A novel cell-permeable peptide prevents protein SUMOylation and supports the mislocalization and aggregation of TDP-43.

SUMOylation is a post-translational modification (PTM) that exerts a regulatory role in different cellular processes, including protein localization, aggregation, and biological activities. It consists of the dynamic formation of covalent isopeptide bonds between a family member of the Small Ubiquitin Like Modifiers (SUMOs) and the target proteins. Interestingly, it is a cellular mechanism implicated in several neurodegenerative pathologies and potentially it could become a new therapeutic target; however, there are very few pharmacological tools to modulate the SUMOylation process. In this study, we have designed and tested the activity of a novel small cell-permeable peptide, COV-1, in a neuroblastoma cell line that specifically prevents protein SUMOylation. COV-1 inhibits UBC9-protein target interaction and efficiently decreases global SUMO-1ylation. Moreover, it can perturb RanGAP-1 perinuclear localization by inducing the downregulation of UBC9. In parallel, we found that COV-1 causes an increase in the ubiquitin degradation system up to its engulfment while enhancing the autophagic flux. Surprisingly, COV-1 modifies protein aggregation, and specifically it mislocalizes TDP-43 within cells, inducing its aggregation and co-localization with SUMO-1. These data suggest that COV-1 could be taken into future consideration as an interesting pharmacological tool to study the cellular cascade effects of SUMOylation prevention.

Acute administration of pioglitazone attenuates morphine withdrawal syndrome in rat: a novel role of pioglitazone.

BACKGROUND: Long-term exposure to opiates such is morphine induces dependence. PURPOSE: The purpose of the present study was to investigate the effects of the acute administration of pioglitazone, a selective agonist of peroxisome proliferator activated receptors gamma (PPAR-γ), on the morphine withdrawal syndrome in the rat. METHODS: Male Wistar rats (200-250 g) were selected randomly and divided into 8 groups including 2 non-dependent groups and 6 morphine-dependent groups which were received additive doses of morphine subcutaneously at an interval of 12 h for 9 continuous days. On the ninth day, only the morning dose of morphine was injected and 2 h later, morphine withdrawal was precipitated by naloxone and then ten distinct withdrawal behaviors were recorded for 45 min. Pioglitazone (5, 10, 20 and 40 mg/kg) was gavaged 2 h before naloxone injection. It is worth noting that 1 h before the pioglitazone (40 mg/kg) gavage, GW-9662 (2 mg/kg), a selective PPAR-γ antagonist, was administrated in order to evaluate the possible role of the PPAR-γ. RESULT AND DISCUSSION: The results of this study showed that administration of pioglitazone (40 mg/kg) decreased all withdrawal signs and the statistical analysis indicated that pioglitazone could attenuate the total withdrawal scores significantly. Administration of GW-9662 had no significant effect on pioglitazone attenuation effect on morphine withdrawal symptoms.Taking together, it was concluded that acute oral administration of pioglitazone prevented naloxone-precipitated withdrawal symptoms and GW-9662 could not revert its effect on morphine withdrawal syndrome. It seems that pioglitazone suppresses morphine withdrawal syndrome through PPAR-γ independent mechanisms.

Non-obstructive lower urinary tract symptoms versus prostate volume in benign prostatic hyperplasia.

This study was aimed to determine the relation between sonographically measured prostate volume and the severity of non-obstructive Lower Urinary Tract Symptoms (LUTS) in Benign Prostatic Hyperplasia (BPH). This was an analytic-descriptive, cross-sectional and prospective study which was carried out on a sequential sample of 60 male patients since 2006 to 2008. The patients were divided to three groups (prostate volume < 40 cc; 40 cc < or = prostate volume < or = 59 cc; prostate volume > or = 60 cc) based on the ultrasonographic volume of the prostate. The American Urological Association scores of frequency, urgency, nocturia and dysuria were compared between three groups. The mean age and the mean total score of non-obstructive symptoms of BPH of the patients were 71.18 +/- 8.74 and 13.38 +/- 2.96, respectively. According to our findings there was no statistical significant difference between three groups in the scores of frequency (p = 0.369), dysuria (p = 0.85) and nocturia (p = 0.861). A statistically significant difference between three groups was found in urgency score (p = 0.037). Only a significant correlation between urgency and the prostate volume was found (p = 0.024, r = 0.291). According to our findings in this work on relation between the non-obstructive symptoms and prostate volume in BPH patients we found that urgency was the only non-obstructive symptom that may be associated with prostate volume. Prospective studies are required in this regard to elucidate the symptom-related causes of LUTS in the patients with BPH.

Features of premature ejaculation in infertile men.

Premature ejaculation (PE) is the most common form of sexual dysfunction and is one of the causes of male factor infertility. The aim of this study was assay of frequency and features of PE in a group of infertile men. This cross-sectional study was carried out since December 2006 to January 2008 on a sequential sample of 300 male patients complaining of infertility referring to the only infertility research center of Tabriz al-Zahra hospital. Data were collected by a designed questionnaire in which there were questions about age, age of marriage, history of sexual transmitted disease, drug use, previous sexual contacts, systemic diseases, masturbation, erectile dysfunction and frequency of intercourse. The mean age of studied patients was 30.39 +/- 5.76 and 43% of patients had PE, that in 74.4% primary PE and in 25.6% secondary PE seen. The most common form of ejaculation latency time was about less than 1 min that was seen in 51.2% of patients with PE. Mean of masturbation times was 5.13 +/- 3.19 times per month, and there is significant relation between the age of patients and type of PE, (p = 0.001) and ejaculation latency time and type of PE (p = 0.035). The high frequency rate of PE in Iranian men with complaint of infertility and also relatively lower age of these patients reflects the necessity of attention and management of this imperative psycho-organic disorder.

Development of morphine induced tolerance and withdrawal symptoms is attenuated by lamotrigine and magnesium sulfate in mice.

The goal of this study was to evaluate the effects of lamotrigine and magnesium sulfate on morphine induced tolerance and withdrawal symptoms in mice. Different groups of mice were received morphine (30 mg kg(-1), s.c.) or morphine (30 mg kg(-1), s.c.)+lamotrigine (10, 20, 30 or 40 mg kg(-1), i.p.) or morphine (30 mg kg(-1), s.c.) + magnesium sulfate (20, 40 or 60 mg kg(-1), i.p.) or morphine (30 mg kg(-1), s.c.) + [lamotrigine (10 mg kg(-1), i.p.) + magnesium sulfate (20mg kg(-1), i.p.)] daily for 4 days. Tolerance was assessed using hot plate after administration of a test dose of morphine (9 mg kg(-1), i.p.) on fifth day. Withdrawal zsymptoms (Jumping and Rearing) were assessed by administration of naloxone (5 mg kg(-1), i.p.) 2 h after the last dose of morphine in fourth day. It was found that administration of lamotrigine or magnesium sulfate or their combination decreased the morphine induced tolerance and withdrawal symptoms. From these results it is concluded that lamotrigine and magnesium sulfate alone or in combination could prevent the development of morphine tolerance and withdrawal symptoms. Glutamate release inhibitory effect of lamotrigine and its possible mechanism and property of magnesium, blocking the N-Methyl-D-Aspartate (NMDA) receptor calcium channel, is probably its mechanism on preventing morphine induced tolerance and dependence.