Distinct correlation network of clinical characteristics in suicide attempters having adolescent major depressive disorder with non-suicidal self-injury.

Suicidal behavior and non-suicidal self-injury (NSSI) are common in adolescent patients with major depressive disorder (MDD). Thus, delineating the unique characteristics of suicide attempters having adolescent MDD with NSSI is important for suicide prediction in the clinical setting. Here, we performed psychological and biochemical assessments of 130 youths having MDD with NSSI. Participants were divided into two groups according to the presence/absence of suicide attempts (SAs). Our results demonstrated that the age of suicide attempters is lower than that of non-attempters in participants having adolescent MDD with NSSI; suicide attempters had higher Barratt Impulsiveness Scale (BIS-11) impulsivity scores and lower serum CRP and cortisol levels than those having MDD with NSSI alone, suggesting levels of cortisol and CRP were inversely correlated with SAs in patients with adolescent MDD with NSSI. Furthermore, multivariate regression analysis revealed that NSSI frequency in the last month and CRP levels were suicidal ideation predictors in adolescent MDD with NSSI, which may indicate that the increased frequency of NSSI behavior is a potential risk factor for suicide. Additionally, we explored the correlation between psychological and blood biochemical indicators to distinguish suicide attempters among participants having adolescent MDD with NSSI and identified a unique correlation network that could serve as a marker for suicide attempters. Our research data further suggested a complex correlation between the psychological and behavioral indicators of impulsivity and anger. Therefore, our study findings may provide clues to identify good clinical warning signs for SA in patients with adolescent MDD with NSSI.

Histone deficiency and hypoacetylation in the aging retinal pigment epithelium.

Histones serve as a major carrier of epigenetic information in the form of post-translational modifications which are vital for controlling gene expression, maintaining cell identity, and ensuring proper cellular function. Loss of histones in the aging genome can drastically impact the epigenetic landscape of the cell leading to altered chromatin structure and changes in gene expression profiles. In this study, we investigated the impact of age-related changes on histone levels and histone acetylation in the retinal pigment epithelium (RPE) and retina of mice. We observed a global reduction of histones H1, H2A, H2B, H3, and H4 in aged RPE/choroid but not in the neural retina. Transcriptomic analyses revealed significant downregulation of histones in aged RPE/choroid including crucial elements of the histone locus body (HLB) complex involved in histone pre-mRNA processing. Knockdown of HINFP, a key HLB component, in human RPE cells induced histone loss, senescence, and the upregulation of senescence-associated secretory phenotype (SASP) markers. Replicative senescence and chronological aging in human RPE cells similarly resulted in progressive histone loss and acquisition of the SASP. Immunostaining of human retina sections revealed histone loss in RPE with age. Acetyl-histone profiling in aged mouse RPE/choroid revealed a specific molecular signature with loss of global acetyl-histone levels, including H3K14ac, H3K56ac, and H4K16ac marks. These findings strongly demonstrate histone loss as a unique feature of RPE aging and provide critical insights into the potential mechanisms linking histone dynamics, cellular senescence, and aging.

Hypothalamic CRF neurons facilitate brain reward function.

Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVNCRF neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVNCRF neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVNCRF neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVNCRF cell bodies, self-stimulation of PVNCRF-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVNCRF-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVNCRF neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVNCRF neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.

Conventional and multi-omics assessments of subacute inhalation toxicity due to propylene glycol and vegetable glycerin aerosol produced by electronic cigarettes.

Propylene glycol (PG) and vegetable glycerin (VG) are the most common solvents used in electronic cigarette liquids. No long-term inhalation toxicity assessments have been performed combining conventional and multi-omics approaches on the potential respiratory effects of the solvents in vivo. In this study, the systemic toxicity of aerosol generated from a ceramic heating coil-based e-cigarette was evaluated. First, the aerosol properties were characterized, including carbonyl emissions, the particle size distribution, and aerosol temperatures. To determine toxicological effects, rats were exposed, through their nose only, to filtered air or a propylene glycol (PG)/ glycerin (VG) (50:50, %W/W) aerosol mixture at the target concentration of 3 mg/L for six hours daily over a continuous 28-day period. Compared with the air group, female rats in the PG/VG group exhibited significantly lower body weights during both the exposure period and recovery period, and this was linked to a reduced food intake. Male rats in the PG/VG group also experienced a significant decline in body weight during the exposure period. Importantly, rats exposed to the PG/VG aerosol showed only minimal biological effects compared to those with only air exposure, with no signs of toxicity. Moreover, the transcriptomic, proteomic, and metabolomic analyses of the rat lung tissues following aerosol exposure revealed a series of candidate pathways linking aerosol inhalation to altered lung functions, especially the inflammatory response and disease. Dysregulated pathways of arachidonic acids, the neuroactive ligand-receptor interaction, and the hematopoietic cell lineage were revealed through integrated multi-omics analysis. Therefore, our integrated multi-omics approach offers novel systemic insights and early evidence of environmental-related health hazards associated with an e-cigarette aerosol using two carrier solvents in a rat model.

A novel dopamine D2 receptor-NR2B protein complex might contribute to morphine use disorders.

Dopamine receptors can form heteromeric interactions with other receptors, including glutamate receptors, and present a novel pharmacological target because it contribute to dopamine-dysregulated brain disorders such as addiction and other motor-related diseases. In addition, dopamine receptors D2 (D2Rs) and glutamate NMDA receptors subtype-NR2B have been implicated in morphine use disorders; however, the molecular mechanism underlying the heteromeric complex of these two receptors in morphine use disorders is unclear. Herein, we focus on interactions between D2R and NR2B in morphine-induced conditioned place preference (CPP) and hyperlocomotion mice models. We found that the D2R-NR2B complex significantly increases in morphine-induced mice models, accompanied by ERK signaling impairment, implying the complex could contribute to the morphine addiction pathophysiological process. Further, we design a brain-penetrant interfering peptide (TAT-D2-KT), which could disrupt interactions of D2R-NR2B and decrease addictive-like behaviors concurrent to ERK signaling improvement. In summary, our data provided the first evidence for a D2R-NMDAR complex formation in morphine use disorders and its underlying mechanism of ERK signaling, which could present a novel therapeutic target with direct implications for morphine acquisition and relapse treatment.

Pharmacokinetic differences in nicotine and nicotine salts mediate reinforcement-related behavior: an animal model study.

Since their introduction in the United States and Europe in 2007, electronic cigarettes (E-Cigs) have become increasingly popular among smokers. Nicotine, a key component in both tobacco and e-cigarettes, can exist in two forms: nicotine-freebase (FBN) and nicotine salts (NS). While nicotine salt is becoming more popular in e-cigarettes, the effect of nicotine salts on reinforcement-related behaviors remains poorly understood. This study aimed to compare the reinforcing effects of nicotine and nicotine salts in animal models of drug self-administration and explore potential mechanisms that may contribute to these differences. The results demonstrated that three nicotine salts (nicotine benzoate, nicotine lactate, and nicotine tartrate) resulted in greater reinforcement-related behaviors in rats compared to nicotine-freebase. Moreover, withdrawal-induced anxiety symptoms were lower in the three nicotine salt groups than in the nicotine-freebase group. The study suggested that differences in the pharmacokinetics of nicotine-freebase and nicotine salts in vivo may explain the observed behavioral differences. Overall, this study provides valuable insights into the reinforcing effects of nicotine as well as potential differences between nicotine-freebase and nicotine salts.

Nicotine transport across calu-3 cell monolayer: effect of nicotine salts and flavored e-liquids.

OBJECTIVE: This study aimed to investigate the transport capability of nicotine across Calu-3 cell monolayer in various nicotine forms, including nicotine freebase, nicotine salts, and flavored e-liquids with nicotine benzoate. SIGNIFICANCE: Nicotine is rapidly absorbed from the respiratory system into systemic circulation during e-cigarettes use. However, the mechanism of nicotine transport in the lung has not been well understood yet. This study may offer critical biological evidence and have implications for the use and regulation of e-cigarettes. METHODS: The viability of Calu-3 cells after administration of nicotine freebase, nicotine salts and representative e-liquid were evaluated using the MTT assay, and the integrity of the Calu-3 cell monolayer was evaluated by transepithelial electrical resistance measurement and morphological analysis. Further, the nicotine transport capacity across the Calu-3 cell monolayer in various formulations of nicotine was investigated by analysis of nicotine transport amount. RESULTS: The findings indicated that nicotine transport occurred passively and was time-dependent across the Calu-3cell monolayer. In addition, the nicotine transport was influenced by the type of nicotine salts and their respective pH value. The nicotine benzoate exhibited the highest apparent permeability coefficient (Papp), and higher nicotine-to-benzoic acid ratios led to higher Papp values. The addition of flavors to e-liquid resulted in increased Papp values, with the most significant increment being observed in tobacco-flavored e-liquid. CONCLUSIONS: In summary, the transport capability of nicotine across the Calu-3 cell monolayer was influenced by the pH values of nicotine salts and flavor additives in e-liquids.

Central and peripheral actions of nicotine that influence blood glucose homeostasis and the development of diabetes.

Cigarette smoking has long been recognized as a risk factor for type 2 diabetes (T2D), although the precise causal mechanisms underlying this relationship remain poorly understood. Recent evidence suggests that nicotine, the primary reinforcing component in tobacco, may play a pivotal role in connecting cigarette smoking and T2D. Extensive research conducted in both humans and animals has demonstrated that nicotine can elevate blood glucose levels, disrupt glucose homeostasis, and induce insulin resistance. The review aims to elucidate the genetic variants of nicotinic acetylcholine receptors associated with diabetes risk and provide a comprehensive overview of the available data on the mechanisms through which nicotine influences blood glucose homeostasis and the development of diabetes. Here we emphasize the central and peripheral actions of nicotine on the release of glucoregulatory hormones, as well as its effects on glucose tolerance and insulin sensitivity. Notably, the central actions of nicotine within the brain, which encompass both insulin-dependent and independent mechanisms, are highlighted as potential targets for intervention strategies in diabetes management.

Dose-dependent action of cordycepin on the microbiome-gut-brain-adipose axis in mice exposed to stress.

The high risk for anxiety and depression among individuals with stress has become a growing concern globally. Stress-related mental disorders are often accompanied by symptoms of metabolic dysfunction. Cordycepin is a Chinese herbal medicine commonly used for its metabolism-enhancing effects. We aimed to investigate the dose-dependent effects of cordycepin on psycho-metabolic disorders induced by stress. Our behavioral tests revealed that 12.5 mg/kg cordycepin by oral gavage significantly attenuated the anxiety- and depression-like behaviors induced by stress in mice. At 25 mg/kg, cordycepin restored the reduced weight and cell size of adipose tissues caused by stress. Besides ameliorating the metabolic dysbiosis of gut microbiota due to stress, cordycepin significantly reduced the elevated contents of 5-hydroxyindoleacetic acid in the serum and prefrontal cortex at 12.5 mg/kg and reversed the decrease in adipose induced by stress at 25 mg/kg. Correlation analyses further revealed that 12.5 mg/kg cordycepin reversed stress-induced changes in the intestinal microbiome of NK4A214_group and decreased serum Myristic acid and PC(15:0/18:1(11Z)) and cytokines, such as IFN-γ and IL-1ß. 25 mg/kg cordycepin reversed stress-induced changes in the abundances of Prevoteaceae_UCG-001 and Desulfovibrio, increased serum L-alanine level, and decreased serum Inosine-5'-monophosphate level. Cordycepin thereby ameliorated the anxiety- and depression-like behaviors as well as disturbances in the adipose metabolism of mice exposed to stress. Overall, these findings offer evidence indicating that the prominent effects of cordycepin in the brain and adipose tissues are dose dependent, thus highlight the importance of evaluating the precise therapeutic effects of different cordycepin doses on psycho-metabolic diseases.

The Molecular Gut-Brain Axis in Early Brain Development.

Millions of nerves, immune factors, and hormones in the circulatory system connect the gut and the brain. In bidirectional communication, the gut microbiota play a crucial role in the gut-brain axis (GBA), wherein microbial metabolites of the gut microbiota regulate intestinal homeostasis, thereby influencing brain activity. Dynamic changes are observed in gut microbiota as well as during brain development. Altering the gut microbiota could serve as a therapeutic target for treating abnormalities associated with brain development. Neurophysiological development and immune regulatory disorders are affected by changes that occur in gut microbiota composition and function. The molecular aspects relevant to the GBA could help develop targeted therapies for neurodevelopmental diseases. Herein, we review the findings of recent studies on the role of the GBA in its underlying molecular mechanisms in the early stages of brain development. Furthermore, we discuss the bidirectional regulation of gut microbiota from mother to infant and the potential signaling pathways and roles of posttranscriptional modifications in brain functions. Our review summarizes the role of molecular GBA in early brain development and related disorders, providing cues for novel therapeutic targets.

Divergent neurocircuitry dissociates two components of the stress response: glucose mobilization and anxiety-like behavior.

Stress is a risk factor for emotion and energy metabolism disorders. However, the neurocircuitry mechanisms for emotion initiation and glucose mobilization underlying stress responses are unclear. Here we demonstrate that photoactivation of Gad2+ projection from the anterior bed nucleus of the stria terminalis (aBNST) to the arcuate nucleus (ARC) induces anxiety-like behavior as well as acute hyperglycemia. Photoinhibition of the circuit is anxiolytic and blocks hyperglycemia induced by restraint stress. Pharmacogenetic inhibition of the ARCGad2+→raphe obscurus nucleus (ROb) and photoactivation of the aBNSTGad2+→ARC circuits simultaneously leads to significant hypoglycemia and anxiety-like behavior. Pharmacogenetic inhibition of the ARCGad2+→nucleus of the solitary tract (NTS) whilst photoactivation of the aBNSTGad2+→ARC circuit only induces hyperglycemia. Our results reveal that the aBNSTGad2+→ARCGad2+→ROb circuit is recruited for the stress response of rapid glucose mobilization and the aBNSTGad2+→ARCGad2+→NTS circuit for behavioral symptoms of stress response. This study identifies a possible general strategy for neurocircuitry structural organization dealing with multiple organs involved in responses, with potential therapeutic targets for emotion and energy metabolism disorders underlying psychiatric disorders.

Serum metabolomic abnormalities in survivors of non-severe COVID-19.

Metabolic reprogramming is a distinctive characteristic of SARS-CoV-2 infection, which refers to metabolic changes in hosts triggered by viruses for their survival and spread. It is current urgent to understand the metabolic health status of COVID-19 survivors and its association with long-term health consequences of infection, especially for the predominant non-severe patients. Herein, we show systemic metabolic signatures of survivors of non-severe COVID-19 from Wuhan, China at six months after discharge using metabolomics approaches. The serum amino acids, organic acids, purine, fatty acids and lipid metabolism were still abnormal in the survivors, but the kynurenine pathway and the level of itaconic acid have returned to normal. These metabolic abnormalities are associated with liver injury, mental health, energy production, and inflammatory responses. Our findings identify and highlight the metabolic abnormalities in survivors of non-severe COVID-19, which provide information on biomarkers and therapeutic targets of infection and cues for post-hospital care and intervention strategies centered on metabolism reprogramming.

The roles of the circadian hormone melatonin in drug addiction.

Given the devastating social and health consequences of drug addiction and the limitations of current treatments, a new strategy is needed. Circadian system disruptions are frequently associated with drug addiction. Correcting abnormal circadian rhythms and improving sleep quality may thus be beneficial in the treatment of patients with drug addiction. Melatonin, an essential circadian hormone that modulates the biological clock, has anti-inflammatory, analgesic, anti-depressive, and neuroprotective effects via gut microbiota regulation and epigenetic modifications. It has attracted scientists' attention as a potential solution to drug abuse. This review summarized scientific evidence on the roles of melatonin in substance use disorders at the cellular, circuitry, and system levels, and discussed its potential applications as an intervention strategy for drug addiction.

Corrigendum: Menthol Flavor in E-Cigarette Vapor Modulates Social Behavior Correlated With Central and Peripheral Changes of Immunometabolic Signalings.

[This corrects the article DOI: 10.3389/fnmol.2022.800406.].

Menthol Flavor in E-Cigarette Vapor Modulates Social Behavior Correlated With Central and Peripheral Changes of Immunometabolic Signalings.

The use of electronic cigarette (e-cigarette) has been increasing dramatically worldwide. More than 8,000 flavors of e-cigarettes are currently marketed and menthol is one of the most popular flavor additives in the electronic nicotine delivery systems (ENDS). There is a controversy over the roles of e-cigarettes in social behavior, and little is known about the potential impacts of flavorings in the ENDS. In our study, we aimed to investigate the effects of menthol flavor in ENDS on the social behavior of long-term vapor-exposed mice with a daily intake limit, and the underlying immunometabolic changes in the central and peripheral systems. We found that the addition of menthol flavor in nicotine vapor enhanced the social activity compared with the nicotine alone. The dramatically reduced activation of cellular energy measured by adenosine 5' monophosphate-activated protein kinase (AMPK) signaling in the hippocampus were observed after the chronic exposure of menthol-flavored ENDS. Multiple sera cytokines including C5, TIMP-1, and CXCL13 were decreased accordingly as per their peripheral immunometabolic responses to menthol flavor in the nicotine vapor. The serum level of C5 was positively correlated with the alteration activity of the AMPK-ERK signaling in the hippocampus. Our current findings provide evidence for the enhancement of menthol flavor in ENDS on social functioning, which is correlated with the central and peripheral immunometabolic disruptions; this raises the vigilance of the cautious addition of various flavorings in e-cigarettes and the urgency of further investigations on the complex interplay and health effects of flavoring additives with nicotine in e-cigarettes.

Evaluation of the inhalation toxicity of arecoline benzoate aerosol in rats.

Arecoline is a pharmacologically active alkaloid isolated from Areca catechu. There are no published data available regarding the inhalation toxicity of arecoline in animals. This study aimed to evaluate the inhalation toxicity of arecoline in vitro and in vivo. For this purpose, arecoline benzoate (ABA) salt was prepared to stabilize arecoline in an aerosol. The MTT assay determined the half-maximal inhibitory concentration values of ABA and arecoline in A549 cell proliferation to be 832 and 412 µg/ml, respectively. The toxicity of acute and subacute inhalation in Sprague-Dawley rats was evaluated using the guidelines of the Organization for Economic Cooperation and Development. For acute inhalation, the median lethal concentration value of ABA solvent was >5175 mg/m3 . After the exposure and during the recovery period, no treatment-related clinical signs were observed. In the 28-Day inhalation toxicity test, daily nose-only exposure to 2510 mg/m3 aerosol of the ABA solvent contained 75 mg/m3 ABA for male rats and 375 mg/m3 ABA for female rats, which caused no observed adverse effects, except for the decreased body weight gain in male rats exposed to 375 mg/m3 ABA. In this study, the no observed adverse effect level (NOAEL) for the 28-day repeated dose inhalation of ABA aerosol was calculated to be around 13 mg/kg/day for male rats and 68.8 mg/kg/day for female rats, respectively.

Establishment and resilience of transplanted gut microbiota in aged mice.

The maintenance of healthy and resilient gut microbiota is critical for the life quality and healthspan of the elderly. Fecal microbiota transplantation (FMT) has been increasingly used to restore healthy gut microbiota. We systemically studied the establishment and resilience of transplanted microbiota after autologous versus heterologous FMT in aged recipients. Gut microbiota of aged mice (20 months old) failed to restore their original diversity and composition over 8 weeks via spontaneous recovery after antibiotics treatment; in contrast, FMT using either autologous or heterologous (2 months old from a different vendor) donors facilitated the recovery successfully, established donor-like microbiota states, and affected host gene expression profile. Furthermore, the transplanted microbiota established by heterologous FMT is not resilient during chemical-induced colonic inflammation, in contrast to that of autologous FMT. Our findings highlighted the need to monitor the long-term stability of transplanted gut microbiota and to perform multiple FMT when necessary.

Tibetan Medicines for the Treatment of Diabetic Nephropathy.

As an important part of the traditional Chinese medicine system, Tibetan medicine has its unique treatment methods for diabetes mellitus and its complications. Diabetic nephropathy (DN) is one of the most serious diabetic microvascular diseases. Tibetan medicine believes that the occurrence of DN is closely related to renal function changes, and it can be effectively prevented and treated by improving renal lesions. In this paper, we consult ancient books of Tibetan medicine and summarize the medicines that treat kidney disease in the Tibetan medicine system. The Chinese name, English name, and Latin name of these drugs were searched as keywords in the online database. Thirty-four drugs were found for the treatment of DN. The most commonly used were Amomum kravanh, Terminalia chebula, and Tribulus terrestris, and we introduced the traditional uses and modern pharmacological activities of these drugs. The results indicate that Tibetan medicines for kidney disease could be used as potential candidate drugs for DN; they would expand the range of medications for DN and provide a new idea for the treatment of DN.

Molecular motor protein KIF5C mediates structural plasticity and long-term memory by constraining local translation.

Synaptic structural plasticity, key to long-term memory storage, requires translation of localized RNAs delivered by long-distance transport from the neuronal cell body. Mechanisms and regulation of this system remain elusive. Here, we explore the roles of KIF5C and KIF3A, two members of kinesin superfamily of molecular motors (Kifs), and find that loss of function of either kinesin decreases dendritic arborization and spine density whereas gain of function of KIF5C enhances it. KIF5C function is a rate-determining component of local translation and is associated with ∼650 RNAs, including EIF3G, a regulator of translation initiation, and plasticity-associated RNAs. Loss of function of KIF5C in dorsal hippocampal CA1 neurons constrains both spatial and contextual fear memory, whereas gain of function specifically enhances spatial memory and extinction of contextual fear. KIF5C-mediated long-distance transport of local translation substrates proves a key mechanism underlying structural plasticity and memory.

Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration.

Alu retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of Alu RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether Alu cDNA is synthesized independently of genomic integration is unknown. Alu RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed Alu cDNA independently of retrotransposition. Alu RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. Alu reverse transcription can be initiated in the cytoplasm via self-priming of Alu RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493-0.770), thus identifying inhibitors of this Alu replication cycle shunt as potential therapies for a major cause of blindness.