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ID PMID Title PublicationDate abstract
32108278 Evaluation of oxysterol levels of patients with silicosis by LC-MS/MS method. 2020 Apr Silicosis is one of the prolonged and irreversible occupational diseases. Crystalline silica dust, which has been linked with silicosis, occurs in different industrial areas such as constructions, ceramic, quarry, and pottery. There are significant numbers of newly diagnosed cases every year in Turkey. Patients with silicosis suffer from inflammatory respiratory disorders and silicosis-related complications such as rheumatoid arthritis, systemic sclerosis, and vasculitis. Oxysterols are defined as 27-carbon intermediates or end products of cholesterol. They are also implicated in the etiology of disease states such as atherosclerosis, neurodegenerative, and inflammatory diseases. The aim of the study is to evaluate cholesterol oxidation products in the patients with silicosis and determination of sphingosine-1-phosphate (S1P) levels which is a sphingolipid metabolite. In addition to these parameters, it is aimed to determine the possible lipid peroxidation by different parameters. For this purpose, blood samples and urine were collected from 47 patients and 30 healthy individual with their consents. In order to evaluate oxysterols, 7-ketocholesterol and cholestan 3β,5α,6β-triol levels were measured by LC-MS/MS method. The measured levels of 7-KC were 0.101 ± 0.005 µmol/l in patient and 0.050 ± 0.003 µmol/l in control plasma samples. Triol levels were measured as 0.038 ± 0.005 µmol/l in patient group and 0.033 ± 0.004 µmol/l in control group (p < 0.001). In addition, lipid peroxidation products were measured by human-8-isoprostane, human-4-hydroxynonenal (4-HNE), and human malondialdehyde (MDA) ELISA kits. The measured levels of HNE in the patient and control groups were 735.14 ± 288.80 pg/ml and 595.72 ± 108.62 pg/ml in plasma and 606.02 + 118.23 pg/ml and 531.84 + 107.18 pg/ml in urine, respectively (p < 0.05). F2-iP results of patients and controls were 450.0 + 101.40 pg/dl and 386.9 + 112.7 pg/ml for urine and 432.7 ± 188,8 pg/dl and 321.9 ± 69.4 pg/dl for plasma, respectively (p < 0.05). MDA levels of plasma were measured as 44.1 ± 14.6 nmol/ml in the patient and 31.9 ± 10.5 nmol/ml in the control (p < 0.05). Levels of MDA for urine samples were 30.15 + 5.06 nmol/ml and 25.15 + 6.07 nmol/ml in patients and controls, respectively (p < 0.05). S1P levels were decreased in patients compared to control group (49.05 ± 10.87 and 67.57 ± 16.25, p < 0.001). The results not only indicate a correlation between cholesterol oxidation, lipid peroxidation, and silicosis, but also provide better understanding of the role of the lipids in the mechanism of this inflammatory disease.
32062385 Deletion of macrophage migration inhibitory factor ameliorates inflammation in mice model 2020 May BACKGROUND: Macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine implicated in sepsis, rheumatoid arthritis and other diseases. However, the role of MIF in acute pancreatitis (AP) remains unclear. This study aims to explore the role of MIF in the pathogenesis of AP using MIF(-/-) mice (referred to as KO) and the biological effects of pharmacological inhibition of MIF in l-arginine induced AP. METHODS: AP was induced in C57BL/6 wild-type (referred to as WT) and KO mice by administration of l-arginine. The severity of AP was assessed by serum analysis of amylase and lipase, and of these pro-inflammatory cytokines TNF-α and IL-1β. Histological hematoxylin and eosin (H&E) and immunohistochemical staining of pancreatic tissues were examined for inflammation and expression of pro-inflammatory mediators. We also investigated the biological effects of pharmacological inhibition of MIF activity using ISO-1((S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester). RESULTS: At 72 h after the induction of AP with l-arginine, significantly lower levels of serum amylase, lipase, TNF-α, and IL-1β were observed in KO mice when compared with WT controls. Histological examination further showed protective effects against pancreatic tissue damage and inflammation, with pancreatic expression of TNF-α, IL-1β and NF-κB p65 markedly reduced. Pharmacological inhibition of MIF activity with ISO-1 markedly mirrored the protective effect seen in the KO AP model providing further evidence that MIF is involved in the pathogenesis of AP. CONCLUSION: Our data provided strong evidence for the participation of MIF in the pathogenesis of AP and subsequent inflammatory response. The genetic ablation of MIF or its inhibition with pharmacological agents significantly ameliorated the severity of AP.
32015952 Antidiabetic activity of standardized dried tubers extract of Aconitum napellus in strepto 2020 Feb India has got rich cultural inheritage in the forms of Ayurveda texts which are a rich and ample source of herbs, shrubs, trees and affluent in medicinally active phytoconstituents. Aconitum napellus is used for the cure of many ailments including rheumatoid arthritis, sciatica and gout. The present work attempts to evaluate the physicochemical and preliminary phytochemical studies on the tubers of Aconitum napellus along with its antidiabetic activity. The herbal standardization was carried out on the basis of organoleptic properties, physical characteristics and physicochemical properties. The body weight of ACON-I (1.25 mg/kg) and ACON-II (2.5 mg/kg) was recorded as 190.40 and 209.40 g, respectively, compared with 163.00 g in diabetic rats at day 28. The body weight of ACON-I and ACON-II was significantly increased compared with diabetic rats (p < 0.01). However, the body weight of ACON-I and ACON-II was decreased significantly (p < 0.01) compared with normal group (222.60 g). The blood glucose levels of diabetic rats and ACON-I group were recorded as 277.800 and 152.400 mg/dl, respectively, compared with 83.600 mg/dl in normal rats (p < 0.01). However, the HbA1c levels of diabetic rats and ACON-I group were recorded as 11.306 and 6.936% Hb, respectively, compared with 4.539% Hb in normal rats. The glucose and HbA1c levels of diabetic and ACON-I groups were significant compared with normal group (p < 0.01). The results of antidiabetic activity showed that the plant can be used as a potent source for the treatment of diabetes and its complications. The results of this work provided the referential information for the identification and standardization of Aconitum napellus along with its role as a hypoglycemic agent.
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.
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.
33141212 Diagnosis and Treatment of Lower Extremity Venous Thromboembolism: A Review. 2020 Nov 3 IMPORTANCE: Incidence rates for lower extremity deep vein thrombosis (DVT) range from 88 to 112 per 100 000 person-years and increase with age. Rates of recurrent VTE range from 20% to 36% during the 10 years after an initial event. OBSERVATIONS: PubMed and Cochrane databases were searched for English-language studies published from January 2015 through June 2020 for randomized clinical trials, meta-analyses, systematic reviews, and observational studies. Risk factors for venous thromboembolism (VTE), such as older age, malignancy (cumulative incidence of 7.4% after a median of 19 months), inflammatory disorders (VTE risk is 4.7% in patients with rheumatoid arthritis and 2.5% in those without), and inherited thrombophilia (factor V Leiden carriers with a 10-year cumulative incidence of 10.9%), are associated with higher risk of VTE. Patients with signs or symptoms of lower extremity DVT, such as swelling (71%) or a cramping or pulling discomfort in the thigh or calf (53%), should undergo assessment of pretest probability followed by D-dimer testing and imaging with venous ultrasonography. A normal D-dimer level (ie, D-dimer <500 ng/mL) excludes acute VTE when combined with a low pretest probability (ie, Wells DVT score ≤1). In patients with a high pretest probability, the negative predictive value of a D-dimer less than 500 ng/mL is 92%. Consequently, D-dimer cannot be used to exclude DVT without an assessment of pretest probability. Postthrombotic syndrome, defined as persistent symptoms, signs of chronic venous insufficiency, or both, occurs in 25% to 50% of patients 3 to 6 months after DVT diagnosis. Catheter-directed fibrinolysis with or without mechanical thrombectomy is appropriate in those with iliofemoral obstruction, severe symptoms, and a low risk of bleeding. The efficacy of direct oral anticoagulants-rivaroxaban, apixaban, dabigatran, and edoxaban-is noninferior to warfarin (absolute rate of recurrent VTE or VTE-related death, 2.0% vs 2.2%). Major bleeding occurs in 1.1% of patients treated with direct oral anticoagulants vs 1.8% treated with warfarin. CONCLUSIONS AND RELEVANCE: Greater recognition of VTE risk factors and advances in anticoagulation have facilitated the clinical evaluation and treatment of patients with DVT. Direct oral anticoagulants are noninferior to warfarin with regard to efficacy and are associated with lower rates of bleeding, but costs limit use for some patients.
33132223 Does Etanercept Biosimilar Prescription in a Rheumatology Center Bend the Medication Cost 2021 Dec OBJECTIVE: The market entry of biosimilars is expected to bring budgetary relief. Our objective was to determine how the introduction of biosimilars influences medication costs in patients with rheumatoid arthritis (RA) and which patients gain access to biologics due to the availability of biosimilars. METHODS: Using hospital data of patients with RA between 2014 and 2018, an interrupted time series was performed. The interruption in the time series was placed at June 2016 (i.e., the introduction of the etanercept biosimilar). The changes in trends for rheumatic medication costs before and after the interruption were measured. Secondary analyses focused on explaining these trends. RESULTS: In the first quarter after the interruption, there was a decrease in total costs for biologic users of -€63,020 (95% CI -€96,487 to -€29,553, P = 0.001). The postinterruption trend did not differ from the preinterruption trend (95% CI -€6695 to €6715, P = 0.998) and after 3 quarters, the medication costs were back at the interruption level. After the interruption, the average cost per biologic user decreased by -€370 (95% CI -€602 to -€138, P = 0.005), followed by a quarterly decrease (relative to the preinterruption trend; 95% CI -€86 to -€14, P = 0.010), bending the average cost curve. The percentage of patients being treated with biologics increased in postinterruption by 0.50 percentage points quarterly (95% CI 0.38-0.62, P < 0.001). Also, the average age at the start of the first biologic increased after the interruption (P = 0.057). CONCLUSION: The average cost per patient treated with biologics decreased after the introduction of biosimilars with a persistent trend. However, the budgetary relief due to market entry of biosimilars vanished quickly due to an increase in patients treated with biologics.
32971928 Semaphorin4A-Plexin D1 Axis Induces Th2 and Th17 While Represses Th1 Skewing in an Autocri 2020 Sep 22 Semaphorin (Sema)4A is a transmembrane glycoprotein that is elevated in several autoimmune diseases such as systemic sclerosis, rheumatoid arthritis and multiple sclerosis. Sema4A has a key role in the regulation of Thelper Th1 and Th2 differentiation and we recently demonstrated that CD4(+) T cell activation induces the expression of Sema4A. However, the autocrine role of Sema4A on Th cell differentiation remains unknown. Naïve Th cells from healthy controls were cell sorted and differentiated into Th1, Th2 and Th17 in the presence or absence of a neutralizing antibody against the Sema4A receptor PlexinD1. Gene expression was determined by quantitative PCR and protein expression by ELISA and flow cytometry. We found that the expression of Sema4A is induced during Th1, Th2 and Th17 differentiation. PlexinD1 neutralization induced the differentiation of Th1 cells, while reduced the Th2 and Th17 skewing. These effects were associated with an upregulation of the transcription factor T-bet by Th1 cells, and to downregulation of GATA3 and RORγt in Th2 cells and Th17 cells, respectively. Finally, PlexinD1 neutralization regulates the systemic sclerosis patients serum-induced cytokine production by CD4(+) T cells. Therefore, the autocrine Sema4A-PlexinD1 signaling acts as a negative regulator of Th1 skewing but is a key mediator on Th2 and Th17 differentiation, suggesting that dysregulation of this axis might be implicated in the pathogenesis of CD4(+) T cell-mediated diseases.
32940963 Impact of COVID-19 outbreak on rheumatic patients' perceptions and behaviors: A cross-sect 2020 Nov AIM: The dynamics of coronavirus disease 2019 (COVID-19) pandemic has become of special concern to the rheumatology community. Rheumatic patients are required to engage in effective health management but their behavior is often influenced by intrinsic and extrinsic factors. This cross-sectional study aims to examine patients' experiences during the current pandemic and its implication on their health perception and behavior. METHOD: A patient-centered electronic survey was used, randomly sampling rheumatic patients in Saudi Arabia during March and April 2020. Questions included patients' socio-demographics, diseases, medications, COVID-19 knowledge, source of information, fear level, disease activity perception, health care utilization, medication accessibility, and therapeutic compliance (measured using a modified version of Medication Adherence Reporting Scale). Correlation and regression coefficients were used to evaluate associations among the aforementioned variables. RESULTS: A total of 637 respondents were included. The majority were rheumatoid arthritis patients (42.7%). Patients' knowledge about COVID-19 was correlated with social media use (P = .012). Fear of COVID-19 infection correlated with healthcare facility for follow-up visits (P = .024) and fear of disease deterioration if contracting the infection correlated with patients' levels of knowledge (P = .035). Both types of fear did not correlate with patients' perceptions of disease activity. However, patients' perceptions of worsened disease activity were correlated with unplanned healthcare visits (P < .001), medication non-adherence, and difficulty accessing medication (P = .010 and .006, respectively). CONCLUSION: The COVID-19 pandemic and surrounding public health measures could affect rheumatic patients' health management which might contribute to disease flare-up and subsequently taxing healthcare systems even further.
32841219 Fc receptor-like 5 and anti-CD20 treatment response in granulomatosis with polyangiitis an 2020 Sep 17 BACKGROUNDBaseline expression of FCRL5, a marker of naive and memory B cells, was shown to predict response to rituximab (RTX) in rheumatoid arthritis. This study investigated baseline expression of FCRL5 as a potential biomarker of clinical response to RTX in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).METHODSA previously validated quantitative PCR-based (qPCR-based) platform was used to assess FCRL5 expression in patients with GPA/MPA (RAVE trial, NCT00104299).RESULTSBaseline FCRL5 expression was significantly higher in patients achieving complete remission (CR) at 6, 12, and 18 months, independent of other clinical and serological variables, among those randomized to RTX but not cyclophosphamide-azathioprine (CYC/AZA). Patients with baseline FCRL5 expression ≥ 0.01 expression units (termed FCRL5hi) exhibited significantly higher CR rates at 6, 12, and 18 months as compared with FCRL5lo subjects (84% versus 57% [P = 0.016], 68% versus 40% [P = 0.02], and 68% versus 29% [P = 0.0009], respectively).CONCLUSIONOur data taken together suggest that FCRL5 is a biomarker of B cell lineage associated with increased achievement and maintenance of complete remission among patients treated with RTX and warrant further investigation in a prospective manner.FUNDINGThe analysis for this study was funded by Genentech Inc.
32519348 Clinical outcomes in T-cell large granular lymphocytic leukaemia: prognostic factors and t 2021 Feb T-cell large granular lymphocytic leukaemia (T-LGLL) is an incurable leukaemia characterised by clonal proliferation of abnormal cytotoxic T cells that can result in severe neutropenia, transfusion-dependent anaemia and pancytopenia requiring treatment. The most commonly used agents, methotrexate (MTX), cyclophosphamide (Cy) and cyclosporine primarily produce partial remissions (PRs), with few complete responses (CRs). We evaluated the clinical course and treatment response of 60 consecutive patients with T-LGLL to evaluate clinical outcomes and future potential treatment directions. Impaired overall survival was noted among male patients, patients with elevated lactate dehydrogenase, and those without rheumatoid arthritis. Cy was the most efficacious second-line agent, with a 70% overall response rate (ORR; three CR, four PR). All patients who failed frontline MTX responded to second-line Cy. In the relapsed or Cy-refractory setting, alemtuzumab (n = 4) and pentostatin (n = 3) had an ORR of 50% and 66%, respectively, while duvelisib induced a long-term response in one patient. In this large, retrospective analysis, our results suggest Cy is a highly effective therapy for second-line treatment in T-LGLL and should be considered a strong candidate for up-front therapy in select high-risk patients. Prospective studies evaluating pentostatin, alemtuzumab and novel agents, such as duvelisib, are needed for patients with relapsed/refractory T-LGLL.
32459524 Obesity and COVID-19: immune and metabolic derangement as a possible link to adverse clini 2020 Jul 1 Recent reports have shown a strong association between obesity and the severity of COVID-19 infection, even in the absence of other comorbidities. After infecting the host cells, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a hyperinflammatory reaction through the excessive release of cytokines, a condition known as "cytokine storm," while inducing lymphopenia and a disrupted immune response. Obesity is associated with chronic low-grade inflammation and immune dysregulation, but the exact mechanisms through which it exacerbates COVID-19 infection are not fully clarified. The production of increased amounts of cytokines such as TNFα, IL-1, IL-6, and monocyte chemoattractant protein (MCP-1) lead to oxidative stress and defective function of innate and adaptive immunity, whereas the activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome seems to play a crucial role in the pathogenesis of the infection. Endothelial dysfunction and arterial stiffness could favor the recently discovered infection of the endothelium by SARS-CoV-2, whereas alterations in cardiac structure and function and the prothrombotic microenvironment in obesity could provide a link for the increased cardiovascular events in these patients. The successful use of anti-inflammatory agents such as IL-1 and IL-6 blockers in similar hyperinflammatory settings, like that of rheumatoid arthritis, has triggered the discussion of whether such agents could be administrated in selected patients with COVID-19 disease.
32459182 Reliability, Feasibility, and Patient Acceptance of an Electronic Version of a Multidimens 2020 May 27 BACKGROUND: A multidimensional health assessment questionnaire (MDHAQ) that was developed primarily for routine rheumatology care has advanced clinical research concerning disease burden, disability, and mortality in rheumatic diseases. Routine Assessment of Patient Index Data 3 (RAPID3), an index within the MDHAQ, is the most widely used index to assess rheumatoid arthritis (RA) in clinical care in the United States, and it recognizes clinical status changes in all studied rheumatic diseases. MDHAQ physical function scores are far more significant in the prognosis of premature RA mortality than laboratory or imaging data. However, electronic medical records (EMRs) generally do not include patient questionnaires. An electronic MDHAQ (eMDHAQ), linked by fast healthcare interoperability resources (FIHR) to an EMR, can facilitate clinical and research advances. OBJECTIVE: This study analyzed the reliability, feasibility, and patient acceptance of an eMDHAQ. METHODS: Since 2006, all Rush University Medical Center rheumatology patients with all diagnoses have been asked to complete a paper MDHAQ at each routine care encounter. In April 2019, patients were invited to complete an eMDHAQ at the conclusion of the encounter. Analyses were conducted to determine the reliability of eMDHAQ versus paper MDHAQ scores, arithmetically and by intraclass correlation coefficient (ICC). The feasibility of the eMDHAQ was analyzed based on the time for patient completion. The patient preference for the electronic or paper version was analyzed through a patient paper questionnaire. RESULTS: The 98 study patients were a typical routine rheumatology patient group. Seven paper versus eMDHAQ scores were within 2%, differences neither clinically nor statistically significant. ICCs of 0.86-0.98 also indicated good to excellent reliability. Mean eMDHAQ completion time was a feasible 8.2 minutes. The eMDHAQ was preferred by 72% of patients; preferences were similar according to age and educational level. CONCLUSIONS: The results on a paper MDHAQ versus eMDHAQ were similar. Most patients preferred an eMDHAQ.
32456348 Joint Reconstituted Signaling of the IL-6 Receptor via Extracellular Vesicles. 2020 May 24 Interleukin-6 (IL-6) signaling is a crucial regulatory event important for many biological functions, such as inflammation and tissue regeneration. Accordingly, several pathological conditions are associated with dysregulated IL-6 activity, making it an attractive therapeutic target. For instance, blockade of IL-6 or its α-receptor (IL-6R) by monoclonal antibodies has been successfully used to treat rheumatoid arthritis. However, based on different signaling modes, IL-6 function varies between pro- and anti-inflammatory activity, which is critical for therapeutic intervention. So far, three modes of IL-6 signaling have been described, the classic anti-inflammatory signaling, as well as pro-inflammatory trans-signaling, and trans-presentation. The IL-6/IL-6R complex requires an additional β-receptor (gp130), which is expressed on almost all cells of the human body, to induce STAT3 (signal transducer and activator of signal transcription 3) phosphorylation and subsequent transcriptional regulation. In contrast, the IL-6R is expressed on a limited number of cells, including hepatocytes and immune cells. However, the proteolytic release of the IL-6R enables trans-signaling on cells expressing gp130 only. Here, we demonstrate a fourth possibility of IL-6 signaling that we termed joint reconstituted signaling (JRS). We show that IL-6R on extracellular vesicles (EVs) can also be transported to and fused with other cells that lack the IL-6R on their surface. Importantly, JRS via EVs induces delayed STAT3 phosphorylation compared to the well-established trans-signaling mode. EVs isolated from human serum were already shown to carry the IL-6R, and thus this new signaling mode should be considered with regard to signal intervention.
32441863 Characterization of the inflammatory-metabolic phenotype of heart failure with a preserved 2020 Sep Accumulating evidence points to the existence of an inflammatory-metabolic phenotype of heart failure with a preserved ejection fraction (HFpEF), which is characterized by biomarkers of inflammation, an expanded epicardial adipose tissue mass, microvascular endothelial dysfunction, normal-to-mildly increased left ventricular volumes and systolic blood pressures, and possibly, altered activity of adipocyte-associated inflammatory mediators. A broad range of adipogenic metabolic and systemic inflammatory disorders - e.g. obesity, diabetes and metabolic syndrome as well as rheumatoid arthritis and psoriasis - can cause this phenotype, independent of the presence of large vessel coronary artery disease. Interestingly, when compared with men, women are both at greater risk of and may suffer greater cardiac consequences from these systemic inflammatory and metabolic disorders. Women show disproportionate increases in left ventricular filling pressures following increases in central blood volume and have greater arterial stiffness than men. Additionally, they are particularly predisposed to epicardial and intramyocardial fat expansion and imbalances in adipocyte-associated proinflammatory mediators. The hormonal interrelationships seen in inflammatory-metabolic phenotype may explain why mineralocorticoid receptor antagonists and neprilysin inhibitors may be more effective in women than in men with HFpEF. Recognition of the inflammatory-metabolic phenotype may improve an understanding of the pathogenesis of HFpEF and enhance the ability to design clinical trials of interventions in this heterogeneous syndrome.
32438470 A novel statistical method for modeling covariate effects in bisulfite sequencing derived 2021 Jun Identifying disease-associated changes in DNA methylation can help us gain a better understanding of disease etiology. Bisulfite sequencing allows the generation of high-throughput methylation profiles at single-base resolution of DNA. However, optimally modeling and analyzing these sparse and discrete sequencing data is still very challenging due to variable read depth, missing data patterns, long-range correlations, data errors, and confounding from cell type mixtures. We propose a regression-based hierarchical model that allows covariate effects to vary smoothly along genomic positions and we have built a specialized EM algorithm, which explicitly allows for experimental errors and cell type mixtures, to make inference about smooth covariate effects in the model. Simulations show that the proposed method provides accurate estimates of covariate effects and captures the major underlying methylation patterns with excellent power. We also apply our method to analyze data from rheumatoid arthritis patients and controls. The method has been implemented in R package SOMNiBUS.
32425294 Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes. 2021 Jan A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.
32349516 Partitioned Extracts of Bauhinia championii Induce G(0)/G(1) Phase Arrest and Apoptosis in 2020 Bauhinia championii (Benth.) is one of the commonly used herbs in Taiwan. The stem of this plant has been used to treat epigastria pain and rheumatoid arthritis. However, the antitumor activities of this herb have never been reported. This study aims to investigate the mechanism of anticancer activity of the extracts from B. championii (BC). BC was fractionated with a series of organic solvents, including n-hexane (H), ethyl acetate (EA), 1-butanol (B), and water (W). We first investigated the effects of BC-H, BC-EA, BC-B and BC-W partitioned fraction on cell viability. In HCT 116 colon cancer cell lines, BC-EA showed the highest inhibition of cell viability and changed the morphology of cells. With dose- and time-dependent manners, BC-EA inhibited the proliferation of HCT 116 cells by inducing apoptosis and G(0)/G(1) phase arrest of cell cycle. To determine the underlying mechanisms, down-regulated CDK2, Cyclin D, and Cyclin E and up-regulated p16, p21, and p53 may account for the cell cycle arrest, while the apoptotic effect of BC-EA may attribute to increased intracellular Ca2+, loss of mitochondria membrane potential (ΔΨm), increase of Bax, Bak, puma, and AIF, and decrease of Bcl-2. Furthermore, the inactivation of Ras signaling pathway by BC-EA also contributed to its apoptotic effect on HCT 116. Our study demonstrates that BC-EA not only inhibits cell growth but also induces apoptosis through inhibiting Ras signal pathway and increasing p53 expression levels. We suggest that BC-EA may be a new dietary supplement and a useful tool to search for therapeutic candidates against colon cancer.
32316183 Development and Study of Semi-Solid Preparations Containing the Model Substance Corticotro 2020 Apr 16 Corticotropin (ACTH, previously an adrenocorticotropic hormone) is used in the diagnosis and treatment of pituitary gland disorders, adrenal cortex disorders, and other diseases, including autoimmune polymyositis, systemic lupus erythematosus, rheumatoid arthritis, Crohn's disease, and ulcerative colitis. So far, the ointment dosage form containing ACTH for use on the skin is unknown. Therefore, it seems appropriate to develop a semi-solid formulation with corticotropin. Emulsion ointments were prepared using an Unguator based on the cream base Lekobaza(®) containing corticotropin in different concentrations, and then the physical and chemical parameters of the ointment formulations, such as pH, spreadability, rheological properties, and texture analysis, were evaluated. In addition, a USP apparatus 2 with enhancer cells was utilized to study the in vitro drug release characteristics of the selected formulations. All the ointments obtained were characterized by good spreadability and viscosity. An analysis of the ointment texture was performed and the dependence of the tested parameters on the ACTH content in the ointment was demonstrated. Examination of the structure of the ointment showed that a high concentration of ACTH increases the hardness and adhesiveness of the ointment. In turn, it adversely affects the cohesiveness and elasticity of the ointments tested. The results of the release study showed that ACTH is released the fastest from the formulation with the lowest concentration, while the slowest from the ointment with the highest concentration of ACTH.