Safety, Tolerability, and Pharmacokinetics of Nebulized GB05-Human IFNα1b Inhalation Solution: A Randomized, Placebo-Controlled, Dose-Escalation Phase I Study in Healthy Chinese Adult Volunteers.

Introduction: Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection, especially in children and older people. However, no effective treatment is currently available. Type I interferons (IFNs) are a group of cytokines that help regulate the activity of the immune system.

Ameliorative effects of Bifidobacterium longum peptide-1 on benzo(α)pyrene induced oxidative damages via daf-16 in Caenorhabditis elegans.

Oxidative stress is implicated in numerous diseases, with benzo(α)pyrene (BaP) known for causing substantial oxidative damage. Bifidobacterium longum (B. longum) is recognized as an antioxidant bacterium for certain hosts, yet its influence on oxidative damages instigated by BaP remains undetermined.

Tubular epithelial cells-derived small extracellular vesicle-VEGF-A promotes peritubular capillary repair in ischemic kidney injury.

Peritubular capillaries (PTCs) are closely related to renal tubules in structure and function, and both are pivotal regulators in the development and progression of acute kidney injury (AKI). However, the mechanisms that underlie the interaction between PTCs and tubules during AKI remain unclear. Here we explored a new mode of tubulovascular crosstalk mediated by small extracellular vesicles (sEV) after AKI.

Ameliorative effect of the probiotic peptide against benzo(α)pyrene-induced inflammatory damages in enterocytes.

Probiotics are living bacteria that provide health benefits to the host when consumed in sufficient quantities. However, the protective effect of the bioactive peptides isolated from the probiotics against benzo(α)pyrene (BaP) induced gastrointestinal injury has never been investigated. The current work used a bio-assay guided technique to identify-four new cyclic peptides in BaP-induced Caco-2 cell culture and mouse colitis model.

Blockade of MerTK Activation by AMPK Inhibits RPE Cell Phagocytosis.

Timely removal of shed photoreceptor outer segments by retinal pigment epithelial cells (RPE) plays a key role in biological renewal of these highly peroxidizable structures and in maintenance of retina health. How environmental stress cause RPE cell dysfunction is undefined however. AMP-activated protein kinase (AMPK), a heterotrimer of a catalytic α subunit and regulatory β and γ subunits, maintains energy homeostasis by limiting energy utilization and/or promoting energy production when energy supply is compromised.

Resveratrol protects RPE cells from sodium iodate by modulating PPARα and PPARδ.

Selective killing of RPE cells in vivo by sodium iodate develops cardinal phenotypes of atrophic age-related macular degeneration. However, the molecular mechanisms are elusive. We tried to search for small cyto-protective molecules against sodium iodate and explore their mechanisms of action.

Glucose-6-phosphate dehydrogenase: a biomarker and potential therapeutic target for cancer.

Re-programming of metabolic pathways is a hallmark of pathological changes in cancer cells. The expression of certain genes that directly control the rate of key metabolic pathways including glycolysis, lipogenesis and nucleotide synthesis is dysregulated for the adaptation and progression of tumor cells to become more aggressive phenotypes. The pentose phosphate pathway controlled by glucose- 6-phosphate dehydrogenase (G6PD) has been appreciated largely to its role as a provider of reducing power and ribose phosphate to the cell for maintenance of redox balance and biosynthesis of nucleotides and lipids.

Roles of αvβ5, FAK and MerTK in oxidative stress inhibition of RPE cell phagocytosis.

Efficient phagocytosis of photoreceptor outer segments (POS) by retinal pigment epithelial cells (RPE) plays a key role in biological renewal of these highly peroxidizable structures and in maintenance of retina health. Here, we used an in vitro RPE cell phagocytosis assay to investigate how sub-lethal oxidative stress modifies the key components of the cell phagocytic machinery leading to severe impairment of phagocytosis. Sub-lethal oxidative treatment, induced by hydrogen peroxide (H(2)O(2)), significantly inhibited binding and uptake of POS by RPE cells.

Inhibition of RPE cell sterile inflammatory responses and endotoxin-induced uveitis by a cell-impermeable HSP90 inhibitor.

Dying cells release pro-inflammatory molecules, functioning as cytokines to trigger cell/tissue inflammation that is relevant to disease pathology. Heat-shock protein 90 (HSP90) is believed to act as a danger signal for tissue damage once released extracellularly. Potential roles of HSP90 were explored in retinal pigment epithelial (RPE) inflammatory responses to necrosis.

Suofu Qin's work on studies of cell survival signaling in cancer and epithelial cells.

Reactive oxygen species (ROS) encompass a variety of diverse chemical species including superoxide anions, hydrogen peroxide, hydroxyl radicals and peroxynitrite, which are mainly produced via mitochondrial oxidative metabolism, enzymatic reactions, and light-initiated lipid peroxidation. Over-production of ROS and/or decrease in the antioxidant capacity cause cells to undergo oxidative stress that damages cellular macromolecules such as proteins, lipids, and DNA. Oxidative stress is associated with ageing and the development of age-related diseases such as cancer and age-related macular degeneration.

Differential roles of AMPKα1 and AMPKα2 in regulating 4-HNE-induced RPE cell death and permeability.

Lipid peroxidation products such as 4-hydroxy-2-nonenal (4-HNE) cause dysfunction and death of retinal pigmented epithelial (RPE) cells, thereby leading to retinal degeneration. The molecular mechanisms underlying their action remain elusive however. In this study, the roles of AMP-activated protein kinase (AMPK) in 4-HNE-induced RPE cell dysfunction and viability were addressed.

Integrities of A/B and C domains of RXR are required for rexinoid-induced caspase activations and apoptosis.

Here we have delineated regions of the retinoid X receptor alpha (RXRalpha) that are required for rexinoid (RXR agonist)-induced growth inhibition and apoptosis. Stable over-expression of RXRalpha in DT40 B lymphoma cells dramatically increased sensitivity to rexinoid-induced growth inhibition. By contrast, DT40 cells that over-expressed RXRalpha with a deletion of either the A/B or DNA binding domain (C domain) were resistant.

Implication of S-adenosylhomocysteine hydrolase in inhibition of TNF-alpha- and IL-1beta-induced expression of inflammatory mediators by AICAR in RPE cells.

Purpose: AMP-activated protein kinase (AMPK) has been suggested to be a novel signaling pathway in regulating inflammation. The role of AMPK in retinal pigment epithelial cell inflammatory response is addressed using AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR).

Methods: Protein expression and activation of signaling molecules were detected by immunoblotting.

alpha2 But not alpha1 AMP-activated protein kinase mediates oxidative stress-induced inhibition of retinal pigment epithelium cell phagocytosis of photoreceptor outer segments.

Oxidative stress causes retinal pigment epithelium (RPE) cell dysfunction and is a major risk factor leading to the development of dry-type age-related macular degeneration. Taking pharmacological and genetic approaches, we address the mechanisms by which sublethal oxidative stress inhibits RPE cell phagocytosis. Sublethal oxidative stress dose-dependently inhibited RPE cell phagocytosis of photoreceptor outer segments (POS) and activated AMP-activated protein kinase (AMPK) as determined by increased Thr172 and Ser79 phosphorylation of AMPKalpha and its substrate acetyl-CoA carboxylase, respectively.

Progress and perspectives on the role of RPE cell inflammatory responses in the development of age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. The etiology of AMD remains poorly understood and no treatment is currently available for the atrophic form of AMD. Atrophic AMD has been proposed to involve abnormalities of the retinal pigment epithelium (RPE), which lies beneath the photoreceptor cells and normally provides critical metabolic support to these light-sensing cells.

Protection of RPE cells from oxidative injury by 15-deoxy-delta12,14-prostaglandin J2 by augmenting GSH and activating MAPK.

Purpose: The goal of this study was to identify the mechanisms by which 15-deoxy-Delta(12,14)-prostaglandin J(2) (dPGJ(2)) protects RPE cells from oxidative injury.

Methods: Cell viability was determined by MTT assay. Protein expression and activation of signaling molecules were detected by Western blot.

Casein kinase 1alpha interacts with retinoid X receptor and interferes with agonist-induced apoptosis.

Agonists of retinoid X receptors (RXRs), which include the natural 9-cis-retinoic acid and synthetic analogs, are potent inducers of growth arrest and apoptosis in some cancer cells. As such, they are being used in clinical trials for the treatment and prevention of solid tumors and are used to treat cutaneous T cell lymphoma. However, the molecular mechanisms that underlie the anti-cancer effects of RXR agonists remain unclear.

A retinoid-related molecule that does not bind to classical retinoid receptors potently induces apoptosis in human prostate cancer cells through rapid caspase activation.

Synthetic retinoid-related molecules, such as N-(4-hydroxyphenyl)retinamide (fenretinide) and 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induce apoptosis in a variety of malignant cells. The mechanism(s) of action of these compounds does not appear to involve retinoic acid receptors (RARs) and retinoid X receptors (RXRs), although some investigators disagree with this view. To clarify whether some retinoid-related molecules can induce apoptosis without involving RARs and/or RXRs, we used 4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-E-propenyl] benzoic acid (AGN193198) that neither binds effectively to RARs and RXRs nor transactivates in RAR- and RXR-mediated reporter assays.

Implication of phosphatidylinositol 3-kinase membrane recruitment in hydrogen peroxide-induced activation of PI3K and Akt.

The effect of tyrosine phosphorylation of PI3K on its enzymatic activity is quite controversial, and the molecular mechanism by which ROS trigger PI3K membrane relocation is unclear. Therefore, we investigated the regulatory mechanism of hydrogen peroxide-induced PI3K activation in DT40 cells, utilizing genetic and pharmacological approaches. Our results revealed that hydrogen peroxide induced tyrosine phosphorylation of the p110 but not the p85 subunit of PI3K in DT40 cells.

Tyrosine phosphatase CD45 regulates hydrogen peroxide-induced calcium mobilization in B cells.

By taking advantage of established CD45-deficient DT40 cells, the roles of CD45 in oxidative stress signaling were investigated. Using p-nitrophenyl phosphate as substrate, it was found that CD45 constituted nearly 40% of the total protein-tyrosine phosphatase activity. Almost 90% of the phosphatase activity was rapidly inactivated upon hydrogen peroxide treatment.