20 results on '"Benatti MN"'
Search Results
2. An update on the genus Parmelinella Elix & Hale (Parmeliaceae, lichenized Ascomycetes)
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Benatti, MN, primary
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- 2014
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3. A review of the genus Bulbothrix Hale: the species with medullary fatty acids or without medullary substances
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Benatti, MN, primary
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- 2013
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4. A review of the genus Bulbothrix Hale: the isidiate, sorediate, and pustulate species with medullary salazinic acid
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Benatti, MN, primary
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- 2012
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5. Colchicine reduces the activation of NLRP3 inflammasome in COVID-19 patients.
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Amaral NB, Rodrigues TS, Giannini MC, Lopes MI, Bonjorno LP, Menezes PISO, Dib SM, Gigante SLG, Benatti MN, Rezek UC, Emrich-Filho LL, Sousa BA, Almeida SCL, Luppino-Assad R, Veras FP, Schneider AH, Leiria LOS, Cunha LD, Alves-Filho JC, Cunha TM, Arruda E, Miranda CH, Pazin-Filho A, Auxiliadora-Martins M, Borges MC, Fonseca BAL, Bollela VR, Del-Ben CM, Cunha FQ, Santana RC, Vilar FC, Zamboni DS, Louzada-Junior P, and Oliveira RDR
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- Humans, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Interleukin-18, NLR Proteins, Colchicine therapeutic use, Interleukin-1beta metabolism, Inflammasomes metabolism, COVID-19
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Objective: To evaluate whether colchicine treatment was associated with the inhibition of NLRP3 inflammasome activation in patients with COVID-19., Methods: We present a post hoc analysis from a double-blinded placebo-controlled randomized clinical trial (RCT) on the effect of colchicine for the treatment of COVID-19. Serum levels of NOD-like receptor protein 3 (NLRP3) inflammasome products-active caspase-1 (Casp1p20), IL-1β, and IL-18-were assessed at enrollment and after 48-72 h of treatment in patients receiving standard-of-care (SOC) plus placebo vs. those receiving SOC plus colchicine. The colchicine regimen was 0.5 mg tid for 5 days, followed by 0.5 mg bid for another 5 days., Results: Thirty-six patients received SOC plus colchicine, and thirty-six received SOC plus placebo. Colchicine reduced the need for supplemental oxygen and the length of hospitalization. On Days 2-3, colchicine lowered the serum levels of Casp1p20 and IL-18, but not IL-1β., Conclusion: Treatment with colchicine inhibited the activation of the NLRP3 inflammasome, an event triggering the 'cytokine storm' in COVID-19., Trial Registration Numbers: RBR-8jyhxh., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2023
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6. The effects of female sexual hormones on the endothelial glycocalyx.
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Potje SR, Martins NS, Benatti MN, Rodrigues D, Bonato VLD, and Tostes RC
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- Pregnancy, Humans, Female, Endothelial Cells metabolism, Vasodilation, Estrogens metabolism, Estrogens pharmacology, Progesterone metabolism, Progesterone pharmacology, Glycocalyx metabolism
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The glycocalyx is a layer composed of carbohydrate side chains bound to core proteins that lines the vascular endothelium. The integrity of the glycocalyx is essential for endothelial cells' performance and vascular homeostasis. The neuroendocrine and immune systems influence the composition, maintenance, activity and degradation of the endothelial glycocalyx. The female organism has unique characteristics, and estrogen and progesterone, the main female hormones are essential to the development and physiology of the reproductive system and to the ability to develop a fetus. Female sex hormones also exert a wide variety of effects on other organs, including the vascular endothelium. They upregulate nitric oxide synthase expression and activity, decrease oxidative stress, increase vasodilation, and protect from vascular injury. This review will discuss how female hormones and pregnancy, which prompts to high levels of estrogen and progesterone, modulate the endothelial glycocalyx. Diseases prevalent in women that alter the glycocalyx, and therapeutic forms to prevent glycocalyx degradation and potential treatments that can reconstitute its structure and function will also be discussed., Competing Interests: Conflict of interest The authors declare that this manuscript was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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7. Morphological, cellular, and molecular basis of brain infection in COVID-19 patients.
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Crunfli F, Carregari VC, Veras FP, Silva LS, Nogueira MH, Antunes ASLM, Vendramini PH, Valença AGF, Brandão-Teles C, Zuccoli GDS, Reis-de-Oliveira G, Silva-Costa LC, Saia-Cereda VM, Smith BJ, Codo AC, de Souza GF, Muraro SP, Parise PL, Toledo-Teixeira DA, Santos de Castro ÍM, Melo BM, Almeida GM, Firmino EMS, Paiva IM, Silva BMS, Guimarães RM, Mendes ND, Ludwig RL, Ruiz GP, Knittel TL, Davanzo GG, Gerhardt JA, Rodrigues PB, Forato J, Amorim MR, Brunetti NS, Martini MC, Benatti MN, Batah SS, Siyuan L, João RB, Aventurato ÍK, Rabelo de Brito M, Mendes MJ, da Costa BA, Alvim MKM, da Silva Júnior JR, Damião LL, de Sousa IMP, da Rocha ED, Gonçalves SM, Lopes da Silva LH, Bettini V, Campos BM, Ludwig G, Tavares LA, Pontelli MC, Viana RMM, Martins RB, Vieira AS, Alves-Filho JC, Arruda E, Podolsky-Gondim GG, Santos MV, Neder L, Damasio A, Rehen S, Vinolo MAR, Munhoz CD, Louzada-Junior P, Oliveira RD, Cunha FQ, Nakaya HI, Mauad T, Duarte-Neto AN, Ferraz da Silva LF, Dolhnikoff M, Saldiva PHN, Farias AS, Cendes F, Moraes-Vieira PMM, Fabro AT, Sebollela A, Proença-Modena JL, Yasuda CL, Mori MA, Cunha TM, and Martins-de-Souza D
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- Astrocytes pathology, Astrocytes virology, Humans, Post-Acute COVID-19 Syndrome, Brain pathology, Brain virology, COVID-19 complications, COVID-19 pathology, Central Nervous System Viral Diseases etiology, Central Nervous System Viral Diseases pathology, SARS-CoV-2
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Although increasing evidence confirms neuropsychiatric manifestations associated mainly with severe COVID-19 infection, long-term neuropsychiatric dysfunction (recently characterized as part of "long COVID-19" syndrome) has been frequently observed after mild infection. We show the spectrum of cerebral impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, ranging from long-term alterations in mildly infected individuals (orbitofrontal cortical atrophy, neurocognitive impairment, excessive fatigue and anxiety symptoms) to severe acute damage confirmed in brain tissue samples extracted from the orbitofrontal region (via endonasal transethmoidal access) from individuals who died of COVID-19. In an independent cohort of 26 individuals who died of COVID-19, we used histopathological signs of brain damage as a guide for possible SARS-CoV-2 brain infection and found that among the 5 individuals who exhibited those signs, all of them had genetic material of the virus in the brain. Brain tissue samples from these five patients also exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. Supporting the hypothesis of astrocyte infection, neural stem cell-derived human astrocytes in vitro are susceptible to SARS-CoV-2 infection through a noncanonical mechanism that involves spike-NRP1 interaction. SARS-CoV-2-infected astrocytes manifested changes in energy metabolism and in key proteins and metabolites used to fuel neurons, as well as in the biogenesis of neurotransmitters. Moreover, human astrocyte infection elicits a secretory phenotype that reduces neuronal viability. Our data support the model in which SARS-CoV-2 reaches the brain, infects astrocytes, and consequently, leads to neuronal death or dysfunction. These deregulated processes could contribute to the structural and functional alterations seen in the brains of COVID-19 patients.
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- 2022
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8. SARS-CoV-2 productively infects primary human immune system cells in vitro and in COVID-19 patients.
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Pontelli MC, Castro ÍA, Martins RB, La Serra L, Veras FP, Nascimento DC, Silva CM, Cardoso RS, Rosales R, Gomes R, Lima TM, Souza JP, Vitti BC, Caetité DB, de Lima MHF, Stumpf SD, Thompson CE, Bloyet LM, Toller-Kawahisa JE, Giannini MC, Bonjorno LP, Lopes MIF, Batah SS, Siyuan L, Luppino-Assad R, Almeida SCL, Oliveira FR, Benatti MN, Pontes LLF, Santana RC, Vilar FC, Auxiliadora-Martins M, Shi PY, Cunha TM, Calado RT, Alves-Filho JC, Zamboni DS, Fabro AT, Louzada-Junior P, Oliveira RDR, Whelan SPJ, Cunha FQ, and Arruda E
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- Cytokine Release Syndrome, Humans, Leukocytes, Mononuclear, Monocytes, COVID-19, SARS-CoV-2
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a hyperinflammatory state and lymphocytopenia, a hallmark that appears as both signature and prognosis of disease severity outcome. Although cytokine storm and a sustained inflammatory state are commonly associated with immune cell depletion, it is still unclear whether direct SARS-CoV-2 infection of immune cells could also play a role in this scenario by harboring viral replication. We found that monocytes, as well as both B and T lymphocytes, were susceptible to SARS-CoV-2 infection in vitro, accumulating double-stranded RNA consistent with viral RNA replication and ultimately leading to expressive T cell apoptosis. In addition, flow cytometry and immunofluorescence analysis revealed that SARS-CoV-2 was frequently detected in monocytes and B lymphocytes from coronavirus disease 2019 (COVID-19) patients. The rates of SARS-CoV-2-infected monocytes in peripheral blood mononuclear cells from COVID-19 patients increased over time from symptom onset, with SARS-CoV-2-positive monocytes, B cells, and CD4+ T lymphocytes also detected in postmortem lung tissue. These results indicated that SARS-CoV-2 infection of blood-circulating leukocytes in COVID-19 patients might have important implications for disease pathogenesis and progression, immune dysfunction, and virus spread within the host., (© The Author(s) (2022). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)
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- 2022
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9. Gasdermin-D activation by SARS-CoV-2 triggers NET and mediate COVID-19 immunopathology.
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Silva CMS, Wanderley CWS, Veras FP, Gonçalves AV, Lima MHF, Toller-Kawahisa JE, Gomes GF, Nascimento DC, Monteiro VVS, Paiva IM, Almeida CJLR, Caetité DB, Silva JC, Lopes MIF, Bonjorno LP, Giannini MC, Amaral NB, Benatti MN, Santana RC, Damasceno LEA, Silva BMS, Schneider AH, Castro IMS, Silva JCS, Vasconcelos AP, Gonçalves TT, Batah SS, Rodrigues TS, Costa VF, Pontelli MC, Martins RB, Martins TV, Espósito DLA, Cebinelli GCM, da Fonseca BAL, Leiria LOS, Cunha LD, Arruda E, Nakaia HI, Fabro AT, Oliveira RDR, Zamboni DS, Louzada-Junior P, Cunha TM, Alves-Filho JCF, and Cunha FQ
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- Animals, Disulfiram metabolism, Mice, Neutrophils metabolism, SARS-CoV-2, Extracellular Traps metabolism, COVID-19 Drug Treatment
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Background: The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear., Objectives: We aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19., Methods: We performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection., Results: We found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage., Conclusion: These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy., (© 2022. The Author(s).)
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- 2022
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10. Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells.
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Salina ACG, Dos-Santos D, Rodrigues TS, Fortes-Rocha M, Freitas-Filho EG, Alzamora-Terrel DL, Castro IMS, Fraga da Silva TFC, de Lima MHF, Nascimento DC, Silva CM, Toller-Kawahisa JE, Becerra A, Oliveira S, Caetité DB, Almeida L, Ishimoto AY, Lima TM, Martins RB, Veras F, do Amaral NB, Giannini MC, Bonjorno LP, Lopes MIF, Benatti MN, Batah SS, Santana RC, Vilar FC, Martins MA, Assad RL, de Almeida SCL, de Oliveira FR, Arruda Neto E, Cunha TM, Alves-Filho JC, Bonato VLD, Cunha FQ, Fabro AT, Nakaya HI, Zamboni DS, Louzada-Junior P, Oliveira RDR, and Cunha LD
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- Anti-Inflammatory Agents pharmacology, Apoptosis, Humans, Macrophages metabolism, Phagocytosis, COVID-19, SARS-CoV-2
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COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV-2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppresses macrophage anti-inflammation and efficient tissue repair programs and provides mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis., Competing Interests: AS, Dd, TR, MF, EF, DA, IC, TF, Md, DN, CS, JT, AB, SO, DC, LA, AI, TL, RM, FV, Nd, MG, LB, ML, MB, SB, RS, FV, MM, RA, Sd, Fd, EA, TC, JA, VB, FC, AF, HN, DZ, PL, RO, LC No competing interests declared, (© 2022, Salina, dos-Santos, Rodrigues et al.)
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- 2022
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11. SARS-Cov-2 pneumonia phenotyping on imaging exams of patients submitted to minimally invasive autopsy.
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Koenigkam-Santos M, Wada DT, Benatti MN, Siyuan L, Batah SS, Cetlin AA, de Menezes MB, and Fabro AT
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Background: Correlation between pathology and imaging of the new SARS-Cov-2 disease (COVID-19) is scarce. This study aimed to characterize SARS-Cov-2 pneumonia on imaging of patients submitted to minimally invasive autopsy (MIA)., Methods: This unicentric retrospective observational study included 46 consecutive patients with confirmed COVID-19 who underwent MIA. All clinical chest images were reviewed and classified for the presence and grade of viral pneumonia, as well as disease evolution. On CT, phenotypes were described as consistent with mild, moderate, or severe viral pneumonia, with or without radiological signs of organizing pneumonia (OP). In severe pneumonia, CT could also be classified as diffuse progressive OP or radiological diffuse alveolar damage (DAD). Specific features on CT were noted, including fibroproliferative signs that could indicate potential or initial fibrosis., Results: MIA showed a heterogeneous panel of alterations, with a high prevalence of OP and acute fibrinous and organizing pneumonia (AFOP). Also, signs of interstitial fibrosis corresponded to the most prevalent pathological feature. Initial chest radiography (CXR) findings were mainly consistent with moderate or severe viral pneumonia. Most patients showed stability or improvement (reduction of opacities) on imaging. CTs were performed on 15 patients. Consolidations were found in most patients, frequently showing features consistent with an OP phenotype. Fibroproliferative changes were also prevalent on CT., Conclusions: In this study, SARS-Cov-2 pneumonia showed heterogeneous radiological and pathological patterns. Signs of organization and potential or initial fibrosis were prevalent on both imaging and pathology. Imaging phenotyping may help to predict post-infection fibrosing interstitial pneumonitis in COVID-19., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-21-4354/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)
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- 2022
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12. Mitochondrial DNA and TLR9 activation contribute to SARS-CoV-2-induced endothelial cell damage.
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Costa TJ, Potje SR, Fraga-Silva TFC, da Silva-Neto JA, Barros PR, Rodrigues D, Machado MR, Martins RB, Santos-Eichler RA, Benatti MN, de Sá KSG, Almado CEL, Castro ÍA, Pontelli MC, Serra L, Carneiro FS, Becari C, Louzada-Junior P, Oliveira RDR, Zamboni DS, Arruda E, Auxiliadora-Martins M, Giachini FRC, Bonato VLD, Zachara NE, Bomfim GF, and Tostes RC
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- Animals, Endothelial Cells metabolism, Humans, Mice, Mitochondria metabolism, SARS-CoV-2, Toll-Like Receptor 9 genetics, Toll-Like Receptor 9 metabolism, COVID-19, DNA, Mitochondrial genetics, DNA, Mitochondrial metabolism
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Background and Purpose: Mitochondria play a central role in the host response to viral infection and immunity, being key to antiviral signaling and exacerbating inflammatory processes. Mitochondria and Toll-like receptor (TLR) have been suggested as potential targets in SARS-CoV-2 infection. However, the involvement of TLR9 in SARS-Cov-2-induced endothelial dysfunction and potential contribution to cardiovascular complications in COVID-19 have not been demonstrated. This study determined whether infection of endothelial cells by SARS-CoV-2 affects mitochondrial function and induces mitochondrial DNA (mtDNA) release. We also questioned whether TLR9 signaling mediates the inflammatory responses induced by SARS-CoV-2 in endothelial cells., Experimental Approach: Human umbilical vein endothelial cells (HUVECs) were infected by SARS-CoV-2 and immunofluorescence was used to confirm the infection. Mitochondrial function was analyzed by specific probes and mtDNA levels by real-time polymerase chain reaction (RT-PCR). Inflammatory markers were measured by ELISA, protein expression by western blot, intracellular calcium (Ca
2+ ) by FLUOR-4, and vascular reactivity with a myography., Key Results: SARS-CoV-2 infected HUVECs, which express ACE2 and TMPRSS2 proteins, and promoted mitochondrial dysfunction, i.e. it increased mitochondria-derived superoxide anion, mitochondrial membrane potential, and mtDNA release, leading to activation of TLR9 and NF-kB, and release of cytokines. SARS-CoV-2 also decreased nitric oxide synthase (eNOS) expression and inhibited Ca2+ responses in endothelial cells. TLR9 blockade reduced SARS-CoV-2-induced IL-6 release and prevented decreased eNOS expression. mtDNA increased vascular reactivity to endothelin-1 (ET-1) in arteries from wild type, but not TLR9 knockout mice. These events were recapitulated in serum samples from COVID-19 patients, that exhibited increased levels of mtDNA compared to sex- and age-matched healthy subjects and patients with comorbidities., Conclusion and Applications: SARS-CoV-2 infection impairs mitochondrial function and activates TLR9 signaling in endothelial cells. TLR9 triggers inflammatory responses that lead to endothelial cell dysfunction, potentially contributing to the severity of symptoms in COVID-19. Targeting mitochondrial metabolic pathways may help to define novel therapeutic strategies for COVID-19., (Copyright © 2021. Published by Elsevier Inc.)- Published
- 2022
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13. COVID-19 bimodal clinical and pathological phenotypes.
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Batah SS, Benatti MN, Siyuan L, Telini WM, Barboza JO, Menezes MB, Nadai TR, Sá KSG, Vaswani CM, Gupta S, Zamboni DS, Wada DT, Calado RT, Oliveira RDR, Louzada-Junior P, Auxiliadora-Martins M, Veras FP, Cunha LD, Cunha TM, Luppino-Assad R, Balancin ML, Morais SS, Martins RB, Arruda E, Chahud F, Santos MK, Cetlin AA, Cunha FQ, Dos Santos C, Capelozzi VL, Fukuoka J, Achcar RD, and Fabro AT
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- COVID-19 virology, Humans, Phenotype, SARS-CoV-2 isolation & purification, COVID-19 pathology
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- 2022
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14. Heparin prevents in vitro glycocalyx shedding induced by plasma from COVID-19 patients.
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Potje SR, Costa TJ, Fraga-Silva TFC, Martins RB, Benatti MN, Almado CEL, de Sá KSG, Bonato VLD, Arruda E, Louzada-Junior P, Oliveira RDR, Zamboni DS, Becari C, Auxiliadora-Martins M, and Tostes RC
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- Aged, Blood Coagulation Disorders blood, Blood Coagulation Disorders virology, COVID-19 metabolism, COVID-19 Testing, Case-Control Studies, Cell Adhesion physiology, Endothelium, Vascular metabolism, Female, Glycocalyx metabolism, Glycocalyx virology, Human Umbilical Vein Endothelial Cells, Humans, Interleukin-1beta blood, Interleukin-6 blood, Male, Middle Aged, Oxidation-Reduction, SARS-CoV-2, Thrombosis metabolism, COVID-19 blood, COVID-19 pathology, Glycocalyx pathology, Heparin pharmacology
- Abstract
The severe forms and worsened outcomes of COVID-19 (coronavirus disease 19) are closely associated with hypertension and cardiovascular disease. Endothelial cells express Angiotensin-Converting Enzyme 2 (ACE2), which is the entrance door for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The hallmarks of severe illness caused by SARS-CoV-2 infection are increased levels of IL-6, C-reactive protein, D-dimer, ferritin, neutrophilia and lymphopenia, pulmonary intravascular coagulopathy and microthrombi of alveolar capillaries. The endothelial glycocalyx, a proteoglycan- and glycoprotein-rich layer covering the luminal side of endothelial cells, contributes to vascular homeostasis. It regulates vascular tonus and permeability, prevents thrombosis, and modulates leukocyte adhesion and inflammatory response. We hypothesized that cytokine production and reactive oxygen species (ROS) generation associated with COVID-19 leads to glycocalyx degradation. A cohort of 20 hospitalized patients with a confirmed COVID-19 diagnosis and healthy subjects were enrolled in this study. Mechanisms associated with glycocalyx degradation in COVID-19 were investigated. Increased plasma concentrations of IL-6 and IL1-β, as well as increased lipid peroxidation and glycocalyx components were detected in plasma from COVID-19 patients compared to plasma from healthy subjects. Plasma from COVID-19 patients induced glycocalyx shedding in cultured human umbilical vein endothelial cells (HUVECs) and disrupted redox balance. Treatment of HUVECs with low molecular weight heparin inhibited the glycocalyx perturbation. In conclusion, plasma from COVID-19 patients promotes glycocalyx shedding and redox imbalance in endothelial cells, and heparin treatment potentially inhibits glycocalyx disruption., (Copyright © 2021 Elsevier Inc. All rights reserved.)
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- 2021
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15. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients.
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Rodrigues TS, de Sá KSG, Ishimoto AY, Becerra A, Oliveira S, Almeida L, Gonçalves AV, Perucello DB, Andrade WA, Castro R, Veras FP, Toller-Kawahisa JE, Nascimento DC, de Lima MHF, Silva CMS, Caetite DB, Martins RB, Castro IA, Pontelli MC, de Barros FC, do Amaral NB, Giannini MC, Bonjorno LP, Lopes MIF, Santana RC, Vilar FC, Auxiliadora-Martins M, Luppino-Assad R, de Almeida SCL, de Oliveira FR, Batah SS, Siyuan L, Benatti MN, Cunha TM, Alves-Filho JC, Cunha FQ, Cunha LD, Frantz FG, Kohlsdorf T, Fabro AT, Arruda E, de Oliveira RDR, Louzada-Junior P, and Zamboni DS
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- Apoptosis, Comorbidity, Cytokines biosynthesis, Humans, Lung pathology, Monocytes metabolism, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Postmortem Changes, Treatment Outcome, COVID-19 pathology, COVID-19 virology, Inflammasomes metabolism, SARS-CoV-2 physiology, Severity of Illness Index
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Severe cases of COVID-19 are characterized by a strong inflammatory process that may ultimately lead to organ failure and patient death. The NLRP3 inflammasome is a molecular platform that promotes inflammation via cleavage and activation of key inflammatory molecules including active caspase-1 (Casp1p20), IL-1β, and IL-18. Although participation of the inflammasome in COVID-19 has been highly speculated, the inflammasome activation and participation in the outcome of the disease are unknown. Here we demonstrate that the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection and is active in COVID-19 patients. Studying moderate and severe COVID-19 patients, we found active NLRP3 inflammasome in PBMCs and tissues of postmortem patients upon autopsy. Inflammasome-derived products such as Casp1p20 and IL-18 in the sera correlated with the markers of COVID-19 severity, including IL-6 and LDH. Moreover, higher levels of IL-18 and Casp1p20 are associated with disease severity and poor clinical outcome. Our results suggest that inflammasomes participate in the pathophysiology of the disease, indicating that these platforms might be a marker of disease severity and a potential therapeutic target for COVID-19., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2020 Rodrigues et al.)
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- 2021
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16. Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial.
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Lopes MI, Bonjorno LP, Giannini MC, Amaral NB, Menezes PI, Dib SM, Gigante SL, Benatti MN, Rezek UC, Emrich-Filho LL, Sousa BAA, Almeida SCL, Luppino Assad R, Veras FP, Schneider A, Rodrigues TS, Leiria LOS, Cunha LD, Alves-Filho JC, Cunha TM, Arruda E, Miranda CH, Pazin-Filho A, Auxiliadora-Martins M, Borges MC, Fonseca BAL, Bollela VR, Del-Ben CM, Cunha FQ, Zamboni DS, Santana RC, Vilar FC, Louzada-Junior P, and Oliveira RDR
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- Adult, Aged, COVID-19 mortality, COVID-19 virology, Colchicine adverse effects, Diarrhea chemically induced, Double-Blind Method, Female, Humans, Intensive Care Units, Male, Middle Aged, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Treatment Outcome, Colchicine administration & dosage, Length of Stay, Oxygen Inhalation Therapy, SARS-CoV-2 genetics, Severity of Illness Index, COVID-19 Drug Treatment
- Abstract
Objective: To evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes., Design: We present the results of a randomised, double-blinded, placebo-controlled clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 75 patients allocated 1:1 from 11 April to 30 August 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The primary endpoints were the need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in intensive care unit and death rate., Results: Seventy-two patients (36 for placebo and 36 for colchicine) completed the study. Median (and IQR) time of need for supplemental oxygen was 4.0 (2.0-6.0) days for the colchicine group and 6.5 (4.0-9.0) days for the placebo group (p<0.001). Median (IQR) time of hospitalisation was 7.0 (5.0-9.0) days for the colchicine group and 9.0 (7.0-12.0) days for the placebo group (p=0.003). At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, the values were 9% versus 42%, in the colchicine and the placebo groups, respectively (log rank; p=0.001). Two patients died, both in placebo group. Diarrhoea was more frequent in the colchicine group (p=0.26)., Conclusion: Colchicine reduced the length of both, supplemental oxygen therapy and hospitalisation. The drug was safe and well tolerated. Once death was an uncommon event, it is not possible to ensure that colchicine reduced mortality of COVID-19., Trial Registration Number: RBR-8jyhxh., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)
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- 2021
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17. SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology.
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Veras FP, Pontelli MC, Silva CM, Toller-Kawahisa JE, de Lima M, Nascimento DC, Schneider AH, Caetité D, Tavares LA, Paiva IM, Rosales R, Colón D, Martins R, Castro IA, Almeida GM, Lopes MIF, Benatti MN, Bonjorno LP, Giannini MC, Luppino-Assad R, Almeida SL, Vilar F, Santana R, Bollela VR, Auxiliadora-Martins M, Borges M, Miranda CH, Pazin-Filho A, da Silva LLP, Cunha LD, Zamboni DS, Dal-Pizzol F, Leiria LO, Siyuan L, Batah S, Fabro A, Mauad T, Dolhnikoff M, Duarte-Neto A, Saldiva P, Cunha TM, Alves-Filho JC, Arruda E, Louzada-Junior P, Oliveira RD, and Cunha FQ
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- A549 Cells, Adult, Angiotensin-Converting Enzyme 2, COVID-19, Cell Death, Coronavirus Infections blood, Coronavirus Infections pathology, Epithelial Cells pathology, Epithelial Cells virology, Female, HeLa Cells, Humans, Male, Neutrophil Activation, Pandemics, Peptidyl-Dipeptidase A metabolism, Pneumonia, Viral blood, Pneumonia, Viral pathology, SARS-CoV-2, Serine Proteases metabolism, Suction, Trachea immunology, Betacoronavirus physiology, Coronavirus Infections immunology, Coronavirus Infections virology, Extracellular Traps physiology, Pneumonia, Viral immunology, Pneumonia, Viral virology
- Abstract
Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2-activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2020 Veras et al.)
- Published
- 2020
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18. Endothelial glycocalyx shedding in the acute respiratory distress syndrome after flu syndrome.
- Author
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Benatti MN, Fabro AT, and Miranda CH
- Abstract
Background: Scientific evidence indicates that endothelial glycocalyx (EG) shedding contributes to the pathophysiological installation of acute respiratory distress syndrome (ARDS) after bacterial sepsis. The aim was to evaluate the EG shedding in ARDS installation after flu syndrome., Methods: This cross-sectional study included patients with flu syndrome during the influenza outbreak divided into two groups: patients with and without ARDS. Healthy subjects without flu syndrome were included in a control group. We measured EG damage biomarkers (hyaluronan, syndecan-1) and endothelial cell injury biomarker (soluble thrombomodulin) during the first medical evaluation. Histological assessment of the perimeter of the hyaline membrane and the number of neutrophils infiltrated in the alveolar septum was performed in patients who died., Results: ARDS group had 30 patients (44 ± 16 years old, 57% men), the non-ARDS group had 36 patients (39 ± 17 years old, 42% men), and the control group had 35 individuals (44 ± 9 years old, 51% men). Hyaluronan levels were significantly higher in the ARDS group than the two groups [31 ng/ml (interquartile range-IQR 12-56) vs. 5 ng/ml (IQR 3-10) vs. 5 ng/ml (IQR 2-8); p < 0.0001]. Hyaluronan levels above 19 ng/ml in patients with flu syndrome were associated with a significant increase in 28-day mortality rate: relative risk (RR): 6.95; (95% confidence interval 1.88-25.67); p = 0.0017. A positive correlation was observed between hyaline membrane perimeter and soluble thrombomodulin levels ( r = 0.89; p = 0.05) as well as between the number of neutrophils in the alveolar septum and hyaluronan levels ( r = 0.89; p = 0.05)., Conclusions: Evidence of EG shedding was found in ARDS established after flu syndrome., Competing Interests: Competing interestsAll authors declare no conflicts of interest., (© The Author(s) 2020.)
- Published
- 2020
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19. Infection of human lymphomononuclear cells by SARS-CoV-2.
- Author
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Pontelli MC, Castro IA, Martins RB, Veras FP, Serra L, Nascimento DC, Cardoso RS, Rosales R, Lima TM, Souza JP, Caetité DB, de Lima MHF, Kawahisa JT, Giannini MC, Bonjorno LP, Lopes MIF, Batah SS, Siyuan L, Assad RL, Almeida SCL, Oliveira FR, Benatti MN, Pontes LLF, Santana RC, Vilar FC, Martins MA, Cunha TM, Calado RT, Alves-Filho JC, Zamboni DS, Fabro A, Louzada-Junior P, Oliveira RDR, Cunha FQ, and Arruda E
- Abstract
Although SARS-CoV-2 severe infection is associated with a hyperinflammatory state, lymphopenia is an immunological hallmark, and correlates with poor prognosis in COVID-19. However, it remains unknown if circulating human lymphocytes and monocytes are susceptible to SARS-CoV-2 infection. In this study, SARS-CoV-2 infection of human peripheral blood mononuclear cells (PBMCs) was investigated both in vitro and in vivo . We found that in vitro infection of whole PBMCs from healthy donors was productive of virus progeny. Results revealed that monocytes, as well as B and T lymphocytes, are susceptible to SARS-CoV-2 active infection and viral replication was indicated by detection of double-stranded RNA. Moreover, flow cytometry and immunofluorescence analysis revealed that SARS-CoV-2 was frequently detected in monocytes and B lymphocytes from COVID-19 patients, and less frequently in CD4
+ T lymphocytes. The rates of SARS-CoV-2-infected monocytes in PBMCs from COVID-19 patients increased over time from symptom onset. Additionally, SARS-CoV-2-positive monocytes and B and CD4+T lymphocytes were detected by immunohistochemistry in post mortem lung tissue. SARS-CoV-2 infection of blood circulating leukocytes in COVID-19 patients may have important implications for disease pathogenesis, immune dysfunction, and virus spread within the host.- Published
- 2020
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20. Evolution of complex symbiotic relationships in a morphologically derived family of lichen-forming fungi.
- Author
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Divakar PK, Crespo A, Wedin M, Leavitt SD, Hawksworth DL, Myllys L, McCune B, Randlane T, Bjerke JW, Ohmura Y, Schmitt I, Boluda CG, Alors D, Roca-Valiente B, Del-Prado R, Ruibal C, Buaruang K, Núñez-Zapata J, Amo de Paz G, Rico VJ, Molina MC, Elix JA, Esslinger TL, Tronstad IK, Lindgren H, Ertz D, Gueidan C, Saag L, Mark K, Singh G, Dal Grande F, Parnmen S, Beck A, Benatti MN, Blanchon D, Candan M, Clerc P, Goward T, Grube M, Hodkinson BP, Hur JS, Kantvilas G, Kirika PM, Lendemer J, Mattsson JE, Messuti MI, Miadlikowska J, Nelsen M, Ohlson JI, Pérez-Ortega S, Saag A, Sipman HJ, Sohrabi M, Thell A, Thor G, Truong C, Yahr R, Upreti DK, Cubas P, and Lumbsch HT
- Subjects
- Classification, Biological Evolution, Genes, Fungal, Lichens genetics, Parmeliaceae genetics, Phylogeny, Symbiosis
- Abstract
We studied the evolutionary history of the Parmeliaceae (Lecanoromycetes, Ascomycota), one of the largest families of lichen-forming fungi with complex and variable morphologies, also including several lichenicolous fungi. We assembled a six-locus data set including nuclear, mitochondrial and low-copy protein-coding genes from 293 operational taxonomic units (OTUs). The lichenicolous lifestyle originated independently three times in lichenized ancestors within Parmeliaceae, and a new generic name is introduced for one of these fungi. In all cases, the independent origins occurred c. 24 million yr ago. Further, we show that the Paleocene, Eocene and Oligocene were key periods when diversification of major lineages within Parmeliaceae occurred, with subsequent radiations occurring primarily during the Oligocene and Miocene. Our phylogenetic hypothesis supports the independent origin of lichenicolous fungi associated with climatic shifts at the Oligocene-Miocene boundary. Moreover, diversification bursts at different times may be crucial factors driving the diversification of Parmeliaceae. Additionally, our study provides novel insight into evolutionary relationships in this large and diverse family of lichen-forming ascomycetes., (© 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.)
- Published
- 2015
- Full Text
- View/download PDF
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