No abstract

Kawasaki disease (KD) is the most common cause of pediatric cardiac disease in developed countries, and can lead to permanent coronary artery damage and long term sequelae such as coronary artery aneurysms. Given the prevalence and severity of KD, further research is warranted on its pathophysiology. It is known that endothelial cell damage and inflammation are two essential processes resulting in the coronary endothelial dysfunction in KD. However, detailed mechanisms are largely unknown. In this study, we investigated the role of pyroptosis in the setting of KD, and hypothesized that pyroptosis may play a central role in its pathophysiology. In vivo experiments of patients with KD demonstrated that serum levels of pyroptosis-related proteins, including ASC, caspase-1, IL-1β, IL-18, GSDMD and lactic dehydrogenase (LDH), were significantly increased in KD compared with healthy controls (HCs). Moreover, western blot analysis showed that the expression of GSDMD and mature IL-1β was notably elevated in KD sera. In vitro, exposure of human umbilical vein endothelial cells (HUVECs) to KD sera-treated THP1 cells resulted in the activation of NLRP3 inflammasome and subsequent pyroptosis induction, as evidenced by elevated expression of caspase-1, GSDMD, cleaved p30 form of GSDMD, IL-1β and IL-18, and increased LDH release and TUNEL and propidium iodide (PI)-positive cells. Furthermore, our results showed that NLRP3-dependent endothelial cell pyroptosis was activated by HMGB1/RAGE/cathepsin B signaling. These findings were also recapitulated in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). Together, our findings suggest that endothelial cell pyroptosis may play a significant role in coronary endothelial damage in KD, providing novel evidence that further elucidates its pathophysiology.

Normally, smooth muscle cells (SMCs) are localized in the tunica media of the vasculature, where they take responsibility for vascular contraction and extracellular matrix (ECM) generation. SMCs also play a significant role in obedience and elastic rebound of the artery in response to the haemodynamic condition. However, under pathological or stressed conditions, phenotype switching from contractile to synthetic state or other cell types will occur in SMCs to positively or negatively contribute to disease progression. Various studies demonstrated that functional changes of SMCs are implicated in several cardiovascular diseases. In this review, we present the function of vascular SMCs (VSMCs) and the involved molecular mechanisms about phenotype switching, and summarize the roles of SMCs in atherosclerosis, hypertension, arterial aneurysms and myocardial infarction, hoping to obtain potential therapeutic targets against cardiovascular disease in the clinical practices.

As the prevalence of systemic fungal infections caused by Candida albicans gradually increases, it is necessary to explore potential and effective antifungals. Carvacrol is reported to be lethally toxic to C. albicans, involving several potential mechanisms. However, the form and specific mechanism of cell death caused by this compound has not been delineated. In this study, we found that carvacrol could significantly decrease C. albicans survival rates, consistent with previous researches. Further examination proved that carvacrol treatment caused cell membrane permeability and depolarization. To elucidate the association between cell death and apoptosis, DNA fragmentation and metacaspase activation were determined; as expected, these two apoptosis-related markers were clearly observed. Moreover, total and mitochondrial reactive oxygen species (ROS) levels were elevated, and both mitochondrial transmembrane potential and morphology were disrupted. Additionally, cytosolic and mitochondrial calcium levels were also increased by carvacrol. Calcineurin inhibition experiments revealed cyclosporine A (CsA) addition notably rescued cell growth and inhibited metacaspase activation, indicating that carvacrol triggered C. albicans apoptosis through inducing calcineurin activation. Carvacrol was demonstrated to both have low toxicity and be effective in alleviating systemic infections with C. albicans, which might be via its antifungal and immunomodulation activities. This study suggests that carvacrol has excellent potential as a natural protective compound against C. albicans infections.

Many studies have reported that hypocrellin A (HA) exhibits effective antimicrobial activities with proper irradiation. However, its antifungal activity and the involved mechanism have not been fully defined. In this study, HA-mediated cytotoxicity in Candida albicans cells was evaluated after antimicrobial photodynamic therapy (aPDT). The results showed that 1.0 μg/ml HA significantly decreased the survival rate of C. albicans cells with light illumination. Moreover, the ROS levels were also remarkably elevated by HA. Further study found that HA combined with illumination led to cell membrane potential depolarization and cell membrane integrity damage. To investigate the form of cell death, a series of apoptosis-related parameters, including mitochondrial transmembrane potential, metacaspase activity, DNA fragmentation, nuclear condensation, and cytosolic and mitochondrial calcium, were analyzed. Data showed that all the above mentioned apoptosis hallmarks were affected after treatment with HA, indicating that HA induced C. albicans cell apoptosis. Finally, HA-mediated aPDT was demonstrated to be low-toxic and effective in treating cutaneous C. albicans infections. This study highlights the antifungal effect and mechanism of HA-mediated aPDT against C. albicans and provides a promising photodynamic antifungal candidate for C. albicans skin infections.