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ID PMID Title PublicationDate abstract
29275836 A cellular and molecular view of T helper 17 cell plasticity in autoimmunity. 2018 Feb Since the original identification of the T helper 17 (Th17) subset in 2005, it has become evident that these cells do not only contribute to host defence against pathogens, such as bacteria and fungi, but that they are also critically involved in the pathogenesis of many autoimmune diseases. In contrast to the classic Th1 and Th2 cells, which represent rather stably polarized subsets, Th17 cells display remarkable heterogeneity and plasticity. This has been attributed to the characteristics of the key transcription factor that guides Th17 differentiation, retinoic acid receptor-related orphan nuclear receptor gamma (RORγ). Unlike the 'master regulators' T-bet and GATA3 that orchestrate Th1 and Th2 differentiation, respectively, RORγ controls transcription at relatively few loci in Th17 cells. Moreover, its expression is not stabilized by positive feedback loops but rather influenced by environmental cues, allowing for substantial functional plasticity. Importantly, a subset of IL-17/IFNγ double-producing Th17 cells was identified in both human and mouse models. Evidence is accumulating that these IL-17/IFNγ double-producing cells are pathogenic drivers in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. In addition, IL-17/IFNγ double-producing cells have been identified in disorders in which the role of autoimmunity remains unclear, such as sarcoidosis. The observed plasticity of Th17 cells towards the Th1 phenotype can be explained by extensive epigenetic priming of the IFNG locus in Th17 cells. In fact, Th17 cells display an IFNG chromatin landscape that is remarkably similar to that of Th1 cells. On the other hand, pathogenic capabilities of Th17 cells can be restrained by stimulating IL-10 production and transdifferentiation into IL-10 producing T regulatory type 1 (Tr1) cells. In this review, we discuss recent advances in our knowledge on the cellular and molecular mechanisms involved in Th17 differentiation, heterogeneity and plasticity. We focus on transcriptional regulation of the Th17 expression program, the epigenetic dynamics involved, and how genetic variants associated with autoimmunity may affect immune responses through distal gene regulatory elements. Finally, the implications of Th17 cell plasticity for the pathogenesis and treatment of human autoimmune diseases will be discussed.
29207792 Clinical Evaluation of Efficacy and Performance of All-Poly Tibial Freedom(®) Total Knee 2017 Sep INTRODUCTION: Advancement in technology in terms of design and building materials has made Total Knee Replacement (TKR) a highly effective, safe, and predictable orthopedic procedure. AIM: To review the clinical outcomes for efficacy and performance of Freedom Total Knee System for the management of Osteoarthritis (OA), at a minimum of three years follow up. MATERIALS AND METHODS: For this retrospective, post-marketing study, clinical data of patients treated with Freedom Total Knee System was retrieved from the clinical records after approval from the Institutional Ethics Committee . All the patients above the age of 18 years who completed at least three years after TKR were observed for the study purpose. Patients treated for OA were included while the patients who received the implant for treatment of rheumatoid arthritis and traumatic injury were excluded. Factors such as aseptic loosening, implant failure, and need for revision surgery were observed to evaluate implant performance. Cases were recruited for clinical assessment of primary efficacy endpoint in terms of post-surgery maximun range of motion. Secondary efficacy endpoint was to determine the clinical and social quality of life as per the American Knee Society Score (AKSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and stiffness scores. RESULTS: A total of 158 patients who had 191 TKR were observed for performance. The mean age of the patients was 67.67 years; mean BMI was 28.97±3.33, and the group comprised of 43% men and 57% women. Telephonic follow up at three years of 158 patients identified that none of them required revision surgery or had aseptic loosening suggesting excellent performance. Final clinical follow up at three years was available for only 35 patients (41 knee implants). The range of motion significantly improved from preoperative 104°±5.67° (range, 85°-119°) to 119.8°±11.05° (98°-123°) at follow-up (p<0.05). There was a significant improvement in clinical and functional AKSS score and WOMAC score at follow-up. CONCLUSION: The evaluation of Freedom Total Knee System for TKR in treating OA, at a minimum of three years follow up showed excellent outcomes in terms of performance, range of motion, reduced postoperative stiffness and pain, and improved functionality.
29128174 Health-related quality of life in MEN1 patients compared with other chronic conditions and 2018 Jan BACKGROUND: Health-related quality of life (HRQOL) in multiple endocrine neoplasia type-1 (MEN-1) is poorly described. HRQOL in MEN-1 was compared with other chronic conditions and the US general population. METHODS: Adults aged ≥18 years recruited from an MEN-1 support group (n=153) completed the Patient-Reported Outcomes Measurement Information System (PROMIS) 29-item profile. MEN-1 scores were compared with PROMIS scores reported in peer-reviewed literature from back pain (n=218), cancer (n=310), congestive heart failure (CHF; n=60), chronic obstructive pulmonary disease (COPD; n=79), major depressive disorder (n=196), rheumatoid arthritis (RA; n=521), neuroendocrine tumors (NET; n=619), and primary hyperparathyroidism (PHPT; n=45) cohorts. RESULTS: Patients with MEN-1 reported worse anxiety (mean=61.7), depression (57.9), fatigue (62.2), pain interference (55.4), sleep disturbance (58.0), physical functioning (44.4), and social functioning (44.7) compared to normative data (50, P < .05) and greater anxiety, depression, and fatigue than patients with back pain, cancer, COPD, RA, NETs, and PHPT (P < .001). MEN-1 respondents had greater pain interference (55.4) than those with cancer (51.9), NETs (52.3), and PHPT (38.4, P < .05). Physical functioning was higher in individuals with MEN-1 (44.4) than in those with back pain (37.5), CHF (34.8), COPD (38.0), and RA (40.7, P < .01). CONCLUSION: This is the first study to describe HRQOL in a large sample of adults with MEN-1. MEN-1respondents reported worse HRQOL across PROMIS 29-item profile measure domains compared with the US general population and higher levels of anxiety, depression, and fatigue compared with many other chronic conditions.
29042208 Antiallodynic activity of leflunomide is partially inhibited by naltrexone and glibenclami 2018 Jan 5 Leflunomide, an immunosuppressive drug approved for the treatment of patients with rheumatoid arthritis, exhibits many mechanisms which may affect the nociceptive processing. Therefore, the present study aimed to evaluate the effect induced by leflunomide on the mechanical allodynia in models of inflammatory and neuropathic pain in mice and investigate mechanisms mediating such effects. Per os (p.o.) administration of leflunomide (25, 50 or 100mg/kg) inhibited the inflammatory edema and mechanical allodynia induced by intraplantar carrageenan. Even ongoing inflammatory edema and mechanical allodynia were reduced by leflunomide. Previous administration of naltrexone (10mg/kg, intraperitoneal) or glibenclamide (40mg/kg, p.o.) partially attenuated leflunomide antiallodynic activity. A single administration of leflunomide (50 or 100mg/kg, p.o.) also partially inhibited ongoing mechanical allodynia induced by chronic constriction injury (CCI) or repeated administrations of paclitaxel. The antiallodynic effect induced by leflunomide (50 or 100mg/kg, p.o.) in the model of neuropathic pain induced by CCI was associated with reduced production of tumor necrosis factor-α both at the injury site and ipsilateral paw. Leflunomide also reduced production of the chemokine CXCL-1 at the paw ipsilateral to the injury site. Concluding, leflunomide partially inhibited ongoing mechanical allodynia in models of inflammatory and neuropathic pain. The antiallodynic effect was associated with activation of opioidergic receptors and ATP-sensitive potassium channels and reduced production of inflammatory mediators. These data indicate leflunomide as a drug that should be further investigated aiming to identify a new analgesic pharmacotherapy and reinforces repositioning as an important strategy to identify new uses for approved drugs.
28895652 Quantitative Proteomics and Targeted Fatty Acids Analysis Reveal the Damage of Triptolide 2017 Nov Triptolide (TP), the major active component in Tripterygium wilfordii Hook. f., is widely used for the treatment of rheumatoid arthritis and autoimmune diseases. However, organ toxicity, especially hepatotoxicity and nephrotoxicity, limits its clinical application. To fully understand the mechanism underlying TP toxicity, iTRAQ-based 2D-LC-MS/MS proteomics is used to detect differentially expressed proteins in the livers and kidneys of mice administered the LD50 dose of TP. Functional annotation revealed that multiple pathways are involved in TP toxicity, including acute-phase response signaling, the antigen presentation pathway, FXR/RXR activation, LPS/IL-1-mediated inhibition of RXR function, and EIF2 signaling. Members of the cytochrome P450 protein family that are involved in fatty acid (FA) metabolism, such as CYP2E1, show significant differences in expression among groups. Additionally, the proteomics data suggested that FAs are involved in TP-induced toxicity. FA analysis is conducted using HPLC-MRM to characterize the differences among various groups exposed to TP for different times. It has been found that 20 FAs in the liver show significant differences in abundance among groups, whereas in the kidneys, six FAs show significant differences in abundance. By integrating the proteomic and targeted FA analyses, it has been found that differently expressed proteins and FAs both participate in pathways including cellular lipolytic activity, peroxisomal fatty acid beta-oxidation, and so on. Our data contribute to understanding the mechanisms underlying TP-induced organ toxicity. The results may help to improve the clinical efficacy and safety of TP in the future.
28824321 The Simultaneous Inhibitory Effect of Niclosamide on RANKL-Induced Osteoclast Formation an 2017 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.
28722163 Risk of cancer in patients with psoriasis on biological therapies: a systematic review. 2018 Jan BACKGROUND: Biological therapies are highly effective in psoriasis, but have profound effects on innate and adaptive immune pathways that may negatively impact on cancer immunosurveillance mechanisms. OBJECTIVES: To investigate the risk of cancer in patients with psoriasis treated with biological therapy. METHODS: We searched MEDLINE, Embase, and the Cochrane Library (up to August 2016) for randomized controlled trials, prospective cohort studies and systematic reviews that reported cancer incidence in people exposed to biological therapy for psoriasis compared with a control population. RESULTS: Eight prospective cohort studies met our inclusion criteria. All the evidence reviewed related to tumour necrosis factor inhibitors (TNFi) with the exception of one study on ustekinumab. An increased risk of nonmelanoma skin cancer (NMSC), particularly squamous cell carcinoma, was reported with TNFi compared with both a general United States population and a rheumatoid arthritis population treated with TNFi. No evidence for increased risk of cancers (reported as all cancers, lymphoma, melanoma, prostate, colorectal and breast cancer) other than NMSC was identified. CONCLUSIONS: There were important limitations to the studies identified including choice of comparator arms, inadequate adjustment for confounding factors and failure to account for latency periods of cancer. There remains a need for ongoing pharmacovigilance in relation to cancer risk and biological therapy; the NMSC signal requires further investigation to determine the risk specifically attributable to biological therapy using prospectively collected data with adjustment for known NMSC risk factors.
28698499 Molecular Mechanisms behind Free Radical Scavengers Function against Oxidative Stress. 2017 Jul 10 Accumulating evidence shows that oxidative stress is involved in a wide variety of human diseases: rheumatoid arthritis, Alzheimer's disease, Parkinson's disease, cancers, etc. Here, we discuss the significance of oxidative conditions in different disease, with the focus on neurodegenerative disease including Parkinson's disease, which is mainly caused by oxidative stress. Reactive oxygen and nitrogen species (ROS and RNS, respectively), collectively known as RONS, are produced by cellular enzymes such as myeloperoxidase, NADPH-oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) and nitric oxide synthase (NOS). Natural antioxidant systems are categorized into enzymatic and non-enzymatic antioxidant groups. The former includes a number of enzymes such as catalase and glutathione peroxidase, while the latter contains a number of antioxidants acquired from dietary sources including vitamin C, carotenoids, flavonoids and polyphenols. There are also scavengers used for therapeutic purposes, such as 3,4-dihydroxyphenylalanine (L-DOPA) used routinely in the treatment of Parkinson's disease (not as a free radical scavenger), and 3-methyl-1-phenyl-2-pyrazolin-5-one (Edaravone) that acts as a free radical detoxifier frequently used in acute ischemic stroke. The cell surviving properties of L-DOPA and Edaravone against oxidative stress conditions rely on the alteration of a number of stress proteins such as Annexin A1, Peroxiredoxin-6 and PARK7/DJ-1 (Parkinson disease protein 7, also known as Protein deglycase DJ-1). Although they share the targets in reversing the cytotoxic effects of Hâ‚‚Oâ‚‚, they seem to have distinct mechanism of function. Exposure to L-DOPA may result in hypoxia condition and further induction of ORP150 (150-kDa oxygen-regulated protein) with its concomitant cytoprotective effects but Edaravone seems to protect cells via direct induction of Peroxiredoxin-2 and inhibition of apoptosis.
28669550 Sulfasalazine-Induced Crystalluria Causing Severe Acute Kidney Injury. 2017 Dec Sulfasalazine is an anti-inflammatory agent commonly used in the treatment of autoimmune conditions such as inflammatory bowel disease and rheumatoid arthritis. Sulfasalazine is converted by gut bacteria into sulfapyridine and the clinically active metabolite 5-aminosalicylic acid (5-ASA), and its efficacy is proportional to the 5-ASA concentration within the intestinal lumen. Renal complications are commonly reported for the chemically similar 5-ASA derivative mesalamine, but are not well-known side effects of sulfasalazine therapy. We report a 72-year-old patient with Crohn's disease managed with sulfasalazine for more than 10 years who presented with severe acute kidney injury (serum creatinine, 9.7mg/dL). Renal ultrasound revealed calculi and he subsequently spontaneously voided innumerable stones, which were composed of sulfasalazine metabolites. His renal calculi cleared and serum creatinine concentration improved to 3.1mg/dL after discontinuing sulfasalazine therapy and intravenous fluid hydration. His kidney function eventually returned to baseline. This case demonstrates that renal complications, in particular nephrolithiasis, may be an under-reported but potentially serious phenomenon in patients with inflammatory bowel disease treated with sulfasalazine and that their hydration status may play an important role in this process.
28479497 Maternal smoking during pregnancy is associated with childhood bone fractures in offspring 2017 Aug In children there is limited understanding about the biological and environmental risk factors of fractures. Therefore, we aimed to study the effect of maternal smoking on preschool children's fractures hypothesizing that the fracture risk might be programmed during intrauterine growth in means of disturbed bone formation. A prospective birth cohort included women living in Northern Finland with an expected date of delivery between July 1st, 1985 and June 30th, 1986 (N=9362), and their offspring (N=9432). Smoking was inquired during pregnancy and when the offspring reached seven years of age. Information on in-hospital-treated fractures among the children was collected from the National Hospital Discharge Register (NHDR). The cases who declined to participate or suffered from any bone dysplasia such as osteogenesis imperfecta or any malignancy were excluded, thus 6718 subjects (71.2%) were finally included. Poisson regression analysis with adjustment for gender, asthma, rheumatoid arthritis, socioeconomic status of the family, maternal age and body mass index (BMI) of the children was used to determine the association between maternal smoking during pregnancy and bone fractures. Maternal smoking during pregnancy was associated with a 1.83-fold (95% CI 1.06-3.02, p=0.022) increased risk of in-hospital-treated fractures at pre-school age. The fracture risk in childhood is perhaps increased as a result of modified bone development of the fetus due to maternal smoking.
28462950 T-cell activation RhoGTPase-activating protein plays an important role in T(H)17-cell diff 2017 Sep T-cell activation RhoGTPase-activating protein (TAGAP) is a GTPase-activating protein specific for RhoA that is exclusively expressed in activated T cells. Genome-wide association studies and metagenome SNPs analyses have indicated that TAGAP is associated with the pathogenesis of multiple autoimmune diseases, including psoriasis, rheumatoid arthritis, Crohn's disease, celiac disease and multiple sclerosis. However, the precise function of TAGAP remains unclear. Because T(H)17 cells contribute to TAGAP-associated autoimmune diseases, we hypothesized that TAGAP plays key roles in the differentiation and/or function of T(H)17 cells. To evaluate this hypothesis, we analyzed the effect of TAGAP on T(H)17 differentiation in vitro and established a line of TAGAP-deficient mice. We found that TAGAP was required for T(H)17 differentiation in vitro and that the loss of TAGAP in mice ameliorated the clinical features of experimental autoimmune encephalomyelitis, indicating that TAGAP is critical for disease progression. We also demonstrated that TAGAP interacts with RhoH, an adapter protein that interacts with lck and ZAP70 in proximal TCR signaling. TAGAP competes with ZAP70 for RhoH binding, thereby inhibiting TCR-associated signal transduction. Consistent with these findings, TCR-induced ERK activation was increased in TAGAP-deficient T cells. Because the upregulation of TCR signaling inhibits Th17 differentiation, TAGAP may prevent TCR signaling activity from reaching the limit of the induction of T(H)17 cells. Collectively, our findings indicate that TAGAP is a novel factor required for T(H)17-cell differentiation and that TAGAP potentially represents a novel target of autoimmune disease therapies.
28462876 [AA amyloidosis]. 2017 Jun AA amyloidosis remains one of the three main types of systemic amyloidosis with AL and ATTR. Its incidence has been however decreasing recently in Western countries. Chronic inflammatory diseases are currently the first cause of AA amyloidosis, including rheumatoid arthritis, spondyloarthritis and autoinflammatory diseases. Castleman's disease is a specific cause of AA amyloidosis that can be cured by surgery. A chronic inflammatory response is required to develop amyloidosis. Other genetic and environmental factors are also involved. The first clinical manifestation is a chronic glomerular nephropathy, which can be detected by urine examination and serum creatinine measure. Immunohistochemistry is mandatory to confirm the clinical diagnosis of AA amyloidosis and to avoid misdiagnosis. Long-term prognosis remains poor on chronic dialysis in case of clinical gut involvement. Current treatment is based on the control of the inflammatory response. Specific treatment aimed at inhibiting amyloid formation targeting serum amyloid P component and heparan sulphate are currently evaluated.
28414822 2-dimensional shear wave elastography: Interobserver agreement and factors related to inte 2017 PURPOSE: To evaluate the interobserver reproducibility of two-dimensional shear wave elastography (2D-SWE) in measuring liver stiffness (LS) and to investigate factors related to liver 2D-SWE. MATERIALS AND METHODS: A prospective study was conducted between August 2011 and August 2012 in rheumatoid arthritis patients who had been treated with methotrexate. Interobserver reproducibility of 2D-SWE was evaluated, and the relationship between interobserver difference in LS and related factors was analyzed using linear regression analyses. We considered age, sex, alanine transaminase, cholesterol, body mass index (BMI), and waist circumference as clinical factors, and the mean value of standard deviation (SDM), its difference between two examiners, mean diameter of the regions of interest (ROIM), and its difference in the elasticity map as investigation factors. The cut-off value for significant factors to predict interobserver discrepancies in LS-based fibrosis stage was also inspected. RESULTS: In total, 176 patients were enrolled. The intraclass correlation coefficient between the two examiners was 0.784. In the univariate analysis, SDM and ROIM were independently associated with interobserver differences in LS as well as BMI, waist circumference, and the difference of ROI, but SDM and ROIM were the only ones significantly related in multivariate analysis (p<0.001 and p = 0.021, respectively). The best cut-off value for SDM in predicting interobserver discrepancy in LS-based fibrosis stage was 1.4. CONCLUSIONS: Interobserver reproducibility of 2D-SWE for measuring LS was good and SDM was the most significantly associated factor with interobserver differences in LS and interobserver discordance in LS-based fibrosis stage.
28369510 Antagonistic Coevolution of MER Tyrosine Kinase Expression and Function. 2017 Jul 1 TYRO3, AXL, and MERTK (TAM) receptors are a family of receptor tyrosine kinases that maintain homeostasis through the clearance of apoptotic cells, and when defective, contribute to chronic inflammatory and autoimmune diseases such as atherosclerosis, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and Crohn's disease. In addition, certain enveloped viruses utilize TAM receptors for immune evasion and entry into host cells, with several viruses preferentially hijacking MERTK for these purposes. Despite the biological importance of TAM receptors, little is understood of their recent evolution and its impact on their function. Using evolutionary analysis of primate TAM receptor sequences, we identified strong, recent positive selection in MERTK's signal peptide and transmembrane domain that was absent from TYRO3 and AXL. Reconstruction of hominid and primate ancestral MERTK sequences revealed three nonsynonymous single nucleotide polymorphisms in the human MERTK signal peptide, with a G14C mutation resulting in a predicted non-B DNA cruciform motif, producing a significant decrease in MERTK expression with no significant effect on MERTK trafficking or half-life. Reconstruction of MERTK's transmembrane domain identified three amino acid substitutions and four amino acid insertions in humans, which led to significantly higher levels of self-clustering through the creation of a new interaction motif. This clustering counteracted the effect of the signal peptide mutations through enhancing MERTK avidity, whereas the lower MERTK expression led to reduced binding of Ebola virus-like particles. The decreased MERTK expression counterbalanced by increased avidity is consistent with antagonistic coevolution to evade viral hijacking of MERTK.
28328803 Incident acute pseudogout and prior bisphosphonate use: Matched case-control study in the 2017 Mar Oral bisphosphonates are the most commonly used drugs to treat postmenopausal osteoporosis. Acute pseudogout is anecdotally reported to occur following bisphosphonate initiation but empirical data are lacking. We investigated whether treatment with oral bisphosphonates is a risk factor for incident acute pseudogout.A matched case-control study was undertaken using data from the UK-Clinical Practice Research Datalink. Adults who consulted for incident acute pseudogout between 1987 and 2012 were each matched for gender, age at pseudogout diagnosis, and general practice to up to 4 control subjects without pseudogout. The exposure of interest was a prescription for an oral bisphosphonate issued within the 60-day period prior to the date of incident acute pseudogout. Associations between incident acute pseudogout and prior bisphosphonate prescription were examined using conditional logistic regression, adjusting for hyperparathyroidism, osteoarthritis, rheumatoid arthritis, hemochromatosis, hypophosphatasia, and prescriptions for diuretics and oral corticosteroids.Two thousand eleven acute pseudogout cases were compared with 8013 matched controls without acute pseudogout (mean age [standard deviation] 72 years [14]; 52% male). One hundred twenty-three cases (6.1%) had received an oral bisphosphonate prescription in the 60-day exposure period compared with 305 controls (3.8%) (adjusted incidence rate ratio [IRR] 1.33; 95% confidence interval [CI] 1.05-1.69). This association was stronger in females (adjusted IRR 1.49; 95% CI 1.15-1.94) and was nonsignificant in males (0.83; 0.48-1.44).Incident acute pseudogout was associated with prescription of an oral bisphosphonate in the preceding 60 days. Prescribers should be aware of acute pseudogout as a possible side effect of bisphosphonate treatment. Further research is needed to explore the risks conferred by different bisphosphonates and the mechanism underlying this association.
28296250 Different genetic alteration of A20 in a Sézary syndrome case with Vα2-Jα22 T cell clon 2018 Apr BACKGROUND: The comprehensive genetic alterations underlying the pathogenesis of Sézary syndrome (SS) remains largely unknown. Previous studies showed that alterations of tumor necrosis factor-α-induced protein 3 gene (TNFAIP3; A20) are frequent in SS. In this study, we characterized the mutation and polymorphisms of A20 in a case with SS and compared with the genetic feature of A20 in T-cell acute lymphoblastic leukemia (T-ALL). METHODS: Using a novel approach based on the combination of fine-tiling array comparative genomic hybridization ( and ligation-mediated polymerase chain reaction (LM-PCR) to identify SS clone, the polymorphisms in the A20 gene (promoter, exons 2-9 [coding region] and 3'UTR) were detected by PCR and sequencing. RESULTS: The malignant SS clone was identified as TCR Vα2-Jα22 rearrangement without deletion at the A20 loci (6q23-27 region) in the SS case. Six polymorphisms were identified, all of them are belonging to single nucleotide polymorphisms (SNPs) that are recorded in genebank: rs5029924, rs5029937, rs2230926, rs582757 and rs77191406, while rs2307859 was not identified in the SS sample, which is found in all T-ALL. The alteration pattern of A20 in this case seemed different from the T-ALL samples, in contrast, it is similar to the alteration of A20 in samples from rheumatoid arthritis or systemic lupus erythematosus with poor clinical outcome and cancer developing. CONCLUSIONS: The genetic alteration of A20 in the SS case was different from the T-ALL samples and similar to the cases with refractory autoimmune disease and related to tumorigenesis. The findings lead to discuss whether such SNPs of A20 may link the refractory autoimmune inflammation and the tumorigenesis.
28263097 Transcriptional and epigenetic regulation of follicular T-helper cells and their role in a 2017 Mar T-follicular helper (Tfh) cells are a specialized subset of T cells that provide help to B cells and promote the formation of germinal centers (GCs). Tfh cells transmit important signals to B cells that drive class switch recombination, somatic hyper-mutation, the generation of high-affinity antibodies, immunological memory and their differentiation into plasma cells or memory B cells in the GCs. Tfh-cell differentiation is regulated by the coordinated functions of distinct cytokines, including interleukin (IL)-6, IL-21, IL-12, IL-23, IL-2, IL-7 and transforming growth factor-β (TGF-β), as well as transcription factors, including B-cell lymphoma 6 protein (Bcl-6), Signal transducers and activators of transcription (STAT)1, STAT3, STAT4, B-cell activating transcription factor (Batf), interferon regulatory factor 4 (IRF4), v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (C-Maf), T-cell-specific transcription factor 1 (TCF-1) and Achaete-scute homolog 2 (Acl2), which have been shown to form a complex transcriptional network. In addition, increasing evidence indicates that epigenetic regulations, such as DNA methylation, histone modifications and non-coding RNA regulations, also coordinately control the differentiation and function of Tfh cells along with transcription factors. Furthermore, abnormalities in the regulation of Tfh cells have been associated with several autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS) and rheumatoid arthritis (RA). Herein, this review aims to summarize the coordinate regulation and interaction of transcription factors, cytokines and epigenetic modifications that control Tfh-cell differentiation as well as the mechanism of dysregulation of Tfh cells in pathogenesis of autoimmune diseases, which highlight potential therapeutic targets.
28085946 OCLI-023, a Novel Pyrimidine Compound, Suppresses Osteoclastogenesis In Vitro and Alveolar 2017 An abnormal increase in osteoclast differentiation and activation results in various bone-resorptive diseases, including periodontitis, rheumatoid arthritis, and osteoporosis. Chemical compounds containing pyrimidine ring have been shown to regulate a variety of biological processes. Therefore, in order to identify an antiresorptive agent, we synthesized a series of pyrimidine ring-containing chemical compounds, and found that OCLI-023 suppressed the differentiation and activation of osteoclasts in vitro. OCLI-023 directly inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced differentiation of bone marrow macrophages into osteoclasts, without a cytotoxic response. OCLI-023 also downregulated the RANKL-induced mRNA expression of osteoclast markers as well as inhibited the formation of actin rings and resorption pits. OCLI-023 attenuated the RANKL-induced activation of c-Jun N-terminal kinase and nuclear factor kappa-light-chain-enhancer of activated B cell signaling pathways. In a mouse model of periodontitis, ligature induced an increase of distance between cementoenamel junction (CEJ) and alveolar bone crest (ABC) in the second molar, and OCLI-023 significantly reduced it. Histological analysis showed ligature-induced increase of osteoclast numbers was also significantly reduced by OCLI-023. These data demonstrated the inhibitory effect of OCLI-023 on osteoclast differentiation and activity of osteoclasts in vitro, as well as on ligature-induced bone loss in vivo, and OCLI-023 can be proposed as a novel anti-resorptive compound.
27816176 A grayanotox-9(11)-ene derivative from Rhododendron brachycarpum and its structural assign 2017 Jan A growing body of evidence points to the useful roles of computational approaches in the structural characterization of natural products. Rhododendron brachycarpum has been traditionally used for the control of diabetes, hepatitis, hypertension, and rheumatoid arthritis and classified as an endangered species in Korea. A grayanotox-9(11)-ene derivative along with five known diterpenoids, were isolated from the MeOH extract of R. brachycarpum. Extensive 1D and 2D NMR experiments were conducted to establish the 2D structure and relative configuration of the grayanotox-9(11)-ene derivative. Comparison of simulated and experimental ECD spectra resulted in an inconclusive outcome to assign its absolute configuration. Alternatively, gauge-including atomic orbitals (GIAO) NMR chemical shift calculations, with support by the advanced statistical method DP4 plus, and acid hydrolysis were employed to establish its absolute configuration. This work exemplifies how NMR analysis, combined with quantum mechanics calculations, is a viable approach to accomplish structural assignment of minor abundance molecules in lieu of X-ray crystallography or chiroptical approaches.
27789680 Mutation-Induced Functional Alterations of CCR6. 2017 Jan The Cys-Cys chemokine receptor 6 (CCR6) is a well-established modulator of inflammation. Although several genetic associations have been identified between CCR6 polymorphisms and immune system disorders (e.g., rheumatoid arthritis and Crohn's disease), the pharmacological effects of naturally occurring missense mutations in this receptor have yet to be characterized. In this study, we initially assessed G protein-mediated signaling and observed that wild-type (WT) CCR6 exhibited ligand-independent activity. In addition, we found that the five most frequent CCR6 missense variants (A89T, A150V, R155W, G345S, and A369V) exhibited decreased basal and/or ligand induced Gαi protein signaling. To complement the study of these loss-of-function variants, we engineered a set of constitutively active CCR6 receptors. Selected mutations enhanced basal G protein-mediated signaling up to 3-fold relative to the WT value. Using a bioluminescence resonance energy transfer assay we investigated the ability of each naturally occurring and engineered CCR6 receptor mutant to recruit β-arrestin. In contrast to G protein-mediated signaling, β-arrestin mobilization was largely unperturbed by the naturally occurring loss-of-function CCR6 variants. Elevated recruitment of β-arrestin was observed in one of the engineered constitutively active mutants (T98P). Our results demonstrate that point mutations in CCR6 can result in either a gain or loss of receptor function. These observations underscore the need to explore how CCR6 natural variants may influence immune cell physiology and human disease.