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1.
J Hazard Mater ; 412: 125028, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33951853

RESUMO

Cyclophosphamide (CP) and Cisplatin (CDDP) are antineoplastic drugs widely used in the treatment of neoplastic diseases that have been detected in the aquatic environment. This review summarizes the current knowledge on the presence in the aquatic environment of these two drugs and their effects on freshwater and marine invertebrates, which includes good model species in ecotoxicology and risk assessment programs. The consumption levels, occurrence in freshwater and marine ecosystems, and the impacts exerted on aquatic organisms, even at low concentrations, justifies this review and the selection of these two drugs. Both pharmaceuticals were detected in different aquatic environments, with concentrations ranging from ng L-1 up to 687.0 µg L-1 (CP) and 250 µg L-1 (CDDP). The available studies showed that CP and CDDP induce individual and sub-individual impacts on aquatic invertebrate species. The most common effects reported were changes in the reproductive function, oxidative stress, genotoxicity, cytotoxicity and neurotoxicity. The literature used in this review supports the need to increase monitoring studies concerning the occurrence of antineoplastic drugs in the aquatic environment since negative effects have been reported even at trace concentrations (ng L-1). Furthermore, marine ecosystems should be considered as a priority since less is known on the occurrence and effects of antineoplastic drugs in this environment comparing to freshwater ecosystems.


Assuntos
Antineoplásicos , Poluentes Químicos da Água , Animais , Antineoplásicos/toxicidade , Organismos Aquáticos , Cisplatino/toxicidade , Ciclofosfamida/toxicidade , Ecossistema , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade
2.
Molecules ; 26(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652778

RESUMO

Cytogenetic analysis is essential to determine the effect of mutagens and antimutagens on genetic material. This study was done to evaluate the protective effect of root bark extract of Morus alba (M. alba) against cyclophosphamide induced somatic and germinal cell damage in male rats. The ethanolic extract of M. alba (0.25, 0.5 and 1 g/kg, 2 weeks) was evaluated against cyclophosphamide (75 mg/kg, single dose) induced nuclear damage. The sampling was done after 48 h of the clastogen treatment. The somatic and germinal nuclear damage was studied by bone marrow micronucleus and sperm analysis, respectively. Serum superoxide and catalase levels were estimated to determine the antioxidant status in each group. The results were analyzed statistically to find the significant variation. The administration of M. alba for 2 weeks suppressed dose-dependently the changes induced by cyclophosphamide. M. alba (0.5 g/kg) decreased the frequency of micronucleated erythrocyte, sperm shape abnormality and enhanced the sperm count, sperm motility and polychromatic-normochromatic erythrocytes ratio significantly (p < 0.05) in comparison with the cyclophosphamide treated group. The highest tested dose of M. alba (1 g/kg) produced more prominent suppression (p < 0.01) in the cyclophosphamide-induced somatic and germinal cell defects. The results also showed significant (p < 0.05) improvement in the serum antioxidant enzymes levels with M. alba when compared with the challenge group. The lower dose of M. alba extract (0.25 g/kg) prevented the CP-induced changes but was found to be statistically insignificant. Therefore, antimutagenic potential of the high dose of the extract of M. alba is possibly due to its antioxidant nature. The ability of the M. alba extract to prevent the nuclear damage could play an important role in overcoming several mutational defects that are associated with anticancer chemotherapy.


Assuntos
Antioxidantes/farmacologia , Morus/química , Extratos Vegetais/farmacologia , Motilidade Espermática/efeitos dos fármacos , Animais , Antimutagênicos/química , Antimutagênicos/farmacologia , Antioxidantes/química , Ciclofosfamida/toxicidade , Etanol/química , Humanos , Masculino , Mutagênicos/toxicidade , Extratos Vegetais/química , Ratos
3.
Life Sci ; 274: 119331, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33716060

RESUMO

AIMS: Cyclophosphamide (CP) is a common therapeutic drug for cancer, but exposure to CP can cause acute hepatotoxicity. This study aimed to elucidate the protective effects of Ligustrazine (2, 3, 5, 6-tetramethylpyrazine, TMP) on hepatotoxicity induced by CP or its active metabolite 4-hydroperoxycyclophosphamide (4-HC). MAIN METHODS: We presented a comprehensive investigation about the hepatoprotection of TMP on CP-induced mice and 4-HC-treated HSC-LX2 cells. Liver function was detected via enzyme-linked immunosorbent assay (ELISA). Hepatic histopathology analysis was performed via hematoxylin and eosin (H&E) and Masson staining. Survival of hepatocytes was detected by TUNEL assay. Related proteins in the thioredoxin (Trx)-interacting protein (Txnip)/Trx/Nuclear factor-kappa B (NF-κB) pathway were measured by western blotting. KEY FINDINGS: The results indicated that CP or 4-HC could increase the levels of alanine aminotransferase and aspartate aminotransferase, enhance inflammatory factors and oxidative indicators, and suppress the activity of oxidoreductases. Moreover, significant changes in liver histological structure, fibrosis, and cell death were observed through the activation of Txnip/Trx/NF-κB pathway. In contrast, administration of TMP significantly reversed these above changes. Furthermore, TMP intervention participated in the inhibition of NLRP3 inflammasome accompanied with pyroptosis, as well as upregulating Trx expression and downregulating p-NF-κB, while the protective effect of TMP was limited to the involvement of Txnip overexpression. SIGNIFICANCE: TMP treatment could significantly alleviate the hepatotoxicity process as evidenced by improving the structure and function of the liver, inhibiting oxidative stress and inflammation accompanied with pyroptosis, which was positively correlated with the inhibition of Txnip/Trx/NF-κB pathway.


Assuntos
Proteínas de Transporte/antagonistas & inibidores , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Ciclofosfamida/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Pirazinas/farmacologia , Tiorredoxinas/antagonistas & inibidores , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Inflamassomos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mutagênicos/toxicidade , Vasodilatadores/farmacologia
4.
Andrologia ; 53(5): e14025, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33749904

RESUMO

Korean herbal formulation, MYOMI-14, has been reported to improve the idiopathic male infertility condition with poor semen. In this study, four MYOMI formulations were modified from MYOMI-14 by reducing the number of constituents. We investigated the therapeutic effect of MYOMI formulations on cyclophosphamide-induced male infertility using mice model. Cyclophosphamide treatment significantly decreased body weight, testicular weight, sperm count, normal-shaped sperm rate and sperm motility compared to untreated control group, whereas MYOMI formulations restore the cyclophosphamide-induced dysfunction, as determined by increased sperm count and motility, and decreased abnormally shaped spermatozoa. In addition, treatment with MYOMI formulations reduced cyclophosphamide-induced apoptosis of germ cells and oxidative stress. MYOMI-treated mice also showed improved spermatogenesis as shown by the increased expression of spermatogenesis-related genes, as cAMP-responsive element modulator (CREM) and cAMP response element-binding (CREB) protein. Among the MYOMI formulations, MYOMI-7 showed better results in terms of recovering CP-induced damages to testis and improving the fertility. Taken together, this study is expected to make significant contribution to the literature by exploring various formulations that reduced constituents of MYOMI-14, a Korean herbal medicine, in treating CP-induced male infertility.


Assuntos
Infertilidade Masculina , Motilidade Espermática , Animais , Ciclofosfamida/toxicidade , Humanos , Infertilidade Masculina/induzido quimicamente , Infertilidade Masculina/tratamento farmacológico , Infertilidade Masculina/prevenção & controle , Masculino , Camundongos , República da Coreia , Contagem de Espermatozoides , Espermatogênese , Espermatozoides , Testículo
5.
Int J Mol Sci ; 22(4)2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33562323

RESUMO

Aggressive chemotherapy treatment may lead to male infertility. Prepubertal boys do not produce sperm at this age, however, they have spermatogonial stem cells in their testes. Here, we examined the effect of intraperitoneal injection of cyclophosphamide (CP) on the capacity of immature mice (IM) to develop spermatogenesis in vivo and in vitro [using methylcellulose culture system (MCS)]. Our results show a significant decrease in testicular weight, total number of testicular cells, and the number of Sertoli, peritubular, premeiotic, and meiotic/post-meiotic cells, but an increase in the percentages of damaged seminiferous tubules in CP-treated IM compared to control. The functionality of Sertoli cells was significantly affected. The addition of testosterone to isolated cells from seminiferous tubules of CP-treated IM significantly increased the percentages of premeiotic (CD9-positive cells) and meiotic/post-meiotic cells (ACROSIN-positive cells) developed in MCS compared to control. The addition of FSH did not affect developed cells in MCS compared to control, but in combination with testosterone, it significantly decreased the percentages of CD9-positive cells and ACROSIN-positive cells. The addition of IL-1 did not affect developed cells in MCS compared to control, but in combination with testosterone, it significantly increased the percentages of VASA-positive cells and BOULE-positive cells compared to IL-1 or testosterone. Addition of TNF significantly increased only CD9-positive cells in MCS compared to control, but in combination with testosterone, it significantly decreased ACROSIN-positive cells compared to testosterone. Our results show a significant impairment of spermatogenesis in the testes of CP-treated IM, and that spermatogonial cells from these mice proliferate and differentiate to meiotic/post-meiotic cells under in vitro culture conditions.


Assuntos
Ciclofosfamida/toxicidade , Citocinas/farmacologia , Hormônios/farmacologia , Infertilidade Masculina/patologia , Tamanho do Órgão/efeitos dos fármacos , Espermatogênese , Espermatogônias/patologia , Animais , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Técnicas In Vitro , Infertilidade Masculina/induzido quimicamente , Infertilidade Masculina/metabolismo , Integrina alfa6/genética , Integrina alfa6/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mutagênicos/toxicidade , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Espermatogônias/efeitos dos fármacos , Espermatogônias/metabolismo , Tetraspanina 29/genética , Tetraspanina 29/metabolismo
6.
Ecotoxicol Environ Saf ; 211: 111889, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33461014

RESUMO

The widespread use of cyclophosphamide (CP) in medical treatment had caused ubiquitous contamination in the environment. To data, many studies have been carried out on the toxic effect of CP. However, among these toxic effects of CP, which are the most sensitive remains unclear. Present study aimed to investigate the toxicity of CP on mice and evaluate the sensitivity of physiological-biochemical parameters upon exposure of mice to CP. Results showed that as compared with the control group, CP caused significant reduction in body weight (p < 0.01), spleen coefficient (p < 0.01), leukocyte density (p < 0.01) and alanine transaminase (ALT) in kidney (p < 0.01); However superoxide dismutase (SOD), malondialdehyde (MDA), ALT in liver and creatinine (Cr) in kidney significantly (p < 0.05) increased. Among the suppressed physiological and biochemical parameters, the sensitivity to CP toxicity was generally ranked as body weight > leukocyte density > ALT in kidney > spleen coefficient; while among the stimulated parameters, the sensitivity was ranked as MDA (liver) > Cr (kidney) > ALT (liver). Overall, the most sensitive parameters to CP toxicity may be associated with growth, immune system and the normal function of liver and kidney.


Assuntos
Ciclofosfamida/toxicidade , Mutagênicos/toxicidade , Alanina Transaminase/metabolismo , Animais , Antioxidantes/metabolismo , Creatinina , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo/fisiologia , Superóxido Dismutase/metabolismo , Testes de Toxicidade
7.
Life Sci ; 266: 118913, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33333050

RESUMO

AIM: Cyclophosphamide (CYP) chemotherapy induces bladder toxicity and hemorrhagic cystitis in cancer patients constituting a current clinical concern. Oxidative inflammatory cascades have been implicated as the mechanism contributing to CYP bladder urotoxicity. We thus assayed to explore whether zinc (Zn) supplementation could mitigate CYP-induced urotoxicity and evaluate the possible underlying mechanism in rats. MAIN METHOD: Rats were orally administered Zn (100 mg/kg b.w./day) for 10 days against urotoxicity induced by single injection of CYP (150 mg/kg b.w., ip) on day 7. KEY FINDINGS: CYP significantly depressed bladder activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH) levels, whereas malondialdehyde level was increased prominently. In addition, CYP induced marked increases in the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and nitric oxide (NO) confirmed by histological alterations. CYP prominently increased bladder inducible nitric oxide synthase (iNOS) activity, nuclear factor-kappa B (NF-ĸB) and expression of caspase-3 protein. Zinc supplementation considerably abrogated the bladder urotoxicity by restoring redox balance, proinflammatory and apoptotic cascades and alleviated histopathological changes. SIGNIFICANCE: This is the first to reveal zinc potential to prevent CYP-induced urotoxic hemorrhagic cystitis via restoring redox balance and enhancing anti-inflammatory and antiapoptotic mechanisms in rat bladder.


Assuntos
Ciclofosfamida/toxicidade , Cistite/prevenção & controle , Suplementos Nutricionais , Regulação da Expressão Gênica/efeitos dos fármacos , Hemorragia/prevenção & controle , Zinco/farmacologia , Animais , Antineoplásicos Alquilantes/toxicidade , Caspase 3/química , Caspase 3/genética , Caspase 3/metabolismo , Cistite/induzido quimicamente , Cistite/metabolismo , Cistite/patologia , Hemorragia/induzido quimicamente , Hemorragia/metabolismo , Hemorragia/patologia , Masculino , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Wistar
8.
Zhonghua Nan Ke Xue ; 26(9): 826-831, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33377708

RESUMO

Objective: To investigate the effect of Bushen Huoxue Recipe (BHR) on cyclophosphamide-induced apoptosis of testicular spermatogenic cells in mice and its possible action mechanisms. METHODS: Fifty male Babl/c mice aged 8-9 weeks were randomly divided into five groups of an equal number: blank control, model control, low-dose BHR, medium-dose BHR and high-dose BHR. The animals in the blank control group were intraperitoneally injected with normal saline, while those in the other four groups with cyclophosphamide at 50 mg/kg/d, all for 7 days. After modeling, the mice in the blank and model control groups were given distilled water via gavage once a day, and those in the low-, medium- and high-dose BHR groups treated intragastrically with BHR at 7.5, 15 and 30 g/kg/d qd for 30 successive days. Then, the apoptosis index of the testicular spermatogenic cells was obtained by TUNEL and the expressions of Bax and Bcl-2 mRNA and proteins determined by RT-PCR and Western blot, respectively. RESULTS: Compared with the mice in the blank control group, the BHR model controls showed dramatically increased apoptosis of testicular spermatogenic cells and up-regulated mRNA and protein expressions of Bax and Bcl-2 in the testis tissue (P < 0.01). In comparison with the model controls, the mice in the BHR treatment groups exhibited significantly reduced apoptosis of testicular spermatogenic cells and down-regulated mRNA and protein expressions of Bax and Bcl-2 in the testis tissue (P < 0.01). CONCLUSIONS: Bushen Huoxue Recipe can reduce cyclophosphamide-induced apoptosis of testicular spermatogenic cells in mice, which may be associated with its ability of regulating the expressions of Bax and Bcl-2 mRNA and proteins in the testis tissue.


Assuntos
Apoptose , Medicamentos de Ervas Chinesas/farmacologia , Testículo/efeitos dos fármacos , Animais , Ciclofosfamida/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Testículo/patologia
9.
Wei Sheng Yan Jiu ; 49(5): 790-794, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33070826

RESUMO

OBJECTIVE: To explore the effect of myrica flavone on male reproductive toxicity induced by cyclophosphamide and its mechanism. METHODS: Thirty 6-week-old male ICR mice were randomly divided into 5 groups: blank control group, cyclophosphamide reproductive injury model group, myricetin low-medium high-dose intervention group. Except the blank control group, the other groups were intraperitoneally injected with cyclophosphamide 50 mg/kg daily for 7 consecutive days. The myricetin group received intragastric administration of 100, 200, and 400 mg/kg myricetin daily for 30 consecutive days since the second day of modeling. The blank control group and the model control group were given an equal volume of a 0. 25% sodium carboxymethyl cellulose solution. The body weight was measured every 3 days, and the day after the last administration, the mice were sacrificed by cervical dislocation, and the epididymis and testes were quickly taken. Testicular weighing, testicular index calculation, epididymis to obtain sperm, sperm analyzer to analyze sperm density and vitality. The expression of Bax and Bcl-2 in testicular tissues was detected by immunoblotting, and the mitochondrial membrane potential of sperm was detected by flow cytometry. RESULTS: After 9 days of modeling, the weight of mice in the model group was lower than that of the blank control group, which was statistically different(P<0. 05). There was no difference between the myricetin treatment group and the model group. The testis index of the model group was(3. 93±0. 91)mg/g, which was significantly lower than that of the blank control group(6. 93±0. 98)mg/g, and the difference was statistically significant(P<0. 05). After treatment with bayberry flavonoids, the testis index increased, in the 100 and 200 groups and 400 mg/kg testis index were(3. 94±1. 21) mg/g, (4. 33±0. 88) mg/g, and(4. 80±0. 43) mg/g, respectively. Compared with model control group, The difference was statistically significant(P<0. 05 and P<0. 01). Compared with the control group, the sperm density, sperm rate of forward movement, sperm rate of non-forward movement, and decreased sperm rate of non-moving sperm increased in the model group. After treatment with bayberry flavonoids, compared with the model group, the sperm density, sperm rate of forward motion, and sperm rate of non-forward motion increased, and the immobility sperm rate decreased. The 200 and 400 mg/kg groups had statistical significance(P<0. 05 or P<0. 01); the normal rate of sperm mitochondrial membrane potential in the model group was(54. 70±5. 45)%, and the normal mitochondrial membrane potential rate after treatment with myricetin of 100, 200 and 400 mg/kg(59. 10±9. 97)%, (62. 10±6. 07)% and(77. 10±8. 87)%, of which the 400 mg/kg group was statistically significant(P<0. 05); the ratio of Bax/Bcl-2 in the model group was 5. 92±1. 45, and the ratio of Bax/Bcl-2 decreased after treatment with myricetin of 100, 200 and 400 mg/kg, which were 2. 52±0. 51, 1. 71±0. 52 and 1. 07±0. 29. There were statistical differences(P<0. 05 or P<0. 01). CONCLUSION: Myrica flavone can protect sperm mitochondrial membrane potential, inhibit testicular cell apoptosis, and protect the male mice from reproductive toxicity induced by cyclophosphamide.


Assuntos
Flavonoides , Motilidade Espermática , Animais , Ciclofosfamida/toxicidade , Flavonoides/toxicidade , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR
10.
Georgian Med News ; (304-305): 141-147, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32965265

RESUMO

Objective - to study the ability of N-oxide-2,6-dimethylpyridine to modify the cytogenetic effects in mouse bone marrow cells caused by an alkylating antitumor cytostatic cyclophosphamide.; The cytogenetic activity and mutagen-modifying effect of the plant growth regulator N-oxide-2,6-dimethylpyridine (Ivin) were studied by the method of accounting for chromosomal aberrations in the bone marrow cells of CD-1 mice (males) with a single joint exposure to cyclophosphamide. In the first variant of the research, Ivin was administered single orally in the form of an aqueous solution at doses of 710, 71, 7.1, 0.7, and 0.07 mg/kg bw, which corresponds to 1/2, 1/20, 1/200, 1/2000 and 1/20000 from LD50. In the second variant - Ivin was administered together with Cyclophosphamide (Ivin - in the same way as in the first research variant, cyclophosphamide was administered intraperitoneally at a dose of 40 mg/kg bw the same as the positive control group). Intact animals (negative control group) were orally administered purified, UV-sterilized, deionized water.; It was shown that with isolated administration of Ivin in the studied doses did not show mutagenic activity. When combined with Cyclophosphamide, Ivin at a dose of 710 mg/kg bw did not induce the frequency of metaphases with chromosome aberrations and at a dose of 71 mg/kg bw reduced the frequency of metaphases with chromosome aberrations by 1.8 times in comparison with the positive control. In both of these dose groups, Ivin reduced the number of chromatid-type aberrations and polyploid cells but increased the number of multi-aberrant cells. This is probably due to the additional chemical load and physicochemical state of the Ivin molecule. When combined with Cyclophosphamide, Ivin at low dose levels (7.1, 0.7 and 0.07 mg/kg bw) significantly reduced the frequency of metaphases with chromosome aberrations (by 55.7%, 62.9% и 72.9%, respectively), the amount of chromatid-type aberrations, polyploid, and multi-aberrant cells. This may be due to the gene protective effect of Ivin, because of the stabilization of membranes and its antioxidant effect.


Assuntos
Células da Medula Óssea , Aberrações Cromossômicas , Animais , Ciclofosfamida/toxicidade , Análise Citogenética , Masculino , Óxidos
11.
Chem Biol Interact ; 330: 109219, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32846153

RESUMO

The lack of tissue selectivity of anticancer drugs generates intense collateral and adverse effects of cancer patients, making the incorporation of vitamins or micronutrients into the diet of individuals to reduce side or adverse effects of antineoplastics. The study aimed to evaluate the effects of retinol palmitate (RP) on the toxicogenic damages induced by cyclophosphamide (CPA), doxorubicin (DOX) and its association with the AC protocol (CPA + DOX), in Sarcoma 180 (S-180) tumor cell line, using the micronuclei test with a block of cytokinesis (CBMN); and in non-tumor cells derived from Mus musculus using the comet assay. The results suggest that CPA, DOX and AC protocol induced significant toxicogenic damages (P < 0.05) on the S-180 cells by induction of micronuclei, cytoplasmic bridges, nuclear buds, apoptosis, and cell necrosis, proving their antitumor effects, and significant damage (P < 0.001) to the genetic material of peripheral blood cells of healthy mice, proving the genotoxic potential of these drugs. However, RP modulated the toxicogenic effects of antineoplastic tested both in the CBMN test (P < 0.05), at the concentrations of 1, 10 and 100 IU/mL; as in the comet assay (P < 0.001) at the concentration of 100 IU/kg for the index and frequency of genotoxic damage. The accumulated results suggest that RP reduced the action of antineoplastics in non-tumor cells as well as the cytotoxic, mutagenic, and cell death in neoplastic cells.


Assuntos
Antineoplásicos/toxicidade , Diterpenos/farmacologia , Vitamina A/análogos & derivados , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Ensaio Cometa , Ciclofosfamida/efeitos adversos , Ciclofosfamida/toxicidade , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Interações Medicamentosas , Humanos , Camundongos , Testes para Micronúcleos , Mutagênese/efeitos dos fármacos , Vitamina A/farmacologia
12.
Chemosphere ; 261: 127678, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32717509

RESUMO

The rise of cancer cases worldwide led to an increase in production and consumption of anticancer drugs, that ultimately end up in the marine environment and are accumulated in aquatic organisms. Cyclophosphamide (CP) is a cytotoxic alkylating agent frequently prescribed in cancer treatments. This study assess ecotoxicological effects of CP on mussels Mytilus galloprovincialis, through in vivo and ex vivo approaches and compares the sensitivity of mussel haemocytes with well-established human cell lines (RPE and HeLa). Mussels were exposed in vivo to CP (1000 ng L-1) and several biomarkers analysed in gills and digestive glands namely neurotoxicity (AChE activity), oxidative stress (GPx activity), biotransformation (GST activity), lipid peroxidation (LPO) and apoptosis (caspase activity), whereas genotoxicity was determined in mussels' haemocytes. Cytotoxicity was also assessed in haemocytes (in vivo and ex vivo) and human cell lines (in vitro) exposed to a range of CP concentrations (50, 100, 250, 500 and 1000 ng L-1) over 24 h, via neutral red assay. In in vivo exposure, detoxification of CP did not efficiently occur in the gills while in digestive glands GPx and GST activities were induced, jointly with a decrease in lipid peroxidation, indicating a potential outcome of the protective antioxidant mechanisms, whereas no apoptosis was noted. Moreover, cytotoxicity and DNA damage were detected in haemocytes. The ex vivo exposure haemocytes to CP caused cytotoxicity (from 100 ng L-1), whereas no effects occurred in human cell lines. This suggests that, at relevant environmental concentrations, CP cause subtle and irreversible impacts on M. galloprovincialis.


Assuntos
Antineoplásicos/toxicidade , Ciclofosfamida/toxicidade , Mytilus/fisiologia , Poluentes Químicos da Água/toxicidade , Animais , Antineoplásicos/metabolismo , Antioxidantes/metabolismo , Organismos Aquáticos/metabolismo , Biomarcadores/metabolismo , Biotransformação , Linhagem Celular , Dano ao DNA , Ecotoxicologia , Brânquias/metabolismo , Humanos , Peroxidação de Lipídeos , Mytilus/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Alimentos Marinhos
13.
Cancer Sci ; 111(6): 2146-2155, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32227405

RESUMO

Chemotherapy-induced alopecia is one of the most difficult adverse events of cancer treatment for patients. However, it is still unknown why anticancer drugs cause hair loss. We aimed to clarify the mechanism of chemotherapy-induced alopecia in mice using an in vivo imaging technique with a two-photon microscope, which enables observation of the deep reaction in the living body in real time. In this study, ICR mice were injected intraperitoneally with cyclophosphamide (120 µg/g). Changes in the hair bulb morphology, subcutaneous vessel permeability, and vessel density were evaluated by two-photon microscopy and conventional methods. In order to determine whether there is a causal relationship between vascular permeability and hair loss, we combined cyclophosphamide (50 µg/g) with subcutaneous histamine. Using two­photon microscopy and conventional examination, we confirmed that the hair bulbs became smaller, blood vessels around the hair follicle decreased, and vascular permeability increased at 24 hours after cyclophosphamide injection [corrected]. Apoptosis occurred in vascular endothelial cells around the hair follicle. Additionally, hair loss was exacerbated by temporarily enhancing vascular permeability with histamine. In conclusion, cyclophosphamide caused a decrease in vascular density and an increase in vascular permeability, therefore increased vascular permeability might be one of the causes of chemotherapy-induced alopecia.


Assuntos
Alopecia/induzido quimicamente , Antineoplásicos/toxicidade , Permeabilidade Capilar/efeitos dos fármacos , Ciclofosfamida/toxicidade , Folículo Piloso/efeitos dos fármacos , Animais , Feminino , Camundongos , Camundongos Endogâmicos ICR
14.
Toxicology ; 437: 152439, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32197949

RESUMO

Cyclophosphamide (CP) is widely used as chemotherapy in various cancers; however, testicular atrophy has been encountered as an associated adverse effect. Oxidative stress, enhanced endoplasmic reticulum (ER) stress, and subsequent apoptosis are involved in the molecular mechanisms of CP-induced testicular toxicity. In addition to the cardiovascular benefits of LCZ696 (sacubitril/valsartan (VAL)), neprilysin inhibition was shown to mediate Ca2+ sequestration inside the ER. Furthermore, long noncoding RNA taurine-upregulated gene 1 (lncRNA TUG1) was shown to ameliorate apoptosis in various diseases. This tempted us to investigate the possible benefit of LCZ696 against CP-induced testicular dysfunction in rats through neprilysin inhibition axis, and the downstream apoptotic cascade, with highlighting the impact of lncRNA TUG1 in regulating testicular toxicity. Sixty adult male Wistar rats were randomly allocated as control, LCZ696, VAL, CP, CP + LCZ696, and CP + VAL. Testicular atrophy was induced by single-dose injection of CP (200 mg/kg; i.p.). LCZ696 treated group received LCZ696 (30 mg/kg; p.o.) for 6 days, with CP (200 mg/kg; i.p.) single-dose on day 5. LCZ696 increased lncRNA TUG1 expression, improved sperm characteristics, hormonal profile, testicular function, antioxidant defences, and Bcl-2. The histopathological picture and reduced oxidative and ER stress markers, aligned with declined Bax, caspase-3 and the expression of CHOP, PUMA, Noxa, Bim, and p53, with a subtle superior effect over VAL-treated group. In conclusion, the current study highlights the promising impact of LCZ696 in ameliorating chemotherapy-induced testicular atrophy; yet, further investigation regarding longer duration and different doses of LCZ696 is warranted.


Assuntos
Aminobutiratos/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Ciclofosfamida/toxicidade , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/farmacologia , RNA Longo não Codificante/metabolismo , Testículo/efeitos dos fármacos , Tetrazóis/farmacologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Atrofia , Combinação de Medicamentos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Masculino , Neprilisina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Longo não Codificante/genética , Ratos Wistar , Transdução de Sinais , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo , Espermatozoides/patologia , Testículo/enzimologia , Testículo/patologia
15.
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
16.
Immunopharmacol Immunotoxicol ; 42(2): 101-109, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32066295

RESUMO

Objectives: Cyclophosphamide (CYC) is the most common cytotoxic alkylating agent which considered as chemotherapy but its clinical usefulness is challenged with different forms of organ damage including hepatotoxicity. Hepatic mast cells (MC) have an important role in the pathophysiology of liver toxicity. We aimed to evaluate the possible protective effect of mast cell stabilizer, ketotifen in CYC induced-hepatotoxicity.Materials and methods: Twenty-four adult male albino Wistar rats were divided into four groups: control group, ketotifen group (received ketotifen 10 mg/kg/day, p.o.) for 14 days, CYC group (received CYC 200 mg/kg i.p.) as a single dose at the ninth day and ketotifen plus CYC group (received ketotifen and CYC). We measured serum enzyme biomarkers [alanine transaminase (ALT) and aspartate transaminase (AST)], total antioxidant capacity (TAC), interluken-1ß (IL-1ß), tissue malondialdehyde (MDA), nitric oxide (NOx), reduced glutathione (GSH), P-glycoprotein (P-gp), Sirtuin type 1 (Sirt1) and Nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Furthermore; histological changes, tumor necrosis factor (TNF) and caspase-3 immuno-expressions were evaluated.Results: CYC group showed hepatotoxic effect in the form of a significant increase in ALT, AST, MDA, NOx, IL-1ß levels; TNF and caspase-3 immuno-expression. Moreover; it showed toxic histological changes of marked liver injury meanwhile, there is a significant decrease in TAC, GSH, P-gp, Sirt1, and Nrf2 levels. Ketotifen showed a significant improvement in all parameters.Conclusion: Mast cell stabilizer, ketotifen possesses potent ameliorative effects against the hepatotoxic effect of CYC by reducing oxidative stress, inflammatory process, and apoptosis through regulation of Sirt1/Nrf2/TNF pathway.


Assuntos
Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Cetotifeno/farmacologia , Mastócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/sangue , Animais , Apoptose/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ciclofosfamida/toxicidade , Modelos Animais de Doenças , Inflamação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Mastócitos/metabolismo , Mastócitos/patologia , Fator 2 Relacionado a NF-E2/sangue , Estresse Oxidativo/imunologia , Ratos Wistar , Transdução de Sinais , Fatores de Necrose Tumoral/sangue
17.
Immunopharmacol Immunotoxicol ; 42(2): 110-118, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32066303

RESUMO

Objective: This paper aims to investigate the dynamic changes of the T-cell receptor (TCR) ß complementarity-determining region 3 (CDR3) repertoire during cyclophosphamide or Cytoxan (CTX) damage or inhibition of bone marrow hematopoiesis caused by a reduction of peripheral blood white blood cells (WBCs) in BALB/c mice.Methods: We analyze TCR CDR3 repertoire of BALB/c mice including (1) NS control group (2) CTX damage group (3) CTX damage + GM-CSF recovery group (4) CTX damage + auto-recovery group.Results: The number of WBCs in the CTX group is significantly lower than that in the NS group and after GM-CSF injection, the GM-CSF group is higher than that in the NS group. The diversity of the CTX damage group is the highest and there is a significant difference in high-frequency clonal proliferation between the CTX damage group and CTX damage + GM-CSF recovery group compared with the NS control group. In addition, the numbers of unique productive CDR3 overlapping numbers in the four experimental groups are similar.Conclusions: These data reveal that CTX significantly reduced the number of WBCs and ratio of high-frequency TCR CDR3 sequences, and indirectly increased the diversity of the TCR CDR3 repertoire. GM-CSF quickly restored the number of WBCs, and partially restored changes in the TCR CDR3 repertoire induced by CTX. Results from monitoring the dynamic changes of the TCR CDR3 repertoire can be used to assess the effects of CTX and GM-CSF on the function of peripheral blood T cells and to explore the possible underlying mechanisms.


Assuntos
Medula Óssea/efeitos dos fármacos , Regiões Determinantes de Complementaridade/metabolismo , Ciclofosfamida/toxicidade , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Hematopoese/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Animais , Medula Óssea/patologia , Relação Dose-Resposta a Droga , Feminino , Contagem de Leucócitos , Leucócitos/patologia , Camundongos Endogâmicos BALB C
18.
Am J Respir Cell Mol Biol ; 62(6): 760-766, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31991091

RESUMO

Invasive pulmonary aspergillosis is a life-threatening disease, particularly in immunocompromised patients, despite currently available therapy. IL-27 is an important regulatory cytokine in infection and immunity. However, its role in the pathogenesis of invasive pulmonary aspergillosis remains unknown. Here we found that Aspergillus fumigatus pulmonary infection induced an elevated production of IL-27 in the lung. As compared with wild-type (WT) mice, IL-27R (IL-27 receptor)-deficient mice developed less severe infection when challenged with A. fumigatus conidia, as evidenced by the decreased fungal colonization and pathology of lungs and the increased survival. IL-27R deficiency led to significantly higher production of IFN-γ in the lung after A. fumigatus infection, and the increased resistance to invasive pulmonary A. fumigatus infection in IL-27R-deficient mice was ablated by neutralizing IFN-γ. Importantly, neutralization of IL-27 could protect WT mice against invasive pulmonary A. fumigatus infection. Our data therefore suggest an important role of IL-27 in impairing anti-A. fumigatus host immunity, which may have translational implications in treating clinical cases of invasive pulmonary aspergillosis.


Assuntos
Aspergillus fumigatus/imunologia , Interações Hospedeiro-Patógeno/imunologia , Interleucinas/fisiologia , Aspergilose Pulmonar Invasiva/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Ciclofosfamida/toxicidade , Resistência à Doença , Feminino , Hospedeiro Imunocomprometido , Imunossupressores/toxicidade , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Interferon gama/fisiologia , Interleucinas/biossíntese , Interleucinas/genética , Aspergilose Pulmonar Invasiva/microbiologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Receptores de Interleucina/fisiologia , Regulação para Cima
19.
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
20.
J Neuroinflammation ; 17(1): 19, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31931832

RESUMO

BACKGROUND: Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we determined that neuroinflammation of the spinal dorsal horn (SDH) was associated with mechanisms of interstitial cystitis. Moreover, it has been shown that brain-derived neurotrophic factor (BDNF) participates in the regulation of neuroinflammation and pathological pain through BDNF-TrkB signaling; however, whether it plays a role in cyclophosphamide (CYP)-induced cystitis remains unclear. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs. METHODS: Systemic intraperitoneal injection of CYP was performed to establish a rat cystitis model. BDNF-TrkB signaling was modulated by intraperitoneal injection of the TrkB receptor antagonist, ANA-12, or intrathecal injection of exogenous BDNF. Mechanical allodynia in the suprapubic region was assessed using the von Frey filaments test. The expression of BDNF, TrkB, p-TrkB, Iba1, GFAP, p-p38, p-JNK, IL-1ß, and TNF-α in the L6-S1 SDH was measured by Western blotting and immunofluorescence analysis. RESULTS: BDNF-TrkB signaling was upregulated significantly in the SDH after CYP was injected. Similarly, the expressions of Iba1, GFAP, p-p38, p-JNK, IL-1ß, and TNF-α in the SDH were all upregulated. Treatment with ANA-12 could attenuate mechanical allodynia, restrain activation of astrocytes and microglia and alleviate neuroinflammation. Besides, the intrathecal injection of exogenous BDNF further decreased the mechanical withdrawal threshold, promoted activation of astrocytes and microglia, and increased the release of TNF-α and IL-1ß in the SDH of our CYP-induced cystitis model. CONCLUSIONS: In our CYP-induced cystitis model, BDNF promoted the activation of astrocytes and microglia to release TNF-α and IL-1ß, aggravating neuroinflammation and leading to mechanical allodynia through BDNF-TrkB-p38/JNK signaling.


Assuntos
Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cistite/complicações , Hiperalgesia/etiologia , Microglia/metabolismo , Animais , Ciclofosfamida/toxicidade , Cistite/induzido quimicamente , Cistite/metabolismo , Feminino , Hiperalgesia/metabolismo , Imunossupressores/toxicidade , Inflamação/etiologia , Inflamação/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Corno Dorsal da Medula Espinal/metabolismo
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