Ferroptosis is an iron- and lipid reactive oxygen species (ROS)-dependent form of programmed cell death that is distinct from other forms of regulatory cell death at the morphological, biological, ...and genetic levels. Emerging evidence suggests critical roles for ferroptosis in cell metabolism, the redox status, and various diseases, such as cancers, nervous system diseases, and ischemia-reperfusion injury, with ferroptosis-related proteins. Ferroptosis is inhibited in diverse cancer types and functions as a dynamic tumor suppressor in cancer development, indicating that the regulation of ferroptosis can be utilized as an interventional target for tumor treatment. Small molecules and nanomaterials that reprogram cancer cells to undergo ferroptosis are considered effective drugs for cancer therapy. Here, we systematically summarize the molecular basis of ferroptosis, the suppressive effect of ferroptosis on tumors, the effect of ferroptosis on cellular metabolism and the tumor microenvironment (TME), and ferroptosis-inducing agents for tumor therapeutics. An understanding of the latest progress in ferroptosis could provide references for proposing new potential targets for the treatment of cancers.
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Ferroptosis, an iron- and lipid ROS-dependent form of programmed cell death, plays critical roles in killing cancer cells. Herein, we summarize the effect of ferroptosis on cellular metabolism and the tumor microenvironment and ferroptosis inducers for tumor therapeutics. This review could provide references for targeting ferroptosis in tumor treatment.
Pro‐inflammatory microglia mainly rely on glycolysis to maintain cytokine production during ischemia, accompanied by an increase in inducible nitric oxide synthase (iNOS) and monocarboxylate ...transporter 1 (MCT1). The role of energy metabolism in the pro‐inflammatory response of microglia is currently unclear. In this study, we tested the response of microglia in mice after cerebral ischemia and simulated an energy environment in vitro using low glucose culture medium. The research results indicate that the expression levels of iNOS and arginase 1 (ARG1) increase in the ischemic mouse brain, but the upregulation of MCT1 expression is mainly present in iNOS positive microglia. In microglia exposed to low glucose conditions, iNOS and MCT1 levels increased, while ARG1 levels decreased. Under the same conditions, knocking down MCT1 in microglia leads to a decrease in iNOS levels, while overexpression of MCT1 leads to the opposite result. The use of NF‐κB inhibitors reduced the expression levels of iNOS and MCT1 in microglia. In summary, our data indicate that pyruvate maintains and enhances the NF‐κB regulated pro‐inflammatory response of microglia induced by low glucose.
Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is highly ...inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient availability remains unclear. In this study, we perform integrated proteomic and functional analyses to reveal that SLC7A11-mediated cystine uptake promotes not only GSH synthesis, but also GPX4 protein synthesis. Mechanistically, we find that cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the Rag-mTORC1-4EBP signaling axis. We show that pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest using combinatorial therapy of mTORC1 inhibitors and ferroptosis inducers in cancer treatment.
In this paper, we define and investigate a novel model-free deep reinforcement learning framework to solve the taxi dispatch problem. The framework can be used to redistribute vehicles when the ...travel demand and taxi supply is either spatially or temporally imbalanced in a transportation network. While previous works mostly focus on using model-based methods, the goal of this paper is to explore the policy-based deep reinforcement learning algorithm as a model-free method to optimize the rebalancing strategy. In particular, we propose an actor-critic algorithm with feed-forward neural networks as approximations of both policy and value functions, where the policy function provides the optimal dispatch strategy and the value function estimates the expected costs at each time stamp. Our numerical studies show that the algorithm converges to the theoretical upper bound with less than 4% optimality gap, whether the system dynamics are deterministic or stochastic. We also investigate the scenario where we consider user priority and fairness, and the results indicate that our learned policy is capable of producing a superior strategy that balances equity, cancellation, and level of service when user priority is considered.
Real-time scene parsing through object detection running on an embedded device is very challenging, due to limited memory and computing power of embedded devices. To deal with these challenges, we ...redesign a lightweight network without notably reducing detection accuracy. Based on the Darknet-53, we use depth separable convolutions and pointwise group convolutions to reduce the parameter size of the network. A feature extraction backbone network with a parameter size of only 16 percent of darknet-53 is constructed. Meanwhile, in order to compensate for the degradation of accuracy, we have added a Multi-Scale Feature Pyramid Network based on a simple U-shaped structure to improve the performance of multi-scale object detection, which called it Mini-YOLOv3. It has smaller model size and fewer trainable parameters and floating point operations (FLOPs) in comparison of YOLOv3. We evaluate Mini-YOLOv3 on MS-COCO benchmark dataset; The parameter size of Mini-YOLOv3 is only 23% of YOLOv3 and achieves comparable detection accuracy as YOLOv3 but only requires 1/2 detect time, Specifically, Mini-YOLOv3 achieves mAP-50 of 52.1 at speed of 67 fps.
As spontaneous Raman spectroscopy is demonstrated to be viable for many applications, it is still held back by its inherently low signal and typically extended acquisition time. While several ...techniques can overcome this by enhancing the scattered signal to quicken acquisition, a parallel field that quickens spectral acquisition using instrumentation has received less focus. In principle, Raman spectra could be obtained by tuning the excitation wavelength and measuring the Raman signal at a fixed wavelength using a single-pixel detector. Before exploring the potential of quicker acquisition, it is important to first study the equivalence of Raman Excitation Spectroscopy and conventional Raman Spectroscopy experimentally. We demonstrate the equivalence between the two techniques for biological and non-biological samples by measuring Raman Excitation Maps. Additionally, we explore the interpolation of low-resolution excitation spectra using excess information in the maps for higher resolution excitation spectra. This work, together with current progression in fast tunable lasers and highly sensitive single-pixel detectors, provides a promising prospect for dedicated Raman Excitation Spectroscopy instruments to be developed.
Targeting ferroptosis, a unique cell death modality triggered by unrestricted lipid peroxidation, in cancer therapy is hindered by our incomplete understanding of ferroptosis mechanisms under ...specific cancer genetic contexts. KEAP1 (kelch-like ECH associated protein 1) is frequently mutated or inactivated in lung cancers, and KEAP1 mutant lung cancers are refractory to most therapies, including radiotherapy. In this study, we identify ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells. We further show that pharmacological inhibition of the CoQ-FSP1 axis sensitizes KEAP1 deficient lung cancer cells or patient-derived xenograft tumors to radiation through inducing ferroptosis. Together, our study identifies CoQ-FSP1 as a key downstream effector of KEAP1-NRF2 pathway and as a potential therapeutic target for treating KEAP1 mutant lung cancers.
The regulatory loop between long noncoding RNAs (lncRNAs) and microRNAs has a dynamic role in transcriptional and translational regulation, and is involved in cancer. However, the regulatory ...circuitry between lncRNAs and microRNAs in tumorigenesis remains elusive. Here we demonstrate that a nuclear lncRNA LINC00336 is upregulated in lung cancer and functions as an oncogene by acting as a competing endogenous RNA (ceRNAs). LINC00336 bound RNA-binding protein ELAVL1 (ELAV-like RNA-binding protein 1) using nucleotides 1901-2107 of LINC00336 and the RRM interaction domain and key amino acids (aa) of ELAVL1 (aa 101-213), inhibiting ferroptosis. Moreover, ELAVL1 increased LINC00336 expression by stabilizing its posttranscriptional level, whereas LSH (lymphoid-specific helicase) increased ELAVL1 expression through the p53 signaling pathway, further supporting the hypothesis that LSH promotes LINC00336 expression. Interestingly, LINC00336 served as an endogenous sponge of microRNA 6852 (MIR6852) to regulate the expression of cystathionine-β-synthase (CBS), a surrogate marker of ferroptosis. Finally, we found that MIR6852 inhibited cell growth by promoting ferroptosis. These data show that the network of lncRNA and ceRNA has an important role in tumorigenesis and ferroptosis.
Input of labile carbon may accelerate the decomposition of existing soil organic matter (priming effect), with the priming intensity depending on changes in soil nitrogen availability after ...permafrost thaw. However, experimental evidence for the linkage between the priming effect and post-thaw nitrogen availability is unavailable. Here we test the hypothesis that elevated nitrogen availability after permafrost collapse inhibits the priming effect by increasing microbial metabolic efficiency based on a combination of thermokarst-induced natural nitrogen gradient and nitrogen addition experiment. We find a negative correlation between the priming intensity and soil total dissolved nitrogen concentration along the thaw sequence. The negative effect is confirmed by the reduced priming effect after nitrogen addition. In contrast to the prevailing view, this nitrogen-regulated priming intensity is independent of extracellular enzyme activities but associated with microbial metabolic efficiency. These findings demonstrate that post-thaw nitrogen availability regulates topsoil carbon dynamics through its modification of microbial metabolic efficiency.
Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. ...Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.
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