Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by their immat Show more
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by their immaturity and heterogeneity. To characterize the source of this heterogeneity, we applied complementary single-cell RNA-seq and bulk RNA-seq technologies over time during hiPSC cardiac differentiation and in the adult heart. Using integrated transcriptomic and splicing analysis, more than half a dozen distinct single-cell populations were observed, several of which were coincident at a single time-point, day 30 of differentiation. To dissect the role of distinct cardiac transcriptional regulators associated with each cell population, we systematically tested the effect of a gain or loss of three transcription factors (NR2F2, TBX5, and HEY2), using CRISPR genome editing and ChIP-seq, in conjunction with patch clamp, calcium imaging, and CyTOF analysis. These targets, data, and integrative genomics analysis methods provide a powerful platform for understanding in vitro cellular heterogeneity. Show less
Chun-Han Chen, Chun A Changou, Tsung-Han Hsieh+9 more · 2018 · Clinical cancer research : an official journal of the American Association for Cancer Research · added 2026-04-24
Multiple evidence has indicated that myelin injury is common in Alzheimer's disease (AD). However, whether myelin injury is an early event in AD and the relationship between it and cognitive function Show more
Multiple evidence has indicated that myelin injury is common in Alzheimer's disease (AD). However, whether myelin injury is an early event in AD and the relationship between it and cognitive function is still elusive. Spatial memory of 5XFAD mice was determined by Morris water maze at 1 and 3 months old. Meanwhile, the deposition of Aβ, the expression of myelin basic protein (MBP), LINGO-1, NgR, and myelin ultrastructure in many memory-associated brain regions were detected in one-month-old and three-month-old mice (before and after LINGO-1 antibody administration) using immunostaining, Western blot (WB), and transmission electron microscopy (TEM), respectively. No abnormal Aβ deposition was found in one-month-old 5XFAD mice. However, spatial memory deficits were proved in accordance with an obvious demyelination in memory-associated brain regions in one-month-old mice and both deteriorated with age. Administration of LINGO-1 antibody could obviously restore the myelin impairments in CA1 and DG region and partially ameliorate spatial memory deficits. Our results demonstrated that myelin injury was an early event in 5XFAD mice even prior to emergence of deposition of Aβ. Intervention with the LINGO-1 antibody could attenuate impaired spatial memory deficits by remyelination, which suggested that myelin injury was involved in spatial memory deficits and remyelination may be a potential therapeutic strategy in early stage of AD or mild cognitive impairments. Show less
Wei-Chan Hsu, Ming-Yu Chen, Shu-Ching Hsu+10 more · 2018 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Activated T cells undergo metabolic reprogramming and effector-cell differentiation but the factors involved are unclear. Utilizing mice lacking DUSP6 (DUSP6
Foot-and-mouth disease (FMD) is a highly contagious disease that results in enormous economic loses worldwide. Although the protection provided by vaccination is limited during early infection, it is Show more
Foot-and-mouth disease (FMD) is a highly contagious disease that results in enormous economic loses worldwide. Although the protection provided by vaccination is limited during early infection, it is recognized as the best method to prevent FMD outbreaks. Furthermore, the mechanism of host early responses against foot-and-mouth disease virus (FMDV) infection remains unclear. In our study, a pig kidney cell line (PK-15) was used as a cell model to reveal the mechanism of early pig responses to FMDV infection. Four non-treated control and four FMDV-treated PK-15 cells were sequenced with RNA-seq technology, and the differentially expressed genes (DEGs) were analyzed. The results showed that 1212 DEGs were in the FMDV-infected PK-15 cells, including 914 up-regulated and 298 down-regulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were significantly enriched in the tumor necrosis factor (TNF), cytokine-cytokine receptor interaction, NOD-like receptor, toll-like receptor, NF-κB, and the chemokine signaling pathways. To verify the results of the DEGs, 30 immune-related DEGs (19 up-regulated and 11 down-regulated) were selected for Quantitative Reverse Transcriptase polymerase chain reaction (RT-qPCR) verification. The results showed that RT-qPCR-measured genes exhibited a similar pattern as the RNA-seq analyses. Based on bioinformatics analysis, during FMDV early infection, we found that a series of cytokines, such as interleukins (IL6), chemokines (CXCL2, CCL20 and CCL4), and transcription factors (ZFP36, FOS, NFKBIA, ZBTB3, ZNF503, ZNF283, dymeclin (DYM), and orthodenticle homeobox 1 (OTX1)) were involved in the battle between FMDV and the host. Combined with their features and functions, we propose inflammation as the main early mechanism by which the host responds to FMDV infection. These data provide an additional panel of candidate genes for deciphering the mechanisms of a host's early response against FMDV infection. Show less
Blood lipids are well-known risk factors for coronary heart disease (CHD). The aim of this study was to explore the association between 17 lipid-related gene polymorphisms and CHD. The current study e Show more
Blood lipids are well-known risk factors for coronary heart disease (CHD). The aim of this study was to explore the association between 17 lipid-related gene polymorphisms and CHD. The current study examined with 784 CHD cases and 739 non-CHD controls. Genotyping was performed on the MassARRAY iPLEX® assay platform. Our analyses revealed a significant association of APOE rs7259620 with CHD (genotype: χ2=6.353, df=2, p=0.042; allele: χ2=5.05, df=1, p=0.025; recessive model: χ2=5.57, df=1, p=0.018). A further gender-based subgroup analysis revealed significant associations of APOE rs7259620 and PPAP2B rs72664392 with CHD in males (genotype: χ2=8.379, df=2, p=0.015; allele: χ2=5.190, df=1, p=0.023; recessive model: χ2=19.3, df=1, p<0.0001) and females (genotype: χ2=9.878, df=2, p=0.007), respectively. Subsequent breakdown analysis by age showed that CETP rs4783961, MLXIPL rs35493868, and PON2 rs12704796 were significantly associated with CHD among individuals younger than 55 years of age (CETP rs4783961: χ2=8.966, df=1, p=0.011 by genotype; MLXIPL rs35493868: χ2=4.87, df=1, p=0.027 by allele; χ2=4.88, df=1, p=0.027 by dominant model; PON2 rs12704796: χ2=6.511, df=2, p=0.039 by genotype; χ2=6.210, df=1, p=0.013 by allele; χ2=5.03, df=1, p=0.025 by dominant model). Significant allelic association was observed between LEPR rs656451 and CHD among individuals older than 65 years of age (χ2=4.410, df=1, p=0.036). Our study revealed significant associations of APOE, PPAP2B, CETP, MLXIPL, PON2, and LEPR gene polymorphisms with CHD among the Han Chinese. Show less
Jian Shi, Xiaohua Li, Fan Zhang+9 more · 2018 · Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology · added 2026-04-24
Current studies have indicated that long non-coding RNAs (lncRNAs) could act as tumor biomarkers for disease diagnosis and prognosis prediction. In this study, we mainly focused on determining the exp Show more
Current studies have indicated that long non-coding RNAs (lncRNAs) could act as tumor biomarkers for disease diagnosis and prognosis prediction. In this study, we mainly focused on determining the expression of circulating lncRNAs in patients suffering for hilar cholangiocarcinoma (HC), aiming to reveal the potential lncRNA as a fingerprint. A total 12 lncRNAs were previously proven to be aberrantly expressed in HC tumor tissues. All of the 12 lncRNAs were selected as candidate targets for subsequent circulating lncRNA assay. The candidate lncRNAs were validated by qRT-PCR arranged in training and validation sets. The risk score analysis was employed. Data was presented with receiver operating characteristic curve (ROC). Circulating PCAT1, MALAT1, and CPS1-IT1 were significantly increased in plasma samples of HC patients in both the training set and validation set. Through ROC analysis, we found that the three plasmatic lncRNAs presented the area under ROC curve value (AUC) as 0.784, 0.860, and 0.677. Further combination with the three factors indicated a higher power (AUC, 0.893; sensitivity, 85.5%; specificity, 93.2%). This was the first time to reveal the potential circulating fingerprints for predicting HC. PCAT1, MALAT1, and CPS1-IT1 may act as novel early diagnosis biomarkers for predicting HC. Show less
The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic "healthy" individuals. A VU Show more
The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic "healthy" individuals. A VUS is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded, and thus cannot be definitively annotated. VUS, therefore, pose critical clinical interpretation and risk-assessment challenges, and new methods are urgently needed to better characterize their pathogenicity. To address this challenge and showcase the uncertainty surrounding genomic variant interpretation, we recruited a "healthy" asymptomatic individual, lacking cardiac-disease clinical history, carrying a hypertrophic cardiomyopathy (HCM)-associated genetic variant (NM₀₀₀₂₅₈.2:c.170C>A, NP₀₀₀₂₄₉.1:p.Ala57Asp) in the sarcomeric gene MYL3, reported by the ClinVar database to be "likely pathogenic." Human-induced pluripotent stem cells (iPSCs) were derived from the heterozygous VUS MYL3 The heterozygous VUS MYL3 Our study illustrates the ability of clustered regularly interspaced short palindromic repeats/Cas9 genome-editing of carrier-specific iPSCs to elucidate both benign and pathogenic HCM functional phenotypes in a carrier-specific manner in a dish. As such, this platform represents a promising VUS risk-assessment tool that can be used for assessing HCM-associated VUS specifically, and VUS in general, and thus significantly contribute to the arsenal of precision medicine tools available in this emerging field. Show less
Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypot Show more
Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypothalamus-mediated energy metabolism during Xenopus limb regeneration. We report that hypothalamus injury inhibits Xenopus tadpole limb regeneration. By loss-of-function and gain-of-function studies, we show that Mc4r signaling is required for limb regeneration in regeneration-competent tadpoles and stimulates limb regeneration in later-stage regeneration-defective tadpoles. It regulates limb regeneration through modulating energy homeostasis and ROS production. Even more interestingly, our results demonstrate that Mc4r signaling is regulated by innervation and α-MSH substitutes for the effect of nerves in limb regeneration. Mc4r signaling is also required for mouse digit regeneration. Thus, our findings link vertebrate limb regeneration with Mc4r-mediated energy homeostasis and provide a new avenue for understanding Mc4r signaling in the peripheral organs. Show less
The overexpression of EGFR often occurs in TNBC, and the anti-EGFR receptor antibody cetuximab is used widely to treat metastatic cancer in the clinic. However, EGFR-targeted therapies have been devel Show more
The overexpression of EGFR often occurs in TNBC, and the anti-EGFR receptor antibody cetuximab is used widely to treat metastatic cancer in the clinic. However, EGFR-targeted therapies have been developed for TNBC without clinical success. In this study, we show that impaired EGFR degradation is crucial for resistance to cetuximab, which depends on the cell surface molecule CD44. To further investigate the role of CD44 in EGFR signaling and its treatment potential, we developed a targeting fusion protein composed of an anti-EGFR scFv generated from cetuximab and truncated protamine, called Ce-tP. CD44 siRNA can be specifically delivered into EGFR-positive TNBC cells by Ce-tP. Efficient knockdown of CD44 and suppression of both EGFR and downstream signaling by the Ce-tP/siRNA complex were observed in EGFR-positive TNBC cells. More importantly, our results also showed that targeted delivery of siRNA specific for CD44 can efficiently overcome resistance to EGFR targeting in TNBC cells both in vitro and in vivo. Overall, our results establish a new principle to achieve EGFR inhibition in TNBC and limit drug resistance. Show less
Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL Show more
Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10 Show less
In the human body, 50-70 billion cells die every day, resulting in the generation of a large number of apoptotic bodies. However, the detailed biological role of apoptotic bodies in regulating tissue Show more
In the human body, 50-70 billion cells die every day, resulting in the generation of a large number of apoptotic bodies. However, the detailed biological role of apoptotic bodies in regulating tissue homeostasis remains unclear. In this study, we used Fas-deficient MRL/lpr and Caspase 3 Show less
To assess the association of genes in the high-density lipoprotein metabolic pathway (HDLMP) with polypoidal choroidal vasculopathy (PCV) and the genetic difference in the HDLMP between PCV and age-re Show more
To assess the association of genes in the high-density lipoprotein metabolic pathway (HDLMP) with polypoidal choroidal vasculopathy (PCV) and the genetic difference in the HDLMP between PCV and age-related macular degeneration (AMD). We performed a literature search in EMBASE, PubMed, and Web of Science for genetic studies on 7 single nucleotide polymorphisms (SNPs) from 5 genes in the HDLMP including cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), ATP-binding cassette transporter A1 (ABCA1), and ATP-binding cassette transporter G1 (ABCG1) in PCV. All studies were published before September 30, 2017, without language restriction. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) of each polymorphism were estimated. We also compared the association profiles between PCV and AMD and performed a sensitivity analysis. Our result is based on 43 articles. After excluding duplicates and articles without complete information, 7 studies were applicable to meta-analysis. 7 polymorphisms were meta-analyzed: CETP rs2303790/rs3764261, LIPC rs10468017/rs493258, LPL rs12678919, ABCA1 rs1883025, and ABCG1 rs57137919. We found that in Asian population, CETP rs3764261 (T allele; OR = 1.46; 95% CI: 1.28-1.665, Our study revealed 7 polymorphisms in 5 genes. Among them, CETP (rs3764261/rs2303790) and ABCG1 (rs57137919) were the major susceptibility genes for PCV in Asian population and ABCG1 (rs57137919) showed allelic diversity between PCV and AMD. Since the size for PCV and AMD was small, we need to study these genes genotyping in larger samples. Show less
Protein kinase N2 (PKN2) is a PKC-related serine/threonine-protein kinase. PKN2 is required for tumor cell migration, invasion and apoptosis. However, the functional role of PKN2 in regulating tumor a Show more
Protein kinase N2 (PKN2) is a PKC-related serine/threonine-protein kinase. PKN2 is required for tumor cell migration, invasion and apoptosis. However, the functional role of PKN2 in regulating tumor associated macrophages (TAMs) polarization in colon cancer has never been reported. PKN2 expression in human colon cancer tissues was examined with immunohistochemistry (IHC). M1/M2 macrophage signatures were evaluated by RT-PCR, IHC and flow cytometry. The effects of PKN2 on tumor growth and TAM polarization were investigated both in vitro and in vivo. PKN2 targeted cytokines/pathway were analyzed by gene expression analysis and further confirmed by PCR, luciferase assay or western blot. Correlations between PKN2 and transcriptional factors for IL4 and IL10 were confirmed by ChIP-qPCR. The catalytic activities of PKN2 and DUSP6 were determined by kinase activity assay. Interactions between PKN2 and DUSP6 were confirmed by Co-IP. The expression of PKN2 in colon cancer cells predicted a favorable prognosis and was associated with low M2 macrophage content in human colon cancer tissues. PKN2 inhibited tumor growth in mice xenograft model and inhibited M2 phenotype polarization both in vitro and in vivo. Mechanistically, PKN2 suppresses the expression of IL4 and IL10 from colon cancer cells by inhibiting Erk1/2 phosphorylation, which is required for phosphorylation and binding of CREB and Elk-1 to the promoters of IL4 and IL10. DUSP6, which is phosphorylated and activated through direct association with PKN2, suppresses Erk1/2 activation. The expression of PKN2 in colon cancer cells suppresses tumor associated M2 macrophage polarization and tumor growth. Targeting PKN2 signaling pathway may provide a potential therapeutic strategy for colon cancer. Show less
Candida albicans is an opportunistic fungal pathogen. In immunocompromised individuals, it can cause bloodstream infections with high mortality rates. The ability to switch between yeast and hyphal mo Show more
Candida albicans is an opportunistic fungal pathogen. In immunocompromised individuals, it can cause bloodstream infections with high mortality rates. The ability to switch between yeast and hyphal morphologies is a critical virulence factor of C. albicans. In response to diverse environmental cues, several signaling pathways are activated resulting in filamentous growth. Interestingly, cell cycle arrest can also trigger filamentous growth although the pathways involved are not well-understood. Here, we demonstrate that the cAMP-PKA pathway is involved in the filamentous growth caused by G1 arrest due to the depletion of the G1 cyclin Cln3 and S phase arrest due to hydroxyurea treatment. The downstream mechanisms involved in filamentation are different between the two cell cycle arrest phenomena. Cln3-depleted cells require HGC1 and UME6 for filamentous growth, but hydroxyurea-induced filamentation does not. Also, the hyphal repressor Nrg1 is not involved in the suppression of Cln3-depletion and hydroxyurea-induced filamentous growth. The findings highlight the complexity of the signaling networks that control filamentous growth in which different mechanisms downstream of the cAMP-PKA pathway are activated based on the nature of the inducing signals. Show less
Colorectal cancer (CRC), one of the most aggressive gastrointestinal malignancies, is a frequently diagnosed life-threatening cancer worldwide. Most CRC patients have poor prognosis mainly because of Show more
Colorectal cancer (CRC), one of the most aggressive gastrointestinal malignancies, is a frequently diagnosed life-threatening cancer worldwide. Most CRC patients have poor prognosis mainly because of frequent metastasis and recurrence. Thus, it is crucial to find out some new biomarkers and to show deeper insights into the mechanisms of CRC. MLLT10, Myeloid/lymphoid or mixed-lineage leukemia translocated to 10, also known as AF10, a recurrent MLL partner. In this study, we found that MLLT10 promotes CRC tumor invasion and metastasis both in vitro and in vivo. Here, the expression of MLLT10 was evaluated by immunohistochemistry. Then, the plasmid and lentivirus particles for MLLT10 overexpression or knockdown were designed and constructed into SW620 and HT29 cells. Finally, cell proliferation assay, cell adhesion assay, transwell migration, and invasion assay were used to detect the migration and invasion ability of MLLT10 in CRC cells. A tail vein injection assay was employed to evaluate the role of MLLT10 in tumor metastases. MLLT10 expression was significantly higher in CRC tissues than in noncancerous tissues and was associated with some clinicopathological factors. In vitro, the overexpression of MLLT10 promoted CRC cell migration and invasion, while after MLLT10 was knocked down, the opposite results were observed. Furthermore, we used animal metastasis models to detect the function of MLLT10 in vivo, the results are same with the outcomes in vitro. In lung metastasis sites, the knockdown of MLLT10 in SW620 cells significantly inhibited Vimentin expression, whereas the E-Cadherin was increased. These results indicate that MLLT10 regulates the metastasis of CRC cells via EMT. Show less
Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and tre Show more
Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 × 10-47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003). CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD. Show less
Seizure-induced brain damage is age-dependent, as evidenced by the different alterations of neural physiopathology in developing and mature brains. However, little is known about the age-dependent cha Show more
Seizure-induced brain damage is age-dependent, as evidenced by the different alterations of neural physiopathology in developing and mature brains. However, little is known about the age-dependent characteristics of myelinated fiber injury induced by seizures. Considering the critical functions of oligodendrocyte progenitor cells (OPCs) in myelination and Lingo-1 signaling in regulating OPCs' differentiation, the present study aimed to explore the effects of Lingo-1 on myelin and axon in immature and adult rats after status convulsion (SC) induced by lithium-pilocarpine, and the differences between immature and adult brains. Dynamic variations in electrophysiological activity and spontaneous recurrent seizures were recorded by electroencephalogram monitoring after SC. The impaired microstructures of myelin sheaths and decrease in myelin basic protein caused by SC were observed through transmission electron microscopy and western blot analysis respectively, which became more severe in adult rats, but improved gradually in immature rats. Aberrant axon sprouting occurred in adult rats, which was more prominent than in immature rats, as shown by a Timm stain. This damage was improved or negatively affected after down or upregulating Lingo-1 expression. These results demonstrated that in both immature and adult brains, Lingo-1 signaling plays important roles in seizure-induced damage to myelin sheaths and axon growth. The plasticity of the developing brain may provide a potential window of opportunity to prevent the brain from damage. Show less
Atherosclerosis is a process of imbalanced lipid metabolism in the vascular walls. The underlying pathology mainly involves the deposition of oxidized lipids in the endothelium and the accumulation of Show more
Atherosclerosis is a process of imbalanced lipid metabolism in the vascular walls. The underlying pathology mainly involves the deposition of oxidized lipids in the endothelium and the accumulation of cholesterol in macrophages. Macrophages export excessive cholesterol (cholesterol efflux) through ATP-binding cassette transporter A1 (ABCA1) to counter the progression of atherosclerosis. We synthesized novel chalcone derivatives and assessed their effects and the underlying mechanisms on ABCA1 expression in macrophages. Human THP-1 macrophages were treated with synthetic chalcone derivatives for 24 h. In Western blot and flow cytometry analyses, a chalcone derivative, ( Show less
Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase. Recent studies have demonstrated that enhancing SIRT1 expression or activity may modulate cholesterol and lipid Show more
Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase. Recent studies have demonstrated that enhancing SIRT1 expression or activity may modulate cholesterol and lipid metabolism. However, pharmacological and molecular regulators for SIRT1 are scarce. Here, we aimed to find novel small molecule modulators of SIRT1 to regulate cholesterol and lipid metabolism. A high-throughput screening assay was established to identify SIRT1 activators. Surface plasmon resonance and immunoprecipitation were performed to confirm the interaction of E1231 with SIRT1. Cholesterol assay was performed to demonstrate the in vitro effect of E1231. The in vivo effect of E1231 was evaluated in experimental models. E1231, a piperazine 1,4-diamide compound, was identified as a SIRT1 activator with EC We identified a novel SIRT1 activator E1231 and elucidated its beneficial effects on lipid and cholesterol metabolism. Our study suggests that E1231 might be developed as a novel drug for treating atherosclerosis. Show less
Presently noninvasive methods were employed to the diagnosis of nonalcoholic fatty liver disease (NAFLD), including fatty liver index (FLI), hepatic steatosis index (HSI), product of fasting triglycer Show more
Presently noninvasive methods were employed to the diagnosis of nonalcoholic fatty liver disease (NAFLD), including fatty liver index (FLI), hepatic steatosis index (HSI), product of fasting triglyceride and glucose levels (TyG), and single nucleotide polymorphism (SNP), whereas the accuracy of those indexes need to be improved. Our study aimed to investigate the feasibility of a new index comprehensive index (CI), consisting of 6 serum biomarkers and anthropometric parameters through multivariate logistic regression analysis, to the earlier detection of NAFLD, and the diagnostic value of 5 SNPs (S1: rs2854116 of apolipoprotein C3 [APOC3], S2: rs4149267 of ATP-binding cassette transporter [ABCA1], S3: rs13702 of lipoprotein lipase [LPL], S4: rs738409 of protein 3 [patatin-like phospholipase domain containing protein 3 (PNPLA3)], S5: rs780094 of glucokinase regulatory protein gene [GCKR]) for NAFLD were also explored. Area under the receiver operating characteristic curves (AUROC) and Youden index (YI) were calculated to assess the diagnostic value. The AUROC of CI was higher than FLI, HSI, and TyG (CI: 0.897, FLI: 0.873, HSI: 0.855, TyG: 0.793). Therefore, CI might be a better index for the diagnosis of NAFLD. Although there had no statistical significance (P = .123), the AUROC and YI were increased when CI combined with rs2854116 (S1) (AUROC = 0.902, YI = 0.6844). The combination of CI with S1 showed even better diagnostic accuracy than CI, which suggests the potential value of rs2854116 for the diagnosis of NAFLD. Show less
Diabetic nephropathy (DN) is one of the most devastating complications of diabetes mellitus. Carbohydrate response element binding protein (ChREBP) is a basic helix-loop-helix leucine zipper transcrip Show more
Diabetic nephropathy (DN) is one of the most devastating complications of diabetes mellitus. Carbohydrate response element binding protein (ChREBP) is a basic helix-loop-helix leucine zipper transcription factor that primarily mediates glucose homeostasis in the body. The present study investigated the role of ChREBP in the pathogenesis of DN. The expression of ChREBP was detected in patients with type 2 diabetes mellitus (T2DM), diabetic mice, and mesangial cells. ELISA was used to measure cytokine production in mesangial cells. Flow cytometry analysis was performed to detect the apoptosis of mesangial cells in the presence of high glucose. The expression levels of ChREBP and several cytokines (TNF-α, IL-1β, and IL-6) were up-regulated in T2DM patients. The mRNA and protein levels of ChREBP were also significantly elevated in the kidneys of diabetic mice. Moreover, glucose treatment promoted mRNA levels of TNF-α, IL-1β, and IL-6 in mesangial cells. Glucose stimulation induced significant apoptosis of SV40 MES 13 cells. In addition, transfection with ChREBP siRNA significantly inhibited ChREBP expression. Consequently, the inflammatory responses and apoptosis were inhibited in SV40 MES 13 cells. These results demonstrated that ChREBP could mediate the inflammatory response and apoptosis of mesangial cells, suggesting that ChREBP may be involved in the pathogenesis of DN. Show less
This research aimed to discover potential biomarkers for evaluating the therapeutic efficacy of intensive therapy in pulmonary tuberculosis (TB). Protein profiles in 2-months intensively treated TB pa Show more
This research aimed to discover potential biomarkers for evaluating the therapeutic efficacy of intensive therapy in pulmonary tuberculosis (TB). Protein profiles in 2-months intensively treated TB patients, untreated TB patients, and healthy controls were investigated with iTRAQ-2DLC-MS/MS technique. 71 differential proteins were identified in 2-months intensively treated TB patients. Significant differences in complement component C7 (CO7), apolipoprotein A-IV (APOA4), apolipoprotein C-II (APOC2), and angiotensinogen (ANGT) were found by ELISA validation. CO7 and ANGT were also found significantly different in sputum negative patients, compared with sputum positive patients after intensive treatment. Clinical analysis showed that after 2-months intensive treatment several indicators were significantly changed, and the one-year cure rate of sputum negative patients were significantly higher than sputum positive patients. Diagnostic models consisting of APOC2, CO7 and APOA4 were established to distinguish intensively treated TB patients from untreated TB patients and healthy controls with the AUC value of 0.910 and 0.935. Meanwhile, ANGT and CO7 were combined to identify sputum negative and sputum positive TB patients after intensive treatment with 89.36% sensitivity, 71.43% specificity, and the AUC value of 0.853. The results showed that APOC2, CO7, APOA4, and ANGT may be potential biomarkers for evaluating the efficacy of intensive anti-TB therapy. Show less
Data from epidemiological studies and clinical trials suggest an influence of dietary and circulating polyunsaturated fatty acids (PUFAs) on the hemostasis profile. Genome-wide association studies (GW Show more
Data from epidemiological studies and clinical trials suggest an influence of dietary and circulating polyunsaturated fatty acids (PUFAs) on the hemostasis profile. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) related to plasma PUFAs levels. We aimed to investigate whether the SNPs related to plasma PUFAs levels were also associated with plasma levels of hemostatic variables. We tested the associations between 9 PUFA-related SNPs and 6 hemostatic variables in 9035 European Americans (EAs) and 2702 African Americans (AAs) in the Atherosclerosis Risk in Communities (ARIC) Study. We then conducted a replication study by looking-up our novel observed associations in three published GWAS for hemostatic factors in different EA populations. We observed a novel linoleic acid-related locus at the JMJD1C region associated with factor VII activity (FVIIc): rs10740118 and rs1935, Beta (p) = -1.31 (1 × 10 Our study identified a novel association for FVIIc at JMJD1C, a histone demethylase that plays a role in DNA repair and possibly transcription regulation and RNA processing. Show less
Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive disorder of the urea cycle, mostly characterized by hyperammonemia and the concomitant leukodystrophy. The onset of CP Show more
Carbamoyl phosphate synthetase 1 deficiency (CPS1D) is a rare autosomal recessive disorder of the urea cycle, mostly characterized by hyperammonemia and the concomitant leukodystrophy. The onset of CPS1D can be at any age, and the clinical manifestations are variable and atypical. Genetic tests are indispensable for accurate diagnosis of CPS1D on the basis of biochemical tests. Blood tandem mass spectrometric analysis and urea organic acidemia screening were performed on a Chinese neonatal patient with low activity, recurrent seizures, and hyperammonemia. Next-generation sequencing and Sanger sequencing were followed up for making a definite diagnosis. Bioinformatics tools were used for the conservation analysis and pathogenicity predictions of the identified mutations. Increased lactate in urea and decreased citrulline in blood were detected in the patient. Two novel mutations (c.173G>T, p.G58V in exon 2 and c.796G>A, p.G266R in exon 8) in CPS1 identified in the neonatal patient were found through coseparation verification. Both of the two mutations were predicted to be deleterious, and the two relevant amino acids exerted highly evolutionarily conserved. The final diagnosis of the patient was compound heterozygous CPS1D. This study described the specific clinical characteristics and the variations of physiological and biochemical indices in a Chinese neonatal patient with CPS1D, which facilitated the diagnosis and mechanism research of the disease. Two novel causative missense mutations were identified, which enriched the mutation spectrum of CPS1D in China and worldwide. Advice of prenatal diagnosis was given to the family for a new pregnancy. Show less
Xiyue Yang, Jing Wang, Zewei Zhou+8 more · 2018 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
Metanephric adenoma is a rare, benign renal neoplasm with occasional misdiagnosis. However, its molecular characterization is not fully understood. In this study, we use the hybrid capture-based Next- Show more
Metanephric adenoma is a rare, benign renal neoplasm with occasional misdiagnosis. However, its molecular characterization is not fully understood. In this study, we use the hybrid capture-based Next-Generation Sequencing to sequence a panel of 295 well-established oncogene or tumor suppressor genes in 28 cases of MA patients in China. Novel clinicopathological markers associated with the mitogen-activated protein kinase (MAPK) pathway in metanephric adenoma were detected by immunohistochemistry. It was found that except for BRAF (22/28) mutations (c.1799 T > A, p.V600E), NF1 (6/28), NOTCH1 (5/28), SPEN (5/28), AKT2 (4/28), APC (4/28), ATRX (3/28), and ETV4 (3/28) mutations could also be detected. Meanwhile, a novel and rare gene fusion of STARD9-BRAF, CUX1-BRAF, and LOC100507389-BRAF was detected in one MA patient. In addition, although MEK phosphorylation was normally activated, the phosphorylation level of ERK was low in metanephric adenoma cases. Highly expressed p16 and DUSP6 may have contributed to these results, which maintained MA as a benign renal tumor. This study provides novel molecular and pathological markers for metanephric adenoma, which could improve its diagnosis and increase the understanding of its pathologic mechanism. Show less
Variants in the lipoprotein lipase (LPL), apolipoprotein C-II (APOC2), apolipoprotein A-V (APOA5), GPIHBP1 and LMF1 genes may cause severe hypertriglyceridemia (HTG), which is now the second-leading a Show more
Variants in the lipoprotein lipase (LPL), apolipoprotein C-II (APOC2), apolipoprotein A-V (APOA5), GPIHBP1 and LMF1 genes may cause severe hypertriglyceridemia (HTG), which is now the second-leading aetiology of acute pancreatitis in China. The patient and his family were assessed for gene variants by Sanger sequencing of exons and exon-intron junctions of the LPL, GPIHBP1, APOA5, APOC2, and LMF1 genes. Post-heparin blood was collected for LPL mass and activity detection. The patient had suffered from long-term severe hypertriglyceridemia and recurrent abdominal pain for over 30 years, since age 26, and 3 bouts of acute pancreatitis. Two heterozygous LPL single-nucleotide polymorphisms (SNPs) were compound but dislinked: a single-nucleotide substitution (c.42G > A) resulting in the substitution of tryptophan with a stop codon (p.W14X) in one allele, and a single-nucleotide substitution (c.835C > G) resulting in a leucine-to-valine substitution (p.L279 V) in another allele. Only one SNP, p.L279 V, was detected in his son. Post-heparin LPL activity and mass were also lower in the patient. Two heterozygous LPL SNPs, W14X and L279 V, were newly found to be compound but dislinked, which may cause long-term severe hypertriglyceridemia and recurrent acute pancreatitis. Show less