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Ethnopharmacological Relevance: The dried succulent stems of Cistanche tubulosa (Schenk) Wight are utilized in traditional medicine for tonifying kidney yang, which have shown to be effective in alleviating depression-like behaviors or male sexual dysfunction, respectively. However, the pharmacological effects and mechanisms of C. tubulosa and its combinations in the treatment of depression in comorbid with sexual dysfunction remain unclear., Aim of the Study: This study aims to elucidate the pharmacological effects and mechanisms of C. tubulosa aqueous extract (CTE) and its combination with fluoxetine (FLX) on depression in comorbid with sexual dysfunction., Materials and Methods: A mouse model of depression in comorbid with sexual dysfunction was created using the chronic unpredictable mild stress (CUMS) procedure. The therapeutic effects of CTE and its combination with FLX were assessed using depressive-like and mating behavior experiments, histopathological analysis, and hypothalamic-pituitary-gonadal (HPG) axis function evaluation. The mechanisms were explored by integrated serum and testicular metabolomics combined with network correlation analysis., Results: CTE was confirmed to significantly improve depressive-like behaviors, reduce mating abilities, testicular histopathological damage, and HPG axis hormone secretion disorders in CUMS mice. Subsequently, mechanism exploration findings indicated that CTE might exert its effect by regulating potential efficacy-related biomarkers (isobutyrylglycine, citric acid, D-galactose) to improve certain metabolic pathways centered around steroid hormone biosynthesis and tricarboxylic acid (TCA) cycle. Furthermore, the combination of CTE and FLX exhibited stronger antidepressant effects than FLX alone, and ameliorated the exacerbated sexual dysfunction induced by FLX. These effects were achieved through the regulation of potential efficacy-related biomarkers (17α-hydroxypregnenolone, tetrahydrodeoxy-corticosterone, sphingosine, cortol, thymine, and L-histidine), thereby improving disorders in glycerophospholipid and histidine metabolism., Conclusion: In conclusion, the amelioration effects of CTE and its combination with FLX on depression in comorbid with sexual dysfunction were confirmed for the first time. This key mechanism may be achieved by modulating the levels of potential efficacy-related biomarkers, and then emphatically intervene in steroid hormone biosynthesis, TCA cycle, glycerophospholipid and histidine metabolism. The study offers a new perspective for the development and utilization of C. tubulosa., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Heat stress, as an environmental stressor, can lead to temperature dysregulation and neuroinflammation, causing depression and anxiety by disrupting brain physiology and functional connectivity. This study looked at how co-enzyme Q10 (Q10) and vitamin E (Vit E), alone and together, affected heat stress-caused anxiety and depression symptoms and inflammation in male mice. Five groups were utilized in the study: control, heat stress (NS), Q10, Vit E, and the combination group (Q10+Vit E). The mice were subjected for 15 min/day to a temperature of 43°C for 14 consecutive days, followed by daily treatments for two weeks with either normal saline, Q10 (500 mg/kg), Vit E (250 mg/kg), or their combination. The forced swimming test (FST) and tail suspension test (TST) were employed to evaluate despair behavior, whereas the elevated plus maze (EPM) and open field test (OFT) were used to assess anxious behaviors. Subsequently, the animals were sacrificed, and serum corticosterone levels, protein expression of inflammasome-related proteins, and hsp70 gene expression were evaluated in the prefrontal cortex (PFC). The study revealed that treatment with Vit E and Q10, alone or together, provided anxiolytic and antidepressant effects in the heat-stress-subjected animals. Also, giving Vit E and Q10 alone or together greatly lowered serum corticosterone levels. In the PFC, they also lowered the levels of hsp70 mRNA and NF-κB, caspase 1, NLRP3, and IL-1β proteins. It is speculated that treatment with Q10 and Vit E can attenuate heat stress-associated anxious and depressive responses by inhibiting the inflammatory pathways and modulating the hypothalamus-pituitary-adrenal axis., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Fluoxetine is widely used as a first-line antidepressant. However, the molecular mechanisms for its antidepressant effects are still not fully understood. Hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis is a core pathogenic mechanism contributing to depression, and fluoxetine treatment prevents this dysfunction. The glucocorticoid receptor (GR) is a major negative feedback regulator of the HPA axis, while Fk506-binding protein 5 (Fkbp5) is a negative regulator of the GR signaling. Therefore, we examined the effects of fluoxetine on Fkbp5 and the GR signaling in the hypothalamic paraventricular nucleus (PVN) of depressed mice., Methods: Mice were exposed to chronic social defeat stress (CSDS), chronic unpredictable mild stress (CUMS), or chronic restraint stress (CRS) with or without fluoxetine treatment (intraperitoneally injected, 20 mg/kg) and examined for changes in depression-like behaviors and HPA axis activity as well as Fkbp5 expression and GR phosphorylation in the PVN. We then examined if adeno-associated virus (AAV)-mediated Fkbp5 overexpression in the PVN affected the antidepressant actions of fluoxetine in mice., Results: Fluoxetine treatment significantly mitigated CSDS-, CUMS-, and CRS-induced depression-like behaviors and HPA axis hyperactivity in mice. Subsequent western blotting analyses showed that fluoxetine treatment fully reversed not only chronic stress-induced upregulation of Fkbp5 and CRH but also chronic stress-induced increase in Ser203 phosphorylation and decrease in Ser211 and Ser234 phosphorylation in GR in the PVN. Moreover, quantitative real-time reverse transcription PCR (qRT-PCR) analyses revealed that the enhanced mRNA levels of Fkbp5 and CRH in PVN neurons of mice subjected to CSDS/CUMS/CRS were also notably reversed by fluoxetine administration. Conversely, Fkbp5 overexpression in the PVN significantly eliminated the antidepressant effects of fluoxetine in mice without affecting their locomotor activity., Conclusion: These results together suggest that fluoxetine treatment reverses chronic stress-induced promotion on Fkbp5 expression and multiple effects on GR phosphorylation in the PVN of mice., Significance Statement: The selective serotonin reuptake inhibitor fluoxetine (sold as Prozac) is a widely used treatment for depression, but the full spectrum of therapeutic mechanisms is still debated. Recent evidence suggests that these therapeutic mechanisms include suppression of chronic stress-activated hypothalamus-pituitary-adrenal (HPA) axis. The current study presents the first in vivo evidence showing that suppression of HPA axis hyperactivity by fluoxetine treatment involves reversal of glucocorticoid receptor (GR) phosphorylation via modulation of the GR negative regulator Fk506-binding protein 5 (Fkbp5) in the hypothalamic paraventricular nucleus (PVN). Fluoxetine treatment not only inhibited chronic stress-induced depression-like behaviors and HPA axis hyperactivity but also reversed Fkbp5 upregulation and GR phosphorylation changes in the PVN, while adeno-associated virus (AAV)-based Fkbp5 overexpression in the PVN eliminated the antidepressant effects of fluoxetine. These findings may expand our understanding of the pharmacological effects of fluoxetine, and further identify Fkbp5 as a possible target for novel antidepressants., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Environmental chemicals (ECs) have been associated with a broad range of disorders and diseases. Daily exposure to various ECs in the environment, or real-life exposure, has raised significant public health concerns. Utilizing the biosolids-treated pasture (BTP) sheep model, this study demonstrates that in-utero exposure to a real-life EC mixture disrupts hypothalamo-pituitary-gonadal (HPG) axis gene expression and reproductive traits in prepubertal (8-week-old, 8w) and adult (11-month-old) male sheep. Ewes were maintained on either BTP or pastures fertilized with inorganic fertilizer [control (C)] from approximately one month prior to insemination until around parturition. Thereafter, all animals were kept under control conditions. Effects on reproductive parameters including testosterone concentrations and the expression of key genes in the HPG axis were evaluated in eight-week-old and adult male offspring from both C and biosolids-exposed (B) groups. Results showed that, at 8w, relative to C (n = 11), B males (n = 11) had lower body weight, and altered testicular expression of HSD3B1, LHR and HSD17B3, BMP4, ABP, P27 kip and CELF1. Principal component analysis (PCA) identified two 8w B subgroups, based on hypothalamic expression of GnRH, ESR1, and AR, and pituitary expression of KISSR. The two subgroups also exhibited different serum testosterone concentrations. The largest biosolids effects were observed in the hypothalamus of adult rams with NKB, ESR1, KISS1, AR, DLK1 and GNRH1 mRNA expression differing between B (n = 10) and C (n = 11) rams. Testicular steroidogenic enzymes CYP11A1 and HSD3B1 mRNA expression also differed between exposure groups. PCA identified two adult B subgroups, with BS1 (n = 6) displaying hypothalamic effects and BS2 (n = 4) both hypothalamic and testicular effects. The subgroups also differed in circulating testosterone concentrations. These findings demonstrate that exposure to a real-life EC mixture may predispose some males to infertility, by disrupting key functional HPG markers before puberty with consequent downstream effects on steroid hormones and spermatogenesis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis during chronic stress is essential for depression neurobiology. As the latest member of the RFamide peptide family in mammals, pyroglutamylated RFamide peptide (QRFP) is closely implicated in neuroendocrine maintenance by activating G-protein-coupled receptor 103 (GPR103). We hypothesized that QRFP and GPR103 might contribute to chronic stress-induced depression by promoting corticotropin-releasing hormone (CRH) release from neurons in the paraventricular nucleus (PVN), and various methods were employed in this study, with male C57BL/6J mice adopted as the experimental subjects. Chronic stress induced not only depression-like behaviors but also significant enhancement in QRFP and GPR103 in the PVN. Genetic overexpression of QRFP/GPR103 and stereotactic infusion of QRFP-26/QRFP-43 peptide in the PVN all mimicked chronic stress that induced various depression-like phenotypes in naïve mice, and this was mediated by promoting CRH biosynthesis and HPA activity. In contrast, genetic knockdown of QRFP/GPR103 in the PVN produced notable antidepressant-like effects in mice exposed to chronic stress. Furthermore, genetic knockout of QRFP also protected against chronic stress in mice. In addition, both the C-terminal biological region of QRFP and the downstream PKA/PKC-CREB signaling coupled to GPR103 stimulation underlie the role of QRFP and GPR103 in depression. Collectively, QRFP and GPR103 in PVN neurons could be viable targets for novel antidepressants., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest for this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The dexamethasone suppression test (DST), which measures HPA-axis functioning, is a potential biomarker for suicidal behavior. The current study aimed (a) to synthesize available knowledge on the association between DST non-suppression and suicidal behavior, and (b) to study potential moderators., Methods: A total of 4236 studies were screened, 43 were included. Suicide attempts and suicide completion were studied separately. The meta-analysis included 37 effect sizes for suicide attempts (n = 3733) and 11 effect sizes for suicide completion (n = 1626)., Results: DST non-suppression was associated with completed suicide (odds ratio (OR) = 2.10, (95 % CI [1.37, 3.23]). For suicide attempts, we found no evidence that DST status was associated in the overall meta-analysis including all patient samples. However, moderator analysis indicated that the DST status was associated with suicide attempts in patient samples that included psychopathology other than just mood disorders, such as psychotic, substance use and personality disorders (OR = 2.34, 95 % CI [1.39-3.93], k = 11)., Limitations: The potential influence of publication bias and exclusion of some relevant published studies (since effect sizes could not be calculated, authors could not supply data or authors could not be reached) are limitations. Furthermore, missing moderator data decreased our ability to explain heterogeneity between studies., Conclusions: The results of this meta-analysis support the hypothesis that DST non-suppression is predictive of suicidal behavior. More research is needed to investigate optimal cut-off values, confounding factors and the potential usefulness of the DST in clinical practice in terms of personalized medicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)