Discovery of small molecules through pharmacophore modeling, docking and molecular dynamics simulation against Plasmodium vivax Vivapain-3 (VP-3)

Vivapain-3(VP-3) protein is a family of cysteine rich proteases of malaria parasite is extensively reported to participate in a range of wide cellular processes including survival. VP-3 of plasmodium recognized as an attractive drug target in vector-borne diseases like malaria. In the present study we robust a homology model of VP-3 protein and generated the pharmacophore based models adapted to screen the best drug like compounds from PubChem database. Our results finds the fourteen best lead molecules were mapped with core pharmacophore features of VP-3 and top hits were further evaluated by molecular dynamics simulation and docking studies. Based on the molecular dynamics simulation and docking results and binding vicinity of ligand molecules, top five i.e., CID 74427945, CID 74427946, CID 360883, CID193721 and CID 51416859 showed the best docking scores with good molecular interactions against VP-3. Furthermore in silico ADMET and in vitro assays clearly exhibited that out of five three CID74427946, CID74427945 and CID360883 ligand molecules showed the best promising inhibition against VP-3. The present study believed to provide significant information of potential ligand inhibitors against VP-3 to design and develop the next generation malaria therapeutics through computational approach

Structure Based Design and Molecular Docking Studies for Phosphorylated Tau Inhibitors in Alzheimer’s Disease

The purpose of our study is to identify phosphorylated tau (p-tau) inhibitors. P-tau has recently received great interest as a potential drug target in Alzheimer’s disease (AD). The continuous failure of Aβ-targeted therapeutics recommends an alternative drug target to treat AD. There is increasing evidence and growing awareness of tau, which plays a central role in AD pathophysiology, including tangles formation, abnormal activation of phosphatases/kinases, leading p-tau aggregation in AD neurons. In the present study, we performed computational pharmacophore models, molecular docking, and simulation studies for p-tau in order to identify hyperphosphorylated sites. We found multiple serine sites that altered the R1/R2 repeats flanking sequences in the tau protein, affecting the microtubule binding ability of tau. The ligand molecules exhibited the p-O ester scaffolds with inhibitory and/or blocking actions against serine residues of p-tau. Our molecular docking results revealed five ligands that showed high docking scores and optimal protein-ligand interactions of p-tau. These five ligands showed the best pharmacokinetic and physicochemical properties, including good absorption, distribution, metabolism, and excretion (ADME) and admetSAR toxicity tests. The p-tau pharmacophore based drug discovery models provide the comprehensive and rapid drug interventions in AD, and tauopathies are expected to be the prospective future therapeutic approach in AD

Bioflavonoid hesperidin possesses the anti-hyperglycemic and hypolipidemic property in STZ induced diabetic myocardial infarction (DMI) in male Wister rats

The aim of our study was to evaluate the hesperidin anti-hyperglycemic and hypo-lipidemic effects on diabetic myocardial infraction (DMI) rats by decreasing the blood glucose and blood cholesterol contents. The object of the study was to examine the 7groups of male Wistar rats, each group contains 6 rats, Group I (normal), Group II diabetic (control) and 5(experimental) groups, i.e., Group III (diabetic + hesperidin), Group IV (diabetic + Glibenclamide), Group V (ISO), Group VI (diabetic + ISO) and Group VII (diabetic + ISO + hesperidin). By that intake of hesperidin regulates the lipid and carbohydrate metabolism by decreasing the cholesterols in blood and plasma insulin by hyperlipidamic and anti-hyperglycemic activity. The rats turns to diabetic with single intraperitonial STZ injection (50 mg/kg BW), and from the second week the rats diet were switched to a high fat diet, i.e., cholesterol (40%), fat (50%), Protein (50%) turns to be hyperlipidamic rats and with Isoproterenol (ISO) single intraperitoneal injection by the (11 mg/kg BW) turns to DMI rats. The DMI rats fed with the hesperidin 100mg/kg BW for 4 weeks had significantly reduced the blood glucose (P < 0.05), total cholesterol (TC), Triglycerides, HDL, LDL and VLDL concentrations, when compared with experimental groups (p < 0.05). A significantly increased blood glucose and body weight was observed in hesperidin treated diabetic groups (P < 0.05) by comparing with the experimental groups. In conclusion, orally supplementation of hesperidin possesses a significant decrease in total blood lipid profiles and plasma insulin concentrations accompanied by the anti-hyperglycemic, hypo-lipidemic activity in DMI rats. Keywords: Hesperidin, Diabetic cardiomyopathy, Anti-hyperglycemic, Hypolipidemi

A study on antimicrobial and anticancer properties of Cissus quadrangulris using lung cancer cell line

Cissus quadrangularis plant from Vitaceae family, native in India. Many parts of this plant have medicinal values but most precious is stem of this plant. In past years number of studies reported their activities and secondary metabolites in Cissus quadrangularis plant and their pharmacological activities and uses in traditional medicine system. It is reported to possess excellent medicinal properties and potent fracture healing properties, antimicrobial, antiulcer, antioxidative, cholinergic activity and beneficial effect on cardiovascular diseases, possesses antiulcer and cytoprotective property in indomethacin-induced gastric mucosal injury. The aim of this study was to determine the qualitative phytochemical analysis, antimicrobial activity, cell viability and in vitro anticancer activity of a potential of Cissus quadrangularis stem extract against A549 human lung cancer cell line. The disc diffusion method was employed to determine the antimicrobial activity of Cissus quadrangularis stem extract and showed potential antibacterial and antifungal activity against various microorganisms. Results have shown that Stem methanolic extract induced a significant decrease of tumour cell viability. The cell viability assay clearly showed that the cells treated with Cissus quadrangularis methanolic extract has significantly reduced the lung cancer cell viability in a dose dependant manner. The stem methanolic extract was tested for the in vitro antiproliferative potential on A549 human lung cancer cell line using different concentrations, namely 1000, 62.5 and 7.8 µg/ml. We observed the IC50 dose at 65.2 μg/ml concentration. In cell culture A549 cells treated with Cissus quadrangularis stem methanolic extract in 24 h the cells growth is controlled

Calcium, zinc and vitamin E ameliorate cadmium-induced renal oxidative damage in albino Wistar rats

This study was aimed to examine the protective effects of supplementation with calcium + zinc (Ca + Zn) or vitamin E (Vit-E) on Cd-induced renal oxidative damage. Young albino Wistar rats (180 ± 10 g) (n = 6) control rats, Cd, Cd + Ca + Zn, and Cd + Vit-E experimental groups and the experimental period was 30 days. Rats were exposed to Cd (20 mg/kg body weight) alone treated as Cd treated group and the absence or presence of Ca + Zn (2 mg/kg each) or Vit-E (20 mg/kg body weight) supplementation treated as two separate groups. The activities of the stress marker enzymes superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and lipid peroxidase (LPx) were determined in renal mitochondrial fractions of experimental rats. We observed quantitative changes in SOD isoenzymatic patterns by non-denaturing PAGE analysis, and quantified band densities. These results showed that Cd exposure leads to decreases in SOD, CAT, GR, and GPx activities and a concomitant increase in LPx and GST activities. Ca + Zn and Vit-E administration with Cd significantly reversed Cd-induced perturbations in oxidative stress marker enzymes. However, Vit-E showed more inhibitory activity against Cd than did Ca + Zn, and it protected against Cd-induced nephrotoxicity. Keywords: Cadmium (Cd), Oxidative stress, Lipid peroxidation, Nephrotoxicity, PAGE analysi

Sunflower-Assisted Bio-Derived ZnO-NPs as an Efficient Nanocatalyst for the Synthesis of Novel Quinazolines with Highly Antioxidant Activities

The present report presents a green method for the rapid biogenic synthesis of nanoparticles that offers several advantages over the current chemical and physical procedures. It is easy and fast, eco-friendly, and does not involve any precious elements, hazardous chemicals, or harmful solvents. The synthesized ZnO nanoparticles were characterized using different techniques, such as UV-Visible spectroscopy. The surface plasmon resonance confirmed the formation of ZnO nanoparticles at 344 nm, using UV-Visible spectroscopy. The leaf extract acts as a source of phytochemicals and is primarily used for the reduction and then the formation of stable ZnO nanoparticles by the characteristic functional groups of the extract; the synthesized ZnO nanoparticles were identified using FTIR spectroscopy. The crystalline nature of ZnO-NPs was confirmed via powder X-ray diffraction (XRD). Size and morphology were measured via high resolution transmission electron microscopy (HR-TEM) analysis. The stability of the nanoparticles is established using dynamic light scattering (DLS) and thermogravimetric analysis (TGA). The synthesized ZnO nanoparticles have been found to be a good and efficient catalyst for the synthesis of novel 1,2-dihydro quinazoline derivatives under the green method via a one-pot reaction of 2-amino benzophenone, 1,3-diphenyl-1H-pyrazole carbaldehydes, and ammonium acetate. The synthesized compounds (4a–o) were characterized by the 1H NMR, 13C NMR, and HRMS spectra and were further validated for free-radical scavenging activity. The synthesized ZnO nanoparticles exhibited good antioxidant activity

Purification, Structural Elucidation, and Anticancerous Properties of a Novel Flavonoid from Flowers of Leucas indica

Previously, we showed that the crude methanol extracts of Leucas indica flowers exhibited antioxidant properties and in the current study, crude methanol flower extracts of L. indica showed anticancerous properties as evidenced cytotoxicity (MTT assay test) against the selected cancerous cell lines HeLa, HCT116, HL-60, and MCF-7. Therefore, further analysis was performed to isolate and purify the bioactive compound using activity-guided repeated fractionation of the methanol extract by silica gel column chromatography. After collection of different fractions, all the fractions were subjected to TLC analysis and the fractions which yielded the same compounds on TLC were further analyzed for physicochemical and spectroscopic analyses, e.g., UV, IR, 1H NMR, 13C NMR, COSY, HSQC, and mass spectroscopy. The bioactive compound isolated was elucidated as 6-hydroxy-3-(4-hydroxyphenyl)-7-(3,4,5-trihydroxy-6-)(hydroxymethyl)tetrahydro-2H-pyran-2yl)-4H-chromen-4-one. Based on the antioxidant and anticancerous properties, L. indica might be a promising source of useful natural products and the newly bioactive compound might offer opportunities to develop new anticancerous drugs

Rlip Reduction Induces Oxidative Stress and Mitochondrial Dysfunction in Mutant Tau-Expressed Immortalized Hippocampal Neurons: Mechanistic Insights

RalBP1 (Rlip) is a stress-activated protein that is believed to play a large role in aging and neurodegenerative diseases such as Alzheimer’s disease (AD) and other tauopathies. The purpose of our study was to understand the role of Rlip in mutant Tau-expressed immortalized hippocampal HT22 cells. In the current study, we used mutant Tau (mTau)-expressed HT22 neurons and HT22 cells transfected with Rlip-cDNA and/or silenced RNA, and studied the cell survival, mitochondrial respiration, mitochondrial function, immunoblotting, and immunofluorescence analysis of synaptic and mitophagy proteins and the colocalization of Rlip and mTau proteins. We found Rlip protein levels were reduced in mTau-HT22 cells, Rlip silenced HT22 cells, and mTau + Rlip RNA silenced HT22 cells; on the other hand, increased Rlip levels were observed in Rlip cDNA transfected HT22 cells. We found cell survival was decreased in mTau-HT22 cells and RNA-silenced HT22 cells. However, cell survival was increased in Rlip-overexpressed mTau-HT22 cells. A significantly reduced oxygen consumption rate (OCR) was found in mTau-HT22 cells and in RNA-silenced Rlip-HT22 cells, with an even greater reduction in mTau-HT22 + Rlip RNA-silenced HT22 cells. A significantly increased OCR was found in Rlip-overexpressed HT22 cells and in all groups of cells that overexpress Rlip cDNA. Mitochondrial function was defective in mTau-HT22 cells, RNA silenced Rlip in HT22 cells, and was further defective in mTau-HT22 + Rlip RNA-silenced HT22 cells; however, it was rescued in Rlip overexpressed in all groups of HT22 cells. Synaptic and mitophagy proteins were decreased in mTau-HT22 cells, and further reductions were found in RNA-silenced mTau-HT22 cells. However, these were increased in mTau + Rlip-overexpressed HT22 cells. An increased number of mitochondria and decreased mitochondrial length were found in mTau-HT22 cells. These were rescued in Rlip-overexpressed mTau-HT22 cells. These observations strongly suggest that Rlip deficiency causes oxidative stress/mitochondrial dysfunction and Rlip overexpression reverses these defects. Overall, our findings revealed that Rlip is a promising new target for aging, AD, and other tauopathies/neurological diseases

Expression and Function of StAR in Cancerous and Non-Cancerous Human and Mouse Breast Tissues: New Insights into Diagnosis and Treatment of Hormone-Sensitive Breast Cancer

Breast cancer (BC) is primarily triggered by estrogens, especially 17β-estradiol (E2), which are synthesized by the aromatase enzyme. While all steroid hormones are derived from cholesterol, the rate-limiting step in steroid biosynthesis is mediated by the steroidogenic acute regulatory (StAR) protein. Herein, we demonstrate that StAR mRNA expression was aberrantly high in human hormone-dependent BC (MCF7, MDA-MB-361, and T-47D), modest in hormone-independent triple negative BC (TNBC; MDA-MB-468, BT-549, and MDA-MB-231), and had little to none in non-cancerous mammary epithelial (HMEC, MCF10A, and MCF12F) cells. In contrast, these cell lines showed abundant expression of aromatase (CYP19A1) mRNA. Immunofluorescence displayed qualitatively similar patterns of both StAR and aromatase expression in various breast cells. Additionally, three different transgenic (Tg) mouse models of spontaneous breast tumors, i.e., MMTV-Neu, MMTV-HRAS, and MMTV-PyMT, demonstrated markedly higher expression of StAR mRNA/protein in breast tumors than in normal mammary tissue. While breast tumors in these mouse models exhibited higher expression of ERα, ERβ, and PR mRNAs, their levels were undetected in TNBC tumors. Accumulation of E2 in plasma and breast tissues, from MMTV-PyMT and non-cancerous Tg mice, correlated with StAR, but not with aromatase, signifying the importance of StAR in governing E2 biosynthesis in mammary tissue. Treatment with a variety of histone deacetylase inhibitors (HDACIs) in primary cultures of enriched breast tumor epithelial cells, from MMTV-PyMT mice, resulted in suppression of StAR and E2 levels. Importantly, inhibition of StAR, concomitant with E2 synthesis, by various HDACIs, at clinical and preclinical doses, in MCF7 cells, indicated therapeutic relevance of StAR in hormone-dependent BCs. These findings provide insights into the molecular events underlying the differential expression of StAR in human and mouse cancerous and non-cancerous breast cells/tissues, highlighting StAR could serve not only as a novel diagnostic maker but also as a therapeutic target for the most prevalent hormone-sensitive BCs