The role of prolylcarboxypeptidase (PRCP) in myocardial ischemia/reperfusion (I/R) injury is unclear. Herein, we aimed to evaluate the protective effect of the PRCP-angiotensin-(1-7) [Ang-(1-7)]/bradykinin-(1-9) [BK-(1-9)] axis on myocardial I/R injury and identify the mechanisms involved. Plasma PRCP level and activity, as well as Ang-(1-7) and BK-(1-9) levels, were compared in healthy subjects, patients with unstable angina, and those with ST-segment-elevated acute myocardial infarction (AMI). Thereafter, the effects of PRCP overexpression and knockdown on left ventricular function, mitophagy, and levels of Ang-(1-7) and BK-(1-9) were examined in rats during myocardial I/R. Finally, the effects of Ang-(1-7) and BK-(1-9) on I/R-induced mitophagy and the signaling pathways involved were investigated in vitro in rat cardiomyocytes. AMI patients showed increased plasma level and activity of PRCP and levels of Ang-(1-7) and BK-(1-9) as compared with healthy subjects and those with unstable angina. PRCP protected against myocardial I/R injury in rats by paradoxical regulation of cardiomyocyte mitophagy during the ischemia and reperfusion phases, which was mediated by downstream Ang-(1-7) and BK-(1-9). We further depicted a possible role of activation of AMPK in mitophagy induction during ischemia and activation of Akt in mitophagy inhibition during reperfusion in the beneficial effects of Ang-(1-7) and BK-(1-9). Thus, the PRCP-Ang-(1-7)/BK-(1-9) axis may protect against myocardial I/R injury by paradoxical regulation of cardiomyocyte mitophagy during ischemia and reperfusion phases.

Although the mineralization in tendon tissue has been reported in a series of aging and disease models, the underlying mechanisms remain unknown. This study aimed to describe the appearance of heterotopic ossification in rat Achilles tendon and further verify whether this tissue metaplasia is related to the enhanced osteogenic differentiation of tendon stem/progenitor cells (TSPCs) owing to the higher expression of bone morphogenetic proteins (BMP-2/4/7) with aging. The male SD rats, aged 4, 8, and 20 months (M), were used. The analyses of ossification and BMP expression in tendon were tested by radiological view (X-ray and CT), histological staining [hematoxylin and eosin (HE), Alcian blue, and Alizarin red], immunohistochemistry, and Western blot. The osteogenic differentiation potential and BMP expression of TSPCs were examined by Alizarin red S staining and real-time PCR. TSPCs were treated with BMP-2 or noggin, and the osteogenic differentiation potential was also examined. X-ray and CT showed the appearance of heterotopic ossification in tendon, and the volume and density of ossification was increased with aging. Histological staining showed the appearance of calcified region surrounded by chondrocyte-like cells and the increased osteogenesis-related gene and BMP expression in ossified tendon with aging. Moreover, the osteogenic differentiation potential and BMP expression in TSPCs isolated from ossified tendon were increased with aging. Additionally, BMP-2 increased the calcium nodule formation and osteogenesis-related gene expression in TSPCs. The addition of noggin inhibited BMP-induced enhancement of osteogenic differentiation. Thus, these findings suggested that the enhanced osteogenic differentiation of TSPCs contributes to the increased heterotopic ossification in aged tendon, which might be induced by the higher expression of BMPs with aging.

Diminished regeneration or healing capacity of tendon occurs during aging. It has been well demonstrated that tendon stem/progenitor cells (TSPCs) play a vital role in tendon maintenance and repair. Here, we identified an accumulation of senescent TSPCs in tendon tissue with aging. In aged TSPCs, the activity of JAK-STAT signaling pathway was increased. Besides, genetic knockdown of JAK2 or STAT3 significantly attenuated TSPC senescence in aged TSPCs. Pharmacological inhibition of JAK-STAT signaling pathway with AG490 similarly attenuated cellular senescence and senescence-associated secretory phenotype (SASP) of aged TSPCs. In addition, inhibition of JAK-STAT signaling pathway also restored the age-related dysfunctions of TSPCs, including self-renewal, migration, actin dynamics, and stemness. Together, our findings reveal the critical role of JAK-STAT signaling pathway in the regulation of TSPC aging and suggest an ideal therapeutic target for the age-related tendon disorders.

Quiescin Q6 sulfhydryl oxidase 2 (QSOX2), an enzyme that can be directly secreted into the extracellular space, is known to be associated with oxidative protein folding. However, whether QSOX2 is abnormally expressed in non-small cell lung cancer (NSCLC) and its role in tumor growth remains unclear.

Filamin A, the first discovered non-muscle actin filament cross-linking protein, plays a crucial role in regulating cell migration that participates in diverse cellular and developmental processes. However, the regulatory mechanism of filamin A stability remains unclear. Here, we find that nuclear distribution gene C (NudC), a cochaperone of heat shock protein 90 (Hsp90), is required to stabilize filamin A in mammalian cells. Immunoprecipitation-mass spectrometry and western blotting analyses reveal that NudC interacts with filamin A. Overexpression of human NudC-L279P (an evolutionarily conserved mutation in NudC that impairs its chaperone activity) not only decreases the protein level of filamin A but also results in actin disorganization and the suppression of cell migration. Ectopic expression of filamin A is able to reverse these defects induced by the overexpression of NudC-L279P. Furthermore, Hsp90 forms a complex with filamin A. The inhibition of Hsp90 ATPase activity by either geldanamycin or radicicol decreases the protein stability of filamin A. In addition, ectopic expression of Hsp90 efficiently restores NudC-L279P overexpression-induced protein stability and functional defects of filamin A. Taken together, these data suggest NudC L279P mutation destabilizes filamin A by inhibiting the Hsp90 chaperoning pathway and suppresses cell migration.

Accurate prediction of lymph-node metastasis in cancers is pivotal for the next targeted clinical interventions that allow favorable prognosis for patients. Different molecular profiles (mRNA and non-coding RNAs) have been widely used to establish classifiers for cancer prediction (e.g., tumor origin, cancerous or non-cancerous state, cancer subtype). However, few studies focus on lymphatic metastasis evaluation using these profiles, and the performance of classifiers based on different profiles has also not been compared. Here, differentially expressed mRNAs, miRNAs, and lncRNAs between lymph-node metastatic and non-metastatic groups were identified as molecular signatures to construct classifiers for lymphatic metastasis prediction in different cancers. With this similar feature selection strategy, support vector machine (SVM) classifiers based on different profiles were systematically compared in their prediction performance. For representative cancers (a total of nine types), these classifiers achieved comparative overall accuracies of 81.00% (67.96-92.19%), 81.97% (70.83-95.24%), and 80.78% (69.61-90.00%) on independent mRNA, miRNA, and lncRNA datasets, with a small set of biomarkers (6, 12, and 4 on average). Therefore, our proposed feature selection strategies are economical and efficient to identify biomarkers that aid in developing competitive classifiers for predicting lymph-node metastasis in cancers. A user-friendly webserver was also deployed to help researchers in metastasis risk determination by submitting their expression profiles of different origins.

Introduction: The incidence of diabetic retinopathy (DR) has been found to be associated with the risk of developing Alzheimer's disease (AD). In addition to the common properties of neurodegeneration, their progressions are involved with abnormal vascular functions. However, the interactions between them have not been fully understood. This study aimed to investigate the key factor for the underlying interactions and shared signaling pathways in the vasculature of DR and AD. Methods: We retrieved single-cell RNA sequencing (scRNA-seq) data regarding human fibrovascular membrane (FVM) of proliferative diabetic retinopathy (PDR) and human hippocampus vessels of AD from the NCBI-GEO database. GSEA analysis was performed to analyze AD-related genes in endothelial cells and pericytes of PDR. CellChat was used for predicting cell-cell communication and the signaling pathway. Results: The data suggested that amyloid-beta precursor protein (APP) signaling was found crucial in the vasculature of PDR and AD. Endothelial cells and pericytes could pose influences on other cells mainly via APP signaling in PDR. The endothelial cells were mainly coordinated with macrophages in the hippocampus vasculature of AD via APP signaling. The bulk RNA-seq in mice with PDR validated that the expression of APP gene had a significant correlation with that of the AD genome-wide association studies (GWAS) gene. Discussion: Our study demonstrates that the vasculopathy of PDR and AD is likely to share a common signaling pathway, of which the APP-related pathway is a potential target.

B7H3 (also known as CD276) is a co-stimulator checkpoint protein of the cell surface B7 superfamily. Recently, the function beyond immune regulation of B7H3 has been widely studied. However, the expression preference and the regulation mechanism underlying B7H3 in different subtypes of gliomas is rarely understood. We show here that B7H3 expression is significantly decreased in IDH-mutated gliomas and in cultured IDH1-R132H glioma cells. Accumulation of 2-HG leads to a remarkable downregulation of B7H3 protein and the activity of IDH1-R132H mutant is responsible for B7H3 reduction in glioma cells. Inhibition of autophagy by inhibitors like leupeptin, chloroquine (CQ), and Bafilomycin A1 (Baf-A1) blocks the degradation of B7H3 in glioma cells. In the meantime, the autophagy flux is more active with higher LC3B-II and lower p62 in IDH1-R132H glioma cells than in IDH1-WT cells. Furthermore, sequence alignment analysis reveals potential LC3-interacting region (LIR) motifs "F-V-S/N-I/V" in B7H3. Moreover, B7H3 interacts with p62 and CQ treatment significantly enhances this interaction. Additionally, we find that B7H3 is positively correlated with VEGFA and MMP2 by bioinformatics analysis in gliomas. B7H3 and VEGFA are decreased in IDH-mutated gliomas and further reduced in 2-HGhigh gliomas compared to 2-HGlow glioma sections by IHC staining. Our study demonstrates that B7H3 is preferentially overexpressed in IDH wild-type gliomas and could serve as a potential theranostic target for the precise treatment of glioma patients with wild-type IDH.