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Metadichol, A Novel ROR Gamma Inverse Agonist and Its Applications in Psoriasis

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Psoriasis affects 3% of the population worldwide, and there is no known cure. Psoriasis is associated with an increased risk of psoriatic arthritis, lymphomas, cardiovascular disease, and Crohn’s disease. Psoriasis treatments today include steroid and vitamin D3 cream, ultraviolet light, and immune systemsuppressing medications such as methotrexate. The T cells responsible for psoriasis are Th1 and Th l7 cells. IL-22, produced by Th17 cells, is crucial for the proliferation of keratinocytes. IL-22 with the help of IL-17 can induce the critical events of psoriasis. To maintain Th17 cells, IL-23 is required, and it is released from tumor necrosis factor-alpha (TNF-alpha) induced pathways. The pathophysiology of psoriasis involves RORC (retinoic acid receptor-related orphan nuclear receptor gamma) as a critical transcription factor for the development of Th17 cells. FDA has approved an antibody Secukinumab® targeting TNF-α for the treatment of psoriasis. Other FDA approved drugs are Tremfya® targeting IL23 for treatment of moderate to severe plaque psoriasis and Taltz® that blocks IL17 for treatment of plaque psoriasis. Metadichol® a nanoformulation of long-chain lipid alcohols derived from food is a TNF-alpha inhibitor and also binds to Vitamin D receptor (VDR) that could have beneficial effects on Psoriasis. VDR modulates Th1-mediated inflammatory disease like psoriasis. We now present evidence that Metadichol is an inverse agonist of RORγt and AHR (Aryl Hydrocarbon Receptor) thus controlling Th17, IL17 and IL22. Being a TNF-alpha inhibitor, it can control IL23 thus blocking the significant pathways that exacerbate psoriasis. We present case studies of 7 patients afflicted with psoriasis and skin related conditions and how treatment with Metadichol resolved the underlying disease. Metadichol® has properties that allow its use as a safe nontoxic solution to combating the growing number of psoriasis cases
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... This paper deals with Metadichol ® expression on UCB cells leading to increased CD33 expression similar to what we saw in CD34 expression. The increased expression observed with CD33 could be one possible mechanism that could explain its diverse pharmacological actions of Metadochol ® on multiple diseases [25][26][27][28][29][30][31][32][33][34][35][36][37][38]. ...
... We have shown previously that Metadichol ® binds to VDR whose natural ligand is Calcitriol. We have published Metadichol's action on biomarkers implicated in various diseases [25][26][27][28]. It exhibits antimicrobial activity against parasites, viruses, and bacteria. ...
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CD33 also known as Siglec-3 is endogenously expressed in stem cells and is a marker for the myeloid lineage of cells. Increased expression of CD33 thus allows it to bind to any Sialic Acids (SIAs). These acids are binding sites for pathogens and toxins. By binding to these acids, CD33 can prevent invasion of hosts by these pathogens. Down-regulation of CD33, increase the release of the pro-inflammatory cytokine TNF-α by monocytes that increases reactive oxygen species that are involved in diseases like diabetes mellitus, Alzheimer's, cardiovascular diseases asthma, and in various cancers. The up-regulation of CD33 using Metadichol ® was studied using Wharton's Jelly Mesenchymal Stem Cells (MSCs) isolated from human umbilical cord and were grown in p-35 dishes until confluent and treatment was carried out with different concentrations. One dish was untreated and considered as control. The treated and untreated cells were analyzed using Flow Cytometry. The cells treated at 100 pg of Metadichol ® has shown the highest increase (>400 fold) in CD33++ expression (48.77%) compared to untreated control (0.11%).
... Given the effect of Metadichol on the expression of critical genes involved in the reprogramming of somatic cells, the effects of Metadichol should be assessed in patients to determine if the in vitro results translate to in vivo effects. Previous studies (37,38) treating various skin diseases with Metadichol showed skin renewal, including wound healing and rejuvenation. Such a strategy to harness the body's cells, thus avoiding the incompatibility issues associated with external donor cell sources, would likely be effective in mitigating many human diseases, including cardiovascular and neurological disorders. ...
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... It is likely that Metadichol® is behaving as a protean agonist. Metadichol is also an inverse agonist of other nuclear receptors VDR, AHR (Aryl hydrocarbon receptor) and RORC (RAR related Orphan receptor C) [24,27,28]. ...
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... It is likely that Metadichol® is behaving as a protean agonist. Metadichol is also an inverse agonist of other nuclear receptors VDR, AHR (Aryl hydrocarbon receptor) and RORC (RAR related Orphan receptor C) [24,27,28]. With the experimental data of binding to the thyroid receptors use a web-based program like EviNet [29] to see the network enrichment analysis of the genes of interest. ...
Article
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An estimated 200 million individuals worldwide have a thyroid disorder. Thyroid diseases affect seven times more women than men. People not diagnosed make up the majority of thyroid patients. There is a need to find novel and safe ways to change the underlying disease processes, rather than merely stop excess thyroid hormone production as in hyperthyroidism. Metadichol® is a nano emulsion of an extract of long-chain alcohols from food that is an inverse agonist of VDR (Vitamin D receptor), AHR (Aryl Hydrocarbon Receptor), and RORC (RAR Related Orphan Receptor C). The work presented here shows that Metadichol® is an inverse agonist of THRA (Thyroid Receptor Alpha) and THRB (Thyroid Receptor Beta). Case studies are presented that show how it can safely treat a multitue of thyroid related diseases. Network and pathway enrichment studies are presented that show how Metadichol® may be involved in action on multiple receptors and exerting its effects through multiple pathways. Metadichol® is the first of a breed of molecules that moves the goal post from the concept of ‘one drug, one target’ toward simultaneously targeting multiple targets, that can potentially lead to successful treatment of many diseases. Given the safety profile of Metadichol®, it would not only mitigate thyroid disease but prevent it and reducing the burden on healthcare budgets worldwide.
... T-helper cell (Th17) cells a subset of T cells are critical to inflammation [74]. VDR leads to a TH2 response, and Metadichol is a inverse agonist of ROR gamma thus blocking the Th17 pathway [75]. Since CCL2, TNF and ICAM 1 are all inhibited and thus IFN gamma the whole process is driven towards a VDR driven ...
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... When constitutive activity is present, the Protean agonist would be an inverse agonist. Metadichol an extract of sugar cane wax exhibits properties that could also be considered as an Adaptogens [33] which are unique in their ability to balance endocrine hormones and the immune system [34][35][36][37]. Adaptogens help maintain optimal homeostasis in the body. ...
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... When constitutive activity is present, the Protean agonist would be an inverse agonist. Metadichol an extract of sugar cane wax exhibits properties that could also be considered as an Adaptogens [33] which are unique in their ability to balance endocrine hormones and the immune system [34][35][36][37]. Adaptogens help maintain optimal homeostasis in the body. ...
Article
Full-text available
Klotho is an anti-aging protein that is mostly secreted by the kidneys, the brain, and the thyroid. It plays a significant role in regulating kidney function and vascular health. Klotho gene is named after "the Spinner" (Clotho from Greek mythology), the goddess who spins the thread of life. Klotho is a transmembrane protein known to be a co-receptor for Fibroblast Growth Factor-23. Klotho gene is expressed in a variety of tissues changes in the levels are associated with many diseases. Klotho is a tumor suppressor in breast cancer and its expression is reduced in human pancreatic adenocarcinoma, and treatment with klotho inhibits the growth of pancreatic cancer cells in vitro and in vivo. Growing evidence suggests that an increase in KL expression may be beneficial for age-related diseases such as arteriosclerosis and diabetes. It remains a challenge today to induce Klotho expression. Herein we show that treating pancreatic cancer cells PANC1, MIAPACA and COLO-205 with Metadichol® a novel food based lipid emulsion of long chain alcohols at picogram/ml, concentration led to a 4-10 fold increase in Klotho expression as seen quantitative RT-PCR. These results suggest the use of Metadichol® given its constituents that are present in foods we consume every day is a novel therapeutic intervention for pancreatic cancer and other diseases.
... It is an inverse agonist of VDR (Vitamin D receptor) AHR (Aryl hydrocarbon receptor), RORC (Retinoic acid receptor gamma) and a TNF alpha inhibitor. We have recently documented how Metadichol is effective against Psoriasis [11]. The gene cluster targeted by Metadichol are predicted by Topp gene cluster program [12] to target other skin diseases as shown in Figure 2. One can also see that Skin diseases are related to each other as predicted by Disease Connect [13], which is based on curated experimental data as shown in Figure 3. ...
... It is an inverse agonist of VDR (Vitamin D receptor) AHR (Aryl hydrocarbon receptor), RORC (Retinoic acid receptor gamma) and a TNF alpha inhibitor. We have recently documented how Metadichol is effective against Psoriasis [11]. The gene cluster targeted by Metadichol are predicted by Topp gene cluster program [12] to target other skin diseases as shown in Figure 2. One can also see that Skin diseases are related to each other as predicted by Disease Connect [13], which is based on curated experimental data as shown in Figure 3. ...
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