Potential of diterpenes as antidiabetic agents: Evidence from clinical and pre-clinical studies.

Diterpenes are a diverse group of structurally complex natural products with a wide spectrum of biological activities, including antidiabetic potential. In the last 25 years, numerous diterpenes have been investigated for antidiabetic activity, with some of them reaching the stage of clinical trials. However, these studies have not been comprehensively reviewed in any previous publication. Herein, we critically discussed the literature on the potential of diterpenes as antidiabetic agents, published from 1995 to September, 2021. In the period under review, 427 diterpenes were reported to have varying degrees of antidiabetic activity. Steviol glycosides, stevioside (1) and rebaudioside A (2), were the most investigated diterpenes with promising antidiabetic property using in vitro and in vivo models, as well as human subjects. All the tested pimaranes consistently showed good activity in preclinical evaluations against diabetes. Inhibitions of α-glucosidase and protein tyrosine phosphatase 1B (PTP 1B) activities and peroxisome proliferator-activated receptors gamma (PPAR-γ) agonistic property, were the most frequently used models for studying the antidiabetic activity of diterpenes. The molecular mechanisms of action of the diterpenes include increased GLUT4 translocation, and activation of phosphoinositide 3-kinase (PI3K) and AMP-activated protein kinase (AMPK)-dependent signaling pathways. This review revealed that diterpenes hold promising antidiabetic potential while stevioside (1) and rebaudioside A (2) are the only diterpenes that were advanced to the clinical trial stage of the drug discovery pipeline. Diterpenes belonging to the abietane, labdane, pimarane and kaurane classes have shown promising activity in in vitro and in vivo models of diabetes and should be further investigated.

Phloroglucinol as a Potential Candidate against Trypanosoma congolense Infection: Insights from In Vivo, In Vitro, Molecular Docking and Molecular Dynamic Simulation Analyses.

Sub-Saharan Africa is profoundly challenged with African Animal Trypanosomiasis and the available trypanocides are faced with drawbacks, necessitating the search for novel agents. Herein, the chemotherapeutic potential of phloroglucinol on T. congolense infection and its inhibitory effects on the partially purified T. congolense sialidase and phospholipase A2 (PLA2) were investigated. Treatment with phloroglucinol for 14 days significantly (p < 0.05) suppressed T. congolense proliferation, increased animal survival and ameliorated anemia induced by the parasite. Using biochemical and histopathological analyses, phloroglucinol was found to prevent renal damages and splenomegaly, besides its protection against T. congolense-associated increase in free serum sialic acids in infected animals. Moreover, the compound inhibited bloodstream T. congolense sialidase via mixed inhibition pattern with inhibition binding constant (Ki) of 0.181 µM, but a very low uncompetitive inhibitory effects against PLA2 (Ki > 9000 µM) was recorded. Molecular docking studies revealed binding energies of -4.9 and -5.3 kcal/mol between phloroglucinol with modeled sialidase and PLA2 respectively, while a 50 ns molecular dynamics simulation using GROMACS revealed the sialidase-phloroglucinol complex to be more compact and stable with higher free binding energy (-67.84 ± 0.50 kJ/mol) than PLA2-phloroglucinol complex (-77.17 ± 0.52 kJ/mol), based on MM-PBSA analysis. The sialidase-phloroglucinol complex had a single hydrogen bond interaction with Ser453 while none was observed for the PLA2-phloroglucinol complex. In conclusion, phloroglucinol showed moderate trypanostatic activity with great potential in ameliorating some of the parasite-induced pathologies and its anti-anemic effects might be linked to inhibition of sialidase rather than PLA2.

Antidiabetic potential of anthraquinones: A review.

The present study was designed to review the antidiabetic potential of anthraquinones (AQs) with emphasis on the extent of blood glucose reduction, the half maximal inhibitory concentration values (in vitro studies), the proposed mechanisms of action, and the structure activity relationship studies. We sourced relevant data from the major scientific databases (Pubmed, Science Direct, Medline, and Google Scholar). According to our search, 25 AQs have shown variable antidiabetic potential, whereas one AQ (morindone-6-O-ß-D-primeveroside) showed no blood glucose-lowering ability. Emodin and rhein showed the most promising antidiabetic potential in various models. The proposed mechanisms of antidiabetic action include upregulation of insulin receptor substrates-1, phosphoinositide-3-kinase, and Akt-ser473 expression and elevation of glucagon-like peptide-1 level in diabetic animal models linked to the potent protein tyrosine phosphatase 1B and dipeptidyl peptidase-4 inhibitions. In addition, activation of peroxisome proliferator-activated receptors gamma and inhibition of α-glucosidase activity are other possible targets proposed as the mechanism of AQs antidiabetic action. The position and the number of hydroxyl group showed great influence on the overall antidiabetic potential of AQs. AQs hold promising antidiabetic activity despite scanty information. We hope that the present study will serve as a template to further explore the antidiabetic potential of AQs and subsequent antidiabetic drug development.

A systematic review of pentacyclic triterpenes and their derivatives as chemotherapeutic agents against tropical parasitic diseases.

Parasitic infections are among the leading global public health problems with very high economic and mortality burdens. Unfortunately, the available treatment drugs are beset with side effects and continuous parasite drug resistance is being reported. However, new findings reveal more promising compounds especially of plant origin. Among the promising leads are the pentacyclic triterpenes (PTs) made up of the oleanane, ursane, taraxastane, lupane and hopane types. This paper reviews the literature published from 1985 to date on the in vitro and in vivo anti-parasitic potency of this class of phytochemicals. Of the 191 natural and synthetic PT reported, 85 have shown high anti-parasitic activity against various species belonging to the genera of Plasmodium, Leishmania, Trypanosoma, as well as various genera of Nematoda. Moreover, structural modification especially at carbon 3 (C3) and C27 of the parent backbone of PT has led to improved anti-parasitic activity in some cases and loss of activity in others. The potential of this group of compounds as future alternatives in the treatment of parasitic diseases is discussed. It is hoped that the information presented herein will contribute to the full exploration of this promising group of compounds as possible drugs for parasitic diseases.

Sesquiterpene lactones from Polydora serratuloides and their quorum sensing inhibitory activity.

The leaves of Polydora serratuloides, with the synonym Vernonia perrottetii are widely used as purgative agents for gastrointestinal problems, and other members of Vernonieae have been used in African traditional medicine for decades. A new sesquiterpene lactone of the keto-hirsutinolide type, 13-acetoxy-1(4ß),5(6)ß-diepoxy-8α-(senecioyloxy)-3-oxo-1,7(11)-germacradiene-12,6-olide 1, was isolated from the hexane extract of its leaves, in addition to the known 13-acetoxy-1,4ß-epoxy-8α-(senecioyloxy)-3-oxo-1,5,7(11)-germacratriene-12,6-olide 2. Three common flavonoids (apigenin 3, luteolin 4 and velutin 5) were also isolated. The antibacterial and quorum sensing inhibitory activities of compounds 1 and 2 and crudes extracts showed limited activity on Bacillus subtilis and Staphylococcus aureus, with no activity on Gram negative bacteria. However, quorum sensing (QSI) experiments indicated that 1 and 2, and the four crude extracts had interesting inhibitory activity on the biosensor organism, Chromobacterium violaceum ATCC 12472 in the range of 0.33-5.25 mg mL-1, with compound 1 being the most effective at 0.33 mg mL-1.

Quorum sensing inhibitory potential and molecular docking studies of sesquiterpene lactones from Vernonia blumeoides.

The increasing incidence of multidrug-resistant Gram-negative bacterial pathogens has focused research on the suppression of bacterial virulence via quorum sensing inhibition strategies, rather than the conventional antimicrobial approach. The anti-virulence potential of eudesmanolide sesquiterpene lactones previously isolated from Vernonia blumeoides was assessed by inhibition of quorum sensing and in silico molecular docking. Inhibition of quorum sensing-controlled violacein production in Chromobacterium violaceum was quantified using violacein inhibition assays. Qualitative modulation of quorum sensing activity and signal synthesis was investigated using agar diffusion double ring assays and C. violaceum and Agrobacterium tumefaciens biosensor systems. Inhibition of violacein production was concentration-dependent, with ⩾90% inhibition being obtained with ⩾2.4 mg ml(-1) of crude extracts. Violacein inhibition was significant for the ethyl acetate extract with decreasing inhibition being observed with dichloromethane, hexane and methanol extracts. Violacein inhibition ⩾80% was obtained with 0.071 mg ml(-1) of blumeoidolide B in comparison with ⩾3.6 mg ml(-1) of blumeoidolide A. Agar diffusion double ring assays indicated that only the activity of the LuxI synthase homologue, CviI, was modulated by blumeoidolides A and B, and V. blumeoides crude extracts, suggesting that quorum sensing signal synthesis was down-regulated or competitively inhibited. Finally, molecular docking was conducted to explore the binding conformations of sesquiterpene lactones into the binding sites of quorum sensing regulator proteins, CviR and CviR'. The computed binding energy data suggested that the blumeoidolides have a tendency to inhibit both CviR and CviR' with varying binding affinities. Vernonia eudesmanolide sesquiterpene lactones have the potential to be novel therapeutic agents, which might be important in reducing virulence and pathogenicity of drug-resistant bacteria in vivo.

Sesquiterpene lactones from the aerial parts of Vernonia blumeoides growing in Nigeria.

Four eudesmanolide sesquiterpene lactones (1-4) were isolated from the aerial parts of Vernonia blumeoides used in Nigerian ethnomedicine for the treatment of diarrhea and malaria. Compound 1 demonstrated limited but interesting antibacterial activity against Bacillus, Staphylococcus and Streptococcus species. The crystal structure of 1 allowed the absolute configuration of the stereocentres in the molecule to be assigned.

Chemical composition and antimicrobial activity of hexane leaf extract of Anisopus mannii (Asclepiadaceae).

OBJECTIVE: The aim was to determine the chemical constituents and antimicrobial activity of the hexane leaf extract of Anisopus mannii against a wide range of human pathogenic microorganisms. METHODS: The chemical constituents of the hexane leaf extract was determined using gas chromatography-mass spectrometry (GC-MS) analysis; and the antimicrobial activity was evaluated on "standard strains", clinical susceptible and resistant bacterial and fungal isolates using the disc diffusion and broth microdilution methods. RESULTS: GC-MS analysis of the hexane leaf extract revealed 32 compounds, representing 73.8% of the identified components. The major compounds were hexadecanoic acid, ethyl ester (34%), oxirane, hexadecyl- (11%) and 9, 12, 15-octadecatrienoic acid, ethyl ester, (Z, Z, Z) (9.6%). Results from the antimicrobial activity demonstrated higher inhibition zones against Bacillus cereus (29 mm), followed by Streptococcus pyogenes (28 mm). Other notable inhibitions were observed with Enterococcus faecalis (27 mm), Proteus vulgaris (26 mm) and MRSA (25 mm). The MIC values ranged from 0.625 mg/mL to 1.25 mg/mL while the MBC/MFC values ranged from 2.5 mg/mL to 5.0 mg/mL. CONCLUSION: These results support the traditional use of the plant and demonstrate the huge potential of A. mannii as a source of antimicrobial compounds.

Anti-trypanosomal activity of African medicinal plants: a review update.

ETHNOPHARMACOLOGICAL RELEVANCE: African trypanosomiasis is one of the neglected tropical diseases caused by different species of trypanosomes that affect both human and livestock with devastating consequences in the continent. Most of the affected populations commonly use traditional medicinal plants for the treatment of the disease. Consequently, this prompted ethnopharmacological research activities on the anti-trypanosomal activity of a number of these African medicinal plants in order to validate their ethnomedicinal use. Furthermore, such studies could lead to the identification of chemical leads for the development of newer anti-trypanosomal agents from those plants. This review aims to provide updated information on the ethnopharmacological evidence of African medicinal plants with anti-trypanosomal activity. METHODS: Literature was collected via electronic search (PubMed, Sciencedirect, Medline and Google Scholar) from published articles that report on the in vitro or in vivo anti-trypanosomal activity of plants that were collected from different parts of Africa. RESULTS: African medicinal plants investigated for in vitro and in vivo anti-trypanosomal activity from January 1993 to October 2013 are systematically compiled and all the in vivo studies are critically discussed. A total of 264 plant species belonging to 79 families were investigated for anti-trypanosomal activity. However, only 48 bioactive anti-trypanosomal compounds were successfully isolated in pure forms. Furthermore, some of the plants were investigated for possible ameliorative effects on the trypanosome-induced pathological changes out of which 18 plants were reported to be effective while a few others were not. In spite of interesting preclinical ethnopharmacological evidence for anti-trypanosomal activity, not a single African medicinal plant was investigated in a clinical study. CONCLUSION: Several African medicinal plants have demonstrated promising anti-trypanosomal effects but the studies on the anti-trypanosomal potentials of these plants are not taken beyond proof of concept stage. It is hoped that the article would stimulate future clinical studies because of the paucity of knowledge in this area.

Saponins-rich fraction of Calotropis procera leaves elicit no antitrypanosomal activity in a rat model.

OBJECTIVE: To examine the in vitro and in vivo anti-Trypanosoma evansi (T. evansi ) activity of saponins-rich fraction of Calotropis procera (cpsf) leaves as well as the effect of the fraction on the parasite-induced anemia. METHODS: A 60-minutes time course experiment was conducted with various concentrations of the fraction using a 96-well microtiter plate technique, and subsequently used to treat experimentally T. evansi infected rats at 100 and 200 mg/kg body weight. Index of anemia was analyzed in all animals during the experiment. RESULTS: The cpsf did not demonstrate an in vitro antitrypanosomal activity. Further, the cpsf treatments did not significantly (P>0.05) keep the parasites lower than the infected untreated groups. At the end of the experiment, all T. evansi infected rats developed anemia whose severity was not significantly (P>0.05) ameliorated by the cpsf treatment. CONCLUSIONS: It was concluded that saponins derived from Calotropis procera leaves could not elicit in vitro and in vivo activities against T. evansi.

Heavy metals and mineral elements of Vernonia ambigua, Vernonia oocephala and Vernonia pupurea used in Northern Nigerian traditional medicine / Metales pesados y elementos minerales de Vernonia ambigua, Vernonia oocephala y Vernonia pupurea usados en la medicina tradicional del Norte de Nigeria

Background: Vernonia species are widely consumed as vegetables or medicinal herbs for the treatment of various human diseases in Nigeria. Nevertheless, there exists a growing concern for consumption safety of those herbal plants, due to increasing environmental pollution. This is because plants can accumulate some heavy metals that constitute a potential risk to human health. Nonetheless, also essential elements may be accumulated in plants, which provide nutrients for combating diseases and maintaining human health. Objectives: The purpose of the study was to analyze some heavy metals and mineral elements on Vernonia ambigua, V. oocephala and V. pupurea commonly used in Northern Nigerian traditional medicine. Methods: Atomic absorption spectrometry (AAS) was used to determine the major elements (calcium and magnesium), trace elements (iron and manganese) and heavy metals (copper, cobalt, chromium, cadmium, lead and zinc). Results: We found a high Ca and Fe content in V. ambigua, Mg and Co in V. oocephala, and Cu and Cr in V. pupurea; in contrast, the last specie, showed low accumulation of Pb and Cd among all studied species. Conclusion: This study revealed that toxic elements concentrations are lower than the allowed dietary intake (ADI) in all the three Vernonia species. The quantitative estimation of these elements is important to understanding the pharmacological and/or toxicological actions of medicinal plants for safe use.

Antecedentes: Las especies de Vernonia son ampliamente consumidas como verduras o hierbas medicinales, para el tratamiento de diversas enfermedades humanas en Nigeria. Sin embargo, existe una creciente preocupación por la seguridad en el consumo de dichas plantas, debido al incremento en la contaminación. Esto es debido a que las plantas pueden acumular algunos metales pesados que constituyen un riesgo potencial para la salud humana. Sin embargo, algunos elementos esenciales también pueden acumularse en las plantas proporcionando nutrientes para combatir las enfermedades y mantener una buena salud. Objetivos: El objetivo del estudio fue analizar algunos metales pesados y minerales en Vernonia ambigua, V. oocephala y V. Pupurea, comúnmente utilizadas en la medicina tradicional del norte de Nigeria. Métodos: La espectrofotometría de absorción atómica (AAS) se utilizó para determinar elementos mayores (calcio y magnesio), elementos trazas (hierro, manganeso) y elementos pesados (cobre, cobalto, cromo, cadmio, plomo y zinc). Resultados: se encontraron altos contenidos de Ca y Fe en V. ambigua, y de Mg y Co en V. oocephala. La cantidad de Cu y Cr fueron altas en V. Pupurea; en contraste, esta última reportó las cantidades más bajas de Pb (0.01200 mg/100g) y Cd (0.00670 mg / 100g) entre las tres especies de Vernonia estudiadas. Conclusión: Este estudio demostró que las concentraciones de elementos tóxicos como Pb, Cd y Co detectadas, son inferiores a la ingesta dietética permitido (ADI) en las tres especies de Vernonia. Las estimaciones cuantitativas de elementos pesados, son importantes para la comprensión de las acciones farmacológicas y/o toxicológicas de plantas medicinales para su uso seguro.