Novel resin-based material containing β-tricalcium phosphate nanoparticles for the reduction of dentin permeability.

Objectives: To synthesize and characterize a novel dentin adhesive containing Beta-Tricalcium Phosphate (β-TCP) nanoparticles and test its ability to reduce dentin permeability (dP).

Methods: Experimental adhesives were prepared by mixing Bis-GMA, TEGDMA, HEMA (50/25/25 wt.%), photo-initiators, and inhibitors.

Carboxyl-terminal modulator protein (CTMP) deficiency mitigates denervation-induced skeletal muscle atrophy.

Denervated skeletal muscles show decreased Akt activity and phosphorylation, resulting in atrophy. Akt inhibits downstream transcription of atrophy-associated ubiquitin ligases like muscle ring-finger protein 1 (MuRF-1). In addition, reduced Akt signaling contributes to aberrant protein synthesis in muscles.

Circadian Clock, Glucocorticoids and NF-κB Signaling in Neuroinflammation- Implicating Glucocorticoid Induced Leucine Zipper as a Molecular Link.

Inflammation including neuroinflammation is considered a protective response and is directed to repair, regenerate, and restore damaged tissues in the central nervous system. Persistent inflammation due to chronic stress, age related accrual of free radicals, subclinical infections or other factors lead to reduced survival and increased neuronal death. Circadian abnormalities secondary to altered sleep/wake cycles is one of the earliest signs of neurodegenerative diseases.

Bisperoxovanadium promotes motor neuron survival and neuromuscular innervation in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease, with no present cure. The progressive loss of MNs is the hallmark of ALS. We have previously shown the therapeutic effects of the phosphatase and tensin homolog (PTEN) inhibitor, potassium bisperoxo (picolinato) vanadium (bpV[pic]), in models of neurological injury and demonstrated significant neuroprotective effects on MN survival.

Facial nerve repair utilizing intraoperative repair strategies.

Objectives: To determine whether functional and anatomical outcomes following suture neurorrhaphy are improved by the addition of electrical stimulation with or without the addition of polyethylene glycol (PEG).

Methods: In a rat model of facial nerve injury, complete facial nerve transection and repair was performed via (a) suture neurorrhaphy alone, (b) neurorrhaphy with the addition of brief (30 minutes) intraoperative electrical stimulation, or (c) neurorrhaphy with the addition electrical stimulation and PEG. Functional recovery was assessed weekly for 16 weeks.

Inactive USP14 and inactive UCHL5 cause accumulation of distinct ubiquitinated proteins in mammalian cells.

USP14 is a cysteine protease deubiquitinase associated with the proteasome and plays important catalytic and allosteric roles in proteasomal degradation. USP14 inhibition has been considered a therapeutic strategy for accelerating degradation of aggregation-prone proteins in neurodegenerative diseases and for inhibiting proteasome function to induce apoptotic cell death in cancers. Here we studied the effects of USP14 inhibition in mammalian cells using small molecule inhibitors and an inactive USP14 mutant C114A.

Systemic Dental Pulp Stem Cell Secretome Therapy in a Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron (MN) disease with no cure. Accumulating evidence indicates ALS involves a complex interaction between central glia and the peripheral immune response and neuromuscular interface. Stem cell secretomes contain various beneficial trophic factors and cytokines, and we recently demonstrated that administration of the secretome of adipose-derived stem cells (ASCs) during early neuromuscular junction (NMJ) denervation in the mutant superoxide dismutase (mSOD1) ALS mouse ameliorated NMJ disruption.

Carboxyl-terminal modulator protein regulates Akt signaling during skeletal muscle atrophy in vitro and a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease involving motor neuron death, paralysis and, ultimately, respiratory failure. Motor neuron dysfunction leads to target skeletal muscle atrophy involving dysregulation of downstream cell survival, growth and metabolic signaling. Decreased Akt activity is linked to muscle atrophy in ALS and is associated with increased atrophy gene expression.

Bisperoxovanadium Mediates Neuronal Protection through Inhibition of PTEN and Activation of PI3K/AKT-mTOR Signaling after Traumatic Spinal Injuries.

Although mechanisms involved in progression of cell death in spinal cord injury (SCI) have been studied extensively, few are clear targets for translation to clinical application. One of the best-understood mechanisms of cell survival in SCI is phosphatidylinositol-3-kinase (PI3K)/Akt and associated downstream signaling. Clear therapeutic efficacy of a phosphatase and tensin homologue (PTEN) inhibitor called bisperoxovanadium (bpV) has been shown in SCI, traumatic brain injury, stroke, and other neurological disease models in both neuroprotection and functional recovery.

Functional and Histological Gender Comparison of Age-Matched Rats after Moderate Thoracic Contusive Spinal Cord Injury.

Spinal cord injury (SCI) afflicts hundreds of thousands of Americans, and most SCI (∼80%) occurs in males. In experimental animal models, however, many studies used females. Funding agencies like the National Institutes of Health recommend that new proposed studies should include both genders due to variations in gender response to injuries, diseases, and treatments.

Adipose-derived stem cell conditioned medium impacts asymptomatic peripheral neuromuscular denervation in the mutant superoxide dismutase (G93A) transgenic mouse model of amyotrophic lateral sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is devastating, leading to paralysis and death. Disease onset begins pre-symptomatically through spinal motor neuron (MN) axon die-back from musculature at ∼47 days of age in the mutant superoxide dismutase 1 (mSOD1G93A) transgenic ALS mouse model. This period may be optimal to assess potential therapies.

Functional and Anatomical Outcomes of Facial Nerve Injury With Application of Polyethylene Glycol in a Rat Model.

Importance: Functional and anatomical outcomes after surgical repair of facial nerve injury may be improved with the addition of polyethylene glycol (PEG) to direct suture neurorrhaphy. The application of PEG has shown promise in treating spinal nerve injuries, but its efficacy has not been evaluated in treatment of cranial nerve injuries.

Objective: To determine whether PEG in addition to neurorrhaphy can improve functional outcomes and synkinesis after facial nerve injury.

Aβ triggers the generation of a retrograde signaling complex from sentinel mRNAs in axons.

Neurons frequently encounter neurodegenerative signals first in their periphery. For example, exposure of axons to oligomeric Aβ is sufficient to induce changes in the neuronal cell body that ultimately lead to degeneration. Currently, it is unclear how the information about the neurodegenerative insult is transmitted to the soma.

Temporospatial Analysis and New Players in the Immunology of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial forms that have evident similarities in clinical symptoms and disease progression. There is a tremendous amount of knowledge on molecular mechanisms leading to loss of MNs and neuromuscular junctions (NMJ) as major determinants of disease onset, severity and progression in ALS.

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA Activation.

Activation of RhoA/Rho kinase leads to growth cone collapse and neurite retraction. Although RhoA/Rho kinase inhibition has been shown to improve axon regeneration, remyelination and functional recovery, its role in neuronal cell death remains unclear. To determine whether RhoA/Rho kinase played a role in neuronal death after injury, we investigated the relationship between RhoA/Rho kinase and cytosolic phospholipase A (cPLA), a lipase that mediates inflammation and cell death, using an in vitro neuronal death model and an in vivo contusive spinal cord injury model performed at the 10th thoracic (T10) vertebral level.

Anatomical and functional effects of lateral cervical hemicontusion in adult rats.

Purpose: Cervical injuries are the most common form of spinal cord injury (SCI), and are often complicated by pathological secondary damage. Therefore, cervical SCI is of great clinical importance for understanding pathology and potential therapies. Here we utilize a weight drop cervical hemi-contusion injury model using a NYU/MASCIS impactor that produced graded anatomical and functional deficits.

CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease.

We have established a physiologically relevant mechanism of CD4+ T cell-mediated neuroprotection involving axotomized wildtype (WT) mouse facial motoneurons (FMN) with significance in the treatment of amyotrophic lateral sclerosis (ALS), a fatal MN disease. Use of the transgenic mouse model of ALS involving expression of human mutant superoxide dismutase genes (SOD1(G93A); abbreviated here as mSOD1) has accelerated basic ALS research. Superimposition of facial nerve axotomy (FNA) on the mSOD1 mouse during pre-symptomatic stages indicates that they behave like immunodeficient mice in terms of increased FMN loss and decreased functional recovery, through a mechanism that, paradoxically, is not inherent within the MN itself, but, instead, involves a defect in peripheral immune: CNS glial cell interactions.

A novel vertebral stabilization method for producing contusive spinal cord injury.

Clinically-relevant animal cervical spinal cord injury (SCI) models are essential for developing and testing potential therapies; however, producing reliable cervical SCI is difficult due to lack of satisfactory methods of vertebral stabilization. The conventional method to stabilize the spine is to suspend the rostral and caudal cervical spine via clamps attached to cervical spinous processes.  However, this method of stabilization fails to prevent tissue yielding during the contusion as the cervical spinal processes are too short to be effectively secured by the clamps (Figure 1).

Biphasic bisperoxovanadium administration and Schwann cell transplantation for repair after cervical contusive spinal cord injury.

Schwann cells (SCs) hold promise for spinal cord injury (SCI) repair; however, there are limitations for its use as a lone treatment. We showed that acute inhibition of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) by bisperoxovanadium (bpV) was neuroprotective and enhanced function following cervical hemicontusion SCI. We hypothesized that combining acute bpV therapy and delayed SC engraftment would further improve neuroprotection and recovery after cervical SCI.

Schwann cell transplantation and descending propriospinal regeneration after spinal cord injury.

After spinal cord injury (SCI), poor ability of damaged axons of the central nervous system (CNS) to regenerate causes very limited functional recovery. Schwann cells (SCs) have been widely explored as promising donors for transplantation to promote axonal regeneration in the CNS including the spinal cord. Compared with other CNS axonal pathways, injured propriospinal tracts display the strongest regenerative response to SC transplantation.

Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions.

In Alzheimer's disease (AD) brain, exposure of axons to Aβ causes pathogenic changes that spread retrogradely by unknown mechanisms, affecting the entire neuron. We found that locally applied Aβ1-42 initiates axonal synthesis of a defined set of proteins including the transcription factor ATF4. Inhibition of local translation and retrograde transport or knockdown of axonal Atf4 mRNA abolished Aβ-induced ATF4 transcriptional activity and cell loss.

A semicircular controlled cortical impact produces long-term motor and cognitive dysfunction that correlates well with damage to both the sensorimotor cortex and hippocampus.

Animal models of traumatic brain injury (TBI) are essential for testing novel hypotheses and therapeutic interventions. Unfortunately, due to the broad heterogeneity of TBI in humans, no single model has been able to reproduce the entire spectrum of these injuries. The controlled cortical impact (CCI) model is one of the most commonly used models of contusion TBI.

Surgical decompression in acute spinal cord injury: A review of clinical evidence, animal model studies, and potential future directions of investigation.

The goal for treatment in acute spinal cord injury (SCI) is to reduce the extent of secondary damage and facilitate neurologic regeneration and functional recovery. Although multiple studies have investigated potential new therapies for the treatment of acute SCI, outcomes and management protocols aimed at ameliorating neurologic injury in patients remain ineffective. More recent clinical and basic science research have shown surgical interventions to be a potentially valuable modality for treatment; however, the role and timing of surgical decompression, in addition to the optimal surgical intervention, remain one of the most controversial topics pertaining to surgical treatment of acute SCI.