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  1. Fulltext Agarwood Oil Nanoemulsion Attenuates Cigarette Smoke-Induced Inflammation and Oxidative Stress Markers in BCi-NS1.1 Airway Epithelial Cells
    De Rubis G, Paudel KR, Manandhar B, Singh SK, Gupta G, Malik R, et al.
    Nutrients, 2023 Feb 17;15(4).
    PMID: 36839377 DOI: 10.3390/nu15041019
    Chronic obstructive pulmonary disease (COPD) is an irreversible inflammatory respiratory disease characterized by frequent exacerbations and symptoms such as cough and wheezing that lead to irreversible airway damage and hyperresponsiveness. The primary risk factor for COPD is chronic cigarette smoke exposure, which promotes oxidative stress and a general pro-inflammatory condition by stimulating pro-oxidant and pro-inflammatory pathways and, simultaneously, inactivating anti-inflammatory and antioxidant detoxification pathways. These events cause progressive damage resulting in impaired cell function and disease progression. Treatments available for COPD are generally aimed at reducing the symptoms of exacerbation. Failure to regulate oxidative stress and inflammation results in lung damage. In the quest for innovative treatment strategies, phytochemicals, and complex plant extracts such as agarwood essential oil are promising sources of molecules with antioxidant and anti-inflammatory activity. However, their clinical use is limited by issues such as low solubility and poor pharmacokinetic properties. These can be overcome by encapsulating the therapeutic molecules using advanced drug delivery systems such as polymeric nanosystems and nanoemulsions. In this study, agarwood oil nanoemulsion (agarwood-NE) was formulated and tested for its antioxidant and anti-inflammatory potential in cigarette smoke extract (CSE)-treated BCi-NS1.1 airway basal epithelial cells. The findings suggest successful counteractivity of agarwood-NE against CSE-mediated pro-inflammatory effects by reducing the expression of the pro-inflammatory cytokines IL-1α, IL-1β, IL-8, and GDF-15. In addition, agarwood-NE induced the expression of the anti-inflammatory mediators IL-10, IL-18BP, TFF3, GH, VDBP, relaxin-2, IFN-γ, and PDGF. Furthermore, agarwood-NE also induced the expression of antioxidant genes such as GCLC and GSTP1, simultaneously activating the PI3K pro-survival signalling pathway. This study provides proof of the dual anti-inflammatory and antioxidant activity of agarwood-NE, highlighting its enormous potential for COPD treatment.
  2. Fulltext 18-β-glycyrrhetinic acid-loaded polymeric nanoparticles attenuate cigarette smoke-induced markers of impaired antiviral response in vitro
    De Rubis G, Paudel KR, Yeung S, Mohamad S, Sudhakar S, Singh SK, et al.
    Pathol Res Pract, 2024 May;257:155295.
    PMID: 38603841 DOI: 10.1016/j.prp.2024.155295
    Tobacco smoking is a leading cause of preventable mortality, and it is the major contributor to diseases such as COPD and lung cancer. Cigarette smoke compromises the pulmonary antiviral immune response, increasing susceptibility to viral infections. There is currently no therapy that specifically addresses the problem of impaired antiviral response in cigarette smokers and COPD patients, highlighting the necessity to develop novel treatment strategies. 18-β-glycyrrhetinic acid (18-β-gly) is a phytoceutical derived from licorice with promising anti-inflammatory, antioxidant, and antiviral activities whose clinical application is hampered by poor solubility. This study explores the therapeutic potential of an advanced drug delivery system encapsulating 18-β-gly in poly lactic-co-glycolic acid (PLGA) nanoparticles in addressing the impaired antiviral immunity observed in smokers and COPD patients. Exposure of BCi-NS1.1 human bronchial epithelial cells to cigarette smoke extract (CSE) resulted in reduced expression of critical antiviral chemokines (IP-10, I-TAC, MIP-1α/1β), mimicking what happens in smokers and COPD patients. Treatment with 18-β-gly-PLGA nanoparticles partially restored the expression of these chemokines, demonstrating promising therapeutic impact. The nanoparticles increased IP-10, I-TAC, and MIP-1α/1β levels, exhibiting potential in attenuating the negative effects of cigarette smoke on the antiviral response. This study provides a novel approach to address the impaired antiviral immune response in vulnerable populations, offering a foundation for further investigations and potential therapeutic interventions. Further studies, including a comprehensive in vitro characterization and in vivo testing, are warranted to validate the therapeutic efficacy of 18-β-gly-PLGA nanoparticles in respiratory disorders associated with compromised antiviral immunity.
  3. Fulltext The impact of airborne particulate matter-based pollution on the cellular and molecular mechanisms in chronic obstructive pulmonary disease (COPD)
    Taylor-Blair HC, Siu ACW, Haysom-McDowell A, Kokkinis S, Bani Saeid A, Chellappan DK, et al.
    Sci Total Environ, 2024 Dec 01;954:176413.
    PMID: 39322084 DOI: 10.1016/j.scitotenv.2024.176413
    Inhalation of particulate matter (PM), one of the many components of air pollution, is associated with the development and exacerbation of chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD). COPD is one of the leading causes of global mortality and morbidity, with a paucity of therapeutic options and a significant contributor to global health expenditure. This review aims to provide a mechanistic understanding of the cellular and molecular pathways that lead to the development of COPD following chronic PM exposure. Our review describes how the inhalation of PM can lead to lung parenchymal destruction and cellular senescence due to chronic pulmonary inflammation and oxidative stress. Following inhalation of PM, significant increases in a range of pro-inflammatory cytokines, mediated by the nuclear factor kappa B pathway are reported. This review also highlights how the inhalation of PM can lead to deleterious chronic oxidative stress persisting in the lung post-exposure. Furthermore, our work summarises how PM inhalation can lead to airway remodelling, with increases in pro-fibrotic cytokines and collagen deposition, typical of COPD. This paper also accentuates the interconnection and possible synergism between the pathophysiological mechanisms leading to COPD. Our work emphasises the serious health consequences of PM exposure on respiratory health. Elucidation of the cellular and molecular mechanisms can provide insight into possible therapeutic options. Finally, this review should serve as a stark reminder of the need for genuine action on air pollution to decrease the associated health burden on our growing global population.
  4. Treatment of chronic airway diseases using nutraceuticals: Mechanistic insight
    Allam VSRR, Chellappan DK, Jha NK, Shastri MD, Gupta G, Shukla SD, et al.
    Crit Rev Food Sci Nutr, 2021 May 12.
    PMID: 33977840 DOI: 10.1080/10408398.2021.1915744
    Respiratory diseases, both acute and chronic, are reported to be the leading cause of morbidity and mortality, affecting millions of people globally, leading to high socio-economic burden for the society in the recent decades. Chronic inflammation and decline in lung function are the common symptoms of respiratory diseases. The current treatment strategies revolve around using appropriate anti-inflammatory agents and bronchodilators. A range of anti-inflammatory agents and bronchodilators are currently available in the market; however, the usage of such medications is limited due to the potential for various adverse effects. To cope with this issue, researchers have been exploring various novel, alternative therapeutic strategies that are safe and effective to treat respiratory diseases. Several studies have been reported on the possible links between food and food-derived products in combating various chronic inflammatory diseases. Nutraceuticals are examples of such food-derived products which are gaining much interest in terms of its usage for the well-being and better human health. As a consequence, intensive research is currently aimed at identifying novel nutraceuticals, and there is an emerging notion that nutraceuticals can have a positive impact in various respiratory diseases. In this review, we discuss the efficacy of nutraceuticals in altering the various cellular and molecular mechanisms involved in mitigating the symptoms of respiratory diseases.
  5. Recent trends of NFκB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases
    Mehta M, Paudel KR, Shukla SD, Allam VSRR, Kannaujiya VK, Panth N, et al.
    J Control Release, 2021 09 10;337:629-644.
    PMID: 34375688 DOI: 10.1016/j.jconrel.2021.08.010
    Nuclear factor κB (NFκB) is a unique protein complex that plays a major role in lung inflammation and respiratory dysfunction. The NFκB signaling pathway, therefore becomes an avenue for the development of potential pharmacological interventions, especially in situations where chronic inflammation is often constitutively active and plays a key role in the pathogenesis and progression of the disease. NFκB decoy oligodeoxynucleotides (ODNs) are double-stranded and carry NFκB binding sequences. They prevent the formation of NFκB-mediated inflammatory cytokines and thus have been employed in the treatment of a variety of chronic inflammatory diseases. However, the systemic administration of naked decoy ODNs restricts their therapeutic effectiveness because of their poor pharmacokinetic profile, instability, degradation by cellular enzymes and their low cellular uptake. Both structural modification and nanotechnology have shown promising results in enhancing the pharmacokinetic profiles of potent therapeutic substances and have also shown great potential in the treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. In this review, we examine the contribution of NFκB activation in respiratory diseases and recent advancements in the therapeutic use of decoy ODNs. In addition, we also highlight the limitations and challenges in use of decoy ODNs as therapeutic molecules, cellular uptake of decoy ODNs, and the current need for novel delivery systems to provide efficient delivery of decoy ODNs. Furthermore, this review provides a common platform for discussion on the existence of decoy ODNs, as well as outlining perspectives on the latest generation of delivery systems that encapsulate decoy ODNs and target NFκB in respiratory diseases.
  6. Agarwood oil nanoemulsion counteracts LPS-induced inflammation and oxidative stress in RAW264.7 mouse macrophages
    Malik R, Paudel KR, Manandhar B, De Rubis G, Shen J, Mujwar S, et al.
    Pathol Res Pract, 2023 Nov;251:154895.
    PMID: 37879146 DOI: 10.1016/j.prp.2023.154895
    PURPOSE: Oxidative stress and inflammation are key pathophysiological features of chronic respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD). Agarwood oil obtained from Aquilaria trees has promising antioxidant and anti-inflammatory activities. However, its clinical application is hampered by poor solubility. A viable approach to overcome this involves formulation of oily constituents into emulsions. Here, we have investigated the antioxidant and anti-inflammatory potential of an agarwood oil-based nanoemulsion (DE'RAAQSIN) against lipopolysaccharide (LPS)-induced RAW264.7 mouse macrophages in vitro.

    METHODS: The antioxidant and anti-inflammatory activity of DE'RAAQSIN was assessed by measuring the levels of ROS and nitric oxide (NO) produced, using the DCF-DA assay and the Griess reagent assay, respectively. The molecular pathways activated by DE'RAAQSIN were investigated via qPCR.

    RESULTS: LPS stimulation of RAW264.7 cells increased the production of nitric oxide (NO) and ROS and resulted in the overexpression of the inducible nitric oxide synthase (iNOS) gene. Furthermore, LPS induced the upregulation of the expression of key proinflammatory genes (IL-6, TNF-α, IL-1β, and CXCL1) and of the antioxidant gene heme oxygenase-1 (HO-1). DE'RAAQSIN demonstrated potent antioxidant and anti-inflammatory activity by significantly reducing the levels of ROS and of secreted NO, simultaneously counteracting the LPS-induced overexpression of iNOS, IL-6, TNF-α, IL-1β, and HO-1. These findings were corroborated by in silico activity prediction and physicochemical analysis of the main agarwood oil components.

    CONCLUSIONS: We propose DE'RAAQSIN as a promising alternative managing inflammatory disorders, opening the platform for further studies aimed at understanding the effectiveness of DE'RAAQSIN.

  7. Nutraceuticals: unlocking newer paradigms in the mitigation of inflammatory lung diseases
    Chan Y, Raju Allam VSR, Paudel KR, Singh SK, Gulati M, Dhanasekaran M, et al.
    Crit Rev Food Sci Nutr, 2023;63(19):3302-3332.
    PMID: 34613853 DOI: 10.1080/10408398.2021.1986467
    Persistent respiratory tract inflammation contributes to the pathogenesis of various chronic respiratory diseases, such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. These inflammatory respiratory diseases have been a major public health concern as they are the leading causes of worldwide mortality and morbidity, resulting in heavy burden on socioeconomic growth throughout these years. Although various therapeutic agents are currently available, the clinical applications of these agents are found to be futile due to their adverse effects, and most patients remained poorly controlled with a low quality of life. These drawbacks have necessitated the development of novel, alternative therapeutic agents that can effectively improve therapeutic outcomes. Recently, nutraceuticals such as probiotics, vitamins, and phytochemicals have gained increasing attention due to their nutritional properties and therapeutic potential in modulating the pathological mechanisms underlying inflammatory respiratory diseases, which could ultimately result in improved disease control and overall health outcomes. As such, nutraceuticals have been held in high regard as the possible alternatives to address the limitations of conventional therapeutics, where intensive research are being performed to identify novel nutraceuticals that can positively impact various inflammatory respiratory diseases. This review provides an insight into the utilization of nutraceuticals with respect to their molecular mechanisms targeting multiple signaling pathways involved in the pathogenesis of inflammatory respiratory diseases.
  8. Fulltext Nutraceuticals and mitochondrial oxidative stress: bridging the gap in the management of bronchial asthma
    Allam VSRR, Paudel KR, Gupta G, Singh SK, Vishwas S, Gulati M, et al.
    Environ Sci Pollut Res Int, 2022 Sep;29(42):62733-62754.
    PMID: 35796922 DOI: 10.1007/s11356-022-21454-w
    Asthma is a chronic inflammatory disease primarily characterized by inflammation and reversible bronchoconstriction. It is currently one of the leading causes of morbidity and mortality in the world. Oxidative stress further complicates the pathology of the disease. The current treatment strategies for asthma mainly involve the use of anti-inflammatory agents and bronchodilators. However, long-term usage of such medications is associated with severe adverse effects and complications. Hence, there is an urgent need to develop newer, novel, and safe treatment modalities for the management of asthma. This has therefore prompted further investigations and detailed research to identify and develop novel therapeutic interventions from potent untapped resources. This review focuses on the significance of oxidative stressors that are primarily derived from both mitochondrial and non-mitochondrial sources in initiating the clinical features of asthma. The review also discusses the biological scavenging system of the body and factors that may lead to its malfunction which could result in altered states. Furthermore, the review provides a detailed insight into the therapeutic role of nutraceuticals as an effective strategy to attenuate the deleterious effects of oxidative stress and may be used in the mitigation of the cardinal features of bronchial asthma.
  9. Berberine-loaded engineered nanoparticles attenuate TGF-β-induced remodelling in human bronchial epithelial cells
    De Rubis G, Paudel KR, Liu G, Agarwal V, MacLoughlin R, de Jesus Andreoli Pinto T, et al.
    Toxicol In Vitro, 2023 Oct;92:105660.
    PMID: 37591407 DOI: 10.1016/j.tiv.2023.105660
    Airway remodelling occurs in chronic respiratory diseases (CRDs) such as asthma and chronic obstructive pulmonary disease (COPD). It is characterized by aberrant activation of epithelial reparation, excessive extracellular matrix (ECM) deposition, epithelial-to-mesenchymal transition (EMT), and airway obstruction. The master regulator is Transforming Growth Factor-β (TGF-β), which activates tissue repair, release of growth factors, EMT, increased cell proliferation, and reduced nitric oxide (NO) secretion. Due to its fundamental role in remodelling, TGF-β is an emerging target in the treatment of CRDs. Berberine is a benzylisoquinoline alkaloid with antioxidant, anti-inflammatory, and anti-fibrotic activities whose clinical application is hampered by poor permeability. To overcome these limitations, in this study, berberine was encapsulated in monoolein-based liquid crystalline nanoparticles (BM-LCNs). The potential of BM-LCNs in inhibiting TGF-β-induced remodelling features in human bronchial epithelial cells (BEAS-2B) was tested. BM-LCNs significantly inhibited TGF-β-induced migration, reducing the levels of proteins upregulated by TGF-β including endoglin, thrombospondin-1, basic fibroblast growth factor, vascular-endothelial growth factor, and myeloperoxidase, and increasing the levels of cystatin C, a protein whose expression was downregulated by TGF-β. Furthermore, BM-LCNs restored baseline NO levels downregulated by TGF-β. The results prove the in vitro therapeutic efficacy of BM-LCNs in counteracting TGF-β-induced remodelling features. This study supports the suitability of berberine-loaded drug delivery systems to counteract airway remodelling, with potential application as a treatment strategy against CRDs.
  10. Emerging applications and prospects of NFκB decoy oligodeoxynucleotides in managing respiratory diseases
    Datsyuk JK, Paudel KR, Rajput R, Kokkinis S, El Sherkawi T, Singh SK, et al.
    Chem Biol Interact, 2023 Nov 01;385:110737.
    PMID: 37774998 DOI: 10.1016/j.cbi.2023.110737
    Chronic respiratory diseases like asthma and Chronic Obstructive Pulmonary Disease (COPD) have been a burden to society for an extended period. Currently, there are only preventative treatments in the form of mono- or multiple-drug therapy available to patients who need to utilize it daily. Hence, throughout the years there has been a substantial amount of research in understanding what causes inflammation in the context of these diseases. For example, the transcription factor NFκB has a pivotal role in causing chronic inflammation. Subsequent research has been exploring ways to block the activation of NFκB as a potential therapeutic strategy for many inflammatory diseases. One of the possible ways through which this is probable is the utilisation of decoy oligodeoxynucleotides, which are synthetic, short, single-stranded DNA fragments that mimic the consensus binding site of a targeted transcription factor, thereby functionally inactivating it. However, limitations to the implementation of decoy oligodeoxynucleotides include their rapid degradation by intracellular nucleases and the lack of targeted tissue specificity. An advantageous approach to overcome these limitations involves using nanoparticles as a vessel for drug delivery. In this review, all of those key elements will be explored as to how they come together as an application to treat chronic inflammation in respiratory diseases.
  11. Fulltext Autoantibodies and autoimmune disorders in SARS-CoV-2 infection: pathogenicity and immune regulation
    Darmarajan T, Paudel KR, Candasamy M, Chellian J, Madheswaran T, Sakthivel LP, et al.
    Environ Sci Pollut Res Int, 2022 Aug;29(36):54072-54087.
    PMID: 35657545 DOI: 10.1007/s11356-022-20984-7
    Coronavirus disease 2019 (COVID-19) is an infectious disease associated with the respiratory system caused by the SARS-CoV-2 virus. The aim of this review article is to establish an understanding about the relationship between autoimmune conditions and COVID-19 infections. Although majority of the population have been protected with vaccines against this virus, there is yet a successful curative medication for this disease. The use of autoimmune medications has been widely considered to control the infection, thus postulating possible relationships between COVID-19 and autoimmune diseases. Several studies have suggested the correlation between autoantibodies detected in patients and the severity of the COVID-19 disease. Studies have indicated that the SARS-CoV-2 virus can disrupt the self-tolerance mechanism of the immune system, thus triggering autoimmune conditions. This review discusses the current scenario and future prospects of promising therapeutic strategies that may be employed to regulate such autoimmune conditions.
  12. Applications and advancements of nanoparticle-based drug delivery in alleviating lung cancer and chronic obstructive pulmonary disease
    De Rubis G, Paudel KR, Corrie L, Mehndiratta S, Patel VK, Kumbhar PS, et al.
    Naunyn Schmiedebergs Arch Pharmacol, 2024 May;397(5):2793-2833.
    PMID: 37991539 DOI: 10.1007/s00210-023-02830-w
    Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are among the leading causes of mortality worldwide. Cigarette smoking is among the main aetiologic factors for both ailments. These diseases share common pathogenetic mechanisms including inflammation, oxidative stress, and tissue remodelling. Current therapeutic approaches are limited by low efficacy and adverse effects. Consequentially, LC has a 5-year survival of < 20%, while COPD is incurable, underlining the necessity for innovative treatment strategies. Two promising emerging classes of therapy against these diseases include plant-derived molecules (phytoceuticals) and nucleic acid-based therapies. The clinical application of both is limited by issues including poor solubility, poor permeability, and, in the case of nucleic acids, susceptibility to enzymatic degradation, large size, and electrostatic charge density. Nanoparticle-based advanced drug delivery systems are currently being explored as flexible systems allowing to overcome these limitations. In this review, an updated summary of the most recent studies using nanoparticle-based advanced drug delivery systems to improve the delivery of nucleic acids and phytoceuticals for the treatment of LC and COPD is provided. This review highlights the enormous relevance of these delivery systems as tools that are set to facilitate the clinical application of novel categories of therapeutics with poor pharmacokinetic properties.
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