Gracesomerville4112

Inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in various cellular functions including neuroprotection. Absence of IP6K2 causes impairment of oxidative phosphorylation regulated by creatine kinase-B. In the present study, we show that IP6K2 is involved in attenuation of PINK1-mediated mitochondrial autophagy (mitophagy) in the brain. Up-regulation of dynamin-related protein (Drp-1), as well as increased expression of mitochondrial biogenesis markers (PGC1-α and NRF-1) in the cerebella of IP6K2-deleted mice (IP6K2-knockout), point to the involvement of IP6K2 in the regulation of mitochondrial fission. Knockdown of IP6K2 also leads to augmented glycolysis, potentially as a compensatory mechanism for decreased mitochondrial respiration. Overexpressing IP6K2 as well as IP6K2-kinase dead mutant in IP6K2-knockdown N2A cells reverses the expression of mitophagy markers, demonstrating that IP6K2-induced mitoprotection is catalytically/kinase independent. IP6K2 supplementation in K2-PINK1 double-knockdown N2A cells fails to reverse the expression of the mitophagic marker, LC3-II, indicating that the mitoprotective effect of IP6K2 is dependent on PINK1. Overall, our study reveals a key neuroprotective role of IP6K2 in the prevention of PINK1-mediated mitophagy in the brain.The receptor for colony stimulating factor 1 (CSF-1R) is important for the survival and function of myeloid cells that mediate pathology during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). CSF-1 and IL-34, the ligands of CSF-1R, have similar bioactivities but distinct tissue and context-dependent expression patterns, suggesting that they have different roles. This could be the case in EAE, given that CSF-1 expression is up-regulated in the CNS, while IL-34 remains constitutively expressed. We found that targeting CSF-1 with neutralizing antibody halted ongoing EAE, with efficacy superior to CSF-1R inhibitor BLZ945, whereas IL-34 neutralization had no effect, suggesting that pathogenic myeloid cells were maintained by CSF-1. Both anti–CSF-1 and BLZ945 treatment greatly reduced the number of monocyte-derived cells and microglia in the CNS. However, anti–CSF-1 selectively depleted inflammatory microglia and monocytes in inflamed CNS areas, whereas BLZ945 depleted virtually all myeloid cells, including quiescent microglia, throughout the CNS. Anti–CSF-1 treatment reduced the size of demyelinated lesions and microglial activation in the gray matter. Lastly, we found that bone marrow–derived immune cells were the major mediators of CSF-1R–dependent pathology, while microglia played a lesser role. Our findings suggest that targeting CSF-1 could be effective in ameliorating MS pathology, while preserving the homeostatic functions of myeloid cells, thereby minimizing risks associated with ablation of CSF-1R–dependent cells.microRNA (miRNA)–mediated gene regulation has been studied as a therapeutic approach, but its functional regulatory mechanism in neuropathic pain is not well understood. Dynasore Here, we identify that miRNA-32-5p (miR-32-5p) is a functional RNA in regulating trigeminal-mediated neuropathic pain. High-throughput sequencing and qPCR analysis showed that miR-32-5p was the most down-regulated miRNA in the injured trigeminal ganglion (TG) of rats. Intra-TG injection of miR-32-5p agomir or overexpression of miR-32-5p by lentiviral delivery in neurons of the injured TG attenuated established trigeminal neuropathic pain. miR-32-5p overexpression did not affect acute physiological pain, while miR-32-5p down-regulation in intact rats was sufficient to cause pain-related behaviors. Nerve injury increased the methylated histone occupancy of binding sites for the transcription factor glucocorticoid receptor in the miR-32-5p promoter region. Inhibition of the enzymes that catalyze H3K9me2 and H3K27me3 restored the expression of miR-32-5p and markedly attenuated pain behaviors. Further, miR-32-5p–targeted Cav3.2 T-type Ca2+ channels and decreased miR-32-5p associated with neuropathic pain caused an increase in Cav3.2 protein expression and T-type channel currents. Conversely, miR-32-5p overexpression in injured TG suppressed the increased expression of Cav3.2 and reversed mechanical allodynia. Together, we conclude that histone methylation-mediated miR-32-5p down-regulation in TG neurons regulates trigeminal neuropathic pain by targeting Cav3.2 channels.An ongoing controversy in brain metabolism is whether increases in neural activity cause a local and rapid decrease in oxygen concentration (i.e., the “initial dip”) preceding functional hyperemia. This initial dip has been suggested to cause a transient increase in vascular deoxyhemoglobin with several imaging techniques and stimulation paradigms, but not consistently. Here, we investigate contributors to this initial dip in a distinct neuronal network, an olfactory bulb (OB) glomerulus most sensitive to a specific odorant (ethyl tiglate [ET]) and a site of strong activation and energy consumption upon ET stimulation. Combining two-photon fluorescence and phosphorescence lifetime microscopy, and calcium, blood flow, and pO2 measurements, we characterized this initial dip in pO2 in mice chronically implanted with a glass cranial window, during both awake and anesthetized conditions. In anesthetized mice, a transient dip in vascular pO2 was detected in this glomerulus when functional hyperemia was slightly delayed, but its amplitude was minute (0.3 SD of resting baseline). This vascular pO2 dip was not observed in other glomeruli responding nonspecifically to ET, and it was poorly influenced by resting pO2. In awake mice, the dip in pO2 was absent in capillaries as well as, surprisingly, in the neuropil. These high-resolution pO2 measurements demonstrate that in awake mice recovered from brain surgery, neurovascular coupling was too fast and efficient to reveal an initial dip in pO2.Prostate epithelial cells have the unique capacity to secrete large amounts of citrate, but the carbon sources and metabolic pathways that maintain this production are not well known. We mapped potential pathways for citrate carbons in the human prostate cancer metastasis cell lines LNCaP and VCaP, for which we first established that they secrete citrate (For LNCaP 5.6 ± 0.9 nmol/h per 106 cells). Using 13C-labeled substrates, we traced the incorporation of 13C into citrate by NMR of extracellular fluid. Our results provide direct evidence that glucose is a main carbon source for secreted citrate. We also demonstrate that carbons from supplied glutamine flow via oxidative Krebs cycle and reductive carboxylation routes to positions in secreted citrate but likely do not contribute to its net synthesis. The potential anaplerotic carbon sources aspartate and asparagine did not contribute to citrate carbons. We developed a quantitative metabolic model employing the 13C distribution in extracellular citrate after 13C glucose and pyruvate application to assess intracellular pathways of carbons for secreted citrate. From this model, it was estimated that in LNCaP about 21% of pyruvate entering the Krebs cycle is converted via pyruvate carboxylase as an anaplerotic route at a rate more than sufficient to compensate carbon loss of this cycle by citrate secretion. This model provides an estimation of the fraction of molecules, including citrate, leaving the Krebs cycle at every turn. The measured ratios of 13C atoms at different positions in extracellular citrate may serve as biomarkers for (malignant) epithelial cell metabolism.Ferroptosis is a novel form of cell death characterized by the iron-dependent accumulation of lipid peroxides and is different from other types of cell death. The mechanisms of ferroptosis are discussed in the review, including System Xc-, Glutathione Peroxidase 4 pathway, Ferroptosis Suppressor Protein 1 and Dihydroorotate Dehydrogenase pathway. Ferroptosis is associated with the occurrence of various diseases, including sepsis. Research in recent years has displayed that ferroptosis is involved in sepsis occurrence and development. Iron chelators can inhibit the development of sepsis and improve the survival rate of septic mice. The ferroptotic cells can release damage-associated molecular patterns and lipid peroxidation, which further mediate inflammatory responses. Ferroptosis inhibitors can resist sepsis-induced multiple organ dysfunction and inflammation. Finally, we reviewed ferroptosis, an iron-dependent form of cell death that is different from other types of cell death in biochemistry, morphology, and major regulatory mechanisms, which is involved in multiple organ injuries caused by sepsis. Exploring the relationship between sepsis and ferroptosis may yield new treatment targets for sepsis.Many studies have assessed the factors associated with overall video visit use during the COVID-19 pandemic, but little is known about who is most likely to continue to use video visits and why. The authors combined a survey with electronic health record data to identify factors affecting the continued use of video visit. In August 2020, a stratified random sample of 20,000 active patients from a large health care system were invited to complete an email survey on health care seeking preferences during the COVID. Weighted logistic regression models were applied, adjusting for sampling frame and response bias, to identify factors associated with video visit experience, and separately for preference of continued use of video visits. Actual video visit utilization was also estimated within 12 months after the survey. Three thousand three hundred fifty-one (17.2%) patients completed the survey. Of these, 1208 (36%) reported having at least 1 video visit in the past, lowest for African American (33%) and highest for Hispanic (41%). Of these, 38% would prefer a video visit in the future. The strongest predictors of future video visit use were comfort using video interactions (odds ratio [OR] = 5.30, 95% confidence interval [95% CI] 3.57-7.85) and satisfaction with the overall quality (OR = 3.94, 95% CI 2.66-5.86). Interestingly, despite a significantly higher satisfaction for Hispanic (40%-55%) and African American (40%-50%) compared with Asian (29%-39%), Hispanic (OR = 0.46, 95% CI 0.12-0.88) and African American (OR = 0.54, 95% CI 0.16-0.90) were less likely to prefer a future video visit. Disparity exists in the use of video visit. The association between patient satisfaction and continued video visit varies by race/ethnicity, which may change the future long-term video visit use among race/ethnicity groups.In the United States, the top 1% and top 5% of health care spenders account for 23% and 50% of total health care spending, respectively. These high spenders have been coined the term super utilizers (SU). The aim of this study was to identify the characteristics associated with these patients to aid in developing public health interventions aimed at transitioning patients out of the SU category and thus ultimately helping to control health care costs. The authors utilized the Utah All-Payer Claims Database and Utah Population Database from 2013 to 2015 to identify demographics, comorbid conditions, health care utilization, and cost characteristics of persistent super utilizers (PSU) (≥3 hospitalizations per year for 3 years) of health care compared with persistent nonsuper utilizers (PNSU) ( less then 3 hospitalizations per year for 3 years). Multivariable logistic regression was utilized to identify the characteristics associated with PSU versus PNSU. Higher outpatient/Emergency Department/noninpatient (eg, visits with imaging and Centers for Medicare & Medicaid Services preventive visits) health care utilization and spending, and prevalence of comorbid disease and psychosocial conditions were associated with PSU.