Targeting tumor-associated macrophages with mannosylated nanotherapeutics delivering TLR7/8 agonist enhances cancer immunotherapy.

Tumor-associated macrophages (TAMs) constitute 50-80% of stromal cells in most solid tumors with high mortality and poor prognosis. Tumor-infiltrating dendritic cells (TIDCs) and TAMs are key components mediating immune responses within the tumor microenvironment (TME). Considering their refractory properties, simultaneous remodeling of TAMs and TIDCs is a potential strategy of boosting tumor immunity and restoring immunosurveillance. In this study, mannose-decorated poly(lactic-co-glycolic acid) nanoparticles loading with R848 (Man-pD-PLGA-NP@R848) were prepared to dually target TAMs and TIDCs for efficient tumor immunotherapy. The three-dimensional (3D) cell culture model can simulate tumor growth as influenced by the TME and its 3D structural arrangement. Consequently, cancer spheroids enriched with tumor-associated macrophages (TAMs) were fabricated to assess the therapeutic effectiveness of Man-pD-PLGA-NP@R848. In the TME, Man-pD-PLGA-NP@R848 targeted both TAMs and TIDCs in a mannose receptor-mediated manner. Subsequently, Man-pD-PLGA-NP@R848 released R848 to activate Toll-like receptors 7 and 8, following dual-reprograming of TIDCs and TAMs. Man-pD-PLGA-NP@R848 could uniquely reprogram TAMs into antitumoral phenotypes, decrease angiogenesis, reprogram the immunosuppressive TME from "cold tumor" into "hot tumor", with high CD4+ and CD8+ T cell infiltration, and consequently hinder tumor development in B16F10 tumor-bearing mice. Therefore, dual-reprograming of TIDCs and TAMs with the Man-pD-PLGA-NP@R848 is a promising cancer immunotherapy strategy.

Regulation of Betaine Homocysteine Methyltransferase by Liver Receptor Homolog-1 in the Methionine Cycle.

Betaine-homocysteine S-methyltransferase (BHMT) is one of the most abundant proteins in the liver and regulates homocysteine metabolism. However, the molecular mechanisms underlying Bhmt transcription have not yet been elucidated. This study aimed to assess the molecular mechanisms underlying Bhmt transcription and the effect of BHMT deficiency on metabolic functions in the liver mediated by liver receptor homolog-1 (LRH-1). During fasting, both Bhmt and Lrh-1 expression increased in the liver of Lrh-1f/f mice; however, Bhmt expression was decreased in LRH-1 liver specific knockout mice. Promoter activity analysis confirmed that LRH-1 binds to a specific site in the Bhmt promoter region. LRH-1 deficiency was associated with elevated production of reactive oxygen species (ROS), lipid peroxidation, and mitochondrial stress in hepatocytes, contributing to hepatic triglyceride (TG) accumulation. In conclusion, this study suggests that the absence of an LRH-1-mediated decrease in Bhmt expression promotes TG accumulation by increasing ROS levels and inducing mitochondrial stress. Therefore, LRH-1 deficiency not only leads to excess ROS production and mitochondrial stress in hepatocytes, but also disrupts the methionine cycle. Understanding these regulatory pathways may pave the way for novel therapeutic interventions against metabolic disorders associated with hepatic lipid accumulation.

Antioxidants and Mechanistic Insights for Managing Dry Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) severely affects central vision due to progressive macular degeneration and its staggering prevalence is rising globally, especially in the elderly population above 55 years. Increased oxidative stress with aging is considered an important contributor to AMD pathogenesis despite multifaceted risk factors including genetic predisposition and environmental agents. Wet AMD can be managed with routine intra-vitreal injection of angiogenesis inhibitors, but no satisfactory medicine has been approved for the successful management of the dry form. The toxic carbonyls due to photo-oxidative degradation of accumulated bisretinoids within lysosomes initiate a series of events including protein adduct formation, impaired autophagy flux, complement activation, and chronic inflammation, which is implicated in dry AMD. Therapy based on antioxidants has been extensively studied for its promising effect in reducing the impact of oxidative stress. This paper reviews the dry AMD pathogenesis, delineates the effectiveness of dietary and nutrition supplements in clinical studies, and explores pre-clinical studies of antioxidant molecules, extracts, and formulations with their mechanistic insights.

The novel psychoactive substance 25E-NBOMe induces reward-related behaviors via dopamine D1 receptor signaling in male rodents.

Novel psychoactive substances (NPSs) are new psychotropic drugs designed to evade substance regulatory policies. 25E-NBOMe (2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine) has recently been identified as an NPS, and its recreational misuse has been reported to be rapidly increasing. However, the psychopharmacological effects and mechanisms of 25E-NBOMe have not been studied. We examined the abuse potential of 25E-NBOMe using the conditioned place preference in male mice and self-administration paradigms in male rats. Additionally, immunoblot assay, enzyme-linked immunosorbent assay, and microdialysis were used to determine the molecular effects of 25E-NBOMe in the nucleus accumbens (NAc). Our data demonstrated that 25E-NBOMe induces conditioned place preference, and the dopaminergic signaling in the NAc mediates these. Following 25E-NBOMe administration, expression of dopamine transporter and dopamine D1 receptor (D1DR) were enhanced in the NAc of male mice, and NAc dopamine levels were reduced in both male mice and rats. Induction of intracellular dopaminergic pathways, DARPP32, and phosphorylation of CREB in the NAc of male mice was also observed. Significantly, pharmacological blockade of D1DR or chemogenetic inhibition of D1DR-expressing medium spiny neurons in the NAc attenuated 25E-NBOMe-induced conditioned place preference in male mice. We also examined the hallucinogenic properties of 25E-NBOMe using the head twitch response test in male mice and found that this behavior was mediated by serotonin 2A receptor activity. Our findings demonstrate that D1DR signaling may govern the addictive potential of 25E-NBOMe. Moreover, our study provides new insights into the potential mechanisms of substance use disorder and the improvement of controlled substance management.

Nanoparticle-based immunoengineering strategies for enhancing cancer immunotherapy.

Cancer immunotherapy is a groundbreaking strategy that has revolutionized the field of oncology compared to other therapeutic strategies, such as surgery, chemotherapy, or radiotherapy. However, cancer complexity, tumor heterogeneity, and immune escape have become the main hurdles to the clinical application of immunotherapy. Moreover, conventional immunotherapies cause many harmful side effects owing to hyperreactivity in patients, long treatment durations and expensive cost. Nanotechnology is considered a transformative approach that enhances the potency of immunotherapy by capitalizing on the superior physicochemical properties of nanocarriers, creating highly targeted tissue delivery systems. These advantageous features include a substantial specific surface area, which enhances the interaction with the immune system. In addition, the capability to finely modify surface chemistry enables the achievement of controlled and sustained release properties. These advances have significantly increased the potential of immunotherapy, making it more powerful than ever before. In this review, we introduce recent nanocarriers for application in cancer immunotherapy based on strategies that target different main immune cells, including T cells, dendritic cells, natural killer cells, and tumor-associated macrophages. We also provide an overview of the role and significance of nanotechnology in cancer immunotherapy.

Exploring new histone deacetylase 6 inhibitors and their effects on reversing the α-tubulin deacetylation and cell morphology changes caused by methamphetamine.

Indazole-based HDAC6 inhibitors with novel zinc-binding modifications were synthesized and evaluated to determine their potential to inhibit HDAC6. The analogs were subjected to a histone deacetylase (HDAC) enzyme assay, which led to identification of compounds 3a and 3b. Both compounds demonstrated higher potency and selectivity as HDAC6 inhibitors with IC50 values of 9.1 nM and 9.0 nM, respectively, and highlighted the importance of the hydroxamic acid moiety for binding to Zn2+ inside the catalytic pocket of HDAC enzymes. In the neuroblastoma SH-SY5Y cell line, both compounds efficiently acetylated α-tubulin but not histone H3 at a low concentration of 0.5 µM. Moreover, compounds 3a and 3b effectively reversed the deacetylation of α-tubulin caused by methamphetamine in the SH-SY5Y cell line, suggesting the potential usefulness of HDAC6 selective inhibition in restoring blood brain barrier integrity by reversing methamphetamine-induced deacetylation.

Designer Drug, 25D-NBOMe, Has Reinforcing and Rewarding Effects through Change of a Dopaminergic Neurochemical System.

2-(2,5-Dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)_ethanamine (25D-NBOMe), an analogue of the 2C family, is a newly synthesized psychoactive substance. It acts as an agonist at the 5-HT2A receptor and has a similar mechanism to that of NBOMe compounds. However, the pharmacological mechanism for its rewarding and reinforcing effects has not been revealed. In the present study, intravenous self-administration (IVSA) test and conditioned place preference (CPP) test were performed to investigate whether 25D-NBOMe has abuse potential. We also evaluated the effects of 25D-NBOMe on neurochemical changes using western blot analysis and microdialysis. The IVSA test revealed increased self-administration in 25D-NBOMe (0.03 mg/kg)-treated rats. In addition, the CPP test revealed rewarding effects in 25D-NBOMe (1 mg/kg)-treated mice. In the neurochemical studies, 25D-NBOMe treatment affected the expression of dopamine (DA) receptor D1 (DRD1), DA receptor D2 (DRD2), tyrosine hydroxylase, DA transporter (DAT), and phospho-DAT (p-DAT) in the nucleus accumbens (NAc). In addition, microdialysis revealed that treatment with progressively increasing doses (1, 3, and 10 mg/kg) of 25D-NBOMe increased the extracellular levels of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the rat NAc. Taken together, our results show the abuse potential and neurochemical changes related to addictive behavior after administration of 25D-NBOMe.

Alcohol perturbed locomotor behavior, metabolism, and pharmacokinetics of gamma-hydroxybutyric acid in rats.

Gamma-hydroxybutyric acid (GHB), both a metabolic precursor and product of gamma-aminobutyric acid (GABA), is a central nervous system depressant used for the treatment of narcolepsy-associated cataplexy and alcohol withdrawal. However, administration of GHB with alcohol (ethanol) is a major cause of hospitalizations related to GHB intoxication. In this study, we investigated locomotor behavior as well as metabolic and pharmacokinetic interactions following co-administration of GHB and ethanol in rats. The locomotor behavior of rats was evaluated following the intraperitoneal administration of GHB (sodium salt, 500 mg/kg) and/or ethanol (2 g/kg). Further, time-course urinary metabolic profiling of GHB and its biomarker metabolites glutamic acid, GABA, succinic acid, 2,4-dihydroxybutyric acid (OH-BA), 3,4-OH-BA, and glycolic acid as well as pharmacokinetic analysis were performed. GHB/ethanol co-administration significantly reduced locomotor activity, compared to the individual administration of GHB or ethanol. The urinary and plasma concentrations of GHB and other target compounds, except for 2,4-OH-BA, were significantly higher in the GHB/ethanol co-administration group than the group administered only GHB. The pharmacokinetic analysis results showed that the co-administration of GHB and ethanol significantly increased the half-life of GHB while the total clearance decreased. Moreover, a comparison of the metabolite-to-parent drug area under the curve ratios demonstrated that the metabolic pathways of GHB, such α- and ß-oxidation, were inhibited by ethanol. Consequently, the co-administration of GHB and ethanol aggravated the metabolism and elimination of GHB and enhanced its sedative effect. These findings will contribute to clinical interpretation of GHB intoxication.

Identification of Potential Biomarkers for Diagnosis of Patients with Methamphetamine Use Disorder.

The current method for diagnosing methamphetamine use disorder (MUD) relies on self-reports and interviews with psychiatrists, which lack scientific rigor. This highlights the need for novel biomarkers to accurately diagnose MUD. In this study, we identified transcriptome biomarkers using hair follicles and proposed a diagnostic model for monitoring the MUD treatment process. We performed RNA sequencing analysis on hair follicle cells from healthy controls and former and current MUD patients who had been detained in the past for illegal use of methamphetamine (MA). We selected candidate genes for monitoring MUD patients by performing multivariate analysis methods, such as PCA and PLS-DA, and PPI network analysis. We developed a two-stage diagnostic model using multivariate ROC analysis based on the PLS-DA method. We constructed a two-step prediction model for MUD diagnosis using multivariate ROC analysis, including 10 biomarkers. The first step model, which distinguishes non-recovered patients from others, showed very high accuracy (prediction accuracy, 98.7%). The second step model, which distinguishes almost-recovered patients from healthy controls, showed high accuracy (prediction accuracy, 81.3%). This study is the first report to use hair follicles of MUD patients and to develop a MUD prediction model based on transcriptomic biomarkers, which offers a potential solution to improve the accuracy of MUD diagnosis and may lead to the development of better pharmacological treatments for the disorder in the future.

A qualitative look at perception and experience of sodium reduction strategies in the food industry through focus groups and individual interviews.

The high incidence of sodium overconsumption in the general population has led sodium reduction in commercial food products to become a topic of importance in the food industry. In order to bridge the gap between sodium reduction understanding in the food industry and academia, focus groups and individual interviews of food industry professionals were conducted. Sodium reduction and influence from external entities such as federal regulations and consumer insight were prominent in the nutritional concerns of food industry professionals. A large variety of sodium reduction strategies were introduced with discussion on the many factors that contribute to their potential for success. Flavor modification methods were most prevalent in the discussion, with particular focus on potassium chloride and incorporating umami taste. Factors that frequently positively contributed to a strategy's success include maintaining functionality and/or important sensory attributes, inexpensive to implement, and being perceived as clean label. Conversely, factors that negatively affect success include adversely impacting flavor, being considered not clean label, and high costs of implementation. Foods important for future sodium reduction varied widely, although those were largely products with high sodium density. Future efforts toward reducing sodium overconsumption and sodium content in the food supply fell into three categories: consumer-focused, industry-focused, and research-focused. Of particular importance for future efforts included greater regulatory pressure and more consumer nutritional education. Findings suggest that future efforts to reduce the incidence of sodium overconsumption should be carried out through multiple avenues rather than focusing on the agency of consumers, the food industry, or research alone.

Interaction between γ-Hydroxybutyric Acid and Ethanol: A Review from Toxicokinetic and Toxicodynamic Perspectives.

Gamma-hydroxybutyric acid (GHB) is a potent, short-acting central nervous system depressant as well as an inhibitory neurotransmitter or neuromodulator derived from gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter. The sodium salt of GHB, sodium oxybate, has been used for the treatment of narcolepsy and cataplexy, whereas GHB was termed as a date rape drug or a club drug in the 1990s. Ethanol is the most co-ingested drug in acute GHB intoxication. In this review, the latest findings on the combined effects of GHB and ethanol are summarized from toxicokinetic and toxicodynamic perspectives. For this purpose, we mainly discussed the pharmacology and toxicology of GHB, GHB intoxication under alcohol consumption, clinical cases of the combined intoxication of GHB and ethanol, and previous studies on the toxicokinetic and toxicodynamic interactions between GHB and ethanol in humans, animals, and an in vitro model. The combined administration of GHB and ethanol enhanced sedation and cardiovascular dysfunction, probably by the additive action of GABA receptors, while toxicokinetic changes of GHB were not significant. The findings of this review will contribute to clinical and forensic interpretation related to GHB intoxication. Furthermore, this review highlights the significance of studies aiming to further understand the enhanced inhibitory effects of GHB induced by the co-ingestion of ethanol.

Characterizing the effect of sodium reduction and monosodium glutamate supplementation on white and multigrain breads.

Sodium overconsumption has become a serious health concern resulting in the Food and Drug Administration (FDA) publishing voluntary sodium reduction guidelines for a wide spectrum of packaged and processed foods. Reducing sodium through the removal of salt may decrease the palatability of foods, thus increasing the need for new approaches to prevent such palatability loss. The objective of this research was to characterize white and multigrain breads with either 43% or 60% reduction in sodium and with and without monosodium glutamate (MSG) using descriptive analysis methodology as well as to identify the drivers of liking for white and multigrain breads of varying sodium contents with and without MSG. Significant differences were identified in the attributes of salty taste and aftertaste, savory aftertaste, and chewy and firm textures in white bread and of salty taste and aftertaste, sweet taste, and density in multigrain bread. By regressing consumer test data of these breads onto their principal component analysis biplots, textural attributes and salty taste and aftertaste were identified as primary drivers of liking in white and multigrain breads. Flavor enhancers such as MSG show promise in mitigating palatability loss that occurs when the sodium content of bread is greatly reduced and thus provide a promising solution to produce breads with an improved nutritional profile. Future research on flavor enhancement in other food matrices would be valuable as well as in other bread and carbohydrate-based food categories. PRACTICAL APPLICATION: The findings of our study suggest that texture and a salty taste and aftertaste drive consumer liking of reduced-sodium white and multigrain breads and liking of breads could be improved with the addition of monosodium glutamate. Increasing the acceptance of reduced-sodium food products could help to improve the health of the American population by resulting in a reduced risk of hypertension and subsequently heart attacks and stroke.

Consumer acceptance of reduced sodium white and multigrain bread: Impact of flavor enhancement and ingredient information on sample liking.

Chronic consumption of sodium in quantities exceeding recommendations has led to sodium being designated as a nutrient of health concern for overconsumption. As a result of the prevalence of sodium overconsumption, the Food and Drug Administration (FDA) released voluntary sodium reduction goals for a wide variety of products on both short- and long-term timespans. As food palatability may decrease when sodium is reduced, flavor enhancers such as monosodium glutamate (MSG) may provide a promising solution to mitigate such palatability loss. The objective of this research was to investigate consumer acceptance of white and multigrain breads with either a 43% or 60% reduction in sodium content and with and without MSG as well as to investigate the influence of information on consumer acceptance of these breads under blind, informed, and informed with education conditions. Seventy-eight frequent bread consumers participated in the evaluations. A significant difference was evidenced across breads with different levels of sodium content and MSG status, although no difference was seen across the different evaluation conditions. Consumer segmentation found multiple consumer clusters showing different liking patterns of the bread treatments for both white and multigrain breads. Breads with sodium content set at the FDA's long-term goal with and without MSG were liked no differently in nearly all attributes evaluated than the full-sodium bread demonstrating the feasibility of producing acceptable reduced-sodium breads. Future research characterizing the predominant sensory attributes of full-sodium and reduced-sodium breads with and without MSG would be valuable for identifying the drivers of liking in such products. Practical Application: The findings of our study suggest that consumer liking of reduced sodium white and multigrain breads could be improved with the addition of monosodium glutamate. Increasing the acceptance of reduced sodium food products could help to reduce the risk of hypertension and subsequently heart attacks and stroke for the American population.

Uncovering transcriptomic biomarkers for enhanced diagnosis of methamphetamine use disorder: a comprehensive review.

Introduction: Methamphetamine use disorder (MUD) is a chronic relapsing disorder characterized by compulsive Methamphetamine (MA) use despite its detrimental effects on physical, psychological, and social well-being. The development of MUD is a complex process that involves the interplay of genetic, epigenetic, and environmental factors. The treatment of MUD remains a significant challenge, with no FDA-approved pharmacotherapies currently available. Current diagnostic criteria for MUD rely primarily on self-reporting and behavioral assessments, which have inherent limitations owing to their subjective nature. This lack of objective biomarkers and unidimensional approaches may not fully capture the unique features and consequences of MA addiction. Methods: We performed a literature search for this review using the Boolean search in the PubMed database. Results: This review explores existing technologies for identifying transcriptomic biomarkers for MUD diagnosis. We examined non-invasive tissues and scrutinized transcriptomic biomarkers relevant to MUD. Additionally, we investigated transcriptomic biomarkers identified for diagnosing, predicting, and monitoring MUD in non-invasive tissues. Discussion: Developing and validating non-invasive MUD biomarkers could address these limitations, foster more precise and reliable diagnostic approaches, and ultimately enhance the quality of care for individuals with MA addiction.

Striatal miR-183-5p inhibits methamphetamine-induced locomotion by regulating glucocorticoid receptor signaling.

MicroRNA (miRNA)-mediated striatal gene regulation may play an important role in methamphetamine (METH) addiction. This study aimed to identify changes in novel miRNAs and their target genes during METH self-administration and investigate their roles in METH-induced locomotion. RNA sequencing analysis revealed that mir-183-5p was upregulated in the striatum of METH self-administered rats, and target gene prediction revealed that the glucocorticoid receptor (GR) gene, Nr3c1, was a potential target gene for mir-183-5p. We confirmed that single and repeated METH administrations increased METH-induced locomotion and plasma corticosterone levels in rats. Additionally, increased miR-185-5p expression and decreased GR gene expression were observed only in the repeated-METH-injection group but not in the single-injection group. We then investigated the effects of miR-183-5p on METH-induced locomotion using a miR-183-5p mimic and inhibitor. Injection of a mir-183-5p mimic in the striatum of rats attenuated METH-induced locomotion, whereas injection of a miR-183-5p inhibitor enhanced the locomotor activity in METH-administered rats. Furthermore, the miR-183-5p mimic reduced the phosphorylation of tyrosine hydroxylase (TH) whereas the inhibitor increased it. Taken together, these results indicate that repeated METH injections increase striatal miR-183-5p expression and regulate METH-induced locomotion by regulating GR expression in rats, thereby suggesting a potential role of miR-183-5p as a novel regulator of METH-induced locomotion.

Characterization of Sugar Reduction in Model Confectionary Gels Using Descriptive Analysis.

Successful sugar reduction in food products mimics the sensory and functional properties of the full sugar counterpart. The initial step of sugar reduction is to determine how the absence of sugar affects these properties. Descriptive analysis was conducted on four gel types (gelatin, ι-carrageenan, κ-carrageenan, and konjac glucomannan) and a range of sugar concentrations from 0-20% w/v to create a sensory profile of model confectionary gels for comparison to instrumental texture profile analysis data. The sensory descriptive data were analyzed using analysis of variance and principal component analysis. Correlation analysis, cluster analysis, and partial least squares regression (PLS-R) were used to compare and correlate sensory and instrumental data. Regardless of sugar concentration, sensory analysis primarily clustered samples by gelling agent type, such as in the case of konjac glucomannan consistently being characterized as chewy. Cohesion and gumminess were correlated highly with melt-in-mouth and a jiggly texture, while adhesion and fracturability were negatively correlated. In the PLS-R samples biplot, gelatin and iota carrageenan samples were located near these attributes indicating their aptness as descriptors. In conclusion, descriptive analysis provided a more discriminating method for characterizing model confectionary gels.

Variations in consumer acceptance, sensory engagement and method practicality across three remote consumer-testing modalities.

In the context of the COVID-19 pandemic, it has become challenging for sensory scientists to conduct in-person sensory tests, particularly large central location tests. Sensory literature comparing central location and home use tests shows no clear consensus about how each methodology affects sample ratings and panelist engagement. Research on instructional delivery suggests that the most effective method of increasing engagement involves interactive video conferencing. The objective of this study was to compare three methods of remote consumer testing regarding sample acceptance, sensory engagement, and method practicality. Eighty-four participants rated five chocolate-chip cookie products on a 9-pt hedonic scale in each of three methods: 1) a live (synchronous) Zoom session, 2) an asynchronous video-guided session, and 3) a fully written protocol session. Results showed no significant differences in sample liking pattern across the methods used. Engagement scores approached the limit of significance for the Active Involvement dimension, indicating panelists were least likely to feel distracted, zoned out or lose interest in the written protocol method. There were no significant differences in the time spent on the test by the panelists across the three methods. Asynchronous methods showed to be most suitable in terms of the convenience of the time of day at which the tests were completed, but showed no significant differences in other aspects of method practicality. Overall, a written protocol method of remote consumer testing is recommended, as it is less time-consuming for researchers while providing similar acceptance and engagement as other methods.

Methamphetamine induced neurotoxic diseases, molecular mechanism, and current treatment strategies.

Methamphetamine (MA) is a extremely addictive psychostimulant drug with a significant abuse potential. Long-term MA exposure can induce neurotoxic effects through oxidative stress, mitochondrial functional impairment, endoplasmic reticulum stress, the activation of astrocytes and microglial cells, axonal transport barriers, autophagy, and apoptosis. However, the molecular and cellular mechanisms underlying MA-induced neurotoxicity remain unclear. MA abuse increases the chances of developing neurotoxic conditions such as Parkinson's disease (PD), Alzheimer's disease (AD) and other neurotoxic diseases. MA increases the risk of PD by increasing the expression of alpha-synuclein (ASYN). Furthermore, MA abuse is linked to high chances of developing AD and subsequent neurodegeneration due to biological variations in the brain region or genetic and epigenetic variations. To date, there is no Food and Drug Administration (FDA)-approved therapy for MA-induced neurotoxicity, although many studies are being conducted to develop effective therapeutic strategies. Most current studies are now focused on developing therapies to diminish the neurotoxic effects of MA, based on the underlying mechanism of neurotoxicity. This review article highlights current research on several therapeutic techniques targeting multiple pathways to reduce the neurotoxic effects of MA in the brain, as well as the putative mechanism of MA-induced neurotoxicity.

Mepirapim, a Novel Synthetic Cannabinoid, Induces Addiction-Related Behaviors through Neurochemical Maladaptation in the Brain of Rodents.

Mepirapim is a synthetic cannabinoid that has recently been abused for recreational purposes. Although serious side effects have been reported from users, the dangerous pharmacological effects of Mepirapim have not been scientifically demonstrated. In this study, we investigated the addictive potential of Mepirapim through an intravenous self-administration test and a conditioned place preference test in rodents. Moreover, to determine whether the pharmacological effects of Mepirapim are mediated by cannabinoid receptors, we investigated whether Mepirapim treatment induces cannabinoid tetrad symptoms in mice. Lastly, to identify Mepirapim induced neurochemical maladaptation in the brains of mice, we performed microdialysis, western blots and neurotransmitter enzyme-linked immunosorbent assays. In the results, Mepirapim supported the maintenance of intravenous self-administration and the development of conditioned place preference. As a molecular mechanism of Mepirapim addiction, we identified a decrease in GABAeric signalling and an increase in dopaminergic signalling in the brain reward circuit. Finally, by confirming the Mepirapim-induced expression of cannabinoid tetrad symptoms, we confirmed that Mepirapim acts pharmacologically through cannabinoid receptor one. Taken together, we found that Mepirapim induces addiction-related behaviours through neurochemical maladaptation in the brain. On the basis of these findings, we propose the strict regulation of recreational abuse of Mepirapim.

Urinary Profile of Endogenous Gamma-Hydroxybutyric Acid and its Biomarker Metabolites in Healthy Korean Females: Determination of Age-Dependent and Intra-Individual Variability and Identification of Metabolites Correlated With Gamma-Hydroxybutyric Acid.

Gamma-hydroxybutyric acid (GHB), used as a therapeutic and an illegal anesthetic, is a human neurotransmitter produced during gamma-aminobutyric acid (GABA) biosynthesis and metabolism. Potential biomarker metabolites of GHB intoxication have been identified previously; however, reference concentrations have not been set due to the lack of clinical study data. Urinary profiling of endogenous GHB and its biomarker metabolites in urine samples (n = 472) of 206 healthy females was performed based on differences in age and time of sample collection using liquid chromatography-tandem mass spectrometry following validation studies. The unadjusted and creatinine-adjusted urinary concentrations ranges were obtained after urinary profiling. The creatinine-adjusted concentrations of glutamic and succinic acids and succinylcarnitine significantly increased, whereas that of glycolic acid significantly decreased with advancing age. Significant inter-day variation of GABA concentration and intra-day variation of 3,4-dihydroxybutyric acid and succinylcarnitine concentrations were observed. The urinary concentrations of 2,4-dihydroxybutyric acid, succinic acid, and 3,4-dihydroxybutyric acid showed the highest correlation with that of GHB. Data from this study suggest population reference limits to facilitate clinical and forensic decisions related to GHB intoxication and could be useful for identification of biomarkers following comparison with urinary profiles of GHB-administered populations.