Langmuir-Blodgett monolayers holding a wound healing active compound and its effect in cell culture. A model for the study of surface mediated drug delivery systems

Langmuir and Langmuir-Blodgett films holding a synthetic bioinspired wound healing active compound were used as drug-delivery platforms. Palmitic acid Langmuir monolayers were able to incorporate 2-methyltriclisine, a synthetic Triclisine derivative that showed wound healing activity. The layers proved to be stable and the nanocomposites were transferred to solid substrates. Normal human lung cells (Medical Research Council cell strain 5, MRC-5) were grown over the monomolecular Langmuir-Blodgett films that acted as a drug reservoir and delivery system. The proliferation and migration of the cells were clearly affected by the presence of 2-methyltriclisine in the amphiphilic layers. The methodology is proposed as a simple and reliable model for the study of the effects of bioactive compounds over cellular cultures.EEA Marcos JuárezFil: Fernández, Luciana. Universidad Nacional de Río Cuarto. Departamento de Física y Departamento de Química; ArgentinaFil: Fernández, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Reviglio, Ana Lucía. Universidad Nacional de Río Cuarto. Departamento de Física y Departamento de Química; ArgentinaFil: Reviglio, Ana Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Heredia, Daniel A. Universidad Nacional de Río Cuarto. Departamento de Física y Departamento de Química; Argentina.Fil: Heredia, Daniel A. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Morales, Gustavo M. Universidad Nacional de Río Cuarto. Departamento de Física y Departamento de Química; ArgentinaFil: Morales, Gustavo M. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Santo, Marisa. Universidad Nacional de Río Cuarto. Departamento de Física y Departamento de Química; ArgentinaFil: Santo, Marisa. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Otero, Luis. Universidad Nacional de Río Cuarto. Departamento de Física y Departamento de Química; ArgentinaFil: Otero, Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alustiza, Fabrisio Eduardo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Marcos Juárez; ArgentinaFil: Liaudat, Ana Cecilia. Universidad Nacional de Río Cuarto. Departamento de Biología Molecular; ArgentinaFil: Bosch, Pablo. Universidad Nacional de Río Cuarto. Departamento de Biología Molecular; ArgentinaFil: Larghi, Enrique L. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Bracca, Andrea B.J. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; ArgentinaFil: Kaufman, Teodoro S. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Química Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química Rosario; Argentin

Time to Diagnosis and Its Predictors in Syndromes Associated With Frontotemporal Lobar Degeneration

Objectives: Frontotemporal Lobar Degeneration (FTLD) causes a heterogeneous group of neurodegenerative disorders with a wide range of clinical features. This might delay time to diagnosis. The aim of the present study is to establish time to diagnosis and its predictors in patients with FTLD-associated syndromes. Design: Retrospective study. Setting: Tertiary referral center. Participants: A total of 1029 patients with FTLD-associated syndromes (age: 68 [61–73] years, females: 46%) from 1999 to 2023 were included in the present study. Measurements: Time to diagnosis was operationalized as the time between symptom onset and the diagnosis of a FTLD-associated syndrome. The associations between time to diagnosis and possible predictors (demographic and clinical variables) were investigated through univariate and multivariate linear models. Results: Median time to diagnosis was 2 [1-3] years. We observed that younger age at onset (β = -0.03, p <0.001), having worked as a professional rather than as a blue (β = 0.52, p = 0.024) or a white (β = 0.46, p = 0.050) collar, and having progressive supranuclear palsy (p <0.05) or the semantic variant of primary progressive aphasia (p <0.05) phenotypes were significantly associated with increased time to diagnosis. No significant changes of time to diagnosis have been observed over 20 years. Conclusions: The identification of predictors of time to diagnosis might improve current diagnostic algorithms, resulting in a timely initiation of symptomatic treatments, early involvement in clinical trials, and more adequate public health policies for patients and their families

Synthesis and interaction of terminal unsaturated chemical probes with Mycobacterium tuberculosis CYP124A1

A series of C15–C20 isoprenyl derivatives bearing terminal alkenyl and alkynyl groups were synthesized as possible substrates of the methyl-branched lipid ω-hydroxylase CYP124A1 from Mycobacterium tuberculosis. The interactions of each compound with the enzyme active site were characterized using UV–vis spectroscopy. We found that C10 and C15 analogs bind with similar affinity to the corresponding parent C10 and C15 substrates geraniol and farnesol, respectively. Three analogs (C10-ω-ene, C10-ω-yne, C15-ω-yne) interact with the proximal side of the heme iron by coordinating to the oxygen atom of the ferric heme, as judged by the appearance of typical Type-IA binding spectra. On the other hand, the C15-ω-ene analog interacts with the ferric heme by displacing the bound water that generates a typical Type I binding spectrum. We were unable to detect P450-mediated oxidation of these probes following extended incubations with CYP124A1 in our reconstituted assay system, whereas a control reaction containing farnesol was converted to ω-hydroxy farnesol under the same conditions. To understand the lack of detectable oxidation, we explored the possibility that the analogs were acting as mechanism-based inhibitors, but we were unable to detect time-dependent loss of enzymatic activity. In order to gain insight into the lack of detectable turnover or time-dependent inhibition, we examined the interaction of each compound with the CYP124A1 active site using molecular docking simulations. The docking studies revealed a binding mode where the terminal unsaturated functional groups were sequestered within the methyl-binding pocket, rather than positioned close to the heme iron for oxidation. These results aid in the design of specific inhibitors of Mtb-CYP124A1, an interesting enzyme that is implicated in the oxidation of methyl-branched lipids, including cholesterol, within a deadly human pathogen

Neocryptolepine: A Promising Indoloisoquinoline Alkaloid with Interesting Biological Activity. Evaluation of the Drug and its Most Relevant Analogs

Plants are one of the most important resources for the discovery of new drugs. The potential of natural compounds as new drug leads is clearly illustrated by the discovery and development of many modern medicines. This is an encouraging factor that drives natural products research in the vegetable kingdom. Neocryptolepine is a tetracyclic nitrogen heterocycle isolated from the African climber Cryptolepis sanguinolenta, which is widely used in traditional African medicine in many countries of Central and West Africa. The natural product is one of the representative examples of the small family of indolo[2,3-b]quinoline alkaloids, being endowed of multiple biological activities, including DNA-binding and inhibition of the enzyme topoisomerase II. It is also cytotoxic, antibacterial, antifungal and molluscicidal, also displaying antiprotozoal activity, particularly as antitrypanosomal, antileishmanial, antischistosomal and antiplasmodial. Some of these activities have been related to the product’s ability to bind to DNA and to inhibit topoisomerase II; however, the exact mechanisms behind all of the observed bioactivities have not been comprehensively clarified. Major research activities regarding neocryptolepine have been focused into two seemingly opposite fields, related to its cytotoxic and antimalarial properties. Optimization of the natural product as a cytotoxic agent implied improvements in its bioavailability and activity, while the need of non-cytotoxic compounds guided the design and optimization of antimalarial agents. Therefore, the aim of the present article is to systematically review the current knowledge about the diversity of the biological activities related to neocryptolepine, its analogs and derivatives.Fil: Larghi, Enrique Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Bracca, Andrea Beatriz Juana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Arrollo Aguilar, Abel A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Heredia, Daniel Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Pergomet, Jorgelina Leonor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Simonetti, Sebastián Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; ArgentinaFil: Kaufman, Teodoro Saul. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Rosario. Instituto de Química Rosario; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentin