Abstract
N6-methyladenosine (m
6
A) methylation is the most universal internal modification in eukaryotic mRNA. With elaborate functions executed by m
6
A writers, erasers, and readers, m
6
A ...modulation is involved in myriad physiological and pathological processes. Extensive studies have demonstrated m
6
A modulation in diverse tumours, with effects on tumorigenesis, metastasis, and resistance. Recent evidence has revealed an emerging role of m
6
A modulation in tumour immunoregulation, and divergent m
6
A methylation patterns have been revealed in the tumour microenvironment. To depict the regulatory role of m
6
A methylation in the tumour immune microenvironment (TIME) and its effect on immune evasion, this review focuses on the TIME, which is characterized by hypoxia, metabolic reprogramming, acidity, and immunosuppression, and outlines the m
6
A-regulated TIME and immune evasion under divergent stimuli. Furthermore, m
6
A modulation patterns in anti-tumour immune cells are summarized.
Rheumatoid arthritis (RA), the most common autoimmune disease, is characterized by symmetrical synovial inflammation of multiple joints with the infiltration of pro-inflammatory immune cells and ...increased cytokines (CKs) levels. In the past few years, numerous studies have indicated that several factors could affect RA, such as mutations in susceptibility genes, epigenetic modifications, age, and race. Recently, environmental factors, particularly polycyclic aromatic hydrocarbons (PAHs), have attracted increasing attention in RA pathogenesis. Therefore, exploring the specific mechanisms of PAHs in RA is vitally critical. In this review, we summarize the recent progress in understanding the mechanisms of PAHs and aryl hydrocarbon receptors (AHRs) in RA. Additionally, the development of therapeutic drugs that target AHR is also reviewed. Finally, we discuss the challenges and perspectives on AHR application in the future.
Rheumatoid arthritis (RA) is a chronic autoimmune disease (AD) characterized by persistent synovial inflammation, bone erosion and progressive joint destruction. This research aimed to elucidate the ...potential roles and molecular mechanisms of N6-methyladenosine (m6A) methylation regulators in RA.
An array of tissues from 233 RA and 126 control samples was profiled and integrated for mRNA expression analysis. Following quality control and normalization, the cohort was split into training and validation sets. Five distinct machine learning feature selection methods were applied to the training set and validated in validation sets.
Among the six models, the LASSO_λ-1se model not only performed better in the validation sets but also exhibited more stringent performance. Two m6A methylation regulators were identified as significant biomarkers by consensus feature selection from all four methods. IGF2BP3 and YTHDC2, which are differentially expressed in patients with RA and controls, were used to predict RA diagnosis with high accuracy. In addition, IGF2BP3 showed higher importance, which can regulate the G2/M transition to promote RA-FLS proliferation and affect M1 macrophage polarization.
This consensus of multiple machine learning approaches identified two m6A methylation regulators that could distinguish patients with RA from controls. These m6A methylation regulators and their target genes may provide insight into RA pathogenesis and reveal novel disease regulators and putative drug targets.
Prolonged exposure to polycyclic aromatic hydrocarbons (PAHs) may result in autoimmune diseases, such as rheumatoid arthritis (RA) and osteoporosis (OP), which are based on an imbalance in bone ...homeostasis. These diseases are characterized by bone erosion and even a disruption in homeostasis, including in osteoblasts and osteoclasts. Current evidence indicates that multiple factors affect the progression of bone homeostasis, such as genetic susceptibility and epigenetic modifications. However, environmental factors, especially PAHs from various sources, have been shown to play an increasingly prominent role in the progression of bone homeostasis. Hence, it is essential to investigate the effects and pathogenesis of PAHs in bone homeostasis. In this review, recent progress is summarized concerning the effects and mechanisms of PAHs and their ligands and receptors in bone homeostasis. Moreover, strategies based on the effects and mechanisms of PAHs in the regulation of the bone balance and alleviation of bone destruction are also reviewed. We further discuss the future challenges and perspectives regarding the roles of PAHs in autoimmune diseases based on bone homeostasis.
Rheumatoid arthritis (RA) is an inflammatory disease that begins with a loss of tolerance to modified self-antigens and immune system abnormalities, eventually leading to synovitis and bone and ...cartilage degradation. Reactive oxygen species (ROS) are commonly used as destructive or modifying agents of cellular components or they act as signaling molecules in the immune system. During the development of RA, a hypoxic and inflammatory situation in the synovium maintains ROS generation, which can be sustained by increased DNA damage and malfunctioning mitochondria in a feedback loop. Oxidative stress caused by abundant ROS production has also been shown to be associated with synovitis in RA. The goal of this review is to examine the functions of ROS and related molecular mechanisms in diverse cells in the synovial microenvironment of RA. The strategies relying on regulating ROS to treat RA are also reviewed.
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation, cartilage destruction, pannus formation and bone erosion. Various immune cells, including ...macrophages, are involved in RA pathogenesis. The heterogeneity and plasticity of macrophages render them pivotal regulators of both the induction and resolution of the inflammatory response. Predominantly, two different phenotypes of macrophages have been identified: classically activated M1 macrophages exacerbate inflammation via the production of cytokines, chemokines and other inflammatory mediators, while alternatively activated M2 macrophages inhibit inflammation and facilitate tissue repair. An imbalance in the M1/M2 macrophage ratio is critical during the initiation and progression of RA. Macrophage polarization is modulated by various transcription factors, epigenetic elements and metabolic reprogramming. Curcumin, an active component of turmeric, exhibits potent immunomodulatory effects and is administered in the treatment of multiple autoimmune diseases, including RA. The regulation of macrophage polarization and subsequent cytokine production as well as macrophage migration is involved in the mechanisms underlying the therapeutic effect of curcumin on RA. In this review, we summarize the underlying mechanisms by which curcumin modulates macrophage function and polarization in the context of RA to provide evidence for the clinical application of curcumin in RA treatment.
Highlights
Large-area production of self-standing graphene nanofilm (~ 20 cm) through a clean ‘substrate replacement’ strategy.
Realizing highly crystalline graphene nanofilms without micro-gasbags ...by introducing polymers.
The graphene nanofilms demonstrate a solid light–matter interaction (photoelectric conversion in the mid-infrared and electromagnetic interference (EMI) shielding in X-band) with performance beyond state-of-the-art graphene/silicon diodes and EMI materials.
Bulk graphene nanofilms feature fast electronic and phonon transport in combination with strong light–matter interaction and thus have great potential for versatile applications, spanning from photonic, electronic, and optoelectronic devices to charge-stripping and electromagnetic shielding, etc. However, large-area flexible close-stacked graphene nanofilms with a wide thickness range have yet to be reported. Here, we report a polyacrylonitrile-assisted ‘substrate replacement’ strategy to fabricate large-area free-standing graphene oxide/polyacrylonitrile nanofilms (lateral size ~ 20 cm). Linear polyacrylonitrile chains-derived nanochannels promote the escape of gases and enable macro-assembled graphene nanofilms (nMAGs) of 50–600 nm thickness following heat treatment at 3,000 °C. The uniform nMAGs exhibit 802–1,540 cm
2
V
−1
s
−1
carrier mobility, 4.3–4.7 ps carrier lifetime, and > 1,581 W m
−1
K
−1
thermal conductivity (nMAG-assembled 10 µm-thick films, mMAGs). nMAGs are highly flexible and show no structure damage even after 1.0 × 10
5
cycles of folding–unfolding. Furthermore, nMAGs broaden the detection region of graphene/silicon heterojunction from near-infrared to mid-infrared and demonstrate higher absolute electromagnetic interference (EMI) shielding effectiveness than state-of-the-art EMI materials of the same thickness. These results are expected to lead to the broad applications of such bulk nanofilms, especially as micro/nanoelectronic and optoelectronic platforms.
Autophagy in macrophages plays a key role in the pathogenesis and progression of atherosclerosis and has become a potential therapeutic target. Here we show that cordycepin (Cpn), a natural ...derivative of adenosine, markedly reduced atherosclerotic plaque and ameliorated associated symptoms such as dyslipidemia, hyperglycemia and inflammation in ApoE
mice. Supplementation of Cpn dose-dependently inhibited oxLDL-elicited foam cell formation and modulated intracellular cholesterol homeostasis by inhibiting cholesterol uptake and promoting cholesterol efflux in RAW264.7 macrophages. Notably, Cpn exhibited significant stimulating effect on macrophage autophagy, as estimated by western blotting, immunofluorescent staining and autophagic vacuoles observation by transmission electron microscopy. The inhibitive effects of Cpn on foam cell formation were dramatically deteriorated in the presence of various autophagy inhibitors, suggesting that autophagy participate, at least in part, in the atheroprotective role of Cpn. Further investigations using different autophagy inhibitors and specific siRNAs for AMP-activated protein kinase (AMPK) gamma1 subunit indicated that Cpn may stimulate macrophage autophagy through AMPK-mTOR pathway. Together, our results demonstrated Cpn as a potential therapeutic agent for the prevention and treatment of atherosclerosis, and the autophagic activity presents a novel mechanism for Cpn-mediated atheroprotection.
Necroptosis has recently been found to be associated with the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). This study was undertaken to explore the role of ...RIPK1-dependent necroptosis in the pathogenesis of RA and the potential new treatment options.
The plasma levels of receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase domain-like pseudokinase (MLKL) in 23 controls and 42 RA patients were detected by ELISA. Collagen-induced arthritis (CIA) rats were treated with KW2449 by gavage for 28 days. Arthritis index score, H&E staining, and Micro-CT analysis were used to evaluate joint inflammation. The levels of RIPK1-dependent necroptosis related proteins and inflammatory cytokines were detected by qRT-PCR, ELISA and Western blot, and the cell death morphology was detected by flow cytometry analysis and high-content imaging analysis.
The plasma levels of RIPK1 and MLKL in RA patients were higher than those in healthy people, and were positively correlated with the severity of RA. KW2449 could reduce joint swelling, joint bone destruction, tissue damage, and the plasma levels of inflammatory cytokines in CIA rats. Lipopolysaccharide combined with zVAD (LZ) could induce necroptosis in RAW 264.7 cells, which could be reduced by KW2449. RIPK1-dependent necroptosis related proteins and inflammatory factors increased after LZ induction and decreased after KW2449 treatment or knockdown of RIPK1.
These findings suggest that the overexpression of RIPK1 is positively correlated with the severity of RA. KW2449, as a small molecule inhibitor targeting RIPK1, has the potential to be a therapeutic strategy for RA treatment by inhibiting RIPK1-dependent necroptosis.
The immune system plays a crucial role in regulating osteoclast formation and function and has significance for the occurrence and development of immune-mediated bone diseases. Kidney-tonifying ...Chinese herbs, based on the theory of traditional Chinese medicine (TCM) to unify the kidney and strengthen the bone, have been widely used in the prevention and treatment of bone diseases. The common botanical drugs are tonifying kidney-yang and nourishing kidney-yin herbs, which are divided into two parts: one is the compound prescription of TCM, and the other is the single preparation of TCM and its active ingredients. These botanical drugs regulate osteoclastogenesis directly and indirectly by immune cells, however, we have limited information on the differences between the two botanical drugs in osteoimmunology. In this review, the mechanism by which kidney-tonifying Chinese herbs inhibiting osteoclastogenesis was investigated, emphasizing the immune response. The differences in the mechanism of action between tonifying kidney-yang herbs and nourishing kidney-yin herbs were analysed, and the therapeutic value for immune-mediated bone diseases was evaluated.
PDF
