Rhema Blog

Rhema Blog

Franco Cavaleri Speaks to: The Impetus Behind the Curcumin Research and Medical Discoveries that Changes Everything

Ivan Leonov - Monday, November 20, 2017

The impetus behind the curcumin research and medical discoveries that changes everything we know about curcumin

As seen in the press release:

Initially driven by a passion to better understand nutraceuticals and nutrition in order to enhance performance during his quest to win the title of several North American bodybuilding competitions, Franco Cavaleri was struck with a serious autoimmune disease. This disease derailed Cavaleri twice with hospitilazation and with a prognosis of surgical intervention with prohibitive lifestyle consequences.
Although he struggled to stay healthy and stay on track with his academic and athletic careers, his struggles eventually led to desperation. In 1991 while preparing for the Mr. North America contest he was hospitalised for the first time in Vancouver’s St Paul’s Hospital. After having lost as much as fifty pounds his drug resistant condition was deemed untreatable.

After much introspection Franco speculated that a specialised curcuminoid extract he had been working in the lab with and using sporadically had taken the edge off his symptoms and allowed him to cope. It wasn’t until he had stopped the treatment that he was hospitalised. He decided to decline the surgical intervention and lean on his hypothesis. His rebound to optimal health led to the win in Redondo Beach, California in 1992 – Mr. IFBB North America.

After nearly 19 years of research and persistence with his unique treatment he decided to terminate the unique curcuminoid treatment that he speculated was no longer needed. Within months of running down his supply of his uniquely extracted curcuminoid compound, he was hospitalised again in 2009 with the same prognosis – drug resistant ulcerative colitis and surgery to resect the colon as the only alternative. This time his speculation about the efficacy of the treatment and its potential role turned to conviction and back he went to successfully treat and maintain long term remission with the unique extract that took several weeks to generate. This point in time generated the impetus that changed Cavaleri’s course of research forever. He made the decision to bring the strategy to formal medical drug research. Moreover, he committed to wed his 20 years of nutraceutical research to a formal initiative to study medicine and establish a medical PhD degree in experimental medicine using this natural medicine as the study subject matter of the thesis. His practical and academic experience and honed intuition in the field converged into a powerful outcome. The research was designed to determine the pharmacological mechanisms involved in this activity; and whether or not this biological activity played the role he believed it did in disease remission.

Cavaleri’s research into anti-inflammatory strategies originally used to support recovery from training, quickly became focused on better understanding the pharmacology of natural medicinal agents to rehabilitate his ulcerative colitis, without surgical intervention. Irrefutably, Cavaleri was able to overcome his disease without surgery!

According to Cavaleri, the key was to isolate an extract instrumental in reducing inflammation. Cavaleri achieved efficient separation of the curcuminoids within the regular curcumin extract more than 18 years ago and with the study of the pharmacology of each constituent independently in isolation, was eventually able to unravel the pharmacology of each constituent at a cellular and subcellular level in multiple cell lines and tissues. Over the decades his in-depth biomedical work mapped the pharmacology of these curcuminoids with regards to targeted subcellular proteins in an attempt to better understand why they worked to effect symptoms differentially. In this way, Cavaleri discovered a way to predict curcumin and curcuminoid activity and augment the curcuminoid proportions within the extract to manipulate the activity to be more target specific and reliable in terms of disease indication. The result is the new potential to design curcumin-based therapies with greater precision, with the ability to more selectively target subcellular proteins involved in development of disease symptoms and pathology, and increased efficacy by indication. These discoveries change everything we knew about curcumin setting in place a new industry standard and a new level of pharmacology for patients and consumers in need. Some of his work has been published. Some is still in peer review.

Cavaleri says there is still lots of work to do; to run more bench work and clinical research to determine more accurately how these natural medicines can be used to treat specific indications. Nevertheless, for now, they will cautiously use what has been discovered, patented and recently approved by the Canadian regulatory agency (NNHPD) while they continue the research at his medical laboratory, Biologic Pharmamedical Research (www.biologic-med.com).


Franco Cavaleri Speaks to: Curcumin BDM30 Supports Improved Recovery Rate From Training

Ivan Leonov - Thursday, November 16, 2017

Imagine being able to get into the gym to train a body part more frequently than your competition can. What does that mean to you in six months of steady training? Imagine recovering faster from a stage-to-stage or day-to-day workload in your competitive sport such as a cycling tour; a triathlon competition; or an all weekend cross-fit event. The advantage is possible with Curcumin BDM30™.

Research demonstrates that myogenic potential and anabolic drive can be limited by mismanaged NF-kB. NF-kB is a transcription factor responsible for regulating as many as 150 genes that manage and beckon the immune system and inflammatory response. Anabolic drive and recovery of lean muscle is meticulously orchestrated by the cytokines that NF-kB manages, including TNFα. TNFα partakes in and advances inflammation that is necessary but can also be a limiting factor in your pursuit to maximum form.

The inflammatory process plays an important role in recovery and regeneration of tissue, including myogenesis (muscle generation). Skeletal muscle cells are said to be one of the most adaptable cells/tissue of the body. The underlying objective with resistance training, for example, is to evoke microtrauma of the working skeletal muscle cells resulting in cell signalling that activates satellite cells in the vicinity of the strained fiber. This activation prompts aggregation and fusing of these cells with mature muscle fibers. This is ultimately the compensatory hypertrophy we expect to occur as an adaptation feature to the extra-ordinary workload, adding muscle mass and strength over time.

That prolonged soreness that often persists to the next training day, however, is a problem. Prolonged survival of that post-workout soreness is indicative of longstanding TNFα and inflammation; and interference with maximum recovery potential. That means interference with your own human potential.

Research shows TNFα also inhibits myogenesis the mechanism of which is repression of MyoD protein. MyoD expression is central to cell restoration and differentiation – it’s essential to the zzzsprinterx generation of muscle tissue. Prolonged survival of the inflammatory process to inhibit MyoD protein interferes with recovery, immunity and myogenic (muscle building) potential. Downregulation of training-related and age-related inflammatory activity has both an anticatabolic influence and promotes anabolic drive to restore maximum muscle protein anabolism.

Although curcumin can deliver an inhibitory effect on NF-kB transactivation and transcription of inflammatory cytokines, including TNFα, the new discoveries showing MSK1 inhibition by BDMC (Curcumin III) changes the game. Curcumin BDM30™ is a result of these discoveries and it stops inflammation at a subcellular level where inflammatory proteins are generated. Investing the time and effort into training to improve health and squating guy advance performance requires the best return possible. Imagine again being able to get into the gym to train a body part or work a training cycle more frequently than your competition can. Imagine again, maximising MyoD expression and anabolic drive. This time get with the program to make it happen with Curcumin BDM30™ taken daily just before or after the workout. If you don’t, someone you know will likely beat you to it and may even do so to the first place podium.

Franco Cavaleri, BSc, PhDc, is The Rhema Group’s Chief Science Officer. He is the principal research scientist at Biologic Pharmamedical. Franco Cavaleri is also a former IFBB Mr. North America having practiced the science.

Conflict of Interest Statement. The author/researcher is the owner of a biomedical research group – Biologic Nutrigenomics Health Research Corp and Biologic Pharmamedical Research, that funds and executes research on the pharmacology of nutritional and nutraceutical agents that are studied in the context of disease pathology including characteristics that have been associated with inflammation and dementias. The research on these findings continues at clinical levels to further investigate the full indication-specific potential of this discovery. The author/researcher is also the owner of related Intellectual Properties. author copyright Franco Cavaleri PhDc

Franco Cavaleri Speaks to: Glucose vs Ketones vs KETOBA for cellular energy

Ivan Leonov - Wednesday, November 15, 2017


Supplementation with exogenous ketones is skyrocketing to new levels. Nevertheless, the information about these supplements is getting more and more confusing with regulatory agencies trying to catch up to the messaging. KETOBA™ is designed based on the patent particulars owned by Biologic Nutrigenomics and the only exogenous ketone product currently approved by the CFIA’s Natural Health Product Directorate with an assigned NPN number approving its sales and safe use. KETOBA™ is not a typical exogenous ketone. It is much more.

KETOBA™ is an activated ketone; activated by the accompaniment of the beta-hydroxybutyrate (ketone body) by butyric acid. Butyric acid, a short chain fatty acid, is an activator of β-oxidation to stimulate ketogenesis. It does not induce the same gastrointestinal distress risks that medium chain triglycerides pose. Butyric acid supports glucose clearance to reduce competition by glucose in serum while facilitating ketone generation (ketogenesis) by the liver. These pharmacological characteristics form the basis of the ‘activated ketone’ description. Butyric acid also plays a central role in gastrointestinal health supporting an environment that voids pathogens and nurtures friendly gut bacteria.

The boiled down distinct difference between KETOBA™ and the typical ketone is very simply rendered down to KETOSIS versus KETOGENESIS. Butyric acid, the short chain fatty acid is the key! The Ketone will induce ketosis to increase serum ketones from an exogenous source. Nevertheless, one needs to burn through these calories before ‘burning’ endogenous fat calories for energy. KETOBA™ is primarily designed to INDUCE KETOGENESIS to get the body to generate ketones from endogenous fat sources; to help you utilise serum fat as an energy source. Best taken on an empty stomach before a fasting workout. Do not use if mental and body energy are not desired.

Conflict of Interest Statement. The author/researcher is the owner of a biomedical research group – Biologic Nutrigenomics Health Research Corp and Biologic Pharmamedical Research, that funds and executes research on the pharmacology of nutritional and nutraceutical agents that are studied in the context of disease pathology including characteristics that have been associated with inflammation and dementias. The author/researcher is also the owner of related Intellectual Properties. author copyright Franco Cavaleri PhDc

Franco Cavaleri, BSc, PhDc, is The Rhema Group’s Chief Science Officer. He is also the principal research scientist at Biologic Pharmamedical; is a former Mr. IFBB North America; and is completing a doctoral degree in Experimental Medicine in the Faculty of Medicine.


Franco Cavaleri Speaks to: The Challenges Around Ketosis

Ivan Leonov - Wednesday, November 15, 2017

Franco Cavaleri, BSc, PhDc Experimental Medicine; Mr. IFBB North America

If you think you’re in ketosis because you’ve decided to will and grunt your way through a carb-limited diet, think again. It’s not that easy even if you sacrificed day in and day out.
Glucogenic amino acids, those that can be converted to glucose, such as alanine, glycine and cysteine are prevalent in most protein sources we consider to be high biological value (BV). High BV protein sources are those typically associated with high anabolic support and maximum tissue nitrogen retention and regeneration, including whey, beef, egg, pork, fish and turkey. Reducing protein intake and elevating dietary fat intake is a common solution that supports a low-carb intake if ketosis is the goal. It can work.

However, if your goal is maximum power and muscle as an athlete, the question you must ask: Is it an effective option to eliminate high BV protein from your diet and still maintain, let alone, build lean muscle amid intensive training? This is good question that has not been convincingly answered. My opinion based on data interpretation and long intense personal experience in the bodybuilding arena is an emphatic NO!

Escalating dietary fat intake with the right sources is certainly a viable option, as long as the carbohydrate intake is limited at the same time. This facilitates ketosis and spares protein for anabolism. It may be enough for sedentary folks; but it won’t be enough if you are lifting heavy or pushing your body to other physical extremes.

Nevertheless, monitoring one’s macronutrient intake to meet daily demands, which can range considerably for each individual based on genetic variance, sleep, stress, exercise changes/intensity, nutrient density, and meal frequency, is a monumental task that usually fails due to lack of knowledge and experience. For those looking to achieve a ketogenic state, staying in the zone and in full cognitive and physical function is a daunting task often riddled by downturns in energy substrate availability.

If you are training hard to build muscle or in extensive endurance programs, glycogen restoration is a MUST as a post-workout endeavour. If you don’t glycogen restore and maintain daily requisite protein, then expect to perform short of maximum. I’ve been there and can tell you with absolute certainty if you are not fully glycogen loaded you can’t perform even if you’re only lifting singles for a maximum bench or squat. I’ve squatted in excess of 7 x 45 lb plates on each side of a bowing bar (>710 lbs) glycogen depleted I wouldn’t even be able to get that bar off the rack, let alone perform the squat. That full muscle belly generates significant turgor pressure from within on a lift that produces physical support from head to toe and this means not just energetic support. If maximum lean muscle and power is the goal, protein intake will be needed far beyond that allowed by the strict ketogenic program; … and as for carb intake… you have to find a way to maintain muscle glycogen in countering proportion to your usage.

Conflict of Interest Statement. The author/researcher is the owner of a biomedical research group – Biologic Nutrigenomics Health Research Corp and Biologic Pharmamedical Research, that funds and executes research on the pharmacology of nutritional and nutraceutical agents that are studied in the context of disease pathology including characteristics that have been associated with inflammation and dementias. The author/researcher is also the owner of related Intellectual Properties. author copyright Franco Cavaleri PhDc

Franco Cavaleri, BSc, PhDc, is The Rhema Group’s Chief Science Officer. He is also the principal research scientist at Biologic Pharmamedical; is a former Mr. IFBB North America; and is completing a doctoral degree in Experimental Medicine in the Faculty of Medicine.

Franco Cavaleri Speaks to: Exploring the Ketogenic Diet

Ivan Leonov - Wednesday, November 15, 2017


Ketogenic diets have become the big buzz today and for good reason! The ultra low-carb, high-fat diet can help with weight loss and improved health. By vastly reducing carbohydrates in your diet, your body is put into a metabolic state called ketosis (if all the other macros fall in place), which results in it becoming more efficient at burning fat for energy. Nevertheless, the benefits far exceed fat meltdown.

The ketogenic diet has taken many forms, from those that merely eliminate high glycemic index carbs, but still incorporate low glycemic alternatives to those that avoid carbohydrate sources from the diet altogether (or as close to zero as possible). Nevertheless, in order for the ketogenic objective to prevail and ketosis to manifest the daily carb intake must be as low as 50 grams or less. If you decide to significantly limit carbohydrate sources from your diet, your cells will require an alternative energy source.

The body is very efficient at ensuring survival and generating glucose from alternative nutrients, including protein, if you choose to drag yourself through a carb-restricted program. Dietary carbohydrate sources serve to spare dietary protein; therefore, on the ketogenic diet where carb intake is limited the precious protein supply can be sacrificed in order to generate glucose and diverted from cell, fluid, hormone and tissue regeneration and maintenance. Although protein catabolism can be limited by increasing dietary fat intake protein intake still needs to be limited if optimal ketosis is desired So for builders and power athletes depending on optimal lean body mass a strict ketogenic diet may not serve the objective maximally.

In such cases following the low carb/high fat (LCHF) feature of the ketogenic diet that is modified to heighten protein intake, however, can play a positive role and produce a positive outcome for athletes relying on a myogenic or muscle building outcome. The million dollar question that we’ll get to see variable answers to in the coming article series is: Does this protein augmentation really support true metabolic ketosis?

The ketogenic diet is not for everyone, as it can be very restrictive and difficult to maintain. In fact, medical ketogenic applications are typically only employed as therapeutic programs, and can work effectively for insulin support and ultimately serum glucose regulation, as well as in support of cognition in cases of neurological deficits associated with dementia. It also has a long history as an effective treatment for drug-resistant epilepsy.

In fact, ketosis can play a monumental role in the treatment of these disorders and for reasons that extend beyond the voidance of serum glucose. The ketone bodies generated by the ketogenic macronutrient profile, themselves serve as cell signalling agents in ways similar to how keys turn on or turn off engines; or buttons control light switches. Ketones are powerful ligands for receptors that set in motion a plethora of metabolic changes that appear to favour healthy outcomes.

The challenge that ketogenic initiatives posed in the past don’t have to be a challenge at all today while the benefits are pursued. There are effective strategies that can be applied to facilitate ketosis and support the metabolism, mind and body through the transition from one energy substrate (glucose) as the primary to the ketone without that mental drag and lag associated with dietary carb restriction.

Conflict of Interest Statement. The author/researcher is the owner of a biomedical research group – Biologic Nutrigenomics Health Research Corp and Biologic Pharmamedical Research, that funds and executes research on the pharmacology of nutritional and nutraceutical agents that are studied in the context of disease pathology including characteristics that have been associated with inflammation and dementias. The author/researcher is also the owner of related Intellectual Properties. author copyright Franco Cavaleri PhDc

Franco Cavaleri, BSc, PhDc, is The Rhema Group’s Chief Science Officer. He is also the principal research scientist at Biologic Pharmamedical; is a former Mr. IFBB North America; and is completing a doctoral degree in Experimental Medicine in the Faculty of Medicine.


Franco Cavaleri Speaks to: Your Metabolism on Ketoba

Ivan Leonov - Wednesday, November 15, 2017


The best builders’ dietary program must keep dietary protein at a level that serves anabolism (building new tissue), which means consuming higher amounts of protein than the strict medical ketogenic diet allows for. Adding the exogenous ketones helps preserve protein for anabolism and prevent lean tissue catabolism (breaking down complex molecules and releasing energy). Using KETOBA twice per day maintains a buffer zone of serum ketones despite dietary choices. This allows for incremental protein intake to meet higher demands created by intense exercise while maintaining functional serum ketone levels that would otherwise be reduced by the introduction of a glucogenic (contributing to glucose production) protein source.

One step further: adding short-chain fatty acids (SCFA) like butyrate/butyric acid (BA) with the ketone body, like β-hydroxybutyrate zzzschematic(BHB), synergises the exogenous ketone serving as a β-oxidation trigger. BA supports the effects of the exogenous ketone by contributing to serum levels from endogenous sources and does so without gastrointestinal (GI) distress. This distress is commonly associated with high dose oral ketone and/or Medium Chain Triglyceride (MCT), and counters performance and immunity by disrupting probiotic stability and interfering with resorption of electrolytes and water.

Dehydration and electrolyte depletion are an athlete’s worst nightmare, compromising muscle mass strength and endurance. GI distress impairs exercise performance, and doesn’t support optimal health and immunity either. BA is a SCFA that facilitates electrolyte and water reabsorption and helps balance probiotic culture in the colon. Colonocytes, epithelial cells in the colon, use BA as an energy source and a down-regulator of inflammation. In addition BA delivers a pharmacology that supports insulin efficiency and blood sugar management, allowing the ketone (BHB) an opportunity to surface in serum as a primary energy (ATP) substrate. BA also supports cognitive performance and cardiovascular health.

The name KETOBA is formed from ketone (BHB) coupled with BA, the short-chain fatty acid. Hence KETO-BA.

Conflict of Interest Statement. The author/researcher is the owner of a biomedical research group – Biologic Nutrigenomics Health Research Corp and Biologic Pharmamedical Research, that funds and executes research on the pharmacology of nutritional and nutraceutical agents that are studied in the context of disease pathology including characteristics that have been associated with inflammation and dementias. The author/researcher is also the owner of related Intellectual Properties. author copyright Franco Cavaleri PhDc

Franco Cavaleri, BSc, PhDc, is The Rhema Group’s Chief Science Officer. He is also the principal research scientist at Biologic Pharmamedical; is a former Mr. IFBB North America; and is completing a doctoral degree in Experimental Medicine in the Faculty of Medicine.


Franco Cavaleri Speaks to: Curcumin III Makes Curcumin BDM30 the New Standard

Ivan Leonov - Wednesday, November 15, 2017


Curcumin BDM30™ is not regular curcumin. Curcumin BDM30™ is based on a recent research discovery that changes what we know about curcumin and how we can use it to deliver therapeutic relief. The discovery made at Biologic Pharmamamedical Research by Franco Cavaleri PhDc has recently been granted full patent status after a lengthy review; and NPN status for approved sales/safety and validation of researched claims. How is it different? Curcumin is typically comprised of three main curcuminoids. Every curcumin extract product supplies all three curcuminoids in a ratio similar to: curcumin I (70-80%); curcumin II (12-20%); curcumin III (0.5-1.5%). The latest discovery made by Franco Cavaleri, PhDc, the principal research scientist at Biologic Pharmamedical (www.biologic-med.com), and the Chief Science Officer at Rhema Health Products, shows for the first time that curcumin III and not curcumins I or II inhibits (helps control) MSK1.

MSK1 is a regulatory protein that regulates production (transactivation) of inflammatory chemicals at a genomic level. leg kneeBy turning this MSK1 level down the, cells – the body – are better able to control inflammation from a second pathway that is additive to the one regular basic curcumin helps control. Curcumin III does everything the other curcuminoids do plus it helps regulate MSK1 for incremental anti-inflammatory support from a second control point.

This same research shows that regular curcumin extract (even the 95%) does not affect MSK1 in any positive way. Curcumin III levels are simply not high enough for functionality in regular curcumin. The new Curcumin BDM30™ is a new standard of anti-inflammatory offering 60x more BDMC (curcumin III) than regular curcumin, providing immense joint pain relief and more rapid recovery from inflammation caused from injuries and exercise.

Conflict of Interest Statement. The author/researcher is the owner of a biomedical research group – Biologic Nutrigenomics Health Research Corp and Biologic Pharmamedical Research, that funds and executes research on the pharmacology of nutritional and nutraceutical agents that are studied in the context of disease pathology including characteristics that have been associated with inflammation and dementias. The author/researcher is also the owner of related Intellectual Properties. author copyright Franco Cavaleri PhDc.

Franco Cavaleri, BSc, PhDc, is The Rhema Group’s Chief Science Officer. He is also the principal research scientist at Biologic Pharmamedical; is a former Mr. IFBB North America; and is completing a doctoral degree in Experimental Medicine in the Faculty of Medicine.


Franco Cavaleri Speaks to: Ketogenic Diets - How Ketosis Factors Into Atkins

Ivan Leonov - Wednesday, November 15, 2017

As we’ve all seen, diets come and go and come again. Most fat-loss strategies deliver horrific consequences, but amazingly they’re kept alive by people desperately seeking magical solutions. Most diets result in weight loss because they lack calories but also deplete the body of glycogen, water, and muscle. You probably know many of these nutrient-deficient prescriptions for disaster: the grapefruit-and-water diet; the banana-and-water diet; the crème-and-protein-diet; the high-carbohydrate, low-to-no-fat diet; the liquids-only diet; the one-meal-per-day diet; the fruit-only diet; the lemon/ water fasting; the high-protein, high-fat diet; the no-carbohydrate diet.

One diet that really scares me, though, is the high-protein, high-fat, no-carbohydrate one popularized by the late Dr. Robert C. Atkins, which has been widely marketed and media-hyped. To my astonishment, this outlandish program has been universally accepted as safe. The Atkins Diet involves the consumption of as much protein from red-meat sources with as much animal fat as desired. I’m a proponent of abundant dietary fat, but not just any old fat. As we’ve seen, there are some fats we need to avoid and others we should consume abundantly.

The Atkins Diet is ketogenic. Few people know what they’re actually doing to their biochemistry by struggling through such a regimen. Within the liver two molecules of acetyl coenzyme A (acetyl CoA) are combined to yield ketone bodies—acetoacetic acid, beta-hydroxybutyric acid, and acetone, which are ultimately produced as a result of ketogenesis. Acetyl CoA can be obtained from dietary fats, dietary protein, or body tissues.

When dietary carbohydrates are depleted, the body quickly uses up its stored glycogen levels. Athletes or those in pursuit of quick weight loss learn to use ketone sticks (which measure ketone body levels in urine) to determine whether ketosis (the abnormal increase of ketone bodies in the body) has been induced by a low- to zero-carbohydrate diet.

Once the ketogenic state is reached, however, most of these athletes know to back away from the carbohydrate restriction and increase dietary carbohydrates to a level that prevents muscle catabolism and ketosis from persisting. It takes about 50 to 70 g (one potato, two apples, or two bananas) of carbohydrates daily to prevent ketosis for the average person. The popular ketogenic Atkins Diet involves the indiscriminate consumption of deep-fried and pan-fried globs of animal fat. This high-fat, high-protein, low- or no-carbohydrate program promotes the production of ketone bodies. Cells in muscles and other tissues have the ability to employ these substances as a source of energy.

When dietary carbohydrates are severely limited, ketone bodies can be produced in greater quantities than the body can use for energy. The Atkins Diet involves severe carbohydrate limitation. When dietary protein and fat are too high, ketone bodies can’t be oxidized in the body fast enough to remove the potential danger they pose. The body expels excessive ketone bodies in the urine and through the lungs. In fact, you can often smell acetone on the breath of an individual who’s been in ketosis for some time. Ketone bodies can also be detected on the breath of a diabetic when he or she fails to metabolize carbohydrates efficiently due to inefficient or insufficient insulin secretions.

The Atkins Diet promotes the abundant consumption of beef and dairy fats, which contain a great deal of arachidonic acid. Overconsumption of these arachidonic-acid-laden sources multiplies the risk of biochemical imbalances that are at the root of a multitude of epidemics, including obesity. That’s especially so when a diet such as the Atkins one is devoid of vegetables, whole grains, and legumes that would otherwise supply antioxidants, vitamins, and fuel for a starving body and friendly intestinal bacteria. The change in colon pH that this diet encourages is a perfect environment for pathogenic bacteria to disrupt friendly bacterial health, increasing the danger of colon cancer (24, 25). Not only does the lack of fiber in this diet contribute to the incidence of colon cancer, the high degree of dietary saturated fat does, as well. The indiscriminate fat consumption advocated by the Atkins Diet can also facilitate cardiovascular problems and interrupt insulin function. Furthermore, abundant red-meat consumption can cause colon cancer through factors independent of fat content (26).

With a nearzero intake of dietary carbohydrates, this diet creates a temporary depletion of hepatic glycogen. Glycogen is the liver’s main fuel for detoxification and metabolic activity. Exhaust this energy source and you’re in trouble.

The ketogenic state induced by the Atkins Diet and others like it alters the pH (acid/base balance) of the blood and body to induce more metabolic havoc (27, 28). The body functions in a pH range that’s quite narrow. Mild deviations result in profound metabolic impairment. Interestingly the ketogenic diet doesn’t change the pH of the brain. Carbohydrate-restricted diets like the one expounded by Dr. Atkins have been in use since the 1920s to help treat epileptic children with great success (29, 30, 31). The ketogenic diet somehow reduces seizure activity, but scientists still don’t know why. And ketogenic diets have been shown through some unknown mechanism to boost brain ATP, as well (32). However, a ketogenic diet must be carefully monitored in these therapeutic applications to help manage the potential acidosis of the body. As the body fights to maintain its functional acid-alkaline balance, nutrient stores, such as calcium and phosphorus from bone mass, might be taxed. Furthermore, cases of renal stone development, gastritis, ulcerative colitis, alteration of mentation, and hyperlipidemia have been reported with the administration of a ketogenic diet. Of course, with professional monitoring the risk of these side effects can be minimized (33). The dangers might be a good trade-off when considering the implications of an uncontrollable epileptic condition, especially when it’s severe. Still, for basic weight management a ketogenic diet isn’t advisable. The risks aren’t lower than those posed by excess body fat.

If an epileptic condition presents significant danger in your life, sure, the ketogenic diet is likely a reasonable choice, but I still believe that ketogenesis might not have anything to do, or at least all to do, with the beneficial effect of the typical ketogenic diet on an epileptic condition. Keep in mind that the biochemical process by which ketogenesis seems to eliminate or reduce seizure activity isn’t known. Many studies demonstrate that polyunsaturated fatty-acid supplementation with linoleic and alpha linolenic acid, as well as with the fish-oil-derived DHA and EPA, also promotes brain health and inhibits epileptic seizures (34, 35, 36, 37, 38). The typical ketogenic diet involves greater intakes of fats, primarily animal ones, that have high essential-fat content as well as healthy EPA and DHA levels. It also entails the consumption of a lot of vegetable oils that consist of a bounty of linoleic and alpha linolenic acids.

Could it be that the method of therapeutic activity for the anti-epileptic ketogenic diet is simply through its rich supply of the essential and other health-promoting polyunsaturated, omega-3 fats that in the absence of dietary carbohydrates and reduced insulin activity leaves more fats for the brain to take up? Likely so. It’s at least one major contributing factor. I’m confident that the high polyunsaturated-fat version of Ageless Performance will prove to be a significant therapy for epileptic seizures the way ketogenic diets have but without the side effects and with a broader array of health benefits. Studies may ensue in the near future.

In addition to increased cardiovascular risk from the abundant dietary saturated fat, the dearth of vegetation and whole grains in the ketogenic Atkins-type diet results in a lack of the vitamin co-factors required to metabolize homocysteine. The accumulation of homocysteine occurs due to inefficient methionine metabolism. Red meats are rich in methionine. Eat them lavishly with few or no vegetables and you’ll likely run into trouble. A shortage of vitamins B6 and B12, folic acid, and methyldonors (such as SAMe and trimethylglycine) can increase the incidence of homocysteine-related problems. Homocysteine buildup has been implicated in cardiovascular disease, cerebrovascular problems, inflammation, chronic fatigue, and cognitive and other brain disorders. The Atkins Diet can create a predisposition for these common risks with the silent killer, cardiovascular disease, creeping up to get you without previous warning.

Although Ageless Performance focuses on limiting dietary carbohydrates, the objective is far from elimination. As part of the program, low-glycemicindex carbohydrates are consumed abundantly to fuel the brain and body without imposing an extreme insulinogenic influence, and ketogenesis doesn’t enter the picture. In the stressed ketogenic state, weight reduction can be significant (as much as 10 to 15 pounds in a week or two); however, most of the weight lost in the first phase of the Atkins Diet is water, glycogen, and muscle, not fat (39).

Although the Atkins Diet weight loss is attributed to the depletion of the body’s carbohydrate (glycogen) stores, most people are fooled into thinking this is a healthy outcome. Earlier I explained the carbohydratedepletion tricks for making weight classes at bodybuilding shows. Low or zero carbohydrate diets cause glycogen to be lost in the body rapidly. This also causes water to leave the body very quickly.

The result is significant:

Immediate weight loss might exceed 10 pounds, though fat won’t necessarily be reduced. Wrestlers use the same techniques to make weight classes, and a 1993 review in the International Journal of Sports Medicine indicates that the weight losses in these cases aren’t necessarily fat, either; worse, the metabolic impairment these practices induce can make fat loss even harder to achieve in future attempts (40).

Conflict of Interest Statement. The author/researcher is the owner of a biomedical research group – Biologic Nutrigenomics Health Research Corp and Biologic Pharmamedical Research, that funds and executes research on the pharmacology of nutritional and nutraceutical agents that are studied in the context of disease pathology including characteristics that have been associated with inflammation and dementias. The author/researcher is also the owner of related Intellectual Properties. author copyright Franco Cavaleri PhDc
Franco Cavaleri, BSc, PhDc, is The Rhema Group’s Chief Science Officer. He is also the principal research scientist at Biologic Pharmamedical; is a former Mr. IFBB North America; and is completing a doctoral degree in Experimental Medicine in the Faculty of Medicine.

Franco Cavaleri Speaks to: The True Nature of Curcumin as Published in the Journal of Preventative Medicine

Ivan Leonov - Wednesday, November 15, 2017


Franco Cavaleri1: William Jia2. 1) Faculty of Medicine; Department of Experimental Medicine; 2) Division of Neurosurgery, Department of Surgery. Center for Brain Health UBC Hospital 2211 Wesbrook Mall Van BC Canada V6T 2B5.

1 Introduction

Curcumin (diferuloylmethane) is a major active constituent of turmeric (Curcuma longa) [1] with an expansive pharmacology including anti-inflammatory [1], anti-carcinogenic [2], wound healing [3] and antibacterial [4] to name just a few features. Its safety is well established by centuries of use in food and traditional medicine [5], [6], [7]. Subcellular signalling proteins such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) [8], c-Jun N-terminal kinase (JNK) [9], Protein Kinase C (PKC) [10], AKT and mechanistic (mammalian) target of rapamycin (mTOR) signalling [11], [12], and mitogen-activated protein kinases (MAPKs) [13] have made a sizeable list of curcumin’s pharmacological targets that continues to evolve. Additionally, these targets are central to the pathology of diseases that are prolific in society today such as neurological disease [14], [15], autoimmunity [16], [17], cardiovascular disease [18], [19] and even cancer [20]. This all makes for a rather exciting story for curcumin as a potential medicinal agent.

The very fact that the list of targets and mechanisms of activity by curcumin continues to grow is, itself, demonstrative of our incomplete understanding of the fundamental underlying mechanism by which curcumin pharmacology modulates disease pathology. Studies have shown curcumin to inhibit growth factors and growth factor receptors as well as the downstream signals including PI3K and extracellular-signal activated kinase (Erk); and oncogenes such as c-jun and c-myc [21], [22]. The extract is shown to inhibit expression of epidermal growth factor receptor (EGFR) and erythroblastosis oncogene B (ErbB2) [23]; inhibit enzymes such as cyclooxygenase (COX) and lipoxygenase (LOX) [24], [25], [26], [27]; facilitate transcription factors such as nuclear factor erythroid 2-related factor (Nrf2) [28] that can contribute to endogenous antioxidant status and protect cells from oxidation; while it inhibits activator protein – 1 (AP-1) and tumor necrosis factor α (TNFα) [29], [30]. Curcumin is shown to inhibit cytokines such as interleukins 1, 2, 6 and 8 [30], [25], [31], [32]. The extract is also shown to suppress Interleukin (IL)-12 in macrophages [33] while promoting the anti-inflammatory IL-10 [34]. How is all this possible and how can this be harnessed and controlled?

Curcumin comprises a subset of active constituents. The three main naturally occurring curcuminoid analogues found within the curcumin extract are diferuloylmethane (curcumin I), desmethoxycurcumin (curcumin II) and bis-desmethoxycurcumin (curcumin III) [35], [36] as seen in Figure 1. They typically exist naturally in proportions that range between 65-80% curcumin I, 10-25% curcumin II and 0.2-3.0% curcumin III [37]. Curcumin delivers a polypharmacology that exhibits a narrower range of activity than the whole herb [38], [39]. However, the curcumin extract is certainly not maximally selective as it is still delivering multiple active constituents each potentially exhibiting a polypharmacology of their own.

There is yet another component of the pharmacology that may be contributing to curcumin’s polypharmacological nature. The sub-constituent curcuminoids readily give rise to auto-oxidative degradation products [40], [41], [42], some of which we know to exhibit pharmacological activity that we may have attributed to the curcuminoids in the past. Despite the conflicting findings on these curcuminoid by-products, they may be playing a monumental role in the pharmacology of this remarkable extract; a role that needs to be viewed with a more focussed lens.

2 Clinical Benefits of Curcumin

Since long ago, oral dosing of curcumin with as little as 20 mg three times daily has been shown to improve acute and chronic hepatitis [43]. Curcumin is a potent cholegogue inducing gall-bladder contraction and bile elimination [44] conducive to bladder stone management. However, the more recent understanding of curcumin’s anti-inflammatory pharmacology and what this means in the context of disease management has elevated interest in the extract as a potential treatment for many modern epidemics.

Curcumin is also shown clinically to enhance cytotoxicity of various drug-resistant strains of cancer [45]. In clinical trials patients with various cancer-related risks including bladder cancer, cervical cancer, intestinal metaplasia and oral leukoplakia were treated with systematically escalating doses up to 8000 mg daily of curcumin for three months [46]. Results were indicative of a significant anti-cancer effect by the curcumin treatment with relatively little to no toxicity. In murine models curcumin is also shown to ameliorate functional and structural abnormalities associated with cancer drug cisplatin-induced neuropathy [47].
In the treatment of orbital pseudotumors curcumin produces significant positive results. After following these patients for as long as two years at three month intervals, four patients recovered completely among five who stayed in the study to completion. One patient experienced complete regression but with some limited movement as a residual symptom [48]. The treatment of psoriasis by oral curcumin administration is shown to produce an excellent therapeutic outcome in two patients encouraging the need for larger controlled trials [49]. Topical application of curcumin preparation shows curcumin treatment to produce a more profound resolution than calcipotriol or non-treated (control) patients with various degrees of psoriasis [50].

A twenty-four week double blind placebo-controlled study resulted in an inconclusive position on curcumin’s effects on Alzheimer’s patients [51]. Curcumin use did show signs of β-Amyloid changes in serum indicative of β-Amyloid disaggregation and a tendency towards fewer adverse events for patients using curcumin. However no improvement in cognitive performance in the curcumin group over controls is established. However, since the control group did not shown cognitive decline during the period of the trial, the study design will need to be modified to be able to better evaluate these outcomes; better controls, larger groups and longer trials are expected requirements acknowledged by the authors.

However, researchers have not given up on the extract when it comes to amyloidogenic diseases. In vivo murine studies show that curcumin does cross the blood brain barrier [52], [53]and binds to amyloid plaques when orally fed or directly injected into the carotid artery [54]. When coupled to the known in vitro results associated with Alzheimer’s disease biomarkers these findings are suggestive of efficacy against Alzheimer’s pathology [55]. Other studies show curcumin improves cognitive function in patients with Alzheimer’s disease [53]. More research is required to further define curcumin’s clinical efficacy and mechanisms involved in the framework of Alzheimer’s pathology.

Curcumin is shown to deliver anti-depressant like activity similar to that of fluoxetine and imipramine [56] and the mechanism might involve increasing brain derived neurotrophic factor (BDNF) [57]. On the other hand curcumin’s anti-depressant-like activity maybe a function of inhibitory activity on IL-6 and IL-1 [35], [58] since dysregulation of these cytokines and the systemic inflammatory activity that can rise from this may contribute to depression pathology [59], [60].

Curcumin is shown to inhibit p300-HAT to improve cardiac hypertrophy and heart failure in animal models [61] [62]. Curcumin delivers better results than diciofenac sodium in a recent study of patients with active rheumatoid arthritis comparing these therapies [6], [63]. Curcumin appears to correct cystic fibrosis transmembrane conductance(CTFR) defects associated with cystic fibrosis (CF) in murine models [64]. Curcumin administration stimulates muscle regeneration after traumatic injury [65]. Curcumin improves COPD-like airway inflammation [66]. All those in a small group of five ulcerative colitis patients improved using 550 mg curcumin twice daily as treatment for a month followed by a month of three daily 550 mg doses [7].

Curcumin pharmacology looks promising to say the least but these remarkable results are also in conflict with similar studies showing lack of success in clinical and preclinical models with curcumin treatment [67] such as in depression models where curcumin’s effects are found to not be significant [68]; where in other independent studies of CTFR (CF) defects curcumin’s benefits were not repeatable [69]; and in research using high curcumin doses to treat inflammatory conditions such as rheumatoid arthritis patients experienced improvements as much as but not more than those receiving phenylbutazone [7].

3 Curcumin Pharmacokinetics

3.1 Curcumin Bioavailability
Despite the abundance of experimental and anecdotal clinical evidence demonstrating the health benefits of orally routed curcumin, limited to no serum curcumin is found in test subjects even at extremely high dosing that exceeds 10,000 mg daily [70] [71]. The reasons for the low tissue or serum availability appear to be due to multiple compounding factors including low bioavailability[72] and expeditious metabolic degradation[73] that causes rapid elimination of the curcuminoids [72]. The naturally occurring curcuminoid analogues are highly hydrophobic [74] [75], a characteristic thought to play a major role in bioavailability [72]. Overcoming the hydrophobic characteristics of the curcuminoids resolves only one of the challenges, however. There are other curcuminoid issues related to pharmacokinetics that are outstanding and are likely far more central to the understanding and efficacy of curcuminoid pharmacology than the bioavailability limitation.

The low bioavailability of curcumin is assumed due to the lack of serum curcuminoids [70] and the common excessive efflux of some curcumin preparations in fecal matter upon oral administration [76]. In comparison with intraperitoneal administration of pure curcumin extract which excludes the tumerone fraction, 75% of orally administered curcumin extract was excreted in feces with more than 10% found in bile [76] in a mouse model. In human patients, Cheng et al report that even with 8000 mg of oral curcumin administered daily, serum concentrations were found to be 1.77 +/- 1.87 microM [46]. In colorectal patients taking up to 3600 mg of curcumin orally daily neither curcumin nor its metabolites were found at quantifiable levels in plasma, blood and urine [77]. In a human Phase I clinical trial, Sharma et al found curcumin and its metabolites in plasma in the 10 nM range after oral dosing as high as 3600 mg daily [70]. In the treatment of pancreatic cancer using orally administered curcumin plasma curcumin levels are found to range between 22-41 ng/ml [71].

Poor curcumin/curcuminoid bioavailability is thought to be caused by the highly hydrophobic property of the phenolic compounds [75]. Many strategies have been applied to overcome the hydrophobicity of curcuminoids in an attempt to improve bioavailability such as interacting them with beta-casein (micellar casein) to improve solubility in aqueous mediums [78]; encapsulation of curcuminoids in hydrophobically modified starch [79], and phosphatidylcholine interactions with curcuminoids to enhance bioavailability and delivery [80],[81]. Administration of complexed curcuminoid-phosphatidylcholine is in fact shown to deliver a higher serum payload of curcumin over curcumin powder alone [82]. However, more detailed studies might be needed to determine if the incremental serum curcuminoids found with this reacted curcuminoid complex is a function of improved solubility and bioavailability. Could the improved survival of serum curcuminoids be a function of recipient-induced alteration in hepatic enzyme activity that may reduce the clearance rate of curcuminoids from blood? In addition, feed type [83], fiber content [84] and many other factors can also play into gastric emptying rate [85] gastrointestinal transition rate and macronutrient digestion and absorption [86]. This all influences drug transition rate and bioavailability as well and are not always fully accounted for in these studies.

The bioavailability limitation of curcumin, however, may be also overstated because studies also show that curcumin can efficiently find its way into serum at concentrations that are rather significant [51]. Thirty-four subjects of a six-month trial using powdered curcumin versus encapsulated curcumin presents a different bioavailability story. This study shows a mean plasma curcumin level of 490 nM amongst both curcumin groups but an interestingly higher (940 nM) level for the curcumin capsule group over the group fed curcumin powder at the daily dose of 1.0 gram daily. A group using 4.0 grams daily was also evaluated but serum curcumin results with this higher dose was not significantly higher.

However, it’s interesting to note that while curcumin levels differed, levels of tetrahydrocurcumin, ferulic acid and vanillic acid did not differ between patients using powdered curcumin and those using capsules. The powder form could be performing less effectively due to the need to mix it in aqueous or other solutions that allow the auto-degradation process to start in on curcuminoid degradation long before it even enters the lumen. Interestingly, serum levels of curcumin could only be detected in the presence of glucuronidase inhibitor [51]. Here we have a clear indication that bioavailability of curcumin can be functional and maybe, the serum limitations are more attributable to shortfalls in curcumin formula design and post absorption modification and degradation that play a larger role in serum survival.
Figure 3 presents a schematic that highlights multiple sources of curcumin/oid degradation that could affect curcumin “apparent” bioavailability. This degradation starts with the type of curcumin delivery form or formula and carries through to the final reagents and solvents used in analysis.

3.2 Curcumin Metabolism
It is well understood that metabolic degradation of curcumin is rapid and efficient. In the preliminary study by Baum et al [51] it was determined that serum curcumin could be increased within 1.5 hours of oral administration with food to 250 nM and to 270 nM by four hours with water only. By twenty-four hours post-administration serum curcumin levels fell to 60 nM. No significant differences were found between the groups taking 1.0 gram curcumin daily versus the group taking 4.0 grams daily. This study proves to be one that highlights the true potential of curcuminoid bioavailability; it can be viable for a properly formulated curcumin treatment. Degradation and metabolic modification, on the other hand, may be the more difficult challenge. In fact, in this same study, at 2.5 hours after oral curcumin administration serum ferulic acid is found to be 110 +/- 20 nM, vanillic acid is 50+/-20 nM, total curcuminoids found to be 1100+/-260 nM, tetrahydrocurcumin is found to be 440+/-100 nM, and no vanillin is found.

Enzymatic metabolism of curcuminoids starts in the intestinal lumen and is quickly followed by hepatic enzyme activity [87], [88]. Although it is not clear whether Phase I metabolic enzymes such as the P450 CYPs are directly involved in curcuminoid metabolism, their influence may be indirect as explained further here. Once in the blood, for example, curcuminoid survival is prolonged or protected by serum albumin [89] which likely forms micellar systems with the systemic curcuminoid. Cationic micelles of curcuminoid [90], for instance, which can be achieved with beta casein are not only said to improve bioavailability but also protect the curcuminoids from premature degradation [78]. Binding of curcuminoids in vitro to bovine serum albumin (BSA), likely in the protein’s hydrophobic pockets, results in a curcumin-BSA complex with improved curcumin stability [91]. In fact, curcumin solubility is increased as much as 10-fold in the presence of BSA [92].

In vivo, curcuminoids are quickly converted to dihydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin, and hexahydrocurcuminol. These metabolites are quickly further subjected to glucuronation and sulfation to form curcumin glucuronide, curcumin sulfate, dihdrocurcumin glucuroside, tetrahydrocurcumin glucuronoside, and hexahydrocurcumin glucuronoside [93], [94], [73], [87]. This likely involves Phase II metabolic enzymes – UDP-glucuronosyltransferases (UGT) and Sulfotransferase enzymes (SULT) [95]. However, the literature is not black and white in this context. To throw another curve in the context of metabolic degradation it must be considered that curcumin metabolic degradation and elimination is shown in some studies to play out differently in the human versus rat model. The human intestinal and hepatic cytosol is more likely to conjugate curcumin and produce the tetrahydrocurcumin metabolite in place of curcumin more abundantly than the rat model does [96]. What this means to total pharmacological potency is unexplored to date but what has been a problem up until now is the direct extrapolation from murine models to human models with lack of scientific support. More work needs to focus on unravelling this mystery.

There is no strong evidence to show that curcumin is subject to metabolism by P450. However, the Phase I P450 and the Phase II enzymes tend to aggregate at the membrane and influence each other. P450 (CYP), for instance, interacts intimately with UDP-glucuronosyltransferases (UGT) responsible for glucuronidation to form heteromers at the plasma membrane [97] that result in their competition for substrates and down- and up-regulation of activity [97]. It is possible that any substance or influence that affects P450 activity, such as changes in membrane phospholipid constitution, may indirectly influence curcumin’s metabolism [98]. Phosphatidylcholine in curcumin complexes that has been shown to improve solubility and bioavailability of curcumin [81] may also affect P450’s since membrane phosphatidylcholine is thought to be the anchoring phospholipid for at least some P450 enzymes such as 2B4 [99].

Failure to detect functional levels of curcumin in the plasma after a steady oral loading period or administration by other route may also be attributed to instability and non-enzymatic degradation of the curcuminoids. Various human and rat studies demonstrate a short half-life for the curcuminoids [100], [101]. Researches have shown that curcumin is more stable in solutions at pH < 7.0 while it tends to be less stable in physiological pH of 7.8 or more [102] characteristic of the distal small intestine. The curcumin non-enzymatic degradation products frequently reported are ferulic aldehyde, trans-6-(40-hydroxy-30- methoxyphenyl)-2, 4-dioxo-5-hexenal, feruloyl methane, ferulic acid and vanillin [102]. Ferulic acid and vanillin, are considered very small phenolic molecules with molecular weights of 151.15 g/mole [103] and 66.8 g/mole [104] respectively. They are soluble in aqueous solution and far more stable than the curcuminoids, themselves, in the biological medium [105], [106], [107]. The status of these non-enzymatic auto-oxidative degradation products is also in question and in conflict in the literature as the ones expected to be the major products in the past, vanillin and ferulic acid [42], are said to more recently be preceded by a bicyclopentadione product or other by-products that may not have yet been precisely identified [102], [108], [109], [105].

Too much conflicting data has been presented in this context and although the multiple view-points are great to see for meta-analysis it must be considered that these conflicting positions on the status of the degradation by-products could also be a function of the variable conditions being used to study the curcuminoids. Variable pH, temperature, serum protein and other conditions that, if even mildly varied, result in varying the stability, degradation dynamic and by-product yield. These variables could factor into the equation at multiple levels when it comes to in vitro work; but even with in vivo work the feed types, curcumin specifications and animal condition all play a changeable role in the outcome. Analysis of the blood work extracted including reagents used to treat final yields also influence the stability of the retained target curcuminoids; biochemicals we now know to be extremely vulnerable to degradation. All of these factors as shown in Figure 3 contribute to the variable results and inconsistencies we see in the literature. Somewhere in all this conflict, however, treatment with the right curcumin therapy successfully delivers relief to patients of many diseases. Ultimately, however, we need to pin down the pharmacokinetics and isolated pharmacology of the curcuminoids and their downstream by-products in order to eliminate inconsistencies and produce a reliable curcumin-treatment. 3.3 Curcuminoids or their degradation product? The enzymatic metabolism of curcumin is shown in some studies to reduce curcumin’s pharmacological potency significantly [110], [111]. However, other studies indicate that at least one of these metabolic by-products could be contributing to curcumin’s polypharmacology in tissues [112].

Tetrahydrocurcumin is purported to deliver a significant anti-inflammatory pharmacology [110], [111], [113]. In fact, more recent studies are pointing to this reduced derivative of curcumin having antioxidant activity and antihyperlipidemic effects at least as potent as curcumin [114]. Tetrahydrocurcumin is shown in some studies to perform well as an inhibitor of NF-kappa-B and protector of oxidative damage after ischemic episodes [115]. While it is shown to deliver more anti-inflammatory activity than curcumin in a carrageenan-induced murine inflammatory model [116] it performs not nearly as well as curcumin in other studies [117]. Other studies again, show varied activity with curcumin performing better than tetrahydrocurcumin on targets like COX-2 inhibition [118]. Aside from metabolic degradation as a factor altering curcuminoid pharmacology, the curcuminoids can exist as different tautomers – the enol and keto tautomers, [119], [120] as shown in Figure 2. The keto form predominates in a solution of pH 3-7 while at a pH above 7.8 the enol form predominates in solution [121]. The enol form (>pH 7.8) serves as an electron donor while the keto form (pH 3-7) serves as a hydrogen atom donor; although both forms can serve as antioxidant. Nevertheless, the environment in which the curcuminoid exists influences its electrochemical properties factoring, yet again, as another source of pharmacological variability.

The story with regards to the non-enzymatic auto-degradation products of curcumin is even more colourful and adds even more mystery. Curcuminoids also undergo non-enzymatic auto-oxidative degradation and as we’ve seen this is more likely to occur at pH> 7.0 [102]. It was shown that as much as 90% of curcuminoids are degraded within 30 minutes in a serum-free medium at pH 7 at 37oC [122]. Even in the presence of serum, 50% of curcumin is degraded to its degradation by-products within eight hours [102]. The true nature of this degradation yield is still not conclusively understood.

Research by Martelli et al show that curcumin activates the transient receptor potential cation channel subfamily V member 1 (TRPV1) also known as the vanilliod receptor 1. This receptor is the target of vanillin, a degradation product of curcumin. By this mechanism vanillin and/or curcumin could be inducing symptomatic relief of Dinitrobenzene sulfonic acid (DNBS) -induced colitis in mice [123]. Multiple studies point to NF-kappa-B inhibition by curcumin and this being the root activity that results in subsequent IL-1, IL-6 and IL-8 inhibition [124], [125] [126]. Similarly, vanillin can also inhibit NF-kappa-B and caspase-1 [127]. COX is inhibited by vanillin [127]. In fact, vanillin’s effects are COX-2 specific delivering the beneficial pharmacology associated with nonsteroidal anti-inflammatory drugs. Interestingly, curcumin is shown to inhibit COX as well [128], [129]. Kim et al also show that vanillin protects rat neurons from oxidative stress [130]. Curcumin does the same by inducing expression of antioxidant defensive genes through Nrf2 activation [131], [28].

Ferulic acid, another curcumin degradation product, displays pharmacological activity similar to curcumin’s as well. Studies demonstrate that ferulic acid supplementation can facilitate hypotension through NO-mediated vasodilation [132]; a result also seen with curcumin administration [133]. Ferulic acid is shown to have significant antitumor activity [134] as does curcumin [135]. Ferulic acid is shown to inhibit NF-kappa -B [136]. Curcumin has been shown to destabilize preformed β-amyloid protein including inhibition of soluble oligomer and fibril aggregation to subsequently or also independently reduce associated neurotoxicity by these proteins [137], [138] [54], [139], [140], [141]. Ferulic acid is shown to have similar activities in vitro [142], [130] [139, 143].

Similar pharmacological activities of curcumin and its oxidative degradation products strongly suggests a contribution by curcumin’s auto-oxidative degradation products to curcumin pharmacology in vivo. This may explain the therapeutic results with curcumin administration despite low bioavailability or more accurately low serum levels of the curcuminoid analogues. The fact that we experience efficacious results with oral curcumin administration with or without the identification of significant serum curcuminoid concentrations, supports the notion that vanillin, ferulic acid and/or other degradation products of curcumin may be responsible at least partially for the clinical benefits of curcuminoids.

The variety of experimental models used to investigate curcumin includes in vitro and in vivo studies using various representations of turmeric and the common extract, curcumin. Curcumin’s pleiotropic properties certainly make it a versatile molecule. The question is whether this pleiotropy is a function of one curcuminoid analogue on multiple targets, the naturally inherent three curcuminoid analogues, the degradation products, or all of these factors? A better understanding of the complex nature of this activity can help us decode and identify the active components contributing to the polypharmacology. With this mapping, improved selectivity by curcumin-based drugs can be established and improved indication-specific drug designs with improved reliability and repeatability can be created. As we have it today, too many variables are at play.

4 Conclusion
One of the challenges faced today with respect to curcumin acceptance in mainstream medicine is its polypharmacology or lack of clear cellular targeting. Drug target selectivity is central to allopathic drug design for reasons that are valid [144], [145]. However, an emerging drug paradigm that centers on polypharmacology [145] [146] to produce a synergistic therapeutic outcome is gaining some momentum for reasons that may also be valid. In essence, polypharmacology as a treatment model is already established in mainstream allopathic medicine and is in use to treat many complex disorders today including autoimmune disease [147], [148] and especially cancers [146], [149]. Interestingly, curcumin falls into this class of drug perfectly, however, in order to better understand the entire scope of this polypharmacology by curcumin much more work needs to be done.

It is evident that curcumin extracts are made up of multiple naturally occurring curcuminoid analogues that must be studied in isolation in order for the distinct pharmacological features for each to be better defined. This may help formulators produce condition-specific products using the curcuminoid analogues with greater precision. In addition, it must be made very clear whether we have an influence in the in vivo model by the auto-oxidative by-products of curcumin or any of the enzymatic degradation products such as tetrahydrocurcumin. The level of contribution not only as constituents to serum bioactives but more accurately the tissue distribution of these potentially active degradation products must be defined.

Serum curcumin levels appear in the literature to not correlate well with efficacy of curcumin-based treatment protocols. Despite low to no serum curcumin upon oral administration in some studies efficacy against various human diseases from cancer to neurological has been well documented [72]. However, as we’ve seen some studies show that serum curcumin levels can be increased significantly with properly designed curcumin therapies. In addition, as serum curcumin/oid levels rise, in just hours the curcumin auto-oxidative degradation by-products can accompany the parent molecules in systemic circulation to contribute synergistic and/or additive pharmacology. This cannot be discounted.

Other challenges seem to compound the curcuminoid mystery including the lack of curcumin extract standardization. Curcumin extracts are notoriously comprised of varying proportions of the naturally inherent curcuminoid analogues. This in itself, produces another layer of inconsistency when testing one curcumin standard against others. Lastly, the reports of the curcuminoid pharmacokinetics in the literature are conflicting and this is expected to be a function of the varying conditions influencing degradation of the variable curcuminoid proportions in multiple additive ways starting with formulation design and delivery form of the curcumin-therapy. This variability continues based on transition time and oxidative status in the lumen to interactions of different biochemicals used in the analysis of blood work as portrayed in Figure 3. Our very attempts to isolate, extract and assay these compounds produces degradation vulnerability that impairs accurate evaluation of curcumin/oid pharmacokinetics.

In fact, we believe the very in vivo pharmacologically active biochemicals have been grossly missed in the past but have not been considered even in tissue distribution analysis – an endeavor that is so easily measured if one accepted the auto-degradation by-products as a plausible source for, at least, part of the curcumin/oid pharmacology. These by-products are relatively stable in aqueous solution where the parent curcuminoids are not. We believe this to more than just plausible; it is cautiously expected to be highly likely.

The future requires a completely different outlook; first off by accepting polypharmacology or Network Pharmacology as a viable drug model by which the accepted Systems Biology is addressed with a pharmacological model that fits it like a glove. Secondly, the possibility that the degradation by-products are playing a significant role in one way or another in the expansive curcumin polypharmacology should be seriously investigated. The role that tetrahydrocurcumin might be playing must also be considered. Tissue distribution analysis must be employed with this objective in mind; and with clear consideration of the degradation potential inherent in the analytical process, itself. After this dust settles we’ll get to a starting line and determine what it is we are really studying and with this curcumin may get the credit it deserves even in mainstream medicine.

Franco Cavaleri1 and William Jia2, 1) Faculty of Medicine; Department of Experimental Medicine, 2) Division of Neurosurgery, Department of Surgery.

Conflict of Interest Statement. The author/researcher is the owner of a biomedical research group – Biologic Nutrigenomics Health Research Corp and Biologic Pharmamedical Research, that funds and executes research on the pharmacology of nutritional and nutraceutical agents that are studied in the context of disease pathology including characteristics that have been associated with inflammation and dementias. The author/researcher is also the owner of related Intellectual Properties. author copyright Franco Cavaleri PhDc
Franco Cavaleri, BSc, PhDc, is The Rhema Group’s Chief Science Officer. He is also the principal research scientist at Biologic Pharmamedical; is a former Mr. IFBB North America; and is completing a doctoral degree in Experimental Medicine in the Faculty of Medicine.

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