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A Multi Gene Targeting Approach to Treating Liver Diseases with Metadichol®

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Liver diseases are becoming a major health concern. In the developing countries it is due to microbial infection. In the rest of the developed world it is due to alcohol abuse. Chronic liver disease and cirrhosis are a significant health concern in western countries. It is the fifth most common cause of death, after heart disease, cancer, stroke, and chest disease. The liver is capable of regeneration, but it can be overwhelmed leading to liver diseases like cirrhosis and hepatocellular cancer (HCC). Vitamin D levels are low in most patients with liver diseases, and this suggests possible therapeutic benefits with use of vitamin D or its analogues. Vitamin D, through the vitamin D nuclear receptor (VDR) plays a crucial role in mineral ion homeostasis. The liver has a central role in vitamin D synthesis and there is a need for an agent that will not lead to hypercalcemia. Metadichol, a nano emulsion of long-chain alcohols derived from food, is an inverse agonist of Vitamin D can fill this void. In Diabetic rat studies, it inhibits TNF alpha, ICAM1 (intracellular adhesion molecule), CCL2 (chemokine CC motif) also referred to as monocyte chemoattractant protein 1 (MCP1). All these cytokines, chemokines are known to have important role in liver diseases. We show that Metadichol indeed does work in liver disease patients by normalizing essential liver enzymes ALT, AST and ALP, and GGT. This approach is an example where Metadichol targets multiple genes and via multiple pathways to bring about homeostasis of the liver and is a useful, safe, non-toxic product in treating liver diseases and alleviating a global threat.
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A Multi Gene Targeting Approach to Treating Liver Diseases with
Metadichol®
P.R Raghavan*
Nanorx Inc., PO Box 131, Chappaqua, NY 10514, USA
*Corresponding author: P.R Raghavan, Nanorx Inc., PO Box 131, Chappaqua, NY 10514, USA, Tel: 9146710224; Email: raghavan@nanorxinc.com
Received date: December 27, 2018; Accepted date: January 07, 2019; Published date: January 14, 2019
Copyright: ©2019 Raghavan P.R. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Liver diseases are becoming a major health concern. In the developing countries it is due to microbial infection. In
the rest of the developed world it is due to alcohol abuse. Chronic liver disease and cirrhosis are a significant health
concern in western countries. It is the fifth most common cause of death, after heart disease, cancer, stroke, and
chest disease. The liver is capable of regeneration, but it can be overwhelmed leading to liver diseases like cirrhosis
and hepatocellular cancer (HCC).
Vitamin D levels are low in most patients with liver diseases, and this suggests possible therapeutic benefits with
use of vitamin D or its analogues. Vitamin D, through the vitamin D nuclear receptor (VDR) plays a crucial role in
mineral ion homeostasis. The liver has a central role in vitamin D synthesis and there is a need for an agent that will
not lead to hypercalcemia. Metadichol, a nano emulsion of long-chain alcohols derived from food, is an
inverse agonist of Vitamin D can fill this void.
In Diabetic rat studies, it inhibits TNF alpha, ICAM1 (intracellular adhesion molecule), CCL2 (chemokine C-C
motif) also referred to as monocyte chemoattractant protein 1 (MCP1). All these cytokines, chemokines are known to
have important role in liver diseases. We show that Metadichol indeed does work in liver disease patients by
normalizing essential liver enzymes ALT, AST and AL P, and GGT. This approach is an example where Metadichol
targets multiple genes and via multiple pathways to bring about homeostasis of the liver and is a useful, safe, non-
toxic product in treating liver diseases and alleviating a global threat.
Keywords: Liver; Cirrhosis; Hepatocellular cancer; Hepatic failure;
NAFLD; NASH; TNF; CCL2; MCP1; PAI1; ICAM1; Inverse agonist;
VDR; Gilbert syndrome
Abbreviations: NAFLD: Non-Alcoholic Fatty Liver Disease; NASH:
Nonalcoholic Steatohepatitis; TNF: Tumor Necrosis Factor; CCL2:
Chemokine Ligand 2; MCP1: Monocyte Chemoattractant Protein 1;
PAI1: Plasminogen Activation Inhibitor; ICAM1: Intercellular
Adhesion Molecule 1; VDR: Vitamin-D Nuclear Receptor:
ALD: Alcoholic liver Disease.
Introduction
Liver diseases are a worldwide problem. e number of drugs for
treating liver diseases is small in number. ere is a need for a safe and
therapeutic treatment with new molecular entities [1,2,3].
e liver helps purify the blood. It produces albumin as well as the
proteins that cause blood clotting. e liver stores sugar fats and
vitamins until they are needed elsewhere in the body and also
manufactures fat, cholesterol, and protein bilirubin. An inamed liver
does not perform these functions well, which brings about many of the
symptom and problems associated with any hepatitis.
Liver diseases
NAFLD (Non-alcoholic fatty liver disease is a condition when there
is an excess of fat in the liver of people who do not consume alcohol
[4]. e standard form of NAFLD is a benign condition called fatty
liver when fat accumulates in the liver cells. NAFLD leads to hepatic
steatosis NAFL (Nonalcoholic fatty liver disease), and aects about
20% of patients and also is present in type 2 diabetes patients.
NASH [5] is a condition where the liver sustains substantial damage,
and the liver cells are gradually replaced by scar tissue impairing liver
function. Some patients who develop cirrhosis may eventually require
a liver transplant to remove the damaged liver.
Hepatitis A B and C are viruses [6] that can impair liver function.
e diseases caused by them are similar and lead (7) to liver
inammation that can be severe or even life-threatening. ere are
eective vaccines for hepatitis A and B but not for type C. Liver failure
and hepatocellular carcinoma (HCC) are caused by alcohol abuse and
obesity the leading causes of chronic liver diseases especially in the
developed world.
In advanced liver diseases, Perez et al. [7] showed that liver cirrhosis
is caused by HBV/HCV infection. Prevention of liver cirrhosis and
HBV/HCV infection is necessary as HCC can result. e solution is to
avoid alcohol, and drugs but treating the underlying causes i.e.
alcoholism and HBV/HCC related infections.
HCC [8] is a serious problem because no treatment is available. e
underlying causes for development of HCC are type 2 diabetes,
alcoholism and chronic HBV/HCV infections that can lead to liver
cirrhosis.
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ISSN: 2576-3881
Journal of Cytokine Biology Raghavan, J Cytokine Biol 2018, 3:2
DOI: 10.4172/2576-3881.1000126
Review Article Open Access
J Cytokine Biol, an open access journal
ISSN:2576-3881
Volume 3 • Issue 2 • 1000126
Nuclear receptors, cytokines, chemokines and liver diseases
Nuclear receptors (NRs) express genes that are involved in clearing
toxic biliary constituents that are the hall mark of cholestasis [9].
Activation of NRs like VDR and FXR modulates many biological
processes like inammation and carcinogenesis. Break down of NR
signaling leads to cholestasis disorders. NRs activation has the
potential to modulate processes in cholestatic liver diseases [10]. Drugs
used today exert their benecia eects in cholestasis via NR activation
for e.g. FXR activation (obeticholic acid) [11].
VDR activation in liver cells leads to anti-inammatory and anti-
brotic eects [12]. Targeting of VDR leads to improved bone density.
Cholestasis leads to low vitamin D levels in Osteoporosis. 1, 25-Vit D3
actions on VDR results in reduced brosis in rat [13] and also lowered
levels of pro-inammatory cytokines in mice studies [14]. Vitamin D
supplementation can help patients with liver diseases.
TNF α
Cirrhosis is considered an advanced stage of liver brosis. It causes
over 1 million deaths per year, being the 14th leading cause of death
worldwide [15]. Liver brosis leads to accumulation of collagen,
elastin, and bronectin, a consequence of hepatocyte death because of
liver inammation [16]. Serum levels of TNF-α is directly related to
the severity of hepatic dysfunction in liver Cirrhosis [17]. TNFα
enhances HSC (Hepatic stellate cella) survival leading to enhanced
liver ibrosis. TNF alpha inhibitors in the market today have serious
side eects [18,19]. Clinical trials using anti-TNFα antibody have failed
in alcoholic hepatitis [20]. erefore, targeting of specific TNFα
signaling pathways could be considered as a new therapeutic approach
for the liver brosis.
ICAM1
Intercellular adhesion molecule 1 (ICAM-1) belongs to
immunoglobulin supergene family that promotes intercellular
adhesion. Present on the cell surface glycoprotein it is an important
early marker of response to inflammatory mediators and immune
activation [21,22].
Capra et al. [23] showed that patients with chronic HCV-related
hepatitis have higher levels of sICAM-1 than do control subjects. e
increase in sICAM-1 level is a result of HCV activity, which damages
both hepatocytes and sinusoidal vessels [24] and, in particular,
endothelial cells. Inflammation and cytolysis lead to an up regulation
in the expression of tissue ICAM-1, which is mediated by
proinflammatory cytokines [25,26].
In knockout mice ICAM-1 and infiltrating leukocytes play essential
roles in early alcohol-induced liver injury [27]. ey suggest that it is
most likely caused by free radicals from NADPH oxidase in the
Kuper cell increasing NF-kB activation, that induces ICAM-1
expression via mechanisms involving TNF-a.
Chen et al. [27] showed that ICAM-1is a critical biomarker
associated with development of future HCC incidence in chronic liver
disease in patients with various chronic liver diseases that were free of
HCC at baseline. eir ndings held across diverse etiologies of liver
disease and in patients with and without cirrhosis, were independent
of established clinical risk factors.
CCL2
CCL2 (also called as MCP1) is a chemokine involved in
immunoregulatory and inammatory processes in the development of
several acute and chronic liver diseases, inflammation and regulation
of immune response, Chemokines have been shown to regulate diverse
conditions such as cardiovascular diseases and cancer [28].
Expression of CCL2 results in the infiltration of monocytes that
predominately express the receptor CCR2.
In liver diseases CCL2 and CCR2 levels are high and results in
increased inflammation, fibrosis, and steatosis [29]. Continuing
inammation leads to chronic liver diseases, like hepatitis C and non-
alcoholic steatohepatitis. CCL2 has a role in alcohol-related damage,
because its liver and plasma levels were associated with disease severity
and with inflammation, including neutrophil infiltration, but not with
steatosis, in patients with the alcoholic liver disease. [30,31]. Plasma
levels and hepatic expression of CCL2 have been shown to be
increased in ALD (alcoholic liver disease) patients. CCL2
over-expression is associated with parameters of disease severity
in all liver diseases. Activation of pro-inammatory pathways
induced by alcohol was controlled in CCL2-deficient mice.
Besides genes of fatty acid metabolism were induced in livers of
alcohol-fed CCL2-KO mice,[32,33,34].
PAI1
PAI-1 (also known as SERPINE1) is the primary inhibitor of
plasminogen activators playing a signicant role in brinoysis [35].
PAI-1 has a major role in mediating brosis during cholestasis. Hyper
brinoysis and ypo-brinoysis are the result of elevated PAI-1 levels
and also the development of alcoholic liver disease (ALD). is results
in inammation, and necrosis (steatohepatitis), and ultimately leads to
brosis and cirrhosis. Inhibition of PAI-1 could mitigate alcohol-
induced liver damage brosis and cirrhosis). It has been shown that
hepatic brosis is eliminated in mice that are decient in PAI-1 [36].
No therapy is available to treat ALD. Treatment goal is on reducing
eects of disease and or transplantation of livers of individuals with
terminal cirrhosis. Hepatic steatosis can be blocked by inhibiting PAI-1
activation [37]. PAI-1 level is an indication of the disease severity [38].
Initially Hepatic changes caused by alcohol lead to steatosis. at
initiation, then leads to ALD [39]. For example, in fatty livers the
degree of fatty infiltration correlates with severity of ALD, fibrosis and
cirrhosis [40,41]. Steatosis is caused by alcohol metabolism [42] that
induces (TNF-α production which up regulates PAI-1 expression) [43].
Gilbert syndrome a liver disorder that results when the body cannot
process bilirubin a waste product of red cells [44] caused by
structural liver damage. is results in elevated levels of bilirubin
caused by a lack of liver enzymes needed for elimination of
bilirubin [45,46,47].
Individuals may only exhibit mild yellowing of the skin and whites
of the eyes (jaundice). Gilbert syndrome is seen more oen in males
than females. e disorder aects approximately 6-7% of individuals in
the general population. Gilbert syndrome aects individuals of all
races. Similar to Gilbert's syndrome are Crigler-Najjar, Rotor
syndrome and Dubin-Johnson syndrome. All these are disorders are
due to high levels of bilirubin in the blood [48].
Levels of liver enzymes serum aminotransferases alanine and
aspartate aminotransferases (ALT and AST), alkaline phosphatase
Citation: Raghavan PR (2018) A Multi Gene Targeting Approach to Treating Liver Diseases with Metadichol®. J Cytokine Biol 3: 126. doi:
10.4172/2576-3881.1000126
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J Cytokine Biol, an open access journal
ISSN:2576-3881
Volume 3 • Issue 2 • 1000126
(ALP) and gamma-glutamyltransferase (GGT) [49,50,51] is what
are used to detect liver diseases and their severity. A high level of
serum ALT, AST is directly related to damaged liver tissues. In
Alcoholic liver disease the AST:ALT ratios are used in
determining presence of damaged liver diseases [52].
Alkaline phosphatase levels has a serum range of 20 to 140 U/L. e
ALP test is used in identifying conditions such as hepatitis, cirrhosis,
inammation of the gallbladder blockage of bile ducts (from a
gallstone, inammation, or cancer. e enzyme alkaline phosphatase is
a vital serum analyte, and its elevation in serum is seen in bone, liver
and other diseases [53] ALP levels lead to bile ducts obstruction.
Elevated ALP levles could indicate hyperparathyroidism, vitamin D
deficiency, or damaged liver cells [54]. Levels are elevated in people
with untreated Celiac disease [55]. Over expression of ALP is seen in
cancer patients [55,56], tumorigenesis [57,58] and also in breast cancer
patients [59-62]. he number of drugs for treating useful liver drugs is
small that there is a void that needs to be filled for safe and efficient
therapeutic agents [63]. Compounds and or extracts from plants have
been used in targeting liver diseases liver but have not been well studied
and there is a need for additional research to justify their use in as it
relates so safety and eicacy. Steroids have been used but have failed to
show any significant results [64].
IFN-α treatment in viral hepatitis is the standard of care today [65].
It has a drawback as serious side eects such as depression and also
nephrotic syndrome, retinal ischemia and decreased visual acuity have
been reported. No FDA-approved drug treatment exists for the
nonalcoholic fatty liver disease.
Metadichol® is a nano emulsion of long chain alcohols derived from
food-based sources. It is safer than salt and sugar and has no known
reported side eects. We have shown that it is a TNF α, ICAM1, CCL2
(also known as MCP1) and PAI1 (Serpine1) inhibitor (Figure 1).
Figure 1: From US patent 8,722,093 . Study of Zucker diabetic fatty
rat. Metadichol dosage 5 mg/kilo.
We have shown that it binds to Vitamin D receptor as an inverse
agonist [66]. Given the importance of these cytokines/chemokines
described above in liver diseases, we present case studies to conrm its
effects on liver diseases.
Case Studies
Patient No. 1
A 29-year-old female on kidney dialysis for last 9 years aer rst
child birth. Not on any liver medication, very high Alkaline
Phosphatase levels and elevated GGT levels. Treated with Metadichol
@ 5 mg daily.
Twice a day, her ALP levels increased in the rst weeks before a
steady decrease began over the next few weeks. ere were also other
improvements in her biomarkers RDW (Red Cell Distribution Width)
which we have documented in other kidney patients [67]. Patient is
still on dialysis as she awaits a donor and showing slow but steady
improvement in other biomarkers (Figure 2).
Figure 2: Graph of Patient No 1 showing the dialysis along with the
eect of metadichol with slow improvement in other biomarkers.
Patient No 2
A 25-year-old Male diagnosed with Autoimmune Hepatitis and
possibly primary schlerosing cholangitis (PSC) since the age of 15 with
elevated ALP, AST and ALT levels(Figure 3). Suered from GI and
food allergies and repeated colon infections. He Tried various
treatments with drugs like prednisone and Imuran and Remicade all
were of no use. Having tried and failed with known therapies the
patient started on Metadichol orally @ 5 mg twice a day. Patient was on
no other treatment, during this 12 week treatment. e patient
reports improved energy levels, and for the first time in 10 years, his
Citation: Raghavan PR (2018) A Multi Gene Targeting Approach to Treating Liver Diseases with Metadichol®. J Cytokine Biol 3: 126. doi:
10.4172/2576-3881.1000126
Page 3 of 7
J Cytokine Biol, an open access journal
ISSN:2576-3881
Volume 3 • Issue 2 • 1000126
AST and ALT returned to normal. He underwent a liver transplant
soon aer and is now normal.
Figure 3: Graph showing elevated levels of ALP, AST and ALT.
Patient No 3
A 47-year-old female diabetic for 6 years mildly elevated liver
enzymes. Metadichol treatment 5 mg twice a day. e liver biomarkers
returned to normal (Figure 4).
Figure 4: Graph showing the liver biomarkers returned to normal
aer treatment dosage of metadichol.
Patient No 4
A 35-year-old female, elevated levels of bilirubin, diagnosed as
Gilbert's syndrome. Metadichol @ 5 mg twice a day. Her levels
returned to normal in 24 weeks (Figure 5).
Figure 5: Graph showing dierent levels of bilirubin when
diagnosed with Gilbert’s syndrome and treated with metadichol.
Discussion and Conclusion:
The application of Metadichol in all the cases presented led to rapid
normalization of the liver biomarkers suggests that it could be
modulating diseases through multiple pathways, binding to VDR and
activating innate immunity pathways and Inhibiting TNF alpha,
ICAM1, and CCL2. Most of the known therapies for today target
one gene and there is a need for a comprehensive targeting of clusters
of genes to target liver and other diseases
via
multiple disease pathways
multiple genes as shown in Figure 6.
Figure 6:
Metadichol binding to VDR and inhibition of TNF, ICAM1 and
CCL2 can be analyzed using a soware program like ToppCluster
[68,69] shows how these clusters of genes target many liver-related
Citation: Raghavan PR (2018) A Multi Gene Targeting Approach to Treating Liver Diseases with Metadichol®. J Cytokine Biol 3: 126. doi:
10.4172/2576-3881.1000126
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J Cytokine Biol, an open access journal
ISSN:2576-3881
Volume 3 • Issue 2 • 1000126
diseases. Using Pathway Commons program [70] has one can further
extend this approach by looking at the known experimentally curated
interactions of TNF, ICAM1, and CCl2 shown in Figure 7. We see that
IFNG (interferon gamma) is regulated by TNF, ICAM1, and CCL2.
IFNG plays an important role in in lammation and autoimmune
disease [71]. Increased levels of IFN-γ are directly related to liver
disease severity [72] and were associated with the progression of liver
disease [73]. T-helper cell (Th17) cells a subset of T cells are critical to
in lammation [74]. VDR leads to a TH2 response, and Metadichol is a
inverse agonist of ROR gamma thus blocking the Th17 pathway
[74]. since CCL2, TNF and ICAM 1 are all inhibited and thus IFN
gamma the whole process is driven towards a VDR driven Th2
pathway [75].
Figure 7: Experimentally curated interactions of TNF, ICAM1 and
CCL2.
Diseases are connected through closely related gene networks, and
this is an approach that can be exploited to modulate multiple targets
to enhance therapeutic eect as ligands today are focused on a single
target and limited by their ecacy. Metadichol is a safe therapeutic
that target multiple genes, pathways and multiple diseases that
conrms the relevance of network-based approach of poly-
pharmacology [76] and this has been demonstrated by our studies on
other diseases [77-91].
References
1. Rowe IA (2017) Lessons from Epidemiology: e Burden of Liver
Disease. Dig Dis 35: 304-309.
2. Udompap P, Kim D, Kim WR (2015) Current and Future Burden of
Chronic Nonmalignant Liver Disease. Clin Gastroenterol Hepatol 13:
2031-2041.
3. Uhl P, Fricker G, Haberkorn U, Mier W (2014) Current Status in the
erapy of Liver Diseases. Int J Mol Sci 15: 7500-7512.
4. Benedict M, Zhang X (2017) Non-alcoholic fatty liver disease: An
expanded review. World J Hepatol 9: 715-732.
5. Wattacheril J, Issa D, Sanyal A (2018) Nonalcoholic Steatohepatitis
(NASH) and Hepatic Fibrosis: Emerging erapies. Annu Rev Pharmacol
Toxicol 58: 649-662.
6. Wood NJ (2011) Viral hepatitis: progress and promise. Nat Rev
Gastroenterol Hepatol 8: 239.
7. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP (2006) e
contributions of hepatitis B virus and hepatitis C virus infections to
cirrhosis and primary liver cancer worldwide. J Hepatol 45: 529-538.
8. Waller LP, Deshpande V, Pyrsopoulos N (2015) Hepatocellular
carcinoma: A comprehensive review. World J Hepatol 7: 2648-2663.
9. Halilbasic E, Baghdasaryan A, Trauner M (2013) Nuclear Receptors as
Drug Targets in Cholestatic Liver Diseases. Clin Liver Dis 17: 161-189.
10. Rudraiah S, Zhang X, Wang L (2016) Nuclear Receptors as erapeutic
Targets in Liver Disease: Are We ere Yet? Annu Rev Pharmacol Toxicol
56: 605-626.
11. Wagner (2011) Hepatology, Nuclear Receptors in Liver Disease. 53:
1023-1024.
12. Abramovitch S, Dahan-Bachar L, Sharvit E, Weisman Y, Ben Tov A, et al.
(2011) Vitamin D inhibits proliferation and probrotic marker expression
in hepatic stellate cells and decreases thioacetamide-induced liver brosis
in rats. Gut 60: 1728-1737.
13. Ogura M, Nishida S, Ishizawa M, Sakurai K, Shimizu M, et al. (2009)
Vitamin D3 modulates the expression of bile acid regulatory genes and
represses inammation in bile duct-ligated mice. J Pharmacol Exp er
28: 64-570.
14. Elangovan H, Chahal S, Gunton JE (2017) Vitamin D in liver disease:
Current evidence and potential directions. Biochimica et Biophysica Acta
1863: 907-916.
15. Tsochatzis EA, Bosch J, Burroughs AK (2014) Liver cirrhosis. Lancet 383:
1749-1761.
16. Bataller R, Brenner DA (2005) Liver brosis. J Clin Invest 115: 209-218.
17. Sabry HS, El-Hendy AK, Mohammed HI, Essa AS, Abdel-Aziz AS (2015)
Study of serum tumor necrosis factor-α in patients with liver cirrhosis.
Menoua Med J 28: 525-531.
18. Aggarwal BB, Gupta SC, Kim JH (2012) Historical perspectives on tumor
necrosis factor and its superfamily: 25 years later, a golden journey. Blood
119: 651-665.
19. Brenner D, Blaser H, Mak TW (2015) Regulation of tumor necrosis factor
signaling: live or let die. Nat Rev Immunol 15: 362-374.
20. Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, et al. (2014)
A double-blind, randomized controlled trial of iniximab associated with
prednisolone in acute alcoholic hepatitis. Hepatology 39: 1390-1397.
21. Springer TA (1990) Adhesion receptors of the immune system. Nature
346: 425-434.
22. Seth R, Raymond FD, Makgoba MW (1991) Circulating ICAM-1
isoforms: diagnostic prospects for inflammatory and immune disorders.
Lancet 38: 83-84.
23. Capra F, Maria ED, Lunardi C, Marchiori L, Mezzelani P, et al. (2000)
Serum Level of Soluble Intercellular Adhesion Molecule 1 in Patients with
Chronic Liver Disease Related to Hepatitis C Virus: A Prognostic Marker
for Responses to Interferon Treatment. J Infect Dis 181: 425-431.
24. Banner BF, Allan C, Savas L, Baker S, Barnard G, et al. (1997)
Inflammatory markers in chronic hepatitis C. Virchows Arch 431:
181-187.
25. Adams DH, Mainol E, Burra P, Neuberger JM, Ayres R, et al. (1992)
Detection of circulating intercellular adhesion molecule–1 in chronic
liver disease. Hepatology 16: 810-814.
26. Zöhrens G, Armbrust T, Pirzer U, Meyer zum Büschenfelde KH,
Ramadori G (1993) Intercellular adhesion molecule–1 concentration in
sera of patients with acute and chronic liver disease: relationship to
disease activity and cirrhosis. Hepatology 18: 798-802.
27. Chen VL, Le AK, Podlaha O, Estevez J, Li B, et al. (2017) Soluble
intercellular adhesion molecule-1 is associated with hepatocellular
Citation: Raghavan PR (2018) A Multi Gene Targeting Approach to Treating Liver Diseases with Metadichol®. J Cytokine Biol 3: 126. doi:
10.4172/2576-3881.1000126
Page 5 of 7
J Cytokine Biol, an open access journal
ISSN:2576-3881
Volume 3 • Issue 2 • 1000126
carcinoma risk: Multiplex analysis of serum markers. Nature Scientic
reports 7: 11169.
28. Schwabe RF, Wiley JW, Section Editors (2014) Roles for Chemokines in
Liver Disease. Gastroenterology 147: 577-594.
29. O’Connor T, Borsig L, Heikenwalder M (2015) CCL2-CCR2 Signaling in
Disease Pathogenesis. Endocr Metab Immune Disord Drug Targets 15:
105-118.
30. Marra F, DeFranco R, Grappone C, Milani S, Pastacaldi S, et al. (1998)
Increased expression of monocyte chemotactic protein-1 during active
hepatic fibrogenesis: correlation with monocyte infiltration. Am J Pathol
152: 423-430.
31. Heymann F, Trautwein C, Tacke F (2009) Monocytes and macrophages as
cellular targets in liver fibrosis. Inflamm Allergy Drug Targets 8: 307-318.
32. Marra F, Valente AJ, Pinzani M, Abboud H E (1993) Cultured human
liver fat-storing cells produce monocyte chemotactic protein-1.
Regulation by proinflammatory cytokines. J Clin Invest 92: 1674-1680.
33. Marra F, Romanelli RG, Giannini C, Failli P, Pastacaldi S, et al. (1999)
Monocyte chemotactic protein-1 as a chemoattractant for human hepatic
stellate cells. Hepatology 29: 140-148.
34. Degre D, Lemmers A, Gustot T, Ouziel R, Trépo E, et al. (2012) Hepatic
expression of CCL2 in alcoholic liver disease is associated with disease
severity and neutrophil infiltrates. Clin Exp Immunol 169: 302-310.
35. Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, et al. (2009) CCR2
promotes hepatic fibrosis in mice. Hepatology 50: 185-197.
36. Arteel GE (2008) New role of plasminogen activator inhibitor-1 in
alcohol-induced liver injury. J Gastroenterol Hepatol 23: S54-S59.
37. Bergheim I, Guo L, Davis MA, Duveau I, Arteel GE (2006) Critical Role
of Plasminogen Activator Inhibitor-1 in Cholestatic Liver Injury and
Fibrosis. J Pharmacol Exper 316: 592-600.
38. Beier JI, Arteel GE (2012) Alcoholic liver disease and the potential role of
plasminogen activator inhibitor-1 and brin metabolism. Exp Biol Med
(Maywood) 237: 1-9.
39. Tran-ang C, Fasel-Felley J, Pralong G, Hofstetter JR, Bachmann F, et al.
(1989) Plasminogen activators and plasminogen activator inhibitors in
liver deciencies caused by chronic alcoholism or infectious hepatitis.
romb Haemost 62: 651-653.
40. Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM (1997) Obesity
increases sensitivity to endotoxin liver injury: implications for the
pathogenesis of steatohepatitis. Proc Natl Acad Sci USA 4: 2557-2562.
41. Sorensen TI, Orholm M, Bentsen KD, Hoybye G, Eghoje K, et al. (1984)
Prospective evaluation of alcohol abuse and alcoholic liver injury in men
as predictors of development of cirrhosis. Lancet 2: 241-244.
42. Teli MR, Day CP, Burt AD, Bennett MK, James OF, et al. (1995)
Determinants of progression to cirrhosis or brosis in pure alcoholic fatty
liver. Lancet 346: 987-990.
43. Pessayre, Mansouri A, Fromenty B (2002) Nonalcoholic steatosis and
steatohepatitis. vs Mitochondrial dysfunction in steatohepatitis. Am J
Physiol Gastrointest Liver Physiol 282: G193-G199.
44. Fearns C, Loskuto DJ (1997) Induction of plasminogen activator
inhibitor one gene expression in murine liver by lipopolysaccharide.
Cellular localization and role of endogenous tumor necrosis factor-alpha.
Am J Pathol 150: 579-590.
45. Rossi F, Francese M, Iodice RM, Falcone E, Vetrella S, et al. (2005)
Inherited disorders of bilirubin metabolism. Minerva Pediatr 57: 53-63.
46. Monaghan G, McLellan A, McGeehan A, Li Volti S, Mollica F, et al.
(1999) Gilbert’s syndrome is a contributory factor in prolonged
unconjugated hyperbilirubinemia of the newborn. J Pediatr 134: 441-446.
47. Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, et al. (1995)
e genetic basis of the reduced expression of bilirubin UDP-
glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 333:
1171-1175.
48. Aono S, Adachi Y, Uyama E, Yamada Y, Keino H, et al. (1995) Analysis of
genes for bilirubin UDP glucuronosyltransferase in Gilbert’s syndrome.
Lancet 345: 958-959.
49. Maier KP (2002) Rare, but important chronic liver diseases. Praxis (Bern
1994) 91: 2077-2085.
50. Kuntz E Laboratory diagnostics (2001) In: Kuntz E, Kuntz HD, eds.
Hepatology, principles, and practice. Heidelberg: Springer -Verlag.
78-112.
51. Pratt DS, Kaplan MM (2000) Evaluation of abnormal liver-enzyme results
in asymptomatic patients. N Engl J Med 342: 1266-1271.
52. Rosalki SB, Tarlow D, Rau D (1971) Plasma gamma-glutamyl
transpeptidase elevation in patients receiving enzyme-inducing drugs.
Lancet 2: 376-377.
53. Sharma U, Pal D, Prasad R (2014) Alkaline Phosphatase: An overview.
Indian J Clin Biochem 29: 269-278.
54. Wolf PL (1999) Biochemical diagnosis of liver disease. Indian J Clin
Biochem 14: 59-90.
55. Sorbi D, Boynton J, Lindor KD (1999) e ratio of aspartate
aminotransferase to alanine transferase: potential value in dierentiating
nonalcoholic steatohepatitis from alcoholic liver disease. Am J
Gastroenterol 94: 1018-1022.
56. Epstein E, Kiechle FL, Artiss JD, Zak B (1986) e clinical use of alkaline
phosphatase enzymes. Clin Lab Med 6: 491-505.
57. Rodan GA, Rodan SB (1984) In: Peck WA, editor. Advances in bone and
mineral research annual II. Amsterdam: Excerpta Medica 244-285.
58. Preussner HT (1998) Detecting coeliac disease in your patients. Am Fam
Physician 57: 1023-1034.
59. Sharma U, Singh SK, Pal D, Khajuria R, Mandal AK, et al. (2012)
Implication of BBM lipid composition and fluidity in mitigated alkaline
phosphatase activity in renal cell carcinoma. Mol Cell Biochem 369:
287-293.
60. Prasad R, Lambe S, Kaler P, Pathania S, Kumar S, Attri S, et al. (2005)
Ectopic expression of alkaline phosphatase in proximal tubular brush
border membrane of human renal cell carcinoma. Biochim Biophys Acta
1741: 240-245.
61. Lange PH, Millan JL, Stigbrand T, Vessella RL, Ruoslahti E, et al. (1982)
Placental alkaline phosphatase as a tumor marker for seminoma. Cancer
Res 42: 3244-3247.
62. Niedermayer I, Feiden W, Henn W, Steilen-Gimbel H, Steudel WI, et al.
(1997) Loss of alkaline phosphatase activity in meningiomas: a rapid
histochemical technique indicating progression associated deletion of a
putative tumor suppressor gene on the distal part of the short arm of
chromosome 1. J Neuropathol Exp Neurol 56: 879-886.
63. Kim JM, David Kwon CH, Joh JW, Park JB, Ko JS, et al. (2013) e eect
of alkaline phosphatase and intrahepatic metastases in sizeable
hepatocellular carcinoma. World J Surg Oncol 11: 40.
64. Muriel P, Rivera-Espinoza Y (2008.) Beneficial drugs for liver diseases. J
Appl Toxicol 28: 93-103.
65. Rambaldi A, Iaquinto G, Gluud C (2002) Anabolic-androgenic steroids
for alcoholic liver disease: a Cochrane review. Am J Gastroenterol 97:
1674-1681.
66. Yeh WS, Armstrong EP, Skrepnek GH, Malone DC (2007) Peginterferon
alfa-2a versus peginterferon alfa-2b as initial treatment of hepatitis C
virus infection: a cost-utility analysis from the perspective of the Veterans
aairs health care system. Pharmacotherapy 27: 813-824.
67. Raghavan PR (2015) US Patent 9,006,292.
68. Raghavan PR (2017) Metadichol® and Red Cell Distribution Width
(RDW) in CKD patients. J Stem Cell Res er 7: 392.
69. Chen J, Bardes EE, Aronow BJ, Jegga AG (2009) ToppGene Suite for gene
list enrichment analysis and candidate gene prioritization. Nucleic Acids
Res 37: W305-311.
70. Kaimal V, Bardes EE, Tabar SC, Jegga AG, Aronow BJ (2010)
ToppCluster: a multiple gene list feature analyzer for comparative
enrichment clustering and network-based dissection of biological
systems. Nucleic Acids Res 38: W96-102.
71. Cerami EG, Gross BE, Demir E, Rodchenkov I, Babur O, et al. (2011)
Pathway Commons, a web resource for biological pathway data. Nucleic
Acids Res 39: D685-690.
Citation: Raghavan PR (2018) A Multi Gene Targeting Approach to Treating Liver Diseases with Metadichol®. J Cytokine Biol 3: 126. doi:
10.4172/2576-3881.1000126
Page 6 of 7
J Cytokine Biol, an open access journal
ISSN:2576-3881
Volume 3 • Issue 2 • 1000126
72. Horras CJ, Lamb CL, Mitchell KA et al. (2011) Regulation of Hepatocyte
Fate by Interferon-γ. Cytokine Growth Factor Rev 22: 35-43.
73. Attallah AM, El-Far M, Zahran F, Shiha GE, Farid K, et al. (2016)
Interferon-gamma is associated with hepatic dysfunction in brosis,
cirrhosis, and hepatocellular carcinoma. J Immunoassay Immunochem
37: 597-610.
74. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coman RL
(1986) Two types of murine helper T cell clone. I. Denition according to
proles of lymphokine activities and secreted proteins. J Immunol 136:
2348-2357.
75. Raghavan PR (2017) Metadichol, A Novel ROR Gamma Inverse Agonist
and Its Applications in Psoriasis. J Clin Exp Dermatol Res 8: 433.
76. Székely JI, Pataki Á (2012) Eects of Vitamin D on Immune Disorders
With Special Regard to Asthma, COPD and Autoimmune Diseases. A
Short Review. Expert Rev Respir Med 6: 683-704.
77. Zhang W, Bai Y, Wang Y, Xiao W (2016) Polypharmacology in Drug
Discovery: A Review from Systems Pharmacology Perspective. Curr
Pharm Des 22: 3171-3181.
78. Raghavan PR (2018) Umbilical Cord Cells Treatment with Metadichol®.
IRS Proteins and GLUT4 Expression and Implications for Diabetes. J
Stem Cell Res er 8: 6.
79. Raghavan PR (2018) Metadichol® and CD34 Expression in Umbilical
Cord Cells. J Stem Cell Res er 8: 409.
80. Raghavan PR (2018) Metadichol®, Vitamin C and GULO Gene
Expression in Mouse Adipocytes. Biol Med 10: 426.
81. Raghavan PR (2017) Metadichol ®. A Novel Inverse Agonist of Aryl
Hydrocarbon Receptor (AHR) and NRF2 Inhibitor. J Cancer Sci er 9:
661-668.
82. Raghavan PR (2017) Metadichol® Induced High Levels of Vitamin C:
Case Studies. Vitam Miner 6: 169.
83. Raghavan PR (2017) Metadichol® and Vitamin C Increase In Vivo, an
Open-Label Study. Vitam Miner 6: 163.
84. Raghavan PR (2017) Rheumatoid Arthritis and Osteoporosis: A Case
Study. J Arthritis 6: 240.
85. Raghavan PR (2017) Systolic and Diastolic BP Control in Metabolic
Syndrome Patients with Metadichol® a Novel Nano Emulsion Lipid. J
Cardiol & Cardiovasc er 5: 555660.
86. Raghavan PR (2017) Metadichol® A Novel Nano Lipid; GPR 120 Agonist.
Int J Diabetes Complications 1: 1-4.
87. Raghavan PR (2017) Metadichol® and MRSA Infections: A Case Report, J
Infect Dis er 5: 2.
88. Raghavan PR (2017) Improving Longevity with Metadichol ® by
inhibiting Bcat-1 Gene. Aging Sci 5: 174.
89. Raghavan PR (2016) In vitro Inhibition of Zika Virus by Metadichol®. A
Novel Nano Emulsion Lipid. J Immunol Tech Infect Dis 5: 4.
90. Raghavan PR (2016) Inhibition of Dengue and other enveloped viruses by
Metadichol®, a novel Nano emulsion Lipid. J Sci Heal Out 8: 19-25.
91. Raghavan PR (2016) Metadichol and Type 2 Diabetes A case report. J Sci
Heal Out 8: 5-10.
Citation: Raghavan PR (2018) A Multi Gene Targeting Approach to Treating Liver Diseases with Metadichol®. J Cytokine Biol 3: 126. doi:
10.4172/2576-3881.1000126
Page 7 of 7
J Cytokine Biol, an open access journal
ISSN:2576-3881
Volume 3 • Issue 2 • 1000126
... Binding and or activation of these nuclear receptors leads to gene transcription and leads to many pathways and thus many targets. Metadichol® has already been shown to impact many diseases through a multidue of pathways [37]. ...
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... Binding and or activation of these nuclear receptors leads to gene transcription and leads to many pathways and thus many targets. Metadichol® has already been shown to impact many diseases through a multidue of pathways [37]. ...
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... This approach aimed at multiple targets offers superior efficacy because to tackle diseases, multiple receptors and pathway need to be impacted. The idea of one disease, one gene, one target, and one drug is no longer a viable concept to be pursued and the concept emerging is what is referred to as polypharmacology [65][66][67], and Metadichol ® is the first example of a new class of molecules that prove the viability of this emerging concept. ...
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