Irfan A. Ansari

Dietary phytochemicals as potent chemotherapeutic agents against breast cancer: Inhibition of NF-κB pathway via molecular interactions in rel homology domain of its precursor protein p105.

Background: Dietary phytochemicals consist of a wide variety of biologically active compounds that are ubiquitous in plants, many of which have been reported to have anti-tumor as well as anti-inflammatory properties. Objective: In the present study, we aimed to validate these findings by using docking protocols and explicate the possible mechanism of action for a dataset of nine phytochemicals namely boswellic acid, 1-caffeoylquinic acid, ellagic acid, emodin, genistein, guggulsterone, quercetin, resveratrol, and sylibinin from different plants against the nuclear factor- kappaB (NF-κB) precursor protein p105, an important transcription factor reported to be overexpressed in breast cancer. Materials and Methods: 2-D structures of all phytochemicals were retrieved from PubChem Compound database and their subsequent conversion into 3-D structures was performed by using online software system CORINA. The X-ray crystallographic structure of the NF-κB precursor p105 was extracted from Brookhaven Protein Data Bank. Molecular docking simulation study was carried out by using AutoDock Tools 4.0. Results: Our results showed significant binding affinity of different phytochemicals with the Rel homology domain of the NF-κB precursor protein p105. Quercetin and 1-caffeoylquinic acid were found to be very effective inhibitors against target molecule as they showed binding energy of −12.11 and −11.50 Kcal/mol, respectively. The order of affinity of other ligands with p105 was found as follows: guggulsterone > sylibinin > emodin > resveratrol > genistein > boswellic acid > ellagic acid. Conclusion: Our in silico study has explored the possible chemopreventive mechanism of these phytochemicals against the NF-κB precursor protein p105 and deciphered that quercetin, 1-caffeoylquinic acid and guggulsterone were the potent inhibitors against target molecule. In addition, large scale preclinical and clinical trials are needed to explore the role of these chemotherapeutic molecules against the NF-κB precursor protein p105 in cure and prevention of breast cancer.

Chemotherapeutic potential of Boerhaavia diffusa Linn: A review.

Boerhaavia diffusa Linn. has been shown to exhibit a wide range of medicinal properties for the treatment of diabetes, inflammation, stress, hepatotoxicity, jaundice and heart failure. The extraordinary antioxidant, hepatoprotective, antibiotic, antidiabetic and anticarcinogenic properties of B. diffusa have attracted pioneers in the field of science and medicine. Moreover, the therapeutic importance of this plant, which is due to presence of polyphenols and flavanoids, makes this plant medically more important to be exploited by clinicians and scientists to gain more insight into its biological and medicinal properties. The present review on B. diffusa focuses over the chemical compositions and its ethno-medicinal uses, linked from ancient times to the present with a scope of development in future. Furthermore, a recent update on mechanistic approaches of B. diffusa has also been discussed, which could be helpful for the researchers working in this field. Eventually, based on its antioxidant and antidiabetic characteristics, it is hypothesized that B. diffusa might exhibit antiglycating properties as well.

Maillard reaction in food allergy: Pros and cons

ABSTRACT Food allergens have a notable potential to induce various health concerns in susceptible individuals. The majority of allergenic foods are usually subjected to thermal processing prior to their consumption. However, during thermal processing and long storage of foods, Maillard reaction (MR) often takes place. The MR is a non-enzymatic glycation reaction between the carbonyl group of reducing sugars and compounds having free amino groups. MR may sometimes be beneficial by damaging epitope of allergens and reducing allergenic potential, while exacerbation in allergic reactions may also occur due to changes in the motifs of epitopes or neoallergen generation. Apart from these modulations, non-enzymatic glycation can also modify the food protein(s) with various type of advance glycation end products (AGEs) such as Nϵ-(carboxymethyl-)lysine (CML), pentosidine, pyrraline, and methylglyoxal-H1 derived from MR. These Maillard products may act as immunogen by inducing the activation and proliferation of various immune cells. Literature is available to understand pathogenesis of glycation in the context of various diseases but there is hardly any review that can provide a thorough insight on the impact of glycation in food allergy. Therefore, present review explores the pathogenesis with special reference to food allergy caused by non-enzymatic glycation as well as AGEs.

Health Risks and Benefits of Chickpea (Cicer arietinum) Consumption

Chickpeas (CPs) are one of the most commonly consumed legumes, especially in the Mediterranean area as well as in the Western world. Being one of the most nutritional elements of the human diet, CP toxicity and allergy have raised health concerns. CPs may contain various antinutritional compounds, including protease inhibitors, phytic acid, lectins, oligosaccharides, and some phenolic compounds that may impair the utilization of the nutrients by people. Also, high consumption rates of CPs have enhanced the allergic problems in sensitive individuals as they contain many allergens. On the other hand, beneficial health aspects of CP consumption have received attention from researchers recently. Phytic acid, lectins, sterols, saponins, dietary fibers, resistant starch, oligosaccharides, unsaturated fatty acids, amylase inhibitors, and certain bioactive compounds such as carotenoids and isoflavones have shown the capability of lowering the clinical complications associated with various human diseases. The aim of this paper is to unravel the health risks as well as health-promoting aspects of CP consumption and to try to fill the gaps that currently exist. The present review also focuses on various prevention strategies to avoid health risks of CP consumption using simple but promising ways.

Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors.

Targeting papain family cysteine proteases is one of the novel strategies in the development of chemotherapy for a number of diseases. Novel cysteine protease inhibitors derived from 1-pyridylimidazo[1,5-a]pyridine representing pharmacologically important class of compounds are being reported here for the first time. The derivatives were initially designed and screened in silico by molecular docking studies against papain to explore the possible mode of action. The molecular interaction between the compounds and cysteine protease (papain) was found to be very similar to the interactions observed with the respective epoxide inhibitor (E-64c) of papain. Subsequently, compounds were synthesized to validate their efficacy in wet lab experiments. When characterized kinetically, these compounds show their Ki and IC50 values in the range of 13.75 to 99.30 µM and 13.40 to 96.50 µM, respectively. The thermodynamics studies suggest their binding with papain hydrophobically and entropically driven. These inhibitors also inhibit the growth of clinically important different types of Gram positive and Gram negative bacteria having MIC50 values in the range of 0.6–1.4 µg/ml. Based on Lipinski’s rule of Five, we also propose these compounds as potent antibacterial prodrugs. The most active antibacterial compound was found to be 1-(2-pyridyl)-3-(2-hydroxyphenyl)imidazo[1,5-a]pyridine (3a).

Glycyrrhizin induces reactive oxygen species-dependent apoptosis and cell cycle arrest at G0/G1 in HPV18+ human cervical cancer HeLa cell line

Cervical cancer is the fourth most common cancer among women worldwide and is a major cause of morbidity and mortality. High-risk Human Papilloma Virus (mostly type 16 & 18) infection is the primary risk factor for the development of cervical carcinoma. The quest for strong, safe and cost effective natural antiproliferative agents that could reduce cervical cancer have been focussed now a day. Recently, glycyrrhizin, a triterpene glycoside (saponin) from licorice (Glycyrrhiza glabra Linn.), has been shown to exhibit potent antiproliferative and anticancer properties in a few preliminary studies. However, potential of this compound in cervical cancer has not been elucidated yet. Therefore the objective of this study was to analyze the antiproliferative and apoptotic properties of glycyrrhizin in human cervical cancer HeLa cells. Our results showed that glycyrrhizin exposure significantly reduced the cell viability of HeLa cells with a concomitant increase in nuclear condensation and DNA fragmentation in a dose dependent manner. The intracellular ROS generation assay showed dose-related increment in ROS production induced by glycyrrhizin. Glycyrrhizin also induced apoptosis in cervical cancer cells by exerting mitochondrial depolarization. Cell cycle study showed that glycyrrhizin induced cell cycle arrest in G0/G1 phase of cell cycle in a dose dependent manner. Thus, this study confirms the efficacy of glycyrrhizin in cervical cancer cells which could be an adjunct in the better prevention and management of cervical cancer worldwide.

Carvacrol Induces Reactive Oxygen Species (ROS)-mediated Apoptosis Along with Cell Cycle Arrest at G0/G1 in Human Prostate Cancer Cells

ABSTRACT Carvacrol, a major monoterpenoid phenol from Origanum and Thymus species, has been shown to exhibit antiproliferative and anticancer properties in a few recent studies. Nevertheless, detailed mechanism of the action of this compound in prostate cancer has not been elucidated yet. Therefore, in the current study, we examined the anticancer activity and mechanism of the action of carvacrol against human prostate cancer cells. It was found that the treatment of DU145 cells with carvacrol decreased cell viability in a concentration and time-dependent manner. The antiproliferative action of carvacrol leads to induction of apoptosis as confirmed by nuclear condensation, Annexin V-FITC/PI positive cells, and caspase-3 activation. In addition, carvacrol augmented reactive oxygen species generation and disruption in the mitochondrial membrane potential which has not been reported in the previous studies of carvacrol with prostate cancer. Moreover, carvacrol-induced apoptosis of prostate cancer cells was also accompanied by significant amount of growth arrest at the G0/G1 phase of the cell cycle which has also not been documented previously. To sum up, this study has established that carvacrol could be a promising chemotherapeutic agent and could have a direct practical implication and translational relevance to prostate cancer patients as Origanum consumption may retard prostate cancer progression.

Potential role of lycopene in targeting proprotein convertase subtilisin/kexin type-9 to combat hypercholesterolemia

Abstract Proprotein convertase subtilisin/kexin type 9 (PCSK‐9) is a serine protease of the proprotien convertase (PC) family that has profound effects on plasma low density lipoprotein cholesterol (LDL‐C) levels, the major risk factor for coronary heart disease (CHD), through its ability to mediate LDL receptor (LDL‐R) protein degradation and reduced recycling to the surface of hepatocytes. Thus, the current study was premeditated not only to evaluate the role of lycopene in targeting the inhibition of PCSK‐9 via modulation of genes involved in cholesterol homeostasis in HFD rats but also to examine a correlation between HFD induced inflammatory cascades and subsequent regulation of PCSK‐9 expression. Besides the effect of lycopene on hepatic PCSK‐9 gene expression, PPI studies for PCSK‐9‐Lycopene complex and EGF‐A of LDL‐R were also performed via molecular informatics approach to assess the dual mode of action of lycopene in LDL‐R recycling and increased removal of circulatory LDL‐C. We for the first time deciphered that lycopene treatment significantly down‐regulates the expression of hepatic PCSK‐9 and HMGR, whereas, hepatic LDL‐R expression was significantly up‐regulated. Furthermore, lycopene ameliorated inflammation stimulated expression of PCSK‐9 via suppressing the expression of inflammatory markers. The results from our molecular informatics studies confirmed that lycopene, while occupying the active site of PCSK‐9 crystal structure, reduces the affinity of PCSK‐9 to complex with EGF‐A of LDL‐R, whereas, atorvastatin makes PCSK‐9‐EGF‐A complex formation more feasible than both of PCSK‐9‐EGF‐A alone and Lycopene‐PCSK‐9‐EGF‐A complex. Based on above results, it can be concluded that lycopene exhibits potent hypolipidemic activities via molecular mechanisms that are either identical (HMGR inhibition) or distinct from that of statins (down‐regulation of PCSK‐9 mRNA synthesis). To the best of our knowledge, this is the first report that lycopene has this specific biological property. Being a natural, safer and alternative therapeutic agent, lycopene could be used as a complete regulator of cholesterol homeostasis and ASCVD. Graphical abstract Figure. No Caption available. HighlightsLycopene combats hypercholesterolemia via down‐regulating the expression of hepatic PCSK‐9 and HMGR.Lycopene increases LDL‐R gene expression and functionality to combat with high LDL‐C.Lycopene reduces the affinity of PCSK‐9 to bind with EGF‐A of LDL‐R.Lycopene negatively regulates inflammation induced PCSK‐9 expression.Lycopene ameliorates plasma PON‐1 activity to enhance HDL functionality in rats.

Lycopene amends LPS induced oxidative stress and hypertriglyceridemia via modulating PCSK-9 expression and Apo-CIII mediated lipoprotein lipase activity

This study was undertaken to uncover the regulatory role of lycopene in targeting lipopolysaccharide (LPS) induced oxidative stress and inflammatory cascades and subsequent regulation of proprotein convertase subtilisin/kexin type-9 (PCSK-9) expression via sterol regulatory element binding protein-2 (SREBP-2) and hepatocyte nuclear factor-1α (HNF-1α). Further, protein-protein interaction (PPI) studies for Lycopene-Apo-CIII complex against lipoprotein lipase (LPL) were also performed to assess its regulatory role behind the enhanced circulatory TG/TRLs clearance. Lycopene treatment down-regulated hepatocyte PCSK-9 expression via down-regulation of HNF-1α, whereas, LDL-receptor (LDL-R) was up-regulated by subsequent up-regulation of SREBP-2. PPI studies showed that lycopene diminishes the affinity of Apo-CIII to complex with LPL (ΔG: -917.1 Kcal/mol) resulting in increased LPL functionality and TRLs clearance. Moreover, lycopene also ameliorated LPS stimulated oxidative-stress via enhanced total antioxidant and HDL associated PON-1 activity in addition to down-regulate the expression and plasma level of inflammatory mediators. Based on above findings, we concluded that lycopene exhibits dual role in targeting LPS induced oxidative stress and hypertriglyceridemia via down-regulation of PCSK-9, making greater no. of surface LDL-R available for LPS processing and clearance, as well as increased LPL activity through inhibition of Apo-CIII.

An Efficient Protocol for Isolation of High Quality Genomic DNA fromSeeds of Apple Cultivars (Malus x Domestica) for Random AmplifiedPolymorphic DNA (RAPD) Analysis

Genomic DNA represents the total genome of an organism and is valuable for different molecular studies. The isolation of high quality DNA is a prerequisite for these molecular techniques. The seeds of apple (Malusdomestica) contain high amount of polysaccharides, polyphenols and other secondary metabolites that can hamper DNA isolation, amplification, restriction digestion and subsequent molecular studies. Here, we report a simple, inexpensive and an effi- cient protocol for the isolation of high quality genomic DNA from seeds of different apple cultivars for random amplified polymorphic DNA (RAPD) analysis. This procedure purifies greater amounts of DNA which can be amplified via PCR or digested with endonucleases. The yield of DNA was 200-300 ng/μL (total 8-12 μg DNA from 1-2 apple seeds). The sim- plicity of the procedure makes it very practical for DNA extraction.