关键词： PM2.5   Apoptosis   Inflammation   ATF3   Ovarian function  

摘要： Particulate matter 2.5 (PM2.5) pollution has emerged as a major global public health concern because of its adverse effects on human health. Our group has previously demonstrated that PM2.5 exposure can seriously impair ovarian function. However, the underlying mechanisms remain a mystery. This study verifies ovarian damage in mice, evidenced by inflammatory cell infiltration and follicular atresia, following 5 months of PM2.5 exposure via tracheal drip (35 mu g/m(3) for low dose and 150 mu g/m(3) for high dose). In addition, PM2.5 exposure inhibited the cell viability of human granulosa cells (KGN) and induced apoptosis at the concentrations of 50, 100, and 150 mu g/mL for 24 h. The apoptosis of KGN cells induced by inflammation contributes to follicular atresia. Furthermore, we conducted RNA-sequencing analysis to identify the genes and pathways triggered by PM2.5 (100 mu g/mL) exposure, which decreases the KGN cell viability. We found a significant increase in Activating Transcription Factor 3 (ATF3). Further mechanistic studies reveal a strong association between PM2.5-induced apoptosis, inflammation, and ATF3 with its downstream oxidative stress signals. In summary, the ATF3 pathway serves a vital role in the ovarian injury caused by PM2.5 exposures.

关键词： miR-378-5p   ATF3   前体脂肪细胞   增殖   分化  

摘要： 肌内脂肪含量是决定肉质的关键要素,受多种因素影响,其中重要的一项成分为遗传因素。ATF3(活化转录因子3)基因被证明可以抑制肌内前体脂肪细胞的分化,但其在绵羊方面的作用尚未被探索。基于实验室前期对2月龄和12月龄绵羊背最长肌的高通量测序结果,筛选出差异表达的miR-378-5p,通过预测发现miR-378-5p与ATF3可能具有靶向关系。本研究探讨了miR-378-5p靶向ATF3基因对绵羊前体脂肪细胞增殖和分化的影响。采用双荧光素酶报告试验验证了miR-378-5p和ATF3之间的靶向关系。过表达和干扰miR-378-5p后,通过分析实时荧光定量PCR和蛋白质免疫印迹结果显示,miR-378-5p通过靶向ATF3负向调控前体脂肪细胞的增殖,正向调控前体脂肪细胞的分化。EdU细胞增殖检测结果显示,miR-378-5p通过靶向ATF3抑制前体脂肪细胞增殖。油红O染色结果显示,miR-378-5p通过靶向ATF3促进前体脂肪细胞分化。本研究结果证实了miR-378-5p靶向ATF3抑制前脂肪细胞的增殖并促进其分化。这一发现提高了目前对绵羊脂肪沉积的理解,为进一步探究绵羊分子育种提供了理论基础。

关键词： Adult neural stem cells   Telencephalon   Pallium   Zebrafish   Direct fate conversion   Apoptosis   Caspase   Atf3  

摘要： Neural stem cells (NSCs) generate neurons over a lifetime in adult vertebrate brains. In the adult zebrafish pallium, NSCs persist long term through balanced fate decisions. These decisions include direct neuronal conversions, i.e. delamination and neurogenesis without a division. To characterize this process, we reanalyze intravital imaging data of adult pallial NSCs, and observe shared delamination dynamics between NSCs and committed neuronal progenitors. Searching for mechanisms predicting direct NSC conversions, we build an NSC-specific genetic tracer of Caspase3/7 activation (Cas3*/ Cas7*) in vivo. We show that non-apoptotic Cas3*/7* events occur in adult NSCs and are biased towards lineage termination under physiological conditions, with a predominant generation of single neurons. We further identify the transcription factor Atf3 as necessary for this bias. Finally, we show that the Cas3*/7* pathway is engaged by NSCs upon parenchymal lesion and correlates with NSCs more prone to lineage termination and neuron formation. These results provide evidence for non-apoptotic caspase events occurring in vertebrate adult NSCs and link these events with the NSC fate decision of direct conversion, which is important for long-term NSC population homeostasis.

关键词： 20-hydroxyecdysone (ecdysterone)   glycolysis   oxidative phosphorylation   one-carbon metabolism   ATP production   c-Myc   ATF3   reactive oxygen species  

摘要： 20-Hydroxyecdysone (20E) is an arthropod steroid hormone that possesses a number of beneficial pharmacological activities in humans, including anabolic, antioxidant, hypoglycemic, cardioprotective, hepatoprotective, neuroprotective, and antineoplastic properties, etc. While several studies have explored the anabolic activity of 20E in muscle cells, they have concentrated on its effects on myofibril size, protein biosynthesis intensity, and myostatin expression, without assessing energy metabolism. In this research, we have demonstrated that 20E boosts both catabolism and anabolism, coupling energy-producing and biosynthetic metabolic processes in mouse myoblasts and fibroblasts in the same way. Using a transcriptomic approach, we identified the 20E-mediated up-regulation of genes involved in different metabolic processes. Further experiments revealed that 20E increased the levels of enzymes involved in glycolysis and one-carbon metabolism. It also increased the uptake of glucose, glycolysis, respiration, the production of ATP, and global protein biosynthesis in mouse myoblasts and fibroblasts. This phenomenon involves the PI3K/AKT/mTOR signaling pathway. Taken together, the observed 20E-dependent upregulation of energy metabolism may be the main reason for 20E's well-known anabolic activity.

关键词： ATF3   CNS   nerve injury   apoptosis   neuronal regeneration   axonal injury  

摘要： within 1 day after spinal cord injury (SCI) or ischemic stroke in mice 8,11 . Additionally, ATF3 protein levels in mouse blood significantly increased 1 day after SCI as well as after ischemic stroke 11 . Most importantly, ATF3 protein levels in human serum were elevated in patients within 24 hours after SCI or ischemic stroke 11 . These results demonstrate the feasibility of using ATF3 level in patients' serum as a potential biomarker for CNS trauma 11 .One of the primary contexts in which ATF3 has been studied is neuronal injury 12 . Following axonal damage, ATF3 expression is markedly increased in affected neurons, which is believed to contribute to the cellular response aimed at repair and regeneration 13 . For instance, in models of peripheral nerve injury, ATF3 has been shown to promote neurite outgrowth and to enhance the intrinsic growth capacity of neurons (reviewed in 14 ).Comparing RNA expression data across species that exhibit different abilities to regenerate their nervous system following traumatic nerve injury reveals that ATF3 is consistently induced in neurons within the first few days after injury. Thus, ATF3 can definitely be considered as an evolutionary conserved regulator of neuronal regeneration 14 .ATF3 also modulates the response of the CNS to inflammation and psychological stress. In conditions of neuroinflammation, such as those observed in multiple sclerosis and other neurodegenerative diseases, ATF3 expression is upregulated in glial cells (reviewed in 4 ), including astrocytes and microglia. This upregulation is associated with the modulation of inflammatory responses 15 , which can be either protective or detrimental depending upon the context and duration of the stressor. It has been mentioned that targeting microglial ATF3 upregulation to mitigate inflammation would be an interesting and necessary therapeutic avenue across a range of CNS disease 16 . Regarding cell death, ATF3 has been reported to be either pro-apoptotic or anti

关键词： Cadmium toxicity   Ferroptosis   Oxidative stress   Testicular injury  

摘要： Cadmium (Cd) has garnered significant attention due to reproductive toxicity in inducing ferroptosis. However, the specific mechanisms underlying Cd-induced germ cell ferroptosis remain poorly understood. This study aimed to systematically explore the molecular mechanisms of germ cell ferroptosis by investigating differential changes in transcription factors and proteins in male mice treated orally with CdCl2 (0.5 g/L) reaching postnatal day 60, alongside Leydig cell (TM3) and Sertoli cell (TM4) lines. Results demonstrated that Cd exposure led to increased iron overload and oxidative stress in mouse testes, disrupted intracellular mitochondrial morphology characteristic of ferroptosis. RNA sequencing revealed significant upregulation of Atf3 and Hmox1 in Cd-exposed germ cells, along with increased expression of ATF3 and HO-1. Intervention in ferroptosis or HO-1 effectively rescued cells from Cd-induced mortality by breaking the detrimental cycle between lipid peroxidation and HO-1 activation. Further findings showed that NRF2 and HO-1 expression was notably elevated upon ATF3 overexpression in TM3 and TM4 cells, activating the Keap1-Nrf2 pathway and triggering ferroptosis in testes, whereas NRF2 and HO-1 expression levels were reversed when ATF3 was silenced. This study provides novel insights into ATF3-mediated NRF2/HO-1 signaling in Cd-induced mitochondrial ferroptosis in testes, shedding light on the mechanisms underlying Cd-induced ferroptosis and testicular injury.

摘要： It is well known that appropriate aerobic exercise can effectively alleviate fatty liver and enhance brain function. The concept of multi-organ crosstalk coordinating disease progression has become the current research hot topic. However， there remains an urgent need to elucidate its specific mechanisms. This study aimed to explore the impact of a high-fat diet （HFD） on liver health and cognitive function， and to further uncover the regulatory effect of aerobic exercise by liver-specific ATF3 knockout (ATF3cKO) mice in a “liver-brain” axis mode. The 5-week-old C57BL/6 and ATF3cKOmice were fed with HFD for 32 weeks， and sequentially subjected to aerobic exercise intervention at the 20thweek for another 12 consecutive weeks. Meanwhile， C57BL/6 mice were provided with a normal diet as the control group. The functional parameters of liver and brain of all mice were assessed. Cognitive capacity of all mice was assessed by the Morris water maze （MWM）. Inflammatory factors in the serum and brain of mice were quantified using enzyme-linked immunosorbent assay （ELISA）， and the expression of inflammasomes was detected by immunohistochemistry （IHC）. Additionally， the activation of NF-κB and PI3K signal pathways was analyzed by Western blotting. In this study， HFD impaired hepatic and brain functions， while aerobic exercise and liver-specific ATF3 knockout suppressed inflammatory factors in the peripheral circulation through hepatoprotective mechanisms， thereby attenuating cerebral inflammation and preserving neurological integrity， as well as mitigating HFD-induced cognitive decline.

摘要： The crosstalk between adipose tissue and the liver is finely controlled to maintain metabolic health. Yet, how adipose tissue controls toxic free fatty acid overflow into the liver remains incompletely understood. Here, we show that adipocyte activating transcription factor 3 (ATF3) was induced in human or mouse obesity. Adipocyte Atf3-/- (Atf3Adi-/-) mice developed obesity, glucose intolerance, and metabolic dysfunction-associated steatohepatitis (MASH) in chow diet, high-fat diet, or Western diet-fed mice. Blocking fatty acid flux by inhibiting hepatocyte CD36, but not the restoration of hepatic AMPK signaling, prevented the aggravation of MASH in Atf3Adi-/- mice. Further studies show that the loss of adipocyte ATF3 increased lipolysis via inducing adipose triglyceride lipase, which in turn induced lipogenesis and inflammation in hepatocytes. Moreover, Atf3Adi-/- mice had reduced energy expenditure and increased adipose lipogenesis and inflammation. Our data demonstrate that adipocyte ATF3 is a gatekeeper in counteracting MASH development under physiological and pathological conditions. Using adipocyte-specific adipocyte activating transcription factor 3 (ATF3) knockout mice, this study demonstrates the crucial role of adipocyte ATF3 in preventing metabolic dysfunction-associated steatohepatitis (MASH)

关键词： Noise-induced hearing loss   Calcitriol   Oxidative stress   DNA repair   ATF3   DUSP1  

摘要： Background: Calcitriol (Cal) is the most active metabolite of vitamin D and has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the role of Cal in noise-induced hearing loss (NIHL) to further elucidate the mechanism of noise-induced oxidative stress in the mouse cochlea. Methods: C57BL/6 J mice were given six intraperitoneal injections of Cal (500 ng/kg/d). After 14 days of noise exposure, auditory brainstem response (ABR) thresholds, and the cochlear outer hair cell loss rate were analysed to evaluate auditory function. Real-time fluorescence quantitative PCR, immunofluorescence and western blotting were performed in vitro after the treatment of cochlear explants with 100 mu M tert-butyl hydroperoxide (TBHP) for 2.5 h and HEI-OC1 cells with 250 mu M TBHP for 1.5 h. Results: In vivo experiments confirmed that Cal pretreatment mitigated NIHL and outer hair cell death. The in vitro results demonstrated that Cal significantly reduced TBHP-induced cochlear auditory nerve fibre degradation and spiral ganglion neuron damage. Moreover, treatment with Cal inhibited the expression of oxidative stress-related factors (3-NT and 4-HNE) and DNA damage-related factors (gamma-H2A.X) gamma- H2A.X) and attenuated TBHPinduced apoptosis in cochlear explants and HEI-OC1 cells. A total of 1479 upregulated genes and 1443 down- regulated genes were screened in cochlear tissue 1 h after noise exposure. The level of transcription factor 3 (ATF3) was significantly elevated in HEI-OC1 cells after TBHP stimulation. Gene Transcription Regulation Database (GTRD)and Cistrome database analyses revealed that the downstream target gene of ATF3 is dual specificity phosphatase 1 (DUSP1). Cistrome DB Toolkit database results showed that the transcription factor of DUSP1 was ATF3. In addition, the ChIP-PCR results indicated that ATF3 might be a direct transcription factor of DUSP1. Conclusion: The results of our study suggest that Cal attenuates NIHL and inhibits n