Non-alcoholic fatty liver disease (NAFLD) is characterized by triglyceride (TG) accumulation and ER stress. Since fatty acids (FAs) may trigger ER stress, we hypothesized that absence of adipose triglyceride lipase (ATGL/PNPLA2) - the main enzyme for intracellular lipolysis, releasing FAs and closest homologue to adiponutrin (PNPLA3) recently implicated in the ...

Estradiol affects hippocampal-dependent spatial memory and underlying structural and electrical synaptic plasticity in female mice and rats. Using estrogen receptor (ER) alpha and beta knockout mice and wild-type littermates, we investigated the role of ERs in estradiol effects on multiple pathways important for hippocampal plasticity and learning. Six hours of ...

Endoplasmic Reticulum (ER) stress and inflammation are important mechanisms that underlie many of the serious consequences of type II diabetes. However, the role of ER stress and inflammation in impaired ischemia-induced neovascularisation in type II diabetes is unknown. We studied ischemia-induced neovascularization in the hind-limb of 4 weeks old db-/db- ...

AIMS/HYPOTHESIS: The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the susceptibility of autophagy-deficient beta cells to the ER stress that is implicated in the development of diabetes. METHODS: Rat ...

We previously demonstrated that baseline synovial overexpression of the interleukin-7 receptor α-chain (IL-7R) is associated with poor response to tumour necrosis factor (TNF) blockade in rheumatoid arthritis (RA). We found that IL-7R gene expression is induced in fibroblast-like synovial cells (FLS) by the addition of TNF-α, IL-1β and combinations of ...

ABSTRACT: BACKGROUND: Successful reproductive efforts require the establishment of a situation favorable for reproduction that requires integration of both behavior and internal physiological events. TR4 nuclear receptor is known to be involved in male fertility via controlling spermatogenesis, yet its roles in regulating other biological events related to reproduction have ...

BACKGROUND: We previously demonstrated that vascular smooth muscle cells (VSMC) proliferation and development of neointimal hyperplasia as well as the ability of nitric oxide (NO) to inhibit these processes is dependent on sex and hormone status. The aim of this study was to evaluate the role of estrogen receptor (ER) ...

MRL/MpJ (MRL) mice, commonly used as a model for autoimmune disease, have a high frequency of ovarian cysts originating from the rete ovarii. In the present study, to clarify how the rete ovarii, which are remnants of mesonephric tubules during embryogenesis, progress to cystic formation with aging, the morphology of ...

The estrogen receptor (ER) is a ligand-dependent transcription factor containing two transcriptional activation domains. AF-1 is in the N terminus of the receptor protein and AF-2 activity is dependent on helix 12 of the C-terminal ligand-binding domain. Two point mutations of leucines 543 and 544 to alanines (L543A, L544A) in ...

Mutations in myocilin (MYOC) are the most common genetic cause of primary open angle glaucoma (POAG), but the mechanisms underlying MYOC-associated glaucoma are not fully understood. Here, we report the development of a transgenic mouse model of POAG caused by the Y437H MYOC mutation; the mice are referred to herein ...

Pyrimidine nucleotides are signaling molecules, which activate G protein-coupled membrane receptors of the P2Y family. P2Y(2) and P2Y(4) receptors are part of the P2Y family, which is composed of 8 subtypes that have been cloned and functionally defined. We have previously found that uridine-5'-triphosphate (UTP) reduces infarct size and improves ...

NADH-cytochrome b5 oxidoreductase (Ncb5or) is an endoplasmic reticulum (ER)-associated redox enzyme involved in fatty acid metabolism, and phenotypic abnormalities of Ncb5or(-/-) mice include diabetes and lipoatrophy. These mice are lean and insulin-sensitive but become hyperglycemic at age 7 weeks as a result of β-cell dysfunction and loss. Here we examine ...

OBJECTIVES: To determine the effects of glucosamine-supplementation on endoplasmic reticulum (ER) stress levels and atherogenesis, and to investigate the potential role of glucosamine in hyperglycemia-associated accelerated atherosclerosis. METHODS: Five week old apolipoprotein E-deficient (apoE-/-) mice were provided with normal drinking water or water supplemented with 5% glucosamine (w/v) or 5% ...

The type 1-transmembrane protein LMAN1 (ERGIC-53) forms a complex with the soluble protein MCFD2 and cycles between the endoplasmic reticulum (ER) and the ER-Golgi intermediate compartment (ERGIC). Mutations in either LMAN1 or MCFD2 cause the combined deficiency of factor V (FV) and factor VIII (FVIII; F5F8D), suggesting an ER-to-Golgi cargo ...

Parkinson's disease (PD) is an age-related neurodegenerative disorder with a higher incidence in the male population. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, 17β-oestradiol but not androgens were shown to protect dopamine (DA) neurones. We report that oestrogen receptors alpha and beta (ERα and ERβ) distinctly contribute to neuroprotection ...

Considering its long latency, prostate cancer (PCa) represents an ideal target for chemoprevention strategies. Green tea extract (GTE) has been proved to be one of the most promising natural substances capable of inhibiting PCa progression in animal models (transgenic adenocarcinoma of mouse prostate), as well as in humans. However, the ...

The pro-inflammatory cytokine TNF-α and the female hormone estrogen have been implicated in the pathophysiology of two common gynecological diseases, endometriosis and endometrial adenocarcinoma. Here we describe a novel capacity of TNF-α to activate ER signaling in endometrial epithelial cells. TNF-α induced luciferase expression in the absence and presence of ...

The 15 kDa selenoprotein (Sep15) is a thioredoxin-like, endoplasmic reticulum (ER)-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose:glycoprotein glucosyltransferase (UGT). Expression of Sep15 is regulated by dietary selenium and the unfolded protein response, but its specific function is not known. In the current ...

Hyperglycemia-linked oxidative stress and/or consequent endoplasmic reticulum (ER) stress are the causative factors of pathogenesis of diabetic retinopathy. Dietary bioactive components which mitigate oxidative stress may serve as potential chemopreventive agents to prevent or slow down the disease progression. Wolfberry is a traditional Asian fruit consumed for years to prevent ...

Estrogen replacement therapy can decrease the risk of developing Alzheimer's disease. Phytoestrogens have been proposed as potential alternatives to estrogen replacement therapy. The purpose of this study was to evaluate the in vitro protective effects of coumestrol on mice astrocytes. Different concentrations of coumestrol were tested for their protective efficacy ...

The basic amino acid-specific proprotein convertase 5/6 (PC5/6) is an essential secretory protease, as knock-out mice die at birth and exhibit multiple homeotic transformation defects, including impaired bone morphogenesis and lung structure. Some of the observed defects were attributed to impaired processing of the TGFβ-like growth differentiating factor 11 precursor ...

Fatty acyl-coenzyme A oxidase 1 (ACOX1) knockout (ACOX1(-/-)) mice manifest hepatic metabolic derangements that lead to the development of steatohepatitis, hepatocellular regeneration, spontaneous peroxisome proliferation, and hepatocellular carcinomas. Deficiency of ACOX1 results in unmetabolized substrates of this enzyme that function as biological ligands for peroxisome proliferator-activated receptor-α (PPARα) in liver. ...

MicroRNA, a class of noncoding RNA, play a role in human diseases. MicroRNA-146a (miR-146a) is a negative regulator of immune and inflammatory responses, and is strongly expressed in rheumatoid arthritis (RA) synovium and peripheral blood mononuclear cells (PBMCs). This study was undertaken to examine whether miR-146a expression inhibits osteoclastogenesis, and ...

Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C). However, the precise molecular pathogenesis of caveolin-3-related muscular dystrophy remains uncertain. Here, we demonstrate the effect of gene dosage on the severity of the myopathic phenotype in P104L mutant caveolin-3 (mCav3(P104L)) transgenic mice, a model of LGMD1C. ...

17β-estradiol is well known to have neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We investigated the neuroprotective contribution of estrogen receptors (ERα and ERβ) against MPTP toxicity by examining the membrane DA transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and tyrosine hydroxylase (TH) in ER knock ...

Renin-angiotensin system (RAS) activation is associated with arrhythmias. We investigated the effects of RAS inhibition in cardiac-specific angiotensin-converting enzyme (ACE) overexpression (ACE 8/8) mice, which exhibit proclivity to ventricular tachycardia (VT) and sudden death because of reduced connexin43 (Cx43). ACE 8/8 mice were treated with an ACE inhibitor (captopril) or ...

OBJECTIVE: Synovial fibroblasts (SF) hyperplasia can contribute to the pathogenesis of rheumatoid arthritis (RA) but quantitative information on this process is scarce. The aims of this study were to evaluate the fibroblast specific marker hsp47 as a quantitative marker for SF and analysing its clinicopathological correlates and evolution after anti-TNF-α ...

In this study, we investigated the mechanisms underlying the anti-inflammatory effects of honokiol in tumor necrosis factor (TNF)-α-stimulated rheumatoid arthritis synovial fibroblasts (RASFs). RASFs pre-treated with honokiol (0-20 μM) were stimulated with TNF-α (20 ng/ml). The levels of prostaglandin E2 (PGE2), nitric oxide (NO), soluble intercellular adhesion molecule-1 (sICAM-1), transforming ...

To develop a simplified and relatively inexpensive version of cartilage proteoglycan-induced arthritis (PGIA), an autoimmunity model of rheumatoid arthritis (RA), and to evaluate the extent to which this new model replicates the disease parameters of PGIA and RA. Recombinant human G1 domain of human cartilage PG containing "arthritogenic" T cell ...

TGF-β is required for both Foxp3(+) regulatory T cell (Treg) and Th17 commitment. Plasmacytoid DCs (pDC) have been shown to participate to both Treg and Th17 commitment as well. However, few studies have evaluated the direct effect of TGF-β on pDC, and to our knowledge, no study has assessed the ...

Background and purpose: Nuclear factor-κB (NF-κB) has been implicated as a therapeutic target for the treatment of rheumatoid arthritis. We previously synthesized a thiourea analog, SPA0355, which suppresses NF-κB activity. Here we sought to find whether SPA0355 has anti-inflammatory and anti-arthritic effects. Experimental approach: We evaluated the effects of SPA0355 ...

Rheumatoid arthritis (RA) is closely related to the pathogenesis of tumor necrosis factor α in lesions. We investigated the suppressive effects of a Citrus flavanone naringin on inflammatory responses in mice with collagen-induced arthritis (CIA), a mouse model for RA. To investigate potential preventive and therapeutic effects of naringin, mice ...

Retinoic acid (all-trans RA and 9-cis RA) enhances embryo developmental competence and quality through multiple mechanisms affecting the oocyte and preimplantation embryo. Folliculogenesis and oocyte maturation are influenced by tumor necrosis factor-alpha (TNF-α) via inhibition of aromatase activity and estradiol secretion in granulosa cells. Retinoic acid inhibits TNF-α production in ...

OBJECTIVE: Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3(+) regulatory T cells (T(reg)), which in turn exert immunosuppression by increasing TGFβ-1. In the SKG mice, activated DC prime autoreactive ...

Objective: Fibrin deposition is integral to the pathogenesis of collagen-induced arthritis (CIA), an experimental model of rheumatoid arthritis (RA). Membrane-associated fibrinogen-like protein 2 (mFGL2), a novel inducible prothrombinase, generates fibrin by an alternate pathway and has been reported to be involved in the pathogenesis of a number of immune-mediated diseases. ...

Methotrexate (MTX) is the most important drug for treating rheumatoid arthritis (RA). It has been stated that cytokines play an important role in the pathogenesis of RA, and that cytokine levels increase and show 24-h rhythms in RA patients. Previously, we found that arthritis was relieved after the administration of ...

Macrophage migration inhibitory factor (MIF) facilitates multiple aspects of inflammatory arthritis, the pathogenesis of which has been significantly linked to the activity of neutrophils. The effects of MIF on neutrophil recruitment are unknown. This study was undertaken to investigate the contribution of MIF to the regulation of neutrophil chemotactic responses. ...

The tumor necrosis factor alpha (TNFα) inhibitors have been used with good clinical results in the treatment of juvenile idiopathic arthritis (JIA). Anti TNFα therapy is generally well tolerated. Besides the site injection reactions, other various cutaneous manifestations have been encountered as adverse events. Here, we report four young patients ...

In postmenopausal rheumatoid arthritis, both the inflammatory disease and estrogen deficiency contribute to the development of osteoporosis. As hormone replacement therapy is no longer an option, we hypothesized that 2-methoxyestradiol (2me2) could be beneficial, and asked if such therapy was associated with effects on reproductive organs. Mice were ovariectomized and ...

The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed ...

Introduction: Anti-TNF-α drugs have dramatically changed treatment of rheumatoid arthritis (RA) in terms of both clinical control and articular damage prevention. Despite this, they hold some important drawbacks, such as frequent therapeutic failures and high costs. Anti-TNF-α active immunization, with a therapeutic vaccine against TNF-α, is a promising alternative anti-TNF-α ...

OBJECTIVE: To determine the mechanism of action of IL-27 against rheumatoid arthritis (RA). METHODS: Adenovirus containing IL-27 transcript was constructed and was locally delivered into the ankles of collagen-induced arthritis (CIA) mice. Progression of arthritis was accessed in treated versus untreated mice by measuring ankle circumference and through histological analysis. ...

Objective. To perform a modelling study on the cost-effectiveness of three outcome-directed strategies in early RA patients: Strategy 1: starting MTX monotherapy, followed by the addition of LEF, followed by MTX with addition of anti-TNF; Strategy 2: start with MTX and LEF combination followed by MTX with anti-TNF; and Strategy ...

ABSTRACT: BACKGROUND: Alpha-1 antitrypsin (AAT) is a multi-functional protein that has anti-inflammatory and tissue protective properties. We previously reported that human AAT (hAAT) gene therapy prevented autoimmune diabetes in non-obese diabetic (NOD) mice and suppressed arthritis development in combination with doxycycline in mice. In the present study we investigated the ...

CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) are involved in several autoimmune diseases, including rheumatoid arthritis. TNF-α blockers induce therapeutic benefits in rheumatoid arthritis via a variety of mechanisms. We aimed to characterize the impact on Treg of TNF-α overexpression in vivo and of TNF-α inhibiting treatments. We used human TNF-α transgenic ...

Rheumatoid arthritis is associated with the development of autoantibodies to citrullinated self-proteins. Citrullinated synovial proteins, which are generated via the actions of the protein arginine deiminases (PADs), are known to develop in the murine collagen-induced arthritis (CIA) model of inflammatory arthritis. Given these findings, we evaluated whether N-α-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine), ...

ABSTRACT: INTRODUCTION: The long-term treatment of rheumatoid arthritis (RA) most often involves a sequence of different therapies. Response to therapy, disease progression and detailed knowledge of the role of different therapies along treatment pathways are key aspects to help physicians identify the best treatment strategy. Thus, understanding the effectiveness of ...

Targeted inhibition of tumor necrosis factor-α (TNF-α) is an effective therapy in rheumatoid arthritis (RA). In some rare cases, autoimmune phenomena, including drug-induced lupus and vasculitis, is described. However, the immunological mechanisms underlying the development of autoimmunity are unknown. We report 3 patients that developed autoimmune phenomena while in use ...

OBJECTIVE: Micro RNAs (miRNAs) are a new class of regulatory elements. Altered expression of miRNAs has been demonstrated in inflamed joints of patients suffering from rheumatoid arthritis (RA). However, the exact role of miRNAs in the pathogenesis of this disease has not been defined so far. METHODS: Collagen induced arthritis ...

The objective of this study was to investigate the catalytic activity of basic aminopeptidase (APB) and its association with periarticular edema and circulating tumor necrosis factor (TNF)-alpha and type II collagen (CII) antibodies (AACII) in a rat model of rheumatoid arthritis (RA) induced by CII (CIA). Edema does not occur ...