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Forkhead box O3a (FOXO3a)-mediated mitochondrial dysfunction plays a pivotal effect on cardiac hypertrophy and heart failure (HF). However, the role and underlying mechanisms of FOXO3a, regulated by breviscapine (BRE), on mitochondrial function in HF therapy remain unclear. This study reveals that BRE-induced nuclear translocation of FOXO3a facilitates mitofusin-1 (MFN-1)-dependent mitochondrial fusion in cardiac hypertrophy and HF. BRE effectively promotes cardiac function and ameliorates cardiac remodeling in pressure overload-induced mice. In addition, BRE mitigates phenylephrine (PE)-induced cardiac hypertrophy in cardiomyocytes and fibrosis remodeling in fibroblasts by inhibiting ROS production and promoting mitochondrial fusion, respectively. Transcriptomics analysis underscores the close association between the FOXO pathway and the protective effect of BRE against HF, with FOXO3a emerging as a potential target of BRE. BRE potentiates the nuclear translocation of FOXO3a by attenuating its phosphorylation, other than its acetylation in cardiac hypertrophy. Mechanistically, over-expression of FOXO3a significantly inhibits cardiac hypertrophy and mitochondrial injury by promoting MFN-1-mediated mitochondrial fusion. Furthermore, BRE demonstrates its ability to substantially curb cardiac hypertrophy, reduce mitochondrial ROS production, and enhance MFN-1-mediated mitochondrial fusion through a FOXO3a-dependent mechanism. In conclusion, nuclear FOXO3a translocation induced by BRE presents a successful therapeutic avenue for addressing cardiac hypertrophy and HF through promoting MFN-1-dependent mitochondrial fusion. [Display omitted] • Breviscapine protects against pathological cardiac hypertrophy and heart failure. • The FOXO3a/MFN-1 signaling is partly involved in the mitochondrial dysfunction in cardiac hypertrophy. • Nuclear FOXO3a translocation by breviscapine promotes MFN-1 mediated mitochondrial fusion. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Ainsliaea fragrans Champ. (A. fragrans) is used to treat infection of the lower genital tract in gynecology, such as cervicitis and pelvic inflammatory disease. This study analyzed the therapeutic efficiency of A. fragrans on cervicitis and the inhibition mechanism of AF-p2 in MALP-2-stimulated RAW264.7 cells. Materials and methods The anti- Ureaplasma urealyticum (Uu) activity of A. fragrans and AF-p2 were determined by antimicrobial susceptibility testing. The activity of A. fragrans extracts (AFext) was evaluated in female BALB/c mice with cervicitis induced by Uu. Furthermore, the therapeutic mechanism of AFext and AF-p2 on myeloid differentiation factor 88 (MyD88) pathway were studied in macrophage activating lipopeptide-2 (MALP-2) irritated RAW264.7 cells. Results AFext could suppress the proliferation of Uu in vitro , including the azithromycin resistant strains. Meanwhile, AFext prevented cervicitis caused by Uu infection in BALB/c mice. Moreover, both AFext and AF-p2 could significantly suppress the nitric oxide (NO) production as well as other proinflammatory cytokines (IL-1β,IL-6,TNF-α) in MALP-2 stimulated RAW264.7 cells. Moreover, AF-p2 also down-regulated iNOS, p65, Iκ-Bα, MyD88 and cyclooxygenase-2 (COX-2) levels in RAW264.7 cells. Conclusion This study indicated that AFext had a therapeutic effect in cervicitis induced by Uu infection. Furthermore, the lead compound AF-p2 showed an anti-infectious effect in MALP-2 irritated RAW264.7 cells through downregulating MyD88-NF-κB signaling pathway. Image 1 [ABSTRACT FROM AUTHOR]

The Ordovician-Silurian (O S) transition witnessed dramatic tectonic, climatic, marine, and biological coevolution, during which organic-rich black shale was widely deposited and is considered an important source rock. However, the potential links between the differential enrichment pattern of organic matter and climate fluctuations and paleoenvironmental evolution during this period are still unclear. In this paper, the Late Ordovician-early Silurian black shale in a JieLong (JL) section in South China was identified by graptolitic fossils, total organic carbon (TOC) content, X-ray diffraction (XRD), scanning electron microscopy (SEM) and geochemical analysis. The results show that the provenances of sedimentary rocks are all granodiorite-like. According to the variations in the TOC content and geochemical indicators, four layers are delineated. Under warm and humid climatic conditions, sea level rise and unstable seasonal upwelling led to Unit 1 organic matter enrichment controlled by high primary productivity, anoxic conditions and effective smectite production. Unit 2 organic matter burial was controlled by cold, arid and oxic environmental conditions, but primary productivity was still relatively high. After the end of the glacial period, warm and humid climatic conditions and rapid transgression were the main factors affecting the burial of organic matter in Unit 3. Under hot and humid climate conditions, higher terrigenous detrital inputs and unfavourable preservation environments, the dilution of organic matter in Unit 4 was accelerated. The corrected chemical index of alteration (CIA corr) values show that the study area experienced a climate change of alternating cold and warm conditions in response to the climate fluctuation during the glacial-interglacial period. The CIA corr value is negatively correlated with the TOC content, while the generation of available clay minerals (smectite) in warm and humid climates is usually consistent with the enhanced burial flux of organic matter, supporting the important role of climate fluctuations in the accumulation of organic matter. Finally, a comparison of the data from the present study with geochemical data from different profiles in South China reveals the role of climatic fluctuations during the O S transition in controlling paleoenvironmental evolution and organic matter enrichment, while such a heterogeneous factor is usually associated with global or regional geological events. Our study highlights this differential enrichment mechanism as a combined response of multiple factors and provides important implications for glacial-interglacial organic matter enrichment mechanisms. • Rapid changes of weathering indices imply climatic fluctuations during the Late Ordovician-Early Silurian. • Four different patterns were established for organic matter accumulation across the O/S. • Climate fluctuations and the heterogeneity nature of ocean systems explain the regional variations of OM accumulation. [ABSTRACT FROM AUTHOR]

• We identified aberrantly activated and differentiated CD4+ and γδ T cells as the immunological mechanisms both in psoriasis and IBD, and IL17 and TNF signaling as the common pathogenesis. • We also found that hub shared genes, LCN2, CXCL1 and PI3, which are involved in psoriasis and IBD, are potential therapeutic targets. Psoriasis and inflammatory bowel disease (IBD) have a similar etiology, including abnormal activation of T cells. Differentially expressed genes (DEGs) analysis was used to search for shared genes. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis were then performed. Secondly, single-cell RNA analysis (scRNA-seq) and immune infiltration were employed to explore the immune imbalance of the diseases. By weighted gene co expression network analysis (WGCNA), we obtained hub shared genes. Furthermore, we analyzed the diagnostic performance and immune association with the hub genes. Finally, functional enrichment of miRNAs related to hub shared genes was carried out. Single-cell analysis showed a high proportion of T cells among infiltrated immune cells and immune infiltration showed CD4+ T and γδ T cells were significantly elevated in diseases. Hub shared genes, LCN2, CXCL1 and PI3 had excellent diagnostic properties and were positively correlated with neutrophils, CD4+ T and γδ T cells. IL17 and TNF signaling pathway were the common pathway. In conclusion, CD4+ and γδ T cells and hub shared genes may play a crucial part in common mechanism between psoriasis and IBD. Moreover, hub shared genes may be potential diagnostic markers. [ABSTRACT FROM AUTHOR]

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with multi-organ involvement, and some studies have found that SLE has a reduced risk of breast cancer (BRCA). So, we tried to find prognostic genes for BRCA related to SLE by integrated analysis and machine learning. First, we downloaded 2 SLE datasets from Gene Expression Omnibus (GEO) and BRCA data from the Cancer Genome Atlas (TCGA). Subsequently, we performed differentially expressed genes (DEGs) and functional enrichment analysis by Metascape in SLE. Genes that were differentially expressed in both datasets were the validated DEGs. And after constructing PPI network, genes with nodes >30 were intersected with survival genes in BRCA to obtain candidate genes. Then, the candidate genes were validated by lasso regression in both training and validation sets to obtain prognostic genes. Afterwards, we investigated the diagnostic potential of prognostic genes for SLE and the predictive efficacy for BRCA prognosis. Moreover, GSEA analysis and immune infiltration were performed for SLE and BRCA. Finally, we constructed a prognostic gene-miRNAs network and did functional enrichment of the shared genes. DEGs for SLE were mainly enriched with neutrophil degranulation and IFN pathways. After the lasso model of BRCA was established, IRF7, IFI35 and EIF2AK2, were identified as prognostic genes for BRCA related to SLE and had good predictive ability for the prognosis of BRCA. Prognostic genes had excellent diagnostic potential for SLE, with IFI35 and EIF2AK2 positively associated with SLE activity and IRF7 positively associated with IFI35. GSEA showed that both SLE and BRCA were associated with ubiquitinated degradation. Immune infiltrates suggest that plasma cells, dendritic cells (DC), neutrophils and monocyte were elevated in SLE. DC, NK and CD8+ T cells were elevated in the BRCA low-risk group. Finally, 5 shared miRNAs were confirmed, which were mainly enriched in the IFN pathway. IRF7, IFI35 and EIF2AK2, were identified as prognostic genes for BRCA related to SLE. IFN pathway played an important role in the etiology of SLE and the prognosis of BRCA. [ABSTRACT FROM AUTHOR]