Publications by authors named "Venkata Sita Rama Raju Allam"

12 Publications

  • Page 1 of 1

Nutraceuticals: unlocking newer paradigms in the mitigation of inflammatory lung diseases.

Crit Rev Food Sci Nutr 2021 Oct 6:1-31. Epub 2021 Oct 6.

Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, India.

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.
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http://dx.doi.org/10.1080/10408398.2021.1986467DOI Listing
October 2021

LL-37 and HMGB1 induce alveolar damage and reduce lung tissue regeneration via RAGE.

Am J Physiol Lung Cell Mol Physiol 2021 10 18;321(4):L641-L652. Epub 2021 Aug 18.

Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

The receptor for advanced glycation end-products (RAGE) has been implicated in the pathophysiology of chronic obstructive pulmonary disease (COPD). However, it is still unknown whether RAGE directly contributes to alveolar epithelial damage and abnormal repair responses. We hypothesize that RAGE activation not only induces lung tissue damage but also hampers alveolar epithelial repair responses. The effects of the RAGE ligands LL-37 and HMGB1 were examined on airway inflammation and alveolar tissue damage in wild-type and RAGE-deficient mice and on lung damage and repair responses using murine precision cut lung slices (PCLS) and organoids. In addition, their effects were studied on the repair response of human alveolar epithelial A549 cells, using siRNA knockdown of RAGE and treatment with the RAGE inhibitor FPS-ZM1. We observed that intranasal installation of LL-37 and HMGB1 induces RAGE-dependent inflammation and severe alveolar tissue damage in mice within 6 h, with stronger effects in a mouse strain susceptible for emphysema compared with a nonsusceptible strain. In PCLS, RAGE inhibition reduced the recovery from elastase-induced alveolar tissue damage. In organoids, RAGE ligands reduced the organoid-forming efficiency and epithelial differentiation into pneumocyte-organoids. Finally, in A549 cells, we confirmed the role of RAGE in impaired repair responses upon exposure to LL-37. Together, our data indicate that activation of RAGE by its ligands LL-37 and HMGB1 induces acute lung tissue damage and that this impedes alveolar epithelial repair, illustrating the therapeutic potential of RAGE inhibitors for lung tissue repair in emphysema.
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http://dx.doi.org/10.1152/ajplung.00138.2021DOI Listing
October 2021

Recent trends of NFκB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases.

J Control Release 2021 09 8;337:629-644. Epub 2021 Aug 8.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia; Centre for Inflammation, Centenary Institute, Sydney, NSW 2050, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jconrel.2021.08.010DOI Listing
September 2021

Interleukin-13: A pivotal target against influenza-induced exacerbation of chronic lung diseases.

Life Sci 2021 Oct 3;283:119871. Epub 2021 Aug 3.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, Australia; Centre for Inflammation, Centenary Institute, Sydney, NSW 2050, Australia; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia. Electronic address:

Non-communicable, chronic respiratory diseases (CRDs) affect millions of individuals worldwide. The course of these CRDs (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) are often punctuated by microbial infections that may result in hospitalization and are associated with increased risk of morbidity and mortality, as well as reduced quality of life. Interleukin-13 (IL-13) is a key protein that regulates airway inflammation and mucus hypersecretion. There has been much interest in IL-13 from the last two decades. This cytokine is believed to play a decisive role in the exacerbation of inflammation during the course of viral infections, especially, in those with pre-existing CRDs. Here, we discuss the common viral infections in CRDs, as well as the potential role that IL-13 plays in the virus-induced disease pathogenesis of CRDs. We also discuss, in detail, the immune-modulation potential of IL-13 that could be translated to in-depth studies to develop IL-13-based therapeutic entities.
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http://dx.doi.org/10.1016/j.lfs.2021.119871DOI Listing
October 2021

Nuclear factor-kappa B and its role in inflammatory lung disease.

Chem Biol Interact 2021 Aug 25;345:109568. Epub 2021 Jun 25.

School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, 302017, Mahal Road, Jaipur, India. Electronic address:

Nuclear factor-kappa B, involved in inflammation, host immune response, cell adhesion, growth signals, cell proliferation, cell differentiation, and apoptosis defense, is a dimeric transcription factor. Inflammation is a key component of many common respiratory disorders, including asthma, chronic obstructive pulmonary disease (COPD), bronchiectasis, and acute respiratory distress syndrome. Many basic transcription factors are found in NF-κB signaling, which is a member of the Rel protein family. Five members of this family c-REL, NF-κB2 (p100/p52), RelA (p65), NF-κB1 (p105/p50), RelB, and RelA (p65) produce 5 transcriptionally active molecules. Proinflammatory cytokines, T lymphocyte, and B lymphocyte cell mitogens, lipopolysaccharides, bacteria, viral proteins, viruses, double-stranded RNA, oxidative stress, physical exertion, various chemotherapeutics are the stimulus responsible for NF-κB activation. NF-κB act as a principal component for several common respiratory illnesses, such as asthma, lung cancer, pulmonary fibrosis, COPD as well as infectious diseases like pneumonia, tuberculosis, COVID-19. Inflammatory lung disease, especially COVID-19, can make NF-κB a key target for drug production.
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http://dx.doi.org/10.1016/j.cbi.2021.109568DOI Listing
August 2021

Treatment of chronic airway diseases using nutraceuticals: Mechanistic insight.

Crit Rev Food Sci Nutr 2021 May 12:1-15. Epub 2021 May 12.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, Australia.

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.
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http://dx.doi.org/10.1080/10408398.2021.1915744DOI Listing
May 2021

A phospholipid-based formulation for the treatment of airway inflammation in chronic respiratory diseases.

Eur J Pharm Biopharm 2020 Dec 13;157:47-58. Epub 2020 Oct 13.

Graduate School of Health, University of Technology Sydney, Chippendale, NSW 2008, Australia. Electronic address:

Inflammation, the major hallmark of all chronic respiratory diseases is generally managed by inhaled corticosteroids. However, long term high dose treatment can result in significant side effects. Hence, there is a medical need for non-steroidal anti-inflammatory therapies to address airway inflammation. Phospholipids have been shown to reduce inflammation in several inflammatory conditions; however, their clinical translation has been limited to liposomal formulations traditionally used as drug carriers and their biological activity has not been investigated. Here we report the first application of empty liposomes as an anti-inflammatory treatment in airway inflammation. In the current study, liposomes (UTS-001) were prepared from cholesterol and a synthetic phospholipid (DOPC). The formulation was characterised in terms of size, charge, polydispersity index, morphology and stability as colloidal suspension and freeze-dried nanoparticles. Time-dependant uptake of UTS-001 in airway epithelial cells was observed which was inhibited by nystatin demonstrating that the uptake is via the caveolae pathway. In-vitro, in primary nasal epithelial cells, UTS-001 treatment successfully attenuated IL-6 levels following TNF-α stimulation. Consistent with the in-vitro findings, in-vivo, in the ovalbumin model of allergic airway inflammation, UTS-001 significantly reduced total immune cell counts in bronchoalveolar lavage fluid and reduced airway hyperresponsiveness in response to increasing doses of methacholine challenge. Therefore, our results establish UTS-001 as a potential anti-inflammatory treatment that may be useful as a therapeutic for lung inflammatory diseases.
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http://dx.doi.org/10.1016/j.ejpb.2020.09.017DOI Listing
December 2020

RAGE and TLR4 differentially regulate airway hyperresponsiveness: Implications for COPD.

Allergy 2021 04 15;76(4):1123-1135. Epub 2020 Oct 15.

Graduate School of Health, Faculty of Health, The University of Technology Sydney, Ultimo, NSW, Australia.

Background: The receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) is implicated in COPD. Although these receptors share common ligands and signalling pathways, it is not known whether they act in concert to drive pathological processes in COPD. We examined the impact of RAGE and/or TLR4 gene deficiency in a mouse model of COPD and also determined whether expression of these receptors correlates with airway neutrophilia and airway hyperresponsiveness (AHR) in COPD patients.

Methods: We measured airway inflammation and AHR in wild-type, RAGE , TLR4 and TLR4 RAGE mice following acute exposure to cigarette smoke (CS). We also examined the impact of smoking status on AGER (encodes RAGE) and TLR4 bronchial gene expression in patients with and without COPD. Finally, we determined whether expression of these receptors correlates with airway neutrophilia and AHR in COPD patients.

Results: RAGE mice were protected against CS-induced neutrophilia and AHR. In contrast, TLR4 mice were not protected against CS-induced neutrophilia and had more severe CS-induced AHR. TLR4 RAGE mice were not protected against CS-induced neutrophilia but were partially protected against CS-induced mediator release and AHR. Current smoking was associated with significantly lower AGER and TLR4 expression irrespective of COPD status, possibly reflecting negative feedback regulation. However, consistent with preclinical findings, AGER expression correlated with higher sputum neutrophil counts and more severe AHR in COPD patients. TLR4 expression did not correlate with neutrophilic inflammation or AHR.

Conclusions: Inhibition of RAGE but not TLR4 signalling may protect against airway neutrophilia and AHR in COPD.
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http://dx.doi.org/10.1111/all.14563DOI Listing
April 2021

Investigating MIF in Mouse Models of Severe Corticosteroid-Resistant Neutrophilic Asthma.

Methods Mol Biol 2020 ;2080:203-212

Graduate School of Health, Faculty of Health, University of Technology Sydney, Ultimo, NSW, Australia.

Experimental mouse models of asthma are widely used to investigate the underlying mechanisms of this complex and heterogeneous disease. Using mouse models of ovalbumin-induced asthma, previous investigators have established a crucial role for MIF in the development of type 2-mediated eosinophilic asthma. Surprisingly, however, the role of MIF in other phenotypes of asthma has received little attention. MIF is an important mediator of neutrophilic inflammation, and also acts to antagonize the actions of corticosteroids. Thus, MIF may play a role in the development of severe forms of asthma in which airway neutrophilia and corticosteroid insensitivity are major features. In this chapter, we provide an experimental protocol that may be used to investigate the role of MIF in a mouse model of severe corticosteroid-resistant neutrophilic asthma.
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http://dx.doi.org/10.1007/978-1-4939-9936-1_18DOI Listing
December 2020

Proteomic Analysis of Extracellular HMGB1 Identifies Binding Partners and Exposes Its Potential Role in Airway Epithelial Cell Homeostasis.

J Proteome Res 2018 01 14;17(1):33-45. Epub 2017 Nov 14.

Discipline of Pharmacy, Graduate School of Health, The University of Technology Sydney , Ultimo, New South Wales 2007, Australia.

The release of damage-associated molecular patterns (DAMPs) by airway epithelial cells is believed to play a crucial role in the initiation and development of chronic airway conditions such as asthma and chronic obstructive pulmonary disease (COPD). Intriguingly, the classic DAMP high-mobility group box-1 (HMGB1) is detected in the culture supernatant of airway epithelial cells under basal conditions, indicating a role for HMGB1 in the regulation of epithelial cellular and immune homeostasis. To gain contextual insight into the potential role of HMGB1 in airway epithelial cell homeostasis, we used the orthogonal and complementary methods of high-resolution clear native electrophoresis, immunoprecipitation, and pull-downs coupled to liquid chromatography-tandem mass spectrometry (LC-MS/MS) to profile HMGB1 and its binding partners in the culture supernatant of unstimulated airway epithelial cells. We found that HMGB1 presents exclusively as a protein complex under basal conditions. Moreover, protein network analysis performed on 185 binding proteins revealed 14 that directly associate with HMGB1: amyloid precursor protein, F-actin-capping protein subunit alpha-1 (CAPZA1), glyceraldehyde-3 phosphate dehydrogenase (GAPDH), ubiquitin, several members of the heat shock protein family (HSPA8, HSP90B1, HSP90AA1), XRCC5 and XRCC6, high mobility group A1 (HMGA1), histone 3 (H3F3B), the FACT (facilitates chromatin transcription) complex constituents SUPT1H and SSRP1, and heterogeneous ribonucleoprotein K (HNRNPK). These studies provide a new understanding of the extracellular functions of HMGB1 in cellular and immune homeostasis at the airway mucosal surface and could have implications for therapeutic targeting.
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http://dx.doi.org/10.1021/acs.jproteome.7b00212DOI Listing
January 2018
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