Understanding the feasibility of chemotherapeutic and immunotherapeutic targets against non-small cell lung cancers: an update of resistant responses and recent combinatorial therapies.

Despite consistent progress in prompt diagnosis and curative therapies in the last decade, lung cancer (LC) continues to threaten mankind, accounting for nearly twice the casualties compared to prostate, breast, and other cancers. Statistics associate ~25% of 2021 cancer-related deaths with LC, more than 80% of which are explicitly caused by tobacco smoking. Prevailing as small and non-small cell pathologies, with respective occurring frequency of nearly 15% and 80-85%, non-small cell LCs (NSCLCs) are prominently distinguished into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), subtypes. Since the first use of epidermal growth factor receptor (EGFR) inhibitor gefitinib for NSCLC treatment in 2002, immense progress has been made for targeted therapies with the next generation of drugs spanning across the chronological generations of small molecule inhibitors. The last two years have overseen the clinical approval of more than 10 therapeutic agents as first-line NSCLC medications. However, uncertain mutational aberrations as well as systemic resistant responses, and abysmal overall survival curtail the combating efficacies. Of late, immune checkpoint inhibitors (ICIs) against various molecules including programmed cell death-1 (PD-1) and its ligand (PD-L1) have been demonstrated as reliable LC treatment targets. Keeping these aspects in mind, this review article discusses the success of NSCLC chemo and immunotherapies with their characteristic effectiveness and future perspectives.

Understanding the Phytoestrogen Genistein Actions on Breast Cancer: Insights on Estrogen Receptor Equivalence, Pleiotropic Essence and Emerging Paradigms in Bioavailability Modulation.

Prevalent as a major phenolic ingredient of soy and soy products, genistein is recognized as an eminent phytoestrogen owing to its interacting ability with estrogen receptors (ERs). The metabolic conversion of plant-derived genistin to genistein by gut microbes and intestinal enzymes enhances its absorption at intestinal pH of ~7.5-7.8. Genistein interferes in breast cancer (BC) development via pleiotropic actions on cell proliferation, survival, angiogenesis, and apoptosis. Though multiple investigations have demonstrated genistein intake-driven reduced BC risk, similar efficacy has not been replicated in clinical trials. Furthermore, multiple studies have structurally and functionally equated genistein extents with 17-ß-estradiol (E2), the most available physiological estrogen in females, culminating in aggravated BC growth. Of note, both genistein and E2 function via interacting with ERs (ERα and ERß). However, although E2 shows almost equal affinity towards both ERα and ERß, genistein shows more affinity towards ERß than ERα. Our cautious literature survey revealed typical intake mode, ER expression pattern and the ratio of ERα and ERß, transactivators/ regulators of ERα and ERß expression and activities, patient age, and menopausal status as decisive factors affecting genistein BC activities. Of further interest are the mechanisms by which genistein inhibits triple-negative breast cancers (TNBCs), which lack ERs, progesterone receptors (PRs), and human epidermal growth factor receptors (HER2). Herein, we attempt to understand the dosage-specific genistein actions in BC cells and patients with an insight into its better response via derivative development, nanocarrier-assisted, and combinatorial delivery with chemotherapeutic drugs.

Recent Advances in Mesoporous Silica Nanoparticle-Mediated Drug Delivery for Breast Cancer Treatment.

Breast cancer (BC) currently occupies the second rank in cancer-related global female deaths. Although consistent awareness and improved diagnosis have reduced mortality in recent years, late diagnosis and resistant response still limit the therapeutic efficacy of chemotherapeutic drugs (CDs), leading to relapse with consequent invasion and metastasis. Treatment with CDs is indeed well-versed but it is badly curtailed with accompanying side effects and inadequacies of site-specific drug delivery. As a result, drug carriers ensuring stealth delivery and sustained drug release with improved pharmacokinetics and biodistribution are urgently needed. Core-shell mesoporous silica nanoparticles (MSNPs) have recently been a cornerstone in this context, attributed to their high surface area, low density, robust functionalization, high drug loading capacity, size-shape-controlled functioning, and homogeneous shell architecture, enabling stealth drug delivery. Recent interest in using MSNPs as drug delivery vehicles has been due to their functionalization and size-shape-driven versatilities. With such insights, this article focuses on the preparation methods and drug delivery mechanisms of MSNPs, before discussing their emerging utility in BC treatment. The information compiled herein could consolidate the database for using inorganic nanoparticles (NPs) as BC drug delivery vehicles in terms of design, application and resolving post-therapy complications.

Recent Progress in the Hesperetin Delivery Regimes: Significance of Pleiotropic Actions and Synergistic Anticancer Efficacy.

BACKGROUND: In the plant kingdom, flavonoids are widely distributed with multifunctional immunomodulatory actions. Hesperetin (HST) remains one of the well-studied compounds in this domain, initially perceived in citrus plants as an aglycone derivative of hesperidin (HDN). OBSERVATIONS: Natural origin, low in vivo toxicity, and pleiotropic functional essence are the foremost fascinations for HST use as an anticancer drug. However, low aqueous solubility accompanied with a prompt degradation by intestinal and hepatocellular enzymes impairs HST physiological absorption. MOTIVATION: Remedies attempted herein comprise the synthesis of derivatives and nanocarrier (NC)-mediated delivery. As the derivative synthesis aggravates the structural complexity, NC-driven HST delivery has emerged as a sustainable approach for its sustained release. Recent interest in HST has been due to its significant anticancer potential, characterized via inhibited cell division (proliferation), new blood vessel formation (angiogenesis), forceful occupation of neighboring cell's space (invasion), migration to erstwhile physiological locations (metastasis) and apoptotic induction. The sensitization of chemotherapeutic drugs (CDs) by HST is driven via stoichiometrically regulated synergistic actions. Purpose and Conclusion: This article sheds light on HST structure-function correlation and pleiotropic anticancer mechanisms, in unaided and NC-administered delivery in singular and with CDs synergy. The discussion could streamline the HST usefulness and long-term anticancer efficacy.

Implication of RAGE Polymorphic Variants in COPD Complication and Anti-COPD Therapeutic Potential of sRAGE.

Chronic obstructive pulmonary disease (COPD) is a slowly progressive and poorly reversible airway obstruction disease. It is caused either alone or in combination of emphysema, chronic bronchitis (CB), and small airways disease. COPD is thought to be a multi-factorial disorder in which genetic susceptibility, environmental factors and tobacco exposure could be doubly or simultaneously implicated. Available medicines against COPD include anti-inflammatory drugs, such as ß2-agonists and anticholinergics, which efficiently reduce airflow limitation but are unable to avert disease progression and mortality. Advanced glycation end products (AGE) and their receptors i.e. receptor for advanced glycation end products (RAGE) are some molecules that have been implicated in the complication of COPD. Several RAGE single nucleotide polymorphic (SNP) variants are produced by the mammalian cells. Based on the ethnicity some SNPs aggravate the COPD severity. Mammalian cells produce several alternative RAGE splice variants including a soluble RAGE (sRAGE) and an endogenous soluble RAGE (esRAGE). Both of these act as decoy receptor and thus may help to arrest the COPD complications. Several lines of evidences indicate a decreased level of sRAGE in the COPD subjects. One of the new strategies to reduce COPD complication may be sRAGE therapeutic administration to the COPD subjects. This comprehensive discussion sheds light on the role of RAGE and its polymorphic variants in the COPD complication along with sRAGE therapeutic significance in the COPD prevention.

The emerging role of estrogen related receptorα in complications of non-small cell lung cancers.

Approximately 85% of lung cancer cases are recognized as non-small cell lung cancer (NSCLC) with a perilous (13-17%) 5-year survival in Europe and the USA. Although tobacco smoking has consistently emerged as the leading cause of NSCLC complications, its consequences are distinctly manifest with respect to sex bias, due to differential gene and sex hormone expression. Estrogen related receptor α (ERRα), a member of the nuclear orphan receptor superfamily is normally expressed in the lungs, and activates various nuclear genes without binding to the ligands, such as estrogens. In NSCLC ERRα expression is significantly higher compared with healthy individuals. It is well established ERα and ERß' have 93% and 60% identity in the DNA and ligand binding domains, respectively. ERα and ERRα have 69% (70% with ERRα-1) and 34% (35% with ERRα-1) identity, respectively; ERRα and ERRß' have 92 and 61% identity, respectively. However, whether there is distinctive ERRα interaction with mammalian estrogens or concurrent involvement in non-ER signalling pathway activation is not known. Relevant to NSCLC, ERRα promotes proliferation, invasion and migration by silencing the tumor suppressor proteins p53 and pRB, and accelerates G2-M transition during cell division. Epithelial to mesenchymal transition (EMT) and activation of Slug (an EMT associated transcription factor) are the prominent mechanisms by which ERRα activates NSCLC metastasis. Based on these observations, the present article focuses on the feasibility of antiERRα therapy alone and in combination with antiER as a therapeutic strategy for NSCLC complications.

Receptor for Advanced Glycation End Products (RAGE) and Its Polymorphic Variants as Predictive Diagnostic and Prognostic Markers of NSCLCs: a Perspective.

PURPOSE OF REVIEW: Non-small cell lung cancers (NSCLCs) account for ~ 85% of all lung cancers, and 5-year survival in Europe and the USA is ~ 13-17%. In this review, we focus on the significance of Receptor for Advanced Glycation End products (RAGE) as a diagnostic or post-therapeutic prognostic marker for various forms of NSCLCs. RECENT FINDINGS: The lungs have the highest levels of basal RAGE expression in mammals. The physiologic RAGE in lungs may be involved in adhesion and spreading of AT-1 cells and maintenance of pulmonary homeostasis. However, high level expression of RAGE complicates various diseases including acute lung injury. In NSCLCs, while a number of studies report decreased RAGE expression, inferring a protective role, others suggest that RAGE expression may contribute to NSCLC pathogenesis. Genetic polymorphisms of RAGE are reportedly associated with NSCLC development and complications. RAGE and its polymorphic variants may be useful diagnostic or post-therapeutic prognostic markers of NSCLCs.

Recent Advances in Curcumin Treated Non-Small Cell Lung Cancers: An Impetus of Pleiotropic Traits and Nanocarrier Aided Delive ry.

Characterized by the abysmal 18% five year survival chances, non-small cell lung cancers (NSCLCs) claim more than half of their sufferers within the first year of being diagnosed. Advances in biomedical engineering and molecular characterization have reduced the NSCLC diagnosis via timid screening of altered gene expressions and impaired cellular responses. While targeted chemotherapy remains a major option for NSCLCs complications, delayed diagnosis, and concurrent multi-drug resistance remain potent hurdles in regaining normalcy, ultimately resulting in relapse. Curcumin administration presents a benign resolve herein, via simultaneous interception of distinctly expressed pathological markers through its pleiotropic attributes and enhanced tumor cell internalization of chemotherapeutic drugs. Studies on NSCLC cell lines and related xenograft models have revealed a consistent decline in tumor progression owing to enhanced chemotherapeutics cellular internalization via co-delivery with curcumin. This presents an optimum readiness for screening the corresponding effectiveness in clinical subjects. Curcumin is delivered to NSCLC cells either (i) alone, (ii) in stoichiometrically optimal combination with chemotherapeutic drugs, (iii) through nanocarriers, and (iv) nanocarrier co-delivered curcumin and chemotherapeutic drugs. Nanocarriers protect the encapsulated drug from accidental and non-specific spillage. A unanimous trait of all nanocarriers is their moderate drug-interactions, whereby native structural expressions are not tampered. With such insights, this article focuses on the implicit NSCLC curative mechanisms viz-a-viz, free curcumin, nanocarrier delivered curcumin, curcumin + chemotherapeutic drug and nanocarrier assisted curcumin + chemotherapeutic drug delivery.

Targeting Estrogens and Various Estrogen-Related Receptors against Non-Small Cell Lung Cancers: A Perspective.

Non-small cell lung cancers (NSCLCs) account for ~85% of lung cancer cases worldwide. Mammalian lungs are exposed to both endogenous and exogenous estrogens. The expression of estrogen receptors (ERs) in lung cancer cells has evoked the necessity to evaluate the role of estrogens in the disease progression. Estrogens, specifically 17ß-estradiol, promote maturation of several tissue types including lungs. Recent epidemiologic data indicate that women have a higher risk of lung adenocarcinoma, a type of NSCLC, when compared to men, independent of smoking status. Besides ERs, pulmonary tissues both in healthy physiology and in NSCLCs also express G-protein-coupled ERs (GPERs), epidermal growth factor receptor (EGFRs), estrogen-related receptors (ERRs) and orphan nuclear receptors. Premenopausal females between the ages of 15 and 50 years synthesize a large contingent of estrogens and are at a greater risk of developing NSCLCs. Estrogen-ER/GPER/EGFR/ERR-mediated activation of various cell signaling molecules regulates NSCLC cell proliferation, survival and apoptosis. This article sheds light on the most recent achievements in the elucidation of sequential biochemical events in estrogen-activated cell signaling pathways involved in NSCLC severity with insight into the mechanism of regulation by ERs/GPERs/EGFRs/ERRs. It further discusses the success of anti-estrogen therapies against NSCLCs.

Ravaging SARS-CoV-2: rudimentary diagnosis and puzzling immunological responses.

INTRODUCTION: In December 2019, the first COVID-19 case, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was reported in Wuhan, China. The SARS-CoV-2 rapidly disseminated throughout the world via community spread, acquiring pandemic status with significant fatality. OBSERVATIONS: Rapid SARS-CoV-2 diagnosis was soon perceived critical for arresting community spread and effective therapy development. Human SARS-CoV-2 infection can be diagnosed either by nucleic acid identification or specific antibody detection. Contrary to nucleic acid identification confirmed active SARS-CoV-2 infection; antibody detection confirms a past infection, even in asymptomatic subjects. SARS-CoV-2 specific antibodies augment the ability to effectively counter the virus. A crucial hurdle limiting the steadfast implementation of antibody detection is the time required for threshold B lymphocyte population generation. This process is dependent on precise antigen recognition and MHC class I molecules presentation. CONCLUSIONS: Thus, nucleic acid and antibody dependent tests complement each other in identifying human SARS-CoV-2 infection and shaping up subsequent immunological responses. This article discusses the complimentary association of nucleic acid identification (corresponding to an active infection) and antibody testing (the yester CoV-2 infection vulnerability) as the diagnostic and screening measures of SARS-CoV-2 infection. Highlights Nucleic acid (RNA) identification and specific antibody detection against SARS-CoV-2 are the noted diagnostic mechanisms for screening human SARS-CoV-2 infection. While nucleic acid identification screens prevailing SARS-CoV-2 infection, detection of SARS-CoV-2 specific antibodies signifies a past infection, even in asymptomatic subjects. Antibodies against SARS-CoV-2 provide a potential therapeutic option via transfer from antibody rich plasma of a recovered subject to an infected individual. Nucleic acid identification may not absolutely confirm the infection because of frequent SARS-CoV-2 genome mutations and possible technical errors, while specific antibody detection also needs at least (8-14) days for detectable screening of B-cell generated antibodies. Nucleic acid and antibody tests are complementary to each other as an early stage diagnostic assay for SARS-CoV-2 infection and possible therapy (antibodies). Sufferers with a high clinical suspicion but negative RT-PCR screening could be examined via combined imaging and repeated swab test.

Recent advances in gold and silver nanoparticle based therapies for lung and breast cancers.

In recent years, gold (Au) and silver (Ag) nanoparticles (NPs) have been the centerstage of improving cancer treatments and therapies, substantially attributed to their size and shape tuneable chemical, optical and photonic properties. Owing to such specialties, diverse shapes of Au and Ag NPs have enabled an efficient cellular uptake along with remarkable improvements in early stage diagnosis of tumors. Robust synthesis methods employing several reducing agents have been the backbone of such enormous strides of Au and Ag NPs, allowing the delivery of much lower drug volumes to minimize the patient sensitization. Probes based on Au and Ag NPs functionalization with biocompatible chemical molecules have substantially improved their in vivo tracking and mediating a site-specific binding leading to improved cancer treatment with minimal risks to normal cells. With a better drug delivery potential of non-spherical shapes, the cylindrical (rod shaped) geometries have recently been investigated to possess higher cellular uptake. The rod shaped surface morphology enables a larger area for drug binding with enhanced possibility to make use of photothermal attributes. The interplay of size and shape dependent biologic activities is regulated by physicochemical changes in the tumor microenvironment, where stable drug-carrier binding is facilitated by surface modification of NPs, through moderate interactive forces ensuring minimal changes in native drug structure. The energy savvy greener methods, like microwave and microemulsions have enabled much better control on the synthesized nanoparticle shapes and geometries, through a regulation of precursor to reducing agent stoichiometries. With this viewpoint, this article focuses on most common synthesis methods of Au and Ag NPs alongside their application in more effective treatment of lung and breast cancers.

Dispersion enhancing effect of sonochemically functionalized graphene oxide for catalysing antioxidant efficacy of curcumin.

The non-hazardous sonochemical approach has been developed for the functionalization of graphene oxide (GrO) with 5-Aminoindazole (5-AIND). The formation of f-(5-AIND) GrO is confirmed with 13C solid state NMR, HRXPS, XRD, Raman, TGA, DSC, FTIR etc. The >80% cell viabilities on MCF-7 and Vero cell lines have confirmed the high cytocompatibility of f-(5-AIND) GrO. Additionally, the morphological impact on Vero cell line has evidently confirmed the biocompatibility of f-(5-AIND) GrO. As compared to GrO, the f-(5-AIND) GrO has demonstrated an enhanced antioxidant efficacy of 69.4-72%, evaluated with 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical assay. With a similar objective (0.01-0.05)mL peanut oil based curcumin micro and nanoemulsions have been prepared using ethanol and glycerol as co-solvent and co-surfactant respectively. The prepared emulsions are subsequently characterised with respect to morphological and physicochemical parameters via density, surface tension, viscosity, friccohesity measurement and DLS analysis. Henceforth, with an expectation to achieve higher dispersion, an ethanolic dispersion of f-(5-AIND) GrO has been mixed with curcumin carrying emulsions in 1:1. Notably, the radical scavenging activities (RSA) of the combined formulations are significantly enhanced to an extent of 26.6%.

Role of receptor for advanced glycation end products in the complication and progression of various types of cancers.

BACKGROUND: Receptor for advanced glycation end-products popularly known as RAGE is a cell surface immunoglobulin class of molecule, binds with multiple ligands and therefore considered as a multi-ligand receptor. Use of RAGE deficient mice (RAGE(-/-)) as well as established mouse models pertaining to inflammation-associated carcinogenesis such as that of chemically induced carcinogenesis and colitis associated cancer provides a direct genetic evidence for a likelihood novel role of RAGE in cancer, with respect to its ability to lead cancer cell proliferation and survival. Besides inflammation, interaction of RAGE with its various ligands enhances oxidative stress both in cancerous and noncancerous cells which further complicates the progression of cancers. SCOPE OF REVIEW: Till date, no single review article has discussed the mechanism of RAGE dependent complication of cancers, particularly the role of RAGE in cancer cell proliferation, angiogenesis, survival and anti-apoptosis needs to be discussed. MAJOR CONCLUSION: RAGE enhances the number of cancer cells by activating the cell cycle proteins (e.g., cyclin D1), anti-apoptotic proteins (e.g., BCl2), prosurvival (AKT) and autophagic proteins. Role of RAGE has also been detected in formation of new blood vessels (angiogenesis) in the cancer cells and activation of myeloid derived suppressor cells (MDSCs). GENERAL SIGNIFICANCE: This review article describes the role of RAGE in the complication of various types of cancers and the possible usefulness of RAGE dependent therapy to confront cancers in a stronger magnitude.