Hypo-high-density lipoprotein cholesterolemia (hypo-HDL-C) contributes to the development of cardiovascular diseases. The hypothesis that the polygenic variants associated with hypo-HDL-C interact wit Show more
Hypo-high-density lipoprotein cholesterolemia (hypo-HDL-C) contributes to the development of cardiovascular diseases. The hypothesis that the polygenic variants associated with hypo-HDL-C interact with lifestyle factors was examined in 58,701 middle-aged Korean adults who participated in the Korean Genome and Epidemiology Study (KoGES). Participants were categorized into the Low-HDL (case; The participants with hypo-HDL-C showed a 1.45 and 1.36-fold higher association with myocardial infarction and stroke, respectively. The High-PRS with four SNPs, namely Adults with a genetic risk for hypo-HDL-C need to modulate their diet and smoking status to reduce their risk. Show less
Current structural and functional investigations of cholesteryl ester transfer protein (CETP) inhibitor design are nearly entirely based on a fully active mutation (CETP
Stroke is a common cerebrovascular disease. The purpose of this study was to explore the association between This study recruited 710 stroke patients and 701 healthy controls. The four SNPs (rs690, rs Show more
Stroke is a common cerebrovascular disease. The purpose of this study was to explore the association between This study recruited 710 stroke patients and 701 healthy controls. The four SNPs (rs690, rs6083, rs3829461, and rs6074) in Overall analysis showed that rs690 was associated with an increased risk of stroke (T vs. G: OR = 1.19, 95% CI: 1.01-1.40, This study indicated that rs690 and rs6074 in 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
Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene Show more
Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined were subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these four algorithms were included for further analysis. AnnotSV was used to annotate these SVs. SVs that overlap with known IRD-associated genes were examined with sequencing coverage, junction reads and discordant read pairs. Polymerase Chain Reaction (PCR) followed by Sanger sequencing was used to further confirm the SVs and identify the breakpoints. Segregation of the candidate pathogenic alleles with the disease was performed when possible. A total of 16 candidate pathogenic SVs were identified in 16 families, including deletions and inversions, representing 2.1% of patients with previously unsolved IRDs. Autosomal dominant, autosomal recessive and X-linked inheritance of disease-causing SVs were observed in 12 different genes. Among these, SVs in CLN3, EYS and PRPF31 were found in multiple families. Our study suggests that the contribution of SVs detected by short-read WGS is about 0.25% of our IRD patient cohort and is significantly lower than that of single nucleotide changes and small insertions and deletions. Show less
Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene Show more
Despite increasing success in determining genetic diagnosis for patients with inherited retinal diseases (IRDs), mutations in about 30% of the IRD cases remain unclear or unsettled after targeted gene panel or whole exome sequencing. In this study, we aimed to investigate the contributions of structural variants (SVs) to settling the molecular diagnosis of IRD with whole-genome sequencing (WGS). A cohort of 755 IRD patients whose pathogenic mutations remain undefined was subjected to WGS. Four SV calling algorithms including include MANTA, DELLY, LUMPY, and CNVnator were used to detect SVs throughout the genome. All SVs identified by any one of these four algorithms were included for further analysis. AnnotSV was used to annotate these SVs. SVs that overlap with known IRD-associated genes were examined with sequencing coverage, junction reads, and discordant read pairs. PCR followed by Sanger sequencing was used to further confirm the SVs and identify the breakpoints. Segregation of the candidate pathogenic alleles with the disease was performed when possible. In total, sixteen candidate pathogenic SVs were identified in sixteen families, including deletions and inversions, representing 2.1% of patients with previously unsolved IRDs. Autosomal dominant, autosomal recessive, and X-linked inheritance of disease-causing SVs were observed in 12 different genes. Among these, SVs in Show less
Zhanming Zhang, Fan Tong, Chi Chen+6 more · 2023 · Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · added 2026-04-24
To investigate genotype-phenotype characteristics and long-term prognosis of neonatal carbamoyl phosphate synthetase 1 (CPS1) deficiency among children through newborn screening in Zhejiang province. Show more
To investigate genotype-phenotype characteristics and long-term prognosis of neonatal carbamoyl phosphate synthetase 1 (CPS1) deficiency among children through newborn screening in Zhejiang province. The clinical and follow-up data of children with CPS1 deficiency detected through neonatal screening and confirmed by tandem mass spectrometry and genetic testing in Zhejiang Province Newborn Disease Screening Center from September 2013 to August 2023 were retrospectively analyzed. A total of 4 056 755 newborns were screened and 6 cases of CPS1 deficiency were diagnosed through phenotypic and genetic testing. Ten different variations of Low citrulline levels and hyperammonemia are common in CPS1 deficiency patients in Zhejiang. Most gene variants identified were specific to individual families, and no hotspot mutations were found. Early diagnosis through newborn screening and following standardized treatment can significantly improve the prognosis of the patients. Show less
To determine whether hyperammonemia has a direct impact on steatohepatitis in mice fed with a high-fat diet (HFD). Male C57BL/6 mice were divided into two groups receiving either chow diet or HFD. Aft Show more
To determine whether hyperammonemia has a direct impact on steatohepatitis in mice fed with a high-fat diet (HFD). Male C57BL/6 mice were divided into two groups receiving either chow diet or HFD. After 12-week NASH modeling, hyperammonemia was induced by intragastric administration of ammonium chloride solution (NH NH Our study revealed a limited role of ammonia in aggravating the progression of NASH. Further studies are needed to clarify the role and mechanism of ammonia in NASH development. Show less
The present study aims to investigate the alterations of serum proteomic and metabolomic profiles in Chinese patients with severe and active Graves' Orbitopathy (GO). Thirty patients with GO and 30 he Show more
The present study aims to investigate the alterations of serum proteomic and metabolomic profiles in Chinese patients with severe and active Graves' Orbitopathy (GO). Thirty patients with GO and 30 healthy volunteers were enrolled. The serum concentrations of FT3, FT4, T3, T4, and thyroid-stimulating hormone (TSH) were analyzed, after which TMT labeling-based proteomics and untargeted metabolomics were performed. Metabo- Analyst and Ingenuity Pathway Analysis (IPA) was used for integrated network analysis. A nomogram was established based on the model to explore the disease prediction ability of the identified feature metabolites. One hundred thirteen proteins (19 up-regulated and 94 down-regulated) and 75 metabolites (20 increased and 55 decreased) were significantly altered in GO compared to the control group. By combining the lasso regression, IPA network, and protein-metabolite-disease sub-networks, we extracted feature proteins (CPS1, GP1BA, and COL6A1) and feature metabolites (glycine, glycerol 3-phosphate, and estrone sulfate). The logistic regression analysis revealed that the full model with the prediction factors and three identified feature metabolites had better prediction performance for GO compared to the baseline model. The ROC curve also indicated better prediction performance (AUC = 0.933 vs. 0.789). A new biomarker cluster combined with three blood metabolites with high statistical power can be used to discriminate patients with GO. These findings provide further insights into the pathogenesis, diagnosis, and potential therapeutic targets for this disease. Show less
Tumor protein 53 (TP53) mutation in bladder carcinoma (BC), upregulates the transcription of carbamoyl phosphate synthetase 1 (CPS1), to reduce intracellular ammonia toxicity. To leverage ammonia comb Show more
Tumor protein 53 (TP53) mutation in bladder carcinoma (BC), upregulates the transcription of carbamoyl phosphate synthetase 1 (CPS1), to reduce intracellular ammonia toxicity. To leverage ammonia combating BC, here, an intravesically perfusable nanoporter-encased hydrogel system is reported. A biomimetic fusogenic liposomalized nanoporter (FLNP) that is decorated with urea transporter-B (UT-B) is first synthesized with protonated chitosan oligosaccharide for bladder tumor-targeted co-delivery of urease and small interfering RNA targeting CPS1 (siCPS1). Mussel-inspired hydrogel featured with dual functions of bio-adhesion and injectability is then fabricated as the reservoir for intravesical immobilization of FLNP. It is found that FLNP-mediated UT-B immobilization dramatically induces urea transportation into tumor cells, and co-delivery of urease and siCPS1 significantly boosts ammonia accumulation in tumor inducing cell apoptosis. Treatment with hybrid system exhibits superior anti-tumor effect in orthotopic bladder tumor mouse model and patient-derived xenograft model, respectively. Combined with high-protein diet, the production of urinary urea increases, leading to an augmented intracellular deposition of ammonia in BC cells, and ultimately an enhanced tumor inhibition. Together, the work establishes that cascade modulation of ammonia in tumor cells could induce tumor apoptosis and may be a practical strategy for eradication of TP53-mutated bladder cancer. 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
Particulate matter (PM), one of the most serious air contaminants, could easily pass through the airway and deposit at the deep alveoli. Thus, it might trigger respiratory diseases like inflammation, Show more
Particulate matter (PM), one of the most serious air contaminants, could easily pass through the airway and deposit at the deep alveoli. Thus, it might trigger respiratory diseases like inflammation, asthma and lung cancer on human. Long non-coding RNAs (lncRNAs) are considered as important regulator in promotion and progression of diverse cancers. However, the molecular mechanism of lncRNAs mediating PM-induced lung carcinogenesis remains unclear. In this study, we established a 16HBE malignant transformed cell induced by PM (Cells were treated with 20 μg/ml PM, which named PM-T cells) and explored the roles and mechanisms of lncRNAs in the malignant transformation induced by PM. Compared with 16HBE cells, various biological functions were changed in PM-T cells, such as cell proliferation, migration, cell cycle and apoptosis. LncRNA SPRY4-IT1 was significant down-regulated expression and associated with these biological effects. Our results showed that lncRNA SPRY4-IT1 overexpression reversed these functional changes mentioned above. The further studies indicated that lncRNA SPRY4-IT1 involved in PM-induced cell transformation by modulating Chk1 expression via negative regulation of DUSP6-ERK1/2. In conclusion, our studies suggested that lncRNA SPRY4-IT1 played the role as a tumor suppressor gene and might mediate 16HBE cells malignant transformation induced by PM through regulating DUSP6-ERK1/2-Chk1 signaling pathway. Show less
Epstein-Barr virus (EBV)-encoded miRNAs within the BamHI-A rightward transcript (BART) region are abundantly expressed in EBV-associated gastric cancer (EBVaGC), suggesting that they play roles in tum Show more
Epstein-Barr virus (EBV)-encoded miRNAs within the BamHI-A rightward transcript (BART) region are abundantly expressed in EBV-associated gastric cancer (EBVaGC), suggesting that they play roles in tumorigenesis. However, how these viral miRNAs contribute to the development of EBVaGC remains largely obscure. In this study, we found that EBV-encoded miR-BART11-3p targets 3' -UTR of dual-specificity phosphatase 6 (DUSP6) mRNA to upregulate ERK phosphorylation and downregulate JNK and p38 phosphorylation. By doing so, miR-BART11-3p promotes gastric cancer (GC) cell proliferation, migration, and invasion Show less
Despite many advances in treatment over the past few years, the poor 5-year survival rate and high recurrence rate of gastric cancer (GC) remain unsatisfactory. As the most abundant epigenetic modific Show more
Despite many advances in treatment over the past few years, the poor 5-year survival rate and high recurrence rate of gastric cancer (GC) remain unsatisfactory. As the most abundant epigenetic modification in the eukaryotic mRNA, N6-methyladenosine (m Show less
Myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limit Show more
Myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed single-cell RNA sequencing on serial MPN and sAML patient stem and progenitor cells, identifying aberrantly increased expression of DUSP6 underlying disease transformation. Pharmacologic dual-specificity phosphatase (DUSP)6 targeting led to inhibition of S6 and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling while also reducing inflammatory cytokine production. DUSP6 perturbation further inhibited ribosomal S6 kinase (RSK)1, which we identified as a second indispensable candidate associated with poor clinical outcome. Ectopic expression of DUSP6 mediated JAK2-inhibitor resistance and exacerbated disease severity in patient-derived xenograft (PDX) models. Contrastingly, DUSP6 inhibition potently suppressed disease development across Jak2 Show less
Circular RNAs (circRNA) are a group of noncoding, covalently uninterrupted loop transcripts, most of which remain to be functionally characterized. Here, we identified circPDIA4 as an oncogenic circRN Show more
Circular RNAs (circRNA) are a group of noncoding, covalently uninterrupted loop transcripts, most of which remain to be functionally characterized. Here, we identified circPDIA4 as an oncogenic circRNA in gastric cancer. Clinically, circPDIA4 was significantly upregulated in malignant tissues and was associated with poor survival of patients with gastric cancer. The biogenesis of circPDIA4 was mediated by the RNA-binding protein Quaking, which bound introns 2 and 4 of PDIA4 pre-mRNA to promote backsplicing of exons 3 and 4. Elevated expression of circPDIA4 promoted distant metastasis in various mouse xenograft models in vivo and accelerated cancer cell invasion in vitro. CircPDIA4 functioned through distinct oncogenic mechanisms in the cytoplasm and the nucleus. Cytoplasmic circPDIA4 bound to ERK1/2 and sustained hyperactivation of the MAPK pathway by preventing DUSP6-mediated ERK1/2 dephosphorylation. Notably, circPDIA4 depletion enhanced the sensitivity of gastric cancer cells to ERK inhibitors. In the nucleus, circPDIA4 interacted with DHX9 as a decoy and repressed its inhibitory functions on circRNA biogenesis to boost expression of multiple oncogenic circRNAs, which promoted gastric cancer progression. These findings reveal a dual tumor-promoting mechanism for circPDIA4 by regulating oncogenic circRNA biogenesis and increasing MAPK activity. CircPDIA4 should be investigated further as a potential prognostic biomarker and therapeutic target in gastric cancer. Quaking-regulated circPDIA4 mediates different mechanisms in the nucleus and cytoplasm that coordinate to promote progression and drug resistance in gastric cancer. Show less
Somatic copy number alterations (SCNAs) are frequently observed in high-grade ovarian serous carcinoma (HGOSC). However, their impact on gene expression levels has not been systematically assessed. In Show more
Somatic copy number alterations (SCNAs) are frequently observed in high-grade ovarian serous carcinoma (HGOSC). However, their impact on gene expression levels has not been systematically assessed. In this study, we explored the relationship between recurrent SCNA and gene expression using The Cancer Genome Atlas Pan Cancer dataset (OSC, TCGA, PanCancer Atlas) to identify cancer-related genes in HGOSC. We then investigated any association between highly correlated cancer genes and clinicopathological parameters, including age of diagnosis, disease stage, overall survival (OS), and progression-free survival (PFS). A total of 772 genes with recurrent SCNAs were observed. SCNA and mRNA expression levels were highly correlated for 274 genes; 24 genes were classified as a Tier 1 gene in the Cancer Gene Census in the Catalogue of Somatic Mutations in Cancer (CGC-COSMIC). Of these, 11 Tier 1 genes had highly correlated SCNA and mRNA expression levels: Show less
The lack of irrigation water in agricultural soils poses a significant constraint on global crop production. In-depth investigation into microRNAs (miRNAs) has been widely used to achieve a comprehens Show more
The lack of irrigation water in agricultural soils poses a significant constraint on global crop production. In-depth investigation into microRNAs (miRNAs) has been widely used to achieve a comprehensive understanding of plant defense mechanisms. However, there is limited knowledge on the association of miRNAs with drought tolerance in cigar tobacco. In this study, a hydroponic experiment was carried out to identify changes in plant physiological characteristics, miRNA expression and metabolite profile under drought stress, and examine the mitigating effects of selenium (Se) application. The shoot dry weight of drought-stressed plants was approximately half (50.3%) of that in non-stressed (control) conditions. However, plants supplied with Se attained 38.8% greater shoot dry weight as compared to plants with no Se supply under drought stress. Thirteen miRNAs were identified to be associated with drought tolerance. These included 7 known (such as nta-miR156b and nta-miR166a) and 6 novel miRNAs (such as novel-nta-miR156-5p and novel-nta-miR209-5p) with the target genes of Show less
Feed efficiency is a major constraint in the beef industry and has a significant negative correlation with residual feed intake (RFI). RFI is widely used as a measure of feed efficiency in beef cattle Show more
Feed efficiency is a major constraint in the beef industry and has a significant negative correlation with residual feed intake (RFI). RFI is widely used as a measure of feed efficiency in beef cattle and is independent of economic traits such as body weight and average daily gain. However, key traits with commonality or specificity among beef cattle breeds at the same level of RFI have not been reported. Accordingly, the present study hypothesized that signatures associated with feed efficiency would have commonality or specificity in the liver of cattle breeds at the same RFI level. By comparing and integrating liver transcriptome data, we investigated the critical signatures closely associated with RFI in beef cattle using weighted co-expression network analysis, consensus module analysis, functional enrichment analysis and protein network interaction analysis. The results showed that the consensus modules in Angus and Charolais cattle were negatively correlated, and four (turquoise, red, tan, yellow) were significantly positively correlated in Angus liver, while (turquoise, red) were significantly negatively correlated in Charolais liver. These consensus modules were found to be primarily involved in biological processes such as substance metabolism, energy metabolism and gene transcription, which may be one of the possible explanations for the difference in feed efficiency between the two beef breeds. This research also identified five key candidate genes, PLA2G12B, LCAT, MTTP, LCAT, ABCA1 and FADS1, which are closely associated with hepatic lipid metabolism. The present study has identified some modules, genes and pathways that may be the major contributors to the variation in feed efficiency among different cattle breeds, providing a new perspective on the molecular mechanisms of feed efficiency in beef cattle and a research basis for investigating molecular markers associated with feed efficiency in beef cattle. Show less
Early-life stress (ELS) was found to increase the risk of adolescent depression, and clinical evidence indicated that eicosapentaenoic acid (EPA) was decreased in patients with adolescent depression, Show more
Early-life stress (ELS) was found to increase the risk of adolescent depression, and clinical evidence indicated that eicosapentaenoic acid (EPA) was decreased in patients with adolescent depression, but the underlying mechanisms are unclear. Here, we utilized an ELS model of maternal separation with early weaning to explore the protective role of EPA in adolescent depression. We found that that ELS induced depression-like behavior rather than anxiety-like behavior in adolescent mice. RNA-sequencing results showed that ELS changed the transcription pattern in the liver, including 863 upregulated genes and 971 downregulated genes, especially those related to the biosynthesis of unsaturated fatty acids metabolism in the liver. Moreover, ELS decreased the expression of the rate-limiting enzymes, fatty acid desaturases 1/2 (FADS1/2), involved in the biosynthesis of EPA in the liver. Additionally, ELS reduced the levels of EPA in the liver, serum, and hippocampus, and EPA administration improved depression-like behavior-induced by ELS. Our results provide transcriptomic evidence that ELS increases the risk of adolescent depression by reducing the synthesis of unsaturated fatty acids in the liver, especially EPA, and suggest that supplementation with EPA should be investigated as a potential treatment for adolescent depression. Show less
Despite the increasing prevalence rate of nonalcoholic fatty liver disease (NAFLD) worldwide, efficient pharmacotherapeutic regimens against NAFLD still need to be explored. Previous studies found tha Show more
Despite the increasing prevalence rate of nonalcoholic fatty liver disease (NAFLD) worldwide, efficient pharmacotherapeutic regimens against NAFLD still need to be explored. Previous studies found that pioglitazone and metformin therapy could partly ameliorate NAFLD, but their combination therapy effects have not been researched. In the present study, we assessed the protective effects of metformin and pioglitazone combination therapy on liver lipid metabolism in high-fat diet (HFD)-fed mice and investigated the molecular mechanism. Male C57BL/6 mice were divided into five groups: normal control; HFD control; metformin monotherapy; pioglitazone monotherapy and combined therapy. After 8 weeks of pharmacological intervention, glucose and lipid metabolism characteristics, hepatic histology, lipidomics profiling and RNA-seq analysis were performed. The combination of pioglitazone and metformin significantly ameliorated HFD-induced metabolic disturbance and the hepatic oil red O area. A lipidomics analysis showed that combined therapy could significantly reduce the high levels of free fatty acids (FFA), diacylglycerol and triglycerides, while a set of glycerophospholipids and sphingolipids were increased in the combined therapy group. Consistently, an RNA-seq analysis also showed a remarkable reduction in genes associated with FFA uptake and de novo lipogenesis, including Pioglitazone and metformin might have a synergistic protective effect on NAFLD by improving hepatic lipid profiles in HFD-induced mice. Further studies are needed to verify the clinical effects. Show less
Eicosanoids are biologically active derivatives of polyunsaturated fatty acids with broad relevance to health and disease. We report a genome-wide association study in 8406 participants of the Atheros Show more
Eicosanoids are biologically active derivatives of polyunsaturated fatty acids with broad relevance to health and disease. We report a genome-wide association study in 8406 participants of the Atherosclerosis Risk in Communities Study, identifying 41 loci associated with 92 eicosanoids and related metabolites. These findings highlight loci required for eicosanoid biosynthesis, including FADS1-3, ELOVL2, and numerous CYP450 loci. In addition, significant associations implicate a range of non-oxidative lipid metabolic processes in eicosanoid regulation, including at PKD2L1/SCD and several loci involved in fatty acyl-CoA metabolism. Further, our findings highlight select clearance mechanisms, for example, through the hepatic transporter encoded by SLCO1B1. Finally, we identify eicosanoids associated with aspirin and non-steroidal anti-inflammatory drug use and demonstrate the substantial impact of genetic variants even for medication-associated eicosanoids. These findings shed light on both known and unknown aspects of eicosanoid metabolism and motivate interest in several gene-eicosanoid associations as potential functional participants in human disease. Show less
Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide associatio Show more
Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P Show less
Temporal oscillations in intestinal nutrient processing and absorption are coordinated by the local clock, which leads to the hypothesis that the intestinal clock has major impacts on shaping peripher Show more
Temporal oscillations in intestinal nutrient processing and absorption are coordinated by the local clock, which leads to the hypothesis that the intestinal clock has major impacts on shaping peripheral rhythms via diurnal nutritional signals. Here, we investigate the role of the intestinal clock in controlling liver rhythmicity and metabolism. Transcriptomic analysis, metabolomics, metabolic assays, histology, quantitative (q)PCR, and immunoblotting were performed with Bmal1-intestine-specific knockout (iKO), Rev-erba-iKO, and control mice. Bmal1 iKO caused large-scale reprogramming of the rhythmic transcriptome of mouse liver with a limited effect on its clock. In the absence of intestinal Bmal1, the liver clock was resistant to entrainment by inverted feeding and a high-fat diet. Importantly, Bmal1 iKO remodelled diurnal hepatic metabolism by shifting to gluconeogenesis from lipogenesis during the dark phase, leading to elevated glucose production (hyperglycaemia) and insulin insensitivity. Conversely, Rev-erba iKO caused a diversion to lipogenesis from gluconeogenesis during the light phase, resulting in enhanced lipogenesis and an increased susceptibility to alcohol-related liver injury. These temporal diversions were attributed to disruption of hepatic SREBP-1c rhythmicity, which was maintained via gut-derived polyunsaturated fatty acids produced by intestinal FADS1/2 under the control of a local clock. Our findings establish a pivotal role for the intestinal clock in dictating liver rhythmicity and diurnal metabolism, and suggest targeting intestinal rhythms as a new avenue for improving metabolic health. Our findings establish the centrality of the intestinal clock among peripheral tissue clocks, and associate liver-related pathologies with its malfunction. Clock modifiers in the intestine are shown to modulate liver metabolism with improved metabolic parameters. Such knowledge will help clinicians improve the diagnosis and treatment of metabolic diseases by incorporating intestinal circadian factors. Show less
Membrane fatty acid desaturase (FADS)-like superfamily proteins (FADSs) are essential for the synthesis of unsaturated fatty acids (UFAs). Recently, studies on FADS in fishes have mostly focused on ma Show more
Membrane fatty acid desaturase (FADS)-like superfamily proteins (FADSs) are essential for the synthesis of unsaturated fatty acids (UFAs). Recently, studies on FADS in fishes have mostly focused on marine species, and a comprehensive analysis of the FADS superfamily, including the FADS, stearoyl-CoA desaturase (SCD), and sphingolipid delta 4-desaturase (DEGS) families, in freshwater economic fishes is urgently required. To this end, we conducted a thorough analysis of the number, gene/protein structure, chromosomal location, gene linkage map, phylogeny, and expression of the FADS superfamily. We identified 156 FADSs genes in the genome of 27 representative species. Notably, FADS1 and SCD5 were lost in most freshwater fish and other teleosts. All FADSs proteins contain 4 transmembrane helices and 2-3 amphipathic α-helices. FADSs in the same family are often linked on the same chromosome; moreover, FADS and SCD or DEGS are frequently collocated on the same chromosome. In addition, FADS, SCD, and DEGS family proteins share similar evolutionary patterns. Interestingly, FADS6, as a member of the FADS family, exhibits a similar gene structure and chromosome location to that of SCD family members, which may be the transitional form of FADS and SCD. This study shed light on the type, structure, and phylogenetic relationship of FADSs in freshwater fishes, offering a new perspective into the functional mechanism analysis of FADSs. Show less
Growth traits are the economically important traits of sheep, and screening for genes related to growth and development is helpful for the genetic improvement of ovine growth traits. The fatty acid de Show more
Growth traits are the economically important traits of sheep, and screening for genes related to growth and development is helpful for the genetic improvement of ovine growth traits. The fatty acid desaturase 3 ( Show less
Prostate cancer is the most common malignant tumor of male urogenital system that occurs in prostate epithelium. However, relationship between CAV1 and KRT5 and prostate cancer remains unclear. The pr Show more
Prostate cancer is the most common malignant tumor of male urogenital system that occurs in prostate epithelium. However, relationship between CAV1 and KRT5 and prostate cancer remains unclear. The prostate cancer datasets GSE114740 and GSE200879 were downloaded from Gene Expression Omnibus generated by GPL11154 and GPL32170. De-batch processing was performed, differentially expressed genes (DEGs) were screened, and weighted gene co-expression network analysis. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis. Gene expression heat map was drawn and immune infiltration analysis was performed. Comparative toxicogenomics database analysis were performed to find the disease most related to core gene. In addition, the cell experiment was performed to verify the role of CAV1 and KRT5 by western blot. Divided into 4 groups: control, prostate cancer, prostate cancer-over expression, and prostate cancer- knock out. TargetScan screened miRNAs that regulated central DEGs; 770 DEGs were identified. According to Gene Ontology analysis, they were mainly concentrated in actin binding and G protein coupled receptor binding. In Kyoto Encyclopedia of Gene and Genome analysis, they were mainly concentrated in PI3K-Akt signal pathway, MAPK signal pathway, and ErbB signal pathway. The intersection of enrichment terms of differentially expressed genes and GOKEGG enrichment terms was mainly concentrated in ErbB signaling pathway and MAPK signaling pathway. Three important modules were generated. The protein-protein interaction network obtained 8 core genes (CAV1, BDNF, TGFB3, FGFR1, PRKCA, DLG4, SNAI2, KRT5). Heat map of gene expression showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) are highly expressed in prostate cancer tissues and low in normal tissues. Comparative toxicogenomics database analysis showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) were associated with prostate tumor, cancer, tumor metastasis, necrosis, and inflammation. CAV1 and KRT5 are up-regulated in prostate cancer. CAV1 and KRT5 are highly expressed in prostate cancer. The higher expression of CAV1 and KRT5, the worse prognosis. Show less
Pemigatinib is a selective fibroblast growth factor receptor (FGFR)1-3 inhibitor and has demonstrated acceptable tolerability and clinical activity in advanced solid tumors in Western population. This Show more
Pemigatinib is a selective fibroblast growth factor receptor (FGFR)1-3 inhibitor and has demonstrated acceptable tolerability and clinical activity in advanced solid tumors in Western population. This phase I trial evaluated pharmacokinetics/pharmacodynamics (PK/PD) characteristics, preliminary safety and efficacy of pemigatinib in Chinese patients with advanced, solid tumors. Patients with unresectable advanced or metastatic solid tumors bearing FGF/FGFR1-3 alterations received oral pemigatinib at 13.5 mg once daily (QD) on a 2-weeks-on/1-week-off schedule. The primary endpoint was PK/PD characteristics; secondary endpoints were safety and efficacy. Twelve patients were enrolled (median age: 61 years, 58.3% males). PK data demonstrated pemigatinib (13.5 mg QD) was rapidly absorbed with a geometric mean elimination half-life of 11.3 h. The geometric mean values of maximum serum concentration and area under the plasma concentration-time curve from 0 to 24 h at steady state were 215.1 nmol/L and 2636.9 h·nmol/L, respectively. The mean clearance adjusted by bioavailability at steady state was low (11.8 L/h), and the apparent oral volume of distribution was moderate (170.5 L). The PD marker, serum phosphate level, increased on days 8 and 15 of cycle 1 (mean: 2.25 mg/dL, CV% [percent coefficient of variation]: 31.3%) and decreased to baseline post 1 week off. Three (25.0%) patients experienced grade ≥ 3 treatment-emergent adverse events. Partial response was confirmed in one patient with FGFR1-mutant esophageal carcinoma and one with FGFR2-mutant cholagiocarcinoma. Pemigatinib had similar PK/PD characteristics to Western population and demonstrated an acceptable safety profile and potential anti-cancer benefit in Chinese patients with FGF/FGFR1-3 altered, advanced, solid tumor. (ClinicalTrials.gov: NCT04258527 [prospectively registered February 6, 2020]). Show less