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In Silico Drug Repurposing Against PSMB8 as a Potential Target for Acute Myeloid Leukemia Treatment.Molecular Biotechnology Jul 2024PSMB8 emerges as a prominent gene associated with cancer survival, yet its potential therapeutic role in acute myeloid leukemia (AML) remains unexplored within the...
PSMB8 emerges as a prominent gene associated with cancer survival, yet its potential therapeutic role in acute myeloid leukemia (AML) remains unexplored within the existing literature. The principal aim of this study is to systematically screen an expansive library of molecular entities, curated from various databases to identify the prospective inhibitory agents with an affinity for PSMB8. A comprehensive assortment of molecular compounds obtained from the ZINC15 database was subjected to molecular docking simulations with PSMB8 by using the AutoDock tool in PyRx (version 0.9.9) to elucidate binding affinities. Following the docking simulations, a select subset of molecules underwent further investigation through comprehensive ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis employing AdmetSar and SwissADME tools. Finally, RMSD, RMSF, Rg, and H bond analyses were conducted via GROMACS to determine the best conformationally dynamic molecule that represents the candidate agent for the study. Following rigorous evaluation, Adozelesin, Fiduxosin, and Rimegepant have been singled out based on considerations encompassing bioavailability scores, compliance with filter criteria, and acute oral toxicity levels. Additionally, ligand interaction analysis indicates that Adozelesin and Fiduxosin exhibit an augmented propensity for hydrogen bond formation, a factor recognized for its facilitative role in protein-ligand interactions. After final analyses, we report that Fiduxosin may offer a treatment possibility by reversing the low survival rates caused by PSMB8 high activation in AML. This study represents a strategic attempt to repurpose readily available pharmaceutical agents, potentially obviating the need for de novo drug development, and thereby offering promising avenues for therapeutic intervention in specific diseases.
PubMed: 38954355
DOI: 10.1007/s12033-024-01224-4 -
CNS Drugs Jul 2024TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) formulation of risperidone that is approved by the United States Food and Drug Administration for the...
BACKGROUND
TV-46000 is a long-acting subcutaneous antipsychotic (LASCA) formulation of risperidone that is approved by the United States Food and Drug Administration for the treatment of schizophrenia in adults. In the phase 3, randomized, double-blind RIsperidone Subcutaneous Extended-release (RISE) study, TV-46000 once monthly (q1m) and once every 2 months (q2m) significantly prolonged time to impending relapse compared with placebo [5.0-fold (q1m) and 2.7-fold (q2m)]. This phase 3, randomized, double-blind Safety in Humans of TV-46000 subcutaneous INjection Evaluation (SHINE) study was designed to evaluate the long-term safety, tolerability, and exposure of TV-46000 in schizophrenia.
METHODS
Patients who completed RISE without relapse (rollover) or who were newly recruited (de novo) were eligible for the SHINE study. Patients were initially stabilized on oral risperidone for 12 weeks (completed in RISE for rollover, or in SHINE for de novo). Patients in the de novo cohort and patients who received placebo in RISE were randomized 1:1 in SHINE to receive TV-46000 q1m or q2m for up to 56 weeks. Primary endpoint for SHINE was frequency of reported adverse events (AEs); event rates [ER; events per 100 patient-years (PYs)] were calculated for each AE by patients upon general questioning.
RESULTS
Overall, 336 patients were randomized in SHINE [TV-46000 q1m, n = 174; TV-46000 q2m, n = 162; of these, de novo, n = 109 and rollover, n = 227 (n = 172 patients were treated and n = 55 received placebo)]. A total of 334 patients were evaluated for safety [q1m, n = 172 (PY = 97.8); q2m, n = 162 (PY = 104.5)]. Proportions of patients (ER) with ≥ 1 AE and ≥ 1 treatment-related AE were 37% (180.0) and 21% (84.9) for TV-46000 q1m and 46% (157.9) and 20% (70.8) for TV-46000 q2m, respectively. Frequent treatment-related AEs [≥ 3% of patients in either group; proportion of patients (ER)] were injection site pain [q1m, 5% (24.5); q2m, 4% (22.0)] and injection site nodule [q1m, 2% (9.2); q2m, 6% (12.4)]. The proportions of patients with serious AEs was 5% for TV-46000 q1m and 7% for TV-46000 q2m; serious AEs reported for ≥ 2 patients overall were worsening schizophrenia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 2 (1%; ER, 1.91)] and hyperglycemia [q1m, n = 1 (< 1%; ER, 1.02); q2m, n = 1 (< 1%; ER, 0.96)]. Of three reported deaths, none were related to treatment. Overall, eight patients discontinued treatment because of AEs. Similar or somewhat lower rates of AEs were reported for patients who rolled over from TV-46000 treatment compared with those who had no prior TV-46000 treatment (de novo and placebo rollover). Most AEs related to injection site reactions were mild; no patient had a severe reaction.
CONCLUSION
Results from this long-term safety study add to the favorable safety profiles of TV-46000 q1m and q2m, consistent with other formulations of risperidone and previous studies with TV-46000.
REGISTRATION
ClinicalTrials.gov, NCT03893825; 27 March 2019.
PubMed: 38954317
DOI: 10.1007/s40263-024-01102-2 -
Advances in Experimental Medicine and... Jun 2024According to the World Health Organization vector-borne diseases account for more than 17% of all infectious diseases, causing more than 700,000 deaths annually. Vectors...
According to the World Health Organization vector-borne diseases account for more than 17% of all infectious diseases, causing more than 700,000 deaths annually. Vectors are organisms that are able to transmit infectious pathogens between humans, or from animals to humans. Many of these vectors are hematophagous insects, which ingest the pathogen from an infected host during a blood meal, and later transmit it into a new host. Malaria, dengue, African trypanosomiasis, yellow fever, leishmaniasis, Chagas disease, and many others are examples of diseases transmitted by insects.Both the diet and the infection with pathogens trigger changes in many metabolic pathways, including lipid metabolism, compared to other insects. Blood contains mostly proteins and is very poor in lipids and carbohydrates. Thus, hematophagous insects attempt to efficiently digest and absorb diet lipids and also rely on a large de novo lipid biosynthesis based on utilization of proteins and carbohydrates as carbon source. Blood meal triggers essential physiological processes as molting, excretion, and oogenesis; therefore, lipid metabolism and utilization of lipid storage should be finely synchronized and regulated regarding that, in order to provide the necessary energy source for these events. Also, pathogens have evolved mechanisms to hijack essential lipids from the insect host by interfering in the biosynthesis, catabolism, and transport of lipids, which pose challenges to reproduction, survival, fitness, and other insect traits.In this chapter, we have tried to collect and highlight the current knowledge and recent discoveries on the metabolism of lipids in insect vectors of diseases related to the hematophagous diet and pathogen infection.
PubMed: 38954247
DOI: 10.1007/5584_2024_811 -
Molecular Diversity Jul 2024Proviral Integrations of Moloney-2 (PIM-2) kinase is a promising target for various cancers and other diseases, and its inhibitors hold potential for treating related...
Proviral Integrations of Moloney-2 (PIM-2) kinase is a promising target for various cancers and other diseases, and its inhibitors hold potential for treating related diseases. However, there is currently no clinically available PIM-2 inhibitor. In this study, we constructed a generative model for de novo PIM-2 inhibitor design based on artificial intelligence, performed molecular docking and molecular dynamics (MD) simulations to develop an efficient PIM-2 inhibitor generative model and discover potential PIM-2 inhibitors. First, we designed a generative model based on a Bi-directional Long Short-Term Memory (BiLSTM) framework combined with a transfer learning strategy and generated a new PIM-2 small molecule library using existing active drug databases. The generated compound library was then virtually screened by molecular docking and scaffold similarity comparison, identifying 10 initial hit compounds with better performance. Next, using the inhibitor in the crystal structure as a positive control, we performed two rounds of MD simulations, with lengths of 100 ns and 500 ns, respectively, to study the dynamic stability of the protein-ligand systems of the 10 compounds with PIM-2. Analyzed the interactions with key hinge region residues, binding free energies, and changes in the ATP pocket size. The generative model demonstrates good molecular generation capability and can generate efficient novel molecules with similar physicochemical properties as active PIM-2 drugs. Among the 10 initially selected hit compounds, 5 compounds C3 (- 29.69 kcal/mol), C4 (- 33.31 kcal/mol), C5 (- 28.59 kcal/mol), C8 (- 34.68 kcal/mol), and C9 (- 25.88 kcal/mol) have higher binding energies with PIM-2 than the positive drug 3YR (- 26.18 kcal/mol). The MD simulation results are consistent with the docking analysis, these compounds have lower and more stable RMSD values for the complex systems with the reported positive drug 3YR and PIM-2 complex system. They can form long-term stable interactions with active site and the hinge region of PIM-2, which suggests these compounds are likely to have potent inhibitory effects on PIM-2. This study provides an efficient generative model for PIM-2 inhibitor research and discovers 5 potential novel PIM-2 inhibitors.
PubMed: 38954072
DOI: 10.1007/s11030-024-10916-7 -
American Journal of Physiology.... Jul 2024Metabolic reprogramming is recognized as a hallmark of cancer, enabling cancer cells to acquire essential biomolecules for cell growth, often characterized by...
Metabolic reprogramming is recognized as a hallmark of cancer, enabling cancer cells to acquire essential biomolecules for cell growth, often characterized by upregulated glycolysis and/or fatty acid synthesis-related genes. The transcription factor forkhead box M1 (FOXM1) has been implicated in various cancers, contributing significantly to their development, including colorectal cancer (CRC), a major global health concern. Despite FOXM1's established role in cancer, its specific involvement in the Warburg effect and fatty acid biosynthesis in CRC remains unclear. We analyzed The Cancer Genome Atlas (TCGA) Colonic Adenocarcinoma and Rectal Adenocarcinoma (COADREAD) datasets to to derive the correlation of the expression levels between and multiple genes and the survival prognosis based on expression. Using two human CRC cell lines, HT29 and HCT116, we conducted RNAi or plasmid transfection procedures, followed by a series of assays, including RNA extraction, quantitative real-time polymerase chain reaction, Western blot analysis, cell metabolic assays, and immunofluorescence analysis. Higher expression levels of FOXM1 correlated with a poorer survival prognosis, and the expression of was positively correlated with glycolysis-related genes and , lipogenesis-related genes and , and . FOXM1 appeared to modulate AKT/mTOR signaling, the expression of c-Myc, proteins related to glycolysis and fatty acid biosynthesis, as well as extracellular acidification rate in HT29 and HCT116 cells. In summary, FOXM1 plays a regulatory role in glycolysis, fatty acid biosynthesis, and cellular energy consumption, thereby influencing CRC cell growth and patient prognosis.
PubMed: 38953837
DOI: 10.1152/ajpgi.00032.2024 -
Epilepsia Jul 2024DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small...
OBJECTIVE
DYNC1H1 variants are involved on a disease spectrum from neuromuscular disorders to neurodevelopmental disorders. DYNC1H1-related epilepsy has been reported in small cohorts. We dissect the electroclinical features of 34 patients harboring de novo DYNC1H1 pathogenic variants, identify subphenotypes on the DYNC1H1-related epilepsy spectrum, and compare the genotype-phenotype correlations observed in our cohort with the literature.
METHODS
Patients harboring de novo DYNC1H1 pathogenic variants were recruited through international collaborations. Clinical data were retrospectively collected. Latent class analysis was performed to identify subphenotypes. Multivariable binary logistic regression analysis was applied to investigate the association with DYNC1H1 protein domains.
RESULTS
DYNC1H1-related epilepsy presented with infantile epileptic spasms syndrome (IESS) in 17 subjects (50%), and in 25% of these individuals the epileptic phenotype evolved into Lennox-Gastaut syndrome (LGS). In 12 patients (35%), focal onset epilepsy was defined. In two patients, the epileptic phenotype consisted of generalized myoclonic epilepsy, with a progressive phenotype in one individual harboring a frameshift variant. In approximately 60% of our cohort, seizures were drug-resistant. Malformations of cortical development were noticed in 79% of our patients, mostly on the lissencephaly-pachygyria spectrum, particularly with posterior predominance in a half of them. Midline and infratentorial abnormalities were additionally reported in 45% and 27% of subjects. We have identified three main classes of subphenotypes on the DYNC1H1-related epilepsy spectrum.
SIGNIFICANCE
We propose a classification in which pathogenic de novo DYNC1H1 variants feature drug-resistant IESS in half of cases with potential evolution to LGS (Class 1), developmental and epileptic encephalopathy other than IESS and LGS (Class 2), or less severe focal or genetic generalized epilepsy including a progressive phenotype (Class 3). We observed an association between stalk domain variants and Class 1 phenotypes. The variants p.Arg309His and p.Arg1962His were common and associated with Class 1 subphenotype in our cohort. These findings may aid genetic counseling of patients with DYNC1H1-related epilepsy.
PubMed: 38953796
DOI: 10.1111/epi.18054 -
Journal of Integrative Plant Biology Jul 2024Aporphine alkaloids have diverse pharmacological activities; however, our understanding of their biosynthesis is relatively limited. Previous studies have classified...
Aporphine alkaloids have diverse pharmacological activities; however, our understanding of their biosynthesis is relatively limited. Previous studies have classified aporphine alkaloids into two categories based on the configuration and number of substituents of the D-ring and have proposed preliminary biosynthetic pathways for each category. In this study, we identified two specific cytochrome P450 enzymes (CYP80G6 and CYP80Q5) with distinct activities toward (S)-configured and (R)-configured substrates from the herbaceous perennial vine Stephania tetrandra, shedding light on the biosynthetic mechanisms and stereochemical features of these two aporphine alkaloid categories. Additionally, we characterized two CYP719C enzymes (CYP719C3 and CYP719C4) that catalyzed the formation of the methylenedioxy bridge, an essential pharmacophoric group, on the A- and D-rings, respectively, of aporphine alkaloids. Leveraging the functional characterization of these crucial cytochrome P450 enzymes, we reconstructed the biosynthetic pathways for the two types of aporphine alkaloids in budding yeast (Saccharomyces cerevisiae) for the de novo production of compounds such as (R)-glaziovine, (S)-glaziovine, and magnoflorine. This study provides key insight into the biosynthesis of aporphine alkaloids and lays a foundation for producing these valuable compounds through synthetic biology.
PubMed: 38953746
DOI: 10.1111/jipb.13724 -
Systematic Biology Jul 2024Advances in genomics have greatly enhanced our understanding of mountain biodiversity, providing new insights into the complex and dynamic mechanisms that drive the...
Advances in genomics have greatly enhanced our understanding of mountain biodiversity, providing new insights into the complex and dynamic mechanisms that drive the formation of mountain biotas. These span from broad biogeographic patterns to population dynamics and adaptations to these environments. However, significant challenges remain in integrating large-scale and fine-scale findings to develop a comprehensive understanding of mountain biodiversity. One significant challenge is the lack of genomic data, particularly in historically understudied arid regions where reptiles are a particularly diverse vertebrate group. In the present study, we assembled a de novo genome-wide SNP dataset for the complete endemic reptile fauna of a mountain range (19 described species with more than 600 specimens sequenced), and integrated state-of-the-art biogeographic analyses at the population, species, and community level. Thus, we provide a holistic integration of how a whole endemic reptile community has originated, diversified and dispersed through a mountain system. Our results show that reptiles independently colonized the Hajar Mountains of southeastern Arabia 11 times. After colonization, species delimitation methods suggest high levels of within-mountain diversification, supporting up to 49 deep lineages. This diversity is strongly structured following local topography, with the highest peaks acting as a broad barrier to gene flow among the entire community. Interestingly, orogenic events do not seem key drivers of the biogeographic history of reptiles in this system. Instead, past climatic events seem to have had a major role in this community assemblage. We observe an increase of vicariant events from Late Pliocene onwards, coinciding with an unstable climatic period of rapid shifts between hyper-arid and semiarid conditions that led to the ongoing desertification of Arabia. We conclude that paleoclimate, and particularly extreme aridification, acted as a main driver of diversification in arid mountain systems which is tangled with the generation of highly adapted endemicity. Overall, our study does not only provide a valuable contribution to understanding the evolution of mountain biodiversity, but also offers a flexible and scalable approach that can be reproduced into any taxonomic group and at any discrete environment.
PubMed: 38953551
DOI: 10.1093/sysbio/syae032 -
Environmental Science & Technology Jul 2024Unhealthy lifestyles, obesity, and environmental pollutants are strongly correlated with the development of nonalcoholic fatty liver disease (NAFLD)....
Unhealthy lifestyles, obesity, and environmental pollutants are strongly correlated with the development of nonalcoholic fatty liver disease (NAFLD). Haloacetaldehyde-associated disinfection byproducts (HAL-DBPs) at various multiples of concentrations found in finished drinking water together with high-fat (HF) were examined to gauge their mixed effects on hepatic lipid metabolism. Using new alternative methods (NAMs), studying effects in human cells for risk assessment, we investigated the combined effects of HF and HAL-DBPs on hepatic lipid metabolism and lipotoxicity in immortalized LO-2 human hepatocytes. Coexposure of HAL-DBPs at various multiples of environmental exposure levels with HF increased the levels of triglycerides, interfered with lipogenesis, enhanced fatty acid oxidation, and inhibited the secretion of very low-density lipoproteins. Lipid accumulation caused by the coexposure of HAL-DBPs and HF also resulted in more severe lipotoxicity in these cells. Our results using an NAM-based method provide novel insights into metabolic reprogramming in hepatocytes due to coexposure of HF and HAL-DBPs and strongly suggest that the risk of NAFLD in sensitive populations due to HAL-DBPs and poor lifestyle deserves further investigation both with laboratory and epidemiological tools. We also discuss how results from our studies could be used in health risk assessments for HAL-DBPs.
PubMed: 38953388
DOI: 10.1021/acs.est.3c11009 -
Molecular Ecology Jul 2024The major histocompatibility complex (MHC) multigene family encodes key pathogen-recognition molecules of the vertebrate adaptive immune system. Hyper-polymorphism of...
The major histocompatibility complex (MHC) multigene family encodes key pathogen-recognition molecules of the vertebrate adaptive immune system. Hyper-polymorphism of MHC genes is de novo generated by point mutations, but new haplotypes may also arise by re-shuffling of existing variation through intra- and inter-locus gene conversion. Although the occurrence of gene conversion at the MHC has been known for decades, we still have limited understanding of its functional importance. Here, I took advantage of extensive genetic resources (~9000 sequences) to investigate broad scale macroevolutionary patterns in gene conversion processes at the MHC across nearly 200 avian species. Gene conversion was found to constitute a universal mechanism in birds, as 83% of species showed footprints of gene conversion at either MHC class and 25% of all allelic variants were attributed to gene conversion. Gene conversion processes were stronger at MHC-II than MHC-I, but inter-specific variation at both MHC classes was explained by similar evolutionary scenarios, reflecting fluctuating selection towards different optima and drift. Gene conversion showed uneven phylogenetic distribution across birds and was driven by gene copy number variation, supporting significant role of inter-locus gene conversion processes in the evolution of the avian MHC. Finally, MHC gene conversion was stronger in species with fast life histories (high fecundity) and in long-distance migrants, likely reflecting variation in population sizes and host-pathogen coevolutionary dynamics. The results provide a robust comparative framework for understanding macroevolutionary variation in gene conversion at the avian MHC and reinforce important contribution of this mechanism to functional MHC diversity.
PubMed: 38953291
DOI: 10.1111/mec.17453