Glucose - effects on survival in Listeria and influenza infection

[2020-07-03]
Presentation by Ruslan Medzhitov from 2018 titled "Inflammation and Disease Tolerance: Surviving Acute Illness"
1:25 cost of inflammation and cost vs. benefit trade-off
4:01 sickness behaviors, includes loss of appetite - observed in all animals including insects 
5:10 Decreased Food Intake After Listeria Infection - disease induced anorexia 
6:32 Anorexia Protects Against Listeria Infection (survival rate) 
7:43 Glucose is Sufficient for Lethality in Listeria Infection - even at only 2% of normal caloric intake 8:26 2DG (inhibits metabolism of glucose) increased survivorship (100% survival vs. 50% without 2DG) 
9:06 Effects of Feeding on Sepsis Survival - sepsis model using lipopolysaccharide (LPS) injection - same results found for feeding, glucose and 2DG experiments 
11:10 Effects of Glucose in LPS Sepsis is Independent of Magnitude of Inflammation 
11:48 Mechanism for Glucose-mediated Death in Bacterial Inflammation - review of fasting metabolism - PPAR alpha, ketogenesis, FGF21
14:18 Glucose Supplementation Suppresses LPS-induced Lypolysis and Ketogenesis
15:09 PPAR alpha and Ketogenic Program are Required for Surviving Bacterial Inflammation - PPARa and FGF21 and necessary for survival 
16:09 LPS sepsis induced oxidative stress in midbrain - incleased by glucose and decreased by 2DG ; increase in glucose uptake in midbrain shown on PET scan 
16:53 Death from LPS sepsis is preceded by convulsions ; can anti-epileptics prevent death by LPS sepsis? 
17:21 anti-epileptic drug valpoic acid rescues mice from LPS sepsis death, but not Keppra 
17:44 Valproic acid protects / 2dg does not protect in PPAR alpla knockout mice 
18:30 Summary of Part 1 - ketones and valproic acid acting as HDAC inhibitors 
20:20 Critical Role of Glucose Maintenance in Bacterial Sepsis - too little glucose also causes increased mortality
21:28 How does Feeding Affect Viral Inflammation? - mouse model of influenza infection
22:24 Feeding is Protective in Influenza Infection 
22:41 Glucose Partially Protects Against Mortality in Influenza Infection - "the rest of the protection is provided by sodium" 
22:57 Inhibition of Glucose Utilization is Lethal in Influenza Infection - (inhibited by 2DG)
23:13 Inhibiting Glucose Does not Affect Lung Pathology in [flu] 
23:47 Effect if Glucose Inhibition on [flu] Independent of [degree of] Inflammation and Viral Burden 24:20 Death from viral inflammation due to reduction in autonomic function; PET scan shows glucose preferentially taken up in brain stem 
25:04 Viral Infection and ER (Endoplasmic Reticulum) Stress - UPR > CHOP (Ddit3) > apoptosis - lack of glucose for protein glycosylation can cause ER stress 
26:35 Inhibition of Glucose Utilization in the Context of Viral Inflammation Induces CHOP in the Brain Stem - Poly(I:C) - mimics viral inflammation 
27:09 CHOP Deficiency is Sufficient to Protect Against POLY(I:C) + 2DG Mortality 
28:02 Summary Part II

Comments

Post a Comment

Popular posts from this blog

Notes - week of 2020/10/26

 Learned about PON1 and PD yesterday by attending web conference presentation by Beate Ritz: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922777/ Anthocyanins increase PON1 and are thought to protective against PD, but they also increase NO production - hmm .... ~ Vitamin D levels are decreased in PD: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267215/ "After the discovery that the VDR and 1α-hydroxylase, the enzyme that converts vitamin D to its active form, were highly expressed in the substantia nigra, it was hypothesized that inadequate levels of circulating vitamin D may lead to dysfunction or cell death within the substantia nigra ( 25 , 26 )." Active vit D (calcitriol) is mainly produced in the kidneys, as is klotho. a-syn is produced in the kidneys throughout lifespan.  ~ Chronic kidney disease prevalence is lower in PD patients: https://www.mdsabstracts.org/abstract/prevalence-of-chronic-kidney-disease-in-patients-with-idiopathic-parkinsons-disease-in-a-tertia
Read more

mouse models of menopause / reproductive aging in social insects - brief notes

Image
    Another in a great series of webinars by NUS Medicine. 5:10 Start of 1st presentation - Berenice A. Benayoun - Why we need age-relevant mouse models of menopause Ovariectomized mice are not good models of menopause.  10:43 Slide - comparison of post-reproductive lifespan among mammalian species 18:46 VCD injection; VCD is 4-vinylcyclohexene diepoxide, an environmental toxicant that causes ovarian failure 20:31 Genetic models - Foxl2 +/- ; Fshr +/- 25:00 Start of 2nd presentation - Ingrid Fetter Pruneda - The molecular and cellular basis of high fertility in social insects Queen ants manage to have extremely high fertility at the same time as longer lifespan relative to worker ants. 35:20 ant reproductive mode can be flexible; some species have cyclic castes - switching from queen to worker and back 51:54 Apart from sex organs,  liver is most sexually dimorphic organ - important implications for drug metabolism { Does this have implications for liver transplantation? }
Read more

Aconitase

Image
Aconitase (aconitate hydratase) is a tricarboxylic acid cycle (TCA) enzyme that converts citrate to iso-citrate via cis-aconitate. It has an iron sulfur cluster that interacts directly with substrate and is prone to oxidation by superoxide. Inactivation of aconitase has been  implicated in neurodegenerative diseases [1]. A mutation in ACO2 is associated with Infantile Cerebellar-Retinal Degeneration [2]. from [2] : "The active (4Fe-4S) cluster was shown to be extremely sensitive to superoxide-mediated inactivation 10 and a decrease in AH activity was observed in several neurodegenerative diseases associated with the development of oxidative stress, in particular Friedreich ataxia [MIM 229300 ], Parkinson [MIM 168600 ], and Alzheimer disease [MIM 104300 ], 11 as well as in mice lacking mitochondrial superoxide dismutase. 12 The reduced AH activity in endomyocardial biopsies of individuals with Friedreich ataxia was attributed not only to oxidative stress but also to the im
Read more

Freidriech ataxia - biochemical mechanisms

Image
Yesterday I watched two excellent presentations on Freidreich ataxia (still trying to use the proper nomenclature convention) from back in 2011: Notes: 5:44 frataxin is essential for muticellular eukaryotes (but not single celled organisms) frataxin is needed for the production of iron-sulfur clusters (aconitase is an important TCA enzyme that includes an iron-sulfur cluster that is particularly vulnerable to oxidation) 13:07 Indeed! & also part of the urea cycle 18:35 Reduction in frataxin leads to iron accumulation in the mitochondrion   38:26 summary of therapeutic approaches in relation to hypothetical vicious cycle in FA EPO - erythropoietin increases expression of genes related to iron utilization (lactoferrin and Wim Hof method breathing increase EPO) HDAC inhibitors increase expression of frataxin (butyrate / tributyrin are HDACi) pioglitozone increases mitochondrial biogenesis (PQQ & urolithin A do the same) I think neuroinflammation should be included as part
Read more