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1.
J Ethnopharmacol ; 301: 115842, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36265674

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Wu-Tang (SWT) has become a common basic prescription for supplementing blood and regulating menstruation, and enjoys the reputation of "the first prescription in gynecology". It is often reported in the treatment of premature ovarian failure (POF). However, knowledge of its specific mechanism is still limited. AIM OF THE STUDY: This study aimed to identify the potential effects and underlying mechanisms of SWT on POF. MATERIALS AND METHODS: After confirming the therapeutic effect of SWT on POF mice induced by cyclophosphamide, we further clarified the promoting effect of SWT on ovarian follicle development by detecting the expression of key factors related to follicle development in the ovary in different ways.Then, network pharmacology and gene expression profiling of POF from the GEO database were used to clarify the underlying mechanisms. Molecular biology and molecular docking analysis were applied for final mechanism verification. RESULTS: Our results showed that SWT increased body weight, ovarian index, reversed disordered serum hormone levels, and menstrual cycle in POF mice. After SWT treatment, the number of follicles at all levels in mice with POF also recovered. Using molecular biology techniques, it was proven that SWT can improve follicle development and angiogenesis in the microenvironment. The network pharmacology and gene expression profiling from the GEO database indicated that the PI3K/Akt signaling pathway may be the reason why SWT improves ovarian function in mice with POF. Subsequently, further Western blot and immunoprecipitation indicated that SWT indeed inhibited the PI3K/Akt signaling pathway in mice with POF. In addition, this conclusion was further confirmed by molecular docking experiments. CONCLUSIONS: SWT can improve ovarian function in POF mice induced by cyclophosphamide, and its mechanism is related to the inhibition of the PI3K/Akt signaling pathway.


Assuntos
Menopausa Precoce , Insuficiência Ovariana Primária , Humanos , Feminino , Camundongos , Animais , Insuficiência Ovariana Primária/induzido quimicamente , Insuficiência Ovariana Primária/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Simulação de Acoplamento Molecular , Ciclofosfamida/toxicidade , Modelos Animais de Doenças
2.
Nutrients ; 14(21)2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36364730

RESUMO

Cyclophosphamide (CYC) is the first-line chemotherapy drug for cancer in clinical practice, and its intestinal toxicity seriously affects the treatment effect and prognosis of patients. Lycopene (LP) is the main pigment of ripe tomatoes and has strong antioxidant activity. However, the mechanism by which LP prevents CYC-induced intestinal injury remains unclear. The aim of this study was to investigate the mechanism of LP in preventing intestinal toxicity caused by CYC chemotherapy in mice. The results showed that LP significantly prevented spleen and thymus atrophy induced by CYC. In terms of intestinal injury, LP significantly increased the levels of superoxide dismutase (SOD), secretory immunoglobulin A (sIgA), interleukin (IL)-4, IL-12, and interferon (IFN)-γ, decreased the content of lipid oxidation (MDA), upregulated the protein expressions of toll-like receptors 4 (TLR4), myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor-associated factor 6 (TRAF6), toll/IL-1receptor domain containing adaptor protein inducing IFN-ß (TRIF), p-P38 MAPK (P38), and p-nuclear factor kappa-B (NF-κB) p65, and improved the small intestine tissue injury induced by CYC. In terms of liver injury, LP significantly increased the content of glutathione (GSH), decreased the contents of MDA, nitric oxide (NO), IL-1ß, IL-6, and tumor necrosis factor (TNF)-α, and repaired the liver tissue injury induced by CYC. Importantly, 10 mg/kg LP significantly prevented intestinal microbiota dysregulation in CYC mice. These results suggested that LP significantly prevented intestinal injury induced by CYC in mice by regulating the TLR4-MyD88/TRIF-TRAF6 signaling pathway and gut-liver axis.


Assuntos
Fator 88 de Diferenciação Mieloide , Fator 6 Associado a Receptor de TNF , Animais , Camundongos , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/farmacologia , Ciclofosfamida/toxicidade , Fígado/metabolismo , Licopeno/farmacologia , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Fator 6 Associado a Receptor de TNF/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Intestinos/metabolismo
3.
Nutrients ; 14(21)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36364753

RESUMO

The carnosine and anserine, which represent histidine dipeptides (HD), are abundant in chicken broth (CB). HD are endogenous dipeptide that has excellent antioxidant and immunomodulatory effects. The immunomodulatory effect of CB hydrolysate (CBH) and HD in cyclophosphamide (CTX)-induced immunosuppressed mice was examined in this study. CBH and HD were given to mice via oral gavage for 15 days, accompanied by intraperitoneal CTX administration to induce immunosuppression. CBH and HD treatment were observed to reduce immune organ atrophy (p < 0.05) and stimulate the proliferation of splenic lymphocytes (p < 0.05) while improving white blood cell, immunoglobulin M (IgM), IgG, and IgA levels (p < 0.05). Moreover, CBH and HD strongly stimulated interleukin-2 (IL-2) and interferon-gamma (IFN-γ) production by up-regulating IL-2 and IFN-γ mRNA expression (p < 0.05) while inhibiting interleukin-10 (IL-10) overproduction and IL-10 mRNA expression (p < 0.05). In addition, CBH and HD prevented the inhibition of the nitric oxide (NP)/cyclic guanosine monophosphate-cyclic adenosine monophosphate (cGMP-cAMP)/protein kinase A (PKA) signaling pathway (p < 0.05). These results indicate that CBH and HD have the potential to prevent immunosuppression induced by CTX. Our data demonstrate that CBH can effectively improve the immune capacity of immunosuppressed mice similar to the same amount of purified HD, which indicates that CBH plays its role through its own HD.


Assuntos
Galinhas , Interleucina-2 , Camundongos , Animais , Galinhas/genética , Interleucina-2/genética , Histidina/farmacologia , Interleucina-10 , Dipeptídeos , Ciclofosfamida/toxicidade , Terapia de Imunossupressão , RNA Mensageiro
4.
Ecotoxicol Environ Saf ; 246: 114150, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36215883

RESUMO

Betulinic acid (BA), an occurring pentacyclic triterpenoid, has various biological activities, such as anti-inflammation and antioxidation. Previous studies found that BA attenuated cyclophosphamide (CYP)-induced intestinal mucosal damage by inhibiting intestinal mucosal barrier dysfunctions and cell apoptosis. However, the effects and regulation mechanisms of BA on CYP-induced renal damage has not been reported in literature. Here, we found that BA pretreatment alleviated the elevation of serum urea level and inhibited the increase in serum neutrophil gelatinase-associated lipocalin level induced by CYP. Meanwhile, BA ameliorated renal tubular epithelial cell edema, and vacuolization of renal cortical tubular and renal glomerulus. Moreover, pretreatment with BA inhibited the mRNA expressions of pro-inflammatory cytokines interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α, and increased mRNA expressions of anti-inflammatory cytokines such as IL-10 and transforming growth factor-ß by inactivation nuclear factor kappa-B. Simultaneously, BA decreased the accumulation of reactive oxygen species and malondialdehyde, and lowered the levels of superoxide dismutase and glutathione, while increased the activity of glutathione peroxidase in CYP-induced kidney damage mice. Besides, BA reduced the phosphorylation of extracellular signal-regulated kinases (ERK), inhibited the ratio of Bcl-2/Bax and cell apoptosis in CYP-triggered kidney damage. Furthermore, BA and/or PD98059 (an inhibitor of ERK) regulated mitigation of CYP-elicited renal injury and deactivation of the ERK pathway and mitochondrial apoptotic pathway, indicating that the protective effect of BA on CYP-induced renal damage may be associated with the down-regulation of ERK-mediated mitochondrial apoptotic pathway. Thus, BA could be a candidate agent against chemotherapy drug-induced nephrotoxicity by reducing inflammation and oxidative stress through suppression of ERK-mediated mitochondrial apoptotic pathway.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Estresse Oxidativo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Rim , Apoptose , Ciclofosfamida/toxicidade , Citocinas/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , RNA Mensageiro/metabolismo
5.
Int J Mol Sci ; 23(19)2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36232918

RESUMO

Cyclophosphamide is an anticancer drug with a wide spectrum of clinical uses, but its typical side effects are multiple complications, including nephron toxicity. The possible molecular mechanism of the nephroprotective action of sesamin (SM) against cyclophosphamide (CP) induced renal toxicity was investigated in rats by understanding oxidative stress and inflammatory cytokines. In this study, rats were arbitrarily grouped into the following four groups: a normal control group (CNT); a CP-induced toxicity group; a treatment group with two doses of sesamin SM10 and SM20; a group with sesamin (SM20) alone. A single dose of CP (150 mg/kg body, i.p.) was administered on day 4 of the experiments, while treatment with SM was given orally for seven days from day 1. The group treated with SM showed a significant protective effect against CP-induced renal damage in rats. Treatment with SM significantly increased the antioxidant enzymes (GSH, CAT, and SOD) and reduced malondialdehyde (MDA) levels. Thus, SM significantly overcame the elevated kidney function markers (creatinine, blood urea nitrogen, and uric acid) by attenuating oxidative stress. The SM also significantly reduced the elevated cytokines (IL-1ß and TNFα) and caspase-3 in the treated group. Histopathological studies confirmed the protective effect of sesamin (SM) on CP-induced nephrotoxicity. In conclusion, the current findings support the nephroprotective effect of sesamin against CP-induced renal injury.


Assuntos
Antineoplásicos , Insuficiência Renal , Animais , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose , Caspase 3/metabolismo , Creatinina/metabolismo , Ciclofosfamida/toxicidade , Citocinas/metabolismo , Dioxóis , Rim/metabolismo , Lignanas , Malondialdeído/metabolismo , Estresse Oxidativo , Ratos , Insuficiência Renal/metabolismo , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ácido Úrico/metabolismo
6.
Biomed Pharmacother ; 156: 113743, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36252358

RESUMO

Ovarian damage and infertility are the main side effects of chemotherapy for women of childbearing age with cancer. The main objective of this study was to investigate the protective effects and mechanisms of hyperoside against cyclophosphamide (Cy) -induced ovarian damage and reduced fertility. This study consists of two parts: in vivo experiments using Cy intraperitoneal injections to simulate clinical chemotherapy sessions and in vitro experiments using 4-HC, a precursor of an activated form of Cy, to intervene in human granulosa-like cell line (KGN). We found that Cy disrupted the estrous cycle in mice, resulting in decreased serum Anti-Mullerian hormone (AMH) levels, loss of primordial follicles, primary follicle and secondary follicle, increased atretic follicles, and diminished ovarian reserve function. Cy prolonged the time between mating and pregnancy in mice and increased the number of absorbed embryos. Western Blot analysis demonstrate that Cy activated key proteins of HIF-1α/BNIP3-associated autophagy both in vivo and in vitro, while in vivo experiments we also found that 4-HC increased KGN cell apoptosis, damaged mitochondrial membrane potential, and activated autophagic flow. Co-treatment with hyperoside diminished follicular depletion of the primordial follicles, decreased follicular atresia, prevented Cy-induced excessive hypoxia and autophagy activation, increased mitochondrial membrane potential, thereby increasing follicular reserve and rescuing fertility in Cy-treated mice. It suggests that HIF-1α/BNIP3-mediated autophagy is an essential mechanism by which Cy impairs ovarian function and fertility in mice, by blocking this activation, hyperoside shows potential as an ovarian protectant that may be capable of preserving fertility in women undergoing chemotherapy.


Assuntos
Atresia Folicular , Folículo Ovariano , Humanos , Gravidez , Feminino , Camundongos , Animais , Ciclofosfamida/toxicidade , Autofagia , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Mitocondriais/metabolismo
7.
Hum Exp Toxicol ; 41: 9603271221132140, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36198566

RESUMO

Herbacetin (HBN) is a glycosylated flavonoid, which possesses numerous pharmacological properties. Cyclophosphamide (CYC) is a chemotherapeutic drug that adversely affects the kidneys. The present investigation aimed to evaluate the curative potential of HBN against CYC-induced nephrotoxicity. Sprague Dawley rats (n = 48) were randomly divided into four groups: control (0.1% DMSO + food), CYC (150 mg/kg b.wt.), CYC+HBN (150 + 40 mg/kg b.wt.), and HBN (40mg/kg b.wt.). CYC treatment significantly decreased the activities of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GSR) while elevating the concentration of reactive oxygen species (ROS) and malondialdehyde (MDA). Treatment with HBN significantly recovered the activity of CAT, SOD, GPx, and GSR while reducing the concentrations of ROS and MDA. Moreover, an increase in the level of renal functional markers, including Urea, creatinine, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), and a decrease in creatinine clearance after CYC administration was recovered to control values by HBN treatment. Furthermore, HBN treatment normalized the increased levels of inflammatory markers such as nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) after CYC administration. Besides, HBN administration increased the expression of anti-apoptotic markers (Bcl-2) while decreasing the apoptotic markers (Bax and Caspase-3). Furthermore, HBN decreased the activities of tricarboxylic acid (TCA) cycle enzymes (ICDH, αKGDH, SDH, and MDH) as well as renal mitochondrial respiratory-chain complexes (I-IV) and repolarized mitochondrial membrane potential (ΔΨm). Additionally, HBN administration significantly protected against renal histological damage induced by CYC. In conclusion, CYC-induced toxicity was effectively ameliorated by the HBN administration. These results indicate that HBN might be considered as a potential protective agent against nephrotoxicity. The observed protection may be due to its antioxidant, anti-inflammatory, and anti-apoptotic potential.


Assuntos
NF-kappa B , Fator de Necrose Tumoral alfa , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose , Caspase 3/metabolismo , Catalase/metabolismo , Creatinina/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ciclofosfamida/uso terapêutico , Ciclofosfamida/toxicidade , Dimetil Sulfóxido/metabolismo , Dimetil Sulfóxido/farmacologia , Dimetil Sulfóxido/uso terapêutico , Flavonoides/farmacologia , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Rim , Lipocalina-2 , Malondialdeído/metabolismo , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Ácidos Tricarboxílicos/metabolismo , Ácidos Tricarboxílicos/farmacologia , Ácidos Tricarboxílicos/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Ureia , Proteína X Associada a bcl-2/metabolismo
8.
Nutrients ; 14(20)2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36296947

RESUMO

Lepidium meyenii Walp. (Maca), as a natural food supplement, has strong antioxidant and energy metabolism-improving characteristics, and Maca polysaccharide (MP) is its effective component. MP has been shown to mitigate liver damage in previous research, and Cyclophosphamide (CYP)-induced hepatotoxicity is also a major concern in clinical practice. We investigated the possible cytoprotective effect of MP on CYP-induced liver injury, and explored its underlying mechanism by analyzing the resulting liver metabolic profiles. MP significantly inhibited increases in serum transaminase, improved pathological changes, reduced oxidative stress, and increased the levels of energy metabolism-related enzymes. Metabolomic analysis showed that MP corrected lipid metabolic problems and regulated the pentose phosphate pathway and acid metabolism, thereby protecting against apoptosis of hepatocytes. The Pearson correlation analysis indicated that antioxidant enzymes and energy metabolism-related enzymes are closely correlated with these differential metabolites. In addition, the upstream Keap1-Nrf2 antioxidant signal transduction pathway was explored to validate the possible mechanism of the cytoprotective effect of MP. In conclusion, MP plays a protective role in CYP-induced hepatotoxicity through these potential metabolic means, where it ameliorates oxidative stress, improves energy metabolism, and restores mitochondrial respiration by regulating the Keap1-Nrf2 signaling pathway, thereby preventing liver damage.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Lepidium , Camundongos , Animais , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Lepidium/metabolismo , Polissacarídeos/farmacologia , Estresse Oxidativo , Ciclofosfamida/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Metabolismo Energético , Transaminases/metabolismo , Lipídeos/farmacologia
9.
Andrologia ; 54(10): e14543, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36177654

RESUMO

Cyclophosphamide (CP) is one of the chemotherapeutic drugs, which plays its role by interfering with all rapidly proliferating tissues like cancer and testis. The aim of this study was to investigate the protective effect of pentoxifylline (PTX) on the sperm parameters, spermatogenesis indices, biochemical alterations and gene expressions, in adult male mice treated with CP. A total of 24 male NMRI mice were divided into four groups: control, CP group (15 mg/kg weekly), PTX (100 mg/kg daily) and CP + PTX and treated for 35 days with the intraperitoneal injection. A significant decrease in the spermatogenesis indices, Leydig cells, sperm motility, viability, count, tail length and daily sperm production was found in the CP group compared to the control group. The results of this study indicate that PTX prevented these adverse effects of CP and decreased the number of apoptotic cells. Moreover, the CP group showed decreased levels of total antioxidant capacity, testosterone, lipid peroxidation and the expression of cytochrome P450 and 3ß-hydroxysteroid, all of which were neutralized in the CP + PTX group. It seems that PTX has the potential to be used in therapeutic regimens of cancer patients to reduce the side effects of CP. However, more research is needed to evaluate this prevention in mice models of cancer.


Assuntos
Pentoxifilina , Testículo , Animais , Antioxidantes/farmacologia , Ciclofosfamida/toxicidade , Hidroxiesteroides/metabolismo , Hidroxiesteroides/farmacologia , Masculino , Camundongos , Pentoxifilina/farmacologia , Sêmen/metabolismo , Contagem de Espermatozoides , Motilidade Espermática , Espermatozoides , Testosterona/metabolismo
10.
Exp Brain Res ; 240(11): 2907-2921, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36123538

RESUMO

Clinical studies suggest that chemotherapy is associated with long-term cognitive impairment in some patients. Several underlying mechanisms have been proposed; however, the etiology of chemotherapy-related cognitive dysfunction remains relatively unknown. There is evidence that oligodendrocytes and white matter tracts within the CNS may be particularly vulnerable to chemotherapy-related damage and dysfunction. Auditory brainstem responses (ABRs) have been used to detect and measure functional integrity of myelin in a variety of animal models of autoimmune disorders and demyelinating diseases. Limited evidence suggests that increases in interpeak latencies, associated with disrupted impulse conduction, can be detected in ABRs following 5-fluorouracil administration in mice. It is unknown if similar functional disruptions can be detected following treatment with other chemotherapeutic compounds and the extent to which alterations in ABR signals represent robust and long-lasting impairments associated with chemotherapy-related cognitive impairment. Thus, C57BL/6 J mice were treated every 3rd day for a total of 3 injections with low or high dose cyclophosphamide, or doxorubicin. ABRs of mice were assessed on days 1, 7, 14, 56 and 6 months following completion of chemotherapy administration. There were timing and amplitude differences in the ABRs of the doxorubicin and the high dose cyclophosphamide groups relative to the control animals. However, despite significant toxic effects as assessed by weight loss, the changes in the ABR were transient.


Assuntos
Doxorrubicina , Potenciais Evocados Auditivos do Tronco Encefálico , Animais , Camundongos , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Camundongos Endogâmicos C57BL , Doxorrubicina/toxicidade , Ciclofosfamida/toxicidade , Fluoruracila
11.
Food Chem Toxicol ; 169: 113433, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36122811

RESUMO

Cyclophosphamide (CTX) is a widely used anticancer drug that can cause liver injury, but there is no effective treatment available at present. The antioxidant properties of Lactobacillus plantarum Lp2 in vitro and its effect on CTX-induced liver injury in mice were investigated thoroughly. The order of antioxidant capacity of the fermentate of Lp2 was as followed: fermented supernatant > cell-free extract > intact cell. BALB/c mice were intraperitoneally injected with 80 mg/kg BW/d CTX for 3 days to build a liver injury model, then treated with Lp2 fermented supernatant (Lp2-s) and Lp2 culture broth (Lp2). After 10 days, the indicators of oxidative stress and liver injury were measured. Both Lp2-s and Lp2 restored the levels of T-SOD, CAT, GSH-Px, MDA, GSH, ALT, and AST. The western blotting results showed that Lp2-s and Lp2 ameliorated CTX-induced oxidative damage and hepatocyte apoptosis via inhibiting MAPKs pathway and strengthening Nrf2/HO-1/NQO1 antioxidant defense system, thus inhibiting the mitochondrial-mediated apoptosis pathway. Therefore, both Lp2-s and Lp2 had similar protective effects on CTX-induced liver injury.


Assuntos
Antineoplásicos , Antioxidantes , Doença Hepática Induzida por Substâncias e Drogas , Lactobacillus plantarum , Estresse Oxidativo , Animais , Camundongos , Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/terapia , Ciclofosfamida/toxicidade , Lactobacillus plantarum/metabolismo , Fígado/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/metabolismo
12.
Mar Drugs ; 20(9)2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36135750

RESUMO

Our study aimed to investigate the immune-enhancing mechanism of the pentadecapeptide (RVAPEEHPVEGRYLV) from Cyclina sinensis (SCSP) in a cyclophosphamide (CTX)-induced murine model of immunosuppression. Our results showed that SCSP treatment significantly increased mouse body weight, immune organ indices, and the production of serum IL-6, IL-1ß, and tumor necrosis factor (TNF)-α in CTX-treated mice. In addition, SCSP treatment enhanced the proliferation of splenic lymphocytes and peritoneal macrophages, as well as phagocytosis of the latter in a dose-dependent manner. Moreover, SCSP elevated the phosphorylation levels of p38, ERK, JNK, PI3K and Akt, and up-regulated IKKα, IKKß, p50 NF-κB and p65 NF-κB protein levels, while down-regulating IκBα protein levels. Our results indicate that SCSP has immune-enhancing activities, and that it can activate the MAPK/NF-κB and PI3K/Akt pathways to enhance immunity in CTX-induced immunosuppressed mice.


Assuntos
Quinase I-kappa B , NF-kappa B , Animais , Ciclofosfamida/toxicidade , Quinase I-kappa B/metabolismo , Quinase I-kappa B/farmacologia , Terapia de Imunossupressão , Interleucina-6 , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
13.
Tissue Cell ; 78: 101877, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35930992

RESUMO

Hemorrhagic cystitis (HC) is considered a fatal complication of cyclophosphamide (CP). Down-regulation of Nrf2 and induction of pro-inflammatory mediators are the main pathological factors. Recently, ameliorative potential of the angiotensin II (AII) type-1 (AT1) receptor blocker olmesartan (OLM) on oxidative stress and inflammatory cytokines was reported. The current study aims to investigate the possible protective effect of OLM on CP-induced HC in Wistar rats. The animals were divided into the control group (0.5% W/V carboxymethylcellulose, p.o.); OLM group (20 mg/kg, p.o., for 21 days); CP group (a single dose of 100 mg/kg, i.p.); and the remaining groups that received CP i.p. with oral OLM 5, 10 and 20 mg/kg for 21 days, respectively. The bladder tissue was collected for histopathology, immunohistochemistry, ELISA, Western blot, and oxidative stress assay. The OLM at doses of 10 and 20 mg/kg attenuated increase in TNF-α, IL-6, NF-kB, iNOS, and COX-2 induced by CP. Additionally, it up-regulated the Nrf2/HO-1 pathway, bladder GSH content, and CAT and SOD activities. The data indicated that OLM inhibited ROS-induced NF-kB, which caused inhibition of pro-inflammatory cytokines and activation of the Nrf2/HO-1 pathway. Hence, OLM holds great promise for preventing CP-induced HC.


Assuntos
Cistite , Fator 2 Relacionado a NF-E2 , Angiotensina II/metabolismo , Animais , Carboximetilcelulose Sódica , Ciclo-Oxigenase 2 , Ciclofosfamida/toxicidade , Cistite/induzido quimicamente , Cistite/tratamento farmacológico , Cistite/patologia , Citocinas/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Imidazóis , Mediadores da Inflamação/metabolismo , Interleucina-6/farmacologia , NF-kappa B/metabolismo , Estresse Oxidativo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Transdução de Sinais , Superóxido Dismutase/metabolismo , Tetrazóis , Fator de Necrose Tumoral alfa/metabolismo
14.
Reprod Toxicol ; 113: 42-51, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35981663

RESUMO

This study was conducted to evaluate the protective effects of epigallocatechin-3-gallate (EGCG) against ovarian toxicity in cyclophosphamide-treated mice and to verify the possible involvement of phosphorylated Akt, FOXO3a and rpS6 in the EGCG actions. Mice received saline solution (i.p.; control) or a single dose of cyclophosphamide (200 mg/kg body weight, i.p.) or mice were pretreated with N-acetylcysteine (150 mg/kg body weight, i.p.; positive control) or with EGCG (5, 25 or 50 mg/kg body weight, i.p.) once daily for three days followed by injection with single dose of cyclophosphamide (200 mg/kg body weight, i.p.). Thereafter, the mice were euthanized, and the ovaries were harvested and destined to histological (follicular morphology and activation), immunohistochemistry (cleaved caspase-3 and TNF-α) and fluorescence (mitochondrial activity and GSH concentrations) analyses. Furthermore, we examined the participation of p-Akt, p-FOXO3a and p-rpS6 in the protective effects of EGCG in cyclophosphamide-induced ovarian damage by immunohistochemical staining. The results showed that pretreatment with N-acetylcysteine or EGCG at 25 and 50 mg/kg before cyclophosphamide administration preserved the normal follicular morphology, prevented primordial follicle loss, reduced atresia, inflammation, and mitochondrial damage, and increased GSH concentrations compared to the only cyclophosphamide treatment. Additionally, pretreatment with 25 mg/kg EGCG regulated phosphorylated Akt, FOXO3a and rpS6 after cyclophosphamide treatment. In conclusion, short-time pretreatment with 25 mg/kg EGCG can prevent follicle loss in cyclophosphamide-treated mice by reducing oxidative damage, inflammation, and apoptosis, and regulating of p-Akt, p-FOXO3a and p-rpS6.


Assuntos
Catequina , Proteínas Proto-Oncogênicas c-akt , Acetilcisteína/farmacologia , Animais , Apoptose , Peso Corporal , Caspase 3/metabolismo , Catequina/análogos & derivados , Catequina/farmacologia , Ciclofosfamida/toxicidade , Feminino , Inflamação/induzido quimicamente , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Solução Salina/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
15.
Comput Math Methods Med ; 2022: 7963146, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35979049

RESUMO

Objective: The cardiac safety of concurrent treatment with anthracycline (A), cyclophosphamide (C), and paclitaxel (T) in an adjuvant BC treatment regimen is still under debate. In this study, we aimed to determine cardiotoxicity events following ACT chemotherapy among operable breast cancer patients without HER2-positive. Methods: We searched PubMed and the Cochrane Library for RCTs prior to July 2019 evaluating the cardiac impairment of ACT chemotherapy regimens in BC patients. The search terms were "BC," "chemotherapy," "docetaxel or "doxorubicin," "paclitaxel," and "cyclophosphamide." Cardiotoxic events included LVEF decline ≥ 10 points, congestive heart failure (CHF), and cardiac death. Results: In total, 12 studies with 4032 subjects were included in this meta-analysis, and all patients received ACT regimen. The analysis results indicated that LVEF decrease ≥ 10 points was the most common cardiotoxic event (16%; (95% CI (8%-24%)) with χ 2 = 95.75, P < 0.001, I 2 = 95.8%). CHF showed the lowest rate (1%; (95% CI (0%-1%)) with χ 2 = 8.00, P = 0.433, I 2 = 0.0%). Subgroup analysis demonstrated that the incidence of CHF due to A → C → T chemotherapy regimen was lower than that of other events, however, without significance. No significant difference was observed in the occurrence of cardiac death. Conclusion: The ACT regimen in patients with HER2-negative BC was associated with an increased risk of adverse cardiactoxic events.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Cardiotoxicidade , Antraciclinas/toxicidade , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/epidemiologia , Ciclofosfamida/toxicidade , Morte , Feminino , Insuficiência Cardíaca/induzido quimicamente , Humanos , Paclitaxel/toxicidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2
16.
Aquat Toxicol ; 250: 106246, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35917676

RESUMO

Cyclophosphamide, one of the earliest prescribed alkylating anticancer drugs, has been frequently detected in aquatic environments. However, its effects on fish behavior and associated mechanisms remain largely unknown. In this study, the behaviors, neurochemicals, and gut microbiota of adult zebrafish were investigated after 2 months of exposure to CP at 0.05, 0.5, 5, and 50 µg/L. Behavioral assays revealed that CP increased locomotion and anxiety, and decreased the cognition of zebrafish. The alteration of neurotransmitters and related gene expressions in the dopamine and gamma-aminobutyric acid pathways induced by CP may be responsible for the observed changes in locomotion and cognition of adult zebrafish. Meanwhile, CP increased the anxiety of adult zebrafish through the serotonin, acetylcholine, and histamine pathways in the brain. In addition, increased abundances of Fusobacteriales, Reyanellales, Staphylococcales, Rhodobacterals, and Patescibateria in the intestine at the CP-50 treatment were observed. The study has demonstrated that CP affects the locomotion, anxiety, and cognition in zebrafish, which might be linked with the dysfunction of neurochemicals in the brain. This study further suggests that the gut-brain axis might interact to modulate fish behaviors upon exposure to CP (maybe other organic pollutants). Further research is warranted to test this hypothesis.


Assuntos
Microbioma Gastrointestinal , Poluentes Químicos da Água , Animais , Comportamento Animal , Ciclofosfamida/toxicidade , Neurotransmissores/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo
17.
Life Sci ; 306: 120850, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35917938

RESUMO

BACKGROUND: Cyclophosphamide (CP) is a widely used chemotherapeutic drug. However, the associated nephrotoxicity restricts its clinical use. AIM: The present research was designed to study the impact of LCZ696 (LCZ); which is a combination of Sacubitril/Valsartan compared to valsartan (VAL) on CP-induced nephrotoxicity. MAIN METHODS: Sixty adult male Wistar rats were randomly and equally assigned into 6 groups as follows: Control, LCZ (30 mg/kg, p.o.), VAL (15 mg/kg, p.o.), CP (200 mg/kg, single dose, i.p.), CP/LCZ, and CP/VAL groups. LCZ and VAL were given once daily for 6 days prior to CP (groups 5 & 6). At the end of the experiment, kidney functions, oxidants/antioxidants, inflammatory and fibrotic biomarkers in renal tissues were assessed. Further, immunohistochemical, and histomorphometric analyses were carried out. KEY FINDINGS: In comparison with CP-treated rats, LCZ resulted in a significant reduction in serum urea (26.6 %) and creatinine (63 %), moreover it decreased renal content of reactive oxygen species (ROS), zinc finger E-box-binding homeobox (ZEB)-1, SMAD2/3, plasminogen activator inhibitor (PAI)-1, fibronectin, histone deacetylase (HDAC)-4, nuclear factor-kappa B (NF-κB) and miR-192 expression by ~40-60 % as well as the immunohistological expressions of transforming growth factor-ß (TGF-ß) and anti-phospho Histone (H2AX) by ~75 % reduction. Whereas the renal total antioxidant capacity (TAC), apelin-13, miR-200 expression, and the immunoreactivity of angiotensin-converting enzyme 2 (ACE2) were enhanced by ~3-4-folds. Noteworthy, the prophylactic effect of LCZ was superior to VAL on the histomorphometric and immunohistological levels. SIGNIFICANCE: Prophylactic administration of LCZ protected against CP-induced nephrotoxicity via up-regulating apelin-13/ACE2, miR-200, and down-regulating TGF-ß/SMAD 2/3 and miR-192.


Assuntos
Enzima de Conversão de Angiotensina 2 , MicroRNAs , Aminobutiratos , Animais , Compostos de Bifenilo , Ciclofosfamida/toxicidade , Regulação para Baixo , Combinação de Medicamentos , Peptídeos e Proteínas de Sinalização Intercelular , Rim/metabolismo , Masculino , MicroRNAs/metabolismo , Ratos , Ratos Wistar , Proteína Smad2 , Proteína Smad3 , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima , Valsartana/farmacologia
18.
Sci Rep ; 12(1): 13076, 2022 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-35906474

RESUMO

Cyclophosphamide (CYP) damages all mucosal defence lines and induces hemorrhagic cystitis (HC) leading to detrusor overactivity. Patients who undergo combined chemio-radiotherapy are at higher risk of HC. Potentilla chinensis extract (PCE) prevent oxidative stress-dependent diseases. Thus, the aim of the study was to investigate the effect of PCE on urinary bladder function in CYP-induced HC in preclinical study. 60 rats were divided into 4 groups, as follows: I-control, II-rats with CYP-induced HC, III-rats received PCE in dose of 500 mg/kg, and IV-rats with CYP-induced HC which received PCE in dose of 500 mg/kg. PCE or vehicle were administered orally for 14 days. The cystometry was performed 3 days after the last dose of the PCE. Next, urothelium thickness and oedema measurement and biochemical analyses were performed. Cyclophosphamide induced hemorrhagic cystitis. PCE had no influence on the urinary bladder function and micturition cycles in normal rats. PCE diminished the severity of CYP-induced hemorrhagic cystitis. In the urothelium the cyclophosphamide induced the elevation of CGRP, TNF-α, IL-6, IL-1ß, OTC3, NIT, and MAL. Also, the level of T-H protein, HB-EGF, and ZO1 was decreased. Moreover, the level of ROCK1 and VAChT in detrusor muscle increased. cyclophosphamide caused an increased concentration of BDNF and NGF in the urine. In turn, PCE in cyclophosphamide-induced hemorrhagic cystitis caused a reversal of the described biochemical changes within urothelium, detrusor muscle and urine. PCE attenuates detrusor overactivity. In conclusion, our results revealed that PCE attenuates detrusor overactivity in case of cyclophosphamide-induced hemorrhagic cystitis. The potential properties of PCE appear to be important in terms of preventing of oxidative stress-dependent dysfunction of urinary bladder. PCE may become a potential supportive treatment in patient to whom cyclophosphamide-based chemotherapy is used.


Assuntos
Cistite , Potentilla , Animais , Ciclofosfamida/toxicidade , Cistite/induzido quimicamente , Cistite/tratamento farmacológico , Cistite/metabolismo , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hemorragia/metabolismo , Ratos , Ratos Wistar , Bexiga Urinária/metabolismo
19.
J Biochem Mol Toxicol ; 36(11): e23179, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35906875

RESUMO

This study investigated the protective effect of quercetin against cyclophosphamide-induced immunosuppressive indoleamine 2,3-dioxygenase (IDO) via the mechanism of oxidative-inflammatory stress and behavioral indices. Cyclophosphamide (CYP) was administered to male Wister rats at a dose of 100 mg/kg with or without quercetin 50 mg/kg every other day for 7 days. Experimental techniques including western blotting, immunohistochemistry analysis, and inflammatory and oxidative stress marker assays were carried out. We also conducted behavioral analyses such as open field, tail suspension, and Y-maze tests for cognitive assessment. The results indicated that quercetin attenuated oxidative-inflammatory stress induced by CYP in the hippocampus and cerebral cortex of male Wister rats by augmenting the activities of antioxidant enzymes and suppressing lipid peroxidation as well as inflammatory mediators such as interleukin-6 and interferon-γ. Concomitantly, quercetin partially prevented the alteration in brain tissue histological architecture and mitigated the activities of IDO/tryptophan 2,3-dioxygenase (TDO) and protein expression of IDO1. This was corroborated by the IDO-quercetin model obtained in silico, revealing a favorable inhibitory interaction between quercetin and the enzyme. Finally, the results of behavioral tests suggested that quercetin significantly prevented the depressive-like posture of the CYP-treated rats. Our study for the first time revealed that quercetin ameliorates the effect of CYP-instigated IDO/TDO activities in the cerebral cortex and hippocampus via restoration of antioxidant enzymes and preventing oxidative-inflammatory stress.


Assuntos
Indolamina-Pirrol 2,3,-Dioxigenase , Quercetina , Animais , Ratos , Masculino , Quercetina/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/farmacologia , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Ratos Wistar , Hipocampo/metabolismo , Ciclofosfamida/toxicidade , Córtex Cerebral/metabolismo
20.
Hum Exp Toxicol ; 41: 9603271221111440, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35762198

RESUMO

Drug-induced cardiotoxicity is a serious adverse effect that occurs during the administration of chemotherapeutic agents such as cyclophosphamide (CYC). Therefore, there is a critical need to find cardioprotective agents to keep the heart healthy. The current study aimed to investigate the protective effect of simvastatin (SIM) against CYC-induced heart damage and evaluate different mechanisms involved in mediating this effect, including the inflammasome/caspase1/interleukin1ß (IL1ß) pathway and endothelial nitric oxide synthase (eNOS). 36 rats were randomly assigned to one of four groups: a control group that received only vehicles, a CYC group that received CYC (150 mg/kg/day) i.p. on the fourth and fifth days, a CYC+SIM group that received SIM (10 mg/kg/day) orally for 5 days and CYC (150 mg/kg/day) i.p. on the fourth and fifth days, and a CYC+SIM+ Nitro- ω-L-arginine (L-NNA) group that received L-NNA (25 mg/kg/day, SIM (10 mg/kg/day) orally for 5 days and CYC (150 mg/kg/day) i.p. on the 4th and 5th days. The CYC group revealed an obvious elevation in cardiac enzymes and heart weights with toxic histopathological changes. Moreover, there was an increase in malondialdehyde (MDA), tumor necrosis factor-alpha (TNFα) levels, and up-regulation of the NLRP3inflammasome/caspase1/IL1ß pathway. In addition, total antioxidant capacity (TAC), eNOS, reduced glutathione (GSH), and superoxide dismutase (SOD) significantly decreased. CYC-induced cardiotoxicity was most properly reversed by SIM through its anti-oxidant, anti-inflammatory, and anti-apoptotic actions with the stimulation of eNOS. The co-administration of L-NNA diminished the protective effect of SIM, indicating the essential role of eNOS in mediating this effect. Therefore, SIM ameliorated CYC-induced cardiotoxicity.


Assuntos
Inflamassomos , Sinvastatina , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/prevenção & controle , Ciclofosfamida/toxicidade , Malondialdeído/metabolismo , Ratos , Sinvastatina/farmacologia , Sinvastatina/uso terapêutico
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