High-fidelity intracellular imaging of multiple miRNAs via stimulus-responsive nanocarriers and catalytic hairpin assembly.

An advanced nanoplatform was developed by integrating catalytic hairpin assembly (CHA) with glutathione-responsive nanocarriers, enabling superior imaging of dual cancer-related miRNAs. Two distinct CHA circuits for the sensing of miRNA-21 and miRNA-155 were functionalized on biodegraded MnO2. In the presence of GSH and the corresponding miRNAs, the degraded MnO2 released the DNA cargos, activating the CHA circuits and recovering the fluorescence. This approach offers a reliable sensing performance with highly selective cell-identification capacity, positioning it as a pivotal tool for imaging multiple biomarkers in living cells.

Full spectrum flow cytometry-powered comprehensive analysis of PBMC as biomarkers for immunotherapy in NSCLC with EGFR-TKI resistance.

BACKGROUND: Clinical studies suggest that immune checkpoint inhibitor (ICI) monotherapy has limited benefits in non-small cell lung cancer (NSCLC) patients after epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure. However, data about efficacy of ICI plus chemotherapy remain controversial, probably attributed to the heterogeneity among such population, and robust efficacy biomarkers are urgent to explore. METHODS: A total of 60 eligible patients who received ICI plus chemotherapy after EGFR-TKI treatment failure were enrolled, 24 of whom peripheral blood mononuclear cell (PBMC) samples were collected at baseline and after 2 cycles of treatment. We have designed a 23-color-antibody panel to detect PBMC by full spectrum flow cytometry. RESULTS: For EGFR-TKI resistant NSCLC patients: 1) ICI plus chemotherapy achieved an objective response rate (ORR) of 21.7% and a median progression-free survival (PFS) of 6.4 months. 2) clinical characteristics associated with worse efficacy included liver metastasis and platelet-to-lymphocyte ratio (PLR) > 200. 3) the proportion of immune cell subset associated with better efficacy was higher baseline effective CD4+T cells (E4). 4) the baseline expression of immune checkpoint proteins (ICPs) on cell subsets associated with better efficacy included: higher expression of CD25 on dendritic cells (DC) and central memory CD8+T cells (CM8), and higher expression of Lymphocyte activation gene 3 (LAG-3) on effective memory CD8+T cells (EM8). 5) the expression of ICPs after 2 cycles of treatment associated with better efficacy included: higher expression of CD25 on CD8+T/EM8 /natural killer (NK) cells. 6) the dynamic changes of ICPs expression associated with worse efficacy included: significantly decrease of T cell immunoglobulin and ITIM domain (TIGIT) expression on regular T cells (Tregs) and decrease of V-domain immunoglobulin suppressor of T cell activation (VISTA) expression on Th1. 7) a prediction model for the efficacy of ICI plus chemotherapy was successfully constructed with a sensitivity of 62.5%, specificity of 100%, and area under curve (AUC) = 0.817. CONCLUSIONS: Some EGFR-TKI-resistant NSCLC patients could indeed benefit from ICI plus chemotherapy, but most patients are primary resistant to immunotherapy. Comprehensive analysis of peripheral immune cells using full spectrum flow cytometry showed that compared to the proportion of cell subsets, the expression type and level of ICPs on immune cells, especially CD25, were significantly correlated with the efficacy of immunotherapy.

The Synergistic Mechanism of Photosynthesis and Antioxidant Metabolism between the Green and White Tissues of Ananas comosus var. bracteatus Chimeric Leaves.

Ananas comosus var. bracteatus (Ac. bracteatus) is a typical leaf-chimeric ornamental plant. The chimeric leaves are composed of central green photosynthetic tissue (GT) and marginal albino tissue (AT). The mosaic existence of GT and AT makes the chimeric leaves an ideal material for the study of the synergistic mechanism of photosynthesis and antioxidant metabolism. The daily changes in net photosynthetic rate (NPR) and stomatal conductance (SCT) of the leaves indicated the typical crassulacean acid metabolism (CAM) characteristic of Ac. bracteatus. Both the GT and AT of chimeric leaves fixed CO2 during the night and released CO2 from malic acid for photosynthesis during the daytime. The malic acid content and NADPH-ME activity of the AT during the night was significantly higher than that of GT, which suggests that the AT may work as a CO2 pool to store CO2 during the night and supply CO2 for photosynthesis in the GT during the daytime. Furthermore, the soluble sugar content (SSC) in the AT was significantly lower than that of GT, while the starch content (SC) of the AT was apparently higher than that of GT, indicating that AT was inefficient in photosynthesis but may function as a photosynthate sink to help the GT maintain high photosynthesis activity. Additionally, the AT maintained peroxide balance by enhancing the non-enzymatic antioxidant system and antioxidant enzyme system to avoid antioxidant damage. The enzyme activities of reductive ascorbic acid (AsA) and the glutathione (GSH) cycle (except DHAR) and superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) were enhanced, apparently to make the AT grow normally. This study indicates that, although the AT of the chimeric leaves was inefficient at photosynthesis because of the lack of chlorophyll, it can cooperate with the GT by working as a CO2 supplier and photosynthate store to enhance the photosynthetic ability of GT to help chimeric plants grow well. Additionally, the AT can avoid peroxide damage caused by the lack of chlorophyll by enhancing the activity of the antioxidant system. The AT plays an active role in the normal growth of the chimeric leaves.

Endogenous glutathione-activated DNA nanoprobes for spatially controllable imaging of microRNA in living cells.

A DNA nanoprobe, activated by glutathione (GSH), was designed to enable spatially selective sensing and imaging of miRNA in living cells. The nanoprobe was constructed using nano-sized metal-organic frameworks (MOFs) and DNA hairpin probes tethered to the surface of the MOFs, with the loop portion of the hairpin structure containing a disulfide bond. Cleavage of the disulfide bond by GSH triggers a strand-displacement reaction with target miRNAs, facilitating in situ readout of the fluorescence signal. The synergy of endogenous GSH activation and MOF improves the spatial resolution of miRNA detection and imaging.

[Progress and Application of Bayesian Approach in the Early Research and Development of New Anticancer Drugs].

Bayesian statistics is an approach for learning from evidences as it accumulates, combining prior distribution with current information on a quantity of interest, in which posterior distribution and inferences are being updated each time new data become available using Bayes' Theorem. Though frequentist approach has dominated medical studies, Bayesian approach has been more and more widely recognized by its flexibility and efficiency. Research and development (R&D) on anti-cancer new drugs have been so hot globally in recent years in spite of relatively high failure rate. It is the common demand of pharmaceutical enterprises and researchers to identify the optimal dose, regime and right population in the early-phase R&D stage more accurately and efficiently, especially when the following three major changes have been observed. The R&D on anticancer drugs have transformed from chemical drugs to biological products, from monotherapy to combination therapy, and the study design has also gradually changed from traditional way to innovative and adaptive mode. This also raises a number of subsequent challenges on decision-making of early R&D, such as inability to determine MTD, flexibility to deal with delayed toxicity, delayed response and dose-response changing relationships. It is because of the above emerging changes and challenges that the Bayesian approach is getting more and more attention from the industry. At least, Bayesian approach has more information for decision-making, which could potentially help enterprises achieve higher efficiency, shorter period and lower investment. This study also expounds the application of Bayesian statistics in the early R&D on anticancer new drugs, and compares and analyzes its idea and application scenarios with frequentist statistics, aiming to provide macroscopic and systematic reference for all related stakeholders.
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Broad Anti-Cancer Activity Produced by Targeted Nutrients Deprivation (TND) of Multiple Non-Essential Amino Acids.

It has been known for close to 100 years that the metabolism of cancer cells is altered and different than that of healthy cells in the body. On that basis, we have developed an entirely novel approach to managing cancer, termed Targeted Nutrients Deprivation (TND). TND employs a formulated diet depleted of multiple non-essential amino acids (NEAAs) that are required by tumor cells but not by normal cells. Cancer cells specifically require those NEAAs due to their heightened and rewired metabolism. We demonstrated that our first proprietary formulated TND diet-FTN203-significantly reduced the growth of multiple human tumor xenografts in mouse. In combination with chemotherapy and immunotherapy, FTN203 further enhanced therapeutic efficacy. Reliance on FTN203 as the sole nutrition source was shown to be safe without causing detrimental body-weight loss or internal organ damage. Our findings indicate that TND is a novel and safe approach to managing cancer.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.2013904 .

Characteristics of oxidative stress and antioxidant defenses by a mixed culture of acidophilic bacteria in response to Co2+ exposure.

During bioleaching of Cobalt from waste lithium-ion batteries, the biooxidation activity of acidophilic bacteria is inhibited by a high concentration of Co ion in the liquid phase. However, the mechanism for Co2+ toxicity to acidophilic bacteria has not been fully elucidated. In this study, the effects of Co2+ concentration on the biooxidation activity for Fe2+, intracellular reactive oxygen species (ROS) level and antioxidant defense systems in a mixed-culture of acidophilic bacteria (MCAB) were investigated. The results showed that the biooxidation activity of the MCAB was inhibited by Co2+. Furthermore, it was indicated that the intracellular ROS contents of the MCAB under conditions of 0.4 M and 0.6 M Co2+ were 2.60 and 3.34 times higher than that under the condition of 0 M Co2+. The increase in intracellular malondialdehyde content indicated that the oxidative damage was induced by Co2+. Moreover, the antioxidant systems in MCAB were affected by Co2+. It was observed that the Co2+ exposure increased the catalase and glutathione peroxidase activities while reducing the superoxide dismutase activity and the intracellular glutathione (GSH) content. It was found that an exogenous GSH supplementation eliminated excess intracellular ROS and improved the biooxidation activity of the MCAB.

Mammalian-adaptive mutation NP-Q357K in Eurasian H1N1 Swine Influenza viruses determines the virulence phenotype in mice.

It has recently been proposed that the Eurasian avian-like H1N1 (EA H1N1) swine influenza virus (SIV) is one of the most likely zoonotic viruses to cause the next influenza pandemic. Two main genotypes EA H1N1 viruses have been recognized to be infected humans in China. Our study finds that one of the genotypes JS1-like viruses are avirulent in mice. However, the other are HuN-like viruses and are virulent in mice. The molecular mechanism underlying this difference shows that the NP gene determines the virulence of the EA H1N1 viruses in mice. In addition, a single substitution, Q357K, in the NP protein of the EA H1N1 viruses alters the virulence phenotype. This substitution is a typical human signature marker, which is prevalent in human viruses but rarely detected in avian influenza viruses. The NP-Q357K substitution is readily to be occurred when avian influenza viruses circulate in pigs, and may facilitate their infection of humans and allow viruses also carrying NP-357K to circulate in humans. Our study demonstrates that the substitution Q357K in the NP protein plays a key role in the virulence phenotype of EA H1N1 SIVs, and provides important information for evaluating the pandemic risk of field influenza strains.

Mechanism underlying the bioleaching process of LiCoO2 by sulfur-oxidizing and iron-oxidizing bacteria.

Benefiting from lower operational costs and energy requirements than do hydrometallurgical and pyrometallurgical processes in metal recovery, the bioleaching of LiCoO2 through the use of sulfur-oxidizing and iron-oxidizing bacteria has drawn increasing attention. However, the bioleaching mechanism of LiCoO2 has not been clearly elaborated. In the present study, the effects of the energy source of bacteria, such as Fe2+, pyrite and S0, and the products of bacterial oxidation, such as Fe3+ and sulfuric acid, on the chemical leaching of LiCoO2 were studied. The results indicated that lithium was dissolved by acid, and cobalt was released by the reduction of Fe2+ and acid dissolution. The recovery of Li+ and Co2+ could be significantly improved by pH adjustment. Finally, optimal recoveries of Li+ and Co2+ were observed in the pyrite group, reaching 91.4% and 94.2%, respectively. By using pyrite as the energy source, the role of bacteria in bioleaching of LiCoO2 was investigated. The results showed that bacteria could produce sulfuric acid by oxidizing pyrite to promote the mobilization of Li+ and Co2+. The recovery of lithium and cobalt could be increased to 100.0% and 99.3% by bacteria. Moreover, extracellular polymeric substances secreted by bacteria were found to be a factor for the improvement of Li+ and Co2+ recovery.

Metformin Affects Heme Function as a Possible Mechanism of Action.

Metformin elicits pleiotropic effects that are beneficial for treating diabetes, as well as particular cancers and aging. In spite of its importance, a convincing and unifying mechanism to explain how metformin operates is lacking. Here we describe investigations into the mechanism of metformin action through heme and hemoprotein(s). Metformin suppresses heme production by 50% in yeast, and this suppression requires mitochondria function, which is necessary for heme synthesis. At high concentrations comparable to those in the clinic, metformin also suppresses heme production in human erythrocytes, erythropoietic cells and hepatocytes by 30-50%; the heme-targeting drug artemisinin operates at a greater potency. Significantly, metformin prevents oxidation of heme in three protein scaffolds, cytochrome c, myoglobin and hemoglobin, with Kd values < 3 mM suggesting a dual oxidation and reduction role in the regulation of heme redox transition. Since heme- and porphyrin-like groups operate in diverse enzymes that control important metabolic processes, we suggest that metformin acts, at least in part, through stabilizing appropriate redox states in heme and other porphyrin-containing groups to control cellular metabolism.

Programmable Metal/Semiconductor Nanostructures for mRNA-Modulated Molecular Delivery.

Cytotoxic chemotherapeutics are important tools for the clinical treatment of a variety of solid tumors. However, their use is often complicated by multidrug resistance that can develop in patients, limiting the potencies of these agents. New strategies are needed to provide versatile systems that can respond to and disable resistance mechanisms. We demonstrate the use of a new family of materials, programmable metal/semiconductor nanostructures, for drug delivery and mRNA sensing in drug-resistant cells. These materials are composed of a central core gold nanoparticle surrounded by a layer of DNA-capped quantum dots. The modularity of these "core-satellite" assemblies allows for the construction of superstructures with controlled size and the incorporation of multiple functionalities for drug delivery. The DNA sequence within the nanoparticle specifically binds to an mRNA encoding an important drug resistance factor, MRP1, inside cancer cells, releasing a potent anticancer drug doxorubicin. This event triggers a turn-on fluorescence emission along with a downregulation of the MRP1 drug efflux pump, a main resistance factor for doxorubicin, yielding a remarkable improvement in therapeutic efficacy against drug-resistant cancer cells. This work paves the way for the development of programmable materials with multiple synergistic functionalities for biomedical applications.

Dynamic Human Environmental Exposome Revealed by Longitudinal Personal Monitoring.

Human health is dependent upon environmental exposures, yet the diversity and variation in exposures are poorly understood. We developed a sensitive method to monitor personal airborne biological and chemical exposures and followed the personal exposomes of 15 individuals for up to 890 days and over 66 distinct geographical locations. We found that individuals are potentially exposed to thousands of pan-domain species and chemical compounds, including insecticides and carcinogens. Personal biological and chemical exposomes are highly dynamic and vary spatiotemporally, even for individuals located in the same general geographical region. Integrated analysis of biological and chemical exposomes revealed strong location-dependent relationships. Finally, construction of an exposome interaction network demonstrated the presence of distinct yet interconnected human- and environment-centric clouds, comprised of interacting ecosystems such as human, flora, pets, and arthropods. Overall, we demonstrate that human exposomes are diverse, dynamic, spatiotemporally-driven interaction networks with the potential to impact human health.

A Gene Constellation in Avian Influenza A (H7N9) Viruses May Have Facilitated the Fifth Wave Outbreak in China.

The 2016-2017 epidemic of influenza A (H7N9) virus in China prompted concern that a genetic change may underlie increased virulence. Based on an evolutionary analysis of H7N9 viruses from all five outbreak waves, we find that additional subclades of the H7 and N9 genes have emerged. Our analysis indicates that H7N9 viruses inherited NP genes from co-circulating H7N9 instead of H9N2 viruses. Genotypic diversity among H7N9 viruses increased following wave I, peaked during wave III, and rapidly deceased thereafter with minimal diversity in wave V, suggesting that the viruses entered a relatively stable evolutionary stage. The ZJ11 genotype caused the majority of human infections in wave V. We suggest that the largest outbreak of wave V may be due to a constellation of genes rather than a single mutation. Therefore, continuous surveillance is necessary to minimize the threat of H7N9 viruses.

Multifunctional quantum dot DNA hydrogels.

Biotemplated nanomaterials offer versatile functionality for multimodal imaging, biosensing, and drug delivery. There remains an unmet need for traceable and biocompatible nanomaterials that can be synthesized in a precisely controllable manner. Here, we report self-assembled quantum dot DNA hydrogels that exhibit both size and spectral tunability. We successfully incorporate DNA-templated quantum dots with high quantum yield, long-term photostability, and low cytotoxicity into a hydrogel network in a single step. By leveraging DNA-guided interactions, we introduce multifunctionality for a variety of applications, including enzyme-responsive drug delivery and cell-specific targeting. We report that quantum dot DNA hydrogels can be used for delivery of doxorubicin, an anticancer drug, to increase potency 9-fold against cancer cells. This approach also demonstrated high biocompatibility, trackability, and in vivo therapeutic efficacy in mice bearing xenografted breast cancer tumors. This work paves the way for the development of new tunable biotemplated nanomaterials with multiple synergistic functionalities for biomedical applications.The development of nanomaterials for imaging and drug delivery has been of great interest to the field. Here, the authors synthesized multifunctional enzyme-responsive hydrogels with self-assembling quantum dots for nucleic acid and drug delivery as well as having imaging capability.

Succinate and its G-protein-coupled receptor stimulates osteoclastogenesis.

The mechanism underlying bone impairment in patients with diabetes mellitus, a metabolic disorder characterized by chronic hyperglycaemia and dysregulation in metabolism, is unclear. Here we show the difference in the metabolomics of bone marrow stromal cells (BMSCs) derived from hyperglycaemic (type 2 diabetes mellitus, T2D) and normoglycaemic mice. One hundred and forty-two metabolites are substantially regulated in BMSCs from T2D mice, with the tricarboxylic acid (TCA) cycle being one of the primary metabolic pathways impaired by hyperglycaemia. Importantly, succinate, an intermediate metabolite in the TCA cycle, is increased by 24-fold in BMSCs from T2D mice. Succinate functions as an extracellular ligand through binding to its specific receptor on osteoclastic lineage cells and stimulates osteoclastogenesis in vitro and in vivo. Strategies targeting the receptor activation inhibit osteoclastogenesis. This study reveals a metabolite-mediated mechanism of osteoclastogenesis modulation that contributes to bone dysregulation in metabolic disorders.

Pharmacological rescue of diabetic skeletal stem cell niches.

Diabetes mellitus (DM) is a metabolic disease frequently associated with impaired bone healing. Despite its increasing prevalence worldwide, the molecular etiology of DM-linked skeletal complications remains poorly defined. Using advanced stem cell characterization techniques, we analyzed intrinsic and extrinsic determinants of mouse skeletal stem cell (mSSC) function to identify specific mSSC niche-related abnormalities that could impair skeletal repair in diabetic (Db) mice. We discovered that high serum concentrations of tumor necrosis factor-α directly repressed the expression of Indian hedgehog (Ihh) in mSSCs and in their downstream skeletogenic progenitors in Db mice. When hedgehog signaling was inhibited during fracture repair, injury-induced mSSC expansion was suppressed, resulting in impaired healing. We reversed this deficiency by precise delivery of purified Ihh to the fracture site via a specially formulated, slow-release hydrogel. In the presence of exogenous Ihh, the injury-induced expansion and osteogenic potential of mSSCs were restored, culminating in the rescue of Db bone healing. Our results present a feasible strategy for precise treatment of molecular aberrations in stem and progenitor cell populations to correct skeletal manifestations of systemic disease.

One family cluster of avian influenza A(H7N9) virus infection in Shandong, China.

BACKGROUND: The first case of human infection with avian influenza A (H7N9) virus was identified in March, 2013 and the new H7N9 virus infected 134 patients and killed 45 people in China as of September 30, 2013. Family clusters with confirmed or suspected the new H7N9 virus infection were previously reported, but the family cluster of H7N9 virus infection in Shandong Province was first reported. CASE PRESENTATION: A 36-year-old man was admitted to Zaozhuang City Hospital with progressive respiratory distress and suspicion of impending acute respiratory distress syndrome on April 21. The chest radiography revealed bilateral ground-glass opacities and pulmonary lesions. The second case, the first case's 4 year old son, was admitted to the same hospital on April 28 with fever and multiple patchy shadows in the bilateral lungs. Both of the two cases were confirmed to infect with H7N9 virus by the results of real-time reverse transcriptase-polymerase-chain reaction (rRT-PCR), virus isolation and serum antibody titer. At the same time, one environment samples was detected positive for H7N9 virus in the living poultry market in Zaozhuang. The homologous analysis of the full genome sequence indicated that both viruses from the patients were almost genetically identical. The field epidemiology investigation showed that the two cases had no recognized exposure to poultry, but had the exposure to the environment. The second case had substantial unprotected close exposure to his ill father and developed symptoms seven days after his last contact with his father. After surgery, the index case and his son were discharged on May 16 and May 6, respectively. 11 close contacts of both patients were identified and tested negative both the throat swabs and the serum antibody. CONCLUSION: The infection of the index case probably resulted from contact with environmentally contaminated material. For the son, the probable infection source was from the index case during unprotected exposure, but the possibility from the environment or other sources could not be completely ruled out.

Biological features of novel avian influenza A (H7N9) virus.

Human infection associated with a novel reassortant avian influenza H7N9 virus has recently been identified in China. A total of 132 confirmed cases and 39 deaths have been reported. Most patients presented with severe pneumonia and acute respiratory distress syndrome. Although the first epidemic has subsided, the presence of a natural reservoir and the disease severity highlight the need to evaluate its risk on human public health and to understand the possible pathogenesis mechanism. Here we show that the emerging H7N9 avian influenza virus poses a potentially high risk to humans. We discover that the H7N9 virus can bind to both avian-type (α2,3-linked sialic acid) and human-type (α2,6-linked sialic acid) receptors. It can invade epithelial cells in the human lower respiratory tract and type II pneumonocytes in alveoli, and replicated efficiently in ex vivo lung and trachea explant culture and several mammalian cell lines. In acute serum samples of H7N9-infected patients, increased levels of the chemokines and cytokines IP-10, MIG, MIP-1ß, MCP-1, IL-6, IL-8 and IFN-α were detected. We note that the human population is naive to the H7N9 virus, and current seasonal vaccination could not provide protection.

Nonpharmacologic control of postoperative supraventricular arrhythmias using AV nodal fat pad stimulation in a young animal open heart surgical model.

BACKGROUND: Supraventricular arrhythmias (junctional ectopic tachycardia [JET] and atrial tachyarrhythmias) frequently complicate recovery from open heart surgery in children and can be difficult to manage. Medical treatment of JET can result in significant morbidity. Our goal was to develop a nonpharmacological approach using autonomic stimulation of selective fat pad (FP) regions of the heart in a young canine model of open heart surgery to control 2 common postoperative supraventricular arrhythmias. METHODS AND RESULTS: Eight mongrel dogs, varying in age from 5 to 8 months and weighting 22±4 kg, underwent open heart surgery replicating a nontransannular approach to tetralogy of Fallot repair. Neural stimulation of the right inferior FP was used to control the ventricular response to supraventricular arrhythmias. Right inferior FP stimulation decreased baseline AV nodal conduction without altering sinus cycle length. AV node Wenckebach cycle length prolonged from 270±33 to 352±89 ms, P=0.02. Atrial fibrillation occurred in 7 animals, simulating a rapid atrial tachyarrhythmias. FP stimulation slowed the ventricular response rate from 166±58 to 63±29 beats per minute, P<0.001. Postoperative JET occurred in 7 dogs. FP stimulation slowed the ventricular rate during postoperative JET from 148±31 to 106±32 beats per minute, P<0.001, and restored sinus rhythm in 7/7 dogs. CONCLUSIONS: Right inferior FP stimulation had a selective effect on the AV node, and slowed the ventricular rate during postoperative JET and atrial tachyarrhythmias in our young canine open heart surgery model. FP stimulation may be a useful new technique for managing children with JET and atrial tachyarrhythmias.

mTOR-mediated dedifferentiation of the retinal pigment epithelium initiates photoreceptor degeneration in mice.

Retinal pigment epithelial (RPE) cell dysfunction plays a central role in various retinal degenerative diseases, but knowledge is limited regarding the pathways responsible for adult RPE stress responses in vivo. RPE mitochondrial dysfunction has been implicated in the pathogenesis of several forms of retinal degeneration. Here we have shown that postnatal ablation of RPE mitochondrial oxidative phosphorylation in mice triggers gradual epithelium dedifferentiation, typified by reduction of RPE-characteristic proteins and cellular hypertrophy. The electrical response of the retina to light decreased and photoreceptors eventually degenerated. Abnormal RPE cell behavior was associated with increased glycolysis and activation of, and dependence upon, the hepatocyte growth factor/met proto-oncogene pathway. RPE dedifferentiation and hypertrophy arose through stimulation of the AKT/mammalian target of rapamycin (AKT/mTOR) pathway. Administration of an oxidant to wild-type mice also caused RPE dedifferentiation and mTOR activation. Importantly, treatment with the mTOR inhibitor rapamycin blunted key aspects of dedifferentiation and preserved photoreceptor function for both insults. These results reveal an in vivo response of the mature RPE to diverse stressors that prolongs RPE cell survival at the expense of epithelial attributes and photoreceptor function. Our findings provide a rationale for mTOR pathway inhibition as a therapeutic strategy for retinal degenerative diseases involving RPE stress.