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1.
Mutat Res ; 849: 503129, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32087850

RESUMO

In vitro genetic toxicology assays are used to assess the genotoxic potential of chemicals or mixtures. They measure chromosome damage (e.g., micronucleus [MN] formation) or gene mutation, and different combinations of data generated from such assays are evaluated in concert in order to identify genotoxic hazards. Mode-of-action (MoA) information is also fundamental to understanding any apparent genotoxic response. In view of the importance of these types of data for full characterization of genotoxic potential, we leveraged relevant endpoints already established in the human TK6 cell line to develop a single integrated assay that measures MN formation, gene mutation (at the thymidine kinase locus), and MoA (DNA damage response biomarkers). Several prototypical direct-acting genotoxins (methyl methanesulfonate, mitomycin C, and 4-nitroquinoline 1-oxide), pro-genotoxins (benzo[a]pyrene and cyclophosphamide monohydrate), and one non-DNA reactive genotoxin (vinblastine sulfate) were assessed in the approach and found to elicit genotoxic profiles that were generally consistent with their MoA. In contrast, the non-genotoxic agents D-mannitol and (2-chloroethyl) trimethyl-ammonium chloride induced negligible effects on all endpoints up to a top concentration of 10 mM. Sodium diclofenac, presumed to be non-genotoxic, provoked an induction in the phosphoserine10-H3-positive cell population within a small window of concentrations (0.157-0.314 mM), as well as increases in γH2AX, nuclear p53, and MN at higher concentrations, although it had no effect on the mutation frequency endpoint. G2M cell cycle arrest was also largely observed in cells that exhibited genotoxicity in the in vitro MN assay. The TK6 cell-based integrated assay represents an in vitro approach that permits comprehensive genotoxicity analysis in a human-relevant test system. Moreover, its vis-à-vis nature may facilitate further comprehension of the range of effects that can manifest in human cells in response to DNA-damaging agents.


Assuntos
Linfócitos/efeitos dos fármacos , Mutagênese , Testes de Mutagenicidade/normas , Mutação , Timidina Quinase/genética , 4-Nitroquinolina-1-Óxido/toxicidade , Benzo(a)pireno/toxicidade , Linhagem Celular Tumoral , Ciclofosfamida/toxicidade , DNA/genética , DNA/metabolismo , Dano ao DNA , Diclofenaco/toxicidade , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Regulação da Expressão Gênica , Humanos , Linfócitos/citologia , Linfócitos/metabolismo , Metanossulfonato de Metila/toxicidade , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Mitomicina/toxicidade , Timidina Quinase/metabolismo , Vimblastina/toxicidade
2.
Artigo em Inglês | MEDLINE | ID: mdl-31982542

RESUMO

Cyclophosphamide (CPA) is an alkylating agent used for cancer chemotherapy, organ transplantation, and autoimmune disease treatment. Here, mRNA sequencing and high-resolution respirometry were performed to evaluate the alterations of Drosophila melanogaster gene expression fed with CPA under acute (0.1 mg/mL, for 24 h) and chronic (0.05 mg/mL, for 35 days) treatments. Differential expression analysis was performed using Cufflinks-Cuffdiff, DESeq2, and edgeR software. CPA affected genes are involved in several biological functions, including stress response and immune-related pathways, oxi-reduction and apoptotic processes, and cuticle and vitelline membrane formation. In particular, this is the first report of CPA-induced mitochondrial dysfunction caused by the downregulation of genes involved with mitochondria constituents. CPA treatment also changed the transcription pattern of transposable elements (TEs) from the gypsy and copia superfamilies. The results presented here provided evidence of CPA mitochondrial toxicity mechanisms and that CPA can modify TEs transcription in Drosophila flies.


Assuntos
Ciclofosfamida/toxicidade , Elementos de DNA Transponíveis/genética , Proteínas de Drosophila/genética , Drosophila melanogaster , Expressão Gênica , Mitocôndrias , Animais , Apoptose , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Oxirredução , Peptídeo Hidrolases/genética , Retroelementos/genética
3.
Life Sci ; 239: 116999, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31654746

RESUMO

AIMS: The present study aimed to investigate the effects of cyclophosphamide (Cytoxan, CTX) on premature ovarian failure (POF) in mice and its regulatory mechanisms by transcriptome analysis. MAIN METHODS: Female C57BL/6 mice were treated with a single intraperitoneal injection of 70 mg/kg CTX. Serum levels of estradiol (E2) and follicle stimulating hormone (FSH) were measured by enzyme-linked immunosorbent assay (ELISA), and follicular structure differences were observed by hematoxylin and eosin (H&E) staining. The main mechanism of POF was investigated by RNA-seq data, protein-protein interaction (PPI) networks and qPCR analysis. KEY FINDINGS: The serum levels of E2 were significantly decreased and those of FSH were significantly increased compared to the control group. The ovarian weights of the mice in the CTX group were reduced, and abnormal follicular structures were also observed in the CTX group. The RNA-seq data show that the downregulated genes were related to the cholesterol biosynthesis pathway. The PPI network and qPCR analyses further confirm that the PPAR signaling pathway and the ovarian infertility genes were also involved in blocking the cholesterol biosynthesis pathway. The differences were statistically significant. SIGNIFICANCE: Our results indicate that CTX may exert its anti-tumor effects by inactivating the cholesterol biosynthesis pathway, and simultaneously reducing the supply of estrogen precursor materials, ultimately leading to the occurrence of POF. Our data provided a preliminary theoretical basis for resolving the clinical toxicity and side effects of CTX.


Assuntos
Antineoplásicos Alquilantes/toxicidade , Colesterol/biossíntese , Ciclofosfamida/toxicidade , Perfilação da Expressão Gênica , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/metabolismo , Animais , Regulação para Baixo/efeitos dos fármacos , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/biossíntese , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Receptores Ativados por Proliferador de Peroxissomo/genética , Insuficiência Ovariana Primária/genética , Mapas de Interação de Proteínas
4.
Regul Toxicol Pharmacol ; 108: 104472, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494191

RESUMO

The OECD guideline 407 outlines the conduct of 28-day studies in rodents to detect systemic toxicity with focus on endocrine and immunotoxic effects. It was validated with the rat as preferred model species. Justification is required for other rodent species, as an increased variability is expected compared to the rat. We investigated the variability of organ weights in the mouse and compared this to data published for the rat in the validation report of test guideline 407. Furthermore, the influence of the immunotoxic model substance cyclophosphamide on spleen and thymus weights in the mouse in immunotoxicity studies (duration 28 days) is reported and discussed, an immunotoxic model substance was not included in the validation report. Historical control data were compiled for mouse studies performed according to OECD 407 and for immunotoxicity studies between 2008 and 2013 at BASF SE. For absolute weights, the coefficient of variation was determined for each study group and compared with the rat. Adrenal glands, ovaries and to lesser degree testes and prostate showed higher coefficients of variation in the mouse (most pronounced in adrenal glands in male animals: rat 5%-17%, CD1 mouse 20%-51%). Effects of cyclophosphamide were best detected measuring the thymus weight.


Assuntos
Variação Biológica Individual , Peso Corporal , Grupos Controle , Tamanho do Órgão , Testes de Toxicidade Subaguda , Glândulas Suprarrenais/anatomia & histologia , Glândulas Suprarrenais/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Ciclofosfamida/toxicidade , Feminino , Genitália/anatomia & histologia , Genitália/efeitos dos fármacos , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Imunossupressores/toxicidade , Rim/anatomia & histologia , Rim/efeitos dos fármacos , Fígado/anatomia & histologia , Fígado/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Ratos , Especificidade da Espécie , Baço/anatomia & histologia , Baço/efeitos dos fármacos , Timo/anatomia & histologia , Timo/efeitos dos fármacos
5.
Chin J Nat Med ; 17(8): 600-607, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31472897

RESUMO

To recognize the potential medicinal value of the Dendrobium sonia, polysaccharide (DSP) was extracted, purified, and investigated for its immunomodulatory activity. In vitro, DSP was shown to enhance the viability (MTT assay) and phagocytosis of macrophages. In cyclophosphamide-induced immunosuppressed mice, DSP increased serum levels of TNF-α, IL-6 and IFN-γ (enzyme-linked immunosorbent assay, ELISA), and ameliorated the imbalance of the community of gut microbiota as detected by 16S ribosomal RNA gene sequencing. These results suggest that DSP might be beneficial for patients under immunosuppressed conditions.


Assuntos
Dendrobium/química , Disbiose/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hospedeiro Imunocomprometido , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Animais , Ciclofosfamida/toxicidade , Citocinas/sangue , Disbiose/induzido quimicamente , Disbiose/imunologia , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos , Monossacarídeos/química , Fagocitose/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polissacarídeos/química , Células RAW 264.7
6.
Chin J Nat Med ; 17(7): 535-544, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31514985

RESUMO

The aim of this study is to investigate the protective effects of a small molecular fraction (SMF) of Polygoni multiflori Radix Praeparata (PMRP) in a cyclophosphamide (CTX) induced anemia mouse model. Small molecular fraction of PMRP was prepared and identified by high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS). In pharmacology, we examined the peripheral hemogram and thymus and spleen index. The content of granulocyte-macrophage colony-stimulating factor (GM-CSF) in serum was mensurated by enzyme-linked immunosorbent assay (ELISA); The level of superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) in serum and spleen tissue homogenate were detected, and glutathione peroxidase (GSH-PX) was assayed in spleen. The results show that SMF can significantly accelerate the recovery of peripheral hemogram, increase the activity of antioxidant enzymes and GM-CSF in serum and spleen. SMF also increases the number of spleen cells, improves bone marrow pathology. In conclusion, the SMF of PMRP promoted the recovery of hematopoietic function in a CTX-induced anemia mouse, which can support SMF to be used as an adjunct to chemotherapy to counteract its side effects.


Assuntos
Anemia/tratamento farmacológico , Ciclofosfamida/toxicidade , Hematopoese/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polygonum/química , Anemia/induzido quimicamente , Animais , Antioxidantes/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Masculino , Camundongos Endogâmicos ICR , Estrutura Molecular , Fitoterapia , Extratos Vegetais/química , Raízes de Plantas/química , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia , Timo/efeitos dos fármacos , Timo/metabolismo
7.
Life Sci ; 236: 116867, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31520598

RESUMO

AIM: Cyclophosphamide (CP) is a potent anticancer and immunosuppressant drug. Studies have shown significant oxidative stress and cognitive impairment but neuroinflammatory and histological aberrations with its administration is underexplored. Nerolidol (NER) is a lipophilic bioactive molecule with antioxidant and anti-inflammatory properties but it has not been explored for neuroprotective potential in CP-induced neurotoxic manifestations. Therefore, in the present study, we aimed to evaluate the neuroprotective potential of NER in CP-induced neuroinflammation and associated comorbid conditions like depression and cognitive dysfunctions. MATERIALS AND METHOD: In-silico study using Schrödinger software was used to assess the binding affinity of NER with Nrf2. In the In vivo study, NER 200 and 400 mg/kg p.o. were given from 1st day to 14th day. CP 200 mg/kg, i.p., was administered on the 7th day. After 24 h of the last dosing, neurobehavioral tests like spontaneous body alternation, passive avoidance and forced swim test were performed. On completion of study, mice were sacrificed, hippocampus and cortex were removed for biochemical estimations, histopathology and immunohistochemistry of p65 NF- κB and Nrf2. KEY FINDINGS: In-silico study showed significant binding of NER into the pocket domain of Nrf2. In-vivo study showed protective effect of NER against CP-induced neuroinflammation, oxidative stress, cognitive impairment and structural abnormalities in the hippocampus and cortex regions. SIGNIFICANCE: Findings of the study suggested that NER is a potential therapeutic molecule which can mitigate CP-induced neurotoxic manifestations via Nrf2 and NF-κB pathway. However, more detailed studies are needed to explicate the mechanism underlying its neuroprotective effect.


Assuntos
Disfunção Cognitiva/prevenção & controle , Ciclofosfamida/toxicidade , Inflamação/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imunossupressores/toxicidade , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Fármacos Neuroprotetores , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Transdução de Sinais
8.
Aquat Toxicol ; 215: 105288, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31526926

RESUMO

Pharmaceuticals are used in medical treatment on a large scale and as a waste contaminate freshwater ecosystems. Growing amount of so-called civilization diseases, such as different type of cancer, significantly contribute to this form of pollution. The aim of the present study was to determine how the exposure to chemotherapeutics: cyclophosphamide (CP) and cisplatin (CDDP), at detected in environment concentrations, influence proteome profile, life history and population parameters of naturally setting surface waters Daphnia pulex and Daphnia pulicaria. The parameters important for crustaceans, survivorship and population growth rate, were importantly decreased by CDDP treatment but not influenced by CP. On the contrary, the individual growth rate was affected only by CP and exclusively in the case of D. pulicaria. In both clones treated with CP or CDDP, decreased number of eggs was observed. Interestingly, Daphnia males were less sensitive to tested chemotherapeutic than females. Proteome profile revealed that tested anticancer pharmaceuticals modified expression of some proteins involved in Daphnia metabolism. Moreover, males exposed to CDDP showed increased level of enzymes participating in DNA repair. Summing up, the contaminating environment chemotherapeutics reduced fitness of naturally occurring Daphnia species. In consequence this may affect functioning of the aquatic food webs.


Assuntos
Antineoplásicos/toxicidade , Daphnia/genética , Poluentes Químicos da Água/toxicidade , Análise de Variância , Animais , Cisplatino/toxicidade , Ciclofosfamida/toxicidade , Daphnia/efeitos dos fármacos , Daphnia/crescimento & desenvolvimento , Feminino , Estágios do Ciclo de Vida/efeitos dos fármacos , Masculino , Proteínas/metabolismo , Proteoma/metabolismo
9.
Chem Biol Interact ; 311: 108776, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31369745

RESUMO

Omeprazole (OM), a prototype proton pump inhibitor, oxidizes thiol groups and induces DNA damage. The aim of this study was to evaluate the oxidative effects of omeprazole and its interactions with ascorbic acid (AA, 50 µM) and retinol palmitate (RP) in proficient and deficient Saccharomyces cerevisiae strains, as well as levels of cytogenetic damage in Sarcoma 180 (S180) cells. Omeprazole was tested at concentrations of 10, 20 and 40 µg/mL, whereas H2O2 (10 mM), cyclophosphamide (20 mg/mL), and saline (0.9% NaCl solution) were employed as stressor, positive control, and negative control, respectively. Results revealed that omeprazole concentration-dependently induces oxidative effects in S. cerevisiae strains. However, omeprazole co-treated with ascorbic acid (50 µM) and retinol palmitate (100 IU) significantly modulated the oxidative damage inflected on the S. cerevisiae strains. Furthermore, omeprazole did not produce micronucleus formation and chromosomal bridges in S180 cells, but induced shoots. Significant increase in karyolysis and karyorrhexis were also observed with the omeprazole treated groups, which was modulated by co-treatment with ascorbic acid and retinol palmitate. Taken all together, it is suggested that ascorbic acid and retinol palmitate can substantially modulate the oxidative damage caused by omeprazole on the S. cerevisiae strains, however, much precaution is recommended with omeprazole and antioxidant co-treatment.


Assuntos
Ácido Ascórbico/farmacologia , Aberrações Cromossômicas/efeitos dos fármacos , Omeprazol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Saccharomyces cerevisiae/efeitos dos fármacos , Vitamina A/análogos & derivados , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclofosfamida/toxicidade , Diterpenos , Peróxido de Hidrogênio/toxicidade , Camundongos , Testes para Micronúcleos , Vitamina A/farmacologia
10.
J Microbiol Biotechnol ; 29(9): 1361-1368, 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31434170

RESUMO

Codium fragile is an edible seaweed in Asian countries that has been used as a thrombolytic, anticoagulant, antioxidant, anti-inflammatory, and immune-stimulatory agent. Ginseng has also been known to maintain immune homeostasis and to regulate the immune system via enhancing resistance to diseases and microorganisms. In this study, anionic macromolecules extracted from C. fragile (CFAM) were orally administered with red ginseng extract (100 mg/kg body weight) to cyclophosphamide-induced immunosuppressed male BALB/c mice to investigate the immune-enhancing cooperative effect of Codium fragile and red ginseng. Our results showed that supplementing CFAM with red ginseng extract significantly increased spleen index, T- and B-cell proliferation, NK cell activity, and splenic lymphocyte immuneassociated gene expression compared to those with red ginseng alone, even though a high concentration of CFAM with red ginseng decreased immune biomarkers. These results suggest that CFAM can be used as a co-stimulant to enhance health and immunity in immunosuppressed conditions.


Assuntos
Adjuvantes Imunológicos/farmacologia , Clorófitas/química , Substâncias Macromoleculares/farmacologia , Panax/química , Extratos Vegetais/farmacologia , Adjuvantes Imunológicos/química , Animais , Ânions/isolamento & purificação , Ânions/farmacologia , Ciclofosfamida/toxicidade , Quimioterapia Combinada , Imunossupressão , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/genética , Linfócitos/citologia , Linfócitos/imunologia , Substâncias Macromoleculares/isolamento & purificação , Masculino , Camundongos Endogâmicos BALB C , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Baço/imunologia
11.
Hum Exp Toxicol ; 38(11): 1266-1274, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446784

RESUMO

Cyclophosphamide (CYP) and methotrexate (MTX) have been evaluated for their ability to induce toxicity in human peripheral blood lymphocytes (PBLs) and the protective role of mitochondrial and lysosomal stabilizing agents. The potential toxicity effects of CYP and MTX were measured in vitro by cellular parameters assays such as cellular viability, reactive oxygen species (ROS) formation, mitochondrial membrane permeability transition (mitochondrial membrane potential (MMP)) collapse, lysosomal membrane damage, intracellular reduced glutathione (GSH), extracellular oxidized glutathione (GSSG), and lipid peroxidation. Separately, human lymphocytes were treated with concentrations of 0.1, 0.2, 0.4, 0.8, and 1.6 ng/mL for CYP and 1, 2, 5, and 10 µg/mL for MTX for 6 h. Statistical evaluations showed that CYP and MTX significantly decreased the cell viability at the three highest concentrations when compared with both the negative and solvent controls. In addition, CYP and MTX were significantly induced ROS formation, MMP collapse, lysosomal membrane damage, lipid peroxidation, and GSH depletion compared with the controls. Mitochondrial and lysosomal protective agents like cyclosporine A and chloroquine, respectively, decreased cytotoxicity and oxidative stress induced by CYP and MTX. The present results indicate that CYP and MTX are toxic to human PBLs and their toxicity could be ameliorated by mitochondrial and lysosomal protective agents.


Assuntos
Antineoplásicos/toxicidade , Ciclofosfamida/toxicidade , Imunossupressores/toxicidade , Linfócitos/efeitos dos fármacos , Metotrexato/toxicidade , Substâncias Protetoras/farmacologia , Adolescente , Adulto , Hidroxitolueno Butilado/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cloroquina/farmacologia , Ciclosporina/farmacologia , Glutationa/metabolismo , Humanos , Linfócitos/metabolismo , Lisossomos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Adulto Jovem
12.
Sci Total Environ ; 692: 503-510, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31351292

RESUMO

Antineoplastic drugs have been identified in surface water and effluents from wastewater treatment and, once in the environment, may be harmful to aquatic organisms, as these compounds are possibly mutagenic, genotoxic, cytotoxic, carcinogenic and teratogenic. This work investigated the photodegradation of cyclophosphamide (CP) and ifosfamide (IF) using ruthenium doped titanate nanowires (Ru-TNW) in distilled water (DW) and in wastewater (WW) from secondary wastewater treatment, under UV-Vis radiation. The results indicated that Ru-TNW showed photocatalytic activity for the two cytotoxic drugs with the half-life (t1/2) of 15.1 min for CP and 12.9 min for IF in WW. Four CP transformation products (TPs) and six IF TPs from the photodegradation process are here reported. These TPs were elucidated by high-resolution mass spectrometry. For both pollutants, the results showed different time profiles for the TPs when WW and DW were used as matrix. Overall, in the WW there was a higher production of TPs and two of them were detected only in this matrix. In other words, environmental matrices may produce different TPs. Degradation pathways were proposed and both drugs bear similarities. Additionally, in silico toxicity were performed by quantitative structure-activity relationship models. The predictions indicated that the TPs, with the exception of one IF TP, presented high mutagenic potential.


Assuntos
Ciclofosfamida/toxicidade , Ifosfamida/toxicidade , Águas Residuárias/análise , Poluentes Químicos da Água/toxicidade , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/toxicidade , Simulação por Computador , Ciclofosfamida/química , Ifosfamida/química , Mutagênicos/química , Mutagênicos/toxicidade , Nanofios/química , Fotólise , Relação Quantitativa Estrutura-Atividade , Titânio/química , Testes de Toxicidade , Raios Ultravioleta , Eliminação de Resíduos Líquidos , Poluentes Químicos da Água/química
13.
BMC Res Notes ; 12(1): 446, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331386

RESUMO

OBJECTIVE: We explored detrimental effects of VCD on non-ovarian tissues such as kidneys and liver 14 days post-drug administration. Twelve rats were randomly assigned into two groups. In VCD group, rats received 160 mg/kgbw VCD intraperitoneally for 15 consequent days. Control rats were injected with VCD-free normal saline. At the respective time point, rats were euthanized, blood and tissue samples were collected. H&E staining was performed to evaluate pathological changes. Serum level of ALT, AST, creatinine and urea were also measured. RESULTS: Histological analysis revealed hyperemia and follicular atresia in the ovaries, indicating successful POF induction in rats. In renal tissue, extensive tubular necrosis, focal hemorrhage, hyaline casts, and interstitial nephritis were observed. Analysis of hepatic tissue showed numerous hemorrhagic foci, chronic cholangitis, and hepatocyte necrosis, indicating apparent VCD toxicity of both hepatic and renal tissues. The biochemical evaluation revealed a tendency of increase in ALT, AST, creatinine, and Urea in VCD-treated rats; however, the values did not reach significant level. In conclusion, the induction of POF in rats by VCD correlates with renal and hepatic damages. Commensurate with data from this study, any conclusions from experiments based on VCD-induced premature ovarian failure rats should be reported with caution.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Ovário/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Aspartato Aminotransferases/sangue , Creatinina/sangue , Ciclofosfamida/administração & dosagem , Ciclofosfamida/toxicidade , Dexametasona/administração & dosagem , Dexametasona/toxicidade , Feminino , Injeções Intraperitoneais , Rim/patologia , Fígado/patologia , Ovário/patologia , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/diagnóstico , Distribuição Aleatória , Ratos Wistar , Teniposídeo/administração & dosagem , Teniposídeo/toxicidade
14.
Fish Shellfish Immunol ; 93: 174-182, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302286

RESUMO

The present study was aimed to evaluate the effects of the cyclophosphamide (CY) exposure (Control, 0.032, 0.32, 1.0, 1.6 and 3.2 mg/mL) on the damage in the peripheral blood leukocytes of blunt snout bream for 24 h, which including cell viability, apoptosis, lactate dehydrogenase (LDH) release, mitochondrial membrane potential (Δѱm), ROS, antioxidant enzyme activity and the relative mRNA levels of apoptosis. Results showed that cell viability and Δѱm effects of CY were greatly reduced, and occurred in a dose-dependent manner. CY exposure (0.32-3.2 mg/mL) significantly increased the LDH release and induced apoptosis accompanied by ΔΨm disruption and ROS generation compared to the control. The cellular ROS was significantly increased with increase of CY level from 0.032 mg/mL to 1 mg/mL and the plateau occurred at 0.32 mg/mL. Additionally CY exposure led to oxidative stress as evidenced by significantly the decrease of SOD and CAT and increase of MDA concentration after treating cells with 3.2 mg/mL of CY. Besides, the relative mRNA levels of caspase-3 in the dose of 0.032, 0.32 mg/mL CY, caspase-9 and interleukins-1ß (IL-1ß) in the dose of 0.32 mg/mL CY, tumor necrosis factor-alpha (TNF-α) in the dose of 0.032 mg/mL CY significantly higher than that of the control. In conclusion, 0.32-3.2 mg/mL CY could lead to cytotoxic effect, inflammatory response and induce the apoptosis of the peripheral blood leukocyte of Megalobrama amblycephala.


Assuntos
Apoptose/efeitos dos fármacos , Ciclofosfamida/toxicidade , Cyprinidae/imunologia , Citotoxinas/toxicidade , Inflamação/veterinária , Estresse Oxidativo/efeitos dos fármacos , Animais , Antineoplásicos/toxicidade , Cyprinidae/fisiologia , Doenças dos Peixes/induzido quimicamente , Doenças dos Peixes/imunologia , Inflamação/induzido quimicamente , Inflamação/imunologia , Leucócitos/imunologia , Poluentes Químicos da Água/toxicidade
15.
Environ Toxicol Pharmacol ; 70: 103201, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31202006

RESUMO

Early and accurate evaluation of immunotoxicity is crucial. However, there are few in vitro models for immunosuppressive evaluation. THP-1 cells has long been used for in vitro sensitivity evaluation. Whether it can be used for immunosuppressive evaluation remains unclear. In this study, effects of immunosuppressant cyclophosphamide (CY) on THP-1 cells were observed while 2, 4-Dinitrochlorobenzene (DNCB) was used as a control. The phenotypes of THP-1 cells, the ability to activate naïve T cells, intracellular reactive oxygen species (ROS) level, gene markers, phagocytic ability and cell apoptosis were detected after THP-1 cells being exposed to different concentrations of CY and DNCB. Both CY and DNCB were able to activate THP-1 cells, but there were a lot of differences in their effects on THP-1 cells, such as the changes in phenotypes, in the ability to activate naïve T cells, in ROS production and in marker gene expression. Firstly, CY down-regulated the expression of CD86 on THP-1 cells while DNCB up-regulated its expression. Secondly, the ability of THP-1 cells to activate naïve T cells was enhanced by CY and suppressed by DNCB. Thirdly, CY raised rapid and transient elevation of ROS level in THP-1 cells, while the effects of DNCB were slower and longer-lasting. Finally, only CY could lead to an increase in heme oxygenase 1 (HMOX1) expression. Taken all these results into account, we suggested that THP-1 cell line possesses the potency to be an in vitro model of immunosuppressive evaluation. And the surface molecule CD86, the ability to activate naïve T cells, the ROS production and the gene marker HMOX1 of THP-1 cells are promising markers.


Assuntos
Ciclofosfamida/toxicidade , Imunossupressores/toxicidade , Linfócitos T/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Técnicas de Cocultura , Humanos , Fagocitose/efeitos dos fármacos , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Células THP-1
16.
Curr Drug Saf ; 14(3): 209-216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31057112

RESUMO

BACKGROUND: Cyclophosphamide (CPA) is the most widely prescribed cancer chemotherapeutic agent which shows serious neurotoxic side effect. Generation of reactive oxygen species at the cellular level is the basic mechanism of cyclophosphamide induced neurotoxicity. Edaravone is the synthetic drug used for brain stroke and has potent antioxidant property. OBJECTIVE: This study aimed to investigate the effect of edaravone on neurobehavioral and neuropathological alteration induced by cyclophosphamide in male rats. METHODS: Twenty eight Sprague-Dawley rats were equally divided into four groups of seven rats in each. The control group received saline, and other groups were given CPA intraperitoneally (100 mg/kg), CPA (100 mg/kg) intraperitoneally + Edaravone (10 mg/kg) orally, or Edaravone (10 mg/kg) orally for one month. RESULTS: Our data showed that CPA significantly elevated brain AChE activity in the hippocampal region. A decrease in the total antioxidant capacity and a reduction in the CAT, SOD, and GPX activity occurred in the brains of the rats exposed to CPA. CPA-treated rats showed a significant impairment in long-termmemory and motor coordination. These results were supported by histopathological observations of the brain. Results revealed that administration of edaravone reversed AChE activity alternation and ameliorated behavioral and histopathological changes induced by CPA. CONCLUSION: This study suggests that co-administration of edaravone with cyclophosphamide may be a useful intriguing therapeutic approach to overcome cyclophosphamide induced neurotoxicity.


Assuntos
Ciclofosfamida/toxicidade , Edaravone/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Proteínas Ligadas por GPI/metabolismo , Masculino , Síndromes Neurotóxicas/enzimologia , Ratos Sprague-Dawley
17.
Chin J Nat Med ; 17(4): 275-290, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31076131

RESUMO

Danggui Buxue Tang (DBT) is a famous Chinese medicinal decoction. Mechanism of DBT action is wide ranging and unclear. Exploring new ways of treatment with DBT is useful. Sprague-Dawley(SD) rats were randomly divided into 3 groups including control (NC, Saline), the DBT (at a dose of 8.10 g-1), and blood deficiency(BD) (Cyclophosphamide (APH)-andCyclophosphamide(CTX)-induced anaemia). A metabolomics approach using Liquid Chromatography-Quadrupole-Time-of-Flight/Mass Spectrometry (LC/Q-TOFMS) was developed to perform the plasma metabolic profiling analysis and differential metaboliteswerescreened according to the multivariate statistical analysiscomparing the NC and BD groups, andthe hub metabolites were outliers with high scores of the centrality indices. Anaemia disease-related protein target and compound of DBT databases were constructed. The TCMSP, ChemMapper and STITCH databases were used to predict the protein targets of DBT. Using the Cytoscape 3.2.1 to establish a phytochemical component-target protein interaction network and establish a component, protein and hub metabolite protein-protein interaction (PPI) network and merging the three PPI networks basing on BisoGenet. The gene enrichment analysis was used to analyse the relationship between proteins based on the relevant genetic similarity by ClueGO. The results shown DBT effectively treated anaemia in vivo. 11 metabolic pathways are involved in the therapeutic effect of DBT in vivo; S-adenosyl-l-methionine, glycine, l-cysteine, arachidonic acid (AA) and phosphatidylcholine(PC) were screened as hub metabolites in APH-and CTX-induced anaemia. A total of 288 targets were identified as major candidates for anaemia progression. The gene-set enrichment analysis revealed that the targets are involved in iron ion binding, haemopoiesis, reactive oxygen species production, inflammation and apoptosis. The results also showed that these targets were associated with iron ion binding, haemopoiesis, ROS production, apoptosis, inflammation and related signalling pathways. DBT can promote iron ion binding and haemopoiesis activities, restrain inflammation, production of reactive oxygen, block apoptosis, and contribute significantly to the DBT treat anaemia.


Assuntos
Anemia/tratamento farmacológico , Anemia/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Metaboloma/efeitos dos fármacos , Metabolômica , Anemia/sangue , Anemia/induzido quimicamente , Animais , Cromatografia Líquida , Ciclofosfamida/toxicidade , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas em Tandem
18.
Toxicol Lett ; 310: 1-6, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30980909

RESUMO

The increased number of cell divisions undergone by spermatogonia of older fathers cannot fully account for the observed increase in germline genetic damage. Studies have shown that the mechanisms induced in germ cells in response to oxidative damage varies with age, that DNA repair efficiency declines, and both sperm DNA damage and spontaneous mutations increase. However, it is not known whether the altered response with age is a cause, or consequence, of an age-associated change in cell susceptibility to genetic damage. Following a single 150 mg/kg dose of cyclophosphamide (CP), young (8-weeks old) and aged (17-month old) male mice were examined 24 h later for induced genetic damage in epididymal spermatozoa using the alkaline comet and sperm chromatin stability assays. Apoptosis among testicular cells was examined on tissue cross-sections using the TUNEL assay. Sperm showed no significant increase in DNA strand breaks with age (detected by the comet assay) and no change in sperm chromatin stability (detected by the SCSA assay). Following CP treatment, there was no effect on DNA-strand breakage but sperm chromatin instability was significantly higher. Furthermore, it was also significantly elevated in old treated, compared with young treated, animals suggesting that increased age affects the sensitivity of epididymal sperm to chromatin damage. There was no difference in apoptosis in testicular germ cells from either young or old control animals, while CP administration resulted in a significant increase in apoptosis among young animals but not old animals. Following genotoxin exposure, an increase in chromatin instability in the spermatozoa of old animals and a decrease in the ability of their testicular germ cells undergo apoptosis suggests an age-related decrease in genome protection mechanisms. Since those germ cells are only transiently present in the testis, it is likely that this age-related deterioration originates in the spermatogonial stem cells. The findings are also evidence that the safety evaluation of reproductive genotoxins should consider young and old individuals separately.


Assuntos
Ciclofosfamida/toxicidade , Epididimo/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Fatores Etários , Animais , Apoptose/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Ensaio Cometa , Dano ao DNA , Epididimo/metabolismo , Epididimo/patologia , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos Endogâmicos C3H , Medição de Risco , Espermatozoides/metabolismo , Espermatozoides/patologia , Testículo/metabolismo , Testículo/patologia
19.
Molecules ; 24(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897728

RESUMO

The objective of the present study was to compare the effects of the immunological activity of various parts (root/stem/leaf/flower/seed) of five-year-old ginseng on the immune system of immunosuppressive mice. Immunosuppression was induced by cyclophosphamide (CTX) in the mouse model, whereas levamisole hydrochloride tablet (LTH) was used for the positive control group. We found that ginseng root (GRT), ginseng leaf (GLF), and ginseng flower (GFR) could relieve immunosuppression by increased viability of NK cells, enhanced immune organ index, improved cell-mediated immune response, increased content of CD4⁺ and ratio of CD4⁺/CD8⁺, and recovery of macrophage function, including carbon clearance, phagocytic rate, and phagocytic index, in immunodeficient mice. However, ginseng stem (GSM) and ginseng seed (GSD) could only enhance the thymus indices, carbon clearance, splenocyte proliferation, NK cell activities, and the level of IL-4 in immunosuppressed mice. In CTX-injected mice, GRT and GFR remarkably increased the protein expression of Nrf2, HO-1, NQO1, SOD1, SOD2, and CAT in the spleen. As expected, oral administration of GRT and GFR markedly enhanced the production of cytokines, such as IL-1ß, IL-4, IL-6, IFN-γ, and TNF-α, compared with the CTX-induced immunosuppressed mice, and GRT and GFR did this relatively better than GSM, GLF, and GSD. This study provides a theoretical basis for further study on different parts of ginseng.


Assuntos
Ciclofosfamida/toxicidade , Imunossupressores/toxicidade , Panax/química , Extratos Vegetais/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Flores/química , Hospedeiro Imunocomprometido , Imunossupressão , Células Matadoras Naturais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fagocitose/efeitos dos fármacos , Extratos Vegetais/química , Folhas de Planta/química , Ovinos
20.
Immunol Invest ; 48(8): 844-859, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30917711

RESUMO

Tubiechong (Eupolyphaga sinensis) is an important material used in traditional Chinese medicine (TCM). However, the immunoregulation effects of E. sinensis Lyophilized Powder (ESL) are unclear. The in vivo study thus designed to elucidate the immuno-enhancement effects of ESL in immunosuppressed mice induced by cyclophosphamide (CTX). Mice were treated with three doses of ESL (0.5, 1.0 and 2.0 g/kg). Compared with model group, ESL notably increased the immune organ index, mononuclear macrophages function and the level of nature killer cell (NK) (p < 0.05 or p < 0.01), delayed type hypersensitivity (DTH) was also improved (p < 0.05). The level of superoxide dismutase (SOD) and catalase (CAT) were enhanced (p < 0.05), while malonyldialdehyde (MDA) and nitrogen monoxide (NO) were reduced (p < 0.05 or p < 0.01). Meanwhile, cluster determinant (CD)3+ T cell, CD4+ T cell and CD4+/CD8+ ratio were increased (p < 0.01). The cytokines secretion such as interleukin (IL)-2 and tumor necrosis factor alpha (TNF-α) were notably increased (p < 0.05 or p < 0.01), and IL-6 and IL-16 were also enhanced (p < 0.05). Furthermore, ESL significantly inhibited the phosphorylation of c-Jun N-terminal kinase (JNK), down-regulated the expression of Bcl-2 associated X protein (Bax), up-regulated the B cell lymphoma-2 protein (Bcl-2) expression and decreased the Bax/Bcl-2 ratio in spleen tissues (p < 0.05). In brief, all these findings suggest that ESL could effectively improve immune functions via modulating oxidative systems and innate immune cells. Abbreviations: TCM: Traditional Chinese Medicine; ESL: Eupolyphaga sinensis Lyophilized Powder; CCl4: Carbon tetrachloride; ERK: Extracellular regulated protein kinases; CTX: Cyclophosphamide; DTH: Delayed type hypersensitivity; SOD: Superoxide dismutase; CAT: Catalase; MDA: Malonyldialdehyde; NO: Nitrogen monoxide; NK: Nature killer cell; CD: Cluster determinant interleukin; TNF-α: Tumor Necrosis Factor alpha; JNK: c-Jun N-terminal kinase; Bax: Bcl-2 associated X protein; Bcl-2: B cell lymphoma-2 protein; Th1: Type-1 helper; Th2: Type-2 helper; FAMEs: Fatty acid methyl esters; DNFB: 2,4 - Dinitrofluorobenzene; ELISA: Enzyme-linked immuno sorbent assay; MAPK: Mitogen activated protein kinase; Cyt-c: Cytochrome c; SCFAs: Short-chain fatty acids; SDS-PAGE: Sodium dodecyl sulfate polyacrylamide gel electrophoresis.


Assuntos
Ciclofosfamida/toxicidade , Sistema Imunitário/efeitos dos fármacos , Tolerância Imunológica/efeitos dos fármacos , Medicina Tradicional Chinesa , Neópteros/química , Pós/farmacologia , Animais , Proteínas Reguladoras de Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Liofilização , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Tolerância Imunológica/imunologia , Imunossupressores/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos ICR , Fagocitose/efeitos dos fármacos , Fagocitose/imunologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo
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