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1.
Cell ; 183(1): 143-157.e13, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32877699

RESUMO

Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.


Assuntos
Infecções por Coronavirus/imunologia , Centro Germinativo/imunologia , Pneumonia Viral/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Feminino , Centro Germinativo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Baço/imunologia , Baço/patologia , Fator de Necrose Tumoral alfa/metabolismo
2.
PLoS Biol ; 18(8): e3000807, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760056

RESUMO

Radiotherapy is a commonly used conditioning regimen for bone marrow transplantation (BMT). Cytotoxicity limits the use of this life-saving therapy, but the underlying mechanisms remain poorly defined. Here, we use the syngeneic mouse BMT model to test the hypothesis that lethal radiation damages tissues, thereby unleashing signals that indiscriminately activate the inflammasome pathways in host and transplanted cells. We find that a clinically relevant high dose of radiation causes severe damage to bones and the spleen through mechanisms involving the NLRP3 and AIM2 inflammasomes but not the NLRC4 inflammasome. Downstream, we demonstrate that gasdermin D (GSDMD), the common effector of the inflammasomes, is also activated by radiation. Remarkably, protection against the injury induced by deadly ionizing radiation occurs only when NLRP3, AIM2, or GSDMD is lost simultaneously in both the donor and host cell compartments. Thus, this study reveals a continuum of the actions of lethal radiation relayed by the inflammasome-GSDMD axis, initially affecting recipient cells and ultimately harming transplanted cells as they grow in the severely injured and toxic environment. This study also suggests that therapeutic targeting of inflammasome-GSDMD signaling has the potential to prevent the collateral effects of intense radiation regimens.


Assuntos
Células da Medula Óssea/efeitos da radiação , Transplante de Medula Óssea , Proteínas de Ligação a DNA/genética , Inflamassomos/efeitos da radiação , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Ligação a Fosfato/genética , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Proteínas de Ligação a DNA/deficiência , Feminino , Fêmur/citologia , Fêmur/metabolismo , Regulação da Expressão Gênica , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteínas de Ligação a Fosfato/deficiência , Piroptose/genética , Piroptose/efeitos da radiação , Transdução de Sinais , Baço/metabolismo , Baço/patologia , Baço/efeitos da radiação , Transplante Isogênico , Irradiação Corporal Total , Raios X
3.
Medicine (Baltimore) ; 99(28): e20581, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664062

RESUMO

INTRODUCTION: Thrombotic microangiopathy (TMA) is characterized by endothelial injury followed by formation of multiple microthrombi in the target organs due to various causes, including malignant hypertension (MHT). Here, we reported a rare case of MHT with splenic TMA changes. CASE CONCERNS: A 27-year-old Chinese Han male with a history of hypertension and proteinuria, admitted to our hospital because of renal failure with MHT and thrombocytopenia. DIAGNOSIS: This case diagnosed with TMA based on the patient's MHT and thrombocytopenia. The patient final diagnosis was confirmed by the spleen pathological findings, other differential diagnoses were ruled out. INTERVENTIONS: The patient was treated with hemodialysis and intravenous antihypertensive agents, and his condition gradually improved. However, he suddenly complained of abdominal pain and went into hemorrhagic shock, which was due to spontaneous spleen rupture on the third day of hospitalization. The pathological evidence after splenectomy showed splenic TMA. OUTCOMES: Hemodialysis was continued and the blood pressure was under control until his discharge from our hospital. CONCLUSION: Spontaneous splenic rupture could be a rare and critical complication associated with MHT-induced TMA, and it requires careful clinical attention.


Assuntos
Hipertensão Maligna/complicações , Baço/patologia , Ruptura Esplênica/etiologia , Microangiopatias Trombóticas/complicações , Adulto , Humanos , Masculino , Ruptura Espontânea , Baço/diagnóstico por imagem , Ruptura Esplênica/diagnóstico por imagem , Ruptura Esplênica/patologia , Microangiopatias Trombóticas/diagnóstico , Tomografia Computadorizada por Raios X
4.
PLoS One ; 15(7): e0235667, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730271

RESUMO

Botswana's Okavango Delta is a World Heritage Site and biodiverse wilderness. In 2016-2018, following arrival of the annual flood of rainwater from Angola's highlands, and using continuous oxygen logging, we documented profound aquatic hypoxia that persisted for 3.5 to 5 months in the river channel. Within these periods, dissolved oxygen rarely exceeded 3 mg/L and dropped below 0.5 mg/L for up to two weeks at a time. Although these dissolved oxygen levels are low enough to qualify parts of the Delta as a dead zone, the region is a biodiversity hotspot, raising the question of how fish survive. In association with the hypoxia, histological samples, collected from native Oreochromis andersonii (threespot tilapia), Coptodon rendalli (redbreast tilapia), and Oreochromis macrochir (greenhead tilapia), exhibited widespread hepatic and splenic inflammation with marked granulocyte infiltration, melanomacrophage aggregates, and ceroid and hemosiderin accumulations. It is likely that direct tissue hypoxia and polycythemia-related iron deposition caused this pathology. We propose that Okavango cichlids respond to extended natural hypoxia by increasing erythrocyte production, but with significant health costs. Our findings highlight seasonal hypoxia as an important recurring stressor, which may limit fishery resilience in the Okavango as concurrent human impacts rise. Moreover, they illustrate how fish might respond to hypoxia elsewhere in the world, where dead zones are becoming more common.


Assuntos
Oxigênio/química , Tilápia/metabolismo , Animais , Ceroide/metabolismo , Eritrócitos/citologia , Eritrócitos/metabolismo , Feminino , Hemossiderina/metabolismo , Hipóxia , Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Oxigênio/metabolismo , Rios , Baço/metabolismo , Baço/patologia
5.
Lancet ; 396(10247): 320-332, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682491

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic, with increasing deaths worldwide. To date, documentation of the histopathological features in fatal cases of the disease caused by SARS-CoV-2 (COVID-19) has been scarce due to sparse autopsy performance and incomplete organ sampling. We aimed to provide a clinicopathological report of severe COVID-19 cases by documenting histopathological changes and evidence of SARS-CoV-2 tissue tropism. METHODS: In this case series, patients with a positive antemortem or post-mortem SARS-CoV-2 result were considered eligible for enrolment. Post-mortem examinations were done on 14 people who died with COVID-19 at the King County Medical Examiner's Office (Seattle, WA, USA) and Snohomish County Medical Examiner's Office (Everett, WA, USA) in negative-pressure isolation suites during February and March, 2020. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR. FINDINGS: The median age of our cohort was 73·5 years (range 42-84; IQR 67·5-77·25). All patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. The major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. Coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. Lymphocytic myocarditis was observed in one patient with viral RNA detected in the tissue. INTERPRETATION: The primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. Microthrombi, where observed, were scarce and endotheliitis was not identified. Although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of SARS-CoV-2 infection requires further examination. FUNDING: None.


Assuntos
Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Células Epiteliais Alveolares/patologia , Células Epiteliais Alveolares/ultraestrutura , Células Epiteliais Alveolares/virologia , Autopsia , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Feminino , Trato Gastrointestinal/patologia , Trato Gastrointestinal/ultraestrutura , Trato Gastrointestinal/virologia , Coração/virologia , Humanos , Rim/patologia , Rim/ultraestrutura , Rim/virologia , Fígado/patologia , Fígado/ultraestrutura , Fígado/virologia , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Miocárdio/ultraestrutura , Pandemias , Pneumonia Viral/epidemiologia , Alvéolos Pulmonares/patologia , Alvéolos Pulmonares/ultraestrutura , Mucosa Respiratória/patologia , Mucosa Respiratória/ultraestrutura , Mucosa Respiratória/virologia , Baço/patologia , Baço/ultraestrutura , Baço/virologia , Trombose/patologia , Traqueia/patologia , Traqueia/ultraestrutura , Traqueia/virologia , Washington/epidemiologia
6.
Am J Clin Pathol ; 154(4): 466-474, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32681166

RESUMO

OBJECTIVES: A subset of coronavirus disease 2019 (COVID-19) patients exhibit clinical features of cytokine storm. However, clinicopathologic features diagnostic of hemophagocytic lymphohistiocytosis (HLH) have not been reported. We studied the reticuloendothelial organs of 4 consecutive patients who died of COVID-19 and correlated with clinical and laboratory parameters to detect HLH. METHODS: Autopsies were performed on 4 patients who died of COVID-19. Routine H&E staining and immunohistochemical staining for CD163 were performed to detect hemophagocytosis. Clinical and laboratory results from premortem blood samples were used to calculate H-scores. RESULTS: All 4 cases demonstrated diffuse alveolar damage within the lungs. Three of the 4 cases had histologic evidence of hemophagocytosis within pulmonary lymph nodes. One case showed hemophagocytosis in the spleen but none showed hemophagocytosis in liver or bone marrow. Lymphophagocytosis was the predominant form of hemophagocytosis observed. One patient showed diagnostic features of HLH with an H-score of 217, while a second patient likely had HLH with a partial H-score of 145 due to a missing triglyceride level. The remaining 2 patients had H-scores of 131 and 96. CONCLUSIONS: This is the first report of severe acute respiratory syndrome coronavirus 2-associated HLH. Identification of HLH in a subset of patients with severe COVID-19 will inform clinical trials of therapeutic strategies.


Assuntos
Betacoronavirus , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/patologia , Linfo-Histiocitose Hemofagocítica/patologia , Linfo-Histiocitose Hemofagocítica/virologia , Pneumonia Viral/diagnóstico , Pneumonia Viral/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Medula Óssea/patologia , Infecções por Coronavirus/complicações , Evolução Fatal , Feminino , Humanos , Fígado/patologia , Pulmão/patologia , Linfonodos/patologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Baço/patologia
7.
Nanotoxicology ; 14(7): 985-1007, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32619159

RESUMO

Recent studies reported adverse liver effects and intestinal tumor formation after oral exposure to titanium dioxide (TiO2). Other oral toxicological studies, however, observed no effects on liver and intestine, despite prolonged exposure and/or high doses. In the present assessment, we aimed to better understand whether TiO2 can induce such effects at conditions relevant for humans. Therefore, we focused not only on the clinical and histopathological observations, but also used Adverse Outcome Pathways (AOPs) to consider earlier steps (Key Events). In addition, aiming for a more accurate risk assessment, the available information on organ concentrations of Ti (resulting from exposure to TiO2) from oral animal studies was compared to recently reported concentrations found in human postmortem organs. The overview obtained with the AOP approach indicates that TiO2 can trigger a number of key events in liver and intestine: Reactive Oxygen Species (ROS) generation, induction of oxidative stress and inflammation. TiO2 seems to be able to exert these early effects in animal studies at Ti liver concentrations that are only a factor of 30 and 6 times higher than the median and highest liver concentration found in humans, respectively. This confirms earlier conclusions that adverse effects on the liver in humans as a result of (oral) TiO2 exposure cannot be excluded. Data for comparison with Ti levels in human intestinal tissue, spleen and kidney with effect concentrations were too limited to draw firm conclusions. The Ti levels, though, are similar or higher than those found in liver, suggesting these tissues may be relevant too.


Assuntos
Mucosa Intestinal/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas/toxicidade , Baço/efeitos dos fármacos , Titânio/toxicidade , Administração Oral , Animais , Aditivos Alimentares/química , Aditivos Alimentares/metabolismo , Aditivos Alimentares/toxicidade , Humanos , Inflamação , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Nanopartículas/química , Nanopartículas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Titânio/química , Titânio/metabolismo
8.
Exp Parasitol ; 216: 107946, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32622941

RESUMO

This study was aimed at investigating the involvement of Receptor for Advanced Glycation End Products (RAGE) during malaria infection and the effects of modulating RAGE on the inflammatory cytokines release and histopathological conditions of affected organs in malarial animal model. Plasmodium berghei (P. berghei) ANKA-infected ICR mice were treated with mRAGE/pAb and rmRAGE/Fc Chimera drugs from day 1 to day 4 post infection. Survival and parasitaemia levels were monitored daily. On day 5 post infection, mice were sacrificed, blood were drawn for cytokines analysis and major organs including kidney, spleen, liver, brain and lungs were extracted for histopathological analysis. RAGE levels were increased systemically during malaria infection. Positive correlation between RAGE plasma concentration and parasitaemia development was observed. Treatment with RAGE related drugs did not improve survival of malaria-infected mice. However, significant reduction on the parasitaemia levels were recorded. On the other hand, inhibition and neutralization of RAGE production during the infection significantly increased the plasma levels of interleukin (IL-4, IL-17A, IL-10 and IL-2) and reduced interferon (IFN)-γ secretion. Histopathological analysis revealed that all treated malarial mice showed a better outcome in histological assessment of affected organs (brain, liver, spleen, lungs and kidney). RAGE is involved in malaria pathogenesis and targeting RAGE could be beneficial in malaria infected host in which RAGE inhibition or neutralization increased the release of anti-inflammatory cytokines (IL-10 and IL-4) and reduce pro-inflammatory cytokine (IFNγ) which may help alleviate tissue injury and improve histopathological conditions of affected organs during the infection.


Assuntos
Citocinas/metabolismo , Malária/imunologia , Malária/patologia , Plasmodium berghei/imunologia , Receptor para Produtos Finais de Glicação Avançada/fisiologia , Animais , Encéfalo/parasitologia , Encéfalo/patologia , Citocinas/sangue , Rim/parasitologia , Rim/patologia , Modelos Lineares , Fígado/parasitologia , Fígado/patologia , Pulmão/parasitologia , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Parasitemia/imunologia , Distribuição Aleatória , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptor para Produtos Finais de Glicação Avançada/imunologia , Baço/parasitologia , Baço/patologia
9.
Anticancer Res ; 40(6): 3361-3370, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487632

RESUMO

BACKGROUND/AIM: We evaluated whether splenic volume (SV) predicts sinusoidal obstruction syndrome (SOS) in colorectal cancer (CRC) patients receiving capecitabine plus oxaliplatin (CapeOX) therapy. PATIENTS AND METHODS: In this retrospective study, we measured SV in 41 patients receiving adjuvant CapeOX for CRC at five different time points. We compared the clinical data of the 18 patients who experienced ≥30% increases in SV immediately after vs. before CapeOX (group A) with data for the remaining 23 patients (group B). RESULTS: Platelet numbers decreased and the levels of hepatobiliary enzymes increased significantly 1 year after CapeOX compared with before CapeOX in group A. However, in group B, significantly decreased platelet numbers and significantly increased aspartate transaminase levels were confirmed only immediately after CapeOX, with no significant subsequent changes. CONCLUSION: SV was significantly associated with thrombocytopenia and liver dysfunction in CRC patients, and predicted SOS.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores/metabolismo , Hepatopatias/etiologia , Oxaliplatina/efeitos adversos , Baço/patologia , Trombocitopenia/induzido quimicamente , Antineoplásicos/farmacologia , Feminino , Humanos , Masculino , Estudos Retrospectivos
10.
Exp Parasitol ; 215: 107933, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32525006

RESUMO

Schistosomiasis is still a public health problem. Praziquantel is the only drug available for treatment of all forms of human schistosomiasis. Although praziquantel is an effective drug against all species of human schistosomes, concerns about resistance have been raised, especially in endemic areas. A hybrid compound containing several pharmacophore within a single molecule is a promising strategy. Here, we described the anti-schistosomal effect of 4-(2-Chloroquinolin-3-yl)-2-oxo-6-(p-tolyl)-1,2-dihydropyridine-3-carbonitrile (PPQ-6), a hybrid drug based on quinoline and pyridine. PPQ-6 was given as two regimens (20 or 40 mg/kg). In both regimens, PPQ-6 significantly reduced liver and spleen indices, nitric oxide production, tissue egg load, hepatic granuloma size and count, immature eggs and total worm burden especially females. Our findings suggested that PPQ-6 is a promising anti-schistosomal agent; however more research is needed to elucidate its mechanism of action and report its activity on juvenile schistosomes and other species of human schistosomes.


Assuntos
Piridinas/farmacologia , Quinolinas/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Feminino , Fígado/parasitologia , Fígado/patologia , Masculino , Camundongos , Óxido Nítrico/análise , Piridinas/química , Piridinas/uso terapêutico , Quinolinas/química , Quinolinas/uso terapêutico , Distribuição Aleatória , Esquistossomicidas/química , Esquistossomicidas/uso terapêutico , Fatores Sexuais , Baço/parasitologia , Baço/patologia
11.
Int J Nanomedicine ; 15: 3497-3509, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547009

RESUMO

Purpose: The existing treatment modalities for rheumatoid arthritis are less effective and safe, therefore it is essential to develop new treatments that particularly target the inflamed joints with decreased off-target side-effects. The current study proposes a nanoparticle-based therapeutic approach to target the anti-oxidant defense system of arthritic Balb/c mice. Methods: Biogenic selenium nanoparticles (SeNPs) were synthesized by using Trachyspermum ammi seed extract and were evaluated for their toxicological, as well as their therapeutic potential in collagen-induced arthritic mice. Results: The tested doses of SeNPs had no significant toxic effects on liver, kidney, spleen, and serum biochemical parameters in comparison to healthy mice. The SeNPs treatment reduced the disease severity, as demonstrated by decreased paw edema along with reduced lymphocytic cellular infiltration in the histopathological findings. SeNPs also revealed dose-independent improvement in the redox state of inflamed synovium by significantly improving the activity of antioxidant enzymes in comparison to the arthritic controls. Conclusion: It is therefore concluded that nano-selenium in combination with TAE extract showed enhanced therapeutic efficacy as compared to their individual effects.


Assuntos
Antirreumáticos/uso terapêutico , Apiaceae/química , Artrite Reumatoide/tratamento farmacológico , Nanopartículas/química , Selênio/toxicidade , Selênio/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antirreumáticos/farmacologia , Artrite Reumatoide/patologia , Peso Corporal/efeitos dos fármacos , Catalase/metabolismo , Bovinos , Edema/patologia , Feminino , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos Endogâmicos BALB C , Nanopartículas/administração & dosagem , Nanopartículas/ultraestrutura , Oxirredução , Extratos Vegetais/química , Selênio/administração & dosagem , Selênio/farmacologia , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Baço/efeitos dos fármacos , Baço/patologia
12.
Nat Commun ; 11(1): 2761, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32487994

RESUMO

Plasmodium vivax is the most widely distributed human malaria parasite. Previous studies have shown that circulating microparticles during P. vivax acute attacks are indirectly associated with severity. Extracellular vesicles (EVs) are therefore major components of circulating plasma holding insights into pathological processes. Here, we demonstrate that plasma-derived EVs from Plasmodium vivax patients (PvEVs) are preferentially uptaken by human spleen fibroblasts (hSFs) as compared to the uptake of EVs from healthy individuals. Moreover, this uptake induces specific upregulation of ICAM-1 associated with the translocation of NF-kB to the nucleus. After this uptake, P. vivax-infected reticulocytes obtained from patients show specific adhesion properties to hSFs, reversed by inhibiting NF-kB translocation to the nucleus. Together, these data provide physiological EV-based insights into the mechanisms of human malaria pathology and support the existence of P. vivax-adherent parasite subpopulations in the microvasculature of the human spleen.


Assuntos
Vesículas Extracelulares/metabolismo , Fibroblastos/metabolismo , NF-kappa B/metabolismo , Plasma , Plasmodium vivax/fisiologia , Reticulócitos/metabolismo , Baço/metabolismo , Animais , Adesão Celular , Micropartículas Derivadas de Células , Modelos Animais de Doenças , Vesículas Extracelulares/parasitologia , Fibroblastos/patologia , Interações Hospedeiro-Parasita/fisiologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Malária Vivax/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/parasitologia , Proteômica , Reticulócitos/parasitologia , Baço/patologia
13.
Int J Nanomedicine ; 15: 3827-3842, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581533

RESUMO

Introduction: Copper oxide nanoparticles (CuO-NPs) are widely used as feed additives for livestock and poultry and implicated in many biomedical applications; however, overload of copper NPs induces various toxicological changes and dysfunction of animal's organs. Thus, this study was designed to evaluate the comparative toxicological effects of biologically and chemically synthesized CuO-NPs on mice. Methods: Transmission electron microscopy (TEM), X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FT-IR) were used to characterize the sizes, shapes and functional groups of CuO-NPs. Forty-five mice were randomly allocated into three groups. Control group received distilled water. The second group was administered a single dose of biologically synthesized CuO-NPs (500 mg/kg bw) orally. The third group was administered a single dose of chemically synthesized CuO-NPs (500 mg/kg bw) orally. Results: TEM revealed that biologically synthesized NPs were spherical in shape, whereas chemically synthesized NPs were spherical or elongated in shape. XRD showed that the size of biologically synthesized NPs ranged from 4.14 to 12.82 nm and that of chemically synthesized NPs ranged from 4.06 to 26.82 nm. FT-IR spectroscopy indicated that the peaks appeared between 779 cm-1 and 425 cm-1 in biologically synthesized NPs and between 858 cm-1 and 524 cm-1 in chemically synthesized NPs were for Cu-O nanostructure. Four mice died due to administration of biologically synthesized CuO-NPs. Both biologically and chemically synthesized CuO-NPs induced leukocytosis, elevated serum activities of alanine aminotransferase and aspartate aminotransferase and serum levels of urea and creatinine and increased P53 mRNA and caspase-3 protein expressions in hepatic tissues. Moreover, CuO-NPs induced degenerative and necrotized changes in hepatic, renal and splenic tissues. Biochemical, apoptotic and pathological changes were more serious in mice administered with biologically synthesized CuO-NPs. Conclusion: This study indicated that a high dose of biologically and chemically synthesized CuO-NPs induced adverse effects on hepatic, renal and splenic tissues. At the same dose level, the biologically synthesized CuO-NPs evoked more potent toxic effects than the chemically synthesized CuO-NPs.


Assuntos
Cobre/toxicidade , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Administração Oral , Animais , Caspase 3/metabolismo , Cobre/administração & dosagem , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Nanopartículas Metálicas/administração & dosagem , Camundongos , Microscopia Eletrônica de Transmissão , Nanopartículas , Espectroscopia de Infravermelho com Transformada de Fourier , Baço/efeitos dos fármacos , Baço/patologia , Ulva/metabolismo , Difração de Raios X
14.
PLoS One ; 15(6): e0234867, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569300

RESUMO

Different modes of exogenous electrical stimulation at physiological strength has been applied to various diseases. Previously, we extensively demonstrated the usability of mild electrical stimulation (MES) with low frequency pulse current at 55 pulses per second (MES55) for several disease conditions. Here we found that MES with high frequency pulse-current (5500 pulse per second; MES5500) suppressed the overproduction of pro-inflammatory cytokines induced by phorbol myristate acetate/ionomycin in Jurkat T cells and primary splenocytes. MES5500 also suppressed the overproduction of inflammatory cytokines, improved liver damage and reduced mouse spleen enlargement in concanavalin-A-treated BALB/c mice. The molecular mechanism underlying these effects included the ability of MES5500 to induce modest amount of hydrogen peroxide and control multiple signaling pathways important for immune regulation, such as NF-κB, NFAT and NRF2. In the treatment of various inflammatory and immune-related diseases, suppression of excessive inflammatory cytokines is key, but because immunosuppressive drugs used in the clinical setting have serious side effects, development of safer methods of inhibiting cytokines is required. Our finding provides evidence that physical medicine in the form of MES5500 may be considered as a novel therapeutic tool or as adjunctive therapy for inflammatory and immune-related diseases.


Assuntos
Citocinas/imunologia , Terapia por Estimulação Elétrica/métodos , Peróxido de Hidrogênio/imunologia , Imunossupressão/métodos , Inflamação/imunologia , Inflamação/terapia , Animais , Concanavalina A , Feminino , Humanos , Inflamação/induzido quimicamente , Células Jurkat , Fígado/imunologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Baço/imunologia , Baço/patologia
15.
PLoS One ; 15(6): e0235090, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32569270

RESUMO

Tumor is a prevalent great threat to public health worldwide and multidrug resistance (MDR) of tumor is a leading cause of chemotherapy failure. Nanomedicine has shown prospects in overcoming the problem. Doxorubicin (DOX), a broad-spectrum anticancer drug, showed limited efficacy due to MDR. Herein, a doxorubicin containing pectin nanocell (DOX-PEC-NC) of core-shell structure, a pectin nanoparticle encapsulated with liposome-like membrane was developed. The DOX-PEC-NC, spheroid in shape and sized around 150 nm, exerted better sustained release behavior than doxorubicin loading pectin nanoparticle (DOX-PEC-NP) or liposome (DOX-LIP). In vitro anticancer study showed marked accumulation of doxorubicin in different tumor cells as well as reversal of MDR in HepG2/ADR cells and MCF-7/ADR cells caused by treatment of DOX-PEC-NC. In H22 tumor-bearing mice, DOX-PEC-NC showed higher anticancer efficacy and lower toxicity than doxorubicin. DOX-PEC-NC can improve anticancer activity and reduce side effect of doxorubicin due to increased intracellular accumulation and reversal of MDR in tumor cells, which may be a promising nanoscale drug delivery vehicle for chemotherapeutic agents.


Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Nanopartículas/química , Pectinas/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Humanos , Concentração Inibidora 50 , Masculino , Camundongos , Nanopartículas/ultraestrutura , Baço/patologia , Timo/patologia
16.
Am J Med Sci ; 360(3): 293-299, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32563569

RESUMO

Hyposplenism is associated with autoimmune diseases, inflammatory bowel disease, severe celiac disease, autoimmune thyroiditis, untreated HIV infection and chronic graft-versus-host disease. The aim of this study was to review the existing data on hyposplenism associated with celiac disease and Hashimoto's autoimmune thyroiditis. Our research was based on a clinical case concerning a 41-year-old female who presented with asthenia, fatigue, dyspepsia and chronic diarrhea. The medical history revealed autoimmune Hashimoto's thyroiditis, type 2 diabetes, fatty liver disease, chronic gastritis and thrombocytosis. Multiple investigations showed hyposplenism and complex autoimmune dysfunction with positive serum markers for celiac disease and type 1 autoimmune hepatitis along with minor symptomatology. The intestinal symptomatology of celiac disease is often hid by hypothyroidism-associated autoimmune thyroiditis. Asymptomatic or minimally symptomatic celiac disease associated with Hashimoto's autoimmune thyroiditis is diagnosed by biomarkers. Hyposplenism in celiac disease can occur regardless of the disease stage, latent or symptomatic.


Assuntos
Doença Celíaca/complicações , Doença de Hashimoto/complicações , Hepatite Autoimune/complicações , Baço/patologia , Adulto , Biópsia , Doença Celíaca/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Duodeno/patologia , Fígado Gorduroso/complicações , Feminino , Gastrite/complicações , Doença de Hashimoto/patologia , Hepatite Autoimune/patologia , Humanos , Imagem por Ressonância Magnética , Trombocitose/complicações
17.
Exp Parasitol ; 216: 107932, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32535113

RESUMO

Neglected tropical diseases, such as Chagas disease caused by the protozoa Trypanosoma cruzi, affect millions of people worldwide but lack effective treatments that are accessible to the entire population, especially patients with the debilitating chronic phase. The recognition of host cells, invasion and its intracellular replicative success are essential stages for progression of the parasite life cycle and the development of Chagas disease. It is predicted that programmed cell death pathways (apoptosis) would be activated in infected cells, either via autocrine secretion or mediated by cytotoxic immune cells. This process should play a key role in resolving infections by hindering the evolutionary success of the parasite. In this research, we performed assays to investigate the role of the lectin galectin-3 (Gal3) in parasite-host signaling pathways. Using cells with endogenous levels of Gal3 compared to Gal3-deficient cells (induced by RNA interference), we demonstrated that T. cruzi mediated the survival pathways and the subverted apoptosis through Gal3 promoting a pro-survival state in infected cells. Infected Gal3-depleted cells showed increased activation of caspase 3 and pro-apoptotic targets, such as poly (ADP-ribose) polymerase (PARP), and lower accumulation of anti-apoptotic proteins, such as c-IAP1, survivin and XIAP. During the early stages of infection, Gal3 translocates from the cytoplasm to the nucleus and must act in survival pathways. In a murine model of experimental infection, Gal3 knockout macrophages showed lower infectivity and viability. In vivo infection revealed a lower parasitemia and longer survival and an increased spleen cellularity in Gal3 knockout mice with consequences on the percentage of T lymphocytes (CD4+ CD11b+) and macrophages. In addition, cytokines such as IL-2, IL-4, IL-6 and TNF-α are increased in Gal3 knockout mice when compared to wild type genotype. These data demonstrate a Gal3-mediated complex interplay in the host cell, keeping infected cells alive long enough for infection and intracellular proliferation of new parasites. However, a continuous knowledge of these signaling pathways should contribute to a better understanding the mechanisms of cell death subversion that are promoted by protozoans in the pathophysiology of neglected diseases such as Chagas disease.


Assuntos
Apoptose/fisiologia , Doença de Chagas/parasitologia , Galectina 3/fisiologia , Trypanosoma cruzi/fisiologia , Análise de Variância , Animais , Western Blotting , Caspase 3/análise , Sobrevivência Celular , Doença de Chagas/mortalidade , Chlorocebus aethiops , Colorimetria , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Galectina 3/análise , Galectina 3/genética , Células HeLa , Humanos , Imunofenotipagem , Macrófagos Peritoneais/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Parasitemia/mortalidade , Parasitemia/parasitologia , Fenótipo , Baço/patologia , Células Vero
18.
Exp Parasitol ; 216: 107935, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32569599

RESUMO

Toxoplasma gondii is an important pathogen that causes serious public health problems. Currently, therapeutic drugs for toxoplasmosis cause serious side effects, and more effective and novel substances with relatively low toxicity are urgently needed. Ursolic acid (UA) has many properties that can be beneficial to healthcare. In this study, we synthesized eight series of UA derivatives bearing a tetrazole moiety and evaluated their anti-T. gondii activity in vitro using spiramycin as a positive control. Most of the synthesized derivatives exhibited better anti-T. gondii activity in vitro than UA, among which compound 12a exhibited the most potent anti-T. gondii activity. Furthermore, the results of biochemical parameter determination indicated that 12a effectively restored the normal body weight of mice infected with T. gondii, reduced hepatotoxicity, and exerted significant anti-oxidative effects compared with the findings for spiramycin. Additionally, our molecular docking study indicated that the synthesized compounds could act as potential inhibitors of T. gondii calcium-dependent protein kinase 1 (TgCDPK1), with 12a possessing strong affinity for TgCDPK1 via binding to the key amino acids GLU129 and TYR131.


Assuntos
Anti-Infecciosos/farmacologia , Toxoplasma/efeitos dos fármacos , Toxoplasmose Animal/tratamento farmacológico , Toxoplasmose/tratamento farmacológico , Triterpenos/farmacologia , Alanina Transaminase/sangue , Animais , Anti-Infecciosos/química , Anti-Infecciosos/uso terapêutico , Aspartato Aminotransferases/sangue , Coccidiostáticos/química , Coccidiostáticos/farmacologia , Modelos Animais de Doenças , Feminino , Glutationa/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Malondialdeído/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Tamanho do Órgão/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases , Distribuição Aleatória , Espiramicina/farmacologia , Baço/efeitos dos fármacos , Baço/patologia , Triterpenos/química , Triterpenos/uso terapêutico
19.
Scand J Immunol ; 92(3): e12920, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32594535

RESUMO

The maintenance of inner integrity of an organism is founded on the proper performance of two immunity branches, innate and adaptive immune responses. Recently, it became apparent that subset of splenic B cells named marginal zone B cells (MZB cells) exhibits unique developmental and functional features that bridge these two immunity branches. Strategically positioned at the site where blood and lymph are filtered, MZB cells represent a population of sentinels that rapidly proliferate and differentiate into IgM plasmablast cells when encountered with blood-borne, thymus-independent (TI) Ags. Moreover, MZB cells have intrinsic capability to induce potent CD4+ helper T cell response and cytokine production upon stimulation with soluble antigens. Due to their ability to overcome a time gap prior the establishment of the full adaptive response towards pathogens, MZB cells connect and direct innate and adaptive immunity. An additional interesting characteristic of MZB cells is capacity to function as regulatory cells in autoimmune processes. MZB cells may also contribute to the control of autoimmunity via the induction of tolerance by apoptotic cells. Importantly, in the clear association with inflammation and autoimmunity, MZB cells may transform into MALT lymphoma, representing a concurrence point for the infection, immunity and malignancy. This paper presents an insight into the complex biology of marginal zone B cells and their role in intertwining and directing innate and adaptive immune processes at the physiological and pathological level.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Suscetibilidade a Doenças , Homeostase , Baço/imunologia , Baço/metabolismo , Imunidade Adaptativa , Animais , Microambiente Celular/imunologia , Humanos , Ativação Linfocitária/imunologia , Baço/patologia
20.
Ann Hematol ; 99(7): 1441-1451, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32417942

RESUMO

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm which can lead to massive splenomegaly secondary to extramedullary hematopoiesis. Patients frequently exhibit debilitating symptoms including pain and early satiety, in addition to cellular sequestration causing severe cytopenias. JAK 1/2 inhibitors, such as ruxolitinib and fedratinib, are the mainstay of therapy and produce significant and durable reductions in spleen volume. However, many patients are not eligible for JAK 2 inhibitor therapy or become refractory to treatment over time. Novel therapies are in development that can reduce the degree of splenomegaly for some of these patients. However, splenectomy, splenic irradiation, and partial splenic artery embolization remain valuable therapeutic options in select patients. In this review, we will discuss currently available pharmacologic therapies and describe promising drugs currently in development. We will also delve into the efficacy and safety concerns of splenectomy, splenic irradiation, and partial splenic artery embolization. Finally, we will propose a treatment algorithm to help guide clinicians in the management of symptomatic splenomegaly in patients with MF.


Assuntos
Mielofibrose Primária/complicações , Mielofibrose Primária/terapia , Esplenomegalia/etiologia , Esplenomegalia/terapia , Embolização Terapêutica/métodos , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Baço/irrigação sanguínea , Baço/patologia , Baço/cirurgia , Esplenectomia/métodos , Artéria Esplênica/patologia , Artéria Esplênica/cirurgia
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