Berberine: A Traditional Natural Product With Novel Biological Activities

Qian Hou, MD, PhD; Wen-Jun He, MD; Yu-Sheng Wu, MD; Hao-Jie Hao, MD; Xiao-Ye Xie, MD; Xiao-Bing Fu, MD, PhD

 


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ABSTRACT

Context Having been used for thousands of years to treat gastrointestinal diseases, the natural isoquinoline alkaloid, berberine, has exhibited a wide spectrum of biochemical and pharmacological effects in studies of recent years.

Objective • The review intended to examine the many novel bioactivities of berberine, including antidiabetic, anticancer, neuroprotective, anti-inflammatory, and anti-atherosclerotic actions.

Design • The research team searched the MEDLINE database using PubMed, using different keyword combinations, including berberine AND diabetes, berberine AND cancer, berberine AND (neuron OR brain), berberine AND inflammation, and “berberine AND atherosclerosis to find studies evaluating the various effects exerted berberine.

Conclusion • Berberine is a promising multipotent agent to combat diabetes, cancer, Alzheimer’s disease, and other diseases. (Altern Ther Health Med. 2020;26(S2):20-27.)

Qian Hou, MD, PhD; Wen-Jun He, MD; Hao Jie Hao, MD;
Xiao-Ye Xie,
MD; Xiao-Bing Fu, MD, PhD; Institute of Basic Medicine, General Hospital of People’s Liberation Army, Beijing, PR China. Yu-sheng Wu, MD; Shandong University School of Medicine, Jinan, Shandong, PR China.

 


Corresponding author: Xiao-Bing Fu, MD, PhD
E-mail address: [email protected]

Corresponding author: Hao-Jie Hao, MD, PhD
E-mail address: [email protected]


 

Alkaloid berberine is a natural isoquinoline present in the plant roots, rhizomes, and stem bark of a variety of traditional Chinese herbs, such as Coptis Chinensis Franch, Phellodendron chinense schneid, and Phellodendron amurense. Alkaloid berberine has been used for thousands of years to treat bacterial diarrhea in oriental medicine (Figure 1).

From a modern medical perspective, berberine also exhibits a wide spectrum of biochemical and pharmacological effects. These effects include antidiabetic, anticancer, and neuroprotective activities. Studies focused on the structure of berberine revealed that the DNA-binding effect may contribute to its biological activities.1,2

Xiao et al found that Sysu-00692, a berberine derivative, could interfere with the binding of human protection of telomeres 1 (POT1) to the telomeric DNA through chromatin immunoprecipitation.3 In addition, Bhowmik et al demonstrated that an amino alkyl berberine was able to bind to the RNA triplex with a remarkably high affinity and stability.4 Furthermore, berberine has been found to inhibit cytochrome P450 in humans, thereby affecting the pharmacokinetics of many drugs.5-7

Many more studies have clarified the mechanism of berberine’s multiple bioactivities and shown some promising results both in vivo and in vitro. The current review intended to examine the many novel bioactivities of berberine, including antidiabetic, anticancer, neuroprotective,
anti-inflammatory, and anti-atherosclerotic actions.

 

METHODS

Procedures

The research team searched the MEDLINE database using PubMed, using different keyword combinations, including berberine AND diabetes, berberine AND cancer, berberine AND (neuron OR brain), berberine AND inflammation, and berberine AND atherosclerosis to find studies evaluating the various effects exerted berberine.

 

Results 

Antidiabetic Effects and Regulation of Metabolic Syndromes

Berberine is an active component of traditional antidiabetic herbal plants. It has been shown to reduce blood glucose and sensitize the effects of insulin in several clinical8-11 and preclinical12-17 studies. The key results of those studies were as follows: (1) lowered fasting and postprandial
blood-glucose levels, (2) improved oral-glucose tolerance, (3) lowered blood-insulin and glycosylated-hemoglobin levels, (4) decreased total and low-density lipoprotein (LDL) cholesterol, and (5) reduction in the homeostasis-model assessment of the insulin resistance (HOMA-IR) index.

Chueh et al13 and Yang et al9 demonstrated that berberine improved insulin sensitivity by inhibiting fat storage and adjusting the adipokine profile in human preadipocytes and metabolic-syndrome patients. Zhou et al16 also reported reduced pathological changes in β cells of a berberine-treated diabetic pancreas.

The antidiabetic potential of berberine has now become a hotspot for investigators in different countries (Figure 2). Cok et al18 proposed that the hypoglycemic effects of berberine might be attributed to the acute activation of the transport activity of glucose transporter-4 (GLUT4). Rayasam et al19 reported that berberine might function as an agonist of fatty acid receptor GPR40. In GPR40-overexpressing cell lines, berberine has been found to stimulate calcium mobilization, which can activate the migration and exocytosis of insulin granules.20 In another study, berberine also stimulated a glucose-dependent insulin secretion from a rat,  pancreatic beta cell line.21

Liu et al21 demonstrated that berberine had exhibited a synergistic effect on insulin-induced glucose uptake and GLUT4 translocation in an insulin-resistant state. The researchers further showed that berberine enhanced the insulin signal transduction by increasing the serine-phosphorylation of insulin receptor species-1 (IRS-1), improving insulin-induced tyrosine phosphorylation (P-Tyr) of IRS-1, and hence, recruitment of p85 to IRS-1. Similar results have been reported by another group of researchers.22 In addition, Liu et al21 proved that the antidiabetic effects of berberine in Hep G2 cells were related to the reduction of endoplasmic reticulum (ER) stress. Also, the researchers showed that that the expression of molecular markers that contribute to ER stress—oxygen-regulated protein 150 (ORP150)—was decreased both in gene and protein levels. In addition, phosphorylation levels of pancreatic endoplasmic reticulum kinase (PERK) and eukaryotic translation initiation factor 2α (eIF2α) were inhibited in cells pretreated with berberine.

Other studies have reported that berberine reduced fat-induced insulin resistance in the liver23 and visceral white adipose tissue.24 Additionally, Li et al24 found that berberine reduced insulin resistance via pathways that involve liver X receptors (LXRs), peroxisome proliferator-activated receptors (PPARs), and sterol regulatory element-binding proteins (SREBPs).

Zhang et al reported that berberine modulated the activity of glucose and lipids via various pathways: PPARα, PPARγ, AMP-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK), GLUT4, and c-jun N-terminal kinase (JNK).25 Berberine also has been found to modulate glucose metabolism by stimulation of glycolysis26 and inhibition of gluconeogenesis in the liver.27 In addition, berberine has been shown to increase glucose consumption, 2-deoxyglucose uptake, and 3-O-methylglucose (3-OMG) uptake, independently of insulin.28

Berberine has also been found to reduce expression of gluconeogenic genes in the liver, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Moreover, berberine has been shown to exert antioxidant and antilipid peroxidation effects via upregulation of positive transcription elongation factor β (composed of cyclin-dependent kinase 9 and cyclin T1), thereby contributing to the therapeutic effects against diabetes.29

Besides diabetes and metabolic syndromes, berberine also has been shown to provide protective effects against complications induced by diabetes. Lan et al found that berberine can be protective against diabetic nephropathy (DN) via inhibition of the Sphingosine Kinase-Sphingosine 1-phosphate (SphK-S1P) signaling pathway.30 In that study, berberine not only inhibited the increases in the kidney/body-weight ratio, blood urea nitrogen, serum creatinine, and 24h albuminuria in DN mice but also prevented renal hypertrophy, expression of transforming growth factor β1 (TGF-β1), and accumulation of fibronectin (FN) and collagen IV (Col IV).

Similarly, berberine has been shown to reduce kidney injury significantly in a DN rat model via inhibition of renal fibrosis,31 which may involve regulation of advanced glycation end products (AGEs)-receptor for advanced glycation end products (RAGE)32 and/or prostaglandin E2-Gαq-Ca2+ signaling pathways.33

Lately, berberine has been demonstrated to protect the brain from diabetic encephalopathy through modulation of the sirtuin-1 (SIRT1)/ER stress-signaling pathway in db/db mice.34 On the other hand, berberine also has been shown to protect against diabetic neuropathy through inhibition of the protein kinase C (PKC)-transient receptor potential vanilloid 1 (TRPV1) pathway.35 In addition, Xing et al found that berberine can have  therapeutic effects against nonalcoholic fatty liver disease (NAFLD) by upregulating expression of insulin receptor substrate 2 (IRS-2), thereby reducing insulin resistance.23

In line with that study, Zhao et al also demonstrated that berberine can significantly ameliorate NAFLD via inhibition of hepatic gluconeogenesis and lipogenesis in rats.36 Another recent study also showed that berberine can ameliorate NAFLD through suppression of the inflammation that is associated with obesity.37 Indeed, the effects of berberine on lipid metabolism is well-documented.

One of the most classic reports regarding the effects of berberine has demonstrated that its oral administration for 3 months in patients with hypercholesterolemia significantly reduced serum cholesterol by 40%.38 In another recent clinical study, berberine also showed significant therapeutic effects in patients with NAFLD through regulation of lipid metabolism.39,40

Of note, clinical evidence has also demonstrated the benefit of including berberine as an adjuvant therapy for patients with type 2 diabetes, in addition to other standard treatments.41 Recently, a meta-analysis—which analyzed 27 randomized, controlled trials (RCTs) with 2569 patients—indicated that berberine showed significant therapeutic effects on type 2 diabetes, hyperlipidemia, and hypertension, without significant side effects in patients.42 However, the authors also noted that the quality of the randomized, controlled trials included in the meta-analysis was inconsistent, which may have limited the conclusions of the analysis. In addition, most of the included studies were written in Chinese, which made it a lot harder for non-Chinese-speaking scientists to assess the methodology and data of those studies.

 

Anticancer Activity

In this section, the current research team discusses and summarizes the anticancer effects of berberine. Berberine has been shown to produce proapoptotic, anti-inflammatory, anti-proliferative, antimetastatic, and anti-angiogenic effects (Figure 3).

Induction of apoptosis and autophagy and inhibition of inflammation. Chidambara et al have demonstrated that berberine can induce apoptosis in colon-cancer cells, through the induction of a series of biochemical events, including loss of mitochondrial-membrane potential, release of cytochrome-c to cytosol, induction of Bcl-2 family proteins and caspases, and cleavage of poly ADP ribose polymerase (PARP).43 Similar results have also been reported by other independent researchers.44,45

Berberine has been shown to inhibit, (B-RAF)/extracellular signal-regulated kinase (ERK) survival signaling and trigger apoptosis in human melanoma cells. In addition, Lu et al45 demonstrated berberine-induced apoptosis in human cervical carcinoma (HeLa cells), through upregulation of first apoptosis signal receptor (Fas) protein, Fas ligand (FasL), tumor necrosis factor α (TNFα), and TNF receptor-associated protein 1 (TRAF-1).

Moreover, berberine has been shown to induce caspase-independent cell death in colon-tumor cells46 by inducing reactive oxygen species (ROS) production, cathepsin B release, and PARP activation-dependent, apoptosis-inducing factor (AIF) activation. Similarly, berberine has been shown to induce oxidative DNA damage in ovarian cancer cells and increased sensitivity to PARP inhibtion.47

Pazhang et al48 demonstrated that the apoptotic activity of berberine in a human, erythro-myeloblastoid-leukemia cell line can be mediated by the reduction of survivin. Similarly, reduction in expression of both cyclooxygenase-2 (COX-2) and survivin have been associated with the pro-apoptotic effects of berberine in a human, ductal-breast, epithelial-tumor cell line.49 In human hepatoma cells, berberine has been shown to induce tumor cell death in a dose- and time-dependent manner via downregulation of CD147.50

In addition, berberine has been shown to inhibit inflammation by induction of nuclear factor-κB (NF-κB) and COX-2.43 In primary-effusion lymphoma cells, berberine also has been shown to induce caspase-dependent apoptosis and to suppress nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity by inhibiting (IκB) kinase phosphorylation, IκB phosphorylation, and IκB degradation, all of which are upstream targets of the NF-κB pathway.51

In addition to apoptosis, berberine has also been found to induce autophagy in cancer cells. Recently, La et al demonstrated that berberine can induce autophagy in colon-cancer cells and hepatic carcinoma cells by elevating glucose-regulated protein 78 (GRP78).52 Similar effects of berberine have also been reported, in which berberine and cinnamaldehyde were shown to induce autophagy in an A549 cell, a lung-carcinoma cell line, through inhibition of AMPK/mechanistic target of rapamycin (mTOR) pathways.53

Antiproliferative effects of berberine. Besides the apoptotic effects of berberine in tumor cells, a few studies54-56 have found another function of berberine—induction of cell circle arrest. In human epidermal growth factor receptor (HER) 2-overexpressing breast-cancer cells54 and thyroid-carcinoma cells,56 berberine has been found to induce G1-phase cell-cycle arrest by interfering with the expression of cyclins D1 and E, and it inhibits cellular growth by downregulating the PI3K Akt signaling pathway. In bladder-cancer cell lines,55 berberine has been found to inhibit cell proliferation and induce cell-cycle arrest at G0/G1 in a dose-dependent manner.

Researchers also observed that oncogenes H-Ras and c-fos mRNA and protein expressions were dose-dependently and time-dependently decreased by berberine treatment. Upregulation of p27 was found to be associated with the antiproliferative effects of berberine in thyroid-cancer cells57 and ovarian-carcinoma cell lines.58 Berberine has been shown to inhibit proliferation of colon-cancer cells by inactivating β-catenin signaling.59,60

In a study by Park et al,57 a papillary thyroid-cancer cell line (TPC1), treated with berberine, showed cell-cycle arrest at the G0/G1 phase. The researchers later reported that 2 cell lines of ovarian carcinoma treated with berberine showed a 5% increase in DNA content in the G2/M phase and 7% in the S phase, respectively.58 In addition, berberine has been shown to induce cytotoxicity in human pancreatic cancer cells, in which the effect was associated with activation of signaling pathways for the breast cancer susceptibility gene (BRCA1)-mediated, DNA-damage response and for p53, a tumor suppressor gene.61 Similarly, it has been observed that berberine, at low concentrations (5, 10, and 20 μM), induced G1 arrest, concomitant with the activation of the p53-p21 cascade, in prostate-cancer cells.62 The same study also demonstrated that cells exhibited G2/M arrest after exposure to berberine at a higher concentration (50μM) for 24h, in which check point kinase-1 (Chk1) was involved in the process.

Antimetastatic and anti-angiogenic effects of berberine. Berberine has been demonstrated to inhibit matrix metalloproteinases (MMPs), which are crucial factors in cancer-cell metastasis.63-65 One study found that berberine can reduce TNFα-induced matrix metalloproteinase-9 (MMP-9) expression and cell invasion in human breast cancer66 via suppression of activator protein-1(AP-1) DNA binding.

A tumor promoter, 12-0-tetradecanoylphorbol-13-acetate (TPA), has been demonstrated to induce protein kinase C-α (PKC-α) phosphorylation, resulting in upregulated expression of MMP-1 and MMP-9; this effect of TPA has been shown to be inhibited by berberine.63 Meanwhile, berberine had previously been found to exert anticancer effects by inducing ROS production and inhibition of the gene expression of MMP-1, -2, and -9 in human gastric-cancer cells.64

In addition, berberine has been shown to inhibit experimental lung metastasis of melanoma cells significantly through suppression of signaling molecules, such as extracellular signal-regulated kinase (ERK) 1/2, NF-κB, activating transcription factor 2 (ATF-2), and CREB, all of which are involved in the transcription signaling pathways for MMP gene expression.67

In another study of melanoma cells,68 berberine has been found to inhibit the metastatic potential of tumor cells through reduction in the activity of the ERK signaling pathway and COX-2 protein levels. In addition, berberine has been shown to inhibit colorectal-cancer-cell invasion and metastasis through downregulation of the COX-2/prostaglandin E2 PGE2-JAK2/signal transducer and activator of transcription 3 (STAT3) signaling pathway.69

Berberine has also been found to inhibit caspase-8-mediated angiogenesis in colon-cancer cells.43 This effect involved modulation of tumor-necrotic-factor-related apoptosis-inducing ligand (TRAIL), vascular endothelial growth factor (VEGF), and survivin. In addition, Jie et al found that berberine can also inhibit the ability of hepatocellular carcinoma (HCC) to stimulate proliferation, migration, and endothelial-tube formation in human umbilical-vein endothelial cells.70 That study further revealed that berberine could influence the cross-talk between the HCC cell and vascular endothelial cells by abolishing the secretion of VEGF from HCC.

Furthermore, various pro-angiogenic factors—such as VEGF, COX-2, inducible nitric oxide synthase (iNOS), and hypoxia-inducible factor (HIF)—were also downregulated in melanoma cells treated with berberine.71 Proinflammatory mediators—such as interleukin 1 beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and granulocyte macrophage colony-stimulating factor (GM-CSF), which are involved in tumor angiogenesis—were all found to be significantly inhibited by berberine treatment. Lastly, berberine also has been shown to inhibit various transcription factors involved in tumor development and angiogenesis, such as NF-κB, c-Fos, CREB, and ATF-2.72

Other genes and protein-target-mediating, anticancer effects of berberine. P53 plays an important role in the carcinogenesis of many kinds of tumors. Many investigators have found that berberine can regulate the gene and protein production of p53. Kim et al73 showed that the basal levels of p53 mRNA and protein expression can increase with berberine treatment and that berberine can prevent TPA-induced downregulation of p53.

Furthermore, a flexible ligand-protein, inverse-docking program in one study predicted that p53 might be the possible direct target of berberine in exerting anticancer effects on human cervical-carcinoma HeLa cells.74 That study further identified heat shock cognate 71 kDa protein (HSPA8) and annexin A5 as molecular targets of berberine in cervical adenocarcinoma HeLa cells.

On the other hand, berberine can effectively target both the host and viral factors responsible for development of cervical cancer by inhibiting activator protein-1 (AP-1) and blocking the expression of viral oncoproteins E6 and E7.75 Moreover, berberine has been shown to decrease the transcriptional activity of the androgen receptor (AR) and induce AR-protein degradation in prostate cancer.76

Interestingly, berberine has also been found to affect the activity of ion channels in human colonic carcinoma cells. Alzamora et al reported that berberine inhibited colonic Cl- secretion through inhibition of basolateral KCNQ1 channels responsible for K+ recycling via a protein kinase C-alpha (PKCα)-dependent pathway.77 In addition, suppression of DNA transcription by berberine in living cell systems has been reported. Wang et al78 demonstrated that berberine could  directly bind and prevent the association between TATA-binding protein (TBP) and the TATA box, thereby inhibiting TATA box-dependent gene expression

Berberine as an adjuvant therapy. Containing 4 herbs, PHY906 is formulated based on an herbal recipe from traditional Chinese medicine and has the same pharmacological activities as berberine. Kummar et al79 demonstrated that PHY906, in a murine Colon 39 tumor model, protected against the weight loss associated with irinotecan treatment and helped mice to tolerate lethal doses of irinotecan. The researchers also observed that the combination of PHY906 with irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) resulted in additive antitumor activity, with no increased host toxicity.

In a Phase I/II study of a large hepatocellular80 and pancreatic81 cancer population, PHY906 has been shown to be an effective adjuvant therapy for capecitabine that could significantly increase the median overall survival of recruited patients. Berberine has been found to effectively increase radiosensitivity in esophageal cancer cells (ESCC) by downregulating RAD51, a protein that overexpresses and confers radio- and chemoresistance in ESCCs.82 In addition, combined treatment using taxol and berberine significantly has been found to slow the growth rate of HER2-overexpressing breast cancer cells54; co-treatment using As2O3 and berberine significantly inhibited the metastasis of glioma cells65; and combined treatment using berberine and evodiamine significantly enhanced the apoptosis of human hepatocellular carcinoma cells.83 More recently, berberine has been demonstrated to increase the sensitivity of ovarian cancer cells to PARP inhibition47 and to suppress microRNA-21, thereby chemosensitizing stem cells of oral carcinomas.84 All of these data highlight the potential of berberine to serve as an adjuvant to other treatments to improve therapeutic efficacy.

Of note, berberine has been found to inhibit CYP3A4 in vivo,5 which can potentiate the effects of other treatments when given together. Therefore, data showing synergic effects for berberine when given with other drugs should be carefully interpreted.

 

Anti-inflammatory, Neuroprotective, and
Anti-atherosclerotic Activities

For over a thousand years, berberine has been used to treat gastrointestinal illnesses like diarrhea due to its anti-inflammatory effects. In fact, many of the protective effects of berberine mentioned above are associated with the anti-inflammatory activity of berberine. The mechanism mediating that anti-inflammatory effect has not been well defined until recently.

Wu et al85 reported that berberine exhibited antiviral effects on the influenza virus both in vitro and in vivo, via inhibition of the viral infection and repression of inflammatory substances, such as nitric oxide (NO), TNF-α, and monocyte specific chemoattractant molecule-1 (MCP-1). In addition, recovery from dextran sulfate sodium (DDS)-induced colitis was promoted by berberine, through reduction in DSS-upregulated, proinflammatory cytokine levels in the colon, including TNF, interferon-γ (IFN-γ), and IL-17.86

Macrophages are able to upregulate MMPs and extracellular matrix metalloproteinase inducer (EMMPRIN), which can lead to rupture of atherosclerotic plaque. Studies have shown that berberine can stabilize atherosclerotic plaque by suppressing the expression of MMP-9 and EMMPRIN via 2 mechanisms: (1) activation of the p38 signaling pathway,87 and (2) phosphorylation of IκB-α and reduced nuclear translocation of p65 protein.88

Many studies have indicated that berberine can serve as an effective treatment for many diseases associated with inflammation, including the aforementioned NAFLD. In a mouse model of acute pancreatitis, berberine significantly reduced damage to the pancreas and lung through inhibition of NFκB, c-Jun, and p38.89 Through inhibition of NFκB, PI3K, and C-X-C chemokine receptor 4 (CXCR4), berberine has been shown to ameliorate nonalcoholic steatohepatitis that was induced by a high-fat, high-cholesterol diet, in ApoE-knock-out mice.90

Sun et al91 also demonstrated that berberine can attenuate hepatic steatosis and control energy balance in mice through induction of autophagy and activation of fibroblast growth factor 21, in addition to NFκB. The hepatoprotective effect of berberine has been shown to be abrogated in SIRT1 deficient mice, suggesting that SIRT1 may be the main target for berberine to exert anti-inflammatory effects in this particular liver inflammation. Another recent study showed that berberine may target nod-like receptor family pyrin domain-containing 3 (NALP3) inflammasome, via activation of AMPK-dependent autophagy in adipose-tissue macrophages, to inhibit inflammation and metabolic disorder in an insulin-resistance model induced by a high-fat diet.92

The neuro-protective effects of berberine against Alzheimer’s Disease (AD) and other neurodegenerative diseases has been systemically reviewed by Ji and Shen93 and Ahmed et al.94 Multiple activities of berberine are considered to be key mechanisms, including antioxidant acetylcholinesterase (AChE)- and butyrylcholinesterase (BChE)-inhibitory, monoamine-oxidase inhibitory, amyloid-β-peptide-level-reducing, and cholesterol-lowering activities. Berberine has been found to reduce the levels of amyloid-β peptide in AD mice via the Akt/glycogen synthase kinase 3 (GSK3) signaling pathway.95 This effect of berberine was associated with significantly reduced levels of C-terminal fragments of amyloid precursor protein (APP), and the hyperphosphorylation of APP and tau proteins.

In addition, berberine has been demonstrated to reduce ischemic brain injury after pMACO, through activation of Akt GSK signaling and claudin-5 and inhibition of NF-κB expression.96 Berberine is also an anti-oxidant that shows a neuroprotective effect against stroke in animals. Berberine has been shown to protect the brain from ischemic injury by decreasing the intracellular ROS level, thereby inhibiting mitochondrial apoptotic pathways.97 It has also been reported that berberine is a potential neuroprotective agent via activation of PI3K/Akt-dependent cytoprotective and antioxidant pathways.98 In addition, berberine has shown an inhibitory effect on AChE,99 in which the berberine-pyrocatechol hybrid had a higher inhibition of AChE than unconjugated berberine.

Many neurodegenerative diseases are regarded as chronic diseases that involve significant neuroinflammation caused by activation of innate immune responses.100 Based on the studies regarding the anti-inflammatory effects of berberine presented in this review, it is reasonable to study whether berberine may be able to control the progression of those neurodegenerative diseases. However, researchers should note that berberine, in concentrations of a micromolar range, has been reported to induce neurotoxic effects on cultured neuron cells101 and a rat model of Parkinson’s disease.102,103 Therefore, although berberine is relatively safe in nature, prospective clinical trials studying the potential therapeutic effects of berberine on neurodegenerative diseases should be cautiously carried out.

 

Conclusion

Berberine appears to be a very promising multipotent agent for treatment of diabetes, metabolic syndromes, different kinds of cancers, neurological diseases such as AD and ischemic brain injuries, atherosclerosis, and the original target disease – diarrhea. Larger-scale, high-quality clinical research, especially on neurodegenerative diseases, should be carried out to test the effects of berberine to confirm its therapeutic value in those aforementioned diseases.

 

Acknowledgments

The authors would like to express their gratitude to Dr. Ding Yu ,Wei Wang, Xin Xiao, and Dr. Da-Wei Zhang for their help in selecting the articles and revising the manuscript. The present study was supported in part by the National Key R&D Program of China (2017YFC1104701 and 2017YFC1103300), the China Postdoctoral Science Foundation (2013M542517 and 2015T81099), the National Natural Science Foundation of China (81830064, 81721092, 81971841, 81121004, 81230041, 31100705, 30901564 and 81101883), the Beijing Novel Program (2008B53 and 2009A038), the Military Logistics Research Key Project (AWS17J005), the National S&T Resource Sharing Service Platform Project of China (YCZYPT[2018]07) and the General Hospital of PLA Medical Big Data R&D Project (MBD2018030). Qian Hou, MD, PhD, and Wen-Jun He, MD, contributed equally to this work.

 

Author’s disclosure statement

The authors have no conflicts of interest related to the study.

 

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