Diana Samaroo

Celiac disease: From gluten to autoimmunity

Celiac disease, also known as gluten-sensitive enteropathy and nontropical sprue, is a prevalent autoimmune disorder that is triggered by the ingestion of wheat gluten and related proteins of rye and barley in genetically susceptible individuals. The immune response in celiac disease involves the adaptive, as well as the innate, and is characterized by the presence of anti-gluten and anti-transglutaminase 2 antibodies, lymphocytic infiltration in the epithelial membrane and the lamina propria, and expression of multiple cytokines and other signaling proteins. The disease leads to inflammation, villous atrophy, and crypt hyperplasia in the small intestine. In addition to the intestinal symptoms, celiac disease is associated with various extra-intestinal complications, including bone and skin disease, anemia, endocrine disorders, and neurologic deficits. Gluten-free diet is currently the only effective mode of treatment for celiac disease, but better understanding of the mechanism of the disease is likely to add other choices for therapy in the future.

Novel Immune Response to Gluten in Individuals with Schizophrenia

A link between celiac disease and schizophrenia has been postulated for several years, based primarily on reports of elevated levels of antibody to gliadin in patients. We sought to examine the proposed connection between schizophrenia and celiac disease by characterizing the molecular specificity and mechanism of the anti-gliadin immune response in a subset of individuals with schizophrenia. Blood samples from individuals with schizophrenia and elevated anti-gliadin antibody titer were examined for celiac disease-associated biomarkers, including antibodies to transglutaminase 2 (TG2) enzyme and deamidated gliadin peptides, as well as the HLA-DQ2 and -DQ8 MHC genes. The anti-gliadin antibody response was further characterized through examination of reactivity towards chromatographically separated gluten proteins. Target proteins of interest were identified by peptide mass mapping. In contrast to celiac disease patients, an association between the anti-gliadin immune response and anti-TG2 antibody or HLA-DQ2 and -DQ8 markers was not found in individuals with schizophrenia. In addition, the majority of individuals with schizophrenia and anti-gliadin antibody did not exhibit antibody reactivity to deamidated gliadin peptides. Further characterization of the antibody specificity revealed preferential reactivity towards different gluten proteins in the schizophrenia and celiac disease groups. These findings indicate that the anti-gliadin immune response in schizophrenia has a different antigenic specificity from that in celiac disease and is independent of the action of transglutaminase enzyme and HLA-DQ2/DQ8. Meanwhile, the presence of elevated levels of antibodies to specific gluten proteins points to shared immunologic abnormalities in a subset of schizophrenia patients. Further characterization and understanding of the immune response to gluten in schizophrenia may provide novel insights into the etiopathogenesis of specific disease phenotypes.

A covalently linked phenanthridine–ruthenium(II) complex as a RNA probe

A phenanthridine derivative covalently linked to a ruthenium complex yields an imaging probe whose fluorescence intensity and lifetime change substantially in the presence of RNA.

Synthesis and photophysical properties of thioglycosylated chlorins, isobacteriochlorins, and bacteriochlorins for bioimaging and diagnostics.

The facile synthesis and photophysical properties of three nonhydrolyzable thioglycosylated porphyrinoids are reported. Starting from meso-perfluorophenylporphyrin, the nonhydrolyzable thioglycosylated porphyrin (PGlc₄), chlorin (CGlc₄), isobacteriochlorin (IGlc₄), and bacteriochlorin (BGlc₄) can be made in 2-3 steps. The ability to append a wide range of targeting agents onto the perfluorophenyl moieties, the chemical stability, and the ability to fine-tune the photophysical properties of the chromophores make this a suitable platform for development of biochemical tags, diagnostics, or as photodynamic therapeutic agents. Compared to the porphyrin in phosphate buffered saline, CGlc₄ has a markedly greater absorbance of red light near 650 nm and a 6-fold increase in fluorescence quantum yield, whereas IGlc₄ has broad Q-bands and a 12-fold increase in fluorescence quantum yield. BGlc₄ has a similar fluorescence quantum yield to PGlc₄ (<10%), but the lowest-energy absorption/emission peaks of BGlc₄ are considerably red-shifted to near 730 nm with a nearly 50-fold greater absorbance, which may allow this conjugate to be an effective PDT agent. The uptake of CGlc₄, IGlc₄, and BGlc₄ derivatives into cells such as human breast cancer cells MDA-MB-231 and K:Molv NIH 3T3 mouse fibroblast cells can be observed at nanomolar concentrations. Photobleaching under these conditions is minimal.

Strategies for delivering porphyrinoid-based photosensitizers in therapeutic applications

Delivery strategies for porphyrinoid-based photosensitizers for use in therapeutic applications are based on a myriad of factors, which include porphyrinoid structure, solubility and cellular targets. These drug-delivery methods include encapsulation, hydrogels, protein carriers, nanoparticles and polymeric micelles among others. This article reviews the strategies for delivering porphyrinoids published to date and will focus on porphyrins, corroles, chlorins, bacteriochlorins, porphyrazines and phthalocyanines. Highlighted are the most recent and different strategies used for each of the corresponding porphyrinoid-based macrocycles.

Responsive porphyrinoid nanoparticles: development and applications

The economy of space and materials and the continuously increasing demand for advanced functionalities for diverse technologies requires the development of new synthetic methods. Many nanomaterials have enhanced photophysical and photochemical properties in solutions and/or on surfaces, while others have enhanced chemical properties, compared to the atomic, molecular, or bulk phases. Nanomaterials have a wide range of applications in catalysis, sensors, photonic devices, drug delivery, and as therapeutics for treatment of a variety of diseases. Inorganic nanoparticles are widely studied, but the formation of organic nanomaterials via supramolecular chemistry is more recent, and porphyrinoids are at the forefront of this research because of their optical, chemical, and structural properties. The formation of nanoscaled materials via self-assembly and/or self-organization of molecular subunits is an attractive approach because of reduced energy requirements, simpler molecular subunits, and the material can be adaptive to environmental changes. The presence of biocompatible groups such as peptides, carbohydrates, polyglycols and mixtures of these on the periphery of the porphyrin macrocycle may make nanoparticles suitable for therapeutics. This perspective focuses on responsive, non-crystalline porphyrinoid nanomaterials that are less than about 100 nm in all dimensions and used for catalytic or therapeutic applications.

Nonlinear optical switching properties of dye-doped inorganic/organic nanocomposite films

The sol–gel method has been employed in the fabrication of composite films consisting of nanometer size self-assembled organic mesostructures surrounded by a silica framework. The hydrophobic domains within the mesostructures make these films an excellent host matrix for the donor/acceptor energy transfer complexes. Time-resolved fluorescence and transient absorption studies revealed that these complexes exhibit ultrafast nonlinear optical responses as a result of the energy transfer process. The optical properties of these composite films may make them suitable for use as the photonic film in future all-optical switching devices.

New porphyrin glyco-conjugates

Porphyrins bearing sugars and other motifs are proposed for a variety of therapeutic applications. Non-hydrolysable glyco conjugates of porphyrins can be formed in rapid, room temperature reacting in greater than 90% yields from tetraperfluorophenyporphyrin. Additional functional groups can be appended using the same chemistry but different stoichiometries of the reagents. Thus sugars, amines, peptides, and cationic moieties designed to target cancer cells or other diseased or disease-causing cells are made rapidly and cleanly. These compounds can then be rapidly screened for cell uptake, or selected from combinatorial libraries by cell uptake assays using a combination of fluorescence microscopy and mass spectrometry. Modifications of the macrocycle allow fine-tuning of the photonic properties for specific medical, imaging, or biochemical applications.