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ID PMID Title PublicationDate abstract
29894742 Association of high 5-hydroxymethylcytosine levels with Ten Eleven Translocation 2 overexp 2018 Nov Here, we determined the 5-hydroxymethylcytosine (5hmC), 5-methylcytosine (5mC), Ten Eleven Translocation (TETs), and DNA methyltransferases (DNMTs) levels in epithelial and inflammatory cells of labial salivary glands (LSG) from Sjögren's syndrome (SS)-patients and the effect of cytokines on HSG cells. LSG from SS-patients, controls and HSG cells incubated with cytokines were analysed. Levels of 5mC, 5hmC, DNMTs, TET2 and MeCP2 were assessed by immunofluorescence. In epithelial cells from SS-patients, an increase in TET2, 5hmC and a decrease in 5mC and MeCP2 were observed, additionally, high levels of 5mC and DNMTs and low levels of 5hmC were detected in inflammatory cells. Cytokines increased TET2 and 5hmC and decreased 5mC levels. Considering that the TET2 gene.promoter contains response elements for transcription factors activated by cytokines, together to in vitro results suggest that changes in DNA hydroxymethylation, resulting from altered levels of TET2 are likely to be relevant in the Sjögren's syndrome etiopathogenesis.
29977900 Analysis of pulmonary features and treatment approaches in the COPA syndrome. 2018 Apr The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered. We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics. All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy. COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment.
30167765 Validation and cultural adaptation of the qualisex questionnaire in patients with axial sp 2018 Nov The Qualisex questionnaire was developed and validated to assess sexuality in patients with rheumatoid arthritis. To the best of our knowledge, there is no instrument to evaluate sexuality in axial spondyloarthritis (axSpA). For this reason, the objective of this study was to validate and adapt the Qualisex questionnaire in axSpA and evaluate the impact of the disease on patients' sexuality. Cross sectional study. Consecutive patients, with ≥ 21 years of age, diagnosed with axSpA according to ASAS'09 criteria were included. Sexual health was assessed using the Qualisex questionnaire. The original version was translated to Spanish and adapted to axSpA. Internal consistency, and test re-test reliability was calculated. Criterion and construct validity were assessed by comparing the Qualisex with parameters of disease activity functional capacity and quality of life. 61 patients were invited to participate in the study, 11 of whom refused. 50 patients were included; 40 (80%) were males, with a median age of 47 years (IQR 21-72) and a median disease duration of 13 years (IQR 1-46). Reproducibility was excellent with an ICC of 0.99 (95% CI 0.65-1). The Qualisex had a good correlation with different disease evaluation parameters. The Qualisex was significantly higher among women (5.4 in women vs. 2.5 in men, p = 0.02), unemployed (4.7 in unemployed vs. 2.3 in employed, p = 0.01), in patients with higher disease activity (4.2 in active patients vs. 1.6 in inactive patients, p = 0.01), and it was lower in patients receiving biologic therapy (BT) (1.9 with BT vs. 3.8 without BT, p = 0.01). Multivariable analysis showed that female sex, longer disease duration and higher disease activity were independently associated with a greater impact on sexuality. The Qualisex adapted to axSpA is a valid and reliable questionnaire. Female axSpA patients, those with longer disease duration and higher disease activity presented a worse sexual life.
30337056 Tumor necrosis factor inhibitors and risk of peripheral neuropathy in patients with rheuma 2019 Jun IMPORTANCE: Tumor necrosis factor inhibitors (TNFi) are widely used in the treatment of a variety of autoimmune diseases. A number of case reports have linked TNFi to neurologic adverse events including peripheral neuropathy (PN) in patients with rheumatic diseases. OBJECTIVES: To quantify the risk of peripheral neuropathy with TNFi in patients with rheumatic diseases. DESIGN: Nested-Case Control study within a cohort of patients with rheumatic diseases. SETTING: PharMetrics Plus™ health claims database from the United States. PARTICIPANTS: From a random sample of 9,053,240 subjects from the PharMetrics Plus™ database a cohort of patients with rheumatic diseases who had two physician visit codes for rheumatoid arthritis, ankylosing spondylitis and psoriasis in addition to a medication used in the treatment of each condition from 2006 to 2016 was created. EXPOSURE: We created different risk periods of current use (day 0-60), recent use (day 61-180) and past use (day 180-365) from the index date. MAIN OUTCOME MEASURES: New cases of PN were identified from the rheumatic disease cohort. Each case was matched to 10 controls by calendar time and age using density based sampling. Rate ratios (RRs) for new users of TNFi were computed using conditional logistic regression adjusting for gender, vitamin B(12) deficiency, fluoroquinolone use, HIV, viral hepatitis, chronic renal failure and diabetes. RESULTS: Among a cohort of 61,570 patients with rheumatic diseases 1358 cases of PN and 13,580 corresponding controls were identified. The adjusted rate ratio (RR) of PN among recent users of TNFi was 1.14 (95% CI:0.90-1.43). The RR for past use of TNFi was 2.77 (95% CI:1.67-4.58). Past users who used three or more prescriptions had a higher risk of PN 3.49 (1.63-7.49). The RRs did not change when the risk of PN with TNFi was compared to those taking methotrexate and one additional disease modifying anti rheumatic drug (DMARD) for recent and past use (RR = 0.95 [95% CI:0.72-1.24] and RR = 2.30 (1.37-3.87), respectively). CONCLUSIONS: Patients with rheumatic diseases who are past users of TNFi are at higher risk of developing PN compared to those taking methotrexate and one additional DMARD.
30139951 The protein tyrosine phosphatase PTPN22 negatively regulates presentation of immune comple 2018 Aug 23 A C1858T single nucleotide polymorphism within PTPN22 (which encodes PTPN22(R620W)) is associated with an enhanced susceptibility to multiple autoimmune diseases including type 1 diabetes and rheumatoid arthritis. Many of the associated autoimmune diseases have an autoantibody component to their pathology. Fc receptors (FcRs) recognise autoantibodies when they bind to autoantigens and form immune complexes. After immune complex binding and receptor crosslinking, FcRs signal via Src and Syk family kinases, leading to antigen uptake, presentation and cytokine secretion. Ptpn22 encodes a protein tyrosine phosphatase that negatively regulates Src and Syk family kinases proximal to immunoreceptor signalling cascades. We therefore hypothesised that PTPN22 regulates immune complex stimulated FcR responses in dendritic cells (DCs). Bone marrow derived DCs (BMDCs) from wild type (WT) or Ptpn22(-/-) mice were pulsed with ovalbumin:anti-ovalbumin immune complexes (ova ICs). Co-culture with WT OT-II T cells revealed that ova IC pulsed Ptpn22(-/-) BMDCs have an enhanced capability to induce T cell proliferation. This was associated with an increased capability of Ptpn22(-/-) BMDCs to present immune complex derived antigens and to form ova IC dependent DC-T cell conjugates. These findings highlight PTPN22 as a regulator of FcR mediated responses and provide a link between the association of PTPN22(R620W) with autoantibody associated autoimmune diseases.
30459279 Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory 2019 Feb OBJECTIVE: Immune complexes (ICs) play a critical role in the pathology of autoimmune diseases. The aim of this study was to generate and characterise a first-in-class anti-FcγRIIA antibody (Ab) VIB9600 (previously known as MEDI9600) that blocks IgG immune complex-mediated cellular activation for clinical development. METHODS: VIB9600 was humanised and optimised from the IV.3 Ab. Binding affinity and specificity were determined by Biacore and ELISA. Confocal microscopy, Flow Cytometry-based assays and binding competition assays were used to assess the mode of action of the antibody. In vitro cell-based assays were used to demonstrate suppression of IC-mediated inflammatory responses. In vivo target suppression and efficacy was demonstrated in FcγRIIA-transgenic mice. Single-dose pharmacokinetic (PK)/pharmacodynamic study multiple dose Good Laboratory Practice (GLP) toxicity studies were conducted in non-human primates. RESULTS: We generated a humanised effector-deficient anti-FcγRIIA antibody (VIB9600) that potently blocks autoantibody and IC-mediated proinflammatory responses. VIB9600 suppresses FcγRIIA activation by blocking ligand engagement and by internalising FcγRIIA from the cell surface. VIB9600 inhibits IC-induced type I interferons from plasmacytoid dendritic cells (involved in SLE), antineutrophil cytoplasmic antibody (ANCA)-induced production of reactive oxygen species by neutrophils (involved in ANCA-associated vasculitis) and IC-induced tumour necrosis factor α and interleukin-6 production (involved in rheumatoid arthritis). In FcγRIIA transgenic mice, VIB9600 suppressed antiplatelet antibody-induced thrombocytopaenia, acute anti-GBM Ab-induced nephritis and anticollagen Ab-induced arthritis. VIB9600 also exhibited favourable PK and safety profiles in cynomolgus monkey studies. CONCLUSIONS: VIB9600 is a specific humanised antibody antagonist of FcγRIIA with null effector function that warrants further clinical development for the treatment of IC-mediated diseases.
29735171 High rates of tuberculin skin test positivity due to methotrexate therapy: False positive 2018 Dec RATIONALE: The tuberculin skin test (TST) and interferon ? release assays (IGRAs) are commonly used for latent tuberculosis infection (LTBI) screening. Unexpectedly high TST positivity rates have been reported in patients with rheumatic diseases, and methotrexate is frequently used in this population. We hypothesized that methotrexate use could be associated with false-positive TST results. OBJECTIVES: To investigate whether treatment with methotrexate and other factors are associated with false-positive TST results in patients with rheumatic diseases. METHODS: Prospective single-center study conducted between April 2013 and March 2016. Adult patients with rheumatic diseases were evaluated with a TST and two IGRAs for LTBI screening. We compared TST and IGRA results in patients treated and not treated with methotrexate and analyzed for factors associated with positive TST results. CONCLUSIONS: Our data suggest false-positive TST results associated with methotrexate therapy. Thus, we recommend against using the TST for LTBI screening in patients receiving methotrexate and the preferential use of IGRAs in such patients. MEASUREMENTS AND MAIN RESULTS: We studied 393 patients with rheumatic diseases, including ankylosing spondylitis (ASP, n = 90), rheumatoid arthritis (RA; n = 120), psoriatic arthritis (PA, n = 126), and other disorders (n = 57). The rate of TST positivity varied across the groups: ASP 22.2%, RA 25%, PA 35.7%, and other disorders (22.8%). Positivity rates were lower with IGRAs. Methotrexate use was associated with a statistically significant two-fold increase in the risk of a positive TST and a dosex96 response relationship was observed. We found no statistically significant associations between methotrexate use and IGRA test positivity.
30428613 The Biological Efficacy of Natural Products against Acute and Chronic Inflammatory Disease 2018 Nov 13 The oral inflammatory diseases are divided into two types: acute and chronic inflammatory diseases. In this review, we summarize the biological efficacy of herbal medicine, natural products, and their active ingredients against acute and chronic inflammatory diseases in the oral region, especially stomatitis and periodontitis. We review the effects of herbal medicines and a biscoclaurin alkaloid preparation, cepharamthin, as a therapy against stomatitis, an acute inflammatory disease. We also summarize the effects of herbal medicines and natural products against periodontitis, a chronic inflammatory disease, and one of its clinical conditions, alveolar bone resorption. Recent studies show that several herbal medicines such as kakkonto and ninjinto reduce LPS-induced PGE 2 production by human gingival fibroblasts. Among herbs constituting these herbal medicines, shokyo (Zingiberis Rhizoma) and kankyo (Zingiberis Processum Rhizoma) strongly reduce PGE 2 production. Moreover, anti-osteoclast activity has been observed in some natural products with anti-inflammatory effects used against rheumatoid arthritis such as carotenoids, flavonoids, limonoids, and polyphenols. These herbal medicines and natural products could be useful for treating oral inflammatory diseases.
30359170 The Oral Microbiota Is Modified by Systemic Diseases. 2019 Feb Periodontal diseases are initiated by bacteria that accumulate in a biofilm on the tooth surface and affect the adjacent periodontal tissue. Systemic diseases such as diabetes, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) increase susceptibility to destructive periodontal diseases. In human studies and in animal models, these diseases have been shown to enhance inflammation in the periodontium and increase the risk or severity of periodontitis. All 3 systemic diseases are linked to a decrease in bacterial taxa associated with health and an increase in taxa associated with disease. Although there is controversy regarding the specific oral bacterial changes associated with each disease, it has been reported that diabetes increases the levels of Capnocytophaga, Porphyromonas, and Pseudomonas, while Prevotella and Selenomonas are increased in RA and Selenomonas, Leptotrichia, and Prevotella in SLE. In an animal model, diabetes increased the pathogenicity of the oral microbiome, as shown by increased inflammation, osteoclastogenesis, and periodontal bone loss when transferred to normal germ-free hosts. Moreover, in diabetic animals, the increased pathogenicity could be substantially reversed by inhibition of IL-17, indicating that host inflammation altered the microbial pathogenicity. Increased IL-17 has also been shown in SLE, RA, and leukocyte adhesion deficiency and may contribute to oral microbial changes in these diseases. Successful RA treatment with anti-inflammatory drugs partially reverses the oral microbial dysbiosis. Together, these data demonstrate that systemic diseases characterized by enhanced inflammation disturb the oral microbiota and point to IL-17 as key mediator in this process.
30098424 Sarcopenia. 2019 May Sarcopenia is defined as a combination of low muscle mass with low muscle function. The term was first used to designate the loss of muscle mass and performance associated with aging. Now, recognized causes of sarcopenia also include chronic disease, a physically inactive lifestyle, loss of mobility, and malnutrition. Sarcopenia should be differentiated from cachexia, which is characterized not only by low muscle mass but also by weight loss and anorexia. Sarcopenia results from complex and interdependent pathophysiological mechanisms that include aging, physical inactivity, neuromuscular compromise, resistance to postprandial anabolism, insulin resistance, lipotoxicity, endocrine factors, oxidative stress, mitochondrial dysfunction, and inflammation. The prevalence of sarcopenia ranges from 3% to 24% depending on the diagnostic criteria used and increases with age. Among patients with rheumatoid arthritis 20% to 30% have sarcopenia, which correlates with disease severity. Sarcopenia exacts a heavy toll of functional impairment, metabolic disorders, morbidity, mortality, and healthcare costs. Thus, the consequences of sarcopenia include disability, quality of life impairments, falls, osteoporosis, dyslipidemia, an increased cardiovascular risk, metabolic syndrome, and immunosuppression. The adverse effects of sarcopenia are particularly great in patients with a high fat mass, a condition known as sarcopenic obesity. The diagnosis of sarcopenia rests on muscle mass measurements and on functional tests that evaluate either muscle strength or physical performance (walking, balance). No specific biomarkers have been identified to date. The management of sarcopenia requires a multimodal approach combining a sufficient intake of high-quality protein and fatty acids, physical exercise, and antiinflammatory medications. Selective androgen receptor modulators and anti-myostatin antibodies are being evaluated as potential stimulators of muscle anabolism.
30084334 A Recent Update on the Effects of Omega-3 Fatty Acids in Alzheimer's Disease. 2018 Dietary long chain polyunsaturated fatty acids belong to omega (ω)-3, -6 or -9 series. Both experimental and clinical studies demonstrated the beneficial effect of ω -3 fatty acids of fish oil, Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) against human ailments including cardiovascular diseases and rheumatoid arthritis. They are metabolized in cyclooxygenase and lipooxygenase pathways and also by cytochrome P450 isozymes. Biological importance of DHA in the development of brain and retina are well established. Recent studies highlighted the beneficial effect of ω-3 fatty acids in Alzheimer's Disease (AD) which may be attributed to their antioxidant, anti-inflammatory, antiapoptotic and neurotrophic properties. The effect was obtained by the consumption of either individual or combination of ω -3 fatty acids. The anti-inflammatory effect can be ascribed to the decreased cytokines and monocytic chemotactic protein-1 level by suppressing the nuclear factor-kappa B. Further, they inhibit cyclooxygenase-2 and nitric oxide synthase-2 activities. The antiapoptotic activity is due to the lowered Bax/Bcl ratio or caspase 3 levels. They can induce the transcription factor, nuclear erythroid factor-2 mediated expression of superoxide dismutase- 2 in order to facilitate the antioxidant effect. Both DHA and EPA can enhance the nerve growth factor level. Overall, they are beneficial to improve the cognitive function in very mild AD and major depressive disorder. Despite the beneficial effects, ω-3 fatty acids are easily prone to peroxidation. This review article discusses the recent update on the roles of ω -3 fatty acids in AD.
29971194 Conditions Associated with Essential Tremor in Veterans: A Potential Role for Chronic Stre 2018 BACKGROUND: Increased depression, hearing loss, dementia, alcoholism, and mortality in essential tremor patients remain unexplained. We investigated whether conditions associated with tremor are linked to chronic stress. METHODS: The FY2013 Veterans Affairs database was queried for 38 selected dual diagnosis combinations in 5,854,223 veterans aged 21-95 years. RESULTS: Post-traumatic stress disorder, anxiety, and depression were the most common psychiatric diagnoses in tremor patients, with the odds ratio exceeding 2 in all 15-year cohorts. Depending on age, patients with essential tremor were more likely than those without to have obsessive-compulsive disorder, bipolar illness, schizophrenia, use tobacco and abuse alcohol, have hypertension, obesity, hyperlipidemia, diabetes, vitamin D deficiency, coronary and cerebrovascular diseases, congestive heart failure, stroke, asthma, hypothyroidism, irritable bowel syndrome, renal insufficiency, alcoholic liver disease, hearing loss, glaucoma, macular degeneration, migraine, epilepsy, idiopathic polyneuropathy, history of head trauma, and 'Alzheimer's dementia. In contrast, lung and colorectal cancer, amyotrophic lateral sclerosis, psychostimulant abuse, and rheumatoid arthritis were not more common. DISCUSSION: Post-traumatic stress disorder, anxiety, and depression, strongly associated with essential tremor, are known risk factors for poor health habits, tobacco use and alcohol abuse; collectively these are risk factors for vascular disease, with further negative health consequences for multiple organ systems. As essential tremor is associated with all these conditions, we propose that chronic stress is not only responsible for the conditions associated with tremor but in some cases itself directly and indirectly induces essential tremor, so that tremor and poor health share a common cause.
29902157 Therapeutic potential of JAK/STAT pathway modulation in mood disorders. 2018 Dec 19 Convergent evidence demonstrates that immune dysfunction (e.g. chronic low-grade inflammatory activation) plays an important role in the development and progression of mood disorders. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway is a pleiotropic cellular cascade that transduces numerous signals, including signals from the release of cytokines and growth factors. The JAK/STAT signaling pathway is involved in mediating several functions of the central nervous system, including neurogenesis, synaptic plasticity, gliogenesis, and microglial activation, all of which have been implicated in the pathophysiology of mood disorders. In addition, the antidepressant actions of current treatments have been shown to be mediated by JAK/STAT-dependent mechanisms. To date, two JAK inhibitors (JAKinibs) have been approved by the U.S. Food and Drug Administration and are primarily indicated for the treatment of inflammatory conditions such as rheumatoid arthritis. Indirect evidence from studies in populations with inflammatory conditions indicates that JAKinibs significantly improve measures of mood and quality of life. There is also direct evidence from studies in populations with depressive disorders, suggesting that JAK/STAT pathways may be involved in the pathophysiology of depression and that the inhibition of specific JAK/STAT pathways (i.e. via JAKinibs) may be a promising novel treatment for depressive disorders.
29845555 [S3 guidelines on treatment of polymyalgia rheumatica : Evidence-based guidelines of the G 2018 Jun Polymyalgia rheumatica (PMR) occurs almost exclusively in persons aged 50 years or older and it is the second most common inflammatory rheumatic disease in older people after rheumatoid arthritis. Since there are no specific tests for PMR, the exclusion of clinically similar differential diagnoses is essential to ascertain the diagnosis. These recommendations for the management of PMR assume an already established diagnosis of PMR. It is recommended to initiate treatment with glucocorticoids immediately after diagnosis and to provide appropriate patient information and education about the impact of the disease and its treatment. Methotrexate should be considered in patients at high risk for relapse and/or glucocorticoid-related adverse events. These guidelines have been elaborated because there is significant heterogeneity in the management of PMR in clinical practice in Germany (but also Europe and worldwide), despite the large number of patients with this disease. These guidelines are primarily based on the 2015 EULAR-ACR recommendations for the management of PMR, which were updated by the guideline committee and adapted to the German speaking countries.
29791652 Inflammatory myopathy in the context of an unusual overlapping laminopathy. 2018 Jun Laminopathies are genetic disorders associated with alterations in nuclear envelope proteins, known as lamins. The LMNA gene encodes lamins A and C, and LMNA mutations have been linked to diseases involving fat (type 2 familial partial lipodystrophy [FPLD2]), muscle (type 2 Emery-Dreifuss muscular dystrophy [EDMD2], type 1B limb-girdle muscular dystrophy [LGMD1B], and dilated cardiomyopathy), nerves (type 2B1 Charcot-Marie-Tooth disease), and premature aging syndromes. Moreover, overlapping syndromes have been reported. This study aimed to determine the genetic basis of an overlapping syndrome in a patient with heart disease, myopathy, and features of lipodystrophy, combined with severe metabolic syndrome. We evaluated a 54-year-old woman with rheumatoid arthritis, chronic hypercortisolism (endogenous and exogenous), and a history of cured adrenal Cushing syndrome. The patient presented with a complex disorder, including metabolic syndrome associated with mild partial lipodystrophy (Köbberling-like); mild hypertrophic cardiomyopathy, with Wolff-Parkinson- White syndrome and atrial fibrillation; and limb-girdle inflammatory myopathy. Mutational analysis of the LMNA gene showed a heterozygous c.1634G>A (p.R545H) variant in exon 10 of LMNA. This variant has previously been independently associated with FPLD2, EDMD2, LGMD1B, and heart disease. We describe a new, LMNA-associated, complex overlapping syndrome in which fat, muscle, and cardiac disturbances are related to a p.R545H variant.
29731716 Protective Effect of Casperome(®), an Orally Bioavailable Frankincense Extract, on Lipopo 2018 Introduction: Despite recent advances in critical care, sepsis remains a crucial cause of morbidity and mortality in intensive care units. Therefore, the identification of new therapeutic strategies is of great importance. Since ancient times, frankincense is used in traditional medicine for the treatment of chronic inflammatory disorders such as rheumatoid arthritis. Thus, the present study intends to evaluate if Casperome(®) (Casp), an orally bioavailable soy lecithin-based formulation of standardized frankincense extract, is able to ameliorate systemic effects and organ damages induced by severe systemic inflammation using a murine model of sepsis, i.e., intraperitoneal administration of lipopolysaccharides (LPS). Methods: Male 60-day-old mice were assigned to six treatment groups: (1) control, (2) LPS, (3) soy lecithin (blank lecithin without frankincense extract), (4) Casp, (5) soy lecithin plus LPS, or (6) Casp plus LPS. Soy lecithin and Casp were given 3 h prior to LPS treatment; 24 h after LPS administration, animals were sacrificed and health status and serum cytokine levels were evaluated. Additionally, parameters representing liver damage or liver function and indicating oxidative stress in different organs were determined. Furthermore, markers for apoptosis and immune cell redistribution were assessed by immunohistochemistry in liver and spleen. Results: LPS treatment caused a decrease in body temperature, blood glucose levels, liver glycogen content, and biotransformation capacity along with an increase in serum cytokine levels and oxidative stress in various organs. Additionally, apoptotic processes were increased in spleen besides a pronounced immune cell infiltration in both liver and spleen. Pretreatment with Casp significantly improved health status, blood glucose values, and body temperature of the animals, while serum levels of pro-inflammatory cytokines and oxidative stress in all organs tested were significantly diminished. Finally, apoptotic processes in spleen, liver glycogen loss, and immune cell infiltration in liver and spleen were distinctly reduced. Casp also appears to induce various cytochromeP450 isoforms, thus causing re-establishment of liver biotransformation capacity in LPS-treated mice. Conclusion: Casp displayed anti-inflammatory, anti-oxidative, and hepatoprotective effects. Thus, orally bioavailable frankincense extracts may serve as a new supportive treatment option in acute systemic inflammation and accompanied liver dysfunction.
29669309 Emodin ameliorates ulcerative colitis by the flagellin-TLR5 dependent pathway in mice. 2018 Jun Emodin is an anthraquinone compound derived from Rheum officinale Baill. Several reports showed that emodin had efficacy on acute pancreatitis, keratitis, myocarditis, and rheumatoid arthritis. However, the potency of emodin on ulcerative colitis(UC) remains unclear. In this study, we investigated the effect of emodin on dextran sodium sulfate (DSS)-induced ulcerative colitis in mice. Our results showed that emodin significantly alleviated the symptoms of DSS-induced UC in mice, involving prevented the loss of body weight and colon shortening, decreased the disease activity index (DAI), intestinal damages and the count of white blood cells (WBC) in peripheral blood. In addition, emodin treatment decreased the level of anti-flagellin antibody in serum and significantly down-regulated the expression of TLR5 and NF-κB p65 in colon of the UC mice. Further study in vitro showed that emodin down-regulated the expression of TLR5 and MyD88, up-regulated the expression of IκB, inhibited the nuclear translocation of NF-κB p65 and decreased the release of IL-8 in flagellin-stimulated HT-29 cells. These results, for the first time, demonstrated that emodin had the therapeutic potential to ameliorate UC symptoms possibly via regulating the flagellin-TLR5 signaling pathway. Emodin may be a potential candidate ingredient for ulcerative colitis.
29545809 The Autoimmune Skin Disease Bullous Pemphigoid: The Role of Mast Cells in Autoantibody-Ind 2018 Bullous pemphigoid (BP) is an autoimmune and inflammatory skin disease associated with subepidermal blistering and autoantibodies directed against the hemidesmosomal components BP180 and BP230. Animal models of BP were developed by passively transferring anti-BP180 IgG into mice, which recapitulates the key features of human BP. By using these in vivo model systems, key cellular and molecular events leading to the BP disease phenotype are identified, including binding of pathogenic IgG to its target, complement activation of the classical pathway, mast cell degranulation, and infiltration and activation of neutrophils. Proteinases released by infiltrating neutrophils cleave BP180 and other hemidesmosome-associated proteins, causing DEJ separation. Mast cells and mast cell-derived mediators including inflammatory cytokines and proteases are increased in lesional skin and blister fluids of BP. BP animal model evidence also implicates mast cells in the pathogenesis of BP. However, recent studies questioned the pathogenic role of mast cells in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and epidermolysis bullosa acquisita. This review highlights the current knowledge on BP pathophysiology with a focus on a potential role for mast cells in BP and mast cell-related critical issues needing to be addressed in the future.
29545794 Influence of Inflammation in the Process of T Lymphocyte Differentiation: Proliferative, M 2018 T lymphocytes, from their first encounter with their specific antigen as naïve cell until the last stages of their differentiation, in a replicative state of senescence, go through a series of phases. In several of these stages, T lymphocytes are subjected to exponential growth in successive encounters with the same antigen. This entire process occurs throughout the life of a human individual and, earlier, in patients with chronic infections/pathologies through inflammatory mediators, first acutely and later in a chronic form. This process plays a fundamental role in amplifying the activating signals on T lymphocytes and directing their clonal proliferation. The mechanisms that control cell growth are high levels of telomerase activity and maintenance of telomeric length that are far superior to other cell types, as well as metabolic adaptation and redox control. Large numbers of highly differentiated memory cells are accumulated in the immunological niches where they will contribute in a significant way to increase the levels of inflammatory mediators that will perpetuate the new state at the systemic level. These levels of inflammation greatly influence the process of T lymphocyte differentiation from naïve T lymphocyte, even before, until the arrival of exhaustion or cell death. The changes observed during lymphocyte differentiation are correlated with changes in cellular metabolism and these in turn are influenced by the inflammatory state of the environment where the cell is located. Reactive oxygen species (ROS) exert a dual action in the population of T lymphocytes. Exposure to high levels of ROS decreases the capacity of activation and T lymphocyte proliferation; however, intermediate levels of oxidation are necessary for the lymphocyte activation, differentiation, and effector functions. In conclusion, we can affirm that the inflammatory levels in the environment greatly influence the differentiation and activity of T lymphocyte populations. However, little is known about the mechanisms involved in these processes. The elucidation of these mechanisms would be of great help in the advance of improvements in pathologies with a large inflammatory base such as rheumatoid arthritis, intestinal inflammatory diseases, several infectious diseases and even, cancerous processes.
29251559 Structural refinement and prediction of potential CCR2 antagonists through validated multi 2019 Jan Chemokines trigger numerous inflammatory responses and modulate the immune system. The interaction between monocyte chemoattractant protein-1 and chemokine receptor 2 (CCR2) may be the cause of atherosclerosis, obesity, and insulin resistance. However, CCR2 is also implicated in other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, asthma, and neuropathic pain. Therefore, there is a paramount importance of designing potent and selective CCR2 antagonists despite a number of drug candidates failed in clinical trials. In this article, 83 CCR2 antagonists by Jhonson and Jhonson Pharmaceuticals have been considered for robust validated multi-QSAR modeling studies to get an idea about the structural and pharmacophoric requirements for designing more potent CCR2 antagonists. All these QSAR models were validated and statistically reliable. Observations resulted from different modeling studies correlated and validated results of other ones. Finally, depending on these QSAR observations, some new molecules were proposed that may exhibit higher activity against CCR2.