Journal of cellular physiology
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It is increasingly recognized that immunomodulation represents an important mechanism underlying the benefits of many stem cell therapies, rather than the classical paradigm of transdifferentiation and cell replacement. In the former paradigm, the beneficial effects of cell therapy result from paracrine mechanism(s) and/or cell-cell interaction as opposed to direct engraftment and repair of diseased tissue and/or dysfunctional organs. Depending on the cell type used, components of the secretome, including microRNA (miRNA) and extracellular vesicles, may be able to either activate or suppress the immune system even without direct immune cell contact. ⋯ Specifically, MSCs appear to be able to effectively attenuate acute and protracted inflammation via interactions with components of both innate and adaptive immune systems. To date, this capacity has been exploited in a large number of preclinical studies and MSC immunomodulatory therapy has been attempted with various degrees of success in a relatively large number of clinical trials. Here, we will explore the various mechanism employed by MSCs to effect immunosuppression as well as review the current status of its use to treat excessive inflammation in the context of acute lung injury (ALI) and sepsis in both preclinical and clinical settings.
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Recent technological advances allow for high throughput profiling of biological systems in a cost-efficient manner. The low cost of data generation is leading us to the "big data" era. ⋯ We note packages for the R programming language that are available to perform machine learning analyses. In addition to programming based solutions, we review webservers that allow users with limited or no programming background to perform these analyses on large data compendia.
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Proteasome modulator 9 (PSMD9) gene single nucleotide polymorphism (SNP) rs1043307/rs2514259 (E197G) is associated with significant clinical response to the anti-depressant desipramine. PSMD9 SNP rs74421874 [intervening sequence (IVS) 3 + nt460 G>A], rs3825172 (IVS3 + nt437 C>T) and rs1043307/rs2514259 (E197G A>G) are all linked to type 2 diabetes (T2D), maturity-onset-diabetes-of the young 3 (MODY3), obesity and waist circumference, hypertension, hypercholesterolemia, T2D-macrovascular and T2D-microvascular disease, T2D-neuropathy, T2D-carpal tunnel syndrome, T2D-nephropathy, T2D-retinopathy, non-diabetic retinopathy and depression. PSMD9 rs149556654 rare SNP (N166S A>G) and the variant S143G A>G also contribute to T2D. ⋯ One-thousand simulation tests were performed to exclude results due to random chance. In our study, the PSMD9 gene SNPs rs74421874, rs3825172, and rs1043307/rs2514259 result in linkage to generalized anxiety disorder. This is the first report describing PSMD9 gene SNPs in linkage to generalized anxiety disorder in T2D families.
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The phosphorylation of c-jun N-terminal kinase (JNK) and the subsequent production of C-C chemokine CCL2 (monocyte chemoattractant protein; MCP-1) in spinal astrocytes contribute to the initiation of neurological disorders including chronic pain. Astrocytes express neurotransmitter receptors which could be targeted to ameliorate neurological disorders. In the current study, the involvement of the β-adrenergic system in the regulation of JNK activity and CCL2 production after stimulation with tumor necrosis factor (TNF)-α, one of many initiators of neuroinflammation, was elucidated. ⋯ The TNF-α-induced JNK1 phosphorylation was significantly blocked by treatment with GSK-3β inhibitors (either LiCl or TWS119), and stimulation of β-adrenergic receptors induced the inhibition of GSK-3β through the phosphorylation of Ser(9). Moreover, treatment with isoproterenol markedly suppressed the TNF-α-induced increase of CCL2 mRNA expression and CCL2 production through a β-adrenergic receptor-PKA pathway mediated by GSK-3β regulation. Thus, activation of β1/2 adrenergic receptors expressed in spinal astrocytes could be a novel method of moderating neurological disorders with endogenous catecholamines or selective agonists.