Another theoretical possibility involves
11B-HSD1 inhibition.
Mastic gum inhibits 11B-HSD1 which converts the inactive cortisone to the active cortisol form. Others here had success with
green tea that contains
EGCG and this is another 11B-HSD1 inhibitor.
Coumestrol (alfalfa) and
glycyrrhetinic acid (liquorice) also inhibit 11B-HSD1, however they inhibit other 17B-HSD types as well, so they are not selective.
Besides
E. japonica Banaba leaf extract also contains
corosolic acid which is an 11B-HSD1 inhibitor and could be a good thing to investigate. Furthermore
fenofibrate is a selective 11B-HSD1 inhibitor while ketoconazole is a selective 11B-HSD2 inhibitor. As a side note Banaba leaf and fenofibrate are PPARA agonists as well.
Although alfalfa and liquorice work for me, recently I have retested matcha tea and green tea and I had to realize that they don't work in my case. This makes it more likely that my case is connected to 17B-HSDs, but I am still going to test mastic gum if I have the opportunity.
The microsomal enzyme 11B-hydroxysteroid deydrogenase type 1 (11B-HSD1) catalyzes the interconversion of glucocorticoid receptor-inert cortisone to receptor-active cortisol, thereby acting as an intracellular switch for regulating the access of glucocorticoid hormones to the glucocorticoid receptor. There is strong evidence for an important aetiological role of 11B-HSD1 in various metabolic disorders including insulin resistance, diabetes type 2, hypertension, dyslipidemia and obesity. Hence, modulation of 11B-HSD1 activity with selective inhibitors is being pursued as a new therapeutic approach for the treatment of the metabolic syndrome.
Indeed we found that tea extracts inhibited 11B-HSD1 mediated cortisone reduction, where green tea exhibited the highest inhibitory potency with an IC50 value of 3.749 mg dried tea leaves per ml.
(?)-Epigallocatechin gallate (EGCG) revealed the highest inhibition of 11B-HSD1 activity (reduction: IC50?=?57.99 uM; oxidation: IC50?=?131.2 uM). Detailed kinetic studies indicate a direct competition mode of EGCG, with substrate and/or cofactor binding. Inhibition constants of EGCG on cortisone reduction were Ki?=?22.68 uM for microsomes and Ki?=?18.74 uM for purified 11B-HSD1.https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084468The short-chain dehydrogenase/reductase (SDR) enzyme family are nicotinamide adenine dinucleotide NAD (phosphate (P))-dependent enzymes.
The SDR family contains HSDs that play key roles in adrenal and gonadal steroidogenesis as well as in the metabolism of steroids in peripheral tissues. Some of these HSDs are considered as promising therapeutic targets for the treatment of estrogen- and androgen-dependent diseases such as osteoporosis, endometriosis, and breast and prostate cancer, and other enzymes gained interest regarding the treatment of corticosteroid-related diseases such as diabetes, visceral obesity and dyslipidemia, atherosclerosis, wound healing, glaucoma, neurodegenerative disease, and cognitive impairment.
The two isoenzymes of 11B-HSD catalyze the interconversion of the biologically inactive cortisone and the active cortisol. The 11B-HSD1 is ubiquitously expressed and mediates the regeneration of active glucocorticoids, whereas 11B-HSD2 catalyzes the inactivation of glucocorticoids mainly in the kidney, colon and placenta. There is evidence for beneficial effects of 11B-HSD1 inhibition in the metabolic syndrome, atherosclerosis, osteoporosis, glaucoma, cognitive functions, skin aging, and wound healing. Thus, inhibition of 11B-HSD1 has substantial therapeutic potential for glucocorticoid-related diseases. Numerous 11B-HSD1 inhibitors have already been identified and some have reached the clinical phase, but to date still no 11B-HSD1 inhibitor is on the market.
These models identified compounds resembling the structure of the known unselective 11B-HSD inhibitor glycyrrhetinic acid (GA), steroid-like compounds, and novel structural classes.
Earlier investigations led to the assumption that extracts from the anti-diabetic medical plant loquat (Eriobotrya japonica) dose-dependently and preferentially inhibit 11B-HSD1 over 11B-HSD2. Therefore, the virtual screening hit corosolic acid, a known constituent of E. japonica, was tested and identified as potent inhibitor of human 11B-HSD1 with an IC50 of 810 nM. Subsequent bioassay-guided phytochemical analyses revealed further secondary metabolites from the triterpenoid ursane type as 11B-HSD1 inhibitors with IC50 in the micromolar range. Importantly, a mixture of the constituents with moderate inhibitory activities displayed an additive effect. This is a common observation in phytotherapy, where a mixture of constituents is often responsible for the therapeutic effect.
Both the refined 11B-HSD1 (A) and 11B-HSD2 (B) model identified novel scaffolds. The inhibitor fenofibrate maps the 11B-HSD1 model (A) and ketoconazole matches the 11B-HSD2 model.
Using the refined 11B-HSD1 model, Vuorinen et al. applied a VS to filter a database consisting of constituents from medicinal plants to identify potential 11B-HSD1 inhibitors focusing on triterpenoids present in Pistacia lentiscus (P. lentiscus), so-called mastic gum that is used in traditional Greek medicine for the treatment of diabetes. The VS hit list contained eight hits of P. lentiscus constituents. The two main constituents of mastic gum, masticadienonic acid and isomasticadienonic acid, were chosen for further biological evaluation. Both compounds were shown to selectively inhibit 11B-HSD1 over 11B-HSD2 with IC50 values of 2.51 uM for masticadienonic acid and 1.94 uM for isomasticadienonic acid, respectively. Examination of the whole resin's activity revealed half the IC50 value of the single molecules, suggesting an additive inhibitory effect. Thus, the hypothesis of 11B-HSD1 involvement in the antidiabetic activity of mastic gum was supported.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332202/
