Research Progress on the Mechanism of Reducing Toxicity and Increasing the Efficacy of Sini Decoction Compatibility

Hao Chen; Yi Huang; Hong Liu; Ming Yang; Hengli Tong; Feipeng Gong; Lingyun Zhong

doi:10.1248/cpb.c22-00380

Abstract

Sini Decoction (SND) is the main prescription for treating Shaoyin disease in Zhang Zhongjing’s Treatise on Typhoid diseases in Han Dynasty. It is composed of Aconitum carmichaeli Debeaux, Glycyrrhiza uralensis Fisch ex DC and Zingiber officinale Roscoe. It has the effects of warming middle-jiao to dispel cold and revive the yang for resuscitation. Nowadays, it is mainly used in diseases in cardiovascular system, nervous system, digestive system and so on. In this paper, the effect and mechanism of the compatibility of Aconitum carmichaelii, Glycyrrhiza uralensis Fisch ex DC and Zingiber officinale Roscoe in SND were described. The results showed that SND performed remarkbly on strengthening heart, promoting blood circulation as well as inhibiting cardiomyocyte apoptosis, anti-inflammatory and anti-hypothyroidism. The toxic effect of Aconitum carmichaelii was relieved by the combination of Glycyrrhiza uralensis Fisch ex DC and Zingiber officinale Roscoe. The mechanism of increasing efficiency and reducing toxicity after the compatibility of medicines in SND was discussed from the perspective of changes in biological effects and chemical compositions. In terms of biological effects, the mechanism of SND in treating heart failure, myocardial ischemia, myocardial hypertrophy and hypothyroidism and protecting cell injury were discussed. As to chemical composition changes, most studies have compared the changes of main components in Aconitum carmichaelii, Glycyrrhiza uralensis Fisch ex DC and Zingiber officinale Roscoe with the whole prescription, drug pair and single Decoction, which further confirmed the effect of Glycyrrhiza uralensis Fisch ex DC on the detoxification of Aconitum carmichaelii and the significance of compatibility efficiency of SND. For the application of differently processed varieties of Aconitum carmichaelii in SND, the treatment of different diseases has siginificant tendencies and differences in the selections of Aconitum carmichaelii processed varieties. This paper will lay a foundation on clarifying the mechanism of drug compatibility of SND and in the future, provide a reference for the proper selection of differently processed products of Aconitum carmichaelii in SND in order to exert better effects in clinical practices.

1. Introduction

Sini Decoction (SND) is the main prescription for treating Shaoyin disease (the description of Shaoyin disease is shown in Table 1) in Treatise on Typhoid Diseases by Zhang Zhongjing in Han Dynasty.¹⁾ It is mainly used for treating cold of insufficiency, including such components as Aconitum carmichaelii, Glycyrrhiza uralensis Fisch ex DC and Zingiber officinale Roscoe^1,2) (Fig. 2). It has the effect of warming the middle-jiao to dispel cold and revive the yang for resuscitation. It can treat aversion to cold, tiredness, cold in extremities, vomiting, diarrhea, profuse sweat, barely palpable pulse and other symptoms caused by excess of Yin due to deficiency of yang.^3–5) Although the prescription is simple, the efficacy is potent and the compatibility is appropriate. It is regarded as “the first important prescription of supporting yang” by physicians over the years.⁶⁾ Item 323 in Treatise on Febrile Diseases records, “SND is appropriate to urgent warming deep pulse patients with Shaoyin diseases.” The prescription is described as follows: Aconitum carmichaelii (one piece, unprepared, peel removed and divided into eight segments), Zingiber officinale Roscoe (one and a half Liang), Glycyrrhiza uralensis Fisch ex DC (two Liang), among which Aconitum carmichaelii is the principal medicine, Zingiber officinale Roscoe is the ministerial medicine, both used unprepared. Glycyrrhiza uralensis Fisch ex DC is the auxiliary medicine and processed as Glycyrrhiza uralensis Fisch ex DC before being used in the prescription.⁷⁾

Table 1. Introduction to Shaoyin Disease

Shaoyin disease	Similar disease	Clinical symptoms	Survival rate and mortality rate	Ref
Strong pathogenic cold, yang qi dissipated, Cold in the Exterior and Heat in the Interior, dysphoria, dry vomiting, diarrhea with undigested food in the stool, spasm of limbs, excessive sweating, cold extremities, deep and moderate pulse or weak and faint pulse.	Diabetic kidney disease	Cold transformation of Shaoyin disease: clear and profuse urination, urine foam, edema starting from top to the bottom, loose skin at the edematous area, whicht is not easy to recover. Heat transformation of Shaoyin disease: Short urine, foam urine, edema starting from the face, from top to bottom, brignt and tense skin of the whole body, which is easy to recover.	In the U.S. National Health and nutrition survey, the 10-year cumulative standardized mortality rate changed from 7.7% of patients with neither diabetes nor kidney disease to 11.5% of patients with type II diabetes but without kidney disease, and then to 31.1% of patients with both diseases. At the time of advanced nephropathy, the annual mortality rate was about 20%. If patients were treated with dialysis, the survival rate should be about 50–60%.	⁸⁾
	Acute myocardial infarction	Cardiodynia, uneasiness caused by internal damage, cold sweat, cold extremities, unconsciousness, cyanosis of the lips and a purplish tongue, cold extremities, cold sweat, diarrhea with undigested food in the stool, pale tongue, weak and faint pulse.	According to statistics, the survival rate of sudden myocardial infarction is more than 90%. If myocardial infarction is not treated, the mortality rate is 30%. After effective drug intervention including monitoring treatment, the mortality rate can be controlled at about 10%. If thrombolysis is used, the mortality can be reduced to 7–8%.	⁹⁾
	Rheumatoid arthritis	Oncotic arthralgia of limbs, fixated pain, morning stiffness, intolerance of cold, thin and white tongue coating, deep and moderate pulse.	The mortality of patients with rheumatoid arthritis was 38% higher than that of the general population; The mortality of female patients is 55% higher than that of the general population. About 70% of patients have extraarticular manifestations, among which rheumatoid vasculitis is a rare and serious complication, with an incidence rate of 1–5%, a 5-year mortality rate of 40%, and a median survival time of only 32 months.	¹⁰⁾

SND has a clinical application history of nearly 2000 years.²⁾ In modern times, SND is mainly used in cardiovascular system diseases,¹¹⁾ nervous system diseases,¹²⁾ digestive system diseases,¹³⁾ endocrine system diseases,¹⁴⁾ bone and joint diseases.¹⁵⁾ It is applied for the treatment of heart failure, shock, coronary heart disease, angina pectoris, and myocardial infarction.¹⁶⁾ It has protective effects on recovering myocardial ischemia-reperfusion injury, correcting heart function injury, inhibiting myocardial ischemia-reperfusion injury, myocardial fibrosis and improving vascular endothelial function.¹⁶⁾

Traditional Chinese medicine (TCM) theory holds that SND aims at generating earth elements by fire elements and bringing fire elements under control by earth elements. In SND, Zingiber officinale Roscoe and Glycyrrhiza uralensis Fisch ex DC are used to match Aconitum carmichaelii, which is considered to be among fire elements and Glycyrrhiza uralensis Fisch ex DC is considered to be among earth elements. Aconitum carmichaelii can help to replenish the dying innate fire elements of body, and Zingiber officinale Roscoe is pungent, warm and dispersing, which can assist the efficacy of Aconitum carmichaelii to revive yang. However, if there is no earth elements covering, the fire elements are easy to extinguish, it can replenish the fire elements but the continuity is not enough. Therefore, the sweet flavor of Glycyrrhiza uralensis Fisch ex DC can ease the healthy qi. Besides, it is also capable of coordination in order to produce the continuous effect of tonifying fire and helping yang.¹⁷⁾

The compatibility of the medicines in SND has its distinguished advantages. Through compatibility, SND can produce better synergism and detoxification.¹⁸⁾ In addition, as Aconitum carmichaelii is the principal medicine in SND, it also has certain toxic and other side effects. Hence, there are many records of different processed products of Aconitum carmichaelii in SND such as raw Aconitum carmichaelii in Treatise on febrile diseases and Danfupian in Chinese Pharmacopoeia (2020).¹⁹⁾ Modern doctors also used other processed varieties of Aconitum carmichaelii in SND, such as Paofupian, Shoufupian as well as Baifupian, etc.²⁰⁾

As to whether the application of differently processed varieties of Aconitum carmichaelii will affect the efficacy of SND or lead a different treatment emphasis, there is no relevant research report. This paper discusses the synergism and detoxification of SND medicines compatibility and its mechanism of action, and preliminarily analyzes the application of different processed Aconitum carmichaelii varieties of SND in the treatment of different diseases, so as to pave the way for the final elucidation of the mechanism of medicines compatibility in SND. In so doing, we intend to provide a reference for the rational application of different processed Aconitum carmichaelii products in SND.

2. Synergism of Medicines Compatibility in SND

SND has a good effect on treating cardiovascular and related diseases, including strenthening cardiotonic action, promoting blood circulation, inhibiting apoptosis, inflammation and hypothyroidism injury.

2.1. Medicines Compatibility Enhances Cardiotonic Effect

SND has a good therapeutic effect on cardiovascular disease. The research results of single medicine in SND showed that Aconitum carmichaelii has cardiotonic, vasopressor, and anti-shock effects but Aconitum carmichaelii is easy to cause arrhythmia; while Zingiber officinale Roscoe has the effect of dispersing cold and dredging collaterals, which can improve blood circulation;²¹⁾ Glycyrrhiza uralensis Fisch ex DC has the effect of scavenging oxygen radicals, anti-myocardial ischemia and anti-arrhythmia.²²⁾ After the application of the medicines compatibility, they can generate cardiotonic, anti-myocardial ischemia, anti-arrhythmia, anti-shock and vasopressor effects and treat the diseases of myocardium, intestinal mucosa and vascular systems, especially in terms of better protection and treatment of cardiovascular system. It shows the regularity and rationality of the whole prescription.¹⁷⁾ Some researchers suggest that the synergism of Glycyrrhiza uralensis Fisch ex DC and Aconitum carmichaelii was mainly manifested in the reaction of the components. For example, the combination of Glycyrrhiza uralensis Fisch ex DC and Aconitum carmichaelii can enhance cardiotonic effects and has antiarrhythmic effects, which may be closely related to the synergistic effects of glycyrrhizic acid on aconitines. Besides, the synergistic effect of Zingiber officinale Roscoe on Aconitum carmichaelii was considered that both Zingiber officinale Roscoe and Aconitum carmichaelii had similar cardiotonic effect.²³⁾ Similarly, myocardial stunning in sepsis belongs to the stage of both yin and yang decline of Shaoyin disease in traditional Chinese medical science, which is in the stage of multiple organ failure and septic shock.²⁴⁾ The clinical manifestations of the patients, such as cold of arms and legs, edema, adverse urination and hypotension were shown.²⁵⁾ Up to now, there is no specific treatment in clinical practice. Some studies used SND with processing variety Heishunpian of Aconitum carmichaelii.²⁶⁾ The results showed that the SND could effectively improve the myocardial contractility, increase the cardiac output per minute, reduce the cardiac load to correct circulatory failure, and exert a good performance on patients with sepsis myocardial stunning.²⁷⁾

2.2. Medicines Compatibility Enhances the Function of Promoting Blood Circulation

It was found that SND can reduce the inflammatory reaction of aortic endothelial cells, kept the aortic wall smooth, reduced the formation of atherosclerotic plaque, and prevented the occurrence and development of atherosclerotic.²⁸⁾

Endothelial cell inflammation is an important pathophysiological process in many cardiovascular diseases. Previous reports have indicated that endothelial cells are essential participants and regulators of inflammatory reactions, which can prevent coagulation, passage of proteins from blood into tissues, control blood flow, and inhibit inflammation in resting state.²⁹⁾ And the productions of nitric oxide (NO) play a crucial role in these processes, while inadequate NO production leading to low NO levels is a major cause of endothelial cell dysfunction.³⁰⁾ Previous research has shown that SND had anti-inflammatory effects in myocardial infarction Rats through decreasing the expression of atrial natriuretic peptide (ANP) levels in plasma and increasing the level of vascular active marker NO, which limits vascular inflammation.³¹⁾ However, the exact components of SND that exert these effects need to be further investigated.

The effect of SND on the expression of vascular endothelial growth factor and stromal cell-derived factor-1 in the serum of rabbits with hyperlipidemia and atherosclerotic were observed. It was discovered that Aconitum carmichaelii Decoction exerted relaxation influence on the isolated rabbit aorta, while the effect of Zingiber officinale Roscoe combined with Aconitum carmichaelii was doubled, which could expand the auricle microvessels of mice, increase the blood flow velocity and fight against microcirculation disturbance.³²⁾ SND has a certain protective effect on the vascular endothelial function of rabbits with experimental atherosclerotic, which can effectively reduce the degree of vascular endothelial damage, thereby reducing the content of vascular endothelial growth factor and stromal cell-derived factor-1 in blood, and effectively slow down the process of atherosclerosis.³³⁾

2.3. Medicines Compatibility Enhances the Inhibition of Apoptosis

Myocardial cell apoptosis is a common pathological phenomenon in a variety of cardiovascular diseases.³⁴⁾ SND can inhibit myocardial cell apoptosis and prevent myocardial cells from injury in rats injured by Adriamycin.³⁵⁾ Chronic heart failure is the end stage of most cardiovascular diseases, and myocardial remodeling is the basic pathological feature of chronic heart failure.³⁶⁾ Cardiomyocyte apoptosis is considered to be one of the important mechanisms of progressive deterioration of myocardial function.³⁷⁾ In Chinese clinical practice, SND has certain therapeutic effects on coronary heart disease, angina pectoris and cerebral infarction.³⁸⁾ Some studies have explored the effects of SND on cardiac function and apoptosis-related protein cytochrome C, caspase-9, and caspase-3 of myocardial myocytes in chronic heart failure mice.³⁹⁾ The results showed that SND could improve the cardiac function of chronic heart failure mice to a certain extent by reducing the expression levels of cytochrome C, caspase-9, and caspase-3. In this study, the theory of TCM holds that the property of Aconitum carmichaelii is highly acrid and highly hot, which can warm and strengthen the vital fire.³⁹⁾ While the acrid and hot property of Zingiber officinale Roscoe is mild, which can warm the stomach and dissipate cold, improve the warming yang effect of Aconitum carmichaelii.³⁹⁾ In addition, Glycyrrhiza uralensis Fisch ex DC can synergistically enhance the effect of warming and tonifying spleen yang of Aconitum carmichaelii and Zingiber officinale Roscoe, relieve the toxicity of Aconitum carmichaelii, and coordinate actions of all medicines. Therefore, although there are only three kinds of medicines, the combination of warming and tonifying can be achieved a better curative performance.^40,41)

2.4. Medicines Compatibility Enhances the Inhibition of Inflammation

In addition to cardiovascular diseases, SND can also be used to treat gastroenteritis and diarrhea. A research showed that SND could be used to treat various types of ulcerative colitis and achieve curative effect well.⁴²⁾ In order to investigate the anti-inflammatory effect of SND on ulcerative colitis in mice, dextran sulfate sodium was used to induce inflammation model.⁴³⁾ The results showed that SND could reduce the symptoms of intestinal tissue inflammation and the disease activity index score and pathological score were lower than those of model group. It could also regulate the expression of Interleukin-6 and Interleukin-7 and increase the expression of Interleukin-10 and Tumor necrosis factor-α in intestinal tissue. SND is considered to protect intestinal mucosa by improving diarrhea and blood circulation, inhibiting the expression of Interleukin-6 and Interleukin-7, promoting the expression of anti-inflammatory factor Interleukin-10, and regulating the balance between them. Meanwhile, it can induce natural immunity by increasing the production of Tumor necrosis factor-α, thus producing a good inhibitory effect on ulcerative colitis. Among all medicines in the prescription, Aconitum carmichaelii is carried out well in treating abdominal cold pain. Zingiber officinale Roscoe can warm the stomach, disperse cold, return yang and dredge the pulse, as well as assist Aconitum carmichaelii to return yang. Besides, Glycyrrhiza uralensis Fisch ex DC can tonify middle-Jiao and qi. On the one hand, it can alleviate the excessive medicine properties of Aconitum carmichaelii and Zingiber officinale Roscoe. On the other hand, it can help Aconitum carmichaelii and Zingiber officinale Roscoe revive the yang for resuscitation. The application of the whole prescription can inhibit ulcerative colitis inflammation.⁴³⁾ The clinical symptoms of membranous nephropathy in TCM have the characteristics of “edema, turbid urine, deficiency and fatigue,” SND can warm and tonify kidney yang and dissolve retained fluid. SND can enhance the pathological changes of nephritis model rats, reduce urinary protein, improve hypoproteinemia, reduce serum creatinine, urea nitrogen, lipid and other indicators, and protect the kidney.⁴⁴⁾

2.5. Medicines Compatibility Enhances the Inhibition of Hypothyroidism Injury

Hypothyroidism can cause renal injury and renal fibrosis is a significant feature. The pathogenesis of renal fibrosis is considered to be deficient in origin and excess in superficiality by TCM theory. Spleen and kidney yang deficiency is the original reason, and retention of turbid damp is superficiality. SND can be applied in the treatment of renal fibrosis. Spicy, sweet and great hot Aconitum carmichaelii can clean up the internal and external cold of the body, warm body and tonify the yang qi in the kidney. Zingiber officinale Roscoe can keep and guard the yang qi. Glycyrrhiza uralensis Fisch ex DC can neutralize the spiciness and turn into yang. In TCM, SND is in line with the pathogenesis of renal fibrosis. Firstly, modern studies have shown that renal tissue injury leads to tissue hypoxia and oxidative stress injury. Next oxidative stress further leads to renal lipid peroxidation and inflammatory response, stimulates Pro fibrogenic factors, finally accelerating the process of renal fibrosis,⁴⁵⁾ Which means reducing oxidative stress can reduce inflammation and renal fibrosis. There was a research on the form of component compatibility; Treatment of renal injury caused by hypothyroidism with SND was observed.⁴⁶⁾ In order to treat hypothyroidism with the best effective dose, Aconitum carmichaelii, Zingiber officinale Roscoe and Glycyrrhiza uralensis Fisch ex DC were used after being weighed. Among those, Aconitum carmichaelii was processed products “Heishunpian.” And Heishunpian were counted by the mass fraction of total alkaloids. Glycyrrhiza uralensis Fisch ex DC was counted by the mass fraction of glycyrrhizin and glycyrrhizic acid. Mass fraction of 6-gingerol was counted as the water extract components of Zingiber officinale Roscoe, and mass fraction of volatile oil was counted as the volatile oil components of Zingiber officinale Roscoe. The components combination was dissolved in 200 mL distilled water to obtain SND. The intervention effect of SND above on oxidative stress reaction and the therapeutic effect on renal fibrosis were studied, and the results showed that the SND of components combination had intervention effect on oxidative stress injury of renal fibrosis, and its therapeutic effect on renal fibrosis may be related to its intervention effect on oxidative stress injury.⁴⁷⁾ In addition, according to the theory of TCM, the symptoms of hypothyroidism are caused by yang deficiency of spleen and kidney. When treated with SND, Aconitum carmichaelii can dispel cold evil, replenish fire and help yang; Zingiber officinale Roscoe can keep and guard fire of yang; Glycyrrhiza uralensis Fisch ex DC guides and transforms yang in line with the pathogenesis. It has been found that SND can increase the serum total triiodothyronine and serum total thyroxine levels of hypothyroidism model, reduce the level of thyrotropin, and improve the pathological damage of thyroid. SND can improve the lipid metabolism disorder and heart function caused by hypothyroidism by regulating apolipoprotein and myosin.⁴⁸⁾ The regulating effect of SND on the dynamic changes of hypothalamus pituitary thyroid axis in hypothyroid rats was investigated. It is found that the regulating effect of SND is dynamic, and the therapeutic effect is not obvious with the aggravation of hypothyroidism. If SND needs to be treated hypothyroidism, it should be treated in time at the initial stage.⁴⁹⁾

3. Detoxification of Medicines Compatibility in SND

SND is a typical representative of medicines compatible detoxification prescriptions. Aconitum carmichaelii contains aconitine, mesaconitine and other toxic diester diterpenoid alkaloids, which are highly toxic. It is necessary to reduce the toxicity of Aconitum carmichaelii, when it is added to the prescription. In SND, Zingiber officinale Roscoe and Glycyrrhiza uralensis Fisch ex DC are used for compatibility, which can not only generate a great curative effect, but also reduce the toxicity of Aconitum carmichaelii.

3.1. Detoxification Effect of the Whole Prescription

Aconitum carmichaelii is considered as a kind of Ranunculaceae with great toxicity recorded since ancient times, even the processed products.⁵⁰⁾ There are strict requirements on the dosage.⁵¹⁾ Modern research found that the main toxic components of Aconitum carmichaelii, such as aconitine, mesaconitine, hypaconitine and other diester diterpenoid alkaloids are mainly toxic to myocardial cells, which may cause myocardial cells to be damaged by ischemia and hypoxia.⁵²⁾ The content of diester diterpenoid alkaloids in SND, Aconitum carmichaelii and Glycyrrhiza uralensis Fisch ex DC mixed Decoction or Aconitum carmichaelii and Zingiber officinale Roscoe mixed Decoction decreased in varying degrees, indicating that both Zingiber officinale Roscoe and Glycyrrhiza uralensis Fisch ex DC can affect the toxic components of Aconitum carmichaelii, so as to reduce the toxic and side effects of the whole prescription. Researchers also observed that the whole prescription injection of SND can improve the left ventricular diastolic function while the single medicine Aconitum carmichaelii injection has no improvement effect on the left ventricular diastolic function caused by acute myocardial ischemia, and the Aconitum carmichaelii injection has certain toxic and side effects, but after having medicine compatibility in SND, the toxicity of the whole prescription is lower than that of the single medicine.⁵³⁾ Other researchers suggest that SND can reduce toxicity by regulating glycolysis, lipid metabolism, tricarboxylic acid cycle, and other metabolic pathways.

3.2. Compatibility and Detoxification of Glycyrrhiza uralensis Fisch ex DC in Sini Decoction

Aconitum carmichaelii and Glycyrrhiza uralensis Fisch ex DC are considered as the representative medicine pair for compatibility and detoxification. At present, the analysis of its detoxification mainly focuses on precipitation reaction, complexation reaction and gastrointestinal absorption: The first one is acid base coprecipitation. Aconitine alkaloids in Aconitum carmichaelii and glycyrrhizic acid and other acidic saponins in Glycyrrhiza uralensis Fisch ex DC will precipitate after co-decoction, thus forming macromolecular complexes insoluble in water, reducing medicine toxicity. The second one is the complexation reaction. Glucuronic acid, the hydrolysate of glycyrrhizic acid in Glycyrrhiza uralensis Fisch, forms a low toxic or non-toxic glucuronic acid complexing with the hydroxyl group of Aconitum alkaloids in Aconitum carmichaelii, which can be excreted in urine. The third one is that Glycyrrhiza uralensis Fisch ex DC can affect the absorption process of toxic components in gastrointestinal tract. Because Glycyrrhiza uralensis Fisch ex DC has the effect of inducing cytochrome P450 proteins (CYP), it can accelerate the metabolism of toxic alkaloids in Aconitum carmichaelii.⁵⁴⁾ The content of Aconitum alkaloids in SND was decreased gradually by increasing the dosage of Glycyrrhiza uralensis Fisch ex DC, which showed the detoxification effect of Glycyrrhiza uralensis Fisch ex DC on Aconitum carmichaelii.¹⁷⁾

It has been reported that the major components of glycyrrhizic acid and liquiritin in Glycyrrhiza uralensis Fisch ex DC can improve bioavailability of toxic components (diester diterpenoid alkaloids) in Aconitum carmichaelli, and the Aconitum carmichaelii can also improve the bioavailability of glycyrrhizic acid in Glycyrrhiza uralensis Fisch.^41,55,56) Besides, studies also found that Zingiber officinale Roscoe could promote the elimination of diester diterpenoid alkaloids, and increase the absorption of monoester diterpenoid alkaloids.⁵⁵⁾ It has been demonstrated that a major component of liquiritin could reduce the toxic effects via forming complexes with aconitine.⁵⁷⁾ Meanwhile, a previous pharmacokinetic research has shown that a major component of 6-gingerol in Aconitum carmichaelii and liquiritin promoted the absorption of aconitine, and enhanced its drug concentration in blood.¹⁸⁾ What is more, compared with Aconitum carmichaelii, the bioavailability of diester diterpenoid alkaloids decreased, and the content of the diester diterpenoid alkaloids was reduced in SND.^58,59)

CYP isozymes can be induced or inhibited by a variety of drugs, which may lead to drug interactions and increase the incidence of clinical adverse reactions.⁶⁰⁾ It is believed that the metabolic pathway of Aconitum alkaloids in Aconitum carmichaelii is mainly mediated by CYP1A2 and CYP3A4 enzymes,⁶¹⁾ which are metabolized into monoester alkaloids with lower toxicity. It can be seen that CYP isoenzyme is an important indicator of drug interaction in the compatibility of SND. It has been reported that the effects of SND on CYP450 enzyme were discussed from two aspects of enzyme activity and gene expression.⁶²⁾ The activities of CYP1A2 and CYP3A4 in rats treated with SND were determined by cocktail probe drugs method. The concentrations of caffeine and midazolam in rat plasma were determined by HPLC. The content of CYP450 in rat liver microsomes was determined by CO differential reduction method. And the expression of CYP1A2 and CYP3A4 mRNA was detected by RT-PCR. The results showed that Aconitum carmichaelii had no effects on the activity of CYP1A2 and CYP3A4 and the content of CYP450, while Glycyrrhiza uralensis Fisch ex DC alone, Aconitum carmichaelii combined with Glycyrrhiza uralensis Fisch ex DC and SND could induce the activity of CYP1A2 and CYP3A4, and increase the content of CYP450. And among them, Glycyrrhiza uralensis Fisch ex DC alone had the most obvious increase in the content of CYP450. It is suggested that Glycyrrhiza uralensis Fisch ex DC Plays a leading role in the change of CYP450 enzyme content in SND; Glycyrrhiza uralensis Fisch ex DC alone, Aconitum carmichaelii combined with Glycyrrhiza uralensis Fisch ex DC and SND could induce the expression of CYP3A4 mRNA in varying degrees. It is concluded that the compatibility of Aconitum carmichaelii and Glycyrrhiza uralensis Fisch ex DC has an effect on the activities of the two enzymes, so as to accelerate the metabolism of the toxic components of Aconitum carmichaelii in vivo.

3.3. Compatibility and Detoxification of Zingiber officinale Roscoe in Sini Decoction

Although the compatibility of Zingiber officinale Roscoe and Aconitum carmichaelii may not be as effective as the toxicity reduction of Glycyrrhiza uralensis Fisch ex DC and Aconitum carmichaelii, Zingiber officinale Roscoe also has similar detoxification effect as Glycyrrhiza uralensis Fisch. It was found that Zingiber officinale Roscoe and Aconitum carmichaelii had no effect on the activity of CYP1A2 and the content of CYP450, but Zingiber officinale Roscoe could inhibit the activity of CYP3A4.⁶²⁾ Some studies have determined the toxic components of three Aconitum alkaloids in SND with different compatibility by TLC scanning method. It is found that Zingiber officinale Roscoe has adjuvant effects similar to Glycyrrhiza uralensis Fisch ex DC.⁶³⁾ The compatibility of Aconitum carmichaelii and Zingiber officinale Roscoe can not only enhance the heat property of Aconitum carmichaelii, but also the cardiotonic effect of Aconitum carmichaelii. The toxicity of Aconitum carmichaelii steamed with fresh or dried ginger can also be weakened.⁶⁴⁾ Zingiber officinale Roscoe can inhibit the absorption of diester alkaloids in Aconitum carmichaelii by inducing P-glycoprotein, so as to reduce the toxicity of SND together with Glycyrrhiza uralensis Fisch ex DC.⁶⁵⁾

The combination of Aconitum carmichaelii, Zingiber officinale Roscoe, and Glycyrrhiza uralensis Fisch ex DC can decrease toxicity and enhance efficacy of each medicinal materials, as shown in Fig. 1.

Fig. 1. Compatibility and Detoxification of Glycyrrhiza uralensis Fisch ex DC in Sini Decoction

3.4. Detoxification of Aconitum carmichaelii Processed Products in Sini Decoction

Although the compatibility can reduce the toxicity of Aconitum carmichaelii to a certain extent. In order to ensure the safety and effectiveness of SND, crude drug of Aconitum carmichaelii is less frquently used in SND, while the processed products of Aconitum carmichaelii are more common in SND. As the principal medicine of SND, processed products of Aconitum carmichaelii come in a great many varieties, and the purpose of almost all processing methods is to reduce toxicity and increase efficiency.⁶⁶⁾

Due to the high yield of Aconitum carmichaelii in the harvest season, and the terrible climate, Aconitum carmichaelii will rot within one week leading that the traditional processing in producing area uses the hypertonic effect of Danba water (high concentration mixed solution of magnesium chloride, calcium sulfate, calcium chloride and sodium chloride) to soak for antisepsis. In the process, the accumulation of Danba in Aconitum carmichaelii can reach 26%.⁶⁷⁾ To a certain extent, it affects the subsequent processing, because in the process of rinsing and removing Danba, it will cause the loss of alkaloids in Aconitum carmichaelii and affect the efficacy, but if the Danba is rinsed and removed not enough, it will affect the clinical medication safety of Aconitum carmichaelii.⁶⁸⁾ Therefore, it is imperative to reform the processing method of Aconitum carmichaelii in producing area. At present, the methods of baking, roasting, sand scalding and steaming are commonly used to prepare Aconitum carmichaelii, which has high content of effective components and low content of toxic components, and also exerts good anti-inflammatory and analgesic effects.⁶⁹⁾ In addition, studies have suggested that the processing of Aconitum carmichaelii with biological enzymes can create an acidic environment and increase the dissolution of alkaloids,⁷⁰⁾ which can play an important role in reducing toxicity and increasing efficiency in combination with other processing processes.

In Treatise on febrile diseases, the original prescription of SND used Aconitum carmichaelii unprocessed, while in Chinese Pharmacopoeia (2020) used Danfupian, and modern doctors will choose different Aconitum carmichaelii processing varieties in SND. SND respectively composed of unprocessed Aconitum carmichaelii, Danfupian, Baifupian, Heishunpian and Paofupian (Fig. 2) has been used to determine the contents of monoester alkaloids and diester alkaloids; the mice model of acute cerebral hypoxia was used to compare the pharmacodynamics of different SNDs above. The results showed that the total content of monoester alkaloids in Heishunpian was the highest, and the diester alkaloids in Paofupian was the highest. Only the effect of the Danfupian SND on the panting times and the panting time was different, and the protective effect of brain hypoxia was obvious.²⁰⁾

Fig. 2. Herbal Pieces of SND

(A): Glycyrrhiza uralensis Fisch; (B): Zingiber officinale Roscoe; (C): Unprocessed Aconitum carmichaelii; (D): Heishunpian; (E): Baifupian; (F): Danfupian; (G): Yinfupian; (H): Yangfupian.

4. The Mechanism of Detoxification and Synergism of SND

4.1. The Perspective of Biological Effect

According to the existing literature reports, the mechanism of toxicity reduction and synergistic effect of SND are mainly discussed based on the biological effects of SND in the treatment of cardiovascular diseases.

4.1.1. Mechanism of Anti-oxidative Stress in the Treatment of Heart Failure

There are many factors involved in the pathogenesis of heart failure, among which oxidative stress is considered to play an important role. Studies have shown that excessive activation of oxidative stress is a risk factor for cardiovascular disease, and the body has an effective antioxidant defense system. In which superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) are involved in the elimination of excessive oxygen radicals, which plays a crucial role in the body’s oxidation and antioxidant balance.⁷¹⁾ SOD can convert O₂·⁻ into H₂O₂ and O₂, and control the O₂·⁻ in low concentration range. It is one of the important antioxidant enzymes in organisms⁷²⁾ (Fig. 3(A)). GSH-Px catalyzes the reduction of organic compounds. Hydroperoxides oxidize active selenol (Se-H) to selenic acid (Se-OH), and GSH reduces selenic acid back to active selenol. Lipid hydroperoxides are reduced to nontoxic lipid alcohols, thus limiting the spread of lipid peroxidation in the membrane⁷³⁾ (Fig. 3(B)).The combination of Malondialdehyde (MDA) with lysine (LYS) residues in vivo and the formation of LYS-LYS cross-linking is the basis and main cause of cardiovascular atherosclerosis^74,75) (Fig. 3(C)). SND can improve myocardial fibrosis by reducing serum MDA level and increasing SOD activity, reducing myocardial collagen content and oxidative stress reaction.⁷⁶⁾ In addition, each single medicine in SND can also increase the content of SOD and GSH-Px in varying degrees and reduce the content of MDA and H₂O₂. The effect of the whole prescription is obviously better than that of single medicine.⁷⁷⁾ The alkaloids in Aconitum carmichaelii, the volatile oil in Zingiber officinale Roscoe, and the crude glycyrrhizic acid in Glycyrrhiza uralensis Fisch ex DC can improve the activity of antioxidant enzymes and eliminate excessive oxygen radicals in varying degrees. And the clinical dose combination of these three effective components (The alkaloids in Aconitum carmichaelii 31.2 mg/kg, the volatile oil in Zingiber officinale Roscoe 1.84 µL/kg, the crude glycyrrhizic acid in Glycyrrhiza uralensis Fisch ex DC 4.68 mg/kg) can exert the best curative performance.⁷⁸⁾

Fig. 3. Mechanism of Anti-oxidative Stress

(A): Catalysis of superoxide dismutase. (B): Catalytic cycle of glutathione peroxidase. (C): Reaction of lysine and malondialdehyde to form intermocular cross-linking. SOD, Superoxide dismutase; GSH-Px, Glutathione peroxidase; LYS, Lysine; MDA, malondialdehyde.

4.1.2. Mechanism in the Treatment of Myocardial Ischemia and Cell Damage

In heart cells, protein kinase C (PKC) mainly exists in the cytoplasm. PKC is a group of phospholipid-dependent serine/threonine kinases, which are activated as a result of hydrolysis of membrane phosphoinositides and the receptor-dependent activation of phospholipase C.⁷⁹⁾ PKC isoforms are one the most important players for inter (intra) cellular signaling, which control crucial cellular functions in the cardiovascular system.⁸⁰⁾ After activating PKC, it can inhibit the opening of mitochondria permeability transition (MPT) pore by opening phosphorylated mitochondrial ATP-sensitive potassium (K_ATP) channel, which inhibits the occurrence of apoptosis.^81,82) Second mitochondria-derived activator of caspases (Smac) is a protein that exists in mitochondria and regulates apoptosis.⁸³⁾ It is found that PKC and Smac participate in the apoptosis of cardiomyocytes after myocardial ischemia-reperfusion. SND can activate PKC to protect mitochondria and inhibit the release of Smac from mitochondria to cytoplasm to block the signal transduction of apoptosis, so as to play a protective role in myocardial ischemia.⁸⁴⁾ It was reported that the main components of SND are aconitum alkaloids, diterpenoid alkaloids, flavonoids, gingerols, and saponins, and found that the mechanism of action of SND in the treatment of myocardial ischemia (MI) may be to restore the unbalanced myocardial energy metabolism, and to reverse the pathological process of MI^85,86) (Fig. 4). Moreover, pharmacological studies have shown that components in Zingiber officinale Roscoe and Aconitum carmichaelii can combine with adrenoceptors. Studies have revealed that mesaconitine component from Aconitum carmichaelii exerts excitatory effects via activation of β-adrenoceptors and initiating the intracellular processes.⁸⁷⁾ It is conducive to myocardial blood circulation and alleviating myocardial ischemia and hypoxia so as to achieve the aim of effective treatment of acute myocardial infarction ischemia-reperfusion injury.^88,89)

Fig. 4. Mechanism in the Treatment of Myocardial Ischemia and Cell Damage (1)

PKC: Protein kinase C; MPTP: mitochondria permeability transition pore; OMM: outer mitochondrial membrane; IMM: inter mitochondrial membrane; KATP: ATP-sensitive potassium; VDAC: Voltage-dependent anion channel; ANT: Adenine nucleotide translocase; ROS: Reactive oxygen species; Smac: Second mitochondria-derived activator of caspases.

MicroRNA-21 (MiR-21) is a potential target for the prophylaxis and treatment of myocardial injury. MiR-21 can be transported into cardiomyocytes by exosomes. It can regulate phosphatase down and tensin homolog (PTEN) and programmed cell death 4 (PDCD4) to reduce the pro apoptotic effect. MiR-21 also canregulate pellino1 (Peli1) down and reduce the activation of nuclear factor kappa-B (NF-κB) to avoid apoptosis induced by myocardial infarction. In addition, MiR-21 can down regulate the factor related to apoptosis ligand (FasL) to inhibit exogenous apoptotic pathway.⁹⁰⁾ Besides, Chen et al. verified that the major components from SND are hypaconitine, mesaconitine, higenamine, quercetin and glycyrrhizic acid, which can exert anti-myocardial cell apoptosis effects for curing heart failure⁵⁵⁾ (Fig. 5). The mechanism of SND in alleviating myocardial injury may be related to up regulating the expression of miR-21 to regulate apoptosis.³⁵⁾

Fig. 5. Mechanism in the Treatment of Myocardial Ischemia and Cell Damage (2)

miR-21: MicroRNA-21; PTEN: Phosphatase and tensin homolog; PIP3: Phosphatidylinositol (3,4,5)-trisphosphate; PIP: Phosphatidylinositol 3-phosphate; PDPK-1: Phosphoinositide-dependent kinase-1; PKB: Protein kinase B; PDCD4: Programmed cell death 4; sFas L: soluble fas ligand; Fas L: fas ligand; Peli 1: Pellino 1; NF-κB: Nuclear factor kappa-B.

SND upregulates miR-21 by acting on signal transducer and activator of transcription 3 (STAT3) protein, which in turn binds to the miR-21 promoter.⁹¹⁾ SND protects against myocardial ischemic injury by acting on a number of important target proteins, such as STAT3, JUN, RELA, SRC, mitogen-activated protein kinase 3 (MAPK3), TP53, NF-κB, and Interleukin 6 (IL-6).^92,93) These targets regulate each other and play important roles, such as negative regulation of apoptosis process, response to hypoxia, and regulation of mitochondrial membrane potential in biological process; besides, it mainly involves protein binding, protein dimerization activity, and peroxidase activity in molecular function.

4.2. The Perspective of Chemical Components

The main active ingredient in Aconitum carmichaelii is alkaloids, especially C19 diterpenoid alkaloids and C20 diterpenoid alkaloids.⁹⁴⁾ Isoquinoline alkaloids (higenamine) and salsolinol as well as quaternary amine alkaloids (coryneine and coryneine chloride), all of which have cardiotonic effects.^95,96) The main components in Zingiber officinale Roscoe are volatile oil in which most are terpenoids and pungent ingredients like gingerols.^97,98) Triterpenoid saponins and flavonoids are the main chemical constituents in Glycyrrhiza uralensis Fisch ex DC.⁹⁹⁾

Gingerols, the main components of Zingiber officinale Roscoe, have great effect on restraining and relieving the toxicity of Aconitum carmichaelii. Not only could the co-decoction of Zingiber officinale Roscoe and Aconitum carmichaelii reduce the content of aconitine (Fig. 6(A)) and other toxic components but also antagonize the cardiotoxicity induced by aconitine.¹⁰⁰⁾ 6-gingerol, 10-gingerol and 6-shogaol (Figs. 6(C–E)) in Zingiber officinale Roscoe can competitively inhibit the binding of aconitine with Pro 1130 amino acid residues and Asp 148 amino acid residues, weaken the inhibitory effect of aconitine on potential targets such as mitochondrial calcium uniporter 4XTB and 4XSJ to weaken the inhibitory effect of aconitine on energy metabolism.¹⁰¹⁾ Higenamine (Fig. 6(B)) in Aconitum carmichaelii combined with 6-gingerol can protect H9C2 cardiomyocytes from Adriamycin injury by improving mitochondrial respiratory function and energy metabolism.¹⁰²⁾

Fig. 6. Main Chemicals in SND

(A): Aconitine; (B): Higenamine; (C): 6-Gingerol; (D): 10-Gingerol; (E): 6-Shogaol; (F): Glycyrrhizic acid; (G): Carbenoxolone; (H): Isoliquiritigenin; (I): Glabridin.

In the co-decoction of Aconitum carmichaelii and Glycyrrhiza uralensis Fisch, the content of aconitine decreased with the increase of the dosage of Glycyrrhiza uralensis Fisch. There is a close relationship between the dosage of Glycyrrhiza uralensis Fisch ex DC and the toxicity of Aconitum carmichaelii: (1) The body’s absorption of aconitine alkaloids was reduced; glycyrrhizic acid and carbenoxolone (Figs. 6(F, G)) in Glycyrrhiza uralensis Fisch ex DC can neutralize aconitine alkaloids and flavonoids in Glycyrrhiza uralensis Fisch ex DC can also be combined with aconitine alkaloids to form precipitation, both of which can delay or reduce the absorption of aconitine and other alkaloids. (2) Antagonistic effect on toxicity: glycyrrhizic acid can be transformed into carbenoxolone and flavonoids in gastrointestinal tract. They contain multiple hydroxyl groups and are acidic combining with the alkaloids in Aconitum carmichaelii to form acid base neutralization products after being absorbed by the body. The carbenoxolone and flavonoids can obviously antagonize the arrhythmia caused by aconitine.¹⁰³⁾ The compatibility of alkaloids in Aconitum carmichaelii and active components in Glycyrrhiza uralensis Fisch ex DC such as triterpenoid saponin and flavone can enhance the cardiotonic effect of isolated frog heart which are more effective than that of the alkaloids in Aconitum carmichaelii alone.¹⁰⁴⁾ It may be that the flavonoids in Glycyrrhiza uralensis Fisch ex DC such as isoliquiritigenin (Fig. 6(H)) can dilate blood vessels and glabridin (Fig. 6(I)) can regulate the process of vascular injury and atherosclerosis.^105,106)

5. Summary and Outlook

The detoxification and synergism of SND and its mechanism were discussed. SND has a good effect on treating cardiovascular and related diseases, including cardiotonic action, invigorating the circulation of blood, inhibiting cardiomyocyte apoptosis, anti-inflammatory and anti-hypothyroidism action. The compatibility of Zingiber officinale Roscoe and Glycyrrhiza uralensis Fisch ex DC can alleviate the toxicity of Aconitum carmichaelii, reduce the toxicity of SND and maintain good clinical efficacy.

The mechanism of enhancing efficacy and reducing toxicity of SND can be discussed from two aspects: biological effects and chemical composition changes. From the aspect of biological effect, the mechanism of SND in the treatment of heart failure may be to inhibit the over activation of oxidative stress and regulate energy metabolism, while the mechanism of protecting myocardial ischemia injury may be to decrease the activity of Caspase-3, activate PKC, protect mitochondria, inhibit the release of Smac, block the signal transduction of apoptosis and inhibit myocardial apoptosis, so as to be of protective effects in myocardial ischemia. From the aspect of chemical composition change, Gingerols in Zingiber officinale Roscoe, glycyrrhizic acids and flavones in Glycyrrhiza uralensis Fisch ex DC can restrict the toxicity of aconitine in Aconitum carmichaelii, and cooperate with cardiotonic components in Aconitum carmichaelii to treat cardiovascular diseases. The effects and mechanisms of SND were summarized in Table 2.

Table 2. Synergism of Medicines Compatibility in SND

Ratio (Aconitum carmichaelii: Zingiber officinale Roscoe: Glycyrrhiza uralensis Fisch)	Effects	Putative mechanism	Ref
15 : 23 : 31	Regulate blood lipids and prevent atherosclerosis	Reduce the content of ET in venous blood and increase the content of NO in arterial blood. Reduce the content of VEGF and SDF-1 in blood.	^28,33)
1 : 1 : 0	Dilate blood vessels and increase blood flow velocity	Activate the functions of pituitary-adrenal system and autonomic nerves-adrenal system	³²⁾
15 : 9 : 6	Protect cardiac cells from severe injury	Regulate the expression of miR-21, target regulate PDCD4.	^35,90)
1 : 1 : 1	Protect cardiac cells from severe injury	Reduce the bioavailability of diester alkaloids in the small intestine.	⁶⁵⁾
15 : 20 : 30	Therapy for chronic heart failure	Inhibiting cardiomyocyte apoptosis related proteins (Cytochrome C, Caspase 9, and Caspase 3). Improve antioxidant capacity and reduce oxidative damage (Increase the content of SOD and GSH-Px, reduce the content of MDA and H₂O₂).	^39,72–78)
—	Therapy for ulcerative colitis	Inhibit the expression of pro-inflammatory factors IL-6 and IL-17, promote the expression of anti-inflammatory factor IL-10.	^42,43)
12 : 52 : 15	Therapy for renal damage caused by hypothyroidism	Improve renal blood flow.	⁴⁶⁾
12 : 52 : 15	Therapy for hypothyroidism	Regulate zinc finger protein and hepatocyte growth factor activating protein to improve the compensatory increase of thyroid cells.	⁴⁸⁾
2.4 : 8 : 3	Therapy for hypothyroidism	Regulate the function of hypothalamic-pituitary-thyroid axis.	⁴⁹⁾
1 : 1 : 1	Therapy for Renal fibrosis	Intervene oxidative stress injury (Reduce the level of MDA, increase the level of SOD and GSH in kidney).	⁴⁷⁾
5 : 3 : 2	Reduce cardiomyocyte apoptosis	Activate PKC, block apoptosis signal transduction.	^81,82,84)
5 : 3 : 3	Therapy for ischemia-reperfusion injury in acute myocardial infarction	Higenamine has the effect similar to isoproterenol. Vasodilation, Promote myocardial blood circulation and alleviate myocardial ischemia and hypoxia.	^88,89)

At present, the experimental researches on SND mainly include chemical composition, pathological treatment, system biology and cytology. However, these studies are still relatively simple. The systematic and clear mechanism of compatibility of SND is not clarified. Moreover, there is no scientific selective research on the types of Aconitum carmichaelii processed products in SND. Therefore, the clinical and experimental studies on the choice of Aconitum carmichaelii processed products and the mechanism of compatibility changes in SND need more explanation.

Acknowledgments

This work funded by the National Natural Science Foundation of China (Grant No. 81860703).

Conflict of Interest

The authors declare no conflict of interest.

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