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

Wadhwa R, Paudel KR, Chin LH, Hon CM, Madheswaran T, Gupta G, et al.

J Food Biochem, 2021 01;45(1):e13572.
PMID: 33249629 DOI: 10.1111/jfbc.13572

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.
Fulltext Advances in pulmonary drug delivery targeting microbial biofilms in respiratory diseases

Sharma A, Kumar D, Dahiya K, Hawthorne S, Jha SK, Jha NK, et al.

Nanomedicine (Lond), 2021 09;16(21):1905-1923.
PMID: 34348474 DOI: 10.2217/nnm-2021-0057

The increasing burden of respiratory diseases caused by microbial infections poses an immense threat to global health. This review focuses on the various types of biofilms that affect the respiratory system and cause pulmonary infections, specifically bacterial biofilms. The article also sheds light on the current strategies employed for the treatment of such pulmonary infection-causing biofilms. The potential of nanocarriers as an effective treatment modality for pulmonary infections is discussed, along with the challenges faced during treatment and the measures that may be implemented to overcome these. Understanding the primary approaches of treatment against biofilm infection and applications of drug-delivery systems that employ nanoparticle-based approaches in the disruption of biofilms are of utmost interest which may guide scientists to explore the vistas of biofilm research while determining suitable treatment modalities for pulmonary respiratory infections.
Molecular and Immunological Mechanisms Underlying the Various Pharmacological Properties of the Potent Bioflavonoid, Rutin

Yong DOC, Saker SR, Chellappan DK, Madheswaran T, Panneerselvam J, Choudhury H, et al.

Endocr Metab Immune Disord Drug Targets, 2020;20(10):1590-1596.
PMID: 32359343 DOI: 10.2174/1871530320666200503053846

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.
Hybrid molecules based on 1,3,5-triazine as potential therapeutics: A focused review

Prasher P, Sharma M, Aljabali AAA, Gupta G, Negi P, Kapoor DN, et al.

Drug Dev Res, 2020 11;81(7):837-858.
PMID: 32579723 DOI: 10.1002/ddr.21704

Majority of the representative drugs customarily interact with multiple targets manifesting unintended side effects. In addition, drug resistance and over expression of the cellular efflux-pumps render certain classes of drugs ineffective. With only a few innovative formulations in development, it is necessary to identify pharmacophores and novel strategies for creating new drugs. The conjugation of dissimilar pharmacophoric moieties to design hybrid molecules with an attractive therapeutic profile is an emerging paradigm in the contemporary drug development regime. The recent decade witnessed the remarkable biological potential of 1,3,5-triazine framework in the development of various chemotherapeutics. The appending of the 1,3,5-triazine nucleus to biologically relevant moieties has delivered exciting results. The present review focuses on 1,3,5-triazine based hybrid molecules in the development of pharmaceuticals.
Fulltext Gene therapy and type 1 diabetes mellitus

Chellappan DK, Sivam NS, Teoh KX, Leong WP, Fui TZ, Chooi K, et al.

Biomed Pharmacother, 2018 Dec;108:1188-1200.
PMID: 30372820 DOI: 10.1016/j.biopha.2018.09.138

BACKGROUND: Type 1 diabetes mellitus (T1DM) is an autoimmune disorder characterized by T cell-mediated self-destruction of insulin-secreting islet β cells. Management of T1DM is challenging and complicated especially with conventional medications. Gene therapy has emerged as one of the potential therapeutic alternatives to treat T1DM. This review primarily focuses on the current status and the future perspectives of gene therapy in the management of T1DM. A vast number of the studies which are reported on gene therapy for the management of T1DM are done in animal models and in preclinical studies. In addition, the safety of such therapies is yet to be established in humans. Currently, there are several gene level interventions that are being investigated, notably, overexpression of genes and proteins needed against T1DM, transplantation of cells that express the genes against T1DM, stem-cells mediated gene therapy, genetic vaccination, immunological precursor cell-mediated gene therapy and vectors.
METHODS: We searched the current literature through searchable online databases, journals and other library sources using relevant keywords and search parameters. Only relevant publications in English, between the years 2000 and 2018, with evidences and proper citations, were considered. The publications were then analyzed and segregated into several subtopics based on common words and content. A total of 126 studies were found suitable for this review.
FINDINGS: Generally, the pros and cons of each of the gene-based therapies have been discussed based on the results collected from the literature. However, there are certain interventions that require further detailed studies to ensure their effectiveness. We have also highlighted the future direction and perspectives in gene therapy, which, researchers could benefit from.
The potential of siRNA based drug delivery in respiratory disorders: Recent advances and progress

Dua K, Wadhwa R, Singhvi G, Rapalli V, Shukla SD, Shastri MD, et al.

Drug Dev Res, 2019 09;80(6):714-730.
PMID: 31691339 DOI: 10.1002/ddr.21571

Lung diseases are the leading cause of mortality worldwide. The currently available therapies are not sufficient, leading to the urgent need for new therapies with sustained anti-inflammatory effects. Small/short or silencing interfering RNA (siRNA) has potential therapeutic implications through post-transcriptional downregulation of the target gene expression. siRNA is essential in gene regulation, so is more favorable over other gene therapies due to its small size, high specificity, potency, and no or low immune response. In chronic respiratory diseases, local and targeted delivery of siRNA is achieved via inhalation. The effectual delivery can be attained by the generation of aerosols via inhalers and nebulizers, which overcomes anatomical barriers, alveolar macrophage clearance and mucociliary clearance. In this review, we discuss the different siRNA nanocarrier systems for chronic respiratory diseases, for safe and effective delivery. siRNA mediated pro-inflammatory gene or miRNA targeting approach can be a useful approach in combating chronic respiratory inflammatory conditions and thus providing sustained drug delivery, reduced therapeutic dose, and improved patient compliance. This review will be of high relevance to the formulation, biological and translational scientists working in the area of respiratory diseases.
Emerging Complexity and the Need for Advanced Drug Delivery in Targeting Candida Species

Wadhwa R, Pandey P, Gupta G, Aggarwal T, Kumar N, Mehta M, et al.

Curr Top Med Chem, 2019;19(28):2593-2609.
PMID: 31746290 DOI: 10.2174/1568026619666191026105308

BACKGROUND: Candida species are the important etiologic agents for candidiasis, the most prevalent cause of opportunistic fungal infections. Candida invasion results in mucosal to systemic infections through immune dysfunction and helps in further invasion and proliferation at several sites in the host. The host defence system utilizes a wide array of the cells, proteins and chemical signals that are distributed in blood and tissues which further constitute the innate and adaptive immune system. The lack of antifungal agents and their limited therapeutic effects have led to high mortality and morbidity related to such infections.
METHODS: The necessary information collated on this review has been gathered from various literature published from 1995 to 2019.
RESULTS: This article sheds light on novel drug delivery approaches to target the immunological axis for several Candida species (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. rugose, C. hemulonii, etc.).
CONCLUSION: It is clear that the novel drug delivery approaches include vaccines, adoptive transfer of primed immune cells, recombinant cytokines, therapeutic antibodies, and nanoparticles, which have immunomodulatory effects. Such advancements in targeting various underpinning mechanisms using the concept of novel drug delivery will provide a new dimension to the fungal infection clinic particularly due to Candida species with improved patient compliance and lesser side effects. This advancement in knowledge can also be extended to target various other similar microbial species and infections.
Cellular signalling pathways mediating the pathogenesis of chronic inflammatory respiratory diseases: an update

Mehta M, Dhanjal DS, Paudel KR, Singh B, Gupta G, Rajeshkumar S, et al.

Inflammopharmacology, 2020 Aug;28(4):795-817.
PMID: 32189104 DOI: 10.1007/s10787-020-00698-3

Respiratory disorders, especially non-communicable, chronic inflammatory diseases, are amongst the leading causes of mortality and morbidity worldwide. Respiratory diseases involve multiple pulmonary components, including airways and lungs that lead to their abnormal physiological functioning. Several signaling pathways have been reported to play an important role in the pathophysiology of respiratory diseases. These pathways, in addition, become the compounding factors contributing to the clinical outcomes in respiratory diseases. A range of signaling components such as Notch, Hedgehog, Wingless/Wnt, bone morphogenetic proteins, epidermal growth factor and fibroblast growth factor is primarily employed by these pathways in the eventual cascade of events. The different aberrations in such cell-signaling processes trigger the onset of respiratory diseases making the conventional therapeutic modalities ineffective. These challenges have prompted us to explore novel and effective approaches for the prevention and/or treatment of respiratory diseases. In this review, we have attempted to deliberate on the current literature describing the role of major cell signaling pathways in the pathogenesis of pulmonary diseases and discuss promising advances in the field of therapeutics that could lead to novel clinical therapies capable of preventing or reversing pulmonary vascular pathology in such patients.
Hypoxia-Inducible Factor (HIF): Fuel for Cancer Progression

Satija S, Kaur H, Tambuwala MM, Sharma P, Vyas M, Khurana N, et al.

Curr Mol Pharmacol, 2021;14(3):321-332.
PMID: 33494692 DOI: 10.2174/1874467214666210120154929

Hypoxia is an integral part of the tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygen-independent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mechanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors.
Hydrogel composite containing azelaic acid and tea tree essential oil as a therapeutic strategy for Propionibacterium and testosterone-induced acne

Bisht A, Hemrajani C, Rathore C, Dhiman T, Rolta R, Upadhyay N, et al.

Drug Deliv Transl Res, 2021 Nov 15.
PMID: 34782995 DOI: 10.1007/s13346-021-01092-4

Azelaic acid (AzA) is a USFDA bioactive prescribed against acne vulgaris. It possesses delivery challenges like poor aqueous solubility, low skin-penetrability, and dose-dependent side effects, which could be overcome by its synergistic combination with tea tree oil (TTO) as a microemulsion (ME)-based hydrogel composite. AzA-TTO ME was prepared to employ pseudo-ternary phase diagram construction. The best AzA-TTO ME was of uniform size (polydispersity index 90%), and negative zeta potential (-1.42 ± 0.25% mV) values. ME hydrogel composite with optimum rheological and textural attributes showed better permeation, retention, and skin-compliant characteristics, vis-a-vis marketed formulation (Aziderm™) when evaluated in Wistar rat skin. In vitro antibacterial efficacy in bacterial strains, i.e., Staphylococcus aureus, Propionibacterium acne, and Staphylococcus epidermidis, was evaluated employing agar well plate diffusion and broth dilution assay. ME hydrogel has shown an increase in zone of inhibition by two folds and a decrease in minimum inhibitory concentration (MIC) by eightfold against P. acnes vis-a-vis AzA. Finally, ME hydrogel composite exhibited a better reduction in the papule density (93.75 ± 1.64%) in comparison to Aziderm™ 72.69 ± 4.67%) on acne as developed in rats by inducing testosterone. Thus, the developed AzA-TTO ME hydrogel composite promises an efficacious and comparatively safer drug delivery system for the topical therapy of acne vulgaris.
Fulltext Biological databases and tools for neurological disorders

Usman MB, Ojha S, Jha SK, Chellappan DK, Gupta G, Singh SK, et al.

J Integr Neurosci, 2022 Jan 28;21(1):41.
PMID: 35164477 DOI: 10.31083/j.jin2101041

Computational approach to study of neuronal impairment is rapidly evolving, as experiments and intuition alone could not explain the complexity of brain system. The increase in an overwhelming amount of new data from both theory and computational modeling necessitate the development of databases and tools for analysis, visualization, and interpretation of neuroscience data. To ensure the sustainability of this development, consistent update and training of young professionals are imperative. For this purpose, relevant articles, chapters, and modules are essential to keep abreast of developments. Therefore, this article seeks to outline the biological databases and analytical tools along with their applications. It's envisaged that knowledge along this line would be a "training recipe" for young talents and guide for professionals and researchers in neuroscience.
Therapeutic potential of Artemisia vulgaris: An insight into underlying immunological mechanisms

Soon L, Ng PQ, Chellian J, Madheswaran T, Panneerselvam J, Gupta G, et al.

J Environ Pathol Toxicol Oncol, 2019;38(3):205-216.
PMID: 31679308 DOI: 10.1615/JEnvironPatholToxicolOncol.2019029397

Artemisia vulgaris is a traditional Chinese herb believed to have a wide range of healing properties; it is traditionally used to treat numerous health ailments. The plant is commonly called mugwort or riverside wormwood. The plant is edible, and in addition to its medicinal properties, it is also used as a culinary herb in Asian cooking in the form of a vegetable or in soup. The plant has garnered the attention of researchers in the past few decades, and several research studies have investigated its biological effects, including antioxidant, anti-inflammatory, anticancer, hypolipidemic, and antimicrobial properties. In this review, various studies on these biological effects are discussed along with the tests conducted, compounds involved, and proposed mechanisms of action. This review will be of interest to the researchers working in the field of herbal medicine, pharmacology, medical sciences, and immunology.
PI3K/Akt/mTOR Pathways Inhibitors with Potential Prospects in Non-Small-Cell Lung Cancer

Alharbi KS, Shaikh MAJ, Almalki WH, Kazmi I, Al-Abbasi FA, Alzarea SI, et al.

J Environ Pathol Toxicol Oncol, 2022;41(4):85-102.
PMID: 36374963 DOI: 10.1615/JEnvironPatholToxicolOncol.2022042281

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.
Short Chain Fatty Acids: Fundamental mediators of the gut-lung axis and their involvement in pulmonary diseases

Ashique S, De Rubis G, Sirohi E, Mishra N, Rihan M, Garg A, et al.

Chem Biol Interact, 2022 Dec 01;368:110231.
PMID: 36288778 DOI: 10.1016/j.cbi.2022.110231

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.
Multifaceted role of synbiotics as nutraceuticals, therapeutics and carrier for drug delivery

Khursheed R, Gulati M, Wadhwa S, Vishwas S, Sharma DS, Corrie L, et al.

Chem Biol Interact, 2022 Dec 01;368:110223.
PMID: 36283466 DOI: 10.1016/j.cbi.2022.110223

Synbiotics, are a combination of probiotics and prebiotics. They play an important role in metabolizing different nutritional substrates and thus helps in the maintenance of human health. Any disbalance in the gut microflora, known as dysbiosis, is known to lead to a number of diseased conditions. It can be reverted by the administration of synbiotics. Present review highlights various mechanistic pathways through which synbiotics act as therapeutics. The dual role of synbiotics as nutraceutical and excipient in developing oral formulations are entailed with case studies. The findings entailed that there exist numerous studies on prebiotics as well as probiotics have been carried out to show their effects in several diseases. However, the concept of combining together them for prevention and treatment of various pathological conditions accruing from dysbiosis is relatively new. Synbiotics, however, face challenge of low stability during their sojourn in the GIT, which is generally overcome by various encapsulation techniques. Various studies also showed potential role of synbiotics in drug delivery. However, it is an emerging area and lacks clinical correlation. It is important to focus on clinical trials of formulations wherein synbiotics have been used as therapeutic moiety as well as pharmaceutical carrier for treating various diseases.
Harnessing the dual role of polysaccharides in treating gastrointestinal diseases: As therapeutics and polymers for drug delivery

Corrie L, Gulati M, Awasthi A, Vishwas S, Kaur J, Khursheed R, et al.

Chem Biol Interact, 2022 Dec 01;368:110238.
PMID: 36306865 DOI: 10.1016/j.cbi.2022.110238

Polysaccharides (PS) represent a broad class of polymer-based compounds that have been extensively researched as therapeutics and excipients for drug delivery. As pharmaceutical carriers, PS have mostly found their use as adsorbents, suspending agents, as well as cross-linking agents for various formulations such as liposomes, nanoparticles, nanoemulsions, nano lipid carriers, microspheres etc. This is due to inherent properties of PS such as porosity, steric stability and swellability, insolubility in pH. There have been emerging reports on the use of PS as therapeutic agent due to its anti-inflammatory and anti-oxidative properties for various diseases. In particular, for Crohn's disease, ulcerative colitis and inflammatory bowel disease. However, determining the dosage, treatment duration and effective technology transfer of these therapeutic moieties have not occurred. This is due to the fact that PS are still at a nascent stage of development to a full proof therapy for a particular disease. Recently, a combination of polysaccharide which act as a prebiotic and a probiotic have been used as a combination to treat various intestinal and colorectal (CRC) related diseases. This has proven to be beneficial, has shown good in vivo correlation and is well reported. The present review entails a detailed description on the role of PS used as a therapeutic agent and as a formulation pertaining to gastrointestinal diseases.
A Potential MRI Agent and an Anticancer Drug Encapsulated within CPMV Virus-Like Particles

Aljabali AAA, Alzoubi L, Hamzat Y, Alqudah A, Obeid MA, Al Zoubi MS, et al.

Comb Chem High Throughput Screen, 2021;24(10):1557-1571.
PMID: 32928083 DOI: 10.2174/1386207323666200914110012

BACKGROUND: Virus nanoparticles have been extensively studied over the past decades for theranostics applications. Viruses are well-characterized, naturally occurring nanoparticles that can be produced in high quantity with a high degree of similarity in both structure and composition.
OBJECTIVES: The plant virus Cowpea Mosaic Virus (CPMV) has been innovatively used as a nanoscaffold. Utilization of the internal cavity of empty Virus-Like Particles (VLPs) for the inclusion of therapeutics within the capsid has opened many opportunities in drug delivery and imaging applications.
METHODS: The encapsidation of magnetic materials and anticancer drugs was achieved. SuperscriptCPMV denotes molecules attached to the external surface of CPMV and CPMVSubscript denotes molecules within the interior of the capsid.
RESULTS: Here, the generation of novel VLPs incorporating iron-platinum nanoparticles TCPMVFePt and cisplatin (Cis) (TCPMVCis) is reported. TCPMVCis exhibited a cytotoxic IC50 of TCPMVCis on both A549 and MDA-MB-231 cell lines of 1.8 μM and 3.9 μM, respectively after 72 hours of incubation. The TCPMVFePt were prepared as potential MRI contrast agents.
CONCLUSION: Cisplatin loaded VLP (TCPMVCis) is shown to enhance cisplatin cytotoxicity in cancer cell lines with its potency increased by 2.3-folds.
A review on epidermal growth factor receptor's role in breast and non-small cell lung cancer

Subramaniyan V, Fuloria S, Gupta G, Kumar DH, Sekar M, Sathasivam KV, et al.

Chem Biol Interact, 2022 Jan 05;351:109735.
PMID: 34742684 DOI: 10.1016/j.cbi.2021.109735

Epithelial growth factor receptor (EGFR) is a cell surface transmembrane receptor that mediates the tyrosine signaling pathway to carry the extracellular messages inside the cell and thereby alter the function of nucleus. This leads to the generation of various protein products to up or downregulate the cellular function. It is encoded by cell erythroblastosis virus oncogene B1, so called C-erb B1/ERBB2/HER-2 gene that acts as a proto-oncogene. It belongs to the HER-2 receptor-family in breast cancer and responds best with anti-Herceptin therapy (anti-tyrosine kinase monoclonal antibody). HER-2 positive breast cancer patient exhibits worse prognosis without Herceptin therapy. Similar incidence and prognosis are reported in other epithelial neoplasms like EGFR + lung non-small cell carcinoma and glioblastoma (grade IV brain glial tumor). Present study highlights the role and connectivity of EGF with various cancers via signaling pathways, cell surface receptors mechanism, macromolecules, mitochondrial genes and neoplasm. Present study describes the EGFR associated gene expression profiling (in breast cancer and NSCLC), relation between mitrochondrial genes and carcinoma, and several in vitro and in vivo models to screen the synergistic effect of various combination treatments. According to this study, although clinical studies including targeted treatments, immunotherapies, radiotherapy, TKi-EGFR combined targeted therapy have been carried out to investigate the synergism of combination therapy; however still there is a gap to apply the scenarios of experimental and clinical studies for further developments. This review will give an idea about the transition from experimental to most advanced clinical studies with different combination drug strategies to treat cancer.
Fulltext The FBXW7-NOTCH interactome: A ubiquitin proteasomal system-induced crosstalk modulating oncogenic transformation in human tissues

Kar R, Jha SK, Ojha S, Sharma A, Dholpuria S, Raju VSR, et al.

Cancer Rep (Hoboken), 2021 08;4(4):e1369.
PMID: 33822486 DOI: 10.1002/cnr2.1369

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.
Targeting the mitochondria in chronic respiratory diseases

Chellappan DK, Paudel KR, Tan NW, Cheong KS, Khoo SSQ, Seow SM, et al.

Mitochondrion, 2022 Nov;67:15-37.
PMID: 36176212 DOI: 10.1016/j.mito.2022.09.003

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.

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