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ID PMID Title PublicationDate abstract
31313244 Gold-Coated Superparamagnetic Iron Oxide Nanoparticles Attenuate Collagen-Induced Arthriti 2020 Apr The aim of the study was to evaluate if gold-coated superparamagnetic iron oxide nanoparticles (AuSPION) magnetic-targeted to the arthritic articulation of collagen induced arthritis (CIA) rats are able to ameliorate rheumatoid arthritis without producing significant biological adverse effects in comparison to colloidal Au nanoparticles (AuC) and metotrexate (MTX). Male Wistar rats were divided into control; arthritic; AuSPION (150 μg kg(-1)); AuC (150 μg kg(-1)) and MTX (2.5 μg kg(-1)). Treatments were administered thrice every other day by the intraperitoneal route 15 min after all groups had a neodymium magnet coupled to the right ankle joint (kept for 1 h). Paw edema and body weight were measured weekly. Joint sections were evaluated by Haematoxylin & Eosin and immunohistochemistry (TNF-α, IL-1β). Biomarkers of oxidative stress were used to evaluate toxicity. Among the evaluated treatments, AuSPION led to significant clinical improvements (decreased edema and infiltration by leukocytes as well as less positively immunostained cells for both TNF-α and IL-1β in synovium) accompanied by a lack of toxicity as indicated by redox state and genotoxicity assays. Our results clearly indicate that the magnetic targeting of AuSPION suppresses joint edema and inflammation, cytokine expression as well as the redox imbalance, thereby contributing to an amelioration of arthritis severity in CIA rats. The results demonstrate for the first time the potentiality of AuSPION administration under a magnetic field as an attractive alternative for future treatments of rheumatic diseases.
31881058 Household air pollution and arthritis in low-and middle-income countries: Cross-sectional 2019 BACKGROUND: Evidence points to a clear link between air pollution exposure and several chronic diseases though investigations regarding arthritis are still lacking. Emerging evidence suggests an association between ambient air pollution and rheumatoid arthritis. Household air pollution exposure, conversely, is largely unstudied but may be an important consideration for arthritis, particularly in low- and middle-income countries (LMICs), where cooking and heating activities can generate high indoor air pollutant levels. METHODS: We investigated the association of household air pollution (electricity vs. gas; kerosene/paraffin; coal/charcoal; wood; or agriculture/crop/animal dung/shrubs/grass as the main fuel used for cooking) and arthritis in six LMICs (China, Ghana, India, Mexico, the Russian Federation, South Africa) using data from Wave I of the World Health Organization Study on Global AGEing and Adult Health (SAGE) (2007-2010). Multivariable analyses were adjusted for sociodemographic, household and lifestyle characteristics and several comorbidities. RESULTS: The use of gas (aOR = 1.76, 95%CI: 1.40-2.21); coal (aOR = 1.74, 95%CI: 1.22-2.47); wood (aOR = 1.69, 95%CI: 1.30-2.19); or agriculture/crop/animal dung/shrubs/grass: aOR = 1.95 (1.46-2.61) fuels for cooking were strongly associated with an increased odds of arthritis, compared to electricity in cluster and stratified adjusted analyses. Gender (female), age (≥50 years), overweight (25.0 ≤BMI<30.0 kg/m2), obesity (BMI ≥30.0 kg/m2), former and current alcohol consumption, and the comorbidities angina pectoris, diabetes, chronic lung disease, depression and hypertension were also associated with a higher odds of arthritis. Underweight (BMI<18.5 kg/m2) and higher education levels (college/university completed/post-graduate studies) were associated with a lower odds of arthritis. CONCLUSIONS: These findings suggest that exposure to household air pollution from cook fuels is associated with an increased odds of arthritis in these regions, which warrants further investigation.
32186041 Effects of Huatan Tongluo decoction on vascular endothelial growth factor receptor 2 expre 2019 Apr OBJECTIVE: To determine the therapeutic effect and potential mechanism of Huatan Tongluo decoction on rats with collagen-induced arthritis. METHODS: Forty specific pathogen-free Wistar rats were selected, and 10 were randomly selected as the control (group 1). The remaining rats were injected intradermally with emulsified type II bovine collagen at the tail base and back, followed by a booster 7 d post first immunization. After establishing collagen-induced arthritis (CIA), rats were randomly divided into three groups (n = 10). The rats were treated orally for 30 d as follows: group 1, saline; group 2, model (saline); group 3, tripterygium polyglycoside (TP; 7.81 mg/kg, positive control); group 4, Huatan Tongluo decoction (HTTL; 7.5 g/kg). Body weight, ankle swelling and arthritis index were measured over the course of the study. The rats were sacrificed 30 d after treatment. Morphological changes in the synovium were observed by hematoxylin and eosin staining. Pannus formation and synovial thickness in the left ankle were observed by color Doppler ultrasoundVascular endothelial growth factor (VEGF) and VEGFR2 protein levels were measured by immunohistochemistry. VEGF/VEGFR2 mRNA levels were measured by real-time quantitative polymerase chain reaction. RESULTS: Compared with the model group, a significantly lower arthritis index was observed in the positive control group (P < 0.05) and HTTL group (P < 0.01), after treatment. Both positive control and HTTL reduced intra-articular pannus formation and synovial thickening. Furthermore, VEGF mRNA, and VEGFR2 protein and mRNA levels were significantly downregulated (P < 0.05) in the treatment groups. CONCLUSION: Inhibition of the expression of VEGF and VEGFR2 in synovial tissues and the formation of pannus and synovial hyperplasia may be part of the mechanism of HTTL for relieving the symptoms of rheumatoid arthritis in CIA rats.
31220958 Biodegradable polymers: an update on drug delivery in bone and cartilage diseases. 2019 Aug Introduction: The unique structure of bone and cartilage makes the systemic delivery of free drugs to those connective tissues very challenging. Consequently, effective and targeted delivery for bone and cartilage is of utmost importance. Engineered biodegradable polymers enable designing carriers for a targeted and temporal controlled release of one or more drugs in concentrations within the therapeutic range. Also, tissue engineering strategies can allow drug delivery to advantageously promote the in situ tissue repair. Areas covered: This review article highlights various drug delivery systems (DDS) based on biodegradable biomaterials to treat bone and/or cartilage diseases. We will review their applications in osteoporosis, inflammatory arthritis (namely osteoarthritis and rheumatoid arthritis), cancer and bone and cartilage tissue engineering. Expert opinion: The increased knowledge about biomaterials science and of the pathophysiology of diseases, biomarkers, and targets as well as the development of innovative tools has led to the design of high value-added DDS. However, some challenges persist and are mainly related to an appropriate residence time and a controlled and sustained release over a prolonged period of time of the therapeutic agents. Additionally, the poor prediction value of some preclinical animal models hinders the translation of many formulations into the clinical practice.
30644131 Ultrasound measurement of knee synovial fluid during external pneumatic compression. 2019 Mar Synovial fluid based biomarker research has been limited by the small volumes of synovial fluid from the knees of some patients. We used ultrasound (US) to determine if synovial fluid could be displaced into an access port during pneumatic compression to 100 mmHg. Forty knees from 37 consecutive arthritis patients with rheumatoid arthritis -25, osteoarthritis -8, psoriatic arthritis -2, and 1 each with systemic lupus erythematosus and gout were evaluated. This group of 28 females and 9 males with a median age of 59 years and an average body mass index of 26.9 kg/m(2) had previously undergone a diagnostic arthrocentesis and or a therapeutic knee injection using this pneumatic compression device. Blinded digital image analysis of the anechoic region on ultrasound demonstrated an increase in fluid within the 9 cm × 6 cm access port (anterolateral or anteromedial joint) during inflation in all patients with a 2.5-3.5 fold increase in fluid area and a 2-3 fold increase in fluid depth after inflation, p < 0.001. Statement of clinical significance: External pneumatic compression to the knee provides a larger volume of synovial fluid under positive pressure which should allow investigators to achieve greater success in obtaining synovial fluid during arthrocentesis for biomarker research or provide more precise therapeutic injections than traditional non image-guided anatomical landmark-based techniques. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
30408582 Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis. 2019 Jan Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care. The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments.
31491724 Interleukin-21-mediated suppression of the Pax3-Id3 pathway exacerbates the development of 2020 Jan Sjögren's syndrome (SS) is a systemic autoimmune disease with severe dysfunction of glandular secretory function mediated by T and B lymphocyte infiltration into the exocrine glands, including the salivary and lacrimal glands. Follicular helper T (Tfh) cells exacerbate the disease by causing B cell hyperactivity. Inhibitor of DNA binding 3 (Id3) deficiency causes activation of Tfh cells and is known to be a clinical manifestation of human SS disease. In this study, we investigated the mechanism of action of Pax3, which is reduced in SS and can interact with Id3, in NOD/ShiLtJ mice as an animal model of SS. Treatment with interleukin (IL)-21, a major cytokine secreted from Tfh cells, suppressed Pax3 and Id3 expression via STAT3 in splenic T cells in vitro. Administration of pCMV14-3xFlag PAX3 vector improved the severity of SS by reducing the number of Tfh cells in NOD/ShiLtJ mice. Application of IL-21R-Fc increased the number of Pax3- and Id3-positive cells in the salivary glands, while reducing the proportion of Tfh cells and IL-17-producing T cells in NOD/ShiLtJ mice. The salivary glands from SS patients showed decreased levels of Pax3 or Id3 expression compared with healthy controls. Our findings regarding reinforcement of the Pax3-Id3 signal pathway may facilitate the development of novel therapeutic strategies for SS.
31015824 Comparative Evaluation of (68)Ga-Citrate PET/CT and (18)F-FDG PET/CT in the Diagnosis of T 2019 Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic, symmetrical, and erosive synovitis. RA is one of the most common disabling diseases in the clinic. The main clinical intervention strategies are early diagnosis and early treatment. This study aims to predict the diagnostic value of (68)Ga-citrate and (18)F-FDG PET/CT in RA by comparing and analyzing the value of (68)Ga-citrate and (18)F-FDG PET/CT for diagnosing type II collagen-induced arthritis (CIA) in rats. Some CIA models were established. Normal rats were selected as the control group, and 23 days and 40 days were selected as the early and late time points of arthritis, respectively. The semiquantitative analysis of CIA rats was carried out with (68)Ga-citrate PET/CT and (18)F-FDG PET/CT, and the ratio of the maximum standardized uptake (SUV(max)) values in the regions of interest (ROIs) of the hind foot ankle joint and thigh muscle was calculated and statistically analyzed. The distribution of CIA rats in vivo at the (68)Ga-citrate 90 min time point was studied, and the ankle tissues were evaluated with hematoxylin and eosin (HE) staining. (68)Ga-citrate PET/CT is obviously superior to (18)F-FDG PET/CT for CIA imaging, and the statistical results show that the difference between the two examination methods is statistically significant (P < 0.001). The uptake of these two radiopharmaceuticals showed the same trend in arthritis rats with different scores. The distribution of (68)Ga-citrate at 90 min is consistent with the trend shown by (68)Ga-citrate PET/CT. (68)Ga-citrate PET/CT can reflect the inflammatory activity of affected joints in CIA rats earlier and more sensitively than (18)F-FDG PET/CT, and this imaging advantage continues until the later stage of inflammation. Therefore, (68)Ga-citrate PET/CT is worthy of further promotion and application in the clinical diagnosis of RA.
30336303 Diarylheptanoid, a constituent isolated from methanol extract of Alpinia officinarum atten 2019 Jan 30 ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a chronic inflammatory and destructive joint disease that affects the worldwide population. Alpinia officinarum Hance (Zingiberaceae), rhizomes are widely used ethnobotanically as an anti-inflammatory, analgesic, and antioxidant agent in traditional medicine. AIM: To investigate the efficacy and possible mechanism of isolated phytoconstituent from the methanol extract of A. officinarum (MEAO) rhizomes against Freund's complete adjuvant (FCA)-induced arthritis in rats. Furthermore, molecular docking was performed to study the binding mode of this compound into the active site of TNF-α. MATERIALS AND METHODS: Diarylheptanoid was isolated from MEAO, well characterized (HPTLC, (1)H NMR, (13)C NMR, and ESI-MS) and evaluated for its antiarthritic activity in female Wistar rats (170-200 g). Diarylheptanoid (5, 10 and 20 mg/kg, p.o.) was administered starting from day 12. Various behavioral, biochemical, molecular and histopathology parameters were evaluated. Molecular docking study was performed using Glide module integrated into Schrodinger molecular modeling software. RESULTS: The structure and molecular weight of the isolated compound (diarylheptanoid) were confirmed by 1D and mass spectral data and characterized as 1-phenyl-5-hydroxy-7- (4''-hydroxy-3''-methoxyphenyl) heptane-3-one (i.e., 5-HPH) with molecular formula C(20)H(24)O(4). Administration of 5-HPH (10 and 20 mg/kg) significantly inhibited (p < 0.05) FCA induced increases in paw volume, joint diameter, thermal hyperalgesia and tactile allodynia. It also significantly decreased oxido-inflammatory markers (SOD, GSH, MDA, and TNF-α). FCA induced a histological alteration in ankle joint also attenuated by 5-HPH. Its Glide docking score was found to be -9.702 with binding energy (Glide energy) of -37.033 kcal/mol. CONCLUSION: 5-HPH may exhibit its anti-arthritic potential via inhibition of elevated oxido-inflammatory markers thus restoring the elevated hyperalgesia, allodynia and reducing destruction in synovial membrane and cartilage. Therefore, 5-HPH is a potential moiety bearing antioxidant and with anti-inflammatory properties to inhibit FCA-induced arthritis in rats. The results of the present investigation should enable the design of potent small-molecule inhibitors that inactivate TNF-α with high affinity and specificity.
31137968 Treatment of spontaneous corneal perforation secondary to undiagnosed Sjögren's syndrome 2021 Jan PURPOSE: The aim of this study was to report a case of sterile corneal ulcer leading to perforation, which was treated effectively with autologous serum eye drops, topical regenerative agent (poly-carboxymethylglucose sulfate), steroids, and systemic immunosuppression in a patient with undiagnosed primary Sjögren's syndrome. METHODS: A 74-year-old female presented with a month's history of gradually worsening blurry vision in her left eye. Ophthalmic examination revealed a central descemetocele with excessive corneal stromal melting and absence of signs of infection. A bandage contact lens was applied for tectonic support along with topical corticosteroid and antibiotic drops. Autoimmune screen disclosed a diagnosis of Sjögren's syndrome, and the patient was commenced on systemic immunosuppression. Forty-eight hours after presentation, the patient developed a localized corneal perforation, presenting with a flat anterior chamber. RESULTS: Urgent amniotic membrane transplantation was arranged while topical dexamethasone, moxifloxacin, and autologous serum eye drops were administered. After 24 h of intensive topical treatment, a significant reforming of the anterior chamber and subsequent gradual regeneration of the corneal stroma were noted, thus postponing amniotic grafting. The patient remained under close monitoring, showing progressive clinical improvement. Regenerating agent eye drops (Cacicol20(®)) were also applied over the next month, with careful and slow tapering of topical dexamethasone. Further improvement of corneal thickness was observed, and visual acuity increased to 20/80. CONCLUSION: This case report demonstrates the successful medical treatment of an autoimmune-related sterile corneal perforation without surgical intervention, highlighting the fact that early diagnosis and rigorous medical treatment with autologous serum and regenerating agent eye drops can effectively aid tissue regeneration and favorable visual rehabilitation.
30986119 Evaluation of the Efficacy and Safety of A Novel 0.05% Cyclosporin A Topical Nanoemulsion 2020 Apr 2 Purpose: To evaluate the efficacy and safety of a novel topical cyclosporin A 0.05% nanoemulsion in comparison with a conventional emulsion in primary Sjögren's syndrome dry eyes.Methods: Prospective, randomized, double-blinded study was conducted.Results: Corneal and conjunctival staining score was improved in both groups, with a faster change noted in the nanoemulsion group at 12 weeks (p < 0.05). Tear film break-up time was significantly improved in the nanoemulsion group at 12 weeks (p < 0.05), while ocular surface disease index score was improved in both groups without a difference at 12 weeks. Schirmer I value and goblet cell grade did not change in both groups. IL-6 and MMP-9 were significantly decreased in both groups at 12 weeks.Conclusions: Both nanoemulsion and conventional cyclosporin A improved ocular signs, symptoms, and conjunctival inflammation. However, the novel cyclosporin A nanoemulsion showed faster improvement of ocular surface staining scores than the conventional emulsion.
29992636 Association of CD28 and CTLA4 haplotypes with susceptibility to primary Sjögren's syndrom 2019 Jan BACKGROUND: Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by destruction of exocrine glands as a result of T and B cells infiltrated in glandular tissue. CD28 and CTLA-4 play a crucial role in T cell activation and inhibition. The aim of this study was to associate CD28 and CTLA4 haplotypes with susceptibility to pSS in patients from western Mexico. METHODS: Polymerase chain reaction and restriction fragment length polymorphism were performed to identify CD28 and CTLA4 genotypes in 111 patients with pSS and 138 control subjects (CS). Haplotype analysis was carried out by SHEsis program. Soluble serum levels of CD28 (sCD28) and CTLA-4 (sCTLA-4) were quantified by ELISA kit. RESULTS: The CD28 GC haplotype was associated with low risk to pSS (2.5-folds, P < 0.001). CTLA4 CAG and CGA were identified as genetic risk factor (P < 0.001;OR = 3.82[CI95%:2.022-7.296] and P < 0.001; OR = 11.38[CI95%:3.282-37.69] respectively). No difference in sCD28 and sCTLA-4 were found between patients and CS. However, pSS patients carriers of CD28 IVS3 + 17TC genotype showed high sCD28 (P = 0.039 vs TT carriers in CS). In regard to sCTLA-4, patient who carry CTLA4-319C>T, +49 A>G, and +6230 G>A, or their haplotypes did not show any difference. CONCLUSION: Our findings suggest that CD28 GC, CTLA4 CAG, and CGA haplotypes are associated with susceptibility to pSS in patients from western Mexico. It seems that genetic control of CD28 and CTLA4 as well as local immune response in glandular tissue may regulate the impact of the gene expression in pSS. It is necessary to confirm this hypothesis in an integrative study.
31329541 Treat-to-target concept implementation for evaluating rheumatoid arthritis patients in dai 2019 Jul OBJECTIVE: We aimed to assess the implementation of the treat-to-target (T2T) concept in rheumatoid arthritis (RA) patients in daily practice. METHODS: All RA patients visiting one of the 7 academic medical centers in Israel in June 2015 with at least 3 previous clinic visits were included in this study. A common questionnaire was used to collect data from patients' medical records, and two independent rheumatologists evaluated the collected data for the implementation of the T2T concept. The associations between T2T implementation and the categorical and continuous variables were assessed. RESULTS: The study included 724 patients with a mean (standard deviation) age of 62.6 (13.97) years and 575 (80.4%) of them were women. Four centers used more than one scoring method, with Disease Activity Score-28 and Clinical Disease Activity Index) being most commonly used. Only 276 (38.1%) patients had disease score results in ≥3 visits, and the T2T recommendations were implemented for 245 (33.8%) of the 724 patients. The rate of implementation was higher in younger (p=0.028) rheumatoid factor-positive patients (p=0.011) and varied between centers (11.1%-87% p<0.0001). T2T implementation did not correlate to gender, place of residence, education, tobacco use, treatment regimens, and presence of erosions or comorbidities. CONCLUSION: The T2T concept was implemented on only 33.8% of patients and was not affected by RA disease severity. Further studies are needed to determine the reasons for this deviation from the T2T standard of care for RA as well as its consequences.
31366407 Proteomic and histopathological characterisation of sicca subjects and primary Sjögren's 2019 Jul 31 BACKGROUND: Mononuclear cell infiltration of exocrine glands, production of Ro/SSA and La/SSB autoantibodies, along with oral and ocular dryness, are characteristic features of primary Sjögren's syndrome (pSS). Non-SS sicca subjects, an underexplored group in relation to pSS, display similar sicca symptoms, with possible mild signs of inflammation in their salivary glands, yet with no serological detection of autoantibody production. In this study, we investigated inflammatory manifestations in the salivary gland tissue, tear fluid and saliva of non-SS subjects, as compared to pSS patients and healthy individuals. METHODS: Fifteen non-SS, 10 pSS and 10 healthy subjects were included in the analyses. Histological evaluation of salivary gland biopsies was performed. Liquid chromatography-mass spectrometry (LC-MS) was conducted on tear fluid and stimulated whole saliva, and proteomic biomarker profiles were generated. Extracellular vesicle (EVs) isolation and characterisation from both fluids were also combined with LC-MS. The LC-MS data were analysed for quantitative differences between patient and control groups using Scaffold. Database for Annotation, Visualization and Integrated Discovery (DAVID) and Functional Enrichment Analysis Tool (FunRich) were applied for functional analyses. RESULTS: Histopathological evaluation of salivary gland biopsies showed implications of milder inflammation in non-SS subjects through mononuclear cell infiltration, fibrosis and fatty replacement, as compared to pSS patients. Although unaffected in the non-SS group, upregulation of proinflammatory pathways and proteins involved in ubiquitination (LMO7 and HUWE1) and B cell differentiation (TPD52) were detected in tear fluid of pSS patients. Moreover, overexpression of proteins STOM, ANXA4 and ANXA1, regulating cellular innate and adaptive immunological pathways, were further identified in EVs from tear fluid of pSS patients. Finally, whole saliva and EVs isolated from whole saliva of pSS patients expressed proteins vital for innate MHC class I cellular regulation (NGAL) and T cell activation (CD44). CONCLUSIONS: Non-SS sicca subjects may show implications of mild inflammation in their glandular tissue, while their protein profile was strikingly more similar to healthy controls than to pSS patients. Hence, the tear and salivary biomarkers identified could be implemented as potential non-invasive diagnostic tools that may aid in increasing diagnostic accuracy when evaluating non-SS subjects and pSS patients and monitoring disease progression.
30307034 miR-31 regulates energy metabolism and is suppressed in T cells from patients with Sjögr 2019 Feb Systemic autoimmune diseases are characterized by the overexpression of type I IFN stimulated genes, and accumulating evidence indicate a role for type I IFNs in these diseases. However, the underlying mechanisms for this are still poorly understood. To explore the role of type I IFN regulated miRNAs in systemic autoimmune disease, we characterized cellular expression of miRNAs during both acute and chronic type I IFN responses. We identified a T cell-specific reduction of miR-31-5p levels, both after intramuscular injection of IFNβ and in patients with Sjögren's syndrome (SjS). To interrogate the role of miR-31-51p in T cells we transfected human CD4(+) T cells with a miR-31-5p inhibitor and performed metabolic measurements. This identified an increase in basal levels of glucose metabolism after inhibition of miR-31-5p. Furthermore, treatment with IFN-α also increased the basal levels of human CD4(+) T-cell metabolism. In all, our results suggest that reduced levels of miR-31-5p in T cells of SjS patients support autoimmune T-cell responses during chronic type I IFN exposure.
32250566 Predictive modeling of aspirin-triggered resolvin D1 pharmacokinetics for the study of Sjà 2020 Apr OBJECTIVES: Sjögren's syndrome (SS) is an autoimmune disease that causes chronic inflammation of the salivary glands leading to secretory dysfunction. Previous studies demonstrated that aspirin-triggered resolvin D1 (AT-RvD1) reduces inflammation and restores tissue integrity in salivary glands. Specifically, progression of SS-like features in NOD/ShiLtJ mice can be systemically halted using AT-RvD1 prior or after disease onset to downregulate proinflammatory cytokines, upregulate anti-inflammatory molecules, and restore saliva production. Therefore, the goal of this paper was to create a physiologically based pharmacokinetic (PBPK) model to offer a reasonable starting point for required total AT-RvD1 dosage to be administered in future mice and humans thereby eliminating the need for excessive use of animals and humans in preclinical and clinical trials, respectively. Likewise, PBPK modeling was employed to increase the range of testable scenarios for elucidating the mechanisms under consideration. MATERIALS AND METHODS: Pharmacokinetics following intravenous administration of a 0.1 mg/kg dose of AT-RvD1 in NOD/ShiLtJ were predicted in both plasma and saliva using PBPK modeling with PK-Sim® and MoBi® Version 7.4 software. RESULTS: The model provides high-value pathways for future validation via in vivo studies in NOD/ShiLtJ to corroborate the findings themselves while also establishing this method as a means to better target drug development and clinical study design. CONCLUSIONS: Clinical and basic research would benefit from knowledge of the potential offered by computer modeling. Specifically, short-term utility of these pharmacokinetic modeling findings involves improved targeting of in vivo studies as well as longer term prospects for drug development and/or better designs for clinical trials.
30653959 Expression of Nod-like Receptors and Clinical Correlations in Patients With Dry Eye Diseas 2019 Apr PURPOSE: To investigate the expression pattern of nucleotide-binding oligomerization domain (Nod)-like receptors that detects "danger" intracellular signaling and its correlation with clinical dry eye (DE) markers. DESIGN: Cross-sectional study. METHODS: A total of 50 participants with 50 eyes were included: 23 eyes with Sjögren syndrome (SS)-DE, 14 eyes with non-SS-DE, and 13 healthy controls with non-DE. Ocular Surface Disease Index (OSDI) was self-answered and clinical tests including the tear film breakup time (TBUT), Schirmer test, and corneal fluorescein staining (CFS) were performed. Specimens for expression pattern analysis were obtained by conjunctival impression cytology and biopsy. Nod-1, inhibitor kappa B kinase-alpha (IκKα), and nuclear factor kappa B (NF-κB) expression was determined by reverse transcription quantitative real-time polymerase chain reaction and Western blot. Correlations between Nod-1 and ocular surface parameters were determined. RESULTS: Patients with SS-DE had significantly higher OSDI and CFS scores and lower TBUT and Schirmer test scores than those with non-SS-DE patients (all P < .05). Compared with the control group, both the SS-DE and non-SS-DE groups showed significant upregulation in mRNA expression levels of Nod-1 (relative 3.48-fold and 1.72-fold upregulation, respectively, P < .01), IκKα (relative 1.83-fold and 1.24-fold upregulation, respectively, P < .01), and NF-κB (relative 1.84-fold and 1.32-fold upregulation, respectively, P < .01). Western blot analysis showed that Nod-1 protein expression increased in both the SS-DE and non-SS-DE groups (relative 2.71-fold and 1.64-fold upregulation, respectively, P < .05) compared with that in the control group. Similar findings were observed for IκKα and NF-κB. In DE participants, the expression of Nod-1 significantly correlated with the OSDI (R(2) = 0.61, r = 0.78, P < .01), Schirmer test score (R(2) = 0.44, r = -0.66, P < .01), and CFS (R(2) = 0.46, r = 0.68, P < .01) but did not significantly correlate with TBUT (R(2) < 0.01, r = 0.08, P = .66). CONCLUSIONS: Nod-1 expression was increased in the conjunctiva of DE, especially SS-DE, and was associated with disease severity. Expression of Nod-like receptors might play an important role in initiating the inflammatory response in DE.
31683054 A novel NFKBIA variant substituting serine 36 of IκBα causes immunodeficiency with warts 2020 Jan Genetic studies have led to identification of an increasing number of monogenic primary immunodeficiency disorders. Monoallelic pathogenic gain-of-function (GOF) variants in NFKBIA, the gene encoding IκBα, result in an immunodeficiency disorder, typically accompanied by anhidrotic ectodermal dysplasia (EDA). So far, 14 patients with immunodeficiency due to NFKBIA GOF mutations have been reported. In this study we report three patients from the same family with immunodeficiency, presenting with recurrent respiratory tract infections, bronchiectasis and viral skin conditions due to a novel pathogenic NFKBIA variant (c.106 T > G, p.Ser36Ala), which results in reduced IκBα degradation. Immunological investigations revealed inadequate antibody responses against vaccine antigens, despite hypergammaglobulinemia. Interestingly, none of the studied patients displayed features of EDA. Therefore, missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA.
33405580 Zinc Gluconate-Loaded Chitosan Nanoparticles Reduce Severity of Collagen-Induced Arthritis 2019 Jul 8 Rheumatoid arthritis (RA) is the most prevalent autoimmune disease affecting about 1% world population. Zinc (Zn) is necessary for the maintenance of bone homeostasis and the level of Zn was reported to be decreased in RA patients and collagen-induced arthritic rats. Effective delivery of Zn has been reported using zinc gluconate but oral absorption of Zn from zinc gluconate (ZG) is very low in humans. Zn supplementation reduces disease severity in patients suffering from chronic, refractory RA and exerts mild and transient side effects. The aim of this study was to synthesize and characterize zinc gluconate-loaded chitosan nanoparticles (ZG-Chit NPs) and to evaluate and compare therapeutic efficacy of ZG-Chit NPs and zinc gluconate against collagen-induced RA in Wistar rats. The nanoparticles were formulated by ionic gelation method and the hydrodynamic diameter was 106.5 ± 79.55 nm as measured using DLS. The particle size, shape, and surface morphology was further confirmed by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. These nanoparticles showed good cytocompatibility against foreskin fibroblasts (BJ) and L929 cells. Arthritic rats were treated with ZG (20 mg/kg body weight, intraperitoneally) and equivalent doses of ZG-Chit NPs. The treatment of both ZG and ZG-Chit NPs reduced the severity of arthritis as evidenced by reduced joint swelling, erythema, and edema but ZG-Chit NPs exhibited superior efficacy. Furthermore, it was found that ZG and ZG-Chit NPs attenuate biomarkers of inflammation (C-reactive protein, myeloperoxidase, nitric oxide, TNF-α, and IL-1β) and oxidative stress (articular elastase, lipid peroxidation, catalase, glutathione, and superoxide dismutase). The results of the histopathology further confirmed that ZG-Chit NPs markedly suppressed infiltration of inflammatory cells as compared to ZG at the ankle joint tissue. Immunohistochemical analysis also revealed that treatment with ZG-Chit NPs resulted in reduced pro-inflammatory marker (TNF-α, IL-6, and iNOS) expression and enhanced SOD1 expression. Overall, this study suggests that ZG and ZG-Chit NPs suppressed the severity of arthritis plausibly mediated by attenuation of inflammation and oxidative stress and more importantly ZG-Chit NPs exhibited superior efficacy as compared to ZG.
32186040 Efficacy of Zhonglun'a-decoction-containing serum on fibroblast-like synoviocyte apoptosis 2019 Apr OBJECTIVE: To investigate the efficacy of Zhonglun'a-decoction-containing serum (ZHONGL-CS) on the in vitro apoptosis of fibroblast-like synoviocytes (FLS) from rats with collagen-induced arthritis (CIA) by investigating the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. METHODS: A CIA rat model was established using bovine type â…¡ collagen. FLS were isolated, cultured and identified. A cell counting kit-8 was used to detect cell activity. The half maximal inhibitory concentration (IC50) was calculated. Experimental subjects were divided into control, CIA, ZHONGL-CS, JAK2 inhibitor AG490, and ZHONGLCS with AG490 groups. The in vitro cell cycle and apoptosis rate were detected in FLS by flow cytometry. Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), caspase-3, cyclin D1, phosphorylated JAK2, STAT1, and STAT3 protein expressions in FLS were examined by Western blotting. JAK2, STAT1 and STAT3 mRNA levels were examined by quantitative real-time polymerase chain reaction. RESULTS: Compared with the CIA group, FLS proliferation was inhibited, the FLS G0/G1 cell cycle was arrested, and the rate of FLS apoptosis was increased in the ZHONGL-CS group. In the ZHONGLCS group, the protein levels of Bcl-2 and cyclin D1 were reduced compared with the CIA group and the levels of Bax and caspase-3 in FLS were increased. In the ZHONGL-CS group, the expressions of JAK2, STAT1, and STAT3 mRNA and the levels of phosphorylated JAK2, STAT1, and STAT3 proteins were reduced. CONCLUSION: ZHONGL-CS may induce FLS apoptosis in CIA rats. Activation of the JAK/STAT signaling pathway was inhibited in FLS in vitro.