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Ulcerative colitis (UC) is an etiologically refractory inflammatory disease, accompanied by dysfunction of epithelial barrier and intestinal inflammation. PDE4 serves as an intracellular proinflammatory enzyme targeting for degradation of cAMP. Though PDE4 inhibitors have been approved for pulmonary and dermatological diseases, the role of PDE4 inhibition in modulating mucosal immunity remains elusive. This study was designed to explore whether PDE4 inhibition by apremilast exerts protective effects in DSS-...
There has been growing interest in stem cell-derived exosomes for their therapeutic and regenerative benefits given their manufacturing and regulatory advantages over cell-based therapies. As existing fibrosis can significantly impede the viability and efficacy of stem cell/exosome-based strategies for treating chronic diseases, we determined if the anti-fibrotic drug, serelaxin, would further benefit the therapeutic efficacy of human amnion epithelial cell (AEC)-derived exosomes in experimental lung diseas...
The nitric oxide-NO/cGMP pathway represents a major physiological signalling controlling pulmonary arterial (PA) tone and drugs activating this pathway are used to treat pulmonary arterial hypertension. Kv channels expressed in PA smooth muscle cells (PASMC) are key determinants of vascular tone. We aimed to analyse the contribution of Kv1.5 and Kv7 channels in the electrophysiological and vasodilating effects evoked by NO donors and the GC stimulator riociguat in PA.
Diabetic retinopathy, a secondary complication of diabetes mellitus, can lead to irreversible vision loss. Currently, no treatment is approved for early phases of diabetic retinopathy. Modifications of the expression pattern of miRNAs could be involved in the early retinal damage of diabetic subjects. Therefore, we aimed at identification of dysregulated miRNAs-mRNA interactions, that could be considered biomarkers and pharmacological targets for diagnosis and treatment of early diabetic retinopathy.
Sunitinib is a small molecule tyrosine kinase inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear.
PIAS1 is phosphorylated by IKKα at Ser-90 in a PIAS1 E3 ligase activity-dependent manner. Whether PIAS1 is also phosphorylated at other residues, and what potential functional significance such additional phosphorylation events might have, are not known. The transcription factor Elk-1 remains SUMOylated under basal conditions, but the role of Elk-1 SUMOylation in the brain is unknown. Here, we examined the functional significance of PIAS1-mediated Elk-1 SUMOylation in the context of Alzheimer's disease (AD...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease typically more common in males, implicating androgens in progression of both patients and mouse models. Androgen effects are mediated by the androgen receptor (AR) which is highly expressed in spinal motor neurons and skeletal muscles. To clarify the role of AR in ALS, we therefore examined the effect of AR antagonism in the SOD1 mouse model.
Among the three enzymes involved in the transsulfuration pathway only cystathionine β-synthase (CBS) converts L-cysteine into L-serine and H S. L-serine is also involved in the de novo sphingolipid biosynthesis through a condensation with palmitoyl-CoA by the action of serine palmitoyltransferase (SPT). Here we have investigated if L-serine is involved in the vasorelaxant effect.
MaR1 is a specialized pro-resolving lipid mediator with anti-inflammatory and analgesic activities. In this study, we addressed the modulation of peripheral and spinal cord cells by MaR1 in inflammatory pain context.
Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor with multiple targets and effects. It protects neurons in the brain but its protective effects on photoreceptors are unclear. In this study, we evaluated the neuroprotective effect of simvastatin on photoreceptors exposed to stress induced by all-trans-retinal (atRAL).
Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease that originates from the defective function of the CFTR protein, a cAMP-dependent anion channel involved in fluid transport across epithelium. Due to their capability to replace the ion transport independently from the genetic mutation that affects the CFTR, small synthetic transmembrane anion transporters, named anionophores, are candidates as new potential CF therapeutics.
PDE upregulation is associated with several vascular diseases and better understanding of the respective role of each PDE family in controlling subcellular pools of cyclic nucleotides in vascular cells is needed. We investigated the respective role of PDE1, PDE5 and PDE9 in controlling intracellular cAMP and/or cGMP concentrations ([cAMP] , [cGMP] ) in cultured rat aortic smooth muscle cells (RASMCs).
Non-small cell lung cancer (NSCLC) accounts for up to 80-85% of all lung cancers with a disappointing prognosis. Flavonoids exert anti-cancer properties, mostly involving stimulation of ROS production without significant toxicity to normal cells. This study was aimed to delineate the effect of diosmetin, a natural flavonoid, on NSCLC cells and the ability to enhance the anti-tumour activity of paclitaxel.
Although protein phosphatases regulate several aspects of cellular function, their expression pattern and modulation under hypoxia remains poorly understood. We investigated the expression of key components of the protein phosphatase system in human cardiovascular cells under normoxic/hypoxic conditions and the mechanism by which hypoxia alters PP2A activity.
Necroptosis is a form of programmed, caspase-independent cell death that is mediated by receptor-interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase domain-like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious and degenerative diseases. Thus, identification of small molecule inhibitors for necroptosis has broad therapeutic relevance. Herein, we identified that TAK-632 was an inhibitor of necroptosis and further generated a more selective, high...
Hydrogen sulfide (H S)-releasing agents are viewed as potential antihypertensive drugs. Recently, natural isothiocyanates emerged as original H S-donor agents. Among them, Erucin, present in some edible Cruciferous plants, shows suitable H S-releasing properties and features of "druggability". The aim of this work was to investigate the Erucin-mediated release of H S inside vascular cells, its vasorelaxing effects and activity on blood pressure of normo- and hypertensive animals.
Vicagrel is a novel promising antiplatelet drug designed for overcoming clopidogrel resistance. Limited evidence indicated that exogenous interleukin (IL)-10 suppresses CYP3A4 activity in healthy subjects, and that IL-10 knock-out (KO) mice exhibit increased clopidogrel bioactivation compared with wild-type (WT) mice. In this study, we sought to determine whether IL-10 could play an important role in the metabolism of and platelet response to vicagrel in mice.
Angiotensin II (AngII) and nitric oxide (NO) regulate cerebral circulation. AngII AT receptors exert ligand-dependent and -independent (myogenic tone, MT) vasoconstriction of cerebral vessels. NO induces post-translational modifications of proteins such as S-nitrosation (redox modification of cysteine residues). In cultured cells, S-nitrosation decreases AngII affinity for AT . The present work evaluated the functional consequences of S-nitrosation on both AngII-dependent and AngII-independent cerebrovascul...
Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that presents with cognitive decline. The current understanding of underlying disease mechanisms remains incomplete. Genetically modified mouse models have been instrumental in deciphering pathomechanisms in AD. While these models were typically generated by classical transgenesis and genome editing, the use of adeno-associated viruses (AAVs) to model and investigate AD in mice, as well as to develop novel gene-therapy approaches are...
Inflammasome mediated pyroptosis is an important neuronal cell death mechanism. Previous studies reported that melanocortin-4 receptor (MC4R) activation exerted neuroprotection in several neurological diseases. The purpose of this study was to investigate the role of MC4R activation with RO27-3225 in suppressing neuronal pyroptosis after experimental intracerebral hemorrhage (ICH) and the underlying mechanism.
Acetylcholine exerts its actions via nicotinic (nAChR) and muscarinic receptors. In the peripheral nervous system, ionotropic nAChR mediate responses in excitable cells. However, recent studies demonstrate the expression of nAChR in the colonic epithelium, which are coupled to an induction of Cl secretion via activation of the Na -K -pump.
Since little is known about the effect of caffeine, one of the most widely consumed substances worldwide, on intestinal function; we aimed to study its action on intestinal anion secretion and the underlying molecular mechanisms.
As an osteoclast differentiation factor, receptor activator of nuclear factor-κB ligand (RANKL) is produced by various immune cells and is suspected in the pathogenesis of osteoporosis and inflammation. Although RANKL isbroadly expressed in most immune cells and tissues, it is not clear how this might affect allergic inflammation.
A new class of heat shock protein co-inducer dihydropyridine derivatives devoid of calcium channel antagonist and vasodilator effects have been recently developed with the purpose to target neurodegeneration selectively. Here we set out to evaluate the action of one of these novel compounds LA1011 on neurovascular coupling in the ischemic rat cerebral cortex. As a reference, we applied nimodipine, a well-known calcium channel antagonist, vasodilator dihydropyridine compound.
Imaging studies have shown that people with schizophrenia exhibit abnormal connectivity termed "dysconnectivity" in several white matter tracts, including the cingulum bundle (CB), corpus callosum (CC), and arcuate fasciculus (AF). This study aimed to elucidate potential contributors to schizophrenia "dysconnectivity."