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Diabetes mellitus (DM) remains one of the pivotal diseases that have drawn the attention of researchers recently and during the last few decades. Due to its devastating symptoms, attempts to develop new drugs with mild side effects have resulted in a number of drugs that are functioning through various mechanisms. Among these, Glycogen phosphorylase (GP) inhibitors emerged as a new strategy for combating DM. GP is an enzyme that regulates blood glucose levels; it catalyses the breakdown of glycogen to glucose-1-phosphate in the liver and tissues with high and fluctuating energy demands. In the present research, we evaluate the possibility of type 2 diabetes therapy with the help of chalcones which are known to have antidiabetic activities. For this purpose, 29 chalcones were modelled, synthesised and investigated for their inhibitory activity against GP using in-vitro methods. Compounds 1, 2, and 3 were found to be the most potent compounds with IC50 values 26.6, 57.1 and 75.6 µM respectively. The observed results were further validated using in-silico methods. Molecular docking simulation revealed interaction patterns that explain the structure-activity relationships of the compounds with GP. Molecular dynamic (MD) simulation demonstrated a stable complex formation between compound 1 and GP through lower value and uniformity in root mean square deviation (RMSD) of the complex and root mean square fluctuation (RMSF) of the protein Cα.
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Leishmaniasis affects more than 12 million humans globally and a further 1 billion people are at risk in leishmaniasis endemic areas. The lack of a vaccine for leishmaniasis coupled with the limitations of existing anti-leishmanial therapies prompted this study. Cheminformatic techniques are widely used in screening large libraries of compounds, studying protein-ligand interactions, analysing pharmacokinetic properties, and designing new drug molecules with great speed, accuracy, and precision. This study was undertaken to evaluate the anti-leishmanial potential of some organoselenium compounds by quantitative structure-activity relationship (QSAR) modeling, molecular docking, pharmacokinetic analysis, and molecular dynamic (MD) simulation. The built QSAR model was validated (R2train = 0.8646, R2test = 0.8864, Q2 = 0.5773) and the predicted inhibitory activity (pIC50) values of the newly designed compounds were higher than that of the template (Compound 6). The new analogues (6a, 6b, and 6c) showed good binding interactions with the target protein (Pyridoxal kinase, PdxK) while also presenting excellent drug-likeness and pharmacokinetic profiles. The results of density functional theory, MD simulation, and molecular mechanics generalized Born surface area (MM/GBSA) analyses suggest the favourability and stability of protein-ligand interactions of the new analogues with PdxK, comparing favourably well with the reference drug (Pentamidine). Conclusively, the newly designed compounds could be synthesized and tested experimentally as potential anti-leishmanial drug molecules.Communicated by Ramaswamy H. Sarma.
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The DNA topoisomerase II (topo II) enzyme plays an important role in the replication, recombination, and repair of DNA. Despite their widespread applications in cancer therapy, new, selective, and potent topo II inhibitors with better pharmaceutical profiles are needed to handle drug resistance and severe adverse effects. In this respect, an array of 36 new anticancer compounds was designed based on a Xanthone core tethered to multifunctional Pyridine-amines and Imidazole scaffold via alkyl chain linkers. An integrated in silico approach was used to understand the structural basis and mechanism of inhibition of the hybrid xanthone derivatives. In this study, we established an initial virtual screening workflow based on pharmacophore mapping, docking, and cancer target association to validate the target selection process. Next, a simulation-based docking was conducted along with pharmacokinetic analysis to filter out the five best compounds (7, 10, 25, 27, and 30) having binding energies within the range of -60.45 to -40.97 kcal/mol. The screened compounds were further subjected to molecular dynamics simulation for 200 ns followed by MM-GBSA and ligand properties analysis to assess the stability and binding affinity to hTOP2α. The top-ranking hits 3,7-bis(3-(2-aminopyridin-3-ylhydroxy)propoxy)-1-hydroxy-9H-xanthen-9-one (ligand 7) and 3,8-bis(3-(2-aminopyridin-3-ylhydroxy)propoxy)-1-hydroxy-9H-xanthen-9-one (ligand 25) were found to have no toxicity, optimum pharmacokinetic and, DFT properties and stable intermolecular interactions with the active site of hTopo IIα protein. In conclusion, further in vitro and in vivo experimental validation of the identified lead molecules is warranted for the discovery of new human Topoisomerase 2 alpha inhibitors.Communicated by Ramaswamy H. Sarma.
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Glycation of biomolecules results in the formation of advanced glycation end products (AGEs). Immunoglobulin G (IgG) has been implicated in the progression of various diseases, including diabetes and cancer. This study purified three IgG subclasses (IgG1, IgG2, and IgG3) from Camelus dromedarius colostrum using ammonium sulfate fractionation and chromatographic procedures. SDS-PAGE was performed to confirm the purity and molecular weight of the IgG subclasses. Several biochemical and biophysical techniques were employed to study the effect of glycation on camel IgG using methylglyoxal (MGO), a dicarbonyl sugar. Early glycation measurement showed an increase in the fructosamine content by ~four-fold in IgG2, ~two-fold in IgG3, and a slight rise in IgG1. AGEs were observed in all classes of IgGs with maximum hyperchromicity (96.6%) in IgG2. Furthermore, glycation-induced oxidation of IgGs led to an increase in carbonyl content and loss of -SH groups. Among subclass, IgG2 showed the highest (39.7%) increase in carbonyl content accompanied by 82.5% decrease in -SH groups. Far UV-CD analysis illustrated perturbation of ß-sheet structure during glycation reaction with MGO. Moreover, glycation of IgG proceeds to various conformational states like aggregation and increased hydrophobicity. In addition, the cytotoxicity assay (MTT) illustrated the proliferation of breast cancer cells (MCF-7) with IgG2 treatment.
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Camelus , Neoplasias , Animais , Reação de Maillard , Óxido de Magnésio , Imunoglobulina G/química , Produtos Finais de Glicação Avançada , Proliferação de CélulasRESUMO
Oxidative stress caused due to the perturbations in the oxidant-antioxidant system can damage molecules and cause cellular alteration leading to the pathogenesis of multiple diseases. This study was designed and performed to investigate the antioxidant and anti-inflammatory effects of an alkaloid, gramine on H2O2-induced oxidative stress on HEK 293 cells. Cell viability and morphometric analysis of cells treated with H2O2 and gramine were studied. Oxidative stress and inflammatory and antioxidant enzymes such as ROS, LPO, NO, SOD, GSH, and CAT were analyzed. Furthermore, mRNA expression of SOD, CAT, and COX-2 was also evaluated. H2O2 at concentration > 0.3 mM and gramine at concentration > 80 µg/mL affect the proliferation. Viability and morphometric analysis showed that gramine has protective effects. Treating cells with gramine suppressed oxidative stress and inflammatory enzymes, whereas antioxidant enzymes were enhanced. SOD and CAT mRNA levels were overexpressed and COX-2 mRNA levels were decreased in the treated groups. Gramine possesses effective antioxidant potential and can regulate oxidative stress and damages associated with it.
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Metformin is a regularly prescribed and low-cost generic medication. Metformin has been proposed as a target for Dipeptidyl-peptidase 4 (DPP4) expression in various clinical disorders. We provide insilco investigations on molecular docking and dynamic modeling of metformin and DPP4 potential interactions. Moreover, we conducted bioinformatic studies to highlight the clinical significance of DPP4 expression and mutation in various types of malignancies, as well as the invasion of different immune cells into the tumor microenvironment. We believe the present proposal's findings have crucial implications for understanding how metformin may confer health advantages by targeting DPP4 expression in malignancies.
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Dipeptidil Peptidase 4 , Metformina , Humanos , Simulação de Acoplamento Molecular , Dipeptidil Peptidase 4/genética , Simulação por Computador , Relevância Clínica , Metformina/farmacologia , Metformina/uso terapêuticoRESUMO
Prediabetes is an increase-risk state for diabetes that is associated with an increase in blood glucose levels to more than normal, but not increased enough to be termed as type 2 diabetes mellitus (T2DM). A timely intervention and management of prediabetes can stop its further progression to the diabetic state. Many cytokines are involved in diseases including diabetes, however, their role in prediabetes is unknown. In this study, we attempted to analyze numerous proinflammatory cytokines in prediabetic patients. A total of 60 adult Saudi prediabetes patients and healthy control individuals were included in this study. To better understand the role of the proinflammatory cytokines in prediabetes patients and its potential link to the disease outcome, the variations in the levels of these cytokines were investigated using Multi-Analyte ELISA technique. The T helper cells (Th1 and Th2) immune response expression profiling of 84 genes was done using Real Time-quantitative PCR (RT-qPCR) technique. The present finding showed that serum Interleukin IL-2, IL-1ß, and IL-1α levels of all prediabetes patients were increased when compared with healthy control cases (P < 0.05). Inductions of proinflammatory cytokines and upregulation of Th1 and Th2 immune genes might play a potential role during prediabetes status and may be linked to the disease outcome. Further studies are needed to investigate the underlying mechanism of these proinflammatory cytokines in diabetes development. A strong positive correlation was found between IL and 1α with glucose levels than with IL-1ß and IL-2. In conclusion, cytokines, especially IL-1, may play a critical role in the development of diabetes.
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COVID-19 is a highly contagious disease caused by SARS-CoV-2. Vaccination against the virus was first approved in Saudi Arabia in December 2020. Vaccinated individuals are still at risk of getting infected with the virus and can transmit the disease. Therefore, the perception of vaccinated individuals regarding the disease can help limit the spread of the virus. OBJECTIVES: To measure the risk perception of COVID-19 following vaccination and factors that have an effect on risk perception; to identify the health protective behaviours of the vaccinated individuals. METHODOLOGY: This is a quantitative analytical cross-sectional, questionnaire-based study. The target population includes individuals aged 18 and above who live in the Riyadh region and have been vaccinated, during the period of June 2021 to December 2021. RESULTS: The perception of 30.2% of participants did not change after vaccination, with many participants continuing to "always" take precautions even after vaccination. Numerous factors, such as age, gender, marital status, occupational status, employment status, and total household income, have shown significant effects towards risk perception. CONCLUSION: Many vaccinated individuals have continued to take precautionary steps and their risk perception has not changed.
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The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a highly challenging and threatening situation worldwide. SARS-CoV-2 patients develop various clinical symptoms. The olfactory and taste dysfunctions are potential neurological manifestations among SARS-CoV-2 patients; however, their relationship with blood groups has rarely been investigated. This study aimed to investigate the prevalence of chemosensitive neurological disorders of smell and taste and their association with blood groups in SARS-CoV-2 patients. The present cross-sectional study was performed in the Department of Pathology, and Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. A well-structured, self-administered questionnaire was designed and distributed through social media platforms. A total of 922 Saudi and non-Saudi adults aged 18 years or older participated in the study. Out of 922 participants, the number of people who had anosmia was 309 (33.5%), 211 (22.9%) had hyposmia, and 45 (4.8%) had dysosmia. Moreover, 180 (19.52%) had ageusia, 47 (5.1%) and 293 (31.8%) had hypogeusia and dysgeusia, respectively. Among all the participants, 565 (61.27%) had smell-related disorders and 520 (56.39%) participants had taste-related clinical symptoms. The occurrence of anosmia and ageusia was relatively high among females compared to males (p = 0.024). The prevalence of smell-related disorders was 25.0% (230) and taste-related disorders was 23.21% (214) among the study participants with blood group O compared to all other blood group (A, B, and AB) participants who have smell allied disorders 30.69% (283), and taste allied disorders 27.98% (258). The prevalence of chemosensitive neurological disorders involving impaired smell and taste was higher in SARS-CoV-2 patients. These clinical symptoms were common among the participants with blood group type O compared to all other ABO blood group types. The role of certain demographic characteristics was consistent throughout multiple studies, notably with female gender and young adults.
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Ageusia , Antígenos de Grupos Sanguíneos , COVID-19 , Transtornos do Olfato , Masculino , Humanos , Feminino , SARS-CoV-2 , Olfato/fisiologia , Paladar/fisiologia , Ageusia/epidemiologia , Ageusia/etiologia , Estudos Transversais , COVID-19/complicações , COVID-19/epidemiologia , Anosmia/epidemiologia , Prevalência , Distúrbios do Paladar/diagnóstico , Transtornos do Olfato/diagnósticoRESUMO
Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME) and have been linked to immunosuppression and poor prognosis. TAMs have been shown to be harmful in ovarian cancer (OC), with a positive correlation between their high levels of tumors and poor overall patient survival. These cells are crucial in the progression and chemoresistance of OC. The primary pro-tumoral role of TAMs is the release of cytokines, chemokines, enzymes, and exosomes that directly enhance the invasion potential and chemoresistance of OC by activating their pro-survival signalling pathways. TAMs play a crucial role in the metastasis of OC in the peritoneum and ascities by assisting in spheroid formation and cancer cell adhesion to the metastatic regions. Furthermore, TAMs interact with tumor protein p53 (TP53), exosomes, and other immune cells, such as stem cells and cancer-associated fibroblasts (CAFs) to support the progression and metastasis of OC. In this review we revisit development, functions and interactions of TAMs in the TME of OC patients to highlight and shed light on challenges and excitement down the road.
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Fibroblastos Associados a Câncer , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/metabolismo , Macrófagos , Transdução de Sinais , Citocinas/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Microambiente TumoralRESUMO
Enterobius vermicularis is a threadlike parasite also known as "pinworms". It is the most common helminth infection, affecting the gastrointestinal tracts of children worldwide, although it seldom causes any fatalities. Enterobius vermicularis infections are usually asymptomatic and may only cause anal pruritis, with occasional reported cases of ectopic migration into the appendix or the female genital tract by adult pinworms. Here, we report a case of a 15-year-old girl who presented to the emergency department with high-grade fever, vomiting, and vague abdominal pain for three days. She was diagnosed with acute abdominal pain and underwent emergency ileocecectomy, but died the following day. Pathological examination of ileocecal junction showed intraluminal and intramural Enterobius vermicularis, which were attributed as the cause of her death in the absence of any other pathologies. Death due to Enterobius vermicularis is rare; this case calls for clinicians to be vigilant in exploring Enterobius vermicularis infections in patients with undiagnosed acute abdominal pain, since it could be a potential cause of death.
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Knipholone is an antiplasmodial phytocompound obtained from the roots of Kniphofia foliosa. Despite several available studies, the molecular drug targets of knipholone in P. falciparum remained unknown. Nowadays, in silico techniques are widely used to study the molecular interactions between compounds and proteins as they provide results quickly with high precision and accuracy. In this study, we aim to identify the potential molecular drug targets of knipholone in P. falciparum. We selected 10 proteins of P. falciparum with unique metabolic functions and we found that knipholone showed better binding affinity than the native ligands of 6 proteins. Out of the 6 proteins, knipholone showed better enzyme inhibitory potential than the native ligands of 4 proteins. We carried out a 100 ns MD simulations for knipholone and the native ligands of four proteins and this was followed by binding free energy calculations. In each step, the performance of knipholone was compared to the native ligands of the proteins. Knipholone outperformed the native ligand of Glutathione-S-Transferase (1OKT) at crucial computational studies as evidence from the lower protein-ligand root mean square deviation value, protein root mean square fluctuation value, and protein-ligand binding free energies. The ligand properties of knipholone provide additional evidence for its stability and it maintains adequate protein-ligand contacts during the entire simulation. The density functional theory study also supported the stability of knipholone at the active binding site of 1OKT. From the studied proteins, we conclude that Glutathione-S-Transferase is the most favorable drug target for knipholone in P. falciparum.Communicated by Ramaswamy H. Sarma.
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Malária Falciparum , Plasmodium falciparum , Humanos , Simulação de Dinâmica Molecular , Glutationa Transferase/metabolismo , Ligantes , Glutationa/metabolismo , Simulação de Acoplamento MolecularRESUMO
There are limited data on inflammatory cytokines and chemokines; the humoral immune response; and main clinical laboratory parameters as indicators for disease severity and mortality in patients with critical and mild COVID-19 without comorbidities or immune-mediated diseases in Saudi Arabia. We determined the expression levels of major proinflammatory cytokines and chemokines; C-reactive protein (CRP); procalcitonin; SARS-CoV-2 IgM antibody and twenty-two clinical laboratory parameters and assessed their usefulness as indicators of disease severity and in-hospital death. Our results showed a significant increase in the expression levels of SARS-CoV-2 IgM antibody; IL1-ß; IL-6; IL-8; TNF-α and CRP in critical COVID-19 patients; neutrophil count; urea; creatinine and troponin were also increased. The elevation of these biomarkers was significantly associated and positively correlated with in-hospital death in critical COVID-19 patients. Our results suggest that the levels of IL1-ß; IL-6; IL-8; TNF-α; and CRP; neutrophil count; urea; creatinine; and troponin could be used to predict disease severity in COVID-19 patients without comorbidities or immune-mediated diseases. These inflammatory mediators could be used as predictive early biomarkers of COVID-19 disease deterioration; shock and death among COVID-19 patients without comorbidities or immune-mediated diseases.
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COVID-19 , Mortalidade Hospitalar , Humanos , Biomarcadores , Proteína C-Reativa , COVID-19/diagnóstico , COVID-19/mortalidade , Creatinina , Citocinas , Interleucina-6 , Interleucina-8 , Gravidade do Paciente , SARS-CoV-2 , Troponina , Fator de Necrose Tumoral alfa , QuimiocinasRESUMO
Burkholderia cepacia is a Gram-negative nosocomial pathogen and is considered as a troublesome bacterium due to its resistance to many common antibiotics. There is no licensed vaccine available to prevent the pathogen infections, thus making the condition more alarming and warrant the search for novel therapeutic and prophylactic approaches. In order to identify protective antigens from pathogen proteome, substantial efforts are put forth to prioritized potential vaccine targets and antigens that can be easily evaluated experimentally. In this vaccine design investigation, it was found that B. cepacia completely sequenced proteomes available in NCBI genome database has a total of 28,966 core proteins. Out of total, 25,282 proteins were found redundant while 3,684 were non-redundant. Subcellular localization revealed that 18 proteins were extracellular, 31 were part of the outer membrane, 75 proteins were localized in the periplasm, and 23 were virulent proteins. Five proteins namely flagellar hook protein (FlgE), fimbria biogenesis outer membrane usher protein, Type IV pilus secretin (PilQ), cytochrome c4, flagellar hook basal body complex protein (FliE) were tested for positive for antigenic, non-toxic, and soluble epitopes during predication of B-cell derived T-cell epitopes. A vaccine peptide of 14 epitopes (joined together via GPGPG linkers) and cholera toxin B subunit (CTBS) adjuvant (joined to epitopes peptide via EAAAK linker) was constructed. Binding interaction of the modeled vaccine with MHC-I, MHC-II, and Toll-like receptor 4 (TLR-4) immune receptors was studied using molecular docking studies and further analyzed in molecular dynamics simulations that affirms strong intermolecular binding and stable dynamics. The maximum root mean square deviation (RMSD) score of complexes in the simulation time touches to 2 Å. Additionally, complexes binding free energies were determined that concluded robust interaction energies dominated by van der Waals. The total energy of each complex is < -190 kcal/mol. In summary, the designed vaccine showed promising protective immunity against B. cepacia and needs to be examined in experiments.
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T cells in the tumor microenvironment (TME) have diverse roles in anti-tumor immunity, including orchestration of immune responses and anti-tumor cytotoxic attack. However, different T cell subsets may have opposing roles in tumor progression, especially in inflammation-related cancers such as colorectal cancer (CRC). In this study, we phenotypically characterized CD3+CD4- (CD8+) T cells in colorectal tumor tissues (TT), normal colon tissues (NT) and in circulation of CRC patients. We investigated the expression levels of key immune checkpoints (ICs) and Treg-related markers in CD8+ T cells. Importantly, we investigated associations between different tumor-infiltrating CD8+ T cell subpopulations and disease-free survival (DFS) in CRC patients. We found that FoxP3 expression and ICs including PD-1, CTLA-4, TIM-3, and LAG-3 were significantly increased in tumor-infiltrating CD8+ T cells compared with NT and peripheral blood. In the TME, we found that TIM-3 expression was significantly increased in patients with early stages and absent lymphovascular invasion (LVI) compared to patients with advanced stages and LVI. Importantly, we report that high levels of certain circulating CD8+ T cell subsets (TIM-3-expressing, FoxP3-Helios-TIM-3+ and FoxP3-Helios+TIM-3+ cells) in CRC patients were associated with better DFS. Moreover, in the TME, we report that elevated levels of CD25+ and TIM-3+ T cells, and FoxP3+Helios-TIM-3+ Tregs were associated with better DFS.
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The vaccination campaign against COVID-19 is an essential public health strategy to reach herd immunity, eradicate diseases, and prevent a pandemic. This study aimed to investigate the acceptance rate of the COVID-19 vaccine among people in Riyadh, Saudi Arabia. This cross-sectional study was conducted in the Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. Out of the 922 participants involved, 294 (31.9%) were male and 628 (68.1%) were female, with a mean age of 30-49 years. A bilingual, self-administered, computer-based questionnaire was designed and distributed through social media platforms. In total, 900 participants (97.6%) showed a high acceptance rate of the vaccine. The vaccine acceptance rate was higher among people aged 60 years and above than in other age groups (p = 0.008) and single individuals compared to other groups (p = 0.003). The results reveal a relatively high acceptance level of the COVID-19 vaccine among study participants. Importantly, regression analysis results show that female gender and elderly participants are more likely to accept the COVID-19 vaccine than their counterparts. Moreover, the main factor that influenced the participants' perception of the COVID-19 vaccine was the proper timely scientific recommendations.
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The complement system, a network of highly-regulated proteins, represents a vital part of the innate immune response. Over-activation of the complement system plays an important role in inflammation, tissue damage, and infectious disease severity. The prevalence of MERS-CoV in Saudi Arabia remains significant and cases are still being reported. The role of complement in Middle East Respiratory Syndrome coronavirus (MERS-CoV) pathogenesis and complement-modulating treatment strategies has received limited attention, and studies involving MERS-CoV-infected patients have not been reported. This study offers the first insight into the pulmonary expression profile including seven complement proteins, complement regulatory factors, IL-8, and RANTES in MERS-CoV infected patients without underlying chronic medical conditions. Our results significantly indicate high expression levels of complement anaphylatoxins (C3a and C5a), IL-8, and RANTES in the lungs of MERS-CoV-infected patients. The upregulation of lung complement anaphylatoxins, C5a, and C3a was positively correlated with IL-8, RANTES, and the fatality rate. Our results also showed upregulation of the positive regulatory complement factor P, suggesting positive regulation of the complement during MERS-CoV infection. High levels of lung C5a, C3a, factor P, IL-8, and RANTES may contribute to the immunopathology, disease severity, ARDS development, and a higher fatality rate in MERS-CoV-infected patients. These findings highlight the potential prognostic utility of C5a, C3a, IL-8, and RANTES as biomarkers for MERS-CoV disease severity and mortality. To further explore the prediction of functional partners (proteins) of highly expressed proteins (C5a, C3a, factor P, IL-8, and RANTES), the computational protein-protein interaction (PPI) network was constructed, and six proteins (hub nodes) were identified.
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Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Complemento C3a/metabolismo , Complemento C5a/metabolismo , Infecções por Coronavirus/diagnóstico , Interleucina-8/metabolismo , Pulmão/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Idoso , Biomarcadores/metabolismo , Complemento C3a/genética , Complemento C5a/genética , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/mortalidade , Feminino , Humanos , Interleucina-8/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Análise de Sobrevida , Regulação para CimaRESUMO
The intestinal epithelium not only provides a vital physical barrier between the host and environment but is also required for uptake of nutrients and the induction of tolerance against commensals. Deregulation of any of these functions leads to several disease states including chronic infection, inflammatory bowel disease, and cancer. Here, we describe a novel role for the complement regulator CD46 in the regulation of intestinal epithelial cell (IEC) barrier function. We found that CD46 directly interacts in IECs with the cytoplasmic kinase SPAK and with transmembrane E-cadherin, both proteins necessary for epithelial cell junction and barrier formation. Further, CD46 activation on Caco-2 cells induced rapid and significant decrease in transepithelial resistance with concomitant increase in paracellular permeability. Importantly, though CD46 activation of IEC layers allowed for increased transgression of pathogenic E. coli, it also increased epithelial cell proliferation and accelerated wound repair. These data suggest a previously unappreciated role for CD46 in the maintenance of epithelial cell barrier integrity as well as barrier repair. However, this role for CD46 as "gate keeper" of the epithelium could also provide reason as to why so many pathogens bind to CD46 as such event would facilitate infection.