Berberine Antidote for a Modern Epidemic

Oregon_Grape_Berberine_Jeffrey_Dach_MDBerberine, Antidote for a Modern Epidemic

The Leaky Gut Epidemic

My previous article discussed the damaging effect of NSAID drugs on small bowel mucosa, producing a syndrome known as “Leaky Gut” .  PPI antacid drugs (or hypochlorhydria) may also cause dysbiosis and Leaky Gut.   In reality, NSAID and PPI antacid drugs are only two of the many causes of dysbiosis and leaky gut, now reaching epidemic proportions in our population.

Wheat Has Been Modified by Norman Borlaug

My previous article, Wheat Gluten and Leaky Gut, placed the blame on the modification of wheat in the 1970’s by Norman Borlaug who created ” Semi-Dwarf, High Yield” strain of wheat which literally saved 3 billion people from starvation.  However, the new strain of wheat may have contributed to increased celiac disease  and other adverse health effects.(47-51) The incidence of celiac disease has quadrupled over the past 40 years. (47)  Likewise, the incidence of autoimmune disease (linked by Dr.Allesio Fasano to wheat induced leaky gut) continues to increase at an alarming rate.(52)

Left Image : Oregon Grape courtesy of wikimedia commons.

elephant-in-the-room Glyphosate Round up2Glyphosate, The Elephant in the Room

Thanks to the efforts of Stephanie Seneff and Nancy Swanson, we are now aware of the adverse  effects of glyphosate, also known as Round-Up, Monsanto’s widely used herbicide.  Although glyphosate is an herbicide commonly sprayed on Round-Up Ready Soy, it is also sprayed on Wheat fields as a drying agent prior to harvest. Left image Elephant in Room courtesy of Stephanie Seneff.

Incidence of Celiac Disease_GlyphosateNancy Swanson’s 2014 article on Genetically engineered crops Glyphosate and the Deterioration of Health is useful here to illustrate the current epidemic of dysbiosis and Leaky Gut  aggravated by glyphosate.  You can see from the left chart, the incidence of celiac disease rising in tandem with the increasing use of glyphosate on wheat fields.  The next chart showDeaths due to intestinal Infection_Glyphosate_Stephanie Seneffs the increasing incidence of deaths due to intestinal infection, ( pathogenic gut dysbiosis) , also rising in tandem with glyphosate usage.   The third chart below shows  incidence of inflammatory bowel disease (Crohns and Ulcerative Colitis) charted with glyphosate usage.  Again, there is very high correlation.  I direct you to Nancy Swanson’s 2014 article, (Genetically engineered crops and Glyphosate), for more of these charts all remarkably similar in appearance for 22 diseases listed here:  1) hypertension 2) Glyphosate_Inflammatory Bowel Disease_Swansonstroke 3) diabetes prevalence 4) diabetes incidence 5) obesity 6) lipoprotein metabolism disorder 7) Alzheimer’s 8) senile dementia 9) Parkinson’s 10) multiple sclerosis 11) autism 12) inflammatory bowel disease 13)
intestinal infections  14) end stage renal disease  15) acute kidney failure 16)
cancers of the thyroid  17 cancer of liver  18) cancer of, bladder 19) cancer of pancreas 20) cancer of  kidney 21) myeloid leukaemia.

Low Level Endo-Toxemia and LPS

One might argue that “Leaky Gut” and low level endotoxemia are causative of many diseases.  Dysbiosis and Leaky Gut with translocated LPS (lipopolysacharide), is a form of low level endotoxemia which triggers inflammatory response in the gut wall, the endothelium and the brain.

What About Glyphosate ?

Dr Seneff has meticulously described the many mechanisms by which glyphosate disrupts normal cellular physiology in her many articles.  The antimicrobial effect of glyphosate kills off our beneficial gut bacteria allowing overgrowth of the resistant Clostridia and other pathogens creating Dysbiosis. The chelating effect of glyphosate causes depletion of important minerals such as cobalt (needed for B12), selenium and Iron.  Another effect of glyphosate is inhibition of  Cytochrome P450 system, preventing degradation and removal of drugs and toxins which then accumulate in the body.

Berberine the Perfect Botanical for Leaky Gut

Clostridium_difficile_sporeThis brings us back to our original topic, the heath benefits of Berberine.  It just so happens that Berberine is perhaps the most effective supplement for dysbiosis and “Leaky Gut”, and can be considered the “Antidote to our Current Epidemic”.

I must give credit and thanks to Dr Jonathan Wright’s newsletter which first alerted me to the benefits of Berberine, a botanical extract available from the Oregon Grape, and other Chinese herbal plants.  My previous article mentions Berberine as an excellent replacement for Metformin as an anti-diabetic agent, both of which upregulate AMP kinase, thereby exerting many of the health benefits.  Two excellent review articles nicely summarize the many health benefitys of Berberine.(1,2)

Berberine Closes the Tight Junctions in Leaky Gut

Getting back to our epidemic of Leaky Gut, the mechanism as described by Alesio Fasano MD in his 2011 article in Physiology Reviews,  involves excess Zonulin release which prolongs the opening of the “Tight Junctions” between gut epithelial cells.  Thus allowing leakage of large food particles, and enteric bacteria (LPS) into the circulation.  This creates a state of low level endotoxemia.  Thankfully this is not severe enough to throw the patient into septic shock with an admission ticket to a ventilator bed in the ICU.  However, this state of low level endotoxemia is plenty bad.  It triggers a cascade of inflammatory cytokines (NF-κB, IL-6) responsible for many of the 22 diseases in Nancy Swanson’s list.

Inflammation in the Brain – Microglial activation

Inflammation in the brain causes micro-glial activation which is associated with depression and chronic fatigue, as well as hypothalmic dysfunction associated with endocrine abnormalities such as inhibition of gonadotropins (LH,FSH), and  TSH producing central hypogonadism and central hypothyroidism.   There is also disturbance of the autonomic nervous system which is associated with hypertension.   The endothelium responds to the low level endotoxemia by forming atherosclerotic plaque at areas of arterial shear injury such as bifurcations.

Berberine Closes the Tight Junctions in Leaky Gut

Berberine has been used for centuries as a folk remedy for watery diarrhea.   More recently, berberine has been found useful in preventing relapse of Clostridia enterocolitis after Vancomycin treatment in a mouse model.(19)

If dysregulation of Zonulin with prolonged opening of the Tight Junctions is the underlying pathophysiology of watery diarhhea (as in Vibrio Cholera Toxin producing diarrhea), then a therapy which closes these Tight Junctions would be beneficial.  That is exactly what berberine does.

Berberine actually closes down  the “Tight Junctions” in the gut epithelial cells.(3-6)  Dr Gu studied the effect of berberine on the Tight Junctions in 2009: “These findings showed the first time that berberine could reduce epithelial gut permeability, and might help explain the possible mechanisms of anti-diarrhea activity of berberine.”(5)   In 2013, Dr Chen suggested berberine as “an efficient treatment option for the adverse effect of NSAIDs in the small intestine.”(6)

Blocking the Inflammatory Cascade in Macrophages

As mentioned above, low level endotoxemia (also called LPS) activates an inflammatory cascade in macrophages, the immune white cells circulating in the blood stream.  Again it would seem logical to devise a therapy to block or down-regulate this inflammatory response.  That is exactly what berberine does. Dr Jeong says in 2009: “berberine represses proinflammatory responses through AMP Kinase activation in macrophages.”(8)  Berberine downregulated expression of pro-inflammatory genes such as TNF-alpha, IL-1beta, IL-6, etc.(8)

Blocking Toll Receptors in Immune Cells

The cells of our immune system are able to recognize LPS-endotoxin by virtue of Toll receptors, which then initiate the inflammatory cytokine cascade .  (NF-κB induces cytokines TNF-α, IFN-γ, IL-1, IL-6).  Therefore, blocking these Toll receptors would prevent the inflammatory response.  That is exactly what berberine does.(9)  In 2014 Dr Chu studied the therapeutic effects of berberine against LPS-induced diseases. (9)  He found that berberine blocks the Toll receptor in LPS treated mice.(9)  Berberine exhibited significant anti-endotoxin effects by blocking LPS signaling.  Dr Chu concludes: “With the advantage of lower cost, faster currative effect, and little side effect, berberine, the newly-discovered LPS antagonist, could be widely utilized as a substitute for expensive drugs in the treatment of LPS-induced diseases. “

Major Depressive Disorder (MDD)

Michael Maes MD and others have discovered translocated LPS induced brain inflammation as the underlying cause of major depressive disorder, chronic fatigue and fibromyalgia.  In their studies, they have found elevated antibodies to LPS, Leaky Gut, and LPS-activation of micro-glia in the hypothalamus and brain in general in these patients. (41-45)

Berberine Acts as an Anti-Depressant

In 2007, Dr Chu studied the effect of berberine In a mouse model of depression.  He found that berberine “exerts antidepressant-like effect. The antidepressant-like mechanism of Berberine may be related to the increase in Noradrenline and 5-Hydroxytryptamine (serotonin) levels in the hippocampus and frontal cortex.”  (10) This was thought to the due to berberine’s inhibition of  monoamine oxidase-A, the enzyme which degrades norepinephrine and serotonin (5-HT).(11)   Dr Kulkarni studied berberine treated mice in 2008 finding “increased levels of norepinephrine (31%), serotonin (47%) and dopamine (31%) in the whole brain” (11)

Berberine Protect Against Brain Inflammation

Microglial Acitvation after LPS Injection Fig 3 Qin 2007Left image: Left column controls. Right Column shows activated microglia after LPS injection in mouse model of brain inflammation. from  Qin, Liya et al. “Systemic LPS Causes Chronic Neuro inflammation and Progressive Neurodegeneration.” Glia 55.5 (2007): 453–462.

In a study published in 2014, using a mouse model of controlled traumatic brain injury, Dr Chen studied the protective effects of berberine. (12)  Dr Chen found that “Berberine reduces trauma-induced brain damage by limiting the production of inflammatory mediators by glial cells, rather than by a direct neuroprotective effect.”(12)  In a 2013 article, Dr Kapoor speculates that berberine would be of considerable benefit in neuropsychiatric disorders including Alzheimer’s dementia.(13)(36)  Dr Kapoor further identified the anti-inflammatory effect of berberine due to inhibition of  “nuclear factor kappaB by blocking the mitogen-activated protein kinase (MAPK)” pathway”(13)  Further studies showed berberine a potent inhibitor of neuro-inflammation by activation of (AMP Kinase) AMPK signaling pathways in micro-glial cells.(14,15)  Other natural products which inhibit micro-glial activation are resveratrol and pterostilbene.(17,18)  Berberine may be a natural neuroprotective agent, as it prevents glutamate release by terminal nerve ending, thus protecting brain tissue form over-activation.(38)

Anti Microbial Effect of Berberine – Treats Infection

Dr Chu reviewed the anti-bacterial qualities of berberine in a 2014 article in Clinical Microbiology.(20)  Dr Chu noted numerous clinical trials showing berberine is effective for acute diarrhea.  Berberine inhibits bio-film formation, and has anti-inflammatory properties, competing with LPS at the Toll receptors. (20)  Berberine’s demonstrates remarkable anti-microbial activity against chlamydia (both Trachoma and Urogenital types). (21-23)

Berberine for the CaBerberine_wikimediardiovascular System

By virtue of its activation of the AMP kinase pathway, berberine inhibits atherosclerosis in genetically modified mice, thus may serve as a treatment to reduce calcium score.(27-29) (35)  Berberine has been found useful in congestive heart failure and cardiomyopathy by increasing the ejection fraction, and preventing arrythmia  in this group.(39-40)   Left Image chemical structure of Berberine courtesy of Wikimedia commons.

Berberine for Type Two Diabetes, Metabolic Syndrome, Obesity

Berberine was found useful in multiple studies for controlling blood sugar, improving lipid profile, and insulin resistance in metabolic syndrome. (30-32)

Pesticides and Herbicides – History Repeats Itself

Polio Incidence and Pesticide ProductionLeft Image: chart shows incidence of polio (blue line), and Pesticide production (dotted line) both peaked in 1952, and thereafter declined. Polio cases peaked and declined in tandem with pesticide production.   The Salk vaccine was announced in April 1955, 3 years after the peak in cases. Courtesy of Jim West. Townsend Letter.  Images of Poliomyelitis – A Critique of Scientific Literature, #203, p.68-75

In the post-war era, 1945 to 1955 there was a striking increase in production and use of agricultural pesticides such as DDT, rising in tandem with an epidemic of neurologic disease characterized by acute flaccid paralysis in children.  Although the epidemic was thought to be caused by a virus (called the polio virus), it was most likely the use of DDT and other neurotoxic  pesticides which caused the epidemic.  The peak of pesticide use coincided with the peak in cases, and declined thereafter.  The polio vaccine was introduced in 1955,  after a considerable decline in cases was already underway.

Glyphosate and DDT – History Repeats Itself

One could say that history is repeating itself.  Glyphosate production and use is rising exponentially in tandem with 22 diseases, yet the manufacturer, Monsanto claims their glyphosate is safe for humans.    The reality is quite different. Glyphosate, a toxic chemical contaminating our food and water is known to cause cancer,  birth defects, and a multitude of diseases described by Drs Swanson and Seneff.  Will we see a decline in this epidemic after halting the use of glyphosate?  The only way to find out is to ban glyphosate and watch the disease incidence plummet. In the mean time, eliminate glyphosate by going gluten free and GMO free.  The botanical, Berberine, is an excellent modality for this epidemic of Leaky Gut and low level endotoxemia, serving to close the tight junctions in the gut, and down-regulate LPS induced inflammation in the gut, endothelium and the brain.

Buy Berberine from Thorne on Amazon.

Articles with Related Interest:

Low Level  Endotoxemia LPS and Leaky Gut

Fecal Transplant and the Sweet Smell of success

The Failure of Global Polio Eradication

Spraying DDT to Eradicate Polio

Metformin the Miracle Drug

Antibiotics Cures Autism

Dr Oz Smear Campaign BAck-Fires

Michael Maes Leaky Gut Depression

Jeffrey Dach MD
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Links and References:

Berberine excellent overview

1) Yao, Jing, WeiJia Kong, and JianDong Jiang. “Learning from berberine Treating chronic diseases through multiple targets Jing 2013.  Learning from berberine: Treating chronic diseases through multiple targets.” Science China Life Sciences (2013): 1-6.

2) Berberine Alkaloid with wide spectrum of pharmacological activities SIngh 2010  Berberine: Alkaloid with wide spectrum of pharmacological activities
1Amritpal Singh*, 2 Sanjiv Duggal, 3 Navpreet Kaur, 4 Jaswinder Singh
1Dept of Dravyaguna, Sri Dhanwantry Ayurvedic College, Sec 46-C, Chandigarh 2Dept of Pharmaceutical Sciences, Lovely Professional

For example, in cultured cells, BBR suppressed lipopolysaccharide (LPS)-induced NF-κB activation and subsequent inflammation [40].

BBR also has effects on the nervous system. In animal models, for example, BBR treatment was shown to improve brain function (memory and learning capacity) and to relieve depression [45, 47].

Berberine closes down the tight junctions in leaky gut !!!

3) Amasheh, Maren, et al. “TNFα-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, Akt and NFκB signaling.” Journal of cell science 123.23 (2010): 4145-4155.

4) http://jid.oxfordjournals.org/content/203/11/1602.full
Gu, Lili, et al. “Berberine ameliorates intestinal epithelial tight-junction damage and down-regulates myosin light chain kinase pathways in a mouse model of endotoxinemia.” Journal of Infectious Diseases 203.11 (2011): 1602-1612.

In conclusion, our data indicate—to our knowledge, for the first time—that BBR can ameliorate intestinal epithelium TJ disruption in a mice model of endotoxinemia, and the possible mechanism for this may be related to the inhibition of NF-κB and the MLCK signaling pathway.

5) http://www.ncbi.nlm.nih.gov/pubmed/19243699
Fitoterapia. 2009 Jun;80(4):241-8.
The effect of berberine in vitro on tight junctions in human Caco-2 intestinal epithelial cells. Gu L1, Li N, Li Q, Zhang Q, Wang C, Zhu W, Li J.
Berberine is one of the main alkaloids of Rhizoma coptidis which has been used for patients with gastrointestinal disorders. The major aim of this study was to investigate the effect of berberine on tight junction. Caco-2 cells were treated with various concentration of berberine. We observed the integrity of tight junction by measuring the transepithelial electrical resistance (TEER), and also studied the effect of berberine on morphology of tight junction and tight junction protein. These findings showed the first time that berberine could reduce epithelial gut permeability, and might help explain the possible mechanisms of anti-diarrhea activity of berberine.

full pdf..

6) Chen, Chunqiu, et al. “Effects of berberine in the gastrointestinal tract—A review of actions and therapeutic implications.” The American journal of Chinese medicine 42.05 (2014): 1053-1070.  Effects of berberine in the gastrointestinal tract Chen Chunqiu 2014

Recently, a novel mechanism has been suggested to explain the anti-diarrheal effect of berberine. It was found that berberine reinforces the tight junctions in the Caco-2 cell line, reduces epithelial permeability in the gut, and significantly increases transepithelial electrical resistance (Gu et al., 2009).

Lipopolysaccharide (LPS) found in the outer membrane of gram-negative bacteria has been recognized as the major initiator of sepsis. LPS released by E. coli can injure the microcirculation and vascular endothelial cells and promote the excessive secretion of immuneassociated cytokines\\

Berberine may be an efficient treatment option for the adverse effect of
NSAIDs in the small intestine.

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Berberine – Anti-inflammatory effect in LPS stimulated macrophages

7) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901384/  full free
Mo, C., et al. “The crosstalk between Nrf2 and AMPK signal pathways is important for the anti-inflammatory effect of berberine in LPS-stimulated macrophages and endotoxin-shocked mice.” Antioxidants & redox signaling 20.4 (2014): 574.

we examined the effect of BBR on inflammatory stress by utilizing LPS-stimulated macrophages and LPS-shocked mice in the present study.

Our results demonstrate the importance of Nrf2 pathway for the anti-inflammatory role of BBR, and provide the evidence showing that AMPK pathway is connected with Nrf2 pathway.

BBR prevented LPS-induced production of inflammatory cytokines and NF-κB activation

Berberine supresses pro-inflammatory response –  AMPK activation in macrophages

8) http://www.ncbi.nlm.nih.gov/pubmed/19208854
Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E955-64.
Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Jeong HW1, Hsu KC, Lee JW, Ham M, Huh JY, Shin HJ, Kim WS, Kim JB.

Berberine (BBR) has been shown to improve several metabolic disorders, such as obesity, type 2 diabetes, and dyslipidemia, by stimulating AMP-activated protein kinase (AMPK). However, the effects of BBR on proinflammatory responses in macrophages are poorly understood. Here we show that BBR represses proinflammatory responses through AMPK activation in macrophages. In adipose tissue of obese db/db mice, BBR treatment significantly downregulated the expression of proinflammatory genes such as TNF-alpha, IL-1beta, IL-6, monocyte chemoattractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Consistently, BBR inhibited LPS-induced expression of proinflammatory genes including IL-1beta, IL-6, iNOS, MCP-1, COX-2, and matrix metalloprotease-9 in peritoneal macrophages and RAW 264.7 cells. Upon various proinflammatory signals including LPS, free fatty acids, and hydrogen peroxide, BBR suppressed the phosphorylation of MAPKs, such as p38, ERK, and JNK, and the level of reactive oxygen species in macrophages. Moreover, these inhibitory effects of BBR on proinflammatory responses were abolished by AMPK inhibition via either compound C, an AMPK inhibitor, or dominant-negative AMPK, implying that BBR would downregulate proinflammatory responses in macrophages via AMPK stimulation.

9) http://www.biomedcentral.com/1472-6882/14/89/   free full
Chu, Ming, et al. “Role of berberine in anti-bacterial as a high-affinity LPS antagonist binding to TLR4/MD-2 receptor.” BMC complementary and alternative medicine 14.1 (2014): 89.

Conclusion: Berberine can act as a LPS antagonist and block the LPS/TLR4 signaling from the sourse, resulting in the anti-bacterial action.

 

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Berberine Neuro-Psychiatric Uses As Antidepressant

10) http://www.ncbi.nlm.nih.gov/pubmed/17804020  full pdf available
Life Sci. 2007 Aug 23;81(11):933-8. Epub 2007 Aug 16.
Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice.  Peng WH1, Lo KL, Lee YH, Hung TH, Lin YC.

This study investigated the effect of berberine (BER) in the mouse forced swim test (FST) and in the tail suspension test (TST), two models predictive of antidepressant activity. We also investigated the antidepressant-like mechanism of BER by the combination of the desipramine [DES, an inhibitor of reuptake of noradrenaline (NA) and serotonin (5-HT)], maprotiline (MAP, selective NA reuptake inhibitor), fluoxetine (FLU, selective 5-HT reuptake inhibitor) and moclobemide [MOC, monoamine oxidase (MAO) A inhibitor). Then we further measured the levels of monoamines [NA, dopamine (DA) and 5-HT) in mice striatum, hippocampus and frontal cortex. The results show that BER (10, 20 mg/kg, p.o.), significantly reduced the immobility time during the FST and the TST. The immobility time after treatment with BER (20 mg/kg, p.o.) in FST was augmented by DES, FLU and MOC, and not affected by MAP. Furthermore, BER (20 mg/kg, p.o.) increased NA and 5-HT levels in the hippocampus and frontal cortex.

Our findings support the view that BER exerts antidepressant-like effect. The antidepressant-like mechanism of BER may be related to the increase in NA and 5-HT levels in the hippocampus and frontal cortex.

11) http://www.ncbi.nlm.nih.gov/pubmed/18585703
Eur J Pharmacol. 2008 Jul 28;589(1-3):163-72.
On the mechanism of antidepressant-like action of berberine chloride.
Kulkarni SK1, Dhir A.

Berberine, an alkaloid isolated from Berberis aristata Linn. has been used in the Indian system of medicines as a stomachic, bitter tonic, antiamoebic and also in the treatment of oriental sores. Evidences have demonstrated that berberine possesses central nervous system activities, particularly the ability to inhibit monoamine oxidase-A, an enzyme involved in the degradation of norepinephrine and serotonin (5-HT). With this background, the present study was carried out to elucidate the antidepressant-like effect of berberine chloride in different behavioural paradigms of despair.

Berberine (5, 10, 20 mg/kg, i.p.) inhibited the immobility period in mice in both forced swim and tail-suspension test, however, the effect was not dose-dependent. Berberine (5 and 10 mg/kg, i.p.) also reversed the reserpine-induced behavioral despair. Berberine (5 mg/kg, i.p.) enhanced the anti-immobility effect of subeffective doses of various typical but not atypical antidepressant drugs in forced swim test. Berberine (5 mg/kg, i.p.) following its acute administration in mice resulted in increased levels of norepinephrine (31%), serotonin (47%) and dopamine (31%) in the whole brain. Chronic administration of berberine (5 mg/kg, i.p.) for 15 days significantly increased the levels of norepinephrine (29%), serotonin (19%) as well as dopamine (52%) but at higher dose (10 mg/kg, i.p.), there was no change in the norepinephrine (12%) levels but a significant increase in the serotonin (53%) and dopamine (31%) levels was found. The antidepressant-like effect of berberine (5 mg/kg, i.p.) in forced swim test was prevented by pretreatment with l-arginine (750 mg/kg, i.p.) or sildenafil (5 mg/kg, i.p.). On the contrary, pretreatment of mice with 7-nitroindazole (7-NI) (25 mg/kg, i.p.) or methylene blue (10 mg/kg, i.p.) potentiated the effect of berberine (2 mg/kg, i.p.) in the forced swim test. Pretreatment of mice with (+)-pentazocine (2.5 mg/kg, i.p.), a high-affinity sigma1 receptor agonist, produced synergism with subeffective dose of berberine (2 mg/kg, i.p.). Pretreatment with various sigma receptor antagonists viz. progesterone (10 mg/kg, s.c.), rimcazole (5 mg/kg, i.p.) and N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD1047; 1 mg/kg, i.p.) reversed the anti-immobility effects of berberine (5 mg/kg, i.p.). Berberine at lower dose did not affect the locomotor activity and barbiturate-induced sleep time. It produced mild hypothermic action in rats and displayed analgesic effect in mice. Taken together, theses findings demonstrate that berberine exerted antidepressant-like effect in various behavioural paradigms of despair possibly by modulating brain biogenic amines (norepinephrine, serotonin and dopamine). Further, nitric oxide pathway and/or sigma receptors are involved in mediating its antidepressant-like activity in mouse forced swim test.

Berberine — Protects against Brain inflammation

12) http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115694  full free
Chen, Chien-Cheng, et al. “Berberine Protects against Neuronal Damage via Suppression of Glia-Mediated Inflammation in Traumatic Brain Injury.” PloS one 9.12 (2014): e115694.
Traumatic brain injury (TBI) triggers a series of neuroinflammatory processes that contribute to evolution of neuronal injury. The present study investigated the neuroprotective effects and anti-inflammatory actions of berberine, an isoquinoline alkaloid, in both in vitro and in vivo TBI models. Mice subjected to controlled cortical impact injury were injected with berberine (10 mg·kg−1) or vehicle 10 min after injury. In addition to behavioral studies and histology analysis, blood-brain barrier (BBB) permeability and brain water content were determined. Expression of PI3K/Akt and Erk signaling and inflammatory mediators were also analyzed. The protective effect of berberine was also investigated in cultured neurons either subjected to stretch injury or exposed to conditioned media with activated microglia. Berberine significantly attenuated functional deficits and brain damage associated with TBI up to day 28 post-injury.

Berberine also reduced neuronal death, apoptosis, BBB permeability, and brain edema at day 1 post-injury. These changes coincided with a marked reduction in leukocyte infiltration, microglial activation, matrix metalloproteinase-9 activity, and expression of inflammatory mediators. Berberine had no effect on Akt or Erk 1/2 phosphorylation. In mixed glial cultures, berberine reduced TLR4/MyD88/NF-κB signaling. Berberine also attenuated neuronal death induced by microglial conditioned media; however, it did not directly protect cultured neurons subjected to stretch injury. Moreover, administration of berberine at 3 h post-injury also reduced TBI-induced neuronal damage, apoptosis and inflammation in vivo. Berberine reduces TBI-induced brain damage by limiting the production of inflammatory mediators by glial cells, rather than by a direct neuroprotective effect.

13) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662308/
Kapoor, Shailendra. “Comment on “Berberine and Its Emerging Benefits in Psychiatric Conditions Especially Alzheimer’s Disease”.” The Scientific World Journal 2013 (2013).
I read with great interest the recent paper by Ji and Shen [1]. Berberine may be of considerable benefit in a number of psychiatric disorders especially in Alzheimer’s disease.

Berberine inhibits the activation of nuclear factor kappaB by blocking the “mitogen-activated protein kinase” pathway [2]. Simultaneous inhibition of the phosphoinositide 3-kinase/protein kinase B pathway is also seen. Tau phosphorylation is also significantly attenuated. As a consequence, amyloid-beta peptide-stimulated production of IL-6 is markedly attenuated resulting in a significant reduction in neuroinflammation. Besides this, berberine markedly attenuates glycogen synthase kinase-3 activity [3]. Berberine also has an attenuating effect on the C-terminal fragments of amyloid precursor protein, thereby ultimately reversing learning defects in animal models. Berberine also activates the ERK1/2 pathway, thereby attenuating the expression of beta secretase which in turn further decreases the beta-amyloid production [4, 5]. Similarly, berberine exerts antidepressant effects in animal models. It mediates this function by altering intracranial dopamine, serotonin, and norepinephrine levels [6]. Its antidepressant effect is also mediated by and modulation of the nitric oxide pathway.

The above examples clearly illustrate the emerging role of berberine in psychiatry and the need for further studies in this regard.

14) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526741/
Lee, Bombi, et al. “Effect of berberine on depression-and anxiety-like behaviors and activation of the noradrenergic system induced by development of morphine dependence in rats.” The Korean Journal of Physiology & Pharmacology 16.6 (2012): 379-386.

15) http://www.ncbi.nlm.nih.gov/pubmed/20512929/
Lu, Dah‐Yuu, et al. “Berberine suppresses neuroinflammatory responses through AMP‐activated protein kinase activation in BV‐2 microglia.” Journal of cellular biochemistry 110.3 (2010): 697-705.

The AMPK cascade is a sensor of cellular energy change, which monitors the AMP/ATP ratio to regulate cellular metabolism by restoring ATP levels, but its regulation of neuroinflammation mechanism remains unclear.

Berberine, one of the major constituents of Chinese herb Rhizoma coptidis, has been shown to improve several metabolic disorders, such as obesity and type II diabetes. However, the effect of berberine on neuroinflammatory responses in microglia are poorly understood.

This study shows that berberine represses proinflammatory responses through AMP-activated protein kinase (AMPK) activation in BV-2 microglia. Our findings also demonstrate that berberine significantly down-regulates LPS- or interferon (IFN)-gamma-induced nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) expression in BV-2 microglia cells.

Berberine also inhibited LPS– or IFN-gamma-induced nitric oxide production. In addition, berberine effectively inhibited proinflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6 expression. On the other hand, upon various inflammatory stimulus including LPS and IFN-gamma, berberine suppressed the phosphorylated of ERK but not p38 and JNK in BV-2 microglia. AMPK activation is catalyzed by upstream kinases such as LKB1 and Ca2+/calmodulin-dependent protein kinase kinase-II (CaMKK II). Moreover, berberine induced LKB1 (Ser428), CaMKII (Thr286), and AMPK (Thr172) phosphorylation, but not AMPK (Ser485). Furthermore, the inhibitory effect of berberine on iNOS and COX-2 expression was abolished by AMPK inhibition via Compound C, an AMPK inhibitor. Berberine-suppressed ERK phosphorylation was also reversed by Compound C treatment. Our data demonstrate that berberine significantly induces AMPK signaling pathways activation, which is involved in anti-neuroinflammation.

 

Berberine is Neurotoxic in Parkinsons’s on Long Term L-Dopa  ????

16) http://www.ncbi.nlm.nih.gov/pubmed/23539311
Arch Pharm Res. 2013 Jun;36(6):759-67. doi: 10.1007/s12272-013-0051-4. Epub 2013 Mar 29.
Neurotoxic effects of berberine on long-term L-DOPA administration in 6-hydroxydopamine-lesioned rat model of Parkinson’s disease.
Shin KS1, Choi HS, Zhao TT, Suh KH, Kwon IH, Choi SO, Lee MK.

The effects of berberine on long-term administration of L-DOPA in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease (PD) were investigated. Rat models of PD were prepared by 6-OHDA lesions in the ipsilateral sides, and then were treated with berberine (5 and 15 mg/kg) and/or L-DOPA (10 mg/kg) once daily for 21 days. Treatments with either concentration of berberine (5 and 15 mg/kg) in 6-OHDA-lesioned groups decreased the numbers of tyrosine hydroxylase (TH)-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum as compared to 6-OHDA-lesioned groups. In addition, dopaminergic neuronal cell death of the ipsilateral sides in 6-OHDA-lesioned groups was attenuated by L-DOPA administration. However, both concentrations of berberine in 6-OHDA-lesioned groups treated with L-DOPA aggravated the numbers of TH-immunopositive neurons in the substantia nigra and the levels of dopamine, norepinephrine, DOPAC and HVA in the striatum as compared to rats not treated with berberine. These results suggest that berberine leads to the degeneration of dopaminergic neuronal cells in the substantia nigra in the rat model of PD with chronic L-DOPA administration. Long-term L-DOPA therapy that may involve possibly neurotoxic isoquinoline agents including berberine should involve monitoring for adverse symptoms.

Inhibitors of Microglial Activation

17) free pdf  Inhibitors of microglial neurotoxicity natural products Choi 2011. Choi, D. K., S. Koppula, and K. Suk. “Inhibitors of microglial neurotoxicity: focus on natural products.” Molecules (Basel, Switzerland) 16.2 (2011): 1021.

Resveratrol and Pterostilbene Prevent microglial activation by LPS

18) http://www.ncbi.nlm.nih.gov/pubmed/18513711
Chem Biol Interact. 2008 Jul 10;174(1):51-9.
Effects of resveratrol and its derivatives on lipopolysaccharide-induced microglial activation and their structure-activity relationships.
Meng XL1, Yang JY, Chen GL, Wang LH, Zhang LJ, Wang S, Li J, Wu CF.
1Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.

The inhibitory effects of 21 resveratrol derivatives on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in microglia and their structure-activity relationships were studied. It was found, for the first time, that certain resveratrol derivatives that have 3,5-dimethoxyl groups in the A-ring, such as (E)-4-(3,5-dimethoxystyryl)phenol (pterostilbene, compound 2), or have substituted the B-ring of resveratrol with quinolyl, such as (E)-5-[2-(quinolin-4-yl)vinyl]benzene-1,3-diol (compound 18) and (E)-4-(3,5-dimethoxystyryl)quinoline (compound 19), strongly inhibited NO production. Compounds 2, 18, and 19 reduced LPS-induced protein and mRNA expression of inducible NO synthase (iNOS), but did not display direct NO-scavenging activity up to 30 microM in sodium nitroprusside (SNP) solution. Moreover, compounds 2, 18, and 19 could also significantly inhibit the production of TNF-alpha by LPS-activated microglia. Further studies revealed that compounds 2, 18, and 19 inhibited LPS-induced NO and TNF-alpha production in microglia by blocking IkappaBalpha phosphorylation and degradation. The potent inhibitory effects of compounds 2, 18, and 19 on microglial activation suggest their potential for treatment of neurodegenerative diseases accompanied by microglial activation.

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19) Berberine Useful in preventing clostridia colitis relapse after Vancomycin

19) http://aac.asm.org/content/early/2015/03/24/AAC.04794-14.abstract
Lv, Zhi, et al. “Berberine blocks the relapse of Clostridium difficile infection in C57BL/6 mice after vancomycin standard treatment.” Antimicrobial agents and chemotherapy (2015): AAC-04794.

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Berberine for Treatment of Infection

20) http://esciencecentral.org/journals/berberine-a-medicinal-compound-for-the-treatment-of-bacterial-infections-2327-5073.1000150.php?aid=26238

Chu, Ming, et al. “Berberine: A Medicinal Compound for the Treatment of Bacterial Infections.” Clinical Microbiology: Open Access (2014).

21) http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZYHS200808075.htm
Clinical Observation of Berberine in Treatment of Non-Gonococcal Urethritis and Cervicitis Due to Chlamydia Trachomatis

Objective:To observation the efficacy and safety of berberine in treating non-gonococcal urethritis and cervicitis due to chlamydia trachomatis.Methods:86 patients with non-gonococcal urethritis and cervicitis were randomized into treatment Group(n=44)and control Group(n=42).Treatment group was treated oral berberine 0.4g,tid for 14 days.Control group was treated oral doxycycline 0.1g,bid for 14 days.The efficacy and safety of all patients were observed before and after the treatment.Results:The overall efficacy rates of berberine and doxycycline were 65.9% and 73.8%,Bacteria elimination rates were 65.9% and 73.8%,and the side effect rates wore 18.2% and 14.3% respectively.No significant differences were observed between the two groups.Conclusion:Berberine is effective and safe in treating non-gonococcal urethritis and cervicitis due to chlamydia trachomatis.

22) http://www.ncbi.nlm.nih.gov/pubmed/1344968
Rev Int Trach Pathol Ocul Trop Subtrop Sante Publique. 1992;69:147-65.
Berberine, a potential drug for trachoma. [Article in English, French]
Khosla PK1, Neeraj VI, Gupta SK, Satpathy G. Author information

The clinical serological response to topical treatment of trachoma with Berberine an indigenous drug has been studied in 32 microbiologically confirmed cases. Efficacy of Berberine 0.2% when compared to sulfacetamide 20% was found to be superior in both the clinical course of trachoma and in achieving a fall in the serum antibody titers (P < 0.05) against chlamydia trachomatis in the treated patients.

Berberine for chronic prostatitis

23) ( full pdf available)  Xu, Gang, Yuan-Fang Zhang, and Qiang Ding. “Efficacy of Prostant on chronic prostatitis in 119 patients.” Acta pharmacologica Sinica 24.6 (2003): 615-618.

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berberine metabolic alchemy

24)  http://www.metabolicalchemy.com/bad-news-for-berberine/
Bad News for Berberine

25) http://www.life-enhancement.com/magazine/article/2901-the-berberine-story-gets-better-and-better  The Berberine Story Gets Better and Better
Improves memory, combats antibiotic resistant micro-organisms, reduces
smoke-induced lung damage, and fights cancer  By Will Block

26) http://toddcaldecott.com/antibiotic-resistance-part-two/
Antibiotic resistance: a herbalist’s perspective (2) By Todd Caldecott

Berberine prevents atherosclerosis in genetically modified mice

27) Wang, Qilong, et al. “Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2.” (2011): e25436.

In summary, we have demonstrated that berberine limits aortic lesions in vivo via AMPK activation.

In addition, the reduction of aortic lesions by berberine appears to be mediated by enhanced expression of UCP2, which suppresses oxidative stress and vascular inflammation. The data presented here support the concept that AMPK may be an important therapeutic target for treating atherosclorosis and other cardiovascular diseases.

28) Chen, Junwen, et al. “Berberine derivatives reduce atherosclerotic plaque size and vulnerability in apoE−/− mice.” Journal of translational medicine 12.1 (2014): 326.

The lesion area was significantly smaller in mice treated with dhBBR and Di-MeBBR compared with control mice (P?<?0.05). There was no difference in lesion area between BBR group and the control group (Figure 4A, B).
Our results demonstrate that BBR derivatives (dhBBR and Di-MeBBR) have better inflammatory and anti-atherosclerotic effects compared with BBR. So, BBR derivatives could have therapeutic advantages over BBR as an adjunct therapy in patients with atherosclerosis.

29) Chronicles of Berberine James Roberts MD Toledo Ohio HeartFixer.com

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Berberine in Diabetes, antiinflammatory, anti-oxidant

30) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942282/  free full text
Li, Zheng, et al. “Antioxidant and anti-inflammatory activities of berberine in the treatment of diabetes mellitus.” Evidence-Based Complementary and Alternative Medicine 2014 (2014).
BBR suppressed oxidative stress and inflammation through multiple mechanisms. In addition to what was mentioned above, recent studies indicated that the anti-inflammatory activity of BBR was also associated with its beneficial effects in the gut [114–116]. Due to the possible low bioavailability [117], high concentration of BBR in the gut after oral administration could modulate the structure of gut microbiota, resulting in the enrichment of short-chain fatty acid (SCFA)-producing bacteria in the gut [114]. SCFA could improve intestinal barrier function and prevent inflammation by blocking exogenous antigen or endotoxin to enter into the blood [118]. This theory was supported by the observations that BBR could ameliorate intestinal barrier damage induced by TNF-α or LPS in cultured human colon monolayer or animal models [119–121].
In summary, natural compound BBR has antioxidant and anti-inflammatory activities which might contribute in part to its therapeutic efficacies against diabetes mellitus and insulin resistance. Multiple cellular kinases as well as signaling pathways such as AMPK, MAPKs, Nrf2/HO pathway, and NF-κB pathway (Figure 1) were verified to be pivotal for BBR in reducing oxidative stress and inflammation.

31) full pdf available Berberine therapy type 2 diabetes mechanism of action to clinical studies Chang 2015.  Chang, W., L. Chen, and G. M. Hatch. “Berberine as a therapy for type 2 diabetes and its complications: From mechanism of action to clinical studies.” Biochemistry and cell biology= Biochimie et biologie cellulaire (2014): 1.

32) http://naturalmedicinejournal.com/journal/2012-12/clinical-applications-berberine
Natual Medicine Journal December 2012 Vol. 4 Issue 12
Clinical Applications for Berberine
Potential therapeutic applications in metabolic syndrome, type 2 diabetes, and dyslipidemia.  By Jacob Schor, ND, FABNO

Reports that berberine activates AMPK were first published in 2006.5 Resveratrol, salicylate, and metformin also activate this chemical pathway.6,7
Berberine activates AMPK in a manner similar to how exercise stimulates increased strength and weight loss. Thus, any condition that would be favorably impacted by a patient losing weight and/or exercising more may be impacted favorably by oral berberine supplementation. It makes sense to consider using berberine in patients with insulin resistance, pre-diabetes, diabetes, metabolic syndrome, hypertension, heart disease, dyslipidemia, cancer, depression, and other neuropsychiatric diseases.

Berberine upregulates vagal innervation…heart

34) http://www.wjgnet.com/1949-8462/full/v5/i7/261.htm
World J Cardiol. 2013 July 26; 5(7): 261-264.
Berberine behind the thriller of marked symptomatic bradycardia
Margherita Cannillo, Simone Frea, Cristina Fornengo, Elisabetta Toso, Giancarlo Mercurio, Stefania Battista and Fiorenzo Gaita.

Patients with chronic aortic dissections are at high risk of catheter-induced complications. We report a Berberine is used in traditional Chinese medicine for the treatment of congestive heart failure, hypertension, diabetes, and dyslipidaemia and has a good safety profile. We report a case of a 53-year-old sportsman referred to our hospital for the onset of fatigue and dyspnoea upon exertion after he started berberine to treat hypercholesterolaemia. An electrocardiogram showed sinus bradycardia (45 bpm), first-degree atrioventricular block, and competitive junctional rhythm. An ergometric stress test showed slightly reduced chronotropic competence and the presence of runs of competitive junctional rhythm, atrial tachycardia, and sinus pauses in the recovery. After 10 d of wash-out from berberine, the patient experienced a complete resolution of symptoms, and an ergometric stress test showed good chronotropic competence. An electrocardiogram Holter showed a latent hypervagotonic state. This is the first case report that shows that berberine could present certain side effects in hypervagotonic people, even in the absence of a situation that could cause drug accumulation. Therefore, berberine’s use should be carefully weighed in hypervagotonic people due to the drug’s bradycardic and antiarrhythmic properties, which could became proarrhythmic, exposing patients to potential health risks.
Keywords: Berberine, Bradyarrhythmia, Side effect, Hypervagotonia, Hypercholesterolaemia, Electrocardiogram

Core tip: Berberine is widely used in traditional Chinese medicine for the treatment of congestive heart failure, hypertension, diabetes, and dyslipidaemia. We report a case of marked symptomatic sinus bradycardia with competitive junctional rhythm caused by berberine, showing that berberine, due to its antiarrhythmic properties, can cause the onset of bradyarrhythmia. In this case report, we focus on the possible side effects of so-called natural medicine based on holistic, home, and herbal remedies, which is considered to be safe only because the treatment is natural. However, under certain conditions, natural medicine can lead to potential health risks in patients.

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Berberine reduces atherosclerosis in genetic mice

35) http://www.ncbi.nlm.nih.gov/pubmed/21980456
PLoS One. 2011;6(9):e25436.
Activation of AMP-activated protein kinase is required for berberine-induced reduction of atherosclerosis in mice: the role of uncoupling protein 2.
Wang Q1, Zhang M, Liang B, Shirwany N, Zhu Y, Zou MH.
Berberine, a botanical alkaloid purified from Coptidis rhizoma, is reported to activate the AMP-activated protein kinase (AMPK). Whether AMPK is required for the protective effects of berberine in cardiovascular diseases remains unknown. This study was designed to determine whether AMPK is required for berberine-induced reduction of oxidative stress and atherosclerosis in vivo.
METHODS: ApoE (ApoE⁻/⁻) mice and ApoE⁻/⁻/AMPK alpha 2⁻/⁻ mice that were fed Western diets were treated with berberine for 8 weeks. Atherosclerotic aortic lesions, expression of uncoupling protein 2 (UCP2), and markers of oxidative stress were evaluated in isolated aortas.
RESULTS: In ApoE⁻/⁻ mice, chronic administration of berberine significantly reduced aortic lesions, markedly reduced oxidative stress and expression of adhesion molecules in aorta, and significantly increased UCP2 levels. In contrast, in ApoE⁻/⁻/AMPK alpha 2⁻/⁻ mice, berberine had little effect on those endpoints. In cultured human umbilical vein endothelial cells (HUVECs), berberine significantly increased UCP2 mRNA and protein expression in an AMPK-dependent manner. Transfection of HUVECs with nuclear respiratory factor 1 (NRF1)-specific siRNA attenuated berberine-induced expression of UCP2, whereas transfection with control siRNA did not. Finally, berberine promoted mitochondrial biogenesis that contributed to up-regulation of UCP2 expression.
CONCLUSION: We conclude that berberine reduces oxidative stress and vascular inflammation, and suppresses atherogenesis via a mechanism that includes stimulation of AMPK-dependent UCP2 expression.

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36) full pdf available
Ye, Minzhong, et al. “Neuropharmacological and pharmacokinetic properties of berberine: a review of recent research.” JPP 61 (2009): 831-837.

Berberine similar to Ouabain ?

Berberine inhibits acetylcholine esterase

37) http://www.ncbi.nlm.nih.gov/pubmed/3736685
Feinauer, M., et al. “Ouabain enhances release of acetylcholine in the heart evoked by unilateral vagal stimulation.” Naunyn-Schmiedeberg’s archives of pharmacology 333.1 (1986): 7-12.
release of ACh caused by unilateral vagal stimulation was augmented by ouabain up to 200% of the control.

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Berberine prevents gluatamate release by nerve terminals

38) Lin, Tzu-Yu, et al. “Berberine inhibits the release of glutamate in nerve terminals from rat cerebral cortex.” (2013): e67215.

berberine has numerous beneficial effects in the central nervous system (CNS), in particular, neuroprotective effect [3]. For example, berberine protects against ischemia- or β-amyloid-induced neuronal death [4], [5], [6], [7], and ameliorates β-amyloid-induced memory impairment [8], [9]. Based on these reports, berberine might be a potential candidate for a natural neuroprotective agent.

Berberine has been confirmed to penetrate the blood-brain barrier [46] and possess neuroprotective activity both in animal and cell culture models of neurotoxicity such as ischaemia and Alzheimer’s disease [5], [6], [7], [8], [47]

Berberine for cardiomyopathy, anti-arrythmic

39) medicalclinic.com/wp-content/uploads/2013/11/Berberine-and-congestive-heart-failure-1.pdf
Marin-Neto, J. A., B. C. Maciel, and A. L. Secches. Berberin: a possible new therapy for heart failure.”  Relationship between the clinical effects of berberine on severe congestive heart failure and its concentration i plasma studied by HPLC

40) http://www.ncbi.nlm.nih.gov/pubmed/12860219
Am J Cardiol. 2003 Jul 15;92(2):173-6. Efficacy and safety ofberberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Zeng XH1, Zeng XJ, Li YY.

This study was designed to assess the efficacy and safety of berberine for chronic congestive heart failure (CHF). One hundred fifty-six patients with CHF and >90 ventricular premature complexes (VPCs) and/or nonsustained ventricular tachycardia (VT) on 24-hour Holter monitoring were randomly divided into 2 groups. All patients were given conventional therapy for CHF, consisting of angiotensin-converting enzyme inhibitors, digoxin, diuretics, and nitrates. Patients in the treatment group (n = 79) were also given berberine 1.2 to 2.0 g/day. The remaining 77 patients were given placebo. Symptoms, a 6-minute walk test, left ventricular (LV) ejection fraction (EF), frequency and complexity of VPCs, and quality of life were assessed after 8 weeks of treatment and during a mean 24-month follow-up. After treatment with berberine, there was a significantly greater increase in LVEF, exercise capacity, improvement of the dyspnea-fatigue index, and a decrease of frequency and complexity of VPCs compared with the control group. There was a significant decrease in mortality in the berberine-treated patients during long-term follow-up (7 patients receiving treatment died vs 13 on placebo, p <0.02). Proarrhythmia was not observed, and there were no apparent side effects. Thus, berberine improved quality of life and decreased VPCs and mortality in patients with CHF.

Articles by Michael Maes. LPS and Depression

41) Leaky gut chronic fatigue review Michael Maes Act Nerv Super Rediviva 2009

42) CFS Chronic Fatigue Syndrome bête noire Belgian Michael Maes euroendocrinology Letters 2009

43) Myalgic Encephalomyelitis and Chronic fatigue Syndrome Gerwyn Morris Michael Maes Neuroendocrinol Lett 2013

44) inflammatory neurodegenerative hypothesis of depression Michael Maes Metab Brain Dis 2009

45) Leaky gut brain barrier in major depression LPS from gram negative bacteria Michael Maes Neuroendocrinology 2008

46) Leaky Gut Syndrome Modern Epidemic Douglas Wyatt Townsend Letter 2014

47) Lebwohl, Benjamin, Jonas F. Ludvigsson, and Peter HR Green. “State of the Art Review: Celiac disease and non-celiac gluten sensitivity.” BMJ: British Medical Journal 351 (2015).
Studies of stored serum show that the prevalence of celiac disease has increased fourfold to fivefold over the past 50 years,

48) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012300/
West, Joe, et al. “Incidence and prevalence of celiac disease and dermatitis herpetiformis in the UK over two decades: population-based study.” The American journal of gastroenterology 109.5 (2014): 757-768.
We found a fourfold increase in the incidence of CD in the United Kingdom over 22 years

49)  Ludvigsson, Jonas F., et al. “Increasing incidence of celiac disease in a North American population.” The American journal of gastroenterology 108.5 (2013): 818-824.
Between 2000 and 2010, 249 individuals (157 female or 63%, median age 37.9 years) were diagnosed with CD in Olmsted County. The overall age- and sex-adjusted incidence of CD in the study period was 17.4 (95% confidence interval [CI] = 15.2–19.6) per 100,000 person-years, increasing from 11.1 (95% CI=6.8–15.5) in 2000–2001 to 17.3 (95% CI=13.3–21.3) in 2008–2010.

50)  Fasano, Alessio, et al. “Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study.” Archives of internal medicine 163.3 (2003): 286-292.

51)   Dydensborg, S., et al. “Increasing prevalence of coeliac disease in Denmark: a linkage study combining national registries.” Acta paediatrica (Oslo, Norway: 1992) 101.2 (2012): 179.

52)  Lerner, Aaron, Patricia Jeremias, and Torsten Matthias. “The World Incidence and Prevalence of Autoimmune Diseases is Increasing.” International Journal of Celiac Disease 3.4 (2015): 151-155.

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Summary
Berberine Antidote for a Modern Epidemic
Article Name
Berberine Antidote for a Modern Epidemic
Description
Berberine is a botanical agent remarkably effective for the Leaky Gut epidemic.
Author