Calcineurin-nuclear factor of activated T cells (NFAT) signaling plays a central role in immune activation and represents a major therapeutic target for immunosuppression. Although calcineurin inhibitors such as tacrolimus are clinically effective, their long-term use is limited by severe systemic toxicities associated in part with broad inhibition of calcineurin catalytic activity. In this study, we investigated whether small-molecule inhibition of NFAT signaling could suppress NFAT activation while limiting direct inhibition of calcineurin catalytic activity. We designed and synthesized fourteen analogs (2-15) based on a small-molecule inhibitor previously identified and derived from the PxIxIT sequence. We assessed the inhibitory activities of structurally modified analogs against NFATc1 and NFATc2 and compared their isoform-specific inhibitory profiles. Our investigation revealed that analog 14 produced closely matched inhibition of NFATc1 and NFATc2, suppressed NFAT-dependent cytokine production, and showed cellular immunosuppressive activities. Importantly, 14 showed only limited inhibition of calcineurin catalytic activity at concentrations associated with its NFAT-inhibitory effects. At concentrations matched for IL-2 suppression, 14 modestly reduced Jurkat T-cell proliferation and activation. It also showed a favorable preliminary safety-related profile across the cellular and zebrafish models tested, including longer-term assessments of cell viability, oxidative stress, and renal injury. Collectively, these findings establish 14 as an early-stage lead compound for selective modulation of NFAT signaling while limiting calcineurin catalytic inhibition, providing a foundation for further pharmacological development.

People perceive more symmetrical individuals as more attractive; therefore, facial symmetry has been linked to mate selection. Being perceived as more attractive could also increase women's indirect reproductive benefits that would follow from pronounced sexuality and enhanced mating. Sexuality can be examined either as long-term, through sociosexual orientation, or through current sexual activity and desire. This study explored the relationship between facial asymmetry and female sexuality, while taking into account a relationship status and, due to the potential differences in facial asymmetry between female from rural and urban areas, the place of residence. Long-term sexuality was measured with the three subscales of the Sociosexual Orientation Inventory (SOI-R): Behavior, Attitude, and Desire. Current sexual activity and desire were assessed with questions about their frequency and intensity (based on the Female Sexual Function Index). Simple correlations revealed a weak, negative association between facial asymmetry and the number of sexual partners in the last year (ρ = - .23, 95% CI [- 0.45, 0.01], p = .047), SOI Attitude (ρ = - .25, 95% CI [- 0.44, - 0.03], p = .031), and sexual desire (ρ = - .21, 95% CI [- 0.43, - 0,00], p = .082). However, these effects were no longer significant after including place of residence as a confounder (.42 < p < .91). These results highlight the importance of external conditions when investigating correlates of facial asymmetry.

Problematic pornography use (PPU) is the most common manifestation of compulsive sexual behavior disorder (CSBD). Many adults seeking help for CSBD report onset during adolescence, yet there is limited knowledge of PPU in adolescents and its predisposing factors. This study investigated the prevalence of self-perceived PPU among Swedish adolescents and explored associated factors as well as pornography use patterns. In this cross-sectional study, data were collected from a representative sample of 3106 Swedish third-year senior high school students. Information on sociodemographic background, pornography use, sexual behaviors, health, and experiences of abuse was collected. PPU was based on self-reported difficulties in refraining from or stopping pornography use. Gender-stratified descriptive statistics and logistic regression analyses were used to examine relationships between groups and variables. PPU was reported by 10.4% of respondents, with a higher prevalence among boys (18.8%) compared to girls (3.9%). It was associated with increased time spent on pornography and higher exposure to violent or other concerning sexual content. Compared to the reference group, adolescents with PPU exhibited higher rates of abusive experiences, mental health issues, risky behaviors, and nonsuicidal self-injury. Gender-specific patterns emerged. PPU is a significant issue among Swedish adolescents, particularly boys. Addressing concerns related to pornography use, underlying vulnerabilities and gender-specific factors is crucial to prevent the progression of PPU into adulthood and in treatment efforts.

For decades, ischemic neuronal death was understood largely as a story about glutamate. Acid-sensing ion channels (ASICs) have revised that account. When cerebral blood flow stops, the penumbra can develop prolonged extracellular acidosis, and experimental studies implicate ASIC1a in mediating sufficient Ca²⁺ entry to injure neurons even when glutamate receptors are blocked, a contribution shaped by channel expression, subunit composition, and the intracellular signaling context. However, sustained acidosis does not necessarily imply sustained channel opening, given ASIC1a desensitization. Besides acidosis, glutamate, polyamines, a paradoxical intracellular alkalization, and oxidative stress can enhance ASIC1a activity or expression, and the channel also signals through a non-conducting route, recruiting RIPK1 to trigger necroptosis independently of ion flux. The relative contributions of these conducting and non-conducting mechanisms in vivo remain incompletely defined. Endogenous mechanisms may constrain injury by internalizing the channel, altering subunit expression, including conditioning-associated ASIC2a upregulation, and degrading ASIC1a through estrogen signaling. We argue that these responses are better understood as constraints on injury than as a genuine survival program, a distinction with mechanistic and therapeutic consequences. Critically, the contribution of these mechanisms may vary over time. The same channel acts as a target of homeostatic regulation before stroke, a driver of death during ischemia, a potential target at reperfusion when acidosis persists but restored flow finally permits drug delivery, and an impediment to repair for weeks afterward. The question in ASIC-targeted neuroprotection is not only whether to inhibit the channel, but also when and for how long.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, affecting approximately 25% of the adult population, yet no approved pharmacotherapy is currently available. Flavonoids have shown promise in improving MASLD, but the structural determinants underlying their lipid-lowering activities remain unclear. This study aimed to systematically investigate whether the presence or absence of the C-2,3 double bond affects the efficacy of flavonoids in ameliorating MASLD. Two pairs of C-2,3 positional isomeric flavonoids-eriodictyol (Compound 1a, dihydro form, C-2,3 single bond)/luteolin (Compound 1b, non-dihydro form, C-2,3 double bond) and dihydromyricetin (Compound 2a, dihydro form, C-2,3 single bond)/myricetin (Compound 2b, non-dihydro form, C-2,3 double bond)-were compared using an FFA-induced HepG2 cell model and an HFD-induced MASLD mouse model. Lipid accumulation, gene expression, target protein thermal stabilization (via CETSA), and compound-target interactions (via molecular docking) were systematically assessed. Both in vitro and in vivo experiments consistently demonstrated that the dihydro forms (C-2,3 single bond) exhibited superior efficacy to their non-dihydro counterparts (C-2,3 double bond) in reducing lipid accumulation and modulating lipid metabolism-related genes. Mechanistically, the dihydro forms showed broader regulatory effects on genes involved in fatty acid oxidation, de novo lipogenesis, and fatty acid uptake. CETSA and molecular docking analyses further suggested that the dihydro forms exhibited greater thermal stabilization of the target proteins and generally lower predicted binding energies across all three targets (PPARγ, ACC1, and FASN). This study provides the first systematic evidence that the C-2,3 single-bond configuration may represent a structural feature associated with enhanced lipid-lowering activity of flavonoids, offering experimental evidence for dietary intervention strategies and flavonoid-based lead compound optimization in MASLD.

Selective serotonin reuptake inhibitors (SSRIs) are reported to be implicated in altering glucose homeostasis and inducing hypoglycemia in diabetic patients and mice. Herein, the effects of paroxetine on glucose homeostasis, insulin secretion, and insulin sensitivity were investigated in both healthy and streptozotocin-induced-insulin deficient mouse model. Mice were administered with paroxetine (1, 10, and 50 mg/kg) and fasting insulin levels and glucose-stimulated insulin secretion were assessed in healthy mice, whereas the glycemic profile in diabetic mice was evaluated after glucose or insulin challenge. Muscle mRNA expression of insulin signaling-relevant genes was analyzed, in addition to protein kinase B (PKB/Akt) activity and glucose transporter 4 (GLUT4) plasma membrane expression assessed in C2C12 myotubes. Paroxetine modulated glucose homeostasis and reduced the spike in blood glucose in diabetic mice in a dose-dependent manner after a glucose tolerance test. On the other hand, a reverse relationship was observed in the insulin tolerance test, with no evidence of acute hypoglycemia, suggesting that paroxetine did not further exacerbate insulin-induced glucose lowering under the tested conditions. Paroxetine (50 mg/kg) significantly increased fasting insulin secretion and upregulated genes involved in insulin receptor and Akt signaling, while reducing Glut4 mRNA expression. At 10 mg/kg, paroxetine significantly elevated Akt phosphorylation (p < 0.01). Paroxetine enhanced GLUT4 translocation and Akt phosphorylation in C2C12 myotubes. These findings suggest that paroxetine influences glucose homeostasis in diabetic conditions without causing acute hypoglycemia. Nevertheless, further preclinical and clinical investigations are warranted to clarify its metabolic effects and to determine the clinical implications for glycemic management in diabetic patients receiving paroxetine.

Gastric cancer (GC) progression is strongly associated with dysregulated proliferation, apoptosis resistance, epithelial-mesenchymal transition, invasion, and aberrant Wnt/β-catenin signaling. Berberine has shown anti-cancer activity in several tumor models; however, its mechanistic effects on Wnt/β-catenin-driven GC phenotypes require further clarification. This study investigated whether berberine suppresses AGS GC cell progression through inhibition of canonical Wnt/β-catenin signaling. AGS cells were treated with berberine at low, medium, and high concentrations, with CHIR99021 used for Wnt/β-catenin pathway activation and XAV939 as a pathway inhibitory control. Cell viability, proliferation, colony formation, cell cycle distribution, apoptosis, migration, invasion, EMT marker expression, β-catenin localization, TOP/FOP luciferase activity, ROS/RNS production, mitochondrial membrane potential, and glucose uptake were assessed using functional, molecular, and fluorescence-based assays. CTNNB1 knockdown was used to validate β-catenin-dependent mechanisms. Berberine reduced AGS cell viability, EdU incorporation, clonogenic survival, migration, invasion, and glucose uptake while inducing G0/G1 arrest, mitochondrial depolarization, oxidative/nitrosative stress, caspase activation, and apoptosis. Berberine increased E-cadherin and decreased N-cadherin, Vimentin, Snail, Slug, ZEB1, and MMP9, indicating suppression of EMT. Mechanistically, berberine reduced β-catenin expression, nuclear localization, TOP/FOP transcriptional activity, and downstream Wnt targets including CCND1, MYC, BIRC5, AXIN2, and MMP9. CHIR99021 partially reversed berberine-induced anti-tumor effects, whereas XAV939 and CTNNB1 knockdown mimicked or enhanced berberine activity. Berberine suppresses AGS GC cell progression by inhibiting canonical Wnt/β-catenin signaling, thereby reducing proliferation, EMT, invasion, metabolic activity, and survival while promoting cell cycle arrest and apoptosis.