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1.
Mol Med ; 27(1): 129, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34663207

RESUMO

BACKGROUND: Host inflammation contributes to determine whether SARS-CoV-2 infection causes mild or life-threatening disease. Tools are needed for early risk assessment. METHODS: We studied in 111 COVID-19 patients prospectively followed at a single reference Hospital fifty-three potential biomarkers including alarmins, cytokines, adipocytokines and growth factors, humoral innate immune and neuroendocrine molecules and regulators of iron metabolism. Biomarkers at hospital admission together with age, degree of hypoxia, neutrophil to lymphocyte ratio (NLR), lactate dehydrogenase (LDH), C-reactive protein (CRP) and creatinine were analysed within a data-driven approach to classify patients with respect to survival and ICU outcomes. Classification and regression tree (CART) models were used to identify prognostic biomarkers. RESULTS: Among the fifty-three potential biomarkers, the classification tree analysis selected CXCL10 at hospital admission, in combination with NLR and time from onset, as the best predictor of ICU transfer (AUC [95% CI] = 0.8374 [0.6233-0.8435]), while it was selected alone to predict death (AUC [95% CI] = 0.7334 [0.7547-0.9201]). CXCL10 concentration abated in COVID-19 survivors after healing and discharge from the hospital. CONCLUSIONS: CXCL10 results from a data-driven analysis, that accounts for presence of confounding factors, as the most robust predictive biomarker of patient outcome in COVID-19.


Assuntos
COVID-19/diagnóstico , Quimiocina CXCL10/sangue , Doença da Artéria Coronariana/diagnóstico , Diabetes Mellitus/diagnóstico , Hipertensão/diagnóstico , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , COVID-19/sangue , COVID-19/imunologia , COVID-19/mortalidade , Comorbidade , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/mortalidade , Creatina/sangue , Diabetes Mellitus/sangue , Diabetes Mellitus/imunologia , Diabetes Mellitus/mortalidade , Feminino , Hospitalização , Humanos , Hipertensão/sangue , Hipertensão/imunologia , Hipertensão/mortalidade , Imunidade Humoral , Imunidade Inata , Inflamação , Unidades de Terapia Intensiva , L-Lactato Desidrogenase/sangue , Contagem de Leucócitos , Linfócitos/imunologia , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/patologia , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Análise de Sobrevida
2.
Biomed Pharmacother ; 144: 112230, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34628168

RESUMO

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has become a serious challenge for medicine and science. Analysis of the molecular mechanisms associated with the clinical manifestations and severity of COVID-19 has identified several key points of immune dysregulation observed in SARS-CoV-2 infection. For diabetic patients, factors including higher binding affinity and virus penetration, decreased virus clearance and decreased T cell function, increased susceptibility to hyperinflammation, and cytokine storm may make these patients susceptible to a more severe course of COVID-19 disease. Metabolic changes induced by diabetes, especially hyperglycemia, can directly affect the immunometabolism of lymphocytes in part by affecting the activity of the mTOR protein kinase signaling pathway. High mTOR activity can enhance the progression of diabetes due to the activation of effector proinflammatory subpopulations of lymphocytes and, conversely, low activity promotes the differentiation of T-regulatory cells. Interestingly, metformin, an extensively used antidiabetic drug, inhibits mTOR by affecting the activity of AMPK. Therefore, activation of AMPK and/or inhibition of the mTOR-mediated signaling pathway may be an important new target for drug therapy in COVID-19 cases mostly by reducing the level of pro-inflammatory signaling and cytokine storm. These suggestions have been partially confirmed by several retrospective analyzes of patients with diabetes mellitus hospitalized for severe COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Imunidade Celular/efeitos dos fármacos , Metformina/uso terapêutico , Índice de Gravidade de Doença , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/metabolismo , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Imunidade Celular/fisiologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Metformina/farmacologia , Mortalidade/tendências , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/imunologia , Serina-Treonina Quinases TOR/metabolismo
3.
Front Immunol ; 12: 656362, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936084

RESUMO

Since March 2020, the outbreak of Sars-CoV-2 pandemic has changed medical practice and daily routine around the world. Huge efforts from pharmacological industries have led to the development of COVID-19 vaccines. In particular two mRNA vaccines, namely the BNT162b2 (Pfizer-BioNTech) and the mRNA-1273 (Moderna), and a viral-vectored vaccine, i.e. ChAdOx1 nCoV-19 (AstraZeneca), have recently been approved in Europe. Clinical trials on these vaccines have been published on the general population showing a high efficacy with minor adverse events. However, specific data about the efficacy and safety of these vaccines in patients with immune-mediated inflammatory diseases (IMIDs) are still lacking. Moreover, the limited availability of these vaccines requires prioritizing some vulnerable categories of patients compared to others. In this position paper, we propose the point of view about the management of COVID-19 vaccination from Italian experts on IMIDs and the identification of high-risk groups according to the different diseases and their chronic therapy.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/complicações , COVID-19/prevenção & controle , Doenças do Sistema Imunitário/virologia , Vacinação/métodos , Diabetes Mellitus/imunologia , Diabetes Mellitus/virologia , Europa (Continente) , Prova Pericial , Glomerulonefrite/complicações , Glomerulonefrite/imunologia , Glomerulonefrite/virologia , Humanos , Inflamação/imunologia , Inflamação/virologia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/virologia , Pneumopatias/complicações , Pneumopatias/imunologia , Pneumopatias/virologia , Pandemias/prevenção & controle , Doenças Reumáticas/complicações , Doenças Reumáticas/imunologia , Doenças Reumáticas/virologia , Dermatopatias/complicações , Dermatopatias/imunologia , Dermatopatias/virologia , Uveíte/complicações , Uveíte/imunologia , Uveíte/virologia
4.
Adv Protein Chem Struct Biol ; 125: 51-72, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33931144

RESUMO

Mitochondria, conserved intracellular organelles best known as the powerhouse of cells for generating ATP, play an important role in apoptosis. Oxidative stress can induce mitochondrial dysfunction and activate mitochondria-mediated apoptotic cell death. TRPM2 is a Ca2+-permeable cation channel that is activated by pathologically relevant concentrations of reactive oxygen species (ROS) and one of its well-recognized roles is to confer susceptibility to ROS-induced cell death. Increasing evidence from recent studies supports TRPM2 channel-mediated cell death as an important cellular mechanism linking miscellaneous oxidative stress-inducing pathological factors to associated diseased conditions. In this chapter, we will discuss the role of the TRPM2 channel in neurons in the brain and pancreatic ß-cells in mediating mitochondrial dysfunction and cell death, focusing mainly on apoptotic cell death, that are induced by pathological stimuli implicated in the pathogenesis of neurodegenerative diseases, ischemic stroke and diabetes.


Assuntos
Apoptose/imunologia , Diabetes Mellitus/imunologia , AVC Isquêmico/imunologia , Mitocôndrias/imunologia , Doenças Neurodegenerativas/imunologia , Estresse Oxidativo/imunologia , Canais de Cátion TRPM/imunologia , Animais , Cálcio/imunologia , Diabetes Mellitus/patologia , Humanos , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , AVC Isquêmico/patologia , Mitocôndrias/patologia , Doenças Neurodegenerativas/patologia , Neurônios/imunologia , Neurônios/patologia
5.
Am J Med ; 134(9): 1155-1159, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33974907

RESUMO

BACKGROUND: Mucormycosis (zygomycosis) is an invasive fungal infection that carries a high risk of morbidity and mortality. Uncontrolled diabetes mellitus and other immunocompromising conditions are risk factors for mucormycosis development. We here describe the differences in characteristics and outcomes of mucormycosis among solid organ transplant, hematological malignancy, and diabetes mellitus groups at our institution. METHODS: We conducted a retrospective chart review over the period of 2009-2020, with identifying patients using the International Classification of Diseases, Ninth and Tenth Revisions. Clinical, laboratory, and outcome data were collected. RESULTS: There were 28 patients identified: 7 solid organ transplant, 3 hematological malignancy, and 18 diabetes mellitus patients were included in the study. Three solid organ transplant patients experienced an episode of rejection, and another 3 had cytomegalovirus infection prior to presenting with mucormycosis. Four of seven solid organ transplant patients had a history of diabetes mellitus, but the median hemoglobin A1C was lower than in the diabetes mellitus group (6.3 vs 11.5; P = .006). The mortality rate difference between solid organ transplant and diabetes mellitus was not statistically significant: 2/7 (28.57%) vs 5/18 (27.78%); P = .66. Patients with bilateral disease (pulmonary or sinus) had significantly higher mortality (80% vs 13%, P = .008). There was no difference in mortality outcomes among the different types of antifungal therapies administered. CONCLUSION: A multispecialty approach is imperative in mucormycosis therapy. While the underlying risk factors were different, the outcomes were comparable for the solid organ transplant and diabetes mellitus groups. Future larger and longitudinal studies are recommended.


Assuntos
Antifúngicos/uso terapêutico , Diabetes Mellitus , Hospedeiro Imunocomprometido/imunologia , Mucormicose , Arizona/epidemiologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/terapia , Feminino , Hemoglobina A Glicada/análise , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Mucormicose/diagnóstico , Mucormicose/imunologia , Mucormicose/mortalidade , Mucormicose/terapia , Estudos Retrospectivos , Fatores de Risco , Transplantados/estatística & dados numéricos
6.
Islets ; 13(3-4): 66-79, 2021 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-33970787

RESUMO

The link between COVID-19 infection and diabetes has been explored in several studies since the start of the pandemic, with associations between comorbid diabetes and poorer prognosis in patients infected with the virus and reports of diabetic ketoacidosis occurring with COVID-19 infection. As such, significant interest has been generated surrounding mechanisms by which the virus may exert effects on the pancreatic ß cells. In this review, we consider possible routes by which SARS-CoV-2 may impact ß cells. Specifically, we outline data that either support or argue against the idea of direct infection and injury of ß cells by SARS-CoV-2. We also discuss ß cell damage due to a "bystander" effect in which infection with the virus leads to damage to surrounding tissues that are essential for ß cell survival and function, such as the pancreatic microvasculature and exocrine tissue. Studies elucidating the provocation of a cytokine storm following COVID-19 infection and potential impacts of systemic inflammation and increases in insulin resistance on ß cells are also reviewed. Finally, we summarize the existing clinical data surrounding diabetes incidence since the start of the COVID-19 pandemic.


Assuntos
Células Secretoras de Insulina/fisiologia , SARS-CoV-2/fisiologia , Efeito Espectador/fisiologia , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/metabolismo , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/virologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/virologia , Humanos , Inflamação/complicações , Inflamação/metabolismo , Inflamação/virologia , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/virologia , Pandemias , SARS-CoV-2/patogenicidade
7.
Drug Discov Ther ; 15(2): 78-86, 2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-33952764

RESUMO

All open wounds are often colonized by commensal microbes as a loss of skin can provide a ready portal of entry for microorganisms. Although the wound microbiota is known to be associated with wound infection and with delayed healing, the factors related to the formations of wound microbiota contributing to such poor clinical outcomes are not clear and have not led to effective infection prevention interventions. This review aimed to scope the factors related to the composition and diversity of wound microbiota that have been investigated using culture-independent molecular methods. Original articles on wound microbiota published from January 1986 to February 2020 were included in this review. Thirty-one articles met the inclusion criteria and were grouped according to wound types: chronic, acute, and animal model wounds. The factors identified were categorized according to patient characteristics, wound characteristics, treatment, and sampling. Although some studies reported the effect size of the factors, the values were small. No studies elucidated the mechanism of wound microbiota formation. The results of this scoping review highlight that the factors associated with the diversity of wound microbiota are poorly understood and that further studies are needed.


Assuntos
Microbiota/genética , Pele/microbiologia , Infecção dos Ferimentos/microbiologia , Idoso , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Biodiversidade , Diabetes Mellitus/imunologia , Diabetes Mellitus/patologia , Feminino , Humanos , Falência Renal Crônica/imunologia , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Modelos Animais , Pele/patologia , Sequenciamento Completo do Genoma/métodos , Cicatrização/genética , Cicatrização/imunologia , Infecção dos Ferimentos/genética
8.
Front Immunol ; 12: 597399, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33796097

RESUMO

There exists increasing evidence that people with preceding medical conditions, such as diabetes and cancer, have a higher risk of infection with SARS-CoV-2 and are more vulnerable to severe disease. To get insights into the possible role of the immune system upon COVID-19 infection, 2811 genes of the gene ontology term "immune system process GO: 0002376" were selected for coexpression analysis of the human targets of SARS-CoV-2 (HT-SARS-CoV-2) ACE2, TMPRSS2, and FURIN in tissue samples from patients with cancer and diabetes mellitus. The network between HT-SARS-CoV-2 and immune system process genes was analyzed based on functional protein associations using STRING. In addition, STITCH was employed to determine druggable targets. DPP4 was the only immune system process gene, which was coexpressed with the three HT-SARS-CoV-2 genes, while eight other immune genes were at least coexpressed with two HT-SARS-CoV-2 genes. STRING analysis between immune and HT-SARS-CoV-2 genes plotted 19 associations of which there were eight common networking genes in mixed healthy (323) and pan-cancer (11003) tissues in addition to normal (87), cancer (90), and diabetic (128) pancreatic tissues. Using this approach, three commonly applicable druggable connections between HT-SARS-CoV-2 and immune system process genes were identified. These include positive associations of ACE2-DPP4 and TMPRSS2-SRC as well as a negative association of FURIN with ADAM17. Furthermore, 16 drugs were extracted from STITCH (score <0.8) with 32 target genes. Thus, an immunological network associated with HT-SARS-CoV-2 using bioinformatics tools was identified leading to novel therapeutic opportunities for COVID-19.


Assuntos
Diabetes Mellitus/metabolismo , Neoplasias/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/química , Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/genética , COVID-19/imunologia , COVID-19/metabolismo , Bases de Dados Genéticas , Diabetes Mellitus/genética , Diabetes Mellitus/imunologia , Diabetes Mellitus/virologia , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Furina/genética , Furina/metabolismo , Regulação da Expressão Gênica/imunologia , Ontologia Genética , Estudo de Associação Genômica Ampla , Genômica , Humanos , Linfócitos/imunologia , Linfócitos/metabolismo , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/virologia , Pâncreas/imunologia , Pâncreas/metabolismo , Pâncreas/virologia , Mapas de Interação de Proteínas/genética , Mapas de Interação de Proteínas/imunologia , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
9.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804135

RESUMO

BACKGROUND: End-stage renal disease (ESRD) is associated with alterations in T-cell immunity, including increased CD28null and reduced regulatory T cells (Tregs). However, whether immune disturbances are due to ESRD or primary disease is not yet clear. As diabetes mellitus is the leading cause of ESRD, we evaluated its impact on the immune profile of ESRD patients. METHODS: CD28null, Tregs, and natural killer cells were initially analyzed by flow cytometry in 30 predialysis ESRD patients due to diabetes (DM), 30 non-DM (NDM), and 25 healthy controls. Measurements were repeated after 6 months on hemodialysis (HD) or peritoneal dialysis (CAPD). RESULTS: The percentage of CD4 + CD28null cells, CD8 + CD28null cells, and Tregs showed significant differences in DM, NDM, and controls; mean rank 33.71 vs. 25.68 vs. 18.88, p = 0.006, 37.79 vs. 28.82 vs. 17.08, p = 0.008, and 20.79 vs. 26.12 vs. 41.33, p = 0.001, respectively. DM vs. NDM had increased CD4 + CD28null and CD8 + CD28null cells, 11.5% (1.5%-24%) vs. 4.1% (0-42.3%), p = 0.02 and 61.3% (24%-76%) vs. 43% (5.7%-85%), p = 0.04, respectively. After 6 months on HD but not CAPD, DM showed a significant further increase in CD4 + CD28null cells, from 30 (14-100) to 52.7 (15-203), p = 0.02; and CD8 + CD28null cells, from 137 (56-275) to 266 (103-456), p = 0.01. CONCLUSIONS: Diabetes mellitus affects T-cell subtypes even at predialysis stage, though changes become more prominent after commencement on HD.


Assuntos
Complicações do Diabetes/imunologia , Diabetes Mellitus/imunologia , Falência Renal Crônica/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Antígenos CD28/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Complicações do Diabetes/genética , Complicações do Diabetes/patologia , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Feminino , Citometria de Fluxo , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/genética , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Diálise Renal
10.
J Neuroimmunol ; 355: 577574, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33894676

RESUMO

A large proportion of older individuals with diabetes go on to develop diabetic peripheral neuropathy (DPN). DPN is associated with an increase in inflammatory cells within the peripheral nerve, activation of nuclear factor kappa-light-chain-enhancer of activated B cells and receptors for advanced glycation end products/advanced glycation end products pathways, aberrant cytokine expression, oxidative stress, ischemia, as well as pro-inflammatory changes in the bone marrow; all processes that may be exacerbated with age. We review the immunological features of DPN and discuss whether age-related changes in relevant immunological areas may contribute to age being a risk factor for DPN.


Assuntos
Envelhecimento/imunologia , Diabetes Mellitus/imunologia , Neuropatias Diabéticas/imunologia , Imunidade/imunologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/patologia , Humanos , Imunidade/efeitos dos fármacos , Imunoterapia/métodos , Imunoterapia/tendências , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/patologia
11.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672515

RESUMO

Immunotherapy is now a recognized treatment option for several types of cancer. However, some cancer patients treated with immune checkpoint inhibitors (ICIs) are subject to immune-related adverse events, including induced diabetes mellitus. The exact role and molecular/genetic action of ICIs in diabetes are still not well understood. Elucidating the underlying mechanisms in a proper fashion would allow better refining of biomarkers that would help diagnose patients at risk of altered immune system homeostasis, but would also hold the potential of new therapeutic options for diabetes. In the present narrative review, we propose to discuss the case of autoimmune diabetes following treatment with ICIs and the role of ICIs in the pathophysiology of diabetes. We also present some scarce available data on interesting potential immune therapies for diabetes.


Assuntos
Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Linfócitos T/imunologia , Animais , Antígeno B7-H1/metabolismo , Diabetes Mellitus/patologia , Humanos , Imunoterapia , Receptor de Morte Celular Programada 1/metabolismo
12.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669239

RESUMO

Irregular inflammatory responses are a major contributor to tissue dysfunction and inefficient repair. Skin has proven to be a powerful model to study mechanisms that regulate inflammation. In particular, skin wound healing is dependent on a rapid, robust immune response and subsequent dampening of inflammatory signaling. While injury-induced inflammation has historically been attributed to keratinocytes and immune cells, a vast body of evidence supports the ability of non-immune cells to coordinate inflammation in numerous tissues and diseases. In this review, we concentrate on the active participation of tissue-resident adipocytes and fibroblasts in pro-inflammatory signaling after injury, and how altered cellular communication from these cells can contribute to irregular inflammation associated with aberrant wound healing. Furthering our understanding of how tissue-resident mesenchymal cells contribute to inflammation will likely reveal new targets that can be manipulated to regulate inflammation and repair.


Assuntos
Adipócitos Brancos/imunologia , Derme/citologia , Derme/lesões , Fibroblastos/imunologia , Cicatrização/imunologia , Envelhecimento/imunologia , Envelhecimento/metabolismo , Animais , Comunicação Celular/imunologia , Polaridade Celular/imunologia , Citocinas/metabolismo , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Células-Tronco Mesenquimais/metabolismo , Transdução de Sinais/imunologia
13.
Int J Immunopathol Pharmacol ; 35: 20587384211005645, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33779346

RESUMO

Protective effects of peroxiredoxin 6 (PRDX6) in RIN-m5F ß-cells and of thymulin in mice with alloxan-induced diabetes were recently reported. The present work was aimed at studying the efficiency of thymulin and PRDX6 in a type 1 diabetes mellitus model induced by streptozotocin in mice. Effects of prolonged treatment with PRDX6 or thymic peptide thymulin on diabetes development were evaluated. We assessed the effects of the drugs on the physiological status of diabetic mice by measuring blood glucose, body weight, and cell counts in several organs, as well as effects of thymulin and PRDX6 on the immune status of diabetic mice measuring concentrations of pro-inflammatory cytokines in blood plasma (TNF-α, interleukin-5 and 17, and interferon-γ), activity of NF-κB and JNK pathways, and Hsp90α expression in immune cells. Both thymulin and PRDX6 reduced the physiological impairments in diabetic mice at various levels. Thymulin and PRDX6 provide beneficial effects in the model of diabetes via very different mechanisms. Taken together, the results of our study indicated that the thymic peptide and the antioxidant enzyme have anti-inflammatory functions. As increasing evidences show diabetes mellitus as a distinct comorbidity leading to acute respiratory distress syndrome and increased mortality in patients with COVID-19 having cytokine storm, thymulin, and PRDX6 might serve as a supporting anti-inflammatory treatment in the therapy of COVID 19 in diabetic patients.


Assuntos
COVID-19 , MAP Quinase Quinase 4/metabolismo , NF-kappa B/metabolismo , Peroxirredoxina VI , Transdução de Sinais , Fator Tímico Circulante , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , COVID-19/tratamento farmacológico , COVID-19/imunologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/terapia , Descoberta de Drogas , Interferon gama/sangue , Interleucinas/sangue , Camundongos , Peroxirredoxina VI/metabolismo , Peroxirredoxina VI/farmacologia , SARS-CoV-2 , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator Tímico Circulante/metabolismo , Fator Tímico Circulante/farmacologia , Fator de Necrose Tumoral alfa/sangue
15.
Expert Rev Clin Immunol ; 17(3): 201-208, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33538189

RESUMO

INTRODUCTION: In people living with HIV (PLWH), immune activation and inflammation levels are high even when viral suppression is maintained, potentially contributing to several comorbidities, and hampering the immune response to infections such as the recent SARS-CoV-2 disease 2019 (COVID-19). AREAS COVERED: Immune activation and inflammation play a role in SARS-CoV-2 infection. Severe COVID-19 patients may experience cytokine release syndrome (CRS), leading to alveolar damage, pulmonary fibrinolysis, dysregulated coagulation, and pulmonary injury. Into the systemic circulation, cytokines in excess might leak out of pulmonary circulation, causing systemic symptoms and possibly a multiple-organ dysfunction syndrome. Preexisting comorbidities are also linked to worse COVID-19 outcome: studies suggest that diabetes and hypertension are linked to higher mortality rates. Such comorbidities are more frequent in PLWH, but it is unclear if they have worse outcomes in the case of COVID-19. The literature was searched in PubMed/MEDLINE and EMBASE, and manually in COVID-19 resources. EXPERT OPINION: A body of evidence shows that HIV and SARS-CoV-2 are able to activate inflammatory pathways, acute in the case of SARS-CoV-2, chronic in the case of HIV, while the comorbidities seem to represent, in the first case, a contributory cause, in the second an effect of the virus-induced damage.


Assuntos
COVID-19/epidemiologia , COVID-19/imunologia , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Transtornos da Coagulação Sanguínea/epidemiologia , Transtornos da Coagulação Sanguínea/imunologia , Comorbidade , Citocinas/imunologia , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/imunologia , Humanos , Hiperglicemia/epidemiologia , Hiperglicemia/imunologia , Hipertensão/epidemiologia , Hipertensão/imunologia , Inflamação , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/imunologia , SARS-CoV-2
16.
Diabet Med ; 38(5): e14547, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33615546

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has posed enormous challenges to healthcare systems worldwide. The negative impact of COVID-19 is widespread and includes not only people who contracted the disease but also those with chronic morbidities such as diabetes whose care is compromised due to diversion of medical resources. People with diabetes are generally more susceptible to infection as a result of altered immunity. People with diabetes have a worse prognosis from COVID-19 and there is evidence to suggest that severe acute respiratory syndrome coronavirus 2 may directly affect pancreatic function precipitating hyperglycaemic crises. In the United Kingdom, one of the most heavily affected countries, guidelines are in place to unify the management of people with diabetes hospitalized for COVID-19. Diabetes services are re-organized to ensure that medical care of people with diabetes is maintained despite resource and other practical constraints. Public health measures including social distancing, hand hygiene and the use of face masks are crucial in containing community transmission of the virus. Hong Kong, one of the most densely populated city in the world, is particularly vulnerable and has in place a stringent containment policy and aggressive contact tracing to ensure public safety during this pandemic.


Assuntos
COVID-19/epidemiologia , Controle de Doenças Transmissíveis/métodos , Diabetes Mellitus/epidemiologia , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/terapia , Comorbidade , Atenção à Saúde/organização & administração , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/terapia , Controle Glicêmico , Higiene das Mãos , Hong Kong/epidemiologia , Humanos , Hospedeiro Imunocomprometido/imunologia , Infecções/epidemiologia , Infecções/imunologia , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Máscaras , Distanciamento Físico , Guias de Prática Clínica como Assunto , Política Pública , Risco , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Reino Unido/epidemiologia
18.
JCI Insight ; 6(6)2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33621211

RESUMO

Comorbid medical illnesses, such as obesity and diabetes, are associated with more severe COVID-19, hospitalization, and death. However, the role of the immune system in mediating these clinical outcomes has not been determined. We used multiparameter flow cytometry and systems serology to comprehensively profile the functions of T cells and antibodies targeting spike, nucleocapsid, and envelope proteins in a convalescent cohort of COVID-19 subjects who were either hospitalized (n = 20) or not hospitalized (n = 40). To avoid confounding, subjects were matched by age, sex, ethnicity, and date of symptom onset. Surprisingly, we found that the magnitude and functional breadth of virus-specific CD4+ T cell and antibody responses were consistently higher among hospitalized subjects, particularly those with medical comorbidities. However, an integrated analysis identified more coordination between polyfunctional CD4+ T cells and antibodies targeting the S1 domain of spike among subjects who were not hospitalized. These data reveal a functionally diverse and coordinated response between T cells and antibodies targeting SARS-CoV-2, which is reduced in the presence of comorbid illnesses that are known risk factors for severe COVID-19.


Assuntos
Anticorpos Antivirais/fisiologia , Linfócitos T CD4-Positivos/fisiologia , COVID-19/virologia , Hospitalização , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus , Vírion , Adulto , Idoso , Anticorpos Neutralizantes/metabolismo , Anticorpos Neutralizantes/fisiologia , Anticorpos Antivirais/metabolismo , Linfócitos T CD4-Positivos/metabolismo , COVID-19/epidemiologia , COVID-19/imunologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/imunologia , Comorbidade , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/imunologia , Feminino , Humanos , Imunidade Humoral , Masculino , Pessoa de Meia-Idade , Nucleocapsídeo , Índice de Gravidade de Doença , Envelope Viral , Proteínas Virais , Adulto Jovem
19.
J Immunol Methods ; 497: 113002, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33640327

RESUMO

Highly sensitive assays for anti-drug antibodies (ADAs) are both a regulatory requirement and requisite for proper evaluation of the effects of immunogenicity on clinical efficacy and safety. Determination of ADA assay sensitivity depends on positive control antibodies to represent naturally occurring or treatment-induced ADA responses. An accurate determination of the proportion of drug-specific antibodies in these polyclonal positive control batches is critical for correct evaluation of assay sensitivity. Target purification of positive control antibodies is commonly applied but infers the risk to lose a proportion of the antibodies. This may lead to an incorrect estimate of the ADA assay sensitivity, especially if high-affinity antibodies are lost that may be representative of natural ADAs with clinical implication. The Surface Plasmon Resonance platform on the Biacore™ systems offers methods for real-time analysis of biomolecular interactions without introducing any modifications to the analysed material. Calibration-free concentration analysis (CFCA) is such an application for determination of the proportion of drug-specific antibodies, which allows direct determination of active antibody concentrations, as defined by the ligand, in a flow-based system. Here, we present a novel CFCA method for ADA quantification developed and validated using polyclonal positive control antibodies against endogenous human insulin, insulin degludec (Tresiba®) and turoctocog alfa (NovoEight®). We find that CFCA precisely and accurately measures concentrations of drug-specific IgG antibodies with a precision of ±10% and 90%-112% recovery of expected values of monoclonal positive control antibodies. Additionally, we have achieved a more accurate measure of the sensitivity of a cell-based bioassay for in vitro neutralising ADAs using the specific concentration determined with CFCA. Moreover, we effectively quantified serum anti-insulin antibodies in high-titre clinical samples from individuals with diabetes mellitus. This application extends the relevance of the CFCA technology to analysis of immunogenicity for accurate quantification of ADAs in both the polyclonal positive control and in clinical samples.


Assuntos
Anticorpos Neutralizantes/sangue , Coagulantes/imunologia , Diabetes Mellitus/imunologia , Fator VIII/imunologia , Hipoglicemiantes/imunologia , Imunoglobulina G/sangue , Técnicas Imunológicas , Insulina de Ação Prolongada/imunologia , Ressonância de Plasmônio de Superfície , Autoanticorpos/sangue , Biomarcadores/sangue , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina de Ação Prolongada/uso terapêutico , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
20.
Sci Rep ; 11(1): 2940, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536563

RESUMO

Non-enzymatic modification of proteins by carbohydrates, known as glycation, leads to generation of advanced glycation end-products (AGEs). In our study we used in vitro generated AGEs to model glycation in vivo. We discovered in vivo analogs of unusual melibiose-adducts designated MAGEs (mel-derived AGEs) synthesized in vitro under anhydrous conditions with bovine serum albumin and myoglobin. Using nuclear magnetic resonance spectroscopy we have identified MAGEs as a set of isomers, with open-chain and cyclic structures, of the fructosamine moiety. We generated a mouse anti-MAGE monoclonal antibody and show for the first time that the native and previously undescribed analogous glycation product exists in living organisms and is naturally present in tissues of both invertebrates and vertebrates, including humans. We also report MAGE cross-reactive auto-antibodies in patients with diabetes. We anticipate our approach for modeling glycation in vivo will be a foundational methodology in cell biology. Further studies relevant to the discovery of MAGE may contribute to clarifying disease mechanisms and to the development of novel therapeutic options for diabetic complications, neuropathology, and cancer.


Assuntos
Diabetes Mellitus/imunologia , Carboidratos da Dieta/imunologia , Epitopos/imunologia , Produtos Finais de Glicação Avançada/imunologia , Melibiose/imunologia , Animais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Reações Cruzadas , Diabetes Mellitus/sangue , Diabetes Mellitus/metabolismo , Carboidratos da Dieta/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Glicosilação , Humanos , Melibiose/metabolismo , Camundongos
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