1  Aconite-Compatibility of rhubarb

"Medicine has the specialty of personality, and only then can it have the wonderful effect of being sociable." the characteristics of traditional Chinese medicine are to make good use of toxic traditional Chinese medicine and correct bias and restrict toxicity through compatibility.

The seven emotions compatibility theory founded in Shennong materia medica classic is the induction and summary of the pharmacological effects produced by the compatibility of different traditional Chinese medicines through long-term clinical practice. It starts from single line, mutual necessity, mutual use, mutual hatred, mutual fear, mutual killing, and the opposite7The compatibility of traditional Chinese medicine revealed the effects of increasing efficiency, reducing toxicity, reducing effect and increasing toxicity4According to the general rule, the compatibility of killing and fearing each other is the main theoretical basis for the compatibility and detoxification of toxic traditional Chinese medicine. Aconite-Rhubarb can reduce the content of toxic components of aconite to reduce its toxic and side effects. Aconite can maintain the purgative effect of rhubarb while reducing the content of cold components of rhubarb to alleviate its severity. The properties of traditional Chinese medicine include four Qi, five tastes, meridian tropism, ups and downs, toxicity, etc., which are a high summary of the basic properties and characteristics of traditional Chinese medicine. Four Qi and five tastes are important components^[7]Zhangjingyue pointed out in Lei Jing that "the so-called poisons are biased by the smell". The smell of some toxic drugs is severe, dry and urgent, and they can win by the nature of hard work, dryness and pungent dispersion, or by the gas of great cold and heat^[8]In order to restrict the toxicity of drugs with strong smell, drugs can be mixed according to the opposite smell, such as aconite-Rhubarb pairs can not complement each other, but can form a containment effect to adjust their bias and control their toxicity^[8]; Rhubarb is cold in nature, which is easy to hurt Yang Qi and stomach qi. The combination of cold and heat can restrict the disadvantages of its cold and heat bias. Aconite can alleviate the bitter and cold nature of rhubarb. Rhubarb can assist in curing the pungent and hot nature of aconite and retain the original diarrhea effect. The two drugs complement each other and play the functions of Warming Yang, dispelling cold, purging and attacking accumulation^[4,8-9]According to the analysis of the five flavors of "sour, bitter, sweet, pungent and salty", aconite flavor is pungent and has the function of dispersing and activating qi, but too much pungent powder can consume Qi and Yin; . The two drugs are painstakingly compatible. Rhubarb can make the pungent powder of aconite, which can warm the meridians, relieve pain and disperse cold, without damaging Yin and consuming Qi. It can play a role in relieving pain, regulating qi, and regulating the spleen and stomach; The bitter taste belongs to Yang and the bitter taste belongs to Yin. The compatibility of the two drugs can also jointly adjust the balance of yin and Yang in the body^[8-10]To sum up, based on the theory of seven emotions compatibility of traditional Chinese medicine and the theory of drug properties, aconite-The compatibility of rhubarb can be divided into three parts: mutual fear and mutual killing, cold and heat, and hard work3.

2  Aconite-Changes of active ingredients after compatibility of rhubarb

2.1  Effects of compatibility of rhubarb on toxicity and effective components of aconite

2.1.1  Effects on toxicity and content changes of active ingredients in vitro  livingAlkaloids are the main effective components of aconite with obvious characteristics, includingC₁₉Type II diterpenoid alkaloidsC₂₀The non alkaloid part can be divided into flavonoids, polysaccharides, saponins, etc. C₁₉Aconitine skeleton is the main type of diterpenoid alkaloids. According to the ester bond connection, they can be divided into alkanolamine type, monoester type and diester type alkaloids. The number of ester bonds is closely related to the toxicity of Aconitum carmichaeli. The toxicity from small to large is followed by alkanolamine type, monoester type and diester type^[11-12]. diester typeC₁₉Diterpenoid alkaloids, including aconitine, are the most abundant and toxic alkaloids in aconite（aconitine，AC）, mesaconitine（mesaconitine，MA）, hypaconitine（hypaconitine，HA）Et al., which leads to the extremely strong acute cardiac toxicity and neurotoxicity of raw aconite, but at low concentrationsIt can exert proper drug effect^[13]The processing or decoction can hydrolyze the diester alkaloids into monoester alkaloids with weak toxicity and milder efficacy, including benzoyl mesaconitine（benzoylmesaconine，BMA）, benzoyl Aconitine（benzoylaconine，BAC）, benzoyl hypaconitine（benzoylhypaconine，BHA）Et al., and can even be further hydrolyzed to less toxic alkanolamine alkaloids, including Aconitine（aconine，ACN）So as to promote the transformation of toxic substances, enhance the biological activity, and weaken the toxicity of aconite to a certain extent^[11-14]。

In addition to following the law, controlling the dose and prolonging the decoction, the commonly used methods of reducing toxicity in traditional medicine also have reasonable compatibility, which can adjust the bias of toxicity to increase the safety of medication and promote the efficacy^[12]. Liangjiajia et al^[15]Aconite-In the solution of rhubarb before and after compatibilityAC、MA、HAAfter extraction, its content was determined, and it was found that after compatibility3The contents of all kinds of diester alkaloids were significantly reduced, which confirmed that rhubarb could significantly reduce the content of diester alkaloids in vitro to weaken the toxicity of aconite. There are studies through the detection of heishun tablets-Rhubarb was mixed in different proportions and decocted for an appropriate time in the water decoctionBMA、BAC、BHAContent, it can be seen from comparison that3The content of monoester alkaloids decreased significantly after compatibility, and the compatibility ratio was1∶1The contents of all three were the lowest, i.e1∶0＞2∶1＞1∶2＞1∶1It showed that rhubarb could reduce the toxicity by reducing the content of monoester alkaloids in heishun tablets during the co decoction process, and1∶1The effect of reducing toxicity is better when compatibility^[16]There are also studies by comparing heishun tablets with different compatibility ratios-Total alkaloid content in rhubarb extract（1∶1＞2∶1＞1∶2＞1∶0）, description1∶1The content of effective components in the extract after compatibility is higher, which is conducive to the efficacy of heishun tablets^[17]. zhoujingbo^[18]The content of ester type alkaloids after the compatibility of Radix Aconiti Lateralis Preparata, Radix Aconiti Lateralis Preparata and heishun tablet with Radix et Rhizoma Rhei was determined. The content of ester type alkaloids in each group decreased after the compatibility, and the content of Radix Aconiti Preparata group decreased the most, indicating that Radix et Rhizoma Rhei can promote the hydrolysis of toxic components of Radix Aconiti Lateralis Preparata and its processed products to achieve toxicity reduction, and has the most obvious effect on Radix Aconiti Lateralis Preparata. -After the compatibility of total alkaloids of Aconitum carmichaeli with total anthraquinones of rhubarbAC、MA、HA. Yeqiang^[17]By observing heishun tablet-Total alkaloids of rhubarb and aconite-Compatible Decoction of rhubarb polysaccharide6 hwithinAC、MA、HAAccording to the dissolution rate curve, the trend is basically the sameAC、MA、HAThe dissolution rate first reached the peak at a faster speed, but its size was lower than that before compatibility, indicating that compatibility of rhubarb or rhubarb polysaccharide at the early stage of decoction can improve the dissolution rate of diester alkaloids but not increase their content in vitro; After that, the dissolution rate gradually decreased with the extension of decoction time, and also decreased with the increase of the proportion of rhubarb polysaccharide, indicating that the compatibility can promote the hydrolysis of diester alkaloids and then reduce their content, and rhubarb polysaccharide is the material basis for Rhubarb to accelerate the dissolution of toxic components of aconite and promote its hydrolysis, so as to achieve toxicity reduction. In addition, it was also found that the total alkaloids of Aconitum carmichaeli combined with rhubarb tannin had no significant difference in the content ofAC、MA、HAThe dissolution of rhubarb tannins also gradually slowed down with the increase of the proportion of rhubarb tannins, indicating that rhubarb tannins can also be the material basis for Rhubarb to achieve toxicity reduction. The mechanism is that the weakly acidic rhubarb tannins will react with diester alkaloids to produce tannic aconitine salt that is not absorbed by the intestine^[17-18]。

2.1.2  Effects on toxicity and metabolism of active ingredients in vivo The attenuation effect of rhubarb on Fuzi is not only realized by affecting the content of diester and monoester alkaloids in vitro, but also by affecting their metabolic processes in vivo, including absorption, distribution, metabolism and excretion. Pharmacokinetic analysis is introduced to more comprehensively explain the mechanism of attenuation and synergism of rhubarb on Fuzi after compatibility.Zhangetc.^[19]rightAC、BAC、CAN(which can represent diester type, monoester type and alkanolamine type alkaloids respectively) were studied in pharmacokinetics3,BAC（t_max）The shortest, whileACPeak concentration of（C_max）Max; The most toxicACElimination half-life（t_1/2）The smallest, in vivoBACandACNEasier metabolism and faster elimination; this3Alkaloids are distributed in all organs, whileACThe distribution speed and the area of is the slowest;ACandACNMainly excreted through urine, whileBACExcrete through feces. .Liuetc.^[20]Single extract of Radix Aconiti Lateralis Preparata and Radix Aconiti Lateralis Preparata DecoctionHA、BMA、BAC、BHAThe pharmacokinetic differences in rat plasma were studied, and it was found that normal ratsigAfter rhubarb and Fuzi DecoctionHA、BMA、BAC、BHAOfC_max, blood concentration-Area under time curve（AUC_0～t）, clearance（CL）Compared with the single extract of Aconitum carmichaeli, it was significantly reduced, among whichBMA、BAC、BHAOft_1/2Average dwell time（MRT_0～t）Apparent volume of distribution（V_d）Were significantly increased,HAOft_maxIt was significantly prolonged, indicating that Dahuang Fuzi decoction can inhibit the growth ofHA、BMA、BAC、BHAAnd significantly slowed the absorption of the more toxicHAAbsorption speed to weaken the toxicity of aconite, and by prolonging the less toxicBMA、BAC、BHAThe retention time in the body and delaying its elimination enhance the curative effect of Dahuang Fuzi decoction. In order to further explore the Radix Aconiti Lateralis Lateralis Preparata in Dahuang Fuzi Decoction-Compatibility mechanism of rhubarb, Ren Changyu^[16]Heishun tablets were studied-Compatibility of rhubarbHA、BMA、BAC、BHAEffects on pharmacokinetics in normal beagle dogs. Results compared with the single decoction of heishun tablets, it was found that heishun tablets-In the decoction of rhubarbHA、BMA、BAC、BHAOft_maxWere significantly prolonged,AUC_0～tandC_maxAll showed a downward trend, indicating that rhubarb can delay the4Absorption of alkaloids and reduce the degree of absorption in the body, thereby weakening the toxicity of aconite. Simultaneous diester alkaloidHAOft_1/2Than another3The short duration of monoester alkaloids also indicates that the elimination of diester alkaloids in vivo is faster than that of monoester alkaloids, thus reducing their toxic and side effects. The results also revealed that itsMRT_0～tandV_dShowed an upward trend, indicating that rhubarb can prolong its in vivoThe retention time of aconite is conducive to its better distribution in target organs so as to promote the effectiveness of aconite. Improving the distribution of toxic components of aconite can also reduce its dose at non targeted sites to reduce the toxic and side effects of aconite.Different physiological and pathological conditions of the body will have different effects on the pharmacokinetic parameters of the index components^[21]. Zhang Yan et al^[22]It was found that after the administration of total alkaloids of aconite combined with anthraquinone of rhubarb, the total alkaloids of aconite7The total blood inflow and metabolism of the three index components in the constipation rats with Yang deficiency were larger and faster than those in the normal rats, indicating that the absorption degree of total alkaloids will increase, metabolism will accelerate, and bioavailability will increase when they play a therapeutic role, so as to promote its efficacy.

2.2  Effects of compatibility of Radix Aconiti Lateralis on toxicity and active ingredients of rhubarb

2.2.1 Effects on toxicity and content changes of active ingredients in vitro  largeYellow contains a variety of chemical substances, mainly including anthraquinones, anthrones, tannins, polysaccharides, stilbenes, phenylbutanones, chromogen ketones, flavonoids and other components^[23]Among them, anthraquinones and anthrones are the characteristic components of rhubarb, and they are also the main active components of rhubarb to exert its efficacy^[24]Anthraquinones have the highest content in the active ingredients of rhubarb, which can be divided into free type and bound type^[25]Free anthraquinones include rhein, chrysophanol, emodin, aloe emodin, emodin methyl ether, etc; Conjugated anthraquinones, such as Rhein glucoside and emodin glucoside, are glycosides formed by the combination of glycosyl and free anthraquinone, which can play a purgative role by hydrolyzing or metabolizing into the corresponding free anthraquinone^[24-26]Anthracones mainly include sennosideA～F, rhubarb DianthroneA～C, palmar leaf dithranoneA～Cetc.^[25], in which sennosideAIt has a strong indirect diarrhea causing effect. It is rarely absorbed in the intestine. After administration, most of it reaches the colon, where it is metabolized by bacteria in the intestine into free components such as anthraquinone and rhein to exert its diarrhea effect^[27]Modern research shows that in rhubarb, in addition to the combined anthraquinones and anthrone components have a certain diarrhea and accumulation effect, free anthraquinones have a certain heat clearing and fire purging and dampness removing and yellow removing effects, which are reflected in the pharmacological effects of rhubarb, such as antipyretic and cooling, anti-inflammatory, anti pathogenic microorganisms, diuresis, liver and gallbladder protection, etc^[23,28]Tannins have certain functions of cooling blood, hemostasis, astringent and antidiarrheal, and can be used as the material basis for Rhubarb to exert the two-way regulating effects of diarrhea and antidiarrheal, but too high content will lead to constipation^[29-30]Rhubarb has bitter cold and severe diarrhea, which can stimulate the gastrointestinal tract when used directly, and has gastrointestinal toxicity, liver toxicity, renal toxicity when taken alone for a long time^[24]Anthraquinones are the main toxic components, such as rhein and emodin, which can induce apoptosis in renal tubular epithelium and have obvious cytotoxic effects^[31]However, it can be processed (roasted with wine, steamed, fried with charcoal)It can change the effective components of raw rhubarb, thus slowing down its bitter cold property and purgative effect, reducing its adverse reactions, and enhancing other effects. For example, wine rhubarb can induce drugs to ascend, and it is good at clearing Shangjiao blood and separating heat and toxin; The effect of cooked rhubarb on activating blood circulation and removing blood stasis was enhanced; ^[32-33]。

In addition to processing and detoxification, rhubarb can also be compatible with Aconite cold and heat to achieve the effect of sexual removal. -The research on Compatibility Mechanism of rhubarb drug pair mostly focuses on the attenuation of rhubarb on aconite, and the compatibility research of raw rhubarb, aconite and its processed products is mostly used. Because raw rhubarb alone is easy to cause adverse reactions, in order to increase the safety of clinical medication, the attenuation mechanism of Aconite on Rhubarb also needs further research. Xupengpeng et al^[34]The study found that the compatibility of heat drugs such as raw aconite with Rhubarb in different proportions had an inhibitory effect on its diarrhea, and the inhibitory effect increased with the increase of the amount of raw aconite, but it still maintained the diarrhea effect compared with the blank group. It shows that aconite, as a hot drug, can not only alleviate the cold of rhubarb, but also slow down and maintain its catharsis effect, so as to achieve sex removal. Yeqiang et al^[4]Research found that heishun tablets-The content of Total Anthraquinone and free anthraquinone in the combined decoction after compatibility of rhubarb was lower than that in the mixed solution after separate decoction, indicating that under the effect of common decoction, the acidic free anthraquinone will react with aconite alkaloids, resulting in the decrease of its and total anthraquinone content, indicating that the compatibility of aconite can ease the severe purgative effect of rhubarb, and change the cold of rhubarb into warm. Zhoujingbo^[18]The contents of Total Anthraquinone, bound anthraquinone and free anthraquinone in raw aconite, white aconite tablets and heishun tablets combined with rhubarb were determined respectively after the appropriate time of decoction. It was found that the contents of the three in each group showed a downward trend after compatibility, which was directly proportional to the amount of compatible aconite, and the content of the three in raw aconite group decreased most significantly, indicating that the compatibility of raw aconite and its processed products can alleviate the purgative effect and drug properties of rhubarb, and the attenuation effect of raw Aconite on rhubarb is the most obvious; compare2According to the content changes of anthraquinones, it was found that the decrease ratio of bound anthraquinone was greater than that of free anthraquinone, indicating that alkaloids are easy to promote the hydrolysis of bound anthraquinone and react with it, and the ability of bound anthraquinone to neutralize alkaloids is greater than that of free anthraquinone. Zeng Lingna et al^[35]By measuring the free anthraquinone content of rhubarb, raw aconite, cooked aconite and other alkaloid containing medicinal materials before and after decoction, it was found that the free anthraquinone content of all the co decocted samples showed a downward trend, and the effect of raw aconite was the largest. Because the alkaloid content of cooked aconite will be reduced after processing, and the alkaloid is easy to combine with free anthraquinone when decocting, resulting in its decoctingThe output is reduced, thus alleviating the medicinal property of rhubarb. According to the group composition, it was found that the content of total anthraquinones and free anthraquinones were also significantly reduced after the compatibility of total alkaloids and polysaccharides of aconite and total anthraquinones of rhubarb, indicating that in addition to total alkaloids of aconite, polysaccharide of aconite can also inhibit the dissolution of free anthraquinones^[17]。Total alkaloids in aconite-In the compatibility study of rhubarb tannins, Aconitum alkaloids will react with rhubarb tannins, so it is presumed that aconite after compatibility can also reduce the content of rhubarb tannins and inhibit its antidiarrheal effect, which is conducive to rhubarb maintaining its antidiarrheal effect while reducing the total anthraquinone content^[17]。

2.2.2  Effects on toxicity and metabolism of active ingredients in vivo  After the compatibility of drug pairs, due to the complex composition of traditional Chinese medicine, there will be interactions between the components in the body, and the metabolic process in the body determines the speed, dose and residence time of drugs entering the systemic circulation, thus affecting the efficacy after compatibility. Therefore, the pharmacokinetics of Rhubarb Anthraquinones can be introduced to further study the metabolic changes in the body after compatibility. A large number of pharmacokinetic studies showed that rhein and other anthraquinones in rhubarb mostly conformed to the two compartment open model and were widely distributed, and the maximum blood concentration and bioavailability of Rhein oral absorption were better than other free anthraquinones in rhubarb, which were the main effective components of rhubarb absorbed into the blood after gastrointestinal administration, with fast absorptionC_maxHight_1/2Lower kinetic characteristics^[21]Therefore, delaying the absorption and elimination of anthraquinones, such as rhein, should be the key to the realization of sex removal, toxicity reduction and efficiency enhancement of rhubarb.Liuetc.^[36]By establishing ultra performance liquid chromatography-The pharmacokinetics of chrysophanol and emodin in the plasma of rats after administration of rhubarb extract and rhubarb Fuzi Decoction were determined and compared by tandem mass spectrometry. The results showed that chrysophanol and emodin in the rhubarb Fuzi Decoction group were less concentrated and susceptible to interferenceC_maxBoth significantly reducedt_maxWere significantly delayed, chrysophanolt_1/2The delay indicates that the compatibility of aconite and asarum can inhibit and slow down its absorption, alleviate the potent purgative and bitter cold properties of rhubarb, and increase the safety of clinical use. Gongxiaohong^[37]By comparing different doses of aconite-The administration of rhubarb combined decoction and its single decoction was normalThe pharmacokinetic characteristics of aloe emodin, rhein, emodin, chrysophanol and other major free anthraquinones in rats were found in normal ratsigAconite-After Rhubarb decoction4Free anthraquinonet_1/2Significantly increased at all doses,t_maxThe changes were not obvious at low and medium doses, but also significantly increased at high doses, indicating that the compatibility of aconite can not only delay the elimination of Rhubarb in the body, prolong the duration of its action in the body, ensure the lasting purgative effect of rhubarb, but also slow down the absorption of anthraquinone of rhubarb, alleviate the severe effect of rhubarb, reflecting the effect of aconite-The compatibility of rhubarb has the characteristics of reducing toxicity and increasing efficiency in absorption and elimination. The study also integrated pharmacokinetics/The pharmacodynamic model found that compatibility of aconite could slow down the balance speed of free anthraquinone in rhubarb between the effector and the central chamber, slow down its absorption rate, enhance its affinity with the receptor, reduce its toxicity while ensuring the lasting purgative effect of rhubarb, and achieve sexual removal.

Aconite-The content changes of active ingredients in vitro after compatibility of rhubarb pair are shown in table1The metabolic changes in vivo are shown in table2。

3  Aconite-Pharmacodynamic changes of rhubarb after compatibility

3.1  Enhance anti-inflammatory、Analgesic effect

Studies have confirmed that aconite has anti-inflammatory and analgesic pharmacological activities^[38], Gao Peng et al^[39]In order to explore the synergistic effect of different compatibility ratios of rhubarb on aconiteThe ear swelling method and the body twisting method were used to give heishun tablets for the effect of survival-The anti-inflammatory and analgesic experiments were carried out in mice with rhubarb combined with extract. In the anti-inflammatory experiment, it was found that the ear swelling inhibition rate of mice in the high-dose compatibility group increased with the increase of the compatibility ratio of rhubarb within a certain range, and hadGood dose effect relationship, compatibility ratio is1∶1and1∶3The anti-inflammatory effect of the high-dose group was the best, indicating that compatibility with rhubarb can enhance the anti-inflammatory activity of aconite, which is proportional to the amount of rhubarb; In the analgesic experiment, it was found that the compatibility ratio was1∶1and1∶3The writhing times of mice in the high-dose and low-dose groups were lower than those in the Fuzi group alone, with a good dose-response relationship, and the compatibility ratio was1∶3The analgesic effect of the high-dose group was the best, indicating that compatibility with rhubarb can also enhance the analgesic activity of aconite, which is also proportional to the amount of rhubarb. In fact, rhubarb itself also has pharmacological activities such as anti-inflammatory and anti pathogenic microorganisms^[23], the Total Anthraquinone of rhubarb also has a certain analgesic effect on the mouse writhing model^[40]Thus, aconite combined with rhubarb can play an important role“1＋1＞2”Therefore, it can be used to treat diseases associated with systemic inflammatory response syndrome.

3.2  Enhance intestinal peristalsis and defecation

There are studies through the determination of aconite-The effects of different proportions of rhubarb on the defecation time, defecation volume and intestinal propulsion rate of Yang deficiency constipation mice and rats were compared. It was found that the first defecation time of animals in each group was significantly shortened after compatibility,3 hThe number of internal defecation granules was significantly increased, and the intestinal propulsion rate was significantly improved. Its curative effect was better than that of aconite or rhubarb single decoction, and aconite-The compatibility ratio of rhubarb was1∶2The curative effect is best when^[41]. Qiu Zhenwen et al^[42]Aconite was also found through research-The compatibility of rhubarb can increase the activity intensity of isolated ileum in rats with Yang deficiency constipation, and the curative effect is also better than that of single decoction of two drugs, and the compatibility ratio is2∶1The enhancement amplitude was the largest. So aconite-The compatibility of rhubarb can maintain the lasting purgative effect of rhubarb, enhance the ability of intestinal smooth muscle peristalsis of Yang deficiency constipation animals, and promote their defecation, which can be used to treat Yang deficiency constipation.

3.3 Enhance cardiotonic effect

Modern research shows that aconite has cardiotoxicity while exerting cardiotonic effect. Cardiotoxicity is caused by the direct or indirect action of diester alkaloids on the heart, and the mechanism is related to lipid peroxidation, etc^[12]Diester alkaloids can reduce superoxide dismutase（superoxide dismutase，SOD）Activity, which weakens the free radical scavenging ability, thus making oxygen free radicals in cardiomyocytes（reactive oxygen species，ROS）Accumulation, causing peroxidation damage to the lipids on the inner mitochondrial membrane, leading to its dysfunction, and eventually causing cardiac toxicity due to abnormal myocardial energy metabolism and myocardial cell damage^[43-44]。On the contrary, rhubarb can reduce the antioxidant activity of many components, such as phenolic acids gallic acid, catechin and so onROSContent, thereby reducingROSOxidative damage to mitochondria and cardiomyocytes^[45-46]Therefore, aconite combined with rhubarb can enhance the body clearanceROSTo enhance the antioxidant capacity of cardiomyocytes. ^[47]Therefore, the compatibility of rhubarb can be conducive to the cardiotonic effect of aconite and can be used to treat cardiovascular disease.

3.4  Enhance anti hypoxia ability

Aconite combined with rhubarb can improveROSBesides oxidative damage to cardiomyocytes, rhubarb can also prevent malondialdehyde and nitric oxideROSRelease of, improveSODActivity of, alleviatingROSIt can antagonize the damage of brain tissue, neurons and blood-brain barrier to different degrees in animal models of acute hypoxia^[20,45]Mice that respond to cerebral ischemia and hypoxia under normal pressureipDahuang Fuzi decoction can effectively improve its survival time, and Dahuang Fuzi decoction can also fight against isoproterenol inducedHypoxia in adult mice and cellular hypoxia caused by sodium nitrite and potassium cyanide poisoning^[48]Therefore, aconite-The compatibility of rhubarb can enhance the anti hypoxia ability, improve the anti stress ability of the body, and can be used to prevent hypoxic cardiovascular and cerebrovascular diseases.

4 Aconite-Application of Rhubarb in the treatment of Yang deficiency diseases after compatibility

4.1  Treating constipation of Yang deficiency type

Functional constipation refers to constipation caused by exclusion of secondary factors such as intestinal organic lesions, systemic diseases and drugs^[49]Deficiency of spleen and kidney yang is a common TCM syndrome type of functional constipation. In addition to the main manifestations of defecation, such as lack of defecation and consciousness, reduced stool frequency, and difficulty in defecation, it also has the characteristics of chilly and warm, cold shape and cold limbs, and low spirit^[50]According to the theory of traditional Chinese medicine, its pathogenesis lies in Yang deficiency, Yin cold endogenesis, and body fluid stagnation leading to abnormal transmission of large intestine. Warming yang and activating constipation are its treatment principles^[51]In the rhubarb Fuzi decoction, aconite warms the interior and dissipates cold, while rhubarb purses bitter cold. Rhubarb gets aconite to make it bitter and cold and keep it for draining, while aconite gets rhubarb to make it toxic and keep it warm yang. The combination of the two drugs plays the effect of Warming Yang and relieving constipation, which can treat constipation of Yang deficiency type^[37]. Wang Hai et al^[52]Through the treatment of rhubarb Fuzi Decoction and mosapride in patients with Spleen Qi weakness constipation, it was found that rhubarb Fuzi decoction has better curative effect on Yang deficiency constipation and high safety. Hollison et al^[51]Studies have shown that Dahuang Fuzi decoction has a definite therapeutic effect on constipation of Yang deficiency type, and its mechanism is related toIncrease intestinal propulsion rate and colonCajalInterstitial cells（interstitial cells of Cajal，ICC）Quantity to improve colon function. Aconite and rhubarb alone can affect colonICCProduce toxicity^[53], so thatICCThe number is reduced and the colon is weak, but the compatibility of two drugs can alleviate the toxicity of aconite and the cold nature of rhubarb by inhibiting the toxicity of aconiteICCOf injury. Wang Lan et al^[41]Aconite was administered to Yang deficient constipated animals by assay-Compared with the positive drug group (Tongbianling capsule), the defecation volume, the first defecation time, and the intestinal propulsion rate of rhubarb combined decoction showed that the curative effect of the combination of two drugs in the treatment of Yang deficiency constipation was more significant, and the mechanism of action was related to its regulation of gastrointestinal hormone and intestinal neurotransmitter secretion. ^[42]It was also confirmed by research that aconite-Rhubarb compatibility has a definite therapeutic effect on Yang deficiency constipation animals, and the mechanism is related to enhancing intestinal peristalsis. Rhubarb is the representative of purgative medicine, which can be used to treat all symptoms of Yang pathogen accumulation and stagnation, such as intestinal accumulation and stagnation, constipation, etc^[23]Aconite, which has the effects of restoring Yang and rescuing adversity, tonifying fire and helping Yang, and expelling wind cold dampness evil, is often used to treat diseases such as the collapse of the dead Yang, cold limbs and weak pulse, Shaofeng et al^[54]It was found that aconite could gradually restore the spleen yang deficiency mice to normal by using the spleen yang deficiency mouse model. In conclusion, aconite-The compatibility of rhubarb has a good therapeutic effect on constipation of Yang deficiency type. The two drugs do their best. Aconite is mainly used to treat Yang deficiency, rhubarb is mainly used to treat constipation, and the effect of Warming Yang and relieving constipation is played together.

4.2  Treatment of chronic renal failure

Chronic renal failure (CRF) is a clinical syndrome with renal dysfunction and failure based on chronic kidney disease^[55]Renal fibrosis, especially renal interstitial fibrosis, is the end of almost all chronic kidney diseasesTherefore, preventing renal fibrosis is the focus of the treatment of chronic renal failure^[56]。A large number of studies have confirmed that Dahuang Fuzi decoction can alleviate renal interstitial fibrosis, improve and enhance renal function, and has high safety, which can be used for clinical effective treatment of chronic renal failure^[57-59]. zhanglinlin et al^[57]It was found that Dahuang Fuzi decoction could effectively reduce the urea nitrogen in mice with chronic renal failure（blood urea nitrogen，BUN）, serum creatinine（serum creatinine，Scr）; Meanwhile, transforming growth factor, which plays a key role in renal fibrosis, is downregulated-β1（transforming growth factor-β1，TGF-β1）, upregulating bone morphogenetic protein-7（bone morphogenetic protein-7，BMP-7）And kidney tissueSmad6Protein expression, improve renal fibrosis. Tu Yue^[58]It was found that Dahuang Fuzi decoction could down regulate the expression ofTGF-β1And phosphorylationc-Jun（phosphorylated c-Jun N-terminal kinase，p-JNK）Expression, interferenceTGF-β1/JNKRelated signal transduction in the pathway, and then alleviate renal tubular epithelial apoptosis, improve renal tubular injury and renal interstitial fibrosis. Aconite and rhubarb as the main ingredients in rhubarb Aconite Decoction2It is the main drug, and after compatibility, concentrated decoction enema can significantly reduce the risk of patients with chronic renal failureBUNandScrTo treat chronic renal failure^[60]According to modern pharmacological analysis, aconite has pharmacological effects such as cardiotonic, anti-inflammatory, analgesic, immune regulation, etc., which can prevent and treat infectious complications and cardiovascular events in patients with chronic renal failure, and can also improve blood circulation, increase renal blood flow, and improve renal function^[38]Some studies have found that succinate is an endogenous marker of rhubarb induced nephrotoxicity through metabolomic methods, and determinedigRhubarb and aconite soup4The content of succinic acid in the urine of rats after weeks showed no significant difference from that of the blank group, and the observation of tissue sections showed that there was no significant lesion in the kidney of rats, indicating that aconite-Compatibility of rhubarb can reduce the kidney damage caused by rhubarb^[61]Meanwhile, rhein in Rhubarb can inhibit the synthesis and deposition of mesangial matrix by inhibiting the proliferation of mesangial cells, and improve glomerulopathy and renal dysfunction^[62]Its emodin can also inhibitTGF-β1To prevent renal interstitial fibrosis and activate autophagy to improve renal tubular epithelial cell injury^[63]According to the analysis of traditional Chinese medicine, the main pathogenesis of chronic renal failure is deficiency in origin and excess in origin. The deficiency in origin lies in the deficiency of many diseases for a long time, involving the spleen and kidney. Deficiency of both spleen and kidney is Yang deficiency; It is marked by chronic illness entering the collaterals, water dampness, turbid poison, damp heat, blood stasis and internal arrest^[57]. aconite-The compatibility of rhubarb can dredge the Fu organs and reduce turbidity, activate blood circulation and remove blood stasis, warm the spleen and kidney with aconite, strengthen health and eliminate evil. The combination of the two drugs can not only warm and tonify the Yang of the spleen and kidney, but also purge turbidity and poisonTreat the symptoms^[64]To sum up, aconite, as the main component of Dahuang Fuzi decoction-.

4.3  Treatment of diabetic nephropathy

Diabetic nephropathy is a serious complication of diabetes and one of the important causes of death of patients. Its clinical characteristics are proteinuria, hypertension, renal function damage and so on. In recent years, the incidence has increased year by year^[65]The nature of this disease is deficiency of yin and Yang of Zang Fu organs, deficiency of Qi and blood, phlegm dampness and blood stasisBlockage and stagnation are the standard and actual symptoms. The TCM syndrome differentiation in the middle and late stage mainly focuses on deficiency of both yin and Yang and stasis blocking the kidney collaterals. Its basic treatment principle is to supplement deficiency and eliminate evil^[66-67]。In the rhubarb Fuzi decoction, the rhubarb Junxia can benefit the water and valley, eliminate the old and bring forth the new, and the aconite and asarum warm the Yang can strengthen the health and dispel the evil,3The combination of cold and heat can be used to treat diabetic nephropathy. The cold will lead to accumulation and stagnation, and the heat will eliminate cold and excess. It can treat both symptoms and symptoms^[66-68]. Ma Derui et al^[66]By comparing with patients with diabetic nephropathy treated with conventional western medicine, the curative effect of modified enema with Dahuang Fuzi decoction was observed4Weeks later, the effective rate of the enema treatment group was higher, indicating that the modified enema of Dahuang Fuzi decoction has a significant effect on patients with diabetic nephropathy. Modern research confirms that aconite polysaccharide, emodin, RheinAnd other active ingredients have hypoglycemic and lipid-lowering effects, can improve insulin resistance, and have a certain therapeutic effect on diabetic nephropathy. Yu Le et al^[69]Through the establishment of adipocyte insulin resistance model, it was found that aconite polysaccharide can promote its consumption and uptake of glucose, thus playing a hypoglycemic role. Honghaimian et al^[70]Studies have found that emodin can also improve the sensitivity of adipocytes to insulin, promote their glucose uptake, and then can be treated2Type 2 diabetes and diabetic nephropathy, mechanism of action and activation of adenylate activated protein kinase（adenosine5′-monophosphate-activated protein kinase，AMPK）And peroxisome proliferator activated receptorsγ（peroxisome proliferator-activated receptor，PPARγ）Signaling pathway. It has also been found that emodin can inhibit nuclear factor-κBInhibition of protein kinases（inhibitor of NF-κB kinase，IKK）Activity to blockNF-κBsignaling pathway， Inhibit the production of inducible nitric oxide synthase and nitric oxide, and protect pancreatic isletsβCells are protected from damage, which in turn delays1Development of type 2 diabetes mellitus and diabetic nephropathy^[71]。Zhengetc.^[72]It has been found that Rhein can inhibit the diabetic glucose transporter of mesangial cell phenotype by inhibiting the hexosamine pathway1（glucose transporter 1，GLUT1）Overexpression, downregulation ofTGF-β1andp21Protein expression, reduce extracellular matrix synthesis, prevent glomerular basement membrane thickening, improve hyperglycemia and glomerular lesions, and delay disease progression. To sum up, rhubarb-Aconite compatibility can improve blood glucose and renal function, and can be used to treat diabetes and diabetic nephropathy.

4.4  Treatment of primary liver cancer

Primary liver cancer is a common malignant tumor, with concealed onset, rapid progress, difficult treatment, poor prognosis and high mortality^[73]The advantage of traditional Chinese medicine in the treatment of liver cancer is that it can effectively stabilize the condition, improve clinical symptoms, reduce adverse reactions of chemotherapy, and improve the quality of life of patients, so it plays an important role in the treatment of liver cancer^[74]According to traditional Chinese medicine, the pathogenesis of liver cancer is based on the deficiency of vital energy, with qi stagnation, blood stasis, evil toxin and phlegm coagulation as the criteria, and the deficiency of Qi and blood in the Zang Fu organs or the loss of circulation due to spleen deficiency are likely to cause liver cancer. Therefore, traditional Chinese medicine should treat liver cancer with the general principle of strengthening the vital energy and eliminating the evil, and then treat liver cancer with heat clearing and detoxification, qi activating and blood activating, Liver Soothing and depression relieving, accumulation eliminating and knot dispersing, etc^[75]Although Rhubarb in the rhubarb Fuzi decoction is bitter and cold, it can be used in combination with Aconite and asarum to warm the cold knot, remove the excess evil from the bottom, and warm and tonify the spleen yang. It can be used to treat liver cancer with deficiency of body Yang and internal knot of cold evil^[75]. lizibo et al^[76]Through the establishment of orthotopic transplantation liver cancer mouse model to evaluate the therapeutic effect of Xinjia Dahuang Fuzi Decoction (rhubarb, Fuzi, cinnamon, Evodia rutaecarpa) on liver cancer, it was found that it can inhibit tumor growth, reduce tumor infiltration, and prolong the survival time of tumor bearing mice. Zhaojinlong et al^[77]Through systematic pharmacological analysis, it was found that the core compounds kaempferolβ-Sitosterol and aloe emodin can cause cancer by regulating chemical carcinogenesis and cytochromeP450And retinol metabolism and other related signaling pathways, so as to exert anticancer activity on multiple targets. Modern research shows that rhubarb can resist tumor, anti inflammation, bacteriostasis, antioxidation, enhance immunity, etc., and has traditional effects such as protecting liver and gallbladder, clearing heat and detoxification, removing blood stasis and dredging channels^[23], including emodin, rhein, chrysophanol-8-O-β-D-Glucopyranoside, chrysophanol-1-O-β-D-Active ingredients such as glucoside and emodin of Salvia miltiorrhiza can act on14Target proteins, which play an anti hepatoma role by regulating signaling pathways related to apoptosis, metastasis, inflammation, and immunity^[78]Especially emodin, which can inhibit the proliferation, promote apoptosis, inhibit migration and invasion of liver cancer cells, has strong anti liver cancer activity^[79]Aconite, as a Yang warming drug, is also commonly used in the treatment of malignant tumors. Studies have found that crude polysaccharide and acidic polysaccharide of aconite can enhance the cellular immune function of tumor bearing mice, improve the expression of tumor suppressor genes and tumor apoptosis rate, and prolong their survival time^[80]Therefore, aconite-The compatibility of rhubarb can be opposite and complement each other, giving full play to the effects of warming the interior, dispersing cold, purging and relieving pain, and realizing the function of tonifying deficiency and strengthening health, so as to better play the role of two drugs in the treatment of liver cancer and other malignant tumors.

4.5  Treatment of severe sepsis

Sepsis is a systemic inflammatory response syndrome induced by infection. In severe cases, it can develop into multiple organ dysfunction syndrome, and the incidence has been increasing^[81]The gastrointestinal tract is the most vulnerable organ in sepsis, and its mucosal damage will lead to the invasion of intestinal flora into the blood, further aggravate the systemic inflammatory response, and induce multiple organ dysfunction syndrome^[82]Therefore, effective prevention and treatment of gastrointestinal barrier function damage is of great significance to improve the clinical efficacy and prognosis of sepsis. A large number of modern clinical studies have confirmed that Dahuang Fuzi decoction can enhance gastrointestinal mucosal function through antibacterial anti-inflammatory, accelerate gastrointestinal motility to reduce intestinal bacterial translocation, treat gastrointestinal mucosal injury in patients, improve gastrointestinal dysfunction, and then treat severe sepsis with high safety^[83-86]From the modern pharmacological analysis, attachedAlkaloids in semen Aconiti have anti-inflammatory, analgesic and other pharmacological effects, which can treat severe inflammatory exudation, but they are highly toxic and easy to cause toxic and side effects^[10]；Anthraquinone derivatives in Rhubarb can not only promote intestinal motility, but also anti inflammation, anti pathogenic microorganisms, antitoxins, etc^[28]. chendechang et al^[87]It was found that rhubarb could significantly reduce the circulating tumor necrosis factor in patients with gastrointestinal dysfunction-αAnd endotoxin content to inhibit endogenous infection and promote the recovery of gastrointestinal function to treat sepsis. From the perspective of traditional Chinese medicine, the six meridians in Treatise on Febrile Diseases believes that sepsis is mainly responsible for the rise and fall of yin and Yang, so the treatment theory of "supporting yang qi and storing Yin fluid" runs through^[88]The compatibility of rhubarb and Fuzi decoction can help Fuzi strengthen health and eliminate pathogens, warm the spleen and stomach, and change the cold of rhubarb into warm; Rhubarb can also assist in the toxicity of aconite; At the same time, it is supplemented with Asarum powder and Wentong, which can help aconite warm the interior, dispel cold and relieve pain, help rhubarb transport water and grains, and boost the power of large intestine to transmit dross^[85-86]In conclusion, the combination of rhubarb Fuzi Decoction with cold and heat, hardness and softness, dredging the abdomen, regulating qi and blood, and removing evil and tranquility can restore the gastrointestinal function of patients with severe sepsis by promoting gastrointestinal motility, accelerating the discharge of endotoxin, inhibiting inflammatory reaction, and then treat severe sepsis.

Aconite-The application and mechanism of Rhubarb in the treatment of Yang deficiency diseases after compatibility are shown in table3。

5  Conclusion and Prospect

Classic drug pairs are simple combinations discovered by physicians through long-term clinical practice, and their compatibility can achieve toxicity reduction and efficiency increase^[1]Aconite from rhubarb and aconite soup-Rhubarb drug pair is a classic drug pair compatible with cold and heat, in which rhubarb can dredge water and valley, purge accumulated stagnation, clear diarrhea and turbidity, eliminate the old and bring forth the new, and aconite can supplement fire and help Yang, dispel cold and pain, warm the spleen and stomach, strengthen health and dispel pathogens. The two drugs complement each other and have the effects of warming, dispersing cold and condensing to open and close the knot, and unblocking the lower accumulation and stagnation to smooth the intestines and stomach. It can treat spleen and kidney yang deficiency syndrome, as well as the "Yin knot" miscellaneous disease caused by cold coagulation and stasis^[22,68,89]After the compatibility of drug pairs, due to the complex composition of traditional Chinese medicine, the interaction between its components will occur in various links such as dissolution in vitro and metabolism in vivo, and the effect of phase preparation, toxicity reduction and synergy is the embodiment of these comprehensive effects^[1]Sort out the modern rhubarb and aconite soup or aconite-The pharmacodynamics and clinical application literature research of rhubarb after compatibility found that compatibility was mostly used to treat Yang deficiency diseases. Compatibility can enhance intestinal peristalsis and defecation, and can be used to treat digestive system diseases such as constipation due to Yang deficiency; Promote the improvement of renal function and blood glucose, which can be used to treat chronic renal failure, diabetic nephropathy and other kidney diseases; ; Enhance anti-inflammatory and antibacterial activity, which can be used to treat severe sepsis andSystemic inflammatory response syndromeRelated diseases; In addition, the compatibility can enhance the cardiotonic effect and anti hypoxia ability to antagonize heart rate slowing and myocardial ischemia, and can also be used to prevent and treat ischemic heart disease and slow arrhythmia in clinic^[89]It can enhance the analgesic effect for treatmentCold excess abdominal pain, acute stomach pain and other pain symptoms^[90]The toxicity and effect of traditional Chinese medicine exist objectively, especially in the highly toxic traditional Chinese medicine with significant curative effect, the toxicity and effect are both contradictory and unified, and can even realize the transformation of toxicity and effect^[11]。The diester alkaloids of Aconitum carmichaeli can be used as toxic substances and can be converted into effective substances under different pathological conditions to achieve toxic effect conversion. Exceeding a certain dose or treatment course will produce cardiac and neurotoxicity; However, anthraquinone and its derivatives of rhubarb exert efficacy when the dosage is appropriate, and toxicity will occur if the dosage is too high; Therefore, the "toxicity" of the drug pair should be comprehensively analyzed when it is used clinically-Effect ", reasonably control the dose, follow the diagnosis and treatment principle of" syndrome differentiation and treatment "of traditional Chinese medicine, and individualize the medication according to the patient's disease status and body state, so as to achieve toxicity reduction and efficiency increase^[91]。

With the progress of science and technology, the intervention of modern research means is aconite-Rhubarb provides a new idea and scientific basis for the study of compatibility mechanism. In terms of the material base (Fig1）In addition to the determination of its compatibility beforeThe toxicity and content changes of active ingredients in vitro after the introduction ofThe study on the dynamic changes of the active ingredients' metabolism in vivo after the compatibility of Aconitum carmichaeli can further explore the changes of the active ingredients before and after the compatibility, and further reveal the more comprehensive characteristics of Aconitum carmichaeli-The mechanism of reducing toxicity and increasing efficiency of rhubarb on compatibility, and it is of great significance to clarify the material basis of drug effect, the time rule of drug effect and the mechanism of action^[21]However, due to the complex and changeable chemical components after the compatibility of traditional Chinese medicine, only analyzing the changes in the content of active ingredients in vitro cannot represent the overall function after the compatibility, nor can it be represented by the in vivo process of several active ingredients1Traditional Chinese Medicine^[2,92]Therefore, the idea of system biology can be used to conduct an overall analysis of all components that have changed after the compatibility of drug pairs. ^[92]。After that, multi omics technology can be applied to aconite-The compatibility mechanism of rhubarb, such as through metabolomics,the research of compatibility mechanism of rhubarb and its application in the treatment of chronic hepatitis B and chronic hepatitis B in the treatment of chronic hepatitis B patients with chronic hepatitis B and chronic hepatitis B patients with chronic hepatitis B and chronic hepatitis B and chronic^[93]To find out the endogenous differential metabolites that exert efficacy in vivo after the compatibility of drug pairs, and integrate and analyze with the chemical components whose content changes in vitro after the compatibility, and further explore the internal pharmacodynamic material basis of the drug pair compatibility and the mechanism of action in the treatment of different diseases such as Yang Deficiency, in order to provide references for clinical rational drug use, and provide ideas and methods for the study of compound compatibility laws and the development of new drugs of traditional Chinese medicine.

Conflict of interest 

References (omitted)  

Come   ; Yue, yuetianxiang, Zhang   Coltan, Li Fanzhu, Pu Jigang. Research progress on Compatibility Mechanism of Fuzi Rhubarb in the treatment of Yang deficiency diseases   [J] . Chinese herbal medicine, 2022, 53 (11): 3518-3530