Major Indole Alkaloids in Evodia Rutaecarpa: The Latest Insights and Review of Their Impact on Gastrointestinal Diseases.

Evodia rutaecarpa, the near-ripe fruit of Euodia rutaecarpa (Juss.) Benth, Euodia rutaecarpa (Juss.) Benth. var. officinalis (Dode) Huang, or Euodia rutaecarpa (Juss.) Benth. var. bodinieri (Dode) Huang, is a famous herbal medicine with several biological activities and therapeutic values, which has been applied for abdominalgia, abdominal distension, vomiting, and diarrhea as a complementary and alternative therapy in clinic. Indole alkaloids, particularly evodiamine (EVO), rutaecarpine (RUT), and dedhydroevodiamine (DHE), are received rising attention as the major bioactivity compounds in Evodia rutaecarpa. Therefore, this review summarizes the physicochemical properties, pharmacological activities, pharmacokinetics, and therapeutic effects on gastrointestinal diseases of these three indole alkaloids with original literature collected by PubMed, Web of Science Core Collection, and CNKI up to June 2023. Despite sharing the same parent nucleus, EVO, RUT, and DHE have different structural and chemical properties, which result in different advantages of biological effects. In their wide range of pharmacological activities, the anti-migratory activity of RUT is less effective than that of EVO, and the neuroprotection of DHE is significant. Additionally, although DHE has a higher bioavailability, EVO and RUT display better permeabilities within blood-brain barrier. These three indole alkaloids can alleviate gastrointestinal inflammatory in particular, and EVO also has outstanding anti-cancer effect, although clinical trials are still required to further support their therapeutic potential.

[Core connotation of compatibility of Aconiti Lateralis Radix Praeparata-Glycyrrhizae Radix et Rhizoma herb pair under physiological/ pathological conditions based on metabolomics and network pharmacology].

This study aims to explore the core connotation of the compatibility of Aconiti Lateralis Radix Praeparata(Fuzi)-Glycyrrhizae Radix et Rhizoma(Gancao) herb pair under physiological and pathological conditions. The biochemical indicators of serum/myocardial tissue, pathological changes of the myocardial tissue, and serum metabolic profiles of normal rats and heart failure model rats treated with Fuzi Decoction and Fuzi Gancao Decoction were determined. Network pharmacology and metabolomics were employed to establish the metabolite-target-pathway network for Glycyrrhizae Radix et Rhizoma in enhancing the efficacy and reducing the toxicity of Aconiti Lateralis Radix Praeparata, Western blotting was employed to verify the representative pathways in the network. The results showed that both decoctions lowered the levels of creatine kinase and other indicators and mitigate myocardial pathological injury in model rats. However, they caused the abnormal rises in creatine kinase and other indicators and myocardial pathological injury in normal rats. The results indicated that the compatibility reduced the toxicity in normal rats and enhanced the efficacy in model rats. The results of metabolomics showed that Fuzi Gancao Decoction recovered more metabolites in model rats and had weaker effect on interfe-ring with the metabolites in normal rats than Fuzi Decoction. The association analysis showed that the network of Glycyrrhizae Radix et Rhizoma enhancing the efficacy of Aconiti Lateralis Radix Praeparata involved 112 metabolites, 89 targets, and 15 pathways, including calcium and cAMP signaling pathways. The network of Glycyrrhizae Radix et Rhizoma reducing the cardiotoxicity of Aconiti Lateralis Radix Praeparata involved 36 metabolites, 59 targets, and 11 pathways, including adrenergic signaling and tricarboxylic acid cycle in cardiomyocytes. The experimental results of protein expression verified the reliability of the association analysis. This study demonstrated that the core connotation of the herb pair of Aconiti Lateralis Radix Praeparata-Glycyrrhizae Radix et Rhizoma changed under physio-logical and pathological states, and the compatibility results of enhancing efficacy and reducing toxicity were achieved with different metabolic pathways and biological processes.

Tou Nong powder obstructs ulcerative colitis through the regulation of NF-κB/NLRP3/Caspase-1/GSDMD inflammasome pyroptotic pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Tou Nong Powder (TNP), a classical Chinese medicinal formula originated from the Chinese Ming Dynasty, has been applied to treat skin ulcers in patients with deficient constitutions. According to theory of traditional Chinese medicine, colonic ulcers share similar pathological conditions with skin ulcers, and consequently, TNP has been applied to ulcerative colitis (UC) safely and effectively. AIM OF STUDY: To investigate whether TNP obstructs 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced enteric inflammation through regulation of NLRP3 inflammasome and attenuating enteric pyroptosis. MATERIALS AND METHODS: Network pharmacology and UPLC-Q-TOF/MS were operated to identify compounds and pharmacological potential targets. The therapeutic effects of TNP were assessed on TNBS induced colitis via general symptoms (disease activity index, colonic weight and length) and histopathological observation. The NF-κB/NLRP3/Caspase-1/GSDMD signaling pathway regulation was investigated by Western blot and real time reverse transcription polymerase chain reaction (RT-qPCR). RESULTS: TNP ameliorates the disease activity index, reverses the increase of colonic weight increase, alleviates colonic shortening and colonic histopathological injury. A decrease in tumor necrosis factor α (TNF-α), diamine oxidase (DAO), intercellular adhesion molecule-1 (ICAM-1), and endo-toxin (ET) were investigated in peripheral circulation. Moreover, TNP significantly obstructed the NF-κB/NLRP3/Caspase-1/GSDMD signaling pathway. CONCLUSION: TNP displays a promising therapeutic effect on UC via suppressing NF-κB/NLRP3/Caspase-1/GSDMD signaling pathway and reducing the expression of IL-1ß and IL-18.

The application of Tong-fu therapeutic method on ulcerative colitis: A systematic review and meta-analysis for efficacy and safety of rhubarb-based therapy.

Background: Tong-fu therapeutic method (TFTM) is a traditional Chinese medicine treatment method for ulcerative colitis, which is a novel treatment strategies and have purgative effect. As the most representative medicinal of TFTM, Rhubarb has been reported to have a therapeutic impact on ulcerative colitis by regulating intestinal flora, anti-inflammation, and improving intestinal microcirculation. Although rhubarb has been widely used in Chinese medicine for the treatment of ulcerative colitis, the appropriate protocol is still demanded to its rational use in clinic, which promoted to evaluate the efficacy and safety for rhubarb-based therapy on ulcerative colitis. Method: Clinical trials were searched through PubMed, Cochrane Library, Web of Science, Excerpta Medica Database, Chinese National Knowledge Infrastructure, WAN FANG Database, Chinese Scientific Journal Database, and Chinese Biomedical Literature Database. The subgroup analyses were performed with three groups: medication, course of treatment, and route of administration. The statistical analyses were performed on Review Manager software (version 5.4.1). Results: A total of 2, 475 patients in 30 original studies were analyzed in this article. It was found that rhubarb-based therapy could increase clinical efficacy and reduce the recurrence rate. Subgroup analyses showed that rhubarb-based therapy was more effective than 5-aminosalicylic acid or sulfasalazine alone. In addition, the hypercoagulable state of ulcerative colitis could be ameliorated by decreasing platelet (PLT) and fibrinogen (FIB), and increasing prothrombin time (PT) significantly. Moreover, C-reaction protein (CRP), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and IL-1ß expression were significantly reduced, while IL-10 production was increased, which mediated the alleviation of intestinal inflammation stress. Conclusion: Rhubarb-based therapy could effectively improve ulcerative colitis. Of note, the rhubarb-based medicinal formulas combined with 5-ASA or SASP are more effective than the 5-ASA or SASP alone. In addition, although rhubarb has side effect, the results of our analysis showed that rhubarb-based therapy did not exhibit significant side effects. This means it has a high safety profile in clinical use. Moreover, the use of rhubarb-based therapy is recommend to use within 1-13 weeks or 3 months via administered orally or by enema, which is contributes to ensure the curative effect and avoid its toxic and side effects. As an important case of TFTM, rhubarb-based therapy provides evidence for the practical application of TFTM.

The Evaluation of Xiaozeng Qianggu Tablets for Treating Postmenopausal Osteoporosis via up-Regulated Autophagy.

Objective: Postmenopausal osteoporosis (PMOP) is a common age-associated disease in the life course. Clinically, Xiaozeng Qianggu Tablets (XQT) have a potent therapeutic effect on the PMOP. However, the bioactive components and the mechanism of XQT underlying the PMOP treatment were unclear and it should be explored to discover the scientific connotation in traditional medical practice. Methods: The components in XQT were identified by UPLC-Q-TOF/MS. The animal model of PMOP was established by surgical ovariectomy in the female Sprague-Dawley rats. After treatment of XQT, the therapeutic effect was assessed by the determination of bone metabolism biomarkers in serum and histopathological examination. The effect of XQT on the autophagy and bone micro-situation were tested using western blot, RT-qPCR, and transmission electron microscope. Results: There were 27 compounds identified in XQT, including catalpol, monotropein, verbascoside, cryptochlorogenic acid, 5,7-dihydroxychromone 7-rutinoside, biorobin, and so on. The bone metabolism markers (alkaline phosphatase, bone alkaline phosphatase, procollagen type I intact N-terminal propeptide, cross-linked carboxy-terminal telopeptide of type I collagen, and tartrate-resistant acid phosphatase) were significantly increased in the PMOP rats and reversed by XQT administration. Moreover, the width of bone trabeculae and the ratio of the area of calcium deposition to bone trabeculae were also improved after treating the middle dose of XQT. Meanwhile, the bone micro-structure was improved by XQT. The mRNA and protein expression of unc-51 like kinase 1, beclin-1, and microtubule-associated protein 1B-light chain 3 in PMOP rats were down-regulated and up-regulated by XQT administration. Conclusions: The compounds in XQT, including catalpol, monotropein, verbascoside cryptochlorogenic acid, and so on, were valuable for further pharmacy evaluation. The pathological changes and bone micro-structure were improved by XQT, and the down-regulated autophagy level was also restored, which suggested a potent effect of XQT on treating PMOP, corresponding to its clinic use.

Corrigendum: The Communication Between Intestinal Microbiota and Ulcerative Colitis: An Exploration of Pathogenesis, Animal Models, and Potential Therapeutic Strategies.

[This corrects the article DOI: 10.3389/fmed.2021.766126.].

Efficacy and Safety of Probiotics Combined With Traditional Chinese Medicine for Ulcerative Colitis: A Systematic Review and Meta-Analysis.

Background: The combination of probiotics and traditional Chinese medicine (TCM) is a prospective therapy for ulcerative colitis (UC), and its efficacy and safety need to be urgently evaluated. Objective: This study aims to comprehensively assess the efficacy and safety of probiotics combined with TCM for the treatment of UC. Methods: The Pubmed, EMBASE, Cochrane library, China Academic Journals (CNKI), Wan-fang database, Chinese biomedical literature service system (CBM), and Chinese Science and Technology Journals (CQVIP) were searched. Subgroup analysis were designed in accordance with different control drugs, treatment courses, and types of probiotics. The Review Manager software (version 5.4.1) was utilized for statistical analysis. Results: 14 original studies containing 1,154 patients were analyzed and showed that probiotics with TCM was more effective than 5-aminosalicylic acid (5-ASA), probiotics or TCM used individually. Moreover, probiotics combined with TCM could inhibit the intestinal inflammation, reduce the recurrence rate and the incidence of adverse events. The subgroup analysis showed that a mixture of different probiotics was more effective than a single strain. Conclusion: It is suggested that probiotics combined with TCM could effectively control clinical symptoms, inhibit intestinal inflammatory response, and finally slow down the disease progress and reduce the disease recurrence with less adverse events. The mixture of different probiotics used in conjunction with individually tailored TCM is a potential clinical strategy for UC.

Corrigendum: The Therapeutic Principle of Combined Strengthening Qi and Eliminating Pathogens in Treating Middle-Advanced Primary Liver Cancer: A Systematic Review and Meta-Analysis.

[This corrects the article DOI: 10.3389/fphar2021.714287.].

The Communication Between Intestinal Microbiota and Ulcerative Colitis: An Exploration of Pathogenesis, Animal Models, and Potential Therapeutic Strategies.

Ulcerative Colitis (UC) is a chronic inflammatory bowel disease. The prolonged course of UC and the lack of effective treatment management make it difficult to cure, affecting the health and life safety of patients. Although UC has received more attention, the etiology and pathogenesis of UC are still unclear. Therefore, it is urgent to establish an updated and comprehensive understanding of UC and explore effective treatment strategies. Notably, sufficient evidence shows that the intestinal microbiota plays an important role in the pathogenesis of UC, and the treating method aimed at improving the balance of the intestinal microbiota exhibits a therapeutic potential for UC. This article reviews the relationship between the genetic, immunological and microbial risk factors with UC. At the same time, the UC animal models related to intestinal microbiota dysbiosis induced by chemical drugs were evaluated. Finally, the potential value of the therapeutic strategies for restoring intestinal microbial homeostasis and treating UC were also investigated. Comprehensively, this study may help to carry out preclinical research, treatment theory and methods, and health management strategy of UC, and provide some theoretical basis for TCM in the treatment of UC.

The Therapeutic Principle of Combined Strengthening Qi and Eliminating Pathogens in Treating Middle-Advanced Primary Liver Cancer: A Systematic Review and Meta-Analysis.

Background: The combination of strengthening Qi and eliminating pathogens is an available therapeutic principle in traditional Chinese medicine (TCM) for primary liver cancer (PLC) at middle-advanced stage. However, there is a lack of reasonable evidence to support the proper application of this therapeutic principle. This meta-analysis aims to evaluate the efficacy and safety of Chinese medicinal formulas (CMFs), including two subgroup analyses of the principle of strengthening Qi and eliminating pathogens. Method: Clinical trials were obtained through searching of EMBASE, Web of Science, PubMed, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang Database, Chinese Scientific Journal Database, Chinese Biomedical Literature Database, and two clinical trial registries. The randomized controlled trials with the combination of CMFs and transcatheter arterial chemoembolization (TACE) in the experiment group were acceptable, in contrast to the TACE alone in the control group. The statistics analysis was performed on Review Manager 5.4. Results: A total of eligible 24 trials were accessed in this work. Overall, CMFs could improve the survival duration of 6 months, 1 year, and 2 years, Karnofsky Performance Status, tumor objective response rate (ORR), AFP, and symptom. In the subgroup analysis, trials complying with the principle of single strengthening Qi did not show any significant difference in increasing tumor ORR. Meanwhile, the principle of combined strengthening Qi and eliminating pathogens was uncertain in improving symptoms and 1-year and 2-year survival time. In addition, the outcome indexes of ALT and AST were heterogeneous. In last, the total occurrence of adverse events could not be reduced via using CMFs. Patients treated with CMFs exhibited liver injury, fever, and white blood cell decline, with mild events occurring more frequently and severe events occurring less. Conclusion: CMFs are an effective treatment method to cure PLC at the middle-advanced stage. Adopting the principle of single strengthening Qi presents better efficacy in the long term by prolonging the survival duration. Following the principle of combined strengthening Qi and eliminating pathogens could be more beneficial to patients in short term by lessening the tumor size. CMFs have the advantage of reducing certain serious adverse events.

Targeted therapy of rheumatoid arthritis via macrophage repolarization.

The polarization of macrophages plays a critical role in the physiological and pathological progression of rheumatoid arthritis (RA). Activated M1 macrophages overexpress folate receptors in arthritic joints. Hence, we developed folic acid (FA)-modified liposomes (FA-Lips) to encapsulate triptolide (TP) (FA-Lips/TP) for the targeted therapy of RA. FA-Lips exhibited significantly higher internalization efficiency in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells than liposomes (Lips) in the absence of folate. Next, an adjuvant-induced arthritis (AIA) rat model was established to explore the biodistribution profiles of FA-Lips which showed markedly selective accumulation in inflammatory paws. Moreover, FA-Lips/TP exhibited greatly improved therapeutic efficacy and low toxicity in AIA rats by targeting M1 macrophages and repolarizing macrophages from M1 to M2 subtypes. Overall, a safe FA-modified liposomal delivery system encapsulating TP was shown to achieve inflammation-targeted therapy against RA via macrophage repolarization.

Houttuynia cordata Thunb: An Ethnopharmacological Review.

Houttuynia cordata Thunb (H. cordata; Saururaceae) is widely distributed in Asian regions. It plays an important role in traditional health care and disease treatment, as its aboveground stems and leaves have a long medicinal history in China and are used in the treatment of pneumonia and lung abscess. In clinical treatment, it can usually be combined with other drugs to treat dysentery, cold, fever, and mumps; additionally, H. cordata is an edible plant. This review summarizes detailed information on the phytochemistry and pharmacological effects of H. cordata. By searching the keywords "H. cordata and lung", "H. cordata and heart", "H. cordata and liver", and "H. cordata and inflammation" in PubMed, Web of Science and ScienceDirect, we screened out articles with high correlation in the past ten years, sorted out the research contents, disease models and research methods of the articles, and provided a new perspective on the therapeutic effects of H. cordata. A variety of its chemical constituents are characteristic of medicinal plants, the chemical constituents were isolated from H. cordata, including volatile oils, alkaloids, flavonoids, and phenolic acids. Flavonoids and volatile oils are the main active components. In pharmacological studies, H. cordata showed organ protective activity, such as reducing the release of inflammatory factors to alleviate lung injury. Moreover, H. cordata regulates immunity, enhances the immune barriers of the vagina, oral cavity, and intestinal tract, and combined with the antibacterial and antiviral activity of its extract, effectively reduces pathogen infection. Furthermore, experiments in vivo and in vitro showed significant anti-inflammatory activity, and its chemical derivatives exert potential therapeutic activity against rheumatoid arthritis. Antitumour action is also an important pharmacological activity of H. cordata, and studies have shown that H. cordata has a notable effect on lung tumour, liver tumour, colon tumour, and breast tumour. This review categorizes the biological activities of H. cordata according to modern research papers, and provides insights into disease prevention and treatment of H. cordata.

Network Pharmacology-Based Analysis of the Underlying Mechanism of Huajiao for Pain Relief.

OBJECTIVE: Pain is a common symptom among patients, and pain management is an important clinical practice topic. The mechanism of Huajiao (HJ; Zanthoxylum bungeanum Maxim.) and its effective components for treating pain was explored using network pharmacology and molecular docking to verify its pain relief function in traditional medical practice. METHODS: HJ's components were collected via the Traditional Chinese Medicine Systems Pharmacology platform and published studies. HJ-associated target proteins were predicted using the drug similarity rule via Swiss Target Prediction. Online Mendelian Inheritance in Man was used to search for pain-related genes and proteins, and the Database of Interacting Proteins was used to obtain the human interactive target proteins. The compound-target-disease network of HJ for pain relief was constructed with protein-protein interaction networks. The obtained target proteins were uploaded on the Database for Annotation, Visualization, and Integrated Discovery to annotate, visualize, and integrally discover the related signaling pathway, and semiflexible molecular docking by Autodock Vina was applied to verify the potential mechanism. RESULTS: A total of 157 molecules in HJ were obtained, and the top 20 active components or active groups were mainly focused on the amide alkaloids (e.g., [6RS]-[2E,7E,9E]-6-hydroxy-N-[2-hydroxy-2-methylpropyl]-11-oxo-2,7,9-dodecatrienamide and [2E,7E,9E]-N-[2-hydroxy-2-methylpropyl]-11-ethoxy-6-hydroxy-dodeca-2,7,9-trienamide). Also, the 66 main targets were filtered from 746 predicted targets and 928 pain-related targets through module Network Analyzer in Cytoscape 3.6.0. Finally, there were 3 critical signaling pathways, including mitogen-activated protein kinase, phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin, and IκB kinase-nuclear factor κB-cyclooxygenase 2 based on integrated discovery with 54 enriched signaling pathways. CONCLUSIONS: HJ is used as a pain relief and has multicomponents, multitargets, and multiapproaches. Amide alkaloids are important substance bases, and HJ is more suitable for treating inflammatory pain.

Molecular basis of neurophysiological and antioxidant roles of Szechuan pepper.

The balance between anti- and pro-oxidant activities is of great important to maintain the biochemical and physiological homeostasis in the human body. Developing new therapeutic strategies to reduce health risks caused by free radicals has always been research focus over the past decades. Szechuan pepper, a characteristic pungent-flavored spice in Sichuanese cuisine, recently attracts the attention of researchers for its widespread therapeutic effects on acute and chronic diseases. The plant produces the innocuous 'tingling and numbing' sensations across the oral cavity by stirring specific neuron types, which are mechanically distinct from those excited by capsaicin. Furthermore, the extracts or the compounds of Szechuan pepper are biochemically proven to possess strong antioxidant activities that could scavenge free radicals and inhibit overactive peroxidase system in pathological models. Herein, the review emphasizes the molecular basis underlying the neurophysiological and antioxidant activities of the plant by a comprehensive analysis of various signaling pathways in disease models treated by Szechuan pepper. Further, we performed a broadening analysis to unearth potential signaling pathways associated with the antioxidant roles of the plant.

Tou Nong San Attenuates Inflammation in TNBS-IBD Model by Inhibiting NF-κB Signaling Pathway.

The incidence of inflammatory bowel disease (IBD), which predominantly comprises Crohn's disease and ulcerative colitis, is increasing worldwide. However, the treatment of IBD still faces great challenges. The involved NF-κB is the main signaling pathway in human IBD and thus is a prime target. There is abundant evidence that Tou Nong San (TNS), which is a traditional Chinese medicinal decoction used for treating sores and carbuncles, has a positive effect on the inflammation. This study investigated the effects of oral administration of TNS on colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) and the underlying mechanism(s). Quality control of the major compounds in TNS was performed by high-performance liquid chromatography, and six chemical constituents were identified in aqueous extracts. TNS led to improvements in weight loss and water and food intake in rats. The macroscopic and microscopic scores of rat tissues greatly decreased. Protein and mRNA levels of proinflammatory cytokines, including interleukin-17 (IL-17), tumour necrosis factor-α, IL-1ß, and IL6, involved in the NF-κB signaling pathway were greatly reduced. The results suggest that the anti-inflammatory effect of TNS is associated with the regulation of the NF-κB signaling pathway, which contributes to the network pharmacological effect of TNS on human IBD in clinical practice.

Combination of chemical fingerprint and bioactivity evaluation to explore the antibacterial components of Salvia miltiorrhizae.

The aim of this study was to explore the possible antibacterial components of Salvia miltiorrhizae on Pseudomonas aeruginosa using a combination of chemical fingerprint and bioactivity evaluation. The chemical fingerprints of 32 batches of S. miltiorrhizae samples from different sources were developed using high-performance liquid chromatography with diode array detection, and then were evaluated by similarity analysis and hierarchical clustering analysis. Anti-P. aeruginosa activity was determined by microcalorimetry. Some crucial thermokinetic parameters obtained from the heat-flow power-time curves of P. aeruginosa growth in the absence or presence of these S. miltiorrhizae samples were evaluated using principal component analysis. Thereafter, multiple linear regression analysis was used to analyze the fingerprint-activity relationship between the chemical fingerprints and anti-P. aeruginosa activity. This established the related equation between the inhibition ratio (I, %) of S. miltiorrhizae samples on P. aeruginosa and the peak areas of the common peaks. The results showed that the 32S. miltiorrhizae samples could be grouped into three clusters according to their chemical fingerprints and anti-P. aeruginosa activities. Protocatechualdehyde, salvianolic acid B, together with three unidentified compounds might be the major components that contributed largely to the antibacterial properties of S. miltiorrhizae and should be the focus of S. miltiorrhizae quality control. Thus, this study provided a preferred way for exploring the bioactive components of medicinal plants.

The protective effects of compatibility of Aconiti Lateralis Radix Praeparata and Zingiberis Rhizoma on rats with heart failure by enhancing mitochondrial biogenesis via Sirt1/PGC-1α pathway.

Aconiti Lateralis Radix Praeparata ("Fuzi" in Chinese) in combination with Zingiberis Rhizoma ("Ganjiang" in Chinese) is commonly applied for the treatment of heart failure for thousands of years in China. However, its therapeutic mechanism is still poorly defined. This study aimed to investigate whether the compatibility of Fuzi and Ganjiang can protect rats with acute heart failure by enhancing mitochondrial biogenesis via Sirt1/PGC-1α signaling pathway. Hemodynamic parameters, including heart rate and left ventricular maximal rate of pressure rise and decline, were recorded in rats with acute heart failure induced by Propafenone hydrochloride. The serum levels of cardiac enzymes, including creatine kinase, lactate dehydrogenase, brain natriuretic peptide and cardiac troponin T, were also determined. The gene and protein levels of Sirtuin 1 (Sirt1), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and their downstream transcription factors were measured as well. The results indicated that Fuzi-Ganjiang herbal couple provided more significant benefits by restoring the left ventricular function and cardiac enzyme activities in comparison with their single use. Moreover, this herbal couple possessed a significant cardio-protection by increasing both gene and protein levels of Sirt1 and PGC-1α. In conclusion, the compatibility of Fuzi and Ganjiang had better therapeutic effect than their single use against failing heart, and the underlying mechanisms were partially through increasing mitochondrial biogenesis via Sirt1/PGC-1α pathway.

Evaluation of the Antibacterial Effects of Flavonoid Combination from the Leaves of Dracontomelon dao by Microcalorimetry and the Quadratic Rotary Combination Design.

Skin infectious disease is a common public health problem due to the emergence of drug-resistant bacteria caused by the antibiotic misuse. Dracontomelon dao (Blanco) Merr. et Rolfe, a traditional Chinese medicine, has been used for the treatment of various skin infectious diseases over 1000 of years. Previous reports have demonstrated that the leaves of D. dao present favorable antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtitles. The flavonoids are the main components of the ethyl acetate extract of D. dao leaf. However, the correlation between flavonoids and antibacterial activities is yet to be determined. In this study, the combined antibacterial activities of these flavonoids were investigated. Three samples with the different concentrations of flavonoids (S1-S3) were obtained. By microcalorimetric measurements, the results showed that the IC50 value of S2 was lower than those of S1 and S3. The contents of main flavonoids (including Luteolin, L-Epicatechin, Cianidanol, and Quercetin) in S1-S3 were various, confirmed by the method of the Ultra High Performance Liquid Chromatography (UPLC). Based on the method of quadratic general rotary unitized design, the antibacterial effect of single flavonoid, and the potential synergistic effects between Luteolin and Quercetin, Luteolin and Cianidanol were calculated, which were also proved by microcalorimetric analysis. The antibacterial activities of main flavonoids were Luteolin > Cianidanol > Quercetin > L-Epicatechin. Meanwhile, the synergistic effects of Luteolin and Cianidanol (PL+C = 1.425), Quercetin and Luteolin (PL+Q = 1.129) on anti-microbial activity were validated. Finally, we found that the contents of Luteolin, L-Epicatechin, Cianidanol, Quercetin were 1061.00-1061.00, 189.14-262.86, 15,990.33-16,973.62, 6799.67-7662.64 ng·ml-1 respectively, with the antibacterial rate over 60.00%. In conclusion, this study could provide reference for quality evaluation and pharmacodynamics research of D. dao.

Spectrum-Effect Relationships Between Chemical Fingerprints and Antibacterial Effects of Lonicerae Japonicae Flos and Lonicerae Flos Base on UPLC and Microcalorimetry.

The traditional Chinese medicines Lonicerae Japonicae Flos (LJF, Jinyinhua in Chinese) and Lonicerae Flos (LF, Shanyinhua in Chinese) refer to the flower buds of five plants belonging to the Caprifoliaceae family. Until 2000, all of these were officially listed as a single item, LJF (Jinyinhua), in the Chinese Pharmacopoeia. However, there have recently been many academic controversies concerning the separation and combination of LJF and LF in administrative regulation. Till now there has been little work completed evaluating the relationships between biological activity and chemical properties among these drugs. Microcalorimetry and UPLC were used along with principal component analysis (PCA), hierarchical cluster analysis (HCA), and canonical correlation analysis (CCA) to investigate the relationships between the chemical ingredients and the antibacterial effects of LJF and LF. Using multivariate statistical analysis, LJF and LF could be initially separated according to their chemical fingerprints, and the antibacterial effects of the two herbal drugs were divided into two clusters. This result supports the disaggregation of LJF and LF by the Pharmacopoeia Committee. However, the sample of Lonicera fulvotomentosa Hsu et S. C. Cheng turned out to be an intermediate species, with similar antibacterial efficacy as LJF. The results of CCA indicated that chlorogenic acid and 3,4-Dicaffeoylquinic acid were the major components generating antibacterial effects. Furthermore, 3,4-Dicaffeoylquinic acid could be used as a new marker ingredient for quality control of LJF and LF.

Metabolomics Coupled with Multivariate Data and Pathway Analysis on Potential Biomarkers in Cholestasis and Intervention Effect of Paeonia lactiflora Pall.

BACKGROUND: The dried root of Paeonia lactiflora Pall. (PLP) is a classical Chinese herbal medicine that has been used to treat hepatic disease for 1000s of years. Our previous work suggested that PLP can be used to treat hepatitis with severe cholestasis. This study explored the mechanism by which PLP affects ANIT-induced cholestasis in rats using a metabolomics approach. METHODS: The effects of PLP on serum indices (TBIL, DBIL, AST, ALT, ALP, and TBA) and the histopathology of the liver were analyzed. Moreover, UHPLC-Q-TOF was performed to identify the possible effect of PLP on metabolites. The pathway analysis was conducted to illustrate the pathways and network by which PLP treats cholestasis. RESULT: High-dose PLP remarkably down-regulated the serum indices and alleviated histological damage to the liver. Metabolomics analyses showed that the therapeutic effect of high-dose PLP is mainly associated with the regulation of several metabolites, such as glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, L(D)-arginine, and L-tryptophan. A pathway analysis showed that the metabolites were related to bile acid secretion and amino acid metabolism. In addition, the significant changes in bile acid transporters also indicated that bile acid metabolism might be involved in the therapeutic effect of PLP on cholestasis. Moreover, a principal component analysis indicated that the metabolites in the high-dose PLP group were closer to those of the control, whereas those of the moderate dose or low-dose PLP group were closer to those of the ANIT group. This finding indicated that metabolites may be responsible for the differences between the effects of low-dose and moderate-dose PLP. CONCLUSION: The therapeutic effect of high-dose PLP on cholestasis is possibly related to regulation of bile acid secretion and amino acid metabolism. Moreover, these findings may help better understand the mechanisms of disease and provide a potential therapy for cholestasis.