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Highlights • 25D-NBOMe and 25C-NBOMe prolonged QT intervals. • 25D-NBOMe inhibited potassium channels in the hERG assay. • 25D-NBOMe and 25C-NBOMe down-regulated PAK1. Abstract Two emerging psychoactive substances, 2-(2,5-dimethoxy-4-methylphenyl)- N -(2-methoxybenzyl)ethanamine (25D-NBOMe) and N -(2-methoxybenzyl)-2,5-dimethoxy-4-chlorophenethylamine (25C-NBOMe), are being abused, leading to fatal and non-fatal intoxications. However, most of their adverse effects have been reported anecdotally. In the present study, cardiotoxicity was evaluated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, rat electrocardiography (ECG), and human ether-a-go-go-related gene (hERG) assay. Expression levels of p21 (CDC42/RAC)-activated kinase 1 (PAK1), one of known biomarkers for cardiotoxicity, were also analyzed. Both 25D-NBOMe and 25C-NBOMe at 100 μM reduced cell viability in MTT assay. At 2.0 mg/kg and 0.75 mg/kg, they prolonged QT intervals in rat ECG. PAK1 was down-regulated by treatment with these two test compounds. Furthermore, potassium channels were inhibited by 25D-NBOMe treatment in hERG assay. Taken together, these results suggest that both 25D-NBOMe and 25C-NBOMe have potential cardiotoxicity, especially regarding cardiac rhythm. Further studies are needed to confirm the relationship between PAK1 down-regulation and cardiotoxicity. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic, autoimmune and neurodegenerative disease in which demyelination sporadically and repeatedly occurs in the central nervous system (CNS). The activity of nuclear factor kappa B (NF-κB), a family of transcription factors, was increased in the cerebrospinal fluid (CSF) and/or the serum and brain and/or spinal cord of MS patients than in a healthy donors. In our study, we investigated whether piperlongumine (PL), which is known to have inhibitory effect on activity of NF-κB, can alleviate an experimental autoimmune encephalomyelitis (EAE). The mice were immunized with myelin oligodendrocyte glycoprotein 35–55 (MOG 35–55 ), and then we injected PL (1.5 mg/kg/day or 3.0 mg/kg/day) into the mice intraperitoneally on every second day from days 2 to 28. For in vitro study, we treated PL (0.5, 1 and 2.5 μM) to RAW 264.7 and Jurkat cells with each stimulator. We observed that the paralytic severity and neuropathology of EAE in PL-treated group were decreased compared with the EAE group. PL showed a suppressed effect on demyelination, immune cells infiltration, astrocytes/microglials activation, level of inflammatory cytokines and proteins as well as NF-κB activity. Production of inflammatory cytokines and proteins as well as translocation of NF-κB into nucleus by treatment stimulators in RAW 264.7 and Jurkat cells were reduced by PL. Moreover, treatment of NF-κB inhibitor further inhibited production of inflammatory cytokines and proteins. These results suggest that PL can mitigate MOG-induced EAE symptoms and activation of macrophages and T cells by inhibiting NF-κB signaling. Therefore, PL could be useful for the treatment for MS. [ABSTRACT FROM AUTHOR]

Methamphetamine (METH) is a psychomotor stimulant that produces hyperlocomotion in rodents. l-tetrahydropalmatine (l-THP) is an active ingredient found in Corydalis ternata which has been used as a traditional herbal preparation in Asian countries for centuries, however, the effect of l-THP on METH-induced phenotypes largely unknown. In this study, to evaluate the effect of l-THP on METH-induced psychotropic effects, rats were pretreated with l-THP (10 and 15 mg/kg) before acute METH injection, following which the total distance the rats moved in an hour was measured. To clarify a possible mechanism underlying the effect of l-THP on METH-induced behavioral changes, dopamine receptor mRNA expression levels in the striatum of the rats was measured following the locomotor activity study. In addition, the effect of l-THP (10 and 15 mg/kg) on serotonergic (5-HTergic) neuronal pathway activation was studied by measurement of 5-HT (80 µg/10 µl/mouse)-induced head twitch response (HTR) in mice. l-THP administration significantly inhibited both hyperlocomotion in rats and HTR in mice. l-THP inhibited climbing behavior-induced by dopaminergic (DAergic) neuronal activation in mice. Furthermore, l-THP attenuated the decrease in dopamine D3 receptor mRNA expression levels in the striatum of the rats induced by METH. These results suggest that l-THP can ameliorate behavioral phenotype induced by METH through regulation of 5-HT neuronal activity and dopamine D3 receptor expression. [ABSTRACT FROM AUTHOR]

Abstract: Methamphetamine is a psychomotor stimulant that produces hyperlocomotion in rodents. Limonene (a cyclic terpene from citrus essential oils) has been reported to induce sedative effects. In this study, we demonstrated that limonene administration significantly inhibited serotonin (5-hydroxytryptamine, 5-HT)-induced head twitch response in mice. In rats, pretreatment with limonene decreased hyperlocomotion induced by methamphetamine injection. In addition, limonene reversed the increase in dopamine levels in the nucleus accumbens of rats given methamphetamine. These results suggest that limonene may inhibit stimulant-induced behavioral changes via regulating dopamine levels and 5-HT receptor function. [Copyright &y& Elsevier]

Neuronal Per Arnt Sim domain protein 4 (NPAS4), a brainspecific basic helix-loop-helix transcription factor, has recently been shown to regulate the development of the GABAergic inhibitory synapses and transcription program for contextual memory formation in the hippocampus. We previously reported that chronic social isolation or restriction stress in mice resulted in an impairment in memory and emotional behavior, which was associated with a decrease in Npas4 mRNA levels. In this study, we investigated the role of NPAS4 in neuronal function in vitro and in vivo. Differentiation medium-induced neurite outgrowth was inhibited in Npas4 knockdown Neuro2a cells, whereas overexpression of NPAS4 accelerated the neurite outgrowth in Neuro2a cells. Furthermore, depolarization-induced neurite outgrowth was abolished in Npas4 KO hippocampal neurons. NPAS4 overexpression increased cyclin-dependent kinase 5 (CDK5)-dependent synapsin I phosphorylation in Neuro2a cells and primary cultured hippocampal neurons. A CDK5 inhibitor, roscovitine, inhibited the neurite outgrowth and the increase in phosphorylated synapsin I (p-SYN I) levels in Npas4-overexpressed Neuro2a cells. Interaction of NPAS4 with promoters of Cdk5 and NeuN genes was demonstrated by a chromatin immunoprecipitation assay. In an in vivo study, pentylenetetrazole- induced convulsions in mice resulted in an increase in NPAS4 and p-SYN I levels in the prefrontal cortex of wild-type mice, although no changes in p-SYN I levels were observed in Npas4 knock-out mice. These results suggest that NPAS4 plays an important role in the structural and functional plasticity of neurons. [ABSTRACT FROM AUTHOR]

Background: Limonene, a common terpene found in citrus fruits, is assumed to reduce stress and mood disorders. Dopamine and γ-aminobutyric acid (GABA) have been reported to play an important role in modulating anxiety in different parts of the brain.Hypothesis/purpose: Herein, we report the anxiolytic activity of limonene. In addition, we identified a possible mechanism underlying the effect of limonene on DAergic and GABAergic neurotransmission.Study Design: In this study, mice were injected with saline in the control group and limonene in the test group before behavioral analysis. We performed immunoblotting and high-performance liquid chromatography (HPLC) analysis after the behavioral study.Results: The limonene treated group showed increased locomotor activity and open-arm preference in the elevated plus maze experiment. Limonene treatment increased the expression of both tyrosine hydroxylase and GAD-67 proteins and significantly upregulated dopamine levels in the striatum. Furthermore, tissue dopamine levels were increased in the striatum of mice following limonene treatment, and depolarization-induced GABA release was enhanced by limonene pre-treatment in PC-12 cells. Interestingly, limonene-induced anxiolytic activity and GABA release augmentation were blocked by an adenosine A2A receptor (A2AR) antagonist.Conclusion: Our results suggest that limonene inhibits anxiety-related behavior through A2A receptor-mediated regulation of DAergic and GABAergic neuronal activity. [ABSTRACT FROM AUTHOR]

Chitinase 3-like-1 protein (CHI3L1) is involved in various infectious diseases, especially sepsis. Aberrant CHI3L1 expression potentially plays a critical role in chronic inflammation because a considerable number of macrophages are associated with immune/inflammatory diseases. In this study, we examined the effect of CHI3L1 on hepatic sepsis injury using a lipopolysaccharide (LPS)-induced model. LPS-treated CHI3L1 knockout (KO) mice exhibited a higher survival rate than LPS-treated CHI3L1 wild-type (WT) mice. In addition, hepatic injury-related enzyme levels (aspartate transaminase, alanine transaminase, and lactate dehydrogenase) decreased in CHI3L1 KO mice sera, suggesting attenuated LPS-induced septic liver damage in CHI3L1 KO mice. A greater reduction in the mRNA and protein expressions of M2 polarization markers, such as MRC1, ARG1, IL-10, and IL-4, was observed in LPS-induced CHI3L1 KO mice livers than in LPS-induced WT mice livers. Nonetheless, no change in the mRNA and protein expressions of M1 polarization markers, such as INOS, CD86, TNF-α, and IL6, was noted in LPS-induced CHI3L1 KO mice livers compared with those in LPS-induced WT and KO mice. Similar to the in vivo scenario, liver CHI3L1 depletion in LPS-treated HEP3B cells significantly decreased M2 polarization marker protein expression. However, M1 polarization marker protein expression did not differ significantly. These results suggest that CHI3L1 depletion decreases M2 macrophage polarization, and this effect is potentially associated with the alleviation of liver sepsis in CHI3L1 KO mice. [Display omitted] • CHI3L1 is a member of the family of mammalian chitinase-like proteins and has a role in cell proliferation, differentiation, inflammation, and immune responses. • The alveolar macrophages exposed to recombinant CHI3L1 produced higher levels of proinflammatory mediators, but silencing CHI3L1 decreased the secretion of pro-inflammatory molecules by macrophages • The CHI3L1 may play a role in chemokine and cytokine production in macrophages, which contributes to tissue injury • The macrophage polarization plays an important role in the development of liver diseases. [ABSTRACT FROM AUTHOR]

• Genetic depletion of GPx-1 potentiates cocaine-induced behavioral sensitization. • Signaling of σ-1 receptor-ERK-oxidative burden mediates the behavioral sensitization. • GPx-1 gene inhibits this signaling, and induces Nrf-2-related GSH system. We demonstrated that the gene of glutathione peroxidase-1 (GPx-1), a major antioxidant enzyme, is a potential protectant against the neurotoxicity and conditioned place preference induced by cocaine. Because the sigma (σ)-1 receptor is implicated in cocaine-induced drug dependence, we investigated whether the GPx-1 gene modulates the σ-1 receptor in the behavioral sensitization induced by cocaine. Cocaine-induced behavioral sensitization was more pronounced in GPx-1 knockout (KO) than wild-type (WT) mice and was less pronounced in GPx-1 overexpressing transgenic (GPx-1 TG) than non-TG mice. Cocaine treatment significantly enhanced the oxidative burden and reduced the GSH levels in the striatum of WT, GPx-1 KO, and non-TG mice but not in that of GPx-1 TG mice. In addition, cocaine significantly increased the nuclear translocation, its DNA binding activity of nuclear factor erythroid-2-related factor 2 (Nrf2) as well as the mRNA expression of γ-glutamylcysteine (GCL). The genetic depletion of GPx-1 inhibited the Nrf2-related glutathione system, whereas the genetic overexpression of GPx-1 activated this system against behavioral sensitization. BD1047, a σ-1 receptor antagonist, and U0126, an ERK inhibitor significantly induced the Nrf2-related antioxidant potential against behavioral sensitization. Unlike BD1047, U0126 did not affect the cocaine-induced σ-1 receptor immunoreactivity, suggesting that the σ-1 receptor is an upstream molecule for ERK signaling. Importantly, BD1047 and U0126 failed to affect the σ-1 receptor immunoreactivity and ERK phosphorylation induced by cocaine in GPx-1 TG mice. Our results suggest that GPx-1 is a critical mediator for the attenuation of cocaine-induced behavioral sensitization via modulating σ-1 receptor-mediated ERK activation by the induction of the Nrf2-related system. [ABSTRACT FROM AUTHOR]

• The ethanol extract of Magnolia obovata leaf attenuate anxiety-like behavior in mice. • The ethanol extract of M. obovata leaf inhibits neuroinflammation in vivo and in vitro. • The ethanol extract of M. obovata leaf anxiolytic effect through the GABA A receptor. Recently, there have been studies that examined the relationship between neuroinflammation and anxiety disorder. Herein, we investigated the anxiolytic effect of a well-studied medicinal plant with anti-inflammatory properties, Magnolia obovata , by conducting cellular and animal studies. At the cellular level, the ethanol extract of M. obovata leaves demonstrated inhibitory effects on the production of nitric oxide and inflammatory cytokines and proteins in cultured BV-2 cells. The extract also enhanced GABA-benzodiazepine receptor activity by increasing chloride ion influx in primary cultured neuronal cells. We also examined the anxiolytic effect of the extract in imprinting control region male mice by conducting several behavioral tests. The mice were administered daily oral dose of M. obovata extract (25 mg/kg and 50 mg/kg) for 2 weeks. The extract increased the number of entries and time spent in open arms in the elevated plus maze test and decreased locomotor activity in the spontaneous locomotor activity test, thus implying that the extract ameliorated anxiety levels in mice. Furthermore, we found that the extract inhibited the expression of inflammatory proteins and cytokines and enhanced the expression of GABA-benzodiazepine receptor. These results suggest that the ethanol extract of M. obovata leaves may have an anxiolytic effect through enhancement of the GABAergic system and anti-neuroinflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Intracranial self-stimulation (ICSS) of the medial forebrain bundle in mice is an experimental model use to assess the relative potential of reward-seeking behaviors. Here, we used the ICSS model to evaluate the abuse potential of 18 abused drugs: 3-Fluoroethamphetamine (3-FEA); methylphenidate; cocaine; dextroamphetamine; alpha-Pyrrolidinobutyrophenone (α-PBT); 4'-Fluoro-4-methylaminorex (4-FPO); methamphetamine; larocaine; phentermine; paramethoxymethamphetamine (PMMA); phendimetrazine; N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide (AKB-48); Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (CB-13); 4-Ethylnaphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-210); Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018); N-(ortho-methoxybenzyl)-4-ethylamphetamine (4-EA-NBOMe); N-[(2-Methoxyphenyl)methyl]-N-methyl-1-(4-methylphenyl)propan-2-amine (4-MMA-NBOMe); and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine (4-MeO-PCP). We determined dopamine transporter (DAT) availability in the medial prefrontal cortex (mPFC), striatum, and nucleus accumbens (NAc) after drug treatment. DAT availability in the mPFC and NAc significantly correlated with the ICSS threshold after drug treatment. Extracellular dopamine and calcium levels in PC-12 cells were measured following drug treatment. After drug treatment, Spearman rank and Pearson correlation analyses showed a significant difference between the extracellular dopamine level and the ICSS threshold. After drug treatment, Spearman rank correlation analysis showed a significant correlation between Ca2+ signaling and the ICSS threshold. A positive correlation exists between the ICSS threshold and DAT availability in the mPFC and NAc provoked by abused drugs. The relative potential of drug-induced reward-seeking behavior may be related to DAT availability-mediated extracellular dopamine levels in the mPFC and NAc. ● Dependence potential induced by abuse drugs with ICSS. ● Correlation between DAT availability and ICSS threshold in mice. ● Drugs induced facilitation of ICSS via altering DAT function in mPFC and NAc. [ABSTRACT FROM AUTHOR]

Ketamine is a widely used anesthetic with N-methyl- D -aspartate (NMDA) receptor antagonism. Exposure to ketamine and NMDA receptor antagonists may induce psychosis. However, the mechanism underlying the effects of ketamine on the immature brain remains unclear. In this study, NMDA receptor antagonists, ketamine and methoxetamine, were administered to pregnant F344 rats (E17). These regimens induce psychosis-like behaviors in the offspring, such as hyperlocomotion induced by MK-801, a non-competitive NMDA receptor antagonist. We also observed that prepulse inhibition (PPI) was significantly reduced. Interestingly, ketamine administration increased the arginine vasopressin receptor 1A (Avpr1a) expression levels in the striatum of offspring with abnormal behaviors. Methoxetamine, another NMDA receptor antagonist, also showed similar results. In addition, we demonstrated a viral vector-induced Avpr1a overexpression in the striatum-inhibited PPI. In the striatum of offspring, ketamine or methoxetamine treatment increased glutamate decarboxylase 67 (GAD67) and δ-aminobutyric acid (GABA) levels. These results show that prenatal NMDA receptor antagonist treatment induces GABAergic neuronal dysfunction and abnormalities in sensorimotor gating via regulating Avpr1a expression in the striatum. [Display omitted] [ABSTRACT FROM AUTHOR]

Although 5-(2-aminopropyl)benzofuran (5-APB) and 7-bromo-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (phenazepam) are being used as recreational drugs, research on their dependence liability or mechanisms of action is lacking. The present study aimed to evaluate the behavioral effects and dependence liability of these drugs using conditioned place preference and self-administration paradigms in rodents. Additionally, biochemical techniques were used to assess the substance-induced alterations in synaptosome-released dopamine. While both of the tested substances elicited increases in conditioned place preference and dopamine, neither of them facilitated self-administration, suggesting that 5-APB and phenazepam have rewarding effects, rather than reinforcing effects. [ABSTRACT FROM AUTHOR]

The abuse of alkyl nitrites is common among adolescents and young adults worldwide. However, the information regarding the effects of alkyl nitrites on the central nervous system and the associated psychological abuse potential is scarce. The abuse potential of 3 representative alkyl nitrites – isobutyl nitrite, isoamyl nitrite, and butyl nitrite – was evaluated in mice using conditioned place preference tests with an unbiased method. The dopamine levels released by synaptosomes extracted from the striatal region were measured using high performance liquid chromatography. Mice treated with the test substances (50 mg/kg, i.p.) exhibited a significantly increased drug-paired place preference. Moreover, greater levels of dopamine were released by striatal region synaptosomes in response to isobutyl nitrite treatment in mice. Thus, our findings suggest that alkyl nitrites could lead to psychological dependence and dopaminergic effects. Furthermore, these results provide scientific evidence to support the regulation of alkyl nitrites as psychoactive substances in the future. [ABSTRACT FROM AUTHOR]

Although alkyl nitrites are used as recreational drugs, there is only little research data regarding their effects on the central nervous system including their neurotoxicity. This study investigated the neurotoxicity of three representative alkyl nitrites (isobutyl nitrite, isoamyl nitrite, and butyl nitrite), and whether it affected learning/memory function and motor coordination in rodents. Morris water maze test was performed in mice after administrating the mice with varying doses of the substances in two different injection schedules of memory acquisition and memory retention. A rota-rod test was then performed in rats. All tested alkyl nitrites lowered the rodents’ capacity for learning and memory, as assessed by both the acquisition and retention tests. The results of the rota-rod test showed that isobutyl nitrite in particular impaired motor coordination in chronically treated rats. The mice chronically injected with isoamyl nitrite also showed impaired function, while butyl nitrite had no significant effect. The results of the water maze test suggest that alkyl nitrites may impair learning and memory. Additionally, isoamyl nitrite affected the rodents’ motor coordination ability. Collectively, our findings suggest that alkyl nitrites may induce neurotoxicity, especially on the aspect of learning and memory function. [ABSTRACT FROM AUTHOR]

Highlights: [•] We examined the effects of saikosaponin A (SSA) on self-administration maintained by intravenous cocaine in rats. [•] SSA dose-dependently reduced cocaine responding in rats. [•] This SSA's effect was abolished by pretreatment with the GABA(B) antagonist SCH 50911, but not the GABA(A) antagonist bicuculline. [ABSTRACT FROM AUTHOR]

Dissociative-based new psychoactive substances (NPSs) are increasingly available through the Internet, and public health problems related to the recreational use of these substances have been increasing globally. Two such NPSs are deschloroketamine and diphenidine, which are primarily used recreationally as ketamine substitutes. However, there is little scientific evidence to describe the dependence liability of NPSs. This study aimed to evaluate the dependence liability of deschloroketamine and diphenidine via animal behavioral experiments. We evaluated the rewarding and reinforcing effects of these NPSs using the conditioned place preference (CPP) and the self-administration (SA) paradigms in mice. Psychomotor effects and behavioral features of these compounds were assessed by quantifying locomotor activity, stereotypic movements, and dopaminergic neurotransmission. Both deschloroketamine (10 mg/kg) and diphenidine (10–60 mg/kg) produced increased locomotor activation and stereotypy that were similar to the effects of ketamine (10 mg/kg). Both deschloroketamine (10 mg/kg) and diphenidine (10, 20 mg/kg) increased the animals' preference for the drug-paired compartment in the CPP testing. In the SA testing, deschloroketamine (1 mg/kg/infusion) increased the number of active lever presses and the number of infusions received, whereas diphenidine administration (1, 2 mg/kg/infusion) did not alter either of these. Furthermore, both deschloroketamine and diphenidine increased dopamine levels in PC-12 cells. Collectively, the data suggest that deschloroketamine may have both rewarding and reinforcing effects, whereas diphenidine only induced rewarding effect. • We evaluated the abuse liabilities of DCK and DPH. • Drug-induced psychomotor and dopaminergic effects were compared with ketamine. • Both DCK and DPH increased psychomotor activity, similar to ketamine. • DCK and DPH modulated dopamine levels in PC-12 cells. • Both DCK and DPH have rewarding and/or reinforcing effects in mice. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we investigated the effects of saikosaponin A (SSA), a major compound of Bupleurum falcatum L., on morphine self-administration behavior. Male Sprague–Dawley rats were trained to self-administer intravenous morphine (0.1mg/kg per injection over 5s) during daily 1-h sessions under a fixed-ratio 1 schedule. Rats were pretreated with SSA (0.25, 0.5, 1.0mg/kg) by intraperitoneal injection 30min prior to the start of the test session. Results demonstrated that pretreatment with SSA reduced morphine-maintained responding dose-dependently. Additionally, SSA inhibition of morphine-reinforced behavior was blocked by the selective GABAB receptor antagonist (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), but not the selective GABAA receptor antagonist bicuculline. Together, these results suggest that SSA may effectively suppress morphine-reinforced behavior by activating GABAB receptors. [Copyright &y& Elsevier]

Abstract: It is well established that the reinforcing effect of drugs of abuse is linked to the mesolimbic dopamine (DA) system. Morphine produces an increase in DA release in the brain, which may provide positive reinforcement contributing to the development of motivational aspects of drug-seeking and maintenance behavior. Several studies suggest that the GABA receptor system may play a significant role in the modulating the mesolimbic DA system. The purpose of this study was to investigate potential roles for GABA agonists in morphine self-administration behavior. Male Sprague–Dawley rats were trained to self-administrated morphine (0.1mg/kg per injection) during daily 1-h sessions under a fixed ratio 1 schedule. Rats received an intravenous injection of the selective GABAB antagonist SCH 50911 (2.0mg/kg) or an intraperitoneal injection of the GABAA antagonist bicuculline (1.0mg/kg), immediately followed by either an intraperitoneal injection of baclofen (1.25 or 1.8mg/kg) or muscimol (0.5 or 1.0mg/kg, i.p.), 30min prior to the start of test session. Results showed that pretreatment with baclofen or muscimol reduced morphine-maintenance response in a dose-dependent fashion and that baclofen and muscimol effects were reversed by injections of SCH 50911 and bicuculline, respectively. These data suggest that activation of both GABAA and GABAB receptors may be effective in suppressing the reinforcing effects of morphine. [Copyright &y& Elsevier]

Phototoxicity due to dermally impregnated compounds exposed to ultraviolet radiation is associated with skin inflammation. The phototoxicity potential of active substances applied to the skin should be evaluated. Pigments are widely used for tattoos, and hypersensitivity reactions, such as photoallergic dermatitis, are possible tattoo-related complications. However, the phototoxicity of these chemicals is not well known. In this study, we evaluated the phototoxicity potential of six tattoo pigments, cadmium sulfide, carbazole, cadmium selenide, mercury (II) sulfide, chromium oxide, and cobalt aluminate, using in vitro methods—3 T3 neutral red uptake (NRU) phototoxicity test (PT) and a 3D human reconstructed skin model (EpiDerm). The validated 3 T3 NRU PT indicated the phototoxicity potential of carbazole and cadmium sulfide. The 3D human skin model confirmed that only carbazole was phototoxic. The 3 T3 NRU PT data corresponded well with those from the 3D skin model and suggested the need to employ several test systems for final phototoxicity assessment. In addition to the results obtained using 3 T3 NRU PT, further testing on 3D skin models may better reflect the bioavailability of a given chemical in the skin. • Skin inflammation caused by tattoo pigments is a health concern. • In the 3 T3 NRU PT test, carbazole and cadmium sulfide showed phototoxicity. • Phototoxicity was confirmed for carbazole in the 3D skin model. • Sequential testing is required for relevant phototoxicity evaluation. [ABSTRACT FROM AUTHOR]

Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein that mediates inflammation, macrophage polarization, apoptosis, and carcinogenesis. The expression of CHI3L1 is strongly increased by various inflammatory and immunological conditions, including rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, and several cancers. However, its physiological and pathophysiological roles in the development of cancer and neurodegenerative and inflammatory diseases remain unclear. Several studies have reported that CHI3L1 promotes cancer proliferation, inflammatory cytokine production, and microglial activation, and that multiple receptors, such as advanced glycation end product, syndecan-1/αVβ3, and IL-13Rα2, are involved. In addition, the pro-inflammatory action of CHI3L1 may be mediated via the protein kinase B and phosphoinositide-3 signaling pathways and responses to various pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and interferon-γ. Therefore, CHI3L1 could contribute to a vast array of inflammatory diseases. In this article, we review recent findings regarding the roles of CHI3L1 and suggest therapeutic approaches targeting CHI3L1 in the development of cancers, neurodegenerative diseases, and inflammatory diseases. [ABSTRACT FROM AUTHOR]