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PubMed2025

Protective effect of ketamine and bone marrow-derived mesenchymal stem cell on ovarian follicular depletion i̇n a rat i̇schaemia/reperfusion model: An experimental study.

This study investigated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) and ketamine in alleviating ovarian ischemia-reperfusion (I/R) injury in a rat model. Forty-nine female rats were randomly divided into seven groups, each consisting of seven animals: Control, MSC (1 ×10⁶ cells via tail vein), I/R, ketamine (10 mg/kg, i.p.), I/R + ketamine, I/R + MSC, and I/R + ketamine + MSC. Biochemical analyses were performed using ELISA to measure malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), total antioxidant status (TAS), and total oxidant status (TOS). Histological evaluation included histopathological assessment and follicle counting, while the expression levels of TNF-α, IL-6, VEGF, and estradiol receptor (ER) were examined using immunohistochemical staining. Apoptotic cell counts were determined by the TUNEL method.I/R injury caused significant follicular degeneration, vascular congestion, edema, hemorrhage, and leukocyte infiltration, which were markedly improved by both MSC and ketamine treatments. The most pronounced improvement was observed in the MSC group. MSC therapy demonstrated strong anti-inflammatory effects by modulating TNF-α and IL-6, enhanced antioxidant defense by reducing MDA levels and increasing SOD and CAT activity. It exerted anti-apoptotic properties by decreasing the number of TUNEL-positive cells. In conclusion, BM-MSCs exhibited superior and longer-lasting protective effects compared to ketamine in repairing ovarian tissue damage induced by I/R injury and preserving fertility.

Animals↗

PubMed2026

Temporal Transcriptomic Profiling of NMBA-Induced Rat Esophageal Squamous Carcinogenesis Identifies Early Inflammatory Activation and Late NRF2-Associated Oxidative-Stress Remodeling.

Temporal molecular events during early esophageal squamous carcinogenesis remain incompletely defined, in part because human precursor tissues are difficult to obtain sequentially. We used the N-nitrosomethylbenzylamine (NMBA)-induced rat model to characterize stage-associated transcriptional programs during esophageal squamous carcinogenesis. Vehicle-control reference esophageal tissues and NMBA-treated esophageal tissues, collected at weeks 6 and 29, were profiled using Affymetrix Rat Genome 230 2.0 arrays, followed by pathway analysis and qRT-PCR validation of selected genes. Relative to vehicle-control reference tissues, 173 genes were differentially expressed at week 6, whereas 1628 genes were differentially expressed at week 29, indicating marked expansion of transcriptional dysregulation during carcinogenic progression. Sixteen genes were differentially expressed only at week 6, while 157 genes were altered at both time points. Pathway analysis suggested that inflammatory and immunologic processes were prominent during the early response to NMBA exposure, whereas late-stage carcinogenesis was characterized by NRF2-associated oxidative-stress response and dysregulation of multiple glutathione S-transferase family members. A subset of progression-associated genes, including Defb4, Gsta2, Sbsn, Spink5, Plcd4, Hbb, and Hba-a2, showed increasing dysregulation from week 6 to week 29. These findings define temporally distinct molecular programs in NMBA-induced esophageal squamous carcinogenesis and provide a framework for prioritizing candidate pathways and genes relevant to esophageal cancer prevention, early detection, and progression biology.

Animals↗

PubMed2026

LCM-Enriched Proteomic Characterization of Antibody-Mediated Glomerular Damage and Complement Activation in Pre-Clinical Models.

Biologics, lipid nanoparticles, and other therapeutic modalities can result in adverse events, often detected as lesions during preclinical pathology assessments. Characterization of these lesions provides valuable information during drug development to contextualize mechanisms of injury and assess species translatability. Here, we investigated the utility of a laser capture microdissection (LCM)-enriched mass spectrometry proteomics approach to analyze two well-characterized preclinical models of regional (glomerular) injury: Passive Heyman Nephritis in rats and bovine gamma globulin-induced glomerular injury in nonhuman primates (NHPs). Using LCM-enriched proteomics, glomeruli were isolated from formalin-fixed paraffin-embedded kidney tissue in the rat model, enabling identification of 4,661 proteins and quantification of 3,410. Proteinuria measurements were compared with digital pathology metrics of glomerular morphology and proteomics results, with all modalities yielding concordant evidence of glomerular injury and proteomics confirming the role of complement activation. The same LCM- enriched proteomics workflow was applied to an NHP model of induced glomerular damage, identifying 4,623 proteins, quantifying 3,000, and confirming qualitative concordance with established features of complement-mediated glomerular injury. Together, these findings illustrate the applicability of LCM-enriched proteomics for region-specific characterization of antibody-mediated tissue injury and support its use as a hypothesis-generating platform in translational toxicologic pathology.

Animals↗

PubMed2024

Gene expression profiles of endothelium, microglia and oligodendrocytes in hippocampus of post-stroke depression rat at single cell resolution.

Post-stroke depression (PSD) is a common but severe mental complication after stroke. However, the cellular and molecular understanding of PSD is still yet to be illustrated. In current study, we prepared PSD rat model (MD) via unilateral middle cerebral artery occlusion (MCAO) and chronic stress stimulation (DEPR), and isolated hippocampal tissues for single cell sequencing of 10x Genomics Chromium. First, we determined the presence of the increased cell population of endothelium and microglia and the compromised oligodendrocytes in MD compared to NC, MCAO and DEPR. The enriched functions of highly variable genes (HVGs) of endothelium and microglia suggested a reinforced blood-brain barrier in MD. Next, cell clusters of endothelium, microglia and oligodendrocytes were individually analyzed, and the subtypes with distinct functions were identified. The presence of expression profiles, intercellular communications and signaling pathways of these three cell populations of PSD displayed a similar but more aggressive appearance with DEPR compared to MCAO and NC. Taken together, this study characterized the specific gene profile of endothelium, microglia and oligodendrocytes of hippocampal PSD by single cell sequencing, emphasizing the crosstalk among them to provide theoretical basis for the in-depth mechanism research and drug therapy of PSD.

Animals↗

PubMed2026

Enteral Nutrition Is Associated with a Distinct Gut Microbiome Composition and Fermentation Capacity Profile After Acute Colonic Injury in Rats.

Enteral nutrition (EN) is known to promote mucosal healing in inflammatory bowel disease, and multi-omics data suggest that the gut microbiome mediates its therapeutic effects. However, the impact of EN and its components on the gut community during recovery from acute epithelial injury remains incompletely understood. We used whole-genome metagenomic sequencing to investigate the effect of an EN formula based on extruded amaranth flour and pea protein on the gut microbiome in a dextran sulfate sodium (DSS) rat model of acute colonic injury. Three groups were compared, as follows: an unchallenged control (n = 9) with standard chow, a colonic injury (5% DSS; n = 9) group with standard chow, and a colonic injury (5% DSS; n = 9) group with EN. Injury was confirmed histologically (median MCHI score was 2, indicating epithelial damage without inflammation). DSS caused significant weight loss. Animals receiving EN regained baseline weight faster, by day 14, whereas animals on standard chow achieved recovery only by day 21. Differences in energy intake should be further investigated to validate the effect of EN on body weight recovery. At day 21, both injury groups demonstrated higher relative abundances of Bacteroidaceae and Erysipelotrichaceae, including the mucin-degrader Allobaculum mucilyticum, compared with the control group. Conversely, Lactobacillus abundance, notably Lactobacillus acidophilus, was higher in the EN group than in both other groups, as was the inferred capacity for lactate-producing fermentation. These findings suggest that EN is associated with a distinct microbial composition and inferred metabolic profile during the post-injury period, with lactobacilli as one of the potential mediators of its effects.

Animals↗

PubMed2026

Alleviation of allergic rhinitis symptoms in an animal model by Lactiplantibacillus plantarum BGI-N6.

Allergic rhinitis (AR) is a chronic inflammatory disease with rising global prevalence and a substantial public health burden. Current treatments have limited efficacy and tolerability, highlighting the need for new strategies. Probiotics represent a promising approach due to their ability to modulate gut microbiota and host immunity. Here, we investigated the preventive potential of Lactiplantibacillus plantarum BGI-N6 in an OVA/ALUM-induced AR rat model. BGI-N6 administration alleviated AR symptoms and nasal mucosal pathology, reduced key allergic mediators, shifted serum immunoglobulin and cytokine levels toward normal, and restored the Th1/Th2/Th17/Treg balance. Metagenomic sequencing of cecal contents showed that these effects were accompanied by expansion of Bacteroidota-affiliated SCFA-producing taxa, restoration of microbial functional capacity, and identification of 41 core functional genes (KEGG Orthologues) consistently shifted across all three dose groups, with Bacteroides showing the strongest enrichment. Correlation analyses further connected these microbial shifts with immune parameters. These findings support BGI-N6 as a probiotic intervention for AR and implicate gut microbiota remodeling as a central correlate of probiotic-induced immunomodulation.

Animals↗

PubMed2026

Sex-Specific Renal Proteomic Responses to Mycotoxins and Their Mitigation by Bioactive Food Ingredients.

This study aimed to evaluate sex-related differences in kidney toxicity induced by aflatoxin B1 (AFB1) and ochratoxin A (OTA), administered either individually or in combination, and to investigate the mitigating potential of fermented whey (FW) and pumpkin (P) using a proteomic approach in a sub-chronic rat model. Diets naturally contaminated with AFB1 and OTA fungal producers, or enriched with FW and P, were administered to 120 Wistar rats for 28 days. Afterwards, kidneys were collected and subjected to protein extraction and digestion to peptides. For proteomic analysis, peptides were separated using an LC-QTOF-MS system, and differentially expressed proteins between control and treated groups were statistically filtered (p < 0.05) to distinguish sex-related differences between males and females. Proteomic analysis revealed that non-supplemented diets induced significant protein alterations, with male kidneys showing greater sensitivity to mycotoxin exposure, particularly to OTA, and exhibiting a distinct expression pattern compared with females. Notably, FW and FW + P supplementation mitigated these adverse effects by reducing the number of differentially expressed proteins, stabilizing mitochondrial function, and enhancing xenobiotic metabolism pathways. These findings underscore the importance of sex-specific factors in evaluating the protective potential of bioactive ingredients against mycotoxin-induced renal injury.

Animals↗

PubMed2024

Integrative omics analysis identifies biomarkers of septic cardiomyopathy.

Septic Cardiomyopathy (SCM) is a syndrome of acute cardiac dysfunction in septic patients, unrelated to cardiac ischemia. Multiomics studies including transcriptomics and proteomics have provided new insights into the mechanisms of SCM. In here, a rat model of SCM was established by intraperitoneal injection of lipopolysaccharide (LPS). Biomarkers of SCM were characterized via a multi-omics analysis. The differentially expressed (DE) mRNAs predominantly appeared in pathways linked to the immune response, inflammatory response, and the complement and coagulation cascades, while DE proteins were mainly enriched in pathways associated with the complement and coagulation cascades. On this basis, the integrated analysis was performed between transcriptome and proteome. The potential biomarkers were further verified by RT-qPCR and WB. The current proteotranscriptomic research has furnished a valuable dataset and fresh perspectives that will enhance our comprehension of the development of SCM. This, in turn, is expected to expedite the formulation of novel approaches for the prevention and management of SCM in patients.

Cardiomyopathies↗

PubMed2026

The association of cardiovascular health with new-onset pulmonary hypertension and the mediating role of proteomic signatures.

BACKGROUND: The cardiovascular health (CVH) metrics have been reported to play an important role in the development of noncommunicable chronic diseases, yet its link to pulmonary hypertension (PH) risk and the underlying biological mechanisms remain unclear. This study aimed to investigate the association of CVH with PH risk and elucidate the mediating role of plasma proteomic signatures. METHODS: A total of 279 220 participants without PH at enrollment of the UK Biobank were included. Cox regression was used to quantify the association between CVH and incident PH. Proteome-wide association analysis, mediation analysis, and functional enrichment analysis were conducted to identify protein mediators. Key hub proteins were further validated at the transcriptional level through quantitative polymerase chain reaction (qPCR) in an animal model of PH, as well as at the protein level, and by macrophage-specific knockdown of interleukin (IL)-6 and CCL4 to evaluate its impact on rat pulmonary artery smooth muscle cell (PASMC) migration and proliferation. RESULTS: Over a median 13.2-year follow-up, 1325 PH cases occurred. Compared to the lowest CVH, participants with moderate and high CVH had 59% [hazard ratio (HR): 0.41; 95% confidence interval (CI): 0.33-0.49] and 82% (HR: 0.18; 95% CI: 0.14-0.23) lower risk, respectively. Proteomic analyses revealed that this association was significantly mediated by a distinct plasma protein signature. Pathway enrichment analysis indicates that proteins are significantly enriched in inflammatory/immune pathways, and key hub proteins were identified as participating in the central mechanism pathway. In the lung tissue of PH rat models, the mRNA and protein expression levels of IL-6 and C-C motif chemokine ligand 4 (CCL4) were significantly elevated. Furthermore, functional assays demonstrated that knockdown of IL-6 or CCL4 in macrophages significantly attenuated the migration and proliferation of rat PASMCs in vitro. CONCLUSION: High CVH level, defined by Life's Essential 8 (LE8), is significantly linked to a reduced risk of developing PH. This protective effect is primarily mediated by a proteomic signature, revealing the role of signaling pathways such as cytokine-cytokine receptor interaction in the prevention of PH.

Hypertension, Pulmonary↗

PubMed2026

Glucose-6-phosphate dehydrogenase variants modify 3D genomic organization to suppress maladaptive gene expression and vascular disease.

The 3D genome architecture is a higher-order organization of chromosomes within the nucleus that is critical to the control of epigenomic modifications. However, our knowledge regarding the role of 3D genomic organization in the regulation of vascular gene expression and function is lacking. In the present study, CRISPR-engineered rats modelled after two common polymorphisms (S188F and N126D) in human glucose-6-phosphate dehydrogenase (G6PD) revealed modifications to the 3D genome in aortas from rats expressing a deficient G6PD variant (S188F), but not a non-deficient one (N126D), is associated with: 1] up-regulated expression of TET enzymes that augmented expression of genes encoding antiproliferative proteins, 2] suppressed expression of genes encoding inflammatory/thrombotic/fibrotic proteins, and 3] reduced angiotensin II-induced aortic stiffness and hypertension. G6PD interacted with MATRIN-3, a nuclear matrix/scaffold protein, and a deficient G6PD variant increased the relative abundance of MATR3 and CCCTC-binding factors, potentially modifying 3D-genome structure. Additionally, G6PD deficiency-induced enrichment of H3K27ac likely influences the establishment and maintenance of the 3D genome. Therefore, we propose that the nexus between metabolism and the 3D genome regulates arterial gene expression and vascular disease.

Animals↗

PubMed2025

High Hcy regulates fluid shear stress pathway activity through histone H3K79 homocysteinylation in hyperhomocysteinemia-related child hypertension.

BACKGROUND: The rise of hypertension in children has been increasingly associated with hyperhomocysteinemia (HHcy), which is recognized as a major risk factor. However, the underlying mechanisms linking homocysteine and hypertension (termed HHYP) are not fully understood. METHODS: This study utilized plasma samples from 27 control children and 27 children with HHYP (aged 8 ~ 16 years) for TMT6-labeled proteomic quantification, identifying significant altered proteins. Bioinformatics analysis revealed pathway alterations. Verification was carried out via parallel reaction monitoring (PRM) and western blot (WB) analyses. Additionally, a rat model of HHYP induced by high methionine diets, and umbilical vein endothelial cell models exposed to high homocysteine (hcy) levels were developed to investigate the molecular underpinnings further. Protein expression changes and epigenetic modifications were assessed using WB, immunohistochemistry (IHC), and ChIP-qPCR techniques. RESULTS: Key findings indicated that 357 proteins and 69 pathways were altered in children with HHYP. Specifically, 12 proteins within the fluid shear stress and atherosclerosis (FSSA) pathway showed differential expression, including the downregulation of TRX1 and GPX1 and the upregulation of ICAM1. The same expression patterns were noted in both the HHYP rat aortic tissues and the high hcy cultured endothelial cells. Moreover, elevated H3K79hcy modification levels were observed alongside epigenetic regulation of genes related to the FSSA pathway. Importantly, folic acid (FA), a medication frequently used in the clinical treatment of HHYP, has been demonstrated to effectively reverse H3K79hcy modifications and restore the disrupted FSSA pathway in both animal models and cell cultures. CONCLUSIONS: The present study suggests that HHcy may contribute to hypertension through the epigenetic dysregulation of the FSSA pathway mediated by H3K79hcy. Furthermore, the pediatric proteomics data gleaned from this study offer new clinical insights into the pathophysiology of HHYP in children.

Hyperhomocysteinemia↗

PubMed2025

Adiponectin receptor agonist, AdipoRon, restores hepatic clock gene expression in PCOS-associated NAFLD.

Persistent lower levels of adiponectin are associated with hyperandrogenism, predisposing PCOS women to NAFLD. This study elucidated the therapeutic potential of a small molecule adiponectin receptor agonist-AdipoRon, utilizing an in-vivo PCOS rat model mimicking the manifestation of PCOS along with hepatosteatosis. Our study demonstrated that Adiporon reduced lipid accumulation in PCOS-associated NAFLD by alleviating insulin resistance & lipogenesis. AdipoRon also reversed hyperandrogenism and adiponectin deficiency in PCOS animals. In addition, AdipoRon was found to restore altered PCOS-induced hepatic circadian gene expression (Bmal1, Clock, Per3, Cry2, Reverba, and Rora). Interestingly, at the epigenetic level, global transcription activation marks, i.e., H3K4me3, H3K9/14ac, and H3K36me2, were upregulated in disease conditions. Furthermore, our ChIP data confirmed that circadian genes Bmal1, Reverba, And Rora are epigenetically regulated. ChIP assay data showed an increased H3K36 dimethylation at the Bmal1 and Rora promoter, whereas a significant decrease was observed at the Reverbα promoter in PCOS-associated NAFLD. AdipoRon ameliorated these PCOS-induced epigenetic alterations, modulating the hepatic circadian gene expression. We present the preliminary evidence illustrating the epigenetic modulation of AdipoRon, thereby regulating hepatic circadian gene expression. This study provides insights regarding the therapeutic potential of AdipoRon in PCOS-associated NAFLD, which can be of profound clinical significance.

Animals↗

PubMed2025

Transcriptome atlases of rat brain regions and their adaptation to diabetes resolution following gastrectomy in the Goto-Kakizaki rat.

Brain regions drive multiple physiological functions through specific gene expression patterns that adapt to environmental influences, drug treatments and disease conditions. To generate a detailed atlas of the brain transcriptome in the context of diabetes, we carried out RNA sequencing in hypothalamus, hippocampus, brainstem and striatum of the Goto-Kakizaki (GK) rat model of spontaneous type 2 diabetes, which was applied to identify gene transcription adaptation to improved glycemic control following vertical sleeve gastrectomy (VSG) in the GK. Over 19,000 distinct transcripts were detected in the rat brain, including 2794 which were consistently expressed in the four brain regions. Region-specific gene expression was identified in hypothalamus (n = 477), hippocampus (n = 468), brainstem (n = 1173) and striatum (n = 791), resulting in differential regulation of biological processes between regions. Differentially expressed genes between VSG and sham operated rats were only found in the hypothalamus and were predominantly involved in the regulation of endothelium and extracellular matrix. These results provide a detailed atlas of regional gene expression in the diabetic rat brain and suggest that the long term effects of gastrectomy-promoted diabetes remission involve functional changes in the hypothalamus endothelium.

Animals↗

PubMed2026

Histone demethylase PHF2 drives olanzapine-induced dyslipidemia via epigenomic rewiring of hepatic lipogenic genes.

Olanzapine, an atypical antipsychotic agent, is widely used in treating psychotic disorders, yet its metabolic side effects remain a clinical concern. Emerging evidence suggests that dynamic alterations in histone methylation are implicated in olanzapine-induced hepatic lipid metabolic disorders. PHF2, a JmjC family histone demethylase mediating H3K9me2 demethylation, functions as a transcriptional repressor by regulating downstream targets. To elucidate PHF2's role in this process, we utilized an olanzapine-induced dyslipidemia rat model. ChIP-qPCR analysis demonstrated a significant reduction in dimethylated histone H3 lysine 9 (H3K9me2) on the promoters of lipogenic genes (Fasn, Acc1, Scd1) in the liver, accompanied by elevated nuclear expression of PHF2 in olanzapine-treated rats. Co-immunoprecipitation (Co-IP) assays revealed a physical interaction between PHF2 and ChREBP, a glucose-responsive lipogenic transcription factor. Olanzapine was found to enhance the formation of this complex. Overexpression of PHF2 led to upregulated protein levels of FASN/ACC1 and intracellular lipid accumulation, whereas knockdown of PHF2 using siRNA attenuated these effects. Notably, the upregulation of FASN/ACC1 expression induced by olanzapine was markedly diminished in PHF2-deficient AML12 cells via ChREBP-PHF2-mediated H3K9me2 demethylation. Additionally, olanzapine inhibited the nuclear translocation of FOXA2, a PHF2 transcriptional regulator, thereby augmenting PHF2 expression. These findings uncover a novel epigenetic mechanism underlying olanzapine-induced dyslipidemia, positioning the FOXA2-PHF2-ChREBP axis as a potential therapeutic target through modulation of hepatic histone methylation.

Animals↗

PubMed2025

A Multi-omics Exploration Revealing SLIT2 as a Prime Therapeutic Target for Peripheral Facial Paralysis: Integrating Single-Cell Transcriptomics and Plasma Proteome Data.

Peripheral facial paralysis (PFP) is a common neurological disorder characterized by facial-nerve dysfunction. Identifying therapeutic targets and understanding the molecular and cellular mechanisms underlying PFP are crucial for developing effective treatment strategies. This study combined Mendelian randomization (MR) analysis and single-cell RNA sequencing (scRNA-seq) to explore potential therapeutic candidates and their roles in PFP pathophysiology. The MR analysis included 1925 publicly available plasma protein cis-heritability instruments. Instrumental variables were selected for MR analysis to identify plasma proteins associated with PFP, followed by colocalization analysis to evaluate shared genetic variants between the identified proteins and PFP. After the initial identification of plasma proteins associated with Bell's palsy using MR analysis, a rat model of facial-nerve injury was established to further dissect underlying mechanisms at cellular and molecular levels. Using scRNA-seq technology, we delved deeply into cellular Heterogeneity and dynamic changes in gene expression in the facial-nerve nucleus tissues under both injured and control conditions, thereby achieving a systematic study ranging from macroscopic genetic associations to microscopic cellular functions. Finally, expression patterns were preliminarily validated by performing in vitro immunofluorescence analysis on the facial-nerve nucleus samples of SD rats. The MR analysis results identified 30 plasma proteins significantly associated with PFP, with nine target genes showing differential expression in the scRNA-seq data. Colocalization analysis demonstrated that slit guidance Ligand 2 (SLIT2), semaphorin 4D (SEMA4D), EGF containing fibulin extracellular matrix protein 1 (EFEMP1), and sprouty related EVH1 domain containing 2 (SPRED2) shared causal variants with PFP. SLIT2 was highly expressed in the microglia and inhibitory neurons in the experimental group, whereas SEMA4D showed elevated expression across multiple glial cell types in the same group. In contrast, EFEMP1 and SPRED2 showed distinct expression patterns in fibroblasts and oligodendrocytes. The role of SLIT2 has been previously well-documented in many central nervous system diseases. However, for the first time, this study detected SLIT2 alteration after facial-nerve injury. Altered intercellular signaling, particularly enhanced SLIT2-ROBO signaling between neurons and glial cells, was observed in the PFP group. Pseudotime analysis revealed dynamic SLIT2 expression during microglia and inhibitory neuron differentiation, mirroring changes in ROBO1 expression. Immunofluorescence analysis of rat facial-nerve nucleus samples verified that SLIT2 protein levels were significantly increased in the facial-nerve nuclei of injured samples. In conclusion, despite the fact that this study is primarily founded on animal models and despite notable differences existing between animals and humans in terms of the facial motor nucleus, this study successfully identified SLIT2 as potential therapeutic targets for PFP. The SLIT2-ROBO axis stands out as a particularly promising candidate. SLIT2 may play a role in modulating neuroimmune interactions and promoting nerve repair. These findings provide a foundation for future clinical studies and targeted interventions to enhance recovery from PFP. Future research should focus on human sample validation to enhance clinical translation.

Animals↗

PubMed2026

DNA Methylation-Mediated Regulation of TAGLN2 Expression Promotes Pulmonary Arterial Hypertension.

BACKGROUND: Succinylation, a key post-translational modification, is implicated in the metabolic reprogramming and vascular remodeling of pulmonary arterial hypertension (PAH). While epigenetic regulation, particularly DNA methylation, potentially governs succinylation-related gene expression, its causal links to PAH remain unclear. METHODS: We performed an integrative causal analysis using two-sample Mendelian randomization (MR) and summary-data-based MR (SMR) to identify succinylation-related genes that influence PAH risk. We leveraged PAH GWAS data (FinnGen) and gene expression quantitative trait loci (eQTLGen). Subsequently, methylation-mediated effect decomposition was applied using DNA methylation data (GoDMC) to explore epigenetic regulation. Experimental validation was conducted in lung tissues from a monocrotaline (MCT)-induced PAH rat model via quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: Genetic analyses identified a significant causal effect of elevated Transgelin 2 (TAGLN2) expression on increased PAH risk. This effect was mediated by two specific DNA methylation sites, cg13892570 and cg16107628, which influenced PAH pathogenesis by regulating TAGLN2 transcription, with mediation proportions of 86.46 and 97.65%, respectively. Sensitivity analyses supported the robustness of these findings. Consistent with the genetic evidence, TAGLN2 mRNA was significantly upregulated in the lungs of MCT-induced PAH rats. CONCLUSIONS: This study establishes a clear epigenetic causal pathway in which DNA methylation regulates TAGLN2 expression to promote PAH. TAGLN2 is validated as a key disease driver and presents a promising target for diagnostic and therapeutic strategies in PAH.

Animals↗

PubMed2026

Disrupted development of the retina in the Ccdc85c knockout rat.

The coiled-coil domain-containing 85c (Ccdc85c) knockout (KO) rat generated by genome editing exhibits hydrocephalus and subcortical heterotopia. In this study, we aimed to further investigate the function of CCDC85C protein in the development of the retina. Expression of CCDC85C, acetylated tubulin, ciliary rootlet coiled-coil protein (CROCC), zonula occludens-1 (ZO-1), glutamine synthetase, and PAX6 were examined immunohistochemically in wild-type F344 rats at embryonic day (ED) 19 and at postnatal days (PNDs) 0, 4, 6, 13, and 20. Immunoelectron microscopy was performed for CCDC85C in the normal rat retina. Retinal lesions in Ccdc85c KO rats were examined using fundus photography, optical coherence tomography (OCT), and histology. In the normal rat retina, CCDC85C was co-localized with ZO-1 in the outer limiting membrane and persistently expressed after ED19. Ultrastructurally, CCDC85C was located between the outer nuclear layer and the inner segments, and showed the same location as the tight junction. In Ccdc85c KO rats, multifocal retinal dysplasia; disarrangement of the inner and outer segments, cilia, and rootlets; and impaired development of Müller cells were observed. In OCT images, Ccdc85c KO rats showed parallel hyperintense striations in the inner nuclear layer, and low reflectivity of the outer limiting membrane and layer of rods and cones. These results suggest that CCDC85C protein is located in the tight junction complex and is involved in retinal layer formation. The Ccdc85c KO rat model provides a novel tool to study retinal development as well as genetic hydrocephalus.

Ccdc85c↗

PubMed2026

A regulatory network underlying idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which genetic susceptibility interacts with epithelial, immune, and mesenchymal remodeling. Although the chromosome 11p15.5 locus contains established IPF susceptibility signals near MUC5B and TOLLIP, the broader regulatory architecture of this region remains incompletely resolved. METHODS: We integrated IPF genome-wide association study summary statistics with methylation, expression, and protein quantitative trait loci using summary-data-based Mendelian randomization (SMR). SMR-prioritized candidates were evaluated in independent transcriptomic and methylation cohorts and further contextualized using microRNA, transcription-factor, protein-interaction, machine-learning, single-cell, and spatial transcriptomic analyses. Fibrosis-associated expression patterns were assessed in a bleomycin-induced pulmonary fibrosis rat model. RESULTS: The analyses recovered the established MUC5B and TOLLIP signals and prioritized BRSK2 as a comparatively underexplored candidate supported by eQTL-based SMR and independent molecular evidence. The BRSK2 pQTL association did not pass the HEIDI test and was therefore not interpreted as convergent protein-level genetic evidence. Network analyses linked BRSK2 to cell-cycle, metabolic-stress, and senescence-related programs, while cross-cohort machine learning prioritized FOXA2, CDC25B, and NFE2 as informative network features. Single-cell and spatial analyses localized BRSK2 preferentially to fibroblast and myofibroblast compartments and to regions with greater histological fibrosis severity. In fibrotic rat lungs, BRSK2 expression increased, whereas FOXA2 and CDC25B decreased at the transcript and protein levels. CONCLUSIONS: These findings refine the molecular landscape of the chromosome 11p15.5 IPF susceptibility locus and prioritize BRSK2 as a candidate component of an IPF-associated profibrotic fibroblast state. Its causal contribution, direct regulatory relationships, and therapeutic tractability require targeted mechanistic validation.

Idiopathic Pulmonary Fibrosis↗