Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7+ mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target.
Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders.
Chronic respiratory diseases have collectively become a major public health concern and have now taken form as one of the leading causes of mortality worldwide. Most chronic respiratory diseases primarily occur due to prolonged airway inflammation. In addition, critical environmental factors such as cigarette smoke, industrial pollutants, farm dust, and pollens may also exacerbate such diseases. Moreover, alterations in the genetic sequence of an individual, abnormalities in the chromosomes or immunosuppression resulting from bacterial, fungal, and viral infections may also play a key role in the pathogenesis of respiratory diseases. Over the years, multiple in vitro models have been employed as the basis of existing as well as emerging advancements in chronic respiratory disease research. These include cell lines, gene expression techniques, single cell RNA sequencing, cytometry, culture techniques, as well as serum/sputum biomarkers that can be used to elucidate the molecular mechanisms underlying these diseases, and to identify novel diagnostic and management options for these diseases. This review summarizes the current understanding of the pathogenesis of various chronic respiratory diseases derived through in vitro experimental models, where the knowledge obtained from these studies can greatly benefit researchers in the discovery and development of novel screening techniques and advanced therapeutic strategies that could be translated into clinical use in the future.
The challenges and difficulties associated with conventional drug delivery systems have led to the emergence of novel, advanced targeted drug delivery systems. Therapeutic drug delivery of proteins and peptides to the lungs is complicated owing to the large size and polar characteristics of the latter. Nevertheless, the pulmonary route has attracted great interest today among formulation scientists, as it has evolved into one of the important targeted drug delivery platforms for the delivery of peptides, and related compounds effectively to the lungs, primarily for the management and treatment of chronic lung diseases. In this review, we have discussed and summarized the current scenario and recent developments in targeted delivery of proteins and peptide-based drugs to the lungs. Moreover, we have also highlighted the advantages of pulmonary drug delivery over conventional drug delivery approaches for peptide-based drugs, in terms of efficacy, retention time and other important pharmacokinetic parameters. The review also highlights the future perspectives and the impact of targeted drug delivery on peptide-based drugs in the coming decade.
Inflammatory responses play a remarkable role in the mechanisms of acute and chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis and lung cancer. Currently, there is a resurgence in the use of drugs from natural sources for various ailments as potent therapeutics. Berberine, an alkaloid prominent in the Chinese traditional system of medicine has been reported to exert therapeutic properties in various diseases. Nevertheless, the number of studies focusing on the curative potential of berberine in inflammatory diseases involving the respiratory system is limited. In this review, we have attempted to discuss the reported anti-inflammatory properties of berberine that function through several pathways such as, the NF-κB, ERK1/2 and p38 MAPK pathways which affect several pro-inflammatory cytokines in the pathophysiological processes involved in chronic respiratory diseases. This review would serve to provide valuable information to researchers who work in this field and a new direction in the field of drug discovery with respect to respiratory diseases.
The application of medicinal plants has captured the interest of researchers in recent times due to their potent therapeutic properties and a better safety profile. The prominent role of herbal products in treating and preventing multiple diseases dates back to ancient history and most of the modern drugs today originated from their significant sources owing to their ability to control multiple targets via different signalling pathways. Among them, flavonoids consist of a large group of polyphenols, which are well known for their various therapeutic benefits. Rutin is considered one of the attractive phytochemicals and important flavonoids in the pharmaceutical industry due to its diverse pharmacological activities via various underlying molecular mechanisms. It is usually prescribed for various disease conditions such as varicosities, haemorrhoids and internal haemorrhage. In this review, we have discussed and highlighted the different molecular mechanisms attributed to the various pharmacological activities of rutin, such as antioxidant, anti-inflammatory, anticancer, anti-allergic and antidiabetic. This review will be beneficial to herbal, biological and molecular scientists in understanding the pharmacological relevance of rutin at the molecular level.
Nutraceuticals are dietary supplements that are used to improve health, postpone aging, prevent illnesses, and maintain the human body's correct functioning. Nutraceuticals are now garnering a lot of interest because of their nutritional and therapeutic benefits. The research indicating the relevance of nutraceuticals as a possible therapeutic candidate against inflammatory lung disease was covered in this review. Nowadays, inflammatory lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, asthma, pneumonia, lung cancer, becoming highly dreadful because of their associated fatality. Inflammation is one of the cores and common factors of these diseases which is mainly associated with nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, NF-κB p65 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) phosphorylation, and initiation of the signaling pathway of the NF-κB. The secondary metabolites from natural sources are the active component that attenuates NF-κB and the associated pathway that inhibits inflammation in lung diseases. Nutraceuticals belonging to the chemical category polyphenols, alkaloids, terpenoids, flavonoids, tannins have the potential to combat the NF-κB pathway. Accordingly, this review discusses the medical value of nutraceuticals briefly and their ability to mitigate various inflammatory lung diseases through targeting inhibition of NF-κB.
Lung cancer is the leading cause of cancer-related mortality across the globe. The most prevalent pathological form of lung cancer is non-small-cell lung cancer (NSCLC). Elevated stimulation of the PI3K/Akt/mTOR pathway causes a slew of cancer-related symptoms, making it a promising target for new anticancer drugs. The PI3K/Akt/mTOR path is involved extensively in carcinogenesis and disease advancement in NSCLC. Several new inhibitors targeting this pathway have been discovered in preclinical investigations and clinical trials. The etiology and epidemiology of NSCLC and biology of the PI3K/Akt/mTOR cascade and its role in NSCLC pathogenesis have all been discussed in this article. In this article, we've reviewed PI3K/Akt/mTOR cascade inhibitors that have been proven in vitro and in preclinical trials to be effective in NSCLC. Drugs targeting the PI3K/Akt/mTOR path in the treatment of NSCLC were also addressed. A better knowledge of the underlying molecular biology, including epigenetic changes, is also critical to detecting relevant biomarkers and guiding combination methods. Additionally, improved clinical trial designs will increase the capacity to test novel drugs and combinations for accounting for genomic variation and eventually improve patient outcomes.
The human microbiota is fundamental to correct immune system development and balance. Dysbiosis, or microbial content alteration in the gut and respiratory tract, is associated with immune system dysfunction and lung disease development. The microbiota's influence on human health and disease is exerted through the abundance of metabolites produced by resident microorganisms, where short-chain fatty acids (SCFAs) represent the fundamental class. SCFAs are mainly produced by the gut microbiota through anaerobic fermentation of dietary fibers, and are known to influence the homeostasis, susceptibility to and outcome of many lung diseases. This article explores the microbial species found in healthy human gastrointestinal and respiratory tracts. We investigate factors contributing to dysbiosis in lung illness, and the gut-lung axis and its association with lung diseases, with a particular focus on the functions and mechanistic roles of SCFAs in these processes. The key focus of this review is a discussion of the main metabolites of the intestinal microbiota that contribute to host-pathogen interactions: SCFAs, which are formed by anaerobic fermentation. These metabolites include propionate, acetate, and butyrate, and are crucial for the preservation of immune homeostasis. Evidence suggests that SCFAs prevent infections by directly affecting host immune signaling. This review covers the various and intricate ways through which SCFAs affect the immune system's response to infections, with a focus on pulmonary diseases including chronic obstructive pulmonary diseases, asthma, lung cystic fibrosis, and tuberculosis. The findings reviewed suggest that the immunological state of the lung may be indirectly influenced by elements produced by the gut microbiota. SCFAs represent valuable potential therapeutic candidates in this context.
Mitochondria are one of the basic essential components for eukaryotic life survival. It is also the source of respiratory ATP. Recently published studies have demonstrated that mitochondria may have more roles to play aside from energy production. There is an increasing body of evidence which suggest that mitochondrial activities involved in normal and pathological states contribute to significant impact to the lung airway morphology and epithelial function in respiratory diseases such as asthma, COPD, and lung cancer. This review summarizes the pathophysiological pathways involved in asthma, COPD, lung cancer and highlights potential treatment strategies that target the malfunctioning mitochondria in such ailments. Mitochondria are responsive to environmental stimuli such as infection, tobacco smoke, and inflammation, which are essential in the pathogenesis of respiratory diseases. They may affect mitochondrial shape, protein production and ultimately cause dysfunction. The impairment of mitochondrial function has downstream impact on the cytosolic components, calcium control, response towards oxidative stress, regulation of genes and proteins and metabolic activities. Several novel compounds and alternative medicines that target mitochondria in asthma and chronic lung diseases have been discussed here. Moreover, mitochondrial enzymes or proteins that may serve as excellent therapeutic targets in COPD are also covered. The role of mitochondria in respiratory diseases is gaining much attention and mitochondria-based treatment strategies and personalized medicine targeting the mitochondria may materialize in the near future. Nevertheless, more in-depth studies are urgently needed to validate the advantages and efficacy of drugs that affect mitochondria in pathological states.
A primary illness that accounts for a significant portion of fatalities worldwide is cancer. Among the main malignancies, lung cancer is recognised as the most chronic kind of cancer around the globe. Radiation treatment, surgery, and chemotherapy are some medical procedures used in the traditional care of lung cancer. However, these methods lack selectivity and damage nearby healthy cells. Several polysaccharide-based nanomaterials have been created to transport chemotherapeutics to reduce harmful and adverse side effects and improve response during anti-tumour reactions. To address these drawbacks, a class of naturally occurring polymers called polysaccharides have special physical, chemical, and biological characteristics. They can interact with the immune system to induce a better immunological response. Furthermore, because of the flexibility of their structures, it is possible to create multifunctional nanocomposites with excellent stability and bioavailability for the delivery of medicines to tumour tissues. This study seeks to present new views on the use of polysaccharide-based chemotherapeutics and to highlight current developments in polysaccharide-based nanomedicines for lung cancer.
Non-small cell lung cancer (NSCLC) is reported to have a high incidence rate and is one of the most prevalent types of cancer contributing towards 85% of all incidences of lung cancer. Berberine is an isoquinoline alkaloid which offers a broad range of therapeutical and pharmacological actions against cancer. However, extremely low water solubility and poor oral bioavailability have largely restricted its therapeutic applications. To overcome these limitations, we formulated berberine-loaded liquid crystalline nanoparticles (LCNs) and investigated their in vitro antiproliferative and antimigratory activity in human lung epithelial cancer cell line (A549). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), trypan blue staining, and colony forming assays were used to evaluate the anti-proliferative activity, while scratch wound healing assay and a modified Boyden chamber assay were carried out to determine the anti-migratory activity. We also investigated major proteins associated with lung cancer progression. The developed nanoparticles were found to have an average particle size of 181.3 nm with spherical shape, high entrapment efficiency (75.35%) and have shown sustained release behaviour. The most remarkable findings reported with berberine-loaded LCNs were significant suppression of proliferation, inhibition of colony formation, inhibition of invasion or migration via epithelial mesenchymal transition, and proliferation related proteins associated with cancer progression. Our findings suggest that anti-cancer compounds with the problem of poor solubility and bioavailability can be overcome by formulating them into nanotechnology-based delivery systems for better efficacy. Further in-depth investigations into anti-cancer mechanistic research will expand and strengthen the current findings of berberine-LCNs as a potential NSCLC treatment option.
Lung cancer is the second most prevalent type of cancer and is responsible for the highest number of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) makes up the majority of lung cancer cases. Zerumbone (ZER) is natural compound commonly found in the roots of Zingiber zerumbet which has recently demonstrated anti-cancer activity in both in vitro and in vivo studies. Despite their medical benefits, ZER has low aqueous solubility, poor GI absorption and oral bioavailability that hinders its effectiveness. Liquid crystalline nanoparticles (LCNs) are novel drug delivery carrier that have tuneable characteristics to enhance and ease the delivery of bioactive compounds. This study aimed to formulate ZER-loaded LCNs and investigate their effectiveness against NSCLC in vitro using A549 lung cancer cells. ZER-LCNs, prepared in the study, inhibited the proliferation and migration of A549 cells. These inhibitory effects were superior to the effects of ZER alone at a concentration 10 times lower than that of free ZER, demonstrating a potent anti-cancer activity of ZER-LCNs. The underlying mechanisms of the anti-cancer effects by ZER-LCNs were associated with the transcriptional regulation of tumor suppressor genes P53 and PTEN, and metastasis-associated gene KRT18. The protein array data showed downregulation of several proliferation associated proteins such as AXL, HER1, PGRN, and BIRC5 and metastasis-associated proteins such as DKK1, CAPG, CTSS, CTSB, CTSD, and PLAU. This study provides evidence of potential for increasing the potency and effectiveness of ZER with LCN formulation and developing ZER-LCNs as a treatment strategy for mitigation and treatment of NSCLC.
The purpose of this study was to evaluate the potential of zerumbone-loaded liquid crystalline nanoparticles (ZER-LCNs) in the protection of broncho-epithelial cells and alveolar macrophages against oxidative stress, inflammation and senescence induced by cigarette smoke extract in vitro. The effect of the treatment of ZER-LCNs on in vitro cell models of cigarette smoke extract (CSE)-treated mouse RAW264.7 and human BCi-NS1.1 basal epithelial cell lines was evaluated for their anti-inflammatory, antioxidant and anti-senescence activities using colorimetric and fluorescence-based assays, fluorescence imaging, RT-qPCR and proteome profiler kit. The ZER-LCNs successfully reduced the expression of pro-inflammatory markers including Il-6, Il-1β and Tnf-α, as well as the production of nitric oxide in RAW 264.7 cells. Additionally, ZER-LCNs successfully inhibited oxidative stress through reduction of reactive oxygen species (ROS) levels and regulation of genes, namely GPX2 and GCLC in BCi-NS1.1 cells. Anti-senescence activity of ZER-LCNs was also observed in BCi-NS1.1 cells, with significant reductions in the expression of SIRT1, CDKN1A and CDKN2A. This study demonstrates strong in vitro anti-inflammatory, antioxidative and anti-senescence activities of ZER-LCNs paving the path for this formulation to be translated into a promising therapeutic agent for chronic respiratory inflammatory conditions including COPD and asthma.
Immune restoration disease (IRD) associated with Mycobacterium tuberculosis parallels the reconstitution of a pathogen-specific Th1 response. However, it is not clear whether humoral responses to M. tuberculosis antigens also rise, or whether antibody levels predict IRD. Here, humoral immunity to M. tuberculosis antigens was investigated in four Asian cohorts.
In the recent years, much attention has been focused on identifying bioactive compounds from medicinal plants that could be employed in therapeutics, which is attributed to their potent pharmacological actions and better toxicological profile. One such example that has come into the light with considerable interest is the pentacyclic triterpenoid, celastrol, which has been found to provide substantial therapeutic properties in a variety of diseases. In an effort to further accelerate its potential to be utilized in clinical practice in the future; along with advancing technologies in the field of drug discovery and development, different researchers have been investigating on the various mechanisms and immunological targets of celastrol that underlie its broad spectrum of pharmacological properties. In this review, we have collated the various research findings related to the molecular modulators responsible for different pharmacological activities shown by celastrol. Our review will be of interest to the herbal, biological, molecular scientist and by providing a quick snapshot about celastrol giving a new direction in the area of herbal drug discovery and development.
Viral respiratory tract infections have significantly impacted global health as well as socio-economic growth. Respiratory viruses such as the influenza virus, respiratory syncytial virus (RSV), and the recent SARS-CoV-2 infection (COVID-19) typically infect the upper respiratory tract by entry through the respiratory mucosa before reaching the lower respiratory tract, resulting in respiratory disease. Generally, vaccination is the primary method in preventing virus pathogenicity and it has been shown to remarkably reduce the burden of various infectious diseases. Nevertheless, the efficacy of conventional vaccines may be hindered by certain limitations, prompting the need to develop novel vaccine delivery vehicles to immunize against various strains of respiratory viruses and to mitigate the risk of a pandemic. In this review, we provide an insight into how polymer-based nanoparticles can be integrated with the development of vaccines to effectively enhance immune responses for combating viral respiratory tract infections.
COVID-19 remains a life-threatening infectious disease worldwide. Several bio-active agents have been tested and evaluated in an effort to contain this disease. Unfortunately, none of the therapies have been successful, owing to their safety concerns and the presence of various adverse effects. Various countries have developed vaccines as a preventive measure; however, they have not been widely accepted as effective strategies. The virus has proven to be exceedingly contagious and lethal, so finding an effective treatment strategy has been a top priority in medical research. The significance of vitamin D in influencing many components of the innate and adaptive immune systems is examined in this study. This review aims to summarize the research on the use of vitamin D for COVID-19 treatment and prevention. Vitamin D supplementation has now become an efficient option to boost the immune response for all ages in preventing the spread of infection. Vitamin D is an immunomodulator that treats infected lung tissue by improving innate and adaptive immune responses and downregulating the inflammatory cascades. The preventive action exerted by vitamin D supplementation (at a specific dose) has been accepted by several observational research investigations and clinical trials on the avoidance of viral and acute respiratory dysfunctions. To assess the existing consensus about vitamin D supplementation as a strategy to treat and prevent the development and progression of COVID-19 disease, this review intends to synthesize the evidence around vitamin D in relation to COVID-19 infection.
The prevalence of lung diseases is increasing year by year and existing drug therapies only provide symptomatic relief rather than targeting the actual cause. Nucleic acids can be used as an alternative therapeutic approach owing to their potential to reform a homeostatic balance by upregulating protective genes or downregulating damaging genes. However, their inherent properties, such as poor stability, ineffective cellular uptake, negative charge and so on, hinder their clinical utility. Such limitations can be overcome by exploiting the functional chemistry of polymeric micelles (PMs) for site-specific delivery, transfection efficiency and improved stability. With this objective, the present work describes the advancements made in designing nucleic acid-based PMs for treating lung diseases followed by approaches requiring consideration for clinical applications.
Chronic lung diseases such as asthma, chronic obstructive pulmonary disease, lung cancer, and the recently emerged COVID-19, are a huge threat to human health, and among the leading causes of global morbidity and mortality every year. Despite availability of various conventional therapeutics, many patients remain poorly controlled and have a poor quality of life. Furthermore, the treatment and diagnosis of these diseases are becoming increasingly challenging. In the recent years, the application of nanomedicine has become increasingly popular as a novel strategy for diagnosis, treatment, prevention, as well as follow-up of chronic lung diseases. This is attributed to the ability of nanoscale drug carriers to achieve targeted delivery of therapeutic moieties with specificity to diseased site within the lung, thereby enhancing therapeutic outcomes of conventional therapies whilst minimizing the risks of adverse reactions. For this instance, monoolein is a polar lipid nanomaterial best known for its versatility, thermodynamic stability, biocompatibility, and biodegradability. As such, it is commonly employed in liquid crystalline systems for various drug delivery applications. In this review, we present the applications of monoolein as a novel nanomaterial-based strategy for targeted drug delivery with the potential to revolutionize therapeutic approaches in chronic lung diseases.