Medical Write Up: Inflammation + Anti-Inflammation Supplements

Inflammation: An Overview

The following was written by professional medical writer Tabitha Block and Dr. Jonathann Kuo MD, founder of Hudson Medical.

Inflammation occurs when cells of the immune system become activated by the presence of infections or ‘sterile’ agents (physical, chemical or metabolic stimuli released in response to cellular damage or stress) (1). The immune system has a wide response spectrum and can thus execute local and systemic inflammatory responses to eliminate threats. When activated, the immune system induces metabolic and neuroendocrine changes to divert nutrients towards the activated immune cells while conserving energy in non-immune cells (1, 2). Further, these changes can lead to biobehavioral alterations, often referred to as “sickness behaviors”, (i.e. sadness, fatigue, social-behavioral withdrawal, altered food intake, altered sleep, increased blood pressure, dyslipidemia and insulin resistance), which, during infections or cellular injury, can be advantageous (1-5). 

Generally, the immune system activates acute (short-term) inflammatory processes in response to microbial infections or cellular damage. During acute infections, the immune system temporarily upregulates inflammatory activity and subsequently downregulates these processes after the threat is cleared (1, 4). Immune cells express receptors which are used to bind to structures on foreign molecules called pathogen-associated molecular patterns (PAMPs) (1, 6). These cells can also be activated by signaling molecules called damage-associated molecular patterns (DAMPs) that are released during cellular damage or stress (1). Thus, immune cells can very quickly identify and terminate foreign molecules, effectively clearing most infections. Immune cell activation stimulates proinflammatory pathways, the release of cytokines, and further stimulation of the immune response (6). Amongst these events, the release of soluble proteins from immune cells known as cytokines plays a key role in regulating the acute inflammatory response and contributes to the initiation of other inflammatory processes (6). 

Acute inflammation is a critical component of a functional immune response. Inflammation-related molecules, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-⍺), function as signaling molecules that eliminate injurious stimuli and stimulate tissue repair mechanisms (7). Many of these molecules serve as defense or protective mechanisms against further injury. However, dysregulation or chronic activation of the inflammatory response can have devastating consequences (1). Chronic inflammation is generally triggered by DAMPs in the absence of injury or infection, and ultimately causes tissue and organ damage through sustained activation of the immune system (1, 8). Chronic inflammation can induce many processes, such as oxidative stress, which may contribute to the development of inflammatory-associated diseases (1, 8). Research suggests that more than 50% of all deaths are attributable to inflammation-related diseases including ischemic heart disease, stroke, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease (NAFLD) and autoimmune and neurodegenerative conditions (9, 10). Chronic inflammation is associated with increased risk of many other conditions including chronic pain, mood and anxiety-related disorders, acne, eczema, psoriasis, asthma, cancer, inflammatory bowel diseases, stroke, and chronic obstructive pulmonary disease (11-12, 19-28). 

At present, many anti-inflammatory drugs or biologics have been designed to specifically target inflammatory signaling molecules in certain inflammatory diseases. At Hudson Medical, we strongly believe in addressing chronic inflammation prophylactically to reduce potential future risk of chronic inflammation-associated diseases. As such, we have developed a daily anti-inflammatory supplement to target chronic inflammation. Our anti-inflammatory supplement harnesses the power of three plant based and naturally occurring molecules, tetrohydrocurcumin, ergothioneine, and dihydroberberine. These molecules were carefully selected based on methodological review of current scientific evidence supporting their safety and efficacy in targeting inflammation. 

Tetrohydrocurcumin

Tetrohydrocurcumin is a reduced form of curcumin, a plant-derived molecule shown to aid in the management of many chronic inflammatory conditions (29-31). Within the intestine, curcumin is enzymatically converted to tetrohydrocurcumin, which is readily absorbed to carry out its biological functions within the body (32). These biological functions include increasing the activity of antioxidant enzymes, preserving hepatocellular membrane integrity against toxins, enhancing insulin sensitivity, and reducing inflammatory cytokine production (33-36). 

The safety and efficacy of tetrohydrocurcumin has been widely studied in the context of many chronic inflammatory conditions, such as ulcerative colitis and rheumatoid arthritis (37, 38). By eliminating harmful molecules called reactive oxygen species and suppressing pro-inflammatory transcription factors like nuclear factor kappa b (NF-𝜅B), tetrohydrocurcumin has potent antioxidant and anti-inflammatory properties that have immense potential in modern medicine (39, 40). Research suggests tetrohydrocurcumin has protective effects against pro-inflammatory diseases including acne, diabetes mellitus, cardiovascular disease, neurological diseases, autoimmune diseases, depression, asthma, psoriasis and chronic obstructive pulmonary disease (41-45).

Ergothioneine

Ergothioneine is a naturally occurring substance with powerful antioxidant and anti-inflammatory properties. Although ergothioneine is present in all cell types, it is referred to as an adaptive cyto-protective agent because it accumulates in injured tissues in response to increased oxidative damage (46-47). As such, ergothioneine is highly concentrated in mitochondria, the epicenter of oxidative stress (46-49). Studies suggest that ergothioneine levels are significantly reduced in the tissues of subjects with neurodegenerative diseases, eye disorders, cardiovascular diseases, kidney diseases, diabetes and cancer (47-48). Further, cells with reduced ergothioneine levels have been shown to be more susceptible to oxidative stress, leading to deleterious cellular events like increased mitochondrial DNA damage (49). Studies indicate ergothioneine blocks the production of pro-inflammatory cytokines known to be important biomarkers of various pathologies (49-51).

Ergothioneine reduces molecules responsible for oxidative damage and may reduce cellular inflammation by inhibiting processes that contribute to mitochondrial dysfunction (52). Recent research suggests ergothioneine may protect against metabolic syndrome, cardiovascular disease, development of lung injury following acute respiratory distress syndrome, chronic pain, diabetes mellitus and Alzheimer’s disease (53-58).

Dihydroberberine

Research indicates that dihydroberberine, a naturally occurring molecule found in some plants, may serve a protective role in the development of many inflammatory-related conditions, such as ulcerative colitis and atherosclerosis (59-60). Dihydroberberine is a derivative of berberine, a molecule found in plants that has been shown to exhibit beneficial effects on metabolism (61). Research suggests that berberine activates AMP-activated protein kinase (AMPK), an enzyme known to improve insulin sensitivity, enhance lipid oxidation (the process in which fat is utilized for energy), inhibit adipocyte (fat cell) growth and improve cardiovascular health (60-61). Results from clinical studies have shown significant improvements in insulin sensitivity, reduction of body weight and decreased waist circumference following berberine supplementation for 3 months (61-62). When orally consumed, berberine can be simultaneously absorbed in the small intestine through two pathways: 1) berberine can be directly absorbed into the bloodstream at a very slow absorption rate 2) an enzyme called nitroreductase (NTR), localized to the intestinal wall tissue, accelerates absorption by transforming berberine into dihydroberberine, which can be rapidly absorbed (66). Dihydroberberine also has an approximately 5 times higher bioavailability than berberine (68). 

 Dihydroberberine has been shown to suppress activation of NF-𝜅B, a pro-inflammatory molecule known to contribute to chronic inflammation (60, 65). Research also indicates dihydroberberine supplementation can significantly reduce atherosclerotic lesions, which are strongly associated with increased risk of emergency cardiothoracic events (60). The anti-inflammatory potential of dihydroberberine may be useful in preventing the development of chronic inflammatory disorders including atherosclerosis, ulcerative colitis, osteoarthritis, cancer, metabolic syndrome-related disorders like hyperuricemia, and diabetes mellitus (66-68). Further, as dihydroberberine has been shown to reduce adiposity (severe fat excess) and improve insulin sensitivity in mouse models, dihydroberberine supplementation may be an effective method for aiding glycemic control in humans (69). 

References

1. Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822-1832. doi:10.1038/s41591-019-0675-0
2. Straub RH, Cutolo M, Buttgereit F, Pongratz G. Energy regulation and neuroendocrine-immune control in chronic inflammatory diseases. J Intern Med. 2010;267(6):543-560. doi:10.1111/j.1365-2796.2010.02218.x
3. ​​Straub RH, Schradin C. Chronic inflammatory systemic diseases: An evolutionary trade-off between acutely beneficial but chronically harmful programs. Evol Med Public Health. 2016;2016(1):37-51. Published 2016 Jan 27. doi:10.1093/emph/eow001
4. Kotas ME, Medzhitov R. Homeostasis, inflammation, and disease susceptibility. Cell. 2015;160(5):816-827. doi:10.1016/j.cell.2015.02.010
5. Slavich GM Psychoneuroimmunology of stress and mental health in The Oxford Handbook of Stress and Mental Health (eds Harkness K & Hayden EP) (Oxford University Press, in the press; ). 
6. Libby P. Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr Rev. 2007;65(12 Pt 2):S140-S146. doi:10.1111/j.1753-4887.2007.tb00352.x
7. Chen L, Deng H, Cui H, et al. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget. 2017;9(6):7204-7218. Published 2017 Dec 14. doi:10.18632/oncotarget.23208
8. Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. Inflammaging and 'Garb-aging'. Trends Endocrinol Metab. 2017;28(3):199-212. doi:10.1016/j.tem.2016.09.005
9. Netea MG, Balkwill F, Chonchol M, et al. A guiding map for inflammation [published correction appears in Nat Immunol. 2021 Feb;22(2):254]. Nat Immunol. 2017;18(8):826-831. doi:10.1038/ni.3790
10. GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017 [published correction appears in Lancet. 2019 Jun 22;393(10190):e44] [published correction appears in Lancet. 2018 Nov 17;392(10160):2170]. Lancet. 2018;392(10159):1736-1788. doi:10.1016/S0140-6736(18)32203-7
11. Breivik H. Systemic inflammation firmly documented in chronic pain patients by measurement of increased levels of many of 92 inflammation-related proteins in blood - normalizing as the pain condition improves with CBT-based multimodal rehabilitation at Uppsala Pain Center. Scand J Pain. 2019;19(2):223-224. doi:10.1515/sjpain-2019-2009
12. Sommer C, Leinders M, Üçeyler N. Inflammation in the pathophysiology of neuropathic pain. Pain. 2018;159(3):595-602. doi:10.1097/j.pain.0000000000001122
13. Tsalamandris S, Antonopoulos AS, Oikonomou E, et al. The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives. Eur Cardiol. 2019;14(1):50-59. doi:10.15420/ecr.2018.33.1
14. Rapone B, Ferrara E, Corsalini M, et al. Inflammatory Status and Glycemic Control Level of Patients with Type 2 Diabetes and Periodontitis: A Randomized Clinical Trial. Int J Environ Res Public Health. 2021;18(6):3018. Published 2021 Mar 15. doi:10.3390/ijerph18063018
15. Burska AN, Sakthiswary R, Sattar N. Effects of Tumour Necrosis Factor Antagonists on Insulin Sensitivity/Resistance in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. PLoS One. 2015;10(6):e0128889. Published 2015 Jun 25. doi:10.1371/journal.pone.0128889
16. Chou RC, Kane M, Ghimire S, Gautam S, Gui J. Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case-Control Analysis. CNS Drugs. 2016;30(11):1111-1120. doi:10.1007/s40263-016-0374-z
17. Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. 2018;15(9):505-522. doi:10.1038/s41569-018-0064-2
18. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119-1131. doi:10.1056/NEJMoa1707914
19. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16(1):22-34. doi:10.1038/nri.2015.5
20. Felger JC. Imaging the Role of Inflammation in Mood and Anxiety-related Disorders. Curr Neuropharmacol. 2018;16(5):533-558. doi:10.2174/1570159X15666171123201142
21. Antiga E, Verdelli A, Bonciani D, Bonciolini V, Caproni M, Fabbri P. Acne: a new model of immune-mediated chronic inflammatory skin disease. G Ital Dermatol Venereol. 2015;150(2):247-254.
22. Bieber T. Interleukin-13: Targeting an underestimated cytokine in atopic dermatitis. Allergy. 2020;75(1):54-62. doi:10.1111/all.13954
23. Johansen C, Mose M, Ommen P, et al. IκBζ is a key driver in the development of psoriasis. Proc Natl Acad Sci U S A. 2015;112(43):E5825-E5833. doi:10.1073/pnas.1509971112
24. Lambrecht BN, Hammad H, Fahy JV. The Cytokines of Asthma. Immunity. 2019;50(4):975-991. doi:10.1016/j.immuni.2019.03.018
25. Greten FR, Grivennikov SI. Inflammation and Cancer: Triggers, Mechanisms, and Consequences. Immunity. 2019;51(1):27-41. doi:10.1016/j.immuni.2019.06.025
26. Dosh RH, Jordan-Mahy N, Sammon C, Le Maitre C. Interleukin 1 is a key driver of inflammatory bowel disease-demonstration in a murine IL-1Ra knockout model. Oncotarget. 2019;10(37):3559-3575. Published 2019 May 28. doi:10.18632/oncotarget.26894
27. Kelly PJ, Lemmens R, Tsivgoulis G. Inflammation and Stroke Risk: A New Target for Prevention. Stroke. 2021;52(8):2697-2706. doi:10.1161/STROKEAHA.121.034388
28. Jasper AE, McIver WJ, Sapey E, Walton GM. Understanding the role of neutrophils in chronic inflammatory airway disease. F1000Res. 2019;8:F1000 Faculty Rev-557. Published 2019 Apr 26. doi:10.12688/f1000research.18411.1
29. Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009;41(1):40-59. doi:10.1016/j.biocel.2008.06.010
30. Panahi Y, Hosseini MS, Khalili N, et al. Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: A post-hoc analysis of a randomized controlled trial. Biomed Pharmacother. 2016;82:578-582. doi:10.1016/j.biopha.2016.05.037
31. Kuptniratsaikul V, Dajpratham P, Taechaarpornkul W, et al. Efficacy and safety of Curcuma domestica extracts compared with ibuprofen in patients with knee osteoarthritis: a multicenter study. Clin Interv Aging. 2014;9:451-458. Published 2014 Mar 20. doi:10.2147/CIA.S58535
32. Okada K, Wangpoengtrakul C, Tanaka T, Toyokuni S, Uchida K, Osawa T. Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice. J Nutr. 2001;131(8):2090-2095. doi:10.1093/jn/131.8.2090
33. Murugan P, Pari L. Influence of tetrahydrocurcumin on hepatic and renal functional markers and protein levels in experimental type 2 diabetic rats. Basic Clin Pharmacol Toxicol. 2007;101(4):241-245. doi:10.1111/j.1742-7843.2007.00109.x
34. Pari L, Murugan P. Protective role of tetrahydrocurcumin against erythromycin estolate-induced hepatotoxicity. Pharmacol Res. 2004;49(5):481-486. doi:10.1016/j.phrs.2003.11.005
35. Chuengsamarn S, Rattanamongkolgul S, Luechapudiporn R, Phisalaphong C, Jirawatnotai S. Curcumin extract for prevention of type 2 diabetes. Diabetes Care. 2012;35(11):2121-2127. doi:10.2337/dc12-0116
36. Panahi Y, Hosseini MS, Khalili N, et al. Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: A post-hoc analysis of a randomized controlled trial. Biomed Pharmacother. 2016;82:578-582. doi:10.1016/j.biopha.2016.05.037
37. Kumar S, Ahuja V, Sankar MJ, Kumar A, Moss AC. Curcumin for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2012;10:CD008424. Published 2012 Oct 17. doi:10.1002/14651858.CD008424.pub2
38. Pourhabibi-Zarandi F, Shojaei-Zarghani S, Rafraf M. Curcumin and rheumatoid arthritis: A systematic review of literature. Int J Clin Pract. 2021;75(10):e14280. doi:10.1111/ijcp.14280
39. Singh S, Aggarwal BB. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected] [published correction appears in J Biol Chem 1995 Dec 15;270(50):30235]. J Biol Chem. 1995;270(42):24995-25000. doi:10.1074/jbc.270.42.24995
40. Nakamura Y, Ohto Y, Murakami A, Osawa T, Ohigashi H. Inhibitory effects of curcumin and tetrahydrocurcuminoids on the tumor promoter-induced reactive oxygen species generation in leukocytes in vitro and in vivo. Jpn J Cancer Res. 1998;89(4):361-370. doi:10.1111/j.1349-7006.1998.tb00572.x
41. Tan J, Thiboutot D, Popp G, et al. Randomized phase 3 evaluation of trifarotene 50 μg/g cream treatment of moderate facial and truncal acne. J Am Acad Dermatol. 2019;80(6):1691-1699. doi:10.1016/j.jaad.2019.02.044
42. Kunnumakkara AB, Bordoloi D, Padmavathi G, et al. Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. Br J Pharmacol. 2017;174(11):1325-1348. doi:10.1111/bph.13621
43. ​​Gupta SC, Sung B, Kim JH, Prasad S, Li S, Aggarwal BB. Multitargeting by turmeric, the golden spice: From kitchen to clinic. Mol Nutr Food Res. 2013;57(9):1510-1528. doi:10.1002/mnfr.201100741
44. Ng QX, Koh SSH, Chan HW, Ho CYX. Clinical Use of Curcumin in Depression: A Meta-Analysis. J Am Med Dir Assoc. 2017;18(6):503-508. doi:10.1016/j.jamda.2016.12.071
45. Aggarwal BB, Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009;41(1):40-59. doi:10.1016/j.biocel.2008.06.010
46. Cheah IK, Halliwell B. Ergothioneine; antioxidant potential, physiological function and role in disease. Biochim Biophys Acta. 2012;1822(5):784-793. doi:10.1016/j.bbadis.2011.09.017
47. Halliwell B, Cheah IK, Tang RMY. Ergothioneine - a diet-derived antioxidant with therapeutic potential. FEBS Lett. 2018;592(20):3357-3366. doi:10.1002/1873-3468.13123
48. Halliwell B, Cheah IK, Drum CL. Ergothioneine, an adaptive antioxidant for the protection of injured tissues? A hypothesis. Biochem Biophys Res Commun. 2016;470(2):245-250. doi:10.1016/j.bbrc.2015.12.124
49. Cheah IK, Tang RM, Yew TS, Lim KH, Halliwell B. Administration of Pure Ergothioneine to Healthy Human Subjects: Uptake, Metabolism, and Effects on Biomarkers of Oxidative Damage and Inflammation. Antioxid Redox Signal. 2017;26(5):193-206. doi:10.1089/ars.2016.6778
50. Rahman I, Gilmour PS, Jimenez LA, Biswas SK, Antonicelli F, Aruoma OI. Ergothioneine inhibits oxidative stress- and TNF-alpha-induced NF-kappa B activation and interleukin-8 release in alveolar epithelial cells. Biochem Biophys Res Commun. 2003;302(4):860-864. doi:10.1016/s0006-291x(03)00224-9
51. Li L, Li J, Gao M, et al. Interleukin-8 as a Biomarker for Disease Prognosis of Coronavirus Disease-2019 Patients. Front Immunol. 2021;11:602395. Published 2021 Jan 8. doi:10.3389/fimmu.2020.602395
52. Tian X, Cioccoloni G, Sier JH, Naseem KM, Thorne JL, Moore JB. Ergothioneine supplementation in people with metabolic syndrome (ErgMS): protocol for a randomised, double-blind, placebo-controlled pilot study. Pilot Feasibility Stud. 2021;7(1):193. Published 2021 Oct 29. doi:10.1186/s40814-021-00929-6
53. Lam-Sidun D, Peters KM, Borradaile NM. Mushroom-Derived Medicine? Preclinical Studies Suggest Potential Benefits of Ergothioneine for Cardiometabolic Health. Int J Mol Sci. 2021;22(6):3246. Published 2021 Mar 23. doi:10.3390/ijms22063246
54. Repine JE, Elkins ND. Effect of ergothioneine on acute lung injury and inflammation in cytokine insufflated rats. Prev Med. 2012;54 Suppl(Suppl):S79-S82. doi:10.1016/j.ypmed.2011.12.006
55. Benson KF, Ager DM, Landes B, Aruoma OI, Jensen GS. Improvement of joint range of motion (ROM) and reduction of chronic pain after consumption of an ergothioneine-containing nutritional supplement. Prev Med. 2012;54 Suppl:S83-S89. doi:10.1016/j.ypmed.2012.02.001
56. Calvo MS, Mehrotra A, Beelman RB, et al. A Retrospective Study in Adults with Metabolic Syndrome: Diabetic Risk Factor Response to Daily Consumption of Agaricus bisporus (White Button Mushrooms). Plant Foods Hum Nutr. 2016;71(3):245-251. doi:10.1007/s11130-016-0552-7
57. Yang NC, Lin HC, Wu JH, et al. Ergothioneine protects against neuronal injury induced by β-amyloid in mice. Food Chem Toxicol. 2012;50(11):3902-3911. doi:10.1016/j.fct.2012.08.021
58. Li C, Dong N, Wu B, Mo Z, Xie J, Lu Q. Dihydroberberine, an isoquinoline alkaloid, exhibits protective effect against dextran sulfate sodium-induced ulcerative colitis in mice. Phytomedicine. 2021;90:153631. doi:10.1016/j.phymed.2021.153631
59. Chen J, Cao J, Fang L, et al. Berberine derivatives reduce atherosclerotic plaque size and vulnerability in apoE(-/-) mice. J Transl Med. 2014;12:326. Published 2014 Nov 26. doi:10.1186/s12967-014-0326-7
60. Abbud W, Habinowski S, Zhang JZ, et al. Stimulation of AMP-activated protein kinase (AMPK) is associated with enhancement of Glut1-mediated glucose transport. Arch Biochem Biophys. 2000;380(2):347-352. doi:10.1006/abbi.2000.1935
61. Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism. 2008;57(5):712-717. doi:10.1016/j.metabol.2008.01.013
62. Feng, R., Shou, JW., Zhao, ZX. et al. Transforming berberine into its intestine-absorbable form by the gut microbiota. Sci Rep 5, 12155 (2015). https://doi.org/10.1038/srep12155
63. Turner N, Li JY, Gosby A, et al. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes. 2008;57(5):1414-1418. doi:10.2337/db07-1552
64. Li CL, Tan LH, Wang YF, et al. Comparison of anti-inflammatory effects of berberine, and its natural oxidative and reduced derivatives from Rhizoma Coptidis in vitro and in vivo. Phytomedicine. 2019;52:272-283. doi:10.1016/j.phymed.2018.09.228
65. Reddi KK, Li H, Li W, Tetali SD. Berberine, A Phytoalkaloid, Inhibits Inflammatory Response Induced by LPS through NF-Kappaβ Pathway: Possible Involvement of the IKKα. Molecules. 2021;26(16):4733. Published 2021 Aug 5. doi:10.3390/molecules26164733
66. Dai B, Ma Y, Wang W, et al. Dihydroberberine exhibits synergistic effects with sunitinib on NSCLC NCI-H460 cells by repressing MAP kinase pathways and inflammatory mediators. J Cell Mol Med. 2017;21(10):2573-2585. doi:10.1111/jcmm.13178
67. Zhou Y, Liu SQ, Yu L, et al. Berberine prevents nitric oxide-induced rat chondrocyte apoptosis and cartilage degeneration in a rat osteoarthritis model via AMPK and p38 MAPK signaling. Apoptosis. 2015;20(9):1187-1199. doi:10.1007/s10495-015-1152-y
68. Xu L, Lin G, Yu Q, et al. Anti-Hyperuricemic and Nephroprotective Effects of Dihydroberberine in Potassium Oxonate- and Hypoxanthine-Induced Hyperuricemic Mice. Front Pharmacol. 2021;12:645879. Published 2021 Apr 20. doi:10.3389/fphar.2021.645879
69. Turner N, Li JY, Gosby A, et al. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes. 2008;57(5):1414-1418. doi:10.2337/db07-1552