HCC-1 Accelerates Atherosclerosis by Inducing Endothelial Cell and Macrophage Pyroptosis and Serves as an Early Diagnostic Biomarker.

BACKGROUND: HCC-1 (hemofiltrate CC chemokine-1), a CC-type chemokine, exerts function to change intracellular calcium concentration, induce leukocyte, and manipulate enzyme release especially in monocytes. It has been reported that HCC-1 could predict the persistent acute kidney injury or suppress hepatocellular carcinoma by modulating cell cycle and promoting apoptosis, while the effect of HCC-1 on atherosclerosis is poorly understood. Here, we aimed to clarify the function and mechanism of HCC-1 in atherosclerosis and whether it could serve as a novel biomarker for the diagnosis of atherosclerosis. METHODS: HCC-1 expression in serum, atherosclerotic plaques, and normal arterial tissue from patients with atherosclerosis and control group was assessed by ELISA, immunohistochemistry and confocal microscope, and bioinformatic analysis. The atherosclerotic model of HCC-1 overexpressing and control mice was generated by tail vein injection of adeno-associated virus serotype 9-HCC-1 on an ApoE-/- background. Cell adhesion, polarization, and pyroptosis were evaluated in vitro. The relationship between HCC-1 concentration in serum and atherosclerosis was analyzed in patients with atherosclerosis. RESULTS: HCC-1 expression was positively correlated with the occurrence and stable-unstable switch of atherosclerosis under bioinformatic analysis, which is further supported by the results of increased HCC-1 expression in AS patients both in serum and atherosclerotic plaque. adeno-associated virus serotype 9-HCC-1 mice had higher levels of inflammatory factors, increased macrophage accumulation and pyroptotic rate in plaque, and decreased atherosclerotic plaque stability. In vitro, HCC-1 promoted monocyte adhesion and M1 polarization and induced inflammation and pyroptosis both in ECs and macrophages. CONCLUSIONS: HCC-1 expression was increased in patients with atherosclerosis, and HCC-1 overexpression accelerated atherosclerotic burden via an enhancement in monocyte recruitment, M1 polarization, and pyroptosis both in ECs and macrophages. Our findings suggested that HCC-1 may serve as an early biomarker for the diagnosis of atherosclerosis, with the capacity to reflect the degree of stenosis.

Characteristics and potential clinical applications of the extracellular vesicles of human pathogenic Fungi.

Extracellular vesicles (EVs) are a heterogeneous group of lipid membrane-enclosed compartments that contain different biomolecules and are released by almost all living cells, including fungal genera. Fungal EVs contain multiple bioactive components that perform various biological functions, such as stimulation of the host immune system, transport of virulence factors, induction of biofilm formation, and mediation of host-pathogen interactions. In this review, we summarize the current knowledge on EVs of human pathogenic fungi, mainly focusing on their biogenesis, composition, and biological effects. We also discuss the potential markers and therapeutic applications of fungal EVs.

Outer membrane vesicles-transmitted virulence genes mediate the emergence of new antimicrobial-resistant hypervirulent Klebsiella pneumoniae.

Hypervirulent Klebsiella pneumoniae (hvKp) is a notorious clinical pathogen that is more likely to cause severe primary and metastatic abscesses. The dissemination of antimicrobial-resistant hvKp isolates has been reported worldwide, posing a great challenge and severe clinical threat. However, the mechanisms of antimicrobial-resistant hvKp isolates prevalent worldwide are not well precise. Outer membrane vesicles (OMVs) secreted from gram-negative bacteria are an important vehicle for delivering effector molecules inter- and intra-species. To explore whether OMVs as the vector of virulence genes horizontal transfer among Klebsiella pneumoniae and to explain the potential mechanism for the development of antimicrobial-resistant hvKp isolates, we isolated OMVs from hvKp and classical Klebsiella pneumoniae (cKp) by sequential differential centrifugation, respectively. Then, the characteristics and contents of hvKp-OMVs and cKp-OMVs were analyzed. These hvKp-OMVs contain virulence genes, which could be transferred from hvKp horizontally to extended-spectrum beta lactamase (ESBL)-producing cKp, leading to the production of antimicrobial-resistant hypervirulent transformants. Further experiments confirmed the transformants exhibited antimicrobial resistance and hypervirulent phenotypes in vitro and in vivo. In short, this work demonstrated that hvKp-OMVs facilitated virulence genes transfer, allowing an increase in the virulence level of ESBL-producing cKp and providing a new mechanism for the emergence of antimicrobial-resistant hvKp isolates.

LncRNA AC105942.1 Downregulates hnRNPA2/B1 to Attenuate Vascular Smooth Muscle Cells Proliferation.

The abnormal proliferation of vascular smooth muscle cells (VSMCs) is crucial in the atherosclerosis. Although long noncoding RNAs (lncRNAs) are implicated in a variety of diseases, their roles in activation of VSMCs proliferation and vascular disorder diseases are not well understood. In addition, heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) was reported to participate in lncRNAs-mediated function. Herein, we propose to investigate the role of lncRNA AC105942.1 and hnRNPA2/B1 in pathological VSMCs proliferation and the possible mechanisms in vitro. We have identified that lncRNA AC105942.1 was downregulated and hnRNPA2/B1 was upregulated in atherosclerotic plaques compared with normal artery tissues. Enhanced lncRNA AC105942.1 could noticeably inhibit Ang II-induced VSMCs proliferation. Further investigation suggested that lncRNA AC105942.1 could downregulate the expression of hnRNPA2/B1 and then regulate the level of CDK4 and p27. Taken together, our study indicated that lncRNA AC105942.1 downregulated hnRNPA2B1 to protect against the atherosclerosis by suppressing VSMCs proliferation. LncRNA AC105942.1 and hnRNPA2/B1 could represent potential therapeutic and diagnostic targets to atherosclerosis-related diseases.

Extracellular Vesicles Derived From Talaromyces marneffei Yeasts Mediate Inflammatory Response in Macrophage Cells by Bioactive Protein Components.

Extracellular vesicles (EVs) loaded with proteins, nucleic acids, membrane lipids, and other virulence factors could participate in pathogenic processes in some fungi such as Cryptococcus neoformans and Candida albicans. However, the specific characteristics of EVs derived from Talaromyces marneffei (TM) still have not been figured out yet. In the present study, it has been observed that TM-derived EVs were a heterogeneous group of nanosized membrane vesicles (30-300 nm) under nanoparticle tracking analysis and transmission electron microscopy. The DiI-labeled EVs could be taken up by RAW 264.7 macrophage cells. Incubation of EVs with macrophages would result in increased expression levels of reactive oxygen species, nitric oxide, and some inflammatory factors including interleukin-1ß, interleukin-6, interleukin-10, and tumor necrosis factor. Furthermore, the expression of co-stimulatory molecules (CD80, CD86, and MHC-II) was also increased in macrophages stimulated with EVs. The level of inflammatory factors secreted by macrophages showed a significant decrease when EVs were hydrolyzed by protease, while that of DNA and RNA hydrolase treatment remained unchanged. Subsequently, some virulence factors in EVs including heat shock protein, mannoprotein 1, and peroxidase were determined by liquid chromatography-tandem mass spectrometry. Taken together, our results indicated that the TM-derived EVs could mediate inflammatory response and its protein would play a key role in regulating the function of RAW 264.7 macrophage cells.