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1.
Am J Forensic Med Pathol ; 41(1): 32-34, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32000220

RESUMO

Thymus glands from 283 autopsy cases were sampled and evaluated with histochemical and immunohistochemical methods. A subpopulation of 41 intravenous drug addicts were compared with age-matched control cases.It was found that an accelerated involution of the thymus occurred in the 20- to 25-year interval and thereafter with a steady pace of 5% per year. Also the size of Hassall bodies declined successively.In drug addicts, an increased dystrophic calcification of the Hassall bodies and a significant difference in thymus size (atrophy) compared with controls were seen. Moreover, a difference was seen in the relative numbers of CD4 and CD8 lymphocytes where CD4+ cells were reduced in drug addicts.It is hypothesized that signs of hepatitis C virus infection that was found in the majority of drug addicts and the reduced number of functionally intact Hassall corpuscles could explain the reduction of CD4+ lymphocytes and thymic hypotrophy in this population.


Assuntos
Usuários de Drogas , Abuso de Substâncias por Via Intravenosa , Timo/patologia , Adolescente , Adulto , Envelhecimento/patologia , Atrofia/patologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Calcinose/patologia , Estudos de Casos e Controles , Feminino , Patologia Legal , Hepatite C Crônica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
2.
Chemosphere ; 238: 124647, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31466007

RESUMO

Ground water arsenic contamination is a global menace. Since arsenic may affect the immune system, leading to immunesuppression, we investigated the effects of acute arsenic exposure on the thymus and spleen using Swiss albino mice, exposed to 5 ppm, 15 ppm and 300 ppm of sodium arsenite for 7 d. Effects on cytokine balance and cell survivability were subsequently analyzed. Our data showed that arsenic treatment induced debilitating alterations in the tissue architecture of thymus and spleen. A dose-dependent decrease in the ratio of CD4+-CD8+ T-cells was observed along with a pro-inflammatory response and redox imbalance. In addition, pioneering evidences established the ability of arsenic to induce an up regulation of Hsp90, eventually resulting in stabilization of its client protein Beclin-1, an important autophagy-initiating factor. This association initiated the autophagic process, confirmed by co-immunoprecipitation assay, acridine orange staining and Western blot, indicating the effort of cells trying to survive at lower doses. However, increased arsenic assault led to apoptotic cell death in the lymphoid organs, possibly by increased ROS generation. There are several instances of autophagy and apoptosis taking place either simultaneously or sequentially due to oxidative stress. Since arsenic is a potent environmental stress factor, exposure to arsenic led to a dose-dependent increase in both autophagy and apoptosis in the thymus and spleen, and cell death could therefore possibly be induced by autophagy. Therefore, exposure to arsenic leads to serious effects on the immune physiology in mice, which may further have dire consequences on the health of exposed animals.


Assuntos
Arsênico/farmacologia , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Animais , Apoptose/efeitos dos fármacos , Arsenitos/farmacologia , Relação CD4-CD8 , Inflamação/induzido quimicamente , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Compostos de Sódio/farmacologia , Baço/efeitos dos fármacos , Baço/patologia , Timo/efeitos dos fármacos , Timo/patologia
3.
Infect Immun ; 88(1)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31636138

RESUMO

Salmonella is an intracellular bacterium found in the gastrointestinal tract of mammalian, avian, and reptilian hosts. Mouse models have been extensively used to model in vivo distinct aspects of human Salmonella infections and have led to the identification of several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross strains to intravenous infection with Salmonella enterica serovar Typhimurium as a model of human systemic invasive infection. In this model, strain CC042/GeniUnc (CC042) mice displayed extreme susceptibility with very high bacterial loads and mortality. CC042 mice showed lower spleen weights and decreased splenocyte numbers before and after infection, affecting mostly CD8+ T cells, B cells, and all myeloid cell populations, compared with control C57BL/6J mice. CC042 mice also had lower thymus weights with a reduced total number of thymocytes and double-negative and double-positive (CD4+, CD8+) thymocytes compared to C57BL/6J mice. Analysis of bone marrow-resident hematopoietic progenitors showed a strong bias against lymphoid-primed multipotent progenitors. An F2 cross between CC042 and C57BL/6N mice identified two loci on chromosome 7 (Stsl6 and Stsl7) associated with differences in bacterial loads. In the Stsl7 region, CC042 carried a loss-of-function variant, unique to this strain, in the integrin alpha L (Itgal) gene, the causative role of which was confirmed by a quantitative complementation test. Notably, Itgal loss of function increased the susceptibility to S. Typhimurium in a (C57BL/6J × CC042)F1 mouse background but not in a C57BL/6J mouse inbred background. These results further emphasize the utility of the Collaborative Cross to identify new host genetic variants controlling susceptibility to infections and improve our understanding of the function of the Itgal gene.


Assuntos
Bacteriemia/genética , Antígeno CD11a/deficiência , Predisposição Genética para Doença , Mutação com Perda de Função , Infecções por Salmonella/genética , Salmonella typhimurium/crescimento & desenvolvimento , Animais , Bacteriemia/imunologia , Bacteriemia/patologia , Carga Bacteriana , Medula Óssea/patologia , Modelos Animais de Doenças , Genes , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Infecções por Salmonella/imunologia , Infecções por Salmonella/patologia , Sorogrupo , Baço/patologia , Análise de Sobrevida , Timo/patologia
4.
Arkh Patol ; 81(5): 53-63, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31626205

RESUMO

OBJECTIVE: To investigate morphological changes in the thymus, the subpopulation composition of lymphocytes and its non-lymphoid cells in dextran-induced experimental acute ulcerative colitis and in different periods of chronic ulcerative colitis. MATERIAL AND METHODS: Acute and chronic ulcerative colitis was simulated in C57BL/6 mice, by replacing drinking water with a 1% aqueous dextran sulfate sodium solution. Thymic changes were morphometrically assessed; the number and absolute area of thymic corpuscles and epithelial cells were calculated; and the subpopulation composition of lymphocytes and thymic stromal cells was determined using flow cytofluorimetry; the Kruskal-Wallis test and the Mann-Whitney test were used to compare the groups. RESULTS: In acute catarrhal and ulcerative colitis, there was acute accidental thymic involution with devastation of the cortical substance and with a decline in its volume fraction, with an increase in the levels of cells dying through the mechanism of apoptosis, and with a decrease in the absolute number of lymphocytes, T-helper cells, cytotoxic T-cells, regulatory T-lymphocytes, B-lymphocytes, and dendritic cells, with a rise in the index of the area of thymic corpuscles and in the content of late-phase corpuscles among them, and with the appearance of thymic corpuscles as cyst-like cavities. In chronic ulcerative colitis, the cortex was expanded and the area of thymic corpuscles and the count of medullary epithelial cells increased. The cyst-like thymic corpuscles formed clusters, the count of dendritic cells increased in early-stage chronic ulcerative colitis, but the levels of macrophages decreased in both periods of its development. CONCLUSION: There is acute accidental involution and thymic hyperplasia with an increase in medullary epithelial cells and thymic corpuscles consisting of cytokeratin 19+ in the epithelial cells in experimental acute and chronic ulcerative colitis, respectively. The more pronounced epithelial cell response found in end-stage experimental chronic ulcerative colitis reflects the enhanced differentiation of regulatory T-lymphocytes and the larger number of which is observed in peripheral blood and in the focus of inflammation in patients with ulcerative colitis, according to the literature.


Assuntos
Colite Ulcerativa/patologia , Linfócitos/citologia , Timo/patologia , Animais , Colite Ulcerativa/induzido quimicamente , Sulfato de Dextrana , Camundongos , Camundongos Endogâmicos C57BL , Timo/citologia
5.
Nat Commun ; 10(1): 4402, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562306

RESUMO

T lymphocytes must be produced throughout life, yet the thymus, where T lymphocytes are made, exhibits accelerated atrophy with age. Even in advanced atrophy, however, the thymus remains plastic, and can be regenerated by appropriate stimuli. Logically, thymic atrophy is thought to reflect senescent cell death, while regeneration requires proliferation of stem or progenitor cells, although evidence is scarce. Here we use conditional reporters to show that accelerated thymic atrophy reflects contraction of complex cell projections unique to cortical epithelial cells, while regeneration requires their regrowth. Both atrophy and regeneration are independent of changes in epithelial cell number, suggesting that the size of the thymus is regulated primarily by rate-limiting morphological changes in cortical stroma, rather than by their cell death or proliferation. Our data also suggest that cortical epithelial morphology is under the control of medullary stromal signals, revealing a previously unrecognized endocrine-paracrine signaling axis in the thymus.


Assuntos
Células Epiteliais/metabolismo , Regeneração/genética , Células Estromais/metabolismo , Linfócitos T/metabolismo , Timo/metabolismo , Animais , Atrofia/genética , Atrofia/metabolismo , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Tamanho do Órgão/genética , Regeneração/fisiologia , Timo/patologia , Timo/fisiopatologia
6.
Nervenarzt ; 90(10): 1055-1066, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31538208

RESUMO

Myasthenia gravis (MG) is an autoimmune disorder caused by antibodies against acetylcholine receptors (AChR) or other structural proteins of the neuromuscular junction. This diminishes cholinergic transmission, thus leading to exercise-induced fatigue and sometimes manifest muscle weakness, including the bulbar and ocular musculature. Whereas ocular MG is as a rule initially symptomatically treated with acetylcholine esterase inhibitors, generalized MG requires long-term immunosuppression. The thymus plays a particular role in the pathophysiology of AChR antibody-positive MG, which can also manifest as a paraneoplastic disorder in the context of a thymoma. This article reviews the basic and advanced treatment options of the different disease subtypes including plasma exchange and immunoglobulins for treatment in a myasthenic crisis. Recently, clinical approval of eculizumab, a complement inhibitor, enriched the pharmacological armamentarium for AChR antibody-positive MG patients not appropriately responding to immunosuppression alone.


Assuntos
Miastenia Gravis , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Imunoglobulinas/uso terapêutico , Imunossupressão , Miastenia Gravis/imunologia , Miastenia Gravis/terapia , Troca Plasmática , Timo/imunologia , Timo/patologia
7.
Food Chem Toxicol ; 133: 110748, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31377140

RESUMO

Hexavalent chromium raises high concern because of its wide industrial applications and reported toxicity. Long-term (135 days) oral exposure of Wistar rats to chromium in the form of K2Cr2O7 (exposed group~20 mg/kg/day) led to a decrease in thymus mass and thymocytes' number and caused structural and functional changes in the lymph nodes and spleen, namely lymphoreticular hyperplasia and plasmocytic macrophage transformation. Programmed cell death was increased in both thymocytes and splenocytes and decreased in lymphocytes in the T-zones of spleen and lymph nodes. Moreover, Cr (VI) administration decreased myeloid cells' and neutrophils' number, while it increased lymphoid and erythroid cells' number in bone marrow. Cr (VI) immune system effects seem to be related to oxidative stress induction, as depicted by the increased levels of diene conjugates and malondialdehyde in the spleen and liver and by the decreased activity of catalase and superoxide dismutase in rats' erythrocytes. In addition, exposure to Cr (VI) decreased copper, nickel and iron concentrations in blood and liver, while Cr levels in blood, spleen and liver were increased, as expected. The observed changes in the series of immunological parameters studied contribute to the development of new approaches for the prevention of low level Cr exposure toxicity.


Assuntos
Cromo/toxicidade , Linfonodos/efeitos dos fármacos , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Imuno-Histoquímica , Linfonodos/metabolismo , Contagem de Linfócitos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Baço/metabolismo , Linfócitos T/metabolismo , Timócitos/metabolismo , Timo/metabolismo , Timo/patologia
8.
Food Funct ; 10(7): 4361-4371, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31276149

RESUMO

The anti-cancer activities of brown algae and some active extracts or components from brown algae have been demonstrated. But the anti-tumor activities of eckol, a new natural phlorotannin derived from marine brown algae, are poorly understood. In order to investigate the in vivo anti-tumor effect and its potential mechanisms of eckol in a sarcoma 180 (S180) xenograft-bearing animal model, S180 xenograft-bearing mice were randomly divided into 4 groups: model control, and eckol low-dose (0.25 mg kg-1), middle-dose (0.5 mg kg-1) and high-dose (1.0 mg kg-1) groups. After eckol administration, the tumor inhibition, tumor tissue histology, thymus index and spleen index were measured. The apoptotic tumor cells were detected using the terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL) assay. The protein expression levels of cleaved Caspase-3 and Caspase-9 (two key apoptotic proteins), Bcl-2 and Bax (two key anti-apoptosis-related genes), as well as epidermal growth factor receptor (EGFR, a well-known cell proliferation-stimulating molecule in tumorigenesis) and p-EGFR in tumor tissues were determined by western blot. A carbon particle clearance test, measurement of serum cytokine levels, a splenic T lymphocyte proliferation test, and T lymphocyte subpopulation analysis were used to evaluate the effect of eckol on the immune function of tumor-bearing mice. Moreover, CD11c+-dendritic cell (DC) infiltration in tumor tissues was detected by immunohistochemistry, and the surface molecules on bone marrow-derived DCs were analyzed using flow cytometry. The pro-apoptosis and anti-proliferation activities of eckol were manifested by the increased TUNEL-positive apoptotic cells, the upregulated Caspase-3 and Caspase-9 expression, and the downregulated expression of Bcl-2, Bax, EGFR and p-EGFR in eckol-treated transplanted S180 tumors. Most importantly, eckol stimulated the mononuclear phagocytic system, recruited and activated DCs, promoted the tumor-specific Th1 responses, increased the CD4+/CD8+ T lymphocyte ratio, and enhanced cytotoxic T lymphocyte responses in the eckol-treated animals, suggesting its potent stimulatory property on innate and adaptive immune responses. This study suggested that eckol might act as a functional food constituent derived from marine brown algae with a potential in vivo anti-tumor effect achieved by improving the immune response.


Assuntos
Antineoplásicos/farmacologia , Dioxinas/farmacologia , Feófitas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Células Dendríticas/patologia , Modelos Animais de Doenças , Regulação para Baixo , Receptores ErbB/metabolismo , Humanos , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sarcoma/tratamento farmacológico , Baço/efeitos dos fármacos , Baço/patologia , Linfócitos T/imunologia , Timo/efeitos dos fármacos , Timo/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/genética
9.
Biomed Res Int ; 2019: 1602895, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179315

RESUMO

The aim was to investigate the effect of dichloroacetate (DCA) on thymus weight, Hassall's corpuscle number (HCs), and NKCC1 RNA expression in Wistar rats aged 4-5 weeks. They were investigated in the controls and DCA-treated gonad-intact and castrated males and females. The treatment lasted 4 weeks with DCA 200 mg/kg/day. At the end of the experiment, rat thymus was weighted, and its lobe was taken for the expression of NKCC1 RNA determined by the PCR method and of Hassall's corpuscles by immunohistochemistry. DCA caused a thymus weight decrease in DCA-treated gonad-intact rats of both genders as compared with their controls (p < 0.05), and no such impact was found in castrated DCA-treated males and females. DCA caused an increase of the HCs in gonad-intact males (p < 0.05), and no such increase in the DCA-treated gonad-intact females was found. There was gender-related difference in the HCs when comparing DCA-treated gonad-intact males and females: males showed significantly higher HCs (p < 0.05); no gender-related differences were found in the castrated DCA-treated groups. The Slc12a2 gene RNA expression level was found to be significantly decreased only in gonad-intact and in castrated DCA-treated males. The authors discuss the gender-related DCA effects on the thymus.


Assuntos
Ácido Dicloroacético/farmacologia , Células Epiteliais/efeitos dos fármacos , RNA/metabolismo , Membro 2 da Família 12 de Carreador de Soluto/metabolismo , Timo/efeitos dos fármacos , Animais , Castração , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Imuno-Histoquímica , Masculino , Orquiectomia , Ratos , Ratos Wistar , Timo/patologia
10.
Biochemistry (Mosc) ; 84(6): 617-626, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31238861

RESUMO

D-Galactose (D-Gal) promotes accumulation of reactive oxygen species and formation of advanced glycation end-products, ultimately resulting in oxidative stress. D-Gal has been widely used to induce accelerated aging in anti-aging medical research. Although thymic epithelial cells are particularly sensitive to oxidative stress, there are few reports on the thymus changes accompanying D-Gal-induced aging in mice. To study the effect of D-Gal on rodent thymus, we investigated the degree of thymus atrophy and changes in the atrophy relative index in C57BL/6J mice following subcutaneous injection of D-Gal at different doses (200, 500, 1000 mg/kg per day) for 60 days. Compared with the vehicle-treated (0.9% saline) and young controls, D-Gal at doses of 500 and 1000 mg/kg per day led to a significant thymic atrophy; the latter dose caused atrophy similar to that observed in naturally aged (18-20-month-old) mice. Mice treated with high-dose D-Gal exhibited greater immunosenescence, defective central immune tolerance, increased levels of activated splenic immune cell, and chronic low-grade inflammation, i.e., outcomes similar to those observed in natural aging in mice. Taken together, our results indicate that mice treated with high-dose D-Gal may be a valid model for studying induced thymic atrophy and effects of aging on the immune system.


Assuntos
Envelhecimento/efeitos dos fármacos , Galactose/administração & dosagem , Tolerância Imunológica , Animais , Relação Dose-Resposta a Droga , Feminino , Galactose/farmacologia , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Timo/efeitos dos fármacos , Timo/patologia
11.
Int J Nanomedicine ; 14: 2995-3013, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118618

RESUMO

Background: Recent years, there occurs heavy haze pollution in northern China during wintertime. The potential influence of airborne particulate matter (PM) on human health attracts great concern. The fuel-derived PM in the inhalable size range is dominated by aggregates of nanoparticles of Carbon black (CB). However, there are still lack of evidences especially regarding long-term exposure to explain the chronic effects of nanoscaled CB and the relative mechanism. Purpose: The objective of this study was to identify the potential mechanism of chronic effects of nanoscale CB. The systemic toxicity, immune suppression or activity and local toxicity were evaluated. Methods: 32 rats were divided into 2 groups: 30 mg/m3 CB exposure (nose only, 90 d, 6h/d) and control (clean air). Half of rats were scarified after exposure and another half of rats recovered for 14 days. Eight rats in each group were executed the lung function tests using a ventilated bias flow whole body plethysmograph (WBP). SDS-PAGE protocol was used to detect the deposition and retention of CB in lung of rats. HE staining was used to observe the changes of histopathology. Cell apoptosis was examined by TUNEL assay or flow cytometry. The levels of IL-6, IL-8, IL-17 and TNF-α in serum and lung tissue were evaluated with commercially available ELISA kit. The peripheral blood cell counts were detected by Auto 5-diff hematology analyzer. Results: The lung burden of CB was 16 mg in lung of rats after a 90-day exposure by MPPD. Fourteen percentages of the amount of CB accumulated at the end of the exposure period was cleared from the lung during the 14 dys recovery period. The lung function was significantly decreased and could not recover after a short time recovery. The fibroblasts and granuloma formation were found in lung. The levels of apoptosis and DNA damages were significantly increased in lung cells after CB inhalation. The cytokines levels in lung but not in serum were significantly increased in CB exposure group. The cell counts of WBC, monocytes and neutrophils had 1.72, 3.13, and 2.73-fold increases after CB exposure, respectively. The percentages of CD4+ lymphocytes and the rates of CD4+/CD8+ were statistically increased after CB exposure. The stimulation indexes of the peripheral blood lymphocytes were significantly decreased after CB exposure. In the CB exposure group, the disrupted histomorphology of thymus and spleen were found as well as the early apoptotic thymocytes had a 2.36-fold increase. Conclusion: CB induced the localized or direct toxicity and systemic immune toxicity. The direct and systemic immune responses had a combined effect on the lung damages caused by CB.


Assuntos
Pulmão/efeitos dos fármacos , Pulmão/imunologia , Nanopartículas/administração & dosagem , Nanopartículas/toxicidade , Fuligem/administração & dosagem , Fuligem/toxicidade , Administração por Inalação , Animais , Apoptose/efeitos dos fármacos , Contagem de Células Sanguíneas , China , Citocinas/metabolismo , Inflamação/patologia , Pulmão/patologia , Pulmão/ultraestrutura , Masculino , Material Particulado/toxicidade , Ratos Sprague-Dawley , Testes de Função Respiratória , Baço/efeitos dos fármacos , Baço/patologia , Timo/efeitos dos fármacos , Timo/patologia
13.
Int Immunopharmacol ; 72: 98-111, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30974284

RESUMO

Ginsenoside Rg3 (Rg3), which comprises Panax ginseng, is commonly used to improve the immunocompetence of cancer patients undergoing chemotherapy. This study was designed to elucidate the immunoenhancement effects of Rg3 in immunosuppressed mice induced by cyclophosphamide (CTX) treatment. Balb/c mice were administered Rg3 intragastrically once daily for 19 consecutive days and were intraperitoneally administered CTX (80 mg/kg) on days 15-19. Weight and immune organ indices were recorded. Hematological tests and cytokines were assessed using ELISA. We measured the activity of LDH and ACP, performed pathological and immunohistochemical staining of immune organs, and evaluated cytokines and transcription factors using RT-PCR. Immunosuppressed mice showed weight loss, decreased thymus and spleen indices and severe pathological damage. CTX attenuated macrophage phagocytosis by decreasing activity of LDH and ACP and decreased the release of related immune factors, IgG, IL-2 and G-CSF. Subsequently, we observed T lymphocyte expression on the surface of the thymus and spleen, which inhibited T cell activity. Further mechanistic analysis showed that CTX decreased the expression of T-bet and IFN-γ and increased the expression of GATA-3 and IL-4 in the thymus and spleen, which affected the Th1/Th2 balance. However, Rg3 treatment reversed CTX-induced immunosuppression. In summary, all the results suggest that Rg3 has protective effects on CTX-induced immunosuppression, which could be partially related to macrophages, T cells and Th1/Th2 balance. Although deeper studies of its mechanism are needed, these findings support the hypothesis that Rg3 can improve the reduced immunocompetence after CTX injury.


Assuntos
Ciclofosfamida/efeitos adversos , Ginsenosídeos/farmacologia , Fatores Imunológicos/farmacologia , Imunossupressão , Animais , Fator Estimulador de Colônias de Granulócitos/sangue , Imunoglobulina G/sangue , Fatores Imunológicos/efeitos adversos , Interleucina-2/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos BALB C , Fagocitose/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Timo/efeitos dos fármacos , Timo/imunologia , Timo/patologia
14.
Adv Anat Pathol ; 26(4): 257-269, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30932971

RESUMO

The thymus is a dynamic organ that undergoes changes throughout life and can demonstrate a myriad of pathologic alterations. A number of benign entities of the thymus prove to be diagnostic dilemmas owing to their resemblance and association with true thymic tumors. These are usually discovered incidentally on routine imaging and most patients are either asymptomatic or present with signs and symptoms of compression of adjacent organs. The radiologic appearance of these lesions varies from simple cysts to complex masses that are suspicious for malignancy. The diagnosis is usually made purely on morphologic grounds, however, immunohistochemical stains can help rule out possible differential diagnoses. Surgical removal is usually curative in these lesions and recurrences are rare. The prognosis is excellent, however, some of these lesions may be associated with myasthenia gravis and/or thymomas. In this review, we describe non-neoplastic lesions and benign tumoral lesions of the thymus, with emphasis on the clinical, radiologic, and pathologic features. The differential diagnosis of each entity is also discussed.


Assuntos
Miastenia Gravis/patologia , Timoma/patologia , Timo/patologia , Neoplasias do Timo/patologia , Diagnóstico Diferencial , Humanos , Miastenia Gravis/diagnóstico , Prognóstico , Timoma/diagnóstico , Neoplasias do Timo/diagnóstico
15.
J Vet Diagn Invest ; 31(4): 601-603, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31006384

RESUMO

Six, 5-6-wk-old pigs, from 3 farms of the same company, with significant loss of body condition were submitted for postmortem evaluation. Macroscopically, the main lesion observed in all of the pigs was thymic atrophy. Microscopically, all of the pigs had thymic atrophy, superficial lymphocytic fundic gastritis, atrophic enteritis, superficial colitis, and neutrophilic and lymphocytic rhinitis, leading to a diagnosis of porcine periweaning failure-to-thrive syndrome. In the pigs from 2 of the farms, many of the thymic corpuscles had infiltrates of neutrophils and degenerate cells, in some cases infiltrating the surrounding parenchyma.


Assuntos
Insuficiência de Crescimento/veterinária , Doenças dos Suínos/diagnóstico , Timo/patologia , Animais , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/patologia , Suínos , Doenças dos Suínos/patologia , Desmame
16.
Ecotoxicol Environ Saf ; 176: 146-152, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30925331

RESUMO

Ammonia (NH3) is one of major air pollutants in intensive poultry houses, affecting chicken health. Circular RNA (circRNA) is a novel type of RNA that can regulate gene expression and be associated with various biological activities. However, the changes of circRNA caused by excess NH3 in chickens have not been investigated. We found differentially expressed genes and morphological changes in the thymuses of chickens exposed to NH3 on day 42. We used a combination of RNA deep sequencing, qRT-PCR, and bioinformatic analysis to explore regulatory mechanism of circRNA and mRNA. Transcriptional profiling results showed that 5 circRNA genes and 100 mRNA genes were significantly dyregulated by high NH3. The results from GO items showed that immune response and the regulation of cytokine production were involved in the mechanisms of chickens exposed to NH3. Co-expression analysis found that circRNA-mRNA network was correlated with oxidative stress and inflammation. NH3 exposure decreased mRNA expression of antioxidant-related genes (GPx and GST4) and increased the mRNA expression of inflammation-related genes (IL-1ß, IL-6, IL-8, and iNOS) in chicken thymuses. Histopathologic analysis demonstrated that NH3 caused inflammatory injury in chicken thymuses. In conclusion, the co-expression of circRNA and mRNA took part in chicken thymus inflammatory injury caused by NH3. Our study further enriches the mechanism of NH3 toxicity on chickens, which may be valuable for human and animal health protection.


Assuntos
Amônia/toxicidade , Galinhas , Expressão Gênica/efeitos dos fármacos , RNA/genética , Timo/efeitos dos fármacos , Animais , Inflamação/genética , Exposição por Inalação/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Timo/imunologia , Timo/patologia
17.
Front Immunol ; 10: 186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30814997

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) has recently been increasingly reported as an important complication after stem cell transplantation, in line with the increase in the number of HLA-mismatched transplantation. Although previous clinical studies have shown an elevation of inflammatory cytokines in patients with HLH after hematopoietic stem cell transplantation, as well as those after viral infection or autoimmune disease, the disease pathogenesis remains poorly understood. Here we explored this issue in humanized mice with functional human lymphohematopoietic systems, which were constructed by transplantation of human CD34+ cells alone, or along with human fetal thymus into NOD/SCID/γc-/- (NSG) or NSG mice carrying human SCF/GM-CSF/IL-3 transgenes (SGM3). In comparison with humanized NSG (huNSG) mice, huSGM3 mice had higher human myeloid reconstitution and aggressive expansion of human CD4+ memory T cells, particularly in the absence of human thymus. Although all huNSG mice appeared healthy throughout the observation period of over 20 weeks, huSGM3 mice developed fatal disease characterized by severe human T cell and macrophage infiltrations to systemic organs. HuSGM3 mice also showed severe anemia and thrombocytopenia with hypoplastic bone marrow, but increased reticulocyte counts in blood. In addition, huSGM3 mice showed a significant elevation in human inflammatory cytokines including IL-6, IL-18, IFN-α, and TNF-γ, faithfully reproducing HLH in clinical situations. Our study suggests that posttransplant HLH is triggered by alloresponses (or xenoresponses in our model), driven by myeloid cytokines, and exacerbated by vicious cycles of T-cell and macrophage activation.


Assuntos
Citocinas/metabolismo , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Ativação de Macrófagos/imunologia , Camundongos , Camundongos Transgênicos , Complicações Pós-Operatórias , Timo/imunologia , Timo/metabolismo , Timo/patologia , Quimeras de Transplante
18.
PLoS One ; 14(3): e0197655, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30897085

RESUMO

The pathogenesis of thymic epithelial tumors remains poorly elucidated. The PIK3/Akt/mTOR pathway plays a key role in various cancers; interestingly, several phase I/II studies have reported a positive effect of mTOR inhibitors in disease control in thymoma patients. A major limit for deciphering cellular and molecular events leading to the transformation of thymic epithelial cells or for testing drug candidates is the lack of reliable in vitro cell system. We analyzed protein expression and activation of key players of the Akt/ mTOR pathway namely Akt, mTOR, and P70S6K in eleven A, B and AB thymomas as well as in normal thymuses. While only Akt and phospho-Akt were expressed in normal thymuses, both Akt and mTOR were activated in thymomas. Phospho-P70S6K was expressed in all thymic tumors whatever their subtypes, and absent in normal thymus. Interestingly, we report the activation of Akt, mTOR and P70S6 proteins in primary thymic epithelial cells maintained for short period of time after their derivation from seven AB and B thymomas. Finally, we showed that rapamycin (100 nM) significantly reduced proliferation of thymoma- derived epithelial cells without inducing cell death. Our results suggest that the activation of the Akt/ mTOR pathway might participate to the cell proliferation associated with tumor growth. Ultimately, our data enhance the potential role of thymic epithelial cells derived from tissue specimens for in vitro exploration of molecular abnormalities in rare thymic tumors.


Assuntos
Neoplasias Epiteliais e Glandulares/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Timoma/metabolismo , Neoplasias do Timo/metabolismo , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Timoma/genética , Timoma/patologia , Timo/metabolismo , Timo/patologia , Neoplasias do Timo/genética , Neoplasias do Timo/patologia , Fatores de Transcrição TFII/genética , Células Tumorais Cultivadas
19.
Oncol Rep ; 41(5): 2762-2774, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30816514

RESUMO

The aim of the present study was to examine the whole­genome DNA methylation status of thymomas and identify differences in thymoma DNA methylation profiles. DNA methylation profiles of tissues (n=12) were studied using the Infinium MethylationEPIC BeadChip microarray (850K) and analyzed in relation to gene expression data. Functional annotation analysis of DNA methylation between the different groups was performed using the online tool GeneCodis3. In order to assess the diagnostic value of candidate DNA methylation markers, receiver operation characteristic (ROC) analysis was performed using the pROC package. A total of 10,014 CpGs were found to be differentially methylated (Δß>0.2) between two thymoma types (type A and B). Combination analysis showed that 36 genes had differentially methylated CpG sites in their promoter region. 'Pathways in cancer', 'focal adhesion' and 'regulation of actin cytoskeleton' were the most enriched KEGG pathways of differentially methylated genes between tumor and controls. Among the 29 genes that were hypomethylated with a high expression, zinc finger protein 396 and Fraser extracellular matrix complex subunit 1 had the largest area under the curve. The present results may provide useful insights into the tumorigenesis of thymomas and a strong basis for future research on the molecular subtyping of epigenetic regulation in thymomas.


Assuntos
Metilação de DNA/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Timoma/genética , Neoplasias do Timo/genética , Adulto , Idoso de 80 Anos ou mais , Carcinogênese/genética , Ilhas de CpG/genética , Feminino , Genoma Humano/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas/genética , Timectomia , Timoma/patologia , Timoma/cirurgia , Timo/patologia , Timo/cirurgia , Neoplasias do Timo/patologia , Neoplasias do Timo/cirurgia
20.
Toxicol Pathol ; 47(2): 129-137, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30700236

RESUMO

Thymomas occur prevalently in aged Wistar Hannover (WH) rats, along with hyperplastic lesions that cannot be categorized as thymomas. We compared the histological features of hyperplastic lesions and thymomas in WH rats, the incidences of these lesions, and the relationship of these lesions to the degree of thymic involution and also compared these lesions with those of Sprague Dawley (SD) rats in 4-, 13-, 26-, and 104-week studies. There were no morphological differences between hyperplastic cells and benign tumor cells in thymomas. The histological difference between hyperplastic lesions and thymomas was the size of the proliferative areas and the number of medullary differentiation areas. The hyperplastic lesions of the thymus in WH rats might have a potential for progression to thymomas due to the observed multiple hyperplastic lesions or mixed lesions with thymomas. The incidence of these proliferative lesions in the thymus was higher in females than in males. Further, the incidence of these proliferative lesions was higher in WH rats than in SD rats. Thymic involution was more severe in males than in females and more severe in SD rats than in WH rats. The differences in involution progression may have been reflected in the incidence of thymic proliferative lesions in SD and WH rats.


Assuntos
Timoma/patologia , Timo/patologia , Neoplasias do Timo/patologia , Animais , Feminino , Hiperplasia/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Wistar
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