Publications by authors named "Keshav Raj Paudel"

36 Publications

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

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

Versatility of liquid crystalline nanoparticles in inflammatory lung diseases.

Nanomedicine (Lond) 2021 08 29;16(18):1545-1548. Epub 2021 Jun 29.

Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, 57000, Malaysia.

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http://dx.doi.org/10.2217/nnm-2021-0114DOI Listing
August 2021

Mitochondrial dysfunctions associated with chronic respiratory diseases and their targeted therapies: an update.

Future Med Chem 2021 08 29;13(15):1249-1251. Epub 2021 Jun 29.

Centre for Inflammation, Centenary Institute, Sydney, NSW, 2050, Australia.

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http://dx.doi.org/10.4155/fmc-2021-0097DOI Listing
August 2021

The FBXW7-NOTCH interactome: A ubiquitin proteasomal system-induced crosstalk modulating oncogenic transformation in human tissues.

Cancer Rep (Hoboken) 2021 08 6;4(4):e1369. Epub 2021 Apr 6.

Department of Biotechnology, School of Engineering & Technology (SET), Sharda University, Greater Noida, Uttar Pradesh, 201310, India.

Background: Ubiquitin ligases or E3 ligases are well programmed to regulate molecular interactions that operate at a post-translational level. Skp, Cullin, F-box containing complex (or SCF complex) is a multidomain E3 ligase known to mediate the degradation of a wide range of proteins through the proteasomal pathway. The three-dimensional domain architecture of SCF family proteins suggests that it operates through a novel and adaptable "super-enzymatic" process that might respond to targeted therapeutic modalities in cancer.

Recent Findings: Several F-box containing proteins have been characterized either as tumor suppressors (FBXW8, FBXL3, FBXW8, FBXL3, FBXO1, FBXO4, and FBXO18) or as oncogenes (FBXO5, FBXO9, and SKP2). Besides, F-box members like βTrcP1 and βTrcP2, the ones with context-dependent functionality, have also been studied and reported. FBXW7 is a well-studied F-box protein and is a tumor suppressor. FBXW7 regulates the activity of a range of substrates, such as c-Myc, cyclin E, mTOR, c-Jun, NOTCH, myeloid cell leukemia sequence-1 (MCL1), AURKA, NOTCH through the well-known ubiquitin-proteasome system (UPS)-mediated degradation pathway. NOTCH signaling is a primitive pathway that plays a crucial role in maintaining normal tissue homeostasis. FBXW7 regulates NOTCH protein activity by controlling its half-life, thereby maintaining optimum protein levels in tissue. However, aberrations in the FBXW7 or NOTCH expression levels can lead to poor prognosis and detrimental outcomes in patients. Therefore, the FBXW7-NOTCH axis has been a subject of intense study and research over the years, especially around the interactome's role in driving cancer development and progression. Several studies have reported the effect of FBXW7 and NOTCH mutations on normal tissue behavior. The current review attempts to critically analyze these mutations prognostic value in a wide range of tumors. Furthermore, the review summarizes the recent findings pertaining to the FBXW7 and NOTCH interactome and its involvement in phosphorylation-related events, cell cycle, proliferation, apoptosis, and metastasis.

Conclusion: The review concludes by positioning FBXW7 as an effective diagnostic marker in tumors and by listing out recent advancements made in cancer therapeutics in identifying protocols targeting the FBXW7-NOTCH aberrations in tumors.
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http://dx.doi.org/10.1002/cnr2.1369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388169PMC
August 2021

Rutin loaded liquid crystalline nanoparticles inhibit non-small cell lung cancer proliferation and migration in vitro.

Life Sci 2021 Jul 28;276:119436. Epub 2021 Mar 28.

Centre for Inflammation, Centenary Institute, Sydney, NSW 2050, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia. Electronic address:

Non-small cell lung cancer (NSCLC) is one of the major causes of cancer-related mortality globally. Despite the availability of therapeutic options, the improvement in patient survival is yet to be achieved. Recent advances in natural product (e.g., Rutin) research, therapeutic nanotechnology and especially the combination of both could aid in achieving significant improvements in the treatment or management of NSCLC. In this study, we explore the anti-cancer activity of Rutin-loaded liquid crystalline nanoparticles (LCNs) in an in vitro model where we have employed the A549 human lung epithelial carcinoma cell line. The anti-proliferative activity was determined by MTT and Trypan blue assays, whereas, the anti-migratory activity was evaluated by the scratch wound healing assay and a modified Boyden chamber assay. We also evaluated the anti-apoptotic activity by Annexin V-FITC staining, and the colony formation activity was studied using crystal violet staining. Here, we report that Rutin-LCNs showed promising anti-proliferative and anti-migratory activities. Furthermore, Rutin-LCNs also induced apoptosis in the A549 cells and inhibited colony formation. The findings warrant further detailed and in-depth anti-cancer mechanistic studies of Rutin-LCNs with a focus towards a potential therapeutic option for NSCLC. LCNs may help to enhance the solubility of Rutin used in the treatment of lung cancer and hence enhance the anticancer effect of Rutin.
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http://dx.doi.org/10.1016/j.lfs.2021.119436DOI Listing
July 2021

Drug delivery advances in mitigating inflammation via matrix metalloproteinases in respiratory diseases.

Nanomedicine (Lond) 2021 03 18;16(6):437-439. Epub 2021 Feb 18.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia.

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http://dx.doi.org/10.2217/nnm-2021-0016DOI Listing
March 2021

Rutin-loaded liquid crystalline nanoparticles attenuate oxidative stress in bronchial epithelial cells: a PCR validation.

Future Med Chem 2021 03 4;13(6):543-549. Epub 2021 Feb 4.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia.

In the present study, the inhibitory potential of rutin-loaded liquid crystalline nanoparticles (LCNs) on oxidative stress was determined in human bronchial epithelial cells (BEAS-2B) by analysing the expression levels of different antioxidant (NADPH quinine oxidoreductase-1 (); γ-glutamyl cysteine synthetase catalytic subunit ()) and pro-oxidant (NADPH oxidase ; ) genes. Our findings revealed that the rutin-loaded LCNs inhibited the genes, namely  and , which caused oxidative stress. In addition, these nanoparticles demonstrated an upregulation in the expression of the antioxidant genes  and in a dose-dependent manner. The study indicates the promising potential of rutin-loaded LCNs as an effective treatment strategy in patients with high oxidant loads in various respiratory diseases.
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http://dx.doi.org/10.4155/fmc-2020-0297DOI Listing
March 2021

Anti-inflammatory and anticancer activities of Naringenin-loaded liquid crystalline nanoparticles in vitro.

J Food Biochem 2021 01 29;45(1):e13572. Epub 2020 Nov 29.

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

In this study, we had developed Naringenin-loaded liquid crystalline nanoparticles (LCNs) and investigated the anti-inflammatory and anticancer activities of Naringenin-LCNs against human airway epithelium-derived basal cells (BCi-NS1.1) and human lung epithelial carcinoma (A549) cell lines, respectively. The anti-inflammatory potential of Naringenin-LCNs evaluated by qPCR revealed a decreased expression of IL-6, IL-8, IL-1β, and TNF-α in lipopolysaccharide-induced BCi-NS1.1 cells. The activity of LCNs was comparable to the positive control drug Fluticasone propionate (10 nM). The anticancer activity was studied by evaluating the antiproliferative (MTT and trypan blue assays), antimigratory (scratch wound healing assay, modified Boyden chamber assay, and immunoblot), and anticolony formation activity in A549 cells. Naringenin LCNs showed promising antiproliferative, antimigratory, and anticolony formation activities in A549 cells, in vitro. Therefore, based on our observations and results, we conclude that Naringenin-LCNs may be employed as a potential therapy-based intervention to ameliorate airway inflammation and to inhibit the progression of lung cancer. PRACTICAL APPLICATIONS: Naringenin was encapsulated into liquid crystalline nanoparticles, thus, attributing to their sustained-release nature. In addition, Naringenin-loaded LCNs efficiently reduced the levels of pro-inflammatory markers, namely, IL-1β, IL-6, TNF-α, and IL-8. In addition, the Naringenin-loaded LCNs also possess potent anticancer activity, when tested in the A549 cell line, as revealed by the inhibition of proliferation and migration of cells. They also attenuated colony formation and induced apoptosis in the A549 cells. The findings from our study could form the basis for future research that may be translated into an in vivo model to validate the possible therapeutic alternative for lung cancer using Naringenin-loaded LCNs. In addition, the applications of Naringenin-loaded LCNs as an intervention would be of great interest to biological, formulation and respiratory scientists and clinicians.
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http://dx.doi.org/10.1111/jfbc.13572DOI Listing
January 2021

Advancing of Cellular Signaling Pathways in Respiratory Diseases Using Nanocarrier Based Drug Delivery Systems.

Curr Pharm Des 2020 ;26(42):5380-5392

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo NSW 2007, Australia.

Cell Signaling pathways form an integral part of our existence that allows the cells to comprehend a stimulus and respond back. Such reactions to external cues from the environment are required and are essential to regulate the normal functioning of our body. Abnormalities in the system arise when there are errors developed in these signals, resulting in a complication or a disease. Presently, respiratory diseases contribute to being the third leading cause of morbidity worldwide. According to the current statistics, over 339 million people are asthmatic, 65 million are suffering from COPD, 2.3 million are lung cancer patients and 10 million are tuberculosis patients. This toll of statistics with chronic respiratory diseases leaves a heavy burden on society and the nation's annual health expenditure. Hence, a better understanding of the processes governing these cellular pathways will enable us to treat and manage these deadly respiratory diseases effectively. Moreover, it is important to comprehend the synergy and interplay of the cellular signaling pathways in respiratory diseases, which will enable us to explore and develop suitable strategies for targeted drug delivery. This review, in particular, focuses on the major respiratory diseases and further provides an in-depth discussion on the various cell signaling pathways that are involved in the pathophysiology of respiratory diseases. Moreover, the review also analyses the defining concepts about advanced nano-drug delivery systems involving various nanocarriers and propose newer prospects to minimize the current challenges faced by researchers and formulation scientists.
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http://dx.doi.org/10.2174/1381612826999201116161143DOI Listing
April 2021

Antiproliferative effects of boswellic acid-loaded chitosan nanoparticles on human lung cancer cell line A549.

Future Med Chem 2020 11 30;12(22):2019-2034. Epub 2020 Oct 30.

Faculty of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, 124001, India.

In the present study boswellic acids-loaded chitosan nanoparticles were synthesized using ionic gelation technique. The influence of independent variables were studied and optimized on dependent variables using central composite design. The designed nanoparticles were observed spherical in shape with an average size of 67.5-187.2 nm and have also shown an excellent entrapment efficiency (80.06 ± 0.48). The cytotoxicity assay revealed enhanced cytotoxicity for drug-loaded nanoparticles in contrast to the free drug having an IC value of 17.29 and 29.59 μM, respectively. Flow cytometry confirmed that treatment of cells with 40 μg/ml had arrested 22.75 ± 0.3% at SubG phase of the cell cycle when compared with untreated A459 cells. The observed results justified the boswellic acids-loaded chitosan nanoparticles were effective due to greater cellular uptake, sustained intercellular drug retention and enhanced antiproliferative effect by inducing apoptosis.
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http://dx.doi.org/10.4155/fmc-2020-0083DOI Listing
November 2020

Beyond the Obvious: Smoking and Respiratory Infection Implications on Alzheimer's Disease.

CNS Neurol Disord Drug Targets 2020 ;19(9):698-708

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo NSW 2007, Australia.

Tobacco smoke is not only a leading cause for chronic obstructive pulmonary disease, cardiovascular disorders, and lung and oral cancers, but also causes neurological disorders such as Alzheimer 's disease. Tobacco smoke consists of more than 4500 toxic chemicals, which form free radicals and can cross blood-brain barrier resulting in oxidative stress, an extracellular amyloid plaque from the aggregation of amyloid β (Aβ) peptide deposition in the brain. Further, respiratory infections such as Chlamydia pneumoniae, respiratory syncytial virus have also been involved in the induction and development of the disease. The necessary information collated on this review has been gathered from various literature published from 1995 to 2019. The review article sheds light on the role of smoking and respiratory infections in causing oxidative stress and neuroinflammation, resulting in Alzheimer's disease (AD). This review will be of interest to scientists and researchers from biological and medical science disciplines, including microbiology, pharmaceutical sciences and the translational researchers, etc. The increasing understanding of the relationship between chronic lung disease and neurological disease is two-fold. First, this would help to identify the risk factors and possible therapeutic interventions to reduce the development and progression of both diseases. Second, this would help to reduce the probable risk of development of AD in the population prone to chronic lung diseases.
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http://dx.doi.org/10.2174/1871527319999200817112427DOI Listing
November 2021

Solid lipid nanoparticles containing anti-tubercular drugs attenuate the Mycobacterium marinum infection.

Tuberculosis (Edinb) 2020 12 10;125:102008. Epub 2020 Oct 10.

Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, India. Electronic address:

The present study aimed to formulate anti-tubercular drugs (Rifampicin, Isoniazid and Pyrazinamide) loaded solid lipid nanoparticles (ATDs-SLNs) using microemulsion technique for oral administration. Central composite designed (CCD) was applied to study the effect of stearic acid (X), Compritol® 888 ATO (X) and equal ratio of poloxamer 188: sodium taurocholate (% w/w) (X) on particle size, zeta potential and entrapment efficiency. The optimised formulation (SLN) was found to be spherical in shape with mean particle size 187.9 ± 10.73 nm and zeta potential -47.4 mV. The maximum percentage entrapment of RIF, INH and PYZ in the optimised formulation was found to be 86.40 ± 0.274, 83.84 ± 0.269 and 81.43 ± 0.576, respectively. The in-vitro drug release study demonstrated that the release of drug from SLNs was slow in comparison to marketed formulation and pure ATDs. Cytotoxicity of the ATDs-SLNs was studied on murine macrophage cell line (RAW 264.7) using modified MTT assay demonstrated two folds growth inhibition of M. marinum as compared to standard antitubercular drugs. Overall, the developed SLNs may be considered as a promising anti-mycobacterial nano-drug, providing a new direction to the tuberculosis clinics.
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http://dx.doi.org/10.1016/j.tube.2020.102008DOI Listing
December 2020

Role of Lung Microbiome in Innate Immune Response Associated With Chronic Lung Diseases.

Front Med (Lausanne) 2020 18;7:554. Epub 2020 Sep 18.

Centre for Inflammation, Centenary Institute, Sydney, NSW, Australia.

Respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung fibrosis, and lung cancer, pose a huge socio-economic burden on society and are one of the leading causes of death worldwide. In the past, culture-dependent techniques could not detect bacteria in the lungs, therefore the lungs were considered a sterile environment. However, the development of culture-independent techniques, particularly 16S rRNA sequencing, allowed for the detection of commensal microbes in the lung and with further investigation, their roles in disease have since emerged. In healthy individuals, the predominant commensal microbes are of phylum Firmicutes and Bacteroidetes, including those of the genera and . In contrast, pathogenic microbes () are often associated with lung diseases. There is growing evidence that microbial metabolites, structural components, and toxins from pathogenic and opportunistic bacteria have the capacity to stimulate both innate and adaptive immune responses, and therefore can contribute to the pathogenesis of lung diseases. Here we review the multiple mechanisms that are altered by pathogenic microbiomes in asthma, COPD, lung cancer, and lung fibrosis. Furthermore, we focus on the recent exciting advancements in therapies that can be used to restore altered microbiomes in the lungs.
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http://dx.doi.org/10.3389/fmed.2020.00554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530186PMC
September 2020

Microparticles-Mediated Vascular Inflammation and its Amelioration by Antioxidant Activity of Baicalin.

Antioxidants (Basel) 2020 Sep 20;9(9). Epub 2020 Sep 20.

Department of Oriental Medicine Resources, Mokpo National University, Muan-gun, Jeonnam 534-729, Korea.

Microparticles (MPs) are extracellular vesicles (0.1-1.0 μm in size), released in response to cell activation or apoptosis. Endothelial microparticles (EC-MP), vascular smooth muscle cell microparticles (VSMC-MP), and macrophage microparticles (MØ-MP) are key hallmarks of atherosclerosis progression. In our current study, we investigated the potent antioxidant activity of baicalin to ameliorate MP-induced vascular smooth muscle cell (VSMC) dysfunction and endothelial cell (EC) dysfunction, as well as the production of inflammatory mediators in macrophage (RAW264.7). In our study, baicalin suppressed the apoptosis, reactive oxygen species (ROS) generation, NO production, foam cell formation, protein expression of inducible nitric oxide synthase and cyclooxygenase-2 in MØ-MP-induced RAW264.7. In addition, VSMC migration induced by VSMC-MP was dose-dependently inhibited by baicalin. Likewise, baicalin inhibits metalloproteinase-9 expression and suppresses VSMC-MP-induced VSMC proliferation by down-regulation of mitogen-activated protein kinase and proliferating cell nuclear antigen protein expressions. Baicalin also inhibited ROS production and apoptosis in VSMC. In EC, the marker of endothelial dysfunction (endothelial senescence, upregulation of ICAM, and ROS production) induced by EC-MP was halted by baicalin. Our results suggested that baicalin exerts potent biological activity to restore the function of EC and VSMC altered by their corresponding microparticles and inhibits the release of inflammation markers from activated macrophages.
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http://dx.doi.org/10.3390/antiox9090890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555600PMC
September 2020

The GSK-3β-FBXL21 Axis Contributes to Circadian TCAP Degradation and Skeletal Muscle Function.

Cell Rep 2020 09;32(11):108140

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA. Electronic address:

FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTOCHROME degradation. How FBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Here we report the sarcomere component TCAP as a cytoplasmic substrate of FBXL21. FBXL21 interacts with TCAP in a circadian manner antiphasic to TCAP accumulation in skeletal muscle, and circadian TCAP oscillation is disrupted in Psttm mice with an Fbxl21 hypomorph mutation. GSK-3β phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3β inhibition or knockdown diminishes FBXL21-Cul1 complex formation and delays FBXL21-mediated TCAP degradation. Finally, Psttm mice show significant skeletal muscle defects, including impaired fiber size, exercise tolerance, grip strength, and response to glucocorticoid-induced atrophy, in conjunction with cardiac dysfunction. These data highlight a circadian regulatory pathway where a GSK-3β-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function.
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http://dx.doi.org/10.1016/j.celrep.2020.108140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299398PMC
September 2020

Genus Blepharis (Acanthaceae): A review of ethnomedicinally used species, and their phytochemistry and pharmacological activities.

J Ethnopharmacol 2021 Jan 13;265:113255. Epub 2020 Aug 13.

Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto City, Kumamoto, 862-0973, Japan; Program for Leading Graduate Schools, Health Life Science: Interdisciplinary and Glocal Oriented (HIGO) Program, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan. Electronic address:

Ethnopharmacological Relevance: Blepharis is an Afro-Asiatic genus belonging to the family Acanthaceae. It comprises about 126 species that occur in arid and semi-arid habitats. Some species of Blepharis are used in traditional medicines in different countries mainly for their anti-inflammatory, wound healing activities along with treatment of gastrointestinal disorders and bone fractures.

Aim Of The Review: The present review aims to collate and analyze the available data and information on distribution, traditional uses, chemical constituents and pharmacological activities of Blepharis.

Methods: Scientific information of genus Blepharis was retrieved from the online bibliographic databases such as MEDLINE/PubMed, SciFinder, Web of Science and Google Scholar and secondary resources including books and proceedings.

Results: Seven species of Blepharis were found to be reported frequently as useful in folklore in African and Asian countries. B. maderaspatensis was found to be widely used in Indian traditional medicines whereas the B. ciliaris and B. edulis were common in folklore of Egypt, Jordan, and Arabia. Active phytochemicals of Blepharis are flavonoids from B. ciliaris, alkaloids from B. sindica, phenolic acid derivatives, and phytosterols, and derivatives of hydroxamic acids from B. edulis resulted in possessing diverse biological properties such as anti-microbial, anti-inflammatory, and anti-cancer.

Conclusions: Various species of Blepharis were found to be used in traditional medicine systems in African and Asian countries. Few of these species were studied for their bioactive chemical constituents however the activity guided isolation studies are not performed. Similarly, detailed pharmacological studies in animal models to explore their mechanism of action are also not reported. Future studies should focus on these aspects related to the medicinally used species of Blepharis. The detailed and comprehensive comparative analysis presented here gives valuable information of the currently used Blepharis species and pave the way to investigate other useful species of Blepharis pertaining to ethnobotany, phytochemistry and discovery of new drugs.
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http://dx.doi.org/10.1016/j.jep.2020.113255DOI Listing
January 2021

Rutin loaded liquid crystalline nanoparticles inhibit lipopolysaccharide induced oxidative stress and apoptosis in bronchial epithelial cells in vitro.

Toxicol In Vitro 2020 Oct 7;68:104961. Epub 2020 Aug 7.

Centre for Inflammation, Centenary Institute, Sydney, NSW 2050, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia. Electronic address:

Airway inflammation and infections are the primary causes of damage in the airway epithelium, that lead to hypersecretion of mucus and airway hyper-responsiveness. The role of reactive oxygen species (ROS) and their components in the pathophysiological mechanisms of airway inflammation have been well-studied and emphasized for the past several decades. Rutin, a potent bioflavonoid, is well-known for its antioxidant, anti-inflammatory, especially in bronchial inflammation. However, poor solubility and rapid metabolism have led to its low bioavailability in biological systems, and hence limit its application. The present study aims to investigate the beneficial effects of rutin-loaded liquid crystalline nanoparticles (LCNs) against lipopolysaccharide (LPS) induced oxidative damage in human bronchial epithelial cell line (BEAS-2-B) cells in vitro. LPS was used to stimulate BEAS-2-B cells, causing the generation of nitric oxide (NO) and other reactive oxygen species (ROS) that had led to cellular apoptosis. The levels of NO and ROS were detected by, Griess reagent kit and dichlorodihydrofluorescein diacetate (DCFH-DA) respectively, whereas, cell apoptosis was studied by Annexin V-FITC and PI staining. The findings revealed that rutin-loaded LCNs significantly reduced NO, ROS levels and prevented apoptosis in BEAS-2B cells. The observations and findings provide a mechanistic understanding of the effectiveness of rutin-loaded LCNs in protecting the bronchial cells against airway inflammation, thus possessing a promising therapeutic option for the management of airway diseases.
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http://dx.doi.org/10.1016/j.tiv.2020.104961DOI Listing
October 2020

Molecular mechanisms of action of naringenin in chronic airway diseases.

Eur J Pharmacol 2020 Jul 25;879:173139. Epub 2020 Apr 25.

Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute (HMRI) & School of Biomedical Sciences and Pharmacy, The University of Newcastle (UoN), Callaghan, NSW, 2308, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney (UTS), Ultimo, NSW, 2007, Australia; Centre for Inflammation, Centenary Institute, Sydney, NSW, 2050, Australia. Electronic address:

Chronic airway inflammatory diseases are characterized by persistent proinflammatory responses in the respiratory tract. Although, several treatment strategies are currently available, lifelong therapy is necessary for most of these diseases. In recent years, phytophenols, namely, flavonoids, derived from fruits and vegetables have been gaining tremendous interest and have been extensively studied due to their low toxicological profile. Naringenin is a bioflavonoid abundantly found in citrus fruits. This substance has shown notable therapeutic potential in various diseases due to its promising diverse biological activities. In this review, we have attempted to review the published studies from the available literature, discussing the molecular level mechanisms of naringenin in different experimental models of airway inflammatory diseases including asthma, chronic obstructive pulmonary disease (COPD), lung cancer, pulmonary fibrosis and cystic fibrosis. Current evidences have proposed that the anti-inflammatory properties of naringenin play a major role in ameliorating inflammatory disease states. In addition, naringenin also possesses several other biological properties. Despite the proposed mechanisms suggesting remarkable therapeutic benefits, the clinical use of naringenin is, however, hampered by its low solubility and bioavailability. Furthermore, this review also discusses on the studies that utilise nanocarriers as a drug delivery system to address the issue of poor solubility.
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http://dx.doi.org/10.1016/j.ejphar.2020.173139DOI Listing
July 2020

MicroRNAs as Biomarker for Breast Cancer.

Endocr Metab Immune Disord Drug Targets 2020 ;20(10):1597-1610

Department of Biochemistry, Central University of Haryana, Jant-Pali, Mahendergarh District, 123031, Haryana, India

Regardless of advances in detection and treatment, breast cancer affects about 1.5 million women all over the world. Since the last decade, genome-wide association studies (GWAS) have been extensively conducted for breast cancer to define the role of miRNA as a tool for diagnosis, prognosis and therapeutics. MicroRNAs are small, non-coding RNAs that are associated with the regulation of key cellular processes such as cell multiplication, differentiation, and death. They cause a disturbance in the cell physiology by interfering directly with the translation and stability of a targeted gene transcript. MicroRNAs (miRNAs) constitute a large family of non-coding RNAs, which regulate target gene expression and protein levels that affect several human diseases and are suggested as the novel markers or therapeutic targets, including breast cancer. MicroRNA (miRNA) alterations are not only associated with metastasis, tumor genesis but also used as biomarkers for breast cancer diagnosis or prognosis. These are explained in detail in the following review. This review will also provide an impetus to study the role of microRNAs in breast cancer.
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http://dx.doi.org/10.2174/1871530320666200428113051DOI Listing
September 2021

Smooth Muscle Cell Derived Microparticles Acts as Autocrine Activation of Smooth Muscle Cell Proliferation by Mitogen Associated Protein Kinase Upregulation.

J Nanosci Nanotechnol 2020 09;20(9):5746-5750

Department of Oriental Medicine Resources, College of Natural Science, Mokpo National University, Muan-gun, Jeonnam 534-729, Republic of Korea.

Microparticles (MP); also know as microvesicles are extracellular vesicles (0.1 to 1.0 m) released by cells in response to cell activation or apoptosis. The high level of circulating MP is one of the important indicators of altered vascular function. Vascular smooth muscle cell (VSMC) derived MP could mediate proliferation and migration of VSMC leading to vascular inflammation. Proliferation of VSMC is mediated by mitogen associated protein kinase (MAPK) and proliferation cell nuclei antigen (PCNA) signaling pathway whereas migration is mediated by metalloproteinase and cytoskeletal remodeling pathway. In this study, VSMC-MP were isolated from confluent VSMC stimulated with tumor necrosis factor (TNF)-. VSMC-MP were treated to VSMC to investigate the VSMC proliferation marker using assay. In comparison to normal (VSMC-MP untreated group), VSMC-MP treatment results in proliferation of VSMC as revealed by MTT assay. VSMC-MP and TNF- induce proliferation by 34% and 67% respectively. VSMC-MP also induce over expression of PCNA in both immuno-fluorescence and western blot experiment. VSMC-MP and TNF- increase the PCNA expression by 1.86-fold and 1.95-fold respectively. Similarly, VSMC-MP treatment results in over expression of MAPK pathway protein expression in VSMC. As compared to normal, the MAPK protein (pERK1/2, pP38 and pJNK) were increased by 1.41-fold, 1.42-fold and 1.48-fold, respectively in VSMC-MP treated VSMC. Our results provide the evidence of VSMC-MP involvement in proliferation of VSMC. Thus, VSMC-MP could be considered as a potential marker of vascular inflammatory disorder such as atherosclerosis.
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http://dx.doi.org/10.1166/jnn.2020.17661DOI Listing
September 2020

Recent advances in experimental animal models of lung cancer.

Future Med Chem 2020 04 16;12(7):567-570. Epub 2020 Mar 16.

Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Chippendale, NSW 2007, Australia.

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http://dx.doi.org/10.4155/fmc-2019-0338DOI Listing
April 2020

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

J Ethnopharmacol 2020 May 13;253:112082. Epub 2019 Jul 13.

Department of Oriental Medicine Resources, Mokpo National University, Muan-gun, 58554, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: Eriobotrya japonica leaves has a very long history of medicinal use as an anti-inflammatory and antitussive agent for bronchial inflammation.

Aim Of The Study: The aim of this study was to evaluate the anti-inflammatory activities of Eriobotrya japonica (EJ) leaf water extract in an ovalbumin (OVA)-induced murine asthma model and human tracheal smooth muscle cell (HTSMC).

Materials And Methods: Mice were sensitized by intra peritoneal OVA and challenged with nebulized OVA. EJ extract was administered orally at various dose. Bronchoalveolar lavage fluid (BALF) was quantified for nitric oxide (NO), eosinophil peroxidase (EPO), interleukin (IL)-4, IL-13 level and immunoglobulin (Ig) E was quantified in serum. Lung tissue sections were stained with hematoxylin and eosin for assessment of inflammatory cell infiltration whereas mucus production and goblet cell hyperplasia were studied by periodic acid schiff staining. Western blot was done for analysis of pERK1/2 expression and NFκB translocation in HTSMC whereas iNOS and COX-2 expression in RAW264.7 cell.

Results: EJ significantly reduced the levels of BALF's NO, EPO, MMPs, IL-4, IL-13, and serum IgE. It also decreases inflammatory cell infiltration and mucus production. EJ also attenuated the proliferation of HTSMC, inhibits overexpression of ERK 1/2 and translocation of NFκB in HTSMC as well as iNOS and COX-2 expression in RAW 264.7 cell.

Conclusion: Present study suggest that, EJ effectively protects against allergic airway inflammation thus possessing potential therapeutic option for allergic asthma management.
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http://dx.doi.org/10.1016/j.jep.2019.112082DOI Listing
May 2020

Vascular Protection by Ethanol Extract of Root Bark: Endothelium-Dependent Relaxation of Rat Aorta and Decrease of Smooth Muscle Cell Migration and Proliferation.

Evid Based Complement Alternat Med 2018 1;2018:7905763. Epub 2018 Nov 1.

College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam 58554, Republic of Korea.

(white mulberry) is native to the northern part of Korea and popularly used as a traditional medicine due to its numerous health benefits against human's disease. However, the possibility that may also affect the cardiovascular system remains unexplored. This study sought to investigate the vascular protective effects of the root bark extract of (MAE). Vascular reactivity was performed in organ baths using isolated rat thoracic aorta, while platelet derived growth factor (PDGF) induced proliferation and migration of vascular smooth muscle cells (VSMCs) were studied by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and wound healing assay, respectively. MAE evoked a concentration dependent vasorelaxation following endothelium-dependent pathway. However, vessel relaxations in response to MAE were markedly reduced after endothelium removal; treatment of endothelial nitric oxide synthase inhibitor, guanylyl cyclase inhibitor, and nonspecific potassium channel inhibitor, however, was not altered by cyclooxygenase inhibitor. Furthermore, MAE also significantly blunted contractile response to vasoconstrictor agent, phenylephrine. Taken together, the current evidence revealed that MAE is a potent endothelium-dependent vasodilator and this effect was involved in, at least in part, nitric oxide cyclic-guanosine monophosphate (NO-cGMP) pathway in combination with potassium (K) channel activation. Moreover, MAE inhibited proliferation and migration of VSMCs induced by PDGF. Therefore, MAE could be a promising candidate of natural medicine for preventing and controlling cardiovascular diseases linked with endothelial dysfunction.
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http://dx.doi.org/10.1155/2018/7905763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236707PMC
November 2018

Phytochemical profile and pharmacological activity of Aegle marmelos Linn.

J Integr Med 2018 05 21;16(3):153-163. Epub 2018 Apr 21.

Department of Oriental Medicine Resources, Mokpo National University, Muan-gun, Jeonnam 534-729, South Korea. Electronic address:

Aegle marmelos Linn. (Rutaceae), commonly known as "bael" in Nepal and India, is a valuable medicinal plant and is considered sacred by the Hindus. It is used to cure several diseases in the Indian traditional medicine system of Ayurveda and has had similar uses among many ethnic communities residing in Indian subcontinent for over 5000 years. Its leaves, bark, stem, fruits and seeds have been used for various medicinal purposes. Bael fruits are especially effective in the treatment of chronic diarrhea, dysentery and peptic ulcers, while they are also useful as a laxative and cure for respiratory infections. Scientific studies have validated many of the ethnomedicinal uses of A. marmelos, which include antibacterial, antiviral, antidiarrheal, gastroprotective, anti-ulcerative colitis, hepatoprotective, antidiabetic, cardioprotective and radioprotective effects. Recently, this plant has also received attention as an anticancer agent for the treatment of various types of cancers. Thus, this review focuses on scientific evidence verifying the important pharmacological activity such as antioxidant, antidiabetic, antimicrobial, hepatoprotective, cardioprotective and anticancer activity of A. marmelos.
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http://dx.doi.org/10.1016/j.joim.2018.04.007DOI Listing
May 2018

Anticancer Activity of Punica granatum (Pomegranate): A Review.

Phytother Res 2017 Apr 10;31(4):568-578. Epub 2017 Feb 10.

Department of Pharmacy, School of Health and Allied Science, Pokhara University, PO Box 427, Dhungepatan, Kaski, Nepal.

Cancer is a pathological condition where excessive and abnormal cell growth leads to widespread invasion within the body to affect various organ functions. It is known that chemotherapeutic agents are themselves possible candidate of cancer generation as they can kill normal cells. So, therapeutic approach for cancer treatment and prevention is weighed in terms of benefit to risk ratio. Nowadays, there is an immense interest for the search herbal formulation with cancer preventive effect because of the problems, generated with existing chemotherapeutic regimens. Research interest in fruits rich in polyphenols is increasing because of their anticancer potential. In this review, we highlight the potential health benefits of pomegranate (Punica granatum) fruit and the underlying mechanism of its inhibition of cancer progression. Pomegranate has demonstrated anti-proliferative, anti-metastatic and anti-invasive effects on various cancer cell line in vitro as well as in vivo animal model or human clinical trial. Although several clinical trials are in progress for identifying the pomegranate as a candidate for various cancer treatment. It is necessary to replicate and validate its therapeutic efficacy by multiple clinical studies in order to formulate pomegranate products as an integral part of the dietary and pharmacological intervention in anticancer therapy. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/ptr.5784DOI Listing
April 2017

Reactive Oxygen Species: A Key Hallmark of Cardiovascular Disease.

Adv Med 2016 28;2016:9152732. Epub 2016 Sep 28.

Department of Pharmacy, School of Health and Allied Sciences, Pokhara University, Dhungepatan, Kaski 33701, Nepal.

Cardiovascular diseases (CVDs) have been the prime cause of mortality worldwide for decades. However, the underlying mechanism of their pathogenesis is not fully clear yet. It has been already established that reactive oxygen species (ROS) play a vital role in the progression of CVDs. ROS are chemically unstable reactive free radicals containing oxygen, normally produced by xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidase, lipoxygenases, or mitochondria or due to the uncoupling of nitric oxide synthase in vascular cells. When the equilibrium between production of free radicals and antioxidant capacity of human physiology gets altered due to several pathophysiological conditions, oxidative stress is induced, which in turn leads to tissue injury. This review focuses on pathways behind the production of ROS, its involvement in various intracellular signaling cascades leading to several cardiovascular disorders (endothelial dysfunction, ischemia-reperfusion, and atherosclerosis), methods for its detection, and therapeutic strategies for treatment of CVDs targeting the sources of ROS. The information generated by this review aims to provide updated insights into the understanding of the mechanisms behind cardiovascular complications mediated by ROS.
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http://dx.doi.org/10.1155/2016/9152732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059509PMC
September 2016

Phytochemical profile and biological activity of Juglans regia.

J Integr Med 2016 Sep;14(5):359-73

Department of Oriental Medicine Resource, Mokpo National University, Muan-gun 534-729, South Korea.

Juglans regia Linn. (Juglandaceae), popularly known as English or Persian walnut, is a valuable medicinal plant with a potency to cure various diseases in traditional medicine. Since ancient time, different local ethnic groups have used various part of J. regia for a wide array of ailments including helminthiasis, diarrhea, sinusitis, stomach ache, arthritis, asthma, eczema, scrofula, skin disorders, diabetes mellitus, anorexia, thyroid dysfunction, cancer and infectious diseases. Biological activities of J. regia have been reported in several peer review journals and scientific attention is increasing. The present review attempts to provide comprehensive information on plant description, ethnobotanical use, toxicity, phytochemical profile, pharmacology, clinical studies and current research prospective of the J. regia. Currently, there is an immense interest on isolation/identification of active constituents from walnut and screening those active compounds for pharmacological activities. In addition, researchers are performing clinical trials as well as screening various solvent extracts or fractions of J. regia in several animal diseases models to identify promising therapeutic benefits. In the present work, we review the latest information based on published scientific investigations of J. regia.
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http://dx.doi.org/10.1016/S2095-4964(16)60274-1DOI Listing
September 2016

Antiatherogenic Effect of Camellia japonica Fruit Extract in High Fat Diet-Fed Rats.

Evid Based Complement Alternat Med 2016 31;2016:9679867. Epub 2016 May 31.

College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam 58554, Republic of Korea.

Hypercholesterolemia is a well-known etiological factor for cardiovascular disease and a common symptom of most types of metabolic disorders. Camellia japonica is a traditional garden plant, and its flower and seed have been used as a base oil of traditional cosmetics in East Asia. The present study was carried out to evaluate the effect of C. japonica fruit extracts (CJF) in a high fat diet- (HFD-) induced hypercholesterolemic rat model. CJF was administered orally at three different doses: 100, 400, and 800 mg·kg(-1)·day(-1) (CJF 100, 400, and 800, resp.). Our results showed that CJF possessed strong cholesterol-lowering potency as indicated by the decrease in serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL), accompanied by an increase in serum high-density lipoprotein (HDL). Furthermore, CJF reduced serum lipid peroxidation by suppressing the formation of thiobarbituric acid reactive substance. In addition, oil red O (ORO) staining of rat arteries showed decreased lipid-positive staining in the CJF-treated groups compared to the control HFD group. Taken together, these results suggest that CJF could be a potent herbal therapeutic option and source of a functional food for the prevention and treatment of atherosclerosis and other diseases associated with hypercholesterolemia.
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http://dx.doi.org/10.1155/2016/9679867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906218PMC
June 2016
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