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Objective: Coinhibitory signals mediated via programmed death 1 (PD-1) receptor play a critical role in downregulating immune responses and in maintaining peripheral tolerance. Programmed death 1 ligand 1 (PD-L1), the interacting ligand for PD-1, widely expressed in many cell types, acts as a tissue-specific negative regulator of pathogenic T-cell responses. We investigated the protective potential of PD-L1 on autoimmune diabetes by transgenically overexpressing PD-L1 in pancreatic beta-cells in nonobese diabetic (NOD) mice.Research Design and Methods: We established an insulin promoter-driven murine PD-L1 transgenic NOD mouse model to directly evaluate the protective effect of an organ-specific PD-L1 transgene against autoimmune diabetes. Transgene expression, insulitis, and diabetic incidence were characterized in these transgenic NOD mice. Lymphocyte development, Th1 cells, and regulatory T-cells were analyzed in these transgenic mice; and T-cell proliferation, adoptive transfer, and islet transplantation were performed to evaluate the PD-L1 transgene-mediated immune-protective mechanisms.Results: The severity of insulitis in these transgenic mice is significantly decreased, disease onset is delayed, and the incidence of diabetes is markedly decreased compared with littermate controls. NOD/SCID mice that received lymphocytes from transgenic mice became diabetic at a slower rate than mice receiving control lymphocytes. Moreover, lymphocytes collected from recipients transferred by lymphocytes from transgenic mice revealed less proliferative potential than lymphocytes obtained from control recipients. Transgenic islets transplanted in diabetic recipients survived moderately longer than control islets.Conclusions: Our results demonstrate the protective potential of transgenic PD-L1 in autoimmune diabetes and illustrate its role in downregulating diabetogenic T-cells in NOD mice. [ABSTRACT FROM AUTHOR]

Competing Interests: Competing interests: None declared.

Understanding the influence of oxygen tension on cellular functions and behaviors is crucial for investigating various physiological and pathological conditions. In vitro cell culture models, particularly those based on hydrogel extracellular matrices, have been developed to study cellular responses in specific oxygen microenvironments. However, accurately characterizing oxygen tension variations with great spatiotemporal resolutions, especially in three dimensions, remains challenging. This paper presents an approach for rapid time-lapse 3D oxygen tension measurements in hydrogels using a widely available inverted fluorescence microscope. Oxygen-sensitive fluorescent microbeads and widefield frequency-domain fluorescence lifetime imaging microscopy (FD-FLIM) are utilized for oxygen tension estimation. To incorporate the third dimension, a motorized sample stage is implanted that enables automated image acquisition in the vertical direction. A machine learning algorithm based on K-means clustering is employed for microbead position identification. Using an upside-down microfluidic device, 3D oxygen gradients are generated within a hydrogel sample, and z -stack images are acquired using the FD-FLIM system. Analyses of the acquired images, involving microbead position identification, lifetime calculation, and oxygen tension conversion, are then performed offline. The results demonstrate the functionality of the developed approach for rapid time-lapse 3D oxygen tension measurements in hydrogels. Furthermore, the 3D oxygen tension adjacent to a tumor spheroid within a hydrogel during media exchange is characterized. The results further confirm that the 3D spatiotemporal oxygen tension profiles can be successfully measured quantitatively using the established setup and analysis process and that the approach may have great potential for investigating cellular activities within oxygen microenvironments.

Oral cancer represents a global health burden, necessitating novel therapeutic strategies. Photodynamic and photothermal therapies using indocyanine green (ICG) have shown promise due to their distinctive near-infrared (NIR) light absorption characteristics and FDA-approved safety profiles. This study develops ICG-loaded liposomes (Lipo-ICGs) to further explore their potential in oral cancer treatments. We synthesized and characterized the Lipo-ICGs, conducted in vitro cell culture experiments to assess cellular uptake and photodynamic/photothermal effects, and performed in vivo animal studies to evaluate their therapeutic efficacy. Quantitative cell apoptosis and gene expression variation were further characterized using flow cytometry and RNA sequencing, respectively. Lipo-ICGs demonstrated a uniform molecular weight distribution among particles. The in vitro studies showed a successful internalization of Lipo-ICGs into the cells and a significant photodynamic treatment effect. The in vivo studies confirmed the efficient delivery of Lipo-ICGs to tumor sites and successful tumor growth inhibition following photodynamic therapy. Moreover, light exposure induced a time-sensitive photothermal effect, facilitating the further release of ICG, and enhancing the treatment efficacy. RNA sequencing data showed significant changes in gene expression patterns upon Lipo-ICG treatment, suggesting the activation of apoptosis and ferroptosis pathways. The findings demonstrate the potential of Lipo-ICGs as a therapeutic tool for oral cancer management, potentially extending to other cancer types.

This prospective longitudinal cohort study analyzed long-term changes in individual subscales of quality-of-life (QOL) measures and explored whether these changes were related to effective QOL predictors after hepatocellular carcinoma (HCC) surgery. All 520 HCC patients in this study had completed QOL surveys before surgery and at 6 months, 2 years, and 5 years after surgery. Generalized estimating equation models were used to compare the 5-year QOL among the three HCC surgical procedures. The QOL was significantly (p < 0.05) improved at 6 months after HCC surgery but plateaued at 2−5 years after surgery. In postoperative surveys, the effect size was largest in the nausea and vomiting subscales in patients who had received robotic surgery, and the effect size was smallest in the dyspnea subscale in patients who had received open surgery. It revealed the following explanatory variables for postoperative QOL: surgical procedure type, gender, age, hepatitis C, smoking, tumor stage, postoperative recurrence, and preoperative QOL. The comparisons revealed that, when evaluating QOL after HCC surgery, several factors other than the surgery itself should be considered. The analysis results also implied that postoperative quality of life might depend not only on the success of the surgical procedure, but also on preoperative quality of life.

Oxygen plays important roles in regulating various biological activities under physiological and pathological conditions. However, the response of cells facing temporal variation in oxygen microenvironments has seldom been studied due to technical limitations. In this paper, an integrated approach to studying hypoxic response under cyclic oxygen gradients is developed. In the experiments, a cell culture system based on a microfluidic device is constructed to generate cyclic oxygen gradients with desired periods by alternately introducing gases with specific compositions into the microfluidic channels next to the cell culture channel separated by thin channel walls. Observation of the hypoxic responses is performed using real-time fluorescence imaging of dyes sensitive to extra- and intracellular oxygen tensions as well as intracellular calcium concentrations. Cellular hypoxic responses of human aortic smooth muscle cells (AoSMCs) and lung carcinoma epithelium (A549) cells, including intracellular oxygen and calcium levels, are measured. The results show that the two types of cells have different hypoxic responses to the applied cyclic oxygen gradients. With the capability of real-time cellular response monitoring under cyclic oxygen gradients, the developed approach provides a useful scheme to investigate hypoxic responses in vitro under microenvironments mimicking various in vivo physiological and pathological conditions.

Background: Overall survival of systemic lupus erythematosus (SLE) patients significantly increased in recent decades, however, the relative risk of mortality is still high. Long-term survival outcome of pediatric SLE remains unclear. This study aims to explore the long-term survival rate and its predictors in patients with systemic lupus erythematosus (SLE)., Methods: A retrospective, hospital-based cohort study was performed between 2004 and 2018 in a tertiary referral medical center in Taiwan. Data on comorbidities, medications, and causes of admission were collected for risk factor analysis using time-dependent multivariate Cox proportional hazards models., Results: A total of 2392 adults and 115 pediatric SLE patients were enrolled (female, n = 2157 and 95, respectively). The 10-year survival rates were 93.2%, 90.2%, 98.9%, and 100% in adult women, adult men, girls, and boys with SLE, respectively. The overall mortality rate was 2.09 case/100 patient-years (PY) for male SLE and 1.39 case/100 PY for female SLE patients. Male SLE patients did not have a statistically significantly higher mortality rate than female SLE patients in each age stratification. Infectious disease (n = 119), heart failure (n = 21), and cerebrovascular accident (n = 14) were the leading causes of death in adult SLE patients. Advanced age (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.03-1.05), treatment with mean dosage of systemic glucocorticoid equivalent to >10 mg/d of prednisolone (HR: 1.71, 95% CI: 1.14-2.57), comorbidities with malignancy (HR: 1.94, 95% CI: 1.22-3.09), chronic kidney disease (HR: 1.86, 95% CI: 1.25-2.77), hypertension (HR: 1.42, 95% CI: 1.01-1.98), and admission due to bacterial pneumonia (HR: 1.92, 95% CI: 1.12-3.31) and sepsis (HR: 2.78, 95% CI: 1.51-5.13) were independent risk factors for mortality in SLE patients., Conclusion: SLE patients with advanced age, malignancy, chronic kidney disease, hypertension, treated with a higher average dosage of glucocorticoids, and admission due to bacterial pneumonia and sepsis have an increased risk of mortality., Competing Interests: Conflicts of interest: Dr. Chang-Youh Tsai and Dr. Deh-Ming Chang, editorial board members at Journal of the Chinese Medical Association, have no roles in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Objective: Phthalates induce inflammation and are ubiquitously used in daily life. We aim to study the impact of di-(2-ethylhexyl) phthalate (DEHP) exposure on inflammation and osteoporosis in premenopausal and postmenopausal females., Methods: Female 8-week-old C57BL/6JNarl mice received an ovariectomy (OVX) or a sham operation and were fed with DEHP or vehicle by oral gavage for 4 or 8 weeks. Their femurs were isolated for micro-computed tomography, and their serum was collected for inflammatory cytokine assays. Correlations between urinary phthalate metabolites and the lumbar spine bone mineral density (BMD) in premenopausal and postmenopausal volunteers were performed., Results: Among the OVX mice treated for 4 weeks, significant lower bone volume, bone volume/tissue volume, and trabecular number but significant higher trabecular bone pattern factor and structure model index were identified in the mice treated with DEHP than with vehicle. The OVX mice treated with DEHP for 4 weeks had significantly higher serum interleukin (IL)-1β, IL-10, IL-17A, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and Dickkopf-1 levels than those treated with vehicle. The sham mice treated with DEHP for 8 weeks showed an impaired femur trabecular microstructure and had significantly higher serum IL-1β, IL-6, IL-10, IL-17A, IFN-γ, and TNF-α than those treated with vehicle. DEHP metabolites were inversely correlated with the BMD of premenopausal women and the T-score of postmenopausal women., Conclusion: DEHP treatment in OVX and sham mice results in osteoporosis and impairs the microstructure of the femur trabecula through inflammation. Phthalate exposure negatively affects the bone mass in both premenopausal and postmenopausal women. Thus, long-term avoidance is suggested., (© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Nonradiographic axial spondyloarthropathies (nr-axSpA) are diagnosed by the absence of radiographic sacroiliitis and the presence of bone marrow edema (BME) on magnetic resonance imaging (MRI). According to the classification criteria of the international Assessment of Spondyloarthritis Society (ASAS), structural changes to sacroiliac joints (SIJs) on MRI cannot be used as criteria in the absence of BME. However, less than half the Asian patients with clinically active axSpA show BME. The incidence of human leukocyte antigen (HLA)-B27 is low in Asian populations, which makes it more difficult to identify nr-axSpA. We used MRI to evaluate the structural damage to SIJs in patients with nr-axSpA with and without BME with the aim of identifying the best methodology for accurate diagnosis, especially in populations with less common BME and HLA-B27., Methods: One hundred three patients with inflammatory back pain were included in this prospective study. No patient's radiograph met the definition of positive modified New York criteria. BME and structural damage to SIJ including sclerosis and erosion were assessed independently on coronal and axial short-tau inversion recovery and T1-weighted spin echo MRI scans by two well-trained musculoskeletal radiologists using the Spondyloarthritis Research Consortium of Canada (SPARCC) score. Demographics of patients were collected. Disease characteristics and structural damage were analyzed in patients with and without BME on SIJ MRI. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of structural damage., Results: All individuals in the cohort had at least one abnormal finding on SIJ MRI, including BME or structural damage; 36 of 103 patients had BME. We identified a significant positive correlation between SPARCC scores and severe erosion assessed by focal joint space widening (fJSW) (p = 0.001) in these 36 patients. Fifty-eight of the 103 enrolled patients fulfilled the ASAS criteria for nr-axSpA in the either absence or presence of BME. Of these 58 patients, 57 and 19 had erosions or fJSW, respectively, and the presence of BME was significantly correlated with fJSW (phi score of 0.319 and p = 0.015). We demonstrated a significant positive correlation between fJSW and either the presence or the severity of BME in patients with nr-axSpA who met the ASAS definition. There was a positive correlation between BME and fJSW across the whole study cohort (phi score of 0.389; p < 0.001). The area under the ROC curve (AUC) for fJSW on SIJ MRI was 0.736, p < 0.001. In both HLA-B27-positive and -negative groups, BME was more common in the presence of fJSW (phi scores of 0.370 and 0.377, p = 0.018 and 0.003, respectively) and SPARCC scores were higher in patients with fJSW (p < 0.001 and p = 0.005). We also identified a positive correlation between fJSW and BME in patients with nr-axSpA and normal serum levels of C-reactive protein (phi score of 0.362 and p = 0.001)., Conclusion: Structural damage detected on SIJ MRI, sclerosis, erosions and fJSW may be present in patients without detectable inflammation on SIJ MRI. However, fJSW is significantly correlated with the severity of inflammation seen on SIJ MRI, which contributes to the accurate diagnosis of nr-axSpA, and it could be used as an alternative diagnostic test for nr-axSpA in the general population, especially for those who do not carry the HLA-B27 gene, Asian patients without BME, or patients with normal serum inflammatory biomarkers., (© 2021. The Author(s).)

Rice bran contains lipolytic enzymes with extremely high activity that facilitate the hydrolysis of triglycerides into glycerol and fatty acids. This also causes rice bran to easily deteriorate, limiting its use, and they are not popular in the market. Researchers look forward to seeing the refined rice brans work well for metabolic syndrome. This study used gas cooling by liquid nitrogen and an instant sterilization system operated at high temperature to stabilize and refine the rice bran. The refined rice bran was compared using in vitro tests with three other types of rice bran that had not been specially treated. The refined rice bran was discovered to have superior solubility, fast absorption, and excellent oxidation resistance compared with the other three rice bran samples. In a human subject test, significant improvements in waistline, systolic pressure, diastolic pressure, fasting plasma glucose, glycated hemoglobin, and triglyceride level were discovered after participants ingested refined rice bran for 8 weeks. This indicated that consuming refined rice bran can reduce the waistline, control blood pressure and blood glucose, and inhibit fate formation. The items for which significance was obtained are also the indicators of metabolic syndrome, as stipulated by the World Health Organization. Therefore, according to the results of the human subject test, ingesting refined rice bran can improve the metabolic syndrome. PRACTICAL APPLICATIONS: This refinement improved the in vivo absorption and stabilized the properties of the rice bran for better preservation. In this study, excellent results were obtained using the refined rice bran in both in vitro tests and a human subject test. Refined rice bran thus has potential for mass production and used as a health supplement. It can alleviate the symptoms of metabolic syndrome and reduce the incidence of cardiovascular diseases., (© 2020 Wiley Periodicals LLC.)

Background: The autoimmune disease rheumatoid arthritis (RA) affects approximately 1% of the global population. RA is characterized with chronic joint inflammation and often associated with chronic pain. The imbalance of pro-inflammatory and anti-inflammatory macrophages is a feature of RA progression. Glial cells affecting neuronal sensitivity at both peripheral and central levels may also be important for RA progression and associated pain. Genetic variants in the T cell death-associated gene 8 (TDAG8) locus are found to associate with spondyloarthritis. TDAG8 was also found involved in RA disease progression and associated hyperalgesia in the RA mouse model. However, its modulation in RA remains unclear., Methods: To address this question, we intra-articularly injected complete Freund's adjuvant (CFA) into TDAG8 +/+ , TDAG8 -/- or wild-type mice, followed by pain behavioral tests. Joints and dorsal root ganglia were taken, sectioned, and stained with antibodies to observe the number of immune cells, macrophages, and satellite glial cells (SGCs). For compound treatments, compounds were intraperitoneally or orally administered weekly for 9 consecutive weeks after CFA injection., Results: We demonstrated that TDAG8 deletion slightly reduced RA pain in the early phase but dramatically attenuated RA progression and pain in the chronic phase (> 7 weeks). TDAG8 deletion inhibited an increase in SGC number and inhibition of SGC function attenuated chronic phase of RA pain, so TDAG8 could regulate SGC number to control chronic pain. TDAG8 deletion also reduced M1 pro-inflammatory macrophage number at 12 weeks, contributing to the attenuation of chronic RA pain. Such results were further confirmed by using salicylanilide derivatives, CCL-2d or LCC-09, to suppress TDAG8 expression and function., Conclusions: This study demonstrates that TDAG8 deletion reduced SGC and M1 macrophage number to relieve RA disease severity and associated chronic pain. M1 macrophages are critical for the development and maintenance of RA disease and pain, but glial activation is also required for the chronic phase of RA pain.

Background: Areca nut has anti-inflammatory, antiparasitic, antihypertensive, and antidepressant properties. The pathological hallmarks of inflammatory joint diseases are an increased number of osteoclasts and impaired differentiation of osteoblasts, which may disrupt the bone remodeling balance and eventually lead to bone loss., Purpose: The present study assessed the effects of arecoline, the main alkaloid found in areca nut, on osteoclast and osteoblast differentiation and function., Method: M-CSF/RANKL-stimulated murine bone marrow-derived macrophages (BMMs) were incubated with several concentrations of arecoline, and TRAP staining and pit formation were assessed to monitor osteoclast formation. Quantitative real-time RT-PCR and western blot analyses were used to analyze the expression of osteoclast-associated genes and signaling pathways. The effects of arecoline on bone were investigated in an in vivo mouse model of lipopolysaccharide (LPS)-induced trabecular bone loss after oral administration of arecoline. Alizarin red S staining and assays to measure ALP activity and the transcription level of osteoblast-related genes were used to evaluate the effects of arecoline on osteoblast differentiation and bone mineralization., Results: In a dose-dependent manner, arecoline at concentrations of 50-100 μM reduced both the development of TRAP-positive multinucleated osteoclasts and the formation of resorption pits in M-CSF/RANKL-stimulated BMMs. In M-CSF/RANKL-stimulated BMMs, arecoline also suppressed the expression and translocation of c-Fos and NFATcl, and osteoclast differentiated-related genes via interference with the AKT, MAPK, and NF-kB activation pathways. Femur bone loss and microcomputed tomography parameters were recovered by oral administration of arecoline in the mouse LPS-induced bone loss model. Lastly, arecoline increased ALP activity, bone mineralization, and the expression of osteoblast differentiation-related genes, such as ALP and Runx2, in MC3T3-E1 cells., Conclusion: Our data suggest that arecoline may attenuate or prevent bone loss by suppressing osteoclastogenesis and promoting osteoblastogenesis. These findings provide evidence supporting arecoline's use as a potential therapeutic agent in bone-loss disorders and diseases., Competing Interests: Declaration of Competing Interest The authors have declared no conflicts of interest., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Background: Patients who have symptoms of sicca, such as dry eyes and mouth, may have Sjögren's syndrome (SS). However, the conservative culture makes patients hesitate to undergo an invasive biopsy, which contributes to the difficulty of confirming a diagnosis. We aimed to identify the characteristics of patients with sicca symptoms to develop a better predictive value for each item included in the three different diagnostic criteria for SS and clarify the best diagnostic tools for the local population., Methods: This is a single-center retrospective case-control study from January 2016 to December 2017. Patients who underwent sialoscintigraphy because of clinical symptoms of xerostomia and xerophthalmia at one medical center were reviewed via the patients' electronic medical records., Results: Of 515 patients enrolled, the severity of results for sialoscintigraphy and Schirmer's test was correlated with a diagnosis of SS and generated receiver operator characteristic curve. The area under curve (AUC) was 0.603 for positive Schirmer's test, 0.687 for positive anti-Ro/La results, 0.893 for a positive salivary gland biopsy. The AUC was 0.626 and 0.602 for Schirmer's test which is redefined as <10 mm/5 minutes in either eye and according to 2016 the American College of Rheumatology/ European League Against Rheumatism criteria, respectively., Conclusion: Our results indicate the cut-off point for defining a positive test result in the Schirmer's test is worth modified to <10 mm/5 minutes in either eye., (Copyright © 2019. Published by Elsevier B.V.)

Aim: Mood disorders are a serious issue for patients with rheumatoid arthritis (RA) because poor mental health can exacerbate the disease course. This study aimed to identify the effect of proinflammatory cytokines on the mood of patients with RA., Methods: This study was conducted at a rheumatology clinic in Northern Taiwan. In total, 113 patients with RA and 42 healthy controls were assessed for anxiety and depression symptoms using Hospital Anxiety and Depression Scale (HADS). RA was assessed using the Disease Activity Score of 28 joints (DAS28). Serum proinflammatory cytokine levels, including interleukin (IL)-1β, IL-6, IL-17 and tumor necrosis factor alpha (TNF-α) were measured and compared between different patient groups according to disease activity and pain level., Results: Serum IL-1β, IL-6, IL-17 and TNF-α levels were significantly higher in patients with RA than in healthy controls, as were the mean anxiety and depression subscale scores. In patients with RA who had different disease activities, pain severity correlated with both anxiety and depression symptoms. When HADS scores were analyzed according to pain levels, age was correlated with depression in the severe pain group. In the mild pain group, patients with higher IL-6 or higher IL-17 had a higher risk of depression. There was no correlation between mood symptoms and cytokine levels in healthy controls., Conclusion: Elevated serum IL-6 and IL-17 levels in patients with RA induce arthritis and cause mood symptoms, especially depression symptoms., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: Deletion of Deltex1 (DTX1) in mice caused hyperactivation of T cells and lupus-like autoimmune syndromes, however, the association of DTX1 with human autoimmune diseases is totally unknown. This study investigated the role of DTX1 in human T cell functions and its correlation with disease activity in patients with SLE., Methods: The influence of DTX1 on T cell function was evaluated using human primary cells. DTX1 expression in peripheral blood mononuclear cells (PBMCs) from healthy controls and SLE patients was measured by quantitative real-time PCR and the SLEDAI was used to assess disease activity., Results: After stimulation with anti-CD3 and anti-CD28, silencing of DTX1 expression enhanced IFN-γ secretion by human T cells. The expression of DTX1 in PBMCs was significantly lower in 100 SLE patients than in 50 age- and sex-matched healthy controls (DTX1/glyceraldehyde 3-phosphate dehydrogenase, 0.452 vs 1.269, P < 0.001). The area under the receiver operator characteristics curve of the model was 0.737 (95% CI 0.658, 0.815). Intriguingly, a low DTX1 level in T cells led to high IFN-γ production in SLE patients and had a correlation with severe disease activity. In addition, low DTX1 expression in SLE patients was associated with active LN, lung involvement or hypocomplementaemia., Conclusion: Knockdown DTX1 expression in human T cells reduced IFN-γ secretion. DTX1 expression in the PBMCs was significantly lower in SLE patients and had an inverse correlation with disease activity, indicating that the DTX1 level may be a good disease marker of SLE., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Serum cytokeratin-18 is believed to be a marker of hepatic cell damage. However, few studies have discussed about the serum cytokeratin-18 concentration in type 2 diabetes mellitus patients and investigated its association with non-alcoholic fatty liver disease as well as metabolic biomarkers., Methods: Healthy participants and type 2 diabetes mellitus patients were enrolled. Physical and metabolic factors were recorded, and non-alcoholic fatty liver disease was screened by abdominal ultrasound and the fatty liver index. The cytokeratin-18 concentration was detected using two commercially available immunoassay kits (M30 and M65 ELISA kit, Previa AB, Sweden)., Results: Overall, 22.8% (29/127) and 35.9% (42/117) of the participants were diagnosed with non-alcoholic fatty liver disease in the non-diabetes mellitus group and type 2 diabetes mellitus group, respectively. In the non-diabetes mellitus group and type 2 diabetes mellitus group, our result showed that participants with non-alcoholic fatty liver disease had a higher serum cytokeratin-18 M30 and cytokeratin-18 M65 concentration as compared with participants without non-alcoholic fatty liver disease. Interestingly, as compared with healthy participants without non-alcoholic fatty liver disease, our result also demonstrated that type 2 diabetes mellitus patients without non-alcoholic fatty liver disease had a higher serum cytokeratin-18 M30 (108.4 ± 66.2 vs. 87.1 ± 34.6 U/L; P = 0.038) and cytokeratin-18 M65 concentration (285.4 ± 115.3 vs. 248.5 ± 111.3 U/L; P = 0.031). The independent relationship between type 2 diabetes mellitus and cytokeratin-18 was further strengthened by the significant positive association between fasting plasma glucose and serum cytokeratin-18 concentration via multivariate regression analyses (cytokeratin-18 M30: β = 0.034, P = 0.029; cytokeratin-18 M65: β = 0.044, P = 0.002)., Conclusions: Independent of non-alcoholic fatty liver disease, our results suggested that the cytokeratin-18 concentration is closely associated with the hyperglycaemic milieu. The association between serum cytokeratin-18 and type 2 diabetes mellitus may be worthy of further investigation.

We evaluated plasma glutamine levels and basal mitochondrial oxygen consumption rate (mOCR B ) and basal extracellular acidification rate (ECAR B ) of peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients and healthy controls (HCs). Lower plasma glutamine levels correlated with higher SLE disease activity indexes (p=0.025). Incubated in DMEM containing 100mg/dL glucose, SLE-PBMCs displayed lower mOCR B (p=0.018) but similar ECAR B (p=0.467) to those of HC-PBMCs, and their mOCR B got elevated (p<0.001) without altering ECAR B (p=0.239) by supplementation with 2 or 4mM glutamine. We conclude that impaired mitochondrial respiration of SLE-PBMCs could be improved by glutamine under euglycemic condition., (Copyright © 2018. Published by Elsevier B.V.)

Background: Laparoscopic sleeve gastrectomy (LSG) has been validated as a safe and effective treatment for morbid obesity. However, data of the long-term outcome remains lacking., Methods: A total of 1759 LSG was performed as primary bariatric procedure from 2005 to 2017 with mean age of 35.2 ± 10.3 years old (14-71), female 69.7%, mean body mass index (BMI) 37.9 ± 7.7 kg/m 2 , and mean waist width 113.7 ± 17.9 cm. All patients were evaluated and managed under a strict multidisciplinary team approach. A retrospective analysis of a prospective bariatric database and telephone interview of patients who defaulted clinic follow-up at 10 years was conducted., Results: The mean operating time, intraoperative blood, and hospital stay of LSG were 121.5 ± 36.5 min, 40.8 ± 69.7 ml, and 2.8 ± 2.7 days, respectively. The 30-day postoperative major complication occurred in 25 (1.4%) patients. The major complication rate was 15% at first year and 0% at the last year. The follow-up rate at 1, 5 and 10 years were 89.3%, 52.1 and 64.4%. At postoperative 1, 5, and 10 years, the mean percentage of total weight loss (%TWL) and excess weight loss (EWL%) of LSG patients were 33.4, 28.3, and 26.6% and 92.2, 80.1, and 70.5%, respectively. The mean BMI became 27, 26.2, and 27.1 kg/m 2 at postoperative 1, 5, and 10 years. At follow-up, a total 69 patients needed surgical revision due to reflux disease (n = 45), weight regain (n = 19), persistent diabetes (n = 2), and chronic fistula (n = 3). The type of revision procedures were hiatal repair and gastropexy (n = 29), Roux-en Y gastric bypass (RYGB) (n = 23), and single anastomosis bypass (n = 17) with median time to revision 33 months (range 3-62). At 10 years, the overall revision rate was 21.5% (14/65) and 11(16.9%) of 65 patients were converted to RYGB. The other 54 patients remained at LSG anatomy, but 45% of them required proton pump inhibitor for reflux symptoms., Conclusions: Our results showed that primary LSG is a durable primary bariatric procedure with sustained weight loss and a high resolution of comorbidities at 10 years, but about half the patients had de novo GERD. The need for conversion to RYGB was 16.9% at 10 years.

SUMOylation is involved in the development of several inflammatory diseases, but the physiological significance of SUMO-modulated c-Maf in autoimmune diabetes is not completely understood. Here, we report that an age-dependent attenuation of c-Maf SUMOylation in CD4+ T cells is positively correlated with the IL-21-mediated diabetogenesis in NOD mice. Using 2 strains of T cell-specific transgenic NOD mice overexpressing wild-type c-Maf (Tg-WTc) or SUMOylation site-mutated c-Maf (Tg-KRc), we demonstrated that Tg-KRc mice developed diabetes more rapidly than Tg-WTc mice in a CD4+ T cell-autonomous manner. Moreover, SUMO-defective c-Maf preferentially transactivated Il21 to promote the development of CD4+ T cells with an extrafollicular helper T cell phenotype and expand the numbers of granzyme B-producing effector/memory CD8+ T cells. Furthermore, SUMO-defective c-Maf selectively inhibited recruitment of Daxx/HDAC2 to the Il21 promoter and enhanced histone acetylation mediated by CREB-binding protein (CBP) and p300. Using pharmacological interference with CBP/p300, we illustrated that CBP30 treatment ameliorated c-Maf-mediated/IL-21-based diabetogenesis. Taken together, our results show that the SUMOylation status of c-Maf has a stronger regulatory effect on IL-21 than the level of c-Maf expression, through an epigenetic mechanism. These findings provide new insights into how SUMOylation modulates the pathogenesis of autoimmune diabetes in a T cell-restricted manner and on the basis of a single transcription factor.

Introduction: Multidrug-resistant Acinetobacter baumannii (MDRAB) pneumonia with severe sepsis in a patient with rheumatoid arthritis (RA), who is predisposed after treatment with tumor necrosis factor inhibitor (TNFI), is a rare severe infection and can be successfully treated with prompt antibiotics., Case Presentation: A 75-year-old woman was diagnosed with RA >30 years previously. After inadequate treatment responses to conventional disease-modifying antirheumatic drugs (DMARDs), she developed progressive RA, including swollen joints in both hands, and had a high disease activity score of 4.96 when presenting at our rheumatology clinic. She had started taking the TNFI, golimumab (50 mg/month), 3 years before and developed a productive cough 4 weeks before this admission. One week after admission, she developed fever, dyspnea, hypoxemia, tachycardia, and increased serum C-reactive protein level., Diagnosis: Chest plain film (CxR) and computed tomography of the chest showed hospital-acquired pneumonia; microbial examination of the sputum showed the presence of MDRAB., Therapeutics: She was prescribed a full course of antibiotics with cefoperazone sulbactam., Outcomes: CxR showed complete remission of pneumonia., Conclusion: Biological DMARDs, such as TNFI, act as a double-edged sword: these drugs are used to treat autoimmune diseases, but they increase the risk of infection. The trend toward antibiotic resistance and persistent environmental survival of MDRAB is an emerging problem in countries with high rates of antibiotic abuse. TNFI may affect intestinal immunity by inducing dysbiosis, which affects T helper 17-mediated mucosal immunity and can contribute to A baumannii colonization and the development of MDRAB in frequently hospitalized patients.

A sensitive tapered optical fiber tip combined with dielectrophoretic (DEP) trapping was used for rapid and label-free detection of bacteria in water. The angular spectrum of the optical field at the fiber tip was changed with the surrounding refractive index (RI). By measuring far-field intensity change at the defocus plane, the intensity sensitivity was up to 95 200%/RIU (RI unit), and the detection limit was 5.2 × 10 -6 RIU at 0.5% intensity stability. By applying an AC voltage to a Ti/Al coated fiber tip and an indium-tin-oxide glass, the DEP force effectively trapped the Escherichia coli ( E. coli) near the fiber tip. Those bacteria can be directly measured from optical intensity change due to the increase of surrounding RI. By immobilizing the antibody on the Ti/Al fiber tip, the tests for specific K12 bacteria and nonspecific BL21 bacteria verified the specificity. The antibody-immobilized Ti/Al coated fiber tip with DEP trapping can detect bacteria at a concentration about 100 CFU/mL.

Background/purpose: To analyze the real-world clinical practice for the treatment of psoriatic arthritis (PsA) and to assess physicians' prescription, difficulties in diagnosis, therapeutic strategy, rationales for biologic therapies and unmet needs in Taiwan., Methods: We conducted a nationwide cross-sectional observational study by face-to-face in depth interviews with 50 rheumatologists and 30 dermatologists who took care of patients with PsA., Results: The major procedures for recognizing PsA included joint, skin and nail examinations, radiographic imaging, and medical history. More dermatologists established the diagnosis when psoriatic patients with arthritis didn't present with rheumatoid factors (p < 0.05). For milder arthritis, physicians tended to prescribe etanercept in combination with conventional disease-modifying antirheumatic drugs (DMARDs). The efficacy, safety, retention rate, and non-parenteral administration are the major concerns of physicians which are also the primary unmet needs in the current management of PsA., Conclusion: This survey showed the status quo in Taiwan of the clinical management for PsA including diagnostic difficulties, therapeutic consideration, rationales for biologic DMARDs selection and unmet needs in treatment. It has indicated that interdisciplinary collaboration may further improve the quality for PsA care. These results may help establish new strategy to develop next generation biologics., (Copyright © 2017. Published by Elsevier B.V.)

The bone destruction disease including osteoporosis and rheumatoid arthritis are caused by the imbalance between osteoblastogenesis and osteoclastogenesis. Inhibition of the NF-κB pathway was responsible for decreased osteoclastogenesis. Recently many studies indicated that niclosamide, the FDA approved an antihelminth drug, inhibits prostate and breast cancer cells growth by targeting NF-κB signaling pathways. This study evaluated the effects of niclosamide on osteoclast and osteoblast differentiation and function in vitro. In RANKL-induced murine osteoclast precursor cell RAW264.7 and M-CSF/RANKL-stimulated primary murine bone marrow-derived macrophages (BMM), niclosamide dose-dependently inhibited the formation of TRAP-positive multinucleated osteoclasts and resorption pits formation between 0.5uM and 1uM. In addition, niclosamide suppressed the expression of nuclear factor of activated T cells c1 (NFATc1) and osteoclast differentiated-related genes in M-CSF/ RANKL-stimulated BMM by interference with TRAF-6, Erk1/2, JNK and NF-κB activation pathways. However, the cytotoxic effects of niclosamide obviously appeared at the effective concentrations for inhibiting osteoclastogenesis (0.5-1uM) with increase of apoptosis through caspase-3 activation in osteoblast precursor cell line, MC3T3-E1. Niclosamide also inhibited ALP activity, bone mineralization and osteoblast differentiation-related genes expression in MC3T3-E1. Therefore, our findings suggest the new standpoint that niclosamide's effects on bones must be considered before applying it in any therapeutic treatment., Competing Interests: Competing Interests: The authors have declared no conflicts of interest.

Aims: Clinical outcome may differ owing to the distinct pharmacological characteristics of insulin sensitizers and insulin. This study was performed to compare the metabolic and renal function changes with add-on pioglitazone treatment versus basal insulin in patients with type 2 diabetes mellitus (DM) in whom sulfonylurea and metformin regimens failed., Methods: Patients who were consecutively managed in the diabetes comprehensive program with add-on pioglitazone or detemir/glargine treatment for at least 2 years following sulfonylurea and metformin treatment failure were included., Results: A total of 1002 patients were enrolled (pioglitazone: 559, detemir: 264, glargine: 179). After propensity score matching, there were 105 patients with matchable baseline characteristics in each group. After a mean of 3.5 years of follow-up, the pioglitazone group showed a greater HbA1c reduction than the detemir group and the glargine group. Despite patients in all three groups exhibiting significant body weight gain, those in the pioglitazone group and the glargine group showed greater body weight increases than the patients in the detemir group (2.1, 1.6 and 0.8 kg, respectively, p < 0.05). Interestingly, Cox regression analysis indicated that patients under detemir or glargine treatment had a higher probability of CKD progression as compared with the pioglitazone group, with hazard ratios of 2.63 (95% CI 1.79-3.88) and 3.13 (95% CI 2.01-4.87), respectively., Conclusions: Our study first showed that treatment with both pioglitazone and basal insulin improved glycemic control, while only pioglitazone treatment was observed to be advantageous in terms of preserving renal function when used as an add-on therapy for patients with type 2 DM in whom sulfonylurea and metformin regimens failed.

We evaluated plasma IL-10, IFN-alpha, IL-23, IFN-gamma, IP-10, MCP-1, 8-OHdG, leukocyte mtDNA, serum anti-dsDNA antibodies and disease activity index (SLEDAI) in SLE patients. 93 patients (35 nephritis, 4 under dialysis, 5 under rituximab) and 50 healthy controls were recruited. Compared with healthy controls, SLE patients had higher IL-10, IFN-alpha, IL-23, IFN-gamma, IP-10 and MCP-1 ( p <0.05). High IFN-alpha ( p =0.031) and IP-10 ( p =0.026) correlated with high SLEDAI; high IFN-alpha ( p< 0.001), IL-23 ( p =0.023) and IP-10 ( p< 0.001) correlated with high anti-dsDNA. High IL-10 ( p =0.014), IL-23 ( p< 0.001), IFN-gamma ( p< 0.001) and MCP-1 ( p =0.002) correlated with high 8-OHdG and high IL-23 ( p <0.001), INF-gamma ( p <0.001), IP-10 ( p =0.023) and MCP-1 ( p =0.002) correlated with low leukocyte mtDNA. mtDNA 4977 deletion correlated with high mtDNA ( p =0.011) and low IL-10 ( p =0.009). MCP-1 ( p =0.043) decreased after rituximab therapy. 54 SLE patients without nephritis, 35 with nephritis but without dialysis, and 4 with nephritis under dialysis exhibited stepwise increases in IL-23 ( p =0.009) and MCP-1 ( p =0.015). These data suggest that oxidative DNA and mtDNA alterations and coordinate changes in cytokines/chemokines are implicated in progression of SLE and rituximab in amelioration of SLE.

Background . It has been reported that circRNAs are differentially expressed in a wide range of cancers and could be used as a new biomarker for diagnosis. However, the correlation between circRNAs and gastric cancer (GC) it is still unclear. Materials and Methods . In this study, by using real-time quantitative reverse transcription-polymerase chain reactions (qRT-PCRs), we detected the expression level of hsa&#95;circ&#95;0001649 in tissue and serum samples from GC patients. Results . We found that hsa&#95;circ&#95;0001649 expression was significantly downregulated in GC tissue compared with their paired paracancerous histological normal tissues (PCHNTs) ( P < 0.01). We next analyzed the expression level of hsa&#95;circ&#95;0001649 in serum samples between preoperative and postoperative GC patients. We found that its level in serum was significantly upregulated after surgery ( P < 0.01). The area under the receiver operating characteristic (ROC) curve was 0.834. Moreover, the expression level of hsa&#95;circ&#95;0001649 was significantly correlated with pathological differentiation ( P = 0.039). Conclusion . Our test suggested that hsa&#95;circ&#95;0001649 was significantly downregulated in GC and may become a novel potential biomarker in the diagnosis of GC., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Objectives: Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150 kb flanking regions containing NMNAT2 and SMG7 in a 15 292 case-control multi-ancestry population and tested functions of identified variants., Methods: We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA., Results: We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10 -8 , OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10 -3 and 6.8×10 -8 , respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=-0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10 -5 and 2.0×10 -4 , respectively)., Conclusion: We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives: Interstitial lung disease (ILD) is one of the major systemic manifestations of primary Sjögren's syndrome (pSS). The aim of this study was to evaluate the therapeutic effect of rituximab on pSS patients with ILD., Methods: Pulmonary function test results, including diffusing capacity for carbon monoxide (DLCO) and DLCO/alveolar volume (Va) ratio, and high-resolution computed tomography (HRCT) findings/scores in ten pSS patients with ILD treated with rituximab were retrospectively investigated. Global disease, fatigue, dryness of eyes and mouth, shortness of breath, and cough were assessed by visual analogue scales (VAS, 0-100 mm)., Results: At 6 months after rituximab treatment, improvement in pulmonary function was observed (from 49.3±12.6 to 56.9±11.4% for DLCO, p=0.011; from 74.4±15.8 to 85.6±10.3% for DLCO/Va, p=0.021). Similarly, significant improvement of subjective symptoms were also noted after treatment (VAS global disease, from 62.0±11.4 to 26.0±10.8 mm, p<0.001; VAS fatigue, from 38.0±23.0 to 18.0±7.9 mm, p=0.006; VAS dryness of eyes, from 53.0±24.4 to 29.0±13.7 mm, p=0.004; VAS dryness of mouth, from 45.0±14.3 to 28.0±9.2 mm, p=0.001; VAS shortness of breath, from 64.0±16.5 to 31.0±16.0 mm, p<0.001; VAS cough, from 42.0±23.5 to 18.0±10.3 mm, p=0.011). The mean HRCT score decreased after rituximab therapy although to a lesser extent (from 8.7±4.1 to 7.6±4.6, p=0.419). An adverse event was observed in only one patient who had non-fatal pneumonia 4 months after rituximab infusion., Conclusions: Rituximab was effective in improving clinical symptoms and gas exchange, and in stabilising HRCT score in pSS patients with ILD.

Study Objectives: To explore associations between obstructive sleep apnea (OSA) and autoimmune diseases and evaluate whether OSA management reduces the incidence of autoimmune diseases., Methods: This was a retrospective cohort study using nationwide database research. The data was from 105,846 adult patients in whom OSA was diagnosed and recorded in the Taiwan National Health Insurance Research Database between 2002 and 2011 were the patients were analyzed retrospectively. Patients with antecedent autoimmune diseases were excluded. A comparison cohort of 423,384 participants without OSA served as age- and sex-matched controls. Multivariable Cox regression analysis was performed on both cohorts to compute risk of autoimmune diseases during follow-up. Time-dependent OSA treatment effect was analyzed among patients with OSA. There were no interventions., Results: Among patients with OSA, overall risk for incident autoimmune diseases was significantly higher than that in controls (adjusted hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.66-2.27). Risk for individual autoimmune diseases, including rheumatoid arthritis (RA), Sjögren syndrome (SS), and Behçet disease, was significantly higher in patients with OSA than in controls (HRs [95% CI]: RA 1.33 [1.03-1.72, SS 3.45 [2.67-4.45] and Behçet disease 5.33 [2.45-12.66]). Increased risk for systemic lupus erythematosus (HR 1.00 [0.54-1.84]) and systemic sclerosis (HR 1.43 [0.51-3.96]) did not reach statistical significance. Patients with OSA receiving treatment had an overall reduced risk of RA and other autoimmune diseases (time-dependent HRs [95% CI]: 0.22 [0.05-0.94] and 0.51 [0.28-0.92], respectively)., Conclusions: Patients with OSA are associated with higher risk for developing RA, SS, and Behçet disease. OSA management is associated with reduced risk of RA., (© 2016 Associated Professional Sleep Societies, LLC.)

Background: To investigate the association of serum uric acid level with renal function change in patients with type 2 diabetes mellitus (T2DM)., Methods: T2DM patients who had been followed-up for at least 3 years were included. Participants were categorized into stable, progression, or regression groups according to their change in chronic kidney disease (CKD) stage. During the follow-up period, all numeric values of metabolic factors, including the uric acid level and the medication possession rate, were calculated in order to investigate their associations with CKD development. Multivariate Cox regression analyses were used to identify independent factors associated with change in CKD., Results: A total of 2367 T2DM patients were enrolled in this study and followed-up for a mean of 4.6 years. The numbers of patients in the stable, progression and regression groups were 1133 (47.9%), 487 (20.6%), and 747 (31.5%), respectively. The progression group had the highest serum uric acid level (6.9 ± 1.8 mg/dL), and the regression group had the lowest uric acid level (5.4 ± 1.5 mg/dL). In addition, we found that the serum uric acid level was an independent factor associated with CKD progression when the value exceeded 6.3 mg/dL. A lower uric acid level could be beneficial for CKD improvement in T2DM patients with stage 3-5 CKD., Conclusions: Our data indicated that the serum uric acid level is associated with CKD regression and progression and suggested that a high normal serum uric acid level should be closely monitored in patients with T2DM. Copyright © 2015 John Wiley & Sons, Ltd., (Copyright © 2015 John Wiley & Sons, Ltd.)

SLE is characterized by an increased production of detrimental autoantigens, exaggerated effects of pro-inflammatory cytokines, dysregulated functioning of immunocompetent cells including lymphocytes and leukocytes, and devastating tissue and organ damage. All of these derangements can be potentiated or attenuated by the abnormal energy expenditure and overproduction of reactive oxygen species (ROS). Mitochondrial heteroplasmy or dysfunction has been recognized to play a role in these abnormalities. Abnormal redox reaction, decreased functioning of biogenesis-related enzymes, increased NETosis, harmful cytokine effects, and aberrant lymphocyte behavior have been shown to be associated with the pathological state of mitochondria. There is accumulating data which support the importance of abnormal oxygen metabolism and mitochondrial disorders in the immunopathogenesis of SLE. Further laboratory as well as clinical data are required to expand our understanding of SLE pathogenesis., (Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Inhibiting osteoclastogenesis is a promising therapeutic target for treating osteoclast-related diseases. Herein, we synthesized a series of modified salicylanilides and their corresponding 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione and 10-phenyldibenzo[b,f][1,4]oxazepin-11(10H)-one derivatives, and investigated the effects of such compounds on RANKL-induced osteoclast formation. Among them, a salicylanilide derivative (A04) and its 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivative (B04) markedly suppressed RANKL-induced osteoclast differentiation and showed no significant cytotoxic effects at doses higher than that required to inhibit osteoclast formation. Both compounds reduced osteoclast formation and bone resorptive activity of osteoclasts in a dose-dependent manner. Further, the anti-osteoclastogenic effects of A04 and B04 may operate through reducing the RANKL-induced nuclear translocation of NFATc1. Accordingly, we present the potent anti-osteoclastogenic compounds A04 and B04 as promising candidates for further optimization as anti-resorptive agents., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

A series of 1-amino-4-(phenylamino)anthraquinone-2-sulfonate sodium derivatives was synthesized and evaluated for osteoclast inhibition using a TRAP-staining assay. Among them, two compounds, LCCY-13 and LCCY-15, dose-dependently suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. Moreover, the cytotoxicity assay on RAW264.7 cells suggested that the inhibition of osteoclastic bone resorption by these compounds was not a result of their cytotoxicity. Further, the inhibitory activities of compounds LCCY-13 and LCCY-15 were further confirmed by including specific inhibition of NFATc1 expression levels in nuclei using an immunofluorescent analysis. In addition, LCCY-13 and LCCY-15 also significantly attenuated the bone resorption activity of osteoclasts according to a pit formation assay. Thus, a new class of 1-amino-4-(phenylamino)anthraquinone-2-sulfonate sodium compounds might be considered as an essential lead structure for the further development of anti-resorptive agents., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This work presents using a tapered fiber tip coated with thin metallic film to detect small particles in water with high sensitivity. When an AC voltage applied to the Ti/Al coated fiber tip and indium tin oxide (ITO) substrate, a gradient electric field at the fiber tip induced attractive/repulsive force to suspended small particles due to the frequency-dependent dielectrophoresis (DEP) effect. Such DEP force greatly enhanced the concentration of the small particles near the tip. The increase of the local concentration also increased the scattering of surface plasmon wave near the fiber tip. Combined both DEP effect and scattering optical near-field, we show the detection limit of the concentration for 1.36 μm polystyrene beads can be down to 1 particle/mL. The detection limit of the Escherichia coli (E. coli) bacteria was 20 CFU/mL. The fiber tip sensor takes advantages of ultrasmall volume, label-free and simple detection system.

Background: The characteristics and therapeutic potential of subtypes of mesenchymal stem cells (MSCs) are largely unknown. In this study, CD146(+) and CD146(-) MSCs were separated from human umbilical cords, and their effects on regulatory T cells (Tregs), Th17 cells, chondrogenesis, and osteogenesis were investigated., Methods: Flow cytometry was used to quantify IL-6 and TGF-β1 expressed on CD146(+) and CD146(-) MSCs. The therapeutic potential of both subpopulations was determined by measuring the clinical score and joint histology after intra-articular (IA) transfer of the cells into mice with collagen-induced arthritis (CIA)., Results: Compared with CD146(-) MSCs, CD146(+) MSCs expressed less IL-6 and had a significantly greater effect on chondrogenesis. After T lymphocyte activation, Th17 cells were activated when exposed to CD146(-) cells but not when exposed to CD146(+) cells both in vitro and in vivo. IA injection of CD146(+) MSCs attenuated the progression of CIA. Immunohistochemistry showed that only HLA-A(+) CD146(+) cells were detected in the cartilage of CIA mice. These cells may help preserve proteoglycan expression., Conclusions: This study suggests that CD146(+) cells have greater potency than CD146(-) cells for cartilage protection and can suppress Th17 cell activation. These data suggest a potential therapeutic application for CD146(+) cells in treating inflammatory arthritis.

Aim: This study was to evaluate the diagnostic value of OSR2, VAV3, and PPFIA3 hypermethylation in gastric cancer (GC) patients., Patients and Methods: By using methylation-specific polymerase chain reaction (MSP), we detected the methylation status in tissue and serum samples from 48 gastric cancer (GC) patients and 25 normal individuals., Results: We found that OSR2, VAV3, and PPFIA3 were methylated in 70.8% (34/48), 54.2% (26/48), and 60.4% (29/48) of GC tissue, respectively. On the contrary, those genes were barely methylated in their paired paracancerous histological normal tissues (PCHNTs) (all P values < 0.01). We next analyzed the methylated OSR2, VAV3, and PPFIA3 in serum DNA. Compared with 25 normal individuals, those three genes were significantly hypermethylated in GC patients serum samples (all P values < 0.01). Regarding their diagnostic value in serum samples, the combined sensitivity of at least one positive among the three markers in serum was 83.3%, with a specificity of 88%., Conclusion: Our test suggested that methylation of OSR2, VAV3, and PPFIA3 genes in serum sample may offer a good alternative in a simple, promising, and noninvasive detection of GC.

Glucosamine has immunomodulatory effects on autoimmune diseases. However, the mechanism(s) through which glucosamine modulates different T cell subsets and diseases remain unclear. We demonstrate that glucosamine impedes Th1, Th2, and iTreg but promotes Th17 differentiation through down-regulating N-linked glycosylation of CD25 and subsequently inhibiting its downstream Stat5 signaling in a dose-dependent manner. The effect of glucosamine on T helper cell differentiation was similar to that induced by anti-IL-2 treatment, further supporting an IL-2 signaling-dependent modulation. Interestingly, excess glucose rescued this glucosamine-mediated regulation, suggesting a functional competition between glucose and glucosamine. High-dose glucosamine significantly decreased Glut1 N-glycosylation in Th1-polarized cells. This finding suggests that both down-regulated IL-2 signaling and Glut1-dependent glycolytic metabolism contribute to the inhibition of Th1 differentiation by glucosamine. Finally, glucosamine treatment inhibited Th1 cells in vivo, prolonged the survival of islet grafts in diabetic recipients, and exacerbated the severity of EAE. Taken together, our results indicate that glucosamine interferes with N-glycosylation of CD25, and thereby attenuates IL-2 downstream signaling. These effects suggest that glucosamine may be an important modulator of T cell differentiation and immune homeostasis., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE., (Copyright © 2015 Elsevier Inc. All rights reserved.)