ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is marked by the excessive intrusion of triglycerides into hepatocytes without any role of alcohol consumption. Various risk factors have been attributed to this disease pathogenesis, including metabolic disorders, immune response, and even an intricate relationship between the two. The role of insulin resistance (IR) in NAFLD has long been known; however, the molecular basis of disease progression under this metabolic backdrop is still being investigated. Similarly, the periodontitis-mediated immune response is another major factor involved in NAFLD manifestation, which has generated huge interest. The prevalence of pathogenic bacteria elicits a strong immune response, which according to the studies shows a strong correlation with NAFLD state. Such pre-existing conditions have a strong probability of explaining the disease onset. Additionally, increasing reports on inflammatory response and its links to insulin resistance have further increased the scope of understanding NAFLD. Through this review, we aim to elaborate on these factors explaining their role in the disease progression.
Subject(s)
Chronic Periodontitis , Insulin Resistance , Non-alcoholic Fatty Liver Disease , Disease Progression , Humans , Liver , Risk FactorsABSTRACT
Phenazine-1-carboxamide (PCN), a naturally occurring simple phenazine derivative isolated from Pseudomonas sp. strain PUP6, exhibited selective cytotoxic activity against lung (A549) and breast (MDA-MB-231) cancer cell lines in differential and dose-dependent manner compared to normal peripheral blood mononuclear cells. PCN-treated cancer cells showed the induction of apoptosis as evidenced by the release of low level of LDH, morphological characteristics, production of reactive oxygen species, loss of mitochondrial membrane potential (ΔΨm) and induction of caspase-3. At molecular level, PCN instigates apoptosis by mitochondrial intrinsic apoptotic pathway via the overexpression of p53, Bax, cytochrome C release and activation of caspase-3 with the inhibition of oncogenic anti-apoptotic proteins such as PARP and Bcl-2 family proteins (Bcl-2, Bcl-w and Bcl-xL). The in silico docking studies of PCN targeted against the anti-apoptotic members of Bcl-2 family proteins revealed the interaction of PCN with the BH3 domain, which might lead to the induction of apoptosis due to the inhibition of antiapoptotic proteins. Due to its innate inhibition potential of antiapoptotic Bcl-2 family proteins, PCN may be used as potent anticancer agent against both lung and breast cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Breast Neoplasms/metabolism , Lung Neoplasms/metabolism , Phenazines/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Apoptosis Regulatory Proteins/metabolism , Cell Line, Tumor , Humans , Membrane Potential, Mitochondrial/drug effects , Molecular Docking Simulation , Pseudomonas/chemistry , Reactive Oxygen Species/metabolismABSTRACT
A new rhizosphere soil bacterium that exhibits antimicrobial potential against human pathogens was isolated. On the basis of 16S ribosomal RNA nucleotide sequence homology and subsequent phylogenetic tree analysis, the strain PUW5 was identified as Pseudomonas putida. A bioactive metabolite was extracted and purified using silica gel column chromatography and preparative HPLC. Characterization of metabolite was done by employing Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR) and mass spectroscopy (MS). On the basis of spectroscopic data, the metabolite was structurally elucidated as 5-methyl phenazine-1-carboxylic acid betaine (MPCAB). The MPCAB exhibits selective cytotoxicity towards lung (A549) and breast (MDA MB-231) cancer cell lines in dose-dependent manner with IC50 value of 488.7±2.52 nM and 458.6±2.48 nM respectively. The MPCAB exhibited inhibition of cell viability, DNA synthesis, induced G1 cell cycle arrest and apoptosis in cancer cells. The docking and interaction studies confirmed the binding potential of MPCAB with Bcl-2 than Bcl-xL and Bcl-w proteins. These results strongly suggest that the MPCAB induces apoptosis in A549 and MDA MB-231 cancer cells through mitochondrial intrinsic pathway via activation of caspase-3 and down regulation of Bcl-2 protein.
