Objective
Increased protein phosphatase magnesium‐dependent 1A (PPM1A) levels in patients with ankylosing spondylitis regulate osteoblast differentiation in bony ankylosis; however, the potential ...mechanisms that regulate osteoclast differentiation in relation to abnormal bone formation remain unclear. This study was undertaken to investigate the relationship of PPM1A to osteoclast differentiation by generating conditional gene‐knockout (PPM1Afl/fl;LysM‐Cre) mice and evaluating their bone phenotype.
Methods
The bone phenotypes of LysM‐Cre mice (n = 6) and PPM1Afl/fl;LysM‐Cre mice (n = 6) were assessed by micro–computed tomography. Osteoclast differentiation was induced by culturing bone marrow–derived macrophages in the presence of RANKL and macrophage colony‐stimulating factor (M‐CSF), and was evaluated by counting tartrate‐resistant acid phosphatase–positive multinucleated cells. Levels of messenger RNA for PPM1A, RANK, and osteoclast‐specific genes were examined by real‐time quantitative polymerase chain reaction, and protein levels were determined by Western blotting. Surface RANK expression was analyzed by fluorescence flow cytometry.
Results
The PPM1Afl/fl;LysM‐Cre mice displayed reduced bone mass (P < 0.001) and increased osteoclast differentiation (P < 0.001) and osteoclast‐specific gene expression (P < 0.05) compared with their LysM‐Cre littermates. Mechanistically, reduced PPM1A function in osteoclast precursors in PPM1Afl/fl;LysM‐Cre mice induced osteoclast lineage commitment by up‐regulating RANK expression (P < 0.01) via p38 MAPK activation in response to M‐CSF. PPM1A expression in macrophages was decreased by Toll‐like receptor 4 activation (P < 0.05). The Ankylosing Spondylitis Disease Activity Score was negatively correlated with the expression of PPM1A in peripheral blood mononuclear cells from patients with axial spondyloarthritis (SpA) (γ = −0.7072, P < 0.0001).
Conclusion
The loss of PPM1A function in osteoclast precursors driven by inflammatory signals contributes to osteoclast lineage commitment and differentiation by elevating RANK expression, reflecting a potential role of PPM1A in dynamic bone metabolism in axial SpA.
The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum ...disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.
Inhibitors of the secretion of cancer exosomes, which promote cancer progression and metastasis, may not only accelerate exosome biology research but also offer therapeutic benefits for cancer ...patients. Here we identify sulfisoxazole (SFX) as an inhibitor of small extracellular vesicles (sEV) secretion from breast cancer cells through interference with endothelin receptor A (ETA). SFX, an FDA-approved oral antibiotic, showed significant anti-tumor and anti-metastatic effects in mouse models of breast cancer xenografts, the reduced expression of proteins involved in biogenesis and secretion of sEV, and triggered co-localization of multivesicular endosomes with lysosomes for degradation. We demonstrate the important role of ETA, as target of SFX, by gain- and loss-of-function studies of the ETA protein, through a direct binding assay, and pharmacological and genetic approaches. These findings may provide a foundation for sEV-targeted cancer therapies and the mechanistic studies on sEV biology.
Extrafollicular responses in humans and SLE Jenks, Scott A.; Cashman, Kevin S.; Woodruff, Matthew C. ...
Immunological reviews,
March 2019, 2019-03-00, 20190301, Volume:
288, Issue:
1
Journal Article
Peer reviewed
Open access
Summary
Chronic autoimmune diseases, and in particular Systemic Lupus Erythematosus (SLE), are endowed with a long‐standing autoreactive B‐cell compartment that is presumed to reactivate periodically ...leading to the generation of new bursts of pathogenic antibody‐secreting cells (ASC). Moreover, pathogenic autoantibodies are typically characterized by a high load of somatic hypermutation and in some cases are highly stable even in the context of prolonged B‐cell depletion. Long‐lived, highly mutated antibodies are typically generated through T‐cell–dependent germinal center (GC) reactions. Accordingly, an important role for GC reactions in the generation of pathogenic autoreactivity has been postulated in SLE. Nevertheless, pathogenic autoantibodies and autoimmune disease can be generated through B‐cell extrafollicular (EF) reactions in multiple mouse models and human SLE flares are characterized by the expansion of naive‐derived activated effector B cells of extrafollicular phenotype. In this review, we will discuss the properties of the EF B‐cell pathway, its relationship to other effector B‐cell populations, its role in autoimmune diseases, and its contribution to human SLE. Furthermore, we discuss the relationship of EF B cells with Age‐Associated B cells (ABCs), a TLR‐7‐driven B‐cell population that mediates murine autoimmune and antiviral responses.
The internet is now a major source of health information. With the growth of internet users, eHealth literacy has emerged as a new concept for digital health care. Therefore, health professionals ...need to consider the eHealth literacy of consumers when providing care utilizing digital health technologies.
This study aimed to identify currently available eHealth literacy instruments and evaluate their measurement properties to provide robust evidence to researchers and clinicians who are selecting an eHealth literacy instrument.
We conducted a systematic review and meta-analysis of self-reported eHealth literacy instruments by applying the updated COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) methodology.
This study included 7 instruments from 41 articles describing 57 psychometric studies, as identified in 4 databases (PubMed, CINAHL, Embase, and PsycInfo). No eHealth literacy instrument provided evidence for all measurement properties. The eHealth literacy scale (eHEALS) was originally developed with a single-factor structure under the definition of eHealth literacy before the rise of social media and the mobile web. That instrument was evaluated in 18 different languages and 26 countries, involving diverse populations. However, various other factor structures were exhibited: 7 types of two-factor structures, 3 types of three-factor structures, and 1 bifactor structure. The transactional eHealth literacy instrument (TeHLI) was developed to reflect the broader concept of eHealth literacy and was demonstrated to have a sufficient low-quality and very low-quality evidence for content validity (relevance, comprehensiveness, and comprehensibility) and sufficient high-quality evidence for structural validity and internal consistency; however, that instrument has rarely been evaluated.
The eHealth literacy scale was the most frequently investigated instrument. However, it is strongly recommended that the instrument's content be updated to reflect recent advancements in digital health technologies. In addition, the transactional eHealth literacy instrument needs improvements in content validity and further psychometric studies to increase the credibility of its synthesized evidence.
Purpose
The Depression Anxiety Stress Scales (DASS)-21 measures emotional symptoms of depression, anxiety, and stress, is relatively short, and is freely available in the public domain, which has ...resulted in it being applied to various clinical and non-clinical populations in many countries. The aim of this study was to systematically review the measurement properties of the DASS-21.
Methods
The MEDLINE, Embase, and CINAHL databases were searched. The methodological quality of each identified study was assessed using the updated COSMIN Risk of Bias checklist. The quality of the measurement properties of the studies was rated using the updated criteria for good measurement properties. The quality of evidence was rated using a modified version of the GRADE approach.
Results
This study included 48 studies in its review. The content validity of the DASS-21 demonstrated sufficient moderate-quality evidence. The instrument exhibited sufficient high-quality evidence for bifactor structural validity and internal consistency. The instrument also showed sufficient high-quality evidence for hypothesis testing of construct validity. Regarding criterion validity, only the DASS-21 Depression subscale demonstrated sufficient high-quality evidence. The measurement invariance across gender demonstrated inconsistent moderate-quality evidence. There was insufficient low-quality evidence for the reliability of each subscale. For responsiveness there was sufficient low-quality evidence for depression and stress subscales, and insufficient very-low-quality evidence for anxiety subscale.
Conclusions
The DASS-21 demonstrated sufficient high-quality evidence for bifactor structural validity, internal consistency (bifactor), criterion validity (Depression subscale), and hypothesis testing for construct validity. Further studies are required to assess the other measurement properties of the DASS-21.
(Radish) belongs to the Brassicaceae family and is a widely consumed root vegetable all around the world. The nutritional and medicinal values of radishes have been proven by several researches. ...Extracts prepared from the aerial and underground parts of radishes have been used in the treatment of stomach disorders, urinary infections, hepatic inflammation, cardiac disorders and ulcers in folk medicine since the ancient times. The pharmaceutical potential of radishes is attributed to the presence of its beneficial secondary metabolites, such as glucosinolates, polyphenols and isothiocyanates. The present review has focused on the impact of radish extract administration under pathological complications, such as cancer, diabetes, hepatic inflammation and oxidative stress. In addition, a comprehensive view of molecular mechanism behind the regulation of molecular drug targets associated with different types of cancers and diabetes by the bioactive compounds present in the radish extracts have been discussed in detail.
Watermelon (
) is an important horticultural crop which belongs to the Curcubitaceae family. The nutraceutical potential of watermelon has been illustrated by several researchers, which makes it a ...better choice of functional food. Watermelon has been used to treat various ailments, such as cardio-vascular diseases, aging related ailments, obesity, diabetes, ulcers, and various types of cancers. The medicinal properties of watermelon are attributed by the presence of important phytochemicals with pharmaceutical values such as lycopene, citrulline, and other polyphenolic compounds. Watermelon acts as vital source of l-citrulline, a neutral-alpha amino acid which is the precursor of l-arginine, an essential amino acid necessary for protein synthesis. Supplementation of l-citrulline and lycopene displayed numerous health benefits in in vitro and in vivo studies. Similarly, the dietary intake of watermelon has proven benefits as functional food in humans for weight management. Apart from the fruits, the extracts prepared from the seeds, sprouts, and leaves also evidenced medicinal properties. The present review provides a comprehensive overview of benefits of watermelon for the treatment of various ailments.
PDF
