Clinical evidence of three traditional Chinese medicine drugs and three herbal formulas for COVID-19: A systematic review and meta-analysis of the Chinese population.

BACKGROUND: The coronavirus disease 2019 (COVID-19) continues to spread worldwide. Integrated Chinese and Western medicine have had some successes in treating COVID-19. OBJECTIVE: This study aims to evaluate the efficacy and safety of three traditional Chinese medicine drugs and three herbal formulas (3-drugs-3-formulas) in patients with COVID-19. SEARCH STRATEGY: Relevant studies were identified from 12 electronic databases searched from their establishment to April 7, 2022. INCLUSION CRITERIA: Randomized controlled trials (RCTs), non-RCTs and cohort studies that evaluated the effects of 3-drugs-3-formulas for COVID-19. The treatment group was treated with one of the 3-drugs-3-formulas plus conventional treatment. The control group was treated with conventional treatment. DATA EXTRACTION AND ANALYSIS: Two evaluators screened and selected literature independently, then extracted basic information and assessed risk of bias. The treatment outcome measures were duration of main symptoms, hospitalization time, aggravation rate and mortality. RevMan 5.4 was used to analyze the pooled results reported as mean difference (MD) with 95% confidence interval (CI) for continuous data and risk ratio (RR) with 95% CI for dichotomous data. RESULTS: Forty-one studies with a total of 13,260 participants were identified. Our analysis suggests that compared with conventional treatment, the combination of 3-drugs-3-formulas might shorten duration of fever (MD = -1.39; 95% CI: -2.19 to -0.59; P < 0.05), cough (MD = -1.57; 95% CI: -2.16 to -0.98; P < 0.05) and fatigue (MD = -1.36; 95% CI: -2.21 to -0.51; P < 0.05), decrease length of hospital stay (MD = -2.62; 95% CI -3.52 to -1.72; P < 0.05), the time for nucleic acid conversion (MD = -2.92; 95% CI: -4.26 to -1.59; P < 0.05), aggravation rate (RR = 0.49; 95% CI: 0.38 to 0.64; P < 0.05) and mortality (RR = 0.34; 95% CI: 0.19 to 0.62; P < 0.05), and increase the recovery rate of chest computerized tomography manifestations (RR = 1.22; 95% CI: 1.14 to 1.3; P < 0.05) and total effectiveness (RR = 1.24; 95% CI: 1.09 to 1.42; P < 0.05). CONCLUSION: The 3-drugs-3-formulas can play an active role in treating all stages of COVID-19. No severe adverse events related to 3-drugs-3-formulas were observed. Hence, 3-drugs-3-formulas combined with conventional therapies have effective therapeutic value for COVID-19 patients. Further long-term high-quality studies are essential to demonstrate the clinical benefits of each formula. Please cite this article as: You LZ, Dai QQ, Zhong XY, Yu DD, Cui HR, Kong YF, Zhao MZ, Zhang XY, Xu QQ, Guan ZY, Wei XX, Zhang XC, Han SJ, Liu WJ, Chen Z, Zhang XY, Zhao C, Jin YH, Shang HC. Clinical evidence of three traditional Chinese medicine drugs and three herbal formulas for COVID-19: A systematic review and meta-analysis of the Chinese population. J Integr Med. 2023; 21(5): 441-454.

Gut microbiota and integrative traditional Chinese and western medicine in prevention and treatment of heart failure.

BACKGROUND: Heart failure (HF) is the terminal stage of multiple cardiovascular diseases, with high mortality and morbidity. More and more studies have proved that gut microbiota may play a role in the process of HF, which is expected to become a new therapeutic target. The combination of traditional Chinese and Western medicine has vast therapeutic potential of complementation against HF. PURPOSE: This manuscript expounds on the research progress of mechanisms of gut microbiota participating in the occurrence and prognosis of HF and the role of integrative traditional Chinese and Western medicine from 1987 to 2022. The combination of traditional Chinese and Western medicine in the prevention and treatment of HF from the perspective of gut microbiota has been discussed. METHODS: Studies focusing on the effects and their mechanisms of gut microbiota in HF and the role of integrative traditional Chinese and Western medicine were identified and summarized, including contributions from February 1987 until August 2022. The investigation was carried out in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. We searched PubMed, Embase, Cochrane Library, CNKI, Wanfang, and VIP databases up to April 2023 by using the relevant keywords and operators. RESULTS: A total of 34 articles were finally included in this review.16 RCTs and 13 basic researches, and 3 clinical research studies involving 7 relevant outcome indicators(cardiac function evaluation index, changes in gut microbiota, inflammatory factors, metabolites of gut microbiota, serum nutritional index protein, quality of life score, intestinal permeability and all-cause mortality). Compared with healthy controls, serum TNF-α and TMAO levels were significantly higher in patients with heart failure [MD = 5.77, 95%CI(4.97, 6.56), p < 0.0001; SMD = 1.92, 95%CI(1.70, 2.14), p < 0.0001]. Escherichia coli and Thick-walled bacteria increased significantly [SMD = -0.99, 95%CI(-1.38, -0.61), p < 0.0001, SMD = 2.58, 95%CI(2.23, 2.93), p < 0.0001];The number of bacteroides and lactobacillus decreased [SMD = -2.29, 95%CI(-2.54, -2.04), p < 0.0001; SMD = -1.55, 95%CI(-1.8, -1.3), p < 0.0001]. There was no difference in bifidobacterium [SMD = 0.16, 95%CI(-0.22, 0.54), p = 0.42]. In the published literature, it is not difficult to see that most of the results are studied and proved based on animal experiments or clinical trials, involving the cellular level, while the mechanism and mode of action of the molecular biology of traditional Chinese medicine are less elaborated, which is related to the characteristics of multi-components and multi-targets of traditional Chinese medicine. The above are the shortcomings of published literature, which can also be the direction of future research. CONCLUSION: Heart failure patients have decreased beneficial bacteria such as Bacillus mimics and Lactobacillus in the intestinal flora and increased harmful flora like thick-walled flora. And increase the inflammatory response of the body and the expression of trimethylamine oxide (TMAO) in the serum. And The prevention and treatment of integrative traditional Chinese and Western medicine against heart failure based on gut microbiota and its metabolites is a promising research direction.

Network pharmacology and molecular docking prediction, combined with experimental validation to explore the potential mechanism of Qishen Yiqi pills against HF-related cognitive dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: Qishen Yiqi Pills (QSYQ) is a classical herbal formula for treating heart failure (HF) and has potential efficacy in improving cognitive function. The latter is one of the most common complications in patients with HF. However, there is no study on treating HF-related cognitive dysfunction by QSYQ. AIMS OF THE STUDY: The study aims to investigate the effect and mechanism of QSYQ on treating post-HF cognitive dysfunction based on network pharmacology and experimental validation. MATERIALS AND METHODS: Network pharmacology analysis and molecular docking was used to explore endogenous targets of QSYQ in treating cognitive impairment. Ligation of the anterior descending branch of the left coronary artery and sleep deprivation (SD) were used to induce HF-related cognitive dysfunction in rats. The efficacy and potential signal targets of QSYQ were then verified by functional evaluation, pathological staining, and molecular biology experiments. RESULTS: 384 common targets were identified by intersecting QSYQ 'compound targets' and 'cognitive dysfunction' disease targets. KEGG analysis showed these targets were enriched to the cAMP signal, and four marks responsible for regulating the cAMP signal were successfully docked with core compounds of QSYQ. Animal experiments demonstrated that QSYQ significantly ameliorated cardiac function and cognitive function in rats suffering from HF and SD, inhibited the reduction of cAMP and BDNF content, reversed the upregulation of PDE4 and downregulation of CREB, suppressed the loss of neurons, and restored the expression of synaptic protein PSD95 in the hippocampus. CONCLUSION: This study clarified that QSYQ could improve HF-related cognitive dysfunction by modulating cAMP-CREB-BDNF signals. It provides a rich basis for the potential mechanism of QSYQ in the treatment of heart failure with cognitive dysfunction.

Chuanxiong improves angiogenesis via the PI3K/AKT/Ras/MAPK pathway based on network pharmacology and DESI-MSI metabolomics.

Introduction: Chuanxiong, a traditional Chinese medicine, has been proved to treat a variety of cardiovascular and cerebrovascular diseases by promoting angiogenesis. However, the mechanisms of Chuanxiong's pro-angiogenesis is currently unknown. This study aimed to uncover the effect and mechanisms of Chuanxiong promoting angiogenesis in vivo and in vitro. Methods: First, potential targets were predicted by network pharmacology analysis, and PPI network was established and the pathways were enriched. Then, the chorioallantoic membrane test on quails was applied to assess the proangiogenic effects in vivo. As well, to evaluate the effects in vitro, real-time PCR, western blot analysis, the scratch test, and the tube formation experiment were used. Subsequently, the major metabolic pathways were analyzed using non-targeted metabolomics. Results: As a result of network pharmacological analysis, 51 collective targets of Chuanxiong and angiogenesis were identified, which are mainly associated with PI3K/AKT/Ras/MAPK pathway. And the biological verification results showed that Chuanxiong could increase the vessel numbers and vessel area in qCAM models. Meanwhile, Chuanxiong contributed to HUVEC proliferation, tube formation, migration, by encouraging scratch healing rates and boosting tube branch points. In addition, the levels of VEGFR2, MAPK and PI3K were elevated compared to the control group. The western blot analysis also confirmed Chuanxiong could promote an increase in AKT, FOXO1 and Ras. Furtheremore, metabolomic results showed that the proangiogenic effect of Chuanxiong is associated with glycine, serine and threonine metabolism. Discussion: In conclusion, this study clarified that Chuanxiong could promote angiogenesis in vivo and in vitro via regulating PI3K/AKT/Ras/MAPK pathway.

Spatial metabolomics reveal mechanisms of dexamethasone against pediatric pneumonia.

Currently, drugs are limited to treating pediatric pneumonia in clinical practice. It is urgent to find one new precise prevention and control therapy. The dynamically changing biomarkers during the development of pediatric pneumonia could help diagnose this disease, determine its severity, assess the risk of future events, and guide its treatment. Dexamethasone has been recognized as an effective agent with anti-inflammatory activity. However, its mechanisms against pediatric pneumonia remain unclear. In this study, spatial metabolomics was used to reveal the potential and characteristics of dexamethasone. Specifically, bioinformatics was first applied to find the critical biomarkers of differential expression in pediatric pneumonia. Subsequently, Desorption Electrospray Ionization mass spectrometry imaging-based metabolomics screened the differential metabolites affected by dexamethasone. Then, a gene-metabolite interaction network was built to mark functional correlation pathways for exploring integrated information and core biomarkers related to the pathogenesis and etiology of pediatric pneumonia. Further, these were validated by molecular biology and targeted metabolomics. As a result, genes of Cluster of Differentiation19, Fc fragment of IgG receptor IIb, Cluster of Differentiation 22, B-cell linker, Cluster of Differentiation 79B and metabolites of Triethanolamine, Lysophosphatidylcholine(18:1(9Z)), Phosphatidylcholine(16:0/16:0), phosphatidylethanolamine(O-18:1(1Z)/20:4(5Z,8Z,11Z,14Z)) were identified as the critical biomarkers in pediatric pneumonia. B cell receptor signaling pathway and glycerophospholipid metabolism were integrally analyzed as the main pathways of these biomarkers. The above data were illustrated using a Lipopolysaccharides-induced lung injury juvenile rat model. This work will provide evidence for the precise treatment of pediatric pneumonia.

[Concept and method of evidence-based toxicology of traditional Chinese medicine from origin and development of evidence-based toxicology].

Advances in science and technology promote the rapid development of toxicological detection technologies. However, there is still a lack of decision-making tools for toxicological risk assessment, such as the lack of transparent schemes to evaluate current toxicological research and practice and the lag of toxicological testing tools to evaluate toxicity, resulting in difficulties in toxicity verification and hindering the transformation of toxicological research paradigm. Some scholars have proposed to integrate the concept of evidence-based medicine with the toxicological practice to improve the technical methods of toxicological research concept and risk assessment decision-making. With the promotion of relevant scholars and academic organizations, the concept and connotation of evidence-based toxicology have gradually become clear and a framework for research and practice has been initially formed. Although there are still many challenges, it also provides a new idea for the toxicity risk assessment and safe medication decision-making of traditional Chinese medicine(TCM). The era of digital intelligence has brought new opportunities and broad space for the development of TCM evidence-based toxicology. The exploration of TCM evidence-based toxicology from concept to method is an important embodiment of the development of TCM evidence-based toxicology, and will also promote the continuous enrichment and improvement of the research and practice system of TCM evidence-based toxicology.

Systems pharmacology and GC-MS metabolomics reveal the efficacy and mechanisms of zedoary oil on acute liver injury induced by oxidative stress.

BACKGROUND: Zedoray oil (ZO) is the main component of Curcuma zedoaria, one traditional herb used for dispersing stasis clinically in China. Previously, the potential of ZO was discovered against lethal and acute liver injury (ALI) mice with little impact on the immune, which deserved further study. METHODS: An approach combined systems pharmacology with GC-MS metabolomics was applied for predicting pathways affected by ZO. Subsequently, H2O2 and tertbutyl hydroperoxide (t-BHP) were respectively applied to induce the ALI model in vitro for validation. RESULTS: First, systems pharmacology and intracellular metabolites suggested that ZO might regulate oxidative stress via PI3K/Akt/FoxO1 pathway, TCA cycle, pantothenate, and CoA biosynthesis, beta-alanine metabolism, and propanoate metabolism. Further, levels of ALT, AST, ROS, T-AOC, MDA, GR, ΔΨm, and related proteins affected by ZO had been detected to validate the above mechanisms using dual cell models. CONCLUSION: ZO could protect the L02 cells against ALI by regulating the PI3K/Akt/FoxO1 pathway, as well as restore the function of mitochondria and redox imbalance damaged by toxicants. This work has uncovered the nonimmune mechanisms of ZO against ALI to provide the basis for relevant research and disease treatment.

[Establishment of multiple evidence-integrated evaluation and prediction method for "toxic" Chinese medicines].

Traditional Chinese medicine(TCM) carries the experience and theoretical knowledge of the ancients, and the use of "toxic" Chinese medicines is a major feature and advantage of TCM. "Toxic" Chinese medicines have unique clinical value and certain medication risk under the guidance of TCM theories such as compatibility for detoxification and treatment based on syndrome differentiation. In recent years, the safety events of Chinese medicines have occurred frequently, which has made the safety of Chinese medicine a public concern in China and abroad. However, limited by conventional cognitive laws and technical methods, basic research on toxicity of Chinese medicines fails to be combined with the clinical application. As a result, it is difficult to identify the clinical characteristics of, predict toxic and side effects of, or form a universal precise medication regimen for "toxic" Chinese medicines, which restricts the clinical application of them. In view of the problem that the toxicity of "toxic" Chinese medicines is difficult to be predicted and restricts the clinical application, the evidence-based research concept will provide new ideas for safe applcation of them in clinical practice. The integrated development of multiple disciplines and techniques in the field of big data and artificial intelligence will also promote the renewal and development of the research models for "toxic" Chinese medicines. Our team tried to propose the academic concept of evidence-based Chinese medicine toxicology and establish the data-intelligence research mode for "toxic" Chinese medicines and the intelligent risk prediction method for medicinal combination in the early stage, which provided methodological supports for solving the above problem. Thus, on the basis of summarizing the research status and problems of the clinical medication regimen of "toxic" Chinese medicines, our team took the evidence-based toxicology of TCM as the core concept, and tried to construct the multiple-evidence integrated evaluation and prediction method for "toxic" Chinese medicine, so as to guide the establishment of the non-toxic medication regimen of "toxic" Chinese medicines. Specifically, through the analysis of multivariate data obtained from the basic research, the evidence-based toxicology database of Chinese medicines and the individualized "toxicity-effect" intelligent prediction platform were built based on the disease-syndrome virtual patients, so as to identify the clinical characteristics and risks of "toxic" Chinese medicines and develop individualized medication regime. This study is expected to provide a methodological reference for the establishment of medication regimen and risk prevention strategy for "toxic" Chinese medicines. The method established in this study will bridge clinical research and basic research, enhance the transformation of the scientific connotation of attenuated compatibility, promote the development of evidence-based Chinese medicine toxicology, and ensure the clinical safety of "toxic" Chinese medicines.

Immunometabolism at the service of traditional Chinese medicine.

To enhance therapeutic efficacy and reduce adverse effects, ancient practitioners of traditional Chinese medicine (TCM) prescribe combinations of plant species/animal species and minerals designated "TCM formulae" developed based on TCM theory and clinical experience. TCM formulae have been shown to exert curative effects on complex diseases via immune regulation but the underlying mechanisms remain unknown at present. Considerable progress in the field of immunometabolism, referring to alterations in the intracellular metabolism of immune cells that regulate their function, has been made over the past decade. The core context of immunometabolism is regulation of the allocation of metabolic resources supporting host defense and survival, which provides a critical additional dimension and emerging insights into how the immune system and metabolism influence each other during disease progression. This review summarizes research findings on the significant association between the immune function and metabolic remodeling in health and disease as well as the therapeutic modulatory effects of TCM formulae on immunometabolism. Progressive elucidation of the immunometabolic mechanisms involved during the course of TCM treatment continues to aid in the identification of novel potential targets against pathogenicity. In this report, we have provided a comprehensive overview of the benefits of TCM based on regulation of immunometabolism that are potentially applicable for the treatment of modern diseases.

Tetrahydropalmatine triggers angiogenesis via regulation of arginine biosynthesis.

Over a short span of two decades, the central role of angiogenesis in the treatment of wound healing, diverse cancers, nerve defect, vascular injury and several ophthalmic diseases has become evident. Tetrahydropalmatine, as the index component of Corydalis yanhusuo W. T. Wang, is inseparable from protecting cardiovascular system, yet its role in angiogenesis has been poorly characterized. We have demonstrated the binding potential of THP and VEGFR2 using molecular docking based on the clinical experience of traditional Chinese medicine in the pretest study. Here, we identified tetrahydropalmatine (THP) as one proangiogenic trigger via regulation of arginine biosynthesis by pharmacological assays and DESI-MSI/GC-MS based metabolomics. First, the proangiogenic effects of THP were evaluated by quail chorioallantoic membrane test in vivo and multiple models of endothelial cells in vitro. According to virtual screening, the main mechanisms of THP (2/5 of the top terms with smaller p-value) were metabolic pathways. Hence, metabolomics was applied for the main mechanisms of THP and results showed the considerable metabolite difference in arginine biosynthesis (p < 0.05) altered by THP. Finally, correlated indicators were deteced using targeted metabolomics and pharmacological assays for validation, and results suggested the efficacy of THP on citrulline to arginine flux, arginine biosynthesis, and endothelial VEGFR2 expression sequentially, leading to the promotion of angiogenesis. Overall, this manuscript identified THP as the proangiogenic trigger with the potential to develop as pharmacological agents for unmet clinical needs.

A Urinary Metabolomics Analysis Based on UPLC-MS and Effects of Moxibustion in APP/PS1 Mice.

OBJECTIVE: Alzheimer's disease (AD) is a common neurodegenerative disorder with the symptoms of cognitive impairment and decreased learning and memory abilities. Metabolomics can reflect the related functional status and physiological and pathological changes in the process of AD. Moxibustion is a unique method in traditional Chinese medicine, which has been used in the treatment and prevention of diseases for thousands of years. METHODS: A total of 32 APP/PS1 mice were randomly divided into the model group, moxibustion group, moxa smoke group and smoke-free moxibustion group (n=8/group), using the random number table method, while eight C57BL/6 mice were used as the control group. The five groups were measured for 20 min/day, 6 days/week, for 4 weeks. After 4 weeks' experiment, all the mice were placed in metabolic cages to collect urine continuously for 24 hours, for UPLC-MS analysis. RESULTS: Principal component analysis (PCA) was used to identify the different metabolites among the five groups, and partial least squares discriminant analysis (PLS-DA) was performed to reveal the effects on the metabolic variance. Sixteen potential biomarkers were identified among the five groups, primarily related to amino acid metabolism, starch metabolism, sucrose metabolism, interconversion of pentose and glucuronate, and aminoacyl biosynthesis. There were 17 differences in the potential metabolites between the control and model groups, involving the metabolism of amino acid, purine, pyrimidine, nicotinic acid and nicotinamide, and biosynthesis of pantothenate and coenzyme A. Fifteen potential biomarkers were identified between the model and moxibustion groups, related to starch metabolism, sucrose metabolism, interconversion of pentose and glucuronate, glyoxylate, dicarboxylate anions and some amino acid metabolism. CONCLUSION: Moxibustion can regulate the metabolism of substance and energy by improving the synthesis and decomposition of carbohydrates and amino acids in APP/PS1 transgenic AD model mice.

Synergistic Effect of Berberine-Based Chinese Medicine Assembled Nanostructures on Diarrhea-Predominant Irritable Bowel Syndrome In Vivo.

Diarrhea-predominant irritable bowel syndrome (IBS-D) is one common chronic functional disease of the digestive system with limited treatments. The microbiota-gut-brain axis (MGBA) has a central function in the pathogeny of IBS-D, which includes the participation of many various factors, such as brain-gut peptides (BGPs), immune inflammation, and intestinal flora. Inspired by the drug combination in traditional Chinese medicine (TCM), our previous study discovered that berberine (BBR) and baicalin (BA) could form natural self-assemblies as BA-BBR nanoparticles (BA-BBR NPs) and showed synergistic effects against IBS-D. Here, we investigated the synergistic effects of BA-BBR NPs on IBS-D model mice induced by chronic restraint stress plus Senna alexandrina Mill decoction with the influence on MGBA. BA-BBR NPs showed the best therapeutic effect on improving visceral hypersensitivity and diarrhea on IBS-D model mice, compared with BBR, BA, and BA/BBR mixture. Furthermore, BA-BBR NPs significantly (P<0.05) reduced the levels of 5-hydroxytryptamine (5-HT), vasoactive intestinal polypeptide (VIP) and choline acety transferase (CHAT) in colon tissues or of serum from BGPs; it lowered the expressions of the nuclear factor kappa-B (NF-κB) in colon tissues and changed the levels of basophil granulocyte (BASO) and leukomonocyte (LYMPH) in whole blood from immune inflammation; it altered the intestinal flora of Bacteroidia, Deferribacteres, Verrucomicrobia, Candidatus_Saccharibacteria, and Cyanobacteria from intestinal flora. In conclusion, BA-BBR NPs, after forming the natural self-assembly between BBR and BA, promoted the synergistic effect on IBS-D mice than the sum of BBR and BA effects, based to the formation of self-assemblies rather than the simple mixing. It further proved that synergistic effect of BA-BBR NPs on IBS-D mice might be related to BGPs, immune inflammation, and intestinal flora from three important interrelated components of MGBA. This study will provide a novel idea for the interpretation of TCM compatibility theory and provide the basis for BA-BBR NPs as a medicinal plant-derived natural and efficient nanomaterial for clinical use.

BA-12 Inhibits Angiogenesis via Glutathione Metabolism Activation.

There is a need for an efficient and low-cost leading compound discovery mode. However, drug development remains slow, expensive, and risky. Here, this manuscript proposes a leading compound discovery strategy based on a combination of traditional Chinese medicine (TCM) formulae and pharmacochemistry, using a ligustrazine-betulinic acid derivative (BA-12) in the treatment of angiogenesis as an example. Blocking angiogenesis to inhibit the growth and metastasis of solid tumors is currently one recognized therapy for cancer in the clinic. Firstly, based on a traditional Prunella vulgaris plaster, BA-12 was synthesized according to our previous study, as it exhibited better antitumor activities than other derivatives on human bladder carcinoma cells (T24); it was then uploaded for target prediction. Secondly, the efficacy and biotoxicity of BA-12 on angiogenesis were evaluated using human umbilical vein endothelial cells (HUVECs), a quail chick chorioallantoic membrane, and Caenorhabditis elegans. According to the prediction results, the main mechanisms of BA-12 were metabolic pathways. Thus, multiple metabolomics approaches were applied to reveal the mechanisms of BA-12. Finally, the predictive mechanisms of BA-12 on glutathione metabolism and glycerophospholipid metabolism activation were validated using targeted metabolomics and pharmacological assays. This strategy may provide a reference for highly efficient drug discovery, with the aim of sharing TCM wisdom for unmet clinical needs.

Identification of a Quality Marker of Vinegar-Processed Curcuma Zedoaria on Oxidative Liver Injury.

Curcuma zedoaria (dry stenophora of Curcuma phaeocaulis Val., Curcuma kwangsiensis S. G. Lee et C. F. Liang, or Curcuma wenyujin Y. H. Chen et C.Ling) is a representative herb with clinical effects on liver diseases after being vinegar-processed. The crude Curcuma zedoaria and the processed Curcuma zedoaria (vinegar-boil) have been widely used as mixtures, but their equivalence has not been fully investigated. In this manuscript, quality markers of processed (vinegar-boil) Curcuma zedoaria were investigated by comparison of the compounds and hepatoprotective activities with the crude (three spices) ones. First, GC-MS-based untargeted metabolomics were applied to reveal the discriminatory components and discover potential markers. As a result, a total of six components were identified as potential markers. Then, the hepatoprotective activities were evaluated by dual cell damage models induced by a certain concentration of H2O2 or tertbutyl hydfroperoxide (t-BHP) (55 µM H2O2 or 40 µM t-BHP), which highlighted the potential of the processed Curcuma zedoaria on oxidative stress. Finally, epicurzerenone was identified as its quality marker on oxidative liver injury based on the above results and the cell-based biological assay. Overall, vinegar-processed Curcuma zedoaria was more suitable for the treatment of oxidative liver diseases, and epicurzerenone could be considered as its quality marker.

A systems pharmacology-oriented discovery of a new therapeutic use of the TCM formula Liuweiwuling for liver failure.

Multiple components of traditional Chinese medicine (TCM) formulae determine their treatment targets for multiple diseases as opposed to a particular disease. However, discovering the unexplored therapeutic potential of a TCM formula remains challenging and costly. Inspired by the drug repositioning methodology, we propose an integrated strategy to feasibly identify new therapeutic uses for a formula composed of six herbs, Liuweiwuling. First, we developed a comprehensive systems approach to enrich drug compound-liver disease networks to analyse the major predicted diseases of Liuweiwuling and discover its potential effect on liver failure. The underlying mechanisms were subsequently predicted to mainly attribute to a blockade of hepatocyte apoptosis via a synergistic combination of multiple effects. Next, a classical pharmacology experiment was designed to validate the effects of Liuweiwuling on different models of fulminant liver failure induced by D-galactosamine/lipopolysaccharide (GalN/LPS) or thioacetamide (TAA). The results indicated that pretreatment with Liuweiwuling restored liver function and reduced lethality induced by GalN/LPS or TAA in a dose-dependent manner, which was partially attributable to the abrogation of hepatocyte apoptosis by multiple synergistic effects. In summary, the integrated strategy discussed in this paper may provide a new approach for the more efficient discovery of new therapeutic uses for TCM formulae.

Untargeted Metabolomics Reveals Intervention Effects of Total Turmeric Extract in a Rat Model of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease. Currently, there are no recognized medical therapies effective for NAFLD. Previous studies have demonstrated the effects of total turmeric extract on rats with NAFLD induced by high-fat diet. In this study, serum metabolomics was employed using UHPLC-Q-TOF-MS to elucidate the underlying mechanisms of HFD-induced NAFLD and the therapeutic effects of TE. Supervised orthogonal partial least-squares-discriminant analysis was used to discover differentiating metabolites, and pathway enrichment analysis suggested that TE had powerful combined effects of regulating lipid metabolism by affecting glycerophospholipid metabolism, glycerolipid metabolism, and steroid hormone biosynthesis signaling pathways. In addition, the significant changes in glycerophospholipid metabolism proteins also indicated that glycerophospholipid metabolism might be involved in the therapeutic effect of TE on NAFLD. Our findings not only supply systematic insight into the mechanisms of NAFLD but also provide a theoretical basis for the prevention or treatment of NAFLD.

[Protective effects of Liuwei Wuling tablet on acute alcoholic-induced liver injury in mice].

The protective action and the relevant mechanism of Liuwei Wuling tablet on acute alcoholic hepatic injury in mice were investigated. All the C57BL/6 mice were divided randomly into 7 groups including blank, model, bifendate (150 mg•kg⁻¹, positive control) and experimental groups consisted of extremely low dose (0.1 g•kg⁻¹), low (0.5 g•kg⁻¹), upper (4 g•kg⁻¹) and high dose (8 g•kg⁻¹) of Liuwei Wuling tablet groups. The acute liver injury model was induced by modified method that the model, positive control and experimental groups were orally administrated 56% alcohol (6 g•kg⁻¹) twice at 12 hour intervals on the fifth day after drugs administration. After 12 hours, the mice were sacrificed to contribute blood and liver for biochemical and histological examinations. Compared with the model, the activities of ALT and AST in serum decreased significantly in different Liuwei Wuling tablet groups. Meanwhile, in liver tissue, the levels of TG, MDA, TNF-α and IL-1ß reduced obviously while the GSH and SOD activities showed markedly increase with a dose-dependent manner. Correspondingly, the microscopically pathological differences of the liver tissue observed by HE and oil red O staining indicated that the liver cell swelling, hydropic degeneration and lipid droplets formation induced by alcohol were significantly improved, which suggested the Liuwei Wuling tablet can reduce the liver injure. In conclusion, the Liuwei Wuling tablet had the protective effect on acute alcoholic hepatic injury which maybe depended on the mechanism of relieving lipid peroxidation, elevating antioxidant enzymes activity, inhibiting oxidative stress and reducing inflammation factors expression.

[Investigation of potential toxic factors for fleece-flower root： from perspective of processing methods evolution].

In recent years, the rapid growth of reports on fleece-flower root-caused liver damages has drawn wide attention of both at home and abroad, however, there were rare literature on toxicology of fleece-flower root in ancient Chinese medicine. But why there are so many reports on toxicology of fleece-flower root now compared with the ancient literature? As a typical tonic medicine, the clinical utility of fleece-flower root was largely limited by its standardization and reliability of processing methods in ancient Chinese medicine. The ancient processing methods of fleece-flower root emphasized nine times of steaming and nine times of drying, while the modern processes have been simplified into one time of steaming. Whether the differences between ancient and modern processing methods are the potential cause of the increased events of fleece-flower root-caused liver damages. We will make deep analysis and provide new clues and perspectives for the research on its toxicity. This article, therefore, would discuss the affecting factors and key problems in toxicity attenuation of fleece-flower root on the basis of sorting out the processing methods of fleece-flower root in ancient medical books and modern standards, in order to provide the reference for establishing specification for toxicity attenuation of fleece-flower root.

[Protective effects of oxymatrine against H2O2-induced damage in L02 cells].

To investigate the protective effects of oxymatrine (OMT) against H2O2-induced damage in L02 cells and research the mechanism,L02 cells were used as the research object. The oxidative stress model of L02 was established by hydrogen peroxide (H2O2). CCK-8 was used to detect the cell activation of L02 cells treated by different OMT. FCM (flow cytometry) assay was used to evaluate the cell proliferation of L02 cells treated by OMT. The apoptosis of L02 cells was detected using Annexin-V/7-AAD apoptosis detection kit. The level of ROS was detected by DCFH-DA fluorescence probe. The GSH-PX and SOD were detected by micro plate and colorimetric method. Results showed that when the concentration of OMT is between 6.25 and 100 mg•L⁻¹, it could promote the production of NADPH and strengthen the activity of GSH-PX and SOD to get rid of the ROS to protect the L02 cell from the apoptosis of L02 cell induced by H2O2.

[Precision medicine-oriented safety assessment strategy for traditional Chinese medicines: disease-syndrome-based toxicology].

Drug toxicity is commonly divided into intrinsic and idiosyncratic types. The former can be generally uncovered in the preclinical safety evaluation stage by conventional toxicological experiments, while the latter is usually found only in the clinical evaluation stage, which is the main cause of severe adverse reactions and withdrawal of post-marketing drugs. Assessment and prediction of idiosyncratic toxicity is a challenging problem worldwide, and is an essential in the development of translational toxicology and precision medicine. Since traditional Chinese medicines (TCMs) have been applied for thousands of years with long experience in clinical efficacy and safety, idiosyncratic toxicity is regarded as an important factor for traditional "non-toxic" medicines and is associated with multiple individual states including different diseases, syndromes, habitus, etc. However, these individual conditions related to disease are often difficult to be resolved in conventional toxicological experiments, leading to insufficient translation of the experimental results into clinical application. We took an approach of systematic analysis of the differences and similarities in toxic property, medication rule and evaluating requirement between TCMs and chemical synthetic medicines. We present a novel and clinic-associated safety assessment strategy, namely as "disease-syndrome-based toxicology", for TCMs. The strategy is able to access the relativity, susceptibility and controllability of the toxicity of TCMs. The new strategy provides a theoretical and methodological guidance to practice and development of the TCM in favor of precision medicine.