Nanotargeting of Drug(s) for Delaying Dementia: Relevance of Covid-19 Impact on Dementia.

By incorporating appropriate drug(s) into lipid (biobased) nanocarriers, one obtains a combination therapeutic for dementia treatment that targets certain cell-surface scavenger receptors (mainly class B type I, or "SR-BI") and thereby crosses the blood-brain barrier. The cardiovascular risk factors for dementia trigger widespread inflammation -- which lead to neurodegeneration, gradual cognitive/memory decline, and eventually (late-onset) dementia. Accordingly, one useful strategy to delay dementia could be based upon nanotargeting drug(s), using lipid nanocarriers, toward a major receptor class responsible for inflammation-associated (cytokine-mediated) cell signaling events.

Biomimetic Nanocarrier Targeting Drug(s) to Upstream-Receptor Mechanisms in Dementia: Focusing on Linking Pathogenic Cascades.

Past published studies have already documented that, subsequent to the intravenous injection of colloidal lipid nanocarriers, apolipoprotein (apo)A-I is adsorbed from the blood onto the nanoparticle surface. The adsorbed apoA-I mediates the interaction of the nanoparticle with scavenger receptors on the blood-brain barrier (BBB), followed by receptor-mediated endocytosis and subsequent transcytosis across the BBB. By incorporating the appropriate drug(s) into biomimetic (lipid cubic phase) nanocarriers, one obtains a multitasking combination therapeutic which targets certain cell-surface scavenger receptors, mainly class B type I (i.

Targeting Early Dementia: Using Lipid Cubic Phase Nanocarriers to Cross the Blood⁻Brain Barrier.

Over the past decades, a frequent co-morbidity of cerebrovascular pathology and Alzheimer's disease has been observed. Numerous published studies indicate that the preservation of a healthy cerebrovascular endothelium can be an important therapeutic target. By incorporating the appropriate drug(s) into biomimetic (lipid cubic phase) nanocarriers, one obtains a multitasking combination therapeutic, which targets certain cell surface scavenger receptors, mainly class B type I (i.

Nanotherapy for Alzheimer's disease and vascular dementia: Targeting senile endothelium.

Due to the complexity of Alzheimer's disease, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted lipid nanoemulsion) are available. Versatile small molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known.

Biological characterization of a heterodimer-selective retinoid X receptor modulator: potential benefits for the treatment of type 2 diabetes.

Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARgamma agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia.

Design, synthesis and structure-activity relationship of novel RXR-selective modulators.

The synthesis and in vitro characterization of novel RXR-selective ligands possessing various substituted 1-benzofuran or 1-benzothiophene moieties are described.

Design, synthesis, and structure-activity relationship studies of novel 6,7-locked-[7-(2-alkoxy-3,5-dialkylbenzene)-3-methylocta]-2,4,6-trienoic acids.

Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain.

The affinity of lipid-coated microbubbles to maturing spinal cord injury sites.

Objective: This laboratory has demonstrated that lipid-coated microbubbles (LCMs) effectively aggregate and deliver chemotherapeutic drugs into rat brain tumor cells and antigliosis agents into maturing rat brain injury sites. In this study, we report the affinity of tail vein-injected LCMs to the injured rat spinal cord by a compressive lesion to the upper thoracic region.

Methods: The accumulation of LCMs in the injured spinal cord was analyzed by labeling it with a lipid-soluble fluorescent dye, 3,3'-dioctadecyloxacarbocyanine perchlorate.

The use of lipid-coated microbubbles as a delivery agent of 7beta-hydroxycholesterol in a radiofrequency lesion in the rat brain.

Objective: This laboratory has previously described the aggregation of intravenously administered lipid-coated microbubbles (LCM) around tumors and areas of injury. 7Beta-hydroxycholesterol has been used to inhibit astrocytic proliferation in nervous system injury models. The compound has been given by direct infusion, by epidural catheter, or in liposomes (delivered stereotactically to the injury site).

Evaluation of lipid-coated microbubbles as a delivery vehicle for Taxol in brain tumor therapy.

Objective: This work evaluates the potential of lipid-coated microbubbles (LCM) as a delivery vehicle for lipid-soluble antineoplastic agents. We have shown, in rats, the selective affinity of intravenously administered LCM for tumor cells. They are internalized by the tumor cells both in vitro and in vivo.

The affinity of lipid-coated microbubbles for maturing brain injury sites.

The availability of a vehicle to deliver lipid soluble agents to a brain injury site may be of potential value in management of brain injury. This work describes the aggregation of intravenously administered Lipid-Coated Microbubbles (LCM) in the injury site following an experimental radiofrequency rat brain lesion. The bubbles can be identified around the region of the injury after the lesion has matured at least 48 h.

Internalization of microbubbles by tumor cells in vivo and in vitro.

Lipid-coated microbubbles (LCM) administered intravenously (i.v.) to rats bearing brain tumor, specifically enhance tumor visualization by ultrasound [1].

Detection of experimental rat liver tumors by contrast-assisted ultrasonography.

Rationale And Objectives: The authors characterized the effect of intravenous lipid-coated microbubbles (LCMs) on the echogenicity of malignant liver tumors.

Methods: Novikoff hepatoma cells were inoculated into the livers of 16 anesthetized Sprague-Dawley rats. Sonograms were obtained weekly after tail-vein injection with either 0.

Applications of lipid-coated microbubble ultrasonic contrast to tumor therapy.

Lipid-coated microbubbles (LCM) make an excellent diagnostic ultrasonic contrast agent in experimental tumor systems. LCM have been shown to aggregate in brain tumors and subcutaneous tumors after intravenous administration, and to provide persistent image enhancement for many minutes. In this work, experimental subcutaneous Walker Carcinosarcoma is insonated after the bubbles are given intravenously.

Quantitative assessment of tumor enhancement by ultrastable lipid-coated microbubbles as a sonographic contrast agent.

We have previously reported that ultrastable lipid-coated microbubbles make a suitable ultrasonic contrast agent in the brain, causing increased intensity of echoes that persists for many hours. We showed that intravenously administered lipid-coated microbubbles accumulate selectively in rat brain gliomas with echogenicity enhancement for up to 1 hour, allowing visualization of the growing lesions 40% (2 days) earlier than can be seen without contrast. This work is a detailed evaluation of the accumulation of the lipid-coated microbubbles in tumor and the effect of the bubbles on the echogenicity of insonified tumors.

Lipid-coated uniform microbubbles for earlier sonographic detection of brain tumors.

Rapid technological improvements have fostered the continued clinical development of intraoperative neurosonology, despite the fact that no suitable contrast media have been available for ultrasound studies. Because they can be made of uniform size (99% are less than 4.5 mum in diameter) and are thought to cross disruptions in the tumor vessels, artificial lipid-coated microbubbles can fill this gap.

Lipid-coated ultrastable microbubbles as a contrast agent in neurosonography.

Lipid-coated microbubbles can be synthesized from selected lipid monolayer systems for use as ultrasonic contrast. These microbubbles have the property of longevity of weeks in vitro (ultrastability) and longevity of hours in vivo. The bubbles can be manufactured with a mean diameter of approximately 2 microns in a tight diameter distribution; all are less than 6 microns and 99% are smaller than 4.

Bubble production in agarose gels subjected to different decompression schedules.

The relative effectiveness of seven different (military, commercial, and experimental) decompression schedules in reducing bubble formation within aqueous gels has been evaluated quantitatively under rigorously controlled conditions. Specifically, visual counts have been conducted of the bubbles formed in highly purified agarose gels subjected to the different decompression schedules. The order of effectiveness among these schedules in reducing bubble formation in the agarose gel samples was as follows: Model 1 greater than Royal Naval Physiological Laboratory approximately French Ministry of Labor greater than Yount et al.

Screening of membrane surface charges by divalent cations: an atomic representation.

To arrive at a clear and atomically realistic representation of the process of ionic screening, a model with the following necessary and justifiable constraints was devised. 1) The minimum internuclear distance (IND) between a negative site on the membrane and a cation screening the site is equal to the sum of the site's "equivalent" radius (rs) + the diameter of a water molecule (approximately 2.8 A) + crystal radius of the cation (rc).

Improved method for studying the surface chemistry of bubble formation.

Bubble formation in agarose gels as a result of rapid decompression following saturation with either N2, CO2, or He has been studied. Bubble number was observed to vary predominantly as a function of decompression magnitude and was virtually independent of the particular gas used. The cavitation threshold (i.

Relationship between CO2 levels and decompression sickness: implications for disease prevention.

Extensive data concerning the incidence of decompression sickness among workers participating in the deepest caisson operation in Japan to date have been collected and analyzed for the period April through August, 1976. When the bottom pressure was between 3.0 and 3.

Covalent labeling of the tetrodotoxin receptor in excitable membranes.

A photoaffinity labeling technique is described by which a tetrodotoxin analog is covalently bound to receptor sites associated with the sodium pores of excitable membranes. The biological activity of the toxin analog is retained after the covalent binding reaction.

Stabilization of gas cavitation nuclei by surface-active compounds.

Gas bubbles are the primary agent in producing the pathogenic effects of decompression sickness. Numerous experiments indicate that bubbles originate in water, and probably also in man, as pre-existing gas nuclei. This is surprising considering that gas phases larger than 1 micron should rise to the surface of a standing liquid, whereas smaller ones should dissolve rapidly due to surface tension.

Structural characteristics of the saxitoxin receptor on nerve.

The effects of uranyl ion (UO22+; at low concentrations binds specifically to phosphate groups) and the cationic dye methylene blue (MB+; binds strongly to carboxyl groups) on saxitoxin (STX) potency in crayfish axon has been studied by means of intracellular microelectrodes. At pH 6.00 +/- 0.