Browse

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

ID PMID Title PublicationDate abstract
33584691 The Influence of B Cell Depletion Therapy on Naturally Acquired Immunity to Streptococcus 2020 The anti-CD20 antibody Rituximab to deplete CD20+ B cells is an effective treatment for rheumatoid arthritis and B cell malignancies, but is associated with an increased incidence of respiratory infections. Using mouse models we have investigated the consequences of B cell depletion on natural and acquired humoral immunity to Streptococcus pneumoniae. B cell depletion of naïve C57Bl/6 mice reduced natural IgM recognition of S. pneumoniae, but did not increase susceptibility to S. pneumoniae pneumonia. ELISA and flow cytometry assays demonstrated significantly reduced IgG and IgM recognition of S. pneumoniae in sera from mice treated with B cell depletion prior to S. pneumoniae nasopharyngeal colonization compared to untreated mice. Colonization induced antibody responses to protein rather than capsular antigen, and when measured using a protein array B cell depletion prior to colonization reduced serum levels of IgG to several protein antigens. However, B cell depleted S. pneumoniae colonized mice were still partially protected against both lung infection and septicemia when challenged with S. pneumoniae after reconstitution of their B cells. These data indicate that although B cell depletion markedly impairs antibody recognition of S. pneumoniae in colonized mice, some protective immunity is maintained, perhaps mediated by cellular immunity.
33560393 A zebrafish model of granulin deficiency reveals essential roles in myeloid cell different 2021 Feb 9 Granulin is a pleiotropic protein involved in inflammation, wound healing, neurodegenerative disease, and tumorigenesis. These roles in human health have prompted research efforts to use granulin to treat rheumatoid arthritis and frontotemporal dementia and to enhance wound healing. But how granulin contributes to each of these diverse biological functions remains largely unknown. Here, we have uncovered a new role for granulin during myeloid cell differentiation. We have taken advantage of the tissue-specific segregation of the zebrafish granulin paralogues to assess the functional role of granulin in hematopoiesis without perturbing other tissues. By using our zebrafish model of granulin deficiency, we revealed that during normal and emergency myelopoiesis, myeloid progenitors are unable to terminally differentiate into neutrophils and macrophages in the absence of granulin a (grna), failing to express the myeloid-specific genes cebpa, rgs2, lyz, mpx, mpeg1, mfap4, and apoeb. Functionally, macrophages fail to recruit to the wound, resulting in abnormal healing. Our CUT&RUN experiments identify Pu.1, which together with Irf8, positively regulates grna expression. In vivo imaging and RNA sequencing experiments show that grna inhibits the expression of gata1, leading to the repression of the erythroid program. Importantly, we demonstrated functional conservation between the mammalian granulin and the zebrafish ortholog grna. Our findings uncover a previously unrecognized role for granulin during myeloid cell differentiation, which opens a new field of study that can potentially have an impact on different aspects of human health and expand the therapeutic options for treating myeloid disorders such as neutropenia or myeloid leukemia.
33527772 Hypertension and endothelial dysfunction in the pristane model of systemic lupus erythemat 2021 Feb Autoimmune diseases such as psoriasis, rheumatoid arthritis, and systemic lupus erythematosus (SLE) have high rates of hypertension and cardiovascular disease. Systemic lupus erythematosus is a prototypic autoimmune disorder that primarily affects women of childbearing age and is associated with a loss of self-tolerance, autoreactive B and T lymphocytes, and the production of autoantibodies, especially to nuclear components. In this study, we hypothesized that the pristane-inducible model of SLE would develop hypertension and vascular dysfunction as the disease progressed. To test this hypothesis, female C57BL/6 mice were administered PBS or pristane. Seven months after pristane administration, mice developed various autoantibodies, including anti-dsDNA IgG, anti-ssDNA IgG, and anti-nRNP IgG, as well as hypergammaglobulinemia. Several other immunological changes, including increased circulating neutrophils and increased CD4(-) CD8(-) (double negative) thymocytes were also detected. Mean arterial pressure (MAP) was elevated in pristane-treated mice when compared to PBS-treated mice. In addition, second-order mesenteric arteries from pristine-treated mice had impaired relaxation to the endothelium-dependent vasodilator acetylcholine compared to PBS-treated mice. These data suggest that the immune system dysfunction present in the pristane model of lupus contributes to the development of hypertension and vascular dysfunction.
33254074 A novel BAFF antagonist, BAFF-Trap, effectively alleviates the disease progression of syst 2021 Jan Abnormal B cells, which produce antibodies against self-antigens, play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). B-cell activating factor (BAFF) is closely associated with abnormal B cells and participates in B cell-mediated autoimmune diseases; thus, neutralizing BAFF is an effective method for treating these diseases. Our group designed a novel fusion protein, BAFF-Trap, that contains the BAFF-binding domains of two BAFF receptors (TACI and BAFF-R) and the Fc domain of human IgG1. In this study, we showed that BAFF-Trap significantly decreased the autoantibody levels, BAFF concentrations and B cells numbers in MRL/lpr mice. BAFF-Trap suppressed the expression of pro-inflammatory cytokines in the kidney and decreased the frequencies of T cell subsets and dendritic cells. Furthermore, BAFF-Trap reduced proteinuria and IgG deposition, relieved glomerular damage in the kidney, and markedly improved the survival rate of mice. These results indicated that BAFF-Trap may be a potential drug for the treatment of SLE.
33183127 Cytokines, 25-OH vit D and disease activity in patients with juvenile-onset systemic lupus 2021 Mar BACKGROUND: Juvenile onset systemic lupus erythematosus JO-SLE patients usually exhibit a more aggressive disease course compared to adult patients. Vitamin D deficiency is proposed to be associated with increased disease activity and flares of numerous autoimmune diseases like SLE, rheumatoid arthritis, and scleroderma. OBJECTIVE: To evaluate the level of IL-17, IFN-γ, and 25-OH Vit D in JO-SLE patients versus healthy controls, and determine the correlation of those inflammatory mediators with SLE disease activity and damage scores. Furthermore, to analyze the relationship between 25-OH Vit D levels with the inflammatory cytokines (IFN-γ and IL-17) in JO-SLE patients. PATIENTS AND METHODS: Fifty JO-SLE patients and 25 controls were included in this study. Clinical and laboratory data of patients at the time of the study were recorded. SLE disease activity and damage were assessed using the SLEDAI-2K disease score and SLICC damage index, respectively. Plasma 25-OH Vit D, IFN-γ, and IL-17 concentrations were determined using the human ELISA kit. RESULTS: Plasma 25-OH Vit D levels (20 ng/mL) were significantly lower in JO-SLE patients compared to (31 ng/mL) controls (P = 0.014). Plasma levels of IFN-γ and IL-17 were significantly higher (163.5 and 25.5 pg./mL) in JO-SLE patients than (68.3 and 3 pg./mL) that of controls (P = 0.016 and P = 0.013). There was a significant negative correlation between 25-OH Vit D levels and SLEDAI-2K (R= -0.431) as well as IFN-γ (R= -0.471) plasma level (P = 0.022 and P = 0.027). CONCLUSION: IFN-γ and IL-17 were significantly higher in JO-SLE patients, while 25-OH Vit D was significantly lower compared to controls. There was a negative correlation between 25-OH Vit D and each of SLEDAI-2K and IFN-γ.
33156550 Exposure-Response Analyses for Upadacitinib Efficacy in Subjects With Atopic Dermatitis-An 2021 May Upadacitinib is a selective Janus kinase 1 inhibitor that was recently approved for treatment of rheumatoid arthritis and is currently being evaluated for treatment of several other autoimmune diseases, including atopic dermatitis (AD). The relationships between upadacitinib plasma exposure and efficacy (assessed as Eczema Area Severity Index [EASI]-75, EASI-90, and Investigator Global Assessment [IGA] 0/1) in subjects with moderate to severe atopic dermatitis were characterized using the data from 167 subjects who were enrolled in a phase 2b dose-ranging study. Subjects were randomized to receive once daily doses of monotherapy treatment with upadacitinib extended-release 7.5, 15, or 30 mg or placebo for 16 weeks. Logistic regression models were developed and utilized to simulate efficacy for upadacitinib with an approximate phase 3 sample size. Based on exposure-response models, 15 mg once daily is predicted to achieve EASI-75, EASI-90, and IGA 0/1 responses in 48%, 26%, and 29% of subjects, respectively, compared with placebo responses of 9%, 2%, and 2%, respectively, whereas 30 mg once daily is predicted to provide an additional approximately 20% greater efficacy for these end points relative to 15 mg once daily. These analyses supported the selection of upadacitinib doses that are being evaluated in ongoing global phase 3 studies in atopic dermatitis.
34943949 Homeostatic Regulation of Glucocorticoid Receptor Activity by Hypoxia-Inducible Factor 1: 2021 Dec 7 Glucocorticoids (GCs) represent a well-known class of lipophilic steroid hormones biosynthesised, with a circadian rhythm, by the adrenal glands in humans and by the inter-renal tissue in teleost fish (e.g., zebrafish). GCs play a key role in the regulation of numerous physiological processes, including inflammation, glucose, lipid, protein metabolism and stress response. This is achieved through binding to their cognate receptor, GR, which functions as a ligand-activated transcription factor. Due to their potent anti-inflammatory and immune-suppressive action, synthetic GCs are broadly used for treating pathological disorders that are very often linked to hypoxia (e.g., rheumatoid arthritis, inflammatory, allergic, infectious, and autoimmune diseases, among others) as well as to prevent graft rejections and against immune system malignancies. However, due to the presence of adverse effects and GC resistance their therapeutic benefits are limited in patients chronically treated with steroids. For this reason, understanding how to fine-tune GR activity is crucial in the search for novel therapeutic strategies aimed at reducing GC-related side effects and effectively restoring homeostasis. Recent research has uncovered novel mechanisms that inhibit GR function, thereby causing glucocorticoid resistance, and has produced some surprising new findings. In this review we analyse these mechanisms and focus on the crosstalk between GR and HIF signalling. Indeed, its comprehension may provide new routes to develop novel therapeutic targets for effectively treating immune and inflammatory response and to simultaneously facilitate the development of innovative GCs with a better benefits-risk ratio.
34683937 Exosomes as a New Delivery Vehicle in Inflammatory Bowel Disease. 2021 Oct 9 Inflammatory bowel disease (IBD) is a type of chronic relapsing inflammatory disease. The pathogenesis of IBD is still unclear, which may involve environmental factors, genetic factors, intestinal microbiota disorder, and abnormal immune responses. Exosomes (30-150 nm) are found in various body fluids, including blood, saliva, urine, and cerebrospinal fluid. Exosomes mediate intercellular communication and regulate cell biological activity by carrying non-coding RNAs, proteins, and lipids. There is evidence that exosomes are involved in the pathogenesis of IBD. In view of the important roles of exosomes in the pathogenesis of IBD, this work systematically reviews the latest research progress of exosomes in IBD, especially the roles of exosomes as non-coding RNA delivery systems in the pathogenesis of IBD, including a disordered immune response, barrier function, and intestinal microbiota. The review will help to clarify the pathogenesis of IBD and explore new diagnostic markers and therapeutic targets for patients with IBD.
34678238 Hypoxia-inducible factor-prolyl hydroxylase inhibitors for renal anemia in chronic kidney 2021 Dec 5 Anemia is a common feature and complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) and recombinant human erythropoietin have been used widely in renal anemia treatment. Recently, hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) that may improve the treatment of renal anemia patients were launched. Previous studies indicated that HIF-PHIs may decrease hepcidin levels and modulate iron metabolism, thereby increasing total iron-binding capacity and reducing the need for iron supplementation. Furthermore, HIF-PHIs can reduce inflammation and oxidative stress in CKD. Recombinant erythropoietin has become a routine treatment for patients with CKD and end-stage renal disease with relatively few adverse effects. However, higher doses of recombinant erythropoietin have been demonstrated to be an independent predictor of mortality in patients under hemodialysis. Phase III clinical trials of HIF-PHIs in patients with anemia and dialysis-dependent CKD have shown their efficacy and safety in both non-dialysis and dialysis CKD patients. However, HIFα binds to specific hypoxia-response elements in the vascular endothelial growth factor or retinoic acid-related orphan receptor gamma t (RORγt) promoter, which may be involved in the progression of cancer, psoriasis, and rheumatoid arthritis. In this paper, we have summarized the mechanism, clinical application, and clinical trials of HIF-PHIs in the treatment of renal anemia and aimed to provide an overview of the new drugs in clinical practice, as well as reconsider the advantages and disadvantages of HIF-PHIs and ESAs. Presently, there are not enough clinical studies examining the effects of long-term administration of HIF-PHIs. Therefore, further studies will be needed.
34586254 Prevalence of chronic diseases and access to health services in Brazil: evidence of three 2021 Sep Chronic non-communicable diseases (NCDs) are the leading causes of death globally, impacting heavily on the most vulnerable populations. This study aimed to analyze changes in the prevalence of these diseases, health conditions, access, and health services in Brazil between 2008 and 2019. Tests of differences and generalized linear models were used as analytical tools, considering complex sampling from the PNAD 2008, PNS 2013, and PNS 2019 surveys, to test temporal changes in the prevalence and the prevalence ratio estimates, adjusted by sociodemographic variables. An increase in the prevalence of Depression, Diabetes, Cancers, Neuropsychiatric Disorders, Chronic Pulmonary problems, and Musculoskeletal problems was observed. A decline in rheumatoid arthritis, chronic renal failure, and diseases of the circulatory system was identified. Among Brazilians with at least one NCD, an increase in coverage by the family health strategy over time was observed. However, there was a reduction in timely medical care and obtaining of free prescription drugs.
34424415 Treatment pattern in postmenopausal women with osteoporosis: a population-based cohort stu 2022 Jan INTRODUCTION: The treatment landscape of postmenopausal osteoporosis (OP) in an Asian population is yet to be explored. MATERIALS AND METHODS: We conducted a retrospective cohort study to explore treatment patterns and characteristics associated with treatment interruption in postmenopausal women diagnosed with OP between 2008 and 2014. Treatment pattern assessment included the initial distribution of OP medications and treatment interruption rate according to the treatment groups during a 3-year follow-up period. We used multivariate logistic regression to estimate odds ratio (OR) and 95% confidence interval (CI) to identify factors associated with treatment interruption. RESULTS: Of 21,813 patients, 87.9% initiated oral bisphosphonates (BP), followed by ibandronate intravenous (IV; 5.4%), selective estrogen receptor modulators (SERMs; 5.2%), pamidronate IV (1.4%) and zoledronic acid (0.06%). Treatment interruption was most notable in the first year of treatment, with cumulative treatment interruption rates highest for oral BP (76.3%) and lowest for pamidronate IV (50.5%). Compared to oral BP users, users of ibandronate IV (OR 0.34, 95% CI 0.30-0.39), pamidronate IV (0.49, 0.39-0.63), zoledronic acid (0.26, 0.09-0.77), and SERMs (0.50, 0.44-0.57) were less likely to interrupt treatment. Of characteristics assessed, presence of rheumatoid arthritis increased the odds of treatment interruption in ibandronate IV group (3.94, 2.12-7.33), and concomitant use of glucocorticoids for oral BP (1.11, 1.03-1.19) and pamidronate IV (2.04, 1.06-3.93) groups, respectively. CONCLUSION: Given the frequent treatment interruptions across all OP medications, our findings on the factors associated with treatment interruption will serve to implement targeted interventions in reinforcing persistence to OP treatment.
34376712 Bioactive recombinant human oncostatin M for NMR-based screening in drug discovery. 2021 Aug 10 Oncostatin M (OSM) is a pleiotropic, interleukin-6 family inflammatory cytokine that plays an important role in inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis, and cancer progression and metastasis. Recently, elevated OSM levels have been found in the serum of COVID-19 patients in intensive care units. Multiple anti-OSM therapeutics have been investigated, but to date no OSM small molecule inhibitors are clinically available. To pursue a high-throughput screening and structure-based drug discovery strategy to design a small molecule inhibitor of OSM, milligram quantities of highly pure, bioactive OSM are required. Here, we developed a reliable protocol to produce highly pure unlabeled and isotope enriched OSM from E. coli for biochemical and NMR studies. High yields (ca. 10 mg/L culture) were obtained in rich and minimal defined media cultures. Purified OSM was characterized by mass spectrometry and circular dichroism. The bioactivity was confirmed by induction of OSM/OSM receptor signaling through STAT3 phosphorylation in human breast cancer cells. Optimized buffer conditions yielded (1)H, (15)N HSQC NMR spectra with intense, well-dispersed peaks. Titration of (15)N OSM with a small molecule inhibitor showed chemical shift perturbations for several key residues with a binding affinity of 12.2 ± 3.9 μM. These results demonstrate the value of bioactive recombinant human OSM for NMR-based small molecule screening.
34358118 Thiophene-Based Compounds with Potential Anti-Inflammatory Activity. 2021 Jul 19 Rheumatoid arthritis, arthrosis and gout, among other chronic inflammatory diseases are public health problems and represent major therapeutic challenges. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed clinical treatments, despite their severe side effects and their exclusive action in improving symptoms, without effectively promoting the cure. However, recent advances in the fields of pharmacology, medicinal chemistry, and chemoinformatics have provided valuable information and opportunities for development of new anti-inflammatory drug candidates. For drug design and discovery, thiophene derivatives are privileged structures. Thiophene-based compounds, like the commercial drugs Tinoridine and Tiaprofenic acid, are known for their anti-inflammatory properties. The present review provides an update on the role of thiophene-based derivatives in inflammation. Studies on mechanisms of action, interactions with receptors (especially against cyclooxygenase (COX) and lipoxygenase (LOX)), and structure-activity relationships are also presented and discussed. The results demonstrate the importance of thiophene-based compounds as privileged structures for the design and discovery of novel anti-inflammatory agents. The studies reveal important structural characteristics. The presence of carboxylic acids, esters, amines, and amides, as well as methyl and methoxy groups, has been frequently described, and highlights the importance of these groups for anti-inflammatory activity and biological target recognition, especially for inhibition of COX and LOX enzymes.
34134513 System-Level Variation in Multiple Sclerosis Care Outcomes: Initial Findings from the Mult 2022 Feb Multiple sclerosis (MS) is a "3C" (complex, chronic, costly) condition that is a common and disabling neurological illness affecting approximately 1 million adults in the United States. MS has been studied at the basic science, individual, and population levels, but not at the system level to assess small-area variation effects on MS population health outcomes. System-level effects have been observed in other 3C conditions including cystic fibrosis, rheumatoid arthritis, and inflammatory bowel disease. The authors report here on system-level variation findings from the baseline period during the first year of the Multiple Sclerosis Continuous Quality Improvement (MS-CQI) study. Stepwise binary logistic regression analyses were conducted to investigate system-level (small-area variation) effects on MS relapses (exacerbations), disease-modifying therapy (DMT) utilization, and brain MRI utilization, controlling for demographics (age and sex) and other potential confounders. Significant differences were observed in people with MS (PwMS) between centers for a number of demographic and disease characteristics, including sex, age, and MS subtype. Controlling for these factors, significant system-level effects were observed on outcomes, including DMT utilization, MRI utilization, and relapses. Significant relationships also were observed between outcomes and urgent care utilization, including emergency department visits and hospitalizations. This initial study provides evidence establishing the presence of system-level variation effects on MS outcomes in a multicenter population study - where PwMS get their care can influence their outcomes. Results support continued systems-level research and improvement initiatives to optimize MS population health outcomes in this challenging and costly complex chronic condition.
34011089 Clinical characteristics, triggering etiologies, and response of plasmapheresis in thrombo 2021 May 21 Thrombotic microangiopathy (TMA) syndromes are extraordinarily diverse in clinical presentations and etiologies. However, there are still a limited number of large cohort studies focusing on the underlying causes, outcomes, and response to plasmapheresis.A retrospective study was designed to understand trigger etiologies, organ dysfunctions, clinical outcomes, and efficacy of plasmapheresis in patients with TMA. The whole population of Taiwan was set up into 2 cohorts: 875 patients with TMA in the 2006 cohort (2006-2010) and 1352 patients with TMA in the 2011 cohort (2011-2015). One hundred ninety-five patients in the 2006 cohort and 272 patients in the 2011 cohort were under plasmapheresis treatment.The common underlying etiologies were pregnancy, followed by systemic lupus erythematosus, rheumatoid arthritis, transplantation and drugs, which were significantly higher than the control group. Stroke, seizure, arterial thrombosis, vascular stenosis, hypertension, myocardial infarction, and pancreatitis were the main clinical signs and extra-renal involvements. In the multivariate regression analysis, stroke, arterial thrombosis, peripheral arterial disease, and uremia were significantly higher compared with the control group. The mortality rate in TMA under plasmapheresis was significantly higher than all TMA cases (39.33% vs 15.39% in the 2006 cohort and 39.27% vs 15.06% in the 2011 cohort).This study indicated the spectrum of underlying causes, extra-renal characteristics, and the response to plasmapheresis of patients with TMA in Taiwan. Of note, the poor clinical outcomes of plasmapheresis in patients with TMA might highlight the masked underlying etiology or worse disease condition that should be noticed.
33983615 Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple S 2021 Jun Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.
33955172 Molecular docking-guided synthesis of NSAID-glucosamine bioconjugates and their evaluation 2021 Jul Non-steroidal anti-inflammatory drugs (NSAIDs) are a powerful class of inhibitors targeting two isoforms of the family of cyclooxygenase enzymes (COX-1 and COX-2). While NSAIDs are widely used in the management of pain, in particular as a treatment for osteo- and rheumatoid arthritis, their long-term use has been associated with numerous on- and off-target effects. As the carboxylic acid moiety present in common NSAIDs is responsible for some of their adverse effects, but is not required for their anti-inflammatory activity, we sought to mask this group through direct coupling to glucosamine, which is thought to prevent cartilage degradation. We report herein the conjugation of commonly prescribed NSAIDs to glucosamine hydrochloride and the use of molecular docking to show that addition of the carbohydrate moiety to the parent NSAID can enhance binding in the active site of COX-2. In a preliminary, in vitro screening assay, the diclofenac-glucosamine bioconjugate exhibited 10-fold greater activity toward COX-2, making it an ideal candidate for future in vivo studies. Furthermore, in an intriguing result, we observed that the mefenamic acid-glucosamine bioconjugate displayed enhanced activity toward COX-1 rather than COX-2.
33799725 Obesity in Saudi Arabia in 2020: Prevalence, Distribution, and Its Current Association wit 2021 Mar 11 The global prevalence of obesity is increasing. Obesity is associated with many chronic diseases and health conditions. This study aims to estimate the current prevalence of obesity in Saudi Arabia and described the current national-level status of the association between obesity and various health conditions. This study is a nationwide cross-sectional survey conducted over phone-interviews in June 2020. In this study, a proportional quota-sampling technique was used to obtain equal distributions of participants, stratified by age and gender, across the 13 regions of Saudi Arabia. Weight and height were self-reported, and the obesity was determined as BMI ≥ 30. Logistic regression adjusted for age and gender was used for exploring current associations between obesity and health conditions. Of the 6239 participants contacted, 4709 participants responded and completed the interview with a response rate of 75.48%. Of them, 50.1% were female, the mean age was 36.4 ± 13.5 (Range: 18-90), and the median age was 36. The national weighted prevalence of obesity (BMI ≥ 30) was 24.7%, and the prevalence in the sample (unweighted) was 21.7%. Obesity was significantly associated with type 2 diabetes [Odd ratio, (OR) = 1.52], hypercholesterolemia (OR = 1.69), hypertension (OR = 1.61), lung diseases (OR = 1.69), rheumatoid arthritis (OR = 1.57), sleep apnea (OR = 1.82), colon diseases (OR = 1.31), and thyroid disorders (OR = 1.8). This study provides an update on the recent prevalence of obesity in Saudi Arabia. It also shows the variation in prevalence rates between different regions, which might be explored further. Although obesity shows a decreasing trend, almost one-quarter of this study sample were obese. Obesity is currently associated with many health conditions that can affect the individuals' quality of life, impose stress on the healthcare system and impose an economic burden on the country. This evidence highlights the need for action to focus more on obesity in Saudi Arabia.
33773981 The Risks of Corneal Surface Damage in Aqueous-Deficient Dry Eye Disease: A 17-Year Popula 2021 Jul PURPOSE: To investigate the epidemiologic characteristics and risk of corneal surface damage in patients with aqueous-deficient dry eye disease (DED) in Taiwan. DESIGN: Retrospective, population-based cohort study. METHODS: We used claims data in the Taiwan National Health Insurance Research Database from 1997 to 2013 of patients with DED, defined according to diagnoses, drug codes, and clinical follow-up. A comparison cohort without DED was selected through propensity score matching. The main outcome measures were corneal surface damage, including corneal erosion, corneal ulcers, or corneal scars. RESULTS: Patients with DED had a significantly higher rate of corneal surface damage (hazard ratio [HR]: 2.70; 95% confidence interval [CI] 2.38-3.06, P < .001), especially higher in patients aged <18 years (HR 6.66; 95% CI 3.58-12.41) than in older patients and in women (HR 2.98; 95% CI 2.57-3.46) than in men (HR 2.22; 95% CI 1.78-2.77), compared to those in the non-DED cohort. DED with diabetes mellitus (P = .002), rheumatoid arthritis (P = .029), or systemic lupus erythematosus (P = .005) was positively associated with corneal surface damage. The overall prevalence of DED was 7.85%, higher among women (10.49%) than men (4.92%), and increased with age (0.53%, 3.94%, 10.08%, and 20.72% for ages <18, 18-39, 40-64, and >65 years, respectively). The prevalence increased gradually during the study period. CONCLUSIONS: The younger age group (<18 years) had the highest risk of corneal surface damage in aqueous-deficient DED. Other predisposing factors included female sex, diabetes, and autoimmune diseases. To improve clinical care, special attention is required for patients with DED with these risk factors.
33741035 Aqueous extracts of Aconite promote thermogenesis in rats with hypothermia via regulating 2021 Mar 19 BACKGROUND: Intermittent or prolonged exposure to severe cold stress disturbs energy homeostasis and can lead to hypothermia, heart failure, Alzheimer's disease, and so on. As the typical "hot" traditional Chinese medicine, Aconite has been widely used to treat cold-associated diseases for thousands of years, but its critical mechanisms for the promotion of thermogenesis are not fully resolved. Gut microbiota and its metabolites play a crucial role in maintaining energy homeostasis. Here, we investigated whether the aqueous extracts of Aconite (AA) can enhance thermogenesis through modulation of the composition and metabolism of gut microbiota in hypothermic rats. METHODS: The therapeutic effects of AA on body temperature, energy intake, and the histopathology of white adipose tissue and brown adipose tissue of hypothermic rats were assessed. Microbiota analysis based on 16 S rRNA and targeted metabolomics for bile acids (BAs) were used to evaluate the composition of gut microbiota and BAs pool. The antibiotic cocktail treatment was adopted to further confirm the relationship between the gut microbiota and the thermogenesis-promoting effects of AA. RESULTS: Our results showed a sharp drop in rectal temperature and body surface temperature in hypothermic rats. Administration of AA can significantly increase core body temperature, surface body temperature, energy intake, browning of white adipose tissue, and thermogenesis of brown adipose tissue. Importantly, these ameliorative effects of AA were accompanied by the shift of the disturbed composition of gut microbiota toward a healthier profile and the increased levels of BAs. In addition, the depletion of gut microbiota and the reduction of BAs caused by antibiotic cocktails reduced the thermogenesis-promoting effect of AA. CONCLUSIONS: Our results demonstrated that AA promoted thermogenesis in rats with hypothermia via regulating gut microbiota and BAs metabolism. Our findings can also provide a novel solution for the treatment of thermogenesis-associated diseases such as rheumatoid arthritis, obesity, and type 2 diabetes.