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1.
Ecotoxicol Environ Saf ; 204: 111049, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32758698

RESUMO

Recent studies identified a novel programmed and regulated cell death that was characterized by a necrotic cell death morphology, termed necroptosis. Lead (Pb) is known as a persistent inorganic environmental pollutant that affects the health of humans and animals worldwide. However, there are no detailed reports of Pb-induced necroptosis of immune tissue. Selenium (Se) is a trace element that antagonizes the toxicity of heavy metals. Here, chickens were randomly divided into four groups, treated with Pb ((CH3OO)2Pb, 150 mg/kg) and/or Se (Na2SeO3, 2 mg/kg), aim to study the effect and mechanism of necroptosis in Pb-induced spleen injury and the antagonistic effects of Se on Pb toxicity. Our results showed that Pb exposure evidently increased the accumulation of Pb in spleen and caused necroptosis by upregulating the expression of RIP1, RIP3 and MLKL, and decreasing Caspase8 expression. Meanwhile, Pb treatment inhibited the activities of SOD, GPX, and CAT, caused the accumulation of NO and MDA, and induced oxidative stress, which promoted the expression of MAPK/NF-κB pathway genes (ERK, JNK, P38, NF-κB and TNF-α) and activated HSPs (HSP27, HSP40, HSP60, HSP70 and HSP90). However, the increased content of Pb in spleen and Pb-caused necroptosis were inhibited by Se cotreatment. Overall, we conclude that Se can prevent Pb-induced necroptosis by restoring antioxidant functions and blocking the MAPK/NF-κB pathway and HSPs activation in chicken spleen.


Assuntos
Galinhas/fisiologia , Poluentes Ambientais/toxicidade , Chumbo/toxicidade , Necroptose/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Selênio/farmacologia , Baço/efeitos dos fármacos , Animais , Proteínas Aviárias/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteínas de Choque Térmico/metabolismo , NF-kappa B/metabolismo , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos , Baço/fisiologia
2.
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
3.
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
4.
Nanotoxicology ; 14(6): 827-846, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32552239

RESUMO

Prior studies showed nanoparticle clearance was different in C57BL/6 versus BALB/c mice, strains prone to Th1 and Th2 immune responses, respectively. Objective: Assess nanoceria (cerium oxide, CeO2 nanoparticle) uptake time course and organ distribution, cellular and oxidative stress, and bioprocessing as a function of mouse strain. Methods: C57BL/6 and BALB/c female mice were i.p. injected with 10 mg/kg nanoceria or vehicle and terminated 0.5 to 24 h later. Organs were collected for cerium analysis; light and electron microscopy with elemental mapping; and protein carbonyl, IL-1ß, and caspase-1 determination. Results: Peripheral organ cerium significantly increased, generally more in C57BL/6 mice. Caspase-1 was significantly elevated in the liver at 6 h, to a greater extent in BALB/c mice, suggesting inflammasome pathway activation. Light microscopy revealed greater liver vacuolation in C57BL/6 mice and a nanoceria-induced decrease in BALB/c but not C57BL/6 mice vacuolation. Nanoceria increased spleen lymphoid white pulp cell density in BALB/c but not C57BL/6 mice. Electron microscopy showed intracellular nanoceria particles bioprocessed to form crystalline cerium phosphate nanoneedles. Ferritin accumulation was greatly increased proximal to the nanoceria, forming core-shell-like structures in C57BL/6 but even distribution in BALB/c mice. Conclusions: BALB/c mice were more responsive to nanoceria-induced effects, e.g. liver caspase-1 activation, reduced liver vacuolation, and increased spleen cell density. Nanoceria uptake, initiation of bioprocessing, and crystalline cerium phosphate nanoneedle formation were rapid. Ferritin greatly increased with a macrophage phenotype-dependent distribution. Further study will be needed to understand the mechanisms underlying the observed differences.


Assuntos
Cério/toxicidade , Fígado/efeitos dos fármacos , Nanopartículas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Baço/efeitos dos fármacos , Animais , Cério/química , Cério/metabolismo , Feminino , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Nanopartículas/química , Nanopartículas/metabolismo , Fosfatos/metabolismo , Especificidade da Espécie , Baço/metabolismo , Propriedades de Superfície , Distribuição Tecidual
5.
Nanotoxicology ; 14(7): 893-907, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32529924

RESUMO

This study aimed to evaluate the effects of an intratesticular injection of silver nanoparticles (AgNPs) on reproductive parameters and health of rats, and to evaluate the AgNPs biodistribution in order to develop a nanotechnological contraceptive agent for male animals. Treated animals received 220 µL of AgNPs solution (0.46 µg-Ag/ml) in each testicle and were euthanized: seven, 14, 28, and 56 days after injection. A significant decrease (p < 0.05) in the percentage of motile sperm in D7 (8.8%) was observed, comparing to the control (73.3%), D14 (86.0%), D28 (68.2%), and D56 (90.0%) groups. D7 group also presented a decrease (p < 0.05) in the percentage of normal spermatozoa. Additionally, D7 group showed an increase (p < 0.05) in abnormal midpiece and sperm head morphology compared to the Control group. Seminiferous tubules presented all germline cell types and spermatozoa for all groups. However, D7 group did not present spermatozoa in the epididymis, whereas some spermatozoa and cellular debris were visible in D14 and D28 groups. All animals presented hematological parameters, creatinine, and alanine aminotransferase values within the normal limits for Wistar rats. The percentage of silver found in the liver was always higher than in the other organs analyzed. A pioneering mathematical model is proposed, from which the half-life time of silver in the liver (17 days), spleen (23 days), lungs (30 days), and kidneys (35 days) was extracted. In conclusion, some acute and severe toxic effects were observed in sperm cells following intratesticular injection of AgNPs, although these effects were reversible. No adverse effects to general animal health were observed.


Assuntos
Nanopartículas Metálicas/toxicidade , Reprodução/efeitos dos fármacos , Prata/toxicidade , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Alanina Transaminase/metabolismo , Animais , Epididimo/efeitos dos fármacos , Epididimo/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Nanopartículas Metálicas/administração & dosagem , Ratos , Ratos Wistar , Prata/administração & dosagem , Prata/farmacocinética , Espermatozoides/metabolismo , Baço/efeitos dos fármacos , Baço/metabolismo , Testículo/metabolismo , Distribuição Tecidual
6.
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
7.
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
8.
Nature ; 581(7807): 204-208, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32405000

RESUMO

It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activity enhances plasma cell production in a manner that requires B-cell responsiveness to acetylcholine mediated by the α9 nicotinic receptor, and T cells that express choline acetyl transferase1,2 probably act as a relay between the noradrenergic nerve and acetylcholine-responding B cells. We show that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve; ablation or pharmacogenetic inhibition of these neurons reduces plasma cell formation, whereas pharmacogenetic activation of these neurons increases plasma cell abundance after immunization. In a newly developed behaviour regimen, mice are made to stand on an elevated platform, leading to activation of CeA and PVN CRH neurons and increased plasma cell formation. In immunized mice, the elevated platform regimen induces an increase in antigen-specific IgG antibodies in a manner that depends on CRH neurons in the CeA and PVN, an intact splenic nerve, and B cell expression of the α9 acetylcholine receptor. By identifying a specific brain-spleen neural connection that autonomically enhances humoral responses and demonstrating immune stimulation by a bodily behaviour, our study reveals brain control of adaptive immunity and suggests the possibility to enhance immunocompetency by behavioural intervention.


Assuntos
Comportamento Animal/fisiologia , Encéfalo/fisiologia , Imunidade Humoral/imunologia , Baço/imunologia , Baço/inervação , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Neurônios Adrenérgicos/metabolismo , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Hemocianinas/imunologia , Imunoglobulina G/imunologia , Ativação Linfocitária , Masculino , Camundongos , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Plasmócitos/citologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Receptores Nicotínicos/deficiência , Receptores Nicotínicos/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Linfócitos T/imunologia
9.
PLoS One ; 15(5): e0226791, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32374764

RESUMO

Over the past two decades, measurements of carbon nanotube toxicity and biodistribution have yielded a wide range of results. Properties such as nanotube type (single-walled vs. multi-walled), purity, length, aggregation state, and functionalization, as well as route of administration, greatly affect both the biocompatibility and biodistribution of carbon nanotubes. These differences suggest that generalizable conclusions may be elusive and that studies must be material- and application-specific. Here, we assess the short- and long-term biodistribution and biocompatibility of a single-chirality DNA-encapsulated single-walled carbon nanotube complex upon intravenous administration that was previously shown to function as an in-vivo reporter of endolysosomal lipid accumulation. Regarding biodistribution and fate, we found bulk specificity to the liver and >90% signal attenuation by 14 days in mice. Using near-infrared hyperspectral microscopy to measure single nanotubes, we found low-level, long-term persistence in organs such as the heart, liver, lung, kidney, and spleen. Measurements of histology, animal weight, complete blood count; biomarkers of organ function all suggest short- and long-term biocompatibility. This work suggests that carbon nanotubes can be used as preclinical research tools in-vivo without affecting acute or long-term health.


Assuntos
Materiais Biocompatíveis/farmacologia , Biomarcadores/sangue , Nanotecnologia , Nanotubos de Carbono/efeitos adversos , Animais , Materiais Biocompatíveis/efeitos adversos , Materiais Biocompatíveis/química , DNA de Cadeia Simples/química , DNA de Cadeia Simples/farmacologia , Endossomos/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Camundongos , Nanotubos de Carbono/química , Imagem Óptica , Baço/efeitos dos fármacos , Baço/metabolismo , Distribuição Tecidual/efeitos dos fármacos
10.
Artigo em Inglês | MEDLINE | ID: mdl-32419600

RESUMO

The mining sector in South Africa is expected to be the fifth largest in the world. Both mining and transport are the most common reasons for an increased risk of human exposure to heavy metal contamination in South Africa. Due to increasing amounts of metals in the environment, this study identified three metals cadmium, chromium and mercury based on the risk of exposure in South Africa. The aim of this study was to investigate the changes in the morphology of the spleen tissue of male Sprague-Dawley rats exposed to these metals alone and in combination by using light microscopy. Forty eight animals in eight experimental groups were exposed, via oral gavage, to these metals at 1000× the World Health Organization's acceptable water limits of each respective metal, alone and in combination, for 28 days. Changes in the histological structure of the spleen were observed using haematoxylin and eosin and picrosirius red staining. Necrosis was observed in all the groups, with the severity varying between the different exposure groups, alone or in combination. Fibrosis in the spleen tissue was only seen in the experimental groups exposed to cadmium and mercury respectively, as well as in the combination of cadmium and mercury.


Assuntos
Cádmio/toxicidade , Cromo/toxicidade , Poluentes Ambientais/toxicidade , Mercúrio/toxicidade , Baço/efeitos dos fármacos , Baço/patologia , Animais , Cádmio/sangue , Cromo/sangue , Poluentes Ambientais/sangue , Fibrose , Humanos , Masculino , Mercúrio/sangue , Mineração , Ratos , Ratos Sprague-Dawley , África do Sul
11.
Ecotoxicol Environ Saf ; 200: 110761, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470682

RESUMO

Benzo()pyrene [B()P], widely originated from environmental pollution or food process such as roasting and frying, is a strong mutagen and potent carcinogen. Utilization of hawthorn has been reported against physical mutagens. Our study found that hawthorn extract (HE) contained abundant phenolic compounds, wherein chlorogenic acid was 2.78 mg/g, procyanidine B2 was 3.58 mg/g, epicatechin was 2.99 mg/g DW, which may contribute to anti-genotoxicity activity. So, the role of HE against B()P-induced genotoxicity in C57BL/6 mice was further assessed. Fifty mice were distributed into five groups: control group, B()P group (30 mg/kg, i.p.), B()P + HE-L group (100 mg/kg, i.g.), B()P + HE-M group (200 mg/kg, i.g.), B()P + HE-H group (400 mg/kg, i.g.). Mice were orally administered with solutions of HE for 10 days and injected intraperitoneally with B()P for 3 days from the 8th day. Results showed that B()P can induce significantly pathological damage in liver, lung and spleen, as well as decrease white blood cells (WBCs). Remarkably elevated levels of reactive oxygen species (ROS), DNA strand breaks (DSBs) and G1 cell cycle arrest were also found in B()P group, with upregulated expressions of p-H2AX, p-p53 and p21 in bone marrow cells. With administration of HE, liver, lung and spleen injury significantly mitigated, while WBCs were evidently increased in B()P-treated mice. Consistently, HE markedly reduced level of ROS, DSBs and G1 cell cycle arrest accompanied by reducing expressions of p-H2AX, p-p53 and p21 in bone marrow cells. Combined, these results indicated a protective role of HE on B()P-induced genotoxicity.


Assuntos
Benzo(a)pireno/toxicidade , Crataegus/química , Dano ao DNA/efeitos dos fármacos , Mutagênicos/toxicidade , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Expressão Gênica/efeitos dos fármacos , Histonas/genética , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Substâncias Protetoras/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Baço/efeitos dos fármacos , Baço/patologia , Proteína Supressora de Tumor p53/genética
12.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(3): 228-235, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32389170

RESUMO

Objective To investigate the effect of inulin on monocytic myeloid-derived suppressor cells (M-MDSCs) and plasma inflammatory cytokines in mouse models with non-alcoholic fatty liver disease (NAFLD). Methods C57BL/6 mice were randomly divided into 4 groups: normal diet group, inulin-treated control group, NAFLD model group and inulin-treated NAFLD model group. The normal diet group and inulin-treated control group were given normal diet daily, while the other two groups were fed high-fat diet (60% fat) instead. Meanwhile, the mice in the two inulin-treated groups were administrated dietary inulin (5 g/kg). After 14 weeks of feeding, the mice were sacrificed and their peripheral blood, liver and spleen cells were collected. The proportion of M-MDSCs in the peripheral blood, spleen and liver cells were separately detected by flow cytometry. Concentrations of plasma inflammatory cytokines including tumor necrosis factor α (TNF-α) and interleukin 10 (IL-10) were determined by flow cytometry CBA. Statistical Pearson was used to analyze the correlation between the proportion of M-MDSCs and plasma inflammatory cytokines. Results Compared with the normal diet group, the proportion of M-MDSCs in the peripheral blood, liver and spleen of the NAFLD model group significantly increased, plasma TNF-α level also dramatically increased, but IL-10 concentration showed no significant difference from that of the normal diet group. Conversely, INU treatment, compared with the NAFLD model group without INU treatment, increased the proportion of M-MDSCs in the peripheral blood, liver and spleen notably, decreased plasma TNF-α level, and increased plasma IL-10 concentration. The proportion of M-MDSCs in the peripheral blood, liver and spleen cells of NAFLD mice were negatively correlated with plasma TNF-α level, but positively correlated with plasma IL-10 concentration. Conclusion INU may alleviate the progression of NAFLD via recruiting M-MDSCs in the peripheral blood, liver and spleen and reducing inflammation in mice.


Assuntos
Citocinas/sangue , Inulina/farmacologia , Células Supressoras Mieloides/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Baço/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Células Supressoras Mieloides/citologia , Distribuição Aleatória , Baço/metabolismo
13.
Exp Parasitol ; 215: 107917, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32446699

RESUMO

Cystic echinococcosis (CE) is a worldwide hazardous zoonotic parasitosis caused by Echinococcus granulosus. CE development involves complex immunological mechanisms, including participation of multiple immune cells and effector molecules. Myeloid-derived suppressor cells (MDSCs) are known to be involved in chronic and acute inflammatory conditions. In this study, we aimed to characterize the immune function of MDSCs in CE to improve the understanding, prevention and treatment of CE. Our results indicated that MDSCs overexpressing Ly6C and Ly6G inhibit the formation and activity of T helper 2 cells in a NO-dependent manner during E. granulosus infection.


Assuntos
Equinococose/imunologia , Echinococcus granulosus/imunologia , Células Supressoras Mieloides/imunologia , Células Th2/imunologia , Análise de Variância , Animais , Anticorpos Monoclonais , Arginase/análise , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Citocinas/análise , Feminino , Citometria de Fluxo , Humanos , Ceratolíticos/farmacologia , Camundongos , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/enzimologia , Óxido Nítrico/análise , Espécies Reativas de Oxigênio/análise , Organismos Livres de Patógenos Específicos , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Tretinoína/farmacologia
14.
PLoS Pathog ; 16(4): e1008505, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32320436

RESUMO

The wild-derived inbred CAST/EiJ mouse, one of eight founder strains in the Collaborative Cross panel, is an exceptional model for studying monkeypox virus (MPXV), an emerging human pathogen, and other orthopoxviruses including vaccinia virus (VACV). Previous studies suggested that the extreme susceptibility of the CAST mouse to orthopoxviruses is due to an insufficient innate immune response. Here, we focused on the low number of natural killer (NK) cells in the naïve CAST mouse as a contributing factor to this condition. Administration of IL-15 to CAST mice transiently increased NK and CD8+ T cells that could express IFN-γ, indicating that the progenitor cells were capable of responding to cytokines. However, the number of NK cells rapidly declined indicating a defect in their homeostasis. Furthermore, IL-15-treated mice were protected from an otherwise lethal challenge with VACV or MPXV. IL-15 decreased virus spread and delayed death even when CD4+/CD8+ T cells were depleted with antibody, supporting an early protective role of the expanded NK cells. Purified splenic NK cells from CAST mice proliferated in vitro in response to IL-15 and could be activated with IL-12/IL-18 to secrete interferon-γ. Passive transfer of non-activated or activated CAST NK cells reduced VACV spread but only the latter completely prevented death at the virus dose used. Moreover, antibodies to interferon-γ abrogated the protection by activated NK cells. Thus, the inherent susceptibility of CAST mice to orthopoxviruses can be explained by a low level of NK cells and this vulnerability can be overcome either by expanding their NK cells in vivo with IL-15 or by passive transfer of purified NK cells that were expanded and activated in vitro.


Assuntos
Interleucina-15/farmacologia , Células Matadoras Naturais/imunologia , Orthopoxvirus/imunologia , Infecções por Poxviridae/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , Feminino , Imunidade Inata/efeitos dos fármacos , Interferon gama/imunologia , Interleucina-15/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Orthopoxvirus/efeitos dos fármacos , Orthopoxvirus/patogenicidade , Infecções por Poxviridae/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/patologia , Baço/virologia , Vírus Vaccinia/imunologia
15.
Cancer Immunol Immunother ; 69(9): 1725-1735, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32328672

RESUMO

Surface exposed phosphatidylserine (PS) of cancer aids it to evade immune surveillance and thereby results in tumor progression. Earlier, we reported that PS targeting cationic liposomes, phosphatidylcholine-stearylamine (PC-SA), alone and in combination with doxorubicin can result in complete remission of B16F10 melanoma in C57BL/6 mice without signs of toxicity. Inducing an immunogenic response is highly crucial for any cancer therapy as it is essential in improving the tumor microenvironment for any drug to act. Herein, we demonstrate that PC-SA, besides having tumor reducing ability, elicits a strong immune response. The combination therapy (PC-SA-DOX) is superior to free DOX in enhancing the anti-tumor immune effect on CD4-positive and CD8-positive T cells for IFN-γ, IL-2 and TNF-α production in sera and splenic culture supernatants of B16F10 tumor-induced mice. An upregulation of IL-12 and NO production is evidenced in spleen cultures of these mice, thereby showing a promising role of both Th1 type and innate immune response for host anti-tumor activity. Complete elimination of cancer is sometimes accomplished by surgery, but its effectiveness is often limited due to the propensity of cancers to spread to distant organs by metastasis. In our present study, we show that in PC-SA-DOX treated mice, the elevated Th1 cytokine levels create an immuno-protective environment which thereby facilitates in curing lung metastasis. Our results, therefore, warrant the need of effective immune stimulation by anticancer formulations for inhibition of solid tumors and metastasis, demonstrated by the liposomal DOX formulation.


Assuntos
Aminas/farmacologia , Citocinas/metabolismo , Doxorrubicina/farmacologia , Lipossomos/farmacologia , Metástase Neoplásica/tratamento farmacológico , Células Th1/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Baço/metabolismo , Células Th1/metabolismo , Microambiente Tumoral/efeitos dos fármacos
16.
Am J Physiol Renal Physiol ; 318(5): F1258-F1270, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249615

RESUMO

B lymphocyte hyperactivity plays a pathogenic role in systemic lupus erythematosus (SLE), and spliced X box-binding protein 1 (XBP1s) has been implicated in B cell maturation and differentiation. We hypothesized that blockade of the XBP1s pathway inhibits the B cell hyperactivity underlying SLE and lupus nephritis (LN) development. In the present study, we systematically evaluated the changes in B cell activation induced by the Xbp1 splicing inhibitor STF083010 in a pristane-induced lupus mouse model. The lupus mouse model was successfully established, as indicated by the presence of LN with markedly increased urine protein levels, renal deposition of Ig, and mesangial cell proliferation. In lupus mice, B cell hyperactivity was confirmed by increased CD40 and B cell-activating factor levels. B cell activation and plasma cell overproduction were determined by increases in CD40-positive and CD138-positive cells in the spleens of lupus mice by flow cytometry and further confirmed by CD45R and Ig light chain staining in the splenic tissues of lupus mice. mRNA and protein expression of XBP1s in B cells was assessed by real-time PCR, Western blot analysis, and immunofluorescence analysis and was increased in lupus mice. In addition, almost all changes were reversed by STF083010 treatment. However, the expression of XBP1s in the kidneys did not change when mice were exposed to pristane and STF083010. Taken together, these findings suggest that expression of XBP1s in B cells plays key roles in SLE and LN development. Blockade of the XBP1s pathway may be a potential strategy for SLE and LN treatment.


Assuntos
Linfócitos B/metabolismo , Rim/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/metabolismo , Ativação Linfocitária , Baço/metabolismo , Terpenos , Proteína 1 de Ligação a X-Box/metabolismo , Animais , Autoanticorpos/sangue , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Imunoglobulina G/sangue , Rim/efeitos dos fármacos , Rim/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Transdução de Sinais , Baço/efeitos dos fármacos , Baço/patologia , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Proteína 1 de Ligação a X-Box/antagonistas & inibidores , Proteína 1 de Ligação a X-Box/genética
17.
Artigo em Inglês | MEDLINE | ID: mdl-32330807

RESUMO

Honey-processed Astragalus is a dosage form of radix Astragali processed with honey, which is deemed to contain better qi-tonifying effects in traditional Chinese medicine theroy. Our previous study has demonstrated that honey-processed Astragalus exhibited a better effect on reinforcing qi (vital energy) and immune improvement toward spleen qi deficiency compared with radix Astragali. However, the detailed mechanisms related to qi-tonifying effects of honey-processed Astragalus is still unclear. In this study, we evaluated the qi-tonifying effects of honey-processed Astragalus on spleen qi deficiency rats and predicted the mechanisms by aggregating metabonomics, lipidomics and network pharmacology. The results revealed that body weights, symptom scores, the levels of red blood cell, white blood cell, lymphocyte, spleen and thymus indexes, and three cytokines (TNF-α, IL-6, IFN-γ) in honey-processed Astragalus treated rats were improved in comparison with spleen qi deficiency rats. In parallel, based on the 26 biomarkers screened in metabonomics and lipidomics, we inferred that glycerophospholipid metabolism significantly regulated in pathway analysis was connected with qi-tonifying effects. Moreover, the network pharmacology analysis concluded that the compounds targets of honey-processed Astragalus CDK2, NOS3, MAPK14, PTGS1 and PTGS2 interacted with markers targets PLA2G(s) family and LYPLA1 could be responsible for regulation of glycerophospholipid metabolism to develop qi-tonifying effects. What's more, the above processes were possibly through VEGF signaling and MAPK signaling pathways.


Assuntos
Astrágalo (Planta)/química , Citocinas/sangue , Medicamentos de Ervas Chinesas/farmacologia , Espectrometria de Massas em Tandem/métodos , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Citocinas/metabolismo , Composição de Medicamentos/métodos , Eritrócitos/efeitos dos fármacos , Feminino , Mel , Humanos , Leucócitos/efeitos dos fármacos , Lipidômica , Linfócitos/efeitos dos fármacos , Qi , Ratos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos
18.
Gene ; 742: 144590, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32179172

RESUMO

BACKGROUND/AIMS: Food preservatives are abundant in many products in the human environment. However, little is known about the impact of many food preservatives on the immune system and the immune related genes. Hence, this study aimed to evaluate the effects of five widespread food preservatives, including butylated hydroxyanisole (BHA), potassium sorbate (PS), sodium benzoate (SB), boric acid (BA), and calcium propionate (CP), on haemato-immune functions. METHOD: Sixty Sprague-Dawley rats were assigned to groups orally administered water (control), BHA (0.09 mg/kg), PS (4.5 mg/kg), SB (0.9 mg/kg), BA (0.16 mg/kg) or CP (0.18 mg/kg) for 90 consecutive days. Leukogram and erythrogram profiles were assessed. Nitric oxide and immunoglobulin levels together with phagocytic and lysozyme activities were estimated. Histologic examinations and histomorphometric analysis of splenic tissues were performed. Variations in the mRNA expression levels of tumour necrosis factor alpha (TNF-α), interferon gamma (IFNγ), interleukin (IL)-1ß, IL-6, and IL-10 were assessed. RESULTS: Anemic conditions, thrombocytopenia, leucocytopaenia simultaneous with lymphocytopaenia, monocytopenia, and esinopenia have been obvious following long term exposure to the tested food additives. Prominent exhaustion was noted in immunoglobulin and NO levels and in lysozyme and phagocytic activities. IFNγ, TNF-α, IL-1ß, IL-6, and IL-10 were obviously upregulated in the groups exposed to food preservatives. CONCLUSION: These results confirmed that continued exposure to high levels of BHA, PS, SB, BA, and CP has haematotoxic and immunotoxic effects. Furthermore, these adverse effects are mediated by cytokine production.


Assuntos
Citocinas/metabolismo , Conservantes de Alimentos/toxicidade , Tolerância Imunológica/efeitos dos fármacos , Administração Oral , Animais , Citocinas/imunologia , Conservantes de Alimentos/administração & dosagem , Perfilação da Expressão Gênica , Masculino , Modelos Animais , Ratos , Baço/efeitos dos fármacos , Baço/metabolismo , Fatores de Tempo , Testes de Toxicidade Crônica , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
19.
PLoS One ; 15(3): e0229463, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32214355

RESUMO

Food and feeds contaminated with mycotoxins have been a threat to the rearing industry by causing some of the most fatal toxic reactions not only in the farm animals but also in humans who consume them. Toxicity to juvenile goats was induced by feed contamination with T-2 toxin (at 10 and 20 ppm dosage; group I and II, respectively). The toxicity impact was assessed on days 15 and 30 post treatment with respect to growth performance, oxidative stress, apoptotic studies and detailed pathomorphology. The study revealed that apart from the obvious clinical toxicosis (weakness, lethargy, and retardation in growth), the toxin fed groups also exhibited significant haematological (reduced hemoglobin, total leukocyte and thrombocyte counts) and biochemical changes (increased levels of oxidative stress markers with concomitant decrease in levels of serum and tissue catalase and superoxide dismutase). The pathomorphological and histological alterations suggested that the liver and intestine were the most affected organs. Ultra-structurally, varying degrees of degeneration, cytoplasmic vacuolations and pleomorphic mitochondria were observed in the hepatocytes and the enterocytes of the intestine. Kidney also revealed extensive degeneration of the cytoplasmic organelles with similar condensation of the heterochromatin whereas the neuronal degeneration was characterized by circular, whirling structures. In addition, the central vein and portal triad of the hepatocytes, cryptic epithelial cells of the intestine, MLNs in the lymphoid follicles, PCT and DCT of the nephronal tissues and the white pulp of the spleen exhibited extensive apoptosis. In this study, it was also observed that the expression of HSPs, pro-apoptotic proteins and pro-inflammatory cytokines were significantly upregulated in response to the toxin treatment. These results suggest that the pathogenesis of T-2 toxicosis in goats employs oxidative, apoptotic and inflammatory mechanisms.


Assuntos
Apoptose , Regulação da Expressão Gênica/efeitos dos fármacos , Cabras/fisiologia , Mediadores da Inflamação/metabolismo , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Toxina T-2/toxicidade , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Proteínas de Choque Térmico/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia
20.
Chemosphere ; 251: 126311, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32169710

RESUMO

The study provides cumulative data on the status of the two water bodies. The study designed revealed physicochemical properties (temperature, dissolved oxygen, pH, total dissolved solids and conductivity) to be in the desirable range, however, amongst the heavy metals excepting for Cd all were found to be higher than the permissible limits set by WHO and USEPA. It was observed that these elements cast their impact on bioindices (hepatosomatic index, condition factor, spleenosomatic index and kidney somatic index), renal marker enzyme (creatine kinase), hepatic marker enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase), histology of immune organs (liver, spleen, head-kidney and thymus) and level of serum immunoglobulin (IgM). Further, expression levels of Metallothionein (MT) and Glutathione peroxidase (GPX) genes in immune-related tissues (liver, spleen, head-kidney, thymus and blood) observed indicates metal pollution and abiotic stresses. These alterations are reliable indicators of the cellular and humoral immune response in Cyprinus carpio.


Assuntos
Carpas/fisiologia , Fatores Imunológicos/toxicidade , Metais Pesados/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Carpas/genética , Carpas/imunologia , Expressão Gênica , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Rim Cefálico/efeitos dos fármacos , Fatores Imunológicos/metabolismo , Rim/metabolismo , Lagos , Fígado/metabolismo , Metalotioneína/genética , Metalotioneína/metabolismo , Metais Pesados/análise , Tanques , Baço/efeitos dos fármacos , Poluentes Químicos da Água/análise , Áreas Alagadas
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