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Life Science Alliance Sep 2024The unfolded protein response can switch from a pro-survival to a maladaptive, pro-apoptotic mode. During ER stress, IRE1α sensors dimerize, become phosphorylated, and...
The unfolded protein response can switch from a pro-survival to a maladaptive, pro-apoptotic mode. During ER stress, IRE1α sensors dimerize, become phosphorylated, and activate XBP1 splicing, increasing folding capacity in the ER protein factory. The steps that turn on the IRE1α endonuclease activity against endogenous mRNAs during maladaptive ER stress are still unknown. Here, we show that although necessary, IRE1α dimerization is not sufficient to trigger phosphorylation. Random and/or guided collisions among IRE1α dimers are needed to elicit cross-phosphorylation and endonuclease activities. Thus, reaching a critical concentration of IRE1α dimers in the ER membrane is a key event. Formation of stable IRE1α clusters is not necessary for RNase activity. However, clustering could modulate the potency of the response, promoting interactions between dimers and decreasing the accessibility of phosphorylated IRE1α to phosphatases. The stepwise activation of IRE1α molecules and their low concentration at the steady state prevent excessive responses, unleashing full-blown IRE1 activity only upon intense stress conditions.
Topics: Endoribonucleases; Phosphorylation; Protein Serine-Threonine Kinases; Humans; Endoplasmic Reticulum Stress; Protein Multimerization; Unfolded Protein Response; Endoplasmic Reticulum; Ribonucleases
PubMed: 38886017
DOI: 10.26508/lsa.202302562 -
PloS One 2024Drug-drug interaction (DDI) is the combined effects of multiple drugs taken together, which can either enhance or reduce each other's efficacy. Thus, drug interaction...
Drug-drug interaction (DDI) is the combined effects of multiple drugs taken together, which can either enhance or reduce each other's efficacy. Thus, drug interaction analysis plays an important role in improving treatment effectiveness and patient safety. It has become a new challenge to use computational methods to accelerate drug interaction time and reduce its cost-effectiveness. The existing methods often do not fully explore the relationship between the structural information and the functional information of drug molecules, resulting in low prediction accuracy for drug interactions, poor generalization, and other issues. In this paper, we propose a novel method, which is a deep graph contrastive learning model for drug-drug interaction prediction (DeepGCL for brevity). DeepGCL incorporates a contrastive learning component to enhance the consistency of information between different views (molecular structure and interaction network), which means that the DeepGCL model predicts drug interactions by integrating molecular structure features and interaction network topology features. Experimental results show that DeepGCL achieves better performance than other methods in all datasets. Moreover, we conducted many experiments to analyze the necessity of each component of the model and the robustness of the model, which also showed promising results. The source code of DeepGCL is freely available at https://github.com/jzysj/DeepGCL.
Topics: Drug Interactions; Deep Learning; Humans
PubMed: 38885206
DOI: 10.1371/journal.pone.0304798 -
Trends in Psychiatry and Psychotherapy Jun 2024Autism spectrum disorder (ASD) is a neurodevelopmental disorder that has been linked to the dysregulation in the cholinergic and endocannabinoid (EC) system. This study...
INTRODUCTION
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that has been linked to the dysregulation in the cholinergic and endocannabinoid (EC) system. This study systematically reviews the present literature on treatment strategies aimed at enhancing the activity of both systems in ASD models.
METHOD
We performed a systematic evaluation of literatures that investigated the effects of different therapeutic interventions on the components of the cholinergic and EC systems in ASD models, following the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Four databases were searched: Google Scholar, Web of science, EMBASE and MEDLINE/PubMed, between August 2012 and February 2023. The selected research papers' references were also examined. Twelve papers (five for cholinergic system, six for EC system and one for the two systems) were reviewed in this study of prior relevant treatment strategies that impact both systems. There were 77 studies cited in total.
RESULTS
The majority of research revealed that different therapeutic interventions down-regulated cannabinoid 1 (CB1) receptors, and the systems hydrolyzing enzymes and up-regulated EC, Alpha7 nicotinic acetylcholine receptor (α7 nAChR), and acetylcholine signaling molecules. The regulation of the components of the cholinergic and EC systems by the therapeutics generally enhanced behaviors in ASD models.
CONCLUSION
It is possible that there are therapeutic interventions assessed in one of the systems that may be effective in treating the core ASD-associated phenotype. The benefits of the reviewed therapeutic interventions in this study need to be further investigated in randomized, blind, placebo-controlled clinical trials.
PubMed: 38885129
DOI: 10.47626/2237-6089-2024-0791 -
ChemistryOpen Jun 2024Quinolone antibiotics are extensively used clinically for human treatment and in agriculture. However, improper and excessive use can lead to the persistence of...
RATIONALE
Quinolone antibiotics are extensively used clinically for human treatment and in agriculture. However, improper and excessive use can lead to the persistence of quinolone residues in animal tissues, potentially accumulating in the human body and posing health risks. Investigating the correlation between mass spectrometry cleavage patterns and molecular structural features enhances the analytical framework for detecting trace or unknown impurities in quinolones.
METHODS
To collect data, we employed triple quadrupole linear ion trap mass spectrometry in electrospray positive ion mode. Primary mass spectrometry scanning was utilized to confirm parent ions, while secondary mass spectrometry scanning enabled the observation of fragment ions. The cleavage characteristics and pathways of the compounds were inferred from accurate mass-to-charge ratios obtained from both primary and secondary mass spectrometry.
RESULTS
Under soft ionization conditions, the compounds generally exhibited characteristic fragment ions of [M+H-HO], [M+H-CO], and [M+H-HO-CO]. Additionally, subtle variations were observed in each compound due to differences in modifying groups. For instance, upon deacidification, the piperazine ring structure underwent breakage and rearrangement, yielding fragment ion peaks devoid of neutral molecules such as CHN, CHN, or CHN. Notably, compounds featuring a cyclopropyl substituent group at the N-1 position typically exhibited characteristic fragments resulting from the loss of the cyclopropyl radical (⋅CH). Moreover, substituents at the N-1 and C-8 positions, when linked to form a six-membered carbocyclic ring, were prone to cleavage, releasing the neutral CH molecule.
CONCLUSION
Quinolone antibiotics share structural similarities in their parent nuclei, leading to partially similar cleavage pathways. Nevertheless, distinct cleavage patterns emerge due to variations in functional groups. According to the difference of mass spectrometry cleavage patterns, it can provide an identification basis for the measured detection of antibiotics.
PubMed: 38884376
DOI: 10.1002/open.202400061 -
Frontiers in Oncology 2024Mitomycin-C (MMC) chemotherapy is a well-established anti-cancer treatment for non-muscle-invasive bladder cancer (NMIBC). However, despite comprehensive biological...
Mitomycin-C (MMC) chemotherapy is a well-established anti-cancer treatment for non-muscle-invasive bladder cancer (NMIBC). However, despite comprehensive biological research, the complete mechanism of action and an ideal regimen of MMC have not been elucidated. In this study, we present a theoretical investigation of NMIBC growth and its treatment by continuous administration of MMC chemotherapy. Using temporal ordinary differential equations (ODEs) to describe cell populations and drug molecules, we formulated the first mathematical model of tumor-immune interactions in the treatment of MMC for NMIBC, based on biological sources. Several hypothetical scenarios for NMIBC under the assumption that tumor size correlates with cell count are presented, depicting the evolution of tumors classified as small, medium, and large. These scenarios align qualitatively with clinical observations of lower recurrence rates for tumor size ≤ 30[mm] with MMC treatment, demonstrating that cure appears up to a theoretical [mm] tumor size threshold, given specific parameters within a feasible biological range. The unique use of mole units allows to introduce a new method for theoretical pre-treatment assessments by determining MMC drug doses required for a cure. In this way, our approach provides initial steps toward personalized MMC chemotherapy for NMIBC patients, offering the possibility of new insights and potentially holding the key to unlocking some of its mysteries.
PubMed: 38884094
DOI: 10.3389/fonc.2024.1352065 -
Evolutionary Bioinformatics Online 2024Pseudogenes are sequences that have lost the ability to transcribe RNA molecules or encode truncated but possibly functional proteins. While they were once considered to...
BACKGROUND
Pseudogenes are sequences that have lost the ability to transcribe RNA molecules or encode truncated but possibly functional proteins. While they were once considered to be meaningless remnants of evolution, recent researches have shown that pseudogenes play important roles in various biological processes. However, the studies of pseudogenes in the silkworm, an important model organism, are limited and have focused on single or only a few specific genes.
OBJECTIVE
To fill these gaps, we present a systematic genome-wide studies of pseudogenes in the silkworm.
METHODS
We identified the pseudogenes in the silkworm using the silkworm genome assemblies, transcriptome, protein sequences from silkworm and its related species. Then we used transcriptome datasets from 832 RNA-seq analyses to construct spatio-temporal expression profiles for these pseudogenes. Additionally, we identified tissue-specifically expressed and differentially expressed pseudogenes to further understand their characteristics. Finally, the functional roles of pseudogenes as lncRNAs were systematically analyzed.
RESULTS
We identified a total of 4410 pseudogenes, which were grouped into 4 groups, including duplications (DUPs), unitary pseudogenes (Unitary), processed pseudogenes (retropseudogenes, RETs), and fragments (FRAGs). The most of pseudogenes in the domestic silkworm were generated before the divergence of wild and domestic silkworm, however, the domestication may also involve in the accumulation of pseudogenes. These pseudogenes were clearly divided into 2 cluster, a highly expressed and a lowly expressed, and the posterior silk gland was the tissue with the most tissue-specific pseudogenes (199), implying these pseudogenes may be involved in the development and function of silkgland. We identified 3299 lncRNAs in these pseudogenes, and the target genes of these lncRNAs in silkworm pseudogenes were enriched in the egg formation and olfactory function.
CONCLUSIONS
This study replenishes the genome annotations for silkworm, provide valuable insights into the biological roles of pseudogenes. It will also contribute to our understanding of the complex gene regulatory networks in the silkworm and will potentially have implications for other organisms as well.
PubMed: 38883803
DOI: 10.1177/11769343241261814 -
MedRxiv : the Preprint Server For... Jun 2024CD4-mimetics (CD4mcs) are small molecule compounds that mimic the interaction of the CD4 receptor with HIV-1 envelope glycoproteins (Env). Env from primary viruses...
UNLABELLED
CD4-mimetics (CD4mcs) are small molecule compounds that mimic the interaction of the CD4 receptor with HIV-1 envelope glycoproteins (Env). Env from primary viruses normally samples a "closed" conformation which occludes epitopes recognized by CD4-induced (CD4i) non-neutralizing antibodies (nnAbs). CD4mcs induce conformational changes on Env resulting in the exposure of these otherwise inaccessible epitopes. Here we evaluated the capacity of plasma from a cohort of 50 people living with HIV to recognize HIV-1-infected cells and eliminate them by antibody-dependent cellular cytotoxicity (ADCC) in the presence of a potent indoline CD4mc. We observed a marked heterogeneity among plasma samples. By measuring the levels of different families of CD4i Abs, we found that the levels of anti-cluster A, anti-coreceptor binding site and anti-gp41 cluster I antibodies are responsible for plasma-mediated ADCC in presence of CD4mc.
IMPORTANCE
There are several reasons that make it difficult to target the HIV reservoir. One of them, is the capacity of infected cells to prevent the recognition of HIV-1 envelope glycoproteins (Env) by commonly-elicited antibodies in people living with HIV. Small CD4-mimetic compounds expose otherwise occluded Env epitopes, thus enabling their recognition by non-neutralizing antibodies. A better understanding of the contribution of these antibodies to eliminate infected cells in presence of CD4mc could lead to the development of therapeutic cure strategies.
PubMed: 38883797
DOI: 10.1101/2024.06.02.24308281 -
Research Square Jun 2024Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin...
Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.
PubMed: 38883782
DOI: 10.21203/rs.3.rs-4362092/v1 -
Research Square Jun 2024Mutations in RNA splicing factor genes including SF3B1, U2AF1, SRSF2, and ZRSR2 have been reported to contribute to development of myeloid neoplasms including...
Mutations in RNA splicing factor genes including SF3B1, U2AF1, SRSF2, and ZRSR2 have been reported to contribute to development of myeloid neoplasms including myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML). Chemical tools targeting cells carrying these mutant genes remain limited and underdeveloped. Among the four proteins, mutant U2AF1 (U2AF1 ) acquires an altered 3' splice site selection preference and co-operates with the wild-type U2AF1 (U2AF1 ) to change various gene isoform patterns to support MDS cells survival and proliferation. U2AF1 mutations in MDS cells are always heterozygous and the cell viability is reduced when exposed to additional insult affecting U2AF1 function. To investigate if the pharmacological inhibition of U2AF1wt function can provoke drug-induced vulnerability of cells harboring U2AF1mut, we conducted a fragment-based library screening campaign to discover compounds targeting the U2AF homology domain (UHM) in U2AF1 that is required for the formation of the U2AF1/U2AF2 complex to define the 3' splice site. The most promising hit (SF1-8) selectively inhibited growth of leukemia cell lines overexpressingU2AF1 and human primary MDS cells carrying U2AF1 . RNA-seq analysis of K562-U2AF1 following treatment with SF1-8 further revealed alteration of isoform patterns for a set of proteins that impair or rescue pathways associated with endocytosis, intracellular vesicle transport, and secretion. Our data suggested that further optimization of SF1-8 is warranted to obtain chemical probes that can be used to evaluate the therapeutic concept of inducing lethality to U2AF1 cells by inhibiting the U2AF1 protein.
PubMed: 38883705
DOI: 10.21203/rs.3.rs-4477663/v1 -
Journal of Thoracic Disease May 2024Ground glass nodules (GGNs) in the lung are considered to be a high-risk factor of lung adenocarcinoma. Immediate surgery is not recommended for GGNs patients, and...
BACKGROUND
Ground glass nodules (GGNs) in the lung are considered to be a high-risk factor of lung adenocarcinoma. Immediate surgery is not recommended for GGNs patients, and low-dose computed tomography (CT) is often used for observation and follow-up, which brings high psychological and economic burden to the patient.
METHODS
Three traditional Chinese medicine (TCM) prescriptions for the treatment of GGNs were found through database including PubMed, Google Scholar, and China National Knowledge Infrastructure (CNKI), Scopus and so on. The possible targets of the active ingredients of the TCM preparations and the gene targets of GGNs were screened out from Traditional Chinese Medicine Systems Pharmacology (TCMSP), UniProt and GeneCards. Network visualization was realized via STRING, Cytoscape 3.7.2, Evenn, DAVID and Hiplot. Finally, molecular docking Vina and PyMOL software were performed to further explore the possibility of drug-target interactions using PubChem compounds, protein data bank (PDB) database, Autodocktools and Autodock.
RESULTS
Three TCM preparations could target the same 13 potential therapeutic targets in GGNs. From network pharmacology, 14 signaling pathways, the functions of the significant targets, an effective ingredient in TCM prescriptions and its functions were obtained.
CONCLUSIONS
Chinese herbal formulas containing quercetin could be a potential treatment for GGNs, targeting C-reactive protein (), tumor necrosis factor (), interferon gamma (), intercellular adhesion molecule 1 (), and vascular endothelial growth factor A () through the hypoxia-inducible factor 1 (HIF-1) pathway, mitogen-activated protein kinase (MAPK) signaling pathway, and leukocyte transendothelial migration.
PubMed: 38883612
DOI: 10.21037/jtd-23-1492