Breast cancer (BC) is the most common malignant tumor in women worldwide. Emerging evidence indicates the significance of fatty acid metabolism in BC. Fatty acid desaturase (FADS) is closely associate Show more
Breast cancer (BC) is the most common malignant tumor in women worldwide. Emerging evidence indicates the significance of fatty acid metabolism in BC. Fatty acid desaturase (FADS) is closely associated with cancer occurrence and development. Here, bioinformatic analysis and experimental validation were applied to investigate the potential functions of FADS in BC. Several public databases, including TCGA, GEO, HPA, Kaplan-Meier plotter, STRING, DAVID, cBioPortal, TIMER, TRRUST, and LinkedOmics were used to determine mRNA/protein expression levels, prognostic significance, functional enrichment, genetic alterations, association with tumor-infiltrating immune cells, and related transcription factors and kinases. BC tissues showed higher and lower mRNA expression of FADS2/6/8 and FADS3/4/5, respectively. FADS1/2/6 and FADS3/4/5 showed higher and lower protein expression levels, respectively, in BC tissues. Moreover, FADS1/7 up- and FADS3/8 down-regulation predicted poor overall and recurrence-free survival, while FADS2/5 up- and FADS4 down-regulation were associated with poor recurrence-free survival. Receiver operating characteristic curves revealed that FADS2/3/4/8 were indicative diagnostic markers. FADS family members showing differential expression levels were associated with various clinical subtypes, clinical stages, lymph node metastasis status, copy number variants, DNA methylation, and miRNA regulation in BC. The mRNA expression level of FADS1/2/3/4/5/7/8 was observed to be significantly negatively correlated with DNA methylation. FADS1/2 upregulation was significantly correlated with clinical stages. FADS1/4 expression was obviously lower in BC patients with higher lymph node metastasis than lower lymph node metastasis, while FADS7/8 expression was obviously higher in BC patients with higher lymph node metastasis than lower lymph node metastasis. FADS family members showed varying degrees of genetic alterations, and Gene Ontology and KEGG pathway enrichment analyses suggested their involvement in lipid metabolism. Their expression level was correlated with immune cell infiltration levels. FADS2 was chosen for further validation analyses. We found FADS2 to be significantly over-expressed in clinical BC tissue samples. The proliferation, migration, and invasion abilities of MDA-MB-231 and BT474 cells were significantly reduced after FADS2 knockdown. Furthermore, FADS2 may promote the occurrence and development of BC cells Show less
Vascular remodelling is an essential pathophysiological state in many circulatory diseases. Abnormal vascular smooth muscle cell (VSMC) behaviour leads to neointimal formation and may eventually resul Show more
Vascular remodelling is an essential pathophysiological state in many circulatory diseases. Abnormal vascular smooth muscle cell (VSMC) behaviour leads to neointimal formation and may eventually results in major adverse cardiovascular events. The C1q/TNF-related protein (C1QTNF) family is closely associated with cardiovascular disease. Notably, C1QTNF4 has unique two C1q domains. However, the role of C1QTNF4 in vascular diseases remains unclear. C1QTNF4 expression was detected in human serum and artery tissues using ELISA and multiplex immunofluorescence (mIF) staining. Scratch assay, transwell assay and confocal microscopy were used to investigate C1QTNF4 effects on VSMC migration. EdU incorporation, MTT assay and cell counting experiment revealed C1QTNF4 effects on VSMC proliferation. C1QTNF4-transgenic, C1QTNF4 Serum C1QTNF4 levels were decreased in patients with arterial stenosis. C1QTNF4 shows colocalisation with VSMC in human renal arteries. In vitro, C1QTNF4 inhibits VSMC proliferation and migration and alters VSMC phenotype. In vivo, an adenovirus-infected rat balloon injury model, C1QTNF4-transgenic and C1QTNF4 Our study demonstrated that C1QTNF4 is a novel inhibitor of VSMC proliferation and migration that acts by downregulating the FAK/PI3K/AKT pathway, thus protecting blood vessels from abnormal neointima formation. These results provide new insights into promising potent treatments for vascular stenosis diseases. Show less
Epilepsy is a chronic brain disease and often occurs suddenly for no reason. Eucommiae folium (EF), an edible herb, can be used in the treatment of various kinds of brain diseases in clinic. From the Show more
Epilepsy is a chronic brain disease and often occurs suddenly for no reason. Eucommiae folium (EF), an edible herb, can be used in the treatment of various kinds of brain diseases in clinic. From the perspective of safety and efficacy, EF is especially suitable for the treatment of chronic brain diseases. With the help of biolabels, this study was aimed to explore the value and feasibility of EF in the treatment of epilepsy. Proteomics and metabolomics were used to explore the biolabels of EF intervention in brain tissues. Bioinformatics was then applied to topologically analyze its neuroprotective effects and mechanisms and material basis based on biolabels, which were validated in an animal model. The biolabel-led research revealed that EF may exert the therapeutic potential to treat brain diseases through the interaction between multiple compounds and multiple targets, among which its therapeutic potential for epilepsy is particularly prominent. In the pentylenetetrazole-induction model, EF and four active compounds (oleamide, catechol, chlorogenic acid, and kaempferol) protected epileptic hippocampal neurons (Nissl and FJB staining) against mitochondrial dysfunction (MYH6, MYL3, and MYBPC3, etc.) and calcium overload (TNNI3, TNNC1, and TNNT2, etc.) through the hypertrophic cardiomyopathy pathway. This study provides new evidence and insights for the neuroprotective effects of EF, in which four active compounds may be potential drug candidates for the treatment of epilepsy. Show less
Schisandra chinensis (sc) is generally demonstrated to improve antioxidant and immune functions in mammal. The present study through physiological and transcriptome analysis revealed alterations in mu Show more
Schisandra chinensis (sc) is generally demonstrated to improve antioxidant and immune functions in mammal. The present study through physiological and transcriptome analysis revealed alterations in muscle metabolisms of triploid crucian carp (Carassius auratus) cultured at different concentrations of S. chinensis diets (sc0, sc0.125%, sc0.25%, sc0.5%, sc1%, sc2%) after 8 weeks. The serum antioxidant enzyme activities analysis showed that dietary S. chinensis could reduce oxidative stress and increase organismic antioxidant capacity. Meanwhile, the detected results of muscle components presented that the amino acids and two flavor nucleotides of GMP and IMP significantly elevated while muscle crude lipid significantly reduced in S. chinensis feeding groups. In addition, springiness, chewiness, and fiber density in S. chinensis feeding groups muscle were significantly upregulated while muscle fiber diameter and area showed an opposite trend. By comparative transcriptome analysis of the muscles, functional enrichments of differentially expressed genes showed that multiple terms were related to purine metabolism, glycerolipid metabolism, regulation of actin cytoskeleton, and peroxisome. Finally, some key hub genes such as egln, gst, ggct, su1b, pi3kr4, myh9, lpl, gcdh, mylk, and col4a were identified by weighted gene co-expression network analysis. Taken together, our findings facilitate the understanding of the molecular basis underlying the muscle quality effect of dietary S. chinensis in triploid crucian carp, which provides valuable insights into the nutritional strategies of the aquaculture industry. Show less
Heterosis, also known as hybrid vigor, is widely used in aquaculture, but the molecular causes for this phenomenon remain obscure. Here, we conducted a transcriptome analysis to unveil the gene expres Show more
Heterosis, also known as hybrid vigor, is widely used in aquaculture, but the molecular causes for this phenomenon remain obscure. Here, we conducted a transcriptome analysis to unveil the gene expression patterns and molecular bases underlying thermo-resistant heterosis in Crassostrea gigas ♀ × Crassostrea angulata ♂ (GA) and C. angulata ♀ × C. gigas ♂ (AG). About 505 million clean reads were obtained, and 38,210 genes were identified, of which 3779 genes were differentially expressed between the reciprocal hybrids and purebreds. The global gene expression levels were toward the C. gigas genome in the reciprocal hybrids. In GA and AG, 95.69% and 92.00% of the differentially expressed genes (DEGs) exhibited a non-additive expression pattern, respectively. We observed all gene expression modes, including additive, partial dominance, high and low dominance, and under- and over-dominance. Of these, 77.52% and 50.00% of the DEGs exhibited under- or over-dominance in GA and AG, respectively. The over-dominance DEGs common to reciprocal hybrids were significantly enriched in protein folding, protein refolding, and intrinsic apoptotic signaling pathway, while the under-dominance DEGs were significantly enriched in cell cycle. As possible candidate genes for thermo-resistant heterosis, GRP78, major egg antigen, BAG, Hsp70, and Hsp27 were over-dominantly expressed, while MCM6 and ANAPC4 were under-dominantly expressed. This study extends our understanding of the thermo-resistant heterosis in oysters. Show less
The meat of Tibetan sheep has a unique flavor, delicious taste, and superior nutritional value. However, the change of grass will lead to a change in meat quality. This study aimed to explore the pote Show more
The meat of Tibetan sheep has a unique flavor, delicious taste, and superior nutritional value. However, the change of grass will lead to a change in meat quality. This study aimed to explore the potential regulatory mechanisms of microbial metabolites with respect to meat quality traits of Tibetan sheep under nutrient stress in the cold season. We determined and analyzed the longissimus dorsi quality, fatty acid composition, expression of genes, and rumen microbial metabolites of Tibetan sheep in cold and warm seasons. The shear force was decreased (P < .05), the meat color a*24 h value was increased (P < .05), and the contents of crude fat (EE) and protein (CP) were decreased in the cold season. Polyunsaturated fatty acids (PUFAs)-linoleic acid and docosahexaenoic acid increased significantly in the cold season (P < .05). The expressions of meat quality genes MC4R, CAPN1, H-FABP, and LPL were significantly higher in the warm season (P < .05), and the CAST gene was significantly expressed in the cold season (P < .01). The different microbial metabolites of Tibetan sheep in the cold and warm seasons were mainly involved in amino acid metabolism, lipid metabolism, and digestive system pathway, and there was some correlation between microbiota and meat quality traits. There are similarities between microbial metabolites enriched in the lipid metabolism pathway and muscle metabolites. Under nutritional stress in the cold season, the muscle tenderness of Tibetan sheep was improved, and the fat deposition capacity was weakened, but the levels of beneficial fatty acids were higher than those in the warm season, which was more conducive to healthy eating. Show less
Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data fr Show more
Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals ( Show less
It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations bet Show more
It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity. Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data. Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan. This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies. 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
Colorectal cancer (CRC) is a fatal malignant tumor with poor prognosis. Cancer stem cells (CSCs) can cause metastasis, recurrence and drug resistance in CRC. This research aimed to analyze stemness-re Show more
Colorectal cancer (CRC) is a fatal malignant tumor with poor prognosis. Cancer stem cells (CSCs) can cause metastasis, recurrence and drug resistance in CRC. This research aimed to analyze stemness-related prognostic genes of CRC based on single-cell RNA-sequencing (scRNA-seq) data. DESeq2 was applied to analyze the differentially expressed genes (DEGs). The mRNA stemness index (mRNAsi) was calculated by one-class logistic regression (OCLR). The stemness-related cells were analyzed based on scRNA-seq dataset GSE166555. Monocle 2 algorithm was used for stemness-related cells pseudotime trajectory analysis. The stemness-related prognostic genes were analyzed by clusterProfiler and survival package. The stemness of CRC cells was detected by spheroid formation assay, and the expression of stemness-related prognostic genes was verified by qRT-PCR and Western blot. 7916 DEGs between the CRC and normal tissues were obtained. The mRNAsi of the CRC tissues was shown to be significantly higher than that of the normal tissues. 7 and 8 cell types were annotated respectively in the normal and CRC tissues through analysis of the scRNA-seq data. Cell-cell interactions (CCIs) in the tumor tissues were revealed to be significantly enhanced than that in the normal tissues. By calculating the 'stemness score', CSCs, epithelial cells (EPCs) and cancer-associated fibroblasts (CAFs) were defined as stemness-related cells. Through pseudotime trajectory analysis, 2111 genes were identified as state 2-specific genes. Then, 41 genes were obtained by taking intersection of the up-regulated genes with state 2-specific genes and marker genes of CSCs, EPCs and CAFs. The univariate COX regression analysis revealed 5 stemness-related prognostic genes (TIMP1, PGF, FSTL3, SNAI1 and FOXC1). Kaplan-Meier curve analysis indicated that the higher the expression of 5 genes, the lower the survival rate. In vitro cell experiment confirmed that the expression of TIMP1, PGF and SNAI1 was consistent with that revealed by bioinformatics analysis. TIMP1, PGF and SNAI1 were identified as stemness-related prognostic genes of CRC, and possibly potential therapeutic targets for CRC. Show less
This study aimed to explore the effect of miR-23b-3p on the differentiation of goat intramuscular preadipocytes, and to confirm whether miR-23b-3p plays its roles
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
The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present Show more
The poor prognosis of serous ovarian cancer (SOC) is due to its high invasive capacity and cisplatin resistance of SOC cells, whereas the molecular mechanisms remain poorly understood. In the present study, the expression and function of non-muscle myosin heavy chain IIB (MYH10) in SOC are identified by immunohistochemistry, in vitro, and in vivo studies, respectively. The mechanism of MYH10 is demonstrated by co-immunoprecipitation, GST pull-down, confocal laser assays, and so on. The results show that the knockdown of MYH10 suppressed SOC cell proliferation, migration, invasion, metastasis, and cisplatin resistance both in vivo and in vitro. Further studies confirm that the MYH10 protein functional domain combines with non-muscle myosin heavy chain IIA (MYH9) to recruit the deubiquitinating enzyme Ubiquitin-specific proteases 45 and deubiquitinates snail to inhibit snail degradation, eventually promoting tumorigenesis, progression, and cisplatin resistance in SOC. In clinical samples, MYH10 expression is significantly elevated in SOC samples compared to the paratumor samples. And the expression of MYH10 is positively correlated with MYH9 expression. MYH10+/MYH9+ co-expression is an independent prognostic factor for predicting SOC patient survival. These findings uncover a key role of the MYH10-MYH9-snail axis in SOC carcinogenesis, progression, and cisplatin resistance, and provide potential novel therapeutic targets for SOC intervention. 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
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
Fenghui Zhao, Kaini Hang, Qingtong Zhou+11 more · 2023 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maint Show more
Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 13 reported splice variants (SVs), more than half of which have sequence variations at either C or N terminus. To explore their roles in endogenous peptide-mediated GIPR signaling, we determined the cryoelectron microscopy (cryo-EM) structures of the two N terminus-altered SVs (referred as GIPR-202 and GIPR-209 in the Ensembl database, SV1 and SV2 here, respectively) and investigated the outcome of coexpressing each of them in question with GIPR in HEK293T cells with respect to ligand binding, receptor expression, cAMP (adenosine 3,5-cyclic monophosphate) accumulation, β-arrestin recruitment, and cell surface localization. It was found that while both N terminus-altered SVs of GIPR neither bound to the hormone nor elicited signal transduction per se, they suppressed ligand binding and cAMP accumulation of GIPR. Meanwhile, SV1 reduced GIPR-mediated β-arrestin 2 responses. The cryo-EM structures of SV1 and SV2 showed that they reorganized the extracellular halves of transmembrane helices 1, 6, and 7 and extracellular loops 2 and 3 to adopt a ligand-binding pocket-occupied conformation, thereby losing binding ability to the peptide. The results suggest a form of signal bias that is constitutive and ligand-independent, thus expanding our knowledge of biased signaling beyond pharmacological manipulation (i.e., ligand specific) as well as constitutive and ligand-independent (e.g., SV1 of the growth hormone-releasing hormone receptor). Show less
Mucosal delivery of IL-27 has been shown to have a therapeutic benefit in murine models of inflammatory bowel disease (IBD). The IL-27 effect was associated with phosphorylated STAT1 (pSTAT1), a produ Show more
Mucosal delivery of IL-27 has been shown to have a therapeutic benefit in murine models of inflammatory bowel disease (IBD). The IL-27 effect was associated with phosphorylated STAT1 (pSTAT1), a product of IL27 receptor signaling, in bowel tissue. To determine whether IL-27 acted directly on colonic epithelium, murine colonoids and primary intact colonic crypts were shown to be unresponsive to IL-27 Show less
Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we Show more
Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we explored whether FGFR1 acted a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL) and the molecular mechanisms underlying T-ALL cell resistance to FGFR1 inhibitors. We showed that FGFR1 was significantly upregulated in human T-ALL and inversely correlated with the prognosis of patients. Knockdown of FGFR1 suppressed T-ALL growth and progression both in vitro and in vivo. However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage. Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2α pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. Targeting FGFR1 and mTOR exhibited synergistically anti-leukemic efficacy. These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL therapy. Show less
Poor outcomes have been widely reported for younger vs. older breast cancer patients, but whether this is due to age itself or the enrichment of aggressive clinical features remains controversial. We Show more
Poor outcomes have been widely reported for younger vs. older breast cancer patients, but whether this is due to age itself or the enrichment of aggressive clinical features remains controversial. We have evaluated the clinicopathologic characteristics and genomic profiles of real-world hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) patients to examine the determinants of outcome for younger vs. older patients in a single clinical subtype undergoing treatment in the same clinic. This study included patients presenting at the Peking University Cancer Hospital with primary stage IV or first-line metastatic HR+/HER2- breast cancer who consented to an additional blood draw for genomic profiling prior to treatment. Plasma samples were analyzed with a targeted 152-gene NGS panel to assess somatic circulating tumor DNA (ctDNA) alterations. Genomic DNA (gDNA) extracted from peripheral blood mononuclear cells was analyzed for germline variants using a targeted 600-gene NGS panel. Kaplan-Meier survival analysis was performed to analyze disease free survival (DFS), progression free survival (PFS) and overall survival (OS) in association with clinicopathologic and genomic variables. Sixty-three patients presenting with HR+/HER2- MBC were enrolled in this study. Fourteen patients were < 40 years, 19 were 40-50 years, and 30 were > 50 years at the time of primary cancer diagnosis. No significant associations were observed between age and DFS, PFS or OS. Shorter OS was associated with In this group of real-world HR+/HER2- MBC breast cancer patients younger age was not associated with poor outcomes. While current guidelines recommend treatment decisions based on tumor biology rather than age, young HR+ breast cancer patients are more likely to receive chemotherapy. Our findings support the development of biomarker-driven treatment strategies for these patients. Show less
Muscle mass development depends on increased protein synthesis and reduced muscle protein degradation. Muscle ring-finger protein-1 (MuRF1) plays a key role in controlling muscle atrophy. Its E3 ubiqu Show more
Muscle mass development depends on increased protein synthesis and reduced muscle protein degradation. Muscle ring-finger protein-1 (MuRF1) plays a key role in controlling muscle atrophy. Its E3 ubiquitin ligase activity recognizes and degrades skeletal muscle proteins through the ubiquitin-proteasome system. The loss of Murf1, which encodes MuRF1, in mice leads to the accumulation of skeletal muscle proteins and alleviation of muscle atrophy. However, the function of Murf1 in agricultural animals remains unclear. Herein, we bred F1 generation Murf1 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
Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the con Show more
Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the contributions of NRCAM to LCSC function and HCC metastasis, and further explore its mechanism in detail. 117 HCC and 29 non-HCC patients with focal liver lesions were collected and analyzed to assess the association between NRCAM and HCC metastasis. Single-cell RNA sequencing (scRNA-seq) was used to explore the biological characteristics of cells with high NRCAM expression in metastatic HCC. The role and mechanism of NRCAM in LCSC dissemination and metastasis was explored in vitro and in vivo using MYC-driven LCSC organoids from murine liver cells. Serum NRCAM is associated with HCC metastasis and poor prognosis. A scRNA-seq analysis identified that NRCAM was highly expressed in LCSCs with MYC activation in metastatic HCC. Moreover, NRCAM facilitated LCSC migration and invasion, which was confirmed in MYC-driven LCSC organoids. The in vivo tumor allografts demonstrated that NRCAM mediated intra-hepatic/lung HCC metastasis by enhancing the ability of LCSCs to escape from tumors into the bloodstream. Nrcam expression inhibition in LCSCs blocked HCC metastasis. Mechanistically, NRCAM activated epithelial-mesenchymal transition (EMT) and metastasis-related matrix metalloproteinases (MMPs) through the MACF1 mediated β-catenin signaling pathway in LCSCs. LCSCs typified by high NRCAM expression have a strong ability to invade and migrate, which is an important factor leading to HCC metastasis. Show less
Small cell lung cancer (SCLC) is the most aggressive lung cancer subtype, with more than 70% of patients having metastatic disease and a poor prognosis. However, no integrated multi-omics analysis has Show more
Small cell lung cancer (SCLC) is the most aggressive lung cancer subtype, with more than 70% of patients having metastatic disease and a poor prognosis. However, no integrated multi-omics analysis has been performed to explore novel differentially expressed genes (DEGs) or significantly mutated genes (SMGs) associated with lymph node metastasis (LNM) in SCLC. In this study, whole-exome sequencing (WES) and RNA-sequencing were performed on tumor specimens to investigate the association between genomic and transcriptome alterations and LNM in SCLC patients with (N+, n=15) or without (N0, n=11) LNM. The results of WES revealed that the most common mutations occurred in To our knowledge, this is the first integrative genomics profiling of LNM in SCLC. Our findings are particularly important for early detection and the provision of reliable therapeutic targets. Show less
The carbon fiber reinforced polyetheretherketone (CFR-PEEK) has been increasingly used in orthopedics dentistry due to its excellent biocompatibility and mechanical properties. However, the biological Show more
The carbon fiber reinforced polyetheretherketone (CFR-PEEK) has been increasingly used in orthopedics dentistry due to its excellent biocompatibility and mechanical properties. However, the biological inertness and poor antibacterial activity limit its clinical applications. This paper focused on the performances of CFR-PEEK with porous morphology that were exposed to different sulfonation periods (1, 3, 5, and 10 min, corresponding to CP-S1, CP-S3, CP-S5, and CP-S10, respectively). Residual sulfuric acid was removed by acetone rinsing, NaOH immersion, and hydrothermal treatment before in vitro and in vivo studies. The results showed some significant difference in the physicochemical properties, including energy dispersive X-ray spectroscopy (EDS) map of sulfur atoms, X-ray photoelectron spectroscopy (XPS) of valences of sulfur ions, Fourier transformation infrared spectroscopy (FTIR), hydrophilicity, hardness, and elastic modulus among CP-S3, CP-S5, and CP-S10. However, CP-S5 and CP-S10 were more effective in promoting the proliferation, adhesion, and osteogenic differentiation of seeded bone mesenchymal stem cells (BMSCs) and growth inhibition of S. aureus and P. gingivalis compared with other groups. Furthermore, the CP-S5 and CP-S10 samples achieved better cranial bone repair than the non-sulfonation group in a rat model. Therefore, it can be inferred that both 5 and 10 min are viable sulfonation durations for 30% CFR-PEEK. These findings provide a theoretical basis for developing CFR-PEEK for clinical applications. Show less
Growth traits are the economically important traits of sheep, and screening for genes related to growth and development is helpful for the genetic improvement of ovine growth traits. The fatty acid de Show more
Growth traits are the economically important traits of sheep, and screening for genes related to growth and development is helpful for the genetic improvement of ovine growth traits. The fatty acid desaturase 3 ( Show less
Pancreatic cancer is associated with high mortality and is one of the most aggressive of malignancies, but studies have not fully evaluated its molecular subtypes, prognosis and response to immunother Show more
Pancreatic cancer is associated with high mortality and is one of the most aggressive of malignancies, but studies have not fully evaluated its molecular subtypes, prognosis and response to immunotherapy of different subtypes. The purpose of this study was to explore the molecular subtypes and the key genes associated with the prognosis of pancreas cancer patients and study the clinical phenotype, prognosis and response to immunotherapy using single-cell seq data and bulk RNA seq data, and data retrieved from GEO and TCGA databases. Single-cell seq data and bioinformatics methods were used in this study. Pancreatic cancer data were retrieved from GEO and TCGA databases, the molecular subtypes of pancreatic cancer were determined using the six cGAS-STING related pathways, and the clinical phenotype, mutation, immunological characteristics and pathways related to pancreatic cancer were evaluated. Pancreatic cancer was classified into 3 molecular subtypes, and survival analysis revealed that patients in Cluster3 (C3) had the worst prognosis, whereas Cluster1 (C1) had the best prognosis. The clinical phenotype and gene mutation were statistically different among the three molecular subtypes. Analysis of immunotherapy response revealed that most immune checkpoint genes were differentially expressed in the three subtypes. A lower risk of immune escape was observed in Cluster1 (C1), indicating higher sensitivity to immunotherapeutic drugs and subjects in this Cluster are more likely to benefit from immunotherapy. The pathways related to pancreatic cancer were differentially enriched among the three subtypes. Five genes, namely SFRP1, GIPR, EMP1, COL17A and CXCL11 were selected to construct a prognostic signature. Single-cell seq data were to classify pancreatic cancer into three molecular subtypes based on differences in clinical phenotype, mutation, immune characteristics and differentially enriched pathways. Five prognosis-related genes were identified for prediction of survival of pancreatic cancer patients and to evaluate the efficacy of immunotherapy in various subtypes. Show less
Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical d Show more
Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical driver facilitating the malignant transformation of chronic inflammatory bowel diseases. In this study, deregulated miRNAs that could play a role in colon cancer are analyzed and investigated for specific functions Show less
Angelicin has been reported to have antitumor effects on many types of cancer. However, few studies on angelicin in oral squamous cell carcinoma (OSCC) have been performed. We performed cell cycle and Show more
Angelicin has been reported to have antitumor effects on many types of cancer. However, few studies on angelicin in oral squamous cell carcinoma (OSCC) have been performed. We performed cell cycle and apoptosis analyses to assess the effect of angelicin on OSCC cells. We conducted RNA-seq studies to reveal differentially expressed genes (DEGs). Dual-specificity phosphatase 6 (DUSP6) and c-MYC were strongly down-regulated differential genes. Silencing RNA (siRNA) was used to knockdown DUSP6. The mouse xenograft model was used to mimic OSCC. Angelicin inhibited OSCC in vitro. We found that DUSP6 interacted with c-MYC. DUSP6 knockdown group and DUSP6 knockdown + angelicin group had similar effects of OSCC cells. Angelicin could reduce tumor formation, DUSP6, and c-MYC expression in vivo. Compared with paclitaxel, the tumor inhibition effect of the two drugs was similar. However, angelicin did not cause weight loss and had lower toxicity. In sum, Angelicin has antitumor effects on OSCC in vitro and vivo by negatively regulating the DUSP6 mediated c-MYC signaling pathway. Show less