Nitric oxide facilitates the S‐nitrosylation and deubiquitination of Notch1 protein to maintain cancer stem cells in human NSCLC DOI Creative Commons
Tenglong Zhang, Jiaxin Lei, Ming Zheng

et al.

Journal of Cellular and Molecular Medicine, Journal Year: 2024, Volume and Issue: 28(21)

Published: Nov. 1, 2024

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality, with tumour heterogeneity, fueled by stem cells (CSCs), intricately linked to treatment resistance. Therefore, it imperative advance therapeutic strategies targeting CSCs in NSCLC. In this study, we utilized RNA sequencing investigate metabolic pathway alterations NSCLC and identified a crucial role nitric oxide (NO) metabolism governing CSC stemness, primarily through modulation Notch1 protein. Mechanistically, NO-induced S-nitrosylation facilitated its interaction deubiquitylase UCHL1, increased protein stability enhanced stemness. By inhibiting NO synthesis downregulating UCHL1 expression, validated impact on Notch signalling Importantly, effectively reduced populations within patient-derived organoids (PDOs) during radiotherapy. This mechanism presents promising target surmount radiotherapy resistance treatment.

Language: Английский

Expanding the Frontiers of Guardian Antioxidant Selenoproteins in Cardiovascular Pathophysiology DOI
Tommaso Angelone, Carmine Rocca, Vincenzo Lionetti

et al.

Antioxidants and Redox Signaling, Journal Year: 2024, Volume and Issue: 40(7-9), P. 369 - 432

Published: Feb. 1, 2024

Physiological levels of reactive oxygen and nitrogen species (ROS/RNS) function as fundamental messengers for many cellular developmental processes in the cardiovascular system. ROS/RNS involved cardiac redox-signaling originate from diverse sources, their are tightly controlled by key endogenous antioxidant systems that counteract accumulation. However, dysregulated redox-stress resulting inefficient removal leads to inflammation, mitochondrial dysfunction, cell death, contributing development progression disease (CVD).

Language: Английский

Citations

18
Mitochondrial Dysfunction in HFpEF: Potential Interventions Through Exercise DOI
Xinxin Cui, Michail Spanos, Cuimei Zhao

et al.

Journal of Cardiovascular Translational Research, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 25, 2025

Language: Английский

Citations

4
Practical Three-Component Regioselective Synthesis of Drug-Like 3-Aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnolines as Potential Non-Covalent Multi-Targeting Inhibitors To Combat Neurodegenerative Diseases DOI
Hossein Mousavi, Mehdi Rimaz, Behzad Zeynizadeh

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(9), P. 1828 - 1881

Published: April 22, 2024

Neurodegenerative diseases (NDs) are one of the prominent health challenges facing contemporary society, and many efforts have been made to overcome (or) control it. In this research paper, we described a practical one-pot two-step three-component reaction between 3,4-dihydronaphthalen-1(2H)-one (1), aryl(or heteroaryl)glyoxal monohydrates (2a–h), hydrazine monohydrate (NH2NH2•H2O) for regioselective preparation some 3-aryl(or heteroaryl)-5,6-dihydrobenzo[h]cinnoline derivatives (3a–h). After synthesis characterization mentioned cinnolines (3a–h), in silico multi-targeting inhibitory properties these heterocyclic scaffolds investigated upon various Homo sapiens-type enzymes, including hMAO-A, hMAO-B, hAChE, hBChE, hBACE-1, hBACE-2, hNQO-1, hNQO-2, hnNOS, hiNOS, hPARP-1, hPARP-2, hLRRK-2(G2019S), hGSK-3β, hp38α MAPK, hJNK-3, hOGA, hNMDA receptor, hnSMase-2, hIDO-1, hCOMT, hLIMK-1, hLIMK-2, hRIPK-1, hUCH-L1, hPARK-7, hDHODH, which confirmed their functions roles neurodegenerative (NDs), based on molecular docking studies, obtained results were compared with wide range approved drugs well-known (with IC50, EC50, etc.) compounds. addition, ADMET prediction analysis was performed examine prospective drug synthesized compounds The from studies ADMET-related data demonstrated that series heteroaryl)-5,6-dihydrobenzo[h]cinnolines especially hit ones, can really be turned into potent core new treatment and/or due having reactionable locations, they able further organic reactions (such as cross-coupling reactions), expansion (for example, using other types monohydrates) makes avenue designing novel efficient purpose.

Language: Английский

Citations

9
NADPH Oxidases in Diastolic Dysfunction and Heart Failure with Preserved Ejection Fraction DOI Creative Commons
James P. Teuber, Kobina Essandoh, Scott L. Hummel

et al.

Antioxidants, Journal Year: 2022, Volume and Issue: 11(9), P. 1822 - 1822

Published: Sept. 16, 2022

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases regulate production of reactive oxygen species (ROS) that cause oxidative damage to cellular components but also redox signaling in many cell types with essential functions the cardiovascular system. Research over past couple decades has uncovered mechanisms by which NADPH oxidase (NOX) enzymes stress and compartmentalize intracellular endothelial cells, smooth muscle macrophages, cardiomyocytes, fibroblasts, other types. NOX2 NOX4, for example, distinct cardiac myocytes pertinent onset progression hypertrophy heart failure. Heart failure preserved ejection fraction (HFpEF), accounts at least half all cases few effective treatments date, is classically associated ventricular diastolic dysfunction, i.e., defects relaxation and/or filling. However, HFpEF afflicts multiple organ systems systemic pathologies including inflammation, stress, arterial stiffening, fibrosis, renal, adipose tissue, skeletal dysfunction. Basic science studies clinical data suggest a role myocardial HFpEF, evidence from animal models demonstrates critical NOX function several HFpEF-associated comorbidities. Here, we discuss roles cells are development dysfunction outline potential implications.

Language: Английский

Citations

28
Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction DOI Creative Commons
Guoxing Li, Huilin Zhao, Zhe Cheng

et al.

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 1, 2024

Despite the high morbidity and mortality, effective therapies for heart failure with preserved fraction (HFpEF) are limited as poor understand of its pathophysiological basis. This study was aimed to characterize cellular heterogeneity potential mechanisms HFpEF at single-cell resolution. An mouse model induced by a high-fat diet N-nitro-L-arginine methyl ester. Cells from hearts were subjected sequencing. The key protein expression measured Immunohistochemistry immunofluorescence staining. In hearts, myocardial fibroblasts exhibited higher levels fibrosis. Furthermore, an increased number differentiated into high-metabolism high-fibrosis phenotypes. genes encoding certain pro-angiogenic secreted proteins decreased in group, confirmed bulk RNA Additionally, proportion endothelial cell (EC) lineages group significantly downregulated, low angiogenesis apoptosis phenotypes observed these EC lineages. Interestingly, might cross-link via over-secretion ANGPTL4, thus displaying anti-angiogenic function. staining then revealed downregulation vascular density upregulation ANGPTL4 hearts. Finally, we predicted ANGPTL4as druggable target using DrugnomeAI. conclusion, this comprehensively characterized impairment resolution proposed that secretion may be mechanism underlying angiogenic abnormality.

Language: Английский

Citations

6
The Aging Heart in Focus: The Advanced Understanding of Heart Failure with Preserved Ejection Fraction DOI

Zhe-Wei Zhang,

Yibin Wang, Xiangqi Chen

et al.

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 101, P. 102542 - 102542

Published: Oct. 12, 2024

Language: Английский

Citations

5
Inflammation in Heart Failure—Future Perspectives DOI Open Access
Alexandru Mircea Arvunescu, Ruxandra Florentina Ionescu, Sanda Maria Crețoiu

et al.

Journal of Clinical Medicine, Journal Year: 2023, Volume and Issue: 12(24), P. 7738 - 7738

Published: Dec. 17, 2023

Chronic heart failure is a terminal point of vast majority cardiac or extracardiac causes affecting around 1-2% the global population and more than 10% people above age 65. Inflammation persistently associated with chronic diseases, contributing in many cases to progression disease. Even low inflammatory state, past studies raised question whether inflammation constant condition, if it is, rather, triggered different amounts, according phenotype failure. By evaluating results clinical which focused on proinflammatory cytokines, this review aims identify ones that are independent risk factors for decompensation cardiovascular death. This assessed current evidence concerning activation cascade, but also future possible targets response modulation, can further impact course

Language: Английский

Citations

12
The importance of the endothelial nitric oxide synthase on the release of 6-nitrodopamine from mouse isolated atria and ventricles and their role on chronotropism DOI

José Britto‐Júnior,

Gustavo L. Pereira do Prado,

Silvana Chiavegatto

et al.

Nitric Oxide, Journal Year: 2023, Volume and Issue: 138-139, P. 26 - 33

Published: June 2, 2023

Language: Английский

Citations

11
Valosin-containing protein acts as a target and mediator of S-nitrosylation in the heart through distinct mechanisms DOI Creative Commons
Xiaomeng Shi, Michael P. O’Connor, Hongyu Qiu

et al.

Redox Biology, Journal Year: 2024, Volume and Issue: 72, P. 103166 - 103166

Published: April 26, 2024

S-nitrosylation (SNO) is an emerging paradigm of redox signaling protecting cells against oxidative stress in the heart. Our previous studies demonstrated that valosin-containing protein (VCP), ATPase-associated protein, a vital mediator heart cardiac and ischemic injury. However, molecular regulations conferred by VCP are not fully understood. In this study, we explored potential role SNO using multiple cardiac-specific genetically modified mouse models various analytical techniques including biotin switch assay, liquid chromatography, mass spectrometry, western blotting. results showed overexpression led to overall increase levels SNO-modified proteins transgenic (TG) vs. wild-type (WT) mice. Mass spectrometry analysis identified mitochondrial involved respiration, metabolism, detoxification as primary targets modification VCP-overexpressing hearts. Particularly, found itself underwent at specific cysteine residue its N-domain. Additionally, our study glyceraldehyde 3-phosphate dehydrogenase (GAPDH), key enzyme glycolysis, also experienced increased response overexpression. While deletion inducible nitric oxide synthase (iNOS) TG mice did affect SNO, it abolish complex proteins, suggesting dual mechanism regulation involving both iNOS-dependent independent pathways. Overall, findings shed light on post-translational heart, unveiling previously unrecognized for regulating offering new insights into function protection.

Language: Английский

Citations

4
Vitamin B12 alleviates myocardial ischemia/reperfusion injury via the SIRT3/AMPK signaling pathway DOI Creative Commons

Yuhong Qin,

Yani Shi, Qi Yu

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 163, P. 114761 - 114761

Published: April 29, 2023

To examine the protective effect of vitamin B12 against myocardial ischemia/reperfusion (I/R) injury and elucidate its underlying mechanism action. Mice were subjected to I/R by left anterior descending coronary artery (LAD) occlusion followed 24 h reperfusion. Cardiac function evaluated echocardiography, triphenyl tetrazolium chloride (TTC) cardiac troponin T (cTnT) staining, measuring lactate dehydrogenase (LDH) levels. In addition, various molecular biochemical methods, as well RNA sequencing used determine effects action on injury. We found that high doses inhibited Furthermore, our data indicated supplementation alleviated dysfunction mitigating oxidative stress apoptosis through downregulation Nox2, Ac-SOD2/SOD2 Bax/Bcl-2 ratios cleaved caspase-3 expression, upregulation SIRT3 expression AMPK activity. However, these largely reversed following treatment with inhibitor, 3-TYP. Our RNA-sequencing further demonstrated reduced inflammation during High supplements improved suppressing accumulation reactive oxygen species tissue modulation SIRT3/AMPK signaling pathway, while reducing inflammation. findings suggested administered at could be a potential therapy for damage.

Language: Английский

Citations

10