Development of pullulan/chitosan/salvianolic acid ternary fibrous membranes and their potential for chemotherapeutic applications.

This study investigates the feasibility of centrifugal spinning for producing fibrous membranes containing pullulan, chitosan, and danshen extract. The danshen extract is composed of 20 wt% salvianolic acid B (SA). Citric acid was added to the mixture as a crosslinking agent to promote its use in the aqueous medium. The influence of the danshen concentration (25 wt% and 33 wt%) on fiber morphology, thermal behavior, and the biochemical effect was analyzed. Developed fiber-based membranes consist of long, continuous, and uniform fibers with a sparse scattering of beads. Fiber diameter analysis shows values ranging from 384 ± 123 nm to 644 ± 141 nm depending on the concentration of danshen. The nanofibers show adequate aqueous stability after crosslinking. Thermal analysis results prove that SA is loaded into nanofibers without compromising their structural integrity. Cell-based results indicate that the developed nanofiber membranes promote cell growth and are not detrimental to fibroblast cells. Anticancer studies reveal a promising inhibition to the proliferation of HCT116 colon cancer cells. The developed systems show potential as innovative systems to be used as a bioactive chemotherapeutic drug that could be placed on the removed tumor site to prevent development of colon cancer microdeposits.

Oxymatrine Loaded Cross-Linked PVA Nanofibrous Scaffold: Design and Characterization and Anticancer Properties.

This study focuses on the fabrication, characterization and anticancer properties of biocompatible and biodegradable composite nanofibers consisting of poly(vinyl alcohol) (PVA), oxymatrine (OM), and citric acid (CA) using a facile and high-yield centrifugal spinning process known as Forcespinning. The effects of varying concentrations of OM and CA on fiber diameter and molecular cross-linking are investigated. The morphological and thermo-physical properties, as well as water absorption of the developed nanofiber-based mats are characterized using microscopical analysis, energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. In vitro anticancer studies are conducted with HCT116 colorectal cancer cells. Results show a high yield of long fibers embedded with beads. Fiber average diameters range between 462 and 528 nm depending on OM concentration. The thermal analysis results show that the fibers are stable at room temperature. The anticancer study reveals that PVA nanofiber membrane with high concentrations of OM can suppress the proliferation of HCT116 colorectal cancer cells. The study provides a comprehensive investigation of OM embedded into nanosized PVA fibers and the prospective application of these membranes as a drug delivery system.

Clinical Biomarkers and Novel Drug Targets to Cut Gordian Knots of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD), the primary cause of dementia, escalating worldwide, has no proper diagnosis or effective treatment. Neuronal cell death and impairment of cognitive abilities, possibly triggered by several brain mechanisms, are the most significant characteristic of this disorder. METHODS: A multitude of pharmacological targets have been identified for potential drug design against AD. Although many advances in treatment strategies have been made to correct various abnormalities, these often exhibit limited clinical significance because this disease aggressively progresses into different regions of the brain, causing severe deterioration. RESULTS: These biomarkers can be game-changers for early detection and timely monitoring of such disorders. CONCLUSION: This review covers clinically significant biomarkers of AD for precise and early monitoring of risk factors and stages of this disease, the potential site of action and novel targets for drugs, and pharmacological approaches to clinical management.

Recent Advancements in CNS Acting Drugs: A Step Towards End of Illness.

Progressive degeneration in the morphology and functions of neuronal cells leads to multifactorial pathogenesis conditions of oxidative stress, mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity, and neuro-inflammation to mediate heterogeneous types of neurodegenerative diseases, such as Epilepsy, Alzheimer's (AD) and Parkinson's (PD), more prominently among aging populations. In this editorial, complex mechanisms, challenges, and advancements made in the discovery of new neurotherapeutics, as well as designing approaches being adopted to fabricate brain-targeted delivery systems, are discussed.

Approaches for Ear-targeted Delivery Systems in Neurosensory Disorders to avoid Chronic Hearing Loss Mediated Neurological Diseases.

BACKGROUND AND OBJECTIVE: Hearing loss is a common audio-vestibular-related neurosensory disability of inner ears, in which patients exhibit clinical symptoms of dizziness, gait unsteadiness, and oscillopsia, at an initial stage. While, if such disorders are untreated for a prolonged duration then the progression of disease into a chronic state significantly decreases GABA level as well as an alteration in the neurotransmission of CNS systems. Hence, to control the progression of disease into a chronic approaches for timely and targeted delivery of the drugs at the site of action in the ear is now attracting the interest of neurologists for effective and safe treatment of such disorders. Among delivery systems, owing to small dimension, better penetration, rate-controlled release, higher bioavailability; nanocarriers are preferred to overcome delivery barriers, improvement in residence time, and enhanced the performance of loaded drugs. Subsequently, these carriers also stabilize encapsulated drugs while also provide an opportunity to modify the surface of carriers to favor guided direction for site-specific targeting. Contrary to this; conventional routes of drug delivery such as oral, intravenous, and intramuscular are poorer in performance because of inadequate blood supply to the inner ear and limited penetration of blood-inner ear barrier. CONCLUSION: This review summarized novel aspects of non-invasive and biocompatible nanoparticles- based approaches for targeted delivery of drugs into the cochlea of the ear to reduce the rate, and extent of the emergence of any hearing loss mediated neurological disorders.

Probiotics for the Chemoprotective Role against the Toxic Effect of Cancer Chemotherapy.

BACKGROUND: Chemo- and radiation therapy-based clinical management of different types of cancers is associated with toxicity and several side effects. Therefore, there is always an unmet need to explore agents that reduce such risk factors. Among these, natural products have attracted much attention because of their potent antioxidant and antitumor effects. In the past, some breakthrough outcomes established that various bacteria in the human intestinal gut are bearing growth-promoting attributes and suppressing the conversion of pro-carcinogens into carcinogens. Hence probiotics integrated approaches are nowadays being explored as rationalized therapeutics in the clinical management of cancer. METHODS: Here, published literature was explored to review chemoprotective roles of probiotics against toxic and side effects of chemotherapeutics. RESULTS: Apart from excellent anti-cancer abilities, probiotics alleviate toxicity & side effects of chemotherapeutics, with a high degree of safety and efficiency. CONCLUSION: Preclinical and clinical evidence suggests that due to the chemoprotective roles of probiotics against side effects and toxicity of chemotherapeutics, their integration in chemotherapy would be a judicious approach.

Lipid Nanocarriers for Neurotherapeutics: Introduction, Challenges, Blood-brain Barrier, and Promises of Delivery Approaches.

Significant efforts have been made in research to discover newer neurotherapeutics, however, the rate of reported neurological disorders has been increasing at an alarming speed. Neurotherapeutics delivery in the brain is still posing a significant challenge, owing to the blood-brain barrier and blood-cerebrospinal fluid barrier. These physiological barriers restrict the passage of systemically available fractions of neurotherapeutics into the brain, owing to low permeability and drug localization factors. Neurotherapeutics encapsulating lipid carriers favor a significant increase in bioavailability of poorly water-soluble drugs by enhancing solubility in the gastrointestinal tract and favoring stability. Due to their small size and lipid-based composition, these carriers offer enhanced permeability across the semi-permeable blood-brain barrier to effectively transport encapsulated loads, such as synthetic drugs, nutraceuticals, phytoconstituents, herbal extracts, and peptides, thereby reducing incidences of off-target mediated adverse impacts and toxicity. The most significant advantage of such lipid-based delivery systems is non-invasive nature and targeting of neurotherapeutics to the central nervous system. Critical attributes of lipid-based carriers modulate release rates in rate-controlled manners, enable higher penetration through the blood-brain barrier, and bypass the hepatic first-pass metabolism leading to higher CNS bioavailability neurotherapeutics. The current review discusses a brief and introductory account of the limitations of neurotherapeutics, pharmacological barriers, challenges in brain-targeted delivery, and the potential of nanotechnology- processed lipid-based carriers in the clinical management of neuronal disorders.

Thymoquinone Lipid Nanoparticles Cut the Gordian Knots of Depression via Neuroprotective BDNF and Downregulation of Neuro-inflammatory NF-κB, IL-6, and TNF-α in LPS Treated Rats.

BACKGROUND: In over 300 million clinical cases, antidepressant drugs seem to provide only symptomatic relief and limited protection in life-threatening depressive events. OBJECTIVES: To compare neuronal-signaling mechanism and neuroprotective roles of Thymoquinone (TQ) suspension and its SLN (TQSLN) against standard antidepressant drug fluoxetine. METHODS: This research investigated in-silico docking at NF-KB p50 active site, CLSM based gut permeation, screening of antidepressant activities and neurosignaling pathways involved. RESULTS: As compared to fluoxetine, TQ reporteda significantly better docking score (-6.83 v/s -6.22) and a better lower free binding energy of (-34.715 Kcal/mol v/s -28.537 Kcal/mol). While poorly oral bioavailable and P-gp substrate TQ reported approximately 250% higher gut permeation if delivered as TQSLN formulation. In locomotor studies, as compared to TQS, TQSLN favored more prominent (p< 0.010) elevation in average time, horizontalactivity, average-velocity, and total-movement with reduced rest time LPS treated groups. However, in the tail suspension test, TQSLN significantly reduced immobility time (p<0.010). Similarly, In the modified force swimming test, TQSLN also significantly reduced immobility time (p<0.010), but swimming time (p<0.010) and climbing time (p<0.050) were significantly elevated. Subsequently, TQSLN reported significantly elevated neuroprotective BDNF (p<0.010) as well as hippocampal 5HT/TRP; accompanied with reduced levels of hippocampal inflammatory markers TNF-α (p<0.001) and IL-6 (p<0.010) as well as lower kynurenine and tryptophan ratio (KYN/TRP). Similarly, the hippocampal CA1 region further revealed TQSL more predominantly attenuated NF-kB nuclear translocation in the brain. CONCLUSION: Despite the poor bioavailability of TQ, TQSLN potentially attenuates neuroinflammatory transmitters and favors BDNF to modulate depressive neurobehavioral states.

Nanotechnological based miRNA intervention in the therapeutic management of neuroblastoma.

Neuroblastoma (NB) is a widely diagnosed cancer in children, characterized by amplification of the gene encoding the MYCN transcription factor, which is highly predictive of poor clinical outcome and metastatic disease. microRNAs (a class of small non-coding RNAs) are regulated by MYCN transcription factor in neuroblastoma cells. The current research is focussed on identifying differential role of miRNAs and their interactions with signalling proteins, which are intricately linked with cellular processes like apoptosis, proliferation or metastasis. However, the therapeutic success of miRNAs is limited by pharmaco-technical issues which are well counteracted by nanotechnological advancements. The nanoformulated miRNAs unload anti-cancer drugs in a controlled and prespecified manner at target sites, to influence the activity of target protein in amelioration of NB. Recent advances and developments in the field of miRNAs-based systems for clinical management of NBs and the role of nanotechnology to overcome challenges with drug delivery of miRNAs have been reviewed in this paper.

Targeted delivery of miRNA based therapeuticals in the clinical management of Glioblastoma Multiforme.

Glioblastoma multiforme (GBM) is the most aggressive (WHO grade IV) form of diffuse glioma endowed with tremendous invasive capacity. The availability of narrow therapeutic choices for GBM management adds to the irony, even the post-treatment median survival time is roughly around 14-16 months. Gene mutations seem to be cardinal to GBM formation, owing to involvement of amplified and mutated receptor tyrosine kinase (RTK)-encoding genes, leading to dysregulation of growth factor signaling pathways. Of-late, the role of different microRNAs (miRNAs) in progression and proliferation of GBM was realized, which lead to their burgeon potential applications for diagnostic and therapeutic purposes. miRNA signatures are intricately linked with onset and progression of GBM. Although, progression of GBM causes significant changes in the BBB to form BBTB, but still efficient passage of cancer therapeutics, including antibodies and miRNAs are prevented, leading to low bioavailability. Recent developments in the nanomedicine field provide novel approaches to manage GBM via efficient and brain targeted delivery of miRNAs either alone or as part of cytotoxic pharmaceutical composition, thereby modulating cell signaling in well predicted manner to promise positive therapeutic outcomes.

Micro-RNAs in the regulation of immune response against SARS CoV-2 and other viral infections.

Background: Micro-RNAs (miRNAS) are non-coding, small RNAs that have essential roles in different biological processes through silencing genes, they consist of 18-24 nucleotide length RNA molecules. Recently, miRNAs have been viewed as important modulators of viral infections they can function as suppressors of gene expression by targeting cellular or viral RNAs during infection. Aim of review: We describe the biological roles and effects of miRNAs on SARS-CoV-2 life-cycle and pathogenicity, and we discuss the modulation of the immune system with micro-RNAs which would serve as a new foundation for the treatment of SARS-CoV-2 and other viral infections. Key scientific concepts of review: miRNAs are the key players that regulate the expression of the gene in the post-transcriptional phase and have important effects on viral infections, thus are potential targets in the development of novel therapeutics for the treatment of viral infections. Besides, micro-RNAs (miRNAs) modulation of immune-pathogenesis responses to viral infection is one of the most-known indirect effects, which leads to suppressing of the interferon (IFN-α/ß) signalling cascade or upregulation of the IFN-α/ß production another IFN-stimulated gene (ISGs) that inhibit replication of the virus. These virus-mediated alterations in miRNA levels lead to an environment that might either enhance or inhibit virus replication.

Withdrawal Notice: Lipid Carriers Mediated Targeted Delivery of Neurotherapeuticals: Challenges, Role of Blood Brain Barrier and Promises of Nanotechnology Based Approaches in Neuronal Disorders

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Polymeric Nanoparticles for Brain Drug Delivery - A Review.

BACKGROUND: Blood-brain barrier (BBB) plays a most hindering role in drug delivery to the brain. Recent research comes out with the nanoparticles approach, is continuously working towards improving the delivery to the brain. Currently, polymeric nanoparticle is extensively involved in many therapies for spatial and temporal targeted areas delivery. METHODS: We did a non-systematic review, and the literature was searched in Google, Science Direct and PubMed. An overview is provided for the formulation of polymeric nanoparticles using different methods, effect of surface modification on the nanoparticle properties with types of polymeric nanoparticles and preparation methods. An account of different nanomedicine employed with therapeutic agent to cross the BBB alone with biodistribution of the drugs. RESULTS: We found that various types of polymeric nanoparticle systems are available and they prosper in delivering the therapeutic amount of the drug to the targeted area. The effect of physicochemical properties on nanoformulation includes change in their size, shape, elasticity, surface charge and hydrophobicity. Surface modification of polymers or nanocarriers is also vital in the formulation of nanoparticles to enhance targeting efficiency to the brain. CONCLUSION: More standardized methods for the preparation of nanoparticles and to assess the relationship of surface modification on drug delivery. While the preparation and its output like drug loading, particle size, and charge, permeation is always conflicted, so it requires more attention for the acceptance of nanoparticles for brain delivery.

Lipid-based nanoformulations in the treatment of neurological disorders.

The neurological disorders affect millions of people worldwide, and are bracketed as the foremost basis of disability-adjusted life years (DALYs). The treatment options are symptomatic and often the movement of drugs is restricted by a specialized network of endothelial cell layers (adjoined by tight cell-to-cell junction proteins; occludin, claudins, and junctional adhesion molecules), pericytes and astroglial foot processes. In recent years, advances in nanomedicine have led to therapies that target central nervous system (CNS) pathobiology via altering signaling mechanisms such as activation of PI3K/Akt pathway in ischemic stroke arrests apoptosis, interruption of α-synuclein aggregation prevents neuronal degeneration in Parkinson's. Often such interactions are limited by insufficient concentrations of drugs reaching neuronal tissues and/or insufficient residence time of drug/s with the receptor. Hence, lipid nanoformulations, SLNs (solid lipid nanoparticles) and NLCs (nanostructured lipid carriers) emerged to overcome these challenges by utilizing physiological transport mechanisms across blood-brain barrier, such as drug-loaded SLN/NLCs adsorb apolipoproteins from the systemic circulation and are taken up by endothelial cells via low-density lipoprotein (LDL)-receptor mediated endocytosis and subsequently unload drugs at target site (neuronal tissue), which imparts selectivity, target ability, and reduction in toxicity. This paper reviews the utilization of SLN/NLCs as carriers for targeted delivery of novel CNS drugs to improve the clinical course of neurological disorders, placing some additional discussion on the metabolism of lipid-based formulations.

Raloxifene potentiates the effect of fluoxetine against maximal electroshock induced seizures in mice.

The evidence to guide clinicians regarding rationale polytherapy with current antiepileptic drugs (AEDs) is lacking, and current practice recommendations are largely empirical.  The excessive drug loading with combinatorial therapies of existing AEDs are associated with escalated neurotoxicity, and that emergence of pharmacoresistant seizures couldn't be averted. In pursuit of judicious selection of novel AEDs in combinatorial therapies with mechanism based evidences, standardized dose of raloxifene, fluoxetine, bromocriptine and their low dose combinations, were experimentally tested for their impact on maximal electroshock (MES) induced tonic hind limb extension (THLE) in mice. Hippocampal neuropeptide Y (NPY) levels, oxidative stress and histopathological studies were undertaken. The results suggest the potentiating effect of 4 mg/kg raloxifene on 14 mg/kg fluoxetine against MES induced THLE, as otherwise monotherapy with 4 mg/kg raloxifene was unable to produce an effect. The results also depicted better efficacy than carbamazepine (20 mg/kg), standard AED. Most profoundly, MES-induced significant (P < 0.001) reduction in hippocampal NPY levels, that were escalated insignificantly with the duo-drug combination, suggesting some other mechanism in mitigation of electroshock induced seizures. These results were later corroborated with assays to assess oxidative stress and neuronal damage. In conclusion, the results demonstrated the propitious therapeutic benefit of duo-drug low dose combination of drugs; raloxifene and fluoxetine, with diverse mode of actions fetching greater effectiveness in the management of generalized tonic clonic seizures (GTCS).

Bioresponse Inspired Nanomaterials for Targeted Drug and Gene Delivery.

The traditional drug delivery techniques are unresponsive to the altering metabolic states of the body and fail to achieve target specific drug delivery, which results in toxic plasma concentrations. In order to harmonize the drug release profiles, diverse biological and pathological pathways and factors involved have been studied and consequently, nanomaterials and nanostructures are engineered in a manner so that they respond and interact with the target cells and tissues in a controlled manner to induce promising pharmacological responses with least undesirable effects. The bioinspired nanoparticles such as carbon nanotubes, metallic nanoparticles, and quantum dots sense the localized host environment for diagnosis and treatment of pathological states. These biocompatible polymeric- based nanostructures bind drugs to the specific receptors, which renders them as ideal vehicles for the delivery of drugs and gene. The ultimate goal of bioinspired nanocomposites is to achieve personalized diagnostic and therapeutic outcomes. This review briefly discussed current trends; role, recent advancements as well as different approaches, which are being used for designing and fabrication of some bioinspired nanocarriers.

Bioinspired Nanocomposites: Applications in Disease Diagnosis and Treatment.

Recent advancement in the field of synthesis and application of nanomaterials provided holistic approach for both diagnosis as well as treatment of diseases. Briefly, three-dimensional scaffold and geometry of bioinspired nanocarriers modulate bulk properties of loaded drug at molecular/ atomic structures in a way to conjointly modulate pathological as well as altered metabolic states of diseases, in very predictable and desired manners at a specific site of the target. While, from the pharmacotechnical point of views, the bioinspired nanotechnology processes carriers either favor to enhance the solubility of poorly aqueous soluble drugs or enable well-controlled sustained release profiles, to reduce the frequency of drug regimen. Consequently, from biopharmaceutical point of view, these composite materials, not only minimize first pass metabolism but also significantly enhance in-vivo biodistribution, permeability, bio-adhesion and diffusivity. In lieu of the above arguments, the nano-processed materials exhibit an important role for diagnosis and treatments. In the diagnostic center, recent emergences and advancement in the tools and techniques to diagnose the unrevealed diseases with the help of instruments such as, computed tomography, magnetic resonance imaging etc; heavily depend upon nanotechnology-based materials. In this paper, a brief introduction and recent application of different types of nanomaterials in the field of tissue engineering, cancer treatment, ocular therapy, orthopedics, and wound healing as well as drug delivery system are thoroughly discussed.

Purple heart plant leaves extract-mediated silver nanoparticle synthesis: Optimization by Box-Behnken design.

The present research work describes a novel method for green synthesis of silver nanoparticles using purple heart plant leaves extract, which is recognized as frequently found in households as an ornamental plant. The aqueous methanolic extract of purple heart plant leaves was prepared and employed in the synthesis of stable silver nanoparticles via biological reduction method. The purple heart plant leaves extract-mediated synthesized silver nanoparticles were systematically optimized using Box-Behnken design considering the effect of various independent variables (factors) like concentration of AgNO3, temperature and volume of purple heart plant leaves extract solution on the responses like particle size and polydispersity index of synthesized silver nanoparticles were optimized. Mathematical modelling was performed using quadratic polynomial model and response surface analysis was done to understand the factor-response relationship. The synthesized silver nanoparticles at optimum condition were found to be of spherical in shape under TEM with particle size of 98 nm and polydispersity index of 0.15. Optimized silver nanoparticles were further characterized through UV-VIS spectrophotometry, FTIR spectroscopy and TEM imaging studies. Also, the silver nanoparticles were evaluated for antibacterial activity on E. coli and S. aureus. In a nutshell, the studies construed successful synthesis of silver nanoparticles along with thorough understanding of the associated factors influencing their quality characteristics and significantly improved antibacterial activity as beneficial effect.