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The absence of dystrophin in Duchenne muscular dystrophy (DMD) and in the mutant mdx mouse causes muscle degeneration and disruption of the neuromuscular junction. Based on evidence from the denervation-like properties of these muscles, we assessed the ligand-binding constants of nicotinic acetylcholine receptors (nAChRs) and the mRNA expression of individual subunits in membrane preparations of diaphragm muscles from adult (4-month-old) and aged (20-month-old) control and mdx mice. The concentration of nAChRs as determined by the maximal specific [125I]-α-bungarotoxin binding (Bmax) in the muscle membranes did not change with aging in both animal strains. When compared to age-matched control groups, the Bmax in mdx muscles was increased by 65% in adults, and by 103% in aged mice with no alteration of toxin affinity for nAChRs. Reverse-transcription polymerase chain reaction assays showed that mRNA transcripts for the nAChR α1, γ, α7, and β2, but not the ϵ subunits, were more abundant in mdx than in control muscles. The results indicate increased expression of extrajunctional nAChRs in the mdx diaphragm and reflect impairment of nAChR regulation in dystrophin-deficient muscles. These observations may be related to the resistance to nondepolarizing muscle relaxants and the high sensitivity to depolarizing agents reported in DMD patients. Muscle Nerve 38: 1585-1594, 2008 [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effects of chrysin on the ventral prostate of spontaneously hypertensive rats (SHR). Ten‐week‐old male Wistar and SHR rats received 100 mg/kg/day of chrysin (TW and TSHR) or 200 µL/day of the dilution vehicle (CW and CSHR) for 70 days. After the treatment, the animals were euthanized and the prostates were dissected out, fixed, and processed for further morphological, immunohistochemical, and biochemical analyses. Blood was collected for serological analysis. Chrysin did not interfere with the blood pressure. Morphologically, the epithelial height increased in TW and decreased in TSHR. Stereology showed an increase in the epithelial and stromal relative frequency, and a decrease in the lumen of TW, whereas the epithelium in TSHR was reduced. Normal alveoli decreased, and hyperplastic alveoli had an increment in TW, whereas in TSHR normal alveoli increased and intense hyperplasia decreased. The secretion area was reduced in TW. Immunohistochemical analysis showed a smaller number of PCNA‐positive cells in TW. Finally, the biochemical analysis showed a reduction in malondialdehyde, carbonylated proteins, superoxide dismutase, and catalase in TW and TSHR. We concluded that the chrysin effect is dependent on the context in which this flavonoid is employed. In normal conditions, the anabolic potential of the chrysin was favored, disrupting the morphology of the prostate. However, when used in animals predisposed to develop hyperplasia, this flavonoid attenuates the hyperplastic status, improving the morphology of the gland. [ABSTRACT FROM AUTHOR]

Molecular modification of compounds remains important strategy towards the discovery of new drugs. In this sense, this study presents a new pyrazole derivative 5-(1-(2-fluorophenyl)-1H-pyrazol-4-yl)-1H-tetrazole (LQFM039) and evaluated the anti-inflammatory, analgesic, and vasorelaxant effects of this compound as well the mechanisms of action involved in the pharmacological effects. For this, mice were orally treated with LQFM039 (17.5, 35, or 70 mg/kg) prior acetic acid-induced abdominal writhing, formalin, tail flick, and carrageenan-induced paw edema protocols. In addition, vascular reactivity protocols were made with aortic rings contraction with phenylephrine and stimulated with graded concentrations of LQFM039. Abdominal writhing and licking time in both neurogenic and inflammatory phases of formalin were reduced with LQFM039 without altering latency to nociceptive response in the tail flick test. Carrageenan-induced paw edema showed that LQFM039 reduces edema and cell migration. In addition, the mechanism of action of LQFM039 involves NO/cGMP pathway and calcium channels, since this new pyrazole derivate elicited concentration-dependent relaxation attenuated by Nω-nitro-l-arginine methyl ester and 1H-[1,2,4] oxadiazolo [4,3-alpha]quinoxalin-1-one, and blockade of CaCl2-induced contraction. Altogether, our finding suggests anti-inflammatory, antinociceptive, and vasorelaxant effect of this new pyrazole derivative with involvement of NO/cGMP pathway and calcium channels. [ABSTRACT FROM AUTHOR]

Abstract Normal prostate development is highly dependent of an equilibrated hormonal regulation, so that sensible interferences during this period may predispose the gland to lesions during aging. Industrial activities have increased the exposure of this gland to active elements found in environment, such as aluminum (Al). Al presents toxic effect for living beings, having the potential to disrupt the development and growth of several organs and systems. Therefore, the aim of this study was to evaluate whether the prenatal exposure to Al may alter the development and morphophysiology of the gerbil prostate (Meriones unguiculatus). Pregnant females were orally exposed to aluminum chloride (100 mg/kg/day) from 17th to 21th gestational day. Following the birth, the male and female pups were euthanized with 1 (PN1) and 90-days-old (PN90). The prostates were collected for biometrical, three-dimensional reconstruction, morphometrical, stereological, and immunohistochemical analysis. Results indicated that Al decreases the body weight of PN1 males and females, and also reduce the anogenital distance of PN1 females. Moreover, Al changed the prostate developmental patterns of PN1 animals, causing an increase in proliferative status and decreasing androgen receptor immunostaining. The results suggest that Al-promoted changes were permanent, since low androgen receptor frequency, increased serum testosterone levels and high proliferation index were observed in adult gerbils. This study demonstrated that body and prostatic changes were more pronounced in females than in males, and that Al performed as an endocrine-disrupting chemical in gerbils. Highlights • Prenatal aluminum exposure disrupted the prostate development pattern in neonate gerbils. • Prenatal aluminum exposure promoted an increase of serum testosterone levels in adult gerbils. • Prenatal aluminum exposure has caused increased cell proliferation in the adult prostate. • Body and prostatic changes induced by aluminum were more pronounced in females than in males. [ABSTRACT FROM AUTHOR]

The pyrazole compound LQFM-021 exhibits vasorelaxant, antinociceptive and anti-inflammatory activities. Furthermore, it has low toxicity, indicating that this compound may be considered to be a good prototype for the development of new analgesic/anti-inflammatory drugs. Therefore, the aim of this study was to investigate the potential anti-inflammatory activity of LQFM-021 using a model of carrageenan-induced inflammation as well as the mechanism of action and role of nitric oxide in this effect. Acute treatments with LQFM-021 (30 and 60 mg/kg p.o.) reduced paw edema formation dose-dependently 2 h after carrageenan injection. In the carrageenan-induced pleurisy test, LQFM-021 (30 mg/kg p.o.) reduced the leukocyte (polymorphonuclear) count in the pleural cavity, as well as decreased protein extravasation and myeloperoxidase activity. This dose of LQFM-021 increased the NO (nitrite/nitrate) and IL-4 levels and decreased the TNF-α and IL-1β levels in the pleural cavity. Moreover, pre-treatment with L-NAME reversed the effect of LQFM-021 on NO, leukocyte migration, and the TNF-α and IL-1β levels. Additionally, we observed that LQFM-021 showed weak inhibitory activity on cyclooxygenases, but reduced the PGE 2 levels in the pleural cavity. Immunoblot analyses showed that LQFM-021 promoted a decrease in COX-2 levels and increase in iNOS levels. In conclusion, we demonstrated that LQFM-021 has marked anti-inflammatory activity by reducing polymorphonuclear recruitment, which is associated with the inhibition of the production of inflammatory cytokines and eicosanoids. In addition, we found that the synthase/release of nitric oxide promoted by LQFM-021 is essential for the anti-inflammatory effect observed. [ABSTRACT FROM AUTHOR]

In this study, we proposed the design, synthesis of a new compound 2-(4-((1-phenyl-1 H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol ( LQFM032), and pharmacological evaluation of its anxiolytic-like effect. This new compound was subjected to pharmacological screening referred to as Irwin test, prior to sodium pentobarbital-induced sleep, open-field and wire tests. The anxiolytic-like effect of this compound was evaluated using elevated plus maze and light-dark box tests. In addition, the mnemonic activity was evaluated through step-down test. In sodium pentobarbital-induced sleep test, LQFM032 decreased latency and increased duration of sleep. In the open-field test, LQFM032 altered behavioral parameter, that suggested anxiolytic-like activity, as increased in crossings and time spent at the center of open field. In the plus maze test and light-dark box test, the LQFM032 showed anxiolytic-like activity, increased entries and time spent on open arms, and increased in number of transitions and time spent on light area, respectively. Those effects was antagonized by flumazenil but not with 1-(2-Methoxyphenyl)-4-(4-phthalimidobutyl)piperazine ( NAN-190). The LQFM032 did not alter mnemonic activity. Moreover, the anxiolytic-like activity of LQFM032 was antagonized by mecamylamine. In summary, LQFM032 showed benzodiazepine and nicotinic pathways mediated anxiolytic-like activity without altering the mnemonic activity. [ABSTRACT FROM AUTHOR]

Background: The role of oxidative stress in schizophrenia has been demonstrated, particularly in subjects with treatment-resistant schizophrenia (TRS). In such patients, the decreased levels of antioxidants in conjunction with the increased generation of reactive oxygen species in the brain exposes the neurons to a higher risk of damage. Methods and findings: We evaluated the association of deletion polymorphisms of two genes of the antioxidant Glutathione S-Transferase family, GSTT1 and GSTM1, with susceptibility to TRS. A total of 54 TRS patients (mean age 38.7 years) and 78 healthy control subjects (mean age 39.0 years) were enrolled in this study. The subjects were matched by sex, age, and smoking and alcohol consumption habits. In the case group, the frequencies of GSTT1-null and GSTM1-null genotypes were 24.1 and 51.9%, respectively, whereas for the control group, the frequencies were 12.8 and 46.2%, respectively. Analysis performed with respect to the risk of developing TRS associated with the GSTT1 and GSTM1 deletion polymorphisms, resulted in odds ratio (OR) values of 2.1 and 1.2, respectively. However, the association was not found to be significant (p = 0.1229 and p = 0.5916, respectively). The analysis performed with respect to the combined genotypes of GSTT1 and GSTM1 revealed that the double-null genotype confers a 4.6-fold increased risk of developing TRS (p = 0.0412). Conclusion: The results of the present study indicate that a combination of GST deficiencies may play a role in enhanced susceptibility to TRS, and the present genotype of one of these genes may buffer the deficiency caused by the lack (null genotype) of the other. The results suggest that combined deletion polymorphisms of GSTT1 and GSTM1 can have implications in the prediction of the clinical course of the disease. [ABSTRACT FROM AUTHOR]

Our study sought to evaluate the anxiolytic and antidepressant activities of oleanolic acid as well as the neural mechanisms involved. Animal models such as barbiturate sleep-induction, light–dark box, elevated plus maze, forced swimming test, tail suspension test and open field test were conducted. Male Albino Swiss mice were treated orally with vehicle 10 mL/kg, fluoxetine 20 mg/kg, imipramine 15 mg/kg, diazepam 1 mg/kg or oleanolic acid 5–40 mg/kg. Pretreatment (intraperitoneal) of animals with pentylenetetrazole (PTZ) 20 mg/kg, 1-(2-methoxyphenyl)-4-[4- (2-phthalimido) butyl]piperazine hydrobromide (NAN-190) 0.5 mg/kg, p-chlorophenylalanine methyl ester (PCPA) 100 mg/kg or α-methyl-p-tyrosine (AMPT) 100 mg/kg, WAY100635 (WAY) 0.3 mg/kg, prazosin (PRAZ) 1 mg/kg, yohimbine 2 mg/kg as well as monoamine oxidase assay and hippocampal brain-derived neurotrophic factor (BDNF) quantification were carried out. Oleanolic acid potentiated the hypnotic effect of barbiturate and demonstrated an anxiolytic effect in both the light–dark box and elevated plus maze. This effect was not reversed by PTZ. Acute and/or chronic oral treatment of mice with oleanolic acid (5−20 mg/kg) elicited an antidepressant effect in the forced swimming test and the tail suspension test without interfering with the locomotor activity. The antidepressant effect of oleanolic acid was attenuated by NAN-190, AMPT, PCPA, WAY and PRAZ. Although monoamine oxidase activity remained unaltered by oleanolic acid, chronic administration of oleanolic acid augmented hippocampal BDNF level. These findings demonstrate multiple mechanisms of the anxiolytic and antidepressant effect of oleanolic acid. [ABSTRACT FROM AUTHOR]

Application of naturally occurring (E) - methyl isoeugenol (MIE) as food flavour has been widely accepted despite the growing concerns over cardiovascular issue. Hence, we sought to investigate hypotensive property of MIE and the involvement of central and/or peripheral mechanism (s). Variation in mean arterial pressure (MAP), heart rate (HR), systolic blood pressure (SBP), baroreflex sensitivity of normotensive rats and vascular reactivity were recorded. MIE (1.11, 2.25 or 4.50 mg/kg, iv) elicited dose-related decrease in MAP (-16.9 ± 1.13; -19.0 ± 4.18 or -27.2 ± 3.65 mm Hg, respectively) and an increase in HR (17.4 ± 1.79; 24.4 ± 5.11 or 29.9 ± 6.62 bmp, respectively). MIE 25 or 50 mg/kg (p.o) reduced the SBP (-13.6 ± 4.18 or -16.6 ± 5.60 mm Hg, respectively) without altering baroreflex sensitivity. The hypotensive effect of MIE remained unaltered by WAY100635 (antagonist of 5-HT1A) and L-NAME (NO synthase inhibitor). Intracerebroventricular injection of MIE did not change MAP. MIE elicited endothelium independent vasorelaxation (endothelium-intact vessels, Emax 92.5 ± 1.75%; Endothelium-denuded vessels, Emax 91.4 ± 2.79%). MIE blocked CaCl2 or BAY K8644 (L-type voltage gated calcium channel activator)-induced vascular contractions. Our findings showed evidence of hypotensive and vasorelaxation effects of MIE with involvement of calcium channel. [ABSTRACT FROM AUTHOR]

Background: Due to the activity of GSTs in the detoxification of oxidative stress products, deletion polymorphisms of GSTM1 and GSTT1 may contribute to susceptibility to T2DM, since B-cells express very low levels of antioxidant enzymes. Recently, some studies have shown an association between GSTM1-null/GSTT1-null genotypes and an increased susceptibility to T2DM. A relationship between these polymorphisms and changes in the clinical parameters of diabetic patients has also been investigated. However, the results diverge considerably among the studies. Thus, this case-control study was designed to contribute to existing knowledge, as there are no studies on this issue performed in the Brazilian population. Methods and Findings: A total of 120 patients and 147 healthy individuals were included in this study. GSTT1 and GSTM1 deletion polymorphisms were genotyped by multiplex SYBR Green Real-Time PCR. The GSTT1-null genotype conferred a 3.2-fold increased risk to T2DM relative to the present genotype. There was no association between GSTM1-null and T2DM risk. In diabetic patients, GSTT1-null conferred higher levels of triglycerides and VLDL-cholesterol, while GSTM1-null was associated with increased levels of fasting blood glucose, glycated hemoglobin and blood pressure. We emphasized a necessity for applying log-linear analysis in order to explore an interaction between these polymorphisms properly. Conclusion: These results suggest that the GSTT1 polymorphism may play an important role in the pathogenesis of T2DM in the Brazilian population. This gene could then be added to a set of genetic markers to identify individuals with an increased risk for developing T2DM and complications associated with dyslipidemia in diabetic patients. Although there was no association of GSTM1 deletion polymorphism with susceptibility to T2DM, the influence of this polymorphism on important clinical parameters related to glycemia and blood pressure levels was verified. This finding suggests that both GSTM1-null and GSTT1-null may contribute to the clinical course of T2DM patients. [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD) is a natural cannabinoid present in the Cannabis sativa plant, widely prescribed as an anticonvulsant drug, especially for pediatric use. However, its effects on male reproduction are still little investigated. Therefore, the present study assessed the effects of CBD on the spermatogenesis and sperm quality. For this, twenty-one-day-old Swiss mice received CBD for 34 consecutive days by gavage at doses of either 15 or 30 mg/kg. Chronic exposure to CBD decreased the frequency of stages VII-VIII and XII of spermatogenesis and an increase in the frequency of stage IX were noted. Furthermore, the seminiferous epithelium height reduced at stage IX and increased at stage XII in both CBD-treated groups. There was a significant rise of sperm DNA damage, while no genotoxic effects were observed in leukocytes. The activities of superoxide dismutase and catalase decreased, while malondialdehyde levels increased in the sperm of mice treated with a higher dose of CBD. Mice exposed to 30 mg/kg of CBD showed a reduction in the mobile spermatozoa percentage and in curvilinear velocity, while straight line and average path velocity decreased in both treated groups. The number of acrosome-intact spermatozoa declined in the CBD 30 group, and the number of abnormal acrosomes raised in both CBD groups. On the other hand, the weight of reproductive organs, sperm count, and hormone levels were not affected by CBD treatment. These findings show that dysregulation of the endocannabinoid system by CBD can reduce sperm quality. The mechanisms responsible may be associated with disorders during spermatogenesis, especially during the final stages of nuclear remodelling and assembly of acrosome. However, changes in mitochondrial function, as well as the reduction on the antioxidant enzyme activities during epididymal transit, at least partly, may also be involved. [Display omitted] • Chronic exposure to cannabidiol (CBD) changed the dynamics of spermatogenesis. • Chronic exposure to CBD induced DNA fragmentation and impairment of motility and acrosome reaction of mice sperm. • CBD exposure decreased the antioxidant enzymes (SOD and CAT) in the sperm. • Chronic exposure to CBD induced lipid peroxidation in the sperm. [ABSTRACT FROM AUTHOR]

The aim of this study was to synthesise the novel di- tert -butylphenol compound, 5-(3,5-di- tert -butyl-4-hydroxybenzylidene)-2-thioxo-dihydropyrimidine-4,6(1H, 5H)-dione (LQFM218), and evaluate the potential anti-nociceptive and anti-inflammatory activities in acute (mice) models in vivo. The compound was tested on acute models of pain such as acetic acid-induced abdominal writhing, formalin-induced nociception and carrageenan-induced mechanical hyperalgesia. The anti-inflammatory activity was observed in paw oedema, carrageenan-induced pleurisy tests and inflammatory mediator quantification. Key findings: oral treatment with the LQFM218 (50, 100 or 200 mg/kg) reduced abdominal writhing (18.8%, 31.6% and 48.3%). The dose intermediate (100 mg/kg) reduced the nociception in the second phase of the formalin test (61.4%), and also showed anti-hyperalgic activity in carrageenan-induced mechanical hyperalgesia (until 42.3%). In acute inflammation models, the treatment of mice LQFM218 (100 mg/kg) reduced the paw oedema all the time (33.8%, 42.6%, 37.4% and 36%) and in pleurisy test reduced: polymorphonuclear cell migration (35.4%), myeloperoxidase activity (52.2%) and the levels of inflammatory mediators such as PGE 2 (23.0%), TNF-α (67.6%) and IL-1β (53.4%). The present study showed that LQFM218 effectively reduced the nociception and inflammation in different models, and its mechanism might be related to the reduction of PGE 2 and pro-inflammatory cytokines. These findings show LQFM218 as a potential anti-inflammatory drug. [ABSTRACT FROM AUTHOR]