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Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
34385106 LncRNA ZFAS1: Role in tumorigenesis and other diseases. 2021 Oct Residing on chromosome 20q13.13, Zinc Finger NFX1-Type Containing 1 (ZNFX1) antisense RNA 1 (ZFAS1) is a transcript which has been primarily recognized as a modulator of differentiation of alveolar and epithelial cell in the mammary gland. This long non-coding RNA (lncRNA) partakes in the molecular cascades leading to several non-neoplastic conditions such as osteoarthritis, epilepsy, rheumatoid arthritis, atherosclerosis, pulmonary fibrosis, myocardial infarction, and cardiac dysfunction. More importantly, ZFAS1 is considered as an oncogene in almost all types of cancers. Using expression amounts of ZFAS1, it is possible to forecast the clinical outcome of patients with different neoplasms such as colorectal cancer, gastric cancer, cholangiocarcinoma, hepatoblastoma, and other types of cancer. We describe the role of ZFAS1 in the development of neoplastic and non-neoplastic disorders.
34337203 Indole Inhibitors of MMP-13 for Arthritic Disorders. 2021 Jul 27 Here, we described the design, by fragment merging and multiparameter optimization, of selective MMP-13 inhibitors that display an appropriate balance of potency and physicochemical properties to qualify as tool compounds suitable for in vivo testing. Optimization of potency was guided by structure-based insights, specifically to replace an ester moiety and introduce polar directional hydrogen bonding interactions in the core of the molecule. By introducing polar enthalpic interactions in this series of inhibitors, the overall beneficial physicochemical properties were maintained. These physicochemical properties translated to excellent drug-like properties beyond potency. In a murine model of rheumatoid arthritis, treatment of mice with selective inhibitors of MMP-13 resulted in a statistically significant reduction in the mean arthritic score vs control when dosed over a 14 day period.
34137627 Groove Switching of Hydroxychloroquine Modulates the Efficacy of Binding and Induced Stabi 2021 Jul 1 Hydroxychloroquine (HCQ) is an important drug for the treatment of rheumatoid arthritis and malaria. HCQ targets specifically to nucleic acids for its action. However, the mechanism of HCQ binding and the effect of its binding on the stability of DNA are elusive. In this study, the binding mechanism of HCQ and the effect of binding on stability of different sequences of DNA have been investigated using spectroscopic and molecular dynamics (MD) simulation techniques. HCQ binds with all of the sequences of DNA and stabilizes them. However, binding efficacy of HCQ with DNA depends on its sequences as the binding constant is highest for pure guanine-cytosine (G-C) rich DNA and decreases with the increase of adenine-thymine (A-T) bases. HCQ prefers to interact with AT DNA through the minor groove whereas the major groove along with intercalation are the favorable binding mode in the case of GC DNA. The binding of HCQ in the major groove of GC DNA enhances the stacking between the bases compared to the case of AT DNA which leads to higher stability for GC DNA. It appears that the groove switching of HCQ is correlated with binding affinity as well as stability of different sequences of DNA.
34083970 Epstein-Barr virus-positive ulcer in the oral cavity. 2021 Mar Epstein-Barr virus-positive ulcer (EBV + U) is a recently reported B cell lymphoproliferative disorder in the oral cavity, oropharynx, gastrointestinal tract and skin, principally in immunosuppressed patients. A 53-year-old female patient with rheumatoid arthritis treated with methotrexate, presenting ulcers of unknown duration on the dorsum and the lateral left border of the tongue. Excisional biopsy, histopathological analysis and histochemical stains for syphilis (Warthin-Starry), mycotic diseases (Grocott silver methenamine), tuberculosis (Ziehl-Neelsen), immunohistochemistry tests for herpesvirus type 8 (CMV), EBV (LMP-1) and DNA extraction for polymerase chain reaction (PCR) assay to CMV, EBV and herpes simplex virus-1 were performed. Posterior to PCR assay, the final diagnosis was EBV + U in the oral cavity. Acyclovir(®) was prescribed, showing clinical improvement. A case of EBV + U with clinical characteristics similar to other lesions or conditions has been reported. Special assays are necessary for an accurate diagnosis and treatment.
34013961 Emerging role of carbonic anhydrase inhibitors. 2021 May 28 Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) was clinically exploited for decades, as most modern diuretics were obtained considering as lead molecule acetazolamide, the prototypical CA inhibitor (CAI). The discovery and characterization of multiple human CA (hCA) isoforms, 15 of which being known today, led to new applications of their inhibitors. They include widely clinically used antiglaucoma, antiepileptic and antiobesity agents, antitumor drugs in clinical development, as well as drugs for the management of acute mountain sickness and idiopathic intracranial hypertension (IIH). Emerging roles of several CA isoforms in areas not generally connected to these enzymes were recently documented, such as in neuropathic pain, cerebral ischemia, rheumatoid arthritis, oxidative stress and Alzheimer's disease. Proof-of-concept studies thus emerged by using isoform-selective inhibitors, which may lead to new clinical applications in such areas. Relevant preclinical models are available for these pathologies due to the availability of isoform-selective CAIs for all human isoforms, belonging to novel classes of compounds, such as coumarins, sulfocoumarins, dithiocarbamates, benzoxaboroles, apart the classical sulfonamide inhibitors. The inhibition of CAs from pathogenic bacteria, fungi, protozoans or nematodes started recently to be considered for obtaining anti-infectives with a new mechanism of action.
33924232 Vitamin D and Microbiota: Is There a Link with Allergies? 2021 Apr 20 There is increasing recognition of the importance of both the microbiome and vitamin D in states of health and disease. Microbiome studies have already demonstrated unique microbial patterns in systemic autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus. Dysbiosis also seems to be associated with allergies, in particular asthma, atopic dermatitis, and food allergy. Even though the effect of vitamin D supplementation on these pathologies is still unknown, vitamin D deficiency deeply influences the microbiome by altering the microbiome composition and the integrity of the gut epithelial barrier. It also influences the immune system mainly through the vitamin D receptor (VDR). In this review, we summarize the influence of the microbiome and vitamin D on the immune system with a particular focus on allergic diseases and we discuss the necessity of further studies on the use of probiotics and of a correct intake of vitamin D.
33911815 Palisaded Neutrophilic and Granulomatous Dermatitis in a Patient with Behçet's Disease: A 2021 Feb Palisaded neutrophilic and granulomatous dermatitis (PNGD) is an uncommon skin eruption and characterized histopathologically by the presence of granulomatous inflammation with or without leukocytoclastic vasculitis. PNGD is known to be associated with various immune-mediated connective tissue diseases such as rheumatoid arthritis and lupus erythematosus. However, to our knowledge, a case of PNGD in a patient with Behçet's disease is extremely rare and only one case has been reported in foreign literature to date. Herein, we report an unusual case of a 60-year-old female with Behçet's disease who presented multiple erythematous to flesh-colored papules on the extremities, buttocks, and ear lobes and was diagnosed with PNGD. After the treatment of systemic corticosteroids, colchicine and azathioprine, the skin lesions and oral ulcers improved. The patient is under observation without recurrence of skin lesions for 6 months.
33823727 Depression in disabling medical conditions - current perspectives. 2021 May Chronic diseases commonly entail disability and are highly comorbid with mental health problems, particularly depression. Prevalence of depression across different disabling conditions affecting adult patients, as well as risk factors for depression in these patient groups are reviewed in the current work, with a particular focus on the literature published in the past 5 years. The prevalence of depression in disabling conditions is higher than in the general population and is associated with different factors. Examples of disease-specific factors include neurological implications of stoke, diabetic related conditions (e.g. amputation), limitations imposed by vision loss caused by age-related eye diseases, fatigue in rheumatoid arthritis, and pain in cancer. Common factors identified across different conditions include pre-morbid depression, history of mental health problems, poor social support, disease-related disability, multi-morbidity, and less adaptive coping strategies. We also reviewed studies suggesting a potential bidirectional relationship between depression and chronic disease, particularly for stroke, cardiovascular disease, diabetes, and potential factors mediating that relationship. Current findings suggested that long-term depression might be associated with an increased risk of subsequent physical health problems, although the nature of that relationship and its underlying mechanisms are still unclear.
33777580 CD26/Dipeptidyl Peptidase IV and Its Multiple Biological Functions. 2021 Feb 22 CD26/Dipeptidyl peptidase IV (DPPIV) is a cell surface glycoprotein with numerous roles including glucose metabolism, immunomodulation, and tumorigenesis. CD26/DPPIV is well recognized in diabetes, with DPPIV inhibitors being a class of oral hypoglycemic drugs called gliptins that are commonly used to treat type two diabetes mellitus. Recent work also indicated a potential role for CD26 in infectious diseases, including COVID-19, and immune-mediated disorders such as rheumatoid arthritis, inflammatory bowel disease, and graft-versus-host disease. In cancer, CD26/DPPIV expression has been characterized in numerous tumors such as hematologic malignancies, malignant pleural mesothelioma (MPM), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), gastrointestinal stromal tumor (GIST), and prostate, lung, colorectal, and ovarian (PLCO) cancer. Hence, CD26 has been frequently studied as a tumor biomarker and therapeutic target. CD26/DPPIV-targeted therapies have been evaluated in various cancers, including the use of anti-CD26 monoclonal antibodies as anticancer treatment in selected neoplasms. This review highlights our current understanding of the role of CD26 in cancer, diabetes, immune-mediated diseases, and infectious diseases. Enhanced understanding of CD26 biology and function may lead to novel therapeutic approaches in multiple human diseases.
33755322 Diagnosis of miliary nodules as lung adenocarcinoma by cryobiopsy: A case report. 2021 May A 62-year-old woman with rheumatoid arthritis and a history of receiving immunosuppressant therapy had a recurrence of lung adenocarcinoma with EGFR L858R mutation. Following 14 months of treatment with erlotinib, computed tomography (CT) findings revealed the presence of small diffuse nodules. Bronchoscopy was performed as metastasis was suspected; however, this was not detected on lung biopsy with forceps. Transbronchial lung cryobiopsy (TBLC) succeeded in detecting metastatic adenocarcinoma, and T790M and L858R gene mutations. Pathological examination revealed a cluster of tumor cells in the intralobular interstitial areas, which was consistent with the CT findings. This report provides important information regarding the role of TBLC in diagnosing metastatic cancer, such as diffuse small miliary nodules, and its genetic mutations.
33559776 Spondyloarthritis in North Africa: an update. 2021 Sep Spondyloarthritis (SpA) has been less well studied than rheumatoid arthritis in North Africa, due to a belief that it is rare and benign in certain populations. The main genetic trait of SpA is its association with human leukocyte antigen (HLA)-B27. The distribution of this allele largely explains the prevalence and severity of SpA. The prevalence of HLA-B27 in the general population of North Africa is estimated at about 4%, and rises to about 60% among people affected with SpA. Coxitis is one of the main features of North African SpA, but the response to treatment is comparable to the literature from the West. The major challenge in North Africa remains accessibility to specialized care and means of early diagnosis. Prevalent infections in North Africa do not seem to be a major obstacle to optimal treatment strategies.
33521454 Roflumilast Reduced the IL-18-Induced Inflammatory Response in Fibroblast-Like Synoviocyte 2021 Jan 26 Pro-inflammatory cytokines, such as the IL-18-induced inflammatory response and associated damage in fibroblast-like synoviocytes (FLS), play an important role in the pathogenesis of rheumatoid arthritis (RA). Roflumilast, an inhibitor of phosphodiesterase-4 (PDE-4), has been licensed for the treatment of chronic obstructive pulmonary disease (COPD). However, it is unknown whether roflumilast possesses a protective effect against the IL-18-induced inflammatory response in FLS. We found that roflumilast attenuated IL-18-induced oxidative stress by reducing the production of reactive oxygen species and malondialdehyde (MDA) in MH7A fibroblast-like synoviocytes (FLS). Additionally, roflumilast prevented IL-18-induced expressions and secretions of pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α. Importantly, we found that roflumilast inhibited IL-18-induced expressions of chemokines such as CCL5, CXCL9, and CXCL10. Further, roflumilast inhibited the expression of extracellular matrix degradative enzymes, such as matrix metalloproteinase-3 (MMP-3) and MMP-13. Mechanistically, we found that roflumilast suppressed the activation of the transcriptional factor AP-1 and NF-κB. Our results suggest that roflumilast might be a potential therapeutic agent for the treatment of RA.
33420569 [Interstitial lung disease associated with connective tissue disease]. 2021 Feb Interstitial lung disease (ILD) is the most frequent organ manifestation in rheumatic autoimmune disease. Depending on the underlying autoimmune disease, differently pronounced affections of small airways, interstitial parenchyma, and vessels are found. The group of rheumatic autoimmune diseases mainly includes connective tissue diseases (CTDs), also known as collagen vascular diseases, such as rheumatoid arthritis (RA), systemic sclerosis, (SSc), systemic lupus erythematosus, primary Sjögren's syndrome, idiopathic inflammatory myositis (IIM), and interstitial pneumonia with autoimmune features (IPAF). Frequency and manifestations of parenchymal lung disorders are described clinically, radiologically, and morphologically in these entities. For the precise diagnosis and for the differentiation between the wide range of parenchymal disorders with known possible cause or with unknown origin, also called unclassifiable or idiopathic interstitial pneumonias (IIPs), high resolution computed tomography (HRCT) findings represent the diagnostic gold standard. A transbronchial biopsy, surgical biopsy, or cryobiopsy will be used in unclassifiable findings to confirm a definitive histological confirmation. A precise diagnosis of these ILDs is crucial since the different pathologies that encompass ILD have different therapeutic options. In this sense, the participation of a pneumologist, rheumatologist, radiologist, and pathologist become essential in the multidisciplinary evolution of ILD.
33197033 RANKL-Based Osteoclastogenic Assay from Murine Bone Marrow Cells. 2021 The osteoclast is the unique type of cell that resorbs bone in vivo and it is required for normal skeletal development and postnatal homeostasis. Osteoclast deficiency impairs skeletal development during embryogenesis and results in osteopetrosis and impaired tooth eruption. In contrast, excessive osteoclast formation in adults results in bone loss in a number of conditions, including osteoporosis, rheumatoid arthritis, and metastatic bone disease. Osteoclasts are derived from monocytes/macrophages; they can be generated in vitro by treatment of these precursor cells with macrophage colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). This chapter describes procedures for generating osteoclasts from mouse bone marrow cells in vitro using M-CSF and RANKL and assessing their ability to form resorption lacunae on thin bone slices.
32844516 To dispense or not to dispense: Lessons to be learnt from ethical challenges faced by phar 2021 Dec The year 2020 is facing one of the worst public health situations in decades. The world is experiencing a pandemic that has triggered significant challenges to healthcare systems in both high and low-middle income countries (LMICs). Government policymakers and healthcare personnel are experiencing real-life ethical dilemmas and are pressed to respond to these situations. Many possible treatments are being investigated, one of which is the use of hydroxychloroquine or chloroquine. These drugs are approved for use by patients with systemic lupus erythematosus (SLE), rheumatoid arthritis, and malaria. The demand for these products has increased, and the stocks are depleting for the patient population for whom the drugs are intended initially. Although both innovator and generic pharmaceutical manufacturers are making plans for increased production, there are challenges with global supply chains disruption and the retention of supplies for local markets. This may cause countries that rely on the importation of pharmaceuticals to be out of stock of supplies for an extended period. There are allegations of off-label prescribing and hoarding. Pharmacists are the custodians and dispensers of medications and are faced with the task of assessing prescriptions and making decisions about the allocation of these products. This paper seeks to 1) highlight some of the ethical challenges of dispensing hydroxychloroquine by pharmacists during the COVID-19 pandemic, 2) identify some of the responses to these issues from various regulatory authorities in the USA, and 3) recommend approaches to assist pharmacists in their decision-making process, especially in LMICs.
34277118 Identification and quantification of the bioactive components in Osmanthus fragrans roots 2021 Jun The roots of O. fragrans are also a valuable resource in addition to its flowers and fruits. In this study, the HPLC-MS/MS method used for analyzing the chemical constituents in O. fragrans roots extract was developed, which showed high sensitivity for both qualitative and quantitative analyses. Thirty-two compounds were first discovered in O. fragrans roots, one compound of which was reported for the first time. The simultaneous determination method for acteoside, isoacteoside, oleuropein and phillyrin was validated to be sensitive and accurate. Then it was applied to determine the content of bioactive components in O. fragrans roots from different cultivars. The content of oleuropein and phillyrin in the twelve batches was relatively stable, while the content of acteoside and isoacteoside varied greatly. Moreover, the therapeutic material basis and mechanism of O. fragrans roots exerting its traditional pharmacodynamics were analyzed by network pharmacology. The results showed that O. fragrans roots might be effective for the treatment of inflammation, cardiovascular diseases, cancer, and rheumatoid arthritis, which is consistent with the traditional pharmacodynamics of O. fragrans roots. This work can provide an analytical method for the comprehensive development of O. fragrans roots.
35139477 Synthesis and evaluation of tofacitinib analogs designed to mitigate metabolic activation. 2022 Apr Tofacitinib (TFT), a JAK inhibitor used for the treatment of rheumatoid arthritis and other diseases, is associated with severe liver injury that is believed to be caused by its reactive aldehyde or epoxide metabolites. In this study, we synthesized six tofacitinib analogs designed to avoid the formation of reactive metabolites and evaluated their JAK3 inhibitory activity, metabolic stability, CYP3A time-dependent inhibition, and cytotoxicity. Our data indicated that purine analog 3, which showed little inhibition of CYP3A and cytotoxicity and inhibited JAK3 in the nanomolar range, could be a safer drug candidate than TFT. In addition, the results of the bioactivation study using TFT and its analogs suggest that the epoxide metabolite might contribute to TFT-induced CYP3A4 mechanism-based inhibition and hepatic toxicity.
34622124 The treatment of Merkel cell carcinoma with immune checkpoint inhibitors: implications for 2021 OBJECTIVES: Merkel cell carcinoma (MCC) is a rare, highly aggressive neuroendocrine skin cancer, which typically affects elderly and immunocompromised and/or immunosuppressed patients. The checkpoint inhibitor avelumab, a mAb targeting the anti-programmed cell death ligand 1 (anti-PD-L1), has revolutionized the treatment of metastatic MCC, achieving dramatic improvements in disease control and overall survival. However, checkpoint inhibitors are associated with the development of immune-related adverse events, such as exacerbation of pre-existing RA. Although most immune-related adverse events can be managed successfully with CSs, their frequent and/or long-term use runs the risk of undermining the efficacy of immune checkpoint inhibition. METHODS: We report two cases of MCC, in which immunosuppressive therapy for the management of RA was administered. RESULTS: Immunosuppression for (i) pre-existing and (ii) immune checkpoint inhibitor-exacerbated RA was associated with progression of metastatic MCC. CONCLUSION: Any decision to initiate immunosuppressive treatment for RA in patients receiving immune checkpoint inhibitor therapy should include careful consideration of the risk of potentially fatal cancer progression and be taken after consultation with the patient's oncologist and rheumatologist. When the immunosuppressive treatment is required, it should be administered for as short a time as possible and under strict clinical and radiological surveillance.
34402274 [Research progress on culture technologies,chemical components,and pharmacological activit 2021 Jul Saussurea involucrata,a traditional Chinese medicinal material,is effective in the treatment of rheumatoid arthritis with cold-dampness blockage syndrome,cold pain in lower abdomen,and menstrual irregularities. However,due to the specific habitat,low natural reproduction rate,slow growth,and overexploitation,it is at the high risk of extinction. S. involucrata cells can be obtained through callus culture,suspension culture,and hairy root culture. This study highlighted the influences of reactor type,culture system,precursor,elicitor type, and light wavelength on the suspension culture of S. involucrate cells. The chemical components of S. involucrata cells mainly include phenylpropanoids,flavonoids,lignans,and steroids,among which phenylpropanoids are the most abundant. S. involucrata cells have multiple pharmacological activities of anti-inflammation,analgesia,activating blood and resolving stasis,immunoregulation,increasing bone density,lowering blood lipids,anti-hypoxia,anti-exercise fatigue,anti-radiation,anti-obesity,and anti-oxidation. Moreover,it has the potential of treating aplastic anemia. This study reviews the cell culture technologies,chemical components,and pharmacological activities of S. involucrata cells,laying a basis for the further research,development,and utilization.
34369050 Granulocyte and monocyte adsorptive apheresis for pyoderma gangrenosum. 2022 Apr Pyoderma gangrenosum (PG), a chronic aseptic inflammatory skin disease characterized by skin ulcers with elevated and undermined borders, is resistant to conventional therapies. PG is elicited by activated neutrophils and macrophages and is often associated with systemic diseases such as inflammatory bowel disease, rheumatoid arthritis, aortitis syndrome, and hematopoietic disorders. This single-center study assessed the efficacy and safety of selectively depleting myeloid-lineage leukocytes in patients with PG. Patients with PG, aged 20 or over, received 5 or 10 treatment sessions of granulocyte and monocyte adsorption apheresis (GMA), once or twice a week. Treatment efficacy was assessed based on the rate of skin ulcer reduction, the visual analog scale of pain, and the physician's global assessment of the skin lesions. A complete response (CR) was obtained in eight patients, a nearly complete response (nCR) in three patients, and a partial response (PR) in two patients. In four of the other six, the disease remained stable (SD) and in two we observed disease progression (PD). No severe adverse events were recorded. Our results suggest that GMA is a useful and safe treatment modality for PG.