX2 cells and adjusted the expression of MMP-1, TIMP-1, COLI, α-SMA, TNF-α, IL-6 and IL-1ß as well as promoted collagen metabolism to show potential in anti-hepatic fibrosis. Mechanically, FA down-regulated NOX4/ROS signaling pathway to improve oxidation imbalances, and subsequently inhibited PI3K/Akt pathway to suppress proliferation. FA also promoted the apoptosis of LX2 cells by Bax/Bcl2 pathway. Furthermore, the effects of FA on TGF-ß1-induced increased ROS levels and α-SMA and COLI expression were weaken by silencing NOX4. In conclusion, FA had potential in anti-hepatic fibrosis at least in part by remolding of extracellular matrix and improving oxidation imbalances to inhibit the activation of HSCs and promote HSCs apoptosis.

Polygoni Multiflori Radix Praeparata Ethanol Extract Exerts a Protective Effect Against High-Fat Diet Induced Non-Alcoholic Fatty Liver Disease in Mice by Remodeling Intestinal Microbial Structure and Maintaining Metabolic Homeostasis of Bile Acids.

In the prescription of Traditional Chinese Medicine for lipid metabolism, Polygoni Multiflori Radix Preparata (ZhiHeShouWu, RPMP) was widely used. In recent years, RPMP ethanol extract has been reported for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the role of RPMP ethanol extract in the treatment of NAFLD has not been fully elucidated. Therefore, we examined the optimal therapeutic dose of RPMP ethanol extracts. Afterward, a mouse model of non-alcoholic fatty liver induced by a high-fat diet (HFD) was treated with RPMP ethanol extract to further evaluate the mechanism of action of RPMP ethanol extract treatment. And the serum lipid metabolism indexes and liver function indexes showed that the RPMP ethanol extract in the 1.35 g/kg dose group exhibited better therapeutic effects than the 2.70 g/kg dose group. Meanwhile, RPMP ethanol extract can regulate the biochemical indicators of serum and liver to normal levels, and effectively reduce liver steatosis and lipid deposition. RPMP ethanol extract treatment restored HFD-induced disruption of the compositional structure of the intestinal microbial (IM) and bile acids (BAs) pools. And restore the reduced expression of intestinal barrier-related genes caused by HFD administration, which also effectively regulates the expression of genes related to the metabolism of BAs in mice. Thus, RPMP ethanol extract can effectively improve the abnormal lipid metabolism and hepatic lipid accumulation caused by HFD, which may be related to the regulation of IM composition, maintenance of intestinal barrier function, and normal cholesterol metabolism in the body.

Inhibiting TGF-[Formula: see text] 1-Mediated Cellular Processes as an Effective Strategy for the Treatment of Pulmonary Fibrosis with Chinese Herbal Medicines.

Pulmonary fibrosis (PF) is a chronic and irreversible interstitial lung disease that even threatens the lives of some patients infected with COVID-19. PF is a multicellular pathological process, including the initial injuries of epithelial cells, recruitment of inflammatory cells, epithelial-mesenchymal transition, activation and differentiation of fibroblasts, etc. TGF-[Formula: see text]1 acts as a key effect factor that participates in these cellular processes of PF. Recently, much attention was paid to inhibiting TGF-[Formula: see text]1 mediated cell processes in the treatment of PF with Chinese herbal medicines (CHM), an important part of traditional Chinese medicine. Here, this review first summarized the effects of TGF-[Formula: see text]1 in different cellular processes of PF. Then, this review summarized the recent research on CHM (compounds, multi-components, single medicines and prescriptions) to directly and/or indirectly inhibit TGF-[Formula: see text]1 signaling (TLRs, PPARs, micrRNA, etc.) in PF. Most of the research focused on CHM natural compounds, including but not limited to alkaloids, flavonoids, phenols and terpenes. After review, the research perspectives of CHM on TGF-[Formula: see text]1 inhibition in PF were further discussed. This review hopes that revealing the inhibiting effects of CHM on TGF-[Formula: see text]1-mediated cellular processes of PF can promote CHM to be better understood and utilized, thus transforming the therapeutic activities of CHM into practice.

Quercetin as a protective agent for liver diseases: A comprehensive descriptive review of the molecular mechanism.

Quercetin is the major representative of the flavonoid subgroup of flavones, with good pharmacological activities for the treatment of liver diseases, including liver steatosis, fatty hepatitis, liver fibrosis, and liver cancer. It can significantly influence the development of liver diseases via multiple targets and multiple pathways via antifat accumulation, anti-inflammatory, and antioxidant activity, as well as the inhibition of cellular apoptosis and proliferation. Despite extensive research on understanding the mechanism of quercetin in the treatment of liver diseases, there are still no targeted therapies available. Thus, we have comprehensively searched and summarized the different targets of quercetin in different stages of liver diseases and concluded that quercetin inhibited inflammation of the liver mainly through NF-κB/TLR/NLRP3, reduced PI3K/Nrf2-mediated oxidative stress, mTOR activation in autophagy, and inhibited the expression of apoptotic factors associated with the development of liver diseases. In addition, quercetin showed different mechanisms of action at different stages of liver diseases, including the regulation of PPAR, UCP, and PLIN2-related factors via brown fat activation in liver steatosis. The compound inhibited stromal ECM deposition at the liver fibrosis stage, affecting TGF1ß, endoplasmic reticulum stress (ERs), and apoptosis. While at the final liver cancer stage, inhibiting cancer cell proliferation and spread via the hTERT, MEK1/ERK1/2, Notch, and Wnt/ß-catenin-related signaling pathways. In conclusion, quercetin is an effective liver protectant. We hope to explore the pathogenesis of quercetin in different stages of liver diseases through the review, so as to provide more accurate targets and theoretical basis for further research of quercetin in the treatment of liver diseases.

The pharmacological activity of berberine, a review for liver protection.

Liver plays an important role in bile synthesis, metabolic function, degradation of toxins, new substances synthesis in body. However, hepatopathy morbidity and mortality are increasing year by year around the world, which become a major public health problem. Traditional Chinese medicine (TCM) has a prominent role in the treatment of liver diseases due to its definite curative effect and small side effects. The hepatoprotective effect of berberine has been extensively studied, so we comprehensively summarize the pharmacological activities of lipid metabolism regulation, bile acid adjustment, anti-inflammation, oxidation resistance, anti-fibrosis and anti-cancer and so on. Besides, the metabolism and toxicity of berberine and its new formulations to improve its effectiveness are expounded, providing a reference for the safe and effective clinical use of berberine.

Quercetin mitigates ethanol-induced hepatic steatosis in zebrafish via P2X7R-mediated PI3K/ Keap1/Nrf2 signaling pathway.

Ethnopharmacological relevanceQuercetin is the active component of the higher content in PCP, which exerts various biological activities such as anti-obesity effect, anti-inflammatory and anti-oxidant activities in alcoholic liver disease (ALD). AIM OF THE STUDY: P2X7 receptor (P2X7R) plays an important role in health and disease, which can be activated by extracellular ATP to induce a variety of downstream events, including lipid metabolism, inflammatory molecule release, oxidative stress. However, whether the mechanism of quercetin on ethanol-induced hepatic steatosis via P2X7R-mediated haven't been elucidated. MATERIAL AND METHODS: Zebrafish transgenic (fabp10: EGFP) larvae were treated with 100 µM, 50 µM, 25 µM quercetin for 48 h at 3 days post fertilization (dpf), then soaked in 350 mmol/L ethanol for 32 h, treated with 1 mM ATP (P2X7R activator) for 30min. Serum lipids, liver steatosis, oxidative stress factors were respectively detected. The mRNA levels in the related pathways were measured by quantitative Real-Time PCR (RT-qPCR) to investigate the mechanisms. RESULTS: Quercetin improved the liver function via decreasing ALT, AST and γ-GT level of zebrafish with acute ethanol-induced hepatic steatosis and attenuated hepatic TG, TC accumulation. Additionally, quercetin significantly reduced the MDA content and suppressed the ethanol-induced reduction of hepatic oxidative stress biomarkers GSH, CAT and SOD and significantly down-regulated the expression of P2X7R, and up-regulated the expression of phosphatidylinositol 3-kinase (PI3K), Kelch like ECH associated protein1 (Keap1), Nuclear Factor E2 related factor 2 (Nrf2). Moreover, ATP stimulation activated P2X7R, which further mediated the mRNA expressions of PI3K, Keap1 and Nrf2. CONCLUSION: Quercetin exhibited hepatoprotective capacity in zebrafish model, via regulating P2X7R-mediated PI3K/Keap1/Nrf2 oxidative stress signaling pathway.

An Overview of the Mechanism of Penthorum chinense Pursh on Alcoholic Fatty Liver.

Alcohol liver disease (ALD) caused by excessive alcohol consumption is a progressive disease, and alcohol fatty liver disease is the primary stage. Currently, there is no approved drug for its treatment. Abstinence is the best way to heal, but patients' compliance is poor. Unlike other chronic diseases, alcohol fatty liver disease is not caused by nutritional deficiencies; it is caused by the molecular action of ingested alcohol and its metabolites. More and more studies have shown the potential of Penthorum chinense Pursh (PCP) in the clinical use of alcohol fatty liver treatment. The purpose of this paper is to reveal from the essence of PCP treatment of alcohol liver mechanism mainly by the ethanol dehydrogenase (ADH) and microsomal ethanol oxidation system-dependent cytochrome P4502E1 (CYP2E1) to exert antilipogenesis, antioxidant, anti-inflammatory, antiapoptotic, and autophagy effects, with special emphasis on its mechanisms related to SIRT1/AMPK, KEAP-1/Nrf2, and TLR4/NF-κB. Overall, data from the literature shows that PCP appears to be a promising hepatoprotective traditional Chinese medicine (TCM).

A Candidate Drug for Nonalcoholic Fatty Liver Disease: A Review of Pharmacological Activities of Polygoni Multiflori Radix.

Nonalcoholic fatty liver disease, a type of metabolic syndrome, continues to rise globally. Currently, there is no approved drug for its treatment. Improving lifestyle and exercise can alleviate symptoms, but patients' compliance is poor. More and more studies have shown the potential of Polygoni Multiflori Radix (PMR) in the treatment of NAFLD and metabolic syndrome. Therefore, this paper reviews the pharmacological effects of PMR and its main chemical components (tetrahydroxystilbene glucoside, emodin, and resveratrol) on NAFLD. PMR can inhibit the production of fatty acids and promote the decomposition of triglycerides, reduce inflammation, and inhibit the occurrence of liver fibrosis. At the same time, it maintains an oxidation equilibrium status in the body, to achieve the therapeutic purpose of NAFLD and metabolic syndrome. Although more standardized studies and clinical trials are needed to confirm its efficacy, PMR may be a potential drug for the treatment of NAFLD and its complications. However, the occurrence of adverse reactions of PMR has affected its extensive clinical application. Therefore, it is necessary to further study its toxicity mechanism, enhance efficacy and control toxicity, and even reduce toxicity, which will contribute to the safe clinical use of PMR.