Mucins are major glycoprotein components of the mucus that coats the surfaces of cells lining the respiratory, digestive, gastrointestinal and urogenital tracts. They function to protect epithelial cells from infection, dehydration and physical or chemical injury, as well as to aid the passage of materials through a tract i.e., lubrication. They are also implicated in the pathogenesis of benign and malignant diseases of secretory epithelial cells. In Human there are two types of mucins, membrane-bound and secreted that are originated from mucous producing goblet cells localized in the epithelial cell layer or in mucous producing glands and encoded by MUC gene. Mucins belong to a heterogeneous family of high molecular weight proteins composed of a long peptidic chain with a large number of tandem repeats that form the so-called mucin domain. The molecular weight is generally high, ranging between 0.2 and 10 million Dalton and all mucins contain one or more domains which are highly glycosylated. The size and number of repeats vary between mucins and the genetic polymorphism represents number of repeats (VNTR polymorphisms), which means the size of individual mucins can differ substantially between individuals which can be used as markers. In human it is only MUC1 and MUC7 that have mucin domains with less than 40% serine and threonine which in turn could reduce number of PTS domains. Mucins can be considered as powerful two-edged sword, as its normal function protects from unwanted substances and organisms at an arm's length while, malfunction of mucus may be an important factor in human diseases. In this review we have unearthed the current status of different mucin proteins in understanding its role and function in various non-communicable diseases in human with special reference to its organ specific locations. The findings described in this review may be of direct relevance to the major research area in biomedicine with reference to mucin and mucin associated diseases.
Outcomes of various clinical studies for the coronavirus disease 2019 (COVID-19) treatment indicated that the drug acts via inhibition of multiple pathways (targets) is likely to be more successful and promising. Keeping this hypothesis intact, the present study describes for the first-time, Grazoprevir, an FDA approved anti-viral drug primarily approved for Hepatitis C Virus (HCV), mediated multiple pathway control via synergistic inhibition of viral entry targeting host cell Angiotensin-Converting Enzyme 2 (ACE-2)/transmembrane serine protease 2 (TMPRSS2) and viral replication targeting RNA-dependent RNA polymerase (RdRP). Molecular modeling followed by in-depth structural analysis clearly demonstrated that Grazoprevir interacts with the key residues of these targets. Futher, Molecular Dynamics (MD) simulations showed stability and burial of key residues after the complex formation. Finally, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis identified the governing force of drug-receptor interactions and stability. Thus, we believe that Grazoprevir could be an effective therapeutics for the treatment of the COVID-19 pandemic with a promise of unlikely drug resistance owing to multiple inhibitions of eukaryotic and viral proteins, thus warrants further clinical studies.
Resistance to anticancer drugs limits the effectiveness of chemotherapy in cancers. Melanoma cell lines B16F10C and A375C (parental) and B16F10R and A375R (drug-resistant sublines) were used to test radiation sensitization potential of valproic acid (VPA), an inhibitor of Histone deacetylase2 (HDAC2) and LDN193189 (BMP inhibitor). Inhibitors of other signaling pathways were tested for cross-resistance with the resistant cell lines. Cells were pretreated with low concentrations of VPA/ LDN193189 and exposed to 2 Gy radiation for radiation sensitization experiments. Assays-3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT), live/dead, clonogenic, and melanin estimation were performed to test the effects of radiation sensitization. Interactions of VPA and HDAC2 were studied in silico. Dose-dependent growth inhibition was observed with all tested drugs. Radiation sensitization of melanoma cells with low dose of VPA induced synergistic cell death, decreased clonogenicity, and decreased melanin content. In silico docking showed two stable interactions between Arg39 of HDAC2 and VPA. In conclusion, pretreatment with low doses of VPA has a potential for sensitizing melanoma cells to low doses of radiation. The binding of VPA to HDAC2 reverses the drug resistance in melanoma and induces the cell death. Sensitization effects of VPA can be used for targeting drug-resistant cancers.
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor and it contributes to breast cancer growth
and metastasis. Hence, NF-κB is considered as a target for anti-breast cancer drugs. NF-κB was retrieved from the UniProtKB Data Base
with UniProt ID P19838, its energy was minimized and subjected to molecular dynamic simulations using Gromacs v5.0.7 software with
GROMOS96 43A1 force field implementing the steepest descent algorithm. The structure of genistein was retrieved from NCBI PubChem
database in .sdf format and convert to .pdb format. The genistein compound was docked into the active site of NF-κB proteins with
AutoDock tools 1.5. The genistein compound displayed the best binding energies at -6.29 (NF-κB) kcal/mol correspondingly. The binding
interactions of this compound with the active site of NF-κB proteins suggested that amino acid residues (Lys52, Ser243, Asp274, Lys, 275)
might play a key role in anti-breast cancer activity. Genistein also inhibited the translocation and expression of NF-κB in the nucleus of
both breast cancer cell lines. These findings might increase our understanding of the molecular and functional role of NF-κB in breast
cancer. It could also help in developing additional druggable NF-κB inhibitors with high potency, specificity and outstanding
bioavailability.
The complex and dynamic consortia of microbiota that harbors the human gastrointestinal tract contributes ominously to the maintenance of health, the onset and progression of diverse spectrum of disorders. The capability of these enteric microbes to bloom within the gut mucosal milieu is often associated to the glycan metabolism of mucin-degrading bacteria. Accruing evidences suggests that the desulfation of mucin is a rate-limiting step in mucin degradation mechanism by colonic bacterial mucin-desulfating sulfatase enzymes (MDS) enzymes. Till date no experimental evidence is available on how conformational flexibility influences structure and substrate specificity by MDS of gut microbe Bacteroides fragilis. Henceforth, to gain deep insights into the missing but very imperative mechanism, we performed a comprehensive molecular dynamics study, principal component analysis and MM/PBSA binding free energies to gain insights into (i) the domain architecture and mode of substrate binding (ii) conformational dynamics and flexibility that influence the orientation of substrate, (iii) energetic contribution that plays very decisive role to the overall negative binding free energy and stabilities of the complexes (iv) critical residues of active site which influence binding and aid in substrate recognition. This is the first ever report, depicting the molecular basis of recognition of substrates and provides insights into the mode of catalysis by mucin desulfating sulfatase enzymes in gut microbiota. Overall, our study shed new insights into the unmapped molecular mechanisms underlying the recognition of various substrates by mucin desulfating sulfatase, which could be of great relevance in therapeutic implications in human gut microbiota associated disorders.
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