Melatonin attenuates thioacetamide-induced liver fibrosis in male rats through modulation of interleukin-6, interleukin-4, apoptosis and urokinase plasminogen activator receptor-associated protein/Endo180.

Liver fibrosis is a chronic progressive disease, its resolution still unclear, and the current study explored the role of melatonin in modulation of interleukin-6 (IL-6), interleukin-4 (IL-4), transforming growth factor beta1 (TGF-ß1) and urokinase plasminogen activator receptor-associated protein/Endo180 (uPARAP/Endo180) pathway in thioacetamide (TAA)-induced hepatotoxicity. Thirty two adult Sprague-Dawley rats were divided into four groups: vehicle control group, TAA-induced liver fibrosis group that was left untreated, melatonin administration before and along with TAA and melatonin along with TAA group. TTA-induced massive liver necrosis, fibrosis around portal tract and increases serum levels of liver enzymes and total bilirubin when compared with control vehicle group. While both melatonin pretreatment and treatment retained liver parenchyma and liver enzymes quite similar to control group and reduced TAA-induced liver injury. Notably, melatonin pretreatment and treatment increased collagen degradation in TAA liver injury by19, 31.7-fold respectively evidence by collagen percentage area. Melatonin also decreased the amount of thiobarbituric acid reactive compounds and retained the reduced glutathione and superoxide dismutase to basal level quite similar to control group. Additionally, melatonin significantly (P value ≤0.05) decreased the levels of TGF-ß1, epidermal growth factor (EGF), hydroxyproline, tissues IL-6, caspase-3, and receptor interacting serine/threonine kinase1 (RIPK1), fibrillin-1, and - smooth muscle actin in the liver tissues while significantly (P value ≤0.05) increasing the levels of IL-4 and uPARAP/Endo180. Due to its anti-inflammatory, anti-apoptotic, and antioxidant capabilities as well as its ability to decrease hepatic stellate cell activation and fibrogenesis, these data imply that melatonin has a powerful anti-fibrotic effect.

Programmed cell death in varicocele-bearing testes.

Accelerated apoptosis is a significant factor in the pathophysiology of male infertility disorders associated with abnormal spermatogenesis. This study aimed to investigate apoptosis in varicocele-bearing testes. Sixty four men with varicocele (18 fertile and 46 infertile) were studied compared with eight men with obstructive azoospermic as controls. Apoptosis was assessed in testicular biopsy specimens using terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) method as well as electron microscopy. The results demonstrated that the occurrence of apoptotic changes comprised all types of germ cells but not affecting Sertoli cells. Mean tubular apoptotic indices of fertile or infertile men with varicocele were significantly higher than controls (mean +/- SD 4.55 +/- 1.03%, 6.29 +/- 1.82% versus 2.71 +/- 0.45%, P < 0.05). Mean Leydig cells apoptotic indices of infertile men with varicocele were significantly higher than those of fertile men without varicocele as well as controls (1.18 +/- 0.38%, 0.68 +/- 0.15%, 0.31 +/- 0.21%, P < 0.05). Apoptotic indices were nonsignificantly correlated with Johnsen score, testicular volume or varicocele grade. It is concluded that testicular apoptosis is increased in varicocele-associated men either fertile or infertile who may be implicated in associated spermatogenic dysfunction.

IL-10 gene expression as a marker for detection of protective immunity levels with irradiated cercarial vaccine against experimental Schistosoma mansoni infection.

Cercariae were obtained in a large number from the maintained life cycle of S. mansoni. They were attenuated at different doses (20 Kr, 50 Kr, 60 Kr, 70 Kr and 80 Kr) of gamma radiation. Laboratory bred Swiss Albino mice were classified into 7 groups. Five groups were immunized with +/-500 S. mansoni cercariae. Two groups were used as positive and negative controls. All animals were sacrificed after 8 weeks. Spleen cell proliferative responses to Phytohaemagglutinin (PHA) were assessed in all groups. IL-10 was measured by ELISA in serum and splenic cells secretion in-vitro. RNA extracted from freshly isolated liver cells was analyzed for detection of mRNA of IL-10 by reverse transcriptase polymerase chain reaction (RT-PCR). The results showed augmentation of proliferative cell from the spleen in all vaccinated groups except with 80 Kr, irradiated cercariae group. The highest percentage of lymphocytes transformation was recorded among the mice immunized with 60 Kr, irradiated cercariae. After challenge, splenic responses in all groups declined progressively to the control level. IL-10 secretion from spleen cells of all vaccinated groups increased after challenge with the least level in 60 Kr, immunized challenged group. IL-10 mRNA expression was higher among 60 Kr, immunized with irradiated cercariae mice group than 70 Kr, one, but with no expression among 80 Kr, cercariae immunized ones.

Vaccination against Schistosoma mansoni infection using 74 kDa Schistosoma protein antigen.

An IgG2a anti-Schistosoma mansoni mouse monoclonal antibody was shown to passively protect Swiss mice. The 74 kDa target antigen was isolated from antigenic extracts of S. mansoni adult worms. Swiss and C57 BL/6J mice were immunized with 30, 50, 100 and 200 microg antigen/mouse doses with and without Freund's adjuvant. Sera of immunized mice showed high reactivity against 74 kDa antigen. The highest protection level (76.6% in Swiss mice and 50.1% in C57 BL/6J mice) was obtained using the 50 microg antigen dose with and without Freund's adjuvant. A marked reduction in granuloma number and intensity of collagen and reticular granuloma fibers was observed. The 74 kDa antigen has the ability to protect mice of different strains and to modulate the host immune system.

Induction of resistance against Schistosoma mansoni infection by passive transfer of an IgG2a monoclonal antibody.

Monoclonal antibodies can confer resistance to schistosome infections. This has led to identification of several protective antigens. An IgG2a monoclonal antibody designated BRL4 mAb identified a 74-kDa antigen in antigenic extract of Schistosoma mansoni adult worms. The target antigen was localized in gut and tegument. In 3 passive transfer experiments, the BRL4 mAb conferred 51.6, 41.9 and 53.8% protection levels into female Swiss mice. Histopathological examination revealed a marked decrease in number, size, collagen and reticular fibers of the liver granulomas. Further experiments using purified 74-kDa-target antigen as a candidate vaccine will be performed.

Mechanism of action of the intrauterine contraceptive device: evidence for a specific biochemical deficiency in the endometrium.

The precise mechanism of action of the intrauterine contraceptive device (IUCD) is uncertain. In this study we compared the circulating concentrations of a specific endometrial protein, placental protein 14 (PP14), in 62 women with an IUCD and 16 controls. The concentrations of PP14 were substantially lower in IUCD users. There was no difference in the concentrations of another and less specific endometrial protein, insulin-like growth factor binding protein-1 (IGFBP-1). There was no difference in PP14 concentrations between those women with and without intermenstrual bleeding. We conclude that the reduced concentrations of PP14 in IUCD users reflect defective endometrial function in these women, probably related to the contraceptive effect. We propose that the measurement of PP14 might be a means of comparing the efficiency of different devices.