Metal-based nanomaterials and nanocomposites as promising frontier in cancer chemotherapy.

Cancer is a disease associated with complex pathology and one of the most prevalent and leading reasons for mortality in the world. Current chemotherapy has challenges with cytotoxicity, selectivity, multidrug resistance, and the formation of stemlike cells. Nanomaterials (NMs) have unique properties that make them useful for various diagnostic and therapeutic purposes in cancer research. NMs can be engineered to target cancer cells for early detection and can deliver drugs directly to cancer cells, reducing side effects and improving treatment efficacy. Several of NMs can also be used for photothermal therapy to destroy cancer cells or enhance immune response to cancer by delivering immune-stimulating molecules to immune cells or modulating the tumor microenvironment. NMs are being modified to overcome issues, such as toxicity, lack of selectivity, increase drug capacity, and bioavailability, for a wide spectrum of cancer therapies. To improve targeted drug delivery using nano-carriers, noteworthy research is required. Several metal-based NMs have been studied with the expectation of finding a cure for cancer treatment. In this review, the current development and the potential of plant and metal-based NMs with their effects on size and shape have been discussed along with their more effective usage in cancer diagnosis and treatment.

Recent Trends in Rationally Designed Molecules as Kinase Inhibitors.

Protein kinases modulate the structure and function of proteins by adding phosphate groups to threonine, tyrosine, and serine residues. The phosphorylation process mediated by the kinases regulates several physiological processes, while their overexpression results in the development of chronic diseases, including cancer. Targeting of receptor tyrosine kinase pathways results in the inhibition of angiogenesis and cell proliferation that validates kinases as a key target in the management of aggressive cancers. As such, the identification of protein kinase inhibitors revolutionized the contemporary anticancer therapy by inducing a paradigm shift in the management of disease pathogenesis. Contemporary drug design programs focus on a broad range of kinase targets for the development of novel pharmacophores to manage the overexpression of kinases and their pathophysiology in cancer pathogenesis. In this review, we present the emerging trends in the development of rationally designed molecular inhibitors of kinases over the last five years (2016-2021) and their incipient role in the development of impending anticancer pharmaceuticals.

Exploring the role of antibiotics and steroids in managing respiratory diseases.

Respiratory diseases (RDs), such as chronic obstructive pulmonary disease, cystic fibrosis, asthma, and pneumonia, are associated with significant morbidity and mortality. Treatment usually consists of antibiotics and steroids. Relevant published literature reviews, studies, and clinical trials were accessed from institutional and electronic databases. The keywords used were respiratory diseases, steroids, antibiotics, and combination of steroids and antibiotics. Selected articles and literature were carefully reviewed. Antibiotics are often prescribed as the standard therapy to manage RDs. Types of causative respiratory pathogens, spectrum of antibiotics activity, route of administration, and course of therapy determine the type of antibiotics that are prescribed. Despite being associated with good clinical outcome, treatment failure and recurrence rate are still high. In addition, antibiotic resistance has been widely reported due to bacterial mutations in response to the use of antibiotics, which render them ineffective. Nevertheless, there has been a growing demand for corticosteroids (CS) and antibiotics to treat a wide variety of diseases, including various airway diseases, due to their immunosuppressive and anti-inflammatory properties. The use of CS is well established and there are different formulations based on the diseases, such as topical administration, tablets, intravenous injections, and inhaled preparations. Both antibiotics and CS possess similar properties in terms of their anti-inflammatory effects, especially regulating cytokine release. Thus, the current review examines and discusses the different applications of antibiotics, CS, and their combination in managing various RDs. Drawbacks of these interventions are also discussed.

Managing Apoptosis in Lung Diseases using Nano-assisted Drug Delivery System.

Several factors exist that limit the efficacy of lung cancer treatment. These may be tumor-specific delivery of therapeutics, airway geometry, humidity, clearance mechanisms, presence of lung diseases, and therapy against tumor cell resistance. Advancements in drug delivery using nanotechnology based multifunctional nanocarriers, have emerged as a viable method for treating lung cancer with more efficacy and fewer adverse effects. This review does a thorough and critical examination of effective nano-enabled approaches for lung cancer treatment, such as nano-assisted drug delivery systems. In addition, to therapeutic effectiveness, researchers have been working to determine several strategies to produce nanotherapeutics by adjusting the size, drug loading, transport, and retention. Personalized lung tumor therapies using sophisticated nano modalities have the potential to provide great therapeutic advantages based on individual unique genetic markers and disease profiles. Overall, this review provides comprehensive information on newer nanotechnological prospects for improving the management of apoptosis in lung cancer.

Genetic associated complications of type 2 diabetes mellitus.

According to the International Diabetes Federation, the number of adults (age of 20-79) being diagnosed with diabetes mellitus (DM) have increased from 285 million in year 2009 to 463 million in year 2019 which comprises of 95% type 2 DM patient (T2DM). Research have claimed that genetic predisposition could be one of the factors causing T2DM complications. In addition, T2DM complications cause an incremental risk to mortality. Therefore, this article aims to discuss some complications of T2DM in and their genetic association. The complications that are discussed in this article are diabetic nephropathy, diabetes induced cardiovascular disease, diabetic neuropathy, diabetic foot ulcer (DFU) and Alzheimer's disease (AD). According to the information obtained, genes associated with diabetic nephropathy (DN) are gene GABRR1 and ELMO1 that cause injury to glomerular. Replication of genes FRMD3, CARS and MYO16/IRS2 shown to have link with DN. The increase of gene THBS2, NGAL, PIP, TRAF6 polymorphism, ICAM-1 encoded for rs5498 polymorphism and C667T increase susceptibility towards DN in T2DM patient. Genes associated with cardiovascular diseases are adiponectin gene (ACRP30) and apolipoprotein E (APOE) polymorphism gene with ξ2 allele. Haptoglobin (Hp) 1-1 genotype and mitochondria superoxide dismutase 2 (SOD2) plays a role in cardiovascular events. As for genes related to diabetic neuropathy, janus kinase (JAK), mutation of SCN9A and TRPA1 gene and destruction of miRNA contribute to pathogenesis of diabetic neuropathy among T2DM patients. Expression of cytokine IL-6, IL-10, miR-146a are found to cause diabetic neuropathy. Besides, A1a16Va1 gene polymorphism, an oxidative stress influence was found as one of the gene factors. Diabetic retinopathy (DR) is believed to have association with monocyte chemoattractant protein-1 (MCP-1) and insulin-like growth factor 1 (IGF1). Over-expression of gene ENPP1, IL-6 pro-inflammatory cytokine, ARHGAP22's protein rs3844492 polymorphism and TLR4 heterozygous genotype are contributing to significant pathophysiological process causing DR, while research found increases level of UCP1 gene protects retina cells from oxidative stress. DFU is manifested by slowing in re-epithelialization of keratinocyte, persistence wound inflammation and healing impairment. Re-epithelialization disturbance was caused by E2F3 gene, reduction of Tacl gene encoded substance P causing persistence inflammation while expression of MMp-9 polymorphism contributes to healing impairment. A decrease in HIF-1a gene expression leads to increased risk of pathogenesis, while downregulation of TLR2 increases severity of wound in DFU patients. SNPs alleles has been shown to have significant association between the genetic dispositions of T2DM and AD. The progression of AD can be due to the change in DNA methylation of CLOCK gene, followed with worsening of AD by APOE4 gene due to dyslipidemia condition in T2DM patients. Insulin resistance is also a factor that contributes to pathogenesis of AD.

Perfluorocarbons Therapeutics in Modern Cancer Nanotechnology for Hypoxiainduced Anti-tumor Therapy.

With an estimated failure rate of about 90%, immunotherapies that are intended for the treatment of solid tumors have caused an anomalous rise in the mortality rate over the past decades. It is apparent that resistance towards such therapies primarily occurs due to elevated levels of HIF-1 (Hypoxia-induced factor) in tumor cells, which are caused by disrupted microcirculation and diffusion mechanisms. With the advent of nanotechnology, several innovative advances were brought to the fore; and, one such promising direction is the use of perfluorocarbon nanoparticles in the management of solid tumors. Perfluorocarbon nanoparticles enhance the response of hypoxia-based agents (HBAs) within the tumor cells and have been found to augment the entry of HBAs into the tumor micro-environment. The heightened penetration of HBAs causes chronic hypoxia, thus aiding in the process of cell quiescence. In addition, this technology has also been applied in photodynamic therapy, where oxygen self-enriched photosensitizers loaded perfluorocarbon nanoparticles are employed. The resulting processes initiate a cascade, depleting tumour oxygen and turning it into a reactive oxygen species eventually to destroy the tumour cell. This review elaborates on the multiple applications of nanotechnology based perfluorocarbon formulations that are being currently employed in the treatment of tumour hypoxia.

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

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.

Targeting LIN28: a new hope in prostate cancer theranostics.

The mortality and morbidity rates for prostate cancer have recently increased to alarming levels, rising higher than lung cancer. Due to a lack of drug targets and molecular probes, existing theranostic techniques are limited. Human LIN28A and its paralog LIN28B overexpression are associated with a number of tumors resulting in a remarkable increase in cancer aggression and poor prognoses. The current review aims to highlight recent work identifying the key roles of LIN28A and LIN28B in prostate cancer, and to instigate further preclinical and clinical research in this important area.

Hypoxia-Inducible Factor (HIF): Fuel for Cancer Progression.

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-1ß (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.

Pharmaceutical Aspects of Green Synthesized Silver Nanoparticles: A Boon to Cancer Treatment.

BACKGROUND: Silver nanoparticles (AgNPs) are among the most investigated nanostructures in recent years, which exhibit more challenging and promising qualities in different biomedical applications. The AgNPs synthesized by the green approach provide potential healthcare benefits over chemical approaches, including improvement of tissue restoration, drug delivery, diagnosis, being environmentally friendly, and a boon to cancer treatment. OBJECTIVE: In the current scenario, the development of safe and effective drug delivery systems is the utmost concern of formulation development scientists as well as clinicians. METHODS: Google, Web of Science, and PubMed portals have been searched for potentially relevant literature to get the latest developments and updated information related to different aspects of green synthesized AgNPs along with their biomedical applications, especially in the treatment of different types of cancers. RESULTS: The present review highlights the latest published research regarding the different green approaches for the synthesis of AgNPs, their characterization techniques as well as various biomedical applications, particularly in cancer treatment. In this context, environment-friendly AgNPs are proving themselves as better candidates in terms of size, drug loading and release efficiency, targeting efficiency, minimal drug-associated side effects, pharmacokinetic profiling, and biocompatibility issues. CONCLUSION: With continuous efforts by multidisciplinary team approaches, nanotechnology-based AgNPs will shed new light on diagnostics and therapeutics in various disease treatments. However, the toxicity issues of AgNPs need greater attention as unanticipated toxic effects must be ruled out for their diversified applications.

Targeting Cancer using Curcumin Encapsulated Vesicular Drug Delivery Systems.

Curcumin is a major curcuminoid present in turmeric. The compound is attributed to various therapeutic properties, which include anti-oxidant, anti-inflammatory, anti-bacterial, anti-malarial, and neuroprotection. Due to its therapeutic potential, curcumin has been employed for centuries in treating different ailments. Curcumin has been investigated lately as a novel therapeutic agent in the treatment of cancer. However, the mechanisms by which curcumin exerts its cytotoxic effects on malignant cells are still not fully understood. One of the main limiting factors in the clinical use of curcumin is its poor bioavailability and rapid elimination. Advancements in drug delivery systems such as nanoparticle-based vesicular drug delivery platforms have improved several parameters, namely, drug bioavailability, solubility, stability, and controlled release properties. The use of curcumin-encapsulated niosomes to improve the physical and pharmacokinetic properties of curcumin is one such approach. This review provides an up-to-date summary of nanoparticle-based vesicular drug carriers and their therapeutic applications. Specifically, we focus on niosomes as novel drug delivery formulations and their potential in improving the delivery of challenging small molecules, including curcumin. Overall, the applications of such carriers will provide a new direction for novel pharmaceutical drug delivery, as well as for biotechnology, nutraceutical, and functional food industries.

Dietary Crocin is Protective in Pancreatic Cancer while Reducing Radiation-Induced Hepatic Oxidative Damage.

Pancreatic cancer is one of the fatal causes of global cancer-related deaths. Although surgery and chemotherapy are standard treatment options, post-treatment outcomes often end in a poor prognosis. In the present study, we investigated anti-pancreatic cancer and amelioration of radiation-induced oxidative damage by crocin. Crocin is a carotenoid isolated from the dietary herb saffron, a prospect for novel leads as an anti-cancer agent. Crocin significantly reduced cell viability of BXPC3 and Capan-2 by triggering caspase signaling via the downregulation of Bcl-2. It modulated the expression of cell cycle signaling proteins P53, P21, P27, CDK2, c-MYC, Cyt-c and P38. Concomitantly, crocin treatment-induced apoptosis by inducing the release of cytochrome c from mitochondria to cytosol. Microarray analysis of the expression signature of genes induced by crocin showed a substantial number of genes involved in cell signaling pathways and checkpoints (723) are significantly affected by crocin. In mice bearing pancreatic tumors, crocin significantly reduced tumor burden without a change in body weight. Additionally, it showed significant protection against radiation-induced hepatic oxidative damage, reduced the levels of hepatic toxicity and preserved liver morphology. These findings indicate that crocin has a potential role in the treatment, prevention and management of pancreatic cancer.

Molecular and Immunological Mechanisms Underlying the Various Pharmacological Properties of the Potent Bioflavonoid, Rutin.

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.

Targeting neutrophils using novel drug delivery systems in chronic respiratory diseases.

Neutrophils are essential effector cells of immune system for clearing the extracellular pathogens during inflammation and immune reactions. Neutrophils play a major role in chronic respiratory diseases. In respiratory diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, lung cancer and others, there occurs extreme infiltration and activation of neutrophils followed by a cascade of events like oxidative stress and dysregulated cellular proteins that eventually result in apoptosis and tissue damage. Dysregulation of neutrophil effector functions including delayed neutropil apoptosis, increased neutrophil extracellular traps in the pathogenesis of asthma, and chronic obstructive pulmonary disease enable neutrophils as a potential therapeutic target. Accounting to their role in pathogenesis, neutrophils present as an excellent therapeutic target for the treatment of chronic respiratory diseases. This review highlights the current status and the emerging trends in novel drug delivery systems such as nanoparticles, liposomes, microspheres, and other newer nanosystems that can target neutrophils and their molecular pathways, in the airways against infections, inflammation, and cancer. These drug delivery systems are promising in providing sustained drug delivery, reduced therapeutic dose, improved patient compliance, and reduced drug toxicity. In addition, the review also discusses emerging strategies and the future perspectives in neutrophil-based therapy.

Nucleic Acid Aptamers as a Potential Nucleus Targeted Drug Delivery System.

BACKGROUND: Nucleus targeted drug delivery provides several opportunities for the treatment of fatal diseases such as cancer. However, the complex nucleocytoplasmic barriers pose significant challenges for delivering a drug directly and efficiently into the nucleus. Aptamers representing singlestranded DNA and RNA qualify as next-generation highly advanced and personalized medicinal agents that successfully inhibit the expression of certain proteins; possess extraordinary gene-expression for manoeuvring the diseased cell's fate with negligible toxicity. In addition, the precisely directed aptamers to the site of action present a tremendous potential to reach the nucleus by escaping the ensuing barriers to exhibit a better drug activity and gene expression. OBJECTIVE: This review epigrammatically highlights the significance of targeted drug delivery and presents a comprehensive description of the principal barriers faced by the nucleus targeted drug delivery paradigm and ensuing complexities thereof. Eventually, the progress of nucleus targeting with nucleic acid aptamers and success achieved so far have also been reviewed. METHODS: Systematic literature search was conducted of research published to date in the field of nucleic acid aptamers. CONCLUSION: The review specifically points out the contribution of individual aptamers as the nucleustargeting agent rather than aptamers in conjugated form.

Adenosine Receptors in Modulation of Central Nervous System Disorders.

The ubiquitous signaling nucleoside molecule, adenosine is found in different cells of the human body to provide its numerous pharmacological role. The associated actions of endogenous adenosine are largely dependent on conformational change of the widely expressed heterodimeric G-protein-coupled A1, A2A, A2B, and A3 adenosine receptors (ARs). These receptors are well conserved on the surface of specific cells, where potent neuromodulatory properties of this bioactive molecule reflected by its easy passage through the rigid blood-brainbarrier, to simultaneously act on the central nervous system (CNS). The minimal concentration of adenosine in body fluids (30-300 nM) is adequate to exert its neuromodulatory action in the CNS, whereas the modulatory effect of adenosine on ARs is the consequence of several neurodegenerative diseases. Modulatory action concerning the activation of such receptors in the CNS could be facilitated towards neuroprotective action against such CNS disorders. Our aim herein is to discuss briefly pathophysiological roles of adenosine on ARs in the modulation of different CNS disorders, which could be focused towards the identification of potential drug targets in recovering accompanying CNS disorders. Researches with active components with AR modulatory action have been extended and already reached to the bedside of the patients through clinical research in the improvement of CNS disorders. Therefore, this review consist of recent findings in literatures concerning the impact of ARs on diverse CNS disease pathways with the possible relevance to neurodegeneration.

Peroxisome proliferator-activated receptor gamma: promising target in glioblastoma.

Glioblastoma, also known as glioblastoma multiforme, is the most common and worldwide-spread cancer that begins within the brain. Glioblastomas represent 15% of brain tumors. The most common length of survival following diagnosis is 12 to 14 months with less than 3% to 5% of people surviving longer than five years. Without treatment, survival is typically 3 months. Among all receptors, special attention has been focused on the role of peroxisome proliferator-activated receptors (PPARs) in glioblastoma. PPARs are ligand-activated intracellular transcription factors. The PPAR subfamily consists of three subtypes encoded by distinct genes named PPARα, PPARß/δ, and PPARγ. PPARγ is the most extensively studied subtype of PPAR. There has been interesting preliminary evidence suggesting that diabetic patients receiving PPARγ agonists, a group of anti-diabetics, thiazolidinedione drugs, have an increased median survival for glioblastoma. In this paper, the recent progresses in understanding the potential mechanism of PPARγ in glioblastoma are summarized.

Current therapies and targets for type 2 diabetes mellitus.

The prevalence of type 2 diabetes mellitus (T2DM) has been increasing at an alarming rate. With an increased understanding of the pathophysiology and pathogenesis of T2DM, various new therapeutic options have been developed to target different key defects in T2DM. Incremental innovations of existing therapies either through unprecedented drug combinations, modified drug molecules, or improved delivery systems are capable to nullify some of the undesirable side effects of traditional therapies as well as to enhance effectiveness. The existing administration routes include inhalation, nasal, buccal, parenteral and oral. Newer drug targets such as protein kinase B (Akt/PKB), AMP-activated protein kinase (AMPK), sirtuin (SIRT), and others are novel approaches that act via different mechanisms and possibly treating T2DM of distinct variations and aetiologies. Other therapies such as endobarrier, gene therapy, and stem cell technology utilize advanced techniques to treat T2DM, and the potential of these therapies are still being explored. Gene therapy is plausible to fix the underlying pathology of T2DM instead of using traditional reactive treatments, especially with the debut of Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein9 (CRISPR-Cas9) gene editing tool. Molecular targets in T2DM are also being extensively studied as it could target the defects at the molecular level. Furthermore, antibody therapies and vaccinations are also being developed against T2DM; but the ongoing clinical trials are relatively lesser and the developmental progress is slower. Although, there are many therapies designed to cure T2DM, each of them has their own advantages and disadvantages. The preference for the treatment plan usually depends on the health status of the patient and the treatment goal. Therefore, an ideal treatment should take patient's compliance, efficacy, potency, bioavailability, and other pharmacological and non-pharmacological properties into account.