Percutaneous Transluminal Angioscopy During Coronary Intervention

To investigate the feasibility of angioscopic-guided percutaneous transluminal coronary angioplasty and to elucidate the mechanism of efficacy of coronary stenting for acute myocardial infarction, we performed coronary angioscopy in 102 patients with stable angina or acute myocardial infarction. Thrombi and intimal flaps were observed in most patients after coronary angioplasty. Large intimal splits were seen in one third of patients. Stents were inserted in 10 patients who were revealed to have a large flap or protruding split to the inner lumen. Thrombolytic agents were administered in 2 patients with large thrombi. Additional treatments were required in 32% of patients. No acute myocardial infarction or unstable angina occurred in patients during hospitalization. Thus, angioscopy of the coronary lumen enables clinicians to determine the most appropriate and least risky coronary intervention strategy. In patients with acute myocardial infarction, angioscopy revealed occlusive or protruding thrombi in 34 of 35 patients. The protruding thrombi disappeared after stenting. The frequency of large intimal flaps increased after predilatation with balloon, but these disappeared after stenting. The present angioscopic study demonstrates that the coronary stent compresses the occlusive or protruding thrombi and covers the ruptured thrombogenic plaque Consequently, smooth-surfaced and wide vessel lumen are obtained

STING signalling is terminated through ESCRT-dependent microautophagy of vesicles originating from recycling endosomes

STING炎症シグナルの終結分子機構 --新規細胞内分解システムの発見--. 京都大学プレスリリース. 2023-03-14.Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation. Although the molecular machinery of STING activation is extensively studied and defined, the one underlying STING degradation and inactivation has not yet been fully elucidated. Here we show that STING is degraded by the endosomal sorting complexes required for transport (ESCRT)-driven microautophagy. Airyscan super-resolution microscopy and correlative light/electron microscopy suggest that STING-positive vesicles of an RE origin are directly encapsulated into Lamp1-positive compartments. Screening of mammalian Vps genes, the yeast homologues of which regulate Golgi-to-vacuole transport, shows that ESCRT proteins are essential for the STING encapsulation into Lamp1-positive compartments. Knockdown of Tsg101 and Vps4, components of ESCRT, results in the accumulation of STING vesicles in the cytosol, leading to the sustained type I interferon response. Knockdown of Tsg101 in human primary T cells leads to an increase the expression of interferon-stimulated genes. STING undergoes K63-linked ubiquitination at lysine 288 during its transit through the Golgi/REs, and this ubiquitination is required for STING degradation. Our results reveal a molecular mechanism that prevents hyperactivation of innate immune signalling, which operates at REs

Disturbance of Intracerebral Fluid Clearance and Blood–Brain Barrier in Vascular Cognitive Impairment

The entry of blood-borne macromolecular substances into the brain parenchyma from cerebral vessels is blocked by the blood−brain barrier (BBB) function. Accordingly, increased permeability of the vessels induced by insult noted in patients suffering from vascular dementia likely contributes to the cognitive impairment. On the other hand, blood-borne substances can enter extracellular spaces of the brain via endothelial cells at specific sites without the BBB, and can move to brain parenchyma, such as the hippocampus and periventricular areas, adjacent to specific sites, indicating the contribution of increased permeability of vessels in the specific sites to brain function. It is necessary to consider influx and efflux of interstitial fluid (ISF) and cerebrospinal fluid (CSF) in considering effects of brain transfer of intravascular substances on brain function. Two pathways of ISF and CSF are recently being established. One is the intramural peri-arterial drainage (IPAD) pathway of ISF. The other is the glymphatic system of CSF. Dysfunction of the two pathways could also contribute to brain dysfunction. We review the effects of several kinds of insult on vascular permeability and the failure of fluid clearance on the brain function

Distribution of Monocarboxylate Transporters in Brain and Choroid Plexus Epithelium

The choroid plexus (CP) plays central roles in regulating the microenvironment of the central nervous system by secreting the majority of cerebrospinal fluid (CSF) and controlling its composition. A monolayer of epithelial cells of CP plays a significant role in forming the blood–CSF barrier to restrict the movement of substances between the blood and ventricles. CP epithelial cells are equipped with transporters for glucose and lactate that are used as energy sources. There are many review papers on glucose transporters in CP epithelial cells. On the other hand, distribution of monocarboxylate transporters (MCTs) in CP epithelial cells has received less attention compared with glucose transporters. Some MCTs are known to transport lactate, pyruvate, and ketone bodies, whereas others transport thyroid hormones. Since CP epithelial cells have significant carrier functions as well as the barrier function, a decline in the expression and function of these transporters leads to a poor supply of thyroid hormones as well as lactate and can contribute to the process of age-associated brain impairment and pathophysiology of neurodegenerative diseases. In this review paper, recent findings regarding the distribution and significance of MCTs in the brain, especially in CP epithelial cells, are summarized

Glucose, Fructose, and Urate Transporters in the Choroid Plexus Epithelium

The choroid plexus plays a central role in the regulation of the microenvironment of the central nervous system by secreting the majority of the cerebrospinal fluid and controlling its composition, despite that it only represents approximately 1% of the total brain weight. In addition to a variety of transporter and channel proteins for solutes and water, the choroid plexus epithelial cells are equipped with glucose, fructose, and urate transporters that are used as energy sources or antioxidative neuroprotective substrates. This review focuses on the recent advances in the understanding of the transporters of the SLC2A and SLC5A families (GLUT1, SGLT2, GLUT5, GLUT8, and GLUT9), as well as on the urate-transporting URAT1 and BCRP/ABCG2, which are expressed in choroid plexus epithelial cells. The glucose, fructose, and urate transporters repertoire in the choroid plexus epithelium share similar features with the renal proximal tubular epithelium, although some of these transporters exhibit inversely polarized submembrane localization. Since choroid plexus epithelial cells have high energy demands for proper functioning, a decline in the expression and function of these transporters can contribute to the process of age-associated brain impairment and pathophysiology of neurodegenerative diseases