Circ_0011058 alleviates RA pathology through the circ_0011058/miR-335-5p/CUL4B signal axis.

Our previous study found that Cullin 4B (CUL4B) inhibited rheumatoid arthritis (RA) pathology through glycogen synthase kinase-3beta (GSK3ß)/canonical Wnt signalling pathway. In this work, pre-experiment and bioinformatics analysis suggested that circ_0011058 may lead to the up-regulation of CUL4B expression by inhibiting miR-335-5p. Therefore, we studied whether circ_0011058 can promote the expression of CUL4B through sponging the miR-335-5p and further promote the pathological development of RA. Bioinformatics prediction, real-time quantitative PCR (RT-qPCR), western blot (WB), double luciferase reporter gene and other relevant methods were used to study the inhibition of circ_0011058 on RA pathology and its molecular mechanism. Results showed that the expression of circ_0011058 was significantly increased in adjuvant arthritis (AA) rats and RA fibroblast-like synoviocytes (FLS). The knockout of circ_0011058 inhibited the proliferation of AA FLS and RA FLS, decreased the levels of interleukin-1 beta (IL-1ß), interleukin 6 (IL-6), interleukin 8 (IL-8), and inhibited the expression of matrix metalloproteinase 3 (MMP3), fibronectin, which showed that circ_0011058 had a strong role in promoting RA pathology. Furthermore, miR-335-5p expression was reduced in AA rats and RA FLS. The highly expressed circ_0011058 directly sponged the miR-335-5p, which led to the increase of CUL4B expression and promoted the activation of the GSK3ß/canonical signalling pathway. Finally, we confirmed that miR-335-5p mediated the roles of circ_0011058 in promoting RA pathological development, which showed that the circ_0011058/miR-335-5p/CUL4B signal axis was involved in RA pathology. This work was of great significance for clarifying the roles of circ_0011058 in RA pathology, and further work was needed to establish whether circ_0011058 was a potential therapeutic target or diagnostic marker for RA.

Epigenetic modification and exosome effects on autophagy in osteoarthritis.

Osteoarthritis (OA) is a degenerative disease that leads to joint pain and stiffness and is one of the leading causes of disability and pain worldwide. Autophagy is a highly conserved self-degradation process, and its abnormal function is closely related to human diseases, including OA. Abnormal autophagy regulates cell aging, matrix metalloproteinase metabolism, and reactive oxygen metabolism, which are key in the occurrence and development of OA. There is evidence that drugs directly or indirectly targeting autophagy significantly hinder the progress of OA. In addition, the occurrence and development of autophagy in OA are regulated by many factors, including epigenetic modification, exosomes, crucial autophagy molecules, and signaling pathway regulation. Autophagy, as a new therapeutic target for OA, has widely influenced the pathological mechanism of OA. However, determining how autophagy affects OA pathology and its use in the treatment and diagnosis of targets still need further research.

Wnt5a: A promising therapeutic target for inflammation, especially rheumatoid arthritis.

BACKGROUND: Wnt5a is a member of the Wnt protein family, which acts on classical or multiple non-classical Wnt signaling pathways by binding to different receptors. The expression regulation and signal transduction of Wnt5a is closely related to the inflammatory response. Abnormal activation of Wnt5a signaling is an important part of inflammation and rheumatoid arthritis (RA). OBJECTIVES: This paper mainly focuses on Wnt5a protein and its mediated signaling pathway, summarizes the latest research progress of Wnt5a in the pathological process of inflammation and RA, and looks forward to the main directions of Wnt5a in RA research, aiming to provide a theoretical basis for the prevention and treatment of RA diseases by targeting Wnt5a. RESULTS: Wnt5a is highly expressed in activated blood vessels, histocytes and synoviocytes in inflammatory diseases such as sepsis, sepsis, atherosclerosis and rheumatoid arthritis. It mediates the production of pro-inflammatory cytokines and chemokines, regulates the migration and recruitment of various immune effector cells, and thus participates in the inflammatory response. Wnt5a plays a pathological role in synovial inflammation and bone destruction of RA, and may be an important clinical therapeutic target for RA. CONCLUSION: Wnt5a is involved in the pathological process of inflammation and interacts with inflammatory factors. Wnt5a may be a new target for regulating the progression of RA disease and intervening therapy because of its multi-modal effects on the etiology of RA, especially as a regulator of osteoclast activity and inflammation.

M6A methylation modification in autoimmune diseases, a promising treatment strategy based on epigenetics.

BACKGROUND: N6-methyladenosine (m6A) methylation modification is involved in the regulation of various biological processes, including inflammation, antitumor, and antiviral immunity. However, the role of m6A modification in the pathogenesis of autoimmune diseases has been rarely reported. METHODS: Based on a description of m6A modification and the corresponding research methods, this review systematically summarizes current insights into the mechanism of m6A methylation modification in autoimmune diseases, especially its contribution to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). RESULTS: By regulating different biological processes, m6A methylation is involved in the pathogenesis of autoimmune diseases and provides a promising biomarker for the diagnosis and treatment of such diseases. Notably, m6A methylation modification is involved in regulating a variety of immune cells and mitochondrial energy metabolism. In addition, m6A methylation modification plays a role in the pathological processes of RA, and m6A methylation-related genes can be used as potential targets in RA therapy. CONCLUSIONS: M6A methylation modification plays an important role in autoimmune pathological processes such as RA and SLE and represents a promising new target for clinical diagnosis and treatment, providing new ideas for the treatment of autoimmune diseases by targeting m6A modification-related pathways.

Efficacy and safety of community-based moxibustion for primary hypertension: A randomized controlled trial with patient preference arms.

Moxibustion has been shown to have a potential antihypertensive effect, but its applicability for the primary care of hypertension is unclear. The authors conducted a multicenter randomized controlled trial (RCT) with patient preference arms to investigate the effect, safety, cost-effectiveness, and compliance of moxibustion in community patients with hypertension. Patients with primary hypertension were enrolled from seven communities randomly or nonrandomly assigned to receive self-administered moxibustion + the original hypertensive regimen or the original hypertensive regimen alone for 6 months. The authors mainly evaluated the effects of moxibustion on hypertensive outcomes and adverse events. As a result, a total of 160 and 240 patients were recruited into the randomized and nonrandomized arms, respectively, with 87.5% completing the follow-up. At month 6, there was a significantly greater reduction in systolic blood pressure (SBP) (difference: -10.57 mmHg), a higher proportion of responders (82.2% vs. 53.7%; odds ratio 4.00), and better improvements in hypertensive symptoms and quality of life (QoL) in the moxibustion group than in the control group in the randomized population, but there was no significant between-group difference in diastolic blood pressure (DBP). The nonrandomized findings showed the same effect direction for all outcomes, except for DBP. All moxibustion-related adverse events were mild. In conclusion, moxibustion can reduce SBP and improve hypertensive symptoms and QoL in community patients with hypertension, with good safety and low cost, although its effect on DBP remains uncertain. The findings suggest that moxibustion may be an appropriate technique for community primary care of hypertension.

Progress in epigenetic regulation of milk synthesis, with particular emphasis on mRNA regulation and DNA methylation.

Inadequate milk secretion and a lack of nutrients in humans and mammals are serious problems. It is of great significance to clarify the mechanisms of milk synthesis and treatment methods. Epigenetic modification, represented by RNA methylation, is an important way of gene expression regulation that profoundly affects human gene expression and participates in various physiological and pathological mechanisms. Epigenetic disorders also have an important impact on the production and secretion of milk. This review systematically summarized the research results of epigenetics in the process of lactation in PubMed, Web of Science, NSTL, and other databases and reviewed the effects of epigenetics on human and mammalian lactation, including miRNAs, circRNAs, lncRNAs, DNA methylations, and RNA methylations. The abnormal expression of miRNAs was closely related to the synthesis and secretion of milk fat, milk protein, and other nutrients in the milk of cattle, sheep, and other mammals. MiRNAs are also involved in the synthesis of human milk and the secretion of nutrients. CircRNAs and lncRNAs mainly target miRNAs and regulate the synthesis of nutrients in milk by ceRNA mechanisms. The abnormal expression of DNA and RNA methylation also has an important impact on milk synthesis. Epigenetic modification has the potential to regulate the milk synthesis of breast epithelial cells. Analyzing the mechanisms of human and mammalian milk secretion deficiency and nutrient deficiency from the perspective of epigenetics will provide a new perspective for the treatment of postpartum milk deficiency in pregnant women and mammalian milk secretion deficiency.

RNA methylations in hepatic fibrosis, a gradually emerging new treatment strategy.

BACKGROUND: Hepatic fibrosis (HF) is a pathological process caused by excessive accumulation of extracellular matrix caused by a series of causes, leading to the formation of fiber scar. RNA methylation is a newly discovered epigenetic modification that exists widely in eukaryotes and prokaryotes and plays a crucial role in the pathogenesis of many diseases. RESULTS: The occurrence and development of HF are regulated by many factors, including excessive deposition of extracellular matrix, activation of hepatic stellate cells, inflammation, and oxidative stress. RNA methylations of different species have become a crucial regulatory mode of transcript expression, And participate in the pathogenesis of tumors, nervous system diseases, autoimmune diseases, and other diseases. In addition, there are five common types of RNA methylation, but only m6A plays a crucial regulatory role in HF. The pathophysiological regulation of m6A on HF is achieved by the combination of the methylated transferase, demethylated enzyme, and methylated reading protein. CONCLUSIONS: RNA methylated methyltransferase, demethylase, and reading protein extensively affect the pathological mechanism of HF, which may be a new therapeutic and diagnostic target, representing a new class of therapeutic strategies.

Dysregulation of circRNAs in rheumatoid arthritis, with special emphasis on circRNAs secreted by exosomes and the crosstalk between circRNAs and RNA methylations.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease caused by a variety of unknown factors. It mainly occurs in the small joints of hands and feet, leading to cartilage destruction and bone erosion. Various pathologic mechanisms such as exosomes and RNA methylations are involved in the pathogenesis of RA. METHODS: This work searches PubMed, Web of Science (SCIE) and Science Direct Online (SDOL) databases, it role of abnormally expressed circulating RNAs (circRNAs) in the pathogenesis of RA was summarized. And the relationship between circRNAs and exosomes and methylations. RESULTS: Both the abnormal expression of circRNAs and the sponge effect of circRNAs on microRNAs (miRNAs) affect the pathogenesis of RA by regulating target genes. CircRNAs affect the proliferation, migration and inflammatory reaction of RA-fibroblast-like synovial cells (FLSs), circRNAs in peripheral blood mononuclear cells (PBMCs) and macrophages also participate in the pathological mechanism of RA (Fig. 1). CircRNAs in exosomes are closely related to the pathogenesis of RA. In addition, exosomal circRNAs and the relationship between circRNAs and RNA methylations are closely related to the pathogenesis of RA. CONCLUSION: CircRNAs play an important role in the pathogenesis of RA and have the potential to be a new target for the diagnosis and treatment of RA. However, the development of mature circRNAs for clinical application is not a small challenge.

CircRNA-mediated ceRNA mechanism in Osteoarthritis: Special emphasis on circRNAs in exosomes and the crosstalk of circRNAs and RNA methylation.

Osteoarthritis (OA) is an age-related joint disease with chronic inflammation, progressive articular cartilage destruction and subchondral bone sclerosis. CircRNAs (circRNAs) are a class of non-coding RNA with a circular structure that participate in a series of important pathophysiological processes of OA, especially its ceRNA mechanisms, and play an important role in OA. CircRNAs may be potential biomarkers for the diagnosis and prognosis of OA. Additionally, differentially expressed circRNAs were found in patients with OA, indicating that circRNAs are involved in the pathogenesis of OA. Experiments have shown that the intra-articular injection of modified circRNAs can effectively relieve OA. Exosomal circRNAs and methylated circRNAs also provide new ideas for the treatment of OA. Clarifying the important roles of circRNAs in OA will deepen people's understanding of the pathogenesis of OA. CircRNAs may be developed as new biomarkers or drug targets for the diagnosis of OA and provide new methods for the treatment of OA.

Gandouling inhibits hepatic fibrosis in Wilson's disease through Wnt-1/ß-catenin signaling pathway.

ETHNOPHARMACOLOGIC SIGNIFICANCE: Wilson's disease (WD) hepatic fibrosis is the result of chronic liver injury induced by Cu2+ deposition in the liver. Gandouling (GDL) is a hospital preparation of the First Affiliated Hospital of Anhui University of Chinese Medicine. Previous studies have found that GDL can play an anti-inflammatory, anti-oxidation, and promote Cu2+ excretion, which has a clear anti-WD effect. AIM OF THE STUDY: We found that Wnt-1 was significantly up-regulated in the liver tissue of toxic-milk (TX) mouse in the WD gene mutant model, and the monomer components of GDL could combine well with Wnt-1. Therefore, in this work, we used RT-qPCR, Western blot, immunofluorescence, network pharmacology, molecular docking, and related methods to study the effects of GDL on hepatic stellate cell (HSC) activation and Wnt-1/ß-catenin pathway in TX mice to clarify the effect of GDL on WD hepatic fibrosis. RESULTS: GDL could alleviate hepatic fibrosis, improve liver function, and inhibit the activation of HSC in TX mice. Network pharmacology predicted that the Wnt-1/ß-catenin was the target of GDL, and molecular dynamics further revealed that GDL has a good binding ability with Wnt-1 and inhibits the Wnt/ß-catenin signaling pathway through Wnt-1. Furthermore, we found that GDL blocked the Wnt-1/ß-catenin signaling pathway in the liver of TX mice in vivo. In vitro, serum containing GDL blocked the Cu2+ ion-induced Wnt-1/ß-catenin signaling pathway in LX-2 cells. Therefore, GDL blocked the Wnt-1/ß-catenin signaling pathway, inhibited HSC activation, and improved WD hepatic fibrosis by binding to Wnt-1. CONCLUSION: GDL improves hepatic fibrosis in WD model mice by blocking the Wnt-1/ß-catenin signaling pathway, and Wnt-1 may be a new target for the diagnosis and treatment of WD. This reveals a new mechanism of GDL against WD, and promotes the clinical promotion of GDL.

CircRnas in atherosclerosis, with special emphasis on the spongy effect of circRnas on miRnas.

Atherosclerosis (AS) is a chronic inflammatory disease, which leads to atherosclerotic rupture, lumen stenosis and thrombosis, and often endangers life. Circular RNAs (circRNAs) are a special class of non-coding RNA molecules, whose abnormal expression has been proved to be closely related to human diseases, including AS. Both the abnormal regulation of circRNAs and the sponging effect on miRNAs would lead to changes in gene expression in the form of epigenetic modification, ultimately leading to the formation of AS. CircRNAs can be used as peripheral blood markers of AS, and play an important regulatory role in the proliferation, migration, inflammation and apoptosis of vascular smooth muscle cells, endothelial cells and macrophage, which are key cells for the development of AS. The in-depth understanding of circRNAs in AS not only provides a new method for the diagnosis of AS, but also provides a new idea for the treatment of AS.

Huangqin Qingre Qubi Capsule inhibits RA pathology by binding FZD8 and further inhibiting the activity of Wnt/ß-catenin signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqin Qingre Qubi Capsule (HQC) is a Chinese herbal compound for the treatment of rheumatoid arthritis (RA), which is made from dry roots of Scutellaria baicalensis Georgi, dry mature seeds of Gardenia jasminoides J.Ellis, dry and mature seeds of Coix lacryma-jobi var. stenocarpa Oliv., dry mature seeds of Amygdalus persica L. and roots and rhizomes of Clematis chinensis Osbeck in the proportion of 10:9:30:5:10. HQC has a significant effect in clinical treatment of RA, which can inhibit RA inflammation, improve oxidative stress state, and effectively relieve symptoms of RA patients. AIM OF THE STUDY: The anti-arthritis effect of HQC and its mechanism, especially whether it improves RA through FZD8-Wnt/ß-catenin signal axis, were studied using adjuvant arthritis (AA) rats and FLS from RA patients. MATERIALS AND METHODS: Real time qPCR (RT-qPCR), Western blot (WB), confocal microscopy and other molecular biological methods were used to study the anti-RA effect of HQC and its mechanism. RESULTS: The expression of FZD8 was significantly up-regulated in synovium and FLS of AA rats and RA FLS. FZD8 significantly activated the Wnt/ß-catenin signaling pathway, promoted abnormal proliferation of FLS, increased the levels of inflammatory factors IL-1ß, IL-6 and IL-8, and significantly increased the expression of matrix metalloproteinase 3 (MMP3) and fibronectin. HQC has significant therapeutic effect on AA rats. Molecular docking and molecular dynamics showed that HQC had a good binding ability with FZD8. We also confirmed that HQC inhibited Wnt/ß-catenin signaling pathway by binding FZD8, and reduced the levels of the above inflammatory factors and pathological genes of RA. CONCLUSIONS: The expression of FZD8 is significantly increased in AA rats and FLS from RA patients. Clarify that HQC improves RA through the FZD8-Wnt/ß-catenin signal axis, provide a clear therapeutic mechanism for HQC to improve RA, and also provide a basis for clinical promotion of HQC.

Circular RNA in autoimmune diseases: special emphasis on regulation mechanism in RA and SLE.

BACKGROUND: Autoimmune diseases are diseases caused by tissue damage caused by the body's immune response to autoantibodies. Circular RNAs (CircRNAs) are a kind of special endogenous non-coding RNA that play a biological role by regulating gene transcription. METHODS: In this work, we searched the PubMed, Web of Science (SCIE), National Science and Technology Library (NSTL), and ScienceDirect Online (SDOL) databases to summarize the impact of circRNAs on autoimmune diseases, especially the results of circRNAs in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). RESULTS: The study on the function of circRNAs and autoimmune diseases further deepened our understanding of the development and pathogenesis of autoimmune diseases. CircRNAs may act as miRNA sponges to regulate biological processes and affect the occurrence and development of autoimmune diseases. CircRNAs are closely related to the pathogenesis of RA and SLE and may become potential biomarkers for the diagnosis and treatment of RA and SLE. CONCLUSION: CircRNAs play an important role in the pathogenesis of RA, SLE and other autoimmune diseases, and are expected to provide new biomarkers for the diagnosis and treatment of autoimmune diseases. However, the function and mechanism of circRNAs in autoimmune diseases need more comprehensive research.

Clematichinenoside AR inhibits the pathology of rheumatoid arthritis by blocking the circPTN/miR-145-5p/FZD4 signal axis.

BACKGROUNDS: Traditional Chinese medicine roots and rhizomes of Clematis chinensis Osbeck (CCO) has the effect of improving rheumatoid arthritis (RA), Clematichinenoside AR (CAR) is an effective monomer of CCO and a promising natural product for the treatment of RA. METHODS: In this work, we aim to systematically evaluate whether CAR can improve RA pathology, inhibit the fibroblast-like synoviocytes (FLS) proliferation and inflammatory response, and further investigate the mechanism of CAR inhibiting RA through molecular docking, molecular dynamics and molecular biology methods. RESULTS: Combined with the research results of CIA mice and FLS from RA patients, we found that CAR significantly improved the severity of CIA mice, and inhibited the proliferation and inflammatory response of FLS. Combined with bioinformatics prediction, we confirmed that circPTN promoted frizzled-4 (FZD4) expression through sponging miR-145-5p, then activating the Wnt/ß-catenin pathway. The circPTN/miR-145-5p/FZD4 signal axis was involved in the pathogenesis of RA. Furthermore, CAR blocked the circPTN/miR-145-5p/FZD4 signal axis by combining with FZD4 and improved RA pathology. CONCLUSIONS: The circPTN/miR-145-5p/FZD4 signal axis plays an important role in promoting the pathogenesis of RA, and CAR from CCO may inhibit RA pathology by combining the FZD4 and further blocking this signal axis.

RNA Methylations in Cardiovascular Diseases, Molecular Structure, Biological Functions and Regulatory Roles in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in the world. Despite considerable progress in the diagnosis, treatment and prognosis of CVDs, new diagnostic biomarkers and new therapeutic measures are urgently needed to reduce the mortality of CVDs and improve the therapeutic effect. RNA methylations regulate almost all aspects of RNA processing, such as RNA nuclear export, translation, splicing and non-coding RNA processing. In view of the importance of RNA methylations in the pathogenesis of diseases, this work reviews the molecular structures, biological functions of five kinds of RNA methylations (m6A, m5C, m1a, m6am and m7G) and their effects on CVDs, including pulmonary hypertension, hypertension, vascular calcification, cardiac hypertrophy, heart failure. In CVDs, m6A "writers" catalyze the installation of m6A on RNAs, while "erasers" remove these modifications. Finally, the "readers" of m6A further influence the mRNA splicing, nuclear export, translation and degradation. M5C, m1A, m6Am and m7G are new types of RNA methylations, their roles in CVDs need to be further explored. RNA methylations have become a new research hotspot and the roles in CVDs is gradually emerging, the review of the molecular characteristics, biological functions and effects of RNA methylation on CVDs will contribute to the elucidation of the pathological mechanisms of CVDs and the discovery of new diagnostic markers and therapeutic targets of CVDs.