Neuregulin-1, a member of the epidermal growth factor family, mitigates STING-mediated pyroptosis and necroptosis in ischaemic flaps

Burns & Trauma, Год журнала: 2024, Номер 12

Опубликована: Янв. 1, 2024

Abstract Background Ensuring the survival of distal end a random flap during hypoperfusion (ischaemia) is difficult in clinical practice. Effective prevention programmed cell death potential strategy for inhibiting ischaemic necrosis. The activation stimulator interferon genes (STING) pathway promotes inflammation and leads to death. epidermal growth factor family member neuregulin-1 (NRG1) reduces by activating protein kinase B (AKT) signalling pathway. Moreover, AKT negatively regulates STING activity. We aimed verify efficacy NRG1 injection protecting against Additionally, we investigated whether effectively enhances ischemic pyroptosis necroptosis through suppression. Methods A random-pattern skin model was generated on backs C57BL/6 mice. area determined. blood supply vascular network assessed laser Doppler flow analysis. Cluster differentiation 34 immunohistochemistry (IHC) haematoxylin eosin (H&E) staining sections revealed microvessels. Transcriptome sequencing analysis mechanism which flaps. levels angiogenesis, oxidative stress, necroptosis, indicators associated with pathways flaps were examined IHC, immunofluorescence Western blotting. Packaging adeno-associated virus (AAV) used activate Results promoted An increased subcutaneous neovascularization found after application NRG1. Transcriptomic gene ontology enrichment level detection indicated that activity reduced group. phosphorylation forkhead box O3a (FOXO3a) treatment. expression induced AAV reversed therapeutic effect ability phosphorylate AKT-FOXO3a, inhibit promote abolished inhibitor MK2206. Conclusions inhibits AKT-FOXO3a suppress survival.

Язык: Английский

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FoxO3 and oxidative stress: a multifaceted role in cellular adaptation

Journal of Molecular Medicine, Год журнала: 2023, Номер 101(1-2), С. 83 - 99

Опубликована: Янв. 4, 2023

Язык: Английский

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FOXO family isoforms

Cell Death and Disease, Год журнала: 2023, Номер 14(10)

Опубликована: Окт. 27, 2023

Abstract FOXO family of proteins are transcription factors involved in many physiological and pathological processes including cellular homeostasis, stem cell maintenance, cancer, metabolic, cardiovascular diseases. Genetic evidence has been accumulating to suggest a prominent role FOXOs lifespan regulation animal systems from hydra, C elegans, Drosophila, mice. Together with the observation that FOXO3 is second most replicated gene associated extreme human longevity suggests pharmacological targeting can be promising approach treat cancer other age-related diseases extend life health span. However, due broad range functions members FOXO1, 3, 4, 6, isoform-specific might lead greater benefits cause fewer side effects. Therefore, deeper understanding common specific features these as well their redundant our cells represents basis strategies. In this review, we provide an overview evolution, structure, function, disease-relevance each members.

Язык: Английский

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SIRT1/FOXO3-mediated autophagy signaling involved in manganese-induced neuroinflammation in microglia

Ecotoxicology and Environmental Safety, Год журнала: 2023, Номер 256, С. 114872 - 114872

Опубликована: Апрель 5, 2023

Manganese (Mn), as one of the environmental risk factors for Parkinson's disease (PD), has been widely studied. Though autophagy dysfunction and neuroinflammation mainly are responsible causative issue Mn neurotoxicity, molecular mechanism parkinsonism caused by not explored clearly. The results in vivo vitro experiments showed that overexposure to impairment dysfunction, accompanied increase IL-1β, IL-6, TNF-α mRNA expression, nerve cell apoptosis, microglia activation, NF-κB poor neurobehavior performance. This is due Mn-induced downregulation SIRT1. Upregulation SIRT1 could alleviate neuroinflammation, yet these beneficial effects were abolished following 3-MA administration. Furthermore, we found interfered with acetylation FOXO3 BV2 cells, leading a decrease nuclear translocation FOXO3, its binding LC3B promoter transcription activity. be antagonized upregulation Finally, it proved SIRT1/FOXO3-LC3B signaling involves impairment.

Язык: Английский

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FoxO1 as a tissue-specific therapeutic target for type 2 diabetes

Frontiers in Endocrinology, Год журнала: 2023, Номер 14

Опубликована: Окт. 23, 2023

Forkhead box O (FoxO) proteins are transcription factors that mediate many aspects of physiology and thus have been targeted as therapeutics for several diseases including metabolic disorders such type 2 diabetes mellitus (T2D). The role FoxO1 in metabolism has well studied, but recently FoxO1’s potential prevention therapy debated. For example, studies shown increased activity certain tissue types contributes to T2D pathology, symptoms, comorbidities, yet other elevated reported alleviate symptoms associated with diabetes. Furthermore, opposite effects active the same type. liver, by increasing hepatic glucose production. However, either increase or decrease lipogenesis adipogenesis white adipose tissue. In skeletal muscle, reduces uptake oxidation, promotes lipid increases muscle atrophy. While show lowers pancreatic insulin production secretion, others opposite, especially response oxidative stress inflammation. Elevated hypothalamus risk developing T2D. may mitigate Alzheimer’s disease, a neurodegenerative disease strongly Conversely, accumulating evidence implicates Parkinson’s pathogenesis. Here we review actions conditions tissues abundantly express highlight some current targeting treatment.

Язык: Английский

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Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice

Journal of Biomedical Science, Год журнала: 2024, Номер 31(1)

Опубликована: Янв. 23, 2024

Abstract Background CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, persistently high level of promotes longevity and ameliorates an age-related skin phenotype transgenic mice. Here we translate the genetic evidence into pharmaceutical application using potent activator, hesperetin, which enhances expression HEK001 human keratinocytes from older person. We also treated naturally aged mice order to study activator’s anti-aging efficacy. Methods studied biological effects hesperetin on aging using, firstly, cell-based platform, namely keratinocyte cell line established Secondly, used mouse model, old at 21-month old. In latter case, investigate efficacy ultraviolet B (UVB)-induced photoaging skin. identify underlying mechanisms potential pathways involved this process carried out transcriptomic analysis. Finally, knockdown Cisd2 knockout were Cisd2-dependent Results Four findings are pinpointed. Firstly , skin, mainly expressed proliferating epidermal basal layer and, furthermore, sun-exposed epidermis. Secondly person, mitochondrial function protects against reactive oxygen species-induced oxidative stress via increased expression; enhancement CISD2-dependent. Additionally, alleviates UVB-induced damage suppresses matrix metalloproteinase-1 expression, being major indicator keratinocytes. Thirdly analysis revealed that modulates panel differentially genes associated with function, redox homeostasis, inflammation attenuate senescence. Intriguingly, activates two known longevity-associated regulators, FOXO3a FOXM1, suppress senescence-associated secretory phenotype. Finally ameliorate occurs mechanism involving CISD2. Most strikingly, late-life treatment started lasting for 5 months, able retard rejuvenate Conclusions Our results reveal pharmacological elevation stage feasible approach effectively mitigating both intrinsic extrinsic could act as functional food or skincare product fighting

Язык: Английский

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The protective effects of esculetin against Doxorubicin‐Induced hepatotoxicity in rats: Insights into the modulation of Caspase, FOXOs, and heat shock protein pathways

Journal of Biochemical and Molecular Toxicology, Год журнала: 2024, Номер 38(10)

Опубликована: Сен. 20, 2024

Abstract Doxorubicin (DOX) is an anthracycline antibiotic widely employed to treat carcinoma. Nevertheless, severe cardiotoxic side effects restrict its clinical use. Esculetin, a natural flavonoid, found abundantly in plants. This study evaluated the protective of esculetin against DOX‐induced hepatotoxicity rat livers. Forty‐eight rats were randomly divided into six groups with eight each group: control (I), DOX (II), (III, 50 mg/kg), (IV, 100 DOX+esculetin (V, and (VI, mg/kg). The administration effectively mitigated alterations measured biochemical parameters induced by DOX. Gene expression analyses demonstrated that treatment significantly reduced Foxo1, Hspa1a, Hsp4a, Hsp5a, Casp3, Casp9 while increasing Foxo3 . These findings suggest esculetin, antioxidant anti‐inflammatory effects, might be therapeutic option for protecting hepatotoxicity.

Язык: Английский

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Advances in SIRT3 involvement in regulating autophagy-related mechanisms

Cell Division, Год журнала: 2024, Номер 19(1)

Опубликована: Июнь 12, 2024

Abstract The silencing regulatory factor 2-like protein 3 (SIRT3) is a nicotinamide adenine dinucleotide (NAD+) dependent deacetylase located primarily in the mitochondria. This plays an important role oxidative stress, energy metabolism, and autophagy multicellular organisms. Autophagy (macroautophagy) cytoprotective mechanism necessary for intracellular homeostasis synthesis, degradation, recycling of cellular products. can influence progression several neural, cardiac, hepatic, renal diseases also contribute to development fibrosis, diabetes, many types cancer. Recent studies have shown that SIRT3 has regulating autophagy. Therefore this study, we aimed perform literature review summarize regulation findings study could be used identify new drug targets SIRT3-related diseases. Methods : A comprehensive involved behind autophagy-related was performed. Relevant published Pubmed Web Science up July 2023 identified using keywords “silencing 3”, “SIRT3” “autophagy”.

Язык: Английский

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The discrete roles of individual FOXO transcription factor family members in B-cell malignancies

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Май 18, 2023

Forkhead box (FOX) class O (FOXO) proteins are a dynamic family of transcription factors composed four members: FOXO1, FOXO3, FOXO4 and FOXO6. As context-dependent transcriptional activators repressors, the FOXO regulates diverse cellular processes including cell cycle arrest, apoptosis, metabolism, longevity fate determination. A central pathway responsible for negative regulation activity is phosphatidylinositol-3-kinase (PI3K)-AKT signalling pathway, enabling survival proliferation. members can be further regulated by distinct kinases, both positively (e.g., JNK, AMPK) negatively ERK-MAPK, CDK2), with additional post-translational modifications impacting on activity. Evidence has suggested that FOXOs behave as ‘ bona fide ’ tumour suppressors, through programmes regulating several behaviours arrest apoptosis. However, an alternative paradigm emerged which indicates operate mediators homeostasis and/or resistance in ‘normal’ pathophysiological scenarios. Distinct fulfil discrete roles during normal B maturation function, it now clear aberrantly expressed mutated B-cell malignancies. While active function generally associated disease suppression chronic lymphocytic leukemia example, expression progression diffuse large lymphoma, observation also seen other cancers. The opposing functions drives debate about circumstances favour or hinder progression, whether targeting FOXO-mediated would effective treatment Here, we discuss disparate lineage cells, regulatory events influence focusing mainly modifications, consider potential future development therapies target

Язык: Английский

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Mechanistic regulation of FOXO transcription factors in the nucleus

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2024, Номер 1879(2), С. 189083 - 189083

Опубликована: Фев. 2, 2024

Язык: Английский

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