All Trans Retinoic Acid (ATRA) progresses alveolar epithelium regeneration by involving diverse signalling pathways in emphysematous rat.

INTRODUCTION: Pulmonary emphysema is characterized by destruction of alveoli leading to inadequate oxygenation, disability and frequently death. This destruction was understood so far as irreversible. Published data has shown that ATRA (All Trans Retinoic Acid) reverses elastase-induced emphysema in rats. However, the molecular mechanisms governing regeneration process are so far unknown. OBJECTIVE: To examine the therapeutic potential of ATRA on various molecular pathways and their coordination towards governance of alveolar epithelial regeneration in emphysematous rats. METHODS: Emphysema was induced by elastase versus saline in Sprague-Dawley rats. On days 26-37, rats received daily intraperitoneal injections with ATRA (500 µg/kg b.w.) versus olive-oil. Lungs were removed at day 38 for histopathology and investigation of relative mRNA and protein expressions. RESULTS: Histopathological analysis has shown that losses of alveoli were recovered in therapy (EA) group. Moreover, expressions of markers genes for alveolar cell proliferation, differentiation and EMT events at mRNA and protein levels were significantly increased in EA group than emphysema group (ES). Upon validation at genomics level, expressions of components of Notch, Hedgehog, Wnt, BMP and TGFß pathways were significantly attenuated in EA group when compared with ES and were well comparable with the healthy group. CONCLUSION: Therapeutic supplementation of ATRA rectifies the deregulated Notch, Hedgehog, Wnt, BMP and TGFß pathways in emphysema condition, resulting in alveolar epithelium regeneration. Hence, ATRA may prove to be a potential drug in the treatment of emphysema. Nevertheless, elaborated studies are to be conducted.

Topological and system-level protein interaction network (PIN) analyses to deduce molecular mechanism of curcumin.

Curcumin is an important bioactive component of turmeric and also one of the important natural products, which has been investigated extensively. The precise mode of action of curcumin and its impact on system level protein networks are still not well studied. To identify the curcumin governed regulatory action on protein interaction network (PIN), an interectome was created based on 788 key proteins, extracted from PubMed literatures, and constructed by using STRING and Cytoscape programs. The PIN rewired by curcumin was a scale-free, extremely linked biological system. MCODE plug-in was used for sub-modulization analysis, wherein we identified 25 modules; ClueGo plug-in was used for the pathway's enrichment analysis, wherein 37 enriched signalling pathways were obtained. Most of them were associated with human diseases groups, particularly carcinogenesis, inflammation, and infectious diseases. Finally, the analysis of topological characteristic like bottleneck, degree, GO term/pathways analysis, bio-kinetics simulation, molecular docking, and dynamics studies were performed for the selection of key regulatory proteins of curcumin-rewired PIN. The current findings deduce a precise molecular mechanism that curcumin might exert in the system. This comprehensive in-silico study will help to understand how curcumin induces its anti-cancerous, anti-inflammatory, and anti-microbial effects in the human body.

Investigation of Precise Molecular Mechanistic Action of Tobacco-Associated Carcinogen `NNK´ Induced Carcinogenesis: A System Biology Approach.

Cancer is the second deadliest disease listed by the WHO. One of the major causes of cancer disease is tobacco and consumption possibly due to its main component, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). A plethora of studies have been conducted in the past aiming to decipher the association of NNK with other diseases. However, it is strongly linked with cancer development. Despite these studies, a clear molecular mechanism and the impact of NNK on various system-level networks is not known. In the present study, system biology tools were employed to understand the key regulatory mechanisms and the perturbations that will happen in the cellular processes due to NNK. To investigate the system level influence of the carcinogen, NNK rewired protein-protein interaction network (PPIN) was generated from 544 reported proteins drawn out from 1317 articles retrieved from PubMed. The noise was removed from PPIN by the method of modulation. Gene ontology (GO) enrichment was performed on the seed proteins extracted from various modules to find the most affected pathways by the genes/proteins. For the modulation, Molecular COmplex DEtection (MCODE) was used to generate 19 modules containing 115 seed proteins. Further, scrutiny of the targeted biomolecules was done by the graph theory and molecular docking. GO enrichment analysis revealed that mostly cell cycle regulatory proteins were affected by NNK.

ATRA reduces inflammation and improves alveolar epithelium regeneration in emphysematous rat lung.

INTRODUCTION: Pulmonary emphysema characterized by alveolar wall destruction is resultant of persistent chronic inflammation. All-trans retinoic acid (ATRA) has been reported to reverse elastase-induced emphysema in rats. However, the underlying molecular mechanisms are so far unknown. OBJECTIVE: To investigate the therapeutic potential effect of ATRA via the amelioration of the ERK/JAK-STAT pathways in the lungs of emphysematous rats. METHODS: In silico analysis was done to find the binding efficiency of ATRA with receptor and ligands of ERK & JAK-STAT pathway. Emphysema was induced by porcine pancreatic elastase in Sprague-Dawley rats and ATRA was supplemented as therapy. Lungs were harvested for histopathological, genomics and proteomics analysis. RESULTS AND DISCUSSION: In silico docking, analysis confirms that ATRA interferes with the normal binding of ligands (TNF-α, IL6ST) and receptors (TNFR1, IL6) of ERK/JAK-STAT pathways respectively. ATRA restored the histology, proteases/antiproteases balance, levels of inflammatory markers, antioxidants, expression of candidate genes of ERK and JAK-STAT pathways in the therapy group. CONCLUSION: ATRA ameliorates ERK/JAK-STAT pathway in emphysema condition, resulting in alveolar epithelium regeneration. Hence, ATRA may prove to be a potential drug in the treatment of emphysema.