Particulate matter 2.5 could induce DNA damage and cell senescence in corneal epithelial cells, probably by promoting ROS formation. Thus, whether long-term exposure of PM2.5 might be related to potential risk of abnormality in corneal epithelium renewal and regeneration should be further investigated.
PM2.5 exposure could result in delay of corneal epithelium wound healing by inhibiting cell migration, thus more attention should be paid to the potential risk of corneal infection and effort should be made to protect eyes against impairment induced by PM2.5.
ABSTRACT:Factors determining the pharmacokinetics of 2-chloro-N-(4-chloro-3-(pyridine-2-yl)phenyl)-4-(methylsulfonyl)benzamide (GDC-0449) were investigated using preclinical studies and physiologically based pharmacokinetic (PBPK) modeling. Multiple-dose studies where dogs were given twice-daily oral doses of either 7.5 or 25 mg/kg GDC-0449 showed less than dose-proportional increases in exposure on day 1. At steady state, exposures were comparable between the two dose groups. Oral administration of activated charcoal to dogs receiving oral or intravenous GDC-0449 (25 mg) showed a more rapid decrease in plasma concentrations, suggesting that the concentration gradient driving intestinal membrane permeation was reversible. The biliary clearance of GDC-0449 in dogs was low (0.04 ml/min/kg) and did not account for the majority of the estimated systemic clearance (ϳ19% of systemic clearance). Likewise, in vitro studies using sandwichcultured human hepatocytes showed negligible biliary excretion. The effect of particle size on oral absorption was shown in a single-dose study where 150 mg of GDC-0449 of two particle sizes was administered. An oral PBPK model was used to investigate mechanisms determining the oral pharmacokinetics of GDC-0449. The overall oral absorption of GDC-0449 appears to depend on the interplay between the dissolution and intestinal membrane permeation processes. A unique feature of GDC-0449 distinguishing it from other Biopharmaceutical Classification System II compounds was that incorporation of the effects of solubility rate-limited absorption and nonsink permeation on the intestinal membrane permeation process was necessary to describe its pharmacokinetic behavior.The hedgehog (Hh) signaling pathway regulates proliferation and differentiation during embryogenesis. Hh ligands bind to Patched (PTCH1), a transmembrane protein on target cells. In the absence of Hh, the role of PTCH1 is to inhibit the activity of Smoothened (SMO), a seven-transmembrane protein that serves as the signaling component of the pathway. Binding of Hh proteins to PTCH1 relieves this inhibition and initiates activation of SMO. The increase in SMO activity causes increases in activated forms of Gli, transcriptional factors that serve to regulate the expression of Hh target genes. Activation of the Hh pathway has been implicated in a number of cancers (Scales and de Sauvage, 2009). Mutations in the Hh receptor components, PTCH1 or SMO, result in constitutive pathway activation and have been identified in basal cell carcinoma (Hahn et al., 1996;Johnson et al., 1996) and medulloblastoma (Pietsch et al., 1997;Raffel et al., 1997;Vorechovský et al., 1997). It has also been observed that aberrant Hh ligand production can contribute to the growth of other tumor types, such as colorectal and pancreatic cancer (Yauch et al., 2008), prostate cancer (Fan et al., 2004), and B cell lymphoma (Dierks et al., 2007), through paracrine activation of the Hh pathway. Paracrine signaling typically involves ligand expressed on the cancer cells ...
Currently,
treatment of chronically infected wounds still remains
a big challenge; thus, a novel strategy with a highly efficient therapeutic
effect is of urgent demand. In the present work, we demonstrated that
combinational use of nitric oxide (NO) and deferoxamine (DFO) is a
promising way for treating hard-to-heal wounds. As a proof of concept,
DFO was first loaded in mesoporous polydopamine (mPDA) and then functionalized
by a chitosan-graft-third generation poly(amidoamine)
polymer with terminal S-nitrosothiol groups (CP-SNO) via a strong electrostatic interaction, obtaining a multifunctional
nanocomposite mPDA@DFO@CP-SNO. Upon near-infrared laser irradiation,
mPDA@DFO@CP-SNO displayed a mild-temperature photothermal effect (MPTT)
and a simultaneous NO and DFO controlled release property. The synergistic
MPTT and NO antibacterial effect of mPDA@DFO@CP-SNO enabled effective
elimination of both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus (S. aureus), as well as the biofilms
formed by both bacteria. An in-depth mechanistic study revealed that
mPDA@DFO@CP-SNO possessed particular binding affinity to the bacterial
membrane, which significantly enhanced the damage effect on the bacterial
membrane followed by boosting intracellular reactive oxygen species
generation to accelerate GSH depletion and DNA dysfunction, finally
leading to bacterial death. Moreover, the anti-inflammation and wound-healing
effectiveness of mPDA@DFO@CP-SNO were demonstrated on an in
vitro cell scratch model and an in vivo
S. aureus-infected rat full-thickness skin wound
model. Thanks to the triple therapeutic effects of MPTT, DFO, and
NO, mPDA@DFO@CP-SNO significantly relieved the inflammation in rats’
infected wounds and promoted wound skin regeneration by upregulating
expression of the hypoxia-inducible factor (HIF)-1α and the
vascular endothelial growth factor.
Recently, alkyl radical has attracted much attention in cancer therapy due to its oxygen-independent generation property. For the first time, alkyl radical and nitric oxide (NO) combined therapy is demonstrated...
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