Ruotong Li, Wenye Zhao, Jiaxin Zhang+7 more · 2025 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
The global increase in muscle weakness poses a critical public health concern. Nutritional interventions that improve muscular function hold promise as a therapeutic potential. Vitamin A (VA) and its Show more
The global increase in muscle weakness poses a critical public health concern. Nutritional interventions that improve muscular function hold promise as a therapeutic potential. Vitamin A (VA) and its active metabolites have been implicated in muscle development and the transformation of muscle fiber types. However, conventional VA formulations are restricted by poor stability and low bioavailability. In this study, a stable Nano VA was utilized to systematically evaluate its effects on muscle development and exercise performance in mice, as well as to explore its underlying mechanisms. A total of 44 male C57BL/6J mice were randomly divided into four groups: (i) normal control (NC), (ii) 5 mg/kg Nano VA (5 NVA), (iii) 10 mg/kg Nano VA (10 NVA), and (iv) 10 mg/kg VA (10 VA). The 10 NVA group demonstrated significantly improved muscle strength and swimming endurance, compared with the NC group. Further examination suggested a significant increase in myofiber diameter, cross-sectional area, and the content of fast-twitch fibers. Additionally, Nano VA treatment improved glucose tolerance and insulin sensitivity. To elucidate the mechanism by which Nano VA enhances muscle locomotor ability, transcriptomics and metabolomics data identified 111 differentially expressed genes and 253 differential metabolites. Of these, Angptl4, Ppp1r3a, and Cyp26b1 were identified as candidate regulators of muscle development and myofiber type transformation. In conclusion, Nano VA regulates muscle development and promotes muscle fiber type conversion, thus improving muscle strength and endurance in mice. Moreover, Nano VA facilitates mitigating and improving myasthenia gravis-related conditions. Show less
Angiopoietin-like 4 (ANGPTL4) expression is increased in wound tissue and contributes to wound healing. However, the underlying mechanisms are not fully understood. Here, we demonstrate that ANGPTL4 e Show more
Angiopoietin-like 4 (ANGPTL4) expression is increased in wound tissue and contributes to wound healing. However, the underlying mechanisms are not fully understood. Here, we demonstrate that ANGPTL4 expression is significantly increased in epidermal stem cells (EpSCs) in the periwound epidermis during wound healing in mice. Increased Angptl4 expression is positively correlated with increased expressions of tumor growth factor-α, interleukin-1β, epidermal growth factor, nerve growth factor, fibroblast growth factor 7, and transforming growth factor-β1. Each of these molecules induces Angptl4 expression in mouse EpSCs. RNA sequencing of EpSCs derived from wild-type and Angptl4 knockout (Angptl4 Show less
Animal models are used widely to study pulmonary hypertension (PH). The cell populations that respond to disease-inducing stimuli in these models and their relationship to human disease remain incompl Show more
Animal models are used widely to study pulmonary hypertension (PH). The cell populations that respond to disease-inducing stimuli in these models and their relationship to human disease remain incompletely defined. This study analyzed the relationship between several rodent models of PH and human disease at single-cell resolution. scRNA-seq was performed on lungs from mice exposed to hypoxia or Sugen/hypoxia, rats exposed to monocrotaline, and controls. A cross-species single-cell dataset was integrated with human lung cell atlas (HLCA) and single-cell dataset from idiopathic pulmonary arterial hypertension (IPAH) to identify overlapping cell subsets between experimental and human disease and species. High levels of overlap were found between species and models of PH, HLCA, and IPAH datasets. Cell subsets perturbed in rat and mouse PH were similar to those found in human disease, with macrophages and endothelial cells being most affected. A novel We established a comprehensive cross-species single-cell atlas of mainstream rodent PH models, highlighting several novel macrophage and endothelial subtypes and signaling motifs potentially contributing to human disease. Show less
The adipocyte-rich tumor microenvironment (TME) is recognized as a key factor in promoting cancer progression. A distinct characteristic of peritumoral adipocytes is their reduced lipid content and th Show more
The adipocyte-rich tumor microenvironment (TME) is recognized as a key factor in promoting cancer progression. A distinct characteristic of peritumoral adipocytes is their reduced lipid content and the acquisition of a proinflammatory phenotype. However, the underlying mechanisms by which adipocytes rewire metabolism and boost tumor progression in triple-negative breast cancer (TNBC) remain poorly understood. We utilized transcriptomic analysis, bioinformatic analysis, metabolic flux analysis, protein-protein docking, gene and protein expression profiling, in vivo metastasis analysis and breast cancer specimens to explore how adipocytes reprogram tumor metabolism and progression in TNBC. Our findings reveal that Angiopoietin-like 4 (ANGPTL4) exhibits significantly higher expression levels in adipocyte-rich tumor circumstance compared to the symbiotic environment lacking of adipocyte. Furthermore, ANGPTL4 expression in tumor cells is essential for adipocyte-driven glycolysis and metastasis. Interleukin 6 (IL-6), enriched in cancer-associated adipocytes, and lipolysis-derived free fatty acids (FFAs) released from adipocytes, amplify ANGPTL4-mediated glycolysis and metastasis through activation of STAT3 and PPARα pathways in TNBC cells. Additionally, ANGPTL4 interacts with transcription factor KLF4 and enhances KLF4 activity, which further drives glycolysis and metastasis, whereas KLF4 knockdown attenuates migration and glycolysis in TNBC cells. Importantly, Elevated ANGPTL4 and KLF4 expression was observed in metastatic breast cancer specimens compared to non-metastatic cases and was positively correlated with poor prognosis. Collectively, our results uncover a complex metabolic interaction between adipocytes and TNBC cells that promotes tumor aggressiveness. ANGPTL4 emerges as a key mediator in this process, making it a promising therapeutic target to inhibit TNBC progression. Show less
The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced Show more
The prognosis for colorectal cancer (CRC) patients with liver metastasis remains poor, and the molecular mechanisms driving CRC liver metastasis are not fully understood. Tumor-derived hypoxia-induced extracellular vesicles have emerged as key players in inducing angiogenesis by transferring noncoding RNAs. However, the specific role of CRC-derived hypoxic extracellular vesicles (H-EVs) in regulating premetastatic microenvironment (PMN) formation by inducing angiogenesis remains unclear. Our study demonstrates that H-EVs induce angiogenesis and liver metastasis. Through microRNA microarray analysis, we identified a reduction in miR-6084 levels within H-EVs. We found that miR-6084 inhibited angiogenesis by being transferred to endothelial cells via EVs. In endothelial cells, miR-6084 directly targeted angiopoietin like 4 (ANGPTL4) mRNA, thereby suppressing angiogenesis through the ANGPTL4-mediated JAK2/STAT3 pathway. Furthermore, we uncovered that specificity protein 1 (SP1) acted as a transcription factor regulating miR-6084 transcription, while hypoxia-inducible factor 1A (HIF1A) decreased miR-6084 expression by promoting SP1 protein dephosphorylation and facilitating ubiquitin-proteasome degradation in SW620 cells. In clinical samples, we observed low expression of miR-6084 in plasma-derived EVs from CRC patients with liver metastasis. In summary, our findings suggest that CRC-derived H-EVs promote angiogenesis and liver metastasis through the HIF1A/SP1/miR-6084/ANGPTL4 axis. Additionally, miR-6084 holds promise as a diagnostic and prognostic biomarker for CRC liver metastasis. Show less
Hyperlipidemia is a common metabolic disorder and a risk factor for cardiovascular disease. The traditional medicine herb, Hippophae rhamnoides L., known as sea buckthorn, has anti-obesity and lipid-l Show more
Hyperlipidemia is a common metabolic disorder and a risk factor for cardiovascular disease. The traditional medicine herb, Hippophae rhamnoides L., known as sea buckthorn, has anti-obesity and lipid-lowering effects, while Silybum marianum (L.) Gaertn, known as milk thistle, has hepatoprotective properties and exhibits antioxidant effects. To evaluate the effect of sea buckthorn and milk thistle solid beverage (H-S solid beverage) in alleviating hyperlipidemia in rats and explore the underlying mechanisms by analyzing plasma and liver metabolomics, lipidomics, and liver transcriptomics. A hyperlipidemic rat model was established after 2 weeks of high-fat diet (HFD) feeding in Sprague Dawley rats. The administered doses of H-S solid beverage were 0.30 g/kg/d, 0.15 g/kg/d and 0.075 g/kg/d. Serum biochemical parameter detection, histopathological section analysis, untargeted plasma and liver metabolomics, lipidomics, and liver transcriptomics were performed to determine the therapeutic effects of H-S solid beverage and predict the related pathways in rats with hyperlipidemia. Changes in genes and proteins related to lipid metabolism were detected using real-time quantitative polymerase chain reaction and western blotting. Eighty-nine components were identified in H-S solid beverage using ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry, with flavonoids being the major constituents. The H-S solid beverage significantly reduced body weight, liver index, body fat percentage, lipid accumulation, and liver injury in HFD-fed rats. Fatty acids (FA), bile acid, phosphatidyl ethanolamine, phosphatidylcholine, triglyceride, cholesterol ester, diglyceride and phosphatidylinositol levels were significantly altered in the liver and plasma. Moreover, the transcriptomic analysis suggested that H-S solid beverage significantly altered the hepatic gene expression of cholesterol synthesis (Pdk4, Hmgcs1, and Dhcr24), lipogenesis (Scd, Angptl4, and Angptl8), and FA β-oxidation (Cpt1α, Pparδ, Acsl, Pgc-1α, and Pla2g2d). The solid beverage of sea buckthorn and milk thistle was firstly demonstrated to ameliorate HFD-induced hyperlipidemia. The lipid-lowering and hepatoprotective effects of H-S solid beverage significantly regulated cholesterol synthesis and de novo lipogenesis, as well as FA β-oxidation. In summary, this study highlights the potential of H-S solid beverages for the treatment of hyperlipidemia. Show less
Male germline development is crucial for the proper establishment of spermatogonial stem cell pool and life-long production of spermatozoa, but the full-term developmental profiling of human male germ Show more
Male germline development is crucial for the proper establishment of spermatogonial stem cell pool and life-long production of spermatozoa, but the full-term developmental profiling of human male germline is not fully understood. Here, by integrating 92,488 human testicular cells spanning from six-week-old embryos to old men, we constructed a comprehensive human male germ cell atlas. Further analysis found that the precursor of undifferentiated spermatogonia underwent regulatory network reconfiguration starting from week 7 post-fertilization, accompanied by WNT6-FZD3/LRP6-JUN/MYC signaling axis. And JUN and MYC were revealed to be candidate core transcription factors that might inhibit spermatogonia differentiation. In addition, the activation of ANGPTL signaling played a role in the maintenance of human spermatogonial stem cells. Finally, by interrogating the scRNA-seq datasets from idiopathic non-obstructive azoospermia (iNOA) patients, we identified several iNOA-dysregulated genes such as CAPN3, FTMT, IZUMO2 and LACE1, which were significantly down-regulated in round spermatids of iNOA patients. Collectively, our work established an atlas of human male germ cell development, revealing the factors that might regulate male germline development and providing iNOA-dysregulated genes for future clinical diagnosis. Show less
To investigate the key regulatory genes and pathways related to growth traits in the Dongtingking crucian carp (Carassius auratus indigentiaus), the transcriptomes of brain, intestine, and muscle tiss Show more
To investigate the key regulatory genes and pathways related to growth traits in the Dongtingking crucian carp (Carassius auratus indigentiaus), the transcriptomes of brain, intestine, and muscle tissues were sequenced at early juvenile stage using RNA-Seq from two groups with extreme growth rates (fast-growing and slow-growing). A total of 65, 184, and 130 differentially expressed genes (DEGs) were detected in the brain, intestine, and muscle, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis highlighted that the PPAR signaling pathway, Insulin/PI3K/Akt/mTOR/FoxO/AMPK pathway, and Protein digestion and absorption pathways are crucial for growth in this species. Based on the transcriptome data, 32 key DEGs were identified, mainly participating in processes such as cell proliferation and differentiation, growth, development, and metabolism. Prominent examples are cyclic AMP-responsive element-binding protein 5 (creb5b), forkhead box protein O1-A (foxo1a), transcription factor AP-1-like (jun), lipoprotein lipase-like (lpl), angiopoietin-like 4 (angptl4), and egl nine homolog 3-like (egln3). This study enhances the understanding of the genetic factors and regulatory mechanisms responsible for variations in growth rates and provides a valuable basis for further studies on the regulatory mechanisms of growth in C. auratus indigentiaus. Show less
Hypertriglyceridemia, characterized by increased triglyceride (TG) concentrations, is considered the most important risk factor for cardiometabolic disorders, including dyslipidemia, atherosclerotic c Show more
Hypertriglyceridemia, characterized by increased triglyceride (TG) concentrations, is considered the most important risk factor for cardiometabolic disorders, including dyslipidemia, atherosclerotic cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). Recently, the angiopoietin-like protein (ANGPTL) family, which comprises ANGPTL1 to ANGPTL8, was confirmed to play an important role in modulating lipoprotein lipase (LPL) activity. However, understanding of the underlying mechanisms remains limited. Importantly, emerging evidence has linked several transcriptional and post-transcriptional factors to the potential alteration of TG metabolism via ANGPTL proteins. This review focused on the similarities and differences in the expression, structural features, and modulatory profile of three ANGPTLs: ANGPTL3, ANGPTL4, and ANGPTL8. In addition, the regulatory functions of those three ANGPTLs in modulating LPL were summarized to provide potential therapeutic and clinical strategies for hypertriglyceridemia and its related cardiometabolic disorders. Show less
In recent years, accumulating evidence has highlighted the critical role of miR-627-5p in the occurrence and progression of various cancers. However, its specific role and mechanism in cervical cancer Show more
In recent years, accumulating evidence has highlighted the critical role of miR-627-5p in the occurrence and progression of various cancers. However, its specific role and mechanism in cervical cancer (CC) remain unclear. This study aimed to elucidate the mechanism by which miR-627-5p inhibits the malignant progression of CC and assess its potential clinical implications. In C33A cells, the mRNA expression levels of ANGPTL4 and miR-627-5p were analyzed using qRT-PCR. The miR-627-5p mimics and their control (miR-NC) were transfected into C33A cells to determine whether miR-627-5p directly regulates ANGPTL4 expression. A comprehensive suite of assays, including CCK-8, migration, transwell, flow cytometry, and Western blotting, was conducted to evaluate how miR-627-5p modulates the malignant biological behavior of CC cells. Rescue experiments were performed by overexpressing ANGPTL4. In C33A cells, miR-627-5p expression was reduced, whereas ANGPTL4 expression was elevated. Further analysis confirmed that miR-627-5p negatively regulates ANGPTL4 by directly targeting its 3'-UTR. Functional assays demonstrated that miR-627-5p inhibits proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) while promoting apoptosis and S-phase arrest in C33A cells, effects that were reversed by ANGPTL4 overexpression. These findings highlight the potential of miR-627-5p as both a biomarker and a therapeutic target for CC. By inhibiting EMT and regulating ANGPTL4 expression, miR-627-5p may provide a novel avenue for improving therapeutic strategies, particularly in advanced or metastatic CC. Moreover, miRNA-based therapies, supported by advanced delivery systems such as nanoparticle carriers, could enhance the stability and precision of miR-627-5p applications. This study lays the groundwork for future research integrating miR-627-5p into precision medicine approaches for CC treatment. Show less
Cervical carcinoma (CC) remains a significant global health issue despite advancements in screening and treatment. To improve prognostic accuracy and therapeutic strategies, we developed a multi-machi Show more
Cervical carcinoma (CC) remains a significant global health issue despite advancements in screening and treatment. To improve prognostic accuracy and therapeutic strategies, we developed a multi-machine learning prognostic model based on metabolic-associated genes. This study integrated genomic, transcriptomic, and spatial data from multiple databases to identify key metabolic genes with a causal relationship to CC. We identified 112 key metabolic genes, which were used to construct and validate a prognostic model through various machine learning algorithms. GO and KEGG enrichment analysis revealed the MAPK cascade plays a crucial role in metabolic processes. To pinpoint key metabolic genes, we constructed WGCNA and extracted 337 key genes. Supervised principal component analysis and random survival forests were incorporated into the final model, which showed strong predictive ability in classifying patients. Furthermore, the model demonstrated notable variations in immune cell infiltration among risk categories, which shown regulatory T cells may be involved in immune suppression, and natural killer cells might have a limited effect in tumor clearance. Spatial transcriptomics and single-cell analyses further validated the model, uncovering tumor heterogeneity and distinct intercellular communication patterns associated with different risk levels. The functional experiment results indicated that down expression of PLOD3 could suppress the proliferation of CC cell. In this study, offer a precision medicine methods for predicting patient outcomes as well as fresh insights into the metabolic foundations, which may contribute to the prognosis and immunotherapy of CC. Additionally, we discovered PLOD3 to be a novel oncogene in CC. These findings imply that this model may be applied to assess prognostic risk and identify potential therapeutic targets for CC patients. Show less
Lipoprotein lipase (LPL) participates in the development of obesity by regulating triglyceride hydrolysis and fat storage or oxidation. In this study, the anti-obesity effects of lotus seed skin catec Show more
Lipoprotein lipase (LPL) participates in the development of obesity by regulating triglyceride hydrolysis and fat storage or oxidation. In this study, the anti-obesity effects of lotus seed skin catechins and its mechanisms associated with LPL modulation were demonstrated. In vivo, catechins reduced body weight in high-fat diet-induced obese mice, improved lipid metabolism and antioxidant indices, and modulated LPL activity in adipose and skeletal muscle tissues. The expression of peroxisome proliferator-activated receptor γ (PPARγ) and (angiopoietin-like 4 proteins) ANGPTL4 mRNA and protein was significantly upregulated in epididymal fat depot but downregulated in skeletal muscle tissue. In vitro cell experiments and chromatin immunoprecipitation (ChIP) assays further revealed that the binding sites of PPARγ protein in the ANGPTL4 promoter region were enriched in adipocytes or reduced in skeletal muscle cells in response to catechin treatment. Therefore, lotus seed skin catechins exhibit anti-obesity activity in vivo and in vitro by specifically regulating the activity and expression of LPL in target tissues. Show less
Angiopoietin-like protein 4 (ANGPTL4) is critical for vascular integrity and reducing inflammation in ischemic and hypoxic brain injuries. However, limited studies have evaluated ANGPTL4's role in acu Show more
Angiopoietin-like protein 4 (ANGPTL4) is critical for vascular integrity and reducing inflammation in ischemic and hypoxic brain injuries. However, limited studies have evaluated ANGPTL4's role in acute ischemic stroke (AIS) assessment, and its expression patterns across AIS phases remain unclear. The severity of AIS at admission was assessed using the National Institutes of Health Stroke Scale (NIHSS). The association between serum ANGPTL4 level and the occurrence of AIS was examined using logistic regression analysis. The diagnostic accuracy of serum ANGPTL4 level for AIS severity was assessed using receiver operating characteristic curves. This study included 389 AIS patients and 133 healthy individuals. There was a notable increase in the occurrence of AIS associated with rising serum ANGPTL4 levels (odds ratio [OR] 1.03, 95% confidence interval [CI]: 1.02-1.06; p < 0.001). A higher serum level of ANGPTL4 was also found to be associated with severe AIS, as indicated by an AUC of 0.848. Additionally, we observed significant dynamic changes in ANGPTL4 levels, with a marked decrease at 1 week or 2 weeks after admission compared with the acute phase (the day after admission; both p < 0.001). Our findings suggest a robust association between elevated serum ANGPTL4 levels and the presence and severity of AIS. Importantly, this study is distinguished by its novel focus on the temporal dynamics of ANGPTL4 levels, which underscores its potential as a biomarker for AIS monitoring and provides new insights into AIS pathophysiology. Show less
Calcific aortic valve disease (CAVD) is characterized by progressive leaflet thickening and calcification, with no available pharmacological treatments. Plasma proteins play a pivotal role in disease Show more
Calcific aortic valve disease (CAVD) is characterized by progressive leaflet thickening and calcification, with no available pharmacological treatments. Plasma proteins play a pivotal role in disease regulation. This study aimed to uncover novel therapeutic targets for CAVD using Mendelian randomization (MR) integrated with transcriptomic analysis. Protein quantitative trait loci (pQTL) from the deCODE and UK Biobank Pharma Proteomics Project (UKB-PPP) plasma protein databases were used as exposure data. The FinnGen cohort (9870 cases, 402,311 controls) served as the discovery set, while the TARGET cohort (13,765 cases, 640,102 controls) provided validation. MR and summary data-based Mendelian randomization (SMR) were employed to screen for potential causal targets of CAVD. Colocalization analysis was conducted to assess whether CAVD and target proteins shared common causal SNPs. Additional analyses included trancriptomic profiling at multiple RNA levels. Protein-level validation was conducted via Western blot and immunostaining. Six proteins (ANGPTL4, PCSK9, ITGAV, CTSB, GNPTG, and FURIN) with strong genetic colocalization were identified by MR and SMR analysis. Among these, cellular trancriptomic analysis revealed ANGPTL4 and ITGAV with significantly greater expression in osteogenic group, which was further validated in calcified aortic valves and osteogenic valvular interstitial cells in protein level. This study identified six causal proteins with strong genetic colocalization for CAVD, with ANGPTL4 and ITGAV emerging as the most promising targets for further investigation. Show less
D-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported the diverse effects of D-2HG in pathophysiological processes, yet its role in Show more
D-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported the diverse effects of D-2HG in pathophysiological processes, yet its role in breast cancer remains largely unexplored. We applied an advanced biosensor approach to detect the D-2HG levels in breast cancer samples. We then investigated the biological functions of D-2HG through multiple in vitro and in vivo assays. A joint MeRIP-seq and RNA-seq strategy was used to identify the target genes regulated by D-2HG-mediated N6-methyladenosine (m We found that D-2HG accumulated in triple-negative breast cancer (TNBC), exerting oncogenic effects both in vitro and in vivo by promoting TNBC cell growth and metastasis. Mechanistically, D-2HG enhanced global m Our study unveils a previously unrecognized role for D-2HG-mediated RNA modification in TNBC progression and targeting the D-2HG/FTO/m Show less
Hepatocellular carcinoma (HCC) represents a particularly aggressive form of cancer, characterized by its rapid progression and a complex interplay with the surrounding immune cellular environment. The Show more
Hepatocellular carcinoma (HCC) represents a particularly aggressive form of cancer, characterized by its rapid progression and a complex interplay with the surrounding immune cellular environment. The primary objective of this study was to comprehensively investigate the role of ANGPTL4 in the context of HCC, utilizing RNA sequencing (RNA-seq) techniques to explore its impact on the M2 polarization of tumor-associated macrophages (TAM) and to uncover potential mechanisms driving HCC progression. To achieve this, we performed a transcriptome analysis of HCC cell lines, alongside cells obtained after co-culturing these lines with macrophages. By comparing gene expression profiles between the experimental groups exposed to ANGPTL4 and control groups, we aimed to identify specific molecular pathways associated with ANGPTL4's function. In addition to gene expression analysis, we employed flow cytometry to assess the polarization status of TAM. Furthermore, we utilized immunohistochemistry to evaluate the distribution of macrophages within HCC tissues and to quantify the expression levels of M2 macrophage markers. The results derived from RNA-seq analysis were particularly revealing; treatment with ANGPTL4 led to a significant upregulation of genes linked to M2 polarization, notably including CD206 and Arg1. In subsequent experimental observations, it became evident that ANGPTL4 not only facilitated the M2 polarization of macrophages but also enhanced the proliferation and migratory capacity of HCC cells through the upregulation of these same cytokines. Show less
Jiangliang Chu, Yifan Yang, Keyu Zhang+2 more · 2025 · Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association · Elsevier · added 2026-04-24
Polyethylene terephthalate microplastics (PET-MPs) have emerged as significant environmental pollutants with potential health risks. This study investigates the cytotoxic effects of PET-MPs on BEAS-2B Show more
Polyethylene terephthalate microplastics (PET-MPs) have emerged as significant environmental pollutants with potential health risks. This study investigates the cytotoxic effects of PET-MPs on BEAS-2B lung epithelial cells through integrated transcriptomic and metabolomic analyses. The results of the CCK8 assay showed a reduction in the viability of BEAS-2B cells following continuous exposure to PET-MPs. Transcriptomic analysis identified 1412 differentially expressed genes (DEGs) mainly enriched in apoptosis and extracellular matrix organization processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that these DEGs are predominantly involved in the PI3K-Akt, TNF, and MAPK signaling pathways. Metabolomic analysis identified 2869 differentially expressed metabolites (DEMs), mainly associated with pyrimidine, arginine, proline, and β-alanine metabolism pathways. Multi-omics analysis indicated that PET-MPs primarily disrupt lipid metabolism, which may lead to an increased risk of apoptosis. We hypothesize that PET-MPs affect lipid metabolism by up-regulating the ANGPTL4 gene, thereby promoting cellular apoptosis. This study reveals the mechanisms of PET-MPs toxicity, emphasizing the potential risks they pose to human health. Show less
The early detection of high-risk individuals is crucial to delay and reduce the incidence of type 2 diabetes. In this study, we aimed to explore the performance of a novel subgroup-specific biomarker Show more
The early detection of high-risk individuals is crucial to delay and reduce the incidence of type 2 diabetes. In this study, we aimed to explore the performance of a novel subgroup-specific biomarker strategy in the prediction of incident diabetes. In the Taiwan Lifestyle Cohort Study, adult subjects without diabetes were included and followed for the incidence of diabetes in 2006-2019. The biomarkers measured included blood secretogranin III (SCG3), vascular adhesion protein-1 (VAP-1), fibrinogen-like protein 1 (FGL1), angiopoietin-like protein 6 (ANGPTL6), and angiopoietin-like protein 4 (ANGPTL4). Among the 1,287 subjects, 12.2% developed diabetes during a 6 year follow-up. Blood VAP-1 was significantly associated with incident diabetes in the overall population (HR = 0.724, P < 0.05), participants under 65 years old (HR = 0.685, P < 0.05), those with a BMI of ≥24 kg/m Gender- and BMI-specific biomarker strategy can improve the prediction of incident diabetes. A subgroup-specific biomarker strategy is a novel approach in the prediction of incident diabetes. Show less
To date, glucocorticoids remain the mainstay of treatment of nephrotic syndrome (NS). However, serious side effects and development of drug-resistance following long-term use limit the application of Show more
To date, glucocorticoids remain the mainstay of treatment of nephrotic syndrome (NS). However, serious side effects and development of drug-resistance following long-term use limit the application of glucocorticoids. Protopanaxadiol (PPD) possesses activity of dissociating transactivation from transrepression by glucocorticoid receptor (GR), which may serve as a potential selective GR modulator. However, steroid-like effects of PPD in vivo are unclear and not defined. How to translate PPD into clinical practice remains to be explored. The current study explored the renoprotection and potential mechanism of PPD and its combination with steroid hormones using adriamycin-induced NS rats. Adriamycin was given intravenously to rats to induce nephropathy. The determination of proteinuria, biochemical changes and inflammatory cytokines were performed, and pathological changes were examined by histopathological examination. Immunostaining and PCR were used to analyze the expression of interesting proteins and genes. The results showed that PPD, alone and in combination with prednisone, efficiently alleviate the symptoms of NS, attenuate nephropathy, improve adriamycin-induced podocyte injury by reducing desmin and increasing synaptopodin expression. In addition, the combined treatment reduced the expression of NF-κB protein and mRNA, as well as cytokine levels, and yet increased the expression of GR protein and mRNA. PPD modulated the transactivation of GR, manifested as repressing TAT, PEPCK and ANGPTL4 mRNA expressions mediated by GR. Meanwhile, PPD inhibited elevation of blood glucose and immune organ atrophy induced by prednisone. In summary, PPD increases the therapeutic effect of prednisone in NS while effectively prevents or decreases the appearance of side effects of glucocorticoids. Show less
Colorectal cancer (CRC) is one of the leading causes of cancer-related death, and most CRCs arise from colorectal adenomas. Early detection and removal of precancerous lesions during the adenoma-carci Show more
Colorectal cancer (CRC) is one of the leading causes of cancer-related death, and most CRCs arise from colorectal adenomas. Early detection and removal of precancerous lesions during the adenoma-carcinoma sequence can significantly reduce CRC risk. However, current clinical practice lacks rapid, noninvasive screening tools for reliable adenoma detection. Proteomic analysis was performed on serum samples from patients with inflammatory polyps (non-neoplastic), patients with adenomas, and healthy controls to identify key differentially expressed proteins capable of distinguishing adenoma patients. The alterations in these candidate proteins were further validated by ELISA to evaluate their potential as diagnostic biomarkers for colorectal adenoma. In two independent cohorts, we identified two candidate biomarkers, apolipoprotein A4 (APOA4) and filamin A (FLNA), through a multi-step selection process involving ANOVA p-value screening, sparse partial least squares discriminant analysis (sPLS-DA), and LASSO regression analysis. These candidates were subsequently validated in a third cohort using ELISA. The ELISA results for APOA4 were discordant with the liquid chromatography-tandem mass spectrometry (LC-MS/MS) findings. In contrast, FLNA levels measured by ELISA showed a progressive decrease from healthy controls to patients with inflammatory polyps and further to those with adenomas. We propose FLNA as a potential biomarker for the diagnosis of colorectal adenomas. The areas under the ROC curves exceeded 0.7 for both key clinical comparisons: 0.810 for adenomas versus healthy controls, and 0.734 for adenomas versus inflammatory polyps. Overall, this study not only enhances our understanding of the serum proteome in colorectal adenoma but also identifies FLNA as a promising biomarker for its clinical diagnosis. Show less
The escalating prevalence of diabetes-depression comorbidity (DDC) necessitates novel therapies targeting shared pathophysiological pathways, which needs to decipher the underlying molecular mechanism Show more
The escalating prevalence of diabetes-depression comorbidity (DDC) necessitates novel therapies targeting shared pathophysiological pathways, which needs to decipher the underlying molecular mechanisms. This study elucidates the therapeutic potential of chrysophanol, a natural anthraquinone, in streptozotocin (STZ) and chronic unpredictable mild stress (CUMS)-induced DDC rat model. Behavioral assessments, biochemical profiling, and integrated multi-omics analyses (RNA-seq and proteomics) were employed to decipher underlying mechanisms. Successful model establishment was confirmed by prolonged immobility time in the tail suspension test (p < 0.01) and reduced general health scores. Chrysophanol treatment restored serum brain-derived neurotrophic factor (BDNF) levels (p < 0.01) and ameliorated dyslipidemia (total cholesterol: p < 0.05). RNA-seq results revealed that chrysophanol regulated expression of hundreds of genes, which were enriched in synaptic vesicle cycling (downregulation of Sh3gl2, Camk5), CNS myelination, and axonal ensheathment pathways. Proteomic profile demonstrated the suppression of neurodegenerative markers and activation of axonal regeneration pathways. Notably, chrysophanol downregulated synaptic proteins associated with leukocyte chemotaxis (Pla2g7, Mdk) and glutamatergic synapses (Itpr2, Slc1a1) while upregulated axonal development, regeneration, and PPARγ signaling proteins (Apoa4, Apoa1, Apod), suggesting anti-inflammatory effects and disease-modifying potential through synaptic/axonal regulation. Integrated multi-omics identified overlapping targets linked to neuronal repair (Ankrd27) and iron metabolism (Fth1). These findings suggest chrysophanol as a multitarget agent alleviating DDC via synergistic restoration of neuroplasticity, suppression of neuroinflammation, and rebalancing of metabolic homeostasis, implying a mechanistic foundation for developing chrysophanol-based therapies of diabetes-associated neuropsychiatric disorders. Show less
The seven-transmembrane (7TM) receptors are the largest superfamily of cell-surface receptors and are involved in various physiological processes of vertebrate species. In our previous study, a new ch Show more
The seven-transmembrane (7TM) receptors are the largest superfamily of cell-surface receptors and are involved in various physiological processes of vertebrate species. In our previous study, a new chicken 7TM receptor (Ch-7TM) was discovered in mononuclear phagocytes (MNPs) derived from chicken peripheral blood mononuclear cells (PBMCs). To explore the functions of Ch-7TM, RNA interference (RNAi) was used to silence the Ch-7TM messenger RNA (mRNA) of MNPs, using small interfering RNA (siRNA) designed with BLOCK-iT™ RNAi Designer. Herein we demonstrated that silencing of the Ch-7TM mRNA induced apoptosis of MNPs, suggesting that Ch-7TM contributed to the survival of MNPs. Moreover, chicken sera could inhibit the Ch-7TM-silencing-induced apoptosis in MNPs. The survival factor presented in fraction 16 (F16) of chicken sera was highly protective against the Ch-7TM-silencing-induced apoptosis in MNPs. The proteins from F16 were identified as vitamin D-binding protein (DBP) and apolipoprotein A-IV (ApoA-IV), which might be potential candidates for survival factors. The protective effect of vitamin D and ApoA-IV indicated that Ch-7TM might involve the intracellular oxidation-reduction balance, although more evidence is needed to confirm this function. The siRNA screening serves as an excellent model for studying the functions of chicken MNPs receptors. Show less
The dysregulation of hepatic lipid metabolism is closely associated with dyslipidemia. Previous research suggested that Hepatic Data regarding circulating lipid traits and hepatic Hepatic This study i Show more
The dysregulation of hepatic lipid metabolism is closely associated with dyslipidemia. Previous research suggested that Hepatic Data regarding circulating lipid traits and hepatic Hepatic This study identifies Show less
Pulmonary nodule with diameters ranging 8-30 mm has a high occurrence rate, and distinguishing benign from malignant nodules can greatly improve the patient outcome of lung cancer. However, sensitive Show more
Pulmonary nodule with diameters ranging 8-30 mm has a high occurrence rate, and distinguishing benign from malignant nodules can greatly improve the patient outcome of lung cancer. However, sensitive and specific liquid-biopsy methods have yet to achieve satisfactory clinical goals. We enrolled three cohorts and a total of 185 patients diagnosed with benign (BE) and malignant (MA) pulmonary nodules. Utilizing data-independent acquisition (DIA) mass spectrometry, we quantified plasma proteome from these patients. We then performed logistic regression analysis to classify benign from malignant nodules, using cohort 1 as discovery data set and cohort 2 and 3 as independent validation data sets. We also developed a targeted multi-reaction monitoring (MRM) method to measure the concentration of the selected six peptide markers in plasma samples. We quantified a total of 451 plasma proteins, with 15 up-regulated and 5 down-regulated proteins from patients diagnosed as having malignant nodules. Logistic regression identified a six-protein panel comprised of APOA4, CD14, PFN1, APOB, PLA2G7, and IGFBP2 that classifies benign and malignant nodules with improved accuracy. In cohort 1, the area under curve (AUC) of the training and testing reached 0.87 and 0.91, respectively. We achieved a sensitivity of 100%, specificity of 40%, positive predictive value (PPV) of 62.5%, and negative predictive value (NPV) of 100%. In two independent cohorts, the 6-biomarker panel showed a sensitivity, specificity, PPV, and NPV of 96.2%, 35%, 65.8%, and 87.5% respectively in cohort 2, and 91.4%, 54.2%, 74.4%, and 81.3% respectively in cohort 3. We performed a targeted LC-MS/MS method to quantify plasma concentration of the six peptides and applied logistic regression to classify benign and malignant nodules with AUC of the training and testing reached 0.758 and 0.751, respectively. Our study identified a panel of plasma protein biomarkers for distinguishing benign from malignant pulmonary nodules that worth further development into a clinically valuable assay. Show less
Cold stress poses a significant challenge to pig farming in northern China, leading to reduced productivity and, in severe cases, even mortality. However, the mechanisms underlying cold resistance in Show more
Cold stress poses a significant challenge to pig farming in northern China, leading to reduced productivity and, in severe cases, even mortality. However, the mechanisms underlying cold resistance in pigs are not well understood. To explore the genetic mechanism of cold resistance in pigs under low-temperature conditions, the cold-tolerant Hezuo pig was selected as a model. DIA proteomics analysis was performed on liver tissues from Hezuo pigs after 24 h of exposure to low-temperature treatments. The results showed that approximately 149 differential abundance proteins (DAPs) were detected (95 up-regulated and 54 down-regulated). GO analysis showed that these DAPs were mainly associated with lipid metabolism, vesicle fusion, and membrane function. KEGG analysis showed that these DAPs were primarily enriched in lipid metabolism-related pathways such as cholesterol metabolism and vitamin digestion and absorption. Comprehensive analysis identified APOA4, APOA2, SREBF2, ATP23, STX2, USO1, ETFA, RAB11FIP1, ETNPPL, and SGMS1 as potential key proteins involved in cold resistance mechanisms. The mRNA expression of the genes for two key candidate proteins (APOA4 and SREBF2), which are involved in lipid metabolism, was analyzed using qRT-PCR, revealing a significant up-regulation after low-temperature treatment. These findings provide significant insights into the mechanisms of cold resistance in animals and may serve as candidate markers for further studies on cold tolerance. SIGNIFICANCE: Cold resistance is one of the key traits in pigs and involves multiple complex coordinated regulatory mechanisms. However, its genetic mechanisms are not completely understood. In this study, a DIA proteomics approach was used to identify proteins and pathways associated with cold resistance in the liver of low-temperature-treated Hezuo pigs. These findings offer novel candidate proteins and key pathways for investigating the molecular mechanisms of cold resistance in Hezuo pigs, providing a base for further elucidating the mechanisms of cold tolerance in pigs. Show less
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the ef Show more
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression. Show less