👤 Lan Mei

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive loss of motor neurons. Insufficiency of neurotrophic factors is suspected to underlie the disease, but direct evidence remains scarce. In this study, we discover that brain-derived neurotrophic factor (BDNF) val/met mutation, which results in a decrease in BDNF secretion, reduces survival time of ALS patients in two separate cohorts. Using a knockin mouse model of the ALS causal gene FUS Show less

Patients with inflammatory bowel disease (IBD) commonly exhibit psychiatric symptoms, such as anxiety and depression. However, studies on drugs addressing the concurrent amelioration of these symptoms in this patient population are rare. Previous studies have suggested that dihydromyricetin (DHM) may show therapeutic potential for IBD. This study investigated the therapeutic effects of DHM on dextran sulfate sodium (DSS)-induced colitis and associated behavioral disorders in mice. The findings of the experiments indicated that DHM could ameliorate colitis symptoms, including changes in body weight, colon length, disease activity index (DAI) scores, and histopathological damage. Furthermore, DHM improved the behavioral impairments observed in colitis mouse model, as evidenced by results from the open field test, elevated plus maze test, and tail suspension test, along with hippocampal histopathological assessments. Molecular analysis revealed that DHM notably suppressed the activation of NLRP3 inflammasome and IL-1β in both the colon and the hippocampus. DHM enhanced the intestinal barrier, elevated brain-derived neurotrophic factor (BDNF) levels in the hippocampus and serum, and concurrently reduced microglia activation. DHM lowered the levels of IL-1β, tumor necrosis factor-α (TNF-α), and lipopolysaccharide (LPS) in the serum. 16S rDNA sequencing results indicated that DHM could modulate DSS-induced gut microbiota dysbiosis, enriching various beneficial metabolic and neuromodulatory pathways. Metabolomic analysis demonstrated that DHM notably elevated acetic acid, propionic acid, and butyric acid levels in intestinal feces. Network pharmacology analysis identified the central intersecting genes of DHM, ulcerative colitis (UC), and neuroinflammation. Differential gene expression analysis underscored IL-1 β as a pivotal target for the co-occurrence of UC and psychiatric conditions. These findings imply that DHM may ameliorate DSS-induced colitis and concomitant behavioral disturbances in mice, underscoring its potential as a natural therapeutic agent for IBD accompanied by psychiatric comorbidities. Show less

This study was designed to investigate the primary targets and possible mechanisms of ranitidine (Ra) against diabetic retinopathy (DR). Single-cell sequencing technology and the SPIED3 platform were employed to characterize key genes in retinal Müller cells (RMCs) of diabetic mice and identify potential small-molecule compounds separately. The effects of small-molecule compounds on the cell viability and proliferative capacity of mouse retinal Müller cells (rMC-1) cultured in high-glucose (HG) were evaluated using the cell counting kit-8 (cck-8) and 5-ethyl-2-deoxyuridine (Edu) assay. Glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS), and Fe2+ were identified as indicators of ferroptosis. Then, network pharmacology was used to predict specific targets for Ra. Western blotting was used to identify ferroptosis-related proteins, including glutathione peroxidase 4 (GPX4), cystine/glutamate transporter (xCT), serine/threonine-protein kinase AKT1, and glycogen synthase kinase-3β (GSK3β). The predicted results suggested that the potential mechanism of RMCs damage in diabetic mice is associated with ferroptosis. The cck-8 results indicated Ra played a regulatory role in HG-induced rMC-1 by enhancing cell viability. Besides, Edu results showed that Ra promoted the proliferation of rMC-1 cells. Network pharmacological analyses predicted a potential mechanism of Ra effect in HG-induced rMC-1, mainly associated with the AKT1 and GSK3β genes. Phenotypically, Ra elevated intracellular GSH levels, while reducing MDA, Fe²⁺, and ROS concentrations. Mechanistically, Ra increased xCT and GPX4 expression through the promotion of AKT1/GSK3β phosphorylation, thereby alleviating ferroptosis in HG-induced rMC-1 cells. The study highlighted that the mechanism of DR is closely associated with ferroptosis and demonstrated that Ra inhibits HG-induced ferroptosis of rMC-1 cells by regulating the AKT1/GSK3β signaling pathway, thereby providing a theoretical basis for using Ra in managing DR. Show less

BackgroundStress is a major trigger for migraine attacks. Stress activates the hypothalamic-pituitary-adrenal (HPA) axis, releasing glucocorticoids (GCs) to maintain homeostasis, and migraine attacks may occur as an adverse effect of this response. We previously demonstrated in a mouse model that inhibiting corticosterone (CORT) synthesis by administering metyrapone before stress prevented stress-induced migraine-like behaviors. Given the unpredictable nature of stressors and their onset or termination, it is critical to better understand the adaptive and maladaptive effects of the HPA stress response. Here, we aimed to evaluate the effects of HPA axis modulation following the end of stress exposure.MethodsRepeated stress induces migraine-like behaviors and priming to sodium nitroprusside (SNP) in mice. Metyrapone (to inhibit CORT synthesis), CORT (to evaluate its effects after exogenous administration), and adrenocorticotropic hormone (ACTH) (to test the effects of a hormone upstream to CORT) were administered post-stress. Additionally, α-melanocyte-stimulating hormone (α-MSH, an ACTH cleavage product) and tetrahydroisoquinoline (THIQ), a melanocortin 4 receptor (MC4R) agonist, were administered to examine melanocortin receptor involvement. Facial hypersensitivity was assessed via von Frey testing and grimace scoring was used to evaluate non-evoked pain. Serum CORT levels were measured in both control and stressed mice following ACTH administration.ResultsWe examined post-stress HPA axis modulation on stress-induced facial hypersensitivity. Metyrapone reduced acute-phase hypersensitivity and reduced priming to SNP, suggesting sustained synthesis of CORT after stress plays a role in development of migraine-like behavior. Surprisingly, both CORT and ACTH treatments at 1- and 24-h post-stress alleviated stress-induced behaviors and priming. To determine if ACTH effects were mediated by an elevation in circulating CORT, metyrapone was administered before the ACTH injection. Metyrapone increased the ACTH reversal of stress effects on facial hypersensitivity. Furthermore, post-stress ACTH injections significantly increased serum CORT levels within 30 min. In addition to ACTH effects on CORT levels, ACTH effects could be mediated by the melanocortin system. Post-stress administration of α-MSH or the MC4R agonist THIQ, reduced migraine-like behaviors.ConclusionsThere is a complex relationship between stress, the HPA axis, and melanocortin signaling, in the effects of repeated stress exposure on migraine-like behaviors. In the early post-stress response phase, there are contributions from both CORT and MC4R signaling in the maintenance of behavioral effects. These findings suggest that targeting the HPA axis and MC4R after stress may be a potential therapeutic approach for stress-induced migraine attacks. Show less

The remodeling of the extracellular matrix (ECM) plays a pivotal role in tumor progression and drug resistance. However, the compositional patterns of ECM in breast cancer and their underlying biological functions remain elusive. Transcriptome and genome data of breast cancer patients from TCGA database was downloaded. Patients were classified into different clusters by using non-negative matrix factorization (NMF) based on signatures of ECM components and regulators. Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify core genes related to ECM clusters. Additional 10 independent public cohorts including Metabric, SCAN_B, GSE12276, GSE16446, GSE19615, GSE20685, GSE21653, GSE58644, GSE58812, and GSE88770 were collected to construct Training or Testing cohort, following machine learning calculating ECM correlated index (ECI) for survival analysis. Pathway enrichment and correlation analysis were used to explore the relationship among ECM clusters, ECI and TME. Single-cell transcriptome data from GSE161529 was processed for uncovering the differences among ECM clusters. Using NMF, we identified three ECM clusters in the TCGA database: C1 (Neuron), C2 (ECM), and C3 (Immune). Subsequently, WGCNA was employed to pinpoint cluster-specific genes and develop a prognostic model. This model demonstrated robust predictive power for breast cancer patient survival in both the Training cohort (n = 5,392, AUC = 0.861) and the Testing cohort (n = 1,344, AUC = 0.711). Upon analyzing the tumor microenvironment (TME), we discovered that fibroblasts and B cell lineage were the core cell types associated with the ECM cluster phenotypes. Single-cell RNA sequencing data further revealed that angiopoietin like 4 (ANGPTL4) We identified distinct ECM clusters in breast cancer patients, irrespective of molecular subtypes. Additionally, we constructed an effective prognostic model based on these ECM clusters and recognized ANGPTL4 Show less

Pork serves as a significant meat commodity, with intramuscular fat (IMF) content being a critical determinant of its quality. However, the epigenetic mechanism of porcine IMF deposition is still unclear. This study integrated proteomics and lactylation profiles from the longissimus thoracis (LT) muscles of pigs with extremely high (IMF_H) and extremely low (IMF_L) IMF content to clarify the association between lactylation and porcine fat deposition. Furthermore, an intramuscular preadipocyte induction and differentiation model was conducted to elucidate the changes in lactylation during adipocyte differentiation. Finally, the regulatory role of lactylation in adipocyte differentiation was explored by modulating lactate production during the induction and differentiation of preadipocytes. Proteomic analysis revealed significantly increased expression of key lipid metabolism related proteins (FASN, APOA4, FABP4, ACLY, PLIN1) in IMF_H pig muscle tissues compared with IMF_L tissues, along with substantial activation of lipid metabolism pathways. Lactylation profiling identified 95 differential lysine sites across 56 proteins, with most showing lower lactylation levels in the IMF_H group. The integrative omics analysis revealed differences in lactylation profiles in porcine LT tissues with varying efficiencies of IMF deposition, highlighted PGK1, PKM, and PYGM as central lactylation-modified proteins in porcine fat deposition regulation. Further in vitro study proved that lactate-mediated lactylation inhibited adipogenic differentiation of porcine intramuscular preadipocytes through PPARγ signaling pathway. This study clarified the changes in the lactylation profile in porcine LT tissues with varying efficiencies of IMF deposition, and demonstrated that lactate-mediated lactylation inhibits the PPARγ signaling pathway and the adipogenic differentiation of porcine intramuscular preadipocyte. This study provided a new insight to understanding the epigenetic regulation mechanisms of lipid deposition in pigs. Show less

Cholesterol is an essential molecule for tumor cell growth and proliferation, and dysregulated cholesterol metabolism has been widely implicated in cancer pathogenesis. However, the specific role and underlying molecular mechanisms of cholesterol metabolism alterations in diffuse large B-cell lymphoma (DLBCL) remain poorly understood. We retrospectively analyzed clinical data from 200 DLBCL patients and 185 healthy controls, focusing on lipid and lipoprotein levels, including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and apolipoprotein E (ApoE). Univariate and multivariate Cox proportional hazard models were used to evaluate the prognostic value of these markers, and Kaplan-Meier analysis assessed their associations with overall survival (OS). Bioinformatics analysis predicted associations between lipid markers and cholesterol metabolism. Cellular experiments further investigated the expression of cholesterol metabolism-related proteins and the effect of the cholesterol-depleting agent Methyl-β-cyclodextrin (MβCD) on DLBCL cells. We confirmed significant alterations in metabolic markers (such as TC and ApoA1) between the healthy control group and patients, which were significantly associated with patient prognosis and overall OS. Bioinformatics analysis revealed a strong correlation between these markers and elevated CD36 expression. In addition, DLBCL cells exhibited increased expression of cholesterol uptake and synthesis proteins (CD36, SREBP2, and HMGCR) and decreased expression of efflux proteins (APOA1, NR1H2 and ABCG1), consistent with cholesterol metabolic reprogramming. Treatment with MβCD disrupted CD36 expression and cholesterol metabolism, leading to reduced DLBCL cell survival. These findings underscore the pivotal role of cholesterol metabolic reprogramming in DLBCL progression. CD36 and related metabolic markers represent promising therapeutic targets, opening novel avenues for the treatment of this malignancy. Show less

Aromatase, encoded by Cyp19a1, is the rate limiting enzyme in biosynthesis of estrogens, and excessive aromatase can reduce the semen quality in roosters. Seminal plasma extracellular vesicles (SPEV) are nanoscale vesicles that carry and transmit signaling molecules, thereby affecting semen quality. Currently it is still unclear whether SPEV are involved in the process of that aromatase affects the quality semen in chicken. To clarify this issue, lentivirus carrying Cyp19a1 (LV-CYP19A1) for over-expression of aromatase was constructed and injected to testis of 35-week-old roosters. Semen quality and seminal plasma hormone were measured, and SPEV were also extracted and proteome sequencing was performed after treatment of LV-CYP19A1. The results indicated that semen volume, fertility, sperm motility, testosterone (T) levels were significantly decreased, and estradiol (E Our results reveal that aromatase can down-regulate the protein expression related to regulation of ATP synthesis and metabolism, and sperm motility in SPEV, thereby reducing semen quality in roosters. Show less

CD11c+ microglia are a functionally specialized subpopulation of microglia that play a crucial role in the pathophysiological processes of various central nervous system diseases. This review synthesizes compelling evidence that CD11c+ microglia exhibit unique transcriptomic and phagocytic characteristics. These characteristics distinguish them from homeostatic microglia and support their specialized functions. During development, CD11c+ microglia are crucial for the maturation of oligodendrocytes and the integrity of white matter, particularly in regions such as the corpus callosum and cerebellum. In preclinical models of neurodegenerative diseases (such as Alzheimer's disease and amyotrophic lateral sclerosis) and central nervous system injuries (such as stroke and spinal cord injury), they are consistently associated with neuroprotective phenotypes. CD11c+ microglia exhibit enhanced phagocytic capacity near amyloid plaques and damaged neurons, helping to clear pathological protein aggregates and cell debris, thereby reducing neurotoxicity and promoting a repair environment. The current consensus is that specific microenvironmental cues, particularly hazard signaling molecules (DAMPs) and cytokines (such as interferon-γ), are the main drivers of the differentiation and activation of CD11c+ microglia. Among these, the TREM2-APOE signaling axis is a key and widely accepted regulatory pathway for their survival, proliferation, and functional status. The plasticity of CD11c+ microglia is regulated by multiple signaling pathways, including CSF1R, SIRPα-CD47, IFN-γ, and the complement cascade. Emerging therapeutic strategies aim to regulate their activities through gene targeting, metabolic intervention, and immune regulation using TREM2 agonists, CSF1R inhibitors, or nanopharmacological methods. However, challenges remain in defining specific CD11c+ biomarkers, understanding environment-dependent functions, and achieving targeted delivery. Future prospects depend on clearly addressing individual developmental issues, deciphering the molecular switches that control phenotypic plasticity, and developing highly specific therapeutic strategies to leverage their beneficial functions, thereby paving the way for new intervention methods for neurological diseases. Show less

Phosphaturic mesenchymal tumors (PMTs) are a rare group of neoplasms most commonly associated with tumor-induced osteocalcin (TIO), a paraneoplastic syndrome that profoundly impairs quality of life. Because the clinical manifestations are nonspecific, diagnosis is often delayed. PMTs are characterized by recurrent molecular alterations, most notably FN1::FGFR1 and KL (Klotho/α-Klotho) rearrangements. Tumor cells secrete fibroblast growth factor 23 (FGF23), which disrupts phosphate homeostasis and results in hypophosphatemia, thereby causing bone pain, fragility fractures, and skeletal deformities. Advanced imaging techniques play a central role in localizing the tumor, while complete surgical resection remains the most effective curative approach. Pathological evaluation provides the diagnostic gold standard; however, both clinical and histological features are heterogeneous, and the criteria for malignancy are not yet well defined. Furthermore, the biological significance of tumor margins remains an open question. This review summarizes the clinical presentation, molecular pathogenesis, pathological features, diagnostic strategies, therapeutic options, and prognostic implications of PMTs, highlighting current challenges and areas for future investigation. Show less

The causal relationships between the gut microbiota and prostate cancer, prostatitis, and benign prostatic hyperplasia remain uncertain. We intend to identify the causal connections between the gut microbiota and prostatic diseases and investigate the potential mechanisms involved. A two-sample Mendelian randomization (MR) analysis was conducted to elucidate the impact of 196 gut microbiota on prostatic diseases risk. Reverse MR, linkage disequilibrium regression score (LDSC), and colocalization analyses were performed to strengthen causal evidence. Phenome-wide MR (Phe-MR) analysis was used to evaluate the potential side effects of targeting the detected gut microbiota. We designed a two-step MR study to assess the mediating effects of sex hormones, blood metabolites, and proteins. According to the MR analyses, 31 bacterial taxa were causally associated with prostatic diseases, of which 23 types were newly identified. In addition, Our study represents the first comprehensive exploration of the causal effects of the gut microbiota on prostatic diseases and reveals the mediating effects of sex hormones and blood metabolites on the "gut-prostate axis." Show less

The gut microbiota influences host immunity and metabolism, and changes in its composition and function have been implicated in several non-communicable diseases. Here, comparing germ-free (GF) and specific pathogen-free (SPF) mice using spatial transcriptomics, single-cell RNA sequencing, and targeted bile acid metabolomics across multiple organs, we systematically assessed how the gut microbiota's absence affected organ morphology, immune homeostasis, bile acid, and lipid metabolism. Through integrated analysis, we detect marked aberration in B, myeloid, and T/natural killer cells, altered mucosal zonation and nutrient uptake, and significant shifts in bile acid profiles in feces, liver, and circulation, with the alternate synthesis pathway predominant in GF mice and pronounced changes in bile acid enterohepatic circulation. Particularly, autophagy-driven lipid droplet breakdown in ileum epithelium and the liver's zinc finger and BTB domain-containing protein (ZBTB20)-Lipoprotein lipase (LPL) (ZBTB20-LPL) axis are key to plasma lipid homeostasis in GF mice. Our results unveil the complexity of microbiota-host interactions in the crosstalk between commensal gut bacteria and the host. Show less

Intracranial aneurysms (IAs) are the major cause of subarachnoid hemorrhage. Stent-assisted coiling, especially with the Neuroform Atlas stent (NAS), has proved more effective than coiling alone for treating these aneurysms. To perform a systematic review and meta-analysis to investigate the efficacy and safety of the NAS in treating IAs. A comprehensive literature search was conducted on PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov from inception until June 2024. We included studies on ruptured and unruptured IAs treated with the NAS, covering experimental, observational, and case series across all age groups. The aneurysm occlusion rate was assessed by using the Raymond-Roy classification (RROC). The mRS and adverse events related to stent use were also recorded. The statistical analysis was conducted on R Version 4.3.2 by using the packages "meta" and "metasens." We reported our results as proportions with their corresponding CIs. Meta-regression, leave-one-out, and sensitivity analyses were conducted to confirm the robustness of our results. A total of 42 studies including 2434 participants with a mean age of 51 to 73 years were included. Among angiographic outcomes, the final RROC 1/RROC 2 was achieved in 95% of the patients, final RROC 1 in 82%, RROC 2 in 12%, and RROC 3 in 5% of the patients. Additionally, 93% of the patients showed mRS grade 0, 5% showed mRS grade 1, 3% showed mRS grade 2, 2% showed mRS grade 3, 0% showed mRS grade 4, 0% showed mRS grade 5, and 1% showed mRS grade 6. All adverse events had a ≤5% rate. Due to limited cause-specific data, we were unable to analyze mortality specific to the stent placement and complications. Despite the large number of studies included, comparative studies were still observed to be scarce. Although the generalizability of our findings is limited, this study demonstrates that the NAS is highly effective for treating IAs, with high occlusion rates and a low incidence of adverse events. The stent's performance, supported by comprehensive analysis, highlights its safety and efficacy in managing both ruptured and unruptured aneurysms. Show less

Phosgene, used in large-scale industrial production, is highly toxic and irritant. Accidental exposure can lead to varying degrees of injuries, with severe cases potentially resulting in acute lung injury or acute respiratory distress syndrome, resulting in a mortality rate of 40%-50%. The indirect damages of phosgene (inflammation and oxidative stress) are considered important factors in phosgene-induced acute lung injury (P-ALI). The expression of Liver X Receptor α (LXRα) significantly reduces during periods of inflammation. LXRs were initially discovered to be highly expressed in the liver, whereas LXRs are expressed in immune cells and vascular endothelial cells, playing a significant role in anti-inflammatory and antioxidant responses. LXRα may have pulmonary protection in P-ALI. However, evidence to verify this association is still lacking. In this study, rats were divided into six groups to explore the potential role of LXRα in P-ALI. This study found that GW3965 effectively activated LXRα, upregulated its expression and downregulated the levels of proinflammatory cytokines, inhibited malondialdehyde activity while enhancing superoxide dismutase activity, suppressed apoptosis and ameliorated the pathological processes of P-ALI, ultimately exerting pulmonary protection in P-ALI. Further validation revealed that the pulmonary protective effect of LXRα may be associated with the PI3K/Akt and NF-kB signalling pathways. Show less

Enhancer RNAs (eRNAs) are a pivotal class of enhancer-derived non-coding RNAs that drive gene expression. Here we identify the SNAI1 enhancer RNA (SNAI1e; SCREEM2) as a key activator of SNAI1 expression and a potent enforcer of transforming growth factor-β (TGF-β)/SMAD signaling in cancer cells. SNAI1e depletion impairs TGF-β-induced epithelial-mesenchymal transition (EMT), migration, in vivo extravasation, stemness, and chemotherapy resistance in breast cancer cells. SNAI1e functions as an eRNA to cis-regulate SNAI1 enhancer activity by binding to and strengthening the enrichment of the transcriptional co-activator bromodomain containing protein 4 (BRD4) at the local enhancer. SNAI1e selectively promotes the expression of SNAI1, which encodes the EMT transcription factor SNAI1. Furthermore, we reveal that SNAI1 interacts with and anchors the inhibitory SMAD7 in the nucleus, and thereby prevents TGF-β type I receptor (TβRI) polyubiquitination and proteasomal degradation. Our findings establish SNAI1e as a critical driver of SNAI1 expression and TGF-β-induced cell plasticity. Show less

Rapid progression of non-target lesions (NTLs) leads to a high incidence of NTL related cardiac events post-PCI, which accounting half of the recurrent cardiac events. It is important to identify the risk factors and establish an accurate clinical prediction model for the rapid progression of NTLs post-PCI. PCSK9 inhibitors lower LDL-c levels significantly, also show the anti-inflammation effect, and may have the potential to reduce the rapid progression of NTLs post-PCI. We tried to test this hypothesis and explore the potential mechanisms. This retrospective study included 1250 patients who underwent the first PCI and underwent repeat coronary angiography for recurrence of chest pain within 24 months. General characteristics, laboratory tests and inflammatory factors(IL-10, IL-6, IL-8, IL-1β, sIL-2R, and TNF-α) were collected. Machine learning (LASSO regression) was mainly employed to select the important characteristic risk factors for the rapid progression of NTLs post-PCI and build prediction models. Finally, mediator analysis was employed to explore the potential mechanisms by which PCSK9 inhibitors reduce the rapid progression of NTLs post-PCI. There were more diabetes, less beta-blockers and PCSK9 inhibitors application, higher HbA1c, LDL-c, ApoB, TG, TC, uric acid, hs-CRP, TNF-α, IL-6, IL-8, and sIL-2R in NTL progressed group. LDL-c, hs-CRP, IL-8, and sIL-2R were characteristic risk factors for the rapid progression of NTLs post-PCI, combining LDL-c, hs-CRP, IL-8, and sIL-2R builds the optimal model for predicting the rapid progression of NTLs post-PCI (AUC = 0.632). LDL-c had a clear and incomplete mediating effect (95% CI, mediating effect: 51.56%) in the reduction of the progression of NTLs by PCSK9 inhibitors, and there was a possible mediating effect of IL-8 (90% CI), and sIL-2R (90% CI). LDL-c, hs-CRP, IL-8, and sIL-2R may be the key characteristic risk factors for the rapid progression of NTLs post-PCI, and combining these parameters might predict the rapid progression of NTLs post-PCI. The application of PCSK9 inhibitors had a negative correlation with the rapid progression of NTLs. In addition to the significant LDL-c-lowering, PCSK9 inhibitors may reduce the rapid progression of NTLs by reducing local inflammation of plaque. ChiCTR2200058529; Date of registration: 2022-04-10. Show less

Lung cancer has a high morbidity and mortality among malignant tumors, and lung adenocarcinoma (LUAD) is the main type of lung cancer. In recent years, circular RNAs (circRNAs) have been confirmed to play an important role in the generation and development of human cancer. However, the specific role and mechanism of circ-NUP98 in LUAD are still unclear and need to be further investigated. Circ-NUP98, microRNA-188-3p (miR-188-3p), and chromobox homolog 1 (CBX1) levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell-counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry, wound healing, and transwell assay were used to observe LUAD cell proliferation, apoptosis, migration, invasion, and cell-cycle progression. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were examined using special assay kits. CyclinD1, Bcl-2-related X protein (Bax), matrix metalloproteinase 9 (MMP9) protein, and CBX1 protein levels were determined using Western blot. The interaction between miR-188-3p and circ-NUP98 or CBX1 was identified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assay. In vivo efficacy of circ-NUP98 was evaluated in a xenograft tumor model. Besides, the expression of CBX1 and KI67 in the tumors was detected by immunohistochemical (IHC) assay. Circ-NUP98 and CBX1 expressions were upregulated in LUAD tissues and cells, and miR-188-3p was decreased. Downregulation of circ-NUP98 could inhibit the proliferation, migration, invasion, and oxidative stress, and promote apoptosis of LUAD cells. Mechanism experiments showed that circ-NUP98 acted as a sponge for miR-188-3p to increase CBX1 expression. Knockdown of circ-NUP98 could inhibit the growth of LUAD tumors in vivo. Circ-NUP98 might promote the malignant development of LUAD via the miR-188-3p/CBX1 axis, which might provide a potential new marker for early diagnosis of LUAD. Show less

Sickle cell disease (SCD) is a common inherited blood disorder among African Americans (AA), with premature mortality which has been associated with prolongation of the heart rate-corrected QT interval (QTc), a known risk factor for sudden cardiac death. Although numerous genetic variants have been identified as contributors to QT interval prolongation in the general population, their impact on SCD patients remains unclear. This study used an unweighted polygenic risk score (PRS) to validate the previously identified associations between SNPs and QTc interval in SCD patients, and to explore possible interactions with other factors that prolong QTc interval in AA individuals with SCD. In SCD patients, candidate genetic variants associated with the QTc interval were genotyped. To identify any risk SNPs that may be correlated with QTc interval prolongation, linear regression was employed, and an unweighted PRS was subsequently constructed. The effect of PRS on the QTc interval was evaluated using linear regression, while stratification analysis was used to assess the influence of serum alanine transaminase (ALT), a biomarker for liver disease, on the PRS effect. We also evaluated the PRS with the two subcomponents of QTc, the QRS and JTc intervals. Out of 26 candidate SNPs, five risk SNPs were identified for QTc duration under the recessive model. For every unit increase in PRS, the QTc interval prolonged by 4.0 ms (95% CI: [2.0, 6.1]; p-value: <0.001) in the additive model and 9.4 ms in the recessive model (95% CI: [4.6, 14.1]; p-value: <0.001). Serum ALT showed a modification effect on PRS-QTc prolongation under the recessive model. In the normal ALT group, each PRS unit increased QTc interval by 11.7 ms (95% CI: [6.3, 17.1]; p-value: 2.60E-5), whereas this effect was not observed in the elevated ALT group (0.9 ms; 95% CI: [-7.0, 8.8]; p-value: 0.823). Several candidate genetic variants are associated with QTc interval prolongation in SCD patients, and serum ALT acts as a modifying factor. The association of a CPS1 gene variant in both QTc and JTc duration adds to NOS1AP as evidence of involvement of the urea cycle and nitric oxide metabolism in cardiac repolarization in SCD. Larger replication studies are needed to confirm these findings and elucidate the underlying mechanisms. Show less

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of invasive non-Hodgkin lymphoma. 60-70% of patients are curable with current chemoimmunotherapy, whereas the rest are refractory or relapsed. Understanding of the interaction between DLBCL cells and tumor microenvironment raises the hope of improving overall survival of DLBCL patients. P2X7, a member of purinergic receptors P2X family, is activated by extracellular ATP and subsequently promotes the progression of various malignancies. However, its role in DLBCL has not been elucidated. In this study, the expression level of P2RX7 in DLBCL patients and cell lines was analyzed. MTS assay and EdU incorporation assay were carried out to study the effect of activated/inhibited P2X7 signaling on the proliferation of DLBCL cells. Bulk RNAseq was performed to explore potential mechanism. The results demonstrated high level expression of P2RX7 in DLBCL patients, typically in patients with relapse DLBCL. 2'(3')-O-(4-benzoylbenzoyl) adenosine 5-triphosphate (Bz-ATP), an agonist of P2X7, significantly accelerated the proliferation of DLBCL cells, whereas delayed proliferation was detected when administrated with antagonist A740003. Furthermore, a urea cycle enzyme named CPS1 (carbamoyl phosphate synthase 1), which up-regulated in P2X7-activated DLBCL cells while down-regulated in P2X7-inhibited group, was demonstrated to involve in such process. Our study reveals the role of P2X7 in the proliferation of DLBCL cells and implies that P2X7 may serve as a potential molecular target for the treatment of DLBCL. Show less

Chronic itch is a common and complex symptom often associated with skin diseases such as atopic dermatitis (AD). Although IL-27 is linked to AD, its role and clinical significance in itch remain undefined. We sought to investigate IL-27 function in itch using tissue-specific transgenic mice, various itch models, behavior scoring, RNA sequencing, and cytokine/kinase array. Our findings show that IL-27 receptors were overexpressed in human AD skin. Intradermal IL-27 injection failed to directly induce itch in mice but upregulated skin protease-activated receptor 2 (PAR2) transcripts, a key factor in itch and AD. IL-27 activated human keratinocytes, increasing PAR2 transcription and activity. Coinjection of SLIGRL (PAR2 agonist) and IL-27 in mice heightened PAR2-mediated itch. In addition, IL-27 boosted BST2 transcription in sensory neurons and keratinocytes. BST2 was upregulated in AD skin, and its injection in mice induced itch-like response. BST2 colocalized with sensory nerve branches in AD skin from both human and murine models. Sensory neurons released BST2, and mice with sensory neuron-specific BST2 knockout displayed reduced itch responses. Overall, this study provides evidence that skin IL-27/PAR2 and neuronal IL-27/BST2 axes are implicated in cutaneous inflammation and pruritus. The discovery of neuronal BST2 in pruritus shed light on BST2 in the itch cascade. Show less

Spurs, which mainly appear in roosters, are protrusions near the tarsometatarsus on both sides of the calves of chickens, and are connected to the tarsometatarsus by a bony core. As a male-biased morphological characteristic, the diameter and length of spurs vary significantly between different individuals, mainly related to genetics and age. As a specific behavior of hens, egg-laying also varies greatly between individuals in terms of traits such as age at first egg ( Show less

This study aims to identify BMI-associated genes by integrating aggregated summary information from different omics data. We conducted a meta-analysis to leverage information from a genome-wide association study (n = 339 224), a transcriptome-wide association study (n = 5619), and an epigenome-wide association study (n = 3743). We prioritized the significant genes with a machine learning-based method, netWAS, which borrows information from adipose tissue-specific interaction networks. We also used the brain-specific network in netWAS to investigate genes potentially involved in brain-adipose interaction. We identified 195 genes that were significantly associated with BMI through meta-analysis. The netWAS analysis narrowed down the list to 21 genes in adipose tissue. Among these 21 genes, six genes, including FUS, STX4, CCNT2, FUBP1, NDUFS3, and RAPSN, were not reported to be BMI-associated in PubMed or GWAS Catalog. We also identified 11 genes that were significantly associated with BMI in both adipose and whole brain tissues. This study integrated three types of omics data and identified a group of genes that have not previously been reported to be associated with BMI. This strategy could provide new insights for future studies to identify molecular mechanisms contributing to BMI regulation. Show less

Tumor heterogeneity is jointly determined by the components of the tumor ecosystem (TES) including tumor cells, immune cells, stromal cells, and non-cellular components. We aimed to identify subtypes using TES-related genes and determine subtype specific drivers and treatments for hepatocellular carcinoma (HCC). We collected 68 genesets depicting tumor biology, immune infiltration, and liver function, totaling 2831 genes, and collected mRNA profiles and clinical data for over 6000 tumors from 65 datasets in the GEO, TCGA, ICGC, and several other databases. We designed a three-step clustering pipeline to identify subtypes. The microenvironment, genomic alteration, and drug response differences were systematically compared among subtypes. Seven subtypes (TES-1/2/3/4/5/6/7) were revealed in 159 tumors from the CHCC-HBV cohort. We constructed a single sample classifier using paired genes (sscpgsTES). TES subtypes were significantly associated with multiple clinical variables including etiology, and survival in 14 of 17 cohorts and the meta-cohort. TES-1 had the poorest prognosis and highest proliferation level. Both TES-2 and TES-7 were immune-enriched, however, TES-2 had a significantly worse prognosis, and hypoxic and immunosuppressive microenvironment. TES-4 had activated Wnt pathway, driven by CTNNB1 mutation. Good prognosis TES-6 exhibited the best differentiation. TES-5 and TES-3 were considered as novel subclasses by comparing with ten previous subtyping systems. TES-5 tumors had high AFP but good overall survival, and ∼45% of them harbored AXIN1 mutation. TES-3 was immune and stromal desert, may be driven by high copy number alteration burden, and had the poorest response to immune checkpoint inhibitor. TES-1 and TES-2 had significantly lower response to transarterial chemoembolization, but they showed significantly higher sensitivity to compound YM-155. Tumor ecosystem subtypes expand existing HCC subtyping systems, have distinct drivers, prognosis, and treatment vulnerabilities. Show less

Consumer demand for tasty and quality meat has been quickly increasing. This study investigated how dietary supplemented rutin affects meat quality, muscle fatty acid profile, and antioxidant capacity in the Chinese indigenous Qingyuan partridge chicken. A cohort of 180 healthy 119-day-old chickens was subjected to a randomized assignment into three groups, identified as the control, R200, and R400 groups, with respective supplementation of 0, 200, and 400 mg/kg of rutin. The results revealed insignificance in growth performance, namely, average daily gain, average daily feed intake, and feed-to-gain ratio, across the various treatment groups ( Show less

Osteoarthritis (OA) is a common degenerative joint disease and causes chronic pain and disability to the elderly. Several risk factors are involved, such as aging, obesity, genetic susceptibility, and environmental factors. We conducted a transcriptome-wide association study (TWAS) and chemical-related gene set enrichment analysis (CGSEA) to investigate the susceptibility genes and environmental factors. TWAS analysis was conducted to identify the susceptibility genes by integrating the summary-level genome-wide association study data of knee OA (KOA) and hip OA (HOA) with the precomputed expression weights from the Genotype-Tissue Expression Project (Version 8). The FUSION software was used for both single-tissue and cross-tissue TWAS, which were combined using an aggregate Cauchy association test. The biological function and pathways of the TWAS genes were explored using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases, and the human cartilage mRNA expression profiles were utilized to validate the TWAS genes. CGSEA analysis was performed to scan the OA-associated chemicals by integrating the TWAS results with the chemical-related gene sets. There were 44 and 93 unique TWAS genes identified in 7 and 11 chromosomes for KOA and HOA, respectively, fourteen and four of which showed significantly differential expression in the mRNA profiles, such as CRHR1, LTBP1, WWP2, LMX1B, and PTHLH. OA-related pathways were found in the KEGG and GO analysis, such as TGF-beta signaling pathway, MAPK signaling pathway, hyaluronan metabolic process, and chondrocyte differentiation. Forty-five OA-associated chemicals were identified, including quercetin, bisphenol A, and cadmium chloride. Several candidate OA-associated genes and chemicals were identified through TWAS and CGSEA analysis, which expanded our understanding of the relationship between genes, chemicals, and their impact on OA. Show less

Brown adipose tissue (BAT) burns fatty acids (FAs) to produce heat, and shows diurnal oscillation in glucose and triglyceride (TG)-derived FA-uptake, peaking around wakening. Here we aimed to gain insight in the diurnal regulation of metabolic BAT activity. RNA-sequencing, chromatin immunoprecipitation (ChIP)-sequencing, and lipidomics analyses were performed on BAT samples of wild type C57BL/6J mice collected at 3-hour intervals throughout the day. Knockout and overexpression models were used to study causal relationships in diurnal lipid handling by BAT. We identified pronounced enrichment of oscillating genes involved in extracellular lipolysis in BAT, accompanied by oscillations of FA and monoacylglycerol content. This coincided with peak lipoprotein lipase (Lpl) expression, and was predicted to be driven by peroxisome proliferator-activated receptor gamma (PPARγ) activity. ChIP-sequencing for PPARγ confirmed oscillation in binding of PPARγ to Lpl. Of the known LPL-modulators, angiopoietin-like 4 (Angptl4) showed the largest diurnal amplitude opposite to Lpl, and both Angptl4 knockout and overexpression attenuated oscillations of LPL activity and TG-derived FA-uptake by BAT. Our findings highlight involvement of PPARγ and a crucial role of ANGPTL4 in mediating the diurnal oscillation of TG-derived FA-uptake by BAT, and imply that time of day is essential when targeting LPL activity in BAT to improve metabolic health. Show less