Biomedical subjects

Lu Chen

Publications and source records attributed to Lu Chen.

8 recordsLinked to original sources

PubMed2026

The Health Benefits of Exercise: Molecular and Cellular Mechanisms.

Exercise is a low-cost lifestyle intervention that can prevent and alleviate various diseases. It is a potent physiological stimulus that activates conserved molecular signaling pathways. Through the coordinated integration of multiple molecules, pathways, and systems, it leads to systemic health benefits. However, most studies focus on individual systems or molecular mechanisms, lacking systematic integration of the cross-system regulation induced by exercise. We summarize the molecular mechanisms of exercise in the musculoskeletal, cardiovascular, nervous systems, among others. Exercise induces the release of exerkines (e.g., irisin, interleukin-6, and brain-derived neurotrophic factor) and extracellular vesicles, which activate key signaling pathways to enhance mitochondrial function, metabolism and physiological adaptation, while suppressing inflammation and oxidative stress, thereby alleviating diseases and delaying aging through cross-system coordination. We further explore exercise-induced adaptive regulation in extreme environments, including microgravity, hyperbaria, and hypoxia, offering a multifaceted perspective on organismal health regulation. Finally, we outline the prospects and challenges of multiomics, artificial intelligence-driven precision medicine, personalized exercise prescriptions, and exercise mimetics. Overall, this review provides a more integrated perspective on the molecular basis of exercise and offers directions for future mechanistic and translational studies.

exercise↗

PubMed2026

Lymphangiogenesis-related gene signature-based risk model for prognostic assessment of cervical cancer: immune-metabolic characterization and molecular subtype analysis.

BACKGROUND: Lymphangiogenesis promotes tumor dissemination and may shape the immune contexture of cervical cancer, yet lymphangiogenesis-related prognostic stratification and its immunometabolic implications remain insufficiently defined in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). METHODS: TCGA-CESC transcriptomes and clinical data were obtained from UCSC Xena and integrated with normal cervix tissues from the Genotype-Tissue Expression Project after batch correction. Prognostic LYMRGs were first identified from the differentially expressed set using univariable Cox proportional hazards analysis. Candidate genes were then reduced using an L1-regularized Cox model (Least Absolute Shrinkage and Selection Operator), and the remaining markers were entered into a multivariable Cox regression to obtain the final coefficients and compute an individualized risk score. The model's prognostic value was further assessed in an independent Gene Expression Omnibus dataset. In addition, expression patterns of the signature genes were leveraged for molecular subtyping of TCGA samples via non-negative matrix factorization (NMF). Immune infiltration and immunotherapy-associated characteristics were interrogated through a multi-algorithm strategy (single-sample gene set enrichment analysis, CIBERSORT, ESTIMATE, Tumor Immune Dysfunction and Exclusion (TIDE), and Immunophenoscore . Additional analyses included pathway enrichment (GSEA/GO/KEGG), drug sensitivity prediction (pRRophetic/CellMiner), and ceRNA network analysis. RESULTS: A six-gene LYMRG signature robustly stratified survival. High-risk patients had significantly worse overall survival in The Cancer Genome Atlas with AUCs of 0.819/0.801/0.801 at 1/3/5 years, and in GSE52903 (P = 0.001) with AUCs of 0.733/0.719/0.725. NMF identified two subtypes with distinct prognosis (P = 0.01) and divergent immune landscapes. Risk groups and subtypes exhibited consistent differences in immune infiltration, checkpoint expression, TIDE/IPS patterns, and pathway enrichment. Predicted chemosensitivity differed by risk group, and the ceRNA network suggested candidate upstream lncRNA regulators of the signature. CONCLUSION: A lymphangiogenesis-related six-gene model enables clinically meaningful prognostic stratification of CESC and links lymphangiogenesis programs to distinct tumor immune phenotypes and therapeutic vulnerabilities.

cancer↗

PubMed2026

Maternal PAN2 selectively maintains mRNA Poly(A) tail homeostasis to regulate RNA degradation during oocyte-to-early embryo transition in mice.

In mammals, the precise degradation of maternal mRNAs is essential for oocyte maturation and early embryonic development, as it facilitates the "maternal-to-zygotic transition (MZT)" by eliminating maternal transcripts and enabling zygotic genome activation (ZGA). However, the physiological role of the poly(A)-specific nuclease 2 (PAN2), a deadenylase that initiates cascade degradation of long-tailed transcripts, remains unknown. Here, we generated oocyte-specific Pan2 conditional knockout (cKO) mice to investigate its role. We found that Pan2 cKO females exhibit severe female subfertility despite normal oocyte maturation and ovulation, with embryos arresting at the 2-cell stage. PAIso-seq2 and transcriptome sequencing reveal that PAN2 coordinates maternal mRNA deadenylation and decay. Mechanistically, PAN2 recognizes its substrates through a PAN3-PABPC1 bridging complex, and it preferentially targets transcripts whose poly(A) tails lack guanosine (G) but are enriched for uridine (U). PAN2 deficiency causes poly(A) tail dyshomeostasis, leading to global accumulation of maternal mRNAs, impaired zygotic genome activation, and abnormal protein accumulation in 2-cell embryos. Overexpression of these proteins phenocopies developmental defects. Notably, the PAN2-regulated transcriptome is largely non-overlapping with the LC3B-mediated degradation pathway, highlighting the unique and non-redundant role of PAN2 in maternal mRNA clearance. Our study establishes maternal PAN2 as a critical regulator of poly(A) tail homeostasis, ensuring timely maternal mRNA clearance and proper ZGA, highlighting the stage-specific and tail-composition-dependent functions of the deadenylase cascade during the maternal-to-zygotic transition. These findings offer new perspectives on post-transcriptional regulatory mechanisms in early mammalian embryogenesis.

Deadenylation↗

PubMed2026

Allelic variation in UVR8 modulates thermotolerance-yield tradeoffs in plants.

Industrial activities have driven stratospheric ozone depletion, increasing surface UV-B radiation while exacerbating global warming. These changes limit crop productivity, alter species distributions, and disrupt plant metabolic processes, but the mechanisms linking energy signaling to heat-stress responses remain unclear. Here, we identify the photoreceptor UV RESISTANCE LOCUS 8b (OsUVR8b) as a substrate of SNF1-related protein kinase 1 (SnRK1) in rice and reveal a natural variation at its SnRK1-mediated phosphorylation site (Ser177) that is correlated with adaptation to tropical climates. The thermotolerant OsUVR8bAla177 accessions show geographic enrichment in low-latitude regions with elevated temperatures. Functional validation through prime editing demonstrated that a Ser177-to-Ala177 substitution enhances heat tolerance, whereas the reverse edit compromises it. Mechanistically, OsUVR8bSer177 exhibits reduced stability and an impaired capacity for scavenging reactive oxygen species under heat stress. The regulatory function of the OsUVR8b Ser177 phosphorylation site, a molecular switch that governs UVR8 stability and thermotolerance, can be functionally re-established across rice, Arabidopsis, tobacco, and soybean, indicating its preservation during domestication. Notably, OsUVR8bSer177 maintains higher fertility and yield under non-stress conditions, indicating a tradeoff between heat adaptation and productivity. Our findings thus establish this switch as a key regulator of the yield-resilience balance and a promising target for breeding of climate-resilient crops.

Thermotolerance↗

PubMed2026

Lactylome Reprogramming Mediates Therapeutic Response and Adaptation to Neoadjuvant Chemotherapy in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) exhibits high prevalence in China and poor prognosis despite neoadjuvant chemotherapy (NACT), with significant chemoresistance development. Tumor-associated metabolic reprogramming and NACT-induced cellular stress promote lactate accumulation, which serves as a precursor for lysine lactylation (Kla), a post-translational modification potentially regulating cancer progression. We hypothesized that systematic characterization of the lactylome in response to NACT could reveal critical molecular mechanisms underlying treatment and identify new therapeutic vulnerabilities in ESCC. Herein, through comprehensive proteomic and lactylome profiling of tumor and adjacent normal adjacent tissues from 31 ESCC patients (with or without NACT treatment), we identified 8281 proteins and 1836 Kla sites across 62 samples. NACT induced substantial lactylome alterations with 307 differentially expressed Kla sites predominantly in nonhistone proteins involved in DNA damage response and metabolic pathways. Our data revealed that while NACT-induced suppression of energy metabolism, coupled with upregulated 3-hydroxy-3-methylglutaryl reductase degradation 1 complex expression, may exert potential proapoptotic effects, the activation of ribosome biogenesis and increased nucleoprotein lactylation triggered tumor-protective mechanisms. Mechanistically, we demonstrated that DNA damage and elevated lactate levels induced poly(ADP-ribose) polymerase 1 K654 lactylation, enhancing its enzymatic activity and augmenting poly(ADP-ribosyl)ation of downstream targets, potentially playing a pivotal role in chemotherapy resistance-associated pathways. This comprehensive tissue-level landscape of Kla dynamics in ESCC response to chemotherapy establishes Kla as a critical regulatory mechanism in treatment response, potentially offering novel therapeutic targets and predictive biomarkers for personalized treatment strategies.

Humans↗

PubMed2025

Characterization of phosphorylation variants for identifying adaptive alleles in Zea.

Large-scale genome sequencing of maize wild species (teosinte) has uncovered thousands of genetic mutations, but distinguishing causal alleles from neutral variations remains a significant challenge. In this study, we conducted a comprehensive analysis of phosphorylation-associated single-nucleotide variations (pSNVs) to enhance our understanding of adaptive variations in the Zea genus. We collected 234 teosinte genomes from seven different taxa and 507 cultivated maize genomes to identify single-nucleotide variants that target phosphorylation machinery, which is crucial for plant development and environmental adaptation. Our analysis identified 33 687 pSNVs within the Zea genus and revealed a reduction in genetic conservation along with an increase in protein abundance and expression for genes harboring pSNVs. Additionally, pSNVs present stronger purifying selection pressures compared with other missense mutations. We found that maize possesses fewer pSNVs than teosinte, likely due to the effects of selection and hitchhiking. By examining the role of pSNVs related to kinase-substrate rewriting events and exhibiting evolutionary divergence jointly, our results suggest that pSNVs impact multiple traits, particularly flowering time variation between teosinte and maize. Furthermore, we documented the widespread presence of pSNVs in Arabidopsis thaliana, rice, and wheat, identifying 46 pSNVs that have convergently evolved between maize and other species. Our study provides another insight into uncovering adaptive alleles in wild species by incorporating protein signaling sites and emphasizes the potential of utilizing wild species for future crop improvement.

Zea mays↗

PubMed2024

DKK1-SE recruits AP1 to activate the target gene DKK1 thereby promoting pancreatic cancer progression.

Super-enhancers are a class of DNA cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis. Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, the current research is far from enough to reveal the complex mechanism behind it. This study found a super-enhancer enriched with abnormally active histone modifications in pancreatic ductal adenocarcinoma (PDAC), called DKK1-super-enhancer (DKK1-SE). The major active component of DKK1-SE is component enhancer e1. Mechanistically, AP1 induces chromatin remodeling in component enhancer e1 and activates the transcriptional activity of DKK1. Moreover, DKK1 was closely related to the malignant clinical features of PDAC. Deletion or knockdown of DKK1-SE significantly inhibited the proliferation, colony formation, motility, migration, and invasion of PDAC cells in vitro, and these phenomena were partly mitigated upon rescuing DKK1 expression. In vivo, DKK1-SE deficiency not only inhibited tumor proliferation but also reduced the complexity of the tumor microenvironment. This study identifies that DKK1-SE drives DKK1 expression by recruiting AP1 transcription factors, exerting oncogenic effects in PDAC, and enhancing the complexity of the tumor microenvironment.

Humans↗

PubMed2022

Temporal associations between leukocytes DNA methylation and blood lipids: a longitudinal study.

BACKGROUND: The associations between blood lipids and DNA methylation have been investigated in epigenome-wide association studies mainly among European ancestry populations. Several studies have explored the direction of the association using cross-sectional data, while evidence of longitudinal data is still lacking. RESULTS: We tested the associations between peripheral blood leukocytes DNA methylation and four lipid measures from Illumina 450 K or EPIC arrays in 1084 participants from the Chinese National Twin Registry and replicated the result in 988 participants from the China Kadoorie Biobank. A total of 23 associations of 19 CpG sites were identified, with 4 CpG sites located in or adjacent to 3 genes (TMEM49, SNX5/SNORD17 and CCDC7) being novel. Among the validated associations, we conducted a cross-lagged analysis to explore the temporal sequence and found temporal associations of methylation levels of 2 CpG sites with triglyceride and 2 CpG sites with high-density lipoprotein-cholesterol (HDL-C) in all twins. In addition, methylation levels of cg11024682 located in SREBF1 at baseline were temporally associated with triglyceride at follow-up in only monozygotic twins. We then performed a mediation analysis with the longitudinal data and the result showed that the association between body mass index and HDL-C was partially mediated by the methylation level of cg06500161 (ABCG1), with a mediation proportion of 10.1%. CONCLUSIONS: Our study indicated that the DNA methylation levels of ABCG1, AKAP1 and SREBF1 may be involved in lipid metabolism and provided evidence for elucidating the regulatory mechanism of lipid homeostasis.

Humans↗