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1.
BMC Public Health ; 23(1): 292, 2023 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-36759802

RESUMO

BACKGROUND: The coronavirus disease (COVID) pandemic caused disruption globally and was particularly distressing in low- and middle-income countries such as India. This study aimed to provide population representative estimates of COVID-related outcomes in India over time and characterize how COVID-related changes and impacts differ by key socioeconomic groups across the life course. METHODS: The sample was leveraged from an existing nationally representative study on cognition and dementia in India: Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD). The wave-1 of LASI-DAD enrolled 4096 older adults aged 60 years and older in 3316 households from 18 states and union territories of India. Out of the 3316 LASI-DAD households, 2704 with valid phone numbers were contacted and invited to participate in the Real-Time Insights COVID-19 in India (RTI COVID-India) study. RTI COVID-India was a bi-monthly phone survey that provided insight into the individual's knowledge, attitudes, and behaviour towards COVID-19 and changes in the household's economic and health conditions throughout the pandemic. The survey was started in May 2020 and 9 rounds of data have been collected. FINDINGS TILL DATE: Out of the 2704 LASI-DAD households with valid phone numbers, 1766 households participated in the RTI COVID-India survey at least once. Participants were in the age range of 18-102 years, 49% were female, 66% resided in rural area. Across all rounds, there was a higher report of infection among respondents aged 60-69 years. There was a greater prevalence of COVID-19 diagnosis reported in urban (23.0%) compared to rural areas (9.8%). Respondents with higher education had a greater prevalence of COVID-19 diagnosis compared to those with lower or no formal education. Highest prevalence of COVID-19 diagnosis was reported from high economic status compared to middle and low economic status households. Comparing education gradients in experiencing COVID-19 symptoms and being diagnosed, we observe an opposite pattern: respondents with no formal schooling reported the highest level of experiencing COVID-19 symptoms, whereas the greatest proportion of the respondents with secondary school or higher education reported being diagnosed with COVID-19. FUTURE PLANS: The study group will analyse the data collected showing the real-time changes throughout the pandemic and will make the data widely available for researchers to conduct further studies.


Assuntos
COVID-19 , Demência , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Adolescente , Adulto Jovem , Adulto , Idoso de 80 Anos ou mais , Masculino , COVID-19/epidemiologia , Teste para COVID-19 , Envelhecimento , Fatores Socioeconômicos , Índia/epidemiologia
2.
Eur J Neurosci ; 56(9): 5442-5452, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-34905657

RESUMO

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common form of dementia in the elderly. Two major pathological hallmarks have been identified for AD: extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT). Recently, proline-rich tyrosine kinase 2 (Pyk2), which belongs to the focal adhesion kinase (FAK) non-receptor tyrosine kinase family, was recognized to contribute significantly towards the pathogenesis of AD. Pyk2 can influence the formation of amyloid plaques as well as NFTs. The kinase can directly phosphorylate tau, which is a significant component of NFTs and enhances tau pathology. Several competitive inhibitors have been developed for Pyk2, tested in several cancer models, as Pyk2 is known to be overexpressed under those conditions. The current review article discusses the possible mechanistic pathways by which Pyk2 can influence the pathogenesis of AD. Besides, it describes various inhibitors for Pyk2 and their potential role as therapeutics for AD in the future.


Assuntos
Doença de Alzheimer , Quinase 2 de Adesão Focal , Idoso , Humanos , Doença de Alzheimer/metabolismo , Quinase 2 de Adesão Focal/metabolismo , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fosforilação , Placa Amiloide/metabolismo , Proteínas tau/metabolismo
3.
Mol Divers ; 25(4): 2261-2270, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32591930

RESUMO

Inhibition of Sirtuin2 (SIRT2) protein rescues the α-synuclein toxicity in vitro and in vivo models of Parkinson's disease (PD). Thioacetyl group can structurally mimic the acetyl group and restrain the deacetylating p53 reaction by SIRT2. This work evaluated the biological activity of designed pentapeptides inhibitor containing N-thioacetyl-lysine against SIRT2. Pentapeptide by introducing thioacetyl-lysine as an inhibitor of SIRT2 was screened by molecular docking and synthesized by solid phase method. The inhibition of pure recombinant SIRT2 as well as SIRT2 in serum of PD patients by peptide was done by fluorescent activity assay. The inhibition of SIRT2 was assessed in PC12 cell line by measuring acetylated α-tubulin level. The peptide YKK(ε-thioAc)AM and HRK(ε-thioAc)AM were found to be SIRT2 inhibitors by molecular docking. However, YKK(ε-thioAc)AM was more specific towards SIRT2 than SIRT1 (Sirtuin1). It inhibited recombinant SIRT2 by IC50 value of 0.15 µM and KD values 9.92 × 10-8/M. It also inhibited serum SIRT2 of PD. It increased the acetylation of α-tubulin in PC12 neuroblastoma cells which is essential for maintaining the microtubular cell functions of brain. It can be concluded that novel peptide YKK(ε-thioAc)AM may be a platform for therapeutic agent for Parkinson's disease targeting SIRT2.


Assuntos
Doença de Parkinson , Sirtuína 2
4.
Aging Clin Exp Res ; 33(5): 1315-1324, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32594460

RESUMO

BACKGROUND: The aging trajectory from a state of robustness and good health proceeds from sarcopenia to frailty followed by disability and death due to decline in skeletal muscle mass and function. Sarcopenia is now formally recognized as a muscle disease with an ICD-10-MC diagnosis code. The autophagic response seems to be affected in the skeletal muscle during aging contributing to sarcopenia. Sestrins (Sesns) proteins play a critical role in autophagy induction under cellular stress conditions. AIMS: The study aims to identify sarcopenia in older adults using Asian Working group guidelines (AWGS) to determine clinically relevant cut-off levels for diagnosis and their association with antioxidant protein Sesns. METHODS: The study recruited 102 older adults attending Geriatric medicine OPD AIIMS, New Delhi, India. The level of serum Sesns were evaluated by Surface Plasmon Resonance (SPR) and validated by immunoblotting. Fifty older adults were diagnosed as sarcopenics according to AWGS. RESULTS: Sesn 1 (p = 0.0448) and Sesn 2 (p < 0.0001) levels were significantly reduced in sarcopenic compared to non-sarcopenic. ROC analysis showed a better cut-off of Sesn 2; 10.104 ng/µL with 92% sensitivity and 84% specificity. Even after adjusting the values with respect to confounding factors, Sesn levels remained significantly reduced in sarcopenics (p < 0.030). DISCUSSION: The level of Sesn 2 showed positive co-relation with the characteristics of sarcopenia. This study first time reported the concentration of serum sestrin in sarcopenic older adults. CONCLUSION: It can be concluded that sarcopenia can be diagnosed at the early stage by using the serum sestrin scale as one of the potential biomarker.


Assuntos
Fragilidade , Sarcopenia , Idoso , Envelhecimento , Avaliação Geriátrica , Humanos , Músculo Esquelético/patologia , Sarcopenia/diagnóstico , Sarcopenia/patologia , Sestrinas
5.
Mol Biol Rep ; 47(1): 269-274, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31659693

RESUMO

The inflammatory process plays a key role in neurodegenerative disorder. The inflammatory molecule, 5-lipooxygenase (5-LOX), protein is involved in the pathologic phenotype of AD which includes Aß amyloid deposition and tau hyperphosphorylation. This study aims to identify the mechanistic role in neuroprotection by 5-LOX inhibitor in neurotoxic SH-SY5Y cell line model by evaluating different cell survival pathway. The neurotoxic SH-SY5Y cells were developed by the treatment of Aß25-35. The cells were then treated with 5-LOX peptide inhibitor, YWCS to prevent neurotoxicity reported earlier from our lab. The effect of 5-LOX inhibition on cell survival pathways were determined by western blot experiment with different doses of peptide by using polyclonal anti body of p53, anti-Akt and anti-phosphorylated Akt. Immunoprecipitation and mass spectroscopic studies were done to identify the altered proteins appeared on the blot. Over expression of phosphorylated Akt and 3 bands on p53 lane blot other than p53 were observed. Three bands were identified as isoforms of p53 which correspond to p73, Δ133p53 and Δ160p53 in the cells treated only with 80 µM of YWCS compare to untreated cells. However, no alteration of total p53 and Akt were observed in treated cells. The results exposed the novel mechanistic pathway of neuroprotection by 5-LOX inhibition is likely to be mediated by DNA DSB repair through p53 isoforms and PI3K/Akt pathway. Our finding has opened a new window in the therapeutic approach for the prevention of AD.


Assuntos
Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/metabolismo , Proteína Supressora de Tumor p53/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Humanos , Neurônios/metabolismo , Neuroproteção , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Isoformas de Proteínas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína Tumoral p73/metabolismo , Proteína Supressora de Tumor p53/metabolismo
6.
Exp Mol Pathol ; 107: 118-123, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30771292

RESUMO

INTRODUCTION: p38 MAPK signaling molecules plays a dual role in cancer, both progression and suppression. Elevated expression of p38α was reported in lung cancer tissue in rat model. Our objective was to explore the concentration of all 4 isoforms of p38MAPK in serum of Non Small Cell Lung Cancer (NSCLC). MATERIAL AND METHODS: The blood samples were collected from 77 NSCLC patients, 52 ethically matched healthy controls and 18 follow up patients were collected as some patients expired and some discontinued the treatment. The concentration of all isoforms of p38 (p38α, p38ß, p38γ, and p38δ) were evaluated by Surface Plasmon Resonance (SPR) technology. RESULT: The levels of all isoforms of serum p38 were significantly elevated at pre-therapy compare to control. Only p38α expression was significantly associated with tumor stage and its expression reduced after treatment which is then validated by western blot. However, no changes were observed in other isoforms after therapy. CONCLUSION: Our study revealed that, p38α is more efficient among all the isoform to predict the disease accurately and it can be concluded that p38 MAPK may be used as diagnostic as well as prognostic marker of NSCLC disease.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , Proteínas Quinases p38 Ativadas por Mitógeno/sangue , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico
7.
J Mol Recognit ; 30(10)2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28470740

RESUMO

An essential protein for bacterial growth, GTPase-Obg (Obg), is known to play an unknown but crucial role in stress response as its expression increases in Mycobacterium under stress conditions. It is well reported that Obg interacts with anti-sigma-F factor Usfx; however, a detailed analysis and structural characterization of their physical interaction remain undone. In view of above-mentioned points, this study was conceptualized for performing binding analysis and structural characterization of Obg-Usfx interaction. The binding studies were performed by surface plasmon resonance, while in silico docking analysis was done to identify crucial residues responsible for Obg-Usfx interaction. Surface plasmon resonance results clearly suggest that N-terminal and G domains of Obg mainly contribute to Usfx binding. Also, binding constants display strong affinity that was further evident by intermolecular hydrogen bonds and hydrophobic interactions in the predicted complex. Strong interaction between Obg and Usfx supports the view that Obg plays an important role in stress response, essentially required for Mycobacterium survival. As concluded by various studies that Obg is crucial for Mycobacterium survival under stress, this structural information may help us in designing novel and potential inhibitors against resistant Mycobacterium strains.


Assuntos
Proteínas de Bactérias/química , Fator F/química , Proteínas de Ligação ao GTP/química , Mycobacterium/metabolismo , Proteínas de Bactérias/metabolismo , Cromatografia em Gel , Simulação por Computador , Sistemas Computacionais , Fator F/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Cinética , Modelos Moleculares , Ligação Proteica
8.
J Pept Sci ; 23(3): 228-235, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28120548

RESUMO

Antifungal peptides have gained interest as therapeutic agents in recent years because of increased multidrug resistance against present antifungal drugs. This study designed, synthesized and characterized antifungal activity of a small peptide analogue, DS6. This peptide was designed using the template from the N-terminal part of the antifungal protein, Aspergillus giganteous. DS6 inhibited Candida tropicalis (ATCC 13803), as well as its clinical isolates. DS6 was found to be a fungicidal, killing the fungus very rapidly. DS6 is also non-toxic to human cells. Synergistic interactions of DS6 with amphotericin B and fluconazole were also evident. DS6 is membrane lytic and exhibits antibiofilm activity against C. tropicalis. In conclusion, DS6 may have utility as an alternative antifungal therapy for C. tropicalis. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida tropicalis/efeitos dos fármacos , Fluconazol/farmacologia , Peptídeos/farmacologia , Motivos de Aminoácidos , Antifúngicos/síntese química , Biofilmes/crescimento & desenvolvimento , Candida/efeitos dos fármacos , Candida/crescimento & desenvolvimento , Candida tropicalis/crescimento & desenvolvimento , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Sinergismo Farmacológico , Eritrócitos/efeitos dos fármacos , Células HEK293 , Humanos , Testes de Sensibilidade Microbiana , Peptídeos/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Especificidade da Espécie
9.
J Clin Lab Anal ; 31(2)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27616735

RESUMO

BACKGROUND: Many studies reported for estimating serum YKL-40 using ELISA or RIA methods. This study introduces the plausible utilization of real-time surface plasmon resonance (SPR) technology in investigating the expression of serum YKL-40 protein levels and ELISA method for serum IgE in bronchial asthma. METHODS: A commercially available BIAcore 2000 instrument, based on SPR technology, was utilized for assessing serum YKL-40 levels in a control sample size of 45 and active sample size of 97. Antibody immobilization was optimized to obtain the best sensor performance and a sensitive analytic detection. A commercially available ELISA kit was utilized for detecting serum IgE to estimate allergic condition-associated asthma. RESULTS: The results of SPR technology could distinctly classify with highly statistical significance, the asthma severities by estimating the elevated levels of YKL-40 in blood sera of minute quantities (up to 0.33 ng/ml), and thus differentiates superior utility in comparison with ELISA method. No statistically significant correlation of YKL-40 and IgE was observed. CONCLUSIONS: Serum YKL-40 may be used as a protein marker in classifying asthma severity by applying SPR technology as a reliable, label-free, highly sensitive, and cost-effective tool.


Assuntos
Asma/sangue , Asma/diagnóstico , Proteína 1 Semelhante à Quitinase-3/sangue , Imunoglobulina E/sangue , Ressonância de Plasmônio de Superfície/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Carcinogenesis ; 37(9): 912-7, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27432812

RESUMO

Lipoxygenase (LOX) pathway has emerged to have a role in carcinogenesis. There is an evidence that both 12-LOX and 5-LOX have procarcinogenic role. We have previously reported the elevated level of serum 12-LOX in breast cancer patients. This study evaluated the serum level of 5-LOX in breast cancer patients and its in vitro inhibition assessment with peptide inhibitor YWCS. The level of 5-LOX was determined by surface plasmon resonance (SPR). The peptide inhibitor of 5-LOX was designed by molecular modeling and kinetic assay was performed by spectrophotometry. The siRNA mediated 5-LOX gene silencing was performed to investigate the effect on proliferation of MDA-MB-231, breast cancer cell line. The serum 5-LOX level in breast cancer (5.69±1.97ng/µl) was almost 2-fold elevated compared to control (3.53±1.0ng/µl) (P < 0.0001). The peptide YWCS had shown competitive inhibitory effects with IC50, 2.2 µM and dissociation constant (K D), 4.92×10(-8) M. The siRNA mediated knockdown of 5-LOX, resulted in the decreased gene expression for 5-LOX and increased cell death in MDA-MB-231 cell line and thereby play a key role in reducing tumor proliferation. Thus, it can be concluded that 5-LOX is one of the potential serum protein marker for breast cancer and a promising therapeutic target for the same.


Assuntos
Araquidonato 5-Lipoxigenase/sangue , Biomarcadores Tumorais/sangue , Neoplasias da Mama/enzimologia , Adulto , Araquidonato 5-Lipoxigenase/fisiologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Inibidores de Lipoxigenase/farmacologia , Inibidores de Lipoxigenase/uso terapêutico , Pessoa de Meia-Idade , Simulação de Acoplamento Molecular , Espectrofotometria
11.
Biochem Biophys Res Commun ; 467(2): 248-53, 2015 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-26435503

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is the major health concern in Indian population. Despite of advanced treatment the mortality rate for this disease has not been improved very much. Current research focused on development of protein marker for the diagnosis and prognosis of HNSCC. The case control study was performed with 125 HNSCC patients and 104 control cases. The level of p50 and IκBα proteins in serum were evaluated at pre and post therapy by label free real time surface plasmon resonance (SPR) and western blot analysis. The serum p50 concentration were significantly (P < 0.0001) higher at the time of diagnosis i.e. pre therapy (Mean ± SD = 27.06 ± 4.88 ng/µl) as compared to controls (Mean ± SD = 16.96 ± 4.04 ng/µl) while it decline at post therapy (Mean ± SD = 21.01 ± 4.98 ng/µl). Similarly, the concentration of IκBα protein in serum were slightly higher at pre therapy (Mean ± SD = 8.33 ± 1.85 ng/µl) as compared to controls (Mean ± SD = 7.27 ± 1.84 ng/µl) and declined at post therapy (Mean ± SD = 7.09 ± 1.24 ng/µl). The level of p50 was also high at the early stage of the disease. The specificity and sensitivity of p50 proteins obtained from ROC analysis revealed the potentiality to be diagnostic protein marker for HNSCC for its accuracy in the study cohort.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/diagnóstico , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/diagnóstico , Subunidade p50 de NF-kappa B/sangue , Adulto , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Diagnóstico Precoce , Feminino , Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Proteínas I-kappa B/sangue , Proteínas I-kappa B/genética , Masculino , Pessoa de Meia-Idade , Inibidor de NF-kappaB alfa , Subunidade p50 de NF-kappa B/genética , Gradação de Tumores , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Curva ROC , Carcinoma de Células Escamosas de Cabeça e Pescoço
12.
Biochemistry ; 53(1): 115-26, 2014 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-24328140

RESUMO

Hypoxic respiratory diseases or hypoxia exposures are frequently accompanied by glucose intolerance and impaired nitric oxide (NO) availability. However, the molecular mechanism responsible for impaired NO production and insulin resistance (IR) during hypoxia remains obscure. In this study, we investigated the possible mechanism of impaired NO production and IR during hypoxia in a mouse model. Mice were exposed to hypoxia for different periods of time (0-24 h), and parameters of IR and endothelial dysfunctions were analyzed. Exposure to hypoxia resulted in a time-dependent increase in IR as well as multimeric forms of von Willebrand factor (vWF) and subsequently a decrease in eNOS activity. Preincubation with plasma of hypoxia-exposed animals (different time points) or human vWF inhibited insulin-induced NO production in a dose-dependent manner; larger doses of insulin reversed the effect. In contrast, preincubation of vWF-immunodepleted plasma failed to inhibit insulin-induced NO production, whereas vWF immunoneutralization abolished the effect of hypoxia-induced IR and D-[U-(14)C]glucose uptake. Furthermore, the interactions between vWF and eNOS were studied by far-Western blotting, co-immunoprecipitation, and surface plasma resonance spectroscopy. Kinetic analyses showed that the dissociation constant (KD), inhibitory constant (Ki), and half-maximal inhibitory concentration (IC50) were 1.79 × 10(-8) M, 250 pM, and 18.31 pM, respectively, suggesting that vWF binds to eNOS with a high affinity and greater efficacy for activator (insulin) inhibition. These results indicated that vWF, an antagonist of eNOS, inhibits insulin-induced NO production and causes IR.


Assuntos
Hipóxia/fisiopatologia , Resistência à Insulina/fisiologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Fator de von Willebrand/fisiologia , Animais , Eritrócitos/metabolismo , Glucose/metabolismo , Humanos , Concentração Inibidora 50 , Insulina/farmacologia , Cinética , Camundongos
13.
Biochim Biophys Acta ; 1828(2): 677-86, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23026014

RESUMO

Lactoferrin (LF) is believed to contribute to the host's defense against microbial infections. This work focuses on the antibacterial and antifungal activities of a designed peptide, L10 (WFRKQLKW) by modifying the first eight N-terminal residues of bovine LF by selective homologous substitution of amino acids on the basis of hydrophobicity, L10 has shown potent antibacterial and antifungal properties against clinically isolated extended spectrum beta lactamases (ESBL), producing gram-negative bacteria as well as Candida strains with minimal inhibitory concentrations (MIC) ranging from 1 to 8 µg/mL and 6.5 µg/mL, respectively. The peptide was found to be least hemolytic at a concentration of 800 µg/mL. Interaction with lipopolysaccharide (LPS) and lipid A (LA) suggests that the peptide targets the membrane of gram-negative bacteria. The membrane interactive nature of the peptide, both antibacterial and antifungal, was further confirmed by visual observations employing electron microscopy. Further analyses, by means of propidium iodide based flow cytometry, also supported the membrane permeabilization of Candida cells. The peptide was also found to possess anti-inflammatory properties, by virtue of its ability to inhibit cyclooxygenase-2 (COX-2). L10 therefore emerges as a potential therapeutic remedial solution for infections caused by ESBL positive, gram-negative bacteria and multidrug-resistant (MDR) fungal strains, on account of its multifunctional activities. This study may open up new approach to develop and design novel antimicrobials.


Assuntos
Antifúngicos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Candida/efeitos dos fármacos , Lactoferrina/química , Animais , Candida/metabolismo , Bovinos , Cromatografia Líquida de Alta Pressão/métodos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/microbiologia , Hemólise , Humanos , Cinética , Lipopolissacarídeos/química , Testes de Sensibilidade Microbiana , Microscopia Eletrônica/métodos , Peptídeos/química , Estrutura Terciária de Proteína , Ressonância de Plasmônio de Superfície , Fatores de Tempo , beta-Lactamases/metabolismo
14.
Biochim Biophys Acta ; 1830(3): 2763-9, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23238519

RESUMO

BACKGROUND: The p38alpha MAP kinase pathway is involved in inflammation, cell differentiation, growth, apoptosis and production of pro-inflammatory cytokines TNF-alpha and IL-1beta. The overproduction of these cytokines plays an important role in cancer. The aim of this work was to design a peptide inhibitor on the basis of structural information of the active site of p38alpha. METHODS: A tetrapeptide, VWCS as p38alpha inhibitor was designed on the basis of structural information of the ATP binding site by molecular modeling. The inhibition study of peptide with p38alpha was performed by ELISA, binding study by Surface Plasmon Resonance and anti-proliferative assays by MTT and flow cytometry. RESULTS: The percentage inhibition of designed VWCS against pure p38alpha protein and serum of HNSCC patients was 70.30 and 71.5%, respectively. The biochemical assay demonstrated the K(D) and IC50 of the selective peptide as 7.22 x 10(-9) M and 20.08 nM, respectively. The VWCS as inhibitor significantly reduced viability of oral cancer KB cell line with an IC50 value of 10 microM and induced apoptosis by activating Caspase 3 and 7. CONCLUSIONS: VWCS efficiently interacted at the ATP binding pocket of p38alpha with high potency and can be used as a potent inhibitor in case of HNSCC. GENERAL SIGNIFICANCE: VWCS can act as an anticancer agent as it potentially inhibits the cell growth and induces apoptosis in oral cancer cell-line in a dose as well as time dependent manner. Hence, p38alpha MAP kinase inhibitor can be a potential therapeutic agent for human oral cancer.


Assuntos
Antineoplásicos/química , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Proteína Quinase 14 Ativada por Mitógeno/química , Proteínas de Neoplasias/química , Oligopeptídeos/química , Trifosfato de Adenosina/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Caspases/genética , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaio de Imunoadsorção Enzimática , Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/enzimologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Concentração Inibidora 50 , Cinética , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/genética , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Oligopeptídeos/síntese química , Oligopeptídeos/farmacologia , Ligação Proteica , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço
15.
Mol Biol Rep ; 41(12): 8255-60, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25218842

RESUMO

5-Lipoxygenase (5-LO) is one of the members of Lipoxygenase family. It breaks down arachidonic acid to pro-inflammatory compounds like leukotrienes. Leukotriene plays a major role in the inflammatory process. In this study, while cloning full length 5-LO, a novel splice variant of 5-LO (t5-LO) was found to be expressed in HepG2 cell line. The complete ORF of t5-LO is 420 bp long, expressing 139 amino acid long proteins from N-terminal. The splice variant of 5-LO was cloned, expressed, purified in bacterial system and characterized by MS/MS and western blot experiments. The full length 5-LO is 674 amino acids long encoded by 2,025 bp long ORF. RT-PCR and western blot revealed that t5-LO is extensively expressed in HepG2 cell line.


Assuntos
Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/metabolismo , Sítios de Splice de RNA/genética , Processamento Alternativo , Araquidonato 5-Lipoxigenase/química , Domínio Catalítico , Linhagem Celular , Clonagem Molecular , Células HL-60 , Células Hep G2 , Humanos , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
16.
J Alzheimers Dis ; 98(2): 699-713, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38427490

RESUMO

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease and symptoms develop gradually over many years. The current direction for medication development in AD is focused on neuro-inflammation and oxidative stress. Amyloid-ß (Aß) deposition activates microglia leading to neuro-inflammation and neurodegeneration induced by activation of COX-2 via NFκB p50 in glioblastoma cells. Objective: The study aimed to evaluate the concentration of COX-2 and NFκB p50 in serum of AD, mild cognitive impairment (MCI), and geriatric control (GC) and to establish a blood-based biomarker for early diagnosis and its therapeutic implications. Methods: Proteins and their mRNA level in blood of study groups were measured by surface plasmon resonance (SPR) and quantitative polymerase chain reaction (qPCR), respectively. The level of protein was further validated by western blot. The binding study of designed peptide against COX-2 by molecular docking was verified by SPR. The rescue of neurotoxicity by peptide was also checked by MTT assay on SH-SY5Y cells (neuroblastoma cell line). Results: Proteins and mRNA were highly expressed in AD and MCI compared to GC. However, COX-2 decreases with disease duration. The peptide showed binding affinity with COX-2 with low dissociation constant in SPR and rescued the neurotoxicity of SH-SY5Y cells by decreasing the level of Aß, tau, and pTau proteins. Conclusions: It can be concluded that COX-2 protein can serve as a potential blood-based biomarker for early detection and can be a good platform for therapeutic intervention for AD.


Assuntos
Doença de Alzheimer , Neuroblastoma , Doenças Neurodegenerativas , Humanos , Idoso , Doença de Alzheimer/genética , Ciclo-Oxigenase 2 , Simulação de Acoplamento Molecular , Peptídeos beta-Amiloides/metabolismo , Inflamação/metabolismo , Biomarcadores , Diagnóstico Precoce , RNA Mensageiro , Proteínas tau/metabolismo , Fragmentos de Peptídeos/uso terapêutico
17.
Pancreas ; 53(7): e595-e602, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38696350

RESUMO

OBJECTIVE: This study primarily aimed to assess the expression of MUC4 in patients with pancreatic ductal adenocarcinoma (PDAC) as compared with controls and assess its clinical relevance. MATERIALS AND METHODS: Serum MUC4 levels and MUC4 gene expression in snap-frozen tissue were analyzed through surface plasmon resonance and quantitative polymerase chain reaction, respectively. Tumor tissues and control tissues were analyzed for MUC4 and other mucins through immunohistochemistry. RESULT: MUC4 expression in tumor tissue was found to be significantly elevated in PDAC patients as compared with chronic pancreatitis tissues and normal pancreatic tissues. Periampullary carcinoma and cholangiocarcinoma tissue also showed increased expression of MUC4 and other mucins. CONCLUSIONS: Differential expression of MUC4 in pancreatic tumor tissues can help to differentiate PDAC from benign conditions.


Assuntos
Carcinoma Ductal Pancreático , Colangiocarcinoma , Imuno-Histoquímica , Mucina-4 , Neoplasias Pancreáticas , Humanos , Mucina-4/metabolismo , Mucina-4/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/sangue , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/diagnóstico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/sangue , Adulto , Pancreatite Crônica/metabolismo , Pancreatite Crônica/genética , Pancreatite Crônica/diagnóstico , Pancreatite Crônica/sangue , Estudos de Casos e Controles , Ampola Hepatopancreática/metabolismo , Ampola Hepatopancreática/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias do Ducto Colédoco/metabolismo , Neoplasias do Ducto Colédoco/genética , Neoplasias do Ducto Colédoco/diagnóstico , Neoplasias do Ducto Colédoco/patologia , Relevância Clínica
18.
BMJ Glob Health ; 9(1)2024 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-38286516

RESUMO

INTRODUCTION: The COVID-19 pandemic had large impacts on mental health; however, most existing evidence is focused on the initial lockdown period and high-income contexts. By assessing trajectories of mental health symptoms in India over 2 years, we aim to understand the effect of later time periods and pandemic characteristics on mental health in a lower-middle income context. METHODS: We used data from the Real-Time Insights of COVID-19 in India cohort study (N=3709). We used covariate-adjusted linear regression models with generalised estimating equations to assess associations between mental health (Patient Health Questionnaire (PHQ-4) score; range 0-12) and pandemic periods as well as pandemic characteristics (COVID-19 cases and deaths, government stringency, self-reported financial impact, COVID-19 infection in the household) and explored effect modification by age, gender and rural/urban residence. RESULTS: Mental health symptoms dropped immediately following the lockdown period but rose again during the delta and omicron waves. Associations between mental health and later pandemic stages were stronger for adults 45 years of age and older (p<0.001). PHQ-4 scores were significantly associated with all pandemic characteristics considered, including estimated COVID-19 deaths (PHQ-4 difference of 0.10 units; 95% CI 0.06 to 0.13), government stringency index (0.14 units; 95% CI 0.11 to 0.18), self-reported major financial impacts (1.20 units; 95% CI 1.09 to 1.32) and COVID-19 infection in the household (0.36 units; 95% CI 0.23 to 0.50). CONCLUSION: While the lockdown period and associated financial stress had the largest mental health impacts on Indian adults, the effects of the pandemic on mental health persisted over time, especially among middle-aged and older adults. Results highlight the importance of investments in mental health supports and services to address the consequences of cyclical waves of infections and disease burden due to COVID-19 or other emerging pandemics.


Assuntos
COVID-19 , Saúde Mental , Pessoa de Meia-Idade , Humanos , Idoso , Pandemias , Estudos de Coortes , COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Índia/epidemiologia
19.
Biomol Biomed ; 2024 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-39284282

RESUMO

The progression of gallbladder inflammatory lesions to invasive cancer remains poorly understood, necessitating research on biomarkers involved in this transition. This study aims to identify and validate proteins associated with this progression, offering insights into potential diagnostic biomarkers for gallbladder cancer (GBC). Label-free liquid chromatography assisted tandem mass spectrometry (LC-MS/MS) proteomics was performed on samples from 10 cases each of GBC and inflammatory lesions, with technical duplicates. Validation was conducted through the enzyme-linked immunosorbent assay (ELISA) using 80 samples (40 GBC and 40 inflammatory lesions). Bioinformatics tools analyzed protein-protein interaction (PPI) networks and pathways. Statistical correlations with clinicopathological variables were assessed. Prognostic evaluation utilized Kaplan-Meier survival analysis and Cox regression analyses. mRNA expressions were studied using real time-polymerase chain reaction (RT-PCR). Out of 5,714 proteins analyzed, 621 were differentially expressed. Three upregulated (the S100 calcium-binding protein P [S100P], polymeric immunoglobulin receptor [PIGR], and complement C1q-binding protein [C1QBP]) and two downregulated (transgelin [TAGLN] and calponin 1 [CNN1]) proteins showed significant expression. Pathway analysis implicated involvement of proteoglycans in cancer and glycosaminoglycan metabolism. Significant correlations were observed between protein concentrations and clinicopathological variables. Prognostic factors such as tumor size, lymph node metastasis, and preoperative bilirubin levels were associated with overall survival. Protein-based assays demonstrated higher resolution compared to mRNA analysis, suggesting their utility in GBC risk stratification. S100P, PIGR, C1QBP, TAGLN, and CNN1 emerge as potential protein-based biomarkers involved in the progression from gallbladder inflammatory lesions to invasive cancer. These findings hold promise for improved diagnostic and prognostic strategies in GBC management.

20.
Res Sq ; 2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-39149469

RESUMO

The prevalence of dementia among South Asians across India is approximately 7.4% in those 60 years and older, yet little is known about genetic risk factors for dementia in this population. Most known risk loci for Alzheimer's disease (AD) have been identified from studies conducted in European Ancestry (EA) but are unknown in South Asians. Using whole-genome sequence data from 2680 participants from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study of India (LASI-DAD), we performed a gene-based analysis of 84 genes previously associated with AD in EA. We investigated associations with the Hindi Mental State Examination (HMSE) score and factor scores for general cognitive function and five cognitive domains. For each gene, we examined missense/loss-of-function (LoF) variants and brain-specific promoter/enhancer variants, separately, both with and without incorporating additional annotation weights (e.g., deleteriousness, conservation scores) using the variant-Set Test for Association using Annotation infoRmation (STAAR). In the missense/LoF analysis without annotation weights and controlling for age, sex, state/territory, and genetic ancestry, three genes had an association with at least one measure of cognitive function (FDR q<0.1). APOE was associated with four measures of cognitive function, PICALM was associated with HMSE score, and TSPOAP1 was associated with executive function. The most strongly associated variants in each gene were rs429358 (APOE ε4), rs779406084 (PICALM), and rs9913145 (TSPOAP1). rs779406084 is a rare missense mutation that is more prevalent in LASI-DAD than in EA (minor allele frequency=0.075% vs. 0.0015%); the other two are common variants. No genes in the brain-specific promoter/enhancer analysis met criteria for significance. Results with and without annotation weights were similar. Missense/LoF variants in some genes previously associated with AD in EA are associated with measures of cognitive function in South Asians from India. Analyzing genome sequence data allows identification of potential novel causal variants enriched in South Asians.

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