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Molecules (Basel, Switzerland) Aug 2023CAG is a burdensome and progressive disease. Numerous studies have shown the effectiveness of RUT in digestive system diseases. The therapeutic effects of RUT on...
CAG is a burdensome and progressive disease. Numerous studies have shown the effectiveness of RUT in digestive system diseases. The therapeutic effects of RUT on MNNG-induced CAG and the potential mechanisms were probed. MNNG administration was employed to establish a CAG model. The HE and ELISA methods were applied to detect the treatment effects. WB, qRT-PCR, immunohistochemistry, TUNEL, and GES-1 cell flow cytometry approaches were employed to probe the mechanisms. The CAG model was successfully established. The ELISA and HE staining data showed that the RUT treatment effects on CAG rats were reflected by the amelioration of histological damage. The qRT-PCR and WB analyses indicated that the protective effect of RUT is related to the upregulation of the SHH pathway and downregulation of the downstream of apoptosis to improve gastric cellular survival. Our data suggest that RUT induces a gastroprotective effect by upregulating the SHH signaling pathway and stimulating anti-apoptosis downstream.
Topics: Mice; Rats; Animals; Hedgehog Proteins; Gastritis, Atrophic; Methylnitronitrosoguanidine; Quinazolines; Nitrosoguanidines; Signal Transduction
PubMed: 37687125
DOI: 10.3390/molecules28176294 -
Proceedings of the National Academy of... Jul 2023Circadian behavioral rhythms in are regulated by about 75 pairs of brain neurons. They all express the core clock genes but have distinct functions and gene expression...
Circadian behavioral rhythms in are regulated by about 75 pairs of brain neurons. They all express the core clock genes but have distinct functions and gene expression profiles. To understand the importance of these distinct molecular programs, neuron-specific gene manipulations are essential. Although RNAi based methods are standard to manipulate gene expression in a cell-specific manner, they are often ineffective, especially in assays involving smaller numbers of neurons or weaker Gal4 drivers. We and others recently exploited a neuron-specific CRISPR-based method to mutagenize genes within circadian neurons. Here, we further explore this approach to mutagenize three well-studied clock genes: the transcription factor gene the photoreceptor gene (), and the neuropeptide gene (pigment dispersing factor). The CRISPR-based strategy not only reproduced their known phenotypes but also assigned function for different light-mediated phenotypes to discrete, different subsets of clock neurons. We further tested two recently published methods for temporal regulation in adult neurons, inducible Cas9 and the auxin-inducible gene expression system. The results were not identical, but both approaches successfully showed that the adult-specific knockout of the neuropeptide reproduces the canonical loss-of-function mutant phenotypes. In summary, a CRISPR-based strategy is a highly effective, reliable, and general method to temporally manipulate gene function in specific adult neurons.
Topics: Animals; Drosophila melanogaster; Drosophila Proteins; Circadian Rhythm; Neuropeptides; Cryptochromes; Neurons; Circadian Clocks
PubMed: 37428902
DOI: 10.1073/pnas.2303779120 -
Nature Communications Nov 2023As observed in cancers, individual mutagens and defects in DNA repair create distinctive mutational signatures that combine to form context-specific spectra within...
As observed in cancers, individual mutagens and defects in DNA repair create distinctive mutational signatures that combine to form context-specific spectra within cells. We reasoned that similar processes must occur in bacterial lineages, potentially allowing decomposition analysis to detect both disruption of DNA repair processes and exposure to niche-specific mutagens. Here we reconstruct mutational spectra for 84 clades from 31 diverse bacterial species and find distinct mutational patterns. We extract signatures driven by specific DNA repair defects using hypermutator lineages, and further deconvolute the spectra into multiple signatures operating within different clades. We show that these signatures are explained by both bacterial phylogeny and replication niche. By comparing mutational spectra of clades from different environmental and biological locations, we identify niche-associated mutational signatures, and then employ these signatures to infer the predominant replication niches for several clades where this was previously obscure. Our results show that mutational spectra may be associated with sites of bacterial replication when mutagen exposures differ, and can be used in these cases to infer transmission routes for established and emergent human bacterial pathogens.
Topics: Humans; Mutation; Neoplasms; DNA Repair; Mutagens; DNA Mutational Analysis
PubMed: 37925514
DOI: 10.1038/s41467-023-42916-w -
Proteins Dec 2023The results of tertiary structure assessment at CASP15 are reported. For the first time, recognizing the outstanding performance of AlphaFold 2 (AF2) at CASP14, all...
The results of tertiary structure assessment at CASP15 are reported. For the first time, recognizing the outstanding performance of AlphaFold 2 (AF2) at CASP14, all single-chain predictions were assessed together, irrespective of whether a template was available. At CASP15, there was no single stand-out group, with most of the best-scoring groups-led by PEZYFoldings, UM-TBM, and Yang Server-employing AF2 in one way or another. Many top groups paid special attention to generating deep Multiple Sequence Alignments (MSAs) and testing variant MSAs, thereby allowing them to successfully address some of the hardest targets. Such difficult targets, as well as lacking templates, were typically proteins with few homologues. Local divergence between prediction and target correlated with localization at crystal lattice or chain interfaces, and with regions exhibiting high B-factor factors in crystal structure targets, and should not necessarily be considered as representing error in the prediction. However, analysis of exposed and buried side chain accuracy showed room for improvement even in the latter. Nevertheless, a majority of groups produced high-quality predictions for most targets, which are valuable for experimental structure determination, functional analysis, and many other tasks across biology. These include those applying methods similar to those used to generate major resources such as the AlphaFold Protein Structure Database and the ESM Metagenomic atlas: the confidence estimates of the former were also notably accurate.
Topics: Furylfuramide; Computational Biology; Models, Molecular; Proteins; Sequence Alignment
PubMed: 37746927
DOI: 10.1002/prot.26593 -
Acta Haematologica 2024Small molecules targeting Bruton's tyrosine kinase (BTK) and B-cell lymphoma-2 have become the standard of care for the treatment of chronic lymphocytic leukemia (CLL),... (Review)
Review
BACKGROUND
Small molecules targeting Bruton's tyrosine kinase (BTK) and B-cell lymphoma-2 have become the standard of care for the treatment of chronic lymphocytic leukemia (CLL), replacing chemoimmunotherapy (CIT) in most clinical settings. Ongoing trials explore targeted combinations and minimal residual disease-driven treatment cessation. These dramatic shifts in the current and upcoming treatment landscape of CLL raise the need to reevaluate existing prognostic markers and develop novel ones.
SUMMARY
This review examines prognostic markers in CLL patients treated with standard and investigational targeted therapies. Specifically, initial treatment of TP53 aberrant patients with a BTK inhibitor can achieve 70% progression-free survival (PFS) at 5 years, outperforming the 15% 5-year PFS with a CIT regimen containing fludarabine, cyclophosphamide, and rituximab (FCR). The prognostic implications of the immunoglobulin heavy chain variable gene (IGHV) mutation status have also changed. Unmutated IGHV is associated with inferior PFS and overall survival after FCR and inferior PFS with fixed-duration therapy with venetoclax and anti-CD20 monoclonal antibody but not with continuous BTK inhibitor treatment.
KEY MESSAGES
(1) Genetic variables (e.g., TP53 aberration, IGHV mutation, complex karyotype) have a prognostic significance in CLL patients treated with targeted therapy. (2) Understanding the prognostic and predictive values of these markers is critical for the development of a risk-adapted treatment strategy in CLL.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Prognosis; Cyclophosphamide; Rituximab; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37703841
DOI: 10.1159/000533704 -
Frontiers in Immunology 2023Allogeneic hematopoietic stem cell transplantation (HSCT) provides the only potentially curative option for multiple hematological conditions. However, allogeneic HSCT... (Review)
Review
Allogeneic hematopoietic stem cell transplantation (HSCT) provides the only potentially curative option for multiple hematological conditions. However, allogeneic HSCT outcomes rely on an optimal balance of effective immune recovery, minimal graft-versus-host disease (GVHD), and lasting control of disease. The quest to attain this balance has proven challenging over the past few decades. The two-step approach to HSCT was conceptualized and pioneered at Thomas Jefferson University in 2005 and remains the main platform for allografting at our institution. Following administration of the transplant conditioning regimen, patients receive a fixed dose of donor CD3+ cells (HSCT step one-DLI) as the lymphoid portion of the graft on day -6 with the aim of optimizing and controlling T cell dosing. Cyclophosphamide (CY) is administered after the DLI (days -3 and -2) to induce donor-recipient bidirectional tolerance. On day 0, a CD34-selected stem cell graft is given as the myeloid portion of the graft (step two). In this two-step approach, the stem cell graft is infused after CY tolerization, which avoids exposure of the stem cells to an alkylating agent, allowing rapid count recovery. Here, the two-step platform is described with a focus on key results from studies over the past two decades. Finally, this review details lessons learned and current strategies to optimize the graft-versus-tumor effect and limit transplant-related toxicities.
Topics: Humans; Antigens, CD34; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation
PubMed: 37720225
DOI: 10.3389/fimmu.2023.1237782 -
Frontiers in Genetics 2023It has been 70 years since Barbara McClintock discovered transposable elements (TE), and the mechanistic studies and functional applications of transposable elements... (Review)
Review
It has been 70 years since Barbara McClintock discovered transposable elements (TE), and the mechanistic studies and functional applications of transposable elements have been at the forefront of life science research. As an essential part of the genome, TEs have been discovered in most species of prokaryotes and eukaryotes, and the relative proportion of the total genetic sequence they comprise gradually increases with the expansion of the genome. In humans, TEs account for about 40% of the genome and are deeply involved in gene regulation, chromosome structure maintenance, inflammatory response, and the etiology of genetic and non-genetic diseases. In-depth functional studies of TEs in mammalian cells and the human body have led to a greater understanding of these fundamental biological processes. At the same time, as a potent mutagen and efficient genome editing tool, TEs have been transformed into biological tools critical for developing new techniques. By controlling the random insertion of TEs into the genome to change the phenotype in cells and model organisms, critical proteins of many diseases have been systematically identified. Exploiting the TE's highly efficient insertion activity has driven the development of cutting-edge sequencing technologies. Recently, a new technology combining CRISPR with TEs was reported, which provides a novel targeted insertion system to both academia and industry. We suggest that interrogating biological processes that generally depend on the actions of TEs with TEs-derived genetic tools is a very efficient strategy. For example, excessive activation of TEs is an essential factor in the occurrence of cancer in humans. As potent mutagens, TEs have also been used to unravel the key regulatory elements and mechanisms of carcinogenesis. Through this review, we aim to effectively combine the traditional views of TEs with recent research progress, systematically link the mechanistic discoveries of TEs with the technological developments of TE-based tools, and provide a comprehensive approach and understanding for researchers in different fields.
PubMed: 38098473
DOI: 10.3389/fgene.2023.1290146 -
Blood Cancer Journal Oct 2023
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; Bendamustine Hydrochloride; B-Cell Maturation Antigen; Cyclophosphamide; Immunotherapy, Adoptive; Cell- and Tissue-Based Therapy
PubMed: 37833271
DOI: 10.1038/s41408-023-00929-0 -
Kidney360 Dec 2023ANCA-associated vasculitis (AAV) belongs to a group of small vessel systemic vasculitides characterized by granulomatous and neutrophilic inflammation of various... (Review)
Review
ANCA-associated vasculitis (AAV) belongs to a group of small vessel systemic vasculitides characterized by granulomatous and neutrophilic inflammation of various tissues. Patients often have circulating autoantibodies targeting neutrophilic antigens. Although AAV was once associated with severe end-organ damage and extremely high mortality rates, the use of glucocorticoids and cyclophosphamide led to a paradigm change in its treatment. Over the past 20 years, significant progress in understanding the immunopathogenesis of AAV has enabled development of targeted immunotherapies, providing a much better prognosis for patients. This review describes the evolution of treatment of AAV, particularly for patients with kidney involvement.
Topics: Humans; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Cyclophosphamide; Prognosis; Glucocorticoids; Kidney
PubMed: 37927005
DOI: 10.34067/KID.0000000000000289 -
DNA Repair Jul 2024Multiple separate repair mechanisms safeguard the genome against various types of DNA damage, and their failure can increase the rate of spontaneous mutagenesis. The... (Review)
Review
Multiple separate repair mechanisms safeguard the genome against various types of DNA damage, and their failure can increase the rate of spontaneous mutagenesis. The malfunction of distinct repair mechanisms leads to genomic instability through different mutagenic processes. For example, defective mismatch repair causes high base substitution rates and microsatellite instability, whereas homologous recombination deficiency is characteristically associated with deletions and chromosome instability. This review presents a comprehensive collection of all mutagenic phenotypes associated with the loss of each DNA repair mechanism, drawing on data from a variety of model organisms and mutagenesis assays, and placing greatest emphasis on systematic analyses of human cancer datasets. We describe the latest theories on the mechanism of each mutagenic process, often explained by reliance on an alternative repair pathway or the error-prone replication of unrepaired, damaged DNA. Aided by the concept of mutational signatures, the genomic phenotypes can be used in cancer diagnosis to identify defective DNA repair pathways.
Topics: Humans; Mutagenesis; DNA Repair; Animals; Neoplasms; DNA Damage; Genomic Instability; DNA Mismatch Repair
PubMed: 38788323
DOI: 10.1016/j.dnarep.2024.103694