It is widely acknowledged that diabetes leads to slow wound healing and ulceration, and severe serious diabetic foot ulceration may result in amputation. In recent years, much emphasis has been placed Show more
It is widely acknowledged that diabetes leads to slow wound healing and ulceration, and severe serious diabetic foot ulceration may result in amputation. In recent years, much emphasis has been placed on exploring diabetic wound healing to protect patients from adverse events. We recently found interleukin-7 (IL-7), a growth factor for B-cells and T-cells, and its receptor was significantly upregulated in high glucose-induced fibroblasts and skin of diabetic mice. Moreover, IL-7 stimulated fibroblasts secreted ANGPTL4, which inhibited angiogenesis of endothelial cells resulting in delayed wound healing. In our previous study, fibroblasts, endothelial cells and keratinocytes were exposed to normal glucose (5.5 mM) or high glucose (30 mM) medium for 24 h, and RNA sequencing showed that IL-7 and IL-7R were significantly upregulated in fibroblasts. To remove the effect of high glucose and explore the influence of IL-7, exogenous rMuIL-7 used to treat normal mice led to delayed wound healing by inhibiting angiogenesis. Vitro experiments revealed that IL-7-induced fibroblasts inhibited endothelial cell proliferation, migration and angiogenesis. Further experiments showed that fibroblast angiopoietin-like-4 (ANGPTL4) secretion exhibited the inhibitory effect which was blocked by culture with the corresponding neutralizing antibody. Overall, our study revealed signaling pathways associated with diabetic wound healing and provided the foothold for further studies on delayed wound healing in this patient population. Mechanism that high glucose activates IL-7-IL-7R-ANGPTL4 signal pathway in delayed wound healing. High glucose upregulates IL-7 and IL-7R in dermal fibroblasts. IL-7 stimulates dermal fibroblasts secreting Angptl4 which inhibits proliferation, migration and angiogenesis of endothelial cells in a paracrine way. Show less
Diabetic retinopathy (DR), one of the most common microangiopathic complications in diabetes, causes severe visual damage among working-age populations. Retinal vascular endothelial cells, the key cel Show more
Diabetic retinopathy (DR), one of the most common microangiopathic complications in diabetes, causes severe visual damage among working-age populations. Retinal vascular endothelial cells, the key cell type in DR pathogenesis, are responsible for abnormal retinal angiogenesis in advanced stages of DR. The roles of exosomes in DR have been largely unknown. In this study, we report the first evidence that exosomes derived from the vitreous humor of patients with proliferative DR (PDR-exo) promote proliferation, migration, and tube formation of human retinal vascular endothelial cells (HRVECs). We identified long noncoding RNA (lncRNA) LOC100132249 enrichment in PDR-exo via high-throughput sequencing. This lncRNA, also mainly derived from HRVECs, promoted angiogenesis both in vitro and in vivo. Mechanistically, LOC100132249 acted as a competing endogenous sponge of miRNA-199a-5p (miR-199a-5p), thus regulating the endothelial-mesenchymal transition promoter SNAI1 via activation of the Wnt/β-catenin pathway and ultimately resulting in endothelial dysfunction. In conclusion, our findings underscored the pathogenic role of endothelial-derived exosomes via the LOC100132249/miR-199a-5p/SNAI1 axis in DR angiogenesis and may shed light on new therapeutic strategies for future treatment of DR. This study provides the first evidence that exosomes derived from vitreous humor from patients with proliferative diabetic retinopathy participate in angiogenesis. The findings demonstrate an unreported long noncoding RNA (lncRNA), LOC100132249, by exosomal sequencing of vitreous humor. The newly found lncRNA LOC100132249, mainly derived from endothelial cells, promotes angiogenesis via an miRNA-199a-5p/SNAI1/Wnt/β-catenin axis in a pro-endothelial-mesenchymal transition manner. Show less
Alzheimer's disease (AD) is a neurodegenerative disease with subtle onset, early diagnosis remains challenging. Accumulating evidence suggests that the emergence of retinal damage in AD precedes cogni Show more
Alzheimer's disease (AD) is a neurodegenerative disease with subtle onset, early diagnosis remains challenging. Accumulating evidence suggests that the emergence of retinal damage in AD precedes cognitive impairment, and may serve as a critical indicator for early diagnosis and disease progression. Salvianolic acid B (Sal B), a bioactive compound isolated from the traditional Chinese medicinal herb Salvia miltiorrhiza, has been shown promise in treating neurodegenerative diseases, such as AD and Parkinson's disease. In this study we investigated the therapeutic effects of Sal B on retinopathy in early-stage AD. One-month-old transgenic mice carrying five familial AD mutations (5×FAD) were treated with Sal B (20 mg·kg Show less
Wnt/β-catenin signaling is a conserved pathway crucially governing development, homeostasis, and oncogenesis. Discoveries of its regulators hold great values in both basic and translational research. Show more
Wnt/β-catenin signaling is a conserved pathway crucially governing development, homeostasis, and oncogenesis. Discoveries of its regulators hold great values in both basic and translational research. Through screening, we identified a deubiquitinase, USP10, as a critical modulator of β-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes Axin1 through K48-linked deubiquitination. Surprisingly, USP10 physically tethers Axin1 and β-catenin and promotes the phase separation for β-catenin suppression regardless of the enzymatic activity. Function-wise, USP10 enzymatic activity preferably regulates embryonic development and both the enzymatic activity and physical function jointly control intestinal homeostasis by antagonizing β-catenin. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical promotion of phase separation and correlates with Wnt/β-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against β-catenin and unearthed the enzyme-dependent and -independent "dual-regulating" mechanism. These two functions of USP10 work in parallel and are context dependent. Show less
HDL-mediated cholesterol efflux capacity (CEC) may protect from cardiovascular disease. Thus, we aimed to identify its genetic and non-genetic determinants. We measured CEC to 2% apolipoprotein B-depl Show more
HDL-mediated cholesterol efflux capacity (CEC) may protect from cardiovascular disease. Thus, we aimed to identify its genetic and non-genetic determinants. We measured CEC to 2% apolipoprotein B-depleted serum using BODIPY-cholesterol and cAMP-stimulated J774A.1 macrophages using serum samples from 4,981 participants in the German Chronic Kidney Disease (GCKD) study. Variance of CEC explained by clinical and biochemical parameters in a multivariable linear regression model was calculated by proportional marginal variance decomposition. A genome-wide association study with 7,746,917 variants was performed based on an additive genetic model. The main model was adjusted for age, sex and principal components 1-10. Further models were selected for sensitivity analysis and to reduce residual variance by known CEC pathways. Variables that explained 1% and more of the variance of CEC were concentrations of triglycerides (12.9%), HDL-cholesterol (11.8%), LDL-cholesterol (3.0%), apolipoprotein A-IV (2.8%), PCSK9 (1.0%), and eGFR (1.0%). The KLKB1 (chr4) and APOE/C1 (chr19) loci were genome-wide significantly (p < 5x10 We identified HDL-cholesterol and triglycerides as the main determinants of CEC. Furthermore, we newly found a significant association of CEC with the KLKB1 and the CLSTN2 locus and confirmed the association with the APOE/C1 locus, likely mediated by triglycerides. Show less
CPS1, the rate-limiting enzyme that controls the first reaction of the urea cycle, is responsible for converting toxic ammonia into non-toxic urea in mammals. While disruption of the functions of CPS1 Show more
CPS1, the rate-limiting enzyme that controls the first reaction of the urea cycle, is responsible for converting toxic ammonia into non-toxic urea in mammals. While disruption of the functions of CPS1 leads to elevated ammonia and nerve damage in the body, mainly manifested as urea cycle disorder. Moreover, accumulating evidence has recently revealed that CPS1 is involved in a variety of human diseases, including CPS1D, cardiovascular disease, cancers, and others. In particular, CPS1 expression varies among cancers, being overexpressed in some cancers and downregulated in others, suggesting that CPS1 may be a promising cancer therapeutic target. In addition, some small-molecule inhibitors of CPS1 have been reported, which have not been confirmed experimentally in malignancies, meaning their future role is far from certain. In this review, we describe the structure and function of CPS1, highlight its important roles in various human diseases, and further discuss the potential diagnostic and therapeutic implications of small molecule compounds targeting CPS1. Show less
Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruptio Show more
Strategies that induce dysfunction in the endoplasmic reticulum (ER) hold great promise for anticancer therapy, but remain unsatisfactory due to the compensatory autophagy induction after ER disruption. Moreover, as autophagy can either promote or suppress cell survival, which direction of autophagy better suits ER-targeting therapy remains controversial. Here, a targeted nanosystem is constructed, which efficiently escorts anticancer therapeutics into the ER, triggering substantial ER stress and autophagy. Concurrently, an autophagy enhancer or inhibitor is combined into the same nanoparticle, and their impacts on ER-related activities are compared. In the orthotopic breast cancer mouse model, the autophagy enhancer increases the antimetastasis effect of ER-targeting therapy and suppresses over 90% of cancer metastasis, while the autophagy inhibitor has a bare effect. Mechanism studies reveal that further enhancing autophagy accelerates central protein snail family transcriptional repressor 1 (SNAI1) degradation, suppressing downstream epithelial-mesenchymal transition, while inhibiting autophagy does the opposite. With the same trend, ER-targeting therapy combined with an autophagy enhancer provokes stronger immune response and tumor inhibition than the autophagy inhibitor. Mechanism studies reveal that the autophagy enhancer elevates Ca Show less
Microplastics and nanoplastics (MPs and NPs) are abundant, persistent, and widespread environmental pollutants that are of increasing concern as they pose a serious threat to ecosystems and aquatic sp Show more
Microplastics and nanoplastics (MPs and NPs) are abundant, persistent, and widespread environmental pollutants that are of increasing concern as they pose a serious threat to ecosystems and aquatic species. Identifying the ecological effects of NPs pollution requires understanding the effects of changing nanoplastics concentrations in aquatic organisms. Monopterus albus were orally fed three different concentrations of 100 nm polystyrene nanoplastics (PS-NPs): 0.05 %, 0.5 %, and 1 % of the feed for 28 days. Nanoplastics significantly activated the PPAR signaling pathway, Acyl-CoA oxidase 1 (ACOX1), carnitine palmitoyltransferase 1a (CPT1A), angiopoietin-like 4 (ANGPTL4), and phosphoenolpyruvate carboxykinase (PCK) at the mRNA level, resulting in disturbed lipid metabolism. Glutathione peroxidase (GSH-px) activity, catalase (CAT) activity, and malondialdehyde (MDA) were significantly elevated in the high nanoplastics-feeding exposure group, leading to oxidative stress in the liver. Overexpression of the cytokines genes Interleukin 1 (IL1B) and Interleukin-8 (IL8), Tumor necrosis factor alpha (TNF-α), activation of MAPK signaling pathway, and increased gene expression of c-Jun amino-terminal kinases (JNK) and p38 indicate that exposure to NPs may lead to hepatopancreas apoptosis through oxidative stress and inflammation. In summary, dietary PS-NPs exposure alters hepatic glycolipid metabolism, triggering inflammatory responses and apoptosis in M. albus. The results of this study provide valuable ecotoxicological data for a better understanding of the biological fate and effects of nanoplastics in M. albus. Show less
Telomere-related genes (TRGs) play a critical role in various types of tumors. However, there is a lack of comprehensive exploration of their relevance in lung cancer. This research aimed to verify th Show more
Telomere-related genes (TRGs) play a critical role in various types of tumors. However, there is a lack of comprehensive exploration of their relevance in lung cancer. This research aimed to verify the relationship between TRGs gene expression and the prognosis of patients with lung adenocarcinoma (LUAD), as well as the prediction of drug treatment efficiency. A total of 2093 TRGs were acquired from TelNet. The clinical information including age, tumor stage, follow up and outcome (death/survival) and TRGs expression profile of LUAD were obtained from the patients in The Cancer Genome Atlas (TCGA) database and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. The two databases were used to construct and verify a prognostic model based on the expression of hubTRGs. The tumor mutation burden, immune infiltration and subtypes, as well as IC50 prediction of multiple targeted drugs were also evaluated in TRGs-divided risk groups. A total of 335 TRGs were significantly differentially expressed in LUAD as compared with normal control. Among them, 9 TRGs (ABCC2, ABCC8, ALDH2, FOXP3, GNMT, JSRP1, MACF1, PLCD3, SULT4A1) were finally identified as hubGenes and used to construct a TRG risk score. The TRG risk score showed favorable performance in constructing a prognostic nomogram in predicting survival of LUAD, and the ROC curves at 1, 3 and 5 years were plotted and the AUROC values were 0.743, 0.754 and 0.735, respectively. Higher TRGs risk score correlated with worse immune subtypes and higher tumor mutation burden in LUAD tissues. In addition, the patients in TRG high risk group harbored a lower TIDE score which indicated potentially better response to immunotherapy. This study proposed a broad molecular signature of telomere-related genes that can be used in further functional and therapeutic investigations, and also represents an integrated modality for characterizing critical molecules when exploring novel targets for lung cancer immunotherapy. Show less
Bidirectional communication between the developing conceptus and endometrium is essential for pregnancy recognition and establishment in ruminants. We dissect the transcriptomic dynamics of sheep conc Show more
Bidirectional communication between the developing conceptus and endometrium is essential for pregnancy recognition and establishment in ruminants. We dissect the transcriptomic dynamics of sheep conceptus and corresponding endometrium at pre- and peri-implantation stages using single-cell RNA sequencing. Spherical blastocysts contain five cell types, with 68.62% trophectoderm cells. Strikingly, elongated conceptuses differentiate into 17 cell types, indicating dramatic cell fate specifications. Cell-type-specific gene expression delineates the features of distinctive trophectoderm lineages and indicates that the transition from polar trophectoderm to trophoblast increases interferon-tau expression and likely drives elongation initiation. We identify 13 endometrium-derived cell types and elucidate their molecular responses to conceptus development. Integrated analyses uncover multiple paired transcripts mediating the dialogues between extraembryonic membrane and endometrium, including IGF2-IGF1R, FGF19-FGFR1, NPY-NPY1R, PROS1-AXL, and ADGRE5-CD55. These data provide insight into the molecular regulation of conceptus elongation and represent a valuable resource for functional investigations of pre- and peri-implantation ruminant development. Show less
The objective of this study was to investigate the phylogenetic and expression analysis of the angiopoietin-like (ANGPTL) gene family and their role in lipid metabolism in pigs. In this study, the ami Show more
The objective of this study was to investigate the phylogenetic and expression analysis of the angiopoietin-like (ANGPTL) gene family and their role in lipid metabolism in pigs. In this study, the amino acid sequence analysis, phylogenetic analysis, and chromosome adjacent gene analysis were performed to identify the ANGPTL gene family in pigs. According to the body weight data from 60 Jinhua pigs, different tissues of 6 pigs with average body weight were used to determine the expression profile of ANGPTL1-8. The ileum, subcutaneous fat, and liver of 8 pigs with distinct fatness were selected to analyze the gene expression of ANGPTL3, ANGPTL4, and ANGPTL8. The sequence length of ANGPTLs in pigs was between 1,186 and 1,991 bp, and the pig ANGPTL family members shared common features with human homologous genes, including the high similarity of the amino acid sequence and chromosome flanking genes. Amino acid sequence analysis showed that ANGPTL1-7 had a highly conserved domain except for ANGPTL8. Phylogenetic analysis showed that each ANGPTL homologous gene shared a common origin. Quantitative reverse-transcription polymerase chain reaction analysis showed that ANGPTL family members had different expression patterns in different tissues. ANGPTL3 and ANGPTL8 were mainly expressed in the liver, while ANGPTL4 was expressed in many other tissues, such as the intestine and subcutaneous fat. The expression levels of ANGPTL3 in the liver and ANGPTL4 in the liver, intestine and subcutaneous fat of Jinhua pigs with low propensity for adipogenesis were significantly higher than those of high propensity for adipogenesis. These results increase our knowledge about the biological role of the ANGPTL family in this important economic species, it will also help to better understand the role of ANGPTL3, ANGPTL4, and ANGPTL8 in lipid metabolism of pigs, and provide innovative ideas for developing strategies to improve meat quality of pigs. Show less
Xiaoding Liu, Xianglin Yin, Dongmei Li+8 more · 2023 · Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · Elsevier · added 2026-04-24
Phosphaturic mesenchymal tumors (PMTs) are rare neoplasms of soft tissue or bone. Although previous studies revealed that approximately 50% of PMTs harbor FN1::FGFR1 fusions, the molecular mechanisms Show more
Phosphaturic mesenchymal tumors (PMTs) are rare neoplasms of soft tissue or bone. Although previous studies revealed that approximately 50% of PMTs harbor FN1::FGFR1 fusions, the molecular mechanisms in the remaining cases are largely unknown. In this study, fusion genes were investigated using RNA-based next-generation sequencing in 76 retrospectively collected PMTs. Novel fusions were validated with Sanger sequencing and fluorescence in situ hybridization. Fusion genes were detected in 52/76 (68.4%) PMTs, and 43/76 (56.6%) harbored FN1::FGFR1 fusions. Fusion transcripts and breakpoints of the FN1::FGFR1 fusions were diverse. The most common fusion transcript was between exon 20 of FN1 and exon 9 of FGFR1 (7/43, 16.3%). The most upstream breakpoint of the FN1 gene was located at the 3' end of exon 12, and the most downstream breakpoint of the FGFR1 gene was at the 5' end of exon 9, suggesting the inessential nature of the third fibronectin-type domain of FN1 and the necessity of the transmembrane domain of FGFR1 in the FN1::FGFR1 fusion protein, respectively. Moreover, the reciprocal FGFR1::FN1 fusions, which had not been identified in previous studies, were detected in 18.6% (8/43) of FN1::FGFR1 fusion-positive PMTs. Novel fusions were identified in 6/76 (7.9%) FN1::FGFR1 fusion-negative PMTs, including 2 involving FGFR: FGFR1::USP33 (1/76, 1.3%) and FGFR1::TLN1 (1/76, 1.3%). Other novel fusions identified were the PDGFRA::USP35 (1/76, 1.3%), SPTBN1::YWHAQ (1/76, 1.3%), GTF2I::RALGPS1 (1/76, 1.3%), and LTBP1::VWA8 (1/76, 1.3%) fusions. In addition to these novel fusions, FN1::FGFR2 (1/76, 1.3%), NIPBL::BEND2 (1/76, 1.3%), and KIAA1549::BRAF fusions (1/76, 1.3%) were also identified in FN1::FGFR1-negative cases arising from the thigh, ilium, and acetabulum, respectively. The frequency of oncogenic fusions was significantly higher (P = .012) in tumors derived from extremities (29/35, 82.9%) compared with other locations (23/41, 56.1%). No significant correlation was identified between fusions and recurrence (P = .786). In conclusion, we report fusion transcripts and breakpoints of FN1::FGFR1 in PMTs in detail, providing insights into fusion protein functions. We also revealed that a considerable proportion of PMTs without FN1::FGFR1 fusion carried novel fusions, providing further insight into the genetic basis of PMTs. Show less
Ferroptosis is an important mode of regulated cell death (RCD). Its inhibition is closely related to therapeutic resistance and poor prognosis in hepatocellular carcinoma (HCC). Previous reports have Show more
Ferroptosis is an important mode of regulated cell death (RCD). Its inhibition is closely related to therapeutic resistance and poor prognosis in hepatocellular carcinoma (HCC). Previous reports have demonstrated ferroptosis as a biological process highly dependent on selective autophagy, such as ferritinophagy, lipophagy, and clockophagy. Our study also revealed a role for ER-phagy-mediated ferroptosis in HCC cells treated with multi-targeted tyrosine kinase inhibitors (TKIs). In the current study, we found that the homologous circular RNA (circRNA) of the family with sequence similarity 134, member B ( Show less
Fangmei Tang, Huai Bai, Linbo Guan+7 more · 2023 · Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · added 2026-04-24
To investigate the apolipoprotein C-3 (APOC3) gene A total of 630 pregnant women with GDM and 1027 normal pregnant controls were covered in the study. The genotype and allele frequencies of The allele Show more
To investigate the apolipoprotein C-3 (APOC3) gene A total of 630 pregnant women with GDM and 1027 normal pregnant controls were covered in the study. The genotype and allele frequencies of The allele frequencies of S1 and S2 of the Show less
This bioinformatics report attempts to explore the cross-talk genes, transcription factors (TFs), and pathways related to myocardial ischemia-reperfusion injury (MIRI) as well as the gut microbiome. T Show more
This bioinformatics report attempts to explore the cross-talk genes, transcription factors (TFs), and pathways related to myocardial ischemia-reperfusion injury (MIRI) as well as the gut microbiome. The datasets GSE61592 (three MIRI and three sham samples) and GSE160516 (twelve MIRI and four sham samples) were selected in the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) identification (p < 0.05 and |log FC (fold change)| ≥1) together with functional annotation (p < 0.05) was implemented. The Cytoscape platform established the protein-protein interaction (PPI) network. Genes associated with gut microbiome disorder were extracted based on the DisGeNET database, and those associated with MIRI were overlapped. The Recursive Feature Elimination (RFE) algorithm was adopted for selecting features, and cross-talk genes were predicted by the Support Vector Machine (SVM) models. A network encompassing cross-talk genes along with the TFs was thereby established. The MIRI datasets comprised 138 shared DEGs, with 101 showing up-regulation whereas 37 showing down-regulation. Notably, the PPI interwork for MIRI contained 2517 edges along with 1818 nodes. By using RFE and SVM methods, six feature genes with the highest prediction were identified: B2m, VCAM-1, PDIA4, Ptgds, Mlxipl, and ACADS. Among these genes, B2m and PDIA4 were most highly expressed in MIRI and the gut microbiome disorder. B2m and PDIA4 were identified to be significantly correlated with candidate cross-talk genes of MIRI with gut microbiome disorder, implying a similarity between MIRI and Gut microbiome disorder (GMD). These genes can serve as an experimental research basis for future studies. Show less
Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24-dehydrochol Show more
Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24-dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti-inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3-Leiden. CETP mice, a well-established translational model that develops diet-induced human-like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet-induced hepatic steatosis and inflammation in a strictly LXRα-dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH. Show less
Both estrogen and apolipoprotein C3 (ApoC3) play crucial roles in lipid metabolism. But the link between them remains unclear, and it is unknown whether estrogen regulates triglyceride (TG) levels via Show more
Both estrogen and apolipoprotein C3 (ApoC3) play crucial roles in lipid metabolism. But the link between them remains unclear, and it is unknown whether estrogen regulates triglyceride (TG) levels via ApoC3. Researchers hypothesized that estrogen exerts a regulatory effect on ApoC3 metabolism, and that this regulation could play a significant role in lipid metabolism. To explore this potential link, the present investigation aimed to examine the associations between estradiol (E2), ApoC3, and TG levels in both males and females. A total of 519 obese people (133 males and 386 premenopausal females) were recruited. Based on their TG levels, the participants were split into two groups [hypertriglyceridemia (HTG) group: TG ≥ 1.7 mmol/L; control group: TG < 1.7 mmol/L]. Serum ApoC3, E2, and TG levels were measured and compared in those two groups for both sexes separately. To ascertain the connection among E2, ApoC3, and TG, linear regression and mediation analysis were used. Participants in the HTG group presented higher levels of ApoC3 (P < 0.001). In contrast, they tend to have lower E2 levels than the control. Linear regression analysis proposed that in both sexes, E2 was negatively associated with ApoC3 levels. The relationship remained significant after adjustment for confounding factors (male: standardized β = -0.144, t = -2.392, P < 0.05; female: standardized β = -0.077, t = -2.360, P < 0.001). Furthermore, mediation analysis revealed the relationship between reduced E2 levels and elevated TG levels is directly mediated by ApoC3. In obese men and premenopausal women, ApoC3 was negatively and linearly correlated with serum E2 levels. The findings showed that estrogen may suppress ApoC3 expression and thus lower TG levels. Show less
Florfenicol is a commonly used antibiotic for the treatment of bacterial diseases of the Chinese soft-shelled turtle (Pelodiscus sinensis). The study investigated the effects of florfenicol on the ant Show more
Florfenicol is a commonly used antibiotic for the treatment of bacterial diseases of the Chinese soft-shelled turtle (Pelodiscus sinensis). The study investigated the effects of florfenicol on the antioxidant and immune system of P. sinensis. Results showed that the total antioxidant capacity (T-AOC), superoxide dismutase (SOD), and catalase (CAT) activities were significantly increased in the 10 mg/kg and 40 mg/kg florfenicol treatment groups compared with the control group. Besides, the malondialdehyde (MDA) content was significantly increased, and the glutathione peroxidase (GSH-Px) activity was significantly decreased with 40 mg/kg florfenicol treatment. In addition, florfenicol has effects on the immune system, 10 mg/kg of florfenicol significantly promoted the activities of acid phosphatase (ACP) and alkaline phosphatase (AKP), whereas 40 mg/kg of florfenicol significantly inhibited their activities. To elucidate the molecular mechanisms, a comparative transcriptome analysis was conducted. A total of 59 differentially expressed genes (DEGs) and 12 significantly enriched KEGG pathways were identified in the 10 mg/kg group; 150 DEGs and 10 significantly enriched KEGG pathways were identified in the 40 mg/kg group. Among them, the complement and coagulation cascade pathways were the most significant which may play an important regulatory role in the immune response. The MADCAM1, STAT3, and IL4I1 genes may be the key genes of florfenicol affecting the immune response. The APOA1, APOA4, SPLA2, FADS1, and FADS2 genes may play a key role in anti-inflammatory and antioxidant effects through redox-related pathways. The study lays the foundation for a deeper understanding of the mechanism of the florfenicol effect on P. sinensis. Show less
Body conformation is the most direct production index, which can fully reflect pig growth status and is closely related to critical economic traits. In this study, we conducted a genome-wide associati Show more
Body conformation is the most direct production index, which can fully reflect pig growth status and is closely related to critical economic traits. In this study, we conducted a genome-wide association study (GWAS) on body conformation traits in a population of 1518 Duroc × (Landrace × Yorkshire) commercial pigs. These traits included body length (BL), body height (BH), chest circumference (CC), abdominal circumference (AC), and waist circumference (WC). Both the mixed linear model (MLM) and fixed and random model circulating probability unification (FarmCPU) approaches were employed for the analysis. Our findings revealed 60 significant single nucleotide polymorphisms (SNPs) associated with these body conformation traits in the crossbred pig population. Specifically, sixteen SNPs were significantly associated with BL, three SNPs with BH, thirteen SNPs with CC, twelve SNPs with AC, and sixteen SNPs with WC. Moreover, we identified several promising candidate genes located within the genomic regions associated with body conformation traits. These candidate genes include Show less
Growth differentiation factor 15 (GDF15) belongs to the Transforming growth factor β(TGF-β) superfamily. The decrease of GDF15 in the serum of pregnant women was associated with miscarriage. Both IHC Show more
Growth differentiation factor 15 (GDF15) belongs to the Transforming growth factor β(TGF-β) superfamily. The decrease of GDF15 in the serum of pregnant women was associated with miscarriage. Both IHC and ELISA assays showed that GDF15 in trophoblast tissue and serum of pregnant women who miscarried was significantly lower than in those who had a live birth. GDF15 deficiency was associated with embryo resorption in GDF15 knockout mice through CRIPSR editing. In addition, the migration and invasion ability of HTR-8/SVneo and JEG-3 cells were promoted by GDF15. Mechanistically, GDF15 increased Smad1/5 phosphorylation, resulting in upregulating SNAI1/2, VIMENTIN and downregulating E-CADHERIN. A dual-luciferase reporter assay confirmed that Smad-binding elements (SBE) and/or GC-rich motifs were activated and target genes such as SNAI1/2, SERPINE1, and TIMP3 were transcriptionally regulated by GDF15/Smad5 signaling. Therefore, our data revealed a crucial role of GDF15 on invasion of trophoblast by upregulating the activity of TGF-β/Smad1/5 pathway. Show less
Skeletal muscle turnover helps support the physiological needs of dairy cows during the transition into lactation. We evaluated effects of feeding ethyl-cellulose rumen-protected methionine (RPM) duri Show more
Skeletal muscle turnover helps support the physiological needs of dairy cows during the transition into lactation. We evaluated effects of feeding ethyl-cellulose rumen-protected methionine (RPM) during the periparturient period on abundance of proteins associated with transport AA and glucose, protein turnover, metabolism, and antioxidant pathways in skeletal muscle. Sixty multiparous Holstein cows were used in a block design and assigned to a control or RPM diet from -28 to 60 d in milk. The RPM was fed at a rate of 0.09% or 0.10% of dry matter intake (DMI) during the prepartal and postpartal periods to achieve a target Lys:Met ratio in the metabolizable protein of ∼2.8:1. Muscle biopsies from the hind leg of 10 clinically healthy cows per diet collected at -21, 1, and 21 d relative to calving were used for western blotting of 38 target proteins. Statistical analysis was performed using the PROC MIXED statement of SAS version 9.4 (SAS Institute Inc.) with cow as random effect, whereas diet, time, and diet × time were the fixed effects. Diet × time tended to affect prepartum DMI, with RPM cows consuming 15.2 kg/d and controls 14.6 kg/d. However, diet had no effect on postpartum DMI (17.2 and 17.1 ± 0.4 kg/d for control and RPM, respectively). Milk yield during the first 30 d in milk was also not affected by diet (38.1 and 37.5 ± 1.9 kg/d for control and RPM, respectively). Diet or time did not affect the abundance of several AA transporters or the insulin-induced glucose transporter (SLC2A4). Among evaluated proteins, feeding RPM led to lower overall abundance of proteins associated with protein synthesis (phosphorylated EEF2, phosphorylated RPS6KB1), mTOR activation (RRAGA), proteasome degradation (UBA1), cellular stress responses (HSP70, phosphorylated MAPK3, phosphorylated EIF2A, ERK1/2), antioxidant response (GPX3), and de novo synthesis of phospholipids (PEMT). Regardless of diet, there was an increase in the abundance of the active form of the master regulator of protein synthesis phosphorylated MTOR and the growth-factor-induced serine/threonine kinase phosphorylated AKT1 and PIK3C3, whereas the abundance of a negative regulator of translation (phosphorylated EEF2K) decreased over time. Compared with d 1 after calving and regardless of diet, the abundance of proteins associated with endoplasmic reticulum stress (XBP1 spliced), cell growth and survival (phosphorylated MAPK3), inflammation (transcription factor p65), antioxidant responses (KEAP1), and circadian regulation (CLOCK, PER2) of oxidative metabolism was upregulated at d 21 relative to parturition. These responses coupled with the upregulation of transporters for Lys, Arg, and His (SLC7A1) and glutamate/aspartate (SLC1A3) over time were suggestive of dynamic adaptations in cellular functions. Overall, management approaches that could take advantage of this physiological plasticity may help cows make a smoother transition into lactation. Show less
Vascular dementia (VD), associated with cerebrovascular injury, is characterized by severe cognitive impairment. Jianpi Tianjing Decoction (JTD) has been widely used to treat VD. However, its molecula Show more
Vascular dementia (VD), associated with cerebrovascular injury, is characterized by severe cognitive impairment. Jianpi Tianjing Decoction (JTD) has been widely used to treat VD. However, its molecular targets and mechanisms of action in this treatment remain unclear. This study integrated network pharmacology and proteomics to identify targets and mechanisms of JTD in the treatment of VD and to provide new insights and goals for clinical treatments. Systematic network pharmacology was used to identify active chemical compositions, potential targets, and mechanisms of JTD in VD treatment. Then, a mouse model of VD was induced via transient bilateral common carotid artery occlusion to verify the identified targets and mechanisms of JTD against VD using 4D label-free quantitative proteomics. By screening active chemical compositions and potential targets in relevant databases, 187 active chemical compositions and 416 disease-related compound targets were identified. JTD may suppress VD development via multiple components, targets, and pathways. It may thus serve as a complementary treatment option for patients with VD. Show less
To determine whether trimethylamine N-oxide (TMAO) would aggravate cognitive dysfunction from APP/PS1 mice and the potential protective effects of voluntary wheel running (VWR). TMAO impaired learning Show more
To determine whether trimethylamine N-oxide (TMAO) would aggravate cognitive dysfunction from APP/PS1 mice and the potential protective effects of voluntary wheel running (VWR). TMAO impaired learning and memory abilities, and exercise reversed TMAO induced cognitive impairment. Serum TMAO, choline, betaine and TMA were significantly elevated from TMAO group, while exercise group had decreased TMAO, betaine and TMA level. TMAO group has significantly upregulated BACE1 from both hippocampus and cortex, also increased cathepsin B, p-Tau at Ser396&Ser404, GFAP, p-NF-κB p65 in cortex, while reduced BDNF, synaptophysin and PSD95 in hippocampus, also reduced occludin and ZO-1 from cortex, and reduced occludin from colon. In contrast, BACE1 from both hippocampus and cortex, also cathepsin B and p-Tauser396 from cortex were reduced, BDNF, snaptophysin, and PSD95 from hippocampus, ZO-1 from cortex, and occludin from colon were elevated post exercise compared to TMAO group. Exercise elevated α diversity index of cecal content, and TMAO and exercise affected gut microbiota profiles differentially. In conclusion, TMAO led to gut microbiota dysbiosis, impaired gut-brain integrity, elevated neuroinflammation, Aβ pathology and tau phosphorylation, disordered synaptic function; and exercise could reverse TMAO induced cognitive dysfunction via improving the above markers. The potential deleterious effects of TMAO on cognitive function need to be validated in humans, also dosages of exercise for exerting neuroprotective effects against TMAO induced cognitive impairment. Show less
Lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer (NSCLC) with a low 5-year survival rate, which may be associated with the presence of metastatic tumors Show more
Lung adenocarcinoma (LUAD) is the most common histological subtype of non-small cell lung cancer (NSCLC) with a low 5-year survival rate, which may be associated with the presence of metastatic tumors at the time of diagnosis, especially lymph node metastasis (LNM). This study aimed to construct a LNM-related gene signature for predicting the prognosis of patients with LUAD. RNA sequencing data and clinical information of LUAD patients were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Samples were divided into metastasis (M) and nonmetastasis (NM) groups based on LNM status. Differentially expressed genes (DEGs) between M and NM groups were screened, and then WGCNA was applied to identify key genes. Furthermore, univariate Cox and LASSO regression analyses were conducted to construct a risk score model, and the predictive performance of model was validated by GSE68465, GSE42127, and GSE50081. The protein and mRNA expression level of LNM-associated genes were detected by human protein atlas (HPA) and GSE68465. A prognostic model based on eight LNM-related genes (ANGPTL4, BARX2, GPR98, KRT6A, PTPRH, RGS20, TCN1, and TNS4) was developed. Patients in the high-risk group had poorer overall survival than those in the low-risk group, and validation analysis showed that this model had potential predictive value for patients with LUAD. HPA analysis supported the upregulation of ANGPTL4, KRT6A, BARX2, RGS20 and the downregulation of GPR98 in LUAD compared with normal tissues. Our results indicated that the eight LNM-related genes signature had potential value in the prognosis of patients with LUAD, which may have important practical implications. Show less
Mi Li, Xian Wang, Lijie Yang+3 more · 2023 · Technology and health care : official journal of the European Society for Engineering and Medicine · added 2026-04-24
Microglia express phosphatidylinositol 3-kinase (PI3K) has been implicated in the induction and maintenance of long-term potentiation (LTP) and in hippocampal synaptic plasticity. However, there are f Show more
Microglia express phosphatidylinositol 3-kinase (PI3K) has been implicated in the induction and maintenance of long-term potentiation (LTP) and in hippocampal synaptic plasticity. However, there are few studies on the interference of PI3K signal pathway in microglia. The study goal is to gain a better understanding of the mechanism by which EA affects synapses provides insights into how electroacupuncture (EA) modulates synaptic plasticity in learning and memory. Rat models of posttraumatic stress disorder (PTSD) were used to explore the effects of EA on microglial PI3K pathway, brain-derived neurotrophic factor (BDNF) and LTP, and the target and mechanism underlying the effects of EA on PI3K from the perspective of protein ubiquitination. EA induced microglial BDNF expression by activating the PI3K-AKT pathway, thereby facilitating LTP and synaptic plasticity. EA inhibited lincRNA 02023 to rescue the binding of WWP2 to PTEN, thereby promoting PTEN ubiquitination and degradation. The mechanism of EA improving the learning and memory ability of PTSD rats may be that it can promote the competitive combination of WWP2 and PTEN by inhibiting Linc RNA02023, and then lead to microglial PI3K and its pathway activation, BDNF up-regulation, and finally induce LTP and repair damaged synaptic plasticity. Show less
Linping Wang, Jingqi Zhang, Yue Zhao+5 more · 2023 · Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) · Elsevier · added 2026-04-24
Studies have shown that aluminum (Al) is one of the environmental risk factors leading to Alzheimer's disease (AD), and Al exposure can cause elevated levels of BACE1mRNA, β-secretase (BACE1), and amy Show more
Studies have shown that aluminum (Al) is one of the environmental risk factors leading to Alzheimer's disease (AD), and Al exposure can cause elevated levels of BACE1mRNA, β-secretase (BACE1), and amyloid beta (Aβ) in vivo and in vitro. Previous studies by our research group have shown that this is partly caused by the negative regulation of BACE1 by miRNA29a/b1 (miR29a/b1). Despite the observed the role of nuclear factor kappa B (NF-κB) on many miRNAs, the upstream regulation of NF-κB protein on miR29 remains poorly understood. The purpose of this study was to better define the relationship between NF-κB and miR29a/b1 and the potentially relevant signaling pathways. On the one hand, we constructed the animal model of Al exposure by the intraperitoneal injection of aluminum-maltolate (Al(mal) We verified that NF-κB shows an increasing trend with Al accumulation in the brain of rats, which is accompanied by a downward trend of miR29a/b1. Notably, the suppression of NF-κB significantly increased miR29a/b1 and affected the expression of BACE1mRNA and downstream proteins. Al-induced NF-κB can negatively regulate the expression of miR29a/b1, which then significantly enhances the expression of BACE1 and Aβ plaques. Show less