Impact of prenatal THC exposure on lipid metabolism and microbiota composition in rat offspring

Objective: Recent studies have demonstrated that prenatal exposure to the psychoactive ingredient of cannabis that is tetrahydrocannabinol (THC) disrupts fatty acid (FA) signaling pathways in the developing brain, potentially linking to psychopathologic consequences. Our research aims to investigate whether changes in midbrain FA metabolism are linked to modifications in peripheral metabolism of FAs and shifts in microbiota composition. Methods: In order to model prenatal exposure to THC (PTE) in rats, Sprague Dawley dams were systemically administered with THC (2 mg/kg, s.c.) or vehicle once daily from gestational day 5–20. To evaluate the metabolic impact of PTE in the offspring during preadolescence (postnatal day, PND, 25–28), we analyzed FA profiles and their bioactive metabolites in liver and midbrain tissues, and microbiota alterations. Results: Our findings indicate that PTE leads to sex-specific metabolic changes. In both sexes, PTE resulted in increased liver de novo lipogenesis (DNL) and alterations in FA profiles, as well as changes in N-acylethanolamines (NAEs), ligands of peroxisome proliferator-activated receptor alpha (PPAR-α). In females only, PTE influenced gene expression of PPAR-α and fibroblast growth factor 21 (Fgf21). In male offspring only, PTE was associated with significantly reduced fasting glycaemia and with alterations in the levels of midbrain NAEs. Our analysis of the progeny gut microbiota revealed sex-dependent effects of PTE, notably an increased abundance of Ileibacterium in PTE-exposed male offspring, a change previously associated with the long-term effects of a maternal unbalanced diet. Conclusions: Our data suggest that in male PTE offspring a reduced fasting glycaemia, resulting from increased liver DNL and the absence of a compensatory effect by Ppar-α and FGF21 on glycemic homeostasis, are associated to alterations in midbrain NAEs ligands of PPAR-α. These metabolic changes within the midbrain, along with Ileibacterium abundance, may partly elucidate the heightened susceptibility to psychopathologic conditions previously observed in male offspring following PTE

LTalpha and LTbeta gene expression in organs of sheep showing different lymphoproliferative changes induced by maedi-visna virus

In lung and mammary gland of sheep, Maedi-Visna virus (MVV) causes lymphoproliferative inflammation often with follicular structures (lymphofollicular inflammation). The aim of this work was to define whether Limphotoxin α and β (LTα, LTβ) play a role in the formation of these peculiar lesions in sheep experimentally infected with MVV

Virtual Screening of acyclovir derivatives as potential antiviral agents: design, synthesis, and biological evaluation of new acyclic nucleoside ProTides

Following our findings on the anti-human immunodeficiency virus (HIV) activity of acyclovir (ACV) phosphate prodrugs, we herein report the ProTide approach applied to a series of acyclic nucleosides aimed at the identification of novel and selective antiviral, in particular anti-HIV agents. Acyclic nucleoside analogues used in this study were identified through a virtual screening using HIV-reverse transcriptase (RT), adenylate/guanylate kinase, and human DNA polymerase γ. A total of 39 new phosphate prodrugs were synthesized and evaluated against HIV-1 (in vitro and ex vivo human tonsillar tissue system) and human herpes viruses. Several ProTide compounds showed substantial potency against HIV-1 at low micromolar range while the parent nucleosides were not effective. Also, pronounced inhibition of herpesvirus replication was observed. A carboxypeptidase-mediated hydrolysis study was performed for a selection of compounds to assess the formation of putative metabolites and support the biological activity observed

Additional polymorphisms of the <i>PRNP</i> gene significantly decrease the susceptibility to scrapie of ARQ/ARQ sheep

The aim of this work was to investigate the risk of scrapie of the ARQ/ARQ genotype carrying at least one point mutation at codons 112, 137, 141, 142, 154 and 176 in comparison with the ARQ/ARQ without any point mutations

Prior Engagement in Physical Activity Correlates with Enhanced Quality of Life Perceptions among Older Adults during COVID-19 Lockdown

Background: This longitudinal study aimed to evaluate whether prior engagement in a physical exercise program correlated with enhanced perceptions of quality-of-life components among older adults during the COVID-19 lockdown period. Methods: The cohort comprised elderly individuals (aged ≥ 65 years) who had previously partaken in a 12-week randomized controlled trial investigating the effects of a mixed aerobic-anaerobic, moderate-intensity exercise program. Participants' health-related quality of life was assessed using the Short Form Health Survey-12 item (SF-12) at the beginning of the initial trial and, again, one year later during the COVID-19 lockdown. In the exercise group, 44 participants were included, while the control group consisted of 49 participants, with computer-based, double-blind randomization conducted in Cagliari, Italy. The differences in scores for each SF-12 item between the two groups from T0 to T1 were compared using one-way ANOVA with Bonferroni corrections. Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 27. Results: No statistically significant differences were observed on average by age (exercise group vs. control group 72.20 ± 4.78 vs. 72.91 ± 4.77; F = 0.513, p = 0.476). A decrease from T0 to T1 towards a better score on the SF-12 was observed in the exercise group compared to the control group in item 1 (F = 67.463, p &lt; 0.0001); in item 5 (F = 4.319, p = 0.041); item 8 (F = 4.269, p = 0.041); item 9 (F = 10.761, p = 0.001); item 10 (F = 170.433, p &lt; 0.001); and item 11 (F = 4.075, p = 0.046). Conclusions: The results suggest that participation in a moderate physical exercise program one year prior may have equipped older adults with better coping mechanisms to navigate the stress and isolation imposed by the COVID-19 lockdown, as reflected by their enhanced scores on quality-of-life components pertaining to mental well-being. Exercise may confer a protective effect against the adverse psychological impacts of stressful events like the pandemic, even among older adults with chronic conditions. This study underscores the potential benefits of exercise interventions for promoting quality of life and preventing mood disorders in the elderly population

Reliability and Factor Structure of the Well-Being and Respect for Human Rights Questionnaire in Measuring Caregivers' Perception

Background: This study has investigated perceptions of respect for users' rights among informal caregivers in mental healthcare settings, aligning with the guidelines outlined in the United Nations Convention on the Rights of Persons with Disabilities (CRPD) and the World Health Organization QualityRights initiative. The study has employed the questionnaire on Well-being at Work and Respect for Human Rights (WWRR) among informal caregivers and tested whether the questionnaire's factor structure among informal caregivers aligns with that of users and health workers. We have hypothesized that informal caregivers prioritize users' needs and rights over the care context's climate. Methods: This was a cross-sectional study. The "Well-being at Work and Respect for Human Rights" questionnaire was distributed to 100 caregivers in 4 territorial mental health facilities in Sardinia, Italy. Confirmatory Factor Analysis (CFA) was utilized to assess the participants' responses. Results: Participants reported high satisfaction with their relatives' treatment, perceiving a high level of respect for human rights among users and healthcare professionals. However, they highlighted insufficient resources for services, particularly the need for additional staff. CFA revealed that a scale with the first five items demonstrated good reliability, convergent validity, and discrimination. Mean scores indicated high satisfaction and perception of respect for human rights across the sample, with no significant differences by age or gender. Conclusion: Satisfaction with users' rights is closely correlated with other factors comprising the notion of organizational well-being within a healthcare service

Informal caregivers compared with users and health workers on well-being and respect for human rights in mental health care services

Background: This study aimed to measure differences among informal caregivers, users, and mental healthcare workers (MHW) regarding job/organizational satisfaction and perceptions of respect for rights in the mental health services of one region of Italy. Methods: A sample of 100 caregivers, 240 MHW, and 200 users completed the “Well-Being at Work and Respect for Human Rights Questionnaire” (WWRR) in community mental health centers in Sardinia. Results: Caregivers reported higher satisfaction toward MHW on perceiving respect for human rights among users (5.2 ± 1.0 vs 5.1 ± 1.1, p &lt; 0.0001) and health professionals (5.3 ± 0.8 vs 4.5 ± 1.3, p &lt; 0.0001) and organization well-being (5.1 ± 1.2 vs 3.9 ± 1.3, p &lt; 0.0001); toward users about respect of rights of MHW (5.3 ± 0.8 vs 4.9 ± 1.2, p &lt; 0.0001) and both toward users and MHW on dissatisfaction on resources (p &lt; 0.0001). Caregivers strongly highlighted insufficient resources for services. Conclusion: Despite caregiver satisfaction, resource deficiencies signal a critical juncture in Italian mental health care. Continued cuts in healthcare spending, especially in mental health, raise concerns for future outcomes

PPAR-Alpha Agonists as Novel Antiepileptic Drugs: Preclinical Findings

Nicotinic acetylcholine receptors (nAChRs) are involved in seizure mechanisms. Hence, nocturnal frontal lobe epilepsy was the first idiopathic epilepsy linked with specific mutations in a4 or b2 nAChR subunit genes. These mutations confer gain of function to nAChRs by increasing sensitivity toward acetylcholine. Consistently, nicotine elicits seizures through nAChRs and mimics the excessive nAChR activation observed in animal models of the disease. Treatments aimed at reducing nicotinic inputs are sought as therapies for epilepsies where these receptors contribute to neuronal excitation and synchronization. Previous studies demonstrated that peroxisome proliferator-activated receptors-a (PPARa), nuclear receptor transcription factors, suppress nicotine-induced behavioral and electrophysiological effects by modulating nAChRs containing b2 subunits. On these bases, we tested whether PPARa agonists were protective against nicotine-induced seizures. To this aim we utilized behavioral and electroencephalographic (EEG) experiments in C57BL/J6 mice and in vitro patch clamp recordings from mice and rats. Convulsive doses of nicotine evoked severe seizures and bursts of spike-waves discharges in ,100% of mice. A single dose of the synthetic PPARa agonist WY14643 (WY, 80 mg/kg, i.p.) or chronic administration of fenofibrate, clinically available for lipid metabolism disorders, in the diet (0.2%) for 14 days significantly reduced or abolished behavioral and EEG expressions of nicotine-induced seizures. Acute WY effects were reverted by the PPARa antagonist MK886 (3 mg/kg, i.p.). Since neocortical networks are crucial in the generation of ictal activity and synchrony, we performed patch clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) from frontal cortex layer II/III pyramidal neurons. We found that both acute and chronic treatment with PPARa agonists abolished nicotine-induced sIPSC increases. PPARa within the CNS are key regulators of neuronal activity through modulation of nAChRs. These effects might be therapeutically exploited for idiopathic or genetically determined forms of epilepsy where nAChRs play a major role