Berberine: A Multi-Target Natural PCSK9 Inhibitor with the Potential to
Treat Diabetes, Alzheimer’s, Cancer and Cardiovascular Disease

Caroline      Coppinger; Briana      Pomales; Mohammad Reza      Movahed; Meredith      Marefat; Mehrnoosh      Hashemzadeh
doi:10.2174/0127724328250471231222094648
Abstract

Berberine is a natural product with a wide range of pharmacological effects. It has antimicrobial, anti-cancer, anti-inflammatory, anti-hyperlipidemic, neuroprotective, and cholesterollowering properties, among others. It has been used in traditional Chinese and Ayurvedic medicine for 3000 years and is generally well-tolerated with few side effects. Its main drawback is low oral bioavailability, which has hindered widespread clinical use. However, recent interest has surged with the emergence of evidence that berberine is effective in treating cancer, diabetes, Alzheimer’s disease, and cardiovascular disease via multiple mechanisms. It enhances insulin sensitivity and secretion by pancreatic β-cells in Type 2 Diabetes Mellitus in addition to reducing pro-inflammatory cytokines such as IL-6, IL-1β, TLR4 and TNF-α. These cytokines are elevated in Alzheimer’s disease, cardiovascular disease, and diabetes. Reductions in pro-inflammatory cytokine levels are associated with positive outcomes such as improved cognition, reduced cardiovascular events, and improved glucose metabolism and insulin sensitivity. Berberine is a natural PCSK9 inhibitor, which contributes to its hypolipidemic effects. It also increases low-density lipoprotein receptor expression, reduces intestinal cholesterol absorption, and promotes cholesterol excretion from the liver to the bile. This translates into a notable decrease in LDL cholesterol levels. High LDL cholesterol levels are associated with increased cardiovascular disease risk. Novel synthetic berberine derivatives are currently being developed that optimize LDL reduction, bioavailability, and other pharmacokinetic properties.
Keywords: Hyperlipidemia, cholesterol, PCSK9 inhibitor, atherosclerosis, low-density lipoprotein cholesterol (LDL-C), Alzheimer’s disease, type 2 diabetes mellitus, inflammation.
« Previous Next »
[1]
Roth GA, Mensah GA, Johnson CO, et al. Global burden of cardiovascular diseases and risk factors, 1990–2019. J Am Coll Cardiol  2020; 76(25): 2982-3021.
 [http://dx.doi.org/10.1016/j.jacc.2020.11.010] [PMID: 33309175]

[2]
Azemawah V, Movahed MR, Centuori P, et al. State of the art comprehensive review of individual statins, their differences, pharmacology, and clinical implications. Cardiovasc Drugs Ther  2019; 33(5): 625-39.
 [http://dx.doi.org/10.1007/s10557-019-06904-x] [PMID: 31773344]

[3]
Coppinger C, Movahed MR, Azemawah V, Peyton L, Gregory J, Hashemzadeh M. A comprehensive review of PCSK9 inhibitors. J Cardiovasc Pharmacol Ther  2022; 27: 10742484221100107.
 [http://dx.doi.org/10.1177/10742484221100107] [PMID: 35593194]

[4]
Kong W, Wei J, Abidi P, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med  2004; 10(12): 1344-51.
 [http://dx.doi.org/10.1038/nm1135] [PMID: 15531889]

[5]
Wang Y, Yi X, Ghanam K, Zhang S, Zhao T, Zhu X. Berberine decreases cholesterol levels in rats through multiple mechanisms, including inhibition of cholesterol absorption. Metabolism  2014; 63(9): 1167-77.
 [http://dx.doi.org/10.1016/j.metabol.2014.05.013] [PMID: 25002181]

[6]
Hu Y, Ehli EA, Kittelsrud J, et al. Lipid-lowering effect of berberine in human subjects and rats. Phytomedicine  2012; 19(10): 861-7.
 [http://dx.doi.org/10.1016/j.phymed.2012.05.009] [PMID: 22739410]

[7]
Dong B, Li H, Singh AB, Cao A, Liu J. Inhibition of PCSK9 transcription by berberine involves down-regulation of hepatic HNF1α protein expression through the ubiquitin-proteasome degradation pathway. J Biol Chem  2015; 290(7): 4047-58.
 [http://dx.doi.org/10.1074/jbc.M114.597229] [PMID: 25540198]

[8]
Wang Y, Jia X, Ghanam K, Beaurepaire C, Zidichouski J, Miller L. Berberine and plant stanols synergistically inhibit cholesterol absorption in hamsters. Atherosclerosis  2010; 209(1): 111-7.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2009.08.050] [PMID: 19782362]

[9]
Abidi P, Zhou Y, Jiang JD, Liu J. Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine. Arterioscler Thromb Vasc Biol  2005; 25(10): 2170-6.
 [http://dx.doi.org/10.1161/01.ATV.0000181761.16341.2b] [PMID: 16100034]

[10]
Poudel A, Zhou JY, Mekala N, Welchko R, Rosca MG, Li L. Berberine hydrochloride protects against cytokine-induced inflammation through multiple pathways in undifferentiated C2C12 myoblast cells. Can J Physiol Pharmacol  2019; 97(8): 699-707.
 [http://dx.doi.org/10.1139/cjpp-2018-0653] [PMID: 31026403]

[11]
Angela P, Catapano A. Berberine, a plant alkaloid with lipid-and glucose-lowering properties: From in vitro evidence to clinical studies. Atherosclerosis  2015; 243(2): 449-61.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2015.09.032]

[12]
Akbar M, Shabbir A, Rehman K, Akash MSH, Shah MA. Neuroprotective potential of berberine in modulating Alzheimer’s disease via multiple signaling pathways. J Food Biochem  2021; 45(10): e13936.
 [http://dx.doi.org/10.1111/jfbc.13936] [PMID: 34523148]

[13]
Hussien HM, Abd-Elmegied A, Ghareeb DA, Hafez HS, Ahmed HEA, El-moneam NA. Neuroprotective effect of berberine against environmental heavy metals-induced neurotoxicity and Alzheimer’s-like disease in rats. Food Chem Toxicol  2018; 111: 432-44.
 [http://dx.doi.org/10.1016/j.fct.2017.11.025] [PMID: 29170048]

[14]
Yang M, Wang J. Berberine ameliorates cognitive disorder via GSK3β/PGC-1α signaling in APP/PS1 mice. J Nutr Sci Vitaminol  2022; 68(3): 228-35.
 [http://dx.doi.org/10.3177/jnsv.68.228] [PMID: 35768254]

[15]
Liu M, Gao L, Zhang N. Berberine reduces neuroglia activation and inflammation in streptozotocin-induced diabetic mice. Int J Immunopathol Pharmacol  2019; 33: 2058738419866379.
 [http://dx.doi.org/10.1177/2058738419866379] [PMID: 31337260]

[16]
Liu D, Zhang Y, Liu Y, et al. Berberine modulates gut microbiota and reduces insulin resistance via the TLR4 signaling pathway. Exp Clin Endocrinol Diabetes  2018; 126(8): 513-20.
 [http://dx.doi.org/10.1055/s-0043-125066] [PMID: 29365334]

[17]
Liu Y, Hua W, Li Y, et al. Berberine suppresses colon cancer cell proliferation by inhibiting the SCAP/SREBP-1 signaling pathway-mediated lipogenesis. Biochem Pharmacol  2020; 174: 113776.
 [http://dx.doi.org/10.1016/j.bcp.2019.113776] [PMID: 31874145]

[18]
Yao M, Fan X, Yuan B, et al. Berberine inhibits NLRP3 Inflammasome pathway in human triple-negative breast cancer MDA-MB-231 cell. BMC Complement Altern Med  2019; 19(1): 216.
 [http://dx.doi.org/10.1186/s12906-019-2615-4] [PMID: 31412862]

[19]
Birdsall TC, Kelly GS. Berberine: Therapeutic Potential of an Alkaloid Found in Several Medicinal Plants. Altern Med Rev  1997; 2(2): 94-103.

[20]
Neag MA, Mocan A, Echeverría J, et al. Berberine: Botanical occurrence, traditional uses, extraction methods, and relevance in cardiovascular, metabolic, hepatic, and renal disorders. Front Pharmacol  2018; 9: 557.
 [http://dx.doi.org/10.3389/fphar.2018.00557] [PMID: 30186157]

[21]
Imenshahidi M, Hosseinzadeh H. Berberine and barberry (Berberis Vulgaris): A clinical review. Phytother Res  2019; 33(3): 504-23.
 [http://dx.doi.org/10.1002/ptr.6252] [PMID: 30637820]

[22]
Cameron J, Ranheim T, Kulseth MA, Leren TP, Berge KE. Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis  2008; 201(2): 266-73.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2008.02.004] [PMID: 18355829]

[23]
Wang L, Kong H, Jin M, et al. Synthesis of disaccharide modified berberine derivatives and their anti-diabetic investigation in zebrafish using a fluorescence-based technology. Org Biomol Chem  2020; 18(18): 3563-74.
 [http://dx.doi.org/10.1039/D0OB00327A] [PMID: 32347284]

[24]
Liu YT, Hao HP, Xie HG, et al. Extensive intestinal first-pass elimination and predominant hepatic distribution of berberine explain its low plasma levels in rats. Drug Metab Dispos  2010; 38(10): 1779-84.
 [http://dx.doi.org/10.1124/dmd.110.033936] [PMID: 20634337]

[25]
Wang K, Feng X, Chai L, Cao S, Qiu F. The metabolism of berberine and its contribution to the pharmacological effects. Drug Metab Rev  2017; 49(2): 139-57.
 [http://dx.doi.org/10.1080/03602532.2017.1306544] [PMID: 28290706]

[26]
Liu X, Wang L, Tan S, Chen Z, Wu B, Wu X. Therapeutic effects of berberine on liver fibrosis are associated with lipid metabolism and intestinal flora. Front Pharmacol  2022; 13: 814871.
 [http://dx.doi.org/10.3389/fphar.2022.814871] [PMID: 35308208]

[27]
Li Y, Ren G, Wang YX, et al. Bioactivities of berberine metabolites after transformation through CYP450 isoenzymes. J Transl Med  2011; 9(1): 62.
 [http://dx.doi.org/10.1186/1479-5876-9-62] [PMID: 21569619]

[28]
Qiu F, Zhu Z, Kang N, Piao S, Qin G, Yao X. Isolation and identification of urinary metabolites of berberine in rats and humans. Drug Metab Dispos  2008; 36(11): 2159-65.
 [http://dx.doi.org/10.1124/dmd.108.021659] [PMID: 18703644]

[29]
Lei C, Yao Y, Shen B, et al. Columbamine suppresses the proliferation and malignization of colon cancer cells via abolishing Wnt/β-catenin signaling pathway. Cancer Manag Res  2019; 11: 8635-45.
 [http://dx.doi.org/10.2147/CMAR.S209861] [PMID: 31572013]

[30]
He L, Zhou X, Huang N, et al. AMPK regulation of glucose, lipid and protein metabolism: Mechanisms and nutritional significance. Curr Protein Pept Sci  2017; 18(6): 562-70.
 [http://dx.doi.org/10.2174/1389203717666160627071125] [PMID: 27356941]

[31]
Almatroodi SA, Alsahli MA, Rahmani AH. Berberine: An important emphasis on its anticancer effects through modulation of various cell signaling pathways. Molecules  2022; 27(18): 5889.
 [http://dx.doi.org/10.3390/molecules27185889] [PMID: 36144625]

[32]
Hu Q, Li L, Zou X, Xu L, Yi P. Berberine attenuated proliferation, invasion and migration by targeting the AMPK/HNF4α/WNT5A pathway in gastric carcinoma. Front Pharmacol  2018; 9: 1150.
 [http://dx.doi.org/10.3389/fphar.2018.01150] [PMID: 30405404]

[33]
Pongkittiphan V, Chavasiri W, Supabphol R. Antioxidant effect of berberine and its phenolic derivatives against human fibrosarcoma cells. Asian Pac J Cancer Prev  2015; 16(13): 5371-6.
 [http://dx.doi.org/10.7314/APJCP.2015.16.13.5371] [PMID: 26225680]

[34]
Wang Y, Liao J, Luo Y, et al. Berberine alleviates doxorubicin-induced myocardial injury and fibrosis by eliminating oxidative stress and mitochondrial damage via promoting Nrf-2 pathway activation. Int J Mol Sci  2023; 24(4): 3257.
 [http://dx.doi.org/10.3390/ijms24043257] [PMID: 36834687]

[35]
Xu M, Ren L, Fan J, et al. Berberine inhibits gastric cancer development and progression by regulating the JAK2/STAT3 pathway and downregulating IL-6. Life Sci  2022; 290: 120266.
 [http://dx.doi.org/10.1016/j.lfs.2021.120266] [PMID: 34968467]

[36]
Hamsa TP, Kuttan G. Antiangiogenic activity of berberine is mediated through the downregulation of hypoxia-inducible factor-1, VEGF, and proinflammatory mediators. Drug Chem Toxicol  2012; 35(1): 57-70.
 [http://dx.doi.org/10.3109/01480545.2011.589437] [PMID: 22145808]

[37]
Hur JM, Hyun MS, Lim SY, Lee WY, Kim D. The combination of berberine and irradiation enhances anti-cancer effects via activation of p38 MAPK pathway and ROS generation in human hepatoma cells. J Cell Biochem  2009; 107(5): 955-64.
 [http://dx.doi.org/10.1002/jcb.22198] [PMID: 19492307]

[38]
Zhang R, Qiao H, Chen S, et al. Berberine reverses lapatinib resistance of HER2-positive breast cancer cells by increasing the level of ROS. Cancer Biol Ther  2016; 17(9): 925-34.
 [http://dx.doi.org/10.1080/15384047.2016.1210728] [PMID: 27416292]

[39]
Meeran SM, Katiyar S, Katiyar SK. Berberine-induced apoptosis in human prostate cancer cells is initiated by reactive oxygen species generation. Toxicol Appl Pharmacol  2008; 229(1): 33-43.
 [http://dx.doi.org/10.1016/j.taap.2007.12.027] [PMID: 18275980]

[40]
Wang N, Feng Y, Zhu M, et al. Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: The cellular mechanism. J Cell Biochem  2010; 111(6): 1426-36.
 [http://dx.doi.org/10.1002/jcb.22869] [PMID: 20830746]

[41]
Zhao Y, Jing Z, Li Y, Mao W. Berberine in combination with cisplatin suppresses breast cancer cell growth through induction of DNA breaks and caspase-3-dependent apoptosis. Oncol Rep  2016; 36(1): 567-72.
 [http://dx.doi.org/10.3892/or.2016.4785] [PMID: 27177238]

[42]
Yip NK, Ho WS. Berberine induces apoptosis via the mitochondrial pathway in liver cancer cells. Oncol Rep  2013; 30(3): 1107-12.
 [http://dx.doi.org/10.3892/or.2013.2543] [PMID: 23784371]

[43]
Park SH, Sung JH, Kim EJ, Chung N. Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines. Braz J Med Biol Res  2015; 48(2): 111-9.
 [http://dx.doi.org/10.1590/1414-431x20144293] [PMID: 25517919]

[44]
Choi SB, Bae GS, Jo IJ, Wang S, Song HJ, Park SJ. Berberine inhibits inflammatory mediators and attenuates acute pancreatitis through deactivation of JNK signaling pathways. Mol Immunol  2016; 74: 27-38.
 [http://dx.doi.org/10.1016/j.molimm.2016.04.011] [PMID: 27148818]

[45]
Zhang Q, Wang X, Cao S, et al. Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways. Biomed Pharmacother  2020; 128: 110245.
 [http://dx.doi.org/10.1016/j.biopha.2020.110245] [PMID: 32454290]

[46]
Huang J, Feng W, Li S, et al. Berberine exerts anti-cancer activity by modulating adenosine monophosphate- activated protein kinase (AMPK) and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathways. Curr Pharm Des  2021; 27(4): 565-74.
 [http://dx.doi.org/10.2174/18734286MTEw2Mjg54] [PMID: 32988344]

[47]
Kim HS, Kim MJ, Kim EJ, Yang Y, Lee MS, Lim JS. Berberine-induced AMPK activation inhibits the metastatic potential of melanoma cells via reduction of ERK activity and COX-2 protein expression. Biochem Pharmacol  2012; 83(3): 385-94.
 [http://dx.doi.org/10.1016/j.bcp.2011.11.008] [PMID: 22120676]

[48]
Pan Y, Shao D, Zhao Y, et al. Berberine reverses hypoxia-induced chemoresistance in breast cancer through the inhibition of AMPK- HIF-1α. Int J Biol Sci  2017; 13(6): 794-803.
 [http://dx.doi.org/10.7150/ijbs.18969] [PMID: 28656004]

[49]
Yu M, Tong X, Qi B, et al. Berberine enhances chemosensitivity to irinotecan in colon cancer via inhibition of NF-κB. Mol Med Rep  2014; 9(1): 249-54.
 [http://dx.doi.org/10.3892/mmr.2013.1762] [PMID: 24173769]

[50]
Grivennikov SI, Karin M. Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev  2010; 21(1): 11-9.
 [http://dx.doi.org/10.1016/j.cytogfr.2009.11.005] [PMID: 20018552]

[51]
Liu W, Zhang X, Liu P, et al. Effects of berberine on matrix accumulation and NF-kappa B signal pathway in alloxan-induced diabetic mice with renal injury. Eur J Pharmacol  2010; 638(1-3): 150-5.
 [http://dx.doi.org/10.1016/j.ejphar.2010.04.033] [PMID: 20447389]

[52]
Hayden MS, Ghosh S. Regulation of NF-κB by TNF family cytokines. Semin Immunol  2014; 26(3): 253-66.
 [http://dx.doi.org/10.1016/j.smim.2014.05.004] [PMID: 24958609]

[53]
Tang M, Yuan D, Liao P. Berberine improves intestinal barrier function and reduces inflammation, immunosuppression, and oxidative stress by regulating the NF-κB/MAPK signaling pathway in deoxynivalenol-challenged piglets. Environ Pollut  2021; 289(289): 117865.
 [http://dx.doi.org/10.1016/j.envpol.2021.117865] [PMID: 34358871]

[54]
Li J, Zhang S, Wu L, Pei M, Jiang Y. Berberine inhibited metastasis through miR-145/MMP16 axis in vitro. J Ovarian Res  2021; 14(1): 4.
 [http://dx.doi.org/10.1186/s13048-020-00752-2] [PMID: 33407764]

[55]
Cui SY, Wang R, Chen LB. Micro RNA -145: A potent tumour suppressor that regulates multiple cellular pathways. J Cell Mol Med  2014; 18(10): 1913-26.
 [http://dx.doi.org/10.1111/jcmm.12358] [PMID: 25124875]

[56]
Dip N, Reis ST, Srougi M, Dall’Oglio MF, Leite KRM. Expression profile of microrna-145 in urothelial bladder cancer. Int Braz J Urol  2013; 39(1): 95-101.

[57]
Du L, Pertsemlidis A. microRNAs and lung cancer: tumors and 22-mers. Cancer Metastasis Rev  2010; 29(1): 109-22.
 [http://dx.doi.org/10.1007/s10555-010-9204-9] [PMID: 20130964]

[58]
Ni L, Sun P, Ai M, Kong L, Xu R, Li J. Berberine inhibited the formation of metastasis by intervening the secondary homing of colorectal cancer cells in the blood circulation to the lung and liver through HEY2. Phytomedicine  2022; 104: 154303.
 [http://dx.doi.org/10.1016/j.phymed.2022.154303] [PMID: 35802997]

[59]
Wu DC, Zhang MF, Su SG, et al. HEY2, a target of miR-137, indicates poor outcomes and promotes cell proliferation and migration in hepatocellular carcinoma. Oncotarget  2016; 7(25): 38052-63.
 [http://dx.doi.org/10.18632/oncotarget.9343] [PMID: 27191260]

[60]
Cheng D, Bao C, Zhang X, Lin X, Huang H, Zhao L. LncRNA PRNCR1 interacts with HEY2 to abolish miR-448-mediated growth inhibition in non-small cell lung cancer. Biomed Pharmacother  2018; 107: 1540-7.
 [http://dx.doi.org/10.1016/j.biopha.2018.08.105] [PMID: 30257372]

[61]
Xiong RG, Huang SY, Wu SX, et al. Anticancer effects and mechanisms of berberine from medicinal herbs: An update review. Molecules  2022; 27(14): 4523.
 [http://dx.doi.org/10.3390/molecules27144523] [PMID: 35889396]

[62]
Pan Y, Zhang F, Zhao Y, et al. Berberine enhances chemosensitivity and induces apoptosis through dose-orchestrated AMPK signaling in breast cancer. J Cancer  2017; 8(9): 1679-89.
 [http://dx.doi.org/10.7150/jca.19106] [PMID: 28775788]

[63]
Zhang S, Zhou L, Zhang M, et al. Berberine maintains the neutrophil N1 phenotype to reverse cancer cell resistance to doxorubicin. Front Pharmacol  2020; 10: 1658.
 [http://dx.doi.org/10.3389/fphar.2019.01658] [PMID: 32063859]

[64]
Peiró C, Lorenzo Ó, Carraro R, Sánchez-Ferrer CF. IL-1β inhibition in cardiovascular complications associated to diabetes mellitus. Front Pharmacol  2017; 8: 363.
 [http://dx.doi.org/10.3389/fphar.2017.00363] [PMID: 28659798]

[65]
Yin J, Xing H, Ye J. Efficacy of berberine in patients with type 2 diabetes mellitus. Metabolism  2008; 57(5): 712-7.
 [http://dx.doi.org/10.1016/j.metabol.2008.01.013] [PMID: 18442638]

[66]
Lou T, Zhang Z, Xi Z, et al. Berberine inhibits inflammatory response and ameliorates insulin resistance in hepatocytes. Inflammation  2011; 34(6): 659-67.
 [http://dx.doi.org/10.1007/s10753-010-9276-2] [PMID: 21110076]

[67]
Jeong HW, Hsu KC, Lee JW, et al. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am J Physiol Endocrinol Metab  2009; 296(4): E955-64.
 [http://dx.doi.org/10.1152/ajpendo.90599.2008] [PMID: 19208854]

[68]
Aryal B, Raut BK, Bhattarai S, et al. Potential therapeutic applications of plant-derived alkaloids against inflammatory and neurodegenerative diseases. Evid Based Complement Alternat Med  2022; 2022: 1-18.
 [http://dx.doi.org/10.1155/2022/7299778] [PMID: 35310033]

[69]
Soleymani S, Farzaei MH, Zargaran A, Niknam S, Rahimi R. Promising plant-derived secondary metabolites for treatment of acne vulgaris: A mechanistic review. Arch Dermatol Res  2020; 312(1): 5-23.
 [http://dx.doi.org/10.1007/s00403-019-01968-z] [PMID: 31448393]

[70]
Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimers Dement  2016; 12(6): 719-32.
 [http://dx.doi.org/10.1016/j.jalz.2016.02.010] [PMID: 27179961]

[71]
Ladefoged M, Buschard K, Hansen AMK. Increased expression of toll-like receptor 4 and inflammatory cytokines, interleukin-6 in particular, in islets from a mouse model of obesity and type 2 diabetes. Acta Pathol Microbiol Scand Suppl  2013; 121(6): 531-8.
 [http://dx.doi.org/10.1111/apm.12018] [PMID: 23134512]

[72]
Taha IM, Abdu Allah AM, Abd El Gayed EM. Expression of toll-like receptor 4 and its connection with type 2 diabetes mellitus. Cell Mol Biol  2018; 64(13): 15-20.
 [http://dx.doi.org/10.14715/cmb/2018.64.13.4] [PMID: 30403590]

[73]
Angela P, Luigi CA. Interleukin 6 in diabetes, chronic kidney disease, and cardiovascular disease: Mechanisms and therapeutic perspectives. Expert Rev Clin Immunol  2022; 18(4): 377-89.

[74]
Malone JE, Elkasaby MI, Lerner AJ. Effects of hypertension on alzheimer’s disease and related disorders. Curr Hypertens Rep  2022; 24(12): 615-25.
 [http://dx.doi.org/10.1007/s11906-022-01221-5] [PMID: 36125695]

[75]
Pugazhenthi S, Qin L, Reddy PH. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis  2017; 1863(5): 1037-45.
 [http://dx.doi.org/10.1016/j.bbadis.2016.04.017] [PMID: 27156888]

[76]
Decourt B, Lahiri DK, Sabbagh MN. Targeting tumor necrosis factor alpha for alzheimer’s disease. Curr Alzheimer Res  2017; 14(4): 412-25.
 [http://dx.doi.org/10.2174/1567205013666160930110551] [PMID: 27697064]

[77]
Italiani P, Puxeddu I, Napoletano S, et al. Circulating levels of IL-1 family cytokines and receptors in Alzheimer’s disease: New markers of disease progression? J Neuroinflammation  2018; 15(1): 342.
 [http://dx.doi.org/10.1186/s12974-018-1376-1] [PMID: 30541566]

[78]
Neta R, Sayers TJ, Oppenheim JJ. Relationship of TNF to interleukins. Immunol Ser  1992; 56: 499-566.
 [PMID: 1550874]

[79]
Huang NQ, Jin H, Zhou S, Shi J, Jin F. TLR4 is a link between diabetes and Alzheimer’s disease. Behav Brain Res  2017; 316: 234-44.
 [http://dx.doi.org/10.1016/j.bbr.2016.08.047] [PMID: 27591966]

[80]
Javed M, Ahmad MI, Javed H, Naseem S. d-ribose and pathogenesis of Alzheimer’s disease. Mol Biol Rep  2020; 47(3): 2289-99.
 [http://dx.doi.org/10.1007/s11033-020-05243-7] [PMID: 31933261]

[81]
Wang C, Zou Q, Pu Y, Cai Z, Tang Y. Berberine rescues D-ribose-induced alzheimer’s pathology via promoting mitophagy. Int J Mol Sci  2023; 24(6): 5896.
 [http://dx.doi.org/10.3390/ijms24065896] [PMID: 36982968]

[82]
Liu X, Zhou J, Abid MDN, et al. Berberine attenuates axonal transport impairment and axonopathy induced by Calyculin A in N2a cells. PLoS One  2014; 9(4): e93974.
 [http://dx.doi.org/10.1371/journal.pone.0093974] [PMID: 24713870]

[83]
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid–induced insulin resistance. J Clin Invest  2006; 116(11): 3015-25.
 [http://dx.doi.org/10.1172/JCI28898] [PMID: 17053832]

[84]
Abbate A, Van Tassell BW, Biondi-Zoccai GGL. Blocking interleukin-1 as a novel therapeutic strategy for secondary prevention of cardiovascular events. BioDrugs  2012; 26(4): 217-33.
 [http://dx.doi.org/10.1007/BF03261881] [PMID: 22571369]

[85]
Yuan S, Carter P, Bruzelius M, et al. Effects of tumour necrosis factor on cardiovascular disease and cancer: A two-sample Mendelian randomization study. EBioMedicine  2020; 59: 102956.
 [http://dx.doi.org/10.1016/j.ebiom.2020.102956] [PMID: 32805626]

[86]
Lona JMF, Martínez MS, Alarcón GV, Rodas AB. Tumor necrosis factor α (TNF-α) in cardiovascular diseases: Molecular biology and genetics. Med Gazett Mexico  2013; 149: 521-30.

[87]
Abbate A, Toldo S, Marchetti C, Kron J, Van Tassell BW, Dinarello CA. Interleukin-1 and the inflammasome as therapeutic targets in cardiovascular disease. Circ Res  2020; 126(9): 1260-80.
 [http://dx.doi.org/10.1161/CIRCRESAHA.120.315937] [PMID: 32324502]

[88]
Libby P. Targeting inflammatory pathways in cardiovascular disease: The inflammasome, interleukin-1, interleukin-6 and beyond. Cells  2021; 10(4): 951.
 [http://dx.doi.org/10.3390/cells10040951] [PMID: 33924019]

[89]
Cicero A, Rovati L, Setnikar I. Eulipidemic effects of berberine administered alone or in combination with other natural cholesterol-lowering agents. A single-blind clinical investigation. Arzneimittelforschung  2011; 57(1): 26-30.
 [http://dx.doi.org/10.1055/s-0031-1296582] [PMID: 17341006]

[90]
Chiang JYL, Ferrell JM, Wu Y, Boehme S. Bile acid and cholesterol metabolism in atherosclerotic cardiovascular disease and therapy. Cardiology Plus  2020; 5(4): 159-70.
 [http://dx.doi.org/10.4103/2470-7511.305419] [PMID: 34350368]

[91]
Liu D, Xu L, Dong H, et al. Inhibition of proprotein convertase subtilisin/kexin type 9: A novel mechanism of berberine and 8-hydroxy dihydroberberine against hyperlipidemia. Chin J Integr Med  2015; 21(2): 132-8.
 [http://dx.doi.org/10.1007/s11655-014-1775-1] [PMID: 24893659]

[92]
Cao S, Xu P, Yan J, et al. Berberrubine and its analog, hydroxypropyl-berberrubine, regulate LDLR and PCSK9 expression via the ERK signal pathway to exert cholesterol-lowering effects in human hepatoma HepG2 cells. J Cell Biochem  2019; 120(2): 1340-9.
 [http://dx.doi.org/10.1002/jcb.27102] [PMID: 30335889]

[93]
Guarnieri F, Kulp JL Jr, Kulp JL III, Cloudsdale IS. Fragment-based design of small molecule PCSK9 inhibitors using simulated annealing of chemical potential simulations. PLoS One  2019; 14(12): e0225780.
 [http://dx.doi.org/10.1371/journal.pone.0225780] [PMID: 31805108]

[94]
Shende VR, Wu M, Singh AB, Dong B, Kan CFK, Liu J. Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice. J Lipid Res  2015; 56(4): 801-9.
 [http://dx.doi.org/10.1194/jlr.M052969] [PMID: 25652089]

[95]
Lee S, Lim HJ, Park JH, Lee KS, Jang Y, Park HY. Berberine-induced LDLR up-regulation involves JNK pathway. Biochem Biophys Res Commun  2007; 362(4): 853-7.
 [http://dx.doi.org/10.1016/j.bbrc.2007.08.060] [PMID: 17767919]

[96]
Li H, Chen W, Zhou Y, et al. Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements. J Lipid Res  2009; 50(5): 820-31.
 [http://dx.doi.org/10.1194/jlr.M800375-JLR200] [PMID: 19141871]

[97]
Kwon HJ, Lagace TA, McNutt MC, Horton JD, Deisenhofer J. Molecular basis for LDL receptor recognition by PCSK9. Proc Natl Acad Sci  2008; 105(6): 1820-5.
 [http://dx.doi.org/10.1073/pnas.0712064105] [PMID: 18250299]

[98]
Zhang DW, Lagace TA, Garuti R, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem  2007; 282(25): 18602-12.
 [http://dx.doi.org/10.1074/jbc.M702027200] [PMID: 17452316]

[99]
Taechalertpaisarn J, Zhao B, Liang X, Burgess K. Small molecule inhibitors of the PCSK9•LDLR interaction. J Am Chem Soc  2018; 140(9): 3242-9.
 [http://dx.doi.org/10.1021/jacs.7b09360] [PMID: 29378408]

[100]
Evison BJ, Palmer JT, Lambert G, et al. A small molecule inhibitor of PCSK9 that antagonizes LDL receptor binding via interaction with a cryptic PCSK9 binding groove. Bioorg Med Chem  2020; 28(6): 115344.
 [http://dx.doi.org/10.1016/j.bmc.2020.115344] [PMID: 32051094]

[101]
Sun H, Wang J, Liu S, et al. Discovery of novel small molecule inhibitors disrupting the PCSK9-LDLR interaction. J Chem Inf Model  2021; 61(10): 5269-79.
 [http://dx.doi.org/10.1021/acs.jcim.1c00521] [PMID: 34553597]

[102]
Brousseau ME, Clairmont KB, Spraggon G, et al. Identification of a PCSK9-LDLR disruptor peptide with in vivo function. Cell Chem Biol  2022; 29(2): 249-258.e5.
 [http://dx.doi.org/10.1016/j.chembiol.2021.08.012] [PMID: 34547225]

[103]
Suchowerska AK, Stokman G, Palmer JT, et al. A novel, orally bioavailable, small-molecule inhibitor of PCSK9 with significant cholesterol-lowering properties in vivo. J Lipid Res  2022; 63(11): 100293.
 [http://dx.doi.org/10.1016/j.jlr.2022.100293] [PMID: 36209894]

[104]
Momtazi AA, Banach M, Pirro M, Katsiki N, Sahebkar A. Regulation of PCSK9 by nutraceuticals. Pharmacol Res  2017; 120: 157-69.
 [http://dx.doi.org/10.1016/j.phrs.2017.03.023] [PMID: 28363723]

[105]
Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA  2016; 316(7): 743-53.
 [http://dx.doi.org/10.1001/jama.2016.11004] [PMID: 27533159]

[106]
Robinson JG, Jayanna MB, Brown AS, et al. Enhancing the value of PCSK9 monoclonal antibodies by identifying patients most likely to benefit. A consensus statement from the National Lipid Association. J Clin Lipidol  2019; 13(4): 525-37.
 [http://dx.doi.org/10.1016/j.jacl.2019.05.005] [PMID: 31281070]

[107]
Desai NR, Campbell C, Electricwala B, et al. Cost effectiveness of inclisiran in atherosclerotic cardiovascular patients with elevated low-density lipoprotein cholesterol despite statin use: A threshold analysis. Am J Cardiovasc Drugs  2022; 22(5): 545-56.
 [http://dx.doi.org/10.1007/s40256-022-00534-9] [PMID: 35595929]

[108]
Li YH, Yang P, Kong WJ, et al. Berberine analogues as a novel class of the low-density-lipoprotein receptor up-regulators: Synthesis, structure-activity relationships, and cholesterol-lowering efficacy. J Med Chem  2009; 52(2): 492-501.
 [http://dx.doi.org/10.1021/jm801157z] [PMID: 19090767]

[109]
Li M, Liu Y, Qiu Y, et al. The effect of berberine adjunctive treatment on glycolipid metabolism in patients with schizophrenia: A randomized, double-blind, placebo-controlled clinical trial. Psychiatry Res  2021; 300: 113899.
 [http://dx.doi.org/10.1016/j.psychres.2021.113899] [PMID: 33812218]

[110]
Derosa G, D’Angelo A, Bonaventura A, Bianchi L, Romano D, Maffioli P. Effects of berberine on lipid profile in subjects with low cardiovascular risk. Expert Opin Biol Ther  2013; 13(4): 475-82.
 [http://dx.doi.org/10.1517/14712598.2013.776037] [PMID: 23441841]

[111]
Kong WJ, Wei J, Zuo ZY, et al. Combination of simvastatin with berberine improves the lipid-lowering efficacy. Metabolism  2008; 57(8): 1029-37.
 [http://dx.doi.org/10.1016/j.metabol.2008.01.037] [PMID: 18640378]

[112]
Galletti F, Fazio V, Gentile M, et al. Efficacy of a nutraceutical combination on lipid metabolism in patients with metabolic syndrome: A multicenter, double blind, randomized, placebo controlled trial. Lipids Health Dis  2019; 18(1): 66.
 [http://dx.doi.org/10.1186/s12944-019-1002-y] [PMID: 30885221]

[113]
Pisciotta L, Bellocchio A, Bertolini S. Nutraceutical pill containing berberine versus ezetimibe on plasma lipid pattern in hypercholesterolemic subjects and its additive effect in patients with familial hypercholesterolemia on stable cholesterol-lowering treatment. Lipids Health Dis  2012; 11(1): 123.
 [http://dx.doi.org/10.1186/1476-511X-11-123] [PMID: 22998978]

[114]
Efficacy and tolerability of a nutraceutical combination (red yeast rice, policosanols, and berberine) in patients with low-moderate risk hypercholesterolemia: A double-blind, placebo-controlled study.  Available from: https://www-clinicalkey-com.ezproxy3. library.arizona.edu/#!/content/playContent/1-s2.0-S0011393X14000162?returnurl=https:%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0011393X14000162%3Fshowall%3Dtrue&referrer=

[115]
Koppen LM, Whitaker A, Rosene A, Beckett RD. Efficacy of berberine alone and in combination for the treatment of hyperlipidemia: A systematic review. J Evid Based Complementary Altern Med  2017; 22(4): 956-68.
 [http://dx.doi.org/10.1177/2156587216687695] [PMID: 29228784]

[116]
Adorni MP, Zimetti F, Lupo MG, Ruscica M, Ferri N. Naturally occurring PCSK9 inhibitors. Nutrients  2020; 12(5): 1440.
 [http://dx.doi.org/10.3390/nu12051440] [PMID: 32429343]

[117]
Wu C, Xi C, Tong J, et al. Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia. Acta Pharm Sin B  2019; 9(6): 1216-30.
 [http://dx.doi.org/10.1016/j.apsb.2019.06.006] [PMID: 31867167]

[118]
Yu C, Liu G, Liu X, et al. Proteomics analysis reveals a potential new target protein for the lipid-lowering effect of Berberine8998. Acta Pharmacol Sin  2018; 39(9): 1473-82.
 [http://dx.doi.org/10.1038/aps.2017.200] [PMID: 29645002]

[119]
Wang YX, Kong WJ, Li YH, et al. Synthesis and structure–activity relationship of berberine analogues in LDLR up-regulation and AMPK activation. Bioorg Med Chem  2012; 20(22): 6552-8.
 [http://dx.doi.org/10.1016/j.bmc.2012.09.029] [PMID: 23058107]

[120]
Li YH, Li Y, Yang P, et al. Design, synthesis, and cholesterol-lowering efficacy for prodrugs of berberrubine. Bioorg Med Chem  2010; 18(17): 6422-8.
 [http://dx.doi.org/10.1016/j.bmc.2010.06.106] [PMID: 20673726]

[121]
Kong Y, Yi YJ, Liu XQ, Yu P, Zhao LG, Li DD. Discovery and structural optimization of 9-O-phenylsulfonyl-berberines as new lipid-lowering agents. Bioorg Chem  2022; 121: 105665.
 [http://dx.doi.org/10.1016/j.bioorg.2022.105665] [PMID: 35152138]

[122]
Fan TY, Yang YX, Zeng QX, et al. Structure–activity relationship and biological evaluation of berberine derivatives as PCSK9 down-regulating agents. Bioorg Chem  2021; 113: 104994.
 [http://dx.doi.org/10.1016/j.bioorg.2021.104994] [PMID: 34052738]

[123]
Li DD, Yu P, Xu H, Wang ZZ, Xiao W, Zhao LG. Discovery of C-9 modified berberine derivatives as novel lipid-lowering agents. Chem Pharm Bull  2021; 69(1): 59-66.
 [http://dx.doi.org/10.1248/cpb.c20-00453] [PMID: 33087641]

[124]
Feng M, Zou Z, Zhou X, et al. Comparative effect of berberine and its derivative 8-cetylberberine on attenuating atherosclerosis in ApoE-/- mice. Int Immunopharmacol  2017; 43: 195-202.
 [http://dx.doi.org/10.1016/j.intimp.2016.12.001] [PMID: 28024280]

[125]
Maharjan B, Payne DT, Ferrarese I, et al. Evaluation of the effects of natural isoquinoline alkaloids on low density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) in hepatocytes, as new potential hypocholesterolemic agents. Bioorg Chem  2022; 121: 105686.
 [http://dx.doi.org/10.1016/j.bioorg.2022.105686] [PMID: 35217376]

[126]
Newcombe EA, Camats-Perna J, Silva ML, Valmas N, Huat TJ, Medeiros R. Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease. J Neuroinflammation  2018; 15(1): 276.
 [http://dx.doi.org/10.1186/s12974-018-1313-3] [PMID: 30249283]

[127]
Heneka MT, Carson MJ, Khoury JE, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol  2015; 14(4): 388-405.
 [http://dx.doi.org/10.1016/S1474-4422(15)70016-5] [PMID: 25792098]

[128]
Seo EJ, Fischer N, Efferth T. Phytochemicals as inhibitors of NF-κB for treatment of Alzheimer’s disease. Pharmacol Res  2018; 129: 262-73.
 [http://dx.doi.org/10.1016/j.phrs.2017.11.030] [PMID: 29179999]

[129]
Jin H, Jin X, Cao B, Wang W. Berberine affects osteosarcoma via downregulating the caspase-1/IL-1β signaling axis. Oncol Rep  2017; 37(2): 729-36.
 [http://dx.doi.org/10.3892/or.2016.5327] [PMID: 28000894]

[130]
Menter DG, Schilsky RL, DuBois RN. Cyclooxygenase-2 and cancer treatment: Understanding the risk should be worth the reward. Clin Cancer Res  2010; 16(5): 1384-90.
 [http://dx.doi.org/10.1158/1078-0432.CCR-09-0788] [PMID: 20179228]

[131]
Alaaeddine RA, Elzahhar PA, AlZaim I, Abou-Kheir W, Belal ASF, El-Yazbi AF. The emerging role of COX-2, 15-LOX and PPARγ in metabolic diseases and cancer: An introduction to novel multi-target directed ligands (MTDLs). Curr Med Chem  2021; 28(11): 2260-300.
 [http://dx.doi.org/10.2174/1875533XMTA54Mzkc0] [PMID: 32867639]

[132]
Yao C, Narumiya S. Prostaglandin-cytokine crosstalk in chronic inflammation. Br J Pharmacol  2019; 176(3): 337-54.
 [http://dx.doi.org/10.1111/bph.14530] [PMID: 30381825]

[133]
Pei C, Zhang Y, Wang P, et al. Berberine alleviates oxidized low-density lipoprotein-κB induced macrophage activation by downregulating galectin-3 via the NF-κB and AMPK signaling pathways. Phytother Res  2019; 33(2): 294-308.
 [http://dx.doi.org/10.1002/ptr.6217] [PMID: 30402951]

[134]
Zhu L, Han J, Yuan R, Xue L, Pang W. Berberine ameliorates diabetic nephropathy by inhibiting TLR4/NF-kB pathway. Biol Res  2018; 51(1): 9.
 [http://dx.doi.org/10.1186/s40659-018-0157-8] [PMID: 29604956]

[135]
Chen H, Liu Q, Liu X, Jin J. Berberine attenuates septic cardiomyopathy by inhibiting TLR4/NF-κB signalling in rats. Pharm Biol  2021; 59(1): 119-26.
 [http://dx.doi.org/10.1080/13880209.2021.1877736] [PMID: 33539718]

[136]
Pérez-Rubio KG, González-Ortiz M, Martínez-Abundis E, Robles-Cervantes JA, Espinel-Bermúdez MC. Effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Metab Syndr Relat Disord  2013; 11(5): 366-9.
 [http://dx.doi.org/10.1089/met.2012.0183] [PMID: 23808999]

[137]
Zhao MM, Lu J, Li S, et al. Berberine is an insulin secretagogue targeting the KCNH6 potassium channel. Nat Commun  2021; 12(1): 5616.
 [http://dx.doi.org/10.1038/s41467-021-25952-2] [PMID: 34556670]

[138]
Zhang Y, Gu Y, Ren H, et al. Gut microbiome-related effects of berberine and probiotics on type 2 diabetes (the PREMOTE study). Nat Commun  2020; 11(1): 5015.
 [http://dx.doi.org/10.1038/s41467-020-18414-8] [PMID: 33024120]

[139]
Wang S, Ren H, Zhong H, et al. Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: A double blinded placebo controlled randomized study. Gut Microbes  2021; 14(1): 2003176.
 [http://dx.doi.org/10.1080/19490976.2021.2003176]

[140]
Harrison SA, Gunn N, Neff GW, et al. A phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes. Nat Commun  2021; 12(1): 5503.
 [http://dx.doi.org/10.1038/s41467-021-25701-5] [PMID: 34535644]

[141]
Meng S, Wang LS, Huang ZQ, et al. Berberine ameliorates inflammation in patients with acute coronary syndrome following percutaneous coronary intervention. Clin Exp Pharmacol Physiol  2012; 39(5): 406-11.
 [http://dx.doi.org/10.1111/j.1440-1681.2012.05670.x] [PMID: 22220931]

[142]
Wei W, Zhao H, Wang A, et al. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol  2012; 166(1): 99-105.
 [http://dx.doi.org/10.1530/EJE-11-0616] [PMID: 22019891]

[143]
An Y, Sun Z, Zhang Y, Liu B, Guan Y, Lu M. The use of berberine for women with polycystic ovary syndrome undergoing IVF treatment. Clin Endocrinol  2014; 80(3): 425-31.
 [http://dx.doi.org/10.1111/cen.12294] [PMID: 23869585]

[144]
Rondanelli M, Gasparri C, Petrangolini G, et al. Berberine phospholipid exerts a positive effect on the glycemic profile of overweight subjects with impaired fasting blood glucose (IFG): A randomized double-blind placebo-controlled clinical trial. Eur Rev Med Pharmacol Sci  2023; 27(14): 6718-27.
 [http://dx.doi.org/10.26355/eurrev_202307_33142] [PMID: 37522683]

[145]
Liu Y, Yu H, Zhang C, et al. Protective effects of berberine on radiation-induced lung injury via intercellular adhesion molecular-1 and transforming growth factor-beta-1 in patients with lung cancer. Eur J Cancer Oxf Engl  2008; 44(16): 2425-32.
 [http://dx.doi.org/10.1016/j.ejca.2008.07.040]

[146]
Chen YX, Gao QY, Zou TH, et al. Berberine versus placebo for the prevention of recurrence of colorectal adenoma: A multicentre, double-blinded, randomised controlled study. Lancet Gastroenterol Hepatol  2020; 5(3): 267-75.
 [http://dx.doi.org/10.1016/S2468-1253(19)30409-1] [PMID: 31926918]

[147]
Li H, Dong B, Park SW, Lee HS, Chen W, Liu J. Hepatocyte nuclear factor 1α plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J Biol Chem  2009; 284(42): 28885-95.
 [http://dx.doi.org/10.1074/jbc.M109.052407] [PMID: 19687008]

[148]
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med  2017; 376(18): 1713-22.
 [http://dx.doi.org/10.1056/NEJMoa1615664] [PMID: 28304224]

[149]
O’Donoghue ML, Giugliano RP, Wiviott SD, et al. Long-term evolocumab in patients with established atherosclerotic cardiovascular disease. Circulation  2022; 146(15): 1109-19.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.122.061620] [PMID: 36031810]

[150]
Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med  2020; 382(16): 1507-19.
 [http://dx.doi.org/10.1056/NEJMoa1912387] [PMID: 32187462]

[151]
Xu X, Dong Y, Ma N, et al. MiR-337-3p lowers serum LDL-C level through targeting PCSK9 in hyperlipidemic mice. Metabolism  2021; 119: 154768.
 [http://dx.doi.org/10.1016/j.metabol.2021.154768] [PMID: 33775647]

[152]
2021 Alzheimer’s disease facts and figures. Alzheimers Dement  2021; 17(3): 327-406.
 [http://dx.doi.org/10.1002/alz.12328] [PMID: 33756057]

[153]
Li C, Ai G, Wang Y, et al. Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-κB pathway. Pharmacol Res  2020; 152: 104603.
 [http://dx.doi.org/10.1016/j.phrs.2019.104603] [PMID: 31863867]

[154]
Liu L, Fan J, Ai G, et al. Berberine in combination with cisplatin induces necroptosis and apoptosis in ovarian cancer cells. Biol Res  2019; 52(1): 37.
 [http://dx.doi.org/10.1186/s40659-019-0243-6] [PMID: 31319879]

[155]
Vlavcheski F, O’Neill EJ, Gagacev F, Tsiani E. Effects of Berberine against Pancreatitis and Pancreatic Cancer. Molecules  2022; 27(23): 8630.
 [http://dx.doi.org/10.3390/molecules27238630] [PMID: 36500723]

[156]
Shen HR, Xu X, Li XL. Berberine exerts a protective effect on rats with polycystic ovary syndrome by inhibiting the inflammatory response and cell apoptosis. Reprod Biol Endocrinol  2021; 19(1): 3.
 [http://dx.doi.org/10.1186/s12958-020-00684-y] [PMID: 33407557]

[157]
Huang ZH, Zheng HF, Wang WL, et al. Berberine targets epidermal growth factor receptor signaling to suppress prostate cancer proliferation in vitro. Mol Med Rep  2015; 11(3): 2125-8.
 [http://dx.doi.org/10.3892/mmr.2014.2929] [PMID: 25394789]
Rights & Permissions Print Cite
Article Metrics
29
2
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0127724328250471231222094648	Print ISSN 2772-4328
Publisher Name Bentham Science Publisher	Online ISSN 2772-4336
Current Reviews in Clinical and Experimental Pharmacology

Berberine: A Multi-Target Natural PCSK9 Inhibitor with the Potential to Treat Diabetes, Alzheimer’s, Cancer and Cardiovascular Disease

Abstract

Related Journals

Related Books

Related Articles
