Copy number variation (CNV) is a genetic structural polymorphism important for phenotypic diversity and important economic traits of livestock breeds, and it plays an important role in the desired gen Show more
Copy number variation (CNV) is a genetic structural polymorphism important for phenotypic diversity and important economic traits of livestock breeds, and it plays an important role in the desired genetic variation. This study used whole genome sequencing to detect the CNV variation in the genome of 6 local Tibetan sheep groups. We detected 69,166 CNV events and 7230 copy number variable regions (CNVRs) after merging the overlapping CNVs, accounting for 2.72% of the reference genome. The CNVR length detected ranged from 1.1 to 1693.5 Kb, with a total length of 118.69 Mb and an average length of 16.42 Kb per CNVR. Functional GO cluster analysis showed that the CNVR genes were mainly involved in sensory perception systems, response to stimulus, and signal transduction. Through CNVR-based Vst analysis, we found that the CACNA2D3 and CTBP1 genes related to hypoxia adaptation, the HTR1A gene related to coat color, and the TRNAS-GGA and PIK3C3 genes related to body weight were all strongly selected. The findings of our study will contribute novel insights into the genetic structural variation underlying hypoxia adaptation and economically important traits in Tibetan sheep. Show less
The goose is an economically important poultry species and was one of the first to be domesticated. However, studies on population genetic structures and domestication in goose are very limited. Here, Show more
The goose is an economically important poultry species and was one of the first to be domesticated. However, studies on population genetic structures and domestication in goose are very limited. Here, we performed whole genome resequencing of geese from two wild ancestral populations, five Chinese domestic breeds, and four European domestic breeds. We found that Chinese domestic geese except Yili geese originated from a common ancestor and exhibited strong geographical distribution patterns and trait differentiation patterns, while the origin of European domestic geese was more complex, with two modern breeds having Chinese admixture. In both Chinese and European domestic geese, the identified selection signatures during domestication primarily involved the nervous system, immunity, and metabolism. Interestingly, genes related to vision, skeleton, and blood-O2 transport were also found to be under selection, indicating genetic adaptation to the captive environment. A forehead knob characterized by thickened skin and protruding bone is a unique trait of Chinese domestic geese. Interestingly, our population differentiation analysis followed by an extended genotype analysis in an additional population suggested that two intronic SNPs in Show less
Lipoprotein lipase (LPL) is the key enzyme responsible for the hydrolysis of triglycerides. Loss-of-function variants in the LPL gene are associated with hypertriglyceridemia (HTG) and HTG-related dis Show more
Lipoprotein lipase (LPL) is the key enzyme responsible for the hydrolysis of triglycerides. Loss-of-function variants in the LPL gene are associated with hypertriglyceridemia (HTG) and HTG-related diseases. Unlike nonsense, frameshift and canonical GT-AG splice site variants, a pathogenic role for clinically identified LPL missense variants should generally be confirmed by functional analysis. Herein, we describe the clinical and functional analysis of a rare LPL missense variant. Chinese patients with HTG-associated acute pancreatitis (HTG-AP) were screened for rare nonsense, frameshift, missense or canonical GT-AG splice site variants in LPL and four other lipid metabolism-related genes (APOC2, APOA5, GPIHBP1 and LMF1) by Sanger sequencing. The functional consequences of the LPL missense variant of interest were characterized by in vitro expression in HEK-293T and COS-7 cells followed by Western blot and LPL activity assays. Five unrelated HTG-AP patients were found to be heterozygous for a rare East Asian-specific LPL missense variant, c.862G > A (p.Ala288Thr). All five patients were adult males, and all were overweight and had a long history of alcohol consumption. Transfection of LPL wild-type and c.862G > A expression vectors into two cell lines followed by Western blot analysis served to exclude the possibility that the p.Ala288Thr missense variant either impaired protein synthesis or increased protein degradation. Contrary to a previous functional study that claimed that p.Ala288Thr had a severe impact on LPL function (reportedly having 36% normal activity), our experiments consistently demonstrated that the variant had a comparatively mild effect on LPL functional activity, which was mediated through its impact upon LPL protein secretion (~ 20% reduced secretion compared to wild-type). In this study, we identified the East Asian-specific LPL c.862G > A (p.Ala288Thr) missense variant in five unrelated HTG-AP patients. We demonstrated that this variant exerted only a relatively mild effect on LPL function in two cell lines. Heterozygosity for this LPL variant may have combined with alcohol consumption to trigger HTG-AP in these patients. Show less
Peripheral blood immune cell profiling of atopic dermatitis patients before and after treatment by single-cell RNA sequencing technique has not been reported. To study the immune Cell Profiling of Ato Show more
Peripheral blood immune cell profiling of atopic dermatitis patients before and after treatment by single-cell RNA sequencing technique has not been reported. To study the immune Cell Profiling of Atopic Dermatitis Patients Before and After Treatment with Halometasone Cream Wet-Wrap Therapy. We used single cell sequencing to detect the proportion change and gene expression change of immune cells in 2 patients before and after treatment, and then used real-time PCR to confirm the mRNA level of differential genes. In this study, scRNA-seq in two patients with severe AD before and after halometasone cream wet-wrap therapy showed that in the mild severity of AD after treatment, Th2 cells were significantly decreased (41.2% vs 13.4%), Th1 and Th17 cells were increased (23.3% vs 43.7%, 2.3% vs 4.8% respectively). The proportion of Th22 cells did not change much (1.3% vs 1.9%). Tregs were significantly increased also (1.5% vs 5.0%). In the regulatory T cells, the expression of IL-27, PD-1, CD103, CTLA-4, ZNF-66, IL-β, CD7 gene was specifically increased after treatment, and CD39, P21, TOX2, CD151, CD79A, S100A12, TRAP1 gene was specifically decreased after treatment. In the TH2 cells, the expression of CD27, CD68, EZH1, RAD1, EGFR, CCR10, BCL11A, KLF4 gene was specifically increased after treatment and CCL26, CD180, IL-31, CCL22, LEF1, OX40 gene was specifically decreased after treatment. These genes may be new target for further study. Show less
Primary Sjogren's Syndrome (pSS) is a chronic autoimmune disease, with unclear pathogenies. Lysine-malonylation (Kmal) as a novel post-translational modification (PTMs) was found associated with metab Show more
Primary Sjogren's Syndrome (pSS) is a chronic autoimmune disease, with unclear pathogenies. Lysine-malonylation (Kmal) as a novel post-translational modification (PTMs) was found associated with metabolic, immune, and inflammatory processes. For purpose of investigating the proteomic profile and functions of kmal in pSS, liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based analysis and bioinformatics analysis are performed based on twenty-eight pSS patients versus twenty-seven healthy controls (HCs). A total of 331 down-regulated proteins and 289 up-regulated proteins are observed in differentially expressed proteins (DEPs) of pSS. We discover the expression of transforming growth factor beta-1 (TGFB1) and CD40 ligand downregulate which enriches in the inflammatory associated pathway. Expression of signal transducer and activator of transcription 1-alpha/beta (STAT1) show upregulation and enrich in type I interferon signaling pathway and IL-27-mediated signaling pathway. In differentially malonylated proteins (DMPs) of pSS, we identify 3 proteins are down-regulated in 7 sites and 18 proteins are up-regulated in 19 sites. Expression of malonylated integrin-linked kinase (ILK) significantly enrich in the focal adhesion pathway. Together, our data provide evidence that downregulation of TGFB1 and CD40LG play a critical role in the inflammatory process of pSS, while upregulation of STAT1 may be associated with IL-27 immunity and pSS immune dysfunction. Moreover, kmal modification at the kinase domain of ILK may destabilize ILK that thus contributing to pSS pathogenies by regulating the focal adhesion pathway. SIGNIFICANCE: Our research offered the first characterization of Kmal, a newly identified form of lysine acylation in pSS, as well as proteomic data on individuals with pSS. In this study, we found that several key DMPs were associated with focal adhesion pathway, which contributes to the development of pSS. The present results provide an informative dataset for the future exploration of Kmal in pSS. Show less
We examined potential sex differences in appetite and blood pressure (BP) responses to melanocortin-4 receptor (MC4R) blockade in offspring from lean and obese parents. Offspring from normal (N) diet- Show more
We examined potential sex differences in appetite and blood pressure (BP) responses to melanocortin-4 receptor (MC4R) blockade in offspring from lean and obese parents. Offspring from normal (N) diet-fed parents were fed N (NN) or high-fat (H) diets (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were also fed N (HN) or H diets (HH). Adult male and female offspring were implanted with BP telemetry probes and intracerebroventricular cannulas to infuse MC4R antagonist or vehicle. Infusion of the MC4R antagonist SHU-9119 (1 nmol/h) for 7 days caused larger increases in calorie intake and body weight in obese compared with lean offspring. In male offspring, HH and HN groups exhibited higher baseline BP compared with NN and NH, and HH showed a greater reduction in BP during SHU-9119 infusion. In female offspring, HH also showed higher baseline BP and greater reduction in BP during MC4R blockade. SHU-9119 reduced heart rate in all groups, but reductions were more pronounced in offspring from lean parents. Combined α and β-adrenergic blockade reduced BP more in male HH offspring compared with NN controls. Losartan reduced BP more in male NH, HN, and HH offspring compared with NN controls. Losartan and α- and β-adrenergic blockade reduced BP similarly in all female groups. These results suggest that endogenous MC4R activity contributes to elevated BP in obese offspring from obese parents. Our findings also indicate important sex differences in the mechanisms of BP control in male and female offspring of obese parents. Show less
Alpine Merino Sheep is a novel breed reared from Australian Merino Sheep as the father and Gansu Alpine Fine-Wool Sheep as the mother, living all year in cold and arid alpine areas with exceptional wo Show more
Alpine Merino Sheep is a novel breed reared from Australian Merino Sheep as the father and Gansu Alpine Fine-Wool Sheep as the mother, living all year in cold and arid alpine areas with exceptional wool quality and meat performance. Body weight is an important economic trait of the Alpine Merino Sheep, but there is limited research on identifying the genes associated with live weight in the 14th month for improving the accuracy of the genomic prediction of this trait. Therefore, this study's sample comprised 1310 Alpine Merino Sheep ewes, and the Fine Wool Sheep 50K Panel was used for genome-wide association study (GWAS) analysis to identify candidate genes. Moreover, the trial population (1310 ewes) in this study was randomly divided into two groups. One group was used as the population for GWAS analysis and screened for the most significant top 5%, top 10%, top 15%, and top 20% SNPs to obtain prior marker information. The other group was used to estimate the genetic parameters based on the weight assigned by heritability combined with different prior marker information. The aim of this study was to compare the accuracy of genomic breeding value estimation when combined with prior marker information from GWAS analysis with the optimal linear unbiased prediction method for genome selection (GBLUP) for the breeding value of target traits. Finally, the accuracy was evaluated using the five-fold cross-validation method. This research provides theoretical and technical support to improve the accuracy of sheep genome selection and better guide breeding. The results demonstrated that eight candidate genes were associated with GWAS analysis, and the gene function query and literature search results suggested that Show less
Polycystic ovary syndrome (PCOS) is a lifelong metabolic disorder and the most common cause of anovulatory infertility affecting women in reproductive age. Our recent study reported that apolipoprotei Show more
Polycystic ovary syndrome (PCOS) is a lifelong metabolic disorder and the most common cause of anovulatory infertility affecting women in reproductive age. Our recent study reported that apolipoprotein C3 (ApoC3) could be a potential diagnostic serum marker for metabolism disturbance in PCOS patients, but whether it is present in the ovaries and what role it plays has not yet been described. Aimed to investigate ApoC3 expression in ovary of PCOS, and to discuss its potential role in PCOS progression. ApoC3 expression in ovarian tissue samples from 12 PCOS patients along with 12 healthy controls were measured via immunohistochemistry (IHC). Also, the level of ApoC3 in follicular fluid from 14 patients diagnosed with PCOS and 13 control subjects were detected by ELISA. The expression and location of ApoC3 in ovaries of PCOS mice were tested weekly for three consecutive weeks during PCOS formation using real time PCR, Western Blot, IHC and immunofluorescence. The relation of ApoC3 and sex hormones was analyzed in mouse plasma. Additionally, the dynamic changes of ApoC3 level in ovaries of healthy mice during postnatal development was also investigated. ApoC3 levels in ovarian tissue and follicular fluid were significantly higher in PCOS patients than in controls (33.87 ± 4.11 vs. 27.71 ± 3.65, P < 0.01; 0.87 ± 0.09 vs. 0.51 ± 0.32 ng/mL, P < 0.05), respectively. In ovary, ApoC3 was found to be located in the cytoplasm of oocyte, and its expression gradually increased with PCOS progression (P < 0.05). Furthermore, correlation analysis showed that plasma ApoC3 level was closely associated with luteinizing hormone (r = 0.709, P = 0.001), testosterone (r = 0.627, P = 0.005) and anti-mullerian hormone (r = 0.680, P = 0.002) in PCOS mice. In addition, ApoC3 level in oocyte was physiologically increased and peaked on postnatal age 21 (P21), then decreased following P21 in healthy mice. We identified ApoC3 expression in oocyte. It may be involved in PCOS progression and possibly participate in the regulation of oocyte development. Show less
Hepatic carcinoma is one of the most common types of malignant tumors in the digestive system, and its biological characteristics determine its high rate of metastasis and recurrence after radical res Show more
Hepatic carcinoma is one of the most common types of malignant tumors in the digestive system, and its biological characteristics determine its high rate of metastasis and recurrence after radical resection, leading to a poor prognosis for patients. Increasing evidence demonstrates that phosphoproteins and phosphorylation-mediated molecular pathways influence the occurrence and development of hepatic carcinoma. It is urgent need to develop early-stage biomarkers for improving diagnosis, therapy, medical service, and prognostic assessment. We hypothesize that phosphoproteome and phosphorylation-mediated signaling pathway networks significantly differ in human early-stage primary hepatic carcinomas relative to control liver tissues, which will identify the key differentially phosphorylated proteins and phosphorylation-mediated signaling pathway network alterations in human early-stage primary hepatic carcinoma to innovate predictive diagnosis, prognostic assessment, and personalized medical services and progress beyond the state of the art in the framework of predictive, preventive, and personalized medicine (PPPM). Tandem mass tag (TMT)-based quantitative proteomics coupled with TiO A total of 1326 phosphopeptides derived from 858 DPPs in human early-stage primary hepatic carcinoma were identified. KEGG pathway network analysis of 858 DPPs revealed 33 statistically significant signaling pathways, including spliceosome, glycolysis/gluconeogenesis, B-cell receptor signaling pathway, HIF-1 signaling pathway, and fatty acid degradation. Gene Ontology (GO) analysis of 858 DPPs revealed that protein phosphorylation was involved in 57 biological processes, 40 cellular components, and 37 molecular functions. Protein-protein interaction (PPI) network constructed multiple high-combined scores and co-expressed DPPs. Integrative analysis of transcriptomic data and DPP data identified 105 overlapped molecules (DPPs; DEGs) between hepatic carcinoma tissues and control tissues and 125 OS-related DPPs. Overlapping Venn plots showed 14 common molecules among datasets of DPPs, DEGs, and OS-related DDPs, including FTCD, NDRG2, CCT2, PECR, SLC23A2, PNPLA7, ANLN, HNRNPM, HJURP, MCM2, STMN1, TCOF1, TOP2A, and SSRP1. The drug sensitivities of OS-related DPPs were identified, including LMOD1, CAV2, UBE2E2, RAPH1, ANXA5, HDLBP, CUEDC1, APBB1IP, VCL, SRSF10, SLC23A2, EPB41L2, ESR1, PLEKHA4, SAFB2, SMARCAD1, VCAN, PSD4, RDH16, NOP56, MEF2C, BAIAP2L2, NAGS, SRSF2, FHOD3, and STMN1. Identification and annotation of phosphoproteomes and phosphorylation-mediated signaling pathways in human early-stage primary hepatic carcinoma tissues provided new directions for tumor prevention and treatment, which (i) helps to enrich phosphorylation functional research and develop new biomarkers; (ii) enriches phosphorylation-mediated signaling pathways to gain a deeper understanding of the underlying mechanisms of early-stage primary hepatic carcinoma; and (iii) develops anti-tumor drugs that facilitate targeted phosphorylated sites. We recommend quantitative phosphoproteomics in early-stage primary hepatic carcinoma, which offers great promise for in-depth insight into the molecular mechanism of early-stage primary hepatic carcinoma, the discovery of effective therapeutic targets/drugs, and the construction of reliable phosphorylation-related biomarkers for patient stratification, predictive diagnosis, prognostic assessment, and personalized medical services in the framework of PPPM. The online version contains supplementary material available at 10.1007/s13167-023-00335-3. Show less
The evidence that dyslipidemia is associated with hyperglycemia calls for an investigation of whether dyslipidemia, as well as lipid-modifying agents, could affect the subsequent development of diabet Show more
The evidence that dyslipidemia is associated with hyperglycemia calls for an investigation of whether dyslipidemia, as well as lipid-modifying agents, could affect the subsequent development of diabetic retinopathy (DR). Therefore, we aimed to address these unanswered questions by utilizing Mendelian randomization (MR) analysis. Genetic variants were selected from the UK Biobank as instruments to serve as proxies for lipid traits [high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), apolipoprotein A-I (APOA-I) and apolipoprotein B (APOB)]. Univariable and multivariable MR analyses were performed to examine the associations of these lipid traits with DR and different levels of severity of DR. Based on the evidence for the effects of lipids on outcomes, we estimated the causal relevance of cholesteryl ester transfer protein (CETP) inhibitors in severe nonproliferative and proliferative DR using protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) as instruments. Genetically determined HDL-C levels were inversely associated with the risk of severe nonproliferative DR (OR = 0.70, 95% CI = 0.52-0.94) and proliferative DR (OR = 0.90, 95% CI = 0.83-0.97) in the main analyses utilizing the inverse variance-weighted (IVW) MR method and a couple of sensitivity analyses. No association was noted between genetically proxied CETP inhibitors and DR. This MR study suggests the casual protective roles of HDL-C in severe nonproliferative DR and proliferative DR, which calls for further studies to confirm these findings. Current lipid-modifying agents acting on HDL-C may not reduce the risk of DR and new treatments are required in the future. Show less
Lipoprotein lipase (LPL) functions as a marker of adipocyte differentiation in mammals, but little is known about its role in fish adipogenesis. The aim of this research is to investigate the function Show more
Lipoprotein lipase (LPL) functions as a marker of adipocyte differentiation in mammals, but little is known about its role in fish adipogenesis. The aim of this research is to investigate the function of Lpl in adipocyte differentiation in fish. In this paper, we isolated and characterized lipoprotein lipase a (lpla) and lipoprotein lipase b (lplb) from grass carp (Ctenopharyngodon idellus). The complete coding sequence of lpla and lplb was 1524 bp and 1503 bp in length, coding for 507 amino acids and 500 amino acids, respectively. Both lpla and lplb mRNA were expressed in a great number of tissues. During adipogenesis, the level of lpla mRNA reached its maximum at day 2 and then dropped gradually, while the level of lplb mRNA had no significant changes, indicating that lpla and lplb may have different function in the differentiation of grass carp adipocyte. Furthermore, inhibition of lpla by inhibitor of LPL(GSK264220A) at early time points most clearly reduced adipogenesis, whereas these effects were less pronounced at later stages, suggesting that lpla predominantly affects early adipogenesis rather than late adipogenesis. Based on these findings, it can be inferred that lpla and lplb in grass carp may have distinct roles in the differentiation of grass carp adipocyte, and lpla may play an important role in the early adipogenesis rather than late adipogenesis in grass carp. Show less
Histone H4 lysine 16 acetylation (H4K16ac), governed by the histone acetyltransferase MOF, orchestrates gene expression regulation and chromatin interaction. However, the roles of MOF and H4K16ac in c Show more
Histone H4 lysine 16 acetylation (H4K16ac), governed by the histone acetyltransferase MOF, orchestrates gene expression regulation and chromatin interaction. However, the roles of MOF and H4K16ac in controlling cellular function and regulating mammalian tissue development remain unclear. Here we show that conditional deletion of Mof in the skin, but not Kansl1, causes severe defects in the self-renewal of basal epithelial progenitors, epidermal differentiation, and hair follicle growth, resulting in barrier defects and perinatal lethality. MOF-regulated genes are highly enriched for essential functions in the mitochondria and cilia. Genetic deletion of Uqcrq, an essential subunit for the electron transport chain (ETC) Complex III, in the skin, recapitulates the defects in epidermal differentiation and hair follicle growth observed in MOF knockout mouse. Together, this study reveals the requirement of MOF-mediated epigenetic mechanism for regulating mitochondrial and ciliary gene expression and underscores the important function of the MOF/ETC axis for mammalian skin development. Show less
Stent-induced tissue hyperplasia remains a challenge for the application of self-expanding metal stents in the management of esophageal stricture. This study aimed to evaluate the efficacy of infigrat Show more
Stent-induced tissue hyperplasia remains a challenge for the application of self-expanding metal stents in the management of esophageal stricture. This study aimed to evaluate the efficacy of infigratinib, which is a selective fibroblast growth factor receptor inhibitor, in the prevention of stent-induced tissue hyperplasia in a rat esophageal model. Twenty-four male Sprague-Dawley rats underwent esophageal stent placement and were randomized to receive 1 ml of vehicle, 5 mg/kg infigratinib in 1 ml of vehicle, or 10 mg/kg infigratinib in 1 ml of vehicle via naso-gastric tube once daily for 28 days. Follow-up fluoroscopy was performed on postoperative day 28, and the stented esophageal tissues were harvested for histological and immunofluorescence examinations. All rats survived until euthanasia on postoperative day 28 without procedure-related adverse events. The incidence of stent migration was 12.5%, 12.5% and 25% in the control group, the 5 mg/kg infigratinib group and, the 10 mg/kg infigratinib group, respectively. The percentage of granulation tissue area, the submucosal fibrosis thickness, the number of epithelial layers, the degree of inflammatory cell infiltration, the degree of collagen deposition, the number of fibroblast growth factor receptor 1 (FGFR1)-expressing myofibroblasts, and the number of proliferating myofibroblasts were all significantly lower in both infigratinib groups than in the control group (P < 0.05) but were not significantly different between the two infigratinib groups (P > 0.05). Infigratinib significantly suppresses stent-induced tissue hyperplasia by inhibiting FGFR1-mediated myofibroblast proliferation and profibrotic activities in a rat esophageal model. Show less
Sepsis engenders an imbalance in the body's inflammatory response, with cytokines assuming a pivotal role in its progression. A relatively recent addition to the interleukin-17 family, denominated int Show more
Sepsis engenders an imbalance in the body's inflammatory response, with cytokines assuming a pivotal role in its progression. A relatively recent addition to the interleukin-17 family, denominated interleukin-17D (IL-17D), is notably abundant within pulmonary confines. Nevertheless, its implication in sepsis remains somewhat enigmatic. The present study endeavors to scrutinize the participation of IL-17D in sepsis-induced acute lung injury (ALI). The levels of IL-17D in the serum and bronchoalveolar lavage fluid (BALF) of both healthy cohorts and septic patients were ascertained through an ELISA protocol. For the creation of a sepsis-induced ALI model, intraperitoneal lipopolysaccharide (LPS) injections were administered to male C57/BL6 mice. Subsequently, we examined the fluctuations and repercussions associated with IL-17D in sepsis-induced ALI, probing its interrelation with nuclear factor erythroid 2-related factor 2 (Nrf2), alveolar epithelial permeability, and heme oxygenase-1. IL-17D levels exhibited significant reduction both in the serum and BALF of septic patients (P<0.001). Similar observations manifested in mice subjected to LPS-induced acute lung injury (ALI) (P=0.002). Intraperitoneal administration of recombinant interleukin 17D protein (rIL-17D) prompted increased expression of claudin 18 and concomitant enhancement of alveolar epithelial permeability, thus, culminating in improved lung injury (P<0.001). Alveolar epithelial type II (ATII) cells were identified as the source of IL-17D, regulated by Nrf2. Furthermore, a deficiency in HO-1 yielded elevated IL-17D levels (P=0.004), albeit administration of rIL-17D ameliorated the exacerbated pulmonary damage resulting from HO-1 deficiency. Nrf2 fosters IL-17D production within AT II cells, thereby conferring a protective role in sepsis-induced ALI. 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
Chicken embryo development is a dynamic process. However, no detailed information is available about the protein abundance changes associated with the lipid mechanism and antioxidant enzyme activity d Show more
Chicken embryo development is a dynamic process. However, no detailed information is available about the protein abundance changes associated with the lipid mechanism and antioxidant enzyme activity during the egg embryo development. Thus, in the present study, an TMT-based proteomic approach was used to quantify protein abundance changes at different stages of chicken embryonic development. A total of 289 significantly differentially abundant hepatic proteins were quantified, of which 180 were upregulated and 109 were downregulated in the comparison of Day 20 with Day 12 in chicken embryos. Pathway analysis showed that metabolic pathways were the most highly enriched pathways, followed by arachidonic acid metabolism and steroid biosynthesis. Integration of proteomic-based studies profiling of three incubation stages revealed that the two compare groups (Day 12 vs Day 20 and Day 16 vs Day 20) shared some key differentially abundant proteins (DAPs), including LBFABP, FABP5, CYP4V2, PDCD4, LAL, APOA1, APOA4, SAA, FABP2, ACBSG2, FABP2, CYP51A1, and FBXO9. The STRING database and GO analysis results showed that there was close connectivity between APOA4, LBFABP, SERPINC1, APOA1, FGB, FGA, ANGPTL3 and these proteins were involved in the oxidation-reduction process, lipid transport, iron ion, heme, and lipid binding. Importantly, APOA4, FABP2, and CYP51A1 might be key factors to control fat deposition and antioxidant enzyme activity during chicken embryonic development. These findings will facilitate a better understanding of antioxidant and lipid mechanisms in chicken embryo and these DAPs can be further investigated as candidate markers to predict lipid deposition and the activity of antioxidant enzymes. Show less
Increasing evidence has shown that the NOD-like receptor protein 1 (NLRP1) inflammasome is associated with Aβ generation and deposition, which contributes to neuronal damage and neuronal-inflammation Show more
Increasing evidence has shown that the NOD-like receptor protein 1 (NLRP1) inflammasome is associated with Aβ generation and deposition, which contributes to neuronal damage and neuronal-inflammation in Alzheimer's disease (AD). However, the specific mechanism of NLRP1 inflammasome in the pathogenesis of AD is still unclear. It has been reported that autophagy dysfunction can aggravate the pathological symptoms of AD and plays an important role in regulating Aβ generation and clearance. We hypothesized that NLRP1 inflammasome activation may induce autophagy dysfunction contributing to the progression of AD. In the present study, we observed the relationship between Aβ generation and NLRP1 inflammasome activation, as well as AMPK/mTOR mediated-autophagy dysfunction in WT 9-month-old (M) mice, APP/PS1 6 M and APP/PS1 9 M mice. Additionally, we further studied the effect of NLRP1 knockdown on cognitive function, Aβ generation, neuroinflammation and AMPK/mTOR mediated autophagy in APP/PS1 9 M mice. Our results indicated that NLRP1 inflammasome activation and AMPK/mTOR mediated-autophagy dysfunction are closely implicated in Aβ generation and deposition in APP/PS1 9 M mice, but not in APP/PS1 6 M mice. Meanwhile, we found that knockdown of NLRP1 significantly improved learning and memory impairments, decreased the expressions of NLRP1, ASC, caspase-1, p-NF-κB, IL-1β, APP, CTF-β, BACE1 and Aβ Show less
Huanan Li, Peifen Li, Shanyi Li+4 more · 2023 · Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · added 2026-04-24
To explore the mechanism of transforming growth factor-β1 (TGF-β1) induce renal fibrosis. Renal fibroblast NRK-49F cells treated with and without TGF-β1 were subjected to RNA-seq analysis. DESeq2 was Show more
To explore the mechanism of transforming growth factor-β1 (TGF-β1) induce renal fibrosis. Renal fibroblast NRK-49F cells treated with and without TGF-β1 were subjected to RNA-seq analysis. DESeq2 was used for analysis. Differentially expressed genes were screened with the criteria of false discovery rate<0.05 and l o g 2 F C >1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for differentially expressed genes. Genes encoding transcription factors were further screened for differential expression genes. Then, the expression of these genes during renal fibrosis was verified using unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis model and a public gene expression dataset (GSE104954). After TGF-β1 treatment for 6, 12 and 24 h, 552, 1209 and 1028 differentially expressed genes were identified, respectively. GO analysis indicated that these genes were significantly enriched in development, cell death, and cell migration. KEGG pathway analysis showed that in the early stage of TGF-β1 induction (TGF-β1 treatment for 6 h), the changes in Hippo, TGF-β and Wnt signaling pathways were observed, while in the late stage of TGF-β1 induction (TGF-β1 treatment for 24 h), the changes of extracellular matrix-receptor interaction, focal adhesion and adherens junction were mainly enriched. Among the 291 up-regulated differentially expressed genes treated with TGF-β1 for 6 h, 13 genes ( TGF-β1 induces differentially expressed genes in renal fibroblasts, among which Show less
An impaired epithelial barrier integrity in the gastrointestinal tract is important to the pathogenesis of many inflammatory diseases. Accordingly, we assessed the potential of biomarkers of epithelia Show more
An impaired epithelial barrier integrity in the gastrointestinal tract is important to the pathogenesis of many inflammatory diseases. Accordingly, we assessed the potential of biomarkers of epithelial barrier dysfunction as predictive of severe COVID-19. Levels of bacterial DNA and zonulin family peptides (ZFP) as markers of bacterial translocation and intestinal permeability and a total of 180 immune and inflammatory proteins were analyzed from the sera of 328 COVID-19 patients and 49 healthy controls. Significantly high levels of circulating bacterial DNA were detected in severe COVID-19 cases. In mild COVID-19 cases, serum bacterial DNA levels were significantly lower than in healthy controls suggesting epithelial barrier tightness as a predictor of a mild disease course. COVID-19 patients were characterized by significantly elevated levels of circulating ZFP. We identified 36 proteins as potential early biomarkers of COVID-19, and six of them (AREG, AXIN1, CLEC4C, CXCL10, CXCL11, and TRANCE) correlated strongly with bacterial translocation and can be used to predict and discriminate severe cases from healthy controls and mild cases (area under the curve (AUC): 1 and 0.88, respectively). Proteomic analysis of the serum of 21 patients with moderate disease at admission which progressed to severe disease revealed 10 proteins associated with disease progression and mortality (AUC: 0.88), including CLEC7A, EIF4EBP1, TRANCE, CXCL10, HGF, KRT19, LAMP3, CKAP4, CXADR, and ITGB6. Our results demonstrate that biomarkers of intact or defective epithelial barriers are associated with disease severity and can provide early information on the prediction at the time of hospital admission. Show less
Lupus nephritis (LN) refers to the injury caused by systemic lupus erythematosus (SLE) involving the kidneys. A previous study identified angiopoietin-like protein 4 (ANGPTL4) as a novel urinary bioma Show more
Lupus nephritis (LN) refers to the injury caused by systemic lupus erythematosus (SLE) involving the kidneys. A previous study identified angiopoietin-like protein 4 (ANGPTL4) as a novel urinary biomarker for tracking disease activity in LN. To investigate the detailed role and regulatory mechanism of ANGPTL4 in experimental models of LN. MRL/lpr mice 11-week-old were injected with adeno-associated virus (AAV)-mediated ANGPTL4 short hairpin RNA (shRNA). At 16 and 20 weeks of age, 24-h urine samples were harvested to measure proteinuria levels. After the mice were sacrificed, blood and kidney tissues were harvested to examine serum creatinine (cr) and blood urea nitrogen (BUN) levels, kidney histological changes, and pro-inflammatory cytokine production. Additionally, the levels of NLRP3 inflammasome-associated molecules in mouse renal tissues were detected to clarify the underlying mechanism. The AAV-sh-ANGPTL4 injection significantly reduced the proteinuria, cr, and BUN levels in MRL/lpr mice. ANGPTL4 silencing ameliorated glomerular, tubular, and interstitial damage in mice, mitigating the pathological alternations of LN. In addition, ANGPTL4 knockdown repressed pro-inflammatory cytokine production in the kidneys. Mechanically, ANGPTL4 suppression inhibited NLRP3 inflammasome expression in renal tissues of mice. ANGPTL4 silencing inhibits the NLRP3 inflammasome-mediated inflammatory response, thereby ameliorating LN in MRL/lpr mice. Show less
Deyu Li, Yingchao Hu, Xin Liu+1 more · 2023 · Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · added 2026-04-24
To explore the mechanism of The active ingredients and targets of Through network pharmacology, 15 potential active ingredients and 103 drug-disease targets were identified. PPI analysis showed that t Show more
To explore the mechanism of The active ingredients and targets of Through network pharmacology, 15 potential active ingredients and 103 drug-disease targets were identified. PPI analysis showed that the Show less
Excessive and chronic inflammation post myocardial infarction (MI) causes cardiac fibrosis and progressive ventricular remodeling, which leads to heart failure. We previously found high levels of IL-2 Show more
Excessive and chronic inflammation post myocardial infarction (MI) causes cardiac fibrosis and progressive ventricular remodeling, which leads to heart failure. We previously found high levels of IL-27 in the heart and serum until day 14 in murine cardiac ischemia‒reperfusion injury models. However, whether IL-27 is involved in chronic inflammation-mediated ventricular remodeling remains unclear. In the present study, we found that MI triggered high IL-27 expression in murine cardiac macrophages. The increased expression of IL-27 in serum is correlated with cardiac dysfunction and aggravated fibrosis after MI. Furthermore, the addition of IL-27 significantly activated the JAK/STAT signaling pathway in cardiac fibroblasts (CFs). Meanwhile, IL-27 treatment promoted the proliferation, migration and extracellular matrix (ECM) production of CFs induced by angiotensin II (Ang II). Collectively, high levels of IL-27 mainly produced by cardiac macrophages post MI contribute to the activation of CFs and aggravate cardiac fibrosis. Show less
17α-Methyltestosterone (MT), a synthetic environmental endocrine disruptor with androgenic effects, has been shown to disrupt the reproductive system and inhibit germ cell maturation in
Diabetic peripheral arterial atherosclerosis is one of the important characteristics of diabetic foot syndrome. Apolipoprotein (Apo A-IV) participates in various physiological processes, and animal st Show more
Diabetic peripheral arterial atherosclerosis is one of the important characteristics of diabetic foot syndrome. Apolipoprotein (Apo A-IV) participates in various physiological processes, and animal studies have shown that it has roles of anti-atherosclerosis, prevention of platelet aggregation and thrombosis. Apo A-IV glycosylation is closely related to the occurrence and development of diabetic peripheral atherosclerosis. This study aimed to explore the mechanism of diabetic peripheral arterial lesions caused by glycosylated Apo A-IV. Type 2 diabetes mellitus (T2DM) and T2DM with diabetic foot patients (T2DM-F; Show less
Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited effective therapies because of the absence of definitive targets. Here, we demonstrate that the expression of ZNF451, a Show more
Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited effective therapies because of the absence of definitive targets. Here, we demonstrate that the expression of ZNF451, a poorly characterized vertebrate zinc-finger protein, is upregulated in TNBC and associated with a poor prognosis. Elevated ZNF451 expression facilitates TNBC progression by interacting with and enhancing the activity of the transcriptional activator snail family transcriptional repressor 2 (SLUG). Mechanistically, the ZNF451-SLUG complex preferentially recruits the acetyltransferase p300/CBP-associated factor (PCAF) to the CCL5 promoter, selectively facilitating CCL5 transcription by enhancing the acetylation of SLUG and local chromatin, leading to recruitment and activation of tumor-associated macrophages (TAMs). Disturbing the ZNF451-SLUG interaction using a peptide suppresses TNBC progression by reducing CCL5 expression and counteracting the migration and activation of TAMs. Collectively, our work provides mechanistic insights into the oncogene-like functions of ZNF451 and suggests that ZNF451 is a potential target for development of effective therapies against TNBC. Show less
Prostate cancer (PCa) is usually considered as cold tumor. Malignancy is associated with cell mechanic changes that contribute to extensive cell deformation required for metastatic dissemination. Thus Show more
Prostate cancer (PCa) is usually considered as cold tumor. Malignancy is associated with cell mechanic changes that contribute to extensive cell deformation required for metastatic dissemination. Thus, we established stiff and soft tumor subtypes for PCa patients from perspective of membrane tension. Nonnegative matrix factorization algorithm was used to identify molecular subtypes. We completed analyses using software R 3.6.3 and its suitable packages. We constructed stiff and soft tumor subtypes using eight membrane tension-related genes through lasso regression and nonnegative matrix factorization analyses. We found that patients in stiff subtype were more prone to biochemical recurrence than those in soft subtype (HR 16.18; p < 0.001), which was externally validated in other three cohorts. The top ten mutation genes between stiff and soft subtypes were DNAH, NYNRIN, PTCHD4, WNK1, ARFGEF1, HRAS, ARHGEF2, MYOM1, ITGB6 and CPS1. E2F targets, base excision repair and notch signaling pathway were highly enriched in stiff subtype. Stiff subtype had significantly higher TMB and T cells follicular helper levels than soft subtype, as well as CTLA4, CD276, CD47 and TNFRSF25. From the perspective of cell membrane tension, we found that stiff and soft tumor subtypes were closely associated with BCR-free survival for PCa patients, which might be important for the future research in the field of PCa. Show less