GSK-3 is presently known to be a key regulator of a wide range of cellular functions. GSK-3 regulates numerous cellular processes through a number of signaling pathways important for cell proliferation, stem cell renewal, apoptosis and development. Because of these diverse roles, dysregulated GSK-3 has been implicated in several diseases including neurodegenerative diseases (Alzheimer’s and Parkinson’s disease), stroke, bipolar disorder, type-2 diabetes, inflammation and cancer.

Phosphorylation of a protein by GSK-3 usually inhibits the activity of its downstream target. Thus, signals that inhibit GSK-3 often cause activation of its diverse array of target proteins. Regulation of GSK-3 is important for normal development, regulation of metabolism, neuronal growth and differentiation and modulation of cell death. GSK-3 is encoded by two genes, GSK-3α and GSK-3β, which are structurally similar, but functionally non-identical. There is a homologous serine on both these isozymes; Ser9 on GSK-3α and Ser-21 on GSK-3β. Phosphorylation of this serine by an upstream kinase, such as Akt, inactivates GSK-3 and prevents it in turn from phosphorylating its own downstream targets.

Glycogen synthase kinase 3: a key regulator of cellular fate. 

GSK3 as a Sensor Determining Cell Fate in the Brain.

Emerging roles of glycogen synthase kinase 3 in the treatment of brain tumors.

What Are the bona fide GSK3 Substrates?

In cancer, GSK-3 modulates the response of the cell death machinery to stress stimuli, including chemotherapeutics. Mitochondria are at the heart of the integration between survival and death signals; therefore, modulation of the mitochondrial functions carried out by GSK-3 is profoundly involved in the apoptosis escape capabilities. In cancer tissues, the high glycolytic activity requires an up-regulation of the key glycolytic enzymes including hexokinase. GSK-3 also regulates tumor cell survival by controlling mitochondrial binding of hexokinase, particularly hexokinase type II, which is highly expressed on the outer mitochondrial membrane of most cancer cells. Hexokinase (type I and II) bind to a protein in the mitochondrial membrane called VDAC. VDAC is a dynamic regulator of global mitochondrial function. 

Hexokinase initiates the process of intracellular glucose utilization and it contributes to the Warburg effect, the aerobic glycolytic metabolism of cancer cells. Hexokinase (type I and II), the rate limiting enzymes in glycolysis, controls cell survival by promoting metabolism and/or inhibiting apoptosis. Inhibition of glycolysis severely depletes ATP in cancer cells and leads to massive cell death. It was found that release of Hexokinase II from mitochondria induces apoptosis in hepatocellular carcinoma and glioma cells. When hexokinase is detached from mitochondria, the mitochondrial membrane undergoes conductibity changes which increases its permeability, promotes the release of cytochrome C into the cytosol and activates caspase-3. Caspase-3 activation leads to apoptotic cell death.

GSK-3 and mitochondria in cancer cells.

The modulation of inter-organelle cross-talk to control apoptosis.

Regulation of hexokinase binding to VDAC.

Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia.

Hexokinase binding to mitochondria: a basis for proliferative energy metabolism.

Hexokinase II detachment from mitochondria triggers apoptosis through the permeability transition pore independent of voltage-dependent anion channels.

Suppression of apoptosis by cyclophilin D via stabilization of hexokinase II mitochondrial binding in cancer cells.

Apoptosis-inducing antitumor efficacy of hexokinase II inhibitor in hepatocellular carcinoma.

Glycogen synthase kinase-3 inhibition induces glioma cell death through c-MYC, nuclear factor-kappaB, and glucose regulation.

Elenantal lithium, a drug widely used to treat bipolar mood disorder, is a well established inhibitor of GSK-3 activity. Lithium binds to GSK-3 to directly inhibit its activity. In an alternate, indirect way, lithium increases the inhibitory phosphorylation of a critical serine residue in GSK-3, causing its inactivation. This makes lithium a powerful inducer of both autophagy and apoptosis by multiple biochemical pathways. Another study shows that lithium also detaches hexokinase from the mitochondrial membrane.

Emerging roles of glycogen synthase kinase 3 in the treatment of brain tumors.

Inhibition of GSK3 by lithium, from single molecules to signaling networks.

Lithium detaches hexokinase from mitochondria and inhibits proliferation of B16 melanoma cells.  

GSK-3 also plays a fundamental role in the initiation of inflammation. Inflammation is a critical component of solid tumor progression. Many cancers arise from sites of infection, chronic irritation, and inflammation. GSK-3 promotes the production of inflammatory molecules and cell migration, which together make GSK-3 a powerful regulator of inflammation, while GSK-3 inhibition provides protection from inflammatory conditions.

NF-kB, a major transcription factor, provides a critical mechanistic link between inflammation and cancer. GSK-3 promotes NF-kB induced gene transcription and enhances inflammation primarily by activating NF-kB activity in the nucleus. GSK-3β has been shown to participate in NF-kB mediated cell survival in pancreatic cancer and acute lymphocyte leukemia (ALL), thus behaving as a cancer promoter. Thus, inhibition of GSK-3β results in inhibition of the NF-kB pathway and reduction of NF-kB-mediated transcription. GSK-3 inhibitor lithium exhibits anti-inflammatory and anti-tumor effects. Lithium modulates pro- versus anti-inflammatory cytokines and pro- versus anti-apoptotic gene expression. Lithium can be considered an anti-inflammatory agent.

Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics.

Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity.

Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB-dependent transcription.

Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells.

Glycogen synthase kinase-3 inhibition disrupts nuclear factor-kappaB activity in pancreatic cancer, but fails to sensitize to gemcitabine chemotherapy.

Glycogen synthase kinase-3β inhibition induces nuclear factor-κB-mediated apoptosis in pediatric acute lymphocyte leukemia cells.

Lithium modulates cancer cell growth, apoptosis, gene expression and cytokine production in HL-60 promyelocytic leukaemia cells and their drug-resistant sub-clones.

TNF-α (tumor necrosis factor-alpha) is a cytokine with antitumorigenic property. The interaction of TNF-α with TNF receptor (TNFR-1, TNFR-2) activates several signal transduction pathways, leading to the diverse functions of TNF-α. TNF-α activates both apoptotic pathways along with survival and proliferation pathways via TNFR-1. Low dose, chronic TNF-α production by tumor cells promotes tumor growth and metastasis.

Lithium promotes TNF-α production, thereby stimulating apoptosis in cancer cells. Lithium-induced cell death is largely mediated by the release of TNF-α. Furthermore, when GSK-3 is inhibited by lithium, apoptosis is promoted by low levels of TNF. That is, lithium enhances the sensitivity of cancer cells to TNF. It was found that the inhibition of GSK-3 has a sensitizing effect on TRAIL-induced apoptosis both in prostate and pancreatic cancer. In addition, the inhibition of GSK-3 promotes the TRAIL (TNF-related apoptosis-inducing ligand) cellular death pathway.

Unfortunately, TNF-α also stimulates the activation of NF-kB which blocks its ability to induce apoptosis in cancer and leukemia cells. Another study claims that GSK-3 inhibition does indeed reduce NF-κB activity but does not result in TNF-mediated apoptosis, potentially due to the activation of pro-survival genes through Wnt signaling. Wnt is secreted by cells. Wnt proteins are ligands, which means they can attach (bind) to other proteins called receptors. The free Wnt molecule binds it’s receptor on the cell membrane and activates a survival/growth pathway. Wnt activates a protein called beta-catenin, and this is thought to contribute to the progression of many cancers. GSK-3 has dual functions in the regulation of cell survival, where it can either activate or inhibit apoptosis, further complicating its involvement in cancer.

TNF-alpha in cancer treatment: molecular insights, antitumor effects, and clinical utility.

Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor.

Glycogen synthase kinase-3beta suppression eliminates tumor necrosis factor-related apoptosis-inducing ligand resistance in prostate cancer. 

Glycogen synthase kinase-3 inhibition sensitizes pancreatic cancer cells to TRAIL-induced apoptosis.

LiCl induces TNF-α and FasL production, thereby stimulating apoptosis in cancer cells.

Inhibition of GSK3 differentially modulates NF-kappaB, CREB, AP-1 and beta-catenin signaling in hepatocytes, but fails to promote TNF-alpha-induced apoptosis.

Wnt/β-catenin signaling pathway upregulates c-Myc expression to promote cell proliferation of P19 teratocarcinoma cells.

Wnt pathway activity confers chemoresistance to cancer stem-like cells in a neuroblastoma cell line.

A Wnt-ow of opportunity: targeting the Wnt/beta-catenin pathway in breast cancer.

APC shuttling to the membrane, nucleus and beyond.

Cancer is caused by mutations in critical genes, such as p53. Mutations in many cancer-related genes can disrupt apoptosis, resulting in resistance to common anticancer therapies. In the absence of apoptosis, autophagic cell death can be an alternative form of cell death by excessive self-digestion. If autophagy is prolonged in cancer cells, they can self destruct. Therefore, autophagic cell death can be considered as a backup cell death mechanism when apoptotic cell death mechanisms fail. GSK-3β signaling is a key mechanism in regulating autophagy activation. NF-kB inhibits the induction of autophagy by both TNF and TRAIL. Lithium inhibits the activation of GSK-3, thereby completely inhibiting the activation, nuclear transport and DNA binding of NF-kB.

Understanding autophagy in cell death control. 

GSK-3beta promotes cell survival by modulating Bif-1-dependent autophagy and cell death. 

GSK-3β signaling determines autophagy activation in the breast tumor cell line MCF7 and inclusion formation in the non-tumor cell line MCF10A in response to proteasome inhibition.

NF-kappaB activation represses tumor necrosis factor-alpha-induced autophagy.

Angiogenesis (blood vessel growth) is critical for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. GSK-3β/beta-catenin axis promotes angiogenesis through activation of VEGF (vascular endothelial growth factor) signaling in endothelial cells. Beta-catenin is an important modulator of angiogenesis. VEGF plays a critical role in angiogenesis due to its specific ability to promote the proliferation and migration of endothelial cells. NF-kB is also involved in the upregulation of VEGF and mediates angiogenesis.

The rate of angiogenesis is related to the rate of glycolysis. To fulfill tumor cell needs, the glycolytic switch is associated with elevated glucose uptake and lactic acid release. Lactic acid also induces angiogenesis. Lithium suppresses angiogenesis through inhibition of GSK-3β signaling pathway. However, another study shows that lithium promotes VEGF expression through PI3-K/GSK-3β-dependent and -independent pathways in brain endothelium and astrocytes, respectively. This growth factor (VEGF) signaling mechanism may contribute to lithium’s reported ability to promote neurovascular remodeling after stroke.

Glycogen-Synthase Kinase3beta/beta-catenin axis promotes angiogenesis through activation of vascular endothelial growth factor signaling in endothelial cells.

Glycogen synthase kinase-3beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium.

Inhibition of NF-kappaB activity decreases the VEGF mRNA expression in MDA-MB-231 breast cancer cells.

Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis. 

Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes. 

GSK-3 is upregulated in many types of tumor, including prostate, colon, stomach, pancreas and liver cancer. GSK-3 is required both for hormone-dependent and hormone-independent prostate cancer growth. However, some studies suggest a conflicting role of GSK-3β in various cancers, either as a tumor suppressor or tumor promoter. For example, GSK-3β has been shown to inhibit androgen receptor-stimulated cell growth in prostate cancer, thus acting as a tumor suppressor. In contrast, other study showed that suppressing GSK-3β activity reduced prostate cancer cell growth. GSK-3β is also highly expressed in colon cancer, prostate cancer, etc. and has been shown to participate in NF-κB mediated cell survival in pancreatic cancer, thus behaving as a tumor promoter. It is clear that different signaling pathways regulate GSK-3 activity by different mechanisms.

Inhibition of GSK-3 beta activity attenuates proliferation of human colon cancer cells in rodents.

GSK-3β: A Bifunctional Role in Cell Death Pathways.

Distinct expression and activity of GSK-3α and GSK-3β in prostate cancer.

Glycogen synthase kinase-3beta activity is required for androgen-stimulated gene expression in prostate cancer.

Suppression of androgen receptor-mediated transactivation and cell growth by the glycogen synthase kinase 3 beta in prostate cells.

Inhibition of glycogen synthase kinase-3β counteracts ligand-independent activity of the androgen receptor in castration resistant prostate cancer.

Suppression of glycogen synthase kinase 3 activity reduces tumor growth of prostate cancer in vivo.

Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation. 

Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells.

Aberrant glycogen synthase kinase 3β in the development of pancreatic cancer.

Glycogen synthase kinase-3β, NF-κB signaling, and tumorigenesis of human osteosarcoma.

Glycogen synthase kinase-3beta positively regulates the proliferation of human ovarian cancer cells.

Regulation of glycogen synthase kinase-3 beta (GSK-3β) by the Akt pathway in gliomas.

GSK-3β inhibition promotes cell death, apoptosis, and in vivo tumor growth delay in neuroblastoma Neuro-2A cell line.

Glycogen synthase kinase–3β inhibitors suppress leukemia cell growth.

Selective growth inhibition by glycogen synthase kinase-3 inhibitors in tumorigenic HeLa hybrid cells is mediated through NF-κB-dependent GLUT3 expression.

GSK-3 inhibitor lithium modulates cancer cell growth, apoptosis, gene expression and cytokine production in many different types of cancer and leukemia. Lithium specifically inhibits Hedgehog signaling pathway through the inhibition of GSK-3β. GSK-3β also plays a significant role in Hedgehog signaling. The Hedgehog signaling pathway plays a critical role in the initiation and development of cancer. Blocking Hedgehog pathways induces cancer stem cell death. In a normal person, the Hedgehog signaling pathway is under inhibition and gets activated upon the binding of Hedgehog ligand to a transmembrane receptor called Patched (PTCH1).

The combined synergistic use of lithium and a few other natural agents can suppress tumor growth through distruption of glycolysis and angiogenesis and induce apoptosis and autophagy. Lithium carbonate and lithium chloride are prescription drugs, but lithium orotate can be purchased as a supplement. Lithium orotate is a salt of orotic acid and lithium. There are no systematic reviews of the efficiency of lithium orotate for any condition. In 1979, it was found that lithium orotate was more dangerous to the kidneys than lithium carbonate. 300 mgs of lithium carbonate contains 56.4 mgs of elemental lithium. The normal oral dose of lithium carbonate for the treatment of bipolar disorder starts at 600-900 mgs a day 2-3 divided doses. These therapeutic doses inhibit GSK-3 activity. The synergistic use of lithium and a few Herbalzym products could have a profound affect on the cellular functions of tumor suppressor genes and the promotion of cancer cell death. But, don’t take lithium unless it’s under the supervision of an occupational therapist. Because toxicity can occur at levels >1.5 mEq/L, lithium levels must be carefully monitored especially during the first few weeks and lithium dosage adjusted as necessary.

Lithium modulates cancer cell growth, apoptosis, gene expression and cytokine production in HL-60 promyelocytic leukaemia cells and their drug-resistant sub-clones.

Hedgehog signaling pathway and cancer therapeutics: progress to date.

Hedgehog signaling pathway: the must, the maybe and the unknown.

Hypoxia triggers hedgehog-mediated tumor-stromal interactions in pancreatic cancer.

Lithium inhibits tumorigenic potential of PDA cells through targeting hedgehog-GLI signaling pathway.

Effect of lithium chloride and antineoplastic drugs on survival and cell cycle of androgen-dependent prostate cancer LNCap cells.

Lithium intoxication.

Kidney function and lithium concentrations of rats given an injection of lithium orotate or lithium carbonate.

Lithium: updated human knowledge using an evidence-based approach. Part II: Clinical pharmacology and therapeutic monitoring.

Attempting to boost the cells of the immune system is especially complicated because there are so many different kinds of cells in the immune system that respond to so many different microbes in so many ways. Which cells should you boost, and to what number? So far, scientists do not know the answer. There is still so much that they do not know about the intricacies and interconnectedness of the immune response. The major components of the immune system include lymph nodes, spleen, bone marrow, lymphocytes, thymus, and leukocytes. Our immune system is controlled by hormones secreted by the brain, thymus, adrenals and other glands, which regulate the production and activity of the many types of immune cells. 

Rather than boosting, however, new science demonstrates that the immune system should be fine-tuned and requires balance and harmony. If your immune system is compromised or otherwise weakened, your body becomes more easily susceptible to infection. Chronic or frequent bacterial, viral or yeast infections may be signs of reduced immunity. In humans, immunodeficiency can either be the result of a genetic disease such as severe combined immunodeficiency, acquired conditions such as HIV/AIDS, or through the use of immunosuppressive medication.

Conversely, if your immune system is overactive, the immune system attacks your own healthy tissues. This is what we call autoimmune diseases. They are all caused by the immune system attacking different organs of the body. A chronic inflammatory disease is a medical condition which is characterized by persistent inflammation. Patients develop a chronic inflammatory disease because the immune system has an inappropriate response to something it has been exposed to. In some cases, this means that the patient develops an autoimmune disease, in which the immune system starts to attack the body. In other instances, the patient experiences chronic inflammation in response to certain foods or environmental factors such as smoke and chronic exposure to air pollution.

Conditions like lupus, rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis, Crohn’s disease), Behcet’s disease, thyroid disease, psoriasis, atopic dermatitis, autoimmune pemphigus, scleroderma, celiac disease, type 1 diabetes, aphthous stomatitis, alopecia areata, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, polyarteritis nodosa, autoimmune kidney disease, autoimmune hepatitis, primary sclerosing cholangitis, idiopathic pulmonary fibrosis, fibromyalgia syndrome, myasthenia gravis, ankylosing spondylitis, CIDP, multiple sclerosis, SjÖgren Syndrome, Guilian-Barre syndrome, Meniers disease (hearing loss, vertigo) autoimmune chronic fatigue syndrome, etc are all autoimmune diseases caused by an incorrect or overreaction of the immune system. 

Since all autoimmune diseases use the same mechanism of action to attack target organs thus their treatment is essentially the same. However, achieving and maintaining immune balance can be a challenge in today’s world. Toxins, environmental hormones (endocrine disruptors), lack of sunlight , physical inactivity, lack of sleep, stress, financial strain, packed schedules, poor diet, overuse or inappropriate use of drugs like NSAID and antibiotics, intestinal dysbiosis (imbalanced gut flora), mutating viruses, antibiotic resistant bacteria, mold exposure, and more—all of these can wear you down. They can also compromise your immune system. Our modern lifestyle also appears to be linked to increases in autoimmune diseases, chronic inflammatory diseases, allergies, and cancers.

According to the following article, more women suffer from autoimmune diseases than men. Three quarters of suffers are women. Some suspected reasons may be genetics, sex hormones, and that women have more sophisticated immune systems with elevated antibody responses. Estrogen is known to stimulate the immune system while androgens are recognized to be immunosuppressive. The gut mucosa is a site of interaction between the gut microbiome and the host immune system. The involvement of the GI tract is well documented in several inflammatory and autoimmune disorders, including Crohn’s disease, ulcerative colitis, and Celiac disease. It is now known that the regulation of intestinal inflammatory response is influenced by sex differences, and baseline gut mucosal gene expression shows increased immune activation and inflammation in women compared to men.

Meanwhile, immune dysregulation is very common in major depression patients, with these individuals incurring increased risk for development of chronic inflammatory disease or autoimmune disease. Depression affects both men and women, but more women than men are likely to be diagnosed with depression. Scientists are examining many potential causes for and contributing factors to women’s increased risk for depression. It is likely that genetic, biological, chemical, hormonal, environmental, psychological, and social factors all intersect to contribute to depression.

In fact, there is extensive bi-directional communication between the immune system and the brain in both health and disease. Our immune system engages the brain in an intricate dialogue that can influence our thought processes, coaxing our brains to work at their best. T cells, white blood cells that are a key part of the immune system, may also play an important role in brain function. An imbalance between pro-inflammatory (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-10) cytokines may play an important role in the pathogenesis of both depression and autoimmune disease.

Women and autoimmune diseases.

Genetic and hormonal factors in female-biased autoimmunity.

The role of gender and organ specific autoimmunity.

Sex differences matter in the gut: effect on mucosal immune activation and inflammation.

Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses.

Depression and immunity: inflammation and depressive symptoms in multiple sclerosis.

Depression, another autoimmune disease from the view of autoantibodies.

Evidence for a Dysregulated Immune System in the Etiology of Psychiatric Disorders.

Relationship between a pro- and anti-inflammatory cytokine imbalance and depression in haemodialysis patients.

Inflammation is the first response of the immune system to infection or irritation. Without inflammation, we won’t be able to survive in a hostile world infested with dangerous microorganisms. However, inflammation is a hot topic in modern medicine. It appears connected to almost every known chronic disease-from allergies to asthma, diabetes to obesity, heart disease to cancer, autism to dementia, and even depression and all autoimmune diseases. Autoimmune diseases are ranked number one cause of heart disease, cancer and all diseases. It is also well established that most cancers develop at sites of chronic inflammation.

Pro-inflammatory T cells known as Th17 cells, pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, and transcription factors such as NF-κB and STAT-3 are intrinsically involved in the initiation and progression of almost all autoimmune diseases. If we can control the activation of these pro-inflammatory factors, all autoimmune diseases will cease to exist. It’s that simple.

Th17 cells play an important role in host defense against bacterial and fungal infection, especially at mucosal surfaces. Th17 cells are localized primarily in tissues that separate the host from the environment, principally the skin and mucosa. Through their activation and subsequent cytokine production, they trigger pro-inflammatory signaling that promotes neutrophil mobilization and the expression of antimicrobial peptides, such as Reg3 gamma. Because of their role in inflammation, Th17 cells are implicated in a broad array of inflammatory and autoimmune responses. They play critical roles in autoimmune diseases such as rheumatioid arthritis, IBD (inflammatory bowel diseases), asthma, multiple sclerosis, psoriasis and many others.

Th17 cells are a novel class of helper CD4⁺ T cells that secrete inflammatory cytokines such as IL-17A, IL-17F, IL-21, IL-22, IL-26 (human) and TNF alpha.  Differentiation of naïve T cells towards a Th17 phenotype is supported by several cytokines including TGF-β, IL-1β, IL-6, IL-21, and IL-23. IL-23 is required for Th17 expansion and stabilization. IL-23, as well as TNF-α, acts as a survival signal for Th17 cells. The current consensus is that IL-6 induces Th17 differentiation together with TGF- β. It has been reported that IL-21, similar to IL-6, can also initiate Th17 differentiation combined with TGF- β.

STAT3 is critical for Th17 differentiation. STAT3 is also necessary for the expression of many transcription factors involved in Th17 differentiation. The inhibition of STAT3 activation can block Th17 activation while promoting Th1 (cell mediated) immune responses. Cytokines such as IFN-gamma, IL-27 and IL-4 are known to inhibit Th17 differentiation. IL-27 is also involved in regulating the balance between pro- and anti-inflammatory T cell responses. The pathogenic potential of Th17 cells are restrained by the co-production of IL-10.  When Th17 cells express T-bet, and cease IL-10 production, they attain stronger pathogenic function. Paradoxically, the pro-inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10 both activate STAT3, yet generate nearly opposing cellular responses.

Th1 and Th17 cells: adversaries and collaborators.

Th17 response and inflammatory autoimmune diseases.

Roles of T helper 17 cells and interleukin-17 in neuroautoimmune diseases with emphasis on multiple sclerosis and Guillain-Barré syndrome as well as their animal models.

increased Th17 response to pathogen stimulation in patients with primary sclerosing cholangitis.

The important role of T cells and receptor expression in Sjögren’s syndrome.

The serum IL-6 profile and Treg/Th17 peripheral cell populations in patients with type 1 diabetes.

The autoimmunity in Graves’s disease.

Transcription factors and th17 cell development in experimental autoimmune encephalomyelitis.

Autoimmune Memory T Helper 17 Cell Function and Expansion Are Dependent on Interleukin-23.

The pathogenic role of interleukin-27 in autoimmune diabetes.

Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. 

Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1. 

Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation.

TNF (tumor necrosis factor) activates the immune response against pathogens, including cancer cells. The TNF/TNF receptor (TNFR) system has a prominent role in the pathogenesis of chronic inflammatory and autoimmune diseases. TNF is usually overproduced in chronic inflammatory and autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. 

IL-6 is released in response to inflammation or infection, and in turn stimulates the production of C-reactive protein (CRP) produced in the liver. The level of CRP rises when there is inflammation throughout the body. Elevated levels of CRP and IL-6 predicted the risk of many diseases, including cardiovascular disease, osteoporosis, type 2 diabetes, periodontal disease, frailty, Alzheimer’s disease, functional decline, muscle cell breakdown, lymphoid cancers like multiple myeloma, and certain cancers. Moreover, IL-6 makes significant contributions to such autoimmune and inflammatory diseases such as rheumatoid arthritis. 

Unfortunately, TNF, IL-1 and IL-6 also act as crucial mediators of inflammation-driven tumorigenesis. NF-κB and STAT-3 also interact at multiple levels and thereby boost tumor-associated inflammation which can suppress anti-tumor immune responses. The protein p53 is the most important tumor suppressor in the body. Inactivation of the p53 tumor suppressor is a frequent event in tumorigenesis. Mutations in p53 are very common in many cancers (more than 50% of all cancers), which contribute to the longevity of the cancer cells. When a cell is stressed, p53 activates a wide number of pathways that promote apoptosis. P53 also induces apoptosis in virally infected cells. Interestingly, recent study shows that p53 activity in T cells suppresses autoimmunity by controlling Th17 effectors and thereby inhibits autoimmune inflammation. Under inflammatory conditions, p53 also suppresses Th17 cell differentiation. Selenium is known to activate p53. So far, we have two more natural agents that can promote p53 activity.

TNF superfamily in inflammatory disease: translating basic insights.

Cellular mechanisms of TNF function in models of inflammation and autoimmunity.

Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir.

Chronic inflammation in cancer development.

TNF: a tumor-suppressing factor or a tumor-promoting factor?

TNF-dependent signaling pathways in liver cancer: promising targets for therapeutic strategies?.

Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer.

NF-κB and STAT3 – key players in liver inflammation and cancer.

Stat3: linking inflammation to (gastrointestinal) tumourigenesis.

Trp53 negatively regulates autoimmunity via the STAT3-Th17 axis.

p53 in fibroblast-like synoviocytes can regulate T helper cell functions in patients with active rheumatoid arthritis.

p53 controls autoimmune arthritis via STAT-mediated regulation of the Th17 cell/Treg cell balance in mice.

Selenium and sulindac are synergistic to inhibit intestinal tumorigenesis in Apc/p21 mice.

Dietary selenomethionine increases exon-specific DNA methylation of the p53 gene in rat liver and colon mucosa.

Adenosine is an endogenous purine nucleoside that modulates many physiological processes. Adenosine is formed inside cells or on their surface. Cellular signaling by adenosine occurs through four known adenosine receptor subtypes (A1, A2A, A2B, and A3). Adenosine is an anti-inflammatory agent at the A2A receptor. A2A activation inhibits the NF-kB pathway and diminished inflammatory cytokines such as TNF-α, IL-1β and IL-6. The anti-inflammatory cytokine IL-10 plays a fundamental role in the development of immunological tolerance and the inhibition of inflammatory responses. Activation of both the A2A and A2B adenosine receptors promotes the synthesis of IL-10. Adenosine, via the activation of the A2A receptor, can also block the development of these dangerous Th17 immune responses. Clearly, adenosine is a major natural feedback molecule for the control of inflammation. Caffeine inhibits the activity of all four adenosine receptors. Caffeine does not cause autoimmune diseases, but it can strongly promote their development. If you have an autoimmune disease, caffeine should be excluded from the diet.

A2A adenosine receptor signaling in lymphocytes and the central nervous system regulates inflammation during experimental autoimmune encephalomyelitis.

Adenosine promotes alternative macrophage activation via A2A and A2B receptors.

A2A adenosine receptors and C/EBPbeta are crucially required for IL-10 production by macrophages exposed to Escherichia coli.

Adenosine inhibits tumor necrosis factor-alpha release from mouse peritoneal macrophages via A2A and A2B but not the A3 adenosine receptor.

A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. 

Adenosine, an endogenous distress signal, modulates tissue damage and repair.

High-salt diets can also lead to a dramatic induction of Th17 cells in a specific cytokine milieu. Recent studies suggest that salt may play a previously unknown role in triggering autoimmune diseases such as multiple sclerosis or type1 diabetes in individuals who are already genetically predisposed. The link between Th17 cell activity and salt is a new line of evidence that probes the relationship between autoimmune diseases and environmental factors such as diet.

Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. 

Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1.

Glycogen synthase kinase-3 (GSK-3) is a cytoplasmic serine/threonine protein kinase that phosphorylates and inhibits glycogen synthase, thereby inhibiting glycogen synthesis from glucose. GSK-3 regulates numerous cellular processes, and is also a critical mediator of Th17 cell production. GSK-3 inhibitors can control Th17-mediated diseases. Lithium inhibits GSK-3 activity both directly and indirectly. Interaction between magnesium and GSK-3 allows GSK-3 to phosphorylate many substrates. Magnesium ions are important for the binding of ATP (substrate) in the active site of GSK-3. In the presence of lithium, magnesium is unable to interact with the active site of GSK-3. In an alternate, indirect way, lithium increases the inhibitory phosphorylation of a critical serine residue in GSK-3, causing its inactivation. Lithium also modulates IFN-gamma signaling. IFN-gamma is associated with a number of autoimmune diseases.

Glycogen synthase kinase-3 is an early determinant in the differentiation of pathogenic Th17 cells.

Suppressive regulatory T cell activity is potentiated by glycogen synthase kinase 3{beta} inhibition.

Regulation by glycogen synthase kinase-3 of inflammation and T cells in CNS diseases.

Regulation of Th1 cells and experimental autoimmune encephalomyelitis by glycogen synthase kinase-3.

Inhibition of GSK3 by lithium, from single molecules to signaling networks. 

Lithium controls central nervous system autoimmunity through modulation of IFN-γ signaling.

Th17 response in an autoimmune disease is associated with the appearance of CD25+ dendritic cells. Retinoic Acid, a lipophilic molecule and a metabolite of Vitamin-A, inhibits CD25+ dendritic cells.

Role of CD25+ dendritic cells in the generation of Th17 autoreactive T cells in autoimmune experimental uveitis.

Retinoic acid inhibits CD25+ dendritic cell expansion and γδ T cell activation in experimental autoimmune uveitis.

Berberine is a natural alkaloid found in a wide variety of traditional herbs including goldenseal, barberry and Oregon grape. It is widely used as an anti-inflammatory remedy. Berberine suppresses Th17 responses. EGCG from green tea also inhibits Th17 differentiation. 

Berberine suppresses Th17 and dendritic cell responses. 

Regulation of Th1 and Th17 cell differentiation and amelioration of experimental autoimmune encephalomyelitis by natural product compound berberine.

Green tea EGCG, T cells, and T cell-mediated autoimmune diseases.

Both chronic stress and age increase the level of IL-6 and TNF-α. Worse, the effects of stress and age are interactive. Psychological stress can both mimic and exacerbate the effects of aging, with older adults often showing greater immunological impairment to stress than younger adults. As compared to young adults, middle aged and particularly elderly adults typically have higher levels of cytokines with pro-inflammatory functions circulating in their blood, such as IL-6 and TNF-α.

Chronic stress stimulates cellular production of IL-6 and TNF-α along with impairments in the capacity of glucocorticoids (a class of steroid hormones) to inhibit this cellular inflammatory response. Chronic stress leads to chronic inflammation linked to obesity, depression, anxiety, insomnia, muscle pain, high blood pressure, heart disease, and dysregulated immune responses such as autoimmune disease. Both chronic stress and major depression are much bigger contributors to autoimmune and chronic inflammatory diseases than most of us really realize. There is a definite relationship between ongoing stressful life events before the onset of autoimmune disease.

Chronic stress and age-related increases in the proinflammatory cytokine IL-6. 

Stress, age, and immune function: toward a lifespan approach.

Chronic stress and regulation of cellular markers of inflammation in rheumatoid arthritis: implications for fatigue.

Stress activation of cellular markers of inflammation in rheumatoid arthritis: protective effects of tumor necrosis factor alpha antagonists.

Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk.

Immune balance is the ‘neutral gear’ of immune health that allows the body to respond most appropriately to the need to either activate or suppress immune function as needed. Our body’s immune system is multidimensional, it needs multidimensional support. All aspects of our life experiences, including spiritual, emotional, nutritional and environmental factors influence immune balance.

Immune modulation is a dynamic process that requires constant support. Unlike other immune supporting formulas out there in the marketplace, Hepazym is a clinically proven immune modulator that balances the function of your immune system. It has been developed in research on viral pathogenesis and mechanistic insights into viral modulation of immune receptor signaling. Hepazym contains the latest research based formula of bio-active fermented 32 naturally-occurring compounds with therapeutic potential in autoimmune and chronic inflammatory diseases based on modulating the immune response.

Hepazym formulas combine ancient wisdom with modern science to provide multidimensional support for your immune system. Hepazym contains a proprietary blend of organic wild mushrooms extracts, polysaccharides, 1-3, 1-6 beta glucans, immune molecules, botanical extracts, antioxidants, ionic plant based minerals, plant enzymes, probiotics, beneficial intestinal bacteria and other specially selected micronutrients to provide broad spectrum immune modulation via multiple pathways- immune cell function support, immune cell metabolism support, methylation support and antioxidant support. Hepazym is the most powerful immune modulator for the treatment of autoimmune and chronic inflammatory diseases. There is no more thoroughly tested for many years before they become available to patients in clinical trials and proven effective product on the market today.

Bloodroot is generally prescribed as an external treatment as it is poisonous if ingested in large amounts. In toxic doses, it causes burning in the stomach, intense thirst, vomiting, faintness vertigo, intense prostration with dimness of eyesight. Bloodroot grows primarily in North America and in India. Sanguinarine, the major active compound found in bloodroot, is a very impressive natural medicine. Sanguinarine is a benzophenanthrene alkaloid. It has also been used as an antimicrobial.

More recently, sanguinarine has been used in toothpaste and mouthwash to prevent gingivitis and other inflammatory conditions of the mouth. It has peculiar ability to kill both gram negative and positive bacteria. In addition, mouthwashes containing sanguinarine are known to be able to control oral fungal infections, such as candida. Other than its anti-inflammatory effects, sanguinarine is currently well known for its anti-cancer effects. Large numbers of studies have demonstrated sanguinarine is able to induce apoptosis, therefore inhibit the growth of tumours.

In cancer, the natural processes that lead to apoptosis are often blocked, preventing the removal of cancer cells and thus facilitating the growth of tumor tissue. Survivin is a member of a group of proteins called IAPs (inhibitor of apoptosis proteins). The inhibition of these IAP proteins is critical for the induction of apoptosis. Survivin is highly expressed in most cancers (lung, colon, breast, prostate, pancreas, high-grade lymphomas, neuroblastomas, gastric) and associated with chemotherapy resistance, increased tumor recurrence, and shorter patient survival.

Survivin has been shown to increase tumor resistance to various apoptotic stimuli, primarily through caspase-dependent mechanisms, although it can also block apoptosis in a caspase-independent fashion. Caspases are a family of enzymes known as cysteine aspartyl proteases that play a central role in process of apoptosis. Activation of these enzymes leads to fragmentation of DNA and ultimately the death and clearance of cancer cells.

Conversely, antagonizing survivin in tumor cells induces apoptosis. Thus, antisurvivin therapy is an attractive cancer treatment strategy. Sanguinarine inhibits survivin. Data showed that the effect of sanguinarine on survivin was not only at the transcriptional level; rather there was degradation of survivin protein. This occurred via a proteasome-dependent pathway; specifically sanguinarine enhanced survivin degradation via the ubiquitin-proteasome system.

Protein degradation through the ubiquitin-proteasome system is a major component in cellular metabolism and regulates numerous cell functions. It plays important roles in a variety of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell trafficking, and modulation of the immune and inflammatory responses. 

The universal character of the tumor-associated antigen survivin. 

Survivin, a cancer target with an emerging role in normal adult tissues.

Recent advances in anti-survivin treatments for cancer.

Critical Role of a Survivin/TGF-β/mTORC1 Axis in IGF-I-Mediated Growth of Prostate Epithelial Cells.

Sanguinarine suppresses prostate tumor growth and inhibits survivin expression.

STAT3 (signal transducer and activator of transcription 3) is an oncogenic transcriptional factor that plays a critical role in carcinogenesis and cancer progression and is a critical therapeutic target. Tumor cells depend on STAT3 for continued rapid growth and avoidance of apoptosis. STAT3 is constitutively activated in a wide variety of tumours, including colorectal cancer, liver cancer, breast cancer, prostate cancer, multiple myeloma, and glioblastoma. Perhaps half or more of human tumors contain persistently active STAT3. Survivin is activated at the genetic level by STAT3. Thus, direct inhibition of STAT3 signaling can block the expression of survivin protein and induce apoptosis. 

Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells.

Furthermore, STAT3 pathway controls cancer stem cell survival. Studies show that the development and maintenance of cancer stem cells are dependent on STAT3 signaling. Tumor-initiating or cancer stem cells are known to have unlimited self-reproductive ability and resistance to anti-cancer drugs.

STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells.

STAT3 is essential for the maintenance of neurosphere-initiating tumor cells in patients with glioblastomas: a potential for targeted therapy?

STAT3 signaling pathway is necessary for cell survival and tumorsphere forming capacity in ALDH⁺/CD133⁺ stem cell-like human colon cancer cells.

Sanguinarine inhibits STAT3 activation, a known promotor of survivin gene activity. Thus, sanguinarine, properly administered, can effectively block both survivin and STAT3 pathways. Sanguinarine also overcomes p-glycoprotein mediated multidrug resistance (MDR). P-glycoprotein is an efflux pump of the MDR genes subfamily. MDR of tumor cells is the main cause of the failure of chemotherapy.

Inhibition of Stat3 activation by sanguinarine suppresses prostate cancer cell growth and invasion.

Sanguinarine overcomes P-glycoprotein-mediated multidrug-resistance via induction of apoptosis and oncosis in CEM-VLB 1000 cells.

In addition, Sanguinarine causes the production of large amounts of reactive oxygen species (ROS), in particular hydrogen peroxide, which may deplete cellular antioxidants and provide a signal for rapid execution of apoptosis. Beyond ROS involvement in carcinogenesis, increased ROS level can inhibit tumor cell growth. Indeed, in tumors in advanced stages, a further increase of oxidative stress, such as that occurs when using several anticancer drugs and radiation therapy, can overcome the antioxidant defenses of cancer cells and drive them to apoptosis.

Glutathione, the primary anti-oxidant in the cell, can be synthesized in the body. Glutathione is a tightly regulated intracellular constituent, and is limited in its production by negative feedback inhibition of its own synthesis. If glutathione levels decline beyond a certain point, cancer cells will die of oxidative stress. Sanguinarine actually interacts directly with the glutathione molecule, thereby depleting it in the cells.

Research has also clearly demonstrated that in prostate cancer cells, continuous treatment with 5 microM sanguinarine induced an early (within 10 min) cellular reduced glutathione depletion, followed by a caspase 3/7-dependent apoptotic response within 2 hr. In 5 microM concentrations, sanguinarine is a powerful inducer of apoptosis. In fact, this research shows antioxidants such as dithiothreitol (DTT) or N-acetylcysteine (NAC) treatment can not prevent this decrease in glutathione. But, antioxidants such as NAC are involved in glutathione regeneration. Thus, pretreatment with the thiol antioxidants NAC and glutathione may abrogate the killing activity of sanguinarine.

Production of hydrogen peroxide and redox cycling can explain how sanguinarine and chelerythrine induce rapid apoptosis. 

Sanguinarine-induced apoptosis: generation of ROS, down-regulation of Bcl-2, c-FLIP, and synergy with TRAIL.

Rapid human melanoma cell death induced by sanguinarine through oxidative stress.

Sanguinarine-induced apoptosis is associated with an early and severe cellular glutathione depletion.

Sanguinarine, a benzophenanthridine alkaloid, induces apoptosis in MDA-MB-231 human breast carcinoma cells through a reactive oxygen species-mediated mitochondrial pathway. 

Sanguinarine also induces apoptosis in primary effusion lymphoma (PEL) cells and pancreatic cancer cells via different mechanisms. Both PEL and pancreatic cancer are known as incurable, aggressive, and develop rapid resistance to conventional chemotherapy. 

Sanguinarine-dependent induction of apoptosis in primary effusion lymphoma cells. 

Sanguinarine induces apoptosis of human pancreatic carcinoma AsPC-1 and BxPC-3 cells via modulations in Bcl-2 family proteins. 

Sanguinarine was added to Prostazym formula, because it can powerfully kill cancer cells by inhibition of Stat3/Survivin signaling pathway and depleting cellular glutathione. Prostazym kills cancer cells only and does not harm your healthy cells. But, it should be avoided during pregnancy. In addition, it has also been proven that gastric problems could be induced when bloodroot is given with herbs that cause gastric irritation, such as ginger and coffee.

Bad breath, also known as Halitosis, is caused by a number of different factors. It may be the result of tooth decay or abscess, chronic gingivitis, disorders of the tonsils, smoking, improper diet and sinuses. Sometimes really bad breath, despite good oral care, comes from dysbiosis (the growth of abnormal bacteria) and yeast infection in the gastrointestinal tract, stomach problems and more seriously, diseases of the lungs and liver.

Maintaining good oral hygiene is one of the most important things you can do for your teeth and gums. If you care about healthy food and healthy bodies, you can extend your concerns to oral care products. Rinsing out the mouth with all natural mouthwash is a large part of good oral hygiene. And there are many benefits of using natural mouthwash. Natural mouthwash freshen your breath instantly for a whole mouth clean and keep your smile bright, without harsh abrasive or irritating chemicals.

Many non-toxic, natural brands exist, but don’t assume all natural mouthwashes are the same. Oralzym-S is the first oral rinse to combine herbal extracts, essential oils, sea salt, natural enzymes, etc to help cleanse your mouth benefiting both your teeth and gums. Oralzym-S is formulated with all natural organic and wild-harvested ingredients for oral hygiene, fresh breath and a naturally brighter smile. It is alcohol and fluoride free, so it’s safe for all ages.

This herbal mouthwash contains a proprietary blend of 7 powerful herbal extracts, natural enzymes, essential oils, and natural grapefruit seed and black seed extracts, and Co Q10, Vitamin K2, zinc and melatonin. It also contains calcium ascorbate, a form of Vitamin C, and aloe vera gel. These ingredients are what help lightly polish your teeth while whitening them right up naturally so they can be sparkle clean and healthy. These ingredients also help fight gum disease, cavities, and bad breathe.

It is clinically proven to whiten teeth within 14 days by gently oxidising stains to reveal the true brightness of your teeth. It is also clinically proven to prevent bad breath by eliminating, not simply masking, odour-causing volatile sulfur compounds (VSC). Oralzym-S is so powerful. It penetrates deep into gum pockets and kills odor-causing bacteria, and whitens without damaging tooth enamel leaving your mouth feeling clean and fresh.

There is no such thing as an ideal natural mouthwash or gargle for stained teeth, bad breath and gum disease i.e. gingivitis and periodontitis. As soon as you start using it, you will feel the power of Oralzym-S. It also helps tighten the gum tissues, stop bleeding and stimulate tissue healing. After dental surgery it will naturally help keep the surgical site clean, aiding in the healing process. The taste of this natural mouthwash definitely differs from the store-bought conventional type.  

Odor-causing bacteria are anaerobic, which means they don’t need oxygen to survive. Instead, they prefer a dry, airless environment. Most of the effort is toward killing odor-causing bacteria, and killing odor-causing bacteria is not effective in most cases. There is no mouthwash that can cure bad breath completely. That said, many a mouthwash can temporarily make bad breath go away, and in some cases – when combined with proper oral hygiene and the use of a tongue scraper – actually vanquish some of the bacteria associated with bad breath. You can try to kill odor-causing bacteria, but by and large, the bacteria grow back quickly and will soon dominate the mouth.

However, some healthy oral bacteria will help in curing bad breath completely with time. Thus, for best results, Oralzym F, a probiotic mouth rinse, is required in conjunction with Oralzym-S. Oralzym-F wins the competition battle because friendly susceptible bacteria have more energy than resistant oral pathogens. Probiotic microbes use their extra energy to produce special enzymes to steal energy resources and block the enzymes of oral pathogens. Oralzym-S kills and weakens odor-causing bacteria, followed by Oralzym-F to destroy the remaining resistant bacteria and replace them with friendly susceptible bacteria

Isolation and characterization of probiotic strains for improving oral health.

Antimicrobial activity of Streptococcus salivarius K12 on bacteria involved in oral malodour.

A preliminary study of the effect of probiotic Streptococcus salivarius K12 on oral malodour parameters.

The rationale and potential for the reduction of oral malodour using Streptococcus salivarius probiotics.

The oral metagenome in health and disease.

Beneficial microbes for the oral cavity: time to harness the oral streptococci?

Growth inhibition of oral mutans streptococci and candida by commercial probiotic lactobacilli–an in vitro study.

The influence of the probiotic Streptococcus salivarius M18 on indices of dental health in children: a randomised double-blind placebo-controlled trial.

An ideal probiotic mouth-rinse must also have a multitude of different bacteria to compete with the existing oral pathogens. Oralzym-F uses a special blend of probiotic cultures to compete with the many oral pathogens. Oralzym-F restores the normal healthy oral flora to help digest food particles, eliminate bad breath and prevent the oral pathogens from returning. It is so important that you don’t use the commercial mouthwash that contains alcohol. Use Oralzym-S in conjunction with Oralzym-F for complete oral care.

EGCG is also able to induce proteasome inhibition in whole cells. Since the inhibition of the proteasome blocks the activation of NF-kB, it is logical to conclude that proteasome inhibitors such as EGCG would have a strong therapeutic effect against cancer, lymphoma and leukemia.

Revisiting the role of EGCG-MAX (Pure Liquid 95% EGCG) in the treatment of all cancers and leukemias

Many studies have investigated the topical use of EGCG to treat cancer. But, human skin is a remarkably efficient barrier designed to keep our insides in and the outside out. The modulation of this efficient barrier’s properties, including its permeability to biologically active agents is the prime target for various dermal and transdermal delivery approaches.

Here is the good news. Topical EGCG-MAX has unique chemical properties that allow it to readily penetrate the skin. This is a unique way to treat cancer cells and leave healthy cells untouched. Topical EGCG-MAX can readily enter the body by absorption via a topical application. It will enter the lymphatic system instead of the blood. This is amazing. It works.

Cancer can appear in the lymph nodes in two ways: it either starts there or spreads there from somewhere else. Cancer that starts in the lymph nodes is called lymphoma. The lymphatics are the primary conduit for the dissemination of metastases from many solid tumours. Distant organ metastasis can occur through both blood vascular and lymphatic vascular routes.

Primary tumors induce new lymphatic vessel growth in draining lymph nodes before metastasis. Increased lymphatic flow and dilation of collecting vessels contributes sentinel lymph node metastasis. The remarkable enlargement of sinusoidal lymphatic endothelium might facilitate tumor cell transport to the lymph nodes, and potentially contribute to the migration, residence, and/or survival of metastatic tumor cancer stem cells by inducing a specific tumor microenvironment. Growth of metastasis inside sentinel lymph nodes may lead to lymphatic dysfunction and a rerouting of flow and metastasis towards alternate lymph nodes.

Lymphatic delivery of EGCG is expected to provide advantages over conventional approaches that focus on the delivery of EGCG via the blood. Localization of EGCG in the lymph and lymph nodes could offer superior outcomes. Therefore, Topical EGCG-MAX could be VERY useful either alone or in combination with conventional therapeutics for the treatment of all cancers, leukemias and lymphomas. Further, Topical EGCG-MAX almost completely stops the transmission of chronic pain impulses in the central nervous system.

Molecular mechanisms and imaging of lymphatic metastasis.

Tumor metastasis and the lymphatic vasculature.

From tumor lymphangiogenesis to lymphvascular niche.

Tumor and lymph node lymphangiogenesis–impact on cancer metastasis.

Prevention of photocarcinogenesis by topical administration of pure epigallocatechin gallate isolated from green tea.

Green tea polyphenol epigallocatechin-3-gallate suppresses melanoma growth by inhibiting inflammasome and IL-1β secretion.

(-)-Epigallocatechin-3-gallate and DZNep reduce polycomb protein level via a proteasome-dependent mechanism in skin cancer cells.

Topical EGCG-MAX allows patients to enjoy the benefits of purified 95% EGCG by applying it directly to their skin in the area(s) where metastasis and primary cancer are found, particularly where the lymph nodes are located. Within one minute after topical application of EGCG-MAX, you could feel the intense sensation in your body. Clearly, topical EGCG-MAX is readily entering the body via a topical application and can kill cancer cells through multiple mechanisms. 

There is a huge literature showing that EGCG kills cancer cells of all kinds. EGCG reactivates epigenetically silenced genes in cancer cells and induces apoptosis and promotes cell growth arrest, by altering the expression of cell cycle regulatory proteins, activating killer caspases, and suppressing nuclear factor kappa-B (NF-kB) activation.

The majority of human cancers demonstrate the inactivation of the p53 pathway. p53 is one of the most frequently mutated tumor suppressor genes in human cancers. EGCG increases p53 transcriptional activity and acetylation by suppressing class I HDACs (histone deacetylases), a function that is likely to be part of the mechanisms that control the physiological activity of p53. Acetylation of p53 at the carboxy-terminal lysine (Lys) residues enhances its transcriptional activity associated with cell cycle arrest and apoptosis.

EGCG-induced stabilization of p53 protein resulted in the regulation of p21 and Bax, thereby positively changing the ratio of Bax/Bcl-2, activating initiator and effector caspases and PARP cleavage, leading to the induction of apoptosis. Besides, EGCG regulates and promotes IL-23 dependent DNA repair and stimulates cytotoxic T cells activities in a tumor microenvironment.

EGCG has been reported to directly bind with the plasma proteins fibronectin, fibrinogen and histidine-rich glycoprotein, Fas, laminin and the 67 kDa laminin receptor, vimentin ZAP-70, Fyn, insulin-like growth factor-I receptor (IGF-IR), and glucose-regulated protein 78 (GRP-78). EGCG also indirectly targets a number of other oncogenic proteins including EGFR, AP-1, and STAT. It also blocks carcinogenesis by modulating the signal transduction pathways, including JAK/STAT, MAPK, PI3K/AKT, Wnt and Notch, involved in cell proliferation, transformation, inflammation and metastasis.

Epigallocatechin Gallate (EGCG) is the most effective cancer chemopreventive polyphenol in green tea.

Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications.

Green tea polyphenols increase p53 transcriptional activity and acetylation by suppressing class I histone deacetylases.

Ablation of either p21 or Bax prevents p53-dependent apoptosis induced by green tea polyphenol epigallocatechin-3-gallate.

Identification of epigallocatechin-3-gallate in green tea polyphenols as a potent inducer of p53-dependent apoptosis in the human lung cancer cell line A549.

Inhibition of PI3K/AKT and MEK/ERK pathways act synergistically to enhance antiangiogenic effects of EGCG through activation of FOXO transcription factor.

Epigallocatechin 3-gallate and green tea catechins: United they work, divided they fail.

Modulation of signaling pathways in prostate cancer by green tea polyphenols.

EGCG suppresses prostate cancer cell growth modulating acetylation of androgen receptor by anti-histone acetyltransferase activity.

Molecular pathway for (-)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells.

Green tea polyphenols and its constituent epigallocatechin gallate inhibits proliferation of human breast cancer cells in vitro and in vivo.

Anti-cancer activities of tea epigallocatechin-3-gallate in breast cancer patients under radiotherapy.

Epigallocatechin-3-gallate inhibits proliferation and migration of human colon cancer SW620 cells in vitro.

EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer.

EGCG inhibits growth of human pancreatic tumors orthotopically implanted in Balb C nude mice through modulation of FKHRL1/FOXO3a and neuropilin.

Furthermore, EGCG stimulates telomere fragmentation through inhibiting telomerase activity, thereby increasing cellular apoptosis and inhibiting cellular proliferation. When cell divide, the ends of the DNA, called telomeres, shorten after every cell division. Eventually, this leads to the death of the cell. Pure and simple, this is a fundamental aspect of normal cell aging.

Unlike normal cells, cancer cells can grow and age without dying. The enzyme telemerase repairs the damaged DNA, thereby increasing the lifespan of the cells. Normal cells contain very low levels of telemerase. The normal cells will divide for a number of divisions and then stop growing. They get old and either they die or they sit there and do nothing. They are mortal. Cancer cells, on the other hand, all cancer cells, contain very high levels of this enzyme.

Cancer cells have very short telomeres. Their telomeres don’t get shortened. This allows cancer cells to escape one of the major aging controls. The only thing keeping these cells alive is their over expression of the enzyme telomerase. Once the ends of the DNA shorten to a prescribed length, the cells will die by programmed cell death. So inhibition of telomerase activity is a major goal of the natural cancer treatment.

Pharmaceutical regulation of telomerase and its clinical potential.

Epigenetic and genetic mechanisms contribute to telomerase inhibition by EGCG.

A novel prodrug of epigallocatechin-3-gallate: differential epigenetic hTERT repression in human breast cancer cells.

EGCG down-regulates telomerase in human breast carcinoma MCF-7 cells, leading to suppression of cell viability and induction of apoptosis.

Apoptosis induction effects of EGCG in laryngeal squamous cell carcinoma cells through telomerase repression.

EGCG, on the other hand, is a powerful natural proteasome inhibitor at very low doses. The proteasome is a multicatalytic proteinase complex responsible for the degradation of most intracellular proteins, including proteins crucial to cell cycle regulation and programmed cell death, or apoptosis. Targeting the proteasome has become an attractive approach in cancer therapy.

Structure-activity study of epi-gallocatechin gallate (EGCG) analogs as proteasome inhibitors.

Green tea polyphenols as a natural tumour cell proteasome inhibitor.

Green tea polyphenols as proteasome inhibitors: implication in chemoprevention.

Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo.

Targeting tumor ubiquitin-proteasome pathway with polyphenols for chemosensitization.

(-)-Epigallocatechin-3-gallate and DZNep reduce polycomb protein level via a proteasome-dependent mechanism in skin cancer cells.

Proteasome inhibitors are much more toxic to leukemia and lymphoma cells than they are to sarcoma and carcinoma cells. The inhibition of the proteasome complex which is absolutely necessary for immune functioning is an excellent way to kill B and T cell lymphomas and leukemias. Immune cells all depend on the activation of NF-kB (a proinflammatory transcription factor) for growth and survival. But, sarcoma and carcinoma cells are less susceptible to the inhibition of NF-kB signaling.

Proteasome inhibitors are known to decrease the level of activated NF-kB in cells. Since the inhibition of the proteasome blocks the activation of NF-kB, proteasome inhibitors such as EGCG would have a stronger therapeutic affect against lymphomas and leulemias than sarcomas and carcinomas.

Velcade (Bortezomib) represents the first proteasome inhibitor to have shown anti-tumor activity in both solid and haematological malignancies. One of the major mechanisms of Velcade is through upregulation of NOXA, which is a proapoptotic protein, and NOXA may interact with the anti-apoptotic proteins of Bcl-2 subfamily Bcl-X(L) and Bcl-2, and result in apoptotic cell death in malignant cells.

Another important mechanism of Velcade is through suppression of the NF-κB signaling pathway, resulting in increased apoptosis, decreased angiogenic cytokine production, and inhibition of tumor cell adhesion to stroma. Moreover, Velcade, mainly by inhibition of the NF-kB pathway, has a chemosensitizing effect when administered together with other antitumoral drugs.

The potential of proteasome inhibitors in cancer therapy.

Proteasome inhibition suppresses essential immune functions of human CD4+ T cells.

Bortezomib in the treatment of cancer.

Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives.

Advances in the understanding of mechanisms and therapeutic use of bortezomib.

Role of NOXA and its ubiquitination in proteasome inhibitor-induced apoptosis in chronic lymphocytic leukemia cells.

Current status of bortezomib in the treatment of multiple myeloma.

Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines.

Proteasomal chymotrypsin-like peptidase activity is required for essential functions of human monocyte-derived dendritic cells.

Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies.

Nuclear factor-kappaB signaling: a contributor in leukemogenesis and a target for pharmacological intervention in human acute myelogenous leukemia.

NF-kappaB as a therapeutic target in chronic lymphocytic leukemia.

The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance.

Although chemotherapy is a therapeutic strategy for cancer treatment, it fails to eliminate all tumor cells due to intrinsic or acquired drug resistance, which is the most common cause of tumor recurrence. Furthermore, NF-kB is induced by all chemotherapy agents and certainly all doses of radiation resulting in a loss of therapeutic effectiveness by these agents.

EGCG has exhibited an appreciable effect on overcoming resistance to various chemotherapeutic drugs as well as multidrug resistance (MDR) in a broad spectrum of tumors ranging from carcinoma and sarcoma to hematological malignances. EGCG acts to enhance the cancer killing properties of the chemo drugs/radiation or the natural medicine, free radical generating drugs.

Tea polyphenols enhance cisplatin chemosensitivity in cervical cancer cells via induction of apoptosis.

Green tea catechins augment the antitumor activity of doxorubicin in an in vivo mouse model for chemoresistant liver cancer.

Modulation of P-glycoprotein function and reversal of multidrug resistance by (-)-epigallocatechin gallate in human cancer cells.

Unfortunately, there isn’t enough EGCG produced in the world to make it useful as a natural treatment for all cancers. EGCG products in supplement form are worthless due to low-purity and (or) low-bioavailability. EGCG is poorly bioavailable orally and extremely unstable. Commercially available EGCG capsules are worthless because the EGCG concentrates in the intestines, and doesn’t enter the body effectively, which means that most of what you swallow goes directly into your gastrointestinal area and is expelled.

In addition, presently commercially available liquid green tea extracts contain low-purity EGCG. Other green tea polyphenols can antagonize the medicinal efficacy of EGCG so it’s important to use a highly pure form of EGCG. In order to introduce the highest purity EGCG into the blood via absorption and maximize the activity in the body, EGCG-MAX can be used. EGCG-MAX is the one and only product in the entire world that has the highest purity and perfect bioavailability of EGCG enough to induce apoptosis of the cancer cells.

EGCG-MAX is pure liquid 95% EGCG, in the form of fat soluble emulsions (alcohol-free). Our expertise in plant extraction, isolation and purification made it possible for them to develop, and produce, a natural liquid green tea extract standardized to 95% EGCG. EGCG-MAX (250 ml bottle) contains 27 g of a green tea extract. 25 g is EGCG. This is the most concentrated form of liquid EGCG on the market (95%).  

Topical EGCG-MAX, on the other hand, can readily enter the body by absorption via a topical application. It will enter the lymphatic system instead of the blood. The lymphatics are the primary conduit for the dissemination of metastases from many solid tumours. Lymphatic delivery of EGCG is expected to provide advantages over conventional approaches that focus on the delivery of EGCG via the blood. Localization of EGCG in the lymph and lymph nodes could offer superior outcomes. Topical EGCG-MAX can be used to treat all cancers including the skin, breast, prostate, and blood cancer.

The main component in nervous system disease is really “autoimmunity”. Such neuropathies as chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré syndrome (GBS), and multifocal motor neuropathy (MMN) are caused by autoimmune mechanisms. Neurological autoimmunity can target virtually any structure within the central or peripheral nervous system and often in a highly specific way, targeting a very specific cell population.

CIDP is the most common chronic inflammatory disease of the peripheral nerves, i.e. nerves outside the brain and spinal cord. An autoimmune attack on the myelin (insulation around individual nerve fibers, called axons) results in demyelination. Demyelination is the degeneration of fatty insulation covering the nerves (the myelin sheath). Loss of myelin can occur in sensory, motor or autonomic nerves. CIDP is a slowly progressive illness with diffuse sensory and motor symptoms.

The symptoms of CIDP begin with a combination of muscle weakness, as well as numbness and pain in the extremities. A person may also have impaired balance and difficulty walking as an early symptom. The disease usually begins in the legs but can begin in the arms at times.  The disease can affect people of any age from childhood through one’s 80’s. Once the disease begins it typically progresses and can cause severe weakness and even death if left untreated.

In contrast, Guillain-Barre syndrome (GBS) patients develop rapidly progressive sensory symptoms such as unusual sensations (paresthesias) and numbness, and motor symptoms such as weakness and cramping in their legs followed by their arms. Patients may also develop weakness of their breathing and difficulty chewing and swallowing. GBS is considered the short-term variant.  From the beginning of the disease and its initial weakness or fatigue to the eventual complete paralysis of the body, most likely takes place within a matter of hours or just a few days.

Multifocal motor neuropathy (MMN) is an inflammatory neuropathy related to an immune attack on motor nerves. It is a purely motor neuropathy affecting multiple motor nerves. MMN is a unique disorder characterized by slowly progressive, asymmetric, distal and upper limb predominant weakness without sensory loss.

Diagnosis, epidemiology and treatment of inflammatory neuropathies. 

Inflammatory neuropathies. 

Chronic neuropathies – chronic inflammatory demyelinating neuropathy and its variants.

Research criteria for defining patients with CIDP.

Chronic inflammatory demyelinating polyneuropathy in common variable immunodeficiency.

Autoimmune neuromuscular disorders in childhood. 

Childhood chronic inflammatory demyelinating polyradiculoneuropathy: Combined analysis of a large cohort and eleven published series.

Multifocal motor neuropathy.

Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies.

Today it is not known what causes autoimmune neuropathies, genetic factors are important, but is not the only explanation for development of an autoimmune neuropathy. Environmental factors, and also some infections, seem to be important as well. Infectious agents that can trigger autoimmunity include bacteria, yeast, and viruses like the Epstein Barr virus.

The autoimmune regulator plays a critical role in central tolerance by promoting thymic expression of self- antigens and deletion of self-reactive T cells. Thus, understanding these disorders ultimately requires an analysis of how the target antigen molecules affect immune cellular interactions both to generate the autoimmune reaction and to produce the immune–mediated injury of the nervous system.

It has been suggested that autoimmunity to peripheral myelin proteins is involved in the pathogenesis of CIDP and GBS. Mutations in myelin proteins (P0, P2 and PMP22) result in a wide spectrum of peripheral neuropathies, from congenital hypomyelinating to late onset sensory and motor axonal forms.

Altered protein level in the cerebrospinal fluid (CSF) is also a characteristic of patients with CIDP and GBS. A recent research shows that GBS is associated with low CSF index levels of prealbumin and fibrinogen, but normal levels of haptoglobin, whereas CIDP is associated with normal CSF index levels of prealbumin, low fibrinogen, and high levels of haptoglobin. 

Humoral and cellular immune responses to myelin protein peptides in chronic inflammatory demyelinating polyradiculoneuropathy.

Immune responses to myelin proteins in Guillain-Barré syndrome.

Defective autoimmune regulator-dependent central tolerance to myelin protein zero is linked to autoimmune peripheral neuropathy. 

Targeting of myelin protein zero in a spontaneous autoimmune polyneuropathy.

Altered cerebrospinal fluid index of prealbumin, fibrinogen, and haptoglobin in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

Viral and bacterial infections can cause indirect nerve damage by provoking conditions referred to as autoimmune disorders, in which specialized cells and antibodies of the immune system attack the body’s own tissues. These attacks typically cause destruction of the nerve’s myelin sheath or axon (the long fiber that extends out from the main nerve cell body).

For example, one theory about GBS involves complications following infection with Campylobacter jejuni, a bacterium commonly associated with food poisoning. This bacterium carries a protein that closely resembles components of myelin. The immune system launches an attack against the bacteria; but, according to the theory, the immune system confuses the myelin with the bacteria in some cases and attacks the myelin sheath as well. 

Infection with certain viruses is also associated with neuropathies. Neuropathy can result from severe vasculitides, a group of disorders in which blood vessels are inflamed. When the blood vessels are inflamed or damaged, blood supply to the nerve can be affected, injuring the nerve.

A novel link between Campylobacter jejuni bacteriophage defence, virulence and Guillain-Barré syndrome. 

Immunoreactivity of glycoproteins isolated from human peripheral nerve and Campylobacter jejuni (O:19).

The neurotropic herpes viruses: herpes simplex and varicella-zoster.

Varicella-zoster virus vasculopathy: immune characteristics of virus-infected arteries.

Neurologic manifestations of varicella zoster virus infections.

As with many neuropathy cases, neurotoxin overload is a common problem that affects many patients. Neurotoxins are substances attracted to our nervous system. They are absorbed through the nerve endings and travel inside the neuron to the cell body. Along the way, they disrupt many nerve cell functions vital to life. The source of neurotoxins may be heavy metals, viruses, bacteria, fungi, molds, parasites and protozoa.

Hihg vitamin intake can also produce neuropathy. Vitamin A toxicity is a good general model of vitamin neurotoxicity, because it shows the importance of the ratio of vitamin and vitamin-binding proteins in producing vitamin toxicity and of CNS permeability barriers. The neurological effects of vitamin deficiency and vitamin excess are similar. There are individual differences in susceptibility to vitamin neurotoxicity, and ordinary vitamin doses may harm occasional patients with genetic disorders.

Many bacteria are able to produce enterotoxins or toxins. The digestive tract is one of the ecosystems that harbors the largest number and greatest variety of bacteria. Among them, certain bacteria have developed various strategies, including the synthesis of virulence factors such as toxins, to interact with the intestinal mucosa, and are responsible for various pathologies.

Various enterotoxins interact with the enteric nervous system, for example by stimulating afferent neurons or inducing neurotransmitter release from enterochromaffin cells which result either in vomiting, in amplification of the diarrhea, or in intestinal inflammation process. Other toxins pass through the intestinal barrier and disseminate by the general circulation to remote organs or tissues, where they are active, and can pass the blood brain barrier and directly act on specific neurons.

Toxins act on the body’s cells, tissues, and organs and interfere with important body processes, thereby interrupting normal body functions. Toxins interfere specifically with key components of critical functions in eukaryotic cells, such as enzyme or hormone receptors on the cell surface or intracellular regulatory proteins. Also, in response to toxins, the body produces special antibodies called antitoxins, which unite with and neutralize the toxins, providing defense against disease.

Medication, toxic, and vitamin-related neuropathies.

Vitamin neurotoxicity.

Microbes and microbial toxins: paradigms for microbial-mucosal interactions II. The integrated response of the intestine to Clostridium difficile toxins.

Bacterial toxins and the nervous system: neurotoxins and multipotential toxins interacting with neuronal cells.

Therefore, the health of the gut bacteria is critical for the immune system. There are literally trillions of bacteria in the gut, and one of their jobs is to regulate the immune system. Gut bacteria influence also development of the CNS and stress responses. Furthermore, the gut is quite literally the second brain, as it originates from the same type of tissue (neural crest) as the brain. During fetal development, one part turns into the CNS, while the other develops into the enteric nervous system (ENS).

These two systems are connected via the vagus nerve, the tenth cranial nerve that runs from the brain stem down to the abdomen. The vagus nerve has also emerged as an important means of communicating signals from gut microbes to the CNS. The brain-gut axis involves interactions among the neural components, including (1) the autonomic nervous system, (2) the central nervous system, (3) the stress system (hypothalamic-pituitary-adrenal axis), (4) the (gastrointestinal) corticotropin-releasing factor system, and (5) the intestinal response (including the intestinal barrier, the luminal microbiota, and the intestinal immune response).

Hence the gut flora, gut and brain work in tandem, each influence the other (the microbiota-gut-brain axis). And this is why the intestinal health can have such a profound influence on the nervous system. This also helps explain the link between neurological disorders (including ADHD and autism) and gastrointestinal dysfunction. The CNS is closely linked to the immune system at several levels.

Thus, an altered immune modulatory balance on nerve cells can be driven by both top-down (ie, CNS pathology) and bottom-up (ie, intestinal immune activation) influences. Dysregulation of the innate and adaptive immune system directed against luminal bacteria or their products found in the intestinal lumen and inappropriate immune responses to organisms in the intestine that normally do not elicit a response, possibly because of alterations in the microbiota-gut-brain axis function.

Biology of the adult enteric neural stem cell. 

The interplay between the intestinal microbiota and the brain. 

The microbiome-gut-brain axis: from bowel to behavior. 

The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. 

On communication between gut microbes and the brain.

The role of probiotics and antibiotics in regulating mucosal inflammation.

Brain-gut interactions in inflammatory bowel disease.

Experimental endotoxemia as a model to study neuroimmune mechanisms in human visceral pain.

Immune system in the brain: a modulatory role on dendritic spine morphophysiology?

Neuro-immune crosstalk in CNS diseases.

Immune activation in the small intestine in patients with rheumatoid arthritis.

In recent decades, our gut flora has been damaged by antibiotics, toxins and by the modern western diet. Imbalance in the gut flora has been shown to directly increase the risk for autoimmunity and other immune disorders. There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases. The overall composition of the microbiota or exposure to specific bacterial strains can modulate neural function, peripherally and centrally. Healthy gut bacteria can provide protection from the central effects of infection and inflammation as well as modulate normal immune responses.

Yet conventional medicine doesn’t take these factors into account when treating autoimmune neuropathies. Instead, it tries to shut down the immune response with powerful medications including nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, immunosuppressive drugs, and new drugs that block the effects of a powerful inflammatory molecule called TNF alpha.

These drugs shut down the immune system so powerfully that they increase the risk of cancer or life-threatening infections. And they have frequent and serious side effects and often give only partial relief. These drugs may be lifesaving for some in the short run — but in the long run they do nothing to deal with the causes.

Our approach to treating autoimmune neuropathy patients is to optimize their immune function which requires optimization of every other body system. We have successfully treated 2 CIDP patiens with Hepazym plus Ginolzym therapy. CIDP and MMN might be controlled and even cured without drugs by this therapy.

Some people with inflammatory bowel disease (IBD) may experience various extra-intestinal symptoms along with their gastrointestinal (GI) symptoms. These can include skin irritation (erythema nodosum), eye problems (episcleritis), and joint pains (arthritis). Some people with IBD also develop mouth sores (oral aphthous ulcers).

Behçet’s syndrome, an inflammatory disease affecting many organs, including the eyes, genitals, skin, joints, blood vessels, brain, and gastrointestinal, can cause recurring, painful mouth sores. Although the gastrointestinal and systemic features of Behcet’s syndrome and IBD overlap to a considerable extent, they are generally viewed as two distinct diseases.

Diagnosis and therapeutic management of extra-intestinal manifestations of inflammatory bowel disease.

A case of intestinal Behcet’s disease similar to Crohn’s colitis.

Potential Infectious Etiology of Behçet’s Disease.

Some studies have suggested that acute gastrointestinal infections with e.g. Salmonella and Campylobacter may initiate the disease process. But these studies have not taken into consideration the fact that patients generally have a lot faecal samples taken during the process of being diagnosed with IBD. Salmonella and Campylobacter infections do not cause chronic IBD. But, the presence of unfriendly bacteria such as Klebsiella pneumoniae and Proteus mirabilis in the digestive tract can be a risk factor for IBD

Much attention has also been focused on the role of measles virus infection and/or vaccination in the pathogenesis of ulcerative colitis (UC) and Crohn’s disease (CD). However, a published report on MMR (measles, mumps, and rubella) vaccination and IBD and pervasive developmental disorders (such as autism) has never been replicated by other studies and has subsequently been retracted by the journal.

There has also been a resurgent interest in potential viral etiologies of IBD, including norovirus (norwalk-like virus) and rotavirus (small bowel) as well as cytomegalovirus (CMV) and herpes simplex virus (HSV) in immune compromised people. CMV colitis is common in patients with IBD (UC and CD) who are on long-term immunosuppressive therapy.

Increased short- and long-term risk of inflammatory bowel disease after salmonella or campylobacter gastroenteritis.

Enteric Salmonella or Campylobacter infections and the risk of inflammatory bowel disease.

Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis.

Measles vaccination and inflammatory bowel disease: controversy laid to rest?

Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine.

Cytomegalovirus in inflammatory bowel disease: pathogen or innocent bystander?

Clinical significance of cytomegalovirus infection in patients with inflammatory bowel disease.

Intestinal epithelial cells play a critical role in mediating the protective responses and there is increasing appreciation of the likely importance of antimicrobial peptides (AMPs) of the defensin family that they express. Defensins are produced at a variety of epithelial surfaces. They are divided into three major groups, α, β and θ-defensins, of which only α and β-defensins have been identified in the intestinal tract.

In the intestinal tract, they contribute to host immunity and assist in maintaining the balance between protection from pathogens and tolerance to normal flora (defensins modulate immune responses). Although it is clear that defensin expression is altered in IBD. However, defensin deficiency is due to mucosal surface destruction as a result of inflammatory changes, indicating that reduced defensin expression is a symptom of the disease and not the cause.

Intestinal antimicrobial peptides during homeostasis, infection, and disease.

Defensins in innate antiviral immunity.

Defensins and inflammation: the role of defensins in inflammatory bowel disease.

Dissecting genetic predisposition to inflammatory bowel disease: current progress and prospective application.

Autophagy (macroautophagy; “self-eating”) has long been recognized as a stress response to nutrient deprivation.  In fact, autophagy is a process by which cells degrade long-lived or insoluble proteins and microorganisms, and it may also regulate inflammation. Thus, autophagy plays critical roles in regulating a wide variety of pathophysiological processes, including tumorigenesis, embryo development, tissue remodeling, and most recently, immunity. The latter shows that a self-eating (autophagy) process could regulate a self-defense (immune) system.

The intestinal mucosa is a site of careful immune regulation where the epithelium and immune cells encounter pathogens as well as a robust and diverse population of indigenous microbes that are predominately bacteria. Autophagy has been shown to modulate the production of pro-inflammatory cytokine production and to contribute to antigen processing and presentation through the major histocompatibility complex.

Recent research suggests several genetic variants linked to IBD, especially CD, are associated with autophagy, a process that is critical for proper responses to viral and bacterial infections. Autophagy plays a critical role in defense against intracellular infection. In turn, evasion or inhibition of autophagy has emerged as an important virulence factor for intracellular pathogens. One of the key proteins involved in the execution of the autophagic process is the modulator, ATG16L1, which is responsible for the membrane localisation of the autophagic machinery and formation of the autophagosome.

The intracellular bacterial sensors, NOD (nucleotide-binding oligomerization domain) 1 and 2, are also important for the autophagic response to invasive bacteria. Colocalisation of NOD1 or NOD2 with ATG16L1 at the cell membrane is a crucial step in the initiation of the autophagic process probably independent of the activation NF-κB (a prototypical proinflammatory signaling pathway).

Defects in this pathway, particularly in individuals that are bearing IBD risk alleles for either NOD2 or ATG16L1, may lead to failed bacterial killing due to impaired lysosomal degradation, inefficient immune-mediated bacterial clearance and consequently to mucosal inflammation. Therefore, it is possible that certain aspects of the autophagy pathway are evolutionarily plastic and critical for a balanced immune response in the face of infectious threats that change over time.

Inflammatory bowel disease: dysfunction of autophagy?.

Autophagy and Intestinal Homeostasis.

Viruses, autophagy genes, and Crohn’s disease.

Role of autophagy and autophagy genes in inflammatory bowel disease.

Autophagy: from basic science to clinical application.

Self-eating and self-defense: autophagy controls innate immunity and adaptive immunity.

Crohn’s disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2.

Innate immune defence: NOD2 and autophagy in the pathogenesis of Crohn’s disease.

Evidence from genetics for a role of autophagy and innate immunity in IBD pathogenesis.

Regulation of innate immune responses by autophagy-related proteins.

Viral infection augments Nod1/2 signaling to potentiate lethality associated with secondary bacterial infections.

Etiology of Crohn’s disease: many roads lead to autophagy. 

Autophagy-related proteins are involved in the innate immune response and may contribute to the development of inflammatory disorders. Proper regulation of innate immune responses by autophagy-related proteins is important for the regulation of innate immunity.  Indeed, the mutations that disrupt autophagy may be the possible trigger for IBD under some infectious conditions.

Intestinal epithelial cells with impaired autophagy lose their adhesive capacity in the presence of TNF-α.

Therefoer, it would be unwise either by adding prednisone (corticosteroid) or increasing the azathioprine (an immunosuppressive drug) in the setting of possible infection. Prednisone can also weaken your immune system. Optimal therapy is orally administered GinolZym and should be initiated promptly for severely ill patients. GinolZym can modulate the autophagic response in the intestinal tract.

The metabolism of both sulfur containing amino acids is closely related. Methionine is one of the essential amino acids with many key roles in mammalian metabolism. It is a precursor for cysteine formation in human liver. Cysteine is classified as semiessential due the variable capacity of the body for its production from methionine. Methionine, although it cannot be regenerated from cysteine, can be recycled through methylation of homocysteine using a single carbon (methyl-) donor such as betaine (from choline), folate, or vitamin B12 (Cobalamin). 

Sulfur is both crucial to life and a potential threat to health. One significant change in the modern diet in areas with high incidence of inflammatory bowel disease (IBD) is the high intake of sulfur-containing food. Sulfur not recycled by an intestinal sulfur salvage pump passes into the colon where it is metabolized, in some, by sulfate-reducing bacteria (SRB), a group of bacteria identified as being much more common in individuals with UC and associated with flares of UC, in particular.

Many bacteria reduce small amounts of sulfates in order to synthesize sulfur-containing cell components. By contrast, the sulfate-reducing bacteria (SRB) reduce sulfate in large amounts to obtain energy and expel the resulting sulfide as waste. Hydrogen sulphide is a by-product of H(2) metabolism by SRB, which are ubiquitous in the colonic mucosa.

Hydrogen sulfide (H2S) is a gas that is toxic in large quantities, but safe in lower quantities for those who are not in vulnerable groups and have developed tolerances. Although higher hydrogen sulphide (H2S) and SRB levels have been detected in patients with IBD, and to a lesser extent in colorectal cancer, this colonic gas might have beneficial effects.

Are we getting enough sulfur in our diet?

Microbial pathways in colonic sulfur metabolism and links with health and disease.

Screening of sulfate-reducing bacteria in colonoscopy samples from healthy and colitic human gut mucosa.

Sulfate-reducing bacteria colonize pouches formed for ulcerative colitis but not for familial adenomatous polyposis.

Emerging role of hydrogen sulfide in colonic physiology and pathophysiology.

Hydrogen sulfide in gastrointestinal and liver physiopathology.

Endogenous production of H2S in the gastrointestinal tract: still in search of a physiologic function.

Impaired detoxication of hydrogen sulfide in ulcerative colitis?

Hydrogen sulfide is an endogenous potentiator of T cell activation.

Some of the large intestine bacteria convert the soluble fiber and resistant starch that are present in undigested food into short-chain fatty acids (SCFAs). One of these fatty acids, called butyric acid, has important health benefits in the colon (the longest section of the large intestine). Green bananas contain a large quantity of resistant starch, which some bacteria can change into butyric acid.

Some foods contain relatively high concentrations of butyric acid, including butter and parmesan cheese. Butter contains 3% to 4% butyric acid. Kombucha tea also contains butyric acid. However, butter also contains longer chained, less healthy fatty acids and consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, can trigger IBD by encouraging the growth of one bacterium in particular, Bilophila wadsworthia, to about six percent of the total bacteria.

Functional interactions between the gut microbiota and host metabolism.

Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature.

Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice.

Butyric acid helps maintain a healthy intestinal lining and has also relieved symptoms in people with inflammatory bowel disease (IBD). In addition, butyric acid lowers the risk of colon cancer. Butyric acid provides the primary fuel for colonocytes. Proper ion transfer, mucus synthesis, phase II detoxification, and lipid synthesis for cell membrane integrity in the colonocytes depend on butyrate oxidation. Impaired metabolism of SCFAs has been implicated as a factor in IBD.

Hydrogen sulphide (H2S) has been shown to inhibit the butyrate oxidation in colonocytes. Study shows that patients with active IBD have significantly lower butyrate oxidation than patients in remission. Because normal oxidation was observed in patients in remission, faulty SCFA oxidation is likely to be a result rather than a primary cause of IBD. High concentrations of SRB with concomitant elevation of hydrogen sulfide (H2S) have been noted in patients with IBD. Therefore, hydrogen sulfide (H2S) can potentially damage the gut mucosa by inhibiting butyrate oxidation in the mitochondria, essentially starving the colonocyte.

Intestinal microbiota in inflammatory bowel disease: friend of foe?

Butyrate and the colonocyte. Implications for neoplasia.

Butyrate and glucose metabolism by colonocytes in experimental colitis in mice.

Effect of butyrate enemas on the colonic mucosa in distal ulcerative colitis.

Combined oral sodium butyrate and mesalazine treatment compared to oral mesalazine alone in ulcerative colitis: randomized, double-blind, placebo-controlled pilot study.

Sulfides impair short chain fatty acid beta-oxidation at acyl-CoA dehydrogenase level in colonocytes: implications for ulcerative colitis.

Methionine is usually found in greater amounts in eggs, fish, red meat, processed meat and dairy products. High dietary intakes methionine (5–6 g/day) on the other hand has been shown to raise plasma levels of homocysteine, despite adequate intakes of B vitamins. Homocysteine is a sulfur-containing, nonproteinogenic amino acid that is an intermediate in methionine metabolism. This raises some concern as one does not want to activate the immune system at the cost of enhancing monocyte adherence to endothelial cells. High homocysteine increases pain and inflammation.

Furthermore, in a study, markedly elevated concentrations of homocysteine in the colonic mucosa were observed in patients suffering from UC and CD. Increased homocysteine levels in the colonic mucosa and plasma of patients with IBD may play a role in the pathogenesis of UC and CD.

The effects of sulfur amino acid intake on immune function in humans.

Homocysteine, cysteine, and glutathione in human colonic mucosa: elevated levels of homocysteine in patients with inflammatory bowel disease.

Summary:  Nutritional factors are important in IBD. The factors currently believed to help prevent or treat IBD are as follows:  

• Diets in the Western world tend to be high in red meat, processed meat, dairy products, saturated fat (milk-derived), total fat, eggs and sugar, and low in fiber and other plant constituents have been associated with a higher risk of IBD. Saturated milk fats may alter gut bacteria causing IBD. Dietary data from Japan suggest that the westernization of traditional Asian diets is associated with increased risk for IBD
• An abnormal host response to the normal intestinal flora (i.e., a cross-reactivity between antibodies produced against bacteria and mucosal proteins) leads to chronic intestinal inflammation. The increase in IBD stemmed from an uncontrolled growth of a certain type of bacteria, including sulfate-reducing bacteria (SRB). These bacteria produce substances that irritate the gut lining and make it more porous, admitting immune cells that trigger inflammation.
• Animal protein (the sulfur-containing amino acids, methionine and cysteine) contributes significantly to the amount of a toxin called hydrogen sulfide (H2S) in the colon, which may increase disease activity in IBD. Additionally, hydrogen sulfide (H2S) may also interfere with the actions of butyrate, an important anti–inflammatory molecule in the colon. Levels of sulfate-reducing bacteria (SRB) tend to be higher in persons with IBD.
• Supplements of B–vitamins may be effective in IBD patients. B–vitamins (vitamin B6, vitamin B12, and folic acid) decrease blood levels of homocysteine, which is thought to play a role in the development of IBD and has been shown to be in higher concentrations in the blood of individuals with IBD.
• Supplements of betaine may be effective at lowering homocysteine levels in your blood. Eat more beets to increase your dietary intake of this nutrient.

GinolZym contains butyrate, a short chain fatty acid (SCFA) that is a potent detoxifier of ammonia and neurotoxins. Butyrate is the single biggest metabolite of fiber. It encourages the formation of friendly bacteria in the gut. Furthermore, GinolZym has an inhibitory effect on most of harmful bacteria in the gut.

UC and CD share many extraintestinal manifestations, although some of these tend to occur more commonly with either condition. UC and CD cause life impairing symptoms (lots of bloody diarrhea, abdominal pain and weight loss), necessitate long-term dependence on powerful anti-inflammatory/immunosuppressant drugs, and often result in debilitating surgery and even death. UC and CD are likely just two symptoms of the same morbidity rather than two different diseases.

IBD is more common among people of Northern European and Anglo-Saxon origin and occurs more frequently in urban communities than in rural areas. Both UC and CD are more common in white-collar workers. The incidence of IBD has risen with the tide of civilization. These suggest that IBD is due to a combination of factors, including genetic predisposition, environmental factors, including diet, pollution, exposure to industrial chemicals, lack of sunlight exposure (lack of vitamin D hormone), infection and chronic stress, and alterations in the function of the immune system.

Inflammatory bowel symptoms are not a disease of the stomach or intestines. That is just where the symptoms have manifested. The true source of this degenerative disease is imbalanced defense mechanism. Therefore, patients with IBD must correct imbalances in the immune system, hormonal system, digestive system and nervous system first, so that the mucus lining of the gut returns to normal and then the body can absorb nutrients again and thus heal itself.

Epithelial tight junctions in intestinal inflammation.

Do we really understand what the immunological disturbances in inflammatory bowel disease mean?

Intestinal bacteria and inflammatory bowel disease.

Role of reactive metabolites of oxygen and nitrogen in inflammatory bowel disease.

Analysis of immediate ex vivo release of nitric oxide from human colonic mucosa in gastrointestinally mediated allergy, inflammatory bowel disease and controls.

Investigating intestinal inflammation in DSS-induced model of IBD.

A variety of changes in the gut flora have been proposed as the root cause of IBD. For example, concentrated milk fats, which are abundant in processed and confectionary foods, alter the composition of bacteria in the intestines. These changes can disrupt the delicate truce between the immune system and the complex but largely beneficial mix of bacteria in the intestines. The emergence of harmful bacterial strains in this setting can unleash an unregulated tissue-damaging immune response that can be difficult to switch off.

The microbial ecosystem in the gut in many different microhabitats can be influenced by diet, leading to formation of metabolic processes that are essential form the bowel metabolism. Current interest therefore focuses on the bacterial community as the source of antigens that fuel the chronic inflammation seen in IBD.  We can’t do much about correcting genes that predispose individuals to increased risk for these diseases. However, the balance between host and microbes can be altered back to a healthy state to treat these diseases.

Current concepts of the intestinal microbiota and the pathogenesis of infection.

Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice.

Patients with inflammatory bowel disease exhibit dysregulated responses to microbial DNA.

Commensal and probiotic bacteria influence intestinal barrier function and susceptibility to colitis in Nod1-/-; Nod2-/- mice.

The role of gut microbiota (commensal bacteria) and the mucosal barrier in the pathogenesis of inflammatory and autoimmune diseases and cancer: contribution of germ-free and gnotobiotic animal models of human diseases.

The gut microbiota and mucosal T cells.

When a person has the wrong species of bacteria and yeasts in the intestines, the condition is called intestinal dysbiosis. Harmful bacteria and fungus spread their toxic humors in the intestines when a natural balance has been disrupted. This can arise in several ways:

• A diet high in sugar, starch and saturated animal fat
• Toxic chemicals and microparticles in food, water, pharmaceutical/supplement excipients or toothpaste constituents.
• Parasites or harmful bacteria or yeast from food or water
• Consumption of food obtained from GMOs (genetically modified organisms)
• Immunosuppression from disease, malnutrition or stress
• Use of antibiotics and NSAIDs
• Use of antibiotics in animal feed
• Natural aging of the GI tract

High intakes of mono- and disaccharides, and total fats consistently increase the risk developing both forms of IBD. High vegetable intake reduces the risk of UC, whereas increased fruit and/or dietary fiber intake appears protective against CD. One significant change in the modern diet in areas with high incidence of UC is the high intake of sulfur-containing food. Sulfur not recycled by an intestinal sulfur salvage pump passes into the colon where it is metabolized, in some, by sulfatereducing bacteria, a group of bacteria identified as being much more common in individuals with UC and associated with flares of UC, in particular.

Low levels of certain micronutrients, especially vitamin D, may increase the risk of both diseases. Some artificial sweeteners (saccharin and sucralose) also can be one of the causes of IBD. Artificial sweeteners reduce beneficial bacteria, damage the intestine, and cause bacterial, antigen, and particle infiltration.

Role of nutrition and microbiota in susceptibility to inflammatory bowel diseases.

Inflammatory bowel disease: role of diet, microbiota, life style.

Screening of sulfate-reducing bacteria in colonoscopy samples from healthy and colitic human gut mucosa.

Sulfate-reducing bacteria colonize pouches formed for ulcerative colitis but not for familial adenomatous polyposis.

Vitamin D and the vitamin D receptor are critical for control of the innate immune response to colonic injury.

Novel role of the vitamin D receptor in maintaining the integrity of the intestinal mucosal barrier.

Etiology of inflammatory bowel disease: a unified hypothesis.

We are exposed to chemicals through the unsafe food we eat, the air we breathe, and the water we drink and bathe in. For example almost all of the dioxin found inside our body got there from eating contaminated food. Whatever its source, somewhere it entered the food chain and made its way into the food we ate. Many seemingly harmless food additives that are in most prepared foods may upset digestion and kill off or damage the friendly intestinal flora.  This is especially the case when these are eaten regularly. They often irritate the intestine and alter its pH or other delicate chemical balances in the intestine.

The mucosal epithelium constitutes a physical and functional barrier between the host and components of the external environment, including nutrients, microbes, and toxicants. Recent study shows that mucosal expression of Elafin, a natural protease (digestive enzyme to help digest proteins) inhibitor expressed in healthy intestinal mucosa, is diminished in patients with IBD. Elafin has pleiotropic anti-inflammatory properties. 

Interaction between food substances and the intestinal epithelium.

Food-grade bacteria expressing elafin protect against inflammation and restore colon homeostasis.

Therapeutic potential of human elafin.

Modifying the protease, antiprotease pattern by elafin overexpression protects mice from colitis.

Allergic and nutritionally related causes also have been the focus of considerable research. Microparticles, which are part of the concept behind toothpaste as a cause, have been suggested more broadly to be the principal factor initiating IBD. It is confirmed that in UK, about 40 mg of exogenous microparticles are ingested per person per day, through exposure to food additives, pharmaceutical/supplement excipients or toothpaste constituents.

Past and current theories of etiology of IBD: toothpaste, worms, and refrigerators.

Dietary microparticles and their impact on tolerance and immune responsiveness of the gastrointestinal tract.

Dietary sources of inorganic microparticles and their intake in healthy subjects and patients with Crohn’s disease.

The presence of harmful bacteria such as Klebsiella pneumoniae and Proteus mirabilis in the gut correlates with IBD. What are these microbes?

Klebsiella is a type of gram-negative bacteria that can cause different types of infections, including pneumonia, bloodstream infections, wound or surgical site infections, and meningitis. Healthy people usually do not get Klebsiella infections. Klebsiella can be spread through person-to-person contact (for example, from patient to patient via the contaminated hands of healthcare personnel, or other persons) or, by consuming contaminated foods. They are also found in human stool (feces).

Proteus mirabilis is another type of gram-negative bacteria that can be found as part of the micro flora in the human intestine. This organism is not usually a pathogen, but does become a problem when it comes into contact with urea in the urinary tract. From there, infection can spread to other parts of the body. It is one of the species responsible for causing urinary tract infections in thousands of people each year in hospitals. P. mirabilis infection can also lead to the production of kidney and bladder stones

Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis.

Antibody responses to gut bacteria in ankylosing spondylitis, rheumatoid arthritis, Crohn’s disease and ulcerative colitis.

A possible link between Crohn’s disease and ankylosing spondylitis via Klebsiella infections.

Chitosan oligosaccharide as potential therapy of inflammatory bowel disease: therapeutic efficacy and possible mechanisms of action.

The gut flora is profoundly influenced by GMOs (genetically modified organisms). GMO is an organism whose genetic structure has been altered by gene splicing. Farm animals have been raised on GM feed for many years. Certainly it means that ill effects may not show up immediately.

Russian researchers fed Campbell hamsters (which have fast reproduction rates) Monsanto GM soy for two years. It should be noted that hamsters do not evolutionarily eat soy—just as cows fed Monsanto corn are actually ruminants and would not naturally eat corn.

After feeding hamsters for two years over three generations, those on the GM diet, and especially the group on the maximum GM soy diet, showed devastating results. By the third generation, most GM soy-fed hamsters lost the ability to have babies. They also suffered slower growth, and a high mortality rate among the pups. And if this isn’t shocking enough, some in the third generation even had hair growing inside their mouths–a phenomenon rarely seen, but apparently more prevalent among hamsters eating GM soy.

When researchers fed male rats GM soy, their testicles changed from the normal pink to dark blue.

A new example of ectopia: oral hair in some rodent species.

Furthermore, a paper shows that consuming GM corn or soybeans leads to significant organ disruptions in rats and mice, particularly in livers and kidneys. Other organs may be affected too, such as the heart and spleen, or blood cells

http://www.enveurope.com/content/pdf/2190-4715-23-10.pdf

The most obvious nutrition concern of GM foods is the risk of allergic reactions. More than 90% of food allergies occur in response to specific proteins in foods. Allergic reactions to GM foods could lead to problems like leaky gut syndrome. Leaky gut syndrome happens when the intestinal lining becomes inflamed, and the microvilli on the lining become damaged. Leaky gut syndrome is also associated with chronic fatigue and depression.

Furthermore, GM foods actually become part of the bacteria in our digestive tracts and reproduce continuously inside us. Even after we stop eating GM foods, we may still have the GM proteins produced continuously inside us. If the antibiotic gene inserted into most GM crops were to transfer, it could create antibiotic-resistant diseases. Bt toxins (produced from Bacillus thuringiensis bacteria—as a method of natural insect control) inserted into GM crops to kill pests could turn bacteria in our intestines into living pesticide. 

Furthermore, animal studies show that DNA in food can travel into organs throughout the body. GM foods genes transferring to our own genes could lead to problems like UC and CD. GM foods could alter our digestive system. The statistical increase in digestive diseases and colorectal cancer can be directly traced to the creation of GM foods. Even after surgery, the UC and CD continued and actually got worse until when to stop eating GM foods and any product containing chemical additives. UC and CD didn’t get there by accident. 

Some producers use GM ingredients in their “natural” breakfast cereals. About 1/2 of U.S. corn crop is grown from GMO seeds. Monsanto provides roughly 90% of GMO seeds in the world. Globally, GM is increasingly seen as a trade issue. However, the US wants to protect its biotechnology industries and is aggressively seeking new markets for its export orientated agricultural sector. For example, despite lingering concerns over the safety of GMO for human consumption, the amount of imported GMO corn and soybeans to South Korea totaled 2.05 million tons in 2010, up 92 per cent from 1.07 million tons in the previous year, according to the data by the Ministry for Food, Agriculture, Forestry and Fisheries. Recent reviews from South Korea also report a sharp increase in the incidence and prevalence of IBD. The incidence of pediatric IBD is increasing rapidly as well.

Genetically modified (GM) foods – renewed threat to Europe

Safety and nutritional assessment of GM plants and derived food and feed: the role of animal feeding trials.

Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut.

The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression.

Most patients with IBD have no idea that oral health and oral bacterial flora are so important to their treatment. Poor oral health and harmful oral bacteria can lead to intestinal failure, irritable bowel syndrome and other digestive disorders. Harmful oral bacteria can enter your bloodstream and attack other tissues. The connection between systemic health and good oral health is well documented. Maintaining good oral health is one of the most important things that patients with IBD can do. You no longer have to put harmful chemicals, toothpastes and irritants into your mouth (most of which can make your symptoms even worse).

Correlation network analysis applied to complex biofilm communities.

The oral microbiome in health and disease and the potential impact on personalized dental medicine.

Deep sequencing of the oral microbiome reveals signatures of periodontal disease.

Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study.

Association between Selected Oral Pathogens and Gastric Precancerous Lesions.

If you are what you eat, then patients with UC and CD are toxic dump sites for the dangerous bacteria residues left in the gut by eating most unsafe foods, factory farmed meats and GM crops. Patients with IBD often note significant improvement in their symptoms within three weeks of starting the GinolZym plus Oralzym (OralZym and OralZym-F) therapy. By twelve weeks, the majority are recovering definitively. GinolZym has an inhibitory effect on gram-negative harmful bacteria such as Klebsiella pneumonia.

One twenty six-year-old patient with UC affecting the rectum had daily bloody diarrhea despite medications for years until initiating the Ginolzym plus Oralzym therapy. She took 4 months to become symptom-free. She now maintains her remission with the Ginolzym plus Oralzym therapy. Another patient with CD, After 3 months, he is completely symptom-free without the aid of medications.