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As a m6A methylation modifier, METTL3 is functionally involved in various biological processes. Nevertheless, the role of METTL3 in osteogenesis is not determined up to date. In the current study, METTL3 is identified as a crucial regulator in the progression of osteogenic differentiation. Loss of METTL3 significantly augments calcium deposition and enhances alkaline phosphatase activity of mesenchymal stem cells, uncovering an inhibitory role of METTL3 in osteogenesis. More importantly, the underlying molecular basis by which METTL3 regulates osteogenesis is illustrated. We find that METTL3 positively regulates expression of MYD88, a critical upstream regulator of NF-κB signaling, by facilitating m6A methylation modification to MYD88-RNA, subsequently inducing the activation of NF-κB which is widely regarded as a repressor of osteogenesis and therefore suppressing osteogenic progression. Moreover, the METTL3-mediated m6A methylation is found to be dynamically reversed by the demethylase ALKBH5. In summary, this study highlights the functional importance of METTL3 in osteogenic differentiation and METTL3 may serve as a promising molecular target in regenerative medicine, as well as in the field of bone tissue engineering.

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.

To analyze the trend changes in the disease burden of depressive disorder (DD) among youth and adolescents aged 10 to 29 years globally from 1990 to 2021 to provide a theoretical basis for the prevention and treatment of DD in young populations. Utilizing data from the Global Burden of Disease Study 2021, prevalence rates and disability-adjusted life years (DALYs) were employed as indicators. Trends in the disease burden of DD among global youth aged 10 to 29 years from 1990 to 2021 were analyzed with joinpoint regression models. The analysis incorporated major risk factors. Concurrently, an age-period-cohort model was used to provide a more comprehensive assessment of the prevalence and burden of DD. Over the past 30 years, the prevalence rates of DD and DALYs rate among the 10–29-year-old age group generally showed an increasing trend, with values for females being consistently higher than values for males. Notably, compared with the other age groups, the 10- to 14- year-old age group presented more significant increases in both prevalence and DALYs. Regional disparity analysis revealed that while high-sociodemographic index (SDI) regions showed an increasing trend in DD prevalence and DALYs, middle- to low-SDI regions showed some decline. This study highlights the global disease burden of depressive disorder among young populations. The significant increase in both prevalence and DALYs in the 10- to 14-year-old age group emphasizes the trend toward an earlier onset of depressive disorder, also underlining the disparities in depressive disorder management between high-SDI and low-SDI regions. Clinical trial number: not applicable.

Kawasaki disease (KD) is an acute vasculitis of pediatric populations that may develop coronary artery aneurysms if untreated. It has been regarded as the principal cause of acquired heart disease in children of the developed countries. Interleukin (IL)-37, as one of the IL-1 family members, is a natural suppressor of inflammation that is caused by activation of innate and adaptive immunity. However, detailed roles of IL-37 in KD are largely unclear. Sera from patients with KD displayed that IL-37 level was significantly decreased compared with healthy controls (HCs). QRT-PCR and western blot analyses showed that the expression level of IL-37 variant, IL-37b, was remarkably downregulated in human umbilical vein endothelial cells (HUVECs) exposed to KD sera-treated THP1 cells. Therefore, we researched the role of IL-37b in the context of KD and hypothesized that IL-37b may have a powerful protective effect in KD patients. We first observed and substantiated the protective role of IL-37b in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). In vitro experiments demonstrated that IL-37b alleviated endothelial cell apoptosis and inflammation via IL-1R8 receptor by inhibiting ERK and NFκB activation, which were also recapitulated in the KD mouse model. Together, our findings suggest that IL-37b play an effective protective role in coronary endothelial damage in KD, providing new evidence that IL-37b is a potential candidate drug to treat KD.

Human umbilical cord mesenchymal stem cell‐derived exosomes (hucMSC‐exosomes) have been implicated as a novel therapeutic approach for tissue injury repair and regeneration, but the effects of hucMSC‐exosomes on coxsackievirus B3 (CVB3)‐induced myocarditis remain unknown. The object of the present study is to investigate whether hucMSC‐exosomes have therapeutic effects on CVB3‐induced myocarditis (VMC). HucMSC‐exosomes were identified using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and Western blot. The purified hucMSC‐exosomes tagged with PKH26 were tail intravenously injected into VMC model mice in vivo and used to administrate CVB3‐infected human cardiomyocytes (HCMs) in vitro, respectively. The effects of hucMSC‐exosomes on myocardial pathology injury, proinflammatory cytokines and cardiac function were evaluated through haematoxylin and eosin (H&E) staining, quantitative polymerase chain reaction (qPCR) and Doppler echocardiography. The anti‐apoptosis role and potential mechanism of hucMSC‐exosomes were explored using TUNEL staining, flow cytometry, immunohistochemistry, Ad‐mRFP‐GFP‐LC3 transduction and Western blot. In vivo results showed that hucMSC‐exosomes (50 μg iv) significantly alleviated myocardium injury, shrank the production of proinflammatory cytokines and improved cardiac function. Moreover, in vitro data showed that hucMSC‐exosomes (50 μg/mL) inhibited the apoptosis of CVB3‐infected HCM through increasing pAMPK/AMPK ratio and up‐regulating autophagy proteins LC3II/I, BECLIN‐1 and anti‐apoptosis protein BCL‐2 as well as decreasing pmTOR/mTOR ratio, promoting the degradation of autophagy flux protein P62 and down‐regulating apoptosis protein BAX. In conclusion, hucMSC‐exosomes could alleviate CVB3‐induced myocarditis via activating AMPK/mTOR‐mediated autophagy flux pathway to attenuate cardiomyocyte apoptosis, which will be benefit for MSC‐exosome therapy of myocarditis in the future.

Coumarin (1,2-benzopyrone), an aromatic oxygen-containing heterocyclic compound, has various biological functions. Previous studies have demonstrated that coumarin and its derivatives exhibit antifungal activity against . In this study, we investigated the exact mechanism by which coumarin works against this fungus using Annexin V-FITC/PI double staining, TUNEL assay, and DAPI staining, and found that it induced a series of apoptotic features, including phosphatidylserine (PS) externalization, DNA fragmentation, and nuclear condensation. Moreover, it also induced cytochrome release from the mitochondria to the cytoplasm and metacaspase activation. Further study revealed that intracellular reactive oxygen species (ROS) levels were increased and mitochondrial functions, such as mitochondrial membrane potential and mitochondrial morphology, were altered after treatment with coumarin. Cytosolic and mitochondrial Ca levels were also found to be elevated. However, pretreatment with ruthenium red (RR), a known mitochondrial Ca channel inhibitor, attenuated coumarin-mediated DNA fragmentation and metacaspase activity, indicating that the coumarin-induced apoptosis is associated with mitochondrial Ca influx. Finally, coumarin was found to be low-toxic and effective in prolonging the survival of -infected mice. This study highlights the antifungal activity and mechanism of coumarin against and provides a potential treatment strategy for infection.

Fibroblast growth factor-18 (FGF18) has diverse organ development and damage repair roles. However, its role in cardiac homeostasis following hypertrophic stimulation remains unknown. Here we investigate the regulation and function of the FGF18 in pressure overload (PO)-induced pathological cardiac hypertrophy. FGF18 heterozygous ( Fgf18 +/− ) and inducible cardiomyocyte-specific FGF18 knockout ( Fgf18-CKO ) male mice exposed to transverse aortic constriction (TAC) demonstrate exacerbated pathological cardiac hypertrophy with increased oxidative stress, cardiomyocyte death, fibrosis, and dysfunction. In contrast, cardiac-specific overexpression of FGF18 alleviates hypertrophy, decreased oxidative stress, attenuates cardiomyocyte apoptosis, and ameliorates fibrosis and cardiac function. Tyrosine-protein kinase FYN (FYN), the downstream factor of FGF18, was identified by bioinformatics analysis, LC-MS/MS and experiment validation. Mechanistic studies indicate that FGF18/FGFR3 promote FYN activity and expression and negatively regulate NADPH oxidase 4 (NOX4), thereby inhibiting reactive oxygen species (ROS) generation and alleviating pathological cardiac hypertrophy. This study uncovered the previously unknown cardioprotective effect of FGF18 mediated by the maintenance of redox homeostasis through the FYN/NOX4 signaling axis in male mice, suggesting a promising therapeutic target for the treatment of cardiac hypertrophy. Although the role of FGFs in cardiovascular disease has attracted extensive attention, the potential role of FGF18 in pathological cardiac hypertrophy remains unknown. Here, the authors show the cardioprotective effect of FGF18 is mediated by maintaining redox homeostasis through FYN/Nox4 signaling.

Kawasaki disease (KD), an acute febrile systemic vasculitis in children, has become the leading cause of acquired heart disease in developed countries. Recently, the altered gut microbiota was found in KD patients during the acute phase. However, little is known about its characteristics and role in the pathogenesis of KD. In our study, an altered gut microbiota composition featured by the reduction in SCFAs-producing bacteria was demonstrated in the KD mouse model. Next, probiotic Clostridium butyricum ( C. butyricum ) and antibiotic cocktails were respectively employed to modulate gut microbiota. The use of C. butyricum significantly increased the abundance of SCFAs-producing bacteria and attenuated the coronary lesions with reduced inflammatory markers IL-1β and IL-6, but antibiotics depleting gut bacteria oppositely deteriorated the inflammation response. The gut leakage induced by dysbiosis to deteriorate the host’s inflammation was confirmed by the decreased intestinal barrier proteins Claudin-1, Jam-1, Occludin, and ZO-1, and increased plasma D-lactate level in KD mice. Mechanistically, SCFAs, the major beneficial metabolites of gut microbes to maintain the intestinal barrier integrity and inhibit inflammation, was also found decreased, especially butyrate, acetate and propionate, in KD mice by gas chromatography-mass spectrometry (GC-MS). Moreover, the reduced expression of SCFAs transporters, monocarboxylate transporter 1 (MCT-1) and sodium-dependent monocarboxylate transporter 1 (SMCT-1), was also shown in KD mice by western blot and RT-qPCR analyses. As expected, the decrease of fecal SCFAs production and barrier dysfunction were improved by oral C. butyricum treatment but was deteriorated by antibiotics. In vitro , butyrate, not acetate or propionate, increased the expression of phosphatase MKP-1 to dephosphorylate activated JNK, ERK1/2 and p38 MAPK against excessive inflammation in RAW264.7 macrophages. It suggests a new insight into probiotics and their metabolites supplements to treat KD.

Purpose Cholestasis is an uncommon complication in Kawasaki disease (KD) that impacts the digestive system. This study aimed to examine the clinical characteristics and associated risk factors of KD complicated by cholestasis. Methods Among the 3026 KD patients admitted to Yuying Children’s Hospital, affiliated with Wenzhou Medical University, from January 1, 2008, to December 31, 2020, all 72 children with cholestasis were included in the study. We performed a comprehensive analysis of the clinical characteristics, prognosis, and potential risk factors associated with KD patients presenting with cholestasis. Results All 72 patients (median age: 34.1 months; 52.8% male) met the diagnostic criteria for cholestatic hepatitis. The mean duration of hospitalization was 10 days. Clinically, the incidence of limb edema and cervical lymphadenitis was relatively low. Pre-treatment assessments of liver function revealed significantly elevated levels of alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase, with median values of 227 U/L, 102 U/L, and 220 U/L, respectively. Abdominal ultrasonography indicated an increased incidence of cholecystitis (12.5%) and hepatosplenomegaly (32.9%), in the absence of gallstones. Additionally, patients demonstrated an increased likelihood of systemic involvement, including pancreatitis and aseptic pyuria, alongside significantly elevated inflammatory markers such as C-reactive protein (CRP), white blood cell count (WBC), and neutrophil levels. All patients received treatment with intravenous immunoglobulin (IVIG) and aspirin, leading to the normalization of liver function indicators within one week. In this study, 25.0% of the patients demonstrated resistance to IVIG therapy, with 2 cases experiencing acute pancreatitis and shock. Furthermore, 25 patients developed coronary artery lesions, which resolved over a 32-month follow-up period as assessed by cardiac ultrasound. Conclusion When KD is complicated by cholestasis, it impacts the liver and bile ducts, leading to liver damage, cholecystitis, and jaundice, while also intensifying systemic inflammatory responses and increasing the likelihood of additional systemic involvements. Despite these complications, the prognosis is generally favorable; however, there is an associated elevated risk of resistance to IVIG therapy.

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.