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Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.
Øystein Fluge, Olav Mella, Ove Bruland, Kristin Risa, Sissel E. Dyrstad, Kine Alme, Ingrid G. Rekeland, Dipak Sapkota, Gro V. Røsland, Alexander Fosså, Irini Ktoridou-Valen, Sigrid Lunde, Kari Sørland, Katarina Lien, Ingrid Herder, Hanne Thürmer, Merete E. Gotaas, Katarzyna A. Baranowska, Louis M.L.J. Bohnen, Christoph Schäfer, Adrian McCann, Kristian Sommerfelt, Lars Helgeland, Per M. Ueland, Olav Dahl, Karl J. Tronstad
Total views: 2508
While strongly implicated in postural tachycardia syndrome (POTS), considerable controversy exists regarding norepinephrine transporter (
Abdul Waheed Khan, Mark Ziemann, Susan J. Corcoran, Harikrishnan K.N, Jun Okabe, Haloom Rafehi, Scott S. Maxwell, Murray D. Esler, Assam El-Osta
Total views: 1485
Fructose has been implicated in the pathogenesis of obesity and type 2 diabetes. In contrast to glucose, CNS delivery of fructose in rodents promotes feeding behavior. However, because circulating plasma fructose levels are exceedingly low, it remains unclear to what extent fructose crosses the blood-brain barrier to exert CNS effects. To determine whether fructose can be endogenously generated from glucose via the polyol pathway (glucose → sorbitol → fructose) in human brain, 8 healthy subjects (4 women/4 men; age, 28.8 ± 6.2 years; BMI, 23.4 ± 2.6; HbA1C, 4.9% ± 0.2%) underwent 1H magnetic resonance spectroscopy scanning to measure intracerebral glucose and fructose levels during a 4-hour hyperglycemic clamp (plasma glucose, 220 mg/dl). Using mixed-effects regression model analysis, intracerebral glucose rose significantly over time and differed from baseline at 20 to 230 minutes. Intracerebral fructose levels also rose over time, differing from baseline at 30 to 230 minutes. The changes in intracerebral fructose were related to changes in intracerebral glucose but not to plasma fructose levels. Our findings suggest that the polyol pathway contributes to endogenous CNS production of fructose and that the effects of fructose in the CNS may extend beyond its direct dietary consumption.
Janice J. Hwang, Lihong Jiang, Muhammad Hamza, Feng Dai, Renata Belfort-DeAguiar, Gary Cline, Douglas L. Rothman, Graeme Mason, Robert S. Sherwin
Total views: 1222
Wiebke Arlt, Katharina Lang, Alice J. Sitch, Anna S. Dietz, Yara Rhayem, Irina Bancos, Annette Feuchtinger, Vasileios Chortis, Lorna C. Gilligan, Philippe Ludwig, Anna Riester, Evelyn Asbach, Beverly A. Hughes, Donna M. O’Neil, Martin Bidlingmaier, Jeremy W. Tomlinson, Zaki K. Hassan-Smith, D. Aled Rees, Christian Adolf, Stefanie Hahner, Marcus Quinkler, Tanja Dekkers, Jaap Deinum, Michael Biehl, Brian G. Keevil, Cedric H.L. Shackleton, Jonathan J. Deeks, Axel K. Walch, Felix Beuschlein, Martin Reincke
Total views: 822
Biliary atresia is an obstructive cholangiopathy of infancy that progresses to end-stage cirrhosis. Although the pathogenesis of the disease is not completely understood, previous reports link TNFα to apoptosis of the bile duct epithelium in the presence of IFNγ. Here, we investigate if TNFα signaling regulates pathogenic mechanisms of biliary atresia. First, we quantified the expression of
Pranavkumar Shivakumar, Tatsuki Mizuochi, Reena Mourya, Sridevi Gutta, Li Yang, Zhenhua Luo, Jorge A. Bezerra
Total views: 709
Surgery can induce cognitive decline, a risk that increases with advancing age. In rodents, postoperative cognitive decline (POCD) is associated with the inflammatory activation of hippocampal microglia. To examine the role of microglia in POCD, we inhibited the colony-stimulating factor 1 receptor (CSF1R) in adult mice, effectively depleting CNS microglia. Surgical trauma (tibial fracture) reduced the ability of mice to remember a conditioned response learned preoperatively, a deficit more pronounced and persistent in mice with diet-induced obesity (DIO). Whereas microglial depletion by itself did not affect learning or memory, perioperative microglial depletion remarkably protected mice, including those with DIO, from POCD. This protection was associated with reduced hippocampal levels of inflammatory mediators, abrogation of hippocampal recruitment of CCR2+ leukocytes, and higher levels of circulating inflammation-resolving factors. Targeting microglia may thus be a viable strategy to mitigate the development of POCD, particularly in those with increased vulnerability.
Xiaomei Feng, Martin Valdearcos, Yosuke Uchida, David Lutrin, Mervyn Maze, Suneil K. Koliwad
Total views: 692
The sympathetic nervous system (SNS) accelerates heart rate, increases cardiac contractility, and constricts resistance vessels. The activity of SNS efferent nerves is generated by a complex neural network containing neurons and glia. Gq G protein–coupled receptor (Gq-GPCR) signaling in glial fibrillary acidic protein–expressing (GFAP+) glia in the central nervous system supports neuronal function and regulates neuronal activity. It is unclear how Gq-GPCR signaling in GFAP+ glia affects the activity of sympathetic neurons or contributes to SNS-regulated cardiovascular functions. In this study, we investigated whether Gq-GPCR activation in GFAP+ glia modulates the regulatory effect of the SNS on the heart; transgenic mice expressing Gq-coupled DREADD (designer receptors exclusively activated by designer drugs) (hM3Dq) selectively in GFAP+ glia were used to address this question in vivo. We found that acute Gq-GPCR activation in peripheral GFAP+ glia significantly accelerated heart rate and increased left ventricle contraction. Pharmacological experiments suggest that the glial-induced cardiac changes were due to Gq-GPCR activation in satellite glial cells within the sympathetic ganglion; this activation led to increased norepinephrine (NE) release and beta-1 adrenergic receptor activation within the heart. Chronic glial Gq-GPCR activation led to hypotension in female
Alison Xiaoqiao Xie, Jakovin J. Lee, Ken D. McCarthy
Total views: 621
Victor Gura, Matthew B. Rivara, Scott Bieber, Raj Munshi, Nancy Colobong Smith, Lori Linke, John Kundzins, Masoud Beizai, Carlos Ezon, Larry Kessler, Jonathan Himmelfarb
Total views: 569
In each influenza season, a distinct group of young, otherwise healthy individuals with no risk factors succumbs to life-threatening infection. To better understand the cause for this, we analyzed a broad range of immune responses in blood from a unique cohort of patients, comprising previously healthy individuals hospitalized with and without respiratory failure during one influenza season, and infected with one specific influenza A strain. This analysis was compared with similarly hospitalized influenza patients with known risk factors (total of
Suzanne L. Cole, Jake Dunning, Wai Ling Kok, Kambez Hajipouran Benam, Adel Benlahrech, Emmanouela Repapi, Fernando O. Martinez, Lydia Drumright, Timothy J. Powell, Michael Bennett, Ruth Elderfield, Catherine Thomas, MOSAIC investigators, Tao Dong, John McCauley, Foo Y. Liew, Stephen Taylor, Maria Zambon, Wendy Barclay, Vincenzo Cerundolo, Peter J. Openshaw, Andrew J. McMichael, Ling-Pei Ho
Total views: 454
Adoptive immunotherapy for solid tumors relies on infusing large numbers of T cells to mediate successful antitumor responses in patients. While long-term rapid-expansion protocols (REPs) produce sufficient numbers of CD8+ T cells for treatment, they also cause decline in the cell’s therapeutic fitness. In contrast, we discovered that IL-17–producing CD4+ T cells (Th17 cells) do not require REPs to expand 5,000-fold over 3 weeks. Also, unlike Th1 cells, Th17 cells do not exhibit hallmarks of senescence or apoptosis, retaining robust antitumor efficacy in vivo. Three-week-expanded Th17 cells eliminated melanoma as effectively as Th17 cells expanded for 1 week when infused in equal numbers into mice. However, treating mice with large recalcitrant tumors required the infusion of all cells generated after 2 or 3 weeks of expansion, while the cell yield obtained after 1-week expansion was insufficient. Long-term-expanded Th17 cells also protected mice from tumor rechallenge including lung metastasis. Importantly, 2-week-expanded human chimeric antigen receptor–positive (CAR+) Th17 cells also retained their ability to regress human mesothelioma, while CAR+ Th1 cells did not. Our results indicate that tumor-reactive Th17 cells are an effective cell therapy for cancer, remaining uncompromised when expanded for a long duration owing to their resistance to senescence.
Jacob S. Bowers, Michelle H. Nelson, Kinga Majchrzak, Stefanie R. Bailey, Baerbel Rohrer, Andrew D.M. Kaiser, Carl Atkinson, Luca Gattinoni, Chrystal M. Paulos
Total views: 450