Cell-based therapy in lung regenerative medicine

Abstract Chronic lung diseases are becoming a leading cause of death worldwide. There are few effective treatments for those patients and less choices to prevent the exacerbation or even reverse the progress of the diseases. Over the past decade, cell-based therapies using stem cells to regenerate lung tissue have experienced a rapid growth in a variety of animal models for distinct lung diseases. This novel approach offers great promise for the treatment of several devastating and incurable lung diseases, including emphysema, idiopathic pulmonary fibrosis, pulmonary hypertension, and the acute respiratory distress syndrome. In this review, we provide a concise summary of the current knowledge on the attributes of endogenous lung epithelial stem/progenitor cells (EpiSPCs), mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) in both animal models and translational studies. We also describe the promise and challenges of tissue bioengineering in lung regenerative medicine. The therapeutic potential of MSCs is further discussed in IPF and chronic obstructive pulmonary diseases (COPD).http://deepblue.lib.umich.edu/bitstream/2027.42/109470/1/40340_2013_Article_11.pd

Dietary Anti-Aging Polyphenols and Potential Mechanisms

For years, the consumption of a diet rich in fruits and vegetables has been considered healthy, increasing longevity, and decreasing morbidities. With the assistance of basic research investigating the potential mechanisms, it has become clear that the beneficial effects of plant-based foods are mainly due to the large amount of bioactive phenolic compounds contained. Indeed, substantial dietary intervention studies in humans have supported that the supplementation of polyphenols have various health-promoting effects, especially in the elderly population. In vitro examinations on the anti-aging mechanisms of polyphenols have been widely performed, using different types of natural and synthetic phenolic compounds. The aim of this review is to critically evaluate the experimental evidence demonstrating the beneficial effects of polyphenols on aging-related diseases. We highlight the potential anti-aging mechanisms of polyphenols, including antioxidant signaling, preventing cellular senescence, targeting microRNA, influencing NO bioavailability, and promoting mitochondrial function. While the trends on utilizing polyphenols in preventing aging-related disorders are getting growing attention, we suggest the exploration of the beneficial effects of the combination of multiple polyphenols or polyphenol-rich foods, as this would be more physiologically relevant to daily lif

Role of leptin as antioxidant in obstructive sleep apnea: an in vitro study using electron paramagnetic resonance method

Introduction: As in obstructive sleep apnea (OSA), the chronic cycles of hypoxia and reoxygenation are thought to be conducive of oxidative stress (OS) with generation of reactive oxygen species, identifying effective mechanisms of protection against oxidant-mediated tissue damage becomes of outmost importance. Leptin’s role had been recently extended into that of participant to OS; while its exact role in this process is yet to be defined, elevated leptin levels correlate significantly with several indices of OSA disease severity such as nocturnal hypoxemia, possibly acting as a counteractive mechanism against the chronic intermittent hypoxia-related OS and serving as a marker of future risk of atherosclerotic disease. We therefore investigated leptin’s antioxidant mechanism on superoxide (O 2 -• ) anions using spectrophotometry and electron paramagnetic resonance (EPR). Methods: The O 2 -• was generated by oxidation of xanthine (XAN) by xanthine oxidase (XO) in the presence of spin trap 5-diethoxyphosphoryl-5-methyl-1-pyrroline N-oxide with various concentrations of leptin (0.001, 0.01, 0.1, and 1 mg/ml) and without leptin. Signal intensity between 3,440 and 3,540 G was expressed as standard means ± SD. The activity of leptin on XO was determined by monitoring the conversion of XAN to uric acid at 293 nm using a Beckman DU 800 UV–visible spectrophotometer. Results: Leptin added to aqueous solutions at 0.1 and 1 mg/ml concentrations was associated with a statistically significant decrease in the EPR signal due to leptin’s direct scavenging activity towards the O 2 -• . Conclusion: Leptin is an antioxidant agent of possible use as a marker of OS and future risk of atherosclerotic disease in OSA

Blueberry Metabolites Attenuate Lipotoxicity-Induced Endothelial Dysfunction

Scope: Lipotoxicity-induced endothelial dysfunction is an important vascular complication associated with diabetes. Clinical studies support the vascular benefits of blueberry anthocyanins, but the underlying mechanism is unclear. The hypothesis that metabolites of blueberry anthocyanins attenuate lipotoxicity-induced endothelial dysfunction was tested. Methods and results: Human aortic endothelial cells (HAECs) were treated for 6 h with either: (i) the parent anthocyanins (malvidin-3-glucoside and cyanidin-3-glucoside); or (ii) the blueberry metabolites (hydroxyhippuric acid, hippuric acid, benzoic acid-4-sulfate, isovanillic acid-3-sulfate, and vanillic acid-4-sulfate), at concentrations known to circulate in humans following blueberry consumption. For the last 5 h HAECs were treated with palmitate or vehicle. HAECs treated with palmitate displayed elevated reactive oxygen species generation, increased mRNA expression of NOX4, chemokines, adhesion molecules, and I?Ba, exaggerated monocyte binding, and suppressed nitric oxide production. Of note, the damaging effects of palmitate were ameliorated in HAECs treated with blueberry metabolites but not parent anthocyanins. Further, important translational relevance of these results was provided by our observation that palmitate-induced endothelial dysfunction was lessened in arterial segments that incubated concurrently with blueberry metabolites. Conclusion: The presented findings indicate that the vascular benefits of blueberry anthocyanins are mediated by their metabolites. Blueberries might complement existing therapies to lessen vascular complications

Dietary supplementation with strawberry induces marked changes in the composition and functional potential of the gut microbiome in diabetic mice

Gut microbiota contributes to the biological activities of berry anthocyanins by transforming them into bioactive metabolites, and anthocyanins support the growth of specific bacteria, indicating a two-way relationship between anthocyanins and microbiota. In the present study, we tested the hypothesis that strawberry supplementation alters gut microbial ecology in diabetic db/db mice. Control (db/+) and diabetic (db/db) mice (7 weeks old) consumed standard diet or diet supplemented with 2.35% freeze-dried strawberry (db/db?+?SB) for 10 weeks. Colon contents were used to isolate bacterial DNA. V4 variable region of 16S rRNA gene was amplified. Data analyses were performed using standardized pipelines (QIIME 1.9 and R packages). Differences in predictive metagenomics function were identified by PICRUSt. Principal coordinate analyses confirmed that the microbial composition was significantly influenced by both host genotype and strawberry consumption. Further, a-diversity indices and ß-diversity were different at the phylum and genus levels, and genus and operational taxonomical units levels, respectively (P<.05). At the phylum level, strawberry supplementation decreased the abundance of Verrucomicrobia in db/db?+?SB vs. db/db mice (P<.05). At the genus level, db/db mice exhibited a decrease in the abundance of Bifidobacterium, and strawberry supplementation increased Bifidobacterium in db/db?+?SB vs. db/db mice (P<.05). PICRUSt revealed significant differences in 45 predicted metabolic functions among the 3 groups. Our study provides evidence for marked changes in the composition and functional potential of the gut microbiome with strawberry supplementation in diabetic mice. Importantly, strawberry supplementation increased the abundance of beneficial bacteria Bifidobacterium which play a pivotal role in the metabolism of anthocyanins

Reactive oxygen species in in vitro pesticide-induced neuronal cell (SH-SY5Y) cytotoxicity: Role of NF?B and caspase-3

Oxidative stress has been implicated in pesticide-induced neurotoxicity, based on its role in the cascade of biochemical changes that lead to dopaminergic neuronal cell death. We have, therefore, examined the role of oxidative stress caused by the pesticides endosulfan and zineb in human neuroblastoma cells (SH-SY5Y) in culture. Upon treatment with 50-200 µM concentrations of either of these pesticides, SH-SY5Y cells generated both superoxide anion and hydrogen peroxide in a dose-and time-dependent manner. Mixtures of the pesticides significantly enhanced the production of these reactive oxygen species compared to individual pesticide exposures. Pesticide treatment decreased superoxide dismutase, glutathione peroxidase, and catalase activities in SH-SY5Y cells. Additionally, these pesticides induced lipid peroxide (thiobarbituric acid reactive products) formation in these cells. While both pesticides individually (at 100 µM) increased caspase-3 activity, cells exposed to a mixture of the pesticides exhibited significantly low levels of this enzyme, probably due to excessive necrotic cell death. Furthermore, exposure to these pesticides increased nuclear NF?B activity. Taken together, these findings suggest that the cytotoxicity of endosulfan and zineb, both individually and in mixtures may, at least in part, be associated with the generation of reactive oxygen species with concomitant increased expression of NF?B

The Highly Expressed and Inducible Endogenous NAD(P)H:quinone Oxidoreductase 1 in Cardiovascular Cells Acts as a Potential Superoxide Scavenger

It has recently been demonstrated that purified NAD(P)H:quinone oxidoreductase 1 (NQO1) is able to scavenge superoxide (O 2 •- ) though the rate of reaction of O 2 •- with NQO1 is much lower than the rate of enzymatic dismutation catalyzed by superoxide dismutase (SOD). This study was undertaken to determine if the endogenously expressed NQO1 in cardiovascular cells could scavenge O 2 •- . We observed thatNQO1 was highly expressed in cardiovascular cells, including rat aortic smooth muscle A10 and cardiac H9c2 cells, as well as normal human aortic smooth muscle and endothelial cells. NQO1, but not SOD in the cardiovascular cells was highly inducible by 3H-1,2-dithiole-3-thione (D3T). Cytosols from H9c2 and human aortic smooth muscle cells (HASMCs) were isolated to determine the O 2 •- scavenging ability of the endogenously expressed NQO1 by using pyrogallol autooxidation assay. We showed that cytosols from the above cells inhibited pyrogallol autooxidation in an NADPH or NADH-dependent manner. The NADH/NADPH-dependent inhibition of pyrogallol autooxidation by the cytosols was completely abolished by the NQO1-specific inhibitor, ES936, suggesting that the endogenously expressed NQO1 could scavenge O 2 •- . In the presence of NADH/NADPH, cytosols from D3T-treated cells showed increased ability to scavenge O 2 •- as compared to cytosols from untreated cells. This increased ability to scavenge O 2 •- was also completely reversed by ES936. 5-(Diethoxyphosphoryl)-5-methyl-1-pyrroline-N-oxide spin-trapping experiments using potassium superoxide as a O 2 •- generator further confirmed the ability of NQO1 from HASMCs to scavenge O 2 •- . The spin-trapping experiments also showed that induction of NQO1 by D3T in HASMCs augmented the O 2 •- scavenging ability. Taken together, these results demonstrate that the highly expressed and inducible endogenous NQO1 in cardiovascular cells may act as a potential O 2 •- scavenger

Genistein Induces Pancreatic ß-Cell Proliferation through Activation of Multiple Signaling Pathways and Prevents Insulin-Deficient Diabetes in Mice

Genistein, a flavonoid in legumes and some herbal medicines, has various biological actions. However, studies on whether genistein has an effect on pancreatic ß-cell function are very limited. In the present study, we investigated the effect of genistein on ß-cell proliferation and cellular signaling related to this effect and further determined its antidiabetic potential in insulin-deficient diabetic mice. Genistein induced both INS1 and human islet ß-cell proliferation after 24 h of incubation, with 5 µm genistein inducing a maximal 27% increase. The effect of genistein on ß-cell proliferation was neither dependent on estrogen receptors nor shared by 17ß-estradiol or a host of structurally related flavonoid compounds. Pharmacological or molecular intervention of protein kinase A (PKA) or ERK1/2 completely abolished genistein-stimulated ß-cell proliferation, suggesting that both molecules are essential for genistein action. Consistent with its effect on cell proliferation, genistein induced cAMP/PKA signaling and subsequent phosphorylation of ERK1/2 in both INS1 cells and human islets. Furthermore, genistein induced protein expression of cyclin D1, a major cell-cycle regulator essential for ß-cell growth. Dietary intake of genistein significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in streptozotocin-induced diabetic mice, concomitant with improved islet ß-cell proliferation, survival, and mass. These results demonstrate that genistein may be a natural antidiabetic agent by directly modulating pancreatic ß-cell function via activation of the cAMP/PKA-dependent ERK1/2 signaling pathway. Genistein may be a natural anti-diabetic agent by directly modulating pancreatic ß-cell function via activation of the cAMP/PKA-dependent ERK1/2 signaling pathway