High Reactive Oxygen Species Generation Research Articles

Morin exerts neuroprotection via attenuation of ROS induced oxidative damage and neuroinflammation in experimental diabetic neuropathy.

Morin, a bioflavonoid with diverse pharmacological effects against various diseases; in most cases morin protective effects were attributed to its detoxifying effect against reactive oxygen species (ROS). Diabetic neuropathy (DN) is a chronic, debilitating neuronal pain associated with intense generation of free radicals and proinflammatory cytokine accumulation in peripheral neurons. We investigated the pharmacological effect of morin against metabolic excess mediated mitochondrial ROS generation and corresponding effect on Nrf2, NF-κB pathways in Streptozotocin (STZ)-induced diabetic rats and in high glucose insulted Mouse neuroblastoma cell line, Neuro 2A (N2A). Animals were evaluated for nerve function parameters, motor and sensory nerve conduction velocities (MNCV and SNCV) and nerve blood flow (NBF) followed by TUNEL and immunoblot analysis. Mitochondrial function was evaluated by performing JC-1 and MitoSOX assays in high glucose (30 mM) incubated N2A cells. Diabetic animals showed significant impairment in MNCV, SNCV, and NBF as well as increased pain hypersensitivity. However, oral administration of morin at 50 and 100 mg/kg improved SNCV, MNCV, and NBF and reduced sensorimotor alterations (hyperalgesia and allodynia) in diabetic animals. Studies in N2A cells have revealed that morin ameliorated the high glucose-induced mitochondrial superoxide production, membrane depolarization, and total ROS generation. Morin effectively counteracted NF-κB-mediated neuroinflammation by reducing ROS mediated IKK activation and increased Nrf2-mediated antioxidant defenses in high glucose-induced N2A cells. The results of our study suggest that morin has exquisite role in offering neuroprotection in experimental DN and further clinical investigation may reward in finding better alternative for the management of DN. © 2017 BioFactors, 44(2):109-122, 2018.

Pendimethalin induces oxidative stress, DNA damage, and mitochondrial dysfunction to trigger apoptosis in human lymphocytes and rat bone-marrow cells.

Pendimethalin (PM) is a dinitroaniline herbicide extensively applied against the annual grasses and broad-leaved weeds. There is no report available on PM-induced low-dose genotoxicity in human primary cells and in vivo test models. Such data gap has prompted us to evaluate the genotoxic potential of PM in human lymphocytes and rats. PM selectively binds in the minor groove of DNA by forming covalent bonds with G and C nitrogenous bases, as well as with the ribose sugar. PM induces micronucleus formation (MN) in human lymphocytes, indicating its clastogenic potential. Comet assay data showed 35.6-fold greater DNA damage in PM (200μM)-treated human lymphocytes. Rat bone-marrow cells, at the highest dose of 50mg/kg bw/day of PM also exhibited 10.5-fold greater DNA damage. PM at 200μM and 50mg/kg bw/day induces 193.4 and 229% higher reactive oxygen species generation in human lymphocytes and rat bone-marrow cells. PM-treated human lymphocytes and rat bone-marrow cells both showed dysfunction of mitochondrial membrane potential (ΔΨ m). PM exposure results in the appearance of 72.2 and 35.2% sub-G1 apoptotic peaks in human lymphocytes and rat bone-marrow cells when treated with 200μM and 50mg/kg bw/day of PM. Rats exposed to PM also showed imbalance in antioxidant enzymes and histological pathology. Overall, our data demonstrated the genotoxic and apoptotic potentials of PM in human and animal test models.

Allopurinol protects human glomerular endothelial cells from high glucose-induced reactive oxygen species generation, p53 overexpression and endothelial dysfunction.

Mitochondrial reactive oxygen species (ROS) overproduction in capillary endothelial cells is a prerequisite for the development of diabetic nephropathy. Inhibition of xanthine oxidase, another ROS generator, ameliorates experimental diabetic nephropathy. To test the hypothesis that the initial high glucose-induced ROS production by the mitochondria activates xanthine oxidase, which afterward remains as the major source of ROS, we cultured primary human glomerular endothelial cells (GEnC) under normal or high-glucose conditions, with or without the xanthine oxidase inhibitor allopurinol. ROS generation and nitric oxide synthase (NOS) activity were assessed by chemiluminescence or colorimetrically. Levels of intercellular adhesion molecule 1 (ICAM-1), p53 and phosphorylated p53 (p-p53) were assessed by western blotting. Allopurinol prevented high glucose-induced ROS generation indicating that xanthine oxidase is the major source of ROS. Allopurinol protected GEnC from endothelial dysfunction since it prevented the high glucose-induced decrease in NOS activity and increase in ICAM-1 expression. Allopurinol reduced p53 and p-p53 levels induced by high glucose suggesting an axis of xanthine oxidase-derived ROS, DNA damage, p53 stabilization and endothelial dysfunction that may contribute to the pathogenesis of diabetic nephropathy. Allopurinol protects GEnC from high glucose-induced ROS generation, p53 overexpression and endothelial dysfunction. These data provide a pathogenetic mechanism that supports the results of experimental and clinical studies about the beneficial effect of xanthine oxidase inhibitors on the development of diabetic nephropathy.

Photochemistry of Hydrochar: Reactive Oxygen Species Generation and Sulfadimidine Degradation.

Biochar, mainly including pyrochar produced via pyrolysis of biomass at moderate temperatures of 350-700 °C and hydrochar formed by hydrothermal carbonization in a range of 150-350 °C, has received increasing attention because of its significant environmental impacts. It is known that pyrochar can generate reactive oxygen species even in the dark owing to the presence of persistent free radicals, but hydrochar is far less studied. In this study, we systematically investigate the photochemistry of hydrochar and check its effects on the sulfadimidine degradation. Different from pyrochar derived from the same biomass, hydrochar could generate much more H2O2 and •OH under daylight irradiation, which could enhance the sulfadimidine degradation rate six times more than that found in the dark. Raman spectroscopy, Fourier transform infrared spectroscopy, electron paramagnetic resonance, and X-ray photoelectron spectroscopy were employed to elucidate this interesting phenomenon. Characterization results revealed that the higher reactive oxygen species generation ability of hydrochar under solar light irradiation was attributed to its abundant photoactive surface oxygenated functional groups. This study clarifies the differences of pyrochar and hydrochar on organic pollutant degradation, and also sheds light on environmental effects of hydrochar.

Novel oxolane derivative DMTD mitigates high glucose-induced erythrocyte apoptosis by regulating oxidative stress

Chronic hyperglycemia is one of the characteristic conditions associated with Diabetes Mellitus (DM), which often exerts deleterious effects on erythrocyte morphology and hemodynamic properties leading to anemia and diabetes-associated vascular complications. High glucose-induced over production of reactive oxygen species (ROS) can alter the blood cell metabolism and biochemical functions subsequently causing eryptosis (red blood cell death), yet another complication of concern in DM. Therefore, blocking high glucose-induced oxidative damage and subsequent eryptosis is of high importance in the better management of DM and associated vascular complications. In this study, we synthesized an oxolane derivative 1-(2,2-dimethyltetrahydrofuro[2,3][1,3]dioxol-5-yl)ethane-1,2-diol (DMTD), and demonstrated its efficacy to mitigate hyperglycemia-induced ROS generation and subsequent eryptosis. We showed that DMTD effectively inhibits high glucose-induced ROS generation, intracellular calcium levels, phosphaditylserine (PS) scrambling, calpain and band 3 activation, LDH leakage, protein glycation and lipid peroxidation, meanwhile enhances the antioxidant indices, osmotic fragility and Na+/K+-ATPase activity in erythrocytes. DMTD dose dependently decreased the glycated hemoglobin level and enhances the glucose utilization by erythrocytes in vitro. Further, DMTD alleviated the increase in ROS production, intracellular Ca2+ level and PS externalization in the erythrocytes of human diabetic subjects and enhanced the Na+/K+-ATPase activity. Taken together, the synthesized oxolane derivative DMTD could be a novel synthetic inhibitor of high glucose-induced oxidative stress and eryptosis. Considering the present results DMTD could be a potential therapeutic to treat DM and associated complications and open new avenues in developing synthetic therapeutic targeting of DM-associated complications.

Enhanced ROS generation by ZnO-ammonia modified graphene oxide nanocomposites for photocatalytic degradation of trypan blue dye and 4-nitrophenol

There has been consistent effort on manipulating surface properties of ZnO NPs to produce higher concentration of reactive oxygen species (ROS) to enhance sustained photocatalytic degradation. Here we present a very simple strategy of synthesizing nanocomposites of ZnO NPs and ammonia modified graphene oxide (ZG) as an efficient photocatalyst for enhanced ROS generation and degradation of trypan blue azo dye and 4-nirophenol. The batch of photocatalyst made of ZnO NPs and 5wt% ammonia modified graphene oxide (ZG5) has been well characterized and its stability in aqueous medium is confirmed from minimal zinc leaching. The photocatalytic degradation of the dye and 4-nitrophenol followed Langmuir-Hinshelwood kinetics model. At optimized conditions, i.e., NH3 concentration for modifying graphene oxide, photocatalyst dose (ZG5), pH of the medium and contact time, the rate of photocatalytic degradation of trypan blue (k=7.3×10−3min−1) and 4-nitrophenol (k=5.5×10−3min−1), were more than 7–10 folds higher than that of pristine ZnO NPs. The enhanced rate of photocatalytic degradation by the ZG5 nanocomposite was correlated with higher ROS generation, owing to diffusion of photoexcited electrons and holes to the surface of the nanocomposite via conducting reduced graphene oxide to favour ROS generation. The ROS scavenger studies confirmed in-situ generation of superoxide radicals, hydroxyl radicals and singlet oxygen in the reaction medium. The degradation pathway for 4-nitrophenol has been proposed via formation of 1,4-benzoquinone as revealed from HPLC studies. The GC–MS studies confirmed nearly complete mineralization of the dye and 4-nitrophenol without formation of any by-product.

Precise Two-Photon Photodynamic Therapy using an Efficient Photosensitizer with Aggregation-Induced Emission Characteristics.

Two-photon photodynamic therapy (PDT) is able to offer precise 3D manipulation of treatment volumes, providing a target level that is unattainable with current therapeutic techniques. The advancement of this technique is greatly hampered by the availability of photosensitizers with large two-photon absorption (TPA) cross section, high reactive-oxygen-species (ROS) generation efficiency, and bright two-photon fluorescence. Here, an effective photosensitizer with aggregation-induced emission (AIE) characteristics is synthesized, characterized, and encapsulated into an amphiphilic block copolymer to form organic dots for two-photon PDT applications. The AIE dots possess large TPA cross section, high ROS generation efficiency, and excellent photostability and biocompatibility, which overcomes the limitations of many conventional two-photon photosensitizers. Outstanding therapeutic performance of the AIE dots in two-photon PDT is demonstrated using in vitro cancer cell ablation and in vivo brain-blood-vessel closure as examples. This shows therapy precision up to 5 µm under two-photon excitation.

Amitriptyline down-regulates coenzyme Q10 biosynthesis in lung cancer cells

Amitriptyline, a tricyclic antidepressant, has been proposed as an antitumoral drug in oxidative therapy. Its pro-apoptotic effects, mediated by high reactive oxygen species generation, have been already described. In this study we analysed the effect of amitriptyline on the biosynthesis of coenzyme Q10 (CoQ), an essential component for electron transport and a potent membrane antioxidant involved in redox signaling. We treated H460 cells, a non-small-cell lung cancer cell line, with amitriptyline and we analysed CoQ levels by HPLC and CoQ biosynthesis rate, as well as the enzymes involved in CoQ biosynthesis by real-time PCR and Western blot. Amitriptyline treatment induced a dose-dependent decrease in CoQ levels in tumor cells. CoQ decreased levels were associated with down-regulation of the expression of COQ4 gene, as well as decreased Coq4 and Coq6 protein levels. Our findings suggest that the effect of amitriptyline on CoQ biosynthesis highlights the potential of this drug for antitumoral oxidative therapy.

Low-power white light triggered AIE polymer nanoparticles with high ROS quantum yield for mitochondria-targeted and image-guided photodynamic therapy.

Photodynamic therapy (PDT) has received enormous attention due to its high specificity in eliminating the malignant tumor cells without interposing normal cells, as compared with chemotherapy. In this work, we fabricated mitochondria-targeted NPs using a new AIE cross-linked copolymer (PAIE-TPP) with far red/near-infrared (FR/NIR) subcellular bioimaging ability and a high reactive oxygen species (ROS) quantum yield of 77.9%. Such high efficiency ROS generation is desirable to increase the efficiency of PDT. The PAIE-TPP NPs possess great cytocompatibility but exert severe cytotoxicity to cancer cells with only 4% of cell viability under ultralow-power-intensity (10 mW cm-2) light irradiation. The AIE cross-linked copolymer NPs not only emit bright FR/NIR fluorescence for efficient in vitro subcellular-mitochondrial bioimaging but also generate high ROS for PDT.

Rosmarinic Acid suppressed high glucose-induced apoptosis in H9c2 cells by ameliorating the mitochondrial function and activating STAT3

Mitochondrial injury characterized by intracellular reactive oxygen species (ROS) accumulation plays a critical role in hyperglycemia-induced myocardium dysfunction. Previous studies have demonstrated that Rosmarinic Acid (RA) treatment and activating Signal transducer and activator of transcription 3 (STAT3) signaling pathway have protective effects on mitochondrial dysfunction in cardiomyocyte, but there is little data regarding cardiomyocyte under condition of high-glucose. The present study was undertaken to determine the relationship between RA and STAT3 activation, as well as their effects on high glucose-induced mitochondrial injury and apoptosis in H9c2 cardiomyocyte. Our results revealed that RA pretreatment suppressed high glucose-induced apoptosis in H9c2 cells. Moreover, the effect of RA on apoptosis was related with improved mitochondrial function, which was demonstrated by that RA attenuated high glucose-induced ROS generation, inhibited mitochondrial permeability transition pore (MPTP) activation, suppressed cytochrome c release and caspase-3 activation. In addition, the phosphorylation of STAT3 in H9c2 cells was inhibited under condition of high-glucose, but RA improved STAT3 phosphorylation. Importantly, inhibition of STAT3 expression by using STAT3-siRNA partly suppressed the effect of RA on high glucose-induced apoptosis. Taken together, pretreatment with RA suppressed high glucose-induced apoptosis in cardiomyocyte by ameliorating mitochondrial function and activating STAT3.

Bromo-Substituted Diketopyrrolopyrrole Derivative with Specific Targeting and High Efficiency for Photodynamic Therapy.

Novel photosensitizers with high reactive oxygen species generation and precise targeting to tumors are crucial for photodynamic therapy (PDT). Here, a bromo-substituted diketopyrrolopyrrole derivative (2,5-bis(6-bromohexyl)-3,6-bis(5-bromothiophene-2-yl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione)-grafted hyaluronic acid is synthesized, which presents excellent targeting and PDT efficiency both in vitro and in vivo.

Upregulation of Periostin Prevents High Glucose-Induced Mitochondrial Apoptosis in Human Umbilical Vein Endothelial Cells via Activation of Nrf2/HO-1 Signaling

Background/Aims: High glucose-induced oxidative damage to endothelial cells plays a central role in the pathogenesis of diabetic vascular complications. This study was undertaken to explore the role of periostin in high glucose-induced endothelial cell apoptosis and associated molecular mechanisms. Methods: Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose (33.3 mmol/L) and examined for the expression of periostin. The effects of periostin upregulation on high glucose-induced apoptosis, mitochondrial dysfunction, and reactive oxygen species (ROS) production were determined. The activation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) by periostin was checked. HO-1 knockdown experiments were done to confirm its role in the action of periostin in high glucose-exposed HUVECs. Results: High glucose significantly upregulated the expression of periostin in HUVECs. Enforced expression of periostin attenuated high glucose-induced apoptosis in HUVECs, as determined by TUNEL staining and caspase-3 activity assay. Periostin overexpression prevented loss of Δψm, release of mitochondrial cytochrome c, and dysregulation of Bcl-2 and Bax in high glucose-exposed HUVECs. Periostin upregulation suppressed high glucose-induced ROS generation and activated the Nrf2/HO-1 signaling. HO-1 silencing restored high glucose-induced ROS generation and apoptotic response in periostin-overexpressing HUVECs. Conclusion: Periostin mitigates high glucose-induced mitochondrial apoptosis in endothelial cells, via activation of Nrf2/HO-1 signaling and reduction of ROS formation. Further studies are warranted to explore the therapeutic potential of periostin in diabetic vascular complications.

Formation of reactive oxygen species by human and bacterial pyruvate and 2-oxoglutarate dehydrogenase multienzyme complexes reconstituted from recombinant components

Individual recombinant components of pyruvate and 2-oxoglutarate dehydrogenase multienzyme complexes (PDHc, OGDHc) of human and Escherichia coli (E. coli) origin were expressed and purified from E. coli with optimized protocols. The four multienzyme complexes were each reconstituted under optimal conditions at different stoichiometric ratios. Binding stoichiometries for the highest catalytic efficiency were determined from the rate of NADH generation by the complexes at physiological pH. Since some of these complexes were shown to possess ‘moonlighting’ activities under pathological conditions often accompanied by acidosis, activities were also determined at pH 6.3. As reactive oxygen species (ROS) generation by the E3 component of hOGDHc is a pathologically relevant feature, superoxide generation by the complexes with optimal stoichiometry was measured by the acetylated cytochrome c reduction method in both the forward and the reverse catalytic directions. Various known affectors of physiological activity and ROS production, including Ca2+, ADP, lipoylation status or pH, were investigated. The human complexes were also reconstituted with the most prevalent human pathological mutant of the E3 component, G194C and characterized; isolated human E3 with the G194C substitution was previously reported to have an enhanced ROS generating capacity. It is demonstrated that: i. PDHc, similarly to OGDHc, is able to generate ROS and this feature is displayed by both the E. coli and human complexes, ii. Reconstituted hPDHc generates ROS at a significantly higher rate as compared to hOGDHc in both the forward and the reverse reactions when ROS generation is calculated for unit mass of their common E3 component, iii. The E1 component or E1-E2 subcomplex generates significant amount of ROS only in hOGDHc; iv. Incorporation of the G194C variant of hE3, the result of a disease-causing mutation, into reconstituted hOGDHc and hPDHc indeed leads to a decreased activity of both complexes and higher ROS generation by only hOGDHc and only in its reverse reaction.

Continuously high reactive oxygen species generation decreased the specific ϵ-poly-l-lysine formation rate in fed-batch fermentation using glucose and glycerol as a mixed carbon source

A glucose–glycerol mixed carbon source led to higher production of both ϵ-poly-l-lysine and biomass, whether in the batch or fed-batch fermentation. However, as the major benefit of the mixed carbon source, the high specific ϵ-poly-l-lysine formation rate in the batch fermentation sharply declined when the feeding strategy was initiated. In this study, we examined the development of cell physiology in ϵ-poly-l-lysine production to obtain an insight into this undesirable phenomenon. The simultaneous consumption of glucose and glycerol generated abundant reactive oxygen species in the batch fermentation stage. Transcriptome analysis further confirmed the existence of excessive oxidative stress with the glucose–glycerol mixed carbon source. Serious oxidative damage in the mixed carbon source resulted in deterioration in cell viability, intracellular levels of ATP and l-lysine in the following fed-batch fermentation. Moreover, the stress situation was worsened by a low antioxidant capacity with the mixed carbon source. As a result, these damaged cells showed decreased specific ϵ-poly-l-lysine formation rate. This study provided information for the understanding of the underlying change of cell physiology in ϵ-poly-l-lysine fed-batch fermentation, which was greatly needed for a further enhancement of ϵ-poly-l-lysine production in culture with an intensive cell respiration.

Natural polysaccharide functionalized gold nanoparticles as biocompatible drug delivery carrier

Biocompatibility is one of the major concerns with inorganic nanoparticles for their applications as drug delivery system. Natural compounds such as sugars, hydrocolloids and plant extracts have shown potential for the green synthesis of biocompatible gold nanoparticles. In this study, we report the synthesis of gum karaya (GK) stabilized gold nanoparticles (GKNP) and the application of prepared nanoparticles in the delivery of anticancer drugs. GKNP were characterized using different analytical techniques. GKNP exhibited high biocompatibility during cell survival study against CHO normal ovary cells and A549 human non-small cell lung cancer cells and during hemolytic toxicity studies. Gemcitabine hydrochloride (GEM), an anticancer drug, was loaded on the surface of nanoparticles with 19.2% drug loading efficiency. GEM loaded nanoparticles (GEM-GNP) showed better inhibition of growth of cancer cells in anti-proliferation and clonogenic assays than native GEM. This effect was correlated with higher reactive oxygen species generation by GEM-GNP in A549 cells than native GEM. In summary, GK has significant potential in the synthesis of biocompatible gold nanoparticles that could be used as prospective drug delivery carrier for anticancer drugs.

The calcium-ROS-pH triangle and mitochondrial permeability transition: challenges to mimic cardiac ischemia-reperfusion.

The calcium-ROS-pH triangle and mitochondrial permeability transition: challenges to mimic cardiac ischemia-reperfusion.

A mouse model to study thrombotic complications of thalassemia

Patients with β-thalassemia major and mainly intermedia have an increased risk for developing venous and arterial thrombosis which may be related to circulating pathological red blood cells (RBC) and continuous platelet activation. In the present study we used a modified thalassemic mice model in conjunction with a "real-time" carotid thrombus formation procedure to investigate thrombotic complications of thalassemia. Heterozygous Th3/+ mice, which lack one copy of their β-major and β-minor globin genes, exhibit anomalies in RBC size and shape, chronic anemia and splenomegaly which recapitulate the phenotype of human β-thalassemia intermedia. Flow cytometry measurements showed higher reactive oxygen species generation, indicating oxidative stress, in platelets and RBC of the thalassemic mice compared with wild type mice concomitant with an increase in reduced glutathione content which may represent a compensatory response to oxidative stress, and exposed phosphatidylserine which indicates platelet activation. To elucidate the effect of thalassemia on the development of arterial thrombosis, we studied photochemical-induced real-time thrombus formation in the carotid artery of these mice. The results indicated a significantly shorter "time to occlusion" in the thalassemic mice compared to wild type mice, which was prolonged following in vivo aspirin treatment. We suggest that this mouse model may contribute to our understanding of platelet activation and the hypercoagulable state in thalassemia and lay foundations to screening of anti-platelet drugs as well as anti-oxidants as possible therapeutics for prevention of thrombosis in thalassemia patients.

Oxygen pathway modeling estimates high reactive oxygen species production above the highest permanent human habitation.

The production of reactive oxygen species (ROS) from the inner mitochondrial membrane is one of many fundamental processes governing the balance between health and disease. It is well known that ROS are necessary signaling molecules in gene expression, yet when expressed at high levels, ROS may cause oxidative stress and cell damage. Both hypoxia and hyperoxia may alter ROS production by changing mitochondrial Po 2 (). Because depends on the balance between O2 transport and utilization, we formulated an integrative mathematical model of O2 transport and utilization in skeletal muscle to predict conditions to cause abnormally high ROS generation. Simulations using data from healthy subjects during maximal exercise at sea level reveal little mitochondrial ROS production. However, altitude triggers high mitochondrial ROS production in muscle regions with high metabolic capacity but limited O2 delivery. This altitude roughly coincides with the highest location of permanent human habitation. Above 25,000 ft., more than 90% of exercising muscle is predicted to produce abnormally high levels of ROS, corresponding to the “death zone” in mountaineering.

P23 Pharmacological induction of CBS-mediated H2S production attenuates renal damage following deep hypothermia and rewarming

Hypothermic static preservation is commonly applied to preserve organ grafts during transplantation. However, cold ischemia is associated with the induction of renal injury, in which reactive oxygen species (ROS) play a major role. We recently reported that cellular uptake of catecholamines prevents hypothermia/rewarming-induced cell death by inhibiting ROS production. We also showed in cultured rat smooth muscle aortic cells that administration of catecholamines such as dopamine boosts endogenous H 2 S production leading to cell survival under hypothermic condition. Therefore in this study, we investigated whether these mechanisms are operational in vivo in the rat kidney, by investigating the effect of dopamine on renal injury induced by hypothermia and rewarming under ketamine anesthesia. Our results show that forced hypothermia followed by rewarming of rats induces glomerular and interstitial injury in animals anesthetized with ketamine, as indicated by histopathological changes, higher KIM-1 expression, influx of neutrophils and macrophages, and high ROS generation. Addition of dopamine on the other hand, reduced renal hypothermia/rewarming injury in animals anesthetized with ketamine and upregulated CBS expression and subsequent H 2 S production. These demonstrate that dopamine has renoprotection via CBS-induced H 2 S production against organ damage induced by hypothermia/rewarming.

Tumor Microenvironment and Metabolic Synergy in Breast Cancers: Critical Importance of Mitochondrial Fuels and Function

Metabolic synergy or metabolic coupling between glycolytic stromal cells (Warburg effect) and oxidative cancer cells occurs in human breast cancers and promotes tumor growth. The Warburg effect or aerobic glycolysis is the catabolism of glucose to lactate to obtain adenosine triphosphate (ATP). This review summarizes the main findings on this stromal metabolic phenotype, and the associated signaling pathways, as well as the critical role of oxidative stress and autophagy, all of which promote carcinoma cell mitochondrial metabolism and tumor growth. Loss of Caveolin 1 (Cav-1) and the upregulation of monocarboxylate transporter 4 (MCT4) in stromal cells are novel markers of the Warburg effect and metabolic synergy between stromal and carcinoma cells. MCT4 and Cav-1 are also breast cancer prognostic biomarkers. Reactive oxygen species (ROS) are key mediators of the stromal Warburg effect. High ROS also favors cancer cell mitochondrial metabolism and tumorigenesis, and anti-oxidants can reverse this altered stromal and carcinoma metabolism. A pseudo-hypoxic state with glycolysis and low mitochondrial metabolism in the absence of hypoxia is a common feature in breast cancer. High ROS induces loss of Cav-1 in stromal cells and is sufficient to generate a pseudo-hypoxic state. Loss of Cav-1 in the stroma drives glycolysis and lactate extrusion via HIF-1α stabilization and the upregulation of MCT4. Stromal cells with loss of Cav-1 and/or high expression of MCT4 also show a catabolic phenotype, with enhanced macroautophagy. This catabolic state in stromal cells is driven by hypoxia-inducible factor (HIF)-1α, nuclear factor κB (NFκB), and JNK activation and high ROS generation. A feed-forward loop in stromal cells regulates pseudo-hypoxia and metabolic synergy, with Cav-1, MCT4, HIF-1α, NFκB, and ROS as its key elements. Metabolic synergy also may occur between cancer cells and cells in distant organs from the tumor. Cancer cachexia, which is due to severe organismal metabolic dysregulation in myocytes and adipocytes, shares similarities with stromal-carcinoma metabolic synergy, as well. In summary, metabolic synergy occurs when breast carcinoma cells induce a nutrient-rich microenvironment to promote tumor growth. The process of tumor metabolic synergy is a multistep process, due to the generation of ROS, and the induction of catabolism with autophagy, mitophagy and glycolysis. Studying epithelial-stromal interactions and metabolic synergy is important to better understand the ecology of cancer and the metabolic role of different cell types in tumor progression.