14 results on '"Rehman, Rakhshinda"'
Search Results
2. Ku70 modulation alleviates murine allergic asthma features and restores mitochondrial function in lungs.
- Author
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Rehman R, Jaiswal A, Agrawal A, and Mabalirajan U
- Subjects
- Animals, Asthma chemically induced, Asthma genetics, Asthma physiopathology, Bronchoalveolar Lavage, Disease Models, Animal, Injections, Intravenous, Lung metabolism, Male, Mice, Plasmids genetics, Transforming Growth Factor beta metabolism, Asthma therapy, Genetic Vectors administration & dosage, Ku Autoantigen genetics, Mitochondria metabolism, Ovalbumin adverse effects
- Abstract
The airway epithelium is continuously exposed to a variety of pollutants and allergens, thanks to both natural and manmade environmental pollution. With numerous protective mechanisms, the airway epithelium protects the lungs. DNA repair mechanism is one such protective response and its failure could lead to the accumulation of DNA mutations. Our lab had earlier demonstrated the dysfunctional mitochondria in airway epithelium of the asthmatic mice lungs. Here, we show that Ku70 modulation by the administration of Ku70 plasmid attenuates asthma features and reduces mitochondrial dysfunction in the lungs of allergen exposed mice. Ku70 is a key DNA repair protein with diverse roles including VDJ recombination, telomere maintenance, and maintenance of cell homeostasis. Recently, we found a reduction in Ku70 expression in asthmatic airway epithelium, and this was associated with mitochondrial dysfunction in asthmatic condition. In this study, we have shown that Ku70 over-expression in asthmatic mice attenuated airway hyperresponsiveness, airway inflammation, sub-epithelial fibrosis along with reduction in TGF-β with no effect in IL-13 levels and goblet cell metaplasia. Ku70 over-expression in asthmatic mice reduced 8-isoprostane, a marker of oxidative stress, and restored the mitochondrial function in asthmatic mice. We further found these roles of Ku70 to be independent of DNA damage as Ku70 overexpressed mice did not show any reduction in DNA tail, an index of DNA damage. Thus, our findings indicate that Ku70 can attenuate crucial features of asthma along with the restoration of mitochondrial function. This implies that Ku70 could be a therapeutic target for asthma without affecting DNA repair function., (Copyright © 2020 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
3. Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-κB.
- Author
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Panda L, Gheware A, Rehman R, Yadav MK, Jayaraj BS, Madhunapantula SV, Mahesh PA, Ghosh B, Agrawal A, and Mabalirajan U
- Subjects
- Animals, Asthma drug therapy, Asthma pathology, Disease Models, Animal, Epithelial Cells drug effects, Epithelial Cells metabolism, Humans, Hypersensitivity drug therapy, Hypersensitivity immunology, Hypersensitivity metabolism, Hypersensitivity pathology, Lipid Metabolism, Mice, Receptors, Glucocorticoid metabolism, Respiratory Mucosa drug effects, Respiratory Mucosa metabolism, Respiratory Mucosa pathology, Anti-Asthmatic Agents pharmacology, Asthma metabolism, Drug Resistance, Linoleic Acid metabolism, NF-kappa B metabolism, Steroids pharmacology
- Abstract
Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. Its 12/15-lipoxygenase metabolite, 13-S-hydroxyoctadecadienoic acid (HODE) induces mitochondrial dysfunction, with severe airway obstruction and neutrophilic airway inflammation. Here we show that HODE administration leads to steroid unresponsiveness in an otherwise steroid responsive model of allergic airway inflammation (AAI). HODE treatment to allergic mice further increased airway hyperresponsiveness and goblet metaplasia. Treatment with dexamethasone was associated with increased neutrophilic inflammation in HODE treated allergic mice; unlike control allergic mice that showed resolution of inflammation. HODE induced loss of steroid sensitivity was associated with increased p-NFkB in mice and reduced GR-α transcript levels in cultured human bronchial epithelia. In summary, HODE modifies typical AAI to recapitulate many of the phenotypic features seen in severe steroid unresponsive asthma. We speculate that since HODE is a natural metabolite, it may be relevant to the increased asthma severity and steroid insensitivity in patients who are obese or consume high fat diets. Further characterization of HODE induced steroid insensitivity may clarify the mechanisms.
- Published
- 2017
- Full Text
- View/download PDF
4. Proficient DNA repair in house dust mite-induced asthma?
- Author
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Rehman R and Mabalirajan U
- Subjects
- Allergens, Animals, DNA Repair, Dust, Mites immunology, Asthma, Pyroglyphidae immunology
- Published
- 2017
- Full Text
- View/download PDF
5. Parabromophenacyl bromide inhibits subepithelial fibrosis by reducing TGF-β1 in a chronic mouse model of allergic asthma.
- Author
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Ram A, Mabalirajan U, Jaiswal A, Rehman R, Singh VP, and Ghosh B
- Subjects
- Actins metabolism, Airway Remodeling drug effects, Animals, Asthma pathology, Asthma physiopathology, Disease Models, Animal, Fibrosis, Goblet Cells drug effects, Goblet Cells pathology, Lung drug effects, Lung pathology, Lung physiopathology, Male, Metaplasia, Mice, Mice, Inbred BALB C, Phospholipase A2 Inhibitors pharmacology, Respiratory Hypersensitivity drug therapy, Respiratory Hypersensitivity pathology, Respiratory Hypersensitivity physiopathology, Signal Transduction drug effects, Transforming Growth Factor beta1 metabolism, Acetophenones pharmacology, Asthma drug therapy, Transforming Growth Factor beta1 antagonists & inhibitors
- Abstract
Background: Our previous study showed that parabromophenacyl bromide (PBPB) inhibits the features of allergic airway inflammation and airway hyperresponsiveness (AHR). However, its effect on airway remodeling, e.g. subepithelial fibrosis in a chronic allergic asthma model, was not investigated. We examined this issue in this study., Methods: PBPB was administered to mice with an induced chronic asthmatic condition. AHR was estimated at the end of the experiment, followed by euthanasia. Lung sections were stained with hematoxylin and eosin, periodic acid-Schiff and Masson's trichrome to determine airway inflammation, goblet cell metaplasia and subepithelial fibrosis, respectively. Transforming growth factor-β1 (TGF-β1) was estimated in lung homogenates. To determine the effect of PBPB on smooth-muscle hyperplasia, immunohistochemistry against α-smooth-muscle actin was performed on the lung sections., Results: Chronic ovalbumin challenges in a mouse model of allergic asthma caused significant subepithelial fibrosis and elevated TGF-β1, along with significant AHR. PBPB attenuated subepithelial fibrosis with a reduction of lung TGF-β1, airway inflammation and AHR without affecting goblet cell metaplasia. It also attenuated smooth-muscle hyperplasia with a reduction in the expression of α-smooth-muscle actin in the lungs., Conclusion: Our findings indicate that PBPB attenuates some crucial features of airway remodeling such as subepithelial fibrosis and smooth-muscle hyperplasia. These data suggest that PBPB could therefore be a therapeutic drug for chronic asthma., (© 2015 S. Karger AG, Basel.)
- Published
- 2015
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6. Chemical chaperones mitigate experimental asthma by attenuating endoplasmic reticulum stress.
- Author
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Makhija L, Krishnan V, Rehman R, Chakraborty S, Maity S, Mabalirajan U, Chakraborty K, Ghosh B, and Agrawal A
- Subjects
- Airway Remodeling drug effects, Animals, Glycerol pharmacology, Inflammation drug therapy, Lung drug effects, Male, Methylamines pharmacology, Mice, Mice, Inbred BALB C, Phenylbutyrates pharmacology, Protein Folding drug effects, Trehalose pharmacology, Unfolded Protein Response drug effects, Asthma drug therapy, Endoplasmic Reticulum drug effects, Endoplasmic Reticulum Stress drug effects, Molecular Chaperones pharmacology
- Abstract
Endoplasmic reticulum (ER) stress and consequent unfolded protein response (UPR) are important in inflammation but have been poorly explored in asthma. We used a mouse model of allergic airway inflammation (AAI) with features of asthma to understand the role of ER stress and to explore potential therapeutic effects of inhaled chemical chaperones, which are small molecules that can promote protein folding and diminish UPR. UPR markers were initially measured on alternate days during a 7-day daily allergen challenge model. UPR markers increased within 24 hours after the first allergen challenge and peaked by the third challenge, before AAI was fully established (from the fifth challenge onward). Three chemical chaperones-glycerol, trehalose, and trimethylamine-N-oxide (TMAO)-were initially administered during allergen challenge (preventive regimen). TMAO, the most effective of these chemical chaperones and 4-phenylbutyric acid, a chemical chaperone currently in clinical trials, were further tested for potential therapeutic activities after AAI was established (therapeutic regimen). Chemical chaperones showed a dose-dependent reduction in UPR markers, airway inflammation, and remodeling in both regimens. Our results indicate an early and important role of the ER stress pathway in asthma pathogenesis and show therapeutic potential for chemical chaperones.
- Published
- 2014
- Full Text
- View/download PDF
7. Baicalein reduces airway injury in allergen and IL-13 induced airway inflammation.
- Author
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Mabalirajan U, Ahmad T, Rehman R, Leishangthem GD, Dinda AK, Agrawal A, Ghosh B, and Sharma SK
- Subjects
- Airway Remodeling drug effects, Airway Remodeling immunology, Allergens adverse effects, Animals, Anti-Asthmatic Agents administration & dosage, Apoptosis drug effects, Arachidonate 15-Lipoxygenase metabolism, Asthma chemically induced, Caspase 12 metabolism, Caspase 3 metabolism, Cytosol metabolism, Electron Transport Complex IV metabolism, Enzyme Activation drug effects, Eosinophilia drug therapy, Eosinophilia immunology, Flavanones administration & dosage, Inflammation drug therapy, Inflammation immunology, Interleukin-13 adverse effects, Male, Mice, Mitochondria drug effects, Mitochondria metabolism, Respiratory Hypersensitivity drug therapy, Respiratory Hypersensitivity immunology, Allergens immunology, Anti-Asthmatic Agents pharmacology, Asthma drug therapy, Asthma immunology, Flavanones pharmacology, Interleukin-13 immunology
- Abstract
Background: Baicalein, a bioflavone present in the dry roots of Scutellaria baicalensis Georgi, is known to reduce eotaxin production in human fibroblasts. However, there are no reports of its anti-asthma activity or its effect on airway injury., Methodology/principal Findings: In a standard experimental asthma model, male Balb/c mice that were sensitized with ovalbumin (OVA), treated with baicalein (10 mg/kg, ip) or a vehicle control, either during (preventive use) or after OVA challenge (therapeutic use). In an alternate model, baicalein was administered to male Balb/c mice which were given either IL-4 or IL-13 intranasally. Features of asthma were determined by estimating airway hyperresponsiveness (AHR), histopathological changes and biochemical assays of key inflammatory molecules. Airway injury was determined with apoptotic assays, transmission electron microscopy and assessing key mitochondrial functions. Baicalein treatment reduced AHR and inflammation in both experimental models. TGF-β₁, sub-epithelial fibrosis and goblet cell metaplasia, were also reduced. Furthermore, baicalein treatment significantly reduced 12/15-LOX activity, features of mitochondrial dysfunctions, and apoptosis of bronchial epithelia., Conclusion/significance: Our findings demonstrate that baicalein can attenuate important features of asthma, possibly through the reduction of airway injury and restoration of mitochondrial function.
- Published
- 2013
- Full Text
- View/download PDF
8. TRPV1 inhibition attenuates IL-13 mediated asthma features in mice by reducing airway epithelial injury.
- Author
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Rehman R, Bhat YA, Panda L, and Mabalirajan U
- Subjects
- Animals, Asthma genetics, Bronchial Hyperreactivity genetics, Cytokines metabolism, Disease Models, Animal, Gene Expression Regulation genetics, Gene Knockdown Techniques, Goblet Cells pathology, Humans, Interleukin-13 immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, RNA, Small Interfering genetics, TRPV Cation Channels genetics, Asthma immunology, Respiratory Mucosa immunology, TRPV Cation Channels metabolism
- Abstract
Even though neurogenic axis is well known in asthma pathogenesis much attention had not been given on this aspect. Recent studies have reported the importance of TRP channels, calcium-permeable ion channels and key molecules in neurogenic axis, in asthma therapeutics. The role of TRPV1 channels has been underestimated in chronic respiratory diseases as TRPV1 knockout mice of C57BL/6 strains did not attenuate the features of these diseases. However, this could be due to strain differences in the distribution of airway capsaicin receptors. Here, we show that TRPV1 inhibition attenuates IL-13 induced asthma features by reducing airway epithelial injury in BALB/c mice. We found that IL-13 increased not only the lung TRPV1 levels but also TRPV1 expression in bronchial epithelia in BALB/c rather than in C57BL/6 mice. TRPV1 knockdown attenuated airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and subepithelial fibrosis induced by IL-13 in BALB/c mice. Further, TRPV1 siRNA treatment reduced not only the cytosolic calpain and mitochondrial calpain 10 activities in the lung but also bronchial epithelial apoptosis indicating that TRPV1 siRNA might have corrected the intracellular and intramitochondrial calcium overload and its consequent apoptosis. Knockdown of IL-13 in allergen induced asthmatic mice reduced TRPV1, cytochrome c, and activities of calpain and caspase 3 in lung cytosol. Thus, these findings suggest that induction of TRPV1 with IL-13 in bronchial epithelia could lead to epithelial injury in in vivo condition. Since TRPV1 expression is correlated with human asthma severity, TRPV1 inhibition could be beneficial in attenuating airway epithelial injury and asthma features., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
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9. 12/15-lipoxygenase expressed in non-epithelial cells causes airway epithelial injury in asthma.
- Author
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Mabalirajan U, Rehman R, Ahmad T, Kumar S, Leishangthem GD, Singh S, Dinda AK, Biswal S, Agrawal A, and Ghosh B
- Subjects
- 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid blood, 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid immunology, 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid metabolism, 3T3 Cells, Animals, Arachidonate 12-Lipoxygenase genetics, Arachidonate 12-Lipoxygenase metabolism, Arachidonate 15-Lipoxygenase genetics, Arachidonate 15-Lipoxygenase metabolism, Asthma genetics, Asthma metabolism, Blotting, Western, Cell Line, Cytochromes c immunology, Cytochromes c metabolism, Epithelium drug effects, Epithelium immunology, Epithelium pathology, Fibroblasts drug effects, Fibroblasts metabolism, Humans, Immunohistochemistry, Interleukin-13 administration & dosage, Interleukin-13 immunology, Interleukin-13 pharmacology, Lactones, Linoleic Acids blood, Linoleic Acids immunology, Linoleic Acids metabolism, Lung immunology, Lung metabolism, Lung ultrastructure, Macrophages drug effects, Macrophages metabolism, Male, Membrane Potential, Mitochondrial drug effects, Membrane Potential, Mitochondrial immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Transmission, Mitochondria immunology, Mitochondria metabolism, Mitochondria physiology, Sesquiterpenes, Eudesmane, Arachidonate 12-Lipoxygenase immunology, Arachidonate 15-Lipoxygenase immunology, Asthma immunology, Fibroblasts immunology, Macrophages immunology
- Abstract
The mechanisms underlying asthmatic airway epithelial injury are not clear. 12/15-lipoxygenase (an ortholog of human 15-LOX-1), which is induced by IL-13, is associated with mitochondrial degradation in reticulocytes at physiological conditions. In this study, we showed that 12/15-LOX expressed in nonepithelial cells caused epithelial injury in asthma pathogenesis. While 12/15-LOX overexpression or IL-13 administration to naïve mice showed airway epithelial injury, 12/15-LOX knockout/knockdown in allergic mice reduced airway epithelial injury. The constitutive expression of 15-LOX-1 in bronchial epithelia of normal human lungs further indicated that epithelial 15-LOX-1 may not cause epithelial injury. 12/15-LOX expression is increased in various inflammatory cells in allergic mice. Though non-epithelial cells such as macrophages or fibroblasts released 12/15-LOX metabolites upon IL-13 induction, bronchial epithelia didn't release. Further 12-S-HETE, arachidonic acid metabolite of 12/15-LOX leads to epithelial injury. These findings suggested 12/15-LOX expressed in non-epithelial cells such as macrophages and fibroblasts leads to bronchial epithelial injury.
- Published
- 2013
- Full Text
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10. A novel cinnamate derivative attenuates asthma features and reduces bronchial epithelial injury in mouse model.
- Author
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Kumar S, Mabalirajan U, Rehman R, Singh BK, Parmar VS, Prasad AK, Biswal S, and Ghosh B
- Subjects
- Allergens, Animals, Anti-Asthmatic Agents pharmacology, Asthma metabolism, Asthma pathology, Asthma physiopathology, Bronchi pathology, Bronchi physiopathology, Bronchial Hyperreactivity drug therapy, Bronchial Hyperreactivity metabolism, Bronchial Hyperreactivity pathology, Bronchial Hyperreactivity physiopathology, Cinnamates pharmacology, Cytokines blood, DNA Damage drug effects, Immunoglobulin E blood, Immunoglobulin G blood, Male, Mice, Mice, Inbred BALB C, NF-kappa B metabolism, Ovalbumin, Respiratory Mucosa injuries, Respiratory Mucosa pathology, Respiratory Mucosa physiopathology, Anti-Asthmatic Agents therapeutic use, Asthma drug therapy, Cinnamates therapeutic use
- Abstract
Airway epithelial injury is the hallmark of various respiratory diseases and therapeutic targeting of epithelial injury could be an effective strategy for controlling these diseases. We recently reported that a novel cinnamate, ethyl 3',4',5'-trimethoxythionocinnamate (ETMTC) derived from Piper longum derivative, was most potent among various cinnamate derivatives in inhibiting inflammatory cell adhesion molecules (CAMs). In this study, we investigated the effects of ETMTC on the features of allergic asthma and epithelial injury in a murine model. ETMTC treatment to ovalbumin sensitized and challenged mice during ovalbumin challenge reduced airway hyperresponsiveness, and airway inflammation. This attenuation of asthma features was associated with the reduction in the expressions of various CAMs, NF-κB activation, Th2 cytokines, eotaxin and 8-isoprostane that were estimated in lung homogenates. Further, it increased activities of mitochondrial complexes I and IV in lung mitochondria and reduced cytochrome c and caspase 9 activities in lung cytosol. In addition, it reduced the levels of oxidative DNA damage marker in bronchoalveolar lavage fluid and DNA fragmentation of bronchial epithelia in lung sections. Further, ETMTC not only increased the levels of 15-(S)-hydroxyeicosatetraenoic acid, suppressor of airway remodeling, but also inhibited goblet cell metaplasia and sub-epithelial fibrosis. These results demonstrate that ETMTC reduces epithelial injury and mitochondrial dysfunction associated with allergic asthma and thus ETMTC could be useful to develop efficient therapeutic molecule against asthma., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2013
- Full Text
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11. Linoleic acid metabolite drives severe asthma by causing airway epithelial injury.
- Author
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Mabalirajan U, Rehman R, Ahmad T, Kumar S, Singh S, Leishangthem GD, Aich J, Kumar M, Khanna K, Singh VP, Dinda AK, Biswal S, Agrawal A, and Ghosh B
- Subjects
- Animals, Asthma genetics, Asthma immunology, Calcium metabolism, Disease Models, Animal, Extracellular Space metabolism, Fatty Acids, Unsaturated metabolism, Gene Knockdown Techniques, Humans, Mice, Mice, Inbred BALB C, Mitochondria metabolism, Mitochondria ultrastructure, Neutrophils immunology, Respiratory Mucosa immunology, Species Specificity, TRPV Cation Channels genetics, TRPV Cation Channels metabolism, Asthma metabolism, Linoleic Acid metabolism, Respiratory Mucosa metabolism, Respiratory Mucosa pathology
- Abstract
Airway epithelial injury is the hallmark of various respiratory diseases, but its mechanisms remain poorly understood. While 13-S-hydroxyoctadecadienoic acid (13-S-HODE) is produced in high concentration during mitochondrial degradation in reticulocytes little is known about its role in asthma pathogenesis. Here, we show that extracellular 13-S-HODE induces mitochondrial dysfunction and airway epithelial apoptosis. This is associated with features of severe airway obstruction, lung remodeling, increase in epithelial stress related proinflammatory cytokines and drastic airway neutrophilia in mouse. Further, 13-S-HODE induced features are attenuated by inhibiting Transient Receptor Potential Cation Channel, Vanilloid-type 1 (TRPV1) both in mouse model and human bronchial epithelial cells. These findings are relevant to human asthma, as 13-S-HODE levels are increased in human asthmatic airways. Blocking of 13-S-HODE activity or disruption of TRPV1 activity attenuated airway injury and asthma mimicking features in murine allergic airway inflammation. These findings indicate that 13-S-HODE induces mitochondrial dysfunction and airway epithelial injury.
- Published
- 2013
- Full Text
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12. Noncanonical role for Ku70/80 in the prevention of allergic airway inflammation via maintenance of airway epithelial cell organelle homeostasis.
- Author
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Rehman, Rakhshinda, Vijayakumar, Vijay Elakkya, Jaiswal, Ashish, Jain, Vaibhav, Mukherjee, Shravani, Vellarikkal, Shamsudheen Karuthedath, Dieffenbach, Paul B., Fredenburgh, Laura E., Prakash, Y. S., Ghosh, Balaram, Agrawal, Anurag, and Mabalirajan, Ulaganathan
- Abstract
Airway epithelial homeostasis is under constant threat due to continuous exposure to the external environment, and abnormally robust sensitivity to external stimuli is critical to the development of airway diseases, including asthma. Ku is a key nonhomologous end-joining DNA repair protein with diverse cellular functions such as VDJ recombination and telomere length maintenance. Here, we show a novel function of Ku in alleviating features of allergic airway inflammation via the regulation of mitochondrial and endoplasmic reticulum (ER) stress. We first determined that airway epithelial cells derived from both asthmatic lungs and murine asthma models demonstrate increased expression of 8-hydroxy-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Ku protein expression was dramatically reduced in the bronchial epithelium of patients with asthma as well as in human bronchial epithelial cells exposed to oxidative stress. Knockdown of Ku70 or Ku80 in naïve mice elicited mitochondrial collapse or ER stress, leading to bronchial epithelial cell apoptosis and spontaneous development of asthma-like features, including airway hyperresponsiveness, airway inflammation, and subepithelial fibrosis. These findings demonstrate an essential noncanonical role for Ku proteins in asthma pathogenesis, likely via maintenance of organelle homeostasis. This novel function of Ku proteins may also be important in other disease processes associated with organelle stress. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
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13. Parabromophenacyl Bromide Inhibits Subepithelial Fibrosis by Reducing TGF-β1 in a Chronic Mouse Model of Allergic Asthma.
- Author
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Ram, Arjun, Mabalirajan, Ulaganathan, Jaiswal, Ashish, Rehman, Rakhshinda, Singh, Vijay Pal, and Ghosh, Balaram
- Subjects
PULMONARY fibrosis treatment ,ASTHMA treatment ,TRANSFORMING growth factors-beta ,BROMIDES ,EPITHELIAL cells ,PHENYL compound derivatives ,ANIMAL models of asthma ,HYPERPLASIA ,THERAPEUTICS - Abstract
Background: Our previous study showed that parabromophenacyl bromide (PBPB) inhibits the features of allergic airway inflammation and airway hyperresponsiveness (AHR). However, its effect on airway remodeling, e.g. subepithelial fibrosis in a chronic allergic asthma model, was not investigated. We examined this issue in this study. Methods: PBPB was administered to mice with an induced chronic asthmatic condition. AHR was estimated at the end of the experiment, followed by euthanasia. Lung sections were stained with hematoxylin and eosin, periodic acid-Schiff and Masson's trichrome to determine airway inflammation, goblet cell metaplasia and subepithelial fibrosis, respectively. Transforming growth factor-β
1 (TGF-β1 ) was estimated in lung homogenates. To determine the effect of PBPB on smooth-muscle hyperplasia, immunohistochemistry against α-smooth-muscle actin was performed on the lung sections. Results: Chronic ovalbumin challenges in a mouse model of allergic asthma caused significant subepithelial fibrosis and elevated TGF-β1 , along with significant AHR. PBPB attenuated subepithelial fibrosis with a reduction of lung TGF-β1 , airway inflammation and AHR without affecting goblet cell metaplasia. It also attenuated smooth-muscle hyperplasia with a reduction in the expression of α-smooth-muscle actin in the lungs. Conclusion: Our findings indicate that PBPB attenuates some crucial features of airway remodeling such as subepithelial fibrosis and smooth-muscle hyperplasia. These data suggest that PBPB could therefore be a therapeutic drug for chronic asthma. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
14. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy.
- Author
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Ahmad, Tanveer, Mukherjee, Shravani, Pattnaik, Bijay, Kumar, Manish, Singh, Suchita, Rehman, Rakhshinda, Tiwari, Brijendra K, Jha, Kumar A, Barhanpurkar, Amruta P, Wani, Mohan R, Roy, Soumya S, Mabalirajan, Ulaganathan, Ghosh, Balaram, and Agrawal, Anurag
- Subjects
MITOCHONDRIA ,MESENCHYMAL stem cells ,ASTHMA treatment ,RHO GTPases ,BIOLOGICAL transport ,LABORATORY mice - Abstract
There is emerging evidence that stem cells can rejuvenate damaged cells by mitochondrial transfer. Earlier studies show that epithelial mitochondrial dysfunction is critical in asthma pathogenesis. Here we show for the first time that Miro1, a mitochondrial Rho- GTPase, regulates intercellular mitochondrial movement from mesenchymal stem cells ( MSC) to epithelial cells ( EC). We demonstrate that overexpression of Miro1 in MSC ( MSCmiro
Hi ) leads to enhanced mitochondrial transfer and rescue of epithelial injury, while Miro1 knockdown ( MSCmiroLo ) leads to loss of efficacy. Treatment with MSCmiroHi was associated with greater therapeutic efficacy, when compared to control MSC, in mouse models of rotenone (Rot) induced airway injury and allergic airway inflammation ( AAI). Notably, airway hyperresponsiveness and remodeling were reversed by MSCmiroHi in three separate allergen-induced asthma models. In a human in vitro system, MSCmiroHi reversed mitochondrial dysfunction in bronchial epithelial cells treated with pro-inflammatory supernatant of IL-13-induced macrophages. Anti-inflammatory MSC products like NO, TGF-β, IL-10 and PGE2, were unchanged by Miro1 overexpression, excluding non-specific paracrine effects. In summary, Miro1 overexpression leads to increased stem cell repair. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
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