关键词： TBBPA   Mitophagy deficiency   Neuronal cytotoxicity   PINK1/Parkin   ATF3  

摘要： Tetrabromobisphenol A (TBBPA), as a widely used brominated flame retardant, has been implicated as a potential neurotoxicant. However, the mechanism of TBBPA-induced neurotoxicity has not been fully elucidated yet. In this study, using mouse hippocampal neuron cell HT22 as the in vitro model, the neuronal cytotoxicity of TBBPA and the mechanism by focusing on mitophagy have been studied. We found that neuronal cytotoxic effects were indeed induced by TBBPA exposure at concentrations of >20 IrM for 24 h, including decreased cell viability (to 92.38 % at 20 IrM;18.25 % at 80 IrM), enhanced ROS (enhanced 53.26 % at IC50 of 60 IrM, compared with that in the control group) and mitochondrial ROS (mtROS) levels (enhanced 24.12 % at 60 IrM), reduced mitochondrial membrane potential (MMP) (decreased 33.60 % at 60 IrM). As a protective mechanism in cells, autophagy was initiated;however, mitophagy was inhibited, where PINK1 (PINK1-Parkin activation is critical in the depolarized MMP-induced mitophagy) expression was found to be repressed and decreased, further leading to the failure of Parkin recruitment to the damaged mitochondria. Mitophagy activator, nicotinamide mono nucleotide (13-NMN) that activates the PINK1-Parkin pathway, could alleviate TBBPA-induced mitophagy deficiency and further reduce the neuronal cytotoxicity, demonstrating that TBBPA-induced PINK1-Parkin-mediated mitophagy deficiency contributed to the neuronal cytotoxicity. Furthermore, we found TBBPA caused the upregulation of Atf3 (activating transcription factor 3) gene transcription and expression levels, alongside reduced Pink1 levels;whereas enhanced Pink1 transcript levels were observed after ATF3 depletion even under TBBPA treatment, demonstrating TBBPA-induced overexpression of ATF3 should be responsible for the reduced PINK1 expression. Therefore, for the first time, here we demonstrate that TBBPA can inhibit PINK1-Parkinmediated mitophagy via upregulating ATF3 expression, which further contributes

关键词： Cancer   Cells   Peptides and proteins   Rodent models   Tumors  

摘要： Homo sapiens caseinolytic protease P (HsClpP) activation is a promising strategy for colon cancer treatment. In this study, CCG1423 was identified as a selective activator of HsClpP. After optimization, NCA029 emerged as the most potent compound, with an EC50 of 0.2 mu M against HsClpP. Molecular dynamics revealed that the affinity of NCA029 for the YYW aromatic network is crucial for its selectivity toward HsClpP. Furthermore, NCA029 displayed favorable pharmacokinetics and safety profiles and significantly inhibited tumor growth in HCT116 xenografts, resulting in 83.6% tumor inhibition. Mechanistically, NCA029 targeted HsClpP, inducing mitochondrial dysfunction and activating the ATF3-dependent integrated stress response, ultimately causing cell death in colorectal adenocarcinoma. These findings highlight NCA029 as an effective HsClpP activator with potential for colon cancer therapy.

关键词： Breast cancer   Bone metastasis   miR-4638-3p   ATF3   Caudal artery injection  

摘要： PurposeSkeletal metastases are increasingly reported in metastatic triple-negative breast cancer (BC) patients. We previously reported that TGF-beta 1 sustains activating transcription factor 3(ATF3) expression and is required for cell proliferation, invasion, and bone metastasis genes. Increasing studies suggest the critical regulatory function of microRNAs (miRNAs) in governing BC pathogenesis. TGF-beta 1 downregulated the expression of miR-4638-3p, which targets ATF3 in human BC cells (MDA-MB-231). In the present study, we aimed to identify the functional role of miR-4638-3p in BC bone metastasis by the caudal artery injection of the MDA-MB-231 cells overexpressing mir-4638 in the ***-MB-231 cells overexpressing miR-4638 were prepared by stable transfections. Reverse transcriptase quantitative PCR was carried out to determine the expression of endogenous miR-4638-3p and bone resorption marker genes. X-ray, micro-CT, and Hematoxylin & Eosin studies were used to determine osteolytic lesions, trabecular structure, bone mineral density, and micrometastasis of *** mice injected with MDA-MB-231 cells overexpressing miR-4638-3p decreased the expression of bone resorption marker genes, compared to MDA-MB-231 cells injection. Reduced osteolytic lesions and restored bone density by MDA-MB-231 cells overexpressing miR-4638-3p were observed. Similarly, the mice injected with MDA-MB-231 cells overexpressing miR-4638-3p showed a better microarchitecture of the trabecular network. A few abnormal cells seen in the femur of MDA-MB-231 cells-injected mice were not found in MDA-MB-231 cells overexpressing *** identified functional role of ATF3 targeting miR-4638-3p in BC bone metastasis in vivo suggests its candidature as BC therapeutics in the future.

关键词： Intestinal ischemia reperfusion injury   Apigenin-7-O-glucoside   Nanoparticle   Ferroptosis   Oxidative stress  

摘要： Intestinal ischemia reperfusion injury (II/R injury) is a common and intractable pathophysiological process in critical patients, for which exploring new treatments and mechanisms is of great importance to improve treatment outcomes. Apigenin-7-O-Glucoside (AGL) is a sugar derivative of apigenin natural product with various pharmacological activities to protect against intestinal diseases. In this study, we synthesized two amphiphilic molecules, namely DTPA-N10-10 and mPEG-TK-DA, which can scavenge free radicals and reactive oxygen species (ROS). They were successfully encapsulated AGL through self-assembly, resulting in the formation of multi-site ROS scavenging nanoparticles called PDN@AGL. In vitro and in vivo experiments demonstrated that PDN@AGL could protect intestinal tissues by reducing lipid peroxidation, lowering ROS levels and inhibiting ferroptosis during II/R injury. Furthermore, our study revealed, for the first time, that the regulation of the ATF3/SLC7A11 pathway by PDN@AGL may play a crucial role in mitigating II/R injury. In conclusion, our study confirmed the beneficial effects of PDN@AGL in combating II/R injury through the ATF3/SLC7A11-mediated regulation of ferroptosis and oxidative stress. These findings lay the groundwork for the potential application of PDN@AGL in the treatment of II/R injury.

关键词： Ferroptosis   SIRT1   AROS   ATF3   Glioma   Oxidative stress   NAD plus  

摘要： Ferroptosis is a type of programmed cell death resulting from iron overload-dependent lipid peroxidation, and could be promoted by activating transcription factor 3 (ATF3). SIRT1 is an enzyme accounting for removing acetylated lysine residues from target proteins by consuming NAD+, but its role remains elusive in ferroptosis and activating ATF3. In this study, we found SIRT1 was activated during the process of RSL3-induced glioma cell ferroptosis. Moreover, the glioma cell death was aggravated by SIRT1 activator SRT2183, but suppressed by SIRT inhibitor EX527 or when SIRT1 was silenced with siRNA. These indicated SIRT1 sensitized glioma cells to ferroptosis. Furthermore, we found SIRT1 promoted RSL3-induced expressional upregulation and nuclear translocation of ATF3. Silence of ATF3 with siRNA attenuated RSL3-induced increases of ferrous iron and lipid peroxidation, downregulation of SLC7A11 and GPX4 and depletion of cysteine and GSH. Thus, SIRT1 promoted glioma cell ferroptosis by inducting ATF3 activation. Mechanistically, ATF3 activation was reinforced when RSL3-induced decline of NAD+ was aggravated by FK866 that could inhibit NAD + synthesis via salvage pathway, but suppressed when intracellular NAD+ was maintained at higher level by supplement of exogenous NAD+. Notably, the NAD + decline caused by RSL3 was enhanced when SIRT1 was further activated by SRT2183, but attenuated when SIRT1 activation was inhibited by EX527. These indicated SIRT1 promoted ATF3 activation via consumption of NAD+. Finally, we found RSL3 activated SIRT1 by inducing reactive oxygen species-dependent upregulation of AROS. Together, our study revealed SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via activation of ATF3-dependent inhibition of SLC7A11 and GPX4.

关键词： ATF3   butyrate   erastin   ferroptosis  

摘要： Ferroptosis is a novel form of programmed cell death triggered by iron-dependent lipid peroxidation and has been associated with various diseases, including cancer. Erastin, an inhibitor of system Xc-, which plays a critical role in regulating ferroptosis, has been identified as an inducer of ferroptosis in cancer cells. In this study, we investigated the impact of butyrate, a short-chain fatty acid produced by gut microbiota, on erastin-induced ferroptosis in lung cancer cells. Our results demonstrated that butyrate significantly enhanced erastin-induced ferroptosis in lung cancer cells, as evidenced by increased lipid peroxidation and reduced expression of glutathione peroxidase 4 (GPX4). Mechanistically, we found that butyrate modulated the pathway involving activating transcription factor 3 (ATF3) and solute carrier family 7 member 11 (SLC7A11), leading to enhanced erastin-induced ferroptosis. Furthermore, partial reversal of the effect of butyrate on ferroptosis was observed upon knockdown of ATF3 or SLC7A11. Collectively, our findings indicate that butyrate enhances erastin-induced ferroptosis in lung cancer cells by modulating the ATF3/SLC7A11 pathway, suggesting its potential as a therapeutic agent for cancer treatment.

关键词： Breast cancer   Curcumol   Anti -metastasis   Self -assembled nanogels   Tumor -targeting   ATF3  

摘要： Chemotherapy proves to be a successful method in treating primary breast cancer. Ironically, some commonly used chemotherapeutics may promote lung metastasis by increasing the activity of activating transcription factor 3 (ATF3). Thus, it is necessary to inhibit tumor metastasis while improving the anti-tumor effect of anti-cancer drugs. Herein, using curcumol (CUR) that possesses both anti-tumor and anti-metastasis activities as a model drug, we designed the nanogels based on temperature-responsive self-assembly and glutathione-triggered disassembly to address the abovementioned conflicts. Briefly, the copolymers (H-SS-P) were synthesized by coupling poly (N-isopropylacrylamide) onto hyaluronic acid (HA) via a disulfide bond-containing linker cystamine dihydrochloride. Copolymers could self-assemble into regular spherical nanogels at 37 degrees C with a 40-nm particle size for PNIPAAm's thermosensitivity. Hydrophobic CUR could be automatically entrapped into the core of nanogels. The H-SS-P@CUR nanogels could release drugs quickly upon exposure to the reductive tumor microenvironment. The superior efficacy of H-SS-P@CUR on inhibiting tumor growth was validated through assays both in vivo and in vitro. Moreover, nanogels may better down-regulate the expression of ATF3 protein by enhancing the cell uptake and tumor targeting of CUR, thereby significantly improving the anti-metastasis effect of CUR. This work not only proposed a novel strategy to simplify the preparation process of nanogels but also achieved effective drug delivery with enhanced anti-cancer and anti-metastasis effects.

关键词： ATF3   Neuroinflammation   White matter injury   Ischemic stroke   Borneol   Telmisartan  

摘要： Cerebral ischemic stroke causes substantial white matter injury, which is further aggravated by neuroinflammation mediated by microglia/astrocytes. Given the anti-neuroinflammatory action of telmisartan and the enhancing blood-brain barrier (BBB) permeability potential of resuscitation-inducing aromatic herbs, 13 hybrids (3a-m) of telmisartan (or its simplified analogues) with resuscitation-inducing aromatic agents were designed, synthesized, and biologically evaluated. Among them, the optimal compound 3a (the ester hybrid of telmisartan and (+)-borneol) potently inhibited neuroinflammation mediated by microglia/astrocytes and ameliorated ischemic stroke. Particularly, 3a significantly conferred protection for white matter integrity after cerebral ischemic stroke via decreasing abnormally dephosphorylated neurofilament protein, upregulating myelin basic protein, and attenuating oligodendrocyte damage. Further RNA-sequencing data revealed that 3a upregulated expression of transcriptional regulator ATF3 to reduce the expression of CH25H, prevented proinflammatory state of lipid-droplet-accumulating microglia/astrocytes to limit excessive inflammation, and eventually protected neighboring oligodendrocytes to prevent white matter injury. Taken with the desirable pharmacokinetics behavior and improved brain distribution, 3a may be a feasible therapeutic agent for ischemic stroke and other neurological disorders with white matter injury.

关键词： Epilepsy   Ferroptosis   FUS   ATF3  

摘要： Background: Epilepsy is a neurological disorder characterized by recurrent seizures and is often unresponsive to current treatment options. Ferroptosis, a recently defined iron-dependent regulated cell death, has been suggested as a potential therapeutic target for epilepsy due to its association with oxidative stress. Additionally, circRNA SLC8A1 (circSLC8A1) has been implicated in various neurological disorders and oxidative stress-related diseases but its involvement in epilepsy progression, particularly in relation to ferroptosis and oxidative stress, remains ***: qRT-PCR, Western blot, IHC and ELISA assays were employed to validate the relative expression of targeted genes and proteins. The levels of ROS, iron, LOP and GSH were detected by commercial kits. RNA pulldown and RIP assays were employed to detect the interactions among circSLC8A1, FUS and ATF3. A rat epilepsy model was established for further in vivo confirmation. Results and conclusion: In this study, we investigated the potential involvement of circSLC8A1 in epilepsy progression and its connection to ferroptosis and oxidative stress. Our findings demonstrate that circSLC8A1 triggers neuronal ferroptosis by stabilizing ATF3 mRNA expression through recruitment with FUS. The induced neuronal ferroptosis contributes to epilepsy progression. These results enhance our understanding of epilepsy pathogenesis and may provide insights for the development of novel therapeutic strategies.

关键词： Ferroptosis   Liver fibrosis   Antioxidant system   ATF3   ROCK1  

摘要： Background and Aims:Development of fibrosis in chronic liver disease requires activation of hepatic stellate cells(HSCs)and leads to a poor ***(Art)is an ester derivative of artemisinin that can induce ferroptosis in HSCs,and activated transcriptional factor 3(ATF3)is an ATF/CREB transcription factor that is induced in response to *** this study,we examined the role of the Rho-associated protein kinase 1(ROCK1)/ATF3 axis in Art-induced ferroptosis in ***:HSC activation and ferroptosis were studied in vitro by western blotting,polymerase chain reaction,immunofluorescence,and other ***3 electrophoretic mobility and ROCK1 protein stability were assayed by western *** was used to detect the interaction of ROCK1 and ATF3,as well as ATF3 phosphorylation.A ubiquitination assay was used to verify ROCK1 ***3-interfering and Rock1-overexpressing mice were constructed to validate the anti-hepatic fibrosis activity of Art in ***:Art induced ferroptosis in HSCs following glutathione-dependent antioxidant system inactivation resulting from nuclear accumulation of unphosphorylated ATF3 mediated by ROCK1-ubiquitination in *** also decreased carbon tetrachloride-induced liver fibrosis in mice,which was reversed by interfering with Atf3 or overexpressing ***:The ROCK1/ATF3 axis was involved in liver fibrosis and regulation of ferroptosis,which provides an experimental basis for further study of Art for the treatment of liver fibrosis.