Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts

Recent evidence has emerged that cancer cells can use various metabolites as fuel sources. Restricting cultured cancer cells to sole metabolite fuel sources can promote metabolic changes leading to enhanced glycolysis or mitochondrial OXPHOS. However, the efect of metabolite-restriction on non-transformed cells remains largely unexplored. Here we examined the efect of restricting media fuel sources, including glucose, pyruvate or lactate, on the metabolic state of cultured human dermal fbroblasts. Fibroblasts cultured in lactate-only medium exhibited reduced PDH phosphorylation, indicative of OXPHOS, and a concurrent elevation of ROS. Lactate exposure primed fbroblasts to switch to glycolysis by increasing transcript abundance of genes encoding glycolytic enzymes and, upon exposure to glucose, increasing glycolytic enzyme levels. Furthermore, lactate treatment stabilized HIF-1α, a master regulator of glycolysis, in a manner attenuated by antioxidant exposure. Our fndings indicate that lactate preconditioning primes fbroblasts to switch from OXPHOS to glycolysis metabolism, in part, through ROS-mediated HIF-1α stabilization. Interestingly, we found that lactate preconditioning results in increased transcript abundance of MYC and SNAI1, key facilitators of early somatic cell reprogramming. Defned metabolite treatment may represent a novel approach to increasing somatic cell reprogramming efciency by amplifying a critical metabolic switch that occurs during iPSC generation

p66Shc activation promotes increased oxidative phosphorylation and renders CNS cells more vulnerable to amyloid beta toxicity

A key pathological feature of Alzheimer’s disease (AD) is the accumulation of the neurotoxic amyloid beta (Aβ) peptide within the brains of affected individuals. Previous studies have shown that neuronal cells selected for resistance to Aβ toxicity display a metabolic shift from mitochondrial-dependent oxidative phosphorylation (OXPHOS) to aerobic glycolysis to meet their energy needs. The Src homology/collagen (Shc) adaptor protein p66Shc is a key regulator of mitochondrial function, ROS production and aging. Moreover, increased expression and activation of p66Shc promotes a shift in the cellular metabolic state from aerobic glycolysis to OXPHOS in cancer cells. Here we evaluated the hypothesis that activation of p66Shc in CNS cells promotes both increased OXPHOS and enhanced sensitivity to Aβ toxicity. The effect of altered p66Shc expression on metabolic activity was assessed in rodent HT22 and B12 cell lines of neuronal and glial origin respectively. Overexpression of p66Shc repressed glycolytic enzyme expression and increased both mitochondrial electron transport chain activity and ROS levels in HT22 cells. The opposite effect was observed when endogenous p66Shc expression was knocked down in B12 cells. Moreover, p66Shc activation in both cell lines increased their sensitivity to Aβ toxicity. Our findings indicate that expression and activation of p66Shc renders CNS cells more sensitive to Aβ toxicity by promoting mitochondrial OXPHOS and ROS production while repressing aerobic glycolysis. Thus, p66Shc may represent a potential therapeutically relevant target for the treatment of AD

Aerobic glycolysis is required for spatial memory acquisition but not memory retrieval in mice

The consolidation of newly formed memories and their retrieval are energetically demanding processes. Aerobic glycolysis (AG), also known as the Warburg effect, consists of the production of lactate from glucose in the presence of oxygen. The astrocyte neuron lactate shuttle hypothesis posits that astrocytes process glucose by AG to generate lactate, which is used as a fuel source within neurons to maintain synaptic activity. Studies in mice have demonstrated that lactate transport between astrocytes and neurons is required for long-term memory formation, yet the role of lactate production in memory acquisition and retrieval has not previously been explored. Here, we examined the effect of dichloroacetate (DCA), a chemical inhibitor of lactate production, on spatial learning and memory in mice using the Morris water maze (MWM). In vivo hyperpolarized 13 C-pyruvate magnetic resonance spectroscopy revealed decreased conversion of pyruvate to lactate in the mouse brain following DCA administration, concomitant with a reduction in the phosphorylation of pyruvate dehydrogenase. DCA exposure before each training session in the MWM impaired learning, which subsequently resulted in impaired memory during the probe trial. In contrast, mice that underwent training without DCA exposure, but received a single DCA injection before the probe trial exhibited normal memory. Our findings indicate that AG plays a key role during memory acquisition but is less important for the retrieval of established memories. Thus, the activation of AG may be important for learning-dependent synaptic plasticity rather than the activation of signaling cascades required for memory retrieval

Iron Deficiency Anaemia In Reproductive Age Women Attending Obstetrics And Gynecology Outpatient Of University Health Centre In Al-Ahsa, Saudi Arabia

Background: Iron deficiency is the most common nutritional disorder in the world. The aim of this questionnaire based survey study was to determine the prevalence of iron deficiency anemia in reproductive age women, and their relation to variables such as age, marital status, education with those attending obstetrics and gynecology outpatient of King Faisal University Health Centre in Al-Ahsa in eastern region of Kingdom of Saudi Arabia.Materials and Methods: This study was conducted for the period of 6 month staring from September 2012 to February 2013. The questionnaire had three sections on personal information: their educational indicators, gynecological clinical history, and hematological indices.Results: The average age was 25.97±7.17 years. According to the  gynecological clinical history of the respondents, 15 (48.4%) respondents were pregnant while 16 (51.6%) were not pregnant. There was significant effect of pregnancy status on Hb level. Majority of the anemic respondents 15/17 were married. Moreover 14/17 anemic women were experiencing severe menstrual bleeding, 11/17 respondents were pregnant. 54.8% of respondents were hemoglobin deficient while 77.4% were found to have low Hct. In 87.1 % of the respondents, transferrin saturation was found to be abnormal.Conclusion: In this study iron deficiency anemia is quite prevalent in the university community especially among pregnant women. The fetus’s and newborn infant’s iron status depends on the iron status of the pregnant woman and therefore, iron deficiency in the mother-to-be means that growing fetus probably will be iron deficient as well. Thus iron deficiency anemia during pregnancy in well-educated set up needs more attention by the concerned authorities.Keywords: Iron deficiency Anemia (IDA), Hemoglobin, Female, Reproductive Age

Abnormal social interactions in a Drosophila mutant of an autism candidate gene: Neuroligin 3

Social interactions are typically impaired in neuropsychiatric disorders such as autism, for which the genetic underpinnings are very complex. Social interactions can be modeled by analysis of behaviors, including social spacing, sociability, and aggression, in simpler organisms such as Drosophila melanogaster. Here, we examined the effects of mutants of the autism-related gene neuroligin 3 (nlg3) on fly social and non-social behaviors. Startled-induced negative geotaxis is affected by a loss of function nlg3 mutation. Social space and aggression are also altered in a sex-and social-experience-specific manner in nlg3 mutant flies. In light of the conserved roles that neuroligins play in social behavior, our results offer insight into the regulation of social behavior in other organisms, including humans

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit

The Adaptor Protein p66Shc Governs Central Nervous System Cell Metabolism and Resistance to Aβ Toxicity

Alzheimer’s disease (AD), a progressive and irreversible neurodegenerative disorder, and is the leading cause of dementia worldwide. It has been posited that AD is caused by the gradual deposition of toxic amyloid-b (Ab) plaques in the brain- that cause oxidative stress and eventually leads to neuronal death and synaptic loss. However, multiple therapies that either interfere with the production, or enhance the removal of Ab from the brain, have ultimately failed to slow or prevent AD. With the ever-increasing burden of AD worldwide, there exists an urgent need for novel therapeutic targets. The adult human brain is an energy demanding organ, and numerous studies have shown pronounced reductions in glucose metabolism in AD brains, which precipitates neurodegeneration and memory loss. Specifically, significant losses in brain glycolysis have been observed, while several lines of evidence also demonstrate that the preservation of glycolysis provides key advantages to central nervous system (CNS) cells in AD. However, the mechanisms governing shifts between mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis for ATP generation are poorly understood. Therefore, I aimed to investigate which proteins are involved in promoting metabolic shifts in CNS cells. I focused on p66Shc, an adaptor protein whose canonical functions include apoptotic signalling and ROS production, but recent studies have implicated p66Shc in cellular metabolism. I demonstrate that in cultured CNS cells, expression and activation of p66Shc promotes OXPHOS, increases mitochondrial ROS- and represses glycolytic enzyme expression. p66Shc silencing, however, upregulates glycolytic enzymes, lowers ROS, and protects cells against Ab toxicity. I also determined that p66Shc silencing lowers levels of kelch-like ECH associated protein 1 (KEAP1), which results in increased stabilization of the transcription factor nuclear erythroid 2-related factor 2 (NRF2). Elevated NRF2 promotes increased levels of hypoxia-inducible factor 1α and subsequent elevations in glycolytic enzyme expression. I also showed that protective effects of p66Shc against Ab are NRF2 mediated, and transgenic AD mouse brains have higher p66Shc and KEAP1, but lower NRF2 levels, relative to wildtype mice. Together, these findings reveal a novel mechanism of cellular metabolic regulation, and highlights p66Shc as a potential therapeutic target for the treatment of AD

Lactate preconditioning promotes a HIF-1α-mediated metabolic shift from OXPHOS to glycolysis in normal human diploid fibroblasts

Recent evidence has emerged that cancer cells can use various metabolites as fuel sources. Restricting cultured cancer cells to sole metabolite fuel sources can promote metabolic changes leading to enhanced glycolysis or mitochondrial OXPHOS. However, the effect of metabolite-restriction on non-transformed cells remains largely unexplored. Here we examined the effect of restricting media fuel sources, including glucose, pyruvate or lactate, on the metabolic state of cultured human dermal fibroblasts. Fibroblasts cultured in lactate-only medium exhibited reduced PDH phosphorylation, indicative of OXPHOS, and a concurrent elevation of ROS. Lactate exposure primed fibroblasts to switch to glycolysis by increasing transcript abundance of genes encoding glycolytic enzymes and, upon exposure to glucose, increasing glycolytic enzyme levels. Furthermore, lactate treatment stabilized HIF-1α, a master regulator of glycolysis, in a manner attenuated by antioxidant exposure. Our findings indicate that lactate preconditioning primes fibroblasts to switch from OXPHOS to glycolysis metabolism, in part, through ROS-mediated HIF-1α stabilization. Interestingly, we found that lactate preconditioning results in increased transcript abundance of MYC and SNAI1, key facilitators of early somatic cell reprogramming. Defined metabolite treatment may represent a novel approach to increasing somatic cell reprogramming efficiency by amplifying a critical metabolic switch that occurs during iPSC generation

Tele ICU: Paradox or panacea?

Telemedicine has been studied in the intensive care unit for several decades, but many questions remain unanswered regarding the costs and the benefits of its application. Telemedicine ICU (Tele-ICU) is an electronic means to link physical ICUs to another location which assists in medical decision making. Given the shortage of intensive care physicians in the US, Tele-ICU systems could be an efficient mechanism for physicians to manage a larger number of critical care patients. This chapter will examine the current state of telemedicine in an age of rapidly expanding medical information technology and increasing demand for intensive care services. While we believe that the future of Tele-ICU is promising, there are multiple issues that must be addressed to increase the benefit of Tele-ICU. Tele-ICU is expensive to deploy and use, it may add burdens to existing intensivists, and it requires organizational and culture changes that can be difficult to accomplish