The Bitter Medicine is Good for Health: Research Progress on the Components and Pharmacological Activities of Coptis Chinensis

Coptis chinensis, a herbace perennial ous plant of the Ranunculaceae family, is also known as "Wei Lian," "Yun Lian," "Ya Lian," "Ji Zhuazhao Lian," and so on. It is mainly produced in Sichuan, Hubei, Yunnan, and other places. Huanglian was first recorded in the "Shen Nong's Herbal Classic" and its rhizome is used medicinally. It has an extremely bitter taste and a cold nature, possessing the effects of clearing heat, drying dampness, purging fire, and detoxifying. It is often used to treat diarrhea, dysentery, diabetes, abscesses, and other toxic swellings. Currently, more than a hundred chemical components have been isolated from Huanglian, including alkaloids, lignans, flavonoids, and acidic components, among which alkaloids are its most important pharmacologically active ingredients. Currently, almost all the alkaloids isolated from Huanglian are isoquinoline alkaloids, most of which belong to the benzylisoquinoline class, including protoberberine, bisbenzylisoquinoline, aporphine, and benzophenanthridine. Protoberberine is mainly composed of coptisine, berberine, epiberberine, jatrorrhizine, palmatine, and other components, accounting for 70% to 80% of the total alkaloids in Huanglian. The 2015 edition of the "Chinese Pharmacopoeia" stipulates that coptisine, berberine, epiberberine, and palmatine are the indicative components of Huanglian. Among them, berberine (also known as coptisine) is the most representative and abundant component in Huanglian, reaching 5% to 8%.

Modern pharmacological research has shown that Huanglian possesses high medicinal value, including the pharmacological effects of protecting cardiovascular and cerebrovascular systems, reducing blood sugar, and anti-inflammation. In recent years, its effects on the cardiovascular and cerebrovascular system, digestive system, and diabetes have attracted increasing attention.

The Effects of Coptis chinensis on the Cardiovascular System

Coptis chinensis exhibits extensive effects on the cardiovascular system, primarily manifesting in anti-arrhythmia, anti-heart failure, and blood pressure reduction. Modern pharmacological research has shown that alkaloids such as berberine, epiberberine, and palmatine in Huanglian can all play a role in anti-arrhythmia. Among them, berberine has significant effects on various types of arrhythmias, demonstrating a broad-spectrum anti-arrhythmic effect. Berberine may exert its anti-arrhythmic effect by inhibiting acetylcholinesterase activity, enhancing the effect of acetylcholine, antagonizing epinephrine, competitively blocking α-receptors, dilating coronary arteries, increasing potassium ion outflow in myocardial cells, blocking delayed rectifier potassium channels, and reducing calcium overload in myocardial cells. Network pharmacology research has shown that the active ingredients in Huanglian can regulate signaling pathways such as PI3K-Akt, HIF-1, MAPK, and Notch, thereby playing a therapeutic role in atrial fibrillation.

Berberine has a positive inotropic effect, which can improve the heart function of patients with congestive heart failure, increase myocardial contractility, and reduce peripheral resistance. Research has shown that berberine can reduce serum BNP and TNF-α levels in rats with heart failure, inhibit the iNOS gene, and thus exert its anti-heart failure effect.

Studies have found that prophylactic administration of berberine can shorten the time for arrhythmias caused by ischemia-reperfusion to return to normal, significantly inhibit the increase in plasma ANP, BNP, and cTn-I levels, and improve myocardial structure, indicating that berberine can play a certain protective role against myocardial injury caused by ischemia-reperfusion. Research has shown that berberine can improve left ventricular remodeling in hypertensive rats by inhibiting the mTOR/p38/ERK1/2 signaling pathway and increasing myocardial autophagy levels. Additionally, berberine can also reduce the expression level of transforming growth factor β1 (TGF-β1) protein and improve myocardial fibrosis.

Platelet aggregation is an important inducing factor for the occurrence of thrombotic cardiovascular and cerebrovascular diseases. Research has shown that berberine has a certain anti-platelet aggregation effect, which can inhibit the formation of thrombi. This may be related to inhibiting platelet aggregation induced by platelet inducers, inhibiting platelet clot contraction, and promoting the disaggregation of platelet aggregates. According to research reports, the mechanism of berberine's anti-platelet aggregation effect may be related to reducing the level of TXA2 in platelets and increasing the level of cAMP, thereby inhibiting platelet-activating factor (PAF). Studies have shown that berberine can regulate the metabolic pathway of Choline/TMA/TMAO flora, reduce the production of intestinal flora, lower the platelet aggregation rate and P-selectin level, and prolong the time of thrombus formation, thus exerting an anti-thrombotic effect.

The mechanism of berberine's antihypertensive effect is related to its inhibition of cholinesterase activity, reduction of peripheral vascular resistance, inhibition of vasoconstriction by reducing calcium influx, and binding to α1 receptors on peripheral blood vessels to dilate them. Recent studies have found that berberine can improve aortic contraction and endothelial-dependent vasodilation in spontaneously hypertensive rats, reducing vascular remodeling. The mechanism may be related to inducing autophagy through the PI3K/Akt signaling pathway.

Hypoglycemic Effect of Huanglian

Diabetes is a metabolic syndrome primarily characterized by defects in insulin secretion from beta cells of the pancreas or insulin resistance. Traditional Chinese medical texts have long documented the use of Huanglian in treating diabetes. For instance, "Mingyi Bielu" mentions that Huanglian "stops thirst." Among the alkaloids in Huanglian, berberine and coptisine primarily play a role in reducing blood sugar, while palmatine, jatrorrhizine, and epiberberine exert different synergistic effects. Modern research has shown that berberine has a good hypoglycemic effect and can exert anti-diabetic effects through multiple pathways. For example, berberine can improve insulin resistance caused by free fatty acids by increasing the expression of insulin receptor substrate-1 and PI3K protein. Some scholars have also found that it can improve insulin resistance in HepG2 cells by promoting the expression of glucokinase. Berberine can stimulate glycolysis, promote cellular glucose metabolism, and exert a significant hypoglycemic effect without the involvement of the AMPK signaling pathway. Research has shown that berberine can also promote the secretion of glucagon-like peptide-1, thereby increasing insulin levels and the number of pancreatic beta cells to achieve hypoglycemic effects.

The liver is an essential organ for sugar metabolism in the body and plays a major role in the regulation of blood sugar homeostasis. Therefore, abnormal hepatic glucose output is an important cause of elevated blood sugar. Berberine can reduce the blood sugar level of diabetic rats by inhibiting hepatic gluconeogenesis through the regulation of the LKB1/AMPK/TORC2 signaling pathway. Recent studies have found that berberine can improve the hepatic glycogen structure of type 2 diabetic mice through the cAMP/GP signaling pathway, repairing damaged glycogen structures to regulate hepatic glucose metabolism, thus exerting a hypoglycemic effect. Dyslipidemia is one of the risk factors for insulin resistance. Research has confirmed that berberine can lower TC, TG, and LDL-C levels, regulate lipid metabolism, and reduce blood sugar levels simultaneously. Additionally, berberine can achieve the purpose of treating diabetes by regulating intestinal microbiota, inhibiting inflammatory responses, and oxidative stress.

The Effects of Huanglian on the Digestive System

Clinically, Huanglian is often used to treat digestive system diseases such as peptic ulcer, gastritis, and enteritis, and has achieved good therapeutic effects. Berberine can inhibit H+-K+-ATP enzyme activity, suppress gastric acid secretion, increase NO and NOS levels in mouse gastric tissue, reduce ET levels, thus promoting the healing of gastric ulcer mucosa. Network pharmacological analysis suggests that the mechanism of Huanglian's therapeutic effect on gastritis is related to biological processes such as cytokine receptor binding, activity regulation, and heme binding, as well as the regulation of signaling pathways such as NF-κB, AGE, IL-17, TNF, HIF-1, and fluid shear stress and atherosclerosis. Relevant clinical studies have shown that berberine can significantly reduce serum VEGF levels, increase PGⅠ and PGR levels, and significantly improve the clinical efficacy for patients with chronic atrophic gastritis.

Berberine can downregulate the levels of endoplasmic reticulum stress markers caspase-12, caspase-3, p-JNK, JNK, and GRP78, thus reducing ulcerative colitis inflammation by improving endoplasmic reticulum stress. Additionally, berberine can also reduce intestinal mucosal inflammation in mice by affecting the secretion of cytokines by intestinal mucosal epithelial cells, participating in the response of intestinal lamina propria lymphocytes, and exerting immune regulatory effects. The total alkaloids of Huanglian can activate PPARγ to inhibit the p38/NF-κB pathway, reduce inflammation, and thus improve intestinal mucosal damage in colitis model rats.

The Anti-Pathogenic Microorganism Effect of Huanglian

Relevant studies have shown that Huanglian has antiviral effects and can inhibit various types of viruses, such as herpes simplex virus, influenza virus, and cytomegalovirus. Berberine can improve the endothelial cell skeleton reconstruction, cell contraction, and cell morphology after influenza virus infection, thereby improving the increased endothelial cell permeability caused by influenza virus infection. Research has found that berberine hydrochloride has a strong inhibitory effect on herpes simplex virus type 1, and its mechanism may be related to inhibiting the expression of viral proteins ICP27, ICP8, and gD.

Modern research has proven that Huanglian possesses broad-spectrum antibacterial activity, significantly inhibiting both Gram-positive bacteria (such as Staphylococcus aureus and Diplococcus pneumoniae) and Gram-negative bacteria (such as Escherichia coli and Salmonella typhi), as well as fungi. Moreover, compared with common antibiotics, Huanglian is less likely to induce drug resistance. Berberine can bind to bacterial single-stranded/double-stranded DNA, forming complexes and reducing the activity of topoisomerases I/II, thereby exerting antibacterial effects by affecting DNA function. The antibacterial effect of berberine is related to inhibiting the activity of Staphylococcus aureus transpeptidases SrtA and SrtB, which subsequently suppresses the pathogenicity of Staphylococcus aureus.

The Anti-Inflammatory Effect of Huanglian

Huanglian has a significant inhibitory effect on both acute and chronic inflammatory responses. Both in vitro and in vivo experiments have demonstrated that Huanglian can downregulate the mRNA levels of STAT4, TNFα, and IL-12, inhibit the transcriptional activity of E2F, and suppress cell proliferation and migration. It exerts its anti-inflammatory effect by bidirectionally regulating the STAT4 signaling pathway. Additionally, berberine can also upregulate the expression of mitochondrial biosynthesis-related genes TRAM and Cytochrome b mRNA, enhance mitochondrial biosynthesis function, and thereby inhibit cellular inflammatory responses.

Using molecular reverse docking technology, a reverse screening was conducted on proteins in the TLR4/NF-κB, JAK2/STAT3, and p38 inflammatory signaling pathways. The results showed that coptisine from Huanglian can competitively inhibit the activity of four inflammatory target proteins: PI3Kα, PI3Kγ, PI3Kδ, and IKKβ, suppressing the transmission of inflammatory signals and affecting the expression of downstream proteins, thereby exerting an anti-inflammatory effect.

As a traditional Chinese medicine with a long history of use in China, Huanglian has a rich foundation for clinical applications. It is chemically diverse, containing alkaloids, lignans, flavonoids, phenylpropanoids, and their derivatives, among other chemical components, and possesses a wide range of biological activities. Not only is its leading position in traditional pharmacological research for antibacterial, anti-inflammatory, and antiviral effects irreplaceable, but its therapeutic effects in treating diabetes, cardiovascular and cerebrovascular diseases, and digestive system diseases have also received widespread attention. With the deepening of modern research, new pharmacological effects of Huanglian are constantly being discovered, and its clinical applications are becoming more extensive.

References

[1] Zhou Rui, Xiang Changpei, Zhang Jingjing, Yang Hongjun. Research Progress on Chemical Constituents of Huanglian and Pharmacological Effects of Berberine [J]. China Journal of Chinese Materia Medica, 2020, 45(19): 4561-4573.

[2] Fu Lin, Fu Qiang, Li Ji, Tong Xin. Research Progress on Chemical Constituents and Pharmacological Effects of Huanglian [J]. Journal of Traditional Chinese Medicine, 2021, 49(02): 87-92.

About the Author

Xiaomichong, a researcher in pharmaceutical quality, has been dedicated to pharmaceutical quality research and verification of drug analysis methods for a long time. Currently, she works in a large domestic pharmaceutical research and development company, engaged in drug inspection analysis and verification of analytical methods.