Curcumin intervention during progressive fibrosis controls inflammatory cytokines and the fibrinolytic system in pulmonary fibrosis.

Persistent injuries and chronic inflammation paired with dysregulated healing process in the lungs leads to scarring and stiffening of the tissue leading to a condition called pulmonary fibrosis. There is no efficacious therapy against the condition because of the poorly understood pathophysiology of the disease. Curcumin is well known anti-inflammatory natural compound and is shown to have beneficial effects in many diseases. It is also reported to show antifibrotic activities in pulmonary fibrosis. There are evidences that fibrinolytic system plays a crucial role in the development of pulmonary fibrosis. We aimed to see whether curcumin could regulate inflammation and fibrinolysis in murine model of pulmonary fibrosis. We prepared BLM induced pulmonary fibrosis model by administering BLM at a dose of 2 mg/ kg bodyweight. Curcumin (75 mg/kg body wt) was instilled intraperitoneally on different time points. The effect of curcumin on inflammatory cytokines and fibrinolytic system was studied using molecular biology techniques like RT-PCR, western blot and immunohistochemistry/immunofluorescence. We observed that BLM brought changes in the expressions of components in the fibrinolytic system, i.e. BLM favoured fibrin deposition by increasing the expression of PAI-1 (plasminogen activator inhibitor) and decreasing the expression of uPA (Urokinase plasminogen activator) and uPAR (Urokinase plasminogen activator receptor). We also demonstrate that curcumin could restore the normal expression of fibrinolytic components, uPA, uPAR and PAI-1. Curcumin could also minimize the expression of key enzymes in tissue remodeling in pulmonary fibrosis, MMP-2 and MMP-9, which were elevated in the BLM treated group. Our data suggest that curcumin exerts an anti-inflammatory and antifibrotic effect in lungs. We highlight curcumin as a feasible adjuvant therapy option against pulmonary fibrosis.

Curcumin attenuates IL-17A mediated pulmonary SMAD dependent and non-dependent mechanism during acute lung injury in vivo.

Acute lung injury (ALI) is a pathologic condition responsible for incurable human chronic respiratory diseases. Recent studies have shown the involvement of the glycoprotein, IL17A secreted by IL-17 producing cells in chronic inflammation. The current investigation was carried out to study the IL-17A mediated activation of SMAD and non- SMAD signaling in alveolar epithelial cells and to assess the putative modulatory role of curcumin. C57BL/6 mice were exposed to IL-17A and curcumin was administered as an intervention to modulate the IL-17A-induced alveolar damage. Techniques like Immunofluorescence and real-time PCR were used. We found elevated expression of IL-17A and IL-17A-associated signaling pathways to be activated in mice lung tissues. Curcumin intervention in vivo promoted the resolution of IL-17A-induced ALI and attenuated pulmonary damage. Increase phosphorylation of non- SMAD proteins like P-EGFR, P-STAT-1, STAT-3, P-JAK-1/2, P-JNK, and also SMAD proteins like P- SMAD 2/3 and TGF-ß1 was encountered upon IL-17A exposure, while curcumin intervention reversed the protein expression levels. Curcumin was found to block mRNA expressions of non- SMAD genes EGFR, JNK-1, JAK1, JAK2, STAT-1, STAT-3, MAPK14, also of TGF-ß1 and SMAD genes like SMAD 2, SMAD 3. However, mRNA expressions of SMAD 6 and SMAD 7 were increased upon curcumin intervention. Our study indicates that IL-17A participates in the development of ALI in both SMAD dependent and independent manner and the IL-17A signaling components were effectively controlled by curcumin, suggesting probable anti-inflammatory use of curcumin during ALI.

Targeting anti-aging protein sirtuin (Sirt) in the diagnosis of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a severe, incurable, age-associated respiratory disorder that has gained significance because of its unknown etiology and lack of therapeutic approaches. IPF causes maximum damage to the alveolar epithelial cells, thereby leading to lung remodeling and initiating epithelial to mesenchymal transition (EMT). The actual molecular mechanisms underlying IPF still remain unclear, and knowledge about these mechanisms would be helpful in its diagnosis. Sirtuins (Sirt) are class of NAD+-dependent proteins, widely known to exert positive and protective effects on age-related diseases such as diabetes, cancer, and so on, and are also involved in regulating IPF. The sirtuin family comprises of seven members (Sirt1 to Sirt7), out of which Sirt1, Sirt3, Sirt6, and Sirt7 exert positive effects on IPF. Sirt1 is associated with aging and inhibits cellular senescence and fibrosis. Sirt1 is well recognized in controlling pulmonary fibrosis and is also considered as a prime positive mediator of EMT. The expressions of Sirt3 protein tend to decline in IPF patients; hence it is known as an anti-fibrotic protein. Sirt6 indeed has been proven to reduce EMT during IPF. Decreased levels of Sirt7 during IPF regulate lung fibroblasts. Hence, active levels of Sirt1, Sirt3, Sirt6, and Sirt7 can be attractive target models to elucidate a novel potential therapeutic approach for IPF. In this prospect, we have discussed the role of Sirtuins in pulmonary fibrosis by exploring the recent research evidence that highlight the role of sirtuins and also describes their protective effects.

Changes in the expression level of IL-17A and p53-fibrinolytic system in smokers with or without COPD.

COPD is a chronic airway inflammatory disease characterized mainly by neutrophil airway infiltrations. The neutrophil airway inflammation is mainly mediated through a key player like the pro-inflammatory cytokine IL-17A which is involved in the modulation of p53-fibrinolytic system. This study was undertaken to examine the molecular changes for the expressions of IL-17A and p53-fibrinolytic system in smokers with or without COPD. Blood and serum samples were collected from ten patients of smokers having COPD and ten samples from smokers without COPD and ten healthy control subjects. Western blot analyses were performed to evaluate the expressions of IL-17A, p53 and PAI-1. Apoptosis was assessed by immunoblot for cleaved caspase-3. In addition, FEV% was also determined of these patients. qRT-PCR was done to detect the gene expression study from the blood samples on p53-fibrinolytic components. A significant difference was found in the expression levels of IL-17A in smokers with COPD patient when compared to smokers without COPD and the control subjects. Similarly the smokers with COPD showed significant increase in the fibrinolytic component PAI-1 as well as in expression levels of p53 when compared to smokers without COPD and normal subjects. Increased cleaved caspase-3 may also promote apoptosis.The expression pattern of the IL-17A in chronic obstructive pulmonary distress syndrome samples was increased as compared of those of normal samples, and their main role in the regulation of and p53-fibrinolytic system makes these components as a predictive prominent component in smokers with COPD.

Inflammatory and Fibrinolytic System in Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is the most advanced form of acute lung injury (ALI). This is characterized by bilateral pulmonary infiltrates and severe hypoxemia. According to Berlin definition of ARDS, this is defined based on the timings, radiographic changes, edema formation, and severity on the PaO2/FiO2 ratio. During ARDS, the loss of integrity of the epithelium causes the septic shock. The degree of epithelial injury is the major prognostic marker of ARDS. In addition to this, inflammatory cell migration, fibro-proliferation, and activation of apoptosis also play an important role in the pathophysiology of ARDS. The alveolar epithelial cell is the prime target during injury where this cell either undergo apoptosis or epithelial-mesenchymal transition (EMT). Injury to the AECs triggers the changes in the DNA fragmentation and activation of certain apoptotic markers such as caspases at the same time some cells undergo biochemical changes and loses its epithelial morphology as well epithelial biomarkers and gain mesenchymal biomarkers and morphology. In both the cases, the fibrinolytic system plays an important role in maintaining the integrity of the disease process efficiently. This review highlights the research evidence of apoptosis and EMT in lung development, injury and its prognosis in ARDS thereby to develop an effective strategy for the treatment of ARDS.

Squamous Cell Carcinoma of the Middle Ear-A Common Tumor at an Uncommon Site.

Squamous cell carcinoma of the middle ear is a very rare tumor. Early detection is uncommon as the tumor usually manifests as persistent ear discharge and otalgia, often misdiagnosed as chronic suppurative otitis media. We present a rare case of squamous cell carcinoma of the middle ear which clinically presented as chronic suppurative otitis media. Therefore, clinicians should have a high index of suspicion for clinically refractive cases of otorrhea, otalgia, excess bleeding, and non-responsiveness to treatment. All polyps and granulation tissue in EAC and middle ear should be submitted for histopathological examination especially in cases refractory to treatment.

Abnormal expression profile of plasma exosomal microRNAs in exclusive electronic cigarette adult users.

Background: Exposure to electronic cigarette (e-cigarette) aerosol has been linked to several health concerns, including DNA damage, elevated oxidative stress, the release of inflammatory cytokine, and dysfunctions in epithelial barriers. However, little is known about the effect of exclusive e-cigarette use on expression profiles of exosomal miRNAs, which play critical regulatory roles in many inflammatory responses and disease processes including cancer. We aim to compare the exosomal microRNA expression profile between exclusive e-cigarette users and normal controls without any tobacco product use (non-users). Methods: Using plasma samples from 15 exclusive e-cigarette users and 15 non-users in the Population Assessment of Tobacco and Health (PATH) Wave 1 study (2013-2014), we examined exosomal microRNAs expression levels through Illumina NextSeq 500/550 sequencing. The differential analyses between exclusive e-cigarette users and non-users were examined using the generalized linear model approach in the DESeq2 package in R/Bioconductor after adjusting the significant confounding effect from race. Gene enrichment analyses were conducted on target genes regulated by significant microRNAs in the differential analyses. Further, molecular-based techniques using the micro RNA mimics and inhibitors were applied for the validation of the expressions of the micro RNAs in vitro. Results: We identified four microRNAs that have significantly higher expression levels in exclusive e-cigarette users than non-users including hsa-miR-100-5p, hsa-miR-125a-5p, hsa-miR-125b-5p, and hsa-miR-99a-5p. GO enrichment analysis on the target genes regulated by the four microRNAs showed that dysregulation of the four microRNAs in exclusive e-cigarette users involved in multiple cell processes such as protein kinase binding and miRNA metabolic process. KEGG pathway enrichment analysis found the four upregulated miRNAs in exclusive e-cigarette users involved in many cancer pathways such as the non-small cell lung cancer, small cell lung cancer, pancreatic cancer, p53 signaling pathway, Hippo signaling pathway, HIF-1 signaling pathway, and MAPK signaling pathway. Overexpression of miRNA hsa-miR-125b-5p was shown to promote DNA damage in bronchial epithelia cells. Conclusions: Four plasma exosomal microRNAs involved in cancer development had higher expression levels in exclusive e-cigarette users than non-users, which might indicate a potentially elevated risk of cancer among exclusive e-cigarette users.

Lung as a target for COVID-19: Mechanistic insights and probable candidate molecules for cure.

Novel coronavirus (SARS nCoV2), belonging to the family coronaviridae, remains a dreadful pathogen affecting the respiratory tract and lungs. COVID-19 declared a global pandemic by WHO, has become a serious cause of concern for clinicians and researchers, who need to understand the significant biology and pathogenicity of this virus to design better treatment modalities. Existing antiretroviral drugs remain partially ineffective in critical subjects with associated co-morbidities. This review provides an insight into the molecular mechanisms by which SARS-CoV2 targets the lungs leading to ARDS in severe cases. This also addresses the possible drug targets and certain anti-inflammatory natural compounds that can be looked upon as promising adjuvant therapeutics for COVID-19.

Emerging roles of senolytics/senomorphics in HIV-related co-morbidities.

Human immunodeficiency virus (HIV) is known to cause cellular senescence and inflammation among infected individuals. While the traditional antiretroviral therapies (ART) have allowed the once fatal infection to be managed effectively, the quality of life of HIV patients on prolonged ART use is still inferior. Most of these individuals suffer from life-threatening comorbidities like chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), and diabetes, to name a few. Interestingly, cellular senescence is known to play a critical role in the pathophysiology of these comorbidities as well. It is therefore important to understand the role of cellular senescence in the disease progression and co-morbidity development in HIV-infected individuals. In this respect, use of senolytic/senomorphic drugs as combination therapy with ART would be beneficial for HIV patients. This review provides a critical analysis of the current literature to determine the potential and efficacy of using senolytics/senotherapeutics in managing HIV infection, latency, and associated co-morbidities in humans. The various classes of senolytics have been studied in detail to focus on their potential to combat against HIV infections and associated pathologies with advancing age.

Impact of aging on immune function in the pathogenesis of pulmonary diseases: potential for therapeutic targets.

INTRODUCTION: Several immunological alterations that occur during pulmonary diseases often mimic alterations observed in the aged lung. From the molecular perspective, pulmonary diseases and aging partake in familiar mechanisms associated with significant dysregulation of the immune systems. Here, we summarized the findings of how aging alters immunity to respiratory conditions to identify age-impacted pathways and mechanisms that contribute to the development of pulmonary diseases. AREAS COVERED: The current review examines the impact of age-related molecular alterations in the aged immune system during various lung diseases, such as COPD, IPF, Asthma, and alongside many others that could possibly improve on current therapeutic interventions. Moreover, our increased understanding of this phenomenon may play a primary role in shaping immunomodulatory strategies to boost outcomes in the elderly. Here, the authors present new insights into the context of lung-related diseases and describe the alterations in the functioning of immune cells during various pulmonary conditions altered with age. EXPERT OPINION: The expert opinion provided the concepts on how aging alters immunity during pulmonary conditions, and suggests the associated mechanisms during the development of lung diseases. As a result, it becomes important to comprehend the complex mechanism of aging in the immune lung system.

Corrigendum to "The role of synthetic coolants, WS-3 and WS-23, in modulating E-cigarette-induced reactive oxygen species (ROS) in lung epithelial cells" [Toxicol. Rep. 9 (2022) 1700-1709].

[This corrects the article DOI: 10.1016/j.toxrep.2022.08.007.].

Alterations in mRNA Expression Levels of Tight Junction Proteins in the Blood Cells of Smokers with or without COPD.

AIM: This study aimed to assess the role of Tight junction proteins (TJPs) and claudins in smokers with and without COPD compared to healthy individuals. BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex chronic respiratory disease, including various inflammatory mediators. The prime etiological element in the development of COPD is cigarette smoking. The lung airway epithelium comprises beneficial immunological barriers to draw in insults, such as environmental particulates, cigarette smoke, etc. Tight junctions (TJ) connected by transmembrane proteins determine epithelial permeability. Cigarette smoke is indicated to defect TJ integrity. The possible involvement of the airway epithelium in the pathogenesis of COPD has recently become apparent; however, its detailed mechanisms remain elusive. The integrity of airway epithelium is crucial for airway homeostasis; defective airway barrier activity contributes to COPD. OBJECTIVE: In the present study, the objective was to investigate mRNA expression levels of TJP's like TJP-1, TJP-2, TJP-3, Tight junction-associated proteins-1, claudin-1, claudin-3, claudin-4, claudin-7, claudin-10, claudin-15, claudin-19, and claudin-25 from blood samples of smokers with COPD and compared them with smokers without COPD and healthy individuals. METHODS: The mRNA expressions were evaluated by the quantitative PCR method. RESULTS: The gene expressions of these TJPs were significantly down-regulated, specifically in COPD patients with a history of smoking (Smokers with COPD). Besides, FEV% was also established for these patients. Similarly, smokers with COPD showed a significant increase in the expression levels of transcription factors, like ZEB-1, ZEB-2, PDGFA, and HDGF, compared to COPD patients without a history of smoking (smokers without COPD) and the healthy subjects. CONCLUSION: In conclusion, cigarette smoke disrupts TJ of the human airway epithelium, and the transcriptional factors counteract this smoke-induced COPD. Thus, TJPs may serve as protective elements for airway epithelial homeostasis during COPD.

Classification, Perception, and Toxicity of Emerging Flavored Oral Nicotine Pouches.

INTRODUCTION: Oral Nicotine Pouches (ONPs) are the new form of nicotine pouches that have become a type of emerging smokeless tobacco product sold by various tobacco companies. These smokeless tobacco products are marketed for usage all over as snus containing tobacco-derived nicotine (natural) or as tobacco-free nicotine (synthetic) as substitutes for other tobacco products. Based on perception and socio-behavioral aspects, ONPs have become popular tobacco products among adolescents/young adults, and over 50% of young adult users of ONP use flavored ONPs, such as menthol/mint, tobacco, dessert/candy, and fruity, which are the most popular flavors. Various new ONP flavors are currently popular locally as well as in the online market. Tobacco, menthol, and fruit-flavored ONPs could motivate cigarette smokers to change to ONPs. METHODS: We expanded our knowledge on natural/synthetic ONP flavor wheels to available data on ONPs, describing, in detail, their flavors and brands (US and Europe) in both natural and synthetic ONP categories. We classified over 152 snus and 228 synthetic ONPs into the following flavor categories: "Tobacco", "Menthol/Mint", "Fruity", "Candy/Deserts", "Drink", "Aroma", "Spices", and "Mixed Flavors". RESULTS: Based on total numbers, we found the most popular ONP flavors, sold as tobacco and menthol, to be among natural ONPs; among synthetic ONPs, fruity and menthol are the most prominent flavors, with varying concentrations of nicotine and other flavoring chemicals, including coolant WS-23. We also showed possible molecular targets and toxicities, due to exposure to ONPs, activating several signaling cascades such as AKT and NF-kappaB, which might possibly lead to apoptosis and epithelial mesenchymal transition (EMT). CONCLUSIONS: Considering the marketing of ONP products with various flavor profiles and with most of these products containing tobacco/menthol/fruit flavor, it is likely to have regulation and a marketing disclaimer on some of these products. Further, it would be logical to determine how the market reacts in terms of compliance and non-compliance with flavor restrictions by the regulatory agencies.

The role of synthetic coolants, WS-3 and WS-23, in modulating E-cigarette-induced reactive oxygen species (ROS) in lung epithelial cells.

There has been a substantial rise in e-cigarette (e-cig) use or vaping in the past decade, prompting growing concerns about their adverse health effects. Recently, e-cig manufacturers have been using synthetic cooling agents, like WS-23 and WS-3, to provide a cooling sensation without the "menthol taste". Studies have shown that aerosols/vapes generated by e-cigs can contain significant levels of reactive oxygen species (ROS). However, studies investigating the role of synthetic coolants in modulating ROS levels generated by e-cigs are lacking. This study seeks to understand how synthetic coolants, e-cig additives that have become increasingly prevalent in e-liquids sold in the United States (US), impact acellular ROS production from e-liquid aerosols as well as cellular ROS levels from pulmonary epithelial cells exposed to these e-liquids. To further explain, our study aims to understand whether the addition of WS-3 and WS-23 to e-liquid base and e-liquid base with nicotine significantly modifies generated acellular ROS levels within aerosolized e-liquids, as well as cellular ROS within BEAS-2B cells treated with these same e-liquids. Aerosols were generated from e-liquids with and without synthetic coolants through a single-puff aerosol generator; subsequently, acellular ROS was semi-quantified in H2O2 equivalents via fluorescence spectroscopy. Our acellular ROS data suggest that adding WS-3 to e-liquid base (PG:VG), regardless of nicotine content, has a minimal impact on modifying e-cig generated acellular ROS levels. Additionally, we also measured cellular ROS in lung epithelial cells using both e-liquids containing and not containing synthetic coolants via the CellROX Green fluorescent sensor. Similar comparable results were found in BEAS2B cells though ROS was increased by WS-3 and WS-23 treated in e-cig nicotine groups. Altogether, our data suggest that neither the addition of WS-23 nor WS-3 to e-liquid base solution, with and without nicotine, significantly modifies e-cig generated acellular ROS levels within aerosolized e-liquids and cellular ROS levels within treated BEAS-2B cells. Together, our data provide insight into whether synthetic coolants added to e-liquids could impact vaping-induced oxidative stress in the lungs.

Flavor Classification/Categorization and Differential Toxicity of Oral Nicotine Pouches (ONPs) in Oral Gingival Epithelial Cells and Bronchial Epithelial Cells.

Oral nicotine pouches (ONPs) are a modern form of smokeless tobacco products sold by several brands in the U.S., which comprise a significant portion of non-combustible nicotine-containing product (NCNP) sales to date. ONPs are available in various flavors and may contain either tobacco-derived nicotine (TDN) or tobacco-free nicotine (TFN). The growth in popularity of these products has raised concerns that flavored ONPs may cause adverse oral health effects and promote systemic toxic effects due to nicotine and other ONP by-products being absorbed into the circulatory system through oral mucosa. We hypothesized that flavored ONPs are unsafe and likely to cause oral and pulmonary inflammation in oral and respiratory epithelial cells. Before analyzing the effects of ONPs, we first classified ONPs sold in the U.S. based on their flavor and the flavor category to which they belonged using a wheel diagram. Human gingival epithelial cells (HGEP) were treated with flavored ONP extracts of tobacco (original, smooth), menthol (wintergreen and cool cider), and fruit flavor (americana and citrus), each from the TDN and TFN groups. The levels of ONP-induced inflammatory cytokine release (TNF-α, IL-6, and IL-8) by ELISA, cellular reactive oxygen species (ROS) production by CellRox Green, and cytotoxicity by lactate dehydrogenase (LDH) release assay in HGEP cells were assessed. Flavored ONP extracts elicited differential toxicities in a dose- and extract-dependent manner in HGEP cells 24 h post-treatment. Both fruit TDN and TFN extracts resulted in the greatest cytotoxicity. Tobacco- and fruit-flavored, but not menthol-flavored, ONPs resulted in increased ROS production 4 h post-treatment. Flavored ONPs led to differential cytokine release (TNF-α, IL-6, and IL-8) which varied by flavor (menthol, tobacco, or fruit) and nicotine (TDN vs. TFN) 24 h post-treatment. Menthol-flavored ONPs led to the most significant TNF-α release; fruit TFN resulted in the most significant IL-6 release; and fruit TDN and tobacco TFN led to the highest release of IL-8. Subsequently, human bronchial epithelial cells (16-HBE and BEAS-2B) were also treated with flavored ONP extracts, and similar assays were evaluated. Here, the lowest concentration treatments displayed increased cytotoxicity. The most striking response was observed among cells treated with spearmint and tobacco flavored ONPs. Our data suggest that flavored ONPs are unsafe and likely to cause systemic and local toxicological responses during chronic usage.

Relevance of Inflammatory Cytokine mRNA Expression of Tumour Necrosis Factor- Alpha (TNF α), Interleukin 17A (IL 17A) and Interleukin 6 (IL 6) in Indian Patients with Psoriasis.

Background: Psoriasis, a chronic, immune-mediated skin disorder, has systemic manifestations as well as an ample negative impact on the quality of life (QOL) of the patient. An abnormal proliferation of keratinocyte and dermal infiltration by immune cells is a characteristic feature. It involves components of both innate and adaptive immunity, and the interaction of T cells with macrophages. Keratinocytes and dendritic cells are mediated by the secreted cytokines. This study was taken up to look into changes at the molecular level that occur during the expression of three cytokines namely tumour necrosis factor-alpha (TNFα), interleukin 17A (IL-17A) and interleukin 6 (IL-6) in Indian patients with psoriasis. Methods: A case-control study was conducted with samples from 15 psoriasis vulgaris patients and 10 healthy control subjects. Clinical parameters were recorded. Blood samples were analysed for peripheral blood messenger ribonucleic acid (mRNA) expression of TNFα, IL-17A and IL-6 using real-time polymerase chain reaction (RT-PCR). Results: The mRNA expression of TNFα, IL-17A and IL-6 in psoriasis patients were increased as compared to that in normal subjects. Conclusions: The elevated levels of Interleukins indicates a systemic inflammatory process that is akin to the cutaneous inflammation. This study indicates that the targeted therapies against these cytokines are likely to be beneficial in Indian psoriasis patients.

Therapeutic properties of Punica granatum L (pomegranate) and its applications in lung-based diseases: A detailed review.

Respiratory diseases are the prime cause of death and disability worldwide. The majority of lung-based diseases are resistant to treatment. Hence, research on unique drugs/compounds with a more efficient and minimum side effect for treating lung diseases is urgent. Punica granatum L (pomegranate) fruit has been used in the prevention and treatment of various respiratory disorders in recent times. In vivo and in vitro studies have demonstrated that pomegranate fruit, as well as its juice, extract, peel powder, and oil, exert anti-proliferative, anti-oxidant, anti-microbial, anti-inflammatory, anti-cancer, and anti-tumorigenic properties by attenuating various respiratory conditions such as asthma, lung fibrosis, lung cancer, chronic obstructive pulmonary disease (COPD), and alveolar inflammation via modulating various signaling pathways. The current review summarizes the potential properties and medical benefits of pomegranate against different lung-based diseases, also highlighting its possible role in the lung fibrinolytic system. The available data suggest that pomegranate is effective in controlling the disease progressions and could be a potential therapeutic target benefiting human health status. Furthermore, this review also outlines the preclinical and clinical studies highlighting the role of pomegranate in lung diseases further evoking future studies to investigate the effect of intake of this anti-oxidant fruit in larger and well-defined human clinical trials. PRACTICAL APPLICATIONS: This review outlines the putative pharmacologic benefits of P. granatum L (pomegranate) in treating various chronic lung-based diseases such as lung cancer, COPD, ARDS, asthma, lung fibrosis, and cystic fibrosis. This review also highlights the possible inhibitory role of P. granatum L (pomegranate) in the lung fibrinolytic system triggering the fibrinolytic markers. This review summarizes the preclinical and clinical studies using in vitro, in vivo, and human models highlighting the potential role of P. granatum L (pomegranate) in lung diseases. This review evokes future research to investigate the effect of intake of pomegranate fruit in well-defined human clinical trials.

Curcumin Targets p53-Fibrinolytic System in TGF-ß1 Mediated Alveolar Epithelial Mesenchymal Transition in Alveolar Epithelial Cells.

AIMS: We aim to investigate curcumin interaction with p53-fibrinolytic system, smad dependent and independent pathways underlying their prime role during lung injury and fibrosis. BACKGROUND: Curcumin, an active component of Curcuma longa plant, substantially modulates respiratory conditions. TGF-ß1 plays a central role in lung remodeling by balancing extracellular matrix (ECM) production and degradation, which is a hallmark for alveolar EMT. However, the crosstalk of curcumin is not known yet with TGF- ß1 mediated p53-Fibrinolytic system regulating alveolar EMT leading to IPF. In the present study, the potential molecular mechanism of curcumin in TGF-ß1 mediated p53-fibrinolytic system in basal alveolar epithelial cells was explored. OBJECTIVES: To understand the potential molecular mechanism of curcumin in TGF-ß1 mediated p53-fibrinolytic system in basal alveolar epithelial cells. METHODS: Basal alveolar epithelial cells were treated with TGF- ß1 to induce alveolar EMT and after 24 hrs curcumin was administered to study its anti-fibrotic effects. Molecular techniques like immunoblot, RT-PCR and immunofluorescence were performed to assess the anti-fibrotic role of curcumin on EMT markers, IL-17A, p53-smad interaction to investigate the anti-fibrotic role of curcumin. RESULTS: The results indicated that TGF-ß1-induced EMT in A549 cells exhibited altered expression of the IL-17A, p53-fibrinolytic markers and EMT markers at the mRNA and protein level. Intervention with curcumin attenuated alveolar EMT and inactivated TGF-ß1 induced Smad/non Smad signaling pathways via blocking p53-fibrinolytic system. CONCLUSION: This study provides the first evidence of the dynamic response of curcumin on TGF- ß1 mediated p53-fibrinolytic system during alveolar injury in vitro.

Comparative protein profiling reveals the inhibitory role of curcumin on IL-17A mediated minichromosome maintenance (MCM) proteins as novel putative markers for acute lung injury in vivo.

The Pro-inflammatory cytokine, Interleukin 17A (IL-17A) plays a vital role in the pathogenesis of inflammatory-induced acute lung injury (ALI). But, the mechanisms of this pro-inflammatory cytokine in response to activation after replication stress are not yet known. Control on DNA replication (DR) is vital for maintaining genome stability. Minichromosome maintenance (MCM) proteins play essential roles in various cancers, but their involvement during ALI is not yet been discussed. The present study was carried out to assess the participation of IL-17A during replication stress and to evaluate the contribution of curcumin on this. Mass spectrometry-based proteomic approach has been used on mice lung tissues treated with IL-17A, as a prime mediator to cause injury and curcumin a natural polyphenol as an intervention. Several trends were identified from the proteomic subset which revealed that IL-17A induces expressions of proteins like MCM2, MCM3, and MCM6 along with other proteins involved in DR. Interestingly, curcumin was found in suppressing the expression levels of these proteins. This was also confirmed via validating LC-MS/MS data using appropriate molecular techniques. Pathway and gene ontology analysis were performed with DAVID GO databases. Apart from this, the present study also reports the unique contribution of curcumin in suppressing the mRNA levels of other MCMs like MCM4, MCM5, and MCM7 as well as of ORC1 and ORC2. Hence, the present study revolves around linking the replication stress by pro-inflammatory effects, highlighting the implications for ALI and therapies. This study, therefore, enhances our capacity to therapeutically target DR-specific proteins.