Suppression of mitochondrial oxygen metabolism mediated by the transcription factor HIF-1 alleviates propofol-induced cell toxicity

A line of studies strongly suggest that the intravenous anesthetic, propofol, suppresses mitochondrial oxygen metabolism. It is also indicated that propofol induces the cell death in a reactive oxygen species (ROS)-dependent manner. Because hypoxia-inducible factor 1 (HIF-1) is a transcription factor which is involved in cellular metabolic reprogramming by modulating gene expressions of enzymes including glycolysis pathway and oxygen utilization of mitochondria, we examined the functional role of HIF-1 activity in propofol-induced cell death. The role of HIF-1 activity on oxygen and energy metabolisms and propofol-induced cell death and caspase activity was examined in renal cell-derived RCC4 cells: RCC4-EV cells which lack von Hippel-Lindau protein (VHL) protein expression and RCC4-VHL cells, which express exogenous VHL, and in neuronal SH-SY5Y cells. It was demonstrated that HIF-1 is involved in suppressing oxygen consumption and facilitating glycolysis in cells and that the resistance to propofol-induced cell death was established in a HIF-1 activation-dependent manner. It was also demonstrated that HIF-1 activation by treatment with HIFα-hydroxylase inhibitors such as n-propyl gallate and dimethyloxaloylglycine, alleviated the toxic effects of propofol. Thus, the resistance to propofol toxicity was conferred by HIF-1 activation by not only genetic deletion of VHL but also exposure to HIFα-hydroxylase inhibitors

Short Baseline Neutrino Oscillation Experiments

8 pages, 1 figure, presented at "NuPhys2013 - prospects in neutrino physics", Institute of Physics, London, UK, Dec. 19-20, 201

Neutrino-nucleus cross sections for oscillation experiments

Neutrino oscillations physics is entered in the precision era. In this context accelerator-based neutrino experiments need a reduction of systematic errors to the level of a few percent. Today one of the most important sources of systematic errors are neutrino-nucleus cross sections which in the hundreds-MeV to few-GeV energy region are known with a precision not exceeding 20%. In this article we review the present experimental and theoretical knowledge of the neutrino-nucleus interaction physics. After introducing neutrino oscillation physics and accelerator-based neutrino experiments, we overview general aspects of the neutrino-nucleus cross sections, both theoretical and experimental views. Then we focus on these quantities in different reaction channels. We start with the quasielastic and quasielastic-like cross section, putting a special emphasis on multinucleon emission channel which attracted a lot of attention in the last few years. We review the main aspects of the different microscopic models for this channel by discussing analogies and differences among them.The discussion is always driven by a comparison with the experimental data. We then consider the one pion production channel where data-theory agreement remains very unsatisfactory. We describe how to interpret pion data, then we analyze in particular the puzzle related to the impossibility of theoretical models and Monte Carlo to simultaneously describe MiniBooNE and MINERvA experimental results. Inclusive cross sections are also discussed, as well as the comparison between the $\nu_\mu$ and $\nu_e$ cross sections, relevant for the CP violation experiments. The impact of the nuclear effects on the reconstruction of neutrino energy and on the determination of the neutrino oscillation parameters is reviewed. A window to the future is finally opened by discussing projects and efforts in future detectors, beams, and analysis

HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death

The local anesthetic lidocaine induces cell death by altering reactive oxygen species (ROS) generation and mitochondrial electron transport chain function. Because hypoxia-inducible factor 1 (HIF-1) is involved in determining oxygen metabolism and mitochondria function, we investigated the involvement of HIF-1 activity in lidocaine-induced cell death. We investigated the role of HIF activation on lidocaine-induced caspase activation and cell death in renal cell-derived RCC4 cells lacking functional von Hippel-Lindau (VHL) protein. We demonstrate that HIF-1 suppressed oxygen consumption and facilitated glycolysis in a pyruvate dehydrogenase kinase-1-dependent manner and that activation of HIF-1 conferred resistance to lidocaine-induced cell death. We also demonstrated that exogenous HIF-1 activation, through HIFα-hydroxylase inhibition or exposure to hypoxic conditions, alleviates lidocaine toxicity by suppressing mitochondria function and generating ROS, not only in RCC4 cells, but also in the neuronal SH-SY5Y cells. In conclusion, we demonstrate that HIF-1 activation due to VHL deletion, treatment with small molecule HIFα-hydroxylase inhibitors, and exposure to hypoxic conditions suppresses mitochondrial respiratory chain function and confers resistance to lidocaine toxicity

Surgeons’ involvement in COVID-19 treatment: a practice by a regional core hospital in Japan to avoid physician burnout

Abstract Background To prevent task accumulation on certain divisions, our institution developed a unique system of allocating inpatient treatment of COVID-19 patients to doctors who were not specialized in respiratory infections. The objective of this study was to investigate whether surgeons can be involved in the COVID-19 inpatient treatment without negatively affecting patient outcome, and how such involvement can affect the wellbeing of surgeons. Methods There were 300 patients diagnosed with COVID-19 and hospitalized from January to June 2021, and 160 of them were treated by the redeployed doctors. They were divided into 3 groups based on the affiliation of the treating doctor. Patient characteristics and outcomes were compared between the groups. In addition, the impact of COVID-19 duty on participating surgeons was investigated from multiple perspectives, and a postduty survey was conducted. Results There were 43 patients assigned to the Department of Surgery. There were no differences in the backgrounds and outcomes of patients compared with other groups. The surgeon’s overtime hours were significantly longer during the duty period, despite no change in the number of operations and the complication rate. The questionnaire revealed that there was a certain amount of mental and physical burden from the COVID-19 duty. Conclusion Surgeons can take part in inpatient COVID-19 treatment without affecting patient outcome. However, as such duty could negatively affect the surgeons’ physical and mental wellbeing, further effort is needed to maintain the balance of fulfilling individual and institutional needs

Toddaculin, Isolated from of <i>Toddalia asiatica</i> (L.) Lam., Inhibited Osteoclastogenesis in RAW 264 Cells and Enhanced Osteoblastogenesis in MC3T3-E1 Cells

<div><p>Osteoporosis with bone loss is widely recognized as a major health problem. Bone homeostasis is maintained by balancing bone formation and bone resorption. The imbalance caused by increased bone resorption over bone formation can lead to various bone-related diseases such as osteoporosis and rheumatoid arthritis. Osteoclasts are the principal cells responsible for bone resorption and the main targets of anti-resorptive therapies. However, excessive inhibition of osteoclast differentiation may lead to inhibition of osteoblast differentiation. Therefore, it is important to screen for new compounds capable of inhibiting bone resorption and enhancing bone formation. <i>Toddalia asiatica</i> (L.) Lam. has been utilized traditionally for medicinal purposes such as the treatment of rheumatism. Currently, the extract is considered to be a good source of pharmacological agents for the treatment of bone-related diseases, but the active compounds have yet to be identified. We investigated whether toddaculin, derived from <i>Toddalia asiatica</i> (L.) Lam., affects both processes by inhibiting bone resorption and enhancing bone formation. Towards this end, we used pre-osteoclastic RAW 264 cells and pre-osteoblastic MC3T3-E1 cells. We found that toddaculin not only inhibited the differentiation of osteoclasts via activation of the NF-κB, ERK 1/2, and p38 MAPK signaling pathways, but it also induced differentiation and mineralization of osteoblasts by regulating differentiation factors. Thus, toddaculin might be beneficial for the prevention and treatment of osteoporosis.</p></div