Cellular long chain acyl-CoA concentrations are controlled by multiple networked and coherent metabolic pathways ( including mitochondrial β-oxidation versus Golgi-ER-PL complex lipid synthesis versus glyceropholipid and sphingolipid hydrolysis), which functionally associate resident acyl-CoA in cellular bioenergetic and signaling pathways. Thus, the regulation of PFK-1 by its direct interaction with acyl-CoA generates downstream interconnected alterations in metabolic flux through glycolysis, t...
Jan 03, 2021•30 min
Naive T lymphocytes, as opposed to memory T cells(which are more common in aging) carry out homolactate fermentitive glycolysis. Memory cells are operating under complete aerobic metabolism involving mitochondrial bioenergetics including the TCA cycle but also fatty acid oxidation as a source for reducing equivelents to drive the electrontransport chain and oxidative phosphorylation. The regulation of these alternative pathways involves allosteric modification of key enymes and trafficking prote...
Jan 01, 2021•30 min
Early stage TCR activated T cells with rampant lactic acid fermentation, fail to maintain adequate ATP levels , especially when glucose is limiting.This decrease in ATP relative to ADP+AMP results in the activation of AMPK, which inhibits mTOR activity and all subsequent anabolism especially assocaited for T cell proliferation. Indeed, induced Loss of AMPKα1, will sythetically restore mTOR signaling and T cell cytokine production, but not proliferation. Although loss of AMPK can restore some fun...
Dec 30, 2020•30 min
Authentic Biochemistry Podcast 29 December 2020 Daniel J. Guerra Ph.D. •All scientific inquiry should start with dialectical method that uses the current knowledge base to generate various specific Theses and then follow each with the counter-argument by employing the Square of Opposition thus producing Anti-theses and then, making the third movement, which allows for a Synthesis that has the flavor of rejection, acceptance or indifference. *Downstream of co-stimulation and PI3K-AKT, the mammali...
Dec 30, 2020•30 min
Human neuroscientific research seeks to uncover patterns of commonality and uniformity to help define mechanisms which reliably result in the experience of thinking and interacting with the world. This scientific mindset is in opposition to real life experience where human bonding is unique to a specific relationship. This may be best understood as a compatibilist approach, where neuroscience may affirm the very real experience of an individual when he makes a judgment or chooses to imagine his ...
Dec 26, 2020•22 min
T cell agency initiates upon the stimulation of the TCR via presentation of cognate peptide-MHC complexes in associative ligand-mediated membrane co-receptor CD28 with co-stimulatory molecules presented on the surface of the APC: this event is called T cell licensure and essentially quits quiescence. The TCR signals through the ERK/MAPK pathways and calcium flux; where as CD28 signaling activates the PI3K-AKT-mTOR axis, and both pathways synergistically engage the NF-κB organon of pleitropic T l...
Dec 23, 2020•30 min
In this episode Dr Guerra provides a concise description of T lymphocytic fatty acid synthesis from glucose via cytosolic glycolysis, mitochondrialpyruvate dehydrogenase, pyruvate carboxylase, and citrate synthase and a return to the cytosol for ATP citrate lyase and the homodimeric polyprotein complex FAS to generate palmitoyl-ACP. This ability of antigen-MHC Antigen Presenting Cell TCR - activated T lymphocytes to prepare for massive cytokine and chemokine expression requires a biochemical poi...
Dec 23, 2020•30 min
Metabolic syndrome (MetSyn)is a dyslipidaemic chronic and aging linked sedentary life-style constellation of disease presentations including metabolic disorganization, prodromal Type 2 diabetes and a prominent connection to hypertension-most prominently associated with over-eating and obesity. MetSyn is often prolegomena to middle-age onset CVD, cancer and neurodegeneration. High caloric density soluble carbohydrate nutrition, lack of fasting and the species-specific metabolic inability to conve...
Dec 17, 2020•29 min
Both the innate and acquired immune systems become senescent during chronological aging. While T cell activation may become disenfranchised from its co-stimulatory control apparatus during aging, the potential for hyper or hypo-immune responses becomes more common. At the same time, CNS microglia and peripheral resident and circulating macrophages are activated following the stimulation of various pattern recognition or phagocytic receptors. In the CNS, this activation state is subsequently cont...
Dec 15, 2020•30 min
Dr. Guerra reminds and extends his decade-long hypothesis that The Immune Response could function to generate the networked synaptic connections in the brain during initiation, development, learning, and aging. The question considered is how do immune cells and immuno-regulatory proteins such as cytokines and chemokines and immunoglobulins recognize certain neurons and not others? The mechanism for maintaining and increasing synaptic strength vs. obsolescence and programmable cell death could be...
Dec 13, 2020•30 min
Aging and chronic stress can obtain activation of CNS-resident microglia and astrocytes, that produce type 1 interferons (T1 IFNs) which signal through the heterodimeric IFN-α/β receptor (IFNAR) where receptor binding of T1 IFNs activates the JAK/STAT thus inducing IFN-stimulated genes (ISGs) which mediate both pro- and anti-inflammatory functions depending upon the cellular micro-environment. Now consider how aging is linked to elevated & activated leukocyte counts and it becomes clear that...
Dec 08, 2020•30 min
In this first pre-Christmas present Authentic Biochemistry Podcast lecture, Dr Guerra examines the multifactorial expansion of NOTCH signalling through early thymocyte development as regulated by paracrine and endocrine hormonal systems in cooperation with the exemplary plenum of IL7 cytokine mediated signalling through the phosphatidylinositol and AKT kinase cascades. References J Cell Physiol. 2003 Mar;194(3):237-55 Development 2019 146: dev172148 Int J Mol Sci. 2020 Nov; 21(21): 7972 SUBSCRIB...
Dec 06, 2020•30 min
In today's lecture, Dr Guerra explains how subclinical hypothyroidism obtains increased serum thyrotropin (thyroid stimulating hormone, TSH) with flat levels of of free thyroxin (T4) and biologically active free triiodothyronine (T3) in the elderly;β1 adrenergic receptors, sodium/potassium ATPase, voltage-gated potassium channels, malic enzyme and atrial and brain natriuretic factor all respond favourably to thyroxin and hese proteins form the primary architecture of the cardiomyocyte and determ...
Dec 03, 2020•30 min
On this 16th of November Authentic Biochemistry Podcast episode acknowledging my sister Carol's birthday, I explain the MST- kinase mediated transcription factor HIPPO pathway and its potentially gravid linkage to aging associated lymphocyte-informed autoimmune disease, cancer and neurodegeneration. Published by Dr.. Daniel J. Guerra. 2020 References Experimental & Molecular Medicine volume 51, Article number: 80 (2019) Pharmacological Research Volume 143, May 2019, Pages 151-165 Trends in C...
Nov 16, 2020•29 min
During thymic T lymphocyte recombinatorial self avoidance, the processing obtained in T cell receptor excision generates small circular DNA byproducts that may be used as a biomarkers for thymic output and for the relative ability of T lymphocytes to fight infection, tumors, and obesity -linked cardiovascular disease and metabolic disorders that may become important pathologies in the aging human population. Transcription factors like Nfil3 are important components of this networked age-related ...
Nov 15, 2020•29 min
1.Id proteins are helix-loop-helix (HLH) proteins lacking the basic amino acid domain necessary to bind DNA.and therefore ID functions in a dominant negative manner by sequestering ubiquitously expressed or cell- restricted basic HLH transcription factors: this results in effective blockade of transcription since ID causes a failure of dimerized basic HLH proteins to bind DNA. 2. Id proteins regulate transcription factors that are involved in developmental processes such as myogenesis, neurogene...
Nov 12, 2020•29 min
Since epithelial clock gene and lymphocyte transcription factor Nfil3 expression is elevated in recombination deficient mice the potential for increased bacterial populations lining the gut may induce an expansion of class 3 innate-like T lymphocytes (ILC3) in the small intestine. thus allowing for circadian clock activity maintenance and effective immune clearance of potential pathogens. This observation may provide a potential pathobiochemical link between obesity and the increasing pathophysi...
Nov 10, 2020•30 min
NFIL3 is a critical transcription factor immunologically linking the microbiome to the circadian clock and lipid metabolism where the Innate Lymphoid Cell subtype 3 and dendritic cells may stipulate the intestinal microfloral associated epithelial temporal chronicity. Subscribe to my Podcast and donate! Published by Dr Daniel J Guerra, Authentic Biochemistry 09 November 2020 Reference: Science. 2017 Sep 1; 357(6354): 912–916.
Nov 10, 2020•29 min
Nuclear factor interleukin 3 (NFIL3, also known as E4-binding protein 4, E4BP4) is a repressor of numerous genes. NFIL3 contains a basic leucine zipper domain, comprising amino acids 73–146, among 462 residues; the N-terminal part of this domain directly binds to DNA, while the C-terminal region is responsible for homo- or heterodimerization of the protein. Amino acids 299–363 comprise a transcriptional repression domain where the N-terminal part of this domain directly binds to DNA, while the C...
Nov 02, 2020•30 min
Dr. Guerra hybridizes multiple strands of published biochemical research to obtain an event ontology for potentiating factors leading to the aging human pathophysio9logical phenotype. In this lecture I include the following detail: 1. Nuclear factor interleukin 3 (NFIL3, also known as E4-binding protein 4, E4BP4) is a repressor of numerous genes. where an N-terminal domain directly binds to its response element, while the C-terminal region is responsible for homo- or heterodimerization to induce...
Oct 29, 2020•29 min
Since space and time are never the same twice and indeed are relatively uncertain, not even the day/night chronicity is a true cycle. It is a pattern or a familiar sequence of events and nothing more. No two moments are identical and so our internal circadian clock tracks these patterns but the means by which this detection operates at the cellular and molecular level, as well as the event itself involving the revolving celestial bodies in constant flux so in time, the pattern becomes less unifo...
Oct 29, 2020•30 min
The pharmaceutical Remelteon may be a better MT1 MT2 agonist mimetic for decreasing melatonin synthesis in the aging pineal because it fails to bind MT3 receptor which is an active quinone reductase 2 synthesizing superoxide system. Published 24 October 2020 by Authentic Biochemistry Podcast; Dr Daniel J. Guerra
Oct 25, 2020•30 min
The artificial enhancement of brain melatonin levels were hoped to suppress the progress of Alzheimer's Disease in humans and for correcting the circadian and sleep-wake disturbances associated with advanced aging.. However, given the complex association of melatonin on NAD+ tonicity and this relationship playing a role in DNA Damage Repair Responses (both SSB and DSB) . melatonin or a surrogate mimetic receptor agonist may have undesirable effects on neurodegeneration and oncogenesis in the CNS...
Oct 22, 2020•29 min
This episode lays the foundation for a common precursor-the essential amino acid L-tryptophan, of both melatonin and NAD+ and the PARP mediated DNA repair pathways linked to tumorigenesis on one hand and in DNA Damage repair-linked cessation of apoptosis on the other, in the aging human Central Nervous System. Cells. 2019 Sep; 8(9): 1047. Int J Alzheimers Dis. 2011: 741974.
Oct 21, 2020•30 min
The pineal endocrine hormone melatonin proximally decreasesIL-1β-induced MMP production by inhibiting Sirt1-dependent NAMPT and NFAT5 signaling in chondrocytes; since autoinflammatory Osteoarthritis (OA) is a degenerative joint (cartilage degradation) disease linked to human aging and Interleukin-1β contributes to OA pathogenesis by enhancing oxidative stress and inflammation the role(s) of sirtuin and NAD+ metabolism is associated with aging morbidity while also being described in Double-Strand...
Oct 20, 2020•29 min
Dr. Guerra offers a deep investigation into the roles of sirtuins in homeostasis , aging and disease as linked to NAD+ metabolism via ecto enzymatic CD38 and intracellular forms of this NAD+ metabolizing enzyme that is associated with T lymphocyte bioenergetics, activation and regulation as embedded within the inflammatory response, disease and aging. Published in Authentic Biochemistry Podcast series on Aging and the immune system. 14 October 2020 Papers mentioned in today's lecture : Hogan, et...
Oct 15, 2020•29 min
Sirtuins are protein deacetylases with multiple isoforms active in the nucleus, cytosol and mitochondria all serving unique functions and requiring NAD+. These sirtuins function to condense chromatin and yet protein abundance has less to do with potency than does the availability of NAD+ which can be synthesized from multiple routes. Furthermore, SIRT1 has been associated with antagonizing age-related decreases in the amplitudes of the SCN output obtaining age-linked differentiating phases of in...
Oct 12, 2020•29 min
It is proposed that the endocrine hormone melatonin may regulate after its synthesis and secretion from the pineal gland, the deacetylase acivity of Sirtuin1 to diminish the SASP repertoire of aging and may be linked to common morbidity of pathophysiology linked to COPD and generic Respiratory Distress Syndrome (RDS)presentation. Papers of Record in this episode Int J Mol Sci. 2019 Mar; 20(5): 1223. Int. J. Mol. Sci. 2014, 15, 16848-16884 International Immunopharmacology Volume 62, September 201...
Oct 08, 2020•29 min
Dr. Guerra temporally organizes the lecture series toward the dialectical event by mindfully schematizing the SASP , the triad of DNA Damage Repair (DDR)responses, transcriptionally activated pro-inflammatory cytokine mediated inflammation, and the pineal-endocrine hormone melatonin circadian clock manifestations in the biochemistry and physiology of the aging human. Please SUBSCRIBE! and when you can PLEASE DONATE to your favorite authentic biochemist so he can continue to provide with august r...
Oct 08, 2020•29 min
Lipids, proteins carbohydrates and nucleotides-may function within an inflammatory and secretory modality. Thus, the SASP-Senescence-Associated Secretory Phenotype might deliver apoptosis, necroptosis, autophagy, oncogenesis or an extended senescence sequalae. An Authentic Biochemistry audio lecture podcast by Dr. Daniel J. Guerra. 04 October 2020. Please SUBSCRIBE , check out my video lectures ( https://www.youtube.com/channel/UCcEoA2N9WSlNvDk1BtuznfQ?view_as=subscriber) and donate! https://pod...
Oct 04, 2020•29 min
