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Background: The CCDC22 gene plays vital roles in regulating the NF-κB pathway, an essential pathway for neuroinflammation, neurodevelopment, and epileptogenesis. Previously, variants in CCDC22 were reported to be associated with intellectual disability. This study aimed to explore the association between CCDC22 and epilepsy., Methods: Trios-based whole-exome sequencing (WES) was performed in a cohort of patients with epilepsy of unknown cause recruited from the China Epilepsy Gene 1.0 Project. Damaging effects of variants were analysed using protein modelling., Results: Hemizygous missense CCDC22 variants were identified in three unrelated cases. These variants had no hemizygous frequencies in controls. All missense variants identified in this study were predicted to be "damaging" by multiple in silico tools and to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients presented with focal epilepsy of varying severity, including one with refractory seizures and focal cortical dysplasia (FCD) and two with seizures responding to antiseizure medicine. Notably, the variant associated with the severe phenotype was located in the coiled-coil domain and predicted to alter hydrogen bonding and protein stability, whereas the two variants associated with mild epilepsy were located outside functional domains and had moderate molecular alterations. Analysis of spatiotemporal expression indicated that CCDC22 was expressed in brain subregions with three peaks in the fetal stage, infancy, and early adulthood, especially in the fetal stage, explaining the occurrence of developmental abnormities., Significance: CCDC22 variants are potentially associated with X-linked focal epilepsy and FCD. The molecular subregional effects supported the occurrence of FCD., Competing Interests: Declaration of competing interest All the authors declare that there are no conflicts of interest., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: The APC2 gene, encoding adenomatous polyposis coli protein-2, is involved in cytoskeletal regulation in neurons responding to endogenous extracellular signals and plays an important role in brain development. Previously, the APC2 variants have been reported to be associated with cortical dysplasia and intellectual disability. This study aims to explore the association between APC2 variants and epilepsy., Methods: Whole-exome sequencing (WES) was performed in cases (trios) with epilepsies of unknown causes. The damaging effects of variants were predicted by protein modeling and in silico tools. Previously reported APC2 variants were reviewed to analyze the genotype-phenotype correlations., Results: Four pairs of compound heterozygous missense variants were identified in four unrelated patients with epilepsy without brain malformation/intellectual disability. All variants presented no or low allele frequencies in the controls. The missense variants were predicted to be damaging by silico tools, and affect hydrogen bonding with surrounding amino acids or decreased protein stability. Patients with variants that resulted in significant changes in protein stability exhibited more severe and intractable epilepsy, whereas patients with variants that had minor effect on protein stability exhibited relatively mild phenotypes. The previously reported APC2 variants in patients with complex cortical dysplasia with other brain malformations-10 (CDCBM10; MIM: 618677) were all truncating variants; in contrast, the variants identified in epilepsy in this study were all missense variants, suggesting a potential genotype-phenotype correlation., Significance: This study suggests that APC2 is potentially associated with epilepsy without brain malformation/intellectual disability. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic heterogeneity., Competing Interests: Declaration of Competing Interest The authors have stated that they had no interests which might be perceived as posing a conflict or bias., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: To provide an updated list of epilepsy-associated genes based on clinical-genetic evidence., Methods: Epilepsy-associated genes were systematically searched and cross-checked from the OMIM, HGMD, and PubMed databases up to July 2023. To facilitate the reference for the epilepsy-associated genes that are potentially common in clinical practice, the epilepsy-associated genes were ranked by the mutation number in the HGMD database and by case number in the China Epilepsy Gene 1.0 project, which targeted common epilepsy., Results: Based on the OMIM database, 1506 genes were identified to be associated with epilepsy and were classified into three categories according to their potential association with epilepsy or other abnormal phenotypes, including 168 epilepsy genes that were associated with epilepsies as pure or core symptoms, 364 genes that were associated with neurodevelopmental disorders as the main symptom and epilepsy, and 974 epilepsy-related genes that were associated with gross physical/systemic abnormalities accompanied by epilepsy/seizures. Among the epilepsy genes, 115 genes (68.5%) were associated with epileptic encephalopathy. After cross-checking with the HGMD and PubMed databases, an additional 1440 genes were listed as potential epilepsy-associated genes, of which 278 genes have been repeatedly identified variants in patients with epilepsy. The top 100 frequently reported/identified epilepsy-associated genes from the HGMD database and the China Epilepsy Gene 1.0 project were listed, among which 40 genes were identical in both sources., Significance: Recognition of epilepsy-associated genes will facilitate genetic screening strategies and be helpful for precise molecular diagnosis and treatment of epilepsy in clinical practice., Competing Interests: Declaration of Competing Interest The authors have stated that they had no interests that might be perceived as posing a conflict or bias., (Copyright © 2023. Published by Elsevier Ltd.)

Objectives: The APC2 gene, encoding adenomatous polyposis coli protein-2, is involved in cytoskeletal regulation in neurons responding to endogenous extracellular signals and plays an important role in brain development. Previously, the APC2 variants have been reported to be associated with cortical dysplasia and intellectual disability. This study aims to explore the association between APC2 variants and epilepsy., Methods: Whole-exome sequencing (WES) was performed in cases (trios) with epilepsies of unknown causes. The damaging effects of variants were predicted by protein modeling and in silico tools. Previously reported APC2 variants were reviewed to analyze the genotype-phenotype correlations., Results: Four pairs of compound heterozygous missense variants were identified in four unrelated patients with epilepsy without brain malformation/intellectual disability. All variants presented no or low allele frequencies in the controls. The missense variants were predicted to be damaging by silico tools, and affect hydrogen bonding with surrounding amino acids or decreased protein stability. Patients with variants that resulted in significant changes in protein stability exhibited more severe and intractable epilepsy, whereas patients with variants that had minor effect on protein stability exhibited relatively mild phenotypes. The previously reported APC2 variants in patients with complex cortical dysplasia with other brain malformations-10 (CDCBM10; MIM: 618677) were all truncating variants; in contrast, the variants identified in epilepsy in this study were all missense variants, suggesting a potential genotype-phenotype correlation., Significance: This study suggests that APC2 is potentially associated with epilepsy without brain malformation/intellectual disability. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic heterogeneity., Competing Interests: Declaration of Competing Interest The authors have stated that they had no interests which might be perceived as posing a conflict or bias., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: TPP1 mutations have been identified in patients with variable phenotypes such as late infantile neuronal ceroid lipofuscinosis (LINCL), juvenile neuronal ceroid lipofuscinosis (JNCL), and spinocerebellar ataxia 7. However, the mechanism underlying phenotype variation is unknown. We screened TPP1 mutations in patients with epilepsies and analyzed the genotype-phenotype correlation to explain the phenotypic variations., Methods: We performed targeted next-generation sequencing in a cohort of 330 patients with epilepsies. All previously reported TPP1 mutations were systematically retrieved from the PubMed and NCL Mutation Database., Results: The homozygous missense TPP1 mutation c.646 G > A/ p.Val216Met was identified in a family with two affected siblings. The proband presented with seizures from three years of age, while no ataxia, cognitive regression, or visual abnormalities were observed. Further analysis of all reported TPP1 mutations revealed that the LINCL group had a significantly higher frequency of truncating and invariant splice-site mutations than the JNCL group. In contrast, the JNCL group had a higher frequency of variant splice-site mutations than LINCL. There was a significant correlation between phenotype severity and the frequency of destructive mutation., Conclusion: This study suggested that the phenotype of mainly epilepsy can be included in the phenotypic spectrum of TPP1 mutations, which are candidate targets for genetic screening in patients with epilepsy. With the development of therapy techniques, early genetic diagnosis may enable the improvement of etiology-targeted treatments. The relationship between phenotype severity and the genotype of TPP1 mutations may help explain the phenotypic variations., (Copyright © 2019. Published by Elsevier Ltd.)

Previously published equations to estimate glomerular filtration rate (GFR) have limited accuracy in Asian populations. We aimed to develop and validate a more accurate equation for estimated GFR (eGFR) in the Chinese population, using data from 8571 adults who were referred for direct measurement of GFR by renal dynamic imaging (mGFR) at 3 representative hospitals in China. Patients from the Third Xiangya Hospital were included in our development (n=1730) and internal validation sets (n=1042) and patients from the other hospitals comprised the external validation set (n=5799). We excluded patients who were prescribed medications known to influence the tubular secretion of creatinine, patients on dialysis, kidney transplant recipients, and patients with missing creatinine values or with creatinine >700 μmol/l. We derived a novel eGFR equation by linear regression analysis and compared the performance to 12 creatinine-based eGFR equations, including previously published equations for use in Chinese or Asian populations. In the development and internal validation sets, the novel Xiangya equation had high accuracy (accuracy within 30% [P30], 79.21% and 84.33%, respectively), low bias (mean difference between mGFR and eGFR, -1.97 and -1.85 ml/min per 1.73 m 2 , respectively), and high precision (interquartile range of the differences, 21.13 and 18.88 ml/min per 1.73 m 2 , respectively). In external validation, the Xiangya equation had the highest P30 among all eGFR equations, with P30 ≤ 75% for the other 12 equations. This novel equation provides more accurate GFR estimates in Chinese adults and could replace existing eGFR equations for use in the Chinese population., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Epileptic encephalopathies comprise a group of catastrophic epilepsies with heterogeneous genetic etiology. Although next-generation sequencing techniques can reveal a number of de novo variants in epileptic encephalopathies, evaluating the pathogenicity of these variants can be challenging. Determining the pathogenic potential of genes in epileptic encephalopathies is critical before evaluating the pathogenicity of variants identified in an individual. We reviewed de novo variants in epileptic encephalopathies, including their genotypes and functional consequences. We then evaluated the pathogenic potential of genes, with the following additional considerations: (1) recurrence of variants in unrelated cases, (2) information of previously defined phenotypes, and (3) data from genetic experimental studies. Genes related to epileptic encephalopathy revealed pathogenicity with distinct functional alterations, i.e., either a gain of function or loss of function in the majority; however, several genes warranted further study to confirm their pathogenic potential. Whether a gene was associated with distinct phenotype, the genotype (or functional alteration)--phenotype correlation, and quantitative correlation between genetic impairment and phenotype severity were suggested to be specific evidence in determining the pathogenic role of genes. Data from epileptic encephalopathy-related genes would be helpful in outlining guidelines for evaluating the pathogenic potential of genes in other genetic disorders.

Voltage-gated sodium channel α-subunit type I (Na V 1.1, encoded by SCN1A gene) plays a critical role in the excitability of brain. Downregulation of SCN1A expression is associated with epilepsy, a common neurological disorder characterized by recurrent seizures. Here we reveal a novel role of malate dehydrogenase 2 (MDH2) in the posttranscriptional regulation of SCN1A expression under seizure condition. We identified that MDH2 was an RNA binding protein that could bind two of the four conserved regions in the 3' UTRs of SCN1A. We further showed that knockdown of MDH2 or inactivation of MDH2 activity in HEK-293 cells increased the reporter gene expression through the 3' UTR of SCN1A, and MDH2 overexpression decreased gene expression by affecting mRNA stability. In the hippocampus of seizure mice, the upregulation of MDH2 expression contributed to the decrease of the Na V 1.1 levels at posttranscriptional level. In addition, we showed that the H 2 O 2 levels increased in the hippocampus of the seizure mice, and H 2 O 2 could promote the binding of MDH2 to the binding sites of Scn1a gene, whereas β-mercaptoethanol decreased the binding capability, indicating an important effect of the seizure-induced oxidation on the MDH2-mediated downregulation of Scn1a expression. Taken together, these data suggest that MDH2, functioning as an RNA-binding protein, is involved in the posttranscriptional downregulation of SCN1A expression under seizure condition., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: To investigate associations between degrees of obesity using correlations between obesity indices and cardiometabolic risk factors in women., Methods: BMI, waist circumference (WC), fasting insulin, fasting glucose, lipids, and visceral adipose tissue (VAT) area using computed tomographic images were measured in 113 women with obesity. Correlations between obesity indices and cardiometabolic risk factors were analyzed in subgroups defined using sequential obesity indices., Results: Mean BMI and WC were 29.6kg/m 2 and 92.8cm. BMI showed significant correlations with all five cardiometabolic risk factors until the BMI cut-off point reached 29kg/m 2 , but when it exceeded 30kg/m 2 , correlations no longer existed. WC was significantly correlated with all five cardiometabolic risk factors up to a value of 85cm, but when WC exceeded 90cm, correlations no longer existed., Conclusions: Our cross-sectional study suggest that significant correlations between obesity indices and cardiometabolic risk factors may disappear, when obesity cut-off points exceed certain limits in women., (Copyright © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Development in genetic technology has led to the identification of an increasing number of genes associated with epilepsy. These discoveries will both provide the basis for including genetic tests in clinical practice and improve diagnosis and treatment of epilepsy. By searching through several databases (OMIM, HGMD, and EpilepsyGene) and recent publications on PubMed, we found 977 genes that are associated with epilepsy. We classified these genes into 4 categories according to the manifestation of epilepsy in phenotypes. We found 84 genes that are considered as epilepsy genes: genes that cause epilepsies or syndromes with epilepsy as the core symptom. 73 genes were listed as neurodevelopment-associated genes: genes associated with both brain-development malformations and epilepsy. Several genes (536) were epilepsy-related: genes associated with both physical or other systemic abnormalities and epilepsy or seizures. We found 284 additional genes putatively associated with epilepsy; this requires further verification. These integrated data will provide new insights useful for both including genetic tests in the clinical practice and evaluating the results of genetic tests. We also summarized the epilepsy-associated genes according to their function, with the goal to better characterize the association between genes and epilepsies and to further understand the mechanisms underlying epilepsy., (Copyright © 2016. Published by Elsevier Ltd.)

Background: Gut hormones secretion is related to habitual mealtimes. However, how fast gut hormones adjust to that change when people change their fixed mealtime remains unknown., Methods: Seven healthy male volunteers were asked to eat a test breakfast at 0700 am for 2 weeks before the start of the study. Then, their fixed mealtime was intentionally changed from 0700 am to 0900 am for next 2 weeks. Blood samples were drawn every half hour from 0500 am until next 3h after breakfast for determining gut hormone levels every week., Results: After a change in fixed mealtime, the release pattern of acylated ghrelin was first adjusted identically according to the change and then total ghrelin was made. The meal-related fluctuations of acylated ghrelin were delayed by 120 min from week 1 after the change, while those of total ghrelin were delayed by 60 min at week 1, by 120 min at week 2. Two weeks was not enough time to adjust completely for PYY(3-36) to the change., Conclusion: Two weeks is enough time until the pattern release of ghrelin, but not PYY(3-36) , is adjusted fully after a fixed mealtime change in human., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Autophagy orchestrates programmed cell death via crossroads of complex vesicle trafficking including autophagosome and lysosome interaction. Phafin1, an endosome proteins composed of Pleckstrin homology (PH) and Fab1-YotB-Vac1p-EEA1 (FYVE) domain membrane-binding domains, is involved in caspase-independent apoptosis. We report here that the increased expression of phafin1 and its FYVE domain caused the formation of enlarged endosomes. Phafin1 also modulates the membrane density of certain receptors and participates in endocytosis and autophagy processes. The PH-domain of phafin1 is dispensable for lysosomal targeting. Moreover, the tail-domain of phafin1 provides lysosomal targeting signature and the ability to induce autophagy that is mediated by Rab7 signaling. The results suggest that in addition to its role in endosome transport, phafin1 is also involved in lysosomal targeting and autophagosome formation., (Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.)

Background: Serum amylase has recently been shown to be associated with ghrelin and adiponectin as well as obesity. We investigated the relationship between total amylase and metabolic syndrome in adults., Methods: 4495 adults were enrolled. All subjects denied any medical history or status of a disorder that could influence their serum amylase. Anthropometry, metabolic risk factors and total amylase concentration were measured. Each participant was categorized into one of 4 subgroups according to their total amylase concentration. Multiple logistic regression analysis was used to assess the independent association between amylase concentration and metabolic syndrome. Receiver-operating characteristics (ROC) curves analyses were used for comparison of the diagnostic value of amylase and other biomarkers for metabolic syndrome., Results: The prevalence of metabolic syndrome by the National Cholesterol Education Program criteria was 13.4%, 15.3%, 19.3%, and 24.2% of those in the fourth, third, second, and lowest quartile of amylase concentration (P for trend <0.001). After adjusting for age, sex, and body mass index, the odds ratios of the lower quartiles were significantly higher compared to the fourth quartile for the presence of metabolic syndrome. In ROC curve analysis, amylase was similar to uric acid as a significant diagnostic indicator for metabolic syndrome, but it had lower diagnostic value than alanine aminotransferase, γ-glutamyltransferase or C-reactive protein., Conclusions: Lower amylase concentration is associated with an increased prevalence of metabolic syndrome. Amylase may contribute to identifying metabolic syndrome, although further research is needed to understand the mechanism behind these associations., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Till now truncation mutations of voltage-gated sodium channel alpha subunit type I (SCN1A) gene were mostly found in severe myoclonic epilepsy of infancy (SMEI) patients. In this research we first identified two novel de novo truncation mutations (S662X and M145fx148) in two patients whose phenotypes were quite milder compared with SMEI patients. One patient was diagnosed as generalized epilepsy with febrile seizures plus (GEFS+); the other had focal seizures. Both patients had good response to anti-epileptic therapy (valproate or the combination of valproate and topiramate). Our findings extended the utility of the SCN1A gene testing and further confirmed the complex relationship between genotype and phenotype of SCN1A mutations. Further work is needed to optimize the protocol for specific genetic testing in children with epilepsy., (2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Echinoside A was isolated from sea cucumber. This study demonstrates its anticancer effects and its mechanisms of action., Materials and Methods: Anticancer effects of echinoside A were evaluated in vitro and in vivo. TUNEL and DNA fragmentation assays were applied to examine its ability to induce apoptosis. A series of biochemical assays were applied to investigate the inhibition of echinoside A on topoisomerase2alpha (Top2alpha). Molecular docking analyses were used to demonstrate the direct interaction between echinoside A and Top2alpha., Results: Echinoside A inhibited the growth of tumors in mouse models and human prostate carcinoma xenografts in nude mouse models. Echinoside A shows the unique characteristics of inhibiting the noncovalent binding of Top2alpha to DNA by competing with DNA for the DNA-binding domain of the enzyme and of interfering predominantly with the Top2alpha-mediated prestrand passage cleavage/religation equilibrium over with the poststrand passage one. These features distinguish echinoside A from other known Top2alpha inhibitors. As a result, echinoside A induced DNA double-strand breaks in a Top2-dependent manner., Conclusion: Echinoside A targets Top2alpha by unique interference with the binding of Top2 to DNA and by imparing the Top2-mediated DNA cleavage and religation, exerting potent in vitro and in vivo antitumor activities.

A new triterpene glycoside (1) along with the known intercedenside B (2) was isolated from the sea cucumber Pseudocolochirus violaceus. Glycoside 1 was elucidated as 3-O-{6-O-sodiumsulfate-3-O-methyl-beta-D-glucopyranosyl-(1-->3)-beta-D-xylopyranosyl-(1-->4)-[beta-D-xylopyranosyl(1-->2)]-beta-D-quinovopyranosyl-(1-->2)-4-O-sodiumsulfate-beta-D-xylopyranosyl}-16beta-acetoxy-holosta-7, 24-diene-3beta-ol on the basis of extensive spectral studies and chemical evidence. Both the glycosides exhibited significant cytotoxicity against cancer cell lines MKN-45 and HCT-116.

Bioassay-guided fractionation of the n-BuOH extract of the starfish Culcita novaeguineae resulted in the isolation of one new sulfated steroidal glycoside (asterosaponin) (1), along with three known asterosaponins, thornasteroside A (2), marthasteroside A(1) (3) and regularoside A (4), as active compounds causing morphological abnormality of Pyricularia oryzae mycelia. Their structures were elucidated by extensive spectral studies and chemical evidences. All the saponins showed moderate cytotoxicity against cancer cell lines K-562 and BEL-7402.

Serotonin (5-hydroxytryptamine) metabolism may be influenced by its precursor tryptophan. A method utilizing reversed-phase high-performance liquid chromatography and electrochemical and ultraviolet detection with a mobile phase composed of acetate buffer and methanol has been developed for determination of tryptophan, its metabolites 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid, as well as 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid) and 3-methoxy-4-hydroxyphenylglycol in human cerebrospinal fluid (CSF). The electrochemical potential is set at 0.6 V in order to reduce the background current. Since tryptophan is not electroactive at this potential, it is detected by ultraviolet absorbance. The present method is simple, rapid, specific and accurate as compared with a previously reported method. No sample pretreatment is necessary and it takes ca. 20 min to run a sample. The concentrations of the compounds measured in CSF are similar to those obtained by HPLC in previous reports, although there are still arguments about the true level of serotonin in CSF.

A new triterpenoid saponin, 3-O-[beta-D-glucopyranosyl(1----4)-beta-D- xylopyranosyl]-28-O-beta-D-glucopyranosyl-30-methyloleanate-9(11), 12-dien- 2,3,23-trihydroxyl-28-oic acid, was isolated from the roots of Phytolacca esculenta. The structure was assigned by chemical methods and spectral analysis (1H, 13C, DEPT NMR, EIMS and FABMS) including 1H-1H COSY, 1H-13C COSY and 1H-1H NOESY.

A new triterpenoid, esculentagenin, and its glycoside, esculentoside M, were isolated from the roots of Phytolacca esculenta and characterized as 11-oxo-3-O-methyloleanata-12-en-2 beta,3 beta,23-trihydroxy-28-oic acid and 3-O-[beta-D-glucopyranosyl(1----4)-beta-D-xylopyranosyl]-28-O-beta-D- glucopyranosyl-11-oxo-30-methyloleanate-12-en-2 beta,3 beta,23-trihydroxy-28-oic acid by spectral and chemical evidence.