Abstract
Autism spectrum disorder is characterized by early postnatal symptoms, although little is known about the mechanistic deviations that produce them and whether correcting them has ...long-lasting preventive effects on adult-stage deficits. ARID1B, a chromatin remodeler implicated in neurodevelopmental disorders, including autism spectrum disorder, exhibits strong embryonic- and early postnatal-stage expression. We report here that
Arid1b
-happloinsufficient (
Arid1b
+/–
) mice display autistic-like behaviors at juvenile and adult stages accompanied by persistent decreases in excitatory synaptic density and transmission. Chronic treatment of
Arid1b
+/–
mice with fluoxetine, a selective serotonin-reuptake inhibitor, during the first three postnatal weeks prevents synaptic and behavioral deficits in adults. Mechanistically, these rescues accompany transcriptomic changes, including upregulation of FMRP targets and normalization of HDAC4/MEF2A-related transcriptional regulation of the synaptic proteins, SynGAP1 and Arc. These results suggest that chronic modulation of serotonergic receptors during critical early postnatal periods prevents synaptic and behavioral deficits in adult
Arid1b
+/–
mice through transcriptional reprogramming.
Glycine transporters (GlyT1 and GlyT2) that regulate levels of brain glycine, an inhibitory neurotransmitter with co‐agonist activity for NMDA receptors (NMDARs), have been considered to be important ...targets for the treatment of brain disorders with suppressed NMDAR function such as schizophrenia. However, it remains unclear whether other amino acid transporters expressed in the brain can also regulate brain glycine levels and NMDAR function. Here, we report that SLC6A20A, an amino acid transporter known to transport proline based on in vitro data but is understudied in the brain, regulates proline and glycine levels and NMDAR function in the mouse brain. SLC6A20A transcript and protein levels were abnormally increased in mice carrying a mutant PTEN protein lacking the C terminus through enhanced β‐catenin binding to the Slc6a20a gene. These mice displayed reduced extracellular levels of brain proline and glycine and decreased NMDAR currents. Elevating glycine levels back to normal ranges by antisense oligonucleotide‐induced SLC6A20 knockdown, or the competitive GlyT1 antagonist sarcosine, normalized NMDAR currents and repetitive climbing behavior observed in these mice. Conversely, mice lacking SLC6A20A displayed increased extracellular glycine levels and NMDAR currents. Lastly, both mouse and human SLC6A20 proteins mediated proline and glycine transports, and SLC6A20 proteins could be detected in human neurons. These results suggest that SLC6A20 regulates proline and glycine homeostasis in the brain and that SLC6A20 inhibition has therapeutic potential for brain disorders involving NMDAR hypofunction.
Synopsis
This study reveals that SLC6A20A, an amino acid transporter previously known to transport proline, also transports glycine, a co‐agonist of NMDA receptors. SLC6A20A inhibition holds therapeutic potential for brain disorders with suppressed NMDAR function such as schizophrenia.
SLC6A20A transports both glycine and proline in mammalian cells.
PTEN C‐terminal deletion enhances SLC6A20A expression, brain glycine levels, and NMDA receptor function in mice.
SLC6A20A haploinsufficient mice display increased brain glycine levels and enhanced NMDA receptor function.
This study reveals that SLC6A20A, an amino acid transporter previously known to transport proline, also transports glycine, a co‐agonist of NMDA receptors. SLC6A20A inhibition holds therapeutic potential for brain disorders with suppressed NMDAR function such as schizophrenia.
Floor mats are commonly used to improve the impact sound performance of existing homes, but actual impact sound reductions do not consistently appear, as they depend on the test-bed conditions used ...to determine impact sound performance. Therefore, this study evaluated the effects of the environmental conditions of the test bed on the impact sound reduction performances of different floor mats. The Korean industrial standard KS F 2865 specifies the measurement method in the test room and sets the thickness range of the available target floor structure to bare slabs with thicknesses ranging from 120 mm to 210 mm. The evaluation method is ∆L, which is the difference in standardized impact sound levels before and after the installation of the floor finishing material. In this study, a total of eight types of floor mats were tested in four different test beds according to KS F 2865. The impact sources used were tapping, bang machines, and a rubber ball, and we used these sources to consider both light-weight and heavy-weight impact sounds. The results were derived as the impact sound reduction performance for each frequency band and a single-number quantity. The results showed that light impact sound had a similar minimum reduction characteristic of at least 38 dB, regardless of the floor structure on which the mat was installed. However, the heavy-weight impact sound showed different tendencies depending on the floor mat and the characteristics of the floor structure of the test bed when a bang machine and a rubber ball were used. In particular, the reduction achieved by the bang machine showed less than half the tendency of the reduction by the rubber ball, and the tendency of the heavy-weight impact sound was shown to be reducible depending on how the floor mat was maintained, but the reductions differed depending on the test bed. The reductions were larger in the box-type test room than in the real-life-type test room, and among the box-type test rooms, the one with a thicker bare slab showed a relatively larger reduction. In addition, the reliability of the measurement results was evaluated through a correlation analysis between the single-number quantities depending on the thicknesses of the bare slabs of the test beds.
Recent studies have indicated that the triglyceride-glucose (TyG) index or subclinical thyroid dysfunction is associated with carotid plaques, a predictor of cardiovascular disease risk. However, ...evidence for this association is limited and inconsistent. This study aimed to evaluate the risk of carotid plaques according to TyG index and thyroid function status in the general population.
A total of 2,931 individuals who underwent carotid ultrasound as part of a comprehensive health examination at the Health Promotion Center of Soonchunhyang University Hospital were retrospectively reviewed. Based on the TyG index and thyroid function status, the participants were divided into six groups: LoTyG-SHyper (low TyG index with subclinical hyperthyroidism), LoTyG-Eu (low TyG index with euthyroidism), LoTyG-SHypo (low TyG index with subclinical hypothyroidism), HiTyG-SHyper (high TyG index with subclinical hyperthyroidism), HiTyG-Eu (high TyG index with euthyroidism), and HiTyG-SHypo (high TyG index with subclinical hypothyroidism). A multivariate logistic regression analysis was conducted to determine the risk of carotid plaques.
The proportion of participants with significant carotid plaques was significantly different among the six groups (p<0.001, p for trend<0.001). The odds ratio (OR) and 95% confidence interval (CI) for significant carotid plaques were significantly higher in the HiTyG-SHypo group than in the LoTyG-Eu group, even after adjusting for confounding variables including sex, age, smoking, obesity, hypertension and diabetes mellitus (OR 1.506, 95% CI 1.045-2.170, p = 0.028). The OR of significant carotid plaques was higher in the HiTyG-Eu group than in the LoTyG-Eu group; however no associations were observed after additional adjustment for confounding variables.
The TyG index and thyroid function status are important predictors of the risk of carotid plaques in healthy individuals. Early evaluation of carotid plaques may be necessary for subjects with high insulin resistance and subclinical hypothyroidism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is currently the leading cause of chronic liver disease worldwide. Metabolic Dysfunction-Associated Steatohepatitis (MASH), ...an advanced form of MASLD, can progress to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Based on recent findings by our team that liver 5HT
2A
knockout male mice suppressed steatosis and reduced fibrosis-related gene expression, we developed a peripheral 5HT
2A
antagonist, compound
11c
for MASH. It shows good in vitro activity, stability, and in vivo pharmacokinetics (PK) in rats and dogs. Compound
11c
also shows good in vivo efficacy in a diet-induced obesity (DIO) male mice model and in a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) male mice model, effectively improving histologic features of MASH and fibrosis. According to the tissue distribution study using
14
C-labeled
11c
, the compound was determined to be a peripheral 5HT
2A
antagonist. Collectively, first-in-class compound
11c
shows promise as a therapeutic agent for the treatment of MASLD and MASH.
Microplastics, small pieces of plastic derived from polystyrene, have recently become an ecological hazard due to their toxicity and widespread occurrence in aquatic ecosystems. In this study, we ...exposed zebrafish larvae to two types of fluorescent polystyrene nanoparticles (PS-NPs) to identify their size-dependent effects. PS-NPs of 50 nm, unlike 100 nm PS-NPs, were found to circulate in the blood vessels and accumulate in the brains of zebrafish larvae. Behavioral and electroencephalogram (EEG) analysis showed that 50 nm PS-NPs induce abnormal behavioral patterns and changes in EEG power spectral densities in zebrafish larvae. In addition, the quantification of endogenous neurochemicals in zebrafish larvae showed that 50 nm PS-NPs disturb dopaminergic metabolites, whereas 100 nm PS-NPs do not. Finally, we assessed the effect of PS-NPs on the permeability of the blood–brain barrier (BBB) using a microfluidic system. The results revealed that 50 nm PS-NPs have high BBB penetration compared with 100 nm PS-NPs. Taken together, we concluded that small nanoparticles disturb the nervous system, especially dopaminergic metabolites.
Radiotherapy is one of the most important modalities in cancer treatment; however, normal tissue damage is a serious concern. Drug development for the protection or reduction of normal tissue damage ...is therefore a clinical issue. Herein, we evaluated the protective properties of Panax ginseng Meyer and its corresponding mechanisms.
C56BL/6 mice were orally pretreated with P. ginseng water extract (PGE; 25 mg/kg, 50 mg/kg, or 100 mg/kg) or intraperitoneally injected melatonin (20 mg/kg) for 4 d consecutively, then exposed to 15-Gy X-ray radiation 1 h after the last administration. After 10 d of irradiation, the biological properties of hematoxicity, fat accumulation, histopathology, oxidative stress, antioxidant activity, pro-inflammatory cytokines, and apoptosis signals were examined in the hepatic tissue.
The irradiation markedly induced myelosuppression as determined by hematological analysis of the peripheral blood. Steatohepatitis was induced by X-ray irradiations, whereas pretreatment with PGE significantly attenuated it. Oxidative stress was drastically increased, whereas antioxidant components were depleted by irradiation. Irradiation also notably increased serum liver enzymes and hepatic protein levels of pro-inflammatory cytokines. Those alterations were markedly normalized by pretreatment with PGE. The degree of irradiation-induced hepatic tissue apoptosis was also attenuated by pretreatment with PGE, which was evidenced by a terminal deoxynucleotidyl transferase 2′-deoxyuridine 5′-triphosphate nick-end labeling assay, western blotting, and gene expressions analysis, particularly of apoptotic molecules.
We suggest that PGE could be applicable for use against radiation-induced liver injury, and its corresponding mechanisms involve the modulation of oxidative stress, inflammatory reactions, and apoptosis.
The radiodensity and volume of epicardial adipose tissue (EAT) on computed tomography angiography (CTA) may provide information regarding cardiovascular risk and long-term outcomes. EAT volume is ...associated with mortality in patients undergoing incident hemodialysis. However, the relationship between EAT radiodensity/volume and all-cause mortality in patients with end-stage renal disease (ESRD) undergoing maintenance hemodialysis remains elusive. In this retrospective study, EAT radiodensity (in Hounsfield units) and volume (in cm
) on coronary CTA were quantified for patients with ESRD using automatic, quantitative measurement software between January 2012 and December 2018. All-cause mortality data (up to December 2019) were obtained from the Korean National Statistical Office. The prognostic values of EAT radiodensity and volume for predicting long-term mortality were assessed using multivariable Cox regression models, which were adjusted for potential confounders. A total of 221 patients (mean age: 64.88 ± 11.09 years; 114 women and 107 men) with ESRD were included. The median follow-up duration (interquartile range) after coronary CTA was 29.63 (range 16.67-44.7) months. During follow-up, 82 (37.1%) deaths occurred. In the multivariable analysis, EAT radiodensity (hazard ratio HR 1.055; 95% confidence interval CI 1.015-1.095; p = 0.006) was an independent predictor of all-cause mortality in patients with ESRD. However, EAT volume was not associated with mortality. Higher EAT radiodensity on CTA is associated with higher long-term all-cause mortality in patients undergoing prevalent hemodialysis, highlighting its potential as a prognostic imaging biomarker in patients undergoing hemodialysis.
•In this study, we show that KDZ-001, a novel anti-melanogenic agent, strongly inhibits melanin synthesis in the developing melanophores of zebrafish, HMV-II cells, and reconstituted human skin with ...no toxicity. We also show that KDZ-001 directly inhibits TYR enzymatic activity. Thus, KDZ-001 is a potential candidate for a skin-whitening agent in the cosmetic industry.
The demand for anti-melanogenic agents is increasing due to the unwanted side effects of current treatments. To find an effective anti-melanogenic agent, we used zebrafish as a whole animal model for phenotype-based drug and cosmetic discovery screening.
The aim of this study was to identify and explore a small molecule that could be used for skin-whitening cosmetics.
Using zebrafish embryos, we examined the effects of 1000 compounds on zebrafish development and pigmentation. Pigmentation production was assessed by tyrosinase (TYR) enzymatic activity and melanin contents. Pigmentation marker expression in the human melanoma cell line HMV-II was analyzed by western blot. We also tested reconstituted human skin tissue and analyzed KDZ-001 with computational molecular modeling.
We identified three compounds that affected the pigmentation of developing melanophores in zebrafish. Among them, we identified KDZ-001, a novel anti-melanogenic agent, which strongly inhibits melanin synthesis in the developing melanophores of zebrafish, HMV-II cells, and reconstituted human skin with no toxicity. We found that KDZ-001 directly inhibits TYR enzymatic activity. Notably, computational molecular modeling of KDZ-001 suggested that its interaction with copper ions in the active site of TYR is essential for melanin synthesis, further demonstrating that KDZ-001 mainly acts as a TYR inhibitor to synthesize melanin.
KDZ-001 inhibits melanin synthesis and has a potential for use in skin-whitening cosmetics.
Epilepsy is one of the most common neurological disorders, and it is characterized by spontaneous seizures. In a previous study, we identified ...4-(2-chloro-4-fluorobenzyl)-3-(2-thienyl)-1,2,4-oxadiazol-5(4H)-one (GM-90432) as a novel anti-epileptic agent in chemically- or genetically-induced epileptic zebrafish and mouse models. In this study, we investigated the anti-epileptic effects of GM-90432 through neurochemical profiling-based approach to understand the neuroprotective mechanism in a pentylenetetrazole (PTZ)-induced epileptic seizure zebrafish model. GM-90432 effectively improved PTZ-induced epileptic behaviors via upregulation of 5-hydroxytryptamine, 17-β-estradiol, dihydrotestosterone, progesterone, 5α -dihydroprogesterone, and allopregnanolone levels, and downregulation of normetanephrine, gamma-aminobutyric acid, and cortisol levels in brain tissue. GM-90432 also had a protective effect against PTZ-induced oxidative stress and zebrafish death, suggesting that it exhibits biphasic neuroprotective effects via scavenging of reactive oxygen species and anti-epileptic activities in a zebrafish model. In conclusion, our results suggest that neurochemical profiling study could be used to better understand of anti-epileptic mechanism of GM-90432, potentially leading to new drug discovery and development of anti-seizure agents.
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