ABSTRACT
The receptor for advanced glycan end products (RAGE) has been identified as a susceptibility gene for chronic obstructive pulmonary disease (COPD) in genome‐wide association studies (GWASs). ...However, less is known about how RAGE is involved in the pathogenesis of COPD. To determine the molecular mechanism by which RAGE influences COPD in experimental COPD models, we investigated the efficacy of the RAGE‐specific antagonist FPS‐ZM1 administration in in vivo and in vitro COPD models. We injected elastase intratracheally and the RAGE antagonist FPS‐ZM1 in mice, and the infiltrated inflammatory cells and cytokines were assessed by ELISA. Cellular expression of RAGE was determined in protein, serum, and bronchoalveolar lavage fluid of mice and lungs and serum of human donors and patients with COPD. Downstream damage‐associated molecular pattern (DAMP) pathway activation in vivo and in vitro and in patients with COPD was assessed by immunofluorescence staining, Western blot analysis, and ELISA. The expression of membrane RAGE in initiating the inflammatory response and of soluble RAGE acting as a decoy were associated with up‐regulation of the DAMP‐related signaling pathway via Nrf2. FPS‐ZM1 administration significantly reversed emphysema in the lung of mice. Moreover, FPS‐ZM1 treatment significantly reduced lung inflammation in Nrf2+/+, but not in Nrf2‒/‒ mice. Thus, our data indicate for the first time that RAGE inhibition has an essential protective role in COPD. Our observation of RAGE inhibition provided novel insight into its potential as a therapeutic target in emphysema/COPD.—Lee, H., Park, J.‐R., Kim, W. J., Sundar, I. K., Rahman, I., Park, S.‐M., Yang. S.‐R. Blockade of RAGE ameliorates elastase‐induced emphysema development and progression via RAGE‐DAMP signaling. FASEB J. 31, 2076–2089 (2017). www.fasebj.org
MSCs have become an emerging cell source with their immune modulation, high proliferation rate, and differentiation potential; indeed, they have been challenged in clinical trials. Recently, it has ...shown that ROS play a dual role as both deleterious and beneficial species depending on their concentration in MSCs. Various environmental stresses-induced excessive production of ROS triggers cellular senescence and abnormal differentiation on MSCs. Moreover, MSCs have been suggested to participate in the treatment of ALI/ARDS and COPD as a major cause of high morbidity and mortality. Therapeutic mechanisms of MSCs in the treatment of ARDS/COPD were focused on cell engraftment and paracrine action. However, ROS-mediated therapeutic mechanisms of MSCs still remain largely unknown. Here, we review the key factors associated with cell cycle and chromatin remodeling to accelerate or delay the MSC aging process. In addition, the enhanced ROS production and its associated pathophysiological pathways will be discussed along with the MSC senescence process. Furthermore, the present review highlights how the excessive amount of ROS-mediated oxidative stress might interfere with homeostasis of lungs and residual lung cells in the pathogenesis of ALI/ARDS and COPD.
•CSE decreased the proliferation of mouse lung fibroblasts, which is essential for the maintenance of extracellular matrix.•CSE caused an abnormal inflammatory response and ROS/RNS-mediated stress by ...an imbalance in the cellular antioxidant defense system (GSH recycling and SOD activity), leading to the apoptosis of lung parenchymal fibroblasts.•The apoptosis of lung fibroblasts, through the phosphorylation of STAT1 at Tyr701/Ser727 and the up-regulation of the MAPK pathway by CSE, contributes to the pathogenesis of COPD.
Cigarette smoking is the major aetiologic factor in chronic obstructive pulmonary disease (COPD). Lung fibroblasts are key participants in the maintenance of the extracellular matrix within the lung parenchyma. However, it still remains unknown how pulmonary fibroblasts are affected by cigarette smoking. Therefore, in this study, we isolated lung fibroblasts from mice and determined the apoptotic mechanism in response to cigarette smoke extract (CSE). When the lung fibroblasts were exposed to CSE, the generation of ROS was increased as shown by H2-DCFDA staining and Flow Cytometry. By immunocytochemistry, Ki67 expressing cells gradually decreased in a dose-dependent manner. The nitrite concentration in the supernatants increased, while the SOD activity and GSH recycling decreased in response to CSE. CSE increased the mRNA levels of TNF-α and COX-2, and the secretory proteins TNF-α and IL-6 increased as measured by ELISA. We next determined whether this inflammatory process is associated with the Bax/Bcl-2 apoptosis pathway. The Bax/Bcl-2 mRNA ratio increased, and cleaved caspase-3 protein was activated in the lung fibroblasts treated with CSE. Moreover, CSE induced the phosphorylation of STAT1 at Tyr701/Ser727 and increased the activation of ERK1/2, p38, and JNK in the MAPK pathway. Taken together, these data suggest that CSE-mediated inflammation alters the redox regulation via the MAPK-STAT1 pathway, leading to intrinsic apoptosis of lung fibroblasts.
High dysadherin expression has been recognized as a biological predictor of metastasis and poor prognosis for many different cancer types; however, the molecular mechanisms of how dysadherin affects ...cancer progression are still poorly understood. In this study, we examined whether AKT signaling could link dysadherin expression with downstream events that promote the metastatic potential of human breast cancer cells. Immunohistochemical analysis of breast cancer tissues showed that dysadherin expression was highly associated with elevated expression of phospho‐AKT. The introduction of dysadherin cDNA into BT‐474, MCF‐7 and T‐47D breast cancer cell lines enhanced their levels of AKT phosphorylation, while knockdown of dysadherin in MDA‐MB‐231 and Hs578T breast cancer cell lines suppressed AKT phosphorylation. Treatment with the AKT inhibitor triciribine suppressed dysadherin‐mediated pro‐metastatic effects, including epithelial–mesenchymal transition, cell motility and drug resistance. These findings suggest that dysadherin might contribute to breast cancer progression through AKT activation. (Cancer Sci 2012; 103: 1280–1289)
Aberrant communication in alveolar epithelium is a major feature of inflammatory response for the airway remodeling leading to chronic obstructive pulmonary disease (COPD). In this study, we ...investigated the effect of protein transduction domains (PTD) conjugated Basic Fibroblast Growth Factor (FGF2) (PTD-FGF2) in response to cigarette smoke extract (CSE) in MLE-12 cells and porcine pancreatic elastase (PPE)-induced emphysematous mice. When PPE-induced mice were intraperitoneally treated with 0.1-0.5 mg/kg PTD-FGF2 or FGF2, the linear intercept, infiltration of inflammatory cells into alveoli and pro-inflammatory cytokines were significantly decreased. In western blot analysis, phosphorylated protein levels of c-Jun N-terminal Kinase 1/2 (JNK1/2), extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein kinases (MAPK) were decreased in PPE-induced mice treated PTD-FGF2. In MLE-12 cells, PTD-FGF2 treatment decreased reactive oxygen species (ROS) production and further decreased Interleukin-6 (IL-6) and IL-1b cytokines in response to CSE. In addition, phosphorylated protein levels of ERK1/2, JNK1/2 and p38 MAPK were reduced. We next determined microRNA expression in the isolated exosomes of MLE-12 cells. In reverse transcription-polymerase chain reaction (RT-PCR) analysis, level of let-7c miRNA was significantly increased while levels of miR-9 and miR-155 were decreased in response to CSE. These data suggest that PTD-FGF2 treatment plays a protective role in regulation of let-7c, miR-9 and miR-155 miRNA expressions and MAPK signaling pathways in CSE-induced MLE-12 cells and PPE-induced emphysematous mice.
Chronic alcohol consumption causes alcohol-induced lipogenesis and promotes hepatic injury by preventing the oxidation of hepatocellular fatty acids through the suppression of the activation of ...AMP-activated protein kinase (AMPK). HIMH0021, an active flavonoid compound, which is a component of the Acer tegmentosum extract, has been shown to protect against liver damage caused by alcohol consumption. Therefore, in this study, we aimed to determine whether HIMH0021 could regulate alcoholic fatty liver and liver injury in mice. Oral administration of 10 days of Lieber-DeCarli ethanol plus a single binge of 30% ethanol (chronic-plus-binge model) induced steatosis and liver injury and inflammation in mice, which appears similar to the condition observed in human patients with alcohol-related diseases. HIMH0021, which was isolated from the active methanol extract of A. tegmentosum, inhibited alcohol-induced steatosis and attenuated the serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) during hepatocellular alcohol metabolism, both of which promote lipogenesis as well as liver inflammation. Treatment with HIMH0021 conferred protection against lipogenesis and liver injury, inhibited the expression of cytochrome P4502E1, and increased serum adiponectin levels in the mice subjected to chronic-plus-binge feeding. Furthermore, in hepatocytes, HIMH0021 activated fatty acid oxidation by activating pAMPK, which comprises pACC and CPT1a. These findings suggested that HIMH0021 could be used to target a TNFα-related pathway for treating patients with alcoholic hepatitis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
► Nanoporous platinum was utilized as nonenzymatic glucose sensor electrode material. ► Layered polymer outer membrane was adopted for sensor application to biological sample. ► Nonenzymatic glucose ...response in 100% human serum and whole blood were successful. ► The sensor's autoclave compatibility and long term stability were characterized.
This paper describes the first devised method for the nonenzymatic and electrochemical glucose monitoring in 100% human whole blood and serum. The nanoporous Pt electrode allows for the selective amplification of glucose oxidation in the presence of electroactive interfering species without the need for enzymatic reaction. The outer membrane was particularly optimized to allow glucose molecules to be electrochemically detected against the numerous constituents of human blood. The proposed sensor provided reproducible amperometric responses to glucose in human serum and whole blood. Its sensitivity was maintained for at least 7h under constantly electrified conditions, and continued to work properly after 30 days of storage in human whole blood and serum. Unlike the enzyme-based glucose sensors, it was found to be minimally affected by thermal fluctuation, so as to remain successful even after steam sterilization at high temperature (134°C) and pressure (0.22Mpa). The unprecedented long-term stability and sterilization compatibility observed herein suggest a promising alternative to conventional enzymatic glucose sensors for many analytical and clinical applications, particularly for continuous glucose monitoring devices designed to potentially lead to a closed-loop artificial pancreas by combining them with an insulin pump.
Follicle-stimulating hormone (FSH) promotes the production and secretion of estrogen, which in turn stimulates the growth and maturation of ovarian follicles. Therefore, consecutive FSH treatment to ...induce ovarian hyperstimulation (superovulation) is still considered the most cost-effective option for the majority of assisted reproductive technologies (ARTs). However, a relatively high cancellation rate and subsequent low pregnancy outcomes (approximately 15%) are the most challenging aspects of this FSH-based ART. Currently, the main cause for this low implantation rate of FSH-based ART has not yet been revealed. Therefore, we hypothesized that these high cancellation rates with FSH-based superovulation protocols might be associated with the harmful effects of consecutive FSH treatment. Importantly, several recent studies have revealed that tissue-resident stem cell deficiency can significantly reduce cyclic endometrial regeneration and subsequently decrease the pregnancy outcome. In this context, we investigated whether FSH treatment could directly inhibit endometrial stem cell functions and consequently suppress endometrial regeneration. Consistent with our hypothesis, our results revealed for the first time that FSH could inhibit various regeneration-associated functions of endometrial stem cells, such as self-renewal, migration, and multilineage differentiation capacities, via the PI3K/Akt and ERK1/2 signaling pathways both in vitro and in vivo.
Luteinizing hormone (LH) stimulates the synthesis and secretion of the key steroid hormone estrogen, which subsequently promotes ovarian follicular growth and development. Therefore, the ...administration of exogenous LH to achieve superovulation (multiple ovulations) and an LH surge is commonly used as the most effective therapeutic option in a majority of in vitro fertilization (IVF) clinics. However, a relatively low pregnancy rate (between 20% and 35%) is one of the most challenging aspects of LH-based infertility treatment. Furthermore, the major cause of this low pregnancy rate in LH-based infertility treatment remains unidentified. Recent studies have shown that endometrial stem cell loss or deficiency can significantly decrease tissue regeneration ability during the menstrual cycle and reduce endometrial receptivity. In this context, we postulated that the low pregnancy rates following LH-based ovarian hyperactivation may be the result of the adverse effects of consecutive exogenous LH administration on endometrial stem cells. To the best of our knowledge, this study revealed for the first time that in addition to its previously reported roles in stimulating ovarian functions through the pituitary-gonadal axis, LH brings about the extragonadal suppression of various tissue regeneration-associated functions in endometrial stem cells, such as self-renewal, migration ability, multilineage differentiation potential, and pluripotency/stemness, by inhibiting pro-survival Akt and ERK1/2 signaling pathways in vitro and in vivo, and as a consequence, it decreases the endometrial receptivity.
Thioredoxin-interacting protein (TXNIP) has multiple functions, including tumor suppression and involvement in cell proliferation and apoptosis. However, its role in the inflammatory process remains ...unclear. In this report, we demonstrate that Txnip⁻/⁻ mice are significantly more susceptible to lipopolysaccharide (LPS)-induced endotoxic shock. In response to LPS, Txnip⁻/⁻ macrophages produced significantly higher levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS), and an iNOS inhibitor rescued Txnip⁻/⁻ mice from endotoxic shock-induced death, demonstrating that NO is a major factor in TXNIP-mediated endotoxic shock. This susceptibility phenotype of Txnip⁻/⁻ mice occurred despite reduced IL-1β secretion due to increased S-nitrosylation of NLRP3 compared to wild-type controls. Taken together, these data demonstrate that TXNIP is a novel molecule that links NO synthesis and NLRP3 inflammasome activation during endotoxic shock.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
