Identification of advanced glycation end products in the gingiva, gingival crevicular fluid, and serum of diabetic patients and non-diabetic patients with or without periodontitis: a pilot-study

开始日期2021-12-01

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Department of Biochemistry

100 项与 Department of Biochemistry 相关的临床结果

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0 项与 Department of Biochemistry 相关的专利（医药）

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3,635

项与 Department of Biochemistry 相关的文献（医药）

2025-04-16·Bioconjugate Chemistry

Choice of an Optimal Modular Strategy for the Synthesis of DOTA-Containing Heterobivalent Agents Targeting PSMA and GRPr

Article

作者: Plotnikov, Evgenii ; Varvashenya, Ruslan ; Bodenko, Vitalina ; Prach, Anastasia ; Grishin, Yuri K. ; Zyk, Nikolay Y. ; Petrova, Juliana V. ; Machulkin, Aleksei E. ; Beloglazkina, Maria A. ; Petrov, Stanislav A. ; Yusubov, Mekhman S. ; Grigoriev, Gleb P. ; Beloglazkina, Elena K. ; Orlov, Grigory A. ; Larkina, Mariia S. ; Roznyatovsky, Vitaly A.

Heterodimeric approaches have emerged as a promising method for simultaneously targeting multiple receptors on tumor cells using a single molecule. Simultaneous targeting of the prostate-specific membrane antigen (PSMA) and the gastrin-releasing peptide receptor (GRPr) holds the potential to improve the accuracy of prostate cancer diagnosis. The aim of this study was to develop a convenient and simple modular strategy for the creation of heterobivalent (HBV) conjugates targeting PSMA/GRPr receptors. For this purpose, we developed and compared six alternative routes for the stereoselective synthesis of HBV conjugates designed to deliver the chelating agent DOTA to PSMA/GRPr receptors. The comparison of these alternative synthetic pathways took into account such factors as efficiency, complexity, synthesis, and purification details, as well as yields of the target compounds. Optimal conditions for the stereoselective synthesis of HBV ligands to PSMA and GRPr, which could serve as molecular platforms for the targeted delivery of therapeutic or diagnostic agents to these receptors, were revealed. For synthesized HBV ligand 26^x and its HBV conjugate with DOTA 27, the complete signal assignment in ¹H, ¹³C, and ¹⁵N NMR spectra was achieved using 2D NMR techniques. Based on these data, comprehensive signal assignments were provided for all final compounds in their NMR spectra. The final HBV conjugate 27 was labeled with Lu-177, with yields >99%, and the obtained radiotracer was studied in vitro for its binding specificity, with determining of the K_D and B_max using LNCaP (PSMA+) and PC-3 (GRPr+) cell lines.

2025-04-16·Bioconjugate Chemistry

Targeted Polymersomes Enable Enhanced Delivery to Peripheral Nerves Post-Injury

Article

作者: Twiss, Jeffery L. ; Montgomery, Dru ; Trumbull, Kayleigh ; Arnold, Noah ; Myers, Olivia ; Larsen, Jessica ; Fetten, Sophia ; Marahrens, Vanessa

The gold standard therapy for peripheral nerve injuries involves surgical repair, which is invasive and leads to major variations in therapeutic outcomes. Because of this, smaller injuries often go untreated. However, alternative, noninvasive routes of administration are currently unviable due to the presence of the blood-nerve barrier (BNB), which prevents passage of small molecules from the blood into the endoneurium and the nerve. This paper demonstrates that ligands on the surface of nanoparticles, called polymersomes, can enable delivery to the nerve through noninvasive intramuscular injections. Polymersomes made from polyethylene glycol (PEG)-b-polylactic acid (PLA) were conjugated with either apolipoprotein E (ApoE) or rabies virus glycoprotein-based peptide RVG29 (RVG) and loaded with near-infrared dye, AlexaFluor647. ApoE was used to target receptors upregulated in post-injury inflammation, while RVG targets neural-specific receptors. Untagged, ApoE-tagged, and RVG-tagged polymersomes were injected at 100 mM either intranerve (IN) or intramuscular (IM) into Sprague-Dawley rats post sciatic nerve injury. The addition of the ApoE and RVG tags enabled increased AlexaFluor647 fluorescence in the injury site at 1 h post IN injection compared to the untagged polymersome control. However, only the RVG-tagged polymersomes increased the AlexaFluor647 fluorescence after IM injection. Ex vivo analysis of sciatic nerves demonstrated that ApoE-tagged polymersomes enabled the greatest retention of AlexaFluor647 regardless of the injection route. This led us to conclude that using ApoE to target inflammation enabled the greatest retention of polymersome-delivered payloads while using RVG to target neural cells more specifically enabled the penetration of polymersome-delivered payloads. Observations were confirmed by calculating the area under the curve pharmacokinetic parameters and the use of a two-compartment pharmacokinetic model.

2025-04-15·Biochemistry

Interaction of CFTR Modulators with Mammalian Membrane Mimetics: The Role of Cholesterol

Article

作者: Ditlev, Jonathon A. ; Hoveyda, Sahar ; Deber, Charles M. ; Ravamehr-Lake, Dorna ; Schlierf, Michael

Lumacaftor and Ivacaftor are two FDA-approved medications currently used to treat cystic fibrosis (CF), a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel located in epithelial cell membranes; however, the detailed mechanism(s) of their action remains to be elucidated. Both drugs, termed modulators, bind CFTR at a protein-lipid interface, yet Lumacaftor acts at the endoplasmic reticulum (ER), while Ivacaftor acts at the plasma membrane (PM). A major difference among biological membranes is their level of cholesterol (viz., the ER, 5% cholesterol; the Golgi apparatus, 12.5%; and the PM, 30%). Therefore, we investigated the ability of each molecule to interact with membranes of the corresponding cholesterol content to determine if lipid cholesterol content provides a physical basis for their observed localized activity. Using differential scanning calorimetry and a terbium-based liposome disruption assay, we show that both Lumacaftor (a corrector) and Ivacaftor (a potentiator) penetrate/diffuse through membranes containing high cholesterol concentrations, such as in Golgi and the PM. The results further suggest that (1) Lumacaftor resides within membranes containing 5% cholesterol, supporting the proposition that Lumacaftor acts as a corrector of the CFTR channel at the ER level where the nascent protein is in its initial folding stage; and (2) Ivacaftor is well-suited to penetrate the PM and reach its binding pocket on CFTR. Our findings provide evidence that membrane cholesterol levels significantly modulate CFTR corrector/potentiator activity and consequently may affect sensitivity to clinical therapeutics in CF patients.

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