Pomegranate products for the nociceptive pain of histamine excess.

Graphical Abstract -> zero additional words to my paper. Hyperinflammation positive feedback loop graphic - updated and with citations.

Abstract

Pomegranate products aid the acute nociceptive pain of histamine excess as well as associated long term degenerative risks. As the causal factors of histamine excess are numerous and include Retinoid Toxicity, helpful solutions are also numerous. Functional foods or mixed supplements would be helpful for a population that is challenged by fatigue, brain fog, anxiety, migraines or other pain conditions, diet sensitivity, microbiome dysbiosis, and GI discomfort. Symptoms of histamine excess, Mast Cell Activation Syndrome (MCAS), or Retinoid Toxicity can be as serious as self-harm or suicidal ideation and chronically can lead to kidney, liver, and brain damage. Histamine excess and/or retinoid excess may affect many other conditions including Long Covid and ME/CFS and can lead to a diagnosis of schizoaffective-disorder and later Alzheimer’s dementia as histamine excess is damaging to the hippocampus. NMDA receptor antagonists can be protective of the hippocampus but have side effect risks. Diagnostic testing for histamine excess may be inconclusive compared to elimination diets and treatment attempts with histamine receptor antagonists or reverse agonists have had limited success due to negative side effects. Retinoid toxicity may occur following a viral infection or drug reaction due to liver injury or gene changes which leads to chronic over-activation of vitamin A. Low levels of inactive vitamin A then increase inflammation along with the active retinoids adding to histamine levels by degranulating mast cells. 

There is a large body of research showing the safety and efficacy of pomegranate products for a variety of conditions including neuroinflammation and mast cell ver-activity. Phytonutrients within pomegranate act synergistically and in a modulatory capacity, up- or down-regulating inflammatory responses and receptor activity protecting against or repairing kidney, liver, lung, and brain injury. Pomegranate products improve microbiome health, Metabolic Syndrome and have antimicrobial benefits. Pomegranate is adsorbant and is used to form nanoparticles for medical or industrial use. The pomegranate is a sustainable crop and potential applications exist for medical, food, agricultural, and industrial uses. The antioxidant content is strong enough to act as an anti-corrosive for steel, or the inner pith can be used directly as a food preservative ingredient or for the fiber.

The focus of this paper will be on the need for product development as well as the support nutrients and trace minerals that may augment the benefits of the pomegranate in a mixed product, and the issues that may face clinical trial design for a symptom (histamine excess) that has a range of possible causal factors and often leads to pain hypersensitivity. TRP channel over expression or hypersensitivity and their regulation by bitter taste receptors and the butyrate/niacin GP109 receptor will also be discussed. Stress can increase histamine and bowel dysbiosis, lack of butyrate would then be likely. Bitter nutrients in pomegranate and the fiber and antioxidants can help along with zinc, niacin, and other mitochondrial support nutrients. Patients need products for the acute hyperexcitability of histamine excess that have shown safety and efficacy in clinical trials, and which likely will also help prevent long-term degeneration associated with chronic hyperexcitability.

Graphical Abstract:

Figure 1. Graphical Abstract - The hyperinflammation positive feed-back loop. Inflammatory triggers from modern life, stress, leptin, (Żelechowska, et al, 2018), EMF, (Kivrak, et al, 2017), diet, glyphosate (Barnett, et al, 2022) and other environmental toxins degranulates mast cells and activates TRP channels. (1) Activated mast cells release histamine and cytokines including TNF-alpha which increases inflammatory NF-kB. (Nizamutdinova, et al, 2016, Schütze, et al, 1995) NF-kB inhibits Nrf2 pathways; the two are linked via a shared CBP-CREB binding protein (Ambrozova, et al, 2017, Figure 4) and Circadian Cycle proteins. Nrf2 can inhibit CLOCK/BMAL1 protein complex (Wible, et al, 2018) and NF-kB transcription of genes can be upregulated by the Circadian cycle CLOCK protein and blocked by the BMAL1 proteins. (Spengler, et al, 2012);; Niacin (Si, Y., et al, 2014, Wei, et al, 2014) and butyrate (Chen, 2018) can down-regulate the inflammatory NF-kB signaling pathway, by activation of the GP109 receptor in mitochondria or coincident to TRP channels. (Zhou and Greka, 2016) Niacin treatment reduced leptin levels in a hypercholesterolemia animal model. (Yang, J. et al, 2008) NF-kB can inhibit mast cell degranulation, a self-controlling feedback mechanism. NF-kB increase inhibits Nrf2 which would have helped reduce inflammation by promoting glutathione production. Ongoing mast cell degranulation promotes more NF-kB and ongoing lack of Nrf2 - a positive feedback loop if inflammation is not inhibited. Pomegranate wine extract containing phytonutrients gallic acid, ellagic acid, and punicalagin, (Li, X., Liu, Pischetsrieder, 2017), and other phytonutrients promote Nrf2 and inhibit NF-kB reducing effects of mast cell degranulation. (Rasheed, et al, 2009) Bitter taste receptors on lymphocytes, down regulate TNF alpha, (Tran, et al., 2018), and the pomegranate phytonutrients are bitter.;; (1) Mast cell degranulation leads to (2) histamine excess and H1 receptor activation and increased sensitivity to inflammatory triggers. (Thangam, 2018) If the excess continues to (3) histamine hyperexcitability and H1 over-activation it causes (4) NMDAR over-activation and results in damage to the hippocampus and can result in cell death. (Langlais, et al, 1994, cited by Hough, 1999) Excess dietary glutamate would increase this risk and/or a high fat diet. (Valladolid-Acebes, et al, 2012) (5) Retinoic Acid degranulates mast cells. Excess activated retinoids may be a result of liver injury (Mawson et al, 2021) and may be a long-term change due to liver enzyme genetic changes following a viral infection or immune challenge. (Jones, et al, 2007, Bonilla, et al, 2022) Gene changes affecting retinoid activation also may occur in Fetal Alcohol Syndrome (FAS) and Attention Deficit Hyperactivity Disorder (ADHD) from alcohol exposure to the sperm from the father of the child. It takes 74 days to grow a sperm. (Luan, et al, 2022) Other toxins may also affect sperm DNA. (Carrell, 2013) (Pourmasumi, et al, 2017);; The hyperinflammation and histamine excess also increases risk of misfolded proteins or prions, post-translational modification of protein, (Laedermann, et al, 2015), and increased risk for more pain and neurological conditions. (Sharma, 2004, Waller, Sampson, 2018) Leaky gut membranes and microbiome dysbiosis also can result from stress effects on the Autonomic Nervous System. (Carabotti, et al, 2015, Martin, et al, 2018) and increased risk for autoimmune and allergy risks, inflammatory bowel conditions, and eczema or other skin conditions and neuropathy may be a later risk. (Kumar, et al, 2013) Mitochondrial dysfunction from oxidative stress and lack of Nrf2 to promote glutathione adds to fatigue and risk of mitochondrial genetic conditions. (Guo, et al, 2013, Chen, et al, 2018) Migraines, fibrotic conditions and cancer may also be risks. Emotional dysregulation and mood imbalance, mania, reckless behavior, anger, paranoia, and schizoaffective symptoms may occur with chronic histamine excess or Retinoid Toxicity. (See: Table 1. Symptoms of Histamine Excess and of Retinoid Toxicity.)

<Jen, Jen, Jen, you can’t do that. I can try. It wouldn’t be as narrow on a journal article digital webpage. Abstracts do not have a word limit and the Footnote of a Figure or Table doesn’t add to the paper word count. >

In normal font and paragraphs:

Figure 1. Graphical Abstract - The hyperinflammation positive feed-back loop. Inflammatory triggers from modern life, stress, leptin, (Żelechowska, et al, 2018), EMF, (Kivrak, et al, 2017), diet, glyphosate (Barnett, et al, 2022) and other environmental toxins degranulates mast cells and activates TRP channels. (1) Activated mast cells release histamine and cytokines including TNF-alpha which increases inflammatory NF-kB. (Nizamutdinova, et al, 2016, Schütze, et al, 1995) NF-kB inhibits Nrf2 pathways; the two are linked via a shared CBP-CREB binding protein (Ambrozova, et al, 2017, Figure 4) and Circadian Cycle proteins. Nrf2 can inhibit CLOCK/BMAL1 protein complex (Wible, et al, 2018) and NF-kB transcription of genes can be upregulated by the Circadian cycle CLOCK protein and blocked by the BMAL1 proteins. (Spengler, et al, 2012);;

Niacin (Si, Y., et al, 2014, Wei, et al, 2014) and butyrate (Chen, 2018) can down-regulate the inflammatory NF-kB signaling pathway, by activation of the GP109 receptor in mitochondria or coincident to TRP channels. (Zhou and Greka, 2016) Niacin treatment reduced leptin levels in a hypercholesterolemia animal model. (Yang, J. et al, 2008) NF-kB can inhibit mast cell degranulation, a self-controlling feedback mechanism. NF-kB increase inhibits Nrf2 which would have helped reduce inflammation by promoting glutathione production. Ongoing mast cell degranulation promotes more NF-kB and ongoing lack of Nrf2 - a positive feedback loop if inflammation is not inhibited. Pomegranate wine extract containing phytonutrients gallic acid, ellagic acid, and punicalagin, (Li, X., Liu, Pischetsrieder, 2017), and other phytonutrients promote Nrf2 and inhibit NF-kB reducing effects of mast cell degranulation. (Rasheed, et al, 2009) Bitter taste receptors on lymphocytes, down regulate TNF alpha, (Tran, et al., 2018), and the pomegranate phytonutrients are bitter.;;

(1) Mast cell degranulation leads to (2) histamine excess and H1 receptor activation and increased sensitivity to inflammatory triggers. (Thangam, 2018) If the excess continues to (3) histamine hyperexcitability and H1 over-activation it causes (4) NMDAR over-activation and results in damage to the hippocampus and can result in cell death. (Langlais, et al, 1994, cited by Hough, 1999) Excess dietary glutamate would increase this risk and/or a high fat diet. (Valladolid-Acebes, et al, 2012) (5) Retinoic Acid degranulates mast cells. Excess activated retinoids may be a result of liver injury (Mawson et al, 2021) and may be a long-term change due to liver enzyme genetic changes following a viral infection or immune challenge. (Jones, et al, 2007, Bonilla, et al, 2022) Gene changes affecting retinoid activation also may occur in Fetal Alcohol Syndrome (FAS) and Attention Deficit Hyperactivity Disorder (ADHD) from alcohol exposure to the sperm from the father of the child. It takes 74 days to grow a sperm. (Luan, et al, 2022) Other toxins may also affect sperm DNA. (Carrell, 2013) (Pourmasumi, et al, 2017);;

The hyperinflammation and histamine excess also increases risk of misfolded proteins or prions, post-translational modification of protein, (Laedermann, et al, 2015), and increased risk for more pain and neurological conditions. (Sharma, 2004, Waller, Sampson, 2018) Leaky gut membranes and microbiome dysbiosis also can result from stress effects on the Autonomic Nervous System. (Carabotti, et al, 2015, Martin, et al, 2018) and increased risk for autoimmune and allergy risks, inflammatory bowel conditions, and eczema or other skin conditions and neuropathy may be a later risk. (Kumar, et al, 2013) Mitochondrial dysfunction from oxidative stress and lack of Nrf2 to promote glutathione adds to fatigue and risk of mitochondrial genetic conditions. (Guo, et al, 2013, Chen, et al, 2018) Migraines, fibrotic conditions and cancer may also be risks. Emotional dysregulation and mood imbalance, mania, reckless behavior, anger, paranoia, and schizoaffective symptoms may occur with chronic histamine excess or Retinoid Toxicity. (See: Table 1. Symptoms of Histamine Excess and of Retinoid Toxicity.)

~~ various notes

“NF-κB activation is triggered by a variety of microbial and viral factors via pattern-recognition receptors, such as Toll-like receptors (TLR), Retinoic acid-inducible gene 1–like receptors, and NOD-like receptors (9, 10), or immunomodulators, such as TNF-α or other cytokines acting via their specific receptors.” (Spengler, et al, 2012)

Excerpt from my book draft, now edited:

Both chemical pathways use one of the same binding proteins (CBP-CREB binding protein) which may be one way the activity of the NF-kB pathway can inhibit the rate of the anti-inflammatory Nrf2 pathway - they can’t both be active at the same time because they both need CREB in order to be active. The inflammatory NF-kB may be inhibited by Nrf2 and may also be able to affect the activity of the Nrf2 protein or gene.

In the center we see the nucleus with a gene to be transcribed and Nrf-2 and NF-kB in competition for CBP coactivators. (CBP-CREB) (CC By: Ambrozova, et al, 2017, Figure 4)

Lack of Nrf2 led to increased risk for DSS-induced colitis in mice deficient in Nrf2. (Li W, et al, 2008) Nrf2 can affect the circadian CLOCK / BMAL1 proteins by binding with Cry2 which repressed CLOCK/BMAL1-regulated E-box transcription in hepatocytes. (Wible, et al, 2018)

(Brown, 2014) (Spiers, et al, 2019) (Pekovic-Vaughn, et al, 2014)

The NF-kB protein is also affected by the CLOCK/BMAL1 complex of proteins. CLOCK in the absence of BMAL1 up-regulates NF-kB leading to more gene transcription of inflammatory proteins. BMAL1 counteracts the increased transcription of NF-kB-responsive genes. (Spengler, et al, 2012)

“Through the use of a mouse model system we show that daily variations in the intensity of the NF-κB response to a variety of immunomodulators are mediated by core circadian protein CLOCK, which can up-regulate NF-κB–mediated transcription in the absence of BMAL1; moreover, BMAL1 counteracts the CLOCK-dependent increase in the activation of NF-κB–responsive genes.”

“Consistent with its regulatory function, CLOCK is found in protein complexes with the p65 subunit of NF-κB, and its overexpression correlates with an increase in specific phosphorylated and acetylated transcriptionally active forms of p65.” (Spengler, et al, 2012)

Other research teams have found several chemicals and gut microbes that can affect how often genes will be turned on or off for protein transcription/production during the night and day stages of circadian biology, (*“oxygen, hormones, gut microbes, cytokines, and inflammation signaling pathways,"* (Hong, et al, 2018) (Spengler, et al, 2012)

 Having adequate antioxidants from dietary sources or our own internal production of glutathione, promoted by Nrf2, helps reduce the oxidative damage that can result from normal or over-active metabolism and lead to neurodegenerative conditions. (Paladino, et al, 2018) Small molecules found to inhibit NF-kB includes phytonutrients (Gupta, et al, 2010) that also have been found to promote Nrf2 - the two pathways are linked. It makes sense that the same chemical would inhibit one and promote the other.

A high fat diet can increase glutamate activity at NMDA receptors and add to Alzheimer’s risk. (Valladolid-Acebes, et al, 2012), High fat or excess saturated or poly-unsaturated or trans-fats and lack of omega 3 fatty acids can increase inflammation and promote NF-kB pathways and may affect mitochondrial function.

Disclaimer: This information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.

Reference List upon request.