- Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis. [Journal Article]
- STSci Transl Med 2018 Feb 07; 10(427)
- We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic ost...
We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human-like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital orN-acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA.
- Intermediary Metabolism and Fatty Acid Oxidation: Novel Targets of Electron Transport Chain Driven Injury During Ischemia and Reperfusion. [Journal Article]
- AJAm J Physiol Heart Circ Physiol 2017 Dec 29
- CONCLUSIONS: Thus, following IR, not only the ETC, but multiple pathways of intermediary metabolism sustain damage initiated by the ETC. If these damaged mitochondria persist in the myocyte, they remain a potent stimulus for ongoing injury and the transition to cardiomyopathy during prolonged reperfusion. Modulation of ETC function during early reperfusion is a key strategy to preserve mitochondrial metabolism and to decrease persistent mitochondria-driven injury during longer periods of reperfusion that predispose to ventricular dysfunction and heart failure.
- The safety and efficacy of propofol as a replacement for amobarbital in intracarotid Wada testing of presurgical patients with epilepsy. [Journal Article]
- EBEpilepsy Behav 2018; 78:25-29
- CONCLUSIONS: These findings support previous studies indicating that propofol is as safe and efficacious as amobarbital, and can continue to be used in Wada procedures with confidence.
- Inhibition of mitochondrial complex I improves glucose metabolism independently of AMPK activation. [Journal Article]
- JCJ Cell Mol Med 2018; 22(2):1316-1328
- Accumulating evidences showed metformin and berberine, well-known glucose-lowering agents, were able to inhibit mitochondrial electron transport chain at complex I. In this study, we aimed to explore...
Accumulating evidences showed metformin and berberine, well-known glucose-lowering agents, were able to inhibit mitochondrial electron transport chain at complex I. In this study, we aimed to explore the antihyperglycaemic effect of complex I inhibition. Rotenone, amobarbital and gene silence of NDUFA13 were used to inhibit complex I. Intraperitoneal glucose tolerance test and insulin tolerance test were performed in db/db mice. Lactate release and glucose consumption were measured to investigate glucose metabolism in HepG2 hepatocytes and C2C12 myotubes. Glucose output was measured in primary hepatocytes. Compound C and adenoviruses expressing dominant negative AMP-activated protein kinase (AMPK) α1/2 were exploited to inactivate AMPK pathway. Cellular NAD+/NADH ratio was assayed to evaluate energy transforming and redox state. Rotenone ameliorated hyperglycaemia and insulin resistance in db/db mice. It induced glucose consumption and glycolysis and reduced hepatic glucose output. Rotenone also activated AMPK. Furthermore, it remained effective with AMPK inactivation. The enhanced glycolysis and repressed gluconeogenesis correlated with a reduction in cellular NAD+/NADH ratio, which resulted from complex I suppression. Amobarbital, another representative complex I inhibitor, stimulated glucose consumption and decreased hepatic glucose output in vitro, too. Similar changes were observed while expression of NDUFA13, a subunit of complex I, was knocked down with gene silencing. These findings reveal mitochondrial complex I emerges as a key drug target for diabetes treatment. Inhibition of complex I improves glucose homoeostasis via non-AMPK pathway, which may relate to the suppression of the cellular NAD+/NADH ratio.
- Assessment of grammar optimizes language tasks for the intracarotid amobarbital procedure. [Journal Article]
- EBEpilepsy Behav 2017; 76:89-100
- CONCLUSIONS: The results may be significant for individuals with epilepsy undergoing IAP. The grammar tests may be a highly efficient measure for lateralizing language function in the recovery phase.
- Comparing the Intracarotid Amobarbital Test and Functional MRI for the Presurgical Evaluation of Language in Epilepsy. [Review]
- CNCurr Neurol Neurosci Rep 2017; 17(7):54
- Surgery is the treatment of choice for drug-resistant temporal lobe epilepsy (TLE). However, such surgery frequently causes deficits in language function, especially if performed on the dominant hemi...
Surgery is the treatment of choice for drug-resistant temporal lobe epilepsy (TLE). However, such surgery frequently causes deficits in language function, especially if performed on the dominant hemisphere. In recent years, the intracarotid amobarbital test (IAT) has been gradually replaced by functional magnetic resonance imaging (fMRI) in the preoperative identification of language areas to estimate the risk of postoperative language decline. In this paper, we review the neural substrates for language processing, how language impairment can result both from TLE itself and from surgical attempts to treat it. Subsequently, we discuss the strengths and limitations of, and current indications for fMRI and IAT during the preoperative workup, both by discussion of the studies that have evaluated them individually and through meta-analysis of data from 31 studies deemed eligible for analysis. Electrocortical stimulation mapping (ESM) is also discussed, as is the usefulness of the novel technique of resting-state fMRI. Finally, surgical techniques designed to avoid or reduce language decline in patients at risk are explored.
- Ruptured Distal Anterior Choroidal Artery Aneurysm Treated with Superselective Provocative Testing and Coil Embolization. [Case Reports]
- WNWorld Neurosurg 2017; 105:1032.e19-1032.e22
- CONCLUSIONS: Endovascular coil embolization for distal anterior choroidal artery aneurysms is technically feasible and may be preferable to embolization with liquid embolic agents for lesions proximal to the plexal point. This case illustrates the utility of provocative testing and efficacy of endovascular coil embolization for lesions in this unique location.
- Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. [Practice Guideline]
- NeurNeurology 2017 Jan 24; 88(4):395-402
- CONCLUSIONS: The use of fMRI may be considered an option for lateralizing language functions in place of intracarotid amobarbital procedure (IAP) in patients with medial temporal lobe epilepsy (MTLE; Level C), temporal epilepsy in general (Level C), or extratemporal epilepsy (Level C). For patients with temporal neocortical epilepsy or temporal tumors, the evidence is insufficient (Level U). fMRI may be considered to predict postsurgical language deficits after anterior temporal lobe resection (Level C). The use of fMRI may be considered for lateralizing memory functions in place of IAP in patients with MTLE (Level C) but is of unclear utility in other epilepsy types (Level U). fMRI of verbal memory or language encoding should be considered for predicting verbal memory outcome (Level B). fMRI using nonverbal memory encoding may be considered for predicting visuospatial memory outcomes (Level C). Presurgical fMRI could be an adequate alternative to IAP memory testing for predicting verbal memory outcome (Level C). Clinicians should carefully advise patients of the risks and benefits of fMRI vs IAP during discussions concerning choice of specific modality in each case.
- 5-Hydroxy-1,4-naphthalenedione exerts anticancer effects on glioma cells through interaction with the mitochondrial electron transport chain. [Journal Article]
- NLNeurosci Lett 2017 Feb 03; 639:207-214
- Survival of patients with glioblastoma remains within the range of several months despite advances in therapeutic options. We have already shown that 5-hydroxy-1,4-naphthalenedione (juglone) exerts a...
Survival of patients with glioblastoma remains within the range of several months despite advances in therapeutic options. We have already shown that 5-hydroxy-1,4-naphthalenedione (juglone) exerts antiproliferative, anti-invasive, and cytotoxic effects on glioma C6 cells. Here, we further revealed that juglone is relatively selective to glioma cells as compared to the normal glial culture, and investigated its mechanisms of action. The incubation of glioma C6 cells with juglone generated high levels of reactive oxygen species (ROS). The produced ROS accounted for the anticancer effect of juglone as antioxidant N-acetylcysteine reduced both cytotoxic and antiproliferative activities of juglone. Furthermore, high resolution respirometry revealed that juglone decreased oxygen consumption mainly by affecting pyruvate/malate- and glutamate/malate-induced mitochondrial respiration. The inhibition of respiratory complex I by amytal decreased juglone-triggered generation of ROS and diminished its anticancer activity. Thus, our results indicate that juglone generates ROS through interaction with respiratory complex I in glioma C6 cells, and, in turn, induces the anticancer effects.
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- [Attempted suicide with barbiturates purchased online]. [Journal Article]
- NTNed Tijdschr Geneeskd 2016; 160(0):D491
- CONCLUSIONS: In patients with coma, respiratory depression, absence of brainstem reflexes and shock with no evident cause one should be aware of the possibility of barbiturate intoxication, even when there is no indication that these have been prescribed or that the patient has direct or indirect access to barbiturates. Prompt, optimal supportive therapy will give a good chance of full somatic recovery.