An insight into the neuroprotective effects and molecular targets of pomegranate (Punica granatum) against Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that still has no permanent cure. The drugs prescribed in the present days are only for symptomatic relief for the patients. Many studies correlating the reduction in the incidence of AD with the diet consumed have been published. These studies showed that a diet rich in polyphenols is associated with a decrease in the incidence of AD. The present review is focused on the ability of pomegranate and its bioactive components to ameliorate the progression of AD and their ability to exert a neuroprotective effect. Various studies showing the ability of pomegranate in inhibiting enzymes, reducing reactive oxygen species, inhibition of microglial activation, inhibition of tau protein hyperphosphorylation, maintenance of synaptic plasticity, anti-inflammatory activity and its ability to inhibit Beta secretase-1 (BACE-1) has been reviewed in this article. In spite of the lack of studies on humans, there are compelling evidence indicating that pomegranate can reduce various risk factors involved in the causation of AD and thus can be used as a persistent nutraceutical to slow ageing and for providing neuroprotection for the treatment of AD.Highlights An overview of traditional and pharmacological uses of pomegranate (POM).Potential of POM in the treatment of neurodegenerative diseases especially in AD.Insight into the molecular mechanisms of neuroprotective effects of POM in AD.Clinical evaluation studies involving POM and its bioactive components.

A comprehensive review on Brigatinib - A wonder drug for targeted cancer therapy in non-small cell lung cancer.

The mortality rate in patients suffering from non-small cell lung cancer (NSCLC) is quite high. This type of cancer mainly occurs due to rearrangements in the anaplastic lymphoma kinase (ALK) gene which leads to form an oncogene of fused gene NPM-ALK. Brigatinib is recently approved by FDA in April 2017 as a potent tyrosine kinase inhibitor (TKI) for the NSCLC therapy. In the present scenario, it is no less than a wonder drug because it is indicated for the treatment of advanced stages of metastatic ALK positive NSCLC, a fatal disease to overcome the resistance of various other ALK inhibitors such as crizotinib, ceritinib and alectinib. In addition to ALK, it is also active against multiple types of kinases such as ROS1, Insulin like growth factor-1Receptor and EGFR. It can be synthesized by using N-[2-methoxy-4-[4-(dimethylamino) piperidin-1-yl] aniline] guanidine and 2,4,5-trichloropyrimidine respectively in two different ways. Its structure consists of mainly dimethylphosphine oxide group which is responsible for its pharmacological activity. It is active against various cell lines such as HCC78, H2228, H23, H358, H838, U937, HepG2 and Karpas- 299. Results of ALTA (ALK in Lung Cancer Trial of AP26113) phase ½ trial shows that 90 mg of brigatinib for 7 days and then 180 mg for next days is effective in the treatment of NSCLC. Brigatinib has been shown to have favorable risk benefit profile and is a safer drug than the available cytotoxic chemotherapeutic agents. In comparison to other FDA approved drugs for the same condition, it causes fewer minor adverse reactions which can be easily managed either by changing the dose or by providing good supportive care. This article is intended to provide readers with an overview of chemistry, pharmacokinetic, pharmacodynamic and safety profile of brigatinib, which addresses an unmet medical need.

Comparative assessment and suitability of iron and the nutritional composition of fortified foods for young children.

AIM: To assess the suitability of iron content and the nutritional benefits of selected fortified food products marketed for 4-8 year old children in Oman. METHODS: Forty-five fortified foods, which are available in Omani markets, were classified into four groups based on food type and composition: ready-to-eat (RTE) breakfast cereals (two groups), malted milk drinks and milk powder formulas. The nutrition panel displayed on the products' outer package was used as a source of content values for iron and other nutrients. RESULTS: Among the selected products, malted milk drinks contain a significant ( p < 0.001) amount of iron that is 6.2±3.1 mg per 30 g serving (recommended daily intake for children 4-8 years old is 10 mg). The way selected products are served, with milk or water, could have a significant impact on the iron absorption and bioavailability, which is influenced by the presence of calcium and vitamin C. The values recorded from malted milk drinks and milk powder formulas were shown to have vitamin C to iron ratios of 3:1 and 8:1, respectively. Such ratios are reportedly effective in reversing the negative effect of calcium on iron absorption. Iron-fortified foods contain low to moderate amount of iron per serving and are considered more nutritious when compared to iron supplements. CONCLUSION: Iron-fortified foods can be conditionally useful to prevent or restore iron deficiency but not be relied on as an only source of iron. Hence these products must be consumed as a part of a healthy diet plan.

Thymoquinone in the clinical treatment of cancer: Fact or fiction?

Thymoquinone (TQ) is the bioactive phytochemical constituent of the seeds oil of Nigella sativa. In vitro and in vivo research has thoroughly investigated the anticancer effects of TQ against several cancer cell lines and animal models. As a result, a considerable amount of information has been generated from research thus providing a better understanding of the anti-proliferating activity of this compound. Therefore, it is appropriate that TQ should move from testing on the bench to clinical experiments. The purpose of this review is to highlight the potential of TQ as an anticancer agent and the chances of this compound in the clinical treatment of cancer, with special attention on breast cancer treatment.

Combinatorial Effects of Thymoquinone on the Anticancer Activity and Hepatotoxicity of the Prodrug CB 1954.

BACKGROUND: One of the major causes of clinical trial termination is the liver toxicity induced by chemotherapeutic agents. Treatment with anticancer drugs like CB 1954 (5-(Aziridin-1-yl)-2,4-dinitrobenzamide) is associated with significant hepatotoxicity. Thymoquinone (TQ), extracted from Nigella sativa, is reported to possess anticancer and hepatoprotective effects. The aims of the present study were to use TQ to reduce hepatotoxicity associated with CB 1954 and to augment its anticancer activity against the resistant mouse mammary gland cell line (66 cl-4-GFP). METHOD: Balb/C mice were transplanted with the 66cl-4-GFP cell line and in vivo antitumor activity was assessed for CB 1954 (141 mg/kg), TQ (10 mg/kg), and a combination of CB 1954 and TQ. Changes in tumor size and body weight were measured for each treatment. Histological examination of tumors and liver tissue samples was performed using the standard hematoxylin/eosin staining protocol, and serum levels of the liver enzymes AST and ALT were used as biomarkers of hepatotoxicity. RESULTS: Severe liver damage and elevated plasma levels of AST and ALT were observed in the group treated with CB 1954. Treatment of tumor-bearing mice with a combination of CB 1954 and TQ caused a significant regression in tumor size and induced extensive necrosis in these tumors. The combination also protected the liver from drug-induced damage and reduced the plasma levels of AST and ALT to their normal ranges. CONCLUSION: These results suggest that the use of TQ with CB 1954 can reduce CB 1954-induced hepatotoxicity and enhance its anticancer activity, indicating the potential use of this combination in clinical studies.

Pharmacophore modeling, homology modeling, and in silico screening reveal mammalian target of rapamycin inhibitory activities for sotalol, glyburide, metipranolol, sulfamethizole, glipizide, and pioglitazone.

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase and member of the PI3K-related kinase (PIKK) family. It plays a central role in integrating signals from metabolism, energy homeostasis, cell cycle, and stress response. Aberrant PI3K/mTOR activation is commonly observed in diseases such as cancer, diabetes and Alzheimer's disease. Accordingly, we developed common feature binding hypotheses for a set of 6 potent mTOR antagonists. The generated models were validated using receiver operating characteristic (ROC) curve analyses. To gain better insight into ligand-mTOR interactions, a homology model for the kinase domain of mTOR was built using the crystallographic structure of PI3Kγ as template. The optimal pharmacophore model was further improved based on detailed docking studies of potent training compound in the homology model. The modified binding model was employed as 3D search query to screen our in-house-built database of established drugs. Subsequent in vitro screening of captured hits showed that six of them have submicromolar to low micromolar bioactivities, namely, glyburide, metipranolol, sulfamethizole, glipizide, pioglitazone, and sotalol.

Acute effects of thymoquinone on the pregnant rat and embryo-fetal development.

The effect of a single intraperitoneal (i.p.) injection of thymoquinone (TQ) on the pregnant rat and embryo-fetal development was investigated. Pregnant female Wistar rats received 15, 35, and 50 mg/kg body weight of TQ i.p. on day 11 or 14 of gestation, and on day 18 of gestation they were sacrificed and laparotomized. Results showed that TQ induces maternal and embryonic toxicities in a dose- and time-dependent manner. With a dose of 50 mg/kg, treated rats experienced a significant decrease in maternal body weight and complete fetal resorption when the dose was given on day 11 of gestation. On the other hand, 46.2% of implants were resorbed and the viable fetuses showed no TQ-related malformations when the dose was given on day 14 of gestation. At a lower TQ dose of 35 mg/kg, maternal and embryonic toxicities were observed only when it was given on day 11 of gestation. The dose of 15 mg/kg was considered to be a dose with no observed adverse effect level for maternal and embryo-fetal toxicities when it was given day 11 or 14 of gestation. Based on the results of this study, TQ, at doses of 50 and 35 mg/kg, has a potentially disruptive effect on embryonic development during the second trimester of rat pregnancy.

Crystallization and preliminary X-ray characterization of the Bacillus amyloliquefaciens YwrO enzyme.

CB1954 is an anticancer prodrug that is currently in clinical trials coupled with the Escherichia coli flavoenzyme nitroreductase (NTR) for use in directed-enzyme prodrug therapy (DEPT). The NTR enzyme is responsible for the conversion of the prodrug into a cytotoxic agent. The bifunctional alkylating agent produced by this bioactivation process leads to DNA damage and death of cancer cells. Recently, a novel flavoenzyme from Bacillus amyloliquefaciens, YwrO (Bam YwrO), was reported to be able to reduce CB1954 from its noncytotoxic form into its active form. The crystallization and preliminary X-ray diffraction analysis of two crystal forms of Bam YwrO are reported. The first crystal form is orthorhombic, with space group P22(1)2(1), and diffracts X-rays to 2.18 A resolution. The second crystal form is tetragonal, with space group P4(1), and diffracts X-rays to 3.4 A. Determination of the Bam YwrO crystal structure will provide an understanding of the molecular recognition between this enzyme and the anticancer prodrug CB1954.

Binding of the anticancer prodrug CB1954 to the activating enzyme NQO2 revealed by the crystal structure of their complex.

CB1954 is an attractive prodrug for directed-enzyme prodrug therapy (DEPT) and a conventional prodrug against tumors in which the enzyme NQO2 is highly expressed. We have determined the crystal structure of the NQO2-CB1954 complex to 2.0 A resolution. The binding of the prodrug is governed by hydrophobic forces, while two key electrostatic contacts determine the specific orientation of the ligand. The structure also reveals an unfavorable interaction, therefore suggesting possible avenues for DEPT-tailored engineering studies.