Novel functional insights into ischemic stroke biology provided by the first genome-wide association study of stroke in indigenous Africans.

BACKGROUND: African ancestry populations have the highest burden of stroke worldwide, yet the genetic basis of stroke in these populations is obscure. The Stroke Investigative Research and Educational Network (SIREN) is a multicenter study involving 16 sites in West Africa. We conducted the first-ever genome-wide association study (GWAS) of stroke in indigenous Africans. METHODS: Cases were consecutively recruited consenting adults (aged > 18 years) with neuroimaging-confirmed ischemic stroke. Stroke-free controls were ascertained using a locally validated Questionnaire for Verifying Stroke-Free Status. DNA genotyping with the H3Africa array was performed, and following initial quality control, GWAS datasets were imputed into the NIH Trans-Omics for Precision Medicine (TOPMed) release2 from BioData Catalyst. Furthermore, we performed fine-mapping, trans-ethnic meta-analysis, and in silico functional characterization to identify likely causal variants with a functional interpretation. RESULTS: We observed genome-wide significant (P-value < 5.0E-8) SNPs associations near AADACL2 and miRNA (MIR5186) genes in chromosome 3 after adjusting for hypertension, diabetes, dyslipidemia, and cardiac status in the base model as covariates. SNPs near the miRNA (MIR4458) gene in chromosome 5 were also associated with stroke (P-value < 1.0E-6). The putative genes near AADACL2, MIR5186, and MIR4458 genes were protective and novel. SNPs associations with stroke in chromosome 2 were more than 77 kb from the closest gene LINC01854 and SNPs in chromosome 7 were more than 116 kb to the closest gene LINC01446 (P-value < 1.0E-6). In addition, we observed SNPs in genes STXBP5-AS1 (chromosome 6), GALTN9 (chromosome 12), FANCA (chromosome 16), and DLGAP1 (chromosome 18) (P-value < 1.0E-6). Both genomic regions near genes AADACL2 and MIR4458 remained significant following fine mapping. CONCLUSIONS: Our findings identify potential roles of regulatory miRNA, intergenic non-coding DNA, and intronic non-coding RNA in the biology of ischemic stroke. These findings reveal new molecular targets that promise to help close the current gaps in accurate African ancestry-based genetic stroke's risk prediction and development of new targeted interventions to prevent or treat stroke.

A Novel Afrocentric Stroke Risk Assessment Score: Models from the Siren Study.

BACKGROUND: Stroke risk can be quantified using risk factors whose effect sizes vary by geography and race. No stroke risk assessment tool exists to estimate aggregate stroke risk for indigenous African. OBJECTIVES: To develop Afrocentric risk-scoring models for stroke occurrence. MATERIALS AND METHODS: We evaluated 3533 radiologically confirmed West African stroke cases paired 1:1 with age-, and sex-matched stroke-free controls in the SIREN study. The 7,066 subjects were randomly split into a training and testing set at the ratio of 85:15. Conditional logistic regression models were constructed by including 17 putative factors linked to stroke occurrence using the training set. Significant risk factors were assigned constant and standardized statistical weights based on regression coefficients (ß) to develop an additive risk scoring system on a scale of 0-100%. Using the testing set, Receiver Operating Characteristics (ROC) curves were constructed to obtain a total score to serve as cut-off to discriminate between cases and controls. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) at this cut-off. RESULTS: For stroke occurrence, we identified 15 traditional vascular factors. Cohen's kappa for validity was maximal at a total risk score of 56% using both statistical weighting approaches to risk quantification and in both datasets. The risk score had a predictive accuracy of 76% (95%CI: 74-79%), sensitivity of 80.3%, specificity of 63.0%, PPV of 68.5% and NPV of 76.2% in the test dataset. For ischemic strokes, 12 risk factors had predictive accuracy of 78% (95%CI: 74-81%). For hemorrhagic strokes, 7 factors had a predictive accuracy of 79% (95%CI: 73-84%). CONCLUSIONS: The SIREN models quantify aggregate stroke risk in indigenous West Africans with good accuracy. Prospective studies are needed to validate this instrument for stroke prevention.

Contribution of Epstein⁻Barr Virus Latent Proteins to the Pathogenesis of Classical Hodgkin Lymphoma.

Pathogenic viruses have evolved to manipulate the host cell utilising a variety of strategies including expression of viral proteins to hijack or mimic the activity of cellular functions. DNA tumour viruses often establish latent infection in which no new virions are produced, characterized by the expression of a restricted repertoire of so-called latent viral genes. These latent genes serve to remodel cellular functions to ensure survival of the virus within host cells, often for the lifetime of the infected individual. However, under certain circumstances, virus infection may contribute to transformation of the host cell; this event is not a usual outcome of infection. Here, we review how the Epstein⁻Barr virus (EBV), the prototypic oncogenic human virus, modulates host cell functions, with a focus on the role of the EBV latent genes in classical Hodgkin lymphoma.

KINETICS OF MODULATORY ROLE OF Cyperus esculentus L. ON THE SPECIFIC ACTIVITY OF KEY CARBOHYDRATE METABOLIZING ENZYMES.

BACKGROUND: The continuous search for new lead compounds as viable inhibitors of specific enzymes linked to carbohydrate metabolism has intensified. Cyperus esculentus L. is one of the therapeutically implicated botanicals against several degenerative diseases including diabetes mellitus. MATERIALS AND METHODS: This study evaluated the antioxidant and mechanism(s) of inhibitory potential of aqueous extract of C. esculentus on α-amylase and α-glucosidase in vitro. The extract was investigated for its radical scavenging and hypoglycaemic potentials using standard experimental procedures. Lineweaver-Burke plot was used to predict the manner in which the enzymes were inhibited. RESULTS: The data obtained revealed that the extract moderately and potently inhibited the specific activities of α-amylase and α-glucosidase, respectively. The inhibition was concentration-related with respective IC50 values of 5.19 and 0.78 mg/mL relative to that of the control (3.72 and 3.55 mg/mL). The extract also significantly scavenged free radicals and the effects elicited could be ascribed to its phytoconstituents. CONCLUSION: The respective competitive and non-competitive mode of action of the extract is due to its inhibitory potentials on the activities of α-amylase and α-glucosidase. Going forward, in addition to completely characterize the exact compound(s) responsible for the elicited activity in this study, pertinent attention will be given to the in vivo evaluation of the identified constituents.

Hepatoprotective potential of Phyllanthus muellarianus leaf extract: studies on hepatic, oxidative stress and inflammatory biomarkers.

CONTEXT: Leaves of Phyllanthus muellarianus (Kuntze) Exell. (Euphorbiacea) are widely used in the management of liver disorders in Nigeria. However, no there is no scientific validation to support this use. OBJECTIVE: Hepatoprotective effect of Phyllanthus muellarianus aqueous leaf extract was investigated in acetaminophen-induced liver injury mice. MATERIALS AND METHODS: Hepatoprotective effect of Phyllanthus muellarianus aqueous leaf extract was evaluated in acetaminophen-induced hepatic damage in Swiss albino mice using biomarkers of hepatocellular indices, oxidative stress, proinflammatory factors and lipid peroxidation. Mice received distilled water, 100, 200, or 400 mg/kg b.w of Phyllanthus muellarianus aqueous leaf extract, respectively, for seven days. Treatment groups were challenged with 300 mg/kg b.w of acetaminophen on the sixth day. RESULTS: Oral administration of Phyllanthus muellarianus aqueous leaf extract significantly (p < 0.05) attenuates acetaminophen-mediated alterations in serum alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, albumin and total bilirubin by 76.56, 85.41, 89.39, 82.77 and 78.38%. Similarly, acetaminophen-mediated decrease in activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase were significantly attenuated in the liver of mice by 85.10, 80.81, 80.45, 76.23 and 95.22%, respectively. Increased levels of conjugated dienes, lipid hydroperoxides, malondialdehyde, protein carbonyl, fragmented DNA, tumor necrosis factor-α, interleukin-6 and -8 were significantly lowered by Phyllanthus muellarianus aqueous leaf extract. CONCLUSION: Overall, results of this study show that Phyllanthus muellarianus halted acetaminophen-mediated hepatotoxicity due to its capability to enhance antioxidant enzymes.

Indomethacin-induced gastric ulceration in rats: Ameliorative roles of Spondias mombin and Ficus exasperata.

CONTEXT: Spondias mombin Linn (Anacardiaceae) and Ficus exasperata Valh (Moraceae) are botanicals with known phytotherapeutic potentials in the traditional system of medicine in the world. OBJECTIVE: The objective of this study is to investigate the quantitative polyphenolic constituents and gastroprotective effects of aqueous leaf extracts of Spondias mombin and Ficus exasperata against indomethacin-induced gastric ulcer in rats. MATERIALS AND METHODS: Ulceration was induced by a single oral administration of indomethacin (30 mg/kg body weight (b.w.)). Ulcerated rats were orally administered with esomeprazole (a reference drug) at a dose of 20 mg/kg body weight, and Spondias mombin and Ficus exasperata at a dose of 100 and 200 mg/kg b.w. once daily for 21 d after ulcer induction. Gastric secretions and antioxidant parameters were thereafter evaluated. RESULTS: The significantly increased (p < 0.05) ulcer index, gastric volume, malondialdehyde level, and pepsin activity by indomethacin were effectively reduced by 65.40, 36.47, 45.71, and 53.79%, respectively, following treatment with F. exasperata at 200 mg/kg b.w. S. mombin at this regimen also attenuated these parameters by 71.70, 46.62, 50.16, and 55.73%. Moreover, the extracts significantly increase the reduced activity of superoxide dismutase as well as pH and mucin content in the ulcerated rats. DISCUSSION AND CONCLUSION: These findings are indicative of gastroprotective and antioxidative potentials of the extracts which is also evident in the degree of % inhibition against ulceration. The available data in this study suggest that the extracts proved to be capable of ameliorating indomethacin-induced gastric ulceration and the probable mechanisms are via antioxidative and proton pump inhibition.

Combined administration of silymarin and vitamin C stalls acetaminophen-mediated hepatic oxidative insults in Wistar rats

Oxidative insult by free radicals has been implicated in drug-induced hepatic damage and this has resulted in frequent episodes of liver disorders. Therapeutic efficacy of antioxidants may provide a possible solution to this menace. This study was carried out to investigate the effect of combined administration of silymarin and vitamin C in rescuing acetaminophen-induced hepatotoxicity in rats. Hepatotoxic rats were orally administered with silymarin and vitamin C at 100 and 200 mg/kg body weight, respectively. At the end of the experiment, liver function indices, antioxidant parameters and histological analysis were evaluated. We observed that the significantly increased (p < 0.05) activities of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, as well as levels of thiobarbituric acid reactive substances and serum total bilirubin, were markedly reduced following co-administration of silymarin and vitamin C. The compounds also effectively reversed the reduced activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase and total protein concentration in the hepatotoxic rats. These findings are indicative of hepatoprotective and antioxidant attributes of the two compounds which are also supported by the histological analysis. The available evidences in this study suggest that the complementary effects of silymarin and vitamin C proved to be capable of ameliorating acetaminophen-mediated hepatic oxidative damage and the probable mechanism is via antioxidative action.

Indomethacin-induced gastric ulceration in rats: Protective roles of Spondias mombin and Ficus exasperata.

This study investigated the quantitative polyphenolic constituents and gastroprotective effects of aqueous leaf extracts of Spondias mombin and Ficus exasperata against indomethacin-induced gastric ulcer in rats. Ulceration was induced by a single oral administration of indomethacin (30 mg/kg body weight). Wistar rats were pretreated with esomeprazole (reference drug) at a dose of 20 mg/kg body weight, S. mombin or F. exasperata at 100 and 200 mg/kg body weight once daily for 21 days prior to ulcer induction. At the end of the experiment, gastric secretions and antioxidant parameters were evaluated. We observed that the significantly increased (p < 0.05) ulcer index, gastric volume, malondialdehyde level and pepsin activity were effectively reduced following treatment with S. mombin and F. exasperata. The extracts also markedly attenuated the reduced activity of superoxide dismutase as well as pH and mucin content in the ulcerated rats. These findings are indicative of gastroprotective and antioxidative potentials of the extracts which is also evident in the degree of % inhibition against ulceration. The available data in this study suggest that the extracts of S. mombin and F. exasperata proved to be capable of ameliorating indomethacin-induced gastric ulceration and the probable mechanisms are via antioxidative and proton pump inhibition.

Phenolic extract of Parkia biglobosa fruit pulp stalls aflatoxin B1 – mediated oxidative rout in the liver of male rats

The effect of phenolic extract of Parkia biglobosa (Jacq.) R. Br. ex G. Don, Fabaceae, pulp on aflatoxin B1 induced oxidative imbalance in rat liver was evaluated. Thirty-five male rats were randomized into seven groups of five animals each. Rats in group A served as control and received vehicle for drug administration (0.5% DMSO) once daily at 24 h intervals for six weeks. Rats in groups B, D, E, F and G, received aflatoxin B1 (167 μg/kg body weight) in 0.5% DMSO for three weeks, starting from the third week of the experimental period. Rats in Group C received 400 mg/kg bodyweight of the extract for six weeks, while groups D, E and F rats were treated with 100, 200 and 400 mg/kg bodyweight of the extract for six weeks respectively. Group G rats received 100 mg/kg body weight of vitamin C. Aflatoxin B1-mediated decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase were significantly attenuated. Aflatoxin B1 mediated the elevation in malondialdehyde, conjugated dienes, lipid hydroperoxides, protein carbonyl, and significantly lowered DNA fragmentation percentage. Overall, the phenolic extract of P. biglobosa pulp stalls aflatoxin B1-mediated oxidative rout by enhancing antioxidant enzyme activities leading to decreased lipid peroxidation, protein oxidation and DNA fragmentation.

A novel inhibitor of cytokinin degradation (INCYDE) influences the biochemical parameters and photosynthetic apparatus in NaCl-stressed tomato plants.

The effect of 2-chloro-6-(3-methoxyphenyl)aminopurine [inhibitor of cytokinin degradation (INCYDE)] at 10 nM on growth, biochemical and photosynthetic efficiency in sodium chloride (NaCl)-stressed (75, 100 and 150 mM) tomato plants was investigated. NaCl-induced decline in plant vigor index was slightly reversed by both drenching and foliar application of INCYDE. Foliar application of INCYDE significantly increased the flower number in the control and 75 mM NaCl-supplemented plants, while drenching was more effective in 150 mM NaCl-stressed plants. Antioxidant enzymes (peroxidase, catalase and superoxide dismutase) were enhanced in the presence of INCYDE in the control and NaCl-stressed plants. Higher concentration of malondialdehyde (MDA) associated with oxidative (lipid peroxidation) damage in leaf tissue which was evident in the presence of NaCl stress was significantly attenuated with the drenching and foliar application of INCYDE. Regardless of NaCl concentration, application of INCYDE had no significant influence on maximum quantum efficiency of photosystem II. However, the reduced quantum yield of photosystem II and coefficient of photochemical quenching under continuous illumination with actinic light at four intensities (264, 488, 800 and 1,200 µmol m(-2) s(-1)) in NaCl-stressed (100 and 150 mM) tomato plants were significantly alleviated by drenching application with INCYDE. Non-photochemical quenching of the singlet excited state of chlorophyll a and relative electron transfer rate were generally higher in INCYDE-treated plants than in the controls. From an agricultural perspective, these findings indicate the potential of INCYDE in protecting plants against NaCl stress and the possibility of enhanced productivity.

Evaluation of Antidiabetic Activity and Associated Toxicity of Artemisia afra Aqueous Extract in Wistar Rats.

Artemisia afra Jacq. ex Willd. is a widely used medicinal plant in South Africa for the treatment of diabetes. This study aimed to evaluate the hypoglycemic activity and possible toxicity effect of aqueous leaf extract of the herb administered at different dosages for 15 days in streptozotocin-induced diabetic rats. Administration of the extract at 50, 100, and 200 mg/kg body weight significantly (P < 0.05) increased body weight, decreased blood glucose levels, increased glucose tolerance, and improved imbalance in lipid metabolism in diabetic rats. These are indications of antidiabetic property of A. afra with 200 mg/kg body weight of the extract showing the best hypoglycemic action by comparing favourably well with glibenclamide, a standard hypoglycemic drug. The extract at all dosages tested also restored liver function indices and haematological parameters to normal control levels in the diabetic rats, whereas the kidney function indices were only normalized in the diabetic animals administered with 50 mg/kg body weight of the extract. This investigation clearly showed that in addition to its hypoglycemic activity, A. afra may also protect the liver and blood against impairment due to diabetes. However, some kidney functions may be compromised at high dosages of the extract.

Protective role of Artemisia afra aqueous extract on tissue antioxidant defense systems in streptozotocin-induced diabetic rats.

Changes in antioxidant capacity in the body as a result of oxidative stress play an important role in the development of diabetic complications. The aim of this study was to evaluate the effect of aqueous extract of Artemisia afra Jacq. ex Willd. on antioxidant defense systems in the liver and kidney of streptozotocin-induced diabetic rats. Administration of the extract to diabetic rats for 21 days significantly reduced blood glucose levels and increased body weight. The diabetic animals exhibited decreased levels of glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD) and reduced glutathione (GSH) in the liver and kidney, which were restored to near normal levels following treatment with the herb. The increased levels of lipid peroxidation observed in the tissues of diabetic rats were also reverted back to near normalcy after administering the extract. These findings revealed the protective role of A. afra on tissues by reducing oxidative stress which could be attributed to its flavonoids content. The efficacy of the plant compared favourably well with glibenclamide, a standard hypoglycemic drug.

Artemisia afra Jacq. ameliorates oxidative stress in the pancreas of streptozotocin-induced diabetic Wistar rats.

Diabetes is characterized by hyperglycemia resulting from defects in pancreatic insulin secretion and/or impaired target cell responsiveness to insulin, and Artemisia afra Jacq. is widely used in South Africa to treat the disease, but the mechanism of action is yet to be elucidated. This study explored the effect of oral administration of aqueous leaf extract of A. afra on the pancreas of streptozotocin-induced diabetic rats. We found that the extract significantly reduced blood glucose levels, accompanied by an increase in the serum insulin concentration. Moreover, the antioxidant enzymic activities of glutathione peroxidase, glutathione reductase, and superoxide dismutase also improved significantly after treatment with the extract. Increased pancreatic lipid peroxidation in the diabetic rats was also normalized by the extract. This study indicates that A. afra possesses hypoglycemic and antioxidant activities. Our findings suggest that the herb might exert its anti-diabetic activity by regenerating pancreatic beta cells, thereby stimulating the release of insulin.

In vivo Studies on Antidiabetic Plants Used in South African Herbal Medicine.

Diabetes is one of the most common metabolic disorders worldwide. It is a major health problem with its frequency increasing every day in most countries. The disease is generally believed to be incurable; and the few orthodox drugs available to manage the disease are not readily affordable to the poor. Based on the historical success of natural products as antidiabetic agents and the ever increasing need for new antidiabetics, a number of South African medicinal plants have been evaluated for their antidiabetic properties. In this article, we review the major studies conducted based on ethnobotanical surveys carried out between 2005 and 2008 in South Africa on plants that are traditionally used for the treatment of diabetes. Overall, the results of the studies conducted confirmed the potential of South African medicinal plants in antidiabetic drug discovery and identified a number of promising taxa for further in vivo investigation as plant-based antidiabetic agents.

The effect of Aloe ferox Mill. in the treatment of loperamide-induced constipation in Wistar rats.

BACKGROUND: Constipation is the most common gastrointestinal complaint all over the world and it is a risk factor of colorectal cancer. In this study, the efficacy of aqueous leaf extract of Aloe ferox Mill. was studied against loperamide-induced constipation in Wistar rats. METHODS: Constipation was induced by oral administration of loperamide (3 mg/kg body weight) while the control rats received normal saline. The constipated rats were treated with 50, 100 and 200 mg/kg body weight/day of the extract for 7 days during which the feeding characteristics, body weight, fecal properties and gastrointestinal transit ratio were monitored. RESULTS: The extract improved intestinal motility, increased fecal volume and normalized body weight in the constipated rats, which are indications of laxative property of the herb with the 200 mg/kg body weight of the extract showing the best efficacy. CONCLUSION: The effect of the extract compares favourably well with senokot, a standard laxative drug. These findings have therefore, lent scientific credence to the folkloric use of the herb as a laxative agent by the people of the Eastern Cape of South Africa.