The effectiveness of immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) is limited by treatment resistance. However, the mechanisms underlying immunotherapy resistance remain Show more
The effectiveness of immune checkpoint inhibitor (ICI) therapy for hepatocellular carcinoma (HCC) is limited by treatment resistance. However, the mechanisms underlying immunotherapy resistance remain elusive. We aimed to identify the role of CT10 regulator of kinase-like (CRKL) in resistance to anti-PD-1 therapy in HCC. Gene expression in HCC specimens from 10 patients receiving anti-PD-1 therapy was identified by RNA-sequencing. A total of 404 HCC samples from tissue microarrays were analyzed by immunohistochemistry. Transgenic mice (Alb-Cre/Trp53 CRKL was identified as a candidate anti-PD-1-resistance gene using a pooled genetic screen. CRKL overexpression nullifies anti-PD-1 treatment efficacy by mobilizing tumor-associated neutrophils (TANs), which block the infiltration and function of CD8 Activation of the CRKL/β-catenin/VEGFα and CXCL1 axis is a critical obstacle to successful anti-PD-1 therapy. Therefore, CRKL inhibitors combined with anti-PD-1 could be useful for the treatment of HCC. Here, we found that CRKL was overexpressed in anti-PD-1-resistant hepatocellular carcinoma (HCC) and that CRKL upregulation promotes anti-PD-1 resistance in HCC. We identified that upregulation of the CRKL/β-catenin/VEGFα and CXCL1 axis contributes to anti-PD-1 tolerance by promoting infiltration of tumor-associated neutrophils. These findings support the strategy of bevacizumab-based immune checkpoint inhibitor combination therapy, and CRKL inhibitors combined with anti-PD-1 therapy may be developed for the treatment of HCC. Show less
Liang Li, Jianzhong Li, Wendeng Li+2 more · 2024 · Translational research : the journal of laboratory and clinical medicine · Elsevier · added 2026-04-24
Hepatopulmonary syndrome (HPS) is a serious pulmonary complication in the advanced stage of liver disease. The occurrence of pulmonary edema in HPS patients is life-threatening. Increased pulmonary va Show more
Hepatopulmonary syndrome (HPS) is a serious pulmonary complication in the advanced stage of liver disease. The occurrence of pulmonary edema in HPS patients is life-threatening. Increased pulmonary vascular permeability is an important mechanism leading to pulmonary edema, and endothelial glycocalyx (EG) is a barrier that maintains stable vascular permeability. However, in HPS, whether the pulmonary vascular EG changes and its regulatory mechanism are still unclear. Spleen derived monocytes are involved in the pathogenesis of HPS. However, whether they regulate the pulmonary vascular permeability in HPS patients or rats and what is the mechanism is still unclear. Healthy volunteers and HPS patients with splenectomy or not were enrolled in this study. We found that the respiration of HPS patients was significantly improved in response to splenectomy, while the EG degradation and pulmonary edema were aggravated. In addition, HPS patients expressed higher levels of oncostatin M (OSM) and fibroblast growth factor (FGF). Subsequently, the co-culture system of monocytes and human umbilical vein endothelial cells (HUVECs) was constructed. It was found that monocytes secreted OSM and activated the FGF/FGFR1 signaling pathway in HUVECs. Then, an HPS rat model was constructed by common bile duct ligation (CBDL) for in vivo verification. HPS rats were intravenously injected with OSM recombinant protein and/or TNF-α into the rats via tail vein 30 min before CBDL. The results showed that the respiration of HPS rats was improved after splenectomy, while the degradation of EG in pulmonary vessels and vascular permeability were increased, and pulmonary edema was aggravated. Moreover, the expression of OSM and FGF was upregulated in HPS rats, while both were downregulated after splenectomy. Intravenous injection of exogenous OSM eliminated the effect of splenectomy on FGF and improved EG degradation. It can be seen that during HPS, spleen-derived monocytes secrete OSM to promote pulmonary vascular EG remodeling by activating the FGF/FGFR1 pathway, thereby maintaining stable vascular permeability, and diminishing pulmonary edema. This study provides a promising therapeutic target for the treatment of HPS. Show less
Nonspecific orbital inflammation (NSOI) is an idiopathic, persistent, and proliferative inflammatory condition affecting the orbit, characterized by polymorphous lymphoid infiltration. Its pathogenesi Show more
Nonspecific orbital inflammation (NSOI) is an idiopathic, persistent, and proliferative inflammatory condition affecting the orbit, characterized by polymorphous lymphoid infiltration. Its pathogenesis and progression have been linked to imbalances in tumor metabolic pathways, with glutamine (Gln) metabolism emerging as a critical aspect in cancer. Metabolic reprogramming is known to influence clinical outcomes in various malignancies. However, comprehensive research on glutamine metabolism's significance in NSOI is lacking. This study conducted a bioinformatics analysis to identify and validate potential glutamine-related molecules (GlnMgs) associated with NSOI. The discovery of GlnMgs involved the intersection of differential expression analysis with a set of 42 candidate GlnMgs. The biological functions and pathways of the identified GlnMgs were analyzed using GSEA and GSVA. Lasso regression and SVM-RFE methods identified hub genes and assessed the diagnostic efficacy of fourteen GlnMgs in NSOI. The correlation between hub GlnMgs and clinical characteristics was also examined. The expression levels of the fourteen GlnMgs were validated using datasets GSE58331 and GSE105149. Fourteen GlnMgs related to NSOI were identified, including FTCD, CPS1, CTPS1, NAGS, DDAH2, PHGDH, GGT1, GCLM, GLUD1, ART4, AADAT, ASNSD1, SLC38A1, and GFPT2. Biological function analysis indicated their involvement in responses to extracellular stimulus, mitochondrial matrix, and lipid transport. The diagnostic performance of these GlnMgs in distinguishing NSOI showed promising results. This study successfully identified fourteen GlnMgs associated with NSOI, providing insights into potential novel biomarkers for NSOI and avenues for monitoring disease progression. Show less
Diabetes and its complications cause a heavy burden of disease worldwide. In recent years, Mendelian randomization (MR) has been widely used to discover the pathogenesis and epidemiology of diseases, Show more
Diabetes and its complications cause a heavy burden of disease worldwide. In recent years, Mendelian randomization (MR) has been widely used to discover the pathogenesis and epidemiology of diseases, as well as to discover new therapeutic targets. Therefore, based on systematic "druggable" genomics, we aim to identify new therapeutic targets for diabetes and analyze its pathophysiological mechanisms to promote its new therapeutic strategies. We used double sample MR to integrate the identified druggable genomics to evaluate the causal effect of quantitative trait loci (eQTLs) expressed by druggable genes in blood on type 1 and 2 diabetes (T1DM and T2DM). Repeat the study using different data sources on diabetes and its complications to verify the identified genes. Not only that, we also use Bayesian co-localization analysis to evaluate the posterior probabilities of different causal variations, shared causal variations, and co-localization probabilities to examine the possibility of genetic confounding. Finally, using diabetes markers with available genome-wide association studies data, we evaluated the causal relationship between established diabetes markers to explore possible mechanisms. Overall, a total of 4,477 unique druggable genes have been gathered. After filtering using methods such as Bonferroni significance (P<1.90e-05), the MR Steiger directionality test, Bayesian co-localization analysis, and validation with different datasets, Finally, 7 potential druggable genes that may affect the results of T1DM and 7 potential druggable genes that may affect the results of T2DM were identified. Reverse MR suggests that C4B may play a bidirectional role in the pathogenesis of T1DM, and none of the other 13 target genes have a reverse causal relationship. And the 7 target genes in T2DM may each affect the biomarkers of T2DM to mediate the pathogenesis of T2DM. This study provides genetic evidence supporting the potential therapeutic benefits of targeting seven druggable genes, namely MAP3K13, KCNJ11, REG4, KIF11, CCNE2, PEAK1, and NRBP1, for T2DM treatment. Similarly, targeting seven druggable genes, namely ERBB3, C4B, CD69, PTPN22, IL27, ATP2A1, and LT-β, has The potential therapeutic benefits of T1DM treatment. This will provide new ideas for the treatment of diabetes and also help to determine the priority of drug development for diabetes. Show less
Epithelial-mesenchymal transition (EMT) is an important biological process by which malignant tumor cells to acquire migration and invasion abilities. This study explored the role of KLF5 in the EMT p Show more
Epithelial-mesenchymal transition (EMT) is an important biological process by which malignant tumor cells to acquire migration and invasion abilities. This study explored the role of KLF5 in the EMT process of in cervical cancer cell lines. Krüpple-like factor 5 (KLF5) is a basic transcriptional factor that plays a key role in cell-cycle arrest and inhibition of apoptosis. However, the molecular mechanism by which KLF5 mediates the biological functions of cervical cancer cell lines has not been elucidated. Here, we focus on the potential function of ELF5 in regulating the EMT process in in vitro model of cervical cancer cell lines. Western-blot and real-time quantitative PCR were used to detect the expression of EMT-related genes in HeLa cells. MTT assays, cell scratch and Transwell assays were used to assess HeLa cells proliferation and invasion capability. Using the bioinformatics tool JASPAR, we identified a high-scoring KLF5-like binding sequence in the SNAI1 gene promoter. Luciferase reporter assays was used to detect transcriptional activity for different SNAI1 promoter truncates. After overexpressing the KLF5 gene in HeLa cells, KLF5 not only significantly inhibited the invasion and migration of HeLa cells, but also increased the expression of E-cadherin and decreased the expression of N-cadherin and MMP9. In addition, the mRNA expression of upstream regulators of E-cadherin, such as SNAI1, SLUG, ZEB1/2 and TWIST1 was also decreased. Furthermore, KLF5 inhibiting the expression of the SNAI1 gene via binding its promoter region, and the EMT of Hela cells was promoted after overexpression of the SNAI1 gene. These results indicate that KLF5 can downregulate the EMT process of HeLa cells by decreasing the expression of the SNAI1 gene, thereby inhibiting the migration and invasion of HeLa cervical cancer cells. Show less
Organic afterglow materials have drawn increasing attention for their great potential in practical applications. Until now, most of them just show the lifetimes in milliseconds or seconds, while the r Show more
Organic afterglow materials have drawn increasing attention for their great potential in practical applications. Until now, most of them just show the lifetimes in milliseconds or seconds, while the realization of long persistent luminescence (LPL) lasting for minutes or even hours is difficult. In 2017, Adachi and Kabe successfully realize the LPL with a duration longer than 1 hour in a purely organic system, which can be even comparable to some excellent inorganic materials. However, partially for the unclear structure-property relationship, organic LPL materials are still rather scarce, especially for the stable ones in air or aqueous solution. In this review, we present the recent progress in organic LPL, mainly focusing on the material design strategy and internal mechanism. It is anticipated that the deep understanding can be beneficial for the further development of organic LPL materials with good stability in air and even aqueous phase. Show less
Parkinson's disease (PD) is a progressive neurodegenerative disease whose etiology is attributed to development of Lewy bodies and degeneration of dopaminergic neurons in the substantia nigra (SN). Cu Show more
Parkinson's disease (PD) is a progressive neurodegenerative disease whose etiology is attributed to development of Lewy bodies and degeneration of dopaminergic neurons in the substantia nigra (SN). Currently, there are no definitive diagnostic indicators for PD. In this study, we aimed to identify potential diagnostic biomarkers for PD and analyzed the impact of immune cell infiltrations on disease pathogenesis. The PD expression profile data for human SN tissue, GSE7621, GSE20141, GSE20159, GSE20163 and GSE20164 were downloaded from the Gene Expression Omnibus (GEO) database for use in the training model. After normalization and merging, we identified differentially expressed genes (DEGs) using the Robust rank aggregation (RRA) analysis. Simultaneously, DEGs after batch correction were identified. Gene interactions were determined through venn Diagram analysis. Functional analyses and protein-protein interaction (PPI) networks were used to the identify hub genes, which were visualized through Cytoscape. A Lasso Cox regression model was employed to identify the potential diagnostic genes. The GSE20292 dataset was used for validation. The proportion of infiltrating immune cells in the samples were determined via the CIBERSORT method. Sixty-two DEGs were screened in this study. They were found to be enriched in nerve conduction, dopamine (DA) metabolism, and DA biosynthesis Gene Ontology (GO) terms. The PPI network and Lasso Cox regression analysis revealed seven potential diagnostic genes, namely SLC18A2, TAC1, PCDH8, KIAA0319, PDE6H, AXIN1, and AGTR1, were subsequently validated in peripheral blood samples obtained from healthy control (HC) and PD patients, as well as in the GSE20292 dataset. The results revealed the exceptional sensitivity and specificity of these genes in PD diagnosis and monitoring. Moreover, PD patients exhibited a higher number of plasma cells, compared to HC individuals. The SLC18A2, TAC1, PCDH8, KIAA0319, PDE6H, AXIN1, and AGTR1 are potential diagnostic biomarkers for PD. Our findings also reveal the essential roles of immune cell infiltration in both disease onset and trajectory. Show less
Colorectal cancer is one of the most common types of cancer worldwide that can lead to serious injury and death. Although polysaccharides are widely recognized as having antitumor activity, there has Show more
Colorectal cancer is one of the most common types of cancer worldwide that can lead to serious injury and death. Although polysaccharides are widely recognized as having antitumor activity, there has been little research on the role of barley polysaccharides (BP) Show less
To investigate the association of polymorphisms in SEC16B rs633715, DNAJC27 rs713586, FTO rs11642015 and MC4R rs6567160 with overweight and obesity in Han Chinese preschool children. A total of 749 Ha Show more
To investigate the association of polymorphisms in SEC16B rs633715, DNAJC27 rs713586, FTO rs11642015 and MC4R rs6567160 with overweight and obesity in Han Chinese preschool children. A total of 749 Han Chinese preschool children from Henan and Guizhou Province of Long-term Health Effects Assessment Project of Infants and Toddlers Nutritional Pack were selected for the study and divided into an overweight and obese group and a normal control group in 2022. rs633715, rs713586, rs11642015 and rs6567160 were genotyped using Kompetitive allele-specific PCR(KASP) technology. The distribution of genotypic polymorphisms was compared using the χ~2 test. The association between the four loci and overweight and obesity in preschool children was analyzed using a multifactorial logistic regression model. The statistical analysis revealed a significant disparity(P<0.05) in the distribution of genotypic polymorphisms of rs633715 and rs6567160 among preschoolers in Henan and Guizhou Province. CC heterozygous mutant and recessive models at rs633715 locus were associated with susceptibility to overweight and obesity in preschool children [OR and 95% CI 2.915(1.163-7.305), and 2.997(1.226-7.323), respectively, both P<0.05]. TC heterozygous mutant and dominant models at rs713586 locus were also associated susceptibility to overweight and obesity in preschool children(OR and 95% CI were 2.362(1.054-5.289)and 2.362(1.054-5.289), respectively, both P<0.05). rs11642015 and rs6567160 loci were not associated with susceptibility to overweight and obesity in preschool children(P>0.05). The result of the analysis of the cumulative effect of rs633715 and rs713586 showed that the number of genotypes carrying the risk genotype was positively associated with the risk of overweight and obesity in preschool children(P₍trend)<0.01). Among Han Chinese preschool children, SEC16B rs633715 and DNAJC27 rs713586 were associated with susceptibility to overweight and obesity in preschool children. Moreover, rs633715 and rs713586 had a cumulative effect on susceptibility to overweight and obesity in preschool children, the number of risk genotypes carried was positively associated with childhood overweight and obesity risk. Show less
no PDFDOI: 10.19813/j.cnki.weishengyanjiu.2024.02.009
The Ningxiang pig, a distinguished local breed in China, is recognized for its good meat quality traits. This study examines the proteomics of Ningxiang pigs at three developmental stages and delves i Show more
The Ningxiang pig, a distinguished local breed in China, is recognized for its good meat quality traits. This study examines the proteomics of Ningxiang pigs at three developmental stages and delves into the upstream transcriptomics of these proteomics. Such an analysis facilitates a deeper understanding of the molecular interplay between proteins and transcriptomes in the Ningxiang pig muscle, influencing muscle growth and development. In this research, we analyzed the muscles of Ningxiang pigs at three developmental stages: 30 days in weaned piglets, 90 days in nursery pigs, and 210 days in late fattening pigs. There a total of 16 differentially co-expressed miRNAs (ssc-miRNA-1, ssc-miRNA-378, ssc-miRNA-143, ssc-miRNA-30e, etc.), 74 differentially co-expressed mRNA ( Show less
The differences in muscle development potential between male and female ducks lead to variations in body weight, significantly affecting the growth of the Muscovy duck meat industry. The aim of this s Show more
The differences in muscle development potential between male and female ducks lead to variations in body weight, significantly affecting the growth of the Muscovy duck meat industry. The aim of this study is to explore the regulatory mechanisms for the muscle development differences between genders. Muscovy ducks of both sexes were selected for measurements of body weight, growth traits, hormone levels, and muscle gene expression. The results show that male ducks compared to females had greater weight and growth traits ( Show less
Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FD Show more
Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC Show less
We aimed to investigate the cardiomyocyte-protective effects of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes on ischemia/reperfusion (I/R)-injured rats and to explore the mechanisms. Ca Show more
We aimed to investigate the cardiomyocyte-protective effects of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes on ischemia/reperfusion (I/R)-injured rats and to explore the mechanisms. Cardiomyocytes were divided into control group, ischemia/reperfusion group (I/R group), ischemia/reperfusion+exosome group (I/R+Exo group) or ischemia/reperfusion+exosomes transfected with miR-101a-3p inhibitor group (I/R+Exo inhibitor group). MiR-101a-3p levels were lower in I/R and I/R+Exo inhibitor groups than in control and I/R+Exo groups. Apoptosis rate and cleaved caspase 3 expression were higher in I/R and I/R+Exo inhibitor groups. The levels of superoxide dismutase (SOD) in cardiomyocytes of I/R group and I/R+Exo inhibitor group were lower than those of control group and I/R+Exo group, and the levels of malondialdehyde (MDA) and the relative production of oxygen species clusters (ROS) in cardiomyocytes of I/R group and I/R+Exo inhibitor group were higher than those of control group and I/R+Exo group. The levels of interleukin-10 (IL-10), interleukin-6 (IL-6), tumour necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) were higher in the I/R group and the I/R +Exo inhibitor group than in the control group and the I/R+Exo group. Bioinformatics analysis suggested that Pik3c3 is the most promising gene involved in miR-101a-3p-mediated apoptosis in cardiomyocytes, and in vitro experiments confirmed that low expression of miR-101a-3p significantly up-regulated the mRNA and protein expression levels of Pik3c3. BMSCs-derived exosomes have a protective effect on cardiomyocytes from I/R-injured rats, and the mechanism may be related to the inhibition of oxidative stress and inflammatory responses in cardiomyocytes by exosome-delivered miR-101a-3p. Show less
Cardiac injury plays a critical role in contributing to the mortality associated with sepsis, a condition marked by various forms of programmed cell deaths. Previous studies hinted at the WW domain-co Show more
Cardiac injury plays a critical role in contributing to the mortality associated with sepsis, a condition marked by various forms of programmed cell deaths. Previous studies hinted at the WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) involving in heart failure and endothelial injury. However, the precise implications of WWP2 in sepsis-induced cardiac injury, along with the underlying mechanisms, remain enigmatic. Sepsis induced cardiac injury were constructed by intraperitoneal injection of lipopolysaccharide. To discover the function of WWP2 during this process, we designed and performed loss/gain-of-function studies with cardiac-specific vectors and WWP2 knockout mice. Combination experiments were performed to investigate the relationship between WWP2 and downstream signaling in septic myocardium injury. The protein level of WWP2 was downregulated in cardiomyocytes during sepsis. Cardiac-specific overexpression of WWP2 protected heart from sepsis induced mitochondrial oxidative stress, programmed cell death and cardiac injury, while knockdown or knockout of WWP2 exacerbated this process. The protective potency of WWP2 was predominantly linked to its ability to suppress cardiomyocyte ferroptosis rather than apoptosis. Mechanistically, our study revealed a direct interaction between WWP2 and acyl-CoA synthetase long-chain family member 4 (FACL4), through which WWP2 facilitated the ubiquitin-dependent degradation of FACL4. Notably, we observed a notable reduction in ferroptosis and cardiac injury within WWP2 knockout mice after FACL4 knockdown during sepsis. WWP2 assumes a critical role in safeguarding the heart against injury induced by sepsis via regulating FACL4 to inhibit LPS-induced cardiomyocytes ferroptosis. Show less
Jiakai Xing, Jiaxin Jia, Hugang Zhang+2 more · 2024 · Journal of controlled release : official journal of the Controlled Release Society · Elsevier · added 2026-04-24
Abnormal expression of microRNAs (miRNAs) plays a significant role in the pathogenesis of rheumatoid arthritis (RA), and thus miRNA-based therapy has emerged as a promising approach for the RA treatme Show more
Abnormal expression of microRNAs (miRNAs) plays a significant role in the pathogenesis of rheumatoid arthritis (RA), and thus miRNA-based therapy has emerged as a promising approach for the RA treatment. Herein, miR-30a was successfully screened and identified to be an essential mediator for the inflammation of RA. MiR-30a could directly target the Snai1 gene and further regulate the Cad11 expression to inhibit the NF-κB and MAPK signaling pathways, contributing to the anti-inflammatory effect. To enhance the therapeutic outcome of miR-30a, fluorinated polyamidoamine dendrimer (FP) was developed as the carrier to achieve the miR-30a delivery in the mice of collagen-induced arthritis. The carrier FP and miR-30a formed stable nanocomplexes and effectively mediated the transfection of miR-30a to execute the anti-inflammatory response in lipopolysaccharide-stimulated macrophages. Further, the intravenous administration of FP/miR-30a showed obvious accumulation in the inflamed joints and inhibited the inflammatory response via the Snai1/Cad11 axis, thereby contributing to the anti-arthritic efficacy. In addition, the FP/miR-30a nanocomplexes displayed favorable biocompatibility, as they did not cause the damage of organs following the systemic administration. Taken together, our study demonstrated that miR-30a is an effective anti-inflammatory oligonucleotide and the fluorinated dendrimer-mediated miR-30a delivery possesses the potential to be a promising approach for the treatment of RA and other autoimmune diseases. Show less
One of abundant DNA lesions induced by reactive oxygen species is 8-oxoguanine (8-oxoG), which compromises genetic instability. 8-oxoG is recognized by the DNA repair protein 8-oxoguanine DNA glycosyl Show more
One of abundant DNA lesions induced by reactive oxygen species is 8-oxoguanine (8-oxoG), which compromises genetic instability. 8-oxoG is recognized by the DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) that not only participates in base excision repair but also involves in transcriptional regulation.OGG1 has an important role inIdiopathic Pulmonary Fibrosis (IPF) processing and targeting fibroblasts is a major strategy for the treatment of pulmonary fibrosis, but whether OGG1 activate fibroblast is not clear. In this study, we show that OGG1 expression level is increased at the fibroblast activation stage in mouse lungs induced by bleomycin (BLM) treatment. OGG1 promoted the expression level of fibroblast activation markers (CTGF, fibronectin, and collagen 1) in a pro-fibrotic gene transcriptional regulation pathway via interacting with Snail1, which dependent on 8-oxoG recognition. Global inhibition of OGG1 at the middle stage of lung fibrosis also relieved BLM-induced lung fibrosis in mice. Our results suggest that OGG1 is a target for inhibiting fibroblast activation and a potential therapeutic target for IPF. Show less
Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknow Show more
Cellular communication (CC) influences tumor development by mediating intercellular junctions between cells. However, the role and underlying mechanisms of CC in malignant transformation remain unknown. Here, we investigated the spatiotemporal heterogeneity of CC molecular expression during malignant transformation. It was found that although both tight junctions (TJs) and gap junctions (GJs) were involved in maintaining the tumor microenvironment (TME), they exhibited opposite characteristics. Mechanistically, for epithelial cells (parenchymal component), the expression of TJ molecules consistently decreased during normal-cancer transformation and is a potential oncogenic factor. For fibroblasts (mesenchymal component), the expression of GJs consistently increased during normal-cancer transformation and is a potential oncogenic factor. In addition, the molecular profiles of TJs and GJs were used to stratify colorectal cancer (CRC) patients, where subtypes characterized by high GJ levels and low TJ levels exhibited enhanced mesenchymal signals. Importantly, we propose that leiomodin 1 (LMOD1) is biphasic, with features of both TJs and GJs. LMOD1 not only promotes the activation of cancer-associated fibroblasts (CAFs) but also inhibits the Epithelial-mesenchymal transition (EMT) program in cancer cells. In conclusion, these findings demonstrate the molecular heterogeneity of CC and provide new insights into further understanding of TME heterogeneity. Show less
Colorectal cancer (CRC) is characterized by high morbidity, high mortality, and limited response to immunotherapies. The peripheral immune system is an important component of tumor immunity, and enhan Show more
Colorectal cancer (CRC) is characterized by high morbidity, high mortality, and limited response to immunotherapies. The peripheral immune system is an important component of tumor immunity, and enhancements of peripheral immunity help to suppress tumor progression. However, the functional alterations of the peripheral immune system in CRC are unclear. Here, we used mass spectrometry-based quantitative proteomics to establish a protein expression atlas for the peripheral immune system in CRC, including plasma and five types of immune cells (CD4 Show less
Peroxisome proliferator-activated receptors (PPARs) are essential for cellular physiological processes. However, there is less research on the PPAR-related genes in lung adenocarcinoma (LUAD). Open-ac Show more
Peroxisome proliferator-activated receptors (PPARs) are essential for cellular physiological processes. However, there is less research on the PPAR-related genes in lung adenocarcinoma (LUAD). Open-access data were get from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. All the analysis were conducted in the R software based on different R packages. In this study, we gauged the PPAR score employing a set of 72 PPAR-associated genes and probed the biological impact of this score on lung adenocarcinoma (LUAD). Subsequently, we established a unique signature composed of eight PPAR-related genes (ANGPTL4, ACSL3, ADIPOQ, FABP1, SLC27A1, ACOX2, PPARD and OLR1) to forecast the prognosis of LUAD. The signature's effectiveness in predicting survival was validated through the receiver operating characteristic curve in the TCGA-LUAD cohort. As per the pathway enrichment analysis, several crucial oncogenic pathways and metabolic processes were enriched in high-risk individuals. Further, we observed that these high-risk patients exhibited heightened genomic instability. Additionally, compared to the low-risk cohort, high-risk patients demonstrated diminished immune components and function. Intriguingly, high-risk patients exhibited a potential heightened sensitivity to immunotherapy and certain drugs, including Gefitinib, Afatinib, Erlotinib, IAP₅₆₂₀, Sapitinib, LCL161, Lapatinib and AZD3759. The prognosis model based on eight PPAR-related genes has satisfactory prognosis prediction efficiency. Meanwhile, our results can provide direction for future studies in the relevant aspects. Show less
The quality and flavor of chicken are affected by muscle metabolites and related regulatory genes, and the molecular regulation mechanism of meat quality is different among different breeds of chicken Show more
The quality and flavor of chicken are affected by muscle metabolites and related regulatory genes, and the molecular regulation mechanism of meat quality is different among different breeds of chicken. In this study, 40 one-day-old Daweishan mini chicken (DM) and Cobb broiler (CB) were selected from each group, with 4 replicates and 10 chickens in each replicate. The chickens were reared until 90 d of age under the same management conditions. Then, metabolomics and transcriptomics data of 90-day-old DM (n = 4) and CB (n = 4) were integrated to analyze metabolites affecting breast muscle quality and flavor, and to explore the important genes regulating meat quality and flavor related metabolites. The results showed that a total of 38 significantly different metabolites (SDMs) and 420 differentially expressed genes (DEGs) were detected in the breast muscle of the 2 breeds. Amino acid and lipid metabolism may be the cause of meat quality and flavor difference between DM and CB chickens, involving metabolites such as L-methionine, betaine, N6, N6, N6-Trimethyl-L-lysine, L-anserine, glutathione, glutathione disulfide, L-threonine, N-Acetyl-L-aspartic acid, succinate, choline, DOPC, SOPC, alpha-linolenic acid, L-palmitoylcarnitine, etc. Important regulatory genes with high correlation with flavor amino acids (GATM, GSTO1) and lipids (PPARG, LPL, PLIN1, SCD, ANGPTL4, FABP7, GK, B4GALT6, UGT8, PLPP4) were identified by correlation analysis, and the gene-metabolite interaction network of breast muscle mass and flavor formation in DM chicken was constructed. This study showed that there were significant differences in breast metabolites between DM and CB chickens, mainly in amino acid and lipid metabolites. These 2 kinds of substances may be the main reasons for the difference in breast muscle quality and flavor between the 2 breeds. In general, this study could provide a theoretical basis for further research on the molecular regulatory mechanism of the formation of breast muscle quality and flavor differences between DM and CB chickens, and provide a reference for the development, utilization and genetic breeding of high-quality meat chicken breeds. Show less
Incubation temperature is a crucial environmental factor affecting embryonic development and chick quality. Metabolism during the embryonic stage, particularly liver lipid metabolism, is essential for Show more
Incubation temperature is a crucial environmental factor affecting embryonic development and chick quality. Metabolism during the embryonic stage, particularly liver lipid metabolism, is essential for the growth and development of poultry. This study aimed to investigate the effects of embryo thermal manipulation with high (TMH, 39.5 °C, 65% RH, 8 h/d) and low (TML, 20 °C, 65% RH, 1 h/d) temperatures during 8th to 15th embryonic age on hatching performance and liver lipid metabolism in layer chicks. Additionally, the duration of TM effects was evaluated through a short-term feeding trial. The results indicated that TMH accelerated the hatching process without significantly affecting hatchability and growth performance. In contrast, TML delayed hatching time and significantly reduced hatchability and chick quality. After hatching, TML also increased residual yolk weight and reduced the relative liver weight in relation to body weight and yolk-free body mass. Moreover, lipid droplets in the liver were stained with Oil Red O, and the lipid content in the liver and serum was further detected. TMH had no significant impact on triglyceride (TG) and total-cholesterol (TCHO) content in the liver and serum but upregulated the expression of lipogenesis-related genes ACC, Fas, and Fatp1 compared to the TML group. Conversely, TML significantly reduced liver TG content, enhanced lipoprotein lipase (LPL) activity, and promoted the expression of lipid oxidation-related genes CPT-1, PGC-1α, and PPARα. At 7 d of age, liver LPL activity was significantly increased in the TMH group. However, there were no significant changes in the content of TG and TCHO in the liver and the expression of lipid metabolism-related genes in the TML group. Overall, these results indicate that embryonic TM alters hatching performance and liver lipid metabolism in layer chicks. TML reduces TG content by increasing liver lipid oxidation capacity. However, this effect is not long-lasting, as the influence of TM diminishes as the chicks develop. Show less
Metformin has pleiotropic effects beyond glucose reduction, including tumor inhibition and immune regulation. It enhanced the anti-tumor effects of programmed cell death protein 1 (PD-1) inhibitors in Show more
Metformin has pleiotropic effects beyond glucose reduction, including tumor inhibition and immune regulation. It enhanced the anti-tumor effects of programmed cell death protein 1 (PD-1) inhibitors in serine/threonine kinase 11 ( We performed untargeted metabolomics using liquid chromatography (LC)-mass spectrometry (MS)/MS system and conducted cell experiments to verify the results of bioinformatics analysis. According to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database, most metabolites were annotated into metabolism, including nucleotide metabolism. Next, the differentially expressed metabolites in H460 (refers to H460 cells), H460_met (refers to metformin-treated H460 cells), and H460_KO_met (refers to metformin-treated Relying on AXIN1, metformin upregulated multiple nucleotide metabolites which promoted STING signaling and the killing of activated T cells in Show less
In recent years, the position of PCSK9 inhibitors as adjuvant therapy to statins in guidelines has further improved. However, there remained a dearth of direct comparative studies among different PCSK Show more
In recent years, the position of PCSK9 inhibitors as adjuvant therapy to statins in guidelines has further improved. However, there remained a dearth of direct comparative studies among different PCSK9 inhibitors. Therefore, this study aimed to conduct a network meta-analysis to evaluate the efficacy and safety of different PCSK9 inhibitors combined with statins. A comprehensive literature search was conducted from the study's inception to 12 November 2023, encompassing multiple online databases including PubMed, Embase, Cochrane Central, Web of Science, and ClinicalTrials.gov to obtain relevant randomized controlled trials. Frequentist network meta-analysis was employed to compare the efficacy and safety of different PCSK9 inhibitors. The efficacy endpoints were low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and lipoprotein (a) (Lp(a)). The safety endpoints were any adverse events (AE), severe adverse events (SAE), AE leading to treatment discontinuation, and injection-site reaction. Compared with placebo and ezetimibe, all PCSK9 inhibitors demonstrated significant reductions in LDL-C levels. Notably, evolocumab exhibited the most pronounced effect with a treatment difference of -63.67% (-68.47% to -58.87%) compared with placebo. Regarding dosage selection for evolocumab, the regimen of 140 mg Q2W (-69.13%, -74.55% to -63.72%) was superior to 420 mg QM (-61.51%, -65.97% to -57.05%). Based on rankings and Compared with placebo and ezetimibe, PCSK9 inhibitors can significantly reduce LDL-C, ApoB, and Lp(a) when combined with statins to treat hypercholesterolemia. Furthermore, PCSK9 inhibitors and ezetimibe exhibit similar safety profiles. [PROSPERO], identifier [CRD42023490506]. Show less
Diabetes mellitus is generally accompanied by dyslipidaemia, but inconsistent relationships between lipid profiles and diabetes are noted. Moreover, genetic variations in insertion/deletion (I/D) poly Show more
Diabetes mellitus is generally accompanied by dyslipidaemia, but inconsistent relationships between lipid profiles and diabetes are noted. Moreover, genetic variations in insertion/deletion (I/D) polymorphisms at angiotensin-converting enzyme gene (ACE) and T/C polymorphisms in the angiotensin type 1 receptor gene (AGTR1) are related to diabetes and lipid levels, but the associations are controversial. Thus, the current research aimed to explore the effects of ACE I/D, AGTR1 rs5182 and diabetes mellitus on serum lipid profiles in 385 Chinese participants with an average age of 75.01 years. The ACE I/D variant was identified using the polymerase chain reaction (PCR) method, whereas the AGTR1 rs5182 polymorphism was identified using the PCR-based restriction fragment length polymorphism (PCR-RFLP) method and verified with DNA sequencing. Total cholesterol (TC), triglyceride (TG), apolipoprotein A (ApoA), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured using routine methods, and the lipid ratios were calculated. ACE I/D, but not AGTR1 rs5182, was a predictor of TG/HDL-C for the whole study population. Both ACE I/D and AGTR1 rs5182 were predictors of HDL-C and LDL-C levels in females but not in males. Moreover, in females, diabetes mellitus and ACE I/D were identified as predictors of TG and TG/HDL-C, whereas AGTR1 rs5182 and diabetes mellitus were predictors of TG/HDL-C. Moreover, diabetes mellitus and the combination of ACE I/D and AGTR1 rs5182 variations were predictors of TG and TG/HDL-C exclusively in females. The results demonstrated the potential for gender-dependent interactions of ACE I/D, AGTR1 rs5182, and diabetes on lipid profiles. These findings may serve as an additional explanation for the inconsistent changes of blood lipids in individuals with diabetes mellitus, thereby offering a novel perspective for the clinical management of blood lipid levels in diabetic patients. Show less
Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid (FA) uptake from triglyceride (TG)-rich lipoproteins such as very low density lipoproteins (VLDL) Show more
Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid (FA) uptake from triglyceride (TG)-rich lipoproteins such as very low density lipoproteins (VLDL). While pharmacological inhibition of ANGPTL3 is being evaluated as a lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aims to compare the therapeutic potential of liver-specific Angptl3 and Angptl4 silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established humanized model for lipoprotein metabolism. Mice were subcutaneously injected twice per week with saline or liver-targeted antisense oligonucleotides against Angptl3, Angptl4, both, or a scrambled oligonucleotide. Plasma lipid levels, VLDL clearance, and hepatic VLDL production were determined, and atherosclerosis development was assessed. For toxicological evaluation, cynomolgus monkeys were treated with three dosages of liver-targeted ANGPTL4-silencing oligonucleotides. Liver-targeted Angptl4 silencing reduced plasma TGs (-48%) and total cholesterol (-56%), explained by higher VLDL-derived FA uptake by brown adipose tissue and lower VLDL production by the liver. Accordingly, Angptl4 silencing reduced atherosclerotic lesion size (-86%) and improved lesion stability. Hepatic Angptl3 silencing similarly attenuated hyperlipidemia and atherosclerosis development. While Angptl3 and Angptl4 silencing lowered plasma TGs in the refed and fasted state, respectively, combined Angptl3/4 silencing lowered plasma TGs independent of the nutritional state. In cynomolgus monkeys, anti-ANGPTL4 ASO treatment was well tolerated without adverse effects. Liver-targeted Angptl4 silencing potently attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, and liver-targeted ANGPTL4 silencing is well tolerated in non-human primates. These data warrant further clinical development of liver-targeted ANGPTL4 silencing. Show less
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, characterized by molecular and clinical heterogeneity. Interleukin (IL)-27, a heterodimeric cytokine composed of p28 and Show more
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, characterized by molecular and clinical heterogeneity. Interleukin (IL)-27, a heterodimeric cytokine composed of p28 and EBI3 subunits, has been reported to exert potent antitumor activity in several cancer models. However, the precise role of IL-27 in the pathogenesis of CRC remains unclear. Here, we show that during the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC development, IL-27p28 levels are dramatically increased in peripheral blood and tumor tissues, and the cytokine is mainly produced by tumor-infiltrating myeloid cells. IL-27p28 deficient mice display tumor resistances in both inflammation-associated CRC model and syngeneic MC38 colon cancer model. Administration with IL-27p28 neutralizing antibody also reduces the tumor formation in AOM/DSS-treated mice. Mechanically, CD8 Show less
Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have no Show more
Bis-chalcone compounds with symmetrical structures, either isolated from natural products or chemically synthesized, have multiple pharmacological activities. Asymmetric Bis-chalcone compounds have not been reported before, which might be attributed to the synthetic challenges involved, and it remains unknown whether these compounds possess any potential pharmacological activities. The aim of this study is to investigate the synthesis route of asymmetric bis-chalcone compounds and identify potential candidates with efficient anti-tumor activity. The two-step structural optimization of the bis-chalcone compounds was carried out sequentially, guided by the screening of the compounds for their growth inhibitory activity against gastric cancer cells by MTT assay. The QSAR model of compounds was established through random forest (RF) algorithm. The activities of the optimal compound J3 on growth inhibition, apoptosis, and apoptosis-inducing protein expression in gastric cancer cells were investigated sequentially by colony formation assay, flow cytometry, and western blotting. Further, the inhibitory effects of J3 on the FGFR1 signaling pathway were explored by Western Blotting, shRNA, and MTT assays. Finally, the 27 asymmetric bis-chalcone compounds, including two types (N and J) were sequentially designed and synthesized. Some N-class compounds have good inhibitory activity on the growth of gastric cancer cells. The vast majority of J-class compounds optimized on the basis of N3 exhibit excellent inhibitory activity on gastric cancer cell growth. We established a QSAR model (R In summary, this study outlines a viable method for the synthesis of novel asymmetric bischalcone compounds. Furthermore, the compound J3 demonstrates substantial promise as a potential candidate for an anti-tumor drug. Show less
Environmental contaminants (ECs) are increasingly recognized as crucial drivers of dyslipidemia and cardiovascular disease (CVD), but the comprehensive impact spectrum and interlinking mechanisms rema Show more
Environmental contaminants (ECs) are increasingly recognized as crucial drivers of dyslipidemia and cardiovascular disease (CVD), but the comprehensive impact spectrum and interlinking mechanisms remain uncertain. We aimed to systematically evaluate the association between exposure to 80 ECs across seven divergent categories and markers of dyslipidemia and investigate their underpinning biomolecular mechanisms via an unbiased integrative approach of internal chemical exposome and multi-omics. A longitudinal study involving 76 healthy older adults was conducted in Jinan, China, and participants were followed five times from 10 September 2018 to 19 January 2019 in 1-month intervals. A broad spectrum of seven chemical categories covering the prototypes and metabolites of 102 ECs in serum or urine as well as six serum dyslipidemia markers [total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein (Apo)A1, ApoB, and ApoE4] were measured. Multi-omics, including the blood transcriptome, serum/urine metabolome, and serum lipidome, were profiled concurrently. Exposome-wide association study and the deletion/substitution/addition algorithms were applied to explore the associations between 80 EC exposures detection frequency Eight main ECs [1-naphthalene, 1-pyrene, 2-fluorene, dibutyl phosphate, tri-phenyl phosphate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, chromium, and vanadium] were significantly associated with most dyslipidemia markers. Multi-omics indicated that the associations were mediated by endogenous biomolecules and pathways, primarily pertinent to CVD, inflammation, and metabolism. Clinical measures of cytokines and electrocardiograms further cross-validated the association of these exogenous ECs with systemic inflammation and cardiac function, demonstrating their potential mechanisms in driving dyslipidemia pathogenesis. It is imperative to prioritize mitigating exposure to these ECs in the primary prevention and control of the dyslipidemia epidemic. https://doi.org/10.1289/EHP13864. Show less
Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted eff Show more
Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aβ-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aβ toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aβ deposition in Aβ Show less