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1.
Cell Biol Toxicol ; 40(1): 16, 2024 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-38472656

RESUMO

Intervertebral disc degeneration (IVDD) is an aging disease that results in a low quality of life and heavy socioeconomic burden. The mitochondrial unfolded protein response (UPRmt) take part in various aging-related diseases. Our research intents to explore the role and underlying mechanism of UPRmt in IVDD. Nucleus pulposus (NP) cells were exposed to IL-1ß and nicotinamide riboside (NR) served as UPRmt inducer to treat NP cells. Detection of ATP, NAD + and NADH were used to determine the function of mitochondria. MRI, Safranin O-fast green and Immunohistochemical examination were used to determine the degree of IVDD in vivo. In this study, we discovered that UPRmt was increased markedly in the NP cells of human IVDD tissues than in healthy controls. In vitro, UPRmt and mitophagy levels were promoted in NP cells treated with IL-1ß. Upregulation of UPRmt by NR and Atf5 overexpression inhibited NP cell apoptosis and further improved mitophagy. Silencing of Pink1 reversed the protective effects of NR and inhibited mitophagy induced by the UPRmt. In vivo, NR might attenuate the degree of IDD by activating the UPRmt in rats. In summary, the UPRmt was involved in IVDD by regulating Pink1-induced mitophagy. Mitophagy induced by the UPRmt might be a latent treated target for IVDD.


Assuntos
Degeneração do Disco Intervertebral , Mitofagia , Animais , Humanos , Ratos , Fatores Ativadores da Transcrição/metabolismo , Fatores Ativadores da Transcrição/farmacologia , Apoptose , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Degeneração do Disco Intervertebral/metabolismo , Mitocôndrias/metabolismo , Proteínas Quinases/metabolismo , Qualidade de Vida , Ratos Sprague-Dawley
2.
BMC Complement Med Ther ; 24(1): 36, 2024 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-38216941

RESUMO

BACKGROUND: Endoplasmic reticulum (ER) stress, promoting lipid metabolism disorders and steatohepatitis, contributes significantly to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Hugan Qingzhi tablets (HQT) has a definite effect in the clinical treatment of NAFLD patients, but its mechanism is still unclear. This study aims to investigate the effects of HQT on ER stress in the liver tissues of NAFLD rats and explore the underlying mechanism. METHODS: The NAFLD rat model was managed with high-fat diet (HFD) for 12weeks. HQT was administrated in a daily basis to the HFD groups. Biochemical markers, pro-inflammatory cytokines, liver histology were assayed to evaluate HQT effects in HFD-induced NAFLD rats. Furthermore, the expression of ER stress-related signal molecules including glucose regulating protein 78 (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), p-PERK, eukaryotic translation initiation factor 2α (EIF2α), p-EIF2α, activating transcription factor 4 (ATF4), acetyl-coenzyme A-carboxylase (ACC), activating transcription factor (ATF6), and nuclear factor-kappa B-p65 (NF-κB-p65) were detected by western blot and/or qRT-PCR. RESULTS: The histopathological characteristics and biochemical data indicated that HQT exhibited protective effects on HFD-induced NAFLD rats. Furthermore, it caused significant reduction in the expression of ERS markers, such as GRP78, PERK, p-PERK, and ATF6, and subsequently downregulated the expression of EIF2α, p-EIF2α ATF4, ACC, and NF-κB-p65. CONCLUSIONS: The results suggested that HQT has protective effect against hepatic steatosis and inflammation in NAFLD rats by attenuating ER stress, and the potential mechanism is through inhibition of PERK and ATF6 pathways.


Assuntos
Medicamentos de Ervas Chinesas , Hepatopatia Gordurosa não Alcoólica , Humanos , Ratos , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Proteínas Quinases , RNA/efeitos adversos , Chaperona BiP do Retículo Endoplasmático , NF-kappa B , Retículo Endoplasmático/metabolismo , Fatores Ativadores da Transcrição/farmacologia , Estresse do Retículo Endoplasmático , Comprimidos/efeitos adversos , Fator 6 Ativador da Transcrição/farmacologia
3.
Environ Toxicol ; 39(3): 1494-1504, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37994244

RESUMO

As a synthetic androgen, 17α-methyltestosterone (MT) is widely used in aquaculture to induce sex reversal and may pose a potential risk to aquatic organisms. This ecological risk has attracted the attention of many scholars, but it is not comprehensive enough. Thus, the adverse effects of MT on zebrafish (Danio rerio) were comprehensively evaluated from gonadal histology, as well as the mRNA expression levels of 47 genes related to hypothalamic-pituitary-gonadal (HPG) axis, germ cell differentiation, sex determination, and hypothalamus-pituitary-thyroid (HPT) axis. Adult zebrafish with a female/male ratio of 5:7 were exposed to a solvent control (0.001% dimethyl sulfoxide) and three measured concentrations of MT (5, 51 and 583 ng/L) for 50 days. The results showed that MT had no significant histological effects on the ovaries of females, but the frequency of late-mature oocytes (LMO) showed a downward trend, indicating that MT could induce ovarian suppression to a certain extent. The transcriptional expression of activating transcription factor 4b1 (atf4b1), activating transcription factor 4b2 (atf4b2), calcium/calmodulin-dependent protein kinase II delta 1 (camk2d1), calcium/calmodulin-dependent protein kinase II delta 2 (camk2d2) and calcium/calmodulin-dependent protein kinase II inhibitor 2 (camk2n2) genes in the brain of females increased significantly at all treatment groups of MT, and the mRNA expression of forkhead box L2a (foxl2) and ovarian cytochrome P450 aromatase (cyp19a1a) genes in the ovaries were down-regulated by 5 and 583 ng/L group, which would translate into inhibition of oocyte development. As compared to females, MT had relatively little effects on the reproductive system of males, and only the transcriptional alterations of synaptonemal complex protein 3 (sycp3) and 17-alpha-hydroxylase/17,20-lyase (cyp17) genes were observed in the testes, not enough to affect testicular histology. In addition, MT at all treatments strongly increased corticotropin-releasing hormone (crh) transcript in the brain of females, as well as deiodinase 2 (dio2) transcript in the brain of males. The paired box protein 8 (pax8) gene was significantly decreased at 51 or 583 ng/L of MT in both female and male brains. The above results suggest that MT can pose potential adverse effects on the reproductive and thyroid endocrine system of fish.


Assuntos
Poluentes Químicos da Água , Peixe-Zebra , Animais , Masculino , Feminino , Peixe-Zebra/metabolismo , Metiltestosterona/metabolismo , Metiltestosterona/farmacologia , Eixo Hipotalâmico-Hipofisário-Gonadal , Glândula Tireoide/metabolismo , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/farmacologia , Gônadas , Expressão Gênica , Células Germinativas , RNA Mensageiro/metabolismo , Fatores Ativadores da Transcrição/genética , Fatores Ativadores da Transcrição/metabolismo , Fatores Ativadores da Transcrição/farmacologia , Poluentes Químicos da Água/metabolismo
4.
Cancer Res Commun ; 3(12): 2518-2530, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38014922

RESUMO

MYCN-amplified neuroblastoma often presents as a highly aggressive metastatic disease with a poor prognosis. Activating transcription factor 5 (ATF5) is implicated in neural cell differentiation and cancer cell survival. Here, we show that ATF5 is highly expressed in patients with stage 4 high-risk neuroblastoma, with increased expression correlating with a poorer prognosis. We demonstrated that ATF5 promotes the metastasis of neuroblastoma cell lines in vivo. Functionally, ATF5 depletion significantly reduced xenograft tumor growth and metastasis of neuroblastoma cells to the bone marrow and liver. Mechanistically, ATF5 endows tumor cells with resistance to anoikis, thereby increasing their survival in systemic circulation and facilitating metastasis. We identified the proapoptotic BCL-2 modifying factor (BMF) as a critical player in ATF5-regulated neuroblastoma anoikis. ATF5 suppresses BMF under suspension conditions at the transcriptional level, promoting anoikis resistance, whereas BMF knockdown significantly prevents ATF5 depletion-induced anoikis. Therapeutically, we showed that a cell-penetrating dominant-negative ATF5 peptide, CP-d/n-ATF5, inhibits neuroblastoma metastasis to the bone marrow and liver by inducing anoikis sensitivity in circulating tumor cells. Our study identified ATF5 as a metastasis promoter and CP-d/n-ATF5 as a potential antimetastatic therapeutic agent for neuroblastoma. SIGNIFICANCE: This study shows that resistance to anoikis in neuroblastoma is mediated by ATF5 and offers a rationale for targeting ATF5 to treat metastatic neuroblastoma.


Assuntos
Antineoplásicos , Neuroblastoma , Humanos , Anoikis/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Neuroblastoma/tratamento farmacológico , Antineoplásicos/farmacologia , Fatores Ativadores da Transcrição
5.
Adv Sci (Weinh) ; 10(34): e2304329, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37870216

RESUMO

PIWI-interacting RNAs (piRNAs) are highly expressed in various cardiovascular diseases. However, their role in cardiomyocyte death caused by ischemia/reperfusion (I/R) injury, especially necroptosis, remains elusive. In this study, a heart necroptosis-associated piRNA (HNEAP) is found that regulates cardiomyocyte necroptosis by targeting DNA methyltransferase 1 (DNMT1)-mediated 5-methylcytosine (m5 C) methylation of the activating transcription factor 7 (Atf7) mRNA transcript. HNEAP expression level is significantly elevated in hypoxia/reoxygenation (H/R)-exposed cardiomyocytes and I/R-injured mouse hearts. Loss of HNEAP inhibited cardiomyocyte necroptosis and ameliorated cardiac function in mice. Mechanistically, HNEAP directly interacts with DNMT1 and attenuates m5 C methylation of the Atf7 mRNA transcript, which increases Atf7 expression level. ATF7 can further downregulate the transcription of Chmp2a, an inhibitor of necroptosis, resulting in the reduction of Chmp2a level and the progression of cardiomyocyte necroptosis. The findings reveal that piRNA-mediated m5 C methylation is involved in the regulation of cardiomyocyte necroptosis. Thus, the HNEAP-DNMT1-ATF7-CHMP2A axis may be a potential target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.


Assuntos
Miócitos Cardíacos , Traumatismo por Reperfusão , Camundongos , Animais , Miócitos Cardíacos/metabolismo , RNA Mensageiro/metabolismo , RNA de Interação com Piwi , Necroptose/genética , Metilação , Traumatismo por Reperfusão/metabolismo , Fatores Ativadores da Transcrição/metabolismo
6.
Fish Physiol Biochem ; 49(6): 1115-1128, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37855969

RESUMO

Glucose-regulated protein 78 (grp78) and activating transcription factor 6α (atf6α) are considered vital endoplasmic reticulum (ER) molecular chaperones and ER stress (ERS) sensors, respectively. In the present study, the full cDNA sequences of these two ERS-related genes were first cloned and characterized from black seabream (Acanthopagrus schlegelii). The grp78 cDNA sequence is 2606 base pair (bp) encoding a protein of 654 amino acids (aa). The atf6α cDNA sequence is 2168 base pair (bp) encoding a protein of 645 aa. The predicted aa sequences of A. schlegelii grp78 and atf6α indicated that the proteins contain all the structural features, which were characteristic of the two genes in other species. Tissues transcript abundance analysis revealed that the mRNAs of grp78 and atf6α were expressed in all measured tissues, but the highest expression of these two genes was all recorded in the gill followed by liver/ brain. Moreover, in vivo experiment found that fish intake of a high lipid diet (HLD) can trigger ERS by activating grp78/Grp78 and atf6α/Atf6α. However, it can be alleviated by dietary betaine supplementation, similar results were also obtained by in vitro experiment using primary hepatocytes of A. schlegelii. These findings will be beneficial for us to evaluate the regulator effects of HLD supplemented with betaine on ERS at the molecular level, and thus provide some novel insights into the functions of betaine in marine fish fed with an HLD.


Assuntos
Perciformes , Dourada , Animais , Chaperona BiP do Retículo Endoplasmático , Dourada/genética , Betaína , DNA Complementar/genética , Perciformes/genética , Estresse do Retículo Endoplasmático , Fatores Ativadores da Transcrição/genética , Clonagem Molecular
7.
Cell Rep ; 42(5): 112479, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37178686

RESUMO

CREB/ATF transcription factor OASIS/CREB3L1 is upregulated in long-term-cultured astrocytes undergoing cell-cycle arrest due to loss of DNA integrity by repeated replication. However, the roles of OASIS in the cell cycle remain unexplored. We find that OASIS arrests the cell cycle at G2/M phase after DNA damage via direct induction of p21. Cell-cycle arrest by OASIS is dominant in astrocytes and osteoblasts, but not in fibroblasts, which are dependent on p53. In a brain injury model, Oasis-/- reactive astrocytes surrounding the lesion core show sustained growth and inhibition of cell-cycle arrest, resulting in prolonged gliosis. We find that some glioma patients exhibit low expression of OASIS due to high methylation of its promoter. Specific removal of this hypermethylation in glioblastomas transplanted into nude mice by epigenomic engineering suppresses the tumorigenesis. These findings suggest OASIS as a critical cell-cycle inhibitor with potential to act as a tumor suppressor.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Proteína Supressora de Tumor p53 , Camundongos , Animais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Camundongos Nus , Pontos de Checagem do Ciclo Celular , Fatores Ativadores da Transcrição/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo
8.
Cell Tissue Res ; 393(2): 343-355, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37256362

RESUMO

Intestinal tuft cells, a chemosensory cell type in mucosal epithelia that secrete interleukin (IL)-25, play a pivotal role in type 2 immune responses triggered by parasitic infections. Tuft cell-derived IL-25 activates type 2 innate lymphoid cells (ILC2) to secrete IL-13, which, in turn, acts on intestinal stem or transient amplifying cells to expand tuft cells themselves and mucus-secreting goblet cells. However, the molecular mechanisms of tuft cell differentiation under type 2 immune responses remain unclear. The present study investigated the effects of the deletion of activating transcription factor 5 (ATF5) on the type 2 immune response triggered by succinate (a metabolite of parasites) in mice. ATF5 mRNAs were expressed in the small intestine, and the loss of the ATF5 gene did not affect the gross morphology of the tissue or the basal differentiation of epithelial cell subtypes. Succinate induced marked increases in tuft and goblet cell numbers in the ATF5-deficient ileum. Tuft cells in the ATF5-deficient ileum are assumed to be a subtype of intestinal tuft cells (Tuft-2 cells) marked by the transcription factor Spib. Exogenous IL-25 induced similar increases in tuft and goblet cell numbers in wild-type and ATF5-deficient ilea. IL-13 at a submaximal dose enhanced tuft cell differentiation more in ATF5-deficient than in wild-type intestinal organoids. These results indicate that the loss of ATF5 enhanced the tuft cell-ILC2 type 2 immune response circuit by promoting tuft cell differentiation in the small intestine, suggesting its novel regulatory role in immune responses against parasitic infections.


Assuntos
Células Caliciformes , Imunidade Inata , Camundongos , Animais , Ácido Succínico/metabolismo , Mucosa Intestinal/metabolismo , Interleucina-13/metabolismo , Linfócitos , Fatores Ativadores da Transcrição/metabolismo
9.
Nat Commun ; 14(1): 2886, 2023 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-37210583

RESUMO

Cisplatin kills proliferating cells via DNA damage but also has profound effects on post-mitotic cells in tumors, kidneys, and neurons. However, the effects of cisplatin on post-mitotic cells are still poorly understood. Among model systems, C. elegans adults are unique in having completely post-mitotic somatic tissues. The p38 MAPK pathway controls ROS detoxification via SKN-1/NRF and immune responses via ATF-7/ATF2. Here, we show that p38 MAPK pathway mutants are sensitive to cisplatin, but while cisplatin exposure increases ROS levels, skn-1 mutants are resistant. Cisplatin exposure leads to phosphorylation of PMK-1/MAPK and ATF-7 and the IRE-1/TRF-1 signaling module functions upstream of the p38 MAPK pathway to activate signaling. We identify the response proteins whose increased abundance depends on IRE-1/p38 MAPK activity as well as cisplatin exposure. Four of these proteins are necessary for protection from cisplatin toxicity, which is characterized by necrotic death. We conclude that the p38 MAPK pathway-driven proteins are crucial for adult cisplatin resilience.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Cisplatino/toxicidade , Cisplatino/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sistema de Sinalização das MAP Quinases , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Fatores Ativadores da Transcrição
10.
Mol Med ; 29(1): 57, 2023 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-37095454

RESUMO

BACKGROUND: Mitochondrial quality control (MQC) plays a critical role in the progression of tubulointerstitial injury in diabetic kidney disease (DKD). The mitochondrial unfolded protein response (UPRmt), which is an important MQC process, is activated to maintain mitochondrial protein homeostasis in response to mitochondrial stress. Activating transcription factor 5 (ATF5) is critical in the mammalian UPRmt via mitochondria-nuclear translocation. However, the role of ATF5 and UPRmt in tubular injury under DKD conditions is unknown. METHODS: ATF5 and UPRmt-related proteins including heat shock protein 60 (HSP60) and Lon peptidase 1 (LONP1), in DKD patients and db/db mice were examined by immunohistochemistry (IHC) and western blot analysis. Eight-week-old db/db mice were injected with ATF5-shRNA lentiviruses via the tail vein, and a negative lentivirus was used as a control. The mice were euthanized at 12 weeks, and dihydroethidium (DHE) and TdT-mediated dUTP nick end labeling (TUNEL) assays were performed to evaluate reactive oxygen species (ROS) production and apoptosis in kidney sections, respectively. In vitro, ATF5-siRNA, ATF5 overexpression plasmids or HSP60-siRNA were transfected into HK-2 cells to evaluate the effect of ATF5 and HSP60 on tubular injury under ambient hyperglycemic conditions. Mitochondrial superoxide (MitoSOX) staining was used to gauge mitochondrial oxidative stress levels, and the early stage of cell apoptosis was examined by Annexin V-FITC kits. RESULTS: Increased ATF5, HSP60 and LONP1 expression was observed in the kidney tissue of DKD patients and db/db mice and was tightly correlated with tubular damage. The inhibition of HSP60 and LONP1, improvements in serum creatinine, tubulointerstitial fibrosis and apoptosis were observed in db/db mice treated with lentiviruses carrying ATF5 shRNA. In vitro, the expression of ATF5 was increased in HK-2 cells exposed to high glucose (HG) in a time-dependent manner, which was accompanied by the overexpression of HSP60, fibronectin (FN) and cleaved-caspase3 (C-CAS3). ATF5-siRNA transfection inhibited the expression of HSP60 and LONP1, which was accompanied by reduced oxidative stress and apoptosis in HK-2 cells exposed to sustained exogenous high glucose. ATF5 overexpression exacerbated these impairments. HSP60-siRNA transfection blocked the effect of ATF5 on HK-2 cells exposed to continuous HG treatment. Interestingly, ATF5 inhibition exacerbated mitochondrial ROS levels and apoptosis in HK-2 cells in the early period of HG intervention (6 h). CONCLUSIONS: ATF5 could exert a protective effect in a very early stage but promoted tubulointerstitial injury by regulating HSP60 and the UPRmt pathway under DKD conditions, providing a potential target for the prevention of DKD progression.


Assuntos
Diabetes Mellitus , Nefropatias Diabéticas , Camundongos , Animais , Nefropatias Diabéticas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Túbulos Renais , Glucose/metabolismo , RNA Interferente Pequeno/genética , Resposta a Proteínas não Dobradas , Mamíferos/metabolismo , Diabetes Mellitus/metabolismo , Fatores Ativadores da Transcrição/genética , Fatores Ativadores da Transcrição/metabolismo , Fatores Ativadores da Transcrição/farmacologia
11.
Biomed Pharmacother ; 161: 114544, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36934558

RESUMO

Activating transcription factors, ATFs, is a family of transcription factors that activate gene expression and transcription by recognizing and combining the cAMP response element binding proteins (CREB). It is present in various viruses as a cellular gene promoter. ATFs is involved in regulating the mammalian gene expression that is associated with various cell physiological processes. Therefore, ATFs play an important role in maintaining the intracellular homeostasis. ATF2 and ATF3 is mostly involved in mediating stress responses. ATF4 regulates the oxidative metabolism, which is associated with the survival of cells. ATF5 is presumed to regulate apoptosis, and ATF6 is involved in the regulation of endoplasmic reticulum stress (ERS). ATFs is actively studied in oncology. At present, there has been an increasing amount of research on ATFs for the treatment of neurological diseases. Here, we have focused on the different types of ATFs and their association with Alzheimer's disease (AD). The level of expression of different ATFs have a significant difference in AD patients when compared to healthy control. Recent studies have suggested that ATFs are implicated in the pathogenesis of AD, such as neuronal repair, maintenance of synaptic activity, maintenance of cell survival, inhibition of apoptosis, and regulation of stress responses. In this review, the potential role of ATFs for the treatment of AD has been highlighted. In addition, we have systematically reviewed the progress of research on ATFs in AD. This review will provide a basic and innovative understanding on the pathogenesis and treatment of AD.


Assuntos
Doença de Alzheimer , Animais , Humanos , Doença de Alzheimer/tratamento farmacológico , Fatores Ativadores da Transcrição/genética , Fatores Ativadores da Transcrição/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Estresse do Retículo Endoplasmático/fisiologia , Mamíferos
12.
Cells ; 12(4)2023 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-36831248

RESUMO

Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies.


Assuntos
Peptídeos Penetradores de Células , Neoplasias , Humanos , Peptídeos Penetradores de Células/farmacologia , Encéfalo/metabolismo , Desenvolvimento de Medicamentos , Proteína delta de Ligação ao Facilitador CCAAT , Fatores Ativadores da Transcrição/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT
13.
Exp Mol Med ; 55(2): 413-425, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36765266

RESUMO

Glutathione (GSH), an abundant nonprotein thiol antioxidant, participates in several biological processes and determines the functionality of stem cells. A detailed understanding of the molecular network mediating GSH dynamics is still lacking. Here, we show that activating transcription factor-2 (ATF2), a cAMP-response element binding protein (CREB), plays a crucial role in maintaining the level and activity of GSH in human mesenchymal stem cells (MSCs) by crosstalking with nuclear factor erythroid-2 like-2 (NRF2), a well-known master regulator of cellular redox homeostasis. Priming with ascorbic acid 2-glucoside (AA2G), a stable vitamin C derivative, increased the expression and activity of ATF2 in MSCs derived from human embryonic stem cells and umbilical cord. Subsequently, activated ATF2 crosstalked with the CREB1-NRF2 pathway to preserve the GSH dynamics of MSCs through the induction of genes involved in GSH synthesis (GCLC and GCLM) and redox cycling (GSR and PRDX1). Accordingly, shRNA-mediated silencing of ATF2 significantly impaired the self-renewal, migratory, proangiogenic, and anti-inflammatory capacities of MSCs, and these defects were rescued by supplementation of the cells with GSH. In addition, silencing ATF2 attenuated the ability of MSCs to alleviate airway inflammatory responses in an ovalbumin-induced mouse model of allergic asthma. Consistently, activation of ATF2 by overexpression or the AA2G-based priming procedure enhanced the core functions of MSCs, improving the in vivo therapeutic efficacy of MSCs for treating asthma. Collectively, our findings suggest that ATF2 is a novel modulator of GSH dynamics that determines the core functionality and therapeutic potency of MSCs used to treat allergic asthma.


Assuntos
Asma , Células-Tronco Mesenquimais , Animais , Humanos , Camundongos , Fatores Ativadores da Transcrição/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Asma/metabolismo , Glutationa/metabolismo , Fatores Imunológicos , Inflamação/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo
14.
Int J Mol Sci ; 24(4)2023 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-36834738

RESUMO

The highly dynamic changes in microglia necessary to achieve a rapid neuroinflammatory response require a supply of energy from mitochondrial respiration, which leads to the accumulation of unfolded mitochondrial proteins. We previously reported that microglial activation is correlated with the mitochondrial unfolded protein response (UPRmt) in a kaolin-induced hydrocephalus model, but we still do not know the extent to which these changes in microglia are involved in cytokine release. Here, we investigated the activation of BV-2 cells and found that treatment with lipopolysaccharide (LPS) for 48 h increased the secretion of pro-inflammatory cytokines. This increase was accompanied by a concurrent decrease in oxygen consumption rate (OCR) and mitochondrial membrane potential (MMP), in association with the up-regulation of the UPRmt. Inhibition of the UPRmt by knockdown of ATF5, a key upstream regulator of the UPRmt, using small-interfering RNA against ATF5 (siATF5) not only increased production of the pro-inflammatory cytokines, interleukin-6 (IL-6), IL-1ß and tumor necrosis factor-α (TNF-α), but also decreased MMP. Our results suggest that ATF5-dependent induction of the UPRmt in microglia acts as a protective mechanism during neuroinflammation and may be a potential therapeutic target for reducing neuroinflammation.


Assuntos
Citocinas , Microglia , Fatores Ativadores da Transcrição/metabolismo , Citocinas/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Doenças Neuroinflamatórias , Fator de Necrose Tumoral alfa/metabolismo
15.
Life Sci ; 315: 121339, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36621538

RESUMO

AIMS: Liver is a pivotal organ for sepsis-induced injury and approximately 40 % of liver injury results from sepsis. During hepatic injury, monocyte-to-macrophage differentiation is a key event because it results in the regulation of immune response. Asialoglycoprotein receptor 1 (ASGR1) is enriched in classical monocyte of peripheral blood mononuclear cells (PBMCs). We aimed to explore the effect of ASGR1 on monocyte-to-macrophage differentiation and the modulation of sepsis-induced liver injury. MAIN METHODS: ASGR1-knockdown/overexpression THP-1 cells and mice bone marrow-derived macrophages (BMDMs) induced by PMA and 30 % L929-cell conditioned medium were utilized to test the impact of ASGR1 on monocyte-to-macrophage differentiation and molecular mechanism respectively. Expression of differentiation specific factors were assessed via flow cytometry and real-time quantitative PCR. RNA-sequencing (RNA-seq) analysis revealed the effect of ASGR1 on monocyte-to-macrophage differentiation. Further, differentiation specific factors ATF5 and NF-κB pathways were examined via Western blot. The interaction between ASGR1 and ATF5 was further examined by co-IP. Finally, LPS-induced ASGR1-knockdown mice sepsis was used to investigate the effect of ASGR1 on monocyte-to-macrophage differentiation, liver injury and survival. KEY FINDINGS: ASGR1 promoted monocyte-to-macrophage differentiation via up-regulating CD68, F4/80 and CD86. Additionally, inhibited-ASGR1 decreased ATF5 expression by suppressing phosphorylation of NF-κB and IKBa in vitro and in vivo. ASGR1-knockdown mice suppressed Ly6Chi inflammatory monocytes in PBMCs, and restrained CD45+CD11bhiF4/80+Ly6Clo monocyte-derived macrophages and CD45+CD11b+F4/80+Ly6C+ inflammatory macrophages in livers. It also suppressed the level of IL-1ß, IL-6, TNF-α and alleviated liver injury and improved survival after sepsis. SIGNIFICANCE: ASGR1 is a negative regulator for sepsis-induced liver injury and survival.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Sepse , Camundongos , Animais , Monócitos/metabolismo , NF-kappa B/metabolismo , Leucócitos Mononucleares/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Macrófagos/metabolismo , Diferenciação Celular , Sepse/complicações , Sepse/metabolismo , Camundongos Endogâmicos C57BL , Fatores Ativadores da Transcrição/metabolismo
16.
Neurochem Res ; 48(1): 62-71, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35939173

RESUMO

The mitochondrial unfolded protein response (mtUPR)-a stress response pathway for maintaining protein homeostasis-is critical in seizures-induced neuronal injury. The activating transcription factor 5 (ATF5) regulates mtUPR; however, whether ATF5-regulated mtUPR has a role in neuronal injury in epilepsy remains uncertain. Here, we investigated the effects of ATF5-regulated mtUPR on neuronal injury in hippocampal neurons with seizures evoked by Mg2+-free medium. HSP60 and ClpP, key proteins of mtUPR, were upregulated, indicating mtUPR activation. ATF5 overexpression by lentiviral vector infection potentiated mtUPR, whereas ATF5 downregulation by lentiviral vector infection attenuated this response. Moreover, ATF5 overexpression elevated mitochondrial membrane potential and reduced reactive oxygen species (ROS) generation, suggesting that ATF5 overexpression protected mitochondrial homeostasis, while ATF5 downregulation had the opposite effect. ATF5 overexpression also reversed Bcl2 downregulation and Bax upregulation and attenuated seizures-induced neuronal apoptosis, while ATF5 downregulation aggravated the injury. Our study demonstrates that ATF5 attenuates seizures-induced neuronal injury, possibly by regulating mtUPR pathways, to prevent mitochondrial dysfunction.


Assuntos
Apoptose , Resposta a Proteínas não Dobradas , Humanos , Mitocôndrias/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Convulsões/induzido quimicamente , Convulsões/metabolismo , Neurônios/metabolismo , Fatores Ativadores da Transcrição/metabolismo
17.
Cell Prolif ; 56(2): e13352, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36254813

RESUMO

BACKGROUND: Activating transcription factor 7 (ATF7) is a member of the ATF/cAMP response element (CRE) B superfamily. ATF2, ATF7, and CRE-BPa are present in vertebrates. Drosophila and fission yeast have only one homologue: dATF2 and Atf1, respectively. Under normal conditions, ATF7 promotes heterochromatin formation by recruiting histone H3K9 di- and tri-methyltransferases. Once the situation changes, all members are phosphorylated by the stress-activated kinase P38 in response to various stressors. However, the role of ATF7 in early porcine embryonic development remains unclear. RESULTS: In this study, we found that ATF7 gradually accumulated in the nucleus and then localized on the pericentric heterochromatin after the late 4-cell stage, while being co-localized with heterochromatin protein 1 (HP1). Knockdown of ATF7 resulted in decreases in the blastocyst rate and blastocyst cell number. ATF7 depletion resulted in downregulation of HP1 and histone 3 lysine 9 dimethylation (H3K9me2) expression. These effects were alleviated when P38 activity was inhibited. High temperatures increased the expression level of pP38, while reducing the quality of porcine embryos, and led to ATF7 phosphorylation. The expression level of H3K9me2 and HP1 was decreased and regulated by P38 activity. CONCLUSION: Stress-induced ATF7-dependent epigenetic changes play important roles in early porcine embryonic development.


Assuntos
Fatores Ativadores da Transcrição , Histonas , Animais , Suínos , Histonas/metabolismo , Fatores Ativadores da Transcrição/genética , Fatores Ativadores da Transcrição/metabolismo , Heterocromatina , Temperatura , Epigênese Genética , Proteínas Cromossômicas não Histona/metabolismo
18.
Cell Signal ; 102: 110535, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36436799

RESUMO

Endoplasmic reticulum (ER) stress is closely associated with type 2 diabetes (T2D). Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP response element binding protein (CREB) family whose levels are increased upon stress in pancreatic islets from mice. Intriguingly, ATF5 deficiency has been shown to contribute to increased ER stress and apoptosis in mouse islet micro-organs. We hypothesized that either deficiency or overexpression of ATF5 is equally deleterious for pancreatic islets in terms of ER stress and apoptosis. To test this, we used a number of in vitro and in vivo models whereby ATF5 levels were overexpressed. We also determined the regulation of ATF5 in the context of metabolic derangements by using various mouse models of obesity and T2D. Our in vitro results show that ATF5 overexpression promoted palmitic acid (PA)-induced lipotoxic apoptosis. In vivo, global ATF5 overexpression in mice was lethal and pancreas-specific ATF5 overexpressing mice exhibit increased ß-cell apoptosis. Interestingly, ATF5 is downregulated in all mouse models of severe obesity and T2D used in the current study. In conclusion, a tight control on ATF5 levels might be considered when developing novel agents targeting ATF5 for prevention and treatment of metabolic diseases.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Camundongos , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fatores Ativadores da Transcrição/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Apoptose/fisiologia , Modelos Animais de Doenças , Dieta , Obesidade/metabolismo , Células Secretoras de Insulina/metabolismo , Estresse do Retículo Endoplasmático/fisiologia
19.
Cancer Immunol Immunother ; 72(4): 815-826, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36063172

RESUMO

Immune suppressive factors of the tumor microenvironment (TME) undermine viability and exhaust the activities of the intratumoral cytotoxic CD8 + T lymphocytes (CTL) thereby evading anti-tumor immunity and decreasing the benefits of immune therapies. To counteract this suppression and improve the efficacy of therapeutic regimens, it is important to identify and understand the critical regulators within CD8 + T cells that respond to TME stress and tumor-derived factors. Here we investigated the regulation and importance of activating transcription factor-4 (ATF4) in CTL using a novel Atf4ΔCD8 mouse model lacking ATF4 specifically in CD8 + cells. Induction of ATF4 in CD8 + T cells occurred in response to antigenic stimulation and was further increased by exposure to tumor-derived factors and TME conditions. Under these conditions, ATF4 played a critical role in the maintenance of survival and activities of CD8 + T cells. Conversely, selective ablation of ATF4 in CD8 + T cells in mice rendered these Atf4ΔCD8 hosts prone to accelerated growth of implanted tumors. Intratumoral ATF4-deficient CD8 + T cells were under-represented compared to wild-type counterparts and exhibited impaired activation and increased apoptosis. These findings identify ATF4 as an important regulator of viability and activity of CD8 + T cells in the TME and argue for caution in using agents that could undermine these functions of ATF4 for anti-cancer therapies.


Assuntos
Linfócitos do Interstício Tumoral , Neoplasias , Camundongos , Animais , Linfócitos T CD8-Positivos , Linfócitos T Citotóxicos , Fatores Ativadores da Transcrição , Microambiente Tumoral
20.
Front Immunol ; 14: 1282996, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38223508

RESUMO

Backgrounds: Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma characterized by skin infiltration of malignant T cells. The biological overlap between malignant T cells and their normal counterparts has brought obstacles in identifying tumor-specific features and mechanisms, limiting current knowledge of CTCL pathogenesis. Transcriptional dysregulation leading to abnormal gene expression profiles contributes to the initiation, progression and drug resistance of cancer. Therefore, we aimed to identify tumor-specific transcription factor underlying CTCL pathology. Methods: We analyzed and validated the differentially expressed genes (DEGs) in malignant T cells based on single-cell sequencing data. Clinical relevance was evaluated based on progression-free survival and time to next treatment. To determine the functional importance, lentivirus-mediated gene knockdown was conducted in two CTCL cell lines Myla and H9. Cell survival was assessed by examining cell viability, colony-forming ability, in-vivo tumor growth in xenograft models, apoptosis rate and cell-cycle distribution. RNA sequencing was employed to investigate the underlying mechanisms. Results: Activating transcription factor 5 (ATF5) was overexpressed in malignant T cells and positively correlated with poor treatment responses in CTCL patients. Mechanistically, ATF5 promoted the survival of malignant T cells partially through the PI3K/AKT/mTOR pathway, and imparted resistance to endoplasmic reticulum (ER) stress-induced apoptosis. Conclusions: These findings revealed the tumor-specific overexpression of the transcription factor ATF5 with its underlying mechanisms in promoting tumor survival in CTCL, providing new insight into the understanding of CTCL's pathology.


Assuntos
Fatores Ativadores da Transcrição , Linfoma Cutâneo de Células T , Neoplasias Cutâneas , Humanos , Fatores Ativadores da Transcrição/genética , Sobrevivência Celular/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Linfoma Cutâneo de Células T/patologia , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Linfócitos T/metabolismo , Serina-Treonina Quinases TOR
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