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ID PMID Title PublicationDate abstract
30412715 Autophagy protects against redox-active trace metal-induced cell death in rabbit synovial 2019 Jan 1 Reactive oxygen species (ROS) are implicated to play a role in initiating rheumatoid arthritis (RA) pathogenesis. We have investigated the mechanism(s) by which essential redox-active trace metals (RATM) may induce cell proliferation and cell death in rabbit synovial fibroblasts. These fibroblast-like synovial (FLS) cells, which express Toll-like receptor 4 (TLR4), were used as a model system that plays a role in potentially initiating RA through oxidative stress. Potassium peroxychromate (PPC, [Cr(5+)]), ferrous chloride (FeCl(2), [Fe(2+)]), and cuprous chloride (CuCl, [Cu(+)]) in the indicated valency states were used as exogenous pro-oxidants that can induce oxidative stress through TLR4 coupled activation that also causes HMGB1 release. We measured the proliferation index (PI) of FLS, and examined the effect of RATM oxidants on apoptosis and autophagy by fluorescence cell-sorting flow cytometry (FC). Cell cycle was analysed by FC and autophagy-related protein expression levels were measured by western blot. Our data showed that as RATM as prooxidants increased intracellular ROS (iROS) that can induce oxidative stress. Whereas iROS increased PI in FLS, these reactive species also protected cells against apoptosis by inducing autophagy. Our results indicate that ROS/TLR4-coupled activation may contribute to the pathogenesis of RA in FLS by induction of autophagy. The signalling pathway by which inflammation and its tissue destructive sequel may occur in RA underlies the need for developing therapeutic agents that can inhibit release of tissue-damaging high mobility group box 1 (HMGB1), cytokines, and possess both trace metal chelating capacity and oxidant scavenging properties in a directed combinatorial therapy for RA.
30399325 Hiding in plain sight: time to unlock autoimmune clues in human CD5+ B cells by using next 2018 Sep CD5+ B cells expand in many autoimmune diseases, including type 1 diabetes (T1D), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Furthermore, CD5+ B cells contain important subsets: IL-10-producing B-reg cells, FasL-expressing subset, and the majority of pre-naive B cells. In addition, they are major sources of natural autoantibodies, which are polyreactive and autoreactive. Thus, CD5+ B cells are clearly loaded with autoimmune clues that are yet to be unlocked and understood. We hypothesize that human CD5+ B cells are likely to yield enormously important novel information about the role of B cells in autoimmune disease if analyzed using the new technological advances in molecular biology and genomics. Use of high-throughput sequencing of B cell receptors (BCR) of CD5+ B cells could reveal public BCRs associated with autoimmune diseases, whereas transcriptional analysis of CD5+ B cells using single-cell RNA-seq may delineate distinct sublineages and their relationship to conventional B cells. If it turns out that autoimmune repertoires are concentrated in CD5+ B cells, given that CD5+ B cells are clearly identifiable by flow cytometry, therapeutic strategies can be developed to safely remove CD5+ B cells to mitigate ongoing autoimmunity and protect at-risk individuals.
30210502 Up-Regulation of TLR7-Mediated IFN-α Production by Plasmacytoid Dendritic Cells in Patien 2018 Objectives: Aberrant and persistent production of interferon-α (IFN-α) by plasmacytoid dendritic cells (pDCs) is known to play a key role in the pathogenesis of systemic lupus erythematosus (SLE). To assess the precise function of pDCs in SLE patients, we investigated the differential regulation of Toll-like receptor 7 (TLR7) and TLR9 responses during IFN-α production by pDCs. Methods: Peripheral blood mononuclear cells (PBMCs) in SLE patients without hydroxychloroquine treatment, rheumatoid arthritis patients and heathy controls were stimulated with TLR7 and TLR9 agonists. To investigate the priming effect by cytokines, PBMCs from healthy controls were pre-treated with various cytokines and stimulated with TLR7 and TLR9 agonists. The IFN-α production in pDCs was detected by flow cytometry. Results: TLR7-mediated IFN-α production was up-regulated and correlated positively with disease activity in SLE. Conversely, TLR9-mediated IFN-α production was down-regulated. Differential regulation of TLR7/9 response in SLE was independent of TLR7 and TLR9 expression levels. Furthermore, in vitro experiments indicated that TLR7-mediated IFN-α production was up-regulated by pre-treatment with type I IFN, whereas TLR9-mediated IFN-α production was down-regulated by pre-treatment with type II IFN. Conclusions: Our study indicates the association between up-regulation of TLR7- mediated IFN-α production by pDCs and disease activity and that TLR7 and TLR9 responses were reversely regulated on pDCs in SLE patients. Thus, type I IFN and TLR7-mediated IFN-α production were involved in a vicious cycle, causing hyper production of IFN-α by pDCs during the pathogenic processes of SLE.
30185612 Disordered haematopoiesis and cardiovascular disease: a focus on myelopoiesis. 2018 Sep 14 Cardiovascular (CV) diseases (CVD) are primarily caused by atherosclerotic vascular disease. Atherogenesis is mainly driven by recruitment of leucocytes to the arterial wall, where macrophages contribute to both lipid retention as well as the inflammatory milieu within the vessel wall. Consequently, diseases which present with an enhanced abundance of circulating leucocytes, particularly monocytes, have also been documented to accelerate CVD. A host of metabolic and inflammatory diseases, such as obesity, diabetes, hypercholesteraemia, and rheumatoid arthritis (RA), have been shown to alter myelopoiesis to exacerbate atherosclerosis. Genetic evidence has emerged in humans with the discovery of clonal haematopoiesis of indeterminate potential (CHIP), resulting in a disordered haematopoietic system linked to accelerated atherogenesis. CHIP, caused by somatic mutations in haematopoietic stem and progenitor cells (HSPCs), consequently provide a proliferative advantage over native HSPCs and, in the case of Tet2 loss of function mutation, gives rise to inflammatory plaque macrophages (i.e. enhanced interleukin (IL)-1β production). Together with the recent findings of the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trial that revealed blocking IL-1β using Canakinumab reduced CV events, these studies collectively have highlighted a pivotal role of IL-1β signalling in a population of people with atherosclerotic CVD. This review will explore how haematopoiesis is altered by risk-factors and inflammatory disorders that promote CVD. Further, we will discuss some of the recent genetic evidence of disordered haematopoiesis in relation to CVD though the association with CHIP and suggest that future studies should explore what initiates HSPC mutations, as well as how current anti-inflammatory agents affect CHIP-driven atherosclerosis.
30134246 Biochemical Properties of TAK-828F, a Potent and Selective Retinoid-Related Orphan Recepto 2018 BACKGROUND/AIMS: Retinoid-related orphan receptor gamma t (RORγt) is a master regulator of T helper 17 cells that plays a pivotal role in the production of inflammatory cytokines including interleukin (IL)-17. Therefore, RORγt has attracted much attention as a target receptor for the treatment of inflammatory diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, and psoriasis. This study aims to characterize TAK-828F, a potent and selective RORγt inverse agonist. METHODS: The biochemical properties of TAK-828F were evaluated using Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) binding assay, surface plasmon resonance (SPR) biosensor assay, cofactor recruitment assay, reporter assay, and IL-17 expression assay. RESULTS: TR-FRET binding assay and SPR biosensor assay revealed rapid, reversible, and high affinity binding of TAK-828F to RORγt. The cofactor recruitment assay showed that TAK-828F inhibited the recruitment of steroid receptor coactivator-1 to RORγt. Furthermore, TAK-828F inhibited the transcriptional activity of human and mouse RORγt with selectivity against human RORα and RORβ. TAK-828F also suppressed IL-17 production in Jurkat cells, overexpressing human RORγt. CONCLUSION: These favorable properties will be of advantage in the evaluation of TAK-828F in clinical studies for inflammatory diseases. Furthermore, these findings demonstrate that TAK-828F could serve as a pharmacological tool for further studies of RORγt and inflammatory diseases.
30118686 Evaluation of Retromode Imaging for Use in Hydroxychloroquine Retinopathy. 2018 Dec PURPOSE: To report on the application of retromode imaging using infrared lasers to eyes with hydroxychloroquine (HCQ) retinopathy, and to compare retromode images with those acquired via conventional objective screening imaging modalities-optical coherence tomography (OCT) and fundus autofluorescence (FAF). DESIGN: Diagnostic validity assessment. METHODS: Setting: Institutional. PATIENT POPULATION: Sixty-two eyes of 31 patients with systemic lupus erythematosus or rheumatoid arthritis who were treated with HCQ and developed HCQ retinopathy (patient group), 270 eyes of 135 patients with the same diseases who were treated with HCQ but exhibit no retinopathy (HCQ-taking control group), and 162 eyes of 81 normal controls (normal control group). OBSERVATION PROCEDURES: Diagnosis of HCQ retinopathy was performed with screening tests recommended by the American Academy of Ophthalmology, including OCT, FAF, and visual field examination. Retromode imaging, using confocal scanning laser ophthalmoscopy, was performed for the patient group and both control groups. The findings on retromode imaging were correlated with outer retinal changes on OCT B-scan images, then compared with the FAF findings. The sensitivity and specificity of retromode imaging were calculated. MAIN OUTCOME MEASURES: Findings of retromode imaging and sensitivity/specificity of the imaging. RESULTS: All patients with HCQ retinopathy showed a parafoveal or pericentral ring-shaped or round area of decreased reflectance with prominent deep choroidal vessels, resulting in 100% sensitivity for the detection of retinopathy. Specificity of the imaging was 73.0% and 76.4% in the HCQ-taking control group and both control groups, respectively. Compared to FAF, retromode imaging enabled the detection of photoreceptor defects with greater sensitivity, particularly in eyes with early retinopathy. However, FAF provided additional information on the status of the retinal pigment epithelium, which could not be discriminated from photoreceptor defects in retromode imaging. CONCLUSIONS: Retromode imaging may be useful for detecting HCQ retinopathy. However, its excellent sensitivity but limited specificity is suggestive of a supplementary role in screening HCQ retinopathy, particularly for early detection.
29916549 The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an 2018 Aug Sepsis‑associated encephalopathy (SAE) is a systemic inflammatory response syndrome of which the precise associated mechanisms remain unclear. Synoviolin (Syvn1) is an E3 ubiquitin ligase involved in conditions associated with chronic inflammation, including rheumatoid arthritis, obesity, fibrosis and liver cirrhosis. However, the role of Syvn1 in acute inflammation is not clear. The aim of the present study was to investigate the role of Syvn1 in a septic mouse model induced by cecal ligation/perforation (CLP). Metabolome analysis revealed that kynurenine (KYN), a key factor for the development of neuroinflammation, was increased in CLP‑induced septic mice. Notably, KYN was not detected in CLP‑induced septic Syvn1‑deficient mice. KYN is converted to kynurenic acid (KYNA) by kynurenine aminotransferases (KATs), which has a neuroprotective effect. The expression of KAT4 was significantly increased in Syvn1‑deficient mice compared to that in wild‑type mice. Promoter analysis demonstrated that Syvn1 knockdown induced the KAT4 promoter activity, as assessed by luciferase reporter activity, whereas Syvn1 overexpression repressed this activity in a dose‑dependent manner. Furthermore, the KAT4 promoter was significantly activated by the transcriptional factors, NF‑E2‑related factor 2 and peroxisome proliferator‑activated receptor coactivator 1β, which are targets of Syvn1‑induced degradation. In conclusion, the results of the current study demonstrates that the repression of Syvn1 expression induces the conversion of neurotoxic KYN to neuroprotective KYNA in a CLP‑induced mouse model of sepsis, and that Syvn1 is a potential novel target for the treatment of SAE.
35548127 SKLB023 protects mice against acute liver injury by inhibiting proinflammatory cytokine pr 2018 Sep 24 Acute liver failure is a severe clinical syndrome accompanied with excessive inflammatory response. Our previous study demonstrated that SKLB023, a novel thiazolidinedione derivative, showed potent anti-inflammatory activity in rheumatoid arthritis. The purpose of the present study is to evaluate the protective effect of SKLB023 on lipopolysaccharide (LPS)/D-GalN-induced liver failure and to explore the underlying molecular mechanisms. Our results showed that SKLB023 significantly improved mortality and liver injury as indicated by reduced serum levels of aminotransferases and alleviated pathological damage. Additionally, SKLB023 decreased the percentage of activated T cells and macrophages as well as the serum levels of cytokines in vivo. Furthermore, SKLB023 decreased levels of TNF-α and IL-6 secreted from liver macrophages (Kupffer cells) stimulated by LPS in vitro. Our results indicated that the protective effects of SKLB023 were associated with its significant impact on the inflammatory cytokines, which were produced by both T cells and macrophages.
30221712 Celastrol inhibits glucocorticoid‑induced osteoporosis in rat via the PI3K/AKT and Wnt s 2018 Nov Modern pharmacological studies revealed that Celastrol exhibits anti‑inflammation, anti‑bacteria, anti‑virus, anti‑fertility, insect‑resistance functions and has been used for the treatment of rheumatism, rheumatoid arthritis, blood diseases, skin diseases and agricultural insecticide. The present study aimed to investigate the effects of Celastrol on glucocorticoid‑induced osteoporosis (GIOP) and the underlying molecular mechanisms. The findings of the current study revealed that Celastrol reduced body weight, urine calcium/creatinine, tartrate‑resistant acid phosphatase 5b, C‑terminal telopeptide of type I collagen, and induced osteocalcin in GIOP rats. In addition, alkaline phosphatase, triiodothyronine receptor auxiliary protein and cathepsin K mRNA expression levels were effectively suppressed, and osteocalcin, bone morphogenetic protein 2, type I collagen and runt‑related transcription factor 2 mRNA expression levels were effectively induced in osteoporosis rats treated with Celastrol. Celastrol inhibited prostaglandin E2 and caspase‑3 protein expression levels, and induced phosphoinositol 3‑kinase (PI3K), phosphorylated‑protein kinase B (AKT) and glycogen synthase kinase‑3 phosphorylation, Wnt and β‑catenin protein expression in GIOP rats. The present study demonstrated that Celastrol may inhibit GIOP in rats via the PI3K/AKT and Wnt signaling pathways.
30075286 Sulfasalazine attenuates chronic constriction injury-induced neuroinflammation and mechani 2018 Sep 14 Neuropathic pain is a severe and chronic neurological disease caused by injury or disease of the somatosensory system. Currently, there are no effective treatments for neuropathic pain. Neuroinflammation, characterized by activation of spinal glial cells and increased production of pro-inflammatory cytokines (for example, IL-1β, TNF-α and IL-6), is a pathophysiological process closely related to neuropathic pain. The anti-inflammatory drug sulfasalazine (SFZ) is approved for inflammatory bowel disease and rheumatoid arthritis. Although the analgesic effect of SFZ has been reported in diabetic mice, its role in neuropathic pain caused by peripheral nerve injury has not been clarified. Here, we show that SFZ significantly alleviated mechanical hypersensitivity and attenuated neuroinflammatory response in neuropathic pain induced by chronic constriction injury (CCI) in rats. Additionally, SFZ inhibited the activation of astrocytes and abolished the CCI-induced increase of NF-κB in the spinal cord. Hence, our results show that SFZ is a potential treatment for neuropathic pain induced by peripheral nerve injury.
30603602 Interstitial Lung Disease in patients with Polymyalgia Rheumatica: A case series. 2019 INTRODUCTION: Severe morning stiffness with painful involvement of the girdles are often referred by patients with Interstitial Lung Disease (ILD), but the association between ILD and Polymyalgia Rheumatica (PMR) is rarely reported. The purpose of the work is to describe a series of patients classified as having PMR with ILD. MATERIAL AND METHODS: We retrospectively enrolled patients with a diagnosis of PMR referred to our center during the previous year for respiratory symptoms. Data concerning clinical and serological manifestations suggesting Connective Tissue Disease (CTD), High-Resolution Chest Tomography (HRCT), and Pulmonary Function Tests (PFTs) were systematically collected in order to verify the diagnosis. RESULTS: Fifteen out of seventeen PMR patients had ILD. Ten patients had a confirmed diagnosis of PMR, while in five patients a CTD was discovered. Seven patients showed a severe restrictive pattern at PFTs requiring oxygen supplementation (five with PMR and two with CTD). In thirteen patients pulmonary symptoms started before or together with muscular symptoms. Regarding HRCT patterns, patients showed a Nonspecific Interstitial Pneumonia in nine cases, Usual Interstitial Pneumonia (UIP) and possible UIP in two and three cases, and a single case of Organizing Pneumonia and Combined Pulmonary Fibrosis and Emphysema Syndrome. CONCLUSIONS: Lung involvement should be evaluated in PMR patients, especially if asthenia is poorly responsive to low doses of steroids. In these cases, the diagnosis should be re-evaluated in depth, looking for a seronegative Rheumatoid Arthritis, a clinically amyopathic myositis or Interstitial Pneumonia with Autoimmune features.
30522105 Taxifolin Inhibits Receptor Activator of NF-κB Ligand-Induced Osteoclastogenesis of Human 2019 It has been reported that taxifolin inhibit osteoclastogenesis in RAW264.7 cells. In our research, the inhibition effects of taxifolin on the osteoclastogenesis of human bone marrow-derived macrophages (BMMs) induced by receptor activator of NF-κB ligand (RANKL) as well as the protection effects in lipopolysaccharide-induced bone lysis mouse model have been demonstrated. In vitro, taxifolin inhibited RANKL-induced osteoclast differentiation of human BMMs without cytotoxicity. Moreover, taxifolin significantly suppressed RANKL-induced gene expression, including tartrate-resistant acid phosphatase, matrix metalloproteinase-9 nuclear factor of activated T cells 1 and cathepsin K, and F-actin ring formation. Further studies showed that taxifolin inhibit osteoclastogenesis via the suppression of the NF-κB signaling pathway. In vivo, taxifolin prevented bone loss in mouse calvarial osteolysis model. In conclusion, the results suggested that taxifolin has a therapeutic potential for osteoclastogenesis-related diseases such as osteoporosis, osteolysis, and rheumatoid arthritis.
30468406 Anti TNF-α therapy in patients with relapsed and refractory Langerhans cell histiocytosis 2018 Aug Tumor necrosis factor alpha (TNF-α) is produced in Langerhans cell histiocytosis (LCH) lesions and is elevated in plasma of patients with active LCH. It has been postulated that TNF-α may play a role in the pathophysiology of LCH. Etanercept, an anti-TNF-α antibody, has been used in TNF-modulated diseases such as rheumatoid arthritis (RA). We conducted a phase II study to determine the efficacy of etanercept for patients with refractory or relapsed LCH. Five LCH patients who had failed at least 2 prior treatments (range 2-9) received etanercept at a dose of 0.4 mg/kg twice weekly for up to a total of 24 doses. Disease response was assessed at 4 and 8 weeks. None of the five patients had improvement in their disease with etanercept treatment. Three progressed at week 4 and 1 progressed at week 8. One subject died after 3 weeks of treatment from disease progression. During the study, only one drug-related toxicity was noted which spontaneously resolved. The study was concluded early due to lack of response to etanercept and insufficient accrual rate. This data suggests that etanercept as given in this study may not be effective for relapsed or refractory LCH. However, the number of patients treated was not adequate enough to power this study and it is possible that a different dose and regimen of etanercept may be required to successfully treat this disease.
30381502 Clinical and laboratory profile of renal amyloidosis: A single-center experience. 2018 Sep The kidney is the most common organ involved in systemic amyloidosis. We aimed to study etiology and clinicopathological profile of renal amyloidosis. This was a retrospective study of 40 consecutive adult patients with biopsy-proven renal amyloidosis evaluated over a period of two years. Emphasis was given to describing the clinical presentation, renal function, proteinuria, type of amyloidosis, and its etiology. Mean age of the study cohort was 44 ± 15 years (with a male-to-female ratio of 3:1). Amyloid A (AA) amyloidosis was the most common type of amyloidosis observed in 72.5% of cases. Amyloid light chain (AL) amyloidosis accounted for 17.5% of cases, and the rest remained undetermined. AA amyloidosis had widespread age distribution while AL amyloidosis was confined to those >40 years. Proteinuria was the most common renal manifestation observed in all patients. Nephrotic syndrome was seen in 70% of patients. Mean 24 h proteinuria was 6.4 g. Renal failure was the second most common manifestation seen in 70% of patients, of whom 21.4% required hemodialysis. Tuberculosis (TB) accounted for 90% cases of AA amyloidosis. The most prevalent form was pulmonary TB while the rest accounted for by rheumatoid arthritis and bronchiectasis. Among patients with TB induced amyloidosis, 61.5% had received adequate treatment for TB in the past. All patients with AL amyloidosis had nephrotic range proteinuria, five had renal failure out of which two required dialysis. Cardiac involvement was seen in two patients. AA amyloidosis was the most common type of renal amyloidosis in the present study and pulmonary TB was the most common etiology.
30378146 Daidzin inhibits RANKL-induced osteoclastogenesis in vitro and prevents LPS-induced bone l 2019 Apr Osteoclasts are multinuclear giant cells responsible for bone resorption in bone loss diseases, including rheumatoid arthritis, periodontitis, and the aseptic loosening of orthopedic implants. Because of injurious side effects with currently available drugs, it is necessary to continue research novel bone-protective therapies. Daidzin, a naturally occurring isoflavone found in leguminous plants, has numerous beneficial pharmacologic effects, including anti-cancer, anti-cholesterol, and anti-angiocardiopathy, promoting osteoblasts differentiation, and even anti-osteoporosis. However, the effect of daidzin on the regulation of osteoclast activity has not yet been investigated. In this study, our study showed that daidzin significantly inhibited receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages and the hydroxyapatite-resorbing activity of mature osteoclasts by inhibiting RANKL-induced NF-kB signaling pathway. In addition, daidzin could inhibit the expression of osteoclast marker genes, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), cellular oncogene fos (c-Fos), tartrate-resistant acid phosphatase (TRAP), and cathepsin K (CTSK). Consistent with in vitro results, daidzin inhibited lipopolysaccharide-induced bone loss by suppressing the osteoclast differentiation. Together our data demonstrated that daidzin inhibits RANKL-induced osteoclastogenesis through suppressing NF-ĸB signaling pathway and that daidzin is a promising agent in the treatment of osteolytic diseases.
30303512 A three-dimensional model to study human synovial pathology. 2019 Therapeutic agents that are used by patients with rheumatic and musculoskeletal diseases were originally developed and tested in animal models, and although retrospective studies show a limited predictive value, it could be explained by the fact that there are no good in vitro alternatives. In this study, we developed a 3-dimensional synovial membrane model made of either human primary synovial cell suspensions or a mix of primary fibroblast-like synoviocytes and CD14+ mononuclear cells. We analyzed the composition of the mature micromasses by immunohistochemical staining and flow cytometry and show that the outer surface forms a lining layer consisting out of fibroblast-like and macrophage-like cells, reflecting the in vivo naïve synovial membrane. To recreate the affected synovial membrane in rheumatoid arthritis (RA), the micromasses were exposed to the pro-inflammatory cytokine Tumor Necrosis Factor Alpha (TNF-α). This led to increased pro-inflammatory cytokine expression and production and to hyperplasia of the membrane. To recreate the synovial membrane in osteoarthritis (OA), the micromasses were exposed to Transforming Growth Factor Beta (TGF-β). This led to fibrosis-like changes of the membrane, including increased Alpha Smooth Muscle Actin and increased expression of fibrosis-related genes PLOD2 and COL1A1. Interestingly, the macrophages in the micromass showed phenotypic plasticity as prolonged TNF-α or TGF-β stimulation strongly reduced the occurrence of Cluster of Differentiation 163-positive M2-like macrophages. We showed the plasticity of the micromasses as a synovial model for studying RA and OA pathology and propose that the synovial lining micromass system can be a good alternative for testing drugs.
30155844 Current Understanding of the Pathophysiology of Osteonecrosis of the Jaw. 2018 Oct PURPOSE OF REVIEW: Osteonecrosis of the jaw (ONJ) is a rare and severe necrotic bone disease reflecting a compromise in the body's osseous healing mechanisms and unique to the craniofacial region. Antiresorptive and antiangiogenic medications have been suggested to be associated with the occurrence of ONJ; yet, the pathophysiology of this disease has not been fully elucidated. This article raises the current theories underlying the pathophysiology of ONJ. RECENT FINDINGS: The proposed mechanisms highlight the unique localization of ONJ. The evidence-based mechanisms of ONJ pathogenesis include disturbed bone remodeling, inflammation or infection, altered immunity, soft tissue toxicity, and angiogenesis inhibition. The role of dental infections and the oral microbiome is central to ONJ, and systemic conditions such as rheumatoid arthritis and diabetes mellitus contribute through their impact on immune resiliency. Current experimental studies on mechanisms of ONJ are summarized. The definitive pathophysiology is as yet unclear. Recent studies are beginning to clarify the relative importance of the proposed mechanisms. A better understanding of osteoimmunology and the relationship of angiogenesis to the development of ONJ is needed along with detailed studies of the impact of drug holidays on the clinical condition of ONJ.
30120052 Eurycoma longifolia, a promising suppressor of RANKL-induced differentiation and activatio 2019 Apr BACKGROUND: Eurycoma longifolia (E. longifolia) has gained remarkable recognition due to its promising efficacy of stimulating bone formation in androgen-deficient osteoporosis. Numerous in vivo studies have explored the effects of E. longifolia on osteoporosis; however, the in vitro cellular mechanism was not discovered yet. OBJECTIVES: The present study was aimed to investigate the effect of E. longifolia on the proliferation, differentiation and maturation of osteoclasts and the translational mechanism of inhibition of osteoclastogenesis using RAW 264.7 cells as an in vitro osteoclastic model. MATERIALS AND METHODS: Having assessed cytotoxicity, the cell viability, cell proliferation rate and osteoclastic differentiation capacity of E. longifolia was investigated by evaluating the tartrate-resistant acid phosphatase (TRAP) activity in receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclasts. Taken together, the time-mannered expression of osteoclast-related protein biomarkers such as matrix metallopeptidase-9 (MMP-9), cathepsin-K, TRAP, nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), superoxide (free radicals) generation and superoxide dismutase activity were also measured to comprehend the mechanism of osteoclastogenesis. RESULTS: E. longifolia did not show significant effects on cytotoxicity and cell proliferation of RAW 264.7 cells; however, a significant inhibition of cells differentiation and maturation of osteoclasts was observed. Moreover, a significant down-regulation of RANKL-induced TRAP activity and expression of MMP-9, cathepsin-K, TRAP, NFATc1 and generation of superoxide and enhanced superoxide dismutase activity was observed in E. longifolia treated cell cultures. CONCLUSION: We anticipated that E. longifolia that enhances bone regeneration on the one hand and suppresses osteoclast's maturation on the other hand may have great therapeutic value in treating osteoporosis and other bone-erosive diseases such as rheumatoid arthritis and metastasis associated with bone loss.
29857140 Hypertension: Focus on autoimmunity and oxidative stress. 2018 Sep Understanding the causal role of the immune and inflammatory responses in hypertension has led to questions regarding the links between hypertension and autoimmunity. Immune pathology in primary hypertension mimics several autoimmune mechanisms observed in the pathogenesis of systemic lupus erythematosus, psoriasis, systemic sclerosis, rheumatoid arthritis and periodontitis. More importantly, the prevalence of hypertension in patients with these autoimmune diseases is significantly increased, when compared to control populations. Clinical and epidemiological evidence is reviewed along with possible mechanisms linking hypertension and autoimmunity. Inflammation and oxidative stress are linked in a self-perpetuating cycle that significantly contributes to the vascular dysfunction and renal damage associated with hypertension. T cell, B cell, macrophage and NK cell infiltration into these organs is essential for this pathology. Effector cytokines such as IFN-γ, TNF-α and IL-17 affect Na(+)/H(+) exchangers in the kidney. In blood vessels, they lead to endothelial dysfunction and loss of nitric oxide bioavailability and cause vasoconstriction. Both renal and vascular effects are, in part, mediated through induction of reactive oxygen species-producing enzymes such as superoxide anion generating NADPH oxidases and dysfunction of anti-oxidant systems. These mechanisms have recently become important therapeutic targets of novel therapies focused on scavenging oxidative (isolevuglandin) modification of neo-antigenic peptides. Effects of classical immune targeted therapies focused on immunosuppression and anti-cytokine treatments are also reviewed.
29731818 Methotrexate remediates spinal cord injury in vivo and in vitro via suppression of endopla 2018 May It has been suggested that endoplasmic reticulum stress (ERS) may induce apoptosis following spinal cord injury (SCI). Methotrexate (MTX) has been used as a long-term therapy regimen for rheumatoid arthritis. However, it is not clear whether MTX remediates SCI by inhibiting ERS. In the present study, to establish an in vitro ERS cell model, PC12 cells were pre-incubated with triglycerides (TG). MTT assays revealed that treatment with 1, 2.5, 5 and 10 µM TG decreased PC12 cell viability in a dose-dependent manner. Additionally, MTX treatment significantly reversed the TG-induced decrease in cell viability and increased apoptosis according to the flow cytometry assay (P<0.05). Notably, western blotting indicated that MTX significantly decreased levels of glucose-regulated protein (GRP)78, CCAAT-enhancer-binding protein homologous protein (CHOP) and caspase-12 expression (P<0.05), which were increased following treatment with TG. Furthermore, the in vivo role of MTX in a rat model of SCI was evaluated. The motor behavioral function of rats was improved following treatment with MTX according to Basso, Beattie and Bresnahan scoring (P<0.05). Terminal deoxynucleotidyl-transferase-mediated dUTP nick end staining indicated that there were no apoptotic cells present in sham rats. In the SCI model group, apoptotic cells were observed at day 7; however, the number of apoptotic cells was reduced following an additional 7 days of MTX administration. Furthermore, levels of ERS-associated proteins, including caspase-3, activating transcription factor 6, serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 α, eukaryotic initiation factor 2 α and GRP78, were significantly increased following SCI; however, administration of MTX for 7 days significantly reversed this effect (P<0.05, P<0.01 and P<0.001). Therefore, MTX may improve SCI by suppressing ERS-induced apoptosis in vitro and in vivo.