- LABA/LAMA Fixed Dose Combination in Chronic Obstructive Pulmonary Disease: The Impact on Health-Related Quality of Life. [Review]
- RRespiration 2018 Sep 18; :1-12
- CONCLUSIONS: LABA/LAMA FDCs may be helpful in improving HRQoL, but because of the heterogeneity of performed trials, strong conclusions cannot be drawn. Moreover, due to the different molecule properties, treatment schedule, and device characteristics of each FDC, a generalized judgment seems inappropriate. Pragmatic trials powered to detect real-life differences in HRQoL and head-to-head comparison are needed to guide clinical practice in terms of PROs.
- ALK3 undergoes ligand-independent homodimerization and BMP-induced heterodimerization with ALK2. [Journal Article]
- FRFree Radic Biol Med 2018 Sep 15
- The bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 are essential for expression of hepcidin, a key iron regulatory hormone. In mice, hepatocyte-specific Alk2 deficiency leads to mode...
The bone morphogenetic protein (BMP) type I receptors ALK2 and ALK3 are essential for expression of hepcidin, a key iron regulatory hormone. In mice, hepatocyte-specific Alk2 deficiency leads to moderate iron overload with periportal liver iron accumulation, while hepatocyte-specific Alk3 deficiency leads to severe iron overload with centrilobular liver iron accumulation and a more marked reduction of basal hepcidin levels. The objective of this study was to investigate whether the two receptors have additive roles in hepcidin regulation. Iron overload in mice with hepatocyte-specific Alk2 and Alk3 (Alk2/3) deficiency was characterized and compared to hepatocyte-specific Alk3 deficient mice. Co-immunoprecipitation studies were performed to detect the formation of ALK2 and ALK3 homodimer and heterodimer complexes in vitro in the presence and absence of ligands. The iron overload phenotype of hepatocyte-specific Alk2/3-deficient mice was more severe than that of hepatocyte-specific Alk3-deficient mice. In vitro co-immunoprecipitation studies in Huh7 cells showed that ALK3 can homodimerize in absence of BMP2 or BMP6. In contrast, ALK2 did not homodimerize in either the presence or absence of BMP ligands. However, ALK2 did form heterodimers with ALK3 in the presence of BMP2 or BMP6. ALK3-ALK3 and ALK2-ALK3 receptor complexes induced hepcidin expression in Huh7 cells. Our data indicate that: (I) ALK2 and ALK3 have additive functions in vivo, as Alk2/3 deficiency leads to a greater degree of iron overload than Alk3 deficiency; (II) ALK3, but not ALK2, undergoes ligand-independent homodimerization; (III) the formation of ALK2-ALK3 heterodimers is ligand-dependent and (IV) both receptor complexes functionally induce hepcidin expression in vitro.
- Increase of histone acetylation in the GABAergic neurons in the rostral ventromedial medulla associated with mechanical hypersensitivity after repeated restraint stress. [Journal Article]
- BRBrain Res Bull 2018 Sep 15
- Psychophysical stresses frequently increase sensitivity and response to pain, which is termed stress-induced hyperalgesia (SIH). However, the mechanism remains unknown. The rostral ventromedial medul...
Psychophysical stresses frequently increase sensitivity and response to pain, which is termed stress-induced hyperalgesia (SIH). However, the mechanism remains unknown. The rostral ventromedial medulla (RVM) and locus coeruleus (LC) are core elements of the descending pain modulatory system, which modulate nociceptive transmission in the spinal dorsal horn. In the present study we examined the acetylation of histone H3 in the RVM and LC after repeated restraint stress for 3 weeks to clarify changes in the descending pain modulatory system in the rat with SIH. The repeated restraint stress induced mechanical hypersensitivity in the hindpaw and an increase in acetylation of histone H3 in the RVM but not the LC. The number of acetylated histone H3-IR cells in the RVM was significantly higher in the repeated restraint group (282.9±43.1) than that in the control group (134.7±15.6, p < 0.05). Furthermore, the repeated restraint stress increased acetylation of histone H3 in the RVM GABAergic neurons but not the RVM serotonergic neurons. The GAD67 protein level in the RVM was significantly higher in repeated restraint group (144.9±17.0%) than that in the control group (100.0±8.9%, p< 0.05). These findings suggest the possibility that the stress-induced neuroplasticity in the RVM GABAergic neurons is involved in the mechanical hypersensitivity due to the dysfunction of the descending pain modulatory system.
- Bcl2L12 plays a critical role in the development of airway allergy via inducing aberrant T helper-2 polarization. [Journal Article]
- JAJ Allergy Clin Immunol 2018 Sep 15
- Bcl2L12 plays an important role in the pathogenesis of allergic asthma by promoting the differentiation of Th2 cells, which may be a novel therapeutic target in the treatment of allergic asthma.
Bcl2L12 plays an important role in the pathogenesis of allergic asthma by promoting the differentiation of Th2 cells, which may be a novel therapeutic target in the treatment of allergic asthma.
- CLEC16A regulates splenocyte and NK cell function in part through MEK signaling. [Journal Article]
- PlosPLoS One 2018; 13(9):e0203952
- CLEC16A is implicated in multiple autoimmune diseases. We generated Clec16a inducible knockout (KO) mice to examine the functional link between CLEC16A auto-inflammation and autoimmunity. Clec16a KO ...
CLEC16A is implicated in multiple autoimmune diseases. We generated Clec16a inducible knockout (KO) mice to examine the functional link between CLEC16A auto-inflammation and autoimmunity. Clec16a KO mice exhibited weight loss and thymic and splenic atrophy. Mitochondrial potential was lowered in KO mice splenocytes resulting in aggregation of unhealthy mitochondria in B, T, and NK cells. In Clec16a KO mice we detected disrupted mitophagy in splenic B and T cells. NK cells from Clec16a KO mice exhibited increased cytotoxicity. Incomplete mitophagy was attenuated with PI3K and/or MEK inhibition in Clec16a KO mice. Our results demonstrate a functional link between CLEC16A and disrupted mitophagy in immune cells and show that incomplete mitophagy predisposes the KO mice to inflammation. Taken together, loss of function variants in CLEC16A that are associated with decreased CLEC16A expression levels may contribute to inflammation in autoimmunity through disrupted mitophagy. Drugs modulating mitophagy reverse the process and may be effective in treating and preventing autoimmunity in individuals with risk associated CLEC16A variants.
- Substrate accumulation and extracellular matrix remodelling promote persistent upper airway disease in mucopolysaccharidosis patients on enzyme replacement therapy. [Journal Article]
- PlosPLoS One 2018; 13(9):e0203216
- CONCLUSIONS: This study suggests a role for ECM remodelling contributing to the obstructive phenotype of airway disease in MPS. Current therapeutic strategies with ERT fail to normalise these pathological alterations within adenotonsillar samples. Our findings lend novel insight into the pathological cascade of events, with primarily structural rather than inflammatory changes contributing to the continuing phenotype seen in patients despite current therapeutic regimes.
- Oxidative/nitrative stress in the pathogenesis of systemic sclerosis: are antioxidants beneficial? [Journal Article]
- FRFree Radic Res 2018 Sep 18; :1-491
- Systemic sclerosis (SSc) is a multisystem autoimmune disease: characterized from the clinical side by progressive vasculopathy and fibrosis of the skin and different organs and from the biochemical s...
Systemic sclerosis (SSc) is a multisystem autoimmune disease: characterized from the clinical side by progressive vasculopathy and fibrosis of the skin and different organs and from the biochemical side by fibroblast deregulation with excessive production of collagen and increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). The latter contributes to an overproduction of reactive oxygen species that via an autocrine loop maintains NOX4 in a state of activation. Reactive oxygen and nitrogen species are implicated in the origin and perpetuation of several clinical manifestations of SSc having vascular damage in common; attempts to dampen oxidative and nitrative stress via different agents with antioxidant properties have not translated into sustained clinical benefit. Objective of this narrative review is to describe the origin and clinical implications of oxidative and nitrative stress in SSc, with particular focus on the central role of NOX4 and its interactions, to re-evaluate the antioxidant approaches so far employed to limit disease progression, to appraise the complexity of antioxidant treatment and to touch on novel pathways elements of which may represent specific treatment targets in the not so distant future.
- [Focus on pediatric rheumatic and immune diseases]. [Journal Article]
- ZDZhejiang Da Xue Xue Bao Yi Xue Ban 2018 May 25; 47(2):213-217
- Associations of Maternal Diabetes During Pregnancy with Overweight in Offspring: Results from the Prospective TEDDY Study. [Journal Article]
- OObesity (Silver Spring) 2018; 26(9):1457-1466
- CONCLUSIONS: Maternal diabetes is associated with increased risk of offspring overweight, and the association appears to get stronger as children grow older. Indeed, intrauterine exposure to maternal T1DM may predispose children to later obesity through increased birth weight, while maternal BMI is more important in children exposed to GDM.
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- Role of corneal nerves in ocular surface homeostasis and disease. [Review]
- AOActa Ophthalmol 2018 Sep 17
- Corneal nerves are key components of the physiological system that controls ocular surface homeostasis. The cornea is primarily innervated by the ophthalmic branch of the trigeminal nerves (cranial n...
Corneal nerves are key components of the physiological system that controls ocular surface homeostasis. The cornea is primarily innervated by the ophthalmic branch of the trigeminal nerves (cranial nerve V), which distend bilaterally from the pons. The nasociliary branch (afferent) of the ophthalmic nerve is sensory for cornea, eyelid and conjunctiva. These nerve fibres play a role in sensing temperature, chemical and mechanical stimuli, and pain, whereas, branches of the facial nerve (cranial nerve VII) contain motor nerves that control blinking and autonomic (sympathetic and a paucity of parasympathetic) fibres that stimulate tear production and secretion via feedback loops between the ocular surface, lacrimal glands and brain. Disruption of these nerves with interruption of neural feedback loops between the ocular surface and lacrimal glands can lead to corneal diseases such as dry eye disease (DED) and neurotrophic keratopathy (NK). Inversely, hypersensitivity of the nerve fibres and/or dysregulation of pain-controlling nervous centres may lead to neuropathic pain. Recently, medications that specifically target regeneration of corneal nerves have started to become available - and considering the high prevalence of diseases associated with corneal nerve dysfunction, these agents promise to fulfil a hitherto important unmet need. In this review, we explore the physiology of corneal nerves, the pathology of corneal nerve diseases and how these relate to neuropathic pain, NK and DED. We also discuss what novel treatments may be useful against diseases involving corneal nerves.