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ID PMID Title PublicationDate abstract
30543834 A dual role of TGF-β in human osteoclast differentiation mediated by Smad1 versus Smad3 s 2019 Feb TGF-β1 is highly expressed in the synovial tissue of patients with rheumatoid arthritis and is known as a cytokine that plays an important role in tissue repair and immune cell regulation. However, the role of TGF-β1 is still unclear in osteoclastogenesis. In this study, we examined the effect of TGF-β1 on osteoclast differentiation and the underlying mechanism using healthy human peripheral blood monocytes. TGF-β1 was found to inhibit osteoclast differentiation and decrease the expression of osteoclast-specific genes such as acid phosphatase 5, tartrate resistant and cathepsin K. Levels of NFAT1, an important transcription factor in osteoclastogenesis, were also reduced. In addition, TGF-β1 suppressed receptor activator of NF-κB (RANK) ligand-induced NF-κB and p38 MAPK signaling. Inhibition of osteoclast differentiation by TGF-β1 was reversed by 1 μM SB431542 (an inhibitor of ALK4/5/7), which inhibited TGF-β1-induced phosphorylation of SMAD1, but not that of SMAD3. TGF-β1 also restricted RANK expression, and this was partially reversed by 1 μM SB431542. In contrast, the inhibition of SMAD3 by SIS3 (an inhibitor of SMAD3) reduced the osteoclast formation. TGF-β1 has both inhibitory and stimulatory effects on human osteoclast differentiation, and that these opposing functions are mediated by SMAD1 and SMAD3 signaling, respectively.
30467458 Augmentation of Physician Assessments with Multi-Omics Enhances Predictability of Drug Res 2018 Aug This work proposes a "learning-augmented clinical assessment" workflow to sequentially augment physician assessments of patients' symptoms and their socio-demographic measures with heterogeneous biological measures to accurately predict treatment outcomes using machine learning. Across many psychiatric illnesses, ranging from major depressive disorder to schizophrenia, symptom severity assessments are subjective and do not include biological measures, making predictability in eventual treatment outcomes a challenge. Using data from the Mayo Clinic PGRN-AMPS SSRI trial as a case study, this work demonstrates a significant improvement in the prediction accuracy for antidepressant treatment outcomes in patients with major depressive disorder from 35% to 80% individualized by patient, compared to using only a physician's assessment as the predictors. This improvement is achieved through an iterative overlay of biological measures, starting with metabolites (blood measures modulated by drug action) associated with symptom severity, and then adding in genes associated with metabolomic concentrations. Hence, therapeutic efficacy for a new patient can be assessed prior to treatment, using prediction models that take as inputs, selected biological measures and physician's assessments of depression severity. Of broader significance extending beyond psychiatry, the approach presented in this work can potentially be applied to predicting treatment outcomes for other medical conditions, such as migraine headaches or rheumatoid arthritis, for which patients are treated according to subject-reported assessments of symptom severity.
30447278 Genes and transcription factors related to the adverse effects of maternal type I diabetes 2019 Feb PURPOSE: Maternal type I diabetes mellitus (T1DM) increases the risk of adverse pregnancy outcomes, but the corresponding mechanism is unclear. This study aims to investigate the mechanism underlying the adverse pregnancy outcomes of maternal T1DM. METHODS: Gene expression microarray (GSE51546) was down-loaded from the Gene Expression Omnibus. This dataset included 12 umbilical cord samples from the newborns of T1DM mothers (T1DM group, N = six) and non-diabetic mothers (control group, N = six). RESULTS: Consequently, 1051 differentially expressed genes (DEGs) were found between the two groups. The up-regulated DEGs enriched in 30 KEGG pathways. HLA-DPA1, HLA-DMA, HLA-DMB, HLA-DQA1, HLA-DQA2 and HLA-DRA enriched in "Type I diabetes mellitus". This pathway was strongly related to 14 pathways, most of which were associated with diseases. Then, a protein-protein interaction network was constructed, and 45 potential key DEGs were identified. The 45 DEGs enriched in pathways such as "Rheumatoid arthritis", "Chemokine signaling pathway" and "Cytokine-cytokine receptor interaction" (e.g. CXCL12 and CCL5). Transcription factors (TFs) of key DEGs were predicted, and a TF-DEG regulatory network was constructed. CONCLUSIONS: Some genes (e.g. CXCL12 and CCL5) and their TFs were significantly and abnormally regulated in the umbilical cord tissue from the pregnancies of T1DM mothers compared to that from non-T1DM mothers.
30385504 Conjugation of urate-derived electrophiles to proteins during normal metabolism and inflam 2018 Dec 21 Urate is often viewed as an antioxidant. Here, we present an alternative perspective by showing that, when oxidized, urate propagates oxidative stress. Oxidation converts urate to the urate radical and the electrophilic products dehydrourate, 5-hydroxyisourate, and urate hydroperoxide, which eventually break down to allantoin. We investigated whether urate-derived electrophiles are intercepted by nucleophilic amino acid residues to form stable adducts on proteins. When urate was oxidized in the presence of various peptides and proteins, two adducts derived from urate (M (r) 167 Da) were detected and had mass additions of 140 and 166 Da, occurring mainly on lysine residues and N-terminal amines. The adduct with a 140-Da mass addition was detected more frequently and was stable. Dehydrourate (M (r) 166 Da) also formed transient adducts with cysteine residues. Urate-derived adducts were detected on human serum albumin in plasma of healthy donors. Basal adduct levels increased when neutrophils were added to plasma and stimulated, and relied on the NADPH oxidase, myeloperoxidase, hydrogen peroxide, and superoxide. Adducts of oxidized urate on serum albumin were elevated in plasma and synovial fluid from individuals with gout and rheumatoid arthritis. We propose that rather than acting as an antioxidant, urate's conversion to electrophiles contributes to oxidative stress. The addition of urate-derived electrophiles to nucleophilic amino acid residues, a process we call oxidative uratylation, will leave a footprint on proteins that could alter their function when critical sites are modified.
30080660 Risk factors and quality of life for the occurrence of hip fracture in postmenopausal wome 2018 Jun BACKGROUND: To identify the risk factors and changes of quality of life in the first occurrence of hip fracture in Taiwanese postmenopausal women. METHODS: In this case-control study, we enrolled 100 postmenopausal women with accidental first-incident hip fracture and 100 women without hip fracture. The control group was matched to the study group according to age. Evaluation consisted of a questionnaire, an interview to both assess quality of life via a 36-item Short Form Health Survey and document risk factors, a physical examination to record height and body weight, and bone mineral density (BMD) of the hip and spine using dual-energy X-ray absorptiometry (DXA). RESULTS: The mean age of the patients was 77.9 years old. Compared with the controls, the patients with first-incident hip fracture had a lower level of education, increased body height, higher parity, no experience of estrogen therapy, prior history of diabetes mellitus and rheumatoid arthritis, walking aid use, less weight-bearing exercise, and steroid use. Total hip BMD was a stronger predictor than BMD at different sites. Quality of life was significantly higher in the control group at the baseline and 4-month follow-up. CONCLUSIONS: Quality of life was related to the first-incident hip fracture. The increased risk of falls, lower level of education, and total hip BMD are the strongest predictors of first-incident hip fracture in Asian elderly postmenopausal women.
29927820 Acetyl-11-Keto-β-Boswellic Acid Promotes Osteoblast Differentiation by Inhibiting Tumor N 2018 Oct Tumor necrosis factor (TNF) -α plays a crucial role in rheumatoid arthritis (RA)-related bone loss disease. The main mechanism of action of RA induced bone loss is the significant inhibitory effect of TNF-α on osteoblast differentiation. TNF-α inhibits osteoblast differentiation mainly by activating nuclear factor (NF) -κB signaling pathway. Owing to the crucial role of TNF-α and NF-κB in the inhibition of osteoblast differentiation, they are considered as targets for the development of therapeutic drugs. In the present study, we evaluated the NF-κB inhibitor Boswellic acid (BA) and its derivatives in the regulation of osteoblast differentiation and the molecular mechanism. Based on the cell model of TNF-α induced inhibition of osteoblast differentiation of MC3T3-E1, the regulatory role of BAs was studied. The result of MTT assay indicated that bone morphogenetic protein (BMP) -2, TNF-α, or acetyl-11-keto-β-BA (AKBA) impact no significant effect for cell viability of MC3T3-E1. The results of alkaline phosphatase (ALP activity assay and real-time polymerase chain reaction indicated that AKBA blocked TNF-α-induced inhibition of the expression of osteoblast markers, suggesting that AKBA rescued osteoblast differentiation from TNF-α-induced inhibition. Additionally, AKBA stimulated the BMP-2-induced expression of osteoblast markers, suggesting that AKBA promotes osteoblast differentiation directly. The results of western blotting and luciferase assay indicated that N-κB signaling was activated by TNF-α. The overexpression of NF-κB component p65 in MC3T3-E1 was found to attenuate the positive effect of AKBA in osteoblast differentiation, suggesting that AKBA potentiates osteoblast differentiation by inhibiting NF-κB signaling. Collectively, AKBA promotes osteoblast differentiation by inhibiting TNF-α and NF-κB. Our study revealed a new discovery of AKBA in regulating osteoblast differentiation, and demonstrated that AKBA may be a potential anabolic agent in the treatment of RA-derived bone loss disease.
29746558 Anti-citrullinated protein antibody response after primary EBV infection in kidney transpl 2018 Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints, characterized by the presence of the highly disease-specific anti-citrullinated protein antibodies (ACPA) in approximately 70% of patients. Epstein-Barr virus (EBV) has previously been suggested to be involved in the pathophysiology of RA. However, given the high incidence of EBV in the general population and the difficulty of detecting initial infection, providing a direct link between EBV infection and RA development has remained elusive. We hypothesized that primary EBV infection may be a trigger for the development of the ACPA response in vivo. Using a unique cohort of 26 kidney transplant patients with a primary EBV infection, the presence of ACPA before and following infection was determined. No increase in IgG anti-CCP2 titers was detected following EBV infection. IgG anti-CCP2 antibodies were present in two patients and borderline positive in another. These three patients were HLA-DR4 negative. To test whether EBV infection may trigger a non-class switched anti-CCP2 response, IgM anti-CCP2 antibodies were analyzed. No general trend in the IgM anti-CCP2 response was observed following EBV infection. Since two out of the three IgG anti-CCP2 (borderline) positive patients were diagnosed with IgA nephropathy, 23 additional IgA nephropathy patients were tested for IgG anti-CCP2, regardless of their EBV status. All of these patients were IgG anti-CCP2 negative, indicating that IgG anti-CCP2 is not commonly present in IgA nephropathy patients. Collectively, these data do not support the hypothesis that EBV does trigger the highly RA specific ACPA response.
29609927 Complementary and alternative medicine for rheumatic diseases: A systematic review of rand 2018 Apr OBJECTIVES: To summarize all good quality randomized controlled trials (RCTs) using complementary and alternative medicine (CAM) interventions in patients with rheumatic diseases. METHODS: A systematic literature review guided by the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) was performed. We excluded non-English language articles and abstract-only publications. Due to the large number of RCTs identified, we only include "good quality" RCTs with Jadad score of five. RESULTS: We identified 60 good quality RCTs using CAM as intervention for patients with rheumatic diseases: acupuncture (9), Ayurvedic treatment (3), homeopathic treatment (3), electricity (2), natural products (31), megavitamin therapies (8), chiropractic or osteopathic manipulation (3), and energy healing therapy (1). The studies do not seem to suggest a particular type of CAM is effective for all types for rheumatic diseases. However, some CAM interventions appear to be more effective for certain types of rheumatic diseases. Acupuncture appears to be beneficial for osteoarthritis but not rheumatoid arthritis. For the other therapeutic modalities, the evidence base either contains too few trials or contains trials with contradictory findings which preclude any definitive summary. There were only minor adverse reactions observed for CAM interventions presented. CONCLUSION: We identified 60 good quality RCTs which were heterogenous in terms of interventions, disease, measures used to assess outcomes, and efficacy of CAM interventions. Evidence indicates that some CAM therapies may be useful for rheumatic diseases, such as acupuncture for osteoarthritis. Further research with larger sample size is required for more conclusive evidence regarding efficacy of CAM interventions.
29575262 Structural basis for tumor necrosis factor blockade with the therapeutic antibody golimuma 2018 Jun Tumor necrosis factor α (TNFα) is a proinflammatory cytokine, and elevated levels of TNFα in serum are associated with various autoimmune diseases, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis, and systemic lupus erythaematosus. TNFα performs its pleiotropic functions by binding to two structurally distinct transmembrane receptors, TNF receptor (TNFR) 1 and TNFR2. Antibody-based therapeutic strategies that block excessive TNFα signaling have been shown to be effective in suppressing such harmful inflammatory conditions. Golimumab (Simponi®) is an FDA-approved fully human monoclonal antibody targeting TNFα that has been widely used for the treatment of RA, AS, and CD. However, the structural basis underlying the inhibitory action of golimumab remains unclear. Here, we report the crystal structure of the Fv fragment of golimumab in complex with TNFα at a resolution of 2.73 Å. The resolved structure reveals that golimumab binds to a distinct epitope on TNFα that does not overlap with the binding residues of TNFR2. Golimumab exerts its inhibitory effect by preventing binding of TNFR1 and TNFR2 to TNFα by steric hindrance. Golimumab does not induce conformational changes in TNFα that could affect receptor binding. This mode of action is specific to golimumab among the four anti-TNFα therapeutic antibodies currently approved for clinical use.
29484638 Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853 2018 Jun GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concentrations peaked 1-3 hours after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 hours. Independent assays demonstrated dose-dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications.
29334260 Crude extract of Origanum vulgare L. induced cell death and suppressed MAPK and PI3/Akt si 2019 Jun Oregano (Origanum vulgare L.) is a common aromatic plant used in Mediterranean and Asian Regions for treating respiratory diseases, painful menstruation, rheumatoid arthritis, etc. Recently its role as an anticancer plant has been suggested, although oregano has been never evaluated into adrenocortical tumour cell models. This study analysed for the first time the anticancer effects of a crude extract of wild mountain oregano (Origanum vulgare L.) in SW13 and H295R cell lines. The crude extract was characterised by GC/MS and the toxic effects of oregano were first analysed by brine shrimp lethality assay. Our findings demonstrated that oregano decreased cell viability, survival, modified cell cycle and induced cell death (through necrotic process) and that the effects can be attributed to a blockade of MAPK and PI3 K/Akt pathways. These results suggest that oregano extract exerts anticancer activities in adrenocortical tumour cell lines, providing evidence for further research in higher models.
30007905 Epidemiology and socioeconomic impact of the rheumatic diseases on indigenous people: an i 2018 Oct Epidemiological studies in Latin America suggest indigenous people lack proper healthcare for musculoskeletal (MSK) and rheumatic diseases. OBJECTIVES: This study aimed to estimate the prevalence of MSK disorders and rheumatic diseases in eight Latin American indigenous communities, and to identify which factors influence such prevalence using network analysis and syndemic approach. METHODS: This is a cross-sectional, community-based census study according to Community-Oriented Program for the Control of Rheumatic Diseases methodology. Individuals with MSK pain, stiffness or swelling in the past and/or during the last 7 days were evaluated by participating physicians. A descriptive, univariable and multivariable analysis was performed, followed by a network analysis. RESULTS: We surveyed 6155 indigenous individuals with a mean age of 41.2 years (SD 17.6; range 18-105); 3757 (61.0%) were women. Point prevalence in rank order was: low back pain in 821 (13.3%); osteoarthritis in 598 (9.7%); rheumatic regional pain syndromes in 368 (5.9%); rheumatoid arthritis in 85 (1.3%); undifferentiated arthritis in 13 (0.2%); and spondyloarthritis in 12 (0.1%). There were marked variations in the prevalence of each rheumatic disease among the communities. Multivariate models and network analysis revealed a complex relationship between rheumatic diseases, comorbidities and socioeconomic conditions. CONCLUSIONS: The overall prevalence of MSK disorders in Latin American indigenous communities was 34.5%. Although low back pain and osteoarthritis were the most prevalent rheumatic diseases, wide variations according to population groups occurred. The relationship between rheumatic diseases, comorbidities and socioeconomic conditions allows taking a syndemic approach to the study.
30484522 Evaluation of the occurrence of sexual dysfunction and general quality of life in female p 2018 Nov/Dec BACKGROUND: Psoriasis has a significant impact on quality of life (QoL). Sexual life can also be affected, with sexual dysfunction being reported by 25-70% of patients. OBJECTIVES: To determine the occurrence of sexual dysfunction and evaluate QoL in women with psoriasis. METHODS: This case-control study included women aged 18-69 years. The validated Brazilian Portuguese versions of the Female Sexual Function Index (FSFI) and of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) were administered to all participants to assess sexual function and QoL, respectively. Patients with psoriasis underwent clinical evaluation for the presence of comorbidities, especially psoriatic arthritis and other rheumatic manifestations. Location of lesions and the extent of skin involvement were also assessed. RESULTS: The sample consisted of 150 women, 75 with diagnosis of psoriasis and 75 healthy controls. Prevalence of sexual dysfunction was high in women with psoriasis (58.6% of the sample). Prevalence was statistically higher in women with psoriasis than in controls (P = 0.014). The SF-36 domain scores were also lower in women with psoriasis, with role limitations due to physical health, limitations due to emotional problems, and mental health being the most affected domains. STUDY LIMITATIONS: Sample size was calculated to evaluate the association between the occurrence of sexual dysfunction and psoriasis, but it did not include the determination of the possible causes of this dysfunction. CONCLUSIONS: QoL and sexual function were altered in women with psoriasis and should be taken into consideration when assessing disease severity.
30425755 The Patient-Reported Outcomes Thermometer-5-Item Scale (5T-PROs): Validation of a New Tool 2018 OBJECTIVE: To investigate the construct validity, reliability (internal consistency and retest reliability), and feasibility of the patient-reported outcomes thermometer-5-item scale (5T-PROs), a new tool to measure overall health status in patients with painful chronic rheumatic diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axialSpA), and fibromyalgia (FM). METHODS: Consecutive patients have been involved in this study. The following analyses were performed to establish the validity of the 5T-PROs: (1) principal component factor analysis was used to identify the presence of a relatively small number of underlying latent factors than can be used to represent relations among sets of many variables; (2) Cronbach's alpha was calculated as an indicator of internal consistency; and (3) Pearson product-moment correlations were conducted to assess the convergent validity. The 5T-PROs was also administered a second time (two weeks after the initial administration) to a subset of sample (n = 426) to allow for calculation of test-retest reliability. We used the intraclass correlation coefficient (ICC) as an estimate of test-retest reliability. Additionally, discriminant validity was tested using analysis of variance (ANOVA) with Bonferroni post hoc multiple comparisons, in different disease conditions. Feasibility was analyzed by the time taken in completing the 5T-PROs and the proportion of patients able to complete the 5 item. RESULTS: 1,199 patients (572 with RA, 251 with axialSpA, 150 with PsA, and 226 with FM) were examined. The mean age was 55.7 (standard deviation: 13.1; range: 20 to 80) years. Factor analysis yielded two factors which accounted for 62.54% of the variance of the 5T-PROs. The first factor "Symptom Summary Score" (35.57% of the variance) revealed a good internal consistency (alpha = 0.88); the internal consistency of the second factor "Psychological Summary Score" (26.97% of the variance) was moderate (alpha = 0.69). The reliability of the whole instrument was good (alpha = 0.82). A very high correlation was obtained between Symptom Summary Score and SF-36 PCS and between pain thermometer intensity and SF-36 bodily pain. For all five items and summary scale scores of the SF-36, there was strong evidence that the mean rank of the scores differs significantly between the groups (Kruskal-Wallis tests, p < 0.001). Discriminant validity, assessed by comparing the 5T-PRO dimensions in patients with different states of disease activity, showed that the 5T-PROs show moderate association with the presence of comorbidities. It was also noted that it was inversely correlated (p=0.01) to years of formal education. CONCLUSION: The 5T-PROs is easily administered, reliable and a valid instrument for evaluating the extensive multidimensional impact associated with chronic painful rheumatic conditions.
30002096 Role of Interstitial Fluid Turnover on Target Suppression by Therapeutic Biologics Using a 2018 Oct For therapeutic biologics against soluble ligands, the magnitude and duration of target suppression affect their therapeutic efficacy. Many factors have been evaluated in relation to target suppression but the interstitial fluid turnover rate in target tissues has not been considered. Inspired by the fact that etanercept exerts limited efficacy in Crohn's disease despite its high efficacy in rheumatoid arthritis, we developed a minimal physiologically based pharmacokinetic model to investigate the role of the tissue fluid turnover rate on soluble target suppression and assessed the interrelationships between binding constants and tissue fluid turnover. Interstitial fluid turnover rates in target tissues were found to strongly influence target binding kinetics. For tissues with low fluid turnover, stable binders (low k(off)) exhibit greater target suppression, but efficacy is often restricted by accumulation of the drug-target complex. For tissues with high fluid turnover, fast binders (high k(on)) are generally favored, but a plateau effect is present for antibodies with low dissociation rates (k(off)). Etanercept is often regarded as a fast tumor necrosis factor-α (TNF-α) binder (high k(on)) despite comparable binding affinity (K(D), k(off)/k(on)) with adalimumab and infliximab. Crohn's disease largely involves the colon, a tissue with relatively slower fluid turnover than arthritis-associated joint synovium; this may explain why etanercept exerts poor TNF-α suppressive effect in Crohn's disease. This study highlights the importance of tissue interstitial fluid turnover in evaluation of therapeutic antibodies bound to soluble antigens.
29247347 Patient and physician perspectives on the impact of health-related quality of life in Mexi 2018 Apr The objective of this study is to describe aspects of health-related quality of life (HRQOL) in Mexican patients with antineutrophil cytoplasmic-associated vasculitis (AAV). Cross-sectional comparison study includes patients with established AAV and a comparison group with rheumatoid arthritis (RA), chronic kidney disease (CKD), and healthy subjects. Variables considered were: socio-demographic data, comorbidities, laboratory, disease activity, damage, and Physician's and Patient's Global Assessment (PhGA and PtGA). The following measurements were done: Pittsburg sleep quality index, Multidimesional Fatigue Inventory (MFI-20), Hospital Anxiety and Depression Scale, Short Form 36 questionnaire (SF-36), and Health Assessment Questionnaire. 60 patients with AAV were included, median age 54 years, and 60% female. Significant differences were found only in the bodily pain domain of the SF-36 (p = 0.01). Aspects of disease relevant for AAV patients were: fatigue and lack of energy; visual abnormalities; neuropathy; renal impairment; arthritis, and sinusitis. Greater total score on MFI-20 (p < 0.001) and worse PtGA (p = 0.01) were associated with worse physical health. Higher PhGA values were associated with worse physical quality of life (p = 0.01). Greater fatigue score (p = 0.002), greater anxiety-depression score (p = 0.005), and worse PtGA (p = 0.01) were associated with worse mental health quality of life. No differences were found in prevalence of sleep impairment, anxiety, depression, or disability between groups. AAV patients experienced more general and physical fatigue (p < 0.0001), and reduced activity (p = 0.01) than healthy subjects, but similar to RA and CKD patients. Vasculitis has negative effects on patients' physical and mental HRQOL.
30061888 Linking CD1-Restricted T Cells With Autoimmunity and Dyslipidemia: Lipid Levels Matter. 2018 Dyslipidemia, or altered blood lipid content, is a risk factor for developing cardiovascular disease. Furthermore, several autoimmune diseases, including systemic lupus erythematosus, psoriasis, diabetes, and rheumatoid arthritis, are correlated highly with dyslipidemia. One common thread between both autoimmune diseases and altered lipid levels is the presence of inflammation, suggesting that the immune system might act as the link between these related pathologies. Deciphering the role of innate and adaptive immune responses in autoimmune diseases and, more recently, obesity-related inflammation, have been active areas of research. The broad picture suggests that antigen-presenting molecules, which present self-peptides to autoreactive T cells, can result in either aggravation or amelioration of inflammation. However, very little is known about the role of self-lipid reactive T cells in dyslipidemia-associated autoimmune events. Given that a range of autoimmune diseases are linked to aberrant lipid profiles and a majority of lipid-specific T cells are reactive to self-antigens, it is important to examine the role of these T cells in dyslipidemia-related autoimmune ailments and determine if dysregulation of these T cells can be drivers of autoimmune conditions. CD1 molecules present lipids to T cells and are divided into two groups based on sequence homology. To date, most of the information available on lipid-reactive T cells comes from the study of group 2 CD1d-restricted natural killer T (NKT) cells while T cells reactive to group 1 CD1 molecules remain understudied, despite their higher abundance in humans compared to NKT cells. This review evaluates the mechanisms by which CD1-reactive, self-lipid specific T cells contribute to dyslipidemia-associated autoimmune disease progression or amelioration by examining available literature on NKT cells and highlighting recent progress made on the study of group 1 CD1-restricted T cells.
29909237 Glycosylation as new pharmacological strategies for diseases associated with excessive ang 2018 Nov Angiogenesis is a complex process describing the growth of new blood vessels from existing vasculature, and is triggered by local pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), which increase the metabolism of endothelial cells (ECs). Angiogenesis takes part in various physiological conditions such as embryogenesis, placental growth, and in pathological conditions such as tumor growth, diabetic retinopathy, rheumatoid arthritis (RA) and ischemic diseases. Current therapies against excessive angiogenesis target vascular growth signaling. However, tumors often counteract these therapies through adaptive mechanisms, thus novel alternative anti-angiogenic strategies are needed. Targeting metabolism is a new anti-angiogenic paradigm, especially through the inhibition of energy metabolism and glycosylation, with the perspective of maintaining the delicate balance between the beneficial and deleterious effects of excessive angiogenesis in patients. Recent studies described a role for EC glycolysis and its main regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the regulation of angiogenesis, but only few studies are related to the role of the hexosamine biosynthesis pathway during angiogenesis. Glycosylation allows the formation of glycoproteins, glycolipids and proteoglycans and impacts many pathways. The addition of glycans to N-linked proteins is catalyzed by the enzymatic activity of N-acetylglucosaminyltransferases (GnTs), which regulates the glycosylation status of key angiogenic factors such as VEGF receptor 2 (VEGFR2) and Notch. In addition, glycan-galectin (Gal) interactions regulate vascular signaling programs and may contribute to tumor adaptations to anti-angiogenic strategies. Herein, we review novel pharmacological strategies targeting glycosylation, which could be used to decrease excessive angiogenesis in pathological conditions.
29895934 Dropping anchor: attachment of peptidylarginine deiminase via A-LPS to secreted outer memb 2018 Jun 12 The periodontal pathogen Porphyromonas gingivalis has been invoked in the autoimmune disease rheumatoid arthritis (RA). This association relates to the peptidylarginine deiminase of P. gingivalis (PPAD), an enzyme capable of citrullinating human proteins and potentially contributing to loss of tolerance to citrullinated proteins in RA. PPAD is both retained in the outer membrane (OM) of P. gingivalis cells and secreted into the extracellular milieu, where it is detected in a soluble form and in association with outer membrane vesicles (OMVs). Recent studies showed that certain P. gingivalis proteins are retained in the OM through modification with an A-type lipopolysaccharide (A-LPS). Here, we investigated the possible involvement of A-LPS modification in the association of PPAD to the OM and OMVs. The results indicate that the OM- and OMV-associated PPAD is A-LPS-modified. The modified PPAD species is of low abundance in particular clinical isolates of P. gingivalis, which is not due to defects in the overall synthesis of A-LPS-modified proteins but, rather, to particular traits of the respective PPAD proteins. Lastly, we show that OMV association protects the A-LPS-modified PPAD from proteolytic degradation. Altogether, our observations show that A-LPS modification contributes to OM(V) sorting and 'protective secretion' of PPAD.
29865197 Biocompatible Gold Nanoparticles Ameliorate Retinoic Acid-Induced Cell Death and Induce Di 2018 Jun 1 The unique properties of gold nanoparticles (AuNPs) have attracted much interest for a range of applications, including biomedical applications in the cosmetic industry. The current study assessed the anti-oxidative effect of AuNPs against retinoic acid (RA)-induced loss of cell viability; cell proliferation; expression of oxidative and anti-oxidative stress markers, pro- and anti-apoptotic genes, and differentiation markers; and mitochondrial dysfunction in F9 teratocarcinoma stem cells. AuNPs were prepared by reduction of gold salts using luteolin as a reducing and stabilizing agent. The prepared AuNPs were spherical in shape with an average diameter of 18 nm. F9 cells exposed to various concentrations of these AuNPs were not harmed, whereas cells exposed to RA exhibited a dose-dependent change in cell viability and cell proliferation. The RA-mediated toxicity was associated with increased leakage of lactate dehydrogenase, reactive oxygen species, increased levels of malondialdehyde and nitric oxide, loss of mitochondrial membrane potential, and a reduced level of ATP. Finally, RA increased the level of pro-apoptotic gene expression and decreased the expression of anti-apoptotic genes. Interestingly, the toxic effect of RA appeared to be decreased in cells treated with RA in the presence of AuNPs, which was coincident with the increased levels of anti-oxidant markers including thioredoxin, glutathione peroxidases, glutathione, glutathione disulfide, catalase, and superoxide dismutase. Concomitantly, AuNPs ameliorated the apoptotic response by decreasing the mRNA expression of p53, p21, Bax, Bak, caspase-3, caspase-9, and increasing the expressions of Bcl-2 and Bcl-Xl. Interestingly, AuNPs not only ameliorated oxidative stress but also induced differentiation in F9 cells by increasing the expression of differentiation markers including retinoic acid binding protein, laminin 1, collagen type IV, and Gata 6 and decreasing the expressions of markers of stem cell pluripotency including Nanog, Rex1, octamer-binding transcription factor 4, and Sox-2. These consistent cellular and biochemical data suggest that AuNPs could ameliorate RA-induced cell death and facilitate F9 cell differentiation. AuNPs could be suitable therapeutic agents for the treatment of oxidative stress-related diseases such as atherosclerosis, cancer, diabetes, rheumatoid arthritis, and neurodegenerative diseases.