Kami-shoyo-san improves ASD-like behaviors caused by decreasing allopregnanolone biosynthesis in an SKF mouse model of autism.

Dysfunctions in the GABAergic system are associated with the pathogenesis of autism spectrum disorder (ASD). However, the mechanisms by which GABAergic system dysfunctions induce the pathophysiology of ASD remain unclear. We previously demonstrated that a selective type I 5α-reductase inhibitor SKF105111 (SKF) induced ASD-like behaviors, such as impaired sociability-related performance and repetitive grooming behaviors, in male mice. Moreover, the effects of SKF were caused by a decrease in the endogenous levels of allopregnanolone (ALLO), a positive allosteric modulator of the GABAA receptor. In this study, we used SKF-treated male mice as a putative animal model of ASD and examined the effects of Kami-shoyo-san (KSS) as an experimental therapeutic strategy for ASD. KSS is a traditional Kampo formula consisting of 10 different crude drugs and has been used for the treatment of neuropsychiatric symptoms. KSS dose-dependently attenuated sociability deficits and suppressed an increase in grooming behaviors in SKF-treated mice without affecting ALLO content in the prefrontal cortex. The systemic administration of the dopamine D1 receptor antagonist SCH23390 reversed the ameliorative effects of KSS. On the other hand, the dopamine D2 receptor antagonist sulpiride and GABAA receptor antagonist bicuculline only attenuated the ameliorative effect of KSS on repetitive self-grooming behaviors. The present results indicate that KSS improves SKF-induced ASD-like behaviors by facilitating dopamine receptor-mediated mechanisms and partly by neurosteroid-independent GABAA receptor-mediated neurotransmission. Therefore, KSS is a potential candidate for the treatment of ASD.

Anti-tumor efficacy of new 7α-substituted androstanes as aromatase inhibitors in hormone-sensitive and resistant breast cancer cells.

The majority of breast cancer cases are estrogen receptor positive (ER+). Although, third-generation aromatase inhibitors (AIs) are used as first-line treatment in post-menopausal women, they cause endocrine resistance and bone loss, which limits their success. Therefore, there is a demand to discover new potent molecules, with less toxicity that can circumvent these drawbacks. Our group has previously demonstrated that new 7α-substituted steroidal molecules, 7α-(2ξ,3ξ-epoxypropyl)androsta-1,4-diene-3,17-dione (3), 7α-allylandrost-4-ene-3,17-dione (6), 7α-allylandrost-4-en-17-one (9), 7α-allyl-3-oxoandrosta-1,4-dien-17ß-ol (10) and 7α-allylandrosta-1,4-diene-3,17-dione (12) are potent AIs in placental microsomes. In this work, it was investigated their anti-aromatase activity and in vitro effects in sensitive and resistant breast cancer cells. All the steroids efficiently inhibit aromatase in breast cancer cells, allowing to establish new structure-activity relationships for this class of compounds. Moreover, the new AIs can inhibit breast cancer cell growth, by causing cell cycle arrest and apoptosis. The effects of AIs 3 and 12 on sensitive cells were dependent on aromatase inhibition and androgen receptor (AR), while for AI 9 and AI 10 were AR- and ER-dependent, respectively. In addition, it was shown that all the AIs can sensitize resistant cancer cells being their behavior similar to the sensitive cells. In summary, this study contributes to the understanding of the structural modifications in steroidal scaffold that are translated into better aromatase inhibition and anti-tumor properties, providing important information for the rational design/synthesis of more effective AIs. In addition, allowed the discovery of new potent 7α-substituted androstane molecules to inhibit tumor growth and prevent endocrine resistance.

Caffeine increases Nr1i3 expression and potentiates the effects of its ligand, TCPOBOP, in mice liver / A cafeína aumenta a expressão Nr1i3 e potencializa os efeitos do seu ligando, TCPOBOP, em fígado de camundongos

Caffeine is one of the world's most consumed substances. It is present in coffee, green tea and guarana, among others. The xenobiotic-sensing nuclear receptor subfamily 1, group I, member 3 (Nr1i3), also known as the Constitutive Androstane Receptor (Car) is a key regulator of drug metabolism and excretion. No consistent description of caffeine effects on this receptor has been described. Thus, to unravel the effects of caffeine on this receptor, we performed experiments in mice. First, C57Bl/6 mice that were treated daily with caffeine (50 mg/kg) for 15 days presented a slight but significant increase in Nr1i3 and Cyp2b10 gene expression. A second experiment was then performed to verify the effects of caffeine on TCPOBOP (1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene, 3,3′,5,5′-tetrachloro-1,4-bis(pyridyloxy)benzene), the most potent agonist known for mice Nr1i3. Interestingly, caffeine potentiated TCPOBOP pleiotropic effects in mice liver, such as hepatomegaly, hepatotoxicity, hepatocyte proliferation and loss of cell-to-cell communication through gap junctions. In addition, caffeine plus TCPOBOP treatment increased liver gene expression of Nr1i3 and Cyp2b10 comparing with only caffeine or TCPOBOP treatments. Together, these results indicate that caffeine increases the expression of Nr1i3 in mice liver, although at this point it is not possible to determine if Nr1i3 directly or indirectly mediates this effect...

A cafeína é uma das substâncias mais consumidas mundialmente, estando presente no café, chá-verde e guaraná, entre outros. O receptor sensor de xenobióticos Receptor Nuclear subfamília 1, grupo I, membro 3 (Nr1i3, mais conhecido como Androstano Consititutivo - Car) é um regulador chave da biotransformação e excreção de substâncias e nenhuma descrição consistente dos efeitos da cafeína sobre este receptor foi feita. Então, para avaliar os efeitos da cafeína sobre este receptor, realizamos experimentos em camundongos. Primeiramente, camundongos C57/Bl/6 foram tratados diariamente com cafeína (50 mg/kg) por 15 dias e apresentaram um leve, mas significativo, aumento na expressão do Car e do seu gene alvo Cyp2b10. Assim, um segundo experimento foi realizado para verificar os efeitos da cafeína sobre o TCPOBOP (1,4-bis-[2-(3,5-dicloropiridiloxi)]benzeno,3,3′,5,5′-tetracloro-1,4-bis(piridiloxi)benzeno), o mais potente agonista do Nr1i3 de camundongos conhecido. Interessantemente, a cafeína potencializou os efeitos pleiotrópicos do TCPOBOP no fígado dos camundongos, como hepatomegalia, hepatotoxicidade, proliferação celular e perda da comunicação intercelular por junções do tipo gap. Os camundongos tratados com cafeína e TCPOBOP apresentaram maior expressão gênica de Nr1i3 e Cyp2b10, quando comparados aos camundongos tratados apenas com cafeína ou TCPOBOP. Juntos, nossos resultados indicam que a cafeína aumenta a expressão do receptor CAR em fígados de camundongos C57/Bl/6, porém nesta etapa ainda não é possível afirmar se estes efeitos são direta ou indiretamente mediados pelo Nr1i3...

Blood, sweat and tears: androgenic-anabolic steroid misuse and recurrent primary post-tonsillectomy haemorrhage.

A 30-year-old male body builder and androgenic-anabolic steroid and insulin abuser was admitted for day case elective tonsillectomy (bipolar). He returned with primary post-tonsillectomy haemorrhage 18 h after the operation and required bipolar cautery to the multiple small bleeding points in the right and left tonsillar fossa. Thorough coagulation screen was normal. Recurrent primary haemorrhage occurred 3 h post-operatively requiring immediate surgical intervention, removal of the inferior poles, precautionary throat packs, intubation and observation on the intensive treatment unit (ITU). Re-examination in theatre revealed a bleeding left superior pole that was under-run to achieve haemostasis and the patient returned to ITU. Hypertensive episodes were noted in the emergency department and intraoperatively including one recording >200 mm Hg. Haemostasis was eventually achieved once the blood pressure was adequately controlled. A slow wean of steroids was also instigated and the patient was managed on a surgical ward for 2 weeks post-tonsillectomy.

Meat intake and reproductive parameters among young men.

BACKGROUND: In the United States, anabolic sex steroids are administered to cattle for growth promotion. There is concern regarding the reproductive consequences of this practice in men who eat beef. We investigated whether meat consumption was associated with semen quality parameters and reproductive hormone levels in young men. METHODS: Semen samples were obtained from 189 men aged 18-22 years. Diet was assessed with a previously validated food frequency questionnaire. We used linear regression to analyze the cross-sectional associations of meat intake with semen quality parameters and reproductive hormones while adjusting for potential confounders. RESULTS: There was an inverse relation between processed red meat intake and total sperm count. The adjusted relative differences in total sperm counts for men in increasing quartiles of processed meat intake were 0 (ref), -3 (95% confidence interval = -67 to 37), -14 (-82 to 28), and -78 (-202 to -5) million (test for trend, P = 0.01). This association was strongest among men with abstinence time less than 2 days and was driven by a strong inverse relation between processed red meat intake and ejaculate volume (test for trend, P = 0.003). CONCLUSIONS: In our population of young men, processed meat intake was associated with lower total sperm count. We cannot distinguish whether this association is because of residual confounding by abstinence time or represents a true biological effect.

Anabolic steroids in sport: biochemical, clinical and analytical perspectives.

International Olympic Committee accredited laboratories play a key role in upholding the principle of fair play and innate ability, as desired by the majority of sports competitors and spectators. Not only does doping damage the image of sport, but it can also be harmful to the individual. The great majority of samples test negative but, when an adverse finding is declared, the analytical data must be of a sufficiently high standard to withstand legal challenges by third parties. The most widely misused performance-enhancing drugs are the anabolic-androgenic steroids, commonly referred to as 'anabolic steroids'. This review attempts to address the complex issues concerning anabolic steroids in sport by considering the clinical, biochemical and analytical perspectives.

Muscular relaxation with atracurium, vecuronium and duador under balanced anaesthesia.

The neuromuscular effects of three new nondepolarizing neuromuscular blocking drugs, atracurium, vecuronium and Duador, were investigated in surgical patients under balanced anaesthesia. (The numbers of patients in each study are given in the tables.) There were no significant differences in the neuromuscular effects of the three agents. None showed any cumulation after repeated administration of maintenance doses. Muscular relaxation for upper abdominal surgery was adequate as long as the isometric twitch tension (P) was no more than 25% of control. Conditions for tracheal intubation were satisfactory within less than 3 min after the start of injection. Spontaneous recovery of P to 90-95% of control, after the last dose of neuromuscular blocker was the fastest with vecuronium (35.8 +/- 2.4 min) and about the same with atracurium (54.3 +/- 2.4 min) and Duador (54.2 +/- 4.7 min). The T4/T1 ratio at the time of greater than 90% recovery of P was 0.44, 0.52 and 0.56 with vecuronium, Duador and atracurium, respectively, indicating the need for the reversal of the residual neuromuscular block. This could be accomplished within 2 min by the i.v. injection of edrophonium 0.5 mg kg-1, preceded by atropine 0.01 mg kg-1. No side-effects were observed with vecuronium. Atracurium caused mild to moderate histamine release in four of 50 patients included in this study, all of whom received an initial dose of 0.5 mg kg-1. The initial dose of Duador caused a 16.7% increase in heart rate. The findings indicate that the three new muscle relaxants merit further clinical trial. In our opinion, until the results of such studies become available, atracurium should not be used in patients with a history of allergic diathesis and Duador in those in whom increased heart rate may be harmful.

Hepatic angiosarcoma associated with androgenic-anabolic steroids.

A retrospective epidemiological study of deaths from hepatic angiosarcoma (HAS) in the U.S. showed that during 1964--74 there were 168 such cases, of which 37 (22%) were associated with previously known causes (vinyl chloride, 'Thorotrast', and inorganic arsenic) and 4 (3.1%) of the remaining 131 cases with the use of androgenic-anabolic steroids. It is suggested that the long-term use of androgenic-anabolic steroids is the fourth cause of HAS, the majority of cases still being of unknown aetiology. Moreover, the presented cases serve as a link in a spectrum of hepatic disorders recently recognised to be caused by environmental agents such as vinyl chloride, arsenic, and thorotrast, and by contraceptive and anabolic steroids. Similar precursor stages, usually not recognised by clinical laboratory tests and consisting of areas of hyperplasia of hepatocytes and sinusoidal cells and sinusoidal dilatation, lead potentially to hepatic adenoma, carcinoma, peliosis, and angiosarcoma.

Therapeutic value of mepitiostane in the treatment of advanced breast cancer.

A new, orally active antiestrogenic steroid, mepitiostane (20 mg/day), was given to 45 patients with advanced breast cancer. The regression rate was 31.1%, or 14 of 45 patients, and a duration of regression of greater than 6 months was obtained in seven patients. Virilizing effects such as hoarseness, hirsutism, and acne were observed relatively often, but there was no evidence of abnormality in the liver function tests or in the serum calcium level.

2alpha, 3alpha-epithio-5alpha-androstan-17beta-yl 1-methoxycyclopentyl ether in the treatment of advanced breast cancer: Japanese Cooperative Group of Hormonal Treatment for Breast Cancer.

A new antiestrogenic steroid, 2alpha, 3alpha-epithio-5alpha-androstand-17beta-yl 1-methoxy-cyclopentyl ether, mepitiostane, given orally 10 mg b.i.d. to 50 patients with advanced breast cancer, produced objective regression of the tumor in 17 cases (34%). Objective regression of the metastases was seen in 20 of the 48 control patients given fluoxymesterone, 10 mg b.i.d. orally (47.7%). These figures do not differ significantly. The study was a prospective, randomized, double-blind trial employing the protocol of the Cooperative Breast Cancer Group. There was a significantly lower incidence of hepatotoxicity in the patients given mepitiostane.