RESUMO
BACKGROUND: Platelets can infiltrate ischemic myocardium and are increasingly recognized as critical regulators of inflammatory processes during myocardial ischemia and reperfusion (I/R). Platelets contain a broad repertoire of microRNAs (miRNAs), which, under certain conditions such as myocardial ischemia, may be transferred to surrounding cells or released into the microenvironment. Recent studies could demonstrate that platelets contribute substantially to the circulating miRNA pool holding the potential for so far undiscovered regulatory functions. The present study aimed to determine the role of platelet-derived miRNAs in myocardial injury and repair following myocardial I/R. METHODS: In vivo model of myocardial I/R, multimodal in vivo and ex vivo imaging approaches (light-sheet fluorescence microscopy, positron emission tomography and magnetic resonance imaging, speckle-tracking echocardiography) of myocardial inflammation and remodeling, and next-generation deep sequencing analysis of platelet miRNA expression. RESULTS: In mice with a megakaryocyte/platelet-specific knockout of pre-miRNA processing ribonuclease Dicer, the present study discloses a key role of platelet-derived miRNAs in the tightly regulated cellular processes orchestrating left ventricular remodeling after myocardial I/R following transient left coronary artery ligation. Disruption of the miRNA processing machinery in platelets by deletion of Dicer resulted in increased myocardial inflammation, impaired angiogenesis, and accelerated development of cardiac fibrosis, culminating in an increased infarct size by d7 that persisted through d28 of myocardial I/R. Worsened cardiac remodeling after myocardial infarction in mice with a platelet-specific Dicer deletion resulted in an increased fibrotic scar formation and distinguishably increased perfusion defect of the apical and anterolateral wall at day 28 post-myocardial infarction. Altogether, these observations culminated in an impaired left ventricular function and hampered long-term cardiac recovery after experimental myocardial infarction and reperfusion therapy. Treatment with the P2Y12 (P2Y purinoceptor 12) antagonist ticagrelor completely reversed increased myocardial damage and adverse cardiac remodeling observed in DicerPf4∆/Pf4∆ mice. CONCLUSIONS: The present study discloses a critical role of platelet-derived miRNA in myocardial inflammation and structural remodeling processes following myocardial I/R.
Assuntos
Doença da Artéria Coronariana , MicroRNAs , Infarto do Miocárdio , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , Camundongos , Animais , Plaquetas/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Remodelação Ventricular , Traumatismo por Reperfusão Miocárdica/metabolismo , Isquemia Miocárdica/metabolismo , Infarto do Miocárdio/patologia , Doença da Artéria Coronariana/metabolismo , Inflamação/metabolismo , Modelos Animais de DoençasRESUMO
We present compelling evidence for the existence of an extended innate viperin-dependent pathway, which provides crucial evidence for an adaptive response to viral agents, such as SARS-CoV-2. We show the in vivo biosynthesis of a family of novel endogenous cytosine metabolites with potential antiviral activities. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy revealed a characteristic spin-system motif, indicating the presence of an extended panel of urinary metabolites during the acute viral replication phase. Mass spectrometry additionally enabled the characterization and quantification of the most abundant serum metabolites, showing the potential diagnostic value of the compounds for viral infections. In total, we unveiled ten nucleoside (cytosine- and uracil-based) analogue structures, eight of which were previously unknown in humans allowing us to propose a new extended viperin pathway for the innate production of antiviral compounds. The molecular structures of the nucleoside analogues and their correlation with an array of serum cytokines, including IFN-α2, IFN-γ, and IL-10, suggest an association with the viperin enzyme contributing to an ancient endogenous innate immune defense mechanism against viral infection.
Assuntos
COVID-19 , Humanos , Estrutura Molecular , SARS-CoV-2 , Imunidade Inata , Citosina , Redes e Vias Metabólicas , AntiviraisRESUMO
Peptides and proteins have recently emerged as efficient therapeutic alternatives to conventional therapies. Although they emerged a few decades back, extensive exploration of various ailments or disorders began recently. The drawbacks of current chemotherapies and irradiation treatments, such as drug resistance and damage to healthy tissues, have enabled the rise of peptides in the quest for better prospects. The chemical tunability and smaller size make them easy to design selectively for target tissues. Other remarkable properties include antifungal, antiviral, anti-inflammatory, protection from hemorrhage stroke, and as therapeutic agents for gastric disorders and Alzheimer and Parkinson diseases. Despite these unmatched properties, their practical applicability is often hindered due to their weak susceptibility to enzymatic digestion, serum degradation, liver metabolism, kidney clearance, and immunogenic reactions. Several methods are adapted to increase the half-life of peptides, such as chemical modifications, fusing with Fc fragment, change in amino acid composition, and carrier-based delivery. Among these, nanocarrier-mediated encapsulation not only increases the half-life of the peptides in vivo but also aids in the targeted delivery. Despite its structural complexity, they also efficiently deliver therapeutic molecules across the blood-brain barrier. Here, in this review, we tried to emphasize the possible potentiality of metallic nanoparticles to be used as an efficient peptide delivery system against brain tumors and neurodegenerative disorders. SIGNIFICANCE STATEMENT: In this review, we have emphasized the various therapeutic applications of peptides/proteins, including antimicrobial, anticancer, anti-inflammatory, and neurodegenerative diseases. We also focused on these peptides' challenges under physiological conditions after administration. We highlighted the importance and potentiality of metallic nanocarriers in the ability to cross the blood-brain barrier, increasing the stability and half-life of peptides, their efficiency in targeting the delivery, and their diagnostic applications.
Assuntos
Nanopartículas , Doenças Neurodegenerativas , Humanos , Portadores de Fármacos/química , Nanopartículas/química , Encéfalo , Barreira Hematoencefálica/metabolismo , Peptídeos/química , Doenças Neurodegenerativas/metabolismo , Anti-Inflamatórios , Sistemas de Liberação de MedicamentosRESUMO
INTRODUCTION: Systemic Lupus Erythematosus (SLE) warrants an early diagnosis and prompt management. Delay in diagnosis can result in repeated flares, permanent damage, and even death. There is a large variability in the time taken to diagnose SLE across the world. We undertook this study to determine the time taken for diagnosis of SLE in India and to identify the factors associated. METHODS: Patients with SLE diagnosed within the previous 1 year as per Systemic Lupus Erythematosus International Collaborating Clinics criteria (SLICC) 2012 criteria were included in a cross-sectional multicentre questionnaire-based survey. Demographic profile, self-reported socioeconomic status as per Kuppuswamy classification of socioeconomic status (version 2022) (SES), and several healthcare related parameters including referral pattern were recorded. Median time taken for diagnosis was used to demarcate early or late diagnosis and associated factors were explored. RESULTS: We included 488 patients with SLE from 10 rheumatology centres. The median time to diagnosis was 6 months Interquartile Range (IQR 3,14.7) and within 3 months in about one third [150(30.7%)]. Very early diagnosis (<1 month) was established in 78(16.0%) patients. The mean SLE Disease Activity Index (SLEDAI) at diagnosis was 10.28+7.24. In univariate analysis, an older age, lower SES, non-southern state of residence and larger family size were significantly associated with late diagnosis. In the multivariate analysis, higher SES (AOR 0.95, 95% CI: 0.92-0.98), multiple organ system involvement at initial presentation (AOR1.75 95%CI: 1.08-2.84) and place of residence in south Indian states (AOR1.92 95%CI: 1.24-2.97) had lesser odds of being associated with late diagnosis. Distance from the closest medical centre/professional did not influence the time to diagnosis. Majority of patients had first consulted a medical graduate (42.5%) or postgraduate doctor (48.2%), and referral to rheumatologist was largely done by postgraduate (65%) doctors. More than half of our patients (61%) self-finance their treatment. CONCLUSION: Median time to diagnosis of SLE was 6 months, 1/3rd being diagnosed within 3 months and 78(16.0%) with 1 month of symptom onset. Delay in diagnosis was noted in those belonging to lower socioeconomic strata and those with single organ disease. Distance to the health care facility did not influence time to diagnosis.
Assuntos
Diagnóstico Precoce , Lúpus Eritematoso Sistêmico , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Feminino , Estudos Transversais , Masculino , Adulto , Índia , Pessoa de Meia-Idade , Diagnóstico Tardio/estatística & dados numéricos , Reumatologia , Adulto Jovem , Índice de Gravidade de Doença , Fatores de Tempo , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: The stratification of individuals suffering from acute and post-acute SARS-CoV-2 infection remains a critical challenge. Notably, biomarkers able to specifically monitor viral progression, providing details about patient clinical status, are still not available. Herein, quantitative metabolomics is progressively recognized as a useful tool to describe the consequences of virus-host interactions considering also clinical metadata. METHODS: The present study characterized the urinary metabolic profile of 243 infected individuals by quantitative nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography mass spectrometry (LC-MS). Results were compared with a historical cohort of noninfected subjects. Moreover, we assessed the concentration of recently identified antiviral nucleosides and their association with other metabolites and clinical data. RESULTS: Urinary metabolomics can stratify patients into classes of disease severity, with a discrimination ability comparable to that of clinical biomarkers. Kynurenines showed the highest fold change in clinically-deteriorated patients and higher-risk subjects. Unique metabolite clusters were also generated based on age, sex, and body mass index (BMI). Changes in the concentration of antiviral nucleosides were associated with either other metabolites or clinical variables. Increased kynurenines and reduced trigonelline excretion indicated a disrupted nicotinamide adenine nucleotide (NAD+) and sirtuin 1 (SIRT1) pathway. CONCLUSIONS: Our results confirm the potential of urinary metabolomics for noninvasive diagnostic/prognostic screening and show that the antiviral nucleosides could represent novel biomarkers linking viral load, immune response, and metabolism. Moreover, we established for the first time a casual link between kynurenine accumulation and deranged NAD+/SIRT1, offering a novel mechanism through which SARS-CoV-2 manipulates host physiology.
Assuntos
COVID-19 , Humanos , COVID-19/diagnóstico , Sirtuína 1 , NAD , SARS-CoV-2 , Metabolômica/métodos , Biomarcadores/urina , Antivirais , Teste para COVID-19RESUMO
After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.
Assuntos
Endométrio , Neovascularização Patológica , Fator de Crescimento Placentário , Pré-Eclâmpsia , Proteínas Serina-Treonina Quinases , Fatores de Transcrição , Feminino , Humanos , Gravidez , Endométrio/metabolismo , Endométrio/irrigação sanguínea , Ensaio de Imunoadsorção Enzimática , Proteínas Imediatamente Precoces/metabolismo , Neovascularização Patológica/metabolismo , Fator de Crescimento Placentário/metabolismo , Pré-Eclâmpsia/metabolismo , Pré-Eclâmpsia/fisiopatologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Fatores de Transcrição/metabolismoRESUMO
INTRODUCTION: Health-related physical fitness, which includes body composition, cardiorespiratory fitness, muscular endurance, flexibility, power, and strength are associated with risks of chronic diseases and promote good health and wellness. There have been reports of increasing levels of physical inactivity among children and adolescents, leading to increasing rates of obesity and decreased physical fitness. The present study was conducted among school going adolescents to estimate the levels and correlates of PF for timely intervention. METHODOLOGY: School based cross-sectional study was done among students of class 8-11th in Government schools of Garhwal division of Uttarakhand. Multistage stratified random sampling was applied for recruitment of study participants. We recruited a final sample size of 634 students. Validated questionnaires and standard methods for assessment of physical fitness, physical activity levels and other variables such as waist circumference, hip circumference, BMI and hemoglobin estimation were done. RESULTS: Average and above average cardiorespiratory fitness score as per Harvard step test among boys (54.3%) was significantly higher as compared to girls (21.3%) (χ2 = 88.93, p < 0.001). There was a significant association between gender and dominant handgrip strength (χ2 = 8.02, p = 0.01) as well as between gender and Shoulder stretch test (SST) of dominant (χ2 = 17.5, p < 0.05) as well as nondominant arm (χ2 = 13.5, p < 0.05). Sit and reach test results also showed a significant association with gender (χ2 = 27.17, p < 0.001). Gender, hemoglobin level, BMI and PAL scores significantly predicted cardiorespiratory fitness scores (R2 = 0.188, F value of the model = 37.69, p =< 0.001)). CONCLUSION: Physical fitness of school going adolescents in Garhwal division of Uttarakhand was better than other parts of India, with significant gender differences. Physical activity levels (PAL) were poor and are also a significant predictor of physical fitness. More emphasis needs to be paid on the health and fitness of girl students. School based policies to increase PAL among students through innovation and rewards may go a long way in improving the long-term health of the students.
Assuntos
Força da Mão , Aptidão Física , Masculino , Feminino , Criança , Humanos , Adolescente , Estudos Transversais , Índice de Massa Corporal , Exercício Físico , HemoglobinasRESUMO
Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; PTGS2) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (HIF1A). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5-HIF-1α-COX2 axis could promote endometrial cancer progression.
Assuntos
Neoplasias do Endométrio , Regulação da Expressão Gênica , Humanos , Feminino , Ciclo-Oxigenase 2/genética , Neoplasias do Endométrio/genética , Fatores de Transcrição NFATC , Transdução de Sinais , Dinoprostona , Fator V , Fatores de TranscriçãoRESUMO
INTRODUCTION: Patients with SLE (systemic lupus erythematosus) have a higher risk of infection due to dysregulated immune system as well as long-term use of immunosuppressants (IS). This could influence the risk of COVID-19 and its outcome. METHODS: We conducted a longitudinal prospective study across 15 rheumatology centres during the first wave of the pandemic to understand the risk factors contributing to COVID-19 in SLE patients. During the 6 months follow-up, those who tested positive for COVID-19, their clinical course and outcome information were recorded. RESULTS: Through the study period (April-December 2020), 36/1379 lupus patients (2.9%) developed COVID-19. On analysing the COVID-19 positive versus negative cohort during the study period, male gender (adjusted RR 3.72, 95% C.I. 1.85,7.51) and diabetes (adjusted RR 2.94, 95% C.I. 1.28, 6.79) emerged as the strongest risk factors for COVID-19, in the adjusted analysis. There was no significant influence of organ involvement, hydroxychloroquine, glucocorticoid dosage (prednisolone< 7.5 mg or ≥ 7.5 mg/day) or IS on the risk of COVID-19. There was only one death (1/36) among the lupus patients due to COVID-19. CONCLUSION: Traditional risk factors rather than lupus disease process or IS influenced the risk of COVID-19 in our cohort.
Assuntos
COVID-19 , Lúpus Eritematoso Sistêmico , Humanos , Masculino , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Estudos Prospectivos , COVID-19/complicações , Estudos Longitudinais , Imunossupressores/efeitos adversos , Fatores de RiscoRESUMO
BACKGROUND: The poor prognosis of ovarian cancer patients is strongly related to peritoneal metastasis with the production of malignant ascites. However, it remains largely unclear how ascites in the peritoneal cavity influences tumor metabolism and recurrence. This study is an explorative approach aimed at for a deeper molecular and physical-chemical characterization of malignant ascites and to investigate their effect on in vitro ovarian cancer cell proliferation. METHODS: This study included 10 malignant ascites specimens from patients undergoing ovarian cancer resection. Ascites samples were deeply phenotyped by 1H-NMR based metabolomics, blood-gas analyzer based gas flow analysis and flow cytomertry based a 13-plex cytokine panel. Characteristics of tumor cells were investigated in a 3D spheroid model by SEM and metabolic activity, adhesion, anti-apoptosis, migratory ability evaluated by MTT assay, adhesion assay, flowcytometry and scratch assay. The effect of different pH values was assessed by adding 10% malignant ascites to the test samples. RESULTS: The overall extracellular (peritoneal) environment was alkaline, with pH of ascites at stage II-III = 7.51 ± 0.16, and stage IV = 7.78 ± 0.16. Ovarian cancer spheroids grew rapidly in a slightly alkaline environment. Decreasing pH of the cell culture medium suppressed tumor features, metabolic activity, adhesion, anti-apoptosis, and migratory ability. However, 10% ascites could prevent tumor cells from being affected by acidic pH. Metabolomics analysis identified stage IV patients had significantly higher concentrations of alanine, isoleucine, phenylalanine, and glutamine than stage II-III patients, while stage II-III patients had significantly higher concentrations of 3-hydroxybutyrate. pH was positively correlated with acetate, and acetate positively correlated with lipid compounds. IL-8 was positively correlated with lipid metabolites and acetate. Glutathione and carnitine were negatively correlated with cytokines IL-6 and chemokines (IL-8 & MCP-1). CONCLUSION: Alkaline malignant ascites facilitated ovarian cancer progression. Additionally, deep ascites phenotyping by metabolomics and cytokine investigations allows for a refined stratification of ovarian cancer patients. These findings contribute to the understanding of ascites pathology in ovarian cancer.
Assuntos
Neoplasias Ovarianas , Neoplasias Peritoneais , Humanos , Feminino , Interleucina-8 , Ascite/metabolismo , Neoplasias Ovarianas/patologia , Proliferação de Células , Citocinas , LipídeosRESUMO
Acute pancreatitis (AP) is a rare but life threatening manifestation of Systemic Lupus Erythematosus (SLE). The current study aims to study the clinical characteristics, severity, mortality, and outcome of SLE-related AP in Indian population. We retrospectively reviewed medical records of patients with SLE who had AP in the past. Data from 13 rheumatology centers across India were compiled. All patients satisfied SLICC criteria for SLE and ATLANTA criteria for AP. AP was classified in to mild, moderate and severe using revised Atlanta classification. Patients with known risk factors like gall stone and alcohol were excluded.Sixty-six patients (six, children) were studied. Majority of patients were females (82%). The median age of presentation was 24 (11-63) years and most patients (57.5%) presented within first year of diagnosis of lupus. AP occurred mostly in the setting of active lupus (89%). Active nephritis was seen in 39% while a fourth had CNS disease. Patients with severe AP had lower C3. Ascites and sepsis were most common local and systemic complications, respectively. Mortality was 17%. Hypocalcemia, presence of sepsis and shock predicted mortality. In the multivariate analysis, only presence of shock remained as independent predictor of death (OR 63.0, 95% CI: 5.2-760.3). Pancreatitis is an early manifestation of SLE and is associated with active disease. Significant mortality is seen particularly with severe pancreatitis.
Assuntos
Lúpus Eritematoso Sistêmico , Pancreatite , Sepse , Doença Aguda , Adulto , Criança , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Pancreatite/diagnóstico , Pancreatite/etiologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
Glucose uptake into lymphocytes is accomplished by non-concentrative glucose carriers of the GLUT family (GLUT1, GLUT3, GLUT4, GLUT6) and/or by the Na+-coupled glucose carrier SGLT1. The latter accumulates glucose against glucose gradients and is still effective at very low extracellular glucose concentrations. Signaling involved in SGLT1 expression and activity includes protein kinase A (PKA), protein kinase C (PKC), serum- and glucocorticoid-inducible kinase (SGK1), AMP-activated kinase (AMPK), and Janus kinases (JAK2 and JAK3). Glucose taken up is partially stored as glycogen. In hypoxic environments, such as in tumors as well as infected and inflamed tissues, lymphocytes depend on energy production from glycogen-dependent glycolysis. The lack of SGLT1 may compromise glycogen storage and thus lymphocyte survival and function in hypoxic tissues. Accordingly, in mice, genetic knockout of sglt1 compromised bacterial clearance following Listeria monocytogenes infection leading to an invariably lethal course of the disease. Whether the effect was due to the lack of sglt1 in lymphocytes or in other cell types still remains to be determined. Clearly, additional experimental effort is required to define the role of glucose transport by GLUTs and particularly by SGLT1 for lymphocyte survival and function, as well as orchestration of the host defense against tumors and bacterial infections.
Assuntos
Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Linfócitos/metabolismo , Proteínas de Transporte de Sódio-Glucose/metabolismo , Animais , Glucose/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Humanos , Proteínas Quinases/metabolismo , Transdução de Sinais , Proteínas de Transporte de Sódio-Glucose/genéticaRESUMO
The consumption of dairy products, particularly of low fat milk, has been shown to be associated with the occurrence of Parkinson's disease. This association does not necessarily reflect a pathophysiological role of milk intake in the development of Parkinson's disease. Nevertheless, the present review discusses a potential mechanism possibly mediating an effect of milk consumption on Parkinson's disease. The case is made that milk is tailored in part to support bone mineralization of the suckling offspring and is thus rich in calcium and phosphate. Milk intake is thus expected to enhance intestinal calcium phosphate uptake. As binding to fatty acids impedes Ca2+ absorption, low fat milk is particularly effective. Calcium and phosphate uptake inhibit the formation of 1,25(OH)2D3 (1,25-dihydroxy-vitamin D3 = calcitriol), the active form of vitamin D. Calcium inhibits 1,25(OH)2D3 production in part by suppressing the release of parathyroid hormone, a powerful stimulator of 1,25(OH)2D3 formation. Phosphate excess stimulates the release of fibroblast growth factor FGF23, which suppresses 1,25(OH)2D3 formation, an effect requiring Klotho. 1,25(OH)2D3 is a main regulator of mineral metabolism, but has powerful effects apparently unrelated to mineral metabolism, including suppression of inflammation and influence of multiple brain functions. In mice, lack of 1,25(OH)2D3 and excessive 1,25(OH)2D3 formation have profound effects on several types of behavior, such as explorative behavior, anxiety, grooming and social behavior. 1,25(OH)2D3 is produced in human brain and influences the function of various structures including substantia nigra. In neurons 1,25(OH)2D3 suppresses oxidative stress, inhibits inflammation and stimulates neurotrophin formation thus providing neuroprotection. As a result, 1,25(OH)2D3 is considered to favorably influence the clinical course of Parkinson's disease. In conclusion, consumption of milk could in theory accelerate the downhill course of neuronal function in Parkinson's disease. However, substantial additional experimentation is required to define the putative causal role of 1,25(OH)2D3 in the pathophysiology of Parkinson's disease and its sensitivity to milk consumption.
Assuntos
Inflamação/prevenção & controle , Leite , Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson/epidemiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cálcio/administração & dosagem , Fator de Crescimento de Fibroblastos 23 , Humanos , Inflamação/metabolismo , Inflamação/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/prevenção & controle , Vitamina D/administração & dosagem , Vitamina D/análogos & derivadosRESUMO
The consumption of dairy products, particularly of low fat milk, has been shown to be associated with the occurrence of Parkinson's disease. This association does not necessarily reflect a pathophysiological role of milk intake in the development of Parkinson's disease. Nevertheless, the present review discusses a potential mechanism possibly mediating an effect of milk consumption on Parkinson's disease. The case is made that milk is tailored in part to support bone mineralization of the suckling offspring and is thus rich in calcium and phosphate. Milk intake is thus expected to enhance intestinal calcium phosphate uptake. As binding to fatty acids impedes Ca2+ absorption, low fat milk is particularly effective. Calcium and phosphate uptake inhibit the formation of 1,25(OH)2D3 (1,25-dihydroxy-vitamin D3 = calcitriol), the active form of vitamin D. Calcium inhibits 1,25(OH)2D3 production in part by suppressing the release of parathyroid hormone, a powerful stimulator of 1,25(OH)2D3 formation. Phosphate excess stimulates the release of fibroblast growth factor FGF23, which suppresses 1,25(OH)2D3 formation, an effect requiring Klotho. 1,25(OH)2D3 is a main regulator of mineral metabolism, but has powerful effects apparently unrelated to mineral metabolism, including suppression of inflammation and influence of multiple brain functions. In mice, lack of 1,25(OH)2D3 and excessive 1,25(OH)2D3 formation have profound effects on several types of behavior, such as explorative behavior, anxiety, grooming and social behavior. 1,25(OH)2D3 is produced in human brain and influences the function of various structures including substantia nigra. In neurons 1,25(OH)2D3 suppresses oxidative stress, inhibits inflammation and stimulates neurotrophin formation thus providing neuroprotection. As a result, 1,25(OH)2D3 is considered to favorably influence the clinical course of Parkinson's disease. In conclusion, consumption of milk could in theory accelerate the downhill course of neuronal function in Parkinson's disease. However, substantial additional experimentation is required to define the putative causal role of 1,25(OH)2D3 in the pathophysiology of Parkinson's disease and its sensitivity to milk consumption.
Assuntos
Encéfalo/metabolismo , Calcitriol/metabolismo , Cálcio da Dieta/metabolismo , Cálcio/metabolismo , Leite/metabolismo , Doença de Parkinson/metabolismo , Animais , Calcitriol/antagonistas & inibidores , Cálcio da Dieta/efeitos adversos , Fator de Crescimento de Fibroblastos 23 , Humanos , Leite/efeitos adversos , Doença de Parkinson/etiologia , Doença de Parkinson/prevenção & controle , Fatores de Risco , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/metabolismoRESUMO
INTRODUCTION: Identifying factors predicting adverse pregnancy outcomes involving systemic lupus erythematosus (SLE) is a research priority. The aims of this study were to investigate (a) the maternal and fetal outcomes of pregnant lupus patients and the factors associated with adverse pregnancy outcomes, and (b) the effect of pregnancy on lupus disease activity of these patients. METHODS: This was an ambi-directional study collecting information from five multi-specialist referral centres across the state of Karnataka, India over 5 years (2013-2018). Clinical details of pregnancies and outcomes that were temporally associated with lupus disease were recorded using a structured pro forma. The Safety of Estrogen in SLE National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) was used to assess lupus activity during the 6 months prior to pregnancy and the intra- and post-partum periods. Modifications suggested in the SLE Pregnancy Disease Activity Index were considered while scoring. RESULTS: A total of 121 pregnancies in 80 SLE patients with a mean age of 27.1 (±4.5) years and with a mean disease duration of 4.6 (±4.1) years were reviewed. Largely patients were in clinical remission (109/121; 90.1%). Antiphospholipid antibody positivity was seen in 45/121 (37.2%) patients. A history of lupus nephritis was noted in 29/121 (24%) patients. Maternal complications (32%) were mainly due to hypertensive disorders of pregnancy (HDP; 19/121; 15.7%). Adverse fetal outcomes (58%) were mainly in the form of spontaneous first-trimester abortions (21/121; 16%), stillbirth (14/121; 11.6%) and prematurity (24/121; 20%). HDP is strongly associated with stillbirth and prematurity and is independent of active lupus. Disease activity was associated with a three-fold increased risk of adverse fetal outcome in univariate analysis. The risk of major flare during pregnancy is low (4.1%) when conception occurs during stable disease. Hydroxychloroquine (HCQ) use was associated with reduced risk of flare (p = 0.001) in patients in remission at the time of conception. CONCLUSIONS: The risk of major flare during pregnancy is low when conception happens during stable disease. HCQ use was associated with reduced risk of flare in patients in remission at the time of conception. HDP was strongly associated with stillbirth and prematurity and are independent of active lupus in our cohort.
Assuntos
Aborto Espontâneo/epidemiologia , Lúpus Eritematoso Sistêmico/complicações , Complicações na Gravidez/diagnóstico , Resultado da Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Adulto , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Índia/epidemiologia , Recém-Nascido , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/complicações , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/etiologia , Gravidez , Complicações na Gravidez/etiologia , Indução de Remissão , Índice de Gravidade de Doença , Adulto JovemRESUMO
Rapid and frequent screening of cytokines as immunomodulation agents is necessary for precise interventions in severe pathophysiological conditions. In addition to high-sensitivity detection of such analytes in complex biological fluids such as blood, saliva, and cell culture medium samples, it is also crucial to work out miniaturized bioanalytical platforms with potential for high-density integration enabling screening of multiple analytes. In this work, we show a compact, point-of-care-ready bioanalytical platform for screening of cytokines such as interleukin-4 (IL-4) and interleukin-2 (IL-2) based on one-dimensional ion-sensitive field-effect transistors arrays (nanoISFETs) of silicon fabricated at wafer-scale via nanoimprint lithography. The nanoISFETs biofunctionalized with receptor proteins alpha IL-4 and alpha IL-2 were deployed for screening cytokine secretion in mouse T helper cell differentiation culture media, respectively. Our nanoISFETs showed robust sensor signals for specific molecular binding and can be readily deployed for real-time screening of cytokines. Quantitative analyses of the nanoISFET-based bioanalytical platform was carried out for IL-4 concentrations ranging from 25 fg/mL (1.92 fM) to 2.5 µg/mL (192 nM), showing a limit of detection down to 3-5 fM, which was found to be in agreement with ELISA results in determining IL-4 concentrations directly in complex cell culture media. Graphical abstract.
Assuntos
Citocinas/análise , Sistemas Automatizados de Assistência Junto ao Leito , Transistores Eletrônicos , Animais , Técnicas Biossensoriais/métodos , Técnicas de Cultura de Células , Meios de Cultura/química , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Limite de Detecção , Camundongos , Microscopia de Força Atômica , Estudo de Prova de ConceitoRESUMO
Background: Problem-solving, critical thinking, communication skills and the ability to interpret data are four core components of scientific literacy, which any student must acquire during the educational process. This is of specific relevance to the medical profession as doctors need to be 'scientific' in their approach. The nine domains of scientific literacy are further grouped under two major abilities: understanding methods of enquiry that lead to scientific knowledge and the ability to organize, analyse and interpret quantitative data and scientific information. Methods: We included all first-year medical students within the first 2 months of admission in four medical colleges of India. We used the Test of Scientific Literacy Skills, a self- administered questionnaire, which is a validated and standardized tool for evaluating scientific literacy among students. Results: A total of 525 medical students participated in our study over 3 years-335 were males and the majority of students (73.5%) had joined medical college from schools affiliated with the Central Board of School Education system. The presence of scientific literacy skills across the study sample was low. Conclusion: The relative lack of scientific literacy uncovered by our study needs to be addressed by medical colleges, using innovative student-centred approaches and incorporating social media literacy. Reforms are urgently required in the school education system, which serves as a feeder to the medical education system.
Assuntos
Estudantes de Medicina , Estudos Transversais , Humanos , Alfabetização , Masculino , Resolução de Problemas , UniversidadesRESUMO
We report on magnetization M(H), dc and ac magnetic susceptibility χ(T), specific heat C_{m}(T) and muon spin relaxation (µSR) measurements of the Kitaev honeycomb iridate Cu_{2}IrO_{3} with quenched disorder. In spite of the chemical disorders, we find no indication of spin glass down to 260 mK from the C_{m}(T) and µSR data. Furthermore, a persistent spin dynamics observed by the zero-field muon spin relaxation evidences an absence of static magnetism. The remarkable observation is a scaling relation of χ[H,T] and M[H,T] in H/T with the scaling exponent α=0.26-0.28, expected from bond randomness. However, C_{m}[H,T]/T disobeys the predicted universal scaling law, pointing towards the presence of additional low-lying excitations on the background of bond-disordered spin liquid. Our results signify a many-faceted impact of quenched disorder in a Kitaev spin system due to its peculiar bond character.
RESUMO
In the present study, the adhesive and viscoelastic properties of polydimethylsiloxane (PDMS) based nanocomposite pressure sensitive adhesives (PSAs) with embedded electrospun polyacrylonitrile (PAN) and polyvinyl alcohol (PVA) nanofibers as fillers were investigated. PDMS nanocomposite adhesive films using PAN and PVA nanofibers were synthesized by dispersing fillers in the matrix by a solvent mixing process. The adhesion strength and reusability of the prepared nanocomposite PSA films were measured using peel tests as the fraction of nanofibers in the polymer matrix is increased. The variations of the adhesive properties of the PSAs as function of the type and loading of filler were related to their rheological properties in terms of shear and elastic moduli. Although 3-fold enhancement of the adhesion strength was achieved with 0.5 wt% loading for both types (PAN and PVA) of nanocomposites as compared to elastic PDMS, the composite adhesive with PAN nanofibers can provide a superior balance of rheological properties, resulting in improved reusability over other PSAs. The differences in the adhesion and viscoelastic properties of the composite PSAs are attributed to the polymer chemistry, processability, and architecture of the electrospun nanofibers in the soft PDMS matrix.
RESUMO
Biologic disease-modifying anti-rheumatic drugs (bDMARD) have transformed the treatment paradigm of chronic autoimmune rheumatic diseases (ARDs), but they are often associated with adverse drug reactions. The present study evaluated the frequency, characteristics and type of infections, other than tuberculosis (TB), in ARD patients receiving bDMARDs. The multicentre, cross-sectional, retrospective, observational study was conducted across 12 centers in Karnataka, India, between January to August 2016. The study included patients receiving bDMARD therapy for various ARDs. Outcome variables considered were any infection, minor infections and major infections, other than TB. Clinical variables were compared between infection and no infection group, and the increase in the likelihood of infection with respect to various clinical variables was assessed. The study involved 209 subjects with a median (range) age of 41 (16-84) years and male to female ratio of 0.97:1. A total of 29 (13.88%) subjects developed infection following bDMARD therapy, out of whom a majority had minor infection (n = 26). The likelihood of developing any infection was noted to be more in subjects receiving anti-TNF (golimumab, P = 0.03) and those on three or more conventional synthetic (cs) DMARDs (P < 0.01). Infection risk was higher in patients with systemic lupus erythematosus (P = 0.04), other connective tissue disease (P < 0.01) and in patients with comorbidities (P = 0.13). The risk of infection was associated with the use of anti-TNF therapy and more than three csDMARDs, co morbidities and Adds such as systemic lupus erythematosus and connective tissue disease.