There is growing interest in the pharmaceutical and medical applications of 20-hydroxyecdysone (20E), a polyhydroxylated steroid which naturally occurs in low but very significant amounts in invertebrates, where it has hormonal roles, and in certain plant species, where it is believed to contribute to the deterrence of invertebrate predators. Studies in vivo and in vitro have revealed beneficial effects in mammals: anabolic, hypolipidemic, anti-diabetic, anti-inflammatory, hepatoprotective, etc. The possible mode of action in mammals has been determined recently, with the main mechanism involving the activation of the Mas1 receptor, a key component of the renin-angiotensin system, which would explain many of the pleiotropic effects observed in the different animal models. Processes have been developed to produce large amounts of pharmaceutical grade 20E, and regulatory preclinical studies have assessed its lack of toxicity. The effects of 20E have been evaluated in early stage clinical trials in healthy volunteers and in patients for the treatment of neuromuscular, cardio-metabolic or respiratory diseases. The prospects and limitations of developing 20E as a drug are discussed, including the requirement for a better evaluation of its safety and pharmacological profile and for developing a production process compliant with pharmaceutical standards.

https://www.mdpi.com/2227-9059/9/5/492/pdf

20-Hydroxyecdysone, from Plant Extracts to Clinical Use: Therapeutic Potential for the Treatment of Neuromuscular, Cardio-Metabolic and Respiratory Diseases

The current Severe Acute Respiratory Syndrome disease caused by Coronavirus-2 (SARS-CoV-2) has been a serious strain on the healthcare infrastructure mainly due to the lack of a reliable treatment option. Alternate therapies aimed at symptomatic relief are currently prescribed along with artificial ventilation to relieve distress. Traditional medicine in the form of Ayurveda has been used since ancient times as a holistic treatment option rather than targeted therapy. The practice of Ayurveda has several potent herbal alternatives for chronic cough, inflammation, and respiratory distress which are often seen in the SARS-CoV-2 infection. In this study we have used the aqueous extracts of Tinospora cordifolia (willd.) Hook. f. and Thomson in the form of Giloy Ghanvati, as a means of treatment to the SARS-CoV-2 spike-protein induced disease phenotype in a humanized zebrafish model. The introduction of spike-protein in the swim bladder transplanted with human lung epithelial cells (A549), caused an infiltration of pro-inflammatory immune cells such as granulocytes and macrophages into the swim bladder. There was also an increased systemic damage as exemplified by renal tissue damage and increased behavioral fever in the disease induction group. These features were reversed in the treatment group, fed with three different dosages of Giloy Ghanvati. The resultant changes in the disease phenotype were comparable to the group that were given the reference compound, Dexamethasone. These findings correlated well with various phyto-compounds detected in the Giloy Ghanvati and their reported roles in the viral disease phenotype amelioration.

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Giloy Ghanvati (Tinospora cordifolia (Willd.) Hook. f. and Thomson) Reversed SARS-CoV-2 Viral Spike-Protein Induced Disease Phenotype in the Xenotransplant Model of Humanized Zebrafish

Developing new drugs that activate the protective arm of the renin-angiotensin system as a potential treatment for respiratory failure in COVID-19 patients.

Since December 2019, coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has changed our lives. Elderly, and those with comorbidities represent the vast majority of patients hospitalized with severe COVID-19 symptoms, including acute respiratory disease syndrome, and cardiac dysfunction. Despite a huge effort of the scientific community, improved treatment modalities limiting the severity and mortality of hospitalized COVID-19 patients, are still required. Here, we compare the effectiveness of virus- and patients-centred strategies to reduce COVID-19 mortality. We also discuss the therapeutic options that might further reduce death rates associated with the disease in the future. Unexpectedly, extensive review of the literature suggests that SARS-CoV-2 viral load seems to be associated neither with the severity of symptoms nor with mortality of hospitalized patients with COVID-19. This may explain why, so far, virus-centred strategies using antivirals aiming to inhibit the viral replicative machinery, have failed to reduce COVID-19 mortality in patients with respiratory failure. By contrast, anti-inflammatory treatments without antiviral capacities but centred on patients, such as dexamethasone or Tocilizumab®, reduce COVID-19 mortality. Finally, since the spike protein of SARS-CoV-2 binds to Angiotensin Converting Enzyme 2 (ACE2) and inhibits its function, we explore the different treatment options focussing on rebalancing the Renin-Angiotensin System (RAS). This new therapeutic strategy could hopefully further reduce the severity of respiratory failure and limit COVID-19 mortality in elderly patients.

https://www.tandfonline.com/doi/pdf/10.1080/22221751.2021.2006579

A comparison between virus- versus patients-centred therapeutic attempts to reduce COVID-19 mortality.

It is established that ecdysterone (20-hydroxyecdysone) in concentration of 10(-8) M and calcitriol (1 alpha, 25-dihydroxyvitamin D3) in concentration 10(-12) M evoke in the studied tissues-targets of rats (brain, heart, liver, intestine mucosa) rapid (0.5-2 min) transit (2.5-4 times) increase of the intracellular pools of arachidonic acid, eicosanoid--total peptidoleukotrienes C4/D4/E4 (2.5-6 times), and, especially prostaglandins--stable metabolite prostacyclin 6-ketoprostaglandin F1 alpha (10-400 times). Ecdysterone in concentration 10(-11)-10(-9) inhibits arachidonic cascade in the brain and heart. Activation of arachidonic cascade and further increase of biosynthesis of cGMP are considered as a single negative link of autoregulation of activity of phospholipid-dependent signal system of cells and ecdysterone as a possible efficient modulator intracellular pools of eicosanoid in the tissues of warm-blooded animals.

[Mechanisms of the early effect of biologically active hydroxysterols: calcitriol and ecdysterone. Modulation of intracellular pools of arachidonic acid and products of its oxidative metabolism].

20-Hydroxyecdysone (20E) is a steroid hormone that plays a key role in insect development through nuclear ecdysone receptors (EcRs) and at least one membrane GPCR receptor (DopEcR) and displays numerous pharmacological effects in mammals. However, its mechanism of action is still debated, involving either an unidentified GPCR or the estrogen ER receptor. The goal of our study was to better understand 20E mechanism of action. A mouse myoblast cell line (C2C12) and the gene expression of myostatin (a negative regulator of muscle growth) was used as a reporter system of anabolic activity. Experiments using protein-bound 20E established the involvement of a membrane receptor. 20E-like effects were also observed with Angiotensin-(1-7), the endogenous ligand of Mas. Additionally, the effect on myostatin gene expression was abolished by Mas receptor knock-down using small interfering RNA (siRNA) or pharmacological inhibitors. 17-Estradiol (E2) also inhibited myostatin gene expression, but protein-bound E2 was inactive, and E2 activity was not abolished by angiotensin-(1-7) antagonists. A mechanism involving cooperation between Mas receptor and a membrane-bound palmitoylated estrogen receptor is proposed.The possibility to activate the Mas receptor with a safe steroid molecule is consistent with the pleiotropic pharmacological effects of ecdysteroids in mammals and indeed this mechanism may explain the close similarity between angiotensin-(1-7) and 20E effects. Our findings open a lot of possible therapeutic developments by stimulating the protective arm of the renin-angiotensin-aldosterone system (RAAS) with 20E.

/pdf/20-hydroxyecdysone-activates-the-protective-arm-of-the-renin-2vdjxamwkz.pdf

20-Hydroxyecdysone activates the protective arm of the renin angiotensin system via Mas receptor

Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Termination is achieved through autophagic degradation or recycling of STING by retrograde Golgi-to-ER transport. Here, we identify the GTPase ARF1 as a crucial negative regulator of cGAS-STING signaling. Heterozygous ARF1 missense mutations cause a novel type I interferonopathy associated with enhanced IFN stimulated gene expression. Disease-associated, GTPase-defective, ARF1 results in increased cGAS-STING dependent type I IFN signalling in cell lines and primary patient cells. Mechanistically, mutated ARF1 perturbs mitochondrial fusion causing cGAS activation by aberrant mitochondrial DNA, and promotes accumulation of active STING at the Golgi/ERGIC due to defective retrograde transport. Our data show that ARF1 has an unexpected dual role in maintaining cGAS-STING homeostasis, through the promotion of mitochondrial fusion and STING recycling.

/pdf/arf1-prevents-aberrant-type-i-ifn-induction-by-regulating-qzsguiid.pdf

Blaise Didry-Barca

Papers

20-Hydroxyecdysone activates the protective arm of the renin angiotensin system via Mas receptor

ARF1 prevents aberrant type I IFN induction by regulating STING activation and recycling