Assessment of superiority of HSP70-targeting aptamer-functionalized drug-nanocarrier over non-targeted commercially available counterpart in HCC therapy: in vitro and in vivo investigations and molecular modeling.

AIMS: This research aims to compare the therapeutic potential of target-specific phosphorothioate backbone-modified aptamer L5 (TLS9a)-functionalized paclitaxel (PTX)-loaded nanocarrier (PTX-NPL5) that we formulated with that of non-targeted commercial formulation, protein albumin-bound nanoparticles of PTX, Abraxane® (CF) against hepatocellular carcinoma (HCC) through a myriad of preclinical investigations. MAIN METHODS: A variety of in vitro and in vivo assays have been executed to compare the therapeutic effects of the formulations under investigation, including the investigation of the degree of apoptosis induction and its mechanism, cell cycle analysis, the level of ROS production, and redox status, the morphological and histological characteristics of malignant livers, and in vivo imaging. The formulations were also compared concerning pharmacokinetic behaviors. Finally, in silico molecular docking has been performed to predict the possible interactions between aptamer and target(s). KEY FINDINGS: PTX-NPL5 exhibited therapeutic superiority over CF in terms of inducing apoptosis, cell cycle arrest, endorsing oxidative stress to neoplastic cells, and reducing hepatic cancerous lesions. Unlike CF, PTX-NPL5 did not exhibit any significant toxicity in healthy hepatocytes, proving enough impetus regarding the distinctive superiority of PTX-NPL5 over CF. The pharmacokinetic analysis further supported superior penetration and retention of PTX-NPL5 in neoplastic hepatocytes compared to CF. A molecular modeling study proposed possible interaction between aptamer L5 and heat shock protein 70 (HSP70). SIGNIFICANCE: The target-specificity of PTX-NPL5 towards neoplastic hepatocytes, probably achieved through HSP70 recognition, enhanced its therapeutic efficacy over CF, which may facilitate its real clinical deployment against HCC in the near future.

Quantum dots: The cutting-edge nanotheranostics in brain cancer management.

Quantum dots (QDs) are semiconductor nanocrystals possessing unique optoelectrical properties in that they can emit light energy of specific tunable wavelengths when excited by photons. They are gaining attention nowadays owing to their all-around ability to allow high-quality bio-imaging along with targeted drug delivery. The most lethal central nervous system (CNS) disorders are brain cancers or malignant brain tumors. CNS is guarded by the blood-brain barrier which poses a selective blockade toward drug delivery into the brain. QDs have displayed strong potential to deliver therapeutic agents into the brain successfully. Their bio-imaging capability due to photoluminescence and specific targeting ability through the attachment of ligand biomolecules make them preferable clinical tools for coming times. Biocompatible QDs are emerging as nanotheranostic tools to identify/diagnose and selectively kill cancer cells. The current review focuses on QDs and associated nanoformulations as potential futuristic clinical aids in the continuous battle against brain cancer.

Hydrogel composite containing azelaic acid and tea tree essential oil as a therapeutic strategy for Propionibacterium and testosterone-induced acne.

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 < 0.7), nano-range (~357.4 ± 2% nm), transmittance (> 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.

Calorie restriction modulates neuro-immune system differently in young and aged rats.

Aging weakens and deregulates the immune system and plays an impact on the central nervous system (CNS). A crosstalk in between the CNS-mediated immune system and the body's overall innate immunity is often found to increase and subsequently accelerate neurodegeneration and behavioural impairment during aging. Dietary calorie restriction (CR) is found to be a beneficial non-invasive anti-aging therapy as it shows rejuvenation of stress response, brain functions and behaviour during aging. The present investigation deals with the consequence of CR diet supplementation for two different duration (one and two consecutive months) on aging-related alteration of the immune response in male albino Wistar rats at the level of (a) lymphocyte viability, proliferation, cytotoxicity, and DNA fragmentation in blood, spleen, and thymus and (b) cytokines (IL-6, IL-10, and TNF-α) in blood, spleen, thymus and different brain-regions to understand the effect of CR diet on neuroimmune system. The results depict that CR diet consumption for consecutive one and two months by the aged (18 and 24 months) rats significantly attenuated the aging-related (a) decrease of blood, splenic and thymic lymphocyte viability, proliferative activity, cytotoxicity, and IL-10 level and (b) increase of (i) blood, splenic and thymic DNA fragmentation and (ii) IL-6 and TNF-α level in those tissues and also in different brain regions. Unlike older rats, in young (4 months) rats, the consumption of CR diet under similar conditions affected those above-mentioned immune parameters reversibly and adversely. This study concludes that (a) aging significantly (p < 0.01) deregulates the above-mentioned immune parameters, (b) consecutive consumption of CR diet for one and two months is (i) beneficial (p < 0.05) to the aging-related immune system [lymphocyte viability, lymphocyte proliferation, cytotoxicity, pro (IL-6 and TNF-α)- and anti (IL-10)-inflammatory cytokines], but (ii) adverse (p < 0.05) to the immune parameters of the young rats, and (c) consumption of CR diet for consecutive two months is more potent (p < 0.05) than that due to one month.

Metabolic disorder in Alzheimer's disease.

Alzheimer's disease (AD), a well known aging-induced neurodegenerative disease is related to amyloid proteinopathy. This proteinopathy occurs due to abnormalities in protein folding, structure and thereby its function in cells. The root cause of such kind of proteinopathy and its related neurodegeneration is a disorder in metabolism, rather metabolomics of the major as well as minor nutrients. Metabolomics is the most relevant "omics" platform that offers a great potential for the diagnosis and prognosis of neurodegenerative diseases as an individual's metabolome. In recent years, the research on such kinds of neurodegenerative diseases, especially aging-related disorders is broadened its scope towards metabolic function. Different neurotransmitter metabolisms are also involved with AD and its associated neurodegeneration. The genetic and epigenetic backgrounds are also noteworthy. In this review, the physiological changes of AD in relation to its corresponding biochemical, genetic and epigenetic involvements including its (AD) therapeutic aspects are discussed.

Calorie restriction improves aging-induced impairment of cognitive function in relation to deregulation of corticosterone status and brain regional GABA system.

Aging is known to affect adversely the corticosterone status and the brain function including cognition. Calorie restricted (CR) diet has been found to improve brain aging. The objective of the present investigation is to study the effect of short-term CR diet without any food deprivation on aging-induced impairment of cognitive function in relation to the corticosterone status and the brain regional GABA system. The result showed that aging-induced deregulation of the brain regional GABA system, increase in plasma and adrenal corticosterone levels and cognitive impairment were attenuated with short-term CR diet supplementation for consecutive 1 and 2 months to the aged (18 and 24 months) rats. But in young rats (4 months) consumption of the same CR diet under similar conditions reversibly affected those above-mentioned parameters. These results, thus suggest that (a) aging down-regulates brain regional GABA system with an up-regulation of corticosterone status and impairment of cognitive function, (b) CR diet consumption improves this aging-induced deregulation of brain regional GABA system, corticosterone status, and cognitive function, (c) these attenuating effects of CR diet are greater with a longer period of consumption but (d) CR diet consumption is harmful to young rats as observed in those parameters.

Aptamer-Conjugated Apigenin Nanoparticles To Target Colorectal Carcinoma: A Promising Safe Alternative of Colorectal Cancer Chemotherapy.

Apigenin has gained interest recently among researchers as a potential chemotherapeutic agent in cancer, including colorectal cancer, due to its established antiproliferative activity in vitro. Despite its impressive anticancer activity in vitro, poor water solubility and nonspecific distribution in vivo make it difficult for its emergence as a drug candidate. To overcome these problems, we formulated an aptamer-conjugated apigenin-loaded nanoparticle (apt-ANP) to target against the overexpressed colorectal cancer cell surface biomarker epithelial cell adhesion molecule (EpCAM). Aptamer conjugation was conducted on the prepared nanoparticle, characterized (by SEM, TEM, and AFM) and evaluated for its antiproliferative activity toward in vitro colon carcinoma cells and in vivo colorectal cancer model. The aptamer-conjugated nanoformulation had an average size about 226 nm, smooth surface, satisfactory drug loading 17.5 ± 1.3%, and sustained drug-release pattern. The pharmacokinetic profile as well as the biodistribution study demonstrated a maximum retention of apt-ANP in the colon as compared to free drug and aptamer-free apigenin-loaded nanoparticle (ANP). Apt-ANP enhanced therapeutic efficacy to colorectal cancer cells, whereas it minimized off-target cytotoxicity to normal cells.