Purpose Diabetic retinopathy (DR) is often recognized as a marker of systemic microvascular disease, but the metabolic links to other complications, such as diabetic nephropathy (DN), remain unclear. We aimed to identify systemic metabolic signatures shared by DR and DN and investigate their potential causal mechanisms. Methods Multi-tissue metabolomic profiling of the retina, plasma, and kidney was performed in streptozotocin-induced diabetic mice. Clinical relevance was supported by public human DR and DN transcriptomic datasets. Causal relationships were assessed by two-sample Mendelian randomization (MR) using eQTLGen and genome-wide association study (GWAS) summary statistics. Single-cell in silico perturbation analysis was performed to predict organ-specific functional consequences. Results Cross-organ metabolomic profiling identified a conserved systemic lipotoxic signature, yielding a predictive plasma panel comprised of free carnitine and two long-chain acylcarnitines. Clinical transcriptomics and MR analyses pinpointed the synchronous downregulation of the SLC22A5 and CPT2 axis as a causal genetic signature of this lipid imbalance. Furthermore, in silico single-cell analyses revealed that this shared metabolic disturbance induced distinct transcriptional responses across tissues, suggesting tissue-specific molecular responses that may contribute to organ-specific microvascular dysfunction. Conclusions Both DR and DN are associated with systemic disruption of acylcarnitine metabolism. A circulating carnitine/acylcarnitine signature may serve as a non-invasive indicator of microvascular risk, and the SLC22A5–CPT2 axis represents a potential therapeutic target.
Qian Liu, Yan Liu, Xiongyi Yang et al.· Investigative Ophthalmology...· 0 citations
Background Diabetic retinopathy (DR) and Alzheimer disease (AD) share metabolic and vascular dysfunctions, but the extent to which they reflect overlapping genetic susceptibility and neurovascular-metabolic regulatory pathways remains unclear. We combined multi-omics analyses with population-based data to examine the genetic convergence, cellular pathways, and longitudinal association between DR and AD. Methods We performed a two-sample Mendelian randomisation (MR) to estimate the association between genetically predicted DR liability and AD risk. We used Bayesian colocalisation analysis to identify shared genomic loci, and summary-data-based MR (SMR) to detect expression-mediated genes jointly associated with DR and AD. We analysed single-cell RNA sequencing data to characterise shared cellular features and related biological pathways. We also conducted an MR-based mediation analysis to explore whether lipid-related, metabolic, or inflammatory traits mediated the observed DR-AD association, and a longitudinal analysis of the UK Biobank cohort to assess the association between DR and incident AD. Results With the MR analysis, we found that genetically predicted liability to DR was associated with a modest increase in AD risk. Colocalisation analysis supported a shared genetic signal. We identified three genes with shared expression-mediated associations across DR and AD through SMR. Functional enrichment analyses revealed partially overlapping neurovascular and metabolic pathways. Using MR-based mediation analysis, we found no significant intermediary traits linking DR and AD. Findings from the UK Biobank cohort were directionally consistent with the genetic analyses. Conclusions Genetic liability to DR is associated with an increased risk of AD and is accompanied by shared expression-mediated effects and convergent neurovascular-metabolic pathways. These findings support the possibility that DR may serve as a clinically accessible indicator of increased neurodegenerative vulnerability.
Jing Li, Qian Liu, Qian Ma et al.· Journal of Global Health· 0 citations
Background Pulmonary hypertension (PH) involves progressive vascular remodeling and perivascular inflammation. Despite modest clinical improvements with current therapies, their limited ability to reverse remodeling or restore immune homeostasis highlights the need for novel agents. Liriodendrin (Lidd), derived from Sargentodoxae caulis, exhibits anti-inflammatory and antiproliferative activities, but its efficacy and molecular targets in PH are unknown. Methods Two well-established PH animal models - the SU5416/hypoxia (SuHx) mice model and monocrotaline (MCT)-induced rat model - were employed for in vivo assessment of Lidd conducted pharmacological effects. Primary human pulmonary artery smooth muscle cells (hPASMCs) were utilized for mechanistic investigations. RNA-sequencing (RNA-seq) analysis was conducted to identify potential signaling pathways modulated by Lidd treatment. The direct molecular target of Lidd was determined through integrated application of drug affinity responsive target stability (DARTS) assay coupled with western blot validation. To delineate histone lactylation-mediated transcriptional regulation, we combined Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing data analysis followed by chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) verification. Genetic validation was achieved using PFKFB3-deficient murine models to verify the specificity of Lidd-mediated pharmacological actions. Results Lidd administration attenuated pulmonary vascular remodeling, perivascular macrophage infiltration and PH progression in both SuHx and MCT models. Transcriptomic profiling of Lidd-treated hPASMCs revealed predominant enrichment of downregulated genes in inflammatory and cytokine-associated pathways. Mechanistically, Lidd directly bound PFKFB3 and enhanced its interaction with FZR1, promoting PFKFB3 ubiquitination and degradation, which reduced glycolysis-driven lactate and consequent histone lactylation. This, in turn, diminished transcriptional activation of proliferative and inflammatory mediators, including CCND1, TNC, and CCL2. Notably, exogenous lactate supplementation or endogenous lactate accumulation restored histone lactylation and paradoxically potentiated Lidd’s inhibitory effects on PASMC proliferation and migration, whereas p300 inhibition abrogated these lactate-mediated effects. Importantly, Lidd failed to confer additional protection in PFKFB3-deficient mice, confirming PFKFB3 as the primary target mediating its therapeutic action. Conclusion Our findings reveal that Lidd selectively targets the PFKFB3-mediated glycolytic-epigenetic axis to suppress PASMC phenotypic transformation and pulmonary vascular remodeling, positioning it as a promising therapeutic candidate for PH.
Qingye Zeng, Zhenzhen Duan, Qian Liu et al.· bioRxiv· 0 citations
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