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34500076 The association between atlantoaxial instability and anomalies of vertebral artery and axi 2022 Feb BACKGROUND CONTEXT: A screw-rod system is the most widely used technique for atlantoaxial instability (AAI). However, neglecting anomalies of the vertebral artery and axis could lead to fatal complications. Whether or not the presence of AAI is associated with a more complicated anatomy for instrumentation is unclear. PURPOSE: To analyze the association between AAI and anomalies of the vertebral artery and axis in patients with and without AAI. STUDY DESIGN: A retrospective comparative study. PATIENT SAMPLE: One hundred and twenty patients who underwent preoperative 3-dimensional computed tomography with vertebral angiography of the cervical spine at our institution from 2012 to 2020. OUTCOME MEASURES: The C2 isthmus height, internal height of the C2 lateral mass, and C2 pedicle width were radiologically assessed. METHODS: A case control study with matched cohort analysis was conducted. One hundred and twenty patients were divided into 2 groups according to presence of AAI, and the presence of high-riding vertebral artery (HRVA) and a narrow pedicle for insertion of the C2 pedicle screw was assessed, as was the prevalence of extraosseous vertebral artery anomaly. RESULTS: The C2 isthmus height, C2 internal height, and C2 pedicle width were significantly narrower in the AAI group (p<.01, <.01, and <.01, respectively). A significantly greater proportion of patients with AAI had HRVA and a narrow pedicle than those without (p<.01 and < 0.01, respectively). Among patients with AAI, the C2 internal height was significantly narrower in patients with rheumatoid arthritis (p<.01). Five patients (8.3%) with AAI had vertebral artery anomaly (3 fenestration, 2 persistent first intersegmental artery), while there were no vertebral artery anomalies in patients without AAI (p<.01). CONCLUSIONS: Vertebral artery anomalies are more common in patients with AAI. Furthermore, posterior instrumentation in patients with AAI has a narrower safe zone compared to that in patients without AAI, which may be caused by a long-lasting deformity rather than a congenital deformity. Therefore, more thorough preoperative evaluation of the anatomy should be performed in these patients.
34492273 Oroxylin A reduces osteoclast formation and bone resorption via suppressing RANKL-induced 2021 Nov Excessive bone erosion by osteoclasts is associated with osteoporosis, rheumatoid arthritis, and periprosthetic osteolysis. Targeting osteoclasts may serve as an effective treatment for osteolytic diseases. Although drugs are currently available for the treatment of these diseases, exploring potential anti-osteoclast natural compounds with safe and effective treatment remains needed. Oroxylin A (OA), a natural flavonoid isolated from the root of Scutellaria baicalensis Georgi, has numerous beneficial pharmacological characteristics, including anti-inflammatory and antioxidant activity. However, its effects and mechanisms on osteoclast formation and bone resorption have not yet been clarified. Our research showed that OA attenuated the formation and function of osteoclast induced by RANKL in a time- and concentration-dependent manner without any cytotoxicity. Mechanistically, OA suppressed intracellular reactive oxygen species (ROS) levels through the Nrf2-mediated antioxidant response. Moreover, OA inhibited the activity of NFATc1, the master transcriptional regulator of RANKL-induced osteoclastogenesis. OA exhibited protective effects in mouse models of post-ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss, in accordance with its in vitro anti-osteoclastogenic effect. Collectively, our findings highlight the potential of OA as a pharmacological agent for the prevention of osteoclast-mediated osteolytic diseases.
34490540 Incidence of fractures in women in the post-menopause: a cohort study in primary care in s 2021 Sep 7 The incidences of total fracture, major fracture, and hip fractures in primary care in Southern Brazil were 22.3, 15.0, and 3.3 per 1000 person/year. The FRAX algorithm showed an adequate discriminatory capacity for the identification of these fractures. OBEJECTIVE: Few studies are evaluating the incidence of fractures in Latin America and Brazil. This study aimed to estimate the incidence of bone fractures in postmenopausal women seen in primary care and evaluate the FRAX algorithm's performance in these women. METHODS: A cohort study was carried out in the municipality of Santa Maria, Southern Brazil. Postmenopausal women aged 55 years and over who attended primary health care were included. The recruitment period was from March 1 to August 31, 2013, and the participants were followed for 5 years. The fracture risk was calculated using the FRAX algorithm. The reported incident fractures were confirmed by imaging studies or surgical reports. RESULTS: Of the 1057 women recruited for the study, 854 were followed. They contributed to 2732 person/year. The mean follow-up time was 3.2 years (SD 1.05). The incidences of total fractures, major fractures, and hip fractures were 22.3, 15.0, and 3.3 per 1000 person/year. The most frequent fracture sites were the wrist, shoulder, and ribs. The fracture predictors were rheumatoid arthritis, previous fracture, and the use of glucocorticoids. The discriminatory capacity of incident fractures calculated by FRAX without the inclusion of BMD was AUC 0.730 (95% CI 0.570, 0.890) for hip fracture and AUC 0.691 (95% CI 0.598, 0.784) for major fractures. CONCLUSION: The FRAX algorithm showed an adequate discriminatory capacity to identify incident fractures in primary care in our study. The incidence of fractures found in our study appears to be lower than that reported in North America and Europe.
34418468 Radiation Toxicity in Patients With Collagen Vascular Disease: A Meta-Analysis of Case-Con 2021 Dec 1 PURPOSE: Several retrospective series have reported that patients with collagen vascular disease (CVD) are at increased risk of radiation (RT) toxicity. However, the evidence is mixed, and many series lack control groups. We performed a meta-analysis including only case-cohort or randomized studies that examined the risk of RT toxicity for patients with CVD compared with controls. METHODS AND MATERIALS: Meta-analysis of Observational Studies in Epidemiology guidelines were used to perform a comprehensive search identifying case-control or randomized studies reporting RT toxicity outcomes for patients with CVD versus controls. Data were synthesized from studies reporting grade 2 to 3 or more (G2/3 +) acute and late RT toxicities. Results were analyzed with fixed effects meta-analysis on the random-effects model for between-study heterogeneity; otherwise, the fixed-effects model was used. Hazard ratio or odds ratio (OR) were the effect-size estimators, as appropriate. RESULTS: Ten studies were included, with 4028 patients (CVD: 406, control: 3622). Patients with CVD had higher rates of acute G2/3 + toxicity (26.2% vs 16.5%, OR [odds ratio] 2.01; P < .001) and late G2/3 + toxicity (18.4% vs 10.1%, OR 2.37; P < .001). Higher rates of late G2/3 + toxicity were observed for CVD patients with systemic lupus erythematous (21% vs 9.7%; OR 2.55, P = .03), systemic scleroderma (31.8% vs 9.7%, OR 3.85; P = .03), rheumatoid arthritis (11.7% vs 8.4%, OR = 2.56; P = .008), and those irradiated to the pelvis/abdomen (32.2% vs 11.9%, OR 3.29; P = .001), breast (14.7% vs 4.4%, OR 3.51; P = .003), thorax (12.5% vs 8.7%, OR 3.46; P < .001), and skin (14.6% vs 5.2%, OR 2.59; P = .02). Late grade 5 toxicities were significantly higher for patients with CVD, although absolute rates were low (3.9% vs 0.6%, OR = 7.81; P = .01). CONCLUSIONS: Moderate and severe toxicities are more likely in patients with CVD, with variable risk depending on toxicity grade, CVD subtype, treatment site, and dose. Severe toxicities are uncommon. These factors should be considered when informing patients of treatment-related risks and monitoring for morbid treatment sequelae.
34304363 Physiologically based pharmacokinetic (PBPK) modeling for prediction of celecoxib pharmaco 2021 Jul Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) and a representative selective cyclooxygenase (COX)-2 inhibitor, which is commonly prescribed for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute pain, and primary dysmenorrhea. It is mainly metabolized by CYP2C9 and partly by CYP3A4 after oral administration. Many studies reported that CYP2C9 genetic polymorphism has significant effects on the pharmacokinetics of celecoxib and the occurrence of adverse drug reactions. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model of celecoxib according to CYP2C9 genetic polymorphism for personalized pharmacotherapy. Initially, a clinical pharmacokinetic study was conducted where a single dose (200 mg) of celecoxib was administered to 39 healthy Korean subjects with CYP2C9*1/*1 or CYP2C9*1/*3 genotypes to obtain data for PBPK development. Based on the conducted pharmacokinetic study and a previous pharmacokinetic study involving subjects with CYP2C9*1/*13 and CYP2C9*3/*3 genotype, PBPK model for celecoxib was developed. A PBPK model for CYP2C9*1/*1 genotype group was developed and then scaled to other genotype groups (CYP2C9*1/*3, CYP2C9*1/*13 and CYP2C9*3/*3). After model development, model validation was performed with comparison of five pharmacokinetic studies. As a result, the developed PBPK model of celecoxib successfully described the pharmacokinetics of each CYP2C9 genotype group and its predicted values were within the acceptance criterion. Additionally, all the predicted values were within two-fold error range in comparison to the previous pharmacokinetic studies. This study demonstrates the possibility of determining the appropriate dosage of celecoxib for each individual through the PBPK modeling with CYP2C9 genomic information. This approach could contribute to the reduction of adverse drug reactions of celecoxib and enable precision medicine.
34304080 Individual functions of the histone acetyl transferases CBP and p300 in regulating the inf 2021 Sep Chromatin remodeling, and a persistent histone 3 lysine 27 acetylation (H3K27ac) in particular, are associated with a sustained inflammatory response of synovial fibroblasts (SF) in rheumatoid arthritis (RA). Here we investigated individual functions of the writers of H3K27ac marks, the homologues histone acetyl transferases (HAT) CBP and p300, in controlling the constitutive and inflammatory gene expression in RA SF. We applied a silencing strategy, followed by RNA-sequencing and pathway analysis, complemented with the treatment of SF with inhibitors targeting the HAT (C646) or bromo domains (I-CBP) of CBP and p300. We showed that CBP and p300 undertook overlapping and, in particular at gene levels, distinct regulatory functions in SF. p300 is the major HAT for H3K27ac in SF and regulated more diverse pathways than CBP. Whereas both factors regulated genes associated with extracellular matrix remodeling, adhesion and proliferation, p300 specifically controlled developmental genes associated with limb development. Silencing of CBP specifically down regulated the TNF-induced expression of interferon-signature genes. In contrast, silencing of p300 resulted in anti- and pro-inflammatory effects. Integration of data sets derived from RNA-sequencing and chromatin immunoprecipitation sequencing for H3K27ac revealed that changes in gene expression after CBP or p300 silencing could be only partially explained by changes in levels of H3K27ac. Inhibition of CBP/p300 using HAT and bromo domain inhibitors strongly mirrored effects obtained by silencing of p300, including anti- and pro-inflammatory effects, indicating that such inhibitors are not sufficient to be used as anti-inflammatory drugs.
34296815 Improving the Efficiency of Clinical Trial Recruitment Using an Ensemble Machine Learning 2021 Sep OBJECTIVE: Efficiently identifying eligible patients is a crucial first step for a successful clinical trial. The objective of this study was to test whether an approach using electronic health record (EHR) data and an ensemble machine learning algorithm incorporating billing codes and data from clinical notes processed by natural language processing (NLP) can improve the efficiency of eligibility screening. METHODS: We studied patients screened for a clinical trial of rheumatoid arthritis (RA) with one or more International Classification of Diseases (ICD) code for RA and age greater than 35 years, from a tertiary care center and a community hospital. The following three groups of EHR features were considered for the algorithm: 1) structured features, 2) the counts of NLP concepts from notes, 3) health care utilization. All features were linked to dates. We applied random forest and logistic regression with least absolute shrinkage and selection operator penalty against the following two standard approaches: 1) one or more RA ICD code and no ICD codes related to exclusion criteria (Screen(RAICD1) (+EX) ) and 2) two or more RA ICD codes (Screen(RAICD2) ). To test the portability, we trained the algorithm at one institution and tested it at the other. RESULTS: In total, 3359 patients at Brigham and Women's Hospital (BWH) and 642 patients at Faulkner Hospital (FH) were studied, with 461 (13.7%) eligible patients at BWH and 84 (13.4%) at FH. The application of the algorithm reduced ineligible patients from chart review by 40.5% at the tertiary care center and by 57.0% at the community hospital. In contrast, Screen(RAICD2) reduced patients for chart review by 2.7% to 11.3%; Screen(RAICD1+EX) reduced patients for chart review by 63% to 65% but excluded 22% to 27% of eligible patients. CONCLUSION: The ensemble machine learning algorithm incorporating billing codes and NLP data increased the efficiency of eligibility screening by reducing the number of patients requiring chart review while not excluding eligible patients. Moreover, this approach can be trained at one institution and applied at another for multicenter clinical trials.
34234401 Ocular Manifestations in Colombian Patients with Systemic Rheumatologic Diseases. 2021 PURPOSE: To establish the prevalence of ocular involvement in a Colombian population with rheumatologic diseases. DESIGN: Observational cross-sectional study. METHODS: We included a probabilistic sample size of 797 patients who attended a rheumatologic disease center in Bogotá, Colombia. Statistical analysis with descriptive measures and Chi-square independence test between rheumatologic diseases and ophthalmological symptoms and diseases was performed. RESULTS: Eighty-four percent of the population were women, and the mean age was 54.61± 15.64 years. The most common condition was rheumatoid arthritis (33.37%), followed by fibromyalgia (22.71%), Sjögren Syndrome (19.72%), and systemic lupus erythematosus (9.91%). Almost 7% of the patients presented polyautoimmunity. Thirty-five percent of the patients reported one or more ophthalmological symptoms, being dry eye sensation the most common (30.86%), followed by ocular pain (2.76%), red-eye, and decreased visual acuity (both 2.63%). Similarly, 21.45% of the patients presented one or more ophthalmological diagnoses, being keratoconjunctivitis sicca the most common (15.93%), followed by cataract, uveitis (1.38% each), and scleritis (1.25%). CONCLUSION: Almost a third of the patients reported any ocular involvement. It is crucial to be aware of the most common ophthalmic manifestations among the different rheumatologic diseases in our population, to offer early specialist referral and timely treatment.
34201265 Genetic Variation and Cardiovascular Risk Factors: A Cohort Study on Migrants from the For 2021 Jun 8 Resettlers are a large migrant group of more than 2 million people in Germany who migrated mainly from the former Soviet Union to Germany after 1989. We sought to compare the distribution of the major risk factors for cardiovascular disease (CVD) and to investigate the overall genetic differences in a study population which consisted of resettlers and native (autochthone) Germans. This was a joint analysis of two cohort studies which were performed in the region of Augsburg, Bavaria, Germany, with 3363 native Germans and 363 resettlers. Data from questionnaires and physical examinations were used to compare the risk factors for cardiovascular diseases between the resettlers and native Germans. A population-based genome-wide association analysis was performed in order to identify the genetic differences between the two groups. The distribution of the major risk factors for CVD differed between the two groups. The resettlers lead a less active lifestyle. While female resettlers smoked less than their German counterparts, the men showed similar smoking behavior. SNPs from three genes (BTNL2, DGKB, TGFBR3) indicated a difference in the two populations. In other studies, these genes have been shown to be associated with CVD, rheumatoid arthritis and osteoporosis, respectively.
34156606 Prevalence and Incidence of Chronic Fibrosing Interstitial Lung Diseases with a Progressiv 2021 Jul INTRODUCTION: Many fibrosing interstitial lung diseases (ILDs) develop a chronic progressive phenotype. While idiopathic pulmonary fibrosis, which is always progressive, is well characterized with established treatment options, the epidemiology of other chronic fibrosing ILDs with a progressive phenotype has not been widely investigated. Treatment options are limited, with a high unmet need. This claims database study estimates the incidence and prevalence of these diseases in the USA. METHODS: Diagnosis, procedure and resource utilization codes from insurance claims were used to identify patients with fibrosing ILD and those with a chronic progressive phenotype among 37,565,644 adult patients in the IBM(®) MarketScan(®) Research Database 2012-2015. Two eligible ILD claims were required for a fibrosing ILD diagnosis. Progression was defined using a novel algorithm constituted by criteria considered proxies for progression. Patients were defined as having incident (new) or existing diagnoses based on claims during a 365-day period before study entry. RESULTS: The estimated age- and sex-adjusted prevalence per 100,000 persons of fibrosing ILD (95% confidence interval) was 117.82 (116.56, 119.08) and of chronic fibrosing ILDs with a progressive phenotype was 70.30 (69.32, 71.27). The estimated adjusted incidence per 100,000 patient-years of fibrosing ILD was 51.56 (50.88, 52.24) and of chronic fibrosing ILDs with a progressive phenotype was 32.55 (32.01, 33.09). Among incident fibrosing ILD patients, 57.3% experienced progression over a median of 117 days (interquartile range 63-224), with largely comparable rates of progression among different diseases. CONCLUSIONS: Chronic fibrosing ILDs with a progressive phenotype comprise a relatively new disease construct requiring varied approaches to obtain reliable estimates of prevalence and incidence. This is the first large claims database study using real-world data to provide estimates of the prevalence and incidence of these diseases among a very large segment of the US population and could form the groundwork for future studies.
34125373 Cholinergic anti-inflammatory pathway and connective tissue diseases. 2021 Aug Connective tissue diseases (CTDs) consist of an extensive range of heterogeneous medical conditions, which are caused by immune-mediated chronic inflammation and influences the various connective tissues of the body. They include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis, Sjögren's syndrome, Behcet's disease, and many other autoimmune CTDs. To date, several anti-inflammatory approaches have been developed to reduce the severity of inflammation or its subsequent organ manifestations. As a logical mechanism to harnesses the undesired inflammation, some studies investigated the role of the intrinsic cholinergic anti-inflammatory pathway (CAP) in the modulation of chronic inflammation. Many different experimental and clinical models have been developed to evaluate the therapeutic significance of the CAP in CTDs. On the other hand, an issue that is less emphasized in this regard is the presence of autonomic neuropathy in CTDs, which influences the efficiency of CAP in such clinical settings. This condition occurs during CTDs and is a well-known complication of patients suffering from them. The advantages and limitations of CAP in the control of inflammatory responses and its possible therapeutic benefits in the treatment of CTDs are the main subjects of the current study. Therefore, this narrative review article is provided based on the recent findings of the complicated role of CAP in CTDs which were retrieved by searching Science Direct, PubMed, Google Scholar, and Web of Science. It seems that delineating the complex influences of CAP would be of great interest in designing novel surgical or pharmacological therapeutic strategies for CTDs therapy.
34125250 Risk factors for a second nonsimultaneous hip fracture in a prospective cohort study. 2021 Jun 14 INTRODUCTION: The risk factors for a second nonsimultaneous hip fracture are unclear, and in general, it is empirically assumed that they are similar to those associated with the first hip fracture. We aimed to determine the incidence of a second hip fracture and define the characteristics of the patients sustaining the event in a prospective cohort study in a Spanish population. MATERIALS AND METHODS: We conducted a multicentric, prospective cohort study in a representative sample of 45 hospitals from 15 autonomic regions in Spain. In total, the study included 994 patients. One hundred and one patients presented a nonsimultaneous contralateral hip fracture, constituting the intervention group. The remaining 893 patients presenting with a hip fracture formed the control group. The main outcome measures of this study were sociodemographic characteristics of the patient, comorbid conditions, and baseline and postfracture clinical outcomes (inpatient complications and acute mortality). RESULTS: The key fracture risk factors were a history of fragility fractures, the need for assistance when walking outdoors and a history of falls. There were no associations between the groups in any of the common fragility risk factors, including rheumatoid arthritis, secondary osteoporosis, or steroid consumption. The results showed that patients suffering a nonsimultaneous hip fracture had an increased risk of mortality after discharge compared with the control group. CONCLUSION: A nonsimultaneous second hip fracture leads to a near-significant increase in four-month mortality. In our study, this fracture was associated with a history of falls, prior fragility fractures, and the need for a walking aid.
34122433 Association of Circulating Vascular Endothelial Growth Factor Levels With Autoimmune Disea 2021 BACKGROUND: Autoimmune diseases (ADs) are characterized by immune-mediated tissue damage, in which angiogenesis is a prominent pathogenic mechanism. Vascular endothelial growth factor (VEGF), an angiogenesis modulator, is significantly elevated in several ADs including rheumatoid arthritis (RA), systemic sclerosis (SSc), and systemic lupus erythematosus (SLE). We determined whether circulating VEGF levels were associated with ADs based on pooled evidence. METHODS: The analyses included 165 studies from the PubMed, EMBASE, Cochrane Library, and Web of Science databases and fulfilled the study criteria. Comparisons of circulating VEGF levels between patients with ADs and healthy controls were performed by determining pooled standard mean differences (SMDs) with 95% confidence intervals (CIs) in a random-effect model using STATA 16.0. Subgroup, sensitivity, and meta-regression analyses were performed to determine heterogeneity and to test robustness. RESULTS: Compared with healthy subjects, circulating VEGF levels were significantly higher in patients with SLE (SMD 0.84, 95% CI 0.25-1.44, P = 0.0056), RA (SMD 1.48, 95% CI 0.82-2.15, P <0.0001), SSc (SMD 0.56, 95% CI 0.36-0.75, P <0.0001), Behcet's disease (SMD 1.65, 95% CI 0.88-2.41, P <0.0001), Kawasaki disease (SMD 2.41, 95% CI 0.10-4.72, P = 0.0406), ankylosing spondylitis (SMD 0.78, 95% CI 0.23-1.33, P = 0.0052), inflammatory bowel disease (SMD 0.57, 95% CI 0.43-0.71, P <0.0001), psoriasis (SMD 0.98, 95% CI 0.62-1.34, P <0.0001), and Graves' disease (SMD 0.69, 95% CI 0.20-1.19, P = 0.0056). Circulating VEGF levels correlated with disease activity and hematological parameters in ADs. CONCLUSION: Circulating VEGF levels were associated with ADs and could predict disease manifestations, severity and activity in patients with ADs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, identifier CRD42021227843.
34067705 Beneficial Modulation of Lipid Mediator Biosynthesis in Innate Immune Cells by Antirheumat 2021 May 17 Tripterygium wilfordii glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation and immune responses and are strongly linked to RA. The mechanism by which TWG affects LM networks in RA treatment remains elusive. Employing LM metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry revealed striking modulation of LM pathways by TWG in human monocyte-derived macrophage (MDM) phenotypes. In inflammatory M1-MDM, TWG (30 µg/mL) potently suppressed agonist-induced formation of 5-LOX products which was confirmed in human PMNL and traced back to direct inhibition of 5-LOX (IC(50) = 2.9 µg/mL). TWG also efficiently blocked thromboxane formation in M1-MDM without inhibiting other prostanoids and COX enzymes. Importantly, in anti-inflammatory M2-MDM, TWG (30 µg/mL) induced pronounced formation of specialized pro-resolving mediators (SPM) and related 12/15-LOX-derived SPM precursors, without COX and 5-LOX activation. During MDM polarization, TWG (1 µg/mL) decreased the capacity to generate pro-inflammatory 5-LOX and COX products, cytokines and markers for M1 phenotypes. Together, suppression of pro-inflammatory LM but SPM induction may contribute to the antirheumatic properties of TWG.
34047648 A PorX/PorY and σ(P) Feedforward Regulatory Loop Controls Gene Expression Essential for P 2021 Jun 30 The PorX/PorY two-component system in the periodontal pathogen Porphyromonas gingivalis controls the expression of the por genes, encoding a type IX secretion system, and the sigP gene, encoding sigma factor σ(P). Previous results implied that PorX/PorY and σ(P) formed a regulatory cascade because the PorX/PorY-activated σ(P) enhanced the por genes, including porT, via binding to their promoters. We recently showed that PorX also binds to the por promoters, thus suggesting that an alternative mechanism is required for the PorX/PorY- and σ(P)-governed expression. Here, our in vitro assays show the PorX response regulator binds to the sigP promoter at a sequence shared with the porT promoter and enhances its transcription, mediated by a reconstituted P. gingivalis RNA polymerase holoenzyme. Merely producing σ(P) in trans fails to reverse the porT transcription in a porX mutant, which further argues against the action of the proposed regulatory cascade. An in vitro transcription assay using a reconstituted RNA polymerase-σ(P) holoenzyme verifies the direct role of PorX in porT transcription, since transcription is enhanced by a pure PorX protein. Accordingly, we propose that the PorX/PorY system coordinates with σ(P) to construct a coherent regulatory mechanism, known as the feedforward loop. Specifically, PorX will not only bind to the sigP promoter to stimulate the expression of σ(P), but also bind to the porT promoter to facilitate the RNA polymerase-σ(P)-dependent transcription. Importantly, mutations at the porX and sigP genes attenuate bacterial virulence in a mouse model, demonstrating that this regulatory mechanism is essential for P. gingivalis pathogenesis. IMPORTANCE The anaerobic bacterium Porphyromonas gingivalis is not only the major etiologic agent for chronic periodontitis, but also prevalent in some common noncommunicable diseases such as cardiovascular disease, Alzheimer's disease, and rheumatoid arthritis. We present genetic, biochemical, and biological results to demonstrate that the PorX/PorY two-component system and sigma factor σ(P) build a specific regulatory network to coordinately control transcription of the genes encoding the type IX secretion system, and perhaps also other virulence factors. Results in this study verify that the response regulator PorX stimulates the expression of the genes encoding both σ(P) and the type IX secretion system by binding to their promoters. This study also provides evidence that σ(P), like the PorX/PorY system, contributes to P. gingivalis virulence in a mouse model.
33984435 Ethnopharmacology, biological activities and chemical compounds of Canarium strictum: An i 2021 Jul The resin of Canarium strictum Roxb. is used for rheumatism and asthma; the bark is used as a mosquito repellent. The major compounds in the resin are triterpenoids, but as no studies have been performed on the bark, this study investigated this economically important resource. Ten folk healers were interviewed about their medicinal uses of C. strictum. Resin and bark were extracted with dichloromethane followed by methanol using accelerated solvent extraction. The extracts were fractionated using different chromatographic methods, and isolated compounds were identified by NMR spectroscopy and GC-MS. Resin and bark extracts were investigated for DPPH radical scavenging, 15-lipoxygenase inhibition, effects on nitric oxide (NO) production in LPS-activated dendritic D2SC/I cells and toxicity against Artemia salina nauplii. Traditional healers used resin to treat colds, airway afflictions and rheumatoid arthritis. α-Amyrin and β-amyrin were identified as the major constituents in the dichloromethane resin extract. From the stem bark, procyanidins, gallic acid, methyl gallate, scopoletin, 3,3'-di-O-methylellagic acid 4-O-α-arabinofuranoside and elephantorrhizol (3,3',4',5,6,7,8-heptahydroxyflavan) were isolated and identified. By GC-MS, α-amyrin and β-amyrin and their acetates, lupeol, and taraxasterol were identified. Radical scavenging, 15-lipoxygenase inhibitory activity and inhibition of NO production was observed from resin and bark extracts, and no toxicity towards Artemia salina nauplii was found. Triterpenoids and procyanidins are the major compounds in C. strictum resin and stem bark, respectively. The high content of triterpenoids might contribute to anti-inflammatory effects and give a rationale for the widespread usage of the resin in India.
33844985 Valdecoxib improves lipid-induced skeletal muscle insulin resistance via simultaneous supp 2021 Jun Valdecoxib (VAL), a non-steroidal anti-inflammatory drug, has been widely used for treatment of rheumatoid arthritis, osteoarthritis, and menstrual pain. It is a selective cyclooxygenase-2 inhibitor. The suppressive effects of VAL on cardiovascular diseases and neuroinflammation have been documented; however, its impact on insulin signaling in skeletal muscle has not been studied in detail. The aim of this study was to investigate the effects of VAL on insulin resistance in mouse skeletal muscle. Treatment of C2C12 myocytes with VAL reversed palmitate-induced aggravation of insulin signaling and glucose uptake. Further, VAL attenuated palmitate-induced inflammation and endoplasmic reticulum (ER) stress in a concentration-dependent manner. Treatment with VAL concentration-dependently upregulated AMP-activated protein kinase (AMPK) and heat shock protein beta 1 (HSPB1) expression. In line with in vitro experiments, treatment with VAL augmented AMPK phosphorylation and HSPB1 expression, thereby alleviating high-fat diet-induced insulin resistance along with inflammation and ER stress in mouse skeletal muscle. However, small interfering RNA-mediated inhibition of AMPK abolished the effects of VAL on insulin resistance, inflammation, and ER stress. These results suggest that VAL alleviates insulin resistance through AMPK/HSPB1-mediated inhibition of inflammation and ER stress in skeletal muscle under hyperlipidemic conditions. Hence, VAL could be used as an effective pharmacotherapeutic agent for management of insulin resistance and type 2 diabetes.
33824581 Development and Validation of the Hospital Outpatients' Information Needs Questionnaire (H 2021 PURPOSE: The main objective was to develop and validate a "Hospital Outpatients' Information Needs Questionnaire" (HOINQ). Secondly, to identify patients' preferred sources of information. Finally, to establish differences depending on the disease, as well as between sociodemographic and clinical variables. PATIENTS AND METHODS: This is a transversal study based on a questionnaire. All adult hospital outpatients' who collected their medication at the Pharmacy Service were consecutively recruited, regardless of their diagnosis time, treatment or disease. The Spanish version of the internationally validated European Organization for Research and Treatment Cancer Quality of Life Questionnaire (EORTC QLQ-25) aimed at oncology patients was used as the starting point. In order to be applicable on new target population, it was crucial to make several changes and ensure that it complies with the validity, viability and reliability criteria. The questionnaire prepared for validation was then obtained by a literature review (face validity), submitting the EORTC QLQ-25 to an expert committee (content validity), by piloting (viability) and Cronbach's alpha statistical analysis (reliability). Once the questionnaire was completed, Cronbach's alpha of the final study (reliability) and factor analysis (construct validity) were performed. Then, pertinent modifications were applied to obtain the HOINQ. RESULTS: A total of 153 outpatients filled the questionnaire, which was widely accepted and required 5-10 min to complete. Cronbach's alpha coefficients met criteria >0.7. Three factors were established by factor analysis: aspects about the disease, pharmacological and no-pharmacological treatment and satisfaction and perception of the information received. Participants felt satisfied (41-52%) with the information amount, quality and usefulness, although 1 out of 3 stated wanting to know more about the different information areas. Younger patients (P-value <0.05) and those who had been attending the Pharmacy Service for a longer time span (P-value <0.01) reported receiving more information. On a 0 to 7 scale, medical specialists (mean = 6.28, SD = 1.38) followed by the rest of health care professionals (mean = 4.23-4.63, SD = 2.25-2.29) were selected as the preferred sources of information. HIV patients reported being more informed, while those with rheumatoid arthritis felt less informed (P-value <0.05). CONCLUSION: The HOINQ was developed. It is a self-completed questionnaire, composed of three blocks: the 16-item information needs questionnaire, demographic and clinical variables, and patients' preferred sources of information. It is an easy tool to use and replicate, both for patients and professionals.
33668814 Immunomodulatory Effects of Dietary Polyphenols. 2021 Feb 25 Functional and nutraceutical foods provide an alternative way to improve immune function to aid in the management of various diseases. Traditionally, many medicinal products have been derived from natural compounds with healing properties. With the development of research into nutraceuticals, it is becoming apparent that many of the beneficial properties of these compounds are at least partly due to the presence of polyphenols. There is evidence that dietary polyphenols can influence dendritic cells, have an immunomodulatory effect on macrophages, increase proliferation of B cells, T cells and suppress Type 1 T helper (Th1), Th2, Th17 and Th9 cells. Polyphenols reduce inflammation by suppressing the pro-inflammatory cytokines in inflammatory bowel disease by inducing Treg cells in the intestine, inhibition of tumor necrosis factor-alpha (TNF-α) and induction of apoptosis, decreasing DNA damage. Polyphenols have a potential role in prevention/treatment of auto-immune diseases like type 1 diabetes, rheumatoid arthritis and multiple sclerosis by regulating signaling pathways, suppressing inflammation and limiting demyelination. In addition, polyphenols cause immunomodulatory effects against allergic reaction and autoimmune disease by inhibition of autoimmune T cell proliferation and downregulation of pro-inflammatory cytokines (interleukin-6 (IL-6), IL-1, interferon-γ (IFN-γ)). Herein, we summarize the immunomodulatory effects of polyphenols and the underlying mechanisms involved in the stimulation of immune responses.
33483502 Integrative computational approach identifies drug targets in CD4(+) T-cell-mediated immun 2021 Jan 22 CD4(+) T cells provide adaptive immunity against pathogens and abnormal cells, and they are also associated with various immune-related diseases. CD4(+) T cells' metabolism is dysregulated in these pathologies and represents an opportunity for drug discovery and development. Genome-scale metabolic modeling offers an opportunity to accelerate drug discovery by providing high-quality information about possible target space in the context of a modeled disease. Here, we develop genome-scale models of naïve, Th1, Th2, and Th17 CD4(+) T-cell subtypes to map metabolic perturbations in rheumatoid arthritis, multiple sclerosis, and primary biliary cholangitis. We subjected these models to in silico simulations for drug response analysis of existing FDA-approved drugs and compounds. Integration of disease-specific differentially expressed genes with altered reactions in response to metabolic perturbations identified 68 drug targets for the three autoimmune diseases. In vitro experimental validation, together with literature-based evidence, showed that modulation of fifty percent of identified drug targets suppressed CD4(+) T cells, further increasing their potential impact as therapeutic interventions. Our approach can be generalized in the context of other diseases, and the metabolic models can be further used to dissect CD4(+) T-cell metabolism.