Biological resilience and aging: Activation of stress response pathways contributes to lifespan extension DOI Creative Commons

Sonja K. Soo,

Zenith D. Rudich,

Bokang Ko

et al.

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 88, P. 101941 - 101941

Published: April 29, 2023

While aging was traditionally viewed as a stochastic process of damage accumulation, it is now clear that strongly influenced by genetics. The identification and characterization long-lived genetic mutants in model organisms has provided insights into the pathways molecular mechanisms involved extending longevity. Long-lived exhibit activation multiple stress response leading to enhanced resistance exogenous stressors. As result, lifespan exhibits significant, positive correlation with stress. Disruption inhibits extension representing different can also reduce wild-type animals. Combined, this suggests key mechanism which achieve their extended longevity many these are required for normal lifespan. These results highlight an important role determining organism.

Language: Английский

T cell receptor (TCR) signaling in health and disease DOI Creative Commons
Kinjal Shah, Amr Al‐Haidari, Jianmin Sun

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Dec. 13, 2021

Interaction of the T cell receptor (TCR) with an MHC-antigenic peptide complex results in changes at molecular and cellular levels cells. The outside environmental cues are translated into various signal transduction pathways within cell, which mediate activation genes help specific transcription factors. These signaling networks propagate effector enzymes, such as kinases, phosphatases, phospholipases. Integration these disparate is done adaptor proteins that non-enzymatic function serve a scaffold for protein-protein interactions. This process aids connecting proximal to distal pathways, thereby contributing full review provides comprehensive snapshot molecules involved regulating signaling, covering both enzymes adaptors, will discuss their role human disease.

Language: Английский

Citations

324
TGF-β signaling in health, disease and therapeutics DOI Creative Commons

Ziqin Deng,

Tao Fan, Xiao Chu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 22, 2024

Abstract Transforming growth factor (TGF)-β is a multifunctional cytokine expressed by almost every tissue and cell type. The signal transduction of TGF-β can stimulate diverse cellular responses particularly critical to embryonic development, wound healing, homeostasis, immune homeostasis in health. dysfunction play key roles many diseases, numerous targeted therapies have been developed rectify its pathogenic activity. In the past decades, large number studies on signaling carried out, covering broad spectrum topics health, disease, therapeutics. Thus, comprehensive overview required for general picture this field. review, we retrace research history introduce molecular mechanisms regarding biosynthesis, activation, transduction. We also provide deep insights into functions physiological conditions as well pathological processes. TGF-β-targeting which brought fresh hope treatment relevant diseases are highlighted. Through summary previous knowledge recent updates, review aims systematic understanding attract more attention interest area.

Language: Английский

Citations

211
Glial Cell-Mediated Neuroinflammation in Alzheimer’s Disease DOI Open Access

Nour F. Al-Ghraiybah,

Junwei Wang, Amer E. Alkhalifa

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(18), P. 10572 - 10572

Published: Sept. 12, 2022

Alzheimer's disease (AD) is a progressive neurodegenerative disorder; it the most common cause of dementia and has no treatment. It characterized by two pathological hallmarks, extracellular deposits amyloid beta (Aβ) intraneuronal Neurofibrillary tangles (NFTs). Yet, those hallmarks do not explain full pathology seen with AD, suggesting involvement other mechanisms. Neuroinflammation could offer another explanation for progression disease. This review provides an overview recent advances on role immune cells' microglia astrocytes in neuroinflammation. In become reactive several mechanisms leading to release proinflammatory cytokines that further neuronal damage. We then provide updates neuroinflammation diagnostic markers investigational therapeutics currently clinical trials target

Language: Английский

Citations

92
P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection DOI Creative Commons
Lea‐Marie Jenster,

Karl-Elmar Lange,

Sabine Normann

et al.

The Journal of Experimental Medicine, Journal Year: 2022, Volume and Issue: 220(1)

Published: Oct. 31, 2022

Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses. The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation the skin. We found that diverse stress signals induce assembly by activating MAP kinase p38: While ribotoxic response UV microbial molecules exclusively activates p38 through MAP3K ZAKα, with arthropod-borne alphaviruses, including Semliki Forest Chikungunya virus, ZAKα potentially other MAP3K. demonstrate directly phosphorylates serine 107 linker region critical for activation. phosphorylation followed ubiquitination NLRP1PYD, N-terminal degradation NLRP1, nucleation inflammasomes NLRP1UPA-CARD. In contrast, activation nanobody-mediated ubiquitination, viral proteases, inhibition DPP9 was independent activity. Taken together, we define as a unifying signaling hub controls integrating variety cellular relevant

Language: Английский

Citations

77
Anti-Inflammatory Therapeutic Mechanisms of Natural Products: Insight from Rosemary Diterpenes, Carnosic Acid and Carnosol DOI Creative Commons
Solomon Habtemariam

Biomedicines, Journal Year: 2023, Volume and Issue: 11(2), P. 545 - 545

Published: Feb. 13, 2023

Carnosic acid (CA) and carnosol (CAR) are two major diterpenes of the rosemary plant (Rosmarinus officinalis). They possess a phenolic structural moiety endowed with power to remove cellular reactive oxygen species (ROS) either through direct scavenging reaction or indirectly upregulation antioxidant defences. Hand in hand these activities their multiple biological effects therapeutic potential orchestrated modulating various signalling pathways inflammation, including NF-κB, MAPK, Nrf2, SIRT1, STAT3 NLRP3 inflammasomes, among others. Consequently, they ameliorate expression pro-inflammatory cytokines (e.g., TNF-α, IL-1 IL-6), adhesion molecules, chemokines prostaglandins. These anti-inflammatory mechanisms action as link compounds, many other natural products, scrutinised.

Language: Английский

Citations

60
ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging DOI
Goda Snieckute, Laura Ryder, Anna Vind

et al.

Science, Journal Year: 2023, Volume and Issue: 382(6675)

Published: Dec. 7, 2023

The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)-activating mitogen-activated protein (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)-generating agents trigger ribosomal impairment activation. Conversely, zebrafish larvae deficient for are protected from ROS-induced pathology. Livers mice fed ROS-generating diet exhibit ZAKα-activating changes elongation dynamics. Highlighting role RSR metabolic regulation, ZAK-knockout developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance liver steatosis. Finally, ZAK ablation slows animals hallmarks aging. Our work highlights as physiological activation signal underlies adaptation obesity

Language: Английский

Citations

59
Cancer chemotherapy resistance: Mechanisms and recent breakthrough in targeted drug delivery DOI
Fatemeh Davodabadi, Seyedeh Fatemeh Sajjadi, Mohammad Sarhadi

et al.

European Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 958, P. 176013 - 176013

Published: Aug. 24, 2023

Language: Английский

Citations

57
Mitochondrial network dynamics in pulmonary disease: Bridging the gap between inflammation, oxidative stress, and bioenergetics DOI Creative Commons
Marissa D. Pokharel, Alejandro Garcia Flores, David Marciano

et al.

Redox Biology, Journal Year: 2024, Volume and Issue: 70, P. 103049 - 103049

Published: Jan. 20, 2024

Once thought of in terms bioenergetics, mitochondria are now widely accepted as both the orchestrator cellular health and gatekeeper cell death. The pulmonary disease field has performed extensive efforts to explore role regulating inflammation, metabolism, apoptosis, oxidative stress. However, a critical component these processes needs be more studied: mitochondrial network dynamics. Mitochondria morphologically change response their environment regulate through fusion, fission, mitophagy. This allows adapt function respond requirements, maintaining homeostasis. For that reason, dynamics can considered bridge brings multiple together, revealing potential pathway for therapeutic intervention. In this review, we discuss modulators how they affected diseases, including chronic obstructive (COPD), idiopathic fibrosis (IPF), acute lung injury (ALI), arterial hypertension (PAH). A dysregulated plays crucial pathobiology, aberrant fission/fusion/mitophagy pathways druggable warrant further exploration. Thus, also candidates therapeutics

Language: Английский

Citations

36
The ribotoxic stress response drives UV-mediated cell death DOI Creative Commons
Niladri K. Sinha, Connor McKenney,

Zhong Y. Yeow

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(14), P. 3652 - 3670.e40

Published: June 5, 2024

While ultraviolet (UV) radiation damages DNA, eliciting the DNA damage response (DDR), it also RNA, triggering transcriptome-wide ribosomal collisions and a ribotoxic stress (RSR). However, relative contributions, timing, regulation of these pathways in determining cell fate is unclear. Here we use time-resolved phosphoproteomic, chemical-genetic, single-cell imaging, biochemical approaches to create chronological atlas signaling events activated cells responding UV damage. We discover that UV-induced apoptosis mediated by RSR kinase ZAK not through DDR. identify two negative-feedback modules regulate ZAK-mediated apoptosis: (1) GCN2 activation limits attenuates (2) activity leads phosphodegron autophosphorylation its subsequent degradation. These tune ZAK's collision levels establish regimes homeostasis, tolerance, death, revealing key role as cellular sentinel for nucleic acid

Language: Английский

Citations

24
First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure DOI Creative Commons

Stefan Zwirner,

Anan Abu Rmilah,

Sabrina Klotz

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(7), P. 1666 - 1684.e26

Published: March 1, 2024

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases after extended resections, resulting in the inability to maintain or restore sufficient functional mass. Therapies are lacking, making transplantation only curative option for end-stage disease. Here, we report on structure-based development characterization (nuclear magnetic resonance [NMR] spectroscopy) first-in-class small molecule inhibitors dual-specificity kinase MKK4 (MKK4i). MKK4i increased upon hepatectomy murine porcine models, allowed survival pigs lethal 85% model, showed antisteatotic antifibrotic effects disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with clinical candidate HRX215 was conducted revealed excellent safety pharmacokinetics. trials probe prevention/treatment failure extensive oncological resections grafts warranted.

Language: Английский

Citations

22