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by Aftab J. Ahmed, PH.D. |
Enzymes play a critical role in nearly every metabolic and physiological response in the body. They ensure that the cellular processes take place at the right time, to the right extent and in the correct context. As such, enzymes are cellular workhorses that carry out their function rapidly and efficiently. With advancing years, failing health, poor nutrition or otherwise complicating circumstances, however, enzymes are either quickly depleted or lose their potency. When one enzyme is even partially functional, a ripple effect on other bodily reactions and in fact, overall function becomes readily discernible. It is for a reason then that over the decades systemic enzymes have been pivotal in the emergence of integrated health care.
Enzymes are characterized as systemic that
when ingested orally, are delivered intact to the
bloodstream over the gastrointestinal (GI) tract.
Routinely composed of proteases, they break
down proteins in circulating blood and as a
result, exert their many beneficial effects. This
property of systemic enzymes has significant
implications for human health and disease.
Traditionally, by virtue of the fact that they
work throughout the body, systemic enzymes
help maintain the bodily homeostasis, which is
critical in the maintenance of good health.
The peripheral circulatory system is impressive
in its structural complexity and fluid
mechanics.1 In the first instance its function is
to transport nutrients and oxygen to tissues
and organs and to whisk away metabolic waste
products. The marvel of the vascular architecture
is its flexibility that allows the blood to
remain at the requisite viscosity—a balance
actually between thickness and fluidity—in
order for the bodily functions to proceed
unfettered. Thus the equilibrium between the
yin of blood thickening and the yang of its
fluidity, or liquefaction, is a prerequisite in
maintaining the circulating blood at a certain
viscosity to prevent uncontrolled bleeding and
conversely, clotting.
At the center of this equilibrium between
normal thickness and liquefaction is the
protein fibrin, which is the “glue” that helps
maintain blood at optimal viscosity. Fibrin is
present in nearly all types of cells in its inactive,
precursor form, called fibrinogen. Upon
proper stimulus, a proteolytic enzyme clips fibrinogen to its biologically active form fibrin.
In fact, there is a series of protein precursors
that are sequentially activated prior to fibrin
activation (Fig. 1). The reason for this convoluted
cascade in fibrin activation is to ensure that it does not spin out of control.
Excessive fibrin release is as deleterious
to human health as its production
in less than required amounts. How so?
Fibrin facilitates a number of metabolic
processes. Whereas on the one hand
it is beneficial in wound healing, on the
other, its out-of-context production
over time could precipitate lifethreatening
occlusion of the arteries.
Accordingly, over-production of fibrin,
or insufficient rate of its breakdown, is
emerging as an important mechanism
in chronic diseases.
Under normal physiological conditions,
controlled release of fibrin coats
the rather fragile inner walls of the
blood vessels to protect them from
sustaining injuries from (ab)errant
particles in the bloodstream and
smooths any unevenness in the vascular
wall to promote unhindered blood flow. Importantly, in case of an injury, fibrin is
released to initiate blood thickening, which
effectively seals off the injury site by forming a
fibrin plug. In wound healing, transforming
growth factor-b (TGF-b) is produced along
with fibrin release to complete the healing
process.2 This sequence of events is regulated
such that, after the repair process is complete,
the blood is liquefied to prevent excessive
fibrin production and therefore, minimize
scarring of the tissue. Under some circumstances,
however, if liquefaction is not initiated
and fibrin release continues unabated, it could
cause fibrosis or hardening of the tissue. The
hardened tissue progressively loses its function.
Fibrosis can occur just as easily in the internal
organs as it does on the skin surface. Among
the internal organs susceptible to fibrosis are
the liver, lungs and the kidneys. Likewise
excessive fibrin release could cause keloids,
fibrous growths resulting from unbridled
production of TGF-b. Simultaneous overproduction
of fibrin and TGF-b desensitizes the
tissue to register the signals to stop the repair
process. Repetitive injuries to one tissue also results in this desensitization. Of course
advanced age, disease, poor nutrition and
other compromising factors contribute to
over-repair as well.
Aside from over-repair, excessive amounts
of fibrin in the circulating blood increase its
viscosity, which could form clots that are sticky
enough to adhere to the vessel walls. Such clots
serve as seeds for progressive accumulation not
only of fibrin but also cholesterol and cellular
debris in the blood. As the clots increase in
size, the blood is forced to circumnavigate
these obstructions, causing the blood vessels to
bulge. This constriction is the root cause of
venous insufficiency, as in the so-called
“economy class” syndrome and varicose veins.
It takes considerable time for these clots to
develop into mature plaques that are responsible
for coronary artery disease (CAD). The
path to maturity is fraught with danger,
however. The younger plaques can easily
erupt, leaving literally millions of micro-clots
in their wake.3 As such they could precipitate a
potentially fatal coronary episode, even in the
absence of symptoms traditionally associated
with CAD. Recent clinical data establish that
such coronary events are almost invariably
caused by chronic inflammation.
In fact inflammation is the major culprit in many chronic diseases, including arthritis, CAD,
Alzheimer’s disease and a host of other agerelated
afflictions. To wit, fibrin is central in
inflammatory conditions. While inflammation
is the healing response of the body to recover
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| Figure 2: Effect of Oral Nattobinase on Plasma tissue Plasmacinogen Activator (each data point represents the mean ±sd) |
from an injury, if unresolved, it can over-activate
the immune system. Considerable evidence
suggests that repeated activation of the body’s
defensive arsenal may keep the immune
system activated constantly, which could
potentially induce autoimmunity. To an extent
the epidemiological data corroborate the
contention that spuriously activated immune
system underlies autoimmune diseases. As the
immune system gears into action, antibodies are
produced, as in arthritis, which then form
aggregates known as circulating immune complexes
(CICs). Circulating ICs clutter the blood
traffic that, in turn, not only increases blood
viscosity but also may give rise to secondary
antibody production, which further aggravates
autoimmunity.
How does fibrin fit in this jigsaw puzzle? If
excessive amounts of fibrin are present, a protective
coat is laid on the surface of CICs making
them “invisible” to the immune system. Each
CIC carries an ID tag, in a manner of speaking,
which makes it vulnerable to detection and
elimination by macrophages, the foot soldiers of
the immune system. Fibrin coating, however,
masks the telltale ID tag and therefore prevents
their clearance from the body.
The foregoing underscores the fact that
diverse mechanisms are involved in the onset of chronic diseases. This is precisely the reason why
chronic diseases progress slowly over long
periods of time. Since the human body has a
wide repertoire of self-healing processes, a
process gone awry is relatively quickly corrected.
If metabolic attrition persists, however, the
ripple effect mentioned initially takes hold. In
essence, it could be likened to the molecular
road rage in which the many different mechanisms
become hopelessly tangled, as in the
wreckage of a roadside pile-up. As a consequence,
when a chronic disease is clinically
presented, it may be too late already to undo the
damage. While intuitively obvious, it demonstrates
how the convergence of numerous
pathways makes chronic diseases less amenable
to therapeutic intervention. This convergence
creates its own dynamics. Each of the contributing mechanisms brings about a
different composite. In a sense, it is not
unlike the pieces viewed through the lens
of a kaleidoscope. With each turn, while the
pieces are the same, a different configuration
ensues. This analogy is recapitulated in the
onset and presentation of chronic diseases.
Several mechanisms, some of which might
be otherwise perfectly innocuous, morph
into abnormal physiology. This complexity
is reflected in chronic diseases and should
underscore the necessity of preventive
regimens. Therefore, a preventive regimen
may be a more expedient approach in its
management.
Notably second-generation systemic
enzymes are instrumental in keeping the
diverse biochemical pathways well
within the normal range. The example of
out-of-context release of activated fibrin
makes the point poignantly. Excessive
fibrin could blunt the immune response over time. By the same token, it may encourage
fibrosis, which may cause hypertension and thus
affect overall function of the cardiovascular tree.
In turn, this may result in less than optimal
blood flow, triggering a domino effect that could
encompass the entire body (for a detailed review,
see Ref. 4). Again the second-generation systemic
enzymes provide an effective regimen to nudge
the underlying mechanisms to retain, and in
some cases restore, homeostasis. Furthermore,
the benefits of systemic enzymes can be augmented
by bioflavonoids, which modulate the
immune system by mitigating the function of
those chemical messengers that stoke the
inflammatory fires.
A protelolytic enzyme activity in fermented
soybeans effectively optimizes blood viscosity.
Thanks to this activity, fermented soybeans have
been used for centuries in Japan to promote
heart health and normalize blood flow. This
enzymatic activity regulates excess fibrin by
primarily mobilizing tissue plasminogen
activator native to the body (Fig. 2). Accordingly,
this proteolytic activity primes the latent
health-promoting potential in the body. In combination
with other plant-derived systemic
enzymes, it also helps slake the inflammatory
response.5
Powerful as this activity is, it can be further
bolstered by bioflavonoids, since different roads
lead to the proverbial Rome of inflammation.
Thus, a proprietary Rutobioflavonoid mix
(RBE) is designed to regulate pro-inflammatory
chemical messengers in favor of those that can
help still the fires raging in the joint.6
Importantly, robust flow of blood to various
tissues is indispensable for health. For example,
joints ravaged by arthritis may have blocked
arteries in close proximity. Therefore, unplugging
of arteries should promote better delivery
of nutrients and oxygen to the joint to heal itself.
In short, in the management of chronic
diseases a nutraceutical approach should
discourage the entanglement of biochemical
pathways detailed above. While metabolic
pile-up depends on numerous factors, nutritional
intervention directed at the underlying
cause helps alleviate pain and suffering, if
not checkmate the molecular road rage over
the long run.
Aftab J. Ahmed, Ph.D. is director of research and development and business development at Marlyn Nutraceuticals, Inc.
E-mail:
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Annotated references*
- Ahmed, A. J. The Cycle of Life: Circulation and The Lymphatic System, Manuscript in Preparation (2002).
- Letterio, J. and Roberts, A. “Regulation of Immune Responses by TGF-b,” Ann. Rev. Immunol. (1998). Vol. 16 p. 137.
- Fuster, V. The Vulnerable Plaque: Understanding, Identification and Modification, (1999). Futura Publishing Co., Inc., Armonk, New York.
- Ahmed, A. J. “C-Reactive Protein: A Coronary Trojan Horse,” totalhealth (1999). Vol. 22, No. 2.
- Sumi, H., Hamada, H., Nakanishi, K. and Hiratani, H. “Enhancement of the Fibrinolytic Activity in Plasma by Oral Administration of Nattokinase: Natto VR 501,” Acta Haematologica (1994). Vol. 84 p. 139.
- Salvemini, D, Wang, Z., Zweier, J., Samouilov, A., Macarthur, H., Misko, T., Currie, M., Cuzzosrea, J. Sikorski, J. and Riley, D., “A Nonpeptidyl Mimic of Superoxide Dismutase with Therapeutic Activity in Rats,” Science (1999). Vol. 286 p. 304.
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*A complete list of references may be obtained by contacting the author at
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