From Ethanol to Salsolinol: Role of Ethanol Metabolites in the Effects of Ethanol

In spite of the global reputation of ethanol as the psychopharmacologically active ingredient of alcoholic drinks, the neurobiological basis of the central effects of ethanol still presents some dark sides due to a number of unanswered questions related to both its precise mechanism of action and its metabolism. Accordingly, ethanol represents the interesting example of a compound whose actions cannot be explained as simply due to the involvement of a single receptor/neurotransmitter, a scenario further complicated by the robust evidence that two main metabolites, acetaldehyde and salsolinol, exert many effects similar to those of their parent compound. The present review recapitulates, in a perspective manner, the major and most recent advances that in the last decades boosted a significant growth in the understanding on the role of ethanol metabolism, in particular, in the neurobiological basis of its central effects

Mental health among university students: The associations of effort-reward imbalance and overcommitment with psychological distress

Background: Mental health problems are highly prevalent among university students, but little is known about their underlying determinants. This study explores mental health among university students, the association between “effort-reward imbalance” (ERI), overcommitment and mental health, and to what extent ERI and overcommitment explain gender differences in mental health. Methods: Cross-sectional data were analyzed from 4760 Italian university students. The Kessler Psychological Distress Scale-10 was used to measure self-reported psychological distress, as an indicator of mental health, and the ERI – Student Questionnaire to measure effort, reward and overcommitment. The associations between ERI and overcommitment with psychological distress were estimated with multinomial logistic regression analyses. Results: 78.5% of the respondents experienced psychological distress, with 21.3%, 21.1%, and 36.1% reporting respectively mild, moderate and severe psychological distress. Female students were more likely to report moderate and severe psychological distress. ERI and overcommitment were strongly associated with severe psychological distress with ORs respectively up to 19.9 (95% CI: 12.2–32.5) and 22.2 (95% CI: 16.1–30.7). ERI and overcommitment explained part of the higher odds of severe psychological distress among female students comparing to males, attenuating the ORs from 2.3 (95% CI: 1.9–2.7) to 1.4 (95% CI: 1.2–1.7). Limitations: This cross-sectional study was performed on a large, but convenient sample. Discussion: More than one out of three students reported severe psychological distress. Decreasing ERI and overcommitment may be beneficial in the prevention of psychological distress among university students and may reduce gender differences in psychological distress. Longitudinal studies are needed to further investigate these associations

Associations of university student life challenges with mental health and self-rated health: A longitudinal study with 6 months follow-up

Background: Mental health problems are highly prevalent among university students. Stress due to student life challenges may be a risk factor for poorer health. This study investigates to what extent student life challenges and changes therein are associated with mental health and self-rated health. Methods: In a longitudinal study with 568 Italian university students mental health was assessed using the Mental Health Inventory-5 (MHI-5) and self-rated health with a single item from the Short Form 36 Health Survey (SF36) (score ranges: 0-100) at baseline and at six months follow-up. Student life challenges were investigated using six subscales (score ranges: 1-4) of the Higher Education Stress Inventory (HESI). A between-within linear regression model was used to investigate whether a higher exposure to life challenges was associated with poorer health (between individuals) and whether changes in student life challenges were associated with changes in health (within individuals). Results: Higher exposure to student life challenges was associated with poorer mental health (b ranging from -5.3 to -10.3) and self-rated health (b ranging from -3.1 to -9.6). An increase in student life challenges within individuals was associated with poorer mental health and self-rated health, in particular for high workload (b up to -5.9), faculty shortcomings (b up to -5.7), and unsupportive climate (b up to -5.6). Discussion: Exposure to student life challenges and changes therein are associated with university students’ health. Our findings suggest that student life challenges may be a target for interventions to improve mental health and self-rated health among university students

Impact of Caffeine on Ethanol-Induced Stimulation and Sensitization: Changes in ERK and DARPP-32 Phosphorylation in Nucleus Accumbens

Background: Caffeine is frequently consumed with ethanol to reduce the impairing effects induced by ethanol, including psychomotor slowing or incoordination. Both drugs modulate dopamine (DA)-related markers in accumbens (Acb), and Acb DA is involved in voluntary locomotion and locomotor sensitization. The present study determined whether caffeine can affect locomotion induced by acute and repeated ethanol administration in adult male CD-1 mice. Methods: Acute administration of caffeine (7.5 to 30.0 mg/kg) was evaluated for its effects on acute ethanol-induced (1.5 to 3.5 g/kg) changes in open-field horizontal locomotion, supported rearing, and rearing not supported by the wall. DA receptor-dependent phosphorylation markers were assessed: extracellular signal-regulated kinase (pERK), and dopamine-and cAMP-regulated phosphoprotein Mr32kDa phosphorylated at threonine 75 site (pDARPP-32-Thr75) in Acb core and shell. Acutely administered caffeine was also evaluated in ethanol-sensitized (1.5 g/kg) mice. Results: Acute ethanol decreased both types of rearing. Caffeine increased supported rearing but did not block ethanol -induced decreases in rearing. Both substances increased horizontal locomotion in a biphasic manner, and caffeine potentiated ethanol-induced locomotion. Although ethanol administered repeatedly induced sensitization of locomotion and unsupported rearing, acute administration of caffeine to ethanol-sensitized mice in an ethanol-free state resulted in blunted stimulant effects compared with those seen in ethanol-naïve mice. Ethanol increased pERK immunoreactivity in both subregions of the Acb, but coadministration with caffeine blunted this increase. There were no effects on pDARPP-32(Thr75) immunoreactivity. Conclusions: The present results demonstrated that, after the first administration, caffeine potentiated the stimulating actions of ethanol, but did not counteract its suppressant or ataxic effects. Moreover, our results show that caffeine has less activating effects in ethanol-sensitized animals

Role of nucleus accumbens μ opioid receptors in the effects of morphine on ERK1/2 phosphorylation

Rationale: Despite the critical role attributed to phosphorylated extracellular signal regulated kinase (pERK1/2) in the nucleus accumbens (Acb) in the actions of addictive drugs, the effects of morphine on ERK1/2 phosphorylation in this area are still controversial. Objectives: In order to investigate further this issue, we studied (1) the ability of morphine to affect ERK1/2 phosphorylation in the shell (AcbSh) and core (AcbC) of Sprague-Dawley and Wistar rats and of CD-1 and C57BL/6J mice and (2) the role of dopamine D1 and μ-opioid receptors in Sprague-Dawley rats and CD-1 mice. Methods: The pERK1/2 expression was assessed by immunohistochemistry. Results: In rats, morphine decreased AcbSh and AcbC pERK1/2 expression, whereas in mice, increased it preferentially in the AcbSh compared with the AcbC. Systemic SCH 39166 decreased pERK1/2 expression on its own in the AcbSh and AcbC of Sprague-Dawley rats and CD-1 mice; furthermore, in rats, SCH 39166 disclosed the ability of morphine to stimulate pERK1/2 expression. Systemic (rats and mice) and intra-Acb (rats) naltrexone prevented both decreases, in rats, and increases, in mice. Conclusions: These findings confirm the differential effects of morphine in rats and mice Acb and that D1 receptors exert a facilitatory role on ERK1/2 phosphorylation; furthermore, they indicate that, in rats, removal of the D1-dependent pERK1/2 expression discloses the stimulatory influence of morphine on ERK1/2 phosphorylation and that the morphine’s ability to decrease pERK1/2 expression is mediated by Acb μ-opioid receptors. Future experiments may disentangle the psychopharmacological significance of the effects of morphine on pERK1/2 in the Acb

Best Possible Maximum Principles for Fully Nonlinear Elliptic Partial Differential Equations

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Hybrid lipid self-assembling nanoparticles for brain delivery of microRNA

Hybrid self-assembling nanoparticles (SANPs) have been previously designed as novel drug delivery system that overcomes stability issues following long-term storage and with an easy scale-up. This system has been successfully used to deliver anionic-charged agents, e.g. bisphosphonates, in different types of tumors, such glioblastoma (GBM). Here, SANPs were tested and optimized for the delivery of nucleic acids, in particular of a specific microRNA, e.g. miR603, used for its potential role in controlling the chemoresistance in different forms of cancer, e.g. (GBM). To this aim, SANPs with different lipids were prepared and characterized, in terms of size, polydispersity index, zeta potential, miRNA encapsulation, stability in BSA, serum and hemolytic activity. Then, SANPs were tested in vitro on two different cell lines of GBM. Finally, miRNA biodistribution was tested in vivo in an orthotopic model of GBM. The majority of the formulations showed good technological characteristics and were stable in BSA and serum with a low hemolytic activity. The intracellular uptake studies on GBM cell lines showed that SANPs allow to achieve a higher miRNA delivery compared to others transfection agents, e.g. lipofectamine. Finally, in vivo biodistribution studies in an orthotopic of GBM demonstrated that the optimized SANP formulations, were able to deliver miRNA in different organs, e.g. the brain

Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan

Poly(ADP-ribose) polymerase inhibitors (PARPi) are currently evaluated in clinical trials in combination with topoisomerase I (Top1) inhibitors against a variety of cancers, including colon carcinoma. Since the mismatch repair component MLH1 is defective in 10-15% of colorectal cancers we have investigated whether MLH1 affects response to the Top1 inhibitor irinotecan, alone or in combination with PARPi. To this end, the colon cancer cell lines HCT116, carrying MLH1 mutations on chromosome 3 and HCT116 in which the wildtype MLH1 gene was replaced via chromosomal transfer (HCT116+3) or by transfection of the corresponding MLH1 cDNA (HCT116 1-2) were used. HCT116 cells or HCT116+3 cells stably silenced for PARP-1 expression were also analysed. The results of in vitro and in vivo experiments indicated that MLH1, together with low levels of Top1, contributed to colon cancer resistance to irinotecan. In the MLH1-proficient cells SN-38, the active metabolite of irinotecan, induced lower levels of DNA damage than in MLH1-deficient cells, as shown by the weaker induction of γ-H2AX and p53 phosphorylation. The presence of MLH1 contributed to induce of prompt Chk1 phosphorylation, restoring G2/M cell cycle checkpoint and repair of DNA damage. On the contrary, in the absence of MLH1, HCT116 cells showed minor Chk1 phosphorylation and underwent apoptosis. Remarkably, inhibition of PARP function by PARPi or by PARP-1 gene silencing always increased the antitumor activity of irinotecan, even in the presence of low PARP-1 expression