Cardiovascular diseases (CVDs) remain the leading cause of global mortality, highlighting the urgent need for innovative therapeutic strategies. Methyltransferase-like proteins (METTLs), which harbor conserved S-adenosylmethionine (SAM)-binding and catalytic domains, dynamically regulate the functions of RNA, DNA, and proteins through diverse methylation modifications (e.g., N6-methyladenosine [m6A], N7-methylguanosine [m7G], 3-methylcytidine/4-methylcytidine [m3C/m4C], N6-methyladenine [6mA]). These modifications play pivotal roles in fundamental cellular processes such as proliferation, apoptosis, inflammation, and metabolism, and their dysregulation is directly implicated in CVD pathogenesis. This review compiles compelling evidence that connects aberrant METTL expression and activity to major CVDs such as myocardial infarction, maladaptive cardiac remodeling, atherosclerosis, and arrhythmias. We detail how METTLs influence myocardial injury/repair, fibrosis, vascular dysfunction, and electrophysiological homeostasis by altering RNA stability, translation efficiency, and signaling cascades. Additionally, we critically assess the emerging translational potential of METTL members as diagnostic/prognostic biomarkers and inhibitor development strategies. By clarifying the complex mechanisms of METTL-mediated epitranscriptomic and epigenetic regulation, this work lays the groundwork for advancing precision medicine approaches in CVD prevention and treatment.

Background Xinfeng Capsule (XFC), a traditional Chinese herbal formulation, has long been used clinically for rheumatoid arthritis (RA); however, its underlying mechanism remains unclear. Objective This study explored ​whether XFC alleviates RA-induced joint damage by suppressing cuproptosis via modulation of the METTL3/miR-221/222-3p/ATP7A axis. Methods Potential therapeutic targets of XFC against RA were predicted using bioinformatic analyses. Adjuvant-induced arthritis (AA) rat models and in vitro chondrocyte injury models were established and allocated to different treatment groups. Dual-luciferase reporter assay confirmed the interaction between miR-221/222-3p and ATP7A. Optimal XFC treatment conditions (10% for 24 h) were determined with a CCK-8 assay. The expression levels of METTL3, miR-221/222-3p, ATP7A, ATP7B, and key cuproptosis-related markers were assessed by RT-qPCR and western blotting. Functional assays were performed to evaluate cell morphology, reactive oxygen species (ROS), inflammatory cytokines, and intracellular copper accumulation. Results Bioinformatic analysis identified METTL3 as a pivotal target. In both animal and cell models, XFC markedly downregulated METTL3 and miR-221/222-3p while upregulating ATP7A and ATP7B. The direct targeting of ATP7A by miR-221/222-3p has been previously validated. Molecular docking revealed favorable binding between active XFC components and METTL3. Functionally, XFC suppressed the METTL3/miR-221/222-3p/ATP7A pathway, leading to reduced levels of cuproptosis drivers (FDX1, LIAS, and DLAT), diminished ROS generation, reduced inflammatory cytokine release, and reduced intracellular copper accumulation, thereby mitigating mitochondrial damage and chondrocyte injury. Conclusion This study demonstrated for the first time that XFC protects against RA-related joint injury by inhibiting chondrocyte cuproptosis and inflammation via the METTL3/miR-221/222-3p/ATP7A axis, offering novel mechanistic insights into the therapeutic action of XFC and suggesting a promising strategy for RA management.

ETHNOPHARMACOLOGICAL RELEVANCE:Curcumae Rhizoma, a traditional Chinese medicine derived from the dried rhizome of Curcuma species, has long been used to treat liver-related disorders. In the classical medical text Taiping Shenghui Fang, it was recorded for the treatment of hepatocellular carcinoma (HCC) characterized by Qi stagnation and blood stasis. Its major chemical constituents include curcumin and Zedoary Turmeric Oil (ZTO). While curcumin has been extensively studied for its pharmacological activities, the therapeutic potential and mechanism of ZTO in HCC remain insufficiently understood. AIM:ZTO is a volatile oil fraction extracted from Curcumae Rhizoma, and preliminary studies have suggested its potential anti-hepatocellular carcinoma effects. However, the underlying mechanisms remain unclear. This study aimed to elucidate the molecular mechanisms of ZTO against HCC through an integrated approach combining network pharmacology and experimental validation. METHODS:An H22 xenograft tumor model was established to evaluate the in vivo anti-tumor efficacy of ZTO. The antiproliferative effects of ZTO on HCC cells were assessed in vitro using MTT and colony formation assays. The synergistic effects of ZTO and sorafenib were evaluated using MTT and tumor sphere-forming assay. The chemical constituents of ZTO were identified by gas chromatography-mass spectrometry (GC-MS). Potential targets of ZTO and HCC were retrieved from public databases, and protein-protein interaction (PPI) networks were constructed using the STRING database. Key hub targets were identified using CytoNCA, CytoHubba, and MCODE, followed by molecular dynamics simulations and molecular docking. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID database. Following network pharmacology predictions of ZTO's potential mechanism against HCC, we systematically validated these computational findings through experiments in vitro and in vivo. Finally, the pharmacokinetic study of the four active components (curcumol, β-elemene, germacrone, and curdione) in ZTO was conducted using GC-MS. RESULTS:ZTO significantly inhibited tumor growth in xenograft model. In vitro, ZTO suppressed the proliferation of HCC cells, and it exhibited a synergistic effect when combined with sorafenib. A total of 174 overlapping targets between ZTO and HCC were identified. Among them, EGFR, p53 and Bcl-2 were recognized as key targets. The major compounds and target proteins had a good binding ability in molecular docking and molecular dynamics. GO and KEGG enrichment analyses suggested that ZTO may regulate apoptosis, cell cycle progression, and migration through the EGFR/p53/Bcl-2 signaling axis. Additionally, pathways associated with stem cell pluripotency were significantly enriched. Subsequent experimental validation confirmed that ZTO promoted apoptosis, induced G1-phase arrest, and inhibited cell migration via the EGFR/p53/Bcl-2 axis. Furthermore, ZTO reduced the size of HCC tumor spheres in a dose-dependent manner and downregulated the expression of stemness-related markers, including CD44, CD133, Oct-4, SOX2, and Nanog, both in vitro and in vivo, potentially through modulation of the Wnt/β-catenin signaling pathway. Pharmacokinetic analysis indicated that curcumol and curdione exhibited higher bioavailability compared to β-elemene and germacrone. CONCLUSION:Through an integrated approach combining network pharmacology and experimental validation, this study demonstrates that ZTO exerts anti-HCC effects by inhibiting cell proliferation and migration, inducing apoptosis, and causing G1-phase cell cycle arrest, primarily through modulation of the EGFR/p53/Bcl-2 signaling axis. In addition, ZTO significantly suppresses cancer stemness in HCC by downregulating key stemness-related markers. Finally, the pharmacokinetic study showed curcumol and curdione have higher bioavailability and faster absorption than β-elemene and germacrone. These findings provide novel mechanistic insights into the anti-HCC activity of ZTO and offer a theoretical foundation for its future clinical application.

BackgroundDespite being widely applied in clinical practice, the wake-promoting effect of acupuncture in poststroke coma patients remains controversial.ObjectiveThis study aimed to evaluate the efficacy of acupuncture for the treatment of poststroke coma.MethodsRandomized controlled trials (RCTs) of acupuncture for treating poststroke coma were identified in PubMed, Cochrane Library, EMBASE, CNKI, WanFang and VIP up to 25 November 2023. The main outcomes were Glasgow Coma Scale (GCS) score, National Institute of Health Stroke Scale (NIHSS) score, awakening ratio and clinically effective ratio. Stata 17 and Review Manager 5.4 software were used for mate analysis.ResultsA total of 34 RCTs involving 2,757 patients were included. GCS (WMD = 1.78; 95% CI: 1.35 to 2.21) and NIHSS score (WMD = -2.84; 95% CI: -3.84 to -1.84) were significantly increased in acupuncture group compared with control group. Acupuncture combined with routine treatment may be better than routine treatment in improving the awakening ratio (RR= 1.65; 95% CI: 1.24 to 2.91) and the clinically effective ratio (RR= 1.20; 95% CI: 1.13 to 1.27). Some methodological flaws were identified in the included studies, including non-implementation of blinding, inappropriate disease assessment and heterogeneous interventions.ConclusionsThe existing evidence suggests that acupuncture combined with conventional treatment may be an effective treatment for poststroke coma patients. In the meantime, more high-quality RCTs are needed to demonstrate these findings due to methodological weaknesses like randomization, blinding, heterogeneous interventions and long-term follow-up.

Background Mitochondrial oxidative stress has been shown to play a critical role in cancer development and progression. But there was relatively less research on the relationship between mitochondrial oxidative stress and LIHC. Methods Mitochondrial oxidative stress-related genes were collected from Genecards portals. Prognosis-linked genes (PLGs) were identified by univariate Cox regression analysis. A risk model was constructed based on PLGs using the least absolute shrinkage and selection operator (LASSO) analysis. The receiver operational feature (ROC) curve was used to detect the model’s prediction ability. The gene expression level of prognostic genes were verified in cell lines. Results We constructed a novel risk model on the basis of 9 prognostic genes (CYP2C19, CASQ2, LPL, TXNRD1, CACNA1S, SLC6A3, OXTR, BIRC5, and MMP1). The Kaplan-Meier survival analysis showed that patients with a low-risk score had a much better overall survival (OS) rate than those with a high-risk score. The prognostic risk score was determined to be an independent predictor of prognosis. Patients in the high-risk group had a less favorable tumor microenvironment, characterized by a lower degree of immune cell infiltration. In contrast, the low-risk group demonstrated a higher degree of immune cell infiltration, which could potentially contribute to a more effective anti-tumor immune response. Conclusion Our investigation uncovered the oncogenic role of mitochondrial oxidative stress in LIHC. For the first time, we established a risk prediction model for mitochondrial oxidative stress in LIHC.

Context di-(2-Ethylhexyl) phthalate (DEHP) has potential reproductive toxicity. Bu-Shen-Tian-Jing formulations (BSTJFs) are beneficial for female reproductive capacity. However, BSTJF2 has much lower cytotoxicity than BSTJF1.Objective To investigate the effects of BSTJFs on ovarian granulosa cells exposed to DEHP and determine the potential molecular mechanisms.Methods and materials Human granulosa-like tumor cell line (KGN) cells were divided into control, DEHP, BSTJF1 and BSTJF2 groups. The DEHP group were given 1 & mu;M DEHP for 24 h. They were then given BSTJF1 at 200 & mu;g/mL or BSTJF2 at 100 & mu;g/mL for 24 h. The control group was treated with the same concentration of DMSO (0.1%). Oxidative stress and mitochondrial function were measured. The mRNA and protein expression levels of HDAC3 and HSP90AA were determined. Integrative network pharmacology analysis of BSTJF2 was also performed.Results DEHP (1 & mu;M) significantly suppressed the proliferation of KGN cells by 17%, significantly increased ROS levels by 28% and MDA levels by 47%, significantly decreased MMP levels by 22% and mtDNA copy by 30%. DEHP significantly increased protein expression of HDAC3 by 21%and HSP90AA by 64%. All these changes were significantly reversed by BSTJFs. Integrative network pharmacology analysis revealed HSP90AA was a key target (degree = 8). Both RGFP966 and BSTJF2 significantly reversed the increased expression of HDAC3 and HSP90AA, attenuated oxidative stress, and mitochondrial damage which were induced by DEHP.Conclusion BSTJFs might have therapeutic potential on oxidative stress and mitochondrial damage through the HDAC3/HSP90AA pathway which encourages further clinical trials.

The interactions between T cells and B cells are essential for antibody responses and the development of autoimmune diseases. Recently, a distinct subset of T cells capable of helping B cells was established in synovial fluid, and they were termed peripheral helper T (Tph) cells. PD-1(hi)CXCR5(-)CD4(+) Tph cells express high levels of CXCL13, which drives the formation of lymphoid aggregates and tertiary lymphoid structures, ultimately facilitating the local production of pathogenic autoantibodies. Tph and T follicular helper cells share some key features but can be distinguished by their surface markers, transcriptional regulation, and migration capability. We summarize recent findings on Tph cells in this review and provide a perspective on their potential roles in a range of autoimmune diseases. More clinical and in-depth mechanistic investigations of Tph cells may help to improve the understanding of pathogenesis and further provide novel therapeutic targets in autoimmune diseases.

ETHNOPHAMACOLOGICAL RELEVANCE:Simiao Pill (SM) as a classic prescription of traditional Chinese medicine treatment of damp-heat arthralgia, the earliest from 'Cheng Fan Bian Du ', written by the Qing Dynasty doctor Zhang Bingcheng. Previous studies have shown that SM has obvious curative effect on rheumatoid arthritis, which provides a basis for the application of SM in rheumatoid arthritis related complications. AIM OF THE STUDY:Interstitial lung disease (ILD), as the most severe complication of rheumatoid arthritis (RA), lacks effective clinical treatments and a corresponding animal model. Simiao pill (SM) is a traditional Chinese medicine prescription extensively used as a complementary and alternative treatment for RA. However, the effect and mechanism of SM on RA-ILD have not yet been reported. This study aimed to investigate an appropriate animal model that can simulate RA-ILD, and the efficacy, safety, and mechanism of SM on RA-ILD. METHODS:Collagen-induced arthritis (CIA) and bleomycin-induced pulmonary fibrosis model were combined to construct the CIA-BLM model. After the intervention of SM, the protective effects of SM on RA-ILD were determined by detecting the CIA mouse arthritis index (AI), Spleen index, and the extent of pulmonary fibrosis. The joint inflammation and pulmonary fibrosis were detected by immunohistochemistry, H&E staining, safranin- O fast green Sirius red staining, trap staining, and Masson staining. Finally, the mechanism was verified by Western blot and immunohistochemistry. RESULTS:Our work showed that SM significantly reduced joint swelling, arthritis index, pulmonary fibrosis score, and spleen index in CIA mice. The pathological examination results indicated Si-Miao Pill suppressed inflammation, pulmonary fibrosis, bone erosion, and cartilage degradation of the ankle joint. Besides, SM up-regulated expressions of E-cadherin, whereas down-regulated expressions of α-SMA. Further studies confirmed that SM regulated JAK2/STAT3 and TGF-β/SMAD2/3. CONCLUSION:SM can not only effectively improve joint inflammation by JAK2/STAT3 Pathway but also inhibit pulmonary fibrosis by TGF-β/SMAD2/3. The fibrosis induced by CIA-BLM model was more stable and obvious than that induced by CIA model alone.

Objective: To assess the efficacy, comparative effectiveness and safety of electroacupuncture (EA) in the treatment of perimenopausal syndrome (PMS). Methods: Nine databases were searched until June 2019. Only relevant randomized controlled trials (RCTs) of EA for PMS were included. Results: Twelve trials involving 746 women were included. EA and hormone therapy (HT) did not significantly differ in terms of effective rate (risk ratio (RR) = 0.98, 95% confidence interval (CI) = 0.93 to 1.04), Kupperman index (KI) (mean difference (MD) = -0.25, 95% CI = -0.76 to 0.26) and serum levels of follicle-stimulating hormone (FSH) (MD = -3.80, 95% CI = -11.59 to 3.98) or luteinizing hormone (LH) (MD = -2.51, 95% CI = -10.72 to 5.70). Serum estradiol (E-2) levels were significantly lower in EA versus HT groups (MD = -60.58, 95% CI = -71.93 to -49.23). Compared with sham EA, EA had a significantly greater effect on reductions in KI (MD = -4.71, 95% CI = -6.57 to -2.86) and hot flushes score/24 h (MD = -2.43, 95% CI = -2.93 to -1.93). There were no significant differences between EA and manual acupuncture (MA) in terms of effective rate (RR = 1.14, 95% CI = 0.98 to 1.33) or serum FSH (MD = -2.87, 95% CI = -29.65 to 23.91), LH (MD = 2.73, 95% CI = -9.65 to 15.11) or E-2 (MD = 26.80, 95% CI = -12.06 to 65.65). However, it seemed that EA had a better effect than MA on KI (MD = -2.44, 95% CI = -4.80 to -0.08). Subgroup analyses indicated that EA may have more of a benefit in the pre-menopausal state (hot flushes score/24 h: MD = -1.66, 95% CI = -3.49 to 0.17) compared to post-menopause (p > 0.05). Conclusion: The effect of EA appeared broadly similar to HT and MA in the treatment of PMS, although EA-associated reductions in KI were superior to MA and sham EA, suggesting effects beyond placebo. The evidence base is limited by a small number of eligible studies, risk of bias and clinical/statistical heterogeneity, limiting our ability to draw firm conclusions. As such, additional larger scale, high-quality RCTs are needed.

Objective Endometriosis is a common benign disease in women of reproductive age. Qu’s formula (QUF) is a patented Chinese herbal medicine for treating endometriosis that has been proven to be effective in treating and preventing the recurrence of endometriosis. This study is aimed to discover its molecular mechanism and to explore the potential drug targets. Methods A QUF target and endometriosis-related gene set was identified by the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM) databases and five disease-gene databases. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed, and a protein–protein interaction (PPI) network was established to discover the potential mechanism. MalaCards was searched for targets and signaling pathways related to endometriosis, and the search results were also used to identify the key factors in QUF. Molecular docking was performed to visualize the interactions between the effective molecules and proteins encoded by critical genes. Cell experiments and molecular dynamics (MD) simulations were used to further validate the therapeutic effects of the active compounds in QUF on endometriosis. Results A compound-target network with 117 nodes (94 genes and 23 active compounds) and 224 edges was generated. The results of GO and KEGG analyses indicated that QUF could act by regulating the immune response, apoptosis and proliferation, oxidative stress, and angiogenesis. VEGFA, CXCL8, CCL2, IL1B and PTGS2 were selected for molecular docking analysis from two critical subnetworks with high correlation scores in MalaCards, and the active compounds of QUF had binding potential and high affinity for them. The mRNA expression levels of CCL2, IL1B and PTGS2 significantly decreased after treatment with quercetin. MD simulations showed that the combinations of quercetin and these proteins were relatively stable. Conclusion The network pharmacological strategy integrates molecular docking to unravel the molecular mechanism by which QUF protects against endometriosis. Our findings not only confirm the clinical effectiveness of QUF but also provide a foundation for further experimental study.

OBJECTIVE:To assess the significance of focal segmental glomerulosclerosis (FSGS) variants on clinicopathological characteristics and short-term outcomes in idiopathic membranous nephropathy (IMN) patients.METHODS:The clinicopathological data of 146 IMN patients diagnosed between December 2016 and March 2019 in our center were collected and analyzed. These patients were divided into the pure IMN group, IMN with glomerular tip lesion (GTL) group, and IMN with non-GTL FSGS group.RESULTS:The IMN with non-GTL FSGS and IMN with GTL groups both had higher proportions of patients with hypertension, lower serum albumin, and severe proteinuria, while the IMN with non-GTL FSGS group additionally showed higher blood pressure and serum cholesterol, and lower serum IgG than the IMN group (all P<0.05). As for pathology, the IMN with non-GTL FSGS group had higher proportions of patients with acute tubular injury and moderate to severe chronic injuries than the IMN group (all P<0.05). In the IMN, IMN with GTL, and IMN with non-GTL FSGS groups, the overall one-year remission rates were 81.6%, 76%, and 58.8%, respectively. Furthermore, the IMN with non-GTL FSGS group showed the lowest cumulative incidence to reach remission within one year. Multivariate Cox logistic analysis demonstrated that higher level of serum anti-M-type phospholipase A2 receptor antibody and the existence of non-GTL FSGS lesion were independent predictors for no remission in IMN patients.CONCLUSION:The non-GTL FSGS lesion was a novel negative predictor in IMN and should be taken into account in the management of IMN.

Objective. Si Miao San (SMS) is a traditional Chinese formula used in China to treat rheumatic diseases. To date, its mechanism in rheumatoid arthritis (RA) treatment is uncertain. Our study aims to assess the antiarthritic effects of SMS in experimental arthritic rats. Materials and Methods. SMS (8.63, 4.31, and 2.16 g/kg/day) was orally administered after the first immunization from day 14 to day 53. The effects of SMS on rats with collagen-induced arthritis (CIA) were evaluated by arthritis score and histological assessment. The levels of cytokines and anti-CII antibodies in rat serum were measured by ELISAs. The expression of oxidative stress parameters was detected by biochemical assay kits. The levels of Nrf2, HO-1, NQO1, and PTEN were determined by western blotting. Results. Medium- and high-dose SMS treatment significantly decreased arthritis scores and alleviated ankle joint histopathology in the rats with CIA. It inhibited the production of IL-6, TNF-α, COX-2, and PGE2 in rat serum. SMS also suppressed the expression of anti-CII antibodies IgG1 and IgG2a. Moreover, SMS significantly suppressed the levels of MDA and MPO in the synovial tissues while increasing the levels of SOD and CAT in the rats with CIA. The levels of Nrf2, HO-1, NQO1, and PTEN were upregulated by SMS in rat synovial tissues. Conclusions. This study demonstrated that SMS effectively alleviated the disease progression of CIA by decreasing the levels of proinflammatory cytokines and reducing oxidative stress damage, as indicated by IL-6, TNF-α, COX-2, and PGE2 levels; inhibiting the overproduction of MDA and MPO; and enhancing antioxidant enzymes by upregulating the Nrf2/ARE/PTEN signalling pathway.

Many studies have shown that aflatoxin B1 (AFB1) can cause cytotoxicity in numerous cells and organs induced by oxidative stress. However, the toxic effects and related mechanism of AFB1 on the microglia cells in the spinal cords have not been studied yet. Our results showed that AFB1 significantly reduced the number of microglia cells, increased the oxidants (malonaldehyde and hydrogen peroxide) but decreased the anti-oxidants (superoxide dismutase and total antioxidant capacity) in a dose dependent manner in mice spinal cords. In addition, AFB1 significantly increased the oxidative stress, promoted apoptosis and cell cycle arrest in G2-M phase, and activated NF-κB phosphorylation in BV2 microglia cells. However, the addition of active oxygen scavenger N-acetylcysteine can significantly reduce the ROS production, improve cell cycle arrest, reduce apoptosis, and the expression of phosphorylated NF-κB in BV2 microglia cells. These results indicate that AFB1 induces microglia cells apoptosis through oxidative stress by activating NF-κB signaling pathway.

Objectives Increasing data about COVID-19 have been acquired from the general population. We aim to further evaluate the clinical characteristics of COVID-19 in patients with systemic autoimmune diseases (AIDs). Methods We included all confirmed inpatients with COVID-19 and systemic AIDs in Wuhan Tongji Hospital from 29 January to 8 March 2020. We retrospectively collected and analysed information on epidemiology of 1255 inpatients and additional clinical characteristics of patients with systemic AIDs. Outcomes were followed up until 16 April 2020. Results Of the 1255 patients with COVID-19, the median age was 64.0 years and 53.1% were male. More than half (63.0%) had chronic comorbidities. The proportions of elderly, male and patients with comorbidities were significantly higher in intensive care unit (ICU) than in the general ward (p<0.001). 17 (0.61%) patients with systemic AIDs were further screened and analysed from 2804 inpatients. The median age was 64.0 years and 82.4% were female. All patients were living in Wuhan and two family clusters were found. 1 (5.9%) patient was admitted to ICU and one died. 10 (62.5%) of 16 patients changed or stopped their anti-AIDs treatments during hospitalisation, and 5 of them felt that the disease had worsened after the quarantine. Conclusions Older males with chronic comorbidities are more vulnerable to severe COVID-19. The lower proportion of COVID-19 in patients with systemic AIDs needs more high-quality human clinical trials and in-depth mechanism researches. Of note, the withdrawal of anti-AIDs treatments during hospitalisation can lead to flares of diseases.

Background: As dysregulation of immunometabolism plays a key role in the immunological diseases, dyslipidemia frequently observed in rheumatoid arthritis (RA) patients (60%) is associated with the disease activity and has been considered as the potential target of anti-inflammatory strategy. However, targeting of metabolic events to develop novel anti-inflammatory therapeutics are far from clear as well as the mechanism of dyslipidemia in RA. Purpose: To explore the therapeutic potential and mechanisms of silybin again RA through the regulation of lipid metabolism. Methods: Adjuvant-induced arthritis (AIA) rat model was used to examine the effects of silybin on modulating dysregulated lipid metabolism and arthritis. Metabolomics, docking technology, and biochemical methods such as western blots, qRT-PCR, immunofluorescence staining were performed to understanding the underlying mechanisms. Moreover, knock-down of LXR alpha and LXR alpha agonist were used on LO2 cell lines to understand the action of silybin. Results: We are the first to demonstrate that silybin can ameliorate dyslipidemia and arthritis in AIA rats. Overexpression of LXR alpha and several key lipogenic enzymes regulated by LXR alpha, including lipoprotein lipase (LPL), cholesterol 7 alpha and 27 alpha hydroxylase (CYP7A, CYP27A), adipocyte fatty acid-binding protein (aP2/FABP4) and fatty acid translocase (CD36/FAT), were observed in AIA rats, which mostly accounted for dyslipidemia during arthritis development. Metabolomics, docking technology, and biochemical results indicated that anti-arthritis effects of silybin related to suppressing the up-regulated LXR alpha and abnormal lipid metabolism. Notably, activation of LXR alpha could potentiate cell inflammatory process induced by LPS through the regulation of NF-kappa B pathway, however, suppression of LXR alpha agonism by siRNA or silybin reduced the nuclear translocation of NF-kappa B as well as the induction of downstream cytokines, indicating LXR alpha agonism is the important factor for the arthritis development and could be a potential target. Conclusion: The up-regulation of LXR alpha can activate lipogenesis enzymes to worsen the inflammatory process in AIA rats as well as the development of dyslipidemia, therefore, rectifying lipid disorder via suppression of LXR alpha agonism pertains the capacity of drug target, which enables to discover and develop new drugs to treat rheumatoid arthritis with dyslipidaemia.

T regulatory (Treg)/T-helper (Th) 17 imbalance has been shown to integrate with epigenetics to result in the development of autoimmune diseases. We aim to investigate the influence of disease staging on Treg/Th17 cells and whether the aberrant DNA methylation is implicated in the development of rheumatoid arthritis (RA). By recruiting 65 patients with multi-staging RA and 20 healthy controls (HC), we found that patients with active RA exhibited relative lymphopenia and higher WBC, neutrophils, and PLT. Circulating Treg/Th17 in patients with early active RA was significantly decreased. The expression of IL-6 and IL-17A was significantly increased in early active RA, whereas that of IL-10 and TGF-β was on the contrary. Furthermore, the frequency of Treg cells and Treg/Th17 were negatively correlated with DAS28, and the frequency of Th17 cells was on the contrary. Levels of DNA methylation related enzymes had significant difference between early active RA and HC. Relative hypermethylation was observed at the gene level for Treg-specific demethylated region (TSDR) and hypomethylation for retinoic acid-related orphan receptor (ROR)-C in early active RA. Thus, manifestations of RA and Treg/Th17 imbalance vary with disease staging, and the aberrant DNA methylation pattern may contribute to RA disease pathogenesis. Our results highlight the importance of disease staging in clinical research.

We explored the effects of dietary supplementation with phlorizin on redox state-related gut microbiota homeostasis in an obesity mouse model. Mice (C57BL/6J) were grouped as follows for 12 weeks: normal chow diet group (NCD), high-fat and cholesterol diet group (HFD), and treatment groups fed with HFD along with three levels of phlorizin. Phlorizin alleviated the hyperlipidemia and redox status and increased the total ccal SCFA content (1.88 ± 0.25 mg/g). Additionally, phlorizin regulated gene expression related to lipid metabolism, redox status, and cecum barrier and rebuilt gut microbiota homeostasis. After interference by antibiotics, the total phloretin content in the feces was decreased about 4-fold, and most of the health-promoting effects were abolished, indicating that phlorizin might be susceptible to microbial biotransformation and that microecology is indispensable for maintaining the redox state capacities of phlorizin. Phlorizin treatment could be an advantageous option for improving HFD-related obesity and redox states related to gut microbiota homeostasis.

Purpose: Total glucosides of paeony (TGP) have been confirmed to reduce hepatotoxicity caused by methotrexate (MTX) and leflunomide (LEF) in rheumatoid arthritis (RA). Nevertheless, high-quality evidence-based meta-analysis data on the issue are unavailable. This study aimed to evaluate the efficacy and safety of this combination treatment for RA. Materials and methods: PubMed, EMBASE, Web of Science, Cochrane Library, ClinicalTrials, Chinese Biomedical Literature database, China National Knowledge Internet, Wan Fang, and VIP were searched up to February 2019. Randomized controlled trials (RCTs) on the efficacy and safety of TGP combined MTX and LEF for RA were included. Results: Eight RCTs were included in the final meta-analysis. Pooled results showed better therapeutic effects against RA in the TGP-treated group (RR =1.10, 95% CI: 1.04 −1.16). The TGP+MTX+LEF group showed a reduced erythrocyte sedimentation rate (MD = −2.80 mm/h, 95% CI: −5.08 - −0.52), C-reactive protein level (MD = −4.17 mg/L, 95% CI: −7.84 - −0.51), and rheumatoid factor (MD = −12.09 IU/mL, 95% CI: −14.05 - −10.14). Besides, the combination treatment tended to benefit lipid profiles (total cholesterol: 95% CI: −1.27–0.06; triglycerides: 95% CI: −0.49 - −0.08; high-density lipoprotein cholesterol: 95% CI: 0.15–0.83; and low-density lipoprotein cholesterol: 95% CI: −0.54 - −0.02). Adverse events, hepatotoxicity in particular, significantly decreased (RR =0.55, 95% CI: 0.38–0.80) in the TGP group. Conclusion: Compared to MTX and LEF therapy, TGP combination treatment may be a more effective and safer strategy. It is advisable to apply TGP as an adjuvant given its hepatoprotective and possible lipid-regulating effect. However, further large-scale and high-quality clinical trials are warranted, and the efficacy of TGP in terms of its effect on lipid profiles should be further confirmed.

Objective. This study aimed to investigate whether berberine exerted anti-inflammatory and antiproliferative effects on the fibroblast-like synoviocytes of rheumatoid arthritis (FLS-RA) through regulating the lysophosphatidic acid (LPA) function. Methods. Firstly, the expression levels of LPA and lysophosphatidic acid receptor 1 (LPA1) in RA patients, osteoarthritis (OA) patients, and healthy controls were detected. Moreover, molecular docking was employed to characterize the binding sites of berberine in the predicted protein targets. Later, FLS-RA were stimulated using berberine, LPA, and the specific inhibitor (Ki16425) of LPA1, thereafter, the effects on the proliferation, apoptosis, the release of inflammatory mediators of FLS-RA, and the MAPK pathway were observed. Results. Compared with healthy controls (n = 25), the plasma LPA level (n = 28) and synovial fluid (n = 10) were markedly higher in RA patients. LPA1 was highly expressed in RA patients (n = 4) relative to that in OA patients (n = 4). Berberine remarkably inhibited the proliferation and the excessive production of IL-6 and TNF-α in FLS-RA, whereas suppressing the expression of K-ras, c-Raf, and p-38/ERK-phosphorylation. In addition, berberine inhibited the LPA-induced p-38/ERK-phosphorylation through binding to LPA1. Conclusions. LPA plays a certain role in promoting the proliferation and inflammation of FLS-RA. Berberine potentially modulates LPA function to suppress the proliferation and inflammation of FLS-RA through blocking the p38/ERK MAPK pathway mediated by LPA1. These findings suggest that, berberine possesses potential lipid-regulating, antiarthritis, and synovial hyperplasia inhibition activities against RA, which may provide a promising therapeutic target for the clinical drug development for RA patients with dyslipidemia and high CVD risk.

The objective of this systematic review was to conduct a meta-analysis of the efficacy and safety of total glucosides of paeony (TGP) for the treatment of ankylosing spondylitis (AS). TGP is commonly applied as a complementary medicine, especially in combination with disease-modifying antirheumatic drugs (DMARDs) and/or non-steroidal anti-inflammatory drugs (NSAIDs) to treat AS in China. Nevertheless, the efficacy and safety of TGP combination treatment still needs more validation. A systematic literature search was conducted using PubMed, EMBASE, Web of Science, the Cochrane library, ClinicalTrials, the Chinese Biomedical Literature database (CBM), the China National Knowledge Internet (CNKI), the Wan Fang Medical Database and the VIP Database for available randomized controlled trials (RCTs) investigating the efficacy and safety of TGP on AS up to November 2018. Review Manager 5.3 software and Stata 12.0 software were used to analyze all included studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. The pooled results of 23 RCTs exhibited better symptoms improvement (SI) (95% CI 1.16 to 1.36), lower erythrocyte sedimentation rate (ESR) (95% CI -5.89 to -1.32), lower levels of C-reactive protein (CRP) (95% CI -5.01 to -1.49), morning stiffness (MS) time (95% CI -3.46 to -1.86), finger to floor distance (FFD) (95% CI -4.80 to -0.86), peripheral joint pain index (PJPI) (95% CI -3.48 to -0.69), and higher level of thoracic expansion (TE) (95% CI 0.18-0.40) in TGP group. While Schober's test (Schober) showed no significant difference between the two groups. Adverse events (AEs) were significantly decreased (95% CI 0.48-0.79) with the usage of TGP. It is worthwhile to apply TGP as an auxiliary medicine on AS for better efficacy and less side effects, especially when considering the impact of traditional treatment on the liver. Still, further clinical trials with larger sample and better methodological quality are warranted to ascertain the potential benefits of TGP on AS.