Evaluating the Use of Selective Serotonin Reuptake Inhibitors (SSRIs) and Male Infertility: A Critical Retrospective Study.

Background: The use of selective serotonin reuptake inhibitors (SSRIs) has been associated with potential effects on male fertility, although the exact mechanisms are not fully understood. The aim of this study was to understand the relationship between SSRIs and male infertility; Methods: A retrospective chart review of Saudi males who were treated with SSRIs and attended an infertility clinic in KSMC was undertaken. The medical records of men from an infertility clinic were reviewed to screen the quality of the sperm parameters in patients taking SSRIs; Results: In total, 299 men were identified, of whom 29 (9.6%) were exposed to SSRIs, while 270 (90.4%) did not receive SSRIs, defined as the control infertile group. When comparing the mean ages, a notable disparity was observed between the control group of infertile men (34.2 ± 6.9 years) and the infertile group using SSRIs (41.5 ± 3.2 years) (p < 0.001). Regarding the sperm analysis and the use of SSRIs, the impact of SSRIs use showed no significant differences in sperm liquefaction (p = 0.1), motility (p = 0.17), viscosity (p = 0.16), or count (p = 0.069) with escitalopram, fluoxetine, or paroxetine use; Conclusions: Our study showed no significant difference in the sperm analysis between the SSRI and non-SSRI cohorts. However, the relationship between SSRI use and sperm count warrants further investigation and consideration in clinical practice.

A content-quality and optimization analysis of YouTube as a source of patient information for bipolar disorder.

Background: The goal of this study was to identify and evaluate the use of Arabic YouTube videos on BD as a resource for patient education. Methods: A cross-sectional evaluation of YouTube videos as a source of information for patients with BD in Arabic was performed. The study was observational and, because it did not involve human subjects, it followed the STROBE guidelines whenever possible. The quality of the videos was assessed using the validated DISCERN instrument. The search strategy involved entering the term "bipolar disorder" in the YouTube search bar, and only YouTube videos in Arabic were included. Results: A total of 58 videos were included in this study after removing duplicates and videos unrelated to BD (Figure 1). The most common source of videos was others (38%), followed by physician (33%), educational (26%), and hospital (3%). Resources covering symptoms and prognosis were mostly in the "others" category (41%). The resources or videos that covered treatment options were mainly created by physicians (41%). However, resources or videos that included a personal story mainly belonged to the "others" category (67%). Conclusion: Visual health-related instructional resources still have a significant shortage. This study highlights the poor quality of videos about serious illnesses like BD. Evaluation and promotion of the creation of visual health-related educational resources should be the primary goal of future study.

Clavulanic Acid Improves Memory Dysfunction and Anxiety Behaviors through Upregulating Glutamatergic Transporters in the Nucleus Accumbens of Mice Repeatedly Exposed to Khat Extract.

Khat (Catha edulis) is an evergreen shrub whose buds and leaves give a state of delight and euphoria when chewed. Cathinone, an amphetamine-like stimulant that is among the active ingredients in khat, is able to downregulate glutamate transporter subtype I (GLT-1). Neurobehavioral dysfunctions such as altered locomotor activity, anorexia, and nociception have been observed in animals exposed to cathinone. Interestingly, treatment with a ß-lactam antibiotic such as ceftriaxone, which upregulates GLT-1, normalizes cathinone-induced conditioned place preference, and alters repetitive movements in rats. However, little is known about the role of the glutamatergic system in memory dysfunction and anxiety-like behaviors in mice exposed to khat. We found here that clavulanic acid, a ß-lactam-containing compound and GLT-1 upregulator, would modulate the neurobehavioral changes, including memory impairment and anxiety-like behaviors, associated with repeated exposure of mice to khat. Our data supported that clavulanic acid could improve memory impairment and anxiety-like behaviors through upregulating GLT-1 in the nucleus accumbens (NAc), an effect abolished with a selective GLT-1 blocker. This upregulation was associated with restored glutamate/cystine antiporter expression in the NAc using a Western blotting assay. Cathine and cathinone were identified in khat extract using the gas chromatography technique. Our work provides preclinical insight into the efficacy of ß-lactam-containing compounds for the attenuation of neurobehavioral changes induced by khat exposure.

Multitargeted Virtual Screening and Molecular Simulation of Natural Product-like Compounds against GSK3ß, NMDA-Receptor, and BACE-1 for the Management of Alzheimer's Disease.

The complexity of Alzheimer's disease (AD) and several side effects of currently available medication inclined us to search for a novel natural cure by targeting multiple key regulatory proteins. We initially virtually screened the natural product-like compounds against GSK3ß, NMDA receptor, and BACE-1 and thereafter validated the best hit through molecular dynamics simulation (MDS). The results demonstrated that out of 2029 compounds, only 51 compounds exhibited better binding interactions than native ligands, with all three protein targets (NMDA, GSK3ß, and BACE) considered multitarget inhibitors. Among them, F1094-0201 is the most potent inhibitor against multiple targets with binding energy -11.7, -10.6, and -12 kcal/mol, respectively. ADME-T analysis results showed that F1094-0201 was found to be suitable for CNS drug-likeness in addition to their other drug-likeness properties. The MDS results of RMSD, RMSF, Rg, SASA, SSE and residue interactions indicated the formation of a strong and stable association in the complex of ligands (F1094-0201) and proteins. These findings confirm the F1094-0201's ability to remain inside target proteins' binding pockets while forming a stable complex of protein-ligand. The free energies (MM/GBSA) of BACE-F1094-0201, GSK3ß-F1094-0201, and NMDA-F1094-0201 complex formation were -73.78 ± 4.31 kcal mol-1, -72.77 ± 3.43 kcal mol-1, and -52.51 ± 2.85 kcal mol-1, respectively. Amongst the target proteins, F1094-0201 have a more stable association with BACE, followed by NMDA and GSK3ß. These attributes of F1094-0201 indicate it as a possible option for the management of pathophysiological pathways associated with AD.

Nano-Curcumin Prevents Copper Reproductive Toxicity by Attenuating Oxidative Stress and Inflammation and Improving Nrf2/HO-1 Signaling and Pituitary-Gonadal Axis in Male Rats.

Copper is essential for several cellular processes and is an important catalytic factor for many proteins. However, excess copper can provoke oxidative stress and reproductive toxicity. This study evaluated the effect of liposomal nano-curcumin (N-CUR) and CUR on testicular oxidative injury, inflammation, and apoptosis, and altered steroidogenesis and Nrf2/HO-1 signaling induced by copper sulfate (CuSO4). Rats received CuSO4 and N-CUR or CUR via oral gavage for 7 days. CuSO4 induced histopathological changes and altered pituitary-gonadal axis manifested by decreased serum gonadotropins and testosterone. Testicular steroidogenesis genes (StAR, 3ß-HSD, CYP17A1, and 17ß-HSD) and androgen receptor (AR) were downregulated in rats that received CuSO4. N-CUR and CUR prevented testicular tissue injury, increased circulating FSH, LH, and testosterone, and upregulated testicular steroidogenesis genes and AR. Additionally, N-CUR and CUR decreased testicular MDA, NO, NF-κB, iNOS, TNF-α, Bax, and caspase-3 while enhanced Bcl-2, Nrf2, and the antioxidants GSH, HO-1, SOD, and catalase. In conclusion, N-CUR and CUR prevented CuSO4-induced reproductive toxicity in male rats by suppressing oxidative injury and inflammatory response and boosting steroidogenesis, sex hormones, and Nrf2/HO-1 signaling. N-CUR was more effective in ameliorating tissue injury, oxidative stress, inflammation, and apoptosis and enhancing steroidogenesis and Nrf2/HO-1 than the native form.

Examining Anxiety, Sleep Quality, and Physical Activity as Predictors of Depression among University Students from Saudi Arabia during the Second Wave of the COVID-19 Pandemic.

Conducted during the second wave of the pandemic, this cross-sectional study examined the link between sleep quality, physical activity, exposure, and the impact of COVID-19 as predictors of mental health in Saudi undergraduate students. A convenience sample of 207 participants were recruited, 89% of whom were females and 94% were single. The measures included questionnaires on the level of exposure and the perceived impact of COVID-19, a physical activity measure, GAD-7, PHQ-9, and PSQI. The results indicated that approximately 43% of participants exhibited moderate anxiety, and 50% were at risk of depression. Overall, 63.93% of students exposed to strict quarantine for at least 14 days (n = 39) exhibited a high risk of developing depression (χ2(1) = 6.49, p < 0.05, ϕ = 0.18). A higher risk of depression was also found in students whose loved ones lost their jobs (χ2(1) = 4.24, p < 0.05, ϕ = 0.14). Moreover, there was also a strong association between depression and anxiety (ß = 0.33, p < 0.01), sleep quality (ß = 0.32, p < 0.01), and the perceived negative impact of COVID-19 on socio-economic status (ß = 0.26, p < 0.05), explaining 66.67% of depression variance. Our study highlights the socio-economic impact of this pandemic and the overwhelming prevalence of depression.

Curcumin and Nano-Curcumin Mitigate Copper Neurotoxicity by Modulating Oxidative Stress, Inflammation, and Akt/GSK-3ß Signaling.

Copper (Cu) is essential for multiple biochemical processes, and copper sulphate (CuSO4) is a pesticide used for repelling pests. Accidental or intentional intoxication can induce multiorgan toxicity and could be fatal. Curcumin (CUR) is a potent antioxidant, but its poor systemic bioavailability is the main drawback in its therapeutic uses. This study investigated the protective effect of CUR and N-CUR on CuSO4-induced cerebral oxidative stress, inflammation, and apoptosis in rats, pointing to the possible involvement of Akt/GSK-3ß. Rats received 100 mg/kg CuSO4 and were concurrently treated with CUR or N-CUR for 7 days. Cu-administered rats exhibited a remarkable increase in cerebral malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 associated with decreased GSH, SOD, and catalase. Cu provoked DNA fragmentation, upregulated BAX, caspase-3, and p53, and decreased BCL-2 in the brain of rats. N-CUR and CUR ameliorated MDA, NF-κB p65, and pro-inflammatory cytokines, downregulated pro-apoptotic genes, upregulated BCL-2, and enhanced antioxidants and DNA integrity. In addition, both N-CUR and CUR increased AKT Ser473 and GSK-3ß Ser9 phosphorylation in the brain of Cu-administered rats. In conclusion, N-CUR and CUR prevent Cu neurotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis and upregulating AKT/GSK-3ß signaling. The neuroprotective effect of N-CUR was more potent than CUR.

Nano-Curcumin Prevents Cardiac Injury, Oxidative Stress and Inflammation, and Modulates TLR4/NF-κB and MAPK Signaling in Copper Sulfate-Intoxicated Rats.

Copper (Cu) is essential for a plethora of biological processes; however, its high redox reactivity renders it potentially toxic. This study investigated the protective effect of curcumin (CUR) and nano-CUR (N-CUR) against Cu cardiotoxicity, emphasizing the role of oxidative stress, TLR4/NF-κB and mitogen-activated protein kinase (MAPK) signaling and cell death in rats. Rats received 100 mg/kg copper sulfate (CuSO4), a pesticide used for repelling pests, and were concurrently treated with CUR or N-CUR for 7 days. Cu caused cardiac injury manifested by elevated serum cardiac troponin I (cTnI), creatine kinase (CK)-MB, and lactate dehydrogenase (LDH), as well as histopathological alterations. Cardiac malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 were increased, and reduced glutathione (GSH), superoxide dismutase (SOD) and catalase were decreased in Cu-treated rats. CUR and N-CUR prevented cardiac tissue injury, decreased serum cTnI, CK-MB, and LDH, and cardiac MDA, NF-κB p65, TNF-α, and IL-6, and enhanced cellular antioxidants. CUR and N-CUR downregulated TLR4 and AP-1, and decreased the phosphorylation levels of p38 MAPK, JNK, and ERK1/2. In addition, CUR and N-CUR increased cardiac Bcl-2 and BAG-1, decreased Bax and caspase-3, and prevented DNA fragmentation. In conclusion, N-CUR prevents Cu cardiotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis, and modulating TLR4/NF-κB and MAPK signaling. The cardioprotective effect of N-CUR was more potent than the native form.

Aß oligomers induce pathophysiological mGluR5 signaling in Alzheimer's disease model mice in a sex-selective manner.

The prevalence, presentation, and progression of Alzheimer's disease (AD) differ between men and women, although ß-amyloid (Aß) deposition is a pathological hallmark of AD in both sexes. Aß-induced activation of the neuronal glutamate receptor mGluR5 is linked to AD progression. However, we found that mGluR5 exhibits distinct sex-dependent profiles. Specifically, mGluR5 isolated from male mouse cortical and hippocampal tissues bound with high affinity to Aß oligomers, whereas mGluR5 from female mice exhibited no such affinity. This sex-selective Aß-mGluR5 interaction did not appear to depend on estrogen, but rather Aß interaction with cellular prion protein (PrPC), which was detected only in male mouse brain homogenates. The ternary complex between mGluR5, Aß oligomers, and PrPC was essential to elicit mGluR5-dependent pathological suppression of autophagy in primary neuronal cultures. Pharmacological inhibition of mGluR5 reactivated autophagy, mitigated Aß pathology, and reversed cognitive decline in male APPswe/PS1ΔE9 mice, but not in their female counterparts. Aß oligomers also bound with high affinity to human mGluR5 isolated from postmortem donor male cortical brain tissue, but not that from female samples, suggesting that this mechanism may be relevant to patients. Our findings indicate that mGluR5 does not contribute to Aß pathology in females, highlighting the complexity of mGluR5 pharmacology and Aß signaling that supports the need for sex-specific stratification in clinical trials assessing AD therapeutics.

mGluR5 Contribution to Neuropathology in Alzheimer Mice Is Disease Stage-Dependent.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and is characterized by a progressive cognitive decline in affected individuals. Current therapeutic strategies are limited in their efficacy and some have proven to be even less effective at later disease stages or after extended use. We previously demonstrated that chronic inhibition of mGluR5 signaling using the selective negative allosteric modulator (NAM) CTEP in APPswe/PS1ΔE9 mice can rescue cognitive function, activating the ZBTB16-mediated autophagy pathway to reduce Aß, the principal neurotoxic species in AD brains. Here, we evaluated the efficacy of long-term treatment with CTEP in 6 month old APPswe/PS1ΔE9 mice for either 24 or 36 weeks. CTEP maintained its efficacy in reversing working and spatial memory deficits and mitigating neurogliosis in APPswe/PS1ΔE9 mice when administered for 24 weeks. This was paralleled by a significant reduction in Aß oligomer and plaque load as a result of autophagy activation via ZBTB16 and mTOR-dependent pathways. However, further extension of CTEP treatment for 36 weeks was found ineffective in reversing memory deficit, neurogliosis, or Aß-related pathology. We found that this loss in CTEP efficacy in 15 month old APPswe/PS1ΔE9 mice was due to the abolished contribution of ZBTB16 and mTOR-mediated signaling to AD neuropathology at this advanced disease stage. Our findings indicate that the contribution of pathological mGluR5-signaling to AD may shift as the disease progresses. Thus, we provide the first evidence that the underlying pathophysiological mechanism(s) of AD may unfold along the course of the disease and treatment strategies should be modified accordingly to ensure maximal therapeutic outcomes.

Structural determinants governing ß-arrestin2 interaction with PDZ proteins and recruitment to CRFR1.

ß-Arrestins are multifunctional adaptor proteins best know for their vital role in regulating G protein coupled receptor (GPCR) trafficking and signaling. ß-arrestin2 recruitment and receptor internalization of corticotropin-releasing factor receptor 1 (CRFR1), a GPCR whose antagonists have been shown to demonstrate both anxiolytic- and antidepressant-like effects, have previously been shown to be modulated by PDZ proteins. Thus, a structural characterization of the interaction between ß-arrestins and PDZ proteins can delineate potential mechanism of PDZ-dependent regulation of GPCR trafficking. Here, we find that the PDZ proteins PSD-95, MAGI1, and PDZK1 interact with ß-arrestin2 in a PDZ domain-dependent manner. Further investigation of such interaction using mutational analyses revealed that mutating the alanine residue at 175 residue of ß-arrestin2 to phenylalanine impairs interaction with PSD-95. Additionally, A175F mutant of ß-arrestin2 shows decreased CRF-stimulated recruitment to CRFR1 and reduced receptor internalization. Thus, our findings show that the interaction between ß-arrestins and PDZ proteins is key for CRFR1 trafficking and may be targeted to mitigate impaired CRFR1 signaling in mental and psychiatric disorders.

Constitutive activities and inverse agonism in dopamine receptors.

The concept of activation in the absence of agonists has been demonstrated for many GPCRs and is now solidified as one of the principal aspects of GPCR signaling. In this chapter, we review how dopamine receptors demonstrate this ability. Although difficult to prove in vivo due to the presence of endogenous dopamine and lack of subtype-selective inverse agonists and "pure" antagonists (neutral ligands), in vitro assays such as measuring intracellular cAMP, [(35)S]GTPγS binding, and [(3)H]thymidine incorporation have uncovered the constitutive activation of D1- and D2-class receptors. Nevertheless, because of limited and inconsistent findings, the existence of constitutive activity for D2-class receptors is currently not well established. Mutagenesis studies have shown that basal signaling, notably by D1-class receptors, is governed by the collective contributions of transmembrane domains and extracellular/intracellular loops, such as the third extracellular loop, the third intracellular loop, and C-terminal tail. Furthermore, constitutive activities of D1-class receptors are subjected to regulation by kinases. Among the dopamine receptor family, the D5 receptor subtype exhibits a higher basal signaling and bears resemblance to constitutively active mutant forms of GPCRs. The presence of its constitutive activity in vivo and its pathophysiological relevance, with a brief mention of other subtypes, are also discussed.