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1.
Front Immunol ; 12: 706186, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484202

RESUMO

Background: Sargramostim [recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)] was approved by US FDA in 1991 to accelerate bone marrow recovery in diverse settings of bone marrow failure and is designated on the list of FDA Essential Medicines, Medical Countermeasures, and Critical Inputs. Other important biological activities including accelerating tissue repair and modulating host immunity to infection and cancer via the innate and adaptive immune systems are reported in pre-clinical models but incompletely studied in humans. Objective: Assess safety and efficacy of sargramostim in cancer and other diverse experimental and clinical settings. Methods and Results: We systematically reviewed PubMed, Cochrane and TRIP databases for clinical data on sargramostim in cancer. In a variety of settings, sargramostim after exposure to bone marrow-suppressing agents accelerated hematologic recovery resulting in fewer infections, less therapy-related toxicity and sometimes improved survival. As an immune modulator, sargramostim also enhanced anti-cancer responses in solid cancers when combined with conventional therapies, for example with immune checkpoint inhibitors and monoclonal antibodies. Conclusions: Sargramostim accelerates hematologic recovery in diverse clinical settings and enhances anti-cancer responses with a favorable safety profile. Uses other than in hematologic recovery are less-well studied; more data are needed on immune-enhancing benefits. We envision significantly expanded use of sargramostim in varied immune settings. Sargramostim has the potential to reverse the immune suppression associated with sepsis, trauma, acute respiratory distress syndrome (ARDS) and COVID-19. Further, sargramostim therapy has been promising in the adjuvant setting with vaccines and for anti-microbial-resistant infections and treating autoimmune pulmonary alveolar proteinosis and gastrointestinal, peripheral arterial and neuro-inflammatory diseases. It also may be useful as an adjuvant in anti-cancer immunotherapy.


Assuntos
COVID-19/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunoterapia , Neoplasias/tratamento farmacológico , COVID-19/tratamento farmacológico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Humanos , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/uso terapêutico , SARS-CoV-2/efeitos dos fármacos
2.
Best Pract Res Clin Anaesthesiol ; 35(3): 351-368, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34511224

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces coronavirus-19 disease (COVID-19) and is a major health concern. Following two SARS-CoV-2 pandemic "waves," intensive care unit (ICU) specialists are treating a large number of COVID19-associated acute respiratory distress syndrome (ARDS) patients. From a pathophysiological perspective, prominent mechanisms of COVID19-associated ARDS (CARDS) include severe pulmonary infiltration/edema and inflammation leading to impaired alveolar homeostasis, alteration of pulmonary physiology resulting in pulmonary fibrosis, endothelial inflammation (endotheliitis), vascular thrombosis, and immune cell activation. Although the syndrome ARDS serves as an umbrella term, distinct, i.e., CARDS-specific pathomechanisms and comorbidities can be noted (e.g., virus-induced endotheliitis associated with thromboembolism) and some aspects of CARDS can be considered ARDS "atypical." Importantly, specific evidence-based medical interventions for CARDS (with the potential exception of corticosteroid use) are currently unavailable, limiting treatment efforts to mostly supportive ICU care. In this article, we will discuss the underlying pulmonary pathophysiology and the clinical management of CARDS. In addition, we will outline current and potential future treatment approaches.


Assuntos
COVID-19/terapia , Cuidados Críticos/normas , Conhecimentos, Atitudes e Prática em Saúde , Unidades de Terapia Intensiva/normas , Síndrome do Desconforto Respiratório/terapia , Corticosteroides/administração & dosagem , Anticoagulantes/administração & dosagem , COVID-19/diagnóstico , COVID-19/fisiopatologia , Cuidados Críticos/tendências , Humanos , Fatores Imunológicos/administração & dosagem , Unidades de Terapia Intensiva/tendências , Respiração Artificial/normas , Respiração Artificial/tendências , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/fisiopatologia
3.
Washington; Pan American Health Organization; 26 ed; Sept. 13, 2021. 357 p.
Não convencional em Inglês | PIE | ID: biblio-1291221

RESUMO

The vast amount of data generated by clinical studies of potential therapeutic options for COVID-19 presents important challenges. The new data must be interpreted quickly so that prescribers can make optimal treatment decisions with as little harm to patients as possible, and so that medicines manufacturers can scale up production rapidly and bolster their supply chains. Rapid interpretation of fresh data will save lives by ensuring that successful drugs can be administered to as many patients as possible as quickly as possible. This publication, the 25th edition of the database of evidence on potential therapeutic options for COVID-19, examines 137 therapeutic options. This information will help investigators, policymakers, and prescribers navigate the flood of relevant data to ensure that management of COVID-19, at both individual and population levels, is based on the best available knowledge. This resource will be continually updated as more research is released into the public space.


Assuntos
Humanos , Antivirais/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , COVID-19/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Ensaios Clínicos como Assunto
4.
Andes Pediatr ; 92(3): 395-405, 2021 Jun.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-34479246

RESUMO

INTRODUCTION: In April 2020, the pediatric multisystem inflammatory syndrome temporarily associated with COVID-19 (MIS-C) was described for the first time. MIS-C could have a severe course and may require critical care support. OBJECTIVE: To describe the clinical, laboratory, and management characteristics of hospitalized children who meet MIS-C criteria with severe presentation in a pediatric critical pa tient unit. PATIENTS AND METHOD: Descriptive prospective study of children with severe MIS-C mana ged by treatment phases with immunoglobulin and methylprednisolone, according to their clinical response. Epidemiological, clinical, laboratory and imaging data were obtained. Phenotypes were classified into Kawasaki and not Kawasaki, comparing their findings. RESULTS: 20 patients were analy zed, the median age was 6 years, 60% were female, and 40% presented comorbidity. SARS-CoV-2 was detected in 90% of the patients. They presented fever as the first symptom, followed by brief and early gastrointestinal symptoms (70%). 75% presented the Kawasaki phenotype. They evolved with lymphopenia, hypoalbuminemia, coagulation alterations, and elevated systemic and cardiac in flammatory parameters. 80% of the cases presented echocardiographic alterations and 90% shock that required critical care support. All the patients had a short and favorable evolution. All patients responded to the established therapy, but 40% required a second phase of treatment. There were no differences when comparing phenotypes. No deaths were reported. CONCLUSION: MIS-C is a new childhood disease whose presentation could be life-threatening. It requires early suspicion, immuno modulatory management, critical care support, and a multidisciplinary approach to obtain the best results and optimize its prognosis.


Assuntos
COVID-19 , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica , Corticosteroides/uso terapêutico , Antibacterianos/uso terapêutico , Anticoagulantes/uso terapêutico , Transtornos da Coagulação Sanguínea/etiologia , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/terapia , Criança , Cuidados Críticos , Feminino , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Hipoalbuminemia/etiologia , Imunoglobulinas Intravenosas/administração & dosagem , Fatores Imunológicos/administração & dosagem , Unidades de Terapia Intensiva Pediátrica , Linfopenia/etiologia , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Estudos Prospectivos , SARS-CoV-2/isolamento & purificação , Choque/etiologia , Choque/terapia , Avaliação de Sintomas , Síndrome de Resposta Inflamatória Sistêmica/complicações , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/terapia
5.
Rinsho Ketsueki ; 62(8): 1167-1177, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497204

RESUMO

Over the past two decades, there have been many advances in the treatment of multiple myeloma (MM), and the median survival continues to increase. The driving force behind this progress has been the development of novel therapeutic agents, such as proteasome inhibitors and immunomodulators. Antibody drugs have a different mechanism of action in comparison with these drugs and can be combined with existing drugs to enhance the therapeutic efficacy. To date, elotuzumab, an anti-SLAMF7 antibody; daratumumab, an anti-CD38 antibody; and isatuximab have been introduced. D-MPB and DLd have become the standard first-line treatment for untreated, newly diagnosed MM; whereas DBd, DLd, DCd, Isa-Pd, ELd, and EPd have become the standard of care for relapsed and refractory MM. New antibody drugs, such as bi-specific antibodies and antibody-drug conjugates, targeting various antigens, including BCMA, are now under development. In this educational lecture, I will review the status on development and clinical trials of these antibody drugs.


Assuntos
Mieloma Múltiplo , Humanos , Fatores Imunológicos , Imunoterapia , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteassoma/uso terapêutico , Radioimunoterapia
6.
Nat Commun ; 12(1): 5263, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489457

RESUMO

Immunomodulatory drugs (IMiDs) are important for the treatment of multiple myeloma and myelodysplastic syndrome. Binding of IMiDs to Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase, induces cancer cell death by targeting key neo-substrates for degradation. Despite this clinical significance, the physiological regulation of CRBN remains largely unknown. Herein we demonstrate that Wnt, the extracellular ligand of an essential signal transduction pathway, promotes the CRBN-dependent degradation of a subset of proteins. These substrates include Casein kinase 1α (CK1α), a negative regulator of Wnt signaling that functions as a key component of the ß-Catenin destruction complex. Wnt stimulation induces the interaction of CRBN with CK1α and its resultant ubiquitination, and in contrast with previous reports does so in the absence of an IMiD. Mechanistically, the destruction complex is critical in maintaining CK1α stability in the absence of Wnt, and in recruiting CRBN to target CK1α for degradation in response to Wnt. CRBN is required for physiological Wnt signaling, as modulation of CRBN in zebrafish and Drosophila yields Wnt-driven phenotypes. These studies demonstrate an IMiD-independent, Wnt-driven mechanism of CRBN regulation and provide a means of controlling Wnt pathway activity by CRBN, with relevance for development and disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Peptídeo Hidrolases/genética , Ubiquitina-Proteína Ligases/metabolismo , Via de Sinalização Wnt/fisiologia , Proteínas de Peixe-Zebra/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Caseína Quinase Ialfa/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Embrião não Mamífero , Evolução Molecular , Células HEK293 , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Lenalidomida/química , Lenalidomida/farmacologia , Camundongos , Organoides , Peptídeo Hidrolases/metabolismo , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
7.
Trop Biomed ; 38(3): 343-352, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34508342

RESUMO

Outbreak of SARS-CoV-2 has been declared a pandemic, which is a serious threat to human health. The disease was named coronavirus disease 2019 (COVID-19). Until now, several vaccines and a few drugs have been approved for the prevention and treatment for COVID-19. Recently, the effect of some macrolides including clarithromycin (CAM) on COVID-19 has attracted attention. CAM is known to have diverse effects including immunomodulatory and immunosuppressive effects, autophagy inhibition, steroid sparing effect, reversibility of drug resistance, antineoplastic effect, antiviral effect as well as bacteriostatic/bactericidal effect. Many patients with COVID-19 died due to an overwhelming response of their own immune system characterized by the uncontrolled release of circulating inflammatory cytokines (cytokine release syndrome [CRS]). This CRS plays a major role in progressing pneumonia to acute respiratory distress syndrome (ARDS) in COVID-19 patients. It is noteworthy that CAM can suppress inflammatory cytokines responsible for CRS and also has anti-SARS-CoV-2 effect. Considering the rapidly progressive global disease burden of COVID 19, the application of CAM for treating COVID-19 needs to be urgently evaluated. Recently, an open-labeled non-randomized trial using CAM for treating COVID-19 (ACHIEVE) was initiated in Greece in May, 2020. Its results, though preprint, indicated that CAM treatment of patients with moderate COVID-19 was associated with early clinical improvement and containment of viral load. Thus, treatment with CAM as a single agent or combined with other anti-SARS CoV-2 drugs should be tried for treating COVID-19. In this article, we discussed the significance and usefulness of CAM in treating COVID-19.


Assuntos
COVID-19/tratamento farmacológico , Claritromicina/uso terapêutico , Reposicionamento de Medicamentos , SARS-CoV-2 , Enzima de Conversão de Angiotensina 2/metabolismo , Azitromicina/uso terapêutico , Claritromicina/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Fatores Imunológicos/farmacologia , SARS-CoV-2/efeitos dos fármacos
8.
Endocr Regul ; 55(3): 174-181, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34523302

RESUMO

The pathophysiology of COVID comprises an exaggerated pro-inflammatory response. Hypothalamic-pituitary-adrenal (HPA) axis has a crucial role in various inflammatory conditions and modulated immunological response. Limited evidence is available regarding the incidence and the effect of HPA dysfunction in COVID-19. Although the cortisol levels have only been estimated in a few studies, the dehydroepiandrosterone sulfate (DHEAS) release from the adrenal gland has not been explored yet. In this mini review, the authors discuss the role of dehydroepiandrosterone (DHEA) and DHEAS in the acute stress response and immunological modulation. Various effects of DHEAS have been demonstrated in different diseases. The specific inhibitory effect of DHEA on interleukin 6 (IL-6) could be of paramount importance in COVID-19. Further, DHEA supplementation has already been proposed in inflammatory conditions, like rheumatoid arthritis. DHEAS levels in COVID-19 may help to understand the HPA axis dysfunction as well as the possibility of repurposing DHEA as a drug for mitigating the pro-inflammatory COVID-19.


Assuntos
COVID-19 , Sulfato de Desidroepiandrosterona/metabolismo , Desidroepiandrosterona/uso terapêutico , Sistema Hipotálamo-Hipofisário , Fatores Imunológicos/uso terapêutico , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/imunologia , Sistema Hipotálamo-Hipofisário/metabolismo
9.
JNMA J Nepal Med Assoc ; 59(238): 593-596, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34508399

RESUMO

Severe coronavirus disease 2019 can be associated with progressive respiratory failure. In addition to respiratory support and other supportive care, use of corticosteroids has shown to improve outcome. Despite the use of steroids, a significant proportion of patients progressively worsen. Adjunct immunomodulators have been studied in addition to steroids in these patients. Here we present a successful use of tofacitinib, a Janus Kinase inhibitor, in conjunction with dexamethasone for a patient with rapid worsening of respiratory status and with high level of serum inflammatory biomarkers.


Assuntos
COVID-19 , Humanos , Fatores Imunológicos/uso terapêutico , Piperidinas , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , SARS-CoV-2
10.
J Neuroimmunol ; 359: 577696, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34418815

RESUMO

AIM: To determine the influence of high-efficacy disease modifying therapy (DMT) on the development of IgG SARS-CoV-2 antibody response in COVID-19 convalescent people with multiple sclerosis (pwMS). METHODS: Seventy-four pwMS taking high-efficacy DMTs (specifically natalizumab, fingolimod, alemtuzumab, ocrelizumab, cladribine and ublituximab) and diagnosed with COVID-19 and 44 healthy persons (HC) were enrolled. SARS-CoV2 antibodies were tested with Elecsys® Anti-SARSCoV-2 S assay. RESULTS: pwMS taking high-efficacy DMTs had a significantly higher chance of having negative titer of SARS-CoV2 antibodies compared to healthy controls (33 negative pwMS [44.6%] compared to one negative HC [2.3%], p < 0.001). pwMS taking B-cell depleting therapy (ocrelizumab and ublituximab) had a significantly higher chance of having negative titer of SARS-CoV2 antibodies compared to pwMS on all other DMTs (29 negative pwMS on B-cell therapy [64.4%] compared to four negative pwMS on all other DMTs [13.8%], p < 0.001). Out of other DMTs, two (33.3%) pwMS taking fingolimod and two (16.7%) pwMS taking cladribine failed to develop IgG SARS-COV-2 antibodies. B-cell depleting therapy independently predicted negative titer of IgG SARS-CoV-2 antibody (Exp[B] =0.014, 95%CI 0.002-0.110, p < 0.001). CONCLUSIONS: A significant proportion of convalescent COVID-19 pwMS on high-efficacy DMTs will not develop IgG SARS-CoV-2 antibodies. B-cell depleting therapies independently predict negative and low titer of IgG SARS-CoV-2 antibody.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/imunologia , Imunidade Humoral/imunologia , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , SARS-CoV-2/imunologia , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/sangue , Estudos de Casos e Controles , Feminino , Humanos , Imunidade Humoral/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Imunossupressores/farmacologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/metabolismo , Resultado do Tratamento
11.
Washington; Pan American Health Organization; 25 ed; Aug. 26, 2021. 346 p. tab..
Não convencional em Inglês | PIE | ID: biblio-1284280

RESUMO

The vast amount of data generated by clinical studies of potential therapeutic options for COVID-19 presents important challenges. The new data must be interpreted quickly so that prescribers can make optimal treatment decisions with as little harm to patients as possible, and so that medicines manufacturers can scale up production rapidly and bolster their supply chains. Rapid interpretation of fresh data will save lives by ensuring that successful drugs can be administered to as many patients as possible as quickly as possible. This publication, the 25th edition of the database of evidence on potential therapeutic options for COVID-19, examines 137 therapeutic options. This information will help investigators, policymakers, and prescribers navigate the flood of relevant data to ensure that management of COVID-19, at both individual and population levels, is based on the best available knowledge. This resource will be continually updated as more research is released into the public space.


Assuntos
Humanos , Antivirais/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , COVID-19/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Ensaios Clínicos como Assunto
12.
Washington; Pan American Health Organization; 24 ed; Aug. 5, 2021. 345 p. tab..
Não convencional em Inglês | PIE | ID: biblio-1284281

RESUMO

The vast amount of data generated by clinical studies of potential therapeutic options for COVID-19 presents important challenges. The new data must be interpreted quickly so that prescribers can make optimal treatment decisions with as little harm to patients as possible, and so that medicines manufacturers can scale up production rapidly and bolster their supply chains. Rapid interpretation of fresh data will save lives by ensuring that successful drugs can be administered to as many patients as possible as quickly as possible. This publication, the 25th edition of the database of evidence on potential therapeutic options for COVID-19, examines 137 therapeutic options. This information will help investigators, policymakers, and prescribers navigate the flood of relevant data to ensure that management of COVID-19, at both individual and population levels, is based on the best available knowledge. This resource will be continually updated as more research is released into the public space.


Assuntos
Humanos , Antivirais/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , COVID-19/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Ensaios Clínicos como Assunto
13.
Stomatologiia (Mosk) ; 100(4): 16-19, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34357722

RESUMO

THE AIM OF THE STUDY: Was to investigate the efficacy of immunomodulatory drug based on muramilpeptides for treatment of chronic generalized periodontitis. MATERIALS AND METHODS: The study group comprised 20 patients aged 25 to 64 with severe chronic periodontal disease. Periodontal pockets content was inoculated for specific microbial pathogens before and after treatment. Twenty patients receiving conventional treatment with no muramilpeptides-based agent served as controls. RESULTS: In the main group prolonged suppression of periodontal disease provoking microbiota was seen, while in controls conventional treatment was not sufficiently effective resulting in germs growth relapse at day 21. CONCLUSION: The dynamics of the microbiological landscape of periodontal pockets after treatment proves the necessity for a correction of innate immunity in inflammatory periodontal disease.


Assuntos
Periodontite Crônica , Microbiota , Antibacterianos , Periodontite Crônica/tratamento farmacológico , Humanos , Fatores Imunológicos , Bolsa Periodontal
14.
Int J Med Mushrooms ; 23(5): 1-11, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34347990

RESUMO

Since December 2019, a de novo pattern of pneumonia, later named coronavirus disease 2019 (COVID-19), has caused grave upset throughout the global population. COVID-19 is associated with several comorbidities; thus, preventive and therapeutic strategies targeting those comorbidities along with the causative agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), seem imperative. In this state-of-the-art review, edible and medicinal mushrooms are featured in the treatment of SARS-CoV-2, COVID-19 pathomanifestations, and comorbid issues. Because this is not an original research article, we admit our shortcomings in inferences. Yet we are hopeful that mushroom-based therapeutic approaches can be used to achieve a COVID-free world. Among various mushroom species, reishi or lingzhi (Ganoderma lucidum) seem most suitable as anti-COVID agents for the global population.


Assuntos
Agaricales/química , Antivirais/uso terapêutico , Produtos Biológicos/uso terapêutico , COVID-19/prevenção & controle , COVID-19/terapia , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Antivirais/administração & dosagem , Produtos Biológicos/administração & dosagem , COVID-19/imunologia , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/prevenção & controle , Síndrome da Liberação de Citocina/terapia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Camundongos , Reishi/química , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade
15.
Nutrients ; 13(7)2021 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-34371956

RESUMO

We examined the immunomodulatory and anti-inflammatory effects of asiatic acid (AA) in atopic dermatitis (AD). AA treatment (5-20 µg/mL) dose-dependently suppressed the tumor necrosis factor (TNF)-α level and interleukin (IL)-6 protein expression in interferon (IFN)-γ + TNF-α-treated HaCaT cells. The 2,4-dinitrocholrlbenzene (DNCB)-induced AD animal model was developed by administering two AA concentrations (30 and 75 mg/kg/d: AD + AA-L and AD + AA-H groups, respectively) for 18 days. Interestingly, AA treatment decreased AD skin lesions formation and affected other AD characteristics, such as increased ear thickness, lymph node and spleen size, dermal and epidermal thickness, collagen deposition, and mast cell infiltration in dorsal skin. In addition, in the DNCB-induced AD animal model, AA treatment downregulated the mRNA expression level of AD-related cytokines, such as Th1- (TNF-α and IL-1ß and -12) and Th2 (IL-4, -5, -6, -13, and -31)-related cytokines as well as that of cyclooxygenase-2 and CXCL9. Moreover, in the AA treatment group, the protein level of inflammatory cytokines, including COX-2, IL-6, TNF-α, and IL-8, as well as the NF-κB and MAPK signaling pathways, were decreased. Overall, our study confirmed that AA administration inhibited AD skin lesion formation via enhancing immunomodulation and inhibiting inflammation. Thus, AA can be used as palliative medication for regulating AD symptoms.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Fatores Imunológicos/farmacologia , Triterpenos Pentacíclicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/uso terapêutico , Linhagem Celular , Sobrevivência Celular , Colágeno/análise , Citocinas/genética , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Derme/patologia , Dinitroclorobenzeno , Modelos Animais de Doenças , Epiderme/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Imunomodulação , Tecido Linfoide/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mastócitos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Triterpenos Pentacíclicos/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Artigo em Inglês | MEDLINE | ID: mdl-34452974

RESUMO

BACKGROUND AND OBJECTIVES: Since the onset of the COVID-19 pandemic, a growing number of reports have described cases of acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalitis (AHLE) following infection with COVID-19. Given their relatively rare occurrence, the primary objective of this systematic review was to synthesize their clinical features, response to treatments, and clinical outcomes to better understand the nature of this neurologic consequence of COVID-19 infection. METHODS: Patients with a history of COVID-19 infection were included if their reports provided adequate detail to confirm a diagnosis of ADEM or AHLE by virtue of clinical features, radiographic abnormalities, and histopathologic findings. Cases purported to be secondary to vaccination against COVID-19 or occurring in the context of a preexisting relapsing CNS demyelinating disease were excluded. Case reports and series were identified via PubMed on May 17, 2021, and 4 additional cases from the authors' hospital files supplemented the systematic review of the literature. Summary statistics were used to describe variables using a complete case analysis approach. RESULTS: Forty-six patients (28 men, median age 49.5 years, 1/3 >50 years old) were analyzed, derived from 26 case reports or series originating from 8 countries alongside 4 patient cases from the authors' hospital files. COVID-19 infection was laboratory confirmed in 91% of cases, and infection severity necessitated intensive care in 67%. ADEM occurred in 31 cases, whereas AHLE occurred in 15, with a median presenting nadir modified Rankin Scale score of 5 (bedridden). Anti-MOG seropositivity was rare (1/15 patients tested). Noninflammatory CSF was present in 30%. Hemorrhage on brain MRI was identified in 42%. Seventy percent received immunomodulatory treatments, most commonly steroids, IV immunoglobulins, or plasmapheresis. The final mRS score was ≥4 in 64% of patients with adequate follow-up information, including 32% who died. DISCUSSION: In contrast to ADEM cases from the prepandemic era, reported post-COVID-19 ADEM and AHLE cases were often advanced in age at onset, experienced severe antecedent infection, displayed an unusually high rate of hemorrhage on neuroimaging, and routinely had poor neurologic outcomes, including a high mortality rate. Findings are limited by nonstandardized reporting of cases, truncated follow-up information, and presumed publication bias.


Assuntos
COVID-19/complicações , Encefalomielite Aguda Disseminada/etiologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encefalomielite Aguda Disseminada/mortalidade , Encefalomielite Aguda Disseminada/fisiopatologia , Encefalomielite Aguda Disseminada/terapia , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Unidades de Terapia Intensiva , Leucoencefalite Hemorrágica Aguda/etiologia , Leucoencefalite Hemorrágica Aguda/mortalidade , Leucoencefalite Hemorrágica Aguda/fisiopatologia , Leucoencefalite Hemorrágica Aguda/terapia , Imageamento por Ressonância Magnética , Plasmaferese , SARS-CoV-2 , Índice de Gravidade de Doença
17.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34413211

RESUMO

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.


Assuntos
Antivirais/farmacologia , Fatores Imunológicos/farmacologia , Lactoferrina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Células CACO-2 , Linhagem Celular Tumoral , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Descoberta de Drogas , Reposicionamento de Medicamentos/métodos , Células Epiteliais , Heparitina Sulfato/antagonistas & inibidores , Heparitina Sulfato/imunologia , Heparitina Sulfato/metabolismo , Hepatócitos , Ensaios de Triagem em Larga Escala , Humanos , SARS-CoV-2/crescimento & desenvolvimento , SARS-CoV-2/patogenicidade , Células Vero
18.
Front Immunol ; 12: 720090, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34434199

RESUMO

Male sex and old age are risk factors for COVID-19 severity, but the underlying causes are unknown. A possible explanation for this might be the differences in immunological profiles in males and the elderly before the infection. With this in mind, we analyzed the abundance of circulating proteins and immune populations associated with severe COVID-19 in 2 healthy cohorts. Besides, given the seasonal profile of COVID-19, the seasonal response against SARS-CoV-2 could also be different in the elderly and males. Therefore, PBMCs of female, male, young, and old subjects in different seasons of the year were stimulated with heat-inactivated SARS-CoV-2 to investigate the season-dependent anti-SARS-CoV-2 immune response. We found that several T cell subsets, which are known to be depleted in severe COVID-19 patients, were intrinsically less abundant in men and older individuals. Plasma proteins increasing with disease severity, including HGF, IL-8, and MCP-1, were more abundant in the elderly and males. Upon in vitro SARS-CoV-2 stimulation, the elderly produced significantly more IL-1RA and had a dysregulated IFNγ response with lower production in the fall compared with young individuals. Our results suggest that the immune characteristics of severe COVID-19, described by a differential abundance of immune cells and circulating inflammatory proteins, are intrinsically present in healthy men and the elderly. This might explain the susceptibility of men and the elderly to SARS-CoV-2 infection.


Assuntos
COVID-19/imunologia , Adolescente , Adulto , Fatores Etários , Idoso , Envelhecimento/imunologia , Proteínas Sanguíneas/imunologia , COVID-19/fisiopatologia , Estudos de Coortes , Suscetibilidade a Doenças , Feminino , Humanos , Imunidade Celular , Fatores Imunológicos , Masculino , Pessoa de Meia-Idade , Gravidade do Paciente , Medição de Risco , Estações do Ano , Fatores Sexuais , Subpopulações de Linfócitos T/imunologia , Adulto Jovem
19.
J Gerontol A Biol Sci Med Sci ; 76(10): 1775-1783, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34396395

RESUMO

Aging and comorbidities make individuals at greatest risk of COVID-19 serious illness and mortality due to senescence-related events and deleterious inflammation. Long-living individuals (LLIs) are less susceptible to inflammation and develop more resiliency to COVID-19. As demonstrated, LLIs are characterized by high circulating levels of BPIFB4, a protein involved in homeostatic response to inflammatory stimuli. Also, LLIs show enrichment of homozygous genotype for the minor alleles of a 4 missense single-nucleotide polymorphism haplotype (longevity-associated variant [LAV]) in BPIFB4, able to counteract progression of diseases in animal models. Thus, the present study was designed to assess the presence and significance of BPIFB4 level in COVID-19 patients and the potential therapeutic use of LAV-BPIFB4 in fighting COVID-19. BPIFB4 plasma concentration was found significantly higher in LLIs compared to old healthy controls while it significantly decreased in 64 COVID-19 patients. Further, the drop in BPIFB4 values correlated with disease severity. Accordingly to the LAV-BPIFB4 immunomodulatory role, while lysates of SARS-CoV-2-infected cells induced an inflammatory response in healthy peripheral blood mononuclear cells in vitro, the co-treatment with recombinant protein (rh) LAV-BPIFB4 resulted in a protective and self-limiting reaction, culminating in the downregulation of CD69 activating-marker for T cells (both TCD4+ and TCD8+) and in MCP-1 reduction. On the contrary, rhLAV-BPIFB4 induced a rapid increase in IL-18 and IL-1b levels, shown largely protective during the early stages of the virus infection. This evidence, along with the ability of rhLAV-BPIFB4 to counteract the cytotoxicity induced by SARS-CoV-2 lysate in selected target cell lines, corroborates BPIFB4 prognostic value and open new therapeutic possibilities in more vulnerable people.


Assuntos
COVID-19 , Peptídeos e Proteínas de Sinalização Intercelular , Longevidade/imunologia , Idoso de 80 Anos ou mais , Biomarcadores/sangue , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/imunologia , Linhagem Celular , Citocinas/sangue , Citotoxicidade Imunológica/efeitos dos fármacos , Feminino , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacologia , Inflamação/sangue , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Itália/epidemiologia , Masculino , Prognóstico , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença
20.
Artigo em Inglês | MEDLINE | ID: mdl-34341094

RESUMO

BACKGROUND AND OBJECTIVES: We sought to define the risk of severe coronavirus disease 2019 (COVID-19) infection requiring hospitalization in patients with CNS demyelinating diseases such as MS and the factors that increase the risk for severe infection to guide decisions regarding patient care during the COVID-19 pandemic. METHODS: A pilot cohort of 91 patients with confirmed or suspected COVID-19 infection from the Northeastern United States was analyzed to characterize patient risk factors and factors associated with an increased severity of COVID-19 infection. Univariate analysis of variance was performed using the Mann-Whitney U test or analysis of variance for continuous variables and the χ2 or Fisher exact test for nominal variables. Univariate and stepwise multivariate logistic regression identified clinical characteristics or symptoms associated with hospitalization. RESULTS: Our cohort demonstrated a 27.5% hospitalization rate and a 4.4% case fatality rate. Performance on Timed 25-Foot Walk before COVID-19 infection, age, number of comorbidities, and presenting symptoms of nausea/vomiting and neurologic symptoms (e.g., paresthesia or weakness) were independent risk factors for hospitalization, whereas headache predicted a milder course without hospitalization. An absolute lymphocyte count was lower in hospitalized patients during COVID-19 infection. Use of disease-modifying therapy did not increase the risk of hospitalization but was associated with an increased need for respiratory support. DISCUSSION: The case fatality and hospitalization rates in our cohort were similar to those found in MS and general population COVID-19 cohorts within the region. Hospitalization was associated with increased disability, age, and comorbidities but not disease-modifying therapy use.


Assuntos
COVID-19 , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central , Hospitalização/estatística & dados numéricos , Fatores Imunológicos/uso terapêutico , Sistema de Registros/estatística & dados numéricos , Respiração Artificial/estatística & dados numéricos , Adulto , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/terapia , Estudos de Coortes , Comorbidade , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/tratamento farmacológico , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/epidemiologia , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mortalidade , New England/epidemiologia , Projetos Piloto , Fatores de Risco , Índice de Gravidade de Doença
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