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
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by their immat Show more
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a powerful tool for human disease modeling and therapeutic testing. However, their use remains limited by their immaturity and heterogeneity. To characterize the source of this heterogeneity, we applied complementary single-cell RNA-seq and bulk RNA-seq technologies over time during hiPSC cardiac differentiation and in the adult heart. Using integrated transcriptomic and splicing analysis, more than half a dozen distinct single-cell populations were observed, several of which were coincident at a single time-point, day 30 of differentiation. To dissect the role of distinct cardiac transcriptional regulators associated with each cell population, we systematically tested the effect of a gain or loss of three transcription factors (NR2F2, TBX5, and HEY2), using CRISPR genome editing and ChIP-seq, in conjunction with patch clamp, calcium imaging, and CyTOF analysis. These targets, data, and integrative genomics analysis methods provide a powerful platform for understanding in vitro cellular heterogeneity. Show less
Mechanical unloading was considered a major threat to bone homeostasis, and has been shown to decrease osteoblast proliferation although the underlying mechanism is unclear. Microtubule actin crosslin Show more
Mechanical unloading was considered a major threat to bone homeostasis, and has been shown to decrease osteoblast proliferation although the underlying mechanism is unclear. Microtubule actin crosslinking factor 1 (MACF1) is a cytoskeletal protein that regulates cellular processes and Wnt/β-catenin pathway, an essential signaling pathway for osteoblasts. However, the relationship between MACF1 expression and mechanical unloading, and the function and the associated mechanisms of MACF1 in regulating osteoblast proliferation are unclear. This study investigated effects of mechanical unloading on MACF1 expression levels in cultured MC3T3-E1 osteoblastic cells and in femurs of mice with hind limb unloading; and it also examined the role and potential action mechanisms of MACF1 in osteoblast proliferation in MACF1-knockdown, overexpressed or control MC3T3-E1 cells treated with or without the mechanical unloading condition. Results showed that the mechanical unloading condition inhibited osteoblast proliferation and MACF1 expression in MC3T3-E1 osteoblastic cells and mouse femurs. MACF1 knockdown decreased osteoblast proliferation, while MACF1 overexpression increased it. The inhibitory effect of mechanical unloading on osteoblast proliferation also changed with MACF1 expression levels. Furthermore, MACF1 was found to enhance β-catenin expression and activity, and mechanical unloading decreased β-catenin expression through MACF1. Moreover, β-catenin was found an important regulator of osteoblast proliferation, as its preservation by treatment with its agonist lithium attenuated the inhibitory effects of MACF1-knockdown or mechanical unloading on osteoblast proliferation. Taken together, mechanical unloading decreases MACF1 expression, and MACF1 up-regulates osteoblast proliferation through enhancing β-catenin signaling. This study has thus provided a mechanism for mechanical unloading-induced inhibited osteoblast proliferation. Show less
Major depressive disorder (MDD) is a highly prevalent mental disorder affecting millions of people worldwide. However, a clear causative etiology of MDD remains unknown. In this study, we aimed to ide Show more
Major depressive disorder (MDD) is a highly prevalent mental disorder affecting millions of people worldwide. However, a clear causative etiology of MDD remains unknown. In this study, we aimed to identify critical protein alterations in plasma from patients with MDD and integrate our proteomics and previous metabolomics data to reveal significantly perturbed pathways in MDD. An isobaric tag for relative and absolute quantification (iTRAQ)-based quantitative proteomics approach was conducted to compare plasma protein expression between patients with depression and healthy controls (CON). For integrative analysis, Ingenuity Pathway Analysis software was used to analyze proteomics and metabolomics data and identify potential relationships among the differential proteins and metabolites. A total of 74 proteins were significantly changed in patients with depression compared with those in healthy CON. Bioinformatics analysis of differential proteins revealed significant alterations in lipid transport and metabolic function, including apolipoproteins (APOE, APOC4 and APOA5), and the serine protease inhibitor. According to canonical pathway analysis, the top five statistically significant pathways were related to lipid transport, inflammation and immunity. Causal network analysis by integrating differential proteins and metabolites suggested that the disturbance of phospholipid metabolism might promote the inflammation in the central nervous system. Show less
Gastric cancer (GC) is one of the most common cancers and is the second-leading cause of cancer-associated morbidity worldwide. Oxysterols are oxidized derivatives of cholesterol that may be important Show more
Gastric cancer (GC) is one of the most common cancers and is the second-leading cause of cancer-associated morbidity worldwide. Oxysterols are oxidized derivatives of cholesterol that may be important in many biological processes, but the levels and roles of oxysterols in gastric tumours remain to be elucidated. The levels of cholesterol, oxysterols and sulfated oxysterols in human gastric tumour tissues, adjacent normal mucosal tissues, cancerous gastric juice and gastric juice obtained from healthy subjects were detected by LC-MS. It was found that the levels of 24(R/S),25-EC and 27HC in human gastric tumour tissues and cancerous gastric juice were significantly increased compared with those of adjacent normal mucosal tissues and gastric juice from healthy subjects. Compared with normal gastric mucosal tissue, the levels of sulfated 25-hydroxycholesterol (25HC3S) and the ratio of 25HC3S/25HC were decreased in human gastric tumour tissues, which might be related to the dramatically decreased SULT2A1 expression in gastric tumour tissue. Both 24(R/S),25-EC and 27HC suppressed gastric cancer proliferation, which was not altered by LXRα-siRNA treatment. The suppression of cell proliferation induced by 27HC was attenuated by LXRβ-siRNA, but the suppression of cell proliferation induced by 24(R/S),25-EC was intensified by LXRβ-siRNA. Both 24(R/S),25-EC and 27HC dramatically inhibited HGC-27 cell migration, which was attenuated by the co-transfection of cells with LXRα-siRNA and LXRβ-siRNA, but not LXRα-siRNA or LXRβ-siRNA alone. In conclusion, the accumulated 24(R/S),25-EC and 27HC in human gastric tumour tissues might play important roles in gastric cancer development. Show less
Wnt/β-catenin signaling activity is maintained in homeostasis by an expanding list of molecular determinants. However, the molecular components and the regulatory mechanisms involved in its fine-tunin Show more
Wnt/β-catenin signaling activity is maintained in homeostasis by an expanding list of molecular determinants. However, the molecular components and the regulatory mechanisms involved in its fine-tuning remain to be determined. Here, we identified C9orf140, a tumor-specific protein, as a novel Axin1-interacting protein by tandem-affinity purification and mass spectrometry. We further showed that C9orf140 is a negative regulator of Wnt/β-catenin signaling in cultured cells as well as in zebrafish embryos. It functions upstream of β-catenin, outcompetes PP2A for binding to Axin1, influences the balance between phosphorylation and de-phosphorylation of β-catenin, and ultimately compromises Wnt3A-induced β-catenin accumulation. Interestingly, Wnt-induced C9orf140 expression via β-catenin. We propose that C9orf140 mediates a negative feedback loop of Wnt/β-catenin signaling by interacting with Axin1. Our results advance the current understanding of the exquisite control of Wnt/β-catenin signaling cascade, and provide evidence of the new role of C9orf140. Show less
The overexpression of EGFR often occurs in TNBC, and the anti-EGFR receptor antibody cetuximab is used widely to treat metastatic cancer in the clinic. However, EGFR-targeted therapies have been devel Show more
The overexpression of EGFR often occurs in TNBC, and the anti-EGFR receptor antibody cetuximab is used widely to treat metastatic cancer in the clinic. However, EGFR-targeted therapies have been developed for TNBC without clinical success. In this study, we show that impaired EGFR degradation is crucial for resistance to cetuximab, which depends on the cell surface molecule CD44. To further investigate the role of CD44 in EGFR signaling and its treatment potential, we developed a targeting fusion protein composed of an anti-EGFR scFv generated from cetuximab and truncated protamine, called Ce-tP. CD44 siRNA can be specifically delivered into EGFR-positive TNBC cells by Ce-tP. Efficient knockdown of CD44 and suppression of both EGFR and downstream signaling by the Ce-tP/siRNA complex were observed in EGFR-positive TNBC cells. More importantly, our results also showed that targeted delivery of siRNA specific for CD44 can efficiently overcome resistance to EGFR targeting in TNBC cells both in vitro and in vivo. Overall, our results establish a new principle to achieve EGFR inhibition in TNBC and limit drug resistance. Show less
The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic "healthy" individuals. A VU Show more
The progression toward low-cost and rapid next-generation sequencing has uncovered a multitude of variants of uncertain significance (VUS) in both patients and asymptomatic "healthy" individuals. A VUS is a rare or novel variant for which disease pathogenicity has not been conclusively demonstrated or excluded, and thus cannot be definitively annotated. VUS, therefore, pose critical clinical interpretation and risk-assessment challenges, and new methods are urgently needed to better characterize their pathogenicity. To address this challenge and showcase the uncertainty surrounding genomic variant interpretation, we recruited a "healthy" asymptomatic individual, lacking cardiac-disease clinical history, carrying a hypertrophic cardiomyopathy (HCM)-associated genetic variant (NM₀₀₀₂₅₈.2:c.170C>A, NP₀₀₀₂₄₉.1:p.Ala57Asp) in the sarcomeric gene MYL3, reported by the ClinVar database to be "likely pathogenic." Human-induced pluripotent stem cells (iPSCs) were derived from the heterozygous VUS MYL3 The heterozygous VUS MYL3 Our study illustrates the ability of clustered regularly interspaced short palindromic repeats/Cas9 genome-editing of carrier-specific iPSCs to elucidate both benign and pathogenic HCM functional phenotypes in a carrier-specific manner in a dish. As such, this platform represents a promising VUS risk-assessment tool that can be used for assessing HCM-associated VUS specifically, and VUS in general, and thus significantly contribute to the arsenal of precision medicine tools available in this emerging field. Show less
We previously showed that complement 3 (C3) is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHR). We targeted C3 gene by zinc-finger nuclease (ZFN) gene-editing technolo Show more
We previously showed that complement 3 (C3) is highly expressed in mesenchymal tissues in spontaneously hypertensive rats (SHR). We targeted C3 gene by zinc-finger nuclease (ZFN) gene-editing technology and investigated blood pressure and phenotype in SHR. Blood pressure was measured by tail-cuff and telemetry methods. Histology and expression of liver X receptor α (LXRα), renin, Krüppel-like factor 5 (KLF5), and E-cadherin were evaluated in kidneys. Mesangial cells (MCs) were removed from glomeruli from three strains, and we evaluated the phenotype in vitro. SHR showed the salt-sensitive hypertension that was abolished in C3 knockout (KO) SHR. Proliferation of MCs from SHR was higher than that from Wistar-Kyoto (WKY) rats and showed a synthetic phenotype. Renal injury scores were higher in SHR than in WKY rats and C3 KO SHR. Expression of E-cadherin was lower, and expression of renin was higher in the nephrotubulus from SHR than WKY rats and C3 KO SHR. Expression of C3 α-chain protein and α-smooth muscle actin protein was significantly higher in renal medulla from SHR than from WKY rats. Expression of angiotensinogen, LXRα, renin, and KLF5 mRNA was increased in kidney from SHR compared with C3 KO SHR. Intrarenal angiotensin II levels were significantly higher in kidney from SHR than WKY rats and C3 KO SHR. Urinary epinephrine and norepinephrine excretions were significantly higher in SHR than in WKY rats and C3 KO SHR. These findings showed that increased C3 induces salt-sensitive hypertension with increases in urinary catecholamine excretion and intrarenal activation of the renin-angiotensin system by the dedifferentiation of mesenchymal tissues in kidney from SHR. Show less
γ-Secretase has been a therapeutical target for its key role in cleaving APP to generate β-amyloid (Aβ), the primary constituents of senile plaques and a hallmark of Alzheimer's disease (AD) pathology Show more
γ-Secretase has been a therapeutical target for its key role in cleaving APP to generate β-amyloid (Aβ), the primary constituents of senile plaques and a hallmark of Alzheimer's disease (AD) pathology. Recently, γ-secretase-associating proteins showed promising role in specifically modulating APP processing while sparing Notch signaling; however, the underlying mechanism is still unclear. A co-immunoprecipitation (Co-IP) coupled with mass spectrometry proteomic assay for Presenilin1 (PS1, the catalytic subunit of γ-secretase) was firstly conducted to find more γ-secretase-associating proteins. Gene ontology analysis of these results identified Rab21 as a potential PS1 interacting protein, and the interaction between them was validated by reciprocal Co-IP and immunofluorescence assay. Then, molecular and biochemical methods were used to investigate the effect of Rab21 on APP processing. Results showed that overexpression of Rab21 enhanced Aβ generation, while silencing of Rab21 reduced the accumulation of Aβ, which resulted due to change in γ-secretase activity rather than α- or β-secretase. Finally, we demonstrated that Rab21 had no effect on γ-secretase complex synthesis or metabolism but enhanced PS1 endocytosis and translocation to late endosome/lysosome. In conclusion, we identified a novel γ-secretase-associating protein Rab21 and illustrate that Rab21 promotes γ-secretase internalization and translocation to late endosome/lysosome. Moreover, silencing of Rab21 decreases the γ-secretase activity in APP processing thus production of Aβ. All these results open new gateways towards the understanding of γ-secretase-associating proteins in APP processing and make inhibition of Rab21 a promising strategy for AD therapy. Show less
Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypot Show more
Melanocortin 4 receptor (Mc4r) plays a crucial role in the central control of energy homeostasis, but its role in peripheral organs has not been fully explored. We have investigated the roles of hypothalamus-mediated energy metabolism during Xenopus limb regeneration. We report that hypothalamus injury inhibits Xenopus tadpole limb regeneration. By loss-of-function and gain-of-function studies, we show that Mc4r signaling is required for limb regeneration in regeneration-competent tadpoles and stimulates limb regeneration in later-stage regeneration-defective tadpoles. It regulates limb regeneration through modulating energy homeostasis and ROS production. Even more interestingly, our results demonstrate that Mc4r signaling is regulated by innervation and α-MSH substitutes for the effect of nerves in limb regeneration. Mc4r signaling is also required for mouse digit regeneration. Thus, our findings link vertebrate limb regeneration with Mc4r-mediated energy homeostasis and provide a new avenue for understanding Mc4r signaling in the peripheral organs. Show less
To characterize the association between epilepsy, use of antiepileptic drugs (AEDs), and the risk of hyperlipidemia, we conducted a nationwide population-based cohort study with data obtained from the Show more
To characterize the association between epilepsy, use of antiepileptic drugs (AEDs), and the risk of hyperlipidemia, we conducted a nationwide population-based cohort study with data obtained from the National Health Insurance Research Database of Taiwan. The effects of AEDs on lipogenic gene expression were also examined in vitro. We identified 3617 cases involving patients, whose epilepsy was newly diagnosed between 2000 and 2011, and selected a comparison cohort comprising 14,468 patients without epilepsy. The Cox proportional hazards model was used to evaluate the association between epilepsy, AED use, and hyperlipidemia. The incidence rate of hyperlipidemia was higher in the epilepsy cohort than in the comparison cohort, with an adjusted hazard ratio (aHR) of 1.21 [95% confidence interval (CI): 1.06-1.38] after adjusting for comorbidities and medications. Epilepsy patients not taking AEDs had a higher risk of hyperlipidemia (aHR 1.65; 95% CI 1.35-2.03). Among AEDs, only valproate treatment showed a higher risk of hyperlipidemia (aHR 1.53; 95% CI 1.01-2.33), although the dose-dependent effect did not reach statistical significance. In vitro studies with two hepatic cell lines showed that valproate may exert its effects by activating the liver X receptor alpha (LXRα) signaling pathway, inducing the expression of lipogenesis-related genes and increasing cellular lipid contents. In silico calculations concluded that valproate can bind stably with the ligand-binding domain of LXRα. Thus, valproate-induced hepatic lipogenic gene expression may occur through LXRα activation. Predicting the 'off-target' effects of valproate may prove valuable in developing antiepileptic agents with fewer adverse reactions. Monitoring blood lipid levels throughout the course of treatment is recommended. Show less
Hereditary multiple osteochondroma (HMO) is one of the most common genetic skeletal disorders. It is caused by mutations in either EXT1 or EXT2 resulting in abnormal skeletal growth and morphogenesis. Show more
Hereditary multiple osteochondroma (HMO) is one of the most common genetic skeletal disorders. It is caused by mutations in either EXT1 or EXT2 resulting in abnormal skeletal growth and morphogenesis. However, the spectrum and frequency of EXT1 and EXT2 mutations in Chinese patients with HMO was not previously investigated.Mutations were identified by performing Sanger sequencing analysis of the complete coding regions and flanking intronic sequences of EXT1 and EXT2, followed by multiplex ligation-dependent probe amplification (MLPA) analysis to detect gene deletions or duplications that could not be identified by the Sanger sequencing method.The present study identified pathogenic mutations in 93% (68/73) of unrelated HMO probands from 73 pedigrees. Mutations in EXT1 and EXT2 were identified in 53% (39/73) and 40% (29/73) of families. We identified 58 distinct mutations in EXT1 and EXT2, including 20 frameshift mutations, 16 nonsense mutations, 7 missense mutations, 9 splice site mutations, 5 large deletions, and 1 in-frame deletion mutation. Twenty-six of these mutations were novel and 32 were previously reported. Most of the mutations in EXT1 were base deletions or insertions (21/33), whereas the majority of those in EXT2 were single base substitution (18/25).Complete sequencing of both the EXT1 and EXT2 followed by MLPA analysis is recommended for genetic analysis of Chinese patients with HMO. This study provides a comprehensive characterization of the genetic aberrations found in Chinese patients with HMO and highlights the diagnostic value of molecular genetic analysis in this particular disease. Show less
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood. We conducted a joint analysis of 5,523,934 imputed SNPs in two n Show more
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood. We conducted a joint analysis of 5,523,934 imputed SNPs in two newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry. We identified 5 associated loci at a genome-wide significance threshold P < 5 × 10 In total, we identified 6 additional significant or suggestive SNP associations with PSP, and discovered genetic overlap with other neurodegenerative diseases. These findings clarify the pathogenesis and genetic architecture of PSP. Show less
In the human body, 50-70 billion cells die every day, resulting in the generation of a large number of apoptotic bodies. However, the detailed biological role of apoptotic bodies in regulating tissue Show more
In the human body, 50-70 billion cells die every day, resulting in the generation of a large number of apoptotic bodies. However, the detailed biological role of apoptotic bodies in regulating tissue homeostasis remains unclear. In this study, we used Fas-deficient MRL/lpr and Caspase 3 Show less
Coronary heart disease (CHD) is the most common cause of death worldwide. This study aimed to validate the association of the rs964184 polymorphism with the CHD risk and included 874 CHD patients and Show more
Coronary heart disease (CHD) is the most common cause of death worldwide. This study aimed to validate the association of the rs964184 polymorphism with the CHD risk and included 874 CHD patients and 776 controls. rs964184 polymorphism genotyping was performed using Tm-shift polymerase chain reaction. A strong association of the rs964184 polymorphism with CHD was found (genotype: X Our results indicate that both gender and age have great impacts on the association of the rs964184 polymorphism with CHD among Chinese. Show less
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding var Show more
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Show less
Jia Wang, Jianhua Gong, Li Li+7 more · 2018 · Autism research : official journal of the International Society for Autism Research · Wiley · added 2026-04-24
Increasing evidence suggests that abnormal synaptic function leads to neuronal developmental disorders and is an important component of the etiology of autism spectrum disorder (ASD). Neurexins are pr Show more
Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers. Metastasis is a major leading of death in patients with CRC and many patients have metastatic disease at diagnosis Show more
Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers. Metastasis is a major leading of death in patients with CRC and many patients have metastatic disease at diagnosis. However, the underlying molecular mechanisms are still elusive. Here, we showed that JMJD1C was overexpressed in colon cancer tissues compared to normal samples and was positively associated with metastasis and poor prognosis. Silencing JMJD1C strongly inhibits CRC migration and invasion both in vitro and in vivo. Further, we found that knockdown of JMJD1C decreased the protein and mRNA levels of ATF2, mechanistically, and JMJD1C regulated the expression of ATF2 by modulating the H3K9me2 but not H3K9me1 activity. In addition, we further performed some "rescues experiments". We found that overexpression of ATF2 could reverse the abrogated migration and invasion ability by knockdown of JMJD1C in CRC. Our results demonstrated that an increase of JMJD1C was observed in colon cancer and knockdown of JMJD1C regulated CRC metastasis by inactivation of the ATF2 pathway. This novel JMJD1C/ATF2 signaling pathway may be a promising therapeutic target for CRC metastasis. Show less
Recombinant human growth hormone (rhGH) has been widely used in clinical treatment and technology has achieved a great development in different long-acting formulations. Genetic polymorphisms may play Show more
Recombinant human growth hormone (rhGH) has been widely used in clinical treatment and technology has achieved a great development in different long-acting formulations. Genetic polymorphisms may play a role in the varies of individual responses in treatment process. This article gives an overview of the genetic polymorphisms research of growth hormone in recent years. We conducted a scoping literature search of PubMed for all English-language publications to identify studies on recombinant human growth hormone and genetic polymorphism from 2000 to 2016. Included studies were all peer-reviewed primary journal articles. Two authors independently screened titles/abstracts, downloading full-text publications meeting inclusion criteria. In all, 96 studies were included and analyzed. We found that besides some well known factors ,such as races, age, gender, weight, several kinds of gene polymorphism reported ever can also affect the growth hormone response in GHD or non-GHD patients, including GHR-Exon 3, IGF(CA)19, IGFBP-3, APOB, CETP, SOCS2, VDR, LEPR and STAT5B. Serum IGF-1 is a good parameter of GH treatment response. But it is influenced by various factors, including races, age, gender, weight, initial IGF-1 level, injection concentration and frequency. Gene polymorphism research has been a research hopspot in recent years, may helping understand the pathogeny and pharmacogenomics of these response varieties during GH treatment. Show less
Brandon Podyma, Hui Sun, Eric A Wilson+5 more · 2018 · The Journal of biological chemistry · American Society for Biochemistry and Molecular Biology · added 2026-04-24
Osteoblast differentiation is a multistep process delicately regulated by many factors, including cytoskeletal dynamics and signaling pathways. Microtubule actin crosslinking factor 1 (MACF1), a key c Show more
Osteoblast differentiation is a multistep process delicately regulated by many factors, including cytoskeletal dynamics and signaling pathways. Microtubule actin crosslinking factor 1 (MACF1), a key cytoskeletal linker, has been shown to play key roles in signal transduction and in diverse cellular processes; however, its role in regulating osteoblast differentiation is still needed to be elucidated. To further uncover the functions and mechanisms of action of MACF1 in osteoblast differentiation, we examined effects of MACF1 knockdown (MACF1-KD) in MC3T3-E1 osteoblastic cells on their osteoblast differentiation and associated molecular mechanisms. The results showed that knockdown of MACF1 significantly suppressed mineralization of MC3T3-E1 cells, down-regulated the expression of key osteogenic genes alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and type I collagen α1 (Col Iα1). Knockdown of MACF1 dramatically reduced the nuclear translocation of β-catenin, decreased the transcriptional activation of T cell factor 1 (TCF1), and down-regulated the expression of TCF1, lymphoid enhancer-binding factor 1 (LEF1), and Runx2, a target gene of β-catenin/TCF1. In addition, MACF1-KD increased the active level of glycogen synthase kinase-3β (GSK-3β), which is a key regulator for β-catenin signal transduction. Moreover, the reduction of nuclear β-catenin amount and decreased expression of TCF1 and Runx2 were significantly reversed in MACF1-KD cells when treated with lithium chloride, an agonist for β-catenin by inhibiting GSK-3β activity. Taken together, these findings suggest that knockdown of MACF1 in osteoblastic cells inhibits osteoblast differentiation through suppressing the β-catenin/TCF1-Runx2 axis. Thus, a novel role of MACF1 in and a new mechanistic insight of osteoblast differentiation are uncovered. Show less
Helicase DHX36 plays essential roles in cell development and differentiation at least partially by resolving G-quadruplex (G4) structures. Here we report crystal structures of the Drosophila homolog o Show more
Helicase DHX36 plays essential roles in cell development and differentiation at least partially by resolving G-quadruplex (G4) structures. Here we report crystal structures of the Drosophila homolog of DHX36 (DmDHX36) in complex with RNA and a series of DNAs. By combining structural, small-angle X-ray scattering, molecular dynamics simulation, and single-molecule fluorescence studies, we revealed that positively charged amino acids in RecA2 and OB-like domains constitute an elaborate structural pocket at the nucleic acid entrance, in which negatively charged G4 DNA is tightly bound and partially destabilized. The G4 DNA is then completely unfolded through the 3'-5' translocation activity of the helicase. Furthermore, crystal structures and DNA binding assays show that G-rich DNA is preferentially recognized and in the presence of ATP, specifically bound by DmDHX36, which may cooperatively enhance the G-rich DNA translocation and G4 unfolding. On the basis of these results, a conceptual G4 DNA-resolving mechanism is proposed. Show less
In obesity, elevated insulin causes fatty liver by activating the gene encoding SREBP-1c, a transcription factor that enhances fatty acid synthesis. Two transcription factors, LXRα and C/EBPβ, are nec Show more
In obesity, elevated insulin causes fatty liver by activating the gene encoding SREBP-1c, a transcription factor that enhances fatty acid synthesis. Two transcription factors, LXRα and C/EBPβ, are necessary but not sufficient for insulin induction of hepatic SREBP-1c mRNA. Here, we show that a third transcription factor, BHLHE40, is required. Immunoprecipitation revealed that BHLHE40 binds to C/EBPβ and LXRα in livers of rats that had fasted and then refed. Hepatic BHLHE40 mRNA rises rapidly when fasted rats are refed and when rat hepatocytes are incubated with insulin. Preventing this rise by gene knockout in mice or siRNAs in hepatocytes reduces the insulin-induced rise in SREBP-1c mRNA. Although BHLHE40 is necessary for insulin induction of SREBP-1c, it is not sufficient as demonstrated by failure of lentiviral BHLHE40 overexpression to increase hepatocyte SREBP-1c mRNA in the absence of insulin. Thus, an additional event is required for insulin to increase SREBP-1c mRNA. Show less
Schizophrenia (SCZ) is associated with differences in subcortical brain volumes and intracranial volume (ICV). However, little is known about the underlying etiology of these brain alterations. Here, Show more
Schizophrenia (SCZ) is associated with differences in subcortical brain volumes and intracranial volume (ICV). However, little is known about the underlying etiology of these brain alterations. Here, we explored whether brain structure volumes and SCZ share genetic risk factors. Using conditional false discovery rate (FDR) analysis, we integrated genome-wide association study (GWAS) data on SCZ (n = 82315) and GWAS data on 7 subcortical brain volumes and ICV (n = 11840). By conditioning the FDR on overlapping associations, this statistical approach increases power to discover genetic loci. To assess the credibility of our approach, we studied the identified loci in larger GWAS samples on ICV (n = 26577) and hippocampal volume (n = 26814). We observed polygenic overlap between SCZ and volumes of hippocampus, putamen, and ICV. Based on conjunctional FDR < 0.05, we identified 2 loci shared between SCZ and ICV implicating genes FOXO3 (rs10457180) and ITIH4 (rs4687658), 2 loci shared between SCZ and hippocampal volume implicating SLC4A10 (rs4664442) and SPATS2L (rs1653290), and 2 loci shared between SCZ and volume of putamen implicating DCC (rs4632195) and DLG2 (rs11233632). The loci shared between SCZ and hippocampal volume or ICV had not reached significance in the primary GWAS on brain phenotypes. Proving our point of increased power, 2 loci did reach genome-wide significance with ICV (rs10457180) and hippocampal volume (rs4664442) in the larger GWAS. Three of the 6 identified loci are novel for SCZ. Altogether, the findings provide new insights into the relationship between SCZ and brain structure volumes, suggesting that their genetic architectures are not independent. Show less
The class III PI3-kinase (PIK3C3) is an enzyme responsible for the generation of phosphatidylinositol 3-phosphate (PI3P), a critical component of vesicular membrane. Here, we report that PIK3C3 defici Show more
The class III PI3-kinase (PIK3C3) is an enzyme responsible for the generation of phosphatidylinositol 3-phosphate (PI3P), a critical component of vesicular membrane. Here, we report that PIK3C3 deficiency in zebrafish results in intestinal injury and inflammation. In pik3c3 mutants, gut tube forms but fails to be maintained. Gene expression analysis reveals that barrier-function-related inflammatory bowel disease (IBD) susceptibility genes (e-cadherin, hnf4a, ttc7a) are suppressed, while inflammatory response genes are stimulated in the mutants. Histological analysis shows neutrophil infiltration into mutant intestinal epithelium and the clearance of gut microbiota. Yet, gut microorganisms appear dispensable as mutants cultured under germ-free condition have similar intestinal defects. Mechanistically, we show that PIK3C3 deficiency suppresses the formation of PI3P and disrupts the polarized distribution of cell-junction proteins in intestinal epithelial cells. These results not only reveal a role of PIK3C3 in gut homeostasis, but also provide a zebrafish IBD model. Show less
Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL Show more
Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 × 10 Show less