关键词： Small cell lung cancer   Shikonin   Ferroptosis   ATF3   ROS   Histone acetylation   APOPTOSIS   ATF3   PROGRESSION   INDUCTION   CYCLE  

摘要： Small cell lung cancer (SCLC) is a subtype of lung cancer with a very poor overall survival rate due to its extremely high proliferation and metastasis predilection. Shikonin is an active ingredient extracted from the roots of Lithospermum erythrorhizon, and exerts multiple anti-tumor functions in many cancers. In the present study, the role and underlying mechanism of shikonin in SCLC were investigated for the first time. We found that shikonin effectively suppressed cell proliferation, apoptosis, migration, invasion, and colony formation and slightly induced apoptosis in SCLC cells. Further experiment indicated the shikonin could also induced ferroptosis in SCLC cells. Shikonin treatment effectively suppressed the activation of ERK, the expression of ferroptosis inhibitor GPX4, and elevated the level of 4-HNE, a biomarker of ferroptosis. Both total ROS and lipid ROS were increased, while the GSH levels were decreased in SCLC cells after shikonin treatment. More importantly, our data identified that the function of shikonin was dependent on the up-regulation of ATF3 by performing rescue experiments using shRNA to silence the expression of ATF3, especially in the total and lipid ROS accumulaiton. Xenograft model was established using SBC-2 cells, and the results revealed that shikonin also significantly inhibited tumor growth by inducing ferroptosis. Finally, our data further confirmed that shikonin activated ATF3 transcription by impairing the recruitment of HDAC1 mediated by c-myc on the ATF3 promoter, and subsequently elevating of histone acetylation. Our data documented that shikonin suppressed SCLC by inducing ferroptosis in a ATF3-dependent manner. Shikonin upregulated the expression of ATF3 expression via promoting the histone acetylation by inhibiting c-myc-mediated HDAC1 binding on ATF3 promoter.

关键词： ATF3   Cardiovascular diseases   Therapy   Mechanisms   ENDOPLASMIC-RETICULUM STRESS   ATF3-DEPENDENT CROSS-TALK   GENE-EXPRESSION   MYOCARDIAL-INFARCTION   CARDIAC-HYPERTROPHY   ATF3 EXPRESSION   GROWTH-CONTROL   HEART-FAILURE   ER STRESS   PROTECTS  

摘要： Activation transcription factor 3 (ATF3), a member of the ATF/cyclic adenosine monophosphate response element binding family, can be induced by a variety of stresses. Numerous studies have indicated that ATF3 plays multiple roles in the development and progression of cardiovascular diseases, including atherosclerosis, hypertrophy, fibrosis, myocardial ischemia-reperfusion, cardiomyopathy, and other cardiac dysfunctions. In past decades, ATF3 has been demonstrated to be detrimental to some cardiac diseases. Current studies have indicated that ATF3 can function as a cardioprotective molecule in antioxidative stress, lipid metabolic metabolism, energy metabolic regulation, and cell death modulation. To unveil the potential therapeutic role of ATF3 in cardiovascular diseases, we organized this review to explore the protective effects and mechanisms of ATF3 on cardiac dysfunction, which might provide rational evidence for the prevention and cure of cardiovascular diseases.

关键词： acute lung injury   acute respiratory distress syndrome   ATF3   chronic obstructive pulmonary disease   posttranslational modifications   pulmonary fibrosis   LUNG INJURY   ATF3   EXPRESSION   PATHOGENESIS   CELLS   TRANSPLANTATION   SUMOYLATION   INFECTION   PROTEINS   FIBROSIS  

摘要： BackgroundActivating transcription factor 3 (ATF3) is a nuclear protein that is widely expressed in a variety of cells. It is a stress-inducible transcription gene and a member of the activating transcription factor/cAMP responsive element-binding protein (ATF/CREB) *** comprehensive literature review was conducted by searching PubMed and Google Scholar. Search terms used were "ATF3", "ATF3 and (ALI or ARDS)", "ATF3 and COPD", "ATF3 and PF", and "ATF3 and Posttranslational modifications".ResultsRecent studies have shown that ATF3 plays a critical role in many inflammatory pulmonary diseases, including acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF). ATF3 participates in many signaling pathways and complex pathophysiological processes, such as inflammation, immunity, endoplasmic reticulum stress, and cell proliferation. However, the role of ATF3 in current studies is controversial, and there are reports showing that ATF3 plays different roles in different pulmonary *** this review, we first summarized the structure, function, and mechanism of ATF3 in various inflammatory pulmonary diseases. The impact of ATF3 on disease pathogenesis and the clinical implications was particularly focused on, with an overall aim to identify new targets for treating inflammatory pulmonary diseases. In this review, we first summarize the structure, function, and signaling pathways of ATF3, and then introduce the mechanism of ATF3 in various inflammatory pulmonary diseases. We focus on the impact of ATF3 on disease pathogenesis and clinical implications, aiming to provide new targets for treating inflammatory pulmonary ***

关键词： ATF3   endoplasmic reticulum stress   myocardial infarction   oxidative stress   SPHK1   MYOCARDIAL-INFARCTION   ER STRESS   SPHINGOSINE   EXPRESSION   CONTRIBUTES   ACTIVATION  

摘要： AimEndoplasmic reticulum (ER) stress is common in different human pathologies, including cardiac diseases. Sphingosine kinase-1 (SPHK1) represents an important player in cardiac growth and function. Nevertheless, its function in cardiomyocyte ER stress remains vague. This study sought to evaluate the mechanism through which SPHK1 might influence ER stress during myocardial infarction (MI).MethodsMI-related GEO data sets were queried to screen differentially expressed genes. Murine HL-1 cells exposed to oxygen-glucose deprivation (OGD) and mice with MI were induced, followed by gene expression manipulation using short hairpin RNAs and overexpression vectors. The activating transcription factor 3 (ATF3) and SPHK1 expression was examined in cells and tissues. Cell counting kit-8, TUNEL, DHE, HE, and Masson's staining were conducted in vitro and in vivo. The inflammatory factor concentrations in mouse serum were measured using ELISA. Finally, the transcriptional regulation of SPHK1 by ATF3 was ***3 and SPHK1 were upregulated in vivo and in vitro. ATF3 downregulation reduced the SPHK1 transcription. ATF3 and SPHK1 downregulation increased the viability of OGD-treated HL-1 cells and decreased apoptosis, oxidative stress, and ER stress. ATF3 and SPHK1 downregulation narrowed the infarction area and attenuated myocardial fibrosis in mice, along with reduced inflammation in the serum and ER stress in the myocardium. In contrast, SPHK1 reduced the protective effect of ATF3 downregulation in vitro and in ***3 downregulation reduced SPHK1 expression to attenuate cardiomyocyte injury in MI. Stimulation of activating transcription factor 3 (ATF3) exerts pro-fibrotic and proinflammatory effect and expedite endoplasmic reticulum (ER) stress in cardiomyocytes via sphingosine kinase 1 (SPHK1). Thus, the inhibition of ATF3 and SPHK1 may have therapeutic potential for MI. Our understanding of ER stress during MI are still rudimentary, and more research

关键词： rno_circRNA_006061   Formaldehyde   Lung injury   rno-miR-128-3p   p38   ATF3  

摘要： Formaldehyde, a common indoor air pollutant, is significantly toxic to the respiratory system, whereas its mechanism is unclear. CircRNAs exert critical functions via sponging microRNAs (miRNAs). To evaluate the effect of long-term formaldehyde exposure on rno_circRNA_006061 expression profiles, the downstream targets and signaling pathways associated with rno_circRNA_006061 were predicted and validated using bioinformatics methods and dual-luciferase reporter assay. Previously, our circRNA microarray showed that rno_-circRNA_006061 was up-regulated in the formaldehyde-exposed lung tissue. Subsequently, bioinformatics analysis predicted that rno_circRNA_006061 bound to rno-miR-128-3p and co-regulated the p38/ATF3 signaling pathway. Meanwhile, the expressions of rno_circRNA_006061, rno-miR-128-3p and p38 were correlated with the lung histomorphopathological injury assessment. Furthermore, TUNEL and Bax/Bcl-2 ratio results revealed that up-regulated rno_circRNA_00606 induced by formaldehyde stimulated apoptosis in the lung. After the knock-down of rno_circRNA_006061, the expression of rno-miR-128-3p increased and the expression of p38 decreased slightly, which partially restored formaldehyde-induced apoptosis in alveolar epithelial cells. In conclusion, our study hinted that the rno_circRNA_006061 might enhance p38/ATF3 pathway expression via sponging the rno-miR-128-3p, thus significantly promoting apoptosis in lung tissues, which may provide potential new targets for preventing and treating lung injury by formaldehyde inhalation.

关键词： INDUCED GENE-EXPRESSION   IMMEDIATE-EARLY GENES   SATELLITE CELLS   TRANSCRIPTION FACTORS   C-FOS   QUIESCENT   GENOME   REPRESSION   REVEALS   AP-1  

摘要： Skeletal muscle stem cells (also called satellite cells, SCs) are important for maintaining muscle tissue homeostasis and damage-induced regeneration. However, it remains poorly understood how SCs enter cell cycle to become activated upon injury. Here we report that AP-1 family member ATF3 (Activating Transcription Factor 3) prevents SC premature activation. Atf3 is rapidly and transiently induced in SCs upon activation. Short-term deletion of Atf3 in SCs accelerates acute injury-induced regeneration, however, its long-term deletion exhausts the SC pool and thus impairs muscle regeneration. The Atf3 loss also provokes SC activation during voluntary exercise and enhances the activation during endurance exercise. Mechanistically, ATF3 directly activates the transcription of Histone 2B genes, whose reduction accelerates nucleosome displacement and gene transcription required for SC activation. Finally, the ATF3-dependent H2B expression also prevents genome instability and replicative senescence in SCs. Therefore, this study has revealed a previously unknown mechanism for preserving the SC population by actively suppressing precocious activation, in which ATF3 is a key regulator. Muscle regeneration relies on activation and expansion of skeletal muscle stem cells. Here, authors show that ATF3 induction prevents precocious activation of skeletal muscle stem cells by binding and promoting the transcription of Histone2B.

关键词： BIOLOGICAL EVALUATION   ACTIVATION   SCAFFOLD   DESIGN   CHOP  

摘要： Liver cancer is one of the most lethal malignancies with an annual death of over 830,000 cases. Although targeted therapeutic drugs have achieved certain clinical efficacy, only sorafenib and lenvatinib are currently marketed as first-line targeted drugs to treat patients with advanced liver cancer. Therefore, developing more drugs are urgently needed. Ferroptosis is an iron-dependent programmed cell death (PCD) distinct from known PCDs including apoptosis, necrosis, and autophagy. Targeting ferroptosis is recognized as a promising potential therapeutic modality for liver cancer. Activating transcription factor 3 (ATF3) is an important ferroptosis inducer and targeting ATF3 offers a potential means to cancer therapy. In the present study, we reported for the first time a sophoridine derivative 6j with promising anti-liver cancer effects in vitro and in vivo. Compound 6j could induce liver cancer cells ferroptosis by promoting the accumulation of intracellular Fe2+, reactive oxygen species (ROS), and MDA. Inhibition of ferroptosis by ferrostatin-1 alleviated 6j induced accumulation of Fe2+, ROS, and MDA and restored cell viability. Further study revealed that compound 6j upregulated the expression of ATF3 via ER stress and knockdown of ATF3 by RNA interference attenuated 6j induced ferroptosis and cell proliferation inhibition. This study would provide new insights for the design of ferroptosis inducers and the development of anti-liver cancer drugs.

关键词： ATF3   Crossbred local chicken   Gene expression   Internal organs   MEF2A   RT-PCR   STRESS   METABOLISM   BROILERS  

摘要： BackgroundMyogenic enhancer transcription factor 2A (MEF2A) is a transcription factor known for its role in controlling skeletal muscle regeneration and metabolic processes, while activating transcription factor 3 (ATF3) is a stress-induced transcription factor that plays a role in modulating metabolic processes, immunity, and oncogenesis. Environmental factors, such as dietary protein, can influence gene expression levels. Insufficient protein intake can negatively affect the metabolic performance of internal organs, leading to the abnormal weight of internal organs. A total of 192 non-sexing crossbred local chickens day-old-chick (DOC) with a completely randomized design (CRD) method of 3 treatments and 8 replicates. Real-time polymerase chain reaction (RT-PCR) is used to measure the gene expression levels. This study aimed to determine the effect of feeding with various protein levels on internal organ weight and gene expression of MEF2A and ATF3 in crossbred local *** analysis of treatment revealed that the results were not significantly different (P > 0.05) on gizzard weight and spleen weight. However, it shows a significantly different result (P < 0.05) on heart weight and a highly significantly different result (P < 0.01) on pancreas weight. These findings suggest that protein levels in the diet had a significant impact on heart and pancreas weights. In terms of gene expression, the increased utilization of protein did not result in an elevation of MEF2A gene expression in both muscle tissue and liver tissue. Specifically, in muscle tissue, MEF2A gene expression was highly expressed at 18% protein feed for the starter phase and 16% for the finisher phase. Conversely, in liver tissue, MEF2A gene expression was highly expressed at 22% protein feed for the starter phase and 20% for the finisher phase. Moreover, ATF3 gene expression in muscle tissue exhibited a negative correlation with increasing feed protein *** results indicate

关键词： AIR-POLLUTION   SIGNALING PATHWAYS   INNATE   PM2.5   DISEASES   PM10   ATF3   PEPTIDES   EXPOSURE  

摘要： Airborne particulate matter produced by industrial sources and automobiles has been linked to increased susceptibility to infectious diseases and it is known to be recognized by cells of the immune system. The molecular mechanisms and changes in gene expression profiles induced in immune cells by PM have not been fully mapped out or systematically integrated. Here, we use RNA-seq to analyze mRNA profiles of human peripheral blood mononuclear cells after exposure to coarse particulate matter (PM10). Our analyses showed that PM10 was able to reprogram the expression of 1,196 genes in immune cells, including activation of a proinflammatory state with an increase in cytokines and chemokines. Activation of the IL-36 signaling pathway and upregulation of chemokines involved in neutrophil and monocyte recruitment suggest mechanisms for inflammation upon PM exposure, while NK cell-recruiting chemokines are repressed. PM exposure also increases transcription factors associated with inflammatory pathways (e.g., JUN, RELB, NFKB2, etc.) and reduces expression of RNases and pathogen response genes CAMP, DEFAs, AZU1, APOBEC3A and LYZ. Our analysis across gene regulatory and signaling pathways suggests that PM plays a role in the dysregulation of immune cell functions, relevant for antiviral responses and general host defense against pathogens.