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.

Multifunctional Tasks and an Energy Crisis are Crucial Players in Determining the Vulnerability of the Entorhinal Cortex to Early Damage in Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating neurological disorder that affects synaptic transmission between neurons. Several theories and concepts have been postulated to explain its etiology and pathogenesis. The disease has no cure, and the drugs available to manage AD symptoms provide only modest benefits.

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).

Computational biology approaches for drug repurposing.

The drug discovery and development (DDD) process greatly relies on the data available in various forms to generate hypotheses for novel drug design. The complex and heterogeneous nature of biological data makes it difficult to utilize or gather meaningful information as such. Computational biology techniques have provided us with opportunities to better understand biological systems through refining and organizing large amounts of data into actionable and systematic purviews.

P66 is a bacterial mimic of CD47 that binds the anti-phagocytic receptor SIRPα and facilitates macrophage evasion by .

Innate immunity, the first line of defense against pathogens, relies on efficient elimination of invading agents by phagocytes. In the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through mimicry at the mammalian anti-phagocytic "don't eat me" signaling axis between CD47 (ligand) and SIRPα (receptor).

Development of chitosan based β-carotene mucoadhesive formulation for skin cancer treatment.

Mucopermeating nanoformulations can enhance mucosal penetration of poorly soluble drugs at their target site. In this work, thiolated chitosan (TCS)-lithocholic acid (LA) nanomicelles loaded with β-carotene, a safe phytochemical with anticancer properties, were designed to improve the pharmaceutical and pharmacological drug profile. The TCS-LA nanomicelles were characterized by FTIR to confirm the presence of the thiol group that favors skin adhesion, and to corroborate the conjugation of hydrophobic LA with hydrophilic CS to form an amphiphilic polymer derivative.

Development of mucoadhesive adapalene gel for biotherapeutic delivery to vaginal tissue.

Alternate formulation strategies need to be devised for improving the absorption and bioavailability of drug molecules administered through the intravaginal route. Enhancing the coating of vaginal mucosa can aid the achievement of this goal. The aim of the current study is to develop a mucoadhesive formulation having adequate adhesiveness, spreading, and viscosity profiles that can ensure good tissue absorption of adapalene upon intravaginal application.

Oral hymecromone decreases hyaluronan in human study participants.

BACKGROUNDHyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans.METHODSWe conducted an open-label, single-center, dose-response study of hymecromone in healthy adults.

Disrupting biological sensors of force promotes tissue regeneration in large organisms.

Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties.

A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke.

The therapeutic efficacy of stem cells transplanted into an ischaemic brain depends primarily on the responses of the neurovascular unit. Here, we report the development and applicability of a functional neurovascular unit on a microfluidic chip as a microphysiological model of ischaemic stroke that recapitulates the function of the blood-brain barrier as well as interactions between therapeutic stem cells and host cells (human brain microvascular endothelial cells, pericytes, astrocytes, microglia and neurons). We used the model to track the infiltration of a number of candidate stem cells and to characterize the expression levels of genes associated with post-stroke pathologies.

Development of Vancomycin Delivery Systems Based on Autologous 3D Platelet-Rich Fibrin Matrices for Bone Tissue Engineering.

Autologous platelet-rich fibrin (PRF) is derived from the blood and its use in the bone tissue engineering has emerged as an effective strategy for novel drug and growth factor delivery systems. Studies have approved that combined therapy with PRF ensures higher biological outcomes, but patients still undergo additional treatment with antibiotic drugs before, during, and even after the implantation of biomaterials with PRF. These systematically used drugs spread throughout the blood and lead not only to positive effects but may also induce adverse side effects on healthy tissues.

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 .

Integrated Ca flux and AFM force analysis in human iPSC-derived cardiomyocytes.

We developed a new approach for combined analysis of calcium (Ca) handling and beating forces in contractile cardiomyocytes. We employed human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from dilated cardiomyopathy (DCM) patients carrying an inherited mutation in the sarcomeric protein troponin T (TnT), and isogenic TnT-KO iPSC-CMs generated via CRISPR/Cas9 gene editing. In these cells, Ca handling as well as beating forces and -rates using single-cell atomic force microscopy (AFM) were assessed.

Dendritic Cells as Targets for Biomaterial-Based Immunomodulation.

Various subtypes of immunocytes react against implanted biomaterials to eliminate the foreign body object from the host's body. Among these cells, dendritic cells (DCs) play a key role in early immune response, later engaging lymphocytes through antigens presentation. Due to their capability to induce tolerogenic or immunogenic responses, DCs have been considered as key therapeutic targets for immunomodulatory products.

Association of serum allopregnanolone with restricted and repetitive behaviors in adult males with autism.

Autism spectrum disorder (ASD) has been associated with imbalance between excitatory and inhibitory (E/I) neurotransmission systems, as well as with neuroinflammation. Sitting at the crossroads between E/I imbalance and neuroinflammation is a class of endogenous hormones known as neurosteroids. Current literature points to dysregulated steroid metabolism and atypical neurosteroid levels in ASD as early as in utero.

The Effect of Ethanol Consumption on Composition and Morphology of Femur Cortical Bone in Wild-Type and ALDH2*2-Homozygous Mice.

ALDH2 inactivating mutation (ALDH2*2) is the most abundant mutation leading to bone morphological aberration. Osteoporosis has long been associated with changes in bone biomaterial in elderly populations. Such changes can be exacerbated with elevated ethanol consumption and in subjects with impaired ethanol metabolism, such as carriers of aldehyde dehydrogenase 2 (ALDH2)-deficient gene, ALDH2*2.

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 .

Upregulation of CD47 Is a Host Checkpoint Response to Pathogen Recognition.

It is well understood that the adaptive immune response to infectious agents includes a modulating suppressive component as well as an activating component. We now show that the very early innate response also has an immunosuppressive component. Infected cells upregulate the CD47 "don't eat me" signal, which slows the phagocytic uptake of dying and viable cells as well as downstream antigen-presenting cell (APC) functions.

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.

Amyloid protein aggregates: new clients for mitochondrial energy production in the brain?

Mitochondria are key organelles, which maintain energy metabolism and cellular homeostasis. Mitochondria support transcriptional regulation and proteostatic signaling mechanisms through crosstalk between the mitochondria itself, the nucleus, and the cytoplasm. Mitochondrial dysfunction leads to impaired proteostasis, and both are key pathological features of age-related neurological disorders.

Pharmacological antagonism of histamine H2R ameliorated L-DOPA-induced dyskinesia via normalization of GRK3 and by suppressing FosB and ERK in PD.

Parkinson's disease (PD) is often managed with L-3,4-dihydroxyphenylalanine (L-DOPA), which is still the gold standard to relieve the clinical motor symptoms of PD. However, chronic use of L-DOPA leads to significant motor complications, especially L-DOPA-induced dyskinesia (LID), which limit the therapeutic benefit. Few options are available for the pharmacological management of LID partly due to the inadequacy of our mechanistic understanding of the syndrome.

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.