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To investigate the direct and indirect relationships between statin use, low-density lipoprotein cholesterol (LDL-C) levels, and intracerebral hemorrhage (ICH), providing new insights into this complex scientific question. In this cohort study, UK Biobank data from 2006 to 2010 were used to construct Structural Equation Models of statin use, LDL-C, and ICH, including 414,253 participants with LDL-C data. Published Genome-Wide Association Studies data were used for drug-target Mendelian Randomization analysis. The study included 414,253 participants, comprising 225,454 women (54.4%) with a mean age of 56.07 (8.11) years. During a median follow-up of 14.01 years, 2973 patients experienced ICH. Structural Equation Modelling showed the indirect effect (path a∗b) of statin on ICH was 0.003 (P < 0.001), the direct effect (path c') was -0.001 (P = 0.568), the total effect (path c) was 0.002 (P = 0.391), and the mediation proportion of LDL-C (a∗b/c) was 150.0%. Mendelian Randomization showed a negative association between LDL-C levels and ICH (β: -0.663, SE: 0.229, P = 0.004), with no causal relationship between statin use and ICH (β: -1.454, SE: 3.133, P = 0.643). Drug-targeted Mendelian Randomization revealed LDL-C levels, predicted by variants in or near HMGCR, PCSK9, CETP, ABCG8/5, and LAP, were negatively associated with ICH risk. This study confirmed that statins increase the risk of ICH primarily through their LDL-C-lowering effects, rather than the direct effects of the statins themselves. LDL-C is negatively associated with ICH, an association not confined to the effects of the HMGCR loci. This advance provides evidence for the controversy between statin use, LDL-C levels, and ICH risk. Show less

The intramuscular fat (IMF) content, as an important meat quality trait, can directly affect the tenderness, juiciness, and flavor of pork. Reasonably increasing the IMF content can improve the palatability of pork. Therefore, identification of important factors for the lipid accumulation among muscles is the breakthrough point for improving meat quality. FGF21, identified as a novel metabolic regulator, has been found to regulate glucose and lipid metabolism in 3T3-L1 adipocytes, but its function in porcine adipocytes remains unclear. In this study, we discovered that the administration of recombinant FGF21 protein promotes adipogenic differentiation and increases triglyceride accumulation in porcine adipocytes. While the expression of FGFR1 in adipocytes under muscle conditions is inhibited, affecting the signal transduction of FGF21. This inhibitory effect is accompanied by activation of the AhR signaling pathway. When treated with the AhR antagonist CH223191, there was a partial restoration of FGFR1 expression levels. This indicates that muscle cells suppress the expression of FGFR1 in adipocytes by activating the AhR signaling pathway, thereby affecting the signal transduction of FGF21. Our results reveal the regulatory role of FGF21 in pig adipocyte differentiation and the regulatory mechanism of muscle environment on FGFR1 expression, providing new theoretical basis for IMF content improvement from the perspective of FGF21-FGFR1 signaling transduction. Show less

Addition of the PCSK9 inhibitor, evolocumab, to statin therapy promoted coronary plaque stabilization after an acute coronary syndrome. While apolipoprotein B (ApoB) has been proposed as a goal for lipid-lowering therapy in the prevention of cardiovascular disease, its association with plaque stability has not been studied. The High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study (HUYGENS) used serial optical coherence tomography to assess coronary plaque phenotypes in patients with non-ST elevation myocardial infarction treated with evolocumab plus statin or placebo plus statin for 52 weeks. Changes in plaque composition were studied in patients according to achievement of a goal ApoB level <65 mg/dL. Of 112 patients, 67 (59.8 %) achieved the ApoB goal and had lower ApoB values at follow-up compared with those not at goal (37.1 ± 15.0 vs 92.7 ± 19.4 mg/dL, P < 0.001). Patients achieving the ApoB goal demonstrated a greater increase in minimum fibrous cap thickness (+44.6 ± 36.0 vs +24.9 ± 38.1 μm, P = 0.007) and a more pronounced decrease in lipid arc (-57.8 ± 52.8 vs -27.0 ± 59.2°, P = 0.005) at follow-up, compared with those who did not achieve the ApoB goal. At follow-up, thin-cap fibroatheroma (TCFA) was less prevalent among patients achieving the ApoB goal compared with those not at goal (9.0 vs. 40.0 %, P < 0.001). Multivariate analysis demonstrated that achieving an ApoB <65 mg/dL at follow-up independently associated with the absence of TCFA at follow-up (P = 0.004). Lower achieved ApoB levels associated with evidence of greater plaque stabilization even after controlling for low-density lipoprotein cholesterol levels. This highlights the importance of optimizing ApoB levels for the reduction of cardiovascular risk. NCT03570697. Show less

Lung cancer is one of the most common cancer and the leading cause of cancer-related death worldwide. Early detection of lung cancer can help reduce the death rate; therefore, the identification of potential biomarkers is crucial. Thus, this study aimed to identify potential biomarkers for lung cancer by integrating bioinformatics analysis and machine learning (ML)-based approaches. Data were normalized using the robust multiarray average method and batch effect were corrected using the ComBat method. Differentially expressed genes were identified by the LIMMA approach and carcinoma-associated genes were selected using Enrichr, based on the DisGeNET database. Protein-protein interaction (PPI) network analysis was performed using STRING, and the PPI network was visualized using Cytoscape. The core hub genes were identified by overlapping genes obtained from degree, betweenness, closeness, and MNC. Moreover, the MCODE plugin for Cytoscape was used to perform module analysis, and optimal modules were selected based on MCODE scores along with their associated genes. Subsequently, Boruta-based ML approach was utilized to identify the important genes. Consequently, the core genes were identified by the overlapping genes obtained from PPI networks, module analysis, and ML-based approach. The prognostic and discriminative power analysis of the core genes was assessed through survival and ROC analysis. We extracted five datasets from USA cohort and three datasets from Taiwan cohort and performed same experimental protocols to determine potential biomarkers. Four genes (LPL, CLDN18, EDNRB, MME) were identified from USA cohort, while three genes (DNRB, MME, ROBO4) were from Taiwan cohort. Finally, two biomarkers (EDNRB and MME) were identified by intersecting genes, obtained from USA and Taiwan cohorts. The proposed biomarkers can significantly improve patient outcomes by enabling earlier detection, precise diagnosis, and tailored treatment, ultimately contributing to better survival rates and quality of life for patients. Show less

To investigate the effects and underlying mechanism of ionizing radiation on the adipogenic of mesenchymal stem cells (MSCs). Mouse MSCs were cultured in vitro and treated with 2 Gy and 6 Gy radiation with Bulk RNA-seq suggested that ionizing radiation promotes adipogenic differentiation of MSCs and up-regulation of oxidative stress-related genes and pathways. The results of Oil Red O staining and qPCR showed that ionizing radiation promoted the adipogenesis of MSCs, with high expression of Ionizing radiation promotes adipogenesis of MSCs in mice, and oxidative stress pathway participates in this effect, blocking Show less

To establish an The 6-8-week-old C57BL/6N female mice and BALB/c female mice were used as the donor and recipient mice of the aGVHD model, respectively. Bone marrow transplantation (BMT) mouse model ( An The adipogenic differentiation capacity of MSCs is inhibited by aGVHD mouse serum. Show less

The characterization of physiological immune signatures in a population-based cohort is a prerequisite for identifying pathological immune signatures associated with inflammatory or autoimmune diseases. Here, 47 plasma cytokines, chemokines, and growth factors were quantified with a bead-based multiplex-assay (Merck HCYTA-60 K) using a FLEXMAP 3D™ instrument in 1175 individuals of the Study of Health in Pomerania (SHIP; TREND cohort, 532 men and 643 women, age: 20 to 81, BMI: 17.7 to 53.6). Associations of cytokine concentrations with age, sex, BMI, season, and blood cell parameters (BCP) were examined by multivariate regression models. The physiological cytokine concentrations differed strongly between analytes, with median concentrations ranging from 0.6 to 7820 pg/mL. Many cytokine levels showed a large dynamic range within the study population. Higher levels of the pro-inflammatory cytokines and chemokines IL-6, IL-8, CXCL9, CXCL10, IL-12p40, CCL2, CCL4, CCL11, IL-27, FLT3LG, and TNFα were significantly associated with increasing age. The strongest age-associated effects were seen for CXCL9 (β The generated cytokine atlas provides detailed information on cytokine variations in the general population and will provide a reference base for disease-related studies in the future. Furthermore, BCPs should be considered as potential confounders in association studies based on plasma cytokine levels. Show less

This study aimed to evaluate the effects of butyrate, butyric glycerides (BG) and their combination with sodium selenite (SeNa) or hydroxy-selenomethionine (OH-SeMet) on the performance and egg quality of the laying hens in post-peak period as well as the potential mechanism. A total of 900 45-week-old Hy-Line brown laying hens were randomly allocated to 5 treatment groups (n = 10 replicates/diet, 18 hens/replicate). The hens were fed the basal diet supplemented with 0.3 mg/kg selenium from SeNa (Control), Control plus 240 mg/kg butyric acid from coated butyrate (CB), Control plus 240 mg/kg butyric acid from butyric glycerides, basal diet supplemented with 0.3 mg/kg selenium from OH-SeMet plus coated butyrate (CB+OH-SeMet) or butyric glycerides (BG+OH-SeMet), respectively, for 20 weeks. Serum, liver, isthmus, uterus, and jejunum were collected at the end of the trial for biochemistry, histology, redox status, and gene expression analysis. Compared with Control, diets supplemented with BG, CB+OH-SeMet and BG+OH-SeMet increased (p < 0.05) the average egg weight (0.6-2.2 %), while only BG+OH-SeMet increased (p < 0.05) the total egg weight (7.1 %) and egg-laying rate (4.6 %) and decreased (p < 0.05) the feed/egg ratio (5.0 %) throughout the whole experiment. Furthermore, BG+OH-SeMet reduced (p < 0.05) the content of IL-6 and alanine aminotransferase (15.4-32.5 %), while elevated (p < 0.05) the content of IgA, IgY, IgM and total protein (18.7-26.8 %) in the serum in comparison to the Control. Notably, dietary supplementation of BG+OH-SeMet performed more effective antioxidant capacity in decreasing (p < 0.05) malondialdehyde (16.4-27.9 %) content and increasing (p < 0.05) the activity of total antioxidant capacity and glutathione peroxidase (17.6-36.3 %) in various tissues. Further experiment revealed that dietary BG+OH-SeMet regulated the lipid metabolism by increasing (p < 0.05) the expression of Carnitine palmitoyltransferase 1A (CPT1A) and Lipoprotein lipase (LPL) in liver. In conclusion, diets supplemented with BG and OH-SeMet could improve the laying performance via the enhancement of antioxidant capacity and regulation of lipid metabolism. Show less

Self-labelling proteins like SNAP- and HaloTag have advanced imaging in life sciences by enabling live-cell labeling with fluorophore-conjugated substrates. However, the typical one-fluorophore-per-protein system limits signal intensity. To address this, we developed a strategy using the ALFA-tag system, a 13-amino acid peptide recognized by a bio-orthogonal and fluorescently labelled nanobody, for signal amplification. We synthesized a pentavalent ALFA Show less

Objective To explore the mechanism of lncRNA-BC200 (BC200) targeting the ubiquitination of Beta-site APP cleaving enzyme 1 (BACE1) and regulating the repair of nerve cell injury. Methods Mouse hippocampal neuron cell line HT22 was divided into four groups: control group, oxygen-glucose deprivation/reoxygenation(OGD/R) group, OGD/R+si-NC group and OGD/R+si-BC200 group. In order to further explore the relationship between BC200 and BACE1, HT22 cells were divided into four groups: OGD/R group, OGD/R+si-BC200 group, OGD/R+si-BC200+NC group and OGD/R+si-BC200+ BACE1 group. Twenty male C57BL/6J mice were randomly assigned to the following four groups: control group, middle cerebral artery occlusion (MCAO) group, MCAO+si-BC200 group and MCAO+si-BC200+BACE1 group. The mRNA expression levels of BC200 and BACE1 in cells were measured by real-time quantitative reverse transcription polymerase chain reaction. The expressions of c-caspase-3, B-cell lymphoma 2 (Bcl2), Bcl2 associated X protein(BAX) and BACE1 were detected by western blot, and the apoptotic cells were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) test. Results Compared with the control group, the activity of HT22 cells in OGD/R group decreased significantly, and the percentage of apoptotic cells increased significantly. Compared with OGD/R+si-NC group, the activity of HT22 cells in OGD/R+si-BC200 group increased significantly, and the percentage of apoptotic cells decreased significantly. Compared with the control group, the expression of BACE1 protein in HT22 cells in OGD/R group was significantly enhanced. Compared with OGD/R+si-NC group, the expression of BACE1 protein in HT22 cells in OGD/R+si-BC200 group decreased significantly. It was observed that after OGD/R treatment, the ubiquitination level of BACE1 decreased significantly and the expression of BACE1 protein increased significantly. After transfection with si-BC200, the ubiquitination level of BACE1 protein increased significantly, while the expression of BACE1 protein decreased significantly. Compared with OGD/R+si-BC200+NC group, the percentage of apoptotic cells, the expression of c-caspase-3 and Bax protein in HT22 cells in OGD/R+si-BC200+BACE1 group increased significantly, and the expression of Bcl2 protein decreased significantly. Compared with the control group, the number of cerebral infarction areas and TUNEL positive cells in MCAO group increased significantly, and the survival number of neurons decreased significantly. Compared with the MCAO group, the number of cerebral infarction areas and TUNEL positive cells in MCAO+si-BC200 group decreased significantly, and the survival number of neurons increased significantly, while the addition of BACE1 reversed the improvement of si-BC200 transfection. Conclusion The combination of BC200 and BACE1 inhibit the ubiquitination of BACE1, and participate in mediating the expression enhancement of BACE1 induced by OGD/R. Specific blocking of BC200/BACE1 axis may be a potential therapeutic target to protect neurons from apoptosis induced by cerebral ischemia/reperfusion. Show less

Obesity is a heritable disease, but its genetic basis is incompletely understood. Canine population history facilitates trait mapping. We performed a canine genome-wide association study for body condition score-a measure of obesity-in 241 Labrador retrievers. Using a cross-species approach, we showed that canine obesity genes are also associated with rare and common forms of obesity in humans. The lead canine association was within the gene DENN domain containing 1B ( Show less

Metal-organic frameworks (MOFs) have been considered as ideal platforms to achieve long persistent luminescence (LPL), to utilize as optical recording devices, security systems and sensors. Despite the rapid emergence, it is still a challenge to develop single-component red LPL MOFs. In this work, two hetero-ligand MOFs are synthesized using a D-π-A-type ligand (source of red phosphorescence) and a monocyclic carboxylic ligand (appropriate void constructer), which show efficient red LPL after removal of wide excitations at ambient conditions. Experiment and calculation suggest that the effective red LPL originates from the D-π-A-type ligand, while the auxiliary carboxylic ligand mediates the orientation/arrangement of the D-π-A linker in MOFs affecting phosphorescence. The MOFs are further used in the field of multiple message encryption, initiating a new perspective for designing new red LPL MOFs. Show less

Post-ischemic inflammation is an essential step in the progression of brain ischemia-reperfusion injury. Cytokines such as interleukins 17 and 23 (IL-17, IL-23) have been involved in stroke. IL-27 is a member of the IL-12 family that consists of IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3), having anti-inflammatory properties and regulating T cell polarization and cytokine production. However, whether IL-27 plays an important role in the acute stage of brain ischemia remains unclear. In the acute stage, IL-27 was upregulated after intracerebral ischemia in wild-type mice while mice lacking IL-27 showed decreased infarction area and suppressed inflammatory cytokines. These findings suggest that IL-27 may be involved in cerebral ischemia and could be a potential therapeutic target for mitigating inflammation and avoiding increasing the initial damage in cerebral ischemia. Show less

17β-hydroxysteroid dehydrogenase type 3 deficiency is a 46,XY difference of sex development (DSD) that may present in childhood with inguinal testes or at puberty following virilization. We present four individuals, assigned female at birth, to highlight complexities and considerations surrounding orchiectomy. We reviewed the literature and created a "FACT sheet" to guide shared decision-making for patients, parents, and providers. "Ruth" presented at 16 months with inguinal herniae and underwent orchiectomy, based on parental preference. "Erica" presented at 13 years with voice deepening; she and her parents chose pubertal suppression and eventual orchiectomy. "Riley" presented at 18 months with inguinal herniae; after pubertal suppression and estrogen replacement, orchiectomy at age 13 years revealed germ cell neoplasia Show less

Diabetes constitutes a risk factor for cognitive impairment, whereas insulin resistance serves as the shared pathogenesis underlying both diabetes and cognitive decline. The use of metformin for treating cognitive impairment remains controversial. The present study found that hesperetin, a flavanone derived from citrus peel, enhanced metformin's efficacy in reducing blood sugar levels, improving insulin sensitivity, and ameliorating cognitive impairment in diabetic rats. Additionally, it reduced the required dosage of metformin to one-third of its conventional dose. Transcriptome analysis and 16S rRNA sequencing revealed that the activation of insulin and cyclic-adenosine monophosphate response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathways benefited from the regulation of gut microbiota and the promotion of short-chain fatty acid (SCFA) producers such as Show less

Time-restricted feeding (TRF) is a dietary intervention that has been shown to have numerous health benefits. However, it is important to further investigate the potential effectiveness of TRF in addressing sarcopenic obesity (SO), which is characterized by a combination of age-related obesity and sarcopenia. In this study, 14-month-old C57BL/6J male mice were fed either regular chow diet or high-fat diet (HFD), and had either ad libitum or restricted access to food for 8 hours daily (Intervention for 7 months). For the human trial (ChiCTR2100052876), obese individuals (n=21) with a Body Mass Index ≥28 were recruited and instructed to adopt an 8-hour eating window and a 16-hour fasting period. Here, we found that the TRF intervention significantly reduced global fat mass (P < .001) and volume (P < .05), and increase lean mass compared to mice fed with HFD. Furthermore, TRF improved overall metabolic mobility (8h TRF+HFD vs. AL+HFD). This intervention also enhanced liver FGF21 protein levels (P < .01) and the expression of FGFR1 and FGF21 target genes in adipose and muscle tissues, thus improving mitochondrial quality control in these tissues. Notably, TRF interventions led to a significant decrease in serum FGF21 levels (P < .05). In the human trial, TRF intervention resulted in a significant reduction in weight (P < .001) and body fat levels (P < .001) among obese individuals, as well as a decrease in serum GLU (P < .001), insulin (P < .001), and TC levels (P < .05). Overall, the findings indicate that TRF intervention improves SO by regulating liver FGF21 expression, thereby enhancing FGF21 sensitivity in adipose and muscle tissues. Show less

Prior research has highlighted the significant roles of circulating retinol, retinol-binding protein 4 (RBP4), and apolipoprotein C (ApoC) in metabolic health. This study investigates the joint association of retinol and RBP4 with metabolic syndrome (MetS) and examines the potential mediating role of ApoCs in these relationships. This prospective study included 3,009 and 2,724 participants with baseline serum retinol and RBP4 data, respectively. Over a 9-year follow-up among 2,621 participants, 1,136, 127, 696, and 662 were categorized into MetS-free, recovered, incident MetS, and persistent MetS groups, respectively. Midway through the study, ApoC1-4 levels were measured in 2316 participants. Adjusted odds ratios (95% CIs) for the highest (vs. lowest) tertile of retinol and RBP4 levels were 3.63 (2.69-4.92) and 5.64 (4.05-7.92) for 9-year persistent MetS, respectively. The corresponding hazard ratios (95% CIs) were 1.67 (1.39-2.01) and 1.67(1.38, 2.03) for incident MetS, and 0.65 (0.41-1.03) and 0.44 (0.28, 0.70) for recovered MetS (all P-trends<.05). A synergistic association of retinol and RBP4 with MetS risk was observed for persistent MetS. Higher levels of retinol or RBP4 were associated with increased concentrations of ApoC1-4, which were linked to a greater risk of incident and persistent MetS. A newly developed composite score (ApoCS), derived from ApoC1-4 levels, explained 30.5% and 24.5% of the association between retinol or RBP4 and MetS, with ApoC2 and ApoC3 contributing predominantly to this connection. Our study identified notable positive correlations between serum retinol and RBP4 levels and MetS progression, explained by increases in circulating ApoC2 and ApoC3 within a Chinese cohort. Show less

The deficiency of fructose-1,6-bisphosphatase 1 (FBP1), a key enzyme of gluconeogenesis, causes fatty liver. However, its underlying mechanism and physiological significance are not fully understood. Here we demonstrate that carbohydrate response element-binding protein (ChREBP) mediates lipid metabolic remodeling and promotes progressive triglyceride accumulation against metabolic injury in adult FBP1-deficient liver. Inducible liver-specific deletion of Fbp1 gene caused progressive hepatomegaly and hepatic steatosis, with a marked increase in hepatic de novo lipogenesis (DNL) as well as a decrease in plasma β-hydroxybutyrate levels. Notably, FBP1 deficiency resulted in a persistent activation of ChREBP and its target genes involved in glycolysis, lipogenesis, and fatty acid oxidation, even under fasting conditions. Furthermore, liver-specific ChREBP disruption could markedly restore the phenotypes of enhanced DNL and triglyceride accumulation in FBP1-deficient liver but exacerbated its hepatomegaly and liver injury, which was associated with remarkable energy deficit, impaired mammalian target of rapamycin (mTOR) activation, and increased oxidative stress. Furthermore, metabolomics analysis revealed a robust elevation of phosphoenolpyruvate, phosphoglycerates, phospholipids, and ceramides caused by ChREBP deletion in FBP1-deficient liver. Put together, these results suggest that overactivation of ChREBP pathway mediates liver metabolic remodeling in the absence of FBP1, which contributes to the pathogenesis of progressive hepatic steatosis and provides a protection against liver injury. Thus, our findings point to a beneficial role of ChREBP in metabolic remodeling in the context of excessive gluconeogenic intermediates. Show less

Aim    Aortic aneurysm is characterized by localized expansion and damage to the vessel wall. While apolipoprotein B (ApoB) has been linked to atherosclerosis, its causal relationship with aortic aneurysm remains unclear. This study used a Mendelian randomization (MR) approach to explore the causal relationships between ApoB, aortic aneurysm, and potential mediators.Material and methods    Single nucleotide polymorphism (SNP) data related to ApoB, apolipoprotein A1 (ApoA1), triglycerides, frailty index, and aortic aneurysm were obtained from large-scale genome-wide association studies. MR analysis was conducted to evaluate causal relationships, using inverse variance weighting (IVW) as the primary statistical method. Additionally, we assessed whether the frailty index mediates the relationship between ApoB and aortic aneurysm.Results    Univariate MR analysis revealed that ApoB is significantly associated with aortic aneurysm (IVW odds ratio (OR) = 1.443, 95 % confidence interval (CI) = 1.273-1.637, p < 0.001). Multivariable MR (MVMR) analysis, adjusted for ApoA1 and triglycerides, confirmed these results. In mediation analysis, the frailty index was found to partially mediate the effect of ApoB on aortic aneurysm (mediation contribution: 20.1 %-23.1 %). The ORs for ApoB and the frailty index with respect to aortic aneurysm were 1.325 (95 % CI = 1.168-1.505) and 4.188 (95 % CI = 1.859-9.435), respectively.Conclusion    ApoB has a causal relationship with aortic aneurysm, with the frailty index acting as a partial mediator in this pathway. Show less

Alzheimer's Disease (AD) constitutes approximately 70 % of dementia cases and is the most prevalent form of dementia. Current therapeutic options, including acetylcholinesterase inhibitors and N-methyl d-aspartate (NMDA) receptor antagonists, provide symptomatic relief but do not cure the disease and often come with side effects. The primary pathological features of AD are amyloid plaques and neurofibrillary tangles, with amyloid plaques formed by the abnormal accumulation of Amyloid-β (Aβ). BACE1 (β-site APP-cleaving enzyme 1), a β-secretase, is a key initiator in amyloidosis. Previous research has shown that G-Bro hydrolysate, produced from the bromelain hydrolysis of gliadin, has optimal BACE1 inhibitory efficiency. This study employs G-Bro hydrolysate for nano UHPLC-ESI Q-TOF mass spectrometry to identify peptide fragment sequences and conducts BACE1 inhibition assays to isolate the most effective peptide, VR-peptide. Using the N2a/PS/APP cell model, we explored the impact of chemically synthesized VR-peptide on BACE1 protein expression, the secretion of soluble APP (sAPP), and levels of Aβ and intracellular Aβ1-42. Results demonstrate that VR-peptide achieves a BACE1 inhibitory rate of 63.8 % and reduces BACE1 expression by over 90 % in comparison with untreated N2a/PS/APP cells. It shifts the balance between extracellular Aβ monomers and aggregates, favoring monomer formation and decreasing intracellular Aβ1-42 levels by over 56 %, underscoring its neuroprotective potential. In conclusion, VR-peptide exhibits promise as a BACE1 inhibitor and a preventive agent against Alzheimer's disease. Derived from hydrolyzed cereal foods, it could be effectively paired with a suitable drug delivery system for enhanced neuronal penetration, paving the way for neuroprotective peptide products targeting Alzheimer's disease. Show less

A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants. We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines. Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. The POC5 protein plays an essential role during cell cycle and cilium formation. Interestingly, POC5 localization studies in 3 proband-derived fibroblast cell lines show aberrant localization suggesting a ciliary defect. The phenotypes of the 12 families in this study fit well within the ciliopathy phenotype spectrum, except for lipodystrophy, which is not common in ciliopathies. We describe a multiorgan syndrome caused by bi-allelic LoF variants in POC5. This underscores the pleiotropic effects of POC5 variants and highlights the significance of adipose tissue and metabolic dysfunction in ciliopathies. Show less

SH003, a novel herbal mixture consisting of NSCLC cell lines (A549, H460, HCC827) were treated with SH003 to evaluate cell viability (MTT assay), colony formation, apoptosis (Annexin V/7-AAD staining, western blot), and cell cycle distribution (PI staining). Phosphorylation of RTKs and related signaling molecules was analyzed using a phospho-RTK array and western blot. NSCLC cell lines A549, H460, and HCC827 treated with SH003 showed significant, dose-dependent cell viability and colony formation reductions. SH003 induced apoptosis, evidenced by increased cleaved PARP and caspase-8 levels, and caused G SH003 is a promising multi-target therapeutic agent for NSCLC, offering a novel strategy to improve patient outcomes. Show less

For decades, studies have tried to identify the cholesterol marker that best reflects risk of atherosclerotic cardiovascular disease(ASCVD). Comparing low-density-lipoprotein(LDL) cholesterol, non-high-density-lipoprotein(non-HDL) cholesterol, and apolipoprotein B(apoB) as ASCVD risk markers has been challenged by high correlation between them. Thus, discordance analyses, directly addressing disagreements between the cholesterol markers, have emerged. Approaches adopted to define discordance originate in one of three methods: discordance by cut-points, discordance by percentiles, or discordance by residuals. Commonly, concordant lipid levels serve as reference examining the association between discordant lipid levels with risk of ASCVD. Importantly, concordant reference groups present heterogeneity of clinical relevance across different discordance methods as concordant low lipid levels associate with lowest ASCVD risk while concordant high lipid levels associate with highest risk. Thus, results from different discordance approaches cannot be directly compared. Moreover, discordance between cholesterol markers is more frequently seen in individuals treated with lipid-lowering medication than in individuals not treated with lipid-lowering medication. Accordingly, studies performing discordance analyses have reported inconsistent and even conflicting results. Discordance by cut-points appears the most intuitive and clinically applicable method; results from these analyses suggest that elevated LDL cholesterol, non-HDL cholesterol, or apoB levels in individuals not treated with lipid-lowering medication confer increased ASCVD risk while in individuals treated with lipid-lowering medication, elevated non-HDL cholesterol and apoB levels best indicate residual risk. Results from discordance analyses comparing LDL cholesterol, non-HDL cholesterol, and apoB in risk of ASCVD as well as complexities of discordance analyses and considerations regarding interpretations are discussed in this review. Show less

The liver is critical in avian reproduction as it is the primary site of de novo lipogenesis and yolk precursor synthesis. Broiler breeder hens, the parents of commercial broiler chickens, have poor reproductive efficiency due to declining egg production from 45 weeks of age. We found that metformin increases fertile egg production in the aging broiler breeder hen, which was correlated with reduced body weight, reduced fat pad weight, and altered reproductive hormone profiles. This study aimed to characterize the liver transcriptome of the same broiler breeder hens supplemented with metformin in the diet at 0 or 75 mg/kg body weight for 40 weeks (25-65 weeks of age; n = 45 hens/treatment). Liver tissue was collected from a subset of hens (n = 12 hens/treatment group) at 65 weeks of age, and RNA was extracted and sequenced using next-generation sequencing. Differential gene abundance analysis revealed that metformin treatment led to significant changes in gene expression. Further transcriptomic analysis highlighted increased expression of genes related to estrogen-stimulated yolk precursor synthesis, insulin-stimulated de novo lipogenesis, and AMPK-mediated glucose homeostasis. Quantitative PCR analysis revealed increased expression of ESR1, APOB, APOV1, VTG2, ADIPOQ, ADIPOR2, and ACACA mRNA and decreased expression of PCK1 mRNA while plasma triglyceride and non-esterified fatty acid levels were lower in metformin-treated animals compared to controls. The present study suggests that metformin supplementation supports prolonged egg production in aging broiler breeder hens by sustaining yolk precursor and fatty acid synthesis that are typically diminished in aging broiler breeder hens. Show less

Cattle body size measurements constitute the conformation traits that facilitate their production, fertility, and longevity status. Prioritizing functional variants and causal genes of conformation traits is essential for understanding their genetic basis. In this study, we conducted single-trait and multitrait GWAS for 20 body conformation traits using imputed sequence data in 7,674 Chinese Holstein individuals and identified 27 QTL regions. Leveraging these QTL regions, we performed multitrait Bayesian fine-mapping to identify 30 independent credible sets of putative causal variants. Incorporating GWAS and cis-acting expression QTL data, Mendelian randomization was used to infer 153 putative causal gene-trait relationships. The previously reported genes, such as CCND2, TMTC2, and NRG3, were confirmed in our study. Of note, several novel candidate causal genes were also identified, such as C1R, RIMS1, SERPINB8, NETO2, TTYH3, TTC3, ANAPC4, and PSMD13. Our results provide new insights into the regulatory mechanisms of body conformation traits in cattle. Show less

Mind bomb 1 (MIB1) is an E3 ubiquitin ligase that promotes the polyubiquitination-mediated degradation of NOTCH ligands and plays an important role in various cancers by enhancing tumor cell proliferation. Also, MIB1 inhibited the cell cycle progression by transcriptional repression of P21 in HCT116 cells. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that plays a significant role in the progression of various cancers. However, the regulatory mechanisms underlying FGFR1-associated signaling in colon cancer remain unclear. We investigated whether MIB1 regulates protein stability of FGFR1 and impairs cell proliferation in HCT116 cells. We conducted immunoprecipitation assay to identify correlation of MIB1 and FGFR1. We also tested mRNA level of FGFR1 in MIB1-depleted HCT116 cells using reverse transcription-quantitative polymerase chain reaction. Furthermore, we transfected HA-MIB1 and FLAG-FGFR1 and analyzed the downstream signaling cascades by western blotting. Cell viability was assessed using colony formation assays and MTT assay. FGFR1 interacts with MIB1 and controls FGFR1 protein level in HCT116 cells. Transcriptome analysis revealed that the mRNA levels of FGFR1 increased when MIB1 was depleted in HCT116 cells. Moreover, histone deacetylase 3 (HDAC3) is involved in histone deacetylation and transcriptional repression, mediating the interaction between MIB1 and FGFR1. These findings suggest the importance of MIB1-mediated transcriptional repression of FGFR1 and its potential therapeutic target in colon cancer. Show less

The current study aimed to clarify the roles of apolipoprotein A5 (ApoA5) and milk fat globule-epidermal growth factor 8 (Mfge8) in regulating myocardial lipid deposition and the regulatory relationship between them. The serum levels of ApoA5 and Mfge8 in obese and healthy people were compared, and the obesity mouse model induced by the high-fat diet (HFD) was established. In addition, primary cardiomyocytes were purified and identified from the hearts of suckling mice. The 0.8 mmol/L sodium palmitate treatment was used to establish the lipid deposition cardiomyocyte model Show less

The aim of the present study was to assess the association between class III malocclusion and genetic polymorphisms in two genes: A total of 60 patients, 30 with skeletal class I and 30 with skeletal class III malocclusion, were included in this study. Salivary DNA samples were collected and analyzed with Sanger sequencing. Digital tracing was performed on lateral cephalometric radiographs loaded into AutoCAD software (Version 2017) to assess the anteroposterior and vertical relationships of the maxillary and mandibular arches. Genotype distribution was compared between groups with the chi-square test to assess Hardy-Weinberg equilibrium. Multiple logistic regression analysis was conducted. The A potential association was observed between class III skeletal malocclusion-related traits and polymorphisms of Show less