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CS BrainSense

CS BrainSense is designed to provide a solid nutritional foundation to help your brain and body perform optimally.Brain- Powered by our proprietary CSTek™ mineral delivery technology combines each mineral with organic molecules. CSTek™ is intended to optimize mineral absorption and enable vital nutrients to cross the blood-brain barrier in order to support neuron structure and function*

Body-Delivers essential vitamins and minerals to fortify your body against chronic stress, anxiety, depression and brain cell degeneration.*

Balance-The level of each ingredient is calculated to maintain the natural ratios of nutrients in your body that are critical to promote optimal cognitive function, mental clarity, focus, and mood stability.*

Suggested Use:

For optimal results, take 4 capsules 3 times daily, or a level recommended by your health professional.* Also acceptable to begin with 1 capsule twice a day, then increase gradually. Take with food. Store in a cool, dry place. Do not use if tamper-evident seal is broken or missing.

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What Are Autoimmune Disorders?

bad and good bacteria

Immune system disorders cause abnormally low activity or over activity of the immune system. In cases of immune system over activity, the body attacks and damages its own tissues (autoimmune diseases). Immune deficiency diseases decrease the body’s ability to fight invaders, causing vulnerability to infections.

In response to an unknown trigger, the immune system may begin producing antibodies that instead of fighting infections, attack the body’s own tissues. Treatment for autoimmune diseases generally focuses on reducing immune system activity. Examples of autoimmune diseases include:

 

click on link to learn more about Gut health.     http://ltl.is/CPbvj

  • Systemic lupus erythematosus (lupus). People with lupus develop autoimmune antibodies that can attach to tissues throughout the body. The joints, lungs, blood cells, nerves, and kidneys are commonly affected in lupus. Treatment often requires daily oral prednisone, a steroid that reduces immune system function.

 

image of gut

 

 

 

 

  • Guillain-Barre syndrome. The immune system attacks the nerves controlling muscles in the legs and sometimes the arms and upper body. Weakness results, which can sometimes be severe. Filtering the blood with a procedure called plasmapheresis is the main treatment for Guillain-Barre syndrome.

 

  • Chronic inflammatory demyelinating polyneuropathy. Similar to Guillian-Barre, the immune system also attacks the nerves in CIDP, but symptoms last much longer. About 30% of patients can become confined to a wheelchair if not diagnosed and treated early. Treatment for CIDP and GBS are essentially the same.

gut & brain

 

  • Psoriasis. In psoriasis, overactive immune system blood cells called T-cells collect in the skin. The immune system activity stimulates skin cells to reproduce rapidly, producing silvery, scaly plaques on the skin.

 

 

  • Graves’ disease. The immune system produces antibodies that stimulate the thyroid gland to release excess amounts of thyroid hormone into the blood (hyperthyroidism). Symptoms of Graves’ disease can include bulging eyes as well as weight loss, nervousness, irritability, rapid heart rate, weakness, and brittle hair. Destruction or removal of the thyroid gland, using medicines or surgery, is usually required to treat Graves’ disease.

 

 

 

  • Hashimoto’s thyroiditis. Antibodies produced by the immune system attack the thyroid gland, slowly destroying the cells that produce thyroid hormone. Low levels of thyroid hormone develop (hypothyroidism), usually over months to years. Symptoms include fatigue, constipation, weight gain, depression, dry skin, and sensitivity to cold. Taking a daily oral synthetic thyroid hormone pill restores normal body functions.

progression

 

  • Myasthenia gravis. Antibodies bind to nerves and make them unable to stimulate muscles properly. Weakness that gets worse with activity is the main symptom of myasthenia gravis. Mestinon (pyridostigmine) is the main medicine used to treat myasthenia gravis.

 

 

  • Vasculitis. The immune system attacks and damages blood vessels in this group of autoimmune diseases. Vasculitis can affect any organ, so symptoms vary widely and can occur almost anywhere in the body. Treatment includes reducing immune system activity, usually with prednisone or another corticosteroid.

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7 Signs and Symptoms You Have Leaky Gut Syndrome.

Leaky gut - Dr. Axe If you’ve been around the natural health world very long, you’ve probably heard of a condition known as leaky gut syndrome. It sounds pretty gross, but it’s an important enough problem to consider. There are several leaky gut symptoms to be aware of, which is particularly important since leaky gut is associated with dozens of related conditions and diseases.As more Americans are affected by poor diet choices, chronic stress, toxic overload and bacterial imbalance, it appears that the prevalence of leaky gut has reached epidemic proportions. The medical profession is just now agreeing this condition may even exist, which is especially shocking to me because “intestinal permeability” (another name for leaky gut) has been discussed in the medical literature for over 100 years!

Why should leaky gut syndrome concern you? Recently leaky gut has been called a “danger signal for autoimmune disease.” (1) If you’re wondering if you may be experiencing leaky gut, the first thing to do is access your symptoms. Keep in mind that it’s very common for people on a Standard American Diet to struggle with poor gut function and high levels of inflammation — but just because digestive issues and autoimmune conditions are common doesn’t make them “normal”!

In this article, I’ve outlined a brief description of common leaky gut syndrome seen in people struggling with this condition. Can you heal leaky gut syndrome? As you’ll learn about below, there are four steps I recommend taking in order to repair leaky gut, which includes removing trigger foods from your diet, taking beneficial supplements and rebalancing your microflora with probiotics.


What Is Leaky Gut Syndrome?

The father of modern medicine, Hippocrates, said, “All disease begins in the gut.” More than two millennia after his death, scientific research has now proven he was onto something all those years ago. For over three decades, study after study has been published (several thousand articles exist to date) discussing our growing understanding of immunity, gut function and how modern diets and lifestyles negatively contribute to overall health by damaging our digestive system.

I (and many others in the medical field) refer to this particular phenomenon as leaky gut syndrome. In the medical literature, leaky gut is also referred to as “intestinal hyperpermeability.”

What Causes Leaky Gut?

The intestines are protected by a single layer of specialized epithelial cells that are linked together by tight junction (or TJ) proteins. Leaky gut symptoms are a consequence of intestinal tight-junction malfunction.

These tight junctionsare the gateway between your intestines and your bloodstream. They control what is allowed to pass into the bloodstream from your digestive system. More than 40 different TJ proteins have now been recognized to play a role in gut health. Tight junctions have a very precise job — they have to maintain the delicate balance between allowing vital nutrients to enter your bloodstream, while remaining small enough to prevent xenobiotics (disease-causing compounds from your diet or lifestyle) from passing out of your digestive system into the rest of your body. (1)

Here’s how a report published in the journal Frontiers in Immunologydescribes the pathology of leaky gut: (2)

The intestinal epithelial lining, together with factors secreted from it, forms a barrier that separates the host from the environment. In pathologic conditions, the permeability of the epithelial lining may be compromised allowing the passage of toxins, antigens, and bacteria in the lumen to enter the bloodstream creating a ‘leaky gut.’

When you have leaky gut, certain tiny particles that should never be able to enter your bloodstream start to make their way through. There’s also commonly abnormalities in the gut stemming from antimicrobial molecules, immunoglobulins and cytokine activities. This presents a major problem, as the vast majority of your immune system is found inside the gut.

The result? A disruption of acute inflammation, and sometimes autoimmune reactions. A normal part of your immune response that serves to fight infections and diseases winds up over-performing, leading to chronic inflammation, which is at the root of most diseases.

Some of the underlying causes of leaky gut include:

  • Genetic predisposition — certain people may be more predisposed to developing leaky gut because they are sensitive to environmental factors that “trigger” their bodies into initiating autoimmune responses.
  • Poor diet — especially a diet that includes allergens and inflammatory foods such as un-sprouted grains, added sugar, GMOs, refined oils, synthetic food additives and conventional dairy products.
  • Chronic stress
  • Toxin overload — including high drug and alcohol consumption. We come into contact with over 80,000 chemicals and toxins every single year, but the worst offenders for causing leaky gut include antibiotics, pesticides, tap water, aspirin and NSAIDS. I recommend buying a high-quality water filter to eliminate chlorine and fluoride and look to natural plant-based herbs to reduce inflammation in your body.
  • Bacterial imbalance — also called dysbiosis, which means an imbalance between beneficial and harmful species of bacteria in your gut. A large body of evidence now shows that gut microbiota is important in supporting the epithelial barrier and preventing autoimmune reactions. At least 10 percent of all gene transcriptions found in intestinal epithelial cells that are related to immunity, cell proliferation and metabolism are regulated by gut microbiota.

pre+probiotics pixies

 

How Serious Is Leaky Gut Syndrome?

Well, according to a 2014 review of the facts and research about intestinal permeability (among other sources), the chronic condition of hyperpermeability is linked to numerous symptoms and health conditions.

What are the symptoms of leaky gut? Some of the most prominent signs you may have leaky gut include: (3)

  • Gastric ulcers
  • Infectious diarrhea
  • Irritable Bowel Syndrome (IBS)
  • Inflammatory bowel diseases (Crohn’s, ulcerative colitis)
  • Small Intestine Bacterial Overgrowth (SIBO)
  • Celiac disease
  • Esophageal and colorectal cancer
  • Allergies
  • Respiratory infections
  • Acute inflammation conditions (sepsis, SIRS, multiple organ failure)
  • Chronic inflammatory conditions (such as arthritis)
  • Thyroid disorders
  • Obesity-related metabolic diseases (fatty liver, Type II diabetes, heart disease)
  • Autoimmune disease (lupus, multiple sclerosis, Type I diabetes, Hashimoto’s, and more) (4)
  • Parkinson’s disease (5)
  • Chronic fatigue syndrome (6)
  • Propensity towards weight gain or obesity (7)

While these diseases are linked to leaky gut syndrome, it hasn’t been proven that there is a causal relationship; in other words, it’s not yet established that leaky gut causes any of these conditions, just that people who have leaky gut are more likely to have a number of other health problems. So while the scientific evidence has not yet proven that intestinal hyperpermiability (leaky gut syndrome) is actually responsible for these conditions, it strongly suggests that leaky gut and other dysfunctions tend to occur simultaneously. (8)


7 Leaky Gut Symptoms and Signs

How do you know if you have leaky gut? Below you’ll find seven leaky gut symptoms and early occurring conditions that may point to an issue with your gut health.

1. Food Sensitivities

Because of the onslaught of toxins that enter the bloodstream, the immune systems of people with intestinal hyperpermeability are on overdrive mass-producing various antibodies, which may make their bodies more susceptible to antigens in certain foods (especially gluten and dairy). In studies involving rats and human children, leaky gut and food allergies have been linked. (9, 10) Allergies are believed to be one of the most common leaky gut symptoms.

2. Inflammatory Bowel Disease 

Researchers from Hungary uncovered in 2012 that elevated gut permeability is oftentimes localized to the colon in people suffering from irritable bowel syndrome and ulcerative colitis. (11) As far back as 1988, scientists suggested that Crohn’s disease may be more of a risk for people with leaky gut. (12)

A small study (observing 12 patients) discovered that zinc supplementation may help resolve the tight junction dysfunction in these cases, although more research is required on a larger scale to confirm these results. (13)

3. Autoimmune Disease

Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur.

Eating gluten may trigger this dangerous cascade. University of Maryland School of Medicine researchers have uncovered that gluten “activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.” (15)

The good news is that, at least as far as leaky gut plays a role in autoimmune conditions, it is reversible and could potentially alleviate some of these problematic immune responses. (16)

4. Thyroid Problems 

One of the autoimmune diseases that leaky gut syndrome may directly affect is Hashimoto’s disease. (17) Also known as “chronic thyroiditis,” this disorder is displayed with hypothyroidism (low thyroid function), impaired metabolism, fatigue, depression, weight gain and a host of other concerns.

5. Nutrient Malabsorption

In my own patients, I’ve observed various nutritional deficiencies resulting from leaky gut, including vitamin B12, magnesium and digestive enzymes. Those common nutrient deficiencies are one reason why many functional medicine practitioners prescribe a whole-food multivitamin in addition to probiotics for people suffering leaky gut problems.

6. Inflammatory Skin Conditions 

First described over 70 years ago, the gut-skin connection theory has described how intestinal hyperpermeability can cause a slew of skin conditions, particularly acne and psoriasis. (18) Creams and drugs with endless lists of (sometimes dangerous) side effects are often prescribed for these skin disorders, yet there has been evidence for several decades that part of the root cause might exist in the gut.

7. Mood Issues and Autism

According to a study published in the journal Neuroendocrinology Letters, leaky gut has been shown to cause various neurocognitive disorders. For example, the inflammatory response characteristic of intestinal hyperpermeability triggers the release of pro-inflammatory cytokines and other chemicals that are thought to induce depression. (19)

A study published in the journal Nutritional Neuroscience described the “vicious circle between immune system impairment and increasing dysbiosis that leads to leaky gut and neurochemical compounds and/or neurotoxic xenobiotics production and absorption.”

The authors go on to describe findings from a number of studies that point to their theory thatautism may be connected to problems in the gut microbiome, particularly within the first year of life. (20) It is actually a common hypothesis in modern science that leaky gut is strongly related to autism. (21)


What the Medical Community Has to Say About Leaky Gut Syndrome

Do most conventional doctors support the idea that leaky gut is real?

WebMD refers to leaky gut as “something of a medical mystery.”(22) This isn’t surprising, since it’s not a diagnosis that most doctors have been taught in medical school. “From an MD’s standpoint, it’s a very gray area,” says gastroenterologist Donald Kirby, MD – Director of the Center for Human Nutrition at the Cleveland Clinic. In his opinion, “Physicians don’t know enough about the gut, which is our biggest immune system organ.” (21)

To make matters worse, government agencies have also contributed to the confusion. According to the United Kingdom’s National Health Service (NHS), “There is currently little evidence to support the theory that a porous bowel is the direct cause of any significant, widespread problems.” (23)

Yet, not everyone agrees. A roundtable review quotes the researchers at seven different European universities in 2014 agreeing upon the following: (24)

Alteration of the gut barrier seems to have multiple consequences facilitating the onset of a variety of diseases depending on other hits and on genetic or epigenetic constellations, respectively. The growing significance of the gut barrier and bacterial translocation raises the questions of how we can improve gut barrier functions and gut microbiota.

So while it’s encouraging that science is coming around to leaky gut syndrome being a real problem, we are by no means at a point where there are standard diagnostic tools for testing and treating leaky gut.

In the Western/conventional medical world, if there are no standard diagnostic criteria for a disease, then there are no specific therapies or treatments available. Moreover, if there are no “proven” treatment models, then most MD’s are left with no other choice than to follow what they believe to be the “safe path” and prescribe drugs that only treat leaky gut symptoms. For example, medications (like proton pump inhibitors or antacids) can be used to manage symptoms like acid reflux medications but these drugs don’t solve the root problem.

Because much of the medical community denies leaky gut’s very existence, it’s critical that you understand what leaky gut is and what to look out for in case you or a loved one is affected by it. The good news is that many functional and integrative medicine practitioners have a greater understanding of this condition than they did even a decade ago. They are much more likely to help you determine if you are suffering from leaky gut syndrome and to give you tools to help repair your gut.


How Do You Get Rid of Leaky Gut?

Now that we’ve been talked about leaky gut symptoms, causes and opinions, let’s talk about how to test for and repair leaky gut.

How do you test for leaky gut?

Several leaky gut syndrome tests are available that can help confirm a diagnosis and point you in the right treatment direction. Tests are helpful for identifying specific sensitivities and uncovering which types of toxins or deficiencies are contributing to your symptoms. Leaky gut tests include:

  • Zonulin or Lactulose Tests
  • IgG Food Intolerance Test
  • Stools Tests
  • Organic Acid Vitamin and Mineral Deficiencies Tests
  • Lactulose Mannitol Test

What leaky gut treatments are available?

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After years of research and patient care, Avisae has developed a gut protocol process for helping to heal leaky gut. . If you’re concerned that you or a loved one may have leaky gut symptoms, I encourage you to read the detailed instructions, food suggestions and recommended leaky gut supplements listed in this article.

The basic steps to healing leaky gut are as follows:

  1. REMOVE foods and factors that damage the gut.
  2. REPLACE these with healing foods as you follow an anti-inflammatory leaky gut diet.
  3. REPAIR the gut with specific leaky gut supplements like butyric acid.
  4. REBALANCE your microbiome with probiotics (beneficial bacteria). This is key because bacteria in your gut are a major component of the intestinal barrier. They help promote resistance to the colonization of harmful or pathogenic bacteria species by competing for nutrients. Gut microbiota also regulate the digestion and absorption of nutrients and help supply epithelial cells with energy.
Two of the most commons questions people ask are: “What can I eat if I have leaky gut syndrome? And what should I NOT eat when I have leaky gut?”
If you’re struggling with leaky gut or other GI issues, remove processed foods— including un-sprouted grains, added sugar, GMO’s, refined oils, synthetic additives and conventional dairy products. A healing leaky gut syndrome diet includes foods like:
  • Bone broth
  • Raw cultured dairy (like kefir, yogurt, amasai, butter and raw cheeses)
  • Fermented vegetables and other probiotics foods. Probiotics may help reverse leaky gut by enhancing the production of tight junction proteins that defend against intestinal permeability.
  • Coconut products
  • Sprouted seeds (like chia seeds, flaxseeds and hemp seeds)
  • Foods with omega-3 fatty acids, especially salmon and other wild-caught fish
  • Herbs and spices
  • Other nutrient-dense, anti-inflammatory foods like grass-fed beef, lamb, other fresh veggies and most fruits, apple cider vinegar, sea veggies, and other superfoods

Final Thoughts on Leaky Gut Syndrome

image of gut

  • Leaky gut syndrome is classified by malfunction in the intestinal tight junctions in the digestive tract, allowing larger-than-usual particles to pass from the digestive system into the bloodstream. When this occurs, the balance of inflammatory immune responses is disrupted, leading to chronic inflammation and poor immunity.
  • Although no causal relationships have yet been officially established, leaky gut is correlated with a large number of issues and diseases, including digestive disorders, depression, autism, celiac disease, autoimmune disease and more.
  • Common leaky gut symptoms include: food sensitivities, digestive issues, autoimmune disease, thyroid dysfunction, nutrient malabsorption, inflammatory skin conditions and brain-related issues such as depression and autism.
  • Leaky gut syndrome is not a recognized diagnosis in the medical community yet — but I’m confident it will be recognized someday, due to the vast body of research that has already been conducted.
  • If you suffer from any leaky gut symptoms, I encourage you to consult with your naturopathic doctor about options for treatment. Many of my patients have seen improvements when adjusting to a healing diet, rather than a disease and inflammation-causing one. In addition, there are helpful dietary supplements many people implement to support better gut health.

 

Depression: It’s Your Serotonin.

“Depression is a serious medical condition that may be due to a chemical imbalance, and Bliss adaptogen mist works to correct this imbalance.”

Bliss_1ozBostonRound

Herein lies the Serotonin Myth

As one of only two countries in the world that permits direct to consumer advertising, you have undoubtedly been subjected to promotion of the “cause of depression.” A cause that is not your fault, but rather, a matter of too few little bubbles passing between the hubs in your brain! Don’t add that to your list of worries, though, because there is a convenient solution awaiting you at your doctor’s office.

What if I told you that, in six decades of research, the serotonin (or norepinephrine, or dopamine) theory of depression and anxiety has not achieved scientific credibility.

You’d want some supporting arguments for this shocking claim, so here you go:

The Science of Psychiatry?

Rather than some embarrassingly reductionist, one-deficiency-one-illness-one-pill model of mental illness, contemporary exploration of human behavior has demonstrated that we may know less than we ever thought we did.  And that what we do know about root causes of mental illness seems to have more to do with the concept of evolutionary mismatch than with genes and chemical deficiencies.

In fact, a meta-analysis of over 14,000 patients and Dr. Insel, head of the NIMH, had this to say:

“Despite high expectations, neither genomics nor imaging has yet impacted the diagnosis or treatment of the 45 million Americans with serious or moderate mental illness each year.”

To understand what imbalance is, we must know what balance looks like, and neuroscience, to date, has not characterized the optimal brain state, nor how to even assess for it. In a review of serotonin theories of depression, Andrews et al. turn the paradigm on its head and conclude:

we propose that depressed states are high serotonin phenomena, which challenges the prominent role the low serotonin hypothesis continues to have in depression research (Albert et al., 2012). We also propose that the direct serotonin-enhancing effects of antidepressants disturb energy homeostasis and worsen symptoms. We argue that symptom reduction, which only occurs over chronic treatment, is attributable to the compensatory responses of the brain attempting to restore energy homeostasis.

In this paper, they work to deconstruct our indoctrination around serotonin as a “happy chemical”, and elucidate its complex role in redirecting energy production when a creature is under duress. It is only when we perturb the system with medication that the body’s response can sometimes result in a chemically adaptive state, that is temporary, at best (accounting for relapse rates, while on medication, of up to 60%). Even this analysis is a theoretical offering in the service of challenging the dominant paradigm.

A New England Journal of Medicinereview on Major Depression, stated:

” … numerous studies of norepinephrine and serotonin metabolites in plasma, urine, and cerebrospinal fluid as well as postmortem studies of the brains of patients with depression, have yet to identify the purported deficiency reliably.”

The data has poked holes in the theory and even the field of psychiatry itself is putting down it’s sword. One of my favorite essays by Lacasse and Leo has compiled sentiments from influential thinkers in the field – mind you, these are conventional clinicians and researchers in mainstream practice – who have broken rank, casting doubt on the entirety of what psychiatry has to offer around antidepressants:

ItsNotSerotonin-3

 

Depression is Not About Low Serotonin

In the 1950s, reserpine, initially introduced to the US market as an anti-seizure medication, was noted to deplete brain serotonin stores in subjects, with resultant lethargy and sedation. These observations colluded with the clinical note that an anti-tuberculosis medication, iproniazid, invoked mood changes after five months of treatment in 70% of a 17 patient cohort. Finally, Dr. Joseph Schildkraut threw fairy dust on these mumbles and grumbles in 1965 with his hypothetical manifesto entitled “The Catecholamine Hypothesis of Affective Disorders” stating:

“At best, drug-induced affective disturbances can only be considered models of the natural disorders, while it remains to be demonstrated that the behavioral changes produced by these drugs have any relation to naturally occurring biochemical abnormalities which might be associated with the illness.”

Contextualized by the ripeness of a field struggling to establish biomedical legitimacy (beyond the therapeutic lobotomy!), psychiatry was ready for a rebranding, and the pharmaceutical industry was all too happy to partner in the effort.

Of course, the risk inherent in “working backwards” in this way (noting effects and presuming mechanisms) is that we tell ourselves that we have learned something about the body, when in fact, all we have learned is that patented synthesized chemicals have effects on our behavior. This is referred to as the drug-based model by Dr. Joanna Moncrieff. In this model, we acknowledge that antidepressants have effects, but that these effects, in no way are curative or reparative.

The most applicable analogy is that of the woman with social phobia who finds that drinking two cocktails eases her symptoms. One could imagine, how, in a 6 week randomized trial, this “treatment” could be found efficacious and recommended for daily use and even prevention of symptoms. How her withdrawal symptoms after 10 years of daily compliance could lead those around her to believe that she “needed” the alcohol to correct an imbalance. This analogy is all too close to the truth.

No Intervention Creates Better Outcomes

Psychiatrist Dr. Daniel Carlat has said: “And where there is a scientific vacuum, drug companies are happy to insert a marketing message and call it science. As a result, psychiatry has become a proving ground for outrageous manipulations of science in the service of profit.”

So, what happens when we let drug companies tell doctors what science is? We have an industry and a profession working together to maintain a house of cards theory in the face of contradictory evidence.

We have a global situation in which increases in prescribing are resulting in increases in severity of illness (including numbers and length of episodes) relative to those who have never been treated with medication.

To truly appreciate the breadth of evidence that states antidepressants are ineffective and unsafe, we have to get behind the walls that the pharmaceutical companies erect. We have to unearth unpublished data, data that they were hoping to keep in the dusty catacombs.

A now famous 2008 study in the New England Journal of Medicine by Turner et al sought to expose the extent of this data manipulation. They demonstrated that, from 1987 to 2004, 12 antidepressants were approved based on 74 studies. Thirty-eight were positive, and 37 of these were published.  Thirty-six were negative (showing no benefit), and 3 of these were published as such while 11 were published with a positive spin (always read the data not the author’s conclusion!), and 22 were unpublished.

In 1998 tour de force, Dr. Irving Kirsch, an expert on the placebo effect, published a metaanalysis of 3,000 patients who were treated with antidepressants, psychotherapy, placebo, or no treatment and found that only 27% of the therapeutic response was attributable to the drug’s action.

This was followed up by a 2008 review, which invoked the Freedom of Information Act to obtain access to unpublished studies, finding that, when these were included, antidepressants outperformed placebo in only 20 of 46 trials (less than half!), and that the overall difference between drugs and placebos was 1.7 points on the 52 point Hamilton Scale.  This small increment is clinically insignificant, and likely accounted for by medication side effects strategically employed (sedation or activation).

When active placebos were used, the Cochrane database found that differences between drugs and placebos disappeared, given credence to the assertion that inert placebos inflate perceived drug effects.

The finding of tremendous placebo effect in the treatment groups was also echoed in two different meta-analysis by Khan et al who found a 10% difference between placebo and antidepressant efficacy, and comparable suicide rates. The most recent trial examining the role of “expectancy” or belief in antidepressant effect, found that patients lost their perceived benefit if they believed that they might be getting a sugar pill even if they were continued on their formerly effective treatment dose of Prozac.

The largest, non-industry funded study, costing the public $35 million dollars, followed 4000 patients treated with Celexa (not blinded, so they knew what they were getting), and found that half of them improved at 8 weeks. Those that didn’t were switched to Wellbutrin, Effexor, or Zoloft OR “augmented” with Buspar or Wellbutrin.

Guess what? It didn’t matter what was done, because they remitted at the same unimpressive rate of 18-30% regardless with only 3% of patients were in remission at 12 months.

How could it be that medications like Wellbutrin, which purportedly primarily disrupt dopamine signaling, and medications like Stablon which theoretically enhances the reuptake of serotonin both work to resolve this underlying imbalance? Why would thyroid, benzodiazepines, beta blockers, and opiates also “work”? And what does depression have in common with panic disorder, phobias, OCD, eating disorders, and social anxiety that all of these diagnoses would warrant the same exact chemical fix?

Are There Alternative Options?

As a holistic clinician, one of my bigger pet peeves is the use of amino acids and other nutraceuticals with  “serotonin-boosting” claims. These integrative practitioners have taken a page from the allopathic playbook and are seeking to copy-cat what they perceive antidepressants to be doing.

The foundational “data” for the modern serotonin theory of mood utilizes tryptophan depletion methods which involve feeding volunteers amino acid mixtures without tryptophan and are rife with complicated interpretations.

Simply put, there has never been a study that demonstrates that this intervention causes mood changes in any patients who have not been treated with antidepressants.

In an important paper entitled Mechanism of acute tryptophan depletion:is it only serotonin?, van Donkelaar et al caution clinicians and researchers about the interpretation of tryptophan research. They clarify that there are many potential effects of this methodology, stating:

In general, several findings support the fact that depression may not be caused solely by an abnormality of 5-HT function, but more likely by a dysfunction of other systems or brain regions modulated by 5-HT or interacting with its dietary precursor. Similarly, the ATD method does not seem to challenge the 5-HT system per se, but rather triggers 5HT-mediated adverse events.

Andrews goes further to include this interpretation in a long list of arguments against the role of low serotonin in depression (Box 1).

Screen Shot 2015-02-25 at 8.23.06 AM So if we cannot confirm the role of serotonin in mood and we have good reason to believe that antidepressant effect is largely based on belief, then why are we trying to “boost serotonin”?

Why Your Prescription Never Expires

All you have to do is spend a few minutes on http://survivingantidepressants.org/ or http://beyondmeds.com/ to appreciate that we have created a monster. Millions of men, women, and children, the world over are suffering, without clinical guidance (because this is NOT a part of medical training) to discontinue psychiatric meds. I have been humbled, as a clinician who seeks to help these patients, by what these medications are capable of. Psychotropic withdrawal can make alcohol and heroin detox look like a breeze.

An important analysis by the former director of the NIMH makes claims that antidepressants “create perturbations in neurotransmitter functions” causing the body to compensate through a series of adaptations which occur after “chronic administration” leading to brains that function, after a few weeks, in a way that is “qualitatively as well as quantitatively different from the normal state.”

Changes in beta-adrenergic receptor density, serotonin autoreceptor sensitivity, and serotonin turnover all struggle to compensate for the assault of the medication.

Andrews calls this “oppositional tolerance,” and demonstrate through a careful meta-analysis of 46 studies demonstrating that patient’s risk of relapse is directly proportionate to how “perturbing” the medication is, and is always higher than placebo (44.6% vs 24.7%). They challenge the notion that findings of decreased relapse on continued medication represent anything other than drug-induced response to discontinuation of a substance to which the body has developed tolerance. They go a step further to add:

“For instance, in naturalistic studies, unmedicated patients have much shorter episodes, and better long-term prospects, than medicated patients. Several of these studies have found that the average duration of an untreated episode of major depression is 12–13 weeks.”

Harvardresearchers also concluded that at least fifty percent of drug-withdrawn patients relapsed within 14 months. In fact:

“Long-term antidepressant use may bedepressogenic . . . it is possible that antidepressant agents modify the hardwiring of neuronal synapses (which) not only render antidepressants ineffective but also induce a resident, refractory depressive state.”

So, when your doctor says, “You see, look how sick you are, you shouldn’t have stopped that medication,” you should know that the data suggests that your symptoms are withdrawal, not relapse.

Longitudinal studies demonstrate poor functional outcomes for those treated with 60% of patients still meeting diagnostic criteria at one year (despite transient improvement within the first 3 months). When baseline severity is controlled for, two prospective studies support a worse outcome in those prescribed medication:

One in which the never-medicated group experienced a 62% improvement by six months, whereas the drug-treated patients experienced only a 33% reduction in symptoms, and another WHO study of depressed patients in 15 cities which found that, at the end of one year, those who weren’t exposed to psychotropic medications enjoyed much better “general health;” that their depressive symptoms were much milder;” and that they were less likely to still be “mentally ill.”

I’m not done yet.

In a retrospective 10-year study in the Netherlands, 76% of those with unmedicated depression recovered without relapse relative to 50% of those treated.

Unlike the mess of contradictory studies around short-term effects, there are no comparable studies that show a better outcome in those prescribed antidepressants long term.

First Do No Harm

So, we have a half-baked theory in a vacuum of science that that pharmaceutical industry raced to fill. We have the illusion of short-term efficacy and assumptions about long-term safety. But are these medications actually killing people?

The answer is yes.

Unequivocally, antidepressants cause suicidal and homicidal behavior. The Russian Roulette of patients vulnerable to these “side effects” is only beginning to be elucidated and may have something to do with genetic variants around metabolism of these chemicals.  Dr. David Healy has worked tirelessly to expose the data that implicates antidepressants in suicidality and violence, maintaining a database for reporting, writing, and lecturing about cases of medication-induced death that could make your soul wince.

What about our most vulnerable?

I have countless patients in my practice who report new onset of suicidal ideation within weeks of starting an antidepressant. In a population where there are only 2 randomized trials, I have grave concerns about postpartum women who are treated with antidepressants before more benign and effective interventions such as dietary modification and thyroid treatment. Hold your heart as you read through thesereports of women who took their own and their children’s’ lives while treated with medications.

Then there is the use of these medications in children as young as 2 years old. How did we ever get the idea that this was a safe and effective treatment for this demographic? Look no further than data like Study 329, which cost Glaxo Smith Klein 3 billion dollars for their efforts to promote antidepressants to children. These efforts required ghost-written and manipulated data that suppressed a signal of suicidality, falsely represented Paxil as outperforming placebo, and contributes to an irrepressible mountainofharm done to our children by the field of psychiatry.

RIP Monoamine Theory

As Moncrieff and Cohen so succinctly state:

“Our analysis indicates that there are no specific antidepressant drugs, that most of the short-term effects of antidepressants are shared by many other drugs, and that long-term drug treatment with antidepressants or any other drugs has not been shown to lead to long-term elevation of mood. We suggest that the term “antidepressant” should be abandoned.”

So, where do we turn?

The field of psychoneuroimmunology dominates the research as an iconic example of how medicine must surpass its own simplistic boundaries if we are going to begin to chip away at the some 50% of Americans who will struggle with mood symptoms, and 11% of whom will be medicated for it.

There are times in our evolution as a cultural species that we need to unlearn what we think we know. We have to move out of the comfort of certainty and into the freeing light of uncertainty. It is from this space of acknowledged unknowing that we can truly grow. From my vantage point, this growth will encompass a sense of wonder – both a curiosity about what symptoms of mental illness may be telling us about our physiology and spirit, as well as a sense of humbled awe at all that we do not yet have the tools to appreciate. For this reason, honoring our co-evolution with the natural world, and sending the body a signal of safety through movement, diet, meditation, and environmental detoxification represents our most primal and most powerful tool for healing.

 

 

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Neutron Analysis on Glaucoma Drugs Offers Clues for Cancer Targets

Glaucoma Drugs Offers Clues About Enzyme Targets for Aggressive Cancers

New insights from neutron analysis of glaucoma drugs and their enzyme target may help scientists design drugs that more effectively target aggressive cancers.

A team of researchers led by the Department of Energy’s Oak Ridge National Laboratory used neutron macromolecular crystallography to investigate the different states of three glaucoma drugs as they interact with the targeted enzyme, human carbonic anhydrase II (hCA II).

“Our goal was to observe differences in the presentation of three clinically used glaucoma drugs while they are bound to the hCA II enzyme,” said Andrey Kovalevsky, an instrument scientist at ORNL and a senior co-author of the study. “By looking at how well these drugs target hCA II in protonated, neutral and deprotonated states, we hoped to obtain insights that would make it possible to improve these medicines so they can better target enzymes linked to cancer.”

Protonation refers to the presence, addition or loss of a proton, which gives the drug a neutral, positive or negative charge, respectively. Altering a drug’s charge could change its ability to recognize and bind with its target protein and consequently, its effectiveness.

The study, published in the journal Structure, found that temperature, pH, and the electrical charge of the three glaucoma drugs affected their ability to target and bind with the hCA II enzyme.

“This discovery was really a proof of principle for us,” said Robert McKenna, a professor at the University of Florida and a senior co-author of the study. “It opened our eyes to how changes in temperature and pH can impact the protonation state of the drug, which in turn makes it more or less effective.”

New information about the hydrogen-bonding networks that make up the active site of hCA II may help other scientists develop new and better drugs for cancer treatment. The family of hCA enzymes contains similar proteins, such as hCA IX and XII, that are associated with aggressive breast cancers, such as triple negative breast cancer.

3D Structures of Brinzolamide and Dorzolamide

“We want to exploit the difference in charge, pH and temperature to see if we can design drugs that are more effective at targeting these enzymes,” said Kovalevsky. “If we can understand binding at the atomic level, we can redesign drugs and turn them into stronger and more selective ‘magnets’ that will be attracted to cancer-associated enzymes. Such drugs would be much more effective at killing cancer cells while leaving healthy cells unhurt, which significantly reduces side effects for patients.”

Many scientists have used X-ray crystallography to analyze the structures of hCA enymes, but these studies lack complete atomic information on drug binding because of X-rays’ inability to visualize hydrogen atoms abundant in proteins and enzymes.

Neutrons are sensitive to lighter elements, so they provide much more detailed information on the location of hydrogen atoms. Seeing hydrogen is critical to studying protonation states of an enzyme and ligand–a molecule that binds to a biological macromolecule–and to analyzing the architecture of hydrogen-bonding networks. Neutrons also offer other experimental advantages.

“When you use neutron diffraction you don’t have radiation damage, so you can do your study at room temperature,” said McKenna. “In addition, freezing crystals may alter the drug and enzyme, introducing a false view into the study, while room temperature studies more closely resemble the environment the drug will be used in.”

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Success That Lasts

Pursuing success can feel like shooting in a landscape of moving targets: Every time you hit one, five more pop up from another direction. We are under constant pressure to do more, get more, be more. But is that really what success is all…more

A 55-year-old, highly successful venture capitalistis thinking about his next investment. He’s not certain he has the energy to start another seven-year round of intense financing and consulting activity. “I just can’t imagine enjoying that pace again, and frankly, it’s time I paid attention to my family. But I’d really feel a loser if I didn’t play the game as hard as everyone else. I guess I should retire.”

The president of a $1 billion divisionof a consumer products company discovers that manufacturing and distribution bugs will delay the scheduled rollout of a new product line. Retailers are eager for the product, pressures on share price are intense, and the president’s bonus is tied to the rollout’s success. If he goes ahead, the product is sure to be on top – but only temporarily. The costs down the road from disappointed consumers and time invested in having to fix mistakes will clearly hurt the bottom line. What is success under these circumstances?

A fast-track 32-year-old software engineerwith a second degree in sacred music feels that something is missing in her career strategy. She wants the lifestyle of a well-paid manager, but software doesn’t feel as socially significant as playing the organ for a congregation. And she someday wants a house and a family. “Why can’t I find the career path that will get me all of these things?” she wonders. “Are they really so unreasonable?”

Different as these examples may be, these individuals have a similar problem: They all need a comprehensive framework for thinking about success. And they’re far from alone.

Survey after survey shows a high degree of job dissatisfaction and burnout among the general working population, even among those with plenty of options. In the collective soul-searching prompted by September 11, 2001, many high achievers revisited their notion of success. The wave of corporate scandals that followed soon after only made the questions more acute. Even the most dedicated employees wondered aloud whether they would ever recommend their own careers and companies to their children.

Pursuing success is like shooting at a series of moving targets. Every time you hit one, five more pop up from another direction. Just when we’ve achieved one goal, we feel pressure to work harder to earn more money, exert more effort, possess more toys. Standards and examples of “making it” constantly shift, while a fast-paced world of technological and social change constantly poses new obstacles to overcome.

During the past decade, traditional career paths suddenly became pointless. Professionals found themselves overworked and undersatisfied in the boom, then overworked and competitively vulnerable in the bust. And far too many businesses discovered they were using the wrong measures to gauge success, winning big in the 1990s only to lose big for their shareholders and employees at the turn of the millennium. The climb to success can feel like an Escher drawing of a staircase that goes nowhere.

In the face of such instability, many people assume success requires a winner-takes-all approach. They believe that success depends on putting all your energy into achieving one goal, be it a single-minded focus on your job or a commitment to being the best soccer mom in your community. But no matter how noble, one goal can’t satisfy all of a person’s complex needs and desires, as the examples at the beginning of the article demonstrate. The same holds true for the goals of a business.

Fortunately, success doesn’t have to be seen as a one-dimensional tug-of-war between achievement and happiness. If developed in the right way, your ideals of the good life for yourself and society can become powerful—and manageable—factors of success. We studied hundreds of high achievers who realize lasting success, make a positive difference, and enjoy the process. And we learned that some of the most successful people have gotten where they are precisely because they have a greater understanding of what success is really about and the versatility to make good on their ideals. In this article, we’ll introduce a practical framework that will help you see success in these same terms. But first, a closer examination of how we arrived at this model.

What Is Enduring Success?

Our research took a fresh look at the assumptions behind success. We were interested in real, enduring success—where getting what you want has rewards that are sustainable for you and those you care about. This type of attainment delivers a sense of legitimacy and importance; its satisfactions endure far beyond the momentary rewards of a bonus or a new position. Lasting success is emotionally renewing, not anxiety provoking.

Unlike an equation for a successful market strategy, no one person or company can fully embody lasting success for others. Everyone (and every business) has a unique vision of real success, and that notion changes over time. A family-oriented person would hardly call the absentee life of a top executive a success but might find travel and adventure just the ticket after the kids grow up. A born investment banker would hardly regard mixing cement as a successful career, whereas a construction worker who just completed an extraordinary bridge might point to the structure with pride for the rest of his or her life. No one, however, has unreserved success, not even the most obvious winner. Recognizing how important it is for each person to understand and develop his or her unique definition of success over time, we chose not to report on one or two well-known examples of success as the perfect model to follow.

Nonetheless, for the purposes of research, we posited five common characteristics of individuals who by most standards had achieved enduring success: high achievement, multiple goals, the ability to experience pleasure, the ability to create positive relationships, and a value on accomplishments that endure.

We held more than 60 interviews with successful professionals, surveyed 90 top executives attending Harvard Business School management programs, and informally observed high achievers with whom we live and work. We conducted more than a dozen model-testing sessions with between 50 and 110 executives in each. Most of these groups were drawn from HBS graduates or current members of the Young Presidents’ Organization. We also reviewed the problems that the general population has reported about success, using sources that ranged from media reports to conversations with friends, students, and colleagues. We talked to people from all different walks of life, at every level of the economy, both in and out of business careers. Some of them were stay-at-home parents who had once worked full time; others were at the pinnacle of their careers.

The Complexity of Success

Success involves more than a heart-pounding race to the finish line. Our research uncovered four irreducible components of enduring success: happiness (feelings of pleasure or contentment about your life); achievement (accomplishments that compare favorably against similar goals others have strived for); significance (the sense that you’ve made a positive impact on people you care about); and legacy (a way to establish your values or accomplishments so as to help others find future success).

These four categories form the basic structure of what people try to gain through the pursuit and enjoyment of success. Take away any one component, and it no longer feels like “real” success. If you were wildly wealthy because you had mastered a certain business problem but couldn’t experience pleasure, for instance, would you consider yourself successful? If building your power base kept you from being there for others, would your success feel morally right? If you left your career to be a full-time parent, would you have enough of an outlet for your talents? Just as a steady diet of the same four foods would hardly be satisfying over the long term, the four components of success cannot be satisfied by the presence of a single flavor in each category. That is why you cannot neatly categorize the realms of your life, assigning happiness to self, achievement to work, significance to family, legacy to community.

Unless you hit on all four categories with regularity, any one win will fail to satisfy. You’ll experience what we call the “wince factor”: You know you’re doing what is right, but it still feels like a loss. You’re preoccupied with thoughts of the other things you could be doing or getting. Your achievements and pleasures fade almost as soon as they occur. By contrast, success that encompasses all four kinds of accomplishment is enriching; it endures. You can create this synergy within a single event, but you can also create it through a juxtaposition of activities. Taking time out in the middle of a high-stress period or stopping to give back to the community while in the midst of pursuing your most self-advancing goals are good examples of this.

If you think about what constitutes a moment of lasting satisfaction in your own life—maybe it’s your daily practice of a musical instrument—it may be surprisingly trivial in comparison with your major commitments at work or at home. The activity draws force from accomplishing something distinctive in each of the four categories over time. The musical instrument provides release and pleasure (happiness), it is a challenge to master and build on (achievement), and it becomes even more fulfilling when you join a band that competes with other bands or play concerts at hospitals (significance). Those who also turn these “lesser” vocations into legacies that build the same opportunity for the next generation—say, through getting involved in recruiting and training younger musicians—will find an even deeper sense of success from so-called hobbies.

Anyone who takes the four elements of success seriously soon realizes how complicated it can be to touch on all four with regularity. As you scale up your goals, the four-part mix becomes more difficult to achieve. Each factor has a different set of characteristics. Satisfying different needs, they draw on distinctive emotional drives and prioritize self and others in different ways. That’s why people who tell you that happiness, achievement, and significance will come automatically if you simply do the work you love are misguided. Regardless of how much you care about your job, you will still feel conflicting desires—between work and home, between working forever on a problem and taking a break from it, between going for more market share today and investing in the company’s needs for tomorrow. The skills you use to compete are totally different from those you employ in moments of enjoyment. You can be there for a friend, and you can care about a customer, but these acts (in the significance category) can’t be substituted for the kind of thinking and prioritization that is necessary to structure favorable financial terms for your own firm (in the achievement category).

People who tell you that happiness, achievement, and significance will come automatically if you simply do the work you love are misguided.

Understanding the distinctive features of the four areas of success can help you articulate what you are seeking in a certain activity. You can then create a diagnostic for determining how to achieve the most appropriate goal. You may be expecting too many categories to be fulfilled without incorporating the right resources and perspectives, or you may be falling prey to a mismatch.

Matching your expectations to the right category is a critical skill for achieving sustainable success. If you expect happiness to come primarily from competition (an achievement skill), you’ll probably turn into someone neither you nor those around you can tolerate—and wonder why success has made you so lonely. People who report having trouble defining the right goals for themselves or for their companies are often caught in such mismatches. For instance, a self-described family-friendly company might hold critical staff meetings over late dinners or during extended weekend retreats.

The act of categorizing in and of itself can help you take more decisive action and channel the right emotions and perspectives to the task at hand. You can stop measuring a job only by how happy it makes you or calculating a business success only in terms of your ability to achieve mastery over something. Instead, you’ll see how one task fits into a larger context. By the same token, you’ll be able to anticipate what kind of emotional capital you’ll need to bring to a task. If you try to bring feelings of happiness or contentment to your achievement goals, you’ll stunt your performance from the start. If you don’t put achievement in its place, however, you’ll trap yourself in a workaholic restlessness.

Those in our research who achieved satisfying, enduring, multidimensional success consciously went after victories in all four categories without losing touch with their values and special talents. They seemed to understand intuitively the paradox we uncovered at the heart of enduring success: To get to more wins on the various important measures that make up your notion of the good life, success has to rest on a paradigm of limitation in any one activity for the sake of the whole. Or, as we call it, “on the reasoned pursuit of just enough.”

This principle flies in the face of the popular opinion that success is all about breaking through limitations, that it’s about having more, being more, doing more. Our research shows that the high-powered people who experienced real satisfaction achieved it through the deliberate imposition of limits. They all shared a versatile talent that we call “switching and linking”: They were able to focus intensely on one task until it gave them a particular sense of satisfaction, then put it down and jump to the next category with a feeling of accomplishment and renewed energy. This versatile refocusing could occur within the same activity (say, when you base your product strategy on accomplishing your profit goal and on caring for the customer), or it can involve switching attention between two realms (taking a break from work to joke with a friend).

The people in our research who were particularly skilled at sifting through the moving targets and going after only those that would produce lasting rewards shared two characteristics. First, they viewed success as a broad and dynamic experience of accomplishment, one that factored in all four categories. They didn’t attribute their success to one single event or even one single realm of life. Second, their concrete examples of what counted as “real” success included accomplishments of wildly varying magnitude. They weren’t setting maximum goals for themselves in each category; rather, they set some at a small scale and some at a scale that demanded sustained effort. The baseline for these individuals wasn’t the amount of activity or number of rewards in any one category, but the securing of a proportionate mix of all four. Anyone can learn to do this; you just need to have a larger framework in which to understand the dynamics of the four categories.

The Kaleidoscope Strategy

We compare an effective success strategy to a kaleidoscope—that simple mechanical device with a lens, mirror, and a long tube housing separate chambers. Each chamber holds pieces of glass that constantly shift as the tube is moved. Although the chambers are separate, the eye sees one unique picture made up of the various chambers. Mirrors reflect the entire set of glass chips and enhance the complexity of the pattern. The beauty of that pattern comes from the variety and symmetry of the design. Although the patterns in a kaleidoscope are inherently unstable, changed by your own movements or by outside forces, the pieces provide ongoing satisfaction as they take their places within new patterns.

Now imagine a slightly different kind of kaleidoscope, one that is your own vision of a successful life. This kaleidoscope also has four chambers—happiness, achievement, significance, and legacy—and you can add brilliant glass pieces (goals sought and fulfilled) over a lifetime, making your unique pattern richer and richer. In this metaphor, success is about choice, movement, pattern, and a structure that holds all the separate activities together. And, just like a kaleidoscope, you have to hold this pattern up to the light. By regularly assessing the picture you are creating in all four chambers, you can quickly spot “holes”—places you feel require more attention—in your activities and be assured that you are justified in interrupting other work to attend to them. The rest of the chips will be enough for the moment, but not enough for the rest of your life.

Success is about choice, movement, pattern, and a structure that holds all the separate activities together.

Through our research, we discovered that the people who achieve enduring success rely on a kaleidoscope strategy to structure their aspirations. Not only do they continually create new chips in each of the four categories, but they also choose their actions so that the whole picture will display a pleasing proportionality. Feeling deep satisfaction in each category strengthens these achievers’ ability to turn away from one category when another needs attention. It allows them to say, “I don’t need to work away at this particular thing until I’m satiated and hate the very sight of it. This is just enough.” They recognize the importance of setting their own standards for “enough” and not falling prey to the lure of the infinite “more.”

This is exactly the kind of thinking you see in good leaders: They anticipate what will be needed in all four dimensions of success despite pressures to deliver to the maximum in one. This is what the subjects in the three examples at the beginning of this article were lacking. They had no framework in which to identify and sort multiple desires so that they could go after their conflicting goals sequentially in a proportionate mix.

The burned-out venture capitalist needs to understand that scaling back his achievement goals is part of a larger picture of expansion in the other categories, rather than a paralyzing prospect of loss and “doing nothing.” This kaleidoscope view will allow him space to cultivate the emotional relationships he craves with his family. That doesn’t mean he should give up all forms of achievement; he simply needs to readjust the level of energy he puts into that category. Doing so will require more creative thought and versatility than he’s exhibiting now.

The executive overseeing the problematic product rollout was framing his dilemma in terms of short-term versus long-term achievement. He would do better to reframe his challenge in terms of legacy: What kind of platform would he be creating for the success of this product and that of future managers in the company if he decided to release incomplete products? Thinking about the problem from this perspective helped him clarify his priorities. Instead of feeling that he had to make a trade-off in a negative sense, he could take a positive view of what needed the most attention and what was worth sacrificing for. In the end, he delayed rolling out the new product line—and not only were the retailers delighted with the final results, but the product division, in crafting the solution, discovered a new way to coordinate and leverage its technological capabilities across three countries.

The software engineer torn between computers and church music needed to shrink or redirect her goals in some activities and develop them in others. When she tried the kaleidoscope strategy, she quickly saw that church music registered high in her significance category but would always be a limited outlet for achievement. She had neither the skill nor the opportunity to become a star musician. Software had more potential for significance than she had previously thought. She needed to learn how to change her job in ways that emphasized the social value she was creating in the products she worked on and the help she provided to others. She began to see benefits in framing church music primarily as an exercise in significance rather than in achievement, with all its competitive and financial associations. But to fill both chambers, she’d need to restructure her job commitments in order to minimize travel and commit to choir practice. When she looked at the whole picture of goals she could satisfy through the sum of these activities, scaling back suddenly seemed more positive. The pieces were enough. And, she recognized, taking this path would require continued growth on her part—something she had forgotten she valued and which she now had the confidence to pursue strategically. Enduring success required enduring commitment.

Building Your Own Kaleidoscope

To create your own kaleidoscope, start by sketching out your framework. Take a piece of paper and draw four intersecting circles. Label them happiness, achievement, significance, and legacy. In each circle, list self, family, work, and community. This will enable you to do a full inventory of the mix and determine how each piece falls in the context of each major domain of your life. (See the exhibit “My Personal Kaleidoscope.”)

My Personal Kaleidoscope

Next, quickly jot down examples of your successes or great satisfactions. You don’t have to come up with one for every item in every circle—this is just a quick sketch of your beliefs about yourself, not the full picture. Don’t spend time worrying about whether you should put a particular target next to a particular item. Just work with your first impulses.

Take your college degree as an example. You may feel that graduating from college was a major achievement, a benchmark in your overall career plans and something you will value for your whole life. Your degree represents a mastery of skills. You had to compete successfully to get there and get the grades. You felt satisfaction when you were successful. So you would write “college” in your achievement chamber, next to the word “work.”

But what if college represented other things for you? Significance in your family life, for example, because your parents or spouse really valued what you were doing? In that case, you might also put college in your significance chamber, next to “family.”

The point is not to compulsively divide your life into little circles and lists. Rather, it is to help you assess the various types of satisfactions you have already experienced and see what they add up to. The answer is often more surprising or richer than you may have suspected.

Depending on your age, you might even want to fill out framework profiles for several periods in your life. Did you want the same things at 40 as you did at 20? Will you want the same things at 60? At 85? Could you ever fully abandon one of the categories and still feel that you were a success? (This is the trap that many retirees and those who downscale their careers to become full-time parents fall into.)

Now, metaphorically speaking, you can hold your kaleidoscope up to the light. Look at it objectively, and ask yourself:

1. How integrated is your profile? Are some of the domains empty? Are others too full? Is each realm of your identity—self, family, work, community—a depository of only one satisfaction, or is there a broader basis for success in each of these areas?

2. How varied is your profile? Where are most of your greatest successes and satisfactions so far? Where are the holes? The obsessions? Are the chambers and realms evolving or repeating the same things over and over?

3. What have you learned about what you actually do? Where is your time going? How does it speak to what you really want from success? Research into success has shown that one of the biggest causes of failure is an overreliance on one’s greatest strengths. Are you favoring what you do best and neglecting your need for fulfillment in all four categories?

Here’s how the kaleidoscope strategy helped John, the owner of a large real estate company, find enduring success. John was having trouble deciding what to do with his business. After a blowout with his teenage child and a series of relentless, debilitating headaches, he decided he had to cut back on his work. He had already bought a plane—against his family’s wishes—and he had increased his time for himself, but he was still suffering. “I know I should sell part of this business for the sake of my happiness,” he said, “but I just can’t do it.”

We suggested he try putting this sale in another category, one that seemed rather empty. Why not think about the sale as an active engagement in legacy rather than as a platform for happiness? The pieces fit. Legacy is about building on your achievements and values to help others succeed after you’re gone. John remembered a young manager who had left the firm, someone who knew John’s values and was quite accomplished in his own right. This person would probably welcome the chance to head the new spin-off, and he’d be likely to extend the kind of business John had spent his life building. The buyers would need such a person, and John would be comfortable doing business with them.

After seeing the situation from a different perspective, John was more decisive about the sale and had a richer platform of concrete goals around which to structure the transaction: the terms in which legacy would be fulfilled, the new time frame for his own enjoyment of life, a revitalizing and more realistic set of achievement goals, and a sense of providing the space to be there for his daughter and wife without giving up all the challenges of the real estate business.

Identifying where his activities were located in the kaleidoscope gave John immediate insight into what he was seeking and getting from his efforts—as well as what was lacking. In channeling your efforts effectively toward what you really seek from success, it’s critical to test your profile against your idealized view of yourself. What do you want your profile of accomplishments in each of the four categories to look like tomorrow? Next month? Over your lifetime?

The Kaleidoscope Strategy for Businesses

What makes for the enduring success of a company? In our view, businesses prosper when they enable individuals and …

Getting to “Just Enough”

If you pay attention to the four categories and their relation to one another, you can enrich the potential for any activity to satisfy you on numerous dimensions, whether at work, in your leisure time, or in some other aspect of your life. The high achievers in our study were able to accomplish great things for themselves and others by recognizing they had multiple goals that were critical to their idea of real success and by being fully committed to whatever activity they were engaged in. By switching and linking, they limited their attention to one task, and when other needs pressed, they were able to make lightning fast changes of focus and emotional energy. Instead of feeling cheated because they couldn’t get it all, they were renewed by following the cycle of attention to each category.

How do you know when it’s time to stop your work in one category and switch your attention to another? That’s where the concept of “just enough” becomes critical. Conventional interpretations of “enough” don’t capture its full potential. People tend to use the term to express dissatisfaction, as in, “That’s it! I’ve had enough!” or as a code for mediocrity or passivity, as in, “If I’m just happy every day, that’s enough.” We mean something else by enough, closer to its root definition: occurring in sufficient quantity or quality to satisfy demands or needs. If you have a firm idea of the big picture in your kaleidoscope of success, it becomes easier to determine and appreciate “enough” in any one activity. Without losing your energy for high aspirations, you set reachable goals. “Just enough” is the antidote to society’s addiction to the infinite “more.” Seen in that light, it becomes a vehicle for actively making choices that allow you to do and get more, not less, through achieving satisfaction in more areas of your life.

“Just enough” is the antidote to society’s addiction to the infinite “more.”

Ganoderma: A Cancer Immunotherapy Review

Yu Cao1,2Xiaowei Xu3Shujing Liu3Linfang Huang1* and Jian Gu2*

  • 1Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
  • 2Department of Pharmacy, Southwest University for Nationalities, Chengdu, China
  • 3Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

Ganoderma is a significant source of natural fungal medicines and has been used for the treatment of various diseases for many years. However, the use of Ganoderma in cancer immunotherapy is poorly elucidated. In this study, we have analyzed 2,398 English-language papers and 6,968 Chinese-language papers published between 1987 and 2017 by using bibliometrics. A steady growth in the number of publications was observed before 2004, followed by an exponential increase between 2004 and 2017. The most common category for publications about Ganoderma was “Pharmacology & Pharmacy,” in which immunomodulation (25.60%) and cancer treatment (21.40%) were the most popular subcategories. Moreover, we have provided an overview of the bioactive components and combinatorial immunomodulatory effects for the use of Ganoderma in the treatment of cancer, including the major pathways of immune cells. Immunomodulatory protein and polysaccharides are the key bioactive factors responsible for cancer immunotherapy, and the NF-κB and MAPK pathways are the most comprehensively investigated major pathways. Our results indicate that Ganoderma has a broad-spectrum application for the treatment of cancer through the regulation of the immune system. This review provides guidance for future research into the role of Ganoderma in cancer immunotherapy.

Introduction

Ganoderma, also called Lingzhi, is one of the most well-known medicinal species. Regarded as the “marvelous herb,” it is used widely in China, America, Japan, Korea, and other countries (Meng et al., 2011). According to traditional Chinese medicine (TCM) theory, Ganoderma has the ability to enhance body resistance, i.e., “Fuzheng Guben” (Yue et al., 2006). “Channel tropism” (Gui-Jing) links the functions of herbal drugs to their corresponding internal organs, channels, and various body parts to allow the interpretation of their functional mechanisms. The channel tropism of Ganoderma is the heart, lung, and liver, according to Gui-Jing theory. The main Ganoderma species are G. lucidum, G. sinensis, G. applanatum, G. tsugae, G. atrum, and G. formosanumG. lucidum and G. sinensis are recorded in ChP2015 (Pharmacopeia of the People’s Republic of China), and G. lucidum is recorded in USP40-NF35 (U.S. Pharmacopeia/National Formulary; Gao et al., 2004). The production of Ganoderma occurs mainly through artificial cultivation, which has provided an abundance of materials for the market; the yield has already surpassed that of wild Ganoderma (Chen et al., 2017). Methods used for Ganoderma identification include microscopy, TLC, spectroscopy, chromatography, chemical fingerprinting, and DNA sequencing. DNA sequencing has recently been used for classification of different Ganoderma species, with HPLC, UPLC, LC-Q-TOF-MS, HPTLC, and GC-MS have been commonly applied for quality evaluation (Toh Choon et al., 2012Hennicke et al., 2016). Ganoderma has been used for the clinical treatment of chronic bronchitis, bronchial asthma, leukopenia, coronary heart disease, arrhythmia, and acute infectious hepatitis. However, at present, it does not have the potential to be used as first-line therapy, but only as an addition to conventional therapy in a clinical setting (Gao and Zhou, 2003Unlu et al., 2016).

Chemical drugs for cancer treatment, such as cisplatin and cyclophosphamide, can cause side effects, such as nephrotoxicity, which are detrimental to the quality of life of patients (Aguirre-Moreno et al., 2013). In addition to this toxicity, the resistance of some cancer cells to treatment has led to the need for the evaluation of alternative approaches. Hence, chemotherapy does not completely meet the treatment need and immunotherapy is a promising alternative method as it results in fewer side effects. The use of cancer immunotherapy has gained acceptance because immune cells play notable roles in the control of cancer (Blattman and Greenberg, 2004). Immune cells can identify cancer cells as dangerous and consequently attack them; thus, the use of cancer vaccines to treat growing tumors is considered an excellent therapeutic strategy (Rosenberg et al., 2004). Herbal medicines have also been examined in clinical trials for cancer immunotherapy. Shing et al. found that a 6 months treatment using G. lucidum increased the mitogen-induced lympho-proliferative responses in immunocompromised children with tumors (Shing et al., 2008).

Bibliometrics is a method of document analysis that can count and analyze a large number of articles and monitor the trends in research (Kim and Park, 2011). Previous studies have reviewed the anticancer and/or immunomodulatory effects of G. lucidum and their potential immunological mechanisms (Lin and Zhang, 2004Xu et al., 2011). However, the bioactive substances and corresponding immunoregulatory effects of Ganoderma in the treatment of cancer have not yet been investigated. Therefore, we have provided an overview of the research trend on Ganoderma determined from bibliometrics and reviewed its bioactive components and combinatorial immunomodulatory effects for use as a cancer treatment. We have also summarized the major diseases and pathways involved, clinical studies, and preliminary assessments of toxicity.

Literature Analysis

Bibliometrics is defined as the application of statistics and mathematics to analyze bibliographical metadata linked to scholarly publications. Bibliometrics uses a literature system and literature metrology characteristics as research objects to quantitatively and qualitatively analyze the studies. Bibliometrics can be used to monitor the trends in the scientific development of a research domain; it can be used to analyze the trends and provide a comprehensive perspective on a topic. Therefore, we analyzed a specific question from the review of published literature by using current software programs (Aggarwal et al., 2016). Using professional bibliometrics software, such as CiteSpaceV (Chen et al., 2014) and RAWGraphs, we performed a bibliometric analysis of the publications on Ganoderma between 1987 and 2017 from the Web of Science (WoS), PubMed, and CNKI databases, which were the most suitable databases for this type of evaluation. We found 2,205 articles in WoS and 1,368 articles in PubMed with “Ganoderma,” “Lingzhi,” or “Reishi” as the key words. After removal of the duplicates, a total of 2,398 English-language articles (included in the Science Citation Index) were retrieved. We also found 6,968 Chinese-language articles on CNKI with the Chinese word for “Lingzhi” as the key word. We analyzed publication counts, cooperation between countries, and research categories. We found that immunomodulation and antitumor research were the most popular research subcategories; subsequently, from examination of the relevant literature, the topic of this review was determined to be cancer immunotherapy.

Publication Counts

The publication counts for each year from 1987 to 2017 are shown in Figure 1. From on the number of publications, This 30 years period was preliminarily divided into three stages: Stage 1, from 1987 to 1993, was considered as the budding period, when <100 papers were published annually; Stage 2, from 1994 to 2003, was known as the development period, when the number of annual publications increased linearly from 100 to 300; Stage 3, from 2004 to 2017, was the “boom period,” when the annual number of papers increased rapidly; in particular, the number of English-language papers doubled annual. Research interest into Ganoderma widened over the years examined; moreover, the number of English-language studies has recently increased rapidly, revealing the potential research value of Ganoderma.FIGURE 1

Figure 1. Statistical analysis for published articles of genus Ganoderma.

Cooperation Between Countries

The relationships between many countries with active Ganoderma researchers, based on their publications included in the Science Citation Index, are illustrated in Figure 2. In total, 84 countries were involved in the study of Ganoderma. China, the United States, Malaysia, Japan, and South Korea have the highest output and the most extensive cooperation was found among these countries.FIGURE 2

Figure 2. Statistical analysis for relationship among countries for Ganoderma research. Different countries are represented by different colors, and the size represents the number of publications.

Subject Categories and Major Historical Developments

The categories of articles about Ganoderma that were included in the Science Citation Index are shown in Figure 3A. After the software analysis, we have displayed only subjects with a frequency of 50 or more. The most abundant category, “Pharmacology & Pharmacy,” had a frequency of 519, followed by the categories of “Chemistry” (422) and “Biochemistry & Molecular Biology” (400). From further reading, we found 1,512 Chinese-language articles and 880 English-language articles included in the Science Citation Index that described the pharmacological effects of Ganoderma. These pharmacological effects were subdivided into several specific effects (Figures 3B,C), such as immunomodulation, cancer treatment, antioxidation, cardiovascular treatment, diabetic treatment, liver protection, and neuropharmacology. The immunomodulation effect-related studies occupied the largest proportion of the eight areas of pharmacology, followed by cancer treatment, both in Chinese-language articles (24.73 and 24.47%, respectively) and in English-language articles (24.72 and 22.57%, respectively). Furthermore, in English-language articles, the number of citations was 17,692 and the average citation per item, which is the average number of articles cited for all items in the results set, was 20.43.FIGURE 3

Figure 3. Analysis for subject categories of Ganoderma(A) Subjects of 50 frequencies or more (included in Science Citation Index). Nodes represent objects analyzed. And the larger nodes, the more frequently they occur. The connections among nodes represent the cooperative relationships. The thicker the connections, the closer they consociate. (B) Classification of pharmacological effects in Chinese articles (C) Classification of pharmacological effects in English articles.

Further analysis of the English-language articles led to the identification of a total of 196 articles related to cancer immunotherapy. The timeline of major historical developments that are related to Ganoderma in cancer immunotherapy is shown in Figure 4. We found three types of fungal immunomodulatory proteins (Fips) that played important roles; Lz-8 was the first of these discovered. Moreover, the first study of the effect of Ganoderma on the inhibition of tumor growth occurred as early as 1991. In 2003, Ganopoly appeared as a new drug, and has since been used widely in clinical practice. Furthermore, the toxicology and immunology of Ganoderma were partly addressed in 2011 and its chemoprotective effects against cyclophosphamide-induced immunosuppression were studied in 2015. In addition, prebiotics were investigated as a novel approach for the treatment of carcinoma in 2017. Cancer immunotherapy has emerged one of the most popular fields of Ganoderma research. Hence, we have focused on the immunomodulatory effects of this genus and its constituent active components for use in cancer treatment.FIGURE 4

Figure 4. Timeline of major historical developments of Ganoderma on cancer treatment.

Immunomodulatory Effects of Ganoderma and Its Active Components on Cancer Treatment

Many pharmacological and clinical studies have shown that Ganoderma can play an antitumor role through the regulation of the immune system (Boh et al., 2007). The therapeutic effects of Ganoderma are attributed to fungal immunomodulation proteins (FIPs), polysaccharides, and triterpenoids. Furthermore, we have specifically summarized active components of Ganoderma and their corresponding pharmacological effects.

Fungal Immunomodulation Proteins

FIPs are small molecular proteins purified from various fungi, such as Ganoderma. These proteins are functional families of Ganoderma components with anticancer effects (Table 1). Four types of immunoregulatory proteins, Lingzhi-8 (Lz-8), Fip-gts, GMI, and Fip-gat, have been isolated and purified from Ganoderma.TABLE 1

Table 1. Pharmacological effects of immunomodulatory proteins of Ganoderma.

Lz-8, an immunomodulatory protein from G. lucidum, was first isolated and cloned in 1989. Primarily composed of 110 amino acids, Lz-8 has an immunoglobulin-like structure that forms non-covalently linked homodimers with biological activity (Kino et al., 1989). Lz-8 exerted significant therapeutic effects on gastric cancer and specific lung cancers. Liang et al. found that recombinant Lz-8 (rLz-8) induced autophagic cell death through aggregation in the endoplasmic reticulum (ER), which triggered ER stress and the ATF4-CHOP pathway in SGC-7901 human gastric cancer cells (Liang et al., 2012). Moreover, rLz-8 might be a useful chemotherapeutic agent for the treatment of lung cancer because owing the key role of FAK targets in metastasis (Lin and Hsu, 2016). In addition, Lin et al. reported a novel anticancer effect of rLz-8 through targeting EGFR mutation or overexpression and EGFR-dependent processes in lung cancer cells (Lin et al., 2017).

Fip-gts is an immunomodulatory protein purified from G. tsugae. The DNA encoding this protein was isolated from a cDNA library by using a reverse transcriptase-polymerase chain reaction (Lin et al., 1997). The recombinant FIP-gts (rFip-gts) suppressed telomerase activity in a dose-dependent manner through the downregulation of the telomerase catalytic subunit (Liao et al., 2006). RFip-gts inhibited telomerase activity in lung cancer cells in vitro through effects on nuclear export mechanisms, which may have been mediated by the ER stress-induced intracellular calcium level (Liao et al., 2007). In vivo studies showed that the growth of A549 cells in nude mice treated with rFIP-gts was significantly slower than those treated with PBS, which confirmed that lung tumor growth could be inhibited by rFIP-gts (Liao et al., 2008). Moreover, this protein was also shown to affect cervical cancer cells.

GMI is an immunomodulatory protein cloned from G. microsporum. The amino acid sequence of this protein shared 83% homology with that of FIP-gts (Chiu et al., 2015). In vitro studies found that GMI inhibited the EGF-induced phosphorylation and activation of EGFR and AKT pathway kinases in a dose-dependent manner (Lin et al., 2010). Hsin et al. found that autophagosomal accumulation induced autophagic cell death in a model of GMI treatment, and ATP6V0A1, a subunit of vesicular H+-ATPases, regulated autophagosome lysosome fusion. Hsin et al. also revealed that GMI and cisplatin induced apoptosis via autophagy/caspase-7-dependent and survivin- and ERCC1-independent pathways (Hsin et al., 2012). In vivo studies suggested that the oral administration of GMI inhibited tumor growth and induced autophagy in nude mice that were administered a subcutaneous injection of A549 cells (Hsin et al., 2011).

Fip-gat is an immunomodulatory protein from G. atrum containing 111 amino acids. Xu et al. treated MDA-MB-231 cells with different concentrations of recombinant Fip-gat in vitro and found that this protein reduced cell viability in a dose-dependent manner (Xu et al., 2016). Treatment with FIP-gat triggered a significant degree of cell cycle arrest in the G1/S transition and a pronounced increase in the apoptotic cell population.

Polysaccharides and Other Active Components

Polysaccharides (Meng et al., 2014) and other active components of Ganoderma also play key roles in its use for cancer treatment owing to their immunomodulatory effects (Table 2). Their effects are described below relative to different diseases.TABLE 2

Table 2. Pharmacological effects of other bioactive components than proteins of Ganoderma.

Lung Cancer

Feng et al. evaluated the inhibitory effect of triterpenes of G. lucidum on cell proliferation and tumor growth. The IC50 of triterpenes on A549 cells was 24.63 μg/mL (Feng et al., 2013). Triterpenes could significantly inhibit tumor growth in Lewis tumor-bearing mice (30, 60, and 120 mg/kg), and the indices of immune organs, including the spleen and thymus, were increased remarkably by the treatment with triterpenes. Moreover, an in vitro study by Liao et al. found that the L-fucose (Fuc)-enriched Reishi polysaccharide fraction (FMS) could inhibit the growth of cancer cells through an increase in the antibody-mediated cytotoxicity and the reduction of the production of tumor-associated inflammatory mediators, particularly monocyte chemoattractant protein-1 (MCP-1). In vivo studies showed a significant increase in the peritoneal B1 B-cell population, suggesting the FMS-mediated anti-glycan IgM production (Liao et al., 2013). Sun et al. recently showed that the plasma of patients with lung cancer suppressed the proliferation, CD69 expression, and perforin and granzyme B production in lymphocytes upon activation by PHA (Sun et al., 2014). These effects were partially or fully reversed by G. lucidum polysaccharides (GLPS). Furthermore, Que et al. suggested that Ganoderic acid Me, a pure lanostane triterpene of G. lucidum contributing to the indoleamine 2,3-dioxygenase, helped create a tolerogenic milieu in lung tumors by directly inducing T cell apoptosis, inhibiting CD8+T cell activation, and enhancing Treg-mediated immunosuppression (Que et al., 2014).

Liver Cancer

Zhang et al. indicated that, in addition to its direct tumoricidal activity, the lipid extract from G. sinensis spores could exert an anticancer effect through the stimulation of the activation of human macrophages/monocytes (Zhang et al., 2009). Furthermore, Shen et al. found that the anticancer mycelia of GLPS could be used to disclose the differential expression of miRNA in human hepatocarcinoma cells through the comprehensive investigation of miRNA expression in polysaccharide-treated cancer cells (Shen et al., 2014). Li et al. elaborated that GLPS significantly suppressed the tumor growth in hepatoma-bearing mice. This effect was associated with an increase in the ratio of the effector T cells (Teffs) to regulatory T cells (Tregs) (Li A. M. et al., 2015). Moreover, GLPS eliminated the Treg-induced suppression Teff proliferation through increased IL-2 secretion.

Melanoma

Sun et al. found that GLPS promoted B16F10 melanoma cells to induce lymphocyte proliferation, CD69 and FasL expression, and IFN-γ production. The authors also indicated that GLPS improved the ability of B16F10 cells to activate lymphocytes (Sun et al., 2011b). In addition, the culture supernatant of B16F10 melanoma cells (B16F10-CS) inhibited lymphocyte proliferation and the production of perforin and granzyme B in lymphocytes after induction with phytohemagglutinin and lymphocyte proliferation in the mixed lymphocyte reaction (Sun et al., 2011a). They also found that GLPS could enhance the activity of major histocompatibility complex (MHC) class I molecules and costimulatory molecules, and improve the efficiency of immune cell-mediated cytotoxicity against B16F10 cells (Sun et al., 2012). Barbieri et al. demonstrated that the ethanolic extracts of G. lucidum significantly inhibited the release of IL-8, IL-6, MMP-2, and MMP-9 in cancer cells under pro-inflammatory conditions (Barbieri et al., 2017). Wang et al. revealed that the continuous administration of the G. formosanum polysaccharide PS-F2 activated the host immune responses against ongoing tumor growth (Wang et al., 20112014).

Leukemia

Wang et al. revealed that GLPS might play an indirect role in potentiating antitumor immunity in vivo through an increase in the levels of IL-1 and IL-6 (Wang et al., 1997). Lin et al. showed that GLPS promoted the cytotoxicity of specific cytotoxic T-lymphocytes (CTL) induced by dendritic cells (DCs) (Cao and Lin, 2003). These lymphocytes were pulsed with P815 tumor antigens during the stage of antigen presentation and the reported mechanisms of cytotoxicity involved the IFNγ and granzyme B pathways. In addition, the found that GLPS (400 or 100 mg/mL), which promoted CIK cell proliferation and cytotoxicity, enhanced IL-2 and TNF production, and the protein and mRNA expression of granzyme B and perforin in CIK cells through a synergistic interaction with cytokines, decreasing doses of IL-2 and anti-CD3 by 75 and 50%, respectively, which might be irrelevant to nitric oxide (NO) (Zhu and Lin, 2006). Moreover, Chan et al. suggested that GLPS could induce selected monocytic leukemic cell differentiation into DCs with immunostimulatory function (Chan et al., 2007). Chang et al. prepared a water extract of G. lucidum and examined its effect on natural killer (NK) cells; they observed that the treatment increased cytotoxicity in NK cells through the stimulation of perforin and granulysin secretion (Chang et al., 2014).

Colon Cancer

Zhang et al. found that G. atrum polysaccharides could activate macrophages via TLR4-dependent signaling pathways, improve immunity, and inhibit tumor growth (Zhang et al., 2013). Wang et al. revealed that the continuous administration of G. formosanum polysaccharide PS-F2 activated the host immune responses against ongoing tumor growth (Wang et al., 2014). In addition, Yu et al. indicated that the chemoprotective effects of G. atrum polysaccharide might be attributable to its ability to activate peritoneal macrophages and spleen lymphocytes in cyclophosphamide-treated mice (Yu et al., 2015a).

Major Pathways of Cancer Immunotherapy of Ganoderma in Immune Cells

Dendritic Cells and T-Lymphocytes

Toll-like receptor (TLR)-4 inhibited the GLPS-induced production of IL-12 and IL-10, which suggested a vital role in DC signaling after incubation with GLPS. Further studies showed that GLPS could augment the activity of κB (IκB) kinase and nuclear factor (NF)-κB inhibitors, as well as the phosphorylation of IκBα and p38 mitogen-activated protein kinase (MAPK) (Lin et al., 2005; Figure 5A).FIGURE 5

Figure 5. Major pathways of cancer immunotherapy of Ganoderma in immune cells. (A) GLPS induces NF-κB activation and p38 mitogen-activated protein kinase (MAPK) phosphorylation in DC. GLPS might activate T cells via inositol triphosphate/Ca2+ (IP3/Ca2+) and protein kinase C (PKC) pathways. (B) F3 induces the expression of Blimp-1mRNA through p38 MAPK pathway and mediates intracellular signal through NF-κB pathway in B cell. The water extract of G. lucidum activates NK cells by the mechanism of activating NKG2D/NCR receptors and MAPK signaling pathway. (C) The polysaccharide of G. atrum induced macrophage activation through MAPK (JNK, ERK1/2) and NF-κB signaling pathways.

Sun et al. revealed that GLPS enhanced the effect of H-2Kb and H-2Db, and B7-1 and B7-2 (two prominent MHC class I molecules in C57BL mice) on B16F10 cells and that the mRNAs of these molecules improved the efficiency of the antitumor cytotoxicity in GLPS-treated cells (Sun et al., 2012). Li et al. inferred that GLPS might activate T cells via the inositol triphosphate/Ca2+ (IP3/Ca2+) and protein kinase C (PKC) pathways, because the extracellular receptor was bound by GLPS (Li et al., 2013Li X. L. et al., 2015; Figure 5A).

B Lymphocytes and Natural Killer Cells

Lin et al. showed that the interaction of F3 (the main polysaccharide fraction of G. lucidum) with TLR4/TLR2, followed by signaling through p38 MAPK, was involved in the induction of Blimp-1 mRNA (Figure 5B) and that the intracellular signal was mediated by the NF-κB pathway (Lin et al., 2006).

Chang et al. indicated that G. lucidum induced cytotoxicity in various cancer cell lines through the activation of the NKG2D/NCR receptors and MAPK signaling pathways, which ultimately culminated in the exocytosis of perforin and granulysin (Chang et al., 2014; Figure 5B).

Macrophage

Kuo et al. revealed that the dried mycelia of G. lucidum also induced NF-κB activation in murine RAW264.7 macrophages, which indicated that NF-κB activation was one of the most important signaling pathways (Kuo et al., 2006). Pro-inflammatory cytokines (TNF-α, IL-1β, or IFN-γ) were able to bind to their respective receptors and induce iNOS expression via the activation of NF-κB. Yu et al. indicated that the signaling mechanism might be that of G. atrum polysaccharide-induced macrophage activation through TLR4-mediated NF-κB and MAPK (p38, ERK1/2, and JNK) signaling pathways, thereby initiating the release of cytokines, such as TNF-α and IL-1β, and effector molecules, such as NO, in macrophages (Yu et al., 2015b). The results suggested that the polysaccharide of G. atrum exerted its antitumor activity through the improvement of immune system functions and acted as an antitumor agent with immunomodulatory activity (Figure 5C). Yu et al. concluded that the polysaccharide of G. atrum induced TNF-α secretion through the TLR4/ROS/PI3K/Akt/MAPKs/NF-κB pathways during macrophage activation (Yu et al., 2014). To investigate the possible signaling pathways involved in the activation of macrophages of S180 tumor-bearing mice by the polysaccharide of G. atrum, Huang et al. simulated macrophages and observed an increase in the phosphorylation of NF-κB, Akt, and MAPK family proteins, which was indicative of the activation of the NF-κB pathway (Huang et al., 2016). These findings further indicated the possible involvement of the NF-κB signaling pathway in TNF-α secretion and mRNA expression (Figure 5C).

Clinical Studies

Selections of clinical studies are presented. In 2003, Gao et al. investigated the effects of Ganopoly on the immune function of 34 patients with advanced-stage cancer. They found that it enhanced the immune responses in patients with advanced-stage cancer through an increase in the number of CD3+ (and similar) cells (Gao et al., 2003). In 2008, Shing et al. found that a 6 months treatment G. lucidum increased the mitogen-induced lympho-proliferative responses in immune-compromised children with tumors (Shing et al., 2008). In 2012, a pilot study suggested that the spore powder of G. lucidum had beneficial effects on cancer-related fatigue and quality of life in 48 patients with breast cancer undergoing endocrine therapy, without any significant adverse effects. The experimental group made statistically significant improvements in the domains of physical well-being and the fatigue subscale after intervention (Zhao et al., 2012). In addition, a study of five patients with gynecological cancer showed that they achieved stability in the disease after the ingestion of Lingzhi in the form of fruit body water extract and spores (Suprasert et al., 2014). Some modest benefit was also found when the mushroom was administered with standard chemotherapy (Chen and Alpert, 2016).

Toxicology

The toxicology and immunology of Ganoderma have been partly investigated in current studies. Wanmuang et al. presented a case in which fatal fulminant hepatitis occurred after taking Lingzhi powder for 1–2 months (Wanmuang et al., 2007). In addition, a patient was diagnosed with non-Hodgkins lymphoma and presented with chronic watery diarrhea whilst taking Lingzhi (Suprasert et al., 2014). However, no abnormal clinical-symptoms or deaths and no significant difference in body weight and food intake rate was found in Wistar rats during the 30 days administration period (Cheng et al., 2008). No mutagenicity was observed, as indicated by negative results from the Ames test, micronucleus test of polychromatic erythrocyte, sperm abnormality test, and chromosome aberration test in Kunming mice (Zhang et al., 2016).

Disscusion

The present review provides the most up-to-date analysis of Ganoderma research over a 30-years period by using CiteSpaceV and RAW Graphs. We found that the number of studies have increased significantly over time, especially during Stage 3 (Figure 1). We inferred that chemical drugs may exhibit certain side effects. Hence, the medicinal capabilities of the Ganoderma fungi have been gradually elucidated. In addition, China, the United States, Malaysia, Japan, and South Korea are the world leaders in Ganoderma research, based on outputs and close cooperation among the 84 countries active in the research area (Figure 2). Remarkably, the output of China is ~20% of the total output, which gives it the highest output of these countries. Based on a large amount of data, we summarized the subject categories of the research and found that “Pharmacology & Pharmacy” is the leading category. In the subcategories within pharmacology, immunomodulatory effects and cancer treatment occupy the largest proportion of the eight areas of pharmacology in Chinese-language and English-language articles. These finding revealed a new trend, which was the use of Ganoderma in cancer immunotherapy research.

Cancer is a disease with a high death rate. Chemotherapy does not completely meet the needs for cancer treatment and immunotherapy is a promising alternative method owing to the fewer side effects observed. Ganoderma, a medicinal mushroom, could be administered as an adjunct to conventional treatment to enhance the tumor response and stimulate host immunity. At the species level, studies on G. lucidum predominate; other species are less well-studied. With regard to the effective components, FIPs and polysaccharides are dominant; of which Lz-8 and polysaccharides from G. lucidum are the most researched. Ganoderma also plays important roles in many aspects of immune regulation for cancer treatment, not only the activation of T or B lymphocytes, macrophages, NK cells, and other immune cells, but in the promotion of the in vitro proliferation of undifferentiated spleen cells, and the production of cytokines and antibodies. NF-κB and MAPK, the most comprehensively investigated major pathways, are shown to be activated and release cytokines that subsequently inhibit the growth of tumor cells. TLR-4 is an effective receptor involved in the host defense mechanism of the immune response to polysaccharides. In addition, some researchers have used Ganoderma in combination with drug treatments for cancer, such as the combination of GMI and cisplatin and the combination of G. atrum polysaccharides with cyclophosphamide to reduce the side effects of the drug. We found that the immunotherapy of lung cancer, liver cancer, melanoma, leukemia, and colon cancer were thoroughly studied in vivo and vitro, particularly lung and liver cancers. This observation was basically consistent with the channel tropism of Ganoderma in TCM theory. Moreover, this review has made a preliminary analysis of the safety of Ganoderma through the exploration of the reported toxicology. With regard to adverse effects, there were generally no serious side effects from the use of Lingzhi, but patients should be monitored while receiving Lingzhi, as liver toxicity and chronic watery diarrhea are reported side effects.

Ganoderma is one of the most widely used herbal fungi and is a promising anticancer immunotherapy agent owing to its low toxicology and efficacy as a combination therapy. However, the mechanistic pathways lack specificity and do not accurately select specific targets; in addition, most results are derived from in vitro studies. Future studies should focus on the combination therapies of Ganoderma and clinical chemotherapy drugs to alleviate the side effects of these drugs. Furthermore, the safety and toxicity should be thoroughly explored. The major bioactive components should to be investigated and corresponding in vivo pharmacokinetic studies should be performed. The mechanisms underlying immune modulation and interactions should be determined.

Author Contributions

YC conducted and designed the review and wrote the MS. XX and SL contributed to the language editing. LH and JG conducted the designed the review.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

Funding from the National Natural Science Foundation of China (No. 81473315) and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2016-12M-3-015) are gratefully acknowledged.

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Keywords: Ganoderma, lingzhi, bibliometrics, cancer immunotherapy, mechanism

Citation: Cao Y, Xu X, Liu S, Huang L and Gu J (2018) Ganoderma: A Cancer Immunotherapy Review. Front. Pharmacol. 9:1217. doi: 10.3389/fphar.2018.01217

Received: 23 May 2018; Accepted: 05 October 2018;
Published: 25 October 2018.

Edited by:Ruiwen Zhang, University of Houston, United States

Reviewed by:Ulrike Lindequist, University of Greifswald, Germany
Dejan S. Stojkovic, University of Belgrade, Serbia

Copyright © 2018 Cao, Xu, Liu, Huang and Gu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Linfang Huang, lfhuang@implad.ac.cn
Jian Gu, gujiancd@163.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

2 Comments – Emmanuella Daniel and Mohammad Imano.

Emmanuella Daniel I have been suffering for the past 3years, I found out I had herpes (type 2) on my genitalia 3years ago when my daughter was 8 weeks old. I was devastated. I get a flare up about twice a year, but it’s only one bump or so. Still, it sends me into depression. I have recently discovered Robinson buckler cure which i took few times a day which too away the herpes quickly but before then, i really tried many prescribed medicine so that i can be cured from this deadly virus but all could not work for me all my prayers to God was to wake up one faithful day and get cured from the virus because i was finding it difficult to work in my office and it was still affecting my family till i came across this Doctor, so i contacted him with doubting mindset but i could not believe it when he helped me with a positive solution and cure my herpes with his herbal cure remedies. You can also be cured if you are suffering from HERPES or any critical sickness that is giving you heartbreak and disturbing your family and job by contacting ..Robinsonbucler {@gmail}}. com……

  • 8:50 AM, 06 November 2020

Mohammad Imano You wrote very well. thank you. Ganoderma is known in the world as King of herbs. Of the thirty-six known species of Ganoderma, Ganoderma lucidum is the most medicinal. Studies on this miraculous herb show that it can support the immune system and slow down the growth of tumors in the body. It can prevent cancer cells from multiplying and migrating. In fact, research has shown that when people with tumors consume these fungi for 30 days, the immune system is greatly improved. Research has even found that these same people experience less radiation chemotherapy and side effects and have a greater rate of recovery after surgery. It has also been shown to help prevent and slow the spread of cancer cells, lower high blood pressure and even increase the risk of herpes sores and herpes. It also makes the body resistant to stroke and heart disease and eliminates fatigue.We study Ganoderma in the Middle East: our website : https://ganoderm.ir

  • 3:35 AM, 09 July 2021
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