Samuel A. Molina

Bio: Samuel A. Molina is an academic researcher from Emory University. The author has contributed to research in topics: Cystic fibrosis & Cellular differentiation. The author has an hindex of 10, co-authored 18 publications receiving 439 citations. Previous affiliations of Samuel A. Molina include Kansas State University.

Regulation of claudin/zonula occludens-1 complexes by hetero-claudin interactions

Abstract: Claudins are tetraspan transmembrane tight-junction proteins that regulate epithelial barriers. In the distal airspaces of the lung, alveolar epithelial tight junctions are crucial to regulate airspace fluid. Chronic alcohol abuse weakens alveolar tight junctions, priming the lung for acute respiratory distress syndrome, a frequently lethal condition caused by airspace flooding. Here we demonstrate that in response to alcohol, increased claudin-5 paradoxically accompanies an increase in paracellular leak and rearrangement of alveolar tight junctions. Claudin-5 is necessary and sufficient to diminish alveolar epithelial barrier function by impairing the ability of claudin-18 to interact with a scaffold protein, zonula occludens 1 (ZO-1), demonstrating that one claudin affects the ability of another claudin to interact with the tight-junction scaffold. Critically, a claudin-5 peptide mimetic reverses the deleterious effects of alcohol on alveolar barrier function. Thus, claudin controlled claudin-scaffold protein interactions are a novel target to regulate tight-junction permeability.

Junctional abnormalities in human airway epithelial cells expressing F508del CFTR

Abstract: Cystic fibrosis (CF) has a profound impact on airway physiology. Accumulating evidence suggests that intercellular junctions are impaired in CF. We examined changes to CF transmembrane conductance ...

Insulin signaling via the PI3-kinase/Akt pathway regulates airway glucose uptake and barrier function in a CFTR-dependent manner

Abstract: Cystic fibrosis-related diabetes is the most common comorbidity associated with cystic fibrosis (CF) and correlates with increased rates of lung function decline. Because glucose is a nutrient present in the airways of patients with bacterial airway infections and because insulin controls glucose metabolism, the effect of insulin on CF airway epithelia was investigated to determine the role of insulin receptors and glucose transport in regulating glucose availability in the airway. The response to insulin by human airway epithelial cells was characterized by quantitative PCR, immunoblot, immunofluorescence, and glucose uptake assays. Phosphatidylinositol 3-kinase/protein kinase B (Akt) signaling and cystic fibrosis transmembrane conductance regulator (CFTR) activity were analyzed by pharmacological and immunoblot assays. We found that normal human primary airway epithelial cells expressed glucose transporter 4 and that application of insulin stimulated cytochalasin B-inhibitable glucose uptake, consistent with a requirement for glucose transporter translocation. Application of insulin to normal primary human airway epithelial cells promoted airway barrier function as demonstrated by increased transepithelial electrical resistance and decreased paracellular flux of small molecules. This provides the first demonstration that airway cells express insulin-regulated glucose transporters that act in concert with tight junctions to form an airway glucose barrier. However, insulin failed to increase glucose uptake or decrease paracellular flux of small molecules in human airway epithelia expressing F508del-CFTR. Insulin stimulation of Akt1 and Akt2 signaling in CF airway cells was diminished compared with that observed in airway cells expressing wild-type CFTR. These results indicate that the airway glucose barrier is regulated by insulin and is dysfunctional in CF.

Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease

Abstract: Mucosal surfaces are lined by epithelial cells In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste secretion while preventing intrusion by luminal materials Intestinal epithelia therefore play a central role in regulating interactions between the mucosal immune system and luminal contents, which include dietary antigens, a diverse intestinal microbiome, and pathogens The paracellular space is sealed by the tight junction, which is maintained by a complex network of protein interactions Tight junction dysfunction has been linked to a variety of local and systemic diseases Two molecularly and biophysically distinct pathways across the intestinal tight junction are selectively and differentially regulated by inflammatory stimuli This review discusses the mechanisms underlying these events, their impact on disease, and the potential of using these as paradigms for development of tight junction-targeted therapeutic interventions

Materials for oral delivery of proteins and peptides

Abstract: Throughout history, oral administration has been regarded as the most convenient mode of drug delivery, as it requires minimal expertise and invasiveness. Although oral delivery works well for small-molecule drugs, oral delivery of macromolecules (particularly proteins and peptides) has been limited by acidic conditions in the stomach and low permeability across the intestinal epithelium. Accordingly, the large numbers of biologic drugs that have become available in the past 10 years typically require administration by injection or infusion. As such, a renewed emphasis has been placed on the development of novel materials that overcome the physiological challenges of oral delivery for macromolecular agents. This Review provides an overview of physiological barriers to the oral delivery of biologics and highlights the advances made in materials across various length scales, from small molecules to macroscopic devices. This Review also describes the current status of materials for oral delivery of protein and peptide drugs. New materials, beyond those that have already obtained regulatory approval, are needed to improve the bioavailability of orally administered proteins. In this Review, barriers to the oral delivery of protein-based therapies are discussed, along with the current translational landscape and state of the art of materials for oral protein delivery.

Pseudomonas aeruginosa Biofilms: Host Response and Clinical Implications in Lung Infections.

Abstract: Pseudomonas aeruginosa is a major health challenge that causes recalcitrant multidrug-resistant infections, especially in immunocompromised and hospitalized patients P aeruginosa is an important cause of nosocomial and ventilator-associated pneumonia characterized by high prevalence and fatality rates P aeruginosa also causes chronic lung infections in individuals with cystic fibrosis Multidrug- and totally drug-resistant strains of P aeruginosa are increasing threats that contribute to high mortality in these patients The pathogenesis of many P aeruginosa infections depends on its ability to form biofilms, structured bacterial communities that can coat mucosal surfaces or invasive devices These biofilms make conditions more favorable for bacterial persistence, as embedded bacteria are inherently more difficult to eradicate than planktonic bacteria The molecular mechanisms that underlie P aeruginosa biofilm pathogenesis and the host response to P aeruginosa biofilms remain to be fully defined However, it is known that biofilms offer protection from the host immune response and are also extremely recalcitrant to antimicrobial therapy Therefore, development of novel therapeutic strategies specifically aimed at biofilms is urgently needed Here, we review the host response, key clinical implications of P aeruginosa biofilms, and novel therapeutic approaches to treat biofilms relevant to lung infections Greater understanding of P aeruginosa biofilms will elucidate novel avenues to improve outcomes for P aeruginosa pulmonary infections

Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications

Abstract: Connexins are ubiquitous channel forming proteins that assemble as plasma membrane hemichannels and as intercellular gap junction channels that directly connect cells. In the heart, gap junction channels electrically connect myocytes and specialized conductive tissues to coordinate the atrial and ventricular contraction/relaxation cycles and pump function. In blood vessels, these channels facilitate long-distance endothelial cell communication, synchronize smooth muscle cell contraction, and support endothelial-smooth muscle cell communication. In the central nervous system they form cellular syncytia and coordinate neural function. Gap junction channels are normally open and hemichannels are normally closed, but pathologic conditions may restrict gap junction communication and promote hemichannel opening, thereby disturbing a delicate cellular communication balance. Until recently, most connexin-targeting agents exhibited little specificity and several off-target effects. Recent work with peptide-based approaches has demonstrated improved specificity and opened avenues for a more rational approach toward independently modulating the function of gap junctions and hemichannels. We here review the role of connexins and their channels in cardiovascular and neurovascular health and disease, focusing on crucial regulatory aspects and identification of potential targets to modify their function. We conclude that peptide-based investigations have raised several new opportunities for interfering with connexins and their channels that may soon allow preservation of gap junction communication, inhibition of hemichannel opening, and mitigation of inflammatory signaling.

Structure, Function, and Regulation of the Blood-Brain Barrier Tight Junction in Central Nervous System Disorders.

Abstract: The blood-brain barrier (BBB) allows the brain to selectively import nutrients and energy critical to neuronal function while simultaneously excluding neurotoxic substances from the peripheral circulation. In contrast to the highly permeable vasculature present in most organs that reside outside of the central nervous system (CNS), the BBB exhibits a high transendothelial electrical resistance (TEER) along with a low rate of transcytosis and greatly restricted paracellular permeability. The property of low paracellular permeability is controlled by tight junction (TJ) protein complexes that seal the paracellular route between apposing brain microvascular endothelial cells. Although tight junction protein complexes are principal contributors to physical barrier properties, they are not static in nature. Rather, tight junction protein complexes are highly dynamic structures, where expression and/or localization of individual constituent proteins can be modified in response to pathophysiological stressors. These stressors induce modifications to tight junction protein complexes that involve de novo synthesis of new protein or discrete trafficking mechanisms. Such responsiveness of BBB tight junctions to diseases indicates that these protein complexes are critical for maintenance of CNS homeostasis. In fulfillment of this vital role, BBB tight junctions are also a major obstacle to therapeutic drug delivery to the brain. There is an opportunity to overcome this substantial obstacle and optimize neuropharmacology via acquisition of a detailed understanding of BBB tight junction structure, function, and regulation. In this review, we discuss physiological characteristics of tight junction protein complexes and how these properties regulate delivery of therapeutics to the CNS for treatment of neurological diseases. Specifically, we will discuss modulation of tight junction structure, function, and regulation both in the context of disease states and in the setting of pharmacotherapy. In particular, we will highlight how these properties can be potentially manipulated at the molecular level to increase CNS drug levels via paracellular transport to the brain.