Immune-and Metabolism-Associated Molecular Classification of Ovarian Cancer.

Ovarian cancer (OV) is a complex gynecological disease, and its molecular characteristics are not clear. In this study, the molecular characteristics of OV subtypes based on metabolic genes were explored through the comprehensive analysis of genomic data. A set of transcriptome data of 2752 known metabolic genes was used as a seed for performing non negative matrix factorization (NMF) clustering. Three subtypes of OV (C1, C2 and C3) were found in analysis. The proportion of various immune cells in C1 was higher than that in C2 and C3 subtypes. The expression level of immune checkpoint genes TNFRSF9 in C1 was higher than that of other subtypes. The activation scores of cell cycle, RTK-RAS, Wnt and angiogenesis pathway and ESTIMATE immune scores in C1 group were higher than those in C2 and C3 groups. In the validation set, grade was significantly correlated with OV subtype C1. Functional analysis showed that the extracellular matrix related items in C1 subtype were significantly different from other subtypes. Drug sensitivity analysis showed that C2 subtype was more sensitive to immunotherapy. Survival analysis of differential genes showed that the expression of PXDN and CXCL11 was significantly correlated with survival. The results of tissue microarray immunohistochemistry showed that the expression of PXDN was significantly correlated with tumor size and pathological grade. Based on the genomics of metabolic genes, a new OV typing method was developed, which improved our understanding of the molecular characteristics of human OV.

Enterococcus faecalis-Induced Macrophage Necroptosis Promotes Refractory Apical Periodontitis.

The persistence of residual bacteria, particularly Enterococcus faecalis, contributes to refractory periapical periodontitis, which still lacks effective therapy. The role of receptor-interacting protein kinase 3 (RIPK3)- and mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis, a highly proinflammatory form of regulated cell death, has recently drawn much attention. However, the role of necroptosis in the pathogenesis of refractory periapical periodontitis remains unclear. We investigated whether the RIPK3/MLKL signaling pathway was activated in periapical lesion specimens obtained from patients diagnosed with refractory periapical periodontitis. RIPK3-deficient mice were then used to determine the role of necroptosis under this condition in vivo. We found that the phosphorylation levels of RIPK3 and MLKL were elevated in periapical lesion specimens of patients with refractory periapical periodontitis. In addition, necroptosis was induced in an E. faecalis-infected refractory periapical periodontitis mouse model, in which inhibition of necroptosis by RIPK3 deficiency could markedly alleviate inflammation and bone destruction. Moreover, double-labeling immunofluorescence suggested that macrophage necroptosis may be involved in the development of refractory periapical periodontitis. Then, we established an in vitro macrophage infection model with E. faecalis. E. faecalis infection was found to induce necroptotic cell death in macrophages through the RIPK3/MLKL signaling pathway, which was markedly alleviated by the RIPK3- or MLKL-specific inhibitor. Our study revealed that RIPK3/MLKL-mediated macrophage necroptosis contributes to the development of refractory periapical periodontitis and suggests that inhibitors or treatments targeting necroptosis represent a plausible strategy for the management of refractory periapical periodontitis. IMPORTANCE Oral infectious diseases represent a major neglected global population health challenge, imposing an increasing burden on public health and economy. Refractory apical periodontitis (RAP), mainly caused by Enterococcus faecalis, is a representative oral infectious disease with considerable therapeutic challenges. The interplay between E. faecalis and the host often leads to the activation of programmed cell death. This study identifies an important role of macrophage necroptosis induced by E. faecalis in the pathogenesis of RAP. Manipulating RIPK3/MLKL-mediated necroptosis may represent novel therapeutic targets, not only for RAP but also for other E. faecalis-associated infectious diseases.

PANoptosis: A New Insight Into Oral Infectious Diseases.

The oral microbiome, one of the most complex and intensive microbial ecosystems in the human body, comprises bacteria, archaea, fungi, protozoa, and viruses. Dysbiosis of the oral microbiome is the initiating factor that leads to oral infectious diseases. Infection is a sophisticated biological process involving interplay between the pathogen and the host, which often leads to activation of programmed cell death. Studies suggest that pyroptosis, apoptosis, and necroptosis are involved in multiple oral infectious diseases. Further understanding of crosstalk between cell death pathways has led to pyroptosis, apoptosis, and necroptosis being integrated into a single term: PANoptosis. PANoptosis is a multifaceted agent of the immune response that has important pathophysiological relevance to infectious diseases, autoimmunity, and cancer. As such, it plays an important role in innate immune cells that detect and eliminate intracellular pathogens. In addition to the classical model of influenza virus-infected and Yersinia-infected macrophages, other studies have expanded the scope of PANoptosis to include other microorganisms, as well as potential roles in cell types other than macrophages. In this review, we will summarize the pathophysiological mechanisms underlying inflammation and tissue destruction caused by oral pathogens. We present an overview of different pathogens that may induce activation of PANoptosis, along with the functional consequences of PANoptosis in the context of oral infectious diseases. To advance our understanding of immunology, we also explore the strategies used by microbes that enable immune evasion and replication within host cells. Improved understanding of the interplay between the host and pathogen through PANoptosis will direct development of therapeutic strategies that target oral infectious diseases.

Remodeling the Epigenetic Landscape of Cancer-Application Potential of Flavonoids in the Prevention and Treatment of Cancer.

Epigenetics, including DNA methylation, histone modification, and noncoding RNA regulation, are physiological regulatory changes that affect gene expression without modifying the DNA sequence. Although epigenetic disorders are considered a sign of cell carcinogenesis and malignant events that affect tumor progression and drug resistance, in view of the reversible nature of epigenetic modifications, clinicians believe that associated mechanisms can be a key target for cancer prevention and treatment. In contrast, epidemiological and preclinical studies indicated that the epigenome is constantly reprogrammed by intake of natural organic compounds and the environment, suggesting the possibility of utilizing natural compounds to influence epigenetics in cancer therapy. Flavonoids, although not synthesized in the human body, can be consumed daily and are common in medicinal plants, vegetables, fruits, and tea. Recently, numerous reports provided evidence for the regulation of cancer epigenetics by flavonoids. Considering their origin in natural and food sources, few side effects, and remarkable biological activity, the epigenetic antitumor effects of flavonoids warrant further investigation. In this article, we summarized and analyzed the multi-dimensional epigenetic effects of all 6 subtypes of flavonoids (including flavonols, flavones, isoflavones, flavanones, flavanols, and anthocyanidin) in different cancer types. Additionally, our report also provides new insights and a promising direction for future research and development of flavonoids in tumor prevention and treatment via epigenetic modification, in order to realize their potential as cancer therapeutic agents.