As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic Show more
As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic understanding of its action is lacking. Here, we found that atorvastatin counteracted angiotensin II-induced vascular endothelial injury in mice with hypertension. Mechanistically, atorvastatin up-regulated WWP2, a E6AP C-terminus (HECT)-type E3 ubiquitin ligase with an essential role in regulating protein ubiquitination and various biological processes, thereby rescuing vascular endothelial injury. By ubiquitinating ATP5A (ATP synthase mitochondrial F1 complex subunit alpha), WWP2 degraded ATP5A via the proteasome pathway, stabilizing Bcl-2/Bax in the mitochondrial pathway of apoptosis. Moreover, atorvastatin further ameliorated death of vascular endothelial cells and improved vascular endothelial functions under WWP2 overexpression, whereas WWP2 knockout abrogated these beneficial effects of atorvastatin. Furthermore, we generated endothelial cell-specific WWP2 knockout mice, and this WWP2-mediated mechanism was faithfully recapitulated in vivo. Thus, we propose that activation of a WWP2-dependent pathway that is pathologically repressed in damaged vascular endothelium under hypertension is a major mechanism of atorvastatin. Our findings are also pertinent to develop novel therapeutic strategies for vascular endothelial injury-related cardiovascular diseases. Show less
Peripheral blood immune cell profiling of atopic dermatitis patients before and after treatment by single-cell RNA sequencing technique has not been reported. To study the immune Cell Profiling of Ato Show more
Peripheral blood immune cell profiling of atopic dermatitis patients before and after treatment by single-cell RNA sequencing technique has not been reported. To study the immune Cell Profiling of Atopic Dermatitis Patients Before and After Treatment with Halometasone Cream Wet-Wrap Therapy. We used single cell sequencing to detect the proportion change and gene expression change of immune cells in 2 patients before and after treatment, and then used real-time PCR to confirm the mRNA level of differential genes. In this study, scRNA-seq in two patients with severe AD before and after halometasone cream wet-wrap therapy showed that in the mild severity of AD after treatment, Th2 cells were significantly decreased (41.2% vs 13.4%), Th1 and Th17 cells were increased (23.3% vs 43.7%, 2.3% vs 4.8% respectively). The proportion of Th22 cells did not change much (1.3% vs 1.9%). Tregs were significantly increased also (1.5% vs 5.0%). In the regulatory T cells, the expression of IL-27, PD-1, CD103, CTLA-4, ZNF-66, IL-β, CD7 gene was specifically increased after treatment, and CD39, P21, TOX2, CD151, CD79A, S100A12, TRAP1 gene was specifically decreased after treatment. In the TH2 cells, the expression of CD27, CD68, EZH1, RAD1, EGFR, CCR10, BCL11A, KLF4 gene was specifically increased after treatment and CCL26, CD180, IL-31, CCL22, LEF1, OX40 gene was specifically decreased after treatment. These genes may be new target for further study. Show less
Increasing evidence has shown that the NOD-like receptor protein 1 (NLRP1) inflammasome is associated with Aβ generation and deposition, which contributes to neuronal damage and neuronal-inflammation Show more
Increasing evidence has shown that the NOD-like receptor protein 1 (NLRP1) inflammasome is associated with Aβ generation and deposition, which contributes to neuronal damage and neuronal-inflammation in Alzheimer's disease (AD). However, the specific mechanism of NLRP1 inflammasome in the pathogenesis of AD is still unclear. It has been reported that autophagy dysfunction can aggravate the pathological symptoms of AD and plays an important role in regulating Aβ generation and clearance. We hypothesized that NLRP1 inflammasome activation may induce autophagy dysfunction contributing to the progression of AD. In the present study, we observed the relationship between Aβ generation and NLRP1 inflammasome activation, as well as AMPK/mTOR mediated-autophagy dysfunction in WT 9-month-old (M) mice, APP/PS1 6 M and APP/PS1 9 M mice. Additionally, we further studied the effect of NLRP1 knockdown on cognitive function, Aβ generation, neuroinflammation and AMPK/mTOR mediated autophagy in APP/PS1 9 M mice. Our results indicated that NLRP1 inflammasome activation and AMPK/mTOR mediated-autophagy dysfunction are closely implicated in Aβ generation and deposition in APP/PS1 9 M mice, but not in APP/PS1 6 M mice. Meanwhile, we found that knockdown of NLRP1 significantly improved learning and memory impairments, decreased the expressions of NLRP1, ASC, caspase-1, p-NF-κB, IL-1β, APP, CTF-β, BACE1 and Aβ Show less
The melanocortin action is well perceived for its ability to regulate body weight bidirectionally with its gain of function reducing body weight and loss of function promoting obesity. However, this n Show more
The melanocortin action is well perceived for its ability to regulate body weight bidirectionally with its gain of function reducing body weight and loss of function promoting obesity. However, this notion cannot explain the difficulty in identifying effective therapeutics toward treating general obesity via activation of the melanocortin action. Here, we provide evidence that altered melanocortin action is only able to cause one-directional obesity development. We demonstrate that chronic inhibition of arcuate neurons expressing proopiomelanocortin (POMC) or paraventricular hypothalamic neurons expressing melanocortin receptor 4 (MC4R) causes massive obesity. However, chronic activation of these neuronal populations failed to reduce body weight. Furthermore, gain of function of the melanocortin action through overexpression of MC4R, POMC or its derived peptides had little effect on obesity prevention or reversal. These results reveal a bias of the melanocortin action towards protection of weight loss and provide a neural basis behind the well-known, but mechanistically ill-defined, predisposition to obesity development. Show less
Sertoli cells are highly polarized testicular cells that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The class III phosphatidylinositol 3-kinase (P Show more
Sertoli cells are highly polarized testicular cells that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The class III phosphatidylinositol 3-kinase (PtdIns3K) plays core roles in macroautophagy in various cell types; however, its role in Sertoli cells remains unclear. Here, we generated a mouse line in which the gene encoding the catalytic subunit, Show less
Dysregulation of RNA-binding proteins (RBP) is one of the characteristics of cancer. Investigating the biological functions and molecular mechanisms of abnormal RBPs can help uncover new cancer biomar Show more
Dysregulation of RNA-binding proteins (RBP) is one of the characteristics of cancer. Investigating the biological functions and molecular mechanisms of abnormal RBPs can help uncover new cancer biomarkers and treatment strategies. To identify oncogenic RBPs in triple-negative breast cancer (TNBC), we employed an in vivo CRISPR screen and a TNBC progression model, which revealed small nuclear ribonucleoprotein polypeptide C (SNRPC), a subunit of the U1 small nuclear ribonucleoprotein particle (U1 snRNP), as a key modulator of TNBC progression. SNRPC was frequently upregulated, which corresponded to poor prognosis in patients with TNBC. SNRPC ablation significantly impaired the proliferation, migration, and invasion of TNBC cells in vitro and in vivo. In addition, SNRPC was essential for the stability of U1 snRNP and contributed to the RNA Pol II-controlled transcriptional program. Knockdown of SNRPC decreased RNA Pol II enrichment on a subset of oncogenes (TNFAIP2, E2F2, and CDK4) and reduced their expression levels. Furthermore, SNRPC deletion was confirmed to inhibit TNBC progression partially through regulation of the TNFAIP2-Rac1-β-catenin signaling pathway. Taken together, this data suggests that SNRPC plays an oncogenic role in TNBC, is a marker of poor prognosis, and may be a valuable therapeutic target for patients with intractable TNBC. A functional CRISPR screen identifies SNRPC as an RNA-binding protein that promotes the aggressiveness of breast cancer by facilitating Pol II-controlled transcription of oncogenes. Show less
We examined potential sex differences in appetite and blood pressure (BP) responses to melanocortin-4 receptor (MC4R) blockade in offspring from lean and obese parents. Offspring from normal (N) diet- Show more
We examined potential sex differences in appetite and blood pressure (BP) responses to melanocortin-4 receptor (MC4R) blockade in offspring from lean and obese parents. Offspring from normal (N) diet-fed parents were fed N (NN) or high-fat (H) diets (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were also fed N (HN) or H diets (HH). Adult male and female offspring were implanted with BP telemetry probes and intracerebroventricular cannulas to infuse MC4R antagonist or vehicle. Infusion of the MC4R antagonist SHU-9119 (1 nmol/h) for 7 days caused larger increases in calorie intake and body weight in obese compared with lean offspring. In male offspring, HH and HN groups exhibited higher baseline BP compared with NN and NH, and HH showed a greater reduction in BP during SHU-9119 infusion. In female offspring, HH also showed higher baseline BP and greater reduction in BP during MC4R blockade. SHU-9119 reduced heart rate in all groups, but reductions were more pronounced in offspring from lean parents. Combined α and β-adrenergic blockade reduced BP more in male HH offspring compared with NN controls. Losartan reduced BP more in male NH, HN, and HH offspring compared with NN controls. Losartan and α- and β-adrenergic blockade reduced BP similarly in all female groups. These results suggest that endogenous MC4R activity contributes to elevated BP in obese offspring from obese parents. Our findings also indicate important sex differences in the mechanisms of BP control in male and female offspring of obese parents. Show less
Growth differentiation factor 15 (GDF15) belongs to the Transforming growth factor β(TGF-β) superfamily. The decrease of GDF15 in the serum of pregnant women was associated with miscarriage. Both IHC Show more
Growth differentiation factor 15 (GDF15) belongs to the Transforming growth factor β(TGF-β) superfamily. The decrease of GDF15 in the serum of pregnant women was associated with miscarriage. Both IHC and ELISA assays showed that GDF15 in trophoblast tissue and serum of pregnant women who miscarried was significantly lower than in those who had a live birth. GDF15 deficiency was associated with embryo resorption in GDF15 knockout mice through CRIPSR editing. In addition, the migration and invasion ability of HTR-8/SVneo and JEG-3 cells were promoted by GDF15. Mechanistically, GDF15 increased Smad1/5 phosphorylation, resulting in upregulating SNAI1/2, VIMENTIN and downregulating E-CADHERIN. A dual-luciferase reporter assay confirmed that Smad-binding elements (SBE) and/or GC-rich motifs were activated and target genes such as SNAI1/2, SERPINE1, and TIMP3 were transcriptionally regulated by GDF15/Smad5 signaling. Therefore, our data revealed a crucial role of GDF15 on invasion of trophoblast by upregulating the activity of TGF-β/Smad1/5 pathway. Show less
The decreased osteogenic differentiation ability of mesenchymal stem cells (MSCs) is one of the important reasons for SOP. Inhibition of Wnt signaling in MSCs is closely related to SOP. Microtubule ac Show more
The decreased osteogenic differentiation ability of mesenchymal stem cells (MSCs) is one of the important reasons for SOP. Inhibition of Wnt signaling in MSCs is closely related to SOP. Microtubule actin crosslinking factor 1 (MACF1) is an important regulator in Wnt/β-catenin signal transduction. However, whether the specific expression of MACF1 in MSC regulates SOP and its mechanism remains unclear. We established MSC-specific Prrx1 (Prx1) promoter-driven MACF1 conditional knock-in (MACF-KI) mice, naturally aged male mice, and ovariectomized female mice models. Micro-CT, H&E staining, double calcein labeling, and the three-point bending test were used to explore the effects of MACF1 on bone formation and bone microstructure in the SOP mice model. Bioinformatics analysis, ChIP-PCR, qPCR, and ALP staining were used to explore the effects and mechanisms of MACF1 on MSCs' osteogenic differentiation. Microarray analysis revealed that the expression of MACF1 and positive regulators of the Wnt pathway (such as TCF4, β-catenin, Dvl) was decreased in human MSCs (hMSCs) isolated from aged osteoporotic than non-osteoporotic patients. The ALP activity and osteogenesis marker genes (Alp, Runx2, and Bglap) expression in mouse MSCs was downregulated during aging. Furthermore, Micro-CT analysis of the femur from 2-month-old MSC-specific Prrx1 (Prx1) promoter-driven MACF1 conditional knock-in (MACF-cKI) mice showed no significant trabecular bone changes compared to wild-type littermate controls, whereas 18- and 21-month-old MACF1 c-KI animals displayed increased bone mineral densities (BMD), improved bone microstructure, and increased maximum compression stress. In addition, the ovariectomy (OVX)-induced osteoporosis model of MACF1 c-KI mice had significantly higher trabecular volume and number, and increased bone formation rate than that in control mice. Mechanistically, ChIP-PCR showed that TCF4 could bind to the promoter region of the host gene miR-335-5p. Moreover, MACF1 could regulate the expression of miR-335-5p by TCF4 during the osteogenic differentiation of MSCs. These data indicate that MACF1 positively regulates MSCs osteogenesis and bone formation through the TCF4/miR-335-5p signaling pathway in SOP, suggesting that targeting MACF1 may be a novel therapeutic approach against SOP. MACF1, an important switch in the Wnt signaling pathway, can alleviate SOP through the TCF4/miR-335-5p signaling pathway in mice model. It might act as a therapeutic target for the treatment of SOP to improve bone function. Show less
As a debilitating condition that can impact a whole spectrum of people and involve multi-organ systems, long COVID has aroused the most attention than ever. However, mechanisms of long COVID are not c Show more
As a debilitating condition that can impact a whole spectrum of people and involve multi-organ systems, long COVID has aroused the most attention than ever. However, mechanisms of long COVID are not clearly understood, and underlying biomarkers that can affect the long-term consequences of COVID-19 are paramount to be identified. Participants for the current study were from a cohort study of COVID-19 survivors discharged from hospital between Jan 7, and May 29, 2020. We profiled the proteomic of plasma samples from hospitalised COVID-19 survivors at 6-month, 1-year, and 2-year after symptom onset and age and sex matched healthy controls. Fold-change of >2 or <0.5, and false-discovery rate adjusted P value of 0.05 were used to filter differentially expressed proteins (DEPs). In-genuity pathway analysis was performed to explore the down-stream effects in the dataset of significantly up- or down-regulated proteins. Proteins were integrated with long-term consequences of COVID-19 survivors to explore potential biomarkers of long COVID. The proteomic of 709 plasma samples from 181 COVID-19 survivors and 181 matched healthy controls was profiled. In both COVID-19 and control group, 114 (63%) were male. The results indicated four major recovery modes of biological processes. Pathways related to cell-matrix interactions and cytoskeletal remodeling and hypertrophic cardiomyopathy and dilated cardiomyopathy pathways recovered relatively earlier which was before 1-year after infection. Majority of immune response pathways, complement and coagulation cascade, and cholesterol metabolism returned to similar status of matched healthy controls later but before 2-year after infection. Fc receptor signaling pathway still did not return to status similar to healthy controls at 2-year follow-up. Pathways related to neuron generation and differentiation showed persistent suppression across 2-year after infection. Among 98 DEPs from the above pathways, evidence was found for association of 11 proteins with lung function recovery, with the associations consistent at two consecutive or all three follow-ups. These proteins were mainly enriched in complement and coagulation (COMP, PLG, SERPINE1, SRGN, COL1A1, FLNA, and APOE) and hypertrophic/dilated cardiomyopathy (TPM2, TPM1, and AGT) pathways. Two DEPs (APOA4 and LRP1) involved in both neuron and cholesterol pathways showed associations with smell disorder. The study findings provided molecular insights into potential mechanism of long COVID, and put forward biomarkers for more precise intervention to reduce burden of long COVID. National Natural Science Foundation of China; Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences; Clinical Research Operating Fund of Central High Level Hospitals; the Talent Program of the Chinese Academy of Medical Science; Training Program of the Big Science Strategy Plan; Ministry of Science and Technology of the People's Republic of China; New Cornerstone Science Foundation; Peking Union Medical College Education Foundation; Research Funds from Health@InnoHK Program. Show less
Huanan Li, Peifen Li, Shanyi Li+4 more · 2023 · Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · added 2026-04-24
To explore the mechanism of transforming growth factor-β1 (TGF-β1) induce renal fibrosis. Renal fibroblast NRK-49F cells treated with and without TGF-β1 were subjected to RNA-seq analysis. DESeq2 was Show more
To explore the mechanism of transforming growth factor-β1 (TGF-β1) induce renal fibrosis. Renal fibroblast NRK-49F cells treated with and without TGF-β1 were subjected to RNA-seq analysis. DESeq2 was used for analysis. Differentially expressed genes were screened with the criteria of false discovery rate<0.05 and l o g 2 F C >1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for differentially expressed genes. Genes encoding transcription factors were further screened for differential expression genes. Then, the expression of these genes during renal fibrosis was verified using unilateral ureteral obstruction (UUO)-induced mouse renal fibrosis model and a public gene expression dataset (GSE104954). After TGF-β1 treatment for 6, 12 and 24 h, 552, 1209 and 1028 differentially expressed genes were identified, respectively. GO analysis indicated that these genes were significantly enriched in development, cell death, and cell migration. KEGG pathway analysis showed that in the early stage of TGF-β1 induction (TGF-β1 treatment for 6 h), the changes in Hippo, TGF-β and Wnt signaling pathways were observed, while in the late stage of TGF-β1 induction (TGF-β1 treatment for 24 h), the changes of extracellular matrix-receptor interaction, focal adhesion and adherens junction were mainly enriched. Among the 291 up-regulated differentially expressed genes treated with TGF-β1 for 6 h, 13 genes ( TGF-β1 induces differentially expressed genes in renal fibroblasts, among which Show less
Branched-chain fatty acids (BCFAs) are natural components with a variety of biological activities. However, the regulation of lipid metabolism by BCFAs is unknown. It was dedicated to examining the im Show more
Branched-chain fatty acids (BCFAs) are natural components with a variety of biological activities. However, the regulation of lipid metabolism by BCFAs is unknown. It was dedicated to examining the impacts of BCFAs inferred from yak ghee on the expression of qualities related to lipid metabolism, natural pathways, and intestinal microbiota in mice. The treatment group (purified BCFAs from yak ghee) exhibited a decrease in cholesterol levels; a decrease in Show less
Branched-chain keto-acid dehydrogenase kinase (BCKDK) is the rate-limiting enzyme of branched-chain amino acid (BCAA) metabolism. In the last six years, BCKDK has been used as a kinase to promote tumo Show more
Branched-chain keto-acid dehydrogenase kinase (BCKDK) is the rate-limiting enzyme of branched-chain amino acid (BCAA) metabolism. In the last six years, BCKDK has been used as a kinase to promote tumor proliferation and metastasis. Renal cell carcinoma (RCC) is a highly vascularized tumor. A high degree of vascularization promotes tumor metastasis. Our objective is to explore the relationship between BCKDK and RCC metastasis and its specific mechanism. In our study, BCKDK is highly expressed in renal clear cell carcinoma and promotes the migration of clear cell renal cell carcinoma (ccRCC). Exosomes from ccRCC cells can promote vascular permeability and angiogenesis, especially when BCKDK is overexpressed in ccRCC cells. BCKDK can also augment the miR-125a-5p expression in ccRCC cells and derived exosomes, thereby decreasing the downstream target protein VE-cadherin level, weakening adhesion junction expression, increasing vascular permeability, and promoting angiogenesis in HUVECs. The novel BCKDK/Exosome-miR-125a-5p/VE-cadherin axis regulates intercellular communication between ccRCC cells and HUVECs. BCKDK plays a critical role in renal cancer metastasis, may be used as a molecular marker of metastatic ccRCC, and even may become a potential target of clinical anti-vascular therapy for ccRCC. Show less
Dental pulp stem cells (DPSCs) can differentiate into vascular endothelial cells and display sprouting ability. During this process, DPSC responses to the extracellular microenvironment and cell-extra Show more
Dental pulp stem cells (DPSCs) can differentiate into vascular endothelial cells and display sprouting ability. During this process, DPSC responses to the extracellular microenvironment and cell-extracellular matrix interactions are critical in regulating their ultimate cell fate. Heparan sulfate (HS) glycosaminoglycan, a major component of extracellular matrix, plays important roles in various biological cell activities by interacting with growth factors and relative receptors. However, the regulatory function of HS on vasculogenesis of mesenchymal stem cells remains unclear. The objective of this study was to investigate the role of HS in endothelial differentiation and vasculogenesis of DPSCs. Our results show that an HS antagonist suppressed the proliferation and sprouting ability of DPSCs undergoing endothelial differentiation. Furthermore, expression of proangiogenic markers significantly declined with increasing dosages of the HS antagonist; in contrast, expression of stemness marker increased. Silencing of exostosin 1 (EXT1), a crucial glycosyltransferase for HS biosynthesis, in DPSCs using a short hairpin RNA significantly altered their gene expression profile. In addition, Show less
Zhen Zhang, Yun-Xin Lu, Fangzhou Liu+16 more · 2023 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing t Show more
Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) Show less
20(S)-protopanaxadiol (PPD), one of the ginsenosides from Panax ginseng, has been reported to improve performance with dementia. This study aimed to investigate the neuroprotective effect of PPD atten Show more
20(S)-protopanaxadiol (PPD), one of the ginsenosides from Panax ginseng, has been reported to improve performance with dementia. This study aimed to investigate the neuroprotective effect of PPD attenuating NLRP3 inflammasome-mediated microglial pyroptosis in vascular dementia (VD) rats induced by bilateral common carotid artery ligation (2-VO). Male Sprague-Dawley rats (SPF, 150-180 g, n = 10/group) were randomly divided into PPD (20, 10, 5 mg/kg, subcutaneous injection once per day for 3 weeks), model, and vehicle-sham group. It was found that PPD significantly reversed 2-VO-induced cognitive impairment by decreasing escape latency and spontaneous alternation and increasing the number of crossing platforms, showing memory-improving effects. PPD improved the pathological morphology of brain tissue in VD rats. PPD significantly reduced the cerebral infarction area and the activation of microglia in the cortex and hippocampal DG, CA1, and CA3 area. Moreover, PPD could attenuate NLRP3 inflammasome-mediated microglial pyroptosis, inhibit the positive expression of NLRP3, decrease IL-1β, and IL-18 levels, and increase IL-10 levels in the brain cortex. PPD also significantly alleviated the neurotoxicity by decreasing the Aβ and p-Tau in hippocampal DG, CA1, and CA3 areas. In addition, the levels of NLRP3, ASC, and IL-1β in the cortex, APP, BACE1, and p-Tau in the hippocampus were significantly reduced by PPD. These results suggested that PPD hinders microglial activation to alleviate neuroinflammation of NLRP3 inflammasome and inhibits neurotoxicity of Aβ deposition and Tau phosphorylation in 2-VO-induced VD rats. Show less
EBV encodes at least 44 miRNAs involved in immune regulation and disease progression. Exosomes can be used as carriers of EBV-miRNA-BART intercellular transmission and affect the biological behavior o Show more
EBV encodes at least 44 miRNAs involved in immune regulation and disease progression. Exosomes can be used as carriers of EBV-miRNA-BART intercellular transmission and affect the biological behavior of cells. We characterized exosomes and established a co-culture experiment of exosomes to explore the mechanism of miR-BART1-3p transmission through the exosome pathway and its influence on tumor cell proliferation and invasion. Exosomes of EBV-positive and EBV-negative gastric cancer cells were characterized by transmission electron microscopy. NanoSight and Western blotting, and miRNA expression profiles in exosomes were sequenced with high throughput. Exosomes with high or low expression of miR-BART1-3p were co-cultured with AGS cells to study the effects on proliferation, invasion, and migration of gastric cancer cells. The target genes of EBV-miR-BART1-3p were screened and predicted by PITA, miRanda, RNAhybrid, virBase, and DIANA-TarBase v.8 databases, and the expression of the target genes after co-culture was detected by qPCR. The exosomes secreted by EBV-positive and negative gastric cancer cells range in diameter from 30 nm to 150 nm and express the exosomal signature proteins CD9 and CD63. Small RNA sequencing showed that exosomes expressed some human miRNAs, among which hsa-miR-23b-3p, hsa-miR-320a-3p, and hsa-miR-4521 were highly expressed in AGS-exo; hsa-miR-21-5p, hsa-miR-148a-3p, and hsa-miR-7-5p were highly expressed in SNU-719-exo. All EBV miRNAs were expressed in SNU-719 cells and their exosomes, among which EBV-miR-BART1-5p, EBV-miR-BART22, and EBV-miR-BART16 were the highest in SNU-719 cells; EBV-miR-BART1-5p, EBV-miR-BART10-3p, and EBV-miR-BART16 were the highest in SNU-719-exo. After miR-BART1-3p silencing in gastric cancer cells, the proliferation, healing, migration, and invasion of tumor cells were significantly improved. Laser confocal microscopy showed that exosomes could carry miRNA into recipient cells. After co-culture with miR-BART1-3p silenced exosomes, the proliferation, healing, migration, and invasion of gastric cancer cells were significantly improved. The target gene of miR-BART1-3p was FAM168A, MACC1, CPEB3, ANKRD28, and USP37 after screening by a targeted database. CPEB3 was not expressed in all exosome co-cultured cells, while ANKRD28, USP37, MACC1, and FAM168A were all expressed to varying degrees. USP37 and MACC1 were down-regulated after up-regulation of miR-BART1-3p, which may be the key target genes for miR-BART1-3p to regulate the proliferation of gastric cancer cells through exosomes. miR-BART1-3p can affect the growth of tumor cells through the exosome pathway. The proliferation, healing, migration, and invasion of gastric cancer cells were significantly improved after co-culture with exosomes of miR-BART1-3p silenced expression. USP37 and MACC1 may be potential target genes of miR-BART1-3p in regulating cell proliferation. 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
Lipid metabolism differs significantly between grazing and stall-feeding lambs, affecting the quality of livestock products. As two critical organs of lipid metabolism, the differences between feeding Show more
Lipid metabolism differs significantly between grazing and stall-feeding lambs, affecting the quality of livestock products. As two critical organs of lipid metabolism, the differences between feeding patterns on rumen and liver metabolism remain unclear. In this study, 16S rRNA, metagenomics, transcriptomics, and untargeted metabolomics were utilized to investigate the key rumen microorganisms and metabolites, as well as liver genes and metabolites associated with fatty acid metabolism under indoor feeding (F) and grazing (G). Compared with grazing, indoor feeding increased ruminal propionate content. Using metagenome sequencing in combination with 16S rRNA amplicon sequencing, the results showed that the abundance of propionate-producing Succiniclasticum and hydrogenating bacteria Tenericutes was enriched in the F group. For rumen metabolism, grazing caused up-regulation of EPA, DHA and oleic acid and down-regulation of decanoic acid, as well as, screening for 2-ketobutyric acid as a vital differential metabolite, which was enriched in the propionate metabolism pathway. In the liver, indoor feeding increased 3-hydroxypropanoate and citric acid content, causing changes in propionate metabolism and citrate cycle, while decreasing the ETA content. Then, the liver transcriptome revealed that 11 lipid-related genes were differentially expressed in the two feeding patterns. Correlation analysis showed that the expression of CYP4A6, FADS1, FADS2, ALDH6A1 and CYP2C23 was significantly associated with the propionate metabolism process, suggesting that propionate metabolism may be an important factor mediating the hepatic lipid metabolism. Besides, the unsaturated fatty acids in muscle, rumen and liver also had a close correlation. Overall, our data demonstrated that rumen microbial-driven metabolite from grazing lambs potentially regulates multiple hepatic lipid-related genes, ultimately affecting body fatty acid metabolism. Show less
IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells and has a potential to be used as a therapeutic for cancer. We have recently demonst Show more
IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells and has a potential to be used as a therapeutic for cancer. We have recently demonstrated that administration of IL-27 producing adeno-associated virus (AAV-IL-27) exhibits potent inhibition of tumor growth in mouse models. In this study, we demonstrate that AAV-IL-27 treatment leads to significant expansion of CD11b+Gr1+ myeloid cells. AAV-IL-27-induced expansion of CD11b+Gr1+ cells is IL-27R-dependent and requires Stat3 signaling, but it is inhibited by Stat1 signaling. AAV-IL-27 treatment does not increase the self-renewal capacity of CD11b+Gr1+ cells but induces significant expansion of Lin-Sca1+c-Kit+ (LSK) and granulocyte-monocyte progenitor cells. Despite exhibiting significant suppression of T cells in vitro, IL-27-induced CD11b+Gr1+ cells lost the tumor-promoting activity in vivo and overall play an antitumor role. In tumors from AAV-IL-27-treated mice, CD11b+Gr1+ cells are largely F4/80+ and express high levels of MHC class I/II and M1 macrophage markers. Thus, IL-27 gene therapy induces Stat3-mediated expansion of CD11b+Gr1+ myeloid cells and promotes accumulation of M1 macrophages in the tumor microenvironment. Show less
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestina Show more
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestinal diseases. However, the research on clinical prevention and treatment is lacking. Therefore, we investigated the molecular mechanisms of the neonate intestinal response against hyperoxia-derived ROS to find targets for intestinal barrier damage prevention. Human intestinal epithelial cells were incubated under hyperoxia (85% oxygen) to build an in vitro model. ROS and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway were inhibited to detect the MAPK/ERK pathway, nuclear factor erythroid factor 2-related factor 2 (Nrf2), hypoxia-inducible factor-1α (Hif-1α), and interleukin-17D (IL-17D) expression. Nrf2 was inhibited to detect Hif-1α and IL-17D expression. Hif-1α was inhibited to detect Nrf2, IL-17D, and tight junction proteins expression and apoptosis. Cells were treated with human recombinant IL-17D to detect TNF-α, IL-1β, IL-10, and tight junction proteins expression. ROS, Nrf2, Hif-1α, and IL-17D were upregulated and the MAPK/ERK pathway was activated under hyperoxia. But ROS inhibition downregulated the MAPK/ERK pathway, Nrf2, Hif-1α, and IL-17D. MAPK/ERK pathway inhibition downregulated Nrf2, Hif-1α, and IL-17D. Nrf2 inhibition downregulated Hif-1α and IL-17D. Hif-1α inhibition downregulated Nrf2, IL-17D, tight junction proteins, and exacerbated apoptosis. The recombinant IL-17D downregulated TNF-α, IL-1β, but upregulated IL-10 and tight junction proteins. We concluded that Hyperoxia-generated ROS activated the MAPK/ERK pathway to regulate Nrf2, Hif-1α, and IL-17D expression. Nrf2 and Hif-1α were interdependent and promoted IL-17D. Importantly, Hif-1α and IL-17D expression protected the intestinal epithelial barrier. Show less
In this work, a simple and sensitive electrochemical sensor was proposed for the detection of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) activity. Firstly, the BACE1 specific peptide w Show more
In this work, a simple and sensitive electrochemical sensor was proposed for the detection of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) activity. Firstly, the BACE1 specific peptide was modified onto the Au electrode to graft a single-strand DNA with polycytosine DNA sequence (dC Show less
Guillain-Barre syndrome (GBS) is an immune-mediated inflammatory peripheral neuropathy. This study aimed to conduct a systematic analysis of the serum lipids profile in GBS. We measured the serum lipi Show more
Guillain-Barre syndrome (GBS) is an immune-mediated inflammatory peripheral neuropathy. This study aimed to conduct a systematic analysis of the serum lipids profile in GBS. We measured the serum lipids profile in 85 GBS patients and compared it with that of 85 healthy controls matched for age and sex. Additionally, we analyzed the correlation between lipids and the severity, subtypes, precursor infections, clinical outcomes, clinical symptoms, immunotherapy, and other laboratory markers of GBS. Compared to the healthy controls, GBS exhibited significantly elevated levels of Apolipoprotein B (APOB), Apolipoprotein C2 (APOC2), Apolipoprotein C3 (APOC3), Apolipoprotein E (APOE), triglycerides (TG), and residual cholesterol (RC). Conversely, Apolipoprotein A1 (APOA1), Apolipoprotein A2 (APOA2), and high-density lipoprotein (HDL) were substantially lower in GBS. Severe GBS displayed noticeably higher levels of APOC3 and total cholesterol (TC) compared to those with mild disease. Regarding different clinical outcomes, readmitted GBS demonstrated higher RC expression than those who were not readmitted. Moreover, GBS who tested positive for neuro-virus antibody IGG in cerebrospinal fluid (CSF) exhibited heightened expression of APOC3 in comparison to those who tested negative. GBS with cranial nerve damage showed significantly reduced expression of HDL and APOA1 than those without such damage. Additionally, GBS experiencing limb pain demonstrated markedly decreased HDL expression. Patients showed a significant reduction in TC after intravenous immunoglobulin therapy. We observed a significant positive correlation between lipids and inflammatory markers, including TNF-α, IL-1β, erythrocyte sedimentation rate (ESR), white blood cells, monocytes, and neutrophils in GBS. Notably, APOA1 exhibited a negative correlation with ESR. Furthermore, our findings suggest a potential association between lipids and the immune status of GBS. The research demonstrated a strong connection between lipids and the severity, subtypes, clinical outcomes, precursor infections, clinical symptoms, immunotherapy, inflammation, and immune status of GBS. This implies that a low-fat diet or the use of lipid-lowering medications may potentially serve as an approach for managing GBS, offering a fresh viewpoint for clinical treatment of this condition. Show less
Primary central nervous system lymphoma (PCNSL) is an uncommon non-Hodgkin's lymphoma with poor prognosis. This study aimed to depict the genetic landscape of Chinese PCNSLs. Whole-genome sequencing w Show more
Primary central nervous system lymphoma (PCNSL) is an uncommon non-Hodgkin's lymphoma with poor prognosis. This study aimed to depict the genetic landscape of Chinese PCNSLs. Whole-genome sequencing was performed on 68 newly diagnosed Chinese PCNSL samples, whose genomic characteristics and clinicopathologic features were also analyzed. Structural variations were identified in all patients with a mean of 349, which did not significantly influence prognosis. Copy loss occurred in all samples, while gains were detected in 77.9% of the samples. The high level of copy number variations was significantly associated with poor progression-free survival (PFS) and overall survival (OS). A total of 263 genes mutated in coding regions were identified, including 6 newly discovered genes (ROBO2, KMT2C, CXCR4, MYOM2, BCLAF1, and NRXN3) detected in ⩾ 10% of the cases. CD79B mutation was significantly associated with lower PFS, TMSB4X mutation and high expression of TMSB4X protein was associated with lower OS. A prognostic risk scoring system was also established for PCNSL, which included Karnofsky performance status and six mutated genes (BRD4, EBF1, BTG1, CCND3, STAG2, and TMSB4X). Collectively, this study comprehensively reveals the genomic landscape of newly diagnosed Chinese PCNSLs, thereby enriching the present understanding of the genetic mechanisms of PCNSL. Show less
Ulcerative colitis (UC) is a chronic and debilitating inflammatory bowel disease that impairs quality of life. Cuproptosis, a recently discovered form of cell death, has been linked to many inflammato Show more
Ulcerative colitis (UC) is a chronic and debilitating inflammatory bowel disease that impairs quality of life. Cuproptosis, a recently discovered form of cell death, has been linked to many inflammatory diseases, including UC. This study aimed to examine the biological and clinical significance of cuproptosis-related genes in UC. Three gene expression profiles of UC were obtained from the Gene Expression Omnibus (GEO) database to form the combined dataset. Differential analysis was performed based on the combined dataset to identify differentially expressed genes, which were intersected with cuproptosis-related genes to obtain differentially expressed cuproptosis-related genes (DECRGs). Machine learning was conducted based on DECRGs to identify signature genes. The prediction model of UC was established using signature genes, and the molecular subtypes related to cuproptosis of UC were identified. Functional enrichment analysis and immune infiltration analysis were used to evaluate the biological characteristics and immune infiltration landscape of signature genes and molecular subtypes. Seven signature genes (ABCB1, AQP1, BACE1, CA3, COX5A, DAPK2, and LDHD) were identified through the machine learning algorithms, and the nomogram built from these genes had excellent predictive performance. The 298 UC samples were divided into two subtypes through consensus cluster analysis. The results of the functional enrichment analysis and immune infiltration analysis revealed significant differences in gene expression patterns, biological functions, and enrichment pathways between the cuproptosis-related molecular subtypes of UC. The immune infiltration analysis also showed that the immune cell infiltration in cluster A was significantly higher than that of cluster B, and six of the characteristic genes (excluding BACE1) had higher expression levels in subtype B than in subtype A. This study identified several promising signature genes and developed a nomogram with strong predictive capabilities. The identification of distinct subtypes of UC enhances our current understanding of UC's underlying pathogenesis and provides a foundation for personalized diagnosis and treatment in the future. Show less
RNA-seq has shown that the DUSP6 and MAPK signaling pathways are associated with the production of high-quality brush hair (type III hair) in Yangtze River Delta white goats. However, there are few re Show more
RNA-seq has shown that the DUSP6 and MAPK signaling pathways are associated with the production of high-quality brush hair (type III hair) in Yangtze River Delta white goats. However, there are few reports on the regulatory effects of DUSP6 expression on hair follicle stem cells (HFSCs) and cellular processes, as well as the underlying mechanism. Here, we investigated the effect of DUSP6 level in HFSCs and the molecular mechanism underlying the functional regulation of HFSCs by DUSP6. Overexpression of DUSP6 significantly suppressed the proliferation of HFSCs by inducing cell cycle arrest in the G1 phase and by promoting apoptosis. Transcriptome analysis revealed a total of 217 differentially expressed genes between DUSP6-overexpressing and control HFSCs, of which 33 (15.2%) were upregulated in DUSP6-overexpressing cells. The two pathways with the most significant enrichment of differentially expressed genes were the TNF signaling pathway and cytokine-cytokine receptor interaction pathway, and the significantly enriched terms in the GO enrichment analysis involved cell attachment and cytokines. These results indicate that DUSP6 can function as an inhibitory factor in HFSCs through the induction of cell cycle arrest in the G1 phase and can promote apoptosis by mediating crosstalk among several pathways and cytokines.HighlightsWe constructed DUSP6 overexpression vectors to detect mRNA and protein expression levels related to high-quality brush hair in MAPK signaling pathway.We found that high expression level of DUSP6 can inhibit the proliferation of hair follicle stem cells (HFSCs) and promote cell apoptosis of HFSCs.DUSP6 may be involved in the growth regulation of HFSCs like Other studies in cancer, tumors by regulating the expression of cytokines, changing the transmission of signals between cells, activating or suppressing immune-related pathways. Show less
Particulate matter (PM), one of the most serious air contaminants, could easily pass through the airway and deposit at the deep alveoli. Thus, it might trigger respiratory diseases like inflammation, Show more
Particulate matter (PM), one of the most serious air contaminants, could easily pass through the airway and deposit at the deep alveoli. Thus, it might trigger respiratory diseases like inflammation, asthma and lung cancer on human. Long non-coding RNAs (lncRNAs) are considered as important regulator in promotion and progression of diverse cancers. However, the molecular mechanism of lncRNAs mediating PM-induced lung carcinogenesis remains unclear. In this study, we established a 16HBE malignant transformed cell induced by PM (Cells were treated with 20 μg/ml PM, which named PM-T cells) and explored the roles and mechanisms of lncRNAs in the malignant transformation induced by PM. Compared with 16HBE cells, various biological functions were changed in PM-T cells, such as cell proliferation, migration, cell cycle and apoptosis. LncRNA SPRY4-IT1 was significant down-regulated expression and associated with these biological effects. Our results showed that lncRNA SPRY4-IT1 overexpression reversed these functional changes mentioned above. The further studies indicated that lncRNA SPRY4-IT1 involved in PM-induced cell transformation by modulating Chk1 expression via negative regulation of DUSP6-ERK1/2. In conclusion, our studies suggested that lncRNA SPRY4-IT1 played the role as a tumor suppressor gene and might mediate 16HBE cells malignant transformation induced by PM through regulating DUSP6-ERK1/2-Chk1 signaling pathway. Show less
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