The hormesis principle of neuroplasticity and neuroprotection

Cell Metabolism, Год журнала: 2024, Номер 36(2), С. 315 - 337

Опубликована: Янв. 10, 2024

Язык: Английский

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The integrated stress response in cancer progression: a force for plasticity and resistance

Frontiers in Oncology, Год журнала: 2023, Номер 13

Опубликована: Авг. 3, 2023

During their quest for growth, adaptation, and survival, cancer cells create a favorable environment through the manipulation of normal cellular mechanisms. They increase anabolic processes, including protein synthesis, to facilitate uncontrolled proliferation deplete tumor microenvironment resources. As dynamic adaptation self-imposed oncogenic stress, promptly hijack translational control alter gene expression. Rewiring proteome shifts phenotypic balance between growth promote therapeutic resistance cell survival. The integrated stress response (ISR) is key program activated by that utilized fine-tune synthesis adjust environmental barriers. Here, we focus on role ISR signaling driving progression. We highlight mechanisms regulation distinct mRNA translation downstream ISR, expand utilizing in stresses, pinpoint impact this has plasticity during therapy. There an ongoing need innovative drug targets treatment, modulating activity may provide unique avenue clinical benefit.

Язык: Английский

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Advances in the roles of ATF4 in osteoporosis

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 169, С. 115864 - 115864

Опубликована: Ноя. 9, 2023

Osteoporosis (OP) is characterized by reduced bone mass, decreased strength, and enhanced fragility fracture risk. Activating transcription factor 4 (ATF4) plays a role in cell differentiation, proliferation, apoptosis, redox balance, amino acid uptake, glycolipid metabolism. ATF4 induces the differentiation of marrow mesenchymal stem cells (BM-MSCs) into osteoblasts, increases osteoblast activity, inhibits osteoclast formation, promoting formation remodeling. In addition, mediates energy metabolism osteoblasts promotes angiogenesis. also involved mediation adipogenesis. can selectively accumulate osteoblasts. directly interact with RUNT-related 2 (RUNX2) up-regulate expression osteocalcin (OCN) osterix (Osx). Several upstream factors, such as Wnt/β-catenin BMP2/Smad signaling pathways, have been ATF4-mediated differentiation. osteoclastogenesis mediating receptor activator nuclear κ-B (NF-κB) ligand (RANKL) signaling. agents, parathyroid (PTH), melatonin, natural compounds, reported to regulate mediate this review, we comprehensively discuss biological activities maintaining homeostasis inhibiting OP development. has become therapeutic target for treatment.

Язык: Английский

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Stem-loop-induced ribosome queuing in the uORF2/ATF4 overlap fine-tunes stress-induced human ATF4 translational control

Cell Reports, Год журнала: 2024, Номер 43(4), С. 113976 - 113976

Опубликована: Март 19, 2024

Activating transcription factor 4 (ATF4) is a master transcriptional regulator of the integrated stress response, leading cells toward adaptation or death. ATF4's induction under was thought to be due delayed translation reinitiation, where reinitiation-permissive upstream open reading frame 1 (uORF1) plays key role. Accumulating evidence challenging this mechanism as sole source ATF4 control prompted us investigate additional regulatory routes. We identified highly conserved stem-loop in uORF2/ATF4 overlap, immediately preceded by near-cognate CUG, which introduces another layer regulation form ribosome queuing. These elements explain how inhibitory uORF2 can translated stress, confirming prior observations but contradicting original model. also two conserved, potentially modified adenines performing antagonistic roles. Finally, we demonstrated that canonical start site substantially leaky scanned. Thus, translational more complex than originally described, underpinning its role diverse biological processes.

Язык: Английский

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OMA1 protease eliminates arrested protein import intermediates upon mitochondrial depolarization

The Journal of Cell Biology, Год журнала: 2024, Номер 223(5)

Опубликована: Март 26, 2024

Most mitochondrial proteins originate from the cytosol and require transport into organelle. Such precursor must be unfolded to pass through translocation channels in membranes. Misfolding of transported can result their arrest failure. Arrested block further import, disturbing functions cellular proteostasis. Cellular responses failure have been defined yeast. We developed cell line-based translocase clogging model discover molecular mechanisms that resolve failed import events humans. The mechanism we uncover differs significantly these described fungi, where ATPase-driven extraction blocked protein is directly coupled with proteasomal processing. found human cells rely primarily on factors clear channel blockage. membrane depolarization triggered proteolytic cleavage stalled protein, which involved protease OMA1. allowed releasing fragment translocase. released was cleared by VCP/p97 proteasome.

Язык: Английский

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Gene Expression Profiling Reveals Fundamental Sex-Specific Differences in SIRT3-Mediated Redox and Metabolic Signaling in Mouse Embryonic Fibroblasts

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3868 - 3868

Опубликована: Март 30, 2024

Sirt-3 is an important regulator of mitochondrial function and cellular energy homeostasis, whose associated with aging various pathologies such as Alzheimer’s disease, Parkinson’s cardiovascular diseases, cancers. Many these conditions show differences in incidence, onset, progression between the sexes. In search hormone-independent, sex-specific roles Sirt-3, we performed mRNA sequencing male female WT KO mouse embryonic fibroblasts (MEFs). The aim this study was to investigate responses loss Sirt-3. By comparing MEF both sexes, global gene expression patterns well metabolic stress have been elucidated. Significant activities basal pathways were found genotypes In-depth pathway analysis revealed several phenomena. Male cells mount adaptive Hif-1a response, shifting their metabolism toward glycolysis production from fatty acids. Furthermore, MEFs leads endoplasmic reticulum stress. Since knock-out permanent, are forced a state persistent oxidative Female able at least partially compensate for by higher antioxidant enzymes. activation neither Hif-1a, nor response observed lacking These findings emphasize role which should be considered future research.

Язык: Английский

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eIF2α Phosphorylation-ATF4 Axis-Mediated Transcriptional Reprogramming Mitigates Mitochondrial Impairment During ER Stress

Molecules and Cells, Год журнала: 2025, Номер unknown, С. 100176 - 100176

Опубликована: Янв. 1, 2025

Eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, which regulates all three unfolded protein response pathways, helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional translational reprogramming. However, regulation of mitochondrial by eIF2α phosphorylation during ER is not fully understood. Here, we report that the phosphorylation-activating transcription 4 (ATF4) axis required for expression multiple factors (TFs) including nuclear erythroid 2-related 2 (Nrf2) their target genes responsible stress. phosphorylation-deficient (A/A) cells displayed dysregulated dynamics DNA replication, decreased oxidative complex proteins, impaired functions ATF4 overexpression suppressed impairment in A/A promoting downstream TFs genes. Our findings underscore importance phosphorylation-ATF4 maintaining reprogramming

Язык: Английский

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SLC7A5 is required for cancer cell growth under arginine-limited conditions

Cell Reports, Год журнала: 2025, Номер 44(1), С. 115130 - 115130

Опубликована: Янв. 1, 2025

Highlights•SLC7A5 is required for proliferation under arginine-free conditions when citrulline present•SLC7A5 loss impairs arginine metabolism•Small-molecule inhibitors of SLC7A5 can be paired with senolytic drugs to drive apoptosis•SLC7A5 knockout decreases import in a xenograft modelSummaryTumor cells must optimize metabolite acquisition between synthesis and uptake from microenvironment characterized by hypoxia, lactate accumulation, depletion many amino acids, including arginine. We performed metabolism-focused functional screen using CRISPR-Cas9 identify pathways factors that enable tumor growth an arginine-depleted environment. Our identified the SLC-family transporter as growth, we hypothesized this protein functions high-affinity transporter. Using isotope tracing experiments, show metabolism into are dependent upon expression SLC7A5. Pharmacological inhibition blocks low-arginine across diverse group cancer cell lines. Loss reduces mouse model. conditionally essential role metabolism, propose SLC7A5-targeting therapeutic strategies may effective context limitation.Graphical abstract

Язык: Английский

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Sodium aescinate-induced hepatotoxicity via ATF4/GSH/GPX4 axis-mediated ferroptosis

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 7, 2025

Sodium aescinate (SA), a natural plant extract with various bioactivities, is widely used to treat oedema and inflammation in clinics. However, adverse events, including liver injury, kidney phlebitis, have been reported patients SA recent years. In this study, we BALB/c mice L02 cells evaluate the role of ferroptosis SA-induced injury. significantly increased AST, ALT, MDA Fe2+, decreased GSH levels, induced pathological changes vivo. also reduced viability LDH release, intracellular cysteine reduction, depletion, iron accumulation, ROS production, lipid peroxidation, indicating that causes ferroptosis. addition, inhibited transcriptional activity activating transcription factor 4 (ATF4) subsequently expression downstream genes xCT (solute carrier family 7a member 11, SLC7A11) Cystathionine gamma-lyase (CTH) which play vital roles biosynthesis. Interestingly, cytotoxic effects were effectively attenuated by ATF4 overexpression, while they aggravated silencing. These results revealed triggers hepatocyte inhibiting ATF4, an oxidative imbalance.

Язык: Английский

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Type 2 Diabetes Mellitus: A Comprehensive Review of Pathophysiology, Comorbidities, and Emerging Therapies

Comprehensive physiology, Год журнала: 2025, Номер 15(1)

Опубликована: Фев. 1, 2025

ABSTRACT Humans are perhaps evolutionarily engineered to get deeply addicted sugar, as it not only provides energy but also helps in storing fats, which survival during starvation. Additionally, sugars (glucose and fructose) stimulate the feel‐good factor, they trigger secretion of serotonin dopamine brain, associated with reward sensation, uplifting mood general. However, when consumed excess, contributes imbalance, weight gain, obesity, leading onset a complex metabolic disorder, generally referred diabetes. Type 2 diabetes mellitus (T2DM) is one most prevalent forms diabetes, nearly affecting all age groups. T2DM clinically diagnosed cardinal sign chronic hyperglycemia (excessive sugar blood). Chronic hyperglycemia, coupled dysfunctions pancreatic β‐cells, insulin resistance, immune inflammation, further exacerbate pathology T2DM. Uncontrolled T2DM, major public health concern, significantly toward progression several micro‐ macrovascular diseases, such diabetic retinopathy, nephropathy, neuropathy, atherosclerosis, cardiovascular including cancer. The current review discusses epidemiology, causative factors, pathophysiology, comorbidities, existing emerging therapies related It future roadmap for alternative drug discovery management

Язык: Английский

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