Zebrafish bioassay-guided natural product discovery: isolation of angiogenesis inhibitors from East African medicinal plants

Natural products represent a significant reservoir of unexplored chemical diversity for early-stage drug discovery. The identification of lead compounds of natural origin would benefit from therapeutically relevant bioassays capable of facilitating the isolation of bioactive molecules from multi-constituent extracts. Towards this end, we developed an in vivo bioassay-guided isolation approach for natural product discovery that combines bioactivity screening in zebrafish embryos with rapid fractionation by analytical thin-layer chromatography (TLC) and initial structural elucidation by high-resolution electrospray mass spectrometry (HRESIMS). Bioactivity screening of East African medicinal plant extracts using fli-1:EGFP transgenic zebrafish embryos identified Oxygonum sinuatum and Plectranthus barbatus as inhibiting vascular development. Zebrafish bioassay-guided fractionation identified the active components of these plants as emodin, an inhibitor of the protein kinase CK2, and coleon A lactone, a rare abietane diterpenoid with no previously described bioactivity. Both emodin and coleon A lactone inhibited mammalian endothelial cell proliferation, migration, and tube formation in vitro, as well as angiogenesis in the chick chorioallantoic membrane (CAM) assay. These results suggest that the combination of zebrafish bioassays with analytical chromatography methods is an effective strategy for the rapid identification of bioactive natural products.     

Drug discovery from natural products

Natural product compounds are the source of numerous therapeutic agents. Recent progress to discover drugs from natural product sources has resulted in compounds that are being developed to treat cancer, resistant bacteria and viruses and immunosuppressive disorders. Many of these compounds were discovered by applying recent advances in understanding the genetics of secondary metabolism in actinomycetes, exploring the marine environment and applying new screening technologies. In many instances, the discovery of a novel natural product serves as a tool to better understand targets and pathways in the disease process. This review describes recent progress in drug discovery from natural sources including several examples of compounds that inhibit novel drug targets.     

Importance of ethnopharmacological studies in drug discovery: role of medicinal plants

Phytochemistry Reviews - Ethnopharmacology can be basically defined as “the interdisciplinary scientific exploration of the biologically active agents that are traditionally employed”....     

Drug discovery opportunities from apoptosis research

Cell suicide is a normal process that participates in a wide variety of physiological processes, including tissue homeostasis, immune regulation, and fertility. Physiological cell death typically occurs by apoptosis, as opposed to necrosis. Defects in apoptotic cell-death regulation contribute to many diseases, including disorders associated with cell accumulation (e.g. cancer, autoimmunity, inflammation and restenosis) or where cell loss occurs (e.g. stroke, heart failure, neurodegeneration, AIDS and osteoporosis). At the center of the apoptosis machinery is a family of intracellular proteases, known as 'caspases', that are responsible directly or indirectly for the morphological and biochemical events that characterize apoptosis. Multiple positive and negative regulators of these cell-death proteases have been discovered in the genomes of mammals, amphibians, insects, nematodes, and other animal species, as well as a variety of animal viruses. Inputs from signal-transduction pathways into the core of the cell-death machinery have also been identified, demonstrating ways of linking environmental stimuli to cell-death responses or cell-survival maintenance. Knowledge of the molecular mechanisms of apoptosis has provided important insights into the causes of multiple diseases where aberrant cell-death regulation occurs and has revealed new approaches for identifying small-molecule drugs for more effectively treating these illnesses.     

List of medicinal plants from Epigraphia Indica

It is of interest to list plants and its usage in olden days. The history of plants is closely related with the history of medicine since time immemorial. Various literature data shows the usage of medicinal plants. It is linked to various system of medicine like Siddha, Ayurveda and Unani. This is in practice for more than 5000 years. People in olden age had a detailed knowledge on these plants. Hence, we collected such data from the first five volumes of Epigraphia Indica, which was published, by the Archeological survey of India from 1882 to 1977. These data provides a framework on various plants and its usage in various ways, in different time period in human history. This helps us to drive valuable bio-medical information for application in modern scientific biomedical methods. We further plan to sort and glean such data so as to help in evaluating the total biomedical data in Epigraphia Indica to extract useful biological knowledge for application in evidence-based biomedicine.     

Anti-HIV-1 efficacy of extracts from medicinal plants

The anti-HIV-1 activities of butanol, hexane, chloroform and water extracts from four widely used folk medicinal plants (Sophora flavescens, Tulipa edulis, Herba ephedra, and Pachyma hoelen Rumph) were evaluated in this study. The hexane extract of Pachyma hoelen Rumph, PH-4, showed effective inhibition against HIV-1. The 50% effective concentration (EC₅₀) of PH-4 was 37.3 μg/ml in the p24 antigen assay and 36.8% in the HIV-1 recombinant RT activity test (at 200 μg/ml). In addition, the PH-4 showed the protective effect on the infected MT-4 cells, with a 58.2% rate of protection. The 50% cytotoxic concentration (CC₅₀) of PH-4 was 100.6 μg/ml. These results suggest that PH-4 from Pachyma hoelen Rumph might be the candidate for the chemotherapy agent against HIV-1 infection with further study.     

Antihyperglycemic activity of compounds isolated from Indian medicinal plants

Eleven antidiabetic Indian medicinal plants were investigated in streptozotocin induced diabetic rat model and provided scientific validation to prove their antihyperglycemic activity. Antidiabetic principles from five plants were isolated. All the compounds isolated were evaluated for antihyperglycemic activity in streptozotocin induced diabetic rat model and activities were compared with standard drug metformin. Some compounds were also screened in db/db mice. Two compounds (PP-1 and PP-2) inhibited significantly the activity of PTPase-1B in an in vitro system. This might be the underlying mechanism of antihyperglycemic activity of these compounds.     

Therapeutic agents from endophytes harbored in Asian medicinal plants

Phytochemistry Reviews - Endophytes are a diverse group of microorganisms present in plant tissues which include fungi and bacteria and have been utilized as therapeutic agents. They are known to...     

植物内生真菌: 获取抗癌药物白藜芦醇的新途径

白藜芦醇(Resveratrol)是一种含有芪类结构的非黄酮类多酚化合物,以游离态和糖苷结合态(白藜芦醇苷)两种形式存在于植物中,是植物受到病菌感染或环境恶化时产生的应激产物.常见的含有白藜芦醇(苷)的植物有葡萄、虎杖、花生、桑椹、藜芦、决明等.近年的研究表明,白藜芦醇(苷)具有显著的抗炎、抗氧化、神经保护和心血管保护等作用,可预防和治疗多种疾病,有较高的使用安全性,已成为抑制和治疗组织癌变和肿瘤发生的最有前途的药物之一.     

Acidic heteroxylans from medicinal plants and their anti-ulcer activity

Xylans are the main hemicelluloses found in higher plants, and are often present in phytotherapic medicines. An acidic heteroxylan was obtained from Maytenus ilicifolia leaves by hot 10% aqueous KOH extraction. This was subjected to freeze-thawing process, giving insoluble and soluble fractions and the latter treated with Fehling solution. Its insoluble fraction (MI-HX) was further examined. The acidic heteroxylan gave xylose, galactose, glucose, and 4-O-methylglucuronic acid in a 76:6:9:9 molar ratio and methylation analyses and ¹³C NMR spectroscopy showed its main chain consists of 4-O-linked β-d-Xylp units. This polysaccharide and another acidic heteroxylan from Phyllanthus niruri had anti-ulcer activity and were able to reduce gastric lesions induced by ethanol by 65% and 78%, with ED₅₀ = 40.0 and 20.4 mg/kg, each respectively. These results suggest that this class of polysaccharide has a protective anti-ulcer effect, and that there is a relation between its chemical structure and biological function.     

Drug discovery in academia

Drug discovery and development is generally done in the commercial rather than the academic realm. Drug discovery involves target discovery and validation, lead identification by high-throughput screening, and lead optimization by medicinal chemistry. Follow-up preclinical evaluation includes analysis in animal models of compound efficacy and pharmacology (ADME: administration, distribution, metabolism, elimination) and studies of toxicology, specificity, and drug interactions. Notwithstanding the high-cost, labor-intensive, and non-hypothesis-driven aspects of drug discovery, the academic setting has a unique and expanding niche in this important area of investigation. For example, academic drug discovery can focus on targets of limited commercial value, such as third-world and rare diseases, and on the development of research reagents such as high-affinity inhibitors for pharmacological "gene knockout" in animal models ("chemical genetics"). This review describes the practical aspects of the preclinical drug discovery process for academic investigators. The discovery of small molecule inhibitors and activators of the cystic fibrosis transmembrane conductance regulator is presented as an example of an academic drug discovery program that has yielded new compounds for physiology research and clinical development. high-throughput screening; drug development; pharmacology; fluorescence; cystic fibrosis transmembrane conductance regulator     

Phenolic compounds in medicinal plants

Compositions of phenolic substances were studied in leaves of 21 species of medicinal plants. Flavonoid levels varied from 1.94 to 5.42%, whereas total amounts of monomeric polyphenols and hydroxybenzoic acids were estimated as 0.27 to 0.57%, and hydroxycinnamic acids and their esters with quinic acid, 0.09 to 0.18%. Condensed and polymerized polyphenols were detected in amounts of 0.41 to 1.20%. Qualitative compositions of flavonoids in leaves of seven plants studied were presented. The developed analytical procedures may be useful for plant polyphenol studies and as the basis of hemotaxonomy.