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BY 4.0 license Open Access Published by De Gruyter Open Access October 3, 2023

Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review

  • Lijiao Wu , Xiangjin Wang , Jihang Jiang , Yong Chen , Bo Peng EMAIL logo and Wei Jin EMAIL logo
From the journal Open Medicine

Abstract

Hyperlipidemia is a metabolic disorder, which is a major risk factor for atherosclerosis, stroke, and coronary heart disease. Although lipid-lowering treatments have been extensively studied, safer treatments with fewer adverse effects are needed. Rhubarb is a traditional Chinese medicine that has lipid-lowering, anti-inflammatory, and antioxidant properties. Disturbance in lipid metabolism is the basis of tissue damage caused by hyperlipidemia and plays a key role in the development of hyperlipidemia; however, the molecular mechanisms by which rhubarb regulates lipid metabolism to lower lipid levels are yet to be elucidated. We conducted this study to summarize the phytochemical constituents of Rheum officinale and provide a comprehensive review of the molecular mechanisms underlying the regulation of lipid metabolism during hyperlipidemia treatment. It was found that rhubarb extracts, including emodin, rhubarb acid, and rhubarb phenol, regulate total cholesterol, triglyceride, TNF-α, and IL-1β levels through signaling pathways such as C/EBP α, 3T3-L1, PPAR α, and AMPK, thereby improving the hyperlipidemic state. This suggests that rhubarb is a natural drug with lipid-lowering potential, and an in-depth exploration of its lipid-lowering mechanism can provide new ideas for the prevention and treatment of hyperlipidemia.

1 Introduction

Hyperlipidemia is a disease characterized by abnormal lipid metabolism, manifested by elevated total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) levels and/or decreased high-density lipoprotein cholesterol (HDL-C) levels [1]. A hypercholesterolemic diet and genetic and environmental factors are important causes of hyperlipidemia [2,3]. The main pathogenesis is an increase in lipoprotein synthesis and a decrease in lipid clearance pathways, leading to abnormally elevated levels of lipids or lipoproteins in the blood, which are mainly involved in inflammatory response and oxidative stress [4,5]. Hyperlipidemia has a wide range of effects on organisms. Abnormalities in lipid metabolism induce oxidative stress and mitochondrial dysfunction, triggering structural and functional changes in the heart such as myocardial hypertrophy, apoptosis or necrosis of cardiomyocytes, atherosclerosis, heart failure, and sudden death [6,7]. Cardiovascular disease (CVD) kills approximately 17.9 million people each year globally. The risk of CVD in patients with hyperlipidemia is approximately twice as high as that in patients without hyperlipidemia [8]. Additionally, hyperlipidemia is associated with several chronic diseases, such as hypertension, fatty liver, cirrhosis, peripheral vascular disease, ischemic cerebrovascular disease, and pancreatitis [9,10]. The incidence of hyperlipidemia has sharply risen in recent years as lifestyle and eating habits have changed significantly [11]. Therefore, the prevention and treatment of hyperlipidemia to reduce the incidence of chronic diseases, such as CVDs, has become an increasing concern for society.

Currently, fibrates, statins, bile acid sequestrants, niacins, and cholesterol absorption inhibitors are commonly used to treat hyperlipidemia [12]. Although these drugs have some therapeutic effects, they cause toxic side effects, such as mild-to-moderate elevation of liver transaminases, nerve damage, myopathy, rhabdomyolysis, and increased risk of diabetes mellitus, after long-term treatment [13,14]. Therefore, it is essential to explore new therapeutic agents, and there is a growing tendency to use natural medicines to treat and prevent diseases [15,16]. A variety of plant-derived substances have excellent lipid-lowering effects, and their beneficial properties include inhibition of pancreatic lipase, reduction of dietary fat absorption, stimulation of lipolysis, and reduction of lipogenesis [17,18].

Rhubarb is a famous traditional Chinese medicine belonging to the genus Rhubarb of the Polygonaceae family. Its application can be traced back to the Shennong’s Classic of Materia Medica (270 BC) [19]. For more than 2,000 years, rhubarb has been cultivated worldwide for the treatment of constipation, diabetic nephropathy, chronic renal failure, acute pancreatitis, and gastrointestinal bleeding [20]. Recent studies have shown that rhubarb has hypolipidemic, antibacterial, anti-inflammatory, and antioxidant activities [21], and it is gradually being applied in the prevention and treatment of hyperlipidemia.

Seven databases, PubMed, SciFinder, Scopus, Web of Science, CNKI, Wipu, and Wanfang, were searched from creation of the database to November 25, 2022. We searched original studies, reviews, and newsletters in English and Chinese for search terms such as “rhubarb,” “hyperlipidemia,” “lipid metabolism,” “pharmacology,” “compounds,” “pharmacology,” “biological activity,” “clinical application,” and “toxicity.” If the literature lacked data or the report was unclear, we corresponded with the authors. If the original data remained unavailable, the literature was excluded. The bibliographies of all selected articles were also scanned for additional relevant articles, and the PubChem database was used to check the IUPAC names of known rhubarb.

2 Phytochemistry

Research on the chemical composition of rhubarb began in the early nineteenth century and approximately 200 chemical components [20], including anthraquinones, anthrone, stilbenes, tannins, acyl glucosides, and other bioactive compounds, have been isolated and identified. Among these components, anthraquinones, including emodin, rhubarb acid, rhubarb phenols, and their derivatives, are dominant [22,23], in addition to stilbenes containing mainly resveratrol and its derivatives. Table 1 shows the composition of 48 common compounds in rhubarb.

Table 1

Common chemical constituents of rhubarb

Class S.N. Compounds References
Anthraquinones 1 Emodin Verma et al. [24]
2 Aloe-emodin Agarwal et al. [25]
3 Emodin-O-d-glucoside Ye et al. [26]
4 Emodin-8-O-β-d-glucopyranoside Verma et al. [24]
5 Emodin 8-O-β-d-glucopyranosyl-6-O-sulfate Krenn et al. [27]
6 Emodin 8-O-(6′-O-malonyl)-glucoside Ye et al. [26]
7 Emodin 8-O-(2′,3′,4′,6′-tetra acetyl)-glucoside Krenn et al. [27]
8 Chrysophanol Agarwal et al. [25]
9 Chrysophanol 1-O-glucoside Ye et al. [26]
10 Chrysophanol 8-O-(6′-O-galloyl)-glucoside Ye et al. [26]
11 Chrysophanol-8-O-β-d-glucopyranoside Suresh Babu et al. [28]
12 Physcion Agarwal et al. [25]
13 Physcion-1-O-β-d-glucopyranoside Wang et al. [29]
14 Physcion-8-O-β-d-glucopyranoside Wang et al. [29]
15 6-Methyl-aloe-emodin Singh et al. [30]
16 6-Methyl-aloe-emodin-triacetate Singh et al. [30]
17 6-Methyl-rhein Singh et al. [30]
18 6-Methyl-rhein-diacetate Singh et al. [30]
19 Rhein Singh et al. [25]
20 Rhein 1-O-glucoside Ye et al. [26]
21 Rhein 8-O-glucoside Ye et al. [26]
22 Torachrysone-8-O-β-d-glucopyranoside Suresh Babu et al. [28]
23 8-O-β-d-(6′-O-acetyl) glucopyranosyl-chrysophanol Krenn et al. [31]
Anthrones 24 10-Hydroxycascaroside D Krenn et al. [31]
25 Anthrone C-glucosides Krenn et al. [31]
26 10R-chrysaloin 1-O-β-d-glucopyranoside Krenn et al. [31]
27 10-Hydroxycascaroside C or anthrone C-glucosides Krenn et al. [31]
28 Cascaroside C Krenn et al. [31]
29 Cascaroside D Krenn et al. [31]
30 Cassialoin Krenn et al. [31]
Stilbenes 31 Resveratrol Rokaya et al. [32]
32 Resveratrol 3-O-β-d-glucopyranoside Ngoc et al. [33]
33 Resveratrol-4′-O-β-d-glucopyranoside Chen et al. [34]
34 Resveratrol-4′-O-β-d-(6″-O-galloyl)-glucoside Chen et al. [34]
35 Resveratrol-4′-O-β-d-(2″-O-galloyl)-glucoside Chen et al. [34]
36 Piceatannol Liu et al. [35], Wang et al. [29]
37 Piceatannol-3′-O-β-d-glucopyranoside Wang et al. [29]
38 Piceatannol-4′-O-β-d-(6″-O-galloyl)-glucopyranoside Liu et al. [35]
39 Piceatannol-4′-O--d-glucopyranoside Liu et al. [35], Wang et al. [29]
40 Desoxyrhaponticin Suresh Babu et al. [28]
41 Desoxyrhapontigenin Suresh Babu et al. [28]
42 Rhaponticin Chen et al. [36]
43 Rhapontigenin Zhang et al. [37]
Tannins 44 d-Catechin Krenn et al. [27]
45 Epicatechin Krenn et al. [27]
Phenylbutanone 46 4-(4′-Hydroxyphenyl)-2-butanone-4′-O-β-d-glucopyranoside Kashiwada et al. [38]
47 4-(4′-Hydroxyphenyl)-2-butanone-4′-O-β-d-(2″,6″-O-cinnamoyl)-glucopyranoside Kashiwada et al. [38]
48 Isolindleyin Nonaka et al. [39]

Anthraquinones are the predominant substances isolated from rhubarb and their most potent active component is emodin, which consists mainly of a 1,8-dihydroxy-9,10-anthraquinone skeleton. If different functional groups are attached to different parts of the backbone structure, they can display different chemical structures (Figure 1), thereby exhibiting different chemical properties and pharmacological effects [40]. For example, two chemical components, rhubarb phenols (1,8-dihydroxy-3-methylanthraquinone) and emodin (1,3,8-trihydroxy-6-methylanthraquinone), have a basic skeleton of 1,8-hydroxy-methylanthraquinone, but their functional groups are in different locations, which leads to differences in their pharmacological effects. Although both have a lowering effect on plasma lipid levels, emodin has stronger antitumor and anti-inflammatory effects and is more influential [41]. Regarding the structure–effect relationship of toxicity, 30 μM emodin induced significant apoptosis in a time-dependent manner, according to the morphological changes in L-02 cells. Additionally, rhodopsin may interfere with the metabolism of glutathione (GSH) and fatty acids in human hepatocytes [42].

Figure 1 
               Chemical structure of the main components of rhubarb.
Figure 1

Chemical structure of the main components of rhubarb.

3 Molecular mechanism of lipid metabolism regulation by rhubarb

Rhubarb is a classical laxative drug, and its pharmacological studies have shown that it can regulate lipid metabolism and has anti-inflammatory effects. Therefore, in addition to constipation, it is also used to treat disorders of lipid metabolism and hyperlipidemia. Emodin, rhubarb acid, rhubarb phenol, and resveratrol are the main substances that regulate lipid metabolism and can inhibit pancreatic lipase, reduce lipogenesis, stimulate lipolysis, and regulate lipid factor expression to achieve lipid lowering.

3.1 Emodin

Emodin is the predominant anthraquinone in rhubarb, and it is recognized as a protein complex kinase inhibitor with activity against a variety of tumor cells, in addition to its antioxidant, lipid metabolism regulating, and antibacterial effects.

Emodin has diverse regulatory mechanisms on lipid metabolism. It was found that rhodopsin is closely related to peroxisome proliferator-activated receptor (PPAR) γ nuclear receptor, and rhodopsin can act as its activator to regulate lipid metabolism, promoting cholesterol efflux from THP1 macrophages, up-regulating scavenger receptor BI, facilitating reverse cholesterol transport, and inhibiting cholesteryl ester accumulation by activating the PPAR γ signaling pathway [4345]. Additionally, emodin acts directly on transcription factors to regulate lipid metabolism. Li et al. found that emodin significantly inhibited the mRNA expression of SREBP-2, a major transcription factor of cholesterol biosynthesis, and reduced the mRNA levels of cholesterol metabolism-related genes HMGCR, SS, LSS, and Sc4mol whereas increased the lipolytic mRNA levels of high-density lipoprotein receptor (SRBI), hepatic lipase, and apolipoprotein E (Apo E), showing an overall reduction in lipid synthesis and enhanced fatty acid oxidation (FAO) [46]. Xue et al. found that emodin has a regulatory effect on LPL and FAT/CD36 mRNA expression and helps improve dyslipidemia. Inflammatory factors can induce lipolysis, and emodin has a clear modulatory effect on inflammatory factors [47]. Zhang et al. found that emodin promotes lipid metabolism by down-regulating TNF-α, thereby inhibiting TNF-α-induced lipolysis [48].

Cholesterol is a precursor of bile acids, which are steroids synthesized from cholesterol in the liver [49], and the conversion of cholesterol to bile acids and their secretion into bile is one of the important ways in which the body removes cholesterol [50]. Wang et al. [51] found that the combination of rhodopsin with bile acids could reduce bile acid levels, thus, promoting the conversion of cholesterol to bile acids and contributing to the reduction of serum cholesterol. Notably, among the various mechanisms underlying the lipid-lowering effects of emodin, it inhibits both 3T3-L1 adipocytes and induces lipolysis [48]. Furthermore, emodin has concentration-dependent effects on 3T3-L1 adipocytes, and it promotes the proliferation of 3T3-L1 preadipocytes at low concentrations and inhibits their proliferation at higher concentrations [52]. Meng et al. suggested that emodin may inhibit the uptake of NPC1L1 cholesterol by human hepatocytes in an anti-competitive manner with cholesterol-lowering potential [53].

The above studies have shown that the specific mechanism of action of rhodopsin in lipid-lowering mainly includes activation of PPAR γ signaling pathway, regulation of mRNA expression of lipid metabolism-related factors such as SREBP-2, SRBI, Sc4mol, etc., as well as inhibition of metabolism in 3T3-L1 adipocytes (Figure 2). Meanwhile, emodin has a scavenging effect on cholesterol, and lowering blood cholesterol in hyperlipidemic patients may have a hepatoprotective effect by improving the severity of fatty liver disease. Therefore, the relationship between emodin level and liver function requires further investigation.

Figure 2 
                  Diagram of the lipid-lowering mechanism of emodin.
Figure 2

Diagram of the lipid-lowering mechanism of emodin.

3.2 Rhubarb acid

Rhubarb acid (4,5-dihydroxyanthraquinone-2-carboxylic acid), with a molecular weight of 284.22, is the most important active component of anthraquinones. It has a variety of pharmacological activities, such as antitumor, anti-inflammatory, anti-fibrotic, and regulation of glucolipid metabolism [54,55]. The hypolipidemic effects of rhubarb acid are of great interest. It inhibits adipocyte differentiation and significantly improves abnormal lipid metabolism in HTG [56]. Fang et al. found that rhubarb anthraquinones inhibit lipid accumulation before and after 3T3-L1 cell differentiation in 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese rats, with rhubarb acid showing stronger inhibition and higher hypolipidemic activity. These effects may be related to the inhibition of PPAR γ and expression of C/EBP α transcription factors by rhubarb acid to block the production of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) [57]. Rhubarb acid may also lower the lipid levels by enhancing lipolysis in adipocytes. Lipolysis is a catabolic reaction in which stored TG are hydrolyzed to release glycerol and free fatty acids. The production/metabolism balance of fat cells is a prerequisite for the regulation of energy balance in body [58]. Rhubarb acid treatment increases the expression of lipolytic enzymes ATGL and HSL, which hydrolyze TG to glycerol and increase lipolysis by downregulating key lipogenic transcription factors in adipocytes [57,59]. The MAPK pathway is closely associated with adipocyte differentiation, and MAPK activation is accompanied by C/EBP β and C/EBP δ expression, which further activates PPAR γ and C/EBP α expression to oversee terminal adipocyte differentiation [60]. Rhubarb acid blocks MAPK signaling in macrophages, thereby inhibiting the transcription of pro-inflammatory mediators TNF-α and IL-1β [61,62].

Taken together, the lipid-lowering effects of rhubarbic acid are mainly mediated by inhibiting 3T3-L1 adipocytes, PPAR γ and C/EBP α transcription factor expression, and MAPK signaling, and promoting the expression of lipolytic enzymes ATGL and HSL (Figure 3). Rhubarbic acid is commonly used for lipid-lowering, weight loss, laxatives, detoxification, cleansing the internal environment, preventing gastric cancer, and delaying aging. Compared to traditional lipid-lowering chemicals, rhubarb acid is less toxic and has a hepatoprotective effect [63]. Rhubarb acid is the only anthraquinone that can be absorbed into the blood after oral administration of rhubarb extract in humans. However, it is difficult to solubilize rhubarb acid in water, and increasing its water solubility and improving the rate of drug dissolution is the breakthrough point for improving the lipid-lowering effect of rhubarb acid.

Figure 3 
                  Diagram of the lipid-lowering mechanism of rhubarb acid.
Figure 3

Diagram of the lipid-lowering mechanism of rhubarb acid.

3.3 Rhubarb phenol

Rhubarb phenols belong to the anthraquinone group and have pharmacological effects such as neuroprotective, anticancer, antibacterial, antiviral, antioxidant, and lipid-regulating effects [64]. Studies have shown that rhubarb phenols can significantly lower blood lipid levels and reduce lipid accumulation in animals fed with HFD [65,66]. Zhang et al. found that rhubarb phenol significantly reduced the expression of FAS and ACC and increased the levels of ACOX1 and CPT1 in obese mice, thus, promoting lipolysis at the cellular and molecular levels [66]. Kwon et al. [67] found that rhubarb phenol similarly reduced lipid accumulation and expression of the lipogenic factors PPAR γ and CCAAT/C/EBP α in 3T3-L1 adipocytes. Meanwhile, Feldman et al. showed that rhubarb phenols significantly up-regulated the r RNA levels of MGLL and HSL, which are key enzymes in lipolysis, and also the expression of β-oxidation-related genes in fatty acids [68]. Liu et al. found that rhubarb phenol increased FAO in 3T3-L1 adipocytes (PPARα, Acadvl, Acadl, Acadm, L1) by exploring the effect of rhubarb phenol on lipid metabolism in obese mice. Expression of FAO (PPARα, Acadvl, Acadl, Acadm, Cpt2), lipolysis (HSL, MGLL), and thermogenic genes (Ppargc-1α, Prdm16) in L1 adipocytes suggests that rhubarb phenol promotes lipolysis, inhibits lipogenesis, and thus, inhibits lipid accumulation [69]. In terms of signaling pathways, AMPK, an AMP-dependent protein kinase, is a cellular energy receptor that promotes fatty acid metabolism and mitochondrial biosynthesis [70]. Liu et al. indicated that rhubarb phenol promotes lipolysis and reduces body weight and fat accumulation in HFD-induced obese mice by activating the AMPK pathway [69]. Li et al. found that the intensity of the hypolipidemic effect of rhubarb phenol may correlate with its concentration. Rhubarb phenol dose-dependently inhibits human SRE promoter activity and reduces intracellular cholesterol and TG levels [71].

The hypolipidemic activity of rhubarb phenol is relatively weaker than that of emodin and rhubarb acid. It inhibits lipogenesis and promotes lipolysis, which is mainly realized through the regulation of FAS, ACC, the key enzymes MGLL and HSL, and oxidative genes (Figure 4). No serious adverse events were observed in studies on rhubarb phenol, suggesting its good safety profile.

Figure 4 
                  Diagram of the lipid-lowering mechanism of rhubarb phenol.
Figure 4

Diagram of the lipid-lowering mechanism of rhubarb phenol.

3.4 Resveratrol

Resveratrol is a large group of astragalus compounds and an important component of rhubarb with anti-inflammatory, antioxidant, and anticancer properties [72]. Resveratrol can alter the gene expression profiles related to lipid metabolism [73]. For the first time, Zhang et al. proposed that resveratrol improves the lipid profile and reduces fat deposition in vivo in a porcine model, which may be mediated through fatty acid uptake, initial lipid synthesis, lipolysis, and FAO [74]. It has also been shown that the lipid-lowering mechanism of resveratrol mainly includes up-regulation of the expression of the cholesterol reverse transporter proteins PPARc and LXR α and some enzymes, modulation of the SIRT1-PPAR γ pathway and its downstream genes FAS and ACC, and increase in the ratio of apolipoproteins (APOs) A-I/ApoB [75,76]. Sahebkar et al. noted that in cell culture studies, resveratrol improved lipoprotein metabolism and reversed cholesterol transport while inhibiting foam cell formation [77]. In experimental models, resveratrol also exhibited antilipidemic activity by lowering LDL-C and TG levels and increasing HDL-C concentrations. Yuan et al. found that HFD-fed mice had dilated hepatocytes with significant lipid droplet accumulation, which was reduced by resveratrol treatment, further suggesting a lipid-modulating effect [78].

In terms of oxidative stress, Sebai et al. found that resveratrol reduces the pro-oxidant effects of the LPS-induced AR42J cell line through a Myd88-dependent signaling pathway [79] and through resveratrol intervention. TG levels can be reduced in T2DM patients [80], effectively reducing insulin resistance, lowering fasting blood glucose, and improving oxidative stress [81]. Its antioxidant effect was also demonstrated by the fact that the combination of resveratrol with antioxidant vitamins was more effective in protecting cells from oxidative stress than the antioxidants alone [82].

Resveratrol, a common polyphenol found in astragalus, plays an important role in several chronic diseases, such as CVDs and obesity [79]. It achieves lipid lowering (Figure 5) and treatment of hyperlipidemia by modulating the lipid profile, SIRT1-PPAR γ pathway, lipoprotein metabolism, as well as promoting cholesterol transport and oxidative stress effects. However, similar to rhubarb acid, pharmacokinetic studies have shown that resveratrol has low solubility, rapid metabolism, and a short initial half-life [83]. To date, few studies have suggested solutions to address the low bioavailability and solubility of resveratrol; however, further definitive studies are needed to maximize its efficacy and increase its solubility.

Figure 5 
                  Diagram of the lipid-lowering mechanism of resveratrol.
Figure 5

Diagram of the lipid-lowering mechanism of resveratrol.

3.5 Other components

In addition to rhodopsin, rhubarb acid, and rhubarb phenol, rhubarb-free anthraquinones, including rhubarb phenol methyl ether and aloe barbadensis rhubarb phenol, also exhibit hypolipidemic activity. Wang et al. found that the dichloromethane part of the ethanolic extract of rhubarb, which is mainly composed of rhubarb-free anthraquinones, has significant lipid-regulating effects that may enhance lipid metabolism, inhibit cholesterol synthesis [84], reduce peripheral LDLC and TC by inhibiting the PCSK9 gene, and promote intestinal cholesterol excretion by activating ABCG8 gene expression. Earth rhubarb glycosides and edible rhubarb sapogenins belong to the class rhubarb stilbenes. A study reported [36] that earth rhubarb glycosides significantly reduced the plasma TG, LDL, cholesterol, non-esterified free fatty acid, and insulin levels in KK/Ay type 2 diabetic mice. Jo et al. found that the consumption of rhubarb glycosides improved the pathological features of degenerative fatty liver in rats with hyperlipidemia induced by a high-cholesterol diet and significantly lowered blood lipid levels [85]. Additionally, rhubarb stem fiber has a hypolipidemic effect, which is thought to be due to its bile acid-binding capacity of rhubarb fiber, which in turn regulates cholesterol 7a-hydroxylase (cyp7a) activity [86].

Squalene cyclooxygenase (SE) (EC 1.14.99.7) is a nonmetallic flavoprotein monooxygenase that catalyzes the rate-limiting step in cholesterol biosynthesis [87]. Therefore, SE inhibitors become potential drugs for lowering cholesterol levels. Gallic acid derivatives of rhubarb are potent inhibitors of SE, a rate-limiting enzyme in cholesterol biosynthesis [88]. The other major constituents of rhubarb, senna A and dianthrone glucoside also showed favorable SE inhibitory effects [39]. In conclusion, the hypolipidemic effect of rhubarb has been clinically confirmed, and its chemical components and derivatives have shown either strong or weak hypolipidemic activity, which has far-reaching implications for the development of natural plant-based drugs against hyperlipidemia.

4 Toxic effects of rhubarb

The mechanisms underlying the toxic effects of rhubarb are not fully understood, and cells and animals in healthy or diseased states do not react to rhubarb in the same way. It has been confirmed that rhubarb has different degrees of toxicity in the liver, kidney, gastrointestinal tract, reproductive system, and blood system [89]. Studies have shown that the toxic effects of rhubarb are more pronounced in the liver and kidneys, and rhubarb affects the metabolism of endogenous substances such as mitochondria and bile acids through a series of adverse reactions, thus, causing liver damage [90,91]. Among these, anthraquinones and siderophores are closely related to the main toxic components of rhubarb [92], particularly because of substances such as emodin, aloe rhodopsin, and rhubarb acid. Animal experiments and clinical applications have confirmed significant bidirectional effects of rhubarb on hepatotoxicity and hepatoprotection. Dong et al. [93] examined the toxicity and target organs of rhubarb in rats using in vivo and in vitro experiments and found that emodin was the main toxic component. Based on the morphological changes in L-02 cells [94], rhodopsin (30 μM) causes significant apoptosis in a time-dependent manner. Additionally, emodin has the potential to interfere with GSH and fatty acid metabolism in human hepatocytes [95]. Wang et al. [96] studied the effect of total rhubarb extract in normal and pathological animals and found that rhubarb has hepatotoxicity in normal animals but has a protective effect against chronic liver injury caused by CCl4 damage. Particularly, cooked rhubarb after concoction has a stronger hepatoprotective effect with lower toxicity. Meanwhile, rhubarb benefits hepatocytes by scavenging free radicals; lowering the level of MDA, a key factor in liver inflammation; and increasing the total antioxidant capacity through oxidative stress, resulting in improved antioxidant damage, reduced lipid peroxidation, and stabilized cell membranes [92]. Rhubarb extract also has significant nephrotoxic and protective effects. The rhubarb extract emodin and rhubarb acid at a dose of 4.5 g/kg per day for 13 weeks induced a significant nephrotoxic effect in Sprague–Dawley rats. Rat renal tubular epithelial cells swell and degenerate [97], with significant cytotoxic effects. In a systematic evaluation, rhubarb showed positive effects in 1,322 patients with chronic kidney disease by alleviating uremic symptoms, lowering blood creatinine levels, improving hemoglobin levels, and regulating lipid metabolism disorders [98]. Another 6 months study showed that the critical dose of rhubarb extract required to induce nephropathy in rats was 10 g/kg body weight per day in raw doses, which recovered upon discontinuation of the drug [91]. No nephropathy was observed in normal rats after repeated administration of rhubarb extract at doses of 3 and 20 g/kg body weight per day (calculated using the crude amount) for 3 weeks [99].

It seems contradictory that rhubarb exhibits both toxic and protective effects on the liver and kidneys. Based on the literature, we found that the toxicity of rhubarb in the liver and kidneys was dose and time dependent. Therefore, we speculate that the reason for this contradiction lies in the dose and duration of administration. High-dose and long-term administration are more likely to induce hepatorenal toxicity, whereas low-dose and short-term administration may have protective effects. Additionally, owing to the bidirectional effect of rhubarb, it has been suggested that rhubarb may have hepatorenal protective potential in hyperlipidemia, fatty liver, and chronic renal failure; however, the specific mechanism requires further study.

5 Discussion

Hyperlipidemia is a serious threat to human health, and long-term hyperlipidemia can lead to atherosclerosis, coronary heart disease, peripheral vascular disease, ischemic cerebrovascular disease, pancreatitis, and other chronic diseases. Disorders in lipid metabolism can significantly affect the occurrence and development of metabolic diseases. As a traditional Chinese medicine, rhubarb, with its precise lipid-lowering efficacy, provides a new direction for the treatment of hyperlipidemia. Based on the large body of literature on the pharmacological components of rhubarb, this study summarizes the lipid-lowering molecular mechanisms of some of its chemical components, providing theoretical support for the clinical application of rhubarb in the treatment of hyperlipidemia. However, most studies have focused on chemical mechanism exploration and preclinical studies, and there is a lack of strong clinical data to confirm the therapeutic effects of rhubarb on hyperlipidemia. Although approximately 200 compounds of rhubarb have been identified in phytochemistry, they are mainly emodin, rhubarb acid, rhubarb phenol, and other important chemical constituents that exert a hypolipidemic effect. Therefore, the lipid-lowering effect of rhubarb is closely related to the contents of these important chemical components. Additionally, we found that the toxic effects of rhubarb are influenced by the content of these chemical components. Particularly, the bidirectional nature of its toxic and protective effects suggests the dose–effect and toxicity–effect relationships of rhubarb in the therapeutic process. The synergistic effect of different substances is a promising research trend, for example, whether better efficacy can be obtained by combining the main lipid-lowering components of rhubarb extract with other existing natural or synthetic drugs.

Despite reviewing the hypolipidemic effects of rhubarb in the present study, some limitations remain. First, the hypolipidemic activity of the chemical constituents of rhubarb has been described in several studies. However, cellular and animal model studies of rhubarb in the treatment of hyperlipidemia are limited, and there is a lack of experimental data from large samples. Second, rhubarb can be used as a lipid-lowering drug; however, there is a lack of comparative toxicity data with existing lipid-lowering drugs, and it is not known whether it can replace commonly used clinical hyperlipidemia drugs. Although rhubarb has a better lipid-lowering effect, there are differences in the specific composition of rhubarb from different regions and varieties, and further investigation is needed to determine whether this affects the lipid-lowering effect of rhubarb.

As a potential candidate for the treatment of hyperlipidemia, we still need to address the following questions before using rhubarb for clinical use: (1) The use of rhubarb as a Chinese herbal medicine will inevitably be disturbed by external factors, such as the boiling method, time, and container, and whether this will affect the lipid-lowering activity and solubility of important components, such as rhodopsin and rhubarb acid. (2) To clarify the reasonable dose and administration time of rhubarb for the treatment of hyperlipidemia, its safety should be improved. (3) The low bioextractability of the main lipid-lowering components of rhubarb is also a considerable challenge in improving its preparation process. Additionally, the combination of rhubarb with nanomaterials or novel drug delivery systems can reduce its toxicity and improve its bioavailability.

6 Conclusion

In this article, we present a complete review of the main active components and mechanisms of action of rhubarb in lowering lipid levels. Our results showed that the main components of rhubarb involved in lipid metabolism were anthraquinones and stilbene compounds, including emodin, rhubarb acid, rhubarb phenol, and resveratrol. Its specific mechanisms of action are mainly related to the reduction of lipogenesis, stimulation of lipolysis, and inhibition of gene expression, especially in 3T3-L1 adipocytes, TNF-α inflammatory mediators, PPAR α, C/EBP α, Myd88, and MAPK signaling pathways, as well as the lipid metabolism of enzymes such as ATGL, HSL, MGLL, and other transcription factors. Therefore, the multi-component and multi-target lipid-lowering effects of rhubarb make it a potential natural drug for the treatment of hyperlipidemia.

Abbreviations

APOs

apolipoproteins

CVD

cardiovascular disease

FAO

fatty acid oxidation

GSH

glutathione

HDL-C

high-density lipoprotein cholesterol

HFD

high-fat diet

LDL-C

low-density lipoprotein cholesterol

PPAR

peroxisome proliferator-activated receptor

SE

squalene cyclooxygenase

TC

total cholesterol

TG

triglyceride


# These authors contributed equally.


Acknowledgments

The author would like to thank Xiaoyu Du for his valuable feedback on this article.

  1. Funding information: This study was supported by Chuan Caishe (2022) No. 79, Cultivation of Chinese Medicine Talents – National Medical Master Chen Shaohong Inheritance Studio Project (Project No. 2100601 – Chinese Medicine); National Famous Traditional Chinese Medicine Expert Inheritance Studio Construction Project [(2022) No. 75].

  2. Author contributions: Lijiao Wu and Xiangjin Wang wrote the manuscript and contributed equally to the study as co-first authors. Wei Jin, Bo Peng, and Yong Chen were responsible for revising the manuscript, and Jihang Jiang was responsible for the images and tables. All authors reviewed the manuscript and approved it for publication.

  3. Conflict of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.

  4. Data availability statement: The authors declare that all data supporting the findings of this study are available within the article and its uploaded attached files.

References

[1] Zhou X, Ren F, Wei H, Liu L, Shen T, Xu S, et al. Combination of berberine and evodiamine inhibits intestinal cholesterol absorption in high fat diet induced hyperlipidemic rats. Lipids Health Dis. 2017;16(1):239. 10.1186/s12944-017-0628-x.Search in Google Scholar PubMed PubMed Central

[2] Wang L, Fan W, Zhang M, Zhang Q, Li L, Wang J, et al. Antiobesity, regulation of lipid metabolism, and attenuation of liver oxidative stress effects of hydroxy-α-sanshool isolated from Zanthoxylum bungeanum on high-fat diet-induced hyperlipidemic rats. Oxid Med Cell Longev. 2019;2019:5852494. 10.1155/2019/5852494.Search in Google Scholar PubMed PubMed Central

[3] Toth PP. High-density lipoprotein: epidemiology, metabolism, and antiatherogenic effects. Dis Mon. 2001;47(8):369–416. 10.1067/mda.2001.118859.Search in Google Scholar PubMed

[4] Yang L, Li Z, Song Y, Liu Y, Zhao H, Liu Y, et al. Study on urine metabolic profiling and pathogenesis of hyperlipidemia. Clin Chim Acta. 2019;495:365–73. 10.1016/j.cca.2019.05.001.Search in Google Scholar PubMed

[5] Skulratanasak P, Larpparisuth N. Lipid management to mitigate poorer postkidney transplant outcomes. Curr Opin Nephrol Hypertens. 2023;32(1):27–34. 10.1097/mnh.0000000000000841.Search in Google Scholar PubMed

[6] Yao YS, Li TD, Zeng ZH. Mechanisms underlying direct actions of hyperlipidemia on myocardium: an updated review. Lipids Health Dis. 2020;19(1):23.10.1186/s12944-019-1171-8Search in Google Scholar PubMed PubMed Central

[7] Balakumar P, Babbar L. Preconditioning the hyperlipidemic myocardium: fact or fantasy? Cell Signal. 2012;24(3):589–95.10.1016/j.cellsig.2011.11.003Search in Google Scholar PubMed

[8] Li G, Han R, Lin M, Wen Z, Chen X. Developing a core outcome set for clinical trials of chinese medicine for hyperlipidemia. Front Pharmacol. 2022;13:847101. 10.3389/fphar.2022.847101.Search in Google Scholar PubMed PubMed Central

[9] Mathur M, Kusum Devi V. Potential of novel drug delivery strategies for the treatment of hyperlipidemia. J Drug Target. 2016;24(10):916–26. 10.3109/1061186x.2016.1172586.Search in Google Scholar PubMed

[10] Zhang C, Li J, Wang J, Song X, Zhang J, Wu S, et al. Antihyperlipidaemic and hepatoprotective activities of acidic and enzymatic hydrolysis exopolysaccharides from Pleurotus eryngii SI-04. BMC Complement Altern Med. 2017;17(1):403. 10.1186/s12906-017-1892-z.Search in Google Scholar PubMed PubMed Central

[11] Lee SE, Lim C, Lim S, Lee B, Cho S. Effect of Ephedrae Herba methanol extract on high-fat diet-induced hyperlipidaemic mice. Pharm Biol. 2019;57(1):676–83. 10.1080/13880209.2019.1666883.Search in Google Scholar PubMed PubMed Central

[12] Insull W, Jr. Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review. South Med J. 2006;99(3):257–73. 10.1097/01.smj.0000208120.73327.db.Search in Google Scholar PubMed

[13] Sun JH, Liu X, Cong LX, Li H, Zhang CY, Chen JG, et al. Metabolomics study of the therapeutic mechanism of Schisandra Chinensis lignans in diet-induced hyperlipidemia mice. Lipids Health Dis. 2017;16(1):145. 10.1186/s12944-017-0533-3.Search in Google Scholar PubMed PubMed Central

[14] Zhao MJ, Wang SS, Jiang Y, Wang Y, Shen H, Xu P, et al. Hypolipidemic effect of XH601 on hamsters of hyperlipidemia and its potential mechanism. Lipids Health Dis. 2017;16(1):85. 10.1186/s12944-017-0472-z.Search in Google Scholar PubMed PubMed Central

[15] Frass M, Strassl RP, Friehs H, Müllner M, Kundi M, Kaye AD. Use and acceptance of complementary and alternative medicine among the general population and medical personnel: a systematic review. Ochsner J. 2012;12(1):45–56.Search in Google Scholar

[16] Huo XQ, He YS, Qiao LS, Sun ZY, Zhang YL. [Study on lipid-lowering traditional Chinese medicines based on pharmacophore technology and patent retrieval]. Zhongguo Zhong Yao Za Zhi. 2014;39(24):4839–43.Search in Google Scholar

[17] Payab M, Hasani-Ranjbar S, Shahbal N, Qorbani M, Aletaha A, Haghi-Aminjan H, et al. Effect of the herbal medicines in obesity and metabolic syndrome: a systematic review and meta-analysis of clinical trials. Phytother Res. 2020;34(3):526–45. 10.1002/ptr.6547.Search in Google Scholar PubMed

[18] Liudvytska O, Kolodziejczyk-Czepas J. A review on rhubarb-derived substances as modulators of cardiovascular risk factors – a special emphasis on anti-obesity action. Nutrients. 2022;14(10):2053. 10.3390/nu14102053.Search in Google Scholar PubMed PubMed Central

[19] Chen JQ, Chen YY, Du X, Tao HJ, Pu ZJ, Shi XQ, et al. Fuzzy identification of bioactive components for different efficacies of rhubarb by the back propagation neural network association analysis of UPLC-Q-TOF/MS(E) and integrated effects. Chin Med. 2022;17(1):50. 10.1186/s13020-022-00612-9.Search in Google Scholar PubMed PubMed Central

[20] Cao YJ, Pu ZJ, Tang YP, Shen J, Chen YY, Kang A, et al. Advances in bio-active constituents, pharmacology and clinical applications of rhubarb. Chin Med. 2017;12:36. 10.1186/s13020-017-0158-5.Search in Google Scholar PubMed PubMed Central

[21] Ghorbani A, Amiri MS, Hosseini A. Pharmacological properties of Rheum turkestanicum Janisch. Heliyon. 2019;5(6):e01986. 10.1016/j.heliyon.2019.e01986.Search in Google Scholar PubMed PubMed Central

[22] YYao M, Li J, He M, Ouyang H, Ruan L, Huang X, et al. Investigation and identification of the multiple components of Rheum officinale Baill. using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry and data mining strategy. J Sep Sci. 2021;44(3):681–90. 10.1002/jssc.202000735.Search in Google Scholar PubMed

[23] Gao LL, Guo T, Xu XD, Yang JS. Rapid identification and simultaneous analysis of multiple constituents from Rheum tanguticum Maxim. ex Balf. by UPLC/Q-TOF-MS. Nat Prod Res. 2017;31(13):1529–35. 10.1080/14786419.2017.1280491.Search in Google Scholar PubMed

[24] Verma SC, Singh NP, Sinha AK. Determination and locational variations in the quantity of hydroxyanthraquinones and their glycosides in rhizomes of Rheum emodi using high-performance liquid chromatography. J Chromatogr A. 2005;1097(1–2):59–65. 10.1016/j.chroma.2005.08.018.Search in Google Scholar PubMed

[25] Agarwal SK, Singh SS, Verma S, Kumar S. Antifungal activity of anthraquinone derivatives from Rheum emodi. J Ethnopharmacol. 2000;72(1–2):43–6. 10.1016/s0378-8741(00)00195-1.Search in Google Scholar PubMed

[26] Ye M, Han J, Chen H, Zheng J, Guo D. Analysis of phenolic compounds in rhubarbs using liquid chromatography coupled with electrospray ionization mass spectrometry. J Am Soc Mass Spectrom. 2007;18(1):82–91. 10.1016/j.jasms.2006.08.009.Search in Google Scholar PubMed

[27] Krenn L, Presser A, Pradhan R, Bahr B, Paper DH, Mayer KK, et al. Sulfemodin 8-O-beta-d-glucoside, a new sulfated anthraquinone glycoside, and antioxidant phenolic compounds from Rheum emodi. J Nat Prod. 2003;66(8):1107–9. 10.1021/np0301442.Search in Google Scholar PubMed

[28] Suresh Babu K, Tiwari AK, Srinivas PV, Ali AZ, China Raju B, Rao JM. Yeast and mammalian alpha-glucosidase inhibitory constituents from Himalayan rhubarb Rheum emodi Wall.ex Meisson. Bioorg Med Chem Lett. 2004;14(14):3841–5. 10.1016/j.bmcl.2004.04.062.Search in Google Scholar PubMed

[29] Wang AQ, Lin JL, Li JS. Chemical constituents of Rheum emodi. Chin Traditional Herbal Drugs. 2010;41:343–7.Search in Google Scholar

[30] Singh SS, Pandey SC, Singh RK, Agarwal SK. 1,8-Dihydroxyanthraquinone derivatives from rhizomes of Rheum emodi wall. Indian J Chem Section B-Organic Chemistry Including Medicinal Chemistry. 2005;44(7).Search in Google Scholar

[31] Krenn L, Pradhan R, Presser A, Reznicek G, Kopp B. Anthrone C-glucosides from Rheum emodi. Chem Pharm Bull (Tokyo). 2004;52(4):391–3. 10.1248/cpb.52.391.Search in Google Scholar PubMed

[32] Rokaya MB, Marsik P, Munzbergova Z. Active constituents in Rheum acuminatum and Rheum australe (Polygonaceae) roots: a variation between cultivated and naturally growing plants. Biochem Syst Ecol. 2012;41(none):83–90. 10.1016/j.bse.2011.11.004.Search in Google Scholar

[33] Ngoc TM, Minh PT, Hung TM, Thuong PT, Lee I, Min BS, et al. Lipoxygenase inhibitory constituents from rhubarb. Arch Pharm Res. 2008;31(5):598–605. 10.1007/s12272-001-1199-0.Search in Google Scholar PubMed

[34] Chen T, Yang X, Wang N, Li H, Zhao J, Li Y. Separation of six compounds including two n-butyrophenone isomers and two stibene isomers from Rheum tanguticum Maxim by recycling high speed counter-current chromatography and preparative high-performance liquid chromatography. J Sep Sci. 2018;41(19):3660–8. 10.1002/jssc.201800411.Search in Google Scholar PubMed

[35] Liu B, Yang J, Wang S. The chemical constituents in rhubarb rhizomes and roots derived from Rheum emodi wall. West China J Pharm Sci. 2007;22(1):33.Search in Google Scholar

[36] Chen J, Ma M, Lu Y, Wang L, Wu C, Duan H. Rhaponticin from rhubarb rhizomes alleviates liver steatosis and improves blood glucose and lipid profiles in KK/Ay diabetic mice. Planta Med. 2009;75(5):472–7. 10.1055/s-0029-1185304.Search in Google Scholar PubMed

[37] Zhang R, Kang KA, Piao MJ, Lee KH, Jang HS, Park MJ, et al. Rhapontigenin from Rheum undulatum protects against oxidative-stress-induced cell damage through antioxidant activity. J Toxicol Environ Health A. 2007;70(13):1155–66. 10.1080/15287390701252766.Search in Google Scholar PubMed

[38] Kashiwada Y, Nonaka G, Nishioka I. Tannins and related compounds. XXIII. Rhubarb (4): isolation and structures of new classes of Gallotannins. Chem Pharm Bull. 1984;32(9):3461–70.10.1248/cpb.32.3461Search in Google Scholar

[39] Nonaka G, Nishioka I, Nagasawa T, Oura H. Tannins and related compounds. I. Rhubarb (1). Chem Pharm Bull. 1981;29(10):2862–70.10.1248/cpb.29.2862Search in Google Scholar

[40] Huang Q, Lu G, Shen HM, Chung MC, Ong CN. Anti-cancer properties of anthraquinones from rhubarb. Med Res Rev. 2007;27(5):609–30. 10.1002/med.20094.Search in Google Scholar PubMed

[41] Mishra SK, Tiwari S, Shrivastava A, Srivastava S, Boudh GK, Chourasia SK, et al. Antidyslipidemic effect and antioxidant activity of anthraquinone derivatives from Rheum emodi rhizomes in dyslipidemic rats. J Nat Med. 2014;68(2):363–71. 10.1007/s11418-013-0810-z.Search in Google Scholar PubMed

[42] Dong X, Fu J, Yin X, Cao S, Li X, Lin L, et al. Emodin: a review of its pharmacology, toxicity and pharmacokinetics. Phytother Res. 2016;30(8):1207–18. 10.1002/ptr.5631.Search in Google Scholar PubMed PubMed Central

[43] Yang Y, Shang W, Zhou L, Jiang B, Jin H, Chen M. Emodin with PPAR gamma ligand-binding activity promotes adipocyte differentiation and increases glucose uptake in 3T3-Ll cells. Biochem Biophys Res Commun. 2007;353(2):225–30. 10.1016/j.bbrc.2006.11.134.Search in Google Scholar PubMed

[44] Fu X, Xu AG, Yao MY, Guo L, Zhao LS. Emodin enhances cholesterol efflux by activating peroxisome proliferator-activated receptor-γ in oxidized low density lipoprotein-loaded THP1 macrophages. Clin Exp Pharmacol Physiol. 2014;41(9):679–84. 10.1111/1440-1681.12262.Search in Google Scholar PubMed

[45] Zhou M, Xu H, Pan L, Wen J, Guo Y, Chen K. Emodin promotes atherosclerotic plaque stability in fat-fed apolipoprotein E-deficient mice. Tohoku J Exp Med. 2008;215(1):61–9. 10.1620/tjem.215.61.Search in Google Scholar PubMed

[46] Li J, Ding L, Song B, Xiao X, Qi M, Yang Q, et al. Emodin improves lipid and glucose metabolism in high fat diet-induced obese mice through regulating SREBP pathway. Eur J Pharmacol. 2016;770:99–109. 10.1016/j.ejphar.2015.11.045.Search in Google Scholar PubMed

[47] Xue J, Ding W, Liu Y. Anti-diabetic effects of emodin involved in the activation of PPARgamma on high-fat diet-fed and low dose of streptozotocin-induced diabetic mice. Fitoterapia. 2010;81(3):173–7. 10.1016/j.fitote.2009.08.020.Search in Google Scholar PubMed

[48] Zhang X, Zhang R, Lv P, Yang J, Deng Y, Xu J, et al. Emodin up-regulates glucose metabolism, decreases lipolysis, and attenuates inflammation in vitro. J Diabetes. 2015;7(3):360–8. 10.1111/1753-0407.12190.Search in Google Scholar PubMed

[49] Murashita K, Yoshiura Y, Chisada S, Furuita H, Sugita T, Matsunari H, et al. Postprandial response and tissue distribution of the bile acid synthesis-related genes, cyp7a1, cyp8b1 and shp, in rainbow trout Oncorhynchus mykiss. Comp Biochem Physiol A Mol Integr Physiol. 2013;166(2):361–9. 10.1016/j.cbpa.2013.07.015.Search in Google Scholar PubMed

[50] Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000;290(5497):1771–5. 10.1126/science.290.5497.1771.Search in Google Scholar PubMed

[51] Wang J, Ji J, Song Z, Zhang W, He X, Li F, et al. Hypocholesterolemic effect of emodin by simultaneous determination of in vitro and in vivo bile salts binding. Fitoterapia. 2016;110:116–22. 10.1016/j.fitote.2016.03.007.Search in Google Scholar PubMed

[52] Semwal RB, Semwal DK, Combrinck S, Viljoen A. Emodin – a natural anthraquinone derivative with diverse pharmacological activities. Phytochemistry. 2021;190:112854. 10.1016/j.phytochem.2021.112854.Search in Google Scholar PubMed

[53] Meng J, Xu J, Yang S, Liu W, Zeng J, Shi L, et al. Emodin lows NPC1L1-mediated cholesterol absorption as an uncompetitive inhibitor. Bioorg Med Chem Lett. 2022;75:128974. 10.1016/j.bmcl.2022.128974.Search in Google Scholar PubMed

[54] Wu C, Cao H, Zhou H, Sun L, Xue J, Li J, et al. Research progress on the antitumor effects of Rhein: literature review. Anticancer Agents Med Chem. 2017;17(12):1624–32. 10.2174/1871520615666150930112631.Search in Google Scholar PubMed

[55] Gao Q, Qin WS, Jia ZH, Zheng JM, Zeng CH, Li LS, et al. Rhein improves renal lesion and ameliorates dyslipidemia in db/db mice with diabetic nephropathy. Planta Med. 2010;76(1):27–33. 10.1055/s-0029-1185948.Search in Google Scholar PubMed

[56] Zhang Y, Fan S, Hu N, Gu M, Chu C, Li Y, et al. Rhein reduces fat weight in db/db mouse and prevents diet-induced obesity in C57Bl/6 mouse through the inhibition of PPARγ signaling. PPAR Res. 2012;2012:374936. 10.1155/2012/374936.Search in Google Scholar PubMed PubMed Central

[57] Fang JY, Huang TH, Chen WJ, Aljuffali IA, Hsu CY. Rhubarb hydroxyanthraquinones act as antiobesity agents to inhibit adipogenesis and enhance lipolysis. Biomed Pharmacother. 2022;146:112497. 10.1016/j.biopha.2021.112497.Search in Google Scholar PubMed

[58] Saponaro C, Gaggini M, Carli F, Gastaldelli A. The subtle balance between lipolysis and lipogenesis: a critical point in metabolic homeostasis. Nutrients. 2015;7(11):9453–74. 10.3390/nu7115475.Search in Google Scholar PubMed PubMed Central

[59] Nielsen TS, Jessen N, Jørgensen JO, Møller N, Lund S. Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease. J Mol Endocrinol. 2014;52(3):R199–222. 10.1530/jme-13-0277.Search in Google Scholar PubMed

[60] Yamamoto M, Nagasawa Y, Fujimori K. Glycyrrhizic acid suppresses early stage of adipogenesis through repression of MEK/ERK-mediated C/EBPβ and C/EBPδ expression in 3T3-L1 cells. Chem Biol Interact. 2021;346:109595. 10.1016/j.cbi.2021.109595.Search in Google Scholar PubMed

[61] Chang WC, Chu MT, Hsu CY, Wu YJ, Lee JY, Chen TJ, et al. Rhein, an anthraquinone drug, suppresses the NLRP3 inflammasome and macrophage activation in urate crystal-induced gouty inflammation. Am J Chin Med. 2019;47(1):135–51. 10.1142/s0192415x19500071.Search in Google Scholar PubMed

[62] Sun H, Luo G, Chen D, Xiang Z. A comprehensive and system review for the pharmacological mechanism of action of rhein, an active anthraquinone ingredient. Front Pharmacol. 2016;7:247. 10.3389/fphar.2016.00247.Search in Google Scholar PubMed PubMed Central

[63] Sheng X, Zhu X, Zhang Y, Cui G, Peng L, Lu X, et al. Rhein protects against obesity and related metabolic disorders through liver X receptor-mediated uncoupling protein 1 upregulation in brown adipose tissue. Int J Biol Sci. 2012;8(10):1375–84. 10.7150/ijbs.4575.Search in Google Scholar PubMed PubMed Central

[64] Qian ZJ, Zhang C, Li YX, Je JY, Kim SK, Jung WK. Protective effects of emodin and chrysophanol isolated from marine fungus Aspergillus sp. on ethanol-induced toxicity in HepG2/CYP2E1 Cells. Evid Based Complement Altern Med. 2011;2011:452621. 10.1155/2011/452621.Search in Google Scholar PubMed PubMed Central

[65] Chen K, Wang CQ, Fan YQ, Han ZH, Zeng HS. Lipid-lowering effect of seven traditional Chinese medicine monomers in zebrafish system. Acta Physiol Sin. 2017;69(1):55.10.1016/B978-0-12-811147-5.00001-7Search in Google Scholar

[66] Zhang J, Kang H, Wang L, Zhao X. Chrysophanol ameliorates high-fat diet-induced obesity and inflammation in neonatal rats. Pharmazie. 2018;73(4):228–33. 10.1691/ph.2018.7980.Search in Google Scholar PubMed

[67] Kwon HC, Kim TY, Lee CM, Lee KS, Lee KK. Active compound chrysophanol of Cassia tora seeds suppresses heat-induced lipogenesis via inactivation of JNK/p38 MAPK signaling in human sebocytes. Lipids Health Dis. 2019;18(1):135. 10.1186/s12944-019-1072-x.Search in Google Scholar PubMed PubMed Central

[68] Feldman JL, Baeza J, Denu JM. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J Biol Chem. 2013;288(43):31350–6. 10.1074/jbc.C113.511261.Search in Google Scholar PubMed PubMed Central

[69] Liu X, Yang Z, Li H, Luo W, Duan W, Zhang J, et al. Chrysophanol alleviates metabolic syndrome by activating the SIRT6/AMPK signaling pathway in brown adipocytes. Oxid Med Cell Longev. 2020;2020:7374086. 10.1155/2020/7374086.Search in Google Scholar PubMed PubMed Central

[70] Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007;8(10):774–85. 10.1038/nrm2249.Search in Google Scholar PubMed

[71] Li JM, Ding LL, Song BL, Yang L, Wang ZT. [Effects of chrysophanol on expression of SREBPs and lipid metabolism in Huh-7 cells]. Yao Xue Xue Bao. 2015;50(2):174–9.Search in Google Scholar

[72] Choi RJ, Chun J, Khan S, Kim YS. Desoxyrhapontigenin, a potent anti-inflammatory phytochemical, inhibits LPS-induced inflammatory responses via suppressing NF-κB and MAPK pathways in RAW 264.7 cells. Int Immunopharmacol. 2014;18(1):182–90. 10.1016/j.intimp.2013.11.022.Search in Google Scholar PubMed

[73] Ahn J, Cho I, Kim S, Kwon D, Ha T. Dietary resveratrol alters lipid metabolism-related gene expression of mice on an atherogenic diet. J Hepatol. 2008;49(6):1019–28. 10.1016/j.jhep.2008.08.012.Search in Google Scholar PubMed

[74] Zhang C, Luo J, Yu B, Chen J, Chen D. Effects of resveratrol on lipid metabolism in muscle and adipose tissues: a reevaluation in a pig model. J Funct Food. 2015;14:590–5.10.1016/j.jff.2015.02.039Search in Google Scholar

[75] Voloshyna I, Hussaini SM, Reiss AB. Resveratrol in cholesterol metabolism and atherosclerosis. J Med Food. 2012;15(9):763–73. 10.1089/jmf.2012.0025.Search in Google Scholar PubMed

[76] Berman AY, Motechin RA, Wiesenfeld MY, Holz MK. The therapeutic potential of resveratrol: a review of clinical trials. NPJ Precis Oncol. 2017;1:35. 10.1038/s41698-017-0038-6.Search in Google Scholar PubMed PubMed Central

[77] Sahebkar A. Effects of resveratrol supplementation on plasma lipids: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2013;71(12):822–35. 10.1111/nure.12081.Search in Google Scholar PubMed

[78] Yuan W, Zhang M, Wang C, Li B, Li L, Ye F, et al. Resveratrol attenuates high-fat diet-induced hepatic lipotoxicity by upregulating Bmi-1 expression. J Pharmacol Exp Ther. 2022;381(2):96–105. 10.1124/jpet.121.001018.Search in Google Scholar PubMed

[79] Sebai H, Ristorcelli E, Sbarra V, Hovsepian S, Fayet G, Aouani E, et al. Protective effect of resveratrol against LPS-induced extracellular lipoperoxidation in AR42J cells partly via a Myd88-dependent signaling pathway. Arch Biochem Biophys. 2010;495(1):56–61. 10.1016/j.abb.2009.12.019.Search in Google Scholar PubMed

[80] Zhao H, Song A, Zhang Y, Shu L, Song G, Ma H. Effect of resveratrol on blood lipid levels in patients with type 2 diabetes: a systematic review and meta-analysis. Obesity (Silver Spring). 2019;27(1):94–102. 10.1002/oby.22348.Search in Google Scholar PubMed

[81] Zhang T, He Q, Liu Y, Chen Z, Hu H. Efficacy and safety of resveratrol supplements on blood lipid and blood glucose control in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Evid Based Complement Altern Med. 2021;2021:5644171. 10.1155/2021/5644171.Search in Google Scholar PubMed PubMed Central

[82] Vanaja K, Wahl MA, Bukarica L, Heinle H. Liposomes as carriers of the lipid soluble antioxidant resveratrol: evaluation of amelioration of oxidative stress by additional antioxidant vitamin. Life Sci. 2013;93(24):917–23. 10.1016/j.lfs.2013.10.019.Search in Google Scholar PubMed

[83] Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006;5(6):493–506. 10.1038/nrd2060.Search in Google Scholar PubMed

[84] Wang Y, Zhang J, Xu Z, Zhang G, Lv H, Wang X, et al. Identification and action mechanism of lipid regulating components from Rhei Radix et rhizoma. J Ethnopharmacol. 2022;292:115179. 10.1016/j.jep.2022.115179.Search in Google Scholar PubMed

[85] Jo SP, Kim JK, Lim YH. Antihyperlipidemic effects of rhapontin and rhapontigenin from Rheum undulatum in rats fed a high-cholesterol diet. Planta Med. 2014;80(13):1067–71. 10.1055/s-0034-1382999.Search in Google Scholar PubMed

[86] Cheema SK, Goel V, Basu TK, Agellon LB. Dietary rhubarb (Rheum rhaponticum) stalk fibre does not lower plasma cholesterol levels in diabetic rats. Br J Nutr. 2003;89(2):201–6. 10.1079/bjn2002768.Search in Google Scholar PubMed

[87] Abe I. 2.10–Squalene epoxidase and oxidosqualene: lanosterol cyclase—key enzymes in cholesterol biosynthesis. Compr Nat Prod Chem. 1999;2:267–98.10.1016/B978-0-08-091283-7.00045-XSearch in Google Scholar

[88] Abe I, Seki T, Noguchi H, Kashiwada Y. Galloyl esters from rhubarb are potent inhibitors of squalene epoxidase, a key enzyme in cholesterol biosynthesis. Planta Med. 2000;66(8):753–6. 10.1055/s-2000-9781.Search in Google Scholar PubMed

[89] Guo P, Zhang TJ, Zhu XY, He YZ. Study on toxicity of Radix et Rhizoma Rhei and countermeasure for its attenuation. Chin Tradit Herb Drugs. 2009;40(10):1671–4.Search in Google Scholar

[90] Lin L, Liu Y, Fu S, Qu C, Li H, Ni J. Inhibition of mitochondrial complex function – the hepatotoxicity mechanism of emodin based on quantitative proteomic analyses. Cells. 2019;8(3):263. 10.3390/cells8030263.Search in Google Scholar PubMed PubMed Central

[91] Ding Y, Xu F, Xiong XL, Li HR. [Effect of emodin on expression of farnesoid X receptor in rats with acute cholestatic hepatitis]. Zhongguo dang dai er ke za zhi = Chin J Contemp Pediatr. 2014;16(4):424–9.Search in Google Scholar

[92] Zhuang T, Gu X, Zhou N, Ding L, Yang L, Zhou M. Hepatoprotection and hepatotoxicity of Chinese herb Rhubarb (Dahuang): how to properly control the “General (Jiang Jun)” in Chinese medical herb. Biomed Pharmacother. 2020;127:110224. 10.1016/j.biopha.2020.110224.Search in Google Scholar PubMed

[93] Dong X, Fu J, Yin X, Cao S, Li X, Lin L, et al. Emodin: A review of the pharmacology, toxicity and pharmacokinetics of rhodopsin. phytother Resphytother Res 2016;30(8):1207–18.10.1002/ptr.5631Search in Google Scholar PubMed PubMed Central

[94] Li CL, Ma J, Zheng L, Li HJ, Li P. Determination of emodin in L-02 cells and cell culture media with liquid chromatography-mass spectrometry: application to a cellular toxicokinetic study. J Pharm Biomed Anal. 2012;71:71–8. 10.1016/j.jpba.2012.07.031.Search in Google Scholar PubMed

[95] Liu XY, Liu YQ, Qu Y, Cheng MC, Xiao HB. Metabolomic profiling of emodin-induced cytotoxicity in human liver cells and mechanistic study. Toxicol Res. 2015;4:948–55.10.1039/C4TX00246FSearch in Google Scholar

[96] Wang YH, Zhao HP, Wang JB, Zhao YL, Xiao XH. [Study on dosage–toxicity/efficacy relationship of prepared rhubarb on basis of symptom-based prescription theory]. Zhongguo Zhong Yao Za Zhi. 2014;39(15):2918–23.Search in Google Scholar

[97] Yan M, Zhang LY, Sun LX, Jiang ZZ, Xiao XH. Nephrotoxicity study of total rhubarb anthraquinones on Sprague Dawley rats using DNA microarrays. J Ethnopharmacol. 2006;107(2):308–11. 10.1016/j.jep.2006.03.031.Search in Google Scholar PubMed

[98] Li Z, Qing P, Ji L, Su BH, Fan JM. Systematic review of rhubarb for chronic renal failure. Chin J Evid-Based Med. 2004;4:468–73.Search in Google Scholar

[99] Wang J, Zhao Y, Xiao X, Li H, Zhao H, Zhang P, et al. Assessment of the renal protection and hepatotoxicity of rhubarb extract in rats. J Ethnopharmacol. 2009;124(1):18–25. 10.1016/j.jep.2009.04.018.Search in Google Scholar PubMed

Received: 2023-04-19
Revised: 2023-09-11
Accepted: 2023-09-11
Published Online: 2023-10-03

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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