Khalid Bashir Dar

Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight

Mitochondria is one of the main source of oxidative stress (ROS), as it utilizes the oxygen for the energy production. ROS and RNS are normally generated by tightly regulated enzymes. Excessive stimulation of NAD(P)H and electron transport chain leads to the overproduction of ROS, results in oxidative stress, which is a good mediator to injure the cell structures, lipids, proteins, and DNA. Various oxidative events implicated in many diseases due to oxidative stress include alteration in mitochondrial proteins, mitochondrial lipids and mitochondrial DNA, Which in turn leads to the damage to nerve cell as they are metabolically very active. ROS/RNS at moderate concentrations also play roles in normal physiology of many processes like signaling pathways, induction of mitogenic response and in defense against infectious pathogens. Oxidative stress has been considered to be the main cause in the etiology of many diseases, which includes Parkinsons and Alzheimer diseases. Several PD associated genes have been found to be involved in mitochondrial function, dynamics and morphology as well. This review includes source of free radical generation, chemistry and biochemistry of ROS/RNS and mitochondrial dysfunction and the mechanism involved in neurodegenerative diseases.

Inflammation: A Multidimensional Insight on Natural Anti-Inflammatory Therapeutic Compounds

Derailed inflammation causes severe damage to the normal tissues resulting in various pathological conditions such as auto-inflammatory disorders, neurodegenerative diseases and cancer. Cure of inflammatory diseases is a big challenge. Medicinal herbs used traditionally represent the best option for obtaining effective anti-inflammatory therapeutics. Present review provides a thorough insight about various pathways, consequences and therapeutic strategies of inflammation with prime focus to expose indigenous anti-inflammatory herbal compounds along with their structures and diverse range of mechanisms of action. Over hundred medicinal plants with scientifically reported anti-inflammatory properties were reviewed. Different parts of the plants like roots, stem, bark, leaves, flowers and seeds contain active compounds with potential anti-inflammatory properties. Such compounds act at multiple targets in the inflammatory response pathways and regulate multitude of chemical mediators, enzymes, genes or cellular functions to alleviate inflammation. Although a large number of antiinflammatory herbal compounds have been isolated but the mechanism of action of bulk of compounds has not been elucidated comprehensively. Besides there is need for conducting well designed clinical trials so that the promising compounds could be used as effective antiinflammatory therapeutic agents in future.

ABC of multifaceted Dystrophin glycoprotein complex (DGC).

Dystrophin protein in association with several other cellular proteins and glycoproteins leads to the formation of a large multifaceted protein complex at the cell membrane referred to as dystrophin glycoprotein complex (DGC), that serves distinct functions in cell signaling and maintaining the membrane stability as well as integrity. In accordance with this, several findings suggest exquisite role of DGC in signaling pathways associated with cell development and/or maintenance of homeostasis. In the present review, we summarize the established facts about the various components of this complex with emphasis on recent insights into specific contribution of the DGC in cell signaling at the membrane. We have also discussed the recent advances made in exploring the molecular associations of DGC components within the cells and the functional implications of these interactions. Our review would help to comprehend the composition, role, and functioning of DGC and may lead to a deeper understanding of its role in several human diseases.

Efficacy of Aqueous and Methanolic Extracts of Rheum Spiciformis against Pathogenic Bacterial and Fungal Strains.

INTRODUCTION Rheum spiciformis is a newly identified edible medicinal plant of genus Rheum. The plant is used to treat various diseases on traditional levels in Kashmir Valley, India. AIM To evaluate the phytochemical screening, antibacterial and antifungal potential of aqueous and methanolic extracts of Rheum spiciformis, a traditionally used edible medicinal plant. MATERIALS AND METHODS Methanolic and aqueous extracts of Rheum spiciformis were tested for their antimicrobial activities against six bacterial strains namely Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus vulgaris and Escherichia coli and four fungal strains Penicillium chrysogenum, Aspergillus fumigatus, Candida albicans and Saccharomyces cerevisiae. The susceptibility of microbial strains to the two extracts was determined using agar well diffusion method. Phytochemical screening was carried out by using various standard procedures. RESULTS Methanolic extract showed potent antimicrobial activity as compared to aqueous extract at the concentrations of 10, 30, 50, 80 and 100mg/ml. The most susceptible bacterial strains were Staphylococcus aureus with zone of inhibition (25±0.10mm), Klebsiella pneumonia (23±0.25mm), Proteus vulgaris (22±0.10mm) at the concentration of 100mg/ml. Aqueous extracts at the higher concentration were found effective against Proteus vulgaris and Bacillus subtilis with zone of inhibition (17±0.24mm) and (17±0.10mm), respectively. Among fungal strains the most susceptible were Aspergillus fumigatus (21±0.10mm), Saccharomyces cerevisiae (20±0.20mm) and Penicillium Chrysogenum (17±0.15mm) at the concentration of 100mg/ml methanol extract. The zone of inhibition for aqueous extract against fungal strains ranged between 14±0.13mm to 16±0.19mm at the highest concentration of plant extract. Phytochemical analysis revealed the presence of various secondary metabolites like flavonoids, saponins, volatile oils, phenols, steroids, terpenoids and alkaloids. CONCLUSION Our results indicate that this plant has enough potential to serve as an excellent candidate for obtaining antimicrobial compounds to combat bacterial and fungal infections.

Modulation of Oxidative Stress and Hyperglycemia by Rheum spiciformis in Alloxan Induced Diabetic Rats and Characterization of Isolated Compound

This study evaluates the ameliorative potential of Rheum spiciformis methanolic (RS-MeOH) extract in reducing oxidative stress and hyperglycemia in albino rats along with characterization of possible therapeutic compound(s). Groups treated with 50 and 100 mg/kg bw plant extract (RS-MeOH ) decrease blood glucose levels from 359.9±8.2 to 209.5±8.5 mg/dl (50 mg/kg bw) and 354.7±13.3 to 162.5±7.4 mg/dl (100 mg/kg bw) on the 0th and 14th day (P<0.001) respectively. This reduction in blood glucose was significant as compared to glibenclamide (20 mg/dl) which reduced glucose levels from 297.7±11.39 to 132.9±8.74 mg/dl on 0th and 14th day respectively. Biochemical parameters triglycerdies, cholesterol, low density lipoprotein (LDL) and creatinine were also reduced in a dose dependent manner. Liver marker enzymes were positively modulated by administration of RS-MeOH (P<0.001). Antioxidant enzyme profile showed an enhanced/better pattern after the administration of RS-MeOH extracts for reduced glutathione, reduced glutathione (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and superoxide dismutase (SOD) in both liver and pancreas. Moreover pancreatic histopathology reports revealed β-cell restorative effects with RS-MeOH, thereby potentiating its role in improving blood glucose levels. RS-MeOH purification and isolation studies involving GC-MS and NMR techniques revealed presence of emodin type compounds in RS-MeOH. Overall Rheum spiciformis showed ameliorative action on oxidative stress and hyperglycemia, however further studies to explore the mechanism of action of possible therapeutic compound in invivo clinical trials will prove beneficial for the advancement of new oral antidiabetic drug.

Exploring Proteomic Drug Targets, Therapeutic Strategies and Protein-Protein Interactions in Cancer: Mechanistic View

Protein-protein interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer. This review explores the candidature of various proteins involved in cellular trafficking (small GTPases, molecular motors, matrix degrading enzymes, integrin), transcription (p53, cMyc), signalling (membrane receptor proteins), angiogenesis (VEGFs) and apoptosis (BCL-2family), which could possibly serve as targets for developing effective anti-cancer regimen. Interactions between Ras/Raf; X-linked inhibitor of apoptosis protein (XIAP)/second mitochondria derived activator of caspases (Smac/DIABLO); Frizzled (FRZ)/Dishevelled (DVL) protein; beta-catenin/T cell factor (TCF) have also been studied as prospective anticancer targets. Efficacy of diverse molecules/drugs targeting such PPIs although evaluated in various animal models/cell lines, there is essential need for human based clinical trials. Therapeutic strategies like the use of biologicals, high throughput screening (HTS) and fragment based technology could play imperative role in designing cancer therapeutics. Moreover, bioinformatic/computational strategies based on genome sequence, protein sequence/structure and domain data could serve as competent tools for predicting PPIs. Exploring hot spots in proteomic networks represents another approach for developing target specific therapeutics. Over-all, this review lays emphasis on productive amalgamation of proteomics, genomics, biochemistry, and molecular dynamics for successful treatment of cancer.

Evaluation of Antibacterial, Antifungal and Phytochemical Screening ofSolanum nigrum

The present study aimed at evaluating the antimicrobial potential of aqueous and methanolic extracts of Solanum nigrum, a traditionally used medicinal plant with multiple therapeutic properties. The susceptibility of microbial strains to the two extracts was determined using agar well diffusion method. The bacterial strains employed were Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus vulgaris and Escherichia coli. The fungal strains used were Penicillium Chrysogenum, Aspergillus fumigatus, Candida albicans and Saccharomyces cerevisiae. Phytochemical screening was performed using standard methods. A dose dependent increase in the antibacterial activity was observed with both the methanol and aqueous extracts. Highest antibacterial activity was exhibited by aqueous extract with Escherichia coli (16 ± 0.23 mm) followed by Staphylococcus aureus (15 ± 0.15 mm) at the concentration of 100 mg/ml plant extract. Methanolic extract showed highest antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa with zone of inhibition (14 ± 0.11 mm) and (14 ± 0.26 mm) at the same concentration (100 mg/ml) respectively. The highest antifungal potential was exhibited by the methanolic extract against Saccharomyces cerevisiae (26 ± 0.27 mm) and Candida albicans (22 ± 0.13 mm), while the aqueous extract exhibits the highest antifungal potential against Saccharomyces cerevisiae (23 ± 0.14 mm) followed by Candida albicans (21 ± 0.10 mm) and Aspergillus fumigatus (16 ± 0.11 mm) at the concentration of 100 mg/ml. Phytochemical analysis revealed the plant is rich in various secondary metabolites like alkaloids, saponins, flavonoids, phenols and volatile oils. Cardenolides and phlobtannins were found absent. The study concludes that the plant possess novel compounds with significant antibacterial and antifungal properties. Isolation and characterization of these novel compounds could provide potent antimicrobial agents to combat pathogenic infections.