Role of serotonin, estrogen, and TNF-α in the paroxetine-impaired steroidogenesis and testicular macrophages polarization.

BACKGROUND: Paroxetine, a selective serotonin reuptake inhibitor (SSRI) antidepressant, has caused male sexual dysfunction; however, the paroxetine mechanisms of action in testes are still unclear. OBJECTIVES: Paroxetine serotonergic effects in testes were evaluated, focusing on steroidogenesis and the correlation between macrophages population and possible TNF-α-derived oxidative stress. We also verified whether the changes are reversible following treatment interruption. MATERIALS AND METHODS: Adult rats received paroxetine (PG35 and PG65) or tap water (CG) for 35 days. PG65 was maintained without treatment for 30 more days. Intratesticular testosterone (IT), nitrite, and malondialdehyde concentrations were measured. To confirm serotonergic and estrogenic effects, Htr1b and Esr1 expressions were analyzed. The daily sperm production (DSP), frequency of abnormal seminiferous tubules (ST), SC number, ST area, and Leydig cells nuclear area (LCnu) were evaluated. TUNEL+ germ cells, M1 (CD68+ ), and M2 (Perls+ ) macrophages were quantified. 17ß-HSD7, CYP19A1, NDRG2, oxytocin, TNF-α, and iNOS were evaluated by immunoreactions. Oxytocin and NDRG2 protein levels as well as Tnfa mRNA expression were also analyzed. RESULTS: The Htr1b downregulation in testes confirmed the paroxetine serotonergic effect. The testicular sections showed abnormal ST frequency, ST atrophy and reduction of DSP, LCnu, SC number and Perls+ macrophages. TUNEL+ germ cells and LC were associated with strong NDRG2 immunoexpression. Paroxetine reduced IT levels and 17ß-HSD7 immunoexpression in parallel to increased CYP19A1, oxytocin, TNF-α and iNOS. Esr1 and Tnfa overexpression and increased number of CD68+ macrophages were also observed together with high nitrite and malondialdehyde levels. Most parameters were not recovered in PG65. CONCLUSIONS: Paroxetine serotonergic effect impairs LC steroidogenesis, via aromatization, increasing estrogen/testosterone ratio, which in turn upregulate NDRG2, promoting apoptosis, and impairing sperm production. Serotonin-estrogen pathways may be responsible for M2/M1 polarization, Tnfa upregulation, and induction of oxidative stress. The unrecovered testicular changes after treatment discontinuation are due to persistent paroxetine serotonin/estrogen effects.

Anchusa italica extract: phytochemical and neuroprotective evaluation on global cerebral ischemia and reperfusion

Abstract Stroke is the third leading cause of mortality and disability in industrial countries. Treatment with herbs with antioxidant properties has been reported to be an alternative to the conventional treatments. This study was conducted to investigate the effect of Anchusa italica extract on hippocampal injury induced by transient global cerebral ischemia and reperfusion in the rat. To do so, 50 rats were randomly assigned to five groups; control, sham, ischemia, and 50 or 100 mg/kg of Anchusa italica treated animals. Ischemia was induced by occlusion of carotid artery for 30 minutes. Afterward, behavioral tests and biochemical analyses were conducted. Induction of ischemia/reperfusion caused a decline in learning and passive avoidance memory in rats. Moreover, Anchusa italica caused an increase in learning and improved the passive avoidance memory. Induction of ischemia/reperfusion caused a decrease in the antioxidant capacity of the brain and serum as well as an increase in the malondialdehyde of the brain and serum. Anchusa italica led to an increase in the antioxidant capacity of the brain and serum and decrease in the malondialdehyde of the brain and serum. Overall, because of its protective effects on spatial memory, passive avoidance learning, antioxidant capacity, and lipid peroxidation during ischemia/reperfusion, Anchusa italica might be beneficial in ischemic patients.

Antitumor function and mechanism of phycoerythrin from Porphyra haitanensis.

The anti-tumor effect of R-Phycoerythrin (R-PE) from Porphyra haitanensis was studied using cell line HeLa as an in vitro model and Sarcoma-180 (S180) tumor-bearing mice as an in vivo model. The results showed that the combination treatment of R-PE and photodynamic therapy PDT) significantly inhibited the growth of HeLa cells up to 81.5%, with a fair dose-effect relationship, but did not inhibit endothelial cells. The annexin v-fitc/PI fluorescence staining experiments demonstrated that at doses between 0~60µg/mL, apoptosis cells and later stage apoptosis cells or necrosis cells increased significantly as the R-PE dosage increased. DNA electrophoresis showed that after R-PE+PDT treatment of HeLa cells for 24 hours, a light "smear" band between 100~400bp appeared to indicate the degradation of genomic DNA. The QRT-PCR results showed that R-PE+PDT treatment increased caspase-3 and caspase-10 gene expression and decreased the Bcl-2 gene expression level significantly as the R-PE dose increased, implying that R-PE promoted HeLa cell apoptosis. Compared with untreated S180 tumor-bearing mice, R-PE injection significantly inhibited the growth of S180 in tumor-bearing mice up to 41.3% at a dose of 300mg-kg⁻¹. Simultaneously, the significant increase of superoxide dismutase (SOD) activity in serum (p < 0.01) and the decrease of the malondialdehyde (MDA) level in liver suggests that R-PE improved the anti-oxidant ability of the S180 tumor-bearing mice, which may related to its antitumor effect. In addition, the R-PE caused a significant increase (p < 0.05) in the spleen index and thymus index, and a significant increase (p < 0.01) in lymphocyte proliferation, NK cell kill activity and the TNF-α level in the serum of S180 tumor-bearing mice. These results strongly suggest that the antitumor effect of R-PE from Porphyra haitanensis functioned by increasing the immunity and antioxidant ability of S180 tumor-bearing mice, promoting apoptosis by increasing protease gene expression and TNF-α secretion.

Antitumor function and mechanism of phycoerythrin from Porphyra haitanensis

The anti-tumor effect of R-Phycoerythrin (R-PE) from Porphyra haitanensis was studied using cell line HeLa as an in vitro model and Sarcoma-180 (S180) tumor-bearing mice as an in vivo model. The results showed that the combination treatment of R-PE and photodynamic therapy PDT) significantly inhibited the growth of HeLa cells up to 81.5%, with a fair dose-effect relationship, but did not inhibit endothelial cells. The annexin v-fitc/PI fluorescence staining experiments demonstrated that at doses between 0~60µg/mL, apoptosis cells and later stage apoptosis cells or necrosis cells increased significantly as the R-PE dosage increased. DNA electrophoresis showed that after R-PE+PDT treatment of HeLa cells for 24 hours, a light "smear" band between 100~400bp appeared to indicate the degradation of genomic DNA. The QRT-PCR results showed that R-PE+PDT treatment increased caspase-3 and caspase-10 gene expression and decreased the Bcl-2 gene expression level significantly as the R-PE dose increased, implying that R-PE promoted HeLa cell apoptosis. Compared with untreated S180 tumor-bearing mice, R-PE injection significantly inhibited the growth of S180 in tumor-bearing mice up to 41.3% at a dose of 300mg-kg-1. Simultaneously, the significant increase of superoxide dismutase (SOD) activity in serum (p < 0.01) and the decrease of the malondialdehyde (MDA) level in liver suggests that R-PE improved the anti-oxidant ability of the S180 tumor-bearing mice, which may related to its antitumor effect. In addition, the R-PE caused a significant increase (p < 0.05) in the spleen index and thymus index, and a significant increase (p < 0.01) in lymphocyte proliferation, NK cell kill activity and the TNF-α level in the serum of S180 tumor-bearing mice. These results strongly suggest that the antitumor effect of R-PE from Porphyra haitanensis functioned by increasing the immunity and antioxidant ability of S180 tumor-bearing mice, promoting apoptosis by increasing protease gene expression and TNF-α secretion.

Promotion of oxidative stress by 3-hydroxyglutaric acid in rat striatum.

The pathophysiology of the striatum degeneration characteristic of patients affected by the inherited neurometabolic disorder glutaryl-CoA dehydrogenase deficiency (GDD), also known as glutaric aciduria type I, is still in debate. We have previously reported that 3-hydroxyglutaric acid (3-OH-GA) considered the main neurotoxin in this disorder, induces oxidative stress in rat cerebral cotex. In the present work, we extended these studies by investigating the in vitro effect of 3-OH-GA, at concentrations ranging from 0.01 to 1.0 mmol/L on the brain antioxidant defences by measuring total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) and glutathione (GSH) levels, and on the production of hydrogen peroxide (H(2)O(2)), nitric oxide (NO) and malondialdehyde in striatum homogenates from young rats. We observed that TRAP, TAR and GSH levels were markedly reduced (by up to 50%) when striatum homogenates were treated with 3-OH-GA. In contrast, H(2)O(2) (up to 44%), NO (up to 95%) and malondialdehyde levels (up to 28%) were significantly increased by 3-OH-GA. These data indicate that total nonenzymatic antioxidant defences (TRAP) and the tissue capacity to handle an increase of reactive species (TAR) were reduced by 3-OH-GA in the striatum. Furthermore, the results also reflect an increase of lipid peroxidation, probably secondary to 3-OH-GA-induced free radical production. Thus, it may be presumed that oxidative stress is involved in the neuropathology in GDD.

Lycopene inhibits DNA damage and liver necrosis in rats treated with ferric nitrilotriacetate.

Experimental and epidemiological evidence suggests that lycopene, a carotenoid present in tomatoes, tomato products, and several fruits and vegetables, may play a role in preventing certain cancers in humans. We have investigated the effect of lycopene pretreatment on lipid peroxidation, oxidative damage to DNA, and histopathological changes in liver of animals subjected to intraperitoneal (ip) ferric nitrilotriacetate (Fe-NTA) administration. Compared with control rats, liver of Fe-NTA-treated animals showed a significant increase in the 8-oxo-7,8-dihydro-2'-deoxyguanosine level and a 75% increase in malondialdehyde accumulation concomitant with histopathological changes. Five days of lycopene pretreatment (10 mg/kg body weight, ip) almost completely prevented liver biomolecule oxidative damage and protected the tissue against the observed histological alterations.

Estudo da peroxidaçäo lipídica em ratos deficientes em vitamina E submetidos à nefrectomia subtotal / Study vitamin E deficiency on lipid peroxidation in rats submitted to subtotal nefrectomy

Evidências experimentais e clínicas têm indicado que as manifestaçöes da Insuficiência Renal Crônica (IRC) estäo relacionadas com um aumento na produçäo dos radicais livres. Pacientes portadores de IRC apresentam aumento da peroxidaçäo lipídica com conseqüente diminuiçäo progressiva da vitamina E, um dos mais importantes antioxidantes. Neste estudo foi avaliado o papel da deficiência da vitamina E sobre a peroxidaçäo lipídica em ratos submetidos à nefrectomia subtotal. O estudo incluiu ratos macho, Wistar, mantidos sob dieta durante 45 dias, de acordo com os seguintes Grupos: GSDN - sham dieta normal; GNDN - nefrectomizado dieta normal; GSDD - sham dieta deficiente; GNDD - nefrectomizado dieta deficiente. Após 30 dias de estudo, os animais Experimentais foram submetidos à 5/6 de nefrectomia, enquanto os ratos Controle ao sham operatório...

Níveles plasmáticos de un marcador de peroxidación lipídica y de vitamina E en mujeres sanas eumenorreicas, en postmenopáusicas sanas y en primigestas que desarrollaron o no hipertensión inducida / Even plasmatic od a marker of lipid peroxidation and E vitamin in women healthy eumenorreicas, in health postmenopausal and in primigravidas that develope or not induced hypertension

Modificaciones en níveles circulantes de malondialdehido y de vitamina E se han asociaado con hipertensión inducida por embarazo, con diabetes gestacional y con parto pretérmino. Hay solo información fragmentaria aa esstos respectos

Níveles plasmáticos de un marcador de peroxidación lipídica y de vitamina E en mujeres sanas eumenorreicas, en postmenopáusicas sanas y en primigestas que desarrollaron o no hipertensión inducida / Even plasmatic od a marker of lipid peroxidation and E vitamin in women healthy eumenorreicas, in health postmenopausal and in primigravidas that develope or not induced hypertension

Modificaciones en níveles circulantes de malondialdehido y de vitamina E se han asociaado con hipertensión inducida por embarazo, con diabetes gestacional y con parto pretérmino. Hay solo información fragmentaria aa esstos respectos(AU)

Efectos de sulfinpirazona sobre tejidos miocárdicos con estimulación eléctrica o sin ella / Effects of sulfinpyrazone on myocardial tissues with or without electrical stimulation

Se estudiaron in vitro los efectos del ácido arquidónico (AAq) y sulfinpirazona (SP) sobre miocardio de rata "suquía" de 240+ ou - 10g. Bandas auriculares y ventriculares fueron instaladas en solución Krebs-bicarbonato a 36 + ou- 1-C, registrado tensión contráctil isométrica (TC) y niveles de malonato (MDA), con electroestimulación o sin ella (1,6 Hz), AAq (2,5 microng/ml) y SP (375, 750, 1.500 y 3.000 microng/ml). AAq deprimió 100% de la TC de ambos preparados, registrándose en tiempos variables (9 a 17 min.) recuperación espontánea en la mayoría de los casos, aunque sin recuperar los valores iniciales. La reactividad eléctrica aumentó en el tejido auricular, pero no en el ventricular. Los efectos de SP dependen de la concentración; 375 microng/ml bajan la TC auricular 87 + ou - 7,3%. La respuesta ventricular a esa dosis fue variable, aunque la TC disminuyó en 61,5% de los preparados; 3 mg/ml son homogéneamente estimulantes. La reactividad eléctrica disminuye con SP. La concentración de MDA en los preparados auriculares cayó muy significativamente (p<0,001) después de SP. En los ventriculares se observó disminución de menor magnitud, también significativa (p<0,02). La suma algebraica de caída y recuperación de TC de los preparados auriculares después de dar SP, da un porcentaje de pérdida similar al descenso del malonato (+ ou - 25%). Se sugiere que: a) AAq deprime el miocardio por acción directa sin descartar alguna transformación inmediata en derivados activos. b) La SP inhibiría distintas enzimas en función de las dosis. c) El MDA parece ser consumido por el tejido miocárdico o metabolizado en el medio. Se plantean explicaciones alternativas para este fenómeno y su relación con el mecanismo de acción de la sulfinpirazona

Efectos de sulfinpirazona sobre tejidos miocárdicos con estimulación eléctrica o sin ella / Effects of sulfinpyrazone on myocardial tissues with or without electrical stimulation

Se estudiaron in vitro los efectos del ácido arquidónico (AAq) y sulfinpirazona (SP) sobre miocardio de rata "suquía" de 240+ ou - 10g. Bandas auriculares y ventriculares fueron instaladas en solución Krebs-bicarbonato a 36 + ou- 1-C, registrado tensión contráctil isométrica (TC) y niveles de malonato (MDA), con electroestimulación o sin ella (1,6 Hz), AAq (2,5 microng/ml) y SP (375, 750, 1.500 y 3.000 microng/ml). AAq deprimió 100% de la TC de ambos preparados, registrándose en tiempos variables (9 a 17 min.) recuperación espontánea en la mayoría de los casos, aunque sin recuperar los valores iniciales. La reactividad eléctrica aumentó en el tejido auricular, pero no en el ventricular. Los efectos de SP dependen de la concentración; 375 microng/ml bajan la TC auricular 87 + ou - 7,3%. La respuesta ventricular a esa dosis fue variable, aunque la TC disminuyó en 61,5% de los preparados; 3 mg/ml son homogéneamente estimulantes. La reactividad eléctrica disminuye con SP. La concentración de MDA en los preparados auriculares cayó muy significativamente (p<0,001) después de SP. En los ventriculares se observó disminución de menor magnitud, también significativa (p<0,02). La suma algebraica de caída y recuperación de TC de los preparados auriculares después de dar SP, da un porcentaje de pérdida similar al descenso del malonato (+ ou - 25%). Se sugiere que: a) AAq deprime el miocardio por acción directa sin descartar alguna transformación inmediata en derivados activos. b) La SP inhibiría distintas enzimas en función de las dosis. c) El MDA parece ser consumido por el tejido miocárdico o metabolizado en el medio. Se plantean explicaciones alternativas para este fenómeno y su relación con el mecanismo de acción de la sulfinpirazona (AU)