Investigating the Effects of Perampanel on Autophagy-mediated Regulation of GluA2 and PSD95 in Epilepsy.

Epilepsy is a chronic neurological disorder characterized by recurrent seizures. Despite various treatment approaches, a significant number of patients continue to experience uncontrolled seizures, leading to refractory epilepsy. The emergence of novel anti-epileptic drugs, such as perampanel (PER), has provided promising options for effective epilepsy treatment. However, the specific mechanisms underlying the therapeutic effects of PER remain unclear. This study aimed to investigate the intrinsic molecular regulatory mechanisms involved in the downregulation of GluA2, a key subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, following epileptic seizures. Primary mouse hippocampal neurons were cultured and subjected to an epilepsy cell model. The expression levels of GluA2 and autophagy-related proteins were assessed using Western blotting and real-time fluorescent quantitative PCR. Immunofluorescence and immunohistochemistry techniques were employed to investigate the nuclear translocation of CREB-regulated transcriptional coactivator 1 (CRTC1). Additionally, status epilepticus animal models were established to further validate the findings. The epilepsy cell model exhibited a significant decrease in GluA2 expression, accompanied by elevated levels of autophagy-related proteins. Immunofluorescence analysis revealed the nuclear translocation of CRTC1, which correlated with the expression of autophagy-related genes. Treatment with an autophagy inhibitor reversed the decreased expression of GluA2 in the epilepsy cell model. Furthermore, the calcium/calmodulin-dependent protein phosphatase inhibitor FK506 and CaN overexpression affected the dephosphorylation and nuclear translocation of CRTC1, consequently influencing GluA2 expression. Animal model results further supported the involvement of these molecular mechanisms in epilepsy. Our findings suggest that the downregulation of GluA2 following epileptic seizures involves the activation of autophagy and the regulation of CRTC1 nuclear translocation. These intrinsic molecular regulatory mechanisms provide potential targets for developing novel therapeutic strategies to alleviate refractory epilepsy and preserve cognitive functions in patients.

Genetic correlation and Mendelian randomization analyses support causal relationships between dietary habits and age at menarche.

Dietary habits are essential in the mean age at menarche (AAM). However, the causal relationship between these factors remains unclear. Therefore, this study aimed to elucidate the genetic relationship between dietary habits and AAM. Genetic summary statistics for dietary habits were obtained from the UK Biobank. GWAS summary data for AAM was obtained from the ReproGen Consortium. Linkage disequilibrium score regression was used to test genetic correlations between dietary habits and AAM. The Mendelian randomization (MR) analyses used the inverse-variance weighted method. Genetic correlations with AAM were identified for 29 candi-date dietary habits, such as milk type (skimmed, semi-skimmed, full cream; coefficient = 0.2704, Pldsc = 1.13 × 10-14). MR evaluations revealed that 19 dietary habits were associated with AAM, including bread type (white vs. any other; OR 1.71, 95% CI 1.28-2.29, Pmr = 3.20 × 10-4), tablespoons of cooked vegetables (OR 0.437, 95% CI 0.29-0.67; Pmr = 1.30 × 10-4), and cups of coffee per day (OR 0.72, 95% CI 0.57-0.92, Pmr = 8.31 × 10-3). These results were observed to be stable under the sensitivity analysis. Our study provides potential insights into the genetic mechanisms underlying AAM and evidence that dietary habits are associated with AAM.

Towards high performance wood composites through interface customization with cellulose-based adhesive.

How to efficiently produce high performance plywood is of particular interest, while its sensitivity to moisture is overcome. This paper presents a simple and scalable strategy for the preparation of high-performance plywood based on the chemical bonding theory; a wood interfacial functionalized platform (WIFP) based on (3-aminopropyl) triethoxysilane (APTES) was established. Interestingly, the APTES-enhanced dialdehyde cellulose-based adhesive (DAC-APTES) was able to effectively establish chemically active adhesive interfaces; the dry/wet shear strength of WIFP/DAC-APTES adhesive was 3.15/1.31 MPa, which was much higher than 0.7 MPa (GB/T 9846-2015). The prepared plywood showed excellent wood-polymer interface adhesion, which exceeded the force that the wood itself could withstand. In addition, the DAC-APTES adhesive exhibits moisture evaporation-induced curing behavior at room temperature and can easily support the weight of an adult weighing 65.7 Kg. This research provides a novel approach for functionalized interface design of wood products, an effective means to prepare high-performance plywood.

A Comprehensive Study on the Association between Plasma NOV/CCN3 Levels and Insulin Resistance in Childhood Obesity.

INTRODUCTION: Childhood obesity is a global health problem that is associated with various metabolic complications, such as insulin resistance, type 2 diabetes, dyslipidemia, and cardiovascular diseases. The mechanisms underlying the development of insulin resistance in childhood obesity are not fully understood. Nephroblastoma overexpressed gene (NOV), also known as CCN3, is a member of the CCN family of matricellular proteins that modulate cell proliferation, differentiation, adhesion, migration, and survival. Previous studies have shown that NOV/CCN3 is involved in glucose metabolism and insulin signaling in various tissues and cell types. However, the role of NOV/CCN3 in childhood obesity and insulin resistance remains unclear. METHODS: In this study, we aimed to investigate the association between plasma NOV/CCN3 levels and insulin resistance in 58 obese and 43 non-obese children aged 6-12 years. We measured plasma NOV/CCN3 levels by enzyme-linked immunosorbent assay (ELISA), and assessed insulin resistance by homeostasis model assessment of insulin resistance (HOMA-IR). We also collected clinical and biochemical data, such as body mass index (BMI), waist circumference (WC), blood pressure (BP), fasting glucose (FG), fasting insulin (FI), lipid profile, and inflammatory markers. RESULTS: We found that plasma NOV/CCN3 levels were significantly higher in obese children than in non-obese children (P<0.001), and positively correlated with BMI (r=0.42, P<0.001), WC (r=0.38, P<0.001), BP (r=0.35, P<0.001), FG (r=0.31, P<0.001), FI (r=0.45, P<0.001), HOMA-IR (r=0.48, P<0.001), triglycerides (r=0.28, P<0.001), low-density lipoprotein cholesterol (LDL-C) (r=0.26, P<0.001), and C-reactive protein (CRP) (r=0.32, P<0.001). Multiple linear regression analysis revealed that plasma NOV/CCN3 levels were independently associated with HOMA-IR after adjusting for age, sex, BMI, WC, BP, FG, FI, lipid profile, and CRP (ß=0.36, P<0.001). CONCLUSION: These results suggest that plasma NOV/CCN3 levels are elevated in childhood obesity and are associated with insulin resistance, indicating that NOV/CCN3 may play a role in the pathogenesis of metabolic disorders in obese children.

Study on network pharmacology of Ginkgo biloba extract against ischaemic stroke mechanism and establishment of UPLC-MS/MS methods for simultaneous determination of 19 main active components.

INTRODUCTION: Ginkgo biloba extract (GBE) is an effective substance from traditional Chinese medicine (TCM) G. biloba for treating ischaemic stroke (IS). However, its active ingredients and mechanism of action remain unclear. OBJECTIVES: This study aimed to reveal the potential active component group and possible anti-IS mechanism of GBE. MATERIALS AND METHODS: The network pharmacology method was used to reveal the possible anti-IS mechanism of these active ingredients in GBE. An ultra-high-performance liquid chromatography triple quadrupole electrospray tandem mass spectrometry (UPLC-MS/MS) method was established for the simultaneous detection of the active ingredients of GBE. RESULTS: The active components of GBE anti-IS were screened by literature integration. Network pharmacology results showed that the anti-IS effect of GBE is achieved through key active components such as protocatechuic acid, bilobalide, ginkgolide A, and so on. Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the possible anti-IS mechanism of GBE is regulating the PI3K-Akt signalling pathway and other signal pathways closely related to inflammatory response and apoptosis regulation combined with AKT1, MAPK, TNF, ALB, CASP3, and other protein targets. Nineteen main constituents in seven batches of GBE were successfully analysed using the established UPLC-MS/MS method, and the results showed that the content of protocatechuic acid, gallic acid, ginkgolide A, and so forth was relatively high, which was consistent with network pharmacology results, indicating that these ingredients may be the key active anti-IS ingredients of GBE. CONCLUSION: This study revealed the key active components and the anti-IS mechanism of GBE. It also provided a simple and sensitive method for the quality control of related preparations.

High-performance bamboo composites based on the chemical bonding of active bamboo interface and chitosan.

Nowadays, green, clean, and efficient sustainable development has become the world's mainstream industrial development. However, the bamboo/wood industry is still in the status quo with high fossil resource dependence and significant greenhouse gas emissions. Herein, a low-carbon and green strategy to produce bamboo composites is developed. The bamboo interface was modified directionally to a bamboo carboxy/aldehyde interface by using a TEMPO/NaIO4 system, and then chemically cross-linked with chitosan to produce active bonding bamboo composite (ABBM). It was confirmed that the chemical bond cross-linking (CN, N-C-N, electrostatic interactions, hydrogen bonding) in the gluing region was helpful to obtain the excellent dry bonding strength (11.74 MPa), water resistance (5.44 MPa), and anti-aging properties (decreased by 20 %). This green production of ABBM solves the problem of poor water resistance and aging resistance of all-biomass-based chitosan adhesives. It can replace bamboo composites produced using fossil-based adhesives to meet the requirements of the construction, furniture, and packaging industries, changing the previous situation of composite materials requiring high temperature pressing and highly dependent on fossil-based adhesives. This provides a greener and cleaner production method for the bamboo industry, as well as more options for the global bamboo industry to achieve green and clean production goals.

Identifying Novel Drug Targets for Epilepsy Through a Brain Transcriptome-Wide Association Study and Protein-Wide Association Study with Chemical-Gene-Interaction Analysis.

Epilepsy is a severe neurological condition affecting 50-65 million individuals worldwide that can lead to brain damage. Nevertheless, the etiology of epilepsy remains poorly understood. Meta-analyses of genome-wide association studies involving 15,212 epilepsy cases and 29,677 controls of the ILAE Consortium cohort were used to conduct transcriptome-wide association studies (TWAS) and protein-wide association studies (PWAS). Furthermore, a protein-protein interaction (PPI) network was generated using the STRING database, and significant epilepsy-susceptible genes were verified using chip data. Chemical-related gene set enrichment analysis (CGSEA) was performed to determine novel drug targets for epilepsy. TWAS analysis identified 21,170 genes, of which 58 were significant (TWASfdr < 0.05) in ten brain regions, and 16 differentially expressed genes were verified based on mRNA expression profiles. The PWAS identified 2249 genes, of which 2 were significant (PWASfdr < 0.05). Through chemical-gene set enrichment analysis, 287 environmental chemicals associated with epilepsy were identified. We identified five significant genes (WIPF1, IQSEC1, JAM2, ICAM3, and ZNF143) that had causal relationships with epilepsy. CGSEA identified 159 chemicals that were significantly correlated with epilepsy (Pcgsea < 0.05), such as pentobarbital, ketone bodies, and polychlorinated biphenyl. In summary, we performed TWAS, PWAS (for genetic factors), and CGSEA (for environmental factors) analyses and identified several epilepsy-associated genes and chemicals. The results of this study will contribute to our understanding of genetic and environmental factors for epilepsy and may predict novel drug targets.

Activated wood surface and functionalized cellulose co-building strong chemical wood bonding performance.

Herein, an activated wood surface rich in CHO groups was constructed by spraying a sodium periodate aqueous solution on a natural wood surface. Besides, microcrystalline cellulose was functionalized to obtain aminated cellulose, which was dissolved in an aqueous solution and used as a specific adhesive. Subsequently, an ultrastrong wood bonding interface was co-constructed with the activated wood surface and aminated cellulose, which was formed by a chemical covalent reaction between aldehyde groups at the activated wood interface and amino groups on aminated cellulose. The dry, hot-water, and boiling-water lap shear strengths of the plywood specimens were 1.47, 1.07, and 1.08 MPa, respectively. The boiling-water strength of the plywood made from the activated wood surface achieved increased to 1.08 MPa from 0 MPa of the plywood constructed on the nonactivated wood surface. The chemical crosslinking reaction and bonding mechanism between the adhesive and activated wood surface were clarified by density functional theory calculations, attenuated total reflectance-Fourier-transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The results showed that chemical bonding (aminal NCN and imine CN) at the bonding interface played an important part in improving the water resistance and bonding strength. This work provides new concepts for designing durable and moisture-resistant wood products.

Identification of candidate genes and pathways associated with juvenile idiopathic arthritis by integrative transcriptome-wide association studies and mRNA expression profiles.

AIM: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood, with genetic susceptibility and pathological processes such as autoimmunity and autoinflammation, but its pathogenesis is unclear. We conducted a transcriptome-wide association study (TWAS) using expression interpolation from a large-scale genome-wide association study (GWAS) dataset to identify genes, biological pathways, and environmental chemicals associated with JIA. METHODS: We obtained published GWAS data on JIA for TWAS and used mRNA expression profiling to validate the genes identified by TWAS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. A protein-protein interaction (PPI) network was generated, and central genes were obtained using Molecular Complex Detection (MCODE). Finally, chemical gene expression datasets were obtained from the Comparative Toxicogenomics database for chemical genome enrichment analysis. RESULTS: TWAS identified 1481 genes associated with JIA, and 154 differentially expressed genes were identified based on mRNA expression profiles. After comparing the results of TWAS and mRNA expression profiles, we obtained eight overlapping genes. GO and KEGG enrichment analyses of the genes identified by TWAS yielded 163 pathways, and PPI network analysis as well as MCODE resolution identified a total of eight clusters. Through chemical gene set enrichment analysis, 287 environmental chemicals associated with JIA were identified. CONCLUSION: By integrating TWAS and mRNA expression profiles, genes, biological pathways, and environmental chemicals associated with JIA were identified. Our findings provide new insights into the pathogenesis of JIA, including candidate genetic and environmental factors contributing to its onset and progression.

Characterization of the complete mitochondrial genome of Neolissochilus hendersoni (Herre, 1940) (Cypriniformes: Cyprinidae).

The differentiation between Neolissochilus and Acrossocheilus species based only on morphology is ambiguous; however, phylogenetic analysis using their mitogenome sequences provides conclusive results. Here, the phylogenetic position of Neolissochilus hendersoni (Herre, 1940) was determined using its mitogenome data. Total DNA from N. hendersoni was sequenced using the Illumina NovaSeq6000 platform, and annotation of mitochondrial genes was performed using MITOS2. Phylogenetic trees were constructed using the complete mitogenomes of 16 fish species. The mitogenome of N. hendersoni was found to be 16584 bp long, containing two ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes, and three non-coding control regions. The genome showed a slight A + T bias (A + T = 56.46%). Most PCGs were found to be located on the L-strand. Results of the phylogenetic analysis showed that N. stracheyi is closely related to N. hendersoni. Our results will help to clarify the phylogenetic relationship between Neolissochilus and Acrossocheilus species.

Lifestyle Improvements and Vitamin D Supplementation Play an Important Role in the Prevention of Childhood Diabetes.

Objective: This study was to investigate the characteristics of insulin secretion and the 25-hydroxyvitamin D3 (25(OH)D3) levels in children with obesity. Methods: A retrospective analysis was conducted among children who underwent health checkups in the pediatric healthcare department of our hospital from January 2018 to January 2021, and they were divided into a normal group and an obese group according to their BMI. The insulin secretion and the 25(OH)D3 levels of the two groups of children were compared. A total of 721 children were included in the study, including 591 in the normal group and 130 in the obese group, with an obesity rate of 18.03%. Results: The blood glucose of the normal group was 4.55 ± 1.75 mmol/L, and the 2 h PG was 7.51 ± 2.11 mmol/L; in the obesity group, they were 6.03 ± 2.16 mmol/L and 8.92 ± 3.24 mmol/L, respectively. The FPG and 2 h PG in the obese group were significantly higher than those in the normal group (all P < 0.05). The incidence of IFG/IGT in the normal group was 5.24% (31/591), and the incidence of DM was 3.71% (22/591); the incidence of IFG/IGT in the obese group was 14.62% (19/130), and the incidence of DM was 13.08% (17/130). The incidences of IFG/IGT and DM in the obese group were significantly higher than those in the normal group (P < 0.05). The FINS of the children in the normal group was 18.46 ± 3.15 µU/mL, and the HOMA-IR was 2.64 ± 0.62; the above indicators in the obese group were 19.11 ± 4.72 µU/mL and 3.01 ± 0.83, respectively. The FINS and HOMA-IR in the obese group were significantly higher than those in the normal group (P < 0.05). The serum 25(OH)D3 level in the normal group was 28.15 ± 5.27 ng/mL, of which 556 cases were normal in 25(OH)D3 and 35 cases were deficient in 25(OH)D3. The serum 25(OH)D3 level in the obese group was 24.35 ± 4.51 ng/mL, of which 112 cases were normal in 25(OH)D3 and 18 cases were deficient in 25(OH)D3. The level of serum 25(OH)D3 in the normal group was significantly higher than that in the normal group, and the ratio of 25(OH)D3 deficiency was significantly lower than that in the normal group (P < 0.05). Conclusions: The blood glucose level of childhood obesity was significantly increased, the incidence of abnormal glucose metabolism and diabetes was significantly increased, and the level of 25(OH) vitamin D3 was significantly decreased. Lifestyle improvements and vitamin D supplementation play an important role in the prevention of childhood diabetes. Because the major causes of childhood obesity are excessive caloric intake and lack of exercise, the most effective and direct measures to prevent obesity are a reasonable lifestyle, reasonable eating habits, and moderate exercise. Although genetics are critical, there is no reliable way to eliminate obesity genes in the human body. Therefore, the role of obesity genes is required to be ultimately eliminated by reduced caloric intake and increased physical activity.

Identifying celiac disease-related chemicals by transcriptome-wide association study and chemical-gene interaction analyses.

Celiac disease (CeD) is one of the most common intestinal inflammatory diseases, and its incidence and prevalence have increased over time. CeD affects multiple organs and systems in the body, and environmental factors play a key role in its complex pathogenesis. Although gluten exposure is known to be the causative agent, many unknown environmental factors can trigger or exacerbate CeD. In this study, we investigated the influence of genetic and environmental factors on CeD. Data from a CeD genome-wide association study that included 12,041 CeD cases and 12,228 controls were used to conduct a transcriptome-wide association study (TWAS) using FUSION software. Gene expression reference data were obtained for the small intestine, whole blood, peripheral blood, and lymphocytes. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses using the significant genes identified by the TWAS and conducted a protein-protein interaction network analysis based on the STRING database to detect the function of TWAS-identified genes for CeD. We also performed a chemical-related gene set enrichment analysis (CGSEA) using the TWAS-identified genes to test the relationships between chemicals and CeD. The TWAS identified 8,692 genes, including 101 significant genes (p adjusted < 0.05). The CGSEA identified 2,559 chemicals, including 178 chemicals that were significantly correlated with CeD. This study performed a TWAS (for genetic factors) and CGSEA (for environmental factors) and identified several CeD-associated genes and chemicals. The findings expand our understanding of the genetic and environmental factors related to immune-mediated diseases.

Adipokines, Hepatokines and Myokines: Focus on Their Role and Molecular Mechanisms in Adipose Tissue Inflammation.

Chronic low-grade inflammation in adipose tissue (AT) is a hallmark of obesity and contributes to various metabolic disorders, such as type 2 diabetes and cardiovascular diseases. Inflammation in ATs is characterized by macrophage infiltration and the activation of inflammatory pathways mediated by NF-κB, JNK, and NLRP3 inflammasomes. Adipokines, hepatokines and myokines - proteins secreted from AT, the liver and skeletal muscle play regulatory roles in AT inflammation via endocrine, paracrine, and autocrine pathways. For example, obesity is associated with elevated levels of pro-inflammatory adipokines (e.g., leptin, resistin, chemerin, progranulin, RBP4, WISP1, FABP4, PAI-1, Follistatin-like1, MCP-1, SPARC, SPARCL1, and SAA) and reduced levels of anti-inflammatory adipokines such as adiponectin, omentin, ZAG, SFRP5, CTRP3, vaspin, and IL-10. Moreover, some hepatokines (Fetuin A, DPP4, FGF21, GDF15, and MANF) and myokines (irisin, IL-6, and DEL-1) also play pro- or anti-inflammatory roles in AT inflammation. This review aims to provide an updated understanding of these organokines and their role in AT inflammation and related metabolic abnormalities. It serves to highlight the molecular mechanisms underlying the effects of these organokines and their clinical significance. Insights into the roles and mechanisms of these organokines could provide novel and potential therapeutic targets for obesity-induced inflammation.

The complete mitochondrial genome of Neolissochilus stracheyi (Osteichthyes:Cyprinidae).

Neolissochilus stracheyi Day 1871 is a rare specie of fish inhabit clear forest streams and rivers. In order to discuss the phylogenetic position of N. stracheyi, the mitochondrial genome was obtained by sequencing. The genome was 16,587 bp in length with an accession number OM203155. The AT contents were 56.59%. The location and composition of genes are consistent with published Cyprinids containing 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 main non-coding regions. Sequence analysis showed that the mitochondrial genome of N. stracheyi has high sequence homology with other cyprinid fishes. Phylogenetic tree results showed that N. stracheyi is most closely related to Neolissochilus heterostomus. The mitochondrial sequence is of great significance for fish conservation, taxonomic status and resource exploitation.

Follistatin-Like 1 and Family with Sequence Similarity to 19 Member A5 Levels Are Decreased in Obese Children and Associated with Glucose Metabolism.

INTRODUCTION: Childhood obesity is a significant and growing problem worldwide. Recent evidence suggests Follistatin-like 1 (FSTL1) and family with sequence similarity to 19 member A5 (FAM19A5) to be novel adipokines. However, very few studies have examined the plasma levels of FSTL1 and FAM19A5 in children. Therefore, this cross-sectional study evaluated the association between serum FSTL1 and FAM19A5 levels and obesity in children and investigated the relationship between FSTL1 and FAM19A5 and glucose metabolism or endothelial injury. METHODS: Fifty-five obese children and 48 healthy controls were recruited. Plasma FSTL1 and FAM19A5 levels were detected using ELISA. In addition, the association between the clinical data and anthropometric parameters was analyzed. RESULTS: Serum FAM19A5 levels were significantly decreased in the obese children, at 189.39 ± 19.10 pg/mL, compared with those without obesity, at 211.08 ± 38.09 pg/mL. Serum concentrations of FSTL1 were also significantly lower in the obese children, at 0.64 (0.37-0.64) ng/mL, compared with those without obesity, at 1.35 (1.05-2.12) ng/mL. In addition, FAM19A5 (OR = 0.943; p = 0.003) was a predictor of insulin resistance in obese children compared with healthy controls. Lastly, serum FAM19A5 and FSTL1 played mediating roles in insulin resistance in children. CONCLUSION: The serum levels of FAM19A5 and FSTL1 were decreased in obese children; therefore, FAM19A5 and FSTL1 likely play important roles in glucose metabolism in obese children.

Identifying Environmental Endocrine Disruptors Associated With the Age at Menarche by Integrating a Transcriptome-Wide Association Study With Chemical-Gene-Interaction Analysis.

Menarche is the first occurrence of menstrual bleeding and one of the most important events of female puberty. Alarmingly, over the last several decades, the mean age at menarche (AAM) has decreased. Environmental endocrine disruptors (EEDs) are chemicals that may interfere with the endocrine system, resulting in adverse developmental, immunological, neurological, and reproductive effects in humans. Thus, the effects of EEDs on fertility and reproduction are growing concerns in modern societies. In this study, we aimed to determine the influence of genetic and environmental factors on AAM. We used data from an AAM genome-wide association study of 329,345 women to conduct a transcriptome-wide association study (TWAS) with FUSION software. As references, we determined the gene-expression levels in the hypothalamus, pituitary gland, ovaries, uterus, and whole blood. We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses using the significantly dysregulated genes identified by the TWAS. Using the STRING database, we also generated a protein-protein-interaction network to analyze common AAM-specific genes identified by the TWAS with different tissues. We performed chemical-related gene set enrichment analysis (CGSEA) and identified significant TWAS genes to uncover relationships between different chemicals and AAM. The TWAS identified 9,848 genes; among these, 1580 genes were significant (P < 0.05), and 11 genes were significant among the hypothalamus, pituitary, ovary, uterus, and whole blood. CGSEA identified 1,634 chemicals, including 120 chemicals significantly correlated with AAM. In summary, we performed a TWAS (for genetic factors) and CGSEA (for environmental factors) focusing on AAM and identified several AAM-associated genes and EEDs. The results of this study expand our understanding of genetic and environmental factors related to the onset of female puberty.

Inhibition of USP15 ameliorates high-glucose-induced oxidative stress and inflammatory injury in podocytes through regulation of the Keap1/Nrf2 signaling.

Ubiquitin-specific peptidase 15 (USP15) is implicated in the pathogenesis of numerous diseases. However, whether USP15 plays a role in diabetic nephropathy remains undetermined. This project was designed to determine the potential role of USP15 in mediating high glucose (HG)-induced podocyte injury, a key event in the pathogenesis of diabetic nephropathy. We found that USP15 levels were elevated in podocytes after HG stimulation. Inhibition of USP15 led to decreases in HG-evoked apoptosis, oxidative stress, and inflammation in podocytes. Further investigation showed that inhibition of USP15 enhanced the activation of NF-E2-related factor 2 (Nrf2) and expression of Nrf2 target genes in HG-simulated podocytes. Moreover, depletion of Kelch-like ECH-associated protein 1 (Keap1) diminished the regulatory effect of USP15 inhibition on Nrf2 activation. In addition, Nrf2 suppression reversed USP15-inhibition-induced protective effects in HG-injured podocytes. Taken together, these data indicate that USP15 inhibition protects podocytes from HG-induced injury by enhancing Nrf2 activation via Keap1.

A randomized controlled trial on the effect of dietary guidance on the treatment of Henoch-Schonlein purpura in children.

The amino acid-based formulae were extensively added to diet of children for the treatment of Henoch-Schonlein purpura (HSP), and the nutrition and growth situation of children were evaluated after giving new dietary intervention. Patients were randomly divided into restricted diet group (n=30) and dietary guidance group (n=30). Besides, 30 cases with bronchiolitis who had normal diet were selected as the control group. The dietary questionnaire was designed to record the types and intakes of various foods taken by children every day, and the intake levels of nutrients were analyzed. Physical examination, biochemical analysis of blood and urine routine were carried out to evaluate the effect of dietary guidance on their growth and development. The results showed that restricted diet group had lower levels of nutrient intake and the actual/recommended percentage. However, overall nutrient intake level of the dietary guidance group was higher, basically equal to the recommended intake level. Besides, the actual intake and actual/recommended percentage of nutrients of dietary guidance group were significantly higher than those of restricted diet group (p<0.05). Dietary guidance can improve nutrients and protein intake of children with HSP, and reduce the relapse of rash and incidence of complications.

SFRP5 mediates downregulation of the wnt5a/caveolin-1/JNK signaling pathway.

This study investigated the effects of Wnt5a/caveolin/JNK signaling pathway and SFRP5 protein on ox-LDL-induced apoptosis of HUVEC cells. The difference of serological indexes between healthy average weight and obese children and the expression of Wnt 5a and SFRP5 was detected by clinical examination, and the correlation between serum SFRP5, Wnt 5a and the vascular endothelial injury was detected. HUVEC cells were induced by ox-LDL to construct an endothelial injury model, siRNA-transfected cells were used to construct downregulated SFRP5 and Wnt 5a expression groups, and recombination methods were used to construct upregulated Wnt5a and SFRP5 expression groups. The expression of Wnt 5a, caveolin-1, JNK and apoptosis-related proteins under different treatments were detected by the Western blot method, and apoptosis was detected by flow cytometry. Serological results showed that the level of Sfrp5 in obese children was significantly lower than that in healthy children, and the level of Wnt5a was significantly higher than that in healthy children. Moreover, Ln Sfrp5 was significantly negatively correlated with Ang-2 in blood circulation, ICAM-1 and E-selectin selectin, but not with VCAM-1. When Wnt5a was upregulated, the expression of caveolin-1 and JNK increased significantly, Bcl-2 decreased significantly, and the apoptotic rate increased significantly. Nevertheless, when Sfrp5 expression was upregulated, the result was the opposite. SFRP5 and Wnt5a are involved in the vascular endothelial injury. Wnt5a can promote apoptosis of HUVEC cells through Wnt5a/JNK/Caveolin-1 pathway, while SFRP5 can inhibit apoptosis by interfering with this pathway.

Copeptin and Nesfatin-1 Are Interrelated Biomarkers with Roles in the Pathogenesis of Insulin Resistance in Chinese Children with Obesity.

BACKGROUND: Copeptin and nesfatin-1 have recently been identified as novel peptides that play a role in the pathogenesis of obesity-related insulin resistance in adults. However, the relationship between them has not yet been elucidated, and their circulating levels in children with obesity have not been adequately studied. Therefore, the current study aimed to investigate whether their levels are altered in Chinese children with obesity, as well as to determine the correlation of these 2 peptides with each other, with insulin resistance, and with other biochemical parameters. METHODS: A total of 156 children were enrolled in this study, including 101 children with obesity and 55 lean controls. Anthropometric parameters and clinical data of all subjects were collected, and circulating tumor necrosis factor-α, adiponectin, leptin, copeptin, and nesfatin-1 levels were measured using ELISA. RESULTS: Serum copeptin and nesfatin-1 levels were significantly elevated in children with obesity and children with insulin resistance compared to control subjects. In addition, nesfatin-1 and copeptin levels were found to be significantly positively correlated with one another by Pearson's correlation and partial correlation. In multiple regression analysis using nesfatin-1 or copeptin as the dependent parameter, a significant correlation was observed between nesfatin-1 and copeptin, and associations between each of them with homeostasis model assessment of insulin resistance (HOMA-IR) were detected. CONCLUSION: These novel findings shed light on the possible interplay role of these 2 molecules in obesity-related insulin resistance.