Authentic Biochemistry

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 this is a patho-biochemical phenocopy to T cell acute lymphoblastc leukaemia  (T-ALL) where signaling through Notch, Jak/Stat, PI3K/Akt/mTOR, and MAPK are shared. IL7-induced glucocorticoid resistance is diagnostic of certain subtypes of T-ALL and this is also associated with the senescence associated secretory phenotype of aging-linked morbidity and mortality. Finally, consider that chronic CNS stress leads to increased  glucocorticoid production leading to  a suppression of cel

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 SUBSCRIBE and give my PODCAST 5 stars and tell a few hundred friends! And by all means donate to my work! --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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 determine contractile strength. ATP drives muscle contraction/relaxation thus active  mitochondrial nadh  oxidation is essential for healthy aging. Ketone and free fatty acid oxidation decreases with aging while glucose oxidation reciprocally increases while thyroid hormone levels decline with aging, suggesting that myocardial metabolic pathology is linked phenomenologically to subclinical hypothyroidism. Indeed,thyroid hormone deficiency found in aging populations inhibits fatty acid oxidation through transcriptio

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 Cancer, May 2019, Vol. 5, No. 5297-307 Nature Reviews Rheumatology volume 13, page389(2017) Adv Immunol . 2019;144:87-119 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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 decline called immunosenescence that has the pathobiochemical signatures of SASP , ROS, mutation, epimutation and epigenetic gene expression pathologies. Dr. Daniel J. Guerra Authentic Biochemistry Podcast Publication. 14 November 2020 References Braz J Med Biol Res. 2019; 52(7): e8292 PLoS One. 2016; 11(6): e0157930 Experimental & Molecular Medicine volume 51, Article number: 80 (2019) --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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, neurogenesis, bone morphogenesis, lymphopoiesis hematopoiesis, and myeloid differentiation 3. Id2−/− mice lack lymph nodes and Peyer's patches*, *Peyer's patches are discrete masses of lymphatic tissue found throughout the ileum of the mammalian small intestine Oncogene volume 22, pages1–9(2003) PNAS January 15, 2019 116 (3) 890-899 SUBSCRIBE and tell a colleague about Authentic Biochemistry And please Donate to my podcast! --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/mess

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 pathophysiology associated with human aging. Dr. Daniel J. Guerra Authentic Biochemistry Publication 10 November 2020  PLEASE SUBSCRIBE and give a 5 star review for my podcast and DONATE!!! --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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-terminal region is responsible for homo- or heterodimerization of the protein and amino acids 299–363 comprise a transcriptional repression domain. Please SUBSCRIBE and help out with $ donations! --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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 a temporally synchronized geometric configuration obtaining as a transcriptional repression domain 2. NFIL3 represses genes by recruiting histone deacetylase 2 and G9a histone methyltransferase in diverse physiological networks including the circadian clock,  acquired immune response, cell fate, and intermediary metabolism. Papers to read: Experimental & Molecular Medicine volume 51, Article number: 80 (2019) Journal of Molecular Endocrinology (2019) 63, R93–R102 SUPPORT AUTHENTIC BIOCHEMISTRY! Su

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 uniform while the ideal presents as fixed and familiar so to be displayed intentionally and subsequently neurologically as apparent classical experiential phenomena. Feedback loops compose the ‘molecular clock’ which is governed by a cascading transcription and translational   regulatory mechanisms that are sufficient to maintain circadian rhythms. Journal of Molecular Endocrinology (2019) 63, R93–R102 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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 and the periphery. Dr Guerra opens this complex biochemical terrain in this and the previous 21 October Authentic Biochemistry podcast lectures. Please donate to AB! I need you ! • --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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-Stranded Break (DBS) DNA Damage Repair (DDR), we have isolated and identified with distinction, pathobiochemical components of the human aging event ontology. Oncotarget. 2017 Aug 22; 8(34): 55967–55983. PLOS One .November 25, 2014https://doi.org/10.1371/journal.pone.0113939 Int J Mol Sci. 2019 Mar; 20(5): 1223. eLife 2020;9:e55828 DOI: 10.7554/eLife.55828 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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 al. Front. Immunol., 31 May 2019 | Cells 2020, 9(1), 228 Camacho-Pereira et al., 2016, Cell Metabolism 23, 1127–1139 Sci. Signal. 10, eaal3024 (2017) 17 October 2017 November 2011 Pharmacological reviews 64(1):166-87 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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 increases and decreases observed within a circadian cycle.. References: Int J Mol Sci. 2019 Mar; 20(5): 1223. PLOS One November 25, 2014 https://doi.org/10.1371/journal.pone.0113939 Circ Res. 2018 Sep 14; 123(7): 868–885 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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 2018, Pages 23-28 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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 research science interrogation and analysis.  --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

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://podbay.fm/p/authentic-biochemistry Grazie! Dr. Guerra Nature Reviews | Cancer Reviews 19 | AUGUST 2019 :pp. 439 Nature Communications Vol. 9, Article number: 1228 (2018) doi:10.1038/s41467-018-03566-5 Front. Genet., 12 March 2015 https://doi.org/10.3389/fgene.2015.00094 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message