Cancer stem cells (CSCs) contribute to metastasis and drug resistance to immunotherapy in lung adenocarcinoma (LUAD), so the stemness evaluation of cancer cells is of great significance. The single-ce Show more
Cancer stem cells (CSCs) contribute to metastasis and drug resistance to immunotherapy in lung adenocarcinoma (LUAD), so the stemness evaluation of cancer cells is of great significance. The single-cell RNA sequencing (scRNA-seq) data of the GSE149655 dataset were collected and analyzed. Malignant cells were distinguished by CopyKAT. CytoTRACE score of marker genes in malignant cells was counted by CytoTRACE to construct the stemness score formula. Sample stemness score in TCGA was determined by the formula and divided into high-, medium- and low-stemness score groups. LASSO and COX regression analyses were carried out to screen the key genes related to the prognosis of LUAD from the differentially expressed genes (DEGs) in high- and low-stemness score groups and a risk score model was constructed. Seven types of cells were identified from a total of 4 samples, and 193 marker genes of 3455 malignant cells were identified. There were 1098 DEGs between low- and high-stemness score groups of TCGA, of which CPS1, CENPK, GJB3, and TPSB2 constituted gene signatures. The 4-gene signature could independently evaluate LUAD survival in the training and validation sets and showed an acceptable area under the receiver operator characteristic (ROC) curves (AUCs). This study provides insights into the cellular heterogeneity of LUAD and develops a new cancer stemness evaluation indicator and a 4-gene signature as a potential tool for evaluating the response of LUAD to immune checkpoint blockade (ICB) therapy or antineoplastic therapy. Show less
Macular edema (ME) has emerged as a leading cause of visual impairment, representing a critical clinical manifestation and complication associated with many eye diseases. In the occurrence and develop Show more
Macular edema (ME) has emerged as a leading cause of visual impairment, representing a critical clinical manifestation and complication associated with many eye diseases. In the occurrence and development of ME, retinal glial cells like Müller cells and microglial cells play vital roles. Moreover, growth factor and cytokines associated with them, such as vascular endothelial growth factor (VEGF), pigment epithelium-derived factor (PEDF), hypoxia-inducible factor-1α (HIF-1α), angiopoietin-like protein 4 (ANGPTL4), interleukin-6(IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), prostaglandin, etc., also take part in the pathogenesis of ME. Changes in these cytokines can lead to retinal angiogenesis, increased vascular permeability, blood-retinal barrier (BRB) breakdown, and fluid leakage, further causing ME to occur or deteriorate. Research on the role of retinal glial cells and related cytokines in ME will provide new therapeutic directions and effective remedies. This article is a literature review on the role of Müller cells, microglial cells and related factors in ME pathogenesis. Show less
The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether Show more
The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr). Hypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice. Gipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance. Acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the β-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice. GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism. Show less
Intestinal homeostasis is maintained by specialized host cells and the gut microbiota. Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis, and its dysregulation has Show more
Intestinal homeostasis is maintained by specialized host cells and the gut microbiota. Wnt/β-catenin signaling is essential for gastrointestinal development and homeostasis, and its dysregulation has been implicated in inflammation and colorectal cancer. Axin1 negatively regulates activated Wnt/β-catenin signaling, but little is known regarding its role in regulating host-microbial interactions in health and disease. Here, we aim to demonstrate that intestinal Axin1 determines gut homeostasis and host response to inflammation. Axin1 expression was analyzed in human inflammatory bowel disease datasets. To explore the effects and mechanism of intestinal Axin1 in regulating intestinal homeostasis and colitis, we generated new mouse models with Show less
This was a study of 12 cerebellar cortical dysplasias (CCDs) fetuses, these cases were characterized by a disorder of cerebellar fissures. Historically, CCD diagnosis was primarily performed using pos Show more
This was a study of 12 cerebellar cortical dysplasias (CCDs) fetuses, these cases were characterized by a disorder of cerebellar fissures. Historically, CCD diagnosis was primarily performed using postnatal imaging. Unique to this study was the case series of CCD for prenatal diagnosis using prenatal ultrasound, as well as we found that AXIN1 and FOXC1 mutations may be related to CCD. 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
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
Lysosomal-associated protein transmembrane 5 (LAPTM5) is increased in tubular epithelial cells in CKD. Conditional knockout of Tubular senescence is a major determinant of CKD, and identification of p Show more
Lysosomal-associated protein transmembrane 5 (LAPTM5) is increased in tubular epithelial cells in CKD. Conditional knockout of Tubular senescence is a major determinant of CKD, and identification of potential therapeutic targets involved in senescent tubular epithelial cells has clinical importance. Lysosomal-associated protein transmembrane 5 (LAPTM5) is a key molecule related to T- and B-cell receptor expression and inflammation. However, the expression pattern of LAPTM5 in the kidney and the contribution of LAPTM5 to the development of CKD are unknown. LAPTM5 expression was significantly induced in the kidney, especially in proximal tubules and distal convoluted tubules, from mice with aristolochic acid nephropathy, bilateral ischemia/reperfusion injury–induced CKD, or unilateral ureter obstruction. Tubule-specific deletion of LAPTM5 contributed to tubular senescence by regulating the WWP2/notch1 intracellular domain signaling pathway and exacerbated kidney injury during the progression of CKD. 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
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
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors originating from the digestive system. Tertiary lymphoid structures (TLS), non-lymphoid tissues outside of the lymphoid organs Show more
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors originating from the digestive system. Tertiary lymphoid structures (TLS), non-lymphoid tissues outside of the lymphoid organs, are closely connected to chronic inflammation and tumorigenesis. However, the detailed relationship between TLS and HCC prognosis remained unclear. In this study, we aimed to construct a TLS-related gene signature for predicting the prognosis of HCC patients. The Cancer Genome Atlas (TCGA) clinical data from 369 HCC tissues and 50 normal liver tissues were utilized to examine the differential expression of TLS-related genes. Based on least absolute shrinkage and selection operator (LASSO) Cox regression analysis, the prognostic model was constructed using the TCGA cohort and validated in the GSE14520 cohort and International Cancer Genome Consortium (ICGC) cohort. The Kaplan-Meier (KM) and receiver operating characteristic (ROC) curves were employed to validate the predictive ability of the prognostic model. Furthermore, Cox regression analysis was applied to identify whether the TLS score could be employed as an independent prognosis factor. A nomogram was developed to predict the survival probability of HCC patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed for TLS-related genes. Genetic mutation analysis, the CIBERSORT algorithm, and single-sample gene set enrichment analysis (ssGSEA) were used to assess the tumor mutation landscape and immune infiltration. Finally, the role of the TLS score in HCC therapy was investigated. Six genes were included in the construction of our prognostic model (CETP, DNASE1L3, PLAC8, SKAP1, C7, and VNN2), and we validated its accuracy. Survival analysis showed that patients in the high-TLS score group had a significantly better overall survival than those in the low-TLS score group. Univariate, multivariate Cox regression analysis and the establishment of a nomogram indicated that the TLS score could independently function as a potential prognostic marker. A significant association between TLS score and immunity was revealed by an analysis of gene alterations and immune cell infiltration. In addition, two subtypes of the TLS score could accurately predict the effectiveness of sorafenib, transcatheter arterial chemoembolization (TACE), and immunotherapy in HCC patients. In this research, we conducted and validated a prognostic model associated with TLS that may be helpful for predicting clinical outcomes and treatment responsiveness for HCC patients. 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
Yanhua Zhou, Dayu Yan, Xiulan Zhang+3 more · 2024 · Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · added 2026-04-24
Pelvic organ prolapse (POP) is a common condition in postmenopausal women, with an increasing prevalence due to aging. Some women experience POP recurrence after surgical treatment, significantly affe Show more
Pelvic organ prolapse (POP) is a common condition in postmenopausal women, with an increasing prevalence due to aging. Some women experience POP recurrence after surgical treatment, significantly affecting their physical and mental health. The uterosacral ligament is a critical pelvic support structure. This study aims to investigate the molecular pathological changes in the uterosacral ligament of postmenopausal women with recurrent POP using transcriptomic analysis. Transcriptomic data of uterosacral ligament tissues were obtained from the public dataset GSE28660, which includes samples from 4 postmenopausal women with recurrent POP, 4 with primary POP, and 4 without POP. Differentially expressed genes (DEGs) were identified between recurrent POP and both primary and non-POP groups. Further analysis included intersection analysis of DEGs, gene ontology enrichment, protein-protein interaction (PPI) network construction, gene set enrichment analysis (GSEA), single-sample GSEA, and xCell immune cell infiltration analysis to explore molecular pathological changes in recurrent POP. Additionally, histological and molecular differences in the uterosacral ligament were compared between simulated vaginal delivery (SVD) rat models with and without ovariectomy. Compared with primary POP and non-POP groups, recurrent POP exhibited activation of adipogenesis and inflammation-related pathways, while pathways related to muscle proliferation and contraction were downregulated in the uterosacral ligament. Nine key DEGs ( Adipogenesis and inflammation in the uterosacral ligament may contribute to its reduced supportive function, potentially leading to recurrence POP in postmenopausal women. Show less
To identify age-related plasma extracellular vehicle (EVs) phenotypes in healthy adults. EV proteomics by high-resolution mass spectrometry to evaluate EV protein stability and discover age-associated Show more
To identify age-related plasma extracellular vehicle (EVs) phenotypes in healthy adults. EV proteomics by high-resolution mass spectrometry to evaluate EV protein stability and discover age-associated EV proteins (n=4 with 4 serial freeze-thaws each); validation by high-resolution flow cytometry and EV cytokine quantification by multiplex ELISA (n=28 healthy donors, aged 18-83 years); quantification of WI-38 fibroblast cell proliferation response to co-culture with PKH67-labeled young and old plasma EVs. The EV samples from these plasma specimens were previously characterized for bilayer structure, intra-vesicle mitochondria and cytokines, and hematopoietic cell-related surface markers. Compared with matched exo-EVs (EV-depleted supernatants), endo-EVs (EV-associated) had higher mean TNF-α and IL-27, lower mean IL-6, IL-11, IFN-γ, and IL-17A/F, and similar mean IL-1β, IL-21, and IL-22 concentrations. Some endo-EV and exo-EV cytokine concentrations were correlated, including TNF-α, IL-27, IL-6, IL-1β, and IFN-γ, but not IL-11, IL-17A/F, IL-21 or IL-22. Endo-EV IFN-γ and exo-EV IL-17A/F and IL-21 declined with age. By proteomics and confirmed by flow cytometry, we identified age-associated decline of fibrinogen (FGA, FGB and FGG) in EVs. Age-related EV proteins indicated predominant origins in the liver and innate immune system. WI-38 cells (>95%) internalized similar amounts of young and old plasma EVs, but cells that internalized PKH67-EVs, particularly young EVs, underwent significantly greater cell proliferation. Endo-EV and exo-EV cytokines function as different biomarkers. The observed healthy aging EV phenotype reflected a downregulation of EV fibrinogen subpopulations consistent with the absence of a pro-coagulant and pro-inflammatory condition common with age-related disease. Show less
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
Chen Chen, Qingxiang Liu, Jianfei Wang+7 more · 2024 · Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association · Elsevier · added 2026-04-24
Early evaluation and intervention for post-stroke cognitive impairment are crucial for improving the prognosis of acute ischemic stroke. The search for specific diagnostic markers and feasible therape Show more
Early evaluation and intervention for post-stroke cognitive impairment are crucial for improving the prognosis of acute ischemic stroke. The search for specific diagnostic markers and feasible therapeutic targets is extremely urgent.The characteristics of circular RNAs make them promising candidates. To screen circular RNAs as novel biomarkers and therapeutic targets for post-stroke cognitive impairment in large-artery atherosclerosis anterior circulation cerebral infarction patients. In this prospective observational study, patients with first-ever large-artery atherosclerosis anterior circulation cerebral infarction were recruited. The Montreal Cognitive Assessment was used to assess the cognitive statuses of patients. Venous blood samples were collected on the seventh day after stroke onset. A circRNA microarray was used to identify differentially expressed circular RNAs in the discovery cohort (four patients with post-stroke cognitive impairment and four patients with post-stroke cognitive normal characteristics), and validation was performed in the validation cohorts (45 patients with post-stroke cognitive impairment and 30 patients with post-stroke cognitive normal characteristics) using quantitative real-time polymerase chain reaction. Receiver operating characteristic curves of the validated circular RNAs and the NIHSS score were constructed, and the area under the curve, sensitivity, and specificity were calculated. Correlation analysis was performed to explore the relationship between the copy number of circular RNAs and the cognitive status. The functions of the differentially expressed circular RNAs were predicted using bioinformatics analysis. CircRNA microarray analysis revealed 189 human circular RNAs (152 upregulated and 37 downregulated) that were differentially expressed in the plasma samples of patients with post-stroke cognitive impairment and PSCN characteristics. The expression of hsa_circ₀₀₈₉₇₆₃, hsa_circ₀₀₆₄₆₄₄, and hsa_circ₀₀₈₉₇₆₂ was validated using quantitative real-time polymerase chain reaction. The area under the curve, sensitivity, and specificity of hsa_circ₀₀₈₉₇₆₂ in post-stroke cognitive impairment diagnosis were 0.993, 97.8%, and 96.7%, respectively, and the correlation coefficient between hsa_circ₀₀₈₉₇₆₂ expression and the Montreal Cognitive Assessment score was -0.693 (p < 0.001), which made it an ideal biomarker. Bioinformatic analysis revealed that the targeted mRNAs of the three circular RNAs were enriched in pathologically related signaling pathways of post-stroke cognitive impairment, such as the MAPK and PI3K-Akt signaling pathways. Based on the circRNA-miRNA-mRNA network, the three circular RNAs play a crucial role in numerous pathological processes of acute ischemic stroke and post-stroke cognitive impairment by sponging miRNAs such as MiR-335, MiR-424, and MiR-670. By building the protein-protein interaction network, we identified cluster 1 according to the MCODE score; cluster 1 was composed of ERBB4, FGFR1, CACNA2D1, NRG1, PPP2R5E, CACNB4, CACNB2, CCND1, NTRK2, and PTCH. Hsa_circ₀₀₈₉₇₆₂, hsa_circ₀₀₆₄₆₄₄, and hsa_circ₀₀₈₉₇₆₃ are potential novel biomarkers and focal points for exploring intervention targets in post-stroke cognitive impairment of large-artery atherosclerosis anterior circulation cerebral infarction patients. ChiCTR2000035074. Show less
no PDFDOI: 10.1016/j.jstrokecerebrovasdis.2024.107945
Studies have shown that uremia, renal failure and heart failure (HF) are closely related. However, whether this association reflects a causal effect is still unclear. The aim of this study was to eval Show more
Studies have shown that uremia, renal failure and heart failure (HF) are closely related. However, whether this association reflects a causal effect is still unclear. The aim of this study was to evaluate the causal effect of uremic metabolites or toxins on HF. Mendelian randomization (MR) analysis was conducted to evaluate the causal effect of 11 uremia-related metabolites on HF risk using single-nucleotide polymorphisms (SNPs) from a genome-wide association study. A protein-protein interaction network was constructed to study the function of SNPs corresponding to HF-related factors. Univariate and multivariate MR analyses demonstrated that lipoprotein A and apolipoprotein B were positively correlated with HF. The SNPs corresponding to these key factors were related mainly to MAP kinase activity and lipid metabolic processes. Overall, we identified 2 uremia-related exposure factors (lipoprotein A and apolipoprotein B) closely related to HF, laying a theoretical foundation for the treatment of HF with renal failure or uremia. Show less
The relationship between insulin resistance-related indices and the outcomes of acute ischemic stroke (AIS) is still unclear. This study aimed to explore the association between the Apo B/Apo A-1 rati Show more
The relationship between insulin resistance-related indices and the outcomes of acute ischemic stroke (AIS) is still unclear. This study aimed to explore the association between the Apo B/Apo A-1 ratio and the Prognostic Nutritional Index (PNI) with the 90-day outcomes of AIS. A total of 2011 AIS patients with a 3-month follow-up were enrolled in the present study from January 2017 to July 2021. Multivariate logistic regression modeling was performed to analyze the relationship between Apo B/Apo A-1 ratio, PNI, and AIS poor outcomes. The mediating effect between the three was analyzed using the Bootstrap method with PNI as the mediating variable. Among the 2011 included AIS patients, 20.3% had a poor outcome. Patients were categorized according to quartiles of Apo B/Apo A-1 ratio and PNI. Multivariate logistic regression revealed that the fourth Apo B/Apo A-1 ratio quartile had poorer outcomes than the first quartile (OR 1.75,95%CL 1.21-2.53, P=0.003), and the fourth PNI quartile exhibited a lower risk of poor outcomes than the first quartile (OR 0.40, 95%CL 0.27-0.61, P<0.001). PNI displayed a significant partially mediating effect (21.4%) between the Apo B/Apo A-1 ratio and poor AIS outcomes. The Apo B/Apo A-1 ratio is a risk factor for poor AIS outcomes, whereas PNI acts as a protective factor. The association between the ApoB/ApoA-1 ratio and poor AIS outcomes was partially mediated by PNI. Show less
Infigratinib, an FGFR1-3 selective oral tyrosine kinase inhibitor, has shown clinical activity in cancers with FGFR alterations. The pharmacokinetics (PK) of infigratinib and its major metabolites hav Show more
Infigratinib, an FGFR1-3 selective oral tyrosine kinase inhibitor, has shown clinical activity in cancers with FGFR alterations. The pharmacokinetics (PK) of infigratinib and its major metabolites have been characterized in global populations. This study examined the PK profile of infigratinib and its metabolites in Chinese patients. In this phase II, open-label, single-arm study in China, patients with advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) harboring FGFR2 gene amplification received 125 mg infigratinib orally once daily in a "3 weeks on, 1 week off" schedule for 28-day cycles. Plasma PK parameters were calculated with a non-compartmental model. Data were available from 21 patients (19 GC and two GEJ). After a single dose, peak infigratinib plasma concentration was reached at a median time of 3.1 h, with geometric mean C Show less
Diabetic retinopathy (DR) is a diabetic microvascular complication and a leading cause of vision loss. However, there is a lack of effective strategies to reduce the risk of DR currently. The present Show more
Diabetic retinopathy (DR) is a diabetic microvascular complication and a leading cause of vision loss. However, there is a lack of effective strategies to reduce the risk of DR currently. The present study is aimed at assessing the causal effect of lipid-regulating targets on DR risk using a two-sample Mendelian randomization (MR) study. Genetic variants within or near drug target genes, including eight lipid-regulating targets for LDL-C (HMGCR, PCSK9, and NPC1L1), HDL-C (CETP, SCARB1, and PPARG), and TG (PPARA and LPL), were selected as exposures. The exposure data were obtained from the IEU OpenGWAS project. The outcome dataset related to DR was obtained from the FinnGen research project. Inverse-variance-weighted MR (IVW-MR) was used to calculate the effect estimates by each target. Sensitivity analyses were performed to verify the robustness of the results. There was suggestive evidence that PCSK9-mediated LDL-C levels were positively associated with DR, with OR (95% CI) of 1.34 (1.02-1.77). No significant association was found between the expression of HMGCR- and NPC1L1-mediated LDL-C levels; CETP-, SCARB1-, and PPARG-mediated HDL-C levels; PPARA- and LPL-mediated TG levels; and DR risk. This is the first study to reveal a genetically causal relationship between lipid-regulating drug targets and DR risk. PCSK9-mediated LDL-C levels maybe positively associated with DR risk at the genetic level. This study provides suggestive evidence that PCSK9 inhibition may reduce the risk of DR. Show less
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. It is also known to be a risk factor for Alzheimer's disease (AD). Insulin plays Show more
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. It is also known to be a risk factor for Alzheimer's disease (AD). Insulin plays a crucial role in regulating the body's metabolism and is responsible for activating the Phosphoinotide-3-Kinase (PI3K)/Protein Kinase B (Akt) signaling pathway. This pathway is activated when insulin binds to the insulin receptor on nerve cells, and it helps regulate the metabolism of glucose and lipids. Dysfunction in the insulin signaling pathway can lead to a decrease in brain insulin levels and insulin sensitivity, thereby inducing disruptions in insulin signal transduction and leading to disorders in brain energy metabolism. Moreover, these dysfunctions also contribute to the accumulation of β-amyloid (Aβ) deposition and the hyperphosphorylation of Tau protein, both of which are characteristic features of AD. Therefore, this article focuses on insulin resistance to reveal the complex mechanism between brain insulin resistance and AD occurrence in T2DM. On this basis, this article further summarizes the biological effects and mechanisms of antidiabetic drugs on the two diseases, aiming to provide new ideas for the discovery of drugs for the treatment of T2DM combined with AD. Show less
The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is Show more
The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role. Show less
The exostosins (EXT), which are responsible for heparan sulfate backbone synthesis and play a vital role in tissue homeostasis, have been reported to be correlated with prognosis of various cancers. H Show more
The exostosins (EXT), which are responsible for heparan sulfate backbone synthesis and play a vital role in tissue homeostasis, have been reported to be correlated with prognosis of various cancers. However, the expression, prognostic value, and immune infiltration of EXT1 and EXT2 in head and neck squamous cell carcinoma (HNSC) remain uncertain. GEPIA, UALCAN, and Xiantao bioinformatics tools were used to explore the EXT1 and EXT2 expression level in HNSC. GEPIA and Sangerbox were utilised to obtain the prognostic value of EXT1 and EXT2 in HNSC. Genetic alterations, immune cell infiltration, and single-cell analysis were conducted in cBioPortal, TIMER, and TISCH2. In addition, the expressions of EXT1 and EXT2 were validated by real-time polymerase chain reaction (PCR) in HNSC samples. EXT1 and EXT2 were highly expressed in HNSC, especially in malignant cells. Only EXT2 was significantly negatively correlated to the prognosis of patients with HNSC. EXT1 and EXT2 were found to be associated with focal adhesin and cell adhesin molecule binding. EXT1 expression levels were considerably connected with CD8+ T cell infiltrating levels, whilst EXT2 expression levels were considerably negatively connected with infiltrating levels of CD4+ T cells, macrophages, neutrophils, and dendritic cells in HNSC. The gene mutation rates of EXT1 and EXT2 in HNSC were 7% and 2.8%, respectively. Moreover, EXT2 was validated to be highly expressed in HNSC samples by real-time PCR. EXT2 was highly expressed and presented negative correlation with the prognosis and immune infiltration of HNSC, which might be a potential biomarker for HNSC. Show less
To provide a theoretical basis for the prevention and treatment of atherosclerosis (AS), the current study aimed to investigate the mechanism underlying the effect of homocysteine (Hcy) on regulating Show more
To provide a theoretical basis for the prevention and treatment of atherosclerosis (AS), the current study aimed to investigate the mechanism underlying the effect of homocysteine (Hcy) on regulating the proliferation, migration and phenotypic transformation of vascular smooth muscle cells (VSMC) via sirtuin-1 (SIRT1)/signal transducer and activator of transcription 3 (STAT3) through Nedd4-like E3 ubiquitin-protein ligase WWP2 (WWP2). Here, Based on the establishment of ApoE-/- mouse models of high Hcy As and the model of Hcy stimulation of VSMC in vitro to observe the interaction between WWP2 and STAT3 and its effect on the proliferation, migration, and phenotypic transformation of Hcy-induced VSMC, which has not been previously reported. This study revealed that WWP2 could promote the proliferation, migration, and phenotype switch of Hcy-induced VSMC by up-regulating the phosphorylation of SIRT1/STAT3 signaling. Furthermore, Hcy might up-regulate WWP2 expression by inhibiting histone H3K27me3 expression through up-regulated UTX. These data suggest that WWP2 is a novel and important regulator of Hcy-induced VSMC proliferation, migration, and phenotypic transformation. Show less
Wenhua Zhang, Ruiming Wang, Fangying Shi · 2024 · Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association · Elsevier · added 2026-04-24
The purpose of this study is to the relationship between peripheral apolipoproteins and the prognosis of patients with acute ischemic stroke (AIS) after thrombolysis. A total of 231 AIS patients with Show more
The purpose of this study is to the relationship between peripheral apolipoproteins and the prognosis of patients with acute ischemic stroke (AIS) after thrombolysis. A total of 231 AIS patients with thrombolysis was enrolled. Serum apolipoproteins were measured on admission after thrombolysis. All patients enrolled were followed up for 90 days. Their functional outcomes were assessed by the modified Rankin Scale (mRS). Good functional outcome was considered as mRS < 3. Logistic regression was applied to assess the association between serum apolipoproteins and the mRS at 90 days. In multivariate analysis,1) ApoB (OR=0.099, 95%CI=0.017∼0.575, p=0.010) and ApoB/ApoA-1(OR=0.113, 95%CI=0.015∼0.868, p=0.036) were independent risk factors of good functional outcome at 90 days. 2). there were significant differences in the mRS score distribution at 90 days in groups according to the ROC cutoff values of ApoB (0.85g/L) and ApoB/ApoA-1 ratio (0.61) (all p<0.05). Our findings demonstrated ApoB and ApoB/apoA-1 ratio were independent risk factors for good functional outcome at 90 days, and the ApoB level below 0.85g/L and ApoB/ApoA-1 ratio below 0.61 could be associated with a better functional outcome in this study population. Show less
no PDFDOI: 10.1016/j.jstrokecerebrovasdis.2024.107944
Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making Show more
Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4 mutants, and their antitumor activity. CXF-007, verified by mass spectrometry and crystal structures to form covalent bonds with Cys552 of FGFR4 and Cys488 of FGFR1, exhibited stronger selectivity and potent inhibitory activity for FGFR4 and FGFR4 cysteine mutants. Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 inhibitor, CXF-007, which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future anticancer drug discovery. Show less
Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-β-catenin signalling antagonist, increase with ag Show more
Ageing increases susceptibility to neurodegenerative disorders, such as Alzheimer's disease (AD). Serum levels of sclerostin, an osteocyte-derived Wnt-β-catenin signalling antagonist, increase with age and inhibit osteoblastogenesis. As Wnt-β-catenin signalling acts as a protective mechanism for memory, we hypothesize that osteocyte-derived sclerostin can impact cognitive function under pathological conditions. Here we show that osteocyte-derived sclerostin can cross the blood-brain barrier of old mice, where it can dysregulate Wnt-β-catenin signalling. Gain-of-function and loss-of-function experiments show that abnormally elevated osteocyte-derived sclerostin impairs synaptic plasticity and memory in old mice of both sexes. Mechanistically, sclerostin increases amyloid β (Aβ) production through β-catenin-β-secretase 1 (BACE1) signalling, indicating a functional role for sclerostin in AD. Accordingly, high sclerostin levels in patients with AD of both sexes are associated with severe cognitive impairment, which is in line with the acceleration of Αβ production in an AD mouse model with bone-specific overexpression of sclerostin. Thus, we demonstrate osteocyte-derived sclerostin-mediated bone-brain crosstalk, which could serve as a target for developing therapeutic interventions against AD. Show less
The aim of this study was to investigate the effects of dietary chitosan supplementation on the muscle composition, digestion, lipid metabolism, and stress resistance, and their related gene expressio Show more
The aim of this study was to investigate the effects of dietary chitosan supplementation on the muscle composition, digestion, lipid metabolism, and stress resistance, and their related gene expression, of juvenile tilapia ( Show less