In People with HIV (PWH), chronic immune activation and systemic inflammation are associated with increased risk to develop comorbidities including bone loss. Numerous cells of the immune system, name Show more
In People with HIV (PWH), chronic immune activation and systemic inflammation are associated with increased risk to develop comorbidities including bone loss. Numerous cells of the immune system, namely, T cells are involved in the regulation of the bone homeostasis and osteoclasts (OCs) activity. IL-27, a cytokine that belongs to the IL-12 family can regulate the secretion of pro- and anti-inflammatory cytokines by T cells, however its role in the setting of HIV is largely unknown. In the present study, we determined the impact of OCs in T cell secretion of cytokines and whether IL-27 can regulate this function. We found that the presence of OCs in the T cell cultures significantly enhanced secretion of IFNγ, TNFα, IL-17, RANKL, and IL-10 in both PWH and healthy controls. In PWH, IL-27 inhibited IL-17 secretion and downregulated surface expression of RANKL in CD4 T cells. All together these results suggest that in the context of HIV infection IL-27 may favor IFNγ and TNFα secretion at the sites of bone remodeling. Show less
Decidualization is an intricate biological process in which extensive remodeling of the endometrium occurs to support the development of an implanting blastocyst. However, the immunometabolic mechanis Show more
Decidualization is an intricate biological process in which extensive remodeling of the endometrium occurs to support the development of an implanting blastocyst. However, the immunometabolic mechanisms underlying this process are still largely unknown. We found that the decidualization process is accompanied by the accumulation of fructose-1,6-bisphosphate (FBP). The combination of FBP with pyruvate kinase M stimulated IL-27 secretion by endometrial stromal cells in an ERK/c-FOS-dependent manner. IL-27 induced decidual COX-2 Show less
Although an increasing number of common variants contributing to Alzheimer's disease (AD) are uncovered by genome-wide association studies, they can only explain less than half of the heritability of Show more
Although an increasing number of common variants contributing to Alzheimer's disease (AD) are uncovered by genome-wide association studies, they can only explain less than half of the heritability of AD. Rare variant association studies (RVAS) has become an increasingly important area to explain the risk or trait variability of AD. To investigate the potential rare variants that cause AD, we screened 70,209 rare variants from two cohorts of a 175 AD cohort and a 214 cognitively normal cohort from the Alzheimer's Disease Neuroimaging Initiative database. MIRARE, a novel RVAS method, was performed on 232 non-synonymous variants selected by ANNOVAR annotation. Molecular docking and molecular dynamics (MD) simulation were adopted to verify the interaction between the chosen functional variants and BACE1. MIRAGE analysis revealed significant associations between AD and six potential pathogenic genes, including According to the literature search, bio-informatics analysis, and molecular docking and MD simulation, we find non-synonymous rare variants in six genes, especially FLG(rs3120654), that may play key roles in AD. Show less
Hepatic steatosis and insulin resistance (IR) are risk factors for many metabolic syndromes such as NAFLD and T2DM. ApoA4 improves glucose hemostasis by increasing glucose-stimulated insulin secretion Show more
Hepatic steatosis and insulin resistance (IR) are risk factors for many metabolic syndromes such as NAFLD and T2DM. ApoA4 improves glucose hemostasis by increasing glucose-stimulated insulin secretion and glucose uptake via PI3K-Akt activation in adipocytes. However, whether ApoA4 has an effect on hepatic steatosis or IR remains unclear. ApoA4-knockout (KO) aggravates diet-induced obesity, hepatic steatosis, and IR in mice promoted by increased hepatic lipogenesis gene expression based on RNA-seq data. Conversely, liver-specific overexpression of ApoA4 via AAV-ApoA4 transduction reverses the effect in ApoA4-KO mice, accompanied by suppressed hepatic lipogenesis, increased lipolysis, and fatty acid oxidation. Short-term treatment with recombinant ApoA4 protein improves glucose clearance and liver insulin sensitivity, and reduces hepatic lipogenesis gene expression in the absence of insulin. Moreover, in primary hepatocytes and a hepatic cell line, ApoA4 improves hepatic glucose uptake via IRS-PI3K-Akt signaling and decreases fat deposition and hepatic lipogenesis gene expression by inhibiting SREBF1 activity. ApoA4 restricts hepatic steatosis by inhibiting SREBF1-mediated lipogenesis and improves insulin sensitivity and glucose uptake via IRS-PI3K-Akt signaling in the liver. These findings indicate that ApoA4 may serve as a therapeutic target for obesity-associated NAFLD. Show less
RNA G-quadruplexes (rG4s) are noncanonical RNA secondary structures formed by guanine (G)-rich sequences. These complexes play important regulatory roles in both animals and plants through their struc Show more
RNA G-quadruplexes (rG4s) are noncanonical RNA secondary structures formed by guanine (G)-rich sequences. These complexes play important regulatory roles in both animals and plants through their structural dynamics and are closely related to human diseases and plant growth, development, and adaption. Thus, studying the structural dynamics of rG4s is fundamentally important; however, their folding pathways and their unfolding by specialized helicases are not well understood. In addition, no plant rG4-specialized helicases have been identified. Here, using single-molecule FRET, we experimentally elucidated for the first time the folding pathway and intermediates, including a G-hairpin and G-triplex. In addition, using proteomics screening and microscale thermophoresis, we identified and validated five rG4-specialized helicases in Arabidopsis thaliana. Furthermore, DExH1, the ortholog of the famous human rG4 helicase RHAU/DHX36, stood out for its robust rG4 unwinding ability. Taken together, these results shed light on the structural dynamics of plant rG4s. Show less
Left ventricular noncompaction cardiomyopathy (LVNC) is a cardiac disorder characterized by an excessive trabecular meshwork of deep intertrabecular recesses within the ventricular myocardium. Sorbin Show more
Left ventricular noncompaction cardiomyopathy (LVNC) is a cardiac disorder characterized by an excessive trabecular meshwork of deep intertrabecular recesses within the ventricular myocardium. Sorbin and SH3 domain-containing protein 2 (SORBS2) converges on the actin and microtubule cytoskeleton. Here, we investigated the proteins interacting with SORBS2 to elucidate the pathogenic mechanism of LVNC. As reported in previous studies, SORBS2 enhances the occurrence of LVNC by potentiating heart failure, but the specific mechanism remains unclear. Building from our previous finding of elevated SORBS2 levels in LVNC hearts, we screened for proteins interacting with SORBS2 by proteomics and conducting IP experiments. Co-IP and immunofluorescence were used to verify the effects. We selected several proteins with high scores and high coverage that could be closely related to SORBS2 according to earlier reports showing a correlation with LVNC for verification. We finally obtained several proteins that were related to the pathogenesis of LVNC and also interacted with SORBS2, such as α-actinin, β-tubulin, MYH7, FLNA, MYBPC3, YWHAQ and DES, and YWHAQ was the most associated. We focused on the YWHAQ protein, and we identified a novel mechanism through which SORBS2 interacts with YWHAQ, having a negative effect on the cell cycle, potentially leading to LVNC. Show less
Podocyte injury is an important cause of proteinuria. Angiopoietin-like protein 4 (Angptl4) is a secreted glycoprotein and has a role in proteinuria. However, the exact role of Angptl4 in podocyte inj Show more
Podocyte injury is an important cause of proteinuria. Angiopoietin-like protein 4 (Angptl4) is a secreted glycoprotein and has a role in proteinuria. However, the exact role of Angptl4 in podocyte injury and its upstream regulators has not been clarified. In this study, we used lipopolysaccharide (LPS)-induced mice and cultured podocytes as podocyte injury models. Our results indicated that LPS increased the expression of podocyte Angptl4 Show less
To investigate the correlation between interleukin-27 and CXCL10 and other cytokines in pulmonary tuberculosis and to further explore the related miRNAs through bioinformatics. Collect the lesion tiss Show more
To investigate the correlation between interleukin-27 and CXCL10 and other cytokines in pulmonary tuberculosis and to further explore the related miRNAs through bioinformatics. Collect the lesion tissue and peripheral blood of pulmonary tuberculosis patients and the peripheral blood of healthy controls. Immunohistochemical staining and qRT-PCR were used to observe the expression of interleukin-27, CXCL9, CXCL10, and CXCL11. Then, predict the key miRNA, qRT-PCR was used to verify the expression of miRNA in the peripheral blood and evaluated the correlation between them. Both immunohistochemical staining and qRT-PCR indicated that the expressions of IL-27, CXCL9, CXCL10, and CXCL11 were significantly increased in tuberculosis patients, and IL-27 was significantly correlated with CXCL10 ( Our data shows that interleukin-27 and CXCL10 are significantly related in pulmonary tuberculosis, and has-let-7b-5p and has-miR-30a-3p are also related to interleukin-27 and CXCL10. It laid the foundation for subsequently exploiting the potential biomarkers in tuberculosis disease. Show less
Effects of CRISPR/Cas9 knockout of the melanocortin-4 receptor (mc4r) gene in channel catfish, Ictalurus punctatus, were investigated. Three sgRNAs targeting the channel catfish mc4r gene in conjuncti Show more
Effects of CRISPR/Cas9 knockout of the melanocortin-4 receptor (mc4r) gene in channel catfish, Ictalurus punctatus, were investigated. Three sgRNAs targeting the channel catfish mc4r gene in conjunction with Cas9 protein were microinjected in embryos and mutation rate, inheritance, and growth were studied. Efficient mutagenesis was achieved as demonstrated by PCR, Surveyor® assay, and DNA sequencing. An overall mutation rate of 33% and 33% homozygosity/bi-allelism was achieved in 2017. Approximately 71% of progeny inherited the mutation. Growth was generally higher in MC4R mutants than controls (CNTRL) at all life stages and in both pond and tank environments. There was a positive relationship between zygosity and growth, with F Show less
Methazolamide (MTZ), a carbonic anhydrase inhibitor, has been shown to inhibit cardiomyocyte hypertrophy and exert a hypoglycemic effect in patients with type 2 diabetes and diabetic db/db mice. Howev Show more
Methazolamide (MTZ), a carbonic anhydrase inhibitor, has been shown to inhibit cardiomyocyte hypertrophy and exert a hypoglycemic effect in patients with type 2 diabetes and diabetic db/db mice. However, whether MTZ has a cardioprotective effect in the setting of diabetic cardiomyopathy is not clear. We investigated the effects of MTZ in a mouse model of streptozotocin-induced type 1 diabetes mellitus (T1DM). Diabetic mice received MTZ by intragastric gavage (10, 25, or 50 mg/kg, daily for 16 weeks). In the diabetic group, MTZ significantly reduced both random and fasting blood glucose levels and improved glucose tolerance in a dose-dependent manner. MTZ ameliorated T1DM-induced changes in cardiac morphology and dysfunction. Mechanistic analysis revealed that MTZ blunted T1DM-induced enhanced expression of β-catenin. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) and adult mouse cardiomyocytes treated with high glucose or Wnt3a (a β-catenin activator). There was no significant change in β-catenin mRNA levels in cardiac tissues or NRCMs. MTZ-mediated β-catenin downregulation was recovered by MG132, a proteasome inhibitor. Immunoprecipitation and immunofluorescence analyses showed augmentation of AXIN1-β-catenin interaction by MTZ in T1DM hearts and in NRCMs treated with Wnt3a; thus, MTZ may potentiate AXIN1-β-catenin linkage to increase β-catenin degradation. Overall, MTZ may alleviate cardiac hypertrophy by mediating AXIN1-β-catenin interaction to promote degradation and inhibition of β-catenin activity. These findings may help inform novel therapeutic strategy to prevent heart failure in patients with diabetes. Show less
Polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamines (TSNA) metabolism-related genes play an important role in the development of cancers. We assessed the associations of genetic v Show more
Polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamines (TSNA) metabolism-related genes play an important role in the development of cancers. We assessed the associations of genetic variants in genes involved in the metabolism of PAHs and TSNA with risk of squamous cell carcinoma of the head and neck (SCCHN) in European populations using two published genome-wide association study datasets. In the single-locus analysis, we identified two SNPs (rs145533669 and rs35246205) in CYP2B6 to be associated with risk of SCCHN (P = 1.57 × 10 Show less
Guillain-Barré syndrome (GBS) is a common autoimmune disease in the peripheral nervous system. This study aimed to elucidate the role of IL-27 gene polymorphisms in elderly people with GBS. A total of Show more
Guillain-Barré syndrome (GBS) is a common autoimmune disease in the peripheral nervous system. This study aimed to elucidate the role of IL-27 gene polymorphisms in elderly people with GBS. A total of 395 healthy subjects and 422 GBS patients with an average age of 63 years old were included in this study. Peripheral blood samples were collected. The 2 single-nucleotide polymorphisms (SNPs) of IL-27, namely, rs153109 and rs785575, of GBS patients were analyzed using the PCR method and compared with those of the healthy controls. The correlations of IL-27 SNPs with disease severity, disease outcome, level of anti-GM1 antibodies, and Campylobacter jejuni infection were assessed. Serum levels of IL-27 of healthy subjects and GBS patients were analyzed using enzyme-linked immunosorbent assay. No significant differences in the frequencies of rs785575 SNPs between GBS and healthy subjects were observed. In analyzing rs153109 SNPs, the G allele was found to be more prevalent in the GBS patients (p = 0.012). More alleles show GG genotype in GBS patients (p = 0.023). The -964A>G allele has a higher prevalence in severely affected and anti-GM1-Ab-positive GBS patients. GBS patients with the rs153109 SNP showed a poor clinical outcome than those without rs153109 SNP (p = 0.012). GBS patients showed higher serum IL-27 levels than healthy subjects (p < 0.001). The levels of IL-27 were also higher in GBS patients with genotypes of AG and GG, and those with GG genotypes showed the highest IL-27 levels. The rs153109 SNP is more prevalent in GBS patients with the GG and G allele and is associated with severer GBS, poorer clinical outcomes, and higher IL-27 levels. Show less
The poor prognosis of hepatocellular carcinoma (HCC) could be attributed to its high metastasis rate. Here, we report the role of nucleoredoxin (NXN), a multifunctional redox-active protein, in HCC me Show more
The poor prognosis of hepatocellular carcinoma (HCC) could be attributed to its high metastasis rate. Here, we report the role of nucleoredoxin (NXN), a multifunctional redox-active protein, in HCC metastasis. The expression of NXN in HCC tissues was measured by immunohistochemistry. The role of NXN on HCC proliferation was determined by CCK-8, EdU and colony formation assays in vitro and subcutaneous tumor formation model in vivo. Transwell and wound healing assays and tail vein injection model were performed to assess the function of NXN on HCC metastasis. Co-immunoprecipitation assay was performed to examine the interaction among NXN, Snail and DUB3. Our results showed that NXN was downregulated in HCC tissues compared to adjacent liver tissues. Patients with low NXN expression had shorter overall survival (OS) time (P < 0.001) than those with high NXN expression. Biologically, ectopic expression of NXN significantly inhibited the proliferation and metastasis of HCC cells both in vitro and in vivo by suppressing epithelial-mesenchymal transition (EMT). Mechanistically, NXN promoted the ubiquitin-proteasome-mediated degradation of Snail through interaction with DUB3. Further, depletion of Snail abolished NXN-inhibited cell proliferation and metastasis. In summary, NXN suppressed the proliferation and metastasis of HCC by inhibiting DUB3-mediated deubiquitylation of Snail protein. Our study demonstrates that NXN, DUB3 and Snail complex functioned as an important regulatory mechanism of HCC progression and indicates a potential therapeutic approach for the treatment of HCC metastasis. Show less
Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular Show more
Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterized by cognitive deficits and memory dysfunction, which is clinically incurable so far. Novel small molecular compound 2JY-OBZ4 is one of structural analogue of Huperzine A (Hup-A), an anti-AD drug in China. In our previous work, 2JY-OBZ4 exhibited potent effects on tau hyperphosphorylation, Aβ production and acetylcholinesterase (AChE) activity. However, 2JY-OBZ4's anti-AD effects and the underlying molecular mechanisms remain unclear. We here reported that 2JY-OBZ4 resisted tau hyperphosphorylation at Thr181 and Ser396 sites in HEK293-hTau cells transfected with GSK-3β, decreased tau phosphorylation via upregulating the activity of PP2A in HEK293-hTau cells and reduced Aβ production through regulating protein levels of APP cleavage enzymes in N2a-hAPP cells. Meanwhile, we found that 2JY-OBZ4 had no adverse effects on cell viability of mice primary neuron even at high concentration, and ameliorated synaptic loss induced by human oligomeric Aβ42. 2JY-OBZ4 had moderate AChE inhibitory activity with the half maximal inhibitory concentration (IC50) to be 39.48 μg/ml Show less
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder with intricate etiology. It is closely associated with metabolic syndrome, insulin resistance and endoplasmic reticulum (ER) Show more
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder with intricate etiology. It is closely associated with metabolic syndrome, insulin resistance and endoplasmic reticulum (ER) stress. Exostosin1 (Ext1) is an ER-resident transmembrane glycosyltransferase, which plays an important role in ER homeostasis. Loss-of-function mutations in Ext1 link to hereditary multiple exostosis (HME). The present research was undertaken to identify the effect of Ext1 in the progress of NAFLD. High-fat-diet induced mice obesity, hepatic steatosis and decreased hepatic Ext1 expression. In consistent with evaluation of NAFLD mice possessing down-regulated Ext1 expression, free fatty acid (FFA) treatment blunted Ext1 expression in hepatocytes. In human subjects, HME patients presented elevated fasting blood glucose-one of the criteria that define insulin resistance. In vitro experiments, Ext1 deficiency promoted FFA-induced insulin resistance in hepatocytes by analysis of glycogen storage and hallmarks of gluconeogenesis, ascertaining its association with insulin resistance. Mechanically, Ext1 silencing exacerbated ER stress triggered by FFA, which severely disrupted autophagy in hepatocytes, and thereby accelerated the progression of NAFLD. In conclusion, our study demonstrates a beneficial role for Ext1 during the development of NAFLD, which establishes a novel correlation between Ext1 and ER stress-induced perturbations of autophagy during NAFLD progression. Show less
The aggregation and interaction of metabolic risk factors leads to highly heterogeneous pathogeneses, manifestations, and outcomes, hindering risk stratification and targeted management. To deconstruc Show more
The aggregation and interaction of metabolic risk factors leads to highly heterogeneous pathogeneses, manifestations, and outcomes, hindering risk stratification and targeted management. To deconstruct the heterogeneity, we used baseline data from phase II of the Fangshan Family-Based Ischemic Stroke Study (FISSIC), and a total of 4632 participants were included. A total of 732 individuals who did not have any component of metabolic syndrome (MetS) were set as a reference group, while 3900 individuals with metabolic abnormalities were clustered into subtypes using multi-trait limited mixed regression (MFMR). Four metabolic subtypes were identified with the dominant characteristics of abdominal obesity, hypertension, hyperglycemia, and dyslipidemia. Multivariate logistic regression showed that the hyperglycemia-dominant subtype had the highest coronary heart disease (CHD) risk (OR: 6.440, 95% CI: 3.177-13.977) and that the dyslipidemia-dominant subtype had the highest stroke risk (OR: 2.450, 95% CI: 1.250-5.265). Exome-wide association studies (EWASs) identified eight SNPs related to the dyslipidemia-dominant subtype with genome-wide significance, which were located in the genes Show less
Depolarized mitochondria can be degraded via mitophagy, a selective form of autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic traffi Show more
Depolarized mitochondria can be degraded via mitophagy, a selective form of autophagy. The RAB GTPase RAB7A was recently shown to play a key role in this process. RAB7A regulates late endocytic trafficking under normal growth conditions but is translocated to the mitochondrial surface following depolarization. However, how RAB7A activity is regulated during mitophagy is not understood. Here, using a proximity-dependent biotinylation approach (miniTurbo), we identified C5orf51 as a specific interactor of GDP-locked RAB7A. C5orf51 also interacts with the RAB7A guanine nucleotide exchange factor (GEF) complex members MON1 and CCZ1. In the absence of C5orf51, localization of RAB7A on depolarized mitochondria is compromised and the protein is degraded by the proteasome. Furthermore, depletion of C5orf51 also inhibited ATG9A recruitment to depolarized mitochondria. Together, these results indicate that C5orf51 is a positive regulator of RAB7A in its shuttling between late endosomes and mitochondria to enable mitophagy. Show less
Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research disco Show more
Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics. Show less
Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can Show more
Chronic pain is defined as pain that persists typically for a period of over six months. Chronic pain is often accompanied by an anxiety disorder, and these two tend to exacerbate each other. This can make the treatment of these conditions more difficult. Glucose-dependent insulinotropic polypeptide (GIP) is a member of the incretin hormone family and plays a critical role in glucose metabolism. Previous research has demonstrated the multiple roles of GIP in both physiological and pathological processes. In the central nervous system (CNS), studies of GIP are mainly focused on neurodegenerative diseases; hence, little is known about the functions of GIP in chronic pain and pain-related anxiety disorders. The chronic inflammatory pain model was established by hind paw injection with complete Freund's adjuvant (CFA) in C57BL/6 mice. GIP receptor (GIPR) agonist (D-Ala In the present study, we found that hind paw injection with CFA induced pain sensitization and anxiety-like behaviors in mice. The expression of GIPR in the ACC was significantly higher in CFA-injected mice. D-Ala GIPR activation was found to produce analgesic and anxiolytic effects, which were partially due to attenuation of neuroinflammation and inhibition of excitatory transmission in the ACC. GIPR may be a suitable target for treatment of chronic inflammatory pain and pain-related anxiety. Show less
The epithelial-mesenchymal transition (EMT) is an important pathological process in the occurrence of pulmonary fibrosis. Changes in histone methylation modifications of key genes play an important ro Show more
The epithelial-mesenchymal transition (EMT) is an important pathological process in the occurrence of pulmonary fibrosis. Changes in histone methylation modifications of key genes play an important role in this process. As a histone methyltransferase, the regulatory mechanism and role of SET domain bifurcated 1 (SETDB1) in pulmonary fibrosis remain unclear. We found that SETDB1 inhibited EMT and that cells attenuated the expression of SETDB1 to relieve this inhibition during transforming growth factor-β (TGF-β)-induced EMT. Silencing SETDB1 expression significantly enhanced the mesenchymal phenotype induced by TGF-β and the expression and deposition of fibronectin and significantly reduced the expression of E-cadherin. The decrease in E-cadherin expression and the induction of EMT led to increased lipid reactive oxygen species (ROS) and ferrous ions, which induced ferroptosis. Chromatin immunoprecipitation (ChIP) results showed that SETDB1 regulates the expression of Snai1 by catalyzing the histone H3 lysine 9 trimethylation (H3K9me3) of Snai1, the main transcription factor that initiates the process of EMT, and thus, indirectly regulates E-cadherin. Surprisingly, when examining the effect of overexpressed SETDB1 on EMT, we found that overexpressed SETDB1 alleviated EMT and also caused ferroptosis. We suggest that the overexpression of SETDB1 partially reverses the mesenchymal phenotype to an epithelial state, while those cells that fail to reverse are depleted by ferroptosis. In conclusion, the histone methylase SETDB1 regulates Snai1 epigenetically, driving EMT gene reprogramming and ferroptosis in response to TGF-β. However, there are unexplored links between the epigenetic reprogramming and transcriptional processes that regulate EMT in a TGF-β-dependent manner. Show less
Developmental dysplasia of the hip (DDH) is a common anomaly leading to adult osteoarthritis. Environmental and genetic factors contribute to DDH, but its exact genetic mechanism is unclear. In this s Show more
Developmental dysplasia of the hip (DDH) is a common anomaly leading to adult osteoarthritis. Environmental and genetic factors contribute to DDH, but its exact genetic mechanism is unclear. In this study, we used whole exome sequencing to identify the causative gene of a DDH pedigree. A rare missense variant in KANSL1 (c.C767T; p.S256F) was identified as the pathogenic cause of DDH. Subsequent mutation screening showed another missense variant in 1 of 200 sporadic patients. Kansl1-mutated mice showed reduced chondrocytes in the acetabulum and a decrease in the cartilage matrix, which may be DDH phenotype-related abnormalities. Furthermore, functional studies showed that cell proliferation was delayed and Mmp13 expression was abnormally upregulated in chondrocytes differentiated from Kansl1 mutant mouse embryonic stem cells. In conclusion, our findings suggest that KANSL1 is a novel pathogenic gene for DDH. The identification of KANSL1 variants has great diagnostic value for identifying individuals with DDH. KEY MESSAGES: Developmental dysplasia of the hip (DDH) is a common anomaly causing adult osteoarthritis. Environmental and genetic factors contribute to DDH, but its exact genetic mechanism is unclear. Using high-throughput whole exome sequencing, we found a novel variant in KANSL1 that was co-inherited by all severely affected individuals diagnosed with DDH from a three-generation family. Further analysis revealed that a Kansl1 variant in mice reduced the number of chondrocytes and decreased cartilage matrix, and mouse embryonic stem differentiation assay showed cartilage defects. These findings indicate a direct association between KANSL1 and hip development, expanding the pathogenic gene spectrum in DDH and providing insight into potential new targets for diagnosing and treating hip dysplasia. Show less
MicroRNAs (miRNAs) are one type of noncoding RNAs that interfere with mRNA translation to downregulate gene expression, which results in posttranscriptional gene silencing. Over the past two decades, Show more
MicroRNAs (miRNAs) are one type of noncoding RNAs that interfere with mRNA translation to downregulate gene expression, which results in posttranscriptional gene silencing. Over the past two decades, miRNAs have been widely reported to impact the progression of malignant tumours by interfering with cancer initiation and progression; therefore, miRNAs represent potential new diagnostic and therapeutic tools. miR-650 is a newly identified miR, and increasing studies have demonstrated that miR-650 plays critical roles in cancer progression, such as mediating the Wnt signalling pathway/AXIN1 (axis inhibition protein 1) axis in hepatocellular carcinoma. Nevertheless, associations between the expression patterns and molecular mechanisms of miR-650 in cancer have not been comprehensively described. In this article, we review the existing evidence regarding the mechanisms by which miR-650 expression is altered and their relation to cancer. Moreover, the promising clinical application of miR-650 for diagnosis and treatment is highlighted. Show less
Cistanche deserticola Ma (cistanche) is a traditional herb with a wide range of therapeutic properties. However, no evidence of cistanche's effect on adipogenesis has been found. The effect of cistanc Show more
Cistanche deserticola Ma (cistanche) is a traditional herb with a wide range of therapeutic properties. However, no evidence of cistanche's effect on adipogenesis has been found. The effect of cistanche that promotes the adipogenesis of 3T3-L1 preadipocytes was proved by using MTT spectrophotometry, Nile Red staining, Oil Red O staining and transcriptome sequencing technology. The mRNA level of key transcription factors for adipogenesis such as PPAR, AP2 and LPL were examined by RT-PCR. The results showed that the intracellular lipid content in cistanche treated cells were notably increased when compared with the non-treated cells. Between the differentiation and cistanche treated groups, the expression of adipogenesis related genes such as grow hormone releasing hormone (Ghrp), BCL2/adenovirus E1B interacting protein 3 (Bnip3) and Gastric inhibitory polypeptide receptor (Gipr) were significantly increased. Our findings also verified that cistanche promoted adipogenesis, which was accompanied by up-regulated level of Bnip3 and PPAR. This study could uncover new signaling pathways involved in adipogenesis regulation. Show less
The tripartite motif (TRIM) family of E3 ubiquitin ligases is well known for its roles in antiviral restriction and innate immunity regulation, in addition to many other cellular pathways. In particul Show more
The tripartite motif (TRIM) family of E3 ubiquitin ligases is well known for its roles in antiviral restriction and innate immunity regulation, in addition to many other cellular pathways. In particular, TRIM25-mediated ubiquitination affects both carcinogenesis and antiviral response. While individual substrates have been identified for TRIM25, it remains unclear how it regulates diverse processes. Here we characterized a mutation, R54P, critical for TRIM25 catalytic activity, which we successfully utilized to "trap" substrates. We demonstrated that TRIM25 targets proteins implicated in stress granule formation (G3BP1/2), nonsense-mediated mRNA decay (UPF1), nucleoside synthesis (NME1), and mRNA translation and stability (PABPC4). The R54P mutation abolishes TRIM25 inhibition of alphaviruses independently of the host interferon response, suggesting that this antiviral effect is a direct consequence of ubiquitination. Consistent with that, we observed diminished antiviral activity upon knockdown of several TRIM25-R54P specific interactors including NME1 and PABPC4. Our findings highlight that multiple substrates mediate the cellular and antiviral activities of TRIM25, illustrating the multi-faceted role of this ubiquitination network in modulating diverse biological processes. Show less
Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)-based therapy has n Show more
Bile acid metabolites have been increasingly recognized as pleiotropic signaling molecules that regulate cardiovascular functions, but their role in mesenchymal stromal cells (MSC)-based therapy has never been investigated. It is found that overexpression of farnesoid X receptor (FXR), a main receptor for bile acids, improves the retention and cardioprotection of adipose tissue-derived MSC (ADSC) administered by intramyocardial injection in mice with myocardial infarction (MI), which shows enhanced antiapoptotic, proangiogenic, and antifibrotic effects. RNA sequencing, LC-MS/MS, and loss-of-function studies reveal that FXR overexpression promotes ADSC paracrine angiogenesis via Angptl4. FXR overexpression improves ADSC survival in vivo but fails in vitro. By performing bile acid-targeted metabolomics using ischemic heart tissue, 19 bile acids are identified. Among them, cholic acid and deoxycholic acid significantly increase Angptl4 secretion from ADSC overexpressing FXR and further improve their proangiogenic capability. Moreover, ADSC overexpressing FXR shows significantly lower apoptosis by upregulating Nqo-1 expression only in the presence of FXR ligands. Retinoid X receptor α is identified as a coactivator of FXR. It is first demonstrated that there is a bile acid pool in the myocardial microenvironment. Targeting the bile acid-FXR axis may be a novel strategy for improving the curative effect of MSC-based therapy for MI. Show less
IL-17D is a new member of the IL-17 family. Currently, it is believed that IL-17D can directly act on immune cells or may indirectly modulate immune responses by regulating cytokine expression. Herein Show more
IL-17D is a new member of the IL-17 family. Currently, it is believed that IL-17D can directly act on immune cells or may indirectly modulate immune responses by regulating cytokine expression. Herein, we hypothesized that IL-17D regulates the expression of chemokines in intestinal epithelial cells, in turn modulating the immune response within intestinal mucosa under hyperoxia. To explore this notion, newborn rats were divided into a hyperoxia group (85 % O Show less