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1.
Eur J Gastroenterol Hepatol ; 33(5): 695-700, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33787541

RESUMO

BACKGROUND: The data on clinical course and outcome of acute pancreatitis among patients with coronavirus disease 2019 (COVID-19) are sparse. In this study, we analyzed the clinical profiles of patients with COVID 19 and acute pancreatitis. METHODS: This retrospective study was conducted on Research Patient Data Registry data which was pooled from five Mass General Brigham Healthcare Network hospitals. We extracted data on demographics, symptoms, ICU transfer, mechanical ventilation, laboratories' profiles, imaging findings, and patient outcomes. RESULT: Of 985 screened adult patients, 17 were eligible for the study, 9 (52.9%) were admitted primarily for respiratory failure and developed acute pancreatitis after a median of 22.5 days (13-76 days) from the onset of COVID-19 symptoms. On contrary, eight patients presented with typical symptoms and were diagnosed with acute pancreatitis, the majority with mild severity (62.5%) on admission. Patients who were admitted primarily with severe COVID-19 illness were younger (median age 57 vs. 63 years), females (55.6 vs. 25%), of Hispanic ethnicity (55.6 vs. 25%), and obese (88.9 vs. 37.5%). The median peak lipase, C reactive protein, ferritin, lactate dehydrogenase, D-dimer were higher among patients who developed acute pancreatitis later during hospitalization. Patients who developed acute pancreatitis later also experienced higher episodes of necrotizing pancreatitis (11.1% vs. 0), thromboembolic complications (55.6 vs. 12.5%), and higher mortality (37.5 vs. 12.5%). CONCLUSION: Acute pancreatitis is not common among patients with COVID-19. Patients with COVID-19 who had acute pancreatitis on admission had more benign course and overall better outcome as compared to the patients who developed acute pancreatitis during hospitalization.


Assuntos
/fisiopatologia , Mortalidade Hospitalar , Pancreatite/fisiopatologia , /fisiopatologia , Adulto , Afro-Americanos , Distribuição por Idade , Idoso , Proteína C-Reativa/metabolismo , /metabolismo , Grupo com Ancestrais do Continente Europeu , Feminino , Ferritinas/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hispano-Americanos , Humanos , L-Lactato Desidrogenase/metabolismo , Tempo de Internação , Lipase/metabolismo , Masculino , Pessoa de Meia-Idade , Pancreatite/complicações , Pancreatite/epidemiologia , Pancreatite/metabolismo , Pancreatite Necrosante Aguda/epidemiologia , /metabolismo , Estudos Retrospectivos , Índice de Gravidade de Doença , Distribuição por Sexo , Tromboembolia/epidemiologia
2.
Biomolecules ; 11(2)2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33671255

RESUMO

SARS-CoV-2, or COVID-19, has a devastating effect on our society, both in terms of quality of life and death rates; hence, there is an urgent need for developing safe and effective therapeutics against SARS-CoV-2. The most promising strategy to fight against this deadly virus is to develop an effective vaccine. Internalization of SARS-CoV-2 into the human host cell mainly occurs through the binding of the coronavirus spike protein (a trimeric surface glycoprotein) to the human angiotensin-converting enzyme 2 (ACE2) receptor. The spike-ACE2 protein-protein interaction is mediated through the receptor-binding domain (RBD) of the spike protein. Mutations in the spike RBD can significantly alter interactions with the ACE2 host receptor. Due to its important role in virus transmission, the spike RBD is considered to be one of the key molecular targets for vaccine development. In this study, a spike RBD-based subunit vaccine was designed by utilizing a ferritin protein nanocage as a scaffold. Several fusion protein constructs were designed in silico by connecting the spike RBD via a synthetic linker (different sizes) to different ferritin subunits (H-ferritin and L-ferritin). The stability and the dynamics of the engineered nanocage constructs were tested by extensive molecular dynamics simulation (MDS). Based on our MDS analysis, a five amino acid-based short linker (S-Linker) was the most effective for displaying the spike RBD over the surface of ferritin. The behavior of the spike RBD binding regions from the designed chimeric nanocages with the ACE2 receptor was highlighted. These data propose an effective multivalent synthetic nanocage, which might form the basis for new vaccine therapeutics designed against viruses such as SARS-CoV-2.


Assuntos
/química , Ferritinas/química , Nanoestruturas/química , Glicoproteína da Espícula de Coronavírus/química , /metabolismo , /metabolismo , Ferritinas/metabolismo , Humanos , Simulação de Dinâmica Molecular , Conformação Proteica , Domínios Proteicos , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Vacinas de Subunidades/química , Vacinas de Subunidades/metabolismo
3.
Nat Commun ; 12(1): 1645, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712594

RESUMO

Anemias of chronic disease and inflammation (ACDI) result from restricted iron delivery to erythroid progenitors. The current studies reveal an organellar response in erythroid iron restriction consisting of disassembly of the microtubule cytoskeleton and associated Golgi disruption. Isocitrate supplementation, known to abrogate the erythroid iron restriction response, induces reassembly of microtubules and Golgi in iron deprived progenitors. Ferritin, based on proteomic profiles, regulation by iron and isocitrate, and putative interaction with microtubules, is assessed as a candidate mediator. Knockdown of ferritin heavy chain (FTH1) in iron replete progenitors induces microtubule collapse and erythropoietic blockade; conversely, enforced ferritin expression rescues erythroid differentiation under conditions of iron restriction. Fumarate, a known ferritin inducer, synergizes with isocitrate in reversing molecular and cellular defects of iron restriction and in oral remediation of murine anemia. These findings identify a cytoskeletal component of erythroid iron restriction and demonstrate potential for its therapeutic targeting in ACDI.


Assuntos
Anemia/metabolismo , Anemia/terapia , Citoesqueleto/metabolismo , Ferro/metabolismo , Microtúbulos/metabolismo , Animais , Proliferação de Células , Modelos Animais de Doenças , Células Eritroides/metabolismo , Eritropoese/fisiologia , Feminino , Ferritinas/metabolismo , Isocitratos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredutases/metabolismo , Proteômica
4.
Trials ; 22(1): 194, 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33685474

RESUMO

OBJECTIVES: We investigate the effects of melatonin, compared to the usual therapeutic regimen on clinical symptoms and laboratory signs in severely ill patients with confirmed COVID-19 who are admitted to the Intensive Care Unit (ICU). TRIAL DESIGN: This is a single-center, open-label, randomized, clinical trial with a parallel-group design. This study is being conducted at Shahid Mohammadi Hospital, Bandar Abbas, Iran. PARTICIPANTS: All patients admitted to the ICU of Shahid Mohammadi Hospital, Bandar Abbas, Iran, will be screened for the following criteria. Inclusion criteria 1. Age >20 years 2. Definitive diagnosis of COVID-19 based on RT-PCR or/and serological testing 3. Severe pneumonia and lung involvement in imaging 4. Signing informed consent Exclusion criteria 1. Underlying diseases, including convulsive disorders, chronic hepatic and renal diseases 2. Use of mechanical ventilation 3. History of known allergy to Melatonin 4. Pregnancy and breastfeeding INTERVENTION AND COMPARATOR: Intervention group: The standard treatment regimen for COVID-19, according to the Iranian Ministry of Health and Medical Education's protocol, along with Melatonin soft gelatin capsule (Danna Pharmaceutical Company) at a dose of 5 mg twice a day for a period of seven days. CONTROL GROUP: The standard treatment for COVID-19 based on the Iranian Ministry of Health and Medical Education's protocol for a period of seven days. MAIN OUTCOMES: The primary outcomes are the recovery rate of clinical symptoms and checking arterial blood gas (ABG), C-reactive protein (C-RP), Ferritin, Lactate dehydrogenase (LDH) within seven days of randomization. The secondary outcomes are time to improvement of clinical and paraclinical features and length of stay in the ICU, need for mechanical ventilation, and mortality rate within seven days of randomization. RANDOMIZATION: Included patients will be allocated to one of the study arms using block randomization in a 1:1 ratio (each block consists of 6 patients). This randomization method ensures a balanced allocation between the arms during the study. A web-based system will generate random numbers for the allocation sequence and concealment of participants. Each number relates to one of the study arms. BLINDING (MASKING): This is an open-label trial without blinding and placebo control. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): A total of 60 participants randomizes (30 patients allocated to the intervention group and 30 patients allocated to the control group). TRIAL STATUS: The protocol is Version 1.0, February 16, 2021. Recruitment began February 28, 2021, and is anticipated to be completed by July 31, 2021. TRIAL REGISTRATION: The trial protocol has been registered in the Iranian Registry of Clinical Trials (IRCT). The registration number is " IRCT20200506047323N7 ". The registration date was February 16, 2021. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Antioxidantes/uso terapêutico , Melatonina/uso terapêutico , Gasometria , Proteína C-Reativa/metabolismo , /fisiopatologia , Ferritinas/metabolismo , Humanos , Unidades de Terapia Intensiva , Irã (Geográfico) , L-Lactato Desidrogenase/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Food Chem ; 349: 129144, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33540218

RESUMO

Ferritin is an iron-containing protein and functions in the maintenance of iron balance in organisms. Currently the interaction among ferritin, ion iron, and food bioactive compounds is still unclear. In this study, the mechanism underlying the interaction of ferritin, ion iron, and chlorogenic acid was investigated, as well as the effect of chlorogenic acid on the physicochemical properties of ferritin. The results showed that chlorogenic acid could interact with Fe(III) to form chlorogenic acid-Fe(III) complexes, which then bonded with ferritin via hydrogen bonds in the ferritin-chlorogenic acid-Fe(III) complexes. The chlorogenic acid showed a high efficiency in Fe(II) chelation and hydroxyl radical (•OH) capture, and could promote iron oxidation and iron release induced by ferritin. Chlorogenic acid could also effectively reduce the polymerization extent of ferritin induced by Fe(III) and Fe(II). This study elucidates the interactions of multiple components in foodstuffs by using a protein-metal-polyphenol model.


Assuntos
Ácido Clorogênico/metabolismo , Ácido Clorogênico/farmacologia , Ferritinas/química , Ferritinas/metabolismo , Ferro/metabolismo , Ferro/farmacologia , Multimerização Proteica/efeitos dos fármacos , Oxirredução , Ligação Proteica , Estrutura Quaternária de Proteína
6.
Clin Appl Thromb Hemost ; 27: 1076029621992128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33539188

RESUMO

Hyperferritinemia is associated with poor outcomes in critically ill patients with sepsis, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndromes (MAS) and coronavirus disease 19 (COVID-19). Autopsies of hyperferritinemic patients that succumbed to either sepsis, HLH, MAS or COVID-19 have revealed disseminated microvascular thromboses with von Willebrand factor (VWF)-, platelets-, and/or fibrin-rich microthrombi. It is unknown whether high plasma ferritin concentration actively promotes microvascular thrombosis, or merely serves as a prognostic biomarker in these patients. Here, we show that secretion of VWF from human umbilical vein endothelial cells (HUVEC) is significantly enhanced by 100,000 ng/ml of recombinant ferritin heavy chain protein (FHC). Ferritin fraction that was isolated by size exclusion chromatography from the plasma of critically ill HLH patients promoted VWF secretion from HUVEC, compared to similar fraction from non-critically ill control plasma. Furthermore, recombinant FHC moderately suppressed the activity of VWF cleaving metalloprotease ADAMTS-13. These observations suggest that a state of marked hyperferritinemia could promote thrombosis and organ injury by inducing endothelial VWF secretion and reducing the ADAMTS-13 activity.


Assuntos
Proteína ADAMTS13/metabolismo , /complicações , Ferritinas/metabolismo , /complicações , Fator de von Willebrand/metabolismo , Proteína ADAMTS13/antagonistas & inibidores , Estado Terminal , Ferritinas/sangue , Células Endoteliais da Veia Umbilical Humana , Humanos , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/complicações , Oxirredutases/sangue , Oxirredutases/metabolismo , Proteínas Recombinantes/sangue , Proteínas Recombinantes/metabolismo , Trombose/sangue , Trombose/etiologia
7.
Int Immunopharmacol ; 93: 107390, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33529907

RESUMO

BACKGROUND: Exposure to viral or bacterial pathogens increases the number of neutrophils with a relative decrease in lymphocytes, leading to elevated neutrophil to lymphocyte ratio (NLR). This study aimed to investigate whether differences in NLR among real-time polymerase chain reaction (PCR)-positive and -negative patients presenting with a prediagnosis of COVID-19 pneumonia could be useful in the differential diagnosis. METHODS: The study included 174 patients admitted because of suspected COVID-19 infection between March and April 2020. Patients were divided into two groups: PCR-negative and PCR-positive. Hemogram, NLR, urea, creatinine, aspartate aminotransferase, alanine aminotransferase, bilirubin, ferritin, D-dimer, C-reactive protein, procalcitonin, troponin, and coagulation parameters were analyzed. RESULTS: On comparison of laboratory parameters between both groups at presentation, PCR-positive patients were significantly more likely to have leukopenia (p < 0.001), thrombocytopenia (p = 0.006), neutropenia (p < 0.001), lymphopenia (p = 0.001), and increased NLR (p = 0.003). Furthermore, PCR-positive patients showed significant elevations of ferritin (p = 0.012) and procalcitonin (p = 0.038) and significant lower potassium levels (p = 0.05). CONCLUSION: COVID-19 pneumonia has become a major global health problem. Early diagnosis and treatment of these patients are crucial, as COVID-19 pneumonia shows a rapid progression in most cases. Thus, leukopenia, thrombocytopenia, elevated NLR, and elevated ferritin may be useful as supplementary diagnostic tests in these patients, which may allow early initiation of treatment and may contribute to preventing progression in patients with abnormal results.


Assuntos
/sangue , Infecções por Coronavirus/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções por Coronavirus/sangue , Feminino , Ferritinas/metabolismo , Humanos , Contagem de Leucócitos , Leucócitos/patologia , Leucopenia/sangue , Leucopenia/virologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Contagem de Plaquetas , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Trombocitopenia/sangue , Trombocitopenia/virologia
8.
Ecotoxicol Environ Saf ; 212: 111995, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33529923

RESUMO

Ferritin is the major intracellular iron storage protein and is essential for iron homeostasis and detoxification. Cadmium affects cellular homeostasis and induces cell toxicity via sophisticated mechanisms. Here, we aimed to explore the mechanisms of cytoprotective effect of Phascolosoma esculenta ferritin (PeFer) on Cd(II)-induced bone marrow mesenchymal stem cell (BMSC) injury. Herein, the effects of different treated groups on apoptosis and cell cycle were assessed using flow cytometric analysis. We further investigated the alterations of the three groups using integrative 2-DE-based proteomics and 1H NMR-based metabolomics profiles. The results indicate that PeFer reduces BMSC apoptosis induced by Cd(II) and delays G0/G1 cell cycle progression. A total of 19 proteins and 70 metabolites were significantly different among BMSC samples of the three groups. Notably, multiomics analysis revealed that Cd(II) might perturb the ER stress-mediated apoptosis pathway and disrupt biological processes related to the TCA cycle, amino acid metabolism, purine and pyrimidine metabolism, thereby suppressing the cell growth rate and initiating apoptosis; however, the addition of PeFer might protect BMSCs against cell apoptosis to improve cell survival by enhancing energy metabolism. This study provides a better understanding of the underlying molecular mechanisms of the protective effect of PeFer in BMSCs against Cd(II) injury.


Assuntos
Apoptose/efeitos dos fármacos , Cádmio/toxicidade , Ferritinas/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Poliquetos/metabolismo , Substâncias Protetoras/farmacologia , Animais , Cádmio/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Ferritinas/metabolismo , Células-Tronco Mesenquimais/patologia , Metabolômica , Camundongos Endogâmicos C57BL , Substâncias Protetoras/metabolismo , Proteômica
9.
Biomark Med ; 15(4): 285-293, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33501850

RESUMO

Background: Troponin levels may be elevated in COVID-19 infection. The aim of this study was to the explore relation between troponin levels and COVID-19 severity. Materials, methods & Results: One hundred and forty consecutive patients with COVID-19 pneumonia were included. Diagnosis of COVID-19 pneumonia was based on positive chest computed tomography (CT) findings. Quantitative PCR test was performed in all patients. Only 74 patients were quantitative PCR-positive. Twenty four patients had severe CT findings and 27 patients had progressive disease. These patients had significantly lower albumin and higher ferritin, D-dimer, lactate dehydrogenase, C-reactive protein, and high-sensitivity cardiac troponin I (hs-cTnI). Conclusion: COVID-19 patients with severe CT findings and progressive disease had higher hs-cTnI levels suggesting the use of hs-cTnI in risk stratification.


Assuntos
Reação em Cadeia da Polimerase em Tempo Real , Tomografia Computadorizada por Raios X , Adulto , Idoso , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , /diagnóstico , Feminino , Ferritinas/metabolismo , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Cardiopatias , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Albumina Sérica Humana/metabolismo , Tórax/diagnóstico por imagem , Troponina I/sangue
10.
J Virol ; 95(6)2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33408172

RESUMO

Intracellular iron concentration is tightly controlled for cell viability. It is known to affect the growth of several viruses, but the molecular mechanisms are not well understood. We found that iron chelators inhibit growth of human parainfluenza virus type 2 (hPIV-2). Furthermore, infection with hPIV-2 alters ferritin localization from granules to a homogenous distribution within cytoplasm of iron-stimulated cells. The V protein of hPIV-2 interacts with ferritin heavy chain 1 (FTH1), a ferritin subunit. It also binds to nuclear receptor coactivator 4 (NCOA4), which mediates autophagic degradation of ferritin, so-called ferritinophagy. V protein consequently interferes with interaction between FTH1 and NCOA4. hPIV-2 growth is inhibited in FTH1 knockdown cell line where severe hPIV-2-induced apoptosis is shown. In contrast, NCOA4 knockdown results in the promotion of hPIV-2 growth and limited apoptosis. Our data collectively suggest that hPIV-2 V protein inhibits FTH1-NCOA4 interaction and subsequent ferritinophagy. This iron homeostasis modulation allows infected cells to avoid apoptotic cell death, resulting in effective growth of hPIV-2.IMPORTANCE hPIV-2 V protein interferes with interaction between FTH1 and NCOA4 and inhibits NCOA4-mediated ferritin degradation, leading to the inhibition of iron release to the cytoplasm. This iron homeostasis modulation allows infected cells to avoid apoptotic cell death, resulting in effective growth of hPIV-2.


Assuntos
Homeostase , Ferro/metabolismo , Vírus da Parainfluenza 2 Humana/fisiologia , Proteínas Estruturais Virais/metabolismo , Apoptose , Linhagem Celular , Ferritinas/genética , Ferritinas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Coativadores de Receptor Nuclear/genética , Coativadores de Receptor Nuclear/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Vírus da Parainfluenza 2 Humana/crescimento & desenvolvimento , Vírus da Parainfluenza 2 Humana/metabolismo , Ligação Proteica
11.
Ann Med ; 53(1): 257-266, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-33410720

RESUMO

OBJECTIVES: To appraise effective predictors for COVID-19 mortality in a retrospective cohort study. METHODS: A total of 1270 COVID-19 patients, including 984 admitted in Sino French New City Branch (training and internal validation sets randomly split at 7:3 ratio) and 286 admitted in Optical Valley Branch (external validation set) of Wuhan Tongji hospital, were included in this study. Forty-eight clinical and laboratory features were screened with LASSO method. Further multi-tree extreme gradient boosting (XGBoost) machine learning-based model was used to rank importance of features selected from LASSO and subsequently constructed death risk prediction model with simple-tree XGBoost model. Performances of models were evaluated by AUC, prediction accuracy, precision, and F1 scores. RESULTS: Six features, including disease severity, age, levels of high-sensitivity C-reactive protein (hs-CRP), lactate dehydrogenase (LDH), ferritin, and interleukin-10 (IL-10), were selected as predictors for COVID-19 mortality. Simple-tree XGBoost model conducted by these features can predict death risk accurately with >90% precision and >85% sensitivity, as well as F1 scores >0.90 in training and validation sets. CONCLUSION: We proposed the disease severity, age, serum levels of hs-CRP, LDH, ferritin, and IL-10 as significant predictors for death risk of COVID-19, which may help to identify the high-risk COVID-19 cases. KEY MESSAGES A machine learning method is used to build death risk model for COVID-19 patients. Disease severity, age, hs-CRP, LDH, ferritin, and IL-10 are death risk factors. These findings may help to identify the high-risk COVID-19 cases.


Assuntos
/mortalidade , Regras de Decisão Clínica , Hospitalização , Aprendizado de Máquina , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/metabolismo , /metabolismo , Doenças Cardiovasculares/epidemiologia , China/epidemiologia , Estudos de Coortes , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Ferritinas/metabolismo , Humanos , Hipertensão/epidemiologia , Interleucina-10/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Índice de Gravidade de Doença
12.
Food Chem ; 346: 128879, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33406454

RESUMO

Ferritin can be widely used as functional nanomaterial. But the physiological activity of ferritin can be damaged under excessive temperatures, which affect the self-assembly property. In this study, point mutation was produced in Asp120 to Gly120 of ferritin amino acid sequence and the heat resistance was improved significantly. The thermal denaturation temperature of mutated ferritin is 89.17 °C and has increased by 13 °C more than the wild-type oyster ferritin. The effect of thermal treatment on the denaturation, aggregation state, particle size and the structure of ferritin was not changed before 90 °C. The computational modeling and analysis indicated that mutated ferritin promotes the overall structural stability assembly via decreasing the interaction energies of 62 percent energies in 3-fold interface. Improving the thermal stability of oyster ferritin by point mutation enhances its applications as a food ingredient.


Assuntos
Crassostrea/metabolismo , Ferritinas/metabolismo , Temperatura Alta , Mutação Puntual , Alimentos Marinhos/análise , Sequência de Aminoácidos , Animais , Crassostrea/química
13.
Trials ; 22(1): 43, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430891

RESUMO

OBJECTIVES: The aim of this study is to assess the effectiveness and safety of glucocorticoid infusion pulse therapy to improve the clinical outcomes of patients with COVID-19 pneumonia with elevated inflammatory biomarkers. TRIAL DESIGN: A parallel-group quadruple-blind (participant, intervention provider, outcome assessor and data manager), randomised controlled trial. PARTICIPANTS: All patients admitted to hospital due to COVID-19 pneumonia will be considered eligible. Potential candidates will be identified and consecutively included in the emergency room or in the COVID-19 admission wards of two hospitals in Spain: Complejo Hospitalario de Navarra (Pamplona) and Hospital Moisès Broggi (Sant Joan Despí, Barcelona). Inclusion criteria are: 1) age ≥18 years old; 2) diagnosis of SARS-CoV-2 pneumonia confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) of nasopharyngeal swabs or sputum in accordance with the recommendations of the Spanish Ministry of Health; 3) history of symptoms compatible with COVID-19 ≥7 days; 4) hospital admission; 5) at least one of the following: C-reactive protein (CRP) >60 mg/dL, interleukin-6 (IL-6) >40 pg/mL, and/or ferritin >1000 µg/L; and 6) provision of informed consent. Exclusion criteria are: 1) allergy or contraindication to any of the drugs under study; 2) oxygen saturation (SpO2) <90% (in air ambient) or partial pressure of oxygen in arterial blood (PaO2) <60 mmHg (in ambient air) or PaO2/FiO2 <300 mmHg; 3) ongoing treatment with glucocorticoids, or other immunosuppressants, including biologics for another indication; 4) decompensated diabetes mellitus; 5) uncontrolled hypertension; 6) psychotic or manic disorder; 7) active cancer; 8) pregnancy or breastfeeding; 9) clinical or biochemical suspicion (procalcitonin >0.5 ng/mL) of active infection other than with SARS-CoV-2; 10) management as an outpatient; 11) conservative or palliative management; 12) participation in another clinical trial; or 13) any major uncontrolled medical, psychological, psychiatric, geographic or social problem that contraindicates the patient's participation in the trial or hinders proper follow-up and adherence to the protocol and evaluation of study outcomes. INTERVENTION AND COMPARATOR: Eligible patients will be randomised to receive standard of care plus methylprednisolone (intervention group) or standard of care plus placebo (control group). Intervention group: standard of care at the discretion of the researcher, including lopinavir/ritonavir (200/50 mg, 2 tablets twice daily, per os, for 7 to 14 days) ± remdesivir (a single intravenous loading dose of 200 mg on day 1 followed by once-daily intravenous maintenance doses of 100 mg from day 2 to 5), or no drug treatment, + methylprednisolone (once-daily intravenous infusion of 120 mg on days 1, 2 and 3). CONTROL GROUP: standard of care at the discretion of the researcher, including lopinavir/ritonavir (200/50 mg, 2 tablets every 12 hours, per os, for 7 to 14 days) ± remdesivir (a single intravenous loading dose of 200 mg on day 1 followed by once-daily intravenous maintenance doses of 100 mg from day 2 to 5), or no drug treatment, + placebo (once-daily intravenous infusion of 100 mL of 0.9% saline on days 1, 2 and 3). MAIN OUTCOMES: The primary outcome is the proportion of patients with treatment failure at 14 days after randomisation, defined as: 1) death, 2) need for admission to an intensive care unit (ICU), 3) initiation of mechanical ventilation, 4) SpO2 falling to <90% (in ambient air) or PaO2 <60 mmHg (in ambient air) or PaO2FiO2 <300 mmHg, not explained by a cause other than COVID-19, and/or 5) decrease in PaO2 ≥15% from baseline, together with laboratory and radiological deterioration. RANDOMISATION: Treatment will be allocated by block randomisation stratified by patient age (< or ≥ 75 years of age). For this purpose, we will use the R randomizeR package using two block sizes (4 and 6) with random permutation. The randomisation sequence will be generated by a unit (the Navarrabiomed Clinical Trials Platform) independent from the researchers who will recruit patients and implement the protocol. BLINDING (MASKING): The study will be quadruple-blinded, specifically, with blinding of patients, intervention providers, outcome assessors and data managers. The pharmacy at each participating hospital will prepare indistinguishable bags of methylprednisolone or placebo (0.9% saline) for patients of the experimental and placebo groups, respectively. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The percentage of patients with treatment failure (primary endpoint) is currently unknown. Assuming an absolute difference of 25% in the primary outcome between the two groups (35% in the control group and 10% in the intervention group), we estimate that 60 patients (30 per group) are required to detect this difference with a two-tailed type I error of 0.05 and a type II error of 0.2. Estimating a loss to follow-up of 20%, we should recruit a total sample size of 72 patients (36 per group). TRIAL STATUS: The Spanish Agency of Medicines and Medical Devices (AEMPS) and the Ethics Committee of the University Hospital La Princesa approved version 7.0 of the protocol on 30 April 2020 as a low intervention clinical trial. Subsequently, the protocol has been amended by researchers and re-approved by AEMPS and the same ethics committee on 1 July 2020 (version 8.0) and on 28 August 2020 (version 9.0). Currently, the trial is in the recruitment phase. Recruitment began on 28 May 2020 and is expected to be completed by February 2021. TRIAL REGISTRATION: This study protocol was registered on the eudract.ema.europa.eu on 5 May 2020 (title "Early treatment of COVID-19 pneumonia with glucocorticoids. Randomized controlled clinical trial"; EudraCT Number: 2020-001827-15 ) and on clinicaltrials.gov on 19 June 2020 (title: "Glucocorticoids in COVID-19 (CORTIVID)"; identifier: NCT04438980 ). FULL PROTOCOL: The full protocol (version 9.0) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
/tratamento farmacológico , Glucocorticoides/uso terapêutico , Metilprednisolona/uso terapêutico , Proteína C-Reativa/metabolismo , Método Duplo-Cego , Ferritinas/metabolismo , Hospitalização , Humanos , Infusões Intravenosas , Interleucina-6/metabolismo , Pulsoterapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
14.
Chembiochem ; 22(8): 1371-1378, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33350032

RESUMO

Infectious diseases are a continues threat to human health and the economy worldwide. The latest example is the global pandemic of COVID-19 caused by SARS-CoV-2. Antibody therapy and vaccines are promising approaches to treat the disease; however, they have bottlenecks: they might have low efficacy or narrow breadth due to the continuous emergence of new strains of the virus or antibodies could cause antibody-dependent enhancement (ADE) of infection. To address these bottlenecks, I propose the use of 24-meric ferritin for the synthesis of mosaic nanocages to deliver a cocktail of antibodies or nanobodies alone or in combination with another therapeutic, like a nucleotide analogue, to mimic the viral entry process and deceive the virus, or to develop mosaic vaccines. I argue that available data showing the effectiveness of ferritin-antibody conjugates in targeting specific cells and ferritin-haemagglutinin nanocages in developing influenza vaccines strongly support my proposals.


Assuntos
Antivirais/química , Ferritinas/química , Nanoestruturas/química , /química , Animais , Anticorpos/química , Anticorpos/uso terapêutico , Antivirais/metabolismo , Antivirais/farmacologia , Antivirais/uso terapêutico , /prevenção & controle , /química , Portadores de Fármacos/química , Ferritinas/metabolismo , Humanos , Camundongos , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Internalização do Vírus/efeitos dos fármacos
15.
Food Chem ; 335: 127671, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32745843

RESUMO

Iron deficiency anaemia (IDA) is a common nutritional disorder worldwide. Sustainable food-based approaches are being advocated to use high and bioavailable dietary iron sources to prevent iron deficiency. The study investigated the bioaccessibility and bioavailability of iron from some plant products. Total iron levels in the samples were measured by inductively coupled plasma optical emission spectrometry (ICP-OES). Fractionation of the iron from the digested extracts was carried out by centrifugation and ultrafiltration. Iron bioavailability was determined using an in vitro simulated peptic-pancreatic digestion, followed by measurement of ferritin in Caco-2 cells. The highest amount of bioaccessible iron was obtained from moringa leaves (9.88% ± 0.45 and 8.44 ± 0.01 mg/100 g), but the highest percentage bioavailability was from baobab fruit pulp (99.7% ± 0.13 and 1.74 ± 0.01 mg/100 g) respectively. All the plant products, except for baobab, significantly inhibited iron uptake from FeSO4 and FAC, with fenugreek sprout being the most inhibitory.


Assuntos
Adansonia/química , Ferro na Dieta/farmacocinética , Moringa/química , Trigonella/química , Disponibilidade Biológica , Células CACO-2 , Digestão , Ferritinas/metabolismo , Frutas/química , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacocinética , Folhas de Planta/química
16.
Methods Mol Biol ; 2201: 139-162, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32975796

RESUMO

Opioid use has substantially increased over recent years and remains a major driver of new HIV infections worldwide. Clinical studies indicate that opioids may exacerbate the symptoms of HIV-associated neurocognitive disorders (HAND), but the mechanisms underlying opioid-induced cognitive decline remain obscure. We recently reported that the µ-opioid agonist morphine increased neuronal iron levels and levels of ferritin proteins that store iron, suggesting that opioids modulate neuronal iron homeostasis. Additionally, increased iron and ferritin heavy chain protein were necessary for morphine's ability to reduce the density of thin and mushroom dendritic spines in cortical neurons, which are considered critical mediators of learning and memory, respectively. As altered iron homeostasis has been reported in HAND and related neurocognitive disorders like Alzheimer's, Parkinson's, and Huntington's disease, understanding how opioids regulate neuronal iron metabolism may help identify novel drug targets in HAND with potential relevance to these other neurocognitive disorders. Here, we review the known mechanisms of opioid-mediated regulation of neuronal iron and corresponding cellular responses and discuss the implications of these findings for patients with HAND. Furthermore, we discuss a new molecular approach that can be used to understand if opioid modulation of iron affects the expression and processing of amyloid precursor protein and the contributions of this pathway to HAND.


Assuntos
Disfunção Cognitiva/metabolismo , Ferro/metabolismo , Receptores Opioides mu/metabolismo , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologia , Animais , Disfunção Cognitiva/fisiopatologia , Espinhas Dendríticas/metabolismo , Ferritinas/metabolismo , Infecções por HIV/complicações , Humanos , Morfina/farmacologia , Transtornos Neurocognitivos/metabolismo , Neurônios/metabolismo , Receptores Opioides/metabolismo
17.
Cardiol Rev ; 29(1): 39-42, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33136582

RESUMO

Patients older than 65 years hospitalized with COVID-19 have higher rates of intensive care unit admission and death when compared with younger patients. Cardiovascular conditions associated with COVID-19 include myocardial injury, acute myocarditis, cardiac arrhythmias, cardiomyopathies, cardiogenic shock, thromboembolic disease, and cardiac arrest. Few studies have described the clinical course of those at the upper extreme of age. We characterize the clinical course and outcomes of 73 patients with 80 years of age or older hospitalized at an academic center between March 15 and May 13, 2020. These patients had multiple comorbidities and often presented with atypical clinical findings such as altered sensorium, generalized weakness and falls. Cardiovascular manifestations observed at the time of presentation included new arrhythmia in 7/73 (10%), stroke/intracranial hemorrhage in 5/73 (7%), and elevated troponin in 27/58 (47%). During hospitalization, 38% of all patients required intensive care, 13% developed a need for renal replacement therapy, and 32% required vasopressor support. All-cause mortality was 47% and was highest in patients who were ever in intensive care (71%), required mechanical ventilation (83%), or vasopressors (91%), or developed a need for renal replacement therapy (100%). Patients older than 80 years old with COVID-19 have multiple unique risk factors which can be associated with increased cardiovascular involvement and death.


Assuntos
Lesão Renal Aguda/terapia , Mortalidade Hospitalar , Terapia de Substituição Renal/estatística & dados numéricos , Respiração Artificial/estatística & dados numéricos , Vasoconstritores/uso terapêutico , Centros Médicos Acadêmicos , Acidentes por Quedas , Lesão Renal Aguda/etiologia , Idoso de 80 Anos ou mais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Aspartato Aminotransferases/metabolismo , Proteína C-Reativa/metabolismo , /metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Causas de Morte , Transtornos da Consciência/fisiopatologia , Dispneia/fisiopatologia , Feminino , Ferritinas/metabolismo , Febre/fisiopatologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hospitalização , Humanos , Hipóxia/fisiopatologia , Hipóxia/terapia , Vida Independente , Unidades de Terapia Intensiva/estatística & dados numéricos , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/fisiopatologia , Contagem de Leucócitos , Hepatopatias/etiologia , Hepatopatias/metabolismo , Contagem de Linfócitos , Masculino , Debilidade Muscular/fisiopatologia , Peptídeo Natriurético Encefálico/metabolismo , Casas de Saúde , Oxigenoterapia , Pró-Calcitonina/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Troponina I/metabolismo
19.
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