The formation of brain vasculature is an essential step during central nervous system development. The molecular mechanism underlying brain angiogenesis remains incompletely understood. The role of Atg7, an autophagy-related protein, in brain angiogenesis was investigated in this study. We found that the microvessel density in mice brains with endothelial-specific knockout of Atg7 (Atg7 EKO) was significantly decreased compared to wild-type control. Consistently, in vitro angiogenesis assays showed that Atg7 knockdown impaired angiogenesis in brain microvascular endothelial cells. Further results indicated that knockdown of Atg7 reduced interleukin-6 (IL-6) expression in brain microvascular endothelial cells, which is mediated by NF-κB-dependent transcriptional control. Interestingly, exogenous IL-6 restored the impaired angiogenesis and reduced cell motility caused by Atg7 knockdown. These results demonstrated that Atg7 has proangiogenic activity in brain angiogenesis which is mediated by IL-6 production in a NF-κB-dependent manner.

Cerebral small vessel disease (CSVD) refers to a group of pathological syndromes that affect the brain’s microcirculation. These conditions involve damage to small arteries, arterioles, capillaries, venules, and small veins. Cerebrovascular risk factors, immunosenescence, and inflammatory responses contribute to the pathogenesis of cerebral small vessel disease. The global impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has drawn significant attention to chronic inflammation caused by infections. Research into the mechanisms by which infections induce CSVD has made continual advancements. It is imperative to reassess the importance of managing infections and the chronic inflammatory phase that follows, highlighting their critical role in the pathogenesis. Our focus encompasses SARS-CoV-2, Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV), Zika Virus(ZIKV), Treponema pallidum, as well as the microbial communities within the gut and oral cavity. These pathogen infections and chronic inflammation can contribute to CSVD through mechanisms such as neuroinflammation, blood-brain barrier disruption, microthrombosis, and endothelial cell damage, thereby promoting the occurrence and progression of the disease. This highlights the need for detailed mechanistic research on CSVD associated with these pathogens. Furthermore, we hope that in the future, we will be able to devise targeted prevention and treatment strategies for CSVD based on the unique characteristics of the pathogenic mechanisms associated with various infections.

Introduction: Coronary involvement in immunoglobulin G4–related disease (IgG4-RD) has remained underexplored despite its risk posed in terms of major adverse cardiovascular events (MACEs). The study provides a comprehensive review, particularly focusing on multimodal imaging characteristics and clinical applicability. Methods: A systematic review was conducted on IgG4-related coronary involvement, supplemented by serial cases from our center included. We analyzed clinical features and multimodal imaging, focusing on the presence or absence of cardiovascular symptoms. Results: A total of 134 IgG4-RD patients with coronary involvement were included and analyzed, including 118 from the literature and 16 from our center. Seven (5%) patients died from secondary myocardial ischemia/infarction. Coronary anomalies commonly affected the left anterior descending artery (LAD) (79%) and presented as diffuse wall thickening or periarterial soft tissue encasement (85%). Stenosis was frequent (47%) and often secondary. Symptoms, primarily induced by myocardial ischemia or infarction (84%), were largely due to stenosis (68%). Chest computed tomography (CT) and coronary computed tomography angiography (CTA) were the primary imaging modalities (81%), particularly in symptomatic cases (88%). Positron emission tomography-computed tomography (PET-CT) was applied in 55 patients (41%) and often in asymptomatic cases (51%). CMR, though less adopted (23%), demonstrated potential in detecting coronary lesions (77%). Glucocorticoid therapy is the most common (76%), with the best response of periarterial encasement (66%). Surgery was less common (32%), primarily being applied to aneurysms (63%). Conclusion: Coronary involvement in IgG4-RD presents four phenotypes, sometimes with an insidious onset and as the sole affected site, poses a potential risk for MACEs. Multimodal imaging is essential for early diagnosis and effective monitoring, with coronary CMR showing promise for early detection without the risk of radiation-induced inflammation and fibrosis.

Psychotic disorders frequently result from repeated ketamine exposure, yet the underlying mechanisms remain elusive. We propose that repeated exposure to ketamine may induce psychotic-like behaviors via DRD1-mediated nuclear signaling pathways. Our investigation focused on phosphorylated DARPP-32 at Thr34, Thr75, and Ser97, alongside transcriptome profiling in both cell and mouse models. We found that DRD1 antagonist mitigated ketamine-induced psychotic-like behaviors and cognitive deficits, whereas DRD1 agonist partially replicated ketamine-like symptoms. In cellular models, ketamine elevated p-Thr34 DARPP-32 levels and facilitated its nuclear accumulation through PKA, while promoting Ser10 H3 phosphorylation by inhibiting PP1 activity. Phosphorylation at Thr75 and Thr97 inhibited p-Thr34 level, with Thr97 enhancing DARPP-32 and PP1 interaction. In vivo, combined approach of RNA-seq and ATAC-seq in the hippocampus indicated that ketamine suppressed neurogenesis. Immunofluorescence showed reduced neonatal neurons and neural stem cells in the dentate gyrus region, while ketamine increased astrocyte numbers. Single-nucleus transcriptome sequencing revealed enhanced neuron-astrocyte interaction post-ketamine treatment. In summary, we identified the DRD1–DARPP-32–Histone H3 pathway as a key mediator of transcriptional abnormalities and impaired hippocampal neurogenesis in ketamine-induced psychotic-like mouse model. Graphical Abstract 1. The generation of neonatal neurons and neural stem was reduced in the dentate gyrus region of the hippocampus in a ketamine-indued schizophrenia-like model. 2. In cellular level, ketamine promoted p-Thr34 DARPP-32 elevation and aggregation into the nucleus via DRD1/PKA, and induced p-Ser10 H3 phosphorylation through inhibition of PP1 activity. 3. The phosphorylation of H3 leads to transcriptional abnormity by chromatin remodeling and ultimately arrests hippocampal neurogenesis and schizophrenia-like behaviors.

Repeated exposure to ketamine leads to mental behavioral disorders and cognitive deficits in mice. As a neurotransmitter receptor, dopamine receptor 1 (DRD1) is involved in mental regulation and memory formation. However, the role of DRD1 in ketamine’s behavioral disorder and neurotoxicity remains unclear. We found that seven-day ketamine exposure induced anxiety-like, depressive-like behavior and cognition dysfunction in mice. DRD1 activation can produce anxiety-like behavior similar to that induced by ketamine. Furthermore, DRD1 activation synergistically exacerbates this effect of ketamine, and DRD1 antagonism partially attenuates the anxiety-like behavior and further aggravated the depressive-like behavior induced by ketamine. Moreover, ketamine induced HT22 cell apoptosis by DRD1 dependent inhibition of Akt/Gsk3β phosphorylation. DRD1 agonist synergistically enhanced the apoptosis induced by ketamine, while DRD1 antagonist or the apoptosis inhibitor partially reversed this apoptosis in vitro. In vivo assay found that ketamine promotes neuronal apoptosis in the hippocampus and prefrontal cortex of mice, and antagonizing DRD1 partially attenuates ketamine-induced apoptosis. In contrast, cell-specific knockdown of DRD1 in neuronal cells exacerbated ketamine-induced neuronal apoptosis and anxiety-like behavior. In summary, ketamine regulates DRD1 to suppress Akt/Gsk3β phosphorylation, inducing neuronal apoptosis, ultimately leading to anxiety-like behaviors in mice. Graphical Abstract 1. Repeated ketamine exposure induced anxiety-like, depressive-like behavior, and neuronal apoptosis in mice. 2. In cellular level, ketamine induced cell apoptosis by DRD1 dependent inhibition of Akt/Gsk3β phosphorylation. 3. Cell-specific knockdown of DRD1 in neuronal cells exacerbated ketamine-induced neuronal apoptosis and anxiety-like behavior.