1,720,987 research outputs found
Structure-activity relationship studies and pharmacological evaluation of 4-phenylthiazoles as dual soluble epoxide hydrolase/fatty acid amide hydrolase inhibitors
Full text linkWith few viable treatment options, glioblastoma (GBM) is still one of the most aggressive and deadly types of brain cancer. Recent developments in lipidomics have demonstrated the potential of lipid metabolism as a therapeutic target in GBM. The thorough examination of lipids in biological systems, or lipidomics, is essential to comprehending the changed lipid profiles found in GBM, which are linked to the tumor's ability to grow, survive, and resist treatment. The use of lipidomics in drug delivery and discovery is examined in this study, focusing on how it may be used to find new biomarkers, create multi-target directed ligands, and improve drug delivery systems. We also cover the use of FDA-approved medications, clinical trials that use lipid-targeted medicines, and the integration of lipidomics with other omics technologies. This study emphasizes lipidomics as a possible tool in developing more effective treatment methods for GBM by exploring various lipid-centric techniques.118112https://doi.org/10.1016/j.bmc.2025.11811
Lipidomics-driven drug discovery and delivery strategies in glioblastoma
Full text linkWith few viable treatment options, glioblastoma (GBM) is still one of the most aggressive and deadly types of brain cancer. Recent developments in lipidomics have demonstrated the potential of lipid metabolism as a therapeutic target in GBM. The thorough examination of lipids in biological systems, or lipidomics, is essential to comprehending the changed lipid profiles found in GBM, which are linked to the tumor's ability to grow, survive, and resist treatment. The use of lipidomics in drug delivery and discovery is examined in this study, focusing on how it may be used to find new biomarkers, create multi-target directed ligands, and improve drug delivery systems. We also cover the use of FDA-approved medications, clinical trials that use lipid-targeted medicines, and the integration of lipidomics with other omics technologies. This study emphasizes lipidomics as a possible tool in developing more effective treatment methods for GBM by exploring various lipid-centric techniques.167637https://doi.org/10.1016/j.bbadis.2024.16763
Developing Dual Inhibitors of Fatty Acid Amide Hydrolase and Soluble Epoxide Hydrolase for the Treatment of Chronic Pain
Full text linkFatty acid amide hydrolase (FAAH) and soluble epoxy hydrolase (sEH) are two enzymes responsible for hydrolyzing AEA (AEA) and epoxyeicosatrienoic acids (EETs), respectively. AEA, an endogenous cannabinoid, is proven to produce an analgesic effect when binding to the CB1 endocannabinoid receptor. This pain-relieving process is terminated when hydrolysis takes place breaking down AEA to arachidonic acid metabolites. Epoxyeicosatrienoic acid, a bioactive lipid, is prevalent in human organs and has been taken as an anti-inflammatory marker. EETs are metabolites of arachidonic acids produced from the aforementioned FAAH hydrolysis and other lipids hydrolysis. Similar to AEA, EETs can be hydrolyzed by sEH enzyme leading to the loss of analgesic effect. Therefore, inhibiting these two enzymes FAAH and sEH, is necessary for alleviating pain. In this research, we aimed to develop a multi-targeted directed ligand that can inhibit FAAH and sEH simultaneously in treating chronic pain. Here, we have synthesized a library of 15 compounds with the assistance of microwave synthesis and evaluated them through in silico molecular modeling and in vitro enzyme assay. The best candidate was additionally tested in vivo on a rat model of nociceptive pain. In conclusion, compound 4f showed competitive activity in suppressing FAAH and sEH enzymes with moderate solubility and microsomal stability. Compound 4f showed an anti-hyperalgesia effect at 3mg/kg in the rat model of the orofacial hyperalgesia pain model. Compound 4o demonstrated exceptional results in enzyme assay, showing promising potential. Future work will consider further compound 4o and related compounds in the library
Biochemical Analysis of the Portal Protein From a dsDNA Virus
No full textPortal proteins play an integral role in viral infection, capsid assembly, and DNA packaging. Bacteriophage lambdas use portal proteins in each of these roles. The portal protein is a dodecameric ring that acts as a nucleation site for capsid assembly proteins to build from, allows the passage of DNA into the capsid during DNA packaging, and the only exit point for DNA to leave the capsid when infection occurs. The goal of this research is to produce a soluble portal protein. Modeling the portal protein of a bacteriophage lambda, gpB, allowed the visualization of the disordered ends that contributed the insolubility of the portal protein. After truncating the portal protein's insoluble ends, the DNA was mutated to also express a Glutathione-S-Transferase (GST) tag. Once the gpB-GST was expressed and solubilized, the portal protein was cleaved from GST and purified using Anion Exchange Chromatography. After obtaining a purified gpB sample, the protein was sequenced to determine sequence of the cleaved product. Using these methods, the cleaved product was able to be produced. The final monomeric form of the protein contains 420 amino acids. By incorporating buffers that contained Tris with a pH of 8.0, gpB was better stabilized throughout this process.https://doi.org/10.5281/zenodo.576496
A Polypharmacology Approach to Developing Multi-Target Directed Ligand Therapeutics for the Treatment of Alzheimer's Disease
Full text linkAlzheimer's disease (AD) is an incurable brain degenerative disease with limited treatments, often in the form of drug therapeutics, that merely alleviate symptoms and often cause side effects. To address these challenges, pharmaceutical research focuses on enhancing the efficacy and safety of AD therapies. Targeting the cholinergic pathway, specifically inhibiting acetylcholinesterase (AChE), has shown promise in improving cognition in AD patients. Additionally, research indicates a link between AD and neuroinflammation. Inhibiting enzymes such as fatty acid amide hydrolase (FAAH) and soluble epoxide hydrolase (sEH) represents a novel strategy for regulating neuroinflammation in central nervous system (CNS) diseases, including Alzheimer's disease (AD). Our lab has previously identified potent AChE inhibitors derived from donepezil, as well as 4-phenylthiazole-derived inhibitors of FAAH and sEH, with competitive IC50 values relative to standard inhibitors. In this research, we employ a polypharmacology approach to design Multi-Target Directed Ligands (MTDLs) by combining the key structural moieties of FAAH and sEH inhibitors with the important structural moiety from the AChE inhibitor donepezil. These MTDLs present an opportunity to develop a single drug with multiple therapeutic effects, potentially avoiding drug interactions and costly studies while providing synergistic benefits. Utilizing environmentally friendly synthesis methods, our compounds were evaluated in vitro and in silico. The results indicate several compounds with dual-inhibitory and multi-inhibitory potential against AChE, sEH, and FAAH, offering new avenues for expanding AD therapy
Dual Inhibitors of Fatty Acid Amide Hydrolase and Soluble Epoxide Hydrolase Enzymes As Potential Therapeutics for Treating Pulmonary Fibrosis
No full textFatty acid amide hydrolase (FAAH) is a membrane protein that hydrolyzes endocannabinoids, such as anandamide, which possesses analgesic, anti-inflammatory, and anti-fibrotic properties, resulting in arachidonic acid. Arachidonic acid is involved in pro-inflammatory pathways, such as cyclooxygenase, lipoxygenase, and soluble epoxide hydrolase (sEH) pathways. sEH hydrolyzes anti-inflammatory and anti-fibrotic epoxyeicosatrienoic acids to pro-inflammatory dihydroxyeicosatetraenoic acids. Designed multiple ligands (DMLs) are small molecules specifically designed to interact with several biological targets involved in multifactorial diseases, such as pain, cancer, Alzheimer's disease, and pulmonary fibroses. In this project, we used DMLs strategies to design drugs that will simultaneously inhibit sEH and FAAH enzymes which could produce a therapeutic effect for those suffering from idiopathic pulmonary fibrosis and chronic pain related to it. Here using in silico methodologies, microwave-assisted green chemistry synthesis, and in vitro assays, we have designed, synthesized, and biologically evaluated over 60 compounds. In addition, the best inhibitor discovered in this study was evaluated in vivo in a rat model of acute pain. We were able to establish a clear structure-activity relationships and identified benzothiazole and 4-phenylthiazole moieties as the important groups to inhibit these two enzymes in the low nanomolar range as well showing favorable predictions of several pharmacokinetic/pharmacodynamic properties.https://doi.org/10.5281/zenodo.657874
Development of Multi-Target Directed Ligands for the Treatment of Chronic Pain in Ehlers-Danlos Syndromes
Full text linkEhlers-Danlos Syndromes (EDS) is a group of genetic connective tissue disorders characterizedby clinical features such as skin hyperextensibility, joint hypermobility, and tissue fragility. About 90%of EDS patients suffer from chronic pain, which is mainly caused by joint instability and hypermobility.Since EDS is a genetic disorder with no cure, chronic pain in these patients is managed by medicationsthat have negative side effects in long-term use. Fatty acid amide hydrolase (FAAH) is a membraneenzyme that hydrolyzes anandamide, which has anti-inflammatory and analgesic properties, intoarachidonic acid (AA). AA is eventually degraded by soluble epoxide hydrolase (sEH) intodihydroxyeicosatrienoic acid (DHET), which is pro-inflammatory. Many animal studies demonstratedthat inhibition of FAAH or sEH resulted in antinociception and anti-inflammation. In this project, weseek to develop a compound that can simultaneously inhibit both sEH and FAAH as a potential noveltherapeutic for non-opioid chronic pain treatment in EDS. We designed, synthesized, and biologicallyevaluated 21 compounds. Additionally, we also evaluated 2 compounds in vivo to evaluate toxicity andantinociception. Our SAR study indicates that strong nonpolar electron-withdrawing groups placed inortho and para positions on the right side of the dual inhibitor are well tolerated. Bulky groups, such asquinoline and thiazole, are tolerated on the left side of the dual inhibitor. In vivo study showed that ourdual inhibitor can inhibit pain and does not affect locomotor activities in rats. It also does not bind to anyopioid receptor subtypes
Mutation of the Atpase Domain in Bacteriophage lambda Stabilizes the Enzyme for Structural and Functional Analysis of the DNA Packaging Motor
Full text linkTerminase enzymes are responsible for packaging viral DNA into empty procapsids. Bacteriophage lambda (λ), a double-stranded DNA virus (dsDNA), utilizes a terminase holoenzyme that is composed of two subunits to package DNA. GpNu1, the smaller subunit, is responsible for site-specific assembly of viral DNA. GpA, the large subunit, is responsible for all the catalytic activity for the enzyme to begin viral assembly. To stabilize the gpA catalytic subunit, a dual point mutation was produced in the DNA packaging ATPase domain (D178E/E179D) and two truncations were made to remove 50 N terminal amino acids and 19 C terminal amino acids. The D178E/E179D mutations inactivate the ATPase domain and stabilize the protein for crystallography. The truncation at the N-terminus prevents interactions with the small subunit, while the truncation at the C-terminus prevents interactions with the viral capsid. Nuclease and helicase studies suggest that the N-terminal truncation destabilized the protein unless the D178E/E179D mutation was performed, which stabilized the mutant. DNA binding studies suggest that in the presence of viral DNA, the wild-type mutant binds to DNA much tighter than the D178E/E179D mutant. Preliminary crystallization structure solutions will confirm logical hypotheses formed about the gpA subunit and its interactions with DNA during viral assembly
Optimization and Product Analysis of Polyalcohols via Split-Ph Direct Liquid Fuel Cell
Full text linkAs the global energy crisis ensues, most energy remains sourced from fossil fuels, causing environmental harm. Recently, alternative sources of energy like the direct liquid fuel cell (DLFC) gained popularity with the goal of reducing pollution and the depletion of nonrenewable resources. This work examined the oxidation products of polyalcohols containing structural isomers, propanediol (PD) and butanediol (BD) utilizing a split-pH DLFC. PD has two isomers: 1,2-PD and 1,3-PD and BD has four isomers: 1,2-BD; 2,3-BD; 1,4-BD; and 1,3-BD. Product collection of these polyalcohols provides insight to the oxidation mechanism of each fuel and allows understanding of oxidation mechanisms for similar molecules. One mechanism of interest involves the cleavage of C-C bonds, which generates more electrons via complete oxidation. It was seen that the vicinal diols, 1,2-PD; 1,2-BD; and 2,3-BD, underwent C-C scission. 1,2-PD produced lactate, acetate, and formate on Pd-based catalysts at a variety of voltages while 1,2-BD generated 2-hydroxybutyrate and propionic acid and 2,3-BD oxidized to acetate and formate. It should be noted that the less oxidized product was the major product in all cases. 1,3-PD and 1,4-BD both contain two terminal alcohols and experienced complete oxidation to some degree, with 1,3-PD producing 3-hydroxypropanoate and malonic acid at high potentials and 1,4-BD producing succinate and gamma-hydroxybutyrate. 1,3-BD generated only one partially-oxidized product, 3-hydroxybutyrate. The BD isomers were also optimized in an electrochemical cell and fuel cell with fuel ranking in order of 1,4-BD > 1,3-BD > 1,2-BD > 2,3-BD to produce power densities of 157, 126, 118, and 29 mW cm-2 respectively. Additionally, the oxidation of another biofuel, ascorbate, was optimized in a split-pH fuel cell on a Cu/C anode and carbon black cathode catalyst. A power density of 51 mW cm-2 was generated at non-noble catalysts, which is significant since this result is comparable to literature utilizing ascorbate and precious metal catalysts.https://doi.org/10.5281/zenodo.657518
Profiles of Science Identity Development in a Diverse, Primarily Undergraduate Institution, and Synthesis of Donepezil Analogs
Full text linkShifting population demographics, STEM attrition, and a global pandemic all point to a need for more STEM graduates. Populations that are expected to grow significantly over the next few decades also tend to be underrepresented in STEM fields. STEM attrition in higher education results in fewer STEM graduates and impacts underrepresented minorities the most. The recent global pandemic lowered trust in scientists and health professionals, which introduces doubt into established medical protocols. Increasing science identity in students can improve student outcomes such as graduation rates, while increasing it in the general population could help them understand the perspective of scientists. Identity has a rich intellectual history spanning from classic Greek philosophers to modern researchers. Research in this field has narrowed to allow for greater understanding in particular fields of study. One such growing field involves science identity, which can be defined as the part of oneself that identifies with the scientific community. The purpose of this study was to investigate how closely students at a primarily undergraduate institution identify with the scientific community and how that differs between students according to self-reported attributes. This study involved the use of an instrument developed at an R1 university and utilized quantitative analysis techniques to determine the statistical significance of any differences between groups of students. The results of the analysis revealed that there was a statistically significant difference between students eligible to receive a Pell grant and those who were not. A statistically significant difference was also found by gender. Validity and reliability evaluations suggest that the instrument was both valid and reliable for the tested population
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