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ID PMID Title PublicationDate abstract
34213581 Evaluation of hyperferritinemia causes in rheumatology practice: a retrospective, single-c 2021 Sep Hyperferritinemia may develop due to various reasons such as inflammation, infection, or malignancy. The purpose of the study to explore the prevalence and to figure out the causes of general hyperferritinemia and extreme hyperferritinemia as detected through the ferritin measurements requested by the rheumatology department. Adult patients at the age of 18 years and older with at least one serum ferritin level measurement at or above 500 ng/mL as requested by the rheumatology department between January 2010 and December 2019 were evaluated retrospectively. Hyperferritinemia was detected in 4.7% of 11,498 serum ferritin tests. The mean age of 242 patients found to have hyperferritinemia was 53.7 ± 17.1 years; of the patients, 63.2% were female, and the mean serum ferritin value was 2820 ± 5080 ng/mL. The most common cause of hyperferritinemia was rheumatological diseases with a ratio of 59.1%, which was followed by infections, iron overload, and solid malignancy. Among the rheumatologic diseases, adult-onset Still's disease (AOSD), rheumatoid arthritis, and vasculitis were the cause accounting for hyperferritinemia. Ferritin levels were significantly higher in the AOSD group compared to the other rheumatologic disease groups (p < 0.0001). While extreme hyperferritinemia (ferritin ≥ 10,000 ng/mL) rate in our cohort was 0.2%, the most common cause was AOSD (15/17). In patients with hyperferritinemia, 3 month mortality was found to be 8.7%. CRP level was identified as the only independent predictor for the 3 month mortality in all patients [OR 1.088 (95% CI 1.004-1.178), p = 0.039]. Although rheumatologic disease activation and infections are the most common causes, the other causes should also be considered for the differential diagnosis.
34147317 De Quervain Tenosynovitis: An Evaluation of the Epidemiology and Utility of Multiple Injec 2022 Mar PURPOSE: We hypothesized that repeat injections are associated with a decreased rate of success and that the success rate of injections correlates with patient comorbidities. METHODS: Using a commercially available insurance database, patients diagnosed with De Quervain tenosynovitis were identified using International Classification of Diseases, Ninth Revision and Tenth Revision codes and stratified by therapeutic interventions, including therapy, injections, and surgery, as well as comorbidities. Injection failure was defined as a patient receiving a repeat injection or subsequent surgical management. Success was defined as no further therapies identified after an intervention. RESULTS: From 2007 to 2017, 33,420 patients with a primary diagnosis of De Quervain tenosynovitis were identified. Women represented 77.5% (25,908) of the total and were 2.6 times more likely to be diagnosed than men. Black patients were more likely to be diagnosed than White patients. Black and White women were found to have the highest incidence (relative risk 3.4 and 2.3, respectively, compared with White men). Age was also significantly correlated with an increased risk of diagnosis of the condition, with a peak incidence at the age of 40-59 years (relative risk, 10.6). Diabetes, rheumatoid arthritis, lupus, and hypothyroidism were associated with an increased risk of diagnosis. Overall, 53.3% of the patients were treated with injections, 11.6% underwent surgery, and 5.2% underwent therapy. Treatment with a single injection was successful in 71.9% of the patients, with 19.7% receiving a repeat injection and 8.4% treated with surgery. The overall success rate of subsequent injections was 66.3% for the second injection and 60.5% for the third. The initial injection had a higher rate of success in diabetics than in nondiabetics; however, the difference (2%) was not clinically relevant. CONCLUSIONS: Although the success rate for the treatment of De Quervains tenosynovitis decreases with multiple injections, repeat injections have a high rate of success and are a viable clinical option. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.
34081176 Prone-positioned knee arthroscopy for isolated retropatellar cartilage defects with gel-ty 2021 Oct OBJECTIVE: Treatment of isolated retropatellar cartilage defects using current gel-type regenerative methods requires settlement of the gel to the underlying subchondral bone under gravity; thus, prone positioned arthroscopy is used. INDICATIONS: Isolated retropatellar contained cartilage defect size >2.5 cm(2). Age <40 years, epiphyseal closure, cartilage defect grade 3/4 (International Cartilage Repair Society). CONTRAINDICATIONS: Cartilage defects at medial or lateral femorotibial compartments, at the trochlea, with degenerative genesis, rheumatoid arthritis, local infection, patellar malalignment, patellofemoral dysplasia, knee instability, knee malalignment >3°, kissing lesions. SURGICAL TECHNIQUE: Two-stage procedure: At initial arthroscopy, chondrocytes were harvested. At the second stage, the patient was positioned prone and the leg with a thigh tourniquet was fixed in a leg holder. Removal of table extension below the knee and support of foot in sling to prevent knee hyperextension. Placement of 2 lateral portals. Lesion visualized and debrided, followed by aspiration of intra-articular fluid. A loop, placed posterior to the patellar ligament using a lasso, was used to suspend a weight to expand the patellofemoral space. The lesion was then dried using a sponge. NOVOCART® Inject (TETEC, Reutlingen, Germany) administered onto the defect. Gel was allowed to solidify for 15 min and operation was completed. POSTOPERATIVE MANAGEMENT: Knee locked in extension using a brace for 6 weeks. Continuous passive motion applied and incrementally increased until full range of motion (ROM) at week 6. Weight-bearing as tolerated was allowed with the knee in extension. Routine clinical follow-up after 3, 6 and 12 months. RESULTS: Mean age of the 5 patients was 23 ± 6 (range 14-30) years; mean follow-up time after surgery 28 ± 7 (range 20-40) months. All patients returned to full activity without residual knee ROM restriction. Clinical examination at the latest follow-up revealed a Kujala score of 90 ± 12 points and Lysholm score of 95 ± 5 points. MRI showed filled cartilage defects in all patients. Mocart score was 63 ± 7 points. Cartilage was inhomogeneous and hyperintense at the repaired site. Quantitative measurement of the patella mobility of the operated knee under a translating force of 10 N showed medial and lateral displacements of 21 ± 5 and 15 ± 2 mm and on the healthy side 22 ± 5 and 19 ± 3 mm, respectively.
33807101 Appropriate Reference Genes for RT-qPCR Normalization in Various Organs of Anemone flaccid 2021 Mar 23 Anemone flaccida Fr. Schmidt is a traditional medicinal herb in southwestern China and has multiple pharmacological effects on bruise injuries and rheumatoid arthritis (RA). A new drug with a good curative effect on RA has recently been developed from the extract of A. flaccida rhizomes, of which the main medicinal ingredients are triterpenoid saponins. Due to excessive exploitation, the wild population has been scarce and endangered in a few of its natural habitats and research on the cultivation of the plant commenced. Studies on the gene expressions related to the biosynthesis of triterpenoid saponins are not only helpful for understanding the effects of environmental factors on the medicinal ingredient accumulations but also necessary for monitoring the herb quality of the cultivated plants. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) as a sensitive and powerful technique has been widely used to detect gene expression across tissues in plants at different stages; however, its accuracy and reliability depend largely on the reference gene selection. In this study, the expressions of 10 candidate reference genes were evaluated in various organs of the wild and cultivated plants at different stages, using the algorithms of geNorm, NormFinder and BestKeeper, respectively. The purpose of this study was to identify the suitable reference genes for RT-qPCR detection in A. flaccida. The results showed that two reference genes were sufficient for RT-qPCR data normalization in A. flaccida. PUBQ and ETIF1a can be used as suitable reference genes in most organs at various stages because of their expression stabilitywhereas the PUBQ and EF1Α genes were desirable in the rhizomes of the plant at the vegetative stage.
33693466 Factors associated with initiation of bone-health medication among older adults in primary 2021 Sep 11 BACKGROUND: Adults at high risk of fragility fracture should be offered pharmacological treatment when not contraindicated, however, under-treatment is common. OBJECTIVE: This study aimed to investigate factors associated with bone-health medication initiation in older patients attending primary care. DESIGN: This was a retrospective cohort study. SETTING: The study used data from forty-four general practices in Ireland from 2011-2017. SUBJECTS: The study included adults aged ≥ 65 years who were naïve to bone-health medication for 12 months. METHODS: Overall fracture-risk (based on QFracture) and individual fracture-risk factors were described for patients initiated and not initiated onto medication and compared using generalised linear model regression with the Poisson distribution. RESULTS: Of 36,799 patients (51% female, mean age 75.4 (SD = 8.4)) included, 8% (n = 2,992) were observed to initiate bone-health medication during the study. One-fifth of all patients (n = 8,193) had osteoporosis or had high fracture-risk but only 21% of them (n = 1,687) initiated on medication. Female sex, older age, state-funded health cover and osteoporosis were associated with initiation. Independently of osteoporosis and co-variates, high 5-year QFracture risk for hip (IRR = 1.33 (95% CI = 1.17-1.50), P < 0.01) and all fractures (IRR = 1.30 (95% CI = 1.17-1.44), P < 0.01) were associated with medication initiation. Previous fracture, rheumatoid arthritis and corticosteroid use were associated with initiation, while liver, kidney, cardiovascular disease, diabetes and oestrogen-only hormone replacement therapy showed an inverse association. CONCLUSIONS: Bone-health medication initiation is targeted at patients at higher fracture-risk but much potential under-treatment remains, particularly in those >80 years and with co-morbidities. This may reflect clinical uncertainty in older multimorbid patients, and further research should explore decision-making in preventive bone medication prescribing.
33652431 Association between Speech Recognition in Noise and Risk Factors of Cardiovascular Disease 2021 INTRODUCTION: Risk factors for cardiovascular disease (CVD) are associated with sensorineural hearing loss. CVD risk factors are known to cluster and interact, thereby increasing the cumulative risk for CVD. Previously, using the database of the Netherlands Longitudinal Study on Hearing (NL-SH), an association was found between a history of smoking and an increased decline in speech recognition in noise over 10 years of follow-up. Prospectively limited data are available on the association between CVD risk factors, interactions of these risk factors, and hearing loss. In this study, data from the NL-SH were used to study the association between CVD risk factors and speech recognition in noise longitudinally. METHODS: Baseline, 5-year, and 10-year follow-up data of the NL-SH were included. The NL-SH is a web-based prospective cohort study which started in 2006. Participants were aged 18-70 years at baseline. Speech recognition in noise was determined with an online digit-triplet speech-in-noise test. In addition, participants completed online questionnaires on demographic, lifestyle, and health-related characteristics. The association of the ability to recognize speech in noise with CVD risk factors (i.e., obesity, rheumatoid arthritis [RA], hypertension, diabetes mellitus, and dyslipidemia) was analyzed longitudinally. We also analyzed the interaction between these risk factors (including age, sex, and history of smoking) and speech recognition in noise. RESULTS: None of the CVD risk factors or interactions of 2 CVD risk factors was significantly associated with a decline in SRT over time. Obesity (p = 0.016), RA (p = 0.027), and hypertension (p = 0.044) were associated with overall higher (more unfavorable) SRTs. No overall interactions between CVD risk factors were found. CONCLUSION: Obesity, RA, and hypertension were overall associated with a higher SRT, but no longitudinal associations between these or other CVD factors with SRTs were found. Also, no interactions between 2 CVD risk factors and SRTs were found. Although no longitudinal associations between CVD risk factors and decline in SRTs were found, clinicians should be alert about the concurrent association between CVD risk factors and hearing loss.
33542028 Potent and Selective Knockdown of Tyrosine Kinase 2 by Antisense Oligonucleotides. 2021 Feb 4 Tyrosine kinase 2 (TYK2) is a member of the JAK family of nonreceptor tyrosine kinase, together with JAK1, JAK2, and JAK3. JAKs are important signaling mediators of many proinflammatory cytokines and represent compelling pharmacological targets for autoimmune and inflammatory diseases. Pan-acting small-molecule JAK inhibitors were approved for the treatment of rheumatoid arthritis and ulcerative colitis. However, their limited selectivity among JAK members have led to undesirable side effects, driving a search toward specific JAK inhibitors. Recently, TYK2 has emerged as a target of choice for the treatment of autoimmune diseases and severe COVID-19 with an optimum balance between efficacy and safety, based on observations from human genetics studies and clinical outcomes of several agents targeting cytokine pathways for which TYK2 plays an essential role. In this article, we address selective targeting of TYK2 from the genetic sequence space through development of antisense oligonucleotides (ASOs) against TYK2 mRNA. Potent ASO candidates were identified from the screening of over 200 ASOs using locked nucleic acid gapmer design. The lead ASOs exhibited potent and selective knockdown of TYK2 mRNA and protein across a panel of model human cell lines in a dose-dependent manner, showing no reduction in the mRNA and protein expression levels of other JAK paralogs. In agreement with the depletion of TYK2 proteins, several TYK2-mediated cytokine signaling pathways, including IFN-α and IL-12, were inhibited upon ASO treatment. Our results established the TYK2 ASOs as investigational tool compound and potential therapeutic agent for the treatment of autoimmune diseases and severe COVID-19.
35153741 An Integrative Network Approach to Identify Common Genes for the Therapeutics in Tuberculo 2021 Tuberculosis (TB) is the leading cause of death from a single infectious agent. The estimated total global TB deaths in 2019 were 1.4 million. The decline in TB incidence rate is very slow, while the burden of noncommunicable diseases (NCDs) is exponentially increasing in low- and middle-income countries, where the prevention and treatment of TB disease remains a great burden, and there is enough empirical evidence (scientific evidence) to justify a greater research emphasis on the syndemic interaction between TB and NCDs. The current study was proposed to build a disease-gene network based on overlapping TB with NCDs (overlapping means genes involved in TB and other/s NCDs), such as Parkinson's disease, cardiovascular disease, diabetes mellitus, rheumatoid arthritis, and lung cancer. We compared the TB-associated genes with genes of its overlapping NCDs to determine the gene-disease relationship. Next, we constructed the gene interaction network of disease-genes by integrating curated and experimentally validated interactions in humans and find the 13 highly clustered modules in the network, which contains a total of 86 hub genes that are commonly associated with TB and its overlapping NCDs, which are largely involved in the Inflammatory response, cellular response to cytokine stimulus, response to cytokine, cytokine-mediated signaling pathway, defense response, response to stress and immune system process. Moreover, the identified hub genes and their respective drugs were exploited to build a bipartite network that assists in deciphering the drug-target interaction, highlighting the influential roles of these drugs on apparently unrelated targets and pathways. Targeting these hub proteins by using drugs combination or drug repurposing approaches will improve the clinical conditions in comorbidity, enhance the potency of a few drugs, and give a synergistic effect with better outcomes. Thus, understanding the Mycobacterium tuberculosis (Mtb) infection and associated NCDs is a high priority to contain its short and long-term effects on human health. Our network-based analysis opens a new horizon for more personalized treatment, drug-repurposing opportunities, investigates new targets, multidrug treatment, and can uncover several side effects of unrelated drugs for TB and its overlapping NCDs.
34945133 The Complex Role of C-Reactive Protein in Systemic Lupus Erythematosus. 2021 Dec 13 C-reactive protein (CRP) is well-known as a sensitive albeit unspecific biomarker of inflammation. In most rheumatic conditions, the level of this evolutionarily highly conserved pattern recognition molecule conveys reliable information regarding the degree of ongoing inflammation, driven mainly by interleukin-6. However, the underlying causes of increased CRP levels are numerous, including both infections and malignancies. In addition, low to moderate increases in CRP predict subsequent cardiovascular events, often occurring years later, in patients with angina and in healthy individuals. However, autoimmune diseases characterized by the Type I interferon gene signature (e.g., systemic lupus erythematosus, primary Sjögren's syndrome and inflammatory myopathies) represent exceptions to the general rule that the concentrations of CRP correlate with the extent and severity of inflammation. In fact, adequate levels of CRP can be beneficial in autoimmune conditions, in that they contribute to efficient clearance of cell remnants and immune complexes through complement activation/modulation, opsonization and phagocytosis. Furthermore, emerging data indicate that CRP constitutes an autoantigen in systemic lupus erythematosus. At the same time, the increased risks of cardiovascular and cerebrovascular diseases in patients diagnosed with systemic lupus erythematosus and rheumatoid arthritis are well-established, with significant impacts on quality of life, accrual of organ damage, and premature mortality. This review describes CRP-mediated biological effects and the regulation of CRP release in relation to aspects of cardiovascular disease and mechanisms of autoimmunity, with particular focus on systemic lupus erythematosus.
34876931 Expression of ANGPTL4 in Nucleus Pulposus Tissues Is Associated with Intervertebral Disc D 2021 OBJECTIVE: Angiopoietin-like protein 4 (ANGPTL4), encoding a glycosylated secreted protein, has been reported to be closely related to many kinds of diseases, including diabetes, tumor, and some musculoskeletal pathologies, such as rheumatoid arthritis, osteoarthritis, and osteoporosis. The aim of the current study is to investigate the role of ANGPTL4 in intervertebral disc degeneration and analyze the association of ANGPTL4 expression with Pfirrmann grades. METHODS: A total of 162 nucleus pulposus tissues were collected from lumbar intervertebral disc herniation patients undergoing interforaminal endoscopic surgery. Real-time quantitative PCR and western blot were performed to determine the mRNA and protein expression of ANGPTL4 in nucleus pulposus samples. Statistical analysis was performed to analyze the association of ANGPTL4 expression with Pfirrmann grades. RESULTS: Based on the clinical data of 162 patients, results showed that Pfirrmann grades were significantly associated with patients' age (r = 0.162, P = 0.047) and were not significantly associated with patients' gender (P > 0.05). RT-qPCR and western blot results showed that the mRNA (r = 0.287, P < 0.05) and protein (r = 0.356, P < 0.05) expressions of ANGPTL4 were both closely associated with Pfirrmann grades. The expression of ANGPTL4 was remarkably increased in the groups of high IVDD Pfirrmann grades. CONCLUSION: The results demonstrated that ANGPTL4 expression was positively associated with the Pfirrmann grades and the severity of intervertebral disc degeneration. ANGPTL4 may be served as a candidate biomarker for intervertebral disc degeneration.
34841684 SMYD2-mediated TRAF2 methylation promotes the NF-κB signaling pathways in inflammatory di 2021 Nov BACKGROUND: The methylation of lysine residues has been involved in the multiple biological and diseases processes. Recently, some particular non-histone proteins have been elucidated to be methylated by SMYD2, a SET and MYND domain protein with lysine methyltransferase activity. METHODS: SMYD2 was evaluated in synovial tissue and cells derived from rheumatoid arthritis patients. We confirmed TRAF2 could be methylated by SMYD2 using Mass spectrometry, pull-down, immunoprecipitation, methyltransferase assay, ubiquitination assay, luciferase reporter assays, and western blot analyses. Using loss- and gain-of function studies, we explored the biological functions of SMYD2 in vitro and in vivo. Using acute and chronic inflammation with different mice models to determine the impact of SMYD2. RESULTS: Here, we first time confirmed that the cytoplasmic protein TRAF2 as the kernel node for NF-κB signaling pathway could be methylated by SMYD2. SMYD2-mediated TRAF2 methylation contributed to the durative sensitization of NF-κB signaling transduction through restraining its own proteolysis and enhancing the activity. In addition, we found knocking down of SMYD2 has different degrees of mitigation in acute and chronic inflammation mice models. Furthermore, as the lysine-specific demethylase, LSD1 could resist methylation on TRAF2 induced by SMYD2. CONCLUSIONS: Our data uncovered an unprecedented cytoplasmic protein network that employed methylation of TRAF2 for the maintenance of NF-κB activation during inflammatory diseases.
34695593 Outcomes of radial head implants in total elbow arthroplasty. 2022 Mar BACKGROUND: There is no consensus on the management of the radial head in total elbow arthroplasty (TEA). In 3-part TEA designs, options include radial head retention, excision, or arthroplasty. Biomechanical studies suggest improved varus-valgus stability with radial head implants in unlinked total elbows. Unfortunately, complications with radial head implants have been common with historical designs. The aim of this study was to evaluate the clinical and radiographic outcomes of radial head implants in a current 3-part TEA and identify risk factors for mechanical failure. METHODS: We performed a retrospective review of radial head implants with a 3-part convertible TEA from 2001 to 2016. Clinical outcomes, functional scores, and radiographic outcomes were recorded. The preoperative radiocapitellar alignment was measured using the radiocapitellar ratio (RCR). Statistics include descriptive statistics, t tests, logistic regression, and Kaplan-Meier survival curves. RESULTS: We identified 44 TEAs in 40 patients, with a mean follow-up period of 7.2 years. The average age at surgery was 58 ± 11 years; 80% of the TEAs were performed in women. The indication for surgery was rheumatoid arthritis in 86%; of the implants, 61% were unlinked. The average preoperative RCR was 10.7 ± 17.9. Postoperatively, 2 radial head implants (5%) were subluxated, 6 (14%) were dissociated, and 2 (5%) were dissociated with implant dislocation on radiographic review. The revision rate for radial head subluxation, dissociation, or dislocation was 7% (n = 3). Univariate logistic regression showed that male sex (P = .002), abnormal preoperative RCR (P = .02), linked implant (P = .03), and older age (P = .04) were risk factors for radial head subluxation, dissociation, or implant dislocation. A multivariate model with all 4 variables did not demonstrate statistical significance. CONCLUSION: The incidence of radial head arthroplasty subluxation, dissociation, or implant dislocation was high (23%). In a univariate logistic regression model, male sex, abnormal preoperative RCR, and linked implants were all statistically significant risk factors for mechanical failure of the radial head implant. Our multivariate model did not show any statistically significant independent risk factors. Polyethylene wear or loosening of the radial head implants was not observed in this study; failure of the bipolar linkage was the principal mode of failure. Although further study is required, caution should be used when considering inserting a radial head implant in male patients with significant preoperative radiocapitellar malalignment. Radial head subluxation or dissociation is not an absolute indication for revision in an asymptomatic patient. Improvements in radial head implant designs in TEA are needed.
34634740 Comprehensive screening and separation of cyclooxygenase-2 inhibitors from Pterocephalus h 2021 Oct 15 Pterocephalus hookeri, a classical Tibetan herb, is mainly used to treat rheumatoid arthritis (RA) and contains various constituents potentially with cyclooxygenase-2 (COX-2) selective inhibition. A novel strategy for screening and target separating COX-2 inhibitors from the extracts of P. hookeri based on affinity solid-phase extraction (ASPE) column combined with preparative high-performance liquid chromatography (pre-HPLC) was successfully developed. The potential COX-2 inhibitors of P. hookeri were screened and recognized by the ASPE-HPLC system, which strategy is to analyze the compounds isolated by the ASPE column. Then, the active compounds were targeted separated by pre-HPLC according to real-time chromatograms. The control drugs celecoxib and glipizide were analyzed to verify the specificity and accuracy of the developed method. As a result, two pure compounds with COX-2 binding affinities were successfully separated from P. hookeri. They were characterized as swertisin and scopoletin using (1)H- and (13)C NMR spectroscopy, and the in vitro COX-2 inhibitory activities were verified. Compounds with COX-2 inhibitory activities could be screened and targeted separated from crude extracts by this strategy, which indicated that the proposed method was feasible, robust and effective for rapid separation of COX-2 inhibitors from natural products.
34580480 Leveraging diet to engineer the gut microbiome. 2021 Dec Autoimmune diseases, including inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, have distinct clinical presentations but share underlying patterns of gut microbiome perturbation and intestinal barrier dysfunction. Their potentially common microbial drivers advocate for treatment strategies aimed at restoring appropriate microbiome function, but individual variation in host factors makes a uniform approach unlikely. In this Perspective, we consolidate knowledge on diet-microbiome interactions in local inflammation, gut microbiota imbalance and host immune dysregulation. By understanding and incorporating the effects of individual dietary components on microbial metabolic output and host physiology, we examine the potential for diet-based therapies for autoimmune disease prevention and treatment. We also discuss tools targeting the gut microbiome, such as faecal microbiota transplantation, probiotics and orthogonal niche engineering, which could be optimized using custom dietary interventions. These approaches highlight paths towards leveraging diet for precise engineering of the gut microbiome at a time of increasing autoimmune disease.
34483908 Dihydroartemisinin Alleviates Imiquimod-Induced Psoriasis-like Skin Lesion in Mice Involvi 2021 Background: Psoriasis is a T help 17 (Th17) cell-mediated chronic inflammatory skin disease. Recent studies have shown that dihydroartemisinin (DHA) can significantly reduce experimental autoimmune encephalomyelitis and rheumatoid arthritis by regulating Th17 cells. Objective: To verify whether DHA can improve the symptoms of psoriasis and to further explore the possible mechanism. Methods: The efficiency of DHA was preliminary detected on human keratinocytes (HaCaT) cells in psoriatic condition. Then, imiquimod-induced psoriasis-like model in BALB/c mice was established to evaluate the effects of DHA in vivo. Results: Under the stimulation of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), DHA inhibited the proliferation of HaCaT cells and significantly affected the mRNA expression levels of IFN-γ, interleukin (IL), IL-17A and IL-23. DHA treatment reduced the severity of psoriasis-like skin and resulted in less infiltration of immune cells in skin lesions. DHA restored the expression of IFN-γ, IL-17A, and IL-23 in skins, as well as a decrease of cytokines and chemokines in skin supernatant. DHA also altered the cellular composition in the spleen, which is the makeup of the T cells, dendritic cells (DCs), and macrophages. DHA recovered Th17-related profile with decreased frequency of IL-17(+)CD4(+)T cells from splenocyte of mice. Furthermore, DHA also inhibited the concentration of IL-17 from Th17 cells and the expression of Th17 cell-related transcription factors retinoid-related orphan receptor-gamma t (ROR-γt) in vitro. In addition, phosphorylation of signal transducer and activator of transcription-3 (STAT3) was significantly reduced in DHA treatment mice, suggesting that the IL-23/Th17 axis plays a pivotal role. Conclusion: DHA inhibits the progression of psoriasis by regulating IL-23/Th17 axis and is expected to be an effective drug for the treatment of psoriasis.
34292518 Alopecia Areata Treatment Patterns, Healthcare Resource Utilization, and Comorbidities in 2021 Sep INTRODUCTION: Alopecia areata (AA) is an autoimmune disorder causing sudden, non-scarring hair loss. There are currently no drugs approved for AA treatment. This study assessed prevalence of comorbidities, treatments, and healthcare costs and resource utilization among patients with AA in the USA. METHODS: Patients diagnosed with AA between January 2011 and December 2018 were identified in IBM MarketScan(®) Research Databases. Eligible patients had no other hair loss-related disorders and were continuously enrolled with medical and pharmacy benefits at least 12 months before and after AA diagnosis. Descriptive statistics were used to summarize comorbid conditions, treatments related to AA or other autoimmune/inflammatory conditions, and all-cause and AA-specific healthcare costs and resource utilization identified from claims data. RESULTS: A total of 68,121 patients with AA were identified. Mean (SD) age was 40.3 (17.8) years and 61.0% were female. The most common comorbidities included hyperlipidemia (22.4%), hypertension (21.8%), thyroid disorders (13.1%), contact dermatitis or eczema (10.8%), depression (9.5%), and anxiety (8.4%). Comorbid autoimmune diseases included atopic dermatitis (2.8%), psoriasis (2.1%), chronic urticaria (1.5%), and rheumatoid arthritis (1.1%). During the 12-month follow-up period, 37,995 patients (55.8%) were prescribed treatment for their AA or other comorbid autoimmune/inflammatory disease; 44.9% of treated patients were prescribed therapy within 7 days of AA diagnosis. Of patients receiving treatment, 80.3% received topical steroids and 30.0% received oral steroids. Mean (SD) total healthcare costs were $11,241.21 ($43,839.69) for all-causes and $419.12 ($1534.99) for AA. AA-related expenses were driven by outpatient and prescription costs. CONCLUSION: Patients with AA have a high comorbidity burden and lack of treatment. Current AA treatments, including systemic therapies other than oral steroids, were not frequently utilized in this study population. Healthcare costs incurred by patients with AA went beyond AA-related expenses. Longitudinal data are needed to better understand treatment trajectories and the disease burden in patients with AA.
33438260 Exogenous ATP modulates PGE(2) release in macrophages through sustained phosphorylation of 2021 Oct An important mediator of inflammation is prostaglandin E(2) (PGE(2) ), whose levels are determined by the activity of the enzyme cyclooxygenase (COX). Of the two isoforms of the enzyme, COX-2 has been shown to be induced in macrophages during inflammation. Although general COX inhibitors, belonging to the class of nonsteroidal anti-inflammatory drugs, or specific COX-2 inhibitors, called coxibs, are useful in the control of acute inflammation, adverse reactions were seen when used chronically in the treatment of rheumatoid arthritis or neurodegenerative diseases. Extracellular ATP (eATP) has been reported as a damage-associated molecular pattern signal. In this report, we show that eATP synergistically increases the levels of COX-2 enzyme and PGE(2) in LPS-activated RAW264.7 macrophages and human monocytes. Activation of macrophages also occurred when cultured in media obtained from dying neurons that contained higher levels of ATP. We show that eATP increases the levels of COX-2 protein, which is sustained up to 36 h poststimulation. This is in turn due to sustained levels of phosphorylated, or activated, cyclin-dependent kinase 9 and p38 MAPK in ATP-treated cells compared to LPS-stimulated cells. The eATP-dependent increase in COX-2/PGE(2) levels in LPS-activated RAW264.7 cells could be abolished using antagonists for purinergic P2X7 -and P2Y6 receptors. Similarly, the increase in COX-2/PGE(2) levels in the peritoneum of LPS-treated mice could be significantly abolished in mice that were preinjected with the nonspecific P2 receptor antagonist, suramin. P2 receptor antagonists, therefore, should be explored in our search for an ideal anti-inflammatory candidate.
33912174 Aberrant Gut Microbiome Contributes to Intestinal Oxidative Stress, Barrier Dysfunction, I 2021 Microbiome composition and function have been implicated as contributing factors in the pathogenesis of autoimmune diseases (ADs), including systemic lupus erythematosus (SLE), rheumatoid arthritis and autoimmune hepatitis (AIH). Furthermore, dysbiosis of gut microbiome is associated with impaired barrier function and mucosal immune dysregulation. However, mechanisms by which gut microbiome contributes to the ADs and whether antioxidant treatment can restore gut homeostasis and ameliorate the disease outcome are not known. This study was, therefore, focused on examining the involvement of gut microbiome and host responses in the pathogenesis of SLE using unique female mouse models (C57BL/6, MRL+/+ and MRL/lpr) of 6 and 18 weeks with varying degrees of disease progression. Fecal microbiome diversity and composition, gut oxidative stress (OS), barrier function and inflammation, as well as systemic autoimmunity were determined. Interestingly, each mouse strain had distinct bacterial community as revealed by β-diversity. A lower Firmicutes/Bacteroidetes ratio in 6-week-old MRL/lpr mice was observed, evidenced by decrease in Peptostreptococcaceae under Firmicutes phylum along with enrichment of Rikenellaceae under Bacteroidetes phylum. Additionally, we observed increases in colonic OS [4-hydroxynonenal (HNE)-adducts and HNE-specific immune complexes], permeability changes (lower tight junction protein ZO-2; increased fecal albumin and IgA levels) and inflammatory responses (increased phos-NF-κB, IL-6 and IgG levels) in 18-week-old MRL/lpr mice. These changes were associated with markedly elevated AD markers (antinuclear and anti-smooth muscle antibodies) along with hepatic portal inflammation and severe glomerulonephritis. Notably, antioxidant N-acetylcysteine treatment influenced the microbial composition (decreased Rikenellaceae; increased Akkeransiaceae, Erysipelotrichaceae and Muribaculaceae) and attenuated the systemic autoimmunity in MRL/lpr mice. Our data thus show that gut microbiome dysbiosis is associated with increased colonic OS, barrier dysfunction, inflammatory responses and systemic autoimmunity markers. These findings apart from delineating a role for gut microbiome dysbiosis, also support the contribution of gut OS, permeability changes and inflammatory responses in the pathogenesis of ADs.
33783320 Emerging views of OPTN (optineurin) function in the autophagic process associated with dis 2022 Jan Macroautophagy/autophagy is a highly conserved process in eukaryotic cells. It plays a critical role in cellular homeostasis by delivering cytoplasmic cargos to lysosomes for selective degradation. OPTN (optineurin), a well-recognized autophagy receptor, has received considerable attention due to its multiple roles in the autophagic process. OPTN is associated with many human disorders that are closely related to autophagy, such as rheumatoid arthritis, osteoporosis, and nephropathy. Here, we review the function of OPTN as an autophagy receptor at different stages of autophagy, focusing on cargo recognition, autophagosome formation, autophagosome maturation, and lysosomal quality control. OPTN tends to be protective in most autophagy associated diseases, though the molecular mechanism of OPTN regulation in these diseases is not well understood. A comprehensive review of the function of OPTN in autophagy provides valuable insight into the pathogenesis of human diseases related to OPTN and facilitates the discovery of potential key regulators and novel therapeutic targets for disease intervention in patients with autophagic diseases.Abbreviations: ATG: autophagy-related; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CC: coiled-coil; HACE1: HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1; MYO6: myosin VI; IKBKG/NEMO: inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; IKK: IκB kinase; LIR: LC3-interacting region; LZ: leucine zipper; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NFKB/NF-κB: nuclear factor kappa B subunit; OPTN: optineurin; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RTECs: renal tubular epithelial cells; SQSTM1/p62: sequestosome 1; TBK1: TANK binding kinase 1; TOM1: target of myb1 membrane trafficking protein; UBD: ubiquitin-binding domain; ULK1: unc-51 like autophagy activating kinase 1; WIPI2: WD repeat domain, phosphoinositide interacting 2; ZF: zinc finger.
33658993 TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mT 2020 During inflammation, neutrophils are one of the first responding cells of innate immunity, contributing to a fast clearance of infection and return to homeostasis. However, excessive neutrophil infiltration accelerates unsolicited disproportionate inflammation for instance in autoimmune diseases such as rheumatoid arthritis. The transient-receptor-potential channel-kinase TRPM7 is an essential regulator of immune system homeostasis. Naïve murine T cells with genetic inactivation of the TRPM7 enzyme, due to a point mutation at the active site, are unable to differentiate into pro-inflammatory T cells, whereas regulatory T cells develop normally. Moreover, TRPM7 is vital for lipopolysaccharides (LPS)-induced activation of murine macrophages. Within this study, we show that the channel-kinase TRPM7 is functionally expressed in neutrophils and has an important impact on neutrophil recruitment during inflammation. We find that human neutrophils cannot transmigrate along a CXCL8 chemokine gradient or produce reactive oxygen species in response to gram-negative bacterial lipopolysaccharide LPS, if TRPM7 channel or kinase activity are blocked. Using a recently identified TRPM7 kinase inhibitor, TG100-115, as well as murine neutrophils with genetic ablation of the kinase activity, we confirm the importance of both TRPM7 channel and kinase function in murine neutrophil transmigration and unravel that TRPM7 kinase affects Akt1/mTOR signaling thereby regulating neutrophil transmigration and effector function. Hence, TRPM7 represents an interesting potential target to treat unwanted excessive neutrophil invasion.