Severe negative energy balance around parturition is an important contributor to ketosis, a metabolic disorder that occurs most frequently in the peripartal period. Autophagy and mitophagy are importa Show more
Severe negative energy balance around parturition is an important contributor to ketosis, a metabolic disorder that occurs most frequently in the peripartal period. Autophagy and mitophagy are important processes responsible for breaking down useless or toxic cellular material, and in particular damaged mitochondria. However, the role of autophagy and mitophagy during the occurrence and development of ketosis is unclear. The objective of this study was to investigate autophagy and mitophagy in the livers of cows with subclinical ketosis (SCK) and clinical ketosis (CK). We assessed autophagy by measuring the protein abundance of microtubule-associated protein 1 light chain 3-II (LC3-II; encoded by MAP1LC3) and sequestosome-1 (p62, encoded by SQSTM1), as well as the mRNA abundance of autophagy-related genes 5 (ATG5), 7 (ATG7), and 12 (ATG12), beclin1 (BECN1), and phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3). Mitophagy was evaluated by measuring the protein abundance of the mitophagy upstream regulators PTEN-induced putative kinase 1 (PINK1) and Parkin. Liver and blood samples were collected from healthy cows [n = 15; blood β-hydroxybutyrate (BHB) concentration <1.2 mM], cows with SCK (n = 15; blood BHB concentration 1.2 to 3.0 mM) and cows with CK (n = 15; blood BHB concentration >3.0 mM with clinical signs) with similar lactation numbers (median = 3, range = 2 to 4) and days in milk (median = 6, range = 3 to 9). The serum activity of aspartate aminotransferase and alanine aminotransferase was greater in cows with CK than in healthy cows. Levels of oxidative stress biomarkers malondialdehyde and hydrogen peroxide were also higher in liver tissue from ketotic cows (SCK and CK) than from healthy cows. Compared with cows with CK and healthy cows, the hepatic mRNA abundance of MAP1LC3, SQSTM1, ATG5, ATG7, ATG12, and PIK3C3 was upregulated in cows with SCK. Compared with healthy cows, cows with SCK had a lower abundance of p62 and a greater abundance of LC3-II, but levels of both were higher in cows with CK. The mRNA abundance of ATG12 was lower in cows with CK than in healthy cows. Furthermore, the hepatic protein abundance of PINK1 and Parkin was greater in cows with SCK and slightly lower in cows with CK than in healthy cows. These data demonstrated differences in the hepatic activities of autophagy and mitophagy in cows with SCK compared with cows with CK. Although the precise mechanisms for these differences could not be discerned, autophagy and mitophagy seem to be involved in ketosis. Show less
MicroRNA-205 (miR-205) is believed to be related to the progress of tumors. HOXD9 has been proved to be expressed abnormally in several kinds of cancers. However, the role of miR-205 and HOXD9 in brea Show more
MicroRNA-205 (miR-205) is believed to be related to the progress of tumors. HOXD9 has been proved to be expressed abnormally in several kinds of cancers. However, the role of miR-205 and HOXD9 in breast cancer remains unclear. The biological role of miR-205 in breast cancer cell proliferation and chemoresistance was investigated. The expression of miR-205 in clinical tissues and breast cancer cell lines were analyzed using quantitative real-time PCR test (qRT-PCR). Overexpression and knockdown models of miR-205 were established to study cell proliferation and chemotherapy-resistant. Moreover, the potential relationships between miR-205 and HOXD9/Snail1 were measured using qRT-PCR, western blot, and chemotherapy-resistant study. miR-205 was lowly expressed in breast cancer tissues and cell lines. Overexpression of miR-205 could inhibit cell proliferation and chemotherapy-resistance. Moreover, we proved that miR-205 could target the HOXD9-Snail1 axis to suppress triple negative breast cancer cell proliferation and chemoresistance. The activation of Snail1 gene by HOXD9 was also proved in this study. The present study may provide a novel insight for the therapeutic strategies of breast cancer through targeting miR-205/HOXD9/Snail1. Show less
SARS-CoV-2 variants of interest and concern will continue to emerge for the duration of the COVID-19 pandemic. To map mutations in the receptor-binding domain (RBD) of the spike protein that affect bi Show more
SARS-CoV-2 variants of interest and concern will continue to emerge for the duration of the COVID-19 pandemic. To map mutations in the receptor-binding domain (RBD) of the spike protein that affect binding to angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, we applied in vitro evolution to affinity-mature the RBD. Multiple rounds of random mutagenic libraries of the RBD were sorted against decreasing concentrations of ACE2, resulting in the selection of higher affinity RBD binders. We found that mutations present in more transmissible viruses (S477N, E484K and N501Y) were preferentially selected in our high-throughput screen. Evolved RBD mutants include prominently the amino acid substitutions found in the RBDs of B.1.620, B.1.1.7 (Alpha), B1.351 (Beta) and P.1 (Gamma) variants. Moreover, the incidence of RBD mutations in the population as presented in the GISAID database (April 2021) is positively correlated with increased binding affinity to ACE2. Further in vitro evolution increased binding by 1,000-fold and identified mutations that may be more infectious if they evolve in the circulating viral population, for example, Q498R is epistatic to N501Y. We show that our high-affinity variant RBD-62 can be used as a drug to inhibit infection with SARS-CoV-2 and variants Alpha, Beta and Gamma in vitro. In a model of SARS-CoV-2 challenge in hamster, RBD-62 significantly reduced clinical disease when administered before or after infection. A 2.9 Å cryo-electron microscopy structure of the high-affinity complex of RBD-62 and ACE2, including all rapidly spreading mutations, provides a structural basis for future drug and vaccine development and for in silico evaluation of known antibodies. Show less
Danhong injection (DHI) is a Chinese medical injection applied to the clinical treatment of cardiovascular diseases that has anti-inflammatory, antiplatelet aggregation and antithrombotic effects. Thi Show more
Danhong injection (DHI) is a Chinese medical injection applied to the clinical treatment of cardiovascular diseases that has anti-inflammatory, antiplatelet aggregation and antithrombotic effects. This study aimed to explore the effects of DHI on dyslipidemia and cholesterol metabolism in high-fat diet-fed rats. Sprague Dawley (SD) rats were randomly divided into six groups: normal group (Normal); hyperlipidemia model group (Model); DHI-treated groups at doses of 1.0 mL/kg, 2.0 mL/kg, 4.0 mL/kg; and simvastatin positive control group (2.0 mg/kg). The hypolipidemic effects of DHI were evaluated by measuring serum lipid levels, hepatic function and oxidative stress, respectively. And pathological changes in liver tissues were determined using hematoxylin-eosin (H&E) and oil red O staining. Moreover, the mRNA and protein expression levels of cholesterol metabolism related genes were detected by real-time PCR (RT-PCR) and Western blot. Compared with the Model group, DHI treatment markedly decreased the liver index and improved the pathological morphology of liver tissues. DHI treatment dose-dependently decreased the levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), malondialdehyde (MDA), and free fatty acids (FFA) in serum or liver tissues (P < 0.01 or P < 0.05), and increased the high-density lipoprotein cholesterol (HDL-C) and tripeptide glutathione (GSH) (P < 0.01 or P < 0.05). The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) were increased in the DHI-treated groups (P < 0.01 or P < 0.05), while the alanine transaminase (ALT) and aspartate transaminase (AST) were decreased (P < 0.01 or P < 0.05). Furthermore, the expression levels of LDL receptor (LDLR), cholesterol 7-α-hydroxylase (CYP7A1), liver X receptor α (LXRα), and peroxisome proliferator-activated receptor α (PPARα) were dose-dependently upregulated in the DHI-treated groups, whereas the expression of sterol regulatory element-binding protein-2 (SREBP-2) was downregulated. Our study demonstrated that DHI markedly ameliorated hyperlipidemia rats by regulating serum lipid levels, inhibiting hepatic lipid accumulation and steatosis, improving hepatic dysfunction, and reducing oxidative stress. The potential mechanism was also tentatively investigated and may be related to the promotion of bile acid synthesis via activation of the PPARα-LXRα-CYP7A1 pathway. Therefore, DHI could be regarded as a potential hypolipidemic drug for the treatment of hyperlipidemia. Show less
Homo- or heterodimerization of G protein-coupled receptors (GPCRs) generally alters the normal functioning of these receptors and mediates their responses to a variety of physiological stimuli in vivo Show more
Homo- or heterodimerization of G protein-coupled receptors (GPCRs) generally alters the normal functioning of these receptors and mediates their responses to a variety of physiological stimuli in vivo. It is well known that melanocortin-3 receptor (MC3R) and melanocortin-4 receptor (MC4R) are key regulators of appetite and energy homeostasis in the central nervous system (CNS). However, the GPCR partners of MC3R and MC4R are not well understood. Our objective is to analyze single cell RNA-seq datasets of the hypothalamus to explore and identify novel GPCR partners of MC3R and MC4R and examine the pharmacological effect on the downstream signal transduction and membrane translocation of melanocortin receptors. We conducted an integrative analysis of multiple single cell RNA-seq datasets to reveal the expression pattern and correlation of GPCR families in the mouse hypothalamus. The emerging GPCRs with important metabolic functions were selected for cloning and co-immunoprecipitation validation. The positive GPCR partners were then tested for the pharmacological activation, competitive binding assay and surface translocation ELISA experiments. Based on the expression pattern of GPCRs and their function enrichment results, we narrowed down the range of potential GPCR interaction with MC3R and MC4R for further confirmation. Co-immunoprecipitation assay verified 23 and 32 novel GPCR partners that interacted with MC3R and MC4R in vitro. The presence of these GPCR partners exhibited different effects in the physiological regulation and signal transduction of MC3R and MC4R. This work represented the first large-scale screen for the functional GPCR complex of central melanocortin receptors and defined a composite metabolic regulatory GPCR network of the hypothalamic nucleuses. Show less
Cell polarity is an intrinsic property of epithelial cells regulated by scaffold proteins. The CRB (crumbs) complex is known to play a predominant role in the dynamic cooperative network of polarity s Show more
Cell polarity is an intrinsic property of epithelial cells regulated by scaffold proteins. The CRB (crumbs) complex is known to play a predominant role in the dynamic cooperative network of polarity scaffold proteins. PATJ (PALS1-associated tight junction) is the core component in the CRB complex and has been highly conserved throughout evolution. PATJ is crucial to several important events in organisms' survival, including embryonic development, cell polarity, and barrier establishment. A recent study shows that PATJ plays an important role in functional outcomes of stroke. In this article, we elaborate on the biological structure and physiological functions of PATJ and explore the underlying mechanisms of Show less
Dingxin Recipe (DXR) is a traditional Chinese medicine formula that has been reported to be effective and safe treatment for cardiovascular diseases, such as arrhythmias, coronary heart disease. Dingx Show more
Dingxin Recipe (DXR) is a traditional Chinese medicine formula that has been reported to be effective and safe treatment for cardiovascular diseases, such as arrhythmias, coronary heart disease. Dingxin Recipe IV (DXR IV) was further improved from the DXR according to the traditional use. However, the mechanism of DXR IV in atherosclerosis is unclear. This study aimed to illustrate whether DXR IV improve atherosclerosis through modulating the lipid metabolism and gut microbiota in atherosclerosis mice. 40 male ApoE DXR IV exerted the anti-atherosclerosis effect by inhibiting the excessive cholesterol deposition in aorta and regulating the level of TG, TC, LDL-C and HDL-C. The composition of gut microbiota was changed. Interestingly, the relative abundance of Muribaculaceae and Ruminococcaceae increased after DXR IV administration, whereas the abundance of Erysipelotrichaceae decreased, which have been beneficial to lipid metabolism. Nine potential metabolic biomarkers, including acetate, butyrate, propionate, alanine, succinate, valerate, xylose, choline, glutamate, were identified, which were related to fatty acid metabolism. Further, the pathway of fatty acid was detected by the RT-qPCR and western blotting. Compared with model group, the level of LXR-α and SREBP1 decreased significantly in DXR IV group while LXR-β, SREBP2 showed no statistical significance. It indicated that DXR IV modulated lipid metabolism by LXR-α/SREBP1 but not LXRβ and SREBP2. DXR IV exhibits potential anti-atherosclerosis effect, which is closely related to lipid metabolism and the gut microbiota. This study may provide novel insights into the mechanism of DXR IV on atherosclerosis and a basis for promising clinical usage. Show less
DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age, epigenetic clocks, for many species. Using a custom methylation array, we generated DNA methylation d Show more
DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age, epigenetic clocks, for many species. Using a custom methylation array, we generated DNA methylation data from n = 238 porcine tissues including blood, bladder, frontal cortex, kidney, liver, and lung, from domestic pigs (Sus scrofa domesticus) and minipigs (Wisconsin Miniature Swine™). Samples used in this study originated from Large White X Landrace crossbred pigs, Large White X Minnesota minipig crossbred pigs, and Wisconsin Miniature Swine™. We present 4 epigenetic clocks for pigs that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (pig and human). Two dual-species human-pig pan-tissue clocks accurately measure chronological age and relative age, respectively. We also characterized CpGs that differ between minipigs and domestic pigs. Strikingly, several genes implicated by our epigenetic studies of minipig status overlap with genes (ADCY3, TFAP2B, SKOR1, and GPR61) implicated by genetic studies of body mass index in humans. In addition, CpGs with different levels of methylation between the two pig breeds were identified proximal to genes involved in blood LDL levels and cholesterol synthesis, of particular interest given the minipig's increased susceptibility to cardiovascular disease compared to domestic pigs. Thus, breed-specific differences of domestic and minipigs may potentially help to identify biological mechanisms underlying weight gain and aging-associated diseases. Our porcine clocks are expected to be useful for elucidating the role of epigenetics in aging and obesity, and the testing of anti-aging interventions. Show less
Glioma is regarded as an aggressive lethal primary brain tumor. Jumonji domain containing 1C (JMJD1C) is a H3K9 demethylase which participates in the progression of various tumors, but its specific fu Show more
Glioma is regarded as an aggressive lethal primary brain tumor. Jumonji domain containing 1C (JMJD1C) is a H3K9 demethylase which participates in the progression of various tumors, but its specific function and underlying mechanism in glioma development remain undefined, which is the purpose of our work. We initially assessed JMJD1C expression in glioma tissues and cells using the assays of RT-qPCR and immunohistochemistry. Meanwhile, the H3K9 level at the microRNA (miR)-302a promoter region was measured by chromatin immunoprecipitation assay, while luciferase-based reporter assay was performed for validation of the binding affinity between miR-302a and methyltransferase-like 3 (METTL3). The effect of METTL3 on suppressor of cytokine signaling 2 (SOCS2) was subsequently analyzed by MeRIP-RT-qPCR. Finally, a xenograft tumor model was established in nude mice, followed by measurement of tumor-associated macrophages using flow cytometry. JMJD1C was poorly expressed in glioma tissues. Furthermore, JMJD1C increased miR-302a expression through promoting H3K9me1 demethylation at the miR-302a promoter region. miR-302a was identified to target METTL3, which could inhibit SOCS2 expression via m6A modification. JMJD1C promoted M1 macrophage polarization and suppressed the growth of glioma xenografts through the miR-302a/METTL3/SOCS2 axis both in vivo and in vitro. In conclusion, JMJD1C could enhance M1 macrophage polarization to inhibit the onset of glioma, bringing a new insight into the contribution of JMJD1C to the pathobiology of glioma, with possible implications for targeted therapeutic method. 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
Although single-gene perturbation screens have revealed a number of new targets, vulnerabilities specific to frequently altered drivers have not been uncovered. An important question is whether the co Show more
Although single-gene perturbation screens have revealed a number of new targets, vulnerabilities specific to frequently altered drivers have not been uncovered. An important question is whether the compensatory relationship between functionally redundant genes masks potential therapeutic targets in single-gene perturbation studies. To identify digenic dependencies, we developed a CRISPR paralog targeting library to investigate the viability effects of disrupting 3,284 genes, 5,065 paralog pairs and 815 paralog families. We identified that dual inactivation of DUSP4 and DUSP6 selectively impairs growth in NRAS and BRAF mutant cells through the hyperactivation of MAPK signaling. Furthermore, cells resistant to MAPK pathway therapeutics become cross-sensitized to DUSP4 and DUSP6 perturbations such that the mechanisms of resistance to the inhibitors reinforce this mechanism of vulnerability. Together, multigene perturbation technologies unveil previously unrecognized digenic vulnerabilities that may be leveraged as new therapeutic targets in cancer. Show less
The establishment of porcine pluripotent stem cells (piPSCs) is critical but remains challenging. All piPSCs are extremely sensitive to minor perturbations of culture conditions and signaling network. Show more
The establishment of porcine pluripotent stem cells (piPSCs) is critical but remains challenging. All piPSCs are extremely sensitive to minor perturbations of culture conditions and signaling network. Inhibitors, such as CHIR99021 and XAV939 targeting the WNT signaling pathway, have been added in a culture medium to modify the cell regulatory network. However, potential side effects of inhibitors could confine the pluripotency and practicability of piPSCs. This study aimed to investigate the roles of AXIN, one component of the WNT pathway in piPSCs. Here, porcine AXIN1 and AXIN2 genes were knocked-down or overexpressed. Digital RNA-seq was performed to explore the mechanism of cell proliferation and apoptosis. We found that (1) overexpression of the porcine AXIN2 gene significantly reduced survival and negatively impacted the pluripotency of piPSCs, and (2) knockdown of AXIN2, a negative effector of the WNT signaling pathway, enhanced the expression of genes involved in cell cycle but reduced the expression of genes related to cell differentiation, death, and apoptosis. Show less
Radiotherapy is one of the main strategies for the treatment of esophageal squamous cell carcinoma (ESCC). However, treatment failure often occurs due to the emergence of radioresistance. In this stud Show more
Radiotherapy is one of the main strategies for the treatment of esophageal squamous cell carcinoma (ESCC). However, treatment failure often occurs due to the emergence of radioresistance. In this study, we report a key regulator of radiation sensitivity, termed TAB182 that may become an ideal biomarker and therapeutic target to overcome radioresistance. By applying qRT-PCR and immunohistochemical staining, the expression of TAB182 was detected in patient tissues. We next assessed the influence of TAB182 downregulation to radiosensitivity using clonogenic survival assay and γ-H2A.X foci analysis in TE-1, TE-10, and radioresistant TE-1R cell lines after ionizing radiation. To unveil the mechanism underlying, TAB182 interacting proteins were identified by mass spectrometry following co-immunoprecipitation. Furthermore, flow cytometry and western blot assay were applied to validate the identified proteins. Our results demonstrated that the expression of TAB182 is higher in cancer tissues than normal tissues and elevated expression of TAB182 correlates with poor outcomes of postoperative radiotherapy. Downregulation of TAB182 sensitized cancer cells to ionizing radiation, particularly in radioresistant TE-1R cells that spontaneously overexpress TAB182. Mechanically, TAB182 interacts with FHL2 to induce G2-M arrest through wiring the CHK2/CDC25C/CDC2 signaling pathway. Finally, overexpression of shRNA-resistant TAB182 restored the checkpoint and radioresistance. TAB182 potentiates the radioresistance of ESCC cells by modulating the G2-M checkpoint through its interaction with FHL2. Thus, TAB182 may become an ideal biomarker and therapeutic target of ESCC radiotherapy. Show less
Lung cancer is one of the most prevalent cancers in both men and women worldwide. The nucleic acid G4 structures have been implicated in the transcriptional programmes of cancer-related genes in some Show more
Lung cancer is one of the most prevalent cancers in both men and women worldwide. The nucleic acid G4 structures have been implicated in the transcriptional programmes of cancer-related genes in some cancers such as lung cancer. However, the role of the dominant G4 resolvase DHX36 in the progression of lung cancer remains unknown. In this study, by bioinformatic analysis of public datasets (TCGA and GEO), we find DHX36 is an independent prognosis indicator in non-small-cell lung carcinoma (NSCLC) with subtype dependence. The stable lentiviral knockdown of the DHX36 results in accelerated migration and aggregation of the S-phase subpopulation in lung cancer cells. The reduction of DHX36 level de-sensitises the proliferation response of lung cancer cells to chemotherapeutic drugs such as paclitaxel with cell dependence. The knockdown of this helicase leads to promoted tumour growth, demonstrated by a 3D fluorescence spheroid lung cancer model, and the stimulation of cell colony formation as shown by single-cell cultivation. High throughput proteomic array indicates that DHX36 functions in lung cancer cells through regulating multiple signalling pathways including activation of protein activity, protein autophosphorylation, Fc-receptor signalling pathway, response to peptide hormone and stress-activated protein kinase signalling cascade. A causal transcriptomic analysis suggests that DHX36 is significantly associated with mRNA surveillance, RNA degradation, DNA replication and Myc targets. Therefore, we unveil that DHX36 presents clinical significance and plays a role in tumour suppression in lung cancer, and propose a potentially new concept for an anti-cancer therapy based on helicase-specific targeting. Show less
One hallmark of renal cell carcinoma (RCC) is metabolic reprogramming, which involves elevation of glycolysis and upregulation of lipid metabolism. However, the mechanism of metabolic reprogramming is Show more
One hallmark of renal cell carcinoma (RCC) is metabolic reprogramming, which involves elevation of glycolysis and upregulation of lipid metabolism. However, the mechanism of metabolic reprogramming is incompletely understood. Monocarboxylate transporter 1 (MCT1) promotes transport for lactate and pyruvate, which are crucial for cell metabolism. The aim of present study was to investigate the function of MCT1 on RCC development and its mechanism on metabolic reprogramming. The results showed that MCT1 messenger RNA and protein levels significantly increased in cancer tissues of ccRCC compared to normal tissue. MCT1 was further found to mainly located in the cell membrane of RCC. The knockdown of MCT1 by RNAi significantly inhibited proliferation and migration of 786-O and ACHN cells. MCT1 also induced the expressions of proliferation marker Ki-67 and invasion marker SNAI1. Moreover, we also showed that acetate treatment could upregulate the expression of MCT1, but not other MCT isoforms. On the other hand, MCT1 was involved in acetate transport and intracellular histone acetylation. In summary, this study revealed that MCT1 is abnormally high in ccRCC and promotes cancer development. The regulatory effect of MCT1 on cell proliferation and invasion maybe mediated by acetate transport. Show less
An interaction between hypoxia and immunity has been confirmed in tumor tissue. However, there is no combined biomarker for diagnosis on this basis. Therefore, we developed a scoring formula based on Show more
An interaction between hypoxia and immunity has been confirmed in tumor tissue. However, there is no combined biomarker for diagnosis on this basis. Therefore, we developed a scoring formula based on markers of hypoxia and immunity. Firstly, the hypoxia-immune formula of lung adenocarcinoma (LUAD) was derived using LASSO-Cox regression in three cohorts from public database, and the corresponding score was calculated for each patient. The formula is as follows: combined hypoxia and immune index (CIHI) = LDHA expression × 0.2252 + GAPDH expression × 0.0727 + ANGPTL4 expression × 0.0724 + VEGFC expression × 0.1911 + DKK1 expression × 0.1355 + ADM expression × 0.0588 + BTK expression × -0.1659. Meanwhile, patients were divided into groups according to high and low CIHI, and expression profiles of hypoxia markers and immune markers were analyzed in different groups. CIHI was used to confirm that patients with high CIHI represented a state of hypoxia Show less
Loss of the cholesteryl ester transfer protein (CETP) function affects HDLc levels, but its effects on major HDL protein component ApoA1 are not well understood in patients with acute myocardial infar Show more
Loss of the cholesteryl ester transfer protein (CETP) function affects HDLc levels, but its effects on major HDL protein component ApoA1 are not well understood in patients with acute myocardial infarction (AMI). We investigated the effects of an East Asian loss-of-function variant (rs2303790; p.D442G) in CETP gene on HDLc and ApoA1 levels and its relationship with AMI. A total of 2327 AMI patients and 2615 age- and sex-matched controls from INTERHEART-China study were included. In controls, both levels of HDLc (1.24 vs. 1.04 mmol/L, P = 0.001) and ApoA1 (1.48 vs. 1.37 mmol/L, P = 0.042) were significantly higher in CETP variant G allele carriers compared to CETP wildtype D allele carriers. In AMI patients, levels of HDLc were significantly higher (1.14 vs. 1.01 mmol/L, P = 0.013) while levels of ApoA1 were not statistically difference (1.31 vs. 1.32 mmol/L, P = 0.468) in CETP variant group compared to CETP wildtype group. Moreover, CETP variant is associated with HDLc increase, but is not associated with AMI risk (P = 0.564), even after adjusting for age, sex, history of hypertension and diabetes, waist to hip ratio, smoking, total cholesterol, LDL cholesterol, triglycerides, physical activity, depression, alcohol, vegetables and fruit consumption. Loss of CETP function is associated with increased HDLc and ApoA1 levels in healthy subjects, and in AMI patients, it is associated with HDLc levels but not ApoA1 levels. The lack of association of CETP variant with AMI may be related to the inability to increase ApoA1 levels and warranted further studies. Show less
Yun Feng, Xin Zhao, Zhengda Li+8 more · 2021 · Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada · added 2026-04-24
Somatic cell nuclear transfer (SCNT) holds vast potential in agriculture. However, its applications are still limited by its low efficiency. Histone 3 lysine 9 trimethylation (H3K9me3) was identified Show more
Somatic cell nuclear transfer (SCNT) holds vast potential in agriculture. However, its applications are still limited by its low efficiency. Histone 3 lysine 9 trimethylation (H3K9me3) was identified as an epigenetic barrier for this. Histone demethylase KDM4D could regulate the level of H3K9me3. However, its effects on buffalo SCNT embryos are still unclear. Thus, we performed this study to explore the effects and underlying mechanism of KDM4D on buffalo SCNT embryos. The results revealed that compared with the IVF embryos, the expression level of KDM4D in SCNT embryos was significantly lower at 8- and 16-cell stage, while the level of H3K9me3 in SCNT embryos was significantly higher at 2-cell, 8-cell, and blastocyst stage. Microinjection of KDM4D mRNA could promote the developmental ability of buffalo SCNT embryos. Furthermore, the expression level of ZGA-related genes such as ZSCAN5B, SNAI1, eIF-3a, and TRC at the 8-cell stage was significantly increased. Meanwhile, the pluripotency-related genes like POU5F1, SOX2, and NANOG were also significantly promoted at the blastocyst stage. The results were reversed after KDM4D was inhibited. Altogether, these results revealed that KDM4D could correct the H3K9me3 level, increase the expression level of ZGA and pluripotency-related genes, and finally, promote the developmental competence of buffalo SCNT embryos. Show less
Multiple genetic studies have confirmed the definitive link among the loss-of-function variants of angiogenin-like protein 4 (ANGPTL4), significantly decreased plasma triglyceride (TG) levels, and red Show more
Multiple genetic studies have confirmed the definitive link among the loss-of-function variants of angiogenin-like protein 4 (ANGPTL4), significantly decreased plasma triglyceride (TG) levels, and reduced risk of coronary heart disease (CHD). The potential therapeutic effect of ANGPTL4 on dyslipidemia and CHD has been widely studied. This review provides a detailed introduction to the research progress on the involvement of ANGPTL4 in lipid metabolism and atherosclerosis and evaluates the efficacy and safety of ANGPTL4 as a therapeutic target for CHD. By inhibiting lipoprotein lipase (LPL) activity, ANGPTL4 plays a vital role in the regulation of lipid metabolism and energy balance. However, the role of ANGPTL4 in regulating lipid metabolism is tissue-specific. ANGPTL4 acts as a locally released LPL inhibitor in the heart, skeletal muscle and small intestine, while ANGPTL4 derived from liver and adipose tissue mainly acts as an endocrine factor that regulates systemic lipid metabolism. As a multifunctional protein, ANGPTL4 also inhibits the formation of foam cells in macrophages, exerting an anti-atherogenic role. The function of ANGPTL4 in endothelial cells is still uncertain. The safety of ANGPTL4 monoclonal antibodies requires further evaluation due to their potential adverse effects. The biological characteristics of ANGPTL4 are much more complex than those demonstrated by genetic studies. Future studies must elucidate how to effectively reduce the risk of CHD while avoiding potential atherogenic effects and other complications before the "prime time" of ANGPTL4-targeted therapy arrives. Show less
Drug resistance is one of the major challenges for treatment of hepatocellular carcinoma (HCC) with sorafenib. Our present study found that sorafenib resistant (SR) HCC cells showed epithelial-mesench Show more
Drug resistance is one of the major challenges for treatment of hepatocellular carcinoma (HCC) with sorafenib. Our present study found that sorafenib resistant (SR) HCC cells showed epithelial-mesenchymal transition (EMT) characteristics with the downregulation of epithelial marker and upregulation of mesenchymal makers. The expression of Snail, a core factor of EMT, was increased in HCC/SR cells, while knockdown of Snail can restore sorafenib sensitivity and EMT potential of HCC/SR cells. Further, the upregulation of protein stability was responsible for the upregulation of Snail in HCC/SR cells. ATM and CSN2, which can stabilize Snail protein, were increased in HCC/SR cells. Knockdown of ATM and CSN2 can suppress the expression of Snail and increase sorafenib sensitivity of HCC/SR cells. It indicated that targeted inhibition of Snail might be helpful to overcome sorafenib resistance of HCC patients. Show less
Simvastatin (SV) is a common hypolipidemic drug in clinical medicine that can reduce endogenous cholesterol biosynthesis by inhibiting hydroxyl-methyl-glutaryl coenzyme A reductase. SV took a large ma Show more
Simvastatin (SV) is a common hypolipidemic drug in clinical medicine that can reduce endogenous cholesterol biosynthesis by inhibiting hydroxyl-methyl-glutaryl coenzyme A reductase. SV took a large market share in the lipid-lowering drugs and it is frequently detected in various water bodies due to its increasing consumption in past years. In the present investigation, we selected a native fish species in the Pearl River Basin in China, Mugilogobius abei (M. abei), to study the effects of SV on non-target aquatic organisms. Results showed that a significant decrease in the volume of adipocytes under SV exposure were observed on oil red O section, and the expression of HMG-CoAR decreased significantly. The mRNA and protein expression of PPARα were significantly up-regulated, the expressions of other genes related to lipid metabolism were up-regulated to varying degrees as well. There was a positive correlation between the concentrations of SV and the protein expressions of plasma phospholipid transfer protein (PLTP) and cholesterolester transfer protein (CETP). In addition, the frozen sections showed that SV led to ROS accumulation in liver in a time and concentration dependent manner. The mRNA and protein expressions of Nrf2 were significantly up-regulated after 24 hours of SV exposure. Some biomarkers associated with antioxidant such as Trx2, TrxR and MDA content were positively correlated with the exposure concentration and time, while the content of GSH decreased sharply. It is noteworthy that the environmentally relevant concentration (0.5 μg/L) of SV exposure caused delayed embryonic development and deformations, decreased hatching rates. We conclude that SV promotes fat metabolism, gives rise to oxidative stress and has significant toxicity on embryo development in M. abei. 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
Clear cell renal cell carcinoma (ccRCC) accounts for 80% of all renal cancers and has a poor prognosis. Chromobox (CBX) family protein expression has been reported in a variety of human malignancies, Show more
Clear cell renal cell carcinoma (ccRCC) accounts for 80% of all renal cancers and has a poor prognosis. Chromobox (CBX) family protein expression has been reported in a variety of human malignancies, but the roles of CBXs in ccRCC remain unclear. In this study, by using ONCOMINE, UALCAN, GEPIA, Kaplan-Meier Plotter, cBioPortal, and TIMER, we found the transcriptional levels of CBX3 and CBX4 in ccRCC tissues were significantly higher than those in normal kidney tissues, whereas the transcriptional levels of CBX1, CBX5, CBX6, and CBX7 were significantly reduced in ccRCC tissues. The promoters of CBX2, CBX3, CBX4, CBX5, CBX6, CBX7, and CBX8 were hypermethylated, whereas the CBX1 promoter was hypomethylated in ccRCC. The expression of CBX1, CBX3, CBX4, CBX5, CBX6, and CBX7 was significantly associated with clinicopathological parameters in ccRCC patients. ccRCC patients with high expression levels of CBX3, CBX4, and CBX8 and low expression levels of CBX1, CBX5, CBX6, and CBX7 showed a strong association with poor overall survival. Genetic alterations in CBXs were correlated with poor overall survival and disease-free survival in patients with ccRCC. Moreover, we found significant associations between the expression of CBXs and infiltration of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells). Our results provide novel insights into the development of CBX-based biomarkers and therapeutic targets for ccRCC. Show less
The RNA-binding motif protein 10 (RBM10) is involved in alternative splicing and modifies mRNA post-transcriptionally. RBM10 is abnormally expressed in the lung, breast, and colorectal cancer, female Show more
The RNA-binding motif protein 10 (RBM10) is involved in alternative splicing and modifies mRNA post-transcriptionally. RBM10 is abnormally expressed in the lung, breast, and colorectal cancer, female genital tumors, osteosarcoma, and other malignant tumors. It can inhibit proliferation, promote apoptosis, and inhibit invasion and metastasis. RBM10 has long been considered a tumor suppressor because it promotes apoptosis through the regulation of the MDM2-p53 negative feedback loop, Bcl-2, Bax, and other apoptotic proteins and inhibits proliferation through the Notch signaling and rap1a/Akt/CREB pathways. However, it has been recently demonstrated that RBM10 can also promote cancer. Given these different views, it is necessary to summarize the research progress of RBM10 in various fields to reasonably analyze the underlying molecular mechanisms, and provide new ideas and directions for the clinical research of RBM10 in various cancer types. In this review, we provide a new perspective on the reasons for these opposing effects on cancer biology, molecular mechanisms, research progress, and clinical value of RBM10. Show less
The prevalence of metabolic syndrome (Mets) is closely related to an increased incidence of cardiovascular events. Angiopoietin-like protein 4 (ANGPTL4) is contributory to the regulation of lipid meta Show more
The prevalence of metabolic syndrome (Mets) is closely related to an increased incidence of cardiovascular events. Angiopoietin-like protein 4 (ANGPTL4) is contributory to the regulation of lipid metabolism, herein, may provide a target for gene-aimed therapy of Mets. This observational case control study was designed to elucidate the relationship between ANGPTL4 gene single nucleotide polymorphism (SNP) rs1044250 and the onset of Mets, and to explore the interaction between SNP rs1044250 and weight management on Mets. We have recruited 1018 Mets cases and 1029 controls in this study. The SNP rs1044250 was genotyped with blood samples, base-line information and Mets-related indicators were collected. A 5-year follow-up survey was carried out to track the lifestyle interventions and changes in Mets-related indicators. ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference (OR 1.618, 95% CI [1.119-2.340]; p = 0.011), elevated blood pressure (OR 1.323, 95% CI [1.002-1.747]; p = 0.048), and Mets (OR 1.875, 95% CI [1.363-2.580]; p < 0.001). The follow-up survey shows that rs1044250 CC genotype patients with weight gain have an increased number of Mets components (M [Q1, Q3]: CC 1 (0, 1), CT + TT 0 [- 1, 1]; p = 0.021); The interaction between SNP rs1044250 and weight management is a risk factor for increased systolic blood pressure (β = 0.075, p < 0.001) and increased diastolic blood pressure (β = 0.097, p < 0.001), the synergistic effect of weight management and SNP rs1044250 is negative (S < 1). ANGPTL4 gene SNP rs1044250 is an independent risk factor for increased waist circumference and elevated blood pressure, therefore, for Mets. However, patients with wild type SNP 1044250 are more likely to have Mets when the body weight is increased, mainly due to elevated blood pressure. Show less
Asprosin, coiled-coil domain-containing 80(CCDC80) and angiopoietin-like4(ANGPTL4) are newly discovered adipocytokine that affects glucose tolerance, insulin resistance and cardiovascular diseases. Th Show more
Asprosin, coiled-coil domain-containing 80(CCDC80) and angiopoietin-like4(ANGPTL4) are newly discovered adipocytokine that affects glucose tolerance, insulin resistance and cardiovascular diseases. The goal of this study was to investigate if a relationship exists among asprosin, CCDC80 and ANGPTL4 and inflammatory bowel disease (IBD). Fifty subjects with newly diagnosed IBD and fifty healthy individuals were enrolled. Patients were treated with standard therapies for 3 months. Plasma asprosin, CCDC80 and ANGPTL4 levels were measured with enzyme-linked immunosorbent assay. High resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperemia (flow-mediated dilation, FMD) and after sublingual glyceryltrinitrate.Compare with healthy individuals, plasma CCDC80,erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels and homeostasis modelassessment of insulin resistance (HOMA-IR) were significantly higher (p < 0.05, respectively), whereas plasma asprosin,ANGPTL4 levels and FMD were significantly lower inboth UC and CD patients(p <0.05). Plasma CCDC80 levels were significantly higher in patients with CD (p<0.05), while plasma asprosin and ANGPTL4 levels were lower (p<0.05) as compared with those in patients with UC. Standard therapies increased plasma asprosin, ANGPTL4 levels and FMD in both UC and CD (p<0.05),UC and CD patientswhile decreased plasma CCDC80, ESR, CRP levels and HOMA-IR (p<0.05). The changes in HOMA-IR and FMD were correlated with the changes in plasma asprosin, CCDC80 and ANGPTL4 levels over the study period (p<0.05). Plasma asprosin, CCDC80 and ANGPTL4 levels may be applied as a significant marker for early stage of insulin resistance and atherosclerosis in IBD, especially of CD. Show less
Myocardial hypertrophy is a pathological thickening of the myocardium, leading to various ailments, such as myocardial infarction and heart failure. RBM38 is critical in modulating mRNA translation fo Show more
Myocardial hypertrophy is a pathological thickening of the myocardium, leading to various ailments, such as myocardial infarction and heart failure. RBM38 is critical in modulating mRNA translation for multiple protective activities such as p53 tumor repressor and p21 kinase cell cycle inhibitors. Liver X receptors (LXR-α) agonists reduce cellular hypertrophy initiated by various hypertrophic stimuli as lipopolysaccharides and Ang II. This research investigates the possible cooperation between RBM38 and LXR-α and mechanisms in modulating myocardial hypertrophy. H9C2 cells were treated with PE, TNF-α, and AngII to induce myocardial hypertrophy. RBM38 and LXR- α were overexpressed or silenced in H9C2 cells, and hypertrophy markers (ANF and Myh7) were determined with Western blot and RT-qPCR. Binding assays were done through RNA immunoprecipitation. H&E and Rhodamine-labeled phalloidin staining assays were used to assess the relative cell surface change. The results demonstrated RBM38 downregulation in in vitro models of myocardial hypertrophy. Modulation of RBM38 expression also exerted inverse effects on myocardial hypertrophy markers. Further observations also showed that LXR-α expression regulates the myocardial hypertrophy markers in H9C2 cells and RBM38 binds with LXR-α mRNA, consequently inhibiting LXR-α expression. Finally, overexpression of RBM38 rescues Angiotensin II-induced myocardial hypertrophy by regulating LXR-α dependent lipogenesis pathway. In conclusion, RBM38 Overexpression rescues Angiotensin II-induced myocardial hypertrophy by regulating LXR-α dependent lipogenesis pathway. Show less
There are few studies on the role of iron metabolism genes in predicting the prognosis of lung adenocarcinoma (LUAD). Therefore, our research aims to screen key genes and to establish a prognostic sig Show more
There are few studies on the role of iron metabolism genes in predicting the prognosis of lung adenocarcinoma (LUAD). Therefore, our research aims to screen key genes and to establish a prognostic signature that can predict the overall survival rate of lung adenocarcinoma patients. RNA-Seq data and corresponding clinical materials of 594 adenocarcinoma patients from The Cancer Genome Atlas(TCGA) were downloaded. GSE42127 of Gene Expression Omnibus (GEO) database was further verified. The multi-gene prognostic signature was constructed by the Cox regression model of the Least Absolute Shrinkage and Selection Operator (LASSO). We constructed a prediction signature with 12 genes (HAVCR1, SPN, GAPDH, ANGPTL4, PRSS3, KRT8, LDHA, HMMR, SLC2A1, CYP24A1, LOXL2, TIMP1), and patients were split into high and low-risk groups. The survival graph results revealed that the survival prognosis between the high and low-risk groups was significantly different (TCGA: P < 0.001, GEO: P = 0.001). Univariate and multivariate Cox regression analysis confirmed that the risk value is a predictor of patient OS (P < 0.001). The area under the time-dependent ROC curve (AUC) indicated that our signature had a relatively high true positive rate when predicting the 1-year, 3-year, and 5-year OS of the TCGA cohort, which was 0.735, 0.711, and 0.601, respectively. In addition, immune-related pathways were highlighted in the functional enrichment analysis. In conclusion, we developed and verified a 12-gene prognostic signature, which may be help predict the prognosis of lung adenocarcinoma and offer a variety of targeted options for the precise treatment of lung cancer. Show less
miRNAs play critical roles in the regulation of many cardiovascular diseases. However, its role and potential mechanism in cardiac injury caused by obstructive sleep apnea (OSA) remain poorly elucidat Show more
miRNAs play critical roles in the regulation of many cardiovascular diseases. However, its role and potential mechanism in cardiac injury caused by obstructive sleep apnea (OSA) remain poorly elucidated. In the present study, we aimed to investigate the effects of miR-3574 on cardiomyocyte injury under intermittent hypoxia (IH). We confirmed that IH inhibited cell viability, induced cell apoptosis and suppressed miR-3574 expression in the H9c2. miR-3574 overexpression could ameliorate the effects of IH on the cell viability and cell apoptosis in the H9c2. Axin1 was a target gene of miR-3574, and miR-3574 overexpression reduced the expression of Axin1. miR-3574 could inhibit the IH-induced cardiomyocyte injury via downregulating Axin1. However, Axin1 could partially reverse these effects of miR-3574. Our study first reveals that miR-3574 could alleviate IH-induced cardiomyocyte injury by targeting Axin1, which may function as a novel and promising therapy target for OSA-associated cardiovascular diseases. H9c2 were exposed to IH condition. CCK-8 assay was applied to determine cell viability of H9c2. qRT-PCR was conducted to measure the expression level of mRNA and miRNA. Western blot assay was then performed to detect the protein levels. Finally, we used dual-luciferase reporter assay identify the potential target of miR-3574. Show less
Upregulation of the neuropeptide neurotensin (NTS) in a subgroup of lung cancers has been linked to poor prognosis. However, the regulatory pathway centered on NTS in lung cancer remains unclear. Here Show more
Upregulation of the neuropeptide neurotensin (NTS) in a subgroup of lung cancers has been linked to poor prognosis. However, the regulatory pathway centered on NTS in lung cancer remains unclear. Here we identified the NTS-specific enhancer in lung adenocarcinoma cells. The AF4/FMR2 (AFF) family protein AFF1 occupies the NTS enhancer and inhibits NTS transcription. Clustering analysis of lung adenocarcinoma gene expression data demonstrated that NTS expression is highly positively correlated with the expression of the oncogenic factor CPS1. Detailed analyses demonstrated that the IL6 pathway antagonizes NTS in regulating CPS1. Thus, our analyses revealed a novel NTS-centered regulatory axis, consisting of AFF1 as a master transcription suppressor and IL6 as an antagonist in lung adenocarcinoma cells. Show less