Kidney cancer undergoes a dramatic metabolic shift and has demonstrated responsiveness to immunotherapeutic intervention. However, metabolic classification and the associations between metabolic alter Show more
Kidney cancer undergoes a dramatic metabolic shift and has demonstrated responsiveness to immunotherapeutic intervention. However, metabolic classification and the associations between metabolic alterations and immune infiltration in Renal cell carcinoma still remain elucidative. Unsupervised consensus clustering was conducted on the TCGA cohorts for metabolic classification. GESA, mRNAsi, prognosis, clinical features, mutation load, immune infiltration and differentially expressed gene differences among different clusters were compared. The prognosis model and nomograms were constructed based on metabolic gene signatures and verified using external ICGC datasets. Immunohistochemical results from Human Protein Atlas database and Tongji hospital were used to validate gene expression levels in normal tissues and tumor samples. CCK8, apoptosis analysis, qPCR, subcutaneously implanted murine models and flowcytometry analysis were applied to investigate the roles of ACAA2 in tumor progression and anti-tumor immunity. Renal cell carcinoma was classified into 3 metabolic subclusters and the subcluster with low metabolic profiles displayed the poorest prognosis, highest invasiveness and AJCC grade, enhanced immune infiltration but suppressive immunophenotypes. ACAA2, ACAT1, ASRGL1, AKR1B10, ABCC2, ANGPTL4 were identified to construct the 6 gene-signature prognosis model and verified both internally and externally with ICGC cohorts. ACAA2 was demonstrated as a tumor suppressor and was associated with higher immune infiltration and elevated PD-1 expression of CD8 Our research proposed a new metabolic classification method for RCC and revealed intrinsic associations between metabolic phenotypes and immune profiles. The identified gene signatures might serve as key factors bridging tumor metabolism and tumor immunity and warrant further in-depth investigations. Show less
Sepsis engenders an imbalance in the body's inflammatory response, with cytokines assuming a pivotal role in its progression. A relatively recent addition to the interleukin-17 family, denominated int Show more
Sepsis engenders an imbalance in the body's inflammatory response, with cytokines assuming a pivotal role in its progression. A relatively recent addition to the interleukin-17 family, denominated interleukin-17D (IL-17D), is notably abundant within pulmonary confines. Nevertheless, its implication in sepsis remains somewhat enigmatic. The present study endeavors to scrutinize the participation of IL-17D in sepsis-induced acute lung injury (ALI). The levels of IL-17D in the serum and bronchoalveolar lavage fluid (BALF) of both healthy cohorts and septic patients were ascertained through an ELISA protocol. For the creation of a sepsis-induced ALI model, intraperitoneal lipopolysaccharide (LPS) injections were administered to male C57/BL6 mice. Subsequently, we examined the fluctuations and repercussions associated with IL-17D in sepsis-induced ALI, probing its interrelation with nuclear factor erythroid 2-related factor 2 (Nrf2), alveolar epithelial permeability, and heme oxygenase-1. IL-17D levels exhibited significant reduction both in the serum and BALF of septic patients (P<0.001). Similar observations manifested in mice subjected to LPS-induced acute lung injury (ALI) (P=0.002). Intraperitoneal administration of recombinant interleukin 17D protein (rIL-17D) prompted increased expression of claudin 18 and concomitant enhancement of alveolar epithelial permeability, thus, culminating in improved lung injury (P<0.001). Alveolar epithelial type II (ATII) cells were identified as the source of IL-17D, regulated by Nrf2. Furthermore, a deficiency in HO-1 yielded elevated IL-17D levels (P=0.004), albeit administration of rIL-17D ameliorated the exacerbated pulmonary damage resulting from HO-1 deficiency. Nrf2 fosters IL-17D production within AT II cells, thereby conferring a protective role in sepsis-induced ALI. Show less
Tumor progression is driven by intrinsic malignant behaviors caused by gene mutation or epigenetic modulation, as well as crosstalk with the components in the tumor microenvironment (TME). Considering Show more
Tumor progression is driven by intrinsic malignant behaviors caused by gene mutation or epigenetic modulation, as well as crosstalk with the components in the tumor microenvironment (TME). Considering the current understanding of the tumor microenvironment, targeting the immunomodulatory stromal cells such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) could provide a potential therapeutic strategy. Here, we investigated the effect of sulfatinib, a multi-targeted tyrosine kinase inhibitor (TKI) of FGFR1, CSF1R, and VEGFR1-3, on the treatment of osteosarcoma (OS). In vitro, the antitumor effect was tested by clony formation assay and apoptosis assay.The inhibition of tumor migration and invasion was detected by Transwell assay, and the de-polarization of macrophage was detected by flow cytometry.In vivo, subcutaneous and orthotopic tumor models were established to verify antitumor effect, and the underlying mechanism was verified by immunohistochemistry(IHC), immunofluorescence(IF) and flow cytometry. Sulfatinib suppressed OS cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT) by blocking the secretion of basic fibroblast growth factor (bFGF) in an autocrine manner. In addition, it regulated immune TME via inhibition of the migration of skeletal stem cells (SSCs) to the TME and the differentiation from SSCs to CAFs. Moreover, sulfatinib can suppress OS by modulation of the TME by inhibiting M2 polarization of macrophages. Systemic treatment of sulfatinib can reduce immunosuppression cells M2-TAMs, Tregs, and myeloid-derived suppressor cells (MDSCs) and increase cytotoxic T-cell infiltration in tumors, the lungs, and the spleens. Our preclinical experiments have shown that sulfatinib can inhibit the proliferation, migration, and invasion of OS by playing a dual role on tumor cells and the tumor microenvironment simultaneously and systematically reverse immunosuppression to immune activation status, which could be translated into clinical trials. Show less
Interleukins (ILs) have been reported to be related to prostate cancer. The aims of this study were to estimate the levels for several key interleukins in prostate cancer and the causal effects betwee Show more
Interleukins (ILs) have been reported to be related to prostate cancer. The aims of this study were to estimate the levels for several key interleukins in prostate cancer and the causal effects between them. We conducted a bi-directional two-sample Mendelian randomization (MR) study to assess the causal associations between ILs and prostate cancer. Genetic instruments and summary-level data for 10 ILs were obtained from three genome-wide association meta-analyses. Prostate cancer related data were obtained from the PRACTICAL (79,148 cases and 61,106 controls), UK Biobank (7,691 cases and 169,762 controls) and FinnGen consortium (10,414 cases and 124,994 controls), respectively. The odds ratio of prostate cancer was 0.92 (95% confidence interval (CI), 0.89, 0.96; This MR study suggests that long-term IL-6 may increase the risk of prostate cancer and IL-1ra may reduce it. Show less
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and irreversible cartilage and bone damage. Despite its predominant osteoarticular and peria Show more
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and irreversible cartilage and bone damage. Despite its predominant osteoarticular and periarticular manifestations, RA is also a systematic disease associated with organ-specific extra-articular manifestation. Increasing evidence indicates that RA patients are susceptible to diabetes mellitus (DM), and RA aggravates metabolic disordered in DM, indicating the close association between RA and DM. Many factors involved in RA stimulate insulin resistance and DM development. These factors include proinflammatory cytokines (such as TNF-α, IL-6, IL-1β), RA autoantibodies (such as rheumatoid factor, cyclic citrullinated peptide antibodies), excess RA related adipokines (such as leptin, resistin, ANGPTL4), C-creative protein, and other protein (such as TXNDC5, NLRP3, RBP4). Furthermore, commonly used RA drugs, such as conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological disease-modifying antirheumatic drugs (bDMARDs), and glucocorticoids, provide potential benefits in improving insulin resistance and inhibiting DM development. This review discusses the mechanistic and therapeutic links between RA and DM, aiming to provide valuable information for the prevention and treatment of DM in RA patients. Show less
Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited effective therapies because of the absence of definitive targets. Here, we demonstrate that the expression of ZNF451, a Show more
Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited effective therapies because of the absence of definitive targets. Here, we demonstrate that the expression of ZNF451, a poorly characterized vertebrate zinc-finger protein, is upregulated in TNBC and associated with a poor prognosis. Elevated ZNF451 expression facilitates TNBC progression by interacting with and enhancing the activity of the transcriptional activator snail family transcriptional repressor 2 (SLUG). Mechanistically, the ZNF451-SLUG complex preferentially recruits the acetyltransferase p300/CBP-associated factor (PCAF) to the CCL5 promoter, selectively facilitating CCL5 transcription by enhancing the acetylation of SLUG and local chromatin, leading to recruitment and activation of tumor-associated macrophages (TAMs). Disturbing the ZNF451-SLUG interaction using a peptide suppresses TNBC progression by reducing CCL5 expression and counteracting the migration and activation of TAMs. Collectively, our work provides mechanistic insights into the oncogene-like functions of ZNF451 and suggests that ZNF451 is a potential target for development of effective therapies against TNBC. Show less
Excessive and chronic inflammation post myocardial infarction (MI) causes cardiac fibrosis and progressive ventricular remodeling, which leads to heart failure. We previously found high levels of IL-2 Show more
Excessive and chronic inflammation post myocardial infarction (MI) causes cardiac fibrosis and progressive ventricular remodeling, which leads to heart failure. We previously found high levels of IL-27 in the heart and serum until day 14 in murine cardiac ischemia‒reperfusion injury models. However, whether IL-27 is involved in chronic inflammation-mediated ventricular remodeling remains unclear. In the present study, we found that MI triggered high IL-27 expression in murine cardiac macrophages. The increased expression of IL-27 in serum is correlated with cardiac dysfunction and aggravated fibrosis after MI. Furthermore, the addition of IL-27 significantly activated the JAK/STAT signaling pathway in cardiac fibroblasts (CFs). Meanwhile, IL-27 treatment promoted the proliferation, migration and extracellular matrix (ECM) production of CFs induced by angiotensin II (Ang II). Collectively, high levels of IL-27 mainly produced by cardiac macrophages post MI contribute to the activation of CFs and aggravate cardiac fibrosis. Show less
The response of macrophages to environmental signals demonstrates its heterogeneity and plasticity. After different forms of polarized activation, macrophages reach the M1 or M2 activation state accor Show more
The response of macrophages to environmental signals demonstrates its heterogeneity and plasticity. After different forms of polarized activation, macrophages reach the M1 or M2 activation state according to their respective environment. Show less
Obesity is a global epidemic around the world. Reticulon-4B (Nogo-B) is an endoplasmic reticulum-resident protein. Our previous work demonstrated that Nogo-B deficiency inhibited obesity and decreased Show more
Obesity is a global epidemic around the world. Reticulon-4B (Nogo-B) is an endoplasmic reticulum-resident protein. Our previous work demonstrated that Nogo-B deficiency inhibited obesity and decreased the size of white adipocytes. However, the underlying molecular mechanism of Nogo-B in white adipogenesis remains poorly understood. This study aims to explore the effect of Nogo-B in white adipogenesis, as well as its underlying molecular mechanisms. The study adopted mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes to induce white adipogenesis and investigate the effect of Nogo-B on adipogenesis using qRT-PCR, Western blotting, immunofluorescence, lipid quantification, and Oil Red O staining. During white adipogenesis, Nogo-B expression was increased accompanied by upregulation of adipogenic markers. In contrast, Nogo-B deficiency inhibited white adipocyte markers expression and lipid accumulation. Furthermore, the mechanism study showed that Nogo-B deficiency decreased the destruction complex [AXIN1-APC-glycogen synthase kinase 3β (GSK3β)] levels through activating protein kinase B 2 (AKT2), resulting in β-catenin translocating into the nucleus and inhibiting the expression of adipogenic markers. Moreover, Nogo-B deficiency promoted the expression of brown/beige adipocytes markers while improving mitochondrial thermogenesis by activating β-catenin pathway. In addition, Nogo-B deficiency reduced the levels of inflammatory molecules during white adipogenic differentiation. This study revealed that Nogo-B deficiency inhibited white adipogenesis through AKT2/GSK3β/β-catenin pathway. Meanwhile, Nogo-B deficiency increased the expression of brown/beige adipocyte markers and promoted mitochondrial thermogenesis. In addition, Nogo-B deficiency reduced inflammatory cytokine levels caused by adipogenesis. Collectively, blocking Nogo-B expression may be a potential strategy to suppress white adipogenesis. Show less
Lipid metabolism differs significantly between grazing and stall-feeding lambs, affecting the quality of livestock products. As two critical organs of lipid metabolism, the differences between feeding Show more
Lipid metabolism differs significantly between grazing and stall-feeding lambs, affecting the quality of livestock products. As two critical organs of lipid metabolism, the differences between feeding patterns on rumen and liver metabolism remain unclear. In this study, 16S rRNA, metagenomics, transcriptomics, and untargeted metabolomics were utilized to investigate the key rumen microorganisms and metabolites, as well as liver genes and metabolites associated with fatty acid metabolism under indoor feeding (F) and grazing (G). Compared with grazing, indoor feeding increased ruminal propionate content. Using metagenome sequencing in combination with 16S rRNA amplicon sequencing, the results showed that the abundance of propionate-producing Succiniclasticum and hydrogenating bacteria Tenericutes was enriched in the F group. For rumen metabolism, grazing caused up-regulation of EPA, DHA and oleic acid and down-regulation of decanoic acid, as well as, screening for 2-ketobutyric acid as a vital differential metabolite, which was enriched in the propionate metabolism pathway. In the liver, indoor feeding increased 3-hydroxypropanoate and citric acid content, causing changes in propionate metabolism and citrate cycle, while decreasing the ETA content. Then, the liver transcriptome revealed that 11 lipid-related genes were differentially expressed in the two feeding patterns. Correlation analysis showed that the expression of CYP4A6, FADS1, FADS2, ALDH6A1 and CYP2C23 was significantly associated with the propionate metabolism process, suggesting that propionate metabolism may be an important factor mediating the hepatic lipid metabolism. Besides, the unsaturated fatty acids in muscle, rumen and liver also had a close correlation. Overall, our data demonstrated that rumen microbial-driven metabolite from grazing lambs potentially regulates multiple hepatic lipid-related genes, ultimately affecting body fatty acid metabolism. Show less
Hypoxia contributes to tumor progression and confers drug resistance. We attempted to microdissect the hypoxia landscape in colon cancer (CC) and explore its correlation with immunotherapy response. T Show more
Hypoxia contributes to tumor progression and confers drug resistance. We attempted to microdissect the hypoxia landscape in colon cancer (CC) and explore its correlation with immunotherapy response. The hypoxia landscape in CC patients was microdissected through unsupervised clustering. The "xCell" algorithms were applied to decipher the tumor immune infiltration characteristics. A hypoxia-related index signature was developed via the LASSO (least absolute shrinkage and selection operator) Cox regression in The Cancer Genome Atlas (TCGA)-colon adenocarcinoma (COAD) cohort and validated in an independent dataset from the Gene Expression Omnibus (GEO) database. The tumor immune dysfunction and exclusion (TIDE) algorithm was utilized to evaluate the correlation between the hypoxia-related index (HRI) signature and immunotherapy response. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting were performed to verify the mRNA expression levels of five key genes. The Cell Counting Kit-8 (CCK-8) assay and flow cytometry were performed to examine the cell viability and cell apoptosis. Patients were classified into hypoxia-high, hypoxia-median, and hypoxia-low clusters in TCGA-COAD and verified in the GSE 17538 dataset. Compared with the hypoxia-low cluster, the hypoxia-high cluster consistently presented an unfavorable prognosis, higher immune scores, and stromal scores and elevated infiltration levels of several critical immune and stromal cells. Otherwise, we also found 600 hypoxia-related differentially expressed genes (HRDEGs) between the hypoxia-high cluster and the hypoxia-low cluster. Based on the 600 HRDEGs, we constructed the HRI signature which consists of 11 genes and shows a good prognostic value in both TCGA-COAD and GSE 17538 (AUC of 6-year survival prediction >0.75). Patients with low HRI scores were consistently predicted to be more responsive to immunotherapy. Of the 11 HRI signature genes, RGS16, SNAI1, CDR2L, FRMD5, and FSTL3 were differently expressed between tumors and adjacent tissues. Low expression of SNAI1, CDR2L, FRMD5, and FSTL3 could induce cell viability and promote tumor cell apoptosis. In our study, we discovered three hypoxia clusters which correlate with the clinical outcome and the tumor immune microenvironment in CC. Based on the hypoxia cluster and HRDEGs, we constructed a reliable HRI signature that could accurately predict the prognosis and immunotherapeutic responsiveness in CC patients and discovered four key genes that could affect tumor cell viability and apoptosis. Show less
RNA-seq has shown that the DUSP6 and MAPK signaling pathways are associated with the production of high-quality brush hair (type III hair) in Yangtze River Delta white goats. However, there are few re Show more
RNA-seq has shown that the DUSP6 and MAPK signaling pathways are associated with the production of high-quality brush hair (type III hair) in Yangtze River Delta white goats. However, there are few reports on the regulatory effects of DUSP6 expression on hair follicle stem cells (HFSCs) and cellular processes, as well as the underlying mechanism. Here, we investigated the effect of DUSP6 level in HFSCs and the molecular mechanism underlying the functional regulation of HFSCs by DUSP6. Overexpression of DUSP6 significantly suppressed the proliferation of HFSCs by inducing cell cycle arrest in the G1 phase and by promoting apoptosis. Transcriptome analysis revealed a total of 217 differentially expressed genes between DUSP6-overexpressing and control HFSCs, of which 33 (15.2%) were upregulated in DUSP6-overexpressing cells. The two pathways with the most significant enrichment of differentially expressed genes were the TNF signaling pathway and cytokine-cytokine receptor interaction pathway, and the significantly enriched terms in the GO enrichment analysis involved cell attachment and cytokines. These results indicate that DUSP6 can function as an inhibitory factor in HFSCs through the induction of cell cycle arrest in the G1 phase and can promote apoptosis by mediating crosstalk among several pathways and cytokines.HighlightsWe constructed DUSP6 overexpression vectors to detect mRNA and protein expression levels related to high-quality brush hair in MAPK signaling pathway.We found that high expression level of DUSP6 can inhibit the proliferation of hair follicle stem cells (HFSCs) and promote cell apoptosis of HFSCs.DUSP6 may be involved in the growth regulation of HFSCs like Other studies in cancer, tumors by regulating the expression of cytokines, changing the transmission of signals between cells, activating or suppressing immune-related pathways. Show less
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
Jun Li, Ying Xia, Shumin Kong+6 more · 2023 · Journal of the European Academy of Dermatology and Venereology : JEADV · Blackwell Publishing · added 2026-04-24
Actinic keratosis (AK) represents an intraepidermal malignant neoplasm with the proliferation of atypical keratinocytes. AK lesions are regarded as early in situ squamous cell carcinomas (SCCs) having Show more
Actinic keratosis (AK) represents an intraepidermal malignant neoplasm with the proliferation of atypical keratinocytes. AK lesions are regarded as early in situ squamous cell carcinomas (SCCs) having the potential to progress into invasive SCC (iSCC) and metastasize, causing death. This study aimed to investigate the heterogeneity of keratinocytes and how this heterogeneity promoted AK development and progression. We employed single-cell RNA sequencing (scRNA-seq) to examine the heterogeneity of keratinocytes and dermal fibroblast clusters in AKs and adjacent normal skins. Cell clustering, pseudotime trajectory construction, gene ontology enrichment analysis, transcription factor network analysis, and cell-cell communication were used to investigate the heterogeneity of keratinocytes in AK. The cellular identity and function were verified by immunohistochemical and immunofluorescence staining. Using scRNA-seq, we revealed 13 keratinocyte subgroups (clusters 0-12) in AK tissues and characterized 2 AK-specific clusters. Cluster 9 displayed high levels of IL1R2 and WFDC2, and cluster 11 showed high levels of FADS2 and FASN. The percentages of cells in these two clusters significantly increased in AK compared with normal tissues. The existence and spatial localization of AK-specific IL1R2+WFDC2+ cluster were verified by immunohistochemical and immunofluorescence staining. Functional studies indicated that the genes identified in the IL1R2+WFDC2+ cluster were crucial for epithelial cell proliferation, migration, and angiogenesis. Further immunofluorescent staining revealed the interactions between AK-specific keratinocytes and secretory-papillary fibroblasts mainly through ANGPTL4-ITGA5 signalling pathway rarely seen in normal tissues. The findings of this study might help better understand AK pathogenesis. Show less
X Wang, M Li, Y Hu · 2023 · Physiological research · added 2026-04-24
The aberrantly expressed microRNAs (miRNAs) including miR-29c-3p have been reported in the brains of Alzheimer's disease (AD) patients in recent researches. Nevertheless, the functional role and under Show more
The aberrantly expressed microRNAs (miRNAs) including miR-29c-3p have been reported in the brains of Alzheimer's disease (AD) patients in recent researches. Nevertheless, the functional role and underlying molecular mechanism of miR-29c-3p in AD pathogenesis are still not well elucidated. The purpose of this study was to examine whether miR-29c-3p regulated beta-Ameyloid (Abeta)-induced neurotoxicity by targeting beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). The expressions of miR 29c 3p and BACE1 mRNA and protein levels in Abeta-treated PC12 cellular AD model were examined by qRT-PCR and western blot analyses. Luciferase reporter assay verified the potential target of miR 29c 3p. Cell viability, apoptosis, and caspase-3 activity in PC12 cells were detected by the MTT assay, flow cytometry, and caspase-3 activity assay, respectively. Our results indicated that miR-29c-3p downregulation and BACE1 upregulation existed in the cellular AD model of PC12 cells. Moreover, miR-29c-3p directly inhibited BACE1 expression. miR-29c-3p overexpression and BACE1 knockdown strengthened Abeta-induced cell apoptosis, and caspase-3 activity in PC12 cells, which was partially eliminated by over-expression of BACE1. Conversely, BACE1 knockdown reversed the miR-29c-3p inhibition- mediated inhibitory effect on Abeta-induced cell toxicity, apoptosis, and caspase-3 activity in PC12 cells. Considering, miR-29c-3p attenuated Abeta-induced neurotoxicity through targeting BACE1 in an cellular AD model of PC12, providing a potential therapeutic target for AD treatment. Show less
Antibiotic misuse has been a severe problem in animal husbandry. It is meaningful to replace antibiotics with Bacillus, as feed additives are indeed a research hotspot. Bacillus pumilus plays a certai Show more
Antibiotic misuse has been a severe problem in animal husbandry. It is meaningful to replace antibiotics with Bacillus, as feed additives are indeed a research hotspot. Bacillus pumilus plays a certain role in promoting the growth performance and immunological indicators of animals. There are few reports about the function of goat-derived B. pumilus in animals until now. This study aimed to investigate the effects of B. pumilus fsznc-09 on growth performance and immune function of Jintang black goats. B. pumilus-treated group was fed with 1 ml freeze-dried agent of B. pumilus fsznc-09 at a concentration of 109 cfu/ml every 2 days. The growth performance, serum biochemical indexes, the expressions of muscle development and metabolism related genes of Jintang black goats were measured after 30 days. The results showed that the average daily gain and average daily feed intake were significantly increased, and feed conversion ratio was significantly decreased. The activities of total superoxide dismutase, alkaline phosphatase, immunoglobulin G and interferon-γ in serum of goats were significantly increased. However, the activity of malondialdehyde in serum was significantly decreased. The diameters and areas in longissimus dorsi fibre and gluteus fibre of goats were significantly decreased, while the densities in gluteus fibre of goats were significantly increased. The expressions of FAS, LPL, PPAR-γ, CAT, MYOD1, MYOG, MYF5 and MyHCI in longissimus dorsi and gluteus of goats were significantly improved. The expressions of TGFβ1, SREBP-1, MyHCIIb and MyHCIIx in longissimus dorsi and gluteus of goats were significantly increased. The expressions of FN1 in longissimus dorsi and MyHCIIa in gluteus of goats were significantly decreased. In conclusion, B. pumilus fsznc-09 can effectively improve the growth performance, immunological indicators and the expressions of muscle development and metabolism related genes of Jintang black goat. Show less
The relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (P Show more
The relationships of the rs17782313 polymorphism near melanocortin 4 receptor gene (MC4R) and the rs8192678 polymorphism in peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (PGC1α) with metabolic abnormalities have been explored in many populations around the world, but the findings were not all consistent and sometimes even a bit contradictory. Electronic databases including Medline, Scopus, Embase, Web of Science, CNKI and Google Scholar were checked for studies that met the inclusion criteria. Data were carefully extracted from eligible studies. Standardized mean differences (SMDs) were calculated by using a random-effects model to examine the differences in the indexes of obesity, glucometabolic disorder and dyslipidemia between the genotypes of the rs17782313 and rs8192678 polymorphisms. Cochran's Q-statistic test and Begg's test were employed to identify heterogeneity among studies and publication bias, respectively. Fifty studies (58,716 subjects) and 51 studies (18,660 subjects) were respectively included in the pooled meta-analyses for the rs17782313 and rs8192678 polymorphisms. The C-allele carriers of the rs17782313 polymorphism had a higher average level of body mass index (SMD = 0.21 kg/m The meta-analysis demonstrates that the C allele of the MC4R rs17782313 polymorphism confers a higher risk of obesity and hyperglycemia, and the PGC1α rs8192678 polymorphism is weakly correlated with glucometabolic disorder. These findings may partly explain the relationships between these variants and diabetes as well as cardiovascular disease. https://www.crd.york.ac.uk/prospero/, identifier CRD42022373543. Show less
Diabetes has been regarded as an independent risk factor for Alzheimer's disease (AD). Our previous study found that diabetes activated autophagy, but lysosome function was impaired. Autophagy-lysosom Show more
Diabetes has been regarded as an independent risk factor for Alzheimer's disease (AD). Our previous study found that diabetes activated autophagy, but lysosome function was impaired. Autophagy-lysosome dysfunction may be involved in Aβ deposition in diabetic cognitive impairment. In the present study, we used STZ-induced diabetic rats and SH-SY5Y cells to investigate whether diabetes inhibits autophagosome fusion with lysosomes. We found that in the in vivo study, STZ-induced diabetic rats exhibited cognitive dysfunction, and the lysosome function-related factors CTSL, CTSD, and Rab7 were decreased (P < 0.05). In an in vitro study, the mRFP-GFP-LC3 assay showed that the fusion of autophagosomes with lysosomes was partly blocked in SH-SY5Y cells. High glucose treatment downregulated the number of autophagolysosomes, downregulated CTSD, CTSL, and Rab7 expression (P < 0.05), and then influenced the function of ACP2 to partly block the fusion of autophagosomes and lysosomes to inhibit Aβ clearance. These findings indicate that high glucose treatment affected lysosome function, interfered with the fusion of autophagosomes with lysosomes, and partly blocked autophagic flux to influence Aβ clearance. 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
The Yangtze River Delta white goats are the sole goat breed producing brush hair of high quality. Owing to the particularities of its wool production, a higher demand is placed on breeding efforts for Show more
The Yangtze River Delta white goats are the sole goat breed producing brush hair of high quality. Owing to the particularities of its wool production, a higher demand is placed on breeding efforts for this animal. Studies on the developmental mechanisms of the aligned hair follicle stem cells (HFSCs) provide a theoretical basis for molecular breeding. In the present study, HFSCs were isolated using the technique of immunohistochemistry from the cervical spinal skin tissue samples from the fetal sheep, and the miR-133a-3p expression was confirmed using quantitative reverse-transcription PCR (RT-qPCR) and western blotting experiments from the isolated HFSCs. Additionally, the effects on the proliferation and apoptosis of HFSCs were detected using flow cytometry and 5-ethynyl-2'-deoxyuridine assays, along with other methods, following the overexpression of miR-133a-3p or its inhibition. The experimental results revealed that miR-133a-3p overexpressed could inhibit the proliferation of HFSCs and promote apoptosis by specifically targeting DUSP6. While the miR-133a-3p knockdown could promote the proliferation but inhibit the apoptosis of the HFSCs. Meanwhile, the miR-133a-3p knockdown experiments showed opposite outcomes. These results illustrate the presence of a relevant network between Show less
Tendinopathy is a disease with surging prevalence. Lacking understanding of molecular mechanisms impedes the development of therapeutic approaches and agents. Lysine lactylation (Kla) is a newly disco Show more
Tendinopathy is a disease with surging prevalence. Lacking understanding of molecular mechanisms impedes the development of therapeutic approaches and agents. Lysine lactylation (Kla) is a newly discovered post-translational modification related to glycolysis. It has long been noted that manipulation of glycolysis metabolism could affect tendon cell function, tendon homeostasis, and healing process of tendon. However, protein lactylation sites in tendinopathy remain unexplored. Here, we conducted the first proteome-wide Kla analysis in tendon samples harvested from patients with rotator cuff tendinopathy (RCT), which identified 872 Kla sites across 284 proteins. Compared with normal counterparts, 136 Kla sites on 77 proteins were identified as upregulated in the pathological tendon, while 56 sites on 32 proteins were downregulated. Function enrichment analysis demonstrated that the majority of proteins with upregulated Kla levels functioned in organization of the tendon matrix and cholesterol metabolism, accompanied by lower expression levels which meant impaired cholesterol metabolism and degeneration of the tendon matrix, indicating potential cross-talk between protein lactylation and expression levels. At last, by western blotting and immunofluorescence, we verified the correlation between high lactylation and the downregulation of matrix and cholesterol-related proteins including BGN, MYL3, TPM3, and APOC3. ProteomeXchange: PXD033146. Show less
Nanoplastics and di(2-ethylhexyl) phthalate (DEHP) are ubiquitous emerging contaminants that are transferred among organisms through food chain in the ecosystem. This study evaluated the trophic trans Show more
Nanoplastics and di(2-ethylhexyl) phthalate (DEHP) are ubiquitous emerging contaminants that are transferred among organisms through food chain in the ecosystem. This study evaluated the trophic transfer of polystyrene nanoplastics (PSNPs) and DEHP in a food chain including Chlorella pyrenoidosa, Daphnia magna and Micropterus salmoides (algae-crustacean-fish) and lipid metabolism at a higher trophic level in fish. Our results showed that the PSNPs and DEHP accumulated in C. pyrenoidosa or D. magna were transferred to the M. salmoides, of which the DEHP were not biomagnified, while the PSNPs were trophically amplified by the food chain. It is suggested that more PSNPs might be accumulated by higher level consumers in a longer food chain. Additionally, the trophic transfer of PSNPs and DEHP resulted in antioxidant response and histopathological damage in M. salmoides. Moreover, the lipid biochemical parameters and lipid metabolism related genes (fasn, hsl, cpt1a, atgl, apob, fabp1, lpl, cetp) of M. salmoides were significantly affected, which indicated disturbance of lipid metabolism. This study offers great insight into the transfer of contaminants by trophic transfer and their negative effects on organisms at higher trophic levels, which cause human exposure to MNPs and organic contaminants in the ecosystem. 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
Our previous study found that increased serum IL-27 could promote rheumatoid arthritis (RA) B cell dysfunction via activating mTOR signaling pathway. This study aimed to explore the effects of IL-27 o Show more
Our previous study found that increased serum IL-27 could promote rheumatoid arthritis (RA) B cell dysfunction via activating mTOR signaling pathway. This study aimed to explore the effects of IL-27 on B cell metabolism and clarify the mechanisms via which IL-27 enhancing glycolysis to induce B cells hyperactivation. Peripheral CD19 Show less
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
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
The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflamm Show more
The pathogenesis of rheumatoid arthritis (RA) is an immune imbalance, in which various inflammatory immune cells and pro-inflammatory factors are involved. Interleukin-17 (IL-17), a potent pro-inflammatory cytokine, has been found to have increased expression in the joints of patients with RA compared to healthy individuals. However, the causal relationship between the expression level of IL-17 or IL-17 receptor (IL-17R) and RA remained unknown. In this study, two-sample Mendelian randomization (MR) was used to investigate the causal relationship between IL-17 and RA. Summary statistics for RA (14,361 RA cases and 43,923 healthy controls) and IL-17 (3,301 samples) were obtained from an available meta-analysis of published genome-wide association studies (GWAS). Relevant single nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. Then we used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality. MR and MVMR analyses progressed mainly using inverse variance weighted (IVW), weighted median (WM), and MR-Egger regression methods, which were applied to the genetic instrumental variables (IVs) of IL-17A/IL-17 RA, IL-17C/IL-17 RC, and IL-17D/IL-17RD and RA. For assessing the robustness of the results, we also carried out a sensitivity analysis to assess heterogeneity and pleiotropy, such as MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO). Two-sample MR Analysis showed the causal relationship between IL-17A/IL-17RA and RA. The presence of genetically high IL-17A/IL-17RA may increase the risk of RA (IL-17A(OR = 1.095; 95% C.I., 0.990-1.210, p.adj = 0.013), IL-17RA(OR = 1.113, 95%CI = 1.006-1.231, p.adj = 0.006)). However, the results indicated that IL-17C/IL-17RC, and IL-17D/IL-17RD demonstrated no causal impact on RA (IL-17C(OR = 1.007, 95%CI = 0.890-1.139, p.adj = 0.152), IL-17RC(OR = 1.006, 95%CI = 0.904-1.119, p.adj = 0.152), IL-17D(OR = 0.979, 95%CI = 0.843-1.137, p.adj = 0.130), IL-17RD(OR = 0.983, 95%CI = 0.876-1.104, p.adj = 0.129)). Furthermore, MVMR analysis shown that IL-17RA(OR = 1.049, 95% CI: 0.997-1.102, p.adj = 0.014) was associated with increased risk of RA. Sensitivity analysis showed no heterogeneity and pleiotropy, suggesting that the above results were robust and reliable. The MR analysis provides evidence that IL-17A/IL-17RA are risk factors for RA. This emphasizes the importance of intervention on IL-17A/IL-17RA in patients with RA. Developing drugs that limit IL-17A may reduce the risk of RA. Show less