An Engineered Probiotic Platform for Cancer Epitope-Independent Targeted Radionuclide Therapy of Solid Tumors.

Targeted radionuclide therapy (TRT) is an emerging therapeutic modality for the treatment of various solid cancers. Current approaches rely on the presence of cancer-specific epitopes and receptors against which a radiolabeled ligand is systemically administered to specifically deliver cytotoxic doses of α and ß particles to tumors. In this proof-of-concept study, tumor-colonizing Escherichia coli Nissle 1917 (EcN) is utilized to deliver a bacteria-specific radiopharmaceutical to solid tumors in a cancer-epitope independent manner. In this microbe-based pretargeted approach, the siderophore-mediated metal uptake pathway is leveraged to selectively concentrate copper radioisotopes, 64 Cu and 67 Cu, complexed to yersiniabactin (YbT) in the genetically modified bacteria. 64 Cu-YbT facilitates positron emission tomography (PET) imaging of the intratumoral bacteria, whereas 67 Cu-YbT delivers a cytotoxic dose to the surrounding cancer cells. PET imaging with 64 Cu-YbT reveals persistence and sustained growth of the bioengineered microbes in the tumor microenvironment. Survival studies with 67 Cu-YbT reveals significant attenuation of tumor growth and extends survival of both MC38 and 4T1  tumor-bearing mice harboring the microbes. Tumor response to this pretargeted approach correlates with promising anti-tumor immunity, with noticeable CD8+ T:Treg cell ratio. Their strategy offers a pathway to target and ablate multiple solid tumors independent of their epitope and receptor phenotype.

Engineered Bacteria Enhance Immunotherapy and Targeted Therapy through Stromal Remodeling of Tumors.

Desmoplastic solid tumors are characterized by the rapid build-up of extracellular matrix (ECM) macromolecules, such as hyaluronic acid (HA). The resulting physiological barrier prevents the infiltration of immune cells and also impedes the delivery of anticancer agents. The development of a hypervesiculating Escherichia coli Nissle (ΔECHy) based tumor targeting bacterial system capable of distributing a fusion peptide, cytolysin A (ClyA)-hyaluronidase (Hy) via outer membrane vesicles (OMVs) is reported. The capability of targeting hypoxic tumors, manufacturing recombinant proteins in situ and the added advantage of an on-site OMV based distribution system makes the engineered bacterial vector a unique candidate for peptide delivery. The HA degrading potential of Hy for stromal modulation is combined with the cytolytic activity of ClyA followed by testing it within syngeneic cancer models. ΔECHy is combined with immune checkpoint antibodies and tyrosine kinase inhibitors (TKIs) to demonstrate that remodeling the tumor stroma results in the improvement of immunotherapy outcomes and enhancing the efficacy of biological signaling inhibitors. The biocompatibility of ΔECHy is also investigated to show that the engineered bacteria are effectively cleared, elicit minimal inflammatory and immune responses, and therefore could be a reliable candidate as a live biotherapeutic.

Design and Development of Novel Transdermal Nanoemulgel for Alzheimer's Disease: Pharmacokinetic, Pharmacodynamic and Biochemical Investigations.

BACKGROUND: Alzheimer's disease is a chronic progressive neurodegenerative disorder associated with depletion of acetylcholine. Oral treatment with tacrine hydrochloride; a reversible inhibitor of acetylcholinesterase, finds limited use in Alzheimer's disease due to frequent dosing, hepatotoxicity and extensive pre-systemic metabolism. OBJECTIVES: The objective of the study was to evaluate pharmacokinetic, pharmacodynamic, safety and stability profile of transdermal w/o nanoemulsion gel of tacrine hydrochloride and determine its relative bioavailability from transdermal nanogel in contrast to marketed capsule and conventional hydrogel. METHODS: The optimized nanoemulsion gel NEGT4 (droplet size 156.4 ±0.48 nm, with poly dispersity index 0.36 ±0.4, permeation flux 6.172±2.94 µg/cm2/h across rat skin) was prepared by spontaneous emulsification followed by sonication. NEGT4 contained 7 mg of drug in 10% w/w distilled water, 30% w/w surfactant (Labrafil M) and cosurfactant (Transcutol P) mixture in ratio 1:4 and 60 % Capryol 90 as oily phase thickened with 98.9 mg ethyl cellulose (20 cps). In vivo studies were carried out on male Wistar rats following standard guidelines. Scopolamine was used to induce amnesia in rats which is a characteristic of Alzheimer's disease. Various formulations were compared by performing pharmacokinetic, histopathological, behavioural and biochemical studies on rats. Stability studies on nanoemulsion gels were carried out in accordance with The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. RESULTS: Pharmacokinetic studies exhibited significantly greater extent of absorption from NEGT4 in comparison to capsule and hydrogel with a 2.18 and 5.26-fold increase respectively. Significant improvement in neurobehavioral parameters was observed with NEGT4 in scopolamine-induced amnesic rats. Biochemical assessment showed superior anti-amnesic activity of NEGT4 through augmentation of antioxidant enzymes, decreased lipid peroxidation and acetylcholinesterase activity. Low value of serum aminotransferase in rats treated with NEGT4 indicated the absence of hepatotoxicity. NEGT4 was found to be non-irritant and possessed a shelf life of 4.11 years. CONCLUSION: Developed nanoemulsion gel of tacrine hydrochloride was found to be safe, stable, and efficacious and has immense potential to be used in the therapy of Alzheimer's disease.

Exploring the multifaceted neuroprotective actions of Emblica officinalis (Amla): a review.

Today, neurological disorders such as epilepsy, depression, tardive dyskinesia, and stress, and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, dementia, and Huntington's disease affect millions of people all over the world. Existing pharmacological interventions do not meet the desired therapeutic benefits for a significant number of patients, and hence, numerous research studies are in progress to find novel therapies for these disorders. Herbal drugs, which have been used in traditional medicine for centuries, are also being explored and scientifically evaluated for the treatment of these neurological disorders. While substantial evidence exists for the antioxidant, anti-inflammatory, anti-hyperlipidemic, and anti-hyperglycemic effects of Emblica officinalis, in vivo and in vitro studies, have also revealed its beneficial therapeutic activities in numerous neurological disorders. These diverse neuroprotective pharmacodynamic actions of E. officinalis corroborated by accumulating evidence in pre-clinical research studies deserve the attention of the scientific community to develop viable pharmacotherapeutic strategies. The present review elaborates upon the latest scientific evidence pertaining to the pharmacological effects of E. officinalis in numerous neurological and neurodegenerative disorders and also gives way for future research in this area.

Ferrites: magnetic materials as an alternate source of green electrical energy.

Ferrites samples Mg1-xLixFe2O4 for x = 0.0, 0.1, 0.2, 0.3, were synthesized by solid-state sintering method. Detailed investigations were made on the structural, morphological, magnetic and electrical proprieties of these samples. A detailed investigation was performed on power generation of these samples and role of Li-doping has been discussed. The X-ray Diffraction (XRD) pattern confirms the spinel phase formation in samples without any impurity. It is observed from Scanning Electron Microscopy that average grain size of samples decreases with lithium doping in MgFe2O4. The saturation magnetization of MgFe2O4 (15.4 emu/g) is found to increase with Lithium percentage and maximum 39.3 emu/g for Mg0.7Li0.3Fe2O4 sample. Ferrites play a crucial role in magnetic recording, microwave magnetic devices and many applications in medical sciences. Recently, it was observed that ferrites can be an alternate source of green energy by inventing hydroelectric cell (HEC). The processes of water adsorption and dissociation on the metal-oxide surface, plays an important role in production of electricity in ferrites. When, water is sprayed on hydroelectric cell the thermodynamic driving force is responsible for the formation of stable metal-oxygen or metal-hydroxyl bonds. The reactivity of ferrite surface towards water is based on the interaction of these ions and the d orbital of the Fe atom. Due to this interaction, water dissociated in H3O+ and OH- ions and migrates toward silver and zinc electrodes respectively. A typical hydroelectric cell of 2 inch diameter produces 17.1 mA of peak current and 949 mV voltage with a maximum output power of 15.85 mW for Li = 0.2 doped MgFe2O4 sample.

Unfolding the pleiotropic facades of rosuvastatin in therapeutic intervention of myriads of neurodegenerative disorders.

Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitor, and one of the most popular antihyperlipidemic medications have been found to possess pharmacodynamic activities much different from its usual indication. Recent research studies have revealed the efficacy of rosuvastatin in attenuating neuroinflammation, reducing the progression of Alzheimer's disease, providing protection against cerebral ischaemia and spinal cord injury as well as ameliorating epilepsy. Mechanisms behind the neuroprotective potential of rosuvastatin can be attributed to its pleiotropic effects, independent of its ability to inhibit HMG-CoA reductase. These processes include modulation of several cellular pathways, isoprenylation, effects on oxidative stress, nitrosative levels, inflammation, and immune response. This review aims to assimilate and summarize recent findings on the pharmacological actions of rosuvastatin in attenuating neurological disorders in order to guide future research in this space.

Rosuvastatin alleviates high-salt and cholesterol diet-induced cognitive impairment in rats via Nrf2-ARE pathway.

OBJECTIVE: The objectives of our study were to investigate the possible effect of rosuvastatin in ameliorating high salt and cholesterol diet (HSCD)-induced cognitive impairment and to also investigate its possible action via the Nrf2-ARE pathway. METHODS: In silico studies were performed to check the theoretical binding of rosuvastatin to the Nrf2 target. HSCD was used to induce cognitive impairment in rats and neurobehavioral studies were performed to evaluate the efficacy of rosuvastatin in enhancing cognition. Biochemical analyses were used to estimate changes in oxidative markers. Western blot and immunohistochemical analyses were done to check Nrf2 translocation. TUNEL and caspase 3 tests were performed to evaluate reversal of apoptosis by rosuvastatin. RESULTS: Rosuvastatin showed good theoretical affinity to Nrf2, significantly reversed changes in oxidative biomarkers which were induced by HSCD, and also improved the performance of rats in the neurobehavioral test. A rise in nuclear translocation of Nrf2 was revealed through immunohistochemical analysis and western blot. TUNEL staining and caspase 3 activity showed attenuation of apoptosis. DISCUSSION: We have investigated a novel mechanism of action for rosuvastatin (via the Nrf2-ARE pathway) and demonstrated that it has the potential to be used in the treatment of cognitive impairment.

Box-Behnken Design of Experiment Assisted Development and Optimization of Bendamustine HCl loaded Hydroxyapatite Nanoparticles.

BACKGROUND: Bendamustine HCl, an antineoplastic drug, has a very short life of about 40 minutes which necessitates administration of large doses which leads to increased side effects as well as costs. OBJECTIVE: The present work describes the fabrication, optimization, and evaluation of bioactive hydroxyapatite nanoparticles to achieve sustained delivery of bendamustine HCl. METHODS: Hydroxyapatite nanoparticles (NPs) were prepared by the wet chemical precipitation method by reacting a calcium and phosphate precursor and the reaction was optimized via Box-Behnken DOE. The drug was loaded on particles by physical adsorption. Various analytical studies were performed on the fabricated nanoparticles in addition to biodistribution studies to establish the physicochemical and biological characteristics of the designed formulation. RESULTS: pH of the reactant solution was found to have a more profound effect on the particle size and size distribution in comparison to reactant concentration. The particles were found to have a spherical morphology by SEM. Size of the blank and drug-loaded nanoparticles was found to be 130±20 nm by TEM. Energy Dispersive X-ray Spectroscopy (EDS) studies confirmed the presence of hydroxyapatite as the dominant phase while DSC studies indicated the presence of the drug in its amorphous form after its adsorption on NPs. Tissue distribution studies further suggested that the majority of drug concentration was released in blood rather than the other organs implying low organ toxicity. CONCLUSION: Bendamustine loaded hydroxyapatite nanoparticles were successfully optimized and fabricated. Favorable results were obtained in in vitro, in vivo, and analytical studies.

Exploring novel pharmacotherapeutic applications and repurposing potential of sodium glucose CoTransporter 2 inhibitors.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of anti-hyperglycaemic drugs with a distinctive mechanism of action focusing on renal absorption of glucose. Apart from its anti-hyperglycaemic effects, a multitude of research studies on this class have revealed that these drugs have far more versatile and comprehensive pharmacological effects than previously believed. Approximately 30% of FDA approved drugs are repurposed and used for indications other than those for which they were initially intended. Repurposing already approved drugs leads to significant reduction in pre-clinical and clinical R&D costs as well as minimizing the burden with respect to obtaining regulatory approval. SGLT2 inhibitors have been found to exhibit cardioprotective, renoprotective, anti-hyperlipidaemic, anti-atherosclerotic, anti-obesity, anti-neoplastic, hepatoprotective, and renoprotective effects in in vitro, pre-clinical, and clinical studies. The pleiotropic effects of this class have been attributed to a variety of its pharmacodynamic actions such as natriuresis, haemoconcentration, deactivation of RAAS, ketone body formation, alterations in energy homeostasis, glycosuria, lipolysis, anti-inflammatory, and anti-oxidative actions. These favourable observations encourage further research on this multifaceted class in order to effectively explore and harness its full potential and consequently lead to clinical outcomes.

Tannins Enriched Fraction of Emblica officinalis Fruits Alleviates High-Salt and Cholesterol Diet-Induced Cognitive Impairment in Rats via Nrf2-ARE Pathway.

Modern diets containing high quantities of salt and cholesterol have exhibited to cause a considerable effect on our health. Such diets, when consumed in the long term, have also shown to be a precursor to several disorders such as the metabolic disorder and consequently, various other diseases, including cognitive deficits. In the present study, we used a high salt and cholesterol diet (HSCD) to induce cognitive impairment in rats and also investigated the pharmacological action of tannins enriched fractions of Emblica officinalis (EOT) - a fruit that has been traditionally used for the treatment of numerous disorders for centuries. Significant alterations in MDA, GSH, TBARS, GPx, mitochondrial ATP, and mitochondrial membrane potential levels were observed in rats fed HSCD, which indicated presence of oxidative stress. Moreover, classic signs of cognitive impairment and deficits in spatial learning and memory were observed in the neurobehavioral tests. E. officinalis tannins exhibited good affinity to Nrf2 receptors in in silico studies, significantly reversed the changes in the aforementioned biomarkers of oxidative stress which were altered in the model group, as well as improved the performance of rats in Morris water maze task. Our results also reflected that EOT supplementation significantly increased the expression of Nrf2 in the CA1 region of hippocampus and cortex. Additionally, TUNEL assay indicated that EOT supplementation led to reversal of DNA fragmentation and apoptosis caused by HSCD. Immunohistochemical analysis and western blot further revealed a surge in the nuclear location of Nrf2. Through our study, we have demonstrated that cognitive impairment can be caused in rats via HSCD as a result of the oxidative stress induced by the same. Additionally, we have investigated a novel mechanism of action for EOT (which strongly suggests to be via the Nrf2-ARE pathway) and demonstrated that it has the potential to be used in the treatment of cognitive impairment.

Appraisal of Transdermal Water-in-Oil Nanoemulgel of Selegiline HCl for the Effective Management of Parkinson's Disease: Pharmacodynamic, Pharmacokinetic, and Biochemical Investigations.

In the present study, the potential of transdermal nanoemulsion gel of selegiline hydrochloride for the treatment of Parkinson's disease was investigated. Water-in-oil nanoemulsions were developed by comparing low- and high-energy methods and were subjected to thermodynamic stability tests, in vitro permeation, and characterization studies. In vitro studies indicated that components of nanoemulsion acted as permeation enhancers with highest flux of 3.531 ± 1.94 µg/cm2/h from nanoemulsion SB6 containing 0.5 mg selegiline hydrochloride, 3% distilled water, 21% S mix (Span 85, Tween 80, PEG 400), and 76% isopropyl myristate by weight. SB6 with the least droplet size of 183.4 ± 0.35 nm, polydispersity index of 0.42 ± 0.06 with pH of 5.9 ± 0.32 and viscosity of 22.42 ± 0.14 cps was converted to nanoemulsion gel NEGS4 (viscosity = 22,200 ± 400 cps) by addition of Viscup160® for ease of application and evaluated for permeation, safety, and pharmacokinetic profile in Wistar rats. It provided enhancement ratio 3.69 times greater than conventional gel. NEGS4 showed 6.56 and 5.53 times increase in bioavailability in comparison to tablet and conventional gel, respectively, along with sustained effect. Therefore, the developed water-in-oil nanoemulsion gel promises to be an effective vehicle for transdermal delivery of selegiline hydrochloride.

Sodium glucose CoTransporter 2 (SGLT2) inhibitors: Current status and future perspective.

Diabetes mellitus is a disease that affects millions of people worldwide and its prevalence is estimated to rise in the future. Billions of dollars are spent each year around the world in health expenditure related to diabetes. There are several anti-diabetic drugs in the market for the treatment of non-insulin dependent diabetes mellitus. In this article, we will be talking about a relatively new class of anti-diabetic drugs called sodium glucose co-transporter 2 (SGLT2) inhibitors. This class of drugs has a unique mechanism of action focusing on inhibition of glucose reabsorption that separates it from other classes. This article covers the mechanism of glucose reabsorption in the kidneys, the mechanism of action of SGLT2 inhibitors, several SGLT2 inhibitors currently available in the market as well as those in various phases of development, their individual pharmacokinetics as well as the discussion about the future role of SGLT2 inhibitors, not only for the treatment of diabetes, but also for various other diseases like obesity, hepatic steatosis, and cardiovascular disorders.