The career trajectory of Christina Erne, a meteorologist formerly at NBC 10, highlights the challenges professionals face when negotiating contracts and seeking financial stability. Beyond individual career paths, the broader scientific landscape reveals intricate connections between hormones like estrogen, metabolic health, and overall well-being. This article explores both Erne's professional decisions and the complex roles of estrogen and metabolic factors in health, drawing from various research findings.
Christina Erne's Career Crossroads
Christina Erne's departure from NBC 10 underscores the difficulties encountered when contract negotiations fail to meet financial needs. Erne stated she could not work under the terms offered by the Sinclair-owned station. According to sources, the offer was similar to past contracts, including a small pay increase, but opportunities for overtime and fill-in hours had diminished, creating a financially unsustainable situation. The station maintained its offer, and the union representing many of the workers, IBEW Local 1228, stated that the station refused to budge from its all-or-nothing offer.
Erne faced online vitriol during this period, even receiving a particularly vicious private message. Erne responded by stating, "PSA: I have no tolerance for cruelty and rudeness. If you have nothing nice to say, don’t say it at all. If you say one comment that doesn’t have to do with my forecasting, my job for the past two and a half years in southern New England, you’re blocked."
The news of Erne’s departure resulted in a large outpouring of support. "The fact that you have taken the high road is not lost,” one fan wrote. “Best wishes for much continued success.”
The Multifaceted Role of Estrogen
Estrogens, including estradiol, estrone, and estriol, are sex hormones primarily produced by the ovaries and placenta. They play a crucial role in various physiological processes, including slowing down aging. Estrogen helps maintain bone mineral density, the elasticity of blood vessels, skin elasticity and moisture, and cognitive functions of the brain. Consequently, estrogen replacement therapy (ERT) is often used to alleviate symptoms in postmenopausal women.
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However, ERT is not without potential adverse effects. Excess estrogen can lead to overexpression of estrogen receptors (ERα and ERβ), which can damage tissues and contribute to autoimmune diseases and tumors. Increased cases of breast and ovarian cancer, systemic lupus erythematosus, and multiple sclerosis suggest that the dangers of too much estrogen are worsening.
Research indicates that estrogen's effects on blood vessels are contradictory and controversial. While some studies suggest short-term estrogen intervention can have an anti-inflammatory effect, long-term use might shift to a pro-inflammatory state. In rats with spinal cord injury, low doses of estrogen reduced inflammation, attenuated cell death, and promoted angiogenesis. Conversely, estrogen or estrogen receptor (ER) signaling is highly expressed in breast cancer, endometriosis, and allergic respiratory inflammation, and it is positively correlated with systemic inflammation.
Experiments involving mice have demonstrated potential adverse effects of prolonged estrogen exposure. X-ray angiography confirmed significant stenotic segments in the suprarenal and subrenal abdominal aorta as well as bead-like changes in the carotid artery, changes in the superior mesenteric artery (including stenosis of secondary arteries), and atrophy of the kidney in the E2 group. Pathological staining of mouse abdominal aorta with HE, Masson’s trichrome, and Picro-Sirius Red revealed thickened arterial wall, disorganized smooth muscle layer structure, VSMCs proliferation, loosely arranged collagen fibers, aggregation of proliferating VSMCs into clusters and bundles, and visible hyaline degeneration of cytoplasm in the E2 group. The detection of mouse serum by ELISA confirmed that serum estrogen, CRP, and IL-6 levels were significantly elevated in the E2 group.
Estrogen and Vascular Smooth Muscle Cells (VSMCs)
Vascular smooth muscle cells (VSMCs) are differentiated cells in the middle layer of arteries, possessing contractile function and expressing marker proteins. Despite their differentiation, VSMCs maintain plasticity and can be activated from a contractile phenotype to a dedifferentiated mesenchymal cell state under harmful stimuli. This phenotypic transformation can induce secondary inflammatory responses and is closely related to the pro-inflammatory molecular environment.
In vascular diseases like atherosclerosis, vascular calcification, diabetes, and aortic aneurysms, VSMCs exhibit a hypodifferentiated state and dedifferentiate to a macrophage-like phenotype. These macrophage-like VSMCs acquire properties of immune cells, including chemotaxis, phagocytosis, and pro-inflammatory factor release, contributing to chronic inflammation in the vessel wall. Stimuli that trigger VSMC phenotypic regulation include injury, mechanical force, intracellular and extracellular microenvironment, abnormal substance accumulation, and intercellular interactions.
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KLF4 and VHL in Estrogen-Induced Inflammation
Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor involved in mammalian embryonic development and various diseases. It acts as a key initiator of VSMC dedifferentiation from a contractile phenotype to a mesenchymal-like phenotype. Von Hippel-Lindau (VHL) is a ubiquitin protein ligase that regulates the stability of KLF4 protein. Binding of estrogen to ERα results in ubiquitin-dependent downregulation of VHL, which in turn leads to accumulation of KLF4.
Studies have shown that estrogen induces transformation of VSMCs into a macrophage-like phenotype. Double staining of the abdominal aorta with ACTA2 and CD68 revealed expression of the CD68 macrophage marker on VSMCs, which was not found in the normal group. Western blot analysis of whole mouse aortas revealed increased expression of KLF4, a key protein for VSMC phenotypic transformation, in the E2 group.
Tamoxifen's Protective Effect
Tamoxifen (TAM) is an estradiol competitive antagonist that binds to ESR1 and inhibits the degradation of VHL, antagonizing the effect of E2. In a mouse model of polyarteritis, TAM ameliorated the E2-induced attenuation of mean arterial pressure and slowing of pulse rate in the tail artery of mice. TAM treatment alone, which had no significant effect on organ weight in mice, attenuated the E2-induced weight gain of the liver and did not show E2-induced kidney atrophy. In addition, TAM reduced the high estrogen, CRP, and IL-6 levels induced by E2, and it also attenuated the inflammatory response.
Estrogen Concentration and Time-Dependent Effects
Estrogen affects the phenotype of VSMCs in a concentration- and time-dependent manner. Research confirms that low concentrations of estrogen maintain the contractile phenotype of VSMCs, while higher concentrations induce significant changes in the phenotype of MOVAS cells. Treatment of MOVAS cells with 10 μM E2 for 4 days significantly upregulated CD68 expression in MOVAS cells according to immunofluorescence analysis. FCM analysis demonstrated that estrogen induced a significant increase in F4/80+ MOVAS cells.
VHL/HIF-1α/KLF4 Axis
Estrogen activates KLF4 by regulating VHL/HIF-1α, which in turn promotes phenotypic transformation of MOVAS cells. Upon binding to its receptor, estrogen inhibits the binding of VHL/VBC. VHL induces both ubiquitination degradation of KLF4 and acts to hydrolyze HIF-1α. When VHL expression is reduced, KLF4 expression rises, which in turn enters the nucleus and participates in the phenotype of vascular smooth muscle cells.
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Obesity, Metabolic Reprogramming, and G6PD
Obesity is a major risk factor for liver and cardiovascular diseases. Obesity-driven mechanisms contribute to the pathogenesis of multiple organ diseases. Increased glucose-6-phosphate dehydrogenase (G6PD), the key rate-limiting enzyme in the pentose shunt, is critical in evoking metabolic reprogramming in multiple organs and is a significant contributor to the pathogenesis of liver and cardiovascular diseases. G6PD is induced by a carbohydrate-rich diet and insulin.
Long-term (8 months) high-fat diet (HFD) feeding increased body weight and elicited metabolic reprogramming in visceral fat, liver, and aorta of wild-type rats. HFD also increased inflammatory chemokines in visceral fat. However, CRISPR-edited loss-of-function Mediterranean G6PD variant (G6PDS188F) rats, which mimic human polymorphism, moderated HFD-induced weight gain and metabolic reprogramming in visceral fat, liver, and aorta. The G6PDS188F variant prevented HFD-induced CCL7 and adipocyte hypertrophy. Furthermore, the G6PDS188F variant increased Magel2 - a gene encoding circadian clock-related protein that suppresses obesity associated with Prader-Willi syndrome - and reduced HFD-induced non-alcoholic fatty liver. Additionally, the G6PDS188F variant reduced aging-induced aortic stiffening.
G6PD and Metabolic Pathways
HFD for 8 months increased G6PD activity in VAT of wild-type rats but not in G6PDS188F rats. Metabolomic analysis revealed that metabolic phenotype was altered in VAT of HFD-fed wild-type and G6PDS188F rats. KEGG enrichment pathway analysis suggested glutathione homeostasis; glycolysis; TCA cycle; PPP; glutamyl pathway; polyamine pathway; sulfur metabolism; indole and tryptophan metabolism; and fatty acid oxidation were altered by HFD feeding in VAT, and were more altered in VAT of wild-type rats than G6PDS188F rats.
Inflammatory Responses and Chemokines
IPA network analysis predicted numerous diseases and functions changed in response to G6PD mutation. The majority of inflammatory responses, including phagocytosis, activation of T lymphocytes, and immune response of cells, changed more in HFD when compared to NC. HFD feeding increased C-C motif chemokines (CCL3, CCL5, and CCL7) in VAT both genotypes. However, HFD-induced CCL2 increase was prevented in VAT of G6PDS188F rats, and HFD-induced CCL7 increase was attenuated in VAT of G6PDS188F rats as compared to their wild-type littermates.
G6PD and Liver Health
G6PD activity was significantly lower in the liver of G6PDS188F rats as compared with wild-type rats. HFD increased G6PD activity in the liver of wild-type rats but not G6PDS188F rats. Metabolomic analysis revealed that metabolic phenotype in the liver was different between wild-type and G6PDS188F rats on NC and HFD. KEGG enrichment pathway analysis suggested glycolysis; lactate; 2-hydroxyglutarate; metabolites of the PPP; 5L-glutamyl-L-glutamine pathway; indole and tryptophan pathway metabolites; acyl-C5:1; and acyl-C18:2-OH, were significantly increased in liver of HFD fed wild-type rats more than G6PDS188F rats.