Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites . Hibernation in thirteen-lined ground squirrels (TLGS), , provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage . Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and α-ketoglutarate-αKG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cells and in mice subjected to permanent ischemic stroke . Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.
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http://dx.doi.org/10.1101/2023.03.29.534718 | DOI Listing |
Vasc Med
December 2024
Vascular & Interventional Specialists of Orange County, Orange, CA, USA.
Background: Preclinical studies have demonstrated that therapeutic ultrasound (TUS) increases perfusion in peripheral artery disease (PAD). This pilot study assessed the safety and effectiveness of a noninvasive TUS device in patients with advanced PAD.
Methods: A phased array of TUS transducers was fabricated on a wearable sleeve, designed to sonicate the posterior and anterior tibial arteries (and their collaterals) at the calf level.
Arthritis Rheumatol
December 2024
Division of Rheumatology, University of California Los Angeles, Los Angeles, CA, USA.
Giant cell arteritis (GCA) is a relapsing large-vessel vasculitis with risk of serious ischemic manifestations including vision loss and vascular damage in the form of large-artery stenosis, aneurysms and dissections. Approximately 50% of patients treated with glucocorticoid (GC) monotherapy and 30% of patients receiving adjunctive therapy with tocilizumab experience disease relapses, often during the first 2 years after diagnosis. Although most relapses in GCA do not involve life- or organ-threatening presentations and can be controlled successfully, frequent relapses may lead to increased use of GC and consequent treatment-related morbidity, in addition to risk of further vascular damage.
View Article and Find Full Text PDFVet Surg
December 2024
Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, USA.
Objectives: To compare end-to-side (ES) and side-to-side (SS) jejunocecostomy (JC) in healthy horses.
Study Design: Experimental study in vivo.
Animals: A total of 14 healthy adult horses underwent ventral midline celiotomy, a resection, and either an ES (n = 7) or stapled SS (n = 7) JC.
Cell Death Dis
December 2024
Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Neuronal necroptosis appears to be suppressed by the deubiquitinating enzyme A20 and is capable to regulate the polarization of microglia/macrophages after cerebral ischemia. We have demonstrated that hypoxic preconditioning (HPC) can alleviate receptor interacting protein 3 (RIP3)-induced necroptosis in CA1 after transient global cerebral ischemia (tGCI). However, it is still unclear whether HPC serves to regulate the phenotypic polarization of microglia/macrophages after cerebral ischemia by mitigating neuronal necroptosis.
View Article and Find Full Text PDFCirc Cardiovasc Interv
December 2024
Cardiovascular Clinical Research Center, Department of Medicine, NYU Grossman School of Medicine, New York, NY (H.R.R., L.P., S.B., J.S.H.).
Background: The relationship between the extent and severity of stress-induced ischemia and the extent and severity of anatomic coronary artery disease (CAD) in patients with obstructive CAD is multifactorial and includes the intensity of stress achieved, type of testing used, presence and extent of prior infarction, collateral blood flow, plaque characteristics, microvascular disease, coronary vasomotor tone, and genetic factors. Among chronic coronary disease participants with site-determined moderate or severe ischemia, we investigated associations between ischemia severity on stress testing and the extent of CAD on coronary computed tomography angiography.
Methods: Clinically indicated stress testing included nuclear imaging, echocardiography, cardiac magnetic resonance imaging, or nonimaging exercise tolerance test.
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