Research Progress On Chemical Composition And Pharmacological Effects Of Jichuan Decoction And Prediction Of Quality Markers Ⅱ

2 Mechanism of action in treating constipation

2.1 Promoting smooth muscle excitation

Constipation is caused by gastrointestinal stagnation, which is often manifested as difficulty in defecation, reduced defecation frequency, and accompanied by abdominal pain. Jichuan Decoction is the first choice for treating constipation. It can treat constipation by enhancing gastrointestinal motility and promoting smooth muscle excitation. Qu Ziyi et al. [35] established a slow transit constipation (STC) rat model to study STC constipation. They found that after intervention with Jichuan Decoction, the discharge time of the first black stool was reduced and the carbon powder in the intestine was increased. This shows that Jichuan Decoction can promote the intestinal motility of rats and improve STC. ICC is an interstitial cell related to gastrointestinal motor neurons in the gastrointestinal tract and is related to smooth muscle. In experimental studies, it was found that the content of intestinal ICC is difficult to measure and the content of c-kitmＲNA is proportional to the number of ICC. Therefore, the content of intestinal c-kitmＲNA is often used to determine the number of ICC [36]. Gu Jinhui et al. [37] found that Jichuan decoction can increase the number of gastrointestinal ICCs in the STC model, accelerate gastrointestinal information transmission, thereby accelerating gastrointestinal smooth muscle motility and promoting defecation.
Some scholars have found that calmodulin-dependent kinase II (CaMKⅡ) can form a complex with CaM through calcium ions, and its conformation changes under the regulation of CaMKⅡ, thereby activating the activity of CaMKⅡ to induce irregular waves and cause slow movement of colon smooth muscle [38]. Liu Cong et al. [39] found that after administration of Jichuan decoction, the intracellular Ca2+ concentration decreased significantly, indicating that Jichuan decoction can effectively reduce the increase of intracellular Ca2+ in colon smooth muscle cells, and can reduce the expression of CaM, CaMKⅡ β, γ, and δ in colon smooth muscle cells of model rats. It can be inferred that Jichuan decoction may regulate the function of colon smooth muscle cells by regulating the Ca2+-CaMKⅡ signaling pathway to achieve the purpose of treating yang deficiency constipation.

NEW HERB CISTANCHE TREATING YANG DEFICIENCY CONSTIPATION

2.2 Influence on the expression of intestinal AQP proteins

Aquaporins (AQPs) are a family of membrane channel proteins that are characterized by their ability to mediate the transmembrane transport of water molecules with high selectivity, playing a key role in human water metabolism. Dry stool is the main cause of constipation. Feces stay in the intestine for too long, water reabsorption increases, and defecation cannot be smooth, which is related to the water transport and distribution of AQPs in the intestinal cavity[40][41][42]. Studies have found[43] that compared with wild-type mice, mice with AQP1 knockout had significantly thinner colon muscle layer and mucosal layer, unbalanced water metabolism, and difficulty in defecation. Wang Xiaojun et al. [44] used immunohistochemistry to detect the level of AQP4 in the colon mucosa of 455 STC patients and found that 36 cases had high expression and 6 cases had low expression. Patients with high AQP4 levels were more likely to have difficulty defecating than those with low levels. It can be speculated that increased AQP4 levels will accelerate the absorption of water in the colon mucosa, thereby leading to constipation. Zhihui et al. [45] showed that colon mucosal water channel proteins play an important role in regulating water metabolism. Yang Ying et al. [46] established an STC mouse model to explore the relationship between the therapeutic effect of Jichuan decoction on STC rats and AQPs. The study found that the mRNA and protein levels of cAMP, PKA, and AQP4 in the colon tissue of rats in the Jichuan decoction group were significantly lower than those in the model group. This indicates that Jichuan decoction may regulate the water metabolism disorder in the gastrointestinal tract by regulating the content of AQP3 and AQP4, thereby achieving the purpose of treating functional constipation by moistening the intestine and promoting bowel movements.

2.3 Regulation of neurotransmitters

Neurotransmitter receptors play an important role in intestinal muscle movement. Current studies have found that some neurotransmitters play a role in gastrointestinal movement, including 5-HT, VIP, SP, etc. [47]. Constipation is one of the complications created by stroke patients. 5-HT is a common neurotransmitter in the brain-gut axis. According to studies, 5-HT in the colon mucosa of STC patients showed a downward trend, indicating that 5-HT plays a pivotal role in the treatment of constipation [48]. For stroke patients, changes in diet, defecation environment, and emotional problems can lead to sympathetic nerve excitement, vagus nerve inhibition, and weakened gastrointestinal motility [49]. Yang Ying et al. [50] selected patients with post-stroke constipation and observed the efficacy of Jichuan decoction in treating post-stroke constipation. They found that the disappearance rate of constipation, 5-HT and bifidobacterium levels in the observation group were higher than those in the control group, and the VIP level was lower than that in the control group. This shows that 5-HT, VIP, and fecal bifidobacteria are closely related to constipation, confirming the effectiveness of Jichuan decoction in treating post-stroke constipation. The study found that before treatment, the serum SP and MTL concentrations of STC patients were low, and the NO and VIP concentrations were high. After treatment with Jichuan decoction, the expression of SP, MTL, VIP, and NO in patients was significantly improved. It can be inferred that the levels of neurotransmitters and intestinal hormones are closely related to the onset of STC [51][52]. 2.4 Regulating the intestinal environment
The occurrence of functional intestinal constipation is likely related to whether the intestinal environment is disordered. Maintaining a steady state of the intestinal environment is very important for the normal physiological function of the body. If the balance of intestinal flora is broken, the internal environment will be disordered, affecting the normal peristalsis of the intestine, it will cause constipation. Xu Nana et al. [53] studied elderly patients with chronic functional constipation and found that the number of anaerobic bacteria such as lactobacillus and bifidobacterium in the intestine of elderly patients decreased, and the number of aerobic bacteria such as yeast increased, which would lead to the disruption of the balance of the colony and then affect the defecation function. Gao Li et al. [54] conducted an animal experiment and found that the number of Escherichia coli in the STC rat model intervened by Jichuan decoction decreased, and the levels of lactobacillus and bifidobacterium increased, indicating that acupuncture combined with Jichuan decoction can regulate the number of flora and improve constipation. Modern pharmacological studies have found that Alisma orientalis in Jichuan decoction can regulate the intestinal environment by intervening in the number of intestinal flora and improving intestinal flora imbalance [55].

2.5 Others

From the analysis of the ingredients of Jichuan Jian, it can be seen that hesperidin and naringenin are the ingredients of Jichuan Jian. Scholars have found [56] that naringenin and hesperidin can improve the expression of CDNF, Ach, and actin. Neuro-ICC smooth muscle overall stability, thereby achieving the purpose of defecation. Other studies have found that Jichuan Jianjia is also effective in treating borderline electrocardiogram-type cardiac neuropathy [57].

Fig.1 The mechanism of action of Jichuan decoction in the treatment of constipation

3 Clinical application

Table1 Clinical application of Jichuan decoction in the treatment of constipation