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

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  • Independent Researcher

Abstract

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 result has a profound impact on the regulation of many biological processes, such as development, metabolism, reproduction, inflammation, and circadian rhythm. Previously we have shown that it binds to VDR, AHR, THRA, THRB, and RORC [12,34,35,36]. . It is not therefore surprising that Metadichol ® effects multiple pathways in diseases. ...
... Similarly, our results suggest that metadichol could be useful in inducing apoptosis in cancer cells by increasing Klotho expression, which also has benefits in other diseases. The current study and previously published results [41][42][43][44] suggest that the observed results could have been due to increased Klotho expression [45]. The potential therapeutic utility of metadichol in elevating Klotho levels warrants further study in vitro and in vivo. ...
... Similarly, our results suggest that Metadichol could be useful in inducing apoptosis in cancer cells by increasing Klotho expression and this also has benefits in other diseases. The current study and previously published results (39)(40)(41)(42) suggest that the observed results could have been been due to increased Klotho expression (43). The potential therapeutic utility of Metadichol in elevating Klotho levels warrants further study in vitro and in vivo. ...
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Klotho is a well-known tumor suppressor hormone that exhibits anti-cancer and anti-aging properties. Klotho levels are low or non-existent in cancer patients. Klotho protein levels decrease with aging; maintaining consistent levels may prevent disease and promote healthier aging. Metadichol is a nano emulsion of long-chain alcohols C26, C28, and C30, of which C-28 constitutes over 85%. Any small molecule that can elevate Klotho can, in principle, help reverse many diseases in which Klotho levels are low. Previously, we showed that treatment of the pancreatic cancer cell lines PANC1, MIA-PACA, and COLO-205, combined with Metadichol, a lipid emulsion consisting of long-chain alcohols at 1-100 pg/mL concentrations, resulted in a 4- to 10-fold increase in Klotho expression as determined by qRT-PCR, This study aimed to demonstrate that Metadichol promotes Klotho expression in a wide variety of cell lines, such as primary cancer, stem, and somatic cell lines. Cells were treated with various concentrations of Metadichol ranging from 1 pg to 1 µg. Three to fifteen fold increase in Klotho expression was observed compared with baseline, as measured by qRT-PCR and qualified by western blot analysis. Metadichol is a natural agonist of Klotho expression and is non-toxic at levels up to 5000 mg/kg in rats. and has a potential therapeutic role in cancer and reversing aging.
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The conversion of somatic cells back into induced pluripotent stem cells (iPSCs) or embryonic-like stem cells involves the introduction of four genes commonly called Yamanaka factors: SOX2, OCT4, KLF4, and c-MYC. One drawback is that these genes and the viral vectors used to introduce them into cells have the potential to cause cancer, and these iPSC lines are not clinically useful. Most instances of direct reprogramming have been achieved by the forced expression of defined factors using viral vectors. In this paper, we show that Metadichol® has the potential to generate iPSCs non-virally and may be helpful in clinical applications. Metadichol is a Nano formulation of long-chain alcohols derived from food. Quantitative real-time PCR (qRT-PCR) and western blotting showed that OCT4, SOX2, and NANOG are expressed when fibroblasts were treated with Metadichol at concentrations of one picogram to 100 nanograms. Reverse-transcription PCR (RT-PCR) resulted in OCT4, KLF4, NANOG, and SOX2 levels increased relative to controls by 4.01, 3.51 and 1.26, and 2.5 times, respectively. Such multifold increases were also seen in A549 cancer cell lines and in Colo-205 cells. Reprogramming human primary cancer cells remains a challenge. We present data that even primary cancer cells show increases in the four Yamanaka factors. Metadichol treatment of triple-negative primary breast cancer (HCAF-TNPBC) primary cancer cells led to increases in OKSM factors by 19.6, 8.07, 2.45, and 6.91 times in concentration ranges of 1 picogram to 100 nanograms. Metadichol induces the expression of Klotho, an antiaging gene, that curbs the expression of the TP53 gene, as this is a pre-requisite for reprogramming somatic cells into iPSCs. Metadichol also increases endogenous vitamin C levels, which is necessary for the efficient reprogramming of somatic cells into iPSCs. Metadichol an extract from food that is nontoxic, which opens the door to direct testing in humans with the potential for applications in stem cell therapy
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The conversion of somatic cells back into induced pluripotent stem cells (iPSCs) or embryonic-like stem cells involves the introduction of four genes commonly called Yamanaka factors, i.e., Sox2, Oct4, Klf4, and c-Myc, into the cells. Because these genes and the viral vectors used to introduce them into cells have the potential to cause cancer, iPSC lines are not clinically useful. Most instances of direct reprogramming have achieved have been by the forced expression of defined factors using viral vectors. Here, we show that Metadichol® has the potential to generate iPSCs non-virally and may be helpful in clinical applications. Metadichol is a nanoformulation of long-chain alcohols derived from food. Quantitative real-time PCR (qRT-PCR) and western blotting showed that OCT4, SOX2, and Nanog are expressed when fibroblasts were treated with Metadichol at one picogram to 100 nanograms. Reverse-transcription PCR (RT-PCR) also revealed that OCT4, KLF4, Nanog, and Sox2 levels increased compared to controls by 4.01, 3.51 and 1.26, and 2.5-fold, respectively, in A549 cancer cells. In Colo-205 cells, OCT4, KLF4, and Sox2 were increased by 1.79, 13.17, and 2.25folds, respectively. Metadichol treatment with triple-negative primary breast cancer (HCAF-TNPBC) primary cancer cells led to multifold increases of OKSM factors by 19.6, 8.07, 2.45, and 6.91, folds increase in Metadichol concentration ranges one picogram to 100 nano grams. Metadichol is a natural product that induces the expression of Yamanaka factors needed for reprogramming and Klotho, an anti-aging gene, and curbs the expression of the TP53 gene, which is critical for reprogramming somatic cells into IPSCs.Metadichol increases endogenous vitamin C levels, leading to the efficient reprogramming of somatic cells into iPSCs. Metadichol is nontoxic and commercially available as a nutritional supplement. Thus, it can be directly tested in vivo in human subjects to confirm that cells can indeed be programmed into a state of induced pluripotency and cause the mitigation of disease conditions.
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Human nuclear receptors (NRs) involve 49 ligand-dependent transcription factors that are important for regulating the cell cycle and processes. There are many literature references to work on NR expression in many organs, abnormal cells, and tissues. However, a simple universal method to study the expression of NR is still missing. Here, we present systematic profiling of NRs in human umbilical cord stem cell lines and assess the expression of the 48 human NRs by quantitative real-time (qRT)-PCR using Metadichol, a nanoemulsion made of natural lipid alcohol. Metadichol-treated umbilical cord cells and fibroblasts, where all cells expressed NRs at a concentration range of 1 pg-100 ng/mL in a dependent manner, were detected by qRT-PCR and qualified by Western blotting. This method will allow the study of many organs and tissues and expand our understanding of the role of NRs and their role in mitigating diseases. Highlights Metadichol treatment of somatic cells leads to nuclear receptor expression Depending on the cell and concentration of Metadichol used, fold changes are different The method could be used to study many cells and disease cells to better understand NR expression patterns and implications. The results suggest that Metadichol is a universal ligand to all nuclear receptors.
Preprint
Full-text available
The conversion of somatic cells back into induced pluripotent stem cells (iPSCs) or embryonic-like stem cells involves the introduction of four genes commonly called Yamanaka factors, i.e., Sox2, Oct4, Klf4, and c-Myc, into the cells. Because these genes and the viral vectors used to introduce them into cells have the potential to cause cancer, iPSC lines are not clinically useful. Most instances of direct reprogramming have been achieved by the forced expression of defined factors using viral vectors. Here, we show that Metadichol® has the potential to generate iPSCs nonvirally and may be helpful in clinical applications. Metadichol is a nanoformulation of long-chain alcohols derived from food. Quantitative real-time PCR (qRT-PCR) and western blotting showed that OCT4, SOX2, and Nanog are expressed when fibroblasts were treated with Metadichol at one picogram to 100 nanograms. Reverse-transcription PCR (RT-PCR) also revealed that OCT4, KLF4, Nanog, and Sox2 levels increased compared to controls by 4.01-, 3.51- and 1.26-, and 2.5-fold, respectively, in A549 cancer cells. In Colo-205 cells, OCT4, KLF4, and Sox2 were increased by 1.79-, 13.17-, and 2.25-fold, respectively. Metadichol treatment with triple-negative primary breast cancer (HCAF-TNPBC) primary cancer cells led to multifold increases in OKSM factors by 19-, 6-, 8.07-, 2.45-, and 6.91-fold in concentration ranges of 1 picogram to 100 nanograms. Metadichol is a natural product that induces the expression of Yamanaka factors needed for reprogramming and Klotho, an antiaging gene, and curbs the expression of the TP53 gene, which is critical for reprogramming somatic cells into IPSCs. Metadichol increases endogenous vitamin C levels, leading to the efficient reprogramming of somatic cells into iPSCs. Metadichol is nontoxic and commercially available as a nutritional supplement. Thus, it can be directly tested in vivo in human subjects to confirm that cells can indeed be programmed into a state of induced pluripotency and cause the mitigation of disease conditions.
Preprint
Full-text available
Human nuclear receptors (NRs) involve 49 ligand-dependent transcription factors that are important for regulating the cell cycle and processes. There are many literature references to work on NR expression in many organs, abnormal cells, and tissues. However, a simple universal method to study the expression of NR is still missing. Here, we present systematic profiling of NRs in human umbilical cord stem cell lines and assess the expression of the 48 human NRs by quantitative real-time (qRT)-PCR using Metadichol, a nanoemulsion made of natural lipid alcohol. Metadichol-treated umbilical cord cells and fibroblasts, where all cells expressed NRs at a concentration range of 1 pg-100 ng/mL in a dependent manner, were detected by qRT-PCR and qualified by Western blotting. This method will allow the study of many organs and tissues and expand our understanding of the role of NRs and their role in mitigating diseases.
Preprint
Full-text available
The human nuclear receptor (NR) consists of 49 ligand-dependent transcription factors that play a critical role in development, metabolism, reproduction, cell cycle, differentiation, and diseases, e.g., cancer and cardiovascular disease, to name a few. Today, we have gene sequencing data on NR presence in many organs, disease cells, and tissues. We do not have a simple universal method to study the expression of NR that small molecules can induce in various cell diseased and non-diseased states. Here in we present systematic profiling of NRs in human umbilical cord stem cell lines and Expression of the 48 human NRs was assessed by quantitative real-time PCR. using Metadichol a nano-emulsion natural lipid alcohol treated Umbilical cord cells, Fibroblasts, cells expressed all the nuclear receptors at a concentration of 1 picogram per ml to 100 nanogram per ml in a concentration-dependent manner as seen by Q-RT-PCR and qualified by Western blot. This method will allow the study of many organs and tissues and expand our understanding of the role of NR in normal and disease states.
Preprint
Full-text available
The conversion of somatic cells back into induced pluripotent stem cells (iPSCs) or embryonic-like stem cells involves the introduction of four genes commonly called Yamanaka factors, i.e., Sox2, Oct4, Klf4, and c-Myc, into the cells. Because these genes and the viral vectors used to introduce them into cells have the potential to cause cancer, iPSC lines are not clinically useful. Most instances of direct reprogramming have achieved have been by the forced expression of defined factors using viral vectors. Here, we show that Metadichol® has the potential to generate iPSCs non-virally and may be helpful in clinical applications. Metadichol is a nanoformulation of long-chain alcohols derived from food. Quantitative real-time PCR (qRT-PCR) and western blotting showed that OCT4, SOX2, and Nanog are expressed when fibroblasts were treated with Metadichol at one picogram to 100 nanograms. Reverse-transcription PCR (RT-PCR) also revealed that OCT4, KLF4, Nanog, and Sox2 levels increased compared to controls by 4.01, 3.51 and 1.26, and 2.5-fold, respectively, in A549 cancer cells. In Colo-205 cells, OCT4, KLF4, and Sox2 were increased by 1.79, 13.17, and 2.25folds, respectively. Metadichol treatment with triple-negative primary breast cancer (HCAF-TNPBC) primary cancer cells led to multifold increases of OKSM factors by 19, 6, 8.07, 2.45, and 6.91folds in concentration ranges one picogram to 100 nano grams. Metadichol is a natural product that induces the expression of Yamanaka factors needed for reprogramming and Klotho, an anti-aging gene, and curbs the expression of the TP53 gene, which is critical for reprogramming somatic cells into IPSCs.Metadichol increases endogenous vitamin C levels, leading to the efficient reprogramming of somatic cells into iPSCs. Metadichol is nontoxic and commercially available as a nutritional supplement. Thus, it can be directly tested in vivo in human subjects to confirm that cells can indeed be programmed into a state of induced pluripotency and cause the mitigation of disease conditions.
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