The glutamate-gated ion channels known as N-methyl-d-aspartate receptors (NMDARs) are important for both normal and pathological brain function. Subunit-selective antagonists have high therapeutic promise since many pathological conditions involve NMDAR over activation, although few clinical successes have been reported. Allosteric inhibitors of GluN2B-containing receptors are among the most potential NMDAR targeting drugs. Since the discovery of ifenprodil, a variety of GluN2B-selective compounds have been discovered, each with remarkably unique structural motifs. These results expand the allosteric and pharmacolog-ical spectrum of NMDARs and provide a new structural basis for the development of next-generation GluN2B antagonists that have therapeutic potential in brain diseases. Small molecule therapeutic inhibitors targeting NMDA have recently been developed to target CNS disorders such as Alzheimer’s disease. In the current study, a cheminformatics method was used to discover potential antagonists and to identify the structural requirements for Gly/NMDA antagonism. In this case we have created a useful pharmacophore model with solid statistical values. Through pharmacophore mapping, the verified model was used to filter out virtual matches from the ZINC database. Assessing receptor-ligand binding mechanisms and affinities used molecular docking. To find the best hits, the GlideScore and the interaction of molecules with important amino acids were considered essential features. We found some molecular inhibitors, namely, ZINC13729211, ZINC07430424, ZINC08614951, ZINC60927204, ZINC12447511, and ZINC18889258 with high binding affinity using computational methods. The molecules in our studies showed characteristics such as good stability, hydrogen bonding and higher binding affinities in the solvation-based assessment method than ifenprodil with acceptable ADMET profile. Moreover, these six leads have been proposed as potential new perspectives for exploring potent Gly/NMDA receptor antagonists. In addition, it can be tested in the laboratory for potential therapeutic strategies for both in vitro and in vivo research.
Fatty acids play an important role in controlling the energy balance of mammals. De novo lipogenesis also generates a significant amount of lipids that are endogenously produced in addition to their ingestion. Fatty acid elongation beyond 16 carbons (palmitic acid), which can lead to the production of very long chain fatty acids (VLCFA), can be caused by the rate-limiting condensation process. Seven elongases, ELOVL1–7, have been identified in mammals and each has a unique substrate specificity. Researchers have recently developed a keen interest in the elongation of very long chain fatty acids protein 1 (ELOVL1) enzyme as a potential treatment for a variety of diseases. A number of neurological disorders directly or indirectly related to ELOVL1 involve the elongation of monounsaturated (C20:1 and C22:1) and saturated (C18:0-C26:0) acyl-CoAs. VLCFAs and ELOVL1 have a direct impact on the neurological disease. Other neurological symptoms such as ichthyotic keratoderma, spasticity, and hypomyelination have also been linked to the major enzyme (ELOVL1). Recently, ELOVL1 has also been heavily used to treat a number of diseases. The current review focuses on in-depth unique insights regarding the role of ELOVL1 as a therapeutic target and associated neurological disorders.
BACKGROUND: Pakistan is a lower middle-income country located in South Asia with a population of nearly 208 million. Sindh is its second largest province. The aim of this survey was to identify the current setup of pediatric services, staffing, equipment, and training infrastructure in the teaching hospitals of Sindh. METHODS: The survey was conducted between June 2018 and September 2018. A questionnaire was designed with input from experts and pretested. One faculty coordinator from each of 12 of the 13 teaching hospitals (7 government and 5 private) completed the form. Information was exported into Statistical Package for the Social Sciences (SPSS) version 22. Frequency and percentages were computed for all variables. Confidentiality was ensured by anonymizing the data. RESULTS: Anesthesia services are provided by consultants with either membership or fellowship in anesthesia of the College of Physicians and Surgeons of Pakistan (CPSP). All drugs on the World Health Organization (WHO) essential medication list were available, although narcotic supply was often inconsistent. Weak areas identified were absence of standardization of practice regarding premedication, preoperative laboratory testing, pain assessment, and management. No national practice guidelines exist. Pulse oximeters and capnometers were available in all private hospitals but in only 86% and 44% of the government hospitals, respectively. Some training centers were not providing the training as outlined by the CPSP criteria. CONCLUSIONS: Several gaps have been identified in the practice and training infrastructure of pediatric anesthesia. There is a need for national guidelines, standardization of protocols, provision of basic equipment, and improved supervision of trainees. One suggestion is to have combined residency programs between private and government hospitals to take advantage of the strengths of both. Recommendations by this group have been shared with all teaching hospitals and training bodies. (Anesth Analg 2022;134:653-60) KEY POINTS• Question: What are the service and training infrastructure facilities for pediatric anesthesia in Sindh province of Pakistan? • Findings: We have identified and documented several gaps in service provision and training of residents in this area. • Meaning: These data can be used to plan improvement both in service and residency training in pediatric anesthesia in the surveyed institutions.
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