ABSTRACT
Astragali Radix is a significant traditional Chinese medication, and has a long history of clinical application in the treatment of diabetes mellitus (DM) and its complications. AS-IV is an active saponin isolated from it. Modern pharmacological study shows that AS-IV has anti-inflammatory, anti-oxidant and immunomodulatory activities. The popular inflammatory etiology of diabetes suggests that DM is a natural immune and low-grade inflammatory disease. Pharmacological intervention of the inflammatory response may provide promising and alternative approaches for the prevention and treatment of DM and its complications. Therefore, this article focuses on the potential of AS-IV in the treatment of DM from the perspective of an anti-inflammatory molecular basis. AS-IV plays a role by regulating a variety of anti-inflammatory pathways in multiple organs, tissues and target cells throughout the body. The blockade of the NF-κB inflammatory signaling pathway may be the central link of AS-IV's anti-inflammatory effect, resulting in a reduction in the tissue structure and function damage stimulated by inflammatory factors. In addition, AS-IV can delay the onset of DM and its complications by inhibiting inflammation-related oxidative stress, fibrosis and apoptosis signals. In conclusion, AS-IV has therapeutic prospects from the perspective of reducing the inflammation of DM and its complications. An in-depth study on the anti-inflammatory mechanism of AS-IV is of great significance for the effective use of Chinese herbal medicine and the promotion of its status and influence on the world.
Subject(s)
Diabetes Mellitus , Saponins , Humans , Diabetes Mellitus/drug therapy , Saponins/pharmacology , Saponins/therapeutic use , Saponins/chemistry , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Inflammation/drug therapy , AntioxidantsABSTRACT
BACKGROUND: Berberine has been shown in clinical studies to have many health benefits, including anti-inflammatory and antioxidant properties, along with gut-flora balancing properties. However, its clinical efficacy is hindered by its low oral bioavailability and rapid metabolism. PURPOSE: This study aims to identify the berberine metabolites' forms and characterize their biodistribution patterns in and out of HepG2 cells. METHODS: The qualitative analysis of metabolites of berberine in HepG2 cells was performed using the LC/MSn-IT-TOF method. Subsequent cellular pharmacokinetics characterization of intracellular and extracellular berberine and its metabolites was performed by LC-MS/MS analysis. RESULTS: Berberine's metabolites of phase I metabolism were demethyleneberberine, jatrorrhizine, columbamine, berberrubine, etc., while its phase II metabolites were sulfate and glucuronide conjugates of phase I metabolites. Among the phase I metabolites of berberine, jatrorrhizine+columbamine accounted for over two-thirds of the total, followed by demethyleneberberine, which accounted for about a quarter. The intracellular demethyleneberberine is 25.14 times more enriched than extracellular demethyleneberberine. On the other hand, jatrorrhizine+columbamine and berberrubine were primarily distributed extracellularly, and their extracellular concentrations were 7.13 times and 15.61 times of their intracellular concentrations, respectively. Berberine metabolites produced in phase II metabolism are predominantly sulfate conjugates. CONCLUSION: Our results show that demethyleneberberine is highly concentrated intracellularly in HepG2, possibly because it is an essential metabolite of berberine that likely contributes to berberine's efficacy. In light of our findings, berberine's poor plasma concentration-effectiveness characteristics have been partially explained.
Subject(s)
Berberine , Berberine/pharmacology , Chromatography, Liquid , Hep G2 Cells , Humans , Sulfates , Tandem Mass Spectrometry , Tissue DistributionABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Zuojin Pill, a traditional poly-herbal drug, comprises Coptis chinensis Franch - Tetradium ruticarpum (A. Juss.) T.G. Hartley (6:1). The significant quantity of alkaloids found in the participating herbs is a key aspect of the Zuojin Pill. According to traditional Chinese medicine (TCM), these numerous alkaloidal compounds within Zuojin Pill have various essential therapeutic effects. AIM OF THE STUDY: The alkaloids in Tetradium are mainly indole alkaloids, while the alkaloids in Coptis are mostly isoquinoline alkaloids with low bioavailability. Alkaloids and their metabolites are nitrogen-containing compounds or weakly alkaline substances that can be partially ionized under physiological pH conditions. Fortunately, organic cation transporters (OCTs) play a crucial role in the cellular uptake of weakly alkaline compounds. Therefore, we speculated that the alkaloidal compounds might interact with liver cation transporters hOCT1 and kidney cation transporters hOCT2 to alter cell drug disposal. In order to clarify our hypothesis, a series of alkaloids-OCTs interaction experiments were conducted. MATERIALS AND METHODS: HEK293 cells stably expressing hOCT1 and hOCT2 were modeled and evaluated. Afterward, high-content screening (HCS) was conducted to analyze whether the main alkaloids and their metabolites of Coptis - Tetradium were inhibitors of hOCT1 and hOCT2 transporters. Meanwhile, LC-MS/MS was used to investigate whether the alkaloidal compounds were substrates of hOCT1 and hOCT2 transporters. Finally, drug interactions at the cellular level were assessed by LC-MS/MS after co-administration of berberine and rutacorine. RESULTS: Berberine, jateorhizine, coptisine, epiberberine, columbamine, demethyleneberberine, and berberrubine could significantly inhibit hOCT1 and hOCT2 activity. Isoquinoline alkaloids, including berberine, jateorhizine, coptisine, epiberberine, columbamine, and palmatine, were substrates of hOCT1 and hOCT2, but not the indole alkaloids evodiamine and rutaecarpine. Furthermore, evodiamine at a concentration of 20 µmol/L had a trivial effect on berberine accumulation in HEK293-hOCT2 cells. CONCLUSIONS: These results support the idea that alkaloidal compounds within Coptis and Tetradium have hOCT1 and hOCT2 inhibitory activity or be their substrates, and the increased oral bioavailability of berberine in vivo was closely related to the potential interactions of small molecules in Coptis- Tetradium. Overall, our study provides a framework for investigating the potential interactions of small molecules in Coptis- Tetradium.
Subject(s)
Alkaloids , Berberine , Coptis , Drugs, Chinese Herbal , Evodia , Cations , Chromatography, Liquid , Coptis/chemistry , Coptis chinensis , Drugs, Chinese Herbal/pharmacology , HEK293 Cells , Humans , Isoquinolines , Tandem Mass SpectrometryABSTRACT
Salvianolate lyophilized injection (SLI), a freeze-dried powder injection derived from aqueous extract of S. miltiorrhiza, is therapeutically used to treat the syndrome of blood stasis and collateral blockage during the recovery period after stroke. To date, it has remained a significant challenge to comprehensively characterize the compounds of SLI, particularly the minor components with potential bioactivities, in one sample injection analysis. Using an integrative four scan modes approach coupled with ultra-high performance liquid chromatography-triple quadrupole-linear ion trap mass spectrometry (UHPLC-QTRAP-MS/MS), we propose a novel, sensitive, and simple strategy for systematic and rapid profiling of the chemical components of SLI. First, an in-house database of constituents from the water-soluble extract of Danshen was created. Second, the fragmentation behaviors of the representative components in SLI were obtained using the untargeted scan mode enhanced MS (EMS)-information dependent acquisition (IDA)-enhanced product ion (EPI). The specific fragments acquired were then utilized to conduct precursor ion (Prec) and neutral loss (NL)-IDA-EPI scans. Following that, a sensitive predictive multiple reaction monitoring (pMRM)-IDA-EPI scan method with 454 transitions was developed based on the prominent fragment ions and plausible predictions. A total of 171 compounds were tentatively identified from SLI. Among them, 27 minor components have not been previously reported. This strategy allows most isomeric compounds at trace levels to be readily distinguished and annotated. Finally, 15 batches of 13 representative components in SLI selected by the qualitative results were accurately quantified. Salvianolic acid A (Sal A), Sal B, Sal D, lithospermic acid (LA), and rosmarinic acid (RA) were proved to be the predominant constituents. Sal B had the highest amount (195.08-350.46 µg·mg-1), followed by LA, Sal A, Sal D, and RA. Moreover, these 15 batches of samples showed good uniformity, and no abnormal batches existed. These results suggest that this novel strategy can accelerate the identification of undiscovered chemical components and serve as an alternative method for in-depth profiling of compounds in other traditional Chinese medicines (TCMs).
Subject(s)
Plant Extracts , Tandem Mass Spectrometry , Chromatography, High Pressure Liquid/methods , Medicine, Chinese Traditional , Tandem Mass Spectrometry/methodsABSTRACT
The genus Uncaria belongs to the family of Rubiaceae, which contains approximately 34 species. It has been widely used as a traditional Chinese medicine (TCM) in China to treat hypertension, fevers, headaches, gastrointestinal illness, epilepsy, wounds, and ulcers. Uncaria rhynchophylla. (Miq.) Miq. ex Hvail.(URM) and Uncaria hirsuta Havil.(UHH) are mainly used as remedies for hypertension, which both belong to the resource of "Gou-teng" in the Chinese Pharmacopoeia. However, the authentic antihypertensive components of Uncaria still have not been fully elucidated until now. In this work, we firstly explored and compared the vasorelaxation effect of URM and UHH on the isolated rat mesenteric artery ring. Then, the variations of metabolite profiles between URM and UHH samples were investigated by UHPLC/Q-Orbitrap-MS, and 16 different metabolites have been found through multivariate statistical analysis. Further, the potential vasodilative compounds which include corynoxeine, isocorynoxeine, isorhynchophylline, rhynchophylline, hirsuteine and hirsutine were screened through the correlation analysis between metabolites and anti-hypertension activities. And the relaxation effects of the six compounds on the mesenteric artery have verified. The results indicated that metabolomics combined with correlation analysis could be effective strategies to rapid explore the active compounds from TCM.
Subject(s)
Uncaria , Animals , China , Chromatography, High Pressure Liquid , Metabolomics , Rats , VasodilationABSTRACT
The efficacy of raw and processed products of Polygonum multiflorum (PM) varies greatly. "Nine cycles of steaming and sunning" (NCSS) is recognized as an effective technology in enhancing efficacy and reducing toxicity for PM. In this paper, PM was prepared differently into three groups (including group R, M, and "9"), which represent raw PM, PM processed using the method of Chinese Pharmacopoeia (ChP) and PM processed using traditional NCSS, respectively. The purpose is to establish an effective method to distinguish raw PM from different processed products and highlight the rationality of processing technology. The main organic compounds that could distinguish these three groups of samples were identified by in-depth mining of mass spectral information and various chemometric methods. Level of related metal cations have been quantified and used as another important distinguishing markers. The electronic tongue was utilized to determine the taste traits of aqueous extract from PM. Furthermore, the material basis that caused the difference in taste was discovered according to correlation analysis. In detail, saltiness has the most important contribution associated with the concentrations of K+ and Na+, however, bitterness and astringency were mainly associated with the contents of epicatechin gallate, catechin, procyanidin B1, procyanidin B2 and epicatechin. This study proposed a novel and effective strategy for identification of processing technology of PM. It lays the foundation for clarifying the modern scientific recommendations of processing technology to PM. On the other hand, it also provides a reference for related researches on other traditional Chinese medicine (TCM).
Subject(s)
Fallopia multiflora , Polygonum , Chromatography, Liquid , Electronic Nose , Tandem Mass Spectrometry , TasteABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum multiflorum Thunb.(PM), (known as Heshouwu () in China) is one of the most important and well mentioned Chinese medicinal herbs in the literature for its use in blackening hair, nourishing liver and kidney, anti-aging, anti-hyperlipidemia, antioxidant, anti-inflammatory, anticancer, hepatoprotection, cardio-protection and improving age-related cognitive dysfunction. The purpose of this review is to give a comprehensive and recent update on PM: new compounds or isolated for the first time, potential hepatotoxic compounds and their mechanisms. Moreover, future perspectives and challenges in the future study of this plant are conversed which will make a new base for further study on PM. MATERIALS AND METHODS: A comprehensive review of relevant published literature on PM using the scientific databases SCOPUS, PubMed, and Science Direct was done. RESULTS: PM is broadly produced in many provinces of China and well known in other Eastern Asian Countries for its ethno-medical uses. Previous phytochemical investigation of PM had led to the isolation of more than 175 compounds including recently isolated 70 new compounds. Most of the new compounds isolated after 2015 are majorly dianthrone glycosides and stilbene glycosides. Processing has also a significant effect on chemical composition, pharmacological activities, and toxicity of PM. PM-induced liver injury is increasing after the first report in Hong Kong in 1996. Hepatotoxicity of PM was constantly reported in Japan, Korea, China, Australia, Britain, Italy, and other countries although its toxicity is related to idiosyncratic hepatotoxicity. More interestingly, although there is indispensable interest to predict idiosyncratic hepatotoxicity of PM and understand its mechanisms, the responsible hepatotoxic compounds and mechanisms of liver damage induced by PM are still not clear. There is a big controversy on the identification of the most responsible constituent. Anthraquinone and stilbene compounds in PM, mainly emodine and TSG are mentioned in the literature to be the main responsible hepatotoxic compounds. However, comparing the two compounds, which one is the more critical toxic agent for PM-induced hepatotoxicity is not well answered. Affecting different physiological and metabolic pathways such as oxidative phosphorylation and TCA cycle pathway, metabolic pathways, bile acid excretion pathway and genetic polymorphisms are among the mechanisms of hepatotoxicity of PM. CONCLUSION: Deeper and effective high throughput experimental studies are still research hotspots to know the most responsible constituent and the mechanism of PM-induced hepatotoxicity.
Subject(s)
Chemical and Drug Induced Liver Injury/etiology , Drugs, Chinese Herbal/adverse effects , Drugs, Chinese Herbal/chemistry , Fallopia multiflora/chemistry , Animals , Drugs, Chinese Herbal/pharmacology , Gastrointestinal Microbiome/drug effects , Humans , Medicine, Chinese Traditional , Phytochemicals/adverse effects , Phytochemicals/analysis , Phytochemicals/chemistry , Phytochemicals/pharmacologyABSTRACT
RELEVANCE: Bisbenzylisoquinoline (BBIQ) alkaloids are generally present in plants of Berberidaceae, Monimiaceae and Ranunculaceae families in tropical and subtropical regions. Some species of these families are used in traditional Chinese medicine, with the effects of clearing away heat and detoxification, promoting dampness and defecation, and eliminating sores and swelling. This article offers essential data focusing on 13 representative BBIQ compounds, which are mainly extracted from five plants. The respective botany, traditional uses, phytochemistry, pharmacokinetics, and toxicity are summarized comprehensively. In addition, the ADME prediction of the 13 BBIQ alkaloids is compared and analyzed with the data obtained. MATERIALS AND METHODS: We have conducted a systematic review of the botanical characteristics, traditional uses, phytochemistry, pharmacokinetics and toxicity of BBIQ alkaloids based on literatures collected from PubMed, Web of Science and Elsevier during 1999-2020. ACD/Percepta software was utilized to predict the pharmacokinetic parameters of BBIQ alkaloids and their affinity with enzymes and transporters. RESULTS: Botany, traditional uses, phytochemistry, pharmacokinetic and toxicity of 13 alkaloids, namely, tetrandrine, dauricine, curine, trilobine, isotrilobine, cepharanthine, daurisoline, thalicarpine, thalidasine, isotetrandrine, liensinine, neferine and isoliensinine, have been summarized in this paper. It can't be denied that these alkaloids are important material basis of pharmacological effects of family Menispermaceae and others, and for traditional and local uses which has been basically reproduced in the current studies. The 13 BBIQ alkaloids in this paper showed strong affinity and inhibitory effect on P-glycoprotein (P-gp), with poor oral absorption and potent binding ability with plasma protein. BBIQ alkaloids represented by tetrandrine play a key role in regulating P-gp or reversing multidrug resistance (MDR) in a variety of tumors. The irrationality of their usage could pose a risk of poisoning in vivo, including renal and liver toxicity, which are related to the formation of quinone methide during metabolism. CONCLUSION: Although there is no further clinical evaluation of BBIQ alkaloids as MDR reversal agents, their effects on P-gp should not be ignored. Considering their diverse distribution, pharmacokinetic characteristics and toxicity reported during clinical therapy, the quality standards in different plant species and the drug dosage remain unresolved problems.
Subject(s)
Alkaloids/pharmacokinetics , Benzylisoquinolines/pharmacokinetics , Drugs, Chinese Herbal/pharmacokinetics , Medicine, Chinese Traditional/methods , Phytochemicals/pharmacokinetics , Plants, Medicinal , Alkaloids/therapeutic use , Alkaloids/toxicity , Animals , Benzylisoquinolines/therapeutic use , Benzylisoquinolines/toxicity , Drugs, Chinese Herbal/therapeutic use , Drugs, Chinese Herbal/toxicity , Ethnobotany/methods , Ethnopharmacology/methods , Humans , Phytochemicals/therapeutic use , Phytochemicals/toxicityABSTRACT
INTRODUCTION: The roots of Polygonum multiflorum (PM) serve as a classical traditional Chinese medicine (TCM), which has multiple biological activities. However, many cases of hepatotoxicity in PM have been reported in recent years. Processing PM with black beans decoction is one of the typical processing methods to reduce the hepatotoxicity of PM since ancient times. OBJECTIVES: To find potential effective constituents, as well as the optimal variety and origin of black beans for the processing of PM. METHODS: Based on ultrahigh-performance liquid chromatography Q-Orbitrap mass spectrometry (UHPLC-Q-Orbitrap-MS) analysis, we measured the contents of the two potential toxic compounds (emodin-8-O-glucoside and torachrysone-O-hexose) in raw PM (R-PM), PM processed with big black beans (B-PM) and PM processed with small black beans (S-PM). The flow cytometry method analysed the effects of different processed products of PM on apoptosis of L02 cells in different drug concentration. Proton nuclear magnetic resonance (1 H-NMR) and UHPLC-Q-Orbitrap-MS together with multivariate statistical analysis were used to systematically analyse the different components between small black beans (Small-BB) and big black beans (Big-BB) from 30 different habitats. RESULTS: The toxicity was ranked from small to large: S-PM < B-PM < R-PM. Processing PM with black beans could significantly decrease the apoptosis rate of L02 cells, especially when the drug concentration is 80 µg/mL. Besides, we find five differential compounds (α-arabinose, α-galactose, proline, isomer of daidzein and isomer of genistein) may be potential active ingredients. In terms of the black beans collected from 30 producing areas, we find that Small-BB from Weifang in Shandong province was optimum to processing PM, followed by Shangqiu in Henan province, Jilin and Liaoning province. CONCLUSION: The ingredients that affect the processing of PM may be attributed to α-arabinose, α-galactose, proline, isomer of daidzein and isomer of genistein in black beans. When the drug concentration is higher, the effect of reducing the hepatotoxicity of PM is better. Besides, Small-BB was more effective than Big-BB for reducing the toxicity of PM, especially Small-BB from Weifang in Shandong, Shangqiu in Henan province and northeast China.
Subject(s)
Fallopia multiflora , Polygonum , Chromatography, High Pressure Liquid , Chromatography, Liquid , Ecosystem , Humans , Medicine, Chinese TraditionalABSTRACT
Acute gut graft-versus-host disease (aGVHD) is a leading threat to the survival of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Abnormal gut microbiota is correlated with poor prognosis in allo-HSCT recipients. A disrupted intestinal microenvironment exacerbates dysbiosis in GVHD patients. We hypothesized that maintaining the integrity of the intestinal barrier may protect gut microbiota and attenuate aGVHD. This hypothesis was tested in a murine aGVHD model and an in vitro intestinal epithelial culture. Millipore cytokine array was utilized to determine the expression of proinflammatory cytokines in the serum. The 16S rRNA sequencing was used to determine the abundance and diversity of gut microbiota. Combining Xuebijing injection (XBJ) with a reduced dose of cyclosporine A (CsA) is superior to CsA alone in improving the survival of aGVHD mice and delayed aGVHD progression. This regimen also reduced interleukin 6 (IL-6) and IL-12 levels in the peripheral blood. 16S rRNA analysis revealed the combination treatment protected gut microbiota in aGVHD mice by reversing the dysbiosis at the phylum, genus, and species level. It inhibited enterococcal expansion, a hallmark of GVHD progression. It inhibited enterococcal expansion, a hallmark of GVHD progression. Furthermore, Escherichia coli expansion was inhibited by this regimen. Pathology analysis revealed that the combination treatment improved the integrity of the intestinal tissue of aGVHD mice. It also reduced the intestinal permeability in aGVHD mice. Besides, XBJ ameliorated doxorubicin-induced intestinal epithelial death in CCK-8 assay. Overall, combining XBJ with CsA protected the intestinal microenvironment to prevent aGVHD. Our findings suggested that protecting the intestinal microenvironment could be a novel strategy to manage aGVHD. Combining XBJ with CsA may reduce the side effects of current aGVHD prevention regimens and improve the quality of life of allo-HSCT recipients.
ABSTRACT
Lapses in the graft-vs.-host disease (GVHD) prophylaxis and side effects of current standard care following allogeneic hematopoietic stem cell transplantation (allo-HSCT) call for novel regimens. Traditional approaches targeting T cells showed limited success in preventing acute GVHD (aGVHD). System medicine showed promising results treating complex diseases such as sepsis and multi-organ dysfunction syndrome (MODS). Adapting established network pharmacology analysis methods, we aimed to develop novel integrative regimens to prevent aGVHD. Our network pharmacology analysis predicted that Xuebijing injection (XBJ) targets a series of key node proteins in aGVHD network. It also unveiled that Salviae miltiorrhizae (Danshen), an herb in Xuebijing formula, which prevented aGVHD in rats, shares five out of six key GVHD node proteins targeted by XBJ. Interestingly, network pharmacology analysis indicated Xuebijing may share multiple aGVHD targets with Cyclosporin A (CsA), a first-line drug for preventing aGVHD in the clinic. Based on current information, we hypothesized that combination of XBJ and CsA may yield superior results in aGVHD prevention than either drug alone. We performed in vitro and in vivo assays to validate the predictions by the network pharmacology analysis. In vitro assays revealed XBJ prevented platelet aggregation and NF-κB nuclear translocation in macrophages. XBJ also promoted angiogenesis in tube-formation assay. Importantly, the combination of CsA and XBJ was effective in rescuing mice subjected to lethal GVHD. XBJ contributed to the rescue through preventing NF-κB nuclear translocation, attenuating inflammation and maintaining viability of macrophages. Overall, network pharmacology is a powerful tool to develop novel integrative regimens. Combination of XBJ and CsA may shed light on preventing aGVHD.
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Xuebijing injection (XBJ), a Chinese herbal medicine containing extracts from 5 herbs, is frequently used as an add-on with standard therapies to treat sepsis or septic shock with fewer side effects in China. Nonetheless, its mechanism of action on septic shock remains to be unveiled. We explored the differential effects of XBJ on subtypes of CD4+ T cell differentiation and septic shock protection in a murine model to understand the contribution of XBJ to regulation of the inflammation-immune axis function. MATERIALS AND METHODS: In vitro T cell differentiation assays were performed to determine the effect of XBJ on CD4+ regulatory T cell and T helper cell differentiation. Besides, 2ml/kg, 6ml/kg- and 18ml/kg of XBJ were administered to different groups of septic mice once/day for 5 days after cecal ligation and puncture (CLP) surgeries. 36h after CLP, serum levels of pro-inflammatory cytokine TNF-α and IL-6 were determined with Elisa. Frequencies of CD4+ T cells were analyzed after staining with Tregs and T helper cell lineage specific antibodies by flow cytometer. RESULTS: XBJ at 18ml/kg stimulated Treg differentiation and moderately inhibited Th17 differentiation in vitro. Accordingly, 18ml/kg XBJ facilitated the expansion of IL-10+ Tregs and normalized pro-inflammatory Th17 population in septic mice. This regimen also significantly reduced serum levels of inflammatory cytokines TNF-α and IL-6 in septic mice. Additionally, 18ml/kg XBJ injection effectively prevented neutrophil infiltration into the lung and kidney and improved survival in this septic shock model. CONCLUSIONS: In summary, XBJ improves survival in septic shock partially through preventing cytokine storm, inhibiting inflammation and regulating the balance of Tregs and Th17 cells. Thus, higher dose of XBJ is a potential regimen to benefit septic shock patients.
Subject(s)
Drugs, Chinese Herbal/therapeutic use , Shock, Septic/drug therapy , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Cytokines/blood , Disease Models, Animal , Drugs, Chinese Herbal/pharmacology , Injections , Male , Mice, Inbred C57BL , Phytotherapy , Shock, Septic/blood , Shock, Septic/immunology , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/immunology , Th17 Cells/drug effects , Th17 Cells/immunologyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Plants of the genus Cimicifuga have long been used as an ethnomedicine in China, Europe, and North America for its high medicinal value and health benefits. Their dried rhizomes are widely used for treating wind-heat headache, toothache, aphtha, sore throat, measles, spot poison, archoptosis, and uterine prolapse. In addition, it is used as a dietary supplement for preventing women menopausal symptoms and osteoporosis. AIM OF THE REVIEW: This paper aims to provide up-to-date information on the genus Cimicifuga, including botanical characterization, medicinal resources, traditional medicinal uses, phytochemistry, quality control, pharmacological research as well as the toxicology. The possible structural-activity relationships and molecular mechanisms of the bioactive constituents are discussed in ways that contribute to the structural optimization and preclinical safety assessment for further drug design. MATERIALS AND METHODS: The relevant information on Cimicifuga was collected from scientific databases (such as Google Scholar, PubMed, SciFinder Scholar, Science Direct, CNKI, Baidu Scholar, Web of Science, China Knowledge Resource Integrated Database), Chinese herbal classics, ethnobotanical books, PhD and MSc dissertations, Chinese Pharmacopoeia, published articles in peer-reviewed journals, local magazines, and unpublished materials. In addition, the Plant List (TPL, www.theplantlist.org) was also used to validate the scientific names and synonyms of this plant. The literature cited in this review dated from 1953 to 2017. RESULTS: The majority of chemical constituents of this plant include triterpenoid glycosides, phenylpropanoids, nitrogenous compounds, chromones, flavonoids and 4α-methyl steroid. Among them, the primary bioactive constituents are believed to be present in the triterpene glycoside fraction. To date, investigation of seven Cimicifuga spp. plants led to the identification of more than 457 compounds. Years of pharmacological research proved that the crude extracts and certain pure compounds obtained from Cimicifuga exhibited menopausal syndrome-treatment, anti-osteoporosis, antiviral, antitumor, antioxidant and antiangiogenic activities. On the other hand, Cimicifuga plant-induced toxicities of liver, cardiovascular, central and peripheral nervous systems have also been reported. Therefore, safety consideration should be placed into a high priority for herbal medicine Cimicifuga therapy in the early stages of development and clinical trials. CONCLUSIONS: This review presents information on botany, medicinal resources, and traditional medicinal history of some Cimicifuga plants. Modern pharmacology researchers have validated many traditional uses of Cimicifuga species. As the quality control and safety assessment of Cimicifuga plants is still incomplete, only a small part of the plant is permitted to be used as medicines. Expansion of medicinal resources in Cimicifuga is urgently needed to enable its full use. Currently research primarily focuses on the triterpenoid glycosides but there are many other types of compounds which may possess new biological activities however the systematic studies of these compounds are lacking. Extensive study is required on Cimicifuga plant before it can be fully used in clinics as a potent drug candidate.
Subject(s)
Cimicifuga/chemistry , Phytochemicals , Phytotherapy , Animals , Ethnopharmacology , Humans , Medicine, Traditional , Plants, MedicinalABSTRACT
A rapid and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of luteolin, luteolin-7-O-ß-D-glucopyranoside, physalin A, physalin D and physalin L in rat plasma. Scutellarein and dexamethasone were used as the internal standards (IS). Plasma samples were prepared by liquid-liquid extraction with ethyl acetate. The five constituents were separated on an Acquity UPLC BEH C18 column (100 mm × 2.1 mm, 1.7 µm). A gradient elution procedure was used with acetonitrile (A)-0.1% aqueous formic acid (B). Mass spectrometric detection was performed in negative ion multiple reaction monitoring mode with an electrospray ionization (ESI) source. This method showed good linearity (r2 > 0.997) over a concentration range of 2.0-500 ng/mL with a lower limit of quantification of 2.0 ng/mL for all five compounds. The inter- and intra-day accuracy ranged from 91.7 to 104%, and precisions (RSD) were <6.46% for all analytes. The extraction recoveries of all analytes were >85%. This validated method was successfully applied for the first time to the pharmacokinetic study of five ingredients after oral administration of 70% ethanol extract of Chinese lantern in rats.
Subject(s)
Chromatography, Liquid/methods , Flavonoids/blood , Physalis/chemistry , Plant Extracts/administration & dosage , Secosteroids/blood , Tandem Mass Spectrometry/methods , Administration, Oral , Animals , Drug Stability , Flavonoids/chemistry , Flavonoids/pharmacokinetics , Limit of Detection , Linear Models , Male , Plant Extracts/chemistry , Plant Extracts/pharmacokinetics , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Secosteroids/chemistry , Secosteroids/pharmacokineticsABSTRACT
Lianhua-Qingwen capsule (LQC) is a commonly used Chinese medical preparation to treat viral influenza and especially played a very important role in the fight against severe acute respiratory syndrome (SARS) in 2002-2003 in China. In this paper, a rapid ultraperformance liquid chromatography coupled with diode-array detector and quadrupole time-of-flight mass spectrometry (UPLC-DAD-QTOF-MS) method was established for qualitative and quantitative analysis of the major constituents of LQC. A total of 61 compounds including flavonoids, phenylpropanoids, anthraquinones, triterpenoids, iridoids, and other types of compounds were unambiguously or tentatively identified by comparing the retention times and accurate mass measurement with reference compounds or literature data. Among them, twelve representative compounds were further quantified as chemical markers in quantitative analysis, including salidroside, chlorogenic acid, forsythoside E, cryptochlorogenic acid, amygdalin, sweroside, hyperin, rutin, forsythoside A, phillyrin, rhein, and glycyrrhizic acid. The UPLC-DAD method was evaluated with linearity, limit of detection (LOD), limit of quantification (LOQ), precision, stability, repeatability, and recovery tests. The results showed that the developed quantitative method was linear, sensitive, and precise for the quality control of LQC.
Subject(s)
Drugs, Chinese Herbal/chemistry , Anthraquinones/analysis , Capsules , Chromatography, High Pressure Liquid , Drugs, Chinese Herbal/analysis , Iridoids/analysis , Mass SpectrometryABSTRACT
BACKGROUND: Pitavastatin, a fully synthetic ß-hydroxy-ß-methylglutaryl-coenzyme A reductase inhibitor, is potent for the treatment of primary hyperlipidemia and mixed dyslipidemia. Recently, the original product and some generic products of pitavastatin calcium have become available in China. However, the intrasubject variability and interchangeability of this newly developed generic product and the branded innovator product have rarely been investigated in the Chinese population. PURPOSE: The aim of this study is to develop and compare the scaled-average, population, and individual bioequivalence (BE) of pitavastatin calcium tablets in healthy Chinese volunteers. This study will be used to allow for the interchangeability (switchability and prescribability) of the 2 products in clinical medication in China. METHODS: A single-dose, reference-replicated, 3-period crossover BE study was conducted in 36 healthy male volunteers. Plasma samples were collected before and after oral administration of 2-mg test or reference tablets. A LC-MS/MS method was used to determine the concentration of pitavastatin calcium. A noncompartmental method was used to investigate the pharmacokinetic parameters. The ANOVA and 90% CIs of ln(AUC0-t) and ln(Cmax) were used for statistical analysis of scaled-average BE. A nonparametric test (Wilcoxon signed rank test) was performed to Tmax. The analyses of population BE and individual BE were used to assess the switchability and prescribability of the 2 products. FINDINGS: Thirty-six volunteers were enrolled in this clinical research; 33 volunteers completed the 3 treatment periods. The mean (SD) relative bioavailability calculated from the ratios (T/R) of AUC0-t was 101.3% (19.7%). The mean ln(AUC0-t) and ln(Cmax) were 98.64 (90% CI, 93.44-104.13) and 98.68 (90% CI, 91.88-105.99) within previously stipulated ranges recommended by the US Food and Drug Administration and the China Food and Drug Administration (CFDA). The intrasubject %CVs of AUC0-t and Cmax were 12.0% and 18.0% for the reference tablet and 13.0% and 17.0% for the test tablet. No significant differences were found among Tmax (0.742 ± 0.276, 0.674 ± 0.202, and 0.689 ± 0.226, respectively) for reference tablet 1, reference Supplemental Table II in the online version at 10.1016/j.clinthera.2014.06.21, and test tablet by a Wilcoxon test (P > 0.05). For ln(AUC0-t) and ln(Cmax), the statistical test-reference ratios were 99.13% and 98.95%, respectively. After inspecting the results for reference and mixed scaling, all the upper confidence limits were <0; therefore, population and individual BE were given. IMPLICATIONS: In the healthy Chinese males, the generic and branded name tablets of pitavastatin calcium are bioequivalent at the rate and extent of absorption after a comparison of scaled-average, population, and individual BE and thus may be used interchangeably. Both the formulations are generally well tolerated. Chinese Clinical Trial identifier: ChiCTR-TTRCC-13003973.
Subject(s)
Drugs, Generic/administration & dosage , Drugs, Generic/pharmacokinetics , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Quinolines/administration & dosage , Quinolines/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , Asian People , Biological Availability , China , Cross-Over Studies , Drug Substitution , Enzyme Inhibitors/blood , Healthy Volunteers , Humans , Male , Quinolines/blood , Tablets , Tandem Mass Spectrometry , Therapeutic Equivalency , Young AdultABSTRACT
A sensitive and rapid LC-MS/MS method has been developed and validated for quantifying swertianolin in rat plasma using rutin as an internal standard (IS). Following liquid-liquid extraction with ethyl acetate, chromatographic separation for swertianolin was achieved on a C18 column with a gradient elution using 0.1% formic acid as mobile phase A and acetonitrile as mobile phase B at a flow rate of 0.3 mL/min. The detection was performed on a tandem mass spectrometer using multiple reaction monitoring via an electrospray ionization source and operating in the negative ionization mode. The optimized mass transition ion pairs (m/z) for quantitation were 435.1/272.0 for swertianolin and 609.2/300.1 for IS. The lower limit of quantitation was 0.5 ng/mL within a linear range of 0.5-500 ng/mL. Intra-day and inter-day precision was less than 6.8%. The accuracy was in the range of -13.9 to 12.0%. The mean recovery of swertianolin was >66.7%. The proposed method was successfully applied in evaluating the pharmacokinetics of swertianolin after an oral dose of 50 mg/kg Swertia mussotii extract in rats.
Subject(s)
Chromatography, Liquid/methods , Glucosides/blood , Swertia/chemistry , Tandem Mass Spectrometry/methods , Xanthones/blood , Administration, Oral , Animals , Glucosides/chemistry , Glucosides/pharmacokinetics , Linear Models , Liquid-Liquid Extraction/methods , Male , Plant Extracts/administration & dosage , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Rutin , Xanthones/chemistry , Xanthones/pharmacokineticsABSTRACT
A new phenolic amide glycoside, cimicifugamide A (1) along with four known compounds, trans-feruloyl tyramine 4-O-beta-D-glucopyranoside (2), (+)-isolariciresinol 3-O-beta-D-glucopyranoside (3), cimidahurine (4), and 24-epi-7, 8-didehydrocimigenol-3-O-beta-D-xylopyranoside (5) were isolated from the rhizomes of Cimicifuga dahurica. Compound 3 was identified as a lignan and has been obtained from Cimicifuga genus for the first time. The structure of compound 1 was elucidated by IR, UV, HR-MS and NMR spectroscopic methods.
Subject(s)
Amides/chemistry , Cimicifuga/chemistry , Glycosides/chemistry , Phenols/chemistry , Amides/isolation & purification , Glycosides/isolation & purification , Lignans/chemistry , Lignans/isolation & purification , Molecular Structure , Phenols/isolation & purification , Plants, Medicinal/chemistry , Rhizome/chemistryABSTRACT
A simple and sensitive LC-MS/MS method has been developed and validated for the determination of rutin, isoquercitrin, astragalin, quercetin, kaempferol and isorhamnetin in rat plasma using naringin as the internal standard (IS). The plasma samples were pretreated and extracted by liquid-liquid extraction. Chromatographic separation was accomplished on a C18 column with a 10 min gradient elution using acetonitrile and 0.1% formic acid aqueous solution as mobile phase at a flow rate of 0.3 mL min(-1). A tandem mass spectrometric detection was conducted using multiple reaction monitoring (MRM) via an electrospray ionization (ESI) source and operating in the negative ionization mode. The lower limit of quantitation (LLOQ) of each analyte was lower than 1 ng mL(-1). Intra-day and inter-day precisions were less than 11.9%. The relative errors of accuracy were in the range of -9.2% to 6.1%. The mean recoveries of flavonoids and IS were higher than 53.8%. The proposed method was further applied to investigate the pharmacokinetics of all analytes after a single oral administration of total flavonoids from mulberry leaves to rats.
Subject(s)
Chromatography, Liquid/methods , Flavonoids/blood , Flavonoids/pharmacokinetics , Morus/chemistry , Plasma/chemistry , Tandem Mass Spectrometry/methods , Animals , Flavonoids/chemistry , Kaempferols/chemistry , Kaempferols/pharmacokinetics , Liquid-Liquid Extraction/methods , Plant Extracts/blood , Plant Extracts/chemistry , Plant Extracts/pharmacokinetics , Plant Leaves/chemistry , Quercetin/analogs & derivatives , Quercetin/chemistry , Quercetin/pharmacokinetics , Rats , Rats, Sprague-Dawley , Rutin/chemistry , Rutin/pharmacokineticsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicine (TCM) operates on the general principle that compatible components of different herbal decoction may work together to synergistically enhance therapeutic efficacy or reduce adverse effects. Cortex Periplocae is an herb that has been used in TCM clinics for a long time in the treatment of chronic heart failure. However, recently, the use of this herb has been restricted because of widespread abuse and misapplications. Radix Notoginseng is another herb that is used in TCM because of its protective role on cardiomyocytes. From our previous studies on these two herbs in a mouse model, we observed an increased LD50 after oral administration of Cortex Periplocae extract (CPE) and Panax notoginseng saponins (PNS) in a ratio of 1:1 compared with Cortex Periplocae extract used alone. AIM OF THE STUDY: This study aimed to investigate whether there are mutual synergistic effects of the two herbal extracts, CPE and PNS, on catecholamines (CAs) secretion, and their possible underlying mechanism(s) for such effects. MATERIALS AND METHODS: CPE and PNS were quantified by the LC-MS/MS method. HPLC-ECD was used to determine the CAs secreted into the medium by bovine adrenal medulla cells (BAMCs) and calcium influx was measured using a Calcium 4 reagent kit. RESULTS: We found that the stimulatory effect of CPE on CAs secretion was inhibited when used together with PNS. For a better clarification of the different constituents of the extracts, a quantitative analysis was carried out. Periplocin was found to be the main active component of CPE valued as 0.99% and saponins were the principal constituents of PNS. These results also showed that CPE increased the secretion of CAs in a dose-dependent manner while the actions of PNS were seen to be inhibitory. Periplocin monomer of CPE could be implicated for the actions of CPE since it plays the role of increasing the ACh-induced CAs secretion in a calcium-dependent manner. We therefore conclude that; CPE and PNS exert antagonistic effects in regulating the concentration of intracellular calcium. CONCLUSIONS: PNS inhibits CPE-induced CAs secretion by suppressing calcium influx in bovine adrenal medulla cells while periplocin, one of the main components of CPE has the same secretagogue effect as CPE.