Syed Hassan Mehdi

Paraquat-induced ultrastructural changes and DNA damage in the nervous system is mediated via oxidative-stress induced cytotoxicity in Drosophila melanogaster

Paraquat (PQ), a quaternary nitrogen herbicide, is commonly used as a pesticide despite of its high toxicity. Our study evaluated the effect of subchronic PQ exposure on the neuropathology, genotoxicity, and antioxidant activity on the nervous tissue of Drosophila melanogaster. We also explored the behavioral effect of PQ on D. melanogaster. Furthermore, we attempted to validate the mechanism by evaluating PQ-induced cytotoxicity on the D-Mel2 cell lines. The fruit fly D. melanogaster serves as a feasible model to understand the mechanism of neurodegenerative diseases. Our study shows a dose-dependent PQ-induced neuropathology in the brain tissue of D. melanogaster as evidenced by hematoxylin and eosin staining, silver nitrate staining, and transmission electron microscopy. Electron microscopic study of D. melanogaster brain tissue exhibited vacuolar degeneration and significant neuronal damage across the nervous tissue structure in comparison with control. Our findings also indicate a dose-dependent locomotor impairment and decreased superoxide dismutase (SOD) specific activity in PQ-treated D. melanogaster. These PQ-induced neuroanatomical changes and decreased SOD specific activity showed a significant association with oxidative DNA damage as observed by alkaline comet assay. Additionally, we show, for the first time, a dose-dependent PQ-induced cytotoxicity in the D-Mel2 cells suggesting loss of neuronal cell viability via cytotoxic damage. Our data suggest that PQ exposure results in neurodegeneration in D. melanogaster and that fruit fly is a suitable in vivo model for correlating the neuroanatomical changes with neurotoxic damages to nervous system.

Therapeutic evolution of benzimidazole derivatives in the last quinquennial period

Benzimidazole, a fused heterocycle bearing benzene and imidazole has gained considerable attention in the field of contemporary medicinal chemistry. The moiety is of substantial importance because of its wide array of pharmacological activities. This nitrogen containing heterocycle is a part of a number of therapeutically used agents. Moreover, a number of patents concerning this moiety in the last few years further highlight its worth. The present review covers the recent work published by scientists across the globe during last five years.

Characterization and anti-proliferative activity of curcumin loaded chitosan nanoparticles in cervical cancer.

In the present study the chitosan nanoparticles (CsNPs) and curcumin loaded chitosan nanoparticles (CLCsNPs) were synthesized by tripolyphosphate (TPP) cross-linking method. The nanoparticles were prepared within a zone of appropriate chitosan and TPP concentrations. The average size of CsNPs and CLCsNPs were approximately 189±11.8nm and 197±16.8nm, exhibited a zeta potential of +76±5.6mV and +71±6.4mV respectively and drug entrapment efficiency was ≈85%. The CLCsNPs and CsNPs were further characterized by different physicochemical methods like transmission electron microscopy (TEM), dynamic light scattering (DLS), HPLC, MALDI-TOF, FT-IR, XRD and UV-vis Spectroscopy. In vitro studies revealed a fast release of ≈35% at pH 5 and ≈25% at pH 7.4 of the drug during the first 3h, followed by controlled release of curcumin over a period of 120h and sustained anti-proliferative activity of the drug in a dose and time dependent manner of CLCsNPs and combination with methyl jasmonate. The higher cytotoxicity effect of CLCsNPs may be due to their higher cellular uptake as compared to curcumin. Chitosan nanoparticles were not only stable but also a nontoxic. Our data suggested that curcumin loaded nanoformulations, therefore, might be promising candidates in cancer therapy.

Characterization and carboplatin loaded chitosan nanoparticles for the chemotherapy against breast cancer in vitro studies

Aim of the studies to synthesized chitosan nanoparticles by an ionic interaction procedure. The nanoparticles were characterized by physicochemical methods like, DLS, TEM, Surface potential measurements, FT-IR and DSC. The average particle size of chitosan and carboplatin nanoparticles was found to be 277.25±11.37nm and 289.30±8.15nm and zeta potential was found to be 31±3.14mV and 33±2.15mV respectively with low polydispersity index. The maximum entrapment of carboplatin in nanoparticles was a spherical shape with a positive charge. The maximum encapsulation and loading efficiencies of carboplatin (5mg/ml) were obtained to be 58.43% and 13.27% respectively. The nanocarboplatin was better blood compatibility as compared to chitosan nanoparticles. Finally, the cytotoxic effects of the carboplatin loaded chitosan nanoparticles were tested in-vitro against breast cancer (MCF-7) cell lines. Our studies showed that the chitosan nanoparticles could be used as a promising candidate for drug delivery for the therapeutic treatment of breast cancer.

Chondroitin sulfate-capped super-paramagnetic iron oxide nanoparticles as potential carriers of doxorubicin hydrochloride

Chondroitin-4-sulfate (CS), a glycosaminoglycan, was used to prepare CS-capped super-paramagnetic iron oxide nanoparticles, which were further employed for loading a water-soluble chemotherapeutic agent (doxorubicin hydrochloride, DOX). CS-capped SPIONs have potential biomedical application in cancer targeting. The optimized formulation had a hydrodynamic size of 91.2±0.8nm (PDI; 0.228±0.004) and zeta potential of -49.1±1.66mV. DOX was loaded onto the formulation up to 2% (w/w) by physical interaction with CS. TEM showed nano-sized particles having a core-shell structure. XRD confirmed crystal phase of iron oxide. FT-IR conceived the interaction of iron oxide with CS as bidentate chelation and also confirmed DOX loading. Vibration sample magnetometry confirmed super-paramagnetic nature of nanoparticles, with saturation magnetization of 0.238emug(-1). In vitro release profile at pH 7.4 showed that 96.67% of DOX was released within 24h (first order kinetics). MTT assay in MCF7 cells showed significantly higher (p<0.0001) cytotoxicity for DOX in SPIONs than DOX solution (IC50 values 6.294±0.4169 and 11.316±0.1102μgmL(-1), respectively).

New insights into the antioxidant and apoptotic potential of Glycyrrhiza glabra L. during hydrogen peroxide mediated oxidative stress: An in vitro and in silico evaluation

Plant-derived substances (phytochemicals) are well recognized as sources of pharmacologically potent drugs in the treatment of several oxidative stress related disorders. Our study aims to evaluate the antioxidant and apoptotic effects of Glycyrrhiza glabra L. in both cell free and cell culture system. Plant fractions have been prepared with hexane, chloroform, ethyl acetate, methanol and water and their antioxidant properties are reviewed. Potent antioxidant activity has been well established in both in vitro and in silico studies which is believed to be responsible for the anticancerous nature of the plant. Results obtained indicate that methanol fraction of G. glabra L. exhibited maximum scavenging activity against DPPH and nitric oxide free radicals comparable to standard antioxidant L-AA. Administration of methanol fraction also considerably reduced the malondialdehyde produced due to lipid peroxidation in mammalian liver tissues. Moreover, the levels of antioxidant enzymes SOD, CAT, GST, GPx and GR in the oxidative stress induced tissues were refurbished significantly after treatment with plants methanol fraction. Moreover, methanol fraction was found to be nontoxic to normal human cell line whereas it inhibited cancer cells HeLa and HepG2 considerably. Apoptosis was established by DAPI fluorescent staining and western blot analysis of pro apoptotic protein caspase-8, caspase-3 and anti-apoptotic protein Bcl-2.There is an up regulation in the levels of pro apoptotic caspase-8 and caspase-3 and down regulation of anti-apoptotic Bcl-2. Furthermore, GC-MS analysis of the methanol fraction revealed the presence of many compounds. In silico experiments using Autodock 4.2 tools showed strong affinity of plant compounds towards antioxidant enzymes (proteins) thus validating with the conclusions of antioxidant enzyme assays and establishing a role in cancer pathogenesis.

Antioxidative and anti-proliferative potential of Curculigo orchioides Gaertn in oxidative stress induced cytotoxicity: In vitro, ex vivo and in silico studies

Plant phytoconstituents have been a valuable source of clinically important anticancer agents. Antioxidant and anticancerous activity of plant Curculigo orchioides Gaertn were explored In vitro antioxidant activity, antioxidant enzyme activity of oxidatively stressed tissue, and cell culture studies on human cancer cell lines HepG2, HeLa and MCF-7 were carried out. Active plant fractions were subjected to GC-MS analysis and compounds selected on the basis of their abundance were screened in silico with the help of Auto Dock 4.2 tools with pre-selected antioxidant enzymes. Curculigo orchioides Gaertn plant fractions exhibited significant antioxidant activities by virtue of scavenging of free radicals having IC50 value of ethylacetate fraction (EA) for DPPH radical scavenging assay to be 52.93 ± 0.66 μg/ml. Further, antioxidant enzyme defense of mammalian tissue when treated with plant fractions revealed that enzyme concentrations were refurbished which were increased during oxidative stress. MTT assay on cell lines HepG2, HeLa and MCF-7 presented IC50 values of ethylacetate (EA) fraction as 171.23 ± 2.1 μg/ml, 144.80 ± 1.08 μg/ml and 153.51 μg/ml and aqueous ethylacetate (AEA) fraction as 133.44 ± 1.1 μg/ml, 136.50 ± 0.8 μg/ml and 145.09 μg/ml respectively. Further EA and AEA plant fractions down regulated the levels of antiapoptotic Bcl-2 expression and upregulated the expression of apoptotic proteins caspase-3 and caspase-8 through an intrinsic ROS-mediated mitochondrial dysfunction pathway. KEY MESSAGE Key findings explained that fractions of Curculigo orchioides Gaertn inhibited oxidative stress by increasing the antioxidant enzyme content and have anticancerous potential on cancer cell lines HepG2, HeLa and MCF-7.

Phytochemical Composition of Extracts Prepared from Dietary Cucurbitsand their Cytoprotective Efficacies against Hydrogen Peroxide InducedOxidative Stress in GI Cell-INT407

Compositions of phytochemicals in aqueous extracts prepared from Lagenaria siceraria (Ls), Luffa cylindrica (Lc) and Cucurbita maxima (Cm) fruits were identified by gas chromatography and mass spectroscopy. GC-MS analysis showed the presence of 83, 72 and 74 number of phytochemicals in Ls, Lc and Cm respectively. Extracts were evaluated for their role in protection of INT407 cells against injurious effect of H2O2. MTT, LDH and colony survival assays (CSA) were employed for evaluating H2O2-induced cytotoxicity. Antioxidant properties of extracts were evaluated by enzymatic assays in H2O2 induced oxidative stress in INT407 cells. LD50 and LD25 of H2O2 at 24 h on INT407 cells were evaluated and found 114.25 ± 0.24 and 64.01 ± 0.11 μM respectively. Macromolecules were found to protect INT407 in dose dependent manner (p ≤ 0.05). CSA showed enhanced growth in extracts of Lagenaria siceraria and Luffa cylindrica in comparison to Cucurbita maxima treated cells (p=0.042). H2O2 treated cells showed depleted superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activities by 71.60, 68.81, 45.79 and 22.95% respectively. Lagenaria siceraria and Luffa cylindrica treated cells showed modulation of SOD by 8.88 and 8.95%, CAT by 22.34 and 14.20%, GPx by 5.56 and 1.42%, and GR by 2.20 and 3.22% respectively. Cucurbita maxima modulated CAT by 1.78%, and GR by 0.70%. Synergistic effects of phytochemicals present in these extracts were found non-toxic on INT407.

Nutraceuticals as Chemopreventive and Therapeutic agents in Gut AssociatedPathogenesis

Nutraceuticals have gained great insights in recent years due to their therapeutic implications. Secondary metabolites like glutamate, flavonoids, polyphenols and terpenoids are widespread in nature and are part of human diet. Polysaccharides of prebiotic nature are used both as therapeutic and prophylactic agents. These nutraceuticals in recent times have been reported to posses great potential to reduce antigenic and oxidative pressure in the human gut. Antioxidant rich diet is a potential therapeutic agent against reactive oxygen species induced pathogenesis. Epegenetic compounds present in antioxidant and prebiotics rich nutraceuticals mitigate and remove the causative factors associated with pathogenesis. Flavonoids and polyphenols exhibit antioxidant properties and have been recognized as potential gastroprotective agents and epigenetic modulators as well. Triterpenoids such as cucurbitacin is reported to posses anticancer activities. Glutamate is an enteric neurotransmitter that is used in improving neonatal gut function. This review comprehensively summarizes the current knowledge of gut modulating nutraceuticals which ultimately can play its role from prophylaxis of gut to its therapeutics by employing various macro and micro molecular pathways.

Chrysin: A Promising Anticancer Agent its Current Trends and Future Perspectives

Cancer is one of the major public health concerns in the United States and in other developed countries, affecting million deaths approximately every year worldwide. Cancer incidences show inconsistency between emerging and developed nations. Epidemiologic findings intensely propose that incidence of cancer are predisposed by environmental factors including diet, which is essentially unavoidable. Strategies to prevent cancer comprise overlapping approaches viz. Dietary cancer prevention or chemoprevention. Naturally occurring constituents or pharmacological agents prevent or reverse the initiation phase of carcinogenesis or arrest at progression of carcinogenesis through chemoprevention. Cancer prevention through diet may be possible by the intake of fruits and vegetables. Significant consideration has been given in finding plant-derived dietary agents, which can be developed as promising chemo preventives. One such compound is chrysin (5,7-dihydroxylflavone). It has been shown to possess significant anti-inflammatory, antioxidant and anti-carcinogenic properties. Recently significant progress has been made in studying the biological effects of chrysin at cellular and molecular levels. This review scrutinizes the anticancer effects of chrysin, its considerable potential for development as a cancer chemo preventive agent.