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1.
Anticancer Res ; 39(8): 4455-4462, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366544

RESUMO

BACKGROUND/AIM: Platinum-based chemotherapy often fails due to its severe adverse effects. The aim of this study was to examine the adverse effects profile and efficacy of dicycloplatin and compare them to those of cisplatin and carboplatin. MATERIALS AND METHODS: Cystoscopy surveillance of the first American cancer patient treated with dicycloplatin was performed quarterly. In vitro and in vivo studies were conducted using immunoblotting and flow cytometry to assess immune status of spleen and bone marrow of mice treated with dicycloplatin, cisplatin and carboplatin. RESULTS: The American patient did not suffer clinically significant myelosuppression; dicycloplatin has sustained remission in this patient to date. Experimental studies showed that dicycloplatin is less toxic to bone marrow and spleen of mice than cisplatin and carboplatin. CONCLUSION: Dicycloplatin is a promising drug in cancer chemotherapy with less aggressive side-effects than those typically associated with cisplatin and carboplatin. This is an important therapeutic advantage in cancer chemotherapy. Clinical investigation of dicycloplatin as an alternative to cisplatin or carboplatin is warranted.


Assuntos
Medula Óssea/efeitos dos fármacos , Glutamatos/administração & dosagem , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/administração & dosagem , Baço/efeitos dos fármacos , Animais , Medula Óssea/patologia , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cistoscopia , Modelos Animais de Doenças , Combinação de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Glutamatos/efeitos adversos , Humanos , Camundongos , Compostos Organoplatínicos/efeitos adversos , Baço/patologia
2.
Ecotoxicol Environ Saf ; 182: 109464, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31398777

RESUMO

Chlorpyrifos (CPF) is an environmental pollutant due to its high toxicity to aquatic animals. Because CPF was detected in aquatic environments in many countries, it has been widely concerned by researchers. Although the immunotoxicity of CPF to fish had been reported, the immunotoxicity mechanism is still not clear. Recently, transcriptome analysis has become a major method to study the toxic mechanism of pollutants in environmental toxicology. However, the immunotoxicity identification of CPF on fish had not been reported by transcriptome analysis. In the present study, we examined the effects of CPF on organismal system in the spleen of common carp by transcriptome analysis. We have successfully constructed a database of transcriptome analysis of carp spleens under exposure to CPF and found 773 differentially expressed genes (DEGs) (including 498 up-regulated DEGs and 275 down-regulated DEGs) and 4 branches (containing 33 known KEGG pathways). Some genes associated with the 4 pathways (Complement and coagulation cascades, PPAR signaling pathway, Fat digestion and absorption, and Collecting duct acid secretion) contained in organismal system were validated by quantitative real-time PCR and showed significant improvement compared with the control group. Our results indicated that exposure to CPF caused a change in the signal pathways of organismal system in carp spleens. The present study provides new insights into the immunotoxicity mechanism and risk assessment of CPF, as well as references for comparative medicine.


Assuntos
Clorpirifos/toxicidade , Baço/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Atrazina/toxicidade , Carpas , Sistema Imunitário/efeitos dos fármacos , Inseticidas/toxicidade , Transdução de Sinais , Baço/fisiologia
3.
Int J Nanomedicine ; 14: 4723-4739, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308655

RESUMO

Background: Much consideration has been paid to the toxicological assessment of nanoparticles prior to clinical and biological applications. While in vitro studies have been expanding continually, in vivo investigations of nanoparticles have not developed a cohesive structure. This study aimed to assess the acute toxicity of different concentrations of chitosan-coated silver nanoparticles (Ch-AgNPs) in main organs, including liver, kidneys, and spleen. Materials and methods: Twenty-eight male albino rats were used and divided into 4 groups (n=7). Group 1 was kept as a negative control group. Groups 2, 3, and 4 were treated intraperitoneally with Ch-AgNPs each day for 14 days at doses of 50, 25, and 10 mg/kg body weight (bwt) respectively. Histopathological, morphometric and immunohistochemical studies were performed as well as oxidative stress evaluations, and specific functional examinations for each organ were elucidated. Results: It was revealed that Ch-AgNPs induced dose-dependent toxicity, and the repeated dosing of rats with 50 mg/kg Ch-AgNPs induced severe toxicities. Histopathological examination showed congestion, hemorrhage, cellular degeneration, apoptosis and necrosis in hepatic and renal tissue as well as lymphocytic depletion with increasing tangible macrophages in the spleen. The highest levels of malondialdehyde, alanine aminotransferase, aspartate aminotransferase (MDA, ALT, AST) and the lowest levels of reduced glutathione, immunoglobulin G, M and total protein (GSH, IgG, IgM, TP) were observed in this group. On the other hand, repeated dosing with 25 mg/kg induced mild to moderate disturbance in the previous parameters, while there was no significant difference in results of pathological examination and biochemical tests between the control group and those treated with 10 mg/kg bwt Ch-AgNPs. Conclusion: Chitosan-coated silver nanoparticles induce dose-dependent adverse effects on rats.


Assuntos
Quitosana/química , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Nitrogênio da Ureia Sanguínea , Caspase 3/metabolismo , Creatinina/sangue , Glutationa/metabolismo , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Nanopartículas Metálicas/ultraestrutura , Estresse Oxidativo/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos Wistar , Baço/efeitos dos fármacos , Baço/patologia
4.
Microbes Environ ; 34(2): 206-214, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31167991

RESUMO

Lactic acid bacteria (LAB) exert beneficial health effects by regulating immune responses. Brassica rapa L., known as Nozawana, is commonly consumed as a lactic acid-fermented food called nozawana-zuke. Few studies have investigated changes in the bacterial community and cytokine production activities during the fermentation of B. rapa L. In order to obtain more detail information, we herein conducted a study on fresh B. rapa L. fermented for 28 d. An amplicon analysis of the 16S rRNA gene revealed that Lactobacillales predominated during fermentation, and the microbiota became less diverse on day 7 or later. Fermented B. rapa L. promoted the production of interferon (IFN)-γ and interleukin (IL)-10 by mouse spleen cells more than non-fermented vegetables. Lactobacillus curvatus was the predominant species during fermentation, followed by L. plantarum and L. brevis. L. sakei was occasionally detected. A correlation analysis showed that IFN-γ concentrations positively correlated with the numbers of L. curvatus and L. plantarum, while those of IL-10 correlated with the numbers of L. sakei in addition to these 2 species. Significantly higher levels of IFN-γ and IL-10 were induced by fermented B. rapa L. when isolated Lactobacillus strains were added as starter cultures. These results suggest that the Lactobacillus species present in fermented B. rapa L. are beneficial for manufacturing vegetables with immunomodulatory effects.


Assuntos
Brassica rapa/imunologia , Brassica rapa/microbiologia , Alimentos Fermentados/microbiologia , Microbiologia de Alimentos , Fatores Imunológicos/farmacologia , Microbiota/fisiologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Biodiversidade , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , DNA Bacteriano/genética , Lactobacillus/classificação , Lactobacillus/genética , Lactobacillus/isolamento & purificação , Lactobacillus/metabolismo , Masculino , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genética , Especificidade da Espécie , Baço/efeitos dos fármacos , Baço/metabolismo
5.
BMC Complement Altern Med ; 19(1): 126, 2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185967

RESUMO

BACKGROUND: Gut microbiota plays a crucial role in the treatment of gastrointestinal (GI) diseases such as chemotherapy-induced diarrhea (CID). Shenzhu Capsule (SZC) is a Chinese herbal formula, which is composed of Renshen (rhizomes of Panax ginseng C. A. Mey.) and Baizhu (rhizomes of Atractylodes macrocephala Koidz.). Many Chinese traditional anti-diarrheal formulae that contain Renshen and Baizhu are capable of effectively alleviating CID. However, the efficacy in vivo and potential mechanism of SZC (the form of compatibility of Renshen and Baizhu) in the treatment of CID had not been elucidated. Here, this study aimed to investigate whether SZC exhibited the anti-diarrheal activity, and whether gut microbiota was involved in the therapeutic effect of SZC on CID. METHODS: High performance liquid chromatography (HPLC), gas chromatography-mass spectrometer (GC-MS) and infrared spectroscopy (IR) analyses were used to characterize the extracted components in SZC. The mice were orally administrated with SZC in a preventive mode on the first 2 days of this experiment, and then intraperitoneally injected with 5-FU (40 mg/kg/d) for 6 days. SZC treatment lasted until the 3rd day after the end of 5-FU chemotherapy. We investigated the effects of SZC on body weights, diarrhea, thymus/spleen indexes, colonic tissues, and gut microbiota. Colonic histology was examined by hematoxylin-eosin (HE) staining. 16S rDNA Amplicon Sequencing was used to analyze the gut microbial structure from fecal samples. RESULTS: SZC significantly increased the body weights and thymus/spleen indexes, alleviated diarrhea, and reversed histopathological changes of colons. In addition, gut microbiota analysis revealed that the overall structure of gut microbiota in CID mice was disturbed, but reversed to the normal state after SZC treatment. At genus level, SZC significantly inhibited the growth of some potential pathogens associated with diarrhea, such as Clostridiumm, Bacteroides, Parabacteroides, Alloprevotella, Acinetobacter and Pseudomonas. CONCLUSIONS: In our study, these data illustrated that SZC inhibited the growth of many potential pathogens during the alleviation of CID. Gut microbial modulation was associated with the anti-diarrheal activity of SZC.


Assuntos
Atractylodes/química , Diarreia/prevenção & controle , Medicamentos de Ervas Chinesas/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Panax/química , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Diarreia/induzido quimicamente , Avaliação Pré-Clínica de Medicamentos , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Fluoruracila/efeitos adversos , Masculino , Camundongos , Fitoterapia , Distribuição Aleatória , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos
6.
Artigo em Chinês | MEDLINE | ID: mdl-31245954

RESUMO

OBJECTIVE: To observe the effects of AdipoRon orally on the functions of spleen and pancreas in type 2 diabetic mice, in order to present data for clinical application. METHODS: Forty C57/BL6 male mice were randomly divided into 2 groups: normal control group (n=10) and model group (n=30), the former group was fed normally, while the later group was fed with high fat and sugar for 4 weeks.After that, type 2 diabetes model was established in DM group induced by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg).As type 2 diabetes model established successfully, the model mice were randomly divided into three groups (n=10): diabetes mellitus (DM) group, high dose of AdipoRon group (DM + H) and low dose of adiponRon group (DM + L).All the four groups were treated with saline, saline, AdipoRon at the doses of 20 mg/kg and 50 mg/kg by gavages respectively, once a day for 10 days.And then put them to death for collecting blood, pancreas and spleen.Pathological changes of pancreas were observed with a light microscope after HE staining.Protein contents of insulin receptor (INSR), insulin receptor substrate 1( IRS-1) and tumor necrosis factor-α(TNF-α) in pancreatic and spleen tissues were detected by ELISA.The protein level of phosphorylation insulin receptor substrate 1(p-IRS-1) in pancreas was determined by Western blot, and the expression of insulin mRNA in pancreas was tested by RT-PCR. RESULTS: Under the light microscope, it was visible that the pancreatic tissue in NC group was full and closely packed, and the islet was big.Pancreatic tissue of DM mice was incompact and the islet of DM mice was smaller than that of normal mice.As for the mice treated with AdipoRon orally, the pancreatic tissue was full and closely arranged, and the islet was slightly smaller.Compared with NC group, the levels of TNF-α in pancreas and spleen of DM group were increased markedly, the levels of INSR and IRS-1 were decreased, the spleen coefficient, p-IR-1 protein level and insulin mRNA expression in pancreas were decreased, all were significant statistically (P<0.05).Compared with DM group, the levels of TNF-α in pancreas and spleen of AdipoRon groups were decreased, the levels of INSR and IRS-1 in pancreas and spleen of AdipoRon groups were increased, while the spleen coefficient was increased (P<0.05).The p-IRS-1 protein level and insulin mRNA expression in pancreas in DM+H group were increased (P<0.05).Compared with DM + L group, the level of TNF-α was decreased, and the levels of INSR and IRS-1 were significantly increased (P<0.05) in DM + H group (P<0.05). CONCLUSION: Oral administration of AdipoRon can protect the spleen and pancreas of diabetic mice by decreasing the inflammatory response, up-regulating the expression of INSR, and increasing p-IRS-1 level in diabetic mice.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Piperidinas , Baço , Animais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inflamação , Insulina , Proteínas Substratos do Receptor de Insulina/efeitos dos fármacos , Masculino , Camundongos , Pâncreas , Piperidinas/farmacologia , Distribuição Aleatória , Receptor de Insulina/efeitos dos fármacos , Baço/efeitos dos fármacos
7.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(2): 140-144, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-31250605

RESUMO

OBJECTIVE: To investigate the therapeutic effects of the black buckwheat leaf (BBL) in type 2 diabetes mellitus mice and its effects on pancreas and spleen. METHODS: Forty male C57 / B16 mice (SPF) were randomly divided into normal control (NC) group (n=10) and the experimental group (n=30), the experimental group were fed with high sugar and high fat, combined with intraperitoneal injection of streptozotocin in small dose to establish the model of type 2 diabetes mellitus (T2DM). Those thirty model mice were randomly divided into 3 groups (n=10), diabetes mellitus group (DM), low dose of BBL (DM+L) treated group, high dose of BBL (DM+H) treated group. The mice in the NC group and the DM group were given normal saline per day, and the DM+L group and DM+H group were treated with black tartary buckwheat at the doses of 0.21g/kg·d-1 and 0.42g/kg·d-1 respectively. After 14 days. All mice were executed by cervical dislocation, then blood samples were collected, pancreas and spleen were removed for subsequent experiments. The serum levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TCH) and insulin were detected. TNF-α protein in spleen tissue was detected by ELISA kit. The morphology of pancreas tissue was observed by HE staining, and the spleen coefficient was calculated. The expression levels of insulin receptor substrate-1(IRS-1) mRNA and IRS-1 protein in pancreatic tissue were detected. RESULTS: Compared with the control group, the serum levels of FBG, TC and TCH in the model group were increased significantly, while the serum level of insulin was decreased significantly (P<0.05), the expression of TNF-α protein in spleen tissues was obviously raised, the expressions of IRS-1 mRNA and IRS-1 protein in pancreatic tissue in model group were decreased significantly (P<0.05). Compared with the model group, the serum levels of FBG, TC and TCH were decreased significantly in the BBL treated groups. The serum insulin level, spleen coefficient, TNF-α protein expression level in spleen tissue, IRS-1 mRNA expression and IRS-1 protein expression levels in pancreatic tissue in BBL treated group were increased significantly (P< 0.05). High-dose black tartary buckwheat leaves (0.42g/kg·d-1) exerted a more significant effect. CONCLUSION: Stem and leaf of black bitter buckwheat has significant therapeutic effects on reducing blood sugar and blood fat in type 2 diabetic mice, and has certain protective effects on pancreas and spleen of diabetic mice.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Fagopyrum/química , Pâncreas/efeitos dos fármacos , Baço/efeitos dos fármacos , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Folhas de Planta/química , Caules de Planta/química , Distribuição Aleatória , Estreptozocina
8.
Ecotoxicol Environ Saf ; 181: 224-230, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31195231

RESUMO

Cadmium (Cd), as a kind of ubiquitous and highly toxic heavy metal pollutants, has been known to result in immunotoxicity in animals. As a multifunctional bioactivity disaccharide, trehalose (Tre) is characterized by antioxidative, antiapoptotic, and accelerating autophagy. In this study, Sprague-Dawley (SD) rats were fed with cadmium chloride (CdCl2) and/or Tre to explore the molecular mechanisms of Tre-protected against spleen injury caused by Cd exposure. Firstly, the results showed that Tre partially recovered splenic pathological changes induced by Cd exposure. Secondly, Tre dramatically declined the level of methane dicarboxylic aldehyde (MDA) and elevated the level of total antioxidant capacity (T-AOC) to weaken oxidative stress caused by Cd exposure in spleen tissue. Moreover, the results showed that Tre significantly suppressed Cd-induced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and up-regulated the protein expression of nuclear Nrf2. Thirdly, Tre remarkably reduced the protein expression of sequestosome 1 (p62/SQSTM1) and microtubule-associated protein light chain 3II (LC-3II) to restore autophagy inhibition induced by Cd exposure. Finally, the results of TUNEL and the expression of apoptosis marker proteins showed that Tre significantly inhibited Cd-induced apoptosis in spleen tissue to exert its protective effects. In summary, the results indicated that Tre modulated Nrf2 signaling pathway, which interacted with apoptosis and autophagy to against Cd-induced spleen injury, providing potential therapeutic strategies for the prevention and treatment of Cd-related immune system diseases.


Assuntos
Cloreto de Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Baço/efeitos dos fármacos , Trealose/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Baço/metabolismo , Baço/patologia
9.
Life Sci ; 231: 116534, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31173782

RESUMO

N-acetylcysteine (NAC) has largely been used as an effective chemo- protective agent owing to their beneficial effect in restoring several physiological parameters and relieving oxidative stress. Interestingly, it has been suggested that NAC mechanisms of action extend beyond being a precursor to the antioxidant glutathione and that they may involve several neurotropic and inflammatory pathways. Exposure to fenitrothion, an organophosphorus insecticide, promotes oxidative stress and induces several deleterious changes in the immune response and various tissues including cerebrum and spleen. The main objective of our study was to investigate ameliorative efficacy of N-acetylcysteine for immunological and neurological alterations and oxidative DNA damage induced by fenitrothion toxicity in cerebrum and spleen tissues of male rats. Our results revealed that oral exposure to fenitrothion for 30 days caused a reduction in the erythrocyte count in addition to leukocytosis, lymphocytosis, and neutrophilia. Also, this route of administration increased the serum levels of LDH, TNF-α, and IL-2 with reduction in serum immunoglobulins (IgG & IgM) concentrations. Furthermore, a significant downregulation in the antioxidant markers (GSH & SOD) with an elevation of free radical (MDA) levels were noticed. Regarding the brain, fenitrothion administration inhibited AchE activity and increased brain GABA, serotonin and dopamine levels. Moreover, it induced an elevation in oxidative DNA damage indicated by 8-hydroxy 2-deoxyguanosine (8OH2dG) and mRNA expression of pro-apoptotic genes, including Bax, and p53, but Bcl-2 expression was reduced. N-acetylcysteine co-treatment restored the normal physiological tone in most of these parameters. Immunostaining for GFAP and Caspase-3 markers in the brain and spleen tissues were increased respectively. In conclusion, N-acetylcysteine supplementation has an ameliorative effect against immunotoxic, neurotoxic and oxidative DNA damage induced by fenitrothion exposure.


Assuntos
Acetilcisteína/farmacologia , Encéfalo/efeitos dos fármacos , Dano ao DNA , Fenitrotion/toxicidade , Inseticidas/toxicidade , Baço/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Caspase 3/metabolismo , Interações de Medicamentos , Fenitrotion/administração & dosagem , Inseticidas/administração & dosagem , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Baço/metabolismo
10.
Life Sci ; 230: 76-83, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31128136

RESUMO

AIM: In this study, in vivo biodistribution, clearness and toxicity of curcumin capped iron oxide nanoparticles (Cur-IONPs) were addressed in different body organs. MATERIALS AND METHODS: The physicochemical properties of the prepared Cur-IONPs were investigated. Long term (3 weeks) biodistribution, clearness and toxicity were assessed for a single-dose administration of Cur-IONPs (5 mg/kg). The iron content in liver, kidney, spleen and brain was quantified using atomic absorption spectroscopy. Serum biochemical parameters were also measured. KEY FINDINGS: The integrated in vivo results demonstrated that Cur-IONPs was mostly taken up in the liver and spleen reaching its highest levels on days 1 and 2, respectively. In the brain, the results showed significant accumulation of Cur-IONPs between 1 h to 1-day post injection. This represented the successful penetration Cur-IONPs across the blood-brain barrier. Serum biochemical analysis demonstrated a temporal disturbance in the performance of body organs. Also, the body weights showed no alteration throughout the experiment. SIGNIFICANCE: It has been deduced that the promising green synthesized Cur-IONPs as an "All in One" nanoplatform is safe enough to be used in diagnostic and therapeutic purposes.


Assuntos
Curcumina/metabolismo , Curcumina/farmacologia , Nanopartículas Metálicas/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Curcumina/toxicidade , Compostos Férricos/metabolismo , Compostos Férricos/farmacologia , Ferro/metabolismo , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Nanopartículas Metálicas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Baço/efeitos dos fármacos , Distribuição Tecidual
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
12.
Eur J Med Chem ; 176: 456-475, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31128448

RESUMO

H2S donors are substitutes of H2S with various biological activities like inhibiting the inflammatory response and protecting myocardial cells from injury. In order to confirm whether the H2S donors have drug-like properties, two series thiophosphamide H2S donors were evaluated including toxicity, bioactivity and pharmacokinetic properties in vivo and in vitro. The following results were obtained. Firstly, all the compounds released H2S under measuring condition; with the increase of pH value, the H2S release rate of all the compounds decreased and the amount reduced, but pH value had little effect on the maximum release of H2S. Secondly, in the organs and tissues of rats, the compounds released H2S in the same way as in PBS. In plasma, compound 1 reached the Cmax after administration 55 min, and no compound 1 was detected after 12 h; for compound 18, the Cmax reached only after administration 100 min, and after 6 h, compound 18 was not detected; in organs and tissues, the H2S-release rates were different from those in PBS, but the mechanism of H2S release was the same. Thirdly, in the test of toxicity, all the compounds displayed low toxicities to 5 cancer cells and W138 cell lines; compounds 1 and 18 had slight effect on the physiological tissue and function of rat liver at low concentration; the compounds had almost no effect on the hatching rate, survival rate of zebrafish embryos, and the spontaneous movement of zebrafish embryos at below 0.5 µM, but when they were over 1 µM, the compounds displayed inhibitory effect in the manner of concentration dependence. Fourthly, in the course of anti-inflammatory test, all the tested compounds significantly reduced the level of TNF-α and increased the level of IL-10; when they were 100 µM, the levels of IL-10 were three times as high as those in the control group. Among them, compounds 10 and 18 displayed stronger activities than the others. In addition, the compounds protected H9c2 cells from injure and improved myocardial injury through anti-oxidation pathway. In summary, the compounds have druglike properties due to low toxicity, better activity and good pharmacokinetic property. Therefore, they have potential to be as candidates to investigate further.


Assuntos
Anti-Inflamatórios/farmacocinética , Cardiotônicos/farmacocinética , Sulfeto de Hidrogênio/metabolismo , Compostos Organotiofosforados/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/toxicidade , Cardiotônicos/síntese química , Cardiotônicos/química , Cardiotônicos/toxicidade , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Feminino , Humanos , Sulfeto de Hidrogênio/sangue , Sulfeto de Hidrogênio/química , Concentração de Íons de Hidrogênio , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Modelos Químicos , Miocárdio/metabolismo , Compostos Organotiofosforados/síntese química , Compostos Organotiofosforados/química , Compostos Organotiofosforados/toxicidade , Células RAW 264.7 , Ratos Wistar , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Temperatura Ambiente , Teratogênios/síntese química , Teratogênios/química , Teratogênios/farmacocinética , Teratogênios/toxicidade , Peixe-Zebra
13.
J Microbiol Biotechnol ; 29(5): 739-748, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31030453

RESUMO

Cheonggukjang and chaga mushrooms have numerous health benefits, and have been used in alternative medicine. Therefore, a powder mixture of 98: Cheonggukjang and 2: Chaga extracts was fermented with Lactobacillus acidophilus KCTC3925 (FCC) and its anti-obesity effects in high-fat diet (HFD)-induced obese mice were determined. Five-week-old male ICR mice were fed a normal diet or HFD in the presence or absence of 3% and 5% FCC by weight (n = 10 per group). After 12 weeks, the mice were sacrificed, and the serum and tissue samples were collected for analysis. Body weight and epididymal fat pad weight were significantly lowered in the 3% and 5% FCC groups compared with those in the HFD control group (p < 0.01). FCC supplementation suppressed serum triglyceride and increased serum HDL-C levels (p < 0.01). Serum GOT, GPT, and leptin levels, hepatic COX-2 mRNA expression, and splenic COX-2 and IL-4 mRNA expression were significantly higher in the HFD groups than in the control group (p > 0.05); however, except for splenic IL-4 levels, the increases were significantly attenuated by FCC supplementation. Expression of ICAM-1, an aortic inflammatory marker, was significantly increased in the HFD group; this effect was suppressed in the 3% FCC group (p < 0.01) but not in the 5% FCC group. FCC suppressed the body weight and epididymal fat pad weight gain, as well as inflammatory responses in the liver and spleen of HFD-fed mice. Thus, FCC supplementation will be beneficial for the treatment of obesity-related effects.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Alimentos Fermentados , Fígado/efeitos dos fármacos , Obesidade/tratamento farmacológico , Baço/efeitos dos fármacos , Tecido Adiposo , Animais , Peso Corporal , Ciclo-Oxigenase 2/metabolismo , Fermentação , Lactobacillus acidophilus , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Obesos , RNA Mensageiro/metabolismo , Baço/patologia , Triglicerídeos/sangue
14.
Exp Parasitol ; 201: 49-56, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31029700

RESUMO

Trypanosoma congolense is an important pathogen that wreaks havoc in the livestock industry of the African continent. This study evaluated the in vivo antitrypanosomal activity of geranylacetone and its ameliorative effect on the disease-induced anaemia and organ damages as well as its inhibitory effects against trypanosomal sialidase using in vitro and in silico techniques. Geranylacetone was used to treat T. congolense infected rats, at a dose of 50 and 100 mg/kg BW, for 14 days where it was found to reduce the parasite burden in the infected animals. Moreover, 100 mg/kg BW of geranylacetone significantly (p < 0.05) ameliorated the anaemia, hepatic and renal damages caused by the parasite. This is in addition to the alleviation of the parasite-induced hepatosplenomegaly and upsurge in free serum sialic acid levels in the infected animals which were associated with the observed anaemia amelioration by the compound. Consequently, bloodstream T. congolense sialidase was partially purified on DEAE cellulose column and inhibition kinetic studies revealed that the enzyme was inhibited by geranylacetone via an uncompetitive inhibition pattern. In silico analysis using molecular docking with Autodock Vina indicated that geranylacetone binds to trypanosomal sialidase with a minimum free binding energy of -5.8 kcal/mol which was mediated by 26 different kinds of non-covalent interactions excluding hydrogen bond whilst Asp163 and Phe421 had the highest number of the interactions. The data suggests that geranylacetone has trypanostatic activity and could protect animals against the T. congolense-induced anaemia through the inhibition of sialidase and/or the protection of the parasite-induced hepatosplenomegaly.


Assuntos
Anemia/prevenção & controle , Terpenos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma congolense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Anemia/tratamento farmacológico , Anemia/parasitologia , Animais , Feminino , Coração/efeitos dos fármacos , Coração/parasitologia , Concentração Inibidora 50 , Rim/efeitos dos fármacos , Rim/parasitologia , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/parasitologia , Fígado/patologia , Masculino , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Neuraminidase/antagonistas & inibidores , Neuraminidase/química , Tamanho do Órgão/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Wistar , Rubiaceae/química , Baço/efeitos dos fármacos , Baço/parasitologia , Baço/patologia , Terpenos/química , Terpenos/uso terapêutico , Tripanossomicidas/química , Tripanossomicidas/uso terapêutico , Trypanosoma congolense/enzimologia , Tripanossomíase Africana/complicações , Tripanossomíase Africana/parasitologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-31028929

RESUMO

This study aimed to evaluate whether dietary supplementation with diphenyl diselenide (Ph2Se2) would prevent the impaired immune and inflammatory responses elicited by methylmercury chloride (CH3HgCl) via protective effects on purinergic signaling in fish immune organs. Tissue and lymphocytic nucleoside triphosphate diphosphohydrolase (NTPDase) activity for adenosine triphosphate (ATP) and adenosine diphosphate (ADP) was downregulated in the head kidney and spleen of grass carp (Ctenopharyngodon idella) exposed to CH3HgCl. Concomitantly, adenosine deaminase (ADA) activity was upregulated. Further, nucleotide-binding oligomerization domain-like receptor (NLRP3) inflammasome gene expression was upregulated in the spleen and head kidney of CH3HgCl-exposed grass carp. Dietary supplementation with Ph2Se2 ameliorated these CH3HgCl-mediated alterations on purinergic enzymes, and their activities returned to baseline levels (except NTPDase activity for ADP). Based on these results, purinergic signaling in immune organs and lymphocytes can be considered a pathway linked to pro-inflammatory effects during exposure to environmental CH3HgCl concentrations, which may contribute to mortality of the affected fish. Since dietary supplementation with 3 mg Ph2Se2/kg in the feed prevented the CH3HgCl-induced alterations, it can be considered a potential suitable treatment to prevent impaired immune and inflammatory responses caused by Hg.


Assuntos
Derivados de Benzeno/farmacologia , Carpas , Doenças dos Peixes/induzido quimicamente , Rim Cefálico/efeitos dos fármacos , Compostos de Metilmercúrio/toxicidade , Compostos Organosselênicos/farmacologia , Baço/efeitos dos fármacos , Ração Animal/análise , Animais , Dieta/veterinária , Suplementos Nutricionais , Doenças dos Peixes/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamassomos/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais
16.
Toxicol Lett ; 311: 49-57, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31014974

RESUMO

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener of dioxins, is a persistent and ubiquitous environmental contaminant. Although the immunotoxic effects of TCDD have been reported, the mechanisms underlying these effects are still unclear. In this study, we have determined the toxic effects of TCDD on thymocytes and splenic T cells with in vitro cell culture systems. Magnetically isolated mouse splenic Th cells, Treg cells and the mixed spleen lymphocytes (SLC) were cultured and treated with TCDD and the differentiation of CD4 Th cells was determined by flow cytometery. Our results showed that different concentrations of TCDD caused immunotoxic effects through different toxicological mechanisms in both the purified mouse splenic Th cells and the mixed SLC. The low dose exposure to TCDD triggered regulatory effects in the immune system, while the high dose TCDD exposure resulted in severe immune toxicity. Notably, a decline of Treg subset was observed, suggesting an imbalanced immune regulation by TCDD treatment, as well as a possible decrease of TCDD's indirect effects on bystander immune cells. Our CD4 Th subset co-culture experiments showed that TCDD-induced pathobiology depended on immune cell balance, suggesting that cytokine-induced microenvironments further modulated toxic effects associated with TCDD exposure.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Baço/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Timócitos/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Microambiente Celular , Técnicas de Cocultura , Citocinas/imunologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Baço/imunologia , Baço/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Timócitos/imunologia , Timócitos/metabolismo
17.
Biomed Pharmacother ; 112: 108709, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30970514

RESUMO

OBJECTIVE: Poria cocos polysaccharide (PCP) is the major active ingredients of P. cocos and possesses various pharmacological effects, including anti-oxidative and anti-apoptosis effects and activity against cancer. This study investigated the immunomodulatory mechanism by which PCP acts on RAW 264.7 macrophages and LLC tumors in mice. METHODS: The concentrations of nitric oxide, and Th1, Th2, and Th17 cytokines were examined by Griess reaction and using a bead-based cytokine assessment kit. qRT-PCR and western blotting were used to investigate relevant signaling molecule expression. RESULTS: Levels of nitric oxide, IL-2, IL-6, IL-17 A, TNF, and IFN-γ were increased by PCP while levels of IL-4 and IL-10 were unaffected. The addition of TAK-242 (TLR4 inhibitor) or assessment in C57BL/10ScNJ (TLR4-deficient) mice markedly reduced this effect. In C57BL/10 J (TLR4+/+wild-type) mice, the indices of organ immune activity were all elevated, and oral PCP delivery resulted in a significant reduction in tumor volume over a 25 day period. Relative to controls, TLR4, MyD88, TRAF-6, p-NF-κB and p-c-JUN expression significantly increased, while TRAM expression did not change. Nevertheless, there was no PCP-dependent activation of MyD88, TRAF-6, TRAM, p-NF-κB or p-c-JUN in TLR4-deficient mice. CONCLUSION: These results support the concept that PCP may exhibit immunomodulatory activity through TLR4/TRAF6/NF-κB signaling both in vitro and in vivo.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , NF-kappa B/metabolismo , Polissacarídeos/uso terapêutico , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/metabolismo , Wolfiporia/química , Animais , Antineoplásicos/isolamento & purificação , Carcinoma Pulmonar de Lewis/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Feminino , Fatores Imunológicos/isolamento & purificação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico/metabolismo , Polissacarídeos/isolamento & purificação , Células RAW 264.7 , Transdução de Sinais , Baço/efeitos dos fármacos , Baço/imunologia , Timo/efeitos dos fármacos , Timo/imunologia
18.
Chem Biodivers ; 16(6): e1900062, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30983116

RESUMO

Seven new polyhydroxypregnane glycosides, named cynotophyllosides P-V, together with three known analogs were isolated from the roots of Cynanchum otophyllum C.K.Schneid. Their structures were elucidated by a variety of spectroscopic techniques, as well as acid-catalyzed hydrolysis. All isolates were tested for their immunological activities in vitro against Con A- and LPS-induced proliferation of mice splenocytes. Immunoenhancing (for 1, 9) and immunosuppressive (for 2) activities were observed. Furthermore, cynotophylloside R (3) showed immunomodulatory as it enhanced the proliferation of splenocytes in low concentration and suppressed immune cells in concentration more than 1.0 µg/ml.


Assuntos
Cynanchum/química , Glicosídeos/química , Pregnanos/química , Animais , Proliferação de Células/efeitos dos fármacos , Cynanchum/metabolismo , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Conformação Molecular , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismo
19.
Int J Mol Sci ; 20(6)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909528

RESUMO

Research has shown that nano-copper (nano-Cu) can cause damage to the spleen and immune system yet their mechanisms of cytotoxicity are poorly understood. Our aim is to explore the potential immunotoxicity in the spleen of rats after nano-Cu exposure. The results of hematologic parameters, lymphocyte subsets, immunoglobulins, and histopathology indicated that copper obviously changed the immune function of the spleen. The levels of antioxidants (SOD, CAT, GSH-Px), oxidants (iNOS, NO, MDA), and anti-oxidative signalling pathway of Nrf2 (Nrf2 and HO-1) were strongly induced by nano-Cu. The expression of mRNA and protein of pro-/anti-inflammatory (IFN-γ, TNF-α, MIP-1α, MCP-1, MIF, IL-1/-2/-4/-6) cytokines were increased by nano-Cu. The expression of regulatory signal pathways, MAPKs and PI3-K/Akt were activated, which might be involved in the inflammatory responses and immunomodulatory processes of sub-acute nano-Cu exposure. The immune function of the spleen was repressed by nano-Cu induced oxidative stress and inflammation.


Assuntos
Cobre/toxicidade , Nanopartículas Metálicas , Baço/efeitos dos fármacos , Animais , Biomarcadores , Cobre/química , Cobre/metabolismo , Expressão Gênica , Masculino , Estresse Oxidativo , Ratos , Baço/metabolismo , Testes de Toxicidade
20.
Environ Toxicol ; 34(7): 788-795, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30843661

RESUMO

The present study was to evaluate the radiomitigative effect of naringenin (NRG) on the modulation of ionizing radiation (IR)-induced spleen injury. Rats were exposed to 12 Gy (3Gy/two times/week). NRG (50mg/Kg), was orally given one hour after the first radiation dose, and daily continued during the irradiation period. Rats were sacrificed 1 day after the last dose of radiation. NRG showed a significant decrease of malondialdehyde, hydrogen peroxide with a significant elevation of superoxide dismutase, catalase and glutathione peroxidase activities and glutathione content. Moreover, NRG confirmed the intracellular defense mechanisms through activation of nuclear factor (erythroid-derived 2)-like2 (Nrf2) and haem oxygenase-1 (HO-1) levels and their protein expression. In addition, NRG deactivated the nuclear factor-κB (NF-κB) and reduced the pro-inflammatory cytokines. Further, NRG showed positive modulation in the haematological values (WBCs, RBCs, Hb, Hct% and PLt). In conclusion, these results suggested that NRG reversed the IR-induced redox-imbalance in the rat spleen.


Assuntos
Flavanonas/farmacologia , Heme Oxigenase-1/fisiologia , Fator 2 Relacionado a NF-E2/fisiologia , Estresse Oxidativo , Lesões por Radiação/prevenção & controle , Esplenopatias/prevenção & controle , Animais , Catalase/metabolismo , Raios gama/efeitos adversos , Glutationa/metabolismo , Heme Oxigenase-1/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Peróxido de Hidrogênio/metabolismo , Masculino , Malondialdeído/metabolismo , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Estresse Oxidativo/efeitos da radiação , Lesões por Radiação/etiologia , Lesões por Radiação/metabolismo , Ratos , Ratos Wistar , Fatores de Risco , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/efeitos da radiação , Esplenopatias/etiologia , Esplenopatias/metabolismo , Superóxido Dismutase/metabolismo
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