Inhibition of dipeptidyl peptidase IV (DPP-IV) activity by NVP-DPP728, a DPP-IV inhibitor, improves the therapeutic efficacy of glucagon-like peptide-1 (GLP-1). CD26 is a membrane-associated glycoprotein with DPP-IV activity and is expressed on lymphocytes. We investigated the effect of NVP-DPP728 on reversing new-onset diabetes in nonobese diabetic (NOD) mice and modulating the inflammatory response and stimulating -cell regeneration. New-onset diabetic NOD mice were treated with NVP-DPP728 for 2, 4, and 6 wk. Blood glucose level was monitored. Regulatory T cells in thymus and secondary lymph nodes, TGF-1 and GLP-1 in plasma, and the insulin content in the pancreas were measured. Immunostaining for insulin and bromodeoxyuridine (BrdU) were performed. The correlation of -cell replication with inflammation was determined. In NVP-DPP728-treated NOD mice, diabetes could be reversed in 57, 74, and 73% of mice after 2, 4, and 6 wk treatment, respectively. Insulitis was reduced and the percentage of CD4 ϩ CD25 ϩ FoxP3 ϩ regulatory T cells was increased in treated NOD mice with remission. Plasma TGF-1 and GLP-1, the insulin content, and both insulin ϩ and BrdU ϩ -cells in pancreas were also significantly increased. No significant correlations were found between numbers of both insulin ϩ and BrdU ϩ -cells in islets and -cell area or islets with different insulitis score in NOD mice with remission of diabetes. In conclusion, NVP-DPP728 treatment can reverse new-onset diabetes in NOD mice by reducing insulitis, increasing CD4 ϩ CD25 ϩ FoxP3 ϩ regulatory T cells, and stimulating -cell replication. -Cell replication is not associated with the degree of inflammation in NVP-DPP728-treated NOD mice. A Small Molecule Inverse Agonist for the Human Thyroid-Stimulating Hormone ReceptorSusanne Neumann, Wenwei Huang, Elena Eliseeva, Steve Titus, Craig J. Thomas, and Marvin C. Gershengorn ABSTRACTSmall molecule inverse agonists for the TSH receptor (TSHR) may be used as probes of the role of basal (or agonist-independent or constitutive) signaling and may have therapeutic potential as orally active drugs to inhibit basal signaling in patients with thyroid cancer and in some patients with hyperthyroidism. We describe the first small-molecule ligand [1, 2-(3-((2,6-dimethylphenoxy)methyl)-4-methoxyphenyl)-3-(furan-2-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one] that exhibits inverse agonist properties at TSHR. 1 inhibits basal and TSH-stimulated signaling, measured as cAMP production, by TSHRs in HEK-EM 293 cells stably expressing wild-type TSHRs; the antagonism of TSH-mediated signaling is competitive. 1 also inhibits basal signaling by wild-type TSHRs, and four constitutively active mutants of TSHR expressed transiently in HEK-EM 293 cells. 1 was active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs where it inhibited basal levels of mRNA transcripts for thyroglobulin, thyroperoxidase, sodium iodide symporter, and TSHR. These data serve as proof of prin...
The possibility of using the apiproducts of the larval origin from the drone larvae in the production of functional foodstuff, such as bakery, confectionery and honey products enriched with high-grade protein, biologically active high-functional substances and complexes that gave them therapeutic and prophylactic, and immune-modulating properties is substantiated in the paper. The recipes for the functional foodstuffs, such as the “Bilar-api” bread, “Pchelka” api-dragee, “Bilar” api-honney, “Bilar” api-honney with bee glue (propolis), enriched with apiproduct from the drone larvae have been developed. To impart an immune-modulating and functional effect to the products, the “Bilar” api-product with a high content of SH-groups, decenoic acids, vitamins, as well as flower pollen, honey, and bee glue in the form of a water-alcohol extract have been used. Preference for these substances has been given because phenolic compounds with P-vitamin activity, unsaturated compounds of isoprene nature, have antioxidant, and fungicidal impacts. They are manifested in their ability to protect the body from the destructive effect of various damaging factors (ionizing radiation, free oxidation radicals, reactive oxygen species, etc.). The “Bilar” powder has a major content of high-grade protein (50-51%), which contains all essential amino acids, and on lysine, tryptophan and histidine exceeds the level of ideal protein on the FAO/WHO scale by almost two times, on the fatty acid composition practically corresponds to the formula of balanced nutrition, vitamins, and decenoic acids (7.9%), as well as sulfhydryl compounds (1160.1 mg/%). Decenoic acid has pronounced antibiotic properties and antitumor effect, exerting an inhibitory effect on the malignant tumors. New functional food products were manufactured on the basis of traditional production technologies using sparing technological regimes and with utilization of apiproducts (the “Bilar” powder, pollen, etc.). Based on the results of the comprehensive study, the increase in the quality and quantity indicators of functional foodstuffs in comparison with control, the increase in biological and nutritional value, as well as improved organoleptic and physics and chemical parameters have been established.
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