Components from Curcuma longa (Turmeric) Against Hepatobiliary Diseases Based on Gut-Liver Axis: Pharmacotherapeutic Properties and Potential Clinical Applications.

Turmeric is widely used worldwide, and there are many examples of its use in treating hepatobiliary diseases. The gut-liver axis is a bidirectional relationship between gut microorganisms and the liver that is closely related to the pathogenesis of hepatobiliary diseases. This review systematically summarizes the components of turmeric. It links the studies on turmeric affecting gut microorganisms to its effects on liver and biliary diseases to explain the potential mechanism of turmeric's regulation of the gut-liver axis. Besides, ethnopharmacology, phytochemicals, and clinical adverse events associated with turmeric have been researched. Furthermore, turmeric is a safe agent with good clinical efficacy and without apparent toxicity at a certain amount. By summarizing the influence of turmeric on the liver by regulating the gut-liver axis, especially the gut microbiota, it provides a preclinical basis for using turmeric as a safe and effective therapeutic agent for the prevention and treatment of hepatobiliary diseases based on the gut-liver axis. However, more efforts should be made to exploit its clinical application further.

Modulating Effects of Turmeric Polysaccharides on Immune Response and Gut Microbiota in Cyclophosphamide-Treated Mice.

Turmeric, a traditional medicinal herb, is commonly used as a dietary and functional ingredient. This study aimed to investigate the effect of turmeric polysaccharides (TPs) on intestinal immunity and gut microbiota in cyclophosphamide (Cy)-induced immunosuppressed BALB/c mice. We verified that the oral administration of TPs-0 and TPs-3 (200 and 400 mg/kg, bw) improved thymus and spleen indexes, increased the whole blood immune cells (WBC) and lymph count index, and stimulated the secretion of serum immunoglobulin IgG. More importantly, TPs-0 and TPs-3 could repair intestinal immune damage and reduce intestinal inflammation. The specific mechanism is ameliorating the intestinal pathological damage, promoting CD4+ T cell secretion, regulating the expression of related cytokines, and reducing the level of critical proteins in the NF-κB/iNOS pathway. Interestingly, the intake of TPs-0 and TPs-3 significantly increased the content of short-chain fatty acids (SCFAs). Moreover, TPs-0 and TPs-3 relieved the intestinal microbiota disorder via the proliferation of the abundance of Lactobacillus and Bacteroides and the inhibition of Staphylococcus. Cumulatively, our study suggests that TPs-0 and TPs-3 can relieve intestinal immune damage by repairing the immune barrier and regulating intestinal flora disorders. TPs have potential applications for enhancing immunity as a functional food.

Herb pairs containing Curcumae Rhizoma (Ezhu): A review of bio-active constituents, compatibility effects and t-copula function analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: An herbal pair is a classic form of clinical dispensing in Traditional Chinese Medicine (TCM), often used in prescriptions to enhance the effect or reduce potential side effects. It is the smallest component unit of Chinese medicine prescription and an essential bridge between Chinese medicine and prescription. Curcumae Rhizoma (called Ezhu in Chinese) is a representative TCM herb that promotes blood circulation and removes blood stasis. It has been used in Chinese medicine for thousands of years. Ezhu is generally used in clinical applications as a part of a "drug pair" to treat heartburn, stomach pain, tumour, amenorrhea and abdominal pain caused by blood stasis, qi stagnation and injury. AIMS OF THE REVIEW: This review aims to summarize the latest and comprehensive situation of the biological activity and clinical application of drug pairs containing Ezhu, find the law of Ezhu compatibility application, and discuss the rationalization of Ezhu drug compatibility. For Ezhu, herb pairs to provide a theoretical basis for clinical research in TCM and serve as a research foundation for developing new drugs. MATERIALS AND METHODS: Using a self-built prescription database and Apriori algorithm for association rule mining. A systematic search for studies on herb pairs containing Ezhu was carried out by using the internet databases of PubMed, CNKI, Baidu Scholar, Google Scholar and Web of Science, as well as other relevant textbooks, reviews and documents (e.g. Chinese Pharmacopoeia, 2020 edition, Chinese herbal classic books and PhD and MSc theses, etc.). Among them with keywords including "Curcumae Rhizoma", "Ezhu", "herb pairs", "clinical application", etc. and their combinations. Moreover, the t-copula function was used to analyse the dose-coupling effect of five drug pairs, including Ezhu. RESULTS: The preliminary statistical analysis retrieved Ezhu prescriptions from self-built prescription database and internet databases. The results showed that the compatibility frequency of Ezhu with the other five Chinese medicines was high. Most of these selected herbal combinations are used to treat internal diseases. In this paper, the progress of the ethnopharmacology of Ezhu was reviewed, emphasizing the changes in bioactive components and compatibility of Chinese traditional medicine combinations such as Ezhu and Astragalus Curcuma (Sparganium stoloniferum Buch. -Ham; called Sanleng in Chinese), Ezhu and Astragali Radix (Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, Astragalus membranaceus (Fisch.) Bge.; called Huangqi in Chinese). Some other varieties, such as Ezhu and Rhizoma Chuanxiong (Ligusticum chuanxiong Hort.; called Chuanxiong in Chinese), Trionycis Carapax (Trionyx sinensis Wiegmann; called Biejia in Chinese), and Coptidis Rhizoma (Coptis chinensis Franch., Coptis deltoidea C. Y. Cheng et Hsiao, Coptis teeta Wall.; called Huanglian in Chinese), are also recorded in ancient books but rarely researched. The dose of Ezhu is strongly correlated with the amount of Sanleng, Huangqi, Biejia, Chuanxiong and Huanglian, respectively. Furthermore, there was a positive correlation between them. CONCLUSIONS: The bioactive components and compatibility effects of Ezhu herb pairs were studied in detail using data mining and t-copula function analysis. Ezhu and Astragalus Curcuma (Sanleng) mainly treat gynecological disorders by activating blood circulation and relieving congestion. Ezhu and Astragali Radix (Huangqi) drug pair and Ezhu and Trionycis Carapax (Biejia) drug pair are all commonly used in the clinical treatment of tumors, the former is mainly used clinically for the treatment of digestive tract-related inflammation and tumors, liver cancer and gynecological tumors, and the latter is commonly used for the treatment of malignant tumors, such as liver cancer and mammary cancer.

The hepatoprotective effects of plant-based foods based on the "gut-liver axis": a prospective review.

The importance of the "gut-liver axis" in the pathogenesis of liver diseases has been revealed recently; which promotes the process of developing preventive and therapeutic strategies. However, considering that there are still many challenges in the medical treatment of liver diseases, potential preventive dietary intervention may be a good alternative choice. Plant-based foods have received much attention due to their reported health-promoting effects in targeting multiple pathways involved in the pathogenesis of liver diseases as well as the relative safety for general use. Based on the PubMed and Web of Science databases, this review emphatically summarizes the plant-based foods and their chemical constituents with reported effects to impact the LPS/TLR4 signaling pathway of gut-liver axis of various liver diseases, reflecting their health benefits in preventing/alleviating liver diseases. Moreover, some plant-based foods with potential gut-liver effects are specifically analyzed from the reported studies and conclusions. This review intends to provide readers an overview of the current progress in the field of this research topic. We expect to see more hepatoprotective measures for alleviating the current prevalence of liver diseases.

Curcumae rhizoma and its major constituents against hepatobiliary disease: Pharmacotherapeutic properties and potential clinical applications.

BACKGROUND: Hepatobiliary disease currently serves as an urgent health issue in public due to health-modulating factors such as extension of life expectancy, increasingly sedentary lifestyles and over-nutrition. A definite treatment remains lacking owing to different stages of the disease itself and its intricate pathogenesis. Traditional Chinese medicine (TCM) has been gradually popularized in clinic with the satisfactory efficacy and good safety. Curcumae Rhizoma (called E Zhu, EZ in Chinese) is a representative herb, which has been used to treat hepatobiliary disease for thousands of years. PURPOSE: To systematically summarize the recent research advances on the pharmacological activities of EZ and its constituents, explain the underlying mechanisms of preventing and treating hepatobiliary diseases, and assess the shortcomings of existing work. Besides, ethnopharmacology, phytochemicals, and toxicology of EZ have been researched. METHODS: The information about EZ was collected from various sources including classic books about Chinese herbal medicine, and scientific databases including Web of Science, PubMed, ScienceDirect, Springer, ACS, SCOPUS, CNKI, CSTJ, and WANFANG using keywords given below and terms like pharmacological and phytochemical details of this plant. RESULTS: The chemical constituents isolated and identified from EZ, such as terpenoids including ß-elemene, furanodiene, germacrone, etc. and curcuminoids including curcumin, demethoxycurcumin, bisdemethoxycurcumin, etc. prove to have hepatoprotective effect, anti-liver fibrotic effect, anti-fatty liver effect, anti-liver neoplastic effect, and cholagogic effect through TGF-ß1/Smad, JNK1/2-ROS, NF-κB and other anti-inflammatory and antioxidant signaling pathways. Also, EZ is often combined with other Chinese herbs in the treatment of hepatobiliary diseases with good clinical efficacy and no obvious adverse reactions. CONCLUSION: It provides a preclinical basis for the efficacy of EZ as an effective therapeutic agent for the prevention and treatment of hepatobiliary diseases. Even so, the further studies still needed to alleviate hepatotoxicity and expand clinical application.

RNA-binding protein p54nrb/NONO potentiates nuclear EGFR-mediated tumorigenesis of triple-negative breast cancer.

Nuclear-localized epidermal growth factor receptor (EGFR) highly correlates with the malignant progression and may be a promising therapeutic target for breast cancer. However, molecular mechanisms of nuclear EGFR in triple-negative breast cancer (TNBC) have not been fully elucidated. Here, we performed gene-annotation enrichment analysis for the interactors of nuclear EGFR and found that RNA-binding proteins (RBPs) were closely associated with nuclear EGFR. We further demonstrated p54nrb/NONO, one of the RBPs, significantly interacted with nuclear EGFR. NONO was upregulated in 80 paired TNBC tissues and indicated a poor prognosis. Furthermore, NONO knockout significantly inhibited TNBC proliferation in vitro and in vivo. Mechanistically, NONO increased the stability of nuclear EGFR and recruited CREB binding protein (CBP) and its accompanying E1A binding protein p300, thereby enhancing the transcriptional activity of EGFR. In turn, EGFR positively regulated the affinity of NONO to mRNAs of nuclear EGFR downstream genes. Furthermore, the results indicated that the nuclear EGFR/NONO complex played a critical role in tumorigenesis and chemotherapy resistance. Taken together, our findings indicate that NONO enhances nuclear EGFR-mediated tumorigenesis and may be a potential therapeutic target for TNBC patients with nuclear EGFR expression.

Isatidis Radix and Isatidis Folium: A systematic review on ethnopharmacology, phytochemistry and pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Isatidis Radix (called Banlangen, BLG in Chinese) and Isatidis Folium (called Daqingye, DQY in Chinese) are common traditional edible-medicinal herbs in detoxifying for thousands of years, have been traditionally applied in traditional Chinese medicine for centuries. Both of them are bitter in taste, coolness in nature, acting on the heart and stomach channels. They are often used to treat influenza and other viral infectious diseases in clinic, as well as could treat fever, dizziness, and cough and sore throat caused by lung heat. AIMS OF THE REVIEW: This review aimed at summarizing the latest and comprehensive information of BLG and DQY on the ethnopharmacology, phytochemistry, pharmacology, toxicity and clinical application to explore the therapeutic potential of them. In addition, outlooks and perspective for possible future researches that related are also discussed. MATERIALS AND METHODS: Related information concerning BLG and DQY were gathered from the internet database of Google Scholar, PubMed, Baidu Scholar, GeenMedical, CNKI and Web of Science, as well as other relevant textbooks, reviews, and documents (e.g., Chinese Pharmacopoeia, 2020 edition, Chinese herbal classic books and PhD and MSc thesis, etc.). Among of them with the keywords including "Isatis indigotica" "Isatidis Radix", "Isatidis Folium", "phytochemistry", "pharmacology", "toxicology", "clinical application" etc. and their combinations. RESULTS: To date, 39 Chinese patent medicines containing BLG and/or DQY have been developed on basis of the data of NMPA. Besides, 304 and 142 compounds have been found in BLG and DQY, respectively. The main chemical differences between BLG and DQY were concentrated on alkaloids and lignans, such as indican, indirubin, (R, S)-epigoitrin, 4(3H)-quinazolinone, clemastanin B and isatindigotindolines A-D. In 2020 Edition ChP, (R, S)-goitrin and indirubin are now used as the official marker to monitor the quality of BLG and DQY, respectively. Modern pharmacology has mainly studied some monomer components such as 4(3H)-quinazolinone, clemastanin B, erucic acid and adenosine, etc., all of which have shown good effects. These active compounds can resist various viruses, such as influenza virus, respiratory syncytial virus, herpes simplex virus, etc.. By regulating the level of immunity and a variety of inflammatory factors, inhibit the growth and reproduction of the virus. At the same time, it is worth noting that different components of BLG and DQY lead to BLG is more powerful in antiviral and immunomodulatory activity than DQY, while DQY possesses a higher intensity than BLG in anti-oxidant activity. CONCLUSION: By collecting and collating a large number of literature and various data websites, we concluded that the common compounds are mainly alkaloids. Recent findings regarding the phytochemical and pharmacological properties of BLG and DQY have confirmed their traditional uses in antiviral, antibacterial and treatment immune diseases. Without doubt, their significant differences on ethnopharmacology, phytochemistry and pharmacology can be used as evidence of separate list of BLG and DQY. For shortcomings, some comprehensive studies should be well designed for further utilization of BLG and DQY.

Nuclear scaffold protein p54nrb/NONO facilitates the hypoxia-enhanced progression of hepatocellular carcinoma.

Hypoxia and related oxidative stress are closely related to the development and treatment of hepatocellular carcinoma (HCC). However, the mechanism mediated by hypoxia in HCC has not yet been elucidated. Here, we found multifunction scaffold protein p54nrb/NONO exerted pleiotropic effects to regulate hypoxia transcription signals, thereby enhancing the progression of liver cancer. Extensive analysis of clinical data demonstrated that NONO was significantly upregulated and represented as a poor prognostic indicator of HCC. The crucial role of NONO in driving angiogenesis and glycolysis, two well-known cancer phenotypes mediated by hypoxia, was examined in vitro an in vivo. Mechanistically, NONO interacted with and stabilized both HIF-1 and HIF-2 complexes thus activating the transcription of hypoxia-induced genes. Besides, NONO bound pre-mRNA and subsequent mRNA of these genes to facilitate them splicing and mRNA stability, respectively. Thus, NONO knockout seriously disrupted the expression of a cluster of HIF-1/2 targets and impeded hypoxia-enhanced progression in HCC. In conclusion, NONO functioned as a multipurpose scaffold that interacted with HIF-1/2 complex and their downstream transcripts to facilitate the expression of hypoxia-induced genes, allowing malignant proliferation, indicating that NONO might be a potential therapeutic target for HCC.

Vinegar-processed Curcuma phaeocaulis promotes anti-angiogenic activity and reduces toxicity in zebrafish and rat models.

CONTEXT: Processing with vinegar could enhance the efficacy and reduce the toxicity of Curcuma phaeocaulis Valeton. (Zingiberaceae), a Chinese herbal medicine with anti-inflammatory and antitumor activities. OBJECTIVE: This study investigated the vinegar processing effects by evaluating anti-angiogenic effect and toxicity of C. phaeocaulis through zebrafish and rat models. MATERIALS AND METHODS: Zebrafish embryos (AB and FLk-GFP strain) were applied to evaluate toxicity, cardiotoxicity and anti-angiogenic activity of volatile oil, and water decoction of the raw and vinegar-processed C. phaeocaulis. Meanwhile, a blood stasis syndrome rat model was applied to study the toxicity by measuring the ovarian and uterine coefficient. RESULTS: Curcuma phaeocaulis volatile oil and its vinegar-processed products in zebrafish had an LC50 of 67.315 and 95.755 µg/mL, respectively. Curcuma phaeocaulis water decoction and its vinegar-processed products had an LC50 of 161.440 and 206.239 µg/mL, respectively. The toxicity of vinegar-processed products was significantly lower than the raw, and the development characteristic of zebrafish embryos at different times confirmed these results. The volatile oil of vinegar-processed products could inhibit the growth of intersegmental blood vessels at the dose of 20 µg/mL, while the raw materials did not exhibit such effect at the same concentration. The rat experiment also confirmed that the volatile oil could reduce toxicity of ovarian and uterine. DISCUSSION AND CONCLUSIONS: The study indicated that processing using vinegar could decrease toxicity and increase anti-angiogenic activity of C. phaeocaulis, which could be applied for clinical treatment. Further in-depth study on the synergism and detoxification mechanism of vinegar processing technology is needed.

Essential oil from the raw and vinegar-processed Rhizoma Curcumae ameliorate CCl4-induced liver fibrosis: integrating network pharmacology and molecular mechanism evaluation.

Liver fibrosis, caused by multiple chronic liver injuries, is a known contributor to cirrhosis and even liver cancer. As a Traditional Chinese Medicine (TCM), Rhizoma curcumae has been extensively used in the treatment of liver fibrosis with satisfying therapeutic effects; however, its mechanism is unclear. The essential oil is the main bioactive component. The purpose of this study was to investigate the chemical profile and the pharmacological mechanisms of the essential oil of Rhizoma curcumae (EORC) against liver fibrosis by combining network pharmacology and transcriptomic technologies. A total of 37 active compounds were identified using the GC/MS system and literature mining, and the corresponding putative targets were predicted. Then, network pharmacology method was applied to identify the 168 candidate targets of EORC-alleviated liver fibrosis. String database and Cytoscape software were used to build the herb-compound-target network and protein-protein interactions (PPIs) network. Functional and pathway enrichment analysis indicated that EORC significantly influenced TGF-ß1/Smads and PI3K/AKT pathways. Experimentally, we verified that EORC attenuated the severity and pathological changes during liver fibrosis progression based on the CCl4-induced liver fibrosis rat model. Transcriptomic technologies demonstrated that EORC ameliorated liver fibrosis partially by regulating the TGF-ß1/Smads and PI3K/AKT pathways. In addition, the effect of vinegar-processed EORC was more significant than that of the raw one. Therefore, EORC can alleviate the severity of liver fibrosis through mechanisms predicted by network pharmacology and provide a basis for the further understanding of the application of EORC in the treatment of liver fibrosis.

Terpenoids from Curcumae Rhizoma: Their anticancer effects and clinical uses on combination and versus drug therapies.

Cancer is a fatal disease with high mortality and low survival rate worldwide. At present, there is still no known cure for most cancers. Traditional Chinese medicine (TCM) represents a noteworthy reservoir for anticancer agents in drug discovery and development. Curcumae Rhizoma (called Ezhu in Chinese) is widely prescribed in TCM for anticancer therapy owing to its broad-spectrum antineoplastic activities. Especially, the terpenoids isolated from the essential oil of Curcumae Rhizoma form an integral part of cancer research and are well established as a potential anticancer agent. For example, ß-elemene has been developed into a new drug for the treatment of solid tumors in China, and is currently undergoing clinical trials in the United States. The review aims to systematically summarize the recent advances on the anticancer effects and related molecular mechanisms of Curcumae Rhizoma, and its terpenoids (ß-elemene, Furanodiene, Furanodienone, Germacrone, Curcumol, Curdione). In addition, we evaluated and compared the anticancer efficacy and clinical use of the terpenoids with combination therapies and traditional therapies. Therefore, this review provides sufficient evidence for the anticancer therapeutic potential of Curcumae Rhizoma and its terpenoids, and will contribute to the development of potential anticancer drugs.

Integrating Network Analysis and Metabolomics to Reveal Mechanism of Huaganjian Decoction in Treatment of Cholestatic Hepatic Injury.

Huaganjian decoction (HGJD) was first recorded in the classic "Jing Yue Quan Shu" during the Ming dynasty, and it has been extensively applied in clinical practice to treat liver diseases for over 300 years in China. However, its bioactive constituents and relevant pharmacological mechanism are still unclear. In this study, a strategy integrating network analysis and metabolomics was applied to reveal mechanism of HGJD in treating cholestatic hepatic injury (CHI). Firstly, we observed the therapeutic effect of HGJD against CHI with an alpha-naphthylisothiocyanate (ANIT) induced CHI rat model. Then, we utilized UPLC-Q-Exactive MS/MS method to analyze the serum migrant compounds of HGJD in CHI rats. Based on these compounds, network analysis was conducted to screen for potential active components, and key signaling pathways interrelated to therapeutic effect of HGJD. Meanwhile, serum metabolomics was utilized to investigate the underlying metabolic mechanism of HGJD against CHI. Finally, the predicted key pathway was verified by western blot and biochemical analysis using rat liver tissue from in vivo efficacy experiment. Our results showed that HGJD significantly alleviated ANIT induced CHI. Totally, 31 compounds originated from HGJD have been identified in the serum sample. PI3K/Akt/Nrf2 signaling pathway related to GSH synthesis was demonstrated as one of the major pathways interrelated to therapeutic effect of HGJD against CHI. This research supplied a helpful strategy to determine the potential bioactive compounds and mechanism of traditional Chinese medicine.

Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth.

Dysregulation of the sterol regulatory element-binding transcription factors sterol regulatory element-binding protein (SREBP) and SREBF activates de novo lipogenesis to high levels in cancer cells, a critical event in driving malignant growth. In this study, we identified an important posttranslational mechanism by which SREBP1a is regulated during metabolic reprogramming in cancer cells. Mass spectrometry revealed protein arginine methyltransferase 5 (PRMT5) as a binding partner of SREBP1a that symmetrically dimethylated it on R321, thereby promoting transcriptional activity. Furthermore, PRMT5-induced methylation prevented phosphorylation of SREBP1a on S430 by GSK3ß, leading to its disassociation from Fbw7 (FBXW7) and its evasion from degradation through the ubiquitin-proteasome pathway. Consequently, methylation-stabilized SREBP1a increased de novo lipogenesis and accelerated the growth of cancer cells in vivo and in vitro. Clinically, R321 symmetric dimethylation status was associated with malignant progression of human hepatocellular carcinoma, where it served as an independent risk factor of poor prognosis. By showing how PRMT5-induced methylation of SREBP1a triggers hyperactivation of lipid biosynthesis, a key event in tumorigenesis, our findings suggest a new generalized strategy to selectively attack tumor metabolism.