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Nathan Goodyear

Sex hormones affect neurotransmitters and shape the adult female brain during hormonal ... - 0 views

  • estrogen administration has been found to increase tryptophan hydroxylase
  • 5-HT2A mRNA levels in brain areas relevant for the control of mood, mental state and cognition (Sumner and Fink, 1998) and 5-HTT mRNA when administered for a longer period
  • n the other hand, estrogen treatment has also been observed to decrease mRNA related to serotonergic neurotransmission
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  • Furthermore, acute estrogen administration decreases 5-HTT mRNA levels (Pecins-Thompson et al., 1998) and 5-HT1A mRNA levels and binding
  • assigning the effects of estrogen on serotonin to a homogenous functional class of stimulation or inhibition seems not to be feasible
  • Progesterone has been suggested to increase serotonergic neurotransmission via the regulation of the expression of serotonin-related genes and proteins
  • menopausal women gain less benefit from antidepressant treatments compared to women during their reproductive years
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    good review of the relationship of the sex hormones and neurotransmitters.
Nathan Goodyear

'Spikeopathy': COVID-19 Spike Protein Is Pathogenic, from Both Virus and Vaccine mRNA -... - 0 views

  • toxicity of the spike protein—both from the virus and also when produced by gene codes in the novel COVID-19 mRNA and adenovectorDNA vaccines
  • ‘spikeopathy’;
  • A central issue has been growing evidence of pathogenic effects of the SARS-CoV-2 spike protein—whether as part of the virus or produced by genetic codes in the mRNA and adenovectorDNA vaccines
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  • It is apparent that the original Wuhan strain and early variants of SARS-CoV-2 in 2020 were more pathogenic than later variants. This is consistent with typical viral adaptive evolution to more infectious but less pathogenic strains, a natural phenomenon
  • SARS-CoV-2 spike protein is pathogenic, whether from the virus or created from genetic code in mRNA and adenovectorDNA vaccines.
  • Evidence suggests reverse transcription of mRNA into a DNA copy is possible
  • further suggests the possibility of intergenerational transmission if germline cells incorporate the DNA copy into the host genome
    • Nathan Goodyear
       
      Intergenerational and transgenerational!
  • (‘spikeopathy’) via several mechanisms that lead to inflammation, thrombogenesis, and endotheliitis-related tissue damage
  • Interaction of the vaccine-encoded spike protein with ACE-2, P53 and BRCA1 suggests a wide range of possible biological interference with oncological potential
  • Repeated COVID-19 vaccine booster doses appear to induce tolerance and may contribute to recurrent COVID-19 infection and ‘long COVID’.
  • spike protein is not only toxic through binding of ACE-2 receptors
  • interaction with cancer suppressor genes BRCA and P53
  • mitochondrial damage
Nathan Goodyear

IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SA... - 0 views

  • These mRNA vaccines represented a new type of vaccine that comprises synthetic mRNA molecules that contain the coding sequence necessary to build the SARS-CoV-2 Spike protein, which is encased in the lipid nanoparticles (LNPs) to allow for the delivery of mRNA to cells.
  • proteins are synthesized within the host cells
  • they can induce significant neutralizing anti-spike IgG and IgA response
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  • Lethal COVID-19 cases have been linked to higher levels of IgG4 antibodies
  • mRNA vaccines trigger their synthesis
  • provide the scientific rationale suggesting that repeated vaccination with mRNA vaccines could generate an immune tolerance mechanism, thereby favoring unopposed SARS-CoV-2 replication.
Nathan Goodyear

Duration of SARS-CoV-2 mRNA vaccine persistence and factors associated with cardiac inv... - 0 views

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    mRNA present long time after vaccination
Nathan Goodyear

Case Report of a Pro-Vaccine Researcher Suggests mRNA Vaccine Might Worsen Lymphoma Cancer - 0 views

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    Not journal article, but to be read.
Nathan Goodyear

ScienceDirect.com - Cell Metabolism - Estrogen Receptors and the Metabolic Network - 0 views

  • The pro-opiomelanocortin (POMC) neurons have an anorexigenic action and, when activated, reduce food intake through the release of two peptides, α-melanocyte-stimulating hormone (α-MSH) and cocaine-and-amphetamine-regulated transcripts (CART). The neuropeptide Y (NPY) neurons, on the other hand, release NPY hormone and agouti gene-related protein (AgRP), which prevent the binding of α-MSH to MC3R and MC4R, increasing food intake
  • This suggests that the central anorexic effects of E2 may occur via ERβ
  • The main hypothalamic areas involved in food intake and satiety are the arcuate nucleus (ARC), the lateral hypothalamus (LH), the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), and the dorsomedial hypothalamus (DMH)
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  • Leptin is a potent anorexigenic and catabolic hormone secreted by adipose cells that reduces food intake and increases energy expenditure
  • E2 not only modulates leptin receptor mRNA in the ARC and VMH, but also increases hypothalamic sensitivity to leptin, altering peripheral fat distribution
  • ghrelin. It acts on growth hormone secretagogue receptors (GHSR1a) located in the ARC and is a potent stimulator of food intake
  • It thus appears that of the two ERs, ERα plays a predominant role in the CNS regulation of lipid and carbohydrate homeostasis.
  • Both ERs have been identified in the ARC
  • Stimulation of MCH neurons increases food intake and fat accumulation while its inhibition leads to decreased food intake and reduced fat accumulation.
  • Both ERs have been identified in the LH
  • both ERs have been identified in this nucleus
  • The PVN is the region of the hypothalamus with the highest expression of ERβ and is reported to be weakly ERα positive
  • The VMH is ERα regulated
  • Skeletal muscle is responsible for 75% of the insulin-induced glucose uptake in the body
  • GLUT4 is highly expressed in muscle and represents a rate-limiting step in the insulin-induced glucose uptake
  • data suggest that in the physiological range, E2 is beneficial for insulin sensitivity, whereas hypo- or hyperestrogenism is related to insulin resistance
  • In aging female rats, E2 treatment improves glucose homeostasis mainly through its ability to increase muscle GLUT4 content on the cell membrane
  • It is evident that ERα and ERβ have distinct actions and that much more research is needed to clearly identify the function of each receptor in muscle.
  • E2 prevents accumulation of visceral fat, increases central sensitivity to leptin, increases the expression of insulin receptors in adipocytes, and decreases the lipogenic activity of lipoprotein lipase in adipose tissue
  • In rats, ovariectomy increases body weight, intra-abdominal fat, fasting glucose and insulin levels, and insulin resistance followed by decreased phosphorylation of AMPK and its substrate acetyl-CoA carboxylase in adipose tissue
  • decreased adiponectin, PPARγ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2) and increased resistin
  • Men with aromatase deficiency have truncal obesity, elevated blood lipids, and severe insulin resistance
  • Although not all studies are in agreement, polymorphisms of ERα in humans have been associated with risk factors for CVDs
  • Human subcutaneous and visceral adipose tissues express both ERα and ERβ, whereas only ERα mRNA has been identified in brown adipose tissue
  • suggesting that ERα is the main regulator of GLUT4 expression in adipose tissue
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    very nice article that looks at the balance of ER-alpha/ER-beta and their role in metabolic syndrome.  This article discusses the balance of  these receptors are tissue dependent in their effect.  I like their conclusion: "...but these mechanisms will never be completely understood if they are not considered in the context of a whole system.
Nathan Goodyear

MicroRNAs in the Aging Female Brain: A Putative Mechanism for Age-Specific Estrogen Eff... - 0 views

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    Estradiol appears to have an age dependent effect on the transcription of mRNA and brain neuroplasticity.  This has a future impact on the risk of cognitive decline and dementia in elderly women.  This is only the abstract, but points to one effect of early Estradiol effect on improved brain health versus late therapy.  
Nathan Goodyear

Progesterone metabolites in breast cancer - 0 views

  • In breast tumor tissue and tumorigenic cell lines, 5α-reductase activity and mRNA expression are significantly higher, whereas 3α- and 20α-HSO activities and mRNA expression are significantly lower than in normal breast tissue and nontumorigenic cells
  • Studies using various breast cell lines have shown that 5αP and 3αHP have opposing actions in terms of cell proliferation and adhesion; 5αP stimulates cell proliferation (through increased mitosis and decreased apoptosis) and cell detachment, whereas 3αHP suppresses cell proliferation (through decreased mitosis and increased apoptosis) and detachment
  • the paracrine/ autocrine functions of 5αP are cancer-promoting and those of 3αHP are cancer-inhibiting
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    Awesome article on progesterone metabolism in breast cancer.  The author, weibe, describes 2 categories of progesterone metabolites in breast tissue: 5alpha-pregnanes and 4-pregnenes.  The author describes 3 primary enzymes that control the balance between these 2 metabolites--5alpha reductase, 3alpha-HSO, and 20alpha-HSO.  The resultant balance of 5alpha-dihydroprogesterone and 3alpha-dihydroprogesterone helps to determine the cancer potential of breast tissue.
Nathan Goodyear

The Androgen 5α-Dihydrotestosterone and Its Metabolite 5α-Androstan-3β, 17β-D... - 0 views

  • Sex steroid hormones are primarily responsible for sex difference in adult HPA function; androgens inhibit whereas estrogens enhance HPA axis activation after a stressor
  • the PVN contains relatively high levels of AR (Bingaman et al., 1994; Zhou et al., 1994) and ERβ (Alves et al., 1998; Hrabovszky et al., 1998; Somponpun and Sladek, 2003) but is essentially devoid of ERα
  • the nonaromatizable androgen DHT and the nonselective ER ligand E2 influence HPA reactivity by acting on neurons within or surrounding the PVN
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  • inhibitory action of DHT is detectable at both the level of hormone secretion as well as PVN c-fos mRNA expression
  • the inhibition can be mimicked by the DHT metabolite 3β-diol and by the subtype selective ERβ agonist DPN
  • E2 acts to enhance HPA reactivity
  • the ability of the ER antagonist tamoxifen, but not the AR antagonist flutamide, to block the inhibitory actions of DHT, speaks to the intracellular mechanism by which this inhibitory signal might be transduced.
    • Nathan Goodyear
       
      that is because the interaction with the DHT metabolite is not with the AR, but with the ER-beta.
  • the DHT metabolite 3β-diol and the ERβ-subtype-selective agonist DPN suppressed ACTH, corticosterone, and c-fos mRNA responses to restraint stress in a manner similar to DHT
  • metabolism of DHT to 3β-diol and subsequent binding to ERβ can be inhibitory to HPA reactivity, and this is one possible mechanism for the action of DHT.
  • Our data also suggest that E2 enhances the reactivity of the HPA axis to stress by acting on or near neurons of the PVN
  • the actions of E2 appear to be through an ERα-dependent mechanism
  • these studies suggest that ERβ, within the male hypothalamus, acts to inhibit the HPA axis and that the inhibitory effects of DHT may be, at least in part, via its intracellular conversion to 3β-diol and subsequent binding to ERβ
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    DHT metabolites: particularly 3beta-androstanediol inhibit HPA axis through ER-beta.
Nathan Goodyear

Vitamin D decreases NFκB activity by increasing IκBα levels - 0 views

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    vitamin D inhibits NF-kappa B via decreased phosporylation of IkappaB-alpha and by increasing mRNA of IkappaB-alpha.
Nathan Goodyear

microRNA Expression in Ethnic Specific Early Stage Breast Cancer: an Integration and Co... - 0 views

  • dysregulated miRNA could be involved in tumor cell proliferation and growth as well as cell cycle progression
  • under-expression of miR-497, 376c and 1271 in Lebanese breast cancer tissues
  • The upregulated miR-183 in our samples was predicted to be responsible for the decrease in expression of the BTG1 mRNA whose protein is involved in cell cycle arrest and apoptosis in breast cancer cells18.
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  • nother molecule related to cell proliferation that was over-expressed in our data and suggested as a target of downregulated miR-376c is AURKA
  • the over-expression of miR-183 and miR-21 in Lebanese breast cancer tissues is consistent with downregulation of two important tumor suppressor predicted targets: AKAP12 whose protein regulates cellular adhesion dynamics by controlling cytoskeletal architecture, cell migration, and mitogenic signaling20; and LATS2 whose protein causes cell cycle arrest
  • dysregulation in cancer particularly in breast cancer highlights their importance in tumor development
  • mRNA-miRNA integration analysis of early breast cancer revealed a potential role of miRNA in increasing cellular proliferation and progression, and decreasing invasion and migration
  • most of the miRNA dysregulated in Lebanese breast cancer patients are similar to those dysregulated in American patients, differences in miRNA expression exist and could be attributed either to the patients’ age at diagnosis or to ethnic variation in miRNA epigenetic regulation and sequence variation of pre-miRNA
  • the number one cancer killer of women worldwide
  • microRNA (miRNA) are small non-coding 18–25 nucleotide RNA molecules currently being studied as potential diagnostic, prognostic and therapeutic biomarkers for cancer and other diseases
  • Extensive research on these post-transcriptional modulators has proven that they are deregulated in breast cancerous tissues and even in biological fluids from breast cancer patients
  • five candidate miRNAs (miR-10b, miR-148b, miR-221, miR-21, and miR-155)
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    Epigenetics plays a role, via disregulated miRNA, in increased cell growth, progression, and invasion in Lebanese women with breast cancer.  It is not just genetics that play a role, but epigenetics.
Nathan Goodyear

Curcumin Down-Regulates DNA Methyltransferase 1 and Plays an Anti-Leukemic Role in Acut... - 0 views

  • In a variety of solid tumors and blood cancers, aberrant hypermethylation of CpG-rich regions (>55% CG content, 0.5-4 kb in length, the so-called “CpG islands”) in the promoters of tumor suppressor genes (TSGs) results in their transcriptional silencing
  • These agents have been reported to suppress tumor growth by reversing aberrantly hypermethylation in the promoters of inactivated TSGs (e.g. p15INK4B), allowing re-expression of TSGs, thereby restoring normal cell cycle regulation, proliferation, apoptosis, and differentiation
  • groups have reported that curcumin acts as a scavenger of free radicals [13], an inhibitor of NF-κB nuclear translocation [14], and a modulator of histone deacetylase (HDAC) and histone acetyltransferase (HAT)
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  • In this study, we found that curcumin down-regulated DNMT1 expression in AML cells. This occurred, at least in part, through down-modulation of two positive regulators of DNMT1: Sp1 and the NF-κB component, p65. We also found that curcumin-mediated down-regulation of DNMT1 was associated with reactivation of TSGs and tumor suppression, both in vivo and in vitro.
  • curcumin may selectively downregulate DNMT1 expression in tumor cells, but not in normal cells
  • DNMT1 expression is positively regulated by Sp1 and the NF-κB signaling component
  • indicating that curcumin may have significant anti-tumor activity in AML
  • We found that, compared to the vehicle control, curcumin treatment reduced tumor weight by 70%
  • Surprisingly, although curcumin significantly inhibited tumor growth in these mice, we were unable to find any obvious toxicity associated with curcumin treatment
  • Consistent with our observations regarding curcumin’s ability to inhibit tumor growth in vivo (Figure 4) and down-regulate DNMT1 expression in vitro and ex vivo (Figure 1), we found that decreased levels of DNMT1 protein and mRNA were expressed by tumor cells isolated from curcumin-treated mice
  • we identified curcumin as a substance which acts as an inhibitor of DNA methyltransferase enzymatic activity and induces significant global DNA hypomethylation in AML cells
  • In this study, we first demonstrated that curcumin decreases DNMT1 mRNA and protein expression levels, most likely through inhibiting expression of positive regulators of DNMT1, such as Sp1 and the p65 component of NF-κB component, and/or altering their ability to bind to the promoter region of DNMT1
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    Curcumin beneficial in AML
Nathan Goodyear

Frontiers | Microbiome-Derived Lipopolysaccharide Enriched in the Perinuclear Region of... - 0 views

  • lipopolysaccharides (LPS), either alone or in combination, have indicated that when compared, bacterial LPSs exhibit the strongest induction of pro-inflammatory signaling in human neuronal–glial cells in primary coculture of any single inducer, and different LPS extracts from different gastrointestinal (GI)-tract resident Gram-negative bacteria appeared to have different pro-inflammatory potential
  • powerful inducer of the NF-κB
  • In both neocortex and hippocampus, LPS has been detected to range from a ~7- to ~21-fold increase abundance in AD brain
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  • Major Gram-negative bacilli of the human GI-tract, such as the abundant B. fragilis and Escherichia coli (E. coli), are capable of discharging a remarkably complex assortment of pro-inflammatory neurotoxins
  • (i) bacterial amyloids (10, 21); (ii) endotoxins and exotoxins (5, 12); (iii) LPS (12, 18); and (iv) small non-coding RNAs (sncRNAs)
  • integral components of the outer leaflet of the outer membrane of Gram-negative bacteria, LPS
  • LPS, the major molecular component of the outer membrane of Gram-negative bacteria normally serves as a physical barrier providing the bacteria protection from its surroundings
  • LPS is also recognized by the immune system as a marker for the detection of bacterial pathogen invasion and responsible for the development of inflammatory response is perhaps the most potent stimulator and trigger of inflammation known
  • AD-affected brains have remarkably large loads of bacterial-derived toxins compared to controls. The transfer of noxious, pro-inflammatory molecules from the GI-tract microbiome to the CNS may be increasingly important during the course of aging when both the GI-tract and blood–brain barriers become significantly more permeable
  • first evidence of a perinuclear association of LPS with AD brain cell nuclei
  • LPS-mediated stimulation of chronic inflammation, beta-amyloid accumulation, and episodic memory decline in murine models of AD (39, 40) and a biophysical association of LPS with amyloid deposits and blood vessels in human AD patients
  • Strong adherence of LPS to the nuclear periphery has recently been shown to inhibit nuclear maturation and function that may impair or block export of mRNA signals from brain cell nuclei, a highly active organelle with extremely high rates of transcription, mRNA processing, and export into the cytoplasm
  • LPS may be further injurious to the nuclear membrane just as LPS contributes to cerebrovascular endothelial cell membrane injury
  • high intake of dietary fiber is a strong inhibitor of B. fragilis abundance and proliferation in the intact human GI-tract and as such is a potent inhibitor of the neurotoxic B. fragilis-derived amyloids, LPS, enterotoxins, and sncRNAs.
  • GI-tract microbiome-derived LPS may be an important initiator and/or significant contributor to inflammatory degeneration in the AD CNS
  • LPS has been recently localized to the same anatomical regions involved in AD-type neuropathology
  • a known pro-inflammatory transcription factor complex that triggers the expression of pathogenic pathways involved in neurodegenerative inflammation
  • pro-inflammatory amyloids, endo- and exotoxins, LPSs, and sncRNAs but also serve as potent sources of membrane-disrupting agents
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    LPS links gut to inflammation in Alzheimer's disease
Nathan Goodyear

Acute Exercise Remodels Promoter Methylation in Human Skeletal Muscle: Cell Metabolism - 0 views

  • our results provide evidence to suggest that acute exercise induces gene-specific DNA hypomethylation in human skeletal muscle
  • Our results suggest that DNA methylation is a component of the exercise-induced effect on expression of these genes.
  • Caffeine exposure decreased promoter methylation of Pgc-1α, Tfam, Mef2a, Cs, and Pdk4
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  • the effect of exercise on DNA methylation in human skeletal muscle and provide evidence that acute exercise alters promoter methylation of exercise-responsive genes in a dose-dependent manner
  • DNA methylation was unaltered 48 hr after a 3-week exercise training program, whereas RNA expression of PGC-1α and TFAM promoters was elevated (data not shown), further suggesting that DNA hypomethylation is a transient mechanism involved in mRNA synthesis
  • Our findings that ionomycin, AICAR, or ROS production increased mRNA expression without altering promoter methylation may support the notion that DNA methylation does not exclusively control exercise-induced gene expression
  • acute exercise leads to transient changes in DNA methylation in adult skeletal muscle
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    Small study finds acute exercise is associated with epigenetic alteration of muscle through methylation.  This study found a hypomethylation of the genes PGC-1alpha, PDK4, and PPAR-delta with a respondent increase in expression.  The methylation activity was in the promoter region of these genes.
Nathan Goodyear

A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern i... - 0 views

  • In skeletal muscle, HDAC4 has been found to be exported from the nucleus during exercise, suggesting that removal of the transcriptional repressive function could be a mechanism for exercise adaptation [50]. For HDAC4, we observed increased levels of DNA methylation and a simultaneous decrease in mRNA expression in adipose tissue in response to the exercise intervention. Additionally, the functional experiments in cultured adipocytes suggested increased lipogenesis when Hdac4 expression was reduced
  • NCOR2 also exhibited increased levels of DNA methylation and a simultaneous decrease in mRNA expression in adipose tissue in response to the exercise intervention, and furthermore we observed increased lipogenesis when Ncor2 expression was down regulated in the 3T3-L1 cell line. NCOR2 is a nuclear co-repressor, involved in the regulation of genes important for adipogenesis and lipid metabolism, and with the ability to recruit different histone deacetylase enzymes, including HDAC4
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    Study finds 6 month exercise program in men induced epigenetic change via DNA methylation of CPG islands in adipose cells effecting metabolism and altering obesity and type II diabetes risk.  The study looked at 2 genes: HDAC4 and NCOR2 and found that exercise decreased expression via methylation altering adipogenesis and lipid metabolism.
Nathan Goodyear

Modulation of hypoxia-inducible factor-1 alpha in cultured primary cells by intracellul... - 0 views

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    "Induction of HIF-1α by hypoxia (1% O2) or by CoCl2 was markedly inhibited by ascorbate and loading with physiological levels resulted in almost complete reversal of HIF-1α stabilisation. Gene expression was similarly affected, with VEGF mRNA and GLUT-1 up-regulation being inhibited by ascorbate"
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