Targeted plasma proteomic analysis uncovers a high-performance biomarker panel for early diagnosis of gastric cancer.

BACKGROUND: Gastric cancer (GC) is characterized by high morbidity, high mortality and low early diagnosis rate. Early diagnosis plays a crucial role in radically treating GC. The aim of this study was to identify plasma biomarkers for GC and early GC diagnosis. METHODS: We quantified 369 protein levels with plasma samples from discovery cohort (n = 88) and validation cohort (n = 50) via high-throughput proximity extension assay (PEA) utilizing the Olink-Explore-384-Cardiometabolic panel. The multi-protein signatures were derived from LASSO and Ridge regression models. RESULTS: In the discovery cohort, 13 proteins (GDF15, ITIH3, BOC, DPP7, EGFR, AMY2A, CCDC80, CD163, GPNMB, LTBP2, CTSZ, CCL18 and NECTIN2) were identified to distinguish GC (Stage I-IV) and early GC (HGIN-I) groups from control group with AUC of 0.994 and AUC of 0.998, severally. The validation cohort yielded AUC of 0.930 and AUC of 0.818 for GC and early GC, respectively. CONCLUSIONS: This study identified a multi-protein signature with the potential to benefit clinical GC diagnosis, especially for Asian and early GC patients, which may contribute to the development of a less-invasive, convenient, and efficient early screening tool, promoting early diagnosis and treatment of GC and ultimately improving patient survival.

Bub1 and Bub3 regulate metabolic adaptation via macrolipophagy in Drosophila.

Lipophagy, the process of selective catabolism of lipid droplets (LDs) by autophagy, maintains lipid homeostasis and provides cellular energy under metabolic adaptation, yet its underlying mechanism remains largely ambiguous. Here, we show that the Bub1-Bub3 complex, the crucial regulator involved in the whole process of chromosome alignment and separation during mitosis, controls the fasting-induced lipid catabolism in the fat body (FB) of Drosophila. Bidirectional deviations of the Bub1 or Bub3 level affect the consumption of triacylglycerol (TAG) of fat bodies and the survival rate of adult flies under starving. Moreover, Bub1 and Bub3 work together to attenuate lipid degradation via macrolipophagy upon fasting. Thus, we uncover physiological roles of the Bub1-Bub3 complex on metabolic adaptation and lipid metabolism beyond their canonical mitotic functions, providing insights into the in vivo functions and molecular mechanisms of macrolipophagy during nutrient deprivation.

Phase separation of BuGZ regulates gut regeneration and aging through interaction with m6A regulators.

Exploring the role of phase separation in intracellular compartment formation is an active area of research. However, the associations of phase separation with intestinal stem cell (ISC)-dependent regeneration and aging remain unclear. Here, we demonstrate that BuGZ, a coacervating mitotic effector, shows age- and injury-associated condensation in Drosophila ISC nuclei during interphase. BuGZ condensation promotes ISC proliferation, affecting Drosophila gut repair and longevity. Moreover, m6A reader YT521-B acts as the transcriptional and functional downstream of BuGZ. The binding of YT521-B promotor or m6A writer Ime4/ Mettl14 to BuGZ controls its coacervation, indicating that the promotor may accelerate the phase transition of its binding transcription factor. Hence, we propose that phase separation and m6A regulators may be critical for ameliorating ISC-dependent gut regeneration and aging and requires further study.

Liquid-Liquid Phase Separation in Cardiovascular Diseases.

Liquid-liquid phase separation (LLPS) is a biochemical process in cells that can drive proteins, RNA, and other molecules to concentrate into droplets. These droplets do not have a lipid membrane but rather exist as distinct organelles relative to the surrounding environment, and act as biochemical reaction chambers. In recent years, significant progress has been made in the study of LLPS, especially in the neurodegenerative disease, cancer, and virology fields, but little is known about LLPS in cardiovascular disease (CVD). In this review, we discuss the current understanding of the mechanism and biological functions of LLPS, particularly its roles in regulating CVD.

Subcellular Localization of miRNAs and Implications in Cellular Homeostasis.

MicroRNAs (miRNAs) are thought to act as post-transcriptional regulators in the cytoplasm by either dampening translation or stimulating degradation of target mRNAs. With the increasing resolution and scope of RNA mapping, recent studies have revealed novel insights into the subcellular localization of miRNAs. Based on miRNA subcellular localization, unconventional functions and mechanisms at the transcriptional and post-transcriptional levels have been identified. This minireview provides an overview of the subcellular localization of miRNAs and the mechanisms by which they regulate transcription and cellular homeostasis in mammals, with a particular focus on the roles of phase-separated biomolecular condensates.

Peroxisome Elevation Induces Stem Cell Differentiation and Intestinal Epithelial Repair.

Epithelial-repair-dependent mucosal healing (MH) is associated with a more favorable prognosis for patients with inflammatory bowel disease (IBD). MH is accomplished via repair and regeneration of the intestinal epithelium. However, the mechanism underlying MH is ill defined. We found a striking upregulation of peroxisomes in the injured crypts of IBD patients. By increasing peroxisome levels in Drosophila midguts, we found that peroxisome elevation enhanced RAB7-dependent late endosome maturation, which then promoted stem and/or progenitor-cell differentiation via modulation of Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT)-SOX21A signaling. This in turn enhanced ISC-mediated regeneration. Importantly, RAB7 and SOX21 were upregulated in the crypts of IBD patients. Moreover, administration of drugs that increased peroxisome levels reversed the symptoms of dextran sulfate sodium (DSS)-induced colitis in mice. This study demonstrates a peroxisome-mediated epithelial repair mechanism, which opens a therapeutic avenue for the enhancement of MH in IBD patients.