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Trypanosoma brucei brucei (T.b.brucei) is an extra-cellular parasite that causes Animal African Trypanosomiasis (AAT) disease in animals. Till day, this disease is more difficult to treat and control due to lack of efficient vaccines and early diagnosis of the parasite infection. T.b.brucei Excretory/Secretory (ES) proteins were involved in pathogenesis and key for understanding the host-parasite interactions. Functions of T.b.brucei's ES proteins were poorly investigated and experimental identification is expensive and time-consuming. Bioinformatics approaches are cost-effective by facilitating the experimental analysis of potential drug targets for parasitic diseases. Here we applied several bioinformatics tools to predict and functionalize the annotation of 1104 ES proteins and immunoinformatics approaches carried out to predict and evaluate the epitopes in T.b.brucei. Secretory information, functional annotations and potential epitopes of each ES proteins were available at http://tbb.insilico.in . This study provides functional information of T.b.brucei for experimental studies to identify potential targets for diagnosis and therapeutics development.

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.

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.

Salmonella typhi are Gram-negative pathogens that infect many hosts including humans and animals and cause diseases ranging from gastroenteritis and diarrhea to life-threatening systemic syndrome. Owing to the metabolic versatility, they will colonize as multi cellular aggregates on various surfaces to enhance the virulence by forming a biofilm in which bacterial cells are more resistant to antibiotics than planktonic cells. Quorum Sensing (QS) is a cell-to-cell communication mechanism in the bacterial system to coordinate group behaviors such as biofilms formation and virulence factors production. In QS system ATP Binding Cassette (ABC) transporter component, LsrA, plays a key role to transport autoinducer-2 (AI-2) to increase the cell density. In order to reduce biofilm formation, patulin was selected as a natural QS inhibitor and its function was studied by biofilm inhibitory assays. Significant differences in the spectroscopic values were obtained between antibiotic resistance of kanamycin (30 μg/ml) and patulin (30 μg/ml). Furthermore, to distinguish the molecular level interaction of LsrA, patulin and AI-2 were docked. Both the compounds were interact in the same pose with Glide score of −4.237 kcal/mol and −7.126 kcal/mol respectively. These results will suggest that patulin is the efficient Quorum Sensing Inhibitor to control biofilm formation in S.typhi. Keywords: Salmonella typhi, Quorum sensing, LsrA, AI-2, Patulin

Matrix metalloproteinases are zinc-dependent protein and peptide hydrolases. They are broadly involved in metabolic regulation through both extensive protein degradation and selective peptide-bond hydrolysis. Stromelysins belong to this group of proteinases and involved in various physiological and pathological functioning of the cell. This study aims at assessing the sequential and structural aspects of stromelysins based on in silico approaches. Deduced stromelysin sequences were predicted to possess regulatory domain, protease domain, and proline-rich hinge regions. Sequential analysis revealed MMP-3 and 10 are more similar than MMP-11 regarding stability and aminoacid distribution. Secondary structure prediction showed that beta-sheets dominated other secondary structural elements (alpha helices, coils, and turns) in stromelysins. Validation of predicted models with different approaches confirms the accuracy and best quality of models. The binding mode of zinc atom provides information regarding their interaction with stromelysins. The predicted models showed little variation in binding mode with their natural inhibitor, TIMP-1. The predicted models will be used in an extensive range of studies for functional analysis and improvement activity of stromelysins. Keywords: Matrix metalloproteinases, Zinc-binding motif, Structure prediction, Ramachandran plot, Stromelysin, Superfamily

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., Graphical abstract

This study focuses on insilico analysis to understand the mechanism between tuberculosis (TB) associated comorbidities such as Human Immunodeficiency Virus (HIV) and lung cancer. Initially, gene expression studies of samples associated with HIV-TB and lung cancer-TB were analyzed and differentially expressed genes were identified. Further, gene networks for the up-regulated genes were constructed and the functionally associated genes were identified. Functional enrichment analysis was also performed for the genes associated. Differentially- regulated genes could be possible drug targets for treatment of TB associated comorbidities. In this regards, Rv2949c which was found to be highly expressed in HIV patients with TB and it could be a candidate drug target for treatment of patients with HIV comorbidity. Similarly, pgsA1 is highly expressed in lung cancer patients with TB, is a candidate drug target for treatment of patients with lung cancer comorbidity. Suitable inhibitors for Rv2949c and pgsA1 have been found through molecular docking studies. Thus the insights gained through this study will be helpful in designing suitable drug candidates for treatment of TB related comorbidities.

Salmonella typhi are Gram-negative pathogens that infect many hosts including humans and animals, and cause diseases ranging from gastroenteritis and diarrhea to life-threatening systemic syndrome. Owing to the metabolic versatility, they will colonize as multicellular aggregates on various surfaces to enhance the virulence by forming a biofilm in which bacterial cells are more resistant to antibiotics than planktonic cells. Quorum Sensing (QS) is a cell-to-cell communication mechanism in the bacterial system which acts to coordinate group behaviors such as biofilms formation and virulence factors production. In the QS system ATP Binding Cassette (ABC) transporter component, LsrA plays a key role to transport autoinducer-2 (AI-2) for increasing cell density. In order to reduce biofilm formation, patulin was selected as a natural QS inhibitor and its function was studied by a biofilm inhibitory assay. Significant differences in the spectroscopic values were obtained between antibiotic resistance of kanamycin (30μg/ml) and patulin (30μg/ml). Furthermore, to distinguish the molecular-level interaction of patulin and AI-2, they were docked with LsrA. Both the compounds were docked in the same pose with Glide scores of −4.237 Kcal/mol and −7.126 Kcal/mol respectively. These preliminary results suggested that patulin is an efficient Quorum Sensing Inhibitor for controlling biofilm formation in S.typhi. Keywords: Salmonella typhi, Quorum sensing, LsrA, AI-2, Patulin