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Smoking is harmful to health. Cigarette smoke (CS) contains a variety of toxic substances. Studies have found that nicotine, tar, polycyclic aromatic hydrocarbons, etc. in CS can pass through the blood-brain barrier and enter the brain to exert their effects. Moreover, some existing studies have pointed out that CS exposure is closely related to the accelerated pathology of Alzheimer's disease (AD). Transgenic mice with the five familial AD mutations (5xFAD), which are 1-month-old, were used for chronic CS exposure for 100 days. Subsequently, cognitive function and behavioral changes were evaluated through morris water maze and new object recognition tests. The acceleration of pathological changes due to CS exposure was assessed by HE, Tunel and Aβ immunohistochemical staining. Differential expression proteins and metabolites were screened through hippocampal proteomics and metabolomics analyses. Finally, the expression levels of key proteins were verified by Western blot. Compared with unexposed 5xFAD mice, the behavioral results of mice showed that FAD mice after CS exposure exhibited poorer cognitive abilities, with longer latencies in the Morris water maze, and decreased time spent and entries in the target quadrant. The results of pathological sections indicated that the total nuclei density in the DG and CA3 regions of the hippocampus of 5xFAD mice decreased significantly after chronic CS exposure, the number of TUNEL-positive cells increased, and the expression of Aβ42 increased. Multi - omics analysis revealed that CS exposure up - regulated the expression of 46 proteins and down - regulated the expression of 80 proteins in the hippocampus of 5xFAD mice, and caused changes in 92 metabolites. Analysis of the correlation between differential proteins and differential metabolites revealed six key cross-node proteins: Kng1, Hbb-b1, Fabp3, Apoa1, Ilk, and Apoa4. CS exposure may accelerate pathological changes and cognitive impairment in 5xFAD mice by affecting energy metabolism through the PPAR signaling pathway. Show less

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized rare condition with 3 primary characteristics: autosomal dominant inheritance, bland urinary sediment (absence of hematuria and proteinuria), and chronic kidney disease (CKD) leading to kidney failure (need for kidney replacement therapy or kidney transplantation) between 20 and 80 years of age, with a mean age of kidney failure of approximately 45 years. Pathogenic variants in UMOD, MUC1, REN, and APOA4 have been identified as causative in ADTKD families. Prior to 2000, ADTKD was only diagnosed clinically and had been described in fewer than 50 families. However, with the advent of genetic testing and a better understanding of this condition, ADTKD is being increasingly recognized and is the third most common monogenic cause of kidney failure. The purpose of this review is to provide an understanding of the clinical characteristics of ADTKD and its subtypes with a practical approach to diagnosis and management for clinical nephrologists. Show less

The dysregulation of hepatic lipid metabolism is closely associated with dyslipidemia. Previous research suggested that Hepatic Data regarding circulating lipid traits and hepatic Hepatic This study identifies Show less

The aim of the present study was to investigate the dietary effects of replacing corn with different proportions of fermented straw on the growth performance and intestinal health of finishing pigs. A total of 275 healthy commercial finishing pigs aged 126 days (average body weight, 82.96 ± 3.07 kg) were randomly allocated into three groups: the control (CTR, basal diet) group, the 5% fermented straw (FJJG5, replacing 5% of the corn) group, and the 10% fermented straw (FJJG10, replacing 10% of the corn) group. There were six replicates in each group and 14-16 pigs per replicate. On day 39 of the experiment, one animal from each replicate was slaughtered for sampling and for further analysis. The results showed that the finishing pigs in the FJJG10 group had a reduced average daily weight gain and an increased feed-to-gain ratio. The FJJG5 group had reduced total cholesterol, high-density lipoprotein, and low-density lipoprotein in their serum, while the FJJG5 and FJJG10 groups had reduced contents of lactate dehydrogenase. In addition, the FJJG5 group exhibited increased T-SOD activity and MDA content in the colon, while the FJJG10 group also showed increased T-AOC activity in their serum and increased contents of MDA in the colon. The FJJG5 group exhibited increased activities of jejunal disaccharidase and lipase, while the FJJG10 group exhibited decreased jejunal crypt depths. Moreover, the FJJG5 group presented an increased relative expression of Show less

The etiology of acute Achilles tendon rupture (ATR) remains unclear. This study conducted a comprehensive case-control study of the proteome profile to gain insights into the potential pathogenesis of acute ATR and identify novel biomarkers. Serum (iTRAQ) and urine (label-free proteomics) from 15 acute ATR patients and 15 healthy controls were analyzed. Significant differential expression was defined as ≥1.2-fold (serum) or ≥2-fold (urine) change with p < 0.05. Bioinformatics analyses (GO, KEGG, PPI) were performed. 44 serum and 198 urine proteins were differentially expressed. Enriched pathways included immune response, metabolism, immune response, and redox regulation. protein-protein interaction analysis of the differentially expressed proteins (P < 0.05) highlighted abnormalities in major protein-protein interaction hubs, specifically pyruvate kinase (PKM), peroxiredoxin-1 (PRDX1), phosphoglycerate kinase 1 (PKG1), profilin-1, and apolipoprotein A-IV, observed in the serum and urine samples of acute ATR patients. Metabolic dysregulation may affect tendon structure/strength; redox imbalance could promote degeneration. Immune-related proteins may reflect injury responses. Glycolytic enzymes (PKM, PGK1) suggest disrupted energy metabolism. Proteomic abnormalities in metabolism, immune, and redox pathways, along with key proteins (PKM, PRDX1, PGK1), may contribute to ATR pathogenesis, offering potential biomarkers warranting further validation. Show less

Canine chronic inflammatory enteropathies (CCIE) is a group of intestinal inflammatory conditions causing chronic or relapsing gastrointestinal symptoms. Accurate diagnosis, treatment and monitoring remain challenging, necessitating novel diagnostic tools. This study aims to investigate the plasma proteome of ten dogs with histologically confirmed CCIE during active disease and clinical remission compared to ten healthy controls. We utilized surplus lithium-heparin plasma and performed label-free quantification mass spectrometry. A significant upregulation of complement factor properdin (CFP) during disease was noted, pointing toward microbial-driven intestinal inflammation. During remission, CFP levels remained elevated compared to controls, indicating persistent subclinical inflammation. We report hepatocyte growth factor activator (HGFAC) as a novel canine plasma protein associated with decreased risk for CCIE and as a potential therapeutic target, similarly, as reported in humans. Linear regression analysis revealed that disease severity was negatively correlated to transcortin/SERPINA6, as negative acute phase protein. Proteins involved in inflammation and tissue repair, such as inter-alpha-trypsin inhibitor heavy chain 4, (ITIH4), and anti-inflammatory molecules like apolipoprotein A-IV (APOA4), were significantly upregulated in remission. Conversely, proteins related to DNA remodeling and methylation, including histone H2B and carboxypeptidase N subunit 2 (CPN2), were downregulated during remission. Gene ontology analysis revealed altered pathways linked to immune response and coagulation. In CCIE patients we identified for the first time markers such as properdin for intestinal inflammation, while transcortin and HGFAC may serve as markers for remission. Future studies with larger cohorts are needed to validate the use of these proteins for monitoring disease progression and remission and refine their clinical applicability. Show less

This study evaluated the protective effects of naringin (NG) against intestinal injury in 7-day-old piglets infected with porcine epidemic diarrhea virus (PEDV). Eighteen piglets (Duroc × Landrace × Large, body weight = 2.58 ± 0.05 kg) were divided into three treatment groups based on similar body weights and equal numbers of males and females: the blank control group (CON group), the PEDV infection group (PEDV group), and the NG intervention + PEDV infection group (NG + PEDV group) ( Show less

Cardiometabolic risks affect cognition during aging, yet genetic basis for both remain understudied in Indians. This study constructs an ancestry-matched Indian haplotype reference panel for genotype imputation of 5111 rural Indians. Single-locus, gene-based, conditional genome-wide association analyses are performed on 20 cognitive and 10 cardiometabolic traits, with subsequent follow-up of identified associations through multimodal functional annotation. Furthermore, causal interrelationships between cardiometabolic and cognitive phenotypes by Mendelian randomization are investigated. One novel memory-associated and 17 novel cardiometabolic phenotypes-associated (high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], triglycerides [TG], total cholesterol [TC], TG:HDL, and visceral adiposity index [VAI]) genome-wide significant loci, and multiple genes are identified. AMIGO1 (delayed-recall) and ZPR1-APOA5 (metabolic syndrome) exhibit distinct haplotype structure compared to other populations. Causal roles of cardiometabolic traits on various cognitive domains are identified via genetic instruments in APOC3-APOA4-APOA5-ZPR1-BUD13 among others. These findings illustrate the impact of cardiometabolic factors on cognition in a rural socioeconomically disadvantaged population, advancing efforts to address health disparities. Our newly constructed ancestry-matched haplotype reference panel gives better genotype imputation accuracy for the Indian population. One and 17 novel genome-wide significant single-loci were identified to be associated with cognitive and cardiometabolic traits, respectively. Several subgenome-wide hits for all phenotypes were identified. Collapsing protein truncating variants (PTVs), there were two genes identified to be associated with cardiometabolic traits at a genome-wide level of significance, correcting for multiple phenotypes tested. Haplotypic differences were identified compared to 1000 Genomes superpopulations for genes influencing delayed recall and metabolic syndrome. Adverse causal roles of cardiometabolic traits on cognition were uncovered via genetic instruments in APOC3-APOA4-APOA5-ZPR1-BUD13, among others, through Mendelian randomization. Show less

The seven-transmembrane (7TM) receptors are the largest superfamily of cell-surface receptors and are involved in various physiological processes of vertebrate species. In our previous study, a new chicken 7TM receptor (Ch-7TM) was discovered in mononuclear phagocytes (MNPs) derived from chicken peripheral blood mononuclear cells (PBMCs). To explore the functions of Ch-7TM, RNA interference (RNAi) was used to silence the Ch-7TM messenger RNA (mRNA) of MNPs, using small interfering RNA (siRNA) designed with BLOCK-iT™ RNAi Designer. Herein we demonstrated that silencing of the Ch-7TM mRNA induced apoptosis of MNPs, suggesting that Ch-7TM contributed to the survival of MNPs. Moreover, chicken sera could inhibit the Ch-7TM-silencing-induced apoptosis in MNPs. The survival factor presented in fraction 16 (F16) of chicken sera was highly protective against the Ch-7TM-silencing-induced apoptosis in MNPs. The proteins from F16 were identified as vitamin D-binding protein (DBP) and apolipoprotein A-IV (ApoA-IV), which might be potential candidates for survival factors. The protective effect of vitamin D and ApoA-IV indicated that Ch-7TM might involve the intracellular oxidation-reduction balance, although more evidence is needed to confirm this function. The siRNA screening serves as an excellent model for studying the functions of chicken MNPs receptors. Show less

Gluconeogenesis is a critical metabolic pathway for maintaining glucose homeostasis, and its dysregulation can lead to glycometabolic disorders. This study aimed to identify hub biomarkers of these disorders to provide a theoretical foundation for enhancing diagnosis and treatment. Gene expression profiles from liver tissues of three well-characterized gluconeogenesis mouse models were analyzed to identify commonly differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA), machine learning techniques, and diagnostic tests on transcriptome data from publicly available datasets of type 2 diabetes mellitus (T2DM) patients were employed to assess the clinical relevance of these DEGs. Subsequently, we identified hub biomarkers associated with gluconeogenesis-related glycometabolic disorders, investigated potential correlations with immune cell types, and validated expression using quantitative polymerase chain reaction in the mouse models. Only a few common DEGs were observed in gluconeogenesis-related glycometabolic disorders across different contributing factors. However, these DEGs were consistently associated with cytokine regulation and oxidative stress (OS). Enrichment analysis highlighted significant alterations in terms related to cytokines and OS. Importantly, osteomodulin ( OMD ), apolipoprotein A4 ( APOA4 ), and insulin like growth factor binding protein 6 ( IGFBP6 ) were identified with potential clinical significance in T2DM patients. These genes demonstrated robust diagnostic performance in T2DM cohorts and were positively correlated with resting dendritic cells. Gluconeogenesis-related glycometabolic disorders exhibit considerable heterogeneity, yet changes in cytokine regulation and OS are universally present. OMD , APOA4 , and IGFBP6  may serve as hub biomarkers for gluconeogenesis-related glycometabolic disorders. Show less

Diabetes-related chronic kidney disease (DKD) is a leading cause of end-stage kidney disease (ESKD), requiring costly dialysis or kidney transplantation. Existing standard- of-care tests for DKD have several limitations, and an alternative is Promarker®D, a validated plasma biomarker test system that predicts DKD in adults with diabetes up to 4 years before symptoms develop. To enable high-throughput application of PromarkerD, a novel CaptSureTM immunoassay version of the test was developed targeting plasma biomarkers Apolipoprotein A4 (ApoA4) and CD5 antigen-like (CD5L). The analytical performance of the assay was assessed, and clinical samples from 2 independent clinical cohorts (>1700 adults with type 2 diabetes [T2D]) were used for the development and external validation of the DKD predictive test. The PromarkerD test system combined ApoA4 and CD5L concentrations with clinical factors age and estimated glomerular filtration rate (eGFR) to calculate risk scores (0% to 100%) and classify study participants as either at low, moderate, or high risk for future kidney decline. PromarkerD demonstrated reliable analytical performance and provided a high discriminative capability in adults with T2D (receiver operating characteristic area under the curve [ROC-AUC]: 0.78 to 0.88) to predict 4-year kidney decline, defined as incident DKD (eGFR <60 mL/min/1.73 m2) or eGFR decline ≥40%, with sensitivity of 75.8% to 85.1% at the moderate-risk cutoff and specificity of >92% at the high-risk cutoff across the two cohorts. The next-generation PromarkerD test system offers a convenient yet highly effective tool for DKD risk assessment. By introducing PromarkerD to standard diabetes care, preventative treatment strategies may be implemented early before permanent kidney function loss occurs. Show less

Declines in skeletal muscle and cognitive function in older adults have been linked to abnormalities in abdominal subcutaneous adipose tissue (ASAT), yet the underlying molecular mediators remain poorly understood. Here, leveraging ASAT transcriptomics and explant-conditioned media proteomics from participants in the Study of Muscle, Mobility and Aging (SOMMA; age ≥70 years, n = 229), we identified ASAT gene clusters and secreted proteins strongly associated with comprehensive assessments of physical and cognitive function in older adults. ASAT inflammation and secreted immunoglobulins were identified as key signatures of aging-associated physical and cognitive performance limitations. Systems genetics analysis confirmed secreted-SERPINF1 as a negative regulator of skeletal muscle contraction and highlighted its potential role in inducing inflammation in the heart Show less

Despite the known impacts of weaning on animal health, the underlying molecular mechanisms remain unclear, particularly how psychological and nutritional stress differentially affect gut health and immune function over time. This study hypothesized that early weaning exerts distinct short- and long-term effects on lamb stress physiology, immunity, and gut health, mediated by specific molecular pathways. Twelve pairs of full-sibling male Hu sheep lambs were assigned to control (CON) or early-weaned (EW) groups. Plasma stress/immune markers were dynamically monitored, and intestinal morphology, antioxidant capacity, apoptosis, and transcriptomic profiles were analyzed at 5 and 28 days post-weaning. Early weaning triggered transient psychological stress, elevating hypothalamic-pituitary-adrenal (HPA) axis hormones (cortisol, catecholamines) and inflammatory cytokines (TNF-α) within 1 day ( Show less

Variants linked to the risk of ischemic stroke have been discovered through genome-wide association studies (GWASs). These variations frequently have little consequences that lack apparent biological significance. Hence, these findings demonstrate that exome sequencing can be highly relevant to stroke, even though stroke is a complex phenotype with various diseases and risk factors. In this case-control investigation, we used ARMS genotyping to investigate the distribution of polymorphic variations in genes associated with stroke susceptibility. In addition to examine the novel gene variations associated with ischemic stroke we utilized the Illumina NovaSeq 6000 platform for whole-exome sequencing (WES). Results identified 11 novel gene variants in the GSTT4 gene by targeted whole-exome sequencing, including one deletion GSTT4p.Asn232LysfsTer6, one insertion c.688₆₈₉insCG, and 9 SNVs c.699 T > C, c.701C > G, c.708G > T, c.710 T > G, c.712A > G, c.712A > G, c.718A > T, c.719G > A, c.721A > T, c.722G > T in the ischemic stroke patients. We also identified several rare, intermediate, and most common gene variants in cholesterol associated genes LDLR, LDLRAD2, LDLRAD3, APOA2, APOA3, APOA4, APOA5, and PCSK9. Also, several common gene variants were reported in MTHFR, KLF14, eNOS3, and ACE by whole-exome sequencing. Furthermore, the eNOS3-GG and eNOS3-GT genotypes were associated with susceptibility to ischemic stroke (OR = 1.95, This case-control study identified 11 novel GSTT4 variants and several known polymorphisms associated with ischemic stroke risk in Saudi patients. These findings highlight population-specific genetic factors that warrant further functional and large-scale validation. Show less

Obesity-driven inflammation disrupts gut barrier integrity and promotes inflammatory bowel disease (IBD). Emerging evidence highlights gut hormones-including glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY), cholecystokinin (CCK), and apolipoprotein A4 (APOA4)-as key regulators of metabolism and mucosal immunity. This review outlines known mechanisms and explores therapeutic prospects in IBD. GLP-1 improves glycemic control, induces weight loss, and preserves intestinal barrier function, while GLP-2 enhances epithelial repair and reduces pro-inflammatory cytokine expression in animal models of colitis. GIP facilitates lipid clearance, enhances insulin sensitivity, and limits systemic inflammation. PYY and CCK slow gastric emptying, suppress appetite, and attenuate colonic inflammation via neural pathways. APOA4 regulates lipid transport, increases energy expenditure, and exerts antioxidant and anti-inflammatory effects that alleviate experimental colitis. Synergistic interactions-such as GLP-1/PYY co-administration, PYY-stimulated APOA4 production, and APOA4-enhanced CCK activity-suggest that multi-hormone combinations may offer amplified therapeutic benefits. While preclinical data are promising, clinical evidence supporting gut hormone therapies in IBD remains limited. Dual GIP/GLP-1 receptor agonists improve metabolic and inflammatory parameters, but in clinical use, they are associated with gastrointestinal side effects that warrant further investigation. Future research should evaluate combination therapies in preclinical IBD models, elucidate shared neural and receptor-mediated pathways, and define optimal strategies for applying gut hormone synergy in human IBD. These efforts may uncover safer, metabolically tailored treatments for IBD, particularly in patients with coexisting obesity or metabolic dysfunction. Show less

Elevated levels of triglycerides in the bloodstream, a condition known as hypertriglyceridemia, represent a significant risk factor for the development of metabolic disorders and cardiovascular diseases. One key regulator of lipid metabolism is the transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3), which is expressed in the liver, intestine, and adipose tissue. CREB3L3 is localized to the endoplasmic reticulum membrane, and in vertebrates plays a crucial role in plasma lipid homeostasis. However, the precise molecular mechanisms underlying Creb3l3's influence on cellular lipid metabolism remains undefined. To address this knowledge gap, we generated zebrafish mutants lacking both creb3l3 orthologs (creb3l3a and creb3l3b). Gene expression analysis revealed that key creb3l3 target genes, such as apoC2 and apoA4, were significantly downregulated in the intestines of these double mutants. Using two zebrafish lipoprotein reporter lines, we assessed lipoprotein dynamics in creb3l3 mutants. Despite producing similar total levels of lipoproteins, creb3l3 mutants exhibited impaired lipoprotein turnover, suggesting a disruption in circulating lipid clearance. Additionally, histological analysis showed an accumulation of intestinal lipids, characterized by an increased number and size of enterocyte lipid droplets. These findings indicate that creb3l3 is essential for regulating postprandial lipid flux in enterocytes through altering the balance between lipid storage and secretion. Our study highlights a critical, unappreciated role of Creb3l3 in maintaining intestinal lipid homeostasis. Show less

Despite the growing burden of knee osteoarthritis on aging populations, our mechanistic understanding of this disease remains lacking. Though knee osteoarthritis is a whole joint disease, the impact of intra-articular structures such as the infrapatellar fat pad (IFP) on cartilage health is unclear. This study investigated the effect of age on paracrine communication between the IFP and chondrocytes. To isolate the effects of the IFP secretome on chondrocytes, aged chondrocytes from male and female mice were incubated with conditioned media from sex-matched young IFPs, aged IFPs, or control media. Extracellular matrix protein expression increased in both male and female chondrocytes exposed to young, but not aged, conditioned media relative to control media. The effect of the young IFP was not concomitant with changes in extracellular matrix degradation proteins, ADAMTS4 or MMP13. To identify factors mediating the effects of the IFP on chondrocytes that are altered with aging, we performed mass spectrometry of young and aged conditioned media and transcriptomics of aged chondrocytes treated with young or aged conditioned media. We then integrated the 2 datasets using network analyses. From the conditioned media, 2 secreted proteins, Mfge8 and Apoa4, were significantly changed with aging. In silico perturbation of the corresponding receptors of these IFP-secreted factors identified multiple enriched pathways in chondrocytes, including negative regulation of nitric oxide synthase activity. Overall, the data suggest that young IFPs release paracrine factors that promote extracellular matrix production in chondrocytes, potentially via regulation of nitric oxide levels, but that this effect is diminished with aging. Show less

Cardiovascular diseases from abnormal lipid metabolism significantly increase mortality in systemic lupus erythematosus (SLE). The causal link between dyslipidemia and SLE is unclear. Lipid metabolism in patients with SLE was evaluated based on clinical data from 511 patients with SLE and 706 healthy individuals. Bidirectional Mendelian randomization (MR) was employed to assess causal links between 179 plasma lipid metabolites, lipid-lowering drug targets, and SLE risk. Genetic instruments from GWAS and eQTL data were used to evaluate CETP and APOA4 effects. Peripheral blood CETP and apolipoprotein levels in SLE patients were validated via ELISA. SLE patients exhibited reduced HDL-C (P < 0.0001), APOA1 (P < 0.0001), and APOA4 (P < 0.0001), alongside elevated triglycerides (TG, P < 0.0001), APOC3, APOD, and APOF. MR identified three lipid metabolites-PC(18:2₂₀:4), TG(56:6), and TG(58:7)-as causal factors for SLE (P < 2.79E-5). CETP inhibition significantly reduced SLE risk via HDL-C modulation (OR = 0.72, P = 3.38E-08) and influenced LDL-C, TG, and apolipoproteins. Clinical validation confirmed elevated CETP and reduced APOA4 in SLE, correlating with disease activity. APOA4 activation showed protective effects, while PCSK9 inhibition lacked relevance. Bidirectional Mendelian randomization analyses confirmed dyslipidemia as a causal antecedent to SLE, with no evidence of reverse causation. A variety of MR analyses and clinical validation indicated that targeting HDL-C regulation offers significant advantages for managing dyslipidemia in patients with SLE, with CETP identified as the optimal pharmacological target. Show less

Apolipoprotein-A4 (Apo-A4) is a plasma protein that plays a role in various physiological and behavioral-emotional reactions when faced with stress. Studies have shown a close relationship between Apo-A4 and the onset of depression and its symptoms. However, there is currently no reliable laboratory approach to confirm the diagnosis of depression. Therefore, the development of a precise and effective technique to assess Apo-A4 might help in the early detection and screening of depression and other related psychiatric diseases, as well as in tracking and managing the course of treatment. As technology advances, biosensors have become quick, accurate, and sensitive tools for personal care and illness diagnosis. Biosensors for measuring and detecting Apo-A4 levels have recently been designed. These studies emphasized the development of accurate and sensitive diagnostic and measurement techniques. This review attempts to give a general overview of the role of Apo-A4 in depression and introduce established biosensors for its detection and measurement. Show less

Insulin resistance (IR) contributes to atherogenic dyslipidemia and elevated ASCVD risk. Apolipoprotein A1 (ApoA1)-associated lipoproteins have diverse anti-atherogenic functions, but it is unclear whether IR drives adverse changes in their proteomic composition. We hypothesized that IR is associated with an atherogenic ApoA1 proteome and that insulin-sensitizing interventions would improve its composition. We studied 861 participants without diabetes (age 47 ± 12 years, 65.5% female). IR was directly measured using the steady-state plasma glucose (SSPG) concentration via the insulin suppression test. ApoA1-associated proteins were quantified by mass spectrometry. A subset underwent interventions for 3 months (N total 108): pioglitazone, PIO Show less

Apolipoprotein A-IV (apoA-IV), the largest member of the exchangeable apolipoprotein family, is a common constituent of amyloid deposits in renal and cardiac amyloidosis. In this study, we characterized the aggregation propensity of the apoA-IV N-terminal fragment to form amyloid fibrils using a variety of biophysical techniques. Thioflavin T fluorescence assay, circular dichroism measurement, and microscopic observations revealed that the N-terminal 1-70 amino acid fragment of apoA-IV readily forms amyloid fibrils by a transition from a random coil to a β-sheet-rich structure. Sequence-based analysis indicated that residues 7-16 and 38-42 are the major aggregation-prone segments within the N-terminal 1-70 residues of apoA-IV. Consistent with this, deletion of these residues strongly inhibited the β-transition and fibril formation of apoA-IV 1-70. Kinetic and thermodynamic analyses of fibril formation by the apoA-IV 1-70 fragment demonstrated that primary nucleation is the dominant step in fibril formation, for which the activation energy barrier is entirely entropic. In addition, we found that the presence of heparin, a representative glycosaminoglycan, accelerated fibril formation kinetics and enhanced the yield of apoA-IV 1-70 fibrils, and the positively charged residues K58-K59 play a critical role in heparin interaction. Overall, our results suggest that the strong amyloid-forming propensity of the N-terminal fragment of apoA-IV may play a key role in amyloid deposition associated with apoA-IV amyloidosis. Show less

As the most common primary malignant bone tumor, further investigation into risk stratification for osteosarcoma (OS) prognosis is of significant clinical importance. Copper is essential for bone metabolism; however, its specific role in OS remains unclear. The expression characteristics of copper metabolism related genes (CORGs) in OS were revealed by single cell sequencing. Prognosis-associated CORGs were identified, and a CORG-related scoring system and risk model were established using bioinformatics approaches, including univariate and multivariate Cox regression analyses and LASSO analysis. We further analyzed immune microenvironment infiltration, molecular subtypes and clinicopathological characteristics. The impact of selected CORG with high-risk coefficient on OS cells was tested by qRT-PCR, western blot, siRNA, colony formation analysis and Transwell in vitro. We successfully developed an OS scoring system related to copper metabolism and validated its independent prognostic value in patients with OS. The potential clinical value of CORG scoring system was analyzed. APOA4 was selected for in vitro experiments and its effect on the proliferation and invasion ability of OS cells was verified. We established a copper metabolism-related scoring system to effectively stratify the risk of OS patients. Our results provide a new basis for the role of copper metabolism in OS and provide new potential targets for the treatment of OS. Show less

Liver diseases are a major contributor to both morbidity and mortality. Conditional knockout animals are always produced through crossing floxed animals with a tissue-specific Cre animal. The use of floxed rat resource has rapidly increased, but the liver-specific Cre rat lines for studying liver diseases and interested genes are limited, especially in a spatially and temporally restricted manner. RNA sequencing and real-time polymerase chain reaction (PCR) were used to screen and confirm the presence of liver-specific genes. Apoa4-Cre rats and Cyp2c11-Cre rats were produced by CRISPR/Cas9 knockin. Rosa26-imCherry rats were employed to hybridize with the Cre rats to obtain the Apoa4-Cre/Rosa26-imCherry and Cyp2c11-Cre/Rosa26-imCherry rats. The temporal and spatial patterns of Cre expression were determined by the observation of red fluorescence on tissue sections. Hematoxylin-eosin stain was used to evaluate the liver histopathologic changes. The blood biochemical analysis of several liver enzymes and liver lipid profile was performed to evaluate the liver function of Cre rats. Apoa4 and Cyp2c11 were identified as two liver-specific genes. Apoa4-Cre and Cyp2c11-Cre rats were produced and hybridized with Rosa26-imCherry rats. The red fluorescence indicated that the Cre recombinases were specially expressed in the juvenile and adult liver and not in other organs of two hybridized rats. All the blood biochemical parameters except low-density lipoprotein (LDL) did not change significantly in the Cre rats. No histological alterations were detected in the livers of the Cre rats. Liver-specific Apoa4-Cre and Cyp2c11-Cre rats have been established successfully and could be used to study gene knockout, specifically in juvenile and adult liver. Show less

Accurate diagnosis of Crohn's disease (CD) is paramount due to its resemblance to other inflammatory bowel diseases. Early and precise diagnosis plays a pivotal role in tailoring personalized treatments, thereby enhancing the quality of life for CD patients. Differential gene expression analysis was conducted to identify genes from the mRNA expression profiles of CD samples, followed by pathway enrichment analysis. The immune cell infiltration levels of each CD patient sample were assessed. Using weighted gene co-expression network analysis, key gene modules linked to CD were found. Hub gene identification was made easier by the construction of protein-protein interaction networks. Next, utilizing the Least Absolute Shrinkage and Selection Operator on the hub genes in the training set, a diagnostic model was created. The accuracy of the model was then confirmed using a different validation set. Our analysis revealed 651 differentially expressed genes, enriched in leukocyte chemotaxis and inflammation-related pathways. Immunization results showed a higher abundance of T cells CD4 memory resting, macrophages M2, and plasma cells in CD patients. Weighted gene co-expression network analysis linked the turquoise module with macrophages M2. Eight hub genes (APOA1, APOA4, CYP2C8, CYP2C9, CYP2J2, EPHX2, HSD3B1, and LPL) formed the diagnostic model, exhibiting excellent diagnostic performance with area under curve values of 0.94 (training set) and 0.941 (validation set). The CD diagnostic model, based on hub genes, shows exceptional diagnostic accuracy, providing a valuable reference for CD diagnosis. Show less

The present study explored for the first time the blood-based proteomic signature that could potentially distinguish older adults with and without cognitive frailty (CF). The participants were recruited under the Malaysian Elders Longitudinal Research (MELoR) study. Cognition and physical frailty were determined using the Montreal Cognitive Assessment (MoCA) and Fried's criteria, respectively. The differential protein expression in the blood samples (38 CF vs 40 robust) were then determined using the Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH) analysis. A total of 294 proteins were found to be differentially expressed in the CF group as opposed to the robust group. Considering proteins with fold change (FC) ≥  ± 2 and p-values < 0.05, 13 proteins were significantly upregulated and nine proteins significantly downregulated in the CF group when compared to the robust group. Subsequent correlation analysis identified nine dysregulated proteins, namely APOA1, APOA2, APOA4, APOC1, APOE, GPX3, RBP4, SERPINC1 and TTR, to exhibit significantly and moderately strong correlations with parameters of cognitive and/or frailty assessments. These proteins could potentially serve as useful proteomic signature of CF given their sensitivity > 78%, specificity > 75%, accuracy > 80% and area under the curve (AUC) > 0.8. The major biological pathways that could be potentially dysregulated by the nine proteins were associated with lipid metabolism and the retinoid system. The present findings warrant further validation in future studies that involve a larger cohort. Show less

The lack of standardized objective approaches hinders the accurate diagnosis and treatment of depression. Herein, a novel electrochemical platform was created utilizing cost-effective and rapid 3D printing technology to overcome the constraints of conventional diagnostic methods. This method allows for highly sensitive detection of Apolipoprotein A4 (Apo-A4), an important biomarker for depression, using dual-signal outputs. The electrode material utilized in this setup consisted of a combination of carbon black/polylactic acid (CB/PLA) and ferrocene-chitosan-gold nanoparticles (Fc-CS-AuNPs). On the other hand, the signal label was composed of gold nanoparticles-thionine-secondary antibody (AuNPs-Thi-Ab Show less