Acetylcholinesterase (AChE) inhibitors are actively used for the effective treatment of Alzheimer’s disease. In recent years, the neuroprotective effects of organoselenium compounds such as ebselen and diselenides on the AChE activity have been investigated as potential therapeutic agents. In this work, we have carried out systematic kinetic and intrinsic fluorescence assays in combination with docking and molecular dynamics (MD) simulations to elucidate the molecular mechanism of the mixed inhibition of AChE by ebselen and diphenyl diselenide (DPDSe) molecules. Our MD simulations demonstrate significant heterogeneity in the binding modes and allosteric hotspots for DPDSe on AChE due to non-specific interactions. We have further identified that both ebselen and DPDSe can strongly bind around the peripheral anionic site (PAS), leading to non-competitive inhibition similar to other PAS-binding inhibitors. We also illustrate the entry of the DPDSe molecule into the gorge through a “side door”, which offers an alternate entry point for AChE inhibitors as compared to the usual substrate entry point of the gorge. Together with results from experiments, these simulations provide mechanistic insights into the mixed type of inhibition for AChE using DPDSe as a promising inhibitor for AChE.
Context:Alcea rosea L. (Malvaceae) has various medicinal uses including anticancer, anti-inflammatory and analgesic properties. However, there is no report on its antidiabetic activity.Objective:Alcea rosea seed extracts were evaluated for antihyperglycaemic and antioxidative potential in diabetic rats.Materials and methods: Single intra-peritoneal injection of alloxan (130 mg/kg b.w.) was used for induction of diabetes in Albino Wistar rats. Antihyperglycaemic and antioxidant activities of methanol and aqueous extracts of Alcea rosea seed (100 and 300 mg/kg b.w.), administered orally on daily basis for 15 days, were assessed in vivo for fasting blood glucose level and antioxidant status of liver and pancreas. Metformin was used as a positive control.Results: Aqueous and methanol extracts (300 mg/kg b.w.) decreased blood glucose level in diabetic rats by 24% and 46%, respectively. Administration of aqueous and methanol extracts at 300 mg/kg b.w. significantly (p < 0.01) modulated the antioxidant status of liver in diabetic rats by increasing levels of GR (22.5 ± 1.0, 24.4 ± 1.02 μg GSSG utilized/min/mg of protein), GPx (20.7 ± 1.2, 23.6 ± 2.04 μg GSH utilized/min/mg of protein), SOD (36.1 ± 1.7, 39.05 ± 1.5 units/mg of protein) and CAT (1744.5 ± 132.5, 1956.6 ± 125.2 nmol H2O2 decomposed/min/mg of protein), respectively. Similar results were observed for pancreas.Discussion and conclusions: Antihyperglycaemic and antioxidative potentials of Alcea rosea seeds suggest its usefulness in management of diabetes and its complications. This is the first report on antidiabetic activity of this plant.
A strong correlation between brain metabolite accumulation and oxidative stress has been observed in Alzheimer’s disease (AD) patients. There are two central hypotheses for this correlation: (i) coaccumulation of toxic amyloid-β and Myo-inositol (MI), a significant brain metabolite, during presymptomatic stages of AD, and (ii) enhanced expression of MI transporter in brain cells during oxidative stress-induced volume changes in the brain. Identifying specific interactive effects of MI with cellular antioxidant enzymes would represent an essential step in understanding the oxidative stress-induced AD pathogenicity. This study demonstrated that MI inhibits catalase, an essential antioxidant enzyme primarily inefficient in AD, by decreasing its k cat (turnover number) and increasing K m (Michaelis–Menten constant) values. This inhibition of catalase by MI under in vivo studies increased cellular H 2 O 2 levels, leading to decreased cell viability. Furthermore, MI induces distortion of the active heme center with an overall loss of structure and stability of catalase. MI also alters distances of the vital active site and substrate channel residues of catalase. The present study provides evidence for the involvement of MI in the inactivation of the antioxidant defense system during oxidative stress-induced pathogenesis of AD. Regulation of MI levels, during early presymptomatic stages of AD, might serve as a potential early-on therapeutic strategy for this disease.
Introduction and Aim: Medicinal plants are widely used in traditional medicine to cure various infectious diseases in human. The medicinal herbs like Onosma hispidium and Alcea rosea have been traditionally used for the variety of clinical disorders like jaundice, Diabetes, malaria, rheumatism and have been used as laxative, anthelmintic, disorder of blood, disease of eyes, bronchitis, abdominal pain, antibacterial and as wound healer. The present study was undertaken to investigate the antibacterial potential of aqueous, ethyl acetate and methanolic extracts of Onosma hispidium and Alcea rosea, a traditionally used medicinal plants with multiple therapeutic properties. Materials and Methods: The susceptibility of microbial strains to the plant extracts was determined using agar well diffusion method. The bacterial strains employed were Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus vulgaris and Escherichia coli. Phytochemical screening was performed using standard methods. Results: A dose dependent increase in the antibacterial activity was observed with both the methanol, ethyl acetate and aqueous extracts. Among the plants screened, in Onosma hispidium the highest antibacterial activity was exhibited by aqueous extract with Pseudomonas aeruginosa (25±1.88) followed by Staphylococcus aureus (22 ± 0.22 mm) and Klebsiella pneumoniae (20.21±1.01) at the concentration of 100 mg/ml respectively. while in case of Alcea rosea, the ethyl acetate extract exhibited the highest antibacterial activity with Escherichia coli (28±1.56) followed by Staphylococcus aureus (25 ± 01.58 mm) Klebsiella pneumoniae (18±0.74) and Proteus vulgaris (13±0.12) at the concentration of 100 mg/ml respectively. Phytochemical analysis revealed the plants are rich in various secondary metabolites like alkaloids, saponins, flavonoids, phenols, terpenoids and volatile oils. Conclusion: The plants contain novel compounds with broad spectrum antibacterial properties. The isolation and characterization of these novel compounds could lead to the development of effective therapeutic antimicrobials to fight pathogenic infections.
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