Adenosine Receptors in Neuropsychiatric Disorders: Fine Regulators of Neurotransmission and Potential Therapeutic Targets

Adenosine exerts an important role in the modulation of central nervous system (CNS) activity. Through the interaction with four G-protein coupled receptor (GPCR) subtypes, adenosine subtly regulates neurotransmission, interfering with the dopaminergic, glutamatergic, noradrenergic, serotoninergic, and endocannabinoid systems. The inhibitory and facilitating actions of adenosine on neurotransmission are mainly mediated by A₁ and A_2A adenosine receptors (ARs), respectively. Given their role in the CNS, ARs are promising therapeutic targets for neuropsychiatric disorders where altered neurotransmission represents the most likely etiological hypothesis. Activating or blocking ARs with specific pharmacological agents could therefore restore the balance of altered neurotransmitter systems, providing the rationale for the potential treatment of these highly debilitating conditions. In this review, we summarize and discuss the most relevant studies concerning AR modulation in psychotic and mood disorders such as schizophrenia, bipolar disorders, depression, and anxiety, as well as neurodevelopment disorders such as autism spectrum disorder (ASD), fragile X syndrome (FXS), attention-deficit hyperactivity disorder (ADHD), and neuropsychiatric aspects of neurodegenerative disorders.     

The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets

Cannabidiol (CBD), the major nonpsychoactive Cannabis constituent, has been proposed for the treatment of a wide panel of neurological and neuropsychiatric disorders, including anxiety, schizophrenia, epilepsy and drug addiction due to the ability of its versatile scaffold to interact with diverse molecular targets that are not restricted to the endocannabinoid system. Albeit the molecular mechanisms responsible for the therapeutic effects of CBD have yet to be fully elucidated, many efforts have been devoted in the last decades to shed light on its complex pharmacological profile. In particular, an ever-increasing number of molecular targets linked to those disorders have been identified for this phytocannabinoid, along with the modulatory effects of CBD on their cascade signaling. In this view, here we will try to provide a comprehensive and up-to-date overview of the molecular basis underlying the therapeutic effects of CBD involved in the treatment of neurological and neuropsychiatric disorders.     

Neuroinflammation as a Common Denominator of Complex Diseases (Cancer,Diabetes Type 2, and Neuropsychiatric Disorders)

The term neuroinflammation refers to inflammation of the nervous tissue, in general, and in the central nervous system (CNS), in particular. It is a driver of neurotoxicity, it is detrimental, and implies that glial cell activation happens prior to neuronal degeneration and, possibly, even causes it. The inflammation-like glial responses may be initiated in response to a variety of cues such as infection, traumatic brain injury, toxic metabolites, or autoimmunity. The inflammatory response of activated microglia engages the immune system and initiates tissue repair. Through translational research the role played by neuroinflammation has been acknowledged in different disease entities. Intriguingly, these entities include both those directly related to the CNS (commonly designated neuropsychiatric disorders) and those not directly related to the CNS (e.g., cancer and diabetes type 2). Interestingly, all the above-mentioned entities belong to the same group of “complex disorders”. This review aims to summarize cumulated data supporting the hypothesis that neuroinflammation is a common denominator of a wide variety of complex diseases. We will concentrate on cancer, type 2 diabetes (T2DM), and neuropsychiatric disorders (focusing on mood disorders).     

The Role of Gut Microbiota and Gut–Brain Interplay in Selected Diseases of the Central Nervous System

The gut microbiome has attracted increasing attention from researchers in recent years. The microbiota can have a specific and complex cross-talk with the host, particularly with the central nervous system (CNS), creating the so-called “gut–brain axis”. Communication between the gut, intestinal microbiota, and the brain involves the secretion of various metabolites such as short-chain fatty acids (SCFAs), structural components of bacteria, and signaling molecules. Moreover, an imbalance in the gut microbiota composition modulates the immune system and function of tissue barriers such as the blood–brain barrier (BBB). Therefore, the aim of this literature review is to describe how the gut–brain interplay may contribute to the development of various neurological disorders, combining the fields of gastroenterology and neuroscience. We present recent findings concerning the effect of the altered microbiota on neurodegeneration and neuroinflammation, including Alzheimer’s and Parkinson’s diseases, as well as multiple sclerosis. Moreover, the impact of the pathological shift in the microbiome on selected neuropsychological disorders, i.e., major depressive disorders (MDD) and autism spectrum disorder (ASD), is also discussed. Future research on the effect of balanced gut microbiota composition on the gut–brain axis would help to identify new potential opportunities for therapeutic interventions in the presented diseases.     

The Central Nervous Mechanism of Stress-Promoting Cancer Progression

Evidence shows that stress can promote the occurrence and development of tumors. In recent years, many studies have shown that stress-related hormones or peripheral neurotransmitters can promote the proliferation, survival, and angiogenesis of tumor cells and impair the body’s immune response, causing tumor cells to escape the “surveillance” of the immune system. However, the perception of stress occurs in the central nervous system (CNS) and the role of the central nervous system in tumor progression is still unclear, as are the underlying mechanisms. This review summarizes what is known of stress-related CNS-network activation during the stress response and the influence of the CNS on tumors and discusses available adjuvant treatment methods for cancer patients with negative emotional states, such as anxiety and depression.     

Abnormal mTOR Activity in Pediatric Autoimmune Neuropsychiatric and MIA-Associated Autism Spectrum Disorders

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by the early onset of communication and behavioral problems. ASD is highly heritable; however, environmental factors also play a considerable role in this disorder. A significant part of both syndromic and idiopathic autism cases could be attributed to disorders caused by mammalian target of rapamycin (mTOR)-dependent translation deregulation. This narrative review analyzes both bioinformatic and experimental evidence that connects mTOR signaling to the maternal autoantibody-related (MAR) autism spectrum and autoimmune neuropsychiatric disorders simultaneously. In addition, we reconstruct a network presenting the interactions between the mTOR signaling and eight MAR ASD genes coding for ASD-specific maternal autoantibody target proteins. The research discussed in this review demonstrates novel perspectives and validates the need for a subtyping of ASD on the grounds of pathogenic mechanisms. The utter necessity of designing ELISA-based test panels to identify all antibodies related to autism-like behavior is also considered.     

The N6-Methyladenosine Regulator ALKBH5 Mediated Stromal Cell–Macrophage Interaction via VEGF Signaling to Promote Recurrent Spontaneous Abortion: A Bioinformatic and In Vitro Study

Successful conception requires the synchrony of multiple systems and organs. Dysregulation of stromal cell–immune cell interactions has been proposed to be associated with recurrent spontaneous abortion. However, the mechanism of this regulation has not been well elucidated. N6-methyladenosine is one of the most common RNA modifications, and is involved in many pathological processes. Our group has demonstrated that abnormal patterns of m6A modification inhibit trophoblast invasion and contribute to adverse pregnancy outcomes. The association between m6A regulators and stromal cell–immune cell interactions is unclear. We obtained RNA-seq profiles from a GEO dataset and identified differentially expressed m6A regulators between healthy controls and patients with a recurrent spontaneous abortion history. ROC curves, functional enrichment and subclassification analysis were applied to elucidate the role of m6A regulators in pregnancy. We verified the expression of m6A regulators and constructed an overexpression cell line in a coculture system to reveal ALKBH5 function in stromal cell–macrophage interactions. We identified 11 differentially expressed m6A regulators between healthy controls and patients with a recurrent spontaneous abortion history. Then, we identified the correlation between “eraser” genes and “writer” genes. We tested the predictive abilities of the 11 m6A regulators based on another dataset and verified their expression in primary human endometrial stromal cells. We then subclassified three distinct patterns using the 11 genes and visualized genes related to immune infiltration and macrophage function in each cluster. ALKBH5 was proven to be correlated with recurrent spontaneous abortion. To verify the role of ALKBH5 in RSA, we constructed an ALKBH5-overexpression cell line. Finally, we cocultured the overexpression cell line with THP-1 cells. A decrease in M2 differentiation was observed, and this bias could be attributed to the hyposecretion of VEGF in stromal cells. N6-methyladenosine regulators play a pivotal role in stromal cell–immune cell interactions at the maternal–fetal interface. Overexpression of the m6A “eraser” gene ALKBH5 in stromal cells resulted in the hyposecretion of VEGF. Dysregulation of VEGF might impair macrophage recruitment and M2 differentiation, which could be the potential cause of recurrent spontaneous abortion.     

From Molecules to Behavior in Long-Term Inorganic Mercury Intoxication: Unraveling Proteomic Features in Cerebellar Neurodegeneration of Rats

Mercury is a severe environmental pollutant with neurotoxic effects, especially when exposed for long periods. Although there are several evidences regarding mercury toxicity, little is known about inorganic mercury (IHg) species and cerebellum, one of the main targets of mercury associated with the neurological symptomatology of mercurial poisoning. Besides that, the global proteomic profile assessment is a valuable tool to screen possible biomarkers and elucidate molecular targets of mercury neurotoxicity; however, the literature is still scarce. Thus, this study aimed to investigate the effects of long-term exposure to IHg in adult rats’ cerebellum and explore the modulation of the cerebellar proteome associated with biochemical and functional outcomes, providing evidence, in a translational perspective, of new mercury toxicity targets and possible biomarkers. Fifty-four adult rats were exposed to 0.375 mg/kg of HgCl₂ or distilled water for 45 days using intragastric gavage. Then, the motor functions were evaluated by rotarod and inclined plane. The cerebellum was collected to quantify mercury levels, to assess the antioxidant activity against peroxyl radicals (ACAPs), the lipid peroxidation (LPO), the proteomic profile, the cell death nature by cytotoxicity and apoptosis, and the Purkinje cells density. The IHg exposure increased mercury levels in the cerebellum, reducing ACAP and increasing LPO. The proteomic approach revealed a total 419 proteins with different statuses of regulation, associated with different biological processes, such as synaptic signaling, energy metabolism and nervous system development, e.g., all these molecular changes are associated with increased cytotoxicity and apoptosis, with a neurodegenerative pattern on Purkinje cells layer and poor motor coordination and balance. In conclusion, all these findings feature a neurodegenerative process triggered by IHg in the cerebellum that culminated into motor functions deficits, which are associated with several molecular features and may be related to the clinical outcomes of people exposed to the toxicant.     

FTO m6A Demethylase in Obesity and Cancer: Implications and Underlying Molecular Mechanisms

Fat mass and obesity-associated protein (FTO) is the first reported RNA N6-methyladenosine (m6A) demethylase in eukaryotic cells. m6A is considered as the most abundant mRNA internal modification, which modulates several cellular processes including alternative splicing, stability, and expression. Genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) within FTO to be associated with obesity, as well as cancer including endometrial cancer, breast cancer, pancreatic cancer, and melanoma. Since the initial classification of FTO as an m6A demethylase, various studies started to unravel a connection between FTO’s demethylase activity and the susceptibility to obesity on the molecular level. FTO was found to facilitate adipogenesis, by regulating adipogenic pathways and inducing pre-adipocyte differentiation. FTO has also been investigated in tumorigenesis, where emerging studies suggest m6A and FTO levels are dysregulated in various cancers, including acute myeloid leukemia (AML), glioblastoma, cervical squamous cell carcinoma (CSCC), breast cancer, and melanoma. Here we review the molecular bases of m6A in tumorigenesis and adipogenesis while highlighting the controversial role of FTO in obesity. We provide recent findings confirming FTO’s causative link to obesity and discuss novel approaches using RNA demethylase inhibitors as targeted oncotherapies. Our review aims to confirm m6A demethylation as a risk factor in obesity and provoke new research in FTO and human disorders.     

Insights into the Pathophysiology of Psychiatric Symptoms in Central Nervous System Disorders: Implications for Early and Differential Diagnosis

Different psychopathological manifestations, such as affective, psychotic, obsessive-compulsive symptoms, and impulse control disturbances, may occur in most central nervous system (CNS) disorders including neurodegenerative and neuroinflammatory diseases. Psychiatric symptoms often represent the clinical onset of such disorders, thus potentially leading to misdiagnosis, delay in treatment, and a worse outcome. In this review, psychiatric symptoms observed along the course of several neurological diseases, namely Alzheimer’s disease, fronto-temporal dementia, Parkinson’s disease, Huntington’s disease, and multiple sclerosis, are discussed, as well as the involved brain circuits and molecular/synaptic alterations. Special attention has been paid to the emerging role of fluid biomarkers in early detection of these neurodegenerative diseases. The frequent occurrence of psychiatric symptoms in neurological diseases, even as the first clinical manifestations, should prompt neurologists and psychiatrists to share a common clinico-biological background and a coordinated diagnostic approach.     

The Role of Phospholipase Activity of Peroxiredoxin 6 in Its Transmembrane Transport and Protective Properties

Peroxiredoxin 6 (Prdx6) is a multifunctional eukaryotic antioxidant enzyme. Mammalian Prdx6 possesses peroxidase activity against a wide range of organic and inorganic hydroperoxides, as well as exhibits phospholipase A2 (aiPLA2) activity, which plays an important role in the reduction of oxidized phospholipids and cell membrane remodeling. Exogenous Prdx6 has recently been shown to be able to penetrate inside the cell. We hypothesized that this entry may be due to the phospholipase activity of Prdx6. Experiments using exogenous Prdx6 in three cell lines (3T3, A549, RAW 264.7) demonstrated that it is the phospholipase activity that promotes its penetration into the cell. Overoxidation of Prdx6 led to a suppression of the peroxidase activity and a 3-to-4-fold growth of aiPLA2, which enhanced the efficiency of its transmembrane transport into the cells by up to 15 times. A mutant form of Prdx6-S32A with an inactivated phospholipase center turned out to be unable to enter the cells in both the reduced and oxidized state of the peroxidase active center. Previously, we have shown that exogenous Prdx6 has a significant radioprotective action. However, the role of phospholipase activity in the radioprotective effects of Prdx6 remained unstudied. Trials with the mutant Prdx6-S32A form, with the use of a total irradiation model in mice, showed a nearly 50% reduction of the radioprotective effect upon aiPLA2 loss. Such a significant decrease in the radioprotective action may be due to the inability of Prdx6-S32A to penetrate animal cells, which prevents its reduction by the natural intracellular reducing agent glutathione S-transferase (πGST) and lowers the efficiency of elimination of peroxides formed from the effect of ionizing radiation. Thus, phospholipase activity may play an important role in the reduction of oxidized Prdx6 and manifestation of its antioxidant properties.     

槐米中槲皮素的提取及其对中枢神经系统作用的研究进展

介绍了槐米中槲皮素的几种常规提取方法,并概括了槲皮素作用于中枢神经系统方面的功效,包括其镇痛作用、抗抑郁作用及对记忆的影响.     

Reduction of Methyltransferase-like 3-Mediated RNA N6-Methyladenosine Exacerbates the Development of Psoriasis Vulgaris in Imiquimod-Induced Psoriasis-like Mouse Model

N6-methyladenosine (m⁶A) methylation is the most pervasive and intensively studied mRNA modification, which regulates gene expression in different physiological processes, such as cell proliferation, differentiation, and inflammation. Studies of aberrant m⁶A in human diseases such as cancer, obesity, infertility, neuronal disorders, immune diseases, and inflammation are rapidly evolving. However, the regulatory mechanism and physiological significance of m⁶A methylation in psoriasis vulgaris are still poorly understood. In this study, we found that m⁶A methylation and Methyltransferase-like 3 (METTL3) were both downregulated in psoriatic skin lesions and were negatively correlated with Psoriasis Area and Severity Index (PASI) scores. Inhibiting m⁶A methylation by knocking down Mettl3 promoted the development of psoriasis and increased its severity in imiquimod-induced psoriasis-like model mice. Our results indicate a critical role of METTL3- mediated m⁶A methylation in the pathogenesis of psoriasis vulgaris.     

The Role of Hydrogen Sulfide Regulation of Autophagy in Liver Disorders

Autophagy is a complex process of degradation of senescent or dysfunctional organelles in cells. Dysfunctional autophagy is associated with many diseases such as cancers, immune dysfunction, and aging. Hydrogen sulfide (H₂S) is considered to be the third gas signal molecule after nitrous oxide and carbon monoxide. In recent years, H₂S has been found to have a variety of important biological functions, and plays an important role in a variety of physiological and pathological processes. In this review, we review the recent role and mechanism of H₂S in regulating autophagy in liver disorders, in order to provide a basis for further research in the future.     

Inflammation-Related Changes in Mood Disorders and the Immunomodulatory Role of Lithium

Mood disorders are chronic, recurrent diseases characterized by changes in mood and emotions. The most common are major depressive disorder (MDD) and bipolar disorder (BD). Molecular biology studies have indicated an involvement of the immune system in the pathogenesis of mood disorders, and showed their correlation with altered levels of inflammatory markers and energy metabolism. Previous reports, including meta-analyses, also suggested the role of microglia activation in the M1 polarized macrophages, reflecting the pro-inflammatory phenotype. Lithium is an effective mood stabilizer used to treat both manic and depressive episodes in bipolar disorder, and as an augmentation of the antidepressant treatment of depression with a multidimensional mode of action. This review aims to summarize the molecular studies regarding inflammation, microglia activation and energy metabolism changes in mood disorders. We also aimed to outline the impact of lithium on these changes and discuss its immunomodulatory effect in mood disorders.     

The Role of Non-Coding RNAs in the Neuroprotective Effects of Glutathione

The establishment of antioxidative defense systems might have been mandatory for most living beings with aerobic metabolisms, because oxygen consumption produces adverse byproducts known as reactive oxygen species (ROS). The brain is especially vulnerable to the effect of ROS, since the brain has large amounts of unsaturated fatty acids, which are a target of lipid oxidation, as well as comparably high-energy consumption compared to other organs that results in ROS release from mitochondria. Thus, dysregulation of the synthesis and/or metabolism of antioxidants—particularly glutathione (GSH), which is one of the most important antioxidants in the human body—caused oxidative stress states that resulted in critical diseases, including neurodegenerative diseases in the brain. GSH plays crucial roles not only as an antioxidant but also as an enzyme cofactor, cysteine storage form, the major redox buffer, and a neuromodulator in the central nervous system. The levels of GSH are precisely regulated by uptake systems for GSH precursors as well as GSH biosynthesis and metabolism. The rapid advance of RNA sequencing technologies has contributed to the discovery of numerous non-coding RNAs with a wide range of functions. Recent lines of evidence show that several types of non-coding RNAs, including microRNA, long non-coding RNA and circular RNA, are abundantly expressed in the brain, and their activation or inhibition could contribute to neuroprotection through the regulation of GSH synthesis and/or metabolism. Interestingly, these non-coding RNAs play key roles in gene regulation and growing evidence indicates that non-coding RNAs interact with each other and are co-regulated. In this review, we focus on how the non-coding RNAs modulate the level of GSH and modify the oxidative stress states in the brain.