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Melanoma possesses the characteristic phenotypic plasticity, enhancing its metastatic formation and drug resistance. Lipid and fatty acid metabolism are usually altered to support melanoma progression and can be targeted for therapeutic development. Fatty acid binding protein 7 (FABP7) is highly expressed in melanomas and is shown to support its proliferation, migration, and invasion, but the mechanisms remain unclear. Our study aimed to link FABP7 to lipid metabolism and phenotypic shift in melanomas. We established the Fabp7 -knockout (KO) B16F10 melanoma cells, which showed an enhanced invasion through matrix-coated membrane, without significant change in proliferation. Similar outcomes were obtained when using RNA interference targeting FABP7. Fabp7 -KO cells injected into mice exhibited slower primary tumor growth, but formed higher metastatic foci count in the lungs. We also discovered a higher saturation in overall lipids, phosphatidylcholines, and triacylglycerols. We observed transcriptional shifts toward the invasive MITF Low /AXL High phenotype, with upregulation of transforming growth factor-beta (TGF-β) receptor mRNAs. In conclusion, FABP7 may help balancing lipid saturation and maintain the proliferative state of melanomas, mitigating invasiveness and metastatic formation.

Lrfn2/SALM1 is a PSD-95-interacting synapse adhesion molecule, and human LRFN2 is associated with learning disabilities. However its role in higher brain function and underlying mechanisms remain unknown. Here, we show that Lrfn2 knockout mice exhibit autism-like behavioural abnormalities, including social withdrawal, decreased vocal communications, increased stereotyped activities and prepulse inhibition deficits, together with enhanced learning and memory. In the hippocampus, the levels of synaptic PSD-95 and GluA1 are decreased. The synapses are structurally and functionally immature with spindle shaped spines, smaller postsynaptic densities, reduced AMPA/NMDA ratio, and enhanced LTP. In vitro experiments reveal that synaptic surface expression of AMPAR depends on the direct interaction between Lrfn2 and PSD-95. Furthermore, we detect functionally defective LRFN2 missense mutations in autism and schizophrenia patients. Together, these findings indicate that Lrfn2/LRFN2 serve as core components of excitatory synapse maturation and maintenance, and their dysfunction causes immature/silent synapses with pathophysiological state. Lrfn2/SALM1 is a synaptic adhesion molecule, and is known to interact with PSD-95. Here the authors show that Lrfn2 regulates excitatory synapse maturation and maintenance, and that Lrfn2 knockout mice exhibit autism-like behaviours as well as enhanced learning and memory.

Hepatic macrophages respond to various microenvironmental signals and play a central role in maintaining hepatic homeostasis, dysregulation of which leads to various liver diseases. Fatty acid‐binding protein 7 (FABP7), an intracellular lipid chaperone for polyunsaturated fatty acids (PUFAs), is highly expressed in liver macrophages. However, the mechanisms by which FABP7 regulates hepatic macrophage activation remain unclear. Therefore, we aimed to elucidate the mechanisms underlying the effects of FABP7 on the functions of hepatic macrophages in metabolic dysfunction‐associated steatohepatitis (MASH) and liver fibrosis models. In this study, we found that FABP7‐deficient macrophages exhibited impaired M2 polarization, which reduced the fibrotic response of myofibroblasts and CD4 + T‐cell infiltration into the liver tissues in a carbon tetrachloride (CCl 4 )‐induced hepatic fibrosis model. In vitro, FABP7‐deficient macrophages exhibited decreased levels of peroxisome proliferator‐activated receptor (PPAR)‐ γ and its target genes, including C–C motif chemokine ligand (CCL)‐17 and transforming growth factor‐ β (TGF‐ β ), compared to the wild‐type (WT) macrophages post‐interleukin (IL)‐4 stimulation. However, these effects were inhibited by a PPAR γ inhibitor. IL‐4‐stimulated WT macrophages also promoted CD4 + T‐cell migration and hepatic fibroblast (TWNT‐1 hepatic stellate cell [HSC]) activation, indicated by increased mRNA levels of actin alpha 2, smooth muscle ( ACTA2 ), and collagen type I alpha 1 ( COL1A1 ); however, these effects were inhibited in FABP7‐deficient macrophages. Overall, FABP7 in hepatic macrophages modulated the crosstalk between hepatic fibroblasts and T cells by regulating M2 polarization. Therefore, regulation of hepatic macrophage function by FABP7 is a potential therapeutic target for liver fibrosis.

Maternal immune activation (MIA) contributes to behavioral abnormalities relevant to schizophrenia in adult offspring, although the molecular mechanisms underlying MIA-induced behavioral changes remain unclear. Here we demonstrated that dietary intake of glucoraphanin (GF), the precursor of a natural antioxidant sulforaphane, during juvenile and adolescent stages prevented cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial prefrontal cortex (mPFC) of adult offspring after MIA. Gene set enrichment analysis by RNA sequencing showed that MIA caused abnormal expression of centrosome-related genes in the PFC and hippocampus of adult offspring, and that dietary intake of GF improved these abnormal gene expressions. Particularly, MIA increased the expression of suppressor of fermentation-induced loss of stress resistance protein 1 ( Sfi1 ) mRNA in the PFC and hippocampus of adult offspring, and dietary intake of GF prevented the expression of Sfi1 mRNA in these regions. Interestingly, we found altered expression of SFI1 in the postmortem brains and SFI1 mRNA in hair follicle cells from patients with schizophrenia compared with controls. Overall, these data suggest that centrosome-related genes may play a role in the onset of psychosis in offspring after MIA. Therefore, dietary intake of GF-rich vegetables in high-risk psychosis subjects may prevent the transition to psychosis in young adulthood.

Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as‐yet‐unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H 2 S)/polysulfide‐producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst ‐deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst ‐transgenic (Tg) mice showed deteriorated PPI, suggesting that “sulfide stress” may be linked to PPI impairment. Analysis of human samples demonstrated that the H 2 S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst‐ Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H 2 S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H 2 S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H 2 S/polysulfides production. Synopsis This study proposes a novel concept that excess hydrogen sulfide production (sulfide stress) underlies a schizophrenia pathophysiology in the realm of neurodevelopmental hypothesis of the disease. Targeting the metabolic pathway of hydrogen sulfide provides a novel therapeutic approach. Mpst‐deficient mice exhibited improved prepulse inhibition (PPI), a typical schizophrenia‐relevant endophenotype, with reduced sulfide levels, while Mpst‐transgenic mice showed deteriorated PPI. Postmortem brains and iPS‐derived cells from a subset of schizophrenia patients displayed evidence for sulfide stress. Sulfide stress condition stemmed from insults in developing brain in mouse models and elicited dampened energy metabolism. MPST expression level in hair follicles has a potential to stratify schizophrenia patients with sulfide stress. Graphical Abstract This study proposes a novel concept that excess hydrogen sulfide production (sulfide stress) underlies a schizophrenia pathophysiology in the realm of neurodevelopmental hypothesis of the disease. Targeting the metabolic pathway of hydrogen sulfide provides a novel therapeutic approach.

Recent evidence has documented the potential roles of histone-modifying enzymes in autism-spectrum disorder (ASD). Aberrant histone H3 lysine 9 (H3K9) dimethylation resulting from genetic variants in histone methyltransferases is known for neurodevelopmental and behavioral anomalies. However, a systematic examination of H3K9 methylation dynamics in ASD is lacking. Here we resequenced nine genes for histone methyltransferases and demethylases involved in H3K9 methylation in individuals with ASD and healthy controls using targeted next-generation sequencing. We identified a novel rare variant (A211S) in the SUV39H2, which was predicted to be deleterious. The variant showed strongly reduced histone methyltransferase activity in vitro. In silico analysis showed that the variant destabilizes the hydrophobic core and allosterically affects the enzyme activity. The Suv39h2-KO mice displayed hyperactivity and reduced behavioral flexibility in learning the tasks that required complex behavioral adaptation, which is relevant for ASD. The Suv39h2 deficit evoked an elevated expression of a subset of protocadherin β (Pcdhb) cluster genes in the embryonic brain, which is attributable to the loss of H3K9 trimethylation (me3) at the gene promoters. Reduced H3K9me3 persisted in the cerebellum of Suv39h2-deficient mice to an adult stage. Congruently, reduced expression of SUV39H1 and SUV39H2 in the postmortem brain samples of ASD individuals was observed, underscoring the role of H3K9me3 deficiency in ASD etiology. The present study provides direct evidence for the role of SUV39H2 in ASD and suggests a molecular cascade of SUV39H2 dysfunction leading to H3K9me3 deficiency followed by an untimely, elevated expression of Pcdhb cluster genes during early neurodevelopment.

Aims Fatty acid binding protein 4, adipocyte (Fabp4), is well known for its role in peripheral lipid metabolism, but its potential role in brain function remains largely unexplored. This study aimed to investigate Fabp4 expression in the adult mouse brain and explore gene expression changes in Fabp4 knockout (KO) mice to assess its potential impact on brain function. Methods We conducted in situ hybridization to assess Fabp4 expression in key brain regions of adult mice. In parallel, differential gene expression analysis using RNA‐seq was conducted in the prefrontal cortex of Fabp4 KO mice to identify genes affected by Fabp4 deficiency. Results No Fabp4 expression was detected in the brains of mice, suggesting a lack of direct involvement in the central nervous system. However, Fabp4 KO mice exhibited significant changes in gene expression in the brain, with 31 genes upregulated and 30 downregulated. Downregulated genes were linked to histone methylation and metabolic processes, while upregulated ones were associated with synaptic organization. Conclusion Although Fabp4 is not expressed in the brain, its deficiency leads to substantial changes in gene expression, likely mediated by peripheral metabolic pathways and epigenetic regulation. These changes may explain the previously observed autism‐like behaviors and increased dendritic spine density in Fabp4 KO mice. This study sheds light on the role of systemic lipid metabolism in neurodevelopmental disorders such as autism spectrum disorder (ASD) and highlights epigenetic mechanisms as potential mediators of these effects. This study investigates the role of Fabp4 in brain function using Fabp4 knockout (KO) mice. Despite negligible Fabp4 expression in the brain, RNA‐seq analysis revealed significant changes in genes associated with synaptic organization and epigenetic regulation. These findings support the concept of an “adipo‐brain axis,” where peripheral metabolic processes influence neural function and behavior.

Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs) in 120 patient-parents trio samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p<0.01 and 473 SNPs of p<0.05 that located in previously reported linkage regions). The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila)-like 2] gene located on 9p21.3 (p = 0.00087). In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals) of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p = 0.026). The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology.

Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis on 1,010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected six major loci for PPI, six for the acoustic startle response, and four for latency to response peak, some of which were sex-dependent. A promising candidate on the Chromosome 10-QTL was Fabp7 (fatty acid binding protein 7, brain), a gene with functional links to the N-methyl-D-aspartic acid (NMDA) receptor and expression in astrocytes. Fabp7-deficient mice showed decreased PPI and a shortened startle response latency, typical of the QTL's proposed effects. A quantitative complementation test supported Fabp7 as a potential PPI-QTL gene, particularly in male mice. Disruption of Fabp7 attenuated neurogenesis in vivo. Human FABP7 showed altered expression in schizophrenic brains and genetic association with schizophrenia, which were both evident in males when samples were divided by sex. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental, and glial theories of schizophrenia pathology and the PPI endophenotype, with larger or overt effects in males. We also discuss the results from the perspective of fetal programming.

We recently reported the results of a genome-wide association study (GWAS) of schizophrenia in the Japanese population. In that study, a single nucleotide polymorphism (SNP) (rs3106653) in the KCNJ3 (potassium inwardly rectifying channel, subfamily J, member 3) gene located at 2q24.1 showed association with schizophrenia in two independent sample sets. KCNJ3, also termed GIRK1 or Kir3.1, is a member of the G protein-activated inwardly rectifying K + channel (GIRK) group. GIRKs are widely distributed in the brain and play an important role in regulating neural excitability through the activation of various G protein-coupled receptors. In this study, we set out to examine this association using a different population. We first performed a gene-centric association study of the KCNJ3 gene, by genotyping 38 tagSNPs in the Chinese population. We detected nine SNPs that displayed significant association with schizophrenia (lowest P  = 0.0016 for rs3106658, Global significance  = 0.036). The initial marker SNP (rs3106653) examined in our prior GWAS in the Japanese population also showed nominally significant association in the Chinese population ( P  = 0.028). Next, we analyzed transcript levels in the dorsolateral prefrontal cortex of postmortem brains from patients with schizophrenia and bipolar disorder and from healthy controls, using real-time quantitative RT-PCR. We found significantly lower KCNJ3 expression in postmortem brains from schizophrenic and bipolar patients compared with controls. These data suggest that the KCNJ3 gene is genetically associated with schizophrenia in Asian populations and add further evidence to the “channelopathy theory of psychiatric illnesses”.