Recently, we discussed herbal blood cleansers and how they work to boost the lymphatic system and actively defend against multiple kinds of cancer in the body. In that article, we mentioned that systemic, proteolytic enzymes also work to clean out the blood, but through entirely different pathways and mechanisms…and to entirely different end results. Although they may have some cancer protective benefits–and there are indeed cancer therapies based on proteolytic enzymes, not to mention a number of studies that support those therapies–the primary benefits we’re looking for when taking systemic, proteolytic enzymes center around their ability to:
- Control inflammation throughout the body, not just in your joints.
- Repair and rebuild the cardiovascular system.
- Optimize blood flow.
- Prevent and dissolve blood clots.
- Dissolve plaque in your arteries and dental plaque in your mouth.
- Clean up your immune system.
- Minimize the impact of allergies.
- Improve the ability to exercise and speed up recovery times.
And all of these benefits stem from one simple ability: proteolytic enzymes facilitate the breakdown of rogue proteins in your bloodstream and in the soft tissues of your body.
In this report, we’re going to take a look at exactly what systemic, proteolytic enzymes are, what they do, how they do it, and what the ideal proteolytic formula looks like.
What are enzymes?
In our previous report, Enzymes Defined, we explored the general nature of enzymes–what they are and what they do. In summary, enzymes are proteins that speed up chemical reactions. There are estimated to be between 50,000 and 70,000 different enzymes in your body that regulate every metabolic function in your body. Without enzymes, all of these metabolic functions would progress through the same steps, but would go too slowly to sustain life. In essence, enzymes make life happen where otherwise there would be none.
Most people, when they think of enzymes, think of digestive enzymes, and in the world of alternative health, that usually means digestive enzyme supplements. But as we’ve already mentioned, there are tens of thousands of different enzymes in the human body, and 99.999% have nothing to do with digestion.
An important concept to understand is that digestive enzyme formulas and systemic/metabolic, proteolytic enzyme formulas, although they may share many of the same enzymes (protease, papain, bromelain, etc.), are not the same thing.
- When you take a digestive enzyme formula with your meal, the enzymes work on speeding up the breakdown of the food in your stomach.
- When you take a proteolytic enzyme formula between meals, the enzymes do not get stuck working in your stomach or wrapped up with your food and passed out through the colon. Instead, they quickly enter your bloodstream. Once in the bloodstream, they help optimize your blood, plus they make their way to all of the tissues throughout your body, where they assist with intelligent, adaptive healing.
Understanding Proteolytic Enzymes
The vast majority of metabolic enzymes in your body, the enzymes that regulate everything from liver function to the immune system, are proteases, or proteolytic enzymes. Proteolytic is a catchall phrase for hydrolytic enzymes that specifically facilitate the chemical breakdown of proteins by severing the bonds between the amino acids that make up those proteins.
Proteolytic enzymes occur naturally in all organisms and constitute 1-5% of all genetic content. They are different from other enzymes in the body in that they are able to adapt to changing needs. For example, the same proteolytic enzyme can meet both digestive and metabolic needs in the body. This is the reason that you will see some of the same proteolytic enzymes in both digestive enzyme formulas and systemic metabolic formulas.
The bottom line is that a healthy supply of these protein specific enzymes is essential for sustaining and maintaining optimal health.
Types of Proteolytic Enzymes
There are six classifications or groups of proteases in the human body:
- Serine protease
- Threonine protease
- Cysteine protease
- Aspartate protease
- Glutamic acid protease
Most of the proteases that we’re going to talk about in this report are serine proteases. Serine proteases are enzymes that break peptide bonds in those proteins in which the amino acid serine plays a key role at the enzyme’s active site.1 Hedstrom, L. (Dec 2002). “Serine protease mechanism and specificity.” Chem Rev 102 (12): 4501–24. http://www.ncbi.nlm.nih.gov/pubmed/12475199 In humans, serine proteases are responsible for coordinating various physiological functions including digestion, immune response, blood coagulation, inflammation, and reproduction. Equally important, serine proteases are widely distributed in nature and found in all kingdoms of cellular life as well as many viral genomes. The ability to break down serine protein bonds in invading viruses carries some obvious advantages when it comes to defending your body.
The two exceptions that commonly figure in supplemental enzyme formulas are bromelain and papain, which are cysteine proteases. In humans, cysteine proteases are responsible for cell aging and cell death, and certain immune responses.2 Chapman HA, Riese RJ, Shi GP (1997). “Emerging roles for cysteine proteases in human biology.” Annu. Rev. Physiol. 59: 63–88. http://www.ncbi.nlm.nih.gov/pubmed/9074757 Thus, enzymes that regulate and enhance those reactions provide a perfect complement in any systemic, proteolytic enzyme formula. In addition, cysteine proteases play a role in bringing macrophages back into line when they are misprogrammed and attacking collagen and elastin at sites of inflammation such as arterial walls in atherosclerosis and lung tissue in emphysema.
Which leads us to the next piece of the puzzle.
Proteolytic Enzymes and Illness
Just about everything that makes us sick is either a protein or is protected by a protein and is therefore subject to control by proteolytic enzymes. For example:
- Your DNA stores the code for all of your body’s proteins and enzymes. In essence, your DNA is a protein manufacturing plant. Genetic diseases are the result of your DNA no longer producing those proteins and enzymes accurately or doing it insufficiently or excessively.
- Bacteria, viruses, yeasts, and fungi are all protected by proteins. Attacking those proteins is key to destroying the invaders.
- Food allergens are almost all proteins.
- Cancer cells are protected by proteins.
Proteolytic enzymes have the ability to digest and destroy the protein based defense shield of each and every pathogen, allergen, and rogue cell, thereby leading to their ultimate elimination. In addition, established cancers reprogram the production of enzymes in the body to both accelerate their own growth and protect themselves from the immune system. Supplemental proteolytic enzymes have the ability to alter that dynamic.
And then there are CIC’s (Circulating Immune Complexes). CIC’s start out as extra-large protein molecules (primarily from wheat, corn, dairy, and soy) that are only partially digested in the small intestine and are absorbed into the bloodstream. Once in the bloodstream, the immune system treats them as invaders because they are too large to be metabolized, provoking an immune reaction. Antibodies couple with these foreign protein invaders to form CIC’s. At first, these CIC’s may be neutralized by the immune system, then eliminated through the lymphatic system and the kidneys. But over time, as too many CIC’s are created, they overwhelm the body’s ability to eliminate them. At that point, the body has no choice but to “store” them in its own soft tissues, where the immune system continues to attack them as allergens, which leads to inflammation3 Arazi A1, Neumann AU. “Modeling immune complex-mediated autoimmune inflammation.” J Theor Biol. 2010 Dec 7;267(3):426-36. http://www.ncbi.nlm.nih.gov/pubmed/20832412 and, ultimately, autoimmune disorders such as lupus.4 P O Cano, L M Jerry, J P Sladowski, and C K Osterland. “Circulating immune complexes in systemic lupus erythematosus.” Clin Exp Immunol. Aug 1977; 29(2): 197–204. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1541106/pdf/clinexpimmunol00234-0013.pdf In fact, studies have shown that diseases that present high CIC-levels can be improved or even cured by eliminating excess CICs.5 Stauder G, Ransberger K, Streichhan P, Van Schaik W, Pollinger W. “The use of hydrolytic enzymes as adjuvant therapy in AIDS/ARC/LAS patients.” Biomed Pharmacother. 1988;42(1):31-4. http://www.ncbi.nlm.nih.gov/pubmed/3408806
It is here that proteolytic enzyme supplements come into play. They compensate for your dietary inadequacies and errors by making their way into your bloodstream, where they set to work breaking down CIC’s in your blood and soft tissues — eventually passing the waste out through your kidneys and lymphatic system.
And finally, some proteolytic enzymes such as nattokinase and seaprose-S are very specialized. They work on specific protein related tasks such as optimizing blood, reducing pain and inflammation, and cleaning out the lungs. (We’ll talk more about those later.)
Why You Need to Supplement?
In a perfect world, we would all eat raw (organic) unprocessed foods that are naturally high in active enzymes.
But this isn’t a perfect world.
Most people eat food that is enzyme deficient (cooking and processing destroy enzymes) and fail to chew food adequately (saliva contains amylase) so their bodies must compensate. The body is forced to divert its production of metabolic proteolytic enzymes into the production of large amounts of pancreatic enzymes in order to break down all of the dead food in our diets. Short term, this is not a problem. Your body can easily handle it. But the long-term consequences of this diversion are enormous. It can lead to everything from a weakened immune system to thickened blood, from pain and inflammation to cardiovascular disease, and from reduced athletic performance to difficulty breathing. Supplementing with proteolytic enzymes offsets this devastating diversion and restores balance.
Absorbing Proteolytic Enzymes
Many so called experts say that you can’t absorb proteolytic enzymes. First, they claim that as proteins, they are broken down by stomach acid unless they are in enterically coated capsules. Then, other “experts” say that even if they do survive the stomach, their molecules are too big to pass through the walls of the small intestine–so you can’t absorb them anyway. Whenever I hear these arguments, I’m reminded of the apocryphal story of the engineer who proved that bumblebees can’t fly.6 Cecil Adams. “Is it aerodynamically impossible for bumblebees to fly?” The Straight Dope. May 4, 1990. (Accessed 24 Jun 2014.) http://www.straightdope.com/columns/read/1076/is-it-aerodynamically-impossible-for-bumblebees-to-fly Applying the principles of aerodynamics, he PROVED, based on their size, weight, the surface area of their wings, and the physiological limits of how fast they could flap them, that bumblebees could not fly. Of course, as we all know, bumblebees can indeed fly. The so-called proof is humorous nonsense.
The absorption of proteolytic enzymes is a lot like that. It really doesn’t matter how many theories you come up with to explain why they can’t be absorbed; in the end, you can both measure their presence in the bloodstream and, more importantly, quantify the results of supplementation in your own body.
In any case, let’s deal with the stomach acid issue first. There are two rebuttals:
- I dealt with this issue in detail in the Enzymes Defined newsletter. In summary, pepsin (which is produced in the stomach), amylase (which is found in saliva), and lactase (which is added to dairy products) are three examples of enzymes that not only survive in high acid environments but actually thrive there. Yes, there are some animal based proteases (serrapeptase from silkworms, for example) that can’t handle acid very well and need to be enterically coated; but for the most part, enzymes, even though they are proteins, are too big and too complex to be unfolded by the acid in the stomach, which means they can’t be digested. Most are merely rendered temporarily inactive by the high acid environment…and then reactivated the moment they enter the more alkaline environment of the intestinal tract.
- And even if all systemic proteolytic enzymes were destroyed by digestive juices, instructions for using most such formulas tell you to take them between meals — when stomach acid levels are extremely low. Thus, the issue is moot…at least for a well-designed formula, used properly.
When I designed my own proteolytic enzyme formula, I specifically selected enzymes that survive the stomach acid environment. It’s actually not that hard to do. The key is to use non-animal derived enzymes. As a rule, fungal and plant-based enzymes easily survive stomach acid. Oral supplementation with non-animal derived enzymes, such as microbial or fungal enzymes — those manufactured by a fermentation process of Aspergillus, for example–possess unusually high stability and activity throughout a wide range of pH conditions (from a pH of 2-10).7 Brad Rachman, “Unique Features and Application of Non-Animal Derived Enzymes.” Clinical Nutrition Insights. 510 8/97 Vol. 5, No. 10. (Accessed 24 Jun 2014.) http://acudoc.com/Digestive%20Enzymes.PDF This not only guarantees their survival in the stomach but enables them to be more consistently active and functional as they are transported through the digestive tract. There have been studies that have specifically verified that plant-based proteolytic enzymes such as bromelain easily survive passage through the stomach.8 Laura P. Hale. “Proteolytic activity and immunogenicity of oral bromelain within the gastrointestinal tract of mice.” International Immunopharmacology. Volume 4, Issue 2, February 2004, Pages 255–264. http://www.sciencedirect.com/science/article/pii/S1567576903002972 Bottom line: most supplemental proteolytic enzymes are not destroyed by stomach acid.
Now let’s address the issue of absorption. The standard medical assumption–and it was taught in medical school for years–is that no dietary protein is absorbed in an undigested form — pretty much without exception. Rather, since their molecules are too large, dietary proteins must first be digested into amino acids or di- and tripeptides before they can be absorbed. At first blush, that seems to exclude undigested enzymes, which are indeed proteins–and extremely large ones at that. But study after study proves that supplemental enzymes do indeed cross the intestinal wall and enter the bloodstream. Although the definitive answer as to how they accomplish this is unknown at this time, studies suggest that proteolytic enzymes are able to increase the permeability of the mucosal epithelium and, hence, facilitate their own absorption by a mechanism of self-enhanced paracellular diffusion.9 KOLAC C., STREICHHAN P., LEHR C.-M. “Oral bioavailability of proteolytic enzymes.” European journal of pharmaceutics and biopharmaceutics. 1996, vol. 42, no4, pp. 222-232 (68 ref.) http://cat.inist.fr/?aModele=afficheN&cpsidt=3191444 Or to translate that for the layperson: unlike food proteins that must be absorbed into the cells that line the small intestine, enzymes pass between those same cells–and thus can pass whole, without being broken down into their constituent peptides and amino acids.
When summarizing the arguments pro and con on the absorption of non-enterically coated proteolytic enzymes in the intestinal tract, I’m reminded of the movie Chicago. The husband of Kitty (Lucy Liu) says to his wife when she catches him in bed with two women, “Come on, darling, you gonna believe what you see or what l tell you?” The correct answer is obvious, so she shoots him. In the end, it doesn’t matter what some experts say, proteolytic enzyme supplements can be measured in the bloodstream…and their benefits can be seen by anyone who uses them.
A Proteolytic Enzyme Absorption Challenge
Several years ago, I issued a challenge to readers to validate the ability of the non-enterically coated, systemic, proteolytic enzyme formula that I had created to dissolve dental plaque. This is significant since, for this to happen, the enzymes have to pass through the stomach unscathed, be absorbed in the intestinal tract, make their way into the bloodstream, pass from there into your salivary glands, and then finally out into your mouth. If they can do that, that proves the case for absorption, in spades! Well, we heard from a number of our readers who took the challenge. The response below was typical.
“Five months ago I had my teeth cleaned. At that time I had the expected, usual amount of plaque on my teeth. So the hygienist cleaned it up. One month ago I began taking the Proteolytic Enzymes for some joint inflammation I was experiencing after taking a round of antibiotics for a strong kidney infection. With the help of the Proteolytics, the pain went away very quickly, as I thought it would. Then 2 days ago, I went to the dentist again to have my teeth cleaned and sealed. The hygienist said I did not need my teeth cleaned because there was no plaque on my teeth at all!” Caitlin W., OH
At this point, it’s probably worth just leaving the critics to argue amongst themselves with their bumblebee like arguments and examine what’s before our eyes. The bottom line is that in addition to the empirical evidence that proves that proteolytic enzymes consumed orally are absorbed and impact internal systems in the body, there are also a plethora of peer-reviewed studies. For example:
- There are now upwards of 80 studies that prove that nattokinase works, and that it works in vivo, which means that it passes through stomach acid unharmed, passes through the intestinal wall, and enters the bloodstream.10 http://www.ncbi.nlm.nih.gov/pubmed/?term=nattokinase
- As with nattokinase, bromelain is backed by upwards of 80 studies over the years that substantiate its efficacy in the treatment of inflammatory disorders of the musculoskeletal system.11 http://www.ncbi.nlm.nih.gov/pubmed/?term=bromelain+inflammation
- And combinations of hydrolytic enzymes have been used for the treatment of a variety of diseases for many years, including the treatment of inflammation, traumatological events, surgical interventions, autoimmune and immune complex diseases, rheumatological diseases, viral infections, and malignant tumors.12 Stauder G. “Pharmacological effects of oral enzyme combinations.” Cas Lek Cesk. 1995 Oct 4;134(19):620-4. http://www.ncbi.nlm.nih.gov/pubmed/7585874
Why We Supplement with Systemic Proteolytic Enzymes
In addition to directly breaking down problematic proteins such as the fibrin that both produces dangerous blood clots and holds arterial plaque together, proteolytic enzymes play a key role in modulating both the immune response and inflammatory cascades.
According to a study published in the Slovakian journal, Bratislavské Lekárske Listy, there is strong evidence that systemic enzyme therapy can improve the composition of blood and the properties of vessel walls, as well as both prevent and dissolve dangerous blood clots and the consequences of venous insufficiency.13 Nouza K. “Systemic enzyme therapy in diseases of the vascular system.” Bratisl Lek Listy. 1995 Oct;96(10):566-9. http://www.ncbi.nlm.nih.gov/pubmed/8620329 The study went on to say that the key feature of enzymotherapy appears to be its immunomodulatory activity. “There exists a strong evidence for the favorable modulation of pathogenic autoantibodies, inhibition of the neogenesis of immune complexes and cleavage of their deposits, [and] normalization of the T cell system, network of cytokines [i.e., rebalancing pro-inflammatory and anti-inflammatory cytokines], adhesion molecules and inflammatory cascades.” Or again, to put things in laymen’s terms: supplemental, proteolytic enzymes can shift your immune system away from an automatic, reactive response to a more measured, moderated response, calm down systemic inflammatory cascades, and, as already discussed, significantly reduce levels of circulating immune complexes, all of which can be extremely beneficial for anyone dealing with any autoimmune conditions such as rheumatoid arthritis–as well as anyone looking to avoid them.
Armed with an understanding of how your body utilizes proteolytic enzymes, it becomes clear that the advantages of supplementing with a good systemic, proteolytic enzyme formula are profound. Possible benefits include:
- Reduced systemic inflammation for: Increased heart health, cancer and disease prevention and recovery, Alzheimer’s prevention, fibromyalgia and chronic fatigue relief, and more.
- Cleanses the blood of debris.
- Breaking down and removes circulating immune complexes.
- Dissolving fibrin in the blood, reducing the risk of clots.
- Dissolving fibrin in arterial plaque, thus leading to the breakup of arterial plaque.
- Eliminating the risk of DVT (Deep Vein Thrombosis) when flying.
- Boosting the immune system.
- Killing bacteria, viruses, and other invading pathogens.
- Improved circulation.
- Eliminating CICs
- Eliminating autoimmune diseases.
- Reduced risk of and response to food and pollen allergies.
- Accelerated recovery from sprains, strains, fractures, bruises, contusions,
- Faster recovery time from workouts.
- Help with MS.
- Help with arthritis.
- Eliminating plaque from teeth.
- Helping with sinusitis and asthma.
- Dissolving arterial scar tissue.
- Aiding in cleansing and detoxification.
- Improved body alkalinity.
- Reduced risk of osteoporosis.
Proteolytic Enzymes and Cancer
Systemic enzyme therapy has been subjected to experimental investigations and to rigorous clinical studies in cancer patients. The results of in vitro and in vivo investigations documented the immunological, anti-inflammatory, anti-infectious, and antitumor/antimetastatic activities of proteolytic enzyme mixtures (containing trypsin, chymotrypsin, and papain) or bromelain. EBM level II clinical studies, which are accepted by the European Union to show both the safety and efficacy of medical treatments, were also performed to evaluate the benefit of complementary systemic enzyme therapy in cancer patients suffering from breast and colorectal cancers and plasmacytoma. These studies demonstrated that systemic enzyme therapy significantly decreases tumor-induced and therapy-induced side effects and complaints such as nausea, gastrointestinal complaints, fatigue, weight loss, and restlessness and obviously stabilized the quality of life. For plasmacytoma patients, complementary systemic enzyme therapy was shown to increase the response rates, the duration of remissions, and the overall survival times.14 Beuth J. “Proteolytic enzyme therapy in evidence-based complementary oncology: fact or fiction?” Integr Cancer Ther. 2008 Dec;7(4):311-6. doi: 10.1177/1534735408327251. http://www.ncbi.nlm.nih.gov/pubmed/19116226 Then again, this is hardly surprising, as previous studies have shown that the treatment of human white blood cells with proteolytic enzymes leads to the production of large amounts of tumor necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-1 beta), and interleukin-6 (IL-6) in a time and dose dependent manner.15 Desser L, Rehberger A, Paukovits W. “Proteolytic enzymes and amylase induce cytokine production in human peripheral blood mononuclear cells in vitro.” Cancer Biother 1994;9:253-63. http://www.ncbi.nlm.nih.gov/pubmed/7529614
What Constitutes a Good Systemic Proteolytic Enzyme Formula?
So what should you look for in a properly designed supplemental proteolytic enzyme formula?
- First, it needs a lot of protease. You want at least 200,000 HUT. This is far more than you will ever find in a digestive formula. 300,000 HUT is even better. And you will want to use vegetarian enzymes since they are much more tolerant of stomach acid and work in a much wider range of pH environments.
- Second, you also want a good variety of enzymes which utilize different biological pathways and whose benefits complement, rather than duplicate, each other.
- Third, there are some non-proteolytic enzyme ingredients that you will also want to include in the formula both because they increase the efficacy of the proteolytic enzymes in the formula and because they provide their own complementary benefits as well.
With that said, let’s now take a look at the ingredients that I include in what I consider the ideal systemic, proteolytic enzyme formula.
Fungal Protease and Fungal Pancreatin
Fungal protease and fungal pancreatin are names for particular strains of vegetarian protease enzymes. These are the general workhorses of the formula. In fact, pretty much the entire newsletter so far has been a discussion of the benefits associated with these enzymes.
Fungal pancreatin is a subset of fungal protease. It specifically refers to a mix of vegetarian sourced enzymes that mimics the enzymes produced by your pancreas. It is primarily a combination of trypsin, amylase, and lipase. The lipase and amylase are not proteolytic (i.e., they don’t work on proteins) but complement the action of proteolytics by working on leftover fats and carbohydrates both in the intestinal tract and the bloodstream–cleaning up what proteolytics cannot touch.
Keeping in mind that this formula is designed to be taken between meals, the amylase and lipase, which are frequently found in digestive enzyme formulas, are not included for the purpose of digesting food. In a systemic proteolytic formula, they, instead, play the role of garbage collectors. The addition of the amylase and lipase is important enough that I recommend augmenting the levels found in the fungal pancreatin with the inclusion of small amounts of pure amylase and lipase as part of the formula.
Bromelain and Papain — The Plant Enzymes
Bromelain actually refers to a mix of two similar enzymes, along with their related compounds, which are extracted from the stems of pineapples. Bromelain has been used by Europeans for many years to inhibit inflammatory factors. It has been suggested by some formulators that bromelain is destroyed by stomach acid and needs to be enterically coated to protect it. That’s simply not true. Consider that the pH of the stomach ranges from 3 or 4 during digestion (with only a quick burst to as low as 1 to 2 immediately after eating a high protein meal). But the stomach’s normal resting pH between meals is about 4 or 5. Now compare that to the pH of pineapple juice at 3.3-3.6 and you can see that bromelain is more than comfortable with the acid ranges found in the stomach–especially keeping in mind that systemic enzymes should be taken between meals, not with them.
Studies have shown that bromelain’s anti-inflammatory properties come from its ability to effectively inhibit neutrophil (immune cell) migration.16 Fitzhugh DJ1, Shan S, Dewhirst MW, Hale LP. “Bromelain treatment decreases neutrophil migration to sites of inflammation.” Clin Immunol. 2008 Jul;128(1):66-74. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2516972/ As such, it is not surprising that studies have shown that bromelain can be helpful in reducing swelling and speeding up the healing of surgical wounds,17 Tassman G, Zafran J, Zayon G. “A double-blind crossover study of a plant proteolytic enzyme in oral surgery.” J Dent Med 1965;20:51–4. http://www.ncbi.nlm.nih.gov/pubmed/14282458 as well as minor sprains, bruises, and sports’ injuries.18 Cirelli MG. “Treatment of inflammation and edema with bromelain.” Delaware Med J 1962;34:159–67. http://www.ncbi.nlm.nih.gov/pubmed/13879585 And bromelain has also been shown to be helpful in treating osteoarthritis.19 Brien S, Lewith G, Walker A, Hicks SM, Middleton D. “Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies.” Evid Based Complement Alternat Med. 2004 Dec;1(3):251-257. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC538506/ Note: studies show that its benefit in regard to osteoarthritis is amplified by the presence of rutin and trypsin–both of which are present in the formula we are now describing.20 Akhtar NM1, Naseer R, Farooqi AZ, Aziz W, Nazir M. “Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee–a double-blind prospective randomized study.” Clin Rheumatol. 2004 Oct;23(5):410-5. http://www.ncbi.nlm.nih.gov/pubmed/15278753
And if that’s not enough, research shows that bromelain may help support healthy blood viscosity and blood platelet aggregation,21 Heinicke R, van der Wal L, Yokoyama M. “Effect of bromelain (Ananase) on human platelet aggregation.” Experientia 1972;28:844–5. http://www.ncbi.nlm.nih.gov/pubmed/4658882 so it should not be surprising that studies show it’s also protective against heart attacks.22 Juhasz B, Thirunavukkarasu M, Pant R, Zhan L, Penumathsa SV, et al. “Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium.” Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1365-70. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581828/
Papain, which is an enzyme found in unripe papayas, has properties similar to bromelain. It is well known for its use as a meat tenderizer, since, as a natural proteolytic enzyme, it breaks down the proteins in meat–thus tenderizing it. This same ability means that we find papain used in many digestive enzyme formulations. But that’s not the reason we use it in a systemic enzyme formula–at least not directly. If papain is taken between meals, it makes its way into the bloodstream where it helps reduce pain and inflammation, as well as fluid retention following trauma and surgery. In fact, studies have shown that papain possesses strongly marked anti-inflammatory activity, and this ability is no less than that of the pharmaceutical drugs, butadion and indomethacin.23 Rakhimov MR. “Anti-inflammatory activity of domestic papain].” Eksp Klin Farmakol. 2001 Jul-Aug;64(4):48-9. http://www.ncbi.nlm.nih.gov/pubmed/11589110 Papain is also used for treating parasitic worms, shingles, and psoriasis, as well as being used along with conventional treatments for tumors.
Nattokinase is extracted and purified from a traditional Japanese food called natto. Natto is made from boiled or steamed soybeans fermented with the beneficial bacteria, Bacillus subtilis natto.24 Fujita M., Nomura K., Hong K., Ito Y., Asada A. and Nishimuro S. “Purification and Characterization of a Strong Fibrinolytic Enzyme (Nattokinase) in the Vegetable Cheese Natto, a Popular Soybean Fermented Food in Japan.” Biochemical and Biophysical Research Communications, Vol. 197, Issue 3, 30 December 1993, pp. 1340-1347. http://www.ncbi.nlm.nih.gov/pubmed/8280151 It is very important to understand that although nattokinase is extracted from natto, a soy based food, it is not natto itself, and it contains no soy. It is a purified enzyme that no longer has any soy characteristics left in it. Nattokinase has a remarkable ability to optimally balance the clotting ability of blood. It rivals pharmaceutical drugs such as warfarin in that ability but without any of the side effects or downsides, making it of value to everyone, not just heart disease patients. Obviously, if you are already using blood thinners, you will need to work with your doctor if you decide to incorporate a proteolytic enzyme formula in your health program–especially one containing nattokinase. Unfortunately, most doctors will opt to play it safe (for them, not you) and choose to keep you on the pharmaceuticals.
Studies have also shown that nattokinase works as an ACE inhibitor to help lower blood pressure.25 Murakami K1, Yamanaka N, Ohnishi K, Fukayama M, Yoshino M. “Inhibition of angiotensin I converting enzyme by subtilisin NAT (nattokinase) in natto, a Japanese traditional fermented food.” Food Funct. 2012 Jun;3(6):674-8. http://www.ncbi.nlm.nih.gov/pubmed/22453301 In fact, a 2008 study conducted over eight weeks, found that nattokinase was able to moderately lower both systolic and diastolic blood pressure in hypertensive human subjects.26 Kim JY, Gum SN, Paik JK, et al. “Effects of nattokinase on blood pressure: a randomized, controlled trial.” Hypertens Res. 2008;31(8):1583-1588. http://www.ncbi.nlm.nih.gov/pubmed/18971533 And finally, a 2009 study out of Taiwan found that the nattokinase has the ability to dissolve amyloid fibrils, which means it may help prevent Alzheimer’s disease. Not a bad incidental benefit.
Seaprose-S is a semi-alkaline, serine, proteolytic enzyme produced by the fungus Aspergillus melleus. As reported in the journal Drugs under Experimental and Clinical Research, seaprose has both anti-inflammatory and anti-cold properties, demonstrating a potent ability to reduce painful inflammation and break up mucus. 27 Fossati A. “Anti-inflammatory effects of seaprose-S on various inflammation models.” Drugs Exp Clin Res. 1999;25(6):263-70. http://www.ncbi.nlm.nih.gov/pubmed/10713864 Specifically, this report pointed out that seaprose has shown anti-inflammatory activity against many different conditions, including arthritis, edema, pleurisy (inflammation of the lung lining), and peritonitis (inflammation of the lining of the abdomen). It also pointed out that in animal studies with arthritis, seaprose-S significantly reduced the primary and secondary lesions–demonstrating an ability to increase proteoglycan synthesis in cartilage.
Seaprose’s ability to break up mucus means it can offer relief for respiratory problems such as bronchitis, pulmonary tuberculosis, pulmonary emphysema, COPD, bronchiolitis, and bronchial asthma. Seaprose is so effective in this regard that it’s actually used as an ingredient in Japanese over-the-counter cold remedies. And in two other studies, researchers found that patients who used seaprose showed significant improvements in bronchial inflammation and in the viscosity of their mucus. In other words, it made the mucus thinner so that it cleared the lungs more easily.28 Moretti M, Bertoli E, Bulgarelli S, Testoni C, et al. “Effects of seaprose on sputum biochemical components in chronic bronchitic patients: a double-blind study vs placebo.” Int J Clin Pharmacol Res. 1993;13(5):275-80. http://www.ncbi.nlm.nih.gov/pubmed/8200722?dopt=Abstract, 29 Braga PC, Rampoldi C et al “In vitro rheological assessment of mucolytic activity induced by seaprose.” Pharmacol Res 1990;22(5):611-617. http://www.ncbi.nlm.nih.gov/pubmed/2277801
And finally, studies have shown that seaprose is highly effective in relieving both the pain and inflammation of veins associated with thrombophlebitis, resulting from blood clot formation in the veins–a painful condition in and of itself but also closely related to deep vein thrombosis (DVT).30 Bracale G, Selvetella L. “Clinical study of the efficacy of and tolerance to seaprose S in inflammatory venous disease. Controlled study versus serratio-peptidase.” Minerva Cardioangiol. 1996 Oct;44(10):515-24. http://www.ncbi.nlm.nih.gov/pubmed/9091835
Whenever we discuss seaprose-S, we have to mention serrapeptase, which is used in many formulas instead of seaprose–and sometimes along with it. Like seaprose, serrapeptase has remarkable anti-inflammatory and anti-edemic (counters swelling and fluid retention) activity in a number of tissues. And like seaprose, it can reduce pain and help clear mucous from the lungs by reducing neutrophil numbers, thus thinning the mucous in the lungs of patients with chronic airway diseases. So why not use serrapeptase in my “ideal” formula? Three reasons:
- Its quality tends to be inconsistent.
- It can cause intestinal distress.
- It is very sensitive to stomach acid, which means it has to be enteric coated. Unfortunately, the technology for enterically coated capsules is not reliable (which is why you normally find enteric coating used only on hard tablets or on hard beads inside capsules (as in cold capsules).
Seaprose-S, on the other hand is:
- Manufactured in Japan and is of consistent high quality.
- Causes virtually no intestinal distress.
- Unaffected by stomach acid so it does not require enteric coating.
- And studies have shown that it is more effective than serrapeptase — 85% vs 65%. Bracale.
The bottom line is that serrapeptase is harder to work with, produces side effects, can’t handle stomach acid, and has to be used in an enterically coated capsule. And since the formula as is already provides all the benefits offered by serrapeptase without those problems, why use it?
The Non-enzymes in a Systemic Proteolytic Enzyme Formula
Rutin is a bioflavonoid found in citrus and buckwheat that helps the body utilize vitamin C and produce collagen (skin’s main building blocks). In addition, it can be used to treat conditions such as hemorrhoids, varicose veins, high blood pressure, and to reduce cholesterol levels. However, the reasons that I include rutin in this formula are that rutin:
- Increases the elasticity of the arterial walls, which, in turn, promotes greater blood flow and improved vascular health.31 Kuzan A1, Chwilkowska A, Kobielarz M, Pezowicz C, Gamian A. “Glycation of extracellular matrix proteins and its role in atherosclerosis. Postepy Hig Med Dosw (Online). 2012 Oct 29;66:804-9. http://www.ncbi.nlm.nih.gov/pubmed/23175335
- Improves capillary strength and helps regulate their permeability.32 James Couch. “Rutin for Capillaries. USDA Yearbook of Agriculture. 1947 p711. http://naldc.nal.usda.gov/download/IND43893991/PDF
- Works as an anti-inflammatory.33 Teresita Guardia, Alejandra Ester Rotelli, et al. “Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat.” Il Farmaco Volume 56, Issue 9, 1 August 2001, Pages 683–687. , 34 Selloum L1, Bouriche H, Tigrine C, Boudoukha C. “Anti-inflammatory effect of rutin on rat paw oedema, and on neutrophils chemotaxis and degranulation.” Exp Toxicol Pathol. 2003 Mar;54(4):313-8. http://www.ncbi.nlm.nih.gov/pubmed/12710715
- And it may be anti-carcinogenic.35 Drewa G, Schachtschabel DO, Palgan K, et al. “The influence of rutin on the weight, metastasis and melanin content of B16 melanotic melanoma in C57BL/6 mice.” Neoplasma 1998;45:266-71. http://www.ncbi.nlm.nih.gov/pubmed/9890672 , 36 Webster RP, Gawde MD, Bhattacharya RK. “Protective effect of rutin, a flavonol glycoside, on the carcinogen-induced DNA damage and repair enzymes in rats.” Cancer Lett 1996;109:185-91.
- Inhibits the formation of blood clots, which can be helpful in preventing DVT. 37Reema Jasuja, Freda H. Passam, Daniel R. Kennedy, Robert Flaumenhaft, et al. “Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents.” J Clin Invest. 2012; 122(6):2104–2113. http://www.jci.org/articles/view/61228/version/2/pdf/render
And finally, as we discussed earlier, rutin–along with trypsin (as found in the fungal pancreatin)–enhances the effect of the bromelain. The bottom line is that rutin mirrors the benefits of the proteolytic enzymes in the formula but does so using different, complementary pathways.
Ginger is a COX-2 inhibitor. The COX-2 enzyme plays a key role in the inflammation process, which is a normal, healthy attempt by the body to heal itself. However, when inflammation gets out of control (such as in the case of arthritis or other chronic inflammatory disorders), ongoing pain and discomfort is the result–not to mention that systemic inflammation is considered to be a contributing factor to catastrophic illnesses such as heart disease and cancer. A botanical COX-2 inhibitor such as found in ginger can block the action of the COX-2 enzyme in much the same way as prescription drugs do, but without the side effects. I’ve written before about ginger’s benefits when it comes to controlling joint inflammation, but the benefits of controlling systemic inflammation go far beyond that.
As it turns out, ginger’s abilities to reduce oxidative stress, apoptosis, and inflammation have a protective effect on the diabetic brain,38 El-Akabawy G, El-Kholy W. “Neuroprotective effect of ginger in the brain of streptozotocin-induced diabetic rats.” Ann Anat. 2014 May;196(2-3):119-28. http://www.ncbi.nlm.nih.gov/pubmed/24680376 as well as sugar induced inflammatory damage to the kidneys.39 Yang M, Liu C, Jiang J, Zuo G, Lin X, et al. “Ginger extract diminishes chronic fructose consumption-induced kidney injury through suppression of renal overexpression of proinflammatory cytokines in rats.” BMC Complement Altern Med. 2014 May 27;14(1):174. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047007/
In addition, a growing number of experimental studies suggest that 6-shogaol, a key bioactive component found in ginger, may play an important role as a memory-enhancing and anti-oxidant agent against neurological diseases. 6-Shogaol has also recently been shown to have anti-neuroinflammatory effects, which is important when it comes to protecting against the loss of brain function and neurological disorders such as Parkinson’s disease.40 Moon M, Kim HG, Choi JG, Oh H, et al. “6-Shogaol, an active constituent of ginger, attenuates neuroinflammation and cognitive deficits in animal models of dementia.” Biochem Biophys Res Commun. 2014 Jun 20;449(1):8-13. http://www.ncbi.nlm.nih.gov/pubmed/24796668 And it may account for ginger’s purported benefits when it comes to Alzheimer’s.41 Zeng GF1, Zhang ZY, Lu L, Xiao DQ, Zong SH, He JM. “Protective effects of ginger root extract on Alzheimer disease-induced behavioral dysfunction in rats.” Rejuvenation Res. 2013 Apr;16(2):124-33. http://www.ncbi.nlm.nih.gov/pubmed/23374025
The bottom line is that ginger’s anti-inflammatory benefits are spread systemically throughout the body and, as with rutin, accomplish these effects using different, complementary pathways than do the proteolytic enzymes in the formula. Like rutin, ginger provides a perfect complement to our systemic, proteolytic enzyme formula.
CMIK-pH+™ Mineral Blend
When it comes to proteolytic enzymes, most of them (other than pepsin) work best in a neutral to slightly alkaline environment. Optimizing that environment, then, becomes crucial for maximizing the beneficial effects of the formula. (Note: enterically coating a capsule does nothing to change the actual environment.)
The big breakthrough in this formula is the addition of a pH buffering system (the CMIK-pH+™ Mineral Blend). This buffer provides a number of benefits, but the primary one is that it helps optimize the pH of all your soft tissue. Since your body will do anything to keep your blood’s pH in a narrow range, that means it robs Peter to pay Paul. It steals minerals and lowers pH in your soft tissue to prevent your blood from changing pH if your diet is too acid forming–as is most people’s. If you eat meat, dairy, cooked grains, desserts, and most fruit, then your diet is indeed too acid forming. The bottom line is that by raising soft tissue pH, you dramatically improve the ability of proteolytic enzymes to root out CIC’s embedded in that soft tissue, thus relieving allergies and reducing the possibility of autoimmune conditions/diseases.
The addition of a pH buffering system to a proteolytic enzyme formula is so revolutionary and effective, it was awarded a US Patent.
Buying a Proteolytic Enzyme Formula
As I’ve stated previously, when comparing enzymes, if you want an apples to apples comparison, you need to compare activity levels, not milligrams. The internationally recognized and accepted standard for measurement is by Food Chemicals Codex (FCC) Units. These are usually expressed in different activity units for each type of enzyme. For the above formula, that would be:
- Protease — 300,000 HUT (Hemoglobin Units, Tyrosine basis).
- Fungal Pancreatin — 1,200 USP (United States Pharmacopeia).
- Nattokinase — 540 FU (Fibrinolytic Units) refers to nattokinase’s ability to break down the blood clotting enzyme, fibrin.
- Seaprose S — 15,000 U (quite simply, an enzyme Unit).
- Papain — 72 MCU (Milk Clotting Units). Based on how fast the enzyme digests milk protein. Sometimes listed as PU (Papain Units), which are equivalent to 0.1 MCU.
- Bromelain — 336 GDU (Gelatin Digesting Units). Based on how fast the enzyme digests gelatin. 1 MCU is equivalent to 0.67 GDU.
- Amylase — 3,000 SKB (named after the creators of the test Sandstedt, Kneen, and Blish ) or DU (used in the brewing industry). SKB and DU match up one to one.
- Lipase — 192 FIP. Formerly measured in LU (Lipase Units), but now more commonly measured in FIP units (i.e., according to the test methods of the Fédération Internationale Pharmaceutique). On a unit to unit basis, 1 FIP is equivalent to 10 LU.
The regular use of systemic, proteolytic enzymes can be an invaluable addition to your daily health regimen. From removing dental plaque to protecting and repairing your cardiovascular system, from reducing inflammation throughout the entire body to speeding up the recovery times of athletes and post-surgical patients.42 Duskova M, Wald M. “Orally administered proteases in aesthetic surgery.” Aesthetic Plast Surg. 1999 Jan;23(1):41-4. http://www.ncbi.nlm.nih.gov/pubmed/10022937 The bottom line is that supplementation with a good systemic proteolytic enzyme formula such as we’ve discussed here today is essential. To summarize the key benefits:
- Reduced inflammation: Inflammation is a natural response of the body to injury. However, excessive inflammation retards the healing process. Proteolytic enzymes reduce inflammation by neutralizing the bio-chemicals of inflammation (bradykinins and pro-inflammatory eicosanoids) to levels where the synthesis, repair and regeneration of injured tissues can take place. Reducing inflammation can have immediate impact on improved heart health, cancer prevention and recovery, and Alzheimer’s prevention. It also helps speed up recovery from sprains, strains, fractures, bruises, contusions, surgery — and arthritis.
- Cleansing the blood of debris: Proteolytic enzymes are the primary tools the body uses to “digest” organic debris in the circulatory and lymph systems. Supplementing merely improves the effectiveness of the process.
- Dissolving fibrin in the blood, reducing the risk of clots: Nattokinase, in particular, is extremely effective at improving the “quality” of blood cells, optimizing the ability of blood to flow through the circulatory system, and reducing the risk of clots. This is extremely important in reducing the risk of stroke. It also makes using proteolytic enzymes during long plane flights to minimize the potential of blood clots in the legs an obvious choice.
- Maximized immune system: The primary vehicle the immune system uses for destroying invaders is enzymes. Macrophages, for example, literally digest invaders with proteolytic enzymes. Supplementation significantly improves the ability of your immune system to do its job.
- Killing of bacteria, viruses, molds, and fungi: Bacteria, viruses, molds, and fungi are protein/amino acid based. Proteolytic enzymes taken between meals literally go into the bloodstream and digest these invaders.
- Elimination of autoimmune diseases: In Lessons from the Miracle Doctors, I cover in detail the process whereby large undigested proteins make their way into the bloodstream and form CICs (Circulating Immune Complexes), which trigger allergies and autoimmune diseases. Supplemental proteolytic enzymes clean CICs out of the body, thereby reducing allergies and autoimmune conditions. In addition, this helps with sinusitis and asthma.
- Dissolving of scar tissue: Scar tissue is made of protein. Proteolytic enzymes can effectively “digest” scar tissue — particularly in the circulatory system.
- And finally, a properly designed supplemental proteolytic enzyme formula can help.reduce the symptoms of MS, clean out the lungs, and aid in detoxing.
The following actions will improve the benefits you derive from supplementing with proteolytics:
- Add more raw foods to your diet.
- Cut out (or at least cut down) on processed foods.
- Cut out (or at least cut down) on cooked foods.
- Chew your food properly so they thoroughly mix with the enzymes in your saliva.
- Drink alkalinized water–but not with your meals as it dilutes your digestive juices.
For most people, taking their proteolytic enzymes in the dosage described above on a daily basis, at least 1 hour before eating is all that’s needed to give you the best shot at maintaining a healthy inner environment. Since that dosage is likely to be contained in more than one capsule, it’s best to spread it out over the course of the day–say one capsule three times a day, assuming the dosage is contained in three capsules.
For detoxification (really more of an overhaul and repair of your entire body), start by doubling the maintenance dosage, then tripling it if needed, and even quadrupling it — until you notice benefits, or as recommended by your health professional. You will want to run a detox program for a minimum of 30 days to as long as 12-24 months — depending on the state of your health and how much damage you are trying to repair.
For performance athletes, or people just interested in optimum cardiovascular health or faster recovery and repair, you can build to (and continue on) three to four times the maintenance dosage per day for as long as required.
Can you take too much? Absolutely! As we discussed, one of the benefits of a good proteolytic enzyme formula is that it works as a natural blood thinner. But as the old saying goes, “Too much of a good thing is bad.” Unlike pharmaceutical blood thinners, though, this is unlikely to ever manifest as bruises suddenly appearing all over your body. However, if your dosage goes higher than your body can handle, you will notice an increased tendency to have spontaneous nose bleeds or increased rectal bleeding if you have any hemorrhoids. If you notice any of these symptoms or have any intestinal discomfort, or discomfort of any kind, back down your dosage until the symptoms disappear.
Also, it should be noted that although supplemental proteolytic enzymes significantly decrease the risk of both ischemic and transient ischemic strokes (those caused by blood clots and that account for 87% of all strokes), they do, on the other hand, increase the risk of damage if you have a hemorrhagic stroke (a bleeding stroke caused by a weakened blood vessel) because clotting may take longer. Then again, proteolytic enzymes are just as likely to strengthen that blood vessel in the first place, thereby reducing your odds of having a hemorrhagic stroke at all.
And finally, one of the best testimonials I ever received on the benefits of systemic, proteolytic enzymes, was sent to me shortly after I released my own version of the formula in December of 2003. And based on the detail included in that testimonial and the breadth of the conditions discussed, plus the fact that it came from a health professional, it’s still one of the best. Check it out.
(Originally published 08/26/2006. Updated 07/21/2014.)
References [ + ]
|1.||↑||Hedstrom, L. (Dec 2002). “Serine protease mechanism and specificity.” Chem Rev 102 (12): 4501–24. http://www.ncbi.nlm.nih.gov/pubmed/12475199|
|2.||↑||Chapman HA, Riese RJ, Shi GP (1997). “Emerging roles for cysteine proteases in human biology.” Annu. Rev. Physiol. 59: 63–88. http://www.ncbi.nlm.nih.gov/pubmed/9074757|
|3.||↑||Arazi A1, Neumann AU. “Modeling immune complex-mediated autoimmune inflammation.” J Theor Biol. 2010 Dec 7;267(3):426-36. http://www.ncbi.nlm.nih.gov/pubmed/20832412|
|4.||↑||P O Cano, L M Jerry, J P Sladowski, and C K Osterland. “Circulating immune complexes in systemic lupus erythematosus.” Clin Exp Immunol. Aug 1977; 29(2): 197–204. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1541106/pdf/clinexpimmunol00234-0013.pdf|
|5.||↑||Stauder G, Ransberger K, Streichhan P, Van Schaik W, Pollinger W. “The use of hydrolytic enzymes as adjuvant therapy in AIDS/ARC/LAS patients.” Biomed Pharmacother. 1988;42(1):31-4. http://www.ncbi.nlm.nih.gov/pubmed/3408806|
|6.||↑||Cecil Adams. “Is it aerodynamically impossible for bumblebees to fly?” The Straight Dope. May 4, 1990. (Accessed 24 Jun 2014.) http://www.straightdope.com/columns/read/1076/is-it-aerodynamically-impossible-for-bumblebees-to-fly|
|7.||↑||Brad Rachman, “Unique Features and Application of Non-Animal Derived Enzymes.” Clinical Nutrition Insights. 510 8/97 Vol. 5, No. 10. (Accessed 24 Jun 2014.) http://acudoc.com/Digestive%20Enzymes.PDF|
|8.||↑||Laura P. Hale. “Proteolytic activity and immunogenicity of oral bromelain within the gastrointestinal tract of mice.” International Immunopharmacology. Volume 4, Issue 2, February 2004, Pages 255–264. http://www.sciencedirect.com/science/article/pii/S1567576903002972|
|9.||↑||KOLAC C., STREICHHAN P., LEHR C.-M. “Oral bioavailability of proteolytic enzymes.” European journal of pharmaceutics and biopharmaceutics. 1996, vol. 42, no4, pp. 222-232 (68 ref.) http://cat.inist.fr/?aModele=afficheN&cpsidt=3191444|
|12.||↑||Stauder G. “Pharmacological effects of oral enzyme combinations.” Cas Lek Cesk. 1995 Oct 4;134(19):620-4. http://www.ncbi.nlm.nih.gov/pubmed/7585874|
|13.||↑||Nouza K. “Systemic enzyme therapy in diseases of the vascular system.” Bratisl Lek Listy. 1995 Oct;96(10):566-9. http://www.ncbi.nlm.nih.gov/pubmed/8620329|
|14.||↑||Beuth J. “Proteolytic enzyme therapy in evidence-based complementary oncology: fact or fiction?” Integr Cancer Ther. 2008 Dec;7(4):311-6. doi: 10.1177/1534735408327251. http://www.ncbi.nlm.nih.gov/pubmed/19116226|
|15.||↑||Desser L, Rehberger A, Paukovits W. “Proteolytic enzymes and amylase induce cytokine production in human peripheral blood mononuclear cells in vitro.” Cancer Biother 1994;9:253-63. http://www.ncbi.nlm.nih.gov/pubmed/7529614|
|16.||↑||Fitzhugh DJ1, Shan S, Dewhirst MW, Hale LP. “Bromelain treatment decreases neutrophil migration to sites of inflammation.” Clin Immunol. 2008 Jul;128(1):66-74. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2516972/|
|17.||↑||Tassman G, Zafran J, Zayon G. “A double-blind crossover study of a plant proteolytic enzyme in oral surgery.” J Dent Med 1965;20:51–4. http://www.ncbi.nlm.nih.gov/pubmed/14282458|
|18.||↑||Cirelli MG. “Treatment of inflammation and edema with bromelain.” Delaware Med J 1962;34:159–67. http://www.ncbi.nlm.nih.gov/pubmed/13879585|
|19.||↑||Brien S, Lewith G, Walker A, Hicks SM, Middleton D. “Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies.” Evid Based Complement Alternat Med. 2004 Dec;1(3):251-257. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC538506/|
|20.||↑||Akhtar NM1, Naseer R, Farooqi AZ, Aziz W, Nazir M. “Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee–a double-blind prospective randomized study.” Clin Rheumatol. 2004 Oct;23(5):410-5. http://www.ncbi.nlm.nih.gov/pubmed/15278753|
|21.||↑||Heinicke R, van der Wal L, Yokoyama M. “Effect of bromelain (Ananase) on human platelet aggregation.” Experientia 1972;28:844–5. http://www.ncbi.nlm.nih.gov/pubmed/4658882|
|22.||↑||Juhasz B, Thirunavukkarasu M, Pant R, Zhan L, Penumathsa SV, et al. “Bromelain induces cardioprotection against ischemia-reperfusion injury through Akt/FOXO pathway in rat myocardium.” Am J Physiol Heart Circ Physiol. 2008 Mar;294(3):H1365-70. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581828/|
|23.||↑||Rakhimov MR. “Anti-inflammatory activity of domestic papain].” Eksp Klin Farmakol. 2001 Jul-Aug;64(4):48-9. http://www.ncbi.nlm.nih.gov/pubmed/11589110|
|24.||↑||Fujita M., Nomura K., Hong K., Ito Y., Asada A. and Nishimuro S. “Purification and Characterization of a Strong Fibrinolytic Enzyme (Nattokinase) in the Vegetable Cheese Natto, a Popular Soybean Fermented Food in Japan.” Biochemical and Biophysical Research Communications, Vol. 197, Issue 3, 30 December 1993, pp. 1340-1347. http://www.ncbi.nlm.nih.gov/pubmed/8280151|
|25.||↑||Murakami K1, Yamanaka N, Ohnishi K, Fukayama M, Yoshino M. “Inhibition of angiotensin I converting enzyme by subtilisin NAT (nattokinase) in natto, a Japanese traditional fermented food.” Food Funct. 2012 Jun;3(6):674-8. http://www.ncbi.nlm.nih.gov/pubmed/22453301|
|26.||↑||Kim JY, Gum SN, Paik JK, et al. “Effects of nattokinase on blood pressure: a randomized, controlled trial.” Hypertens Res. 2008;31(8):1583-1588. http://www.ncbi.nlm.nih.gov/pubmed/18971533|
|27.||↑||Fossati A. “Anti-inflammatory effects of seaprose-S on various inflammation models.” Drugs Exp Clin Res. 1999;25(6):263-70. http://www.ncbi.nlm.nih.gov/pubmed/10713864|
|28.||↑||Moretti M, Bertoli E, Bulgarelli S, Testoni C, et al. “Effects of seaprose on sputum biochemical components in chronic bronchitic patients: a double-blind study vs placebo.” Int J Clin Pharmacol Res. 1993;13(5):275-80. http://www.ncbi.nlm.nih.gov/pubmed/8200722?dopt=Abstract|
|29.||↑||Braga PC, Rampoldi C et al “In vitro rheological assessment of mucolytic activity induced by seaprose.” Pharmacol Res 1990;22(5):611-617. http://www.ncbi.nlm.nih.gov/pubmed/2277801|
|30.||↑||Bracale G, Selvetella L. “Clinical study of the efficacy of and tolerance to seaprose S in inflammatory venous disease. Controlled study versus serratio-peptidase.” Minerva Cardioangiol. 1996 Oct;44(10):515-24. http://www.ncbi.nlm.nih.gov/pubmed/9091835|
|31.||↑||Kuzan A1, Chwilkowska A, Kobielarz M, Pezowicz C, Gamian A. “Glycation of extracellular matrix proteins and its role in atherosclerosis. Postepy Hig Med Dosw (Online). 2012 Oct 29;66:804-9. http://www.ncbi.nlm.nih.gov/pubmed/23175335|
|32.||↑||James Couch. “Rutin for Capillaries. USDA Yearbook of Agriculture. 1947 p711. http://naldc.nal.usda.gov/download/IND43893991/PDF|
|33.||↑||Teresita Guardia, Alejandra Ester Rotelli, et al. “Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat.” Il Farmaco Volume 56, Issue 9, 1 August 2001, Pages 683–687.|
|34.||↑||Selloum L1, Bouriche H, Tigrine C, Boudoukha C. “Anti-inflammatory effect of rutin on rat paw oedema, and on neutrophils chemotaxis and degranulation.” Exp Toxicol Pathol. 2003 Mar;54(4):313-8. http://www.ncbi.nlm.nih.gov/pubmed/12710715|
|35.||↑||Drewa G, Schachtschabel DO, Palgan K, et al. “The influence of rutin on the weight, metastasis and melanin content of B16 melanotic melanoma in C57BL/6 mice.” Neoplasma 1998;45:266-71. http://www.ncbi.nlm.nih.gov/pubmed/9890672|
|36.||↑||Webster RP, Gawde MD, Bhattacharya RK. “Protective effect of rutin, a flavonol glycoside, on the carcinogen-induced DNA damage and repair enzymes in rats.” Cancer Lett 1996;109:185-91.|
|37.||↑||Reema Jasuja, Freda H. Passam, Daniel R. Kennedy, Robert Flaumenhaft, et al. “Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents.” J Clin Invest. 2012; 122(6):2104–2113. http://www.jci.org/articles/view/61228/version/2/pdf/render|
|38.||↑||El-Akabawy G, El-Kholy W. “Neuroprotective effect of ginger in the brain of streptozotocin-induced diabetic rats.” Ann Anat. 2014 May;196(2-3):119-28. http://www.ncbi.nlm.nih.gov/pubmed/24680376|
|39.||↑||Yang M, Liu C, Jiang J, Zuo G, Lin X, et al. “Ginger extract diminishes chronic fructose consumption-induced kidney injury through suppression of renal overexpression of proinflammatory cytokines in rats.” BMC Complement Altern Med. 2014 May 27;14(1):174. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047007/|
|40.||↑||Moon M, Kim HG, Choi JG, Oh H, et al. “6-Shogaol, an active constituent of ginger, attenuates neuroinflammation and cognitive deficits in animal models of dementia.” Biochem Biophys Res Commun. 2014 Jun 20;449(1):8-13. http://www.ncbi.nlm.nih.gov/pubmed/24796668|
|41.||↑||Zeng GF1, Zhang ZY, Lu L, Xiao DQ, Zong SH, He JM. “Protective effects of ginger root extract on Alzheimer disease-induced behavioral dysfunction in rats.” Rejuvenation Res. 2013 Apr;16(2):124-33. http://www.ncbi.nlm.nih.gov/pubmed/23374025|
|42.||↑||Duskova M, Wald M. “Orally administered proteases in aesthetic surgery.” Aesthetic Plast Surg. 1999 Jan;23(1):41-4. http://www.ncbi.nlm.nih.gov/pubmed/10022937|