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Scientific Reports Jul 2024Ulcerative colitis (UC) is a chronic inflammatory bowel disease with intricate pathogenesis and varied presentation. Accurate diagnostic tools are imperative to detect...
Ulcerative colitis (UC) is a chronic inflammatory bowel disease with intricate pathogenesis and varied presentation. Accurate diagnostic tools are imperative to detect and manage UC. This study sought to construct a robust diagnostic model using gene expression profiles and to identify key genes that differentiate UC patients from healthy controls. Gene expression profiles from eight cohorts, encompassing a total of 335 UC patients and 129 healthy controls, were analyzed. A total of 7530 gene sets were computed using the GSEA method. Subsequent batch correction, PCA plots, and intersection analysis identified crucial pathways and genes. Machine learning, incorporating 101 algorithm combinations, was employed to develop diagnostic models. Verification was done using four external cohorts, adding depth to the sample repertoire. Evaluation of immune cell infiltration was undertaken through single-sample GSEA. All statistical analyses were conducted using R (Version: 4.2.2), with significance set at a P value below 0.05. Employing the GSEA method, 7530 gene sets were computed. From this, 19 intersecting pathways were discerned to be consistently upregulated across all cohorts, which pertained to cell adhesion, development, metabolism, immune response, and protein regulation. This corresponded to 83 unique genes. Machine learning insights culminated in the LASSO regression model, which outperformed others with an average AUC of 0.942. This model's efficacy was further ratified across four external cohorts, with AUC values ranging from 0.694 to 0.873 and significant Kappa statistics indicating its predictive accuracy. The LASSO logistic regression model highlighted 13 genes, with LCN2, ASS1, and IRAK3 emerging as pivotal. Notably, LCN2 showcased significantly heightened expression in active UC patients compared to both non-active patients and healthy controls (P < 0.05). Investigations into the correlation between these genes and immune cell infiltration in UC highlighted activated dendritic cells, with statistically significant positive correlations noted for LCN2 and IRAK3 across multiple datasets. Through comprehensive gene expression analysis and machine learning, a potent LASSO-based diagnostic model for UC was developed. Genes such as LCN2, ASS1, and IRAK3 hold potential as both diagnostic markers and therapeutic targets, offering a promising direction for future UC research and clinical application.
Topics: Humans; Machine Learning; Colitis, Ulcerative; Algorithms; Gene Expression Profiling; Transcriptome; Interleukin-1 Receptor-Associated Kinases; Male; Female; Lipocalin-2; Case-Control Studies; Biomarkers; Adult
PubMed: 38951638
DOI: 10.1038/s41598-024-65481-8 -
The EMBO Journal Jul 2024Transposable elements (TEs) are mobile genetic modules of viral derivation that have been co-opted to become modulators of mammalian gene expression. TEs are a major...
Transposable elements (TEs) are mobile genetic modules of viral derivation that have been co-opted to become modulators of mammalian gene expression. TEs are a major source of endogenous dsRNAs, signaling molecules able to coordinate inflammatory responses in various physiological processes. Here, we provide evidence for a positive involvement of TEs in inflammation-driven bone repair and mineralization. In newly fractured mice bone, we observed an early transient upregulation of repeats occurring concurrently with the initiation of the inflammatory stage. In human bone biopsies, analysis revealed a significant correlation between repeats expression, mechanical stress and bone mineral density. We investigated a potential link between LINE-1 (L1) expression and bone mineralization by delivering a synthetic L1 RNA to osteoporotic patient-derived mesenchymal stem cells and observed a dsRNA-triggered protein kinase (PKR)-mediated stress response that led to strongly increased mineralization. This response was associated with a strong and transient inflammation, accompanied by a global translation attenuation induced by eIF2α phosphorylation. We demonstrated that L1 transfection reshaped the secretory profile of osteoblasts, triggering a paracrine activity that stimulated the mineralization of recipient cells.
PubMed: 38951609
DOI: 10.1038/s44318-024-00143-z -
Scientific Reports Jul 2024Proline 4-hydroxylase 2 (P4HA2) is known for its hydroxylase activity, primarily involved in hydroxylating collagen precursors and promoting collagen cross-linking under...
Proline 4-hydroxylase 2 (P4HA2) is known for its hydroxylase activity, primarily involved in hydroxylating collagen precursors and promoting collagen cross-linking under physiological conditions. Although its overexpression influences a wide variety of malignant tumors' occurrence and development, its specific effects and mechanisms in oral squamous cell carcinoma (OSCC) remain unclear. This study focused on investigating the expression patterns, carcinogenic functions, and underlying mechanisms of P4HA2 in OSCC cells. Various databases, including TCGA, TIMER, UALCAN, GEPIA, and K-M plotter, along with paraffin-embedded samples, were used to ascertain P4HA2 expression in cancer and its correlation with clinicopathological features. P4HA2 knockdown and overexpression cell models were developed to assess its oncogenic roles and mechanisms. The results indicated that P4HA2 was overexpressed in OSCC and inversely correlated with patient survival. Knockdown of P4HA2 suppressed invasion, migration, and proliferation of OSCC cells both in vitro and in vivo, whereas overexpression of P4HA2 had the opposite effects. Mechanistically, the phosphorylation levels of the PI3K/AKT pathway were reduced following P4HA2 silencing. The study reveals that P4HA2 acts as a promising biomarker for predicting prognosis in OSCC and significantly affects metastasis, invasion, and proliferation of OSCC cells through the regulation of the PI3K/AKT signaling pathway.
Topics: Humans; Proto-Oncogene Proteins c-akt; Mouth Neoplasms; Cell Proliferation; Phosphatidylinositol 3-Kinases; Signal Transduction; Cell Line, Tumor; Neoplasm Invasiveness; Cell Movement; Procollagen-Proline Dioxygenase; Carcinoma, Squamous Cell; Gene Expression Regulation, Neoplastic; Animals; Mice; Female; Male; Neoplasm Metastasis; Middle Aged; Mice, Nude
PubMed: 38951593
DOI: 10.1038/s41598-024-64264-5 -
Scientific Reports Jun 2024Sepsis, marked by organ dysfunction, necessitates reliable biomarkers. Ribonuclease inhibitor 1 (RNH1), a ribonuclease (RNase) inhibitor, emerged as a potential...
Sepsis, marked by organ dysfunction, necessitates reliable biomarkers. Ribonuclease inhibitor 1 (RNH1), a ribonuclease (RNase) inhibitor, emerged as a potential biomarker for acute kidney injury and mortality in thoracoabdominal aortic aneurysm patients. Our study investigates RNH1 dynamics in sepsis, its links to mortality and organ dysfunction, and the interplay with RNase 1 and RNase 5. Furthermore, we explore RNH1 as a therapeutic target in sepsis-related processes like inflammation, non-canonical inflammasome activation, and iron homeostasis. We showed that RNH1 levels are significantly higher in deceased patients compared to sepsis survivors and correlate with creatine kinase, aspartate and alanine transaminase, bilirubin, serum creatinine and RNase 5, but not RNase 1. RNH1 mitigated LPS-induced TNFα and RNase 5 secretion, and relative mRNA expression of ferroptosis-associated genes HMOX1, FTH1 and HAMP in PBMCs. Monocytes were identified as the predominant type of LPS-positive PBMCs. Exogenous RNH1 attenuated LPS-induced CASP5 expression, while increasing IL-1β secretion in PBMCs and THP-1 macrophages. As RNH1 has contradictory effects on inflammation and non-canonical inflammasome activation, its use as a therapeutic agent is limited. However, RNH1 levels may play a central role in iron homeostasis during sepsis, supporting our clinical observations. Hence, RNH1 shows promise as biomarkers for renal and hepatic dysfunction and hepatocyte injury, and may be useful in predicting the outcome of septic patients.
Topics: Humans; Sepsis; Biomarkers; Iron; Homeostasis; Inflammation; Male; Female; Middle Aged; Aged; Inflammasomes; Lipopolysaccharides; THP-1 Cells; Carrier Proteins
PubMed: 38951571
DOI: 10.1038/s41598-024-65778-8 -
Nature Communications Jul 2024The conversion of a soluble protein into polymeric amyloid structures is a process that is poorly understood. Here, we describe a fully redox-regulated amyloid system in...
The conversion of a soluble protein into polymeric amyloid structures is a process that is poorly understood. Here, we describe a fully redox-regulated amyloid system in which cysteine oxidation of the tumor suppressor protein p16 leads to rapid amyloid formation. We identify a partially-structured disulfide-bonded dimeric intermediate species that subsequently assembles into fibrils. The stable amyloid structures disassemble when the disulfide bond is reduced. p16 is frequently mutated in cancers and is considered highly vulnerable to single-point mutations. We find that multiple cancer-related mutations show increased amyloid formation propensity whereas mutations stabilizing the fold prevent transition into amyloid. The complex transition into amyloids and their structural stability is therefore strictly governed by redox reactions and a single regulatory disulfide bond.
Topics: Oxidation-Reduction; Amyloid; Humans; Cyclin-Dependent Kinase Inhibitor p16; Cysteine; Disulfides; Sulfhydryl Compounds; Mutation; Polymerization
PubMed: 38951545
DOI: 10.1038/s41467-024-49581-7 -
Nature Communications Jun 2024Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying...
Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.
Topics: Drug Resistance, Neoplasm; Humans; Cell Line, Tumor; Antineoplastic Agents; Oxaliplatin; Irinotecan; CRISPR-Cas Systems; Protein Serine-Threonine Kinases; Colorectal Neoplasms; Animals; Neoplasms; Clustered Regularly Interspaced Short Palindromic Repeats; Mice; Gene Expression Regulation, Neoplastic
PubMed: 38951519
DOI: 10.1038/s41467-024-49673-4 -
Nature Communications Jun 2024HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein...
HIV-1 Vpr promotes efficient spread of HIV-1 from macrophages to T cells by transcriptionally downmodulating restriction factors that target HIV-1 Envelope protein (Env). Here we find that Vpr induces broad transcriptomic changes by targeting PU.1, a transcription factor necessary for expression of host innate immune response genes, including those that target Env. Consistent with this, we find silencing PU.1 in infected macrophages lacking Vpr rescues Env. Vpr downmodulates PU.1 through a proteasomal degradation pathway that depends on physical interactions with PU.1 and DCAF1, a component of the Cul4A E3 ubiquitin ligase. The capacity for Vpr to target PU.1 is highly conserved across primate lentiviruses. In addition to impacting infected cells, we find that Vpr suppresses expression of innate immune response genes in uninfected bystander cells, and that virion-associated Vpr can degrade PU.1. Together, we demonstrate Vpr counteracts PU.1 in macrophages to blunt antiviral immune responses and promote viral spread.
Topics: Humans; Macrophages; vpr Gene Products, Human Immunodeficiency Virus; HIV-1; Trans-Activators; Proto-Oncogene Proteins; Immunity, Innate; Ubiquitin-Protein Ligases; HIV Infections; HEK293 Cells; Virion; Protein Serine-Threonine Kinases
PubMed: 38951492
DOI: 10.1038/s41467-024-49635-w -
Molecular Biology Reports Jun 2024Kaempferia parviflora Wall. ex. Baker (KP) has been reported to exhibit anti-obesity effects. However, the detailed mechanism of the anti-obesity effect of KP extract...
Kaempferia parviflora extract and its component polymethoxyflavones suppress adipogenic differentiation of human bone marrow-derived mesenchymal stem cells via the AMPK pathway.
BACKGROUND
Kaempferia parviflora Wall. ex. Baker (KP) has been reported to exhibit anti-obesity effects. However, the detailed mechanism of the anti-obesity effect of KP extract (KPE) is yet to be clarified. Here, we investigated the effect of KPE and its component polymethoxyflavones (PMFs) on the adipogenic differentiation of human mesenchymal stem cells (MSCs).
METHODS AND RESULTS
KPE and PMFs fraction (2.5 µg/mL) significantly inhibited lipid and triacylglyceride accumulation in MSCs; lipid accumulation in MSCs was suppressed during the early stages of differentiation (days 0-3) but not during the mid (days 3-7) or late (days 7-14) stages. Treatment with KPE and PMFs fractions significantly suppressed peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), and various adipogenic metabolic factors. Treatment with KPE and PMFs fraction induced the activation of AMP-activated protein kinase (AMPK) signaling, and pretreatment with an AMPK signaling inhibitor significantly attenuated KPE- and PMFs fraction-induced suppression of lipid formation.
CONCLUSIONS
Our findings demonstrate that KPE and PMFs fraction inhibit lipid formation by inhibiting the differentiation of undifferentiated MSCs into adipocyte lineages via AMPK signaling, and this may be the mechanism underlying the anti-obesity effects of KPE and PMFs. Our study lays the foundation for the elucidation of the anti-obesity mechanism of KPE and PMFs.
Topics: Humans; Mesenchymal Stem Cells; Adipogenesis; Plant Extracts; Zingiberaceae; AMP-Activated Protein Kinases; Flavones; Cell Differentiation; Signal Transduction; PPAR gamma; Adipocytes; Cells, Cultured
PubMed: 38951450
DOI: 10.1007/s11033-024-09739-4 -
Clinical and Experimental Medicine Jun 2024Although renal cell carcinoma (RCC) is a prevalent type of cancer, the most common pathological subtype, clear cell renal cell carcinoma (ccRCC), still has poorly...
Although renal cell carcinoma (RCC) is a prevalent type of cancer, the most common pathological subtype, clear cell renal cell carcinoma (ccRCC), still has poorly understood molecular mechanisms of progression. Moreover, interferon-stimulated gene 15 (ISG15) is associated with various types of cancer; however, its biological role in ccRCC remains unclear.This study aimed to explore the role of ISG15 in ccRCC progression.ISG15 expression was upregulated in ccRCC and associated with poor prognosis. RNA sequence analysis and subsequent experiments indicated that ISG15 modulated IL6/JAK2/STAT3 signaling to promote ccRCC proliferation, migration, and invasion. Additionally, our animal experiments confirmed that sustained ISG15 knockdown reduced tumor growth rate in nude mice and promoted cell apoptosis. ISG15 modulates the IL6/JAK2/STAT3 pathway, making it a potential therapeutic target and prognostic biomarker for ccRCC.
Topics: Humans; Carcinoma, Renal Cell; Signal Transduction; Animals; STAT3 Transcription Factor; Janus Kinase 2; Interleukin-6; Mice, Nude; Cytokines; Ubiquitins; Kidney Neoplasms; Cell Proliferation; Mice; Cell Line, Tumor; Male; Cell Movement; Female; Apoptosis; Gene Expression Regulation, Neoplastic; Prognosis; Disease Progression
PubMed: 38951255
DOI: 10.1007/s10238-024-01414-z -
Zhonghua Yi Xue Za Zhi Jul 2024To investigate the risk factors of venous thrombosis in patients with polycythemia vera (PV) and establish a prediction model for venous thrombosis. PV patients with...
To investigate the risk factors of venous thrombosis in patients with polycythemia vera (PV) and establish a prediction model for venous thrombosis. PV patients with JAK2 gene mutation positive in the Second Hospital of Tianjin Medical University from September 2017 to November 2023 were retrospectively included. The patients were divided into groups according to whether they had venous thrombosis. After matching age and gender factors with propensity scores, 102 patients were included in the venous thrombosis group [46 males, 56 females, with a median age (, ) of 52 (44, 60) years] and 204 cases were included in the group without venous thrombosis [92 males, 112 females, with a median age of 52 (44, 59) years]. The clinical and laboratory characteristics, disease progression and incidence of gene mutation were compared between the two groups. The follow-up cohort ended on November 20, 2023, with a median follow-up [ (, )] of 11 (1, 53) years. Multivariate Cox risk model was used to analyze the influencing factors of venous thrombosis in PV patients, and establish a scoring system for the venous thrombosis risk factor prediction model of PV patients. Receiver operating characteristic (ROC) curve was used to evaluate the predictive efficiency of the model. Hemoglobin concentration, the ratio of hematopoietic volume≥55%, neutrophil to lymphocyte ratio≥5, hypertension, subcostal spleen≥5 cm and secondary myelofibrosis in venous thrombosis group were higher than those in non-venous thrombosis group (all <0.05). In addition, the proportion of history of thromboembolism, V617F gene mutation load (V617F%)≥50%, diabetes mellitus, ASXL1 mutation and secondary reticular silver staining≥3 in the venous thrombosis group were higher than those in the non-venous thrombosis group (all <0.05). The proportion of PV patients with 3 or more gene mutations was 44.1% (45/102) in venous thrombosis group, which was higher than that of PV patients without venous thrombosis 29.9% (61/204) (=0.014). The proportion of ASXL1 gene mutation in venous thrombosis group was 17.6% (18/102), which was higher than the 4.9% (10/204) in non-venous thrombosis group (<0.001). Multivariate Cox risk model analysis showed that previous thromboembolism history (2.031, 95%: 1.297-3.179, =0.002), V617F%≥50% (2.141 95%: 1.370-3.347, 0.001), ASXL1 mutation (=4.632, 95%: 1.497-14.336, =0.008), spleen subcostal≥5 cm (=1.771, 95% 1.047-2.996, =0.033) are the risk factors of venous thrombosis in PV patients. According to values, a score system for predicting risk of venous thrombosis in PV patients was established: previous history of thromboembolism, V617F%≥50% and spleen subcostoal≥5 cm were assigned 1 point respectively, and ASXL1 mutation was assigned 2 points. Low risk group: score 0, medium risk group: score 1-2, high risk group: score≥3. The ROC curve analysis of the model for predicting venous thrombosis in PV patients showed that the area under the curve (AUC) was 0.807 (95% 0.755-0.860), with the sensitivity of 88.2% and the specificity of 59.8% when the Youden index was 0.48. Previous thromboembolism history, V617F%≥50%, ASXL1 mutation, spleen subcostoal≥5 cm are risk factors of venous thrombosis in PV patients. The established prediction model has good prediction efficiency.
Topics: Humans; Polycythemia Vera; Male; Risk Factors; Middle Aged; Female; Venous Thromboembolism; Adult; Janus Kinase 2; Mutation; Venous Thrombosis
PubMed: 38951106
DOI: 10.3760/cma.j.cn112137-20240304-00476