Rheum palmatum is a Polygonaceae plantRheum palmatum L.、 Tanggu rhubarbR. tanguticum Maxim. ex balf. or medicinal rhubarbR. officinale Dried roots and rhizomes of baill[1]It mainly contains anthraquinone, anthrone, tannin, stilbene, flavone, polysaccharide and other chemical components, and has the effects of reducing diarrhea and accumulation, clearing heat and fire, cooling blood and detoxifying, removing blood stasis and dredging meridians, removing dampness and eliminating jaundice[2-4]Research shows that more than 100 compounds have been isolated from Rheum palmatum, Rheum tanguticum and Rheum officinale, mainly including anthraquinones, anthrones, stilbenes, phenylbutanones, chromogen ketones, flavonoids, tannins, etc. Among them, anthraquinones are the main pharmacodynamic components of rhubarb (mass fraction 3% - 5%), and they are also the quality control components of Rhubarb in the 2020 edition of Chinese Pharmacopoeia[1]。
Inflammation is a reaction of the body to the injury of inflammatory factors. The body has congestion, swelling, exudation, degeneration, local tissue ischemia, hypoxia with metabolic function changes, circulation disorders and other processes. Its clinical manifestations are mainly redness, swelling, fever, pain, etc. Under normal physiological conditions, inflammatory reaction can prevent further damage to the body and remove damaged tissues; Under pathological conditions, inflammation can lead to tissue destruction and even organ dysfunction[5-6]Inflammation is a universal physiological phenomenon in human body. Its significance is to reduce and eliminate the damaging effects of harmful factors on human body, and lay the foundation for tissue repair thereafter. Severe inflammatory reactions can also be life-threatening, and are fatal in diseases such as osteoarthritis, rheumatoid arthritis, and inflammatory bowel disease[7]。
Scholars combine the traditional theory of traditional Chinese medicine with modern medicine, and refer to the record in "synopsis of the Golden Chamber" that "where heat passes, its blood will coagulate", and believe that heat toxin and blood stasis syndrome is inflammation in western medicine [7]. Rhubarb has the effects of purging heat from the bowels, weeding out the old and bringing forth the new, cleaning the gastrointestinal tract and removing blood stasis, which can improve clinical symptoms and reduce the level of inflammatory factors. This paper summarizes the anti-inflammatory mechanism of rhubarb and its active ingredients, and provides a reference for its in-depth research and application in medicine and health products.
1 anti acute pancreatitis effect and mechanism
Acute pancreatitis (AP) refers to the chemical inflammation of pancreatic tissue digestion caused by digestive enzymes secreted by the pancreas. It is one of the common multiple critical diseases in the Department of Gastroenterology. According to traditional Chinese medicine, acute pancreatitis belongs to the categories of "spleen and heart pain", "abdominal pain" and "pancreatodynia", which are mostly caused by exogenous evil Qi, diet and internal injury, emotional disorder and other etiologies, resulting in dampness, heat, blood stasis, and toxin in the middle energizer. The Middle Earth is out of luck, the air machine is dysregulated, the blood circulation is not smooth, the body fluid is obstructed, and the intestines are blocked, causing pain, which occurs as acute pancreatitis. While "the six Fu organs are used for dredging, and the descending ones are used for smoothing", rhubarb can relieve heat in the Fu organs, expel blood stasis and dredge meridians, but also promote dampness, cool blood and detoxify, and can take advantage of the situation, which can improve clinical symptoms, reduce the level of inflammatory factors, promote the recovery of gastrointestinal function, reduce complications, and improve clinical efficacy[8]。
1.1 rhubarb and its extract
Studies have found that rhubarb regulates inflammatory cytokines[9-10]、 [11]Play a therapeutic role in AP. Another study found that rhubarb extract can inhibit monocyte chemoattractant protein (MCP-1), macrophage inflammatory protein (MIP-2)[12], inhibit the expression of Toll like receptor 4 (TLR4), nod like receptor protein 3 inflammasome (NLRP3), caspase-1 protein, and reduce the activation of Caspase-1, thereby reducing the secretion of tumor necrosis factor - α (tnf- α), interleukin-1 β (IL-1 β), IL-6, IL-18 proinflammatory factors, and inhibiting the occurrence of systemic inflammatory cascade[13]In addition, the levels of serum amylase (AMS), IL-6, trypsinogen activating peptide (TAP) and other blood biochemical indicators of rhubarb free anthraquinone intervention combined with adipose stem cell transplantation in the treatment of acute pancreatitis in rats; And can significantly reduce the degree of acute pancreatitis and pancreatic histomorphological lesions in rats[14]。
1.2 monomer composition of rhubarb
. Studies have found that in the treatment of inflammatory diseases, emodin can inhibit mitogen activated protein kinase (MAPK) signaling pathway[15], inhibit inflammatory response and oxidative stress damage [16], inhibit the neurogenic gene notch homologous protein 1 (Notch1) and RAS homologous gene family member a/ Rho kinase 1 (rhoa/rock) pathway[17], dysregulated eicosane metabolism and restoration or promotion of pancreatic cell protection[18], inhibiting P2X ligand gated ion channel 7 (P2X7) /nlrp3signaling pathway reduces the concentration of IL-1 β and IL-18 in plasma, thereby delaying AP progression and improving systemic inflammation[19]。
In terms of immune regulation, emodin can increase the CD4 of T lymphocyte subsets by+Content and CD4+/CD8+The ratio can enhance the immune function of the body, or reduce the immunosuppressive state of the body by reducing the proportion of Treg, and increase the proportion of bregs to promote the secretion and release of interleukin-10 (IL-10) and transforming growth factor - β 1 (tgf- β 1), thereby inhibiting the inflammatory response[20]At the same time, emodin can inhibit the activity of nuclear factor - κ B (nf- κ b)[21], inhibiting nuclear factor E2 related factor 2/ heme oxygenase 1 (nrf2/ HO-1) signaling pathway[22], inhibiting intestinal apoptosis induced by acute severe pancreatitis[17], improve intestinal function and lung function injury caused by AP. In addition, emodin treatment can improve pancreatitis and edema, reduce paracellular permeability, and promote the expression of pancreatic tight junction protein-5 (claudin-5) and occludin[23]Its action and mechanism are shown in Table 1 and figure 1.
2 anti sepsis effect and mechanism
Sepsis is a systemic inflammatory response syndrome (SIRS). Inflammation is a protective response of the body caused by harmful stimuli or the environment to resist harmful stimuli and repair tissues during treatment. The main pathogenesis of this disease is blood stasis block, heat toxin accumulation, visceral Qi obstruction, and lack of healthy qi. Rhubarb has the effects of weeding out the old and bringing forth the new, cleaning up the gastrointestinal tract and lower blood stasis, and some studies have applied it to sepsis[25]。
2.1 rhubarb and its extract
Rhubarb can correct the balance of intestinal flora by regulating the expression of colonic tight junction proteins, promoting the excretion of free bacteria, reducing bacterial translocation and the production of toxic substances, and protecting the intestinal biological barrier to treat sepsis[26-27]Other studies have shown that rhubarb extract can inhibit nf- κ B and erksignaling pathway[28], inhibition of kelch like ECH associated protein 1 (Keap1) /nrf2signaling pathway[29]To treat SIRS.
2.2 monomer composition of rhubarb
It was found that emodin could down regulate P-selectin[30-31], reduce myocardial oxidative stress, apoptosis and inflammatory factor levels[32]To exert anti-inflammatory effects. Meanwhile, emodin can protect hyperglycemia and lung injury caused by sepsis by inhibiting the secretion of inflammatory cytokines and inhibiting the nf- κ B pathway[33-35]In addition, emodin can exert its anti sepsis effect by inhibiting nf- κ B and p38 mapksignaling pathway, and inhibiting the expression of tnf- α and interleukin-8 (IL-8) in combination with nano silver[36]. Huang Huina et al[37]It was found that Rhein could inhibit the expression of high mobility group box 1 (HMGB1) in RAW264.7 cells stimulated by lipopolysaccharide (LPS) through serine / threonine protein kinase (Akt) / ekrsignaling pathway. Chrysophanol inhibits NF - κ B p65 and ERK1 / 2 pathways[38], inhibition of peroxisome proliferator activated receptor (ppar- γ) / NF KB pathway[39], inhibiting inflammatory cytokines and downregulating the expression of TLR2 and TLR4[40]To prevent sepsis. See Table 2 and table 2 for its anti sepsis effect and mechanism.
3 anti arthritis effect and mechanism
The etiology of arthritis is complex, which is related to autoimmune reaction, trauma, degenerative disease and other factors. It can be divided into rheumatoid arthritis (RA), osteoarthritis (OA), ankylosis, gout, suppurative arthritis and other arthritis. [41]Osteoarthritis is caused by the combined action of internal and external pathological factors, including the deficiency of kidney yang in old age and the invasion of wind heat and dampness pathogens, resulting in blood stasis blocking collaterals, blocked tendons and channels, and blocked Qi and blood[42]。
Rhubarb has the effects of weeding out the old and bringing forth the new, cleaning up the gastrointestinal tract and lower blood stasis, and can be used in the treatment of arthritis. Emodin can inhibit nf- κ bsignaling pathway[43-44], inhibit the activation of erk1/2 and p38mapksignaling pathway, reduce the release of inflammatory factors, and effectively control RA synovial inflammation[45]In addition, emodin can effectively inhibit the production of inflammation related substances such as iNOS, no, cyclooxygenase-2 (COX-2), prostaglandin 2 (PGE2), reduce the expression of MMP-3, MMP-13, proteolytic integrin metallopeptidase (ADAMTS-4) related to cartilage matrix degradation, and slow down the cutting speed of type II collagen gene (COL2A1)[46]。
Other studies have found that Rhein can reduce the content of IL-1 β, iNOS and no by inhibiting the activation of nf- к B, inhibiting the formation of NLRP3 inflammasome complex and inhibiting caspase-1 activity, so as to achieve the anti-inflammatory effect[47-49]Geng et al [50] found that emodin methyl ether could treat arthritis by inhibiting tgf- β /nf- κ b/ MAPK pathway and regulating the expression of inflammatory cytokines. Its anti arthritis effect and mechanism are shown in Table 3 and figure 3.
4 others
4.1 atherosclerosis
Atherosclerosis is a chronic inflammatory disease, which is characterized by the presence of atherosclerotic lesions in the intima of arteries, leading to large artery sclerosis and stenosis. . According to the required reading of the medical school, "only the spleen soil is deficient and wet, and it is difficult for those who are clear to rise and those who are turbid to fall, leaving the middle stagnant diaphragm and blood stasis to form phlegm." rhubarb can treat atherosclerosis by activating blood circulation and removing blood stasis[51]Emodin inhibits the production of C-reactive protein in vascular endothelial cells induced by homocysteine by inhibiting ros-erk1/2/p38signaling pathway and upregulating PPAR γ expression, thus exerting anti-inflammatory effects[52]Emodin exerts anti-inflammatory effects by inhibiting the nf- κ B pathway, reducing cytokines such as IL-1 β and IL-6, and inhibiting the expression of MMP-2 and MMP-9[53]Emodin inhibits the inflammatory response of atherosclerosis by regulating MCP-1 and interferon gamma (ifn- γ)[54]In addition, yanghaohong et al[55]The study found that the Total Anthraquinone of Rheum tanguticum could slow down the symptoms of atherosclerosis in rats by reducing the inflammation and cellular degeneration in the liver.
4.2 ulcerative colitis
Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease of unknown cause. According to traditional Chinese medicine, UC belongs to the categories of "intestinal congestion", "dysentery" and "diarrhea" in traditional Chinese medicine. The disease is mainly located in the intestine and is closely related to the liver, spleen, lung and kidney[56]Rhubarb has always been one of the commonly used traditional Chinese medicines for the treatment of UC. It can treat UC by clearing away heat, removing dampness, and promoting aging according to the pathogenesis of "Damp heat accumulating in the intestine". Rhein can indirectly change intestinal purine metabolism by regulating intestinal flora, thereby alleviating colitis[57]Chrysophanol plays an anti-inflammatory role by inhibiting the activation of nf- κ B and caspase-1 in LPS stimulated macrophages and reducing the expression of tnf- α, IL-6 and COX-2, which is a representative drug for the treatment of UC with the "Tongyin universal" method[58]。
4.3 keratitis
Bacterial keratitis is a common severe ocular infection and one of the major causes of blindness and blindness worldwide[59-60]Bacterial infection after corneal injury or under other pathological conditions can cause inflammatory cell infiltration, hinder corneal transparency, and even cause permanent vision loss due to scar and perforation. Research findings[61-62]Emodin alleviates the injury of corneal inflammation by inhibiting the activation of nf- κ B in corneal tissue of keratitis rats. In addition, Gou Xiaomei et al[63]The study found that emodin could improve the levels of tnf- α, IL-6, intercellular adhesion molecule-1 (ICAM-1) inflammatory factors by regulating PPAR, MAPK, nf- κ B protein, and play an anti-inflammatory role in rats with Aspergillus fumigatus keratitis. The anti-inflammatory mechanism of rhubarb and its active ingredients is shown in Figure 4.
Clinical study on Rhubarb and its active ingredients in the treatment of inflammatory diseases
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6 Conclusion and Outlook
The anti-inflammatory effect of rhubarb is mainly reflected in the effects on inflammatory cytokines, inflammation related proteins and related signaling pathways (such as nf- κ B, MAPK, ERK, Nrf2). In addition to the above inflammatory diseases, researchers found that rhubarb also has a certain application prospect for the treatment of myocarditis and neuroinflammation. [69]Rhein can improve the changes of intestinal flora, reduce macrophage accumulation, and reduce neuroinflammatory response in diet induced obese mice[70]Chrysophanol can inhibit the activation of nalp3 inflammasome and has a protective effect on ischemic stroke[71]The rhubarb extract can significantly up regulate the expression of IL-4 and IL-10, down regulate the expression of tnf- α, IL-6 and ifn- γ, and play an anti-inflammatory role in cerebral hemorrhage model rats[72]According to the correlation between rhubarb and its active components (anthraquinones) and anti-inflammatory efficacy, this paper selects anthraquinones as an important reference for Rhubarb quality marker screening, in order to provide a theoretical basis for the quality control of rhubarb.
Although a large number of studies have been done on the chemical constituents and anti-inflammatory effects of rhubarb at home and abroad, most of them still focus on anthraquinones, lacking systematic screening and evaluation of pharmacodynamic substances. Therefore, in the future, the anti-inflammatory active components or ingredients of rhubarb can be systematically screened from its overall chemical composition, and based on this, the component extraction and compatibility optimization can be carried out, so as to improve the effective utilization of the drug resources and provide quality marker reference for the quality control of related functional products. In addition, the main active ingredients of rhubarb (such as aloe emodin and rhein) have poor solubility. Based on this, the structure of anthraquinones in Rhubarb can be modified to increase its dissolution, so as to obtain compounds with high valence and strength and clinical medicinal value. .
References (omitted)
Source: Cao Qiang, Guo Yafei, ye Leilei, Zhang Chengyuan, Kou Renbo, Guo Mei rhubarb and the research progress of anti-inflammatory effect and mechanism of its active ingredients [j]. Chinese herbal medicine, 2022, 53 (22): 7285-7294