Association of serum 25-hydroxyvitamin D concentrations with all-cause and cause-specific mortality among individuals with gout and hyperuricemia.

BACKGROUND: We aimed to probe the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cause-specific mortality among patients with gout and hyperuricemia (HUA). METHODS: The study included 1169 gout patients and 7029 HUA patients from the National Health and Nutrition Examination Survey (NHANES) 2007-2018 and 2001-2018, respectively. The association between serum 25(OH)D and mortality was evaluated by Cox proportional hazard and restricted cubic spline models. RESULTS: Among participants with gout and HUA, the weighted mean concentrations of serum 25(OH)D were 71.49 ± 30.09 nmol/L and 64.81 ± 26.92 nmol/L, respectively. Vitamin D deficiency occurred in 29.68% of gout patients and 37.83% of HUA patients. During 6783 person-years of follow-up among gout patients, 248 all-cause deaths occurred, among which 76 died from cardiovascular disease (CVD) and 49 died from cancer. 1375 HUA patients were recorded for all-cause mortality during 59,859 person-years of follow-up, including 427 CVD deaths and 232 cancer deaths. After multifactorial adjustment, per one-unit increment in natural log-transformed 25(OH)D was associated with lower risk of 55% all-cause mortality and 61% CVD mortality among gout patients, and a 45% reduced risk of cancer mortality among HUA patients. Restricted cubic splines showed a U-shaped relationship with all-cause and CVD mortality among HUA patients, with inflection points of 72.7 nmol/L and 38.0 nmol/L, respectively. The results were robust in subgroup and sensitivity analyses. CONCLUSIONS: Serum 25(OH)D was negatively linearly correlated with mortality among gout patients, whereas U-shaped correlated with mortality in HUA patients. These results indicate that adequate vitamin D status could prevent premature death.

Qinghao-Biejia Herb Pair attenuates SLE atherosclerosis by regulating macrophage polarization via ABCA1/G1-mediated cholesterol efflux.

ETHNOPHARMACOLOGICAL RELEVANCE: Qinghao-Biejia herb pair (QB) is the core herb pair of "Jieduquyuziyin prescription" and is one of the commonly used herb pairs for the clinical treatment of systemic lupus erythematosus (SLE). Previous studies have shown that QB reduces the expression of inflammatory cytokines like IL-6 and TNF-α in the serum and kidney of MRL/lpr mice. Additionally, it inhibits the expression of TLR4 and MyD88 in the kidney and aorta and reduces the deposition of renal complement C3 and aortic plaque after treatment. These findings suggest that QB has a preventive and therapeutic effect on lupus rats. AIM OF THE STUDY: This study sought to investigate the mechanisms underlying the anti-SLE combined with atherosclerosis activity of the Qinghao-Biejia herb pair. MATERIALS AND METHODS: Drug targets for QB were identified using the HERB database, while targets associated with SLE and atherosclerosis were retrieved from the GeneCards database. The intersection of these drug and disease targets was then analyzed using a protein-protein interaction (PPI) network with GO and KEGG pathway enrichment analysis. In vivo, apolipoprotein E-deficient (ApoE-/-) mice were induced to develop SLE-AS by intraperitoneal injection of pristane and continued feeding of a high-fat diet. The changes in relevant indexes were observed after 12 weeks of gavage treatment with hydroxychloroquine, QB, Q (Qinghao alone), and B (Biejia alone). Bone marrow-derived macrophages from ApoE-/- mice and Raw 264.7 macrophages were used to explore the mechanisms of QB treatment. RESULTS: The levels of inflammatory cytokines in serum and pathological liver changes in mice were improved to varying degrees in the treatment groups. Additionally, there was a reduction in aortic atheromatous plaque formation and some improvement in cholesterol efflux. Furthermore, QB suppressed the expression of inflammatory cytokines in M1 macrophages, suggesting a role in regulating macrophage polarization. CONCLUSION: QB demonstrates clear efficacy for treating SLE-AS, and its therapeutic mechanism may involve the regulation of macrophage phenotypes by promoting cholesterol efflux.

Vaccination and the risk of systemic lupus erythematosus: a meta-analysis of observational studies.

OBJECTIVE: This meta-analysis aims to explore the potential link between vaccines and systemic lupus erythematosus (SLE). METHODS: We systematically searched PubMed, Cochrane Library, and Embase for observational studies from inception to September 3, 2023, using medical subject headings (MeSH) and keywords. Study quality was assessed using the NOS scale. Statistical analyses were conducted using STATA software (version 14.0). Publication bias was evaluated using funnel plots and Egger's regression. RESULTS: The meta-analysis incorporated 17 studies, encompassing 45,067,349 individuals with follow-up periods ranging from 0.5 to 2 years. The pooled analysis revealed no significant association between vaccinations and an increased risk of SLE [OR = 1.14, 95% CI (0.86-1.52), I2 = 78.1%, P = 0.348]. Subgroup analyses indicated that HBV vaccination was significantly associated with an elevated risk of SLE [OR =2.11, 95% CI (1.11-4.00), I2 = 63.3%, P = 0.02], HPV vaccination was slightly associated with an increased risk of SLE [OR = 1.43, 95% CI (0.88-2.31), I2 = 72.4%, P = 0.148], influenza vaccination showed no association with an increased risk of SLE [OR = 0.96, 95% CI (0.82-1.12), I2 = 0.0%, P = 0.559], and COVID-19 vaccine was marginally associated with a decreased risk of SLE [OR = 0.44, 95% CI (0.18-1.21), I2 = 91.3%, P = 0.118]. CONCLUSIONS: This study suggests that vaccinations are not linked to an increased risk of SLE. Our meta-analysis results provide valuable insights, alleviating concerns about SLE risk post-vaccination and supporting further vaccine development efforts.

Lipidomics Analysis Deepen Understanding the Molecular Mechanisms in a Gouty Model Induced by Combination of MSU Crystals Injection and High-Fat Diet Feeding and the Intervention Mechanisms of Allopurinol.

Background: Gouty arthritis (GA) is a common inflammatory disease caused by deposition of monosodium urate (MSU) crystals in diarthrodial joints. GA attacks commonly involved in joint with red, swollen, heat and pain, and often happened in unilateral foot-first metatarsophalangeal. Accumulated studies have proved that lipids play critical roles in biological processes and lipids biomarkers can substitute for the diagnosis of various diseases. Methods: Herein, shotgun lipidomics was used to quantitatively analyze serum lipidomes of a gouty model which was induced by injecting MSU crystals and feeding high-fat diet with/without treatment with allopurinol. Meanwhile, ELISA kit was used to detect mouse serum levels of inflammatory cytokines (eg, tumor necrosis factor-α, interleukin 1 beta) and HE staining was used to observe the infiltration of inflammatory cells in the foot pad. Results: A total of 9 types of serum lipids were detected in lipidomics by shotguns, and the result of NMDS' analysis demonstrated significant differences in lipids profiles between the control and model group. It is worth noting that lipid abnormality in GA (such as Ceramide (Cer), sphingomyelin (SM), 4-hydroxyalkenals (HNE), phosphatidylinositol (PI), ethanolamine glycerophospholipid (PE), etc.) is related with phospholipid and energy metabolism, and allopurinol treatment could correct the aberrant metabolism of lipid to some extent. Conclusion: Our results indicated that various aberrant lipid metabolisms were present in the established gouty model, and allopurinol treatment could relief this aberrant metabolism of lipids to some degree.

Association between systemic immune-inflammation index and chronic kidney disease: A population-based study.

BACKGROUND: Systemic immune-inflammation index (SII) is a new indicator of inflammation, and chronic kidney disease (CKD) has a connection to inflammation. However, the relationship between SII and CKD is still unsure. The aim of this study was whether there is an association between SII and CKD in the adult US population. METHODS: Data were from the National Health and Nutrition Examination Survey (NHANES) in 2003-2018, and multivariate logistic regression was used to explore the independent linear association between SII and CKD. Smoothing curves and threshold effect analyses were utilized to describe the nonlinear association between SII and CKD. RESULTS: The analysis comprised 40,660 adults in total. After adjusting for a number of factors, we found a positive association between SII and CKD [1.06 (1.04, 1.07)]. In subgroup analysis and interaction tests, this positive correlation showed differences in the age, hypertension, and diabetes strata (p for interaction<0.05), but remained constant in the sex, BMI, abdominal obesity, smoking, and alcohol consumption strata. Smoothing curve fitting revealed a non-linear positive correlation between SII and CKD. Threshold analysis revealed a saturation effect of SII at the inflection point of 2100 (1,000 cells/µl). When SII < 2100 (1,000 cells/µl), SII was an independent risk element for CKD. CONCLUSIONS: In the adult US population, our study found a positive association between SII and CKD (inflection point: 2100). The SII can be considered a positive indicator to identify CKD promptly and guide therapy.

Artesunate attenuates serum amyloid A-induced M1 macrophage differentiation through the promotion of PHGDH.

Clinical studies indicated that Serum Amyloid A (SAA) might be a promising biomarker for forecasting the activity, severity, and adverse prognosis of systemic lupus erythematosus (SLE). Simultaneously, a positive correlation has been observed between macrophages, Th17 cells, and SLE disease activity, with both these immune cells being affected by SAA. Presently, the relationship between SAA and the aforementioned immune cell types in SLE remains to be elucidated. To discern the immune cell type most closely associated with SAA, we undertook a single-cell RNA sequencing data analysis via the GEO database. Subsequent results revealed a strong association between macrophages and SAA, a relationship further validated through flow cytometry of spleen macrophages in the MRL/lpr model. We discovered that SAA stimulate M1 macrophage differentiation along with the upregulation of pro-inflammatory cytokines such as IL-6 and IL-1ß. Our findings suggest that SAA may promote M1 macrophage differentiation via the downregulation of phosphoglycerate dehydrogenase (PHGDH). Artesunate (ART), primarily utilized for malaria treatment, was shown to inhibit M1 macrophage differentiation and pro-inflammatory cytokine levels via upregulating the PHGDH expression, thereby attenuating the disease activity in SLE.

Fibromyalgia and risk of all-cause, specific mortality: A meta-analysis of observational studies.

OBJECTIVES: To evaluate the risk of all-cause, specific mortality among patients with fibromyalgia, which is a controversial topic. METHODS: We conducted a thorough search for cohort studies across the PubMed, Cochrane Library, and Embase databases, from their inception to 1 March 2023, using medical subject headings and relevant keywords. All data were meticulously analyzed using Stata statistical software version 16.0. The protocol was registered on PROSPERO (CRD42023402337). RESULTS: After analyzing seven cohort studies involving 152 933 individuals published between 2001 and 2020, we found no clear evidence linking fibromyalgia or widespread pain to all-cause mortality risk (odds ratio [OR] 1.11, 95% confidence interval [CI] 0.81-1.53; I2 = 82.6%, p = .505). However, our subgroup analysis revealed that the risk of suicide was significantly higher in fibromyalgia patients compared with non-fibromyalgia patients (OR 5.39, 95% CI 2.16-13.43; I2 = 69.9%, p < .05). CONCLUSIONS: Our research did not discover any proof indicating a link between fibromyalgia or widespread pain and all-cause mortality. However, it is worth noting that there may be a potential correlation between individuals with fibromyalgia or widespread pain and a higher likelihood of suicide. As we had a limited number of participants in our study, further research is necessary to thoroughly investigate the relationship between these factors.

Gas Chromatography-Mass Spectrometry Reveals Stage-Specific Metabolic Signatures of Ankylosing Spondylitis.

Ankylosing spondylitis (AS) is a type of chronic rheumatic immune disease, and the crucial point of AS treatment is identifying the correct stage of the disease. However, there is a lack of effective diagnostic methods for AS staging. The primary objective of this study was to perform an untargeted metabolomic approach in AS patients in an effort to reveal metabolic differences between patients in remission and acute stages. Serum samples from 40 controls and 57 AS patients were analyzed via gas chromatography-mass spectrometry (GC-MS). Twenty-four kinds of differential metabolites were identified between the healthy controls and AS patients, mainly involving valine/leucine/isoleucine biosynthesis and degradation, phenylalanine/tyrosine/tryptophan biosynthesis, glutathione metabolism, etc. Furthermore, the levels of fatty acids (linoleate, dodecanoate, hexadecanoate, and octadecanoate), amino acids (serine and pyroglutamate), 2-hydroxybutanoate, glucose, etc., were lower in patients in the acute stage than those in the remission stage, which may be associated with the aggravated inflammatory response and elevated oxidative stress in the acute stage. Multiple stage-specific metabolites were significantly correlated with inflammatory indicators (CRP and ESR). In addition, the combination of serum 2-hydroxybutanoate and hexadecanoate plays a significant role in the diagnosis of AS stages. These metabolomics-based findings provide new perspectives for AS staging, treatment, and pathogenesis studies.

B1-cell-produced anti-phosphatidylserine antibodies contribute to lupus nephritis development via TLR-mediated Syk activation.

Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). However, both the cellular source of antiphospholipid antibodies and their contributions to the development of lupus nephritis (LN) remain largely unclear. Here, we report a pathogenic role of anti-phosphatidylserine (PS) autoantibodies in the development of LN. Elevated serum PS-specific IgG levels were measured in model mice and SLE patients, especially in those with LN. PS-specific IgG accumulation was found in the kidney biopsies of LN patients. Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice. ELISPOT analysis identified B1a cells as the main cell type that secretes PS-specific IgG in both lupus model mice and patients. Adoptive transfer of PS-specific B1a cells accelerated the PS-specific autoimmune response and renal damage in recipient lupus model mice, whereas depletion of B1a cells attenuated lupus progression. In culture, PS-specific B1a cells were significantly expanded upon treatment with chromatin components, while blockade of TLR signal cascades by DNase I digestion and inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells. Thus, our study has demonstrated that the anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development. Our findings that blockade of the TLR/Syk signaling cascade inhibits PS-specific B1-cell expansion provide new insights into lupus pathogenesis and may facilitate the development of novel therapeutic targets for the treatment of LN in SLE.

Integrated network pharmacology and gut microbiome analysis to reveal the mechanism of Qu-Zhuo-Tong-Bi decoction against hyperuricemia and gout.

ETHNOPHARMACOLOGICAL RELEVANCE: Qu-zhuo-tong-bi decoction (QZTBD) is a classic Chinese herbal medicine that has shown therapeutic efficacy in clinical practice against hyperuricemia and gout. However, the potential mechanisms of QZTBD remain poorly investigated. AIM OF THE STUDY: To assess the therapeutic effects of QZTBD on hyperuricemia and gout and to reveal its mechanisms of action. MATERIALS AND METHODS: A Uox-KO mouse model of hyperuricemia and gout was established, and QZTBD was administered at a dosage of 18.0 g/kg/d. Throughout the experimental period, the effects of QZTBD on gout symptoms were monitored and analyzed. The integrated network pharmacology and gut microbiota analysis strategy was conducted to explore the mechanism of QZTBD in the treatment of hyperuricemia and gout. Targeted metabolomic analysis was performed to investigate the variation of amino acids and Spearman's rank correlation analysis was conducted to reveal the relationship between the discrepant bacterial genera and the altered amino acid. Flow cytometry was utilized to analysis the proportion of Th17 and Treg cells, and the production of pro-inflammatory cytokines was measured by ELISA. qRT-PCR and Western blot assay were applied to detect the expression of mRNA and protein respectively. Autodock vina 1.1.2 was used to evaluate the docking interactions. RESULTS: QZTBD treatment showed remarkable efficacy against hyperuricemia and gout with respect to attenuation of disease activity metrics through gut microbiome recovery and intestinal immune homeostasis. The administration of QZTBD significantly elevated the abundance of Allobaculum and Candidatus sacchairmonas, corrected the aberrant amino acid patterns, repaired the impaired intestinal barrier, restored the balance of Th17/Treg cells via PI3K-AKT-mTOR pathway, and reduced the levels of inflammatory cytokines such as IL-1ß, IL-6, TNF-α and IL-17. Fecal microbiota transplantation from QZTBD treated mice demonstrated convincing evidence of efficacy and mechanism of QZTBD. CONCLUSION: Taken together, our study explores the therapeutic mechanism of an effective herbal formula, QZTBD, for gout treatment through remodeling gut microbiome and regulating the differentiation of CD4+ T cells via PI3K-AKT-mTOR pathway.

Impacts of polypropylene microplastics on lipid profiles of mouse liver uncovered by lipidomics analysis and Raman spectroscopy.

Microplastics (MPs) are emerging contaminants, and there are only limited studies reporting the impacts of some MPs on liver lipid metabolism in animals. In this study, we investigated the accumulation of polypropylene-MPs in mouse liver and unraveled the change in lipid metabolic profiles by both lipidomics and Raman spectroscopy. Polypropylene-MP exposure did not cause obvious health symptoms, but hematoxylin-eosin staining showed pathological changes that polypropylene-MPs induced lipid droplet accumulation in liver. Lipidomics results showed a significant change in lipid metabolic profiles and the most influenced categories were triglycerides, fatty acids, free fatty acids and lysophosphatidylcholine, implying the effects of polypropylene-MPs on the hemostasis of lipid droplet biogenesis and catabolism. Most altered lipids contained unsaturated bonds and polyunsaturated phospholipids, possibly affecting the fluidity and curvature of membrane surfaces. Raman spectroscopy confirmed that the major spectral alterations of liver tissues were related to lipids, evidencing the altered lipid metabolism and cell membrane components in the presence of polypropylene-MPs. Our findings firstly disclosed the impacts of polypropylene-MPs on lipid metabolisms in mouse liver and hinted at their detrimental disturbance on membrane properties, cellular lipid storage and oxidation regulation, helping our deeper understanding on the toxicities and corresponding risks of polypropylene-MPs to mammals.

Methotrexate and Triptolide regulate Notch signaling pathway by targeting the Nedd4-Numb axis.

Methotrexate (MTX) is used to treat rheumatoid arthritis, acute leukemia, and psoriasis. MTX can cause certain side effects, such as myelosuppression, while the exact mechanism of myelosuppression caused by MTX is unknown. Notch signaling pathway has been considered to be essential to regulate hematopoietic stem cell (HSC) regeneration and homeostasis, thus contributing to bone marrow hematopoiesis. However, whether MTX affects Notch signaling remains unexplored. Here, our study provides evidence that MTX strongly suppresses the Notch signaling pathway. We found that MTX inhibited the interaction between Nedd4 with Numb, thus restricting K48-linked polyubiquitination of Numb and stabilizing Numb proteins. This in turn inhibited the Notch signaling pathway by reducing Notch1 protein levels. Interestingly, we found that a monomeric drug, Triptolide, is capable of alleviating the inhibitory effect of MTX on Notch signaling pathway. This study promotes our understanding of MTX-mediated regulation of Notch signaling and could provide ideas to alleviate MTX-induced myelosuppression.

Qinghao-Biejia Herb Pair Alleviates Pristane-Induced Lupus-Like Disease and Associated Renal and Aortic Lesions in ApoE-/- Mice.

Backgroud: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple systems with a high prevalence of nephritis and atherosclerosis. Jieduquyuziyin prescription is a famous prescription with immune modulating and inflammation controlling effects, which is efficacious in the treatment of SLE. The most critical herbs in this prescription are Qinghao and Biejia. The aim of this study was to evaluate the therapeutic effect of Qinghao-Biejia herb hair (QB) on mice with SLE combined with atherosclerosis. Materials and Methods: The effect of QB (identification using UPLC-TOF-MS) was assessed in female ApoE-/- mice intraperitoneally injected with 0.5 ml of pristane. Serum autoantibodies and lipid metabolic parameters were tested every 4 weeks, and spleen index, serum inflammatory biomarkers, renal injury, and aortic injury were observed after 16 weeks. The expression of signaling pathway in kidney tissues was observed by RT-qPCR and Western blot. Results: The mice of QB-treated group exhibited a significant reduced serum autoantibodies level, urine protein, and renal immune complex deposition. QB treatment reduced the levels of inflammatory cytokines and improved the renal pathological changes. In addition, there was a reduction in aortic atheromatous plaque and some improvement in dyslipidemia. Moreover, QB suppressed the expression of HMGB1, TLR4, and MyD88 to some extent. Conclusion: The present study implied that QB has clear efficacy for the treatment of SLE combined with atherosclerosis, and that inhibition of the HMGB1/TLR4 signaling pathway may be one of the therapeutic targets of QB for SLE combined with atherosclerosis.

Norcantharidin ameliorates the development of murine lupus via inhibiting the generation of IL-17 producing cells.

Systemic lupus erythematosus (SLE) is a devastating autoimmune disorder associated with severe organ damage. The abnormality of T cell apoptosis is considered as an important pathogenetic mechanism of SLE. Norcantharidin (NCTD), a derivative of Cantharidin, is an efficacious anti-cancer drug by inhibiting cell proliferation and inducing cell apoptosis. Besides, NCTD has also been proved to protect the function of kidneys, while damaged renal function is the most important predictor of morbidity and mortality in SLE. All these suggest the potential effects of NCTD in SLE treatment. In this study we investigated whether NCTD exerted therapeutic effects in a mouse SLE model. Lupus prone female MRL/lpr mice were treated with NCTD (1, 2 mg·kg-1·d-1, ip) for 8 weeks. We showed that NCTD administration significantly decreased mortality rate, diminished the expression of anti-dsDNA IgG antibody, a diagnostic marker for SLE, as well as restored renal structure and function in MRL/lpr mice. Moreover, NCTD administration dose-dependently inhibited lymphoproliferation and T cell accumulation in the spleens of MRL/lpr mice. We further revealed that NCTD specifically inhibited DN T cell proliferation and Th17 cell differentiation both via blocking activation of signal transducer and activator of transcription 3 (STAT3) signaling pathway. On the other hand, NCTD did not affect T cell apoptosis in MRL/lpr mice. Taken together, our data suggest that NCTD may be as a promising therapeutic drug through targeting T cells for the treatment of SLE.

The Flavonoid Naringenin Alleviates Collagen-Induced Arthritis through Curbing the Migration and Polarization of CD4+ T Lymphocyte Driven by Regulating Mitochondrial Fission.

Rheumatoid arthritis (RA) is a progressive autoimmune disease. Due to local infiltration and damage to the joints, activated CD4+ T cells play a crucial role in the progression of RA. However, the exact regulatory mechanisms are perplexing, which makes the effective management of RA frustrating. This study aimed to investigate the effect of mitochondria fission on the polarization and migration of CD4+ T cells as well as the regulatory mechanism of NAR, so as to provide enlightenment on therapeutic targets and novel strategies for the treatment of RA. In this study, a collagen-induced arthritis (CIA) model was established, and rats were randomly given saline or naringenin (NAR, 10 mg/kg, 20 mg/kg, 50 mg/kg, i.p.) once a day, before being euthanized on the 42nd day of primary immunization. The pain-like behavior, articular index scores, account of synovial-infiltrated CD4+ T cells, and inflammatory factors were investigated in each group. In vitro, spleen CD4+ T lymphocytes were derived from each group. In addition, mitochondrial division inhibitor 1 (Mdivi-1) or NAR was added to the cell medium containing C-X-C motif chemokine ligand 12 (CXCL12) in order to induce CD4+ T lymphocytes, respectively. The polarization capacity of CD4+ T cells was evaluated through the immunofluorescence intensity of the F-actin and myosin light chain phosphorylated at Ser19 (pMLC S19), and the mitochondrial distribution was determined by co-localization analysis of the translocase of outer mitochondrial membrane 20 (TOM20, the mitochondrial marker) and intercellular adhesion molecule 1 (ICAM1, the uropod marker). The mitochondrial fission was investigated by detecting dynamin-related protein 1 (Drp1) and mitochondrial fission protein 1 (Fis1) using Western blot and immunofluorescence. This study revealed that high-dose NAR (50 mg/kg, i.p.) alleviated pain-like behavior and articular index scores, reduced the serum level of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), and accounted for CD4+ T lymphocytes that infiltrated into the synovial membrane of the CIA group. Meanwhile, NAR (50 mg/kg, i.p.) suppressed the polarization of spleen CD4+ T lymphocytes, reduced the redistribution of mitochondria in the uropod, and inhibited the expression of Drp1 and Fis1 in the CIA model. Furthermore, the in vitro experiments confirmed that NAR reduced mitochondrial fission, which in turn inhibited the CXCL12-induced polarization and migration of CD4+ T lymphocytes. Our results demonstrated that the flavonoid NAR was a promising drug for the treatment of RA, which could effectively interfere with mitochondrial fission, thus inhibiting the polarization and migration of CD4+ T cells in the synovial membrane.

The major cardiovascular events of febuxostat versus allopurinol in treating gout or asymptomatic hyperuricemia: a systematic review and meta-analysis.

BACKGROUND: To evaluate the major cardiovascular (CV) events of febuxostat compared to allopurinol for the treatment of gout or asymptomatic hyperuricemia. METHODS: Relevant studies published until August 15, 2020 were identified by a systematic search of the PubMed and Wiley Online Library databases. Any controlled clinical trial, randomised controlled trial (RCT), retrospective cohort study or open label trial (OLT) comparing febuxostat in patients with gout or hyperuricemia with allopurinol. The quality of all identified studies was assessed based on Cochrane Collaboration's risk of bias tool. Odds ratios (OR) were calculated with random effects and reported with corresponding 95% confidence intervals (CI). RESULTS: Eighteen studies were ultimately included in the analysis, among them 6 articles mentioned serum uric acid (sUA) level before and after treatment, 14 articles mentioned major cardiovascular events, 5 articles mentioned cardiovascular death, 6 articles mentioned skin reactions, 6 articles mentioned musculoskeletal and connective tissue signs and symptoms, 4 articles mentioned joint-related signs and symptoms, 6 articles mentioned upper respiratory infection, 5 articles mentioned gastrointestinal reaction and 7 articles mentioned all-cause mortality. The febuxostat group showed significantly lower sUA levels than allopurinol group (MD =-0.83, 95% CI: -1.22 to -0.44, P<0.0001, I2=98%). There was no markedly difference between the febuxostat and allopurinol (OR 1.01, 95% CI: 0.83 to 1.23, P=0.84, I2=95%) in the major cardiovascular events. The occurrence of skin reactions of febuxostat was significantly fewer than allopurinol (OR 0.55, 95% CI: 0.42 to 0.73, P<0.0001, I2=49%). Regarding to occurrence of CV death, musculoskeletal and connective tissue signs and symptoms, febuxostat group was higher than allopurinol group. However, among patients with gout or hyperuricemia, treatment with febuxostat resulted in other adverse reactions, including all-causes mortality similar to those associated with allopurinol. DISCUSSION: The limitation of the study was the included studies show high heterogeneity in regard to their design. There was no difference in the incidence of major cardiovascular events between febuxostat and allopurinol, and febuxostat was better in lowering uric acid and has less adverse skin reactions than allopurinol, but the risk of CV death of febuxostat was higher than allopurinol.

Lipidomics Revealed Aberrant Metabolism of Lipids Including FAHFAs in Renal Tissue in the Progression of Lupus Nephritis in a Murine Model.

Lupus nephritis (LN) is an inflammatory renal disease of patients with systemic lupus erythematosus with lots of immune complexes deposited in kidneys. Accumulated studies have demonstrated the close relationships among dyslipidaemia, inflammation, and autoimmune response, and oxidative stress in the patients. Lipids play numerous important roles in biological process and cellular functions. Herein, shotgun lipidomics was employed to quantitatively analyze cellular lipidomes in the renal tissue of MRL/lpr mice in the progression of LN (including pre-LN and LN state) with/without treated with glucocorticoids (GCs). The levels of cytokines (i.e., TNF-α (Tumor necrosis factor alpha) and IL-6 (Interleukin 6)) in the serum were measured by ELISA (enzyme-linked immunosorbent assay) kits. Renal histopathological changes and C3 deposition in the glomeruli of the mice were also determined. Lipidomics analysis revealed that the ectopic fat deposition and the aberrant metabolism of lipids that were relevant to oxidative stress (e.g., 4-hydroxyalkenal, ceramide, lysophospholipid species, etc.) always existed in the development of LN. Moreover, the anti-inflammatory FAHFA (fatty acid ester of hydroxyl fatty acid) species in the kidney tissue could largely reflect the severity of LN. Thus, they were a potential early biomarker for LN. In addition, the study also revealed that treatment with GCs could prevent the progression of LN, but greatly aggravate the aberrant metabolism of the lipids, particularly when used for a long time.

Genetically Predicted Serum Iron Status Is Associated with Altered Risk of Systemic Lupus Erythematosus among European Populations.

BACKGROUND: Observational epidemiological studies have reported an inconsistent relation between iron status and risk of systemic lupus erythematosus (SLE). Moreover, it remains uncertain whether the observed association is causal or due to confounding or reverse causality. OBJECTIVES: We aimed to investigate the association between serum iron status and risk of SLE using a 2-sample Mendelian randomization (MR) approach. METHODS: Genetic instruments for iron status including serum iron, log-transformed ferritin, transferrin saturation, and transferrin were identified from a large-scale genome-wide association study (GWAS) performed by the Genetics of Iron Status Consortium among 48,972 individuals of European ancestry (55% female). Three independent single nucleotide polymorphisms (rs1800562, rs1799945, and rs855791) concordantly related with 4 iron status biomarkers were selected as instrumental variables. Summary statistics of SLE were obtained from a publicly available GWAS of 4036 patients with SLE and 6959 controls of European descent. The MR study was conducted using the inverse-variance weighted (IVW) method, supplemented with MR-Egger regression and simple- and weighted-median methods. Leave-one-out analysis was further performed to test the robustness of our findings. ORs with 95% CIs were calculated. RESULTS: Genetically predicted iron status was associated with altered risk of SLE, with ORs of 0.79 (95% CI: 0.66, 0.94), 0.54 (95% CI: 0.34, 0.85), 0.82 (95% CI: 0.71, 0.94), and 1.36 (95% CI: 1.06, 1.76) per 1-SD increase in iron, log-transformed ferritin, transferrin saturation, and transferrin using the IVW method, respectively. MR-Egger regression did not indicate potential pleiotropic bias. Sensitivity analyses produced similar findings, suggesting the robustness of the association. CONCLUSIONS: Our study suggested that high iron status may be associated with a reduced risk of SLE among European populations. Further studies are warranted to elucidate the mechanism underlying the protective role of iron against susceptibility to SLE.

Lifestyle factors associated with incidence of rheumatoid arthritis in US adults: analysis of National Health and Nutrition Examination Survey database and meta-analysis.

OBJECTIVE: To quantify rheumatoid arthritis (RA) cases attributable to selected non-genetic risk factors. DESIGN: National Health and Nutrition Examination Survey (NHANES) and meta-analysis. PARTICIPANTS: US adults. DATA SOURCES: The prevalence of exposure was obtained from NHANES. Weighted analysis was performed to account for the complex sampling design in NHANES. PubMed and Web of Science up to 31 March 2019 were searched to identify epidemiological studies reported the association between non-genetic risk factors and RA in US adults. Relative risk (RR) value and the corresponding CI were pooled by meta-analysis to evaluate the associations between modifiable risk factors and RA. Population attributable fraction (PAF) was calculated based on the prevalence and RR data. RESULTS: The weighted percentages of former smokers, current smokers and overweight or obese people were 24.84%, 23.93% and 63.97%, and the average alcohol consumption was 51.34 g/week. In the meta-analysis, we found that former smokers (RR 1.22, 95% CI 1.10 to 1.36) and current smokers (RR 1.47, 95% CI 1.29 to 1.68) had higher risks of RA. Overweight and obese individuals had 1.27-fold (95% CI 1.09 to 1.48) increased risk of RA. Each per 50 g/week increment of alcohol consumption was associated with 8% (95% CI 0% to 16%) reduction in the risk of RA. Therefore, PAF value of smoking was 14.00% (95% CI 8.13% to 23.33%). Excess body mass index (BMI) was found to account for 14.73% (95% CI 5.45% to 23.50%) of RA incidence. The fraction of RA risk attributed by low alcohol intake was 8.21% (95% CI 0.31% to 16.39%). Collectively, we found that 32.69% (95% CI 13.41% to 50.96%) of RA cases were attributable to smoking, overweight or obesity and low alcohol drinking. CONCLUSION: Nearly 33% of RA incidence was attributed to smoking, excess BMI and low alcohol drinking in USA. Our findings could provide a basis for developing guidelines of RA prevention and control in USA.

Inflammasome and Its Therapeutic Targeting in Rheumatoid Arthritis.

Inflammasome is a cytoplasmic multiprotein complex that facilitates the clearance of exogenous microorganisms or the recognition of endogenous danger signals, which is critically involved in innate inflammatory response. Excessive or abnormal activation of inflammasomes has been shown to contribute to the development of various diseases including autoimmune diseases, neurodegenerative changes, and cancers. Rheumatoid arthritis (RA) is a chronic and complex autoimmune disease, in which inflammasome activation plays a pivotal role in immune dysregulation and joint inflammation. This review summarizes recent findings on inflammasome activation and its effector mechanisms in the pathogenesis of RA and potential development of therapeutic targeting of inflammasome for the immunotherapy of RA.