Iguratimod inhibits protein citrullination and inflammation by downregulating NBCe2 in patients with rheumatoid arthritis.

BACKGROUND: Bicarbonate has recently been identified as a crucial factor affecting peptidylarginine deiminase (PAD) activity; however, the mechanism underlying its role in rheumatoid arthritis (RA) remains unclear. Iguratimod (IGU), a small-molecule disease-modifying anti-rheumatic drug, requires further investigation. This study aimed to explore the mechanism by which bicarbonate affects citrullination and inflammation in RA and identify new targets for IGU. METHODS: We enrolled 20 patients with RA in the study. Sodium bicarbonate cotransporter 2 (NBCe2) was detected in the peripheral blood neutrophils and peripheral blood mononuclear cells (PBMCs) of these patients. The effects of varying concentrations of IGU, methotrexate (MTX), dexamethasone (DXM), and S0859 (an NBCe2 inhibitor) on NBCe2, PAD2, PAD4, and citrullinated histone H3 (cit-H3) levels in, migration ability of, and cytokine production from neutrophils and PBMCs were examined. RESULTS: Our findings showed that in patients with RA, citrullinated protein production by peripheral blood neutrophils instead of PBMCs, which showed higher NBCe2 expression levels, increased with an increase in the bicarbonate concentration. In addition, tumor necrosis factor-alpha (TNF-α) promoted NBCe2 expression in neutrophils from patients with RA. Furthermore, we revealed that the inhibitory effects of IGU on neutrophil NBCe2 and cit-H3 levels, degrees of inhibition of neutrophil and PBMC migration, and suppression of interleukin 6, TNF-α, and metalloproteinase-9 secretion from neutrophil-like differentiated HL-60 cells did not substantially differ from those of MTX, DXM, and S0859 at specific doses. CONCLUSIONS: Bicarbonate promotes protein citrullination and inflammation in RA via NBCe2, and IGU can downregulate NBCe2.

Pd(II)-Catalyzed ß-C(sp3)-H Alkynylation of Alanine in Di- and Tripeptides with Asn as an Endogenous Directing Group.

The introduction of alkyne moieties into peptides remains in demand as it represents a promising approach for further structural diversification of peptides. Herein, we describe the Pd(II)-catalyzed C(sp3)-H alkynylation of Ala-Asn-embedded di- and tripeptides using Asn as the endogenous lead group. In addition, a key building block for the glycopeptide Tyc4PG-14 and Tyc4PG-15 was produced by our methodology.

New insights into MAIT cells in autoimmune diseases.

Mucosal-associated invariant T (MAIT) cells are resident T cells that express semi-invariant TCR chains and are restricted by monomorphic major histocompatibility complex (MHC) class I-related molecules (MR1). MAIT cells can be activated by microbial-specific metabolites (MR1-dependent mode) or cytokines (MR1-independent mode). Activated MAIT cells produce chemokines, cytotoxic molecules (granzyme B and perforin), and proinflammatory cytokines (IFN-γ, TNF-α, and IL-17), to clear pathogens and target infected cells involved in the pro-inflammatory, migratory, and cytolytic properties of MAIT cells. MAIT cells produce pro-inflammatory cytokines in the target organs of autoimmune diseases and contribute to the development and progression of autoimmune diseases. This article reviews the biological characteristics, activation mechanism, dynamic migration, and dual functions of MAIT cells, and focuses on the mechanism and potential application of MAIT cells in the early diagnosis, disease activity monitoring, and therapeutic targets of autoimmune diseases, to lay a foundation for future research.

The Role of Different Circulating T Follicular Helper Cell Markers in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic incurable inflammatory autoimmune disease. T follicular helper (Tfh) cells expressing different markers play critical roles in the development of RA. However, their specific mechanisms of action and association with RA clinical parameters are not clear. We therefore performed a cohort study to investigate the effects of different Tfh cell markers on RA pathogenesis. We retrospectively reviewed clinical data from 30 patients diagnosed with RA and 30 healthy controls (HCs) who visited our hospital. Based on X-ray findings, the patients were divided into a joint bone erosion group (n = 17) and a non-erosive joint bone group (n = 13). Using flow cytometry, we determined the frequencies of five peripheral blood CD4+ Tfh cell types characterized by different markers, and examined these cell types for correlations with clinical parameters. RA patients exhibited higher frequencies of CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+OX40+, and CD4+CXCR5+CD40L+ Tfh cells than HCs. CD4+CXCR5+, CD4+CXCR5+CD40L+, and CD4+CXCR5+OX40+ Tfh cell frequencies positively correlated with disease activity score-28 with erythrocyte sedimentation rate (DAS28-ESR), while those of CD4+CXCR5+ and CD4+CXCR5+CD40L+ Tfh cells were related to rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies. In RA patients without joint bone erosion, CD4+CXCR5+CD40L+ Tfh cell frequencies were positively correlated with both RF and DAS28-ESR. Serum anti-CCP antibody levels and CD4+CXCR5+ICOS+ Tfh cell frequencies were also positively correlated. Circulating CD4+CXCR5+CD40L+ Tfh cells appear to play critical roles in RA pathogenesis, and restricting CD4+CXCR5+CD40L+ Tfh cells may be a therapeutic strategy for controlling RA.

Comparative efficacy of treatments for patients with knee osteoarthritis: a network meta-analysis.

BACKGROUND: Knee osteoarthritis is a common cause of musculoskeletal pain and a leading cause of disability and healthcare economic burden. The optimum treatment for knee osteoarthritis is still inconclusive. A network meta-analysis is required to assess the efficacy and safety of treatments and provide more scientific medical evidence. METHODS: Relevant studies were searched through PubMed, Embase, and Cochrane Library electronic databases from the inception to October 2018. Continuous outcomes such as pain, stiffness, physical function and total scores were expressed as the mean differences with 95% credible interval. Surface under the cumulative ranking curve illustrated the rank probability of each therapy under different outcomes. RESULTS: Nineteen studies were included in this study, with a total of 2395 patients. For knee pain, platelet-rich plasma (0.691) was ranked at the first place, followed by hyaluronic acid combined with platelet-rich plasma (0.670) and hyaluronic acid (0.402). In terms of stiffness, hyaluronic acid combined with platelet-rich plasma (0.743) enjoyed the highest value, platelet-rich plasma (0.603) was the next and hyaluronic acid (0.386) was the third. As for physical function, the rank was hyaluronic acid combined with platelet-rich plasma (0.772), platelet-rich plasma (0.608) and hyaluronic acid (0.343). For total scores, the order given by surface under the cumulative ranking was hyaluronic acid combined with platelet-rich plasma (0.765), platelet-rich plasma (0.624) and hyaluronic acid (0.37). CONCLUSIONS: Hyaluronic acid combined with platelet-rich plasma showed the best efficacy in improving stiffness, physical function, and total scores, while platelet-rich plasma appeared the best in terms of pain reduction.

Iguratimod dose dependently inhibits the expression of citrullinated proteins and peptidylarginine deiminases 2 and 4 in neutrophils from rheumatoid arthritis patients.

INTRODUCTION: Anti-citrullinated protein antibodies (ACPAs) play an important role in rheumatoid arthritis (RA). Citrullinated proteins (CPs), which are produced by post-translational modification via peptidylarginine deiminase (PAD), are the target antigen of ACPAs and promote the generation thereof. Herein, we investigated whether iguratimod (IGU) affects the generation of CPs via PAD. METHODS: Neutrophils and peripheral blood mononuclear cells (PBMCs) were isolated from three patients diagnosed with RA and treated with various concentrations of IGU, methotrexate (MTX), or dexamethasone (DXM) or without any drugs as a control for 8 h. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-8 in culture supernatants were tested by ELISA. CPs were measured by western blot, and the expression of PAD2 and PAD4 in cells was detected by qRT-PCR and western blot. RESULTS: PAD2 and PAD4 expressions in neutrophils but not in PBMCs were decreased by IGU at both the protein and mRNA levels (P < 0.05). CP expression in neutrophils but not in PBMCs was also inhibited by IGU. The inhibitory effect of IGU was dose-dependent. IGU, MTX, and DXM dose dependently decreased the secretion of TNF-α, IL-1ß, IL-6, and IL-8 in neutrophils and PBMCs (P < 0.05); the inhibitory effect of IGU was not significantly different from that of MTX and DXM. CONCLUSIONS: IGU inhibited the expression of CPs by downregulating PADs in neutrophils from RA patients, and the effect was comparable to that of MTX and DXM at appropriate concentrations. These findings may provide guidance for more appropriate treatment of RA.Key Points• Iguratimod inhibited citrullinated protein expression in neutrophils from rheumatoid arthritis patients similarly to methotrexate and dexamethasone at appropriate concentrations.• The inhibitory effect was mediated by downregulation of peptidylarginine deiminases, providing insight into the mechanism of iguratimod as a treatment for rheumatoid arthritis.• This study may guide rheumatoid arthritis treatment and facilitate identification of other therapeutic targets.

Efficacy of different analgesic or sedative drug therapies in pediatric patients with congenital heart disease undergoing surgery: a network meta-analysis.

BACKGROUND: Surgery is an effective therapy for congenital heart disease (CHD) and the management after surgery poses challenges for the clinical workers. We performed this network meta-analysis to enhance the corresponding evidence with respect to the relative efficacy of different drug treatments applied after the CHD surgery. METHODS: Embase and PubMed were systematically retrieved to identify all published controlled trials investigating the effectiveness of drugs for patients up to 25 August, 2018. Mean differences (MD), odds ratios and their 95% credible intervals (CrIs) were used to evaluate multi-aspect comparisons. Surface under cumulative ranking curve (SUCRA) was used to analyze the relative ranking of different treatments in each endpoint. RESULTS: Compared to saline, all the drugs achieved better preference under the efficacy endpoints except fentanyl in JET. As for ventilator time, all drugs were more effective than saline while only the difference of dexmedetomidine was statistically obvious (MD = 6.92, 95% CrIs 1.77-12.54). Under the endpoint of ICU time, dexmedetomidine was superior to saline as well (MD = 1.26, 95% CrIs 0.11-2.45). When all the endpoints were taken into consideration and with the help of ranking probabilities and SUCRA values, fentanyl combined with dexmedetomidine was one of the recommended drugs due to its shorter time on ventilator and stay in hospital as well as lower mortality. CONCLUSIONS: Overall, based on the comprehensive consideration of all the endpoints, fentanyl combined with dexmedetomidine was considered to be the best-recommended clinical interventions among all the methods.