Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.988
Filtrar
1.
Medicine (Baltimore) ; 100(29): e26533, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34398008

RESUMO

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, keeps spreading globally. Evidence suggests that a subgroup of patients with severe symptomatology might have cytokine storms, which increases mortality. The use of interleukin-6 (IL-6) inhibitors may help in controlling the pathological immune response to the virus. Tocilizumab, a monoclonal antibody against IL-6, stands as an optional treatment for COVID-19 patients presenting this inflammatory hyper-response.We conducted a retrospective, observational, cohort study including 50 patients affected by COVID-19 with severe pneumonia and poor prognosis criteria, who have also undergone standard treatment; 36 of these patients additionally received tocilizumab in an early stage. The need for intensive care unit (ICU) admission, mortality, recovery of respiratory function, and improvement of biochemical and hematological parameters were compared between cohorts.Most patients were men, non-smokers and the most frequently reported comorbidities were hypertension and diabetes. Recurrent symptoms were fever, cough, and dyspnoea. 54.8% of patients from the tocilizumab group needed intubation, while in the control group 85.7% needed it. Treatment with tocilizumab significatively increased IL-6 levels, (554.45; CI 95% 186.69, 1032.93; P < .05) while C-reactive protein mean levels were reduced (-108.19; CI 95% -140.15, -75.33; P < .05), but no significant difference was found between cohorts. In comparison with the controls, tocilizumab reduced mortality (25.0% vs 42.9%, P = .021) and the number of ICU admissions (63.9% vs 100.0%, P = .021). 44.1% of patients treated with tocilizumab showed favorable radiological evolution, when compared with 15.4% of patients from the control group.Tocilizumab may improve clinical symptoms and mitigate deterioration observed in severe COVID-19 patients, and could be considered as an effective therapeutic option in subjects experiencing a significant inflammatory response to the disease.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Unidades de Terapia Intensiva/estatística & dados numéricos , Interleucina-6/antagonistas & inibidores , Pneumonia Viral/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/diagnóstico , Pneumonia Viral/etiologia , Pneumonia Viral/mortalidade , Prognóstico , Estudos Retrospectivos
2.
FASEB J ; 35(9): e21795, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403508

RESUMO

Intervertebral disc degeneration is an irreversible process associated with accumulation of senescent nucleus pulposus (NP) cells. This study investigates the hypothesis that Tumor necrosis factor-α (TNF-α)-treated senescent NP cells propagate senescence of neighboring healthy cells via a paracrine effect that involves p-Stat3 signaling and the cytokine interleukin-6 (IL-6). NP cells isolated from bovine caudal intervertebral disc (IVD) were treated with TNF-α to induce senescence which was confirmed by demonstrating upregulation of senescence-associated ß-galactosidase and p16. This was correlated with downregulation of NP-associated markers, Aggrecan, Col2A1, and Sox9. Direct contact and non-contact co-culture of healthy and senescent cells showed that TNF-α-treated cells increased the senescence in healthy cells via a paracrine effect. The senescent cells have a secretory phenotype as indicated by increased gene and protein levels of IL-6. Phosphorylated Signal Transducer and Activator of Transcription 3 (pStat3) levels were also high in treated cells and appeared to upregulate IL-6 as inhibition of Stat3 phosphorylation by StatticV downregulated IL-6 mRNA expression in cells and protein levels in the culture media. All trans retinoic acid, an IL-6 inhibitor, also decreased the secretion of IL-6 and reduced the paracrine effect of senescent cells on healthy cells. Decreased pStat3 levels and inhibition of IL-6 secretion did not fully restore NP gene expression of Col2A1 but importantly, appeared to cause senescent cells to undergo apoptosis and cell death. This study demonstrated the paracrine effect of senescent NP cells which involves Stat3 and IL-6 and may explain why senescent NP cells accumulate in IVD with age. The role of pSTAT3 and IL-6 in mediating NP senescence requires further study as it may be a novel strategy for modulating the senescent-inducing effects of TNF-α.


Assuntos
Senescência Celular/efeitos dos fármacos , Núcleo Pulposo/citologia , Núcleo Pulposo/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Animais , Apoptose/efeitos dos fármacos , Bovinos , Morte Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Núcleo Pulposo/metabolismo , Fosforilação , Fator de Transcrição STAT3/metabolismo
3.
Medicine (Baltimore) ; 100(32): e26843, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397890

RESUMO

INTRODUCTION: Secondary amyloidosis is a rare complication of rheumatoid arthritis (RA) that is histologically characterized by the deposition of amyloid fibrils in target organs, such as the kidneys and gastrointestinal tract. Controlling the inflammatory response is essential to prevent organ dysfunction in amyloid A (AA) amyloidosis secondary to RA, and no clear treatment strategy exists. PATIENT CONCERNS AND DIAGNOSIS: A 66-year-old woman with RA, who had been treated with disease-modifying anti-rheumatic drugs for 1 year, presented with recurrent abdominal pain and prolonged diarrhea. Endoscopy showed chronic inflammation, and colon tissue histology confirmed AA amyloidosis. INTERVENTIONS AND OUTCOMES: After tocilizumab therapy was begun, her diarrhea and abdominal pain subsided, and articular symptoms improved. Biologic drugs for RA have been used in patients with secondary AA amyloidosis, including tumor necrosis factor and Janus kinase inhibitors, interleukin 6 blockers, and a T cell modulator. Here, we systematically review existing case reports and compare the outcomes of RA-related AA amyloidosis after treatment with various drugs. CONCLUSION: The data indicate that biologic drugs like tocilizumab might be treatments of choice for AA amyloidosis secondary to RA.


Assuntos
Amiloidose , Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Reumatoide , Terapia Biológica/métodos , Colo , Proteína Amiloide A Sérica/análise , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Idoso , Amiloidose/etiologia , Amiloidose/imunologia , Amiloidose/fisiopatologia , Amiloidose/terapia , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Produtos Biológicos/administração & dosagem , Colo/imunologia , Colo/patologia , Diarreia/diagnóstico , Diarreia/etiologia , Feminino , Humanos , Interleucina-6/antagonistas & inibidores , Resultado do Tratamento
4.
JAMA ; 326(6): 499-518, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34228774

RESUMO

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Idoso , COVID-19/complicações , COVID-19/mortalidade , COVID-19/terapia , Causas de Morte , Coinfecção , Progressão da Doença , Quimioterapia Combinada , Feminino , Glucocorticoides/uso terapêutico , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial
5.
Exp Mol Med ; 53(7): 1116-1123, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34253862

RESUMO

Interleukin-6 (IL-6) plays a crucial role in host defense against infection and tissue injuries and is a bioindicator of multiple distinct types of cytokine storms. In this review, we present the current understanding of the diverse roles of IL-6, its receptors, and its signaling during acute severe systemic inflammation. IL-6 directly affects vascular endothelial cells, which produce several types of cytokines and chemokines and activate the coagulation cascade. Endothelial cell dysregulation, characterized by abnormal coagulation and vascular leakage, is a common complication in cytokine storms. Emerging evidence indicates that a humanized anti-IL-6 receptor antibody, tocilizumab, can effectively block IL-6 signaling and has beneficial effects in rheumatoid arthritis, juvenile systemic idiopathic arthritis, and Castleman's disease. Recent work has also demonstrated the beneficial effect of tocilizumab in chimeric antigen receptor T-cell therapy-induced cytokine storms as well as coronavirus disease 2019 (COVID-19). Here, we highlight the distinct contributions of IL-6 signaling to the pathogenesis of several types of cytokine storms and discuss potential therapeutic strategies for the management of cytokine storms, including those associated with sepsis and COVID-19.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/prevenção & controle , Interleucina-6/genética , Receptores de Interleucina-6/genética , Anticorpos Monoclonais Humanizados/imunologia , COVID-19/genética , COVID-19/imunologia , COVID-19/patologia , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/imunologia , Citocinas/genética , Citocinas/metabolismo , Endotélio Vascular/imunologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Sepse/genética , Sepse/imunologia , Sepse/patologia , Sepse/prevenção & controle
6.
Theranostics ; 11(14): 7029-7044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093869

RESUMO

Background: Increased IL-6 level, M2 macrophages and PD-1+CD8+ T cells in tumor microenvironments (TME) have been identified to correlate with resistance to checkpoint blockade immunotherapy, yet the mechanism remains poorly understood. Rab small GTPase-mediated trafficking of cytokines is critical in immuno-modulation. We have previously reported dysregulation of Rab37 in lung cancer cells, whereas the roles of Rab37 in tumor-infiltrating immune cells and cancer immunotherapy are unclear. Methods: The tumor growth of the syngeneic mouse allograft in wild type or Rab37 knockout mice was analyzed. Imaging analyses and vesicle isolation were conducted to determine Rab37-mediated IL-6 secretion. STAT3 binding sites at PD-1 promoter in T cells were identified by chromatin immunoprecipitation assay. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37, IL-6 and PD-1 and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from lung cancer patients. Results: We revealed that Rab37 regulates the secretion of IL-6 in a GTPase-dependent manner in macrophages to trigger M2 polarization. Macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells. Clinically, tumors with high stromal Rab37 and IL-6 expression coincide with tumor infiltrating M2-macrophages and PD1+CD8+ T cells that predicts poor prognosis in lung cancer patients. In addition, lung cancer patients with an increase in plasma IL-6 level are found to be associated with immunotherapeutic resistance. Importantly, combined blockade of IL-6 and CTLA-4 improves survival of tumor-bearing mice by reducing infiltration of PD1+CD8+ T cells and M2 macrophages in TME. Conclusions: Rab37/IL-6 trafficking pathway links with IL-6/STAT3/PD-1 transcription regulation to foster an immunosuppressive TME and combined IL-6/CTLA-4 blockade therapy exerts potent anti-tumor efficacy.


Assuntos
Interleucina-6/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral/imunologia , Proteínas rab de Ligação ao GTP/metabolismo , Aloenxertos , Animais , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/metabolismo , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica , Prognóstico , Receptor de Morte Celular Programada 1/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Microambiente Tumoral/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/ultraestrutura
8.
9.
J Immunother Cancer ; 9(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33986127

RESUMO

COVID-19, the syndrome caused by the infection with SARS-CoV-2 coronavirus, is characterized, in its severe form, by interstitial diffuse pneumonitis and acute respiratory distress syndrome (ARDS). ARDS and systemic manifestations of COVID-19 are mainly due to an exaggerated immune response triggered by the viral infection. Cytokine release syndrome (CRS), an inflammatory syndrome characterized by elevated levels of circulating cytokines, and endothelial dysfunction are systemic manifestations of COVID-19. CRS is also an adverse event of immunotherapy (IMTX), the treatment of diseases using drugs, cells, and antibodies to stimulate or suppress the immune system. Graft-versus-host disease complications after an allogeneic stem cell transplant, toxicity after the infusion of chimeric antigen receptor-T cell therapy and monoclonal antibodies can all lead to CRS. It is hypothesized that anti-inflammatory drugs used for treatment of CRS in IMTX may be useful in reducing the mortality in COVID-19, whereas IMTX itself may help in ameliorating effects of SARS-CoV-2 infection. In this paper, we focused on the potential shared mechanisms and differences between COVID-19 and IMTX-related toxicities. We performed a systematic review of the clinical trials testing anti-inflammatory therapies and of the data published from prospective trials. Preliminary evidence suggests there might be a benefit in targeting the cytokines involved in the pathogenesis of COVID-19, especially by inhibiting the interleukin-6 pathway. Many other approaches based on novel drugs and cell therapies are currently under investigation and may lead to a reduction in hospitalization and mortality due to COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/terapia , Síndrome da Liberação de Citocina/tratamento farmacológico , Imunoterapia/métodos , Interleucina-6/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/patologia , Síndrome da Liberação de Citocina/patologia , Humanos , Imunização Passiva/métodos , Imunoterapia/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/sangue , Interleucina-6/sangue , Pirazóis/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Fator de Necrose Tumoral alfa/sangue
10.
Rev Esp Quimioter ; 34(4): 337-341, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33982984

RESUMO

OBJECTIVE: The study aims to describe characteristics and clinical outcome of patients with SARS-CoV-2 infection that received siltuximab according to a protocol that aimed to early block the activity of IL-6 to avoid the progression of the inflammatory flare. METHODS: Retrospective review of the first 31 patients with SARS-CoV-2 treated with siltuximab, in Hospital Clinic of Barcelona or Hospital Universitario Salamanca, from March to April 2020 with positive polymerase-chain reaction (PCR) from a nasopharyngeal swab. RESULTS: The cohort included 31 cases that received siltuximab with a median (IQR) age of 62 (56-71) and 71% were males. The most frequent comorbidity was hypertension (48%). The median dose of siltuximab was 800 mg ranging between 785 and 900 mg. 7 patients received siltuximab as a salvage therapy after one dose of tocilizumab. At the end of the study, a total of 26 (83.9) patients had been discharged alive and the mortality rate was 16.1% but only 1 out of 24 that received siltuximab as a first line option (4%). CONCLUSIONS: Siltuximab is a well-tolerated alternative to tocilizumab when administered as a first line option in patients with COVID-19 pneumonia within the first 10 days from symptoms onset and high C-reactive protein.


Assuntos
Anticorpos Monoclonais/uso terapêutico , COVID-19/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Proteína C-Reativa/análise , COVID-19/mortalidade , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Progressão da Doença , Feminino , Humanos , Hipertensão/complicações , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Terapia de Salvação , Resultado do Tratamento
11.
Phytomedicine ; 87: 153552, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33994251

RESUMO

BACKGROUND: The naturally occurring flavonol fisetin (3,3',4',7-tetrahydroxyflavone), widely dispersed in fruits, vegetables and nuts, has been reported to exert anti-inflammatory, antioxidant and anti-angiogenic effects. Our previous study indicated fisetin ameliorated inflammation and apoptosis in septic kidneys. However, the potential nephroprotective effect of fisetin in hyperuricemic mice remains unknown. PURPOSE: The current study was designed to investigate the effect of fisetin on hyperuricemic nephropathy (HN) and explore the underlying mechanisms. METHODS: The HN was induced in mice by mixing of potassium oxonate (2400 mg/kg) and adenine (160 mg/kg) in male C57BL/6J mice. Fisetin (50 or 100 mg/kg) was orally administrated either simultaneously with the establishment of HN or after HN was induced. As a positive control, allopurinol of 10 mg/kg was included. Uric acid levels in the serum and urine as well as renal function parameters were measured. Renal histological changes were measured by periodic acid-Schiff (PAS) and Masson's trichrome stainings. The expression of gene/protein in relation to inflammation, fibrosis, and uric acid excretion in the kidneys of HN mice or uric acid-treated mouse tubular epithelial (TCMK-1) cells were measured by RNA-seq, RT-PCR, western blot and immunohistochemical analysis. RESULTS: Treatment with fisetin, regardless of administration regimen, dose-dependently attenuated hyperuricemia-induced kidney injury as indicated by the improved renal function, preserved tissue architecture, and decreased urinary albumin-to-creatinine ratio. Additionally, fisetin lowered uricemia by modulating the expression of kidney urate transporters including urate transporter 1(URAT1), organic anion transporter 1 (OAT1), organic anion transporter 3 (OAT3) and ATP binding cassette subfamily G member 2 (ABCG2). Moreover, hyperuricemia-induced secretions of proinflammatory factors including tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and monocyte chemoattractant protein-1(MCP-1) in HN mice and uric acid-stimulated TCMK-1 cells were mitigated by fisetin treatment. Meanwhile, fisetin attenuated kidney fibrosis in HN mice with restored expressions of alpha-smooth muscle actin (α-SMA), collagen I and fibronectin. Mechanistically, fisetin regulated the aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling and transforming growth factor-ß (TGF-ß) signaling in the HN kidneys and uric acid-stimulated TCMK-1 cells. CONCLUSION: Fisetin lowered uricemia, suppressed renal inflammatory response, and improved kidney fibrosis to protect against hyperuricemic nephropathy via modulation of STAT3 and TGF-ß signaling pathways. The results highlighted that fisetin might represent a potential therapeutic strategy against hyperuricemic nephropathy.


Assuntos
Flavonóis/farmacologia , Hiperuricemia/tratamento farmacológico , Interleucina-6/metabolismo , Nefropatias/tratamento farmacológico , Fator de Crescimento Transformador beta/metabolismo , Administração Oral , Animais , Fibrose , Flavonóis/administração & dosagem , Flavonóis/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperuricemia/patologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/sangue , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/genética , Ácido Úrico/sangue , Ácido Úrico/urina
12.
Anticancer Res ; 41(5): 2277-2286, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952453

RESUMO

BACKGROUND/AIM: Poly (ADP-ribose) polymerase inhibitors (PARPis) are one of the targeted therapies proven to treat breast cancer gene (BRCA)-mutant ovarian cancer. Because most ovarian cancers are BRCA wild-type, it is necessary to extend the usage of PARPis. In the present study, we combined the PARPi, talazoparib, and the IL-6 inhibitor, bazedoxifene, for the treatment of human ovarian cancer cells. MATERIALS AND METHODS: The human ovarian cancer cell lines, SKOV3, UWB1.289 (BRCA1-null) and OV75, were treated with talazoparib and bazedoxifene, as monotherapy or combination treatment. The effects of treatment on cell viability, migration, growth and colony formation were examined. Western blot was used to investigate pathways that may be involved in the antitumor effects of the two agents. RESULTS: The combination of talazoparib and bazedoxifene showed synergistic inhibition of cell viability, cell migration, cell growth, and cell colony formation on all the studied cell lines. The expression of p-AKT, c-myc, p-ERK, ERα was inhibited, and γ-H2AX expression was induced. CONCLUSION: Combined inhibition of PARP and IL-6 may be an efficacious treatment for ovarian cancer, independently of BRCA mutation status.


Assuntos
Proteína BRCA1/genética , Indóis/farmacologia , Mutação , Neoplasias Ovarianas/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fatores de Tempo
13.
Front Immunol ; 12: 675678, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995419

RESUMO

Background: Restraining maladaptive inflammation is considered a rationale strategy to treat severe coronavirus disease-19 (COVID-19) but available studies with selective inhibitors of pro-inflammatory cytokines have not provided unequivocal evidence of survival advantage. Late administration is commonly regarded as a major cause of treatment failure but the optimal timing for anti-cytokine therapy initiation in COVID-19 patients has never been clearly established. Objectives: To identify a window of therapeutic opportunity for maximizing the efficacy of interleukin (IL)-1 and IL-6 blockade in COVID-19. Methods: Survival at the longest available follow-up was assessed in severe hyper-inflamed COVID-19 patients treated with anakinra, tocilizumab, sarilumab, or standard of care, stratified according to respiratory impairment at the time of treatment initiation. Results: 107 patients treated with biologics and 103 contemporary patients treated with standard of care were studied. After a median of 106 days of follow-up (range 3-186), treatment with biologics was associated with a significantly higher survival rate compared to standard therapy when initiated in patients with a PaO2/FiO2 ≥ 100 mmHg (p < 0.001). Anakinra reduced mortality also in patients with PaO2/FiO2 < 100 mmHg (p = 0.04). Conclusions: IL-1 and IL-6 blocking therapies are more likely to provide survival advantage in hyper-inflamed COVID-19 patients when initiated before the establishment of severe respiratory failure.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , COVID-19 , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Interleucina-1/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , SARS-CoV-2/imunologia , Idoso , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/mortalidade , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Interleucina-1/imunologia , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Taxa de Sobrevida
14.
Clin Microbiol Rev ; 34(3)2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-33980688

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a rapidly evolving pandemic worldwide with at least 68 million COVID-19-positive cases and a mortality rate of about 2.2%, as of 10 December 2020. About 20% of COVID-19 patients exhibit moderate to severe symptoms. Severe COVID-19 manifests as acute respiratory distress syndrome (ARDS) with elevated plasma proinflammatory cytokines, including interleukin 1ß (IL-1ß), IL-6, tumor necrosis factor α (TNF-α), C-X-C motif chemokine ligand 10 (CXCL10/IP10), macrophage inflammatory protein 1 alpha (MIP-1α), and chemokine (C-C motif) ligand 2 (CCL2), with low levels of interferon type I (IFN-I) in the early stage and elevated levels of IFN-I during the advanced stage of COVID-19. Most of the severe and critically ill COVID-19 patients have had preexisting comorbidities, including hypertension, diabetes, cardiovascular diseases, and respiratory diseases. These conditions are known to perturb the levels of cytokines, chemokines, and angiotensin-converting enzyme 2 (ACE2), an essential receptor involved in SARS-CoV-2 entry into the host cells. ACE2 downregulation during SARS-CoV-2 infection activates the angiotensin II/angiotensin receptor (AT1R)-mediated hypercytokinemia and hyperinflammatory syndrome. However, several SARS-CoV-2 proteins, including open reading frame 3b (ORF3b), ORF6, ORF7, ORF8, and the nucleocapsid (N) protein, can inhibit IFN type I and II (IFN-I and -II) production. Thus, hyperinflammation, in combination with the lack of IFN responses against SARS-CoV-2 early on during infection, makes the patients succumb rapidly to COVID-19. Therefore, therapeutic approaches involving anti-cytokine/anti-cytokine-signaling and IFN therapy would favor the disease prognosis in COVID-19. This review describes critical host and viral factors underpinning the inflammatory "cytokine storm" induction and IFN antagonism during COVID-19 pathogenesis. Therapeutic approaches to reduce hyperinflammation and their limitations are also discussed.


Assuntos
COVID-19/patologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/patologia , Interferon Tipo I/sangue , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/sangue , COVID-19/terapia , Comorbidade , Humanos , Imunidade Inata/imunologia , Imunização Passiva/métodos , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Glicoproteína da Espícula de Coronavírus/metabolismo
15.
Biol Chem ; 402(4): 461-468, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33938176

RESUMO

The chemoresistance is one of the major challenges for acute myeloid leukemia (AML) treatment. We found that the expression of histone deacetylase 8 (HDAC8) was increased in daunorubicin (DNR) resistant AML cells, while targeted inhibition of HDAC8 by its specific siRNA or inhibitor can restore sensitivity of DNR treatment . Further, targeted inhibition of HDAC8 can suppress expression of interleukin 6 (IL-6) and IL-8. While recombinant IL-6 (rIL-6) and rIL-8 can reverse si-HDAC8-resored DNR sensitivity of AML cells. Mechanistical study revealed that HDAC8 increased the expression of p65, one of key components of NF-κB complex, to promote the expression of IL-6 and IL-8. It might be due to that HDAC8 can directly bind with the promoter of p65 to increase its transcription and expression. Collectively, our data suggested that HDAC8 promotes DNR resistance of human AML cells via regulation of IL-6 and IL-8.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Daunorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Histona Desacetilases/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas Repressoras/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Histona Desacetilases/genética , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/antagonistas & inibidores , Interleucina-8/genética , Interleucina-8/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , RNA Interferente Pequeno/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Células Tumorais Cultivadas
17.
FASEB J ; 35(5): e21596, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33871073

RESUMO

Severe burns remain a leading cause of death and disability worldwide. Despite advances in patient care, the excessive and uncontrolled hypermetabolic stress response induced by this trauma inevitably affects every organ system causing substantial morbidity and mortality. Recent evidence suggests interleukin-6 (IL-6) is a major culprit underlying post-burn hypermetabolism. Indeed, genetic deletion of IL-6 alleviates various complications associated with poor clinical outcomes including the adverse remodeling of adipose tissue, cachexia and hepatic steatosis. Thus, pharmacological blockade of IL-6 may be a more favorable treatment option to fully restore metabolic function after injury. To test this, we investigated the safety and effectiveness of blocking IL-6 for post-burn hypermetabolism using a validated anti-IL-6 monoclonal antibody (mAb) in our experimental murine model. Here, we show daily anti-IL-6 mAb administration protects against burn-induced weight loss (P < .0001) without any adverse effect on mortality. At the organ level, post-burn treatment with the IL-6 blocker suppressed the thermogenic activation of adipose tissue (P < .01) and its associated wasting (P < .05). The reduction of browning-induced lipolysis (P < .0001) indirectly decreased hepatic lipotoxicity (P < .01) which improved liver dysfunction (P < .05). Importantly, the beneficial effects of this anti-IL-6 agent extended to the skin, reflected by the decrease in excessive collagen deposition (P < .001) and genes involved in pathologic fibrosis and scarring (P < .05). Together, our results indicate that post-burn IL-6 blockade leads to significant improvements in systemic hypermetabolism by inhibiting pathological alterations in key immunometabolic organs. These findings support the therapeutic potential of anti-IL-6 interventions to improve care, quality of life, and survival in burned patients.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Anticorpos Monoclonais/farmacologia , Queimaduras/complicações , Fibrose/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Doenças Metabólicas/tratamento farmacológico , Animais , Fibrose/etiologia , Fibrose/patologia , Lipólise , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/patologia , Camundongos , Camundongos Endogâmicos C57BL
18.
Clin Microbiol Infect ; 27(8): 1076-1082, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33915284

RESUMO

OBJECTIVES: Cytokine release syndrome with elevated interleukin-6 (IL-6) levels is associated with multiorgan damage and death in severe coronavirus disease 2019 (COVID-19). Our objective was to update the data in a living systematic review of the literature concerning the efficacy and toxicity of the IL-6 receptor antagonist tocilizumab in COVID-19 patients. METHODS: Data sources were Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, Scopus up, preprint servers and Google from 8th October 2020 till 24th February 2021. Eligible studies were randomized controlled trials (RCTs) and observational studies at low or moderate risk of bias. The participants were hospitalized COVID-19 patients, and intervention was tocilizumab versus placebo or standard of care. We pooled crude risk ratios (RRs) of RCTs with a random effects model and evaluated inconsistency between studies with I2. We assessed the certainty of evidence using the GRADE approach. RESULTS: Of 1600 citations, eight RCTs and 28 cohorts were eligible. The eight RCTs had low risk of bias, and with 6311 patients they examined the effect of tocilizumab on short-term mortality; pooled RR was 0.91 (95%CI 0.78-1.07, I2 25%). Only the REMAP-CAP and RECOVERY trials, with the majority of their patients on concomitant corticosteroids, showed lower 30-day mortality with tocilizumab use: RR 0.74 (95%CI 0.59-0.93) and 0.89 (95%CI 0.81-0.97), respectively. Seven RCTs, with 5391 patients, examined the effect of tocilizumab on risk of mechanical ventilation; pooled RR was 0.84 (95%CI 0.76-0.93), I2 0%, with a corresponding number needed to treat of 20 (95%CI 14.3-33.3). Eight RCTs, with 5340 patients, examined the effect of tocilizumab on a composite of poor outcome; pooled RR was 0.82 (95%CI 0.76-0.90, I2 3%). Data from the RCTs showed a lower risk of infections and no higher risk of serious adverse events with tocilizumab: pooled RR 0.67 (95%CI 0.45-0.99, eight RCTs) and 0.85 (95%CI 0.63-1.16, seven RCTs), respectively. Among 28 cohorts with 15 484 patients, the pooled adjusted RR for mortality was 0.53 (95%CI 0.43-0.67, I2 76%). CONCLUSIONS: Cumulative high-certainty evidence shows that tocilizumab reduces the risk of mechanical ventilation in hospitalized patients with severe COVID-19. Moderate-certainty evidence shows that tocilizumab reduces the risk of poor outcome and the risk of secondary infections in hospitalized COVID-19 patients. This review will continuously evaluate the role of tocilizumab in COVID-19 treatment.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Imunossupressores/uso terapêutico , Interleucina-6/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , COVID-19/epidemiologia , COVID-19/virologia , Humanos , Interleucina-6/sangue , Razão de Chances , Placebos , Respiração Artificial , Padrão de Cuidado , Resultado do Tratamento
19.
Expert Rev Clin Immunol ; 17(6): 601-618, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33874829

RESUMO

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a dysregulated hyperinflammatory response. AREAS COVERED: Authors review evidence on IL-6 and IL-6 blockade in coronavirus disease 2019 (COVID-19) and discuss the pathophysiological and prognostic roles of this cytokine and the clinical impact of pharmacological blockade of IL-6 . The material includes original articles and reviews published from March 2020 to March 2021 and searched on PubMed, medRxiv, and bioRxiv. EXPERT OPINION: IL-6 is one of the most prominent pro-inflammatory cytokines. Increased levels are recorded in COVID-19 patients, especially those with severe-to-critical disease. Evidence is accumulating on the relevance of IL-6 as a prognostic marker in COVID-19. Since IL-6 is a druggable target for several inflammatory diseases, pharmacological blockers of the IL-6 signaling pathway were repurposed to blunt the abnormal SARS-CoV-2-induced cytokine release. Data are limited to few randomized controlled trials that reported encouraging, though not conclusive, results, indicating the usefulness of IL-6 blockade early in the course of the disease in patients with hyperinflammation and no or limited organ damage. Further research is warranted to explore the role of IL-6 in different COVID-19 phenotypes and identify subgroups of patients who may mostly benefit from IL-6 pathway inhibition.


Assuntos
Anti-Inflamatórios/uso terapêutico , COVID-19/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/antagonistas & inibidores , SARS-CoV-2/patogenicidade , Animais , Anti-Inflamatórios/efeitos adversos , COVID-19/imunologia , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Interleucina-6/metabolismo , Receptores de Interleucina-6/metabolismo , SARS-CoV-2/imunologia , Transdução de Sinais , Resultado do Tratamento
20.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802761

RESUMO

Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab's therapeutic effects in patients with life-threatening SARS-CoV-2 infection.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , SARS-CoV-2/imunologia , Anticorpos Monoclonais Humanizados/química , COVID-19/complicações , COVID-19/imunologia , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/fisiopatologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...