RESUMEN
Radiotherapy is one of the principal approaches employed in the treatment of pelvic cancers. Nevertheless, testicular dysfunction and infertility are among the most common adverse effects in young adult cancer survivors. Clinically, alpha-lipoic acid (LA) has been applied to improve the quality of sperm with a satisfactory effect. Therefore, the present study investigated the underlying mechanisms of the radioprotective effects of LA against testicular damage. Male Sprague-Dawley rats were exposed to 10â¯Gy of whole-body Ï-radiation and LA (50â¯mg/kg, P.O.) was administered one week before and three days post-irradiation. LA showed remarkable capacity in preserving testicular tissue against radiation damage by improving histological and ultrastructural changes of disorganized seminiferous tubules, besides enhancing its diameter, germinal epithelial thickness, and Johnsen's score. Radiation instigated a significant decrease in sperm quality and quantity associated with depletion of serum testosterone levels, while the LA administration maintained spermatogenesis. Strikingly, LA exhibited antioxidant properties by restoring reduced glutathione levels and antioxidant enzyme activities such as catalase and glutathione-s-transferase, besides diminishing malondialdehyde levels in the testis of irradiated group. Furthermore, LA alleviated testicular inflammation through downregulation of nuclear factor-ĸB (NF-ĸB) expression with a subsequent reduction in interleukin (IL)-6 and cyclooxygenase-2 expression, accompanied by the augmented expression of the anti-inflammatory cytokine IL-10. Additionally, testicular fibrosis markers including Masson's trichrome and transforming growth factor (TGF)-ß expression were noticeably declined in LA-treated irradiated rats, together with the upregulation of peroxisome proliferator-activated receptor-Ï expression. Collectively, LA ameliorates radiation-mediated spermatogenesis-defects and testicular-damage via suppression of oxidative stress/NF-ĸB/TGF-ß signaling.
Asunto(s)
Rayos gamma , Traumatismos Experimentales por Radiación/prevención & control , Protectores contra Radiación/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/efectos de la radiación , Enfermedades Testiculares/prevención & control , Ácido Tióctico/farmacología , Animales , Antioxidantes/farmacología , Citocinas/biosíntesis , Epitelio/efectos de los fármacos , Epitelio/efectos de la radiación , Masculino , FN-kappa B/efectos de los fármacos , FN-kappa B/efectos de la radiación , PPAR gamma/efectos de los fármacos , PPAR gamma/efectos de la radiación , Traumatismos Experimentales por Radiación/patología , Ratas , Ratas Sprague-Dawley , Espermatozoides/efectos de los fármacos , Espermatozoides/efectos de la radiación , Enfermedades Testiculares/patología , Testículo/patología , Testículo/efectos de la radiación , Testosterona/sangre , Factor de Crecimiento Transformador beta/efectos de los fármacos , Factor de Crecimiento Transformador beta/efectos de la radiación , Irradiación Corporal TotalRESUMEN
Radiation-induced intestinal injuries, including inflammation and immune response, remain a limiting factor in the effectiveness of pelvic radiotherapy and in the patient's quality of life during and after treatment. Peroxisome proliferation-activated receptor (PPAR) agonists are now emerging as therapeutic drugs for various inflammatory diseases that are characterized by impaired PPAR expression. The purpose of this study was to investigate the profile of PPAR expression in rat colonic mucosa 3 and 7 days after abdominal gamma-irradiation (10 Gy). We tested whether irradiation-induced acute inflammatory response could be modulated pharmacologically with the antiinflammatory properties of 5-aminosalicylic acid (5-ASA) (250 mg/kg/day), which is a PPAR activator. Irradiation drastically reduced mRNA and protein levels of PPARalpha and -gamma and of the heterodimer retinoid X receptor (RXR)alpha at 3 days postirradiation. 5-ASA treatment normalized both PPARgamma and RXRalpha expression at 3 days postirradiation and PPARalpha at 7 days. By promoting PPAR expression and its nuclear translocation, 5-ASA interfered with the nuclear factor (NF)-kappaB pathway, both by reducing irradiation-induced NF-kappaB p65 translocation/activation and increasing the expression of nuclear factor-kappaB inhibitor (IkappaB) mRNA and protein. Therefore, 5-ASA prevents irradiation-induced inflammatory processes as well as expression of tumor necrosis factor alpha, monocyte chemotactic protein-1, inducible nitric-oxide synthase, and macrophage infiltration. In addition, 5-ASA restores the interferon gamma/signal transducer and activator of transcription (STAT)-1 and STAT-3 concentrations that were impaired at 3 and 7 days postirradiation and are correlated with suppressor of cytokine signaling-3 repression. Collectively, these results indicate that PPAR agonists may be effective in the prevention of inflammatory processes and immune responses during and after pelvic radiotherapy.
Asunto(s)
Colitis/metabolismo , Rayos gamma , Regulación de la Expresión Génica/efectos de la radiación , Mesalamina/farmacología , PPAR gamma/agonistas , PPAR gamma/efectos de la radiación , Animales , Colitis/tratamiento farmacológico , Colitis/patología , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Masculino , Mesalamina/uso terapéutico , PPAR gamma/metabolismo , Ratas , Ratas WistarRESUMEN
Ultraviolet B radiation (UVB) is a pro-oxidative stressor with profound effects on skin in part through its ability to stimulate cytokine production. Peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to regulate inflammatory processes and cytokine release in various cell types. Since the oxidized glycerophospholipid 1-hexadecyl-2-azelaoyl glycerophosphocholine (azPC) has been shown to be a potent PPAR gamma agonist, this study was designed to assess whether the PPAR gamma system is a target for UVB irradiation and involved in UVB-induced inflammation in epidermal cells. The present studies demonstrated the presence of PPAR gamma mRNA and functional protein in human keratinocytes and epithelial cell lines HaCaT, KB, and A431. The treatment of epidermal cells with the PPAR gamma-specific agonist ciglitazone or azPC augmented cyclooxygenase-2 expression and enzyme activity induced by phorbol 12-myristate-13-acetate or interleukin-1 beta. Lipid extracts from the cell homogenate of UVB-irradiated, but not control, cells contained a PPAR gamma-agonistic activity identified by reporter assay, and this activity up-regulated cyclooxygenase-2 expression induced by phorbol 12-myristate-13-acetate. Subjecting purified 1-hexadecyl-2-arachidonoyl-glycerophosphocholine to UVB irradiation generated a PPAR gamma-agonistic activity, among which the specific PPAR gamma agonist azPC was identified by mass spectrometry. These findings suggested that UVB-generated PPAR gamma-agonistic activity was due to the free radical mediated non-enzymatic cleavage of endogenous glycerophosphocholines. Treatment with the specific PPAR gamma antagonist GW9662 or expression of a dominant-negative PPAR gamma mutant in KB cells inhibited UVB-induced epidermal cell prostaglandin E(2) production. These findings suggested that UVB-generated PPAR gamma activity is necessary for the optimal production of epidermal prostaglandins. These studies demonstrated that epithelial cells contain a functional PPAR gamma system, and this system is a target for UVB through the production of novel oxidatively modified endogenous phospholipids.