Valproic acid (VPA) is frequently used in the treatment of epilepsy. The adverse effects of VPA include hyperammonemia (HA) which is characterized by abnormally elevated blood ammonia level. Carbamoyl Show more
Valproic acid (VPA) is frequently used in the treatment of epilepsy. The adverse effects of VPA include hyperammonemia (HA) which is characterized by abnormally elevated blood ammonia level. Carbamoyl-Phosphate Synthase 1 (CPS1) is an enzyme catalyzing the initial step of removing ammonia from blood. Studies have demonstrated that the CPS1 polymorphism rs1047891-A allele carriers were susceptible to VPA-induced HA. However, the evidences remained controversial. In this study, we sought to validate the association between rs1047891 and VPA-induced HA by combining the association results from previous studies together. We first conducted a systematic meta-analysis to determine whether rs1047891 was statistically significant. Then, we further evaluated the pleiotropic effects of rs1047891 using published genome-wide association studies (GWAS) and UKBB results. A conditional analysis was conducted to investigate whether the association between rs1047891 and VPA-induced HA was mediated by cardiovascular or renal disease risk factors or vice versa. The allelic, dominant and recessive ORs of rs1047891-A were all significant in our fixed-effect meta-analysis. In GWAS catalog and UKBB data, rs1047891 was associated with basal metabolic rate, adiposity and hematology traits, cardiovascular and renal disease risk factors. We further proved that plasma HDL cholesterol and homocysteine level, in addition to eGFR by serum creatinine, were associated with VPA-induced HA risk independently from rs1047891 polymorphism. In conclusion, the SNP rs1047891 was associated with VPA-induce HA among epilepsy patients. Meanwhile, plasma HDL cholesterol and homocysteine level had independent effects from it. Show less
The aberrant expression of ceroid-lipofuscinosis 3 (CLN3) has been reported in a variety of human malignancies. However, the role of CLN3 in the progression and prognosis of hepatocellular carcinoma ( Show more
The aberrant expression of ceroid-lipofuscinosis 3 (CLN3) has been reported in a variety of human malignancies. However, the role of CLN3 in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. In this study, we found that CLN3 was frequently upregulated in HCC clinical samples and HCC-derived cell lines and was significantly correlated with an APF serum level ≥20 μg/L, a tumour size ≥5 cm, multiple tumours, and the absence of encapsulation. Kaplan-Meier showed that CLN3 upregulation predicted shorter recurrence-free survival (RFS) and overall survival (OS) time in HCC patients. Cox regression analysis revealed that CLN3 upregulation was an independent risk factor for RFS and OS. A functional study demonstrated that the knockdown of CLN3 expression profoundly suppressed the growth and metastasis of HCC cells both in vitro and in vivo. Mechanistic investigation revealed that the EGFR/PI3K/AKT pathway was essential for mediating CLN3 function. In conclusion, our results provide the first evidence that CLN3 contributes to tumour progression and metastasis and offer a potential prognostic predictor and therapeutic target for HCC. Show less
The current study reports a new, simple and fast method using a flake-like dysprosium molybdate (Dy2MoO6; FL-DyM) nanostructured material to detect the antibiotic drug metronidazole (METZ). This nanoc Show more
The current study reports a new, simple and fast method using a flake-like dysprosium molybdate (Dy2MoO6; FL-DyM) nanostructured material to detect the antibiotic drug metronidazole (METZ). This nanocomposite material was employed on the surface of a glassy carbon electrode (GCE) to develop the electrode (FL-DyM/GCE). Further, the synthesized FL-DyM was systematically characterized by powder X-ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray diffraction (EDS), elemental mapping, X-ray photoelectron spectroscopy (XPS), and Brunauer-Emmett-Teller (BET) analyses. Cyclic (CV) and differential pulse voltammetry (DPV) techniques were used to study the electrochemical properties. The FL-DyM/GCE-based sensor demonstrated excellent selectivity and sensitivity for the detection of the drug METZ, which could be attributed to the strong affinity of FL-DyM towards the -NO2 group in METZ, and the good electrocatalytic activity and conductivity of FL-DyM. The fabrication and optimization of the working electrode were accomplished with CV and DPV obtained by scan rate and pH studies. Compared to the bare GCE and other rare-earth metal molybdates, the FL-DyM/GCE sensor displayed a superior electrocatalytic activity response for METZ detection. The sensor demonstrated a good linear relationship over the concentration range of 0.01-2363 μM. The quantification and detection limits were found to be 0.010 μM and 0.0030 μM, respectively. The FL-DyM/GCE sensor displayed excellent selectivity, repeatability, reproducibility, and stability for the detection of METZ in human urine and commercial METZ tablet samples, which validates the new technique for efficient drug sensing in practical applications. Show less
Recently, the role of microRNA-31-5p (miR-31-5p) in gene expression regulation has been reported in various cancers. Studies have shown that Wnt/β-catenin signaling pathway is involved in the prolifer Show more
Recently, the role of microRNA-31-5p (miR-31-5p) in gene expression regulation has been reported in various cancers. Studies have shown that Wnt/β-catenin signaling pathway is involved in the proliferation and invasion of osteosarcoma (OS) cells. Therefore, this study aims to probe into the regulatory role of miR-31-5p targeting AXIN1 in OS cells through Wnt/β-catenin signaling pathway. Firstly, microarray expression profiles were used to screen differentially expressed miRNAs associated with OS. Next, OS and normal fibrous connective tissues as well as OS cell lines were obtained for investigating the role of miR-31-5p on OS. Then, the putative binding sites between miR-31-5p and AXIN1 were predicted and verified. The regulatory effects of miR-31-5p on proliferation and invasion as well as tumorigenic potential of OS cells targeting AXIN1 were also analyzed. Besides, the relationship between miR-31-5p and Wnt/β-catenin signaling pathway was assessed by immunofluorescence staining. The microarray dataset GSE63939 showed that miR-31-5p and AXIN1 were involved in OS. miR-31-5p expression increased while the expression of AXIN1 decreased in OS tissues and cells. AXIN1 was identified as a target gene of miR-31-5p, intense expression of which inhibited the transcription of AXIN1. Down-regulated miR-31-5p suppressed proliferation, invasion and tumorigenicity of OS cells through promoting AXIN1. Decreased miR-31-5p activated Wnt/β-catenin signaling pathway, as reflected by increased β-catenin translocation into nuclei, through up-regulating the transcription of AXIN1. All in all, repression of miR-31-5p targets AXIN1 to activate the Wnt/β-catenin signaling pathway, thus suppressing proliferation, invasion and tumorigenicity of OS cells. Show less
Via promoting synovitis, pannus growth and cartilage/bone destruction, fibroblast-like synovial cells (FLSs) play a significant role in the pathogenesis of rheumatoid arthritis (RA). In our study, rat Show more
Via promoting synovitis, pannus growth and cartilage/bone destruction, fibroblast-like synovial cells (FLSs) play a significant role in the pathogenesis of rheumatoid arthritis (RA). In our study, rats were induced with complete freund's adjuvant (CFA) to be animal models for studying the RA pathogenesis. Microtubule-associated Serine/Threonine-protein kinase 3 (MAST3) has been documented to play a critical role in regulating the immune response of IBD (Inflammatory bowel disease) and involved in the process of cytoskeleton organization, intracellular signal transduction and peptidyl-serine phosphorylation, but its role in the progression of RA remains unknown and is warranted for investigation. So, we tried our best to investigate the mechanism and signaling pathway of MAST3 in RA progression. In the synovial tissue and FLSs of AA rats, we have found that MAST3 was significantly up-regulated than normal. Furthermore, MAST3 overexpression could promote proliferation and inflammatory response of FLSs. In the aspect of mechanism, we discovered that the expression of MAST3 might involve in NF-κB signaling pathway in RA. On the whole, our results suggested that MAST3 might promote the proliferation and inflammation of FLSs by regulating NF-κB signaling pathway. Show less
Neuromuscular junction is a synapse between motoneurons and skeletal muscles, where acetylcholine receptors (AChRs) are concentrated to control muscle contraction. Studies of this synapse have contrib Show more
Neuromuscular junction is a synapse between motoneurons and skeletal muscles, where acetylcholine receptors (AChRs) are concentrated to control muscle contraction. Studies of this synapse have contributed to our understanding of synapse assembly and pathological mechanisms of neuromuscular disorders. Nevertheless, underlying mechanisms of NMJ formation was not well understood. To this end, we took a novel approach - studying mutant genes implicated in congenital myasthenic syndrome (CMS). We showed that knock-in mice carrying N88K, a prevalent CMS mutation of Rapsyn (Rapsn), died soon after birth with profound NMJ deficits. Rapsn is an adapter protein that bridges AChRs to the cytoskeleton and possesses E3 ligase activity. In investigating how N88K impairs the NMJ, we uncovered a novel signaling pathway by which Agrin-LRP4-MuSK induces tyrosine phosphorylation of Rapsn, which is required for its self-association and E3 ligase activity. Our results also provide insight into pathological mechanisms of CMS. Show less
Micro-RNAs regulate multiple biological behaviors of cancers, making them potential targets of new cancer therapies. MiR-1181 has been demonstrated to perform oncogenic or tumor-suppressing function i Show more
Micro-RNAs regulate multiple biological behaviors of cancers, making them potential targets of new cancer therapies. MiR-1181 has been demonstrated to perform oncogenic or tumor-suppressing function in a tissue-dependent way, but its role in hepatocellular carcinoma (HCC) was unclear. Here, we showed that miR-1181 was significantly overexpressed in HCC tissues when compared with tumor-adjacent normal ones or normal liver tissues from donated organ, and that inhibition of miR-1181 could repress the growth of HCC cells. Through bioinformatics analysis and luciferase reporter assays, we found that axis inhibition protein 1 (AXIN1) was a direct target of miR-1181, and the expression of AXIN1 showed a negative correlation with that of miR-1181 in HCC. Therefore, these data indicated an oncogenic function of miRNA-1181 in the development of HCC and a potential target for the clinical treatment of HCC. Show less
Alzheimer's disease (AD) is a chronic neurodegenerative disease that often occurs at a slow pace yet deteriorates with time. MicroRNAs (miRs) have been demonstrated to offer novel therapeutic hope for Show more
Alzheimer's disease (AD) is a chronic neurodegenerative disease that often occurs at a slow pace yet deteriorates with time. MicroRNAs (miRs) have been demonstrated to offer novel therapeutic hope for disease treatment. The aim of the present study was to investigate the effect of miR‑98 on amyloid β (Aβ)‑protein production, oxidative stress and mitochondrial dysfunction through the Notch signaling pathway by targeting hairy and enhancer of split (Hes)‑related with YRPW motif protein 2 (HEY2) in mice with AD. A total of 70 Kunming mice were obtained and subjected to behavioral assessment. The levels of oxidative stress‑related proteins glutathione peroxidase, reduced glutathione, superoxide dismutase, malondialdehyde, acetylcholinesterase and Na+‑K+‑ATP were measured. Morphological changes in brain tissue, HEY2‑positivity levels, neuronal apoptotic index (AI) and neuron mitochondrial DNA (mtDNA) levels were also determined. Subsequently, the levels of miR‑98 and the mRNA and protein levels of HEY2, Jagged1, Notch1, Hes1, Hes5, β‑amyloid precursor protein, B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein in tissues and hippocampal neurons were determined by reverse transcription‑quantitative polymerase chain reaction and western blot analyses, respectively. Finally, hippocampal neuron viability and apoptosis were determined using an MTT assay and flow cytometry, respectively. The levels of miR‑98‑targeted HEY2 and miR‑98 were low and the levels of HEY2 were high in the AD mice. The AD mice exhibited poorer learning and memory abilities, oxidative stress function, and morphological changes of pyramidal cells in the hippocampal CA1 region. Furthermore, the AD mice exhibited increased protein levels of HEY2 and AI in the CA1 region of brain tissues with reduced mtDNA levels and dysfunctional neuronal mitochondria. miR‑98 suppressed hippocampal neuron apoptosis and promoted hippocampal neuron viability by inactivating the Notch signaling pathway via the inhibition of HEY2. In conclusion, the results demonstrated that miR‑98 reduced the production of Aβ and improved oxidative stress and mitochondrial dysfunction through activation of the Notch signaling pathway by binding to HEY2 in AD mice. Show less
Osteoarthritis (OA) in the temporomandibular joint (TMJ) is a degenerative disease in the adult, which is characterized by the pathological degeneration of condylar cartilage. Axin1 plays a critical r Show more
Osteoarthritis (OA) in the temporomandibular joint (TMJ) is a degenerative disease in the adult, which is characterized by the pathological degeneration of condylar cartilage. Axin1 plays a critical role in the regulation of cartilage development and homeostasis. To determine the role of Axin1 in TMJ tissue at the adult stage, we generated Axin1 Show less
Neuropeptide Y (NPY) is the most powerful central neuropeptide implicated in feeding regulation via its receptors. Understanding the role of NPY system is critical to elucidate animal feeding regulati Show more
Neuropeptide Y (NPY) is the most powerful central neuropeptide implicated in feeding regulation via its receptors. Understanding the role of NPY system is critical to elucidate animal feeding regulation. Unlike mammal, the possible mechanisms of NPY system in the food intake of teleost fish are mostly unknown. Therefore, we investigated the regulatory mechanism of NPY and NPY receptors in Siberian sturgeon. In this study, we cloned the cDNA encoding NPY, and assessed the effects of different energy status on npy mRNAs abundance. The expression of npy was decreased in the brain after feeding 1 and 3 h. Besides, the expression of npy was increased after fasting within 15 days, while exhibiting significant decrease after refeeding. In order to further characterize the role of NPY receptor in fish, we performed acute intraperitoneal (i.p.) injection of NPY Y1 and Y2 receptor agonists, which is [Leu 31, Pro 34] NPY and NPY13-36 respectively. The results showed that the food intake of Siberian sturgeon was increased within 30 mins after injection of both Y1 and Y2 receptor agonist. To explore the relationship between NPY, NPY receptors and another appetite peptides, we examined the level of npy, cocaine- and amphetamine-regulated transcript (cart) and melanocortin-4 receptor (mc4r) by injected Y1 and Y2 receptor agonist. The results suggested that cart expression was regulated by NPY which acts on Y1 receptor or Y2 receptor. While mc4r expression just was mediated by NPY and Y1 receptor. Show less
The therapeutic strategies for advanced gastric cancer (GC) remain unsatisfying and limited. Therefore, it is still imperative to fully elucidate the mechanisms underlying GC aggressive progression. T Show more
The therapeutic strategies for advanced gastric cancer (GC) remain unsatisfying and limited. Therefore, it is still imperative to fully elucidate the mechanisms underlying GC aggressive progression. The prognostic value and biological functions of low density lipoprotein receptor class A domain containing protein 2 (LDLRAD2) in GC have never been studied yet. We found that LDLRAD2 expression was significantly upregulated in GC and closely correlated with poor prognosis in GC patients. Functionally, LDLRAD2 promoted epithelial-mesenchymal transition, migration and invasion, and metastasis of GC cells. Mechanistically, LDLRAD2 interacted with and inhibited Axin1 from binding to cytoplasmic β-catenin, which facilitated the nuclear translocation of β-catenin, thereby activating Wnt/β-catenin pathway. Inhibition of β-catenin activity markedly abolished LDLRAD2-induced migration, invasion and metastasis. Together, these results suggested that LDLRAD2 contributed to invasion and metastasis of GC through activating Wnt/β-catenin pathway. LDLRAD2/ Wnt/β-catenin axis may be a potential therapeutic target for GC treatment. Show less
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis and atherogenesis. However, there are only limited rodent models, with a functional low-density lipopr Show more
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis and atherogenesis. However, there are only limited rodent models, with a functional low-density lipoprotein receptor (LDLR) pathway and cholesteryl ester transfer protein (CETP) to evaluate the drug candidates targeting the PCSK9/LDLR pathway, that are translatable to humans. Here, by using our recently generated LDLR heterozygote ( Show less
Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP) previously under development as a lipid-modifying agent that reduces LDL-cholesterol and increases HDL-cholesterol in hyperchol Show more
Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP) previously under development as a lipid-modifying agent that reduces LDL-cholesterol and increases HDL-cholesterol in hypercholesterolemic patients. Anacetrapib demonstrates a long terminal half-life and accumulates in adipose tissue, which contributes to a long residence time of anacetrapib. Given our previous report that anacetrapib distributes into the lipid droplet of adipose tissue, we sought to understand whether anacetrapib affected adipose function, using a diet-induced obese (DIO) mouse model. Following 20 weeks of treatment with anacetrapib (100 mg/kg/day), levels of the drug increased to approximately 0.6 mmol/L in white adipose tissue. This level of anacetrapib was not associated with any impairment in adipose functionality as evidenced by a lack of any reduction in biomarkers of adipose functionality (plasma adiponectin, leptin, insulin; adipose adiponectin, leptin mRNA). In DIO wild-type (WT) mice treated with anacetrapib for 2 weeks and then subjected to 30% food restriction during washout to induce weight loss (18%) and fat mass loss (7%), levels of anacetrapib in adipose and plasma were not different between food restricted and ad lib-fed mice. These data indicate that despite deposition and long-term residence of ~0.6 mmol/L levels of anacetrapib in adipose tissue, adipose tissue function appears to be unaffected in mice. In addition, these data also indicate that even with severe caloric restriction and acute loss of fat mass, anacetrapib does not appear to be mobilized from the fat depot, thereby solidifying the role of adipose as a long-term storage site of anacetrapib. Show less
Neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are sight-threatening maculopathies with both environmental and genetic risk factors. We have previously Show more
Neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are sight-threatening maculopathies with both environmental and genetic risk factors. We have previously shown relative risks posed by genes of the complement pathways to neovascular AMD and PCV. In this study, we investigated the haplotype-tagging single nucleotide polymorphisms (SNPs) in the The results revealed none of the six tagging SNPs of the This study showed no statistical significance in the genetic association of Show less
Family with sequence similarity 83, member A (FAM83A), as a potential tumor promoter, was reported to contribute to the progression of several malignant tumors. However, the significance of FAM83A in Show more
Family with sequence similarity 83, member A (FAM83A), as a potential tumor promoter, was reported to contribute to the progression of several malignant tumors. However, the significance of FAM83A in invasion and metastasis of non-small cell lung cancer (NSCLC) remains largely unknown. In this study, we found that FAM83A expression was significantly increased in NSCLC tissues. High expression of FAM83A was positively associated with tumor metastasis and poor survival of NSCLC patients. Functional experiments revealed that FAM83A knockdown could suppress NSCLC cell migration and invasion both Show less
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. This study was performed Show more
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. This study was performed to examine the effects of long noncoding RNA CPS1 intronic transcript 1 (CPS1-IT) on PAH in rat models of obstructive sleep apnea (OSA) through regulating interleukin (IL)-1β expression. The OSA models were induced in rats, for determination of the CPS1-IT expression. The binding of CPS1-IT and hypoxia-inducible factor 1 (HIF1) was verified. To analyze the effects of CPS1-IT on PAH, the overexpression vector of CPS1-IT and HIF1, shRNA against IL-1β and pyrrolidine dithiocarbamate (PDTC, inhibitor of the NF-κB signaling pathway) were injected into rat models, respectively. The blood pressure and activity of biochemical indicators including nitric oxide (NO), nitric oxide synthase (NOS), superoxide dismutase (SOD), and lipid peroxide (LPO) were assessed. The expression of IL-1β, HIF1, α-smooth muscle actin (α-SMA), proliferating cell nuclear antigen (PCNA), and fibronectin (FN) was determined. The relationship of CPS1-IT to IL-1β and NF-κB was evaluated. CPS1-IT was downregulated in the OSA rat model. Overexpressed CPS1-IT increased the activity of NO, NOS, and SOD as well as α-SMA expression, whereas decreasing LPO activity and expression of PCNA and FN, whereby PAH was suppressed. Notably, overexpressed CPS1-IT reduced IL-1β expression through NF-κB signaling pathway via inhibiting the HIF1 transcriptional activity, suggesting a mechanism affecting PAH. To conclude, overexpressed CPS1-IT alleviated PAH in OSA by reducing IL-1β expression, the mechanism of which was involved with inhibited HIF1 transcriptional activity and the NF-κB signaling pathway. Show less
Inactivating mutations of axis inhibition protein 1 (AXIN1), a negative regulator of the Wnt/β-Catenin cascade, are among the common genetic events in human hepatocellular carcinoma (HCC), affecting a Show more
Inactivating mutations of axis inhibition protein 1 (AXIN1), a negative regulator of the Wnt/β-Catenin cascade, are among the common genetic events in human hepatocellular carcinoma (HCC), affecting approximately 10% of cases. In the present manuscript, we sought to define the genetic crosstalk between Axin1 mutants and Wnt/β-catenin as well as Notch signaling cascades along hepatocarcinogenesis. We discovered that c-MET activation and AXIN1 mutations occur concomitantly in ~3%-5% of human HCC samples. Subsequently, we generated a murine HCC model by means of CRISPR/Cas9-based gene deletion of Axin1 (sgAxin1) in combination with transposon-based expression of c-Met in the mouse liver (c-Met/sgAxin1). Global gene expression analysis of mouse normal liver, HCCs induced by c-Met/sgAxin1, and HCCs induced by c-Met/∆N90-β-Catenin revealed activation of the Wnt/β-Catenin and Notch signaling in c-Met/sgAxin1 HCCs. However, only a few of the canonical Wnt/β-Catenin target genes were induced in c-Met/sgAxin1 HCC when compared with corresponding lesions from c-Met/∆N90-β-Catenin mice. To study whether endogenous β-Catenin is required for c-Met/sgAxin1-driven HCC development, we expressed c-Met/sgAxin1 in liver-specific Ctnnb1 null mice, which completely prevented HCC development. Consistently, in AXIN1 mutant or null human HCC cell lines, silencing of β-Catenin strongly inhibited cell proliferation. In striking contrast, blocking the Notch cascade through expression of either the dominant negative form of the recombinant signal-binding protein for immunoglobulin kappa J region (RBP-J) or the ablation of Notch2 did not significantly affect c-Met/sgAxin1-driven hepatocarcinogenesis. Conclusion: We demonstrated here that loss of Axin1 cooperates with c-Met to induce HCC in mice, in a β-Catenin signaling-dependent but Notch cascade-independent way. Show less
Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with onl Show more
Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci. Show less
Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP), associated with reduction in LDL cholesterol and increase in HDL cholesterol in hypercholesterolemic patients. Anacetrapib was Show more
Anacetrapib is an inhibitor of cholesteryl ester transfer protein (CETP), associated with reduction in LDL cholesterol and increase in HDL cholesterol in hypercholesterolemic patients. Anacetrapib was not taken forward into filing/registration as a new drug for coronary artery diease, despite the observation of a ∼9% reduction in cardiovascular risk in a large phase III cardiovascular outcomes trial (REVEAL). Anacetrapib displayed no adverse effects throughout extensive preclinical safety evaluation, and no major safety signals were observed in clinical trials studying anacetrapib, including REVEAL. However, anacetrapib demonstrated a long terminal half-life in all species, thought to be due, in part, to distribution into adipose tissue. We sought to understand the dependence of anacetrapib's long half-life on adipose tissue and to explore potential mechanisms that might contribute to the phenomenon. In mice, anacetrapib localized primarily to the lipid droplet of adipocytes in white adipose tissue; in vitro, anacetrapib entry into cultured human adipocytes depended on the presence of a mature adipocyte and lipid droplet but did not require active transport. In vivo, the entry of anacetrapib into adipose tissue did not require lipase activity, as the distribution of anacetrapib into adipose was-not affected by systemic lipase inhibition using poloaxamer-407, a systemic lipase inhibitor. The data from these studies support the notion that the entry of anacetrapib into adipose tissue/lipid droplets does not require active transport, nor does it require mobilization or entry of fat into adipose via lipolysis. Show less
DHX36 is a DEAH-box helicase that resolves parallel G-quadruplex structures formed in DNA and RNA. The recent co-crystal structure of DHX36 bound G4-DNA revealed an intimate contact, but did not addre Show more
DHX36 is a DEAH-box helicase that resolves parallel G-quadruplex structures formed in DNA and RNA. The recent co-crystal structure of DHX36 bound G4-DNA revealed an intimate contact, but did not address the role of ATP hydrolysis in G4 resolving activity. Here, we demonstrate that unlike on G4-DNA, DHX36 displays ATP-independent unfolding of G4-RNA followed by ATP-dependent refolding, generating a highly asymmetric pattern of activity. Interestingly, DHX36 refolds G4-RNA in several steps, reflecting the discrete steps in forming the G4 structure. We show that the ATP-dependent activity of DHX36 arises from the RNA tail rather than the G4. Mutations that perturb G4 contact result in quick dissociation of the protein from RNA upon ATP hydrolysis, while mutations that interfere with binding the RNA tail induce dysregulated activity. We propose that the ATP-dependent activity of DHX36 may be useful for dynamically resolving various G4-RNA structures in cells. Show less
Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce Show more
Lean body mass (LM) plays an important role in mobility and metabolic function. We previously identified five loci associated with LM adjusted for fat mass in kilograms. Such an adjustment may reduce the power to identify genetic signals having an association with both lean mass and fat mass. To determine the impact of different fat mass adjustments on genetic architecture of LM and identify additional LM loci. We performed genome-wide association analyses for whole-body LM (20 cohorts of European ancestry with n = 38,292) measured using dual-energy X-ray absorptiometry) or bioelectrical impedance analysis, adjusted for sex, age, age2, and height with or without fat mass adjustments (Model 1 no fat adjustment; Model 2 adjustment for fat mass as a percentage of body mass; Model 3 adjustment for fat mass in kilograms). Seven single-nucleotide polymorphisms (SNPs) in separate loci, including one novel LM locus (TNRC6B), were successfully replicated in an additional 47,227 individuals from 29 cohorts. Based on the strengths of the associations in Model 1 vs Model 3, we divided the LM loci into those with an effect on both lean mass and fat mass in the same direction and refer to those as "sumo wrestler" loci (FTO and MC4R). In contrast, loci with an impact specifically on LM were termed "body builder" loci (VCAN and ADAMTSL3). Using existing available genome-wide association study databases, LM increasing alleles of SNPs in sumo wrestler loci were associated with an adverse metabolic profile, whereas LM increasing alleles of SNPs in "body builder" loci were associated with metabolic protection. In conclusion, we identified one novel LM locus (TNRC6B). Our results suggest that a genetically determined increase in lean mass might exert either harmful or protective effects on metabolic traits, depending on its relation to fat mass. Show less
Natural and synthetic progestins in receiving streams can disrupt the normal endocrine systems of fish. Norethindrone (NET) is a widely used synthetic progestin that often appears in wastewater efflue Show more
Natural and synthetic progestins in receiving streams can disrupt the normal endocrine systems of fish. Norethindrone (NET) is a widely used synthetic progestin that often appears in wastewater effluents. For this research, adult female western mosquitofish (Gambusia affinis) were exposed to NET at three concentrations. The effects of NET on the following biological factors were evaluated: the histology of the ovaries and livers, the anal fin morphology, and transcription of genes related to steroidogenesis signaling pathways in the livers. After 42 d exposure to NET at 33.0 ng L Show less
Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study an Show more
Post-traumatic stress disorder (PTSD) is a major problem among military veterans and civilians alike, yet its pathophysiology remains poorly understood. We performed a genome-wide association study and bioinformatic analyses, which included 146,660 European Americans and 19,983 African Americans in the US Million Veteran Program, to identify genetic risk factors relevant to intrusive reexperiencing of trauma, which is the most characteristic symptom cluster of PTSD. In European Americans, eight distinct significant regions were identified. Three regions had values of P < 5 × 10 Show less
Jae Young Lee, Shebli Mehrazarin, Abdullah Alshaikh+6 more · 2019 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
Histone Lys-specific demethylases (KDMs) play a key role in many biological processes through epigenetic mechanisms. However, the role of KDMs in inflammatory responses to oral bacterial infection is Show more
Histone Lys-specific demethylases (KDMs) play a key role in many biological processes through epigenetic mechanisms. However, the role of KDMs in inflammatory responses to oral bacterial infection is poorly understood. Here, we show a novel regulatory role of KDM3C in inflammatory responses to oral bacterial infection. KDM3C expression is transiently suppressed in human and mouse macrophages exposed to LPS from Show less
Osteoclasts are responsible for bone resorption and play essential roles in causing bone diseases such as osteoporosis. Microtubule actin crosslinking factor 1 (MACF1) is a large spectraplakin protein Show more
Osteoclasts are responsible for bone resorption and play essential roles in causing bone diseases such as osteoporosis. Microtubule actin crosslinking factor 1 (MACF1) is a large spectraplakin protein that has been implicated in regulating cytoskeletal distribution, cell migration, cell survival and cell differentiation. However, whether MACF1 regulates the differentiation of osteoclasts has not been elucidated. In this study, we found that the expression of MACF1 was increased in primary bone marrow-derived monocytes (BMMs) of osteoporotic mice and was downregulated during receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis of pre-osteoclast cell lines RAW264.7 cells. RAW264.7 cells were transfected with shMACF1 using a lentiviral vector to study the role of MACF1 in osteoclastogenic differentiation. Knockdown of MACF1 in RAW264.7 cells inhibited the formation of multinucleated osteoclasts and decreased the expression of osteoclast-marker genes (Ctsk, Acp5, Mmp9 and Oscar) during RANKL-induced osteoclastogenesis. Additionally, knockdown of MACF1 disrupted actin ring formation in osteoclasts and further blocked the bone resorption activity of osteoclasts by reducing the area and depth of pits. Knockdown of MACF1 had no effect on the survival of pre-osteoclasts and mature osteoclasts. We further established that knockdown of MACF1 attenuated the phosphorylation of Akt and GSK3β and inhibited the expression of its downstream target NFATc1. Akt activator rescued the inhibition of osteoclast differentiation by MACF1 knockdown. These data demonstrate that MACF1 positively regulates osteoclast differentiation via the Akt/GSK3β/NFATc1 signalling pathway, suggesting that targeting MACF1 may be a novel therapeutic approach against osteoporosis. Show less
Shipeng Gong, Yongning Chen, Fanliang Meng+4 more · 2019 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
Currently, cisplatin (DDP) is the first-line chemotherapeutic agent used for treatment of ovarian cancer, but gradually acquired drug resistance minimizes its therapeutic outcomes. We aimed to identif Show more
Currently, cisplatin (DDP) is the first-line chemotherapeutic agent used for treatment of ovarian cancer, but gradually acquired drug resistance minimizes its therapeutic outcomes. We aimed to identify crucial genes associated with DDP resistance in ovarian cancer and uncover potential mechanisms. Two sets of gene expression data were downloaded from Gene Expression Omnibus, and bioinformatics analysis was conducted. In our study, the differentially expressed genes between DDP-sensitive and DDP-resistant ovarian cancer were screened in GSE15709 and GSE51373 database, and chromosome condensation 2 regulator (RCC2) and nucleoporin 160 were identified as 2 genes that significantly up-regulated in DDP-resistant ovarian cancer cell lines compared with DDP-sensitive cell lines. Moreover, RCC2, Ral small GTPase (RalA), and Ral binding protein-1 (RalBP1) expression was found to be significantly higher in DDP-resistant ovarian cancer tissues than in DDP-sensitive tissues. RCC2 plays a positive role in cell proliferation, apoptosis, and migration in DDP-resistant ovarian cancer cell lines in vitro and in vivo. Furthermore, RCC2 could interact with RalA, thus promoting its downstream effector RalBP1. RalA knockdown could reverse the effects of RCC2 overexpression on DDP-resistant ovarian cancer cell proliferation, apoptosis, and migration. Similarly, RalA overexpression could alleviate the effects of RCC2 knockdown in DDP-resistant ovarian cancer cells. Taken together, RCC2 may function as an oncogene, regulating the RalA signaling pathway, and intervention of RCC2 expression might be a promising therapeutic strategy for DDP-resistant ovarian cancer.-Gong, S., Chen, Y., Meng, F., Zhang, Y., Wu, H., Li, C., Zhang, G. RCC2, a regulator of the RalA signaling pathway, is identified as a novel therapeutic target in cisplatin-resistant ovarian cancer. Show less
Bacterial meningitis is currently recognized as one of the most important life-threatening infections of the central nervous system (CNS) with high morbidity and mortality, despite the advancements in Show more
Bacterial meningitis is currently recognized as one of the most important life-threatening infections of the central nervous system (CNS) with high morbidity and mortality, despite the advancements in antimicrobial treatment. The disruption of blood-brain barrier (BBB) induced by meningitis bacteria is crucial for the development of bacterial meningitis. However, the complete mechanisms involving in the BBB disruption remain to be elucidated. Here, we found meningitic Show less