Jianhua Ran

The high incidence and mortality rates of anxiety disorders in patients with chronic kidney disease (CKD) have drawn attention. Prior studies identified urea as an independent risk factor for mental disorders in CKD. While urea accumulation is known to impair synaptic plasticity, its effects on glial cells remain unclear. How urea influences oligodendrocyte lineage differentiation may represent a critical node in neuron–glia interactions. Previous studies have shown that OL‐lineage cells may be underrepresented in scRNA‐seq datasets. We selected amygdala tissue from wild‐type and high‐urea (UT‐B ⁻ / ⁻ ) mice and performed single‐nucleus RNA sequencing (snRNA‐seq), behavioral tests, and cellular experiments to delineate the impact of urea on oligodendrocyte lineage dynamics. In UT‐B ⁻ / ⁻ mice, the relative abundance of oligodendrocyte subpopulations enriched for mitochondrial transcripts decreased, suggesting vulnerability to urea toxicity. Dlat and MDH1, genes associated with TCA cycle‐related metabolism, were downregulated alongside alterations in mitochondrial and oxidative phosphorylation‐related transcriptional programs. Urea dose‐dependently decreased MDH1 expression, mitochondrial membrane potential, and intracellular ATP content in MO3.13 cells. Regulatory analyses linked MDH1 to energy metabolism and neurodegenerative pathways. Trajectory reconstruction suggested altered differentiation‐ and myelination‐related transcriptional programs in mitochondria‐related oligodendrocytes (MitOLs). The cytoplasmic concentration and fate of oxaloacetic acid (OAA) are regulated by the reversible catalysis of MDH1. OAA supplementation partially restored amygdalar MDH1 expression and alleviated anxiety‐like behaviors in UT‐B ⁻ / ⁻ mice, while improving mitochondrial bioenergetics in urea‐exposed MO3.13 cells. These findings support a candidate metabolic–glial model linking elevated urea, MDH1 dysregulation, oligodendrocyte bioenergetic dysfunction, and anxiety‐like behavior, with potential relevance to CKD‐associated anxiety.

Aging is an inevitable physiological process characterized by progressive functional decline and degenerative alterations across organ systems. Metabolic disturbance, particularly the disruption of substance and energy metabolism, is increasingly recognized as a central hallmark of aging. Emerging evidence suggests that dysregulation of the urea cycle (UC) contributes to aging-related pathological processes, including cognitive impairment; however, its role in astrocyte-mediated brain aging remains unclear. In this study, we used a D-galactose-induced mouse aging model to investigate the involvement of UC activation in age-related cognitive decline. Aging mice exhibited marked cognitive impairment, accompanied by an increased proportion of reactive astrocytes in the hippocampus, a key pathological feature of brain aging. Metabolic analysis and molecular validation revealed enhanced UC activity and increased urea production in aging mice. Inhibition of UC activation reduced urea production and decreased the proportion of hippocampal reactive astrocytes. Mechanistically, the expression of key UC-related enzymes, including ornithine decarboxylase 1 (ODC1) and arginase 1 (ARG1), was significantly downregulated, accompanied by improved mitochondrial dynamics, particularly the restoration of mitochondrial fusion and fission balance. Furthermore, ODC1 knockdown confirmed its critical role in mediating UC activation in astrocytes and significantly alleviated aging-like cellular phenotypes. Notably, Ganoderma lucidum polysaccharide peptides (GLPs) effectively suppressed UC activation in aging astrocytes by downregulating ODC1 and ARG1. Collectively, this study identifies dysregulated astrocytic UC activity as a novel metabolic mechanism linking astrocyte reactivity, mitochondrial dysfunction, and age-related cognitive decline, suggesting that targeting ODC1-mediated UC activation and mitochondrial dynamics may provide a promising dual strategy for combating brain aging.

The understanding of Alzheimer’s disease is shifting from a traditional focus on Aβ/tau pathology to an emerging consensus that positions immune dysregulation as a central synergistic driver in the early stages of the disease. However, the causal relationships between peripheral immune cells, plasma proteins, and Alzheimer’s disease, as well as the mediating effects of plasma proteins on the disease, remain poorly understood. Moreover, there are no effective drug combination therapies targeting plasma proteins for Alzheimer’s disease. This study investigated the causal associations between immune cells, plasma proteins, and Alzheimer’s disease, with a focus on the role of Fc gamma receptor 3A in disease progression. Using a two-sample Mendelian randomization approach, we identified 59 plasma proteins and 65 immune cell types significantly associated with Alzheimer’s disease. We performed data mining of a large Alzheimer’s disease cohort and drug databases and established a biofactor-regulated neural network for rapidly screening and optimizing compound drug pairs. Among the immune cells, CD8 ⁺ T cells, particularly CD8 ⁺ CD28 ⁺ CD45RA. T cells, were found to have a protective effect against Alzheimer’s disease. Furthermore, increased expression of Fc gamma receptor 3A (also known as CD16a, an activating receptors of NK cells) in plasma and the hippocampus correlated with enhanced CD8 ⁺ T-cell infiltration and accelerated Alzheimer’s disease progression in 5×FAD mice. Mediation analysis revealed that Fc gamma receptor 3A mediates the effects of CD8 ⁺ T cells on Alzheimer’s disease risk. Additionally, Fc gamma receptor 3A gene expression levels were significantly higher in patients with Alzheimer’s disease compared with individuals with mild cognitive impairment and cognitively normal participants, as revealed by an analysis of the Alzheimer’s Disease Neuroimaging Initiative database. These findings suggest that CD8 ⁺ T-cell infiltration and Fcγ receptor 3A expression play critical roles in the pathophysiology of Alzheimer’s disease and may serve as therapeutic targets. Molecular docking analysis further identified 19 candidate drugs targeting Fcγ receptor 3A. This study proposes novel immune-based therapeutic strategies and introduces an omics-based intelligent drug discovery framework for repurposing existing drugs for the treatment of complex diseases. The key contributions of this study include the identification of potential immune-based therapeutic targets for Alzheimer’s disease and demonstration of the utility of bioinformatics and drug repurposing approaches in addressing complex neurodegenerative diseases.

GlycoRNA, newly identified RNA molecules bearing glycan modifications on cell membranes, is implicated in cell communication and immune regulation. However, current technological limitations impede a thorough elucidation of their biological roles and clinical significance. Here, we developed N ucleotides H ybridization and A ptamer-based P roximity L igation (NHAPL), a homogeneous assay enabling sensitive and quantitative glycoRNA analysis from 160pg total cell RNA and 1µl serum. NHAPL integrates dual recognition by a sialic acid aptamer and RNA binding probe, followed by ligation and qPCR amplification. We further established multiplexed NHAPL for simultaneous detection of multiple glycoRNA. Using NHAPL, we uncover for the first time that protein-coding mRNAs, specifically 3′ untranslated region (3′UTR) fragments of FNDC3B and CTSS, undergo sialic acid-containing N-glycosylation on the cell surface. These glycoRNAs functionally promote monocyte adhesion to endothelial cells and hepatoma cell migration, revealing a direct role in cell–cell interactions and cancer-related phenotypes. Applying multiplexed NHAPL to human serum, we identify glycoRNA signatures highly specific to systemic lupus erythematosus (SLE). In particular, glycoY5 and glycoU1 achieve near-complete discrimination between patients and healthy controls (area under the curve (AUC) = 1.00 and 0.9977), whereas conventional total RNA analysis fails to capture these differences, highlighting RNA glycosylation modification as a distinct regulatory layer. Its simplicity and flexibility make it well suited for clinical glycoRNA profiling and biomarker discovery. Overall, NHAPL represents a robust and versatile platform for advancing glycoRNA research and diagnostic development.

Background: Argininosuccinate synthase 1 (ASS1), a key enzyme in arginine biosynthesis, is highly expressed in colorectal cancer (CRC) and promotes cancer progression, making it a potential therapeutic target. Evodiamine (EVO), a natural alkaloid from Evodia rutaecarpa acts as a novel Wnt signaling pathway inhibitor with strong anticancer activity against various cancers. However, its exact therapeutic mechanism in CRC remains unclear. Methods: To address this gap, experiments included enzyme-linked immunosorbent assay (ELISA) to test EVO’s effect on CRC arginine production; CCK-8, EdU, colony formation, and wound-healing assays to assess CRC cell proliferation and migration; RT-qPCR, Western blot, immunofluorescence (IF), and ShASS1 for mechanism exploration and target validation; and a syngeneic tumor allograft model to study EVO’s metabolic regulation and anticancer efficacy in CRC. Results: In vitro, EVO significantly inhibited arginine synthesis metabolism and reduced CRC cell proliferation/migration. In vivo, it suppressed tumor tissue arginine metabolism, slowed allograft tumor growth, and decreased ASS1 expression. Mechanistically, EVO concentration-dependently reduced ASS1 via the Wnt/β-catenin/c-MYC pathway; ShASS1 replicated EVO’s anticancer effects, confirming ASS1’s mediating role. Conclusions: EVO downregulates ASS1 via the Wnt/β-catenin/c-MYC pathway disrupts CRC arginine synthesis metabolism and inhibits CRC cell proliferation/migration. These results support the interaction between metabolic regulation and signaling pathways, highlighting EVO as a promising CRC therapeutic candidate.

Parkinson's disease (PD), common neurodegenerative disorder, involves substantia nigra dopaminergic neuron loss and α-synuclein accumulation in Lewy bodies. While pathogenesis remains unclear, dysregulated urea metabolism may play a central role. This study detected elevated serum urea levels in PD patients with upregulated urea cycle enzymes. In MPTP-induced PD mice, urea accumulated in the substantia nigra and striatum, alongside increased activity of urea cycle enzymes (ODC1, ARG1, OTC) and urea transporter UT-B. Mechanistically, brain urea accumulation likely stems from imbalanced urea cycle activity and impaired UT-B-mediated clearance, with compensatory UT-B upregulation specifically in the substantia nigra. In vitro, MPTP-treated neuronal cells showed increased enzyme and UT-B expression, while high urea directly suppressed tyrosine hydroxylase (TH). Importantly, ODC1 knockdown reversed urea dysmetabolism, restored TH, and alleviated neuronal damage. These findings establish ODC1-mediated urea cycle dysregulation as a core metabolic feature of PD, proposing ODC1 or urea metabolism as novel therapeutic targets.