NAD_MCNN: Combining Protein Language Models and Multiwindow Convolutional Neural Networks for Deacetylase NAD+ Binding Site Prediction DOI
Van‐The Le, Yuchen Liu,

Yan‐Yun Chang

et al.

Chemical Biology & Drug Design, Journal Year: 2025, Volume and Issue: 105(4)

Published: April 1, 2025

Sirtuins, a class of NAD+ -dependent deacetylases, play key role in aging, metabolism, and longevity. Their interaction with at the catalytic site is crucial for function, but experimental methods to map binding sites are time consuming. To address this, we developed computational method integrating pretrained protein language models multiwindow convolutional neural networks (CNNs). This captures sequence information diverse local patterns, achieving state-of-the-art performance, AUC 0.9733 human sirtuin proteins 0.9701 other NAD-dependent deacylation enzymes. These findings offer insights into sirtuins aging their broader biological functions while providing new path identifying therapeutic targets aging-related diseases.

Language: Английский

Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis DOI Creative Commons
Milton Packer

Circulation, Journal Year: 2022, Volume and Issue: 146(18), P. 1383 - 1405

Published: Oct. 31, 2022

SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression cardiomyopathy nephropathy, which is characterized by reduction in oxidative endoplasmic reticulum stress, restoration mitochondrial health enhanced biogenesis, decrease proinflammatory profibrotic pathways, preservation cellular organ integrity viability. A substantial body evidence indicates that this characteristic responses can be explained action to promote housekeeping enhancing autophagic flux, an effect may related these drugs simultaneous upregulation nutrient deprivation signaling downregulation surplus signaling, as manifested increase expression activity AMPK (adenosine monophosphate-activated protein kinase), SIRT1 (sirtuin 1), SIRT3 3), SIRT6 6), PGC1-α (peroxisome proliferator-activated receptor γ coactivator 1-α) decreased activation mTOR (mammalian target rapamycin). The cardioprotective renoprotective effects abolished specific inhibition or knockdown autophagy, AMPK, sirtuins. In clinical setting, differentially increased proteins identified proteomics analyses blood collected randomized trials consistent with findings. Clinical studies have also shown gluconeogenesis, ketogenesis, erythrocytosis reduce uricemia, hallmarks principal statistical mediators ability risk heart failure serious renal events. augment flux seen isolated cells tissues do not express are exposed changes environmental glucose ketones bind directly sirtuins mTOR. Changes cardiovascular physiology metabolism cannot explain either experimentally clinically. direct molecular concept acts sensor, thus, its causes attendant cytoprotective effects, sirtuins, flux.

Language: Английский

Citations

252
Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy DOI Creative Commons

Saixian Shi,

Ye Chen,

Zhijian Luo

et al.

Cell Communication and Signaling, Journal Year: 2023, Volume and Issue: 21(1)

Published: March 14, 2023

Doxorubicin (DOX) is a powerful and commonly used chemotherapeutic drug, alone or in combination variety of cancers, while it has been found to cause serious cardiac side effects clinical application. More more researchers are trying explore the molecular mechanisms DOX-induced cardiomyopathy (DIC), which oxidative stress inflammation considered play significant role. This review summarizes signaling pathways related DIC compounds that exert cardioprotective by acting on relevant pathways, including role Nrf2/Keap1/ARE, Sirt1/p66Shc, Sirt1/PPAR/PGC-1α NOS, NOX, Fe2+ stress, as well NLRP3/caspase-1/GSDMD, HMGB1/TLR4/MAPKs/NF-κB, mTOR/TFEB/NF-κB inflammation. Hence, we attempt explain terms inflammation, provide theoretical basis new idea for further drug research reducing DIC. Video Abstract.

Language: Английский

Citations

108
SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism DOI Open Access
Milton Packer

Nature Reviews Cardiology, Journal Year: 2023, Volume and Issue: 20(7), P. 443 - 462

Published: Jan. 6, 2023

Language: Английский

Citations

95
PANoptosis: Mechanisms, biology, and role in disease DOI Open Access

Xu Sun,

Yanpeng Yang,

Xiaona Meng

et al.

Immunological Reviews, Journal Year: 2023, Volume and Issue: 321(1), P. 246 - 262

Published: Oct. 12, 2023

Summary Cell death can be executed through distinct subroutines. PANoptosis is a unique inflammatory cell modality involving the interactions between pyroptosis, apoptosis, and necroptosis, which mediated by multifaceted PANoptosome complexes assembled via integrating components from other modalities. There growing interest in process function of PANoptosis. Accumulating evidence suggests that occurs under diverse stimuli, for example, viral or bacterial infection, cytokine storm, cancer. Given impact across disease spectrum, this review briefly describes relationships highlights key molecules formation activation, outlines roles diseases together with potential therapeutic targeting. We also discuss important concepts pressing issues future research. Improved understanding its mechanisms crucial identifying novel targets strategies.

Language: Английский

Citations

67
Roles of Sirtuins in Cardiovascular Diseases: Mechanisms and Therapeutics DOI

Yang-Nan Ding,

Hui-Yu Wang,

Xiaofeng Chen

et al.

Circulation Research, Journal Year: 2025, Volume and Issue: 136(5), P. 524 - 550

Published: Feb. 27, 2025

Cardiovascular diseases (CVDs) are experiencing a rapid surge and widely recognized as the leading cause of mortality in current aging society. Given multifactorial etiology CVDs, understanding intricate molecular cellular mechanisms is imperative. Over past 2 decades, many scientists have focused on Sirtuins, family nicotinamide adenine dinucleotide–dependent deacylases. Sirtuins highly conserved across species, from yeasts to primates, play crucial role linking diseases. participate nearly all key physiological pathological processes, ranging embryogenic development stress response aging. Abnormal expression activity exist aging-related diseases, while their activation has shown efficacy mitigating these (eg, CVDs). In terms research, this field maintained fast, sustained growth recent years, fundamental studies clinical trials. review, we present comprehensive, up-to-date discussion biological functions roles regulating cardiovascular biology CVDs. Furthermore, highlight latest advancements utilizing Sirtuin-activating compounds dinucleotide boosters potential pharmacological targets for preventing treating The unresolved issues field—from chemicobiological regulation Sirtuin-targeted CVD investigations—are also discussed. This timely review could be critical updated knowledge Sirtuin CVDs facilitating accessibility Sirtuin-targeting interventions.

Language: Английский

Citations

3
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

2
Hippo pathway activation mediates chemotherapy-induced anti-cancer effect and cardiomyopathy through causing mitochondrial damage and dysfunction DOI Creative Commons
Gang She,

Jin-Chan Du,

Wei Wu

et al.

Theranostics, Journal Year: 2023, Volume and Issue: 13(2), P. 560 - 577

Published: Jan. 1, 2023

Rationale: Chemotherapy is a common clinical strategy for cancer treatment.However, the accompanied cardiomyopathy renders patients under risk of another life-threatening condition.Whereas Hippo pathway known to play key roles in both cancerogenesis and heart disease, it remains unclear whether activation mediates chemotherapy-induced cardiomyopathy.Methods Results: In human breast cells, doxorubicin (DOX) significantly induced upregulation kinase Mst1, inhibitory phosphorylation YAP, mitochondrial damage, reduced cell viability increased apoptosis.Hippo inactivation by Mst1-siRNA transfection effectively improved survival mitigated damage apoptosis.Another anti-cancer drug YAP inhibitor verteporfin also lower viability, apoptosis injury.Chronic treatment with DOX vivo (4 mg/kg/week 6 weeks) caused dysfunction, oxidative stress cardiac fibrosis, while acute (16 mg/kg single bolus) myocardial abnormalities.Chronic (2 months) resulted phenotypes comparable that chronic regimen.In transgenic mice overexpression kinase-dead mutant Mst1 gene, these adverse effects were attenuated relative wild-type littermates.Conclusions: Anti-cancer action associated activation.Such on cardiomyopathy.

Language: Английский

Citations

37
A fibroblast-associated signature predicts prognosis and immunotherapy in esophageal squamous cell cancer DOI Creative Commons

Qianhe Ren,

Pengpeng Zhang, Xiao Zhang

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 29, 2023

Background Current paradigms of anti-tumor therapies are not qualified to evacuate the malignancy ascribing cancer stroma’s functions in accelerating tumor relapse and therapeutic resistance. Cancer-associated fibroblasts (CAFs) has been identified significantly correlated with progression therapy Thus, we aimed probe into CAFs characteristics esophageal squamous (ESCC) construct a risk signature based on predict prognosis ESCC patients. Methods The GEO database provided single-cell RNA sequencing (scRNA-seq) data. TCGA databases were used obtain bulk RNA-seq data microarray ESCC, respectively. CAF clusters from scRNA-seq using Seurat R package. CAF-related prognostic genes subsequently univariate Cox regression analysis. A was constructed Lasso regression. Then, nomogram model clinicopathological developed. Consensus clustering conducted explore heterogeneity ESCC. Finally, PCR utilized validate that hub play Results Six data, three which had associations. total 642 found be pool 17080 DEGs, 9 selected generate signature, mainly involved 10 pathways such as NRF1, MYC, TGF-Beta. stromal immune scores, well some cells. Multivariate analysis demonstrated an independent factor for its potential predicting immunotherapeutic outcomes confirmed. novel integrating CAF-based clinical stage developed, exhibited favorable predictability reliability prediction. consensus further confirmed Conclusion can effectively predicted by signatures, comprehensive characterization may aid interpreting response immunotherapy offer new strategies treatment.

Language: Английский

Citations

35
Mitochondrial quality control in health and cardiovascular diseases DOI Creative Commons
Asli E. Atici, Timothy R. Crother, Magali Noval Rivas

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Nov. 6, 2023

Cardiovascular diseases (CVDs) are one of the primary causes mortality worldwide. An optimal mitochondrial function is central to supplying tissues with high energy demand, such as cardiovascular system. In addition producing ATP a power source, mitochondria also heavily involved in adaptation environmental stress and fine-tuning tissue functions. Mitochondrial quality control (MQC) through fission, fusion, mitophagy, biogenesis ensures clearance dysfunctional preserves homeostasis tissues. Furthermore, generate reactive oxygen species (ROS), which trigger production pro-inflammatory cytokines regulate cell survival. dysfunction has been implicated multiple CVDs, including ischemia-reperfusion (I/R), atherosclerosis, heart failure, cardiac hypertrophy, hypertension, diabetic genetic cardiomyopathies, Kawasaki Disease (KD). Thus, MQC pivotal promoting health. Here, we outline mechanisms discuss current literature on CVDs.

Language: Английский

Citations

23
Sirtuin dysregulation in Parkinson's disease: Implications of acetylation and deacetylation processes DOI
Sonia Dhiman, Ashi Mannan, Ayushi Taneja

et al.

Life Sciences, Journal Year: 2024, Volume and Issue: 342, P. 122537 - 122537

Published: Feb. 29, 2024

Language: Английский

Citations

8