DDIAS Regulation of STAT3/CCL2 Promotes Macrophage Polarization to M1 type in Kawasaki Disease.

OBJECTIVE: To investigate the molecular mechanism by which DNA damage induced apoptosis suppressor (DDIAS) regulates STAT3/CCL2 to enhance macrophage polarization to M1 type in Kawasaki disease (KD). METHODS: A KD vascular model was established by culturing human coronary artery endothelial cells (HCAECs) in vitro. Small interfering RNA of DDIAS (si-DDIAS) was transfected into the KD cell model. The human macrophage cell line THP-1 was induced into M1 macrophages using phorbol myristate acetate (PMA) and lipopolysaccharide (LPS) and co-cultured with the endothelial cells using the HCAECs medium. Western blot analysis was utilized to assess cellular DDIAS, p-STAT3, STAT3, and CCL2 protein expression. MTT was utilized to detect cell proliferation. ELISA was utilized to assess the expression levels of TNF-α, IL-4, IL-6, IL-8 and CCL2 in cell supernatants. Flow cytometry was utilized to examine cell apoptosis and the expression of M1 macrophage surface marker CD86. RESULTS: The expression level of DDIAS was elevated in the KD group compared to the Control group. Serum inhibition of HCAEC proliferation in the KD group was concentration-dependent and pro-inflammatory cytokines were substantially elevated, while the anti-inflammatory cytokines were substantially reduced (P<0.05). Compared to the si-NC group, cell proliferation was considerably enhanced; pro-inflammatory cytokines were substantially reduced; anti-inflammatory cytokines were substantially elevated, and the expression of p-STAT3 and CCL2 was lowered in the si-DDIAS group (P<0.05). The percentage of M1 macrophages was substantially elevated in the THP-1+LPS group compared to the THP-1 group (P<0.05). Compared to the THP-1+LPS+si-NC group, macrophage CCL2 expression was decreased in the THP-1+LPS+si-DDIAS group; the percentage of M1 macrophages was substantially lowered (P<0.05); and the levels of pro-inflammatory cytokines and CCL2 in the cell supernatant were substantially reduced. Incubation of macrophages with STAT3 agonist reversed these changes, which were exacerbated by the addition of neutralizing antibody CCL2. CONCLUSIONS: Downregulation of DDIAS inhibits macrophage polarization toward the M1 type through inhibition of the STAT3/CCL2 signaling pathway and can ameliorate vascular injury and inflammation in KD coronary arteries.

Necrotic Change of Tunica Media Plays a Key Role in the Development of Coronary Artery Lesions in Kawasaki Disease.

BACKGROUND: Alarmins resulting from cell death or oxidative stress are involved in the development of Kawasaki disease (KD) vasculitis. In a previous study, we demonstrated the potential role of interleukin (IL)-33 as an alarmin in the development of KD vasculitis. Although edematous dissociation (necrotic change) of the tunica media is thought to be a major source of IL-33 in KD vasculitis, it has not yet been elucidated. METHODS AND RESULTS: We investigated the impact of IL-33 released from necrotic human coronary artery smooth muscle cells (HCASMCs) on human coronary artery endothelial cells (HCAECs) using a coculture assay. Subsequently, we evaluated the anti-inflammatory effects of anti-IL-33 and anti-suppression of tumorigenicity 2 (ST2) antibodies compared with conventional therapies of KD, such as high-dose IgG or anti-tumor necrosis factor (TNF)-α antibody. Primary necrosis of HCASMCs induced significant release of IL-33. In cocultures of necrotic HCASMCs with HCAECs, the necrotic HCASMCs significantly induced the production of various proinflammatory cytokines in the HCAECs. Anti-IL-33 and anti-ST2 antibodies exhibited unique inhibitory effects on the production of platelet-derived growth factor-BB or IL-12(p70) in HCAECs. CONCLUSIONS: There is potential involvement of edematous dissociation of the tunica media in the development of KD vasculitis. Furthermore, the distinctive anti-inflammatory effects of the anti-IL-33/ST2 axis drugs suggest novel therapeutic options for patients with refractory KD.

Mycoplasma pneumoniae-induced Kawasaki disease via PINK1/Parkin-mediated mitophagy.

Kawasaki disease (KD) is a systemic vasculitis with an unknown cause that primarily affects children. The objective of this study was to explore the function and underlying mechanism of mitophagy in Mycoplasma pneumoniae (MP)-induced KD. To create MP-induced KD models, Human coronary endothelial cells (HCAECs) and DBA/2 mice were employed and treated with Mp-Lipid-associated membrane proteins （LAMPs）. Lactate dehydrogenase (LDH) levels were tested to determine cellular damage or death. The inflammatory cytokines tumor necrosis factor (TNF)--α and interleukin (IL)-6 were measured using the Enzyme-Linked Immunosorbent Assay (ELISA) method. RT-qPCR and Western blotting were used to determine the expression of Intercellular Adhesion Molecule(ICAM)-1, vascular cell adhesion molecule (VCAM)-1, inducible nitric oxide synthase(iNOS), LC3, p62, PINK1(a mitochondrial serine/threonine-protein kinase), and PARKIN(a cytosolic E3-ubiquitin ligase). The adenosine triphosphate （ATP）, reactive oxygen species （ROS）, and mitochondrial membrane potential（MMP） levels were measured to determine mitochondrial function. Mitophagy was investigated using immunofluorescence and a mitophagy detection test. Autophagosome and mitochondrial morphology were examined using transmission electron microscopy. To identify inflammatory cell infiltration, hematoxylin and eosin staining was utilized. Mp-LAMPs increased the levels of TNF-α, IL-6, ICAM-1, VCAM-1, and iNOS in an HCAEC cell model, along with LDH release. After Mp-LAMPs exposure, there was a rise in LC3 and a reduction in p62. Meanwhile, the expression of PINK1 and Parkin was increased. Cyclosporin A dramatically increased ATP synthesis and MMP in HCAEC cells treated with Mp-LAMPs, while suppressing ROS generation, demonstrating excessive mitophagy-related mitochondrial dysfunction. Additionally, neither body weight nor artery tissue were affected due to PINK1 and Parkin suppression Cyclosporin A in Mp-LAMPs-treated mice. These findings indicated that PINK1/Parkin-mediated mitophagy inhibition may be a therapeutic target for MP-induced KD.

Mitochondrial DNA release via the mitochondrial permeability transition pore activates the cGAS-STING pathway, exacerbating inflammation in acute Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an immune vasculitis of unknown origin, characterized by transient inflammation. The activation of the cGAS-STING pathway, triggered by mitochondrial DNA (mtDNA) release, has been implicated in the onset of KD. However, its specific role in the progression of inflammation during KD's acute phase remains unclear. METHODS: We measured mtDNA and 2'3'-cGAMP expression in KD patient serum using RT-qPCR and ELISA. A murine model of KD was induced by injecting Lactobacillus casei cell wall extract (LCWE), after which cGAS-STING pathway activation and inflammatory markers were assessed via immunohistochemistry, western blot, and RT-qPCR. Human umbilical vein endothelial cells (HUVECs) were treated with KD serum and modulators of the cGAS-STING pathway for comparative analysis. Mitochondrial function was evaluated using Mitosox staining, mPTP opening was quantified by fluorescence microscopy, and mitochondrial membrane potential (MMP) was determined with JC-1 staining. RESULTS: KD patient serum exhibited increased mtDNA and 2'3'-cGAMP expression, with elevated levels of pathway-related proteins and inflammatory markers observed in both in vivo and in vitro models. TEM confirmed mitochondrial damage, and further studies demonstrated that inhibition of mPTP opening reduced mtDNA release, abrogated cGAS-STING pathway activation, and mitigated inflammation. CONCLUSION: These findings indicate that mtDNA released through the mPTP is a critical activator of the cGAS-STING pathway, contributing significantly to KD-associated inflammation. Targeting mtDNA release or the cGAS-STING pathway may offer novel therapeutic approaches for KD management.

A pathological study on the efficacy of Syk inhibitors in a Candida albicans-induced aortic root vasculitis murine model.

BACKGROUND: The activation of innate immunity may be involved in the development of Candida albicans-induced murine vasculitis, which resembles Kawasaki disease (KD) vasculitis. This study aimed to histologically clarify the time course of the development of vasculitis in this model in detail and to estimate the potential role of spleen tyrosine kinase (Syk) inhibitors in KD vasculitis. METHODS AND RESULTS: DBA/2 male mice were intraperitoneally injected with a vasculitis-inducing substance and treated with a Syk inhibitor (R788 or GS-9973). Systemic vasculitis, especially in the aortic annulus area, was histologically evaluated. Regarding lesions in the aortic annulus area, some mice in the untreated control group already showed initiation of vasculitis 1 day after the final injection of a vasculitis-inducing substance. The vasculitis expanded over time. Inflammation occurred more frequently at the aortic root than at the coronary artery. The distribution of inflammatory cells was limited to the intima, intima plus adventitia, or all layers. In the Syk inhibitor-treated groups, only one mouse had vasculitis at all observation periods. The severity and area of the vasculitis were reduced by both Syk inhibitors. CONCLUSION: Candida albicans-induced murine vasculitis may occur within 1 day after the injection of a vasculitis-inducing substance. Additionally, Syk inhibitors suppress murine vasculitis.

Autopsy report of a sudden infant death that was strongly suspicious of Kawasaki disease.

We conducted an autopsy on a 3-month-old boy in whom Kawasaki disease (KD) was strongly suspected based on the autopsy findings. The infant had a fever and was brought to a nearby clinic, where he was prescribed antipyretics and kept under observation. However, 15 days after onset of the fever, he suddenly died in bed. He exhibited no obvious redness of the lips, tongue, or conjunctiva. Membranous desquamation was present on his distal fingers. Vasculitis was observed in the coronary arteries, renal artery, splenic artery, and pulmonary vein. In addition, coronary artery aneurysms were present in the right coronary artery and left anterior descending artery. Thrombotic occlusion was observed in one aneurysm in the right coronary artery, resulting in acute myocardial infarction. The coronary artery wall showed infiltration of numerous macrophages and neutrophils. This case was classified as incomplete KD because the coronary artery aneurysm could not be demonstrated before death and was only recognized at autopsy. Pathologists and forensic scientists need to be aware that there are cases in which KD goes undiagnosed and untreated, leading to coronary artery aneurysm formation and sudden death.

Expression of PCT, BNP and Inflammatory Factors in Children with Kawasaki Disease and Their Correlation with Coronary Artery Lesions.

Background: Kawasaki disease (KD), as one of the most common vascular diseases in children, will cause the risk of coronary artery lesions (CAL) without treatment. This study is to explore the expression of procalcitonin (PCT), brain natriuretic peptide (BNP), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and interleukin-6 (IL-6) in children with KD and their correlation with CAL. Methods: 86 KD children in Baoding Hospital of Beijing Children's Hospital were selected as the study subjects from January 2020 to June 2021. According to whether CAL occurred, they were divided into the CAL group (n=30) and NCAL group (n=56). The clinical data of the two groups were collected from the medical record system. The levels of PCT and BNP were detected by chemiluminescence microparticle assay, the CRP level was detected by immunoturbidimetry, and the levels of TNF-α and IL-6 were detected by flow immunofluorescence method. The relationship of PCT, BNP, and inflammatory factors with CAL in KD children was explored by Pearson correlation analysis. Results: The comparative result of clinical data showed no overt difference in gender, disease types, age and blood routine indexes between the two groups, except for coronary artery diameter (P >.05). The levels of PCT, BNP, CRP, TNF-α and IL-6 in CAL group were (1.70±0.39) µg/L, (289.21±29.78) ng/L, (83.16±17.35) mg/L, (9.38±1.23) pg/mL and (59.97±0.97) ng/mL, respectively. The levels of PCT, BNP, CRP, TNF-α and IL-6 in NCAL group were (1.04±0.18) µg/L, (170.85±23.58) ng/L, (69.70±16.64) mg/L, (6.32±0.73) pg/mL and (44.16±11.97) ng/mL, respectively. The levels of each index in the CAL group were notably higher than in the NCAL group (P < .001). Pearson correlation analysis revealed that PCT, BNP, CRP, TNF-α and IL-6 were positively correlated with CAL in KD children (r=0.829, 0.865, 0.823, 0.894, 0.784, P < .001). Conclusion: The increase of PCT, BNP, and inflammatory factors has a certain warning effect on CAL in KD children. In clinical practice, health care professionals should strengthen the detection of PCT, BNP and inflammatory factors in KD children, carry out early monitoring of CAL in children with high expression of biomarkers, and formulate personalized preventive intervention based on the disease progress, so as to reduce the risk of cardiovascular disease. However, due to the limitations of research conditions and methods, the sample size of this study is small, which may affect the reliability and representativeness of the conclusion. In order to provide a new direction for the clinical prevention and treatment of the disease, future work will improve the research design, expand the sample size, and carry out more in-depth exploration on the prediction of CAL in KD children.

Using nomogram scores to predict the early regression of coronary artery aneurysms of Kawasaki disease.

BACKGROUND: Coronary artery aneurysms have been considered the most serious complication of Kawasaki disease. However, some coronary artery aneurysms do regress. Therefore, the ability to predict the expected time of coronary artery aneurysm regression is critical. Herein, we have created a nomogram prediction system to determine the early regression (<1 month) among patients with small to medium coronary artery aneurysms. METHODS: Seventy-six Kawasaki disease patients identified with coronary artery aneurysms during the acute or subacute phase were included. All the patients who met inclusion criteria demonstrated regression of coronary artery aneurysms within the first-year post Kawasaki disease diagnosis. The clinical and laboratory parameters were compared between the groups of coronary artery aneurysms regression duration within and beyond 1 month. Multivariate logistic regression analysis was used to identify the independent parameters for early regression based on the results from the univariable analysis. Then nomogram prediction systems were established with associated receiver operating characteristic curves. RESULTS: Among the 76 included patients, 40 cases recovered within 1 month. Haemoglobin, globulin, activated partial thromboplastin time, the number of lesions, location of the aneurysm, and coronary artery aneurysm size were identified as independent factors for early regression of coronary artery aneurysms in Kawasaki disease patients. The predictive nomogram models revealed a high efficacy in predicting early regression of coronary artery aneurysms. CONCLUSION: The size of coronary artery aneurysms, the number of lesions, and the location of aneurysms presented better predictive value for predicting coronary artery aneurysms regression. The nomogram system created from the identified risk factors successfully predicted early coronary artery aneurysm regression.

[Role and mechanisms of CHI3L1 in coronary artery lesions in a mouse model of Kawasaki disease-like vasculitis]. / CHI3L1åœ¨å·å´Žç— æ ·è¡€ç®¡ç‚Žå°é¼ æ¨¡åž‹å† çŠ¶åŠ¨è„‰æŸä¼¤ä¸­çš„ä½œç”¨åŠæœºåˆ¶ç ”ç©¶.

OBJECTIVES: To explore the role and potential mechanisms of chitinase-3-like protein 1 (CHI3L1) in coronary artery lesions in a mouse model of Kawasaki disease (KD)-like vasculitis. METHODS: Four-week-old male SPF-grade C57BL/6 mice were randomly divided into a control group and a model group, with 10 mice in each group. The model group mice were intraperitoneally injected with 0.5 mL of lactobacillus casei cell wall extract (LCWE) to establish a mouse model of KD-like vasculitis, while the control group mice were injected with an equal volume of normal saline. The general conditions of the mice were observed on the 3rd, 7th, and 14th day after injection. Changes in coronary artery tissue pathology were observed using hematoxylin-eosin staining. The level of CHI3L1 in mouse serum was measured by enzyme-linked immunosorbent assay. Immunofluorescence staining was used to detect the expression and localization of CHI3L1, von Willebrand factor (vWF), and α-smooth muscle actin (α-SMA) in coronary artery tissue. Western blot analysis was used to detect the expression of CHI3L1, vWF, vascular endothelial cadherin (VE cadherin), Caspase-3, B cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), nuclear factor κB (NF-κB), and phosphorylated NF-κB (p-NF-κB) in coronary artery tissue. RESULTS: The serum level of CHI3L1 in the model group was significantly higher than that in the control group (P<0.05). Compared to the control group, the expression of CHI3L1 in the coronary artery tissue was higher, while the expression of vWF was lower in the model group. The relative expression levels of CHI3L1, Bax, Caspase-3, NF-κB, and p-NF-κB were significantly higher in the model group than in the control group (P<0.05). The relative expression levels of vWF, VE cadherin, and Bcl-2 were lower in the model group than in the control group (P<0.05). CONCLUSIONS: In the LCWE-induced mouse model of KD-like vasculitis, the expression levels of CHI3L1 in serum and coronary arteries increase, and it may play a role in coronary artery lesions through endothelial cell apoptosis mediated by inflammatory reactions.

[Platelet-to-lymphocyte ratio as a biomarker for predicting coronary artery lesions in Chinese children with Kawasaki disease: a Meta analysis]. / è¡€å°æ¿ä¸Žæ·‹å·´ç»†èƒžæ¯”å€¼å¯¹ä¸­å›½å·å´Žç— æ‚£å„¿å† çŠ¶åŠ¨è„‰ç— å˜é¢„æµ‹ä»·å€¼çš„Meta分析.

OBJECTIVES: To systematically evaluate the value of the platelet-to-lymphocyte ratio (PLR) in predicting coronary artery lesions (CAL) in Chinese children with Kawasaki Disease (KD). METHODS: A comprehensive search was conducted in databases including PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang Data, China Biomedical Literature Database, and China Science and Technology Journal Database from inception to December 2022. The quality of the included literature was assessed using the Newcastle-Ottawa Scale, and a Meta analysis was performed using Stata 15.1. RESULTS: A total of ten published reports, involving 3 664 Chinese children with KD, were included in this Meta analysis, of whom 1 328 developed CAL. The Meta analysis revealed a sensitivity of 0.78 (95%CI: 0.71-0.83), specificity of 0.71 (95%CI: 0.61-0.80), overall diagnostic odds ratio of 8.69 (95%CI: 5.02-15.06), and an area under the curve of the summary receiver operating characteristic of 0.82 (95%CI: 0.78-0.85) for PLR in predicting CAL in the children with KD. The sensitivity, specificity, and area under the curve of summary receiver operating characteristic were lower for PLR alone compared to PLR in combination with other indicators. Sensitivity analysis demonstrated the stability of the Meta analysis results with no significant changes upon excluding individual studies. However, a significant publication bias was observed (P<0.001). CONCLUSIONS: PLR demonstrates certain predictive value for CAL in Chinese children with KD.

MiR-223-3p affects the proliferation and apoptosis of HCAECs in Kawasaki disease by regulating the expression of FOXP3.

OBJECTIVE: Kawasaki disease (KD) can lead to permanent damage to coronary structures, the pathogenesis of which remains unknown. This experiment was designed to investigate whether miR-223-3p secreted in the serum of KD patients affects the proliferation and apoptosis of HCAECs in KD by regulating FOXP3. METHODS: Blood samples were collected in acute febrile phase of KD, after IVIG treatment, and from healthy controls. Transfected into HCAECs cells by synthetic FOXP3 siRNA/NC. A co-culture system was established between HCAECs cells transfected with FOXP3 siRNA/NC and THP1 cells added with three sera. RESULTS: Compared with the control group, the expressions of miR-223-3p, RORγt, and Th17 in serum of KD patients were significantly upregulated, and the expressions of TGF-ß1, FOXP3 and Treg were significantly downregulated. At the same time, the levels of IL-6, IL-17, and IL-23 were significantly increased, and the levels of IL-10 and FOXP3 were significantly decreased. After IVIG treatment, the patient's above results were reversed. The serum of KD patients increased the expression of miR-223-3p and inhibited the expression of FOXP3 in HCAECs cells. IVIG serum is the opposite. Overexpression of miR-223-3p also promoted the apoptosis of HCAECs. In addition, serum from KD patients promoted apoptosis, whereas serum after IVIG treatment inhibited apoptosis. KD patient serum downregulated the expression of FOXP3, Bcl2, TGF-ß1 and IL-10 in cells, and upregulated the expression of caspase3, Bax, IL-17, IL-6, and IL-23. The opposite results were obtained with IVIG-treated sera. CONCLUSION: miR-223-3p secreted in serum of KD patients can regulate the expression of FOXP3 and affect the proliferation, apoptosis, and inflammation of cells.

CircRNA7632 down-regulation alleviates endothelial cell dysfunction in Kawasaki disease via regulating IL-33 expression.

Kawasaki disease (KD) is a form of idiopathic vasculitis frequently accompanied by coronary artery lesions, which involves endothelial dysfunction. Recent studies have demonstrated that circular RNAs (circRNAs) are implicated in many cardiovascular diseases. However, few studies have examined the role of circRNAs on endothelial dysfunction in KD. In this study, we investigated the role of circ7632 on endothelial-mesenchymal transition (EndoMT) in KD and then explored the underlying mechanism. Children diagnosed with KD and age-matched healthy controls (HC) were included. Sera samples were collected. Primary human umbilical vein endothelial cells (HUVECs) were obtained and incubated with 15% HC and KD serum for 48 h. The mRNA and protein expression of mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) and endothelial marker zonula occludens-1 (ZO-1) in HUVECs transfected with plasmid-circ7632 and si-circ7632 were detected by RT-qPCR and Western blot analysis. CCK8, scratch test, and migration test were performed to examine the effect of circ7632 on the cell proliferation and migration. The circ7632 level was higher in HUVECs treated by KD serum than in HUVECs treated with HC serum. Overexpression of circ7632 significantly increased vimentin and α-SMA expression, decreased ZO-1 expression, and also decreased cell proliferation. Down-regulation of circ7632 expression got the opposite results. RNA-seq analysis, and confirmatory experiment displayed that down-regulation of circ7632 decreased IL-33 expression, and IL-33 silencing mitigated KD serum-mediated EndoMT. Our study revealed that circ7632 level was elevated in KD serum-treated HUVECs. Circ7632 down-regulation could alleviate EndoMT likely through decreasing IL-33 expression. The circ7632 may become a potential therapeutic target for KD.

Potential roles of NLRP3 inflammasome in the pathogenesis of Kawasaki disease.

There is a heterogeneous group of rare illnesses that fall into the vasculitis category and are characterized mostly by blood vessel inflammation. Ischemia and disrupted blood flow will cause harm to the organs whose blood arteries become inflamed. Kawasaki disease (KD) is the most prevalent kind of vasculitis in children aged 5 years or younger. Because KD's cardiovascular problems might persist into adulthood, it is no longer thought of as a self-limiting disease. KD is a systemic vasculitis with unknown initiating factors. Numerous factors, such as genetic predisposition and infectious pathogens, are implicated in the etiology of KD. As endothelial cell damage and inflammation can lead to coronary endothelial dysfunction in KD, some studies hypothesized the crucial role of pyroptosis in the pathogenesis of KD. Additionally, pyroptosis-related proteins like caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), proinflammatory cytokines like IL-1 and IL-18, lactic dehydrogenase, and Gasdermin D (GSDMD) have been found to be overexpressed in KD patients when compared to healthy controls. These occurrences may point to an involvement of inflammasomes and pyroptotic cell death in the etiology of KD and suggest potential treatment targets. Based on these shreds of evidence, in this review, we aim to focus on one of the well-defined inflammasomes, NLRP3, and its role in the pathophysiology of KD.

Protective Roles of Xijiao Dihuang Tang on Coronary Artery Injury in Kawasaki Disease.

PURPOSE: Xijiao Dihuang Tang (XJDHT) is a classical formula of traditional Chinese medicine constituted of Cornu Bubali, Rehmannia glutinosa (Gaertn.) DC., Paeonia lactiflora Pall., and Paeonia suffruticosa Andrews. It was first mentioned in the medical classic "Beiji Qianjin Yaofang" written by Simiao Sun in Tang Dynasty. It shows very strong antipyretic and anticoagulant effects and has been clinically applied to treat various type of blood loss, purple and black spots, heat stroke, and glossitis. Kawasaki disease (KD) is considered as a kind of acute febrile illness in children with systemic vasculitis as the main lesions. The aim of this research is to clarify whether XJDHT can play a protective role in KD. METHODS: A mouse model of Candida albicans water-soluble fraction (CAWS)-induced coronary arteritis and a KD cell model with tumor necrosis factor (TNF)-α induction were employed to investigate the potential effect and mechanism of XJDHT on coronary artery injury in KD. RESULTS: Data showed that XJDHT remarkably alleviated the coronary artery injury of KD mice, as evidenced by reduced inflammation and downregulated expression of pro-inflammatory cytokines interleukin (IL)-1ß and TNF-α. In vitro investigation showed that XJDHT could promote cell proliferation, inhibit cell apoptosis, and improve mitochondrial functions. Subsequent studies demonstrated that XJDHT rescued endothelial cell injury by PI3K/Akt-NFκB signaling pathway. Component analysis of XJDHT detected thirty-eight chemically active ingredients, including paeoniflorin, albiflorin, and paeoniflorigenone, which in in vitro experiments exhibited significant rescue effects on TNF-α-mediated endothelial cell injury. CONCLUSION: Our findings demonstrated that XJDHT mitigated coronary artery injury of KD through suppressing endothelial cell damage via PI3K/Akt-NFκB signaling.

Post-COVID-19 Kawasaki-Like Syndrome.

A 42-year-old man was referred for a week history of severe dysphagia, odynophagia, fever (39 °C), fatigue, abdominal pain, pharyngeal swelling, and multiple neck lymphadenopathies. The medical history reported a mild form of COVID-19 one month ago. The biology reported an unspecified inflammatory syndrome. The patient developed peritonitis, myocarditis, and hepatitis. A myocardium biopsy was performed. A diagnosis of Kawasaki-like disease (KLD) was performed. The occurrence of KLD in adults is rare but has to be known by otolaryngologists regarding the otolaryngological clinical presentation that may precede the multiple organ failure.

MCM8-mediated mitophagy protects vascular health in response to nitric oxide signaling in a mouse model of Kawasaki disease.

Mitophagy is a major quality control pathway that removes unwanted or dysfunctional mitochondria and plays an essential role in vascular health. Here we show that MCM8 expression is significantly decreased in children with Kawasaki disease (KD) who developed coronary artery aneurysms. Mechanistically, we discovered that nitric oxide signaling promotes TRIM21-mediated MCM8 ubiquitination, which disrupts its interaction with MCM9 and promotes its cytosolic export. In the cytosol, MCM8 relocates to the mitochondria pore-forming proteins and promotes their ubiquitination by TRIM21. In addition, MCM8 directly recruits LC3 via its LC3-interacting region (LIR) motif and initiates mitophagy. This suppresses mitochondrial DNA-mediated activation of type I interferon via cGAS and STING. Mice that are deficient in Mcm8, Trim21 and Nos2 or reconstituted with the East-Asian-specific MCM8-P276 variant develop more severe coronary artery vasculopathy in the Lactobacillus casei extract-induced KD model. Collectively, the data suggest that MCM8 protects vascular health in the KD setting.

Kawasaki disease: Surgical treatment.

Kawasaki disease (KD) is a systemic vasculitis of small and medium arteries, preferably affecting coronary arteries. It is one of the most frequent causes of acquired heart disease in children. Despite being comprehensively studied, its etiopathogenesis is not totally explained. The surgical procedures usually become necessary during the late follow-up and may be coronary artery bypass grafting, cardiac defibrillator implantation with or without cardiac resynchronization therapy, or cardiac transplantation.

Surgical treatment of coronary artery lesions in children with Kawasaki disease.

OBJECTIVES: This study aimed to explore the efficacy of different surgical treatment for coronary artery lesions (CALs) caused by Kawasaki disease (KD) in children. METHODS: We retrospectively analyzed the records of children with KD who presented with CALs to our hospital between 2015 and 2022. The patients were aged 126 ± 44.3 months (range: 84-180 months), and their body weight was 37.1 ± 18.6 kg (range: 17-60 kg). All patients were diagnosed with KD and were treated with standard medications. The patients had CALs for an average of 78 months (range: 24-156 months). All children underwent surgical treatment. In addition, one patient underwent cardiac defibrillator implantation, two underwent coronary artery bypass grafting (CABG), and one underwent heart bypass transplantation. The internal thoracic artery was used as the source of the left anterior descending branch bridge tube. The no-touch technique was used to obtain the free right thigh great saphenous vein as the bridge tube of the right coronary artery. RESULTS: All four patients had good postoperative recovery and the cardiac ultrasonography showed improved cardiac function and smooth coronary artery blood flow. The preoperative left ventricular ejection fraction was 44 ± 23.4%, which was significantly improved to 61.4 ± 14.0% postoperatively (p > .05). The preoperative left ventricle size was 5.6 ± 1.6 cm, which was significantly improved to 4.0 ± 0.6 cm postoperatively (p > .05). The two patients who underwent CABG received oral aspirin (5 mg/kg) and clopidogrel (1 mg/kg) antiplatelet therapy. The patients received oral tacrolimus antirejection drugs after the heart transplantation. The postoperative cardiac function was above grade II, and there were no symptoms of cardiac insufficiency, such as syncope, chest tightness, and orthopnea. CONCLUSIONS: Patients with CALs due to KD should be treated in a timely manner. The selection of an appropriate surgical treatment leads to prolonged survival and improved quality of life of patients.

Humoral cross-coronavirus responses against the S2 region in children with Kawasaki disease.

Multisystem Inflammatory Syndrome in Children (MIS-C), a post infectious complication of SARS CoV-2 infection, shares enough features with Kawasaki Disease (KD) that some have hypothesized cross-coronavirus (CoV) immunity may explain the shared pathology. Recent studies have shown that humoral cross-reactivity of the CoVs, particularly of OC43, is focused on the S2 region of the Spike protein. Due to efforts utilizing CoV S2 regions to produce a cross-CoV vaccine, we wished to assess SARS-CoV-2 S2 reactivity in children with KD and assess if cardiac involvement in KD correlated with S2 CoV antibody targeting. The presence of cross-reactivity does not distinguish KD from febrile controls and does not correlate with cardiac involvement in KD. These findings support that, in relation to cardiac vascular inflammation, vaccines targeting the S2 region appear to be a safe approach, but there is disparity in the ability of CoV species to raise cross-reactive S2 targeted antibodies.