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Advanced Science (Weinheim,... Feb 2024Glioblastoma (GBM) is a lethal cancer characterized by hypervascularity and necrosis associated with hypoxia. Here, it is found that hypoxia preferentially induces the...
Glioblastoma (GBM) is a lethal cancer characterized by hypervascularity and necrosis associated with hypoxia. Here, it is found that hypoxia preferentially induces the actin-binding protein, Transgelin (TAGLN), in GBM stem cells (GSCs). Mechanistically, TAGLN regulates HIF1α transcription and stabilizes HDAC2 to deacetylate p53 and maintain GSC self-renewal. To translate these findings into preclinical therapeutic paradigm, it is found that sodium valproate (VPA) is a specific inhibitor of TAGLN/HDAC2 function, with augmented efficacy when combined with natural borneol (NB) in vivo. Thus, TAGLN promotes cancer stem cell survival in hypoxia and informs a novel therapeutic paradigm.
Topics: Humans; Glioblastoma; Tumor Suppressor Protein p53; Acetylation; Brain Neoplasms; Microfilament Proteins; Hypoxia; Neoplastic Stem Cells; Muscle Proteins
PubMed: 38087889
DOI: 10.1002/advs.202305620 -
British Journal of Cancer Aug 2023Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the...
BACKGROUND
Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis.
METHODS
We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test).
RESULTS
Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - OR: 1.62, 95% CI: 1.34-1.96; OR: 1.41, 95% CI: 1.30-1.54; OR: 1.22, 95% CI: 1.13-1.31; p-value: 5.46 × 10) and 13q14.13 (rs9526201, LRCH1 - OR: 2.11, 95% CI: 1.56-2.83; OR: 1.52, 95% CI: 1.38-1.68; OR: 1.13, 95% CI: 1.06-1.21; p-value: 7.84 × 10).
DISCUSSION
These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.
Topics: Humans; Gene-Environment Interaction; Genetic Predisposition to Disease; Risk Factors; Diabetes Mellitus; Colorectal Neoplasms; Polymorphism, Single Nucleotide; Genome-Wide Association Study; Microfilament Proteins
PubMed: 37365285
DOI: 10.1038/s41416-023-02312-z -
Proceedings of the National Academy of... Sep 2023Cellular form and function are controlled by the assembly and stability of actin cytoskeletal structures-but disassembling/pruning these structures is equally essential...
Cellular form and function are controlled by the assembly and stability of actin cytoskeletal structures-but disassembling/pruning these structures is equally essential for the plasticity and remodeling that underlie behavioral adaptations. Importantly, the mechanisms of actin assembly have been well-defined-including that it is driven by actin's polymerization into filaments (F-actin) and then often bundling by crosslinking proteins into stable higher-order structures. In contrast, it remains less clear how these stable bundled F-actin structures are rapidly disassembled. We now uncover mechanisms that rapidly and extensively disassemble bundled F-actin. Using biochemical, structural, and imaging assays with purified proteins, we show that F-actin bundled with one of the most prominent crosslinkers, fascin, is extensively disassembled by Mical, the F-actin disassembly enzyme. Furthermore, the product of this Mical effect, Mical-oxidized actin, is poorly bundled by fascin, thereby further amplifying Mical's disassembly effects on bundled F-actin. Moreover, another critical F-actin regulator, cofilin, also affects fascin-bundled filaments, but we find herein that it synergizes with Mical to dramatically amplify its disassembly of bundled F-actin compared to the sum of their individual effects. Genetic and high-resolution cellular assays reveal that Mical also counteracts crosslinking proteins/bundled F-actin in vivo to control cellular extension, axon guidance, and Semaphorin/Plexin cell-cell repulsion. Yet, our results also support the idea that fascin-bundling serves to dampen Mical's F-actin disassembly in vitro and in vivo-and that physiologically relevant cellular remodeling requires a fine-tuned interplay between the factors that build bundled F-actin networks and those that disassemble them.
Topics: Actins; Actin Depolymerizing Factors; Actin Cytoskeleton; Cytoskeleton; Axon Guidance
PubMed: 37725655
DOI: 10.1073/pnas.2309955120 -
Arteriosclerosis, Thrombosis, and... Aug 2023Thoracic aortic aneurysms (TAAs) are abnormal aortic dilatations and a major cardiovascular complication of Marfan syndrome. We previously demonstrated a critical role...
BACKGROUND
Thoracic aortic aneurysms (TAAs) are abnormal aortic dilatations and a major cardiovascular complication of Marfan syndrome. We previously demonstrated a critical role for vascular smooth muscle (VSM) SirT1 (sirtuin-1), a lysine deacetylase, against maladaptive aortic remodeling associated with chronic oxidative stress and aberrant activation of MMPs (matrix metalloproteinases).
METHODS
In this study, we investigated whether redox dysregulation of SirT1 contributed to the pathogenesis of TAA using fibrillin-1 hypomorphic mice (Fbn1), an established model of Marfan syndrome prone to aortic dissection/rupture.
RESULTS
Oxidative stress markers 3-nitrotyrosine and 4-hydroxynonenal were significantly elevated in aortas of patients with Marfan syndrome. Moreover, reversible oxidative post-translational modifications (rOPTM) of protein cysteines, particularly S-glutathionylation, were dramatically increased in aortas of Fbn1 mice, before induction of severe oxidative stress markers. Fbn1 aortas and VSM cells exhibited an increase in rOPTM of SirT1, coinciding with the upregulation of acetylated proteins, an index of decreased SirT1 activity, and increased MMP2/9 activity. Mechanistically, we demonstrated that TGFβ (transforming growth factor beta), which was increased in Fbn1 aortas, stimulated rOPTM of SirT1, decreasing its deacetylase activity in VSM cells. VSM cell-specific deletion of SirT1 in Fbn1 mice (SMKO-Fbn1) caused a dramatic increase in aortic MMP2 expression and worsened TAA progression, leading to aortic rupture in 50% of SMKO-Fbn1 mice, compared with 25% of Fbn1 mice. rOPTM of SirT1, rOPTM-mediated inhibition of SirT1 activity, and increased MMP2/9 activity were all exacerbated by the deletion of Glrx (glutaredoxin-1), a specific deglutathionylation enzyme, while being corrected by overexpression of Glrx or of an oxidation-resistant SirT1 mutant in VSM cells.
CONCLUSIONS
Our novel findings strongly suggest a causal role of S-glutathionylation of SirT1 in the pathogenesis of TAA. Prevention or reversal of SirT1 rOPTM may be a novel therapeutic strategy to prevent TAA and TAA dissection/ruptures in individuals with Marfan syndrome, for which, thus far, no targeted therapy has been developed.
Topics: Mice; Animals; Marfan Syndrome; Matrix Metalloproteinase 2; Fibrillins; Muscle, Smooth, Vascular; Sirtuin 1; Microfilament Proteins; Aortic Aneurysm, Thoracic; Fibrillin-1; Aortic Rupture; Transforming Growth Factor beta; Oxidation-Reduction; Disease Models, Animal; Glutaredoxins
PubMed: 37288573
DOI: 10.1161/ATVBAHA.123.319145 -
Cell Reports Jul 2023Cytokinesis relies on membrane trafficking pathways regulated by Rabs and guanine nucleotide exchange factors (GEFs). During cytokinesis, the intercellular cytokinetic...
Cytokinesis relies on membrane trafficking pathways regulated by Rabs and guanine nucleotide exchange factors (GEFs). During cytokinesis, the intercellular cytokinetic bridge (ICB) connecting daughter cells undergoes abscission, which requires actin depolymerization. Rab35 recruits MICAL1 to oxidize and depolymerize actin filaments. We show that DENND2B, a protein linked to cancer and congenital disorders, functions as a Rab35 GEF, recruiting and activating Rab35 at the ICB. DENND2B's N-terminal region also interacts with an active form of Rab35, suggesting that DENND2B is both a Rab35 GEF and effector. Knockdown of DENND2B delays abscission, leading to multinucleated cells and filamentous actin (F-actin) accumulation at the ICB, impairing recruitment of ESCRT-III at the abscission site. Additionally, F-actin accumulation triggers the formation of a chromatin bridge, activating the NoCut/abscission checkpoint, and DENND2B knockdown activates Aurora B kinase, a hallmark of checkpoint activation. Thus, our study identifies DENND2B as a crucial player in cytokinetic abscission.
Topics: Humans; Actin Cytoskeleton; Actins; Cytokinesis; Endosomal Sorting Complexes Required for Transport; Guanine Nucleotide Exchange Factors; HeLa Cells; Microfilament Proteins; Mixed Function Oxygenases; Tetraploidy; rab GTP-Binding Proteins; DNA-Binding Proteins
PubMed: 37454296
DOI: 10.1016/j.celrep.2023.112795 -
International Journal of Molecular... Nov 2023The aim of this article review is to analyze some models and clinical issues related to the implementation of accelerated diagnostic protocols based on specific cardiac... (Review)
Review
The aim of this article review is to analyze some models and clinical issues related to the implementation of accelerated diagnostic protocols based on specific cardiac biomarkers in patients admitted to the emergency department (ED) with symptoms compatible with acute cardiac disorders. Four specific clinical issues will be discussed in detail: (a) pathophysiological and clinical interpretations of circulating hs-cTnI and hs-cTnT levels; (b) the clinical relevance and estimation of the biological variation of biomarkers in patients admitted to the ED with acute and severe diseases; (c) the role and advantages of the point-of-care testing (POCT) methods for cardiac-specific biomarkers in pre-hospital and hospital clinical practice; and (d) the clinical role of specific cardiac biomarkers in patients with acute heart failure (AHF). In order to balance the risk between a hasty discharge versus the potential harms caused by a cardiac assessment in patients admitted to the ED with suspected acute cardiovascular disease, the measurement of specific cardiac biomarkers is essential for the early identification of the presence of myocardial dysfunction and/or injury and to significantly reduce the length and costs of hospitalization. Moreover, specific cardiac biomarkers (especially hs-cTnI and hs-cTnT) are useful predictors of mortality and major adverse cardiovascular events (MACE) in patients admitted to the ED with suspected acute cardiovascular disease. To guide the implementation of the most rapid algorithms for the diagnosis of Non-ST-Elevation Myocardial Infarction (NSTEMI) into routine clinical practice, clinical scientific societies and laboratory medicine societies should promote collaborative studies specifically designed for the evaluation of the analytical performance and, especially, the cost/benefit ratio resulting from the use of these clinical protocols and POCT methods in the ED clinical practice.
Topics: Humans; Myocardial Infarction; Troponin T; Troponin I; Emergency Service, Hospital; Biomarkers
PubMed: 37958981
DOI: 10.3390/ijms242115998 -
European Heart Journal Aug 2023Whether a single cardiac troponin measurement can safely rule out myocardial infarction in patients presenting within a few hours of symptom onset is uncertain. The...
AIMS
Whether a single cardiac troponin measurement can safely rule out myocardial infarction in patients presenting within a few hours of symptom onset is uncertain. The study aim was to assess the performance of troponin in early presenters.
METHODS AND RESULTS
In patients with possible myocardial infarction, the diagnostic performance of a single measurement of high-sensitivity cardiac troponin I at presentation was evaluated and externally validated in those tested ≤3, 4-12, and >12 h from symptom onset. The limit-of-detection (2 ng/L), rule-out (5 ng/L), and sex-specific 99th centile (16 ng/L in women; 34 ng/L in men) thresholds were compared. In 41 103 consecutive patients [60 (17) years, 46% women], 12 595 (31%) presented within 3 h, and 3728 (9%) had myocardial infarction. In those presenting ≤3 h, a threshold of 2 ng/L had greater sensitivity and negative predictive value [99.4% (95% confidence interval 99.2%-99.5%) and 99.7% (99.6%-99.8%)] compared with 5 ng/L [96.5% (96.2%-96.8%) and 99.3% (99.1%-99.4%)]. In those presenting ≥3 h, the sensitivity and negative predictive value were similar for both thresholds. The sensitivity of the 99th centile was low in early and late presenters at 71.4% (70.6%-72.2%) and 92.5% (92.0%-93.0%), respectively. Findings were consistent in an external validation cohort of 7088 patients.
CONCLUSION
In early presenters, a single measurement of high-sensitivity cardiac troponin I below the limit of detection may facilitate the safe rule out of myocardial infarction. The 99th centile should not be used to rule out myocardial infarction at presentation even in those presenting later following symptom onset.
Topics: Male; Humans; Female; Troponin I; Biomarkers; Myocardial Infarction; Predictive Value of Tests; Troponin T; Emergency Service, Hospital
PubMed: 37350492
DOI: 10.1093/eurheartj/ehad376 -
Molecules and Cells Jul 2023
Topics: Actins; Cytoskeleton
PubMed: 37431161
DOI: 10.14348/molcells.2023.0060 -
Biochemical Society Transactions Feb 2024The Arp2/3 complex, which generates both branched but also linear actin filaments via activation of SPIN90, is evolutionarily conserved in eukaryotes. Several factors... (Review)
Review
The Arp2/3 complex, which generates both branched but also linear actin filaments via activation of SPIN90, is evolutionarily conserved in eukaryotes. Several factors regulate the stability of filaments generated by the Arp2/3 complex to maintain the dynamics and architecture of actin networks. In this review, we summarise recent studies on the molecular mechanisms governing the tuning of Arp2/3 complex nucleated actin filaments, which includes investigations using microfluidics and single-molecule imaging to reveal the mechanosensitivity, dissociation and regeneration of actin branches. We also discuss the high-resolution cryo-EM structure of cortactin bound to actin branches, as well as the differences and similarities between the stability of Arp2/3 complex nucleated branches and linear filaments. These new studies provide a clearer picture of the stabilisation of Arp2/3 nucleated filaments at the molecular level. We also identified gaps in our understanding of how different factors collectively contribute to the stabilisation of Arp2/3 complex-generated actin networks.
Topics: Actin-Related Protein 2-3 Complex; Actins; Actin Cytoskeleton; Cytoskeleton
PubMed: 38288872
DOI: 10.1042/BST20230638 -
Journal of Molecular and Cellular... Sep 2023Hypertension-induced tunica media thickening (TMT) is the most important fundamental for the subsequent complications like stroke and cardiovascular diseases....
Hypertension-induced tunica media thickening (TMT) is the most important fundamental for the subsequent complications like stroke and cardiovascular diseases. Pathogenically, TMT originates from both vascular smooth muscle cells (VSMCs) hypertrophy due to synthesizing more amount of intracellular contractile proteins and excess secretion of extracellular matrix. However, what key molecules are involved in the pathogenesis of TMT is unknown. We hypothesize that formin homology 2 domain-containing protein 1 (FHOD1), an amply expressed mediator for assembly of thin actin filament in VSMCs, is a key regulator for the pathogenesis of TMT. In this study, we found that FHOD1 expression and its phosphorylation/activation were both upregulated in the arteries of three kinds of hypertensive rats. Ang-II induced actin filament formation and hypertrophy through activation and upregulation of FHOD1 in VSMCs. Active FHOD1-mediated actin filament assembly and secretions of collagen-1α/collagen-3α played crucial roles in Ang-II-induced VSMCs hypertrophy in vitro and hypertensive TMT in vivo. Proteomics demonstrated that activated FL-FHOD1 or its C-terminal diaphanous-autoregulatory domain significantly upregulated RNF213 (ring finger protein 213), a 591-kDa cytosolic E3 ubiquitin ligase with its loss-of-functional mutations being a susceptibility gene for Moyamoya disease which has prominent tunica media thinning in both intracranial and systemic arteries. Mechanistically, activated FHOD1 upregulated its downstream effector RNF213 independently of its classical pathway of decreasing G-actin/F-actin ratio, transcription, and translation, but dependently on its C-terminus-mediated stabilization of RNF213 protein. FHOD1-RNF213 signaling dramatically promoted collagen-1α/collagen-3α syntheses in VSMCs. Our results discovered a novel signaling axis of FHOD1-RNF213-collagen-1α/collagen-3α and its key role in the pathogenesis of hypertensive TMT.
Topics: Animals; Rats; Actins; Hypertension; Hypertrophy; Signal Transduction; Transcription Factors; Tunica Media; Formins; Fetal Proteins
PubMed: 37482037
DOI: 10.1016/j.yjmcc.2023.07.008