Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 28472749 | Neutral PEGylated liposomal formulation for efficient folate-mediated delivery of MCL1 siR | 2017 Jul 1 | Cationic liposomes are efficient vectors for systemic delivery of therapeutic small interfering RNA (siRNA), taking advantage of RNA interference (RNAi), a naturally occurring gene-silencing mechanism in mammalian cells. However, toxicity at high concentrations, short circulating half-lives and lack of specificity restrict their successful application in a wider scale. The purpose of this study was to evaluate the efficiency of neutral liposomes containing polyethylene glycol (PEG) to encapsulate siRNA in their aqueous core. This formulation will reduce drastically the toxicity associated to cationic liposomes by bringing surface charge to almost zero, increasing stealth degree and therefore circulation time. In this study, we evaluate the efficiency of folate-targeted liposomes for specific delivery of siRNA to activated macrophages, key effector cells in rheumatoid arthritis (RA) pathology which specifically express folate receptor β (FRβ). Myeloid cell leukaemia-1 (Mcl-1) is a protein essential for synovial macrophage survival, since Mcl-1 suppression results in the induction of apoptosis. The effect of MCL1 siRNA incorporated in liposomal formulation was assessed in primary human macrophages and successful inhibition of Mcl-1 expression was achieved. Here we show that the neutral liposomal derived from DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) formulation developed is efficient to encapsulate MCL1 siRNA and silencing gene expression in activated human macrophages. | |
| 28421357 | Incidence of autoimmune diseases in patients with scabies: a nationwide population-based s | 2017 Jul | Scabies is a commonly occurring infectious immune-mediated inflammatory skin disease. Immune-mediated inflammatory processes are also observed in autoimmune diseases. There have been very few previous studies; however, that have investigated the possible association between scabies and autoimmune diseases. To address this research gap, we conducted a nationwide population-based cohort study that included a total of 4481 scabies patients and 16,559 control subjects matched by gender, age, insured region, urbanization and income. We tracked both cohorts for a 7-year period to identify the incidence of autoimmune diseases in both groups during that follow-up period. Relatedly, a Cox regression analysis was performed to calculate and compare the hazard ratio (HR) for autoimmune diseases of both groups. An overall increased risk for 19 autoimmune diseases was observed in the scabies patients, with an adjusted HR (aHR) of 1.14 (95% CI 1.04-1.25). Compared with the control group, the scabies patients exhibited increased risks of hypersensitivity vasculitis (aHR 5.44, 95% CI 1.64-18.07), dermatomyositis (aHR 4.91, 95% CI 1.80-13.38), polyarteritis nodosa (aHR 2.89, 95% CI 1.46-5.73), systemic lupus erythematosus (aHR 2.73, 95% CI 1.33-5.64), psoriasis (aHR 2.31, 95% CI 1.85-2.88), myasthenia gravis (aHR 2.01, 95% CI 1.31-3.12), type 1 diabetes mellitus (aHR 1.93, 95% CI 1.53-2.44), pernicious anemia (aHR 1.92, 95% CI 1.42-2.61), and rheumatoid arthritis (aHR 1.43, 95% CI 1.12-1.83). In conclusion, the associations between scabies and a variety of autoimmune diseases may exist. Further studies are needed to clarify the shared etiologies and relationships between scabies and autoimmune diseases. | |
| 28399605 | Cementless Total Knee Arthroplasty in Patients Older Than 75 Years. | 2017 Nov | Some surgeons have been hesitant to use cementless fixation for total knee arthroplasty (TKA) in elderly patients due to concerns regarding successful bone biological fixation. Therefore, this study evaluated: (1) implant survivorship, (2) functional outcomes, (3) radiographic outcomes, and (4) complications in patients over 75 years of age who underwent cementless total knee arthroplasty. A total of 134 patients (142 TKAs) older than 75 years at a single institution between June 2008 and June 2014 were retrospectively reviewed. Their mean follow-up was 4 years (range: 2-8 years). The cohort consisted of 91 women and 43 men who had a mean age of 80 years (range: 76 to 88 years). The preoperative diagnoses were osteoarthritis (n = 107 patients), rheumatoid arthritis (n = 21 patients), and osteonecrosis (n = 6 patients). Descriptive statistics were used to calculate the means and ranges and a Kaplan-Meier analysis was performed to determine the aseptic and all cause implant survivorship. Radiographic evaluation was performed using the new Knee Society Radiographic Evaluation and Scoring System. Functional outcomes at the final follow-up as well as all medical and surgical complications were recorded for each patient. The aseptic implant survivorship was 99.3% (95% CI: 7.9-8.1), and the all cause implant survivorship was 98.6% (95% CI: 7.9-8.1). There was one aseptic revision and one septic revision. At the latest follow-up the mean Knee Society pain score was 93 points (range, 80-100 points), and the mean Knee Society function score was 84 points (range, 70-90 points). On radiographic evaluation, there were no progressive radiolucencies, subsidence, and loosening of prostheses at the latest follow-up. The use of cementless TKA demonstrated excellent survivorship, mid-term clinical and functional outcomes, as well as no progressive radiolucencies or subsidence in patients older than 75 years. In addition, there was a low rate of surgical and medical complications. Therefore, cementless TKA may be a good option for patients older than 75 years. | |
| 28335003 | Identification of genetic variants affecting vitamin D receptor binding and associations w | 2017 Jun 1 | Large numbers of statistically significant associations between sentinel SNPs and case-control status have been replicated by genome-wide association studies. Nevertheless, few underlying molecular mechanisms of complex disease are currently known. We investigated whether variation in binding of a transcription factor, the vitamin D receptor (VDR), whose activating ligand vitamin D has been proposed as a modifiable factor in multiple disorders, could explain any of these associations. VDR modifies gene expression by binding DNA as a heterodimer with the Retinoid X receptor (RXR). We identified 43,332 genetic variants significantly associated with altered VDR binding affinity (VDR-BVs) using a high-resolution (ChIP-exo) genome-wide analysis of 27 HapMap lymphoblastoid cell lines. VDR-BVs are enriched in consensus RXR::VDR binding motifs, yet most fell outside of these motifs, implying that genetic variation often affects the binding affinity only indirectly. Finally, we compared 341 VDR-BVs replicating by position in multiple individuals against background sets of variants lying within VDR-binding regions that had been matched in allele frequency and were independent with respect to linkage disequilibrium. In this stringent test, these replicated VDR-BVs were significantly (q < 0.1) and substantially (>2-fold) enriched in genomic intervals associated with autoimmune and other diseases, including inflammatory bowel disease, Crohn's disease and rheumatoid arthritis. The approach's validity is underscored by RXR::VDR motif sequence being predictive of binding strength and being evolutionarily constrained. Our findings are consistent with altered RXR::VDR binding contributing to immunity-related diseases. Replicated VDR-BVs associated with these disorders could represent causal disease risk alleles whose effect may be modifiable by vitamin D levels. | |
| 28333140 | Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltran | 2017 Mar 23 | Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecular mechanisms of NAMPT in these physiological and pathological processes are not fully understood. Here, we provide experimental evidence that a Nampt gene homozygous knockout (Nampt(-/-)) resulted in lethality at an early stage of mouse embryonic development and death within 5-10 days in adult mice accompanied by a 25.24±2.22% body weight loss, after the tamoxifen induction of Nampt(F/F) × Cre mice. These results substantiate that Nampt is an essential gene for life. In Nampt(-/-) mice versus Nampt(+/+) mice, biochemical assays indicated that liver and intestinal tissue NAD levels were decreased significantly; histological examination showed that mouse intestinal villi were atrophic and disrupted, and visceral fat was depleted; mass spectrometry detected unusual higher serum polyunsaturated fatty acid containing triglycerides. RNA-seq analyses of both mouse and human pediatric liver transcriptomes have convergently revealed that NAMPT is involved in key basic cellular functions such as transcription, translation, cell signaling, and fundamental metabolism. Notably, the expression of all eight enzymes in the tricarboxylic acid cycle were decreased significantly in the Nampt(-/-) mice. These findings prompt us to posit that adult Nampt(-/-) mouse lethality is a result of a short supply of ATP from compromised intestinal absorption of nutrients from digested food, which leads to the exhaustion of body fat stores. | |
| 28250648 | The Influence of Pluronic F68 and F127 Nanocarrier on Physicochemical Properties, In vitro | 2017 Jan | BACKGROUND: This study reports on hydrophobic drug thymoquinone (TQ), an active compound found in the volatile oil of Nigella sativa that exhibits anticancer activities. Nanoformulation of this drug could potentially increase its bioavailability to specific target cells. OBJECTIVE: The aim of this study was to formulate TQ into polymer micelle, Pluronic F127 (5.0 wt %) and Pluronic F68 (0.1 wt %), as a drug carrier to enhance its solubility and instability in aqueous media. MATERIALS AND METHODS: Polymeric micelles encapsulated TQ were prepared by the microwave-assisted solvent evaporation technique. Fourier transform infrared spectroscopy and ultraviolet-visible spectrophotometer were utilized for qualitative confirmation of micelles encapsulation. The surface morphology and mean particle size of the prepared micelles were determined by using transmission electron microscopy (TEM). Cytotoxicity effect was studied using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. RESULTS: Dynamic laser light scattering (DLS) technique showed hydrodynamic size distribution of optimized micelles of 50 nm, which was in close agreement with the mean particle size obtained from TEM of about 51 nm. Drug release study showed the maximum percentage of TQ release at 61% after 72 h, while the entrapment efficiency of TQ obtained was 46% using PF127. The cytotoxic effect of PF127-encapsulated TQ was considerably higher compared to PF68-encapsulated TQ against MCF7 cells, as they exhibited IC(50)value of 8 μM and 18 μM, respectively. CONCLUSION: This study suggests higher molecular weight Pluronic polymer micelles (F127) with hydrophilic-hydrophobic segments which could be used as a suitable candidate for sustainable delivery of TQ. However, comprehensive studies should be carried out to establish the suitability of Pluronic F127 as a carrier for other drugs with similar challenges as TQ. SUMMARY: There is a rising interest in integrating nanotechnology with medicine, creating a nanomedicine aiming for high efficiency and efficacy of disease diagnosis and treatment. In drug delivery, the term nanomedicine describes the nanometer-sized range (1-1000 nm) of a multi-component drug for disease treatments. As such, liposome-based nanoparticulate delivery vehicles have been approved by the Food and Drug Administration (FDA) for clinical applications. The main purpose of introducing nanoscale drug delivery is to improve the pharmacological and pharmacokinetic profiles of therapeutic molecules. Drug or therapeutic molecules can be either released through the cleavage of a covalent linkage between drug molecules and polymers (conjugation) or through the diffusion from a drug and polymer blended matrix (physical encapsulation). Polymers play an important role in the design of nanocarriers for therapeutic deliveries. In Asia, Nigella sativa seed oil has been used traditionally for its various medicinal benefits. One of its most potent compound which is thymoquinone has been intensively investigated for its anti-cancer effects in colorectal carcinoma, breast adenocarcinoma, osteosarcoma, ovarian carcinoma, myeloblastic leukemia, and pancreatic carcinoma. In addition, it is reported to show anti-inflammatory potential, antidiabetic, antihistaminic effects, as well as the ability to alleviate respiratory diseases, rheumatoid arthritis, multiple sclerosis, and Parkinson's disease. This study aims to formulate and characterize different pluronic-based thymoquinone nanocarrier and investigate its effect against breast cancer cells Abbreviations Used: ATR-IR: Attenuated Total Reflectance-Infrared Spectroscopy, CH(3)CN: Acetonitrile, DLS: Dynamic Light Scattering, MTS: [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, NPs: Nanoparticles, PF127/TQ: Pluronic F127 encapsulated TQ, PF68/TQ: Pluronic F68 encapsulated TQ, PLGA: Poly-(D,L-lactide-co-glycolide), PVA: Poly-vinylalcohol, TQ: Thymoquinone, UV/VIS: Ultravioletvisible spectrophotometry. | |
| 28237724 | The common, autoimmunity-predisposing 620Arg > Trp variant of PTPN22 modulates macrophag | 2017 May | The C1858T single nucleotide polymorphism (SNP) in PTPN22 (protein tyrosine phosphatase nonreceptor 22) leads to the 620 Arg to Trp polymorphism in its encoded human protein LYP. This allelic variant is associated with multiple autoimmune diseases, including type 1 diabetes (T1D), Crohn's disease, rheumatoid arthritis and systemic lupus erythematosus. However, the underlying mechanisms are poorly understood. To study how this polymorphism influences the immune system, we generated a mouse strain with a knock-in of the Trp allele, imitating the human disease-associated variant. We did not find significant difference between the polymorphic and the wild type mice on the proportion of total CD4 T cell, CD8 T cell, NK cell, memory T lymphocyte, macrophage, dendritic cells in both peripheral lymph nodes and spleen. However, macrophages from Trp/Trp mice showed altered morphology and enhanced function, including higher expression of MHCII and B7 molecules and increased phagocytic ability, which further leads to a higher T-cell activation by specific antigen. Our model shows no alteration in immune cell profile by the Trp allele, but brings up macrophages as an important player to consider in explaining the PTPN22 Trp allele effect on autoimmune disease risk. | |
| 28192119 | Leflunomide induces NAD(P)H quinone dehydrogenase 1 enzyme via the aryl hydrocarbon recept | 2017 Mar 25 | Aryl hydrocarbon receptor (AhR) has been increasingly recognized to play a crucial role in normal physiological homeostasis. Additionally, disrupted AhR signaling leads to several pathological states in the lung and liver. AhR activation transcriptionally induces detoxifying enzymes such as cytochrome P450 (CYP) 1A and NAD(P)H quinone dehydrogenase 1 (NQO1). The toxicity profiles of the classical AhR ligands such as 3-methylcholanthrene and dioxins limit their use as a therapeutic agent in humans. Hence, there is a need to identify nontoxic AhR ligands to develop AhR as a clinically relevant druggable target. Recently, we demonstrated that leflunomide, a FDA approved drug, used to treat rheumatoid arthritis in humans, induces CYP1A enzymes in adult mice via the AhR. However, the mechanisms by which this drug induces NQO1 in vivo are unknown. Therefore, we tested the hypothesis that leflunomide will induce pulmonary and hepatic NQO1 enzyme in neonatal mice via AhR-dependent mechanism(s). Leflunomide elicited significant induction of pulmonary CYP1A1 and NQO1 expression in neonatal mice. Interestingly, the dose at which leflunomide increased NQO1 was significantly higher than that required to induce CYP1A1 enzyme. Likewise, it also enhanced hepatic CYP1A1, 1A2 and NQO1 expression in WT mice. In contrast, leflunomide failed to induce these enzymes in AhR-null mice. Our results indicate that leflunomide induces pulmonary and hepatic CYP1A and NQO1 enzymes via the AhR in neonatal mice. These findings have important implications to prevent and/or treat disorders such as bronchopulmonary dysplasia in human infants where AhR may play a crucial role in the disease pathogenesis. | |
| 27913299 | The inhibitory effect of beta-lapachone on RANKL-induced osteoclastogenesis. | 2017 Jan 22 | β-lapachone (β-L) is a substrate of reduced nicotinamide adenine dinucleotide (NADH): quinone oxidoreductase 1 (NQO1). NQO1 reduces quinones to hydroquinones using NADH as an electron donor and consequently increases the intracellular NAD+/NADH ratio. The activation of NQO1 by β-L has beneficial effects on several metabolic syndromes, such as obesity, hypertension, and renal injury. However, the effect of β-L on bone metabolism remains unclear. Here, we show that β-L might be a potent inhibitor of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. β-L inhibited osteoclast formation in a dose-dependent manner and also reduced the expression of osteoclast differentiation marker genes, such as tartrate-resistant acid phosphatase (Acp5 or TRAP), cathepsin K (CtsK), the d2 isoform of vacuolar ATPase V0 domain (Atp6v0d2), osteoclast-associated receptor (Oscar), and dendritic cell-specific transmembrane protein (Dc-stamp). β-L treatment of RANKL-induced osteoclastogenesis significantly increased the cellular NAD+/NADH ratio and resulted in the activation of 5' AMP-activated protein kinase (AMPK), a negative regulator of osteoclast differentiation. In addition, β-L treatment led to significant suppression of the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β), which can stimulate osteoclastogenesis. β-L treatment downregulated c-Fos and nuclear factor of activated T-cells 1 (NFATc1), which are master transcription factors for osteoclastogenesis. Taken together, the results demonstrated that β-L inhibits RANKL-induced osteoclastogenesis and could be considered a potent inhibitor of RANKL-mediated bone diseases, such as postmenopausal osteoporosis, rheumatoid arthritis, and periodontitis. | |
| 27836739 | Docosahexaenoic acid signaling attenuates the proliferation and differentiation of bone ma | 2017 Jan | Docosahexaenoic acid (DHA), a component of omega-3 fatty acids, has been reported to protect against inflammatory bone diseases such as osteoporosis and rheumatoid arthritis. However, its exact mechanism in bone resorbing cells has not been elucidated. In this study, we investigated the effects and the molecular mechanism of DHA on the proliferation, differentiation, and survival of osteoclast lineage cells using mouse bone marrow-derived macrophages (BMMs). DHA suppressed the macrophage colony-stimulating factor (M-CSF)-induced proliferation of osteoclast precursors, BMMs, in a dose-dependent manner. The attenuated proliferation of DHA-treated BMMs was related to M-CSF inhibition that selectively decreased Akt activation and downregulated cyclin D1 and cyclin D2 expression. DHA also blocked receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation from BMMs. At the molecular level, DHA inhibited JNK, ERK, and p38 MAPKs. In addition, it inhibited NF-κB signaling cascades, as demonstrated by the suppression of RANKL-mediated IκBα phosphorylation, NF-κB subunit p65 nuclear translocation, and NF-κB transcriptional activation. Accordingly, DHA attenuated the induction of c-Fos and nuclear factor of activated T cells c1 (NFATc1). Furthermore, DHA accelerated the apoptosis of mature osteoclasts by inducing Bim expression, a critical modulator of osteoclast apoptosis. Collectively, our data demonstrate that DHA exerts an anti-osteoclastogenic effect by suppressing the proliferation and differentiation of BMMs and enhancing the apoptosis of mature osteoclasts, thereby resulting in a diminished number of bone-resorptive cells. | |
| 27406735 | Quadrivalent human papillomavirus vaccine and autoimmune adverse events: a case-control as | 2017 Feb | Gardasil is a quadrivalent human papillomavirus (HPV4) vaccine that was approved for use by the US Food and Drug Administration in June 2006. HPV4 vaccine is routinely recommended for administration to women in the USA who are 11-12 years old by the Advisory Committee on Immunization Practices. Previous studies suggest HPV4 vaccine administration was associated with autoimmune diseases. As a consequence, an epidemiological assessment of the vaccine adverse event reporting system database was undertaken for adverse event reports associated with vaccines administered from 2006 to 2014 to 6-39 year-old recipients with a listed US residence and a specified female gender. Cases with the serious autoimmune adverse event (SAAE) outcomes of gastroenteritis (odds ratio (OR) 4.627, 95 % confidence interval (CI) 1.892-12.389), rheumatoid arthritis (OR 5.629, 95 % CI 2.809-12.039), thrombocytopenia (OR 2.178, 95 % CI 1.222-3.885), systemic lupus erythematosus (OR 7.626, 95 % CI 3.385-19.366), vasculitis (OR 3.420, 95 % CI 1.211-10.408), alopecia (OR 8.894, 95 % CI 6.255-12.914), CNS demyelinating conditions (OR 1.585, 95 % CI 1.129-2.213), ovarian damage (OR 14.961, 95 % CI 6.728-39.199), or irritable bowel syndrome (OR 10.021, 95 % CI 3.725-33.749) were significantly more likely than controls to have received HPV4 vaccine (median onset of initial symptoms ranged from 3 to 37 days post-HPV4 vaccination). Cases with the outcome of Guillain-Barre syndrome (OR 0.839, 95 % CI 0.601-1.145) were no more likely than controls to have received HPV4 vaccine. In addition, cases with the known HPV4-related outcome of syncope were significantly more likely than controls to have received HPV4 vaccine (OR 5.342, 95 % CI 4.942-5.777). Cases with the general health outcomes of infection (OR 0.765, 95 % CI 0.428-1.312), conjunctivitis (OR 1.010, 95 % CI 0.480-2.016), diarrhea (OR 0.927, 95 % CI 0.809-1.059), or pneumonia (OR 0.785, 95 % CI 0.481-1.246) were no more likely than controls to have received HPV4 vaccine. Confirmatory epidemiological studies in other databases should be undertaken and long-term clinical consequences of HPV-linked SAAEs should be examined. | |
| 28895912 | CD64: An Attractive Immunotherapeutic Target for M1-type Macrophage Mediated Chronic Infla | 2017 Sep 12 | To date, no curative therapy is available for the treatment of most chronic inflammatory diseases such as atopic dermatitis, rheumatoid arthritis, or autoimmune disorders. Current treatments require a lifetime supply for patients to alleviate clinical symptoms and are unable to stop the course of disease. In contrast, a new series of immunotherapeutic agents targeting the Fc γ receptor I (CD64) have emerged and demonstrated significant clinical potential to actually resolving chronic inflammation driven by M1-type dysregulated macrophages. This subpopulation plays a key role in the initiation and maintenance of a series of chronic diseases. The novel recombinant M1-specific immunotherapeutics offer the prospect of highly effective treatment strategies as they have been shown to selectively eliminate the disease-causing macrophage subpopulations. In this review, we provide a detailed summary of the data generated, together with the advantages and the clinical potential of CD64-based targeted therapies for the treatment of chronic inflammatory diseases. | |
| 28587313 | MicroRNA-223-3p Regulates Ovarian Cancer Cell Proliferation and Invasion by Targeting SOX1 | 2017 Jun 6 | MicroRNAs (miRNAs) often display different expression in many cancers and other diseases in current research studies. miR-223 expression is upregulated in rheumatoid arthritis. Also, miR-223 expression has been demonstrated to be highly expressed in pancreatic cancer and gastric cancer in comparison with normal tissue. However, whether miR-223 displays different expression in ovarian cancer and what its underlying functions are in ovarian cancer have remained unclear. In this study, we demonstrated that miR-223-3p was upregulated in ovarian cancer tissue. Next, we explored the functional role of miR-223-3p in ovarian cancer using SKOV3 and OVCAR3 cell lines. Our results suggested that miR-223-3p mimic promoted ovarian cancer cell proliferation, migration, and invasion in vitro. However, miR-223-3p inhibitor displayed the opposite effects. In addition, we demonstrated that miR-223-3p mimic promoted tumor growth in vivo. Furthermore, we found SOX11 (sex determining region Y-box 11) was inversely expressed with miR-223-3p in ovarian cancer (OC) cell lines and tissue specimens. miR-223-3p mimic decreased SOX11 expression. Overexpressing SOX11 inhibited ovarian cancer cell proliferation and invasion, which indicated that miR-223-3p regulated OC cell proliferation and invasion through targeting SOX11 expression. In conclusion, the findings of the present study demonstrated that miR-223-3p could be a potential therapeutic for ovarian cancer. | |
| 28570825 | Effects of Cinnamoyloxy-mammeisin from Geopropolis on Osteoclast Differentiation and Porph | 2017 Jun 23 | Bone-loss-related diseases such as rheumatoid arthritis, osteomyelitis, osteoporosis, and periodontitis are associated with high rates of morbidity worldwide. These disorders are characterized by an imbalance between the formation and activity of osteoblasts and osteoclasts, leading to bone loss. In this context, we evaluated the effect of cinnamoyloxy-mammeisin (CNM), an anti-inflammatory coumarin found in Melipona scutellaris geopropolis, on key targets related to bone remodeling. In the present study we investigated the in vitro effects of CNM on osteoclast differentiation and M-CSF+RANKL-induced osteoclastogenic marker expression. Additionally, the interference of CNM treatment on osteoclast activity was evaluated by zymography and resorption area. Finally, we assessed the capacity of the compound to mitigate alveolar bone loss in vivo in experimental murine periodontitis induced by Porphyromonas gingivalis. We observed that treatment with CNM impaired osteoclast differentiation, as evidenced by a reduced number of tartrate-resistant acid-phosphatase-positive multinucleated cells (TRAP+) as well as the expression of osteoclastogenic markers upon M-CSF+RANKL-induced stimulation. Similarly, we observed reduced gelatinolytic and resorption capacity in M-CSF+RANKL-induced cells in vitro. Lastly, CNM attenuated alveolar bone loss in an experimental murine periodontitis model. These findings indicate that CNM may be considered a promising treatment for bone loss diseases. | |
| 29279329 | Purine nucleotide metabolism regulates expression of the human immune ligand MICA. | 2018 Mar 16 | Expression of the cell-surface glycoprotein MHC class I polypeptide-related sequence A (MICA) is induced in dangerous, abnormal, or "stressed" cells, including cancer cells, virus-infected cells, and rapidly proliferating cells. MICA is recognized by the activating immune cell receptor natural killer group 2D (NKG2D), providing a mechanism by which immune cells can identify and potentially eliminate pathological cells. Immune recognition through NKG2D is implicated in cancer, atherosclerosis, transplant rejection, and inflammatory diseases, such as rheumatoid arthritis. Despite the wide range of potential therapeutic applications of MICA manipulation, the factors that control MICA expression are unclear. Here we use metabolic interventions and metabolomic analyses to show that the transition from quiescent cellular metabolism to a "Warburg" or biosynthetic metabolic state induces MICA expression. Specifically, we show that glucose transport into the cell and active glycolytic metabolism are necessary to up-regulate MICA expression. Active purine synthesis is necessary to support this effect of glucose, and increases in purine nucleotide levels are sufficient to induce MICA expression. Metabolic induction of MICA expression directly influences NKG2D-dependent cytotoxicity by immune cells. These findings support a model of MICA regulation whereby the purine metabolic activity of individual cells is reflected by cell-surface MICA expression and is the subject of surveillance by NKG2D receptor-expressing immune cells. | |
| 29134648 | Pharmacokinetics, Pharmacodynamics, and Proposed Dosing of the Oral JAK1 and JAK2 Inhibito | 2018 Aug | Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance, respectively. The half-life of baricitinib in patients less than 40 kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area-under-the-concentration-vs.-time curve was 2,388 nM*hr, which is 1.83-fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4 mg once-daily. Dose-dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type-1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight- and estimated glomerular filtration rate-based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies. | |
| 29093269 | B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement. | 2017 Nov 2 | The efficacy of B cell depletion therapies in diseases such as nephrotic syndrome and rheumatoid arthritis suggests a broader role in B cells in human disease than previously recognized. In some of these diseases, such as the minimal change disease subtype of nephrotic syndrome, pathogenic antibodies and immune complexes are not involved. We hypothesized that B cells, activated in the kidney, might produce cytokines capable of directly inducing cell injury and proteinuria. To directly test our hypothesis, we targeted a model antigen to the kidney glomerulus and showed that transfer of antigen-specific B cells could induce glomerular injury and proteinuria. This effect was mediated by IL-4, as transfer of IL-4-deficient B cells did not induce proteinuria. Overexpression of IL-4 in mice was sufficient to induce kidney injury and proteinuria and could be attenuated by JAK kinase inhibitors. Since IL-4 is a specific activator of STAT6, we analyzed kidney biopsies and demonstrated STAT6 activation in up to 1 of 3 of minimal change disease patients, suggesting IL-4 or IL-13 exposure in these patients. These data suggest that the role of B cells in nephrotic syndrome could be mediated by cytokines. | |
| 29046115 | Bone and the Immune System. | 2017 Oct | Osteoporosis increases fracture risk, a cause of crippling morbidity and mortality. The immunoskeletal interface (ISI) is a centralization of cell and cytokine effectors shared between skeletal and immune systems. Consequently, the immune system mediates powerful effects on bone turnover. Physiologically, B cells secrete osteoprotegerin (OPG), a potent anti-osteoclastogenic factor that preserves bone mass. However, activated T cells and B cells secrete pro-osteoclastogenic factors including receptor activator of Nuclear factor-kappaB (NF-kB) ligand (RANKL), Interleukin (IL)-17A, and tumor necrosis factor (TNF)-α promoting bone loss in inflammatory states such as rheumatoid arthritis. Recently, ISI disruption has been linked to osteoporosis in human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS), where elevated B cell RANKL and diminished OPG drive bone resorption. HIV-antiretroviral therapy paradoxically intensifies bone loss during disease reversal, as immune reconstitution produces osteoclastogenic cytokines. Interestingly, in estrogen deficiency, activated T cells secrete RANKL, TNF, and IL-17A that amplify bone resorption and contribute to postmenopausal osteoporosis. T cell-produced TNF and IL-17A further contribute to bone loss in hyperparathyroidism, while T cell production of the anabolic Wingless integration site (Wnt) ligand, Wnt10b, promotes bone formation in response to anabolic parathyroid hormone and the immunomodulatory costimulation inhibitor cytotoxic T lymphocyte-associated protein-4-IgG (abatacept). These findings provide a window into the workings of the ISI and suggest novel targets for future therapeutic interventions to reduce fracture risk. | |
| 29296847 | HSC extrinsic sex-related and intrinsic autoimmune disease-related human B-cell variation | 2017 Oct 24 | B cells play a major role in antigen presentation and antibody production in the development of autoimmune diseases, and some of these diseases disproportionally occur in females. Moreover, immune responses tend to be stronger in female vs male humans and mice. Because it is challenging to distinguish intrinsic from extrinsic influences on human immune responses, we used a personalized immune (PI) humanized mouse model, in which immune systems were generated de novo from adult human hematopoietic stem cells (HSCs) in immunodeficient mice. We assessed the effect of recipient sex and of donor autoimmune diseases (type 1 diabetes [T1D] and rheumatoid arthritis [RA]) on human B-cell development in PI mice. We observed that human B-cell levels were increased in female recipients regardless of the source of human HSCs or the strain of immunodeficient recipient mice. Moreover, mice injected with T1D- or RA-derived HSCs displayed B-cell abnormalities compared with healthy control HSC-derived mice, including altered B-cell levels, increased proportions of mature B cells and reduced CD19 expression. Our study revealed an HSC-extrinsic effect of recipient sex on human B-cell reconstitution. Moreover, the PI humanized mouse model revealed HSC-intrinsic defects in central B-cell tolerance that recapitulated those in patients with autoimmune diseases. These results demonstrate the utility of humanized mouse models as a tool to better understand human immune cell development and regulation. | |
| 29191397 | The inhibitory effect of Aconiti Sinomontani Radix extracts on the proliferation and migra | 2018 Mar 1 | ETHNOPHARMACOLOGICAL RELEVANCE: Aconiti Sinomontani Radix is frequently used in the treatment of Bi syndrome in traditional Chinese medicine. Several reports indicate that Aconiti Sinomontani Radix has therapeutic effects for rheumatoid arthritis (RA). However, the cellular mode of action is still unclear. To investigate the effect of alkaloid extracts of Aconiti Sinomontani Radix on proliferation and migration of human synovial sarcoma SW982 cells as well as the molecular mechanism underlying. MATERIALS AND METHODS: SW982 cells were examined for proliferation by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) method. Wound scratch assays were performed to assess the migrated rate of SW982 cells. Quantitative real-time PCR was used to measure the mRNA expression levels of Wnt5a, Runx2, MMP3, and Bmp2. Western blotting was used to measure the phosphorylated levels of JNK and NF-κB as well as the expression of MMP3. RESULTS: The alkaloid extract from Aconiti Sinomontani Radix (MQA) and MQB, which removed lappaconitine from MQA significantly inhibited the proliferation of SW982 in a dose-dependent manner. The proliferation inhibitory effect of MQB was more potent. Incubation with 10μg/ml MQB for 12, 24, and 36h inhibited the migration of SW982 cells by 83%, 58%, and 42%, respectively. Treatment with different concentrations of MQB for 24h inhibited mRNA expression of Wnt5a, Runx2, and MMP3, but Bmp2 mRNA expression was elevated by MQB. Further, MQB inhibited phosphorylation of JNK and NF-κB p65 as well as MMP3 expression by Western blotting analysis. CONCLUSION: The results showed that MQB inhibited proliferation and migration of SW982 cells possibly through suppressing Wnt5a-mediated JNK and NF-κB pathways. These results indicated that MQB might be an active extract of Aconiti Sinomontani Radix for targeting fibroblast-like synoviocytes (FLS) and be potential for RA therapy. |