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1.
Arch Microbiol ; 206(3): 118, 2024 Feb 23.
Article in English | MEDLINE | ID: mdl-38393407

ABSTRACT

Candida albicans is a member of the ascomycetes class of fungi and it is an opportunistic pathogen species responsible for a wide range of fungal infections in humans. Bioinformatics and sequencing analysis of Candida proteomics has disclosed that around 69% proteome is still uncharacterized which needs to be annotated with functions. The NCBI-Genome has termed them as hypothetical proteins (HPs) in the whole proteome of Candida. Interpretation of this substantial portion of the proteome can reveal novel pharmacological targets for markers, drug development, and other therapeutics and so on. In this article, we have assigned functional annotation to these hypothetical proteins using bioinformatics methodologies. The advanced and robust computational models have been used to assign the preliminary functions to these putative HPs with high level of confidence. The findings of this study unveil some novel pharmacological targets for drug therapy and vaccines and it would help to identify novel molecular mechanisms underlying the fungal pathogenesis.


Subject(s)
Candida albicans , Proteome , Humans , Candida albicans/genetics , Proteome/genetics , Candida , Computational Biology , Fungal Proteins/genetics
2.
BMC Cancer ; 23(1): 387, 2023 May 01.
Article in English | MEDLINE | ID: mdl-37127581

ABSTRACT

BACKGROUND: The "Differentiation therapy" has been emerging as a promising and more effective strategy against acute leukemia relapses. OBJECTIVE: In extension to the revolutionising therapeutic outcomes of All Trans Retinoic Acid (ATRA) to induce terminal differentiation of Acute Promyelocytic Leukemic (APL) blast cells, we decipher the potential effect of a natural compound "Esculetin" to serve as a differentiating agent in Acute Myeloid Leukemia (AML). Underlaying role of Wnt signaling pathways in esculetin mediated blast cell differentiation was also evaluated. METHODS: Human acute myeloid leukemic cells (Kasumi-1) with t(8;21/AML-ETO) translocation were used as a model system. Growth inhibitory and cytotoxic activity of esculetin were analysed using growth kinetics and MTT assay. Morphological alterations, cell scatter characteristics, NBT reduction assay and cell surface marker expression patterns were analysed to detect terminally differentiated phenotypes. We employed RT2profiler PCR array system for the analysis of transcriptome profile of Wnt signaling components. Calcium inhibitors (TMB8 and Amlodipine) and Transforming growth factor beta (TGF-ß) were used to modulate the Wnt signaling axes. RESULTS: We illustrate cytotoxic as well as blast cell differentiation potential of esculetin on Kasumi-1 cells. Morphological alterations akin to neutrophilic differentiation as well as the corresponding acquisition of myeloid lineage markers indicate terminal differentiation potential of esculetin in leukemic blast cells. Exposure to esculetin also resulted in downregulation of canonical Wnt axis while upto ~ 21 fold upregulation of non-canonical axis associated genes. CONCLUSIONS: Our study highlights the importance of selective use of calcium pools as well as "axis shift" of the canonical to non-canonical Wnt signaling upon esculetin treatment which might abrogate the inherent proliferation to release maturation arrest and induce the differentiation in leukemic blast cells. The current findings provide further therapeutic interventions to consider esculetin as a potent differentiating agent to counteract AML relapses.


Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Humans , Wnt Signaling Pathway , Calcium , Leukemia, Myeloid, Acute/genetics , Tretinoin/pharmacology , Antineoplastic Agents/pharmacology , Cell Differentiation
3.
Mol Divers ; 2023 Oct 25.
Article in English | MEDLINE | ID: mdl-37880544

ABSTRACT

Neisseria gonorrhoeae (NG), the causative organism of gonorrhea, has been classified by the World Health Organization as 'Priority' two organism owing to its increased resistance to antibiotics and even failure of recommended dual therapy with ceftriaxone and azithromycin. As a result, the general and reproductive health of infected individuals is severely compromised. The imminent public health catastrophe of antimicrobial-resistant gonococci cannot be understated, as t he of severe complications and sequelae of infection are not only increasing but their treatment has also become more expensive. Tenacious attempts are underway to discover novel drug targets as well as new drugs to fight against NG. Therefore, a considerable number of phytochemicals have been tested for their remedial intercession via targeting bacterial proteins. The MurI gene encodes for an enzyme called glutamate racemase (MurI) that is primarily involved in peptidoglycan (PG) biosynthesis and is specific to the bacterial kingdom and hence can be exploited as a potential drug target for the treatment of bacterial diseases. Accordingly, diverse families of phytochemicals were screened in silico for their binding affinity with N. Gonorrhoeae MurI (NG-MurI) protein. Esculetin, one of the shortlisted compounds, was evaluated for its functional, structural, and anti-bacterial activity. Treatment with esculetin resulted in growth inhibition, cell wall damage, and altered permeability as revealed by fluorescence and electron microscopy. Furthermore, esculetin inhibited the racemization activity of recombinant, purified NG-MurI protein, one of the enzymes required for peptidoglycan biosynthesis. Our results suggest that esculetin could be further explored as a lead compound for developing new drug molecules against multidrug-resistant strains.

4.
J Med Virol ; 94(7): 3147-3154, 2022 07.
Article in English | MEDLINE | ID: mdl-35261064

ABSTRACT

Vaccines against COVID-19 provide immunity to deter severe morbidities associated with the infection. However, it does not prevent infection altogether in all exposed individuals. Furthermore, emerging variants of SARS-CoV-2 impose a threat concerning the competency of the vaccines in combating the infection. This study aims to determine the variability in adverse events and the extent of breakthrough infections in the Indian population. A retrospective study was conducted using a pre-validated questionnaire encompassing social, demographic, general health, the status of SARS-CoV-2 infection, vaccination, associated adverse events, and breakthrough infections in the Indian population. Informed consent and ethical approval were obtained as per Indian Council of Medical Research (ICMR) guidelines. Participants, who provided the complete information, were Indian citizens, above 18 years, and if vaccinated, administered with either Covishield or Covaxin, were considered for the study. Data have been compiled in Microsoft Excel and analyzed for statistical differences using STATA 11. The responses from 2051 individuals fulfilling the inclusion criteria were analyzed. Among 2051, 1119 respondents were vaccinated and 932 respondents were non-vaccinated. Among 1119 vaccinated respondents, 7 were excluded because of missing data. Therefore, out of 1112 vaccinated, 413 experienced adverse events with a major fraction of younger individuals, age 18-40 years, getting affected (74.82%; 309/413). Furthermore, considerably more females than males encountered adverse consequences to vaccination (p < 0.05). Among vaccinated participants, breakthrough infections were observed in 7.91% (88/1112; 57.96% males and 42.04% females) with the older age group, 61 years and above (odds ratio, 3.25 [1.32-8.03]; p = 0.011), and males were found to be at higher risk. Further research is needed to find the age and sex-related factors in determining vaccine effectiveness and adverse events.


Subject(s)
COVID-19 Vaccines , COVID-19 , Vaccines , Adolescent , Adult , COVID-19/epidemiology , COVID-19/etiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/therapeutic use , ChAdOx1 nCoV-19/adverse effects , ChAdOx1 nCoV-19/therapeutic use , Female , Humans , India , Male , Middle Aged , Retrospective Studies , SARS-CoV-2 , Vaccination/adverse effects , Vaccines/adverse effects , Vaccines/therapeutic use , Young Adult
5.
J Theor Biol ; 490: 110172, 2020 04 07.
Article in English | MEDLINE | ID: mdl-31972174

ABSTRACT

Neisseria gonorrhoeae is a gram negative diplococcus bacterium and the causative agent of the sexually transmitted disease Gonorrhea. It has been recently given the status of "superbug" by World Health Organization because of the increasing antibiotic resistance and unavailability of a viable vaccine candidate. Over recent years, there have been increasing reports about the use of subtractive genomics to identify potential drug and vaccine targets. Our study utilizes codon biasing, a tool to identify the essential genes, in N. gonorrhoeae that could be utilized as novel therapeutic targets for drug or vaccine development. Through the screening of 2350 total genes, we present a list of 29 such drug candidate genes based on codon adaptation. Through the data-mining with BLAST2GO and InterProScan databases, we could predict the function of these 29 genes. These genes are involved in pivotal cellular functions like DNA replication, energy synthesis and metabolites production. This study also shortlists the essential genes of N. gonorrhoeae that could be used to target Neisseria. We identified a molecule/drug which can be used to target essential protein DapD (succinyltransferase).


Subject(s)
Gonorrhea , Neisseria gonorrhoeae , Computer Simulation , Genomics , Gonorrhea/drug therapy , Humans , Neisseria gonorrhoeae/genetics
6.
Indian J Microbiol ; 60(1): 96-106, 2020 Mar.
Article in English | MEDLINE | ID: mdl-32089579

ABSTRACT

Microbial biofilms act as reservoirs for pathogenic sessile microbes which reside inside the three dimensional matrix of the biofilm, and are thus protected against anti-microbial drugs. Most of the anti-microbial drugs fail to completely abolish the biofilm associated infections. In the present study, we provide evidence of Hibiscus sabdariffa (Hs) extract having possible anti-microbial activity, with emphasis on Candida albicans biofilm. The Hs extract was shown to be effective against C. albicans pre-formed biofilm at 3.125 mg/ml and was able to inhibit the hyphae initiation and adherence of cells. Furthermore, Hs extract was able to reduce the C. albicans load in C. elegans by effectively killing the Candida cells thereby reducing the viable colony count and effectively increasing the lifespan of worms. The percentage of viable hatched progeny of worms exposed to Hs extract (both at conc. 1.5 mg/ml and 6.25 mg/ml), was also comparable to that of the control untreated eggs. The Hs extract was also found to be significantly effective against fluconazole resistant C. albicans isolated from patients. Thus, we, for the first time, propose Hs extract as a prospective drug candidate and substitute for eradicating pre-formed biofilm and inhibiting the growth of C. albicans.

7.
Appl Microbiol Biotechnol ; 103(2): 843-851, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30456576

ABSTRACT

Increasing drug resistance in pathogens including Mycobacterium tuberculosis (MTB) has been ascribed to mutations in the known target genes. However, many of these drugs have multiple targets; some of which have not been identified so far. Understanding the mechanism of action of these drugs holds a great promise in better management of disease especially by drug-resistant strains. In this study, we report glutamate racemase (MurI), a crucial enzyme of phase I peptidoglycan (PG) biosynthesis pathway of MTB, as an additional target of ethambutol (EMB). The effect on EMB on the MurI protein at structural and functional level was studied using different spectroscopic, biochemical, and insilico approaches. Spectroscopic analysis revealed that EMB-modified protein undergoes conformational alterations. Furthermore, in vitro racemization studies of the MurI protein suggest that EMB decreases its functional activity. Docking studies revealed that EMB interacts with most of the active residues at the binding site and blocks the binding pocket. Overall, data suggests that EMB, a primary drug used for the treatment of tuberculosis (TB), acts as a competitive inhibitor of substrate for binding to mycobacterial MurI protein. The study also points out to our lacunae in understanding the site and mechanism of action of existing drugs. Furthermore, glutamate racemase is a conserved protein of the bacterial kingdom; therefore, ethambutol could be a promising candidate as a broad-spectrum antibiotic for many other bacterial diseases.


Subject(s)
Amino Acid Isomerases/antagonists & inhibitors , Antitubercular Agents/pharmacology , Enzyme Inhibitors/pharmacology , Ethambutol/pharmacology , Mycobacterium tuberculosis/drug effects , Peptidoglycan/biosynthesis , Amino Acid Isomerases/chemistry , Amino Acid Isomerases/metabolism , Binding Sites , Cell Wall/metabolism , Molecular Docking Simulation , Mycobacterium tuberculosis/enzymology , Protein Binding , Protein Conformation , Spectrum Analysis
8.
Eur J Clin Invest ; 48(1)2018 Jan.
Article in English | MEDLINE | ID: mdl-29178542

ABSTRACT

BACKGROUND: Hypertension is associated with endothelial cell dysfunction. E-selectin, an endothelial cell adhesion molecule, is specific for endothelial cell activation. Polymorphism in E-selectin gene has recently been identified among which Leu554Phe E-selectin gene polymorphism is least investigated in essential hypertension. This study reports the association of E-selectin gene Leu554Phe polymorphism and the expression of E-selectin gene in patients with essential hypertension. MATERIALS AND METHODS: We analysed the Leu554Phe polymorphism and expression of E-selectin gene in 250 patients with essential hypertension and 250 normal healthy controls. Genotyping of Leu554Phe polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and the expression of E-selectin gene at mRNA and protein levels were carried out by real-time PCR and Western blot, respectively. RESULTS: A significant association of E-selectin genotypes (CT + TT) with essential hypertension (P < .0001, Odds ratio = 2.2 [1.58-3.24] at 95% CI) was observed. The expression of mRNA for E-selectin gene in patients with essential hypertension was ~12-fold higher as compared to control. We observed an elevated level of E-selectin protein expression (up to 1.9 times) in patients as compared to controls. CONCLUSIONS: A significant association of E-selectin (Leu554Phe) gene and increased expression of E-selectin gene at mRNA and protein levels in patients might be related to the genetic predisposition to develop essential hypertension.


Subject(s)
E-Selectin/genetics , Essential Hypertension/genetics , Polymorphism, Single Nucleotide/genetics , Blood Pressure/genetics , Case-Control Studies , E-Selectin/metabolism , Female , Gene Expression , Gene Frequency , Genetic Predisposition to Disease/genetics , Genotype , Humans , Male , Middle Aged , Up-Regulation/physiology
9.
Microbiology (Reading) ; 163(7): 1081-1092, 2017 07.
Article in English | MEDLINE | ID: mdl-28691898

ABSTRACT

Small non-coding RNAs (sRNAs) are well-established post-transcriptional regulators of gene expression in bacteria that respond to a variety of environmental stimuli. They usually act by base-pairing with their target mRNAs, which is commonly facilitated by the RNA chaperone Hfq. In this study we initiated the analysis of the sRNA FnrS of Neisseria gonorrhoeae, which is induced under anaerobic conditions. We identified four putative FnrS target genes using bioinformatics approaches and validated these target genes using translational reporter gene fusions in both Escherichia coli and N. gonorrhoeae, thereby demonstrating their downregulation by direct base-pairing between the respective mRNA and FnrS. We demonstrate deregulation of target mRNAs upon deletion of fnrS and provide evidence that the isc gene cluster required for iron-sulfur cluster biosynthesis, which harbours iscS, which is a direct target of FnrS, is coordinately downregulated by the sRNA. By mutational analysis we show that, surprisingly, three distinct regions of FnrS are employed for interaction with different target genes.


Subject(s)
Gene Expression Regulation, Bacterial , Neisseria gonorrhoeae/genetics , RNA, Bacterial/metabolism , RNA, Small Untranslated/metabolism , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Iron-Sulfur Proteins/genetics , Iron-Sulfur Proteins/metabolism , Multigene Family , Neisseria gonorrhoeae/metabolism , RNA, Bacterial/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Untranslated/genetics
10.
Anal Biochem ; 534: 24-27, 2017 10 01.
Article in English | MEDLINE | ID: mdl-28690181

ABSTRACT

Efficient electrophoretic separation of isolated total RNA utilizes chemicals and agents to aid in nuclease free environment. However cost, extensive pre-run processing protocols as well as toxic byproducts limit the usage of such protocols. Moreover, these treatments affect the overall electrophoretic results by altering the conductivity of the running buffer and weaken the gel strength. We here provide a protocol for RNA visualization that obviates these shortcomings by preparation of agarose gel with hydrogen peroxide using the regular TAE buffer. The simple, inexpensive protocol exhibits superior results in a horizontal agarose gel electrophoresis.


Subject(s)
Gels/chemistry , Hydrogen Peroxide/chemistry , RNA/analysis , Sepharose/chemistry , Electrophoresis, Agar Gel
11.
Mol Cancer ; 15(1): 64, 2016 10 18.
Article in English | MEDLINE | ID: mdl-27756327

ABSTRACT

BACKGROUND: A handful of studies have exploited antitumor potential of esculetin, a dihydroxy coumarine derivative; the targets to which it binds and the possible downstream mechanism for its cytotoxicity in cancer cells remain to be elucidated. Using pancreatic cancer cell lines as a model system, herein the study was initiated to check the efficacy of esculetin in inhibiting growth of these cancer cells, to decipher mechanism of its action and to predict its direct binding target protein. METHODS: The cytotoxicity of esculetin was determined in PANC-1, MIA PaCa-2 and AsPC-1 cell lines; followed by an inspection of intracellular levels of ROS and its associated transcription factor, p65-NF-κB. The interaction between transcription factor, Nrf2 and its regulator KEAP1 was studied in the presence and absence of esculetin. The effect of Nrf2 on gene expression of antioxidant response element pathway was monitored by real time PCR. Thereafter, potential binding target of esculetin was predicted through molecular docking and then confirmed in vitro. RESULTS: Esculetin treatment in all three pancreatic cancer cell lines resulted in significant growth inhibition with G1-phase cell cycle arrest and induction of mitochondrial dependent apoptosis through activation of caspases 3, 8 and 9. A notable decrease was observed in intracellular ROS and protein levels of p65-NF-κB in PANC-1 cells on esculetin treatment. Antioxidant response regulator Nrf2 has been reportedly involved in crosstalk with NF-κB. Interaction between Nrf2 and KEAP1 was found to be lost upon esculetin treatment in PANC-1 and MIA Paca-2 cells. Nuclear accumulation of Nrf2 and an upregulation of expression of Nrf2 regulated gene NQO1, observed on esculetin treatment in PANC-1 further supported the activation of Nrf2. To account for the loss of Nrf2-KEAP1 interaction on esculetin treatment, direct binding potential between esculetin and KEAP1 was depicted in silico using molecular docking studies. Pull down assay using esculetin conjugated sepharose beads confirmed the binding between esculetin and KEAP1. CONCLUSIONS: We propose that esculetin binds to KEAP1 and inhibits its interaction with Nrf2 in pancreatic cancer cells. This thereby promotes nuclear accumulation of Nrf2 in PANC-1 cells that induces antiproliferative and apoptotic response possibly by attenuating NF-κB.


Subject(s)
Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Apoptosis/drug effects , Kelch-Like ECH-Associated Protein 1/metabolism , Pancreatic Neoplasms/metabolism , Umbelliferones/pharmacology , Antineoplastic Agents/chemistry , Antioxidants/chemistry , Caspases/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Kelch-Like ECH-Associated Protein 1/chemistry , Membrane Potential, Mitochondrial/drug effects , Models, Molecular , Molecular Conformation , NF-kappa B/metabolism , Protein Binding , Reactive Oxygen Species/metabolism , Umbelliferones/chemistry
12.
J Theor Biol ; 410: 36-43, 2016 12 07.
Article in English | MEDLINE | ID: mdl-27596531

ABSTRACT

OBJECTIVES: Resistance to the currently recommended extended-spectrum cephalosporins, which is used to treat Gonorrhea, is increasing continuously and leading to a threat of untreatable infection. It is, therefore, becoming extremely essential to search for new therapeutic strategies to control Gonorrhea. Vaccination may be considered as an effective control measure to control this disease, which is caused by Neisseria gonorrhoeae. METHODS: In-silico hierarchical approach was used to help identify candidate proteins of N. gonorrhoeae that might contribute significantly in vaccine research. In contrast to the conventional vaccine research which requires at least 10-12 years, the present approach would reduce the time period drastically and help to identify Potential Universal Vaccine Candidates (PUVCs). These proteins were further analyzed for the presence of T-cell and linear B-cell epitopes, by using HLAPred and ABCpred servers respectively, in order to facilitate the identification of Multi Epitope Peptide Vaccine Constructs. RESULTS: We have identified 23 non-host candidate proteins, using the proteomic information of four sequenced strains of N. gonorrhoeae namely FA 1090, TCDC_NG08107, NCCP11945 and MS11 and labeled them as PUVCs. Since all these identified 23 PUVCs contained both T cell and B cell epitopes, these have been further reiterated as PUVCs which could be used as promising leads for vaccine development. CONCLUSIONS: This hierarchical approach is the first comprehensive study to identify potential vaccine candidates which once utilized for vaccine development would surely serve as promising tools for effective control of Gonorrhea.


Subject(s)
Bacterial Vaccines/immunology , Computer Simulation , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Neisseria gonorrhoeae/immunology , Bacterial Vaccines/chemistry , Bacterial Vaccines/therapeutic use , Epitopes, B-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/chemistry , Gonorrhea/immunology , Gonorrhea/prevention & control , Humans , Neisseria gonorrhoeae/chemistry , Proteomics
13.
Biochemistry (Mosc) ; 80(4): 424-32, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25869359

ABSTRACT

Human Sin3B (hSin3B), a transcription regulator, is a scaffold protein that binds to different transcription factors and regulates transcription. It consists of six conserved domains that include four paired amphipathic helices (PAH 1-4), histone deacetylase interaction domain (HID), and highly conserved region (HCR). Interestingly, the PAH domains of hSin3B are significantly homologous to each other, yet each one interacts with a specific set of unique transcription factors. Though various partners interacting with hSin3B PAH domains have been characterized, there is no structural information available on the individual PAH domains of hSin3B. Here we characterize the structure and stability of different PAH domains of hSin3B at both nuclear and physiological pH values by using different optical probes. We found that the native state structure and stability of different PAH domains are different at nuclear pH where hSin3B performs its biological function. We also found that PAH2 and PAH3 behave differently at both nuclear and physiological pH in terms of native state structure and thermodynamic stability, while the structural identity of PAH1 remains unaltered at both pH values. The study indicates that the structural heterogeneity of different PAH domains might be responsible for having a unique set of interacting transcription factors.


Subject(s)
Repressor Proteins/chemistry , Thermodynamics , Humans , Hydrogen-Ion Concentration , Protein Structure, Secondary , Repressor Proteins/metabolism , Repressor Proteins/physiology
14.
J Clin Microbiol ; 52(7): 2662-4, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24789191

ABSTRACT

A rapid and sensitive loop-mediated isothermal amplification assay for the sdaA gene of Mycobacterium tuberculosis was developed using a dUTP-uracil-N-glycosylase (dUTP-UNG) strategy to prevent carryover contamination. Evaluation of the assay using clinical specimens (n = 648) showed high specificity (97.2%) and sensitivity (100%), demonstrating its potential as a diagnostic test for tuberculosis, especially in resource-limited settings.


Subject(s)
Molecular Diagnostic Techniques/methods , Mycobacterium tuberculosis/isolation & purification , Nucleic Acid Amplification Techniques/methods , Tuberculosis/diagnosis , Humans , Mycobacterium tuberculosis/genetics , Sensitivity and Specificity , Temperature , Time Factors
15.
Biomarkers ; 19(4): 314-8, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24811208

ABSTRACT

OBJECTIVE: The present study aims to investigate the correlation of the angiotensin-converting enzyme (ACE) gene expression and protein expression in patients with essential hypertension in whole blood. METHODS: ACE gene expression was analyzed by Real Time PCR and western blot in 52 patients with essential hypertension and 42 healthy controls. RESULTS: We observed a significant increase in Delta threshold cycle (ΔCT) values in the circulating ACE gene and ACE protein expression in patients as compared to controls. CONCLUSIONS: The up-regulation in relative expression of circulating Angiotensin converting enzyme mRNA and protein in patients with respect to controls might be correlated with high blood pressure in patients with essential hypertension.


Subject(s)
Hypertension/enzymology , Peptidyl-Dipeptidase A/genetics , Adult , Base Sequence , Blotting, Western , Case-Control Studies , DNA Primers , Female , Humans , Male , Middle Aged , Peptidyl-Dipeptidase A/blood , Real-Time Polymerase Chain Reaction
16.
Epilepsy Behav ; 41: 98-102, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25461197

ABSTRACT

Oxidative stress and cognitive impairment are associated with PTZ-induced convulsions. Naringin is a bioflavonoid present in the grapefruit. It is a potent antioxidant, and we evaluated its effect on PTZ-induced convulsions. Rats were pretreated with normal saline, naringin (20, 40, and 80 mg/kg, i.p.), or diazepam (5mg/kg, i.p.) 30 min prior to the administration of PTZ. The administration of PTZ induced myoclonic jerks and generalized tonic-clonic seizures (GTSs). We observed that naringin significantly prolonged the induction of myoclonic jerks dose-dependently. Naringin (80 mg/kg, i.p.) pretreatment protected all rats, and this protective effect was annulled by the GABAA receptor antagonist, flumazenil. In addition, naringin reduced brain MDA and TNF-α levels and conserved GSH. The pretreatment also enhanced the performance of rats in the passive avoidance task. Our observations highlight the antioxidant, antiinflammatory, and anticonvulsant potential of naringin. Also, naringin modulates the GABAA receptor to produce anticonvulsant effects and to ameliorate cognitive impairment.


Subject(s)
Cognition Disorders/prevention & control , Flavanones/pharmacology , Inflammation/prevention & control , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Seizures/prevention & control , Animals , Cognition Disorders/chemically induced , Convulsants/pharmacology , Inflammation/chemically induced , Pentylenetetrazole/pharmacology , Rats , Seizures/chemically induced
17.
Article in English | MEDLINE | ID: mdl-38894529

ABSTRACT

Aging is the process of gradual physio-biochemical deterioration. While aging is inevitable, healthy aging is the key to individual and communal well-being. Therefore, it is essential to understand the regulation of aging. SIN-3/Sin3 is a unique regulatory protein that regulates aging without DNA binding activity. It functions by establishing multiple protein interactions. To understand the functional mechanism of this transcriptional regulator, the Caenorhabditis elegans protein interactome was assessed for SIN-3 interactions. DAF-16/FOXO emerged as one of the leading contenders for SIN-3-mediated regulation of aging. This study looks at the concerted role of SIN-3 and DAF-16 proteins in lifespan regulation. Phenotypic profiling for the mutants of these genes shows the functional accord between these two proteins with similar functions in stress response and vital biological processes. However, there were no significant physical interactions when checked for protein-protein interaction between SIN-3 and DAF-16 proteins. C. elegans genomics and transcriptomics data also indicated the possibilities of concerted gene regulation. This genetic regulation is more likely related to SIN-3 dominance on DAF-16 function. Overall, SIN-3 and DAF-16 proteins have strong functional interactions that ensure healthy aging. The influence of SIN-3 on DAF-16 mediated stress response is one of their convergence points in longevity regulation.

18.
J Biomol Struct Dyn ; : 1-19, 2024 Jan 04.
Article in English | MEDLINE | ID: mdl-38174578

ABSTRACT

After the emergence of the COVID-19 pandemic in late 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has undergone a dynamic evolution driven by the acquisition of genetic modifications, resulting in several variants that are further classified as variants of interest (VOIs), variants under monitoring (VUM) and variants of concern (VOC) by World Health Organization (WHO). Currently, there are five SARS-CoV-2 VOCs (Alpha, Beta, Delta, Gamma and Omicron), two VOIs (Lambda and Mu) and several other VOIs that have been reported globally. In this study, we report a natural compound, Curcumin, as the potential inhibitor to the interactions between receptor binding domain (RBD(S1)) and human angiotensin-converting enzyme 2 (hACE2) domains and showcased its inhibitory potential for the Delta and Omicron variants through a computational approach by implementing state of the art methods. The study for the first time revealed a higher efficiency of Curcumin, especially for hindering the interaction between RBD(S1) and hACE-2 domains of Delta and Omicron variants as compared to other lead compounds. We investigated that the mutations in the RBD(S1) of VOC especially Delta and Omicron variants affect its structure compared to that of the wild type and other variants and therefore altered its binding to the hACE2 receptor. Molecular docking and molecular dynamics (MD) simulation analyses substantially supported the findings in terms of the stability of the docked complexes. This study offers compelling evidence, warranting a more in-depth exploration into the impact of these alterations on the binding of identified drug molecules with the Spike protein. Further investigation into their potential therapeutic effects in vivo is highly recommended.Communicated by Ramaswamy H. Sarma.

19.
Gene ; 909: 148308, 2024 May 30.
Article in English | MEDLINE | ID: mdl-38395240

ABSTRACT

BACKGROUND: Genome-wide association studies identify SORT1 gene associated with risk of coronary artery disease (CAD). Sortilin protein enhances LDL absorption, form cell development, and atherosclerosis in macrophages. AIM: We therefore explored SORT1 expression in CAD patients and its gene expression's predictive usefulness for the severity of the disease. METHODOLOGY: This is a case control study and Quantitative real-time PCR; Sandwich ELISA and western blotting were used to determine the expression of SORT1 gene at the mRNA and protein level in two hundred healthy controls and two hundred patients with various CAD syndromes. RESULTS: CAD patients exhibit higher SORT1 gene expression in CAD patients, a higher concentration of sortilin in their plasma, and distinct expression patterns in various CAD syndromes. The study reveals a positive correlation between gene expression and the severity of coronary artery stenosis, the number of diseased vessels, and the presence of diabetes. ROC curve analysis of SORT1 gene expression both at mRNA and protein level showed strong discrimination between significant CAD and control subjects. CONCLUSION: Therefore, elevated SORT1 gene expression in various CAD syndromes may be a potential biomarker for the disease.


Subject(s)
Atherosclerosis , Coronary Artery Disease , Humans , Coronary Artery Disease/diagnosis , Coronary Artery Disease/genetics , Genome-Wide Association Study , Case-Control Studies , Atherosclerosis/genetics , RNA, Messenger/genetics , Coronary Angiography
20.
J Family Med Prim Care ; 13(4): 1481-1487, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38827713

ABSTRACT

Background: Irrespective of the availability of a safe and effective COVID-19 vaccine and its success rate in adults, administering vaccines to children remains a challenge for healthcare workers. Children's vaccine hesitancy among parents remains substantial and is exacerbated due to misleading information. In the present study, we aimed to investigate the hesitancy of parents and their concern about the vaccination and clinical characteristics of COVID-19 in their children. Methods: A cross-sectional web-based and offline survey comprised of questions about the demographic of children, the status of COVID-19 infection, its severity, vaccination status, sources of information, willingness, concerns and attitude of parents to vaccinate their children against the COVID-19 virus, was conducted. Overall, 846 responses from parents fulfilling the inclusion criteria were analysed by GraphPad Prism 5. Results: Out of the 846 responses, 51.2% (n = 433) of children were vaccinated against COVID-19. Out of vaccinated children (51.2%), 60.3% (n = 261) had experienced adverse events. Around 21% (n = 98) of children had a history of exposure to the SARS-CoV-2 virus. Among the infected children, 14.3% were asymptomatic and 85.7% had symptoms. Approximately 8% of children had comorbidities, with chronic lung diseases and asthma being the most common. Among the 846 participating parents, 59.5% were mothers and the remaining 40.5% were fathers. A total of 2.7% and 22.2% of parents were found hesitant to administer the COVID-19 vaccine to their children aged 15-18 years and below 15 years, respectively. Among hesitant parents, mothers were found slightly more hesitant as compared to fathers. Also, 35.5% of parents were found hesitant about their own COVID-19 vaccination. Furthermore, the concern for COVID-19 vaccine unwillingness among parents is that a child has already achieved natural immunity after COVID-19 infections (76.8%) followed by vaccine safety and its side effects. The motivating factors to convince parents for their children's COVID-19 vaccination were if their doctors recommend it, followed by detailed information on vaccine side effects and efficacy in children. The most trusted source of information for the parents was found to be the healthcare workers. Conclusion: These results suggest that data and reviews regarding the safety and efficacy of the COVID-19 vaccine readily available in the public domain could serve as a highly effective strategy for promoting and implementing widespread vaccination among children. By providing easily accessible and comprehensive information, public health authorities can address parental concerns, dispel misconceptions and foster a greater sense of trust in the vaccination process.

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