- Activation of retinal glial (Müller) cells by extracellular ATP induces pronounced increases in extracellular H+ flux. [Journal Article]
- PlosPLoS One 2018; 13(2):e0190893
- Small alterations in extracellular acidity are potentially important modulators of neuronal signaling within the vertebrate retina. Here we report a novel extracellular acidification mechanism mediat...
Small alterations in extracellular acidity are potentially important modulators of neuronal signaling within the vertebrate retina. Here we report a novel extracellular acidification mechanism mediated by glial cells in the retina. Using self-referencing H+-selective microelectrodes to measure extracellular H+ fluxes, we show that activation of retinal Müller (glial) cells of the tiger salamander by micromolar concentrations of extracellular ATP induces a pronounced extracellular H+ flux independent of bicarbonate transport. ADP, UTP and the non-hydrolyzable analog ATPγs at micromolar concentrations were also potent stimulators of extracellular H+ fluxes, but adenosine was not. The extracellular H+ fluxes induced by ATP were mimicked by the P2Y1 agonist MRS 2365 and were significantly reduced by the P2 receptor blockers suramin and PPADS, suggesting activation of P2Y receptors. Bath-applied ATP induced an intracellular rise in calcium in Müller cells; both the calcium rise and the extracellular H+ fluxes were significantly attenuated when calcium re-loading into the endoplasmic reticulum was inhibited by thapsigargin and when the PLC-IP3 signaling pathway was disrupted with 2-APB and U73122. The anion transport inhibitor DIDS also markedly reduced the ATP-induced increase in H+ flux while SITS had no effect. ATP-induced H+ fluxes were also observed from Müller cells isolated from human, rat, monkey, skate and lamprey retinae, suggesting a highly evolutionarily conserved mechanism of potential general importance. Extracellular ATP also induced significant increases in extracellular H+ flux at the level of both the outer and inner plexiform layers in retinal slices of tiger salamander which was significantly reduced by suramin and PPADS. We suggest that the novel H+ flux mediated by ATP-activation of Müller cells and of other glia as well may be a key mechanism modulating neuronal signaling in the vertebrate retina and throughout the brain.
- Comparison of Inhibitory Capacities of 6-, 8- and 10-Gingerols/Shogaols on the Canonical NLRP3 Inflammasome-Mediated IL-1β Secretion. [Journal Article]
- MMolecules 2018 Feb 21; 23(2)
- Endogenous noninfectious substances that mediate the nucleotide oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and interleukin (IL)-1β sec...
Endogenous noninfectious substances that mediate the nucleotide oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and interleukin (IL)-1β secretion causes inappropriate sterile inflammation and is implicated in the pathogenesis of several chronic diseases, such as type 2 diabetes mellitus, gout, atherosclerosis and Alzheimer's disease. Consequently, dietary phytochemicals exhibiting capacities to suppress canonical NLRP3 inflammasome-mediated IL-1β secretion can be a reliable supplement to prevent such diseases. The purpose of this study was to investigate and compare the inhibitory effects of ginger phytochemicals, including 6-, 8- and 10-gingerols/shogaols on the canonical NLRP3 inflammasome-mediated IL-1β secretion in THP-1 macrophages with ordered stimulations of lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP). At 20 μM, the 10-gingerol and all the shogaols significantly inhibited canonical IL-1β secretion. The shogaols had a more potent inhibitory capacity than that of corresponding gingerols. Increase of alkyl chain length impacted negatively the inhibitory activity of shogaols. Additionally, these effective ginger phytochemicals not only inhibited the LPS-primed expression of pro-IL-1β and NLRP3, but also decreased ATP-activated caspase-1. The results demonstrated that ginger phytochemicals, especially the most potent, 6-shogaol, might be promising for developing as an inhibitor of the canonical NLRP3 inflammasome-mediated IL-1β secretion and further applied in prevention of NLRP3 inflammasome-associated diseases.
- Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5'-Adenosine Monophosphate-activated Protein Kinase (AMPK). [Journal Article]
- JMJ Med Chem 2018 Feb 21
- . Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously-described 5-aryl...
. Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously-described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys, as well as desirable oral absorption, low plasma clearance and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by rat and human renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole, or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group, provided improved metabolic stability while minimizing propensity for active transport by OAT3.
- Polyarteritis nodosa revisited: a review of historical approaches, subphenotypes and a research agenda. [Review]
- CEClin Exp Rheumatol 2018 Feb 20
- Polyarteritis nodosa (PAN) is a rare form of primary systemic vasculitis with heterogeneous presentations, treatments and disease course. Historical approaches to classification and diagnostic termin...
Polyarteritis nodosa (PAN) is a rare form of primary systemic vasculitis with heterogeneous presentations, treatments and disease course. Historical approaches to classification and diagnostic terminology are reviewed. Since differentiation of PAN from microscopic polyangiitis (MPA) and other ANCA vasculitides by the Chapel Hill conference statements, and with hepatitis associated PAN defined as a secondary vasculitis, the phenotyping and subclassification of PAN has received little attention. Monogenic disorders similar to PAN have been described (familial Mediterranean fever, Adenosine Deaminase-2 deficiency), and cutaneous PAN and single organ vasculitis, discussed. The overlapping phenotypes between PAN and other primary vasculitic syndromes and subphenotypes within PAN are explored. This work will underpin development of newer treatment regimens and future genetic and related aetiologic studies.
- The influence of chemotherapy on adenosine-producing B cells in patients with head and neck squamous cell carcinoma. [Journal Article]
- OOncotarget 2018 Jan 19; 9(5):5834-5847
- CONCLUSIONS: Platinum-based anti-tumor-therapy reduces the number of adenosine-producing B cells and, consequently, potential immunosuppression within the tumor environment. Breg function in terms of ADO production and their potential capacity to suppress CD4+T cells are promoted by methotrexate treatment amplifying anti-inflammatory therapeutic effects. Our results add to the understanding of how chemotherapeutic drugs can influence the human immune system and may therefore help to orchestrate standard oncologic therapy with new immune modulating approaches.
- Clinical and genetic spectrum of AMPD2-related pontocerebellar hypoplasia type 9. [Journal Article]
- EJEur J Hum Genet 2018 Feb 20
- Pontocerebellar hypoplasia (PCH) represents a group of autosomal-recessive progressive neurodegenerative disorders of prenatal onset. Eleven PCH subtypes are classified according to clinical, neuroim...
Pontocerebellar hypoplasia (PCH) represents a group of autosomal-recessive progressive neurodegenerative disorders of prenatal onset. Eleven PCH subtypes are classified according to clinical, neuroimaging and genetic findings. Individuals with PCH type 9 (PCH9) have a unique combination of postnatal microcephaly, hypoplastic cerebellum and pons, and hypoplastic or absent corpus callosum. PCH9 is caused by biallelic variants in AMPD2 encoding adenosine monophosphate deaminase 2; however, a homozygous AMPD2 frameshift variant has recently been reported in two family members with spastic paraplegia type 63 (SPG63). We identified homozygous or compound heterozygous AMPD2 variants in eight PCH-affected individuals from six families. The eight variants likely affect function and comprise one frameshift, one nonsense and six missense variants; seven of which were novel. The main clinical manifestations in the eight new patients and 17 previously reported individuals with biallelic AMPD2 variants were postnatal microcephaly, severe global developmental delay, spasticity, and central visual impairment. Brain imaging data identified hypomyelination, hypoplasia of the cerebellum and pons, atrophy of the cerebral cortex, complete or partial agenesis of the corpus callosum and the "figure 8" shape of the hypoplastic midbrain as consistent features. We broaden the AMPD2-related clinical spectrum by describing one individual without microcephaly and absence of the characteristic "figure 8" shape of the midbrain. The existence of various AMPD2 isoforms with different functions possibly explains the variability in phenotypes associated with AMPD2 variants: variants leaving some of the isoforms intact may cause SPG63, while those affecting all isoforms may result in the severe and early-onset PCH9.
- Carbon monoxide protects the kidney through the central circadian clock and CD39. [Journal Article]
- PNProc Natl Acad Sci U S A 2018 Feb 20
- Ischemia reperfusion injury (IRI) is the predominant tissue insult associated with organ transplantation. Treatment with carbon monoxide (CO) modulates the innate immune response associated with IRI ...
Ischemia reperfusion injury (IRI) is the predominant tissue insult associated with organ transplantation. Treatment with carbon monoxide (CO) modulates the innate immune response associated with IRI and accelerates tissue recovery. The mechanism has been primarily descriptive and ascribed to the ability of CO to influence inflammation, cell death, and repair. In a model of bilateral kidney IRI in mice, we elucidate an intricate relationship between CO and purinergic signaling involving increased CD39 ectonucleotidase expression, decreased expression of Adora1, with concomitant increased expression of Adora2a/2b. This response is linked to a >20-fold increase in expression of the circadian rhythm protein Period 2 (Per2) and a fivefold increase in serum erythropoietin (EPO), both of which contribute to abrogation of kidney IRI. CO is ineffective against IRI inCd39-/- andPer2 -/- mice or in the presence of a neutralizing antibody to EPO. Collectively, these data elucidate a cellular signaling mechanism whereby CO modulates purinergic responses and circadian rhythm to protect against injury. Moreover, these effects involve CD39- and adenosinergic-dependent stabilization of Per2. As CO also increases serum EPO levels in human volunteers, these findings continue to support therapeutic use of CO to treat IRI in association with organ transplantation, stroke, and myocardial infarction.
- Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity. [Journal Article]
- EEBioMedicine 2018 Feb 13
- Classical activation of M1 macrophages with lipopolysaccharide (LPS) is associated with a metabolic switch from oxidative phosphorylation to glycolysis. However, the generalizability of such metaboli...
Classical activation of M1 macrophages with lipopolysaccharide (LPS) is associated with a metabolic switch from oxidative phosphorylation to glycolysis. However, the generalizability of such metabolic remodeling to other modes of M1 macrophage stimulation, e.g. type II interferons (IFNs) such as IFNγ, has remained unknown as has the functional significance of aerobic glycolysis during macrophage activation. Here we demonstrate that IFNγ induces a rapid activation of aerobic glycolysis followed by a reduction in oxidative phosphorylation in M1 macrophages. Elevated glycolytic flux sustains cell viability and inflammatory activity, while limiting reliance on mitochondrial oxidative metabolism. Adenosine triphosphate (ATP) distributed by aerobic glycolysis is critical for sustaining IFN-γ triggered JAK (Janus tyrosine kinase)-STAT-1 (Signal Transducer and Activator of Transcription 1) signaling with phosphorylation of the transcription factor STAT-1 as its signature trait. Inhibition of aerobic glycolysis not only blocks the M1 phenotype and pro-inflammatory cytokine/chemokine production in murine macrophages and also human monocytes/macrophages. These findings extend on the potential functional role of immuno-metabolism from LPS- to IFNγ-linked diseases such as atherosclerosis and autoimmune disease.
- Functional brain-specific microvessels from iPSC-derived human brain microvascular endothelial cells: the role of matrix composition on monolayer formation. [Journal Article]
- FBFluids Barriers CNS 2018 Feb 20; 15(1):7
- CONCLUSIONS: Having identified matrix compositions that promote monolayer formation and barrier function, we successfully fabricated dhBMEC microvessels in cross-linked collagen I gels coated with fibronectin and collagen IV, and treated with ROCK inhibitor and cAMP. We measured apparent permeability values for Lucifer yellow, comparable to values obtained in the transwell assay. During these experiments we observed no focal leaks, suggesting the formation of tight junctions that effectively block paracellular transport.
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- Glycolysis is essential for chemoresistance induced by transient receptor potential channel C5 in colorectal cancer. [Journal Article]
- BCBMC Cancer 2018 Feb 20; 18(1):207
- CONCLUSIONS: We demonstrated the essential role of glycolysis in TRPC5 induced chemoresistance in human CRC cells via maintaining [Ca2+]ihomeostasis.