Network pharmacology and pharmacokinetics integrated strategy to investigate the pharmacological mechanism of Xianglian pill on ulcerative colitis

BackgroundUlcerative colitis (UC) is a chronic inflammatory bowel disease with high morbidity, which leads to poor quality of life. The Xianglian pill (XLP) is a classical Chinese patent medicine and has been clinically proven to be an effective treatment for UC.PurposeThe pharmacological mechanism of the key bioactive ingredients of XLP for the treatment of UC was investigated by a network pharmacology and pharmacokinetics integrated strategy.Study design and methodsNetwork pharmacology was used to analyze the treatment effect of nine quantified XLP ingredients on UC. Key pathways were enriched and analyzed by protein-protein interaction and Kyoto Encyclopedia of Genes and Genomes analyses. The effect of XLP on Th17 cell differentiation was validated using a mouse model of UC. The binding of nine compounds with JAk2, STAT3, HIF-1α, and HSP90AB1 was assessed using molecular docking. A simple and reliable ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous quantification of nine ingredients from XLP in plasma and applied to a pharmacokinetic study following oral administration.ResultsNine compounds of XLP, including coptisine, berberine, magnoflorine,berberrubine, jatrorrhizine, palmatine, evodiamine, rutaecarpine, and dehydrocostus lactone, were detected. Network pharmacology revealed 50 crossover genes between the nine compoundsand UC. XLP treats UC mainly by regulating key pathways of the immune system, including Th17 cell differentiation, Jak-Stat, and PI3K-Akt signaling pathways. An in vivo validation in mice found that XLP inhibits Th17 cell differentiation by suppressing the Jak2-Stat3 pathway, which alleviates mucosal inflammation in UC. Molecular docking confirmed that eight compounds are capable of binding with JAk2, HIF-1α, and HSP90AB1, further confirming the inhibitory effect of XLP on the Jak2-Stat3 pathway. Moreover, apharmacokinetic study revealed that the nine ingredients of XLP are exposed in the plasma and colon tissue, which demonstrates its pharmacological effect on UC.ConclusionThis study evaluates the clinical treatment efficacy of XLP for UC. The network pharmacology and pharmacokinetics integrated strategy evaluation paradigm is efficient in discovering the key pharmacological mechanism of herbal formulae.     

Esculentosides: Insights into the potential health benefits,mechanisms of action and molecular targets

BackgroundEsculentosides and related phytolaccosides form a group of oleanene-type saponins isolated from plants of the Phytolaccaceae family, essentially Phytolacca esculenta, P. americana and P. acinosa. This chemical family offers a diversity of glycosylated compounds, including molecules with a mono-, di- or tri-saccharide unit at position C-3, and with or without a glucose residue at position C-28. The esculentosides, which derive essentially from the sapogenin jaligonic acid or its 30-methyl ester phytolaccagenin, exhibit anti-inflammatory, antifungal and anticancer activities.PurposeThe objective of the review was to identify the 26 esculentosides (ES) and phytolaccosides known to date, including 16 monodesmosidic and 10 bidesmosidic saponins, and to review their pharmacological properties and molecular targets.MethodologyThe retrieval of potentially relevant studies was done by systematically searching of scientific databases like Google Scholar and PubMed in January-May 2020. The main keywords used as search terms were related to esculentosides, phytolaccosides and Phytolaccaceae. The systematic search retrieved about 110 papers that were potentially relevant and after an abstract-based selection, 68 studies were analyzed in details and discussed.ResultsThe structural relationship between the compounds and their sapogenin precursors has been studied. In addition, the pharmacological properties of the main ES, such as ES-A, -B and -H, have been analyzed to highlight their mode of action and potential targets. ES-A is a potent inhibitor of the release of cytokines and this anti-inflammatory activity contributes to the anticancer effects observed in vitro and in vivo. Potential molecular targets of ES-A/B include the enzymes cyclooxygenase 2 (COX-2) and casein kinase 2 (CK2). In addition, the targeting of the protein high-mobility group box 1 (HGMB1) by ES-A/B is proposed, based on molecular modeling and the structural analogy with the related saponin glycyrrhizin, a potent HGMB1 alarmin inhibitor.ConclusionMore work is needed to properly characterize the molecular targets but otherwise compounds like ES-A and ES-H emerge as potent anti-inflammatory and anticancer agents and ES-B as an antifungal agent. A preclinical development of these three compounds should be considered.     

Chaiqin chengqi decoction alleviates severity of acute pancreatitis via inhibition of TLR4 and NLRP3 inflammasome: Identification of bioactive ingredients via pharmacological sub-network analysis and experimental validation

BackgroundChaiqin chengqi decoction (CQCQD) is a Chinese herbal formula derived from dachengqi decoction. CQCQD has been used for the management of acute pancreatitis (AP) in the West China Hospital for more than 30 years. Although CQCQD has a well-established clinical efficacy, little is known about its bioactive ingredients, how they interact with different therapeutic targets and the pathways to produce anti-inflammatory effects.PurposeToll-like receptor 4 (TLR4) and the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated pro-inflammatory signaling pathways, play a central role in AP in determining the extent of pancreatic injury and systemic inflammation. In this study, we screened the bioactive ingredients using a pharmacological sub-network analysis based on the TLR4/NLRP3 signaling pathways followed by experimental validation.MethodsThe main CQCQD bioactive compounds were identified by UPLC-QTOF/MS. The TLR4/NLRP3 targets in AP for CQCQD active ingredients were confirmed through a pharmacological sub-network analysis. Mice received 7 intraperitoneal injections of cerulein (50 μg/kg; hourly) to induce AP (CER-AP), while oral gavage of CQCQD (5, 10, 15 and 20 g/kg; 3 doses, 2 hourly) was commenced at the 3rd injection of cerulein. Histopathology and biochemical indices were used for assessing AP severity, while polymerase chain reaction, Western blot and immunohistochemistry analyses were used to study the mechanisms. Identified active CQCQD compounds were further validated in freshly isolated mouse pancreatic acinar cells and cultured RAW264.7 macrophages.ResultsThe main compounds from CQCQD belonged to flavonoids, iridoids, phenols, lignans, anthraquinones and corresponding glycosides. The sub-network analysis revealed that emodin, rhein, baicalin and chrysin were the compounds most relevant for directly regulating the TLR4/NLRP3-related proteins TLR4, RelA, NF-κB and TNF-α. In vivo, CQCQD attenuated the pancreatic injury and systemic inflammation of CER-AP and was associated with reduced expression of TLR4/NLRP3-related mRNAs and proteins. Emodin, rhein, baicalin and chrysin significantly diminished pancreatic acinar cell necrosis with varied effects on suppressing the expression of TLR4/NLRP3-related mRNAs. Emodin, rhein and chrysin also decreased nitric oxide production in macrophages and their combination had synergistic effects on alleviating cell death as well as expression of TLR4/NLRP3-related proteins.ConclusionsCQCQD attenuated the severity of AP at least in part by inhibiting the TLR4/NLRP3 pro-inflammatory pathways. Its active ingredients, emodin, baicalin, rhein and chrysin contributed to these beneficial effects.     

Phytosterols of marine algae: Insights into the potential health benefits and molecular pharmacology

BackgroundMarine algae are rich in some unique biologically active secondary metabolites having diverse pharmacological benefits. Of these, sterols comprise a group of functional lipid compounds that have attracted much attention to natural product scientists.PurposeThis review was aimed to update information on the health effects of algae-derived phytosterols and their molecular interactions in various aspects of human health and diseases and to address some future perspectives that may open up a new dimension of pharmacological potentials of algal sterols.MethodsA literature-based search was carried out to retrieve published research information on the potential health effects of algal phytosterols with their pharmacological mechanisms from accessible online databases, such as Pubmed, Google Scholar, Web of Science, and Scopus, using the key search terms of ‘marine algae sterol’ and ‘health potentials such as antioxidant or anti-inflammatory or anti-Alzheimer's or anti-obesity or cholesterol homeostasis or hepatoprotective, antiproliferative, etc.’ResultsPhytosterols of marine algae, particularly fucosterol, have been investigated for a plethora of health benefits, including anti-diabetes, anti-obesity, anti-Alzheimer's, antiaging, anticancer, and hepatoprotection, among many others, which are attributed to their antioxidant, anti-inflammatory, immunomodulatory and cholesterol-lowering properties, indicating their potentiality as therapeutic leads. These sterols interact with enzymes and various other proteins that are actively participating in different cellular pathways, including antioxidant defense system, apoptosis and cell survival, metabolism, and homeostasis.ConclusionIn this review, we briefly overview the chemistry, pharmacokinetics, and distribution of algal sterols, and provide critical insights into their potential health effects and the underlying pharmacological mechanisms, beyond the well-known cholesterol-lowering paradigm.     

Bergenia crassifolia (L.) Fritsch – Pharmacology and phytochemistry

PurposeBergenia crassifolia (L.) Fritsch, a species in the Bergenia genus belongs to the family Saxifragaceae, is valuated for its medicinal application. The review focuses on the medicinal uses, phytochemistry, and the biological activities of B. crassifolia to explore its benefits and potential uses.MethodsIn this review, we summarized data, published in Russia and in other countries related to B. crassifolia.ResultsRhizomes and leaves of this plant are in use as traditional remedies for the treatment of different disorders in the folk medicine systems of Russia and Asia. The plant is a potential source of tannins, benzanoids, flavonoids, polysaccharides and other active compounds. Due to the presence of a multitude of bioactives, a wide array of pharmacological activities have been ascribed to different parts of this herb and individual compounds, which include adaptogenic, antiinflammatory, antihypertensive, antimicrobial, antioxidant, antiobesity, antitussive, cerebro-protective, hepatoprotective, immunomodulating, and diuretic.ConclusionThe review highlights the potential of B. crassifolia for further development of herbal medicines on its base.     

Cardamonin inhibits LPS-induced inflammatory responses and prevents acute lung injury by targeting myeloid differentiation factor 2

BackgroundAcute lung injury (ALI) is a systemic inflammatory process, which has no pharmacological therapy in clinic. Accumulating evidence has demonstrated that natural compounds from herbs have potent anti-inflammatory efficacy in several disease models, which could be the potential candidates for the treatment of ALI.Hypothesis/PurposeAnti-inflammatory screening from natural product bank may provide new anti-inflammatory compounds for therapeutic target discovery and ALI treatment.Methods165 natural compounds were screened for their anti-inflammatory activity in LPS-stimulated macrophages. PCR array, SPR and ELISA were used to determine the potential target of the most active compound, Cardamonin (CAR). The pharmacological effect of CAR was further evaluated in both LPS-stimulated macrophages and ALI mice model.ResultsOut of the screened 165 compounds, CAR significantly inhibited LPS-induced inflammatory cytokine secretion in macrophages. We further showed that CAR significantly inhibited NF-κB and JNK signaling activation, and thereby inflammatory cytokine production via directly interacting with MD2 in vitro. In vivo, our data show that CAR treatment inhibited LPS-induced lung damage, systemic inflammatory cytokine production, and reduced macrophage infiltration in the lungs, accompanied with reduced TLR4/MD2 complex in lung tissues, Treatment with CAR also dose-dependently increased survival in the septic mice induced by DH5α bacterial infection.ConclusionWe demonstrate that a natural product, CAR, attenuates LPS-induced lung injury and sepsis by inhibiting inflammation via interacting with MD2, leading to the inactivation of the TLR4/MD2-MyD88-MAPK/NF-κB pathway.     

Honokiol: A review of its pharmacological potential and therapeutic insights

BackgroundHonokiol is a pleiotropic compound which been isolated from Magnolia species such as Magnolia grandiflora and Magnolia dealbata. Magnolia species Magnolia grandiflora is used in traditional medicine for the treatment of various diseases.PurposeThe objective of this review is to summarize the pharmacological potential and therapeutic insights of honokiol.Study designHonokiol has been specified as a novel alternative to treat various disorders such as liver cancer, neuroprotective, anti-spasmodic, antidepressant, anti-tumorigenic, antithrombotic, antimicrobial, analgesic properties and others. Therefore, this study designed to represent the in-depth therapeutic potential of honokiol.MethodsLiterature searches in electronic databases, such as Web of Science, Science Direct, PubMed, Google Scholar, and Scopus, were performed using the keywords ‘Honokiol’, ‘Health Benefits’ and ‘Therapeutic Insights’ as the keywords for primary searches and secondary search terms were used as follows: ‘Anticancer’, ‘Oxidative Stress’, ‘Neuroprotective’, ‘Antimicrobial’, ‘Cardioprotection’, ‘Hepatoprotective’, ‘Anti-inflammatory’, ‘Arthritis’, ‘Reproductive Disorders’.ResultsThis promising bioactive compound presented an wide range of therapeutic and biological activities which include liver cancer, neuroprotective, anti-spasmodic, antidepressant, anti-tumorigenic, antithrombotic, antimicrobial, analgesic properties, and others. Its pharmacokinetics has been established in experimental animals, while in humans, this is still speculative. Some of its mechanism for exhibiting its pharmacological effects includes apoptosis of diseased cells, reduction in the expression of defective proteins like P-glycoproteins, inhibition of oxidative stress, suppression of pro-inflammatory cytokines (TNF-α, IL-10 and IL-6), amelioration of impaired hepatic enzymes and reversal of morphological alterations, among others.ConclusionAll these actions displayed by this novel compound could make it serve as a lead in the formulation of drugs with higher efficacy and negligible side effects utilized in the treatment of several human diseases.     

Investigating the medicinal potential,material basis and mechanism of Polygoni Orientalis Fructus based on multi-technology integrated network pharmacology

BackgroundPolygoni Orientalis Fructus (POF) refers to the dried ripe fruit of Polygonum orientale L. which has a long historical application in clinic for treatment of various conditions in China. However, its chemical constituents, pharmacological effects and their coupled correlation have not been intensively investigated.PurposeIn present work, we aimed to elucidate the medicinal material basis, optimum indication and corresponding therapeutic mechanism of POF.MethodsThe main phytochemical ingredients in POF were characterized by liquid chromatography-mass spectrometry (LC-MS) analysis. The optimum medicinal potential and corresponding molecular mechanism of POF were deduced based on integrated statistic pattern recognition and network pharmacology. The deduced pharmacologic efficacy and mechanism of POF were further validated through in vitro study in free-fatty acid (FFA)-induced LO₂ cells.ResultsTotal 30 main phytochemical ingredients were identified in POF in which 18 ingredients were screened to yield 277 potential targets. Based on analyzing the quantitative data matrix of drug-disease targets by statistic pattern recognition, non-alcoholic fatty liver disease (NAFLD) was screened as the optimum indication of POF from 23 candidate diseases. Promising action targets (PPARG, IL6, TNF, IL1B, IKBKB, RELA, etc.) and signaling pathways (AMPK signaling pathway, NF-κB signaling pathway, etc.) were screened and refined to elucidate the therapeutic mechanism of POF against NAFLD based on network pharmacology. In vitro study demonstrated that POF effectively alleviated FFA-induced steatosis, oxidative stress, mitochondrial dysfunction and inflammation, and these beneficial effects were attributed to the activation of AMPK signaling pathway and suppression of NF-κB signaling pathway.ConclusionPOF could be exploited as a promising phytotherapy in the treatment of NAFLD.     

小叶丁香引种栽培条件下种子败育的解剖学研究

为探讨小叶丁香在北京栽培条件下种子败育的问题,对其胚胎发育过程进行了解剖学观察研究。结果显示:(1)小叶丁香人工异花授粉坐果率为20.37%,天然授粉坐果率为9.13%,人工自花授粉以及去雄套袋授粉均未坐果;各种授粉方式结实率均为0。(2)小叶丁香花药壁发育为基本型,腺质绒毡层,胞质分裂为同时型,小孢子四分体排列方式以四面体型为主,2-胞成熟花粉;倒生胚珠,单珠被,薄珠心,直线型大孢子四分体,胚囊发育为蓼型,核型胚乳,胚发育为紫菀型,先后形成球形胚、心形胚、鱼雷形胚和子叶胚;9月1日以后,子叶胚发育停滞,细胞逐渐降解。研究表明,栽培条件下,小叶丁香为异花授粉植物,人工异花授粉可提高植株坐果率,但未获得种子;其大小孢子及雌雄配子体发育、传粉受精过程、胚胎发育初期均正常,但后期发育停止,是小叶丁香引种栽培条件下种子败育的关键环节。     

Echinacea in hepatopathy: A review of its phytochemistry,pharmacology, and safety

BackgroundEchinacea, one of the most popular herbs with double function of immunity and anti-inflammatory activity, has now attracted much interest for a possible alternative for the treatment of hepatopathy. This review is aimed at providing a comprehensive overview of Echinacea regarding its chemical composition, pharmacological action against various hepatopathy, and safety.MethodsA comprehensive search of published articles was conducted to focus on original publications related to Echinacea and hepatopathy till the end of 2020 using various literature databases, including China National Knowledge Infrastructure, PubMed, and Web of Science database.ResultsEchinacea exhibited excellent activities in resisting a variety of hepatopathy induced by different causes in preclinical experiments and clinical trials by regulating cell proliferation and apoptosis, antioxidant defense mechanism, voltage-gated sodium channels, lipid metabolism, circadian rhythm, p38 MAPK signaling pathway, JNK signaling pathway, Nrf2/HO-1 signaling pathway, PI3K/AKT signaling pathway, and Akt/GSK3 beta signaling pathways. The high efficacy of Echinacea is related to its immunomodulatory and anti-inflammatory activities. The main ingredients of Echinacea include caffeic acid derivatives, alkylamides, and polysaccharides, which have been well established in preclinical studies of liver diseases. Studies on acute and subacute toxicity show that Echinacea preparations are well-tolerated herbal medicines.ConclusionEchinacea may offer a novel potential strategy for clinical prevention and treatment of liver diseases and related diseases. Extensive studies are necessary to identify the underlying mechanisms and establish future therapeutic potentials of this herb. Well-designed clinical trials are still warranted to confirm the safety and effectiveness of Echinacea for hepatopathy.     

Evodiamine and rutaecarpine from Tetradium ruticarpum in the treatment of liver diseases

BackgroundLiver is the pivotal organ responsible for plasma protein production, biliary secretion, xenobiotic elimination, glucose and lipid homeostasis. Dysregulation of these functions usually leads to liver diseases and further related complications. The incidence of liver diseases is increasing worldwide, with high morbidity and mortality when at advanced stages, and has become significant public health concern and substential economic burden. Thus, novel therapeutic strategies for managing liver diseases progression are urgently required. T. ruticarpum is one of the most famous and frequently used herbal medicine and has been prescribed in traditional Chinese medicine (TCM) formulas for the treatment of various ailments, including liver diseases. A considerable amount of bioactive ingredients have been isolated and identified from the roots of T. ruticarpum, including alkaloids, saponins, phenols, volatile oils and other compounds. Among these compounds, evodiamine (EVO) and rutaecarpine (RUT) are believed to be the most bioactive compounds.PurposeTo summarize recent findings regarding to the metabolism, pharmacological/toxicological effects of EVO and RUT and to highlight the potential therapeutic effects of them against liver diseases.MethodsOnline academic databases (including PubMed, Google Scholar, Web of Science and CNKI) were searched using search terms of “T. ruticarpum”, “Wu Zhu Yu”, “evodiamine”, “rutaecarpine”, “liver” and combinations to include published studies of EVO and RUT primarily from 2004–2019. Several critical previous studies beyond this period were also included.ResultsEvodiamine (EVO) and rutaecarpine (RUT) are believed to be the most bioactive alkaloids in T. ruticarpum, having anti-inflammation, anti-fibrosis, anti-lipotoxicity, anti-cancer activities, and thus having potential to improve liver disorders. In the current review, we comprehensively summarized recent progresses in the studies of EVO- and RUT-mediated promising hepatoprotective effects and also provide novel insights regarding the potential use of EVO and RUT as therapeutic options for the treatment of liver diseases.ConclusionWith further in-depth pharmacology and pharmacokinetic studies, we believe that natural products in T. ruticarpum and their derivatives will become promising medicines with improved clinical efficacy for the treatment of liver diseases in the immediate future.     

Development of a standardized and effect-optimized herbal extract of Wedelia chinensis for prostate cancer

Herbal medicine is a popular complementary or alternative treatment for prostate cancer. Wedelia chinensis has at least three active compounds, wedelolactone, luteolin, and apigenin synergistically inhibiting prostate cancer cell growth in vitro. Here, we report a systematic study to develop a standardized and effect-optimized herbal extract, designated as W. chinensis extract (WCE) to facilitate its future scientific validation and clinical use. Ethanolic extract of dried W. chinensis plant was further condensed, acid hydrolyzed, and enriched with preparative chromatography. The chemical compositions of multiple batches of the standardized preparation WCE were quantified by LC/MS/MS, and biological activities were analyzed by in vitro and in vivo assays. Furthermore, the pharmacokinetics of the holistic WCE were compared with the combination of the equivalent principal active compounds through oral administration. The results indicated that quantitative chemical assay and PSA (prostate-specific antigen)-reporter assay together are suitable to measure the quality and efficacy of a standardized Wedelia extract on a xenograft tumor model. The presence of minor concomitant compounds in WCE prolonged the systemic exposure to the active compounds, thus augmented the anti-tumor efficacy of WCE. In conclusion, a combination of LC/MS/MS and PSA reporter assay is suitable to qualify a standardized preparation of WCE. Furthermore, the pharmacokinetics and oral bioavailability of active compounds demonstrate that holistic WCE exerted additional pharmacological synergy beyond the multi-targeted therapeutic effects caused by more than one active compound. WCE merits a higher priority to be studied for use in prostate cancer treatment.     

Discovery of quality-marker ingredients of Panax quinquefolius driven by high-throughput chinmedomics approach

BackgroundQuality control of traditional Chinese medicine (TCM) has always been a hot issue to TCM. However, due to the complexity of TCM ingredients, the current quality standards of TCM have problems that are difficult to guarantee clinical efficacy. American ginseng, the dried roots of Pawajc quinquefolium L. (Araliaceae), is a valuable herbal medicine due to various pharmacological effects and huge health benefit, which are associated with numerous active ingredients such as ginsenosides. Although a large number of studies have investigated the active ingredients of American ginseng, Q-markers reflecting comprehensive review on its efficacies has yet been unrevealed.PurposeThe study aims to discover the Q-markers of Panax quinquefolius (American ginseng), provides a powerful method to clarify the significant ingredents of TCM and help further discovering extensive quality evaluation model,contributing to a significant improvement of TCM quality standard.MethodsMice general status, biochemical indexes assay, urine metabolic profile, and serum metabolic profile were utilized for model replication and efficacy evaluation. The in vitro and in vivo constituents of American ginseng using ultra-high performance liquid chromatography coupled with mass spectrometry (UPLC-MS) with Serum Pharmacochemistry of TCM were in-depth investigated. Q-markers that were associated with core markers of therapeutic effects were excavated by a plotting of correlation between marker metabolites and serum constituents (PCMS) approach.ResultsCorrelation analysis of 41 blood and urine labeled metabolites with 14 serum components showed that 24-methyl-7-cholesten-3β-ol, zizybeoside II, betulin, ginsenoside Rd, cinnamyl alcohol, pseudoginsenoside F11 is highly correlated with the therapeutic effects of Compound Zaofan Pill (CZP), while pseudoginsenoside F11 and ginsenoside Rd are highly correlated with the therapeutic effects of American ginseng. The six absorbed blood compounds can be considered as potential Q-markers for compound, of which two compounds, such as pseudoginsenoside F11 and ginsenoside Rd, can be considered as potential Q-markers for American ginseng.ConclusionThe study has demonstrated that the Chinmedomics is an effective, comprehensive and fire-new method for discovering the Q-markers of TCM, and it may be more reasonable choices to establish quality standards of TCM.     

Identification of a novel BACE1 inhibitor,timosaponin A-III,for treatment of Alzheimer's disease by a cell extraction and chemogenomics target knowledgebase-guided method

BackgroundRhizoma Anemarrhenae (RA) has been conventionally used for treatment of Alzheimer's disease (AD) in Traditional Chinese Medicine, and thus, the active components from RA can be screened.PurposeThis research aimed to identify the active components of RA and their targets and further clarify the molecular mechanisms underlying its anti-AD activity.MethodsFirst, the potential active compounds from RA were screened by neurocyte extraction and micro-dialysis methods. Second, the potential targets were predicted by a chemogenomics target knowledgebase and further explored by surface plasmon resonance and enzyme activity assays. Third, the pharmacological effects were evaluated by employing APP/PS1 transgenic mice and SH-SY5Y-APP cells. ELISAs and Western blot analyses were used to evaluate the expression of key molecules in the amyloidogenic and NMDAR/ERK pathways.ResultsTimosaponin A-III (TA-III) was screened and identified as a potential active component for the anti-AD activity, and BACE1 was proven to be a potential high-affinity target. Enzyme kinetic analysis showed that TA-III had strong noncompetitive inhibitory activity against BACE1. The in vitro and in vivo assays indicated that TA-III had pharmacological effects through improving memory impairment, reducing Aβ aggregation via the amyloidogenic pathway and preventing neuronal impairment through downregulating the NMDAR/ERK signaling pathway.ConclusionTA-III targets BACE1 to reduce Aβ aggregation through down-regulating the NMDAR/ERK pathway for treating AD.     

Botany,traditional uses,phytochemistry and pharmacological properties of Saussurea costus – An endangered plant from Himalaya- A review

Saussurea costus (Falc.) Lipsch. Syn. Saussurea lappa C.B. Clarke belongs to family Asteraceae and is a critically endangered plant that is monetarily very vital as a therapeutic herb of North - West Himalaya. Saussurea costus has been traditionally used to treat a variety of ailments in different indigenous health systems viz., carminative, expectorant, antiarthritic, antiseptic, aphrodisiac, anodyne and vermifuge without any noticeable adverse effects. Textbooks on ethnobotany, peer-reviewed academic publications, unpublished materials, and research repositories were used to collect the widespread review of literature on Saussurea costus. The scientific names were authenticated by using Kew Botanical Garden, International Plant Name Index and Plant List databases. Costunolide, dihydrocostunolide, sesquiterpene lactones and cynaropicrin have been identified as major phytoconstituents of Saussurea costus with great potency to develop as a drug candidate. Different pharmacological experiments convincingly confirmed the potential of Saussurea costus with anticancer, anti-ulcer, hepatoprotective activities, etc. providing support to the various traditional uses associated with Saussurea costus. Saussurea costus will be a preferable alternative for novel drug discovery due to its notable pharmacological properties. Although the existing information to far indicates the security and possibly efficacy of Saussurea costus, bioactive ingredients, physiological mechanisms, pharmacokinetics, accessibility, and the impact on human health are not fully understood. The present review piles up the up-to-date and widespread information on botany, traditional uses, phytochemistry and pharmacology of Saussurea costus, to assess its therapeutic potential, with a focus on in vitro, biomedical, and histopathological experiments.     

Synthesis and antibacterial property of quinolines with potent DNA gyrase activity

Synthesis of a series of novel tetrahydroquinoline annulated heterocycles has been accomplished by intramolecular imino and bisimino Diels–Alder reaction. These compounds were evaluated for their antibacterial activity. All the synthetic compounds, exhibited good antibacterial activity against microorganisms of which one of them 7 was found to be as active as the antibiotic ciplofloxacin and is found to have MIC value of 2.5 mg/mL against Escherichia coli.     

Overview of therapeutic potentiality of Angelica sinensis for ischemic stroke

BackgroundIschemic stroke is a common cerebrovascular disease. Due to sudden interruption of blood flow by arterial thrombus, amounts of neurons in ischemic central and penumbral regions occur necrosis and apoptosis resulting in serious injury of neurological function. Chinese medicines have a great advantage in ischemic stroke treatment and recovery, especially Angelica sinensis.PurposeThere are a large number of studies reported that Angelica injection and A. sinensis active compounds. We systematically reviewed the effects and mechanisms of A. sinensis in recent years according to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statements, and excavated its therapeutic potentiality for exploring more effective and safe compounds for ischemic stroke precision treatment.ResultsA. sinensis extracts and active compounds, such as Z-ligustilide, 3-n-Butylphthalide, and ferulic acid have significant effects of anti-inflammation, anti-oxidative stress, angiogenesis, neurogenesis, anti-platelet aggregation, anti-atherosclerosis, protection of vessels, which contributes to improvement of neurological function on ischemic stroke.ConclusionA. sinensis is a key agent for ischemic stroke treatment, and worth deeply excavating its therapeutic potentiality with the aid of pharmacological network, computer-aided drug design, artificial intelligence, big data and multi-scale modelling techniques.     

Huperzine A from <Emphasis Type="Italic">Huperzia serrata:</Emphasis> a review of its sources,chemistry, pharmacology and toxicology

The use and popularity of herbal medicines has been increasing worldwide. In fact, today, the traditional Chinese medicine offers a vast repertory for pharmaceutical research, as is the case of Huperzia serrata, a member of Huperziaceae family. This review reports the Lycopodium alkaloids that have been isolated from this plant. However, it was mainly focused on the huperzine A (HupA), a promising therapeutic option in several acute and chronic disorders. The major therapeutic interest described for HupA has been directed to the treatment of acetylcholine-deficit dementia, including Alzheimer’s disease. However, HupA was also shown to be effective on cerebrovascular dementia and other neurodegenerative disorders with an ischemic component, as well as on other kind of cognitive impairments; the value of HupA on myasthenia gravis, organophosphate poisoning and schizophrenia has also been described. In addition, many other pharmacological properties have been ascribed to HupA, namely its anti-inflammatory, antinociceptive and anticonvulsant properties, which was recently identified, promoting a growing interest on HupA research. Furthermore, its particular chemical structure and the fact that HupA is well tolerated in humans, even at doses well above those clinically required, along with its favorable pharmacokinetics, also boosted an intense research in the pharmaceutical industry. Therefore, several HupA-related features are addressed in this review, including not only its therapeutic properties, but also its chemistry, biological and chemical sources, structure–activity relationship, pharmacokinetics and toxicology, which are discussed in detail covering the literature published from 1962 to 2014.     

A novel strategy for screening bioavailable quality markers of traditional Chinese medicine by integrating intestinal absorption and network pharmacology: Application to Wu Ji Bai Feng Pill

BackgroundMajor components are often used as marker compounds for quality control of traditional Chinese medicines (TCMs). However, these compounds may not necessarily bioavailable and active in vivo, thereby, failing to control the “quality”.PurposeThe purpose of this paper is to develop a novel strategy integrating absorption and activity deduced from network pharmacology to identify more reasonable markers for quality control of TCM formulas using Wu Ji Bai Feng Pill (WJBFP) as an example.Study DesignHuman Caucasian colon adenocarcinoma (Caco-2) cell transport studies and a bioavailability-enhanced network pharmacological approach were integrated to identify better phytochemical markers for quality control.MethodsThe absorption of multiple components in WJBFP was evaluated by a Caco-2 cell culture model. Nine databases were used to identify potential targets in the network pharmacology analysis. Cytoscape 3.7.2 was employed for the network data integration, visualization, and centrality analysis. Molecular docking was carried out to investigate the binding affinity of the identified markers to their candidate targets.ResultsThe apparent permeability coefficient (Papp) and efflux ratio (ER) of 66 compounds were determined. Five hundred and two putative targets and 187 primary dysmenorrhea (PD) related targets were identified. Twenty-two candidate targets interacting with 20 potential active compounds were screened with the putative PD related targets intersection network using Degree Centrality (DC) ranking. By integrating absorption, 16 candidate targets interacting with 8 potential active compounds were identified. Besides, 53 compounds hitting candidate targets were divided into two classes according to their DC values. Then each of the two classes of DC was stratified into two groups based on the Papp for a total of four classes. Finally, five compounds belonging to Class 1 with higher DC and higher Papp, formononetin, ferulic acid, isoliquiritigenin, neocryptotanshinone and senkyunolide A, were identified as potential bioavailable phytochemical markers for the quality control of WJBFP against PD. Furthermore, molecular docking analysis validated the interplay between candidate targets and marker ingredients.ConclusionA novel strategy combining intestinal absorption with network pharmacology analysis was successfully established to identify bioavailable and bioactive markers for quality control of WJBFP against PD.     

The Ethanol Extract of Syringa oblata Heartwood,a Mongolian Folk Medicine Containing Major Lignans,Exerts Analgesic and Sedative Effects on Mice

The heartwood of Syringa oblata Lindl. (SO) is one of Mongolian folk medicines to treat insomnia and pain, while its pharmacological evaluation and underlying mechanism remain unclear. In this study, the sedative effect of ethanol extract of SO (ESO) was evaluated with the locomotor activity test and the threshold dose of pentobarbital sodium-induced sleep test in mice, and the hot plate test, acetic acid-induced writhing test, and formalin test in mice were used to evaluate its analgesic effect. The underlying mechanism of ESO analgesia was explored by RT-PCR and western blot analysis, which is associated with the regulation of the NF-κB signaling pathway. Besides, the main constituents of ESO were characterized by LC/MS data analysis and comparison with isolated pure compounds. The current findings brought evidence for clinical application and further pharmacological and phytochemical studies on SO.