Bile salt biotransformations by human intestinal bacteria.

There have been many advances in our knowledge about different aspects of P2Y receptor signaling since the last review published by our International Union of Pharmacology subcommittee. More receptor subtypes have been cloned and characterized and most orphan receptors deorphanized, so that it is now possible to provide a basis for a future subdivision of P2Y receptor subtypes. More is known about the functional elements of the P2Y receptor molecules and the signaling pathways involved, including interactions with ion channels. There have been substantial developments in the design of selective agonists and antagonists to some of the P2Y receptor subtypes. There are new findings about the mechanisms underlying nucleotide release and ectoenzymatic nucleotide breakdown. Interactions between P2Y receptors and receptors to other signaling molecules have been explored as well as P2Y-mediated control of gene transcription. The distribution and roles of P2Y receptor subtypes in many different cell types are better understood and P2Y receptor-related compounds are being explored for therapeutic purposes. These and other advances are discussed in the present review.

https://pharmrev.aspetjournals.org/content/pharmrev/58/3/281.full.pdf

International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy

https://www.gastrojournal.org/article/0016-5085(95)90267-8/pdf

Altered Rectal Perception Is a Biological Marker of Patients With Irritable Bowel Syndrome

Cholera caused by toxigenic Vibrio cholerae is a major public health problem confronting developing countries, where outbreaks occur in a regular seasonal pattern and are particularly associated with poverty and poor sanitation. The disease is characterized by a devastating watery diarrhea which leads to rapid dehydration, and death occurs in 50 to 70% of untreated patients. Cholera is a waterborne disease, and the importance of water ecology is suggested by the close association of V. cholerae with surface water and the population interacting with the water. Cholera toxin (CT), which is responsible for the profuse diarrhea, is encoded by a lysogenic bacteriophage designated CTXΦ. Although the mechanism by which CT causes diarrhea is known, it is not clear why V. cholerae should infect and elaborate the lethal toxin in the host. Molecular epidemiological surveillance has revealed clonal diversity among toxigenic V. cholerae strains and a continual emergence of new epidemic clones. In view of lysogenic conversion by CTXΦ as a possible mechanism of origination of new toxigenic clones of V. cholerae, it appears that the continual emergence of new toxigenic strains and their selective enrichment during cholera outbreaks constitute an essential component of the natural ecosystem for the evolution of epidemic V. cholerae strains and genetic elements that mediate the transfer of virulence genes. The ecosystem comprising V. cholerae, CTXΦ, the aquatic environment, and the mammalian host offers an understanding of the complex relationship between pathogenesis and the natural selection of a pathogen.

Epidemiology, Genetics, and Ecology of Toxigenic Vibrio cholerae

Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the cell and mitochondrial membrane potentials, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this Review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes, and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

/pdf/mitochondria-targeted-triphenylphosphonium-based-compounds-4xqo2evab5.pdf

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

In ‘leaky‘ epithelia, ions move through both a transcellular and a paracellular (serial alignment of tight junction and intercellular space) path. The efficiency of transepithelial transport could therefore be regulated if the cell was able to alter reversibly the permeability of tight junctions. (These are specialized regions of the apical cell membranes common to all epithelia.) We now report that such a mechanism indeed exists in the Necturus gallbladder. It is effected by cyclic AMP, which is already known to mediate surface membrane phenomena in a variety of cell systems through its interaction with the cytoskeletal system1,2. In gallbladders mounted and perfused with electrolyte solutions in an Ussing-type chamber, exposure of the mucosal surface to cyclic AMP analogues increased transepithelial electrical resistance, potential difference and short-circuit current and decreased NaCl dilution potentials in a rapid and reversible manner. We also observed rapid depolarization of cell membrane electrical potentials and a slow decline in intracellular K+ activity. Freeze-fracture electron microscopy of tissues fixed with glutaraldehyde during the peak electrical response showed a reorientation of intramembranous junctional fibrils, suggesting that cyclic AMP reduces the ionic permeability of the paracellular pathway in this epithelium by altering the structure of tight junctions.

Regulation of epithelial tight junction permeability by cyclic AMP.

To explore the role of Ca2+ in tight-junction permeability, the Necturus gallbladder was exposed to varying Ca2+ concentrations and to the Ca2+ ionophore A23187 added to the mucosal side (1.9 X 10(-6) to 6.8 X 10(-5) M). Electrophysiological parameters measured in an Ussing-type chamber were correlated with tight-junction morphology revealed by freeze-fracture electron microscopy. In Ca2+-free bathing media, transepithelial resistance decreases and tight-junctional ultrastructure is fragmented. In 1.8 mM Ca2+ media, A23187 induces an initial drop in transepithelial resistance, followed by an increase in transepithelial resistance to a value 20% above base line. At peak response to A23187, NaCl diffusion potentials decrease. Freeze-fracture replicas reveal that the number of junctional strands increase pari passu with junctional depth. Both physiological and morphological changes were partially reversible. The initial decrease in transepithelial resistance coincided with a persistent hyperpolarization of the mucosal cell membrane potential difference and a decrease in the mucosal-to-serosal cell membrane resistance ratio. Thus A23187 alters both the transcellular and paracellular pathway, resulting in opposing effects on transepithelial resistance.

Ca2+ regulation of tight-junction permeability and structure in Necturus gallbladder

cordingly, almost h~lf the text is devoted to inherited neuropathies. The authors state that they prefer to express an opinion rather than to equivocate, and in difficult areas, such as the classification of hereditary neuropathies, their views are clearly expressed without being dogmatic. In the -chapters on inherited and inflammatory-demyelinating neuropathies, the authors convey that they have grappled with problems of diagnosis and management numerous times. This acknowledgment is complemented with liberal use of illustrative case histories, which bring the text to life. Of particular interest, specific details of the authors' approaches to treating the inflammatory-demyelinating neuropathies are provided. The chapters that address neuropathies associated with systemic diseases and toxins are less informative. The difficulty partially arises from mechanically discussing the effects of a list of toxins or systemic illnesses, which is unavoidable, yet at times, the focus on pediatric aspects ofthese conditions seems lost. For example, four pages and several illustrations are devoted to a review of amyloidosis, a condition that the authors acknowledge does not occur in childhood. Some readers may think that the introductory chapters on the pathophysiologic features and investigation of neuropathy are basic. Nevertheless, these chapters containsome useful tables ofdifferential diagnosis and a helpful summary ofpublished normal values for nerve conduction studies in infants and children. The book is well produced. Illustrations are abundant, and the light and electron micrographs are ofhigh quality and have been clearly reproduced. One annoying aspect is the bibliographic citations at the end ofeach chapter that omit the titles ofarticles. Overall, despite some deficiencies, this book is concise; it effectively displays the authors' experienced perspectives on the subject and combines the scattered literature. It will be a useful addition to the libraries of neurologists and pediatricians.

https://www.mayoclinicproceedings.org/article/S0025-6196(12)61211-7/pdf

Textbook of Secretory Diarrhea

Intracellular chloride activities, (Cl)c, in rabbit gallbladder were determined by using conventional (KCl-filled) microelectrodes and Cl-selective, liquid ionexchanger, microelectrodes. The results indicate that in the presence of a normal Ringer's solution, (Cl)c averages 35 mM; this value is 2.3 times that predicted for an equilibrium distribution across the mucosal and baso-lateral membranes. On the other hand, when the tissue is bathed by Na-free solutions, (Cl)c declines to a value that does not differ significantly from that predicted for an equilibrium distribution.

Intracellular chloride activities in rabbit gallbladder: direct evidence for the role of the sodium-gradient in energizing "uphill" chloride transport.

Sjogren's syndrome is a chronic autoimmune disorder characterized by inflammation of salivary glands resulting in impaired secretory function. Our present studies indicate that chronic exposure of salivary epithelium to TNF-α and/or IFN-γ alters tight junction integrity, leading to secretory dysfunction. Resolvins of the D-series (RvDs) are endogenous lipid mediators derived from DHA that regulate excessive inflammatory responses leading to resolution and tissue homeostasis. In this study, we addressed the hypothesis that activation of the RvD1 receptor ALX/FPR2 in salivary epithelium prevents and/or resolves the TNF-α-mediated disruption of acinar organization and enhances monolayer formation. Our results indicate that 1) the RvD1 receptor ALX/FPR2 is present in fresh, isolated cells from mouse salivary glands and in cell lines of salivary origin; and 2) the agonist RvD1 (100 ng/ml) abolished tight junction and cytoskeletal disruption caused by TNF-α and enhanced cell migration and polarity in salivary epithelium. These effects were blocked by the ALX/FPR2 antagonist butyloxycarbonyl-Phe-Leu-Phe-Leu-Phe. The ALX/FPR2 receptor signals via modulation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways since, in our study, blocking PI3K activation with LY294002, a potent and selective PI3K inhibitor, prevented RvD1-induced cell migration. Furthermore, Akt gene silencing with the corresponding siRNA almost completely blocked the ability of Par-C10 cells to migrate. Our findings suggest that RvD1 receptor activation promotes resolution of inflammation and tissue repair in salivary epithelium, which may have relevance in the restoration of salivary gland dysfunction associated with Sjogren's syndrome.

https://www.physiology.org/doi/pdf/10.1152/ajpcell.00207.2011

Michael E. Duffey

Papers

Regulation of epithelial tight junction permeability by cyclic AMP.

Ca2+ regulation of tight-junction permeability and structure in Necturus gallbladder

Textbook of Secretory Diarrhea

Intracellular chloride activities in rabbit gallbladder: direct evidence for the role of the sodium-gradient in energizing "uphill" chloride transport.

Resolvin D1 prevents TNF-α-mediated disruption of salivary epithelial formation.