Li Su

Background: Atherosclerosis (AS) is a chronic inflammatory disorder with substantial global prevalence, wherein macrophage polarization and vascular smooth muscle cells (VSMCs) phenotypic switching are critical pathogenic events. Although G protein-coupled receptor 132 (GPR132) is markedly expressed in macrophages, its specific role and mechanism in AS-associated macrophage polarization remain incompletely understood. Methods: Pharmacological antagonism of GPR132 was evaluated in high-fat diet-fed ApoE ^−/− mice. Integrated single-cell RNA sequencing and transcriptome analyses from GEO datasets were performed to profile GPR132 expression in murine and human atherosclerotic plaques. In vitro, GPR132 overexpression and knockout macrophages were generated to assess M1/M2 polarization markers, and an indirect co‑culture system with VSMCs was established. Mechanistic investigations employed RNA‑sequencing and Western blotting, with pathway inhibition using SB203580 or GPR132 antagonists. Results: GPR132 antagonism attenuated atherosclerotic lesion progression and reduced pro‑inflammatory cytokine secretion without altering lipid profiles. GPR132 was enriched in pro‑inflammatory (M1‑like) macrophage subpopulations within plaques, which also upregulated VSMC‑promoting growth factors. GPR132 overexpression promoted M1 macrophage polarization and suppressed IL‑4‑induced M2 macrophage polarization, whereas knockout enhanced M2 and attenuated M1. Conditioned medium from GPR132‑overexpressing macrophages significantly enhanced VSMCs proliferation and migration. Mechanistically, GPR132 drove M1 macrophage polarization primarily through activation of the p38/MAPK signaling pathway, an effect reversible by SB203580 or GPR132 antagonists. Conclusions: GPR132 promotes pro‑inflammatory macrophage polarization via p38/MAPK signaling, and its antagonism mitigates atherosclerotic progression by suppressing inflammatory microenvironments and VSMCs proliferation/migration, highlighting GPR132 as a potential therapeutic target for AS.

Periodontitis is a predominant persistent inflammatory disease marked by consistent destruction of tooth‐supporting tissues including periodontal ligament and alveolar bone. Although some cytokines have been identified as key mediators, the upstream regulatory molecules that drives this pathological bone loss remains elusive. This study explores the mechanistic role of lncRNA ZFAS1 in the dysregulated bone remodeling of periodontitis microenvironment. We utilized single‐cell and bulk RNA sequencing to profile cellular and molecular landscape in healthy and diseased periodontal tissues. GSEA analysis of bulk transcriptomes confirmed a significant activation of osteoclast‐related pathways in disease (NES = 1.7, FDR q = 0.025). Findings were validated through qPCR, histology, and immunohistochemistry. The gain‐ and loss‐of‐function models in RAW264.7 and MC3T3‐E1 cells to characterize the role of lncRNA ZFAS1 in vitro. The scRNA‐seq analysis unveiled a marked 11‐fold increase in osteoclast‐osteoblast ratio in periodontitis, which was further confirmed histologically. This shift was accompanied by a specific inflammatory profile, and a marked upregulation of lncRNA ZFAS1 in diseased tissues. Notably, ZFAS1 expression showed a robust positive correlation with early osteoclast marker genes NFATC1 (R ² = 0.2056, p = 0.015) and TRAP1 (R ² = 0.784, p < 0.0001) but not the late‐stage effector CTSK (R ² = 0.0011, p = 0.792). We confirmed that lncRNA ZFAS1 expression was precisely induced by the synergetic effect of differentiation (RANKL) and inflammatory (LPS) signals. Functionally, lncRNA ZFAS1 overexpression in RAW264.7 potentiated osteoclastogenesis, enhanced TRAP‐positive osteoclasts and increased resorptive gene expression (NFATC1, Dcstamp, ACP5, CTSK, V‐ATPase d2), while its knockdown exhibited the opposite effect. In contrast, lncRNA ZFAS1 knockdown in MC3T3‐E1 boosted differentiation and matrix mineralization, augmented osteoblast‐related gene expression (Runx2, ALP, OCN). In summary, lncRNA ZFAS1 is a critical driver of inflammatory bone loss, functioning as a dual‐path regulator that promotes osteoclastogenesis and inhibits osteoblastogenesis. Its physiological role as a negative osteogenic regulator is evidenced by its downregulation during normal differentiation, highlighting its therapeutic potential for periodontitis and related conditions.

Genetically modified (GM) crops have been provided as food and feed in over 70 countries in the world. But the concern is persisting on their comprehensive effects on human health status as feedstock. Physiological indicators detected in human beings or animals were explored to assess the health status after GM crop consumption. Here, a mammalian physiological indicators data set with seven metrics containing 25 physiological indicators was constructed by extracting the experimental raw data from the open access research articles published from January 2000 to September 2024 on GM maize, rice, and soybean consumption. To overcome the experimental heterogeneity in disparate model animals, limited animal number in each independent research, and statistical errors caused by different statistical methods, the multi-sourced data correlation analysis with DerSimonian and Laird random-effect model was employed. The result revealed that the concentration of glucose increased after nutritionally changed maize consumption (GLU, p < .01), but within the safe reference concentration range; the relative weight of liver increased after non-nutritional GM maize consumption (p < .05); the relative weight of kidney was the physiological indicators that significantly increased after nutritionally changed GM rice consumption (p < .05). No pathological characterizations in respective organs were reported. The findings indicated no pathological risks from GM crop consumption, though they emphasized the need for continued research into their metabolic and biochemical effects to ensure comprehensive food safety.

Transcription factors (TFs) regulate the expression of genes responsible for cell growth, differentiation, and responses to environmental factors. In this study, we demonstrated that signal-induced proliferation-associated 1 (SIPA1), known as a Rap-GTPase-activating protein, bound DNA and served as a TF. Importin β1 was found to interact with SIPA1 upon fibronectin treatment. A TGAGTCAB motif was recognized and bound by DNA-binding region (DBR) of SIPA1, which was confirmed by electrophoretic mobility shift assay. SIPA1 regulated the transcription of multiple genes responsible for signal transduction, DNA synthesis, cell adhesion, cell migration, and so on. Transcription of fibronectin 1, which is crucial for cell junction and migration of triple-negative breast cancer (TNBC) cells, was regulated by SIPA1 in a DBR-dependent manner both in vivo and in vitro. Furthermore, single-cell transcriptome sequencing analysis of specimens from a metastatic TNBC patient revealed that SIPA1 was highly expressed in metastatic TNBC. Hence, this study demonstrated that SIPA1 served as a TF, promoting TNBC migration, invasion, and metastasis.

Article: Visualization analysis of rheumatoid arthritis and ankylosing spondylitis treated with Fuzheng method - Minerva Medica 2023 Jun 16 - Minerva Medica - Journals

Breast cancer is one of the most serious and terrifying threats to the health of women. Recent studies have demonstrated that interaction among cancer cells themselves and those with other cells, including immune cells, in a tumor microenvironment potentially and intrinsically regulate and determine cancer progression and metastasis. Small extracellular vesicles (sEVs), a type of lipid-bilayer particles derived from cells, with a size of less than 200 nm, are recognized as one form of important mediators in cell-to-cell communication. sEVs can transport a variety of bioactive substances, including proteins, RNAs, and lipids. Accumulating evidence has revealed that sEVs play a crucial role in cancer development and progression, with a significant impact on proliferation, invasion, and metastasis. In addition, sEVs systematically coordinate physiological and pathological processes, such as coagulation, vascular leakage, and stromal cell reprogramming, to bring about premetastatic niche formation and to determine metastatic organ tropism. There are a variety of oncogenic factors in tumor-derived sEVs that mediate cellular communication between local stromal cells and distal microenvironment, both of which are important in cancer progression and metastasis. Tumor-derived sEVs contain substances that are similar to parental tumor cells, and as such, sEVs could be biomarkers in cancer progression and potential therapeutic targets, particularly for predicting and preventing future metastatic development. Here, we review the mechanisms underlying the regulation by tumor-derived sEVs on cancer development and progression, including proliferation, metastasis, drug resistance, and immunosuppression, which coordinately shape the pro-metastatic microenvironment. In addition, we describe the application of sEVs to the development of cancer biomarkers and potential therapeutic modalities and discuss how they can be engineered and translated into clinical practice.

Long non-coding RNAs (lncRNAs) are reported to play an important regulatory effect in carcinogenesis and malignancy. We found by high-throughput sequencing that LINC01615 is upregulated in breast cancer patients and reduces patients’ overall survival. In vivo and in vitro experiments, we clarified that overexpression of LINC01615 can promote breast cancer cell metastasis ability. The expression of LINC01615 is regulated by the transcriptional activator SIPA1, thereby promoting carcinogenesis in breast cancer cells. Our research clarified that LINC01615 can act as an oncogenic factor in promoting the development of breast cancer.

Tumour cell metastasis can be genetically regulated by proteins contained in cancer cell-derived extracellular vesicles (EVs) released to the tumour microenvironment. Here, we found that the number of infiltrated macrophages was positively correlated with the expression of signal-induced proliferation-associated 1 (SIPA1) in invasive breast ductal carcinoma tissues and MDA-MB-231 xenograft tumours. EVs derived from MDA-MB-231 cells (231-EVs) significantly enhanced macrophage migration, compared with that from SIPA1-knockdown MDA-MB-231 cells (231/si-EVs) both in vitro and in vivo. We revealed that SIPA1 promoted the transcription of MYH9, which encodes myosin-9, and up-regulated the expression level of myosin-9 in breast cancer cells and their EVs. We also found that blocking myosin-9 by either down-regulating SIPA1 expression or blebbistatin treatment led to the suppression of macrophage infiltration. Survival analysis showed that breast cancer patients with high expression of SIPA1 and MYH9 molecules had worse relapse-free survival (p = 0.028). In summary, SIPA1^high breast cancer can enhance macrophage infiltration through EVs enriched with myosin-9, which might aggravate the malignancy of breast cancer.