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The reaction of 5-aminosalicylic acid (5-ASA) with nitrous acid has been studied at low pH under conditions that simulate a gastric environment. The course of the reaction was followed by UV-visible and fluorescence spectroscopy and the products were analyzed by high performance liquid chromatography (HPLC) with UV-visible and mass spectroscopic detectors. In addition, the formation of nitric oxide (NO) was estimated electrochemically. 5-ASA was readily consumed in a process catalyzed by chloride and thiocyanate, whose rate is first order in 5-ASA and second order in nitrous acid. 2-Hydroxy-5-diazonium benzoic acid (diazonium derivative) and NO were detected as products of the reaction. From the NO formation profiles, it is concluded that NO is produced as a minor product in a process parallel to the path that leads to generation of the diazonium derivative. While the formation of NO could be beneficial for the protection of the stomach, the generation of the diazonium derivative could be considered a potentially toxic process. Key words: 5-aminosalicylic acid, mesalazine, nitrous acid, nitrite, diazonium derivative, nitric oxide. On a etudie la reaction de l'acide 5-aminosalicylique (5-AAS) avec l'acide nitreux, a un pH faible, dans des conditions qui simulent un environnement gastrique. On a suivi l'evolution de la reaction par spectroscopies UV-visible et de fluorescence et on a analyse les produits par chromatographie liquide a haute performance (CLHP) avec des detecteurs par spectroscopie UV-visible et de masse. De plus, on a fait appel a une methode electrochimique pour evaluer la formation d'oxyde nitrique (NO). L'acide 5-aminosalicylique est rapidement consomme dans un processus catalyse par les ions chlorure et thiocyanate et pour lequel la vitesse est du premier ordre en 5-AAS et du second ordre en acide nitreux. On a detecte de l'acide 2-hydroxy-5-diazoniumbenzoique (derive diazonium) et du NO comme produis de la reaction. D'apres les profils de formation du NO, on en conclut que le NO se forme comme produit mineur dans un processus parallele a la voie qui conduit a la formation du derive diazonium. Alors que la formation du NO pourrait etre benefique pour la protection de l'estomac, la formation du derive diazonium peut etre consideree comme un processus potentiellement toxique. Mots-cles : acide 5-aminosalicylique, mesalazine, acide nitreux, nitrite, derive diazonium, oxyde nitrique., Introduction Chronic inflammatory bowel pathologies such as ulcerative colitis and Crohn's disease cause inflammatory changes and ulcers of different types in the gastrointestinal mucosa. (1) 5-Aminosalicylic acid (5-ASA), the active [...]

Background: Vitamin C plays key roles in cellular homeostasis, functioning as a potent antioxidant and a positive regulator of cell differentiation. In skeletal muscle, the vitamin C/sodium co-transporter SVCT2 is preferentially expressed in oxidative slow fibers. SVCT2 is up-regulated during the early fusion of primary myoblasts and decreases during initial myotube growth, indicating the relevance of vitamin C uptake via SVCT2 for early skeletal muscle differentiation and fiber-type definition. However, our understanding of SVCT2 expression and function in adult skeletal muscles is still limited., Results: In this study, we demonstrate that SVCT2 exhibits an intracellular distribution in chicken slow skeletal muscles, following a highly organized striated pattern. A similar distribution was observed in human muscle samples, chicken cultured myotubes, and isolated mouse myofibers. Immunohistochemical analyses, combined with biochemical cell fractionation experiments, reveal a strong co-localization of SVCT2 with intracellular detergent-soluble membrane fractions at the central sarcomeric M-band, where it co-solubilizes with sarcoplasmic reticulum proteins. Remarkably, electrical stimulation of cultured myofibers induces the redistribution of SVCT2 into a vesicular pattern., Conclusions: Our results provide novel insights into the dynamic roles of SVCT2 in different intracellular compartments in response to functional demands., (© 2024. The Author(s).)

The neuromuscular junction (NMJ) is the peripheral synapse controlling the contraction of skeletal muscle fibers to allow the coordinated movement of many organisms. At the NMJ, a presynaptic motor axon terminal contacts a muscle postsynaptic domain and is covered by terminal Schwann cells. The integrity and function of the NMJ is compromised under several conditions, including aging, neuromuscular diseases, and traumatic injuries. To analyze the potential contribution of muscle-derived proteins to NMJ maintenance and regeneration, an in vivo gene transfer strategy has been combined with the denervation of the cranial levator auris longus (LAL) muscle after mechanical nerve injury. Previous findings showed that the forced expression of control fluorescent proteins does not alter NMJ organization or neurotransmission. This procedure aims to describe a detailed method of in vivo electroporation of the LAL muscle followed by transection or crushing of the specific branch of the facial nerve innervating cranial muscles, leading to NMJ denervation and reinnervation, respectively. The combination of these experimental strategies in the convenient LAL muscle constitutes an efficient method to study the potential contribution of muscle protein overexpression or silencing in the context of short-term NMJ reinnervation.

Background: Hearing loss in older adults affects general, generic health-related and disease-specific quality of life (QoL). The conventional strategy to address it is through hearing aids, which have been shown to improve disease-specific QoL. However, the long-term results regarding general quality of life are unknown, and communication problems and stigma associated with hearing loss may persist. An effective intervention strategy to address these problems is group communication programs, most notably Active Communication Education (ACE). This program has been shown to increase communication strategies and reduce communication activity limitations and participation restrictions. These precedents allow us to hypothesize that this program could improve general QoL., Methods: A randomized clinical trial was conducted on 114 older adult hearing aid users. Fifty-four subjects composed the intervention group that received the ACE program, while 60 subjects composed the control group that received an informational-lectures type intervention. The WHOQOL-BREF questionnaire was used to measure general QoL. Measurements were taken before and right after the intervention, with follow-ups at 6 and 12 months. Multilevel linear mixed models were estimated, considering the WHOQOL-BREF dimension scores and total score as the outcomes, and an interaction term between time since intervention and group as the predictor. Within- and between-group comparisons were made., Results: Compared to the baseline time-point, the ACE group showed significant improvements right after the intervention, and at the 6-month and 12-month follow-ups for the dimensions of psychological health, social relationships, environment, and total score. Compared to the control group, the ACE group exhibited significantly greater improvements in the social dimension at all postintervention assessments, as well as in the environment dimension and total score at the 12-month follow-up., Conclusions: The ACE program improved general QoL in terms of social relationships and environment dimensions, which lasted up to 12 months after the intervention. Therefore, ACE is positioned as an effective complement for HA users, enhancing and delivering new benefits related to broader aspects of QoL not necessarily tied to health., Trial Registration: ISRCTN54021189 (retrospectively registered on 18/07/2023)., (© 2024. The Author(s).)

Malaria is an infectious disease caused by Plasmodium spp. parasites, with widespread drug resistance to most antimalarial drugs. We report the development of two 3D-QSAR models based on comparative molecular field analysis (CoMFA), comparative molecular similarity index analysis (CoMSIA), and a 2D-QSAR model, using a database of 349 compounds with activity against the P. falciparum 3D7 strain. The models were validated internally and externally, complying with all metrics (q 2 > 0.5, r 2 test > 0.6, r 2 m > 0.5, etc.). The final models have shown the following statistical values: r 2 test CoMFA = 0.878, r 2 test CoMSIA = 0.876, and r 2 test 2D-QSAR = 0.845. The models were experimentally tested through the synthesis and biological evaluation of ten quinoline derivatives against P. falciparum 3D7. The CoMSIA and 2D-QSAR models outperformed CoMFA in terms of better predictive capacity (MAE = 0.7006, 0.4849, and 1.2803, respectively). The physicochemical and pharmacokinetic properties of three selected quinoline derivatives were similar to chloroquine. Finally, the compounds showed low cytotoxicity (IC 50 > 100 µM) on human HepG2 cells. These results suggest that the QSAR models accurately predict the toxicological profile, correlating well with experimental in vivo data.

The dinoflagellate Alexandrium catenella is a well-known paralytic shellfish toxin producer that forms harmful algal blooms, repeatedly causing damage to Chilean coastal waters. The causes and behavior of algal blooms are complex and vary across different regions. As bacterial interactions with algal species are increasingly recognized as a key factor driving algal blooms, the present study identifies several bacterial candidates potentially associated with Chilean Alexandrium catenella. This research narrowed down the selection of bacteria from the Chilean A. catenella culture using antibiotic treatment and 16S rRNA metabarcoding analysis. Subsequently, seawater from two Chilean coastal stations, Isla Julia and Isla San Pedro, was monitored for two years to detect Alexandrium species and the selected bacteria, utilizing 16S and 18S rRNA gene metabarcoding analyses. The results suggested a potential association between Alexandrium species and Spongiibacteraceae at both stations. The proposed candidate bacteria within the Spongiibacteraceae family, potentially engaging in mutualistic relationships with Alexandrium species, included the genus of BD1-7 clade, Spongiibbacter, and Zhongshania., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yarimizu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Access to audiology services for older adults residing in sparsely populated regions is often limited compared to those in central urban areas. The geographic accessibility to follow-up care, particularly the influence of distance, may contribute to an increased risk of hearing aid abandonment., Objective: To assess the association between the home-to-healthcare-calibration-center distance and hearing aid abandonment among older adults fitted in the Chilean public health system., Methods: 455 patients who received hearing aids from two public hospitals in two regions were considered. Univariate and multivariate Poisson regression models with robust variance estimation were used to analyze the association between the geographical distance and hearing aid abandonment, accounting for confounding effects., Results: Approximately 18% of the sample abandoned the hearing aid, and around 50% reported using the hearing aid every day. A twofold increase in distance between home and the hearing center yielded a 35% (RR = 1.35; 95% CI: 1.04-1.74; p  = 0.022) increased risk of hearing aid abandonment. Also, those in the second quintile had a 2.17 times the risk of abandoning the hearing aid compared to the first quintile (up to 2.3 km). Under the assumption that patients reside within the first quintile of distance, a potential reduction of 45% in the incidence of hearing aid abandonment would be observed. The observed risk remained consistent across different statistical models to assess sensitivity., Conclusion: A higher distance between the residence and the healthcare center increases hearing aid abandonment risk. The association may be explained by barriers in purchasing supplies required to maintain the device (batteries, cleaning elements, potential repairs, or maintenance)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fuentes-López, Galaz-Mella, Ayala, De la Fuente, Luna-Monsalve, Nieman and Marcotti.)

A non-structural SARS-CoV-2 protein, PLpro, is involved in post-translational modifications in cells, allowing the evasion of antiviral immune response mechanisms. In this study, potential PLpro inhibitory drugs were designed using QSAR, molecular docking, and molecular dynamics. A combined QSAR equation with physicochemical and Free-Wilson descriptors was formulated. The r 2 , q 2 , and r 2 test values were 0.833, 0.770, and 0.721, respectively. From the equation, it was found that the presence of an aromatic ring and a basic nitrogen atom is crucial for obtaining good antiviral activity. Then, a series of structures for the binding sites of C111, Y268, and H73 of PLpro were created. The best compounds were found to exhibit pIC 50 values of 9.124 and docking scoring values of -14 kcal/mol. The stability of the compounds in the cavities was confirmed by molecular dynamics studies. A high number of stable contacts and good interactions over time were exhibited by the aryl-thiophenes Pred14 and Pred15, making them potential antiviral candidates.

Reconstructing the nose poses considerable challenges, even for the most skilled surgeons. Significant nasal reconstructions often require later revisions to address persistent issues in both form and function, and it is crucial to discuss this possibility with the patient before embarking on the reconstructive process. Minor revisions can often be managed by making direct incisions between nasal subunits, coupled with soft tissue sculpting or the use of structural grafts for augmentation. When minor adjustments prove insufficient, the initial reconstruction may need to be entirely revised with a second forehead flap., Competing Interests: Disclosure The authors have no financial disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

According to the WHO, antimicrobial resistance is among the top 10 threats to global health. Due to increased resistance rates, an increase in the mortality and morbidity of patients has been observed, with projections of more than 10 million deaths associated with infections caused by antibacterial resistant microorganisms. Our research group has developed a new family of pyrimido-isoquinolin-quinones showing antibacterial activities against multidrug-resistant Staphylococcus aureus . We have developed 3D-QSAR CoMFA and CoMSIA studies (r 2 = 0.938; 0.895), from which 13 new derivatives were designed and synthesized. The compounds were tested in antibacterial assays against methicillin-resistant Staphylococcus aureus and other bacterial pathogens. There were 12 synthesized compounds active against Gram-positive pathogens in concentrations ranging from 2 to 32 µg/mL. The antibacterial activity of the derivatives is explained by the steric, electronic, and hydrogen-bond acceptor properties of the compounds.

Resistance to antibacterial agents is a growing global public health problem that reduces the efficacy of available antibacterial agents, leading to increased patient mortality and morbidity. Unfortunately, only 16 antibacterial drugs have been approved by the FDA in the last 10 years, so it is necessary to develop new agents with novel chemical structures and/or mechanisms of action. In response to this, our group takes up the challenge of designing a new family of pyrimidoisoquinolinquinones displaying antimicrobial activities against multidrug-resistant Gram-positive bacteria. Accordingly, the objective of this study was to establish the necessary structural requirements to obtain compounds with high antibacterial activity, along with the parameters controlling antibacterial activity. To achieve this goal, we designed a family of compounds using different strategies for drug design. Forty structural candidates were synthesized and characterized, and antibacterial assays were carried out against high-priority bacterial pathogens. A variety of structural properties were modified, such as hydrophobicity and chain length of functional groups attached to specific carbon positions of the quinone core. All the synthesized compounds inhibited Gram-positive pathogens in concentrations ranging from 0.5 to 64 µg/mL. Two derivatives exhibited minimum inhibitory concentrations of 64 µg/mL against Klebsiella pneumoniae , while compound 28 demonstrated higher potency against MRSA than vancomycin.

In this study, we aimed to evaluate two sets of sesquiterpene-aryl derivatives linked by an ester bond, their cytotoxic activities, and their capacity to activate caspases 3/7 and inhibit human topoisomerase I (TOP1). A total of 13 compounds were synthesized from the natural sesquiterpene (-)-drimenol and their cytotoxic activity was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and an immortalized non-tumoral cell line (MCF-10). From the results, it was observed that 6a was the most promising compound due to its cytotoxic effect on three cancer cell lines and its selectivity, 6a was 100-fold more selective than 5-FU in MCF-7 and 20-fold in PC-3. It was observed that 6a also induced apoptosis by caspases 3/7 activity using a Capsase-Glo-3/7 assay kit and inhibited TOP1. A possible binding mode of 6a in a complex with TOP1-DNA was proposed by docking and molecular dynamics studies. In addition, 6a was predicted to have a good pharmacokinetic profile for oral administration. Therefore, through this study, it was demonstrated that the drimane scaffold should be considered in the search of new antitumoral agents.

Throughout the evolution of functional rhinoplasty, numerous techniques have been described and shown to be successful. Controversy exists regarding which techniques are most effective to address various deformities. The goal of this article is to review the available literature to examine the question, which surgical techniques within functional rhinoplasty are most successful in treating nasal airway obstruction. Based on the available data, it is not currently possible to draw conclusions about the superiority of a single graft or technique in functional rhinoplasty., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)