SPP1, a potential therapeutic target and biomarker for lung cancer: functional insights through computational studies.

NIH reported 128 different types of cancer of which lung cancer is the leading cause of mortality. Globally, it is estimated that on average one in every seventeen hospitalized patients was deceased. There are plenty of studies that have been reported on lung cancer draggability and therapeutics, but yet a protein that plays a central specific to cure the disease remains unclear. So, this study is designed to identify the possible therapeutic targets and biomarkers that can be used for the potential treatment of lung cancers. In order to identify differentially expressed genes, 39 microarray datasets of lung cancer patients were obtained from various demographic regions of the GEO database available at NCBI. After annotating statistically, 6229 up-regulated genes and 10324 down-regulated genes were found. Out of 17 up-regulated genes and significant genes, we selected SPP1 (osteopontin) through virtual screening studies. We found functional interactions with the other cancer-associated genes such as VEGF, FGA, JUN, EGFR, and TGFB1. For the virtual screening studies,198 biological compounds were retrieved from the ACNPD database and docked with SPP1 protein (PDBID: 3DSF). In the results, two highly potential compounds secoisolariciresinol diglucoside (-12.9 kcal/mol), and Hesperidin (-12.0 kcal/mol) showed the highest binding affinity. The stability of the complex was accessed by 100 ns simulation in an SPC water model. From the functional insights obtained through these computational studies, we report that SPP1 could be a potential biomarker and successive therapeutic protein target for lung cancer treatment.

A comprehensive review on human disease-causing bacterial proteases and their impeding agents.

Proteases are enzymes that catalyze the amide bond dissociation in polypeptide and protein peptide units. They are categorized into seven families and are responsible for a wide spectrum of human ailments, such as various types of cancers, skin infections, urinary tract infections etc. Specifically, the bacterial proteases cause a huge impact in the disease progression. Extracellular bacterial proteases break down the host defense proteins, while intracellular proteases are essential for pathogens virulence. Due to its involvement in disease pathogenesis and virulence, bacterial proteases are considered to be potential drug targets. Several studies have reported potential bacterial protease inhibitors in both Gram-positive and Gram-negative disease causing pathogens. In this study, we have comprehensively reviewed about the various human disease-causing cysteine, metallo, and serine bacterial proteases as well as their potential inhibitors.

Diosgenin inhibits ER stress-induced inflammation in aorta via iRhom2/TACE mediated signaling in experimental diabetic rats: An in vivo and in silico approach.

Hyperglycemia, hyperlipidemia, and atherosclerotic lesions may cause inflammation, which leads to chemokine production and changes in vascular responses. Hyperglycemia can impair normal protein folding by producing reactive oxygen species (ROS) and interacting with various signaling molecules, resulting in the activation of ER stress responses, that stimulates NF-kB, which regulates the expression of numerous genes involved in inflammation and vascular remodeling. Our previous studies have shown that diosgenin has a protective effect against streptozotocin (STZ) - induced oxidative damage in rat aorta. However, the therapeutic role of diosgenin on iRhom2/TACE signaling which has primarily been linked to the endoplasmic reticulum (ER)-stress induced inflammation is unknown. Diosgenin was administered (40 mg/kg b. wt, orally, for 4 weeks) to STZ-induced male albino rats. Fasting plasma glucose, blood pressure, nitrite level, lipid profile, and lipoprotein were assessed. Serum insulin and pro-inflammatory markers were analyzed using ELISA, mRNA and protein expression of iRhom2/TACE signaling molecules were analyzed using RT-PCR and western blotting analysis respectively. In silico study was also performed to find out the possible binding affinity of diosgenin with the ER stress signaling molecules. Through regulation of the iRhom2/TACE signaling molecules, diosgenin lowered dyslipidemia, hypertension, and pro-inflammatory cytokines (TNF-α, IL-1, IL-6, and IL-4) in the aorta of STZ induced diabetic rats. Results of molecular docking analysis also confirmed the potential binding interaction with iRhom2/TACE and TNF- α. These in silico and in vivo results indicated that a change in lipid profile and hypertension led to diabetes-related inflammation by promoting ER stress and, as a result, accelerating the aorta by generating proinflammatory cytokines and lipid deposition. This study concludes that diosgenin attenuates ER stress-induced inflammation in diabetic rat aorta by modulating the expression of pro-inflammatory, iRhom2/TACE mediated mechanism and hence diosgenin can be a therapeutic drug for the treatment of diabetes-induced inflammation.

GalNAc-siRNA conjugates: Prospective tools on the frontier of anti-viral therapeutics.

The growing use of short-interfering RNA (siRNA)-based therapeutics for viral diseases reflects the most recent innovations in anti-viral vaccines and drugs. These drugs play crucial roles in the fight against many hitherto incurable diseases, the causes, pathophysiologies, and molecular processes of which remain unknown. Targeted liver drug delivery systems are in clinical trials. The receptor-mediated endocytosis approach involving the abundant asialoglycoprotein receptors (ASGPRs) on the surfaces of liver cells show great promise. We here review N-acetylgalactosamine (GalNAc)-siRNA conjugates that treat viral diseases such as hepatitis B infection, but we also mention that novel, native conjugate-based, targeted siRNA anti-viral drugs may also cure several life-threatening diseases such as hemorrhagic cystitis, multifocal leukoencephalopathy, and severe acute respiratory syndrome caused by coronaviruses and human herpes virus.

Molecular docking analysis of antimicrobial peptides with the CXCL1 protein target for colorectal cancer.

Antimicrobial peptides (AMPs) play a prominent role in drug discovery due to the rapid increase in drug resistant infections. Hence, we report the molecular docking analysis of antimicrobial peptides MREEKKERKRD and MVQGAKRGGRLHRV with the target protein CXCL1 in the context of colorectal cancer for further consideration in drug discovery.

Molecular docking analysis of CDK-1 inhibitors from Chrysophyllum cainito leaves.

It is of interest to document the molecular docking analysis of Cyclin-dependent kinase 1 (CDK-1) inhibitors from Chrysophyllum cainito leaves towards the treatment of tumors using the known structure of PDB ID: 5HQ0. Data shows that molecules such as 8- (Dimethylamino)-7-(3-(4-ethylphenoxy)-2d, ethyl 6-oxo-5-propylheptanoate, 2,3-dihydro-3, 5-dihydroxy-6-methyl-4h-pyran-4-one, 1,2,3-benzenetriol and 1,4-benzenediol 2,5-bis (1,1-dimethylethyl) identified in methanolic extract of C. cainito have binding features with CDK1 for further consideration.

B-cell and T-cell epitope identification with stability analysis of AI-2 import ATP-binding cassette LsrA from S. typhiIn silico approach.

Typhoid fever is a severe illness in humans, caused by Salmonella typhi, a Gram-negative bacterium. Membrane proteins of S. typhi have strong potential for its use in development of subunit vaccine against typhoid. In current study, peptide-based subunit vaccine constructed from AI-2 import ATP-binding cassette transporter protein (LsrA) against S. typhi. B-cell and T-cell epitopes were identified at fold level with validated 3-D theoretical modelled structure. T-cell epitope from LsrA (LELPGSRPQ) has binds to maximum number (82.93%) of MHC class I and class II alleles. LsrA epitope was docked with HLA-DR4 and contact map were constructed to analyze molecular interaction (docking) studies. Simulation search for the binding site for full flexibility of the peptide from CABS-dock shows the stable interactions. MD simulation analysis reveals that LsrA epitope was binding and interacting firmly with the HLA-DR4. Hence, we are proposing that LsrA epitope would be a prominent epitope vaccine for human specific pathogen of S. typhi, which requires further steps to be elevated as a vaccine drug in near future.

Bioassay directed isolation and biological evaluation of compounds isolated from Rubus fairholmianus Gard.

The in vitro and in silico analysis of Rubus fairholmianus acetone extract for antioxidant, antiproliferative, and anti-inflammatory activity led to the isolation of six compounds. Amongst all the six isolated compounds tested, 1-(2-hydroxyphenyl)-4-methylpentan-1-one (compound 1) and 2-[(3-methylbutoxy) carbonyl] benzoic acid (compound 2) were found to be more active in inhibiting BRCA and COX target proteins, which also showed the better results for DPPH and ABTS radical scavenging assays. The promising results of this investigation emphasize the importance of using R. fairholmianus in the treatment of radical generated disorders mainly cancer and other inflammatory diseases.