Angiotensin II is a growth factor that plays a key role in the physiopathology of idiopathic pulmonary fibrosis (IPF). A nucleotide substitution of an adenine instead of a guanine (G-6A) in the proximal promoter region of angiotensinogen (AGT), the precursor of angiotensin II, has been associated with an increased gene transcription rate.In order to investigate whether the G-6A polymorphism of the AGT gene is associated with IPF development, severity and progression, the present study utilised a case-control study design and genotyped G-6A in 219 patients with IPF and 224 control subjects.The distribution of G-6A genotypes and alleles did not significantly differ between cases and controls. The G-6A polymorphism of the AGT gene was not associated with disease severity at diagnosis. The presence of the A allele was strongly associated with increased alveolar arterial oxygen tension difference during follow-up, after controlling for the confounding factors. Higher alveolar arterial oxygen tension changes over time were observed in patients with the AA genotype (0.37¡0.7 mmHg (0.049¡0.093 kPa) per month) compared to GA genotype (0.12¡1 mmHg (0.016¡0.133 kPa) per month) and GG genotype (0.2¡0.6 mmHg (0.027¡0.080 kPa) per month).G-6A polymorphism of the angiotensinogen gene is associated with idiopathic pulmonary fibrosis progression but not with disease predisposition. This polymorphism could have a predictive significance in idiopathic pulmonary fibrosis patients.
Melatonin and steroid hormones are cytochrome P450 (CYP or P450; EC 1.14.14.1) substrates that have antioxidant properties and mitochondrial protective activities. IMS (Mitochondrial intermembrane space) SOD1 (Cu,Zn-superoxide dismutase) is activated following oxidative modification of its critical thiol moieties by superoxide anion (O2.− ). This study was aimed at investigating the potential association between the hormonal protective antioxidant actions in mitochondria and regulation of IMS SOD1 activity. Melatonin, testosterone, dihydrotestosterone, estradiol, and vitamin D induced a sustained activation over time of SOD1 in intact mitochondria showing a bell-shaped enzyme activation dose-response with a threshold at 50 nM and a maximum effect at 1 μM concentration. Enzyme activation was not affected by furafylline, but it was inhibited by omeprazole, ketoconazole, and tiron, thereby supporting the occurrence of a mitochondrial P450 activity and O2.− requirements. Mitochondrial P450–dependent activation of IMS SOD1 prevented O2.− -induced loss of aconitase activity in intact mitochondria respiring at state 3 respiration. Optimal protection of aconitase activity was observed at 0.1 μM P450 substrate concentration evidencing a likely oxidative effect on the mitochondrial matrix by higher substrate concentrations. Likewise, enzyme activation mediated by mitochondrial P450 activity delayed CaCl2-induced loss of trans-membrane potential, and decreased cytochrome c release. Omeprazole and ketoconazole abrogated both protecting mitochondrial functions promoted by melatonin and steroid hormones.
Blood platelets have been widely proposed as biomarkers in studies of mitochondrial function and aging-related and neurodegenerative diseases. Defects in mitochondrial function were found not only in the substantia nigra of Parkinson's disease patients but also in their blood platelets. Similarly, it has also been described in the blood platelet mitochondria of Alzheimer's disease patients. To study mitochondrial aerobic metabolism function and protein expression in platelets of multiple sclerosis (MS) patients and control subjects, mitochondrial aconitase, mitochondrial superoxide dismutases 1 and 2 (SOD1 and SOD2), and respiratory complex enzyme activities in platelets of MS patients and control subjects were determined. Likewise, mitochondrial lipid peroxidation and mitochondrial SOD1 and cytochrome c expressions were investigated. Mitochondrial aconitase activity was higher in MS patients than in controls (P < 0.05). A significant increase on all respiratory complex activities in MS patients was observed (P < 0.05). Mitochondrial lipid peroxidation was significantly higher in MS patients than in controls (P < 0.05). Significant changes of cytochrome c and mitochondrial SOD1 expressions were detected (P < 0.05), with a decrease of 44 ± 5 % and an increase of 46 ± 6 %, respectively. Our study reveals that significant changes in mitochondrial aerobic metabolism function and mitochondrial SOD1 and cytochrome c expressions are produced in platelets of MS patients.
Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.
This work describes the synthesis of nitrogendoped carbon nanodots (CNDs) synthesized from ethylenediaminetetraacetic acid (EDTA) as aprecursor and their application as luminescent agentsw ith ad ual-mode theranostic role as near-infrared (NIR)t riggered imaging and photodynamic therapy agents.I nterestingly,t hese fluorescent CNDs are more rapidlya nd selectively internalized by tumorc ells and exhibit very limited cytotoxicity until remotelya ctivated with aN IR illumination source. These CNDsa re excellent candidates forp hototheranostic purposes, for example, si-multaneousi maging and therapy can be carriedo ut on cancer cells by using their luminescent properties and the in situ generation of reactive oxidative species(ROS) upon excitation in the NIR range. In the presence of CNDs,N IR remote activation induces the in vitro killing of U251MG cells. Through the use of flow imaging cytometry,w eh ave been able to successfully mapa nd quantify the different types of cell deaths induced by the presence of intracellular superoxide anions (CO 2 À )a nd hydrogen peroxide (H 2 O 2 )R OS generated in situ upon NIR irradiation. [a] Dr.M.C.O rtega-Liebana, Dr.M.M.Encabo-Berzosa,D r.Supporting information and the ORCID identification number(s) for the author(s) of this articlecan be found under: https://doi.
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