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PubMed2024

Angiopoietin-like protein 8 directs DNA damage responses towards apoptosis by stabilizing PARP1-DNA condensates.

Upon genotoxic stresses, cells employ various DNA damage responses (DDRs), including DNA damage repair or apoptosis, to safeguard genome integrity. However, the determinants among different DDRs choices are largely unknown. Here, we report angiopoietin-like protein 8 (ANGPTL8), a secreted regulator of lipid metabolism, localizes to the nucleus and acts as a dynamic switch that directs DDRs towards apoptosis rather than DNA repair after genotoxin exposure. ANGPTL8 deficiency alleviates DNA damage and apoptosis in cells exposed to genotoxins, as well as in the liver or kidney of mice injured by hepatic ischemia/reperfusion or cisplatin treatment. Mechanistically, ANGPTL8 physically interacts with Poly (ADP-ribose) polymerase 1 (PARP1), in a PARylation-independent manner, and reduces the fluidity of PARP1-DNA condensates, thereby enhancing the pro-apoptotic accumulation of PARP1 and PAR chains on DNA lesions. However, the transcription of ANGPTL8 is gradually decreased following genotoxin treatment, partly due to downregulation of CCAAT enhancer binding protein alpha (CEBPA), presumably to avoid further cytotoxicity. Together, we provide new insights by which genotoxic stress induced DDRs are channeled to suicidal apoptosis to safeguard genome integrity.

Animals↗

PubMed2025

Predictors of response to terlipressin therapy in hepatorenal syndrome: Metabolomic and proteomic analysis from the CONFIRM trial.

BACKGROUND: Terlipressin is the only FDA-approved vasoconstrictor for hepatorenal syndrome (HRS). The CONFIRM study is the largest trial of terlipressin versus placebo. Novel predictors of HRS response are required to enrich patient selection and optimize outcomes. METHODS: Samples at treatment initiation were tested using (a) liquid chromatography-mass spectrometry of 1594 plasma/1420 urine metabolites (Metabolon Inc.), (b) aptamer-based array of 7289 plasma proteins (SomaScan), and (c) 14 plasma/urine pre-specified assays. The CONFIRM trial's original definition of HRS response [2 serum creatinine (SCr) <1.5 mg/dL separated by >2 h] was used as the primary outcome. RESULTS: In all, 115 patients [79 terlipressin-treated (TT) and 36 placebo-treated (PT)] provided samples. Baseline characteristics, outcomes, and 2:1 TT:PT allocation were preserved from the original 300-patient trial. A total of 36 out of 116 (31.0%) patients achieved HRS reversal. HRS reversal was associated with lower SCr (p=0.001), cystatin C (p=0.005), angiopoietin-2 (p=0.04), and beta-2 microglobulin (p=0.006). In metabolite analysis, PT had the most significant differences in HRS reversal [n=26 plasma, n=50 urine, including lower urine levels of those centered on sulfated secondary bile acids (microbiome-derived), N-acetylated amino acids, catechols (both uremic toxins), and phosphocholines (cell membrane integrity)], with fewer in TT (n=1 plasma, n=2 urine), and in all patients (n=3 plasma, n=7 urine). There were no significant aptamers associated with HRS reversal after false-discovery correction. CONCLUSIONS: SCr, cystatin C, angiopoietin-2, and beta-2 microglobulin were associated with HRS reversal. Protein and metabolite signals centered on microbiome function and uremic toxins appeared more robust in PT patients, likely selecting a subgroup that may recover without terlipressin. Use of novel biomarkers may enrich for terlipressin response.

Humans↗

PubMed2025

Transcriptome-wide analysis reveals potential roles of CFD and ANGPTL4 in fibroblasts regulating B cell lineage for extracellular matrix-driven clustering and novel avenues for immunotherapy in breast cancer.

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

Humans↗

PubMed2026

Furmonertinib inhibits non-small cell lung cancer progression through ANGPT1-mediated regulation of cell migration and apoptosis.

BACKGROUND: Lung cancer remains one of the leading causes of cancer-related mortality worldwide, highlighting the urgent need for effective therapeutic agents. This study investigates the antitumor effects and underlying mechanisms of furmonertinib (FUR) in lung cancer cells. METHODS: Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to identify FUR target genes, followed by functional enrichment, survival, and protein-protein interaction (PPI) network analyses. Human lung cancer cell line A549 was treated with FUR and/or ANGPT1-specific siRNA. Cell migration, apoptosis, and protein expression were assessed by wound healing, flow cytometry, and Western blotting. Cellular thermal shift assay (CETSA) and drug affinity response target stability (DARTS) assays were used to assess FUR-induced stabilization of angiopoietin-1 (ANGPT1) protein. RESULTS: FUR treatment significantly inhibited cell migration and increased apoptosis in NSCLC cells. Bioinformatics analysis revealed 12 overlapping target genes of FUR from the PharmMapper and SwissTargetPrediction databases, with ANGPT1 emerging as a key candidate. ANGPT1 expression was downregulated in tumor tissues and positively correlated with patient survival. Western blotting confirmed that FUR upregulated ANGPT1 protein levels in a dose-dependent manner. Knockdown of ANGPT1 enhanced migration and suppressed apoptosis, while FUR reversed these effects. FUR treatment enhanced the stability of ANGPT1 under high-temperature conditions while reducing its sensitivity to protease. ANGPT1 may have affected tumor cell migration through cell adhesion and extracellular matrix (ECM) pathways. CONCLUSIONS: FUR suppresses lung cancer progression by upregulating ANGPT1, thereby inhibiting cell migration and promoting apoptosis. ANGPT1 is a potential therapeutic target and provides new insights into the anti-tumor mechanism of FUR in lung cancer.

Lung cancer↗

PubMed2025

Pitavastatin, Procollagen Pathways, and Plaque Stabilization in Patients With HIV: A Secondary Analysis of the REPRIEVE Randomized Clinical Trial.

IMPORTANCE: In a mechanistic substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) randomized clinical trial, pitavastatin reduced noncalcified plaque (NCP) volume, but specific protein and gene pathways contributing to changes in coronary plaque remain unknown. OBJECTIVE: To use targeted discovery proteomics and transcriptomics approaches to interrogate biological pathways beyond low-density lipoprotein cholesterol (LDL-C), relating statin outcomes to reduce NCP volume and promote plaque stabilization among people with HIV (PWH). DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of the double-blind, placebo-controlled, REPRIEVE randomized clinical trial. Participants underwent coronary computed tomography angiography (CTA), plasma protein analysis, and transcriptomic analysis at baseline and 2-year follow-up. The trial enrolled PWH from April 2015 to February 2018 at 31 US research sites. PWH without known cardiovascular diseases taking antiretroviral therapy and with low to moderate 10-year cardiovascular risk were eligible. Data analyses were conducted from October 2023 to February 2024. INTERVENTION: Oral pitavastatin calcium, 4 mg per day. MAIN OUTCOMES AND MEASURES: Relative change in plasma proteomics, transcriptomics, and noncalcified plaque volume among those receiving treatment vs placebo. RESULTS: Among 558 individuals (mean [SD] age, 51 [6] years; 455 male [82%]) included in the proteomics assessment, 272 (48.7%) received pitavastatin and 286 (51.3%) received placebo. After adjusting for false discovery rates, pitavastatin increased abundance of procollagen C-endopeptidase enhancer 1 (PCOLCE), neuropilin 1 (NRP-1), major histocompatibility complex class I polypeptide-related sequence A (MIC-A) and B (MIC-B), and decreased abundance of tissue factor pathway inhibitor (TFPI), tumor necrosis factor ligand superfamily member 10 (TRAIL), angiopoietin-related protein 3 (ANGPTL3), and mannose-binding protein C (MBL2). Among these proteins, the association of pitavastatin with PCOLCE (a rate-limiting enzyme of collagen deposition) was greatest, with an effect size of 24.3% (95% CI, 18.0%-30.8%; P < .001). In a transcriptomic analysis, individual collagen genes and collagen gene sets showed increased expression. Among the 195 individuals with plaque at baseline (88 [45.1%] taking pitavastatin, 107 [54.9%] taking placebo), changes in NCP volume were most strongly associated with changes in PCOLCE (%change NCP volume/log2-fold change = -31.9%; 95% CI, -42.9% to -18.7%; P < .001), independent of changes in LDL-C level. Increases in PCOLCE related most strongly to change in the fibro-fatty (<130 Hounsfield units) component of NCP (%change fibro-fatty volume/log2-fold change = -38.5%; 95% CI, -58.1% to -9.7%; P = .01) with a directionally opposite, although nonsignificant, increase in calcified plaque (%change calcified volume/log2-fold change = 34.4%; 95% CI, -7.9% to 96.2%; P = .12). CONCLUSIONS AND RELEVANCE: Results of this secondary analysis of the REPRIEVE randomized clinical trial suggest that PCOLCE may be associated with the atherosclerotic plaque stabilization effects of statins by promoting collagen deposition in the extracellular matrix transforming vulnerable plaque phenotypes to more stable coronary lesions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02344290.

Humans↗

PubMed2025

The proteogenomic landscape of the human kidney and implications for cardio-kidney-metabolic health.

Nearly one-third of the global population is affected by cardio-kidney-metabolic (CKM) diseases; however, the molecular mechanisms underlying CKM diseases are poorly understood. Here we show that tissue proteomics provide critical insights not captured by tissue gene expression or blood proteomics information by performing whole-genome and RNA sequencing and proteomics analysis of human kidney samples (n = 337), and we generated a publicly available database. Via Bayesian co-localization and Mendelian randomization analyses of kidney protein quantitative trait loci and 36 CKM genome-wide association studies, we prioritized 89 proteins for CKM traits. We prioritized relationships that could underlie the interconnectedness of CKM traits and discovered multiple and targetable mechanisms for CKM diseases, including the potential role of kidney angiopoietin-like protein 3 (ANGPTL3) in serum lipid levels and kidney function as well as the role of charged multivesicular body protein 1A in kidney function and hypertension. Notably, we identify pathways with confluence of evidence from genetic loci, tissue gene expression and protein levels for CKM traits. In summary, our large-scale kidney proteomics study uncovers proteins and targetable mechanisms prioritized for CKM diseases.

Humans↗

PubMed2024

Acute physical exercise and ambulatory blood pressure in resistant hypertension.

OBJECTIVES: The effects of acute physical exercise in patients with resistant hypertension remain largely unexplored compared with hypertensive patients in general. We assessed the short-term effects of acute moderate-intensity (MICE) and high-intensity interval exercise (HIIE) on the clinic (BP) and 24-h ambulatory blood pressure (ABP) of patients with resistant hypertension. METHODS: Using a crossover randomized controlled design, 10 participants (56 ± 7 years) with resistant hypertension performed three experimental sessions: MICE, HIIE, and control. MICE consisted of continuous treadmill exercise at an intensity of 3-4 metabolic equivalents of energy (METs) until completing 3 kcal/kg and was energy-matched to HIIE (which included six to eight intervals of 3 min duration at 6-7 METs interspersed with 1.5-min rests at 3 METs). In the control session, participants remained seated for 50 min. Flow-mediated vasodilation, autonomic nervous system balance (heart rate variability), exerkines [interleukin (IL)-6, IL-8, IL-15, vascular endothelial growth factor A, irisin, adiponectin, and angiopoietin] and 71 inflammatory-related proteins were also measured. RESULTS: Compared with baseline, HIIE and MICE reduced clinic SBP immediately ( P  < 0.001 for both) and 90 min ( P  = 0.001 and P  = 0.041, respectively) postexercise. HIIE and MICE also reduced clinic DBP immediately postexercise ( P  = 0.003 and P  = 0.025). By contrast, no changes were found in the control session. On the other hand, no significant effects were noted for 24 h ABP measures or for the rest of variables. CONCLUSION: Although in patients with resistant hypertension, acute aerobic exercise induces short-term reductions in clinic BP, this stimulus does not suffice to reduce 24 h ABP or to impact on potential biological mechanisms.

Humans↗

PubMed2026

Nebivolol treatment improves hypertension-induced endothelial cell dysfunction by reducing TGF-β1-dependent senescence and normalizing mitochondrial indices.

OBJECTIVES: Serum from patients with hypertension (HT) causes endothelial cell (EC) damage, leading to senescence and dysfunctional phenotype. This study investigated whether serum from patients treated with the antihypertensive drugs could normalize EC activity. METHODS: This study involved 71 patients with newly diagnosed HT, who were randomly assigned to one of three groups based on the antihypertensive treatment: amlodipine, nebivolol, or perindopril. Serum samples collected before and 6 weeks after treatment were applied to ECs in vitro to assess their angiogenic activity, cellular senescence, mitochondrial metabolism, and oxidative stress. RESULTS: Results showed that exposure of ECs to serum from patients treated for 6 weeks significantly altered EC function, with varying effects among the drugs. Serum from nebivolol-treated patients produced the most consistent benefits, reducing EC proliferation and HIF-1α expression, likely due to lower levels of angiogenic factors such as angiopoietin-1, basic fibroblast growth factor (bFGF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). Additionally, this serum contained reduced levels of pro-inflammatory cytokines (E-selectin, P-selectin, monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor α (TNFα)) and lower TGF-β1, which are linked to HT-related EC senescence. Nebivolol treatment decreased senescence biomarkers such as SA-β-Gal, 53BP1, and p16, with SA-β-Gal reduction comparable to that of TGF-β1 neutralizing antibodies. Oxidative stress was reduced, indicated by lower oxidized DNA product levels. CONCLUSIONS: Nebivolol was the most effective at reducing the factors, associated with HT induced cellular senescence of endothelium, through reducing TGF-β1.

Humans↗

PubMed2024

Inflammatory and tissue injury marker dynamics in pediatric acute respiratory distress syndrome.

BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).

Humans↗

PubMed2025

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer's disease.

BACKGROUND: A significant proportion of individuals maintain cognition despite extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. METHODS: This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. RESULTS: Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+ inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. CONCLUSIONS: We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Humans↗

PubMed2026

Mechanism of Shoutai Wan against recurrent spontaneous abortion: regulation of decidual vascular remodeling via ERβ-ANGPT2 signaling axis.

Shoutai Wan (STW), a classic traditional Chinese medicine formula used to tonify the kidney and prevent miscarriage, has been widely applied in the clinical management of recurrent spontaneous abortion (RSA). Increasing clinical evidence supports its efficacy in reducing miscarriage rates and improving pregnancy outcomes. However, the molecular basis by which STW alleviates defective decidual vascular remodeling in unexplained RSA remains insufficiently understood. Clinically, decidual ERβ and ANGPT2 expression, as well as serum estradiol, ANGPT2 and VEGFA levels were significantly decreased in RSA patients, accompanied by reduced decidual microvascular density. Furthermore, ERβ expression was positively correlated with ANGPT2 and microvascular density. In vivo, STW dose-dependently reduced embryo loss in RSA mice, repaired the damaged decidual-placental interface structure, and improved vascular maturation, structural stability and endothelial-pericyte ultrastructural connections. Mechanistically, STW upregulated ERβ expression. We demonstrated that ERβ binds to the ANGPT2 promoter, suggesting transcriptional upregulation of ANGPT2, thereby activating Tie2 and the downstream PI3K/AKT pathway and increasing NO and VEGFA secretion. In vitro, hypoxia inhibited ERβ nuclear translocation and ANGPT2 secretion in mDSCs, while STW-containing serum reversed these abnormalities. ERβ knockdown impaired the pro-angiogenic capacity of mDSCs, which was partially rescued by exogenous ANGPT2 supplementation. Network pharmacology predicted that STW targets were mainly enriched in PI3K-Akt, estrogen, VEGF and angiogenesis-related pathways. Transcriptomic GSEA further revealed that the gene signatures of angiogenesis and PI3K-Akt signaling were markedly suppressed in the RSA model, and STW treatment significantly normalized these transcriptional signatures.

Female↗