👤 Aiping Sun

Poor proliferative capacity of adult cardiomyocytes is the primary cause of heart failure after myocardial infarction (MI), thus exploring the molecules and mechanisms that promote the proliferation of adult cardiomyocytes is crucially useful for cardiac repair after MI. Here, we found that miR-130b-5p was highly expressed in mouse embryonic and neonatal hearts and able to promote cardiomyocyte proliferation both in vitro and in vivo. Mechanistic studies revealed that miR-130b-5p mainly promoted the cardiomyocyte proliferation through the MAPK-ERK signaling pathway, and the dual-specific phosphatase 6 (Dusp6), a negative regulator of the MAPK-ERK signaling, was the direct target of miR-130b-5p. Moreover, we found that overexpression of miR-130b-5p could promote the proliferation of cardiomyocytes and improve cardiac function in mice after MI. These studies thus revealed the critical role of miR-130b-5p and its targeted MAPK-ERK signaling in the cardiomyocyte proliferation of adult hearts and proved that miR-130b-5p could be a potential target for cardiac repair after MI. Show less

Tumor microenvironent contains prognostic molecular markers and therapeutic targets from different cellular sources, which are still not fully revealed in the resistance and recurrence after radiotherapy for rectal cancer. By integrating the scRNA-seq data, we deconvoluted the bulk transcriptomics of rectal cancer collected before preoperative neoadjuvant radiotherapy (nRT) into fractions and gene expression of the six cell types. The inferred cell-type-associated DEGs, abbreviated as caDEGs, of myeloid and stromal cells were enriched for overlapping yet unique biological processes including immunity, angiogenesis, and metabolism, respectively. Ecotyper analysis indicates that the caDEGs reflects cell states and ecotypes in association with nRT response. By mapping the caDEGs onto the context-free and newly built ligand-receptor and collagen-integrin lists from scRNA-Seq data, respectively, we inferred 297 cell-type-specific trans- and/or cis-collagen-integrin and 219 heterotypic ligand-receptor interactions potentially associated with nRT response, including interactions between stromal-associated COL1A2/COL6A1/COL6A2 and stromal or CMS1-associated ITGA1/B1, between epithelial-associated JAG1 and stromal-associated NOTCHs, between CMS2 epithelial-associated CCL15 and proliferating myeloid-associated CCR1, between myeloid-associated CCL4/CD86 and lymphatic endothelial-associated ACKR2, and between myeloid-associated TNFS13B and B cell-associated TNFRSF13B/C, etc. Intriguingly, results suggest a greater number of down-regulated cell-type-related markers in resistant cancers to nRT. Favorable myeloid-associated CD14, epithelial-associated DYM, stromal-associated COL1A2 and COL3A1, and unfavorable epithelial-associated CELSR3 and KCNH8 markers were inferred at least from two independent nCRT datasets of GSE119409, GSE35452, and GSE45404. The results provide insights into roles of the stromal and immune cells beside epithelial cells in resistance to radiotherapy for rectal cancers. The proposed approach can be applicable to other diseases as well. Codes and additional data are available at https://github.com/Xueling21/rectalNRT_deconv. Show less

CA2 pyramidal neurons (PNs) are associated with social behaviors. The mechanisms, however, remain to be fully investigated. Here, we report that Efr3b, a protein essential for phospholipid metabolism at the plasma membrane, is widely expressed in the brain, especially in the hippocampal CA2/CA3 areas. To assess the functional significance of Efr3b in the brain, we generated Efr3b Show less

Astrocyte elevated gene-1 (AEG-1) is overexpressed in various malignancies. Exostosin-1 (EXT-1), a tumor suppressor, is an intermediate for malignant tumors. Understanding the mechanism behind the interaction between AEG-1 and EXT-1 may provide insights into colon cancer metastasis. AOM/DSS was used to induce tumor in BALB/c mice. Using an In BALB/c mice, the AOM+DSS treated mice developed necrotic, inflammatory and dysplastic changes in the colon with definite clinical symptoms such as loss of goblet cells, colon shortening, and collagen deposition. Administration of AEG-1 siRNA resulted in a substantial decrease in the disease activity index. Mice treated with EXT-1 siRNA showed diffusely reduced goblet cells. In vivo investigations revealed that PTCH-1 activity was influenced by upstream gene AEG-1, which in turn may affect EXT-1 activity. Data from The Cancer Genomic Atlas and GEO databases confirmed the upregulation of AEG-1 and downregulation of EXT-1 in cancer patients. This study revealed that AEG-1 silencing might alter EXT-1 expression indirectly through PTCH-1, influencing cell-ECM interactions, and decreasing dysplastic changes, proliferation and invasion. Show less

A fatty acid desaturase (FADS) insertion-deletion (Indel) polymorphism (rs66698963) influences the expression of FADS1, which controls the synthesis of n-6 highly unsaturated fatty acid (HUFA) arachidonic acid (AA). The anti-inflammatory activity of the n-3 HUFA eicosapentaenoic acid (EPA) may be explained by competition with AA for proinflammatory lipid mediator synthesis. A precision medicine approach based on stratification by FADS Indel genotype could identify individuals, who benefit from greatest disease risk reduction by n-3 HUFAs. We tested the hypothesis that the FADS insertion (I) allele predicts colorectal polyp risk reduction in a secondary analysis of the randomized, placebo-controlled, 2×2 factorial seAFOod polyp prevention trial of EPA 2000 mg daily and aspirin 300 mg daily for 12 mo (ISRCTN05926847). Participant Indel genotype was determined by polymerase chain reaction (PCR) blind to trial outcomes. Colorectal polyp outcomes were included in negative binomial (polyp number) and logistic (polyp detection rate [PDR; percentage with one or more polyps]) regression models comparing each active intervention with its placebo. Presence of ≥1 Indel I allele and an interaction term (I allele × active intervention) were covariates. In 528 participants with colonoscopy and FADS Indel data, EPA use irrespective of Indel genotype, was not associated with reduced colorectal polyp number (incidence rate ratio [IRR]: 0.92; 95% confidence interval: 0.74, 1.16), mirroring original seAFOod trial analysis. However, the presence of ≥1 I allele identified EPA users with a significant reduction in colorectal polyp number (IRR: 0.50 [0.28, 0.90]), unlike aspirin, for which there was no interaction. Similar findings were obtained for the PDR. The FADS Indel I allele identified individuals, who displayed colorectal polyp prevention by EPA with a similar effect size to aspirin. Assessment of rs66698963 as a biomarker of therapeutic response to n-3 HUFAs in other populations and healthcare settings is warranted. The seAFOod polyp prevention trial and STOP-ADENOMA study were registered at International Standard Randomised Controlled Trial Number registry as ISRCTN05926847. Show less

This study replicated a mouse model of sperm DNA damage induced by benzo(a)pyrene (BaP), and the transcriptomic and proteomic features of the model were examined to clarify the pathways related to BaP-induced damage to sperm DNA. Male mice in the BaP group were subjected to BaP at a dosage of 100 mg/kg/d or an equivalent quantity of saline solution in the control group for 60 days. Subsequently, the DNA fragmentation index (DFI) in sperm was assessed using a sperm chromatin structure assay (SCSA). RNA-seq and data-independent acquisition (DIA) were used to identify the mRNA and protein expression patterns in the testis. The sperm DFI significantly increased in the BaP group. Compared to the control group, the BaP group exhibited differential expression of 240 genes (referred to as DEGs) and 616 proteins (referred to as DEPs). These molecules included Aldh1a1, Cyb5r3, Fads1, Oxsm, Rcn3, and Prss45. Pathways in cancer, the PI3K-Akt signaling pathway, metabolic pathways, and the MAPK signaling pathway were the primary areas where these genes showed enrichment. BaP can damage the DNA of sperm and affect metabolism, the PI3K-Akt pathway, and pathways associated with cancer signaling. Show less

Infigratinib, an FGFR1-3 selective oral tyrosine kinase inhibitor, has shown clinical activity in cancers with FGFR alterations. The pharmacokinetics (PK) of infigratinib and its major metabolites have been characterized in global populations. This study examined the PK profile of infigratinib and its metabolites in Chinese patients. In this phase II, open-label, single-arm study in China, patients with advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) harboring FGFR2 gene amplification received 125 mg infigratinib orally once daily in a "3 weeks on, 1 week off" schedule for 28-day cycles. Plasma PK parameters were calculated with a non-compartmental model. Data were available from 21 patients (19 GC and two GEJ). After a single dose, peak infigratinib plasma concentration was reached at a median time of 3.1 h, with geometric mean C Show less

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide and lacks biomarkers for personalized therapy. Herein, it is reported that MCB1 could be a novel oncofetal protein that is upregulated in the preneoplastic lesions and serum of early HCC patients. Functional studies reveal that MCB1 modulated p53 protein degradation to promote T-IC generation and drive HCC initiation. Furthermore, the MCB1/p53 axis is shown to determine the responses of hepatoma cells to conventional chemotherapeutics and predict transcatheter arterial chemoembolization (TACE) benefits in patients. Importantly, MCB1 can mediate sorafenib/lenvatinib resistance by downregulating two essential drug targets fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 3 (VEGFR3) expression in a proteasome-dependent manner. Patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs), and patient cohorts analysis suggested that MCB1 levels in HCCs may determine the distinct responses to conventional therapeutics and targeted drugs. Furthermore, treatment of targeted drugs-resistant HCC with adeno-associated virus (AAV) targeting MCB1 or a proteasome inhibitor restores targeted drug response, suggesting their clinical significance in HCC combinational therapy. In conclusion, these findings demonstrate that MCB1 could act as a driver for HCC initiation, a contributor to drug resistance, and a biomarker for individualized HCC therapy. Show less

The cell development atlas of transition stage from late Carnegie to fetal development (7-9 weeks) remain unclear. It can be seen that the early period of human embryos (7-9 weeks) is a critical research gap. Therefore, we employed single‑cell RNA sequencing to identify cell types and elucidate differentiation relationships. The single‑cell RNA sequencing analysis determines eighteen cell clusters in human embryos during the 7-9 weeks period. We uncover two distinct pathways of cellular development and differentiation. Initially, mesenchymal progenitor cells differentiated into osteoblast progenitor cells and neural stem cells, respectively. Neural stem cells further differentiated into neurons. Alternatively, multipotential stem cells differentiated into adipocyte, hematopoietic stem cells and neutrophil, respectively. Additionally, COL1A2-(ITGA1 + ITGB1) mediated the cell communication between mesenchymal progenitor cells and osteoblast progenitor cells. NCAM1-FGFR1 facilitated the cell communication between mesenchymal progenitor cells and neural stem cells. Notably, NCAM1-NCAM1 as a major contributor mediated the cell communication between neural stem cells and neurons. Moreover, CGA-FSHR simultaneously mediated the communication between multipotential stem cells, adipocyte, hematopoietic stem cells and neutrophil. Distinct cell clusters activated specific transcription factors such as HIC1, LMX1B, TWIST1, and et al., which were responsible for their specific functions. These coregulators, such as HOXB13, VSX2, PAX5, and et al., may mediate cell development and differentiation in human embryos. We provide the cell development atlas for human embryos (7-9 weeks). Two distinct cell development and differentiation pathways are revealed. Show less

Foot-and-mouth disease virus (FMDV), a member of picornavirus, can enter into host cell via macropinocytosis. Although it is known that receptor tyrosine kinases (RTKs) play a crucial role in FMDV macropinocytic entry, the specific RTK responsible for regulating this process and the intricacies of RTK-mediated downstream signaling remain to be elucidated. Here, we conducted a screening of RTK inhibitors to assess their efficacy against FMDV. Our findings revealed that two compounds specifically targeting fibroblast growth factor receptor 1 (FGFR1) and FMS-like tyrosine kinase 3 (FLT3) significantly disrupted FMDV entry. Furthermore, additional evaluation through gene knockdown and overexpression confirmed the promotion effect of FGFR1 and FLT3 on FMDV entry. Interestingly, we discovered that the increasement of FMDV entry facilitated by FGFR1 and FLT3 can be ascribed to increased macropinocytic uptake. Additionally, in-depth mechanistic study demonstrated that FGFR1 interacts with FMDV VP3 and undergoes phosphorylation during FMDV entry. Furthermore, the FGFR1 inhibitor inhibited FMDV-induced activation of p21-activated kinase 1 (PAK1) on Thr212 and Thr423 sites. Consistent with these findings, the ectopic expression of FGFR1 resulted in a concomitant increase in phosphorylation level of PAK1 on Thr212 and Thr423 sites. Taken together, our findings represent the initial exploration of FGFR1's involvement in FMDV macropinocytic entry, providing novel insights with potential implications for the development of antiviral strategies. Show less

Lung cancer, the leading cause of cancer-related incidence and mortality worldwide, is characterised by high invasiveness and poor prognosis. Novel therapeutic targets are required, especially for patients with inoperable metastatic disease requiring systemic therapies to improve patients' welfare. Recently, studies indicated that TMEM176B is a positive regulator in breast and gastric cancers, and it could be a potential target for treatment. In this study, we used single-cell sequencing, proteomics, Co-IP, and in vivo and in vitro experimental models to investigate the role of TMEM176B in lung adenocarcinoma development. Our study indicated that TMEM176B expression was enhanced in lung adenocarcinoma tissues, and it was associated with shorter overall survival (OS). TMEM176B promoted cellular functions, including cell proliferation, invasion, migration and adhesion in vitro and tumour growth in vivo. Moreover, the tube formation ability of endothelial cells was enhanced by treating with the tumour cell-conditioned medium. We have also demonstrated that TMEM176B regulated EMT via the FGFR1/JNK/Vimentin/Snail signalling cascade. Overall, our study suggests TMEM176B could be a potential therapeutic target in lung adenocarcinoma. Show less

Gynecomastia denotes the benign proliferation of glandular breast tissue and stands as a recognized risk factor for male breast cancer. Nonetheless, the underlying carcinogenic mechanisms orchestrating the progression from gynecomastia to cancer remain poorly understood. This study employed single-cell RNA sequencing (scRNA-seq) to meticulously dissect the cellular landscape of gynecomastia and unravel potential associations with male breast cancer at a single-cell resolution. Pseudotime and evolutionary analyses were executed to delineate the distinct features characterizing gynecomastia and male breast cancer. The TCGA database, along with cell-cell communication analysis and immunohistochemistry staining, was harnessed to validate differential gene expression, specifically focusing on CD13. From the copy number variation profiles and evolutionary tree, we inferred shared mutation characteristics (18p Our investigation provides novel insights into the evolutionary progression from gynecomastia to male breast cancer, shedding light on the pivotal role of CD13 in driving this transition. The identification of CD13 as a potential therapeutic target suggests the feasibility of CD13-targeted interventions, specifically tailored for male breast cancer treatment. Show less

Understanding the liver stem cells (LSCs) holds great promise for new insights into liver diseases and liver regeneration. However, the heterogenicity and plasticity of liver cells have made it controversial. Here, by employing single-cell RNA-sequencing technology, transcriptome features of Krt19 Show less

Abnormal hippocampal neurodevelopment, particularly in the dentate gyrus region, may be a key mechanism of attention-deficit/hyperactivity disorder (ADHD). In this study, we investigate the effect of the most commonly used Chinese herb for the treatment of ADHD, Rehmanniae Radix Preparata (RRP), on behavior and hippocampal neurodevelopment in spontaneously hypertensive rats (SHR). Behavior tests, including Morris water maze (MWM) test, open field test (OFT) and elevated plus maze (EPM) test were performed to assess the effect of RRP on hyperactive and impulsive behavior. Hippocampal neurodevelopment was characterized by transmission electron microscopy, immunofluorescence, Golgi staining and Nissl staining approaches. Regulatory proteins such as Trkb, CDK5, FGF2/FGFR1 were examined by Western blot analysis. The results showed that RRP could effectively control the impulsive and spontaneous behavior and improve the spatial learning and memory ability. RRP significantly reduced neuronal loss and increased the number of hippocampal stem cells, and promoted synaptic plasticity. In addition, FGF/FGFR signaling was upregulated after RRP treatment. RRP can effectively reduce impulsive and spontaneous behavior and ameliorate hippocampal neurodevelopmental abnormalities in ADHD rat model. Show less

The angiotensin-converting enzyme 2 (ACE2) is a primary cell surface viral binding receptor for SARS-CoV-2, so finding new regulatory molecules to modulate ACE2 expression levels is a promising strategy against COVID-19. In the current study, we utilized islet organoids derived from human embryonic stem cells (hESCs), animal models and COVID-19 patients to discover that fibroblast growth factor 7 (FGF7) enhances ACE2 expression within the islets, facilitating SARS-CoV-2 infection and resulting in impaired insulin secretion. Using hESC-derived islet organoids, we demonstrated that FGF7 interacts with FGF receptor 2 (FGFR2) and FGFR1 to upregulate ACE2 expression predominantly in β cells. This upregulation increases both insulin secretion and susceptibility of β cells to SARS-CoV-2 infection. Inhibiting FGFR counteracts the FGF7-induced ACE2 upregulation, subsequently reducing viral infection and replication in the islets. Furthermore, retrospective clinical data revealed that diabetic patients with severe COVID-19 symptoms exhibited elevated serum FGF7 levels compared to those with mild symptoms. Finally, animal experiments indicated that SARS-CoV-2 infection increased pancreatic FGF7 levels, resulting in a reduction of insulin concentrations in situ. Taken together, our research offers a potential regulatory strategy for ACE2 by controlling FGF7, thereby protecting islets from SARS-CoV-2 infection and preventing the progression of diabetes in the context of COVID-19. Show less

Obesity, a multifactorial disease with many complications, has become a global epidemic. Weight management, including dietary supplementation, has been confirmed to provide relevant health benefits. However, experimental evidence and mechanistic elucidation of dietary supplements in this regard are limited. Here, the weight loss efficacy of MHP, a commercial solid beverage consisting of mulberry leaf aqueous extract and Show less

Breast cancer brain metastasis (BCBM) is a crucial issue in the treatment of breast cancer and is associated with poor prognosis. Therefore, novel therapeutic targets are urgently needed in clinical practice. In this study, we aimed to identify potential actionable targets in brain metastases (BMs) utilising the FoundationOne® CDx (F1CDx). Formalin-fixed paraffin-embedded archived specimens including 16 primary breast tumours (PTs), 49 BCBMs and 7 extracranial metastases (ECMs) from 54 patients who underwent surgery for BCBM were tested using F1CDx. Tumour-infiltrated lymphocytes (TILs) of BMs were also tested using haematoxylin-eosin staining. The median tumour mutational burden (TMB) and TILs in BMs were 5.0 (range 0-29) mut/Mb and 1.0% (range 0%-5.0%), respectively. High TMB (≥10 mut/Mb) was detected in four cases (8%). Genomic alterations (GAs) were detected in all samples. The top-ranked somatic mutations in BMs were TP53 (82%), PIK3CA (35%), MLL2 (22%), BRCA2 (14%) and ATM (14%) and the most prevalent copy number alterations were ERBB2 (64%), RAD21 (36%), CCND1 (32%), FGF19 (30%) and FGF3 (30%). The most prevalent GAs were relatively consistent between paired PTs and BMs. Actionable GAs were detected in 94% of all BMs. Consistent rate in actionable GAs was 38% (6/16) between paired PTs/ECMs and BMs. Compared to matched PTs/ECMs, additional actionable GAs (BRAF, FGFR1, PTEN, KIT and CCND1) were discovered in 31% (5/16) of the BMs. TMB and TILs were relatively low in BCBMs. Comparable consistency in actionable GAs was identified between BCBMs and matched PTs/ECMs. It was, therefore, logical to carry out genomic testing for BCBMs to identify potential new therapeutic targets when BCBM specimens were available, as ∼31% of samples carried additional actionable GAs. Show less

This study aimed to investigate the clinicopathological characteristics, diagnostic indicators, and critical factors for the differential diagnosis of rosette-forming glioneuronal tumor (RGNT). This retrospective study included six surgically treated RGNT cases. We analyzed and summarized their clinical manifestations, radiological features, histological morphology, immunophenotype, and molecular genetic changes, supplemented with a literature review. The patients comprised four males and two females with a mean age of 35 years. The tumors were located in the cerebellum (two cases); the fourth ventricle, quadrigeminal cistern, and third ventricle (one case each); and the fourth ventricle and brainstem (one case). Clinical manifestations included headaches in four cases, left eyelid ptosis in one case, and one asymptomatic case only identified during physical examination. Microscopically, the tumor cells were uniform in size and were marked by rosette-like or pseudorosette-like structures around the neuropil and blood vessels. Immunohistochemistry revealed biphasic patterns. The central neuropil components of the rosette-like structures around the neuropil and the pseudorosette structures of the perivascular regions expressed Syn, while the cells surrounding the rosettes expressed Olig2 and not GFAP. GFAP and S-100 were expressed in the glial components but not in the rosette or pseudorosette regions. The Ki-67 proliferation index was typically low. Molecular genetic analysis showed that the main molecular changes involved FGFR1 mutation accompanied by PIK3R1 mutation. None of the patients received chemoradiotherapy postoperatively. Follow-up durations varied between 4 and 23 months with no recorded recurrence or metastasis. RGNT is a comparatively rare mixed glioneuronal tumor that occurs in the midline structures. Its morphology shows certain overlaps with other low-grade neuroepithelial tumors. Identifying the rosettes around the neuropil is critical for morphological diagnosis, and the molecular identification of FGFR1 mutations accompanied by PIK3R1 mutations can facilitate diagnosis. Show less

Papillary thyroid carcinoma (PTC) is the most prevalent type of thyroid cancer and its incidence is rising globally. The molecular mechanisms of PTC progression remain unclear, hindering the development of effective treatments. This study focuses on hsa_circ₀₀₀₈₀₁₆ (circFGFR1), a circular RNA significantly up-regulated in PTC cells. Silencing circFGFR1 inhibited PTC cell proliferation and increased cell apoptosis, suggesting its role in PTC progression. The RNA-binding protein FUS was identified as a promoter of circFGFR1 formation. While circFGFR1 does not influence FGFR1 mRNA translation, it inhibits ubiquitination and degradation of FGFR1 protein, prolonging its half-life. CircFGFR1 also interacts with protein CBL, inhibiting CBL-mediated ubiquitination of FGFR1 proteins. Rescue assays confirmed circFGFR1 promotes PTC cell growth through mediating FGFR1. This study highlights the potential of circFGFR1 as a therapeutic target, offering insights into PTC's molecular mechanisms, and paving the way for novel treatment strategies. Show less

Previously characterized as an oncogenic player in breast cancer, the function of circular RNA NINL (circNINL) in lung cancer (LC) remained elusive. This study aimed to delineate the biological role of circNINL in LC and to unveil its potential molecular mechanisms. We discovered elevated expression levels of circNINL and Fibroblast Growth Factor Receptor 1 (FGFR1) concomitant with diminished expression of microRNA-3918 (miR-3918) in LC specimens. Knockdown of circNINL led to a marked decrease in cell proliferation, migration, invasion, and aerobic glycolysis, alongside an upsurge in apoptosis in LC cells. Either downregulation of miR-3918 or overexpression of FGFR1 mitigated the suppressive impact of circNINL knockdown on LC pathogenesis. Mechanistic studies validated that circNINL served as a competitive endogenous RNA for miR-3918, thus influencing FGFR1 expression. Further, in vivo experiments using nude mouse xenograft models underscored that silencing circNINL substantially curtailed tumor growth in LC. Collectively, these findings illuminate that circNINL exacerbates LC malignancy via the miR-3918/FGFR1 axis, a process integrally linked with the activation of aerobic glycolysis. Show less

KDM6A (Lysine-Specific Demethylase 6A) is a specific demethylase for histone 3 lysine (K) 27 trimethylation (H3K27me3). The purpose of this study is to investigate whether KDM6A in renal tubule cells plays a role in the regulation of kidney function and blood pressure. We first crossed Notably, conditional knockout of This study provides the first evidence that KDM6A plays an essential role in maintaining normal tubular function and blood pressure. Renal tubule cell specific KDM6A deficiency causes hypertension due to increased H3K27me3 levels and the resultant downregulation of Show less

The Gualou-Xiebai-Banxia decoction (GXBD), a classical traditional Chinese medicine (TCM) formula, has beneficial effects in turbid phlegm obstruction syndrome, a type of coronary heart disease (CHD). However, the underlying mechanism and effective constituents of GXBD remain elusive. Our previous studies have shown that the effective constituents of GXBD may be enriched in the n-butanol fraction (GXB-N) and water fraction (GXB-W), the targets of which remain unknown. To investigate whether GXB-N and GXB-W protect myocardial cells (MCs) via fibroblast growth factor 21 (FGF21) signaling and, if so, to elucidate the underlying mechanisms. Furthermore, to investigate the targets of GXB-N and GXB-W as potential therapeutic targets for cardiovascular disease (CVD). Cell viability and apoptosis were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, respectively. The content of FGF21 in the medium was measured using enzyme-linked immunosorbent assay (ELISA). Protein expression was detected using immunofluorescence and western blotting. Apoptosis increased markedly in MCs exposed to oxidized low density lipoprotein (ox-LDL) 100 μg/mL, with increased expression of FGF21, FGFR1 and βKlotho, phosphorylation of fibroblast receptor substrate 2α (FRS2α) was suppressed. Following incubation with GXB-N and GXB-W 200 μg/mL, the expression of FGF21, FGFR1, and βKlotho and the phosphorylation of FRS2α were increased. Ox-LDL may inhibit the phosphorylation of FRS2α, inducing considerable FGF21 resistance and resulting in MC apoptosis. GXB-N and GXB-W restored and enhanced FGF21 sensitivity in MCs, consequently rescuing cells from ox-LDL-induced apoptosis. The FGF21-FRS2α signal pathway may be part action targets of these two effective fractions of GXBD. Show less

Fibroblast-like synoviocytes (FLSs) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLSs in relapse and remission of RA remain unknown. Identifying FLS heterogeneity and their underlying pathogenic roles may lead to discovering novel disease-modifying antirheumatic drugs. Combining single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, we sequenced six matched synovial tissue samples from three patients with relapse RA and three patients in remission. We analyzed the differences in the transcriptomes of the FLS subsets between the relapse and remitted phases. We validated several key signaling pathways using quantitative real-time PCR (qPCR) and multiplex immunohistochemistry (mIHC). We further targeted the critical signals in vitro and in vivo using the collagen-induced arthritis (CIA) model in rats. Lining and sublining FLS subsets were identified using scRNA-seq. Differential analyses indicated that the fibroblast growth factor (FGF) pathway was highly activated in the lining FLSs from patients with relapse RA for which mIHC confirmed the increased expression of FGF10. Although the type I interferon pathway was also activated in the lining FLSs, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by small interfering RNA in FLSs significantly reduced the expression of receptor activator of NF-κB ligand. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human-derived pannus cell culture, whereas the FGF receptor (FGFR) 1 inhibitor attenuated this process. Finally, administering an FGFR1 inhibitor displayed a therapeutic effect in a CIA rat model. The FGF pathway is a critical signaling pathway in relapse RA. Targeted tissue-specific inhibition of FGF10/FGFR1 may provide new opportunities to treat patients with relapse RA. Show less

Retinopathy of Prematurity (ROP) is a proliferative retinal vascular disease occurring in the retina of premature infants and is the main cause of childhood blindness. Nowadays anti-VEGF and retinal photocoagulation are mainstream treatments for ROP, but they develop a variety of complications. Hydrogen (H In this study, mice that were seven days old and either wild-type (WT) or Nrf2-deficient (Nrf2-/-) were exposed to 75% oxygen for 5 days and then returned to normal air conditions. Different stages of hydrogen gas (H Our results indicate that 3-4% H Collectively, our results indicate that H Show less

Currently, there is a lack of serum biomarkers that can accurately predict the short-term prognosis of enterogenic sepsis. 99 patients with enterogenic sepsis were categorized based on their Acute Gastrointestinal Injury (AGI) grade on the third day of ICU admission into four groups: no AGI, AGI grade I, AGI grade II, and AGI (III+IV). Additionally, patients were classified into survival and death groups according to their 28-day clinical outcomes. Peripheral venous blood samples were collected to measure levels of interleukin (IL)-27, intestinal fatty acid-binding protein (IFABP), and diamine oxidase (DAO). Receiver operating characteristic (ROC) curves were generated to assess the ability of IL-27, IFABP, and DAO to predict the short-term prognosis of patients with enterogenic sepsis. On the third day, both the survival and death groups exhibited elevated serum levels of IL-27 and IFABP compared to the first day, while levels of DAO were lower than those observed on day one. Furthermore, a significant positive correlation was observed between IL-27 and both IFABP and DAO, with stronger correlations evident on day three compared to day one. As the Acute Gastrointestinal Injury (AGI) grading increased, levels of IL-27, IFABP, and DAO rose correspondingly, correlating with a gradual decrease in survival rates, all demonstrating statistical significance (all P < 0.05). The Area Under the Curve (AUC) values for IL-27, IFABP, and DAO on the third day, predicting short-term prognosis for intestinal sepsis patients, were 0.714, 0.772, and 0.724, respectively. Notably, these values surpassed those of the first day, with IFABP on the third day exhibiting the highest predictive capability. IL-27, IFABP, and DAO levels measured on the third day of hospitalization can accurately predict the short-term prognosis of enterogenic sepsis. Show less

Psoriasis and inflammatory bowel disease (IBD) are chronic immune-mediated diseases that adversely affect patients' quality of life. Interleukin (IL)-27 plays an important role in a variety of infectious diseases, autoimmune disorders, and cancers. However, its therapeutic effects in psoriasis and colitis remain underexplored. In this study, we evaluated the therapeutic potential of recombinant Lactococcus lactis (L. lactis) expressing IL-27 (pIL-27) in imiquimod-induced psoriasis and dextran sodium sulfate-induced colitis mouse models. In the psoriasis mouse model, oral administration of pIL-27 significantly reduced skin scaling, mitigated weight loss, lowered psoriasis area and severity index scores, diminished epidermal hyperplasia and inflammatory cell infiltration, and decreased inflammatory cytokine levels. In the colitis mouse model, oral administration of pIL-27 alleviated weight loss, improved disease activity index scores, prevented colon shortening, ameliorated histopathological changes, and decreased inflammatory cytokine levels. Furthermore, recombinant L. lactis expressing IL-27 could modulate the gut microbiota, increasing the amount of beneficial bacteria and reducing harmful bacteria in the intestine, thereby alleviating the progression of psoriasis and colitis. These results suggest the potential of IL-27 as a therapeutic option for treating psoriasis and IBD. Show less

To elucidate the relationships between depression level and serum inflammatory factors and thyroxine levels in patients with malignant bone tumors associated with depression. The depression ( The IL-1β, IL-6, and IL-21 levels were lower and TGF-β1, IL-10, and IL-27 were higher in the depression group after treatment than before treatment. After treatment, T3 levels were higher and T4 levels were lower in the depression group. T4 levels were higher in patients with major depression than those with mild depression. IL-1β and IL-21 levels were elevated in moderately depressed patients [(11.13 ± 1.49) ng/L、(9.71 ± 1.26) ng/L], and IL-1β levels were elevated in severely depressed patients [(11.26 ± 1.95) ng/L], compared to mildly depressed patients [(9.36 ± 1.25) ng/L, (7.95 ± 1.31) ng/L] (all Depression degree in patients with malignant bone tumors correlates with serum inflammatory factors and thyroxine levels. Measurement of serum inflammatory factors and thyroxine levels can assess the progression and prognosis of depressed patients. Show less

IL-17+ γδ T cells (γδ T17) are kick-starters of inflammation due to their strict immunosurveillance of xenobiotics or cellular damages and rapid response to pro-inflammatory stimulators. IL-27 is a well-recognized pleiotropic immune regulator with potent inhibitory effects on type 17 immune responses. However, its actions on γδ T17 mediated inflammation and the underlying mechanisms are less well understood. Here we find that IL-27 inhibits the production of IL-17 from γδ T cells. Mechanistically, IL-27 promotes lipolysis while inhibits lipogenesis, thus reduces the accumulation of lipids and subsequent membrane phospholipids, which leads to mitochondrial deactivation and ensuing reduction of IL-17. More importantly, Il27ra deficient γδ T cells are more pathogenic in an imiquimod-induced murine psoriasis model, while intracutaneous injection of rmIL-27 ameliorates psoriatic inflammation. In summary, this work uncovered the metabolic basis for the immune regulatory activity of IL-27 in restraining γδ T17 mediated inflammation, which provides novel insights into IL-27/IL-27Ra signaling, γδ T17 biology and the pathogenesis of psoriasis. Show less

Diabetic kidney disease (DKD) is one of the most common microvascular complications in patients with diabetes mellitus. In this condition, renal tubular epithelial mesenchymal transition (EMT) is an important factor accelerating the progression of DKD and a major cause of renal fibrosis and end-stage renal disease. However, the therapeutic effect is unsatisfactory because of the lack of effective drugs. Jia Wei Qingxin Lotus Seed Drink (QISD) is a traditional Chinese medicine compound formula that has shown to be effective in the clinical treatment of DKD. However, the potential of QISD in DKD-EMT treatment has yet to be fully explored. This study aimed to investigate the role of QISD in ameliorating DKD-EMT injury and its mechanism. The active ingredients of QISD were identified via ultra-performance liquid chromatography-mass spectrometry/mass spectrometry (UHPLC-MS/MS). A DKD mouse model was constructed by high-fat diet feeding and intraperitoneal injection of STZ (60 mg/kg), and QISD (14.46, 28.92, and 57.84 g/kg/day) was administered by gavage for 12 consecutive weeks. Dapagliflozin (1 mg/kg/d) was used as a positive control. Renal pathological damage was observed by HE, PAS, and Masson staining. The expression levels of EMT-related proteins and pathway proteins were detected via immunohistochemistry, RT-qPCR, and western blot. In in vitro experiments, EMT injury was induced in human kidney tubular epithelial cells (HK-2) by using lipopolysaccharide (LPS). A combination of CCK8 assay, wound healing assay, small-molecule inhibitor intervention, and overexpression lentiviral transfection was used to investigate the effects of QISD on cell migration ability, adhesion ability, fibrotic factor formation, and mesenchymal properties. Animal experiments showed that QISD improved blood glucose, body weight, symptoms of excessive drinking and eating, and renal pathological injury in mice, reduced extracellular matrix deposition, delayed renal EMT injury, and inhibited the activation of the histone demethylase JMJD1C. UHPLC-MS/MS and molecular docking indicated that baicalin, wogonoside, oroxylin A-7-O-β-D-glucuronide, and glulisine A found in QISD could bind to JMJD1C. The ameliorating effect of QISD on DKD-EMT injury might be related to JMJD1C. The improvement of DKD-EMT injury by QISD was accompanied by the reduction of SP1 and ZEB1 expression. The SP1 overexpression not only reversed the therapeutic effect of JIB-04, an inhibitor of JMJD1C, on DKD-EMT but also exacerbated the expression of ZEB1 and downstream EMT-related factors. Thus, QISD might affect the expression of the epithelial marker E-cadherin by inhibiting the JMJD1C/SP1/ZEB1 signaling pathway, consequently preventing the transformation of epithelial cells to mesenchymal cells and ameliorating DKD-EMT injury. This study was the first to demonstrate that QISD might ameliorate DKD-EMT injury by inhibiting the JMJD1C/SP1/ZEB1 signaling pathway. These findings provide strong pharmacologic evidence for the clinical use of QISD in the treatment of DKD. Show less