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ID PMID Title PublicationDate abstract
33054864 Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal i 2020 Oct 14 BACKGROUND: Necroptosis is a form of regulated necrosis that is involved in various autoimmune diseases. Mixed lineage kinase domain-like pseudokinase (MLKL) has been identified as a key executor of necroptosis; however, the significance of MLKL in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) has not been investigated. In this study, we aimed to determine the mRNA level of MLKL in PBMCs and examine its relationship with clinical features and serological parameters in SLE. METHODS: Real-time transcription-polymerase chain reaction (RT-PCR) analysis was used to determine the expression of MLKL mRNA in PBMCs from 59 patients with SLE, 25 patients with rheumatoid arthritis (RA), and 30 age- and sex-matched healthy controls (HC). Spearman's correlation test was performed to assess the correlation of MLKL mRNA with clinical variables. The receiver operating characteristic (ROC) curve was created to evaluate the diagnostic value. RESULTS: Our results showed MLKL mRNA in PBMCs was upregulated in SLE patients compared to that in RA and HC individuals. SLE patients positive for antinuclear antibodies had significantly higher MLKL mRNA than antibody-negative patients. In SLE patients, MLKL mRNA was found to be upregulated in patients with lupus nephritis (LN) as compared with patients without LN, and also higher in active patients than in stable patients. MLKL mRNA level was significantly and positively correlated with c-reaction protein (CRP) (r = 0.3577, p = 0.0237), erythrocyte sedimentation rate (ESR) (r = 0.4091, p = 0.0043), serum immunoglobulin G (IgG) concentration (r = 0.3546, p = 0.0289), and the numbers of positive antinuclear antibodies (ANAs) (r = 0.3945, p = 0.0432). ROC analysis showed that MLKL mRNA in PBMCs had an area under the curve of 0.9277 (95% CI 0.8779-0.9775, p < 0.001) to discriminate SLE from controls. CONCLUSIONS: These results suggest that increased MLKL mRNA level in the PBMCs of SLE patients is correlated with renal involvement and disease activity, identifying a subgroup of patients with SLE or LN who may benefit from early diagnosis and therapies targeting MLKL.
32504194 Prevalence of musculoskeletal disorders and rheumatic diseases in an Argentinean indigenou 2021 Jan OBJECTIVE: To estimate the prevalence of musculoskeletal disorders (MSK) and rheumatic diseases in an indigenous Wichi population in Argentina. METHODS: This is a cross-sectional, community-based study using the Community-Oriented Program for the Control of Rheumatic Diseases (COPCORD) methodology in ≥ 18-year-old subjects. Validated surveys were conducted by trained interviewers. Subjects with MSK pain (positive cases) were evaluated by internists and rheumatologists for diagnosis and treatment. RESULTS: A total of 648 interviews were performed (90.4% of the census population). Mean age was 37.5 years (SD 14.8), and 379 (58.5%) were female. The mean years of education was 7.0 (SD 3.7); 552 subjects (85.2%) were covered by the public health care system. A total of 216 (33.3%) subjects had MSK pain in the last 7 days. Rheumatic disease prevalence was as follows: mechanical back pain (19.0%), rheumatic regional pain syndrome (5.2%), osteoarthritis (3.2%), rheumatoid arthritis (RA) (3.2%), inflammatory back pain (1.2%), undifferentiated arthritis (0.3%), Sjögren syndrome (0.15%), and fibromyalgia (0.15%). RA patients included 19 (90.5%) women and 9 (42.9%) with RA family history. One hundred percent were seropositive and 66.7% showed radiologic erosions. The mean of Disease Activity Score [DAS-28 (ESR)] at the time of diagnosis was 5.1 (SD 1.5) and the Health Assessment Questionnaire Disability Index (HAQ-DI) was 0.8 (SD 0.4). CONCLUSION: RA prevalence was 3.2%, one of the highest reported using the COPCORD methodology in indigenous and non-indigenous peoples in Latin America, with a high percentage of family cases. Pain and functional capacity were the variables allowing patients' early referral to a specialist. Key Points • The RA prevalence was 3.2%, one of the highest reported using COPCORD methodology in indigenous and non-indigenous peoples in Latin America. • The patients with RA had high percentage of familiar history of RA. • The pain and functional capacity were the variables associated with a diagnosis of any rheumatic disease and should be considered for early referral. • The mean of the delay in the diagnosis was 5.8 years. In this community, the lack of the "migration health" phenomenon may be a social determinant that negatively impacts their health.
31325227 Association of Traditional Chinese Medicine Use With Adherence to Prescribed Western Rheum 2020 Oct OBJECTIVE: Chinese Americans are a fast-growing immigrant group with worse rheumatic disease outcomes compared to white populations and frequently use traditional Chinese medicine (TCM). Whether TCM use is associated with lower adherence to Western rheumatic medications is unknown. The present study was undertaken to examine adherence to Western medications for systemic rheumatic diseases in the Chinese American immigrant population and its association with TCM use. METHODS: Chinese Americans actively treated for a systemic rheumatic disease were recruited from 2 Chinatown clinics. Sociodemographic, TCM use, and clinical data were gathered. Self-reported health status was assessed using Patient-Reported Outcome Measurement Information System short forms. Adherence was stratified using the 8-item Morisky Medication Adherence Scale. Factors independently associated with high adherence were identified using multivariable logistic regression. RESULTS: Of 230 subjects, the median age was 55 years (range 20-97 years), 65% were female, 71% had a high school education or less, 70% were enrolled in Medicaid, and 22% reported fluency in English. The most common rheumatic diagnoses were rheumatoid arthritis (41%), systemic lupus erythematosus (17%), and seronegative spondyloarthropathies (15%). One-half reported TCM use in the past year, and 28% reported high adherence to Western rheumatic medications. In multivariable analysis, high adherence was associated with TCM use (odds ratio [OR] 3.96, P < 0.001), being married (OR 3.69, P = 0.004), medication regimen complexity (OR 1.13, P = 0.004), and older age (OR 1.06, P < 0.001), and was negatively associated with anxiety (OR 0.94, P = 0.001). CONCLUSION: While adherence to Western rheumatic medications was low in this cohort, interestingly, it was higher among TCM users compared to nonusers. TCM use appears to represent a complementary rather than an alternate approach to disease management for these patients. Future studies should evaluate whether TCM use is associated with better disease outcomes.
33447289 Clinical perspective and practices on pleural effusions in chronic systemic inflammatory d 2020 Dec Systemic inflammatory diseases are a heterogeneous family of autoimmune chronic inflammatory disorders that affect multiple systems within the human body. Connective tissue disease (CTD) is a large group within this family characterised by immune-mediated inflammation of the connective tissue. This group of disorders are often associated with pleural manifestations. CTD-induced pleuritis exhibits a wide variety of symptoms and signs including exudative pleural effusions and chest pain. Accurate estimation of prevalence for CTD-related pleuritis is challenging as small effusions are asymptomatic and remain undetected. Rheumatoid arthritis and systemic lupus erythematosus are frequent CTDs and present with pleural pathology in approximately 5-20% and 17-60% of cases, respectively. By contrast, pleural involvement in systemic sclerosis, eosinophilia-myalgia syndrome, mixed connective tissue disease, ankylosing spondylitis, polymyositis and dermatomyositis syndrome is rare. Clinical management depends on the severity of symptoms; however, most effusions resolve spontaneously. In this review we discuss the pathophysiological mechanisms and the clinical considerations of CTD-induced pleuritis.
33443168 Spinal and paraspinal inflammatory reactions after epidural steroid injection in a patient 2021 Apr BackgroundDisease-modifying anti-rheumatic drugs (DMARDs) are used in the management of rheumatoid arthritis (RA) and are classified as conventional DMARDs and biologic agents. A concern with DMARDs is the increased risk of infection after surgery. A practice advisory from the American Society of Anesthesiologists recommend alternatives to neuraxial injections in patients who are immunocompromized. We describe a patient who was on several DMARDs and developed inflammatory reactions in her bilateral paraspinal muscles and lumbar spine after an epidural steroid injection (ESI). CASE PRESENTATION: The patient was a 79-year-old woman; she was taking methotrexate, adalimumab and prednisone for her RA. She had a left L5-S1 paramedian ESI for her L5 radiculitis. After relief of her back and radicular pain for 5 weeks, she had an acute exacerbation of her back pain. MRI showed bilateral paraspinal fluid accumulations and enhancement in her ligamentum flavum. Cultures of the aspirated fluid and biopsy specimens were negative for fungal, aerobic and anaerobic organisms. A repeat MRI 2 months later showed diminution of the fluid collection but with a new fluid accumulation near the left L4-5 facet and left L4 pedicle. Repeat cultures and gram stain of the specimens taken from the pedicle and the paraspinal muscles were negative. The patient was followed by her rheumatologist and in the pain clinic until resolution of her symptoms. CONCLUSIONS: Several society guidelines recommend the continuation of methotrexate but stoppage of the biologic DMARDS before surgery. The occurrence of an intense inflammatory reaction after an ESI in our patient calls for additional research on the subject and shared decision-making between the pain physician, patient and rheumatologist especially in patients on several DMARDs.
33758816 Evaluation of Asymptomatic Bacteriuria and Urinary Tract Infection in Patients With Primar 2020 Dec OBJECTIVES: This study aims to determine the frequency and risk factors of bacteriuria and urinary tract infection (UTI) in patients with primary Sjögren's syndrome (SS) and their differences from healthy individuals and rheumatoid arthritis (RA) patients. PATIENTS AND METHODS: The study included 107 female primary SS patients (mean age 50.7±11.6 years; range, 23 to 76 years), 53 healthy female control subjects (mean age 46.8±15.5 years; range 21 to 80 years), and 40 females with RA (mean age 51.7±14.2 years; range, 25 to 79 years). Participants were questioned for UTI risk factors and symptoms. Middle stream urine samples were taken and cultured. All participants were examined with urinary symptom questioning survey of American Urological Association (AUA-7). RESULTS: The urine cultures were positive in 18 primary SS patients (16.8%), eight RA patients (20%), and two healthy controls (3.7%). Escherichia coli, enterococci, Klebsiella, streptococci, and candida were detected in SS patients' cultures. Extended-spectrum beta-lactamase was positive in three cultures. Asymptomatic bacteriuria was not detected in any SS patient. The highest AUA-7 score was determined in SS group (p=0.031). Nineteen SS patients had vaginal dryness symptom and their AUA-7 scores were higher than the rest of the SS group. The risk of UTI development was not different between those who had or did not have vaginal dryness. CONCLUSION: Urinary tract infections are seen more often in SS patients rather than normal population, which may be caused by SS' urinary system effects. It is difficult to distinguish between asymptomatic bacteriuria and infection because of the underlying urinary symptoms. Clinicians must be careful in patients receiving immunosuppressive therapy due to the high frequency of UTIs.
33597943 Recombinant Adiponectin Induces the Production of Pro-Inflammatory Chemokines and Cytokine 2020 Adiponectin is an adipokine with a modulatory role in metabolism and exerting both anti- and pro-inflammatory effects. Levels of adiponectin are increased in serum and synovial fluid from patients with rheumatoid arthritis (RA). Adiponectin is able to stimulate the production of different pro-inflammatory factors from peripheral blood mononuclear cells (PBMCs) and fibroblast-like synoviocytes (FLS) from subjects with established RA. As increased circulating adiponectin levels are a risk factor for future development of RA in subjects with obesity, we hypothesize that adiponectin is implicated in the development of RA at an early stage by initiating the pro-inflammatory processes associated with the disease pathogenesis. Therefore, we aimed to determine if adiponectin is able to induce pro-inflammatory responses in cells involved in the pathogenesis of RA, but collected from subjects without any known inflammatory disease. PBMCs and FLS were obtained from non-inflamed subjects and stimulated with 5 μg/ml human recombinant adiponectin. Supernatants collected after 48 h were analyzed for the production of 13 chemokines and 12 cytokines using multiplex assay and ELISA. Adiponectin significantly stimulated the production of CXCL1, CXCL5, and interleukin (IL)-6 in both PBMCs and FLS, whereas it induced CCL20, CCL4, CCL3, CCL17, tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor and IL-10 only in PBMCs, and CXCL8, CXCL10, CCL5, CCL11, and CCL2 only in FLS. Pre-stimulation with TNF of FLS from non-inflamed subjects did not significantly enhance the release of most pro-inflammatory factors compared to adiponectin alone. Our findings indicate that PBMCs and FLS from non-inflamed subjects react to adiponectin stimulation with the secretion of several pro-inflammatory chemokines and cytokines. These results suggest that adiponectin is able to initiate pro-inflammatory responses in cells from non-inflamed subjects and support the hypothesis that adiponectin is implicated in the early phases of RA pathogenesis.
33340765 In vitro display evolution of IL-6R-binding unnatural peptides ribosomally initiated and 2021 Jan 8 The interaction of the multifunctional cytokine interleukin (IL)-6 and its receptor (IL-6R) is involved in various diseases, including not only autoimmune diseases such as rheumatoid arthritis but also cancer and cytokine storms in coronavirus disease 2019 (COVID-19). In this study, systematic evolution of ligands by exponential enrichment (SELEX) against human IL-6R from mRNA-displayed unnatural peptide library ribosomally initiated and cyclized with m-(chloromethyl)benzoic acid (mClPh) incorporated by genetic code expansion (sense suppression) was performed using the PURE (Protein synthesis Using Recombinant Elements) system. A novel 13-mer unnatural mClPh-cyclized peptide that binds to the extracellular domain of IL-6R was discovered from an extremely diverse random peptide library. In vitro affinity maturation of IL-6R-binding unnatural mClPh-cyclized peptide from focused libraries was performed, identifying two IL-6R-binding unnatural mClPh-cyclized peptides by next-generation sequencing. Because cyclization can increase the protease resistance of peptides, novel IL-6R-binding mClPh-cyclized peptides discovered in this study have the potential to be used for a variety of research, therapeutic, and diagnostic applications involving IL-6/IL-6R signaling.
33321883 CD146/sCD146 in the Pathogenesis and Monitoring of Angiogenic and Inflammatory Diseases. 2020 Dec 10 CD146 is a cell adhesion molecule expressed on endothelial cells, as well as on other cells such as mesenchymal stem cells and Th17 lymphocytes. This protein also exists in a soluble form, whereby it can be detected in biological fluids, including the serum or the cerebrospinal fluid (CSF). Some studies have highlighted the significance of CD146 and its soluble form in angiogenesis and inflammation, having been shown to contribute to the pathogenesis of many inflammatory autoimmune diseases, such as systemic sclerosis, mellitus diabetes, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis. In this review, we will focus on how CD146 and sCD146 contribute to the pathogenesis of the aforementioned autoimmune diseases and discuss the relevance of considering it as a biomarker in these pathologies.
33288791 The role of IgE specific for galactose-α-1,3-galactose in predicting cetuximab induced hy 2020 Dec 7 Recombinant monoclonal antibodies are used for treating various diseases, from asthma, rheumatoid arthritis, and inflammatory bowel disease to cancer. Although monoclonal antibodies are known to have fewer toxic reactions compared with the conventional cytotoxic antineoplastic drugs, the cases of severe systemic hypersensitivity reaction (HSR) should be acknowledged. Our aim was to assess the diagnostic accuracy of the anti-IgE for galactose-α-1,3-galactose in patients with HSRs to cetuximab. We searched in PubMed, Cochrane Library, Scopus, and World of Science databases to July 1st, 2020. We included a total of 6 studies, with 1074 patients. Meta-analysis was performed using bivariate analysis and the random-effect model. The pooled sensitivity was 73% (95% CI 62-81%) and the pooled specificity was 88% (95% CI 79-94%). We had not found significant heterogeneity and, despite some discrepancies in the nature of data available in the analysed studies, we draw the conclusion that the presence of cetuximab specific IgE (anti cetuximab antibody) and/or galactose-α-1,3-galactose shows moderate to high sensitivity and specificity of developing an HSR. More studies are needed to establish a protocol necessary for the proper prediction and avoidance of HSR related to cetuximab.
33222113 Evaluation of Adherence and Persistence Differences Between Adalimumab Citrate-Free and Ci 2021 Mar INTRODUCTION: Our aim was to evaluate patient adherence and persistence with citrate-free adalimumab (ADA-CF), introduced in 2018 to reduce injection-site pain, compared with citrate-containing adalimumab (ADA-C). METHODS: This was a retrospective cohort study using a US claims database (IBM(®) MarketScan(®) Commercial and Medicare Supplemental Claims Database) from February 2018 to January 2020. Patients at least 18 years of age who were naïve to adalimumab 6 months before the index date (date of first adalimumab claim) and with at least 12 months of continuous medical and pharmacy coverage were eligible for the study. Adherence was assessed by determining the proportion of days covered (PDC) and the percentage of patients with PDC ≥ 80% during the 12-month follow-up period. Persistence was evaluated by measuring the rate of discontinuation and days to discontinuation (i.e., time on treatment) from the index date over the 12-month follow-up period. Continuous adherence outcomes (PDC) were evaluated using linear regression models. Binary adherence outcomes (PDC ≥ 80%) were assessed using logistic regression models. Kaplan-Meier analysis and Cox proportional hazards models were used to assess persistence outcomes. RESULTS: There were 2195 and 1005 patients in the ADA-CF and ADA-C cohorts, respectively, with most using adalimumab for rheumatoid arthritis (ADA-CF 29.7%, ADA-C 27.2%) and psoriasis (ADA-CF 24.5%, ADA-C 31.9%). Significantly greater adherence was achieved with ADA-CF compared with ADA-C (mean PDC [standard deviation] 0.68 [0.30] vs 0.61 [0.32], P < 0.0001). A significantly greater percentage of patients receiving ADA-CF (47.2%) vs ADA-C (39.6%) had PDC ≥ 80% (P < 0.0001). The discontinuation rate was significantly lower for the ADA-CF cohort (46.4%) compared with ADA-C (55.9%, P < 0.0001), resulting in a 27% lower likelihood of discontinuation during the 12-month follow-up period (hazard ratio 0.73; 95% confidence interval 0.66, 0.82; P < 0.0001) and longer time on treatment (260 vs 232 days, P < 0.0001). CONCLUSION: Adherence and persistence are significantly improved with ADA-CF compared with ADA-C.
33204994 Transcatheter aortic valve-in-valve post-dilatation as an overlooked risk factor of delaye 2020 Oct BACKGROUND: The risk of coronary obstruction during transcatheter aortic valve-in-valve replacement (VIV-TAVR) in patients deemed at high risk for surgical re-intervention is still a concerning issue. CASE SUMMARY: A 78-year-old woman with a past medical history of hypertension, chronic kidney disease, and rheumatoid arthritis was referred for a symptomatic and severely stenotic surgical Mitroflow n.21 bio-prosthesis and was subsequently recommended for a VIV procedure. Multiple anatomical risk factors for coronary occlusion required a pre-emptive coronary chimney stenting protection. The implantation of an Evolut-R 23 mm valve resulted in a gradient of 21 mmHg thus, a post-dilatation with an 18 mm balloon was performed. Both electrocardiographic and haemodynamic parameters remained excellent, however, a hazardous leaflet dislodgment became evident. Regardless, a prophylactic chimney stenting was performed because of the operator's perceived high risk of late coronary occlusion. DISCUSSION: The implantation of transcatheter valves inside failed surgically implanted aortic bio-prosthesis is broadly recognized as a safe and less-invasive alternative to repeated high-risk surgery. Although procedural success is achieved in the great majority of patients, this therapy may be jeopardized by rare but serious complications such as impending or established acute coronary occlusion. Several specific anatomical and procedural risk factors have been identified and primary coronary prevention strategies are often mandatory when they arise. Valve-in-valve post-dilation has been overlooked in its role as an additional risk factor of late coronary obstruction. Therefore, chimney stenting, performed after balloon post-dilation to prevent delayed coronary obstruction, even if the acute coronary event does not occur intra-procedurally, is strongly advisable.
33188704 The role of the gut microbiota and microbial metabolites in neuroinflammation. 2020 Dec Recent literature indicates a potential importance of the gut microbiota for immune-mediated diseases. For instance, decreased diversity of commensals or an outgrowth of some bacterial strains, referred to as gut dysbiosis, was recently linked to hypertension, colitis, lupus, rheumatoid arthritis, and multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE) as pivotal animal model of MS revealed a potential importance of microbial metabolites, including short-chain fatty acids or tryptophan metabolites. Both metabolites may influence the disease by modulation of the immune system, mainly by inducing Treg. These studies prompted researchers to investigate the contribution of the gut microbiota and microbial metabolites in the pathogenesis of MS. This review summarizes recent findings on the gut microbiota in MS patients and discusses the potential mechanisms how microbial metabolites may affect neuroinflammation. Many of these studies have been performed in the EAE model and were later reversely translated to humans. We also give a short summary on dietary high-salt effects on microbiota components and discuss the potential relevance of high-salt as a risk factor in MS.
33103259 Recent advances in the design of choline kinase α inhibitors and the molecular basis of t 2021 Mar Upregulated choline metabolism, characterized by an increase in phosphocholine (PCho), is a hallmark of oncogenesis and tumor progression. Choline kinase (ChoK), the enzyme responsible for PCho synthesis, has consequently become a promising drug target for cancer therapy and as such a significant number of ChoK inhibitors have been developed over the last few decades. More recently, due to the role of this enzyme in other pathologies, ChoK inhibitors have also been used in new therapeutic approaches against malaria and rheumatoid arthritis. Here, we review research results in the field of ChoKα inhibitors from their synthesis to the molecular basis of their binding mode. Strategies for the development of inhibitors and their selectivity on ChoKα over ChoKβ, the plasticity of the choline-binding site, the discovery of new exploitable binding sites, and the allosteric properties of this enzyme are highlighted. The outcomes summarized in this review will be a useful guide to develop new multifunctional potent drugs for the treatment of various human diseases.
33071096 Acute chloroquine and hydroxychloroquine toxicity: A review for emergency clinicians. 2020 Oct BACKGROUND: Acute chloroquine and hydroxychloroquine toxicity is characterized by a combination of direct cardiovascular effects and electrolyte derangements with resultant dysrhythmias and is associated with significant morbidity and mortality. OBJECTIVE: This review describes acute chloroquine and hydroxychloroquine toxicity, outlines the complex pathophysiologic derangements, and addresses the emergency department (ED) management of this patient population. DISCUSSION: Chloroquine and hydroxychloroquine are aminoquinoline derivatives widely used in the treatment of rheumatologic diseases including systemic lupus erythematosus and rheumatoid arthritis as well as for malaria prophylaxis. In early 2020, anecdotal reports and preliminary data suggested utility of hydroxychloroquine in attenuating viral loads and symptoms in patients with SARS-CoV-2 infection. Aminoquinoline drugs pose unique and significant toxicological risks, both during their intended use as well as in unsupervised settings by laypersons. The therapeutic range for chloroquine is narrow. Acute severe toxicity is associated with 10-30% mortality owing to a combination of direct cardiovascular effects and electrolyte derangements with resultant dysrhythmias. Treatment in the ED is focused on decontamination, stabilization of cardiac dysrhythmias, hemodynamic support, electrolyte correction, and seizure prevention. CONCLUSIONS: An understanding of the pathophysiology of acute chloroquine and hydroxychloroquine toxicity and available emergency treatments can assist emergency clinicians in reducing the immediate morbidity and mortality associated with this disease.
32981005 Coronavirus disease 2019 (COVID-19) in patients with systemic autoimmune diseases or vascu 2021 Feb Coronavirus disease 2019 (COVID-19) has transformed into a worldwide challenge, since its outbreak in December 2019. Generally, patients with underlying medical conditions are at a higher risk of complications and fatality of pneumonias. Whether patients with systemic autoimmune diseases or vasculitides, are at increased risk for serious complications associated with COVID-19, is not established yet. Computed tomography (CT) has been employed as a diagnostic tool in the evaluation of patients with clinical suspicion of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection with a reported sensitivity of higher than reverse transcription polymerase chain reaction (RT-PCR) test. Multifocal bilateral ground-glass opacities (GGOs) with peripheral and posterior distribution and subsequent superimposition of consolidations are considered the main imaging features of the disease in chest CT. However, chest CT images of underlying rheumatologic or autoimmune diseases or vasculitides, such as systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, Behçet disease, and granulomatosis with polyangiitis, especially those with extensive lung involvement can overshadow or obliterate features of COVID-19. In addition, CT findings of such diseases may resemble manifestations of COVID-19 (such as ground glass opacities with or without superimposed consolidation), making the diagnosis of viral infections, more challenging on imaging. Comparing the imaging findings with prior studies (if available) for any interval change is the most helpful approach. Otherwise, the diagnosis of COVID-19 in such patients must be cautiously made according to the clinical context and laboratory results, considering a very high clinical index of suspicion on imaging.
32964757 Identification of the metabolites of isochlorogenic acid A in rats by UHPLC-Q-Exactive Orb 2020 Dec CONTENT: Isochlorogenic acid A, one of the main components of Duhaldea nervosa (Wallich ex Candolle) A. Anderberg (Asteraceae), is a folk medicine used to treat a variety of diseases including fracture and rheumatoid arthritis. Despite its widespread use, the metabolism of isochlorogenic acid A in vivo has not been fully studied. OBJECTIVE: An analytical strategy based on UHPLC-Q-Exactive Orbitrap MS is proposed for the detection and identification of the metabolites of isochlorogenic acid A in rats. MATERIALS AND METHODS: Six male Sprague-Dawley rats (180 ± 20 g) were randomly divided into two groups. Then, blood and tissue samples were obtained after oral administration of isochlorogenic acid A (200 mg/kg). All the samples were pre-treated by the Solid Phase Extraction (SPE) method. Next, the samples were analysed by UHPLC-Q-Exactive Orbitrap MS. Finally, the metabolites were identified based on the metabolomic workflow template. RESULTS: A total of 33 metabolites were identified in rat plasma, with 30 of them being reported for the first time. The distribution of all metabolites in tissues was first investigated, three of them were widely distributed in liver, lungs, and kidneys. The corresponding reactions including methylation, hydrolysis, sulphate conjugation, glucuronide conjugation, as well as their composite reactions, are reported in this study. DISCUSSION AND CONCLUSIONS: This method has wide-scale application prospects in the identification of metabolites. Considering that limited research has been conducted in this area, this study proposes metabolic pathways to further understand mechanisms of isochlorogenic acid A and the forms that are truly effective in vivo.
32901877 SDF1/CXCR4 axis facilitates the angiogenesis via activating the PI3K/AKT pathway in degene 2020 Nov Symptomatic degenerative disc disease (DDD) is considered the leading cause of chronic lower back pain (LBP). As one of the main features of intervertebral disc degeneration (IDD), vascular ingrowth plays a crucial role in the progression of LBP. Stromal cell‑derived factor 1 (SDF1) and its receptor C‑X‑C receptor 4 (CXCR4) were reported to be overexpressed in the degenerated intervertebral discs, suggesting that they may be involved in the pathogenesis of IDD. Moreover, SDF1 has been identified to induce neovascularization in rheumatoid arthritis disease. However, the roles of the SDF1/CXCR4 axis in the neovascularization of IDD remain unclear. Therefore, the objective of the present study was to elucidate whether the SDF1/CXCR4 axis takes part in neovascularization in degenerated intervertebral discs and its underlying mechanisms. Adenovirus infection was used to upregulate SDF1 expression in primary nucleus pulposus cells (NPCs). The effects of SDF1 on the proliferation and angiogenesis of vascular endothelial cells (VECs) were assessed by Cell Counting Kit‑8 and tube formation assays after VECs were treated with the supernatants derived from SDF1 overexpressed or not treated NPCs. Transwell chambers using the supernatants from NPCs as chemokines were applied to assess VEC migration and invasion. AMD3100, MK‑2206 and SF1670 were used to antagonize CXCR4, AKT serine/threonine kinase 1 (AKT) and phosphatase and tensin homolog (PTEN) in VECs. The results revealed that SDF1 overexpression significantly increased the ratio of phosphorylated AKT to AKT and decreased PTEN expression in NPCs, as well as enhanced the proliferation, migration, invasion and angiogenesis abilities of VECs. However, these effects induced by SDF1 overexpression in NPCs were all reversed when VECs were pretreated with AMD3100 or MK‑2206, whereas enhanced by SF1670 treatment. Collectively, the present study indicated that enhancement of the SDF1/CXCR4 axis in NPCs can significantly accelerate angiogenesis by regulating the PTEN/phosphatidylinositol‑3‑kinase/AKT pathway.
32853526 The Ubiquitin System and A20: Implications in Health and Disease. 2021 Jan Inflammation is triggered by stimulation of innate sensors that recognize pathogens, chemical and physical irritants, and damaged cells subsequently initiating a well-orchestrated adaptive immune response. Immune cell activation is a strictly regulated and self-resolving process supported by an array of negative feedback mechanisms to sustain tissue homeostasis. The disruption of these regulatory pathways forms the basis of chronic inflammatory diseases, including periodontitis. Ubiquitination, a covalent posttranslational modification of target proteins with ubiquitin, has a profound effect on the stability and activity of its substrates, thereby regulating the immune system at molecular and cellular levels. Through the cooperative actions of E3 ubiquitin ligases and deubiquitinases, ubiquitin modifications are implicated in several biological processes, including proteasomal degradation, transcriptional regulation, regulation of protein-protein interactions, endocytosis, autophagy, DNA repair, and cell cycle regulation. A20 (tumor necrosis factor α-induced protein 3 or TNFAIP3) is a ubiquitin-editing enzyme that mainly functions as an endogenous regulator of inflammation through termination of nuclear factor (NF)-κB activation as part of a negative feedback loop. A20 interacts with substrates that reside downstream of immune sensors, including Toll-like receptors, nucleotide-binding oligomerization domain-containing receptors, lymphocyte receptors, and cytokine receptors. Due to its pleiotropic functions as a ubiquitin binding protein, deubiquitinase and ubiquitin ligase, and its versatile role in various signaling pathways, aberrant A20 levels are associated with numerous conditions such as rheumatoid arthritis, diabetes, systemic lupus erythematosus, inflammatory bowel disease, psoriasis, Sjögren syndrome, coronary artery disease, multiple sclerosis, cystic fibrosis, asthma, cancer, neurological disorders, and aging-related sequelae. Similarly, A20 has recently been implicated as an essential regulator of inflammation in the oral cavity. This review presents information on the ubiquitin system and regulation of NF-κB by ubiquitination using A20 as a representative molecule and highlights how the dysregulation of this system can lead to several immune pathologies, including oral cavity-related disorders mainly focusing on periodontitis.
32827097 The role of Th17 cells in psoriasis. 2020 Oct T helper 17 (Th17) cells have been involved in the pathogenesis of many autoimmune and inflammatory diseases, like psoriasis, multiple sclerosis (MS), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). However, the role of Th17 cells in psoriasis has not been clarified completely. Th17-derived proinflammatory cytokines including IL-17A, IL-17F, IL-21, IL-22, and IL-26 have a critical role in the pathogenesis of these disorders. In this review, we introduced the signaling and transcriptional regulation of Th17 cells. And then, we demonstrate the immunopathology role of Th17 cells and functions of the related cytokines in the psoriasis to get a better understanding of the inflammatory mechanisms mediated by Th17 cells in this disease.