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N-acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzesN-acyl-phosphatidylethanolamine (NAPEs) to formN-acyl-ethanolamides (NAEs) and phosphatidic acid. Several lines of evidence suggest that reduced NAPE-PLD activity could contribute to cardiometabolic diseases. For instance,NAPEPLDexpression is reduced in human coronary arteries with unstable atherosclerotic lesions, defective efferocytosis is implicated in the enlargement of necrotic cores of these lesions, and NAPE-PLD products such as palmitoylethanolamide and oleoylethanolamide have been shown to enhance efferocytosis. Thus, enzyme activation mediated by a small molecule may serve as a therapeutic treatment for cardiometabolic diseases. As a proof-of-concept study, we sought to identify small molecule activators of NAPE-PLD. High-throughput screening followed by hit validation and primary lead optimization studies identified a series of benzothiazole phenylsulfonyl-piperidine carboxamides that variably increased activity of both mouse and human NAPE-PLD. From this set of small molecules, two NAPE-PLD activators (VU534 and VU533) were shown to increase efferocytosis by bone-marrow derived macrophages isolated from wild-type mice, while efferocytosis was significantly reduced inNapepld-/-BMDM or after Nape-pld inhibition. Together these studies demonstrate an essential role for NAPE-PLD in the regulation of efferocytosis and the potential value of NAPE-PLD activators as a strategy to treat cardiometabolic diseases.

Curcumin shows antiglycemic effects in animals. Curcumin is chemically unstable at physiological pH, and its oxidative degradation products were shown to contribute to its anti-inflammatory effects. Since the degradation products may also contribute to other effects, we analyzed their role in the antiglycemic activity of curcumin. We quantified curcumin-induced release of glucagon-like peptide 1 (GLP-1) from mouse STC-1 cells that represent enteroendocrine L-cells as a major source of this anti-diabetic hormone. Curcumin induced secretion of GLP-1 in a dose-dependent manner. Two chemically stable analogues of curcumin that do not readily undergo degradation, were less active while two unstable analogues were active secretagogues. Chromatographically isolated spiroepoxide, an unstable oxidative metabolite of curcumin with anti-inflammatory activity, also induced secretion of GLP-1. Stable compounds like the final oxidative metabolite bicyclopentadione, and the major plasma metabolite, curcumin-glucuronide, were inactive. GLP-1 secretion induced by curcumin and its oxidative degradation products was associated with activation of PKC, ERK, and CaM kinase II. Since activity largely correlated with instability of curcumin and the analogues, we tested the extent of covalent binding to proteins in STC-1 cells and found it occurred with similar affinity as N-ethylmaleimide, indicating covalent binding occurred with nucleophilic cysteine residues. These results suggest that oxidative metabolites of curcumin are involved in the antiglycemic effects of curcumin. Our findings support the hypothesis that curcumin functions as a pro-drug requiring oxidative activation to reveal its bioactive metabolites that act by binding to target proteins thereby causing a change in function.

Background Telfairia occidentalis (TO), a plant consumed for its nutritional and medicinal values, exhibits hypoglycaemic effect. However, the metabolic fate of the glucose following TO-induced insulin secretion and consequent hypoglycaemia is not clear. Objective This study determined the effect of ethyl acetate and n-hexane fractions of TO leaf extracts on some biochemical parameters in the glucose metabolic pathway to explain the possible fate of blood glucose following TO-induced hypoglycaemia. Methods Eighteen male Wistar rats (180–200 g) divided into control, n-hexane TO fraction- and ethyl acetate TO fraction-treated groups (n = 6/group) were used. The control animals received normal saline while the treated groups received TO at 100 mg/kg for seven days. After 24 h following the last dose, the animals were anaesthetised using ketamine; blood samples were collected and livers harvested to determine some biochemical parameters. Results Ethyl acetate TO fraction significantly increased plasma insulin, liver glucokinase activity and plasma pyruvate concentration, but significantly decreased plasma glucose and liver glycogen, without significant changes in plasma lactate, glucose-6-phosphate, liver glucose-6-phosphatase and lactate dehydrogenase activities when compared with control. N-hexane TO fraction significantly reduced liver glucose-6-phosphatase activity and glycogen but significantly increased plasma pyruvate, without significant changes in plasma glucose, insulin, glucose-6-phosphate and lactate concentrations; and liver glucokinase and lactate dehydrogenase activities. Conclusion The present study showed that insulin-mediated TO-induced hypoglycaemia resulted in the stimulation of glycolysis and pyruvate production via insulin-dependent and insulin-independent mechanisms.

Despite reports that quinoline antimalarials including chloroquine (Chq) exhibit idiosyncratic neuropsychiatric effects even at low doses, the drug continues to be in widespread use during pregnancy. Surprisingly, very few studies have examined the potential neurotoxic action of Chq exposure at different points of gestation or how this phenomenon may affect neurophysiological well-being in later life. We therefore studied behavior, and the expression of specific genes and neurochemicals modulating crucial neural processes in offspring of rats exposed to prophylactic dose of Chq during different stages of gestation. Pregnant rats were injected 5 mg/kg/day (3 times) of Chq either during early- (first week), mid- (second week), late- (third week), or throughout- (all weeks) gestation, while controls received PBS injection. Behavioral characterization of offspring between postnatal days 15-20 in the open field, Y-maze, elevated plus and elevated zero mazes revealed that Chq evoked anxiogenic responses and perturbed spatial memory in rats, although locomotor activity was generally unaltered. In the prefrontal cortex (PFC), hippocampus and cerebellum of rats prenatally exposed to Chq, RT-qPCR analysis revealed decreased mRNA expression of presynaptic marker synaptophysin, which was accompanied by downregulation of postsynaptic marker PSD95. Synaptic marker PICK1 expression was also downregulated in the hippocampus but was unperturbed in the PFC and cerebellum. In addition to recorded SOD downregulation in cortical and hippocampal lysates, induction of oxidative stress in rats prenatally exposed to Chq was corroborated by lipid peroxidation as evinced by increased MDA levels. Offspring of rats infused with Chq at mid-gestation and weekly treatment throughout gestation were particularly susceptible to neurotoxic changes, especially in the hippocampus. Interestingly, Chq did not cause histopathological changes in any of the brain areas. Taken together, our findings causally link intrauterine exposure to Chq with postnatal behavioral impairment and neurotoxic changes in rats.

Nature and size of rodent cages vary from one laboratory or country to another. Little is however known about the physiological implications of exposure to diverse cage sizes in animal-based experiments.Here, two groups of male Swiss mice (Control group - Cage stationed, and Test group - Cage migrated) were used for this study. The cage-migrated mice were exposed daily to various cage sizes used across laboratories in Nigeria while the cage-stationed mice exposed daily to different but the same cage size and shape. At the end of the 30 days exposure, top-rated paradigms were used to profile changes in physiological behaviours, and this was followed by evaluation of histological and biochemical metrics.The study showed a significant (p 0.05) decrease in blood glucose levels (at 60 and 120 min of oral glucose tolerance test) in the cage-migrated mice compared to cage-stationed mice. Strikingly, peripheral oxidative stress (plasma malondialdehyde) and pain sensitivity (formalin test, hot-and-cold plate test, and von Frey test) decreased significantly in cage-migrated mice compared to cage-stationed animals. Also, the pro-inflammation mediators (IL-6 and NF-κB) increased significantly in cage-migrated mice compared to cage-stationed mice. However, emotion-linked behaviours, neurotransmitters (serotonin, noradrenaline and GABA), brain and plasma electrolytes were not significantly difference in cage-migrated animals compared to cage-stationed mice.Taken together, these results suggest that varied size cage-to-cage exposure of experimental mice could affect targeted behavioural and biomolecular parameters of pain and inflammation, thus diminishing research reproducibility, precipitating false negative/positive results and leading to poor translational outcomes.

Background: The emergence of a multidrug-resistant strain of Plasmodium falciparum (Pf Pailin) raises concern about malaria control strategies. Unfortunately, the role(s) of natural plants...

Background: Exposure to environmental toxins such as organophosphates poses a great threat to the health of the public. In this work, we investigated the effects of continuous exposure to dichlorvos (DDVP) on kidney function and hematological parameters, and the possible antidote activity of Nigella sativa oil (NSO). Methods: This research was conducted in 2016, at The Animal Holding and Research Laboratory of Faculty Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria. Twenty-four Wistar rats were randomly divided into four groups, six rats each. The four groups received: 1. phosphate buffer solution as controls, 2. DDVP, 3. DDVP+NSO and 4. NSO alone. After 2 wk of treatment, blood samples were collected and hematological profile (RBC, Hb), erythrocyte indices (MCV, MCH, MCHC, and Plt), renal function parameters (albumin, urea, total protein, chloride, sodium, and potassium ions) and nonspecific immune response (WBC) were measured. Results: Rat exposed to DDVP showed red blood cell count, hemoglobin, packed cell volume, albumin, and total protein levels was reduced from control, while white blood cell count and urea significantly increased as compared to controls, the change in K+ level was not significant. NSO maintained optimal levels of red blood cell count, hemoglobin, packed cell volume, albumin, white blood cell count, and urea, indicative of its protective effect against hemo-, immuno- and nephrotoxicity of DDVP. Conclusion: N. sativa (Black Caraway) oil might be a potential antidote in hematotoxicity, immunosuppression and renal dysfunction in organophosphate poisoning, especially dichlorvos. The protective effect of NSO against dichlorvos toxicity can be attributed to its antioxidant capacity.

Background Nature and size of rodent cages vary from one laboratory or country to another. Little is however known about the physiological implications of exposure to diverse cage sizes in animal-based experiment. Here, we exposed male Swiss mice to various cage sizes used across laboratories in Nigeria, top-rated paradigms were used to profile changes in physiological behaviours, and this was followed by evaluation of modified biochemical metrics. Results The study showed a better systemic regulation of glucose metabolism in cage migrated mice compared to cage stationed. Strikingly, peripheral oxidative stress and pain sensitivity decreased significantly in cage-to-cage migrated mice despite increased pro-inflammation mediators (IL-6 and NF-κB) which contrast the norm reported in inflammatory conditions. Interestingly, emotion-linked behaviours, neurotransmitters (serotonin, noradrenaline and GABA) and body electrolytes were not altered by cage-to-cage migration. Conclusion Taken together, these results suggest that varied size cage-to-cage migration of experimental mice could affect targeted behavioural and biomolecular parameters of pain and inflammation, thus diminishing research reproducibility, precipitating false negative/positive results and leading to poor translational outcomes.

This study was conducted to evaluate cognitive enhancing effect and ameliorative effects of black seed oil in scopolamine induced rat model of cognitive impairment. These effects were investigated on scopolamine-induced dementia model in Morris water maze test (MWM) and Y maze test. The hippocampal histoarchitectural responses to scopolamine and Nigella sativa oil were also examined. Scopolamine (1 mg/kg ip) was given to induce dementia, followed by oral administration of BSO (1 ml/kg) for 14 consecutive days. MWM and Y-maze paradigms were used to assess hippocampal and frontal dependent memory respectively, thereafter the rats were sacrificed and brains were removed for histopathologic studies. Scopolamine resulted in memory impairment, by delayed latency in the MWM, reduced percentage alternation in the Y maze that was coupled by alterations in the cortico-hippocampal neurons. Posttreatment of rats with BSO mitigated scopolamine-induced amnesia, by reducing latency period and increasing percentage alternation and histological changes. The observed anti-amnestic effect of BSO makes it a promising anti-amnesic agent for clinical trials in patients with cognitive impairment.

Carica papaya L. is an herbaceous laticiferous plant commonly cultivated in the tropics as a food and cash crop. C. papaya cultivars have been developed to increase yield, fruit quality, and nutritional content. The whole plant, parts, and extracts are used traditionally for the treatment of ailments. Phytochemicals from C. papaya are increasingly investigated and have shown great pharmacologic promise as a result of their antioxidant, antiinflammatory, immunomodulatory, and antimicrobial properties. Therefore, some C. papaya products (fermented papaya, papain) are now used alone or in combination with drugs or herbs to treat diseases such as dengue fever, diabetes mellitus, and periodontitis and to heal wounds. However, the safety of papaya–drug and papaya–herb combinations for treatment of diseases is still being investigated. Such combinations are potentially fatal in some cases and beneficial in others. More studies are required to understand the nature of C. papaya interactions with drugs and herbs and implications for body structure and function.

Aim: Nigella sativa oil has been shown to improve metabolic syndrome-associated dyslipidemia and oxidative stress. Effects of N. sativa oil on letrozole-induced polycystic ovary syndrome (PCOS)-associated hormonal, metabolic, redox, and lipid dysregulation in rats were investigated. Methods: Female Sprague-Dawley rats were randomly assigned into four groups (n=10 per group): control, PCOS, and PCOS treated with N. sativa oil (5 mL/kg/day or 10 mL/kg/day) once daily p.o. starting at day 7 after the commencement of letrozole (1mg/kg) until day 56. Body weight and estrous cycle were recorded starting from days 7 and 28 respectively until day 56. Rats were dissected and serum and ovaries were collected for biochemical and histomorphological assessments. Results: N. sativa oil (10 mL/kg/day) treatment significantly increased: number of rats undergoing regular cycle (80% vs 20%; p< 0.05), average number of regular cycles (5.00±0.59 vs 0.20±0.42; p< 0.05), appearance of corpus luteum; but reduced number of cystic follicles (7.60±1.51 vs 6.10±0.19; p< 0.05) in PCOS rats. Body weight was also reduced by the oil in PCOS rats. However, ovarian weight, granulose and theca cells layers showed no significant change. The oil also restored altered circulating levels of gonadotropins, steroids and reduced fasting blood glucose. The ovarian total cholesterol, triglycerides, low density lipoprotein-cholesterol, malondialdehyde were markedly reduced while insulin sensitivity and ovarian high density lipoprotein-cholesterol, superoxide dismutase and glutathione peroxidase activities were greatly increased. Conclusion: N. sativa oil improved polycystic ovarian-morphology and metabolic disorders via its anti-androgenic and insulin-sensitizing actions to ameliorate PCOS-associated dyslipidemia and redox disturbances.