A 14-year-old castrated male spitz dog was presented with intermittent coughing. Physical examination revealed bradycardia and a grade 3/6 left apical systolic murmur. Thoracic radiographs demonstrated severe bulging of the aortic arch with focal dorsal deviation of the trachea. Echocardiography revealed marked dilation involving the sinotubular junction and extending into the ascending aorta without discernible physiologic causes, with moderate aortic regurgitation and mild mitral regurgitation secondary to myxomatous degeneration. Electrocardiography showed a 2:1 second-degree atrioventricular block. Idiopathic thoracic aortic aneurysm was presumptively diagnosed. The dog was managed medically with pimobendan, theophylline, and famotidine. Clinical signs and electrocardiographic abnormalities improved, and the dog remained stable for 13 mo. Key clinical message: This case report demonstrates the diagnostic and therapeutic challenges and clinical relevance of idiopathic thoracic aortic aneurysm in dogs.

TGR5 and FXR are key regulators of metabolic homeostasis and cardiovascular health. Since the cardioprotective capacity of TGR5 activation and FXR inhibition has been recognized, dual modulation of these targets offers a promising therapeutic strategy for myocardial ischemia/reperfusion injury. Herein, sulfonyl benzoic acid derivatives were identified as effective bidirectional modulators, with compound E6 emerging as a potent lead compound. E6 demonstrated robust dual-target activity, significantly preserving cardiomyocyte viability and attenuated reactive oxygen specie overproduction in hypoxia/reoxygenation models. Moreover, oral administration of E6 markedly reduced infarct size and improved cardiac contractile function after ischemia/reperfusion in vivo, without inducing gallbladder-related side effects. Notably, E6 demonstrated superior efficacy in restoring systolic function compared to mono-regulators. Transcriptomic analysis and subsequent validation studies suggested that its therapeutic effects are mediated through favorable modulation of inflammatory response, attenuation of apoptosis, and enhanced cardiomyocytes survival. Our findings underscore the therapeutic advantages of dual TGR5/FXR targeting and establish E6 as a promising bifunctional lead compound for the treatment of myocardial ischemia/reperfusion injury.

Renal ischemia-reperfusion injury (RIRI) is one of the main causes of acute kidney injury (AKI), and its pathological mechanism is complex, mainly involving multiple pathological processes such as oxidative stress outbreak, uncontrolled inflammatory response, abnormal cell apoptosis, and microcirculatory disorders. Currently, there is a lack of efficient and accurate diagnosis and treatment strategies in clinical practice. As a cross discipline integrating nanomaterials, medicine and biology, nanomedicine has shown unique advantages and broad application prospects in the diagnosis and treatment field of RIRI in recent years. Its core carriers include inorganic nanoparticles, polymeric nanoparticles, nanoenzymes, extracellular vesicles, cell membrane camouflage nanoparticles and injectable nanohydrogels. The diagnosis and treatment system based on nanomedicine can breakthrough the limitations of traditional diagnosis and treatment models, and play an important role in early accurate diagnosis, targeted drug delivery, precise treatment of lesion sites, and prolonged drug circulation time in RIRI. It effectively solves pain points such as strong toxicity, short circulation time, and poor targeting of single drugs. However, the specific mechanism of action of nanomedicine in RIRI has not been fully elucidated, and issues such as the biosafety, in vivo metabolic patterns, and clinical translation bottlenecks of nanomedicine still need to be urgently addressed. This review aims to systematically review the application and mechanism research progress of nanomedicine in RIRI, briefly explain the core pathological mechanism of RIRI, focus on the application effects and mechanisms of nanomedicine systems composed of different types of nanocarriers in RIRI diagnosis and treatment, summarize the current research challenges and look forward to future development directions, providing theoretical basis and practical reference for in-depth research, technological breakthroughs, and clinical translation of nanomedicine in the field of RIRI.

Hypoxic-ischemic brain damage (HIBD) involves profound metabolic reprogramming, where aberrant glycolysis links to neuronal injury. This study aimed to identify and characterize glycolysis-related hub genes in HIBD.

Glycolysis-related differentially expressed genes (DEGs) were screened from the HIBD dataset GSE144456 by combining differential expression analysis, weighted gene co-expression network analysis (WGCNA), and a glycolysis gene set. Hub genes were further identified via enrichment and protein-protein interaction (PPI) network analyses and validated in an independent dataset (GSE23317) and our internal RNA-seq. The key hub gene was confirmed in a mouse HIBD model using RT-qPCR and Western blot. To perturb Hexokinase 2 (Hk2), 3-bromopyruvate (3-BrPA, 1 mg/kg) was administered 1 hour post-HIBD, and its effects were evaluated by MRI, molecular assays, and behavioral tests.

Bioinformatics analysis identified Hk2 as a key hub gene that was consistently upregulated in HIBD. In vivo experiments demonstrated that both HK2 protein and mRNA levels were significantly elevated 24 hours after HIBD (P < 0.001). Double immunofluorescence staining further revealed that the upregulated HK2 was predominantly localized to Iba1⁺ microglia. Early administration of 3-BrPA reduced acute cerebral infarction volume (P < 0.001), improved neurological function scores (P < 0.001), and concurrently​ downregulated HK2 protein levels (P < 0.05). 3-BrPA treatment also significantly reduced lactate accumulation in the injured brain tissue (P < 0.001). ​It also​ suppressed the mRNA expression of pro-inflammatory cytokines (Tnf, Il1b, and Il6; all P < 0.001) and modulated the protein levels of inflammatory markers (iNOS, ARG1; P < 0.05 and P < 0.01, respectively). Moreover, this single early intervention significantly mitigated long-term brain tissue loss and improved motor coordination and exploratory behavior at 30 days post-injury (P < 0.05).

Hk2 is highlighted as a critical node associated with both glycolytic reprogramming and neuroinflammation in HIBD, with upregulation primarily in microglia. Early perturbation of glycolysis with 3-BrPA is associated with multifaceted benefits. Our findings link the Hk2-glycolysis axis to neuroinflammation, offering a rationale for exploring metabolic interventions in HIBD.

To report a rare case of overlapping features of Behçet's uveitis and multizonal outer retinopathy and retinal pigment epitheliopathy (MORR), documented by longitudinal multimodal imaging.

A single case report.

A 37-year-old male presented with unilateral, painless, progressive vision loss and a history of recurrent oral ulcers. Multimodal imaging with longitudinal follow-up documented bilateral, progressive outer retinopathy concurrent with retinal vasculitis. These features characterize an acute progressive episode not previously described.

This case highlights the importance of multimodal imaging and reminds clinicians to remain vigilant to possible concurrent outer retinopathy in Behçet's uveitis. Furthermore, given the favorable treatment response observed here, this case also offers a reference for the therapeutic strategy of MORR.

Microvascular alterations can be detected with nailfold videocapillaroscopy, useful for systemic sclerosis (SSc) diagnosis upon identification of the "scleroderma pattern" (NVC-SP). However, this pattern is missing in a subset of SSc patients.

This retrospective analysis on the multicenter Italian SPRING cohort of SSc patients assessed the prevalence and characteristics of patients without NVC-SP. Associations with demographic and clinical features were evaluated using logistic regression (cross-sectional) and mixed-effects models (longitudinal).

Out of 1689 SSc patients with available NVC information, 90 (5.3%) did not have the NVC-SP. These patients were older at SSc onset (53 vs. 49 years) and more frequently sine scleroderma (31% vs 12%, p < 0.001). The overall burden of vascular complications was milder in this subset, with a lower prevalence of pitting scars (33% vs 48%), telangiectasias (52% vs 74%), and calcinosis (3.4% vs 12%). During the follow-up, mRSS remained lower (60-month mean 4 vs 7, p = 0.002), as well as the estimated probability of vascular complications. Moreover, despite comparable values at baseline, DLCO remained significantly higher in patients without NVC-SP at the following time points (12, 24, and 60 months, p < 0.05). The presence of "late" NVC-SP was independently associated with ILD (OR 1.83, 95% CI 1.05-3.18).

The absence of NVC-SP in 5.3% of SPRING SSc patients may identify a subset characterized by milder disease, with a lower burden of vascular and organ complications. Conversely, lung involvement was more frequently observed in patients with more severe NVC microangiopathy.

We describe a unique case where a combination of aortic bioprosthetic failure, mitral bioprosthetic thrombosis and a previously untreated pseudoaneurysm of the intervalvular fibrosa mimicked infective endocarditis. Clinical examination, review of patient's history and old imaging studies together with an extensive negative infectious workup allowed the correct diagnosis and appropriate management. Multimodality imaging, including echocardiography, 4D-CT and PET-CT were critical in confirming a non-infectious etiology. TAKE-HOME MESSAGE: A unifying diagnosis of infective endocarditis was incorrect, with multiple diseases responsible for the clinical findings. This is yet another instance when Hickam's dictum trumps Occam's razor - all due to multimodality imaging.

Cardiomyopathies frequently arise from rare, highly penetrant coding variants with variable clinical expressivity. Genome-wide association studies (GWAS) suggest significant polygenic contributions to cardiovascular diseases, including cardiomyopathy. Most GWAS loci map to poorly conserved noncoding regions, requiring human genome context for experimental validation.

We created engineered heart tissues (EHTs) from human induced pluripotent stem cell-derived cardiomyocytes and primary cardiac fibroblasts. We assayed single-cell gene expression and chromatin accessibility to generate comprehensive genome-wide regulatory maps. Open chromatin regions were integrated with chromatin contact information and used to fine-map cardiomyopathy GWAS single-nucleotide polymorphisms. Single-nucleotide polymorphisms and their associated open chromatin regions were assessed using reporter assays, genome editing, and expression profiling.

EHT Single-cell RNA-seq recapitulated major cardiac cell types, with advanced cardiomyocyte maturation compared with monolayer human induced pluripotent stem cell cardiomyocytes. More than 400 000 open chromatin regions were resolved to cell types and assayed for transcription factor motifs. Functional fine-mapping of GWAS loci prioritized 5817 variants, and reporter assays validated allele-specific enhancer activity. We identified an intergenic chr3p25.1 locus harboring significant GWAS signals from both dilated cardiomyopathy and left ventricular ejection fraction. Several of these variants lie in open chromatin regions participating in long-range chromatin interactions with SLC6A6 and GRIP2. Haplotype-resolved and synthetic reporter assays confirmed enhancer activity and narrowed candidate single-nucleotide polymorphisms. CRISPR-deletion of this region reduced expression of both SLC6A6 and GRIP2, indicating the enhancer regulates the expression of multiple genes. EHTs with the enhancer deletion displayed markedly reduced contractile function, confirming that this enhancer region contributes to myocardial function.

EHTs are an experimentally tractable platform for testing the function of noncoding variants as modifiers of cardiomyopathy. Variants fine-mapped from cardiomyopathies using EHT regulatory maps have functional consequences and provide a set of prioritized sites to advance the study of polygenic heart failure.

SUMOylation plays critical roles in both initiation and development of atherosclerosis. SUMO-specific protease 3 (SENP3), a SUMO-specific protease that targets SUMO2/3 for deSUMOylation, is involved in vascular remodeling and the modulation of macrophage functions. Here, we probed for the role of SENP3 in macrophages in the development of atherosclerosis. Stable and unstable plaques were collected from patients with atherosclerosis. A macrophage-specific SENP3 knockout mouse (Senp3^Mac-KO) was generated and performed for a murine atherosclerosis model. Transcriptional sequencing was performed to identify potential mechanisms. SENP3 expression in macrophages was increased in unstable plaques, compared to stable plaques. The mean fluorescence intensity of SENP3 in macrophages infiltrating carotid plaques was positively correlated with circulating pro-inflammatory cytokines, low density lipoprotein (LDL-C), and triglycerides in atherosclerosis patients. Senp3^Mac-KO mice exhibited a markedly reduced atherosclerotic plaque area in the aorta, compared to wild-type mice. Knockdown of SENP3 in macrophages resulted in decreased secretion of pro-inflammatory cytokines, increased secretion of anti-inflammatory factors, and reduced foam cell formation. Transcriptional analysis identified significant enrichment in Toll-like receptor (TLR4) signaling pathway modulated by SENP3. Genetic deletion of either TLR4 (Tlr4^-/-) or Sterol O-Acyltransferase 2 (SOAT2) (Soat2^-/-) attenuated the exacerbation of atherosclerosis development induced by SENP3 overexpression. Furthermore, SENP3 regulated TLR4 and SOAT2 expression indirectly via the transcription factor MYC rather than through direct deSUMOylation of TLR4 or SOAT2 themselves. Downregulation of SENP3 in macrophages suppresses pro-inflammatory cytokine release by inhibiting TLR4 signaling and reduces foam cell formation by impeding SOAT2 expression, both mediated by the transcription factor MYC, thereby attenuating the development of atherosclerosis. Hence, SENP3 may represent a potential therapeutic target in atherosclerosis.