Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance

The frog skin host-defense peptide esculentin-2CHa (GFSSIFRGVA¹⁰KFASKGLGK D²⁰LAKLGVDLVA³⁰CKISKQC) displays antimicrobial, antitumor, and immunomodulatory properties. This study investigated the antidiabetic actions of the peptide and selected analogues. Esculentin-2CHa stimulated insulin secretion from rat BRIN-BD11 clonal pancreatic β-cells at concentrations greater than 0.3 nM without cytotoxicity by a mechanism involving membrane depolarization and increase of intracellular Ca²⁺. Insulinotropic activity was attenuated by activation of K_ATP channels, inhibition of voltage-dependent Ca²⁺ channels and chelation of extracellular Ca²⁺. The [L21K], [L24K], [D20K, D27K] and [C31S,C37S] analogues were more potent but less effective than esculentin-2CHa whereas the [L28K] and [C31K] analogues were both more potent and produced a significantly (P < 0.001) greater maximum response. Acute administration of [L28K]esculentin-2CHa (75 nmol/kg body weight) to high fat fed mice with obesity and insulin resistance enhanced glucose tolerance and insulin secretion. Twice-daily administration of this dose of [L28K]esculentin-2CHa for 28 days had no significant effect on body weight, food intake, indirect calorimetry or body composition. However, mice exhibited decreased non-fasting plasma glucose (P < 0.05), increased non-fasting plasma insulin (P < 0.05) as well as improved glucose tolerance and insulin secretion (P < 0.01) following both oral and intraperitoneal glucose loads. Impaired responses of isolated islets from high fat fed mice to established insulin secretagogues were restored by [L28K]esculentin-2CHa treatment. Peptide treatment was accompanied by significantly lower plasma and pancreatic glucagon levels and normalization of α-cell mass. Circulating triglyceride concentrations were decreased but plasma cholesterol and LDL concentrations were not significantly affected. The data encourage further investigation of the potential of esculentin-2CHa related peptides for treatment of patients with type 2 diabetes.     

Association between Inflammation and Cardiac Geometry in Chronic Kidney Disease: Findings from the CRIC Study

Background

Left ventricular hypertrophy (LVH) and myocardial contractile dysfunction are independent predictors of mortality in patients with chronic kidney disease (CKD). The association between inflammatory biomarkers and cardiac geometry has not yet been studied in a large cohort of CKD patients with a wide range of kidney function.

Methods

Plasma levels of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, high-sensitivity C-Reactive protein (hs-CRP), fibrinogen and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Echocardiography was performed according to the recommendations of the American Society of Echocardiography and interpreted at a centralized core laboratory.

Results

LVH, systolic dysfunction and diastolic dysfunction were present in 52.3%, 11.8% and 76.3% of the study subjects, respectively. In logistic regression analysis adjusted for age, sex, race/ethnicity, diabetic status, current smoking status, systolic blood pressure, urinary albumin- creatinine ratio and estimated glomerular filtration rate, hs-CRP (OR 1.26 [95% CI 1.16, 1.37], p<0.001), IL-1RA (1.23 [1.13, 1.34], p<0.0001), IL-6 (1.25 [1.14, 1.36], p<0.001) and TNF-α (1.14 [1.04, 1.25], p = 0.004) were associated with LVH. The odds for systolic dysfunction were greater for subjects with elevated levels of hs-CRP (1.32 [1.18, 1.48], p<0.001) and IL-6 (1.34 [1.21, 1.49], p<0.001). Only hs-CRP was associated with diastolic dysfunction (1.14 [1.04, 1.26], p = 0.005).

Conclusion

In patients with CKD, elevated plasma levels of hs-CRP and IL-6 are associated with LVH and systolic dysfunction.     

Benzoylbenzimidazole-based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1

Calcium-dependent protein kinase-1 (CDPK1) from Cryptosporidium parvum (CpCDPK1) and Toxoplasma gondii (TgCDPK1) have become attractive targets for discovering selective inhibitors to combat infections caused by these protozoa. We used structure-based design to improve a series of benzoylbenzimidazole-based compounds in terms of solubility, selectivity, and potency against CpCDPK1 and TgCDPK1. The best inhibitors show inhibitory potencies below 50nM and selectivity well above 200-fold over two human kinases with small gatekeeper residues.     

First record of Melampodium divaricatum (Asteraceae) in West Tropical Africa

A plant that showed morphological closeness to Aspilia africana (Pers) C. D. Adams (Asteraceae) was spotted and collected in 2015 along Afe Babalola University road, Ado‐Ekiti, Ekiti State, Nigeria with coordinates 7°36′59.99″N, 5°12′60.00″E. However, upon closer observation some distinct and peculiar characteristics that clearly distinguished it from Aspilia africana were revealed, e.g. sterility of the disc florets and production of achenes by ray florets only. Another striking character of the plant was total emptying of the capitulum after achene maturation, leaving an empty capitulum cup on the plant. Literature and herbarium searches revealed that the plant had neither been reported from West Tropical Africa nor collected in any herbarium in Nigeria before. The plant was eventually identified as Melampodium divaricatum (L.) which is an annual erect herb, distributed in tropical and subtropical regions but mostly restricted to Mexico, North America and Central America. Morphological, reproductive and cytological studies carried out on the plant revealed it to possess a highly branched erect pigmented stem, simple opposite sub sessile leaves with acute apex and distantly serrated margins, capitula with yellow unisexual disc and ray florets, sterile disc florets, fertile ray florets, relatively high pollen fertility (92.85%), a somatic chromosome number of 2n = 24 and regular formation of 12 bivalents, indicating the plant to be a diploid species. Further studies on Melampodium in Nigeria and a general revision of the flora of West Tropical Africa is suggested as well as the need to monitor M. divaricatum in the region since it appears to have the capacity to become invasive.     

Bridelia ferruginea Inhibit Rat Heart and Liver Mitochondrial Membrane Permeability Transition Pore Opening Following Myocardial Infarction

International Journal of Peptide Research and Therapeutics - Despite advances in therapy, myocardial infarction (MI) remains a leading cause of death worldwide. Recently, the mitochondrion has been...     

Evaluation of cowpea mini core accessions for resistance to flower bud thrips Megalurothrips sjostedti Trybom (Thysanoptera: Thripidae)

The flower bud thrips, Megalurothrips sjostedti Trybom (Thysanoptera: Thripidae), is an economically important pest of cowpea in sub‐Saharan Africa. Varietal resistance is the most preferred, environmentally friendly, cost‐effective and sustainable option for controlling this pest. The objective of this study was to identify sources of resistance to M. sjostedti among mini core accessions from the largest world cowpea germplasm collection maintained at the International Institute of Tropical Agriculture (IITA). The study was conducted during the 2015 and 2016 cropping seasons where 365 accessions were screened under field conditions. Each accession was rated visually for thrips damage score, flower abortion rate, number of pods per plant and number of thrips per flower. The resistance levels observed in genotypes TVu8631, TVu16368, TVu8671 and TVu7325 were similar to that of the resistant check “Sanzisabinli” (called Sanzi) during both seasons. In addition, 56 mini core genotypes showed moderate resistance to thrips damage. High heritability values were associated with thrips damage scores at 65 days after planting (0.60), percentage of effective peduncles (0.59), flower bud abortion rate (0.59), number of pods per plant (0.51) and number of peduncles with pods (0.5). The accessions identified with good levels of resistance to flower bud thrips will be used in cowpea breeding programs to develop improved resistant varieties.     

Structures of glyceraldehyde 3‐phosphate dehydrogenase in Neisseria gonorrhoeae and Chlamydia trachomatis

Neisseria gonorrhoeae (Ng) and Chlamydia trachomatis (Ct) are the most commonly reported sexually transmitted bacteria worldwide and usually present as co‐infections. Increasing resistance of Ng to currently recommended dual therapy of azithromycin and ceftriaxone presents therapeutic challenges for syndromic management of Ng‐Ct co‐infections. Development of a safe, effective, and inexpensive dual therapy for Ng‐Ct co‐infections is an effective strategy for the global control and prevention of these two most prevalent bacterial sexually transmitted infections. Glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) is a validated drug target with two approved drugs for indications other than antibacterials. Nonetheless, any new drugs targeting GAPDH in Ng and Ct must be specific inhibitors of bacterial GAPDH that do not inhibit human GAPDH, and structural information of Ng and Ct GAPDH will aid in finding such selective inhibitors. Here, we report the X‐ray crystal structures of Ng and Ct GAPDH. Analysis of the structures demonstrates significant differences in amino acid residues in the active sites of human GAPDH from those of the two bacterial enzymes suggesting design of compounds to selectively inhibit Ng and Ct is possible. We also describe an efficient in vitro assay of recombinant GAPDH enzyme activity amenable to high‐throughput drug screening to aid in identifying inhibitory compounds and begin to address selectivity.     

Biochemical evaluation and molecular docking assessment of Cymbopogon citratus as a natural source of acetylcholine esterase (AChE)- targeting insecticides

Acetylcholinesterase (AChE) has been an effective target for insecticide development which is a very important aspect of the global fight against insect-borne diseases. The drastic reduction in the sensitivity of insects to AChE-targeting insecticides like organophosphates and carbamates have increased the need for insecticides of natural origin. In this study, we used Drosophila melanogaster as a model to investigate the insecticidal and AChE inhibitory potentials of Cymbopogon citratus and its bioactive compounds. Flies were exposed to 100 and 200 mg/mL C. citratus leaf extract for a 3-h survival assay followed by 45 min exposure for negative geotaxis and biochemical assays. Molecular docking analysis of 45 bioactive compounds of the plant was conducted against Drosophila melanogaster AChE (DmAChE). Exposure to C. citratus significantly reduced the survival rate of flies throughout the exposure period and this was accompanied by a significant decrease in percentage negative geotaxis, AChE activity, catalase activity, total thiol level and a significant increase in glutathione-S-transferase (GST) activity. The bioactive compounds of C. citratus showed varying levels of binding affinities for the enzyme. (+)-Cymbodiacetal scored highest (?9.407 kcal/mol) followed by proximadiol (?8.253 kcal/mol), geranylacetone (?8.177 kcal/mol), and rutin (?8.148 kcal/mol). The four compounds occupied the same binding pocket and interacted with important active site amino acid residues as the co-crystallized ligand (1qon). These compounds could be responsible for the insecticidal and AChE inhibitory potentials of C. citratus and they could be further explored in the development of AChE-targeting insecticides.