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1.
J Pak Med Assoc ; 73(1): 28-32, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36842002

RESUMO

Objective: To assess the perceptions of 2nd year medical students regarding certain approaches introduced in the course of Nutrition and Metabolism module. METHODS: The descriptive study was conducted at the Shifa College of Medicine, Islamabad, Pakistan, in December 2020, and comprised all 2nd year medical students who completed the Nutrition and Metabolism module in which new components had been added, including introduction to community nutrition, school visits, Islamic perspective of nutrition, journal club and e-posters. Data was collected using a questionnaire based on the modified Dundee Ready Education Environment Measure, and had 5 categories with a total of 25 questions that were scored on a 5-point Likert scale. Data was analysed using SPSS 22. RESULTS: Of the 100 students, 65(65%) were females and 35(35%) were males. The overall mean age was 20.5 ± 0.5 years. The total mean score was 74.68±2.53. Mean score for student's perception of learning was 38.17±0.17, student's perception of teachers 9.27±0.18, student's academic self-perceptions 12.1±0.11, student's perceptions of atmosphere 9.03±0.03 and student's social self-perceptions 6.11± 0.01. Conclusion: The perceptions medical students about innovations were positive, showing an encouraging attitude in terms of learning approach and outcome.


Assuntos
Educação de Graduação em Medicina , Estudantes de Medicina , Masculino , Feminino , Humanos , Adulto Jovem , Adulto , Estudos Transversais , Aprendizagem , Percepção Social , Inquéritos e Questionários
2.
Proteins ; 90(4): 993-1004, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34881468

RESUMO

Tribbles pseudokinases, Tribbles homolog 1 (TRIB1), Tribbles homolog 2 (TRIB2), and Tribbles homolog 3 (TRIB3), bind to constitutive photomorphogenesis protein 1 (COP1) E3 ligase to mediate the regulation of ß-catenin expression. The interaction mechanism between COP1 E3 ligase and ß-catenin has not been addressed to date. Based on the functional presence of TRIBs in wingless-related integration site (WNT) signaling, we analyzed their interaction patterns with ß-catenin and COP1. Here, through in silico approaches, we ascribe the COP1 binding pattern against TRIBs and ß-catenin. TRIB1 (355-DQIVPEY-361), TRIB2 (326-DQLVPDV-332), and TRIB3 (333-AQVVPDG-339) peptides revealed a shallow binding pocket at the COP1 interface to accommodate the V-P sequence motif. Reinvigoration of the comparative binding pattern and subtle structural analysis via docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area, topological, and tunnel analysis revealed that both ß-catenin phosphodegron (DSGXXS) and TRIB (D/E/AQXVPD/E) motifs occupied a common COP1 binding site. Current study suggests a structural paradigm of TRIB homologs bearing a conserved motif that may compete with ß-catenin phosphodegron signature for binding to WD40 domain of COP1. Thorough understanding of the structural basis for TRIB-mediated regulation of WNT/ß-catenin signaling may help in devising more promising therapeutic strategy for liver and colorectal cancers.


Assuntos
Ubiquitina-Proteína Ligases , beta Catenina , Sítios de Ligação , Simulação de Dinâmica Molecular , Transdução de Sinais , Ubiquitina-Proteína Ligases/química , beta Catenina/genética , beta Catenina/metabolismo
3.
Toxicol Appl Pharmacol ; 446: 116055, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35550883

RESUMO

Peroxisome proliferator-activated receptor-gamma (PPARγ) has been shown to have therapeutic promise in the treatment of ischemic stroke and is supported by several studies. To identify possible PPARγ activators, the current study used an in silico technique in conjunction with molecular simulations and in vivo validation. FDA-approved drugs were evaluated using molecular docking to determine their affinity for PPARγ. The findings of molecular simulations support the repurposing of rabeprazole and ethambutol for the treatment of ischemic stroke. Adult Sprague Dawley rats were subjected to transient middle cerebral artery occlusion (t-MCAO). Five groups were made as a sham-operated, t-MCAO group, rabeprazole +t-MCAO, ethambutol +t-MCAO, and pioglitazone +t-MCAO. The neuroprotective effects of these drugs were evaluated using the neurological deficit score and the infarct area. The inflammatory mediators and signaling transduction proteins were quantified using Western blotting, ELISA, and immunohistochemistry. The repurposed drugs mitigated cerebral ischemic injury by PPARγ mediated downregulation of nods like receptor protein 3 inflammasomes (NLRP3), tumor necrosis factor-alpha (TNF-α), cyclooxygenase 2 (COX-2), nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-kB), and c-Jun N-terminal kinase (p-JNK). Our data demonstrated that rabeprazole and ethambutol have neuroprotective potential via modulating the cytoprotective stress response, increasing cellular survival, and balancing homeostatic processes, and so may be suitable for future research in stroke therapy.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Animais , Encéfalo , Isquemia Encefálica/metabolismo , Etambutol/farmacologia , Etambutol/uso terapêutico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Simulação de Acoplamento Molecular , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , PPAR gama/metabolismo , Rabeprazol/farmacologia , Rabeprazol/uso terapêutico , Ratos , Ratos Sprague-Dawley
4.
Arch Biochem Biophys ; 719: 109171, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35248545

RESUMO

Cardiac hypertrophy results in the higher rate of heart failures among aged groups. Klotho is an anti-aging protein that is involved in the regulation of VEGF-mediated Ca2+ entry by direct interaction with Vascular endothelial growth factor receptor 2 (VEGFR2) and transient receptor potential canonical Ca2+ channel 1 (TRPC1). Here, in this study, through in silico analysis, we modeled TRPC1 3-dimensional structure and followed by its optimization, characterized the interaction pattern of TRPC1, Klotho and VEGFR2. Subsequent molecular dynamics (MD) simulation analysis revealed that Klotho-specific (P520-N630) region exhibited interaction with VEGFR2, while its C-terminal region (I822-A931) demonstrated binding to the 3rd extracellular loop of TRPC1 that is adjacent to pore region. Through TRPC1 homotetramer formation, the residues in the periphery of pore region were carefully evaluated. In order to scrutinize known Ca2+ channel blockers for their ability to bind at the pore region of TRPC1, 31 known compounds were tested through docking runs and three hits, named as diltiazem impurity B (b3), diltiazem (b5) and felodipine (b6) were selected for detailed binding analysis through MD runs. Evidently, inhibitor-bound TRPC1 pore area was more constricted (8.6 Å2, 25.1 Å2 and 18.8 Å2, respectively) than apo-TRPC1 (60 Å2). These findings suggest that Ca+2 channel blockers may serve as promising agents to impair the TRPC1 functional store-operated calcium channel (SOCC) activity in the old patients lacking Klotho expression. Thus, pore region of homotetrameric TRPC1 may be blocked via repurposing of known Ca+2 blockers to antagonize TRPC signaling for the treatment of cardiac hypertrophy.


Assuntos
Bloqueadores dos Canais de Cálcio , Canais de Cátion TRPC , Idoso , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Sinalização do Cálcio , Cardiomegalia/tratamento farmacológico , Diltiazem , Humanos , Canais de Cátion TRPC/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
5.
Pak J Med Sci ; 37(5): 1451-1455, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34475929

RESUMO

OBJECTIVES: To determine the effectiveness of mechanical traction in supine versus prone lying position for lumbosacral radiculopathy. METHODS: A quasi experimental trial was conducted from April to September 2020 among sixty patients of chronic lumbosacral radiculopathy at Ibn e Siena Hospital, Multan. Participants were divided into two groups. Group-A (Supine) participants received lumbar traction in supine lying along with conventional treatment. Group-B (Prone) underwent the same treatment except the lumbar traction being applied in prone lying position. Participants were evaluated twice: at pre- treatment (week 0) and at the post treatment (week 2). Oswestry Disability Index and Numeric Pain Rating Scale were used as outcome measure. Data was analyzed on SPSS 23. RESULTS: The mean (±S.D) age of the patients was 39±5.7 vs. 40±5.3 years in supine vs. prone group respectively. Mean ODI score was 25.2±6.13 vs. 26.0±6.26 at the start of treatment in supine vs. prone position respectively while it was 19.45±7.12 vs. 11.05±4.40 at end of treatment in supine vs. prone position respectively. Mean NPRS score was 7.73±1.23 vs. 7.67±0.96 at start of treatment in supine vs. prone position respectively while it was 4.63±0.89 vs. 3.13±0.90 at the end of treatment in supine vs. prone position respectively. CONCLUSION: Lumbar traction in prone lying position is more effective than lumbar traction in supine lying position for the treatment of chronic lumbosacral radiculopathy.

6.
Pak J Med Sci ; 37(2): 489-493, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679937

RESUMO

OBJECTIVE: To find out inter-professional collaboration among speech-language pathologists and nurses in acute care in Pakistan. METHODS: This was a cross sectional study which was conducted in all government and private hospitals of Islamabad and Rawalpindi having facility of ICUs after taking consent from authorities. The duration of study was six months from October 2018 to February 2019. A total number of 350 participants (200 nurses, 150 speech language pathologists) working in ICU of different private and government hospitals of Pakistan were included in the study. Standardized questionnaire of ": assessment of inter-professioal collaboration scale": (AITCS) was circulated to nurses and speech language pathologists (SLPS) working in ICU with its subscale's partnership, coordination, cooperation and shared decision making on a 5-point likert scale. Data was analyzed using SPSS version 21.Measure of mean was obtained by independent sample t-test. P- Value less than 0.05 was considered as significant. RESULTS: Statistical analysis showed measures of mean differences obtained by t-test revealed significant differences at p<0.001 level between partnership scores of SLPS and nurses. This reveals good partnership between two disciplines. Measures of mean differences obtained by t-test revealed significant differences at p<0.001 level between partnership scores of SLPS and nurses. Both do not value each other in cooperation. Measures of mean differences obtained by t-test showed significant differences at p<0.001 level amongst coordination scores of SLPS and nurses. Both have good coordination. Measures of mean differences obtained by t-test revealed significant differences at p<0.001 level amongst shared decision-making scores of SLPS and nurses. Both are involved in shared decision making. CONCLUSION: Results show significant difference in partnership, coordination, and shared decision making. There is no significant difference in cooperation.

7.
Pak J Med Sci ; 37(4): 1185-1189, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34290805

RESUMO

OBJECTIVES: To determine the Prevalence and associated risk factors among patients with overactive bladder syndrome in Pakistan. METHODS: This was a community-based, face to face, cross sectional survey to calculate the prevalence and its associated risk factors. A sample of 1058 patients, women and men aged between 35 to 60 years having symptoms of overactive bladder was selected through convenience sampling from different cities of Pakistan during September to December 2020. Data was collected by using an Overactive Bladder Scoring System (OABSS) tool for prevalence and a developed questionnaire to rule out the risk factors. RESULTS: The prevalence was 27.4% (n=289) and it increased with age. The average ages for women and men were 44.60±7.88 and 46.14±7.69 years respectively. The OAB prevalence was the lowest among the participants aged 35-43 years 15.2% (n=55) while it was highest among those who were aged 53-60 years 49.6%, (n=127). The age, body mass index, diabetes mellitus, income, family history, parity and urinary tract infection were found to be significant associated risk factors for overactive bladder with p value <0.05. CONCLUSION: The overall prevalence of overactive bladder was 27.4% and it does not differ by gender, hypertension, pelvic surgery, smoking, constipation and sleep while it has significant association with age, body mass index, diabetes mellitus, income, parity and urinary tract infections.

8.
J Chem Inf Model ; 60(3): 1892-1909, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-32031799

RESUMO

Myocyte enhancer factor 2 (MEF2; MEF2A-MEF2D) transcription factors regulate gene expression in a variety of developmental processes by binding to AT-rich DNA motifs via highly conserved N-terminal extensions known as MADS-box and MEF2 domains. Despite the fact that MEF2 proteins exhibit high similarity at their N-terminal regions and share a common consensus DNA binding motif, their functional preferences may vary significantly in the adjacent regions to the DNA binding core segment. The current study delineates the conformational paradigm, clustered recognition, and comparative DNA binding preferences for MEF2A and MEF2B-specific MADS-box/MEF2 domains at the YTA(A/T)4TAR consensus motif. In both MEF2A and MEF2B proteins, α1-helix plays a crucial role through acquiring more flexibility by attaining loop conformation. In comparison to apo-MEF2, an outward disposition of the distal portion of α1-helix and movement of its proximal part to ß1 allows synergistic repositioning of the α1-α2 linker, C-terminal region, and MEF2 domain, resulting in the formation of a hydrophobic groove for DNA binding. In both instances, conformational switching of the helical content is the main contributing factor while preserving the overall ß-topology to maintain the inside-out conformation of subdivided α1-helix flip. Multivariate statistical analysis reveals that MEF2B obscures less accessible conformational space for DNA binding as compared to the MEF2A-DNA complex. The presence of similar structural requirements and conserved residues including Arg10, Phe21, and Arg24 in accentuating the MEF2-specific DNA recognition mechanism led us to perform structure-based virtual screening for isolating novel inhibitors that are able to target MEF2-DNA binding regions. The top hits (acetamide, benzamide, carboxamide, and enamide) obtained through preliminary assay were scrutinized to binding potential analysis at the MEF2-DNA binding groove, energy values, absorption, distribution, toxicity, and Lipinski's rule of five assessments. Based on these findings, we propose valuable active drug-like molecules for selective applications against MEF2A and MEF2B. The current study may help in uncovering the atomistic-level mechanistic DNA binding patterns of MEF2 proteins, and data may be valuable in devising effective therapeutic strategies for MEF2-associated disorders.


Assuntos
DNA , Sequência de Aminoácidos , Simulação por Computador , DNA/metabolismo , Fatores de Transcrição MEF2 , Ligação Proteica
9.
Mol Biol Rep ; 47(1): 683-692, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31701475

RESUMO

This study aimed to investigate the role of MLH1 polymorphisms, respective protein structure prediction, survival analysis, related clinicopathological details and MLH1 expression in breast cancer (BC). Genotyping of selected SNPs in BC patients (493) and age matched controls (387) were performed by Tetra-ARMS PCR. Gene expression among breast tumors (127) and adjacent control tissues were analysed using reverse transcriptase PCR (RT-PCR) and immunohistochemistry. Statistical analysis was performed by SPSS and MedCalc. Conditional logistic regression analysis was applied to compute the odds ratio and confidence interval. Phyre2 and I-TASSER were used to generate MLH1 protein structures and verified by a variety of computational tools. Genotyping illustrated that MLH1 polymorphisms (rs63749795 and rs63749820) were significantly associated (P ≤ 0.05) with risk of developing BC. Down regulation of MLH1 gene expression/loss of the MLH1 protein (OR 12; CI 2.8-53.1) was observed in BC cases, illustrating its potential role in disease development. Moreover, loss of the MLH1 protein was found to be associated with higher grade cancer (P = 0.02) and lymph node positivity (P = 0.03), highlighting its essential role, as a component of the mismatch repair (MMR) machinery. Bioinformatics analysis confirmed that nonsense mutations produce a truncated MLH1 protein, causing a reduction in MMR efficiency. No association between MLH1 polymorphisms and overall and progression free survival statistics was observed among BC cases, possibly due to short follow-up study. Results at DNA, RNA and protein levels, along with in silico analysis, highlights the potential role of MLH1 in DNA repair mechanisms, within BC. Therefore, it was concluded that MLH1 may contribute towards BC development and progression.


Assuntos
Neoplasias da Mama , Proteína 1 Homóloga a MutL , Adulto , Mama/química , Neoplasias da Mama/química , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Análise Mutacional de DNA , Regulação para Baixo/genética , Feminino , Humanos , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/análise , Proteína 1 Homóloga a MutL/química , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Polimorfismo de Nucleotídeo Único/genética
10.
Arch Biochem Biophys ; 671: 87-102, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31247164

RESUMO

Sortases (Srts) are transpeptidase enzymes that anchor plethora of surface proteins with LPXTG and NPQTN motifs to the cell wall of Gram-positive bacteria, and they are potential targets for the development of anti-infective agents. Despite the existence of numerous inhibitors for Staphylococcus aureus SrtA (SaSrtA), only two inhibitors are known for Staphylococcus aureus SrtB (SaSrtB). Moreover, no study has yet documented the anti-virulence potential of cone snail venom conopeptides against these virulence factors. Here we report M2-conotoxin and contryphan-R as effective inhibitory agents that may competitively block the binding of natural substrates with SaSrtA and SrtB, respectively, via molecular docking and dynamic simulation assays. M2-conotoxin also exhibited strong binding inside the catalytic grooves of distantly related SrtA homologs from Streptococcus mutans (SmSrtA) and Streptococcus agalactiae (SgSrtA). On the other hand, contryphan-R failed to occupy the substrate binding site of closely related Bacillus anthracis SrtB (BaSrtB), but successfully blocked the catalytic site of very divergent C. Perfringens SrtB (CpSrtB). Hence, these naturally existing venom peptides and their mimetics may serve as promising candidates for further development of therapeutically useful anti-infectives for the treatment of infections caused by multi-drug resistant bacterial pathogens having SrtA and SrtB in their enzymatic set.


Assuntos
Aminoaciltransferases/metabolismo , Proteínas de Bactérias/metabolismo , Conotoxinas/metabolismo , Cisteína Endopeptidases/metabolismo , Inibidores Enzimáticos/metabolismo , Peptídeos Cíclicos/metabolismo , Aminoaciltransferases/antagonistas & inibidores , Aminoaciltransferases/química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Domínio Catalítico , Cisteína Endopeptidases/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Staphylococcus aureus/enzimologia
11.
Arch Biochem Biophys ; 651: 34-42, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29856966

RESUMO

Circadian rhythm is rhythmic gene expression that is involved in various processes of life over a day and night cycle. The rhythmic sleep disorders arise due to misalignment of sleep-wake cycle influenced by phosphorylation of PERIOD2 (PER2) phosphodegron (SSGYGS), the conserved interaction site of ß-transducin repeat-containing protein (ßTrCP1). Here, we employed in silico approach to study the interaction pattern of ßTrCP1 with PER2WT, PER2SER480ALA and PER2SER484ALA phosphodegron peptides. Substitution of phosphorylatable SER480 or SER484 into ALA resulted in the shifting of PER2 phosphodegron binding at the lower face of ß-propeller, by involvement of both SER residues. PER2 binding at the shallow cavity of ßTrCP1 induced conformational readjustment in ARG524 residue that connected the upper hemisphere base (10.5 Å) with the roof of lower hemisphere (6.6 Å) to create a uniform tunnel-like structure. In the absence of phosphorylation, PER2 and ßTrCP1 binding stability may be compromised resulting in the enhancement of PER2 level in the cytoplasm that may disrupt circadian clock and aging. Taken together, this study will help in understanding the structural basis of conserved phosphoswitch mechanism in the mammalian circadian oscillation.


Assuntos
Proteínas Circadianas Period/metabolismo , Proteínas Contendo Repetições de beta-Transducina/metabolismo , Sequência de Aminoácidos , Ritmo Circadiano , Cristalografia por Raios X , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas Circadianas Period/química , Fosforilação , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Mapas de Interação de Proteínas , Termodinâmica , Proteínas Contendo Repetições de beta-Transducina/química
12.
Environ Monit Assess ; 190(3): 128, 2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29427155

RESUMO

The present study was conducted to investigate the pollutant load in surface water of the Sattukatla drain in Lahore, Pakistan. This drain is receiving high volumes of pollutants from industries and municipal sewage. To study the pollution status of this urban drain, different parameters such as pH, EC, TDS, BOD, NO3, PO4, COD, K, Mg, Ca, Ni, Fe, Co, Pb, Cu, Cd, and Zn were analyzed. These 17 parameters were monitored along the longitudinal gradient of drain consisting of 15 key sampling sites. The studied parameters were subjected to hierarchical cluster analysis (HCA) and factor analysis (FA). The HCA divided 15 sampling sites into three zones, i.e., low pollution, medium pollution, and high pollution. The PCA identified three major contributors, industrial followed by municipal sewage and agricultural sources. The trend of heavy metal levels was observed as Cu > Zn > Fe > Pb > Co > Ni > Cd. The results indicate levels of pollutants above the permissible limits described by NEQS, Pakistan for wastewater. There is an urgent need to address the issue and install treatment plants to reduce the pollution load on this urban drain in Lahore city.


Assuntos
Drenagem Sanitária , Poluentes Químicos da Água/análise , Agricultura , Análise da Demanda Biológica de Oxigênio , Cidades , Análise por Conglomerados , Monitoramento Ambiental/métodos , Monitoramento Ambiental/estatística & dados numéricos , Concentração de Íons de Hidrogênio , Metais/análise , Nitratos/análise , Paquistão , Fosfatos/análise , Águas Residuárias
13.
Pak J Med Sci ; 33(6): 1333-1338, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29492054

RESUMO

OBJECTIVE: To compare the effectiveness of intermittent cervical Traction in sitting vs. supine position for the management of cervical radiculopathy. METHODS: A randomized clinical trial was done to compare pain and disability modification of cervical radiculopathy patients by using cervical traction in sitting and supine positions. Forty patients (males and females aged between 18-60 years with chronic cervical radiculopathy) were recruited for the trial. Participants were randomized into two homogeneous groups by dice method. The Group-A (n=20) received 3-weeks of intermittent cervical traction in sitting position along with Transcutaneous Electric Nerve Stimulation (TENS) and hot pack. The Group-B (n=20) received the same treatment except the intermittent cervical traction that was applied in supine position. Participants were assessed two times: at baseline (week 0) and at the termination of rehabilitation (week 3). Neck disability index was used to collect the data before and after the treatment. RESULTS: The mean age of the patients was 43.15±8.99 vs. 48.80±6.89 years in Group-A vs. Group-B respectively. Mean (±S.D.) weight of the patients was 74.75±12.11 vs. 74.60±11.24 kg in Group-A vs. Group-B respectively. Mean Neck Disability Index score at start of treatment was 30.30±7.46 vs. 30.75±7.85 in Group-A and Group-B respectively. There was a significant difference in Group-A and Group-B regarding aggregate NDI score at the end of treatment (19.45±7.12 vs. 11.05±4.40; p<0.0001). CONCLUSION: Supine position is better choice for applying cervical traction as compared to sitting position for the management of cervical radiculopathy comparing post interventional NDI score.

14.
J Theor Biol ; 388: 72-84, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26493360

RESUMO

Polo like kinase (Plk1) is a master regulator of cell cycle and considered as next generation antimitotic target in human. As Plk1 predominantly expresses in the dividing cells with a much higher expression in cancerous cells, it serves as a discriminative target for cancer therapeutics. Here we implied a novel and promising integrative strategy to identify "bifunctional" Plk1 inhibitors that compete simultaneously with ATP and substrate for their binding sites. We integrated structure-based virtual screening (SBVS) and molecular dynamics simulations with emphasis on unique structural properties of Plk1. Through screening of 20,000 compounds, nearly ~2000 hits were enriched and subjected to SBVS against ATP and substrate binding sites of Plk1. Subsequently, on the basis of their binding abilities to Plk1 kinase and polo box domains, filtration of candidate hits resulted in the isolation of 26 compounds. By exclusion of close analogs or isomers, 10 unique compounds were selected for detailed study. A representative compound was subjected to molecular dynamics simulation assay to have deep structural insights and to gauge critical structural crunch for inhibitor binding against kinase and polo box domains. Our integrative approach may complement high-throughput screening and identify bifunctional Plk1 inhibitors that may contribute in selective targeting of Plk1 to elicit desired biological process.


Assuntos
Proteínas de Ciclo Celular/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/química , Proteínas Proto-Oncogênicas/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Ligação Competitiva , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Humanos , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Especificidade por Substrato , Quinase 1 Polo-Like
15.
Pak J Med Sci ; 32(2): 423-6, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27182253

RESUMO

BACKGROUND & OBJECTIVE: Neck and shoulder are the most susceptible areas for developing musculoskeletal symptoms among computer users. The modifiable risk factors for these work related musculoskeletal disorders include physical office environment and psychosocial work related factors. Computer workstation layout had been shown to be an important physical aspect of work environment that influences the upper quadrant symptoms. Our objective was to find the frequency of neck and shoulder pain and use of adjustable computer workstation among bankers of Islamabad/Rawalpindi/Multan. METHODS: A cross sectional study was conducted and 120 participants were questioned. Purposive sampling technique was used in this study. Maastricht Upper Extremity Questionnaire (MUEQ) was remodeled and important questions were extracted from its detailed version. The tool was then validated by taking expert opinion. Frequencies and percentages were calculated for categorical variables. RESULTS: Pain in the neck during working hours was experienced by 71.67% of the respondents and 48.33% of the participants had experienced shoulder pain during working hours. Adjustable keyboards were used by 16.67% of respondents. Back care material was used by 40% bankers. Adjustable chairs were used by 95.83% of the participants. Only 3% of the bankers did not have chairs with adjustable heights. Chairs with adjustable armrests were used by 25% bankers. CONCLUSION: Neck and shoulder pain are common occurrences among bankers. Most of the components of workstations of bankers were adjustable but some of them still need attention.

16.
Arch Pharm (Weinheim) ; 347(12): 896-907, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25251696

RESUMO

A new series of pregnenonlone analogs were synthesized and evaluated for their inhibitory activity against cytochrome P450 (CYP17 hydroxylase enzyme). In general, the 5-aryl-1,3,4-thiadiazol-2-yl)-imino-pregnenolone derivatives 11-15 were more active than the sulfonate 24-31 and the ester 37-41 analogs. Derivative 12 showed optimal activity in this series, with IC50 values of 2.5 µM compared with the standard abiraterone (IC50 = 0.07 µM). However, the analogs 11 and 25 showed a better selectivity profile (81.5 and 82.7% inhibition of hydroxylase, respectively), which may be a useful lead in CYP17 inhibition studies. Molecular docking studies demonstrated quite similar binding patterns of all new pregnenolone derivatives at the active site of CYP17 through hydrogen bonding and hydrophobic interaction.


Assuntos
Desenho Assistido por Computador , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Desenho de Fármacos , Simulação de Acoplamento Molecular , Pregnenolona/síntese química , Pregnenolona/farmacologia , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Inibidores das Enzimas do Citocromo P-450/metabolismo , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Pregnenolona/análogos & derivados , Pregnenolona/metabolismo , Relação Quantitativa Estrutura-Atividade , Proteínas Recombinantes/metabolismo , Esteroide 17-alfa-Hidroxilase/metabolismo
17.
Chemosphere ; 361: 142438, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38797203

RESUMO

In this research, the interactions of two azo dyes, Methyl Orange (MO) and Eriochrome Black T (EBT), with dissolved organic matter (DOM) in surface water were studied, emphasizing their removal using nano-filtration membranes (NF-270 and NF-90). High-Performance Size Exclusion Chromatography (HPSEC) findings indicated that the dyes' molecular weight in deionized (DI) water ranged from 500 to 15k Dalton (Da), adjusting peak intensities with Jingmi River (JM) water Beijing. Notably, when dyes were diluted in JM water, ultraviolet (UV533 & 466, and UV254), together with total organic carbon (TOC) parameters, revealed color removal rates of 99.49% (EBT), 94.2% (MO), 87.6% DOM removal, and 86% TOC removal for NF-90. The NF-90 membrane demonstrated a 75% flux decline for 50 mL permeate volume due to its finer pore structure and higher rejection effectiveness. In contrast, the NF-270 membrane showed a 60% decline in flux under the same conditions. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) analysis of dye-treated membranes in JM water revealed that the NF-270 showed a CC bond peak at 1660 cm-1 across various samples, while analyzing NF-90, the peaks at 1400 cm-1, 1040 cm-1, 750 cm-1, and 620 cm-1 disappeared for composite sample removal. The hydrophobicity of each membrane is measured by the contact angle (CA), which identified that initial CAs for NF-270 and NF-90 were 460 and 700, respectively, that were rapidly declined but stabilized after a few seconds of processing. Overall, this investigation shows that azo dyes interact with DOM in surface waters and enhance the removal efficiency of NF membranes.


Assuntos
Compostos Azo , Corantes , Filtração , Poluentes Químicos da Água , Purificação da Água , Compostos Azo/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/análise , Corantes/química , Purificação da Água/métodos , Filtração/métodos , Membranas Artificiais , Espectroscopia de Infravermelho com Transformada de Fourier
18.
Chemosphere ; 364: 143221, 2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39233299

RESUMO

Environmental pollution due to plastic waste is a global challenge causing adverse impacts on the ecosystem and public health. Microplastic (MP) originates at the upstream processes such as industrial and household activities; however, their existence is affecting the downstream environment. Even though many governments and non-government organizations have taken technological and regulatory steps, these current efforts and strategies are insufficient to prevent the MP release in the environment. Thus, a multidisciplinary global approach is required, which must prioritize the reducing of plastic inputs to the environment. To regulate MP levels in the environment, worldwide reformative and preventive strategies are required because the issue is not limited to a single nation or region. In relation to marine plastic waste, a number of multilateral agreements and measures exist at global level. Several regulatory measures have been examined by regulatory bodies with the intention of safeguarding the environment from excessive MP contamination. However, neither of the frameworks in place is specifically made to stop the increased MP pollution in the environment. Therefore, this review focused on the preventive measures taken by the government and non-government organizations for MP control through legislations. The study also critically discussed MP-related policies aiming to increase the viability and efficiency of implementing future plastic management. This review is expected to provide the basic guidelines for formulating MP standards in the environment.

19.
Water Res ; 256: 121539, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38583335

RESUMO

Inorganic coagulants such as poly aluminum ferric chloride (Al/Fe) are applied conventionally to sewage sludge dewatering and can be retained in the sludge cake, causing its conductivity to increase and generate secondary pollution. To reduce these disadvantages, there is a need to develop alternative, more sustainable chemicals as substitutes for conventional inorganic coagulants. In the present investigation, the application of a polymeric chitosan quaternary ammonium salt (CQAS) is explored as a complete, or partial, replacement for Al/Fe in the context of sludge dewatering processes. Laboratory experiments using digested sewage sludge showed that CQAS could effectively substitute for over 80 % of the Al/Fe inorganic coagulant in the sludge dewatering process. This substitution resulted in a reduction of sludge cake conductivity by more than 50 %. Simulation of sludge dewatering curves and imaging of the sludge surface indicated that the addition of CQAS led to an increase in nanosized pores, and a decrease in the specific resistance of the sludge filter cake as the dosage of Al/Fe decreased to around 30 %. The variations of fluorescence emission, quantum yield and carboxylic and amino groups, suggested that the chelating of Al/Fe decreased due to the bridging effects of CQAS. The CQAS had different flocculation bridging effects on various EPS fractions, which varied the amount of protein chelated with Al/Fe in each fraction. This study provides new information about the benefits of replacing conventional inorganic coagulants with natural organic polymers for sewage sludge dewatering, in terms of reduced sludge cake conductivity and greater dry solids content.


Assuntos
Quitosana , Compostos Férricos , Esgotos , Esgotos/química , Quitosana/química , Compostos Férricos/química , Compostos de Amônio Quaternário/química , Floculação , Cloretos/química , Eliminação de Resíduos Líquidos/métodos , Alumínio/química
20.
Pak J Med Sci ; 29(6): 1406-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24550963

RESUMO

OBJECTIVE: Mobilization techniques are frequently used by physiotherapists to reduce pain, improve joint movement and facilitate return to activities after injury. The objective of this study was to explore differences in the efficacy of Mobilization Techniques in Post-Traumatic stiff ankle with and without Paraffin Wax Bath. METHODS: Thirty seven patients of Post Traumatic stiff ankle were recruited for the study at Sajid Physiotherapy & Rehabilitation center, Multan from March 2011 to February 2013. It was a randomized controlled trial and the patients with equal grades of severity were placed in control and study groups. Group A had nineteen patients and Group B had 18 patients. The inclusion criteria were age range from 20-60 years, pain, loss of ROM, with history of trauma and fracture of ankle. The patients with similar complaints but with surgical treatment were excluded. Group A was given mobilization techniques with paraffin wax bath while group B was treated without paraffin wax bath. Improvement was observed by EscolaPaulista de Medicina Range of Motion (EPM-ROM) scale and visual analogue scale (VAS). After ten weeks of treatment, the patients were re-evaluated by an orthopedic surgeon and a Physiotherapist for their symptoms and ROM. t-test was applied to compare outcome between two groups and p < 0.05 was considered to be statistically significant. RESULTS: Group A had nineteen patients and Group B had 18 patients and both were treated for ten weeks. There were 12 male and 7 female patients in group A and 10 male and 8 female in group B. At the start of treatment the basic characteristic were similar in both the groups. Deficits in dorsiflexion, planterflexion, inversion, eversion pain and stiffness were measured before and after the treatment period. Pain relief was found better in both groups which were considered statistically significant with p=0.001, group A (1.135 ± 0.359) vs. group B (1.135 ± 0.359). ROM in pre and post treatment degrees showed that dorsiflexion was significantly increased in group A (1.135 ± 0.359) vs. group B (1.135 ± 0.0359).) and planterflexion was in group A (1.337 ± 0.422) vs. group B (0.841 ± 0.264). Functional movement showed improvement in inversion in group A (0.875 ± 0.276) vs. group B (0.966 ± 0.305) and in eversion in group A (0.948 ± 0.300) vs. group B (0.674 ± 0.213). Mobilization Techniques followed by wax bath resulted in significant improvements of range of motion (ROM), clinical and functional changes. Wax bath alone had no significant effect. After ten weeks intervention treatment, t-test was applied to compare outcome between the two groups and p=0.001to 0.004 in group A and p= 0.104 to 0.168 in group B, (p<0.05) was obtained which shows statistical significance. CONCLUSION: Joint mobilization and wax bath therapy is an effective and beneficial tool to improve the symptoms and quality of life in post traumatic stiff ankle patients. Joint mobilization techniques combined with wax bath are more effective in the management of post-traumatic stiff ankle as compared to wax therapy alone.

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