The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflamm Show more
The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been found to have increased expression in the joints of patients with RA compared to healthy individuals. However, the causal relationship between the expression level of IL-17 or IL-17 receptor (IL-17R) and RA remained unknown. In this study, two-sample Mendelian randomization (MR) was used to investigate the causal relationship between IL-17 and RA. Summary statistics for RA (14,361 RA cases and 43,923 healthy controls) and IL-17 (3,301 samples) were obtained from an available meta-analysis of published genome-wide association studies (GWAS). Relevant single nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. Then we used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality. MR and MVMR analyses progressed mainly using inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods, which were applied to the genetic instrumental variables (IVs) of IL-17A/IL-17 RA, IL-17C/IL-17 RC, and IL-17D/IL-17RD and RA. For assessing the robustness of the results, we also carried out a sensitivity analysis to assess heterogeneity and pleiotropy, such as MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO). Two-sample MR Analysis showed the causal relationship between IL-17A/IL-17RA and RA. The presence of genetically high IL-17A/IL-17RA may increase the risk of RA (IL-17A(OR = 1.095; 95% C.I., 0.990-1.210, p.adj = 0.013), IL-17RA(OR = 1.113, 95%CI = 1.006-1.231, p.adj = 0.006)). However, the results indicated that IL-17C/IL-17RC, and IL-17D/IL-17RD demonstrated no causal impact on RA (IL-17C(OR = 1.007, 95%CI = 0.890-1.139, p.adj = 0.152), IL-17RC(OR = 1.006, 95%CI = 0.904-1.119, p.adj = 0.152), IL-17D(OR = 0.979, 95%CI = 0.843-1.137, p.adj = 0.130), IL-17RD(OR = 0.983, 95%CI = 0.876-1.104, p.adj = 0.129)). Furthermore, MVMR analysis shown that IL-17RA(OR = 1.049, 95% CI: 0.997-1.102, p.adj = 0.014) was associated with increased risk of RA. Sensitivity analysis showed no heterogeneity and pleiotropy, suggesting that the above results were robust and reliable. The MR analysis provides evidence that IL-17A/IL-17RA are risk factors for RA. This emphasizes the importance of intervention on IL-17A/IL-17RA in patients with RA. Developing drugs that limit IL-17A may reduce the risk of RA. Show less
There are no reliable molecular targets for early diagnosis and effective treatment in the clinical management of diabetic kidney disease (DKD). To identify novel gene factors underlying the progressi Show more
There are no reliable molecular targets for early diagnosis and effective treatment in the clinical management of diabetic kidney disease (DKD). To identify novel gene factors underlying the progression of DKD. The public transcriptomic datasets of the alloxan-induced DKD model and the streptozotocin-induced DKD model were retrieved to perform an integrative bioinformatic analysis of differentially expressed genes (DEGs) shared by two experimental animal models. The dominant biological processes and pathways associated with DEGs were identified through enrichment analysis. The expression changes of the key DEGs were validated in the classic db/db DKD mouse model. The downregulated and upregulated genes in DKD models were uncovered from GSE139317 and GSE131221 microarray datasets. Enrichment analysis revealed that metabolic process, extracellular exosomes, and hydrolase activity are shared biological processes and molecular activity is altered in the DEGs. Importantly, Hmgcs2, angptl4, and Slco1a1 displayed a consistent expression pattern across the two DKD models. In the classic db/db DKD mice, Hmgcs2 and angptl4 were also found to be upregulated while Slco1a1 was downregulated in comparison to the control animals. In summary, we identified the common biological processes and molecular activity being altered in two DKD experimental models, as well as the novel gene factors (Hmgcs2, Angptl4, and Slco1a1) which may be implicated in DKD. Future works are warranted to decipher the biological role of these genes in the pathogenesis of DKD. Show less
The accumulation of amyloid β (Aβ) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophag Show more
The accumulation of amyloid β (Aβ) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophagy in Aβ clearance. Recent studies implied that extracts from Semiaquilegia adoxoides (DC.) Makino could ameliorate the memory of D-galactose induced aging mice. However, the bioactive substance and underlying mechanism remains unknown. Thus, the present study sought to explore the effects of a novel homogenous peptidoglycan on Aβ Show less
Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole- Show more
Vogt-Koyanagi-Harada (VKH) disease is a leading cause of blindness in young and middle-aged people. However, the etiology of VKH disease remains unclear. Here, we performed the first trio-based whole-exome sequencing study, which enrolled 25 VKH patients and 50 controls, followed by a study of 2081 VKH patients from a Han Chinese population to uncover detrimental mutations. A total of 15 de novo mutations in VKH patients were identified, with one of the most important being the membrane palmitoylated protein 2 (MPP2) p.K315N (MPP2-N315) mutation. The MPP2-N315 mutation was highly deleterious according to bioinformatic predictions. Additionally, this mutation appears rare, being absent from the 1000 Genome Project and Genome Aggregation Database, and it is highly conserved in 10 species, including humans and mice. Subsequent studies showed that pathological phenotypes and retinal vascular leakage were aggravated in MPP2-N315 mutation knock-in or MPP2-N315 adeno-associated virus-treated mice with experimental autoimmune uveitis (EAU). In vitro, we used clustered regularly interspaced short palindromic repeats (CRISPR‒Cas9) gene editing technology to delete intrinsic MPP2 before overexpressing wild-type MPP2 or MPP2-N315. Levels of cytokines, such as IL-1β, IL-17E, and vascular endothelial growth factor A, were increased, and barrier function was destroyed in the MPP2-N315 mutant ARPE19 cells. Mechanistically, the MPP2-N315 mutation had a stronger ability to directly bind to ANXA2 than MPP2-K315, as shown by LC‒MS/MS and Co-IP, and resulted in activation of the ERK3/IL-17E pathway. Overall, our results demonstrated that the MPP2-K315N mutation may increase susceptibility to VKH disease. Show less
Schisandra chinensis (sc) is generally demonstrated to improve antioxidant and immune functions in mammal. The present study through physiological and transcriptome analysis revealed alterations in mu Show more
Schisandra chinensis (sc) is generally demonstrated to improve antioxidant and immune functions in mammal. The present study through physiological and transcriptome analysis revealed alterations in muscle metabolisms of triploid crucian carp (Carassius auratus) cultured at different concentrations of S. chinensis diets (sc0, sc0.125%, sc0.25%, sc0.5%, sc1%, sc2%) after 8 weeks. The serum antioxidant enzyme activities analysis showed that dietary S. chinensis could reduce oxidative stress and increase organismic antioxidant capacity. Meanwhile, the detected results of muscle components presented that the amino acids and two flavor nucleotides of GMP and IMP significantly elevated while muscle crude lipid significantly reduced in S. chinensis feeding groups. In addition, springiness, chewiness, and fiber density in S. chinensis feeding groups muscle were significantly upregulated while muscle fiber diameter and area showed an opposite trend. By comparative transcriptome analysis of the muscles, functional enrichments of differentially expressed genes showed that multiple terms were related to purine metabolism, glycerolipid metabolism, regulation of actin cytoskeleton, and peroxisome. Finally, some key hub genes such as egln, gst, ggct, su1b, pi3kr4, myh9, lpl, gcdh, mylk, and col4a were identified by weighted gene co-expression network analysis. Taken together, our findings facilitate the understanding of the molecular basis underlying the muscle quality effect of dietary S. chinensis in triploid crucian carp, which provides valuable insights into the nutritional strategies of the aquaculture industry. Show less
Learning effective molecular feature representation to facilitate molecular property prediction is of great significance for drug discovery. Recently, there has been a surge of interest in pre-trainin Show more
Learning effective molecular feature representation to facilitate molecular property prediction is of great significance for drug discovery. Recently, there has been a surge of interest in pre-training graph neural networks (GNNs) via self-supervised learning techniques to overcome the challenge of data scarcity in molecular property prediction. However, current self-supervised learning-based methods suffer from two main obstacles: the lack of a well-defined self-supervised learning strategy and the limited capacity of GNNs. Here, we propose Knowledge-guided Pre-training of Graph Transformer (KPGT), a self-supervised learning framework to alleviate the aforementioned issues and provide generalizable and robust molecular representations. The KPGT framework integrates a graph transformer specifically designed for molecular graphs and a knowledge-guided pre-training strategy, to fully capture both structural and semantic knowledge of molecules. Through extensive computational tests on 63 datasets, KPGT exhibits superior performance in predicting molecular properties across various domains. Moreover, the practical applicability of KPGT in drug discovery has been validated by identifying potential inhibitors of two antitumor targets: hematopoietic progenitor kinase 1 (HPK1) and fibroblast growth factor receptor 1 (FGFR1). Overall, KPGT can provide a powerful and useful tool for advancing the artificial intelligence (AI)-aided drug discovery process. Show less
Our previous study found that increased serum IL-27 could promote rheumatoid arthritis (RA) B cell dysfunction via activating mTOR signaling pathway. This study aimed to explore the effects of IL-27 o Show more
Our previous study found that increased serum IL-27 could promote rheumatoid arthritis (RA) B cell dysfunction via activating mTOR signaling pathway. This study aimed to explore the effects of IL-27 on B cell metabolism and clarify the mechanisms via which IL-27 enhancing glycolysis to induce B cells hyperactivation. Peripheral CD19 Show less
Branched-chain fatty acids (BCFAs) are natural components with a variety of biological activities. However, the regulation of lipid metabolism by BCFAs is unknown. It was dedicated to examining the im Show more
Branched-chain fatty acids (BCFAs) are natural components with a variety of biological activities. However, the regulation of lipid metabolism by BCFAs is unknown. It was dedicated to examining the impacts of BCFAs inferred from yak ghee on the expression of qualities related to lipid metabolism, natural pathways, and intestinal microbiota in mice. The treatment group (purified BCFAs from yak ghee) exhibited a decrease in cholesterol levels; a decrease in Show less
Wen Zheng, Wenjun Li, Yini Zeng+7 more · 2023 · Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · added 2026-04-24
Restoration of blood circulation within "time window" is the principal treating goal for treating acute ischemic stroke. Previous studies revealed that delayed recanalization might cause serious ische Show more
Restoration of blood circulation within "time window" is the principal treating goal for treating acute ischemic stroke. Previous studies revealed that delayed recanalization might cause serious ischemia/reperfusion injury. However, plenty of evidences showed delayed recanalization improved neurological outcomes in acute ischemic stroke. This study aims to explore the role of delayed recanalization on blood-brain barrier (BBB) in the penumbra (surrounding ischemic core) and neurological outcomes after middle cerebral artery occlusion (MCAO). Recanalization was performed on the 3rd day after MCAO. BBB disruption was tested by Western blotting, Evans blue dye, and immunofluorescence staining. Infarct volume and neurological outcomes were evaluated on the 7th day after MCAO. The expression of fibroblast growth factor 21 (FGF21), fibroblast growth factor receptor 1 (FGFR1), phosphatidylinositol-3-kinase (PI3K), and serine/threonine kinase (Akt) in the penumbra were observed by immunofluorescence staining and/or Western blotting. The extraversion of Evans blue, IgG, and albumin increased surrounding ischemic core after MCAO, but significantly decreased after recanalization. The expression of Claudin-5, Occludin, and zona occludens 1 (ZO-1) decreased surrounding ischemic core after MCAO, but significantly increased after recanalization. Infarct volume reduced and neurological outcomes improved following recanalization (on the 7th day after MCAO). The expressions of Claudin-5, Occludin, and ZO-1 decreased surrounding ischemic core following MCAO, which were up-regulated corresponding to the increases of FGF21, p-FGFR1, PI3K, and p-Akt after recanalization. Intra-cerebroventricular injection of FGFR1 inhibitor SU5402 down-regulated the expression of PI3K, p-Akt, Occludin, Claudin-5, and ZO-1 in the penumbra, which weakened the beneficial effects of recanalization on neurological outcomes after MCAO. Delayed recanalization on the 3rd day after MCAO increases endogenous FGF21 in the penumbra and activates FGFR1/PI3K/Akt pathway, which attenuates BBB disruption in the penumbra and improves neurobehavior in MCAO rats. Show less
Melanocortin 3 and 4 receptors are two important neural G protein-coupled receptors that regulate energy homeostasis in vertebrates. Melanocortin receptor accessory protein 2 (MRAP2) is also involved Show more
Melanocortin 3 and 4 receptors are two important neural G protein-coupled receptors that regulate energy homeostasis in vertebrates. Melanocortin receptor accessory protein 2 (MRAP2) is also involved in the regulation of food intake and body weight as a variable regulator of melanocortin receptors. Rainbow trout (Oncorhynchus mykiss) is a valuable cold-water fish cultured worldwide. In the rainbow trout model, we cloned and identified mrap2a, a paralog of mrap2. Rainbow trout mrap2a consisted of a 690 bp ORF and was expected to encode a putative protein of 229 amino acids. The qPCR results showed that rainbow trout mrap2a was expressed at high levels in brain tissue similar to mc3r and mc4r. In addition, co-immunoprecipitation verified that MRAP2a interacts with MC3R and MC4R in vitro and that MRAP2a is involved in and regulates the constitutive activity and signaling of MC3R and MC4R. MRAP2a reduced constitutive and agonist-stimulated cAMP levels of MC3R; furthermore, MRAP2a increased constitutive ERK1/2 activation but reduced ligand-induced stimulation at high levels of expression. For MC4R, MRAP2a showed decreased cAMP basal activity but increased agonist-stimulated cAMP signaling and increased ACTH ligand sensitivity. However, MRAP2a failed to affect MC4R constitutive activity and agonist-induced ERK1/2 signaling. Undoubtedly, our study will have great significance for revealing the conserved role of MC4R and MC3R signaling in teleost fish, especially in cold-water fish growth and energy homeostasis. Show less
Therapies for cholangiocarcinoma are largely limited and ineffective. Herein, we examined the role of the FGF and VEGF pathways in regulating lymphangiogenesis and PD-L1 expression in intrahepatic cho Show more
Therapies for cholangiocarcinoma are largely limited and ineffective. Herein, we examined the role of the FGF and VEGF pathways in regulating lymphangiogenesis and PD-L1 expression in intrahepatic cholangiocarcinoma (iCCA). The lymphangiogenic functions of FGF and VEGF were evaluated in lymphatic endothelial cells (LECs) and iCCA xenograft mouse models. The relationship between VEGF and hexokinase 2 (HK2) was validated in LECs by western blot, immunofluorescence, ChIP and luciferase reporter assays. The efficacy of the combination therapy was assessed in LECs and xenograft models. Microarray analysis was used to evaluate the pathological relationships of FGFR1 and VEGFR3 with HK2 in human lymphatic vessels. FGF promoted lymphangiogenesis through c-MYC-dependent modulation of HK2 expression. VEGFC also upregulated HK2 expression. Mechanistically, VEGFC phosphorylated components of the PI3K/Akt/mTOR axis to upregulate HIF-1α expression at the translational level, and HIF-1α then bound to the HK2 promoter region to activate its transcription. More importantly, dual FGFR and VEGFR inhibition with infigratinib and SAR131675 almost completely inhibited lymphangiogenesis, and significantly suppressed iCCA tumor growth and progression by reducing PD-L1 expression in LECs. Dual FGFR and VEGFR inhibition inhibits lymphangiogenesis through suppression of c-MYC-dependent and HIF-1α-mediated HK2 expression, respectively. HK2 downregulation decreased glycolytic activity and further attenuated PD-L1 expression. Our findings suggest that dual FGFR and VEGFR blockade is an effective novel combination strategy to inhibit lymphangiogenesis and improve immunocompetence in iCCA. Show less
The glucocorticoid receptor (GR) is an important anti-cancer target in lymphoid cancers but has been understudied in solid tumors like lung cancer, although glucocorticoids are often given with chemot Show more
The glucocorticoid receptor (GR) is an important anti-cancer target in lymphoid cancers but has been understudied in solid tumors like lung cancer, although glucocorticoids are often given with chemotherapy regimens to mitigate side effects. Here, we identify a dexamethasone-GR mediated anti-cancer response in a subset of aggressive non-small cell lung cancers (NSCLCs) that harbor Serine/Threonine Kinase 11 (STK11/LKB1) mutations. High tumor expression of carbamoyl phosphate synthase 1 (CPS1) was strongly linked to the presence of LKB1 mutations, was the best predictor of NSCLC dexamethasone (DEX) sensitivity ( Show less
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and Show more
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate Show less
Several studies have confirmed that the pathophysiological progression of Alzheimer's disease (AD) is closely related to changes in the intestinal microbiota; thus, modifying the intestinal microbiota Show more
Several studies have confirmed that the pathophysiological progression of Alzheimer's disease (AD) is closely related to changes in the intestinal microbiota; thus, modifying the intestinal microbiota has emerged as a new way to treat AD. Effective interventions for gut microbiota include the application of probiotics and other measures such as fecal microbiota transplantation (FMT). However, the application of probiotics ignores that the intestine is a complete microecosystem with competition among microorganisms. FMT also has issues when applied to patient treatment. In a previous study, we found that eight species of bacteria that are isolated with high frequency in the normal intestinal microbiota (i.e., intestinal dominant microbiota) have biological activities consistent with the effects of FMT. In this article, we confirmed that the treatment of intestinal dominant microbiota significantly restored intestinal microbiota abundance and composition to normal levels in APP/PS1 mice; downregulated brain tissue pro-inflammatory cytokines (IL-1β and IL-6) and amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE1) expression levels; and reduced the area of Aβ plaque deposition in the brain hippocampus. Our study provides a new therapeutic concept for the treatment of AD, adjusting the intestinal microecological balance through dominant intestinal microbiota may be an alternative to FMT. Show less
Jie Li, Lijuan Zhang, Yun Tao+3 more · 2023 · European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · Elsevier · added 2026-04-24
Hepatocellular carcinoma (HCC) is a serious life-threatened tumor with high morbidity and mortality. This study aimed to study the effects of combination TACE and anti-PD-L1 liposome drug in treating Show more
Hepatocellular carcinoma (HCC) is a serious life-threatened tumor with high morbidity and mortality. This study aimed to study the effects of combination TACE and anti-PD-L1 liposome drug in treating HCC in mice models. We constructed the liposome drug with phosphatidylcholine and cholesterol and mannitol, etc. Besides, the HCC mice model was established through abdominal subcutaneous injection HepG2 cancer cells in mice, then the PE-10 polyethylene catheter was used for TACE therapy. The mice were separately received transcatheter arterial chemoembolization treatment, avelumab liposome drug therapy, and TACE combined with avelumab liposome drug therapy. Flow cytometry was used to analyze cell apoptosis. Western blot, Immunofluorescence staining, real-time PCR were performed to detect protein and gene expressions. The liposomes drug was successfully constructed with a diameter of (125.5 ± 15.3) nm. After the mice received TACE and (or) immunotherapy, the combined liposome drug therapy significantly reduced the volume of hepatic carcinoma tissues, besides, the apoptotic rate of hepatic carcinoma cells in the combined liposome drug treatment group was increased obviously compared with other groups. Moreover, the protein TGFβR2 located in the cellular membrane was obviously down-regulated in the combined liposome drug therapy, while the expression of SMAD7 and PTPN14 was up-regulated in the treatment groups compared with the mice without treatment, besides, the protein PTPN14 was mainly located in the nucleus. Additionally, the mRNA expression of genes SNAI1 and Vimentin was significantly down-regulated in the combined liposome drug therapy. Combination of transcatheter arterial chemoembolization and anti-PD-L1 liposome drug therapy significantly suppressed hepatocellular carcinoma proliferation and metastasis in mice models. Show less
Poor outcomes have been widely reported for younger vs. older breast cancer patients, but whether this is due to age itself or the enrichment of aggressive clinical features remains controversial. We Show more
Poor outcomes have been widely reported for younger vs. older breast cancer patients, but whether this is due to age itself or the enrichment of aggressive clinical features remains controversial. We have evaluated the clinicopathologic characteristics and genomic profiles of real-world hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) patients to examine the determinants of outcome for younger vs. older patients in a single clinical subtype undergoing treatment in the same clinic. This study included patients presenting at the Peking University Cancer Hospital with primary stage IV or first-line metastatic HR+/HER2- breast cancer who consented to an additional blood draw for genomic profiling prior to treatment. Plasma samples were analyzed with a targeted 152-gene NGS panel to assess somatic circulating tumor DNA (ctDNA) alterations. Genomic DNA (gDNA) extracted from peripheral blood mononuclear cells was analyzed for germline variants using a targeted 600-gene NGS panel. Kaplan-Meier survival analysis was performed to analyze disease free survival (DFS), progression free survival (PFS) and overall survival (OS) in association with clinicopathologic and genomic variables. Sixty-three patients presenting with HR+/HER2- MBC were enrolled in this study. Fourteen patients were < 40 years, 19 were 40-50 years, and 30 were > 50 years at the time of primary cancer diagnosis. No significant associations were observed between age and DFS, PFS or OS. Shorter OS was associated with In this group of real-world HR+/HER2- MBC breast cancer patients younger age was not associated with poor outcomes. While current guidelines recommend treatment decisions based on tumor biology rather than age, young HR+ breast cancer patients are more likely to receive chemotherapy. Our findings support the development of biomarker-driven treatment strategies for these patients. Show less
Fenghui Zhao, Kaini Hang, Qingtong Zhou+11 more · 2023 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maint Show more
Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 13 reported splice variants (SVs), more than half of which have sequence variations at either C or N terminus. To explore their roles in endogenous peptide-mediated GIPR signaling, we determined the cryoelectron microscopy (cryo-EM) structures of the two N terminus-altered SVs (referred as GIPR-202 and GIPR-209 in the Ensembl database, SV1 and SV2 here, respectively) and investigated the outcome of coexpressing each of them in question with GIPR in HEK293T cells with respect to ligand binding, receptor expression, cAMP (adenosine 3,5-cyclic monophosphate) accumulation, β-arrestin recruitment, and cell surface localization. It was found that while both N terminus-altered SVs of GIPR neither bound to the hormone nor elicited signal transduction per se, they suppressed ligand binding and cAMP accumulation of GIPR. Meanwhile, SV1 reduced GIPR-mediated β-arrestin 2 responses. The cryo-EM structures of SV1 and SV2 showed that they reorganized the extracellular halves of transmembrane helices 1, 6, and 7 and extracellular loops 2 and 3 to adopt a ligand-binding pocket-occupied conformation, thereby losing binding ability to the peptide. The results suggest a form of signal bias that is constitutive and ligand-independent, thus expanding our knowledge of biased signaling beyond pharmacological manipulation (i.e., ligand specific) as well as constitutive and ligand-independent (e.g., SV1 of the growth hormone-releasing hormone receptor). Show less
Colorectal cancer (CRC) is a fatal malignant tumor with poor prognosis. Cancer stem cells (CSCs) can cause metastasis, recurrence and drug resistance in CRC. This research aimed to analyze stemness-re Show more
Colorectal cancer (CRC) is a fatal malignant tumor with poor prognosis. Cancer stem cells (CSCs) can cause metastasis, recurrence and drug resistance in CRC. This research aimed to analyze stemness-related prognostic genes of CRC based on single-cell RNA-sequencing (scRNA-seq) data. DESeq2 was applied to analyze the differentially expressed genes (DEGs). The mRNA stemness index (mRNAsi) was calculated by one-class logistic regression (OCLR). The stemness-related cells were analyzed based on scRNA-seq dataset GSE166555. Monocle 2 algorithm was used for stemness-related cells pseudotime trajectory analysis. The stemness-related prognostic genes were analyzed by clusterProfiler and survival package. The stemness of CRC cells was detected by spheroid formation assay, and the expression of stemness-related prognostic genes was verified by qRT-PCR and Western blot. 7916 DEGs between the CRC and normal tissues were obtained. The mRNAsi of the CRC tissues was shown to be significantly higher than that of the normal tissues. 7 and 8 cell types were annotated respectively in the normal and CRC tissues through analysis of the scRNA-seq data. Cell-cell interactions (CCIs) in the tumor tissues were revealed to be significantly enhanced than that in the normal tissues. By calculating the 'stemness score', CSCs, epithelial cells (EPCs) and cancer-associated fibroblasts (CAFs) were defined as stemness-related cells. Through pseudotime trajectory analysis, 2111 genes were identified as state 2-specific genes. Then, 41 genes were obtained by taking intersection of the up-regulated genes with state 2-specific genes and marker genes of CSCs, EPCs and CAFs. The univariate COX regression analysis revealed 5 stemness-related prognostic genes (TIMP1, PGF, FSTL3, SNAI1 and FOXC1). Kaplan-Meier curve analysis indicated that the higher the expression of 5 genes, the lower the survival rate. In vitro cell experiment confirmed that the expression of TIMP1, PGF and SNAI1 was consistent with that revealed by bioinformatics analysis. TIMP1, PGF and SNAI1 were identified as stemness-related prognostic genes of CRC, and possibly potential therapeutic targets for CRC. Show less
Analysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient's treatment course. We Show more
Analysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient's treatment course. We evaluated whether the presence of specific gene amplifications (GAs) and plasma copy number (PCN) alterations are associated with disease features. This is a single-institution retrospective study of patients with mPC who underwent ctDNA profiling using Guardant360 The presence of liver and/or lung metastases was associated with GAs of The association of select GAs with survival provides an additional tool for assessing mCRPC prognosis and informing management. Serial monitoring of ctDNA GAs is also useful to guide prognosis and therapeutic response. Show less
Gestational diabetes mellitus (GDM) refers to abnormal glucose tolerance that occurs or is firstly diagnosed during pregnancy. GDM is related to various adverse pregnancy outcomes, but GDM pathogeny h Show more
Gestational diabetes mellitus (GDM) refers to abnormal glucose tolerance that occurs or is firstly diagnosed during pregnancy. GDM is related to various adverse pregnancy outcomes, but GDM pathogeny has not been fully elucidated. Nevertheless, previous studies have observed that many proteins in the placentas of patients with GDM are dysregulated. The present study aimed to establish a novel differentially expressed protein (DEP) landscape of GDM and normal maternal placentas and to explore the possible connection between DEPs and GDM pathogenesis. This study provides new insights into the mechanism of GDM and should make an important contribution to the development of biomarkers. The morphological characteristics of the placenta were observed on 30 GDM and normal maternal placental tissues stained with haematoxylin and eosin. Isobaric tags for relative and absolute quantitation (iTRAQ) was used in the proteomics screening of the DEPs of the normal and GDM maternal placentas. Bioinformatics analysis was performed on the DEPs, and parallel reaction monitoring (PRM) was performed to verify the DEPs. Finally, the quantitative analysis of iTRAQ and PRM was verified by immunohistochemical assay. A total of 68 DEPs in the GDM placenta were identified with iTRAQ proteomics experiment, comprising 21 up-regulated and 47 down-regulated DEPs. Bioinformatics analysis showed that the regulation of transport, catabolic process of non-coding RNA, cytoskeleton and cell binding were the most abundant Gene Ontology terms, and RNA degradation was an important pathway for significant enrichment. Protein-protein interaction network analysis showed that heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1), heterogeneous nuclear ribonucleoprotein A/B (HNRNPAB), heterogeneous nuclear ribonucleoprotein L (HNRNPL) and heterogeneous nuclear ribonucleoprotein A3 (HNRNPA3) were the cores of the up-regulated proteins. Band 3 anion transport protein (SLC4A1), spectrin beta chain erythrocytic (SPTB), ankyrin-1 (ANK1), spectrin beta chain non-erythrocytic 2 (SPTBN2), D-3-phosphoglycerate dehydrogenase (PHGDH) and exosome complex component RRP42 (EXOSC7) were the cores of the down-regulated proteins. These proteins are involved in the binding, splicing, processing, transport and degradation of RNA and in the formation and maintenance of the cytoskeleton. PRM verification results showed that seven proteins, namely, epiplakin (EPPK1), cold-inducible RNA-binding protein (CIRBP), HNRNPA2B1, HNRNPAB, HNRNPL, Ras-related protein Rab-21 (RAB21) and Ras-related protein Rab-3B (RAB3B), were up-regulated, whereas SPTB and SLC4A1 were down-regulated. The results of immunohistochemical assay also showed that the expression of five proteins, namely EPPK1, HNRNPA2B1, HNRNPAB, CIRBP and RAB21, were significantly higher in GDM placental tissues (P < 0.01). The GDM placentas showed changes in the morphological evaluation, including poor villous maturation, obvious increase in the number of syncytiotrophoblast nodules, thickening of the wall of dry villous arterioles with lumen stenosis, increased fibrinous exudation and excessive filling of villous interstitial vessels. Differentially expressed proteins related to a variety of biological processes in the GDM placenta were found. Fourteen proteins, namely, HNRNPA2B1, HNRNPAB, HNRNPL, HNRNPA3, EPPK1, CIRBP, RAB21, RAB3B, SLC4A1, SPTB, ANK1, SPTBN2, PHGDH and EXOSC7, which were differentially expressed in the placenta, may play an important role in regulating the occurrence and development of gestational diabetes through multi-channel and multi-link regulation. Show less
Mucosal delivery of IL-27 has been shown to have a therapeutic benefit in murine models of inflammatory bowel disease (IBD). The IL-27 effect was associated with phosphorylated STAT1 (pSTAT1), a produ Show more
Mucosal delivery of IL-27 has been shown to have a therapeutic benefit in murine models of inflammatory bowel disease (IBD). The IL-27 effect was associated with phosphorylated STAT1 (pSTAT1), a product of IL27 receptor signaling, in bowel tissue. To determine whether IL-27 acted directly on colonic epithelium, murine colonoids and primary intact colonic crypts were shown to be unresponsive to IL-27 Show less
LMNA gene encodes lamin A/C protein which participates in the construction of nuclear lamina, the mutations of LMNA result in a wide variety of diseases known as laminopathies. LMNA-related dilated ca Show more
LMNA gene encodes lamin A/C protein which participates in the construction of nuclear lamina, the mutations of LMNA result in a wide variety of diseases known as laminopathies. LMNA-related dilated cardiomyopathy(LMNA-DCM) is one of the more common laminopathy which characterized by progressive heart failure and arrhythmia. However, the mutation features of LMNA-DCM are yet to be elucidated. Herein we described a dilated cardiomyopathy family carrying novel variant c.467G > C(p.Arg156Pro) of LMNA as heterozygous pathogenic variant identified by whole-exome sequencing. With the help of Alphafold2, we predicted mutant protein structure and found an interrupted α-helix region in lamin A/C. In the analysis of 49 confirmed pathogenic missense of laminopathies, Chi-square test showed the DCM phenotype was related to the α-helix region mutation (p < 0.017). After screening the differentially expressed genes (DEGs) in both mice models and human patients in Gene Expression Omnibus database, we found the variation of α-helix-coding region in LMNA caused abnormal transcriptomic features in cell migration, collagen-containing extracellular matrix, and PI3K-Akt signaling pathway. Subsequently we constructed (TF)-mRNA-microRNA (miRNA) regulatory network and identified 7 key genes (FMOD, CYP1B1, CA3, F2RL1, HAPLIN1, SNAP91, and KANSL1) as potential biomarkers or therapeutic targets in LMNA-DCM patients. Show less
Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear funct Show more
Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear functions. This study aims to explore the role of AQP11 in the pathogenesis of intracellular edema of Müller glia in diabetic retinopathy (DR). Here, we found that AQP11 expression, primarily located at the endfeet of Müller glia, was down-regulated with diabetes progression, accompanied by intracellular edema, which was alleviated by intravitreal injection of lentivirus-mediated AQP11 overexpression. Similarly, intracellular edema of hypoxia-treated rat Müller cell line (rMC-1) was aggravated by AQP11 inhibition, while attenuated by AQP11 overexpression, accompanied by enhanced function in glutamate metabolism and reduced cell death. The down-regulation of AQP11 was also verified in the Müller glia from the epiretinal membranes (ERMs) of proliferative DR (PDR) patients. Mechanistically, down-regulation of AQP11 in DR was mediated by the HIF-1α-dependent and independent miRNA-AQP11 axis. Overall, we deciphered the AQP11 down-regulation, mediated by miRNA-AQP11 axis, resulted in Müller drainage dysfunction and subsequent intracellular edema in DR, which was partially reversed by AQP11 overexpression. Our findings propose a novel mechanism for the pathogenesis of DME, thus targeting AQP11 regulation provides a new therapeutic strategy for DME. Show less
The promotion of intersystem crossing (ISC) is critical for achieving a high-efficiency long-persistent luminescence (LPL) from organic materials. However, the use of a transition-metal complex for LP Show more
The promotion of intersystem crossing (ISC) is critical for achieving a high-efficiency long-persistent luminescence (LPL) from organic materials. However, the use of a transition-metal complex for LPL materials has not been explored because it can also shorten the emission lifetime by accelerating the phosphorescence decay. Here, we report a new class of LPL materials by doping a monovalent Au-carbene complex into a boron-embedded molecular host. The donor-acceptor systems exhibit photoluminescence with both high efficiencies (>57 %) and long lifetimes (ca. 40 ms) at room temperature. It is revealed that the Au atom promotes the population of low-lying triplet excited states of the host aggregate (T Show less
Tumor heterogeneity is jointly determined by the components of the tumor ecosystem (TES) including tumor cells, immune cells, stromal cells, and non-cellular components. We aimed to identify subtypes Show more
Tumor heterogeneity is jointly determined by the components of the tumor ecosystem (TES) including tumor cells, immune cells, stromal cells, and non-cellular components. We aimed to identify subtypes using TES-related genes and determine subtype specific drivers and treatments for hepatocellular carcinoma (HCC). We collected 68 genesets depicting tumor biology, immune infiltration, and liver function, totaling 2831 genes, and collected mRNA profiles and clinical data for over 6000 tumors from 65 datasets in the GEO, TCGA, ICGC, and several other databases. We designed a three-step clustering pipeline to identify subtypes. The microenvironment, genomic alteration, and drug response differences were systematically compared among subtypes. Seven subtypes (TES-1/2/3/4/5/6/7) were revealed in 159 tumors from the CHCC-HBV cohort. We constructed a single sample classifier using paired genes (sscpgsTES). TES subtypes were significantly associated with multiple clinical variables including etiology, and survival in 14 of 17 cohorts and the meta-cohort. TES-1 had the poorest prognosis and highest proliferation level. Both TES-2 and TES-7 were immune-enriched, however, TES-2 had a significantly worse prognosis, and hypoxic and immunosuppressive microenvironment. TES-4 had activated Wnt pathway, driven by CTNNB1 mutation. Good prognosis TES-6 exhibited the best differentiation. TES-5 and TES-3 were considered as novel subclasses by comparing with ten previous subtyping systems. TES-5 tumors had high AFP but good overall survival, and ∼45% of them harbored AXIN1 mutation. TES-3 was immune and stromal desert, may be driven by high copy number alteration burden, and had the poorest response to immune checkpoint inhibitor. TES-1 and TES-2 had significantly lower response to transarterial chemoembolization, but they showed significantly higher sensitivity to compound YM-155. Tumor ecosystem subtypes expand existing HCC subtyping systems, have distinct drivers, prognosis, and treatment vulnerabilities. Show less
A major consequence of acute myocardial infarction is myocardial ischemia-reperfusion (I/R) injury. Collecting proof demonstrates that AXIN1 assume a basic part in different disease; however, the role Show more
A major consequence of acute myocardial infarction is myocardial ischemia-reperfusion (I/R) injury. Collecting proof demonstrates that AXIN1 assume a basic part in different disease; however, the role of AXIN1 in I/R injury remains to a great extent obscure. The I/R injury model on AC16 cells was constructed. siRNA transfection was used to knockdown AXIN1. The qRT-PCR assays and western blot assays were used to detect the expression level of AXIN1 and other key proteins. CCK-8 assays and cell apoptosis assays were used to detect cell proliferation and cell apoptosis. AXIN1 was significantly overexpressed in an in vitro model of I/R injury. Knockdown of AXIN1 significantly restored the cell proliferation inhibition caused by IR injury, while inhibiting apoptosis and inflammation. Further mechanistic studies revealed that the transcription factor c-Myc could regulate the expression of AXIN1. The effects of I/R injury on AC16 cells after overexpression of c-Myc were reversed by knockdown of AXIN1. Meanwhile, AXIN1 could regulate the SIRT1/p53/Nrf 2 pathway. Our results show an important role for AXIN1 and provide new targets for avoiding and treating I/R injury. Show less
Hepatocellular carcinoma (HCC) remains imposing an enormous economic and healthcare burden worldwide. In this present study, we constructed and validated a novel autophagy-related gene signature to pr Show more
Hepatocellular carcinoma (HCC) remains imposing an enormous economic and healthcare burden worldwide. In this present study, we constructed and validated a novel autophagy-related gene signature to predict the recurrence of HCC patients. A total of 29 autophagy-related differentially expressed genes were identified. A five-gene signature (CLN3, HGF, TRIM22, SNRPD1, and SNRPE) was constructed for HCC recurrence prediction. Patients in high-risk groups exhibited a significantly poor prognosis compared with low-risk patients both in the training set (GSE14520 dataset) and the validation set (TCGA and GSE76427 dataset). Multivariate cox regression analysis demonstrated that the 5-gene signature was an independent risk factor for recurrence-free survival (RFS) in HCC patients. The nomograms incorporating 5-gene signature and clinical prognostic risk factors were able to effectively predict RFS. KEGG and GSEA analysis revealed that the high-risk group was enriched with multiple oncology characteristics and invasive-related pathways. Besides, the high-risk group had a higher level of immune cells and higher levels of immune checkpoint-related gene expression in the tumor microenvironment, suggesting that they might be more likely to benefit from immunotherapy. Finally, the immunohistochemistry and cell experiments confirmed the role of SNRPE, the most significant gene in the gene signature. SNRPE was significantly overexpressed in HCC. After SNRPE knockdown, the proliferation, migration and invasion ability of the HepG2 cell line were significantly inhibited. Our study established a novel five-gene signature and nomogram to predict RFS of HCC, which may help in clinical decision-making for individual treatment. Show less