Cannabis sativa demonstrates anti-hepatocellular carcinoma potentials in animal model: in silico and in vivo studies of the involvement of Akt.

BACKGROUND: Targeting protein kinase B (Akt) and its downstream signaling proteins are promising options in designing novel and potent drug candidates against hepatocellular carcinoma (HCC). The present study explores the anti-HCC potentials of Cannabis sativa (C. sativa) extract via the involvement of Akt using both in silico and in vivo animal models of HCC approaches. METHODS: Phytoconstituents of C. sativa extract obtained from Gas Chromatography Mass-spectrometry (GCSM) were docked into the catalytic domain of Akt-2. The Diethylnitrosamine (DEN) model of HCC was treated with C. sativa extract. The effects of C. sativa extract treatments on DEN model of hepatocellular carcinoma were assessed by One-way analysis of variance (ANOVA) of the treated and untreated groups RESULT: The lead phytoconstituents of C. sativa extract, Δ-9-tetrahydrocannabinol (Δ-9-THC) and cannabidiol form stable hydrophobic and hydrogen bond interactions within the catalytic domain of Akt-2. C. sativa extract (15 mg/kg and 30 mg/kg) respectively gives a 3-fold decrease in the activities of liver function enzymes when compared with the positive control (group 2). It also gives a 1.5-fold decrease in hepatic lipid peroxidation and elevates serum antioxidant enzymes' activities by 1-fold in HCC treated Wistar rats when compared with the positive control (group 2). In an animal model of hepatocellular carcinoma, C. sativa extract significantly downregulated Akt and HIF mRNAs in groups 3, 4, and 5 with 2, 1.5, 2.5-fold decrease relative to group 2. VEGF mRNA was downregulated by 1.5-fold decrease in groups 3-5 when compared to group 2. The expression of XIAP mRNA was downregulated by 1.5, 2, and 1.25-folds in groups 3, 4, and 5 respectively, in comparison with group 2. In comparison to group 2, COX-2 mRNA levels were downregulated by 1.5, 1, and 1-folds in groups 3-5. In groups 3-5, CRP mRNA was downregulated by 2-fold in comparison with group 2. In groups 3-5, p21 mRNA was upregulated by 2, 2.5, and 3-folds, respectively when compared with group 2. It upregulated p53 mRNA by 2.5, 3.5, and 2.5-folds in groups 3-5 in comparison with group 2. It downregulated AFP mRNA by 3.5, 2.5, .2.5-folds in groups 3, 4, and 5 respectively when compared with group 2. Histologic analysis showed that C. sativa extract reduced necrosis and inflammation in HCC. CONCLUSION: C. sativa demonstrates anti-hepatocellular carcinoma potentials in an animal model of HCC and with the involvement of Akt. Its anticancer potential is mediated through antiangiogenic, proapoptotic, cycle arrest, and anti-inflammatory mechanisms. In future studies, the mechanisms of anti-HCC effects of Δ-9-tetrahydrocannabinol (Δ-9- THC) and cannabidiol via the PI3K-Akt signaling pathways should be explored.

Cnidoscolus aconitifolius leaf extract and ascorbate confer amelioration and protection against dimethyl nitrosamine-induced renal toxicity and testicular abnormalities in rats.

Extracts of Cnidoscolus aconitifolius (CA) have been reported to possess medicinal properties ranging from potential hepatoprotective, anti-diabetic, and anti-cardiovascular. In our previous study, gas chromatography mass spectroscopy check of CA extract showed the inclusion of 2,4-bis(1,1-dimethylethyl)-phenol, a phenolic phyto-compound that constitutes about 45 %, carotene and linoleic acid sources, and silicon-rich components. Hence we compare the preventive and ameliorative potentials of CA with ascorbate in dimethyl nitrosamine (DMN)-induced renal toxicity and sperm abnormalities in rats. Renal toxicity was investigated by quantifying the levels and activities of endogenous antioxidant parameters. Renal damage marked by significant reduction in GSH level, as well as significant elevation in MDA concentration, and activities of GPx, GST, CAT, and SOD were restored after the intervention of CA and ascorbate. Also, there was decrease in live sperm, sperm concentration, sperm gross and individual motility, and normal sperm morphology, following DMN administration. Based on the gathered results, it is concluded that ascorbate and CA demonstrate comparable ameliorative and protective effects against DMN-induced renal and testicular toxicities in rats.

Phytochemistry, nutritional composition, and pharmacological activities of Thaumatococcus daniellii (Benth): a review.

Thaumatococcus daniellii (Benth) is a member of a diverse family of plants known as Marantaceae. Native to the tropical forest zones of West Africa, the plant is globally famous for its low calorie, nondiabetic natural sweetener called thaumatin found in its aril. T. daniellii thrives in deep shade, and it is used locally as a taste modifier and for preparing fish traps, ornamental bags, and mats. Organs of the plant are used in folkloric medicine as a laxative and in treating ailments such as mental disorders, high blood sugar, and lung diseases. The seeds and leaf sap are potent as an antidote against snake venom and bee stings and for preventing dystocia and prolonged child labor. Proximate analysis, phytochemical screening, and gas chromatography-mass spectrophotometry revealed that the plant contains proteins, important macro- and microelements (calcium, magnesium, zinc, sodium, phosphorus, potassium, iron, and manganese), and abundant active principles and compounds such as squalene tannin, alkaloids, saponins, epicatechin, steroids, phlobatannins, anthraquinones, terpenoids, spartein, ribalinidine, rutin, phytic acid, and kaempferol. Biological activities include hypolipidemic, antihyperglycemic, antioxidant, insecticidal, bioremediative, and antimicrobial activities. T. daniellii could be used in the formulation of food supplements and drug development.

Terpenoids from Azadirachta indica are potent inhibitors of Akt: Validation of the anticancer potentials in hepatocellular carcinoma in male Wistar rats.

Hepatocellular carcinoma (HCC) is the commonest primary malignancy with poor patient prognosis and a high mortality rate. In this study, phytochemicals characterized from Azadirachta indica were screened against the catalytic site of Akt, and the anticancer potentials of the extracted leads (terpenoids) were determined in hepatocellular carcinoma in male Wistar rats. The lead compounds are terpenoids; hence, the extraction of terpenoids from A. indica. Gas chromatography-mass spectrometry (GCMS) was employed for the characterization of the extract. Diethylnitrosamine (DEN)-induced hepatocellular carcinoma in male Wistar rats were treated with the terpenoids extract. The hit, lupeol demonstrates inhibition of Akt and is a potential drug candidate. The terpenoids extract downregulate Akt mRNA and demonstrated anti-Akt downstream signaling effects; anti-inflammatory, anti-angiogenesis, pro-apoptotic, and cell cycle arrest, it also demonstrated cellular regeneration, hepatoprotection, antioxidant potentials, and cellular repairs in hepatocellular carcinoma in male Wistar rats. PRACTICAL APPLICATIONS: Hepatocellular Carcinoma (HCC) is the most common primary malignancy with poor patient prognosis and a high mortality rate. Akt, a serine/threonine kinase is at the crossroad of cell survival, the progression of the cell cycle, cell signaling, cell growth, cell division, and inactivation of pro-apoptotic factors. The inhibition of Akt is an effective therapeutic strategy against HCC. In this study, terpenoids from Azadirachta indica are potent inhibitors of Akt and hitherto demonstrate anticancer potentials. A. indica leaves are readily available globally and more also it is readily cultivated in African and Asia, continents with the highest prevalence of HCC. A. indica terpenoids extract demonstrate anti-HCC potentials and hence should be exploited in this regard.

Rat model of food-induced non-obese-type 2 diabetes mellitus: comparative pathophysiology and histopathology.

Based on the hypothesis that consistent hyperglycemia can result in insulin resistance, we explored the induction of non-insulin dependent diabetes mellitus (NIDDM) using diet of high glycemic/low fat index and compared the effects on the physiology and histology of the rats. The rats were divided into 3 groups. DM was induced in the first group by single intraperitoneal injection of 150mg/kg alloxan monohydrate and in the second group by feeding the rats with diet of high glycemic index/low fat for 8 weeks. The pathophysiology and histopathology of DM were studied. Hyperglycemia was recorded in the alloxan and food-induced groups respectively. Both groups were also positive for glycosuria, which confirmed the induction of DM. Concentrations of plasma potassium, calcium, protein and urea were higher (p<0.05) in the alloxan-induced than the food-induced diabetic rats, whereas food-induced rats recorded higher hematological indices than the alloxan-induced group. Coronary risk indices were higher in food-induced diabetic rats than the alloxan-induced, while activities of antioxidant enzymes were significantly higher (p<0.05) in alloxan-induced diabetic rats than the food-induced rats. Marked degenerations of the Islets of Langerhans was observed in pancreas of alloxan-induced diabetic rats, whereas, histological examination of the pancreas of food-induced and control rats revealed no visible lesion. Liver and kidney of all food and alloxan-induced diabetic rats showed marked degeneration of the hepatocytes and the glomeruli respectively. This study presents a rat model of type II diabetes mellitus using food of high glycemic/low fat index with its consequent ionoregulatory disruptions, acute anemia, hyperlipidemia, nephropathy and hepatopathy.

Assessment of blood and urine lead levels of some pregnant women residing in Lagos, Nigeria.

Assessment of lead in blood (BLL) and lead in urine (ULL) of some non-occupationally exposed, nonsmoking 214 pregnant Nigerian women, aged 17 to 49 years, and resident in Lagos was carried out using atomic absorption spectrometry with control subjects consisting of 113 nonpregnant women. From results, the mean BLL and ULL (µg/dL) for pregnant women (59.5±2.1; 29.4±1.1) were significantly (p<0.01) higher than the values obtained for nonpregnant women (27.7±1.1; 9.2±0.6). BLL found in women in the first, second, and third trimesters were 57.2±2.3, 61.6±2.2, and 63.1±1.8, respectively. ULL could not serve to predict BLL due to weak correlations (r=-0.06 to +0.15; p>0.10). Study is a contribution to blood and urine lead status of Nigerian pregnant women, being relevant for healthcare management purposes, public health decision making, and possible primary prevention activities.