Pain is the most common symptom in patients with rheumatoid arthritis (RA). Although in recent years, through the implementation of targeted treatment and the introduction of disease-modifying ...antirheumatic drugs (DMARDs), the treatment of RA patients has made a significant progress, a large proportion of patients still feel pain. Finding appropriate treatment to alleviate the pain is very important for RA patients. Current research showed that, in addition to inflammation, RA pain involves peripheral sensitization and abnormalities in the central nervous system (CNS) pain regulatory mechanisms. This review summarized the literature on pain mechanisms of RA published in recent years. A better understanding of pain mechanisms will help to develop new analgesic targets and deploy new and existing therapies.
Triptolide (TP), a major extract of the herb
Hook F (TWHF), has been shown to exert potent pharmacological effects, especially an immunosuppressive effect in the treatment of rheumatoid arthritis ...(RA). However, its multiorgan toxicity prevents it from being widely used in clinical practice. Recently, several attempts are being performed to reduce TP toxicity. In this review, recent progress in the use of TP for RA, including its pharmacological effects and toxicity, is summarized. Meanwhile, strategies relying on chemical structural modifications, innovative delivery systems, and drug combinations to alleviate the disadvantages of TP are also reviewed. Furthermore, we also discuss the challenges and perspectives in their clinical translation.
RIPK1 is a protein kinase that simultaneously regulates inflammation, apoptosis, and necroptosis. It is thought that RIPK1 has separate functions through its scaffold structure and kinase domains. ...Moreover, different post-translational modifications in RIPK1 play distinct or even opposing roles. Under different conditions, in different cells and species, and/or upon exposure to different stimuli, infections, and substrates, RIPK1 activation can lead to diverse results. Despite continuous research, many of the conclusions that have been drawn regarding the complex interactions of RIPK1 are controversial. This review is based on an examination and analysis of recent studies on the RIPK1 structure, post-translational modifications, and activation conditions, which can affect its functions. Finally, because of the diverse functions of RIPK1 and their relevance to the pathogenesis of many diseases, we briefly introduce the roles of RIPK1 in inflammatory and autoimmune diseases and the prospects of its use in future diagnostics and treatments.
One of the most common urological diseases is benign prostatic hyperplasia (BPH), with a high prevalence in the middle-aged and elderly male population. Patient's mental and physical health is ...affected significantly by this condition, causing them considerable discomfort. During the development of BPH, a synergistic effect occurs in response to inflammation, oxidative stress, and apoptosis induced by the activation of macrophages. The nuclear factor erythroid2-related factor 2 (Nrf2) signaling pathway can mediate macrophage activation and inhibit prostate hyperplasia by suppressing pro-inflammatory factors, anti-oxidative stress disorder, and initiating apoptosis. The purpose of this study was to review the mechanism of action of Nrf2 signaling pathway-mediated macrophage activation on the immune microenvironment of BPH and to summarize the Chinese medicine based on Nrf2 to provide an overview of BPH treatment options.
•This article reviews the Nrf2 signaling -mediated macrophage activation mechanism on the BPH immune microenvironment.•The Nrf2 signaling mediates macrophage activation and inhibits BPH by inhibiting pro-inflammatory factors.•The Nrf2 signaling mediates macrophage activation and inhibits BPH by inhibiting oxidative stress disorders.•The Nrf2 signaling mediates macrophage activation and inhibits BPH by initiating apoptosis.•The traditional Chinese medicine based on Nrf2 were summarized to provide ideas for the BPH treatment.
•The classical TCM formulation Yu Ping Feng San (YPFS) was chemically characterized.•Metabolomics based chemical profiles of YPFS were obtained by a HPLC-DAD-ESI-MS/MS.•24 metabolites were assigned ...in the chemical profiles of YPFS.•Extracts of YPFS inhibited expression of TNF-α, IFN-γ and IL-1β in U937 cells.•MVA by means of OPLS-DA allowed the tentative identification of active components.
Yu Ping Feng San (YPFS) is a classical TCM formulation which has been traditionally used for treatment of immune system related diseases such as chronic bronchitis, allergic rhinitis and asthma. The formula is a mixture of Radix Saposhnikoviae (Fangfeng), Radix Astragali (Huangqi), and Rhizoma Atractylodis macrocephalae (Baizhu). TLC- and LC-DAD-ESI-MS/MS methods have been developed for the analysis of the metabolic profiles of the single herbs and of the formula. Decoctions and ASE extracts were analyzed in order to trace components of the individual herbs in YPFS. Nine constituents of Radix Saposhnikoviae, ten constituents of Radix Astragali and five constituents of Rhizoma Atractylodis macrocephalae have been assigned in the chemical profiles of the formula, which now allow the standardisation of YPFS. The pharmacological testing showed that all extracts significantly inhibited expression of TNF-α, IFN-γ, and IL-1β in U937 cells, while the inhibition of IL-4 was consistently low. Compared to conventional analyses which are focused on a limited set of compounds, metabolomics approaches, together with novel data processing tools, enable a more holistic comparison of the herbal extracts. In order to identify the constituents which are relevant for the immunomodulatory effects of the formula, metabolomics studies (PCA, OPLS-DA) have been performed using UPLC/QTOF MS data.
Rheumatoid arthritis (RA) is one of the most common autoimmune diseases caused by abnormal immune activation and immune tolerance. Immunomodulatory cells (ICs) play a critical role in the maintenance ...and homeostasis of normal immune function and in the pathogenesis of RA. The human gastrointestinal tract is inhabited by trillions of commensal microbiota on the mucosal surface that play a fundamental role in the induction, maintenance, and function of the host immune system. Gut microbiota dysbiosis can impact both the local and systemic immune systems and further contribute to various diseases, such as RA. The neighbouring intestinal ICs located in distinct intestinal mucosa may be the most likely intermediary by which the gut microbiota can affect the occurrence and development of RA. However, the reciprocal interaction between the components of the gut microbiota and their microbial metabolites with distinct ICs and how this interaction may impact the development of RA are not well studied. Therefore, a better understanding of the gut microbiota, ICs, and their interactions might improve our knowledge of the mechanisms by which the gut microbiota contribute to RA and facilitate the further development of novel therapeutic approaches. In this review, we have summarized the roles of the gut microbiota in the immunopathogenesis of RA, especially the interactions between the gut microbiota and ICs, and further discussed the strategies for treating RA by targeting/regulating the gut microbiota.
The human gut-resident commensal microbiota is a unique ecosystem associated with various bodily functions, especially immunity. Gut microbiota dysbiosis plays a crucial role in autoimmune disease ...pathogenesis as well as in bowel-related diseases. However, the role of the gut microbiota, which causes or influences systemic immunity in autoimmune diseases, remains elusive. Aryl hydrocarbon receptor, a ligand-activated transcription factor, is a master moderator of host-microbiota interactions because it shapes the immune system and impacts host metabolism. In addition, treatment optimization while minimizing potential adverse effects in autoimmune diseases remains essential, and modulation of the gut microbiota constitutes a potential clinical therapy. Here, we present evidence linking gut microbiota dysbiosis with autoimmune mechanisms involved in disease development to identify future effective approaches based on the gut microbiota for preventing autoimmune diseases.
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.
Triptolide (TP), an active component isolated from Tripterygiumwilfordii Hook F, has therapeutic potential against rheumatoid arthritis (RA). However, the underlying molecular mechanism has not been ...fully elucidated. The aim of this study is to investigate the mechanisms of TP acting on RA by combining bioinformatics analysis with experiment validation. The human protein targets of TP and the human genes of RA were found in the PubChem database and NCBI, respectively. These two dataset were then imported into Ingenuity Pathway Analysis (IPA) software online, and then the molecular network of TP on RA could be set up and analyzed. After that, both in vitro and in vivo experiments were done to further verify the prediction. The results indicated that the main canonical signal pathways of TP protein targets networks were mainly centered on cytokine and cellular immune signaling, and triggering receptors expressed on myeloid cells (TREM)-1 signaling was searched to be the top one shared signaling pathway and involved in the cytokine and cellular immune signaling. Further in vitro experiments indicated that TP not only remarkably lowered the levels of TREM-1 and DNAX-associated protein (DAP)12, but also significantly suppressed the activation of janus activating kinase (JAK)2 and signal transducers and activators of transcription (STAT)3. The expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in lipopolysaccharides (LPS)-stimulated U937 cells also decreased after treatment with TP. Furthermore, TREM-1 knockdown was able to interfere with the inhibition effects of TP on these cytokines production. In vivo experiments showed that TP not only significantly inhibited the TREM-1 mRNA and DAP12 mRNA expression, and activation of JAK2 and STAT3 in ankle of rats with collagen-induced arthritis (CIA), but also remarkably decreased production of TNF-α, IL-1β and IL-6 in serum and joint. These findings demonstrated that TP could modulate the TREM1 signal pathway to inhibit the inflammatory response in RA.
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.
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