Frontiers in bioscience (Landmark edition)最新文献

Osteoarthritis (OA) is a prevalent, chronic joint disorder affecting millions of people worldwide, characterized by articular cartilage degradation, subchondral bone remodeling, synovial cytokine secretion, and osteophyte formation. OA primarily affects the hips, knees, hands, and spine. Patients with OA exhibit a higher prevalence of cardiovascular comorbidities and potentially important associations between OA and cardiovascular diseases have prompted investigations into potentially similar pathophysiological associations. This review explores the coexistence of atherosclerotic peripheral vascular disease (ASPVD) in OA patients, including evidence from a contemporary study suggesting associations between OA and arterial wall thickness and blood flow changes which are characteristic of early atherosclerosis, and which stimulate reactive pathology in endothelial cells. Observations from this study demonstrate elevated arterial flow volume and increased intima-media thickness in arteries ipsilateral to OA knees, suggesting a potential link between OA and arterial wall disease. We further explore the intricate relationship between the vascular system and skeletal health, highlighting bidirectional interactions among endothelial cells, inflammatory cells, and various bone cells. Mechanical endothelial cell dysfunction is discussed, emphasizing the impact of vessel wall material changes and endothelial cell responses to alterations in fluid shear stress. Inflammatory changes in OA and ASPVD are also explored, showcasing shared pathophysiological processes involving immune cell infiltration and pro-inflammatory cytokines. Additionally, the role of hypofibrinolysis in OA and ASPVD is discussed, highlighting similarities in elevations of the hypercoagulative and hypofibrinolytic factor, plasminogen activator inhibitor (PAI-1). The review suggests a provocative relationship among low-grade chronic inflammation, endothelial dysfunction, and hypofibrinolytic states in OA and ASPVD, warranting further investigation. In conclusion, this review provides an exploration of the possible associations between OA and ASPVD. While the ongoing study's findings and other reports are observational, they suggest shared pathophysiological processes and emphasize the need for further research to elucidate additional potentially correlative linkages between these conditions. Understanding common molecular pathways may pave a way for targeted interventions that address both OA and ASPVD.

Oxidative stress, caused by the formation of free radicals, such as reactive oxygen species (ROS), leads to cell and tissue degradation, contributing to various diseases and aging. While oxygen is essential for aerobic organisms, it inevitably causes oxidative stress. Antioxidants protect against damage from free radicals, and oxidative stress arises when an imbalance occurs between free radical production and antioxidant defenses. However, when investigating whether an excess of antioxidants, almost eliminating oxidative stress, could benefit aging and disease susceptibility, it was observed that a basic level of oxidative stress appears necessary to maintain the correct homeostasis of tissues and organs and life in general. Therefore, this review aimed to compile the most significant and recent papers characterizing and describing the dual role of oxygen as a molecule essential for life and as a precursor of oxidative stress, which can be detrimental to life. We conducted targeted searches in PubMed and Google browsers to gather all relevant papers. We then focused on the eye, an organ particularly vulnerable due to its high metabolic activity combined with direct exposure to light and environmental pollutants, which produces a substantial number of free radicals (mainly ROS). We present a curated selection of relevant literature describing the main ocular pathologies of the posterior and anterior segments of the eye, highlighting oxidative stress as a significant contributing factor. Additionally, we report how endogenous and exogenous antioxidants can mitigate the development and progression of these diseases. Finally, we consider a frequently overlooked aspect: the balance between oxidants and antioxidants in maintaining the homeostatic equilibrium of tissues and organs. It is widely recognized that when oxidants overwhelm antioxidants, oxidative stress occurs, leading to negative consequences for the organism's homeostasis. However, we emphasize that a similarly dangerous situation can arise when the presence of antioxidants overwhelms the production of free radicals, drastically reducing their amount and adversely affecting aging and longevity. Unfortunately, no specific studies have addressed this particular situation in the eye.

Background: The deadly cardiovascular condition known as Stanford type A aortic dissection (TAAD) carries a high risk of morbidity and mortality. One important step in the pathophysiology of the condition is the influx of immune cells into the aorta media, which causes medial degeneration. The purpose of this work was to investigate the potential pathogenic significance of immune cell infiltration in TAAD and to test for associated biomarkers.

Methods: The National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database provided the RNA sequencing microarray data (GSE153434, GPL20795, GSE52093). Immune cell infiltration abundance was predicted using ImmuCellAI. GEO2R was used to select differentially expressed genes (DEGs), which were then processed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Additionally, hub genes linked to immune infiltration were found using functional and pathway enrichment, least absolute shrinkage and selection operator (LASSO), weighted gene co-expression network analysis (WGCNA), and differential expression analysis. Lastly, hub genes were validated and assessed using receiver operating characteristic (ROC) curves in the microarray dataset GSE52093. The hub gene expression and its connection to immune infiltration in TAAD were confirmed using both animal models and clinic data.

Results: We identified the most important connections between macrophages, T helper cell 17 (Th17), iTreg cells, B cells, natural killer cells and TAAD. And screened seven hub genes associated with immune cell infiltration: ABCG2, FAM20C, ELL2, MTHFD2, ANKRD6, GLRX, and CDCP1. The diagnostic model in TAAD diagnosis with the area under ROC (AUC) was 0.996, and the sensitivity was 99.21%, the specificity was 98.67%, which demonstrated a surprisingly strong diagnostic power of TAAD in the validation datasets. The expression pattern of four hub DEGs (ABCG2, FAM20C, MTHFD2, CDCP1) in clinic samples and animal models matched bioinformatics analysis, and ABCG2, FAM20C, MTHFD2 up-regulation, and the of CDCP1 down-regulation were also linked to poor cardiovascular function.

Conclusions: This study developed and verified an effective diagnostic model linked to immune infiltration in TAAD, providing new approaches to studying the potential pathogenesis of TAAD and discovering new medication intervention targets.

Background: The centrosome is one of the principal cell hubs, where numerous proteins important for intracellular regulatory processes are concentrated. One of them, serine-threonine kinase 6, alias Aurora A, is involved in centrosome duplication and mitotic spindle formation and maintenance.

Methods: Long-term vital observations of cells, immunofluorescence analysis of protein localization, synchronization of cells at different phases of the cell cycle, Western blot analysis of protein content were used in the work.

Results: In this study, we investigated the dynamics of Aurora A protein accumulation and degradation in the XL2 Xenopus cell line during its 28-hour cell cycle. Using Western blot and immunofluorescence analyses, we demonstrated that Aurora A disappeared from the centrosome within one hour following mitosis and was not redistributed to other cell compartments. Using double Aurora A/Bromodeoxyuridine immunofluorescence labeling of the cells with precisely determined cell cycle stages, we observed that Aurora A reappeared in the centrosome during the S-phase, which was earlier than reported for all other known proteins with mitosis-specific centrosomal localization. Moreover, Aurora A accumulation in the centrosomal region and centrosome separation were asynchronous in the sister cells.

Conclusions: The reported data allowed us to hypothesize that Aurora A is one of the primary links in coordinating centrosome separation and constructing the mitotic spindle.

Interleukin 31 (IL-31) is a proinflammatory cytokine, mainly secreted by Type II helper T cells. It signals through a heterodimeric receptor complex composed of IL-31 receptor α and oncostatin-M receptor β chain. The hallmark feature of IL-31, in its pathological role, is its ability to induce pruritus in mammals. Pruritus is a common symptom and major reason of morbidity in cancer patients, compromising their quality of life. Although, IL-31 is differentially expressed in different tumor types and could promote or inhibit cancer progression, high expression of IL-31 is a contributing factor to advanced stage tumor and severity of pruritus. The simultaneous existence of pruritus and cancer could either result from the aberrations in common proteins that co-exist in both cancer and pruritus or the therapeutic treatment of cancer could indirectly induce pruritus. Although the biology of IL-31 has predominantly been described in skin diseases such as atopic dermatitis and other inflammatory diseases, the precise role of IL-31 in the tumor biology of different cancer types remains elusive. Herein, we summarize the current understanding on the role of this cytokine in the pathogenesis of different cancers.

Background: Psoriasis is a common, chronic, and multifactorial inflammatory cutaneous disorder that involves genetic and epigenetic factors. N6-methyladenosine methylation (m⁶A) is the most prevalent RNA modification implicated in various diseases; however, its role in psoriasis still needs to be further explored. We aimed to explore the mechanisms underlying the effects of m⁶A in psoriasis pathogenesis, prompting new therapeutic targets.

Methods: Three psoriasis-related datasets, including GSE155702, GSE109248, and GSE142582, were collected. Differentially m⁶A methylated genes (DMGs) between psoriasis lesions of psoriasis patients and healthy skin controls were identified from the GSE155702 dataset, and corresponding Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Differentially expressed genes (DEGs) and the common DEGs between the two groups were screened from the GSE109248 and GSE142582 datasets; the expression and interactions of the m⁶A regulators were analyzed. The m⁶A levels of total RNAs and the protein expression levels of METTL3, WTAP, ALKBH5, FTO, and METTL14 in imiquimod (IMQ)-induced psoriasiform lesions were evaluated.

Results: 66 significantly upregulated and 381 significantly downregulated m⁶A peaks were identified, corresponding to 414 genes which were particularly associated with cell and tissue development processes and cell cycle related items. 271 common DEGs were identified, associating with keratinocyte differentiation, epidermis development, cytokine-cytokine receptor interaction, and fatty acid metabolic processes. 15 crucial m⁶A related differentially expressed genes were obtained after the intersection of the DMGs and common DEGs, including NEU2, GALNT6, MTCL1, DOC2B, CAMK2N1, SNTB1, RNF150, CGNL1, CCDC102A, MEOX2, EEF2K, OBSCN, SLC46A2, CCDC85A, and DACH1. In addition, we found that m⁶A methylation and these five m⁶A regulators were both upregulated in psoriatic lesions.

Conclusions: It revealed that psoriasis pathophysiological processes encompass m⁶A epigenetic alterations, and that m⁶A alterations may specifically influence cell proliferation and neural regulation, and closely associated with osteoarticular involvement and metabolic syndrome in psoriasis.

Background: Lung adenocarcinoma (LUAD) is the predominant histological subtype among non-small cell lung cancer cases, representing approximately 40% of all cases. Shugoshin 2 (SGO2) is implicated in tumorigenesis and tumor progression. This study aimed to uncover a potential role of SGO2 in the LUAD.

Methods: Data related to gene mRNA expression and clinical information were obtained from The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and the Cancer Cell Line Encyclopedia (CCLE) databases. Cell Counting Kit-8 (CCK-8), Transwell, scratch assay, and flow cytometry were applied to investigate the biological functions of SGO2 in the LUAD. Western blot was conducted to detect the protein expression.

Results: Through pan-cancer analysis, SGO2 was found to be consistently overexpressed in 25 of 33 cancer types, including LUAD. In vitro assays revealed that SGO2 knockdown significantly impeded cell proliferation, cell migration, invasion and epithelial-mesenchymal transition (EMT), whereas its overexpression promoted these abilities. Flow cytometry confirmed that SGO2 contributed to cell cycle progression and reduced cell apoptosis. Furthermore, SGO2 facilitated cell proliferation and regulated cell cycle through upregulating recombinant E2F transcription factor 1 (E2F1).

Conclusions: Our study demonstrated that SGO2 was up-regulated in pan-cancers including LUAD and its high expression was strongly associated with poor overall survival (OS) and progression-free survival (PFS) of patients with LUAD. SGO2 promoted cell proliferation, cell migration, invasion and EMT of A549 cells. Additionally, E2F1 was involved in regulation of cell cycle and cell proliferation mediated by SGO2. This research elucidated the oncogenic significance of SGO2 in LUAD, proposing its potential as a prognostic biomarker and a promising target for therapeutic interventions.

Luteinizing hormone (LH) and human chorionic gonadotropin (CG), like follicle-stimulating hormone, are the most important regulators of the reproductive system. They exert their effect on the cell through the LH/CG receptor (LHCGR), which belongs to the family of G protein-coupled receptors. Binding to gonadotropin induces the interaction of LHCGR with various types of heterotrimeric G proteins (G_s, G_q/11, G_i) and β-arrestins, which leads to stimulation (G_s) or inhibition (G_i) of cyclic adenosine monophosphate-dependent cascades, activation of the phospholipase pathway (G_q/11), and also to the formation of signalosomes that mediate the stimulation of mitogen-activated protein kinases (β-arrestins). The efficiency and selectivity of activation of intracellular cascades by different gonadotropins varies, which is due to differences in their interaction with the ligand-binding site of LHCGR. Gonadotropin signaling largely depends on the status of N- and O-glycosylation of LH and CG, on the formation of homo- and heterodimeric receptor complexes, on the cell-specific microenvironment of LHCGR and the presence of autoantibodies to it, and allosteric mechanisms are important in the implementation of these influences, which is due to the multiplicity of allosteric sites in different loci of the LHCGR. The development of low-molecular-weight allosteric regulators of LHCGR with different profiles of pharmacological activity, which can be used in medicine for the correction of reproductive disorders and in assisted reproductive technologies, is promising. These and other issues regarding the hormonal and allosteric regulation of LHCGR are summarized and discussed in this review.

Background: Liver cancer is a highly lethal malignancy with frequent recurrence, widespread metastasis, and low survival rates. The aim of this study was to explore the role of Endoglin (ENG) in liver cancer progression, as well as its impacts on angiogenesis, immune cell infiltration, and the therapeutic efficacy of sorafenib.

Methods: A comprehensive evaluation was conducted using online databases Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), 76 pairs of clinical specimens of tumor and adjacent non-tumor liver tissue, and tissue samples from 32 hepatocellular carcinoma (HCC) patients treated with sorafenib. ENG expression levels were evaluated using quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), Western blot, and immunohistochemical analysis. Cox regression analysis, Spearman rank correlation analysis, and survival analysis were used to assess the results. Functional experiments included Transwell migration assays and tube formation assays with Human Umbilical Vein Endothelial Cells (HUVECs).

Results: Tumor cells exhibited retro-differentiation into endothelial-like cells, with a significant increase in ENG expression in these tumor-derived endothelial cells (TDECs). High expression of ENG was associated with more aggressive cancer characteristics and worse patient prognosis. Pathway enrichment and functional analyses identified ENG as a key regulator of immune responses and angiogenesis in liver cancer. Further studies confirmed that ENG increases the expression of Collagen type Iα1 (COL1A1), thereby promoting angiogenesis in liver cancer. Additionally, HCC patients with elevated ENG levels responded well to sorafenib treatment.

Conclusions: This study found that ENG is an important biomarker of prognosis in liver cancer. Moreover, ENG is associated with endothelial cell differentiation in liver cancer and plays a crucial role in formation of the tumor vasculature. The assessment of ENG expression could be a promising strategy to identify liver cancer patients who might benefit from targeted immunotherapies.