key: cord-0948887-qzbc11bd
authors: Prasher, Parteek; Sharma, Mousmee; Mehta, Meenu; Paudel, Keshav R.; Satija, Saurabh; Chellappan, Dinesh K.; Dureja, Harish; Gupta, Gaurav; Tambuwala, Murtaza M.; Negi, Poonam; Wich, Peter R.; Hansbro, Nicole; Hansbro, Philip M.; Dua, Kamal
title: Plants derived therapeutic strategies targeting chronic respiratory diseases: Chemical and immunological perspective
date: 2020-05-04
journal: Chem Biol Interact
DOI: 10.1016/j.cbi.2020.109125
sha: 94304b2a4bd84ea829e977b10600f096ec1d4726
doc_id: 948887
cord_uid: qzbc11bd

The apparent predicament of the representative chemotherapy for managing respiratory distress calls for an obligatory deliberation for identifying the pharmaceuticals that effectively counter the contemporary intricacies associated with target disease. Multiple, complex regulatory pathways manifest chronic pulmonary disorders, which require chemotherapeutics that produce composite inhibitory effect. The cost effective natural product based molecules hold a high fervor to meet the prospects posed by current respiratory-distress therapy by sparing the tedious drug design and development archetypes, present a robust standing for the possible replacement of the fading practice of poly-pharmacology, and ensure the subversion of a potential disease relapse. This study summarizes the experimental evidences on natural products moieties and their components that illustrates therapeutic efficacy on respiratory disorders.

The chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), pulmonary sarcoidosis, asthma, pneumoconiosis, and lung cancer pose major healthcare and economic strain across the globe. As per the annual report by World Health Organization (WHO) on 'The Global Impact of Respiratory Disease', COPD alone claims a global morbidity of 65 million, including 3 million annual mortalities. The figures for asthma further raise the alarm with 334 million people suffering from the disease, which includes 14% of children [1] . Notably, pneumonia; caused by bacteria streptococcus pneumonia raises the mortality rate among children below 5 years of age. Tuberculosis, a chronic respiratory ailment caused by bacteria mycobacterium tuberculosis affects 10 million people annually, out of which 1.4 million lose lives. In addition, lung cancer represents a fatal, yet most common neoplasm claiming roughly 2 million lives annually [2] .

The pathophysiology of COPD manifests chronic inflammation in the lung parenchyma mediated by macrophages, neutrophils, and cytotoxic (CD8+) T lymphocytes. The subsequent fibrosis results in narrowing of small airways and obliteration of parenchyma by proteases.

Reportedly, the development of COPD focused precision medicine faces considerable challenges due to dearth of animal models for preliminary drug testing, and due to a lack of information about the surrogate markers for monitoring the efficacy of rationally designed drugs [3] .

Bronchial asthma, an inflammatory condition develops due to the abnormal activity of enzymes and prostanoids [4] , coupled with oxidative stress in the airways resulting in hypertrophy and hyperplasia of bronchial smooth muscles, hyper-responsiveness and hypersecretion of mucins in the airway passages [5] . Besides the anti-asthma drugs targeting cysteinyl leukotrienes, immunoglobulin E, anticholinergics, and β-AR agonists, the contemporary chemotherapy development efforts against asthma could not yield clinically efficacious results in the last 3 decades [6] . The emergence of multi-drug resistance microbial strains tainted the drug development efforts directed at pneumonia and tuberculosis [7] , which are emerging as leading cause of excessive and unregulated antibiotic consumption [8] . Similarly, adenocarcinoma presents the recurring and most prevalent cancer type among the various lung cancer forms [9] .

Various cell signaling pathway are involved in inflammatory and oxidative response, remodeling of extracellular matrix leading to asthma, COPD and pulmonary fibrosis whereas cell migration and proliferation pathway leading to lung cancer progression [10] [11] [12] [13] . In asthma and COPD, oxidative stress leads to inflammation in airway by through redox sensitive transcription factor, nuclear factor (NF)-kappaB (NF-kB) pathway [14] . The activation NF-κB in cytoplasm and subsequent translocation to nucleus is induced by inflammatory cytokines such as interleukin (IL)-1β and tumour necrosis factor (TNF)-α whereas via activation of toll like receptors (TLRs) during pathogenic infections (bacterial or viral) [15] . Similarly, increase in transforming growth factor (TGF)-b by airway epithelial cells and inflammatory cells are involved in the pathogenesis of pulmonary fibrosis. High level of TGF-b results in activation, migration, and proliferation of resident fibroblasts. These fibroblasts can differentiation into activated myofibroblasts promoting abundant extracellular matrix (ECM) deposition and abnormal collagen build-up [16] . Likewise, activation of pathway such as epidermal growth factor receptor-tyrosine kinase, anaplastic lymphoma kinase (ALK), c-ros oncogene-1 (ROS1), programmed cell-death-1/program cell death ligand -1 (PD-1/PD-L1), mitogen activated protein kinases (MAPK), phosphoinositide 3kinases (PI3Ks) are involved in migration and proliferation pathway leading to lung cancer progression [17] [18] [19] [20] [21] .

Various natural compound are able to target the cell-signaling pathway showing beneficial activity against respiratory disease ( Figure 1 ). The natural products containing alkaloids, flavonoids and terpenes serve as storehouse of essential chemotherapeutics [22] [23] [24] , which produce desirable effects against chronic respiratory ailments (Table 1) . These also prompt the development of novel drug systems by providing suitable pharmacophores for producing optimum effect against the target pathways associated with the manifestation of respiratory disorders [25] . This review presents a succinct discussion on the potential of natural product derived drugs based on alkaloids, flavones and terpenes for capping the conventional and emerging respiratory disorders. Lu et al. 2007 ; reported the medicinal properties of tetrahydroquinoline alkaloid 'Antidesmone'

(1, Figure 2 ) for the treatment of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), which represent prolonged inflammatory disorders instigated by membrane lipopolysaccharide (LPS) present on gram-negative bacteria, characterized by lung parenchymal injury and interstitial edema [26] . The microbial LPS instigate neutrophil infiltration, and trigger the production of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), mitogen-activated protein kinase (MAPK) [27] , cyclooxygenase-2 (COX-2) [28] , interleukin-1β (IL-1β) [29] , inducible nitric oxide synthase (iNOS) [30] , nuclear factor-kappa B (NF-κβ) [31] and interleukin-6 (IL-6) [32] at the target site, thereby inducing acute lung injury.

Exposure with antidesmone significantly down-regulated MAPK and TNF-α signaling pathway and apparently lowered the expression of NF-κβ by offsetting the nuclear translocation of RELassociated protein p65, responsible for its activation [33] . Interestingly, the antidesmone exposure demonstrated significant inhibition of pulmonary myeloperoxidase (MPO), the biomarker for accumulation of neutrophils in the morbid lungs [34] , further validating the therapeutic privilege of the alkaloid.

Reportedly, cigarette smoke (CS) potentiates the redox imbalance by activating lung epithelial cells and macrophages, thereby resulting in chronic respiratory ailments [35] . The heightened oxidative stress caused by CS dissociates transcription factor Nrf2 from kelch-like ECHassociated protein 1 (Keap1) [36] , eventually translocating into nucleus followed by binding to antioxidant response elements (ARE). These events regulate downstream gene expression for phase II detoxification enzymes such as glutamate cysteine ligase (GCL), glutathione Stransferase (GST), and heme oxygenase 1 (HO-1) [37] , that promote in maintaining cellular redox balance [38] . Therefore, Nrf2 signaling pathways present potential therapeutic target against the physiological redox imbalance [39] . Liu et al. 2020 ; investigated the therapeutic potential of six isosteroid alkaloids (2-7, Figure 2) obtained from F. cirrhosa bulbus against the CS induced oxidative stress in RAW264.7 macrophages. Reportedly, the identified six test alkaloids significantly attenuated the production of reactive oxygen species (ROS), upregulated the level of antioxidant molecule glutathione (GSH), and promoted the Nrf2 induced expression of HO-1 protein. Notably, the presence of glucoside moiety at C-3 position in alkaloid 5, and absence of β-OH at C-17 position in alkaloid 6 resulted in higher GSH/GSSG ratio. Similarly, the presence of β-CH 3 substituent at C-20 position in alkaloid 3 favored its efficacy and tolerable cytotoxicity. The presence of -OH substitution at C-3 position in all the test alkaloids demonstrated a paramount importance for inducing HO-1 expression, which diminished in the presence of C=O group at the same position [40] . Zhao et al. 2017 ; investigated the curative effects and pharmacokinetics of alkaloids 8-11, Figure   2 , obtained from A. scholaris on ovalbumin induced airways allergic inflammatory model [41] .

Exposure to the test alkaloids lowered the levels of leukocytes and eosinophils, further confirmed by histopathological analysis of lungs. Notably, the test alkaloids downregulated the secretion of proinflammatory cytokine IL-4, a key mediator of allergic responses eventually resulting in a significant reduction of pulmonary eosinophils, and balancing the rise of immunoglobulin E (IgE) in serum.

Importantly, the animal models administered with the test alkaloids 3 times a day demonstrated lower levels of eotaxin in the serum. Eotaxin overexpressed in the serum and airways of asthmatics serves as a biomarker for the pathogenesis of chronic asthma [42] . Therefore, its elimination from the systemic circulation in the morbid groups further validates the anti-asthma efficacy of test alkaloids. The administration of total alkaloids produced marked effect as compared to the single test alkaloid, hence confirming a synergistic effect. Moreover, these alkaloids proved useful for the treatment of post-infectious symptoms in animal models by mitigating the levels of inflammatory cytokines followed by down-regulation of the expression of IL-6. Histopathological examination of the morbid lungs further confirmed these observations [43] . Liu et al. 2015 ; isolated quinazoline alkaloids 12-14, Figure 2 , from the aerial parts of Peganum harmala L [44] , and tested their antitussive, expectorant, and bronchodilating effects in animal models.

The alkaloids effectively lowered the symptoms associated with capsaicin induced acute pulmonary inflammation at doses 5, 15, and 45 mg/ kg, compared to codeine phosphate administered at 30 mg/ kg. The test alkaloids appreciably promoted expectorant activity as indicated by phenol red secretion in mice trachea, compared to the standard drug ammonium chloride. Further, the bronchodilating test verified that the test alkaloids considerably prolonged the pre-convulsive times in animal models, superior to the standard drug aminophylline, thereby validating the potency of these alkaloids for treating bronchial asthma.

Alkaloids from Cissampelos sympodialis 'warifteine' (15, Figure 2 ) display notable efficacy in airway hyperreactivity in animal model of asthma [45] . Oral pretreatment of animal models with the test alkaloid warifteine significantly reduced the allergen induced airway hyperreactivity (AHR) to inhaled methacholine. Moreover, it also reduced the IL-13 levels in bronchoalveolar lavage, which serves as the key regulator of AHR [46] . The test alkaloid checked the ovalbumin (OVA)-induced eosinophil intrusion in the tissues, and downregulated the mucus production and subepithelial fibrosis. Further analysis of airway mucins by periodic acid-Schiff (PAS) staining revealed OVA induced metaplasia and mucus accumulation in animal models, which reduced significantly after warifteine administration. Kim et al. 2015 ; reported attenuation of IL-4 and eotaxin-2 mediated eosinophilic airway inflammation in asthmatic animal models by the alkaloid 'chelidonine' (16, Figure 2 ) isolated from Chelidonium majus [47] . The test alkaloid significantly suppressed the level of eosinophils in the airways, in addition to downregulation of eotaxin-2, interleukins, and cytokines in the bronchoalveolar lavage fluid. Notably, chelidonine treated animal models exhibited considerable decrease of CD4 + and CD8 + T cells, Gr-1 + /CD11b + and 351 CD3/CCR3 + positive cells, which otherwise intensify inflammation process by secreting Th2 cytokines and degranulation of eosinophils [48] . Histological analysis suggested marked attenuation of OVA-induced eosinophil subversion, goblet cell hyperplasia, and accumulation of collagen in ling tissues in the presence of chelidonine. These findings validated the therapeutic potency of this alkaloid in the treatment of pathologic inflammatory disorders associated with respiratory airways. catabolism pathway in the host microbe, which is essential for its survival and for the persistence of ensuing infection. In addition, the metabolic breakdown of test alkaloid by cholesterol degradation pathway yields toxic products fatal to the host microbe [52] .

Coronaridine alkaloid 23 ( Figure 3 ) isolated from Tabernaemontana ternifolia displayed marked antibacterial potency against Mycobacterium tuberculosis strain H37Rv with IC50 = 82.64 µg/ ml. The activity, however was lower than the commercial drug rifampicin (IC50 = 0.05 µg/ ml) [53] . Chen et al. 2017 ; isolated the alkaloid 'Talaramide A' (24, Figure 3 ) from Talaromyces sp.

(strain HZ-YX1) and investigated its antimycobacterial potency by targeting mycobacterial protein kinase G (PknG), which plays a key role in the persistent localization of mycobacteria in macrophages. The alkaloid displayed significant inhibition of PknG with IC50 = 55 µM, thereby validating its potential for the treatment of chronic tuberculosis [54] .

Besides several contemporary targets for capping tuberculosis, shikimate pathway represents the [56] . Also referred to as cyclostellettamines when isolated from sponge Pachychalina sp., the test alkaloids with longer alkyl chains connecting the pyridinium moieties exhibited excellent activity against Mycobacterium Tuberculosis strain H37Rv [57] . The precise mechanism of action for the test alkaloids 31 ( Figure 3) is still under investigation. Besides the active mycobacterium, the nonreplicating persistent Mycobacterium tuberculosis pathogen requires uninterrupted treatment for several months to prevent the relapse of disease [58] .

The dormant mycobacterium requires hypoxic conditions for survival and displays considerable resistance against the representative drugs [59] . The marine sponge Aaptos sp. served as an excellent source for the isolation of aaptamine alkaloids 32 to 38 ( Figure 3 ). Oxygen depletion instigated dormancy response of the mycobacterium in the form of resistance towards the antibiotic isoniazid served as the model for evaluating the anti-dormant mycobacterial efficacy of the test alkaloids. The test alkaloids displayed highly effective anti-dormant mycobacterial activity with IC50 in the range 1.5-6.25 µg/ ml. Further investigations suggested that the presence of carbonyl groups at C-3 and/ or C-9 position of the candidate alkaloids played a critical role in the expression of bioactivity against non-replicating dormant Mycobacterium tuberculosis [60] . These alkaloids formed the basis of identification of suitable pharmacophores for rationally designing the pharmaceuticals against dormant mycobacterium. injury caused by H1N1 virus [63] . The animal models exposed to test flavonoids maintained the morphology of diseased lung microstructures, attenuated the penetration of proinflammatory factors MCP-1, IL-8, TNF-α, and malondialdehyde that play crucial role in the recruitment of macrophages and neutrophils at the site of stimulus [64] . However, the levels of interferon-β elevated, which played a key role in restricting the replication of virus [65] . In addition, the expression of TLR3/4/7 and level of NF-κ β p65 phosphorylation lowered in the lung tissues, which are associated with heightened activation and secretion of interferon-β [66] . Hence, the test flavonoids directed anti-inflammatory therapy served deliberated approach for countering IAV induced pathological processed manifesting acute lung injury. Reportedly, the flavonoids 54 and 56 ( Figure 4 ) displayed enhanced biocidal potential against Mycobacterium tuberculosis H37Rv strain with IC50 = 6.25 and 25 µg/ ml respectively [67] . The biocidal potential of the test flavonoids proved better than the standard anti-TB drugs isoniazid and rifampicin.

Besides numerous efforts entailing anti-TB drug development, the emergence of drug-resistant mycobacterial strains necessitated the identification of novel drug targets by highly efficacious pharmacophores. MtPKnG, a protein kinase G produced by Mycobacterium tuberculosis represents serine/ threonine kinase enzyme, which prolongs the survival rate of the bacterium in host macrophages by preventing the phagosome-lysosome fusion [68] . The enzyme mediates phosphorylation of proteins associated with essential signal transduction pathways in bacteria and allegedly sustains the tuberculosis infection in the host [69] . Notably, the MtPKnG enzyme prompts anti-TB drug resistance in mycobacteria and serves as a key component for mycobacterial biofilms production. Hence, it forms a desirable target for anti-TB drug discovery against resistant mycobacteria. The drug resistance in microbes arises due to over-activity of the membrane bound efflux pumps that prevent the drug internalization in cells. The lack of clinically approved efflux pump inhibitors further aggravate the disease pathogenesis. Polymethoxylated flavonoids 60-64 ( Figure   5 ) reportedly reduced the rifampicin resistance and adversely affected the survival of Mycobacterium tuberculosis. Importantly, the bioactivity of anti-TB drug isoniazid enhanced in the presence of test flavonoids [71] . However, further investigations could not quantify the insight mechanism for the behavior of test flavonoids towards mycobacterium efflux pumps.

Reportedly, the flavonoid 60 ( In virus, the NA enzyme promotes reproduction and spread, whereas in the bacterium, NA enzyme facilitates the cleavage of sialic acid from glycoproteins present on the cell surface thereby affording receptors for attaching of microbe hence providing the host cell nutrients for further growth and colonization [78] . Hence, it makes a desirable target for attenuating the pathogenesis caused by Influenza virus and S. pneumoniae. These events allow the release of virus from infected cells and provides defense against representative drugs. The prenylated flavonoids effectively break this synergism thereby preventing the bacterial coinfection in the subjects with influenza [79] . responsiveness in ovalbumin treated animal models. Interestingly, the treatment of animal models with carvacrol considerably lowered the levels of nitric oxide in serum, produced by endothelial nitric oxide synthase, which reportedly triggers plasma extravasation and lung edema [82] . Similarly, the higher levels of iNOS-derived nitric oxide raises vascular permeability, instigates mucus hypersecretion, and worsenes the inflammatory cell permeation, and epithelial cell damage that contribute to asthma pathology [83] . In addition, thymoquinone administration attenuated the expression of NF-κB, TNFα, and IL-1β in the respiratory airways produced due to the LPS sensitization [86] . Thymoquinone also protects against lung damage caused by cigarette smoke by mitigating the expression of proinflammatory leukotrienes, prostaglandins, thromboxanes and importantly IL-1β, the principal biomarker cytokine in cigarette smoker's lung [87] . Su however with a low selectivity index which indicated physiological toxicity [91] .

Andrographolide (86, Figure 7) reportedly ameliorates LPS-induced acute lung injury by an effective downregulation of MAPK and NF-κB pathways, which regulate the production of inflammatory cytokines such as TNF-α and IL-6 in bronchoalveolar lavage fluid [92] . The antioxidative potency of andrographolide effectively restores the steroid sensitivity for blocking LPS-induced production of IL-27 and airway hyper-responsiveness. Moreover, andrographolide considerably restored the levels of nuclear HDAC2 protein and their total activity, whereas it contracted the total activity of histone acetyltransferase/HDAC in the animal lungs exposed to LPS/IFN-γ. These events occurred due to the suppression of phosphorylation of PI3K/Akt/HDAC2, and the upregulation of antioxidant transcription factor NF erythroid-2- Figure 7 ) on ovalbumin-induced airway inflammation and airway hyper-responsiveness in animal asthma models. Ursolic acid displayed significant inhibition of airway inflammation via suppression of Th2 cytokines such as IL-5, IgE, and CCR3 expression [98] . Ursolic acid reportedly displays chemotherapeutic effect on COPD, and provides protection against cigarette smoke induced cell injury by suppressing the lung tumor metastasis [99] . The therapeutic effect of allergic asthma arises due to increase in the expression of PPARg and attenuated GATA-3 and STAT6 expression, resulting in a decrease of antigen-induced Penh, eosinophilia, lung inflammation, and the production of cytokines and antigen-specific IgE that play vital role in coordinating and intensifying the allergic inflammation in asthma [100] . Reportedly, the treatment with ursolic acid alleviates emphysema instigated by cigarette smoke by PERK pathway, as well as Nrf2 pathway [101] . The activation of PERK discourages protein synthesis via phosphorylation of eukaryotic translation initiator factor, thereby causing a selective translation of ATF4, which controls the expression of critical apoptotic association genes.

Nuclear erythroid-related factor 2 (Nrf2) represents a transcription factor regulating several antioxidant and detoxification genes [102] . Nrf2 signaling pathway plays a critical role in cigarette smoke-induced emphysema. Reportedly, ursolic acid demonstrates protective effects against cigarette smoke-induced emphysema through PERK andNrf2 signaling pathway. Further investigations on beneficial pulmonary effects of ursolic acid suggested that the terpene effectively alleviates cigarette smoke induced emphysema and airway remodeling involving unfolded protein response (UPR) pathways by suppression of ERS-associated apoptosis, and downregulation of IGF1, TGF-β1, and p-Smad2/3 expression [103, 104] . These factors mediate bronchial epithelial and muscle cell regeneration in COPD patients through effects on airway vessel remodeling and muscle atrophy. Conversely, the expression of Iκ-B α augmented in lung tissues and bronchoalveolar lavage fluid [107] . Wang et al. 2016 ; further verified the protective effects of oridonin by studying its antiasthma potential in ovalbumin-sensitized animal models. Reportedly, oridonin sustains Th1/Th2 cytokines balance in sensitized animal models and demonstrated anti-asthmatic effects in acute asthma model [108] .

Structurally diverse, plant derived natural products bear a privileged status in rational designing of commercially successful medicines. The identification of plant based natural molecules with therapeutic properties prompted systemic efforts to explore and commercially exploit the naturederived drugs for countering clinical intricacies associated with the chronic diseases [109] . The natural product based drugs present considerable commercial representation under various brand names, as well as a significant number of candidate molecules in clinical trials [110] . However, the nature-derived molecules in chronic respiratory diseases present only a limited clinical profile, with even fewer molecules in commercial scaling [111] .

A randomized controlled trial conducted in 60 patients with moderate to severe asthma suggested the safety and efficacy of Squill oxymel (a popular Iranian medicine obtained from Drimia maritima). Squill oxymel was able to significantly increases the force expiratory volume (FEV) 1 liter, FEV1%, FEV1/force vital capacity (FVC%), and maximal mid expiratory flow (MEF) as compared to placebo. There was a remarkable improvement in symptoms, activity, and total score in the patients administered Squill Oxymel but not in the placebo group. Moreover, there was no serious adverse observed except minor nausea and vomiting reported in five patients in Squill oxymel group. This trail showed a strong potential of Squill Oxymel in terms of safety and efficacy for asthma patient [112] . concentrations as well as Th1 switch in the Th1/Th2 balance [113] . The alkaloids such as theophylline, lobeline, and narceine have been commercialized as adenovasin, citotal, and peneraj respectively for relieving chronic symptoms associated with asthma, however several molecules fail to clear the clinical trials prior to successful commercialization [114, 115] .

Sulforaphane is a derivative of broccoli and commonly found in cruciferous vegetables. A phase 2 randomized trail conducted in 89 COPD patients were given either placebo or 25 µmoles or 150 µmoles of sulforaphane orally for 4 wks. The changes in nuclear factor erythroid-2 related factor 2 (Nrf2) target gene expression in bronchial epithelial cells and alveolar macrophages as well as measurement of oxidative damage, airway inflammation, and pulmonary function tests were tested. However, sulforaphane did not induce the Nrf2 target gene expression and no significant anti-oxidant and anti-inflammatory activity appeared as compared to placebo control [116] . Thyme herb, ivy leaves and primose roots exhibit beneficial effects against acute bronchitis and productive cough [117] . to more patients with symptom free in combination therapy as compared to placebo group at the end of study. Both groups tolerate the treatment very well as there was no serious adverse events observed [118] . Similarly in Kemmerich B study, 183 patients with acute bronchitis were given with 1 tablet of thyme-primose combination thrice a day for 11 days and the efficacy was compared with placebo (N= 178 patients). There was a mean reduction of 67.1% of coughing fits in combination therapy group compared to 51.3% in placebo group on day 7 to 9. The combination therapy reduces the coughing fits to 50% two days earlier than placebo group.

Further, no severe adverse events appeared in both groups, which concludes the well tolerability of thyme-primose combination therapy [119] . promising natural moieties need further validation with multiple evidence [120] .

In Table 2 , we present the clinical studies on natural product-based molecules for countering the chronic respiratory disorders in human subjects.

Chronic respiratory disorders mainly arise due to the bronchial and pulmonary inflammation arising due to the heightened innate response causing an upsurge of proinflammatory metabolites, and over activity of enzyme such as cyclooxygenases, and lipoxygenases. The Notably, erdosteine displays significant antibiotic effect thereby attenuating the bacterial load during the respiratory distress. Similarly, the pulmonary disorders caused by multidrug-resistant microbes such as mycobacterium tuberculosis, and streptococcus pneumoniae requires innovative pharmaceuticals with multifarious targeting potential. Reportedly, the isoniazid monotherapy or rifampicin or pyrazinamide bitherapy proved inadequate for the disease management and resulted in its recurrent cycles. Hence, the recommended anti-TB regimen suggests polypharmacy as preliminary combination therapy of rifampin, isoniazid, pyrazinamide, ethambutol, and pyridoxine to prevent the recurrence of disease. Nevertheless, the amenability of the subjects to the combination of drugs, and the probability of microbial susceptibility to the administered doses raises compulsion for the identification of physiologically tolerable, novel pharmacophores for which the natural products present an ideal profile. The levels of 

Global and National Burden of Diseases and Injuries Among Children and Adolescents Between 1990 and 2013: Findings From the Global Burden of Disease 2013 Study

Chronic obstructive pulmonary disease

Oligonucleotide therapy: An emerging focus area for drug delivery in chronic inflammatory respiratory diseases

Interactions with the macrophages: An emerging targeted approach using novel drug delivery systems in respiratory diseases

Increasing complexity and interactions of oxidative stress in chronic respiratory diseases: An emerging need for novel drug delivery systems

The increasing challenge of discovering asthma drugs

Multi-drug resistant Mycobacterium tuberculosis & oxidative stress complexity: Emerging need for novel drug delivery approaches

Duration of pneumonia therapy and the role of biomarkers

Emerging trends in the novel drug delivery approaches for the treatment of lung cancer

Targeting neutrophils using novel drug delivery systems in chronic respiratory diseases

Recent advances in experimental animal models of lung cancer

Eriobotrya japonica leaf extract attenuates airway inflammation in ovalbumin-induced mice model of asthma

Cellular signalling pathways mediating the pathogenesis of chronic inflammatory respiratory diseases: an update

NF-kappaB Signaling in Chronic Inflammatory Airway Disease

Targeting the NF-kappaB pathway in asthma and chronic obstructive pulmonary disease

The impact of TGF-beta on lung fibrosis: from targeting to biomarkers

Role of epidermal growth factor receptor in lung cancer and targeted therapies

Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations

The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC)

Biomarkers for ALK and ROS1 in Lung Cancer: Immunohistochemistry and Fluorescent In Situ Hybridization

Signaling intermediates (MAPK and PI3K) as therapeutic targets in NSCLC

Enzymatic in vitro anti-diabetic activity of few traditional Indian medicinal plants

Cytotoxic potential of few Indian fruit peels through 3-(4, 5-dimethylthiazol-yl)-2, 5-diphenyltetrazolium bromide assay on HepG2 cells

Invitro Antioxidant evaluation of Psidium guajava strem extracts

Natural products in medicinal chemistry

Antidesmone, a unique tetrahydroquinoline alkaloid, prevents acute lung injury via regulating MAPK and NF-κB activities

ARL11 regulates lipopolysaccharide-stimulated macrophage activation by promoting mitogen-activated protein kinase (MAPK) signaling

Lipopolysaccharide Cross-Tolerance Delays Platelet-Activating Factor-Induced Sudden Death in Swiss Albino Mice: Involvement of Cyclooxygenase in Cross-Tolerance

Telmisartan, an angiotensin II receptor blocker, attenuates Prevotella intermedia lipopolysaccharide-induced production of nitric oxide and interleukin-1beta in murine macrophages

Induction of Inducible Nitric Oxide Synthase by Lipopolysaccharide and the Influences of Cell Volume Changes, Stress Hormones and Oxidative Stress on Nitric Oxide Efflux from the Perfused Liver of Air-Breathing Catfish, Heteropneustes fossilis

Lipopolysaccharide promotes the development of murine endometriosis-like lesions via the nuclear factor-kappa B pathway

Lipopolysaccharide induced Interleukin-6 production is mediated through activation of ERK 1/2, p38 MAPK, MEK, and NFkappaB in chicken thrombocytes

Mechanisms of NF-kappaB p65 and strategies for therapeutic manipulation

Myeloperoxidase inhibition decreases morbidity and oxidative stress in mice with cystic fibrosis-like lung inflammation

Functional and metabolic impairment in cigarette smoke-exposed macrophages is tied to oxidative stress

KEAP1) differentially regulates nuclear factor erythroid-2-related factors 1 and 2 (NRF1 and NRF2)

Molecular basis of the Keap1-Nrf2 system

The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer

The Keap1-Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

Isosteroid alkaloids from Fritillaria cirrhosa bulbus as inhibitors of cigarette smoke-induced oxidative stress

Airways antiallergic effect and pharmacokinetics of alkaloids from Alstonia scholaris

Eotaxin and asthma: some answers, more questions

Effects of indole alkaloids from leaf of Alstonia scholaris on post-infectious cough in mice

Antitussive, expectorant, and bronchodilating effects of quinazoline alkaloids (+/-)-vasicine, deoxyvasicine, and (+/-)-vasicinone from aerial parts of Peganum harmala L

Effectiveness of Cissampelos sympodialis and its isolated alkaloid warifteine in airway hyperreactivity and lung remodeling in a mouse model of asthma

Role of interleukin-13 in asthma

Chelidonine, a principal isoquinoline alkaloid of Chelidonium majus, attenuates eosinophilic airway inflammation by suppressing IL-4 and eotaxin-2 expression in asthmatic mice

Human CD8+ T Cells in Asthma: Possible Pathways and Roles for NK-Like Subtypes

Anti-asthmatic activity of alkaloid compounds from Pericarpium Citri Reticulatae (Citrus reticulata 'Chachi')

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Natural Bis-Benzylisoquinoline Alkaloids-Tetrandrine, Fangchinoline, and Cepharanthine, Inhibit Human Coronavirus OC43 Infection of MRC-5 Human Lung Cells

A Steroidal Alkaloid with Bactericidal Activity against Mycobacterium tuberculosis

An iboga alkaloid chemotaxonomic marker from endemic Tabernaemontana ternifolia with antitubercular activity

Talaramide A, an unusual alkaloid from the mangrove endophytic fungus Talaromyces sp.(HZ-YX1) as an inhibitor of mycobacterial PknG

Slow-Binding Inhibition of Mycobacterium tuberculosis Shikimate Kinase by Manzamine Alkaloids

Denigrins A-C: new antitubercular 3,4-diarylpyrrole alkaloids from Dendrilla nigra

Antimicrobial and antimycobacterial activity of cyclostellettamine alkaloids from sponge Pachychalina sp

Hypoxic Non-replicating Persistent Mycobacterium tuberculosis Develops Thickened Outer Layer That Helps in Restricting Rifampicin Entry

The enduring hypoxic response of Mycobacterium tuberculosis

Aaptamines, marine spongean alkaloids, as anti-dormant mycobacterial substances

Exploring the effective materials of flavonoidsenriched extract from Scutellaria baicalensis roots based on the metabolic activation in influenza A virus induced acute lung injury

In vivo effect of quantified flavonoids-enriched extract of Scutellaria baicalensis root on acute lung injury induced by influenza A virus

Flavonoids from Houttuynia cordata attenuate H1N1-induced acute lung injury in mice via inhibition of influenza virus and Toll-like receptor signalling

MCP-1, KC-like and IL-8 as critical mediators of pathogenesis caused by Babesia canis

Inhibitors of the interferon response enhance virus replication in vitro

Toll-like receptor signaling pathways

Antimycobacterial potentials of quercetin and rutin against Mycobacterium tuberculosis H37Rv, 3 Biotech

Mycobacterium tuberculosis lipolytic enzymes as potential biomarkers for the diagnosis of active tuberculosis

CitE enzymes are essential for Mycobacterium tuberculosis to establish infection in macrophages and Guinea pigs

Predictive binding affinity of plantderived natural products towards the protein kinase G enzyme of Mycobacterium tuberculosis (MtPknG)

Flavonoids as Novel Efflux Pump Inhibitors and Antimicrobials Against Both Environmental and Pathogenic Intracellular Mycobacterial Species

Skullcapflavone II inhibits ovalbumin-induced airway inflammation in a mouse model of asthma

Phloretin Exerts Anti-Tuberculosis Activity and Suppresses Lung Inflammation

Inhibitory effects and related molecular mechanisms of total flavonoids in Mosla chinensis Maxim against H1N1 influenza virus

Screening of natural compounds that targets glutamate racemase of Mycobacterium tuberculosis reveals the anti-tubercular potential of flavonoids

Inhibition of SARS-CoV 3CL protease by flavonoids

Influenza Virus Neuraminidase Structure and Functions

Role of Pneumococcal NanA Neuraminidase Activity in Peripheral Blood

Discovery of prenylated flavonoids with dual activity against influenza virus and Streptococcus pneumoniae

Limonene inhalation reduces allergic airway inflammation in Dermatophagoides farinae-treated mice

Possible therapeutic effect of carvacrol on asthmatic patients: A randomized, double blind, placebo-controlled, Phase II clinical trial

Effect of carvacrol on tracheal responsiveness, inflammatory mediators, total and differential WBC count in blood of sensitized guinea pigs

Nitric oxide in health and disease of the respiratory system

Preventive and Therapeutic Effects of Thymol in a Lipopolysaccharide-Induced Acute Lung Injury Mice Model

Immunomodulatory effects of Thymol through modulation of redox status and trace element content in experimental model of asthma

Thymoquinone ameliorates pulmonary vascular damage induced byEscherichia coli-derived lipopolysaccharide via cytokine downregulation in rats

The protective effects of thymoquinone on lung damage caused by cigarette smoke

Thymoquinone inhibits inflammation, neoangiogenesis and vascular remodeling in asthma mice

Farnesol ameliorates massive inflammation, oxidative stress and lung injury induced by intratracheal instillation of cigarette smoke extract in rats: an initial step in lung chemoprevention

Benzo(a)pyreneinduced pulmonary inflammation, edema, surfactant dysfunction, and injuries in rats: alleviation by farnesol

Antimycobacterial terpenoids from Juniperus communis L. (Cuppressaceae)

Andrographolide sulfonate ameliorates lipopolysaccharide-induced acute lung injury in mice by down-regulating MAPK and NF-kappaB pathways

Andrographolide Restores Steroid Sensitivity To Block

Lipopolysaccharide/IFN-gamma-Induced IL-27 and Airway Hyperresponsiveness in Mice

The cell-cell adhesion molecule E-cadherin, Cellular and molecular life sciences

Andrographolide prevented toluene diisocyanate-induced occupational asthma and aberrant airway E-cadherin distribution via p38 MAPKdependent Nrf2 induction

beta-Sitosterol Reduces the Expression of Chemotactic Cytokine Genes in Cystic Fibrosis Bronchial Epithelial Cells

Effects of beta-Sitosterol from Corn Silk on TGF-beta1-Induced Epithelial-Mesenchymal Transition in Lung Alveolar Epithelial Cells

Effects of Corni fructus on ovalbumin-induced airway inflammation and airway hyper-responsiveness in a mouse model of allergic asthma

Ursolic acid inhibits cigarette smoke extract-induced human bronchial epithelial cell injury and prevents development of lung cancer

Ursolic acid, a potential PPARgamma agonist, suppresses ovalbumininduced airway inflammation and Penh by down-regulating IL-5, IL-13, and IL-17 in a mouse model of allergic asthma

Ursolic acid attenuates cigarette smoke-induced emphysema in rats by regulating PERK and Nrf2 pathways

PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress

Ursolic Acid Protected Lung of Rats From Damage Induced by Cigarette Smoke Extract

Ursolic acid alleviates airway-vessel remodeling and muscle consumption in cigarette smoke-induced emphysema rats

Effects of hydroxy pentacyclic triterpene acids from Forsythia viridissima on asthmatic responses to ovalbumin challenge in conscious guinea pigs

Antiinflammatory properties of betulinic acid and xylopic acid in the carrageenan-induced pleurisy model of lung inflammation in mice

Effects and mechanisms of oridonin in the treatment of acute respiratory distress syndrome mice

Investigation of the anti-asthmatic activity of Oridonin on a mouse model of asthma

Discovery and resupply of pharmacologically active plantderived natural products: A review

Plants as factories for Human Pharmaceuticals: Applications and Challenges

Drug discovery from medicinal plants

Oxymel, a traditional formulation from Drimia Maritima (L.) Stearn, as an add-on treatment in patients with moderate to severe persistent asthma: A pilot, triple-blind, randomized clinical trial

Dietary plant stanol ester consumption improves immune function in asthma patients: results of a randomized, double-blind clinical trial

History of the introduction of theophylline into the treatment of asthma

Alkaloids as drug leads -a predictive structural and biodiversity-based analysis

Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind

Efficacy and tolerability of a fixed combination of thyme and primrose root in patients with acute bronchitis. A double-blind, randomized, placebo-controlled clinical trial

Efficacy and tolerability of a fluid extract combination of thyme herb and ivy leaves and matched placebo in adults suffering from acute bronchitis with productive cough. A prospective, double-blind, placebo-controlled clinical trial

Evaluation of efficacy and tolerability of a fixed combination of dry extracts of thyme herb and primrose root in adults suffering from acute bronchitis with productive cough. A prospective, double-blind, placebo-controlled multicentre clinical trial

Safety and Efficacy Profile of Echinacea purpurea to Prevent Common Cold Episodes: A Randomized, Double-Blind, Placebo-Controlled Trial

Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients with COPDA Randomized Clinical Trial

A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression

Specific inhibiting characteristics of tetramethylpyrazine, one of the active ingredients of the Chinese herbal medicine 'Chuanxiong', on platelet thrombus formation under high shear rates

Plasma endothelin-1 and nitric oxide correlate with ligustrazine alleviation of pulmonary artery hypertension in patients of chronic cor pulmonale from high altitude plateau during acute exacerbation (in Chinese)

Effect of atropine on sputum production

Puerarin induces mitochondria-dependent apoptosis in hypoxic human pulmonary arterial smooth muscle cells

Possible therapeutic effect of carvacrol on asthmatic patients: A randomized, double blind, placebo-controlled, Phase II clinical trial

Anti-inflammatory activity of1.8-cineol (eucalyptol) in bronchial asthma: a double-blind placebo-controlled trial

Therapy for Acute Nonpurulent Rhinosinusitis With Cineole: Results of a Double-Blind, Randomized, Placebo-Controlled Trial

A novel herbal composition containing extracts of Boswellia serrata gum resin and Aegle marmelos fruit alleviates symptoms of asthma in a placebo controlled double-blind clinical study

Oral sulforaphane increases Phase II antioxidant enzymes in the human upper airway

Highly absorptive curcumin reduces serum atherosclerotic low-density lipoprotein levels in patients with mild COPD

Inhibition of NF-κB activation and MMP-9 secretion by plasma of human volunteers after ingestion of maritime pine bark extract (Pycnogenol)

Effect of dietary intake of omega-3 and omega-6 fatty acids on severity of asthma in children

Conjugated linoleic acid improves airway hyper-reactivity in overweight mild asthmatics

Effects of a dietary intervention with conjugated linoleic acid on immunological and metabolic parameters in children and adolescents with allergic asthma -a placebo-controlled pilot trial

A clinical pharmacological study of the potential beneficial effects of a propolis food product as an adjuvant in asthmatic patients

Meenu is supported by the Graduate School of Health and University of Technology Sydney 

• Plant derived therapeutics for managing chronic respiratory disorders.• Activity of natural product based molecules on key regulatory pathways of COPD.• Preclinical evidence for the efficacy of natural product moieties.• Clinical significance of plant derived molecules in pulmonary distress.

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: