Currently, the pathogenesis of depression remains poorly understood, leading to many patients receiving ineffective treatment. Resveratrol has demonstrated beneficial effects in the prevention and treatment of depression. However, it remains unknown whether resveratrol administration can counteract depression-like behaviors by regulating the SIRT1/NF-κB signaling pathway.

Male C57BL/6 mice were randomly assigned to a control group, a depression group, and a resveratrol group. The depression model was established using chronic unpredictable mild stress (CUMS) for 5 weeks. Behavioral tests were conducted to assess depressive-like behaviors. The expression levels of SIRT1 and NF-κB in the hippocampus of mice and BV2 microglial cells were measured. After 5 weeks of modeling, the results indicated that mice in the depression group exhibited significant depressive-like behaviors and inhibited activation of the SIRT1/NF-κB signaling pathway. In contrast, resveratrol administration effectively reversed these changes. Results from in vitro experiments showed that LPS stimulation increased microglial activity and downregulated the SIRT1/NF-κB signaling pathway in microglia; however, resveratrol treatment mitigated these effects.

Our findings suggested that resveratrol can alleviate CUMS-induced depression-like behaviors via the activation of the Sirt1/NF-κB pathway in microglia.

According to statistics, more than one-third of the global population currently experiences sleep problems, and about 10% of adults have been diagnosed with insomnia, a proportion that is increasing annually. Most currently used insomnia medications are not specifically developed but are discovered by chance, often resulting in unavoidable side effects like addiction. Thus, there is an urgent need to find safer and more effective therapeutic options. Resveratrol, a natural polyphenolic compound, shows significant potential in improving insomnia. Research shows that its effects may be achieved through multiple biological processes, including antiapoptosis, antioxidant activity, anti-inflammation, circadian rhythm regulation, modulation of neurotransmitters (gamma-aminobutyric acid (GABA), DA, 5-HT, cortisol), and increased levels of neurotrophic factor BDNF. Additionally, resveratrol's treatment of insomnia is closely linked to the SIRT1, AMPK, NF-κB, mTOR, PI3K/Akt, and MAPK pathways. This review summarizes the mechanisms of resveratrol in treating insomnia to provide researchers with a deeper understanding of its action, which can aid in the development of novel targeted drugs and offer innovative ideas and methods for clinical insomnia treatment.

Depression is a common mental disorder characterized by prolonged loss of interest and low mood, accompanied by symptoms such as sleep disturbances and cognitive impairments. In severe cases, there may be a tendency toward suicide. Depression can be caused by a series of highly complex pathological mechanisms; However, its key pathogenic mechanism remains unclear. As a novel programmed cell death (PCD) pathway and inflammatory cell death mode, pyroptosis involves a series of tightly regulated gene expression events. It may play a significant role in the pathogenesis and management of depression by modulating neuroinflammatory processes. In addition, a large number of studies have shown that various pharmacologically active natural products can regulate pyroptosis through multiple targets and pathways, demonstrating significant potential in the treatment of depression. These natural products offer advantages such as low costs and minimal side effects, making them a viable supplement or alternative to traditional antidepressants. In this review, we summarized recent research on natural products that regulate pyroptosis and neuroinflammation to improve depression. The aim of this review was to contribute to a scientific basis for the discovery and development of more natural antidepressants in the future.

To review the antidepressant effects of natural products targeting pyroptosis-mediated neuroinflammation, data were collected from the Web of Science, ScienceDirect databases, and PubMed to classify and summarize the relationship between pyroptosis and neuroinflammation in depression, as well as the pharmacological mechanisms of natural products.

Multiple researches have revealed that pyroptosis-mediated neuroinflammation serves as a pivotal contributory factor in the pathological process of depression. Natural products, such as terpenoids, terpenes, phenylethanol glycosides, and alkaloids, have antidepressant effects by regulating pyroptosis to alleviate neuroinflammation.

We comprehensively reviewed the regulatory effects of natural products in depression-related pyroptosis pathways, providing a uniquely insightful perspective for the research, development, and application of natural antidepressants. However, future research should further explore the modulatory mechanisms of natural products in regulating pyroptosis, which is of great importance for the genration of effective antidepressants.

Prenatal stress has been reported to harm the physiological and biochemical functions of the brain of the offspring, potentially resulting in anxiety- and depression-like behaviors later in life. Trans-Resveratrol (RESV) is known for its anti-inflammatory, anxiolytic, and antidepressant properties. However, whether administering RESV during pregnancy can counteract the anxiety- and depression-like behaviors induced by maternal stress is unknown.

This study aimed to assess the protective potential of RESV against molecular and behavioral changes induced by prenatal stress.

During pregnancy, the dams received 50 mg/kg BW/day of RESV orally. They underwent a movement restriction for forty-five minutes, three times a day, in addition to being exposed to artificial light 24 h before delivery. The male offspring were left undisturbed until early adulthood, at which point they underwent behavioral assessments, including the open field test, elevated plus maze, and forced swim test. Subsequently, they were euthanized, and the hippocampus and prefrontal cortex were extracted for RT-qPCR analysis to measure Bdnf mRNA expression.

By weaning, results showed that prenatal stress led to reduced weight gain and, in adulthood, increased anxiety- and depression-like behaviors and changes in Bdnf mRNA expression. However, these effects were attenuated by maternal RESV supplementation.

The findings suggest that RESV can prevent anxiety- and depression-like behaviors induced by prenatal stress by modulating Bdnf mRNA expression.

In numerous observational studies, circulating inflammation-related proteins have been linked with major depressive disorder (MDD), yet the precise causal direction of this relationship remains unclear. This study aims to investigate the potential causal link between inflammation-related proteins and the risk of developing MDD.

We utilized summary data from a genome-wide association study (GWAS) of 91 circulating inflammation-associated proteins in 14,824 individuals of European descent. Additionally, we incorporated findings from a substantial GWAS on MDD, which included 294,322 cases and 741,438 controls. Our analysis employed a two-sample bidirectional Mendelian randomization (MR) approach, with inverse variance weighting (IVW) as the primary method. We augmented this with two supplementary techniques (MR-Egger and weighted median approaches) to detect and address potential pleiotropy. Furthermore, to identify and evaluate possible drug targets, we conducted a thorough search within the Drug-Gene Interaction Database (DGIdb).

Analysis using MR unveiled significant and causative associations between genetically determined CASP-8 (odds ratio (OR): 0.97), CD40 (OR: 0.96), IL-18 (OR: 0.98), SLAMF1 (OR: 0.97), and uPA (OR: 0.98) with MDD. Conversely, reverse MR analysis indicated causal associations between MDD and CCL19 (OR: 1.15), HGF (OR: 1.15), IL-8 (OR: 1.10), IL-18 (OR: 1.11), IL20RA (OR: 1.12), TGFA (OR: 1.12) and TNFSF14 (OR: 1.16). Notably, a significant bidirectional causal link was observed between IL-18 and MDD. Gene-drug analysis identified CD40, HGF, IL-8, IL-18, SLAMF1, and TGFA as potential therapeutic targets.

We've pinpointed causal links between inflammation-related proteins and MDD, offering compelling and innovative evidence to enhance our understanding of the inflammatory mechanisms involved in MDD and to investigate potential targets for anti-MDD medications.

This review aims to elucidate the role of estrogen-sensitive microRNAs (miRNAs) in modulating brain functions and disorders, highlighting the protective effects of estrogen on the central nervous system.

A comprehensive literature review was conducted, examining the relationship between estrogen, miRNAs, and cognitive health. The study focused on experimental data comparing cognitive impairments between genders and the mechanisms of estrogen's effects on brain function.

Cognitive impairments are less prevalent in women of reproductive age compared to men, indicating estrogen's neuroprotective role. Estrogen modulates gene expression through specific receptors, while miRNAs regulate approximately 30% of protein-coding genes in mammals. These miRNAs play critical roles in synaptic plasticity and neuronal survival. The review identifies several estrogen-sensitive miRNAs and their potential involvement in brain disorders.

The interplay between estrogen and miRNAs offers valuable insights into the molecular mechanisms underlying cognitive health and disease. Understanding these relationships may lead to novel therapeutic strategies for addressing various brain disorders, particularly those associated with hormonal changes and aging.

Osteoporosis is a disease characterized by disruption of the bone microarchitecture. It is observed in both sexes, but to a greater extent in women. It affects the whole body, including the jaws. The main indicator of the presence of osteoporosis accepted by the World Health Organization is bone mineral density. The aim of this article is to find data on the influence of osteoporosis on apical periodontitis, to investigate how the intake of osteoporosis drugs affects apical periodontitis, and to establish various data that may be of benefit to the dental practitioner when treating patients with osteoporosis and apical periodontitis. Open-access publications are included. The presence of osteoporosis is important to the dentist. Apical periodontitis in these patients has a faster progression. They are characterized by inflammation and destruction of the tissues located around the tooth root. Osteoporosis has a destructive effect on bone tissue through different mechanisms: nuclear factor-κβ ligand and NLRP3/Caspase-1/IL-1β cascade. It is also associated with low estrogen levels. Various medications such as corticosteroids, bisphosphonates (alendronate, zoledronate (Zoledronic acid), calcitonin, raloxifene, and strontium used to treat osteoporosis can affect the course of apical periodontitis. When treating patients with periapical lesions, the dentist must take a proper medical history and general medical history. In cases of osteoporosis or taking bisphosphonates and other medications, consideration should be given to whether consultation with a specialist is necessary, what treatment approach would be most appropriate, and what the prognosis will be. Chronic diseases affect both the general state of the body and dental health. It has been found that in patients with osteoporosis, inflammation of the apical periodontium develops with faster bone resorption. Before starting dental treatment, it is important to specify the etiology of osteoporosis, the bone density of each patient, as well as the medications they are taking.

Menopausal depression, often associated with hormonal fluctuations such as decreased estrogen levels, imposes significant mental health burdens. Despite the antidepressant biological properties of standardized rice bran supplement (RBS), its impact on menopausal depression and underlying mechanisms remains largely unexplored. In this study, we investigated the antidepressant effects of RBS in a mouse model of estrogen deficiency-induced depression. Ovariectomized (OVX) mice received oral doses of RBS (250 and 1000 mg/kg) and 17β estradiol over a 20-week period. RBS administration resulted in decreased immobility time in the tail suspension and forced swim tests, along with increased locomotor activity in the open field test. Furthermore, RBS enhanced nitric oxide production and neuronal nitric oxide synthase (nNOS) expression in the hippocampi of OVX mice. Additionally, RBS administration phosphorylated extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), and tropomyosin receptor kinase B and increased the protein expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. These findings suggest that RBS alleviated depressive behaviors in OVX mice by augmenting hippocampal nNOS expression and activating the ERK-CREB-BDNF signaling pathway. Therefore, based on these results, we propose that RBS is a promising agent to treat menopausal depression, a challenging condition.

The prevalence of Alzheimer's disease (AD) is significantly gender-differentiated, with the number of female AD patients far exceeding that of males, accounting for two-thirds of the total prevalence. Although postmenopausal AD mice have been shown to have more prominent pathologic features and memory impairments than normal AD mice, the relevant molecular mechanisms leading to these outcomes have not been well elucidated. In the present study, we used the disturbance of excitation-inhibition balance in the postmenopausal brain as an entry point to explore the link between estrogen deficiency, disorders of the glutamatergic-GABAergic nervous system, and memory impairment.

Wild-type (WT) mice and APP/PS1/tau (3 × Tg-AD) mice (10 months old) were randomly divided into four groups: WT+Sham group, WT+OVX group, 3 × Tg-AD+Sham group and 3 × Tg-AD+OVX group. Ovariectomy (OVX) was performed in the WT+OVX group and the 3 × Tg-AD+OVX group, and sham surgery was performed in the WT+Sham group and the 3 × Tg-AD+Sham group. The learning and memory ability and the anxiety and depression-like behavior changes of mice were evaluated by behavioral experiments, and the association between estrogen-estrogen receptors pathway and glutamatergic/GABAergic nervous system and female AD was evaluated by neurochemical experiments.

In WT and 3 × Tg-AD mice, OVX resulted in impaired learning and memory abilities and anxiety and depression-like behaviors; reduced estrogen levels and downregulated the expression of estrogen receptors; upregulated the expression of amyloid-β, amyloid precursor protein, presenilin 1, and p-tau; upregulated the expression of Bcl-2-associated X protein and downregulated the expression of B-cell lymphoma-2, promoting cell apoptosis; reduced the number of neuronal dendrites and downregulated the expression of postsynaptic density protein-95; more importantly, OVX increased brain glutamate levels but downregulated the expression of N-methyl-D-aspartate receptor-2B, excitatory amino acid transporter 1, excitatory amino acid transporter 2, γ-aminobutyric acid receptor-A and γ-aminobutyric acid receptor-B.

Our results suggested that OVX-induced estrogen-estrogen receptors pathway disruption caused learning and memory impairment and anxiety and depression-like behaviors, upregulated the expression of AD pathological markers, promoted apoptosis, destroyed neuronal structure, and most importantly, caused glutamatergic/GABAergic nervous system disorders.

A significant decrease in estrogen levels puts menopausal women at high risk for major depression, which remains difficult to cure despite its relatively clear etiology. With the discovery of abnormally elevated inflammation in menopausal depressed women, immune imbalance has become a novel focus in the study of menopausal depression. In this paper, we examined the characteristics and possible mechanisms of immune imbalance caused by decreased estrogen levels during menopause and found that estrogen deficiency disrupted immune homeostasis, especially the levels of inflammatory cytokines through the ERα/ERβ/GPER-associated NLRP3/NF-κB signaling pathways. We also analyzed the destruction of the blood-brain barrier, dysfunction of neurotransmitters, blockade of BDNF synthesis, and attenuation of neuroplasticity caused by inflammatory cytokine activity, and investigated estrogen-immuno-neuromodulation disorders in menopausal depression. Current research suggests that drugs targeting inflammatory cytokines and NLRP3/NF-κB signaling molecules are promising for restoring homeostasis of the estrogen-immuno-neuromodulation system and may play a positive role in the intervention and treatment of menopausal depression.

Essential tremor (ET) is a neurological disease that impairs motor and cognitive functioning. A variant of the Lingo-1 genetic locus is associated with a heightened ET risk, and increased expression of cerebellar Lingo-1. Lingo-1 has been associated with neurodegenerative processes; however, neuroprotection from ET-associated degeneration can be conferred by the protein Sirt1. Sirt1 activity can be promoted by Resveratrol (Res) and 1,25-dihydroxyvitamin D3 (VitD3), and thus these factors may exert neuroprotective properties through a Sirt1 mechanism. As Res and VitD3 are linked to Sirt1, enhancing Sirt1 could counteract the negative effects of increased Lingo-1. Therefore, we hypothesized that a combination of Res-VitD3 in a harmaline injection model of ET would modulate Sirt1 and Lingo-1 levels. As expected, harmaline exposure (10 mg/kg/every other day; i.p.) impaired motor coordination, enhanced tremors, rearing, and cognitive dysfunction. When Res (5 mg/kg/day; i.p.) and VitD3 (0.1 mg/kg/day; i.p.) were given to adult rats (n = 8 per group) an hour before harmaline, tremor severity, rearing, and memory impairment were reduced. Individual treatment with Res and VitD3 decreased Lingo-1 gene expression levels in qPCR assays. Co-treatment with Res and VitD3 increased and decreased Sirt1 and Lingo-1 gene expression levels, respectively, and in some cases, beneficial effects on behavior were noted, which were not seen when Res or VitD3 were individually applied. Taken together, our study found that Res and VitD3 improved locomotor and cognitive deficits, modulated Sirt1 and Lingo-1. Therefore, we would recommend co-treatment of VitD3 and Res to leverage complementary effects for the management of ET symptoms.

Depression is a common disease that affects physical and mental health and imposes a considerable burden on afflicted individuals and their families worldwide. Depression is associated with a high rate of disability and suicide. It causes a severe decline in productivity and quality of life. Unfortunately, the pathophysiological mechanisms underlying depression have not been fully elucidated, and the risk of its treatment is still presented. Studies have shown that the expression of autophagic markers in the brain and peripheral inflammatory mediators are dysregulated in depression. Autophagy-related genes regulate the level of autophagy and change the inflammatory response in depression. Depression is related to several aspects of immunity. The regulation of the immune system and inflammation by autophagy may lead to the development or deterioration of mental disorders. This review highlights the role of autophagy and neuroinflammation in the pathophysiology of depression, sumaries the autophagy-targeting small moleculars, and discusses a novel therapeutic strategy based on anti-inflammatory mechanisms that target autophagy to treat the disease.

Introduction: Depression is a complex psychiatric disorder with substantial societal impact. While current antidepressants offer moderate efficacy, their adverse effects and limited understanding of depression's pathophysiology hinder the development of more effective treatments. Amidst this complexity, the role of neuroinflammation, a recognized but poorly understood associate of depression, has gained increasing attention. This study investigates hydroxytyrosol (HT), an olive-derived phenolic antioxidant, for its antidepressant and anti-neuroinflammatory properties based on mitochondrial protection. Methods: In vitro studies on neuronal injury models, the protective effect of HT on mitochondrial ultrastructure from inflammatory damage was investigated in combination with high-resolution imaging of mitochondrial substructures. In animal models, depressive-like behaviors of chronic restraint stress (CRS) mice and chronic unpredictable mild stress (CUMS) rats were examined to investigate the alleviating effects of HT. Targeted metabolomics and RNA-Seq in CUMS rats were used to analyze the potential antidepressant pathways of HT. Results: HT protected mitochondrial ultrastructure from inflammatory damage, thus exerting neuroprotective effects in neuronal injury models. Moreover, HT reduced depressive-like behaviors in mice and rats exposed to CRS and CUMS, respectively. HT's influence in the CRS model included alleviating hippocampal neuronal damage and modulating cytokine production, mitochondrial dysfunction, and brain-derived neurotrophic factor (BDNF) signaling. Targeted metabolomics in CUMS rats revealed HT's effect on neurotransmitter levels and tryptophan-kynurenine metabolism. RNA-Seq data underscored HT's antidepressant mechanism through the BDNF/TrkB signaling pathways, key in nerve fiber functions, myelin formation, microglial differentiation, and neural regeneration. Discussion: The findings underscore HT's potential as an anti-neuroinflammatory treatment for depression, shedding light on its antidepressant effects and its relevance in nutritional psychiatry. Further investigations are warranted to comprehensively delineate its mechanisms and optimize its clinical application in depression treatment.

Neuropsychiatric disorders are anticipated to be a leading health concern in the near future, emphasizing an outstanding need for the development of new effective therapeutics to treat them. Stilbenes, with resveratrol attracting the most attention, are an example of multi-target compounds with promising therapeutic potential for a broad array of neuropsychiatric and neurological conditions. This review is a comprehensive summary of the current state of research on stilbenes in several neuropsychiatric and neurological disorders such as depression, anxiety, schizophrenia, autism spectrum disorders, epilepsy, traumatic brain injury, and neurodegenerative disorders. We describe and discuss the results of both in vitro and in vivo studies. The majority of studies concentrate on resveratrol, with limited findings exploring other stilbenes such as pterostilbene, piceatannol, polydatin, tetrahydroxystilbene glucoside, or synthetic resveratrol derivatives. Overall, although extensive preclinical studies show the potential benefits of stilbenes in various central nervous system disorders, clinical evidence on their therapeutic efficacy is largely missing.

Objective: Our preliminary research indicates that acacetin modulates the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome, providing protection against Alzheimer's Disease (AD) and cerebral ischemic reperfusion injury. The mechanisms of acacetin to inhibit the activation of the NLRP3 inflammasome remain fully elucidated. This study aims to investigate the effects and potential mechanisms of acacetin on various agonists induced NLRP3 inflammasome activation. Methods: A model for the NLRP3 inflammasome activation was established in mouse bone marrow-derived macrophages (BMDMs) using Monosodium Urate (MSU), Nigericin, Adenosine Triphosphate (ATP), and Pam3CSK4, separately. Western blot analysis (WB) was employed to detect Pro-caspase-1, Pro-Interleukin-1β (Pro-IL-1β) in cell lysates, and caspase-1, IL-1β in supernatants. Enzyme-Linked Immunosorbent Assay (ELISA) was used to measured the release of IL-1β, IL-18, and Tumor Necrosis Factor-alpha (TNF-α) in cell supernatants to assess the impact of acacetin on NLRP3 inflammasome activation. The lactate dehydrogenase (LDH) release was also assessed. The Nuclear Factor Kappa B (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways related proteins were evaluated by WB, and NF-κB nuclear translocation was observed via laser scanning confocal microscopy (LSCM). Disuccinimidyl Suberate (DSS) cross-linking was employed to detect oligomerization of Apoptosis-associated Speck-like protein containing a Caspase Recruitment Domain (ASC), and LSCM was also used to observe Reactive Oxygen Species (ROS) production. Inductively Coupled Plasma (ICP) and N-(6-methoxyquinolyl) acetoethyl ester (MQAE) assays were utilized to determined the effects of acacetin on the efflux of potassium (K+) and chloride (Cl-) ions. Results: Acacetin inhibited NLRP3 inflammasome activation induced by various agonists, reducing the release of TNF-α, IL-1β, IL-18, and LDH. It suppressed the expression of Lipopolysaccharides (LPS)-activated Phosphorylated ERK (p-ERK), p-JNK, and p-p38, inhibited NF-κB p65 phosphorylation and nuclear translocation. Acacetin also reduced ROS production and inhibited ASC aggregation, thus suppressing NLRP3 inflammasome activation. Notably, acacetin did not affect K+ and Cl-ions efflux during the activation process. Conclusion: Acacetin shows inhibitory effects on both the priming and assembly processes of the NLRP3 inflammasome, positioning it as a promising new candidate for the treatment of NLRP3 inflammasome-related diseases.

There is a growing body of evidence supporting the involvement of central nervous system inflammation in the pathophysiology of depression. Polyphenols are a diverse group of compounds known for their antioxidative and anti-inflammatory properties. They offer a promising and effective supplementary approach to alleviating neuropsychiatric symptoms associated with inflammation-induced depression. This paper provides a summary of the potential anti-neuroinflammatory mechanisms of plant polyphenol extracts against depression. This includes direct interference with inflammatory regulators and inhibition of the expression of pro-inflammatory cytokines. Additionally, it covers downregulating the expression of pro-inflammatory cytokines by altering protein kinases or affecting the activity of the signaling pathways that they activate. These pathways interfere with the conduction of signaling molecules, resulting in the destruction and reduced synthesis of all inflammatory mediators and cytokines. This reduces the apoptosis of neurons and plays a neuroprotective role. This paper provides a theoretical basis for the clinical application of plant polyphenols.

Sleep deprivation (SD) is common during spaceflight. SD is known to cause cognitive deficits and depression, requiring treatment and prevention. Hemerocallis citrina Baroni (Liliaceae) is a perennial herb with antidepressant, antioxidant, antitumor, anti-inflammatory, and neuroprotective effects.The aim of our study was to investigate the effects of H. citrina extract (HCE) on SD-induced cognitive decline and depression-like behavior and possible neuroinflammation-related mechanisms. HCE (2 g/kg/day, i.g.) or vortioxetine (10 mg/kg/day, i.g.) were given to mice by oral gavage for a total of 28 days during the SD process. HCE treatment was found to ameliorate SD-induced impairment of short- and long-term spatial and nonspatial memory, measured using Y-maze, object recognition, and Morris water maze tests, as well as mitigating SD-induced depression-like behaviors, measured by tail suspension and forced swimming tests. HCE also reduced the levels of inflammatory cytokines (IL-1β, IL-18, and IL-6) in the serum and hippocampus. Furthermore, HCE suppressed SD-induced microglial activation in the prefrontal cortex (PFC) and the CA1 and dentate gyrus (DG) regions of the hippocampus. HCE also inhibited the expression of phosphorylated NF-κB and activation of the NLRP3 inflammasome. In summary, our findings indicated that HCE attenuated SD-induced cognitive impairment and depression-like behavior and that this effect may be mediated by the inhibition of inflammatory progression and microglial activation in the hippocampus, as well as the down-regulation of NF-κB and NLRP3 signaling. The findings of these studies showingTthese results indicate that HCE exerts neuroprotective effects and are consistent with the findings of previous studies, suggesting that HCE is beneficial for the prevention and treatment of cognitive decline and depression in SD.

Depression is a severe mental condition, common among menopausal women. γ-Oryzanol (ORY) has various biological properties; however, the effect of ORY on menopausal depression and its underlying mechanisms have not been investigated.

ORY is orally administered to ovariectomized (OVX) mice for 20 weeks. ORY administration results in lower immobility time in the tail suspension and forced swim test and increases locomotor activity in the open field test. In the primary hippocampal neurons and hippocampi of OVX mice, ORY treatment increases nitric oxide (NO) production and neuronal NO synthase (nNOS) expression. Further, the phosphorylation of extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), and tropomyosin receptor kinase B, along with the expression of brain-derived neurotrophic factior (BDNF), is upregulated. These stimulatory effects of ORY are diminished by treatment with estrogen receptor β (ERβ) antagonist. ORY similarly interacts with ERβ in the molecular docking analysis. Moreover, intracerebroventricular injection of 7-nitroindazole, a nNOS inhibitor, abolishes the antidepressant effects of ORY.

The results indicate that ORY attenuates depressive behavior in OVX mice by upregulating ERβ-mediated hippocampal nNOS expression and activating the ERK-CREB-BDNF signaling networks. The findings suggest that ORY is a potential therapeutic agent for attenuating menopausal depression.

Emerging evidence indicates that synaptic plasticity is significantly involved in the pathophysiology and treatment of perinatal depression. Animal models have demonstrated the effects of overstimulated or weakened synapses in various circuits of the brain in causing affective disturbances. GABAergic theory of depression, stress, and the neuroplasticity model of depression indicate the role of synaptic plasticity in the pathogenesis of depression. Multiple factors related to perinatal depression like hormonal shifts, newer antidepressants, mood stabilizers, monoamine systems, biomarkers, neurotrophins, cytokines, psychotherapy and electroconvulsive therapy have demonstrated direct and indirect effects on synaptic plasticity. In this review, we discuss and summarize the various patho-physiology-related effects of synaptic plasticity in depression. We also discuss the association of treatment-related aspects related to psychotropics, electroconvulsive therapy, neuromodulation, psychotherapy, physical exercise and yoga with synaptic plasticity in perinatal depression. Future insights into newer methods of treatment directed towards the modulation of neuroplasticity for perinatal depression will be discussed.

Poor therapeutic outcomes of antioxidants in ophthalmologic clinical applications, including glutathione during photoreceptor degeneration in retinitis pigmentosa (RP), are caused by limited anti-oxidative capacity. In this study, fullerenols are synthesized and proven to be highly efficient in vitro radical scavengers. Fullerenol-based intravitreal injections significantly improve the flash electroretinogram and light/dark transition tests performed for 28 days on rd1 mice, reduce the thinning of retinal outer nuclear layers, and preserve the Rhodopsin, Gnat-1, and Arrestin expressions of photoreceptors. RNA-sequencing, RT-qPCR, and Western blotting validate that mitochondrial DNA (mt-DNA)-encoded genes of the electron transport chain (ETC), such as mt-Nd4l, mt-Co1, mt-Cytb, and mt-Atp6, are drastically downregulated in the retinas of rd1 mice, whereas nuclear DNA (n-DNA)-encoded genes, such as Ndufa1 and Atp5g3, are abnormally upregulated. Fullerenols thoroughly reverse the abnormal mt-DNA and n-DNA expression patterns of the ETC and restore mitochondrial function in degenerating photoreceptors. Additionally, fullerenols simultaneously repress Flap endonuclease 1 (FEN1)-mediated mt-DNA cleavage and mt-DNA leakage via voltage-dependent anion channel (VDAC) pores by downregulating the transcription of Fen1 and Vdac1, thereby inactivating the downstream pro-inflammatory cGAS-STING pathway. These findings demonstrate that fullerenols can effectively alleviate photoreceptor degeneration in rd1 mice and serve as a viable treatment for RP.

The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is an important part of the natural immune system that plays an important role in many diseases. Estrogen is a sex hormone that plays an important role in controlling reproduction and regulates many physiological and pathological processes. Recent studies have indicated that estrogen is associated with disease progression. Estrogen can ameliorate some diseases (e. g, sepsis, mood disturbances, cerebral ischemia, some hepatopathy, Parkinson's disease, amyotrophic lateral sclerosis, inflammatory bowel disease, spinal cord injury, multiple sclerosis, myocardial ischemia/reperfusion injury, osteoarthritis, and renal fibrosis) by inhibiting the NLRP3 inflammasome. Estrogen can also promote the development of diseases (e.g., ovarian endometriosis, dry eye disease, and systemic lupus erythematosus) by upregulating the NLRP3 inflammasome. In addition, estrogen has a dual effect on the development of cancers and asthma. However, the mechanism of these effects is not summarized. This article reviewed the progress in understanding the effects of estrogen on the NLRP3 inflammasome and its mechanisms in recent years to provide a theoretical basis for an in-depth study.

Supplementing with edible herbal medicine is an important strategy because of its role in nutrition. Many polyphenols, which are universal components in edible herbal medicines, have low bioavailability. Therefore, gut microbiota is a key determinant of polyphenol bioactivity. Polyphenols can alter the abundance of flora associated with neuroinflammation by reversing intestinal microbiota dysbiosis. Intestinal flora-mediated chemical modification of polyphenols can result in their conversion into active secondary metabolites. The current review summarizes the main edible medicines used in anti-depression and details the interactions between polyphenols and gut microbiota; in addition, it provides insights into the mechanisms underlying the possible suppression of neuroinflammation associated with depression, by polyphenols in edible herbal medicine. A better understanding of polyphenols with bioactivities that are crucial in edible herbal medicine may facilitate their use in the prevention and treatment of neuroinflammation associated with depression.

There is a growing body of evidence about the potential of diet and nutrients to improve the population's mental health and the treatment of psychiatric disorders. Some studies have suggested that resveratrol has therapeutic properties in mental disorders, such as major depressive disorder, bipolar disorder, Alzheimer's disease, and autism. In addition, resveratrol is known to induce several benefits modulated by multiple synergistic pathways, which control oxidative stress, inflammation, and cell death. This review collects the currently available data from animal and human studies and discusses the potential mechanisms of action of resveratrol in prevention and therapy for psychiatric disorders.

The multifaceted microbiota characterizing our gut plays a crucial role in maintaining immune, metabolic and tissue homeostasis of the intestine as well as of distal organs, including the central nervous system. Microbial dysbiosis is reported in several inflammatory intestinal diseases characterized by the impairment of the gut epithelial and vascular barriers, defined as leaky gut, and it is reported as a potential danger condition associated with the development of metabolic, inflammatory and neurodegenerative diseases. Recently, we pointed out the strict connection between the gut and the brain via a novel vascular axis. Here we want to deepen our knowledge on the gut-brain axis, with particular emphasis on the connection between microbial dysbiosis, leaky gut, cerebral and gut vascular barriers, and neurodegenerative diseases. The firm association between microbial dysbiosis and impairment of the vascular gut-brain axis will be summarized in the context of protection, amelioration or boosting of Alzheimer, Parkinson, Major depressive and Anxiety disorders. Understanding the relationship between disease pathophysiology, mucosal barrier function and host-microbe interaction will foster the use of the microbiome as biomarker for health and disease as well as a target for therapeutic and nutritional advances.

Di-(2-Ethylhexyl) phthalate (DEHP) is widely used as an additive in many plastic products. Studies have revealed that DEHP persistent exposure can affect embryonic development and lead to adverse female reproductive disorders. The establishment of pregnancy involves extensive changes in the endometrial tissue, including massive extracellular matrix (ECM) remodeling. Decidualization of the endometrium provides a suitable environment for subsequent growth by causing changes in the morphology of the uterine stromal cells, is a key process in human pregnancy. Resveratrol (RSV) is a natural polyphenolic plant antitoxin with a wide range of pharmacological effects. Growing evidence indicates that RSV has therapeutic effects on certain female reproductive disorders. In this study, the effect of DEHP on cell viability was investigated by cell proliferation assay. Cell decidualization was induced in vitro, and the downregulation of molecules associated with decidualization was confirmed through quantitative real-time PCR and western blot analysis. Immunofluorescence analysis revealed alteration in cell morphology, and found that administration of DEHP sufficiently induced ERα entry into the nucleus. The effect of DEHP on cells was fully verified by RNA-seq analysis. Interestingly, an upregulation of decidual molecules was observed after rescue with RSV, which was confirmed by RNA-seq transcriptome analysis and quantitative real-time PCR assay. Additionally, the expression of ECM remodeling-related genes was significantly restored by RSV administration. The study revealed the potential mechanisms of DEHP-induced decidualization defects and the functional relieving roles of RSV while providing a perspective therapeutic candidate for alleviating the DEHP-induced deficiencies in decidualization.

Epidemiological studies have demonstrated that women are less susceptible to Parkinson's disease (PD) than men. Estrogen exposure is hypothesized to confer protection against dopaminergic neuronal loss in patients with PD. Although the accumulation and propagation of α-synuclein (α-Syn) are closely linked to the clinical progression of PD, no relevant research has examined whether α-Syn proteostasis in the brain is altered in women after menopause. In this study, we established long-term ovariectomized (OVX) mice to simulate late post-menopause and investigated the expression and aggregation of α-Syn following the ovariectomy procedure. We observed that the OVX mice exhibited a significant increase in the expression and aggregation of α-Syn in the striatum and midbrain accompanied by impaired motor performance at 3 months after ovariectomy. The accumulation of α-Syn did not result in a significant loss of nigral dopaminergic neurons but did enhance autophagy and neuroglial activation. These findings imply that menopause may disrupt α-Syn proteostasis and exacerbate the accumulation of α-Syn in the basal ganglia circuit.

Maternal separation in early life has a detrimental effect on the physiological and biochemical functions of the brains of offspring and can lead to anxiety- and depression-like behaviors later in life. Resveratrol possesses a variety of pharmacological properties, including anti-inflammatory, anxiolytic, and anti-depressive effects. In rodents, resveratrol can attenuate anxiety- and depression-like behaviors induced by chronic unpredictable mild stress, estrogen deficiency, and lipopolysaccharide. However, whether resveratrol administration during adolescence can counteract these behaviors when they result from maternal separation is unknown. In this study, male C57BL/6J mice were separated from their mothers for 4 h per day from postnatal day 2 (PND 2) to PND 21; starting on PND 61, resveratrol was administered intraperitoneally at 40 mg/(kg/day^-1) for 4 weeks. At 3 months of age, anxiety and depression-like behaviors were assessed in the male offspring using a series of tasks consisting of an open field test, an elevated plus maze test, a forced swimming test, and a tail suspension test. The hippocampal levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) were measured by ELISA, while those of sirtuin 1 (Sirt1) and nuclear factor kappa B (NF-κB) p65 were determined by western blotting and PCR. The results showed that maternal separation led to increased anxiety- and depression-like behaviors, enhanced the levels of pro-inflammatory cytokines, and downregulated the Sirt1/NF-κB signaling pathway in the male offspring; however, these effects could be reversed by treatment with resveratrol. Our findings suggested that resveratrol can ameliorate inflammation and anxiety- and depression-like behaviors induced by maternal separation via the activation of the Sirt1/NF-κB pathway.

Numerous animal and human studies have assessed the relationship between polyphenols and outcomes related to depression. However, no comprehensive synthesis of the main findings has been conducted. The aim of this manuscript was to systematically review the available evidence from animal and human studies on the association and the effects of dietary polyphenols on depression and provide recommendations for future research. We based our review on 163 preclinical animal, 16 observational and 44 intervention articles assessing the relationship between polyphenols and outcomes related to depression. Most animal studies demonstrated that exposure to polyphenols alleviated behaviours reported to be associated with depression. However, human studies are less clear, with some studies reporting and inverse relationship between the intake of some polyphenols, and polyphenol rich foods and depression risk and symptoms, while others reporting no association or effect. Hence, while there has been extensive research conducted in animals and there is some supporting evidence in humans, further human studies are required, particularly in younger and clinical populations.

Aluminum (Al) has been classified as a cumulative environmental pollutant that endangers human health. There is increasing evidence to suggest the toxic effects of Al, but the specific action on human brain development remains unclear. Al hydroxide (Al(OH)₃), the most common vaccine adjuvant, is the major source of Al and poses risks to the environment and early childhood neurodevelopment. In this study, we explored the neurotoxic effect of 5 μg/ml or 25 μg/ml Al(OH)₃ for six days on neurogenesis by utilizing human cerebral organoids from human embryonic stem cells (hESCs). We found that early Al(OH)₃ exposure in organoids caused a reduction in the size, deficits in basal neural progenitor cell (NPC) proliferation, and premature neuron differentiation in a time and dose-dependent manner. Transcriptomes analysis revealed a markedly altered Hippo-YAP1 signaling pathway in Al(OH)₃ exposed cerebral organoid, uncovering a novel mechanism for Al(OH)₃-induced detrimental to neurogenesis during human cortical development. We further identified that Al(OH)₃ exposure at day 90 mainly decreased the production of outer radial glia-like cells(oRGs) but promoted NPC toward astrocyte differentiation. Taken together, we established a tractable experimental model to facilitate a better understanding of the impact and mechanism of Al(OH)₃ exposure on human brain development.

The mechanism behind the onset of depression has been the focus of current research in the neuroscience field. Silent information regulator 1 (SIRT1) is a key player in regulating energy metabolism, and it can regulate depression by mediating the inflammatory response (e.g., nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β)), gene expression in the nucleus accumben (NAc) and CA1 region of the hippocampus (e.g., nescient helix-loop-helix2 (NHLH2), monoamine oxidase (MAO-A), and 5-Hydroxyindole-3-acetic acid (5-HIAA)), and neuronal regeneration in the CA3 region of the hippocampus. Exercise is an important means to improve energy metabolism and depression, but it remains to be established how SIRT1 acts during exercise and improves depression. By induction and analysis, SIRT1 can be activated by exercise and then improve the function of the hypothalamic-pituitary-adrenal (HPA) axis by upregulating brain-derived neurotrophic factors (BDNF), inhibit the inflammatory response (suppression of the NF-κB and TNF-α/indoleamine 2,3-dioxygenase (IDO)/5-Hydroxytryptamine (5-HT) pathways), and promote neurogenesis (activation of the insulin-like growth factor1 (IGF-1) and growth-associated protein-43 (GAP-43) pathways, etc.), thereby improving depression. The present review gives a summary and an outlook based on this finding and makes an analysis, which will provide a new rationale and insight for the mechanism by which exercise improves depression.

Substance addiction causes anxiety, which in turn reinforces the maintaining of substance use, resulting in a vicious circle. And this circle is one of the reasons why addiction is so hard to cure. However, there is no treatment involved in addiction-induced anxiety at present. We tested whether VNS (vagus nerve stimulation) can improve heroin-induced anxiety, and made a comparison between nVNS (transcervical vagus nerve stimulation) and taVNS (transauricular vagus nerve stimulation) on therapeutic effect. Mice were subjected to nVNS or taVNS before heroin administration. By observing c-Fos expression in the NTS (nucleus of the solitary tract), we assessed vagal fiber activation. Using the OFT (open field test) and the EPM (elevated cross maze test), we evaluated the anxiety-like behaviors of the mice. Using immunofluorescence, we observed the proliferation and activation of microglia in the hippocampus. And ELISA was used to measure the levels of proinflammatory factors in the hippocampus. Both nVNS and taVNS significantly increased the expression of c-Fos in the nucleus of solitary tract, suggesting the feasibility of nVNS and taVNS. The anxiety level of heroin-treated mice was significantly increased, microglia in the hippocampus was significantly proliferated and activated, and the proinflammatory factors (IL-1β, IL-6, TNF-α) in the hippocampus were significantly up-regulated. Crucially, both nVNS and taVNS reversed the above changes caused by heroin addiction. SIGNIFICANCE: It was confirmed that the therapeutic effect of VNS on heroin-induced anxiety may be an effective treatment method to break the "addiction-anxiety" cycle and provides some insights for subsequent treatment of addiction.

Autism spectrum disorder (ASD) is a complicated, heterogeneous disorder characterized by social interaction deficits and repetitive stereotypical behaviors. Neuroinflammation and synaptic protein dysregulation have been implicated in ASD pathogenesis. Icariin (ICA) has proven to exert neuroprotective function through anti-inflammatory function. Therefore, this study aimed to clarify the effects of ICA treatment on autism-like behavioral deficits in BTBR mice and whether these changes were related to modifications in the hippocampal inflammation and the balance of excitatory/inhibitory synapses. ICA supplementation (80 mg/kg, once daily for ten days, i.g.) ameliorated social deficits, repetitive stereotypical behaviors, and short-term memory deficit without affecting locomotor activity or anxiety-like behaviors of BTBR mice. Furthermore, ICA treatment inhibited neuroinflammation via decreasing microglia number and the soma size in the CA1 region of the hippocampus, as well as the protein levels of proinflammatory cytokines in the hippocampus of BTBR mice. In addition, ICA treatment also rescued excitatory-inhibitory synaptic protein imbalance by inhibiting the increased vGlut1 level without affecting the vGAT level in the BTBR mouse hippocampus. Collectively, the observed results indicate that ICA treatment alleviates ASD-like features, mitigates disturbed balance of excitatory-inhibitory synaptic protein, and inhibits hippocampal inflammation in BTBR mice, and may represent a novel promising drug for ASD treatment.

Globally, inflammation and metabolic disorders pose serious public health problems and are major health concerns. It has been shown that natural polyphenols are effective in the treatment of metabolic diseases, including anti-inflammation, anti-diabetes, anti-obesity, neuron-protection, and cardio-protection. NLRP3 inflammasome, which are multiprotein complexes located within the cytosol, play an important role in the innate immune system. However, aberrant activation of the NLRP3 inflammasome were discovered as essential molecular mechanisms in triggering inflammatory processes as well as implicating it in several major metabolic diseases, such as type 2 diabetes mellitus, obesity, atherosclerosis or cardiovascular disease. Recent studies indicate that natural polyphenols can inhibit NLRP3 inflammasome activation. In this review, the progress of natural polyphenols preventing inflammation and metabolic disorders via targeting NLRP3 inflammasome is systemically summarized. From the viewpoint of interfering NLRP3 inflammasome activation, the health effects of natural polyphenols are explained. Recent advances in other beneficial effects, clinical trials, and nano-delivery systems for targeting NLRP3 inflammasome are also reviewed. NLRP3 inflammasome is targeted by natural polyphenols to exert multiple health effects, which broadens the understanding of polyphenol mechanisms and provides valuable guidance to new researchers in this field.

Depression is a common mental disease and is highly prevalent in populations. Dysregulated neuroinflammation and concomitant-activated microglia are involved in the pathogenesis of depression. Experimental evidence has indicated that fullerenol exerts anti-neuroinflammation and protective effects against neurological diseases. Here, we evaluated fullerenol's effects against lipopolysaccharide (LPS)-induced mouse depressive-like behaviors. Fullerenol treatment produced an antidepressant-like effect, as indicated by preventing the LPS-induced reduction in the sucrose preference and shortening the immobility durations in both the tail suspension test and the forced swim test. We found that fullerenol treatment mitigated LPS-induced hippocampal microglia activation and released proinflammatory cytokines. Meanwhile, fullerenol promoted hippocampus neurogenesis, evidenced by increased DCX-positive cells in LPS-treated mice. Hippocampal RNA-Seq analysis revealed proinflammatory cytokine and neurogenesis involved in fullerenol's antidepressant-like effects. Our data indicate that fullerenol exerts antidepressant effects, which might be due to beneficial functions in reducing neuroinflammatory processes and promoting neurogenesis in the hippocampus.

Post-stroke anxiety (PSA) is a kind of affective disorder occurring after a stroke, with anxiety as the primary clinical manifestation. PSA's mechanism is unclear, and there are few prevention and treatment measures. Our previous study found that HDAC3 could activate NF-κB signaling through mediated p65 deacetylation, which further influenced microglia activation. That implies HDAC3 may be the key mediator in ischemic stroke mice and modulates anxiety susceptibility to stress. This study established a PSA model in male C57BL/6 mice through photothrombotic stroke combined with chronic restrain stress. We focused on exploring whether esketamine administration can alleviate anxiety-like behavior and neuroinflammation, which may be associated with inhibiting HDAC3 expression and NF-κB pathway activation. The results showed that esketamine administration alleviated anxiety-like behavior in PSA mice. And the results showed that esketamine alleviated cortical microglial activation, altered microglial number, and kept morphology features. Furthermore, the results showed that the expression of HDAC3, phosphor-p65/p65, and COX1 significantly decreased in esketamine-treated PSA mice. Besides, we also found that esketamine reduced PGE2 expression, one of the primary regulators of negative emotions. Interestingly, our results indicate that esketamine reduced the perineuronal net (PNN) number in the pathological process of PSA. In conclusion, this study suggests esketamine could alleviate microglial activation, reduces inflammatory cytokine, and inhibits the expression of HDAC3 and NF-κB in the cortex of PSA mice to attenuate anxiety-like behavior. Our results provided a new potential therapeutic target for applying esketamine to PSA.

Postpartum depression (PPD) causes maternal mortality, and has a high disability rate. In recent years, studies have suggested the Sirt1 gene to be involved in the pathogenesis of depression. Resveratrol (RSV), an activator of Sirt1, has been investigated in depressive behavior. However, its effect on PPD remains to be thoroughly elucidated.

We employed a mice model with bilateral oophorectomy combined with hormone-simulated pregnancy to assess postpartum depression-like behavior. The behavioral tests were performed 2 days after the withdrawal of estradiol benzoate. RSV was administered subcutaneously to the PPD model mice. Several behavioral tests were executed, including the open field test, forced swimming test, and tail suspension test. Western blot analyses and immunofluorescence staining were used to evaluate protein expression levels of SIRT1, autophagy markers, and the AKT/mTOR.

Postpartum depressive-like behavior was triggered following the withdrawal of estradiol benzoate after hormone-stimulated-pregnancy. RSV improved postpartum depressive-like behavior of mice via its upregulation of the SIRT1 and autophagy markers, such as Beclin1, ATG5 and LC3B. Also, the downregulation of the p62 protein expression was observed. More importantly, we also detected the inhibition of phosphorylated AKT and mTOR in the hippocampus of postpartum depressive-like mice.

RSV could alleviate postpartum depression-like behavior in mice by stimulating the SIRT1, induce autophagy and inhibit the AKT/ mTOR signaling pathway.

Chronic alcohol exposure (CAE) during late adolescence increases the risk of anxiety development. Alcohol-induced prefrontal cortex (PFC) microglial activation, characterized by morphological changes and increased associations with neurons, plays a critical role in the pathogenesis of anxiety. Alcohol exposure increases NLRP3 inflammasome expression, increasing cytokine secretion by activated microglia. Cannabinoid type 2 receptor (CB2R), an essential receptor of the endocannabinoid system, regulates microglial activation and neuroinflammatory reactions. We aimed to investigate the role of CB2R activation in ameliorating late adolescent CAE-induced anxiety-like behaviors and microglial activation in C57BL/6J mice.

Six-week-old C57BL/6J mice were acclimated for 7 days and then were administered alcohol by gavage (4 g/kg, 25 % w/v) for 28 days. The mice were intraperitoneally injected with the specific CB2R agonist AM1241 1 h before alcohol treatment. Anxiety-like behaviors during withdrawal were assessed by open field test and elevated plus maze test 24 h after the last alcohol administration. Microglial activation, microglia-neuron interactions, and CB2R and NLRP3 inflammasome-related molecule expression in the PFC were measured using immunofluorescence, immunohistochemical, qPCR, and Western blotting assays. Microglial morphology was evaluated by Sholl analysis and the cell body-to-total cell size index. Additionally, N9 microglia were activated by LPS in vitro, and the effects of AM1241 on NLRP3 and N9 microglial activation were investigated.

After CAE, mice exhibited severe anxiety-like behaviors during withdrawal. CAE induced obvious microglia-neuron associations, and increased expression of microglial activation markers, CB2R, and NLRP3 inflammasome-related molecules in the PFC. Microglia also showed marked filament retraction and reduction and cell body enlargement after CAE. AM1241 treatment ameliorated anxiety-like behaviors in CAE model mice, and it prevented microglial morphological changes, reduced microglial activation marker expression, and suppressed the microglial NLRP3 inflammasome activation and proinflammatory cytokine secretion induced by CAE. AM1241 suppressed the LPS-induced increase in NLRP3 inflammasome-related molecules, IL-1β release, and M1 phenotype markers (iNOS and CD86) in N9 cell, which was reversed by CB2R antagonist treatment.

CAE caused anxiety-like behaviors in late adolescent mice at least partly by inducing microglial activation and increasing microglia-neuron associations in the PFC. CB2R activation ameliorated these effects by preventing morphological changes and suppressing NLRP3 inflammasome activation in PFC microglia.

In this study, we aimed to evaluate the anti-inflammatory and anti-apoptotic effects of melatonin (MLT) on neuropathic pain (NP)-induced anxiety and depression in a rat model. Adult male rats were separated into four groups, i.e., Sham-VEH: healthy animals received a vehicle, Sham-MLT (10 mg/kg), and chronic constrictive injury (CCI)-VEH: nerve ligation received the vehicle, and CCI-MLT. Next, we used behavioral tests to evaluate pain severity, anxiety, and depression. Finally, rats were sacrificed for molecular and histopathological studies. Behavioral tests showed that NP could induce depressive- and anxiety-like behaviors. NP activated NF-κB/NLRP3 inflammasome pathways by upregulating NF-κB, NLRP3, ASC, active Caspase-1, also enhancing the concentrations of cytokines (IL-1β and IL-18) in the prefrontal cortex (PFC) and hippocampus (HC). NP upregulated Bax, downregulated Bcl2, and increased cell apoptosis in the HC and PFC. The rats treated with MLT eliminated the effects of NP, as the reduced pain severity, improved anxiety- and depressive-like behaviors, ameliorated NF-κB/NLRP3 inflammasome pathways, and modulated levels of cytokines in the HC and PFC. MLT could promote cell survival from apoptosis by modulating Bax and Bcl2. Therefore, it might be inferred that its anti-inflammatory and anti-apoptotic properties mediate the beneficial effects of MLT in NP-induced affective disorders.

Major Depressive Disorder (MDD) is a common mental illness that causes significant disability and declining quality of life. An overlap of multiple factors can be involved in the pathophysiology of this mood disorder, including increased inflammation and oxidative stress, change in neurotransmitters, decreased brain-derived neurotrophic factor (BDNF), activation of the hypothalamicpituitary- adrenal (HPA) axis, and changes in the microbiota-gut-brain axis. Although the classic treatment for MDD is safe, it is far from ideal, with delay to start the best clinic, side effects, and a large number of non-responses or partial-responses. Therefore, other alternatives are being studied to improve depressive symptoms, and, among them, the role of phytochemicals in food stands out. This mini-review will discuss the main phytochemicals present in foods with clinical and preclinical studies showing benefits for MDD treatment. In addition, the main mechanisms of action that are being proposed for each of these compounds will be addressed.

Increasing evidence suggests that the failure of clinical antidepressants may be related with neuroinflammation. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is an intracellular multiprotein complex, and has been considered as a key contributor to the development of neuroinflammation. Inhibition of NLRP3 inflammasome is an effective method for depression treatment. In this review, we summarized current researches highlighting the role of NLRP3 inflammasome in the pathology of depression. Firstly, we discussed NLRP3 inflammasome activation in patients with depression and animal models. Secondly, we outlined the possible mechanisms driving the activation of NLRP3 inflammasome. Thirdly, we discussed the pathogenetic role of NLRP3 inflammasome in depression. Finally, we overviewed the current and potential antidepressants targeting the NLRP3 inflammasome. Overall, the inhibition of NLRP3 inflammasome activation may be a potential therapeutic strategy for inflammation-related depression.

The present study aimed to assess whether treatment with combined resveratrol and myoinositol is more effective in ameliorating the altered parameters associated with PCOS when compared to the combined metformin and pioglitazone therapy.

One hundred and ten obese, oligo-anovulatory PCOS women, aged 20-35 years were randomly assigned into two treatment arms. Participants in arm-1 (n = 55), received combination of metformin and pioglitazone (500 mg and 15 mg, respectively), twice daily, while those in arm-2 (n = 55) received combination of resveratrol and myoinositol (1000 mg and 1000 mg, respectively) twice daily for 12 weeks. Evaluations performed at baseline were repeated after 3 months of therapy. The endocrine and metabolic derangements were assessed by measuring serum levels of testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), adiponectin and insulin using ELISA. Cohen's perceived stress scale (PSS) was employed as a subjective measure of stress.

Pre-treatment PCOS women in both the arms (arm-1 and arm-2) had remarkably elevated serum testosterone and insulin concentrations, low serum adiponectin and high perceived stress response scores. The treatment reduced the altered endocrine indices in arm-2 (resveratrol and myoinositol) participants, manifested by statistically significant reduction in serum testosterone level (p = 0.001) and notably increased serum adiponectin level (p = 0.001). Interestingly, the hormonal profile, including serum LH and FSH levels also decreased (p < 0.001) along with a marked reduction in the ovarian volume (p = 0.001) in arm-2 participants. There was a significant reduction in weight (<0.001), BMI (p < 0.001) and an improvement in waist-hip ratio (p < 0.001) in arm-2 participants compared to arm-1 group. The PSS scores of the arm-2 subjects improved significantly (p < 0.001) whereas, the Ferrimen-Gallwey score was improved in both the arms (arm-1 and arm-2; p = 0.010 and 0.008 respectively) however, the change was highly significant in arm-2. Interestingly, the menstrual regularity was 81.4% in arm-2 while 18.2% in arm-1. We conclude that the therapeutic intervention with combined resveratrol and myoinositol is more effective in ameliorating altered endocrine, metabolic indices and stress burden and could be of clinical importance in high risk group of obese, oligo-anovulatory married PCOS affected women.

ClinicalTials.gov Trial No: NCT04867252. Registered 24 April, 2021, https://clinicaltrials.gov/ct2/show/NCT04867252.

Since chronic inflammation can be seen in severe, long-lasting diseases such as cancer, there is a high demand for effective methods to modulate inflammatory responses. Among many therapeutic candidates, lignans, absorbed from various plant sources, represent a type of phytoestrogen classified into secoisolariciresionol (Seco), pinoresinol (Pino), matairesinol (Mat), medioresinol (Med), sesamin (Ses), syringaresinol (Syr), and lariciresinol (Lari). Lignans consumed by humans can be further modified into END or ENL by the activities of gut microbiota. Lignans are known to exert antioxidant and anti-inflammatory activities, together with activity in estrogen receptor-dependent pathways. Lignans may have therapeutic potential for postmenopausal symptoms, including cardiovascular disease, osteoporosis, and psychological disorders. Moreover, the antitumor efficacy of lignans has been demonstrated in various cancer cell lines, including hormone-dependent breast cancer and prostate cancer, as well as colorectal cancer. Interestingly, the molecular mechanisms of lignans in these diseases involve the inhibition of inflammatory signals, including the nuclear factor (NF)-κB pathway. Therefore, we summarize the recent in vitro and in vivo studies evaluating the biological effects of various lignans, focusing on their values as effective anti-inflammatory agents.

Neohesperidin (hesperetin 7-O-neohesperidoside), a well-known flavanone glycoside widely found in citrus fruits, exhibits a variety of biological activities, with potential applications ranging from food ingredients to therapeutics. The purpose of this manuscript is to provide a comprehensive overview of the chemical, biosynthesis, and pharmacokinetics profiles of neohesperidin, as well as the therapeutic effects and mechanisms of neohesperidin against potential diseases. This literature review covers a wide range of pharmacological responses elicited by Neohesperidin, including neuroprotective, anti-inflammatory, antidiabetic, antimicrobial, and anticancer activities, with a focus on the mechanisms of those pharmacological responses. Additionally, the mechanistic pathways underlying the compound's osteoporosis, antiulcer, cardioprotective, and hepatoprotective effects have been outlined. This review includes detailed illustrations of the biosynthesis, biopharmacokinetics, toxicology, and controlled release of neohesperidine. Neohesperidin demonstrated a broad range of therapeutic and biological activities in the treatment of a variety of complex disorders, including neurodegenerative, hepato-cardiac, cancer, diabetes, obesity, infectious, allergic, and inflammatory diseases. Neohesperidin is a promising therapeutic candidate for the management of various etiologically complex diseases. However, further in vivo and in vitro studies on mechanistic potential are required before clinical trials to confirm the safety, bioavailability, and toxicity profiles of neohesperidin.

Social isolation (SI) is a major risk factor for mood disorders in adolescents. The nucleus accumbens (NAc) is an important reward center implicated in psychiatric disorders. Resveratrol (RSV) is one of the most effective natural polyphenols with anti-anxiety and depression effects. However, little is known about the therapeutic effects and mechanisms of RSV on behavioral abnormality of adolescent social stress. Therefore, this study aimed to investigate the underlying mechanism of RSV on the amelioration of SI-induced behavioral abnormality. We found that SI induced anxiety-like behavior and social dysfunction in isolated female rats. Moreover, SI reduced mitochondrial number and ATP levels and increased thin spine density in the NAc. RNA sequencing results showed that SI changed the transcription pattern in the NAc, including 519 upregulated genes and 610 downregulated genes, especially those related to mitochondrial function. Importantly, RSV ameliorated behavioral and spine abnormalities induced by SI and increased NAc ATP levels and mitochondria number. Furthermore, RSV increased the activity of cytochrome C oxidase (COX) and upregulated mRNA levels of Cox5a, Cox6a1 and Cox7c. These results demonstrate that the modulation of spine plasticity and mitochondrial function in the NAc by RSV has a therapeutic effect on mood disorders induced by social isolation.