Repurposing an epithelial sodium channel inhibitor as a therapy for murine and human skin inflammation.

Inflammatory skin disease is characterized by a pathologic interplay between skin cells and immunocytes and can result in disfiguring cutaneous lesions and systemic inflammation. Immunosuppression is commonly used to target the inflammatory component; however, these drugs are often expensive and associated with side effects. To identify previously unidentified targets, we carried out a nonbiased informatics screen to identify drug compounds with an inverse transcriptional signature to keratinocyte inflammatory signals.

Intranasal delivery of liposome encapsulated flavonoids ameliorates l-DOPA induced dyskinesia in hemiparkinsonian mice.

In the present study, we explored the development of a novel noninvasive liposomal drug delivery material for use in intranasal drug delivery applications in human diseases. We used drug entrapment into liposomal nanoparticle assembly to efficiently deliver the drugs to the nasal mucosa to be delivered to the brain. The naturally occurring flavonoid 7,8-dihydroxyflavone (7,8-DHF) has previously been shown to have beneficial effects in ameliorating Parkinson's disease (PD).

In situ T-cell transfection by anti-CD3-conjugated lipid nanoparticles leads to T-cell activation, migration, and phenotypic shift.

Ex vivo programming of T cells can be efficacious but is complex and expensive; therefore, the development of methods to transfect T cells in situ is important. We developed and optimized anti-CD3-targeted lipid nanoparticles (aCD3-LNPs) to deliver tightly packed, reporter gene mRNA specifically to T cells. In vitro, targeted LNPs efficiently delivered mCherry mRNA to Jurkat T cells, and T-cell activation and depletion were associated with aCD3 antibody coating on the surface of LNPs.

Adipose-Derived Stromal Cells Seeded in Pullulan-Collagen Hydrogels Improve Healing in Murine Burns.

Burn scars and scar contractures cause significant morbidity for patients. Recently, cell-based therapies have been proposed as an option for improving healing and reducing scarring after burn injury, through their known proangiogenic and immunomodulatory paracrine effects. Our laboratory has developed a pullulan-collagen hydrogel that, when seeded with mesenchymal stem cells (MSCs), improves cell viability and augments their proangiogenic capacity .

Repurposing Disulfiram (Tetraethylthiuram Disulfide) as a Potential Drug Candidate against In Vitro and In Vivo.

Lyme disease caused by the () is the most common vector-borne, multi-systemic disease in the USA. Although most Lyme disease patients can be cured with a course of the first line of antibiotic treatment, some patients are intolerant to currently available antibiotics, necessitating the development of more effective therapeutics. We previously found several drugs, including disulfiram, that exhibited effective activity against .

Azlocillin can be the potential drug candidate against drug-tolerant Borrelia burgdorferi sensu stricto JLB31.

Lyme disease is one of most common vector-borne diseases, reporting more than 300,000 cases annually in the United States. Treating Lyme disease during its initial stages with traditional tetracycline antibiotics is effective. However, 10-20% of patients treated with antibiotic therapy still shows prolonged symptoms of fatigue, musculoskeletal pain, and perceived cognitive impairment.

Optimization of transdermal deferoxamine leads to enhanced efficacy in healing skin wounds.

Chronic wounds remain a significant burden to both the healthcare system and individual patients, indicating an urgent need for new interventions. Deferoxamine (DFO), an iron-chelating agent clinically used to treat iron toxicity, has been shown to reduce oxidative stress and increase hypoxia-inducible factor-1 alpha (HIF-1α) activation, thereby promoting neovascularization and enhancing regeneration in chronic wounds. However due to its short half-life and adverse side effects associated with systemic absorption, there is a pressing need for targeted DFO delivery.

Fidgetin-Like 2 siRNA Enhances the Wound Healing Capability of a Surfactant Polymer Dressing.

Microtubules (MTs) are intracellular polymers that provide structure to the cell, serve as railways for intracellular transport, and regulate many cellular activities, including cell migration. The dynamicity and function of the MT cytoskeleton are determined in large part by its regulatory proteins, including the recently discovered MT severing enzyme Fidgetin-like 2 (FL2). Downregulation of FL2 expression with small interfering RNA (siRNA) results in a more than twofold increase in cell migration rate as well as translates into improved wound-healing outcomes in mouse models.

Anti-hyperlipidaemic effects of synthetic analogues of nordihydroguaiaretic acid in dyslipidaemic rats.

Background And Purpose: Previous studies have shown that Creosote bush-derived nordihydroguaiaretic acid (NDGA) exerts beneficial actions on the key components of metabolic syndrome including dyslipidaemia, insulin resistance and hypertension in several relevant rodent models. Here, we synthesized and screened a total of 6 anti-hyperlipidaemic analogues of NDGA and tested their efficacy against hepatic lipid metabolism in a high-fructose diet (HFrD) fed dyslipidaemic rat model.

Experimental Approach: HFrD fed Sprague-Dawley rats treated with NDGA or one of the six analogues were used.

In vitro and in vivo evaluation of cephalosporins for the treatment of Lyme disease.

Background: Lyme disease accounts for >90% of all vector-borne disease cases in the United States and affect ~300,000 persons annually in North America. Though traditional tetracycline antibiotic therapy is generally prescribed for Lyme disease, still 10%-20% of patients treated with current antibiotic therapy still show lingering symptoms.

Methods: In order to identify new drugs, we have evaluated four cephalosporins as a therapeutic alternative to commonly used antibiotics for the treatment of Lyme disease by using microdilution techniques like minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC).

Cytokines as therapeutic agents and targets in heart disease.

Cytokine therapies have emerged during the past decade as promising noninvasive treatments for heart disease. In general, current drug treatments are directed towards symptom control and prevention of disease progression; however, many agents also produce cause side effects that alter quality of life. Cytokine based therapies have the potential to reduce post-infarct heart failure and chronic ischemia by stimulating the proliferation and differentiation of endothelial cells and bone marrow hematopoietic stem cells and mobilizing these cells toward ischemic tissue.

Deferoxamine can prevent pressure ulcers and accelerate healing in aged mice.

Chronic wounds are a significant medical and economic problem worldwide. Individuals over the age of 65 are particularly vulnerable to pressure ulcers and impaired wound healing. With this demographic growing rapidly, there is a need for effective treatments.

Controlled Delivery of a Focal Adhesion Kinase Inhibitor Results in Accelerated Wound Closure with Decreased Scar Formation.

Formation of scars after wounding or trauma represents a significant health care burden costing the economy billions of dollars every year. Activation of focal adhesion kinase (FAK) has been shown to play a pivotal role in transducing mechanical signals to elicit fibrotic responses and scar formation during wound repair. We have previously shown that inhibition of FAK using local injections of a small molecule FAK inhibitor (FAKI) can attenuate scar development in a hypertrophic scar model.

PEG/Dextran Double Layer Influences Fe Ion Release and Colloidal Stability of Iron Oxide Nanoparticles.

Despite preliminary confidence on biosafety of polymer coated iron oxide nanoparticles (SPIONs), toxicity concerns have hampered their clinical translation. SPIONs toxicity is known to be due to catalytic activity of their surface and release of toxic Fe ions originating from the core biodegradation, leading to the generation of reactive oxygen species (ROS). Here, we hypothesized that a double-layer polymeric corona comprising of dextran as an interior, and polyethylene glycol (PEG) as an exterior layer better shields the core SPIONs.

Nordihydroguaiaretic Acid, a Lignan from (Creosote Bush), Protects Against American Lifestyle-Induced Obesity Syndrome Diet-Induced Metabolic Dysfunction in Mice.

To determine the effects of nordihydroguaiaretic acid (NDGA) on metabolic and molecular changes in response to feeding a typical American fast food or Western diet, mice were fed an American lifestyle-induced obesity syndrome (ALIOS) diet and subjected to metabolic analysis. Male C57BL/6J mice were randomly assigned to the ALIOS diet, the ALIOS diet supplemented with NDGA (NDGA+ALIOS), or a control diet and were maintained on the specific diet for 8 weeks. Mice fed the ALIOS diet showed increased body, liver, and epididymal fat pad weight as well as increased plasma alanine transaminase (ALT) and aspartate aminotransferase (AST) levels (a measure of liver injury) and liver triglyceride content.

Microhemorrhage-associated tissue iron enhances the risk for invasion in a mouse model of airway transplantation.

Invasive pulmonary disease due to the mold can be life-threatening in lung transplant recipients, but the risk factors remain poorly understood. To study this process, we used a tracheal allograft mouse model that recapitulates large airway changes observed in patients undergoing lung transplantation. We report that microhemorrhage-related iron content may be a major determinant of invasion and, consequently, its virulence.

Identification of key regions and residues controlling Aβ folding and assembly.

Amyloid β-protein (Aβ) assembly is hypothesized to be a seminal neuropathologic event in Alzheimer's disease (AD). We used an unbiased D-amino acid substitution strategy to determine structure-assembly relationships of 76 different Aβ40 and Aβ42 peptides. We determined the effects of the substitutions on peptide oligomerization, secondary structure dynamics, fibril assembly dynamics, and fibril morphology.

Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects.

Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined.

Nanomaterials engineering for drug delivery: a hybridization approach.

The last twenty years have witnessed great advances in biology, medicine, and materials science, leading to the development of various nanoparticle (NP)-mediated drug delivery systems. Innovation in materials science has led the generation of biodegradable, biocompatible, stimuli-responsive, and targeted delivery systems. However, currently available nanotherapeutic technologies are not efficient, which has culminated in the failure of their clinical trials.

Enhanced Electrochemical Sensing with Carbon Nanotubes Modified with Bismuth and Magnetic Nanoparticles in a Lab-on-a-Chip.

Iron plays an especially important role in human physiological functions and pathological impairments. The superior properties of carbon nanotubes (CNTs) and their modification with bismuth and magnetic nanoparticles as developed in this work have led to an extraordinary and novel material to facilitate ultrasensitive detection in the nanomolar range. Here, we present the development of an electrochemical sensor for detection of ferrous (Fe) and ferric (Fe) iron by means of CNTs modified with bismuth and magnetic nanoparticles for higher sensitivity of detection.

Attenuation of synaptic toxicity and MARK4/PAR1-mediated Tau phosphorylation by methylene blue for Alzheimer's disease treatment.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by genotypic and phenotypic heterogeneity. Critical components of the two AD pathological pathways, Aβ-amyloidosis and Tauopathy, have been considered as therapeutic targets. Among them, much effort is focused on aberrant Tau phosphorylation and targeting Tau-phosphorylating kinases.

Effect of osmolytes on the conformation and aggregation of some amyloid peptides: CD spectroscopic data.

Protein misfolding and aggregation are responsible for a large number of diseases called protein conformational diseases or disorders that include Alzheimer׳s disease, Huntington׳s diseases, Prion related encephalopathies and type-II diabetes (http://dx.doi.org/10.