Polycyclic aromatic hydrocarbons regulate the pigmentation pathway and induce DNA damage responses in keratinocytes, a process driven by systemic immunity.

Background: Urban pollution is correlated with an increased prevalence of skin pigmentation disorders, however the physiological processes underlying this association are unclear.

Objectives: To delineate the relationship between polycyclic aromatic hydrocarbons (PAHs), a key constituent of atmospheric pollution, and immunity/skin pigmentation pathways.

Methods: We exposed peripheral blood mononuclear cells (PBMC) to PAHs and performed cytokines/chemokine profiling.

Glycosaminoglycans: Sweet as Sugar Targets for Topical Skin Anti-Aging.

Glycosaminoglycans (GAGs) are long, linear polysaccharides comprised of repeating disaccharide units with pleiotropic biological functions, with the non-sulfated GAG hyaluronic acid (HA), and sulfated GAGs dermatan sulfate, chondroitin sulfate, heparan sulfate, keratan sulfate, and to a lesser extent heparin all being expressed in skin. Their ability to regulate keratinocyte proliferation and differentiation, inflammatory processes and extracellular matrix composition and quality demonstrates their critical role in regulating skin physiology. Similarly, the water-binding properties of GAGs and structural qualities, particularly for HA, are crucial for maintaining proper skin form and hydration.

cGMP-Manufactured Human Induced Pluripotent Stem Cells Are Available for Pre-clinical and Clinical Applications.

The discovery of induced pluripotent stem cells (iPSCs) and the concurrent development of protocols for their cell-type-specific differentiation have revolutionized our approach to cell therapy. It has now become critical to address the challenges related to the generation of iPSCs under current good manufacturing practice (cGMP) compliant conditions, including tissue sourcing, manufacturing, testing, and storage. Furthermore, regarding the technical challenges, it is very important to keep the costs of manufacturing and testing reasonable and solve logistic hurdles that permit the global distribution of these products.

Dehydroepiandrosterone promotes pulmonary artery relaxation by NADPH oxidation-elicited subunit dimerization of protein kinase G 1α.

The activity of glucose-6-phosphate dehydrogenase (G6PD) controls a vascular smooth muscle relaxing mechanism promoted by the oxidation of cytosolic NADPH, which has been associated with activation of the 1α form of protein kinase G (PKG-1α) by a thiol oxidation-elicited subunit dimerization. This PKG-1α-activation mechanism appears to contribute to responses of isolated endothelium-removed bovine pulmonary arteries (BPA) elicited by peroxide, cytosolic NADPH oxidation resulting from G6PD inhibition, and hypoxia. Dehydroepiandrosterone (DHEA) is a steroid hormone with pulmonary vasodilator activity, which has beneficial effects in treating pulmonary hypertension.

Roles for cytosolic NADPH redox in regulating pulmonary artery relaxation by thiol oxidation-elicited subunit dimerization of protein kinase G1α.

The activity of glucose-6-phosphate dehydrogenase (G6PD) appears to control a vascular smooth muscle relaxing mechanism regulated through cytosolic NADPH oxidation. Since our recent studies suggest that thiol oxidation-elicited dimerization of the 1α form of protein kinase G (PKG1α) contributes to the relaxation of isolated endothelium-removed bovine pulmonary arteries (BPA) to peroxide and responses to hypoxia, we investigated whether cytosolic NADPH oxidation promoted relaxation by PKG1α dimerization. Relaxation of BPA to G6PD inhibitors 6-aminonicotinamide (6-AN) and epiandrosterone (studied under hypoxia to minimize basal levels of NADPH oxidation and PKG1α dimerization) was associated with increased PKG1α dimerization and PKG-mediated vasodilator-stimulated phosphoprotein (VASP) phosphorylation.

Roles for redox mechanisms controlling protein kinase G in pulmonary and coronary artery responses to hypoxia.

We previously reported that isolated endothelium-removed bovine pulmonary arteries (BPAs) contract to hypoxia associated with removal of peroxide- and cGMP-mediated relaxation. In contrast, bovine coronary arteries (BCAs) relax to hypoxia associated with cytosolic NADPH oxidation coordinating multiple relaxing mechanisms. Since we recently found that H(2)O(2) relaxes BPAs through PKG activation by both soluble guanylate cyclase (sGC)/cGMP-dependent and cGMP-independent thiol oxidation/subunit dimerization mechanisms, we investigated if these mechanisms participate in BPA contraction and BCA relaxation to hypoxia.

Redox regulation of guanylate cyclase and protein kinase G in vascular responses to hypoxia.

The production of cGMP by the soluble form of guanylate cyclase (sGC) in bovine pulmonary arteries (BPA) is controlled by cytosolic NADPH maintaining reduced thiol and heme sites on sGC needed for activation by NO, and the levels of Nox oxidase-derived superoxide and peroxide that influence pathways regulating sGC activity. Our recent studies in BPA suggest that the activities of peroxide metabolizing pathways in vascular smooth muscle potentially determine the balance between sGC stimulation by peroxide and a cGMP-independent activation of cGMP-dependent protein kinase (PKG) by a disulfide-mediated subunit dimerization. Cytosolic NADPH oxidation also appears to function in BPA through its influence on protein thiol redox control as an additional mechanism promoting vascular relaxation through PKG activation.

Redox regulation of responses to hypoxia and NO-cGMP signaling in pulmonary vascular pathophysiology.

Pulmonary vascular responses elicited by hypoxia and NO-cGMP signaling are potentially influenced by ROS and redox mechanisms that change during the progression of disease processes. Our studies in endothelium-rubbed bovine pulmonary arteries suggest increased glucose-6-phosphate dehydrogenase levels (compared to coronary arteries) seem to maintain a tonic peroxide-mediated relaxation removed by hypoxia through NADPH fueling superoxide generation from Nox oxidase. The activities of glucose-6-phosphate dehydrogenase, oxidases (i.

Roles for soluble guanylate cyclase and a thiol oxidation-elicited subunit dimerization of protein kinase G in pulmonary artery relaxation to hydrogen peroxide.

We have previously provided evidence that hydrogen peroxide (H(2)O(2)) stimulates soluble guanylate cyclase (sGC) under conditions where it relaxes isolated endothelium-removed bovine pulmonary arteries (BPAs). Since it was recently reported that H(2)O(2) induces coronary vasorelaxation associated with a nitric oxide/cGMP-independent thiol oxidation/subunit dimerization-elicited activation of protein kinase G (PKG), we investigated whether this mechanism participates in the relaxation of BPAs to H(2)O(2). BPAs precontracted with serotonin (incubated under hypoxia to lower endogenous H(2)O(2)) were exposed to increasing concentrations of H(2)O(2).

Oxidant-redox regulation of pulmonary vascular responses to hypoxia and nitric oxide-cGMP signaling.

Most current theories for the mechanism of hypoxic pulmonary vasoconstriction (HPV) include a role for reactive oxygen species and/or changes in redox regulation, but extreme controversy exists regarding which systems and redox changes mediate the HPV response. Nitric oxide (NO) appears to help to maintain low pulmonary arterial pressure, suppress HPV, and prevent the development of pulmonary hypertension. Our studies have found a key role for glucose-6-phosphate dehydrogenase in bovine pulmonary arterial smooth muscle functioning to maintain elevated levels of cytosolic NADPH which fuels the generation of vasodilator levels of hydrogen peroxide.