👤 Jia-Xin Yu

Currently, only the general control of the risk factors is known to prevent lacunar cerebral infarction, but it is unknown which type of medication for controlling the risk factors has a causal relationship with reducing the risk of lacunar infarction. To unlock this medical mystery, drug-target Mendelian randomization analysis was applied to estimate the effect of common antihypertensive agents, hypolipidemic agents, and hypoglycemic agents on lacunar stroke. Lacunar stroke data for the transethnic analysis were derived from meta-analyses comprising 7338 cases and 254,798 controls. We have confirmed that genetic variants mimicking calcium channel blockers were found to most stably prevent lacunar stroke. The genetic variants at or near Show less

Tendinopathy is a disease with surging prevalence. Lacking understanding of molecular mechanisms impedes the development of therapeutic approaches and agents. Lysine lactylation (Kla) is a newly discovered post-translational modification related to glycolysis. It has long been noted that manipulation of glycolysis metabolism could affect tendon cell function, tendon homeostasis, and healing process of tendon. However, protein lactylation sites in tendinopathy remain unexplored. Here, we conducted the first proteome-wide Kla analysis in tendon samples harvested from patients with rotator cuff tendinopathy (RCT), which identified 872 Kla sites across 284 proteins. Compared with normal counterparts, 136 Kla sites on 77 proteins were identified as upregulated in the pathological tendon, while 56 sites on 32 proteins were downregulated. Function enrichment analysis demonstrated that the majority of proteins with upregulated Kla levels functioned in organization of the tendon matrix and cholesterol metabolism, accompanied by lower expression levels which meant impaired cholesterol metabolism and degeneration of the tendon matrix, indicating potential cross-talk between protein lactylation and expression levels. At last, by western blotting and immunofluorescence, we verified the correlation between high lactylation and the downregulation of matrix and cholesterol-related proteins including BGN, MYL3, TPM3, and APOC3. ProteomeXchange: PXD033146. Show less

Estrogen deficiency causes mitochondrial defects that precede pathological changes related to Alzheimer's disease (AD) in the mouse model of postmenopause. The aim of this study was to investigate in such a mouse model whether and how estrogen receptor β (ERβ) was involved in prevention of mitochondrial damage and protection of neurons in the hippocampus. A mouse model of postmenopausal AD was created by ovariectomizing female 3xTg-AD mice, some of which were subcutaneously injected for six weeks with the non-steroidal ERβ agonist diarylpropionitrile. ERβ expression in female C57BL/6J mice was knocked down using shRNA interference. The different groups of animals were compared in terms of cognitive function using the Y-maze test, new object recognition test, and Morris water maze test, expression of numerous proteins related to mitochondrial biogenesis, mitophagy, apoptosis, and mitochondrial membrane potential, as well as deposition of amyloid β and neurofibrillary tangles. To complement these in vivo studies, we probed the effects of diarylpropionitrile on ERβ expression, apoptosis, and mitochondrial homeostasis in primary rat hippocampal neurons treated with amyloid β. ERβ knockdown in C57BL/6J mice produced cognitive impairment, reduced mitochondrial biogenesis by downregulating PGC-1α, NRF1, mtTFA, and TOM20, and decreased mitophagy by downregulating Pink1, Parkin, and LC3B while upregulating PARIS and p62. ERβ knockdown promoted neuronal apoptosis by upregulating Cleaved-Caspase 9, Cleaved-Caspase 3, and Bax, while downregulating Bcl2 in hippocampus. Diarylpropionitrile mitigated cognitive decline in ovariectomized 3xTg-AD mice, which was associated with downregulation of BACE1, reduction of Aβ deposition, neurofibrillary tangles, and tau hyperphosphorylation, and upregulation of ERβ, increases in mitochondrial biogenesis and mitophagy, and decreases in apoptosis. The effects of diarylpropionitrile in mice were recapitulated in Aβ-injured primary rat hippocampal neurons. ERβ activation can support learning and memory and alleviate AD symptoms in the postmenopausal AD model, which may involve regulation of neuronal mitochondrial biogenesis and mitophagy via NRF1/PGC-1α. This study supports further research on ERβ as a therapeutic target for postmenopausal women with AD. Show less

To explore the mechanism of The active ingredients and targets of Through network pharmacology, 15 potential active ingredients and 103 drug-disease targets were identified. PPI analysis showed that the Show less

Liver metastasis is one of the most important reasons for high mortality of colorectal cancer (CRC). Growing evidence illustrates that lncRNAs play a critical role in CRC liver metastasis. Here we described a novel function and mechanisms of BACE1-AS promoting CRC liver metastasis. qRT-PCR and in situ hybridization were performed to examine the BACE1-AS level in CRC. IGF2BP2 binding to m6A motifs in BACE1-AS was determined by RIP assay and S1m-tagged immunoprecipitation. Transwell assay and liver metastasis mice model experiments were performed to examine the metastasis capabilities of BACE1-AS knockout cells. Stemness-like properties was examined by tumor sphere assay and the expression of stemness biomarkers. Microarray data were acquired to analyze the signaling pathways involved in BACE1-AS promoting CRC metastasis. BACE1-AS is the most up-regulated in metastatic CRC associated with unfavorable prognosis. Sequence blast revealed two m6A motifs in BACE1-AS. IGF2BP2 binding to these two m6A motifs is required for BACE1-AS boost in metastatic CRC. m6A modified BACE1-AS drives CRC cells migration and invasion and liver metastasis both in vitro and in vivo. Moreover, BACE1-AS maintains the stemness-like properties of CRC cells. Mechanically, BACE1-AS promoted TUFT1 expression by ceRNA network through miR-214-3p. CRC patients with such ceRNA network suffer poorer prognosis than ceRNA-negative patients. Depletion of TUFT1 mimics BACE1-AS loss. BACE1-AS activated Wnt signaling pathway in a TUFT1 dependent manner. BACE1-AS/miR-214-3p/TUFT1/Wnt signaling regulatory axis is essential for CRC liver metastasis. Pharmacologic inhibition of Wnt signaling pathway repressed liver metastasis and stemness-like features in BACE1-AS over-expressed CRC cells. Our study demonstrated BACE1-AS as a novel target of IGF2BP2 through m6A modification. m6A modified BACE1-AS promotes CRC liver metastasis through TUFT1 dependent activation of Wnt signaling pathway. Thus, targeting BACE1-AS and its downstream Wnt signaling pathways may provide a new opportunity for metastatic CRC intervention and treatment. Show less

Orexin and its receptors are closely related to the pathogenesis of Alzheimer's disease (AD). Although the expression of orexin system genes under physiological condition has circadian rhythm, the diurnal characteristics of orexin system genes, and its potential role in the pathogenesis in AD are unknown. In the present study, we hope to elucidate the diurnal characteristics of orexin system genes at the early stage of AD, and to investigate its potential role in the development of AD neuropathology. We firstly detected the mRNA levels of orexin system genes, AD risk genes and core clock genes (CCGs) in hypothalamus and hippocampus in 6-month-old male 3xTg-AD mice and C57BL/6J (wild type, WT) control mice, then analyzed diurnal expression profiles of all genes using JTK_CYCLE algorithm, and did the correlation analysis between expression of orexin system genes and AD risk genes or CCGs. In addition, the expression of β-amyloid protein (Aβ) and phosphorylated tau (p-tau) protein were measured. The results showed that the diurnal mRNA expression profiles of PPO, OX1R, OX2R, Bace2, Bmal1, Per1, Per2 and Cry1 in the hypothalamus, and gene expression of OX1R, OX2R, Bace1, Bmal1, Per1 and Cry2 in the hippocampus in 3xTg-AD mice were different from that in WT mice. Furthermore, there is positive correlation between orexin system genes and AD risk genes or CCGs in the brain in 3xTg-AD mice. In addition, the expression of Aβ and p-tau in hippocampus in 3xTg-AD mice were significantly increased, and the expression of p-tau is higher in night than in day. These results indicate that the abnormal expression profiles of orexin system genes and its interaction with AD risk genes or CCGs might exert important role in the pathogenesis of AD, which will increase the expression of Aβ and p-tau, and accelerate the development of AD. Show less

The Keap1-Nrf2 pathway has been established as a therapeutic target for Alzheimer's disease (AD). Directly inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 has been reported as an effective strategy for treating AD. Our group has validated this in an AD mouse model for the first time using the inhibitor 1,4-diaminonaphthalene NXPZ-2 with high concentrations. In the present study, we reported a new phosphodiester containing diaminonaphthalene compound, POZL, designed to target the PPI interface using a structure-based design strategy to combat oxidative stress in AD pathogenesis. Our crystallographic verification confirms that POZL shows potent Keap1-Nrf2 inhibition. Remarkably, POZL showed its high in vivo anti-AD efficacy at a much lower dosage compared to NXPZ-2 in the transgenic APP/PS1 AD mouse model. POZL treatment in the transgenic mice could effectively ameliorate learning and memory dysfunction by promoting the Nrf2 nuclear translocation. As a result, the oxidative stress and AD biomarker expression such as BACE1 and hyperphosphorylation of Tau were significantly reduced, and the synaptic function was recovered. HE and Nissl staining confirmed that POZL improved brain tissue pathological changes by enhancing neuron quantity and function. Furthermore, it was confirmed that POZL could effectively reverse Aβ-caused synaptic damage by activating Nrf2 in primary cultured cortical neurons. Collectively, our findings demonstrated that the phosphodiester diaminonaphthalene Keap1-Nrf2 PPI inhibitor could be regarded as a promising preclinical candidate of AD. Show less

BACE1 is essential for the generation of amyloid-β (Aβ) that likely initiates the toxicity in Alzheimer's disease (AD). BACE1 activity is mainly regulated by post-translational modifications, but the relationship between these modifications is not fully characterized. Here, we studied the effects of BACE1 SUMOylation on its phosphorylation and ubiquitination. We demonstrate that SUMOylation of BACE1 inhibits its phosphorylation at S498 and its ubiquitination in vitro. Conversely, BACE1 phosphorylation at S498 suppresses its SUMOylation, which results in promoting BACE1 degradation in vitro. Furthermore, an increase in BACE1 SUMOylation is associated with the progression of AD pathology, while its phosphorylation and ubiquitination are decreased in an AD mouse model. Our findings suggest that BACE1 SUMOylation reciprocally influences its phosphorylation and competes against its ubiquitination, which might provide a new insight into the regulations of BACE1 activity and Aβ accumulation. Show less

Danggui Buxue decoction (DBD) is a classic herbal decoction consisting of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) with a 5:1 wt ratio, which can supplement 'blood' and 'qi' (vital energy) for the treatment of clinical diseases. According to Traditional Chinese Medicine (TCM) theory, dementia is induced by Blood deficiency and Qi weakness, which causes a decline in cognition. However, the underlying mechanisms of DBD improving cognition deficits in neurodegenerative disease are no clear. This study aims at revealing the underlying mechanisms of DBD plays a protective role in the cognitive deficits and pathology process of Alzheimer's disease (AD). The APP/PS1 (Mo/HuAPP695swe/PS1-dE9) double transgenic mice were adopted as an experimental model of AD. Qualitative and quantitative analysis of 3 compounds in DBT was analyzed by HPLC. Morris water maze test, Golgi staining and electrophysiology assays were used to evaluate the effects of DBD on cognitive function and synaptic plasticity in APP/PS1 mice. Western blot, immunofluorescence and Thioflavin S staining were used for the pathological evaluation of AD. Monitoring the level of ATP, mitochondrial membrane potential, SOD and MDA to evaluate the mitochondrial function, and with the usage of qPCR and CHIP for the changes of histone post-translational modification. In the current study, we found that DBD could effectively attenuate memory impairments and enhance long-term potentiation (LTP) with concurrent increased expression of memory-associated proteins. DBD markedly decreased Aβ accumulation in APP/PS1 mice by decreasing the phosphorylation of APP at the Thr668 level but not APP, PS1 or BACE1. Further studies demonstrated that DBD restored mitochondrial biogenesis deficits and mitochondrial dysfunction. Finally, the restored mitochondrial biogenesis and cognitive deficits are under HADC2-mediated histone H4 lysine 12 (H4K12) acetylation at the peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) and N-methyl-D-aspartate receptor type 2B (GluN2B) promoters. These findings reveal that DBD could ameliorate mitochondrial biogenesis and cognitive deficits by improving H4K12 acetylation. DBD might be a promising complementary drug candidate for AD treatment. Show less

Dementia is the main clinical feature of Alzheimer's disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APP/PS1 mice. However, the effects of OXA on other types of cognitive deficits, especially in 3xTg-AD mice exhibiting both plaque and tangle pathologies, have not been reported. Furthermore, the potential electrophysiological mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid β (Aβ) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, Aβ levels, tau hyperphosphorylation, BACE1 and NEP expression, and circadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased Aβ and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA aggravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing Aβ production and decreasing Aβ clearance through disruption of the circadian rhythm and sleep-wake cycle. Show less

Alzheimer's disease presents an abnormal cognitive behavior. TgCtwh6 is one of the predominant T. gondii strains prevalent in China. Although T. gondii type II strain infection can cause host cognitive behavioral abnormalities, we do not know whether TgCtwh6 could also cause host cognitive behavioral changes. So, in this study, we will focus on the effect of TgCtwh6 on mouse cognitive behavior and try in vivo and in vitro to explore the underlying mechanism by which TgCtwh6 give rise to mice cognitive behavior changes at the cellular and molecular level. C57BL/6 mice were infected orally with TgCtwh6 cysts. From day 90 post-infection on, all mice were conducted through the open field test and then Morris water maze test to evaluate cognitive behavior. The morphology and number of cells in hippocampus were examined with hematoxylin-eosin (H&E) and Nissl staining; moreover, Aβ protein in hippocampus was determined with immunohistochemistry and thioflavin S plaque staining. Synaptotagmin 1, apoptosis-related proteins, BACE1 and APP proteins and genes from hippocampus were assessed by western blotting or qRT-PCR. Hippocampal neuronal cell line or mouse microglial cell line was challenged with TgCtwh6 tachyzoites and then separately cultured in a well or co-cultured in a transwell device. The target proteins and genes were analyzed by immunofluorescence staining, western blotting and qRT-PCR. In addition, mouse microglial cell line polarization state and hippocampal neuronal cell line apoptosis were estimated using flow cytometry assay. The OFT and MWMT indicated that infected mice had cognitive behavioral impairments. The hippocampal tissue assay showed abnormal neuron morphology and a decreased number in infected mice. Moreover, pro-apoptotic proteins, as well as BACE1, APP and Aβ proteins, increased in the infected mouse hippocampus. The experiments in vitro showed that pro-apoptotic proteins and p-NF-κBp65, NF-κBp65, BACE1, APP and Aβ proteins or genes were significantly increased in the infected HT22. In addition, CD80, pro-inflammatory factors, notch, hes1 proteins and genes were enhanced in the infected BV2. Interestingly, not only the APP and pro-apoptotic proteins in HT22, but also the apoptosis rate of HT22 increased after the infected BV2 were co-cultured with the HT22 in a transwell device. Neuron apoptosis, Aβ deposition and neuroinflammatory response involved with microglia polarization are the molecular and cellular mechanisms by which TgCtwh6 causes mouse cognitive behavioral abnormalities. Show less

In Alzheimer's disease (AD) brain, inflammatory activation regulates protein levels of amyloid-β-peptide (Aβ) and phosphorylated tau (p-tau), as well as neurodegeneration; however, the regulatory mechanisms remain unclear. We constructed APP- and tau-transgenic AD mice with deletion of IKKβ specifically in neurons, and observed that IKKβ deficiency reduced cerebral Aβ and p-tau, and modified inflammatory activation in both AD mice. However, neuronal deficiency of IKKβ decreased apoptosis and maintained synaptic proteins (e.g., PSD-95 and Munc18-1) in the brain and improved cognitive function only in APP-transgenic mice, but not in tau-transgenic mice. Additionally, IKKβ deficiency decreased BACE1 protein and activity in APP-transgenic mouse brain and cultured SH-SY5Y cells. IKKβ deficiency increased expression of PP2A catalytic subunit isoform A, an enzyme dephosphorylating cerebral p-tau, in the brain of tau-transgenic mice. Interestingly, deficiency of IKKβ in neurons enhanced autophagy as indicated by the increased ratio of LC3B-II/I in brains of both APP- and tau-transgenic mice. Thus, IKKβ deficiency in neurons ameliorates AD-associated pathology in APP- and tau-transgenic mice, perhaps by decreasing Aβ production, increasing p-tau dephosphorylation, and promoting autophagy-mediated degradation of BACE1 and p-tau aggregates in the brain. However, IKKβ deficiency differently protects neurons in APP- and tau-transgenic mice. Further studies are needed, particularly in the context of interaction between Aβ and p-tau, before IKKβ/NF-κB can be targeted for AD therapies. Show less

Alzheimer's disease (AD) is a critical neurodegenerative disease that manifests as progressive intellectual decline and is pathologically characterized by a progressive loss of neurons in the brain. Despite extensive research on this topic, the pathogenesis of AD is not fully understood, while the beta-amyloid (A Show less

To determine whether trimethylamine N-oxide (TMAO) would aggravate cognitive dysfunction from APP/PS1 mice and the potential protective effects of voluntary wheel running (VWR). TMAO impaired learning and memory abilities, and exercise reversed TMAO induced cognitive impairment. Serum TMAO, choline, betaine and TMA were significantly elevated from TMAO group, while exercise group had decreased TMAO, betaine and TMA level. TMAO group has significantly upregulated BACE1 from both hippocampus and cortex, also increased cathepsin B, p-Tau at Ser396&Ser404, GFAP, p-NF-κB p65 in cortex, while reduced BDNF, synaptophysin and PSD95 in hippocampus, also reduced occludin and ZO-1 from cortex, and reduced occludin from colon. In contrast, BACE1 from both hippocampus and cortex, also cathepsin B and p-Tauser396 from cortex were reduced, BDNF, snaptophysin, and PSD95 from hippocampus, ZO-1 from cortex, and occludin from colon were elevated post exercise compared to TMAO group. Exercise elevated α diversity index of cecal content, and TMAO and exercise affected gut microbiota profiles differentially. In conclusion, TMAO led to gut microbiota dysbiosis, impaired gut-brain integrity, elevated neuroinflammation, Aβ pathology and tau phosphorylation, disordered synaptic function; and exercise could reverse TMAO induced cognitive dysfunction via improving the above markers. The potential deleterious effects of TMAO on cognitive function need to be validated in humans, also dosages of exercise for exerting neuroprotective effects against TMAO induced cognitive impairment. Show less

Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy. Show less

Background The risk of atherosclerotic cardiovascular disease (ASCVD) increases sharply with age. Some older individuals, however, remain unaffected despite high predicted risk. These individuals may carry cardioprotective genetic variants that contribute to resilience. Our aim was to assess whether asymptomatic older individuals without prevalent ASCVD carry cardioprotective genetic variants that contribute to ASCVD resilience. Methods and Results We performed a genome-wide association study using a 10-year predicted ASCVD risk score as a quantitative trait, calculated only in asymptomatic older individuals aged ≥70 years without prevalent ASCVD. Our discovery genome-wide association study of N=12 031 ASCVD event-free individuals from the ASPREE (Aspirin in Reducing Events in the Elderly) trial identified 2 independent variants, rs9939224 ( Show less

Observational studies have suggested an association between lipid-lowering drugs and inflammatory bowel disease (IBD) risk. This study aimed to assess the causal influence of lipid-lowering agents on IBD risk using Mendelian randomization analysis. In a population of 173,082 individuals of European ancestry, 55 single-nucleotide polymorphisms were identified as instrumental variables for 6 lipid-lowering drug targets (HMGCR, NPC1LC, PCSK9, LDLR, CETP and APOB). Summary statistics for the genome-wide association study of IBD, ulcerative colitis (UC) and Crohn's disease (CD) were obtained from the FinnGen consortium, Program in Complex Trait Genomics and UK Biobank. Inverse-variance weighted was employed as the primary MR method, and odds ratios (ORs) with 95% confidence intervals were reported as the results. Sensitivity analyses using conventional MR methods were conducted to assess result robustness. Gene-proxied inhibition of Niemann-Pick C1-like 1 (NPC1L1) was associated with an increased IBD risk (OR [95% CI]: 2.31 [1.38, 3.85]; p = .001), particularly in UC (OR [95% CI]: 2.40 [1.21, 4.74], p = .012), but not in CD. This finding was replicated in the validation cohort. Additionally, gene-proxied inhibition of low-density lipoprotein receptor was associated with reduced IBD (OR [95% CI]: .72 [.60, .87], p < .001) and UC risk (OR [95% CI]: .74 [.59, .92], p = .006), although this result was not replicated in the validation cohort. Other drug targets did not show significant associations with IBD, UC or CD risk. Inhibition of the lipid-lowering drug-target NPC1L1 leads to an increased IBD risk, mainly in the UC population. Show less

To assess the causal role of lipid traits and lipid-lowering agents in inflammatory bowel disease (IBD). Univariable mendelian randomization (MR) and multivariable MR (MVMR) analyses were conducted to evaluate the causal association between low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and IBD. Drug-targeted MR analyzed the effects of lipid-lowering drugs on IBD, and network MR was used to analyze potential mediation effects. The levels of HDL-C had an inverse relationship with the risk of Crohn's disease (CD, OR: 0.85, 95% CI: 0.73-0.98, Our study suggested a causal association between HDL-C and IBD, UC and CD. Genetically proxied inhibition of Show less

The development of site-specific, target-selective and biocompatible small molecule ligands as a fluorescent tool for real-time study of cellular functions of RNA G-quadruplexes (G4s), which are associated with human cancers, is of significance in cancer biology. We report a fluorescent ligand that is a cytoplasm-specific and RNA G4-selective fluorescent biosensor in live HeLa cells. The in vitro results show that the ligand is highly selective targeting RNA G4s including VEGF, NRAS, BCL2 and TERRA. These G4s are recognized as human cancer hallmarks. Moreover, intracellular competition studies with BRACO19 and PDS, and the colocalization study with G4-specific antibody (BG4) in HeLa cells may support that the ligand selectively binds to G4s in cellulo. Furthermore, the ligand was demonstrated for the first time in the visualization and monitoring of dynamic resolving process of RNA G4s by the overexpressed RFP-tagged DHX36 helicase in live HeLa cells. 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 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

Transglutaminase 2 (TG2) is a multifunctional protein that promotes or suppresses tumorigenesis, depending on intracellular location and conformational structure. Acyclic retinoid (ACR) is an orally administered vitamin A derivative that prevents hepatocellular carcinoma (HCC) recurrence by targeting liver cancer stem cells (CSCs). In this study, we examined the subcellular location-dependent effects of ACR on TG2 activity at a structural level and characterized the functional role of TG2 and its downstream molecular mechanism in the selective depletion of liver CSCs. A binding assay with high-performance magnetic nanobeads and structural dynamic analysis with native gel electrophoresis and size-exclusion chromatography-coupled multi-angle light scattering or small-angle X-ray scattering showed that ACR binds directly to TG2, induces oligomer formation of TG2, and inhibits the transamidase activity of cytoplasmic TG2 in HCC cells. The loss-of-function of TG2 suppressed the expression of stemness-related genes, spheroid proliferation and selectively induced cell death in an EpCAM+ liver CSC subpopulation in HCC cells. Proteome analysis revealed that TG2 inhibition suppressed the gene and protein expression of exostosin glycosyltransferase 1 (EXT1) and heparan sulfate biosynthesis in HCC cells. In contrast, high levels of ACR increased intracellular Ca 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 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

Metabolic pathways are related to physiological functions and disease states and are influenced by genetic variation and environmental factors. Hispanics/Latino individuals have ancestry-derived genomic regions (local ancestry) from their recent admixture that have been less characterized for associations with metabolite abundance and disease risk. We performed admixture mapping of 640 circulating metabolites in 3887 Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Metabolites were quantified in fasting serum through non-targeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Replication was performed in 1856 nonoverlapping HCHS/SOL participants with metabolomic data. By leveraging local ancestry, this study identified significant ancestry-enriched associations for 78 circulating metabolites at 484 independent regions, including 116 novel metabolite-genomic region associations that replicated in an independent sample. Among the main findings, we identified Native American enriched genomic regions at chromosomes 11 and 15, mapping to FADS1/FADS2 and LIPC, respectively, associated with reduced long-chain polyunsaturated fatty acid metabolites implicated in metabolic and inflammatory pathways. An African-derived genomic region at chromosome 2 was associated with N-acetylated amino acid metabolites. This region, mapped to ALMS1, is associated with chronic kidney disease, a disease that disproportionately burdens individuals of African descent. Our findings provide important insights into differences in metabolite quantities related to ancestry in admixed populations including metabolites related to regulation of lipid polyunsaturated fatty acids and N-acetylated amino acids, which may have implications for common diseases in populations. Show less

High-fat diet (HFD) consumption is an important reason for promoting depression, but the mechanism is unclear. The present study aims to explore the relationship between metabolic disturbance and HFD-induced depression-like behaviors. Depression models were established by HFD consumption and chronic unpredictable mild stress (CUMS) in mice. Enzyme-linked immunosorbent assay, western blotting, real-time polymerase chain reaction, gas chromatography and metabolomic analysis were undertaken to investigate the 5-hydroxytryptamine (5-HT) system, neuroinflammation and to identify altered lipid metabolic pathways. Depression-like behaviors, impaired 5-HT neurotransmission and disordered lipid metabolism were observed upon HFD consumption. Despite a similar reduction of high-density lipoprotein cholesterol in CUMS and HFD group, high levels of body low-density lipoprotein cholesterol in the HFD group could help distinguish HFD from CUMS. Levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and inflammation-related metabolites were increased in HFD mice, so a link between depression and inflammation was postulated. Different metabolites were enriched in the two groups. The linoleic acid (LA) metabolic pathway and expression of fatty acid desaturase (FADS)1 and FADS2 (key enzymes in LA metabolic pathway) were enhanced significantly in HFD mice compared with the control group. Causality analyses for HFD and inflammation-related features were not undertaken. HFD-induced depression-like behaviors was characterized by more severely disordered metabolism of lipids (especially in the LA metabolic pathway) and increased levels of inflammatory mediators, which might be the reasons for the disturbance of serotonergic system in hippocampus. Show less

Consumer demand for tasty and quality meat has been quickly increasing. This study investigated how dietary supplemented rutin affects meat quality, muscle fatty acid profile, and antioxidant capacity in the Chinese indigenous Qingyuan partridge chicken. A cohort of 180 healthy 119-day-old chickens was subjected to a randomized assignment into three groups, identified as the control, R200, and R400 groups, with respective supplementation of 0, 200, and 400 mg/kg of rutin. The results revealed insignificance in growth performance, namely, average daily gain, average daily feed intake, and feed-to-gain ratio, across the various treatment groups ( 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 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

Fibroblast growth factor receptor 1 (FGFR1) is a core component of the FGFs/FGFR pathway that activates multiple signalling pathways, including ERK1/2, PI3K/AKT, PLCγ, and NF-κB. Aberrant expression of FGFR1 due to gene amplification, chromosome rearrangement, point mutation, and epigenetic deregulations, have been reported in various cancers. FGFR1 overexpression has also been reported in prostate cancer (PCa), but the underlining mechanisms are not clear. Here we report a novel circular RNA, circFGFR1 Show less

Fetal bovine serum (FBS), which contains various nutrients, comprises 20% of the growth medium for cell-cultivated meat. However, ethical, cost, and scientific issues, necesitates identification of alternatives. In this study, we investigated commercially manufactured serum-free media capable of culturing Hanwoo satellite cells (HWSCs) to identify constituent proliferation enhancing factors. Six different serum-free media were selected, and the HWSC proliferation rates in these serum-free media were compared with that of control medium supplemented with 20% FBS. Among the six media, cell proliferation rates were higher only in StemFlex Show less

Osteosarcoma is a malignant tumor with high metastatic potential, such that the overall 5-year survival rate of patients with metastatic osteosarcoma is only 20%. Therefore, it is necessary to unravel the mechanisms of osteosarcoma metastasis to identify predictors of metastasis by which to develop new therapies. Fibroblast growth factor 2 (FGF2) is a growth factor involved in embryonic development, cell migration, and proliferation. The overexpression of FGF2 and FGF receptors (FGFRs) has been shown to enhance cancer cell proliferation in lung, breast, gastric, and prostate cancers as well as melanoma. Nonetheless, the roles of FGF2 and FGFRs in human osteosarcoma cells remain unknown. In the present study, we found that FGF2 was overexpressed in human osteosarcoma sections and correlated with lung metastasis. Treatment of FGF2 induced migration activity, invasion activity, and intercellular adhesion molecule (ICAM)-1 expression in osteosarcoma cells. In particular, the downregulation or antagonism of FGFR1-4 suppressed FGF2-induced ICAM-1 expression and cancer cell migration. Furthermore, FGFR1, FGFR2, FGFR3, and FGFR4 were involved in FGF2-induced the phospholipase Cβ/protein kinase Cα/proto-oncogene c-Src signaling pathway and triggered c-Jun nuclear translocation. Subsequent c-Jun upregulation of activator protein-1 transcription activity on the ICAM-1 promoter led to an increased migration of osteosarcoma cells. Moreover, the knockdown of endogenous FGF2 suppressed ICAM-1 expression and migration of osteosarcoma cells. These findings suggest that FGF2/FGFR1-4 signaling promotes metastasis via its direct downstream target gene ICAM-1, revealing a novel potential therapeutic target for osteosarcoma. Show less

The mechanism by which aerobic exercise promotes cardiac function after myocardial infarction (MI) is still not fully understand. In this study, we investigated the role of fibroblast growth factor 21 (FGF21) in exercise protecting the cardiac function of MI mice. In vivo, MI was induced by left anterior descending coronary artery ligation in wild-type and Show less