Huangqin Qingre Chubi Capsule inhibits rheumatoid arthritis by regulating intestinal flora and improving intestinal barrier.

Background: Changes in intestinal flora and intestinal barrier in patients with preclinical and diagnosed rheumatoid arthritis (RA) suggest that intestinal flora and intestinal barrier play an important role in the induction and persistence of RA. Huangqin Qingre Chubi Capsule (HQC) is a clinically effective herbal formula for the treatment of RA, but its therapeutic mechanism has not been fully clarified. Materials and methods: In this study, real-time qPCR (RT-qPCR), 16SrRNA sequencing, Western blot (WB), immunofluorescence and other methods were used to investigate whether HQC inhibited RA. Results: Based on research in collages-induced arthritis (CIA) model in mice, human colon cancer cell line (Caco-2), and fibroblast-like synoviocytes (FLS) from RA patients, we found that intestinal flora was disturbed in CIA model group, intestinal barrier was damaged, and lipolyaccharide (LPS) level was increased, and HQC could regulate intestinal flora and intestinal barrier and reduce LPS translocation into blood. Antibiotic depletion weakened the anti-RA effect of HQC, and HQC fecal microbiota transplantation alleviated RA pathology. In addition, LPS increased the expression of RA pathologic factors MMP3, Fibronectin and inflammatory factors IL-6, TNF-α, IL-1ß and IL-8, indicating that elevated peripheral blood level of LPS was related to RA pathology. Conclusion: The dysregulation of intestinal flora and the disruption of intestinal barrier are significant factors in the development of RA. HQC improves RA by regulating intestinal flora, intestinal barrier and inhibiting LPS translocation into blood. The study unveiles RA's new pathogenesis and laid a scientific groundwork for advancing HQC therapy for RA.

[Mechanism of Huangqin Qingre Chubi Capsules in improving rheumatoid arthritis based on METTL3-SFRP4/Wnt/ß-catenin pathway].

The effect and mechanism of Huangqin Qingre Chubi Capsules(HQC) on rheumatoid arthritis(RA) were studied.Seventy male SPF rats were randomly divided into normal group, model group, low-(0. 18 g·kg~(-1)), middle-(0. 36 g·kg~(-1)), and high-(0. 72 g·kg~(-1)) dose groups of HQC, methotrexate group(MTX, 0. 75 mg·kg~(-1)), and negative control group(NC group, model +saline). Adjuvant arthritis fibroblast-like synoviocytes(AA-FLS) were divided into normal group, model group, low-, middle-, and high-dose groups of HQC, and negative control group. RT-qPCR and Western blot were used to detect the m RNA and protein expressions of METTL3, SFRP4, ß-catenin, CCND1, c-Myc, MMP3, and fibronectin. The protein expression of MMP3 and ß-catenin was detected by immunofluorescence. The gene expression level of METTL3 on AA-FLS was knocked down to further examine the expression of each gene. ELISA measured the levels of IL-1ß, IL-6, and IL-8. The results showed that compared with the normal group, rats in the model group found redness and swelling in their limbs and significantly increased joint swelling. Compared with the model group, the joint swelling degree of each treatment group significantly decreased(P<0. 05). The paw retraction threshold and body weight mass index both significantly increased(P<0. 05). METTL3 was highly expressed on AA and negatively correlated with the expression of SFRP4. After treatment, the m RNA and protein expression of METTL3, ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 were significantly decreased on AA-FLS(P< 0. 05). Compared with the model group, knocking down METTL3 resulted in reduced m RNA and protein expression of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3(P< 0. 05). At the same time, the m RNA and protein expressions of ß-catenin, CCND1, c-Myc, fibronectin, and MMP3 in the HQC+METTL3 knockdown group were significantly lower than those in the METTL3 knockdown group(P<0. 05). HQC could reduce the levels of IL-1ß, IL-6, and IL-8 to varying degrees(P<0. 05). The results indicate that HQC has a significant improvement effect on arthritis in AA rats. The expression of METTL3 is significantly increased in synovial tissue and AA-FLS of AA rats, which may be a potential target for the diagnosis and treatment of RA. HQC improves RA through the METTL3-SFRP4/Wnt/ß-catenin signaling pathway and has significant antiinflammatory and anti-rheumatic effects.

[Cuiru Keli Improves Postpartum Hypogalactia in Rats Through Secreted Frizzled-Related Protein 2-Wnt/ß-catenin Signaling Pathway]. / 催乳颗粒通过分泌Frizzledç›¸å ³è›‹ç™½2-Wnt/ß-cateninä¿¡å·é€šè·¯æ”¹å–„å¤§é¼ äº§åŽç¼ºä¹³.

Objective: Based on the secreted frizzled-related protein 2 (SFRP2)-Wnt/ß-catenin signaling pathway, this study explored the effect and mechanism of Cuiru Keli (CRKL) in the treatment of postpartum hypogalactia. Methods: A rat model of postpartum hypogalactia was established by gavaging 2 mL of 1.6 mg/mL bromocriptine mesylate to female rats on the third day after delivery. Female rats with a delivery time difference of less than 48 hours were selected and randomly assigned to 7 groups, including a normal group (without any modeling or medication), a model group, a CRKL low-dose group of model group model rats receiving CRKL at the dose of 3 g/kg, a CRKL medium-dose group of model rats receiving CRKL at the dose of 6 g/kg, a CRKL high-dose group of model rats receiving CRKL at the dose of 9 g/kg, a positive drug group of model rats receiving domperidone at the dose of 3 mg/kg, and a negative control (NC) group of model rats receiving normal saline. Each group contained 6 rats. Except for the normal and model groups, the remaining 5 groups were continuously administered with the respective intervention drugs at the specified doses by gavage once a day for 10 days. Changes in the total litter mass of the offspring in the 7 groups within 10 days were measured, and HE staining was performed to identify pathological changes in the mammary tissue (MT). Six groups of rats (excluding the positive control group) were used to observe the pathological changes of eosinophils in pituitary tissue. ELISA was performed to determine the content of prolactin (PRL) in serum, immunohistochemical staining was used to determine the expression of prolactin receptor (PRLR) in MT, and RT-qPCR was used to determine the mRNA expression of genes related to lactation in MT. Network pharmacology and molecular docking were used to study the therapeutic effect and mechanism of CRKL on postpartum hypogalactia, particularly whether it acted through the SFRP2-Wnt/ß-catenin signaling pathway. The mechanism of CRKL treatment was further validated by detecting mRNA (RT-qPCR) and protein expression (Western blot) of related pathway genes. Cell experiments were conducted using primary culture rat mammary epithelial cells (RMEC) from rat MT. RMEC were divided into four groups, including a normal group (primary culture RMEC, untreated), SFRP2 overexpression group (primary cultured RMEC treated with SFRP2 overexpression vector), SFRP2 overexpression+CRKL group (receiving treatment for SFRP2 overexpression group plus 10% drug-containing serum), and negative control group (primary culture RMEC treated with empty vector). The effect of CRKL on the expression of lactation-related genes FASN, CSN2, and GLUT1 mRNA after SFRP2 overexpression was detected by RT-qPCR. Results: In this study, CRKL was administered at a dose of 3 g/kg in the CRKL low-dose group, 6 g/kg in the medium-dose group, and 9 g/kg in the high-dose group (P<0.05 or P<0.01). Compared with the model group, CRKL at all doses significantly increased the total litter weight gain of the offsprings within 10 days (P<0.05 or P<0.01), and effectively increased lactation (P<0.01), the area of mammary lobules, and the size and filling of acinar cavities. CRKL at all doses also increased the number of eosinophils that secreted PRL in the pituitary gland of the postpartum hypogalactia rat model, and increased the content of PRL in the serum (P<0.05 or P<0.01). CRKL promoted the secretion and expression of PRL in postpartum hypogalactic model rats. In addition, it significantly promoted the expression of genes related to milk fat, milk protein, and lactose synthesis in MT (P<0.05 or P<0.01). Network pharmacology predicted that the Wnt signaling pathway might be a key pathway for CRKL in treating postpartum hypogalactia. The molecular docking results showed that related chemical components in CRKL had good binding ability with CCND1 and SFRP2. Compared with the model group, CRKL at all doses inhibited the expression of SFRP2 gene in vivo (P<0.01) and activated the mRNA and protein expression of CCND1 and c-Myc in the Wnt/ß-catenin signaling pathway in MT (P<0.05 or P<0.01). Cell experiments showed that, compared to the normal group, SFRP2 overexpression reduced the mRNA expression of milk synthesis-related genes FASN, CSN2, and GLUT1 in RMEC (P<0.01). The CCK8 results indicated that 10% of the drug-containing serum was the effective concentration administered to cells (P<0.01). After administering drug-containing serum, the expression of the lactation-related genes FASN, CSN2, and GLUT1 were up-regulated (compared with the SFRP2 overexpression group, P<0.01). Conclusion: CRKL alleviates postpartum hypogalactia through the SFRP2-Wnt/ß-catenin signaling pathway. SFRP2 might be a potential new target for the diagnosis and treatment of postpartum hypogalactia. This reveals a new mechanism of CRKL in treating postpartum hypogalactia and promotes its clinical application.

Huangqin Qingre Chubi Capsule improves rheumatoid arthritis accompanied depression through the Wnt1/ß-catenin signaling pathway.

AIM OF THE STUDY: Research on the mechanism of Huangqin Qingre Chubi Capsules (HQC) in improving rheumatoid arthritis accompanied depression (RA-dep) model rats. METHODS: We employed real-time qPCR (RT-qPCR), western blotting (WB), confocal microscopy, bioinformatics, and other methods to investigate the anti-RA-dep effects of HQC and its underlying mechanisms. RESULTS: HQC alleviated the pathological indexes of inflammation and depression in RA-dep model rats, decreased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6, increased the levels of norepinephrine(NE) and serotonin(5-HT), and improved the injury of hippocampus. The analysis of network pharmacology suggests that HQC may target the Wnt/ß-catenin pathway in the treatment of RA-dep. Furthermore, molecular dynamics simulations revealed a strong affinity between HQC and the Wnt1 molecule. RT-qPCR and Western Blot (WB) experiments confirmed the critical role of the Wnt1/ß-catenin signaling pathway in the treatment of RA-dep model rats with HQC. In vitro, the HQC drug-containing serum (HQC-serum) activates the Wnt1/ß-catenin signaling pathway in hippocampal cells and, in conjunction with Wnt1, ameliorates RA-dep. In summary, HQC exerts its anti-inflammatory and antidepressant effects in the treatment of RA-dep by binding to Wnt1 and regulating the Wnt1/ß-catenin signaling pathway. CONCLUSIONS: HQC improved the inflammatory reaction and depression-like behavior of RA-dep model rats by activating Wnt1/ß-catenin signal pathway. This study revealed a new pathogenesis of RA-dep and contributes to the clinical promotion of HQC in the treatment of RA-dep.

Associations between rheumatoid arthritis and intestinal flora, with special emphasis on RA pathologic mechanisms to treatment strategies.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that primarily affects the joints. Individuals at risk for RA and people with RA develop intestinal dysbiosis. The changes in intestinal flora composition in preclinical and confirmed RA patients suggest that intestinal flora imbalance may play an important role in the induction and persistence of RA. METHODS: Based on the current research on the interaction between RA and intestinal microbiota, intestinal microbiota metabolites and intestinal barrier changes. This paper systematically summarized the changes in intestinal microbiota in RA patients, the metabolites of intestinal flora, and the influence mechanism of intestinal barrier on RA, and further discussed the influence of drugs for RA on intestinal flora and its mechanism of action. RESULTS: Compared with healthy controls, α diversity analysis of intestinal flora showed no significant difference, ß diversity analysis showed significant differences. The intestinal flora produces bioactive metabolites, such as short-chain fatty acids and aromatic amino acids, which have anti-inflammatory effects. Abnormal intestinal flora leads to impaired barrier function and mucosal immune dysfunction, promoting the development of inflammation. Traditional Chinese medicine (TCM) and chemical drugs can also alleviate RA by regulating intestinal flora, intestinal flora metabolites, and intestinal barrier. Intestinal flora is closely related to the pathogenesis of RA and may become potential biomarkers for the diagnosis and treatment of RA. CONCLUSIONS: Intestinal flora and its metabolites play an important role in the pathogenesis of autoimmune diseases such as RA, and are expected to become a new target for clinical diagnosis and treatment, providing a new idea for targeted treatment of RA.

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.

Fat mass and obesity-associated protein inhibit the pathology of rheumatoid arthritis through the NSUN2/SFRP1/Wnt/ß-catenin signal axis.

OBJECTIVES: The purpose of this study is to investigate whether fat mass and obesity-associated protein (FTO) and NOL1/NOP2/Sun domain family member 2 (NSUN2) mediated RNA methylation is associated with RA pathology. METHODS: We studied the anti-rheumatoid arthritis (RA) mechanism mediated by FTO and NSUN2 in RA samples and collagen-induced arthritis (CIA) rats using real time qPCR (RT-qPCR), western blot, immunofluorescence, and other methods. KEY FINDINGS: The expression of NSUN2 was significantly increased in both RA patients and CIA rats compared with normal controls. Knockdown of NSUN2 blocked the Wnt/ß-catenin signaling pathway and inhibited RA pathological factors such as MMP3, fibronectin, and interleukins. FTO overexpression inhibited RA by inhibiting the expression of NSUN2, up-regulating the level of SFRP1 protein, and blocking the Wnt/ß-catenin signaling pathway. NSUN2 overexpression interfered with the inhibitory effects of FTO on the Wnt/ß-catenin signaling pathway and RA pathology, which further verified that FTO inhibited RA through the NSUN2/SFRP1/Wnt/ß-catenin signal axis. CONCLUSIONS: FTO and NSUN2 are important factors of RA, and this work provides new potential diagnostic biomarkers and therapeutic targets for RA. We also reveal a gene expression regulation pattern of the interaction between m6A and m5C. revealing the pathogenesis of RA from the perspective of RNA methylation.

Maackiain suppresses the development of cervical cancer via AMPK priming autophagy.

BACKGROUND: Maackiain (Mac), a flavonoid analog isolated from Sophora flavescens, exhibits neuroprotective, anti-allergic, anti-inflammatory, and pro-apoptotic effects. It is not clear whether Mac has a therapeutic effect on cervical cancer. METHOD: In this work, we used RT-qPCR, western blot, immunofluorescence, and related methods to detect the therapeutic mechanism of Mac for cervical cancer. RESULTS: We demonstrated that Mac significantly inhibited the proliferation, migration, and invasion of human cervical cancer cell lines HeLa and SiHa. And, Mac enhanced the pro-apoptotic effects of cisplatin in treating cervical cancer cells. Mac has shown good efficacy in treating cervical cancer. Furthermore, Mac inhibited the mammalian target of the rapamycin (mTOR) pathway, thereby inducing autophagy in cervical cancer cells. The regulation of mTOR/autophagy pathway by Mac relied on the activation of AMP-activated protein kinase (AMPK), and the inhibition of the AMPK reversed the Mac's anti-cervical cancer activity. In addition, experimental study of Mac in mouse xenograft tumor model further confirmed its good anti-cervical cancer activity. CONCLUSION: Mac inhibits human cervical cancer by activating the AMPK/mTOR/autophagy pathway, indicating that it is a potential natural compound for the treatment of cervical cancer. This study also provides a feasible molecular mechanism for the treatment of cervical cancer.

Wilforine inhibits rheumatoid arthritis pathology through the Wnt11/ß-catenin signaling pathway axis.

BACKGROUND: Wilforine (WFR) is a monomeric compound of the anti-RA plant Tripterygium wilfordii Hook. f. (TwHF). Whether WFR has anti-RA effect, its molecular mechanism has not been elucidated. AIM OF THE STUDY: Our study aims to clarify how WFR inhibits fibroblast-like synovial cells (FLS) activation and improves RA through Wnt11 action on the Wnt11/ß-catenin signaling pathway. METHODS: The therapeutic effect of WFR on collagen-induced arthritis (CIA) rats was evaluated using methods such as rat arthritis score. The inhibitory effects and signaling pathways of WFR on the proliferation and inflammatory response of CIA FLS and RA FLS were studied using ELISA, CCK-8, RT-qPCR, Western blot, and immunofluorescence methods. RESULTS: WFR could effectively alleviate the arthritis symptoms of CIA rats; reduce the levels of IL-6, IL-1ß, and TNF-α in the peripheral blood of CIA rats; and inhibit the expression of MMP3 and fibronectin. The data showed that WFR has a significant inhibitory effect on FLS proliferation. Furthermore, WFR inhibited the activation of Wnt/ß-catenin signaling pathway and decreased the expression of Wnt11, ß-catenin, CCND1, GSK-3ß, and c-Myc, while the effects of WFR were reversed after overexpression of Wnt11. CONCLUSIONS: WFR improves RA by inhibiting the Wnt11/ß-catenin signaling pathway, and Wnt11 is the direct target of WFR. This study provides a new molecular mechanism for WFR to improve RA and contributes to the clinical promotion of WFR.

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.

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.

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.

RNA methylations in depression, from pathological mechanism to therapeutic potential.

Depression is caused by a variety of factors such as genetic factors, biological factors, and psychosocial factors, and the pathogenesis is complex. RNA methylations and related downstream signaling pathways influence a variety of biological mechanisms, including cell differentiation, tumorigenesis, sex determination, and stress response. In this work, we searched the PubMed, Web of Science, National Library of Science and Technology (NSTL), and ScienceDirect Online (SDOL) databases to summarize the biological roles of RNA methylations and their impact on the pathological mechanisms of depression. RNA methylations play a key role in the development of many diseases, and current research shows that RNA methylations are also closely linked to depression. RNA methylations in depression mainly involve "writers" (mediating the methylation modification process of RNAs), "erasers" (mediating the demethylation modification process of RNA methylation). Fat Mass and Obesity Associated (FTO) influences the development of depression by increasing body mass index (BMI), decreases the dopamine level, inhibits the adrenoceptor beta 2 (ADRB2)-c-Myc-sirt1 pathway, results in the m6A/m6Am dysregulation in brain, and may be involved in the pathogenesis of depression. The study of RNA methylations in depression has further deepened our understanding of the pathogenesis and development process of depression, provides new perspectives for the study of the pathological mechanism of depression, and provides new targets for the prevention and treatment of this disease.

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.

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.

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.

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.