Positive Health Online

The subject of macrophage polarization has many practical applications in treating immune dysfunction in diseases like cancer, diabetes, chronic fatigue, AIDS, sepsis and any diseases with fibrosis occurring. Macrophages or our white blood cells respond to an enzyme called Indoleamine-2,3-dioxygenase (IDO) and change. IDO is a type of signal used by baby or foetal cells [1], stem cells [2] or any new cells to tell the M1 macrophages to avoid any area of growth and repair and not gobble it up. Hence cancer cells [3] releasing IDO can avoid our own immune system and stay alive.

https://commons.wikimedia.org/wiki/File:Macrophage_Polarization_%28M1_and_M2_Macrophage%29.jpg

Different stimuli, surface markers, secreted cytokines, and biological functions
between M1 and M2 macrophages

Credit: Yongli Yao, Xiang-Hong Xu, Liping Jin  on Wikipedia

To summarise a complex subject, our white blood cells (macrophages) have 2 types:

M1 macrophages get in and dig out rubbish whether it is old collagen or infections from bacteria and fungus, cancer cells or fat cells.

The other types are M2 macrophages, they seem to have 2 main functions, one is collagen deposition, while the other function is to dig out large scale infections [4] such as TB and malaria or anything big stuck in the body, a fungal infection or a solid object can cause an M2 reaction.

To do this the baby macrophages bind together like a rugby scrum and these are called giant cell multinucleated macrophages [4]. They also work with other immune cells to deposit collagen for repairing damaged areas [5] of the body.

If there is a large infected area say with TB, fungus or malaria the white blood cells encircle the area first with collagen like a wall and then pour peroxide and nitric oxide in to dissolve everything and kill it. To become M2 macrophages [6], the white blood cells use our own retroviruses to fuse together [7] into the giant multinucleated cells.

In the last decade retroviruses have been found to fuse sperm [8] and eggs [9], they are needed in pregnancy [10], are used fuse osteoclasts [11] to remove bone, and fuse muscles [12] together so our retroviruses have function in immune activity and structure.

When cancer occurs the tumours release IDO [13] which in effect tells the immune system to leave the cancer cells alone.

Much worse than that is the white blood cells then become M2 macrophages, the macrophages get confused and fuse to the tumour cells [14], then the macrophages release collagen destroying enzymes (MMPs) [15] and allow the tumour to spread and get new blood flow.

Immune stimulants like zinc are involved in breaking down our collagen [16], if someone has cancer and IDO is active [17] and M2 macrophages are active then the zinc is like adding petrol to the site and can help the tumour to spread.  Zinc is best obtained from a good diet but may be needed in a supplement if a person has poor blood flow, fibrosis and needs the immune system to heat up. Just some caution is needed with zinc and cancer.

“Tumour cells escape the immune surveillance system of the host through a process called immune tolerance. Immunotherapy targets molecules that serve as checks and balances in the regulation of immune response. Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme, which through the process of tryptophan depletion exerts an immunosuppressive effect, facilitating immune escape of tumours. This review summarizes our current knowledge on IDO expression in malignancies, the IDO inhibitors that are currently available and those under clinical development.”

Targeting the indoleamine 2,3-dioxygenase pathway in cancer [18]

Ways to Lower IDO Enzymes

Any means of lowering IDO can helps to flick the immune system back to the M1 macrophage mode and our white blood cells can then see our cancer cells, recognise them and remove them.

Aloe Vera, Myoga ginger and Papaya leaf tea [19] are IDO inhibitors, green tea [20] works. Broccoli, cauliflower and cabbage seem to be IDO inhibitors which also prevent t-cell autoimmunity. The IDO inhibition may be because all the cruciferous vegetables inhibit estrogen, and estrogen suppresses t-cells and raises IDO [21].

“The aqueous dissolved Aloe exudate can be used as a source of novel natural IDO inhibitors and merit testing as therapeutic agents in the treatments of cancer and immunopathologic diseases, such as autoimmune, inflammatory, and allergic disorders.”

Chemical Components from Aloe and their Inhibition of Indoleamine 2, 3-dioxygenase [22]

“Indoleamine 2,3-dioxygenase (IDO) 1, that catalyzes the first and rate-limiting step in the degradation of L-tryptophan, has an important immunomodulatory function. The activity of IDO1 increases in various inflammatory diseases, including tumours, autoimmune diseases, and different kinds of inflammation.’

“As a result, the methanol extracts of Myoga flower buds, which are traditional Japanese foods, and labdane-type diterpene galanal derived from Myoga flowers significantly suppressed IDO1 activity.”

“‘Because the inhibitory effect of galanal on IDO1 activity was stronger than that of 1-methyl tryptophan, a tryptophan analog, galanal may have great potential as the novel drug for various immune-related disease.”

Effects of various phytochemicals on indoleamine 2,3-dioxygenase 1 activity: galanal is a novel, competitive inhibitor of the enzyme [23]

Papaya leaf tea or extract diverts macrophages and t-cells towards an anti-tumour mode, papaya leaf has proven anti-cancer effects with few side effects. Papaya leaf also can increase platelets [24] to prevent bleeding problems.

“The leaves of Carica papaya have been used as remedy for various disorders, including cancer.

In this paper, we demonstrate that the aqueous-extracted fraction of Carica papaya leaf has several in vitro biological effects: (1) anti-proliferative effect on tumour cells; (2) promotion of Th1 type cytokine production; (3) enhancement of cytotoxicity against tumour cells; (4) upregulation of anti-tumor related genes on PBMC; and (5) the active components of Carica papaya extract to be the fraction with MW. less than 1000.

These findings are the first report that demonstrated anti-tumour effect of the leaves of Carica papaya, and suggested possibility of inducing a shift to Th1 type immune responses.’

Aqueous extract of Carica papaya leaves exhibits anti-tumor activity and immunomodulatory effects [25]

Foods that prevent the cell fusion [26] of tumour cells and macrophages [27] are bromelain [28] from pineapples [29], green tea [30], turmeric [31] or curcumin [32], and black cumin [33].

Preventing cell fusion is a way to stop tumour spread so these foods listed can be quite potent.

Bromelain and turmeric are strong blood thinners so not to be used with Warfarin or other blood thinning drugs and not near or after surgery.

Other foods that suppress tumours are selenium foods like brazil nuts [34], only 2 or 3 a day to be safe. Sulphur foods like broccoli and garlic [35], olives [36] and olive oil, resveratrol [37] from grapes [38] and berries, all purple foods [39] like beetroot [40], pomegranates [41] and berries, herbs like sage [42], thyme [43], rosemary [44], oregano [45], plus tomatoes [46], can you see the Mediterranean diet here?

Vitamin B3 or Nicotinamide may be one of the most important IDO lowering vitamins.

Summarised below, IDO may be breaking down tryptophan to use for Nicotinamide synthesis used in the NAD+ energy needs of cells.

“A key enzyme upregulated in alternatively activated macrophages is indoleamine 2,3‐dioxygenase, which converts tryptophan to kynurenine for de novo synthesis of nicotinamide. Nicotinamide can be used to replenish cellular NAD+ supplies. We hypothesize that an insufficient cellular NAD+ supply is the root cause of metabolic shifts in macrophages. We assert that manipulation of nicotinamide pathways may correct deleterious immune responses. We propose evaluation of nicotinamide (Vitamin B3) and analogues, including isoniazid, nicotinamide mononucleotide and nicotinamide riboside, as potential therapy for infectious causes of sepsis, including COVID‐19.”

Nicotinamide pathways as the root cause of sepsis – an evolutionary perspective on macrophage energetic shifts [47]

Vitamin B6 [48] is also an IDO inhibitor [49] because it is need to make tryptophan and serotonin.

If people get depressed they chew through tryptophan [50], this indicates that therapies like massage, meditation, watching comedies [51], doing art, playing music or moderate exercise are physical and psychological antidepressants which could lower IDO and turn on your immune system. Excessive exercise [52] is counter-productive because it lowers tryptophan and can raise IDO – take note fitness junkies.

Cheese has a good amount of tryptophan, I use cheese as a source of tryptophan to help sleep at night. Anyone on a low protein diet is likely to have low tryptophan.

This is a basic list of tryptophan foods, “chocolate, oats, dried dates, milk, yoghurt, cottage cheese, red meat, eggs, fish, poultry, sesame, chickpeas, almonds, sunflower seeds, pumpkin seeds, buckwheat, spirulina, and peanuts.”

Protein therefore should be part of anti-depressant/immune boosting therapy.

“The enzyme indoleamine 2,3-dioxygenase is induced by proinflammatory cytokines and may form a link between immune functioning and altered neurotransmission, which results in depression. Increased indoleamine 2,3-dioxygenase activity may cause both tryptophan depletion and increased neurotoxic metabolites of the kynurenine pathway, two alterations which have been hypothesized to cause depression.”

A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase [53]

The basic dose a day is around 500mg of B3 and 100mg of B6 for adults with adequate protein containing tryptophan to lower IDO and reduce depression.

‘Trytophan, vitamin B6, and nicotinamide-containing supplements loading between meals can quickly improve depressed mood in quite low dose in young adults with severe subclinical depression.’ [54]

IDO Enzymes, Macrophages and Fibrosis

Below is the effect IDO has on T-cells which are like road markers for the macrophages to either come in and rip up the tarmac (damaged or infected areas) or come in and lay down concrete (collagen).

If the collagen or tarmac is damaged or too old then this gets called fibrosis and becomes a problem.

A good example is pulmonary fibrosis or COPD where the collagen deposits in the lungs as scarring tissue and block breathing.

Too much IDO flicks Th1 t-cells off so they fail to remove bad collagen.

“In conclusion, IDO through GCN2 kinase activation inhibits CD4(+) T-cell proliferation and down-regulates key enzymes that directly or indirectly promote Fatty Acid synthesis, a prerequisite for CD4(+) T-cell proliferation and differentiation into effector cell lineages.” [55]

It should be noted that white blood cells are as busy taking out old collagen and making new collagen in all diseases like heart disease, arthritis, osteoarthritis, Crohn’s disease, nerve diseases and so on.

The immune system is not there merely for infections, if you are poisoning your body with too much sugar and alcohol then cells are dying so the immune system then must also keep up with removing the debris that is clogging up arteries and organs.

The Catch 22 with inflammatory diseases like heart disease, arthritis and osteoarthritis, is that the immune system is in the inflammatory M1 macrophage mode with CD4 T-cells causing much of the inflammation [56] and collagen breakdown [57] as the immune system tries to dig out rubbish.

While the M2 macrophages can be causing bad fibrosis [58] or clogging arteries [59].

The other aspect of Aloe Vera apart from being an IDO inhibitor is that its mannose sugars seem to allow the white blood cells to attach to old collagen [60] and remove it, so a deficiency in mannose sugars may cause fibrosis (too much collagen) and poor blood flow.

Aloe Vera or Mannose can tag damaged collagen for removal, but it stimulates the immune system so care needs to be taken with Aloe Vera use if there are any signs of autoimmune disease.

Mannose from Aloe Vera or the supplemental form seems to be necessary for preventing fibrosis which can occur in cancer, autoimmune diseases and diabetes but the D-Mannose supplement may be the safer form to use.

This fibrosis occurs in many diseases, so the concept is like this: long term inflammation causes lesions and wounds which the immune system tries to fix by plugging it up with collagen, this is fibrosis.

Short examples and explanations of mannose, collagen repair and the M2 macrophage function are below.

“We show that Mannose Receptor is able to bind and internalise collagen in a carbohydrate‐independent manner and that Mannose Receptor deficient macrophages have a marked defect in collagen IV and gelatine internalisation.”

Carbohydrate‐independent recognition of collagens by the macrophage mannose receptor [61]

Successful tissue remodelling and maintaining body structure is an essential part of our ‘immunity’.

“Tissue remodelling processes critically depend on the timely removal and remodelling of pre-existing collagen scaffolds”

“Morphogenesis, tissue remodelling, and tissue repair all require the targeted remodelling of interstitial and basement membrane collagen to allow for organ growth, cell migration, and translation of contextual cues that are embedded within the extracellular matrix. Perturbed collagen homeostasis underlies a remarkable array of important human diseases, including fibrosis, that are attributable to excess interstitial deposition of collagen and degenerative diseases, such as osteoporosis, osteoarthritis, and rheumatoid arthritis, which are characterized by a loss of collagen from tissues. Finally, the ability of tumour cells to leave their site of origin and seed at novel locations is dependent on their ability to orchestrate the local degradation of collagen”

M2-like macrophages are responsible for collagen degradation through a mannose receptor–mediated pathway [60]

To treat heart disease, arthritis and osteoarthritis you also need a lot of vitamin C for white blood cells [62] or new collagen [63] (lemons are excellent source of vitamin C for example as they reduce acidity and uric acid [64] via potassium citrate [65].

Citrus like Grapefruit have Naringin which helps bone formation.

Uric acid also keeps our white blood cells or macrophages busy trying to remove the uric acid crystals, so uric acid [66] and gout drives us towards cancer with inflammation.

Celery is also very useful if uric acid is high.

Lemons with orange juice or pineapple should be eaten before meals as they help digest food. Vitamin C is a basic, simple and cheap anti-inflammatory [62].

“Inflammation is the physiological response of the body to harmful stimuli, such as injury, pathogens, damaged cells, or irritants. Inflammatory response can be either acute or chronic, which leads to pathology. The major function of innate immune cells is identification and recognition of the injurious and/or foreign substances causing the defence response. Macrophages are actively involved in all phases of inflammation, and their role as effector and regulatory cells is now widely recognized. Another interesting and important role of macrophages is their high level of specialization and tissue specificity. While all tissue-bound macrophages differentiate from circulating monocytes, they acquire distinct characteristics and functions locally due to their response profiles. One of the major factors for this diversity is the complexity of microbial load as well as tissue architecture.”

Remarkable Role of Indoleamine 2,3-Dioxygenase and Tryptophan Metabolites in Infectious Diseases: Potential Role in Macrophage-Mediated Inflammatory Diseases [67]

In Conclusion

These are some diseases where IDO activity may rise as people get ill.

Sepsis [47], bacterial infections [68], pneumonia [69], tuberculosis [70], influenza [71], systemic lupus erythematosus or SLE [72], Epstein-Barr and cancer [73], liver diseases and fibrosis [74], HIV [75] and COVID-19 [76].

This review explains the effect of IDO on t-cells and immunity, well worth checking.

Indoleamine 2, 3-Dioxygenase-Mediated Tryptophan Catabolism: A Leading Star or Supporting Act in the Tuberculosis and HIV Pas-de-Deux? [77]

As a final point on how depression could trigger the IDO enzymes by depleting Tryptophan, the approach to how we give a pessimistic diagnosis should be mentioned.

Voodoo and bone pointing curses are still a reality in our modern world because hi-tech testing machines that detect a ‘possible’ life threatening illness can have the same effect as bone pointing curses, we can make patients depressed and ill.

Knowing the effect and telling a patient about the effect can help their immunity.

For practitioners this means all types of therapy that help a better mood works, an example is a left field study like this, happiness is possibly an IDO inhibitor.

“Intervention: Viewing of a humour video for 1 hour. Blood samples were taken 10 minutes before, 30 minutes into, and 30 minutes and 12 hours after the intervention.”

“Results: Increases were found in natural killer cell activity; immunoglobulins G, A, and M, with several immunoglobulin effects lasting 12 hours into recovery from initiation of the humour intervention; functional phenotypic markers for leukocyte subsets such as activated T cells, active cytotoxic T cells, natural killer cells, B cells, helper T cells, uncommitted T cells with helper and suppressor markers, helper/suppressor ratio with several leukocyte subset increase effects lasting 12 hours after the humour experience; the cytokine interferon-gamma, with increases lasting 12 hours; total leukocytes, with specific subpopulation lymphocytes during the intervention and 90 minutes into recovery; and granulocytes during the intervention and 90 minutes following the intervention”

Modulation of neuroimmune parameters during the eustress of humor-associated mirthful laughter [78]

For anyone interested this is a list of things to look at that may help our macrophages to work properly, I’m still researching this subject.

Lupeol, Resveratrol, Geraniin, Aloe-emodin, Quercetin, Curcumin, Naringenin, Apigenin, Chrysin, Procyanidins, Epigallocatechin gallate, Berberine, Apocynin, Paeonol and Terpenes.

Phytochemicals as modulators of M1-M2 macrophages in inflammation [79]

Quinones, Polyphenols and Alkaloids

Indoleamine 2, 3-dioxygenase 1 inhibitory compounds from natural sources [80]

References

1. R-Q Chang et al. The role of indoleamine-2,3-dioxygenase in normal and pathological pregnancies. American Journal of Reproductive Technologies. 79(4). Nov 2017.
2. E. Manole et al. Macrophages and Stem Cells—Two to Tango for Tissue Repair?Biomolecules. 11(5): 697. May 2021.
3. Y. Ozawa et al. Indoleamine 2,3-dioxygenase 1 is highly expressed in glioma stem cells. Communications. 524(3): 723-729. Apr 2020.
4. R. Milde et al. Multinucleated Giant Cells Are Specialized for Complement-Mediated Phagocytosis and Large Target Destruction. Cell Reports. 13(9): 1937–1948. Dec 2015.
5. M. Lech and H-J Anders. Macrophages and fibrosis: How resident and infiltrating mononuclear phagocytes orchestrate all phases of tissue injury and repair. Biochima Biophysa Acta. 1832(7): 989-997. Jul 2013.
6. AK. McNally and JM Anderson. Macrophage Fusion and Multinucleated Giant Cells of Inflammation. Cell Fusion in Health and Disease. 713:97-111. 2011.
7. PS. Aguilar et al. Genetic basis of cell-cell fusion mechanisms. Trends Genetics. 29(7): 427–437. Jul 2013.
8. RC Crowell and AA Kiessling. Endogenous retrovirus expression in testis and epididymis. Biochemical Society transactions. 35(3):629-33. Jun 2007.
9. P. Sutovsky. Sperm–egg adhesion and fusion in mammals. Expert Reviews in Modern Medicine. 11:e11. Apr 2009.
10. CG. Crilly. The Pregnancy Cancer Connection. Positive Health Online. 205. Apr 2013
11. AMJ Moller et al. Osteoclast Fusion: Time-Lapse Reveals Involvement of CD47 and Syncytin-1 at Different Stages of Nuclearity. Journal of Cellular Physiology. 232(6):1396-1403. Jun 2017.
12. S. Freze et al. Long-Term Endurance Exercise in Humans Stimulates Cell Fusion of Myoblasts along with Fusogenic Endogenous Retroviral Genes In Vivo. PLoS ONE. https://doi.org/10.1371/journal.pone.0132099 Jul 2018
13. L. Hornyak et al. The Role of Indoleamine-2,3-Dioxygenase in Cancer Development, Diagnostics, and Therapy. Frontiers in Immunology. Vol 9-2018 https://doi.org/10.3389/fimmu.2018.00151 Jan 2018
14. Y. Pan et al. Tumor-Associated Macrophages in Tumor Immunity. Frontiers in Immunology. 11: 583084. Dec 2020.
15. S. Quintero-Fabián et al. Role of Matrix Metalloproteinases in Angiogenesis and Cancer. Frontiers in Oncology. https://doi.org/10.3389/fonc.2019.01370 Dec 2019.
16. N. Reunanen and VM Kähäri. Matrix Metalloproteinases in Cancer Cell Invasion. Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience. 2000-2013.
17. DH Munn and A Mellor, Indoleamine 2,3-dioxygenase and tumor-induced tolerance. The Journal of Clinical Investigation. 117(5): 1147–1154. May 2007.
18. YW Moon et al. Targeting the indoleamine 2,3-dioxygenase pathway in cancer. Journal for ImmunoTherapy of Cancer. 15(3): 51. Dec 2015.
19. S Pandey et al. Anti-inflammatory and immunomodulatory properties of Carica papaya. Journal of Immunotoxicology. 13(4): 590-602. Jul 2016.
20. K Ogawa et al. (-)-Epigallocatechin gallate inhibits the expression of indoleamine 2,3-dioxygenase in human colorectal cancer cells. Oncology Letters. 4 (3): 546-550. June 2012.
21. S Li et al. Estrogen induces indoleamine 2,3-dioxygenase expression via suppressors of cytokine signaling 3 in the chorionic villi and decidua of women in early pregnancy. American Journal of Reproductive Immunology. 83(1):e13197. Jan 2020.
22. YN Sun et al. Chemical Components from Aloe and their Inhibition of Indoleamine 2, 3-dioxygenase. Pharmacognosy Magazine.13(49): 58–63. Jan-Mar 2017
23. R Yamamoto et al. Effects of Various Phytochemicals on Indoleamine 2,3-Dioxygenase 1 Activity: Galanal Is a Novel, Competitive Inhibitor of the Enzyme. PLoS ONE. 9(2): e88789. Feb 2014.
24. K Hampilos et al. Effect Of Carica Papaya Leaf Extract On Platelet Count In Chronic Immune Thrombocytopenic Purpura: A Case Series. Integrative Medicine. A Clinician’s Journal. 18(5): 30–35. Oct 2019.
25. N Otsuki et al. Aqueous extract of Carica papaya leaves exhibits anti-tumor activity and immunomodulatory effects. Journal of Ethnopharmacology. 127(3): 760-767. Feb 2010.
26. D Bastida-Ruiz et al. The Dark Side of Cell Fusion. International Journal of Molecular Sciences. 17(5): 638. May 2016.
27. W Cui et al. The intracellular domain of CD44 promotes the fusion of macrophages. Blood. 107(2): 796–805. Jan 2006.
28. T Harrach et al. Bromelain proteinases modulate the cd44 expression on human molt-4/8 leukemia and sk-mel-28 melanoma-cells in-vitro. International Journal of Oncology. 5(3):485-8. Sep 1994.
29. AJ Chakraborty et al. Bromelain a Potential Bioactive Compound: A Comprehensive Overview from a Pharmacological Perspective. Life. 11(4): 317. Apr 2021.
30. YD Jung and LM Ellis. Inhibition of tumour invasion and angiogenesis by epigallocatechin gallate (EGCG), a major component of green tea. International Journal of Experimental Pathology. 82(6): 309–316. Dec 2001.
31. J Ravindran et al. Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively? AAPS Journal. 11(3): 495–510. Sep 2009.
32. GM Calaf et al. Effect of curcumin on the cell surface markers CD44 and CD24 in breast cancer. Oncology reports. 39(6): 2741-2748. Apr 2018.
33. MA Khan et al. Anticancer Activities of Nigella Sativa (Black Cumin). African Journal of Traditional and Complementary Medicines. 8(5): 226–232. Jul 2011.
34. C Ip and DJ Isk. Bioactivity of selenium from Brazil nut for cancer prevention and selenoenzyme maintenance. Nutrition and Cancer. 21(3):203-12. Jan 1994.
35. SH Omar and NA Al-Webel. Organosulfur compounds and possible mechanism of garlic in cancer. Saudi Pharmaceutical Journal. 18(1): 51–58. Jan 2010.
36. J Han et al. Anti-proliferative and apoptotic effects of oleuropein and hydroxytyrosol on human breast cancer MCF-7 cells. Cytotechnology. 59(1): 45–53. Jan 2009.
37. A Zulueta et al. Resveratrol: A potential challenger against gastric cancer. World Journal of Gastroenterology. 21(37): 10636–10643. Oct 2015.
38. M Kaur et al. Anticancer and Cancer Chemopreventive Potential of Grape Seed Extract and Other Grape-Based Products. The Journal of Nutrition. 139(9): 1806S–1812S. Sep 2009.
39. L-S Wang and GD Stoner. Anthocyanins and their role in cancer prevention. Cancer Letters. 269(2): 281–290. Oct 2008.
40. ML Tan and SBS Hamid. Beetroot as a Potential Functional Food for Cancer Chemoprevention, a Narrative Review. Journal of Cancer Prevention. 26(1): 1-17. Mar 2021.
41. E Turrini et al. Potential Effects of Pomegranate Polyphenols in Cancer Prevention and Therapy. Oxidative Medicine and Cellular Longevity. https://doi.org/10.1155/2015/938475 2015.
42. CPR Xavier et al. Induction of apoptosis and inhibition of proliferation in colon cancer cells by Salvia fruticosa, Salvia officinalis and rosmarinic acid. Planta Medica. DOI: 10.1016/j.biopha.2022.113384 2022.
43. A Al-Menhali et al. Thymus vulgaris (thyme) inhibits proliferation, adhesion, migration, and invasion of human colorectal cancer cells. Journal of Medicinal Food. 18(1):54-9. Jan 2015.
44. J Moore et al. Anticancer Effects of Rosemary (Rosmarinus officinalis L.) Extract and Rosemary Extract Polyphenols. Nutrients. 8(11):731. Nov 2016.
45. I. Savini et al. Origanum Vulgare Induces Apoptosis in Human Colon Cancer Caco 2 Cells. Nutrition and Cancer. 61(3):381-9. Feb 2009.
46. P. Palozza et al. Tomato Lycopene and Lung Cancer Prevention: From Experimental to Human Studies. Cancers. 3(2): 2333–2357. Jun 2011.
47. MS Suchard and DM Savulescu, Nicotinamide pathways as the root cause of sepsis – an evolutionary perspective on macrophage energetic shifts. The FEBS Journal. 289(4): 955–964. Mar 2021.
48. Vitamin B6. J Higdon. Linus Pauling Institute. Oregon State University. 2000 updated 2014.
49. MA Ciorba. Kynurenine pathway metabolites: relevant to vitamin B-6 deficiency and beyond. The American Journal of Clinical Nutrition. 98(4): 863–864. Oct 2013.
50. A Neumeister. Tryptophan depletion, serotonin, and depression: where do we stand? Psychopharmacology Bulletin. 37(4):99-115. 2003.
51. S Brod et al. ‘As above, so below’ examining the interplay between emotion and the immune system. Immunology. 143(3): 311–318. Nov 2014.
52. B Strasser et al. Effects of Exhaustive Aerobic Exercise on Tryptophan-Kynurenine Metabolism in Trained Athletes. PLoS ONE. https://doi.org/10.1371/journal.pone.0153617 Apr 2016.
53. DM Christmas et al. A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase. Neuropsychiatric Disease and Treatment. 7: 431–439. Jul 2011.
54. N Tsujita et al. Effect of Tryptophan, Vitamin B6, and Nicotinamide-Containing Supplement Loading between Meals on Mood and Autonomic Nervous System Activity in Young Adults with Subclinical Depression: A Randomized, Double-Blind, and Placebo-Controlled Study. Journal of Nutritional Science and Vitaminology. 65(6):507-514. 2019.
55. T Eleftheriadis et al. Indoleamine 2,3-dioxygenase depletes tryptophan, activates general control non-derepressible 2 kinase and down-regulates key enzymes involved in fatty acid synthesis in primary human CD4+ T cells. Immunology. 146(2): 292–300. Oct 2015.
56. X Zhou. CD4+ T cells in atherosclerosis. Biomedicine & Pharmacotherapy. 57(7): 287-291. Sep 2003.
57. M Mikko et al. Human T cells stimulate fibroblast-mediated degradation of extracellular matrix in vitro. Clinical and Experimental Immunology. 151(2): 317–325. Feb 2008.
58. TT Braga et al. Macrophages During the Fibrotic Process: M2 as Friend and Foe. Frontiers in Immunology. 6: 602. Nov 2015.
59. SV Linthout et al. Crosstalk between fibroblasts and inflammatory cell. Cardiovascular Research. 102(2): 258–269. May 2014.
60. DH Madsen et al. M2-like macrophages are responsible for collagen degradation through a mannose receptor–mediated pathway. Journal of Cell Biology. 202(6): 951–966. Sep 2013.
61. L Martinez-Pomares et al. Carbohydrate-independent recognition of collagens by the macrophage mannose receptor. European Journal of Immunology. 36(5): 1074-1082. May 2006.
62. BM Mohammed et al. Resolution of Sterile Inflammation: Role for Vitamin C. Mediators of Inflammation. https://doi.org/10.1155/2014/173403 2014.
63. P Libby and M Aikawa. Vitamin C, Collagen, and Cracks in the Plaque. Circulation. 105(12):1396–1398. Mar 2002.
64. SP Juraschek et al. Effect of Oral Vitamin C Supplementation on Serum Uric Acid: A Meta-analysis of Randomized Controlled Trials. Arthritis Care and Research. 63(9): 1295–1306. Sep 2011.
65. B Aras et al. Can lemon juice be an alternative to potassium citrate in the treatment of urinary calcium stones in patients with hypocitraturia? A prospective randomized study. Urology Research. 36(6):313-7. Dec 2008.
66. MA Fini et al. Contribution of uric acid to cancer risk, recurrence, and mortality. Clinical and Translational Medicine. 1: 16. Aug 2012.
67. Y Murakami et al. Remarkable Role of Indoleamine 2,3-Dioxygenase and Tryptophan Metabolites in Infectious Diseases: Potential Role in Macrophage-Mediated Inflammatory Diseases. Mediators of Inflammation. https://doi.org/10.1155/2013/391984 2013.
68. R Huttenen et al. High activity of indoleamine 2,3 dioxygenase enzyme predicts disease severity and case fatality in bacteremic patients. Shock. 33(2):149-54. Feb 2010.
69. Y Suzuki et al. Serum activity of indoleamine 2,3-dioxygenase predicts prognosis of community-acquired pneumonia. The Journal of Infection. 63(3):215-22. Sep 2011.
70. Y Suzuki et al. Serum indoleamine 2,3-dioxygenase activity predicts prognosis of pulmonary tuberculosis. Clinical and Vaccine Immunology. 19(3):436-42. Mar 2012.
71. SL Pett et al. Increased Indoleamine-2,3-Dioxygenase Activity Is Associated With Poor Clinical Outcome in Adults Hospitalized With Influenza in the INSIGHT FLU003Plus Study. Open Forum Infectious Diseases. 5(1):ofx228. Jan 2018.
72. M Pertovaara et al. Indoleamine 2,3-dioxygenase activity is increased in patients with systemic lupus erythematosus and predicts disease activation in the sunny season. Clinical and Experimental Immunology. 150(2): 274–278. Nov 2007.
73. W-L Lui et al. Epstein-Barr Virus Infection Induces Indoleamine 2,3-Dioxygenase Expression in Human Monocyte-Derived Macrophages through p38/Mitogen-Activated Protein Kinase and NF-κB Pathways: Impairment in T Cell Functions. Journal of Virology. 88(12): 6660–6671. Jun 2014.
74. Q Zhou et al. A narrative review of the roles of indoleamine 2,3-dioxygenase and tryptophan-2,3-dioxygenase in liver diseases. Annals of Translational Medicine. 9(2). Jan 2021.
75. J Chen et al. Anti-Retroviral Therapy Decreases but Does Not Normalize Indoleamine 2,3-Dioxygenase Activity in HIV-Infected Patients. PLoS One. 9(7): e100446. Jul 2014.
76. L Ghou et al. Indoleamine 2,3‐dioxygenase (IDO)‐1 and IDO‐2 activity and severe course of COVID‐19. The Journal of Pathology. 256(3): 256–261. Mar 2022.
77. CG Adu-Gyamfi et al. Indoleamine 2, 3-Dioxygenase-Mediated Tryptophan Catabolism: A Leading Star or Supporting Act in the Tuberculosis and HIV Pas-de-Deux? Frontiers in Cellular and Infection Microbiology. https://doi.org/10.3389/fcimb.2019.00372 2019.
78. LS Berk et al. Modulation of neuroimmune parameters during the eustress of humor-associated mirthful laughter. Alternative Therapies in Health and Medicine. 7(2):62-72, 74-6. Mar 2001.
79. U Saqib et al. Phytochemicals as modulators of M1-M2 macrophages in inflammation. Oncotarget. 9(25): 17937–17950. Apr 2018.
80. Y Tan et al. Indoleamine 2, 3-dioxygenase 1 inhibitory compounds from natural sources. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2022.1046818 Nov 2022.