Int J Environ Res Public Health
February 2024
Neurofibromatosis type 1 (NF1) is a disorder in which RAS is constitutively activated due to the loss of the Ras-GTPase-activating activity of neurofibromin. RAS must be prenylated (i.e.
View Article and Find Full Text PDFAir pollution is associated with preterm birth (PTB), potentially via inflammation. We recently showed the mixture benzene, toluene, ethylbenzene, and xylene (BTEX) is associated with PTB. We examined if ambient BTEX exposure is associated with mid-pregnancy inflammation in a sample of 140 African-American women residing in Detroit, Michigan.
View Article and Find Full Text PDFDetroit, Michigan, currently has the highest preterm birth (PTB) rate of large cities in the United States. Disproportionate exposure to ambient air pollutants, including particulate matter ≤2.5 μm (PM), PM ≤ 10 μm (PM), nitrogen dioxide (NO) and benzene, toluene, ethylbenzene, and xylenes (BTEX) may contribute to PTB.
View Article and Find Full Text PDFMacroautophagy/autophagy can play a cytoprotective role after photodynamic damage to malignant cells, depending on the site of subcellular damage initiated by reactive oxygen species. There is evidence for such protection when mitochondria are among the targets. Targeting lysosomes has been reported to be more effective for photokilling, perhaps because autophagy offers no cytoprotection.
View Article and Find Full Text PDFWe previously reported that a low level of lysosomal photodamage potentiated the phototoxic effect of subsequent mitochondrial photodamage mediated by the benzoporphyrin derivative (BPD) in murine hepatoma 1c1c7 cells. This was attributed to release of Ca from damaged lysosomes and a calpain-mediated conversion of the autophagy-related protein ATG5 to a pro-apoptotic fragment. We now report a comparison of these results with those obtained with the human non-small-cell lung cancer A549 cell line.
View Article and Find Full Text PDFForty eight potential outliers in air pollution measurements taken simultaneously in Detroit, Michigan, USA and Windsor, Ontario, Canada in 2008 and 2009 were identified using four independent methods: box plots, variogram clouds, difference maps, and the Local Moran's I statistic. These methods were subsequently used in combination to reduce and select a final set of 13 outliers for nitrogen dioxide (NO), volatile organic compounds (VOCs), total benzene, toluene, ethyl benzene, and xylene (BTEX), and particulate matter in two size fractions (PM and PM). The selected outliers were excluded from the measurement datasets and used to revise air pollution models.
View Article and Find Full Text PDFAccumulating evidence suggests that mitogen-activated protein kinases (MAPKs) regulate macroautophagy/autophagy. However, the involvement of dual-specificity protein phosphatases (DUSPs), endogenous inhibitors for MAPKs, in autophagy remains to be determined. Here we report that DUSP1/MKP-1, the founding member of the DUSP family, plays a critical role in regulating autophagy.
View Article and Find Full Text PDFCYP1A1 and CYP1A2 are transcriptionally activated in the human normal breast epithelial cell line MCF10A following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Shifting MCF10A cultures to medium deficient in serum and epidermal growth factor (EGF) caused rapid reductions in the activated (i.e.
View Article and Find Full Text PDFOncogenic Ras proteins are a driving force in a significant set of human cancers and wildtype, unmutated Ras proteins likely contribute to the malignant phenotype of many more. The overall challenge of targeting activated Ras proteins has great promise to treat cancer, but this goal has yet to be achieved. Significant efforts and resources have been committed to inhibiting Ras, but these energies have so far made little impact in the clinic.
View Article and Find Full Text PDFWe previously reported that low-level lysosomal photodamage enhanced the efficacy of subsequent mitochondrial photodamage, resulting in a substantial promotion of apoptotic cell death. We now extend our analysis of the sequential PDT protocol to include two additional lysosomal-targeting photosensitizers. These agents, because of enhanced permeability, are more potent than the agent (N-aspartyl chlorin E6, NPe6) used in the initial study.
View Article and Find Full Text PDFPhotochem Photobiol
September 2015
This study was designed to examine determinants of the discovery that low-dose lysosomal photodamage (lyso-PDT) could potentiate the efficacy of subsequent low-dose mitochondrial photodamage (mito-PDT). The chlorin NPe6 and the benzoporphyrin derivative (BPD) were used to separately target lysosomes and mitochondria, respectively, in murine hepatoma cells. Lyso-PDT (LD(5) conditions) followed by mito-PDT (LD(15) conditions) enhanced the loss of the mitochondrial membrane potential, activation of procaspases-3/7 and photokilling.
View Article and Find Full Text PDFThe Geospatial Determinants of Health Outcomes Consortium (GeoDHOC) study investigated ambient air quality across the international border between Detroit, Michigan, USA and Windsor, Ontario, Canada and its association with acute asthma events in 5- to 89-year-old residents of these cities. NO2, SO2, and volatile organic compounds (VOCs) were measured at 100 sites, and particulate matter (PM) and polycyclic aromatic hydrocarbons (PAHs) at 50 sites during two 2-week sampling periods in 2008 and 2009. Acute asthma event rates across neighborhoods in each city were calculated using emergency room visits and hospitalizations and standardized to the overall age and gender distribution of the population in the two cities combined.
View Article and Find Full Text PDFIn 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding.
View Article and Find Full Text PDFPhotodynamic therapy (PDT) involves photosensitizing agents that, in the presence of oxygen and light, initiate formation of cytotoxic reactive oxygen species (ROS). PDT commonly induces both apoptosis and autophagy. Previous studies with murine hepatoma 1c1c7 cells indicated that loss of autophagy-related protein 7 (ATG7) inhibited autophagy and enhanced the cytotoxicity of photosensitizers that mediate photodamage to mitochondria or the endoplasmic reticulum.
View Article and Find Full Text PDFThe aryl hydrocarbon receptor (AhR) is targeted by ubiquitination for degradation by the proteasome shortly after its activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In silico screening identified p-anilinoaniline (pAA) as a putative inhibitor of an E2 ligase that partners with an E3 ligase implicated in AhR ubiquitination. We investigated whether pAA could modify AhR-dependent activation of its target gene CYP1A1.
View Article and Find Full Text PDFExposure of the human malignant peripheral nerve sheath tumor cell lines STS-26T, ST88-14, and NF90-8 to nanomolar concentrations of both lovastatin and farnesyl transferase inhibitor (FTI)-1 but not to either drug alone induced cell death. ST88-14 and NF90-8 cells underwent apoptosis, yet dying STS-26T cells did not. FTI-1 cotreatment induced a strong and sustained autophagic response as indicated by analyses of microtubule-associated protein-1 light chain 3 (LC3)-II accumulation in STS-26T cultures.
View Article and Find Full Text PDFReactive oxygen species (ROS) can induce lysosomal membrane permeabilization (LMP). Photoirradiation of murine hepatoma 1c1c7 cultures preloaded with the photosensitizer NPe6 generates singlet oxygen within acidic organelles and causes LMP and the activation of procaspases. Treatment with the cationic amphiphilic drugs (CADs) U18666A, imipramine, and clozapine stimulated the accumulation of filipin-stainable nonesterified cholesterol/sterols in late endosomes/lysosomes, but not in mitochondria.
View Article and Find Full Text PDFPlexiform neurofibromas commonly found in patients with Neurofibromatosis type I (NF1) have a 5% risk of being transformed into malignant peripheral nerve sheath tumors (MPNST). Germline mutations in the NF1 gene coding for neurofibromin, which is a Ras GTPase activating protein (RasGAP) and a negative regulator of Ras, result in an upregulation of the Ras pathway. We established a direct connection between neurofibromin deficiency and downstream effectors of Ras in cell lines from MPNST patients by demonstrating that knockdown of NF1 expression using siRNA in a NF1 wild type MPNST cell line, STS-26T, activates the Ras/ERK1,2 pathway and increases AP-1 binding and activity.
View Article and Find Full Text PDFPrenylation inhibitors have gained increasing attention as potential therapeutics for cancer. Initial work focused on inhibitors of farnesylation, but more recently geranylgeranyl transferase inhibitors (GGTIs) have begun to be evaluated for their potential antitumor activity in vitro and in vivo. In this study, we have developed a nonpeptidomimetic GGTI, termed GGTI-2Z [(5-nitrofuran-2-yl)methyl-(2Z,6E,10E)-3,7,11,15-tetramethylhexadeca-2,6,10,14-tetraenyl 4-chlorobutyl(methyl)phosphoramidate], which in combination with lovastatin inhibits geranylgeranyl transferase I (GGTase I) and GGTase II/RabGGTase, without affecting farnesylation.
View Article and Find Full Text PDFPhotodynamic therapy (PDT) is a procedure that has applications in the selective eradication of neoplasia where sites of malignant lesions are clearly delineated. It is a two-step process whereby cells are first sensitized to light and then photoirradiated. This results in the formation of singlet molecular oxygen and other reactive oxygen species that can cause photodamage at sites where the photosensitizing agent has localized.
View Article and Find Full Text PDFSinglet oxygen (1O2) is the primary oxidant generated in photodynamic therapy (PDT) protocols involving sensitizers resulting in type II reactions. 1O2 can give rise to additional reactive oxygen species (ROS) such as the hydroxyl radical (*OH). The current study was designed to assess 3'-p-(aminophenyl) fluorescein (APF) and 3'-p-(hydroxyphenyl) fluorescein (HPF) as probes for the detection of 1O2 and *OH under conditions relevant to PDT.
View Article and Find Full Text PDFThe therapeutic usefulness of the quinoxaline derivatives XK469 (2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid) and SH80 (2-{4-[(7-bromo-2-quinolinyl)oxy]phenoxy}propionic acid) has been attributed to their abilities to induce G(2)/M arrest and apoptotic or autophagic cell death. Concentrations of XK469 or SH80 > or = 5 microM were cytostatic to cultures of the normal murine melanocyte cell line Melan-a. Higher concentrations caused dose-dependent cytotoxicity.
View Article and Find Full Text PDFNeurofibromatosis Type 1 (NF1) is characterized by the abnormal proliferation of neuroectodermal tissues and the development of certain tumors, particularly neurofibromas, which may progress into malignant peripheral nerve sheath tumors (MPNSTs). Effective pharmacological therapy for the treatment of NF1 tumors is currently unavailable and the prognosis for patients with MPNSTs is poor. Loss of neurofibromin correlates with increased expression of the epidermal growth factor receptor (EGFR) and ErbB2 tyrosine kinases and these kinases have been shown to promote NF1 tumor-associated pathologies in vivo.
View Article and Find Full Text PDFToxicol Appl Pharmacol
October 2008
p-Anilinoaniline (pAA) is an aromatic amine that is widely used in hair dying applications. It is also a metabolite of metanil yellow, an azo dye that is commonly used as a food coloring agent. Concentrations of pAA between 10 and 25 microM were cytostatic to cultures of the normal human mammary epithelia cell line MCF10A.
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