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Nucleic Acids Research Jun 2024R-loops cause genome instability, disrupting normal cellular functions. Histone acetylation, particularly by p300/CBP-associated factor (PCAF), is essential for...
R-loops cause genome instability, disrupting normal cellular functions. Histone acetylation, particularly by p300/CBP-associated factor (PCAF), is essential for maintaining genome stability and regulating cellular processes. Understanding how R-loop formation and resolution are regulated is important because dysregulation of these processes can lead to multiple diseases, including cancer. This study explores the role of PCAF in maintaining genome stability, specifically for R-loop resolution. We found that PCAF depletion promotes the generation of R-loop structures, especially during ongoing transcription, thereby compromising genome stability. Mechanistically, we found that PCAF facilitates histone H4K8 acetylation, leading to recruitment of the a double-strand break repair protein (MRE11) and exonuclease 1 (EXO1) to R-loop sites. These in turn recruit Fanconi anemia (FA) proteins, including FANCM and BLM, to resolve the R-loop structure. Our findings suggest that PCAF, histone acetylation, and FA proteins collaborate to resolve R-loops and ensure genome stability. This study therefore provides novel mechanistic insights into the dynamics of R-loops as well as the role of PCAF in preserving genome stability. These results may help develop therapeutic strategies to target diseases associated with genome instability.
PubMed: 38936834
DOI: 10.1093/nar/gkae558 -
Life Sciences Jun 2024Infertility is intricately linked with alterations in circadian rhythms along with physiological decline and stem cell senescence. Yet, the direct involvement of...
Nicotine induces senescence in spermatogonia stem cells by disrupting homeostasis between circadian oscillation and rhythmic mitochondrial dynamics via the SIRT6/Bmal1 pathway.
Infertility is intricately linked with alterations in circadian rhythms along with physiological decline and stem cell senescence. Yet, the direct involvement of circadian mechanisms in nicotine-induced injury to the testes, especially the senescence of spermatogonia stem cells (SSCs), is not well comprehended. This study revealed that nicotine exposure induced testis injury by triggering SSCs senescence along with the upregulation of senescence marker genes and senescence-associated secretory phenotype components. Moreover, nicotine treatment caused mitochondrial hyper-fusion, increased oxidative stress, and DNA damage. Exposure to nicotine was found to suppress the expression of sirtuin 6 (SIRT6), which accelerated the senescence of spermatogonia stem cells (SSCs). This acceleration led to increased acetylation of brain and muscle ARNT-like protein (Bmal1), consequently reducing the expression of Bmal1 protein. Conversely, the overexpression of Bmal1 alleviated mitochondrial hyper-fusion and senescence phenotypes induced by nicotine. Overall, this study unveiled a novel molecular mechanism behind nicotine-induced disorders in spermatogenesis and highlighted the SIRT6/Bmal1 regulatory pathway as a potential therapeutic target for combating nicotine-associated infertility.
PubMed: 38936603
DOI: 10.1016/j.lfs.2024.122860 -
Molecular and Cellular Endocrinology Jun 2024The tricarboxylic acid (TCA) cycle is an essential interface that coordinates cellular metabolism and is as a primary route determining the fate of a variety of fuel...
The tricarboxylic acid (TCA) cycle is an essential interface that coordinates cellular metabolism and is as a primary route determining the fate of a variety of fuel sources, including glucose, fatty acid and glutamate. The crosstalk of nutrients replenished TCA cycle regulates breast cancer (BC) progression by changing substrate levels-induced epigenetic alterations, especially the methylation, acetylation, succinylation and lactylation. Long non-coding RNAs (lncRNA) have dual roles in inhibiting or promoting energy reprogramming, and so altering the metabolic flux of fuel sources to the TCA cycle, which may regulate epigenetic modifications at the cellular level of BC. This narrative review discussed the central role of the TCA cycle in interconnecting numerous fuels and the induced epigenetic modifications, and the underlying regulatory mechanisms of lncRNAs in BC.
PubMed: 38936596
DOI: 10.1016/j.mce.2024.112321 -
International Journal of Biological... Jun 2024Chitin is the second most abundant natural biopolymer, which is composed of N-acetyl glucosamine units linked by β-(1 → 4) Chitosan is an N-deacetylated product of... (Review)
Review
Chitin is the second most abundant natural biopolymer, which is composed of N-acetyl glucosamine units linked by β-(1 → 4) Chitosan is an N-deacetylated product of chitin. Properties of chitosan and chitin, such as biocompatibility, non-toxic nature, and biodegradability, make them successful alternatives for energy and environmental applications. However, their low mechanical properties, small surface area, reduced thermal properties, and greater pore volume restrict the potential for adsorption applications. Multiple investigations have demonstrated that these flaws can be prevented by fabricating chitosan and chitin with carbon-based composites. This review presents a comprehensive analysis of the fabrication of chitosan/chitin carbon-based materials. Furthermore, this review examines the prevalent technologies of functionalizing chitosan/chitin biopolymers and applications of chitin and chitosan as well as chitosan/chitin carbon-based composites, in various environmental fields (mitigating diverse water contaminants and developing biosensors). Also, the subsequent regeneration and reuse of adsorbents were also discussed. Finally, we summarize a concise overview of the difficulties and potential opportunities associated with the utilization of chitosan/chitin carbon-based composites as adsorbents to remove water contaminants.
PubMed: 38936571
DOI: 10.1016/j.ijbiomac.2024.133379 -
Chemico-biological Interactions Jun 2024Hepatic stellate cells (HSCs) are a major source of fibrogenic cells and play a central role in liver fibrogenesis. HSC activation depends on metabolic activation, for...
Hepatic stellate cells (HSCs) are a major source of fibrogenic cells and play a central role in liver fibrogenesis. HSC activation depends on metabolic activation, for which it is well established that fatty acid oxidation (FAO) sustains their rapid proliferative rate. Studies have indicated that tanshinones inhibit HSC activation, however, the anti-fibrosis mechanisms of tanshinones are remain unclear. Herein, we reported that cryptotanshinone (CTS), a lipid-soluble ingredient of Salvia miltiorrhiza Bunge, exhibited the strongest inhibitory effects on HSC-LX2 proliferation and activation. CTS could induce lipocyte phenotype in mouse primary HSC and HSC-LX2. Transcriptomic sequencing and qPCR revealed that CTS regulated fatty acid metabolism and inhibited CPT1A and CPT1B expression. Target prediction suggested CTS regulates lipid metabolism by targeting STAT3. Mechanistically, the level of ATP and acetyl-CoA were reduced by the treatment of CTS, indicating that CTS could inhibit the level of FAO. Furthermore, CTS could inhibit the phosphorylation and nuclear translocation of STAT3. Additionally, CPT1A overexpression reversed the efficacy of CTS. Finally, CTS (40 mg/kg/day) attenuated CCl-induced liver fibrosis and inhibited collagen production and HSC activation. Moreover, the results of immunofluorescence showed that α-SMA and p-STAT3 were co-located, and CTS could reduce the levels of p-STAT3 and α-SMA. In summary, CTS alleviated liver fibrosis by inhibiting the p-STAT3/CPT1A-dependent FAO both in vitro and in vivo, making it a potential candidate drug for the treatment of liver fibrosis.
PubMed: 38936533
DOI: 10.1016/j.cbi.2024.111119 -
MSphere Jun 2024Bacterial ribonuclease E (RNase E) is vital for posttranscriptional regulation by degrading and processing RNA. The RraA protein inhibits RNase E activity through...
Bacterial ribonuclease E (RNase E) is vital for posttranscriptional regulation by degrading and processing RNA. The RraA protein inhibits RNase E activity through protein-protein interactions, exerting a global regulatory effect on gene expression. However, the specific role of RraA remains unclear. In this study, we investigated expression in ZJ-T and identified three promoters responsible for its expression, resulting in transcripts with varying 5'-UTR lengths. During the stationary phase, was significantly posttranscriptionally inhibited. Deletion of had no impact on bacterial growth in rich medium Luria-Bertani broth with salt (LBS) but resulted in decreased biofilm formation and increased resistance to polymyxin B. Transcriptome analysis revealed 350 differentially expressed genes (DEGs) between the wild type and the mutant, while proteome analysis identified 267 differentially expressed proteins (DEPs). Integrative analysis identified 55 genes common to both DEGs and DEPs, suggesting that RraA primarily affects gene expression at the posttranscriptional level. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis demonstrated that RraA facilitates the conversion of fatty acids, propionic acid, and branched-chain amino acids to acetyl-CoA while enhancing amino acid and peptide uptake. Notably, RraA positively regulates the expression of virulence-associated genes, including those involved in biofilm formation and the type VI secretion system. This study expands the understanding of the regulatory network of RraA through transcriptome analysis, emphasizing the importance of proteomic analysis in investigating posttranscriptional regulation.IMPORTANCERraA is an inhibitor protein of ribonuclease E that interacts with and suppresses its endonucleolytic activity, thereby playing a widespread regulatory role in the degradation and maturation of diverse mRNAs and noncoding small RNAs. However, the physiological functions and associated regulon of RraA in have not been fully elucidated. Here, we report that RraA impacts virulence-associated physiological processes, namely, antibiotic resistance and biofilm formation, in . By conducting an integrative analysis of both the transcriptome and proteome, we revealed the involvement of RraA in carbon metabolism, amino acid catabolism, and transport, as well as in the type VI secretion system. Collectively, these findings elucidate the regulatory influence of RraA on multiple pathways associated with metabolism and pathogenesis in .
PubMed: 38934599
DOI: 10.1128/msphere.00020-24 -
Organic & Biomolecular Chemistry Jun 2024Sialyl Lewis (sLe), also known as cancer antigen 19-9, is a tumor-associated carbohydrate antigen. In this article, chemical and chemoenzymatic syntheses of a...
Sialyl Lewis (sLe), also known as cancer antigen 19-9, is a tumor-associated carbohydrate antigen. In this article, chemical and chemoenzymatic syntheses of a tetrasaccharide glycan 1 structurally derived from sLe are reported. Challenges involved in the chemical synthesis include the highly stereoselective construction of 1,2--α-L-fucoside and α-D-sialoside, as well as the assembly of the 3,4-disubstituted -acetylglucosamine subunit. Perbenzylated thiofucoside and -acetyl-5-,4--oxazolidinone protected sialic acid thioglycoside were employed as glycosyl donors, respectively, for the efficient preparation of the desired α-fucoside and α-sialoside. The 3,4-branched glucosamine backbone was established through a 3- and then 4- glycosylation sequence in which the 3-hydroxyl group of the glucosamine moiety was glycosylated first and then the 4-hydroxyl. A facile chemoenzymatic approach was also exploited to synthesize the target molecule. The chemically obtained free disaccharide 30 was sequentially sialylated and fucosylated in an enzyme-catalyzed regio- and stereospecific manner to form 1 in high yields. The linker appended 1 can be covalently attached to a carrier protein for further immunological studies.
PubMed: 38934561
DOI: 10.1039/d4ob00809j -
Neural Regeneration Research Jun 2024TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon. TAU is missorted and aggregated in an array of diseases known as...
TAU is a microtubule-associated protein that promotes microtubule assembly and stability in the axon. TAU is missorted and aggregated in an array of diseases known as tauopathies. Microtubules are essential for neuronal function and regulated via a complex set of post-translational modifications (PTMs), changes of which affect microtubule stability and dynamics, microtubule interaction with other proteins and cellular structures, and mediate recruitment of microtubule-severing enzymes. As impairment of microtubule dynamics causes neuronal dysfunction, we hypothesize cognitive impairment in human disease to be impacted by impairment of microtubule dynamics. We therefore aimed to study the effects of a disease-causing mutation of TAU (P301L) on the levels and localization of microtubule PTMs indicative of microtubule stability and dynamics, to assess whether P301L-TAU causes stability-changing modifications to microtubules. To investigate TAU localization, phosphorylation, and effects on tubulin PTMs, we expressed wild-type or P301L-TAU in human MAPT-KO induced pluripotent stem cell-derived neurons (iNeurons) and studied TAU in neurons in the hippocampus of mice transgenic for human P301L-TAU (pR5 mice). Human neurons expressing the longest TAU isoform (2N4R) with the P301L mutation showed increased TAU phosphorylation at the AT8, but not the p-Ser-262 epitope, and increased polyglutamylation and acetylation of microtubules compared with endogenous TAU-expressing neurons. P301L-TAU showed pronounced somatodendritic presence, but also successful axonal enrichment and a similar axodendritic distribution comparable to exogenously expressed 2N4R-wildtype-TAU. P301L-TAU-expressing hippocampal neurons in transgenic mice showed prominent missorting and tauopathy-typical AT8-phosphorylation of TAU and increased polyglutamylation, but reduced acetylation, of microtubules compared with non-transgenic littermates. In sum, P301L-TAU results in changes in microtubule PTMs, suggestive of impairment of microtubule stability. This is accompanied by missorting and aggregation of TAU in mice but not in iNeurons. Microtubule PTMs/impairment may be of key importance in tauopathies.
PubMed: 38934386
DOI: 10.4103/NRR.NRR-D-23-01742 -
The New Phytologist Jun 2024Climate warming poses a significant threat to global crop production and food security. However, our understanding of the molecular mechanisms governing thermoresponsive...
Climate warming poses a significant threat to global crop production and food security. However, our understanding of the molecular mechanisms governing thermoresponsive development in crops remains limited. Here we report that the auxiliary subunit of N-terminal acetyltransferase A (NatA) in rice OsNAA15 is a prerequisite for rice thermoresponsive growth. OsNAA15 produces two isoforms OsNAA15.1 and OsNAA15.2, via temperature-dependent alternative splicing. Among the two, OsNAA15.1 is more likely to form a stable and functional NatA complex with the potential catalytic subunit OsNAA10, leading to a thermoresponsive N-terminal acetylome. Intriguingly, while OsNAA15.1 promotes plant growth under elevated temperatures, OsNAA15.2 exhibits an inhibitory effect. We identified two glycolate oxidases (GLO1/5) as major substrates from the thermoresponsive acetylome. These enzymes are involved in hydrogen peroxide (HO) biosynthesis via glycolate oxidation. N-terminally acetylated GLO1/5 undergo their degradation through the ubiquitin-proteasome system. This leads to reduced reactive oxygen species (ROS) production, thereby promoting plant growth, particularly under high ambient temperatures. Conclusively, our findings highlight the pivotal role of N-terminal acetylation in orchestrating the glycolate-mediated ROS homeostasis to facilitate thermoresponsive growth in rice.
PubMed: 38934055
DOI: 10.1111/nph.19928 -
Kidney Research and Clinical Practice Jun 2024Traditional acute kidney injury (AKI) classifications, which are centered around semi-anatomical lines, can no longer capture the complexity of AKI. By employing...
Traditional acute kidney injury (AKI) classifications, which are centered around semi-anatomical lines, can no longer capture the complexity of AKI. By employing strategies to identify predictive and prognostic enrichment targets, experts could gain a deeper comprehension of AKI's pathophysiology, allowing for the development of treatment-specific targets and enhancing individualized care. Subphenotyping, which is enriched with AKI biomarkers, holds insights into distinct risk profiles and tailored treatment strategies that redefine AKI and contribute to improved clinical management. The utilization of biomarkers such as N-acetyl-β-D-glucosaminidase, tissue inhibitor of metalloprotease-2•insulin-like growth factor-binding protein 7, kidney injury molecule-1, and liver fatty acid-binding protein garnered significant attention as a means to predict subclinical AKI. Novel biomarkers offer promise in predicting persistent AKI, with urinary motif chemokine ligand 14 displaying significant sensitivity and specificity. Furthermore, they serve as predictive markers for weaning patients from acute dialysis and offer valuable insights into distinct AKI subgroups. The proposed management of AKI, which is encapsulated in a structured flowchart, bridges the gap between research and clinical practice. It streamlines the utilization of biomarkers and subphenotyping, promising a future in which AKI is swiftly identified and managed with unprecedented precision. Incorporating kidney biomarkers into strategies for early AKI detection and the initiation of AKI care bundles has proven to be more effective than using care bundles without these novel biomarkers. This comprehensive approach represents a significant stride toward precision medicine, enabling the identification of high-risk subphenotypes in patients with AKI.
PubMed: 38934040
DOI: 10.23876/j.krcp.23.284