Soyasaponins are triterpenoid glycosides discovered in soybean and have anti-cancer properties. Soyasaponin A was reported to repress estrogen-insensitive breast cancer cell proliferation. This study Show more
Soyasaponins are triterpenoid glycosides discovered in soybean and have anti-cancer properties. Soyasaponin A was reported to repress estrogen-insensitive breast cancer cell proliferation. This study intends to explore the role of one isomer of soyasaponin A, i.e. soyasaponin Ag (Ssa Ag), in triple-negative breast cancer (TNBC) development. Bioinformatic databases were used to predict DUSP6 expression in breast cancer (BC) as well as the correlation between the expression of DUSP6 (or MAPK1, MAPK14) with the prognosis of patients with BC. The expression of DUSP6/MAPK signaling-related genes (DUSP6, MAPK1, and MAPK14) in TNBC cell lines was assessed via Western blot analysis and RT-qPCR. Levels of cell apoptosis proteins (Bax and Bcl-2) in TNBC cells were assessed via Western blot analysis. CCK-8 assay, colony formation assay, and flow cytometry analysis were conducted for the measurement of TNBC cell growth and apoptosis. In vivo xenograft assay was employed for investigating the biological influence of Ssa Ag on tumor growth. The poor prognosis of BC patients was linked to the aberrant expression of DUSP6/MAPK pathway genes. Low expression of DUSP6 or high expression of MAPK1 (or MAPK14) was correlated to poor prognosis. DUSP6 was downregulated while MAPK1 and MAPK14 were upregulated in TNBC cells versus normal cells. Ssa Ag upregulated DUSP6 expression while downregulated MAPK1 and MAPK14 expression, inhibiting the MAPK signaling pathway. Additionally, Ssa Ag promoted in vitro TNBC cell apoptosis and restrained cell growth, and repressed in vivo tumor growth. Ssa Ag inhibited TNBC progression via upregulating DUSP6 and inactivating the MAPK signaling pathway. Show less
Osteoporosis is a common aging-related metabolic disease that mainly occurs in older adults and postmenopausal women. Despite advances in anti-osteoporosis treatment, outcomes remain unsatisfactory du Show more
Osteoporosis is a common aging-related metabolic disease that mainly occurs in older adults and postmenopausal women. Despite advances in anti-osteoporosis treatment, outcomes remain unsatisfactory due to detrimental side effects. BCI hydrochloride (BCI), a selective dual-specificity phosphatase 6 (DUSP6) inhibitor, is associated with multiple cellular functions, including inhibiting tumor growth and macrophage inflammation; however, its role in regulating osteoclast differentiation remains unknown. Here, we revealed that treatment with BCI attenuated RANKL-mediated osteoclast differentiation Show less
Intestinal mucositis is a common side effect of cancer chemotherapy and it limits the dose of chemotherapy given to a patient. Tripartite motif family (TRIM) proteins have been reported to be implicat Show more
Intestinal mucositis is a common side effect of cancer chemotherapy and it limits the dose of chemotherapy given to a patient. Tripartite motif family (TRIM) proteins have been reported to be implicated in the regulation of cancer chemotherapy. The present study aimed to investigate the effect of TRIM9 on irinotecan‑induced intestinal mucositis in the rat intestinal epithelial cell line IEC‑6. The expression of several TRIMs, such as TRIM1, TRIM9, TRIM18, TRIM36, TRIM46 and TRIM67, was examined. After TRIM9 knockdown or overexpression by lentivirus infection, cell proliferation and apoptosis, epithelial barrier tight‑junction proteins, inflammatory cytokines, transepithelial electrical resistance (TEER) and FITC dextran were measured. Treatment with irinotecan significantly inhibited cell proliferation and induced cell apoptosis, TRIM9 expression, intestinal mucosal barrier impairment, the levels of inflammatory cytokines and P38 phosphorylation in IEC‑6 cells, while the expression levels of epithelial barrier tight‑junction protein ZO‑1 and Claudin‑4 were decreased. Knockdown of TRIM9 partly counteracted the effect of irinotecan treatment, and inhibition of P38 potently reversed the effect of TRIM9 overexpression in IEC‑6 cells. Moreover, co‑immunoprecipitation showed an interaction between TRIM9 and DUSP6 in IEC‑6 cells, and overexpression of DUSP6 notably counteracted the effect of TRIM9 overexpression. The results demonstrated that TRIM9 knockdown may benefit patients with intestinal mucositis by inhibiting inflammatory cytokine expression and repairing intestinal barrier functions, which was probably due to inhibition of the activation of the P38 pathway via targeting DUSP6. Show less
Breast cancer has surpassed lung cancer as the most commonly diagnosed cancer in women worldwide. Some therapeutic drugs and approaches could cause side effects and weaken the immune system. The combi Show more
Breast cancer has surpassed lung cancer as the most commonly diagnosed cancer in women worldwide. Some therapeutic drugs and approaches could cause side effects and weaken the immune system. The combination of conventional therapies and traditional Chinese medicine (TCM) significantly improves treatment efficacy in breast cancer. However, the chemical composition and underlying anti-tumor mechanisms of TCM still need to be investigated. The primary aim of this study is to provide unique insights to screen the natural components for breast cancer therapy using high-throughput transcriptome analysis. Differentially expressed genes were identified based on two conditions: single samples and groups were classified according to their pharmaceutical effect. Subsequently, the sample treated with Show less
Osteoporosis-related fractures, such as femoral neck and vertebral fractures, are common in aged people, resulting in increased disability rate and health-care costs. Thus, it is of great importance t Show more
Osteoporosis-related fractures, such as femoral neck and vertebral fractures, are common in aged people, resulting in increased disability rate and health-care costs. Thus, it is of great importance to clarify the mechanism of osteoclast-related osteoporosis and find effective ways to avoid its complication. In this study, gene expression profile analysis and real-time polymerase chain reaction revealed that DUSP6 expression was suppressed in human and mice osteoporosis cases. In vitro experiments confirmed that DUSP6 overexpression prevented osteoclastogenesis, whereas inhibition of DUSP6 by small interference RNA or with a chemical inhibitor, (E/Z)-BCI, had the opposite effect. (E/Z)-BCl significantly accelerated the bone loss process in vivo by enhancing osteoclastogenesis. Bioinformatics analyses and in vitro experiments indicated that miR-181a was an upstream regulator of DUSP6. Moreover, miR-181a positively induced the differentiation and negatively regulated the apoptosis of osteoclasts via DUSP6. Furthermore, downstream signals by ERK2 and SMAD2 were also found to be involved in this process. Evaluation of ERK2-deficiency bone marrow-derived macrophages confirmed the role of ERK2 signaling in the DUSP6-mediated osteoclastogenesis. Additionally, immunoprecipitation assays confirmed that DUSP6 directly modified the phosphorylation status of SMAD2 and the subsequent nuclear transportation of NFATC1 to regulate osteoclast differentiation. Altogether, this study demonstrated for the first time the role of miRNA-181a/DUSP6 in the progression of osteoporosis via the ERK2 and SMAD2 signaling pathway. Hence, DUSP6 may represent a novel target for the treatment of osteoclast-related diseases in the future. Show less
The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (L Show more
The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment. Show less
Previous studies report that fibroblast growth factor 2 (FGF2) modulates Sproutys (SPRYs)/dual specificity phosphatase 6 (DUSP6)/extracellular signal-regulated kinase (ERK) signaling pathway in endome Show more
Previous studies report that fibroblast growth factor 2 (FGF2) modulates Sproutys (SPRYs)/dual specificity phosphatase 6 (DUSP6)/extracellular signal-regulated kinase (ERK) signaling pathway in endometrial glandular epithelial cells. However, its role in endometriosis remains unclear. The expression patterns and localization of related proteins in endometrium patients' samples were determined using quantitative reverse transcription PCR, Western blotting, and immunohistochemistry, respectively. Human endometrial stromal cells (HESCs) were isolated and transfected with small interfering RNA (siRNA) targeting FGF2 (FGF2-siRNA). Cell viability was determined using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. It was found that FGF2 mRNA and protein levels were increased in the ectopic endometrium, whilst the mRNA and protein levels of SPRYs/DUSP6/ERK signaling pathway related-genes were dysregulated. Spearman's rank correlation analysis revealed a negative correlation between FGF2 and SPRYs/DUSP6 signaling pathway-related proteins. In vitro study demonstrated that FGF2 silencing suppressed cell proliferation. Our results suggest that FGF2 upregulation might contribute to endometriosis via the regulation of the SPRYs/DUSP6/ERK signaling pathway. Show less
The pituitary is a vital endocrine organ that regulates animal seasonal reproduction by controlling the synthesis and secretion of the hormone. The change of photoperiod is the key factor affecting th Show more
The pituitary is a vital endocrine organ that regulates animal seasonal reproduction by controlling the synthesis and secretion of the hormone. The change of photoperiod is the key factor affecting the function of the pituitary in animals, but the mechanism is unclear. Here, we studied the transcriptomic variation in pars distalis (PD) of the pituitary between short photoperiod (SP) and long photoperiod (LP) using RNA sequencing based on the OVX+E Show less
Evidence suggests that Tripartite Motif Containing 11 (TRIM11) has pro-tumor activity in human non-small cell lung cancer (NSCLC). However, the roles and underlying mechanisms of TRIM11 in NSCLC have Show more
Evidence suggests that Tripartite Motif Containing 11 (TRIM11) has pro-tumor activity in human non-small cell lung cancer (NSCLC). However, the roles and underlying mechanisms of TRIM11 in NSCLC have not yet been fully elucidated. In this work, human lung cancer cell lines (A549, H446, and H1975) were transfected with siRNA or lentiviruses to knockdown or overexpress TRIM11 and dual-specificity phosphatase 6 (DUSP6). The cell tumor response was assessed by determining the rate of proliferation, apoptosis, the uptake of 2-[N-(7-nitrobenz-2-oxa-1, 3-diaxol-4-yl) amino]-2-deoxyglucose (2-NBDG), and the secretion of lactic acid (LD). Dominant-negative (dn)-MEK1 was used to block the ERK1/2 pathway. The mechanism was investigated by assessing the protein levels of pyruvate kinase isozymes M2 (PKM2) and DUSP6, as well as the activation of ERK1/2 pathway. Our data confirmed the anti-cancer effect of siTRIM11 in human lung cancer by demonstrating inhibition of cancer cell proliferation, induction of apoptosis, prevention of 2-NBDG uptake, suppression of LD production, and prevention of lung cancer cell (A549) tumorigenicity in nude mice. The underlying mechanism involved the up-regulation of DUSP6 and the inhibition of ERK1/2 activity. Overexpression of TRIM11 induced tumorigenesis of NSCLC Show less
Elucidating virus-cell interactions is fundamental to understanding viral replication and identifying targets for therapeutic control of viral infection. The extracellular signal-regulated kinase (ERK Show more
Elucidating virus-cell interactions is fundamental to understanding viral replication and identifying targets for therapeutic control of viral infection. The extracellular signal-regulated kinase (ERK) pathway has been shown to regulate pathogenesis during many viral infections, but its role during coronavirus infection is undetermined. Infectious bronchitis virus is the representative strain of Gammacoronavirus, which causes acute and highly contagious diseases in the poultry farm. In this study, we investigated the role of ERK1/2 signaling pathway in IBV infection. We found that IBV infection activated ERK1/2 signaling and the up-regulation of phosphatase DUSP6 formed a negative regulation loop. Pharmacological inhibition of MEK1/2-ERK1/2 signaling suppressed the expression of DUSP6, promoted cell death, and restricted virus replication. In contrast, suppression of DUSP6 by chemical inhibitor or siRNA increased the phosphorylation of ERK1/2, protected cells from apoptosis, and facilitated IBV replication. Overexpression of DUSP6 decreased the level of phospho-ERK1/2, promoted apoptosis, while dominant negative mutant DUSP6-DN lost the regulation function on ERK1/2 signaling and apoptosis. In conclusion, these data suggest that MEK-ERK1/2 signaling pathway facilitates IBV infection, probably by promoting cell survival; meanwhile, induction of DUSP6 forms a negative regulation loop to restrict ERK1/2 signaling, correlated with increased apoptosis and reduced viral load. Consequently, components of the ERK pathway, such as MEK1/2 and DUSP6, represent excellent targets for the development of antiviral drugs. Show less
FGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH). Recently, several n Show more
FGF8-FGFR1 signalling is involved in multiple biological processes, while impairment of this signalling is one of the main reasons for isolated hypogonadotropic hypogonadism (IHH). Recently, several negative modulators of FGF8-FGFR1 signalling were also found to be involved in IHH, including A total of 196 patients with IHH were enrolled in this study. Whole-exome sequencing was performed to identify variants, which was verified by PCR and Sanger sequencing. Four heterozygous Our study greatly enriched the genotypic and phenotypic spectra of Show less
Atomic force microscopy-single-molecule force spectroscopy (AFM-SMFS) is a powerful methodology to probe intermolecular and intramolecular interactions in biological systems because of its operability Show more
Atomic force microscopy-single-molecule force spectroscopy (AFM-SMFS) is a powerful methodology to probe intermolecular and intramolecular interactions in biological systems because of its operability in physiological conditions, facile and rapid sample preparation, versatile molecular manipulation, and combined functionality with high-resolution imaging. Since a huge number of AFM-SMFS force-distance curves are collected to avoid human bias and errors and to save time, numerous algorithms have been developed to analyze the AFM-SMFS curves. Nevertheless, there is still a need to develop new algorithms for the analysis of AFM-SMFS data since the current algorithms cannot specify an unbinding force to a corresponding/each binding site due to the lack of networking functionality to model the relationship between the unbinding forces. To address this challenge, herein, we develop an unsupervised method, i.e., a network-based automatic clustering algorithm (NASA), to decode the details of specific molecules, e.g., the unbinding force of each binding site, given the input of AFM-SMFS curves. Using the interaction of heparan sulfate (HS)-antithrombin (AT) on different endothelial cell surfaces as a model system, we demonstrate that NASA is able to automatically detect the peak and calculate the unbinding force. More importantly, NASA successfully identifies three unbinding force clusters, which could belong to three different binding sites, for both Ext1 Show less
Hereditary multiple exostoses (HME), also referred to as multiple osteochondromas, is an autosomal dominant skeletal disease characterized by the development of multiple overgrown benign bony tumors c Show more
Hereditary multiple exostoses (HME), also referred to as multiple osteochondromas, is an autosomal dominant skeletal disease characterized by the development of multiple overgrown benign bony tumors capped by cartilage and is associated with bone deformity, joint limitation, and short stature. Mutations in exostosin glycosyltransferase (EXT)1 and EXT2 genes, which are located on chromosomes 8q24.1 and 11p13, contribute to the pathogenesis of HME. In the present study, a genetic analysis of a four-generation Chinese family with HME was conducted using whole-exome sequencing (WES), followed by validation using Sanger sequencing. A novel heterozygous frameshift mutation in exon 5 of EXT2 (c.944dupT, p.Leu316fs) was identified in all affected individuals but was not detected in any unaffected individuals. This mutation results in a frameshift that introduces a premature termination codon at position 318 (p.Leu316fs) with the ability to produce a truncated EXT2 protein that lacks the last 433 amino acids at its C-terminal to indicate a defective exostosin domain and the absence of the glycosyltransferase family 64 domain, or to lead to the degradation of mRNAs by nonsense-mediated mRNA decay, which is critical for the function of EXT2. Our results indicate that WES is effective in extending the EXT mutational spectra and is advantageous for genetic counseling and the subsequent prenatal diagnosis. Show less
Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-de Show more
Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits. PCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration. In vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2 (ALX antagonist) or EX527 (SIRT1 inhibitor) abolished the restoration of HS in response to PCTR1. PCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury. Show less
Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have bee Show more
Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies. Show less
Multiple osteochondromas (MO) is an autosomal dominant hereditary disorder, which typically manifests as skeletal dysplasia, mainly involving long bones and knees, ankles, elbows, wrists, shoulders, a Show more
Multiple osteochondromas (MO) is an autosomal dominant hereditary disorder, which typically manifests as skeletal dysplasia, mainly involving long bones and knees, ankles, elbows, wrists, shoulders, and pelvis. Previous studies have demonstrated that mutations in exostosin glycosyl transferase-1 ( Show less
Emilie J Richards, Joseph A McGirr, Jeremy R Wang+6 more · 2021 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
To investigate the origins and stages of vertebrate adaptive radiation, we reconstructed the spatial and temporal histories of adaptive alleles underlying major phenotypic axes of diversification from Show more
To investigate the origins and stages of vertebrate adaptive radiation, we reconstructed the spatial and temporal histories of adaptive alleles underlying major phenotypic axes of diversification from the genomes of 202 Caribbean pupfishes. On a single Bahamian island, ancient standing variation from disjunct geographic sources was reassembled into new combinations under strong directional selection for adaptation to the novel trophic niches of scale-eating and molluscivory. We found evidence for two longstanding hypotheses of adaptive radiation: hybrid swarm origins and temporal stages of adaptation. Using a combination of population genomics, transcriptomics, and genome-wide association mapping, we demonstrate that this microendemic adaptive radiation of novel trophic specialists on San Salvador Island, Bahamas experienced twice as much adaptive introgression as generalist populations on neighboring islands and that adaptive divergence occurred in stages. First, standing regulatory variation in genes associated with feeding behavior ( Show less
DNA methylation is important for lung cancer prognosis. In this work, it is aimed to seek novel biomarkers with DNA methylation-expression-pathway pattern and explore its underlying mechanism. Prognos Show more
DNA methylation is important for lung cancer prognosis. In this work, it is aimed to seek novel biomarkers with DNA methylation-expression-pathway pattern and explore its underlying mechanism. Prognostic DNA methylation sites and mRNAs were screened in NSCLC data set from TCGA, and further validated using the samples retrospectively collected, and EXT1 was identified as a potential target. Gene body methylation of three CpG sites (cg03276982, cg11592677, cg16286281) on EXT1 was significantly associated with clinical outcome, and the EXT1 gene expression also predicted prognosis. The expression level of EXT1 was also correlated with its DNA methylation level. This observation was further validated in a new data set consist of 170 samples. Knocking down of EXT1 resulted in decreased proliferation and migration. EXT1 targets were analysed using GSEA. It is found that the WNT signalling is the potential downstream target of EXT1. Further analyses revealed that the EXT1 targets the beta-catenin and effect migration rate of NSCLC cell lines. The WNT signalling inhibitor, XAV-939, effectively disrupted the migration promotion effect induced by EXT1. In summary, EXT1 methylation regulates the gene expression, effects the proliferation and migration via WNT pathway and predicted a poor prognosis for NSCLC. Show less
Multiple Osteochondroma is an abnormal skeleton development autosomal dominant genetic disease which caused by the mutation of EXT1 gene. In this study, we generated induced pluripotent stem cells (iP Show more
Multiple Osteochondroma is an abnormal skeleton development autosomal dominant genetic disease which caused by the mutation of EXT1 gene. In this study, we generated induced pluripotent stem cells (iPSCs) from the mesenchymal stem cells (MSCs) of a 12-year-old male patient by reprogramming MSCs with non-integrative vectors. The iPSCs line expresses pluripotent markers, has a normal male karyotype and can differentiate into the three germ layers. Show less
Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in whi Show more
Recent studies suggest that mitochondria can be transferred between cells to support the survival of metabolically compromised cells. However, whether intercellular mitochondria transfer occurs in white adipose tissue (WAT) or regulates metabolic homeostasis in vivo remains unknown. We found that macrophages acquire mitochondria from neighboring adipocytes in vivo and that this process defines a transcriptionally distinct macrophage subpopulation. A genome-wide CRISPR-Cas9 knockout screen revealed that mitochondria uptake depends on heparan sulfates (HS). High-fat diet (HFD)-induced obese mice exhibit lower HS levels on WAT macrophages and decreased intercellular mitochondria transfer from adipocytes to macrophages. Deletion of the HS biosynthetic gene Ext1 in myeloid cells decreases mitochondria uptake by WAT macrophages, increases WAT mass, lowers energy expenditure, and exacerbates HFD-induced obesity in vivo. Collectively, this study suggests that adipocytes and macrophages employ intercellular mitochondria transfer as a mechanism of immunometabolic crosstalk that regulates metabolic homeostasis and is impaired in obesity. Show less
Acne is a common and chronic inflammatory dermatosis of sebaceous gland units of the human hair follicle. Acne is closely related to immune cytokines and cells including T helper 17cells (Th17 cells). Show more
Acne is a common and chronic inflammatory dermatosis of sebaceous gland units of the human hair follicle. Acne is closely related to immune cytokines and cells including T helper 17cells (Th17 cells). Mis-regulated glycolipid metabolism also plays a vital role in the process. This investigation aimed to explore the role of IL-17 in signaling pathways controlling sebaceous gland lipoprotein metabolism in a rat model of acne. We generated the rat ear acne model, and investigated the pathological changes of acne skin tissue by histological analysis and the changes in the critical factors including DEFB1, GPR65, FADS1, and FADS2 by Western Blot in this model. There were more Th17 cells in the rat ear acne model than in the control mice. The expression levels of DEFB1, GPR65, FADS1, FADS2 and MOGAT1 were significantly upregulated in serum and tissue from rat acne model, which could be concluded that the Th17 cells play a major role in the pathogenesis of acne based. Although acne is associated with immune effects and glycolipid metabolism, inhibition of IL-17 signaling pathway might be a novel way for acne therapy. Our findings also suggest a new strategy for targeted therapy of acne. Show less
Understanding heat stress physiology and identifying reliable biomarkers are paramount for developing effective management and mitigation strategies. However, little is known about the molecular mecha Show more
Understanding heat stress physiology and identifying reliable biomarkers are paramount for developing effective management and mitigation strategies. However, little is known about the molecular mechanisms underlying thermal tolerance in animals. In an experimental model of Sprague-Dawley rats subjected to temperatures of 22 ± 1°C (control group; CT) and 42°C for 30 min (H30), 60 min (H60), and 120 min (H120), RNA-sequencing (RNA-Seq) assays were performed for blood (CT and H120), liver (CT, H30, H60, and H120), and adrenal glands (CT, H30, H60, and H120). A total of 53, 1,310, and 1,501 differentially expressed genes (DEGs) were significantly identified in the blood ( Show less
In a Chinese prospective cohort, 500 patients with new-onset type 2 diabetes (T2D) within 4.61 years and 500 matched healthy participants are selected as case and control groups, and randomized into d Show more
In a Chinese prospective cohort, 500 patients with new-onset type 2 diabetes (T2D) within 4.61 years and 500 matched healthy participants are selected as case and control groups, and randomized into discovery and validation sets to discover the metabolite changes before T2D onset and the related diabetogenic loci. A serum metabolomics analysis reveals that 81 metabolites changed significantly before T2D onset. Based on binary logistic regression, eight metabolites are defined as a biomarker panel for T2D prediction. Pipecolinic acid, carnitine C14:0, epinephrine and phosphatidylethanolamine 34:2 are first found associated with future T2D. The addition of the biomarker panel to the clinical markers (BMI, triglycerides, and fasting glucose) significantly improves the predictive ability in the discovery and validation sets, respectively. By associating metabolomics with genomics, a significant correlation ( Show less
The fatty acid desaturase 1 (FADS1), also known as delta-5 desaturase (D5D), is one of the rate-limiting enzymes involved in the desaturation and elongation cascade of polyunsaturated fatty acids (PUF Show more
The fatty acid desaturase 1 (FADS1), also known as delta-5 desaturase (D5D), is one of the rate-limiting enzymes involved in the desaturation and elongation cascade of polyunsaturated fatty acids (PUFAs) to generate long-chain PUFAs (LC-PUFAs). Reduced function of D5D and decreased hepatic Show less
In the present study, we analysed the effects of SNP rs174547 (T/C) in the fatty acid desaturase 1 (FADS1) gene on long-chain PUFA levels. Four databases were searched to retrieve related literature w Show more
In the present study, we analysed the effects of SNP rs174547 (T/C) in the fatty acid desaturase 1 (FADS1) gene on long-chain PUFA levels. Four databases were searched to retrieve related literature with keywords such as fatty acid (FA), SNP, FADS1 and rs174547. A meta-analysis of the data was performed using Stata12.0 software, including summary statistics, test for heterogeneity, evaluation of publication bias, subgroup analysis and sensitivity analysis. The associations between rs174547 in FADS1 and seven types of FA, and Δ-5 (D5D) and Δ-6 fatty acid desaturase (D6D) activity were assessed based on the pooled results from eleven papers. A total of 3713 individuals (1529 TT and 2184 TC + CC) were included. The results demonstrated that minor C allele carriers of rs174547 had higher linoleic acid (LA; P < 0·001) and α-linolenic acid (P = 0·020) levels, lower γ-linolenic acid (GLA; P = 0·001) and arachidonic acid (P = 0·024) levels, and lower D5D (P = 0·005) and D6D (P = 0·004) activities than the TT genotype group. Stratification analysis showed that minor C allele carriers of rs174547 had higher LA and lower GLA levels and lower D6D activities in plasma (LA, P < 0·001; GLA, P < 0·001; D6D activity, P < 0·001) samples and in Asian populations (LA, P < 0·001; GLA, P = 0·001; D6D activity, P = 0·001) than the TT genotype group. In conclusion, minor C allele carriers of the SNP rs174547 were associated with decreased activity of D5D and D6D. Show less
Microribonucleic acid-155 (microRNA155) and microRNA29 are reported to inhibit glucose metabolism in some cell and animal models, but no evidence from susceptible populations that examines the relatio Show more
Microribonucleic acid-155 (microRNA155) and microRNA29 are reported to inhibit glucose metabolism in some cell and animal models, but no evidence from susceptible populations that examines the relationship between microRNA155 or microRNA29 and type 2 diabetes mellitus currently exists. Furthermore, target genes regulated by microRNA155 and microRNA29 that affect glucose and lipid metabolism remain unknown. Human participants were divided into normal weight (n = 72), obesity (n = 120) and type 2 diabetes (n = 59) groups. The contents of microRNA155 and microRNA29 abundance in serum were measured, and candidate genes potentially related to glucose and lipid metabolism targeted by either microRNA155 or microRNA29 were screened. Overexpression of microRNA155 and microRNA29 in HepG2 cells was used to verify candidate gene expression, and measure the effects on glucose and lipid metabolism. Serum levels of microRNA155 and microRNA29 show a significant increase in individuals with obesity and type 2 diabetes compared with normal weight individuals. Identified target genes for microRNA155 were MAPK14, MAP3K10, DUSP14 and PRKAR2B. Identified target genes for microRNA29 were PEX11A and FADS1. Overexpression of microRNA155 or microRNA29 in HepG2 cells was found to downregulate the expression of identified target genes, and result in inhibition of triglyceride synthesis and glucose incorporation. MicroRNA155 and microRNA29 were significantly higher in type 2 diabetes patients compared with the control patients, their levels were also positively correlated with fasting plasma glucose levels, and over-expression of microRNA155 or microRNA29 were found to downregulate glucose and lipid metabolism target genes, and reduce lipid synthesis and glucose incorporation in HepG2 cells. Show less
Currently, a comprehensive method for exploration of transcriptional regulation has not been well established. We explored a novel pipeline to analyze transcriptional regulation using co-analysis of R Show more
Currently, a comprehensive method for exploration of transcriptional regulation has not been well established. We explored a novel pipeline to analyze transcriptional regulation using co-analysis of RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq). The G protein-coupled receptors (GPCRs) possibly associated with macrophages were further filtered using a reduced-Cox regression model. ATAC-seq profiles were used to map the chromatin accessibility of the GPRC5B promoter region. Pearson analysis was performed to identify the transcription factor (TF) whose expression was correlated with open chromatin regions of GPRC5B promoter. ChIP-seq profiles were obtained to confirm the physical binding of GATA4 and its predicted binding regions. For verification, quantitative polymerase chain reaction (qPCR) and multidimensional database validations were performed. The reduced-Cox regression model revealed the prognostic value of GPRC5B. A novel pipeline for TF exploration was proposed. With our novel pipeline, we first identified chr16:19884686-19885185 as a reproducible open chromatin region in the GPRC5B promoter. Thereafter, we confirmed the correlation between GATA4 expression and the accessibility of this region, confirmed its physical binding, and proved GPRC5B, correlated with macrophages, was a key GPCR affecting COAD prognosis. Further, with our novel pipeline, TF GATA4 was identified as a direct upstream of GPRC5B. This study proposed a novel pipeline for TF exploration and provided a theoretical basis for COAD therapy. Show less
RNA editing is a feature of RNA maturation resulting in the formation of transcripts whose sequence differs from the genome template. Brain RNA editing may be altered in Alzheimer's disease (AD). Here Show more
RNA editing is a feature of RNA maturation resulting in the formation of transcripts whose sequence differs from the genome template. Brain RNA editing may be altered in Alzheimer's disease (AD). Here, we analyzed data from 1,865 brain samples covering 9 brain regions from 1,074 unrelated subjects on a transcriptome-wide scale to identify inter-regional differences in RNA editing. We expand the list of known brain editing events by identifying 58,761 previously unreported events. We note that only a small proportion of these editing events are found at the protein level in our proteome-wide validation effort. We also identified the occurrence of editing events associated with AD dementia, neuropathological measures and longitudinal cognitive decline in: SYT11, MCUR1, SOD2, ORAI2, HSDL2, PFKP, and GPRC5B. Thus, we present an extended reference set of brain RNA editing events, identify a subset that are found to be expressed at the protein level, and extend the narrative of transcriptomic perturbation in AD to RNA editing. Show less