Publications by authors named "Subbiah Rajasekaran"

27 Publications

  • Page 1 of 1

Anti-asthmatic effects of tannic acid from Chinese natural gall nuts in a mouse model of allergic asthma.

Int Immunopharmacol 2021 Jun 11;98:107847. Epub 2021 Jun 11.

Department of Biochemistry, ICMR-National Institute for Research in Environmental Health, Bhopal, Madhya Pradesh, India. Electronic address:

Asthma is a chronic inflammatory disease of the airways, which is characterized by infiltration of inflammatory cells, airway hyperresponsiveness (AHR), and airway remodeling. This study aimed to explore the role and mechanism of tannic acid (TA), a naturally occurring plant-derived polyphenol, in murine asthma model. BALB/c mice were given ovalbumin (OVA) to establish an allergic asthma model. The results revealed that TA treatment significantly decreased OVA-induced AHR, inflammatory cells infiltration, and the expression of various inflammatory mediators (Th2 and Th1 cytokines, eotaxin, and total IgE). Additionally, TA treatment also attenuated increases in mucins (Muc5ac and Muc5b) expression, mucus production in airway goblet cells, mast cells infiltration, and airway remodeling induced by OVA exposure. Furthermore, OVA-induced NF-κB (nuclear factor- kappa B) activation and cell adhesion molecules expression in the lungs was suppressed by TA treatment. In conclusion, TA effectively attenuated AHR, inflammatory response, and airway remodeling in OVA-challenged asthmatic mice. Therefore, TA may be a potential therapeutic option against allergic asthma in clinical settings.
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http://dx.doi.org/10.1016/j.intimp.2021.107847DOI Listing
June 2021

An overview on the role of plant-derived tannins for the treatment of lung cancer.

Phytochemistry 2021 Aug 8;188:112799. Epub 2021 May 8.

Department of Biochemistry, ICMR-National Institute for Research in Environmental Health, Bhopal, Madhya Pradesh, India. Electronic address:

Lung cancer is the leading cause of cancer-related death globally. Despite many advanced approaches to treat cancer, they are often ineffective due to resistance to classical anti-cancer drugs and distant metastases. Currently, alternative medicinal agents derived from plants are the major interest due to high bioavailability and fewer adverse effects. Tannins are polyphenolic compounds existing as specialized products in a wide variety of vegetables, fruits, and nuts. Many tannins have been found to possess protective properties, such as anti-inflammatory, anti-fibrotic, anti-microbial, anti-diabetic, and so on. This review aims to summarize the current knowledge addressing the anti-cancer effects of dietary tannins and their underlying molecular mechanisms. In vivo and in vitro studies provide evidences that anti-cancer effects of various tannins are predominantly mediated through negative regulation of transcription factors, growth factors, receptor kinases, and many oncogenic molecules. In addition, we also discussed the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of tannins, clinical trial results as well as our perspective on future research with tannins.
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http://dx.doi.org/10.1016/j.phytochem.2021.112799DOI Listing
August 2021

Therapeutic potential of plant-derived tannins in non-malignant respiratory diseases.

J Nutr Biochem 2021 Aug 29;94:108632. Epub 2021 Mar 29.

Department of Biotechnology, BIT-Campus, Anna University, Tiruchirappalli, Tamil Nadu, India.

Respiratory diseases are the major cause of human illness and death around the world. Despite advances in detection and treatment, very few classes of safe and effective therapy have been introduced to date. At present, phytochemicals are getting more attention because of their diverse beneficial activities and minimal toxicity. Tannins are polyphenolic secondary metabolites with high molecular weights, which are naturally present in a wide variety of fruits, vegetables, cereals, and leguminous seeds. Many tannins are endowed with well-recognized protective properties, such as anti-cancer, anti-microbial, anti-oxidant, anti-hyperglycemic, and many others. This review summarizes a large body of experimental evidence implicating that tannins are helpful in tackling a wide range of non-malignant respiratory diseases including acute lung injury (ALI), pulmonary fibrosis, asthma, pulmonary hypertension, and chronic obstructive pulmonary disease (COPD). Mechanistic pathways by which various classes of tannins execute their beneficial effects are discussed. In addition, clinical trials and our perspective on future research with tannins are also reviewed.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108632DOI Listing
August 2021

The herbicide paraquat-induced molecular mechanisms in the development of acute lung injury and lung fibrosis.

Crit Rev Toxicol 2021 Jan 2;51(1):36-64. Epub 2021 Feb 2.

Department of Biochemistry, ICMR-National Institute for Research in Environmental Health, Bhopal, India.

The herbicide paraquat (PQ; 1,1'-dimethyl-4,4'-bipyridylium dichloride) is a highly toxic organic heterocyclic herbicide that has been widely used in agricultural settings. Since its commercial introduction in the early 1960s, numerous cases of fatal PQ poisonings attributed to accidental and/or intentional ingestion of PQ concentrated formulations have been reported. The clinical manifestations of the respiratory system during the acute phase of PQ poisoning mainly include acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), followed by pulmonary fibrosis in a later phase. The focus of this review is to summarize the most recent publications related to PQ-induced lung toxicity as well as the underlying molecular mechanisms for PQ-mediated pathologic processes. Growing sets of data from in vitro and in vivo models have demonstrated the involvement of the PQ in regulating lung oxidative stress, inflammatory response, epigenetics, apoptosis, autophagy, and the progression of lung fibrosis. The article also summarizes novel therapeutic avenues based on a literature review, which can be explored as potential means to combat PQ-induced lung toxicity. Finally, we also presented clinical studies on the association of PQ exposure with the incidence of lung injury and pulmonary fibrosis.
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http://dx.doi.org/10.1080/10408444.2020.1864721DOI Listing
January 2021

Repurposing of histone deacetylase inhibitors: A promising strategy to combat pulmonary fibrosis promoted by TGF-β signalling in COVID-19 survivors.

Life Sci 2021 Feb 11;266:118883. Epub 2020 Dec 11.

Cancer Biology Laboratory, Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India. Electronic address:

Coronavirus disease 2019 (COVID-19) has rapidly spread around the world causing global public health emergency. In the last twenty years, we have witnessed several viral epidemics such as severe acute respiratory syndrome coronavirus (SARS-CoV), Influenza A virus subtype H1N1 and most recently Middle East respiratory syndrome coronavirus (MERS-CoV). There were tremendous efforts endeavoured globally by scientists to combat these viral diseases and now for SARS-CoV-2. Several drugs such as chloroquine, arbidol, remdesivir, favipiravir and dexamethasone are adopted for use against COVID-19 and currently clinical studies are underway to test their safety and efficacy for treating COVID-19 patients. As per World Health Organization reports, so far more than 16 million people are affected by COVID-19 with a recovery of close to 10 million and deaths at 600,000 globally. SARS-CoV-2 infection is reported to cause extensive pulmonary damages in affected people. Given the large number of recoveries, it is important to follow-up the recovered patients for apparent lung function abnormalities. In this review, we discuss our understanding about the development of long-term pulmonary abnormalities such as lung fibrosis observed in patients recovered from coronavirus infections (SARS-CoV and MERS-CoV) and probable epigenetic therapeutic strategy to prevent the development of similar pulmonary abnormalities in SARS-CoV-2 recovered patients. In this regard, we address the use of U.S. Food and Drug Administration (FDA) approved histone deacetylase (HDAC) inhibitors therapy to manage pulmonary fibrosis and their underlying molecular mechanisms in managing the pathologic processes in COVID-19 recovered patients.
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http://dx.doi.org/10.1016/j.lfs.2020.118883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831549PMC
February 2021

Tannic acid alleviates experimental pulmonary fibrosis in mice by inhibiting inflammatory response and fibrotic process.

Inflammopharmacology 2020 Oct 5;28(5):1301-1314. Epub 2020 May 5.

Department of Biotechnology, BIT-Campus, Anna University, Tiruchirappalli, Tamil Nadu, 620024, India.

Pulmonary fibrosis (PF) is a chronic and irreversible scarring disease in the lung with limited treatment options. Therefore, it is critical to identify new therapeutic options. This study was undertaken to identify the effects of tannic acid (TA), a naturally occurring dietary polyphenol, in a mouse model of PF. Bleomycin (BLM) was intratracheally administered to induce PF. Administration of TA significantly reduced BLM-induced histological alterations, inflammatory cell infiltration and the levels of various inflammatory mediators (nitric oxide, leukotriene B and cytokines). Additionally, treatment with TA also impaired BLM-mediated increases in pro-fibrotic (transforming growth factor-β1) and fibrotic markers (alpha-smooth muscle actin, vimentin, collagen 1 alpha and fibronectin) expression. Further investigation indicated that BLM-induced phosphorylation of Erk1/2 (extracellular signal-regulated kinases 1 and 2) in lungs was suppressed by TA treatment. Findings of this study suggest that TA has the potential to mitigate PF through inhibiting the inflammatory response and fibrotic process in lungs and that TA might be useful for the treatment of PF in clinical practice.
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http://dx.doi.org/10.1007/s10787-020-00707-5DOI Listing
October 2020

Tannic acid prevents macrophage-induced pro-fibrotic response in lung epithelial cells via suppressing TLR4-mediated macrophage polarization.

Inflamm Res 2019 Dec 5;68(12):1011-1024. Epub 2019 Sep 5.

Department of Biotechnology, BIT-Campus, Anna University, Tiruchirappalli, Tamil Nadu, India.

Background: Polarized macrophages induce fibrosis through multiple mechanisms, including a process termed epithelial-to-mesenchymal transition (EMT). Mesenchymal cells contribute to the excessive accumulation of fibrous connective tissues, leading to organ failure. This study was aimed to investigate the effect of tannic acid (TA), a natural dietary polyphenol on M1 macrophage-induced EMT and its underlying mechanisms.

Materials: First, we induced M1 polarization in macrophage cell lines (RAW 264.7 and THP-1). Then, the conditioned-medium (CM) from these polarized macrophages was used to induce EMT in the human adenocarcinomic alveolar epithelial (A549) cells. We also analysed the role of TA on macrophage polarization.

Results: We found that TA pre-treated CM did not induce EMT in epithelial cells. Further, TA pre-treated CM showed diminished activation of MAPK in epithelial cells. Subsequently, TA was shown to inhibit LPS-induced M1 polarization in macrophages by directly targeting toll-like receptor 4 (TLR4), thereby repressing LPS binding to TLR4/MD2 complex and subsequent signal transduction.

Conclusion: It was concluded that TA prevented M1 macrophage-induced EMT by suppressing the macrophage polarization possibly through inhibiting the formation of LPS-TLR4/MD2 complex and blockage of subsequent downstream signal activation. Further, our findings may provide beneficial information to develop new therapeutic strategies against chronic inflammatory diseases.
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http://dx.doi.org/10.1007/s00011-019-01282-4DOI Listing
December 2019

Tannic acid protects against experimental acute lung injury through downregulation of TLR4 and MAPK.

J Cell Physiol 2019 05 24;234(5):6463-6476. Epub 2018 Sep 24.

Department of Biotechnology, BIT-Campus, Anna University, Tiruchirappalli, India.

Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) remain a major cause of morbidity and mortality in critically ill patients, and no specific therapies are still available to control the mortality rate. Thus, we explored the preventive and therapeutic effects of tannic acid (TA), a natural polyphenol in the context of ALI. We used in vivo and in vitro models, respectively, using lipopolysaccharide (LPS) to induce ALI in mice and exposing J774 and BEAS-2B cells to LPS. In both preventive and therapeutic approaches, TA attenuated LPS-induced histopathological alterations, lipid peroxidation, lung permeability, infiltration of inflammatory cells, and the expression of proinflammatory mediators. In addition, in-vitro study showed that TA treatment could reduce the expression of proinflammatory mediators. Further studies revealed that TA-dampened inflammatory responses by downregulating the LPS-induced toll-like receptor 4 (TLR4) expression and inhibiting extracellular-signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) activation. Furthermore, cells treated with the inhibitors of ERK1/2 (PD98059) and p38 (SB203580) mitigated the expression of cytokines induced by LPS, thus suggesting that ERK1/2 and p38 activity are required for the inflammatory response. In conclusion, TA could attenuate LPS-induced inflammation and may be a potential therapeutic agent for ALI-associated inflammation in clinical settings.
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http://dx.doi.org/10.1002/jcp.27383DOI Listing
May 2019

Tannic acid modulates fibroblast proliferation and differentiation in response to pro-fibrotic stimuli.

J Cell Biochem 2018 08 17;119(8):6732-6742. Epub 2018 Apr 17.

Department of Biotechnology, Anna University, BIT-Campus, Tiruchirappalli, Tamil Nadu, India.

In response to tissue injury, fibroblasts migrate into the wound, where they undergo proliferation and differentiation. The persistence of these differentiated fibroblasts (myofibroblasts) is associated with excessive scarring in various organs. We aimed to investigate the effects of Tannic acid (TA) on fibroblast proliferation and differentiation, and found that TA inhibited fibroblast differentiation as assessed by reduced expression of α-smooth muscle actin, N-cadherin, and type-1-collagen. TA also prevented the TGF-β1-induced alteration in the expression of two classes of genes involved in the remodeling of extracellular matrix (ECM) proteins, namely matrix metalloproteinases (Mmp-2 and -9) and tissue inhibitors of metalloproteinases (Timp-1 and -3). Further, TA suppressed TGF-β1-induced cell proliferation and induced cell cycle arrest at G0/G1 phase via targeting Cyclins expression. Finally, TA exerted its inhibitory effects by decreasing the phosphorylation of Smad and ERK signaling. In sum, our results suggesting that TA may be a potential therapeutic agent for pathological fibrosis.
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http://dx.doi.org/10.1002/jcb.26866DOI Listing
August 2018

Design, synthesis, and characterization of α, β-unsaturated carboxylic acid, and its urea based derivatives that explores novel epigenetic modulators in human non-small cell lung cancer A549 cell line.

J Cell Physiol 2018 07 25;233(7):5293-5309. Epub 2018 Jan 25.

Department of Biochemistry, School of Life Sciences, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India.

Histone deacetylase inhibitors (HDACi) are a small molecule chemotherapeutics that target the chromatin remodeling through the regulation of histone and non-histone proteins. These inhibitors directed against histone deacetylase (HDAC) enzymes have become an important therapeutic tool in oncology; consequently, scientific efforts have fortified the quest for newer and novel HDACi, which forces the design of structurally innovative HDACi. Various urea containing compounds exhibited admirable anticancer activity. On the basis of these observations, we design and synthesize HDAC specific blocker molecules which are specifically besieged towards class I, class II, and class IV HDAC isoforms to enhance the structural assortment for HDACi. Through docking experiments, we identified that the compounds were tightly bound to the isoforms of the HDAC enzymes at their receptor regions. These derivatives potently inhibited the different isoforms, namely, class I, II, and IV of HDACs, by hyperacetylation of lysine residues in A549 cells. The mechanism of apoptosis is evident, regulating tumor suppressor genes and proteins, thereby facilitating the activation of the death receptor pathway by the tumor necrosis factor (TNF) receptor. These derivative facilitated the induction of reactive oxygen species (ROS) generation leading to downregulation of Bcl , and upregulation of Bax expression, thereby dysregulating mitochondrial membrane potential (ΔΨ ) to release cytochrome c, and activation of intrinsic pathway. These compounds downregulate the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway to inhibit cell growth, proliferation, and metastasis through the matrix metalloproteinases (MMPs) MMP2 and MMP9 in A549 cells. These results suggest that our designed urea based derivatives act as epigenetic targeting agents through HDAC inhibition.
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http://dx.doi.org/10.1002/jcp.26333DOI Listing
July 2018

Tannic acid attenuates TGF-β1-induced epithelial-to-mesenchymal transition by effectively intervening TGF-β signaling in lung epithelial cells.

J Cell Physiol 2018 Mar 30;233(3):2513-2525. Epub 2017 Aug 30.

Department of Biotechnology, Anna University, BIT-Campus, Tiruchirappalli, Tamil Nadu, India.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and an irreversible lung disorder characterized by the accumulation of fibroblasts and myofibroblasts in the extracellular matrix. The transforming growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) is thought to be one of the possible sources for a substantial increase in the number of fibroblasts/myofibroblasts in IPF lungs. Tannic acid (TA), a natural dietary polyphenolic compound has been shown to possess diverse pharmacological effects. However, whether TA can inhibit TGF-β1-mediated EMT in lung epithelial cells remains enigmatic. Both the human adenocarcinomic alveolar epithelial (A549) and normal bronchial epithelial (BEAS-2B) cells were treated with TGF-β1 with or without TA. Results showed that TA addition, markedly inhibited TGF-β1-induced EMT as assessed by reduced expression of N-cadherin, type-1-collagen, fibronectin, and vimentin. Furthermore, TA inhibited TGF-β1-induced cell proliferation through inducing cell cycle arrest at G0/G1 phase. TGF-β1-induced increase in the phosphorylation of Smad (Smad2 and 3), Akt as well as that of mitogen activated protein kinase (ERK1/2, JNK1/2, and p38) mediators was effectively inhibited by TA. On the other hand, TA reduced the TGF-β1-induced increase in TGF-β receptors expression. Using molecular docking approach, FTIR, HPLC and Western blot analyses, we further identified the direct binding of TA to TGF-β1. Finally, we conclude that TA might directly interact with TGF-β1, thereby repressing TGF-β signaling and subsequent EMT process in lung epithelial cells. Further animal studies are needed to clarify its potential therapeutic benefit in pulmonary fibrosis.
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http://dx.doi.org/10.1002/jcp.26127DOI Listing
March 2018

C-phycocyanin suppresses transforming growth factor-β1-induced epithelial mesenchymal transition in human epithelial cells.

Pharmacol Rep 2017 May 5;69(3):426-431. Epub 2017 Jan 5.

Department of Biotechnology, Anna University, BIT-Campus, Tiruchirappalli, Tamil Nadu, India.

Background: Epithelial mesenchymal transition (EMT) is a process through which epithelial cells undergo multiple biochemical changes, causing them to differentiate into a mesenchymal-cell phenotype. This process has been shown to contribute to the development of fibrotic diseases. C-phycocyanin (C-PC) is a phycobiliprotein extracted from Spirulina platensis. This study was done to investigate the effect of C-PC on transforming growth factor-β1 (TGF-β1)-induced EMT and an EMT associated proliferation in human epithelial cell lines.

Methods: Human adenocarcinoma cell line, A549 and breast cancer cell line, MCF-7 were treated with TGF-β1, and EMT-related genes expression, cell proliferation and cell cycle arrest were examined.

Results: C-PC suppressed the EMT as assessed by reduced expression of vimentin, type-1-collagen and fibronectin, and increased E-cadherin expression in TGF-β1 treated cells. Further, TGF-β1 treatment induced cell cycle arrest in S and G2/M phase in A549 cells. However, TGF-β1-mediated cell cycle arrest was significantly reversed by combined treatment with C-PC.

Conclusions: The overall data suggested that C-PC suppresses TGF- β1-induced EMT and warrants further in vivo studies for future evaluation of C-PC as a potential antifibrotic agent.
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http://dx.doi.org/10.1016/j.pharep.2016.12.013DOI Listing
May 2017

C-phycocyanin suppresses transforming growth factor-β1-induced epithelial mesenchymal transition in human epithelial cells.

Pharmacol Rep 2017 Jun 5;69(3):426-431. Epub 2017 Jan 5.

Department of Biotechnology, Anna University, BIT-Campus, Tiruchirappalli, Tamil Nadu, India. Electronic address:

Background: Epithelial mesenchymal transition (EMT) is a process through which epithelial cells undergo multiple biochemical changes, causing them to differentiate into a mesenchymal-cell phenotype. This process has been shown to contribute to the development of fibrotic diseases. C-phycocyanin (C-PC) is a phycobiliprotein extracted from Spirulina platensis. This study was done to investigate the effect of C-PC on transforming growth factor-β1 (TGF-β1)-induced EMT and an EMT associated proliferation in human epithelial cell lines.

Methods: Human adenocarcinoma cell line, A549 and breast cancer cell line, MCF-7 were treated with TGF-β1, and EMT-related genes expression, cell proliferation and cell cycle arrest were examined.

Results: C-PC suppressed the EMT as assessed by reduced expression of vimentin, type-1-collagen and fibronectin, and increased E-cadherin expression in TGF-β1 treated cells. Further, TGF-β1 treatment induced cell cycle arrest in S and G2/M phase in A549 cells. However, TGF-β1-mediated cell cycle arrest was significantly reversed by combined treatment with C-PC.

Conclusions: The overall data suggested that C-PC suppresses TGF- β1-induced EMT and warrants further in vivo studies for future evaluation of C-PC as a potential antifibrotic agent.
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http://dx.doi.org/10.1016/j.pharep.2016.12.013DOI Listing
June 2017

Plant Isoquinoline Alkaloid Berberine Exhibits Chromatin Remodeling by Modulation of Histone Deacetylase To Induce Growth Arrest and Apoptosis in the A549 Cell Line.

J Agric Food Chem 2016 Dec 12;64(50):9542-9550. Epub 2016 Dec 12.

Department of Biochemistry, School of Life Sciences, Bharathidasan University , Tiruchirappalli, Tamil Nadu 620 024, India.

Histone deacetylases (HDACs) are a group of epigenetic enzymes that control gene expression through their repressive influence on histone deacetylation transcription. HDACs are probable therapeutic targets for cancer treatment, spurring the progress of different types of HDAC inhibitors. Further, natural-source-based derived bioactive compounds possess HDAC inhibitor property. In this way, we hypothesized that plant isoquinoline alkaloid berberine (BBR) could be a HDAC inhibitor in the human lung cancer A549 cell line. BBR represses total HDAC and also class I, II, and IV HDAC activity through hyperacetylation of histones. Furthermore, BBR triggers positive regulation of the sub-G/G cell cycle progression phase in A549 cells. Moreover, BBR-induced A549 cell growth arrest and morphological changes were confirmed using different fluorescence-dye-based microscope techniques. Additionally, BBR downregulates oncogenes (TNF-α, COX-2, MMP-2, and MMP-9) and upregulates tumor suppressor genes (p21 and p53) mRNA and protein expressions. Besides, BBR actively regulates Bcl-2/Bax family proteins and also triggered the caspase cascade apoptotic pathway in A549 cells. Our finding suggests that BBR mediates epigenetic reprogramming by HDAC inhibition, which may be the key mechanism for its antineoplastic activity.
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http://dx.doi.org/10.1021/acs.jafc.6b04453DOI Listing
December 2016

Diagnostic Potential of Extracellular MicroRNA in Respiratory Diseases.

Clin Rev Allergy Immunol 2018 Jun;54(3):480-492

Department of Biotechnology, BIT-Campus, Anna University, Tiruchirappalli, Tamil Nadu, India.

Lack of markers of subclinical disease state and clinical phenotype other than pulmonary function test has made the diagnosis and interventions of environmental respiratory diseases a major challenge. MicroRNAs (miRNAs), small non-coding single stranded RNAs, have emerged as potential disease-modifier in various environmental respiratory diseases. They can also be found in various body fluids and are remarkably stable. Because of their high stability, disease-specific expression, and the ease to detect and quantify them have raised the potential of miRNAs in body fluids to be useful clinical diagnostic biomarkers for lung disease phenotyping. In the present review, we provide a comprehensive overview of progress made in identifying miRNAs in various body fluids including blood, serum, plasma, bronchoalveolar lavage (BAL) fluid, and sputum as biomarkers for a wide range of human respiratory diseases such as acute lung injury/acute respiratory distress syndrome (ALI/ARDS), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and asthma. Finally, we discuss several challenges remain to be concerned and suggest few disease-specific and non-specific miRNAs to become part of future clinical practice.
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http://dx.doi.org/10.1007/s12016-016-8589-9DOI Listing
June 2018

MicroRNA Regulation of Acute Lung Injury and Acute Respiratory Distress Syndrome.

J Cell Physiol 2016 10 4;231(10):2097-106. Epub 2016 Feb 4.

Department of Pulmonary Medicine, JSS Hospital, JSS University, Sri Shivarathreeshwara Nagara, Mysore, Karnataka, India.

The acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), is a very common condition associated with critically ill patients, which causes substantial morbidity and mortality worldwide. Despite decades of research, effective therapeutic strategies for clinical ALI/ARDS are not available. In recent years, microRNAs (miRNAs), small non-coding molecules have emerged as a major area of biomedical research as they post-transcriptionally regulate gene expression in diverse biological and pathological processes, including ALI/ARDS. In this context, this present review summarizes a large body of evidence implicating miRNAs and their target molecules in ALI/ARDS originating largely from studies using animal and cell culture model systems of ALI/ARDS. We have also focused on the involvement of miRNAs in macrophage polarization, which play a critical role in regulating the pathogenesis of ALI/ARDS. Finally, the possible future directions that might lead to novel therapeutic strategies for the treatment of ALI/ARDS are also reviewed. J. Cell. Physiol. 231: 2097-2106, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcp.25316DOI Listing
October 2016

MicroRNAs as potential targets for progressive pulmonary fibrosis.

Front Pharmacol 2015 5;6:254. Epub 2015 Nov 5.

Department of Biotechnology, Bharathidasan Institute of Technology Campus, Anna University Tiruchirappalli, India.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and devastating disorder. It is characterized by alveolar epithelial cell injury and activation, infiltration of inflammatory cells, initiation of epithelial mesenchymal transition (EMT), aberrant proliferation and activation of fibroblasts, exaggerated deposition of extracellular matrix (ECM) proteins, and finally leading to the destruction of lung parenchyma. MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that post-transcriptionally regulate gene expression in diverse biological and pathological processes, including cell proliferation, differentiation, apoptosis and metastasis. As a result, miRNAs have emerged as a major area of biomedical research with relevance to pulmonary fibrosis. In this context, the present review discusses specific patterns of dysregulated miRNAs in patients with IPF. Further, we discuss the current understanding of miRNAs involvement in regulating lung inflammation, TGF-β1-mediated EMT and fibroblast differentiation processes, ECM genes expression, and in the progression of lung fibrosis. The possible future directions that might lead to novel therapeutic strategies for the treatment of pulmonary fibrosis are also reviewed.
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http://dx.doi.org/10.3389/fphar.2015.00254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633493PMC
November 2015

Sirtuin 1 Promotes Hyperoxia-Induced Lung Epithelial Cell Death Independent of NF-E2-Related Factor 2 Activation.

Am J Respir Cell Mol Biol 2016 05;54(5):697-706

Division of Developmental Biology and Basic Research, Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.

Lung epithelial cell damage accompanied by death is a cardinal feature of toxicant- and prooxidant-induced acute lung injury. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (NEF2L2 or NRF2) activates several antioxidant enzymes (AOEs) and prosurvival genes in response to oxidant stress, and its deficiency enhances susceptibility to hyperoxic lung injury and other oxidant-induced lung pathologies. Sirtuin 1 (SIRT1) regulates cell growth and survival in response to both physiological and pathological stresses by selectively deacetylating multiple proteins required for chromatin remodeling and transcription; therefore, we sought to examine potential SIRT1-NRF2 cross-talk in the regulation of AOE expression during hyperoxia-induced lung epithelial cell death. Unexpectedly, pharmacological inhibition or small interfering RNA-mediated depletion of SIRT1 caused a reduction in cell death, accompanied by reduced levels of NRF2-dependent AOE expression in chronic hyperoxia. NRF2 acetylation was markedly and transiently higher in cells exposed to acute (6 h) hyperoxia. Sirtinol blocked this acute effect, but NRF2 acetylation was low or undetectable in cells exposed to chronic hyperoxia (24-36 h) both with and without sirtinol. SIRT1 activation by resveratrol augmented hyperoxia-induced death in cells with NRF2 deficiency. SIRT1 inhibition or depletion led to a reduced activation of the cell-death executioner caspase 3, whereas caspase inhibition prevented death. Consistent with these results, sirtinol attenuated hyperoxia-induced lung alveolar permeability and toxicity in vivo. Collectively, these results reveal that, in chronic hyperoxia, SIRT1 promotes hyperoxia-induced lung epithelial cell damage and death by altering pro- and antiapoptotic balance, not by dampening optimal NRF2-dependent AOE expression.
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http://dx.doi.org/10.1165/rcmb.2014-0056OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942191PMC
May 2016

Visualization of Fra-1/AP-1 activation during LPS-induced inflammatory lung injury using fluorescence optical imaging.

Am J Physiol Lung Cell Mol Physiol 2015 Aug 12;309(4):L414-24. Epub 2015 Jun 12.

Division of Developmental Biology and Basic Research, Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois;

Inappropriate lung inflammatory response following oxidant and toxicant exposure can lead to abnormal repair and disease pathogenesis, including fibrosis. Thus early detection of molecular and cellular processes and mediators promoting lung inflammation is necessary to develop better strategies for therapeutic intervention and disease management. Previously, we have shown that transcription factor Fra-1/AP-1 plays key roles in lung inflammatory response, as Fra-1-null mice are less susceptible than wild-type mice to LPS-induced lung injury and mortality. Herein, we developed a transgenic reporter mouse model expressing tdTomato under the control of FRA-1 (human) promoter (referred to as FRA-1(TdTg) mice) to monitor its activation during inflammatory lung injury using fluorescence protein-based optical imaging and molecular analysis in vivo and ex vivo. A higher red fluorescent signal was observed in the lungs of LPS-treated FRA-1(TdTg) mice compared with vehicle controls, and Western blot and qRT-PCR analyses revealed a significant correlation with the FRA-1-tdTomato reporter expression. Immunocolocalization demonstrated expression of FRA-1-tdTomato largely in lung alveolar macrophages and to some extent in epithelial cells. Moreover, we validated these results with a second reporter mouse model that expressed green fluorescent protein upon activation of endogenous Fra-1 promoter. Additionally, we demonstrated increased expression of FRA-1 in alveolar macrophages in human lung instilled with Escherichia coli ex vivo. Collectively, our data obtained from two independent reporter mouse models and from human samples underscore the significance of Fra-1 activation in alveolar macrophages during inflammatory lung injury and may aid in developing strategies to target this transcription factor in lung injury and repair.
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http://dx.doi.org/10.1152/ajplung.00315.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538236PMC
August 2015

Myeloid-specific Fos-related antigen-1 regulates cigarette smoke-induced lung inflammation, not emphysema, in mice.

Am J Respir Cell Mol Biol 2015 Jul;53(1):125-34

2 Division of Developmental Biology and Basic Research, Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois.

Heightened lung inflammation is a cardinal feature of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS)-induced macrophage recruitment and activation, accompanied by abnormal secretion of a number of inflammatory cytokines and matrix metalloproteinases, play a major role in the pathophysiology of COPD. The Fos-related antigen-1 (Fra-1) transcription factor differentially regulates several cellular processes that are implicated in COPD, such as inflammation and immune responses, cell proliferation and death, and extracellular remodeling. Although CS stimulates Fra-1 expression in the lung, the precise role of this transcription factor in the regulation of CS-induced lung inflammation in vivo is poorly understood. Here, we report that myeloid-specific Fra-1 signaling is important for CS-induced lung macrophagic inflammatory response. In response to chronic CS exposure, mice with Fra-1 specifically deleted in myeloid cells showed reduced levels of CS-induced lung macrophagic inflammation, accompanied by decreased expression levels of proinflammatory cytokines compared with their wild-type counterparts. Consistent with this result, bone marrow-derived Fra-1-null macrophages treated with CS showed decreased levels of proinflammatory mediators and matrix metalloproteinases. Interestingly, deletion of Fra-1 in myeloid cells did not affect the severity of emphysema. We propose that Fra-1 plays a key role in promoting chronic CS-induced lung macrophagic inflammation in vivo, and that targeting this transcription factor may be useful in dampening persistent lung inflammation in patients with COPD.
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http://dx.doi.org/10.1165/rcmb.2014-0118OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566106PMC
July 2015

Expression profiling of genes regulated by Fra-1/AP-1 transcription factor during bleomycin-induced pulmonary fibrosis.

BMC Genomics 2013 Jun 7;14:381. Epub 2013 Jun 7.

Division of Developmental Biology and Basic Research, Department of Pediatrics, University of Illinois at Chicago, Chicago, IL 60612, USA.

Background: The Fra-1/AP-1 transcription factor regulates the expression of genes controlling various processes including migration, invasion, and survival as well as extracellular remodeling. We recently demonstrated that loss of Fra-1 leads to exacerbated bleomycin-induced pulmonary fibrosis, accompanied by enhanced expression of various inflammatory and fibrotic genes. To better understand the molecular mechanisms by which Fra-1 confers protection during bleomycin-induced lung injury, genome-wide mRNA expression profiling was performed.

Results: We found that Fra-1 regulates gene expression programs that include: 1) several cytokines and chemokines involved in inflammation, 2) several genes involved in the extracellular remodeling and cell adhesion, and 3) several genes involved in programmed cell death.

Conclusion: Loss of Fra-1 leads to the enhanced expression of genes regulating inflammation and immune responses and decreased the expression of genes involved in apoptosis, suggesting that this transcription factor distinctly modulates early pro-fibrotic cellular responses.
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http://dx.doi.org/10.1186/1471-2164-14-381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685523PMC
June 2013

Fra-1/AP-1 transcription factor negatively regulates pulmonary fibrosis in vivo.

PLoS One 2012 24;7(7):e41611. Epub 2012 Jul 24.

Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois, United States of America.

The Fra-1/AP-1 transcription factor plays a key role in tumor epithelial cell progression; however, its role in pathogenic lung fibrosis remains unclear. In the present study, using a genetic approach (Fra-1 deficient mice), we have demonstrated a novel regulatory (protective) role for Fra-1 in lung fibrosis. We found greater levels of progressive interstitial fibrosis, characterized by increased levels of inflammation, collagen accumulation, and profibrotic and fibrotic gene expression in the lungs of Fra-1(Δ/Δ) mice than in those of Fra-1(+/+) mice following bleomycin treatment. Fra-1 knockdown in human lung epithelial cells caused the upregulation of mesenchymal marker N-cadherin, concomitant with a downregulation of the epithelial phenotype marker E-cadherin, under basal conditions and in response to bleomycin and TGF-β1. Furthermore, Fra-1 knockdown caused an enhanced expression of type 1 collagen and the downregulation of collagenase (MMP-1 and MMP-13) gene expression in human lung epithelial cells. Collectively, our findings demonstrate that Fra-1 mediates anti-fibrotic effects in the lung through the modulation of proinflammatory, profibrotic and fibrotic gene expression, and suggests that the Fra-1 transcription factor may be a potential target for pulmonary fibrosis, a progressive disorder with poor prognosis and treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041611PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404039PMC
February 2013

Genetic disruption of Fra-1 decreases susceptibility to endotoxin-induced acute lung injury and mortality in mice.

Am J Respir Cell Mol Biol 2012 Jan;46(1):55-62

Department of Pediatrics, University of Illinois at Chicago, 60612, USA.

The activator protein-1 (AP-1) transcription factor, comprising Jun and Fos family proteins, distinctly regulates various cellular processes, including those involved in inflammation. FOS like antigen 1 (Fra-1), a member of the Fos family, dimerizes with members of the Jun family and regulates gene expression in a context-dependent manner. Although respiratory toxicants are known to stimulate the expression of Fra-1 in the lung, whether Fra-1 promotes or decreases susceptibility to the development and progression of toxicant-induced lung disease in vivo is not well established. To determine the role of Fra-1 in LPS-induced acute lung injury and mortality, we administered LPS either intraperitoneally or intratracheally to Fra-1-sufficient (Fra-11(+/+)) and Fra-1-deficient (Fra-1(Δ/Δ)) mice. LPS-induced mortality, lung injury, inflammation, cytokine measurements, and AP-1 and NF-κB activities were then assessed in these mice. Fra-1(Δ/Δ) mice showed a greater resistance to LPS-induced mortality than did their Fra-1(+/+) counterparts. Consistent with this result, LPS-induced lung injury and inflammatory responses were markedly lower in Fra-1(Δ/Δ) mice than in Fra-1(+/+) mice. Compared with Fra-1(+/+) mice, Fra-1(Δ/Δ) mice showed a reduced influx of neutrophils into the lungs, accompanied by a decreased expression of proinflammatory cytokines in response to treatment with LPS. The decreased inflammatory responses in Fra-1(Δ/Δ) mice coincided with diminished and increased levels of NF-κB and c-Jun/AP-1 binding, respectively. These results demonstrate that Fra-1/AP-1 plays a key role in promoting LPS-induced injury and mortality in mice, and they suggest that targeting (i.e., inhibiting) this transcription factor may be a useful approach to dampening the adverse effects of exposure to endotoxins.
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http://dx.doi.org/10.1165/rcmb.2011-0169OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262652PMC
January 2012

Detection of experimentally induced pulmonary granuloma inflammation in monocyte chemoattractant protein-1 reporter mice.

Mol Imaging Biol 2010 Apr 6;12(2):163-73. Epub 2009 Oct 6.

Division of Medical Engineering Research, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, Republic of China.

Purpose: Among different chemokines, monocyte chemoattractant protein-1 (MCP-1) plays an important role in inflammatory disorders of lung. In response to stimuli, MCP-1 increases its transcription as an immediate early gene. In this paper, we describe the MCP-1-enhanced green fluorescent protein(EGFP) transgenic mouse in which EGFP expression is driven by human MCP-1 promoter and mimics the MCP-1 expression in situ. Thus, the MCP-1 reporter mouse model is designed to facilitate a better understanding of its role in various diseases. We employed this mouse model in a pulmonary granulomatous inflammation model using intratracheal instillation of Sephadex (SDX) beads and compared the EGFP reporter expression to endogenous MCP-1 expression through the course of inflammation.

Procedures: We analyzed the temporal pattern of SDX-induced infiltration of inflammatory cells in lung and in bronchoalveolar lavage fluid (BALF). The changes in tissue fluorescence, gene, and protein expressions for both MCP-1 and EGFP were analyzed.

Results: SDX instillation caused massive infiltration of inflammatory cells in BALF and lung tissue at the end of day 3. There was an increase of fluorescence in SDX-treated lung and BALF cells. By using lipopolysaccharide-induced systemic inflammation model, increase of fluorescence was found in bone marrow Gr-1(+) cells with high Mac-1 expression. MCP-1 and EGFP gene expression and MCP-1 protein level were increased after day 1, peaked at day 3, and declined toward basal levels at day 5. In contrast, EGFP protein level peaked after day 3 and remained elevated after day 5. Immunohistochemical staining revealed the MCP-1 and EGFP expression primarily at alveolar macrophages, macrophages infiltrating the granulomatous lesions and in bronchiolar epithelial cells.

Conclusions: By using a pulmonary granuloma model, we showed that EGFP transgene reporter expression in MCP-1-EGFP mouse was correlated to the endogenous MCP-1 induction. The establishment of this mouse model will provide a valuable tool for monitoring the activation of monocytes/macrophages and facilitate the studies on the roles of MCP-1 gene in various inflammatory diseases.
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http://dx.doi.org/10.1007/s11307-009-0261-9DOI Listing
April 2010

Angiogenic evaluation of ginsenoside Rg 1 from Panax ginseng in fluorescent transgenic mice.

Vascul Pharmacol 2008 Jul 17;49(1):37-43. Epub 2008 May 17.

Division of Medical Engineering Research, National Health Research Institute, Zhunan Town, Miaoli County, Taiwan, ROC.

Background: Evaluation of angiogenesis-inducing compounds is essential in tissue engineering to develop biological substitutes for the repair or regeneration of tissue function. In this report, we evaluated the angiogenic ability of ginsenoside Rg 1 from Panax ginseng, in Matrigel implanted on fluorescent transgenic mice.

Methods: The in vitro proliferation ability of each test agent was estimated by MTS assay. The Matrigel loaded with basic fibroblast growth factor (bFGF) or Rg 1 and Matrigel alone were implanted on fluorescent transgenic mice and were retrieved at 1, 4, 6 and 8 weeks after implantation to measure various conventional markers for angiogenesis including neo-vascular density and hemoglobin content. Additionally, the functional neo-vasculature in the implanted Matrigel was visualized using confocal laser scanning microscopy (CLSM).

Results: The in vitro results indicated that the stimulating effect of Rg 1 on HUVECs proliferation remained unchanged after dissolved for 30 days in culture medium at 37 degrees C when compared with the effect of bFGF. One week after implantation in transgenic mice, bFGF or Rg 1 mixed in Matrigel plug significantly enhanced angiogenesis; however, at 6 weeks a significant decrease in angiogenic effect was observed in Matrigel with bFGF, but not in Matrigel with Rg 1. The neo-vessels structure was visualized in three dimensions (3D) by CLSM and the results were in agreement with other conventional measurements for angiogenesis.

Conclusion: These findings confirm that Rg 1 could be used in tissue tissue-engineering applications and that the fluorescent transgenic mice can be a useful experimental model for studying angiogenesis.
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http://dx.doi.org/10.1016/j.vph.2008.05.002DOI Listing
July 2008

Beneficial effects of aloe vera leaf gel extract on lipid profile status in rats with streptozotocin diabetes.

Clin Exp Pharmacol Physiol 2006 Mar;33(3):232-7

Department of Biochemistry and Molecular Biology, University of Madras, Guindy Campus, Chennai, Tamil Nadu, India.

The effect of diabetes mellitus on lipid metabolism is well established. The association of hyperglycaemia with an alteration of lipid parameters presents a major risk for cardiovascular complications in diabetes. Many secondary plant metabolites have been reported to possess lipid-lowering properties. The present study was designed to examine the potential anti-hyperlipidaemic efficacy of the ethanolic extract from Aloe vera leaf gel in streptozotocin (STZ)-induced diabetic rats. 2. Oral administration of Aloe vera gel extract at a dose of 300 mg/kg bodyweight per day to STZ-induced diabetic rats for a period of 21 days resulted in a significant reduction in fasting blood glucose, hepatic transaminases (aspartate aminotransferase and alanine aminotransferase), plasma and tissue (liver and kidney) cholesterol, triglycerides, free fatty acids and phospholipids and a significant improvement in plasma insulin. 3. In addition, the decreased plasma levels of high-density lipoprotein-cholesterol and increased plasma levels of low-density lipoprotein-and very low-density lipoprotein-cholesterol in diabetic rats were restored to near normal levels following treatment with the extract. 4. The fatty acid composition of the liver and kidney was analysed by gas chromatography. The altered fatty acid composition in the liver and kidney of diabetic rats was restored following treatment with the extract. 5. Thus, the results of the present study provide a scientific rationale for the use of Aloe vera as an antidiabetic agent.
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http://dx.doi.org/10.1111/j.1440-1681.2006.04351.xDOI Listing
March 2006

Antioxidant effect of Aloe vera gel extract in streptozotocin-induced diabetes in rats.

Pharmacol Rep 2005 Jan-Feb;57(1):90-6

Department of Biochemistry and Molecular Biology, University of Madras, Guindy Campus, Chennai - 600 025, Tamil Nadu, India.

In the present study, an attempt has been made to evaluate the presence of antioxidant property in the alcoholic extract of Aloe vera leaf gel. Oral administration of Aloe vera gel extract at a concentration of 300 mg/kg to diabetic rats significantly decreased the levels of blood glucose, glycosylated hemoglobin and increased hemoglobin. The increased levels of lipid peroxidation and hydroperoxides in tissues of diabetic rats were reverted back to near normal levels after the treatment with gel extract. The extract treatment also resulted in a significant increase in reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase in the liver and kidney of diabetic rats. These results clearly show the antioxidant property of Aloe vera gel extract. The extract was also more effective than glibenclamide in restoring the values of these parameters.
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June 2005