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Plant sterols and sterolins: A review of their immune-modulating properties

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Beta-sitosterol (BSS) and its glycoside (BSSG) are sterol molecules which are synthesized by plants. When humans eat plant foods phytosterols are ingested, and are found in the serum and tissues of healthy individuals, but at concentrations orders of magnitude lower than endogenous cholesterol. Epidemiological studies have correlated a reduced risk of numerous diseases with a diet high in fruits and vegetables, and have concluded that specific molecules, including b-carotene, tocopherols, vitamin C, and flavonoids, confer some of this protective benefit. However, these epidemiologic studies have not examined the potential effect that phytosterols ingested with fruits and vegetables might have on disease risk reduction. In animals, BSS and BSSG have been shown to exhibit anti-inflammatory, anti-neoplastic, anti-pyretic, and immune-modulating activity. A proprietary BSS:BSSG mixture has demonstrated promising results in a number of studies, including in vitro studies, animal models, and human clinical trials. This phytosterol complex seems to target specific T-helper lymphocytes, the Th1 and Th2 cells, helping normalize their functioning and resulting in improved T-lymphocyte and natural killer cell activity. A dampening effect on overactive antibody responses has also been seen, as well as normalization of the DHEA:cortisol ratio. The re-establishment of these immune parameters may be of help in numerous disease processes relating to chronic immune-mediated abnormalities, including chronic viral infections, tuberculosis, rheumatoid arthritis, allergies, cancer, and auto-immune diseases.
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Page 170 Alternative Medicine Review
Volume 4, Number 3 1999
Copyright©1999 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Plant Sterols and Sterolins: A Review of Their
Immune-Modulating Properties
Patrick J.D. Bouic, PhD and Johan H. Lamprecht, MD
Abstract
Beta-sitosterol (BSS) and its glycoside (BSSG) are sterol molecules which are
synthesized by plants. When humans eat plant foods phytosterols are ingested, and
are found in the serum and tissues of healthy individuals, but at concentrations orders
of magnitude lower than endogenous cholesterol. Epidemiological studies have corre-
lated a reduced risk of numerous diseases with a diet high in fruits and vegetables, and
have concluded that specific molecules, including b-carotene, tocopherols, vitamin C,
and flavonoids, confer some of this protective benefit. However, these epidemiologic
studies have not examined the potential effect that phytosterols ingested with fruits
and vegetables might have on disease risk reduction. In animals, BSS and BSSG have
been shown to exhibit anti-inflammatory, anti-neoplastic, anti-pyretic, and immune-
modulating activity. A proprietary BSS:BSSG mixture has demonstrated promising re-
sults in a number of studies, including
in vitro
studies, animal models, and human
clinical trials. This phytosterol complex seems to target specific T-helper lymphocytes,
the T
H
1 and T
H
2 cells, helping normalize their functioning and resulting in improved T-
lymphocyte and natural killer cell activity. A dampening effect on overactive antibody
responses has also been seen, as well as normalization of the DHEA:cortisol ratio.
The re-establishment of these immune parameters may be of help in numerous dis-
ease processes relating to chronic immune-mediated abnormalities, including chronic
viral infections, tuberculosis, rheumatoid arthritis, allergies, cancer, and auto-immune
diseases.
(Altern Med Rev 1999;4(3):170-177)
Introduction
Beta-sitosterol (BSS) is the major phytosterol in higher plants, and is found in the serum
and tissues of healthy individuals at concentrations 800-1000 times lower than that of endogenous
cholesterol. Its glycoside, β-sitosterol glycoside (BSSG), is also present in serum in even lower
concentrations.
1
These molecules are synthesized in plants; whereas animals obtain them through
diet. Many epidemiological studies of groups consuming diets rich in vegetables and fruits
have indicated a reduced incidence of various types of cancer, cardiovascular disease, diabetes,
and other chronic diseases.
2
Many of these studies have concentrated on the protective effects
of well-characterized molecules such as b-carotene, tocopherols, vitamin C, and flavonoids.
P.J.D. Bouic, Ph.D and Johan H. Lamprecht, M.D. - Departments of Medical Microbiology and Pharmacology, Medical Faculty,
University of Stellenbosch.
Correspondence address: P.O. Box 19063, Tygerberg 7505, South Africa. E-mail: pjdb@gerga.sun.ac.za
Copyright©1999 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Sterols & Sterolins
Alternative Medicine Review
Volume 4, Number 3 1999 Page 171
However, such studies have ignored the
relative importance of fats in the plants
consumed.
The scientific literature is replete with
reports of the biological activities of sterols or
their glycosides in various animal models. For
instance, BSS and its glycoside have been
shown to reduce carcinogen-induced cancer
of the colon in rats,
3
as well as exhibiting anti-
inflammatory,
4
anti-pyretic,
5
anti-complement
activity,
6
and insulin-releasing effects.
7
A proprietary mixture of BSS and
BSSG (BSS:BSSG) was studied and found to
have profound immune modulating activities.
Initial in vitro studies were followed by clini-
cal trials in patients with chronic infectious dis-
eases (tuberculosis, HIV, Human Papilloma
Virus [HPV]) and non-infectious conditions,
such as allergies and rheumatoid arthritis. The
trials confirmed the importance of BSS:BSSG
in the management of such conditions.
The Functioning of the Immune
System
The immune system is an intricate net-
work of cells and soluble factors released by
these cells. B-lymphocytes produce antibod-
ies in response to antigenic stimulation. T-lym-
phocytes induce either a humoral or cellular
response depending on the subset of T cells
that are primed upon initial contact with the
antigen.
8
T cells are made up of two
distinct subsets, the CD4 helper
cell and the CD8 cytotoxic/sup-
pressor cells. Within the CD4
subset there are two types of
helper cells. One is the T
H
1-type,
which releases interleukin-2 (IL-
2) and gamma interferon (IFN-γ).
These cytokines bind to and acti-
vate the CD8 cytotoxic cells to
become effective killers. This
type of cellular response is vital
to clearing the host of pathogens
which use the intracellular milieu to survive
attack by the immune response. Should this
cellular response fail, the infection becomes
chronic. The second type of helper cell is the
T
H
2-type, which secretes IL-4, IL-6, and IL-
10, cytokines which are involved in B-lym-
phocyte differentiation (Table 1). The antibody
response is capable of limiting the damage
induced by most extracellular organisms.
In health, there is a delicate balance
maintained between the activity of T
H
1 and
T
H
2 helper cells in that the activity of T
H
1 cells
is directly cross-regulated by the T
H
2 cells, and
vice versa. However, under certain pathologi-
cal conditions, especially chronic viral and
bacterial diseases, the functioning of T
H
1 cells
may be superseded by that of the T
H
2 cells
leading to a humoral immune response (anti-
body production) at the expense of the more
protective cellular response. A similar imbal-
ance exists in other chronic conditions, such
as allergies and autoimmune disorders. Main-
taining the delicate balance between T
H
1 and
T
H
2 cells is vital. Many researchers are cur-
rently attempting to enhance the activity of T
H
1
helper cells in order to eradicate latent and
chronic pathogens.
BSS and BSSG as Immune
Modulators
Initial observations using human pe-
ripheral blood lymphocytes showed a mixture
Cell Cytokine profile Function of TH subset
T
H1
T
H2
IFN-
γ
, IL2
IL4, IL6, IL10, IL5
Activation of cytotoxic cells
Antogonism of T
H
2 cells
Activation and maturation of B cells
Antogonism of T
H
1 cells
Table 1. The dichotomy of T helper cells based on their
defining cytokine profiles and functions
Page 172 Alternative Medicine Review
Volume 4, Number 3 1999
Copyright©1999 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
of BSS:BSSG in a ratio of 100:1 could influ-
ence the cellular proliferation of T-lympho-
cytes when these were activated by mitogens
in vitro. The in vitro results were confirmed in
a small pilot study in which volunteers took a
BSS:BSSG complex orally. The ex vivo test-
ing of lymphocyte proliferation showed a
greatly enhanced response to mitogens. In par-
allel the lytic ability of the natural killer cells
(NK cells) to a cancer cell line in vitro was
greatly increased in the presence of the
BSS:BSSG mixture.
9
When the profile of cytokine secretion
by activated T cells was measured it was dis-
covered that the BSS:BSSG mixture was se-
lective in the above-mentioned activities. Lym-
phokines belonging to T
H
1-type helper cells
were increased, whereas those associated with
T
H
2-type helper cells were inhibited or re-
mained unchanged. The BSS:BSSG mixture
enhanced the secretion of IL-2 and IFN-γ, but
inhibited the secretion of IL-4.
10
The specific-
ity toward certain T-helper cells indicates
BSS:BSSG could have important regulatory
and modulatory activities in diseases where
enhancement of the T
H
1-type helper cells is
vital for the effective clearance of particular
pathogens. Furthermore, since these plant con-
stituents are able to switch off the secretion of
IL-4 in conditions where an overt T
H
2 response
predominates, these natural substances should
reinstate balance in conditions such as aller-
gies and auto-immune diseases.
Further in vitro testing of physiologi-
cal concentrations of BSS:BSSG on monocyte
activity revealed anti-inflammatory properties,
via inhibition of both IL-6 and tumor necrosis
factor alpha (TNF-α), in a dose-dependent
manner (Figure 1). Diseases characterized by
elevated levels of TNF-α and IL-6, which in-
duce tissue damage, include rheumatoid arthri-
tis and systemic lupus erythematosus (SLE).
BSS:BSSG as an Adjuvant in the
Treatment of Patients with
Pulmonary Tuberculosis
A clinical study of BSS:BSSG com-
plex examined its effect in culture-proven pul-
monary tuberculosis (PTB). This was a
1800
1400
1200
1000
800
600
0
1600
400
200
IL6 (pg/ml)
Medium Lipopoly-
saccharide
(endotoxin)
BSS:BSSG
1mM
BSS:BSSG
100µM
BSS:BSSG
10µM
Addition
Figure 1. IL6 Secretion in vitro.
Sterols & Sterolins
Alternative Medicine Review
Volume 4, Number 3 1999 Page 173
Copyright©1999 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
blinded, randomized, placebo-controlled trial
in drug-sensitive PTB. Patients were hospital-
ized for the duration of treatment, and sputum
culture positivity, chest radiography, weight
gain, Mantoux test response, routine hematol-
ogy, and liver function were evaluated at
monthly intervals. Forty-seven patients were
enrolled in the six-month study, and all pa-
tients were treated with the standard anti-tu-
berculous regimen of isoniazid, rifampicin and
pyrazinamide. No significant differences ex-
isted between the variables of each group
evaluated at the time of entry into the study.
Sputum conversion in the patient
groups were very similar; by the end of the
first month of therapy, 58 percent in the treat-
ment group and 61 percent in the placebo
group were still sputum culture positive. By
the end of the second month, 11 percent of the
patients in each group were still positive, but
thereafter, no patients had positive sputum
cultures. An independent physician and radi-
ologist evaluated the radiological changes seen
on the chest radiographs. Although improve-
ment seemed to occur faster
in the sterol treated group
when compared to their pla-
cebo counterparts, the differ-
ences were difficult to quan-
tify. Therefore, this param-
eter was not included in the
final analysis of the data.
The most significant
differences observed be-
tween the groups were in the
hematological parameters,
including higher lymphocyte
(p=0.0001), eosinophil
(p=0.0001), and monocyte
counts in the BSS:BSSG
group. The placebo group
showed higher sedimenta-
tion rates when compared to
the study group (p = 0.0001).
Possibly the most remark-
able difference between the
two groups was the difference in weight gain
over the six-month period, with the sterol-
treated group demonstrating a faster and more
pronounced weight recovery.
11
This was the first study to find a ben-
eficial effect of BSS:BSSG complex in PTB
patients. Although the study was small, the sta-
tistically significant differences observed be-
tween the patient groups suggest further analy-
sis of the immune modulatory activities of
BSS:BSSG in multi-drug resistant tuber-
culosis.
BSS:BSSG Complex in Felines: A
Model of HIV
Domestic cats infected with the
retrovirus FIV (considered equivalent to HIV
because it induces the same pathogenic
mechanisms of CD4 cell loss and opportunistic
infections) were examined. Infected cats
typically succumb to the infection due to
immunosuppression. A group of 33 infected
cats was divided into a treatment group (n=16)
05112337 49 62 74 87 99 113 125
1200
1000
800
600
400
200
Time (weeks)
0
Median CD4 cells
Gp 1: Rx (n=16)
Linear {Gp 1: Rx N=16)}
Gp 2: Placebo (n=17)
Linear {Gp 2: Placebo (n=17)}
Figure 2. FIV Pilot Study number 2.
Page 174 Alternative Medicine Review
Volume 4, Number 3 1999
Copyright©1999 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
or a placebo group (n=17).
12
Linear regression
of the median CD4 cell numbers of the two
groups revealed that the treated group
maintained stable immune cell numbers over
a period of 168 weeks, whereas those who
received the placebo capsules showed disease
progression with the typical CD4 cell loss over
the same period of time (Figure 2). The end
point of such a model is the analysis of
mortality in both groups of cats. At present,
cats treated with BSS:BSSG complex have
exhibited 20 percent mortality compared to 75
percent in the non-treated group.
Use of BSS:BSSG for Management
of HIV Infected Patients
A clinical study (open-labeled trial) is
in progress in patients presenting at an infec-
tious disease clinic with a diagnosis of HIV.
Pregnant women and children were excluded
from the study. Surrogate markers include both
the number of CD4 cells (percentages and ab-
solute numbers) as well as other lymphocyte
markers, plasma viral loads, and body weight.
Basic hematological and chemical parameters
are also being monitored. The initial database
consisted of 80 patients who
were entered into the trial and
followed for 36 months. At the
time of this writing over 150
patients are enrolled, with a
follow-up period of at least 15
months.
Irrespective of baseline CD4
cell numbers, the median CD4
cell count within the total
group of patients has shown
relative stability over the ana-
lytical period (Figure 3). The
data was compared to that ob-
tained from a group of patients
attending the same infectious
disease clinic but who were not
participating in the clinical
study. These patients exhibited
the classical decline in CD4 cell numbers. Sta-
tistical analysis has found no significant dif-
ferences between the CD4 counts at entry and
at other times during the study in the treated
patients, confirming that to date there has been
stability in the CD4 counts with no further pro-
gression of disease.
12
Similar positive results were obtained
when plasma levels of the pro-inflammatory
monokine IL-6 were compared at baseline and
again after six months. IL-6 levels decreased
significantly, indicating less inflammation,
which could explain the CD4 cell stability in
these individuals.
Plasma viral loads also gradually de-
clined over time.
12
Sterols and sterolins do not
have innate anti-viral properties; the decrease
in viral loads is attributable to enhanced ac-
tivity of the cell-mediated immune response
which controls viral replication.
Evaluation of a small participating
group found the T
H
1/ T
H
2 profile, after at least
12 months of therapy with BSS:BSSG, was
comparable to that observed in healthy HIV-
negative controls.
13
In contrast, a group of in-
fected patients not on any therapy exhibited
0369121518212427
500
400
350
300
250
200
Time (months)
0
Median CD4 cells
450
150
Phytosterols Control Linear (Phytosterols) Linear (Control)
Figure 3. HIV Clinical trial (phytosterols vs. control).
Sterols & Sterolins
Alternative Medicine Review
Volume 4, Number 3 1999 Page 175
Copyright©1999 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
the typical predominance of T
H
2 responses
after in vitro activation of CD4 cells (Table
2). The ability to maintain a protective T
H
1
cellular response has long-term prognostic
value, as disease progression is attributed to a
failure of this response to control viral repli-
cation.
14
BSS:BSSG for Preventing Stress-
Induced Immune Suppression
Individuals participating in marathon
running or other endurance events are prone
to bacterial and viral respiratory infections.
Research has shown this susceptibility is due
to a transient, hormone-induced redistribution
in immune cells, as well as a decline in the
functionality of the cells.
15
The potential of BSS: BSSG complex
to inhibit immune suppression in a group of
volunteers participating in an ultra-
marathon event was investigated in
a double blind, placebo-controlled
study. The study found the hema-
tological changes which accom-
pany endurance exercise were more
pronounced in individuals who re-
ceived placebo than in those who
received the active capsules. The
placebo individuals demonstrated
neutrophilia with severe lymphope-
nia characterized by a profound
decrease in the total number of T
cells, especially the T helper (CD4
positive) subset. These abnormali-
ties were primarily negated or re-
versed in volunteers in the treat-
ment group.
16
Possibly the most dramatic
differences between the groups in the study
were the changes in serum IL-6 and the
cortisol:dehydroepiandrosterone sulfate
(DHEAs) ratio. Volunteers in the BSS:BSSG
group showed a decline in cortisol, with a par-
allel increase in serum DHEAs levels, and a
decline in IL-6.
16
Modulation of these hor-
mones has a direct impact on the redistribu-
tion of lymphocytes during stress episodes and
significantly affects the immune system’s abil-
ity to respond to potential or ongoing immune
challenges. Abnormally high levels of IL-6
(such as is seen in chronic inflammatory con-
ditions) and decreased levels of DHEAs (such
as is seen in HIV, SLE, and other autoimmune
conditions) characterize many pathological
states.
On-Going Clinical Studies with
BSS:BSSG Complex
At present, new clinical studies of the
following conditions are being conducted:
• Rheumatoid arthritis: This chronic in-
flammatory and destructive autoimmune dis-
ease is typified by increased levels of IL-6
within the affected joints and an abnormal
regulation of immune cells, due to the pre-
dominance of T
H
2-type helper cells which pro-
mote inflammation and antibody synthesis.
17
• Cervical lesions induced by the
Human Papilloma Virus (as detected by
7 Hours 18 Hours
Healthy HIV-
(n=15)
HIV+ BSS:BSSG treated
(n=15)
HIV+ No treatment
(n=15)
15.8 9.5
30.7 24.6
5.6 5.0
Table 2. The maintenance of T
H
1 responses by HIV positive
patients receiving Sterinol™: Ratio of T
H
1 versus
T
H
2 CD4+ cells activated in vitro.
Page 176 Alternative Medicine Review
Volume 4, Number 3 1999
Copyright©1999 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
cytology): Current literature reports such
lesions are indicative of an abnormal clearance
of the virus and, if left untreated, can lead to
carcinoma requiring conization and possibly
hysterectomy. Many anecdotal cases of women
having used BSS:BSSG complex for this
condition have been reported.
• Chronic rhinitis and sinusitis: A
small, placebo-controlled study in affected in-
dividuals indicates this allergic condition can
be controlled by BSS:BSSG complex.
• Hepatitis C virus carrier status: New
clinical data from physicians using BSS:BSSG
complex report control of liver damage, with
a concomitant improvement in liver function
and decline of virus within the plasma in these
patients.
Conclusions
The BSS:BSSG complex is a new,
natural immune modulator which has demon-
strated promising results in a number of clini-
cal trials. These important plant constituents
seem to specifically target T-helper cells, and
may help to restore balance between T
H
1 and
T
H
2 cells. The end result of this immune modu-
lation is an increase in T
H
1-related cytokines,
a decrease in T
H
2-related cytokines, increased
lymphocyte proliferation, and greater NK cell
activity. The BSS:BSSG complex has also
been shown to help normalize the
DHEA:cortisol ratio, which can have profound
positive results on the immune system. The
re-establishment of these immune parameters
may be of help in numerous disease processes
relating to chronic immune-mediated abnor-
malities, including chronic viral infections,
tuberculosis, rheumatoid arthritis, allergies,
cancer, and auto-immune diseases.
Acknowledgements: The authors wish
to thank Essential Sterolin Products (Pty) Ltd.,
of South Africa, the worldwide distributor of
Moducare™ Sterinol,™ the BSS:BSSG com-
plex used in the clinical studies mentioned
above.
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... immunomodulating activity [1]. It has also been evident from current literature that in Upper Respiratory Infections such as Chronic rhinitis and sinusitis: A small, placebo-controlled study on affected individuals indicated that this allergic condition was controlled by BSS: BSSG complex [1]. ...
... immunomodulating activity [1]. It has also been evident from current literature that in Upper Respiratory Infections such as Chronic rhinitis and sinusitis: A small, placebo-controlled study on affected individuals indicated that this allergic condition was controlled by BSS: BSSG complex [1]. ...
... The BSS: BSSG complex is now considered a new, natural immune modulator which has demonstrated promising results in few studies [1,2]. These important plant constituents that seem to speci ically target T-helper cells and may help to restore balance between TH1 and TH2 cells. ...
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The majority of Volunteers were in the age group 20-30 years (52.5%), Female (70%), Class 12th Passed (52.5%), Housewife (70%), and had a total family income between 3-4 lakhs per annum (40%) (Table no:01). Out of 40 Volunteers who participated in the study, 10% had a history of covid19 Infection,15% had recent COVID + ve antigen. After the use of Naϐlan spray for 1 month, No Covid +VE Volunteer was found. Symptoms such as Cough and Diarrhoea were Reduced (improved) by 120% after use of Immune (Naϐlan Spray), but no effect on high fever, headache, and Common cold was seen after use of Naϐlan Immune Spray. So in the Immune spray user group, the maximum reduction was seen in Cough & Diarrhoea (45% each respectively). The use of Spray gave a significant reduction (p<0.05) in few symptoms such as Cough. (Table no: 02). Discussion There has been a growth in scientiϐic interest in many nutritional supplements such as Nutraceuticals, which can be extracted, used for food supplements, or added to foods. There has long been interesting in the antiviral properties of Nutraceuticals, which are especially topical in the context of the ongoing COVID-19 pandemic [15]. Article Highlights  There is no side effect of Volunteers after use of Naϐlan Spray for 1 month  There is a positive effect on Respiratory & Gut Immunity after the use of Naϐlan spray.  Nafalan Spray can be useful in the Prevention of Cough in Respiratory Infections (including COVID 19). Use of Naϐlan Spray for 1 month did not affect high fever, headache, and Common cold.  Naϐlan Spray in Oro- Nasal form can be a potential Food Supplement for Prevention of COVID 19
... βS has been shown to have antiatherogenic potential through its anti-inflammatory action on human aortic endothelial cells [13]. Similarly, it has been reported that βS causes a dose-dependent inhibition of IL-6 and TNF-α in endotoxin-activated human monocytes [13,14]. It has been found that βS has beneficial effects on the immune system by increasing the number of viable peripheral blood mononuclear cells (PBMCs) and activating the swine dendritic cells (DCs) [15]. ...
... Anti-inflammatory and immunomodulatory properties of βS have been demonstrated in several animal models, including fattener pigs after receiving a mod-ified live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine [15], rats with oxazolone-induced contact-delayed type hypersensitivity [16], and mice with ovalbumin-induced lung inflammation [17]. Clinical studies represented the potential immunomodulatory effects of βS in patients with pulmonary tuberculosis, human immunodeficiency virus (HIV), human papillomavirus (HPV), stressinduced immune suppression, rheumatoid arthritis, and allergic rhinitis and sinusitis [14]. ...
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