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Friday Hope: Finerenone: Preventing Endothelial Dysfunction, Inflammation and Fibrosis 周五希望：菲尼酮：预防内皮功能障碍、炎症和纤维化

This mineralocorticoid receptor antagonist (MRA) may prove highly effective in treating Long COVID and in preventing Spike Protein Endothelial Disease and sequelae.
WALTER M CHESNUT
JAN 31

https://open.substack.com/pub/wmcresearch/p/friday-hope-finerenone-preventing

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The direct deleterious effects of aldosterone/MR activation in the heart and kidneys and the common pathophysiological mechanisms involved. The benefits of MRAs in interrupting these pathways are also illustrated. 11-BHSD2 indicates 11β-hydroxysteroid dehydrogenase type 2; AP-1, activator protein-1; CTGF, connective tissue growth factor; NADPH oxidase, nicotinamide adenine dinucleotide phosphate-oxidase; MAPK, mitogen-activated protein kinase; MR, mineralocorticoid receptor; MRA, mineralocorticoid receptor antagonist; NF-κB, nuclear factor-κB; NO, nitric oxide; ROS, reactive oxygen species; SGK-1, serum- and glucocorticoid-induced protein kinase-1; and TGF-β, transforming growth factor-β.

It has been shown that the Spike Protein of SARS-CoV-2, through either infection or transfection, can cause kidney (multiple-organ) and endothelial damage.

According to recent studies, the SARS-CoV-2 spike protein found in vaccines may lead to kidney damage, either directly or indirectly (Figure 2). These studies have shown that certain tissue antigens, including transglutaminase 3, antiextraction nuclear antigen and thyroid peroxidase, can strongly react with SARS-CoV-2 antibodies.147 COVID-19 vaccines activate antigen-presenting cells (APCs), which, upon receiving a second vaccination, trigger robust CD4+ T-cell and CD8+ T-cell responses. This process results in the release of significant amounts of inflammatory cytokines (IFN-c, TNF-α, IL-2, IFN-γ and TNF), which can promote a cytokine storm and lead to damage to renal tissue.148,149 The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (S) has the ability to bind to natural antibodies in the body, which can lead to the formation of circulating immune complexes and their deposition in the glomeruli.150

It is currently speculated that COVID-19 vaccines, which target the spike protein as an immunogenic target, may also activate the complement system and lead to endothelial damage.

New insights into kidney disease after COVID-19 infection and vaccination: histopathological and clinical findings
https://academic.oup.com/qjmed/article/117/5/317/7218935

Several mechanisms are discussed above explaining how the Spike Protein may induce kidney and endothelial damage. However, there is one mechanism which is not mentioned. This is the mechanism of mineralocorticoid receptor activation. Please note that we will be discussing activation in not only the kidney, but also the heart, endothelium and immune system.

What is mineralocorticoid receptor (MR) activation?

MR expression has been demonstrated in vivo in vascular endothelial cells and vascular smooth muscle cells of interlobar arteries in mouse kidneys and ex vivo in cultured podocytes, mesangial cells, and renal fibroblasts.3 The MR is also expressed in multiple cell types in the heart, including cardiomyocytes, coronary endothelial and vascular smooth muscle cells, fibroblasts, and inflammatory cells, such as macrophages.5

Aldosterone and the glucocorticoid cortisol bind to the MR with similar affinities. Plasma concentrations of glucocorticoids are 100- to 1000-fold higher than those of aldosterone. Overstimulation of the MR is prevented by the coexpression of 11β-hydroxysteroid dehydrogenase type 2 (11-BHSD2). This enzyme converts cortisol into cortisone, which has a lower affinity for the MR. 11-BHSD2 activity has been demonstrated in both the kidneys and heart;6,7 however, expression of 11-BHSD2 varies in different cell types, with some cells, such as cardiomyocytes, having very low levels of 11-BHSD2. There is not yet consensus on whether aldosterone or cortisol activates the MR in these cells, but direct effects of aldosterone have still been observed, suggesting mechanisms yet to be determined fully may operate to allow the binding of aldosterone to the MR.8,9

Once aldosterone binds to the MR, the hormone–receptor complex dimerizes, migrates into the nucleus, and binds to a specific DNA sequence, triggering the transcription of target genes. It takes ≈1 hour for the classic genomic action of aldosterone to start to have a biological effect, with complete changes in gene expression not apparent for hours or days.10 A second, more rapid, nongenomic pathway, the effects of which are short-lived, has also been described, although the physiological and clinical relevance of this pathway remains to be established.11,12

The principal functional role of the MR in normal kidneys is to control sodium reabsorption and potassium secretion.3 The function of the MR in the healthy heart is not fully understood, but may include regulation of cardiomyocyte growth and cardiac electrophysiology.6,13

Mineralocorticoid Receptor Activation and Mineralocorticoid Receptor Antagonist Treatment in Cardiac and Renal Diseases
https://www.ahajournals.org/doi/10.1161/hypertensionaha.114.04488

In endothelial cells, aldosterone promotes oxidative injury and endothelial disfunction [19,20] as MR activation is involved in vascular calcification and fibrosis, stiffness, and inflammation [21]. Furthermore, the activation of mineralocorticoid receptors (MR) has been found to have additional pathological effects on the immune system and pro-inflammatory cells. This includes the stimulation of the infiltration of pro-inflammatory M1 macrophages as opposed to M2 macrophages, increased proliferation of fibroblasts, the production of molecules that promote fibrosis [22], and a reduction in nitric oxide levels due to the influence of MR on the expression of the epithelial sodium channel in the endothelium [23].

Finerenone: Questions and Answers—The Four Fundamental Arguments on the New-Born Promising Non-Steroidal Mineralocorticoid Receptor Antagonist
https://pmc.ncbi.nlm.nih.gov/articles/PMC10299719/

So, why look at Finerenone as a possible therapeutic for Long COVID/Spike Protein exposure? Because the Spike Protein activates mineralcorticoid receptors!

Vascular endothelial cells activation and dysfunction mediate inflammation and abnormal coagulation in COVID-19 patients. Mineralocorticoid receptor (MR) signaling and its downstream target Galectin-3 (Gal-3) are known to mediate cardiovascular inflammation and might be involved in the pathogenesis of COVID-19 complications. Accordingly, we aimed to investigate the potential beneficial effects of MR antagonism and Gal-3 inhibition on the inflammatory response induced by SARS-CoV-2 Spike protein in human aortic endothelial cells (HAECs). Methods: HAECs were treated with recombinant SARS-COV2 Spike (S) protein. MR antagonists (namely spironolactone and eplerenone) or the Gal-3 inhibitor G3P-01 were supplemented before and after S protein challenge. HAECs supernatants were assessed by ELISA or Western blotting. Results: HAECs treated with recombinant S protein resulted in enhanced secretion of inflammatory molecules (interleukin-6, monocyte chemoattractant protein-1, interleukin-18, interleukin-27, and interferon-γ) as well as in the thrombosis marker plasminogen activator inhibitor (PAI)-1. This was prevented and reversed by both MR antagonists and G3P-01. Conclusions: These findings indicate that MR/Gal-3 pathway blockade could be a promising option to reduce endothelial inflammation in SARS-CoV-2 infection.

Beneficial Effects of Mineralocorticoid Receptor Pathway Blockade against Endothelial Inflammation Induced by SARS-CoV-2 Spike Protein
https://pmc.ncbi.nlm.nih.gov/articles/PMC8228852/

It is my hope that clinicians will evaluate these findings and consider Finerenone in the treatment of their patients suffering from Long COVID/Spike Protein disease/injury. Please remember this is a work of medical research and not medical advice. Always consult your Primary Care Provider before using any medication or supplement.

We need clinical trials, clearly. I am quite optimistic that Finerenone may become a very prominent, effective player in treating those suffering from Long COVID/Spike Protein disease/injury. It is very cold here in northern Vermont. I look forward to keeping warm with a good game of chess tomorrow. Thank you for your gracious and generous support, readership and dialogue. I will continue to search for answers. 星期五希望：Finerenone：预防内皮功能障碍，炎症和纤维化该矿物质激素受体拮抗剂（MRA）可以证明高效治疗长的Covid和预防穗蛋白内皮疾病和后遗症 沃尔特M Chesnut Jan 31在aldosterone / Mr激活的直接有害影响中阅读，心脏和肾脏和常见的病理生理机制。 还说明了MRAS中断这些途径的益处。 11-BHSD2表明11β-羟类脱氢酶2型; AP-1，活化剂蛋白-1; CTGF，结缔组织生长因子; NADPH氧化酶，烟酰胺腺嘌呤二核苷酸磷酸氧化酶; MAPK，丝裂原激活蛋白激酶; Mr，Mineralocortoidoid受体; MRA，Mineralocortoid受体拮抗剂; NF-κB，核因子-κB; 不，一氧化氮; ROS，反应性氧气; SGK-1，血清和糖皮质激素诱导的蛋白激酶-1; 和TGF-β，转化生长因子-β。 已经证明，通过感染或转染的SARS-COV-2的尖峰蛋白可导致肾（多器官）和内皮损伤。 根据最近的研究，疫苗中发现的SARS-COV-2尖峰蛋白可能导致直接或间接肾脏损伤（图2）。 这些研究表明，某些组织抗原，包括转谷氨酰胺酶3，抗表达核抗原和甲状过氧化物酶，可以强烈地与SARS-COV-2抗体反应.147 Covid-19疫苗活化抗原 - 该方法导致释放大量的炎性细胞因子（IFN-C，TNF-α，IL-2，IFN-γ和TNF），其可以促进细胞因子风暴并导致肾组织损伤.148,149 Covid-19感染和疫苗接种后对肾病的新见解：组织病理学和临床发现HTTPS://…上面讨论了多种机制 然而，有一种没有提及的机制。 这是矿物质激素受体激活的机制。 请注意，我们将不仅讨论活化，不仅是肾脏，还要讨论心脏，内皮和免疫系统。 什么是矿物皮质激素受体（MR）活化？ 在血管内皮细胞和小鼠肾脏中的血管内皮细胞和血管平滑肌细胞中的体内表达先生表达，在培养的致统治的致统粒细胞，乳房细胞和肾纤维细胞中，血管平滑肌细胞。 糖皮质激素的血浆浓度高于醛固酮100至1000倍。 通过11β-羟类脱氢酶2（11-BHSD2）的共表达预防MR的过度刺激。 该酶将皮质醇转化为可可酮，其对MR具有较低的亲和力。 在肾脏和心脏中都证明了11-BHSD2活性;然而，6,7然而，11-BHSD2的表达在不同的细胞类型中变化，具有一些细胞，例如心肌细胞，具有极低的11-BHSD2。 尚未对这些细胞中的MR激活的尚未观察到这些细胞中的先生的共识，但仍然观察到醛固酮的直接效果，表明尚未确定的机制可以进行操作，以便允许醛固酮与醛固酮的结合一次ALD。 醛固酮的经典基因组作用开始具有生物学效应的经典基因组作用需要，在基因表达的完全变化不明显，几乎没有明显的数小时或天.10秒，更快速，不良途径，其效果是短暂的，也是如此 此外，已发现矿物质皮质激素受体（MR）的活化对免疫系统和促炎细胞具有额外的病理作用。 这包括刺激促炎M1巨噬细胞的浸润，而不是M2巨噬细胞，增加成纤维细胞的增殖，促进纤维化的分子的产生[22]，以及降低一氧化氮水平 FINERENONE：问题和答案 - 新出生的非甾体矿物皮质激素受体拮抗剂HTTPS:/…因为尖峰蛋白激活了矿物质激素受体！ 血管内皮细胞活化和功能障碍在Covid-19患者中介导和异常凝固。 已知矿物皮质激素受体（MR）信号传导及其下游靶Galectin-3（Gal-3）介导心血管炎症，并且可能参与Covid-19并发症的发病机制。 因此，我们旨在探讨先生拮抗作用和GAL-3抑制对人主动脉内皮细胞（HAECs）中SARS-COV-2穗蛋白诱导的炎症反应的潜在有益效果。 方法：用重组SARS-COV2穗蛋白处理HAECs。 在S蛋白质攻击之前和之后，补充了拮抗剂（即锭骨内酯和ePLERENONE）或GAL-3抑制剂G3P-01。 通过ELISA或Western Blotting评估HAECS上清液。 结果：用重组蛋白处理的HAECS导致炎性分子的分泌增强（白细胞介素-6，单核细胞化学蛋白-1，白细胞介素-18，白细胞介素-27和干扰素-γ）。 这是由拮抗剂和G3P-01的预防和逆转的。 结论：这些发现表明，MR / GAL-3途径阻断可能是减少SARS-COV-2感染中内皮炎症的有希望的选择。 矿物质激素受体途径阻断对SARS-COV-2穗蛋白HTTPS:/…诱导的诱导的内皮炎症 请记住这是医学研究的工作，而不是医疗建议。 在使用任何药物或补充之前，请始终咨询您的初级保健提供者。 我们需要清楚地需要临床试验。 我非常乐观地，Finerenone可能成为一种非常突出的有效的球员，治疗患有长的Covid /穗蛋白疾病/损伤的人。 在佛蒙特北部，这里很冷。 我期待着明天的棋子很好的温暖。 感谢您的慷慨和慷慨的支持，读者和对话。 我将继续寻找答案。