Alzheimer's disease (AD), a common form of dementia, has been reported to influence 27 million individuals globally. Several risk factors including oxidative stress, gut microbiota imbalance, and cogn Show more
Alzheimer's disease (AD), a common form of dementia, has been reported to influence 27 million individuals globally. Several risk factors including oxidative stress, gut microbiota imbalance, and cognitive activity are reported to be closely associated with the initiation or progression of AD. Although miR-483-3p was identified to be downregulated in AD patient serum. However, the biological role and mechanism of miR-483-3p remained unknown in AD. Here, we explored the role of miR-483-3p in AD. Sprague-Dawley rats were injected with homocysteine (Hcy) to establish an AD animal model. The Morris water maze tests and contextual fear tests were conducted to assess the cognitive and memory abilities of rats. TUNEL staining was utilized to determine cell apoptosis. Luciferase reporter assay was used to evaluate the binding relation between miR-483-3p and exportin 1 (XPO1). Homocysteine treatment (400 μg/kg) induced the learning, cognitive and memory defects of rats. miR-483-3p was downregulated in Hcy-treated rat hippocampus. Functionally, miR-483-3p alleviated cell apoptosis and impairments of learning and memory abilities in Hcy-treated rats. In addition, miR-483-3p inhibited cell apoptosis and protein level of AD-associated factors (APP, BACE1, and Aβ1-42) in PC12 cells. In mechanism, miR-483-3p was confirmed to target XPO1 in PC12 cells. XPO1 displayed high level in rat hippocampus and was negatively correlated with miR-483-3p levels. Finally, XPO1 overexpression rescued the suppressive effect of miR-483-3p on cell apoptosis and protein levels of AD-associated factors. miR-483-3p alleviates neural cell apoptosis and impairments of learning and memory abilities by targeting XPO1 in AD. Show less
Glucocorticoid (GC), secreted by adrenal cortex, plays important roles in regulating many physiological functions, while chronic stress level of GC exposure has many adverse effects on the structure a Show more
Glucocorticoid (GC), secreted by adrenal cortex, plays important roles in regulating many physiological functions, while chronic stress level of GC exposure has many adverse effects on the structure and function of hippocampal neurons, and is closely implicated to the deterioration of Alzheimer's disease (AD). Oxidative stress and neuroinflammation play an important role in the occurrence and development of AD. However, it is still unclear whether chronic GC exposure promotes beta-amyloid (Aβ) accumulation and neuronal injury by increasing oxidative stress and neuroinflammation. In this study, we investigated the effects of chronic GC exposure on NOX2-NLRP1 inflammasome activation and the protective effects of NLRP1-siRNA against GC-induced neuronal injury in primary hippocampal neurons of APP/PS1 mice. The results showed that chronic dexamethasone (DEX, 1 µM) exposure 72 h had no significant effect on the primary hippocampal neurons of WT mice, but significantly increased Aβ Show less
Arctigenin (Arc) is a phenylpropanoid dibenzylbutyrolactone lignan in Arctium lappa L, which has been widely applied as a traditional Chinese herbal medicine for treating inflammation. In the present Show more
Arctigenin (Arc) is a phenylpropanoid dibenzylbutyrolactone lignan in Arctium lappa L, which has been widely applied as a traditional Chinese herbal medicine for treating inflammation. In the present study, we explored the neuroprotective effect and the potential mechanisms of arctigenin against LPS-evoked neuroinflammation, neurodegeneration, and memory impairments in the mice hippocampus. Daily administration of arctigenin (50 mg/kg per day, i.g.) for 28 days revealed noticeable improvements in spatial learning and memory deficits after exposure to LPS treatment. Arctigenin prevented LPS-induced neuronal/synaptic injury and inhibited the increases in Abeta (Aβ) generation and the levels of amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1). Moreover, arctigenin treatment also suppressed glial activation and reduced the production of proinflammatory cytokines. In LPS-treated BV-2 microglial cells and mice, activation of the TLR4 mediated NF-κB signaling pathway was significantly suppressed by arctigenin administration. Mechanistically, arctigenin reduced the LPS-induced interaction of adiponectin receptor 1 (AdipoR1) with TLR4 and its coreceptor CD14 and inhibited the TLR4-mediated downstream inflammatory response. The outcomes of the current study indicate that arctigenin mitigates LPS-induced apoptotic neurodegeneration, amyloidogenesis and neuroinflammation as well as cognitive impairments, and suggest that arctigenin may be a potential therapeutic candidate for neuroinflammation/neurodegeneration-related diseases. Show less
Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid β plaques (Aβ) is a central hallmark of AD. Accumulating evidence suggest that shifting amyloid precursor p Show more
Alzheimer's disease (AD) is the most common neurodegenerative disease. Deposition of amyloid β plaques (Aβ) is a central hallmark of AD. Accumulating evidence suggest that shifting amyloid precursor protein (APP) metabolism pathway to non-amyloidogenic ways and inducing autophagy play key roles in AD pathology. In published reports, there is no research on the APP metabolic process of Terminalia chebula Retz. (T. Chebula). The study aims to assess the effects of T. Chebula in AD transgenic SH-SY5Y cells to determine its underlying mechanisms on reducing Aβ level by regulating APP metabolic process. The effects of T. Chebula water extract (TWE) on APPswe transgenic SH-SY5Y cells were analyzed by cell viability. ELISA used to quantify extracellular Aβ Treatment with TWE significantly suppressed the Aβ In summary, our finding first time expounded that TWE can inhibit the generation of Aβ Show less
Memory deficits and loss are the earliest and most prominent features of Alzheimer's disease (AD). This study was aimed to clarify the mechanistic basis of an active fraction of
To explore the expression relationship and significance of long chain non-coding RNA nuclear-enriched abundant transcript 1 (LncRNA NEAT1) and miR-27a-3p in serum and cerebrospinal fluid of patients w Show more
To explore the expression relationship and significance of long chain non-coding RNA nuclear-enriched abundant transcript 1 (LncRNA NEAT1) and miR-27a-3p in serum and cerebrospinal fluid of patients with Alzheimer's disease (AD). Sixty-six AD patients received by the Department of Neurology of our hospital from October 2019 to September 2021 were gathered, according to the Clinical Dementia Rating Scale (CDR) score, they were grouped into mild group (≤1 point, n = 41) and moderate-to-severe group (> 1 point, n = 25). Another 32 cases of serum and cerebrospinal fluid samples from outpatient physical examination personnel were regarded as the control group. The general materials on all subjects was recorded and cognition was assessed;real-time quantitative PCR was performed to measure the expression levels of miR-27a-3p and NEAT1 in serum and cerebrospinal fluid;enzyme-linked immunosorbent assay was performed to measure the protein levels of β-amyloid precursor protein cleaving enzyme 1 (BACE1), β-amyloid (Aβ) 40 and Aβ42 in cerebrospinal fluid;Spearman's method was performed to analyze the correlation of serum miR-27a-3p and NEAT1 levels with MMSE and MoCA scores;Pearson method was performed to analyze the correlation between serum miR-27a-3p and NEAT1 levels and Aβ deposition standard uptake value ratio (SUVR) and cerebrospinal fluid miR-27a-3p, NEAT1, BACE1, Aβ42 and Aβ40 levels. The MMSE score, MoCA score, serum miR-27a-3p level, cerebrospinal fluid miR-27a-3p, Aβ42 levels and Aβ42/Aβ40 ratio of AD patients in mild group and moderate-to-severe group were all lower than those in the control group, and the moderate-to-severe group were lower than the mild group (all P < 0.05);the serum NEAT1 level, SUVR, and cerebrospinal fluid NEAT1 and BACE1 levels were higher than those in the control group, and the moderate-to-severe group were higher than the mild group (all P < 0.05). Serum NEAT1 level in AD patients was positively correlated with SUVR, cerebrospinal fluid NEAT1 and BACE1 (r = 0.350, 0.606, 0.341, all P < 0.05);serum miR-27a-3p level was positively correlated with cerebrospinal fluid miR-27a-3p level (r = 0.695, P < 0.05), and negatively correlated with SUVR and cerebrospinal fluid BACE1 level (r = - 0.521, - 0.447, both P < 0.05). The expression trends of NEAT1 and miR-27a-3p in the serum and cerebrospinal fluid of AD patients are consistent, the level of NEAT1 is increased, and the level of miR-27a-3p is decreased. The levels of the two are negatively correlated, which is related to the degree of Aβ deposition in the brain of AD patients and is involved in the progression of AD. Show less
Methamphetamine (Meth), a central nervous system (CNS) stimulant with strong neurotoxicity, causes progressive cognitive impairment with characterized neurodegenerative changes. However, the mechanism Show more
Methamphetamine (Meth), a central nervous system (CNS) stimulant with strong neurotoxicity, causes progressive cognitive impairment with characterized neurodegenerative changes. However, the mechanism underlying Meth-induced pathological changes remains poorly understood. In the current study, Meth elicited a striking accumulation of the pathological proteins hyperphosphorylated tau (p-tau) and amyloid beta (A Show less
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been appli Show more
Traditional Chinese herbal medicine draws more attention to explore an effective therapeutic strategy for Alzheimer's disease (AD). Shenqi Yizhi granule (SQYG), a Chinese herbal recipe, has been applied to ameliorate cognitive impairment in mild-to-moderate AD patients. However, the overall molecular mechanism of SQYG in treating AD has not been clarified. This study aimed to investigate the molecular mechanism of SQYG on AD using an integration strategy of network pharmacology and molecular docking. The active compounds of SQYG and common targets between SQYG and AD were screened from databases. The herb-compound network, compound-target network, and protein-protein interaction network were constructed. The enrichment analysis of common targets and molecular docking were performed. 816 compounds and 307 common targets between SQYG and AD were screened. KEGG analysis revealed that common targets were mainly enriched in lipid metabolism, metal ion metabolism, IL-17 signaling pathway, GABA receptor signaling, and neuroactive ligand-receptor interaction. Molecular docking analysis showed high binding affinity between ginsenoside Rg1 and A The therapeutic mechanisms of SQYG on AD were associated with regulating lipid metabolism, metal ion metabolism, IL-17 signaling pathway, and GABA receptor signaling. Ginsenoside Rg1, tanshinone IIA, baicalin, astragaloside IV, and folic acid may play an important role in AD treatment. Show less
Branched-chain amino acids (BCAAs) are essential amino acids in human bodies. They have complex metabolic pathways and various metabolites. Both BCAAs and its metabolites are involved in various proce Show more
Branched-chain amino acids (BCAAs) are essential amino acids in human bodies. They have complex metabolic pathways and various metabolites. Both BCAAs and its metabolites are involved in various processes such as protein anabolism and catabolism, energy supply, signaling transduction and so on. Previous studies have observed the widely alternations of BCAAs and its related proteins in multiple tumor phenotypes, which suggests that BCAAs metabolic disorders may have emerged as a powerful factor for tumor metabolism reprogramming. BCAAs metabolism has a pivotal role in tumorigenesis and progression, including cell growth, proliferation, migration, invasion, and so on. In this review, we try to shed light on the crucial role of BCAAs metabolic disorders in different tumor types by focusing on the impacts of metabolic disorders of BCAAs and discussing the notable proteins involved in cancer metabolic reprogramming of BCAAs, such as BCAT1/2, BCKDH-BCKDK-PPM1K complex, transporters of BCAAs and its metabolites, transcription factors and so on, and present several possible diagnose approaches and therapies to BCAAs-related cancers. Show less
Empagliflozin (EMPA) is the first sodium-glucose co-transporter 2 inhibitor to significantly reduce cardiovascular and kidney complications in type 2 diabetes mellitus. Given this, we speculate that E Show more
Empagliflozin (EMPA) is the first sodium-glucose co-transporter 2 inhibitor to significantly reduce cardiovascular and kidney complications in type 2 diabetes mellitus. Given this, we speculate that EMPA may have the potential to intervene in diabetic retinopathy (DR), which is another diabetes-specific microvascular complication. Db/db mice were treated with EMPA for different periods to observe the retinas and related mechanisms. EMPA effectively balanced body weight and blood glucose levels, mitigated ocular edema and microaneurysm in db/db mice. EMPA significantly inhibited oxidative stress, apoptosis and recovered tight junction in diabetic retinas. MS/MS analyses showed that EMPA suppressed aberrant branched-chain amino acid (BCAAs) accumulation in db/db retinas, which led to the inhibition of the mammalian target of rapamycin activation, downregulation of inflammation, and angiogenic factors, including TNF-ɑ, IL-6, VCAM-1, and VEGF induced by diabetes. Furthermore, branched-chain α-keto acids (BCKAs), which are catabolites of BCAAs, were increased in diabetic retinas and decreased with EMPA application. Moreover, branched-chain ketoacid dehydrogenase kinase (BCKDK) was enhanced, BCKDHA and BCKDHB were decreased in diabetic retinas. This could be reversed by EMPA treatment, thus promoting BCAAs catabolism to decrease BCAAs and BCKAs accumulation in diabetic retinas. The high levels of BCAAs in the plasma and enhanced L-type amino acid transporter 1 (LAT1) were responsible for the high levels of BCAAs in diabetic retinas, which could be inhibited by EMPA. Overall, EMPA could ameliorate DR manifestations. The normalization of BCAAs catabolism and intake may play a role in this process. This study supports EMPA as a protective drug against DR. Show less
Platelet activation is commonly detected after infection by multiple viruses such as human immunodeficiency virus (HIV), H1N1 influenza, Hepatitis C virus (HCV), Ebola virus (EBV), and Dengue virus (D Show more
Platelet activation is commonly detected after infection by multiple viruses such as human immunodeficiency virus (HIV), H1N1 influenza, Hepatitis C virus (HCV), Ebola virus (EBV), and Dengue virus (DENV). Non-coding RNAs (ncRNAs) constitute the majority of the human transcribed genome, but the biology of platelet ncRNAs is largely unexplored. In this study, we performed microarray profiling to characterize the expression profile of human platelets infected with EBV in vitro after 2 h. A total of 187 long non-coding RNAs (lncRNAs) displayed differences, of which 114 were upregulated and 73 were downregulated; 78 microRNAs (miRNAs) showed differences, including 73 upregulated and 5 downregulated; 808 mRNAs displayed differences, among which 367 were upregulated and 441 were downregulated. Gene ontology (GO) analysis mostly related to G protein-coupled receptor signaling pathway, detection of chemical stimulus involved in sensory perception of smell and regulation of transcription by RNA polymerase II. Pathway analysis showed that the differentially expressed genes were mainly enriched in cell metabolism and immune-related response. A ceRNA network was established based on predicting regulatory pairs in differentially expressed genes, in which hsa-miR-6877-3p had the highest regulatory capability (degree = 31), FAM230A was the lncRNA with the highest regulatory capability (degree = 28). According to the EBV related miRNA regulation network, it revealed that ebv-miR-BART19-3p had the most target genes and BRWD1, FAM126B, TFRC and JMY were the genes most regulated by EBV-related miRNAs. After overlapping the three networks, we found that the EIFAK2 gene was strongly correlated with autologous ncRNAs, including hsa-miR-1972, hsa-miR-504-3p and hsa-miR-6825-5p, as well as with EBV ncRNAs, including EBER1, EBER2, miR-BART7-3p and miR-BART16. The present study contributes to a better understanding of the expression profiling of ncRNAs and their functions in platelets activated by EBV in vitro, and paves the way to further study on platelet function. Show less
Neuroblastoma is the most common extracranial solid tumor of childhood, arising from the sympathetic nervous system. High-risk neuroblastoma (HRNB) remains a major therapeutic challenge with low survi Show more
Neuroblastoma is the most common extracranial solid tumor of childhood, arising from the sympathetic nervous system. High-risk neuroblastoma (HRNB) remains a major therapeutic challenge with low survival rates despite the intensification of therapy. This study aimed to develop a malignant-cell marker gene signature (MMGS) that might serve as a prognostic indicator in HRNB patients. Multi-omics datasets, including mRNA expression (single-cell and bulk), DNA methylation, and clinical information of HRNB patients, were used to identify prognostic malignant cell marker genes. MMGS was established by univariate Cox analysis, LASSO, and stepwise multivariable Cox regression analysis. Kaplan-Meier (KM) curve and time-dependent receiver operating characteristic curve (tROC) were used to evaluate the prognostic value and performance of MMGS, respectively. MMGS further verified its reliability and accuracy in the independent validation set. Finally, the characteristics of functional enrichment, tumor immune features, and inflammatory activity between different MMGS risk groups were also investigated. We constructed a prognostic model consisting of six malignant cell maker genes (MAPT, C1QTNF4, MEG3, NPW, RAMP1, and CDT1), which stratified patients into ultra-high-risk (UHR) and common-high-risk (CHR) group. Patients in the UHR group had significantly worse overall survival (OS) than those in the CHR group. MMGS was verified as an independent predictor for the OS of HRNB patients. The area under the curve (AUC) values of MMGS at 1-, 3-, and 5-year were 0.78, 0.693, and 0.618, respectively. Notably, functional enrichment, tumor immune features, and inflammatory activity analyses preliminarily indicated that the poor prognosis in the UHR group might result from the dysregulation of the metabolic process and immunosuppressive microenvironment. This study established a novel six-malignant cell maker gene prognostic model that can be used to predict the prognosis of HRNB patients, which may provide new insight for the treatment and personalized monitoring of HRNB patients. Show less
To evaluate the correlation of circulating C1q tumor necrosis factor-related protein 4 (CTRP4) with coronary artery disease (CAD) in type 2 diabetes mellitus patients. A total of 240 individuals with Show more
To evaluate the correlation of circulating C1q tumor necrosis factor-related protein 4 (CTRP4) with coronary artery disease (CAD) in type 2 diabetes mellitus patients. A total of 240 individuals with type 2 diabetes mellitus were enrolled in our center between January 2020 and December 2020. They were assigned into two groups, including the CAD and non-CAD groups, based on coronary angiography or computed tomography angiography findings. Serum CTRP4 levels were detected by an enzyme-linked immunosorbent assay kit. The association of CTRP4 with CAD was determined by logistic regression analysis. The predictive value of CTRP4 for CAD was calculated by receiver operating characteristic curve analysis. Median serum CTRP4 amounts were markedly elevated in the CAD group in comparison with the non-CAD group (10.37 vs 3.75 ng/mL, P < 0.01). Binary logistic regression showed that CTRP4 was associated with CAD and even the amount of coronary artery lesions (P < 0.05). In receiver operating characteristic curve analysis, the area under the receiver operating characteristic curve was greater for CTRP4 compared with HbA1c or CRP (0.87 vs 0.74, 0.87 vs 0.80, P < 0.01). The area under the curve for CTRP4 and glycated hemoglobin in combination was larger than that obtained for CTRP4 combined with CRP (0.91 vs 0.87, P < 0.01). According to the maximum Youden index criteria, the optimal cut-off of CTRP4 was 5.42 ng/mL, which yielded a sensitivity of 84.4% and a specificity of 76.7% in predicting CAD in type 2 diabetes mellitus patients. Serum CTRP4 levels are positively correlated with CAD occurrence and severity. Combining CTRP4 and glycated hemoglobin has a better predictive value for CAD in type 2 diabetes mellitus patients. Show less
Carotid atherosclerosis (CAS) is a common manifestation of macroangiopathy in type 2 diabetes mellitus (T2DM). C1Q/TNF-related protein 4 (CTRP4) was found to be involved in regulation of food intake b Show more
Carotid atherosclerosis (CAS) is a common manifestation of macroangiopathy in type 2 diabetes mellitus (T2DM). C1Q/TNF-related protein 4 (CTRP4) was found to be involved in regulation of food intake behaviors and glucolipid metabolism, which were also key factors in the development of CAS. However, the relationship between serum CTRP4 and CAS in T2DM remains unclear. A total of 111 participants with T2DM were enrolled in the study and were divided into 2 groups (T2DM group and T2DM + CAS group) according to the result of carotid ultrasound examinations. Serum CTRP4 levels were measured by enzyme linked immunosorbent assay (ELISA). Trend χ Serum CTRP4 concentrations in T2DM + CAS group were significantly lower compared with those in T2DM group [7.98 (5.53) vs. 11.29 (7.36) ng/ml, P < 0.01]. The risk of CAS in T2DM decreased with the increasing of CTRP4 quartiles (P for trend < 0.01). Binary stepwise logistic regression suggested that serum CTRP4 might be an independent influence factor for CAS in patients with T2DM (P < 0.01) and high concentrations of serum CTRP4 were related to low risk of CAS in T2DM. The concentrations of serum CTRP4 are lower in T2DM patients with CAS compared to those without CAS. Serum CTRP4 levels are negatively related to the risk of CAS in T2DM. Show less
Esophageal cancer (EC) is one of the most common human malignant tumors worldwide. Chromobox (CBX) family proteins are significant components of epigenetic regulatory complexes. It is reported that CB Show more
Esophageal cancer (EC) is one of the most common human malignant tumors worldwide. Chromobox (CBX) family proteins are significant components of epigenetic regulatory complexes. It is reported that CBXs play critical roles in the oncogenesis and development of various tumors. Nonetheless, their functions and specific roles in EC remain vague and obscure. We used multiple bioinformatics tools, including Oncomine, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), UALCAN, Kaplan-Meier plotter, cBioPortal, Metascape, TIMER2 and TISIDB, to investigate the expression profile, gene alterations and prognostic roles of CBX family proteins, as well as their association with clinicopathologic parameters, immune cells and immune regulators. In addition, RT-qPCR, Western blot, CCK8, colony formation, wound healing and transwell assays were performed to investigate the biological functions of CBX3 in EC cells. CBX3 and CBX5 were overexpressed in EC compared to normal tissues. Survival analysis revealed that high expression of CBX1 predicted worse disease-free survival (DFS) in EC patients. Functionally, CBXs might participate in mismatch repair, spliceosome, cell cycle, the Fanconi anemia pathway, tight junction, the mRNA surveillance pathway and the Hippo signaling pathway in EC development. Furthermore, CBXs were related to distinct immune cells infiltration and immune regulators. Additionally, depletion of CBX3 inhibited the proliferation, migration and invasion abilities of EC cells. Our study comprehensively investigated the expression pattern, prognostic value, and gene alterations of CBXs in EC, as well as their relationships with clinicopathologic variables, immune cells infiltration and immune regulators. These results suggested that CBX family proteins, especially CBX3, might be potential biomarkers in the progression of EC. Show less
The chromobox family, a critical component of epigenetic regulators, participates in the tumorigenesis and progression of many malignancies. However, the roles of the CBX family members (CBXs) in glio Show more
The chromobox family, a critical component of epigenetic regulators, participates in the tumorigenesis and progression of many malignancies. However, the roles of the CBX family members (CBXs) in glioblastoma (GBM) remain unclear. The mRNA expression of CBXs was analyzed in tissues and cell lines by Oncomine and Cancer Cell Line Encyclopedia (CCLE). The differential expression of CBXs at the mRNA level was explored in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases with the "beeswarm" R package. The protein expression of CBXs in GBM was further examined on Human Protein Atlas (HPA). The correlations between CBXs and IDH mutation and between CBXs and GBM subtypes were investigated in the TCGA portal and CGGA database with the "survminer" R package. The alteration of CBXs and their prognostic value were further determined CBXs presented significantly differential expressions in pan-cancers. CBX2/3/5/8 were upregulated, whereas CBX6/7 were downregulated at mRNA level in GBM of TCGA and CGGA databases. Similarly, high expression of CBX2/3/5 and low expression of CBX6/8 were further confirmed at the protein level in the HPA. CBX2/6/7 were positively correlated with IDH mutation and CBX1/2/4/5/8 were closely related to GBM subtypes. CBX7 and CBX8 presented the independent prognostic factors for GBM patient survival. GO and KEGG analyses indicated that CBXs were closely related to the histone H3-K36, PcG protein complex, ATPase, and Wnt pathway. The overexpression of CBX7 and underexpression of CBX8 significantly inhibited the proliferation and invasion of glioma cells Our results suggested that CBX7 and CBX8 served as independent prognostic indicators that promoted the proliferation and invasion of glioma cells, providing a promising strategy for diagnosing and treating GBM. Show less
Liver cancer is the fifth most prevalent malignant tumor, while hepatocellular carcinoma represents the most prevalent subtype worldwide. Previous studies have associated the chromobox family, critica Show more
Liver cancer is the fifth most prevalent malignant tumor, while hepatocellular carcinoma represents the most prevalent subtype worldwide. Previous studies have associated the chromobox family, critical components of epigenetic regulatory complexes, with development of many malignancies owing to their role in inhibiting differentiation and promoting proliferation of cancer cells. However, little is known regarding their function in development and progression of hepatocellular carcinoma. In the present study, we analyzed differential expression, prognostic value, immune cell infiltration, and gene pathway enrichment of chromobox family in hepatocellular carcinoma patients. Next, we performed Pearson's correlation analysis to determine the relationships between chromobox family proteins with tumor-immune infiltration. Results revealed that high expression of CBX1, CBX2, CBX3, CBX6, and CBX8 was associated with poor survival rates of hepatocellular carcinoma patients. These five factors were used to build prognostic gene models using LASSO Cox regression analysis. Results indicated that high expression of CBX2 and CBX3 proteins was significantly associated with poor prognosis for hepatocellular carcinoma patients. The resulting nomogram revealed that CBX3 and T stages were significantly correlated with prognosis of hepatocellular carcinoma patients. Notably, predictive CBX3 was strongly correlated with immune cell infiltration. Furthermore, results from functional enrichment analysis revealed that CBX3 was mainly involved in regulation of methylation of Histone H3-K27. Collectively, these findings suggest that CBX3 could be a biomarker for predicting prognosis of hepatocellular carcinoma patients. Show less
Clear cell renal cell carcinoma (ccRCC) accounts for 85% of all malignant renal tumors. Currently, the pathogenesis of ccRCC is not fully understood. Chromobox (CBX) family proteins are the major subu Show more
Clear cell renal cell carcinoma (ccRCC) accounts for 85% of all malignant renal tumors. Currently, the pathogenesis of ccRCC is not fully understood. Chromobox (CBX) family proteins are the major subunits of PcG complexes and are implicated in regulating mammalian development. The CBX family consists of eight members, namely, CBX1-8. Numerous studies have highlighted that each CBX protein exhibits distinct functions and prognostic roles in specific cancer types. In this study, in silico analysis indicated that CBX7 was downregulated in ccRCC and correlated with favorable prognosis in a ccRCC cohort. Subsequent studies showed that CBX7 inhibited cancer cell proliferation and invasion. Then, we showed that CBX7 downregulated ETS1 to inactivate the tumor necrosis factor (TNF) signaling pathway, which inhibited tumor proliferation and enhanced the sensitivity of ccRCC cells to tyrosine kinase inhibitors (TKIs). Moreover, we found that CBX7 was a bona fide substrate of RNF26. RNF26 promoted the degradation of CBX7 and enhanced ccRCC tumor growth. Therefore, our results revealed a novel RNF26/CBX7 axis that modulates the TNF signaling pathway in ccRCC. Show less
Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic an Show more
Within the human population, considerable variability exists between individuals in their susceptibility to develop obesity and dyslipidemia. In humans, this is thought to be caused by both genetic and environmental variation. APOE*3-Leiden.CETP mice, as part of an inbred mouse model in which mice develop the metabolic syndrome upon being fed a high-fat high-cholesterol diet, show large inter-individual variation in the parameters of the metabolic syndrome, despite a lack of genetic and environmental variation. In the present study, we set out to resolve what mechanisms could underlie this variation. We used measurements of glucose and lipid metabolism from a six-month longitudinal study on the development of the metabolic syndrome. Mice were classified as mice with either high plasma triglyceride (responders) or low plasma triglyceride (non-responders) at the baseline. Subsequently, we fitted the data to a dynamic computational model of whole-body glucose and lipid metabolism (MINGLeD) by making use of a hybrid modelling method called Adaptations in Parameter Trajectories (ADAPT). ADAPT integrates longitudinal data, and predicts how the parameters of the model must change through time in order to comply with the data and model constraints. To explain the phenotypic variation in plasma triglycerides, the ADAPT analysis suggested a decreased cholesterol absorption, higher energy expenditure and increased fecal fatty acid excretion in non-responders. While decreased cholesterol absorption and higher energy expenditure could not be confirmed, the experimental validation demonstrated that the non-responders were indeed characterized by increased fecal fatty acid excretion. Furthermore, the amount of fatty acids excreted strongly correlated with bile acid excretion, in particular deoxycholate. Since bile acids play an important role in the solubilization of lipids in the intestine, these results suggest that variation in bile acid homeostasis may in part drive the phenotypic variation in the APOE*3-Leiden.CETP mice. Show less
Choline has been shown to exert atherogenic effects in Apoe Female APOE*3-Leiden.CETP mice were fed an atherogenic diet alone or supplemented with choline, butyrate or their combination for 16 weeks. Show more
Choline has been shown to exert atherogenic effects in Apoe Female APOE*3-Leiden.CETP mice were fed an atherogenic diet alone or supplemented with choline, butyrate or their combination for 16 weeks. Interestingly, choline protected against fat mass gain, increased the abundance of anti-inflammatory gut microbes, and increased the expression of gut microbial genes involved in TMA and TMAO degradation. Butyrate similarly attenuated fat mass gain and beneficially modulated the gut microbiome, as shown by increased abundance of anti-inflammatory and short chain fatty acid-producing microbes, and inhibited expression of gut microbial genes involved in lipopolysaccharide synthesis. Both choline and butyrate upregulated hepatic expression of flavin-containing monooxygenases, and their combination resulted in highest circulating TMAO levels. Nonetheless, choline, butyrate and their combination did not influence atherosclerosis development, and TMAO levels were not associated with atherosclerotic lesion size. While choline and butyrate have been reported to oppositely modulate atherosclerosis development in Apoe Show less
Despite advances in colorectal cancer (CRC) treatment, most advanced CRC patients who experience disease progression after chemotherapy, targeted therapy, and immunotherapy face a situation in which t Show more
Despite advances in colorectal cancer (CRC) treatment, most advanced CRC patients who experience disease progression after chemotherapy, targeted therapy, and immunotherapy face a situation in which there is no available medicine. Thus, new therapeutic drugs for CRC are urgently needed. Studies have shown that cholesteryl ester transfer protein (CETP) has a vital role in tumor development and is a possible target for CRC therapy. We found that Evacetrapib, a CETP inhibitor, suppressed CRC cell growth by inhibiting the Wnt/β-catenin signaling pathway and activating the c-Jun NH2-terminal kinase (JNK) signaling pathway in CRC. Therefore, Evacetrapib displays an anti-cancer effect and is a possible option for treating CRC. Show less
Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by asthma-like attacks in its early stage, which is easily misdiagnosed as severe asthma. Therefore, new biomarkers for the early Show more
Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by asthma-like attacks in its early stage, which is easily misdiagnosed as severe asthma. Therefore, new biomarkers for the early diagnosis of EGPA are needed, especially for differentiating the diagnosis of asthma. To identify serum biomarkers that can be used for early diagnosis of EGPA and to distinguish EGPA from severe asthma. Data-independent acquisition (DIA) analysis was performed to identify 45 healthy controls (HC), severe asthma (S-A), and EGPA patients in a cohort to screen biomarkers for early diagnosis of EGPA and to differentiate asthma diagnosis. Subsequently, parallel reaction monitoring (PRM) analysis was applied to a validation cohort of 71 HC, S-A, and EGPA patients. Four candidate biomarkers were identified from DIA and PRM analysis-i.e., serum amyloid A1 (SAA1), fibrinogen-α (FGA), and serum amyloid P component (SAP)-and were upregulated in the EGPA group, while cholesteryl ester transfer protein (CETP) was downregulated in the EGPA group compared with the S-A group. Receiver operating characteristics analysis shows that, as biomarkers for early diagnosis of EGPA, the combination of SAA1, FGA, and SAP has an area under the curve (AUC) of 0.947, a sensitivity of 82.35%, and a specificity of 100%. The combination of SAA1, FGA, SAP, and CETP as biomarkers for differential diagnosis of asthma had an AUC of 0.921, a sensitivity of 78.13%, and a specificity of 100%, which were all larger than single markers. Moreover, SAA1, FGA, and SAP were positively and CETP was negatively correlated with eosinophil count. DIA-PRM combined analysis screened and validated four previously unexplored but potentially useful biomarkers for early diagnosis of EGPA and differential diagnosis of asthma. Show less
Inflammatory responses by the innate and adaptive immune systems protect against infections and are essential to health and survival. Many diseases including atherosclerosis, osteoarthritis, rheumatoi Show more
Inflammatory responses by the innate and adaptive immune systems protect against infections and are essential to health and survival. Many diseases including atherosclerosis, osteoarthritis, rheumatoid arthritis, psoriasis, and obesity involve persistent chronic inflammation. Currently available anti-inflammatory agents, including non-steroidal anti-inflammatory drugs, steroids, and biologics, are often unsafe for chronic use due to adverse effects. The development of effective non-toxic anti-inflammatory agents for chronic use remains an important research arena. We previously reported that oral administration of Oxy210, a semi-synthetic oxysterol, ameliorates non-alcoholic steatohepatitis (NASH) induced by a high-fat diet in APOE*3-Leiden.CETP humanized mouse model of NASH and inhibits expression of hepatic and circulating levels of inflammatory cytokines. Here, we show that Oxy210 also inhibits diet-induced white adipose tissue inflammation in APOE*3-Leiden.CETP mice, evidenced by the inhibition of adipose tissue expression of IL-6, MCP-1, and CD68 macrophage marker. Oxy210 and related analogs exhibit anti-inflammatory effects in macrophages treated with lipopolysaccharide in vitro, mediated through inhibition of toll-like receptor 4 (TLR4), TLR2, and AP-1 signaling, independent of cyclooxygenase enzymes or steroid receptors. The anti-inflammatory effects of Oxy210 are correlated with the inhibition of macrophage polarization. We propose that Oxy210 and its structural analogs may be attractive candidates for future therapeutic development for targeting inflammatory diseases. Show less
The search for potential gene loci that affect the pharmacodynamics and pharmacokinetics of ticagrelor is a matter of broad clinical interest. The objective of this study was to investigate the effect Show more
The search for potential gene loci that affect the pharmacodynamics and pharmacokinetics of ticagrelor is a matter of broad clinical interest. The objective of this study was to investigate the effect of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese subjects. This is a multi-center study in China, including three hospitals from Beijing, Nanchang, and Changsha. Healthy Chinese subjects aged 18-45 years with unknown genotypes were included. All subjects received a single oral dose of 90 mg of ticagrelor. Platelet aggregation and the area under the concentration-time curve for ticagrelor and its major active metabolite in plasma samples were assessed. Genome-wide association studies and candidate gene association analysis related to ticagrelor were performed. One hundred and seventy-five native Chinese subjects were enrolled and completed the study. According to the p value, the threshold of ticagrelor population was 6.57 × 10 Genetic variation affects the pharmacokinetics and pharmacodynamics of ticagrelor in healthy individuals. The detection of NUP153, SVEP1 gene variation will be helpful for pharmacodynamic prediction and evaluation, and the regulation of these genes may be the target of new drug development. Further studies are required to confirm the results and explore whether these single-nucleotide polymorphisms are associated only with platelet activity or also with cardiovascular events and all-cause mortality. NCT03161002. Show less
The aim of the study was to identify additional factors that contributed to coronary artery disease (CAD). We conducted integrative analysis on publicly available data from genome-wide association stu Show more
The aim of the study was to identify additional factors that contributed to coronary artery disease (CAD). We conducted integrative analysis on publicly available data from genome-wide association studies and quantitative trait locus studies by employing Mendelian randomization methods to examine the associations of gene expression in liver cells and circulating protein levels with LDL-C and CAD. We found that the mRNA expression levels of This study showed that regulatory SNPs in Show less
To explore the correlation of cytochrome B-245 alpha chain ( The study was a case-control trial. A total of 372 GAgP patients and 133 periodontally healthy controls were recruited. The The mean age of Show more
To explore the correlation of cytochrome B-245 alpha chain ( The study was a case-control trial. A total of 372 GAgP patients and 133 periodontally healthy controls were recruited. The The mean age of GAgP group and control group was (27.5±5.2) years and (28.8±7.1) years respectively. There was significant difference in age between the two groups ( Show less
Inhibition of the cholesteryl ester transfer protein (CETP) has been considered as a promising way for the treatment of cardiovascular disease (CVD) for three decades. However, clinical trials of seve Show more
Inhibition of the cholesteryl ester transfer protein (CETP) has been considered as a promising way for the treatment of cardiovascular disease (CVD) for three decades. However, clinical trials of several CETP inhibitors with various potencies have been marginally successful at best, raising doubts on the target drugability of CETP. The in-depth understanding of the glycosylated CETP structure could be beneficial to more definitive descriptions of the CETP function and the underlying mechanism. In this work, large-scale molecular dynamics simulations were performed to thoroughly explore the mechanism of glycans modulating CETP. Here, the extensive simulation results intensely suggest that glycan88 tends to assist CETP in forming a continuous tunnel throughout interacting with the upper-right region of the N-barrel, while it also could prevent the formation of a continuous tunnel by swinging toward the right-rear of the N-barrel. Furthermore, glycan240 formed stable H-bonds with Helix-B and might further stabilize the central cavity of CETP. Furthermore, the nonspecific involvement of the hydroxyl groups from the various glycans with protein core interactions and the similar influence of different glycans trapped at similar regions on the protein structure suggest that physiological glycan may lead to a similar effect. This study would provide valuable insights into devising novel methods for CVD treatment targeting CETP and functional studies about glycosylation for other systems. Show less