Authentic Biochemistry

If  γ-aminobutyric acid (GABA) concentration drops significantly in the synaptic cleft, excitotoxicity can obtain, sometimes presenting with epileptic convulsions.This can be reversed by decreasing the concentration of L-glutamate via control over the activity of glutamate dehydrogenase, glutamine synthetase and glutamate transporters or by  the inhibition of  γ-aminobutyric acid aminotransferase (GABA-AT), which catalyzes the conversion of GABA to the excitatory neurotransmitter l-glutamic acid. Trends in Cell Biology 2020. 30.6: 440-451. Chem. Rev. 2018. 118. 7: 4037–4070 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

A basic lecture on reactive oxygen synthesis and reduction coupled with glutathione, folic acid and amino acid metabolism. This lecture is foundational for subsequent synthesis with neural transmission, microglial activation and exicitotoxicity leading to neurodegeneration in the aging human CNS. Please subscribe, rate and review, and  contribute to Authentic Biochemistry! djgphd@gmail.com Published 9 March 2021 by Dr Daniel J. Guerra. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

CPS-1 activity is regulated by liver enriched transcription factors as well as Sirtuin-mediated de-acylation. Glutaminase breaks down glutamine into glutamate and ammonia. Glutamate also yields additional NH4+ via the enzyme glutamate dehydrogenase. From here, ammonia is initially incorporated into hepatocyte mitochondria and ultimately results in the formation of urea. Urea subsequently leaves the hepatocyte cytoplasm and is ultimately excreted in urine. Glutaminase-1 (GLS1) is a mitochondrial enzyme found in endothelial cells (ECs) that metabolizes glutamine to glutamate and ammonia and glutaminolysis modulates the function of human umbilical vein endothelia.Glutamine deprivation or GLS1 inhibition also stimulated the production of reactive oxygen species and this was associated with a marked decline in heme oxygenase-1 (HO-1) expression. GLS1 inhibition also sensitized umbilical endothelia to the cytotoxic effect of hydrogen peroxide; a process that is blocked by the overexpression of Heme oxygenase 1. In

Glutaminase breaks down glutamine into glutamate and ammonia. Glutamate also yields additional urea via the enzyme glutamate dehydrogenase. From here, ammonia is initially incorporated into hepatocyte mitochondria and ultimately results in the formation of urea. Urea subsequently leaves the hepatocyte cytoplasm and is ultimately excreted in urine. Sirtuin mediated control over glutamate dehydrogenase and carbamoyl-P synthetase via discrete and potentiating  ADP ribosylation and deacylation is associated with pancreatic insulin secretion, hepatic amino acid utilization and the potential for pathobiochemical sequalae --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

SIRT5 causes deglutarylation and functional activation of glutamate dehydrogenase 1  which is  essential to cellular glutaminolysis.Indeed, SIRT5 supports the anaplerotic transamination entry of glutamine and other amino acids as alpho ketoglutarate into the TCA cycle in malignant phenotypes of colorectal cancer via activation of the glutamate dehydrogenase1. Sirt5 is known to regulate the activity of the urea cycle enzyme, carbamoyl phosphate synthase 1 (CPS1). SIRT5 mediated de-glutarylated CPS1 is elevated in activity to maintain urea cycle competency during active amino acid incorporation into the bioenergetic machinery thus promoting the potentiation of tumorigenesis. Science. 2011 Nov11; 334(6057): 806–809 Cell Metab 2014 Apr 1;19(4):605-17. Nat Commun. 2018 Feb7;9(1):545 Cell. 2006 Sep 8;126(5):941-54 Mol Cell. 2013 Jun 6; 50(5): 686–698 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

The Pyruvate dehydrogenase hydrated E1-E2 interface is  enthalpy driven, while the dehydrated  E3-peripheral subunit binding domain complex is driven by entropy obtaining a favourable  delta G= delta H-T delta S=  -33.4kj mol where the domain interfacial hydration obtains surface  thermal complementarity  and contributes finally to an aggregate  strength of multiple affinities of individual non-covalent binding interactions via enthalpy-driven catalysis. Lipoamidase activity of mitochondrial Sirtuin 4 modulates cellular fate by generating a  debilitating removal of PDH-E2 dihydrolipoyllysine acetyltransferase-bound lipoic acid  thus driving glutaminolysis over glucose oxidation. Cell. 2014 Dec 18; 159(7): 1615–1625. PNAS | August 23, 2016 | vol. 113 | no. 34 Structure VOLUME 13, ISSUE 8, P1119-1130, AUGUST 01, 2005 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

•Free energy change(chemical potential difference) for transporting 1 mole of a substance from region where its concentration is C1 (e.g., Cout) to region where its concentration is C2 (e.g., Cin): ∆G= RTln(C2/C1) (favorable with ∆G< 0 if C2< C1) •Transport of ionsacross membrane (must consider electrical potential in addition to concentration difference): ∆G= RTln(C2/C1) + ZF ∆Y (Z=charge of ion, F=Faraday’s constant, ∆Y=membrane  electrical potential in volts) •Coupled transport (active transport): ∆G= RTln(C2/C1) + ∆G´ (∆G´ of coupled process, such as ATP hydrolysis, may be  negative enough to compensate for unfavorable transport  against concentration gradient when RT ln (C2/C1) > 0) •Diffusional transport: movement of substance from high to low concentration across membrane (down concentration gradient) –Non-facilitated diffusion across lipid bilayer (slow for most biological substances) –Facilitated diffusion (accelerated diffusion by making membrane more permeable to specific tr

Mini Lecture 1 on Membrane Physiological Biochemistry. The amino acid sequence of membrane associated polypeptides obtains secondary structure, glycosylation, acylation and hydropathy which confer functionality (in part) by targeting specific membrane domains. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

For Valentine's Day Eve. A bouquet assortment of  biochemical  thermodynamic principles and  metaphysical event ontologies. To finish my thoughts:  Is life necessary? How to answer this question? One way is to ask if there is sufficient reason for its existence. Outside of spiritual or theological discussion, the answer is compellingly obscure especially since we find no authentic examples except on our planet.  If life is contingent, where does it come from, how does it come about and why does it exist? You see where this is going. Why is there a physical universe? Why isn’t there just nothingness? Answering with the typical “it just is!” only further confounds the question. The word “just” here, operates syntactically with contingency. By that I mean,  proposing that the modality of an event, life in this context, simply "is" a state function, makes no claim that the event "must be". And so…we are back to the beginning. A beginning that has no source. The Big Bang could be such

*Oncogenesis eventuates genetic mutation to epigenetic gene expression mechanisms with molecular signatures either inappropriately proscribed, incorrectly prescribed upon writing as  dangerous and deleterious, or erasure;  leaving a corrupted  chromatin result.  *Tumor cells obtain proliferative autonomy, autophagous –self-maintenance in growth and signaling, neovascularization for nutrient and oxygen supply, and resistance to anti-proliferative and apoptotic stimuli  *In resting cells, the cell cycle is strictly managed by a set of regulatory proteins that control the various cell cycle checkpoints and this will become dysfunction during the early transforming stage of the tumorigenesis via the unregulated dismantling of tumor suppressor genes  *Suppression is the programmed deliberative  inhibition of biochemical events while repression is the unintentional inhibition of biochemical events *When a biochemical  event is de-repressed it is brought back to register, rega

Intra abdominal adiposity (IAA)  linked obesity may be the most significant contributory factor to high mortality human disease after aging. IAA  presents with systemic and chronic inflammation and enlarged White Adipose Tissue (WAT) adipocytes that have been infiltrated with lymphocytes and macrophages that secrete pro-inflammatory cytokines, chemokines, growth factors and inappropriate levels of pro-inflammatory adipokines.  Aging combined with chronic obesity not only promotes cardiovascular disease and cancer but further promotes autoimmune disease, dementia and high morbidity metabolic dysfunction, respiratory disease, and hyperimmune response to otherwise non-virulent pathogens linked to mortality. International Scholarly Research Notices, vol. 2013, Article ID 139239, 12 pages, 2013. https://doi.org/10.1155/2013/139239 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

*Adipose tissue is the endocrine organ that secretes “adipokines” *Nothing new to the Authentic Biochemistry crew; adipokines have been very well discussed here and their function as mediators of the feeding/appetitive/satiety response through the arcuate nucleus of the hypothalamus (POMCvNPY neurons) was most recently addressed. *Adipokines mediate the BMI, heart rate, serum glucose &fatty acid/TAG, and pro- inflammatory cytokine production;they are released by adipocytes (e.g. leptin and adiponectin) or preadipocytes, adipose tissue-infiltrated immune cells, or the gastric system Indeed, Th2 lymphocytes promote adipose glucose homeostasis by enhancing insulin sensitivity in adipocytes and browning/brown adipose tissue (BAT) activation but chronic inflammation of white adipose tissue (WAT) leads to the activation of pro-inflammatory pathways in adipocytes and resident immune cells following obesity involving the shutting down of Tregs and anti-inflammatory cytokines. Front Physiol. 2020; 11: 578966 India

Proceedings of The Nutrition Society.2012 71(4):521-33 Autophagy. 2009 May; 5(4): 558–560 Molecular and Cellular Endocrinology Volume 472, 5 September 2018, Pages 40-49 Int J Mol Sci. 2020 Nov; 21(21): 8220. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Fear-conditioning  learning is a low-threshold  enduring psychiatric  process that prepares a defense against dangerous phenomena and reduces the need to iteratively  relearn the signal. It is a pattern recognition response that can be modulated by experience and the severity of the stress signal and it is  a response that deteriorates in the elderly and in certain neuropsycoses  and anxiety disorders throughout life. Fear conditioning must be fluid  to readjust according to reverse learning.  Persistent fear and avoidance of the potential for fear-associated events are common presentations of social anxiety disorder (SAD) and avoidant behavior  maintains SAD, thus it prevents the reversal of fear in social situations. The best treatment outcomes are CBT including exposure therapy, which leads to  fear extinction. Pharmacotherapy including  antidepressants, benzodiazepines, beta-blockers, anticonvulsants, or neuroleptics, are commonly administered with lo

Homeostatic  chronic  low stress results in low to moderate levels of CRF in the LC in association with  enhanced Extra-Dimensional Shifting and optimal executive decision making. However, acute or chronic severe stress is linked to  high levels of CRF in the LC and this may  contribute to a shift from optimal executive function necessary for goal-directed behavior toward an iterative decision response.  In healthy environments, this variable tonicity is a readout for adaptation  when goal-oriented behavior is relaxed so that the individual uses pro-forma decisions  even when novel environmental stimuli are encountered. During aging these pathways lose flexibility due to a decrease in executive decision making linked to the senescence phenotype that may impair neural circuitry via inflammation, over or under activation and lack of control over  immune cell responses. J Neurosci. 2008 Nov 5; 28(45): 11517–11525. GeroScience. 2017 Feb; 39(1): 61–72. Neuroscience. 201

Adaptation to stress-such as the fear response obtains dopaminergic input to striatum and prefrontal cortex and  is thought to signal unexpected events and facilitate a shift in attention to promote new learning within the contralateral primary somatosensory cortex (SI) which has been associated with the agentic categories of both the quality and quantity of thought event ontology. This process works in conjunction with  the bilateral secondary somatosensory cortex (SII) process  involved in executive  decision making. Where stimulated, the primary sensory motor-neuronal process  is integrated with novel extra-dimensional learning . Recall that this fear stress response can lose functional valency upon immune-regulating, senescent secretory phenotypes.   In the aging brain, where CRF axon terminals are widely distributed, (including within catecholamine and serotonin  nuclei) there are widespread cortical projections into the medial prefrontal cortex; linking  exec

The anti-inflammatory IL-10 pathway in the CNS can lead to Glioblastoma which is a disease presented 3-4 fold higher in people ≥65 years old, and with a mortality rate for the same age group some 7 fold higher. Activation of the IL-10 Receptor bound ligand induces the JAK1 signal transducer and activator of transcription 3 (STAT3) pathway in APCs. This results in the subsequent translocation of STAT3 homodimers into the nucleus. This STAT3 homodimer binds to STAT-binding elements which promotes the expression of the suppressor of cytokine signaling 3 (SOCS-3) and IL-1 receptor antagonist (IL-1RN).  IL-10 reduces the production of pro-inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor alpha) and diminished expression of both major histocompatibility complex II. The anti-inflammatory  MiDAS phenotype can also induce heart failure in the aging population. References: Front Pharmacol. 2019; 10: 200 Aging Cell. 2018 Oct;17(5) Int Heart J. 2018 Jul 31;59(4):837-844 Front. Immunol., 19 March 2018 N

Non-uniform ageing is a major associative risk factor for cancer and degenerative diseases and mitochondrial dysfunction is linked to cellular senescence in association with cell cycle arrest, telomerase decline and nucleic acid/lipid/protein oxidation. Indeed, mitochondrial dysfunction comprises a distinct type of cellular senescence; mitochondrial SIRT3 or SIRT5, can induce Mitochondrial Dysfunction Associated-Senescence (MiDAS) Senescence is a chronological and pathophysiological sequenced event response that restricts mitotic division and thus aberrant proliferation of damaged, infected and/or tumor inducing cells. Because these cells are senescent and exhibit low anabolic currency to present self-produced antigen epitopes as displayed by HLA, they are not targeted by immune responses but rather, may become secretory and induce inflammation by instantiating the Senescence Associated Secretory Phenotype-SASP. Senescence presents with metabolic reprogramming, epigenetic chromatin remodeling, and the secreti

LC axonal projections to the mPFC modulate a diversity of cognitive processes, including working memory, sustained attention, and flexible attention and under moderate rates of LC activity and NE release, high-affinity postsvnaptic α2 adrenergic receptors in the PFC are preferentially engaged and promote working memory However, with elevated LC firing and activation of lower affinity α1 adrenergic receptors, working memory is impaired while agentic  focused attention becomes prominent so it seems that LC projections to the PFC modulate different cognitive processes in a context-sensitive manner. his latter mechanism could correlate with the experienced rapid response such as in “fight or flee” decision making upon immediate threatening danger. The sensation perception recognition and response behaviour all works sequentially from these neuronal loci post encounter to the stimulus and as such fit well into Kantian epistemology which obtains that the individual is presented with a particular stimulus-sense

•Intensive and chronic or excessive stress diminishes intellectual performance and general cognition: this is a form of negative reinforcement and can be related to learning disability and anxiety about future events. Indeed, •Individual responses and the magnitude of stressor as well as its association with self identity and goals will influence endurance, resilience, and self-empowerment vs. dissatisfaction and defeat. •Stresses  first become recognized in the developing fetus since the fetal brain attains awareness during the first trimester and maternal stress is well established as an epigenetic mechanism involved in fetal neural development and  stress is lifelong , contributing to  one’s character and ability to overcome fear and anxiety. •Stress response is an element of the hypothalamic-pituitary-adrenocortical (HPA) axis where  Corticotropin-releasing factor (CRF) serves as a gate keeper for fear conditioning playing dual roles as hormone and as neuromodulator. •CRH exerts multip