Acute histoplasmosis is a rare fungal disease in China. This study is aimed to summarize the clinical characteristics of the first large-scale outbreak of imported acute histoplasmosis in Chinese, so Show more
Acute histoplasmosis is a rare fungal disease in China. This study is aimed to summarize the clinical characteristics of the first large-scale outbreak of imported acute histoplasmosis in Chinese, so as to provide suggestions for clinical diagnosis and treatment. We collected the symptoms, signs, laboratory examination and imaging data of 10 patients in so far the biggest outbreak of imported acute histoplasmosis in immunocompetent Chinese. Their clinical characteristics and time-varying cytokine/chemokine levels were analyzed, and rank correlation analysis between these markers was utilized to show their condition. The 10 patients of imported acute histoplasmosis were working without any respiratory protection in an abandoned mine tunnel in Guyana. The most common symptoms were fever and cough. Their chest CT imaging showed multiple nodular shadows in lungs. Laboratory examination showed that at admission the CRP, PCT, LDH, CysC, G-test, β2-MG were all increased in at least 9 patients, and the CD4/CD8 was decreased to < 1 in all patients. Most cytokines/chemokines (other than IL-4, IL-12, INF-α, TNF-α) varied widely with patients and time, but their overall trend is higher at admission and decreasing gradually during hospitalization, especially for the IL-6, IL-8, IL-10 and IFN-γ. The LDH, CysC, G-test, β2-MG, N/L, IL-6, IL-8, IL-10, IFN-γ, IL-27 are in positive associations to both CRP and PCT. The diagnosis of acute histoplasmosis needs a comprehensive analysis of epidemiological history, clinical symptoms and signs, and results of imaging, laboratory, microbiological and pathological examinations. Although none of the CRP, PCT, G-test, N/L, LDH, CysC, β2-MG, IL-6, IL-8, IL-10, IFN-γ shows specificity in the diagnosis of acute histoplasmosis, there is possibility that the above factors might help in the inflammation and prognosis estimation. However, more studies and further investigation are still required for the verification. Show less
To investigate the correlation between interleukin-27 and CXCL10 and other cytokines in pulmonary tuberculosis and to further explore the related miRNAs through bioinformatics. Collect the lesion tiss Show more
To investigate the correlation between interleukin-27 and CXCL10 and other cytokines in pulmonary tuberculosis and to further explore the related miRNAs through bioinformatics. Collect the lesion tissue and peripheral blood of pulmonary tuberculosis patients and the peripheral blood of healthy controls. Immunohistochemical staining and qRT-PCR were used to observe the expression of interleukin-27, CXCL9, CXCL10, and CXCL11. Then, predict the key miRNA, qRT-PCR was used to verify the expression of miRNA in the peripheral blood and evaluated the correlation between them. Both immunohistochemical staining and qRT-PCR indicated that the expressions of IL-27, CXCL9, CXCL10, and CXCL11 were significantly increased in tuberculosis patients, and IL-27 was significantly correlated with CXCL10 ( Our data shows that interleukin-27 and CXCL10 are significantly related in pulmonary tuberculosis, and has-let-7b-5p and has-miR-30a-3p are also related to interleukin-27 and CXCL10. It laid the foundation for subsequently exploiting the potential biomarkers in tuberculosis disease. Show less
The poor prognosis of hepatocellular carcinoma (HCC) could be attributed to its high metastasis rate. Here, we report the role of nucleoredoxin (NXN), a multifunctional redox-active protein, in HCC me Show more
The poor prognosis of hepatocellular carcinoma (HCC) could be attributed to its high metastasis rate. Here, we report the role of nucleoredoxin (NXN), a multifunctional redox-active protein, in HCC metastasis. The expression of NXN in HCC tissues was measured by immunohistochemistry. The role of NXN on HCC proliferation was determined by CCK-8, EdU and colony formation assays in vitro and subcutaneous tumor formation model in vivo. Transwell and wound healing assays and tail vein injection model were performed to assess the function of NXN on HCC metastasis. Co-immunoprecipitation assay was performed to examine the interaction among NXN, Snail and DUB3. Our results showed that NXN was downregulated in HCC tissues compared to adjacent liver tissues. Patients with low NXN expression had shorter overall survival (OS) time (P < 0.001) than those with high NXN expression. Biologically, ectopic expression of NXN significantly inhibited the proliferation and metastasis of HCC cells both in vitro and in vivo by suppressing epithelial-mesenchymal transition (EMT). Mechanistically, NXN promoted the ubiquitin-proteasome-mediated degradation of Snail through interaction with DUB3. Further, depletion of Snail abolished NXN-inhibited cell proliferation and metastasis. In summary, NXN suppressed the proliferation and metastasis of HCC by inhibiting DUB3-mediated deubiquitylation of Snail protein. Our study demonstrates that NXN, DUB3 and Snail complex functioned as an important regulatory mechanism of HCC progression and indicates a potential therapeutic approach for the treatment of HCC metastasis. Show less
Hypertension is a leading risk factor of cardiovascular disease and mortality in the population worldwide. Recently, hundreds of genomic loci were reported for hypertension by GWAS, however, the most Show more
Hypertension is a leading risk factor of cardiovascular disease and mortality in the population worldwide. Recently, hundreds of genomic loci were reported for hypertension by GWAS, however, the most SNPs are located in intergenic regions of genome, where a functional cause is difficult to determine. In the current study, a TWAS of hypertension was conducted using 452,264 individuals including 84,640 patients. KEGG and GO enrichment analyses were performed for the hypertension-related genes identified via TWAS. PPI network analysis based on the STRING database was also performed to detect TWAS-identified genes in hypertension. We have identified 18,420 genes from the GWAS summary data, and of those 1010 non-overlapping genes expression were significantly associated with hypertension after FDR correction (PFDR <0.05) in four tissues (left heart ventricle, aorta, whole blood, and peripheral blood). The KEGG and GO terms were mostly related to autoimmune mechanisms, and the autoimmune-related pathways have also been enriched using GO analysis for PPI genes. We further performed Mendelian randomization analysis, and the results supported a significant association between autoimmunity and hypertension. Moreover, 15 novel hypertension-susceptible genes were identified in all tissues, and five of the genes ( Show less
Arginyl-tRNA-protein transferase 1 (ATE1) catalyses N-terminal protein arginylation, a post-translational modification implicated in cell migration, invasion and the cellular stress response. Herein, Show more
Arginyl-tRNA-protein transferase 1 (ATE1) catalyses N-terminal protein arginylation, a post-translational modification implicated in cell migration, invasion and the cellular stress response. Herein, we report that ATE1 is overexpressed in NRAS-mutant melanomas, while it is downregulated in BRAF-mutant melanomas. ATE1 expression was higher in metastatic tumours, compared with primary tumours. Consistent with these findings, ATE1 depletion reduced melanoma cell viability, migration and colony formation. Reduced ATE1 expression also affected cell responses to mTOR and MEK inhibitors and to serum deprivation. Among putative ATE1 substrates is the tumour suppressor AXIN1, pointing to the possibility that ATE1 may fine-tune AXIN1 function in melanoma. Our findings highlight an unexpected role for ATE1 in melanoma cell aggressiveness and suggest that ATE1 constitutes a potential new therapeutic target. Show less
Growing pieces of evidence suggest that Alzheimer's disease (AD) is interlinked with Type 2 diabetes mellitus (DM), which has been described as "type 3 DM". In this study, we investigate the neuronal Show more
Growing pieces of evidence suggest that Alzheimer's disease (AD) is interlinked with Type 2 diabetes mellitus (DM), which has been described as "type 3 DM". In this study, we investigate the neuronal insult attributable to advanced glycation end products (AGEs) as the models of DM-related AD to understand the effects exerted by calycosin on neurodegenerative changes both in vivo and in vitro studies and also studied the associated molecular mechanisms. The results reported herein revealed that the viability of the PC12 cells induced by AGEs increased when treated with calycosin. It was also observed that the learning and memory abilities of AGE-induced DM-related AD rats improved under these conditions. Analysis of the reported results indicates that calycosin can effectively down-regulate the activity of GSK-3β to result in the reversal of the process of tau hyperphosphorylation, inhibit the expression of RAGE and BACE-1 proteins, resulting in a decrease in the production of β-amyloid and regulate the PGC-1α/TFAM signaling pathway to repair mitochondrial dysfunction. It can be inferred that calycosin can potentially exhibit important therapeutic properties that can be exploited during the treatment of AD, especially DM-related AD. Show less
Mei Wang, Shaoqi Xu, Ya Li+8 more · 2022 · Comparative biochemistry and physiology. Part A, Molecular & integrative physiology · Elsevier · added 2026-04-24
Amylin is a 37-amino acid polypeptide that has been found to be involved in feeding regulation in some mammals, birds, and goldfish. We cloned amylin of Siberian sturgeon and detected its distribution Show more
Amylin is a 37-amino acid polypeptide that has been found to be involved in feeding regulation in some mammals, birds, and goldfish. We cloned amylin of Siberian sturgeon and detected its distribution pattern in 15 tissues. The expression levels in the periprandial period (pre-and post-feeding), the changes in the food intake, and the expression levels of related appetite factors after the intraperitoneal injection of amylin were detected. The expression of amylin was found to be the highest in the hypothalamus. Compared with 1 h pre-feeding, the expression levels of amylin in the hypothalamus and duodenum were increased significantly 1 h post-feeding. Compared with the control group (saline), intraperitoneal injection of 50 ng/g, 100 ng/g, and 200 ng/g of amylin significantly inhibited food intake at 1 h post injection, but not at 3 h and 6 h. The injection of 50 ng/g, 100 ng/g, and 200 ng/g amylin significantly inhibited the cumulative feed. After 1 h of 50 ng/g amylin injection, the levels of MC4R and somatostatin in the hypothalamus increased significantly, while the levels of amylin and NPY decreased significantly. The levels of CCK in the valvular intestine were increased significantly. Insulin in the duodenum was also increased significantly, but there was no significant change in ghrelin in the duodenum. These results show that amylin inhibits feeding in Siberian sturgeon by down-regulating the appetite-stimulating factor NPY and up-regulating the appetite-suppressing factors somatostatin, MC4R, CCK, and insulin. This study provides a theoretical basis for studying the feeding function and action mechanisms of amylin in Siberian sturgeon. Show less
Neuroblastoma is the most common extracranial solid tumor of childhood, arising from the sympathetic nervous system. High-risk neuroblastoma (HRNB) remains a major therapeutic challenge with low survi Show more
Neuroblastoma is the most common extracranial solid tumor of childhood, arising from the sympathetic nervous system. High-risk neuroblastoma (HRNB) remains a major therapeutic challenge with low survival rates despite the intensification of therapy. This study aimed to develop a malignant-cell marker gene signature (MMGS) that might serve as a prognostic indicator in HRNB patients. Multi-omics datasets, including mRNA expression (single-cell and bulk), DNA methylation, and clinical information of HRNB patients, were used to identify prognostic malignant cell marker genes. MMGS was established by univariate Cox analysis, LASSO, and stepwise multivariable Cox regression analysis. Kaplan-Meier (KM) curve and time-dependent receiver operating characteristic curve (tROC) were used to evaluate the prognostic value and performance of MMGS, respectively. MMGS further verified its reliability and accuracy in the independent validation set. Finally, the characteristics of functional enrichment, tumor immune features, and inflammatory activity between different MMGS risk groups were also investigated. We constructed a prognostic model consisting of six malignant cell maker genes (MAPT, C1QTNF4, MEG3, NPW, RAMP1, and CDT1), which stratified patients into ultra-high-risk (UHR) and common-high-risk (CHR) group. Patients in the UHR group had significantly worse overall survival (OS) than those in the CHR group. MMGS was verified as an independent predictor for the OS of HRNB patients. The area under the curve (AUC) values of MMGS at 1-, 3-, and 5-year were 0.78, 0.693, and 0.618, respectively. Notably, functional enrichment, tumor immune features, and inflammatory activity analyses preliminarily indicated that the poor prognosis in the UHR group might result from the dysregulation of the metabolic process and immunosuppressive microenvironment. This study established a novel six-malignant cell maker gene prognostic model that can be used to predict the prognosis of HRNB patients, which may provide new insight for the treatment and personalized monitoring of HRNB patients. Show less
PIK3C3/VPS34 is a key player in macroautophagy/autophagy and MAP1LC3/LC3-associated phagocytosis (LAP), which play critical roles in dendritic cell (DC) function. In this study, we assessed the contri Show more
PIK3C3/VPS34 is a key player in macroautophagy/autophagy and MAP1LC3/LC3-associated phagocytosis (LAP), which play critical roles in dendritic cell (DC) function. In this study, we assessed the contribution of PIK3C3 to DC function during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We found that Show less
The search for potential gene loci that affect the pharmacodynamics and pharmacokinetics of ticagrelor is a matter of broad clinical interest. The objective of this study was to investigate the effect Show more
The search for potential gene loci that affect the pharmacodynamics and pharmacokinetics of ticagrelor is a matter of broad clinical interest. The objective of this study was to investigate the effect of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese subjects. This is a multi-center study in China, including three hospitals from Beijing, Nanchang, and Changsha. Healthy Chinese subjects aged 18-45 years with unknown genotypes were included. All subjects received a single oral dose of 90 mg of ticagrelor. Platelet aggregation and the area under the concentration-time curve for ticagrelor and its major active metabolite in plasma samples were assessed. Genome-wide association studies and candidate gene association analysis related to ticagrelor were performed. One hundred and seventy-five native Chinese subjects were enrolled and completed the study. According to the p value, the threshold of ticagrelor population was 6.57 × 10 Genetic variation affects the pharmacokinetics and pharmacodynamics of ticagrelor in healthy individuals. The detection of NUP153, SVEP1 gene variation will be helpful for pharmacodynamic prediction and evaluation, and the regulation of these genes may be the target of new drug development. Further studies are required to confirm the results and explore whether these single-nucleotide polymorphisms are associated only with platelet activity or also with cardiovascular events and all-cause mortality. NCT03161002. Show less
MicroRNAs (miRNAs) are a group of regulatory noncoding RNAs, serving as major regulators with a sequence-specific manner in multifarious biological processes. Although a series of viral families have Show more
MicroRNAs (miRNAs) are a group of regulatory noncoding RNAs, serving as major regulators with a sequence-specific manner in multifarious biological processes. Although a series of viral families have been proved to encode miRNAs, few reports were available regarding the function of ALV-J-encoded miRNA. Here, we reported a novel miRNA (designated ALV-miRNA-p19-01) in ALV-J-infected DF-1 cells. We found that ALV-miRNA-p19-01 is encoded by the genome of the ALV-J SCAU1903 strain (located at nucleotides site 779 to 801) in a classic miRNA biogenesis manner. The transfection of DF-1 cells with ALV-miRNA-p19-01 enhanced ALV-J replication, while the blockage of ALV-miRNA-p19-01 suppressed ALV-J replication. Furthermore, our data showed that ALV-miRNA-p19-01 promotes ALV-J replication by directly targeting the cellular gene dual specificity phosphatase 6 through regulating ERK2 activity. Show less
WW domain-containing E3 Ubiquitin-protein ligase 2 (WWP2) has been found to positively regulate odontoblastic differentiation by monoubiquitinating the transcription factor Kruppel-like factor 5 (KLF5 Show more
WW domain-containing E3 Ubiquitin-protein ligase 2 (WWP2) has been found to positively regulate odontoblastic differentiation by monoubiquitinating the transcription factor Kruppel-like factor 5 (KLF5) in a cell culture system. However, the in vivo role of WWP2 in mouse teeth remains unknown. To explore this, here we generated Wwp2 knockout (Wwp2 KO) mice. We found that molars in Wwp2 KO mice exhibited thinner dentin, widened predentin, and reduced numbers of dentinal tubules. In addition, expression of the odontoblast differentiation markers Dspp and Dmp1 was decreased in the odontoblast layers of Wwp2 KO mice. These findings demonstrate that WWP2 may facilitate odontoblast differentiation and dentinogenesis. Furthermore, we show for the first time that phosphatase and tensin homolog (PTEN), a tumor suppressor, is expressed in dental papilla cells and odontoblasts of mouse molars and acts as a negative regulator of odontoblastic differentiation. Further investigation indicated that PTEN is targeted by WWP2 for degradation during odontoblastic differentiation. We demonstrate PTEN physically interacts with and inhibits the transcriptional activity of KLF5 on Dspp and Dmp1. Finally, we found WWP2 was able to suppress the interaction between PTEN and KLF5, which diminished the inhibition effect of PTEN on KLF5. Taken together, this study confirms the essential role of WWP2 and the WWP2-PTEN-KLF5 signaling axis in odontoblast differentiation and dentinogenesis in vivo. Show less
Appropriate decidualization is of great importance for embryo implantation, placental development and successful pregnancy. Although it has been well-acknowledged that decidualization relies on activa Show more
Appropriate decidualization is of great importance for embryo implantation, placental development and successful pregnancy. Although it has been well-acknowledged that decidualization relies on activation of progesterone-mediated signaling pathway, the exact mechanisms have not been elucidated. Here, we demonstrated that both IL-27 and IL27RA were highly expressed in decidua than those in endometrium during secretory phase. Estrogen plus progesterone significantly upregulated the expression of IL-27 and IL-27RA in endometrium stromal cells (ESCs). In addition, inhibiting IL-27 signaling with IL-27 neutralization antibody (anti-IL-27) suppressed the expression of decidualization-related molecules, receptors of estrogen (gene coded by ESR) and progesterone (PGR) induced by cAMP or estrogen plus progesterone. Similar results were obtained from Il27ra Show less
Angiopoietin-like 4 (ANGPTL4) is highly expressed in a variety of neoplasms and promotes cancer progression. Nevertheless, the mechanism of ANGPTL4 in ovarian cancer (OC) metastasis remains unclear. T Show more
Angiopoietin-like 4 (ANGPTL4) is highly expressed in a variety of neoplasms and promotes cancer progression. Nevertheless, the mechanism of ANGPTL4 in ovarian cancer (OC) metastasis remains unclear. This study aimeds to explore whether ANGPTL4 regulates OC progression and elucidate the underlying mechanism. ANGPTL4 expression in clinical patient tumor samples was determined by immunohistochemistry (IHC) and high-throughput sequencing. ANGPTL4 knockdown (KD) and the addition of exogeneous cANGPTL4 protein were used to investigate its function. An in vivo xenograft tumor experiment was performed by intraperitoneal injection of SKOV3 cells transfected with short hairpin RNAs (shRNAs) targeting ANGPTL4 in nude mice. Western blotting and qRT-PCR were used to detect the levels of ANGPTL4, CDH5, p-AKT, AKT, ETV5, MMP2 and MMP9 in SKOV3 and HO8910 cells transfected with sh-ANGPTL4 or shRNAs targeting ETV5. Increased levels of ANGPTL4 were associated with poor prognosis and metastasis in OC and induced the angiogenesis and metastasis of OC cells both in vivo and in vitro. This tumorigenic effect was dependent on CDH5, and the expression levels of ANGPTL4 and CDH5 in human OC werepositively correlated. In addition, CDH5 activated p-AKT, and upregulated the expression of MMP2 and MMP9. We also found that the expression of ETV5 was upregulated by ANGPTL4, which could bind the promoter region of CDH5, leading to increased CDH5 expression. Our data indicated that an increase in the ANGPTL4 level results in increased ETV5 expression in OC, leading to metastasis via activation of the CDH5/AKT/MMP9 signaling pathway. Show less
A better understanding of the biological and environmental variables that contribute to exceptional longevity has the potential to inform the treatment of geriatric diseases and help achieve healthy a Show more
A better understanding of the biological and environmental variables that contribute to exceptional longevity has the potential to inform the treatment of geriatric diseases and help achieve healthy aging. Here, we compared the gut microbiome and blood metabolome of extremely long-lived individuals (94-105 years old) to that of their children (50-79 years old) in 116 Han Chinese families. We found extensive metagenomic and metabolomic remodeling in advanced age and observed a generational divergence in the correlations with socioeconomic factors. An analysis of quantitative trait loci revealed that genetic associations with metagenomic and metabolomic features were largely generation-specific, but we also found 131 plasma metabolic quantitative trait loci associations that were cross-generational with the genetic variants concentrated in six loci. These included associations between FADS1/2 and arachidonate, PTPA and succinylcarnitine and FLVCR1 and choline. Our characterization of the extensive metagenomic and metabolomic remodeling that occurs in people reaching extreme ages may offer new targets for aging-related interventions. Show less
Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by asthma-like attacks in its early stage, which is easily misdiagnosed as severe asthma. Therefore, new biomarkers for the early Show more
Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by asthma-like attacks in its early stage, which is easily misdiagnosed as severe asthma. Therefore, new biomarkers for the early diagnosis of EGPA are needed, especially for differentiating the diagnosis of asthma. To identify serum biomarkers that can be used for early diagnosis of EGPA and to distinguish EGPA from severe asthma. Data-independent acquisition (DIA) analysis was performed to identify 45 healthy controls (HC), severe asthma (S-A), and EGPA patients in a cohort to screen biomarkers for early diagnosis of EGPA and to differentiate asthma diagnosis. Subsequently, parallel reaction monitoring (PRM) analysis was applied to a validation cohort of 71 HC, S-A, and EGPA patients. Four candidate biomarkers were identified from DIA and PRM analysis-i.e., serum amyloid A1 (SAA1), fibrinogen-α (FGA), and serum amyloid P component (SAP)-and were upregulated in the EGPA group, while cholesteryl ester transfer protein (CETP) was downregulated in the EGPA group compared with the S-A group. Receiver operating characteristics analysis shows that, as biomarkers for early diagnosis of EGPA, the combination of SAA1, FGA, and SAP has an area under the curve (AUC) of 0.947, a sensitivity of 82.35%, and a specificity of 100%. The combination of SAA1, FGA, SAP, and CETP as biomarkers for differential diagnosis of asthma had an AUC of 0.921, a sensitivity of 78.13%, and a specificity of 100%, which were all larger than single markers. Moreover, SAA1, FGA, and SAP were positively and CETP was negatively correlated with eosinophil count. DIA-PRM combined analysis screened and validated four previously unexplored but potentially useful biomarkers for early diagnosis of EGPA and differential diagnosis of asthma. Show less
The aim of this study is to identify potential serum biomarkers of Alzheimer's disease (AD) for early diagnosis and to evaluate these markers on a large cohort. We performed two-dimensional difference Show more
The aim of this study is to identify potential serum biomarkers of Alzheimer's disease (AD) for early diagnosis and to evaluate these markers on a large cohort. We performed two-dimensional difference gel electrophoresis to compare the serum of AD patients and normal controls. Western blot or enzyme-linked immunosorbent assay (ELISA) was used to identify the expression levels of proteins. In this study, a total of 13 differentially expressed proteins were identified. Among them, 2 proteins (inter-alpha-trypsin inhibitor heavy chain H4 [ITI-H4], Apolipoprotein A-IV) were validated by Western blot and 4 proteins (Cofilin 2, Tetranectin, Zinc-alpha-2-glycoprotein [AZGP1], Alpha-1-microglobulin/bikunin precursor [AMBP]) were validated by ELISA, respectively. Western blot results showed that the full size of the ITI-H4 protein was increased, while a fragment of ITI-H4 was decreased in AD patients. In contrast, 1 fragment of Apo A-IV was mainly found in control group and rare to be detected in AD patients. On the other hand, ELISA results showed that Cofilin 2, Tetranectin, AZGP1, and AMBP were significantly increased in AD patients, and Cofilin 2 is strongly correlated with the Mini-Mental State Examination scores of the AD patients. Serum Cofilin 2 was unchanged in Parkinson disease patients as compared to the control group, indicating a specific correlation of serum Cofilin 2 with AD. Moreover, Cofilin 2 was increased in both the serum and brain tissue in the APP/PS1 transgenic mice. Our study identified several potential serum biomarkers of AD, including: ITI-H4, ApoA-IV, Cofilin 2, Tetranectin, AZGP1, and AMBP. Cofilin 2 was upregulated in different AD animal models and might play important roles in AD pathology. Show less
This study aims to explore the prognostic values of CT83 and CT83- related genes in lung adenocarcinoma (LUAD). We downloaded the mRNA profiles of 513 LUAD patients (RNA sequencing data) and 246 NSCLC Show more
This study aims to explore the prognostic values of CT83 and CT83- related genes in lung adenocarcinoma (LUAD). We downloaded the mRNA profiles of 513 LUAD patients (RNA sequencing data) and 246 NSCLC patients (Affymetrix Human Genome U133 Plus 2.0 Array) from TCGA and GEO databases. According to the median expression of CT83, the TCGA samples were divided into high and low expression groups, and differential expression analysis between them was performed. Functional enrichment analysis of differential expression genes (DEGs) was conducted. Univariate Cox regression analysis and LASSO Cox regression analysis were performed to screen the optimal prognostic DEGs. Then we established the prognostic model. A Nomogram model was constructed to predict the overall survival (OS) probability of LUAD patients. CT83 expression was significantly correlated to the prognosis of LUAD patients. A total of 59 DEGs were identified, and a predictive model was constructed based on six optimal CT83- related DEGs, including CPS1, RHOV, TNNT1, FAM83A, IGF2BP1, and GRIN2A, which could effectively predict the prognosis of LUAD patients. The nomogram could reliably predict the OS of LUAD patients. Moreover, the six important immune checkpoints (CTLA4, PD1, IDO1, TDO2, LAG3, and TIGIT) were closely correlated with the risk score, which were also differentially expressed between the LUAD samples with high and low risk scores, suggesting that the poor prognosis of LUAD patients with high risk score might be due to the immunosuppressive microenvironments. A prognostic model based on six optimal CT83 related genes could effectively predict the prognosis of LUAD patients. Show less
Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)-based therapy has n Show more
Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)-based therapy has never been investigated. It is found that overexpression of farnesoid X receptor (FXR), a main receptor for bile acids, improves the retention and cardioprotection of adipose tissue-derived MSC (ADSC) administered by intramyocardial injection in mice with myocardial infarction (MI), which shows enhanced antiapoptotic, proangiogenic, and antifibrotic effects. RNA sequencing, LC-MS/MS, and loss-of-function studies reveal that FXR overexpression promotes ADSC paracrine angiogenesis via Angptl4. FXR overexpression improves ADSC survival in vivo but fails in vitro. By performing bile acid-targeted metabolomics using ischemic heart tissue, 19 bile acids are identified. Among them, cholic acid and deoxycholic acid significantly increase Angptl4 secretion from ADSC overexpressing FXR and further improve their proangiogenic capability. Moreover, ADSC overexpressing FXR shows significantly lower apoptosis by upregulating Nqo-1 expression only in the presence of FXR ligands. Retinoid X receptor α is identified as a coactivator of FXR. It is first demonstrated that there is a bile acid pool in the myocardial microenvironment. Targeting the bile acid-FXR axis may be a novel strategy for improving the curative effect of MSC-based therapy for MI. Show less
Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists a Show more
Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20. Show less
Ren Zhang, Kezhong Zhang · 2022 · Progress in lipid research · Elsevier · added 2026-04-24
In mammals, triglyceride (TG), the main form of lipids for storing and providing energy, is stored in white adipose tissue (WAT) after food intake, while during fasting it is routed to oxidative tissu Show more
In mammals, triglyceride (TG), the main form of lipids for storing and providing energy, is stored in white adipose tissue (WAT) after food intake, while during fasting it is routed to oxidative tissues (heart and skeletal muscle) for energy production, a process referred to as TG partitioning. Lipoprotein lipase (LPL), a rate-limiting enzyme in this fundamental physiological process, hydrolyzes circulating TG to generate free fatty acids that are taken up by peripheral tissues. The postprandial activity of LPL declines in oxidative tissues but rises in WAT, directing TG to WAT; the reverse is true during fasting. However, the molecular mechanism in regulating tissue-specific LPL activity during the fed-fast cycle has not been completely understood. Research on angiopoietin-like (ANGPTL) proteins (A3, A4, and A8) has resulted in an ANGPTL3-4-8 model to explain the TG partitioning between WAT and oxidative tissues. Food intake induces A8 expression in the liver and WAT. Liver A8 activates A3 by forming the A3-8 complex, which is then secreted into the circulation. The A3-8 complex acts in an endocrine manner to inhibit LPL in oxidative tissues. WAT A8 forms the A4-8 complex, which acts locally to block A4's LPL-inhibiting activity. Therefore, the postprandial activity of LPL is low in oxidative tissues but high in WAT, directing circulating TG to WAT. Conversely, during fasting, reduced A8 expression in the liver and WAT disables A3 from inhibiting oxidative-tissue LPL and restores WAT A4's LPL-inhibiting activity, respectively. Thus, the fasting LPL activity is high in oxidative tissues but low in WAT, directing TG to the former. According to the model, we hypothesize that A8 antagonism has the potential to simultaneously reduce TG and increase HDL-cholesterol plasma levels. Future research on A3, A4, and A8 can hopefully provide more insights into human health, disease, and therapeutics. Show less
Salivary adenoid cystic carcinoma (SACC) is a malignant tumor, which is characterized by a higher incidence of distant metastasis. The aim of this study was to investigate the role and mechanism of pr Show more
Salivary adenoid cystic carcinoma (SACC) is a malignant tumor, which is characterized by a higher incidence of distant metastasis. The aim of this study was to investigate the role and mechanism of protein kinase D1 (PKD1) in regulating the epithelial-mesenchymal transition (EMT) and promotes the metastasis in SACC. We analyzed the expression of PKD1 in 40 SACC patients and different metastatic potential cell lines. Then, we investigated whether the migration and growth of SACC were regulated by PKD1 using shRNA interference or inhibition of kinase active in vitro cell. Moreover, the mechanism by which PKD1 regulates the stability of Snail protein was determined. Finally, nude mice were used to testify the function of PKD1 via tail vein injection. PKD1 was correlated with metastasis and poor prognosis of SACC patients. PKD1 inhibition attenuated proliferation, migration, invasion, and EMT of SACC cells. Conversely, kinase active PKD1 could induce EMT and promoted cell migration in human HSG cell. Furthermore, downregulation of PKD1 regulated Snail via phosphorylation at Ser-11 on Snail protein and promotion of proteasome-mediated degradation, and reduced lung metastasis in vivo. Our results suggest that PKD1 induces the EMT and promotes the metastasis, which illustrate that PKD1 may be a potential prognostic biomarker and serve as a potential therapeutic target for SACC patients. Show less
The skin serves as the interface between the body and the environment and plays a fundamental role in innate antimicrobial host immunity. Antiviral proteins (AVPs) are part of the innate host defense Show more
The skin serves as the interface between the body and the environment and plays a fundamental role in innate antimicrobial host immunity. Antiviral proteins (AVPs) are part of the innate host defense system and provide protection against viral pathogens. How breach of the skin barrier influences innate AVP production remains largely unknown. In this study, we characterized the induction and regulation of AVPs after skin injury and identified a key role of TRPV1 in this process. Transcriptional and phenotypic profiling of cutaneous wounds revealed that skin injury induces high levels of AVPs in both mice and humans. Remarkably, pharmacologic and genetic ablation of TRPV1-mediated nociception abrogated the induction of AVPs, including Oas2, Oasl2, and Isg15 after skin injury in mice. Conversely, stimulation of TRPV1 nociceptors was sufficient to induce AVP production involving the CD301b Show less
Guillain-Barré syndrome (GBS) is an acute inflammatory autoimmune and demyelinating disease of the peripheral nervous system. Currently, valid biomarkers are unavailable for the diagnosis of GBS. A co Show more
Guillain-Barré syndrome (GBS) is an acute inflammatory autoimmune and demyelinating disease of the peripheral nervous system. Currently, valid biomarkers are unavailable for the diagnosis of GBS. A comparative proteomics analysis was performed on the cerebrospinal fluid (CSF) from 10 patients with GBS and 10 patients with noninflammatory neurological disease (NND) using the tandem mass tags technique. The differentially expressed proteins were analyzed by bioinformatics, and then the candidate proteins were validated by the enzyme-linked immunosorbent assay method in another cohort containing 160 samples (paired CSF and plasma of 40 patients with GBS, CSF of 40 NND patients and plasma of 40 healthy individuals). In all, 298 proteins were successfully identified in the CSF samples, of which 97 differentially expressed proteins were identified in the GBS and NND groups. Three key molecules were identified as candidate molecules for further validation. The CSF levels of TGOLN2 and NCAM1 decreased in GBS patients compared with NND patients, whereas the CSF levels of APOC3 increased. The enzyme-linked immunosorbent assay results were consistent with our proteomics analysis. Interestingly, in the validation cohort, serum APOC3 levels in the GBS group were consistent with those in the CSF samples and significantly higher than those in the healthy control group. Our preliminary data suggest that the CSF protein expression profile of patients with GBS is different from that of patients with NND. Moreover, alterations of TGOLN2, NCAM1and APOC3 may be used as novel biomarkers for identifying patients with GBS. Show less
Risk of tumors of the breast, ovary, and meninges has been associated with hormonal factors and with one another. Genome-wide association studies (GWAS) identified a meningioma risk locus on 10p12 nea Show more
Risk of tumors of the breast, ovary, and meninges has been associated with hormonal factors and with one another. Genome-wide association studies (GWAS) identified a meningioma risk locus on 10p12 near previous GWAS hits for breast and ovarian cancers, raising the possibility of genetic pleiotropy. We performed imputation-based fine-mapping in three case-control datasets of meningioma (927 cases, 790 controls), female breast cancer (28 108 cases, 22 209 controls), and ovarian cancer (25 509 cases, 40 941 controls). Analyses were stratified by sex (meningioma), estrogen receptor (ER) status (breast), and histotype (ovarian), then combined using subset-based meta-analysis in ASSET. Lead variants were assessed for association with additional traits in UK Biobank to identify potential effect-mediators. Two-sided subset-based meta-analysis identified rs7084454, an expression quantitative trait locus (eQTL) near the We identify a Show less
Malignant meningiomas often show invasive growth that makes complete tumor resection challenging, and they are more prone to recur after radical resection. Invasive meningioma associated transcript 1 Show more
Malignant meningiomas often show invasive growth that makes complete tumor resection challenging, and they are more prone to recur after radical resection. Invasive meningioma associated transcript 1 (IMAT1) is a long noncoding RNA located on Show less
Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of Wh Show more
Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate analyses in 822 White and 687 Black study participants. Trans-ethnic meta-analysis was then applied to improve fine-mapping of potential causal variants. Mean estimated glomerular filtration rate was 44.4 and 41.5 mL/min/1.73m Show less
As the most prevalent aboriginal group on Hainan Island located between South China and the mainland of Southeast Asia, the Li people are believed to preserve some unique genetic information due to th Show more
As the most prevalent aboriginal group on Hainan Island located between South China and the mainland of Southeast Asia, the Li people are believed to preserve some unique genetic information due to their isolated circumstances, although this has been largely uninvestigated. We performed the first whole-genome sequencing of 55 Hainan Li (HNL) individuals with high coverage (∼30-50×) to gain insight into their genetic history and potential adaptations. We identified the ancestry enriched in HNL (∼85%) is well preserved in present-day Tai-Kadai speakers residing in South China and North Vietnam, that is, Bai-Yue populations. A lack of admixture signature due to the geographical restriction exacerbated the bottleneck in the present-day HNL. The genetic divergence among Bai-Yue populations began ∼4,000-3,000 years ago when the proto-HNL underwent migration and the settling of Hainan Island. Finally, we identified signatures of positive selection in the HNL, some outstanding examples included FADS1 and FADS2 related to a diet rich in polyunsaturated fatty acids. In addition, we observed that malaria-driven selection had occurred in the HNL, with population-specific variants of malaria-related genes (e.g., CR1) present. Interestingly, HNL harbors a high prevalence of malaria leveraged gene variants related to hematopoietic function (e.g., CD3G) that may explain the high incidence of blood disorders such as B-cell lymphomas in the present-day HNL. The results have advanced our understanding of the genetic history of the Bai-Yue populations and have provided new insights into the adaptive scenarios of the Li people. Show less
Pancreatic cancer (PC) is a highly devastating neoplasm due to its irrepressible characteristics and propensity to override the available treatment strategies. Rapid prevalence and enormous severity o Show more
Pancreatic cancer (PC) is a highly devastating neoplasm due to its irrepressible characteristics and propensity to override the available treatment strategies. Rapid prevalence and enormous severity of this cancer urgently demand the exploration of novel approaches for the development of effective therapeutic measures. Metabolic derangement is one of the hallmarks of cancers which restructures mitochondrial activities and biological pathways. Apart from their bioenergetic and biosynthetic functions, mitochondria are also implicated in a myriad of cellular functions including proliferation, differentiation, apoptosis, senescence, homeostasis, and other cell regulatory mechanisms. It has been noted that PC, like other types of cancers, exploits these activities in favor of tumor growth and survival by inducing mitochondrial dysfunctions such as mitochondrial-DNA mutation, metabolic enzyme modification, ROS generation, mitophagy, evasion of apoptosis, and mitochondrial biogenesis. During pancreatic carcinogenesis, a large number of onco-factors including Bcl-2 family proteins, NF-κB, HIFs, NRF2, NOX, MFNs, DRP1, DUSP6, Cyp-D, PARKIN, and others are dysregulated, resulting into reprogramming of metabolic pathways and cellular kinetics. Hence, targeted interventions in these metabolic derangements may present some effective anticancer approaches. The current review gives an insight into various mitochondrial disorders and their targetable molecules in PC which may provide certain novel opportunities in the pursuit of therapeutic development. Furthermore, we have also discussed certain treatment perspectives in PC based on specific mitochondrial activities. Show less