Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

Biofilm is a complex structure of microbiome having different bacterial colonies or single type of cells in a group; adhere to the surface. These cells are embedded in extracellular polymeric substances, a matrix which is generally composed of eDNA, proteins and polysaccharides, showed high resistance to antibiotics. It is one of the major causes of infection persistence especially in nosocomial settings through indwelling devices. Quorum sensing plays an important role in regulating the biofilm formation. There are many approaches being used to control infections by suppressing its formation but CRISPR-CAS (gene editing technique) and photo dynamic therapy (PDT) are proposed to be used as therapeutic approaches to subside bacterial biofim infections, especially caused by deadly drug resistant bad bugs.

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Antibiotics versus biofilm: an emerging battleground in microbial communities

Antibacterial resistance is a great concern and requires global action. A critical question is whether enough new antibacterial drugs are being discovered and developed. A review of the clinical antibacterial drug pipeline was recently published, but comprehensive information about the global preclinical pipeline is unavailable. This Review focuses on discovery and preclinical development projects and has found, as of 1 May 2019, 407 antibacterial projects from 314 institutions. The focus is on Gram-negative pathogens, particularly bacteria on the WHO priority bacteria list. The preclinical pipeline is characterized by high levels of diversity and interesting scientific concepts, with 135 projects on direct-acting small molecules that represent new classes, new targets or new mechanisms of action. There is also a strong trend towards non-traditional approaches, including diverse antivirulence approaches, microbiome-modifying strategies, and engineered phages and probiotics. The high number of pathogen-specific and adjunctive approaches is unprecedented in antibiotic history. Translational hurdles are not adequately addressed yet, especially development pathways to show clinical impact of non-traditional approaches. The innovative potential of the preclinical pipeline compared with the clinical pipeline is encouraging but fragile. Much more work, focus and funding are needed for the novel approaches to result in effective antibacterial therapies to sustainably combat antibacterial resistance.

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The global preclinical antibacterial pipeline.

The evolutionarily conserved p53 protein and its cellular pathways mediate tumour suppression through an informed, regulated and integrated set of responses to environmental perturbations resulting in either cellular death or the maintenance of cellular homeostasis. The p53 and MDM2 proteins form a central hub in this pathway that receives stressful inputs via MDM2 and respond via p53 by informing and altering a great many other pathways and functions in the cell. The MDM2-p53 hub is one of the hubs most highly connected to other signalling pathways in the cell, and this may be why TP53 is the most commonly mutated gene in human cancers. Initial or truncal TP53 gene mutations (the first mutations in a stem cell) are selected for early in cancer development inectodermal and mesodermal-derived tissue-specific stem and progenitor cells and then, following additional mutations, produce tumours from those tissue types. In endodermal-derived tissue-specific stem or progenitor cells, TP53 mutations are functionally selected as late mutations transitioning the mutated cell into a malignant tumour. The order in which oncogenes or tumour suppressor genes are functionally selected for in a stem cell impacts the timing and development of a tumour.

p53: 800 million years of evolution and 40 years of discovery

Identifying the molecular alterations that underlie the pathophysiology of critical clinical features of schizophrenia is an essential step in the rational development of new therapeutic interventions for this devastating illness. Cognitive deficits, such as the impairments in working memory that arise from dysfunction of the dorsolateral prefrontal cortex, are a major determinant of functional outcome in schizophrenia. Here we consider the contributions of disturbances in glutamate, dopamine and GABA neurotransmission to the pathophysiology of working memory impairments in schizophrenia, suggest a cascade of molecular events that might link these disturbances, and argue that the molecular alterations most proximal to the pathophysiology of prefrontal dysfunction offer the most promise as targets for new drug development.

Pathophysiologically based treatment interventions in schizophrenia

Programmed cell death has a vital role in embryonic development and tissue homeostasis. Necroptosis is an alternative mode of regulated cell death mimicking features of apoptosis and necrosis. Necroptosis requires protein RIPK3 (previously well recognized as regulator of inflammation, cell survival, and disease) and its substrate MLKL, the crucial players of this pathway. Necroptosis is induced by toll-like receptor, death receptor, interferon, and some other mediators. Shreds of evidence based on a mouse model reveals that deregulation of necroptosis has been found to be associated with pathological conditions like cancer, neurodegenerative diseases, and inflammatory diseases. In this timeline article, we are discussing the molecular mechanisms of necroptosis and its relevance to diseases.

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Necroptosis: a regulated inflammatory mode of cell death.

In the present study, zinc oxide nanoparticles (ZnO NPs) were synthesized using leaf extract of Catharanthus roseus (C. roseus) under different physical parameters. Biosynthesis of ZnO NPs was confirmed by UV-Visible spectrophotometer and further, characterized by X-Ray Diffraction (XRD), Fourier Transform Infrared spectroscopy (FTIR), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Energy-Dispersive X-ray spectroscopy (EDX), Atomic Force Microscopy (AFM), Photoluminescence study and Dynamic Light Scattering (DLS). We have also confirmed that several physical parameters such as pH, temperature, concentration of metal ions and reaction time were able to regulate shape and size of synthesized ZnO NPs. XRD and TEM analysis provided the information about the average size and hexagonal morphology of ZnO NPs. FTIR spectra analysis suggested that phenolic compounds played crucial role in the biosynthesis of ZnO NPs. The significant antibacterial activity of ZnO NPs was observed against Staphylococcus aureus MTCC 9760 (S. aureus), Streptococcus pyogenes MTCC 1926 (S. pyogenes), Bacillus cereus MTCC 430 (B. cereus), Pseudomonas aeruginosa MTCC 424 (P. aeruginosa), Proteus mirabilis MTCC 3310 (P. mirabilis) and Escherichia coli MTCC 40 (E. coli). The synthesized ZnO NPs have shown antibacterial efficacy against both Gram-positive and Gram-negative pathogens. Synergistic effects of ZnO NPs and streptomycin showed increased efficacy as indicated by the increased zone of clearance in comparison to their individual effects (either ZnO NPs or streptomycin). Overall, the results elucidated a rapid, cost-effective, environmentally friendly and convenient method for ZnO NPs synthesis, which could be used as a potential antimicrobial agent against drug resistant microbes.

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Effective Antimicrobial Activity of Green ZnO Nano Particles of Catharanthus roseus.

Proteomic analysis of Mycobacterium tuberculosis isolates resistant to kanamycin and amikacin.

Aminoglycosides, amikacin (AK) and kanamycin (KM) are second line anti-tuberculosis drugs used to treat tuberculosis (TB) and resistance to them affects the treatment. Membrane and membrane associated proteins have an anticipated role in biological processes and pathogenesis and are potential targets for the development of new diagnostics/vaccine/therapeutics. In this study we compared membrane and membrane associated proteins of AK and KM resistant and susceptible Mycobacterium tuberculosis isolates by 2DE coupled with MALDI-TOF/TOF-MS and bioinformatic tools. Twelve proteins were found to have increased intensities (PDQuest Advanced Software) in resistant isolates and were identified as ATP synthase subunit alpha (Rv1308), Trigger factor (Rv2462c), Dihydrolipoyl dehydrogenase (Rv0462), Elongation factor Tu (Rv0685), Transcriptional regulator MoxR1(Rv1479), Universal stress protein (Rv2005c), 35kDa hypothetical protein (Rv2744c), Proteasome subunit alpha (Rv2109c), Putative short-chain type dehydrogenase/reductase (Rv0148), Bacterioferritin (Rv1876), Ferritin (Rv3841) and Alpha-crystallin/HspX (Rv2031c). Among these Rv2005c, Rv2744c and Rv0148 are proteins with unknown functions. Docking showed that both drugs bind to the conserved domain (Usp, PspA and SDR domain) of these hypothetical proteins and GPS-PUP predicted potential pupylation sites within them. Increased intensities of these proteins and proteasome subunit alpha might not only be neutralized/modulated the drug molecules but also involved in protein turnover to overcome the AK and KM resistance. Besides that Rv1876, Rv3841 and Rv0685 were found to be associated with iron regulation signifying the role of iron in resistance. Further research is needed to explore how these potential protein targets contribute to resistance of AK and KM.

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Comparative Proteomic Analysis of Aminoglycosides Resistant and Susceptible Mycobacterium tuberculosis Clinical Isolates for Exploring Potential Drug Targets.

Divakar Sharma

Papers

Antibiotics versus biofilm: an emerging battleground in microbial communities

Necroptosis: a regulated inflammatory mode of cell death.

Effective Antimicrobial Activity of Green ZnO Nano Particles of Catharanthus roseus.

Proteomic analysis of Mycobacterium tuberculosis isolates resistant to kanamycin and amikacin.

Comparative Proteomic Analysis of Aminoglycosides Resistant and Susceptible Mycobacterium tuberculosis Clinical Isolates for Exploring Potential Drug Targets.