Abstract and Figures

Humans face a constant threat from pathogens like influenza varieties H1N1, H5N1, and others and there is a need to prevent these from epidemics. The pathogens depend on successful colonization of the host in order to reproduce and multiply. Sialidases are known as neuraminidases are a group of enzymes, the most abundant of these being the exo-sialidases that can catalyze the cleavage of sialic acids from carbohydrates, glycoproteins or glycolipids. Sialidases have been thoroughly studied since their discovery 75 years ago and their occurrence in bacteria and viruses is widespread. They are found in diverse virus families and bacteria and other microbes. Moreover, sialic acids serve as a receptor for various pathogens. This allows bacteria like H1N1 or other influenza viruses, to enter the host cell. There is a need to block sialidases as they release sialic acid that serves as nutrition for the microbes and as well allows them to bind and invade the host cell where they can proliferate. This makes sialidases an interesting target to control pathogenic activity. Metadichol ® is nanoemulsion of long-chain lipid alcohols derived from food ingredients. In rats, it has an LD50 of 5000 mg/kilo and its ingredients are present in many foods we consume on a daily basis. It has antiviral and antibacterial and anti-parasitic properties. We studied inhibition of Sialidases by inducing it with Lipopolysaccharide (LPS) using THP1 cells. Metadichol showed inhibition at 1 picogram per ml to 1 nanogram per/ml. Compared to Prednisone. It is 100 times more active. Previous studies on Metadichol ® showed that it is toxic to cancer cells at higher concentrations. Since it is safer, it has the potential of being directly tested on humans without side effects and could have a potential role in mitigating the pathogens that a burden on the Public health system.
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Metadichol® a Novel Sialidase Inhibitor
Raghavan PR1*, Yogisha S2, Anand S2 and Purushotham GV2
1Nanorx Inc, PO Box 131, Chappaqua, NY, 10514, USA
2Skanda Life Sciences, R and D Center, Bangalore, India
*Corresponding authors: PR Raghavan, Nanorx Inc, PO Box 131, Chappaqua, NY, 10514, USA, E-mail: raghavan@nanorxinc.com
Received date: April 12, 2019; Accepted date: April 30, 2019; Published date: May 10, 2019
Copyright: © 2019 Raghavan PR, et al. 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
Humans face a constant threat from pathogens like influenza varieties H1N1, H5N1, and others and there is a
need to prevent these from epidemics. The pathogens depend on successful colonization of the host in order to
reproduce and multiply. Sialidases are known as neuraminidases are a group of enzymes, the most abundant of
these being the exo-sialidases that can catalyze the cleavage of sialic acids from carbohydrates, glycoproteins or
glycolipids. Sialidases have been thoroughly studied since their discovery 75 years ago and their occurrence in
bacteria and viruses is widespread. They are found in diverse virus families and bacteria and other microbes.
Moreover, sialic acids serve as a receptor for various pathogens. This allows bacteria like H1N1 or other influenza
viruses, to enter the host cell. There is a need to block sialidases as they release sialic acid that serves as nutrition
for the microbes and as well allows them to bind and invade the host cell where they can proliferate. This makes
sialidases an interesting target to control pathogenic activity.
Metadichol® is nanoemulsion of long-chain lipid alcohols derived from food ingredients. In rats, it has an LD50 of
5000 mg/kilo and its ingredients are present in many foods we consume on a daily basis. It has antiviral and
antibacterial and anti-parasitic properties. We studied inhibition of Sialidases by inducing it with Lipopolysaccharide
(LPS) using THP1 cells. Metadichol showed inhibition at 1 picogram per ml to 1 nanogram per/ml. Compared to
Prednisone. It is 100 times more active. Previous studies on Metadichol® showed that it is toxic to cancer cells at
higher concentrations.
Since it is safer, it has the potential of being directly tested on humans without side effects and could have a
potential role in mitigating the pathogens that a burden on the Public health system.
Keywords: Sialidases; CD33; Sialic acid; Viruses; Bacteria; Inuenza
Introduction
Sialidases are also known as neuraminidases are enzymes, the
majority of which are exo-Sialidases that catalyze the cleavage of
terminal sialic acids from glycoproteins or glycolipids [1,2]. Sialidase
activity is seen in many infectious and also autoimmune diseases [3-5].
Sialidases are involved in pathways like immunosuppression and
rapidly multiply within the host. Sialidase activity is seen in cancer and
also in biolm formation [6,7]. Neu3, a sialidase, is upregulated in
these diseases [8,9]. Defects in the sialidase activity of the brain have
been shown to have a role in dierent psychiatric and neurological
disorders like epilepsy, alcoholism, schizophrenia and severe
depression [10]. Sialic acids are found at terminal positions of many
surface-exposed glycoconjugates and are vulnerable to cleavage by
sialidases [2,11].
Sialidases are not only expressed in humans but also in bacteria,
Viruses, as well as fungi species and are involved in the modulation of
molecules linked to biological processes [12,13]. Sialic acid is
synthesized de novo or obtained exogenously. Many pathogens
camouage their surface molecules, polysaccharides and LPS with
sialic acid, which makes their entry into host cell surfaces easier. is
action helps them evade the immune response by the host immune
system [14,15]. Bacteria acquire sialic acid by synthesizing it or acquire
it from the environment [16,17]. Many pathogens use a sialidase to
release sialic acid from the host sialoglycoconjugates [18]. Other
bacteria that cannot secrete a sialidase are dependent on host-derived
sialic acid [19].
Chen et al. in their work with intestinal sepsis came to the
conclusion that inammatory response is exacerbated by bacterial
sialidases, keeping immune responses in check when ‘host cells are
damaged. Inhibiting sialidase activity leads to a substantial reduction
of the inammatory response and increases in subsequent morbidity
[20]. e cleavage of human sialic acids from glycoproteins or
glycolipids by pathogenic sialidases is involved in many infectious,
chronic as well as autoimmune diseases. e inuenza viral drugs
Tamiu and Relenza inhibit the inuenza virus sialidase, which is
required for viral replication from infected cells.
Our work is an extension of the previous work that Metadichol® a
food-based nanoemulsion of long-chain based alcohols inhibits H1N1
and other viruses including Zika and Ebola [21-23]. To understand the
mechanism of the antiviral, antibacterial property of Metadichol®, we
recently showed that Metadichol increases CD33 expression by up to
400 fold at 100 picograms per ml in Umbilical cord cells and CD33
binds to related Siglecs [24].
In this study, THP-1 cells were used as an in-vitro model for human
monocytes for its response to LPS induced sialidase production. LPS is
a surface component of gram-negative bacteria that plays a critical role
in mediating inammation and inducing cells to secrete pro-
inammatory cytokines.
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ISSN: 2157-7633
Journal of Stem Cell Research &
Therapy
Raghavan et al., J Stem Cell Res Ther 2019, 9:4
DOI: 10.4172/2157-7633.1000449
Research Article Open Access
J Stem Cell Res er, an open access journal
ISSN: 2157-7633 Volume 9 • Issue 4 • 1000449
Materials and Methods
p-1 (ATCC® TIB-202) cells were procured from ATCC, USA,
RPMI media, Fetal Bovine Serum (FBS) and PenStrep were obtained
from Life Technologies, USA. 4-methylumbelliferyl-α-N-acetyl-D-
neuraminic acid, Phorbol 12-myristate 13-acetate (PMA), L-
glutamine, β-mercaptoethanol, PMA and phenyl methyl sulphonyl
chloride (PMSF) were all obtained from Sigma Aldrich, USA.
Preparation of test samples
Metadichol (5 mg/ml) stock was diluted to obtain desired
concentrations of 0.001, 0.1, 1, 100, 1000 ng/ml test solutions.
Cell lines and treatment
Cell culture: THP-1, a promonocytic cell line was obtained from the
ATCC. Cells were cultured in T25 cm2 ask with RPMI-1640
supplemented with 10% inactivated fetal bovine serum, 50 µM 2-
mercaptoethanol, 2 mM L-Glutamine and penicillin and streptomycin
(100 IU/ml) in a humidied atmosphere of 5% CO2 at 37°C until
conuent.
Treatment to determine the eects of a sample on sialidase activity:
e cells were aspirated from the 80% conuence culture ask and
centrifuged at 1500 rpm for 5 mins. e cell pellet was then
resuspended in 1mL of RPMI complete media and counted
conventionally using Hemocytometer. e cells (5 × 106) were
incubated with PMA (10 ng/ml) in separate dishes to dierentiate
THP1 cells. To determine the sialidase activity, THP-1 cells were
pretreated for 1hr with Metadichol at various concentrations prepared
in culture media without FBS and Prednisone at 100 and 1000 ng/mL
as a positive control followed by 24 hr LPS (1 µg/ml) stimulation. Post
incubation, the cells are carried over to determine the sialidase activity.
e sialidase activity was found to be maximum at16-hour time point.
Determination of Sialidase activity: Cells were washed with
phosphate-buered saline and resuspended in ice-cold buer
containing 0.25 M sucrose, 1 mM EDTA, and 0.2 mM
phenylmethylsulphonyl uoride. e cell suspension was sonicated on
ice for 15 s on a low setting (6% amplitude) (VibracellTM; Sonics and
Materials Inc., Newtown, CT) followed by centrifugation at 25,000 g
for 15 min at 4°C. e resulting supernatant was used to determine the
lysosomal sialidase activity. Protein quantication of the supernatant
was performed using the Bio-Rad protein determination kit as
described above. For the determination of lysosomal sialidase activity,
200 µg of total protein was mixed with 40 nmol of 4-
methylumbelliferyl- α-N-acetyl-D-neuraminic acid (Sigma), the
lysosomal sialidase-specic substrate, 10 µmol sodium acetate buer,
pH 4.6, and 200 µg of bovine serum albumin in a total volume of 200
µl. e sialidase reaction was allowed to proceed for 1 h at 37°C and
was terminated by the addition of 0.25 M glycine NaOH, pH 10.4.
Released 4-methylumbelliferyl-N-acetyl-D-neuraminic acid was
measured uorometrically (Synergy 2 multi-mode microplate reader)
at an excitation wavelength of 365 nm and an emission wavelength of
448 nm.
Results and Discussion
e results show the sialidase activity assessed by the isolation of
whole protein. With Metadichol the relative sialidase activity/mg of
protein at 1 ng/ml was found to be 0.79 compared to LPS control. In
the case of Prednisone (Figures 1 and 2) relative sialidase activity at
1000 ng/ml treatment was 0.67 compared to LPS control. Prednisone
shows no activity below 100 nanograms per ml and Metadichol shows
activity at 1 picogram per ml (0.001 ng/ml) (Tables 1 and 2). e
sialidase activity was found to be higher at 16 hour time point post LPS
(1µg/mL) treatment. Sialidase activity declined to post 16 hrs.
Sample Concentrations Mean Relative sialidase activity/mg
of protein (Time points) (n=2)
4 hr 8 hr 16 hr 24 hr
Media control 0 0.12 0.04 0.03 0.03
LPS (1µg/ml) LPS 1.00 1.00 1.00 1.00
Metadichol+LPS
(1µg/ml)
0.001 ng/ml+LPS 0.91 0.91 0.95 0.92
0.1 ng/ml+PS 0.87 0.87 0.90 0.87
1 ng/ml+LPS 0.81 0.80 0.83 0.79
Table 1: Relative sialidase activity/mg of protein (Metadichol).
Figure 1: Representation of relative sialidase activity/mg of protein
(Metadichol).
Sample Concentrations Mean Relative sialidase
activity/mg of protein (Time
points) (n=2)
4 hr 8 hr 16 hr 24 hr
Media control 0 0.12 0.04 0.03 0.03
LPS (1µg/ml) LPS 1.00 1.00 1.00 1.00
Prednisone (Positive
Control)+LPS (1
µg/ml)
0.1 µg/mL+LPS 0.87 0.86 0.82 0.81
1 µg/mL+LPS 0.68 0.69 0.68 0.67
Table 2: Relative sialidase activity/mg of protein (Prednisone).
Citation: Raghavan PR, Yogisha S, Anand S, Purushotham GV (2019) Metadichol® a Novel Sialidase Inhibitor. J Stem Cell Res Ther 9: 449. doi:
10.4172/2157-7633.1000449
Page 2 of 4
J Stem Cell Res er, an open access journal
ISSN: 2157-7633 Volume 9 • Issue 4 • 1000449
Figure 2: Representation of Relative sialidase activity/mg of protein
(Prednisone).
We could not compare activity at higher concentration with
Metadichol as it is toxic to the cancer cell lines. We have documented
that pancreatic cancer cell line, express klotho genes on Metadichol
treatment at picogram levels as Klotho gene blocks cancer cell growth
[25]. Metadichol increases CD33 expression of 400 fold. CD33 binds to
sialic acid so any excess sialic is soaked up by CD33 removing the
access to pathological agents to use it either a source of energy or to
circumvent the immune response from the host. Viruses and bacteria
use sialic acid as a mimicry’’ to enter hosts cells then the increased
CD33 and also sialidase downregulation plays a key role in the
documented antimicrobial activity of Metadichol [24,26,27]
Sialic acid concentration is strongly related to microvascular
complications in type I diabetes [28-30]. In type II diabetes, Sialic acid
concentration is elevated when compared with non-diabetic subjects
[31]. Sialic acid is the risk factors for vascular disease, blood lipids, and
lipoprotein [32,33].
We have shown that Metadichol modulates biomarkers like
hypertension, Lipid proles, sugar levels in diabetes (Type 1 and 2) and
in addition to other pathways CD33 and inhibition of Sialidases have a
role in mitigating the biomarkers of these diseases [34].
Metadichol® is derived from food-based ingredients with an LD50 of
5000 mg/kilo [35]. It has no toxic eects on humans and can directly
be tested in human subjects in mitigating infectious and other chronic
diseases [36-38].
Conclusion
e inhibition of sialidases by Metadichol is important. Tamiu
and Relenza by inhibiting sialidases in inuenza virus prevent its
spread to normal cells from infected cells. is property has utility in
treatment of sepsis infection as well in other viral diseases. Metadichol
is the rst known nutraceutical to inhibit sialidases and would allow
researchers to study in detail the mechanism of how viruses that
threaten mankind can be controlled without the need to worry about
toxic eects of drugs.
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Citation: Raghavan PR, Yogisha S, Anand S, Purushotham GV (2019) Metadichol® a Novel Sialidase Inhibitor. J Stem Cell Res Ther 9: 449. doi:
10.4172/2157-7633.1000449
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ISSN: 2157-7633 Volume 9 • Issue 4 • 1000449
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Background Metadichol (1,2) is a Nano emulsion of long-chain alcohols called policosanols which are found in many foods like rice, wheat, grapes, sugar cane, apple and many others (3). It acts on membrane receptors in cells throughout the body to stimulate the immune system and inhibit a variety of disease processes, including those that result in metabolic diseases such as diabetes, obesity and hypertension. Methods A 38-year-old male of middle eastern origin was diagnosed as diabetic after complaining of tiredness and bouts of hunger. He was not on any medication and chose to be treated with Metadichol @ 10 mg per day. Findings Metadichol helped to lower his fasting blood sugar level from 300 mg/dl to normal in 6 weeks. His HBA1C was reduced from 9.8% to 6.2% in 12 weeks. After 32 more months, his diabetic indicators remain normal. Interpretation Metadichol is safe and effective in controlling blood sugar and HbA1C levels in humans. Metadichol has been shown to bind to the vitamin D receptor (2) as an inverse agonist. However, it acts more like a protean agonist ligand (4) to increase or decrease activity depending on the system. Since Metadichol has no known negative side effects and consists of natural components of common foods, Metadichol has the potential to serve as a novel treatment for type 2 diabetes.
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