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1.
Network ; : 1-21, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38975754

RESUMO

Cloud computing is an on-demand virtual-based technology to develop, configure, and modify applications online through the internet. It enables the users to handle various operations such as storage, back-up, and recovery of data, data analysis, delivery of software applications, implementation of new services and applications, hosting websites and blogs, and streaming of audio and video files. Thereby, it provides us many benefits although it is backlashed due to problems related to cloud security like data leakage, data loss, cyber attacks, etc. To address the security concerns, researchers have developed a variety of authentication mechanisms. This means that the authentication procedure used in the suggested method is multi-levelled. As a result, a better QKD method is offered to strengthen cloud security against different types of security risks. Key generation for enhanced QKD is based on the ABE public key cryptography approach. Here, an approach named CPABE is used in improved QKD. The Improved QKD scored the reduced KCA attack ratings of 0.3193, this is superior to CMMLA (0.7915), CPABE (0.8916), AES (0.5277), Blowfish (0.6144), and ECC (0.4287), accordingly. Finally, this multi-level authentication using an improved QKD approach is analysed under various measures and validates the enhancement over the state-of-the-art models.

2.
Eur J Pharmacol ; 970: 176484, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38467235

RESUMO

Protein kinases play pivotal roles in various biological functions, influencing cell differentiation, promoting survival, and regulating the cell cycle. The disruption of protein kinase activity is intricately linked to pathways in tumor development. This manuscript explores the transformative impact of protein kinase inhibitors on cancer therapy, particularly their efficacy in cases driven by targeted mutations. Focusing on key tyrosine kinase inhibitors (TKIs) like Bcr-Abl, Epidermal Growth Factor Receptor (EGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR), it targets critical kinase families in cancer progression. Clinical trial details of these TKIs offer insights into their therapeutic potentials. Learning from FDA-approved kinase inhibitors, the review dissects trends in kinase drug development since imatinib's paradigm-shifting approval in 2001. TKIs have evolved into pivotal drugs, extending beyond oncology. Ongoing clinical trials explore novel kinase targets, revealing the vast potential within the human kinome. The manuscript provides a detailed analysis of advancements until 2022, discussing the roles of specific oncogenic protein kinases in cancer development and carcinogenesis. Our exploration on PubMed for relevant and significant TKIs undergoing pre-FDA approval phase III clinical trials enriches the discussion with valuable findings. While kinase inhibitors exhibit lower toxicity than traditional chemotherapy in cancer treatment, challenges like resistance and side effects emphasize the necessity of understanding resistance mechanisms, prompting the development of novel inhibitors like osimertinib targeting specific mutant proteins. The review advocates thorough research on effective combination therapies, highlighting the future development of more selective RTKIs to optimize patient-specific cancer treatment and reduce adverse events.


Assuntos
Neoplasias Pulmonares , Neoplasias , Humanos , Fator A de Crescimento do Endotélio Vascular , Neoplasias/tratamento farmacológico , Neoplasias/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Quinases/metabolismo , Mutação , Neoplasias Pulmonares/tratamento farmacológico
3.
IUBMB Life ; 2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38063433

RESUMO

Diabetes, a chronic metabolic disorder disrupting blood sugar regulation, has emerged as a prominent silent pandemic. Uncontrolled diabetes predisposes an individual to develop fatal complications like cardiovascular disorders, kidney damage, and neuropathies and aggravates the severity of treatable infections. Escalating cases of Type 1 and Type 2 diabetes correlate with a global upswing in diabetes-linked mortality. As a growing global concern with limited preventive interventions, diabetes necessitates extensive research to mitigate its healthcare burden and assist ailing patients. An altered immune system exacerbated by chronic hyperinflammation heightens the susceptibility of diabetic individuals to microbial infections, including notable viruses like SARS-CoV-2, dengue, and influenza. Given such a scenario, we scrutinized the literature and compiled molecular pathways and signaling cascades related to immune compartments in diabetics that escalate the severity associated with the above-mentioned viral infections in them as compared to healthy individuals. The pathogenesis of these viral infections that trigger diabetes compromises both innate and adaptive immune functions and pre-existing diabetes also leads to heightened disease severity. Lastly, this review succinctly outlines available treatments for diabetics, which may hold promise as preventive or supportive measures to effectively combat these viral infections in the former.

4.
Res Sq ; 2023 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-37790487

RESUMO

Background: Postnatal care, crucial for preventing and assessing complications after birth, remains low in India. An interactive mHealth community-based postnatal intervention was implemented to promote healthy maternal behaviors through knowledge and social support in rural Northern India. However, there is limited information on how virtual health interventions in resource-constrained settings are perceived by the users and which elements influence their engagement and sustained participation. Objective: We explored the user perceptions of acceptability and impact of a virtual interactive maternal and child health intervention pilot tested in Punjab State, India, including their perspectives on barriers and facilitators to engage with this intervention. Methods: This qualitative study was embedded within extensive mixed-method research, and oriented by the Realist Evaluation approach. Sixteen participants were recruited from the parent study. They were identified by purposive sampling to cover diverse levels of attendance and engagement with the intervention. In-depth interviews were conducted by phone. Following translation, a framework analysis was completed to search for the main themes. Feedback was requested from intervention moderators during the process to prioritize local interpretation. Results: Study participants reported overall satisfaction with the intervention. The mothers appreciated the educational material provided and the communication with other participants and health professionals. Across context, intervention, and actor domains, the barriers most commented on were network and connectivity challenges, lack of time due to household responsibilities, and feeling uncomfortable sharing personal experiences. Family buy-in and support were fundamental for overcoming the high domestic workload and baby care. Another facilitator mentioned was moderators' guidance on using the different intervention modalities. Regarding perceived impact, participants shared that MeSSSSage increased their capability and motivation to breastfeed, seek care as needed, and use contraception according to their preferences. Finally, participants suggested adding more topics to the educational content and adjusting the dynamics within the group calls to improve the intervention. Conclusions: This study identifies the high acceptability and perceived impact of a novel postnatal care program in a rural setting, including the users' perceived barriers to engaging with the intervention and possible solutions to overcome them. These findings enable refinement of the ongoing intervention, providing a more robust framing for its scalability and long-term sustainability. On a larger scale, conclusions from this research provide new insights and encouragement to global stakeholders who aspire to improve maternal and neonatal outcomes in low-income and middle-income countries through mHealth.

5.
Pol J Radiol ; 88: e445-e454, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37808172

RESUMO

Purpose: To detect tuberculosis (TB) at an early stage by analyzing chest X-ray images using a deep neural network, and to evaluate the efficacy of proposed model by comparing it with existing studies. Material and methods: For the study, an open-source X-ray images were used. Dataset consisted of two types of images, i.e., standard and tuberculosis. Total number of images in the dataset was 4,200, among which, 3,500 were normal chest X-rays, and the remaining 700 X-ray images were of tuberculosis patients. The study proposed and simulated a deep learning prediction model for early TB diagnosis by combining deep features with hand-engineered features. Gabor filter and Canny edge detection method were applied to enhance the performance and reduce computation cost. Results: The proposed model simulated two scenarios: without filter and edge detection techniques and only a pre-trained model with automatic feature extraction, and filter and edge detection techniques. The results achieved from both the models were 95.7% and 97.9%, respectively. Conclusions: The proposed study can assist in the detection if a radiologist is not available. Also, the model was tested with real-time images to examine the efficacy, and was better than other available models.

6.
Medicina (Kaunas) ; 59(10)2023 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-37893466

RESUMO

Background and Objectives: Curcumin, derived from Curcuma longa, is a well-known traditional medicinal compound recognized for its therapeutic attributes. Nevertheless, its efficacy is hampered by limited bioavailability, prompting researchers to explore the application of nanoemulsion as a potential alternative. Materials and Methods: This study delves into the antihypertensive effects of curcumin nanoemulsion (SNEC) by targeting the renin-angiotensin-aldosterone system (RAAS) and oxidative stress in deoxycorticosterone acetate (DOCA) salt-induced hypertensive rats. To gauge the cardio-protective impact of SNEC in DOCA salt-induced hypertension, molecular docking was undertaken, uncovering curcumin's high affinity and adept binding capabilities to the active site of angiotensin-converting enzyme (ACE). Additionally, the investigation employed uninephrectomized rats to assess hemodynamic parameters via an AD instrument. Serum ACE, angiotensin II, blood urea nitrogen (BUN), and creatinine levels were quantified using ELISA kits, while antioxidant parameters were evaluated through chemical assays. Result: The outcomes of the molecular docking analysis revealed robust binding of curcumin to the ACE active site. Furthermore, oral administration of SNEC significantly mitigated systolic, diastolic, and mean arterial blood pressure in contrast to the DOCA-induced hypertensive group. SNEC administration also led to a reduction in left ventricular end-diastolic pressure (LVEDP) and an elevation in the maximum rate of left ventricular pressure rise (LV (dP/dt) max). Moreover, SNEC administration distinctly lowered serum levels of ACE and angiotensin II compared to the hypertensive DOCA group. Renal markers, including serum creatinine and BUN, displayed a shift toward normalized levels with SNEC treatment. Additionally, SNEC showcased potent antioxidant characteristics by elevating reduced glutathione, catalase, and superoxide dismutase levels, while decreasing the concentration of thiobarbituric acid reactive substances. Conclusions: Collectively, these findings underscore that curcumin nanoemulsion exerts noteworthy cardio-protective effects through ACE activity inhibition and remarkable antioxidant properties.


Assuntos
Curcumina , Acetato de Desoxicorticosterona , Hipertensão , Ratos , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Curcumina/farmacologia , Curcumina/uso terapêutico , Acetato de Desoxicorticosterona/efeitos adversos , Angiotensina II/efeitos adversos , Simulação de Acoplamento Molecular , Ratos Wistar , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea
7.
Clin Exp Immunol ; 214(2): 197-208, 2023 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-37498307

RESUMO

The interplay between platelets and leukocytes contributes to the pathogenesis of inflammation, thrombosis, and cardiovascular diseases (CVDs) in type 2 diabetes (T2D). Our recent studies described alpha-ketoglutarate (αKG), a Krebs cycle intermediate metabolite as an inhibitor to platelets and leukocytes activation by suppressing phosphorylated-Akt (pAkt) through augmentation of prolyl hydroxylase-2 (PHD2). Dietary supplementation with a pharmacological concentration of αKG significantly inhibited lung inflammation in mice with either SARS-CoV-2 infection or exposed to hypoxia treatment. We therefore investigated if αKG supplementation could suppress hyperactivation of these blood cells and reduce thromboinflammatory complications in T2D. Our study describes that dietary supplementation with αKG (8 mg/100 g body wt. daily) for 7 days significantly reduced the activation of platelets and leukocytes (neutrophils and monocytes), and accumulation of IL1ß, TNFα, and IL6 in peripheral blood of T2D mice. αKG also reduced the infiltration of platelets and leukocytes, and accumulation of inflammatory cytokines in lungs by suppressing pAkt and pP65 signaling. In a cross-sectional investigation, our study also described the elevated platelet-leukocyte aggregates and pro-inflammatory cytokines in circulation of T2D patients. T2D platelets and leukocytes showed an increased aggregation and thrombus formation in vitro. Interestingly, a pre-incubation of T2D blood samples with octyl αKG significantly suppressed the activation of these blood cells and ameliorated aggregate/thrombus formation in vitro. Thus, suggesting a potential therapeutic role of αKG against inflammation, thrombosis, and CVDs in T2D.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Trombose , Humanos , Camundongos , Animais , Ácidos Cetoglutáricos/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ativação Plaquetária , Inflamação/metabolismo , Leucócitos/patologia , Plaquetas/patologia , Trombose/tratamento farmacológico , Trombose/etiologia , Doenças Cardiovasculares/patologia , Citocinas/metabolismo , Suplementos Nutricionais
8.
J Biomol Struct Dyn ; 41(17): 8121-8164, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36218071

RESUMO

The spread of antimalarial drug resistance is a substantial challenge in achieving global malaria elimination. Consequently, the identification of novel therapeutic candidates is a global health priority. Malaria parasite necessitates hemoglobin degradation for its survival, which is mediated by Falcipain 2 (FP2), a promising antimalarial target. In particular, FP2 is a key enzyme in the erythrocytic stage of the parasite's life cycle. Here, we report the screening of approved drugs listed in DrugBank using a computational pipeline that includes drug-likeness, toxicity assessments, oral toxicity evaluation, oral bioavailability, docking analysis, maximum common substructure (MCS) and molecular dynamics (MD) Simulations analysis to identify capable FP2 inhibitors, which are hence potential antiplasmodial agents. A total of 45 drugs were identified, which have positive drug-likeness, no toxic features and good bioavailability. Among these, six drugs showed good binding affinity towards FP2 compared to E64, an epoxide known to inhibit FP2. Notably, two of them, Cefalotin and Cefoxitin, shared the highest MCS with E64, which suggests that they possess similar biological activity as E64. In an investigation using MD for 100 ns, Cefalotin and Cefoxitin showed adequate protein compactness as well as satisfactory complex stability. Overall, these computational approach findings can be applied for designing and developing specific inhibitors or new antimalarial agents for the treatment of malaria infections.Communicated by Ramaswamy H. Sarma.

9.
Indian J Occup Environ Med ; 26(3): 193-197, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36408427

RESUMO

Background: Government bus conductors are at high risk for work-related musculoskeletal disorders (MSDs) due to the work environment and work conditions. Thus, the present study was undertaken to assess the prevalence and associated factors of musculoskeletal problems among bus conductors. Materials and Methods: This cross-sectional study included 237 bus conductors of government bus depots. The data were collected by interview technique on a structured questionnaire. Self-reported musculoskeletal pain over the last 12 months was the case definition. Results: The present study revealed that 62.4% of bus conductors had musculoskeletal pain. The multivariate analysis suggested that tobacco smoking, overweight or obesity, and lack of enough breaks during work were significant risk factors for the occurrence of musculoskeletal pain in study participants. Conclusion: Thus, to conclude, the conductors are at risk of musculoskeletal problems, which can be attributed to occupational as well as non-occupational factors.

10.
Work ; 73(1): 301-307, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35912769

RESUMO

BACKGROUND: The Indian salon industry is increasing rapidly due to demand for various kinds of beauty and personal care products. Working ability and health conditions of salon workers may be affected by specific work-related activities. Prolonged non-neutral postures, repetitive movements, lack of adequate breaks during work, working at a fast pace, general distress or prolonged standing periods make them vulnerable to musculoskeletal symptoms. OBJECTIVE: The present study was carried out to assess work-related musculoskeletal symptoms among the beauty salon workers of Udupi taluk. METHOD: A total of 240 salon workers were recruited for the study. A semi-structured, interviewer-led questionnaire based on a modified Nordic questionnaire was used to collect data. RESULTS: As many as 80.4% study participants reported work related musculoskeletal pain in one or more body parts. The common body parts affected by pain were neck, shoulder, elbow, wrist/hand, upper back, lower back, legs and ankles/feet. The analysis according to work postures suggested that short repetitive movements, stretching of hands to reach objects, working in the same posture for a longer time and the lack of weekly break from work was significantly associated with musculoskeletal symptoms. CONCLUSION: The beauty salon workers are at risk of developing musculoskeletal symptoms which could benefit from preventive structural, operational and educational measures.


Assuntos
Doenças Musculoesqueléticas , Dor Musculoesquelética , Doenças Profissionais , Humanos , Índia/epidemiologia , Indústrias , Doenças Musculoesqueléticas/epidemiologia , Doenças Musculoesqueléticas/etiologia , Doenças Musculoesqueléticas/prevenção & controle , Dor Musculoesquelética/epidemiologia , Dor Musculoesquelética/etiologia , Doenças Profissionais/epidemiologia , Doenças Profissionais/etiologia , Doenças Profissionais/prevenção & controle , Postura , Fatores de Risco , Inquéritos e Questionários
11.
Int J Occup Saf Ergon ; 28(2): 716-720, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32972325

RESUMO

Although studies have reported lower back pain (LBP) in professional drivers, the conductors travelling in the same bus who share the same working environment are often neglected. Thus, the present study was undertaken to assess the prevalence of LBP and the factors associated with it. The study included 237 bus conductors from government bus depots. The data regarding occupational, non-occupational and environmental factors were collected by interview technique using a structured questionnaire. Self-reported back pain in the last 12 months in or near the lumbosacral spine was considered a case of LBP. The study revealed that 27.4% had LBP. The multivariate analysis suggested that tobacco smoking, self-reported bad road conditions and lack of enough breaks during work were significant risk factors. Thus, to conclude, the conductors are at risk of LBP that can be attributed to occupational as well as non-occupational factors.


Assuntos
Condução de Veículo , Dor Lombar , Doenças Profissionais , Humanos , Índia/epidemiologia , Dor Lombar/epidemiologia , Dor Lombar/etiologia , Doenças Profissionais/epidemiologia , Doenças Profissionais/etiologia , Prevalência , Fatores de Risco , Inquéritos e Questionários
12.
Mini Rev Med Chem ; 22(12): 1648-1706, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34939540

RESUMO

'Epigenetic' regulation of genes via post-translational modulation of proteins is a wellexplored approach for disease therapies, particularly cancer chemotherapeutics. Histone deacetylases (HDACs) are one of the important epigenetic targets and are mainly responsible for balancing the acetylation/deacetylation of lysine amino acids on histone/nonhistone proteins along with histone acetyltransferase (HAT). HDAC inhibitors (HDACIs) have become important biologically active compounds for the treatment of cancers due to cell cycle arrest, differentiation, and apoptosis in tumor cells, thus leading to anticancer activity. Out of the four classes of HDAC, i.e., Class I, II, III, and IV, HDACIs act on Class IV (Zinc dependent HDAC), and various FDA-approved drugs belong to this category. The required canonical pharmacophore model (zinc-binding group, surface recognition cap, and appropriate linker) supported by HDACIs, various heterocyclic moieties containing compounds exhibiting HDAC inhibitory activity, and structure-activity relationship of different synthetic derivatives reported during the last twelve years have been summarized in this review.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/química , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Zinco
13.
Sci Rep ; 11(1): 15972, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354142

RESUMO

India became one of the most COVID-19 affected countries with more than 4 million infected cases and 71,000 deaths by September 2020. We studied the temporal dynamics and geographic distribution of SARS-CoV-2 subtypes in India. Moreover, we analysed the RGD motif and D614G mutation in the spike protein of SARS-CoV-2. We used a previously proposed viral subtyping method based upon informative subtype markers (ISMs). The ISMs were identified on the basis of information entropy using 94,515 genome sequences of SARS-CoV-2 available publicly at the Global Initiative on Sharing All Influenza Data (GISAID). We identified 11 distinct positions in the SARS-CoV-2 genomes for defining ISMs resulting in 798 unique ISMs. The most abundant ISM in India was transferred from European countries. In contrast, the second most abundant ISM in India was found to be transferred via Australia. Moreover, the eastern regions in India were infected by the ISM most abundant in China due to geographical linkage. Our analysis confirmed higher rates of new cases in the countries abundant with S-G614 strain compared to countries with abundant S-D614 strain. In India, overall S-G614 was most prevalent compared to S-D614, except a few regions including New Delhi, Bihar, and Rajasthan.


Assuntos
COVID-19/transmissão , SARS-CoV-2/genética , COVID-19/diagnóstico , COVID-19/epidemiologia , Entropia , Genoma Viral , Humanos , Índia/epidemiologia , Mutação , Filogenia , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/genética
14.
Rev Socionetwork Strateg ; 15(2): 471-488, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35506052

RESUMO

This study addressed the critical problems of depression, anxiety, and stress, which are prevalent among students pursuing higher education. Specifically, this article aimed to study the level of psychological distress due to the COVID-19 pandemic experienced by young people studying in higher education institutions in India. The study also attempted to identify various coping strategies students adopted to overcome this difficult time. Following a descriptive research design, this study used surveys to collect primary data from 235 students in graduate and undergraduate programs in India. The DASS-21 scale was used to check the levels of depression, anxiety, and stress students experienced. Furthermore, a four-point COPE scale was used to identify coping strategies students adopted. The results showed that students experienced high levels of stress and anxiety during the ongoing COVID-19 pandemic. Although depression levels were not alarming, most students were worried about several aspects of their lives and careers. However, because the data were collected from a relatively small sample, the study is likely not generalisable. Furthermore, most of the data were collected online, which has its limitations. This research likely has significant implications for various stakeholders, such as students, parents, institutions, counsellors, and government and non-government bodies, because it may help them take appropriate actions. These research contributions are original and novel, because the COVID-19 pandemic has posed unprecedented challenges and inspired new solutions to the problems of students and society.

15.
Am J Ind Med ; 63(10): 902-906, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32803802

RESUMO

BACKGROUND: The Indian hair and beauty salon industry is growing rapidly due to the demand for beauty and personal care services and products. Workers in the industry are vulnerable to several occupational factors such as chemicals, confined space, and poor ventilation. Chemicals in the products used are known or suspected to cause allergies, respiratory, neurological and reproductive health problems and cancer. METHODS: The present study was carried out to determine the factors associated with the occurrence of respiratory morbidity among hair and beauty salon workers of Udupi taluk, Karnataka, India. A total of 240 salon workers were recruited for the study. A semistructured, interviewer-led questionnaire was used to collect data. Peak expiratory flow rate (PEFR) was done using a JSB peak flow meter. RESULTS: The frequency of respiratory morbidity among participating beauty salon workers was 19%. Men reported respiratory symptoms more frequently than women. Receiving training on work materials and practices was a significant protective factor (odds ratio = 0.3; 95% confidence interval: 0.1-0.7) for the occurrence of respiratory morbidity. The mean observed PEFR in these workers was significantly lower than their predicted values. While 61.2% of the workers were using some form of personal protective equipment, only 4% of workers used a mask or respiratory protection. CONCLUSION: Hair and beauty salon workers are at risk of developing respiratory morbidity potentially from harmful exposures and lack of effective control measures at the workplace.


Assuntos
Indústria da Beleza/estatística & dados numéricos , Doenças Profissionais/epidemiologia , Exposição Ocupacional/efeitos adversos , Saúde Ocupacional/estatística & dados numéricos , Transtornos Respiratórios/epidemiologia , Adulto , Feminino , Humanos , Índia/epidemiologia , Masculino , Doenças Profissionais/etiologia , Exposição Ocupacional/análise , Pico do Fluxo Expiratório , Transtornos Respiratórios/etiologia , Fatores de Risco
16.
FEBS Lett ; 594(18): 3057-3066, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32649775

RESUMO

Cell surface pili assembled by the chaperone-usher (CU) pathway play a crucial role in the adhesion of uropathogenic Escherichia coli. YadV is the chaperone component of the CU pathway of Yad pili. Here, we report the crystal structure of YadV from E. coli. In contrast to major usher chaperones, YadV is a monomer in solution as well as in the crystallographic symmetry, and the monomeric form is a preferred state for interacting with pilus subunits. Moreover, we observed a closed conformation for the proline lock, a crucial structural element for chaperone-pilus subunit interaction. MD simulation shows that the closed state of the proline lock is not energetically stable. Thus, the structure of monomeric YadV with its closed proline lock may serve as an intermediate state to provide suitable access to pilus subunits.


Assuntos
Proteínas de Escherichia coli/química , Chaperonas Moleculares/química , Escherichia coli Uropatogênica/química , Cristalografia por Raios X , Prolina/química , Domínios Proteicos
17.
Artigo em Inglês | MEDLINE | ID: mdl-31334132

RESUMO

Thrombospondin type I repeat (TSR) domains are commonly O-fucosylated by protein O-fucosyltransferase 2 (PoFUT2), and this modification is required for optimal folding and secretion of TSR-containing proteins. The human malaria parasite Plasmodium falciparum expresses proteins containing TSR domains, such as the thrombospondin-related anonymous protein (TRAP) and circumsporozoite surface protein (CSP), which are O-fucosylated. TRAP and CSP are present on the surface of sporozoites and play essential roles in mosquito and human host invasion processes during the transmission stages. Here, we have generated PoFUT2 null-mutant P. falciparum and Plasmodium berghei (rodent) malaria parasites and, by phenotyping them throughout their complete life cycle, we show that PoFUT2 disruption does not affect the growth through the mosquito stages for both species. However, contrary to what has been described previously by others, P. berghei PoFUT2 null mutant sporozoites showed no deleterious motility phenotypes and successfully established blood stage infection in mice. This unexpected result indicates that the importance of O-fucosylation of TSR domains may differ between human and RODENT malaria parasites; complicating our understanding of glycosylation modifications in malaria biology.


Assuntos
Fucosiltransferases/metabolismo , Plasmodium berghei/enzimologia , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium berghei/metabolismo , Animais , Linhagem Celular , Culicidae/parasitologia , Modelos Animais de Doenças , Fucosiltransferases/genética , Glicosilação , Humanos , Estágios do Ciclo de Vida , Malária/parasitologia , Malária/transmissão , Malária Falciparum/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Oocistos/metabolismo , Plasmodium berghei/genética , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Esporozoítos/enzimologia , Esporozoítos/genética , Esporozoítos/crescimento & desenvolvimento , Esporozoítos/metabolismo
18.
Comput Biol Med ; 110: 175-185, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31173941

RESUMO

In the present study, a series of dibenzepinones, dibenzoxepines, and benzosuberones targeting p38α MAP kinase were subjected to pharmacophore modelling, 3D-QSAR and molecular docking studies. The IC50 values for these 67 compounds ranged between 0.003 and 6.80 µM. A five-point model (DDHHR.8) was generated using these compounds. This model was found to be statistically significant and was found to have high correlation (R2 = 0.98), cross-validation coefficient (Q2 = 0.95) and F (330) values at six component PLS factor. Tests were performed to ascertain the efficacy of the generated model. These tests included external validation, Tropsha's test for predictive ability, Y-randomisation test and domain of applicability (APD). In order to check the restrictivity of the model, enrichment studies were performed with inactive compounds by using decoy set molecules. To evaluate the effectiveness of the docking protocol, the co-crystallised ligand was extracted from the ligand-binding domain of the protein and was re-docked into the same position. Both the conformers were then superimposed, suggesting satisfactory docking parameters with an RMSD value of less than 1.0 Š(0.853 Å). A 10 ns molecular dynamics simulation confirmed the docking results of the 3UVP-ligand complex and the presumed active conformation. The outcome of the present study provides insight into the molecular features that promote bioactivity and can be exploited for the prediction of novel potent p38α MAP kinase inhibitors before carrying out their synthesis and anticancer evaluation.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Humanos , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/química , Relação Quantitativa Estrutura-Atividade
19.
Bioorg Chem ; 89: 102986, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31146198

RESUMO

In continuance with earlier reported work, an extension has been carried out by the same research group. Mulling over the ongoing condition of resistance to existing antimalarial agents, we had reported synthesis and antimalarial activity of certain pyrazole-1,3,4-oxadiazole hybrid compounds. Bearing previous results in mind, our research group ideated to design and synthesize some more derivatives with varied substitutions of acetophenone and hydrazide. Following this, derivatives 5a-r were synthesized and tested for antimalarial efficacy by schizont maturation inhibition assay. Further, depending on the literature support and results of our previous series, certain potent compounds (5f, 5n and 5r) were subjected to Falcipain-2 inhibitory assay. Results obtained for these particular compounds further strengthened our hypothesis. Here, in this series, compound 5f having unsubstituted acetophenone part and a furan moiety linked to oxadiazole ring emerged as the most potent compound and results were found to be comparable to that of the most potent compound (indole bearing) of previous series. Additionally, depending on the available literature, compounds (5a-r) were tested for their antileishmanial potential. Compounds 5a, 5c and 5r demonstrated dose-dependent killing of the promastigotes. Their IC50 values were found to be 33.3 ±â€¯1.68, 40.1 ±â€¯1.0 and 19.0 ±â€¯1.47 µg/mL respectively. These compounds (5a, 5c and 5r) also had effects on amastigote infectivity with IC50 of 44.2 ±â€¯2.72, 66.8 ±â€¯2.05 and 73.1 ±â€¯1.69 µg/mL respectively. Further target validation was done using molecular docking studies. Acute oral toxicity studies for most active compounds were also performed.


Assuntos
Antimaláricos/farmacologia , Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Oxidiazóis/química , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/química , Antimaláricos/metabolismo , Antiprotozoários/síntese química , Antiprotozoários/química , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Desenho de Fármacos , Concentração Inibidora 50 , Leishmania/fisiologia , Macrófagos/citologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Camundongos , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Estrutura Terciária de Proteína , Pirazóis/química , Células RAW 264.7 , Ratos , Ratos Wistar , Relação Estrutura-Atividade
20.
J Family Community Med ; 26(2): 118-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31143084

RESUMO

BACKGROUND: Iron deficiency anemia in pregnant women may affect the iron reserves of their infants and lead to anemia later. The objective of the study was to compare hemoglobin and iron store status of infants born to anemic and non-anemic mothers and to determine any correlation. MATERIALS AND METHODS: A cohort study was conducted in the Department of Pediatrics of a Teaching hospital after obtaining ethical approval and written informed consent from all participants. Total 180 mother-infant pairs were enrolled in the study were divided into two groups; Group I: 90 term infants born to anemic mothers (Hb <11 g/dl), Group II: 90 term infants born to non-anemic mothers (Hb >11 g/dl). Hemoglobin and ferritin levels were assessed in cord blood at birth and at 14 weeks after birth in the infants of both groups. Data was analyzed using SPSS 20.0; Chi-square test and t-test were applied to test for statistical significance. RESULTS: The final sample size was 85 for Group I and 78 for Group II. For Group I, mean hemoglobin and ferritin levels in the cord blood of infants at birth were 16.33 ± 1.19 and 135.40 ± 25.94, respectively. For Group II, Mean hemoglobin and ferritin levels in the cord blood of infants at birth were 17.62 ± 1.35 and 160.45 ± 28.50, respectively; differences were statistically significant. At 14 weeks, the mean Hb and ferritin was 11.24 ± 1.03 and 55.92 ± 10.44 in Group I and 13.18 ± 0.82 and 63.56 ± 10.15 in Group II; the differences were statistically significant. A significant correlation between maternal and infant hemoglobin and ferritin levels was observed at birth and 14 weeks after birth. CONCLUSION: Maternal iron deficiency may have an effect on the iron status of their infants. Thus, timely appropriate interventions are necessary.

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