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ID PMID Title PublicationDate abstract
30798208 Systematic screening and characterization of prototype constituents and metabolites of tri 2019 May 10 Triterpenoid saponins are the main bioactive components in Caulopphyllum Robustum Maxim (CRM), and they have been reported to have extensive pharmacological properties, such as anti-inflammatory, immunomodulatory, and anti-tumor effects. Cauloside C, Cauloside D, Leonticin D and Cauloside H are the main active chemical constituents of CRM in the treatment of rheumatoid arthritis (RA). However, their metabolic processes and products remain unclear. Therefore, the purpose of this study was to analyze the metabolic components and metabolic pathways of total saponins after oral administration of CRM effective part (CRME) in rats. In this work, we collected plasma, bile, urine and feces of rats at different sampling time points after intragastric administration. The saponins and reference substances were separated from CRME and analyzed via Thermo Scientific(â„¢) Ultra Performance Liquid Chromatography-Orbitrap Elite Combined High resolution Mass Spectrometry. According to the structural characteristics of the compounds in CRM, the pyrolysis behavior of various components was inferred in the negative ion mode. Twenty-two components were found in rat plasma, bile, urine and stool; among these components, there were 8 prototypes and 14 metabolites. Seven prototypes and 8 metabolites were found in rat plasma; no prototype and 6 metabolites were found in bile; 5 prototypes and 8 metabolites were found in urine; and 4 prototypes and 9 metabolites were found in stool. The metabolites include deglycosylation products, sapogenin products, sulfides, and glucuronide conjugates. The same metabolites were also found in biological samples, and these products may be important metabolic pathways of triterpene saponins in rats. The current findings clarified the metabolic pathways of the main active ingredients in CRME and further elucidated the anti-RA drug-responsive substance basis of CRM.
30737767 Trial of labor after cesarean section in risk pregnancies: A population-based cohort study 2019 Jul INTRODUCTION: In most pregnancies after a cesarean section, a trial of labor is an option. The objective of the study was to explore trial of labor and its failure in pregnancies with medical risk conditions, in a population with a high trial of labor rate. MATERIAL AND METHODS: In a cohort study (n = 57 109), using data from the Medical Birth Registry of Norway 1989-2014, women with a second delivery after a first pregnancy cesarean section were included. Preterm, multiple, and non-cephalic deliveries were excluded. The outcomes were trial of labor and failed trial of labor, assessed as rates and relative risk, using deliveries without risk conditions as reference. Temporal trends were assessed by 3-year periods. The exposures were selected medical risk conditions, ie previous offspring death, labor dystocia, diabetes, heart conditions, chronic hypertension, chronic kidney disease, rheumatoid arthritis, thyroid disease, asthma, prepregnancy psychiatric conditions, epilepsy, obesity, gestational diabetes, eclampsia and preeclampsia, gestational hypertension, major malformations, second-pregnancy psychiatric conditions, assisted reproduction, macrosomia, and small-for-gestational-age neonates. Induced onset of labor was compared with spontaneous onset of labor for each condition studied. RESULTS: In risk pregnancies (n = 31 994) the trial of labor rate was 64.9% and failure rate was 27.6%, compared with 74.6% and 16.4% in pregnancies without any of the risk conditions studied (n = 25 115). The lowest trial of labor rates were observed in diabetes type 1 (49.5%), diabetes type 2 (46.7%), maternal heart conditions (54.5%), and pregnancy-related psychiatric conditions (19.7%). The highest failure rates were observed in diabetes type 1 (43.1%), diabetes type 2 (40.3%), maternal obesity (36.9%), gestational diabetes (36.0%), and offspring macrosomia (43.0%). Induced labor was associated with failed trial of labor (P < .05), whereas after spontaneous labor, failure rates were less than 40% in all conditions studied. CONCLUSIONS: In conditions with high rates of failed trial of labor, eg diabetes, macrosomia, and obesity, a planned cesarean section might be a better option than a trial of labor, particularly if induction of delivery might be needed.
30668419 Ganomycin I from Ganoderma lucidum attenuates RANKL-mediated osteoclastogenesis by inhibit 2019 Mar 1 BACKGROUND: Many bone-related diseases such as osteoporosis and rheumatoid arthritis are commonly associated with excessive activity of the osteoclast. Ganomycin I (GMI), a meroterpenoid isolated from Vietnamese mushroom Ganoderma lucidum, possesses a variety of beneficial effects on human health. However, its impact and underlying mechanism on osteoclastogenesis remain unclear. In the present study, we investigated the effect of GMI on RANKL-induced osteoclast formation in mouse BMMs and RAW264.7 cells. METHODS: BMMs or RAW264.7 cells were treated with GMI followed by an evaluation of cell viability, RANKL-induced osteoclast differentiation, actin-ring formation, and resorption pits activity. Effects of GMI on RANKL-induced phosphorylation of MAPKs as well as the expression levels of NFATc1 and c-Fos were evaluated by Western blot analysis. Expression levels of osteoclast marker genes were evaluated by Western blot analysis and reverse transcription-qPCR. RESULTS: GMI significantly inhibited RANKL-induced osteoclast differentiation by decreasing the number of osteoclasts, osteoclast actin-ring formation, and bone resorption in a dose-dependent manner without affecting cell viability. At molecular level, GMI inhibited the RANKL-induced phosphorylation of ERK, JNK, and p38 MAPKs, as well as the expression levels of c-Fos and NFATc1, which are known to be crucial transcription factors for osteoclast formation. In addition, GMI decreased expression levels of osteoclastogenesis specific marker genes including c-Src, CtsK, TRAP, MMP-9, OSCAR, and DC-STAMP in RANKL-stimulated BMMs. CONCLUSION: Our findings suggest that GMI can attenuate osteoclast formation by suppressing RANKL-mediated MAPKs and NFATc1 signaling pathways and the anti-osteoclastogenic activity of GMI may extend our understanding of molecular mechanisms underlying biological activities and pharmacological use of G. lucidum as a traditional anti-osteoporotic medicine.
30105475 Macrolide sesquiterpene pyridine alkaloids from the stems of Tripterygium regelii. 2019 Jan Nine new monomacrolide sesquiterpene pyridine alkaloids, macroregelines A-I (1-9), were isolated from the stems of Tripterygium regelii, along with a known alkaloid, tripfordine B. The structures of all the isolated compounds were characterized by extensive one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopic analyses, as well as high-resolution electrospray-ionization mass spectrometry (HRESIMS) data. Compounds 4, 5, 6, and 8 showed antiproliferative effect on human rheumatoid arthritis synovial cell line MH7A at concentration of 20 μM, reducing their viability by 7.5, 18.0, 9.0, and 18.2 %, respectively.
29663644 Biomimetic sulfated polyethylene glycol hydrogel inhibits proteoglycan loss and tumor necr 2019 Apr This study aimed to evaluate the potential of an anti-inflammatory polyethylene glycol (PEG) hydrogel for osteoarthritis (OA) management in an OA in vitro model. Freshly isolated porcine chondrocytes were maintained in high-density cultures to form cartilage-like three-dimensional micromasses. Recombinant porcine tumor necrosis factor-alpha (TNF-α) was used to induce OA-like changes. Normal and OA-like micromasses were treated with dendritic polyglycerol sulfate-based PEG hydrogel. Live/dead staining showed that all micromasses remained vital and presented similar morphological characteristics. Safranin-O staining demonstrated a typical depletion of glycosaminoglycans in TNF-α-treated micromasses but not in the presence of the hydrogel. There was no distinct difference in immunohistochemical detection of type II collagen. Microarray data showed that rheumatoid arthritis and TNF signaling pathways were down regulated in hydrogel-treated OA-like micromasses compared to nontreated OA-like micromasses. The hydrogel alone did not affect genes related to OA such as ANPEP, COMP, CXCL12, PTGS2, and TNFSF10, but it prevented their regulation caused by TNF-α. This study provides valuable insights toward a fully synthetic hydrogel for the intra-articular treatment of OA. The findings proved the potential of this hydrogel to prevent the development of TNF-α-induced OA with regard to proteoglycan loss and TNF-α-induced expression pattern without additional signs of differentiation and inflammation. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 490-500, 2019.
31745335 Interferon target-gene expression and epigenomic signatures in health and disease. 2019 Dec Multiple type I interferons and interferon-γ (IFN-γ) are expressed under physiological conditions and are increased by stress and infections, and in autoinflammatory and autoimmune diseases. Interferons activate the Jak-STAT signaling pathway and induce overlapping patterns of expression, called 'interferon signatures', of canonical interferon-stimulated genes (ISGs) encoding molecules important for antiviral responses, antigen presentation, autoimmunity and inflammation. It has now become clear that interferons also induce an 'interferon epigenomic signature' by activating latent enhancers and 'bookmarking' chromatin, thus reprogramming cell responses to environmental cues. The interferon epigenomic signature affects ISGs and other gene sets, including canonical targets of the transcription factor NF-κB that encode inflammatory molecules, and is involved in the priming of immune cells, tolerance and the training of innate immune memory. Here we review the mechanisms through which interferon signatures and interferon epigenomic signatures are generated, as well as the expression and functional consequences of these signatures in homeostasis and autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis.
31725294 Insights to the Binding of a Selective Adenosine A(3) Receptor Antagonist Using Molecular 2019 Dec 23 Adenosine A(3) receptor (A(3)R) is a promising drug target cancer and for a number of other conditions like inflammatory diseases, including asthma and rheumatoid arthritis, glaucoma, chronic obstructive pulmonary disease, and ischemic injury. Currently, there is no experimentally determined structure of A(3)R. We explored the binding profile of O4-{[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]carbonyl}-2-methyl-1,3-thiazole-4-carbohydroximamide (K18), which is a new specific and competitive antagonist at the orthosteric binding site of A(3)R. MD simulations and MM-GBSA calculations of the WT A(3)R in complex with K18 combined with in vitro mutagenic studies show that the most plausible binding conformation for the dichlorophenyl group of K18 is oriented toward trans-membrane helices (TM) 5, 6 and reveal important residues for binding. Further, MM-GBSA calculations distinguish mutations that reduce or maintain or increase antagonistic activity. Our studies show that selectivity of K18 toward A(3)R is defined not only by direct interactions with residues within the orthosteric binding area but also by remote residues playing a significant role. Although V169(5.30) is considered to be a selectivity filter for A(3)R binders, when it was mutated to glutamic acid, K18 maintained antagonistic potency, in agreement with our previous results obtained for agonists binding profile investigation. Mutation of the direct interacting residue L90(3.32) in the low region and the remote L264(7.35) in the middle/upper region to alanine increases antagonistic potency, suggesting an empty space in the orthosteric area available for increasing antagonist potency. These results approve the computational model for the description of K18 binding at A(3)R, which we previously performed for agonists binding to A(3)R, and the design of more effective antagonists based on K18.
31721234 Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and p 2019 Nov A role for B cells in autoimmune diseases is now clearly established both in mouse models and humans by successful treatment of multiple sclerosis and rheumatoid arthritis with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells promote the development of autoimmune diseases remain poorly understood. Here, we review evidence that patients with autoimmune disease suffer from defects in early B-cell tolerance checkpoints and therefore fail to counterselect developing autoreactive B cells. These B-cell tolerance defects are primary to autoimmune diseases and may result from altered B-cell receptor signaling and dysregulated T-cell/regulatory T-cell compartment. As a consequence, large numbers of autoreactive naive B cells accumulate in the blood of patients with autoimmune diseases and may promote autoimmunity through the presentation of self-antigen to T cells. In addition, new evidence suggests that this reservoir of autoreactive naive B cells contains clones that may develop into CD27(-) CD21(-/lo) B cells associated with increased disease severity and plasma cells secreting potentially pathogenic autoantibodies after the acquisition of somatic hypermutations that improve affinity for self-antigens.
31623242 Water Extracts of Hull-less Waxy Barley (Hordeum vulgare L.) Cultivar 'Boseokchal' Inhibit 2019 Oct 16 Osteoporosis is a disease that leads to reduced bone mineral density. The increase in patient and medical costs because of global aging is recognized as a problem. Decreased bone mass is a common symptom of bone diseases such as Paget's disease, rheumatoid arthritis, and multiple myeloma. Osteoclasts, which directly affect bone mass, show a marked increase in differentiation and activation in the aforementioned diseases. Moreover, these multinucleated cells made from monocytes/macrophages under the influence of RANKL and M-CSF, are the only cells capable of resorbing bones. In this study, we found that the water extracts of Boseokchal (BSC-W) inhibited osteoclast differentiation in vitro and investigated its inhibitory mechanism. BSC-W was obtained by extracting flour of Boseokchal using hexane and water. To osteoclast differentiation, bone marrow-derived macrophage cells (BMMs) were cultured with the vehicle (0.1% DMSO) or BSC-W in the presence of M-CSF and RANKL for 4 days. Cytotoxicity was measured by CCK-8. Gene expression of cells was confirmed by real-time PCR. Protein expression of cells was observed by western blot assay. Bone resorption activity of osteoclast evaluated by bone pit formation assay using an Osteo Assay Plate. BSC-W inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner without exerting a cytotoxic effect on BMMs. BSC-W decreased the transcriptional and translational expression of c-Fos and NFATc1, which are regulators of osteoclastogenesis and reduced the mRNA expression level of TRAP, DC-STAMP, and cathepsin K, which are osteoclast differentiation marker. Furthermore, BSC-W reduced the resorption activity of osteoclasts. Taken together, our results indicate that BSC-W is a useful candidate for health functional foods or therapeutic agents that can help treat bone diseases such as osteoporosis.
31512452 [Mid- and long-term effectiveness of total hip arthroplasty with Ribbed femoral stem prost 2019 Sep 15 OBJECTIVE: To evaluate the mid- and long-term effectiveness of total hip arthroplasty (THA) with Ribbed femoral stem prosthesis. METHODS: A clinical data of 354 patients (384 hips) with hip disease who underwent THA with Ribbed femoral stem prostheses between October 2006 and May 2016 was retrospectively analyzed. There were 171 males and 183 females, with an average age of 53.4 years (range, 20-82 years). There were 324 cases of single hip and 30 cases of bilateral hips. The cause of THA included the avascular necrosis of the femoral head in 151 cases (159 hips), hip osteoarthritis in 134 cases (136 hips), rheumatoid arthritis in 43 cases (43 hips), ankylosing spondylitis in 20 cases (40 hips), and trauma in 6 cases (6 hips). The Harris score of total 354 patients before operation was 42.34±8.89. Harris scores were used to evaluate hip function after operation. X-ray films were used to determine the length of the lower limb, the radiolucent line on the femur side, the stability of the prosthesis, and the occurrence of stress shielding. RESULTS: The incisions healed by first intention. All patients were followed up 2-11 years with an average of 7.4 years. The Harris score at last follow-up was 80.52±7.61, which significantly increased when compared with preoperative score ( t=134.804, P=0.000). Two cases (2 hips) of prosthetic infections, 3 cases (3 hips) of prothesis loosening, and 4 cases (4 hips) of periprosthetic fractures, and 48 cases (48 hips) of mild to moderate thigh pain occurred after operation. X-ray films showed 76 cases (78 hips) with radiolucent lines on the femur side and stress shielding. According to the Engh's method, there were 364 hips of bone ingrowth, 15 hips of fibrosis ingrowth, and 5 hips of prosthesis instability. The femoral stem subsidence occurred in 25 cases (25 hips), and the difference in leg length discrepancy was more than 10 mm in 5 patients. CONCLUSION: THA with Ribbed femoral stem prosthesis can achieve satisfactory effectiveness with good initial stability and rapid bone growth. The incidence of stress shielding is relatively high, but the stress shielding has no significant impact on the mid- and long-term survival rate and effectiveness of femoral prosthesis.
31438874 Case report: a peculiar glomerulopathy in a patient suffering from nephrotic syndrome. 2019 Aug 22 BACKGROUND: Podocyte infolding glomerulopathy (PIG) is a rare histopathologic finding with global infolding of the podocytes into the glomerular basement membrane (GBM), accompanied by microstructures underneath. Described in 2002 for the first time, PIG was proposed as a new pathological entity in 2008 based on the largest case series so far. Yet all of the described cases derive from Asian countries. We report a case from Germany fulfilling the diagnostic criteria of PIG. Considering the scarcity of data on this entity especially in Western countries, collecting cases like ours and multicentric meta-analyses will be crucial to obtain a better understanding of PIG, its causes, clinical course and potential treatment options. CASE PRESENTATION: A 56-year-old Caucasian woman with a history of rheumatoid arthritis (RA), no other comorbidities and no known renal disease was admitted to the hospital with acute kidney injury (AKI) and nephrotic syndrome. Physical examination was unremarkable except for anasarca. Renal ultrasound revealed no abnormalities. Laboratory and urine analyses were consistent with the nephrotic syndrome and renal failure. Serological studies regarding ANA, ANCA, anti-PLA2R autoantibodies, complement, virus infections, immunofixation and quantitative light chain analysis were unremarkable. A renal biopsy was performed. Light microscopic examination showed flattened tubular epithelium consistent with acute tubular damage, no infiltrates and unremarkable glomeruli except diffuse and global holes in the GBM (Fig. 1a) and negative staining for immunoglobulin heavy-chains, light-chains and complement split products. Electron microscopy revealed a rare correlate for these holes: global peculiar infolding of podocyte cytoplasm into the GBM. Most of these infoldings were accompanied by condensation of the GBM underneath. No such condensation or electron dense deposits were found without these infoldings or outside the GBM. CONCLUSION: Here we report the first case of PIG outside of Asia. Since there are only few reports about this specific finding, we feel there is a need to share information in an attempt to accumulate knowledge about this possible new entity and potential treatment options.
31139654 Network Analyses of Differentially Expressed Genes in Osteoarthritis to Identify Hub Genes 2019 BACKGROUND: Osteoarthritis (OA) is the most common degenerative disease in orthopedics. However, the cause and underlying molecular mechanisms are not clear. This study aims to identify the hub genes and pathways involved in the occurrence of osteoarthritis. METHODS: The raw data of GSE89408 were downloaded from the Gene Expression Omnibus (GEO) database, and the differentially expressed genes (DEGs) were identified by R software. The DAVID database was used for pathway and gene ontology analysis, and p<0.05 and gene count >2 were set as the cut-off point. Moreover, protein-protein interaction (PPI) network construction was applied for exploring the hub genes in osteoarthritis. The expression levels of the top ten hub genes in knee osteoarthritis synovial membranes and controls were detected by quantitative real-time PCR system. RESULTS: A total of 229 DEGs were identified in osteoarthritis synovial membranes compared with normal synovial membranes, including 145 upregulated and 84 downregulated differentially expressed genes. The KEGG pathway analysis results showed that up-DEGs were enriched in proteoglycans in cytokine-cytokine receptor interaction, chemokine signaling pathway, rheumatoid arthritis, and TNF signaling pathway, whereas down-DEGs were enriched in the PPAR signaling pathway and AMPK signaling pathway. The qRT-PCR results showed that the expression levels of ADIPOQ, IL6, and CXCR1 in the synovium of osteoarthritis were significantly increased (p <0.05).
31809599 Deciphering crucial genes in coeliac disease by bioinformatics analysis. 2020 Mar Coeliac disease (CD) is a chronic autoimmune disease that is characterized by malabsorption in sensitive individuals. CD is triggered by the ingestion of grains containing gluten. CD is concomitant with several other disorders, including dermatitis herpetiformis, selective IgA deficiency, thyroid disorders, diabetes mellitus, various connective tissue disorders, inflammatory bowel disease, and rheumatoid arthritis. The advent of high throughput technologies has provided a massive wealth of data which are processed in various omics scale fields. These approaches have revolutionized the medical research and monitoring of the biological systems. In this regard, omics scaled analyses of CD by Comparative Toxicogenomics Database (CTD), DISEASES, and GeneCards databases have retrieved 2656 CD associated genes. Amongst, 54 genes were assigned by Venn Diagram of the intersection to be shared by these 3 databases for CD. These common genes were subjected to further analysis and screening. The Enrich database, GeneMANIA, Cytoscape, and WebGestalt (WEB-based GEne SeT AnaLysis Toolkit) were employed for functional analysis. These analyses indicated that the obtained genes are mainly involved in the immune system and signalling pathways related to autoimmune diseases. The STAT1, ALB, IL10, IL2, IL4, IL17A, TGFB1, IL1B, IL6, TNF, IFNG hub genes were particularly indicated to have significant roles in CD. Functional analyses of these hub genes by GeneMANIA indicated that they are involved in immune systems regulation. Moreover, 25 out of 54 genes were identified to be seed genes by the WebGestalt database. Gene set analysis with GEO2R tool from Gene Expression Omnibus (GEO) showed that there were 15 significant genes in GSE76168, 29 significant genes in GSE87460, 12 significant genes in GSE87458, 9 significant genes in GSE87457, 3753 significant genes in GSE112102 and 1043 significant genes in GSE102991 with differential expression in coeliac patients compared to controls. The IRF1and STAT1 genes were common between the significant genes from GEO and the 54 CD related genes from three public databases. In the light these results, nine key genes, including IRF1, STAT1, IL17A, TGFB1, ALB, IL10, IL2, IL4, and IL1B, were identified to be associated with CD. These findings could be used to find novel diagnostic biomarkers, understand the pathology of disease, and devise more efficient treatments.
31608437 Retroviral sero-reactivity in LGL leukaemia patients and family members. 2020 Feb T-cell large granular lymphocyte (T-LGL) leukaemia is characterized by a clonal proliferation of cytotoxic T cells and is frequently associated with rheumatoid arthritis. Sera from some LGL leukaemia patients react to a portion of the human T-cell leukaemia virus (HTLV-1/2) transmembrane envelope protein, BA21, although HTLV-1/2 infection is rare in LGL leukaemia patients. Here we show that family members, including spouses, of an LGL leukaemia patient had elevated LGL counts, BA21 reactivity and, additionally, recognition of HIV-1 gp41. Thus, both LGL leukaemia patients and clinically normal contacts sharing the same environment have evidence of exposure to a retrovirus.
31416296 Patients with ANCA-Associated Glomerulonephritis and Connective Tissue Diseases: A Compara 2019 Aug 14 BACKGROUND AND OBJECTIVES: The overlap between antineutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis (ANCA-GN) and connective tissue diseases (CTD) has been reported mainly as case series in the literature. Frequency of this association, as well as presentation and outcomes are unknown. MATERIALS AND METHODS: Patients from the Maine-Anjou ANCA-associated vasculitides (AAV) registry with ANCA-GN diagnosed between 01/01/2000 and 01/01/2018, ANCA positivity, and at least six months of follow-up, were included. RESULTS: 106 out of 142 patients fulfilled the inclusion criteria and were analyzed. CTD was present at ANCA-GN diagnosis in 16 (15.1%) patients. The most common CTD were rheumatoid arthritis, Sjogren syndrome and systemic sclerosis. Compared to the control group, females were more represented in the CTD group (75%, p = 0.001). Renal presentation was comparable between groups, including the pathological analysis of renal biopsies. Patients of CTD group presented a higher rate of non-renal relapse (25% versus 7.7%, p = 0.037), and experienced more frequently a venous thrombotic event (31.2% versus 10%, p = 0.021). No difference between groups was observed according to major outcomes. CONCLUSION: Association between CTD and ANCA-GN is not a rare condition and predominantly affects females. While AAV presentation is not significantly different, CTD patients experience more frequently non-renal relapse and venous thrombotic events.
31222845 Histone deacetylases 1 and 2 inhibition suppresses cytokine production and osteoclast bone 2020 Jan The regulation of epigenetic factors is an emerging therapeutic target of immune function in a variety of osteolytic pathologies. Histone deacetylases (HDAC) modify core histone proteins and transcriptional processes, in addition to nonhistone protein activity. The activated immune response in rheumatoid arthritis, periodontitis, and prosthetic implant particle release stimulates the catabolic activity of osteoclasts. In this study, we investigated the effects of novel therapeutic agents targeting HDAC isozymes (HDAC 1, 2, and 5), previously shown to be upregulated in inflammatory bone disorders, in cytokine-stimulated human monocytes and osteoclasts in vitro. Inhibiting HDAC 1 and 2 significantly reduced gene expression of IL-1β, TNF, MCP-1, and MIP-1α in TNF-stimulated monocytes, while suppressing secretions of IL-1β, IL-10, INF-γ, and MCP-1 (P < .05). Osteoclast formation and bone resorption were also significantly diminished with HDAC 1 and 2 inhibition, through reduced NFATc1 expression and osteoclast specific target genes, TRAF6, CTR, TRAP, and Cathepsin K (P < .05). Similar trends were observed when inhibiting HDAC 1 and to a lesser extent, HDAC 2, in isolation. However, their combined inhibition had the greatest anti-inflammatory and antiosteoclastic effects. Targeting HDAC 5 had minimal effects on these processes investigated in this study, whereas a broad acting HDACi, 1179.4b, had widespread suppressive outcomes. This study demonstrates that targeting HDACs is a potent and effective way of regulating the inflammatory and catabolic processes in human monocytes and osteoclasts. It also demonstrates the importance of targeting individual HDACs with an overall aim to improve efficiency and reduce any potential off target effects.
31190735 Spotlight on anifrolumab and its potential for the treatment of moderate-to-severe systemi 2019 Previous reports have described the appearance of systemic lupus erythematosus (SLE) cases following interferon-α (IFN-α) therapy, IFN-regulated gene expression is significantly increased in SLE, and an association between SLE and gene variants belonging to IFN downstream pathways has been shown. Based on this, targeting of IFN and of their signaling pathways has appeared to be interesting developments within the field of SLE therapy. Different specific type I IFN antagonists have been studied in clinical trials and some of those have already reached Phase III. A potential approach would be to target IFN receptors rather than IFN themselves. Anifrolumab (previously MEDI-546) is a fully human monoclonal antibody (Ab) that binds to subunit 1 of the type I IFN receptor (IFNAR1), blocking the action of different type I IFNs (IFN-α, IFN-β and IFN-ω). This drug has been assessed in 11 clinical studies: 9 in SLE, 1 in systemic sclerosis and 1 in rheumatoid arthritis. In SLE, clinical development reached Phase I for 1 study and Phases II and III for 5 and 3 trials, respectively. The Phase IIb, randomized control trial (RCT), double-blind, placebo-controlled study of adults with moderate-to-severe SLE (MUSE trial) showed positive results on the composite primary endpoint SRI-4. Greater efficacy was seen in patients with high baseline IFN gene signature compared with those with low baseline IFN gene signature. Anifrolumab also demonstrated promising results on cutaneous and arthritic manifestations, especially among patients with a high IFN gene signature. The pivotal Treatment of Uncontrolled Lupus via the Interferon IFN Pathway (TULIP 1 and 2 studies are now completed. In August 2018, the promoter announced that the TULIP 1 Phase III trial did not reach its primary endpoint. The release of the completed but not yet published Phase II studies and of the TULIP pivotal trials results will further inform us on the actual therapeutic potential of anifrolumab.
31060590 Endoscopic transnasal anterior release and posterior reduction without odontoidectomy for 2019 May 6 BACKGROUND: To investigate the efficacy and safety of endoscopic transnasal anterior release and posterior reduction without odontoidectomy to treat irreducible atlantoaxial dislocation (IAAD). METHODS: A series of 9 patients with IAAD underwent endoscopic transnasal anterior release and posterior reduction without odontoidectomy. Etiology, instrumentation, fusion rate, and complications were documented. All patients were assessed clinically and radiologically for neurological recovery using the Japanese Orthopedic Association (JOA) score, atlantodontoid interval (ADI), and cervicomedullary angle (CMA). RESULTS: The mean age of the patients was 41.6 years, ranging from 14 to 60 years. Pathology showed os odontoideum in 3 patients, old traumatic dens fracture in 3 patients, occipitalization of C1 in 2 patients, and rheumatoid arthritis in 1 patient. Seven patients underwent C1-C2 pedicle screw fixations, and 2 patients required occipitocervical fixation. Eight cases resulted in complete reduction and 1 in partial reduction. Complications included one superficial infection related to the posterior approach. All patients were followed up for an average of 17 (range 13-32) months. Bony fusion was confirmed in all cases under radiologic assessment at 1 year postoperatively, and the bony fusion rate reached 100%. Moreover, no instrumental failure occurred during the entire follow-up period. The JOA score improved from 7.21 ± 1.62 to 12.28 ± 0.81 at the last follow-up. The ADI of 9 cases was 7.06 ± 0.85 mm preoperatively, which decreased to 2.26 ± 0.56 mm at the final follow-up. CMA improved from 103.80° ± 4.16° to 143.23° ± 7.47° postoperatively. CONCLUSION: With transnasal approach and lack of odontoidectomy, this method could not only treat IAAD safely and effectively, but also reduce the possibility of many complications associated with the traditional transoral approach and odontoidectomy.
30844238 Protein Arginine Deiminases (PADs): Biochemistry and Chemical Biology of Protein Citrullin 2019 Mar 19 Proteins are well-known to undergo a variety of post-translational modifications (PTMs). One such PTM is citrullination, an arginine modification that is catalyzed by a group of hydrolases called protein arginine deiminases (PADs). Hundreds of proteins are known to be citrullinated and hypercitrullination is associated with autoimmune diseases including rheumatoid arthritis (RA), lupus, ulcerative colitis (UC), Alzheimer's disease, multiple sclerosis (MS), and certain cancers. In this Account, we summarize our efforts to understand the structure and mechanism of the PADs and to develop small molecule chemical probes of protein citrullination. PAD activity is highly regulated by calcium. Structural studies with PAD2 revealed that calcium-binding occurs in a stepwise fashion and induces a series of dramatic conformational changes to form a catalytically competent active site. These studies also identified the presence of a calcium-switch that controls the overall calcium-dependence and a gatekeeper residue that shields the active site in the absence of calcium. Using biochemical and site-directed mutagenesis studies, we identified the key residues (two aspartates, a cysteine, and a histidine) responsible for catalysis and proposed a general mechanism of citrullination. Although all PADs follow this mechanism, substrate binding to the thiolate or thiol form of the enzyme varies for different isozymes. Substrate-specificity studies revealed that PADs 1-4 prefer peptidyl-arginine over free arginine and certain citrullination sites on a peptide substrate. Using high-throughput screening and activity-based protein profiling (ABPP), we identified several reversible (streptomycin, minocycline, and chlorotetracycline) and irreversible (streptonigrin, NSC 95397) PAD-inhibitors. Screening of a DNA-encoded library and lead-optimization led to the development of GSK199 and GSK484 as highly potent PAD4-selective inhibitors. Furthermore, use of an electrophilic, cysteine-targeted haloacetamidine warhead to mimic the guanidinium group in arginine afforded several mechanism-based pan-PAD-inhibitors including Cl-amidine and BB-Cl-amidine. These compounds are highly efficacious in various animal models, including those mimicking RA, UC, and lupus. Structure-activity relationships identified numerous covalent PAD-inhibitors with different bioavailability, in vivo stability, and isozyme-selectivity (PAD1-selective: D-Cl-amidine; PAD2-selective: compounds 16-20; PAD3-selective: Cl4-amidine; and PAD4-selective: TDFA). Finally, this Account describes the development of PAD-targeted and citrulline-specific chemical probes. While PAD-targeted probes were utilized for identifying off-targets and developing high-throughput inhibitor screening platforms, citrulline-specific probes enabled the proteomic identification of novel diagnostic biomarkers of hypercitrullination-related autoimmune diseases.
30829813 Longitudinal Effects of Medical Comorbidities on Functional Outcome and Life Satisfaction 2019 Sep/Oct OBJECTIVE: To explore associations of specific physical and neuropsychiatric medical conditions to motor and cognitive functioning and life satisfaction over the first 10 years following traumatic brain injury (TBI). SETTING: Telephone follow-up through 6 TBI Model System centers. PARTICIPANTS: In total, 404 individuals or proxies with TBI enrolled in the TBI Model System longitudinal study participating in 10-year follow-up. DESIGN: Individual growth curve analysis. MAIN MEASURES: FIM Motor and Cognitive subscales, Satisfaction With Life Scales, and Medical and Mental Health Comorbidities Interview. RESULTS: Hypertension, diabetes, cancers, rheumatoid arthritis, and anxiety negatively affected the trajectory of motor functioning over time. Diabetes, cancers, chronic bronchitis, anxiety, and depression negatively impacted cognitive functioning. Numerous neuropsychiatric conditions (sleep disorder, alcoholism, drug addiction, anxiety, panic attacks, posttraumatic stress disorder, depression, and bipolar disorder), as well as hypertension, liver disease, and cancers, diminished life satisfaction. Other medical conditions had a negative effect on functioning and satisfaction at specific follow-up periods. CONCLUSION: Natural recovery after TBI may include delayed onset of functional decline or early recovery, followed by progressive deterioration, and is negatively affected by medical comorbidities. Results contribute to the growing evidence that TBI is most appropriately treated as a chronic medical condition complicated by a variety of comorbid conditions.