Our previous study found that increased serum IL-27 could promote rheumatoid arthritis (RA) B cell dysfunction via activating mTOR signaling pathway. This study aimed to explore the effects of IL-27 o Show more
Our previous study found that increased serum IL-27 could promote rheumatoid arthritis (RA) B cell dysfunction via activating mTOR signaling pathway. This study aimed to explore the effects of IL-27 on B cell metabolism and clarify the mechanisms via which IL-27 enhancing glycolysis to induce B cells hyperactivation. Peripheral CD19 Show less
Hypoxia contributes to tumor progression and confers drug resistance. We attempted to microdissect the hypoxia landscape in colon cancer (CC) and explore its correlation with immunotherapy response. T Show more
Hypoxia contributes to tumor progression and confers drug resistance. We attempted to microdissect the hypoxia landscape in colon cancer (CC) and explore its correlation with immunotherapy response. The hypoxia landscape in CC patients was microdissected through unsupervised clustering. The "xCell" algorithms were applied to decipher the tumor immune infiltration characteristics. A hypoxia-related index signature was developed via the LASSO (least absolute shrinkage and selection operator) Cox regression in The Cancer Genome Atlas (TCGA)-colon adenocarcinoma (COAD) cohort and validated in an independent dataset from the Gene Expression Omnibus (GEO) database. The tumor immune dysfunction and exclusion (TIDE) algorithm was utilized to evaluate the correlation between the hypoxia-related index (HRI) signature and immunotherapy response. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting were performed to verify the mRNA expression levels of five key genes. The Cell Counting Kit-8 (CCK-8) assay and flow cytometry were performed to examine the cell viability and cell apoptosis. Patients were classified into hypoxia-high, hypoxia-median, and hypoxia-low clusters in TCGA-COAD and verified in the GSE 17538 dataset. Compared with the hypoxia-low cluster, the hypoxia-high cluster consistently presented an unfavorable prognosis, higher immune scores, and stromal scores and elevated infiltration levels of several critical immune and stromal cells. Otherwise, we also found 600 hypoxia-related differentially expressed genes (HRDEGs) between the hypoxia-high cluster and the hypoxia-low cluster. Based on the 600 HRDEGs, we constructed the HRI signature which consists of 11 genes and shows a good prognostic value in both TCGA-COAD and GSE 17538 (AUC of 6-year survival prediction >0.75). Patients with low HRI scores were consistently predicted to be more responsive to immunotherapy. Of the 11 HRI signature genes, RGS16, SNAI1, CDR2L, FRMD5, and FSTL3 were differently expressed between tumors and adjacent tissues. Low expression of SNAI1, CDR2L, FRMD5, and FSTL3 could induce cell viability and promote tumor cell apoptosis. In our study, we discovered three hypoxia clusters which correlate with the clinical outcome and the tumor immune microenvironment in CC. Based on the hypoxia cluster and HRDEGs, we constructed a reliable HRI signature that could accurately predict the prognosis and immunotherapeutic responsiveness in CC patients and discovered four key genes that could affect tumor cell viability and apoptosis. Show less
What is the central question of this study? Is there a risk of developing diabetes associated with statin treatment? What is the underlying mechanism of the increased incidence rate of new-onset diabe Show more
What is the central question of this study? Is there a risk of developing diabetes associated with statin treatment? What is the underlying mechanism of the increased incidence rate of new-onset diabetes in patients treated with rosuvastatin? What is the main finding and its importance? Rosuvastatin therapy reduced intraperitoneal glucose tolerance and changed the catabolism of branched-chain amino acid (BCAAs) in white adipose tissue and skeletal muscle. Protein phosphatase 2Cm knockdown completely abolished the effects of insulin and rosuvastatin on glucose absorption. This study provides mechanistic support for recent clinical data on rosuvastatin-related new-onset diabetes and underscores the logic for intervening in BCAA catabolism to prevent the harmful effects of rosuvastatin. Accumulating evidence indicates that patients treated with rosuvastatin have an increased risk of developing new-onset diabetes. However, the underlying mechanism remains unclear. In this study, we administered rosuvastatin (10 mg/kg body weight) to male C57BL/6J mice for 12 weeks and found that oral rosuvastatin dramatically reduced intraperitoneal glucose tolerance. Rosuvastatin-treated mice showed considerably higher serum levels of branched-chain amino acids (BCAAs) than control mice. They also showed dramatically altered expression of BCAA catabolism-related enzymes in white adipose tissue and skeletal muscle, including downregulated mRNA expression of BCAT2 and protein phosphatase 2Cm (PP2Cm) and upregulated mRNA expression of branched-chain ketoacid dehydrogenase kinase (BCKDK). The levels of BCKD in the skeletal muscle were reduced in rosuvastatin-treated mice, which was associated with lower PP2Cm protein levels and increased BCKDK levels. We also investigated the effects of rosuvastatin and insulin administration on glucose metabolism and BCAA catabolism in C2C12 myoblasts. We observed that incubation with insulin enhanced glucose uptake and facilitated BCAA catabolism in C2C12 cells, which was accompanied by elevated Akt and glycogen synthase kinase 3 β (GSK3β) phosphorylation. These effects of insulin were prevented by co-incubation of the cells with 25 μM rosuvastatin. Moreover, the effects of insulin and rosuvastatin administration on glucose uptake and Akt and GSK3β signaling in C2C12 cells were abolished when PP2Cm was knocked down. Although the relevance of these data, obtained with high doses of rosuvastatin in mice, to therapeutic doses in humans remains to be elucidated, this study highlights a potential mechanism for the diabetogenic effects of rosuvastatin, and suggests that BCAA catabolism could be a pharmacological target for preventing the adverse effects of rosuvastatin. Show less
Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target Show more
Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy. Show less
Pingping Wang, Suhong Yang, Qiong Zhou+3 more · 2023 · Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics · added 2026-04-24
To explore the clinical phenotype and genetic etiology of a child with early-onset severe obesity. A child who presented at the Department of Endocrinology, Hangzhou Children's Hospital on August 5, 2 Show more
To explore the clinical phenotype and genetic etiology of a child with early-onset severe obesity. A child who presented at the Department of Endocrinology, Hangzhou Children's Hospital on August 5, 2020 was selected as the study subject. Clinical data of the child were reviewed. Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing (WES) was carried out on the child. Candidate variants were verified by Sanger sequencing and bioinformatic analysis. This child was a 2-year-and-9-month girl featuring severe obesity with hyperpigmentation on the neck and armpit skin. WES revealed that she has harbored compound heterozygous variants of the MC4R gene, namely c.831T>A (p.Cys277*) and c.184A>G (p.Asn62Asp). Sanger sequencing confirmed that they were respectively inherited from her father and mother. The c.831T>A (p.Cys277*) has been recorded by the ClinVar database. Its carrier frequency among normal East Asians was 0.000 4 according to the 1000 Genomes, ExAC, and gnomAD databases. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), it was rated as pathogenic. The c.184A>G (p.Asn62Asp) has not been recorded in the ClinVar, 1000 Genomes, ExAC and gnomAD databases. Prediction using IFT and PolyPhen-2 online software suggested it to be deleterious. Based on the guidelines from the ACMG, it was determined as likely pathogenic. The c.831T>A (p.Cys277*) and c.184A>G (p.Asn62Asp) compound heterozygous variants of the MC4R gene probably underlay the early-onset severe obesity in this child. Above finding has further expanded the spectrum of MC4R gene variants and provided a reference for the diagnosis and genetic counseling for this family. Show less
LMNA gene encodes lamin A/C protein which participates in the construction of nuclear lamina, the mutations of LMNA result in a wide variety of diseases known as laminopathies. LMNA-related dilated ca Show more
LMNA gene encodes lamin A/C protein which participates in the construction of nuclear lamina, the mutations of LMNA result in a wide variety of diseases known as laminopathies. LMNA-related dilated cardiomyopathy(LMNA-DCM) is one of the more common laminopathy which characterized by progressive heart failure and arrhythmia. However, the mutation features of LMNA-DCM are yet to be elucidated. Herein we described a dilated cardiomyopathy family carrying novel variant c.467G > C(p.Arg156Pro) of LMNA as heterozygous pathogenic variant identified by whole-exome sequencing. With the help of Alphafold2, we predicted mutant protein structure and found an interrupted α-helix region in lamin A/C. In the analysis of 49 confirmed pathogenic missense of laminopathies, Chi-square test showed the DCM phenotype was related to the α-helix region mutation (p < 0.017). After screening the differentially expressed genes (DEGs) in both mice models and human patients in Gene Expression Omnibus database, we found the variation of α-helix-coding region in LMNA caused abnormal transcriptomic features in cell migration, collagen-containing extracellular matrix, and PI3K-Akt signaling pathway. Subsequently we constructed (TF)-mRNA-microRNA (miRNA) regulatory network and identified 7 key genes (FMOD, CYP1B1, CA3, F2RL1, HAPLIN1, SNAP91, and KANSL1) as potential biomarkers or therapeutic targets in LMNA-DCM patients. Show less
Rab proteins are important components of small GTPases and play crucial roles in regulating intracellular transportation and cargo delivery. Maintaining the proper functions of Rab proteins is essenti Show more
Rab proteins are important components of small GTPases and play crucial roles in regulating intracellular transportation and cargo delivery. Maintaining the proper functions of Rab proteins is essential for normal cellular activities such as cell signaling, division, and survival. Due to their vital and irreplaceable role in regulating intracellular vesicle transportation, accumulated researches have shown that the abnormalities of Rab proteins and their effectors are closely related to human diseases. Here, this review focused on Rab21, a member of the Rab family, and introduced the structures and functions of Rab21, as well as the regulatory mechanisms of Rab21 in human diseases, including neurodegenerative diseases, cancer, and inflammation. In summary, we described in detail the role of Rab21 in human diseases and provide insights into the potential of Rab21 as a therapeutic target for diseases. Show less
The melanocortin pathway is well established to be critical for body-weight regulation in both rodents and humans. Despite extensive studies focusing on this pathway, the downstream brain sites that m Show more
The melanocortin pathway is well established to be critical for body-weight regulation in both rodents and humans. Despite extensive studies focusing on this pathway, the downstream brain sites that mediate its action are not clear. Here, we found that, among the known paraventricular hypothalamic (PVH) neuron groups, those expressing melanocortin receptors 4 (PVH Show less
Different subtypes of dendritic cells (DCs) can induce different types of immune responses. Our previous study found that Echinococcus granulosus (E. granulosus) antigens (Eg.ferritin, Eg.mMDH and Eg. Show more
Different subtypes of dendritic cells (DCs) can induce different types of immune responses. Our previous study found that Echinococcus granulosus (E. granulosus) antigens (Eg.ferritin, Eg.mMDH and Eg.10) stimulated DC differentiation to different subtypes and produced different immune responses. To further understand whether Eg.ferritin, Eg.mMDH and Eg.10 affect the DC-mediated immune response by promoting the differentiation of monocytes to DCs. Bone marrow-derived monocytes were exposed to three antigens of E. granulosus on days 0, 3, 5, and 7. The percentage of monocyte-derived DCs (moDCs), DCs subsets, and the expression of surface molecules of DCs at different time points in different groups were assessed by flow cytometry. The levels of cytokines of IL-1β, IL-4, IL-6, IL-10, IL-13, IFN-γ, TNF-α, IL-12p70, IL-18, IL-23, and IL-27 in the cell culture supernatant were detected by multi-factorial detection technology. The percentage of moDCs revealed that none of the three antigens blocked monocyte differentiation to DCs. The monocytes of 7-day-old cultures showed increased sensitivity to these antigens. The Eg.ferritin induced more mature DCs, which expressed high levels of MHC II and costimulatory molecules, and secreted Th1 cytokines. Eg10 and Eg.mMDH induced lower degrees of DC maturation, however differentiated DCs were in a semi-mature state due to low expression of MHC II and costimulatory molecules and secretion of higher Th2 and lower Th1 cytokines. Eg.ferritin promotes full maturation of DCs and induces Th1 immune response, whereas Eg.10 and Eg.mMDH induce semi-mature DCs producing higher levels of Th2 cytokines. Show less
Chronic stress induces depression and insulin resistance, between which there is a bidirectional relationship. However, the mechanisms underlying this comorbidity remain unclear. White adipose tissue Show more
Chronic stress induces depression and insulin resistance, between which there is a bidirectional relationship. However, the mechanisms underlying this comorbidity remain unclear. White adipose tissue (WAT), innervated by sympathetic nerves, serves as a central node in the interorgan crosstalk through adipokines. Abnormal secretion of adipokines is involved in mood disorders and metabolic morbidities. We describe here a brain-sympathetic nerve-adipose circuit originating in the hypothalamic paraventricular nucleus (PVN) with a role in depression and insulin resistance induced by chronic stress. PVN neurons are labelled after inoculation of pseudorabies virus (PRV) into WAT and are activated under restraint stress. Chemogenetic manipulations suggest a role for the PVN in depression and insulin resistance. Chronic stress increases the sympathetic innervation of WAT and downregulates several antidepressant and insulin-sensitizing adipokines, including leptin, adiponectin, Angptl4 and Sfrp5. Chronic activation of the PVN has similar effects. β-adrenergic receptors translate sympathetic tone into an adipose response, inducing downregulation of those adipokines and depressive-like behaviours and insulin resistance. We finally show that AP-1 has a role in the regulation of adipokine expression under chronic stress. Show less
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and Show more
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate Show less
The promotion of intersystem crossing (ISC) is critical for achieving a high-efficiency long-persistent luminescence (LPL) from organic materials. However, the use of a transition-metal complex for LP Show more
The promotion of intersystem crossing (ISC) is critical for achieving a high-efficiency long-persistent luminescence (LPL) from organic materials. However, the use of a transition-metal complex for LPL materials has not been explored because it can also shorten the emission lifetime by accelerating the phosphorescence decay. Here, we report a new class of LPL materials by doping a monovalent Au-carbene complex into a boron-embedded molecular host. The donor-acceptor systems exhibit photoluminescence with both high efficiencies (>57 %) and long lifetimes (ca. 40 ms) at room temperature. It is revealed that the Au atom promotes the population of low-lying triplet excited states of the host aggregate (T Show less
Jie Li, Lijuan Zhang, Yun Tao+3 more · 2023 · European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences · Elsevier · added 2026-04-24
Hepatocellular carcinoma (HCC) is a serious life-threatened tumor with high morbidity and mortality. This study aimed to study the effects of combination TACE and anti-PD-L1 liposome drug in treating Show more
Hepatocellular carcinoma (HCC) is a serious life-threatened tumor with high morbidity and mortality. This study aimed to study the effects of combination TACE and anti-PD-L1 liposome drug in treating HCC in mice models. We constructed the liposome drug with phosphatidylcholine and cholesterol and mannitol, etc. Besides, the HCC mice model was established through abdominal subcutaneous injection HepG2 cancer cells in mice, then the PE-10 polyethylene catheter was used for TACE therapy. The mice were separately received transcatheter arterial chemoembolization treatment, avelumab liposome drug therapy, and TACE combined with avelumab liposome drug therapy. Flow cytometry was used to analyze cell apoptosis. Western blot, Immunofluorescence staining, real-time PCR were performed to detect protein and gene expressions. The liposomes drug was successfully constructed with a diameter of (125.5 ± 15.3) nm. After the mice received TACE and (or) immunotherapy, the combined liposome drug therapy significantly reduced the volume of hepatic carcinoma tissues, besides, the apoptotic rate of hepatic carcinoma cells in the combined liposome drug treatment group was increased obviously compared with other groups. Moreover, the protein TGFβR2 located in the cellular membrane was obviously down-regulated in the combined liposome drug therapy, while the expression of SMAD7 and PTPN14 was up-regulated in the treatment groups compared with the mice without treatment, besides, the protein PTPN14 was mainly located in the nucleus. Additionally, the mRNA expression of genes SNAI1 and Vimentin was significantly down-regulated in the combined liposome drug therapy. Combination of transcatheter arterial chemoembolization and anti-PD-L1 liposome drug therapy significantly suppressed hepatocellular carcinoma proliferation and metastasis in mice models. Show less
Prostate cancer is the most common malignant tumor of male urogenital system that occurs in prostate epithelium. However, relationship between CAV1 and KRT5 and prostate cancer remains unclear. The pr Show more
Prostate cancer is the most common malignant tumor of male urogenital system that occurs in prostate epithelium. However, relationship between CAV1 and KRT5 and prostate cancer remains unclear. The prostate cancer datasets GSE114740 and GSE200879 were downloaded from Gene Expression Omnibus generated by GPL11154 and GPL32170. De-batch processing was performed, differentially expressed genes (DEGs) were screened, and weighted gene co-expression network analysis. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis. Gene expression heat map was drawn and immune infiltration analysis was performed. Comparative toxicogenomics database analysis were performed to find the disease most related to core gene. In addition, the cell experiment was performed to verify the role of CAV1 and KRT5 by western blot. Divided into 4 groups: control, prostate cancer, prostate cancer-over expression, and prostate cancer- knock out. TargetScan screened miRNAs that regulated central DEGs; 770 DEGs were identified. According to Gene Ontology analysis, they were mainly concentrated in actin binding and G protein coupled receptor binding. In Kyoto Encyclopedia of Gene and Genome analysis, they were mainly concentrated in PI3K-Akt signal pathway, MAPK signal pathway, and ErbB signal pathway. The intersection of enrichment terms of differentially expressed genes and GOKEGG enrichment terms was mainly concentrated in ErbB signaling pathway and MAPK signaling pathway. Three important modules were generated. The protein-protein interaction network obtained 8 core genes (CAV1, BDNF, TGFB3, FGFR1, PRKCA, DLG4, SNAI2, KRT5). Heat map of gene expression showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) are highly expressed in prostate cancer tissues and low in normal tissues. Comparative toxicogenomics database analysis showed that core genes (CAV1, TGFB3, FGFR1, SNAI2, KRT5) were associated with prostate tumor, cancer, tumor metastasis, necrosis, and inflammation. CAV1 and KRT5 are up-regulated in prostate cancer. CAV1 and KRT5 are highly expressed in prostate cancer. The higher expression of CAV1 and KRT5, the worse prognosis. Show less
Globally, lung adenocarcinoma (LUAD) is the most common type of lung cancer. The secreted protein angiopoietin-like 4 (ANGPTL4) has been implicated in a number of physiological and pathological proces Show more
Globally, lung adenocarcinoma (LUAD) is the most common type of lung cancer. The secreted protein angiopoietin-like 4 (ANGPTL4) has been implicated in a number of physiological and pathological processes, including angiogenesis and lipid metabolism. But the role of ANGPTL4 in LUAD remains unknown. The expression of ANGPTL4 and miR-133a-3p was confirmed by public database analysis. Xenograft model, MTT, Clone formation and EdU analysis were used to confirm the effects of miR-133a-3p/ANGPTL4 on LUAD cell proliferation and growth. Wound healing and Transwell analysis were used to elucidate the role of miR-133a-3p/ANGPTL4 in LUAD cell migration and invasion. Oil red O staining was used to confirm ANGPTL4 in LUAD lipids production. Dual-luciferase reporter gene analysis was used to demonstrate miR-133a-3p could directly bind ANGPTL4 3'-UTR. WB and PCR were used to confirm the protein expression of ANGPTL4. ANGPTL4 was significantly increased in LUAD samples, which could promote LUAD cell proliferation, migration, invasion, growth and lipid production. miR-133a-3p could directly bind to ANGPTL4 mRNA, and repress the expression ANGPTL4, resulting in suppressing LUAD proliferation and metastasis. In conclusion, miR-133a-3p/ANGPTL4 axis might be a potential biomarker and therapeutic target for LUAD patients. Show less
A major consequence of acute myocardial infarction is myocardial ischemia-reperfusion (I/R) injury. Collecting proof demonstrates that AXIN1 assume a basic part in different disease; however, the role Show more
A major consequence of acute myocardial infarction is myocardial ischemia-reperfusion (I/R) injury. Collecting proof demonstrates that AXIN1 assume a basic part in different disease; however, the role of AXIN1 in I/R injury remains to a great extent obscure. The I/R injury model on AC16 cells was constructed. siRNA transfection was used to knockdown AXIN1. The qRT-PCR assays and western blot assays were used to detect the expression level of AXIN1 and other key proteins. CCK-8 assays and cell apoptosis assays were used to detect cell proliferation and cell apoptosis. AXIN1 was significantly overexpressed in an in vitro model of I/R injury. Knockdown of AXIN1 significantly restored the cell proliferation inhibition caused by IR injury, while inhibiting apoptosis and inflammation. Further mechanistic studies revealed that the transcription factor c-Myc could regulate the expression of AXIN1. The effects of I/R injury on AC16 cells after overexpression of c-Myc were reversed by knockdown of AXIN1. Meanwhile, AXIN1 could regulate the SIRT1/p53/Nrf 2 pathway. Our results show an important role for AXIN1 and provide new targets for avoiding and treating I/R injury. Show less
Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear funct Show more
Retinal Müller glial dysfunction and intracellular edema are important mechanisms leading to diabetic macular edema (DME). Aquaporin 11 (AQP11) is primarily expressed in Müller glia with unclear functions. This study aims to explore the role of AQP11 in the pathogenesis of intracellular edema of Müller glia in diabetic retinopathy (DR). Here, we found that AQP11 expression, primarily located at the endfeet of Müller glia, was down-regulated with diabetes progression, accompanied by intracellular edema, which was alleviated by intravitreal injection of lentivirus-mediated AQP11 overexpression. Similarly, intracellular edema of hypoxia-treated rat Müller cell line (rMC-1) was aggravated by AQP11 inhibition, while attenuated by AQP11 overexpression, accompanied by enhanced function in glutamate metabolism and reduced cell death. The down-regulation of AQP11 was also verified in the Müller glia from the epiretinal membranes (ERMs) of proliferative DR (PDR) patients. Mechanistically, down-regulation of AQP11 in DR was mediated by the HIF-1α-dependent and independent miRNA-AQP11 axis. Overall, we deciphered the AQP11 down-regulation, mediated by miRNA-AQP11 axis, resulted in Müller drainage dysfunction and subsequent intracellular edema in DR, which was partially reversed by AQP11 overexpression. Our findings propose a novel mechanism for the pathogenesis of DME, thus targeting AQP11 regulation provides a new therapeutic strategy for DME. Show less
Antibiotic misuse has been a severe problem in animal husbandry. It is meaningful to replace antibiotics with Bacillus, as feed additives are indeed a research hotspot. Bacillus pumilus plays a certai Show more
Antibiotic misuse has been a severe problem in animal husbandry. It is meaningful to replace antibiotics with Bacillus, as feed additives are indeed a research hotspot. Bacillus pumilus plays a certain role in promoting the growth performance and immunological indicators of animals. There are few reports about the function of goat-derived B. pumilus in animals until now. This study aimed to investigate the effects of B. pumilus fsznc-09 on growth performance and immune function of Jintang black goats. B. pumilus-treated group was fed with 1 ml freeze-dried agent of B. pumilus fsznc-09 at a concentration of 109 cfu/ml every 2 days. The growth performance, serum biochemical indexes, the expressions of muscle development and metabolism related genes of Jintang black goats were measured after 30 days. The results showed that the average daily gain and average daily feed intake were significantly increased, and feed conversion ratio was significantly decreased. The activities of total superoxide dismutase, alkaline phosphatase, immunoglobulin G and interferon-γ in serum of goats were significantly increased. However, the activity of malondialdehyde in serum was significantly decreased. The diameters and areas in longissimus dorsi fibre and gluteus fibre of goats were significantly decreased, while the densities in gluteus fibre of goats were significantly increased. The expressions of FAS, LPL, PPAR-γ, CAT, MYOD1, MYOG, MYF5 and MyHCI in longissimus dorsi and gluteus of goats were significantly improved. The expressions of TGFβ1, SREBP-1, MyHCIIb and MyHCIIx in longissimus dorsi and gluteus of goats were significantly increased. The expressions of FN1 in longissimus dorsi and MyHCIIa in gluteus of goats were significantly decreased. In conclusion, B. pumilus fsznc-09 can effectively improve the growth performance, immunological indicators and the expressions of muscle development and metabolism related genes of Jintang black goat. Show less
Hepatocellular carcinoma (HCC) remains imposing an enormous economic and healthcare burden worldwide. In this present study, we constructed and validated a novel autophagy-related gene signature to pr Show more
Hepatocellular carcinoma (HCC) remains imposing an enormous economic and healthcare burden worldwide. In this present study, we constructed and validated a novel autophagy-related gene signature to predict the recurrence of HCC patients. A total of 29 autophagy-related differentially expressed genes were identified. A five-gene signature (CLN3, HGF, TRIM22, SNRPD1, and SNRPE) was constructed for HCC recurrence prediction. Patients in high-risk groups exhibited a significantly poor prognosis compared with low-risk patients both in the training set (GSE14520 dataset) and the validation set (TCGA and GSE76427 dataset). Multivariate cox regression analysis demonstrated that the 5-gene signature was an independent risk factor for recurrence-free survival (RFS) in HCC patients. The nomograms incorporating 5-gene signature and clinical prognostic risk factors were able to effectively predict RFS. KEGG and GSEA analysis revealed that the high-risk group was enriched with multiple oncology characteristics and invasive-related pathways. Besides, the high-risk group had a higher level of immune cells and higher levels of immune checkpoint-related gene expression in the tumor microenvironment, suggesting that they might be more likely to benefit from immunotherapy. Finally, the immunohistochemistry and cell experiments confirmed the role of SNRPE, the most significant gene in the gene signature. SNRPE was significantly overexpressed in HCC. After SNRPE knockdown, the proliferation, migration and invasion ability of the HepG2 cell line were significantly inhibited. Our study established a novel five-gene signature and nomogram to predict RFS of HCC, which may help in clinical decision-making for individual treatment. Show less
Rabbits are well-domesticated animals. As a crucial economic animal, rabbit has been successfully bred into wool-use, meat-use and fur-use breeds. Hair length is one of the most economically important Show more
Rabbits are well-domesticated animals. As a crucial economic animal, rabbit has been successfully bred into wool-use, meat-use and fur-use breeds. Hair length is one of the most economically important traits affecting profitability in wool rabbits. In this study, to identify selection signatures with the long-hair trait, whole-genomic resequencing of long-haired rabbits (Angora rabbits) and short-haired rabbits (Rex and New Zealand rabbits) was performed. By genome-wide selective sweeping analysis based on population comparison, we identified a total of 5.85 Mb regions (containing 174 candidate genes) with strong selection signals. Six of these genes (Dusp1, Ihh, Fam134a, Map3k1, Spata16, and Fgf5) were enriched in the MAPK signalling and Hedgehog signalling pathways, both of which are closely associated with hair growth regulation. Among these genes, Fgf5 encodes the FGF5 protein, which is a well-established regulator of hair growth. There was a nonsynonymous nucleotide substitution (T19234C) in the Fgf5 gene. At this locus, the C allele was present in all of the tested Angora rabbits, while the T allele was dominant in New Zealand and Rex rabbits. We further confirmed that the C allele was conserved in Angora rabbits by screening an additional 135 rabbits. Moreover, the results of functional predictions and co-immunoprecipitation revealed that the T19234C mutation impaired the binding capacity of FGF5 to its receptor FGFR1. We discovered that the homozygous missense mutation T19234C within Fgf5 might contribute to the long-hair trait of Angora rabbits by reducing its receptor binding capacity. This finding will provide new insights into the genetic basis underlying the genetic improvement of Angora rabbits and benefit the improvement of rabbit breeding in the future. Show less
Jun Li, Ying Xia, Shumin Kong+6 more · 2023 · Journal of the European Academy of Dermatology and Venereology : JEADV · Blackwell Publishing · added 2026-04-24
Actinic keratosis (AK) represents an intraepidermal malignant neoplasm with the proliferation of atypical keratinocytes. AK lesions are regarded as early in situ squamous cell carcinomas (SCCs) having Show more
Actinic keratosis (AK) represents an intraepidermal malignant neoplasm with the proliferation of atypical keratinocytes. AK lesions are regarded as early in situ squamous cell carcinomas (SCCs) having the potential to progress into invasive SCC (iSCC) and metastasize, causing death. This study aimed to investigate the heterogeneity of keratinocytes and how this heterogeneity promoted AK development and progression. We employed single-cell RNA sequencing (scRNA-seq) to examine the heterogeneity of keratinocytes and dermal fibroblast clusters in AKs and adjacent normal skins. Cell clustering, pseudotime trajectory construction, gene ontology enrichment analysis, transcription factor network analysis, and cell-cell communication were used to investigate the heterogeneity of keratinocytes in AK. The cellular identity and function were verified by immunohistochemical and immunofluorescence staining. Using scRNA-seq, we revealed 13 keratinocyte subgroups (clusters 0-12) in AK tissues and characterized 2 AK-specific clusters. Cluster 9 displayed high levels of IL1R2 and WFDC2, and cluster 11 showed high levels of FADS2 and FASN. The percentages of cells in these two clusters significantly increased in AK compared with normal tissues. The existence and spatial localization of AK-specific IL1R2+WFDC2+ cluster were verified by immunohistochemical and immunofluorescence staining. Functional studies indicated that the genes identified in the IL1R2+WFDC2+ cluster were crucial for epithelial cell proliferation, migration, and angiogenesis. Further immunofluorescent staining revealed the interactions between AK-specific keratinocytes and secretory-papillary fibroblasts mainly through ANGPTL4-ITGA5 signalling pathway rarely seen in normal tissues. The findings of this study might help better understand AK pathogenesis. Show less
Phthalates are widely used synthetic chemicals that determine endocrine disruption effects on female reproductivity and oviposition. Our study demonstrated that the mitochondrial quality in ovarian gr Show more
Phthalates are widely used synthetic chemicals that determine endocrine disruption effects on female reproductivity and oviposition. Our study demonstrated that the mitochondrial quality in ovarian granulosa cells (GCs) is associated with a poor prognosis in female reproduction. However, the molecular mechanism of di-(2-ethylhexyl) phthalate (DEHP) exposure on the quail ovarian GC layer is still unknown. To validate the effects of DEHP on the GC layer, 8 days' old 150 female Japanese quail were treated orally with DEHP (250, 500, and 750 mg/kg BW/day) for 45 days to explore the toxic effects of DEHP on the ovarian GC layer. Histopathological assessment and ultrastructure observation found that DEHP decreased the thickness of the GC layer, resulted in mitochondrial damage, and activated mitocytosis. Additionally, the results further suggested that DEHP impacted the secretion of steroid hormones (reduced FSH, E2, and T levels and boosted Prog, PRL, and LH levels) by triggering mitocytosis (enhanced transcription of Show less
Hematoma-induced neuroinflammation is the cause of poor prognosis in intracerebral hemorrhage (ICH); therefore, promoting blood clearance and blocking overactivated inflammation are rational approache Show more
Hematoma-induced neuroinflammation is the cause of poor prognosis in intracerebral hemorrhage (ICH); therefore, promoting blood clearance and blocking overactivated inflammation are rational approaches for ICH treatment. β-site amyloid precursor protein (APP) lyase-1 (BACE1) is a key molecule regulating the microglial phenotype transition in neurodegenerative diseases. Therefore, the aim of this study was to investigate the role of BACE1 in microglial phagocytosis and inflammatory features in ICH. Here, we demonstrated the unique advantages of targeting BACE1 in microglia using an autologous blood model and primary microglia hemoglobin stimulation. When BACE1 was inhibited early in ICH, fewer residual hematomas remained, consistent with an increase in genetic features that favor phagocytosis and anti-inflammation. In addition, inhibition of BACE1 enhanced the secretion of anti-inflammatory cytokines and substantially reduced the expression of proinflammatory genes, which was regulated by signal transduction and phosphorylation of activator of transcription 3 (STAT3). Further pharmacological inhibition of STAT3 phosphorylation effectively blocked the proinflammatory and weak phagocytic phenotype of microglia due to BACE1 induction. In summary, BACE1 is the critical molecule regulating the inflammatory and phagocytic phenotypes of microglia after ICH, and targeted inhibition of the BACE1/STAT3 pathway is an important strategy for the future treatment of ICH-induced neurological injury. Show less
Psoriasis is a systemic inflammatory disease, and the mechanism that links psoriasis to depression is still elusive. Hence, this study aimed to elucidate the potential pathogenesis of psoriasis and de Show more
Psoriasis is a systemic inflammatory disease, and the mechanism that links psoriasis to depression is still elusive. Hence, this study aimed to elucidate the potential pathogenesis of psoriasis and depression comorbidity. The gene expression profiles of psoriasis (GSE34248, GSE78097 and GSE161683) and depression (GSE39653) were downloaded from the Gene Expression Omnibus (GEO) DataSets. Functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis were performed, following identification of the common differentially expressed genes (DEGs) of psoriasis and depression. A total of 115 common DEGs (55 up-regulated and 60 down-regulated) were identified between psoriasis and depression. Functional analysis indicated that T cell activation and differentiation were predominantly implicated in the potential pathogenesis of these two diseases. In addition, Th17 cell differentiation and cytokines is closely related to both. Finally, 17 hub genes were screened, including CTLA4, LCK, ITK, IL7R, CD3D, SOCS1, IL4R, PRKCQ, SOCS3, IL23A, PDGFB, PAG1, TGFA, FGFR1, RELN, ITGB5 and TNXB, which re-emphasized the importance of the immune system in psoriasis and depression. Our study reveals the common pathogenesis of psoriasis and depression. These common pathways and hub genes may apply to a molecular screening tool for depression in psoriasis patients, which could help dermatologists optimize patient management in routine care. Show less
Analysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient's treatment course. We Show more
Analysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient's treatment course. We evaluated whether the presence of specific gene amplifications (GAs) and plasma copy number (PCN) alterations are associated with disease features. This is a single-institution retrospective study of patients with mPC who underwent ctDNA profiling using Guardant360 The presence of liver and/or lung metastases was associated with GAs of The association of select GAs with survival provides an additional tool for assessing mCRPC prognosis and informing management. Serial monitoring of ctDNA GAs is also useful to guide prognosis and therapeutic response. Show less
Type 2 diabetes (T2D) is a major health and economic burden worldwide. Despite the availability of multiple drugs for short-term management, sustained remission of T2D is currently not achievable phar Show more
Type 2 diabetes (T2D) is a major health and economic burden worldwide. Despite the availability of multiple drugs for short-term management, sustained remission of T2D is currently not achievable pharmacologically. Intracerebroventricular administration of fibroblast growth factor 1 (icvFGF1) induces sustained remission in T2D rodents, propelling intense research efforts to understand its mechanism of action. Whether other FGFs possess similar therapeutic benefits is currently unknown. Here, we show that icvFGF4 also elicits a sustained antidiabetic effect in both male db/db mice and diet-induced obese mice by activating FGF receptor 1 (FGFR1) expressed in glucose-sensing neurons within the mediobasal hypothalamus. Specifically, FGF4 excites glucose-excited (GE) neurons while inhibiting glucose-inhibited (GI) neurons. Moreover, icvFGF4 restores the percentage of GI neurons in db/db mice. Importantly, intranasal delivery of FGF4 alleviates hyperglycemia in db/db mice, paving the way for non-invasive therapy. We conclude that icvFGF4 holds significant therapeutic potential for achieving sustained remission of T2D. Show less
Angiopoietin-like 4 (ANGPTL4) is a secreted metabolism-modulating glycoprotein involved in the progression of tumours, cardiovascular diseases, metabolic syndrome and infectious diseases. In this stud Show more
Angiopoietin-like 4 (ANGPTL4) is a secreted metabolism-modulating glycoprotein involved in the progression of tumours, cardiovascular diseases, metabolic syndrome and infectious diseases. In this study, more CD8 Show less
Scutellarein hybrids were designed, synthesized and evaluated as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds 11a-i, containing a 2-hydroxymethyl-3,5,6-t Show more
Scutellarein hybrids were designed, synthesized and evaluated as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). Compounds 11a-i, containing a 2-hydroxymethyl-3,5,6-trimethylpyrazine fragment at the 7-position of scutellarein, were found to have balanced and effective multi-target potencies against AD. Among them, compound 11e exhibited the most potent inhibition of electric eel and human acetylcholinesterase enzymes with IC Show less
In this study, to screen for candidate markers of temozolomide (TMZ) resistance in glioblastoma, we artificially established TMZ drug-resistant glioblastoma (GBM) cell lines, U251-TMZ and U87-TMZ. In Show more
In this study, to screen for candidate markers of temozolomide (TMZ) resistance in glioblastoma, we artificially established TMZ drug-resistant glioblastoma (GBM) cell lines, U251-TMZ and U87-TMZ. In the U251-TMZ and U87-TMZ cell lines, we screened and analyzed differentially expressed proteins using ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) differential proteomics. Compared with the U251 and U87 control cell lines, 95 differential proteins were screened in the U251-TMZ and U87-TMZ cell lines, of which 28 proteins were upregulated and 67 proteins were down-regulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the co-upregulated proteins showed that most of the differentially expressed proteins were located in the cytoplasm and were significantly upregulated in the biological processes related to vesicular transport in the intimal system and inflammatory response mediated by myeloid leukocytes. Seven candidates were identified as potential GBM markers of TMZ resistance. Combined with existing research findings, our study supports that UAP1L1 and BCKDK are promising potential markers of TMZ resistance in GBM. This is important for further understanding the molecular mechanisms that drive the development and enhancement of TMZ resistance. Show less