Title: Metadichol® is a nano lipid emulsion that expresses all 48 nuclear receptors in stem and somatic cells

Abstract

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.

Full text

Research Article
Volume 7 • Issue 3 524
Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear
Receptors in Stem and Somatic Cells
Palayakotai R. Raghavan1*
Abstract
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 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 proling
of NRs in human umbilical cord stem cell lines and assess the expression
of the 49 human NRs by quantitative real-time (qRT)-PCR using
Metadichol, a nanoemulsion made of natural lipid alcohol. Metadichol-
treated umbilical cord cells and broblasts, where all cells expressed NRs
at a concentration range of 1 picogram per ml to 100 ng per ml in a dose
dependent manner, were detected by qRT-PCR and qualied by Western
blotting. This method will allow the study of many organs and tissues and
expand our understanding of the role of NRs in mitigating diseases.
Highlights:
Metadichol treatment of somatic cells leads to all 49 nuclear receptors
being expressed.
Depending on the cell and concentration of Metadichol used, fold changes
are dierent
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.
Metadichol is controlling regulation of the expression of Nuclear receptors
Aliation:
1Nanorx Inc, PO Box 1131, Chappaqua, NY 10514,
USA
*Corresponding author:
Palayakotai R. Raghavan. Nanorx Inc, PO Box 1131,
Chappaqua, NY 10514, USA.
E-mail: raghavan@nanorxinc.com
Citation: Palayakotai R. Raghavan. Metadichol®
A Nano Lipid Emulsion that Expresses All 49
Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7
(2023): 524-536.
Received: October 03, 2023
Accepted: October 10, 2023
Published: October 18, 2023
Keywords: Nuclear receptors; Stem cells; Fibroblasts; Ahr; Vitamin C;
Sertolli cells; Chromatin; Qrt-Pcr; Metadichol; Nanoemulsion.
Introduction
Nuclear receptors (NRs) are transcription factors usually activated by
small lipophilic molecules [1]. The 49 AHR (aryl hydrocarbon receptor)
NRs, which are highly conserved in the human genome, are subdivided
into seven subfamilies based on amino acid sequences (NOR, NR1, NR2,
NR3, NR4, NR5, and NR6) [2]. Many NRs are classied as orphan receptors
because they lack a specic ligand for activation [3]. Unliganded NRs are
bound to heat shock protein 90 (HSP90) and can be found in the cytosol
and nucleus. Receptors may also bind to corepressors without ligands [4].
1,25-dihydroxyvitamin D3 is a small molecule that can diuse through the
cell membrane and bind to NRs located in the cytosol or nucleus of the cell
[5]. This binding leads to several downstream events that eventually result
in up- or downregulation of gene expression. The NR ligands exhibit a

Raghavan PR., Arch Clin Biomed Res 2023
DOI:10.26502/acbr.50170368
Citation: Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
Volume 7 • Issue 3 525
broad spectrum of full, partial, inverse agonist, or antagonist
activities. Selective NR modulators activate only a subset
of the functions induced by the ligand or act in a cell-type-
selective manner [6]. Chromatin plays a crucial role in the
actions of NR by modulating interactions with regulatory
elements in the genome. However, when receptor binding
occurs, chromatin changes that impact receptor signaling [7].
NRs bind to sDNA sequences, leading to modication of the
chromatin structure. The nal outcome leads to modulation
of RNA polymerase activity resulting in increased or
decreased transcription. transcription (Zaret and Yamamoto,
1984). Chromatin modication leads to pathways that impact
NR action in various cells. Chromatin remodeling leads
to numerous processes that involve pluripotency, cellular
dierentiation, inflammation, DNA damage and repair
and tumor suppression [8]. NR regulation and its tissue-
expression prole along with the associated cofactors are
necessary to separate desirable therapeutic ecacies from
undesirable side eects. One of the least studied areas is the
regulation of NR ligands by NRs themselves. [8] reported
NR expression proles in human and mouse embryonic stem
cell lines and during their early dierentiation into embryoid
bodies [9]. The expression of the 49 human and mouse NRs
was assessed by quantitative real-time (qRT)-PCR. Hong et
al. evaluated the expression of the receptors for estrogen,
progesterone, and glucocorticoids [10]. Very little is known
about systemic NR expression in human cell lines. In this
research, we present the specic roles of NRs in human
cell lines by characterizing the RNA and cDNA expression
proles of the NR superfamily while treating stem cells and
broblasts with metadichol [11], which is a nanoemulsion
of long-chain alcohols [12], using qRT-PCR and Western
blotting methods.
Methods
The methods, including qRT-PCR, Western blotting,
and cell culture, were carried out by a commercial service
provider, Skanda Life sciences, Bangalore, India. The
procurement of chemicals and reagents was as follows.
Human mesenchymal stem cells and normal human dermal
broblast cells were procured from ATCC (USA). Primary
antibodies were from either ABclonal, Woburn, (both in
Massachusetts, USA) or Elabscience, Maryland, USA.
The primers were from Sahagene, Hyderabad, India. Other
molecular biology reagents were from Sigma-Aldrich, India.
Cell maintenance and seeding
We preserved the cells in a suitable medium with
1% antibiotics in a wet atmosphere of 5% CO2 at 37 °C.
We changed the medium every two days until the cells
reached confluency, and we assessed their viability using a
hemocytometer. At 70%-80% confluency, we prepared and
seeded single-cell suspensions containing 106 cells/mL in
six-well plates at a density of 106 cells/well. We incubated the
cells for 24 h at 37 °C in 5% CO2, rinsed the cell monolayer
with serum-free medium and treated it with Metadichol at
preset concentrations.
Cell treatment
We prepared Metadichol in serum-free media at dierent
concentrations (1 pg/mL, 100 pg/mL, 1 ng/mL, and 100 ng/
mL) and then added them to predesignated wells. Note that
the control cells were drug-free. We incubated the cells for 24
h. Next, we washed them gently with sterile PBS. We isolated
RNA using TRIzol following the manufacturer’s instructions
and prepared cDNA followed by the analysis of several
biomarkers using qPCR and Western blotting.
RNA isolation
We separated total RNA using TRIzol reagent
(Invitrogen) and collected approximately 106 cells in 1.5 mL
microcentrifuge tubes. The cells were centrifuged at 5,000
rpm for 5 min at 4 °C, and the supernatant was removed.
Next, we added 650 µL of TRIzol to the pellet and mixed the
solution to be incubated on ice for 20 min. Subsequently, we
added 300 µL of chloroform and mixed the samples well by
gentle inversion for 1–2 min and then incubated them on ice
for 10 min. We centrifuged the samples at 12,000 rpm for 15
min at 4 °C and carefully transferred the upper aqueous layer
to a new sterile 1.5 mL centrifuge tube, to which we added
an equal amount of prechilled isopropanol and incubated the
samples at −20 °C for 60 min. Afterward, we centrifuged
the mixture at 12,000 rpm for 15 min at 4 °C and prudently
removed the supernatant. The RNA pellets were retained and
washed with 1.0 mL of 100% ethanol, followed by 700 µL of
70% ethanol via centrifugation as described previously after
each step. We air-dried the RNA pellets at room temperature
for almost 15–20 min and then resuspended them in 30 µL of
DEPC-treated water. We quantied the RNA concentration
using a SpectraMax i3x  SpectraDrop Micro-Volume
Microplate (Molecular Devices, USA) and synthesized
cDNA using reverse transcription-PCR.
cDNA synthesis
Following the manufacturer’s guidelines, we synthesized
cDNA from 2 µg of RNA using the PrimeScript cDNA
synthesis kit (Takara, France) and oligo dT primers. The
reaction volume was 20 μL, and cDNA synthesis was
performed at 50 °C for 30 min, followed by 85 °C for 5 min
on an Applied Biosystems instrument (Veritii). The obtained
cDNA was used in the following step for qPCR.
Primers and qPCR
The PCR blend (nal volume of 20 µL) contained 1 µL
of cDNA, 10 µL of SYBR green Master Mix, and 1 µM
complementary primers specic for the particular target
genes. We ran the samples at the following settings: primary

Raghavan PR., Arch Clin Biomed Res 2023
DOI:10.26502/acbr.50170368
Citation: Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
Volume 7 • Issue 3 526
Protein isolation
We isolated total protein from 106 cells using RIPA
buer supplemented with the protease inhibitor PMSF. We
applied a mild inversion for 30 min at 4 °C to lyse the cells
and then centrifuged them at 10,000 rpm for 15 min. Finally,
we transferred the supernatant to a fresh tube and determined
the protein concentration using the Bradford method, where
25 µg of protein was mixed with 1X sample loading dye
containing SDS and loaded on a gel. Under denaturing
conditions, we separated the proteins using Tris-glycine
running buer.
Western blotting
We transferred the proteins to methanol activated PVDF
membranes (Invitrogen, USA) using a Turbo transblot
system (Bio Rad, USA). We blocked the membranes with
5% BSA for 1 h and incubated them with the respective
primary antibody overnight at 4 °C followed by a species-
specic secondary antibody for 1 h at room temperature.
We rinsed the blots and incubated them with ECL substrate
(Merck, USA) for 1 min in the dark and captured the images
at suitable exposure settings using a ChemiDoc XRS system
(Bio Rad, USA).
denaturation at 95 °C for 5 min followed by 30 cycles of a
secondary at 95 °C for 30 s, then hardening at the optimized
temperature for 30 s, with an extension at 72 °C for 1 min.
We identied the number of cycles that allowed amplication
in the exponential range without reaching a plateau as the
optimal number of cycles. We evaluated the results using
CFX Maestro software and computed the fold change via the
following equation.
ΔΔCT method
We determined the relative expression of the target gene
in relation to the housekeeping gene (β-actin) and untreated
control cells by the comparative CT method.
The ΔCT for each treatment was calculated using the
formula:
ΔCT = CT (target gene) – CT (reference genes).
To obtain a ΔΔCT, we subtracted the individual samples
between the treated and control groups as follows:
ΔΔCT = ΔCT (treatment group) – ΔCT (control group).
Similarly, we calculated the fold change in the target gene
expression for each treatment using the formula.
Fold change = 2^ (-ΔΔCT)
Gene Primers Base pairs
NR1C2/PPARD F CCTTCTCAAGTATGGCGTGC 226
R GATGGCCGCAATGAATAGGG
RXRG F CAGGAAAGCACTACGGGGTA 254
R CCTCACTCTCAGCTCGCTCT
PPARG F AGAAGCCTGCATTTCTGCAT 236
R TCAAAGGAGTGGGAGTGGTC
NR2F1 F CATTTTTGGGCGATCTCCAGG 261
R GCCTTCTTCTTTCGGGAGGT
HNF4A F ACTGCCACGTACCTGTGCCT 274
R AGGCATGCGAGTTGTGACCA
HNF4G F AGCTGGCATATCTCAGCTGGC 185
R AACACCTGGCTGGCAATCGG
NR2F2 F CTCAACTGCCACTCGTACCT 253
R TCAACACAAACAGCTCGCTC
NR1I3 F CAGCAAACACCTGTGCAACT 189
R TGCGAAGTGTGTGACCAGAG
NR1H4 F AACAGAACAAGTGGCAGGTC 201
R AGAGTCTCAGCTGGCATACG
ESR1 F GATGTGGGAGAGGATGAGGA 165
R TCAGGCATGCGAGTAACAAG
Table 1: List of primers used for Q-RT-PCR

Raghavan PR., Arch Clin Biomed Res 2023
DOI:10.26502/acbr.50170368
Citation: Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
Volume 7 • Issue 3 527
ESR2 F TTCAGCCTGTGACCTCTGTG 178
R CTTGGTTTGTCCAGGACGTT
ESRRA F CAGGGGAGCATCGAGTACAG 303
R CTTCTCAGGCTCAACCACCA
NR1D2 F AGTTCTTCCAGCTCAGCCTC 226
R TTGTCATCCCAGGTGCACTC
ESRRB F CTTGGTTTGTCCAGGACGTT 264
R TTTTCCATCATGGCTTGACA
NR5A2 F TCCAGCTTCCAGGCAGCCTC 234
R GATCTGTGAATCTGCGTT
NR3C2 F CTGCCTCGTTTCCCTTTTCC 231
R CCATGATCTGTGCGTTCCTG
NR0B2 F GCTGTCTGGAGTCCTTCTGG 164
R CTGGGTATGAATCCCAGCAC
ESRRG F GACTTGACTCGCCACCTCTC 174
R GTGGTACCCAGAAGCGATGT
NR4A2 F CCGGTGTCTAGTTGCCAGAT 275
R ACGCCGTAGTGTTGGCAG
NR2F6 F GGACTCTGGCTTCTCTCCTC 187
R TAGGGGTGCTGAGGAACAAG
NR6A1 F GAGGAACAGGTGCCAGTACT 175
R GGCCTCTTCCTCAAACTCCT
THRB F GCCTCCAATAGCTCCAGGAT 201
R CACCCAGTTCCAGGATTCCT
VDR F GACGCCCACCATAAGACCTA 247
R AGATTGGAGAAGCTGGACGA
NR1H2 F CCTCCTGAAGGCATCCACTA 261
R GAACTCGAAGATGGGGTTGA
NR1D1 F AGGCAGCAAGCAAGCAGT 291
R ACAGCGCATCCTTCCCCATA
NR2C1 F CCCAAGGCAAGCAGTTCATT 157
R GCAGACAGATCAGGAGTGGT
NR2C2 F TCACCACCTCAGACAACCTC 164
R ACTGACAGCCCCATAGTGAC
NR1I2 F AACGCAGATGAGGAAGTCGG 103
R AGCCCTTGCATCCTTCACAT
NR4A3 F GCCCAATATAGCCCTTCCCC 224
R TGCATTTGGTACACGCAGGA
NR3C1 F CTTGCATATTTGTGCCTTCA 174
R CTTGATGATTTGTGTTGTGC
AR F GGGGCTAGACTGCTCAACTG 169
R GCCAAGTTTTGGCTGAAGAG
NR0B1 F CAGAGGCCAGGGGGTAAAG 137
R TGCGCTTGATTTGTGCTCGT

Raghavan PR., Arch Clin Biomed Res 2023
DOI:10.26502/acbr.50170368
Citation: Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
Volume 7 • Issue 3 528
PGR F ACATGGTAGCTGTGGGAAGG 198
R GCTAAGCCAGCAAGAAATGG
RORA F TCGAACCAGTAGAAACCGCT 219
R TTGGCCGAGATGTTGTAGGT
RORB F CTCACTTCTCCACCTGCTCA 212
R GGAGTTGGTGGCTGGGATAT
RORC F AGTCGGAAGGCAAGATCAGA 204
R CAAGAGAGGTTCTGGGCAAG
NR2E3 F GGAGTCCAACACTGAGTCCC 289
R GGCCATGAAGAGTAGGCGAG
NR5A1 F AGGCACCAGGGAAGATCA 241
R TGCCAGGCCAGGGAATACA
NR2E1 F CAAGTGGGCTAAGAGTGTGC 158
R CGTTCATGCCAGATACAGCC
NR4A1 F GCCAATCTCCTCACTTCCCT 202
R CAGCAAAGCCAGGGATCTTC
RARA F GTGTCACCGGGACAAGAACT 146
R CGTCAGCGTGTAGCTCTCAG
RXRA F CTCTGTTGTGTCCTGTTGCC 155
R CTTCTCCCTTTGCGTGTTCC
PPARA F CTGTCTGCTCTGTGGACTCA 247
R AGAACTATCCTCGCCGATGG
RARB F GGTTTCACTGGCTTGACCAT 216
R GGCAAAGGTGAACACAAGGT
AHR F GGTTTCACTGGCTTGACCAT 274
R CAGAGGACCAAATCCAGCAT
RARG F GAAGACCGCGACACAACTTCC 180
R GTTGAGTTAAGACATGAGGG
RXRB F GCAGGAGTAGGAGCCATCTT 188
R GCATACACTTTCTCCCGCAG
THRA F ACCTCCATCCCACCTATTCC 242
R CTCTTCAGGAGTGGGCTCTG
NR1H3 F GAGATCCTCCCGTGGCATTA 151
R GAGAACCCTGTGCAAAGTGG
F, forward; R, reverse
Metadichol concentrations 1 pg 100 pg 1 ng 100 ng
Common name Nomenclature name
DAX1 0.19 0.33 0.38 0.11 NR0B1
SHP 1.39 0.75 1.06 0.29 NR0B2
TRα 16.16 12.24 7.7 5.32 NR1A1
TRβ 7.71 1.94 15.11 8.71 NR1A2
RARα 1.27 0.79 0.52 0.44 NR1B1
Table 2: Metadichol and Human Mesenchymal Stem Cells and fold changes of NR’s

Raghavan PR., Arch Clin Biomed Res 2023
DOI:10.26502/acbr.50170368
Citation: Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
Volume 7 • Issue 3 529
RARB 1.67 1.39 0.48 0.73 NR1B2
RARγ 2.52 1.04 0.96 0.82 NR1B3
PPARα 4.66 3.48 3.92 1.35 NR1C1
PPAR-β/δ 3.74 4.5 4.5 0.44 NR1C2
PPARG 1.82 1.7 1.03 1 NR1C3
Rev-ErbAα 1.93 1.29 0.8 0.6 NR1D1
Rev-ErbAβ 0.89 0.47 0.35 0.15 NR1D2
RORα 1.77 1.39 0.94 0.67 NR1F1
RORβ 0.81 0.84 0.7 0.33 NR1F2
RORγ 0.52 0.74 1.19 1.08 NR1F3
LXRB 1.28 0.97 0.55 0.19 NR1H2
LXRα 1.28 1.17 0.84 0.18 NR1H3
FXR 1.98 1.09 0.53 0.6 NR1H4
VDR 2.03 0.92 3.67 0.54 NR1I1
PXR 0.6 0.74 1.11 0.39 NR1I2
CAR 8.03 1.49 2.91 10.61 NR1I3
HNF4A 0.99 0.72 0.51 0.13 NR2A1
HNF4γ 1.39 1.51 0.36 0.26 NR2A2
RXRA 1.4 1.21 0.99 0.79 NR2B1
RXRB 1.87 1.13 1.05 0.69 NR2B2
RXRG 2.15 2.2 1.5 0.76 NR2B3
TR2 1.3 1.27 0.74 0.39 NR2C1
TR4 1.6 1.5 0.74 0.51 NR2C2
TLX 0.95 1.37 1.18 0.57 NR2E1
PNR 2.18 1.23 1.51 1.25 NR2E3
COUP-TFI 1.78 1.57 1.04 0.65 NR2F1
COUP-TFII 1.81 1.48 1.15 1.07 NR2F2
EAR-2 0.98 0.95 0.43 0.08 NR2F6
ERα 1.86 1.17 1.94 0.4 NR3A1
ERβ 1.81 1.37 1.09 0.66 NR3A2
ERRα 1 0.88 0.59 0.35 NR3B1
ERRβ 1.11 2.32 1.45 1.36 NR3B2
ERRγ 1.84 1.02 0.55 0.18 NR3B3
GR 0.99 0.86 0.82 0.09 NR3C1
MR 1.15 0.78 0.52 0.21 NR3C2
PR 1.19 0.94 0.67 0.12 NR3C3
AR 1.15 0.37 0.11 0.33 NR3C4
NGFIB 1.82 0.67 1.16 0.61 NR4A1
NURR1 1.06 0.61 0.45 0 NR4A2
NOR1 5.43 1.89 0.35 0.5 NR4A3
SF1 3.2 2.56 1.92 5.09 NR5A1
LRH1 1.3 0.72 0.29 0.15 NR5A2
GCNF 1.7 0.86 0.65 0.15 NR6A1
AHR 0.39 0.58 0.79 0.51 AHR

Raghavan PR., Arch Clin Biomed Res 2023
DOI:10.26502/acbr.50170368
Citation: Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
Volume 7 • Issue 3 530
Metadichol concentrations 1pg 100pg 1ng 100ng
Common Name Nomenclature
DAX1 1.76 0.14 0.44 0.24 NR0B1
SHP No Detectable
expression
No Detectable
expression
No Detectable
expression
No Detectable
expression NR0B2
TRα 1.2 0.65 0.55 0.69 NR1A1
TRβ 1.15 1.18 2.4 0.92 NR1A2
RARα 2.15 1.81 0.63 1.06 NR1B1
RARB 2.68 1.3 1.18 1.1 NR1B2
RARγ 2.84 2.95 3.9 1.09 NR1B3
PPARα 1.9 1.24 0.72 1.8 NR1C1
PPAR-β/δ 2.48 2.59 2.83 0.84 NR1C2
PPARG 3.78 6.11 7.31 3.07 NR1C3
Rev-ErbAα 1.5 0.64 0.07 0.75 NR1D1
Rev-ErbAβ 2.19 1.18 1.8 1.82 NR1D2
RORα 0.9 1.14 1.33 1.01 NR1F1
RORβ 2.71 0.99 0.69 0.88 NR1F2
RORγ 1.86 1.02 0.91 1.04 NR1F3
LXRB 4.95 1.03 0.03 1.71 NR1H2
LXRα 1.63 1.79 3.84 0.71 NR1H3
FXR 2.69 1.32 1.27 0.87 NR1H4
VDR 1.83 2.34 2.35 1.54 NR1I1
PXR 1.81 0.37 0.97 1 NR1I2
CAR 0.98 0.67 0.49 0.53 NR1I3
HNF4A 6.03 3.4 2.69 3.64 NR2A1
HNF4γ 2.15 1.39 1.2 1.95 NR2A2
RXRA 2.5 0.86 1.32 0.98 NR2B1
RXRB 4.21 1.65 1.03 2.7 NR2B2
RXRG 2.84 2.95 3.9 1.09 NR2B3
TR2 1.08 1.16 1.7 0.85 NR2C1
TR4 3.66 1.38 1.09 4.17 NR2C2
TLX 3.38 1.49 1.69 0.88 NR2E1
PNR 1.43 1.46 2.48 1.27 NR2E3
COUP-TFI 0.16 0.9 4.18 0.5 NR2F1
COUP-TFII 1.05 1.19 2.98 0.59 NR2F2
EAR-2 2.84 1.22 1.66 1.02 NR2F6
ERα 2.42 1.58 0.73 2.02 NR3A1
ERβ 3.04 3.04 1.25 1.52 NR3A2
ERRα 10.31 8.3 6.58 11.1 NR3B1
ERRβ 0.92 0.74 0.48 1.76 NR3B2
ERRγ 0.81 1.07 1.86 0.45 NR3B3
GR 1.71 0.14 0.77 0.45 NR3C1
MR 3.7 0.26 1.04 0.42 NR3C2
PR 0.71 1.25 2.19 0.51 NR3C3
AR 2.54 0.15 0.57 0.11 NR3C4
NGFIB 2.36 1.55 0.93 3.42 NR4A1
NURR1 3.56 6.02 8.63 7.62 NR4A2
NOR1 2.14 0.72 1.48 1.59 NR4A3
SF1 27.27 13.78 13.28 2.69 NR5A1
LRH1 3.32 1.79 1.74 2.02 NR5A2
GCNF 2.46 0.83 0.39 2.19 NR6A1
AHR 10.17 4.32 3.79 1.52 AHR
Table 3: Metadichol and normal human dermal broblasts and Fold changes of NR’s

Raghavan PR., Arch Clin Biomed Res 2023
DOI:10.26502/acbr.50170368
Citation: Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
Volume 7 • Issue 3 531
Discussion
Assuming a threshold of plus or minus 50% for the
fold increase/decrease, 25 NRs were upregulated with stem
cells and 36 with broblasts at a one pg ( picogram per ml)
concentration. SF1 (NR5A1) showed the highest increase of
27-fold in broblasts and 5-fold in stem cells. NR5A1 plays
an essential role in Steroidogenesis, a biological process by
which the body needs key steroid hormones for functioning
that are generated from cholesterol. This process aects
sexual dierentiation, reproduction, fertility, hypertension,
obesity, and physiological homeostasis [13]. NR5A1 guides
somatic cells to fetal Sertoli cells [14]. The latter are vital
nurse cells located in the testis that aim at controlling
spermatogenesis, i.e., production of the male germ cells.
Sertoli cells also secrete cytokines and growth factors;
therefore, they control immune processes that defend germ
cells from immunological attack [15,16,17]. Additionally,
they aid in blocking the multiplication of T, B, and NK cells.
These observations lead to lowering the immune response in
cell transplantation in diabetes and neurogenerative diseases,
skin implants, and other illnesses [18]. However, defects
in Sertoli cells can cause infertility. Alternately, Oct 4, a
pluripotent transcription factor, is involved in maintaining
self-renewal in stem cells and somatic cells [19, 20]. In this
context, SF1 is critical in regulating the transcription of
Oct4. However, NR5A2 (LRH-1) can program somatic cells,
leading to iPSCs, and thus can replace Oct4 and result in
a better yield of iPSCs [21]. The substantial fold increases
of NR5A1 is of enormous signicance for the reproduction
and survival of the human species. We did not detect SHP
(NROB2) expressed in broblasts but it is down regulated
in stem cells. [22]. normal cells, such as embryonic stem
cells or early embryos, down-regulation of SHP-1 can also
aect the expression of Nanog, a key pluripotency factor
that maintains the self-renewal and dierentiation potential
of these cells. Nanog expression is regulated by STAT3
phosphorylation, which is negatively controlled by SHP-
1 (23) . Therefore, down-regulation of SHP-1 can increase
STAT3 phosphorylation and Nanog expression, which
enhances the pluripotency and reprogramming of these
cells. This can have implications for regenerative medicine
and stem cell. Another possible explanation is that SHP
gene transcription is constantly induced by the expression
and activation of nuclear factor-erythroid two (NRF2),
which encodes NFE2L2 [24]. In addition, NRF2 is vital in
controlling the adverse eects of electrophilic and oxidative
stress [23] and does so by activating the expression of a
wide array of antioxidant response genes. On the one hand,
applying NRF2 activators in clinical trials [24] could prevent
cancer and treat some diseases related to oxidative stress
but on the other hand, integral triggering of NRF2 in many
cancers can lead to the survival and proliferation of tumor
cells, as well as resistance to anticancer therapy [26]. [27]
revealed that the NRF2 signaling pathway can be regulated
and inhibited with NRs such as RARα, RXRα, PPARγ, ERα,
ERRβ, and GR [28]. These Nuclear receptors are expressed
by both stem cells and broblasts, and we see SHP is
downregulated in stem cells and not expressed in broblasts.
Figure 1: Feedback-loop Network Nuclear Receptor Interactions

Raghavan PR., Arch Clin Biomed Res 2023
DOI:10.26502/acbr.50170368
Citation: Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
Volume 7 • Issue 3 532
Cell processes
regulated by
entities enriched
in the input
Total
# of
Neighbors
Gene Set Seed Overlap Percent
Overlap Overlapping Entities p-value
Protein regulators
of energy
homeostasis
1185 energy
homeostasis 39 3
PPARD,RXRG,PPARG,HNF4A,NR2F2,NR1I3,NR1H4,
ESR1,ESR2,ESRRA,NR1D2,ESRRB,NR5A2,NR3C2,N
R0B2,ESRRG,NR4A2,THRB,VDR,NR1H2,NR1D1,NR
2C2,NR1I2,NR4A3,NR3C1,AR,RORA,RORB,RORC,N
R5A1,NR4A1,RARA,RXRA,PPARA,RARB,AHR,RARG
,THRA,NR1H3
8.3839E-34
Protein regulators
of gene
repression
737 gene repression 33 4
PPARD,PPARG,NR2F1,HNF4A,NR2F2,NR1H4,E
SR1,ESR2,NR1D2,NR5A2,NR3C2,NR0B2,NR2F
6,NR6A1,THRB,VDR,NR1D1,NR1I2,NR3C1,AR,N
R0B1,PGR,RORA,NR5A1,NR2E1,NR4A1,RARA,-
RXRA,PPARA,RARB,AHR,RXRB,THRA
1.6368E-31
Protein regulators
of transcription
activation
3198 transcription
activation 48 1
PPARD,PPARG,HNF4A,HNF4G,NR1I3,NR1H4,ESR1,
ESR2,ESRRA,NR1D2,ESRRB,ESRRG,THRB,NR1H2,
NR2C1,NR2C2,NR1I2,NR4A3,AR,NR0B1,PGR,NR2E3
,NR2E1,RXRA,AHR,RXRB,NR2F1,NR2F2,NR5A2,NR3
C2,NR0B2,NR4A2,NR2F6,NR6A1,VDR,NR1D1,NR3C1
,RORA,RORB,RORC,NR5A1,NR4A1,RARA,PPARA,R
ARB,RARG,THRA,NR1H3
9.7744E-31
Protein
regulators of liver
metabolism
524 liver metabolism 27 5
PPARD,RXRG,PPARG,HNF4A,NR1I3,NR1H4,ESR1,E
SRRA,NR5A2,NR0B2,ESRRG,THRB,VDR,NR1H2,NR
1D1,NR1I2,NR4A3,NR3C1,AR,RORA,RORC,NR5A1,N
R4A1,RXRA,PPARA,AHR,NR1H3
1.4922E-26
Protein
regulators of lipid
homeostasis
652 lipid
homeostasis 28 4
PPARD,RXRG,PPARG,HNF4A,NR1I3,NR1H4,ESR1,E
SR2,ESRRA,NR1D2,NR5A2,NR3C2,NR0B2,VDR,NR1
H2,NR1D1,NR2C2,NR1I2,NR3C1,AR,NR0B1,RORA,N
R4A1,RXRA,PPARA,AHR,THRA,NR1H3
1.8223E-25
Protein
regulators of lipid
metabolism
2420 lipid metabolism 41 1
PPARD,RXRG,PPARG,HNF4A,HNF4G,NR2F2,NR1I3,
NR1H4,ESR1,ESR2,ESRRA,NR1D2,NR5A2,NR3C2,N
R0B2,ESRRG,NR6A1,THRB,VDR,NR1H2,NR1D1,NR2
C2,NR1I2,NR4A3,NR3C1,AR,NR0B1,PGR,RORA,ROR
B,RORC,NR5A1,NR4A1,RARA,RXRA,PPARA,AHR,RA
RG,RXRB,THRA,NR1H3
1.1817E-24
Protein
regulators of
steroidogenesis
879 steroidogenesis 29 3
PPARD,PPARG,NR2F1,NR2F2,NR1H4,ESR1,ESR2,E
SRRA,NR1D2,ESRRB,NR5A2,NR0B2,ESRRG,THRB,
VDR,NR1H2,NR1D1,NR1I2,NR3C1,AR,NR0B1,PGR,N
R5A1,NR4A1,RXRA,PPARA,AHR,RXRB,NR1H3
2.9507E-23
Protein regulators
of cholesterol
homeostasis
393 cholesterol
homeostasis 22 5
PPARD,PPARG,NR1I2,HNF4A,HNF4G,NR3C1,AR,NR
1I3,NR1H4,RORA,ESR1,NR1D2,NR5A2,NR0B2,RXRA
,PPARA,THRB,AHR,NR1H2,NR1D1,RXRB,NR1H3
4.9509E-22
Protein
regulators of
gluconeogenesis
1164 gluconeogenesis 30 2
PPARD,PPARG,HNF4A,HNF4G,NR1I3,NR1H4,E
SR1,ESRRA,NR1D2,NR3C2,NR0B2,ESRRG,VD
R,NR1H2,NR1D1,NR2C2,NR1I2,NR4A3,NR3C1,
AR,NR0B1,RORA,RORC,NR5A1,NR4A1,RARA,P
PARA,AHR,THRA,NR1H3
4.2944E-21
Protein regulators
of lipogenesis 1428 lipogenesis 32 2
PPARD,RXRG,PPARG,HNF4A,HNF4G,NR1I3,N
R1H4,ESR1,ESR2,ESRRA,NR1D2,NR5A2,NR3C
2,NR0B2,ESRRG,NR6A1,THRB,VDR,NR1H2,NR
1D1,NR2C2,NR1I2,NR3C1,AR,NR0B1,RORA,NR
4A1,RXRA,PPARA,AHR,RARG,NR1H3
5.7662E-21
Table 4: Cell processes regulated by the nuclear receptors

Raghavan PR., Arch Clin Biomed Res 2023
DOI:10.26502/acbr.50170368
Citation: Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
Volume 7 • Issue 3 533
Protein regulators
of fatty acid
oxidation
1046 fatty acid
oxidation 28 2
PPARD,PPARG,HNF4A,NR2F2,NR1I3,NR1H4,ESR1,E
SRRA,NR0B2,ESRRG,NR4A2,THRB,VDR,NR1H2,NR
1D1,NR1I2,NR4A3,NR3C1,RORA,RORC,NR4A1,RXR
A,PPARA,RARB,AHR,RARG,THRA,NR1H3
7.108E-20
Protein regulators
of chromatin
remodeling
1626 chromatin
remodeling 32 1
PPARD,RXRG,PPARG,NR2F1,HNF4A,NR1H4,E
SR1,ESR2,ESRRB,NR5A2,NR3C2,NR0B2,THRB,
VDR,NR1D1,NR2C1,NR2C2,NR4A3,NR3C1,AR,P
GR,RORA,RORC,NR5A1,NR4A1,RARA,RXRA,P
PARA,RARB,AHR,THRA,NR1H3
2.9862E-19
Protein regulators
of fatty acid beta-
oxidation
537 fatty acid beta-
oxidation 22 4
PPARD,RXRG,PPARG,NR1I2,NR2F1,HNF4A,AR,NR1
I3,NR1H4,PGR,ESR1,ESRRA,NR0B2,ESRRG,NR4A1,
RARA,RXRA,PPARA,VDR,AHR,NR1H2,NR1H3
4.2967E-19
Protein regulators
of adipocyte
di󰀨erentiation
1455 adipocyte
di󰀨erentiation 30 2
PPARD,PPARG,NR2F2,NR1H4,ESR1,ESR2,ESRRA,N
R1D2,NR5A2,NR3C2,ESRRG,NR4A2,NR2F6,VDR,NR
1D1,NR4A3,NR3C1,AR,NR0B1,RORA,RORC,NR4A1,
RARA,RXRA,PPARA,RARB,AHR,RARG,THRA,NR1H3
2.4971E-18
Protein
regulators of cell
development
4071 cell development 43 1
PPARD,PPARG,NR2F1,HNF4A,NR2F2,NR1H4,ESR1,
ESR2,ESRRA,NR1D2,ESRRB,NR5A2,NR3C2,NR0B2,
ESRRG,NR4A2,NR2F6,NR6A1,THRB,VDR,NR1H2,NR
1D1,NR2C2,NR1I2,NR4A3,NR3C1,AR,NR0B1,PGR,R
ORA,RORB,RORC,NR2E3,NR5A1,NR2E1,NR4A1,RA
RA,RXRA,PPARA,AHR,RARG,THRA,NR1H3
3.6059E-18
Protein regulators
of adipogenesis 2019 adipogenesis 33 1
PPARD,RXRG,PPARG,NR2F1,NR2F2,NR1H4,E
SR1,ESR2,ESRRA,NR5A2,NR3C2,ESRRG,NR4A
2,NR2F6,THRB,VDR,NR1D1,NR2C2,NR4A3,NR3
C1,AR,NR0B1,RORA,RORC,NR4A1,RARA,RXRA
,PPARA,RARB,AHR,RARG,THRA,NR1H3
1.5873E-17
Protein regulators
of circadian
rhythm
906 circadian rhythm 24 2
PPARD,PPARG,HNF4A,NR1I3,ESR1,ESRRA,NR1D2,
NR3C2,NR0B2,NR4A2,THRB,NR1H2,NR1D1,NR1I2,N
R3C1,RORA,RORB,RORC,NR2E3,NR4A1,RXRA,PPA
RA,AHR,NR1H3
1.3695E-16
Protein regulators
of lipid storage 2174 lipid storage 33 1
PPARD,PPARG,HNF4A,NR2F2,NR1I3,NR1H4,E
SR1,ESR2,ESRRA,NR3C2,NR0B2,ESRRG,NR2
F6,NR6A1,VDR,NR1H2,NR1D1,NR2C2,NR1I2,N
R3C1,AR,NR0B1,PGR,RORA,NR5A1,NR4A1,RA
RA,RXRA,PPARA,AHR,RXRB,THRA,NR1H3
1.5312E-16
Protein regulators
of fatty acid
metabolism
733 fatty acid
metabolism 21 2
PPARD,RXRG,PPARG,NR1I2,HNF4A,NR4A3,NR2F2,
AR,NR1I3,NR1H4,ESR2,ESRRA,NR5A2,NR4A2,NR4A
1,RXRA,PPARA,VDR,AHR,NR1H2,NR1H3
4.7993E-15
Protein regulators
of cellular aging 1834 cellular aging 29 1
PPARD,PPARG,HNF4A,NR2F2,NR1H4,ESR1,ESR2,E
SRRA,ESRRB,NR5A2,NR3C2,ESRRG,NR4A2,THRB,
VDR,NR1H2,NR1D1,NR4A3,NR3C1,AR,PGR,RORA,N
R2E1,NR4A1,RARA,RXRA,PPARA,RARB,AHR
1.7007E-14
Protein regulators
of cellular
senescence
1563 cellular
senescence 27 1
PPARD,PPARG,HNF4A,NR2F2,NR1H4,ESR1,ESR2,E
SRRA,ESRRB,NR5A2,NR3C2,ESRRG,NR4A2,THRB,
VDR,NR1H2,NR1D1,AR,PGR,RORA,NR2E1,NR4A1,R
ARA,RXRA,PPARA,RARB,AHR
2.9963E-14

Raghavan PR., Arch Clin Biomed Res 2023
DOI:10.26502/acbr.50170368
Citation: Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
Volume 7 • Issue 3 534
The expression of AHR is increased in skin broblasts (10-
fold increase) compared to stem cells (60% downregulated).
AHR [29,30], is involved in the function of the skin as the
rst barrier against many pathogens and environmental
threats. Moreover, AHR controls [31] immune-mediated
skin reactions and many physiological functions by acting
as a sensor that mediates environment–cell interactions,
predominantly during immune and inflammatory responses.
Consequently, AHR plays a crucial role in skin integrity and
immunity [32] in homeostasis and disease. This might explain
the increased AHR expression. To further understand the
direct interactions among NRs, we analyzed gene networks
using Pathway Studio [33]. Nuclear receptor interaction maps
showed the presence of a closed-loop network, as shown in
Figure 1. The 25 most signicantly enriched cell processes
regulated by the gene set (p<E-9) are shown in Table 4. A
complete list of processes regulated by the gene subsets is
available in supplementary material. The key process is
regulation of biological pathways like protein regulation
of energy homeostasis, regulation of gene expression,
cellular senescence and many others. These process lead to
a complete regulation of biological processes in the body
brought about by Metadichol and its expression of all nuclear
receptors. and many others are regulated to that maintain
homeostasis in the body.
Conclusion
Metadichol, is potentially a natural ligand for all 49 NRs.
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 ® eects multiple pathways in diseases.
Cholesterol, long chain lipid alcohols like Metadichol
(a mixture of C26-C28-C30 alcohols (C28 is major
constituent > 80%), fatty acids, fat-soluble vitamins, and
other lipids in our meals are critical nutrients and precursors
to nucleus receptor-binding ligands [37, 38 ]. To the best of
our knowledge, this research is the rst to show that NRs can
be expressed from undierentiated and dierentiated cells.
Our procedure is generic and can be applied to study variety
of cells. NR’s are dierentially expressed in the two groups
of cells stems and broblasts. Studies of normal and diseases
cells could reveal the role that nuclear receptors play and lead
to a better understanding of diseases processes. More studies
need to be carried out with dierent types of cells to better
understand the nature of nuclear expression by treatment with
Metadichol. Ongoing research based on this approach will be
reported soon.
Declaration of Interest
The author is Founder and sole stake holder of privately
held company Nanorx Inc NY 10514, USA. The author was
involved with study, design data collection and analysis. The
author declares no other competing interests.
Funding
R&D budget of Nanorx Inc
Availability of data and materials
All data are presented in manuscript and in the
supplementary materials.
Supplementary materials Consist of the
following Files
1. Raw RT-PCR data of Regulation of Nuclear receptor
genes in HMSC cells treated with Metadichol
2. RAW RT-PCR Regulation of Nuclear Receptor genes in
NHDF cells treated with Metadichol.
3. Western Blot studies of Nuclear Receptor Protein
expression using HMSC cells
4. Western Blot studies of Nuclear Receptor Protein
expression using NHDF-C adult cells
5. Cell Processes regulated and enriched by Nuclear
Receptors.
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Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
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Citation: Palayakotai R. Raghavan. Metadichol® A Nano Lipid Emulsion that Expresses All 49 Nuclear Receptors in Stem and Somatic Cells.
Archives of Clinical and Biomedical Research. 7 (2023): 524-536.
Volume 7 • Issue 3 536
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