The association between night shift work and osteoporosis risk in adults: A cross-sectional analysis using NHANES.

Purpose: Through this study, we assess whether night shift work increases the risk of osteoporosis, and explore the effects of age, gender, or lifestyle differences. Methods: This cross-sectional study included the collection of data from a sample of the US adults who participated in the National Health and Nutrition Examination Survey (NHANES) over a 7.3-year period (2007-2008, 2009-2010, 2017-March2020), including 4408 participants (2351[52.8%] men and 2057[47.2%] women), with an age range of 20-80 years. The primary variables, health status, nutrition, harmful lifestyle habits, and bone mineral density (BMD), were segregated, and analyzed according to different work schedules. Linear regression models were conducted to evaluate correlations of night shift work and T-scores. Associations between night shift work and osteoporosis were examined using logistic regression analyses. All regression models were stratified by gender and age ≥50 years. Osteoporosis was defined as BMD at the femoral neck or total spine equal to or less than 2.5 standard deviations below the mean for youthful people of the same gender. All data were obtained using questionnaires and examinations collected in mobile examination center (MEC) from NHANES. Results: After multivariate adjustment, night shift work was related to statistically significant decreases of the total spine in T-scores of females aged ≥50 years. Furthermore, night shift work of the overall population (OR = 2.31 [95% CI, 1.03-5.18]; P = 0.043) and females aged ≥50 years (OR = 4.6 [95% CI, 1.21-17.54]; P = 0.025) was related to an increased prevalence of osteoporosis. Conclusion: Night shift work correlates with a higher risk of osteoporosis in the population of the US adults, with the combined effect of age, gender, and harmful lifestyle.

Signaling pathways in rheumatoid arthritis: implications for targeted therapy.

Rheumatoid arthritis (RA) is an incurable systemic autoimmune disease. Disease progression leads to joint deformity and associated loss of function, which significantly impacts the quality of life for sufferers and adds to losses in the labor force. In the past few decades, RA has attracted increased attention from researchers, the abnormal signaling pathways in RA are a very important research field in the diagnosis and treatment of RA, which provides important evidence for understanding this complex disease and developing novel RA-linked intervention targets. The current review intends to provide a comprehensive overview of RA, including a general introduction to the disease, historical events, epidemiology, risk factors, and pathological process, highlight the primary research progress of the disease and various signaling pathways and molecular mechanisms, including genetic factors, epigenetic factors, summarize the most recent developments in identifying novel signaling pathways in RA and new inhibitors for treating RA. therapeutic interventions including approved drugs, clinical drugs, pre-clinical drugs, and cutting-edge therapeutic technologies. These developments will hopefully drive progress in new strategically targeted therapies and hope to provide novel ideas for RA treatment options in the future.

The combination of Chinese and Western Medicine in the management of rheumatoid arthritis: A real-world cohort study across China.

Objective: To investigate the efficacy of Integrative medicine (IM), compare with Western medicine (WM), in the treatment of rheumatoid arthritis (RA) in a cohort study. Methods: This is a cohort study with recruitment of RA patients from 10 hospitals in China. The primary outcome was change in disease activity score 28 (DAS28) during 4 follow-up visits. Generalized estimating equation (GEE) models that controlled for variables were used to investigate a time trend and assess group differences in the primary outcome and secondary outcomes after propensity score matching (PSM). Results: A total of 3195 patients with RA received IM (n = 1379, 43.2%) or WM (n = 1816, 56.8%). Following 1:1 propensity score matching, 1,331 eligible patients prescribed IM were compared to 1,331 matched patients prescribed WM. The GEE analysis with PSM showed that the IM was more beneficial to significantly decrease the levels of VAS, PGA and PhGA (VAS: odds ratio (OR), 0.76; 95% CI, 0.63-0.92; p = 0.004; PGA: OR, 0.76; 95% CI, 0.64-0.92; p = 0.007; and PhGA: OR, 0.77; 95% CI, 0.64, 0.93; p = 0.004), and reduce DAS28 (OR, 0.84; 95% CI, 0.73-0.98; p = 0.030) in the per-protocol population. Conclusion: This study suggests that compare to WM, IM has advantages in improving RA-related outcomes. However, the statistical significance might not reveal significant clinical difference. Further studies should be focused on specific treatment strategies and/or disease stages.

SMYD2-mediated TRAF2 methylation promotes the NF-κB signaling pathways in inflammatory diseases.

BACKGROUND: The methylation of lysine residues has been involved in the multiple biological and diseases processes. Recently, some particular non-histone proteins have been elucidated to be methylated by SMYD2, a SET and MYND domain protein with lysine methyltransferase activity. METHODS: SMYD2 was evaluated in synovial tissue and cells derived from rheumatoid arthritis patients. We confirmed TRAF2 could be methylated by SMYD2 using Mass spectrometry, pull-down, immunoprecipitation, methyltransferase assay, ubiquitination assay, luciferase reporter assays, and western blot analyses. Using loss- and gain-of function studies, we explored the biological functions of SMYD2 in vitro and in vivo. Using acute and chronic inflammation with different mice models to determine the impact of SMYD2. RESULTS: Here, we first time confirmed that the cytoplasmic protein TRAF2 as the kernel node for NF-κB signaling pathway could be methylated by SMYD2. SMYD2-mediated TRAF2 methylation contributed to the durative sensitization of NF-κB signaling transduction through restraining its own proteolysis and enhancing the activity. In addition, we found knocking down of SMYD2 has different degrees of mitigation in acute and chronic inflammation mice models. Furthermore, as the lysine-specific demethylase, LSD1 could resist methylation on TRAF2 induced by SMYD2. CONCLUSIONS: Our data uncovered an unprecedented cytoplasmic protein network that employed methylation of TRAF2 for the maintenance of NF-κB activation during inflammatory diseases.

Hydrogen Sulfide: a Novel Immunoinflammatory Regulator in Rheumatoid Arthritis.

Hydrogen sulfide (H2S), an endogenous, gaseous, signaling transmitter, has been shown to have vasodilative, anti-oxidative, anti-inflammatory, and cytoprotective activities. Increasing evidence also indicates that H2S can suppress the production of inflammatory mediators by immune cells, for example, T cells and macrophages. Inflammation is closely related to an immune response in several diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and cancer. Considering these biological effects of H2S, a potential role in the treatment of immune-related RA is being exploited. In the present review, we will provide an overview of the therapeutic potential of H2S in RA treatment.

Epidemiology of Takayasu arteritis in Shanghai: A hospital-based study and systematic review.

BACKGROUND: Takayasu arteritis (TAK) is a rare large vessel vasculitis, and epidemiological data on TAK are lacking in China. Thus, we designed this study to estimate the TAK prevalence and incidence in residential Shanghai, China. METHODS: Data on diagnosed TAK cases aged over 16 years were retrieved from 22 tertiary hospitals in Shanghai through hospital electronic medical record systems between January 1, 2015 and December 31, 2017 to estimate the prevalence and incidence. A systematic literature review based on searches in PubMed, Ovid-Medline, Excerpta Medica Database (EMBASE), Web of Science, and China National Knowledge Infrastructure (CNKI) was performed to summarize TAK distribution across the world. RESULTS: In total 102 TAK patients, with 64% female, were identified. The point prevalence (2015-2017) was 7.01 (95% CI 5.65-8.37) cases per million, and the mean annual incidence was 2.33 (1.97-3.21) cases per million. The average age of TAK patients was 44 ± 16 years, with the highest prevalence (11.59 [9.23-19.50] cases per million) and incidence (3.55 [0.72 3.74] cases per million) in the 16 to 34 years population. Seventeen reports were included in the system review, showing that the epidemiology of TAK varied greatly across the world. The incidence and prevalence were both relatively higher in Asian countries, with the prevalence ranging 3.3-40 cases per million and annual incidence ranging 0.34-2.4 cases per million. CONCLUSIONS: The prevalence and incidence of TAK in Shanghai was at moderate to high levels among the previous reports. The disease burden varied globally among racial populations.

New Therapeutic Approaches Using Hydrogen Sulfide Donors in Inflammation and Immune Response.

Significance: Inflammation and immune response are associated with many pathological disorders, including rheumatoid arthritis, lupus, heart failure, and cancer(s). In recent times, important roles of hydrogen sulfide (H2S) have been evidenced by researchers in inflammatory responses, as well as immunomodulatory effects in several disease models. Recent Advances: Numerous biological targets, including cytochrome c oxidase, various kinases, enzymes involved in epigenetic changes, transcription factors, namely nuclear factor kappa B and nuclear factor erythroid 2-related factor 2, and several membrane ion channels, are shown to be sensitive to H2S and have been widely investigated in various preclinical models. Critical Issues: A complete understanding of the effects of H2S in inflammatory and immune response is vital in the development of novel H2S generating therapeutics. In this review, the biological effects and pharmacological properties of H2S in inflammation and immune response are addressed. The review also covers some of the novel H2S releasing prodrugs developed in recent years as tools to study this fascinating molecule. Future Directions: H2S plays important roles in inflammation and immunity-related processes. Future researches are needed to further assess the immunomodulatory effects of H2S and to assist in the design of more efficient H2S carrier systems, or drug formulations, for the management of immune-related conditions in humans. Antioxid. Redox Signal. 35, 341-356.

Modified Zhibai Dihuang pill, a traditional Chinese medicine formula, on steroid withdrawal in systemic lupus erythematosus: A systematic review and meta-analysis.

BACKGROUND: Zhibai Dihuang pill (ZBDH), a Chinese herbal formula, has been widely used as an adjunctive therapy to help reduce the patient's steroid dose and maintain low disease activity in systemic lupus erythematosus (SLE). OBJECTIVE: This systematic review evaluates the therapeutic effect of modified ZBDH in reducing steroid use in patients with SLE. SEARCH STRATEGY: A systematic literature search was carried out using seven databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, Chinese VIP Information and Wanfang Database, from their inception to June 1st, 2019. The search terms included "systemic lupus erythematosus," "Chinese medicine" and "clinical trial," and their synonyms. Subject headings matching the above terms were also used. INCLUSION CRITERIA: This meta-analysis included randomized controlled trials that evaluated the reduction of steroid dose in patients with SLE. Traditional Chinese medicine (TCM) formulas in experimental group should be prescribed based on ZBDH and used as adjunctive therapy and the comparator should contain steroids. DATA EXTRACTION AND ANALYSIS: Two authors independently conducted database search, study selection, data extraction and quality assessment. The extracted information contained study design, sample size, recruitment mode, diagnostic criteria, inclusion and exclusion criteria, participant characteristics, TCM patterns, TCM formulas and treatment outcomes. The primary outcome was the change of steroid dose. Secondary outcomes included SLE Disease Activity Index (SLEDAI), biomarkers of disease activity and clinical response rate. STATA 15.0 was used to analyze the pooled effects reported as weighted mean difference (WMD) or odds ratio, with a 95% confidence interval (CI). RESULTS: In total, 20 trials involving 1470 SLE patients were included. The pooled result showed that modified ZBDH taken in combination with standard care led to a larger reduction in steroid dose, compared to standard care alone (WMD: 3.79; 95% CI: 2.58-5.01; P < 0.001). Favorable outcomes were also seen in secondary outcome criteria, such as SLEDAI and complement 3. The modified ZBDH treatments were well tolerated without increasing adverse effects. CONCLUSION: The systematic review provided preliminary evidence supporting the use of ZBDH as a co-therapy to aid steroid dose reduction in patients with SLE. However, more rigorous studies should be conducted to validate these findings, and explore the mechanisms of ZBDH's relevant bioactive constituents.

Traditional Chinese medicine on treating active rheumatoid arthritis: A protocol for systematic review and meta-analysis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with progressive joint damage and disability. There is a lack of effective methods in the treatment of RA currently. Many clinical trials have proved that traditional Chinese medicine (TCM) has obvious advantages in the treatment of RA. In this systematic review, we intend to evaluate the efficacy and safety of TCM for active RA. METHODS: We will search PubMed, the Cochrane Library, Embase, Web of Science, the Chinese National Knowledge Infrastructure Database, Wanfang Data, and Chinese Science and Technology Periodical Database. Simultaneously we will retrieval relevant meeting minutes, eligible research reference lists, symposium abstracts, and grey literatures. Included criteria are randomized controlled trials (RCTs) about TCM for active RA to assess its efficacy and safety. We will use the Revman 5.3 and Stata 13.0 software for data synthesis, sensitivity analysis, meta regression, subgroup analysis, and risk of bias assessment. The Grading of Recommendations Assessment, Development, and Evaluation standard will be used to evaluate the quality of evidence. RESULTS: This systematic review will provide a synthesis of TCM for patients with active RA from various evaluation aspects including tender joint count, swollen joint count, RF, CRP, ESR, DAS28, TCM syndrome evaluation criteria, and adverse events. CONCLUSION: The systematic review will provide evidence to assess the efficacy and safety of TCM in the treatment of patients with active RA. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42019146726.

A multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of Huangqi Guizhi Wuwutang granule in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by swelling, pain, and synovial damage. Effective methods lack in the treatment of RA. A traditional prescription in use for thousands of years in China, Huangqi Guizhi Wuwutang granule (HGWG) is still chosen to relieve pain and prevent joint malformation in RA patients. However, no evidence-based medical research has been organized to assess the effectiveness and safety of HGWG for RA. METHODS/DESIGN: We will conduct a multicenter, randomized, double-blind, placebo-controlled clinical trial to determine whether HGWG can relieve pain and protect joints. We will randomly divide 120 patients with active RA into 2 groups, treated for 12 weeks. Main measurement is the rate of ACR50 score (American College of Rheumatology) from the baseline to 12 weeks. Secondary measurements include rate of ACR20/70, change of Disease Activity Score (DAS) 28, Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient Assessment of Arthritis Pain, Patient Global Assessment of Arthritis, and AIS score. The time points are set as baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 24 weeks, and 48 weeks. In addition, the rate of ACR50 from the baseline to 2 weeks, 4 weeks, 8 weeks, 24 weeks, and 48 weeks' follow-up are also the secondary outcome measures. DISCUSSION: The findings of this research will elucidate the efficacy and safety of HGWG and provide an alternative treatment for RA. In addition, our data will benefit the clinical decision-making on active RA and possibly be incorporated into future guidelines. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03593837.

The efficacy of the traditional Chinese medicine Jia Wei Niu Bang Zi granule combined with methotrexate in treating active rheumatoid arthritis: A multicenter, randomized, double-blinded controlled clinical trial.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic systemic and autoimmune inflammatory disease ending with the destruction of joints. Current therapies can relieve RA symptoms, but some also bring severe adverse events. Therefore, an effective and safe therapeutic strategy remains to be created to benefit patients with RA by large. Jia Wei Niu Bang Zi granule (NBZG) consisting of RA-fighting Chinese herbals has been used in Longhua Hospital in the last several decades. NBZG has potential therapeutic effect on RA, which should be evaluated by larger sample clinical trial. METHODS: A multicenter, randomized, double-blind, placebo-controlled clinical trials will be conducted to determine the efficiency of NBZG in pain relief and joint protection. A total of 120 patients with active RA will be enrolled, and treated with NBZG or placebo for 12 weeks. The primary outcome measurements include rate of American College of Rheumatology (ACR) 50 at 12 weeks' treatment. The 2nd outcome measurements include rate change of ACR20, ACR70, the disease activity score (DAS) 28, 36-item Short-Form Health Survey Questionnaire, Health Assessment Questionnaire - Disability Index, score changes of Patient Assessment of Arthritis Pain, Patient Global Assessment of Arthritis, and the Athens insomnia scale at the same time points. DISCUSSION: Although NBZG has shown efficacy in treating RA in Longhua Hospital for decades, the universality of this efficacy needs evaluated. The results of this trial will provide a convincing evidence about NBZG's efficacy in treating active RA in a large population. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03173040 (registered on May 30, 2017).

Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis.

Cystathionine-γ-lyase (CSE), an enzyme associated with hydrogen sulfide (H2S) production, is an important endogenous regulator of inflammation. Jumonji domain-containing protein 3 (JMJD3) is implicated in the immune response and inflammation. Here, we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis (RA). Upregulated CSE and JMJD3 were identified in synovial fibroblasts (SFs) from RA patients as well as in the joints of arthritic mice. Knocking down CSE augmented inflammation in IL-1ß-induced SFs by increasing JMJD3 expression. In addition, CSE-/- mice with collagen-induced arthritis (CIA) developed severe joint inflammation and bone erosion. Conversely, overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1ß-treated SFs. Furthermore, JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1ß-treated SFs, mainly by controlling the methylation status of H3K27me3 at the promoter of its target genes. GSK-J4 markedly attenuated the severity of arthritis in CIA mice. In conclusion, suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.

Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an immune-mediated disease with the characteristics of progressive joint destruction, deformity, and disability. Epigenetic changes have been implicated in the development of some autoimmune disorders, resulting in an alteration of gene transcription. Here, we investigated how Jumonji C family of histone demethylases (JMJD3) regulated the proliferation and activation of fibroblast-like synoviocytes (FLSs), which are involved in RA joint destruction and pathologic process. The JMJD3 expression and proliferation markers in RA-FLS were higher than those in healthy-FLS and were upregulated in platelet-derived growth factor (PDGF)-induced FLS. Elevated JMJD3 promoted the proliferation and migration of FLS. Treatment with JMJD3 small interfering RNA or inhibitor glycogen synthase kinase (GSK) J4 led to decreased proliferation and migration of FLS. Interestingly, induction of proliferating cell nuclear antigen (PCNA), a major player of the cell-cycle regulation, was correlated with trimethylated lysine 27 in histone H3 loss around the gene promoters. The knockdown of JMJD3 abolished PCNA expression in PDGF-induced FLS and further inhibited cell proliferation and migration, suggesting that JMJD3/PCNA played a crucial role in aspects of FLS proliferation and migration. In vivo, the ability of GSK J4 to hinder collagen-induced arthritis (CIA) in DBA/1 mice was evaluated. We found that GSK J4 markedly attenuated the severity of arthritis in CIA mice. The therapeutic effects were associated with ameliorated joint swelling and reduced bone erosion and destruction. This study revealed how JMJD3 integrated with epigenetic processes to regulate RA-FLS proliferation and invasion. These data suggested that JMJD3 might contribute to rheumatoid synovial hyperplasia and have the potential as a novel therapeutic target for RA.-Jia, W., Wu, W., Yang, D., Xiao, C., Su, Z., Huang, Z., Li, Z., Qin, M., Huang, M., Liu, S., Long, F., Mao, J., Liu, X., Zhu, Y. Z. Histone demethylase JMJD3 regulates fibroblast-like synoviocyte-mediated proliferation and joint destruction in rheumatoid arthritis.

[Application of bron-kerbosch algorithm for discovery of basic formulas of traditional Chinese medicine].

OBJECTIVE: To study the feasibility of applying the Bron-Kerbosch (BK) algorithm on the discovery of basic formulas (BFs) of traditional Chinese medicine. METHOD: This essay introduces the BK algorithm for the discovery of BFs of traditional Chinese medicine and relevant indicators. On the basis of the compatibility network of drugs, with the confidence coefficient of basic formulas anti the support degree to the decline of alpha level as indicators, the BK algorithm was used for the discovery of BFs of traditional Chinese medicine. And prescriptions of Professor Ma Shaoyao, a traditional Chinese medicine (TCM) dermatologist of Longhua hospital, were taken as examples for analysis. RESULT: After the parameters were optimized, three BFs for psoriasis and four BFs for eczema were found using the BK algorithm, which had a relatively high confidence coefficient and basically conformed to the clinical practices. CONCLUSION: The BK algorithm can be used for the discovery of basic formulas (BF) of traditional Chinese medicine, and therefore it is one of the effective methods to study and summarize the diagnosis and treatment experiences and prescription thoughts of famous and experienced TCM doctors.

[Effect of intravenous drip infusion of cyclophosphamide with high-dose Astragalus injection in treating lupus nephritis].

OBJECTIVE: To observe the effect of high-dose Astragalus injection and cyclophosphamide (CTX) on infection, urine protein and immune function of the patients with lupus nephritis. METHODS: Forty-three patients diagnosed as systemic lupus erythematosus (SLE) complicated by kidney damage and qi-deficiency syndrome were randomly divided into trial group (n=23) and control group (n=20). Patients in both groups were treated for 3 months. Intravenous drip infusion of 0.8 g CTX was administered to all patients once a month, while intravenous drip infusion of 20 ml Astragalus injection was only administered to patients in the trial group every day for 12 days in each month. RESULTS: The decrease of active clinical symptom score after the treatment in the trial group was greater than that in the control group (P<0.05). The infection rates of the trial group and the control group were 4.35% and 25% respectively. The decrease of 24-hour urine protein and CD8, and the increase of red blood cell count and serum albumin in the trial group were greater than those in the control group, and there were significant differences between the two groups (P<0.05). White blood cell count in the trial group was decreased less than that in the control group after the treatment (P<0.05). CONCLUSION: High-dose Astragalus injection used together with CTX is more effective than CTX alone in decreasing infection rate and urine protein and improving immune function for patients with lupus nephritis.