Decoding molecular signature on heart of septic mice with distinct left ventricular ejection fraction.

Dysregulated cardiac function after sepsis in intensive care unit is known to predict poor long-term outcome and increase mortality. Their pathological feature and molecular mechanism remain unclear. We observed that septic patients with depressed left ventricular ejection fraction (LVEF) have the highest in-hospital and 28 days mortality comparing to patients with hyperdynamic LVEF or with heart failure with preserved LVEF. Echocardiograms reveal that survivors post cecum ligation and puncture (CLP) on rodents have stable LVEF and non-survivors have fluctuated LVEF at CLP early phase. CLP-induced mice fall into three groups based on LVEF 24 h post-surgery: high-, low-, and normal-LVEF. Transcriptomic and proteomic analyses identify jointly and distinctively changed genes, proteins and biologically essential pathways in left ventricles from three CLP groups. Notably, transmission electron microscopy shows different mitochondrial and sarcomere defects associated with LVEF variances. Together, this study systematically characterizes the molecular, morphological, and functional alterations in CLP-induced cardiac injury.

CRISPR/Cas9 editing reveals IRF8 regulated gene signatures restraining plasmablast differentiation.

The transcription factor Interferon regulatory factor 8 (IRF8) is involved in maintaining B cell identity. However, how IRF8 regulates T cell independent B cell responses are not fully characterized. Here, an in vivo CRISPR/Cas9 system was optimized to generate Irf8-deficient murine B cells and used to determine the role of IRF8 in B cells responding to LPS stimulation. Irf8-deficient B cells more readily formed CD138+ plasmablasts in response to LPS with the principal dysregulation occurring at the activated B cell stage. Transcriptional profiling revealed an upregulation of plasma cell associated genes prematurely in activated B cells and a failure to repress the gene expression programs of IRF1 and IRF7 in Irf8-deficient cells. These data expand on the known roles of IRF8 in regulating B cell identity by preventing premature plasma cell formation and highlight how IRF8 helps evolve TLR responses away from the initial activation towards those driving humoral immunity.

Epidemiology of Hand, Foot, and Mouth Disease and Genetic Evolutionary Characteristics of Coxsackievirus A10 in Taiyuan City, Shanxi Province from 2016 to 2020.

In recent years, the prevalence of hand, foot, and mouth disease (HFMD) caused by enteroviruses other than enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16) has gradually increased. The throat swab specimens of 2701 HFMD cases were tested, the VP1 regions of CVA10 RNA were amplified using RT-PCR, and phylogenetic analysis of CVA10 was performed. Children aged 1-5 years accounted for the majority (81.65%) and boys were more than girls. The positivity rates of EV-A71, CVA16, and other EVs were 15.22% (219/1439), 28.77% (414/1439), and 56.01% (806/1439), respectively. CVA10 is one of the important viruses of other EVs. A total of 52 CVA10 strains were used for phylogenetic analysis based on the VP1 region, 31 were from this study, and 21 were downloaded from GenBank. All CVA10 sequences could be assigned to seven genotypes (A, B, C, D, E, F, and G), and genotype C was further divided into C1 and C2 subtypes, only one belonged to subtype C1 and the remaining 30 belonged to C2 in this study. This study emphasized the importance of strengthening the surveillance of HFMD to understand the mechanisms of pathogen variation and evolution, and to provide a scientific basis for HFMD prevention, control, and vaccine development.

Efficacy and safety profile of elexacaftor-tezacaftor-ivacaftor triple therapy on cystic fibrosis: a systematic review and single arm meta-analysis.

Background: Elexacaftor-Tezacaftor-Ivacaftor (ELE/TEZ/IVA) is believed to be an effective and well-tolerated treatment for cystic fibrosis (CF), but the exact efficacy and safety profile are still unknown. Objective: This study aimed to clarify the extent of functional restoration when patients are given with triple combination treatment and demonstrate the prevalence of adverse events, to evaluate the overall profile of ELE/TEZ/IVA on CF. Methods: A literature search was conducted in PubMed, Web of Science and Cochrane Library. Random effects single-arm meta-analysis was performed to decipher the basal characteristics of CF, the improvement and safety profile after ELE/TEZ/IVA treatment. Results: A total 53 studies were included in this analysis. For all the patients in included studies. 4 weeks after ELE/TEZ/IVA treatment, the increasement of percentage of predicted Forced Expiratory Volume in the first second (ppFEV1) was 9.23% (95%CI, 7.77%-10.70%), the change of percentage of predicted Forced Vital Capacity (ppFVC) was 7.67% (95%CI, 2.15%-13.20%), and the absolute change of Cystic Fibrosis Questionnaire-Revised (CFQ-R) score was 21.46 points (95%CI, 18.26-24.67 points). The Sweat chloride (SwCl) was significantly decreased with the absolute change of -41.82 mmol/L (95%CI, -44.38 to -39.25 mmol/L). 24 weeks after treatment, the increasement of ppFEV1 was 12.57% (95%CI, 11.24%-13.90%), the increasement of ppFVC was 10.44% (95%CI, 7.26%-13.63%), and the absolute change of CFQ-R score was 19.29 points (95%CI, 17.19-21.39 points). The SwCl was significantly decreased with the absolute change of -51.53 mmol/L (95%CI, -56.12 to -46.94 mmol/L). The lung clearance index2.5 (LCI2.5) was also decreased by 1.74 units (95%CI, -2.42 to -1.07 units). The body mass index increased by 1.23 kg/m2 (95%CI, 0.89-1.57 kg/m2). As for adverse events, 0.824 (95%CI, 0.769-0.879) occurred during ELE/TEZ/IVA period, while the incidence of severe adverse events was 0.066 (95%CI, 0.028-0.104). Conclusion: ELE/TEZ/IVA is a highly effective strategy and relatively safe for CF patients and needs to be sustained to achieve better efficacy. Systematic Review Registration: Identifier: CRD42023441840.

Evaluation of current medical approaches for COVID-19: a systematic review and meta-analysis.

BACKGROUND: Because of the lack of vaccination, it is urgent to find effective antiviral agents for COVID-19 treatment. METHOD: Online databases were searched for articles published before or on 22 June 2020. Studies reporting the effectiveness and safety of antiviral agents for COVID-19 were analysed. RESULTS: A total of 42 studies were included in this analysis. Hydroxychloroquine (HCQ) was not associated with the incidence of death (risk ratio (RR)=1.08; 95% CI 0.81 to 1.44) and severe cases (RR=1.05; 95% CI 0.61 to 1.81). Patients treated with HCQ obtained few benefits with respect to the clearance of viral RNA and were more likely to have adverse reactions. HCQ treatment could shorten the body temperature recovery time (weighted mean difference = -1.04; 95% CI -1.64 to -0.45). Lopinavir/ritonavir (LPV/r) (RR=0.90; 95% CI 0.76 to 1.07) and Arbidol (RR=1.09; 95% CI 0.92 to 1.29) were not associated with the negative conversion rate. Integrative Chinese-Western medicine alleviated clinical symptoms and decreased the incidence of severe cases (RR=0.38; 95% CI 0.25 to 0.59). Remdesivir treatment reduced the 14-day mortality rate of patients with severe COVID-19 (RR=0.64; 95% CI 0.44 to 0.94). Convalescent plasma (CP) tended to increase the negative conversion rate (RR=2.47; 95% CI 1.70 to 3.57). CONCLUSION: HCQ, LPV/r and Arbidol bring little benefit in COVID-19 treatment. Integrative Chinese-Western medicine improved the clinical symptoms of patients with COVID-19. Remdesivir and CP might be the potential treatments for patients with severe COVID-19. However, large-scale clinical randomised trials are needed to validate our conclusions.

Skincare Habits and Rosacea in 3,439 Chinese Adolescents: A University-based Cross-sectional Study.

The pathogenesis of rosacea remains unclear but has been reported to correlate with skin barrier function. The objective of this study was to elucidate the skincare habits of Chinese adolescents and determine the relationship between skincare habits and rosacea. A university-based cross-sectional investigation included 310 rosacea cases and 3,129 healthy controls who underwent health examinations and completed a questionnaire about daily skincare habits. Fitzpatrick skin phototype IV is a protective factor against rosacea (adjusted adds ratio (aOR) 0.40; 95% confidence interval (CI) 0.22-0.72). Long bath duration (≥ 11 min, aOR 2.60; 95% CI 1.01-6.72) and frequent use of facial cleansers (≥ 2 times/day, aOR 1.70; 95% CI 1.17-2.36) were positively associated with rosacea, but bath frequency (p = 0.22), water temperature (p = 0.53), and sun protection (p = 0.65) were not associated with rosacea. Inappropriate skincare habits, including extended bath durations and frequent use of facial cleansers, significantly increase the risk of rosacea in Chinese adolescents.

Artemisinin, a potential option to inhibit inflammation and angiogenesis in rosacea.

BACKGROUND: Rosacea is a facial chronic inflammatory skin disease with dysfunction of immune and vascular system. Artemisinin (ART), an anti-malaria drug, was reported to have several effects including anti-inflammation and anti-angiogenesis activities. However, the role of ART on rosacea remains unclear. OBJECTIVES: To investigate the effects and molecular mechanism of ART on rosacea. METHOD: In rosacea-like mouse model, the phenotype of rosacea lesions was evaluated by redness score, the inflammatory biomarkers were analyzed by qPCR, and the infiltration of inflammatory cells were assessed by IHC analysis and immunofluorescence. In vitro, LL37-induced expression of inflammatory factors in HaCaT cells was detected by qPCR, potential signaling pathways were detected by Western blotting or immunofluorescence. Migration ability of human umbilical vein endothelial cells (HUVECs) was evaluated by cell scratch and transwell assays. RESULT: The skin erythema and histopathological alteration, as well as the elevated pro-inflammatory factors (IL-1ß, IL6, TNFα) and TLR2 were significantly ameliorated by ART treatment in LL37-induced rosacea-like mice. In addition, ART reduced the infiltration of CD4+ T cells, macrophages and neutrophils, and repressed the expression of immune cells related chemokines (CXCL10, CCL20, CCL2 and CXCL2) in mouse lesions. In HaCaT cells, ART significantly decreased the LL37-induced expression of inflammatory biomarkers. Moreover, we found that ART inhibited rosacea-like inflammation via NF-kB signaling pathways in HaCaT cells. Finally, for vascular dysregulation, ART repressed the angiogenesis in mouse model and inhibited the LL37-induced HUVECs migration in vitro. CONCLUSION: ART ameliorated rosacea-like dermatitis by regulating immune response and angiogenesis, indicating that it could represent an effective therapeutic option for patients with rosacea.

Tranexamic acid ameliorates rosacea symptoms through regulating immune response and angiogenesis.

Rosacea is a chronic inflammatory cutaneous disease characterized by immune system anomalies and vascular hyperreactivity. Recently, therapy of rosacea has improved substantially with the approval of Tranexamic acid (TXA), an antifibrinolytic agent. However, we know little about the underlying mechanism. In this study, we evaluated the effects of TXA and its molecular mechanism on rosacea by using LL37-induced mouse model and HaCaT cell model. Rosacea-like symptoms including skin erythema and histopathological alterations, as well as the elevated pro-inflammatory cytokines (IL-6 and TNFα) and MMP9 expression were significantly ameliorated by TXA treatment. In addition, TXA reduced the expression levels of innate immune gene (TLR2, KLK5 and Camp) and neutrophils relative gene in rosacea-like lesion. For adaptive immune, CD4+ T cell infiltration and the gene expression of Th cytokines and chemokines were regulated by TXA in skin lesion. Furthermore, the anti-inflammatory effects of TXA were associated with the inhibition of TLR2, pro-inflammatory cytokines (IL-6 and TNFα) and chemokines (CCL10) expression in LL37-activated HaCaT cells. Finally, TXA repressed the angiogenesis by reducing the number of CD31+ cell and downregulating the expression levels of VEGF in rosacea. In conclusion, our finding defines a treatment mechanism by which TXA ameliorates rosacea symptoms by regulating the immune response and angiogenesis.

Endoplasmic reticulum stress-mediated autophagy contributes to 5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium-mediated photodynamic therapy via the PERK-eIF2α pathway.

INTRODUCTION: 5-ethylamino-9-diethylaminobenzo[a]phenoselenazinium (EtNBSe) is a novel synthetic bipolar photosensitizer with many promising applications. This study investigated the impact of EtNBSe-mediated photodynamic therapy (EtNBSe-PDT) on the autophagy and endoplasmic reticulum (ER) stress of squamous carcinoma cells (A-431 cells), as well as the related molecular mechanisms. METHODS: The potency of EtNBSe-PDT against squamous cell carcinoma was evaluated in BALB/c nude mice. Cell viability was evaluated using MTT. Western blotting and immunofluorescence were used to determine the expression levels of ER stress- and autophagy-related proteins. RESULTS: Both morphological and microscopic findings showed that the tumor on the xenograft mice exhibited an apparent reduction in volume and was replaced with fibrosis 20 days after EtNBSe-PDT. Additionally, in an in vitro study using A-431 cells, EtNBSe-PDT was found to inhibit A-431 cell survival in an EtNBSe concentration- and light dose- dependent manner, and to induce ER stress via the PERK-eIF2α signaling pathway. Additionally, EtNBSe-PDT could also induce autophagy of A-431 cells. Furthermore, the ER stress inhibitor 4-PBA and the eIF2α inhibitor salubrinal were found to inhibit the autophagy induced by EtNBSe-PDT. CONCLUSION: This study demonstrated that the PERK-eIF2α signaling pathway was involved in the ER stress induced by EtNBSe-PDT. Meanwhile, the ER stress via the PERK-eIF2α pathway promoted the occurrence of autophagy in A-431 cells.