Diet Affects Your Brain Function

The bacteria, fungi, viruses and other microorganisms that comprise your body’s microflora actually outnumber your body’s cells 10 to 1, and it’s now becoming increasingly clear that these tiny organisms play a MAJOR role in your health—both physical and mental.
The impact of your microflora on your brain function has again been confirmed by UCLA researchers who, in a proof-of-concept study, found that probiotics (beneficial bacteria) indeed altered the brain function in the participants.
As reported by UCLA:

“Researchers have known that the brain sends signals to your gut, which is why stress and other emotions can contribute to gastrointestinal symptoms. This study shows what has been suspected but until now had been proved only in animal studies: that signals travel the opposite way as well.
‘Time and time again, we hear from patients that they never felt depressed or anxious until they started experiencing problems with their gut,’ [Dr. Kirsten]Tillisch said. ‘Our study shows that the gut–brain connection is a two-way street.’”

The study, published in the peer-reviewed journal Gastroenterology, claims the discovery “carries significant implications for future research that could point the way toward dietary or drug interventions to improve brain function.” Naturally, I urge you to embrace dietary changes here, opposed to waiting for some “miracle drug” to do the work for you…

Yes, Your Diet Affects Your Brain Function

The study enlisted 36 women between the ages of 18 and 55 who were divided into three groups:

• The treatment group ate yogurt containing several probiotics thought to have a beneficial impact on intestinal health, twice a day for one month
• Another group ate a “sham” product that looked and tasted like the yogurt but contained no probiotics
• Control group ate no product at all

Before and after the four-week study, participants’ underwent functional magnetic resonance imaging (fMRI) scans, both while in a state of rest, and in response to an “emotion-recognition task.” For the latter, the women were shown a series of pictures of people with angry or frightened faces, which they had to match to other faces showing the same emotions.

“This task, designed to measure the engagement of affective and cognitive brain regions in response to a visual stimulus, was chosen because previous research in animals had linked changes in gut flora to changes in affective behaviors,” UCLA explains.

Interestingly, compared to the controls, the women who consumed probiotic yogurt had decreased activity in two brain regions that control central processing of emotion and sensation:

• The insular cortex (insula), which plays a role in functions typically linked to emotion (including perception, motor control, self-awareness, cognitive functioning, and interpersonal experience) and the regulation of your body’s homeostasis, and
• The somatosensory cortex, which plays a role in your body’s ability to interpret a wide variety of sensations

During the resting brain scan, the treatment group also showed greater connectivity between a region known as the “periaqueductal grey” and areas of the prefrontal cortex associated with cognition. In contrast, the control group showed greater connectivity of the periaqueductal grey to emotion- and sensation-related regions. According to UCLA:

“’The researchers were surprised to find that the brain effects could be seen in many areas, including those involved in sensory processing and not merely those associated with emotion,’ Tillisch said…
‘There are studies showing that what we eat can alter the composition and products of the gut flora — in particular, that people with high-vegetable, fiber-based diets have a different composition of their microbiota, or gut environment, than people who eat the more typical Western diet that is high in fat and carbohydrates,’ [senior author Dr. Emeran] Mayer said. ‘Now we know that this has an effect not only on the metabolism but also affects brain function.’”

What is really remarkable to me is that this study showed any improvement at all, since they used commercial yogurt preparations that are notoriously unhealthy foods loaded with artificial sweeteners, colors, flavorings, and sugar. Most importantly the vast majority have virtually clinically insignificant levels of beneficial bacteria. Clearly, you would be far better off making your own yogurt from raw milk.

Your Gut May Hold the Key to Better Brain Health

You may not be aware that you actually have two nervous systems:

• Central nervous system, composed of your brain and spinal cord
• Enteric nervous system, which is the intrinsic nervous system of your gastrointestinal tract

Both are created from identical tissue during fetal development—one part turns into your central nervous system while the other develops into your enteric nervous system. These two systems are connected via the vagus nerve, the tenth cranial nerve that runs from your brain stem down to your abdomen. It is now well established that the vagus nerve is the primary route your gut bacteria use to transmit information to your brain.
While many think of their brain as the organ in charge, your gut actually sends far more information to your brain than your brain sends to your gut… To put this into more concrete terms, you’ve probably experienced the visceral sensation of butterflies in your stomach when you’re nervous, or had an upset stomach when you were very angry or stressed. The flip side is also true, in that problems in your gut can directly impact your mental health, leading to issues like anxiety and depression.
For instance, in December 2011, the Journal of Neurogastroenterology and Motility reported the novel finding that the probiotic (good bacteria) known as Bifidobacterium longum NCC3001 has been shown to help normalize anxiety-like behavior in mice with infectious colitis. Separate research also found the probiotic Lactobacillus rhamnosus had a marked effect on GABA (an inhibitory neurotransmitter that is significantly involved in regulating many physiological and psychological processes) levels in certain brain regions and lowered the stress-induced hormone corticosterone, resulting in reduced anxiety- and depression-related behavior.
Just as you have neurons in your brain, you also have neurons in your gut — including neurons that produce neurotransmitters like serotonin, which is also found in your brain. In fact, the greatest concentration of serotonin, which is involved in mood control, depression and aggression, is found in your intestines, not your brain. It’s quite possible that this might be one reason why antidepressants, which raise serotonin levels in your brain, are often ineffective in treating depression, whereas proper dietary changes often help…

Your Gut Microbes Can Affect Your Health in Numerous Ways

In recent years, it’s become increasingly clear that the microbes in your gut play a much more vital role in your health than previously thought possible. In fact, probiotics, along with a host of other gut microorganisms, are so crucial to your health that researchers have compared them to “a newly recognized organ.” Besides research implicating gut bacteria in mental health and behavior, other research has shown that your microbiota also has an impact on:

1. Immune system function: Biologist Sarkis Mazmanian believes bacteria can train your immune system to distinguish between “foreign” microbes and those originating in your body. His work is laying the groundwork for new therapies using probiotics to treat a variety of diseases, particularly autoimmune diseases such as multiple sclerosis and Alzheimer’s. Mazmanian and colleagues were recently awarded the MacArthur Foundation “genius grant” for identifying an organism that originates in the human body (opposed to a fermented food) that has demonstrable health benefits in both animal and human cells. The organism has been named Bacteroides fragillis, and is found in 15-20 percent of humans. His group hopes to one day be able to test this body-originated bacteria in human clinical trials.
2. Gene expression: Researchers have discovered that the absence or presence of gut microorganisms during infancy permanently alters gene expression. Through gene profiling, they were able to discern that absence of gut bacteria altered genes and signaling pathways involved in learning, memory, and motor control. This suggests that gut bacteria are closely tied to early brain development and subsequent behavior. These behavioral changes could be reversed as long as the mice were exposed to normal microorganisms early in life. But once the germ-free mice had reached adulthood, colonizing them with bacteria did not influence their behavior. In a similar way, probiotics have also been found to influence the activity of hundreds of your genes, helping them to express in a positive, disease-fighting manner.
3. Diabetes: Bacterial populations in the gut of diabetics differ from non-diabetics, according to a study from Denmark. In particular, diabetics had fewer Firmicutes and more plentiful amounts of Bacteroidetes and Proteobacteria, compared to non-diabetics. The study also found a positive correlation for the ratios of Bacteroidetes to Firmicutes and reduced glucose tolerance. The researchers concluded: “The results of this study indicate that type 2 diabetes in humans is associated with compositional changes in intestinal microbiota.”
4. Obesity: The make-up of gut bacteria tends to differ in lean vs. obese people. This is one of the strongest areas of probiotic research to date, and you can read about a handful of such studies here. The bottom line is that restoring your gut flora should be an important consideration if you’re struggling to lose weight.
5. Autism: Establishment of normal gut flora in the first 20 days or so of life plays a crucial role in appropriate maturation of your baby’s immune system. Hence, babies who develop abnormal gut flora are left with compromised immune systems and are particularly at risk for developing such disorders as ADHD, learning disabilities and autism, particularly if they are vaccinated before restoring balance to their gut flora.

To get a solid understanding of just how this connection works, I highly recommend reviewing the information shared by Dr. Natasha Campbell-McBride in this previous interview.
Total Video Length: 1:13:21 Download Interview Transcript

Your Gut Flora Is Constantly Under Attack

Your gut bacteria are vulnerable to your diet and lifestyle. If you eat a lot of sugar, refined grains, and genetically engineered foods (i.e. processed foods and beverages of all kinds, as they are typically loaded with high fructose corn syrup and/or soy, both of which are primary GE crops in the US), your gut bacteria are going to be compromised because processed foods in general will destroy healthy microflora and feed bad bacteria and yeast. Your gut bacteria are also very sensitive to and can be harmed by:

• Antibiotics, unless absolutely necessary (and when you do, make sure to reseed your gut with fermented foods and/or a probiotic supplement)
• Conventionally-raised meats and other animal products, as CAFO animals are routinely fed low-dose antibiotics, plus genetically engineered grains, which have also been implicated in the destruction of gut flora
• Processed foods (as the excessive sugars, along with otherwise “dead” nutrients, feed pathogenic bacteria)
• Chlorinated and/or fluoridated water
• Antibacterial soap
• Agricultural chemicals

How to Optimize Your Gut Flora

Considering the fact that an estimated 80 percent of your immune system is located in your gut, reseeding your gut with healthy bacteria is important for the prevention of virtually ALL diseases, from colds to cancer. To do so, I recommend the following strategies:
1. Avoid processed, refined foods in your diet.
2. Eat traditionally fermented, unpasteurized foods: Fermented foods are the best route to optimal digestive health, as long as you eat the traditionally made, unpasteurized versions. Some of the beneficial bacteria found in fermented foods are also excellent chelators of heavy metals and pesticides, which will also have a beneficial health effect by reducing your toxic load. Healthy choices include:

• Fermented vegetables
• Lassi (an Indian yoghurt drink, traditionally enjoyed before dinner)
• Fermented milk, such as kefir
• Natto (fermented soy)

Ideally, you want to eat a variety of fermented foods to maximize the variety of bacteria you’re consuming. Fermented vegetables, which are one of my new passions, are an excellent way to supply beneficial bacteria back into our gut. And, unlike some other fermented foods, they tend to be palatable, if not downright delicious, to most people.
As an added bonus, they can also be a great source of vitamin K2 if you ferment your own using the proper starter culture. We tested samples of high-quality fermented organic vegetables made with our specific starter culture, and a typical serving (about two to three ounces) contained not only 10 trillion beneficial bacteria, it also had 500 mcg of vitamin K2, which we now know is a vital co-nutrient to both vitamin D and calcium. Most high-quality probiotic supplements will only supply you with a fraction of the beneficial bacteria found in such homemade fermented veggies, so it’s your most economical route to optimal gut health as well.

3. Take a high-quality probiotic supplement. Although I’m not a major proponent of taking many supplements (as I believe the majority of your nutrients need to come from food), probiotics is an exception if you don’t eat fermented foods on a regular basis.

Nurturing Your Gut Flora Is One of the Foundations of Optimal Health

Mounting research indicates the bacterial colonies residing in your gut may play key roles in the development of cancer, asthma, allergies, obesity, diabetes, autoimmune diseases and even brain, behavioral and emotional problems like ADHD, autism and depression. When you consider the fact that the gut-brain connection is recognized as a basic tenet of physiology and medicine, and that there’s no shortage of evidence of gastrointestinal involvement in a variety of neurological diseases, it’s easy to see how the balance of gut bacteria can play a significant role in your psychology and behavior as well.
With this in mind, it should also be crystal clear that nourishing your gut flora is extremely important, from cradle to grave, because in a very real sense you have two brains, one inside your skull and one in your gut, and each needs its own vital nourishment. Eating fermented foods should be your primary strategy, but if you don’t enjoy the taste of fermented foods, taking a probiotic supplement is definitely advised. I recommend looking for a probiotic supplement that fulfills the following criteria, to ensure quality and efficacy:

• The bacteria strains in the product must be able to survive your stomach acid and bile, so that they reach your intestines alive in adequate numbers
• The bacteria strains must have health-promoting features
• The probiotic activity must be guaranteed throughout the entire production process, storage period and shelf life of the product

Cancer Prevention and Treatment

Ketogenic Diet in Combination with Calorie Restriction and Hyperbaric Treatment Offer New Hope in Quest for Non-Toxic Cancer Treatment

By Dr. Mercola

Cancer is now so common it affects about one of two of us and most will face it at some point in their lives, either personally or through a friend or relative. Compelling research indicates that the answer to our burgeoning cancer epidemic could be far closer than previously imagined, in the form of a ketogenic diet.
Personally, I believe this is an absolutely crucial facet of cancer prevention and treatment, for whatever type of cancer you’re trying to address, and hopefully, some day it will be adopted as a first line of treatment by mainstream medicine.
A ketogenic diet calls for eliminating all but non-starchy vegetable carbohydrates, and replacing them with high amounts of healthy fats and low to moderate amounts of high-quality protein.
The premise is that since cancer cells need glucose to thrive, and carbohydrates turn into glucose in your body, then lowering the glucose level in your blood through carb and protein restriction literally starves the cancer cells to death. Additionally, low protein intake tends to minimize the mTOR pathway that accelerates cell proliferation and lowers the amount of one particular amino acid, glutamine, which is also known to drive certain cancers.
This type of diet is what I recommend for everyone, whether you have cancer or not, because it will help you convert from carb burning mode to fat burning, which will help you optimize your weight and prevent virtually all chronic degenerative disease.

The Ketogenic Diet—An Excellent Approach to Cancer Prevention and Treatment

Dr. Dominic D’Agostino, PhD is an assistant professor at the University of South Florida College of Medicine.
He teaches courses in molecular pharmacology and physiology, and maintains involvement in several studies researching metabolic treatments for neurological disorders such as seizures, Alzheimer’s, ALS, and cancer—all of which are metabolically linked.
His entry in to this field began when, in 2007, the Office of Naval Research funded his study into seizures related to oxygen toxicity experienced by Navy SEAL divers using closed-circuit breathing apparatus. At this juncture, he came across the ketogenic diet, which has already been confirmed as an effective treatment for epilepsy and a variety of seizure disorders.

“I came across the work of Thomas Seyfried,” he says. “I found a large amount of evidence that suggested that cancer was metabolically unique. Genetically, it was very heterogeneous. There are a host of different genetic anomalies in the cancer cells, but one characteristic is that it had this ubiquitous metabolic phenotype, which was aerobic glycolysis.

Even in the presence of oxygen, it was shown that cancer cells continue to pump out lactate, suggesting that they’re fuelling their metabolism from excess glucose consumption.

From my perspective, the only reason cancer cells would be pumping out lactate and deriving energy from glucose at such a high rate would be because they are metabolically compromised with mitochondrial deficiency.”

A mounting body of evidence suggests cancer is responsive to therapeutic ketosis—a natural physiologic state induced during prolonged states of decreased glucose. Nutritional ketosis involves restricting carbohydrates in order to decrease the availability of glucose. Restricting carbs also increases production of ketone bodies from your liver. Nearly all of your normal cells have the flexibility to readily adapt to using ketone bodies for fuel in lieu of glucose, but cancer cells do not have this metabolic flexibility. Hence, they effectively starve to death while all your normal cells actually operate more efficiently than before.

Another Key Component for Cancer Prevention and Treatment: Calorie Restriction

When you restrict carbohydrates, you prevent spikes in blood sugar, insulin and IGF-1 from occurring. These spikes are actually very pro-inflammatory, and can activate oncogenes (genes that contribute to the conversion of a normal cell into a cancerous cell), and enhance both cancer cell proliferation and the metastatic process.
But here’s a key point: While carb restriction will reduce these spikes, it will not have a major impact on baseline levels of blood glucose, unless you also restrict your calorie and protein intake. So for cancer prevention and treatment, carb restriction must be combined with calorie restriction and moderate protein restriction in order to effectively “starve” cancer cells of their preferred fuel (glucose and glutamine).

“The ketogenic diet is, I think, a very good strategy to make calorie restriction tolerable,” Dr. D’Agostino says. “Because when your brain in particular is craving glucose, and, say, for example, you go on a calorie-restricted diet, but it’s a high-carbohydrate diet, you’re still getting fluctuations in blood glucose. Your brain goes through these intermittent periods of glucose deprivation and you get very hungry. It’s not a very comfortable feeling.

Nutritional ketosis, which occurs with carbohydrate restriction and is further enhanced with calorie restriction, forces the physiological shift from a glucose-based metabolism to a fatty acid and ketone metabolism. When your body is, shall we say, keto-adapted, your brain energy metabolism is more stable and your mood is more stable. It may take a few weeks to adapt physiologically to this. But nutritional ketosis can be maintained and sustained with carbohydrate restriction and is further enhanced with calorie restriction.

The total calories really need to be restricted, and also protein. Protein is gluconeogenic. There are gluconeogenic amino acids in protein. If protein is at, say, for example, two or three grams per kilogram per day that is probably going to feed in through the gluconeogenic pathway and contribute to glutaminolysis. It will be hard to deplete your glycogen stores, which is necessary to drive the ketogenesis in your liver.”

How Much Protein Is Advisable?

So to summarize, in order to maintain and sustain nutritional ketosis, you need to decrease both carbohydrates and protein. But how much protein is enough, or too much?
As Dr. D’Agostino mentions above, eating two to three grams of protein per kilogram of bodyweight—which translates to 100-300 grams of protein per day for some people—is an enormous overload. Many bodybuilders will consume this much though, and many non-athletes as well. The bodybuilding industry has fostered the idea that you need tons of protein to build muscle, but as Dr. D’Agostino explains, if you restrict protein, and replace both the lost protein and carbs with healthful fats, the elevation in your blood ketones will have a protein-sparing, or anti-catabolic, effect.

“It will help you preserve lean body mass and a physical performance during a calorie deficit. This is why the ketogenic diet is an effective strategy for losing weight and retaining muscle, especially if it’s complemented with resistance exercise or some kind of physical activity,” he says.

Your end goal needs to be taken into consideration here though. A bodybuilder’s purpose for embarking on a ketogenic diet will be different from someone with cancer or a seizure disorder. In the latter case, you’d need to be far more strict with reducing protein in order to achieve and maintain ketosis.
Personally, I’m intrigued with the concept promoted by one of my mentors, Dr. Ron Rosedale, who advocates restricting protein to one gram per kilogram of lean body mass. Typically, for someone like myself, that amounts to about 50-70 grams of protein per day. The reason he promotes this so much is because of the stimulatory effect protein (branch-chained amino acids specifically) has on mammalian target of rapamycin (mTOR)—a pathway that seems to be largely responsible for the pathology seen in cancer growth.
When you reduce protein to just what your body needs, mTOR remains inhibited, which helps lessen your chances of cancer growth.

“I agree that mTOR is an important signal once you have cancer,” Dr. D’Agostino says. “The amino acid leucine is a powerful activator of the mTOR pathway, and stimulates skeletal muscle protein synthesis. Now, if a normal healthy person consumes boluses of leucine [a branch-chained amino acid], say five grams a couple of times a day, which a lot of bodybuilders and athletes do, can this enhance cancer growth?

This is an interesting question, and one that I’ve been researching. We’re about to set up a study where we give large doses of branch-chained amino acids in a metastatic model of cancer. My opinion is that branch-chained amino acids, which activate mTOR, in a normal healthy person are not counterproductive. They do not increase one’s susceptibility to cancer and may even prevent muscle wasting (e.g. cachexia) associated with cancer.”

The 'Meat' of the Ketogenic Diet—FATS

Most people who follow a ketogenic diet inadvertently restrict their calories without actually reaping the metabolic benefits of a calorie deficit, which include reductions in blood glucose, insulin, and triglycerides. The reason for this is that they don’t replace the carbs (and protein) they’ve eliminated with high enough amounts of healthy fats.

“Paradoxically, when you’re eating more fat, your blood fats will go down, due to a calorie deficit, and HDL [so-called ‘good’ cholesterol] goes up. Almost everyone that I see on these high-fat ketogenic diets has improved HDL levels,” Dr. D’Agostino says.

Now, when we say increase the fat, we’re not talking about the most common fat that people eat, which are primarily highly processed vegetable oils that are full of omega-6 fats, or trans fats found in French fries and doughnuts. We’re talking about high-quality fats like avocados, butter, coconut oil, macadamia nuts, and olives. These types of fats, which Dr. Rosedale believes are metabolically neutral because they don’t tend to trigger hormonal signaling events like leptin, insulin, and the mTOR pathway.

“I think a lot of the fats can be used in place of protein. And fats are very protein sparing, decreasing your need for protein,” Dr. D’Agostino says.

Bear in mind that while a traditional ketogenic diet calls for quite a bit of dairy products, dairy can actually be problematic and may prevent many of the health benefits that you can get from the ketogenic diet described by D’Agostino and Seyfried. Lactose is a sugar made from galactose and glucose that is found in milk, making up anywhere from two to eight percent of milk by weight. These extra sugars can be problematic when seeking to lose weight or treat cancer, even if from raw organic sources. Dairy fat is acceptable (e.g. sour cream, butter, etc.), but foods high in dairy protein or lactose should be minimized or avoided.

Why You’d Want to Become a Fat-Burner

Your body can burn two types of fuel: fat and carbs. In my estimation, I suspect about 99 percent of Americans are adapted to burning carbs as their primary fuel. It’s important to realize that when your body is adapted to burning carbs, you’re quite inflexible, metabolically speaking. Without fail, your body will be screaming for food about every two to three hours. These kinds of hunger pangs vanish once you become fat adapted, however. Then you can go all day and not be hungry, because you have far more fat in your body to burn than glucose.
So how do you achieve this metabolic switch-over?
In my experience, intermittent fasting, where you gradually restrict the window of time during which you eat food down to about six to eight hours, is one of the most effective ways to make this transition.

“I think from a practical standpoint, the important question is what’s a person going to follow? From my perspective, the biggest hurdle here is compliance; compliance to a dietary strategy that makes calorie restriction feasible and possible. And you know, carbohydrate restriction, high-fat diet, and intermittent fasting is one way to achieve that,” Dr. D’Agostino says.

“There are a lot of advantages to this pattern of intermittent fasting. I think that it is a good strategy to promote metabolic health and to maintain nutritional ketosis, if you can adapt to it. In some lifestyles, people cannot readily adapt to it. But I’ve found that most people can if they give it a try for at least several weeks. Most people are resistant. Even with people that are resistant- once they try it, they’re amazed at how much better they feel.”

It’s not an ideal course for everyone, however. As a general rule, intermittent fasting is contraindicated if you’re:

• An elite athlete
• Pregnant
• Suffer with adrenal stress
• Already at a low BMI (< 19)

Hyperbaric Treatment Works Synergistically with Ketogenic Diet Against Cancer

Dr. D’Agostino recently published a paper in the journal PLoS One, titled “The Ketogenic Diet and Hyperbaric Oxygen Therapy Prolong Survival in Mice with Systemic Metastatic Cancer¹.” Most people who die of cancer die from the metastatic process, rather than from the tumor itself. There’s really no treatment or cure for metastatic cancer. Dr. D’Agostino’s team has demonstrated that the ketogenic diet by itself can extend survival in animal models of metastatic cancer, but when it’s combined with hyperbaric oxygen therapy three times per week, there is an additive effect².

“You get a significant reduction in tumor growth, decrease in tumor size, and significant extension of life when the therapeutic ketosis achieved through the ketogenic diet is combined with hyperbaric oxygen,” he says.

“Tumors thrive in a low-oxygen environment. As a tumor grows, it exceeds its ability to supply oxygen to the center of the tumor. That low level of oxygen, called hypoxia, further activates the oncogenes; cancer promoting genes. It activates things like HIF-1-alpha and VEGF. IGF-1 signaling goes up. Hyperbaric oxygen can reverse tumor hypoxia intermittently. In doing that, it can actually turn off the oncogenes. There are published reports on this.

... [T]he tumor thrives in a low-oxygen environment, and it’s adapted to that low-oxygen environment. When you saturate a tumor with oxygen, because the mitochondria are damaged, it overproduces oxygen free radicals in the form of superoxide anion. This oxygen-induced increase in free radicals can actually cause the tumor to kill itself.”

How to Determine if You’re in Ketosis

To help you determine if you’re in ketosis, you can purchase a blood ketone and glucose meter, both of which are available in most drug stores. Amazon.com also sells them. Dr. D’Agostino recommends the Precision Xtra by Abbott Labs. Their ketone test strips are called Precision Xtra. Glucose meter strips typically sell for about 50 cents per strip, while ketone strips can range from $3-6 each.

 “Another option is the CardioChek meter. This is an interesting meter, because it can measure glucose, ketones, HDL, LDL, triglycerides, and a number of things.”

By testing your glucose and ketones, you can monitor your response to a nutritional intervention, and then adjust your calories and the macronutrient ratios to optimize your body to be in what Dr. D’Agostino calls the “metabolic zone.” The metabolic zone is defined as sustained hypoglycemia (55-75 mg/dl) with elevated blood ketones (>2 mM). 

“If you can produce sustained hypoglycemia with carbohydrate and calorie restriction and simultaneously elevate blood ketones, it actually makes the hypoglycemia tolerable,” he explains. “The ketones replace the glucose as the primary energy fuel for your brain. It basically keeps your brain metabolism optimized and prevents fluctuations in your mood and your energy levels, if you can sustain therapeutic ketosis with a properly balanced ketogenic diet.”

As you implement the ketogenic diet, you can just check your glucose and ketones once a week if you find the cost of the strips to be prohibitively expensive for more frequent testing. Typically, if your blood glucose stays at 75 or below with carbohydrate restriction, there’s a good chance that you’ll be in nutritional ketosis, which is where you want to be.
If you’re in ketosis by evidence of ketones in your urine, you’re in a situation where you likely have depleted glycogen stores in your liver. This means you’re maintaining a low blood glucose, which is good. The driver for hepatic ketogenesis is low blood glucose and low glycogen levels in the liver, as this means your body is depleted of glycogen. Your body will not really make adequate ketones (>2 mM), and they won’t spill over in your urine, unless you’ve achieved that level of glycogen depletion. So remember, when your levels of blood ketones are 1-3 millimolar (mM) that’s a good biomarker of nutritional ketosis.

More Information

While Dr. D’Agostino does not treat patients, he has plenty of resources to offer for anyone interested in learning more. If you have cancer, you could bring these resources to your oncologist for discussion. For everyone else, a ketogenic diet is an excellent way to optimize your health and prevent chronic diseases of all kinds. Helpful books and websites where you can learn more include:

• KetogenicDietResource.com³. This site is maintained by a friend of Dr. D’Agostino. Here you can also find a ketogenic diet handbook for cancer patients called Fight Cancer with a Ketogenic Diet
• Dr. D’Agostino’s website KetoNutrition.org⁴ contains a wide variety of therapy resources for patients
• Miriam Kalamian, EdM, MS, CNS offers ketogenic diet consulting services for cancer patients. For information, see dietarytherapies.com⁵
• The book, Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer, by Thomas Seyfried
• The book, The Cantin Ketogenic Diet: For Cancer, Type I Diabetes & Other Ailments, by Elaine Cantin, which specifically outlines a dairy-free ketogenic diet

Last but not least, ketoresearchchem.com⁶ is a resource for scientists interested in ketone research. Please note that the ketone supplements offered there are strictly for research only, and are NOT available for sale to cancer patients.

The Ketogenic Diet for Optimal Health and Disease Prevention

I firmly believe the ketogenic diet can be a tremendously beneficial strategy for optimizing your health and disease prevention and treatment plan, including cancer. It’s already a well-established first line of treatment against many seizure disorders. While most of your body’s cells have the metabolic flexibility to use either fat or sugar for fuel, cancer cells differ in that they cannot use fat (ketones) to survive—they need glucose, and a low-oxygen environment.
Back in the 1930’s, Dr. Otto Warburg actually received a Nobel Prize for his discovery that sugar is the primary fuel substrate for cancer cells. The “Warburg effect” in cancer cells is the basis of positron emission tomography (18-FDG PET), a medical imaging technique to visualize cancer. Oncologists have ignored this vital information for over 80 years and don’t use it therapeutically, which in my view is just reprehensible malpractice... So many people suffer needlessly because they don’t have access to this simple nutritional therapeutic strategy, which, in a nutshell, takes advantage of this intrinsic metabolic differential between healthy and cancerous cells.
Your body has a limited storage of sugar, stored in the form of glycogen, typically in your muscles and liver. These glycogen stores are depleted in about 12 hours or so, at which point your body has to switch to burning fat. This is part of what makes intermittent fasting so beneficial, because by not eating for 12-18 hours or longer each day, your body shifts into this fat-burning mode. While frequent hunger is a major issue for most people who are reliant on burning carbs for energy, fat-burners can go all day, or a number of days if necessary, without food, since most of us have plenty of fat to be used for fuel.
While most people can still eat some carbs, along with moderate amounts of high-quality protein, those with cancer need to be far more strict. Cancer patients also need to combine a ketogenic diet with calorie restriction to achieve glucose depletion that will effectively starve the cancer cells. Recent research also shows that adding hyperbaric oxygen treatment will dramatically reduce cancer growth and shrink tumors. All in all, I can find no drawbacks to eating this way, which is why I highly recommend it for everyone.

Aspartame 101: Why It Can Wreck Your Health

Aspartame -- best known by the names of Nutrasweet and Equal -- is believed to be carcinogenic and accounts for more reports of adverse reactions than all other foods and food additives combined.
Yet, this artificial sweetener continues to be used in more than 6,000 products (often sugar-free or "diet" versions), and millions of people consume this toxic chemical daily, believing it to be a healthy alternative to sugar.
If you’re one of them, or know someone who is, watching the 90-minute documentary Sweet Misery, above, could literally save your life. You might find you have something in common with filmmaker and narrator Cori Brackett’s own personal story, which starts out the film.
Like many others, Cori noticed a connection between the diet sodas she was drinking and negative effects on her health, including double vision, slurred speech and weak limbs. She was even diagnosed with multiple sclerosis and forced to use a wheelchair.
When she learned of aspartame’s link to the health issues described, she stopped using them and, as if by magic, her symptoms disappeared. But this is only the start of the incredibly eye-opening story behind aspartame, revealed in full detail in Sweet Misery.

A Detective Story of Corporate Fraud and Manipulation

Sweet Misery includes many heartfelt conversations with aspartame victims, including one woman serving a prison sentence for poisoning her late husband, even though his health signs suggest aspartame may have been to blame.
You’ll also hear from medical experts, including Dr. Russell Blaylock, a renowned neurosurgeon, who explain why aspartame acts as a poison to your brain and body.
But perhaps the most riveting aspect of the film is the evidence showing the extensive corporate fraud and manipulation that lead to aspartame's approval. The film has archival footage from G.D. Searle, the producer of aspartame, and federal officials describing the extensive propaganda used to push aspartame on the market.
Additionally, dialogue from a former US Food and Drug Administration (FDA) investigator also detailing the manipulation that took place to get this chemical approved will leave you with the "big picture" of conspiracy and even criminal negligence surrounding this popular artificial sweetener. There’s even an exchange described with Donald Rumsfeld, who was the CEO of Searle and, at the same time, part of Reagan's transition team when the FDA's board of inquiry was overruled to allow the marketing of aspartame as a food additive. Prior to this time, aspartame was unanimously rejected by the FDA because the scientific data just did not support it as a safe product.

Aspartame Breakdown

Aspartame is primarily made up of aspartic acid and phenylalanine. The phenylalanine has been synthetically modified to carry a methyl group, which provides the majority of the sweetness. That phenylalanine methyl bond, called a methyl ester, is very weak, which allows the methyl group on the phenylalanine to easily break off and form methanol.
You may have heard the claim that aspartame is harmless because methanol is also found in fruits and vegetables. However, in fruits and vegetables, the methanol is firmly bonded to pectin, allowing it to be safely passed through your digestive tract. Not so with the methanol created by aspartame; it’s not bonded to anything that can help eliminate it from your body.
Methanol is a serious neurotoxin because it acts as a Trojan horse and it's carried into susceptible tissues in your body, like your brain and bone marrow, where the alcohol dehydrogenase (ADH) enzyme converts it into formaldehyde, which wreaks havoc with sensitive proteins and DNA.
All animals except humans have a protective mechanism that allows methanol to be broken down into harmless formic acid. While humans do have the same number of peroxisomes (small structures in cells designed to detoxify chemicals) in comparable cells as animals, human peroxisomes cannot convert the toxic formaldehyde into harmless formic acid, so the formaldehyde is free to cause enormous damage in your tissues.

There IS an Obvious Biological Explanation for Aspartame Reactions...

The industry is fond of claiming that there’s “no biological explanation” for the health problems reported by so many after consuming aspartame. Of course, this is meant to make you think such reports aren’t true, or are unrelated to aspartame. Alas, there is in fact an obvious biological explanation according to Dr. Monte:

"Here is the story: there is a major biochemical problem here," he says. "Methyl alcohol is known now, and has been known since 1940, to be metabolized differently by humans from every other animal."

Here’s how it works: Both animals and humans have small structures called peroxisomes in each cell. There are a couple of hundred in every cell of your body, which are designed to detoxify a variety of chemicals. Peroxisome contains catalase, which help detoxify methanol. Other chemicals in the peroxisome convert the formaldehyde to formic acid, which is harmless, but this last step occurs only in animals. When methanol enters the peroxisome of every animal except humans, it gets into that mechanism. Humans do have the same number of peroxisomes in comparable cells as animals, but human peroxisomes cannot convert the toxic formaldehyde into harmless formic acid.
So to recap: In humans, the methyl alcohol travels through your blood vessels into sensitive areas, such as your brain, that are loaded with ADH, which converts methanol to formaldehyde. And since there's no catalase present, the formaldehyde is free to cause enormous damage in your tissues.

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Symptoms from methanol poisoning are many, and include:

• Headaches
• Ear buzzing
• Dizziness
• Nausea
• Gastrointestinal disturbances
• Weakness
• Vertigo
• Chills
• Memory lapses
• Numbness and shooting pains in the extremities
• Behavioral disturbances
• Neuritis

The most well-known problems from methanol poisoning are vision problems including misty vision, progressive contraction of visual fields, blurring of vision, obscuration of vision, retinal damage, and blindness. Formaldehyde is a known carcinogen that causes retinal damage, interferes with DNA replication and may cause birth defects.

A Historical Timeline of Aspartame

Aspartame is the number one source of side-effect complaints to the US Food and Drug Administration (FDA), with over 10,000 complaints filed and over 91 symptoms documented that are related to its consumption. With that many reports of adverse effects, it's hard to believe aspartame is still allowed on the market — let alone being weaseled in as an unlabeled ingredient in dairy products of all kinds.
Unfortunately, aspartame's approval was and still is largely a political affair. Many readers have long forgotten what 60 Minutes' correspondent Mike Wallace stated in his 1996 report on aspartame — that the approval of aspartame was "the most contested in FDA history." And for good reason. At the time, independent studies had found it caused brain cancer in lab animals, and the studies submitted by G.D. Searle to the FDA for the approval were quickly suspected of being sloppy at best. To get an idea of of how aspartame made it through the FDA approval process despite warning signs of potential health hazards and alleged scientific fraud, take a look at the historical timeline of aspartame:

Blood Cancer, Brain Damage and Weight Gain

Sweet Misery was released in 2004, and the serious risks of aspartame were already well established. But since then, the research has continued to reveal even more striking risks. Last year, the longest ever human aspartame study, spanning 22 years, found a clear association between aspartame consumption and non-Hodgkin’s Lymphoma and leukemia in men.¹ Other research revealed that long-term consumption of aspartame leads to oxidative stress, vascular congestion and an imbalance in the antioxidant/pro-oxidant status in the brain.² Of course, as detailed in Sweet Misery, aspartame has also been previously linked to brain tumors.³
The fact that aspartame is NOT a dieter's best friend has also been known by scientists for some time, and this was again confirmed last year in a study that found compared with sucrose (regular table sugar), aspartame and another artificial sweetener, saccharin, caused greater weight gain in adult rats, and this weight gain was unrelated to caloric intake.⁴ The underlying mechanism was not determined.
However, a number of studies have already shown that consuming artificial sweeteners disassociates the sensation of sweetness with caloric content, thereby changing your body's ability to regulate caloric intake naturally. So if you’re consuming artificial sweeteners because you think they’re going to help you lose weight, think again. In all, about 90 different adverse effects have been linked to aspartame, including:

Headaches/migraines	Muscle spasms	Tachycardia/heart palpitations	Anxiety attacks
Dizziness/vertigo	Weight gain	Insomnia	Slurred speech
Seizures	Rashes	Vision problems	Loss of taste
Nausea	Irritability and depression	Tinnitus and hearing loss	Memory loss
Numbness	Fatigue	Breathing difficulties	Joint pain

According to researchers and physicians studying the adverse effects of aspartame, the following chronic illnesses can also be triggered or worsened by ingesting aspartame:

Brain tumors	Multiple sclerosis	Epilepsy	Chronic fatigue syndrome	Parkinson's disease
Alzheimer's disease	Mental retardation	Lymphoma	Fibromyalgia	Diabetes

The Most Dangerous Food Additive on the Market: Are You Being Affected?

After watching Sweet Misery, many people belatedly realize they may have been suffering reactions to aspartame without realizing it. If you suspect an artificial sweetener might be to blame for a symptom you're having, a good way to help you weed out the culprit is to do an elimination challenge. It's easy to do, but you must read the ingredient labels for everything you put in your mouth to make sure you're avoiding ALL artificial sweeteners.
Unfortunately, aspartame toxicity is not well known by physicians, despite its frequency. Diagnosis is also hampered by the fact that it mimics several other common health conditions. It’s quite possible that you could be having a reaction to artificial sweeteners and not even know it, or be blaming it on another cause. To determine if you're having a reaction to artificial sweeteners, such as aspartame, take the following steps:

• Eliminate all artificial sweeteners from your diet for two weeks.
• After two weeks of being artificial sweetener-free, reintroduce your artificial sweetener of choice in a significant quantity (about three servings daily). Avoid other artificial sweeteners during this period.
• Do this for one to three days and notice how you feel, especially as compared to when you were consuming no artificial sweeteners.
• If you don't notice a difference in how you feel after re-introducing your primary artificial sweetener for a few days, it's a safe bet you're able to tolerate it acutely, meaning your body doesn't have an immediate, adverse response. However, this doesn't mean your health won't be damaged in the long run.
• If you've been consuming more than one type of artificial sweetener, you can repeat steps 2 through 4 with the next one on your list.

Let me make it abundantly clear that even though you may not show immediate signs of any noticeable reaction after consuming aspartame, please don't make the mistake of telling yourself "it must be fine for me." I strongly urge you to avoid aspartame, and other artificial sweeteners, at all costs.
Also, if you do experience side effects from aspartame, please report them to the FDA (if you live in the US) without delay. It's easy to make a report — just go to the FDA Consumer Complaint Coordinator page, find the phone number for your state, and make a call reporting your reaction. There's no telling just how many reports they might need to receive before taking another look at aspartame's safety and reconsidering their stance. But, the more reports they get, the more likely that is to happen. So if you suspect you have experienced an adverse reaction to aspartame (or any other drug or food additive), please take a moment to make this important call.
Finally, if you or someone you love is currently consuming aspartame, please take the 90 minutes to watch Sweet Misery... then decide if it’s really worth the risk

The effect of curcumin (turmeric) on Alzheimer's disease: An overview

Shrikant Mishra and Kalpana Palanivelu

Abstract

This paper discusses the effects of curcumin on patients with Alzheimer's disease (AD). Curcumin (Turmeric), an ancient Indian herb used in curry powder, has been extensively studied in modern medicine and Indian systems of medicine for the treatment of various medical conditions, including cystic fibrosis, haemorrhoids, gastric ulcer, colon cancer, breast cancer, atherosclerosis, liver diseases and arthritis. It has been used in various types of treatments for dementia and traumatic brain injury. Curcumin also has a potential role in the prevention and treatment of AD. Curcumin as an antioxidant, anti-inflammatory and lipophilic action improves the cognitive functions in patients with AD. A growing body of evidence indicates that oxidative stress, free radicals, beta amyloid, cerebral deregulation caused by bio-metal toxicity and abnormal inflammatory reactions contribute to the key event in Alzheimer's disease pathology. Due to various effects of curcumin, such as decreased Beta-amyloid plaques, delayed degradation of neurons, metal-chelation, anti-inflammatory, antioxidant and decreased microglia formation, the overall memory in patients with AD has improved. This paper reviews the various mechanisms of actions of curcumin in AD and pathology.

Keywords: Alternative approach to Alzheimer's, beta amyloid plaques, curcumin, curcumin and dementia, epidemiology, turmeric

Introduction

Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease. It is characterized by progressive cognitive deterioration together with declining activities of daily living and behavioral changes. It is the most common type of pre-senile and senile dementia. According to the World Health Organization (WHO), 5% of men and 6% of woman of above the age of 60 years are affected with Alzheimer's type dementia worldwide.[

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Destroy user interface control1] In India, the total prevalence of dementia per 1000 people is 33.6%, of which AD constitutes approximately 54% and vascular dementia constitutes approximately 39%. AD affects approximately 4.5 million people in the United States or approximately 10% of the population over the age of 65, and this number is projected to reach four times by 2050. The frequency increases to 50% by the age of 80 years. Every year more than $100 billion is spent for health care in the U.S. to treat AD in primary care settings alone.

Neuropathology of AD:

The neuropathological process consists of neuronal loss and atrophy, principally in the temporoparietal and frontal cortex, with an inflammatory response to the deposition of amyloid plaques and an abnormal cluster of protein fragments and tangled bundles of fibres (neurofibillary tangles). Neurotic plaques are relatively insoluble dense cores of 5-10 nm thick amyloid fibrils with a pallor staining “halo” surrounded by dystrophic neuritis, reactive astrocytes and activated microglia. There is an increased presence of monocytes/macrophages in the cerebral vessel wall and reactive or activated microglial cells in the adjacent parenchyma.[

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Destroy user interface control3] The main protein component of amyloid in AD is the 39-42 amino acid (beta) amyloid peptide (A-beta) [Figure 1].

Figure 1

Neuritic plaques are one of the characteristic structural abnormalities found in the brains of Alzheimer patients

Curcumin

Curcumin (Curcuma longa - Haldi) is the source of the spice Turmeric [Figure 2] and is used in curries and other spicy dishes from India, Asia and the Middle East. Similar to many other herbal remedies, people first used curcumin as a food and later discovered that it also had impressive medicinal qualities. It has been used extensively in Ayurveda (Indian system of Medicine) for centuries as a pain relieving, anti-inflammatory agent to relieve pain and inflammation in the skin and muscles. It has also proven to have anti-cancer properties.[

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Destroy user interface control5] Curcumin holds a high place in Ayurvedic medicine as a “cleanser of the body,” and today, science is finding a growing list of diseased conditions that can be healed by the active ingredients of turmeric.[

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Figure 2

(2a) Turmeric, (2b) Turmeric plant, (2c) Keto and enol form of curcumin

The Plant

Botanical name: Curcuma longa; Family: Zingiberaceae, the ginger family. Turmeric is a sterile plant and does not produce any seeds [Figure 2]. The plant grows up to 3-5 ft tall and has dull yellow flowers. The underground rhizomes or roots of the plant are used for medicinal and food preparation. The rhizome is an underground stem that is thick and fleshy ringed with the bases of old leaves. Rhizomes are boiled and then dried and ground to make the distinctive bright yellow spice, turmeric.

Turmeric History:

Probably originating from India, turmeric has been used in India for at least 2500 years. It is most common in southern Asia and particularly in India. Turmeric was probably cultivated at first as a dye and later on it was used as cosmetic and as an auspicious and aromatic food substance. It possesses antiseptic, anti-inflammatory detoxifying properties as well as carminative properties. Turmeric has a long history of medicinal use in South Asia and was widely used in Ayurvedic, Siddha and Unani systems. It is thought to be a hybrid selection and vegetative propagation of wild turmeric (Curcuma aromatica), which is native to India, Sri Lanka and the eastern Himalayas and some other closely related species.

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Curcumin and Alzheimer's Disease

Worldwide, there are over 1000 published animal and human studies, both in vivo and in vitro in which the effects of curcumin on various diseases have been examined. Studies include epidemiological, basic and clinical research on AD.

Bio Chemical properties

Epidemiological Studies

Various studies and research[

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Destroy user interface control10] results indicate a lower incidence and prevalence of AD in India. The prevalence of AD among adults aged 70-79 years in India is 4.4 times less than that of adults aged 70-79 years in the United States.[

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Destroy user interface control9] Researchers investigated the association between the curry consumption and cognitive level in 1010 Asians between 60 and 93 years of age. The study found that those who occasionally ate curry (less than once a month) and often (more than once a month) performed better on a standard test (MMSE) of cognitive function than those who ate curry never or rarely.[

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Mechanism of action of curcumin on Alzheimer's disease:

The process through which AD degrades the nerve cells is believed to involve certain properties: inflammation, oxidative damage and most notably, the formation of beta-amyloid plaques, metal toxicity [Figure 3]. There have been several studies on effects of curcumin on AD. Outlined below are some of the studies and their conclusions.

Figure 3

Different mechanisms of action of curcumin in AD

Effects of Curcumin on Macrophages

A study conducted at UCLA found that curcumin may help the macrophages to clear the amyloid plaques found in Alzheimer's disease. Macrophages play an important role in the immune system. They help the body to fight against foreign proteins and then effectively clear them. Curcumin was treated with macrophages in blood taken from nine volunteers: six AD patients and three healthy controls. Beta amyloid was then introduced. The AD patients, whose macrophages were treated with curcumin, when compared with patients whose macrophages were not treated with curcumin, showed an improved uptake and ingestion of the plaques. Thus, curcumin may support the immune system to clear the amyloid protein.[

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Curcumin on glial cells:

Recent histological studies reveal the presence of activated microglia and reactive astrocytes around A-beta plaques in brains from patients with AD. The chronic activation of microglia secretes cytokines and some reactive substances that exacerbate A-beta pathology. So neuroglia is an important part in the pathogenesis of AD. Curcumin has a lipophilic property and can pass through all cell membranes and thus exerts its intracellular effects. Curcumin has anti-proliferative actions on microglia. A minimal dose of curcumin affects neuroglial proliferation and differentiation. Its inhibition of microglial proliferation and differentiation were studied and researched by the University of Southern California Los Angeles (UCLA). Researchers[

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Destroy user interface control12] using doses of 4, 5, 10, 15, 20 microM concentration of curcumin in C-6 rat glioma 2B-clone cells, a mixed colony of both neuroglial cells in a six- day trial, showed that curcumin dose dependently stops the proliferation of neuroglial cells, by differentiate into a mature cell or undergo apoptosis. It inhibits neuroglial cells proliferation dose dependently (i.e.) higher the concentration, the greater the inhibition. It has shown to decrease the glutamine synthetase (GS) assay, a marker enzyme for astrocytes. In the same study, curcumin was shown to increase CNP (2′3′- cyclic Nucleotide 3′-phosphohydrolase), a marker enzyme for oligodendrocytes. The overall effect of curcumin on neuroglial cells involves decreased astrocytes proliferation, improved myelogenesis and increased activity and differentiation of oligodendrocytes.

Curcumin as an Anti Inflammatory in Alzheimer's

One of the important pathogenesis in Alzheimer's disease is the chronic inflammation of nerve cells. Several studies have demonstrated the associated inflammatory changes such as microgliosis, astrocytosis and the presence of pro-inflammatory substances that accompany the deposition of amyloid-β (Aβ) peptide. Patients with the prolonged use of certain nonsteroidal anti-inflammatory (NSAID) drugs such as ibuprofen have been shown to have a reduced risk of developing the symptoms of AD; however, the chronic use of NSAID can cause a toxic effect on the kidneys, liver and GI track. Curcumin has a potent anti-inflammatory effect. Through its various anti-inflammatory effects, it may have a role in the cure of AD. Curcumin inhibits Aβ-induced expression of Egr-1 protein and Egr-1 DNA-binding activity in THP-1 monocytic cells. Studies have shown the role of Egr-1 in amyloid peptide-induced cytochemokine gene expression in monocytes. By inhibition of Egr-1 DNA-binding activity by curcumin, it reduces the inflammation. The chemotaxis of monocytes, which can occur in response to chemokines from activated microglia and astrocytes in the brain, can be decreased by curcumin.[

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Curcumin is found to inhibit cyclooxygenase (COX-2), phospholipases, transcription factor and enzymes involved in metabolizing the membrane phospholipids into prostaglandins. The reduction of the release of ROS by stimulated neutrophils, inhibition of AP-1 and NF-Kappa B inhibit the activation of the pro-inflammatory cytokines TNF (tumor necrosis factor)-alpha and IL (interleukin)-1 beta.[

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Destroy user interface control16] Overall, curcumin decreases the main chemical for inflammation and the transcription of inflammatory cytokines. Curcumin inhibits intracellular IL-12 p40/p70 and IL-12 p70 expression. The exposure to curcumin also impaired the production of pro-inflammatory cytokines (IL-1, IL-6 and TNF-). These studies indicate a potent inhibitor of pro-inflammatory cytokine production by curcumin and it may differ according to the nature of the target cells.

Curcumin as an Anti-oxidant

Curcumin inhibits the activity of AP-1, a transcription factor involved in expression of amyloid, which is linked to AD. Curcuminoids are proven to have strong antioxidant action demonstrated by the inhibition of the formation and propagation of free radicals. It decreases the low-density lipoprotein oxidation and the free radicals that cause the deterioration of neurons, not only in AD but also in other neuron degenerative disorders such as Huntington's and Parkinson's disease.[

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Destroy user interface control16] In one study, curcuma oil (500 mg Kg(-1) i.p.) was given 15 min before 2 h middle cerebral artery occlusion, followed by 24 h reflow in rats. This significantly diminished the infarct volume, improved neurological deficit and counteracted oxidative stress.[

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A study conducted at Nanjing Medical University (China) showed that a single injection of curcumin (1 and 2 mg/kg, i.v.) after focal cerebral ischemia/reperfusion in rats significantly diminished the infarct volume, improved neurological deficit, decreased mortality and reduced the water content in the brain.[

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Curcumin has powerful antioxidant and anti-inflammatory properties; according to the scientists, these properties believe help ease Alzheimer's symptoms caused by oxidation and inflammation.[

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Destroy user interface control19] A study conducted at Jawaharlal Nehru University (India) demonstrated that the administration of curcumin significantly reduced lipid peroxidation and lipofuscin accumulation that is normally increased with aging.[

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Destroy user interface control20] It also increased the activity of superoxide dismutase, sodium-potassium ATPase that normally decreased with aging. In another study, curcumin has been shown to protect the cells from betaA (1-42) insult through antioxidant pathway.[

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Destroy user interface control21] Curcumin protects brain mitochondria against various oxidative stress. Pre-treatment with curcumin protects brain mitochondria against peroxynitrite (a product of the reaction of nitric oxide with superoxide) a potent and versatile oxidant that can attack a wide range of cells in vitro by direct detoxification and in vivo by the elevation of total cellular glutathione levels.[

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Curcumin on Haemoxygenase Pathway

Natural antioxidant curcumin has been identified as a potent inducer of hemoxygenase, a protein that provides efficient cytoprotection against various forms of oxidative stress. By promoting the inactivation of Nrf2-keap1 complex and increased binding to no-1ARE, curcumin induces hemoxygenase activity. The incubation of astrocytes with curcumin at a concentration that promoted hemoxygenase activity resulted in an early increase in reduced glutathione, followed by a significant elevation in oxidized glutathione content.[

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Destroy user interface control25] Glutathione is an important water-phase antioxidant and essential cofactor for antioxidant enzymes protecting the mitochondria against endogenous oxygen radicals. Its level reflects the free radical scavenging capacity of the body. GSH depletion leads to tissue damage due to lipid peroxidation and oxidative damage.

Beta-Amyloid Plaques

The most prominent characteristic feature in AD is the presence of beta-amyloid plaques. These plaques are basically an accumulation of small fibers called beta amyloid fibrils. Because the deposition of beta-amyloid protein is a consistent pathological hallmark of brains affected by AD, the inhibition of A-beta generation, prevention of A-beta fibril formation, destabilization of pre-formed A-beta would be an attractive therapeutic strategy for the treatment of AD. The levels of beta-amyloid in AD mice that were given low doses of curcumin were decreased by around 40% in comparison to those that were not treated with curcumin. In addition, low doses of curcumin also caused a 43% decrease in the so-called “plaque burden” that these beta-amyloid have on the brains of AD mice. Surprisingly low doses of curcumin given over longer period were actually more effective than high doses in combating the neurodegenerative process of AD.[

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Destroy user interface control26] At higher concentration, curcumin binds to amyloid beta and blocks its self assembly. The key chemical features in amyloid beta are the presence of two aromatic end groups and any alterations in these groups has profound effect on its activity.

Because of the lipophilic nature of curcumin, it crosses the blood brain barrier and binds to plaques. Curcumin was a better A-beta 40 aggregation inhibitor and it destabilizes the A-beta polymer. In in vitro studies, curcumin inhibits aggregation as well as disaggregates to form fibrillar A-beta 40. A Japanese study showed that using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies, curcumin destabilizes the fA-beta(1-40) and fA-beta(1-42) as well as their extension.[

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Destroy user interface control27] Curcumin-derived isoxazoles and pyrazoles bind to the amyloid beta peptide (Abeta) and inhibit amyloid precursor protein (APP) metabolism.[

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Destroy user interface control28] Curcumin given to APPswe/PS1dE9 mice for 7 days crosses the blood-brain barrier as demonstrated by muliti-photon microscopy and reduces the existing senile plaques.[

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Destroy user interface control29] In another study, curcumin has been shown to increase the phagocytosis of amyloid-beta, effectively clearing them from the brains of patients with AD.[

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Metal Chelation

Studies showed that metals can induce A-beta aggregation and toxicity and are concentrated on Alzheimer's brain. Chelators' desferroxamine and cliquinol have exhibited anti-Alzheimer's effects. A study at Capital University Beijing demonstrated the toxicity of copper on neurons. A greater amount of H₂O₂ was released when copper (2)-A(beta)-40 complexes were added to the xanthene oxidase system. Copper was bound to A(beta)1-40 and was observed by electron paramagnetic resonance spectroscopy. In addition, copper chelators could cause a structural transition of A(beta). There was an increase on beta sheet as well as alpha-helix when copper was introduced.[

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Destroy user interface control31] Another study reveals that copper and zinc bind A-beta inducing aggregation and give rise to reactive oxygen species. There was a conformational change from beta sheet to alpha helix followed by peptide oligomerization and membrane penetration, when copper (or) zinc is added to A-beta in a negatively charged lipid environment.[

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Destroy user interface control32] Brain iron deregulation and its association with amyloid precursor protein plaque formation are implicated in the pathology of AD.[

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Curcumin, by interaction with heavy metals such as cadmium and lead, prevents neurotoxicity caused by these metals. The intraperitoneal injection of lead acetate in rats in the presence of curcumin was studied microscopically. The results show lead-induced damage to neurons was significantly reduced in rats injected with curcumin.[

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Destroy user interface control34] A study at Chinese University of Hong Kong showed that by using spectrophotometry, the curcumin effectively binds to copper, zinc and iron. In addition, curcumin binds more effectively with redox-active metals such as iron and copper than the redox-inactive zinc. It is suggested that curcumin suppresses inflammatory damage by preventing metal induction of NF-kappa.[

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Cholesterol Lowering Effect

High-fat diets and increased blood cholesterol are linked to increased amyloid plaques by the intracellular accumulation of cholestryl esters.[

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Destroy user interface control37] Researchers believe that by inhibiting cholesterol formation and decreasing serum peroxides, curcumin might exert beneficial effects on AD.[

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Safety

Oral bioavailability:

Curcumin has poor bioavailability. Because curcumin readily conjugated in the intestine and liver to form curcumin glucuronides.[

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Destroy user interface control39] In a clinical trial conducted in Taiwan, serum curcumin concentrations peaked one to two hours after an oral dose. Peak serum concentrations were 0.5, 0.6 and 1.8 micromoles/L at doses of 4, 6 and 8 g/day respectively.[

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Destroy user interface control40] It is also measured in urine at a dose of 3.6 g/day. Absorption is poor following ingestion in mice and rats. 38% to 75% of an ingested dose of curcumin is excreted in the feces. Absorption appears to be better with food. Curcumin crosses the blood brain barrier and is detected in CSF.

Side Effect

No apparent side effects have been reported thus far. GI upset, chest tightness, skin rashes, swollen skin are said to occur with high dose. A few cases of allergic contact dermatitis from curcumin have been reported.[

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The chronic use of curcumin can cause liver toxicity. For this reason, turmeric products should probably be avoided by individuals with liver disease, heavy drinkers and those who take prescription medications that are metabolized by liver. Curcumin was found to be pharmacologically safe in human clinical trials with doses up to 10 g/day. A phase 1 human trial with 25 subjects using up to 8000 mg of curcumin per day for three months found no toxicity from curcumin.[

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Interaction

Curcumin is said to interact with certain drugs such as blood thinning agents, NSAIDs, reserpin. Co-supplementation with 20 mg of piperine (extracted from black pepper) significantly increase the bioavailablity of curcumin by 2000%.[

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Contraindication

Curcumin is not recommended for persons with biliary tract obstruction because it stimulates bile secretion. It is also not recommended for people with gallstones, obstructive jaundice and acute biliary colic. Curcumin supplementation of 20-40 mg have been reported to increase gallbladder contractions in healthy people.[

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Human

Epidemiological studies have shown that prevalence of AD is 4.4 lower amongst Indian Asians as compared to people of western origin.[

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Destroy user interface control9] D ementia incidence in western countries (P < 0.21) and East Asian countries were lower than that of Europe (P < 0.0004).[

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Destroy user interface control49]

Experimental studies: Statistical significance

Clinical -Vivo: Blood from six patients with AD and three healthy controls was taken and the macrophage cells were isolated. After treatment of macrophages with curcuminoids, Aβ uptake by macrophages of three of the six AD patients was found to have significantly increased (P < 0.001 to 0.081).[

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Five animal and two human studies showed statistically significant P values.

Conclusion

Based on the main findings detailed above, curcumin will lead to a promising treatment for Alzheimer's disease. The clinically studied chemical properties of curcumin and its various effects on AD shows the possibility to do further research and develop better drugs based on curcumin for treating AD. The recent review paper of John Ringman also supports some of the abovementioned properties of curcumin in AD;[

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Destroy user interface control50] however, large-scale human studies are required to identify the prophylactic and therapeutic effect of curcumin.

Several unanswered questions remain: What is the one main chemical property of curcumin that can be exploited in treating AD? What is the role of curcumin in other neurological disorders such as Parkinson's, Huntington's and other dementias? How does curcumin interact with neuronal plaques? Is it effective only as a food additive? Would it be effective when used alone or with other anti inflammatory drugs?