Costus afer Possesses Carbohydrate Hydrolyzing Enzymes Inhibitory Activity and Antioxidant Capacity In Vitro

Diabetes mellitus is a metabolic disorder of glucose metabolism which correlates with postprandial hyperglycemia and oxidative stress. Control of blood glucose level is imperative in the management of diabetes. The present study tested the hypothesis that Costus afer, an antihyperglycemic medicinal plant, possesses inhibitory activity against carbohydrate hydrolyzing enzymes. Hexane, ethyl acetate, methanol, and water extracts were prepared from the leaf, stem, and rhizome of C. afer and subjected to phytochemical screening, assayed for α-amylase and α-glucosidase inhibitory activities and antioxidant capacity (determined by total phenolic and total flavonoids contents, ferric reducing antioxidant power (FRAP), and DPPH radical scavenging activity). All extracts inhibited α-amylase and α-glucosidase activities. Ethyl acetate rhizome and methanol leaf extracts exhibited the best inhibitory activity against α-amylase and α-glucosidase (IC50: 0.10 and 5.99 mg/mL), respectively. Kinetic analysis revealed two modes of enzyme inhibition (competitive and mixed). All extracts showed antioxidant capacity, with hexane extracts exhibiting the best activity. DPPH assay revealed that methanol leaf, rhizome, and ethyl acetate stem extracts (IC50 < 5 mg/mL) were the best antioxidants. The presence of bioactive compounds such as flavonoids, alkaloids, phenols, and tannins may account for the antioxidant capacity and carbohydrate hydrolyzing enzyme inhibitory activity of C. afer

Costus afer Protects Cardio-, Hepato-, and Reno-Antioxidant Status in Streptozotocin-Intoxicated Wistar Rats

Medicinal plants are efficient modulators of oxidative stress associated with diabetes mellitus. This study evaluated the cardio-, reno-, and hepato-antioxidant status of hydroethanolic extract of Costus afer on streptozotocin-intoxicated diabetic rats. Experimental animals were daily administered with hydroethanolic extract of C. afer by oral intubation for eight weeks (60 days), after which the levels of catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and lipid peroxidation marker (MDA) were evaluated in the heart, liver, and kidney homogenates. Plasma biochemical parameters such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), total protein, creatinine, and urea were determined. Meanwhile, parts of the heart, kidneys, and liver were histopathologically examined. Streptozotocin administration induced toxicity in the cardiac, hepatic, and renal tissues by stimulating significant increases (p<0.05) in the levels of CAT and SOD, GSH, and MDA. Similarly, significant increases (P<0.05) in the levels of ALT, AST, urea, and total protein were observed in streptozotocin treated rats, whereas decreases were observed in the levels of ALP, LDH, and creatinine. Following the treatments with C. afer hydroethanolic extract prevented the effect of streptozotocin by maintaining the tissue antioxidant status (CAT, SOD, GSH, and MDA) and the plasma biochemical parameters (AST, ALT, ALP, LDH, creatinine, and urea) towards the normal ranges. The histopathological examination revealed hepatovascular congestion and leucocyte infiltration as well as renovascular congestion, glomerulosclerosis, and tubular clarification in the untreated diabetic control and their absence in the group of animals treated with a high dose of C. afer extract. The findings of the present investigation suggest that C. afer possesses antioxidant activities capable of regulating drug induced tissue damage

Antileishmanial and cytotoxic activities of a new limonoid and a new phenyl alkene from the stem bark of Trichilia gilgiana (Meliaceae)

AbstractOne new limonoid, trigilgianin (1), one new phenyl alkene, epoxy gilgialkene (2), together with five known compounds: scopoletin (3), sitosteryl-6’-O-undecanoate-β-D-glucoside (4), sitosteryl-O-β-D-glucopyranoside (5), cinchonain A (6) and cinchonain B (7) were isolated from the stem bark of Trichilia gilgiana Harms. (Meliaceae). All compounds were isolated for the first time from this species. The structures were elucidated on the basis of spectral studies and by comparison of these data with those from the literature. Compounds 1, 2, 3, 6 and 7 were tested for in vitro antileishmanial activity against visceral leishmaniasis parasite Leishmania donovani and cytotoxicity against macrophage RAW 264.7 cell line. Compounds 1 and 3 showed the highest antileishmanial activity (IC50 values of 6.044 and 6.804 µg/mL, respectively) with low cytotoxicity (CC50 values of >200 and 47.47 µg/mL, respectively), while compound 2 was moderately active on L. donovani promastigotes (IC50 56.81 µg/mL)

Potent antiplasmodial extracts and fractions from Terminalia mantaly and Terminalia superba

Abstract Background The emergence and spread of malaria parasites resistant to artemisinin-based combination therapy stresses the need for novel drugs against malaria. Investigating plants used in traditional medicine to treat malaria remains a credible option for new anti-malarial drug development. This study was aimed at investigating the antiplasmodial activity and selectivity of extracts and fractions from Terminalia mantaly and Terminalia superba (Combretaceae) that are used in Cameroon to treat malaria. Methods Twelve methanolic (m) and water (w) extracts obtained by maceration of powdered dried leaves (l), stem bark (sb) and root (r) of Terminalia mantaly (Tm) and Terminalia superba (Ts) and 12 derived fractions of hexane, chloroform, ethyl acetate and 4 final residues of selected extracts were assessed for antiplasmodial potential in vitro against the chloroquine-resistant PfINDO and the chloroquine-sensitive Pf3D7 strains of Plasmodium falciparum using the SYBR green I-based fluorescence assay. The cytotoxicity of potent extracts and fractions was evaluated in vitro using the MTT assay on HEK239T cell line. Results The antiplasmodial IC50 of extracts from both plants ranged from 0.26 to > 25 µg/mL. Apart from the extracts Tmrm and Tsrw that exerted moderate antiplasmodial activities (IC50: 5–20 µg/mL) and Tmrw that was found to be non-active at the tested concentrations (IC50 > 25 µg/mL), all other tested crude extracts exhibited potent activities with IC50  158) on both resistant PfINDO and sensitive Pf3D7 strains. Four fractions upon further extraction with chloroform and ethyl acetate (TmlwChl, TmsbwChl, TmsbwEA, TsrmEA) afforded from three selected crude extracts (Tmlw, Tmsbw, Tsrm) exhibited highly potent activities against both P. falciparum strains (IC50  109). Conclusions The results achieved in this work validate the reported traditional use of Terminalia mantaly and Terminalia superba to treat malaria. Moreover, the highly potent and selective fractions warrant further investigation to characterize the active antiplasmodial principles and progress them to rodent malaria models studies if activity and selectivity are evidenced

Cafeteria Diet-Induced Metabolic and Cardiovascular Changes in Rats: The Role of Piper nigrum Leaf Extract

Background. Cafeteria diet is known to induce excessive body fat accumulation (obesity) that could cause metabolic and cardiovascular changes and even death. The increase in prevalence over time and the failure in treatment options make obesity a real public health problem. The present study assessed the preventive effect of the hydro-ethanolic extract of the Piper nigrum leaf on the development of metabolic and cardiovascular changes in cafeteria diet fed Wistar rats. Methods. Thirty-six male rats were divided into 5 groups of 6 rats each: a normal control group (Nor.), a negative control group (Neg.), two groups administered different doses of extract in mg/kg (E250 and E500), and a group administered atorvastatin 10 mg/kg (Ator., reference drug). The animals were fed with experimental diets (standard and cafeteria) for a period of 5 weeks. Food and water intake were assessed daily, and the body weight assessed weekly. At the end of the feeding, plasma lipid profile and markers of hepatic and renal function were assessed. Furthermore, the relative weights of the adipose tissue and the organs were assessed. The liver, kidneys, and heart homogenates were assessed for markers of oxidative stress while the aorta was histopathologically examined. Results. Cafeteria diet-induced weight gain of 30% and increased triglyceride, total cholesterol, and low-density lipoprotein cholesterol level of more than 50%. Equally, an increase in the relative weight of accumulated adipose tissues of more than 90%, oxidative stress, and alteration in the organ structure were visible in cafeteria diet fed rats (Neg). Treatment with P. nigrum extract significantly prevented weight gain, dyslipidemia, oxidative stress, and alteration in the architecture of the aorta. The effect of P. nigrum extract was comparable to that of the reference drug. Conclusion. Piper nigrum leaf may prevent weight gain and possess cardioprotective activity with a strong antioxidant activity

On Cartan matrices with two parameters (Cohomology theory of finite groups and related topics)

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts

Metabolomic and chemogenomic profiling.

<p>(A) Metabolic profiling: Heat map showing metabolic fingerprints of 80 Malaria Box compounds and atovaquone control. Parasite extracts were analyzed by LC-MS, and changes in metabolite pools were calculated for drug-treated parasites as compared to untreated controls. Hierarchical clustering was performed on ²log-fold changes in metabolites (data in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005763#ppat.1005763.s003" target="_blank">S2 Table</a>), scaled from -3 to +3. Six of seven compounds (indicated in red) reported to target <i>Pf</i>ATP4 [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005763#ppat.1005763.ref025" target="_blank">25</a>] showed a distinct metabolic response characterized by the accumulation of dNTPs and a decrease in hemoglobin-derived peptides. A large cluster of compounds (indicated in blue) clustered with the atovaquone control (indicated in orange), and exhibit an atovaquone-like signature characterized by dysregulation of pyrimidine biosynthesis, and showed a distinct metabolic response characterized by the accumulation of dNTPs and a decrease in hemoglobin-derived peptides. (B) Chemogenomic profiling: A collection of 35 <i>P</i>. <i>falciparum</i> single insertion <i>piggyBac</i> mutants were profiled with 53 MMV compounds and 3 artemisinin (ART) compounds [Artesunate (AS), Artelinic acid (AL) and Artemether (AM)] for changes in IC₅₀ relative to the wild-type parent NF54 (data in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005763#ppat.1005763.s004" target="_blank">S3 Table</a>, genes queried in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005763#ppat.1005763.s005" target="_blank">S4 Table</a>). Clone PB58 carried a <i>piggyBac</i> insertion in the promoter region of the K13 gene and has an increased sensitivity to ART compounds as do PB54 and PB55 [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1005763#ppat.1005763.ref033" target="_blank">33</a>]. Drug-drug relationships based on similarities in IC₅₀ deviations of compounds generated with <i>piggyBac</i> mutants created chemogenomic profiles used to define drug-drug relationships. The significance of similarity in MoA between Malaria Box compounds and ART was evaluated by Pearson’s correlation calculations from pairwise comparisons. The X axis shows the chemogenomic profile correlation between a Malaria Box compound and AS, the Y axis with AM; the color gradient indicates the average correlation with all ART derivatives tested. Five Malaria Box compounds (MMV006087, MMV006427, MMV020492, MMV665876, MMV396797) were identified as having similar drug-drug chemogenomic profiles to the ART sensitivity cluster.</p

Antiprotozoal Malaria Box compounds with activity in biological assays and lacking toxicity at therapeutic levels.

<p>Selectivity Index, SI, is toxicity level/activity level; p, probe-like; d, drug-like.</p