Rasd2 regulates depression-like behaviors via DRD2 neurons in the prelimbic cortex afferent to nucleus accumbens core circuit.

Depressive symptoms, such as anhedonia, decreased social interaction, and lack of motivation, implicate brain reward systems in the pathophysiology of depression. Exposure to chronic stress impairs the function of brain reward circuits and is well-known to be involved in the etiology of depression. A transcriptomic analysis found that stress alters the expression of Rasd2 in mice prefrontal cortex (PFC). Similarly, in our previous study, acute fasting decreased Rasd2 expression in mice PFC, and RASD2 modulated dopamine D2 receptor (DRD2)-mediated antidepressant-like effects in ovariectomized mice. This research suggests the role of RASD2 in stress-induced depression and its underlying neural mechanisms that require further investigation. Here, we show that 5-day unpredictable mild stress (5-d UMS) exposure reduces RASD2 expression in both the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) of mice, while overexpression (but not knock-down) of Rasd2 in the NAc core (NAcc) alleviates 5-d UMS-induced depression-like behaviors and activates the DRD2-cAMP-PKA-DARPP-32 signaling pathway. Further studies investigated neuronal projections between the mPFC (Cg1, PrL, and IL) and NAcc, labeled by the retrograde tracer Fluorogold. Depression-like behaviors induced by 5-d UMS were only related to inhibition of the PrL-NAcc circuit. DREADD (Designer receptors exclusively activated by designer drug) analysis found that the activation of PrL-NAcc glutaminergic projection alleviated depression-like behaviors and increased DRD2- and RASD2-positive neurons in the NAcc. Using Drd2-cre transgenic mice, we constructed mice with Rasd2 overexpression in DRD2PrL-NAcc neurons, finding that Rasd2 overexpression ameliorated 5-d UMS-induced depression-like behaviors. These findings demonstrate a critical role for RASD2 modulation of DRD2PrL-NAcc neurons in 5-d UMS-induced depression-like behaviors. In addition, the study identifies a new potential strategy for precision medical treatment of depression.

Therapeutic potential and possible mechanisms of ginseng for depression associated with COVID-19.

Recently, a global outbreak of COVID-19 has rapidly spread to various national regions. As the number of COVID-19 patients has increased, some of those infected with SARS-CoV-2 have developed a variety of psychiatric symptoms, including depression, cognitive impairment, and fatigue. A distinct storm of inflammatory factors that contribute to the initial disease but also a persistent post-acute phase syndrome has been reported in patients with COVID-19. Neuropsychological symptoms including depression, cognitive impairment, and fatigue are closely related to circulating and local (brain) inflammatory factors. Natural products are currently being examined for their ability to treat numerous complications caused by COVID-19. Among them, ginseng has anti-inflammatory, immune system stimulating, neuroendocrine modulating, and other effects, which may help improve psychiatric symptoms. This review summarizes the basic mechanisms of COVID-19 pneumonia, psychiatric symptoms following coronavirus infections, effects of ginseng on depression, restlessness, and other psychiatric symptoms associated with post-COVID syn-dromes, as well as possible mechanisms underlying these effects.

Rasd2 Mediates Acute Fasting-Induced Antidepressant-Like Effects via Dopamine D2 Receptor Activation in Ovariectomized Mice.

BACKGROUND: Previous studies have shown that estrogen and acute fasting for 9 hours have antidepressant-like effects by reducing immobility time in the forced swimming test. Estrogen and acute fasting share a common regulatory gene, Rasd2. RASD2 regulates dopamine D2 receptor (DRD2) transmission, but the role of Rasd2 in the DRD2-mediated antidepressant-like effect of acute fasting has not been examined. METHODS: In this study, open field test, forced swimming test, tail suspension test and sucrose preference test were used for behavioral assessments. RNA-seq, western blot, enzyme-linked immunosorbent assay, and co-immunoprecipitation were used to explore the role of Rasd2 in a depression model induced by ovariectomy and the antidepressant-like effects of 9-hour fasting. RESULTS: The RNA seq results showed that acute fasting induced a significant change in Rasd2 gene expression. Depression-like behaviors induced by ovariectomy were associated with decreased RASD2 and DRD2 protein levels in the hippocampus, and Rasd2 overexpression in the hippocampus alleviated depression-like behaviors and increased DRD2 expression. Nine-hour fasting had antidepressant-like effects in ovariectomized mice by upregulating the protein levels of RASD2, DRD2, CREB-BDNF, Akt, and estrogen receptor beta, and these effects can be blocked by DRD2 antagonists. CONCLUSIONS: Our results suggest that Rasd2 and DRD2 play pivotal roles in depression-like behavior induced by ovariectomy. Rasd2 regulates DRD2-mediated antidepressant-like effects of acute fasting in ovariectomized mice. Rasd2 can therefore be postulated to be a potential therapeutic target for depression and perhaps also a potential predictive marker for depression.

Antidepressant-like Effects of Representative Types of Food and Their Possible Mechanisms.

Depression is a mental disorder characterized by low mood, lack of motivation, negative cognitive outlook, and sleep problems. Suicide may occur in severe cases, although suicidal thoughts are not seen in all cases. Globally, an estimated 350 million individuals grapple with depression, as reported by the World Health Organization. At present, drug and psychological treatments are the main treatments, but they produce insufficient responses in many patients and fail to work at all in many others. Consequently, treating depression has long been an important topic in society. Given the escalating prevalence of depression, a comprehensive strategy for managing its symptoms and impacts has garnered significant attention. In this context, nutritional psychiatry emerges as a promising avenue. Extensive research has underscored the potential benefits of a well-rounded diet rich in fruits, vegetables, fish, and meat in alleviating depressive symptoms. However, the intricate mechanisms linking dietary interventions to brain function alterations remain largely unexplored. This review delves into the intricate relationship between dietary patterns and depression, while exploring the plausible mechanisms underlying the impact of dietary interventions on depression management. As we endeavor to unveil the pathways through which nutrition influences mental well-being, a holistic perspective that encompasses multidisciplinary strategies gains prominence, potentially reshaping how we approach and address depression.

Transcription factors are potential therapeutic targets in epilepsy.

Academics generally believe that imbalance between excitation and inhibition of the nervous system is the root cause of epilepsy. However, the aetiology of epilepsy is complex, and its pathogenesis remains unclear. Many studies have shown that epilepsy is closely related to genetic factors. Additionally, the involvement of a variety of tumour-related transcription factors in the pathogenesis of epilepsy has been confirmed, which also confirms the heredity of epilepsy. In this review, we summarize the existing research on a variety of transcription factors and epilepsy and present relevant evidence related to transcription factors that may be targets in epilepsy. This information is of great significance for revealing the in-depth molecular and cellular mechanisms of epilepsy.

Stress induced microglial activation contributes to depression.

Major depressive disorder (MDD) is a debilitating neuropsychological disorder, which has caused serious health and socio-economic burdens worldwide. A growing body of evidence indicates that inflated neuroinflammation and aberrant microglial activity are associated with depressive-like symptoms. In the central nervous system (CNS), microglia constantly survey the internal environment, playing crucial roles in injury response and pathogen defense. From developmental stage through the whole adult life, microglia dynamically sculpt neural circuits by modulation of synaptic plasticity or engulfment of redundant synapses. Dysregulated microglia may impact these fundamental biophysiological processes and contribute to the pathogenesis of depressive disorder. In this review, we discuss candidate mechanisms by which stress induces microglia to deviate from its fine-tuned homeostasis in clinical and preclinical studies. These triggering factors include the neuroendocrine system, the noradrenergic system, gut-brain axis, and unbalanced pro- v.s. anti-inflammatory milieu composed of diversified cytokines and neurotransmitters. We argue that functional changes in microglia can strongly influence neuronal network activity due to dysregulated secretion of cytokines and elevated release of neurotoxic metabolites, therefore contributing to the pathological outcomes in stress. Understanding the role that microglia play in the etiology of depression may provide a tantalizing therapeutic target and help with the development of novel intervention strategies against this devastating mental health problem.

Role of neuroglia in neuropathic pain and depression.

Patients with neuropathic pain induced by nerve injury usually present with co-morbid affective changes, such as depression. Neuroglia was reported to play an important role in the development and maintenance of neuropathic pain both centrally and peripherally. Meanwhile, there have been studies showing that neuroglia participated in the development of depression. However, the specific role of neuroglia in neuropathic pain and depression has not been reviewed comprehensively. Therefore, we summarized the recent findings on the role of neuroglia in neuropathic pain and depression. Based on this review, we found a bridge-like role of neuroglia in neuropathic pain co-morbid with depression. This review may provide therapeutic implications in the treatment of neuropathic pain and offer potential help in the studies of mechanisms in the future.

Gut microbiota and neuropsychiatric disorders: Implications for neuroendocrine-immune regulation.

Recently, increasing evidence has shown gut microbiota dysbiosis might be implicated in the physiological mechanisms of neuropsychiatric disorders. Altered microbial community composition, diversity and distribution traits have been reported in neuropsychiatric disorders. However, the exact pathways by which the intestinal microbiota contribute to neuropsychiatric disorders remain largely unknown. Given that the onset and progression of neuropsychiatric disorders are characterized with complicated alterations of neuroendocrine and immunology, both of which can be continually affected by gut microbiota via "microbiome-gut-brain axis". Thus, we assess the complicated crosstalk between neuroendocrine and immunological regulation might underlie the mechanisms of gut microbiota associated with neuropsychiatric disorders. In this review, we summarized clinical and preclinical evidence on the role of the gut microbiota in neuropsychiatry disorders, especially in mood disorders and neurodevelopmental disorders. This review may elaborate the potential mechanisms of gut microbiota implicating in neuroendocrine-immune regulation and provide a comprehensive understanding of physiological mechanisms for neuropsychiatric disorders.

Role of BDNF-mTORC1 Signaling Pathway in Female Depression.

Depression is a common psychological and mental disorder, characterized by low mood, slow thinking and low will, and even suicidal tendencies in severe cases. It imposes a huge mental and economic burden on patients and their families, and its prevention and treatment have become an urgent public health problem. It is worth noting that there is a significant gender difference in the incidence of depression. Studies have shown that females are far more likely to suffer from depression than males, confirming a close relationship between estrogen and the onset of depression. Moreover, recent studies suggest that the brain-derived neurotrophic factor- (BDNF-) mammalian target of rapamycin complex-1 (mTORC1) signaling pathway is a crucial target pathway for improving depression and mediates the rapid antidepressant-like effects of various antidepressants. However, it is not clear whether the BDNF-mTORC1 signaling pathway mediates the regulation of female depression and how to regulate female depression. Hence, we focused on the modulation of estrogen-BDNF-mTORC1 signaling in depression and its possible mechanisms in recent years.

Optogenetics: What it has uncovered in potential pathways of depression.

Optogenetics is a biological technique, which involves controlling the biological functions of target cells using light. In recent years, optogenetics has become one of the most advanced experimental techniques in neuroscience. It provides precise control on target cells in addition to rapidly and specifically altering the neuronal activity both in vivo and ex vivo. The emergence of optogenetic technology enabled researchers to study the pathogenesis of diseases at the level of neurons and explore new ideas for the treatment of brain diseases. Depression is a highly prevalent and disabling mental disorder, which seriously impacts people's work and life. Currently, our understanding of the occurrence, development, and treatment of depression has made great progress, but the exact pathogenesis of depression is still unclear. In this article, we summarize the applications of optogenetics in improving our understanding of depression and provide new insight for uncovering the potential pathways of depression.

Neuropharmacological effects of Aconiti Lateralis Radix Praeparata.

Aconiti Lateralis Radix Praeparata (Fuzi in Chinese), which are the lateral roots of Aconitum Carmichaelii Debx, is widely used in China to treat many neurological diseases. Fuzi, in its various forms, has many neuropharmacological effects. It can act as an analgesic and help with depression, epilepsy, and dementia. However, the neuropharmacological effects of Aconiti Lateralis Radix Praeparata are seldom comprehensively reviewed. In this review, the neuropharmacological activities of some components contained in Aconiti Lateralis Radix Praeparata are considered. These include aconitine, mesaconitine, hypaconitine, total alkaloid, polysaccharide-1, benzoylmesaconine, fuziline, songorine, and napelline. We also specifically discuss the antidepressant effects of total alkaloids and polysaccharide-1. This review may provide a theoretical basis for further utilization of Aconiti Lateralis Radix Praeparata for diseases that affect the central nervous system.

Changes in Hippocampal Plasticity in Depression and Therapeutic Approaches Influencing These Changes.

Depression is a common neurological disease that seriously affects human health. There are many hypotheses about the pathogenesis of depression, and the most widely recognized and applied is the monoamine hypothesis. However, no hypothesis can fully explain the pathogenesis of depression. At present, the brain-derived neurotrophic factor (BDNF) and neurogenesis hypotheses have highlighted the important role of plasticity in depression. The plasticity of neurons and glial cells plays a vital role in the transmission and integration of signals in the central nervous system. Plasticity is the adaptive change in the nervous system in response to changes in external signals. The hippocampus is an important anatomical area associated with depression. Studies have shown that some antidepressants can treat depression by changing the plasticity of the hippocampus. Furthermore, caloric restriction has also been shown to affect antidepressant and hippocampal plasticity changes. In this review, we summarize the latest research, focusing on changes in the plasticity of hippocampal neurons and glial cells in depression and the role of BDNF in the changes in hippocampal plasticity in depression, as well as caloric restriction and mitochondrial plasticity. This review may contribute to the development of antidepressant drugs and elucidating the mechanism of depression.

Additive antidepressant-like effects of fasting with ß-estradiol in mice.

Our recent study has shown that acute fasting produces antidepressant-like effects in male mice. However, there is little evidence regarding the antidepressant-like effects of acute fasting in female mice. Moreover, it is not yet clear whether estrogen produces additive effects with acute fasting. Therefore, this study aims to investigate the antidepressant-like effects of acute fasting plus estrogen treatment. In this study, the acute fasting produced antidepressant-like effects in female mice and the antidepressant-like effects of 9 hours fasting with those of ß-estradiol (E2) were additive. Activity of the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF) pathway in the prefrontal cortex (PFC) and hippocampus (HP) was increased, as well as neurogenesis in the subgranular zone of the hippocampus. Serum ghrelin and estrogen were also increased by fasting plus E2. Furthermore, RNA-seq analysis indicated that fasting and E2 co-regulate similar gene expression pathways, underlying similar neurological functions. Taken together, these data suggest that E2 produces additive antidepressant-like effects with fasting by activating the CREB-BDNF pathway in the PFC and HP. Genome-wide transcriptome mapping suggests that fasting may be used as an adjunct to estrogen replacement therapy for the treatment of depression associated with reduced estrogen function.

The mechanism of acute fasting-induced antidepressant-like effects in mice.

Acute fasting induced antidepressant-like effects. However, the exact brain region and mechanism of these actions are still largely unknown. Therefore, in this study the antidepressant-like effects of acute fasting on c-Fos expression and BDNF levels were investigated. Consistent with our previous findings, immobility time was remarkably shortened by 9 hrs fasting in the forced swimming test. Furthermore, these antidepressant-like effects of 9 fasting were inhibited by a 5-HT2A/2C receptor agonist (±)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), and the effect of DOI was blocked by pretreatment with a selective 5-HT2A receptor antagonist ketanserin. Immunohistochemical study has shown that c-Fos level was significantly increased by 9 hrs fasting in prefrontal cortex but not hippocampus and habenular. Fasting-induced c-Fos expression was further enhanced by DOI in prefrontal cortex, and these enhancements were inhibited by ketanserin. The increased BDNF levels by fasting were markedly inhibited by DOI in frontal cortex and hippocampus, and these effects of DOI on BDNF levels were also blocked by ketanserin. These findings suggest that the antidepressant-like effects of acute fasting may be exerted via 5-HT2A receptor and particularly sensitive to neural activity in the prefrontal cortex. Furthermore, these antidepressant-like effects are also mediated by CREB and BDNF pathway in hippocampus and frontal cortex. Therefore, fasting may be potentially helpful against depression.

Evolving Roles for Targeting CTLA-4 in Cancer Immunotherapy.

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a membrane glycoprotein expressed by activated effector T cells (Teffs) and participates in the repression of T cell proliferation, cell cycle progression and cytokine production. Currently, antibodies targeting CTLA-4, ipilimumab and tremelimumab are widely used as a therapeutic approach in a variety of human malignancies. However, their detailed mechanism remains unclear. Therefore, in this review, we focused specifically on recent findings concerning the role of CTLA-4 in immune response and also discussed clinical studies of targeting CTLA-4, alone or in combination with other therapies for the treatment of cancers. CTLA-4 blockade is used as a therapeutic approach for the treatment of cancer through competing with CD28-positive costimulation for binding to their shared B7 ligands or exhibiting direct inhibitory effect on signaling molecules in the cytoplasmic tail. At present, antibodies for targeting CTLA-4 or in combination with other therapies significantly reinforced the anti-tumor effect and improved the prognosis of malignant disease. In addition, severe adverse events of targeting CTLA-4 therapy could be a challenge for the development of this therapeutic strategy. This review may provide some new insights for clinical studies of targeting CTLA-4.

MicroRNA-200c and microRNA- 141 are regulated by a FOXP3-KAT2B axis and associated with tumor metastasis in breast cancer.

BACKGROUND: Members of the microRNA (miR)-200 family, which are involved in tumor metastasis, have potential as cancer biomarkers, but their regulatory mechanisms remain elusive. METHODS: We investigated FOXP3-inducible breast cancer cells, Foxp3 heterozygous Scurfy mutant (Foxp3 sf/+ ) female mice, and patients with breast cancer for characterization of the formation and regulation of the miR-200 family in breast cancer cells and circulation. Participants (259), including patients with breast cancer or benign breast tumors, members of breast cancer families, and healthy controls, were assessed for tumor and circulating levels of the miR-200 family. RESULTS: First, we identified a FOXP3-KAT2B-miR-200c/141 axis in breast cancer cells. Second, aging Foxp3 sf/+ female mice developed spontaneous breast cancers and lung metastases. Levels of miR-200c and miR-141 were lower in Foxp3 sf/+ tumor cells than in normal breast epithelial cells, but plasma levels of miR-200c and miR-141 in the Foxp3 sf/+ mice increased during tumor progression and metastasis. Third, in patients with breast cancer, the levels of miR-200c and 141 were lower in FOXP3 low relative to those with FOXP3 high breast cancer cells, especially in late-stage and metastatic cancer cells. The levels of miR-200c and miR-141 were higher in plasma from patients with metastatic breast cancer than in plasma from those with localized breast cancer, with benign breast tumors, with a family history of breast cancer, or from healthy controls. Finally, in Foxp3 sf/+ mice, plasma miR-200c and miR-141 appeared to be released from tumor cells. CONCLUSIONS: miR-200c and miR-141 are regulated by a FOXP3-KAT2B axis in breast cancer cells, and circulating levels of miR-200c and miR-141 are potential biomarkers for early detection of breast cancer metastases.

CD24 is a genetic modifier for risk and progression of prostate cancer.

CD24 plays an oncogenic role in the onset and progression of various human cancers, including prostate cancer. In the present study, we identified two linkage disequilibrium blocks with four recombination hotspot motifs in human CD24 locus. To elucidate whether genetic variants of CD24 are associated with susceptibility to prostate cancer and its disease status, we conducted a case-control association study with two P170 C/T and P-534 A/C polymorphisms of CD24 in 590 patients with prostate cancer and 590 healthy controls. A significant increased risk of prostate cancer was found in men with the P170T/T genotype over the P170C/C genotype (odd ratio = 1.74, 95% confidence interval = 1.16-2.63, P = 0.008), and in men with the P-534C/C genotype over the P-534A/A genotype (odd ratio = 1.47, 95% CI = 1.18-2.26, P = 0.003). Cochran-Armitage trend analysis showed that the P170T allele was significantly correlated with an increased risk of prostate cancer progression (P = 0.029, trend between genotypes and stages) and this observation was also validated in an independent sample cohort. Next, we found that tumors with P170T or P-534C alleles had more twofold increased protein expressions of CD24 as compared to those with P170C or P-534A alleles, respectively. Likewise, tumors with a combination of P170T/T and P-534C/C genotypes were associated with a high mRNA level of CD24. Our data suggest a significant association of CD24 genetic variants with prostate cancer onset and progression, which provides new insight into molecular genetics of prostate cancer; however, these findings need to be validated in multiple independent cohorts. © 2016 Wiley Periodicals, Inc.

The role of 5-HT2c receptor on corticosterone-mediated food intake.

Corticosterone plays an important role in feeding behavior. However, its mechanism remains unclear. Therefore, the present study aimed to investigate the effect of corticosterone on feeding behavior. In this study, cumulative food intake was increased by acute corticosterone administration in a dose-dependent manner. Administration of the 5-HT2c receptor agonist m-chlorophenylpiperazin (mCPP) reversed the effect of corticosterone on food intake. The anorectic effects of mCPP were also blocked by the 5-HT2c receptor antagonist RS102221 in corticosterone-treated mice. Both corticosterone and mCPP increased c-Fos expression in hypothalamic nuclei, but not the nucleus of the solitary tract. RS102221 inhibited c-Fos expression induced by mCPP, but not corticosterone. In addition, mCPP had little effect on TH and POMC levels in the hypothalamus. Furthermore, mCPP antagonized decreasing effect of the leptin produced by corticosterone. Taken together, our findings suggest that 5-HT2c receptors and leptin may be involved in the effects of corticosterone-induced hyperphagia.

Costunolide Induces Apoptosis through Generation of ROS and Activation of P53 in Human Esophageal Cancer Eca-109 Cells.

Costunolide is a sesquiterpene lactone, which possesses potent anti-cancer properties. However, there is little report about its effects on esophageal cancer. In our study, we investigated the effects of costunolide on the cell viability, cell cycle, and apoptosis in human esophageal cancer Eca-109 cells. It was found that costunolide inhibited the growth of Eca-109 cells in a dose-dependent manner, which was associated with the loss of mitochondrial membrane potential (Δψm ) and the production of ROS. Costunolide induced apoptosis of Eca-109 cells as well as cell cycle arrest in G1/S phase by upregulation of P53 and P21. Costunolide triggered apoptosis in esophageal cancer cells via the upregulation of Bax, downregulation of Bcl-2, and significant activation of caspase-3 and poly ADP-ribose polymerase. These effects were markedly abrogated when cells were pretreated with N-acetylcysteine, a specific reactive oxygen specie inhibitor. These results suggest that costunolide is a potential candidate for the treatment of esophageal cancer.

Expression and localization of GEN1 in mouse mammary epithelial cells.

GEN1, a Holliday junction resolvase, is involved in homologous repair of DNA double strand break and in maintaining centrosome integrity. Although GEN1 mutants have been reported in breast cancer patients and cell lines, little is currently known about the functions of GEN1 in the development and oncogenic transformation of mammary gland. In the present study, we demonstrate that GEN1 expression is correlated with mammary epithelial cell proliferation, differentiation in various physiological stages as well as casein. By immunofluorescence analysis, the centrosomal association of GEN1 is confirmed in mammary epithelial cells. Additionally, GEN1 is likely involved in DNA damage response of breast cancer cell lines. These results suggest that GEN1 may play an important role in the development of mammary gland; its response upon DNA damage indicates that GEN1 gene alteration may contribute to breast cancer formation.