RESUMEN
Methotrexate (MTX) is a commonly used chemotherapeutic agent. Oxidative stress and inflammation have been proved in the development of MTX toxicity. Paeonol is a natural phenolic compound with various pharmacological activities including antioxidant and anti-inflammatory properties. The aim of the present study was to evaluate the protective effect of paeonol against MTX-induced cardiac toxicity in rats and to evaluate the various mechanisms that underlie this effect. Paeonol (100 mg/kg) was administered orally for 10 days. MTX cardiac toxicity was induced at the end of the fifth day of the experiment, with or without paeonol pretreatment. MTX-induced cardiac damage is evidenced by a distortion in the normal cardiac histological structure, with significant oxidative and nitrosative stress shown as a significant increase in NADPH oxidase-2, malondialdehyde, and nitric oxide levels along with a decrease in reduced glutathione concentration and superoxide dismutase activity compared to the control group. MTX-induced inflammatory effects are evidenced by the increased cardiac toll-like receptor 4 (TLR4) mRNA expression and protein level as well as increased cardiac tumor necrosis factor- (TNF-) α and interleukin- (IL-) 6 levels along with increased nuclear factor- (NF-) κB/p65 immunostaining. MTX increased apoptosis as shown by the upregulation of cardiac caspase 3 immunostaining. Paeonol was able to correct the oxidative and nitrosative stress as well as the inflammatory and apoptotic parameters and restore the normal histological structure compared to MTX alone. In conclusion, paeonol has a protective effect against MTX-induced cardiac toxicity through inhibiting oxidative and nitrosative stress and suppressing the TLR4/NF-κB/TNF-α/IL-6 inflammatory pathway, as well as causing an associated reduction in the proapoptotic marker, caspase 3.
Asunto(s)
Acetofenonas/uso terapéutico , Cardiotoxicidad/tratamiento farmacológico , Cardiotoxicidad/metabolismo , Metotrexato/toxicidad , FN-kappa B/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Caspasa 3/metabolismo , Inmunohistoquímica , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIA/metabolismoRESUMEN
Essential oils extracted by hydro-distillation form date palm spathe (byproduct from date palm plants) were tested for their antibacterial activity against some food-borne pathogens. Listeria monocytogenes ATCC 7644, Staphylococcus aureus ATCC 29243, Salmonella enterica subsp. enterica serovar Enteritidis ATCC 13076 and E. coli ATCC 25922 were inhibited (11-13â¯mm inhibition zones) by spathe essential oils (SEOs) using the agar well assay (in vitro test). Staphylococcus aureus ATCC 29243 and E. coli ATCC 25922 were not detected in chicken meat treated with 1% (v/w) SEOs and subjected to abusive storage conditions (20⯰C for 18â¯h). When treated with 0.5% SEO, counts of S. aureus and E. coli increased by only 0.2 and 0.7â¯log10â¯cfu/g, respectively, compared to the initial inoculated level in meat samples stored at 20⯰C for 18â¯h. SEOs possessed DPPH radical scavenging activity with IC50 of 0.61⯵g/ml. Forty one compounds were major constituents detected by GC-MS analysis of SEOs. 3,4-Dimethoxytoluene (38.12%) and 5,9-Undecadien-2-one (12.45%) were major compounds in extracted oils. Density and refractive index of SEOs were 0.987 and 1.5905, respectively. SOEs are added-value products from date palm, which could be employed in food industry and pharmaceuticals. The study is the first report on antibacterial activity of SEOs against L. monocytogenes ATCC 7644 and other standard food-borne pathogens in agar diffusion assay and food model (chicken meat). DPPH radical scavenging activity of SEOs has not previously been documented.
Asunto(s)
Bacterias/efectos de los fármacos , Microbiología de Alimentos/métodos , Aceites Volátiles/farmacología , Phoeniceae/química , Animales , Antibacterianos/farmacología , Pollos , Escherichia coli/efectos de los fármacos , Cromatografía de Gases y Espectrometría de Masas , Concentración 50 Inhibidora , Listeria monocytogenes/efectos de los fármacos , Carne/microbiología , Salmonella enteritidis/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacosRESUMEN
To investigate compound-protein binding mode and molecular dynamic simulation of P-glycoprotein (P-gp), in silico studies were performed to compare 12 naturally occurring compounds using two softwares. The net results showed that piperine (PIP) had the best binding affinity. In vitro studies on doxorubicin (DOX)-resistant NCI/ADR-RES cells, known to express P-gp, showed that, dose-dependently, PIP significantly increased intracellular accumulation of rhodamine-123 and had cytotoxic effects accessed by MTT assay. In addition, PIP at 25 and 50µM significantly potentiated DOX-induced cytotoxicity on the same cell line. P-gp ATPase assay showed that both DOX and PIP had dose-dependent inhibition of orthovandate-sensitive ATPase activity, indicating they are both P-gp inhibitors, with IC50 of 84±1 and 37±2µM, respectively. PIP did not show any activation of ATPase activity, while DOX did, indicating that P-gp does not accept PIP as a substrate. Using DOX at concentration 33.33µM together with PIP (100µM), DOX-mediated P-gp ATPase activity was decreased to levels 4-folds lower than DOX alone. In conclusion, both in silico and in vitro studies confirm that PIP is an inhibitor of P-gp mediated DOX efflux, suggesting PIP as a promising adjuvant to DOX cancer chemotherapy.
Asunto(s)
Alcaloides/farmacología , Antibióticos Antineoplásicos/farmacología , Benzodioxoles/farmacología , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Adenosina Trifosfatasas/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Simulación del Acoplamiento MolecularRESUMEN
Resveratrol (RES) is a well-known polyphenol antioxidant. We have previously shown that testicular protective effect of RES against the anticancer drug methotrexate (MTX)-induced toxicity involves transporter-mediated mechanisms. Here, we investigated the effect of RES on MTX-induced nephrotoxicity. Rats were administered RES (10 mg/kg/day) for 8 days, with or without a single MTX dose (20 mg/kg i.p.) at day 4 of the experiment. MTX induced nephrotoxicity, as evidenced by a significant increase in serum blood urea nitrogen and creatinine compared to the control, as well as distortion of kidney microscopic structure. MTX also significantly increased renal nitric oxide level along with inducible nitric oxide synthase, fas ligand, and caspase 3 expressions. Administering RES prior to MTX significantly improved kidney function and microscopic picture and also significantly decreased nitrosative and apoptotic markers compared to MTX alone. RES, but not MTX, caused a significant increase in expression of breast cancer resistance protein (BCRP), an apical efflux renal transporter that participates in urinary elimination of both MTX and RES. Interestingly, concomitant MTX and RES caused further upregulation of renal BCRP compared to RES alone. Using Human BCRP ATPase assay, both RES and MTX exhibited a dose-dependent increase in ATPase activity, with Km values of 0.52 ± 0.03 and 30.9 ± 4.2 µm, respectively. Furthermore, combined RES and MTX caused ATPase activity which was significantly less than maximum ATPase activity attained by the positive control, sulfasalazine (12.5 µm). In conclusion, RES exerted nephroprotection against MTX-induced toxicity through antinitrosative and anti-apoptotic effects, as well as via upregulation of renal BCRP.
Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/biosíntesis , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/prevención & control , Antioxidantes/uso terapéutico , Metotrexato/toxicidad , Proteínas de Neoplasias/biosíntesis , Estilbenos/uso terapéutico , Lesión Renal Aguda/inducido químicamente , Animales , Antimetabolitos Antineoplásicos/toxicidad , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Sustancias Protectoras/uso terapéutico , Ratas , Ratas Wistar , ResveratrolRESUMEN
AIMS: To investigate the effect of resveratrol (RES) on methotrexate (MTX)-induced testicular damage. MAIN METHODS: RES (10mg/kg/day) was given for 8 days orally and MTX (20mg/kg i.p.) was given at day 4 of the experiment, with or without RES in rat. KEY FINDINGS: MTX decreased serum testosterone, induced histopathological testicular damage, and increased testicular tumor necrosis factor-α level and expression of nuclear factor-κB and cyclooxygenase-2. In MTX/RES group, significant reversal of these parameters was noticed, compared to MTX group. Testicular expression of multidrug resistance protein (Mrp) 3 was three- and five-folds higher in RES- and MTX/RES-treated groups, respectively. In vitro, using prostate cancer cells, each of MTX and RES alone induced cytotoxicity with IC50 0.18 ± 0.08 and 20.5 ± 3.6 µM, respectively. RES also significantly enhanced cytotoxicity of MTX. SIGNIFICANCE: Thus, RES has dual beneficial effects, as it promotes MTX tumor cytotoxicity, while protecting the testes, probably via up-regulation of testicular Mrp3 as a novel mechanism.