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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
Published/Copyright: October 3, 2023
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Open Medicine
From the journal Open Medicine Volume 18 Issue 1

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.

Keywords: rhubarb; lipid metabolism; Chinese herbal medicine; hyperlipidemia; mechanism; lipid lowering

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 [43–45]. 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.

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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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  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
  32. Effects of osteogenic growth peptide C-terminal pentapeptide and its analogue on bone remodeling in an osteoporosis rat model
  33. A novel autophagy-related long non-coding RNAs signature predicting progression-free interval and I-131 therapy benefits in papillary thyroid carcinoma
  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
https://doi.org/10.1515/med-2023-0812
Keywords for this article
rhubarb; lipid metabolism; Chinese herbal medicine; hyperlipidemia; mechanism; lipid lowering
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. Exosomes derived from mesenchymal stem cells overexpressing miR-210 inhibits neuronal inflammation and contribute to neurite outgrowth through modulating microglia polarization
  3. Current situation of acute ST-segment elevation myocardial infarction in a county hospital chest pain center during an epidemic of novel coronavirus pneumonia
  4. circ-IARS depletion inhibits the progression of non-small-cell lung cancer by circ-IARS/miR-1252-5p/HDGF ceRNA pathway
  5. circRNA ITGA7 restrains growth and enhances radiosensitivity by up-regulating SMAD4 in colorectal carcinoma
  6. WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4
  7. Up-regulation of collagen type V alpha 2 (COL5A2) promotes malignant phenotypes in gastric cancer cell via inducing epithelial–mesenchymal transition (EMT)
  8. Inhibition of TERC inhibits neural apoptosis and inflammation in spinal cord injury through Akt activation and p-38 inhibition via the miR-34a-5p/XBP-1 axis
  9. 3D-printed polyether-ether-ketone/n-TiO2 composite enhances the cytocompatibility and osteogenic differentiation of MC3T3-E1 cells by downregulating miR-154-5p
  10. Propofol-mediated circ_0000735 downregulation restrains tumor growth by decreasing integrin-β1 expression in non-small cell lung cancer
  11. PVT1/miR-16/CCND1 axis regulates gastric cancer progression
  12. Silencing of circ_002136 sensitizes gastric cancer to paclitaxel by targeting the miR-16-5p/HMGA1 axis
  13. Short-term outcomes after simultaneous gastrectomy plus cholecystectomy in gastric cancer: A pooling up analysis
  14. SCARA5 inhibits oral squamous cell carcinoma via inactivating the STAT3 and PI3K/AKT signaling pathways
  15. Molecular mechanism by which the Notch signaling pathway regulates autophagy in a rat model of pulmonary fibrosis in pigeon breeder’s lung
  16. lncRNA TPT1-AS1 promotes cell migration and invasion in esophageal squamous-cell carcinomas by regulating the miR-26a/HMGA1 axis
  17. SIRT1/APE1 promotes the viability of gastric cancer cells by inhibiting p53 to suppress ferroptosis
  18. Glycoprotein non-metastatic melanoma B interacts with epidermal growth factor receptor to regulate neural stem cell survival and differentiation
  19. Treatments for brain metastases from EGFR/ALK-negative/unselected NSCLC: A network meta-analysis
  20. Association of osteoporosis and skeletal muscle loss with serum type I collagen carboxyl-terminal peptide β glypeptide: A cross-sectional study in elder Chinese population
  21. circ_0000376 knockdown suppresses non-small cell lung cancer cell tumor properties by the miR-545-3p/PDPK1 pathway
  22. Delivery in a vertical birth chair supported by freedom of movement during labor: A randomized control trial
  23. UBE2J1 knockdown promotes cell apoptosis in endometrial cancer via regulating PI3K/AKT and MDM2/p53 signaling
  24. Metabolic resuscitation therapy in critically ill patients with sepsis and septic shock: A pilot prospective randomized controlled trial
  25. Lycopene ameliorates locomotor activity and urinary frequency induced by pelvic venous congestion in rats
  26. UHRF1-induced connexin26 methylation is involved in hearing damage triggered by intermittent hypoxia in neonatal rats
  27. LINC00511 promotes melanoma progression by targeting miR-610/NUCB2
  28. Ultra-high-performance liquid chromatography-tandem mass spectrometry analysis of serum metabolomic characteristics in people with different vitamin D levels
  29. Role of Jumonji domain-containing protein D3 and its inhibitor GSK-J4 in Hashimoto’s thyroiditis
  30. circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia
  31. Monitoring of sirolimus in the whole blood samples from pediatric patients with lymphatic anomalies
  32. Effects of osteogenic growth peptide C-terminal pentapeptide and its analogue on bone remodeling in an osteoporosis rat model
  33. A novel autophagy-related long non-coding RNAs signature predicting progression-free interval and I-131 therapy benefits in papillary thyroid carcinoma
  34. WGCNA-based identification of potential targets and pathways in response to treatment in locally advanced breast cancer patients
  35. Radiomics model using preoperative computed tomography angiography images to differentiate new from old emboli of acute lower limb arterial embolism
  36. Dysregulated lncRNAs are involved in the progress of myocardial infarction by constructing regulatory networks
  37. Single-arm trial to evaluate the efficacy and safety of baclofen in treatment of intractable hiccup caused by malignant tumor chemotherapy
  38. Genetic polymorphisms of MRPS30-DT and NINJ2 may influence lung cancer risk
  39. Efficacy of immune checkpoint inhibitors in patients with KRAS-mutant advanced non-small cell lung cancer: A retrospective analysis
  40. Pyroptosis-based risk score predicts prognosis and drug sensitivity in lung adenocarcinoma
  41. Upregulation of lncRNA LANCL1-AS1 inhibits the progression of non-small-cell lung cancer via the miR-3680-3p/GMFG axis
  42. CircRANBP17 modulated KDM1A to regulate neuroblastoma progression by sponging miR-27b-3p
  43. Exosomal miR-93-5p regulated the progression of osteoarthritis by targeting ADAMTS9
  44. Downregulation of RBM17 enhances cisplatin sensitivity and inhibits cell invasion in human hypopharyngeal cancer cells
  45. HDAC5-mediated PRAME regulates the proliferation, migration, invasion, and EMT of laryngeal squamous cell carcinoma via the PI3K/AKT/mTOR signaling pathway
  46. The association between sleep duration, quality, and nonalcoholic fatty liver disease: A cross-sectional study
  47. Myostatin silencing inhibits podocyte apoptosis in membranous nephropathy through Smad3/PKA/NOX4 signaling pathway
  48. A novel long noncoding RNA AC125257.1 facilitates colorectal cancer progression by targeting miR-133a-3p/CASC5 axis
  49. Impact of omicron wave and associated control measures in Shanghai on health management and psychosocial well-being of patients with chronic conditions
  50. Clinicopathological characteristics and prognosis of young patients aged ≤45 years old with non-small cell lung cancer
  51. TMT-based comprehensive proteomic profiling identifies serum prognostic signatures of acute myeloid leukemia
  52. The dose limits of teeth protection for patients with nasopharyngeal carcinoma undergoing radiotherapy based on the early oral health-related quality of life
  53. miR-30b-5p targeting GRIN2A inhibits hippocampal damage in epilepsy
  54. Long non-coding RNA AL137789.1 promoted malignant biological behaviors and immune escape of pancreatic carcinoma cells
  55. IRF6 and FGF1 polymorphisms in non-syndromic cleft lip with or without cleft palate in the Polish population
  56. Comprehensive analysis of the role of SFXN family in breast cancer
  57. Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy
  58. Silencing of long noncoding RNA MIAT inhibits the viability and proliferation of breast cancer cells by promoting miR-378a-5p expression
  59. AG1024, an IGF-1 receptor inhibitor, ameliorates renal injury in rats with diabetic nephropathy via the SOCS/JAK2/STAT pathway
  60. Downregulation of KIAA1199 alleviated the activation, proliferation, and migration of hepatic stellate cells by the inhibition of epithelial–mesenchymal transition
  61. Exendin-4 regulates the MAPK and WNT signaling pathways to alleviate the osteogenic inhibition of periodontal ligament stem cells in a high glucose environment
  62. Inhibition of glycolysis represses the growth and alleviates the endoplasmic reticulum stress of breast cancer cells by regulating TMTC3
  63. The function of lncRNA EMX2OS/miR-653-5p and its regulatory mechanism in lung adenocarcinoma
  64. Tectorigenin alleviates the apoptosis and inflammation in spinal cord injury cell model through inhibiting insulin-like growth factor-binding protein 6
  65. Ultrasound examination supporting CT or MRI in the evaluation of cervical lymphadenopathy in patients with irradiation-treated head and neck cancer
  66. F-box and WD repeat domain containing 7 inhibits the activation of hepatic stellate cells by degrading delta-like ligand 1 to block Notch signaling pathway
  67. Knockdown of circ_0005615 enhances the radiosensitivity of colorectal cancer by regulating the miR-665/NOTCH1 axis
  68. Long noncoding RNA Mhrt alleviates angiotensin II-induced cardiac hypertrophy phenotypes by mediating the miR-765/Wnt family member 7B pathway
  69. Effect of miR-499-5p/SOX6 axis on atrial fibrosis in rats with atrial fibrillation
  70. Cholesterol induces inflammation and reduces glucose utilization
  71. circ_0004904 regulates the trophoblast cell in preeclampsia via miR-19b-3p/ARRDC3 axis
  72. NECAB3 promotes the migration and invasion of liver cancer cells through HIF-1α/RIT1 signaling pathway
  73. The poor performance of cardiovascular risk scores in identifying patients with idiopathic inflammatory myopathies at high cardiovascular risk
  74. miR-2053 inhibits the growth of ovarian cancer cells by downregulating SOX4
  75. Nucleophosmin 1 associating with engulfment and cell motility protein 1 regulates hepatocellular carcinoma cell chemotaxis and metastasis
  76. α-Hederin regulates macrophage polarization to relieve sepsis-induced lung and liver injuries in mice
  77. Changes of microbiota level in urinary tract infections: A meta-analysis
  78. Identification of key enzalutamide-resistance-related genes in castration-resistant prostate cancer and verification of RAD51 functions
  79. Falls during oxaliplatin-based chemotherapy for gastrointestinal malignancies – (lessons learned from) a prospective study
  80. Outcomes of low-risk birth care during the Covid-19 pandemic: A cohort study from a tertiary care center in Lithuania
  81. Vitamin D protects intestines from liver cirrhosis-induced inflammation and oxidative stress by inhibiting the TLR4/MyD88/NF-κB signaling pathway
  82. Integrated transcriptome analysis identifies APPL1/RPS6KB2/GALK1 as immune-related metastasis factors in breast cancer
  83. Genomic analysis of immunogenic cell death-related subtypes for predicting prognosis and immunotherapy outcomes in glioblastoma multiforme
  84. Circular RNA Circ_0038467 promotes the maturation of miRNA-203 to increase lipopolysaccharide-induced apoptosis of chondrocytes
  85. An economic evaluation of fine-needle cytology as the primary diagnostic tool in the diagnosis of lymphadenopathy
  86. Midazolam impedes lung carcinoma cell proliferation and migration via EGFR/MEK/ERK signaling pathway
  87. Network pharmacology combined with molecular docking and experimental validation to reveal the pharmacological mechanism of naringin against renal fibrosis
  88. PTPN12 down-regulated by miR-146b-3p gene affects the malignant progression of laryngeal squamous cell carcinoma
  89. miR-141-3p accelerates ovarian cancer progression and promotes M2-like macrophage polarization by targeting the Keap1-Nrf2 pathway
  90. lncRNA OIP5-AS1 attenuates the osteoarthritis progression in IL-1β-stimulated chondrocytes
  91. Overexpression of LINC00607 inhibits cell growth and aggressiveness by regulating the miR-1289/EFNA5 axis in non-small-cell lung cancer
  92. Subjective well-being in informal caregivers during the COVID-19 pandemic
  93. Nrf2 protects against myocardial ischemia-reperfusion injury in diabetic rats by inhibiting Drp1-mediated mitochondrial fission
  94. Unfolded protein response inhibits KAT2B/MLKL-mediated necroptosis of hepatocytes by promoting BMI1 level to ubiquitinate KAT2B
  95. Bladder cancer screening: The new selection and prediction model
  96. circNFATC3 facilitated the progression of oral squamous cell carcinoma via the miR-520h/LDHA axis
  97. Prone position effect in intensive care patients with SARS-COV-2 pneumonia
  98. Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children
  99. Dihydroartemisinin ameliorates cerebral I/R injury in rats via regulating VWF and autophagy-mediated SIRT1/FOXO1 pathway
  100. Knockdown of circ_0113656 assuages oxidized low-density lipoprotein-induced vascular smooth muscle cell injury through the miR-188-3p/IGF2 pathway
  101. Low Ang-(1–7) and high des-Arg9 bradykinin serum levels are correlated with cardiovascular risk factors in patients with COVID-19
  102. Effect of maternal age and body mass index on induction of labor with oral misoprostol for premature rupture of membrane at term: A retrospective cross-sectional study
  103. Potential protective effects of Huanglian Jiedu Decoction against COVID-19-associated acute kidney injury: A network-based pharmacological and molecular docking study
  104. Clinical significance of serum MBD3 detection in girls with central precocious puberty
  105. Clinical features of varicella-zoster virus caused neurological diseases detected by metagenomic next-generation sequencing
  106. Collagen treatment of complex anorectal fistula: 3 years follow-up
  107. LncRNA CASC15 inhibition relieves renal fibrosis in diabetic nephropathy through down-regulating SP-A by sponging to miR-424
  108. Efficacy analysis of empirical bismuth quadruple therapy, high-dose dual therapy, and resistance gene-based triple therapy as a first-line Helicobacter pylori eradication regimen – An open-label, randomized trial
  109. SMOC2 plays a role in heart failure via regulating TGF-β1/Smad3 pathway-mediated autophagy
  110. A prospective cohort study of the impact of chronic disease on fall injuries in middle-aged and older adults
  111. circRNA THBS1 silencing inhibits the malignant biological behavior of cervical cancer cells via the regulation of miR-543/HMGB2 axis
  112. hsa_circ_0000285 sponging miR-582-3p promotes neuroblastoma progression by regulating the Wnt/β-catenin signaling pathway
  113. Long non-coding RNA GNAS-AS1 knockdown inhibits proliferation and epithelial–mesenchymal transition of lung adenocarcinoma cells via the microRNA-433-3p/Rab3A axis
  114. lncRNA UCA1 regulates miR-132/Lrrfip1 axis to promote vascular smooth muscle cell proliferation
  115. Twenty-four-color full spectrum flow cytometry panel for minimal residual disease detection in acute myeloid leukemia
  116. Hsa-miR-223-3p participates in the process of anthracycline-induced cardiomyocyte damage by regulating NFIA gene
  117. Anti-inflammatory effect of ApoE23 on Salmonella typhimurium-induced sepsis in mice
  118. Analysis of somatic mutations and key driving factors of cervical cancer progression
  119. Hsa_circ_0028007 regulates the progression of nasopharyngeal carcinoma through the miR-1179/SQLE axis
  120. Variations in sexual function after laparoendoscopic single-site hysterectomy in women with benign gynecologic diseases
  121. Effects of pharmacological delay with roxadustat on multi-territory perforator flap survival in rats
  122. Analysis of heroin effects on calcium channels in rat cardiomyocytes based on transcriptomics and metabolomics
  123. Risk factors of recurrent bacterial vaginosis among women of reproductive age: A cross-sectional study
  124. Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells
  125. Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients
  126. Correlation between microvessel maturity and ISUP grades assessed using contrast-enhanced transrectal ultrasonography in prostate cancer
  127. The protective effect of caffeic acid phenethyl ester in the nephrotoxicity induced by α-cypermethrin
  128. Norepinephrine alleviates cyclosporin A-induced nephrotoxicity by enhancing the expression of SFRP1
  129. Effect of RUNX1/FOXP3 axis on apoptosis of T and B lymphocytes and immunosuppression in sepsis
  130. The function of Foxp1 represses β-adrenergic receptor transcription in the occurrence and development of bladder cancer through STAT3 activity
  131. Risk model and validation of carbapenem-resistant Klebsiella pneumoniae infection in patients with cerebrovascular disease in the ICU
  132. Calycosin protects against chronic prostatitis in rats via inhibition of the p38MAPK/NF-κB pathway
  133. Pan-cancer analysis of the PDE4DIP gene with potential prognostic and immunotherapeutic values in multiple cancers including acute myeloid leukemia
  134. The safety and immunogenicity to inactivated COVID-19 vaccine in patients with hyperlipemia
  135. Circ-UBR4 regulates the proliferation, migration, inflammation, and apoptosis in ox-LDL-induced vascular smooth muscle cells via miR-515-5p/IGF2 axis
  136. Clinical characteristics of current COVID-19 rehabilitation outpatients in China
  137. Luteolin alleviates ulcerative colitis in rats via regulating immune response, oxidative stress, and metabolic profiling
  138. miR-199a-5p inhibits aortic valve calcification by targeting ATF6 and GRP78 in valve interstitial cells
  139. The application of iliac fascia space block combined with esketamine intravenous general anesthesia in PFNA surgery of the elderly: A prospective, single-center, controlled trial
  140. Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction
  141. The effects of progesterone on the healing of obstetric anal sphincter damage in female rats
  142. Identification of cuproptosis-related genes for predicting the development of prostate cancer
  143. Lumican silencing ameliorates β-glycerophosphate-mediated vascular smooth muscle cell calcification by attenuating the inhibition of APOB on KIF2C activity
  144. Targeting PTBP1 blocks glutamine metabolism to improve the cisplatin sensitivity of hepatocarcinoma cells through modulating the mRNA stability of glutaminase
  145. A single center prospective study: Influences of different hip flexion angles on the measurement of lumbar spine bone mineral density by dual energy X-ray absorptiometry
  146. Clinical analysis of AN69ST membrane continuous venous hemofiltration in the treatment of severe sepsis
  147. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis
  148. Construction of a ceRNA network to reveal a vascular invasion associated prognostic model in hepatocellular carcinoma
  149. A pan-cancer analysis of STAT3 expression and genetic alterations in human tumors
  150. A prognostic signature based on seven T-cell-related cell clustering genes in bladder urothelial carcinoma
  151. Pepsin concentration in oral lavage fluid of rabbit reflux model constructed by dilating the lower esophageal sphincter
  152. The antihypertensive felodipine shows synergistic activity with immune checkpoint blockade and inhibits tumor growth via NFAT1 in LUSC
  153. Tanshinone IIA attenuates valvular interstitial cells’ calcification induced by oxidized low density lipoprotein via reducing endoplasmic reticulum stress
  154. AS-IV enhances the antitumor effects of propofol in NSCLC cells by inhibiting autophagy
  155. Establishment of two oxaliplatin-resistant gallbladder cancer cell lines and comprehensive analysis of dysregulated genes
  156. Trial protocol: Feasibility of neuromodulation with connectivity-guided intermittent theta-burst stimulation for improving cognition in multiple sclerosis
  157. LncRNA LINC00592 mediates the promoter methylation of WIF1 to promote the development of bladder cancer
  158. Factors associated with gastrointestinal dysmotility in critically ill patients
  159. Mechanisms by which spinal cord stimulation intervenes in atrial fibrillation: The involvement of the endothelin-1 and nerve growth factor/p75NTR pathways
  160. Analysis of two-gene signatures and related drugs in small-cell lung cancer by bioinformatics
  161. Silencing USP19 alleviates cigarette smoke extract-induced mitochondrial dysfunction in BEAS-2B cells by targeting FUNDC1
  162. Menstrual irregularities associated with COVID-19 vaccines among women in Saudi Arabia: A survey during 2022
  163. Ferroptosis involves in Schwann cell death in diabetic peripheral neuropathy
  164. The effect of AQP4 on tau protein aggregation in neurodegeneration and persistent neuroinflammation after cerebral microinfarcts
  165. Activation of UBEC2 by transcription factor MYBL2 affects DNA damage and promotes gastric cancer progression and cisplatin resistance
  166. Analysis of clinical characteristics in proximal and distal reflux monitoring among patients with gastroesophageal reflux disease
  167. Exosomal circ-0020887 and circ-0009590 as novel biomarkers for the diagnosis and prediction of short-term adverse cardiovascular outcomes in STEMI patients
  168. Upregulated microRNA-429 confers endometrial stromal cell dysfunction by targeting HIF1AN and regulating the HIF1A/VEGF pathway
  169. Bibliometrics and knowledge map analysis of ultrasound-guided regional anesthesia
  170. Knockdown of NUPR1 inhibits angiogenesis in lung cancer through IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways
  171. D-dimer trends predict COVID-19 patient’s prognosis: A retrospective chart review study
  172. WTAP affects intracranial aneurysm progression by regulating m6A methylation modification
  173. Using of endoscopic polypectomy in patients with diagnosed malignant colorectal polyp – The cross-sectional clinical study
  174. Anti-S100A4 antibody administration alleviates bronchial epithelial–mesenchymal transition in asthmatic mice
  175. Prognostic evaluation of system immune-inflammatory index and prognostic nutritional index in double expressor diffuse large B-cell lymphoma
  176. Prevalence and antibiogram of bacteria causing urinary tract infection among patients with chronic kidney disease
  177. Reactive oxygen species within the vaginal space: An additional promoter of cervical intraepithelial neoplasia and uterine cervical cancer development?
  178. Identification of disulfidptosis-related genes and immune infiltration in lower-grade glioma
  179. A new technique for uterine-preserving pelvic organ prolapse surgery: Laparoscopic rectus abdominis hysteropexy for uterine prolapse by comparing with traditional techniques
  180. Self-isolation of an Italian long-term care facility during COVID-19 pandemic: A comparison study on care-related infectious episodes
  181. A comparative study on the overlapping effects of clinically applicable therapeutic interventions in patients with central nervous system damage
  182. Low intensity extracorporeal shockwave therapy for chronic pelvic pain syndrome: Long-term follow-up
  183. The diagnostic accuracy of touch imprint cytology for sentinel lymph node metastases of breast cancer: An up-to-date meta-analysis of 4,073 patients
  184. Mortality associated with Sjögren’s syndrome in the United States in the 1999–2020 period: A multiple cause-of-death study
  185. CircMMP11 as a prognostic biomarker mediates miR-361-3p/HMGB1 axis to accelerate malignant progression of hepatocellular carcinoma
  186. Analysis of the clinical characteristics and prognosis of adult de novo acute myeloid leukemia (none APL) with PTPN11 mutations
  187. KMT2A maintains stemness of gastric cancer cells through regulating Wnt/β-catenin signaling-activated transcriptional factor KLF11
  188. Evaluation of placental oxygenation by near-infrared spectroscopy in relation to ultrasound maturation grade in physiological term pregnancies
  189. The role of ultrasonographic findings for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative breast cancer
  190. Construction of immunogenic cell death-related molecular subtypes and prognostic signature in colorectal cancer
  191. Long-term prognostic value of high-sensitivity cardiac troponin-I in patients with idiopathic dilated cardiomyopathy
  192. Establishing a novel Fanconi anemia signaling pathway-associated prognostic model and tumor clustering for pediatric acute myeloid leukemia patients
  193. Integrative bioinformatics analysis reveals STAT2 as a novel biomarker of inflammation-related cardiac dysfunction in atrial fibrillation
  194. Adipose-derived stem cells repair radiation-induced chronic lung injury via inhibiting TGF-β1/Smad 3 signaling pathway
  195. Real-world practice of idiopathic pulmonary fibrosis: Results from a 2000–2016 cohort
  196. lncRNA LENGA sponges miR-378 to promote myocardial fibrosis in atrial fibrillation
  197. Diagnostic value of urinary Tamm-Horsfall protein and 24 h urine osmolality for recurrent calcium oxalate stones of the upper urinary tract: Cross-sectional study
  198. The value of color Doppler ultrasonography combined with serum tumor markers in differential diagnosis of gastric stromal tumor and gastric cancer
  199. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A
  200. Mycophenolate mofetil versus cyclophosphamide plus in patients with connective tissue disease-associated interstitial lung disease: Efficacy and safety analysis
  201. MiR-1278 targets CALD1 and suppresses the progression of gastric cancer via the MAPK pathway
  202. Metabolomic analysis of serum short-chain fatty acid concentrations in a mouse of MPTP-induced Parkinson’s disease after dietary supplementation with branched-chain amino acids
  203. Cimifugin inhibits adipogenesis and TNF-α-induced insulin resistance in 3T3-L1 cells
  204. Predictors of gastrointestinal complaints in patients on metformin therapy
  205. Prescribing patterns in patients with chronic obstructive pulmonary disease and atrial fibrillation
  206. A retrospective analysis of the effect of latent tuberculosis infection on clinical pregnancy outcomes of in vitro fertilization–fresh embryo transferred in infertile women
  207. Appropriateness and clinical outcomes of short sustained low-efficiency dialysis: A national experience
  208. miR-29 regulates metabolism by inhibiting JNK-1 expression in non-obese patients with type 2 diabetes mellitus and NAFLD
  209. Clinical features and management of lymphoepithelial cyst
  210. Serum VEGF, high-sensitivity CRP, and cystatin-C assist in the diagnosis of type 2 diabetic retinopathy complicated with hyperuricemia
  211. ENPP1 ameliorates vascular calcification via inhibiting the osteogenic transformation of VSMCs and generating PPi
  212. Significance of monitoring the levels of thyroid hormone antibodies and glucose and lipid metabolism antibodies in patients suffer from type 2 diabetes
  213. The causal relationship between immune cells and different kidney diseases: A Mendelian randomization study
  214. Interleukin 33, soluble suppression of tumorigenicity 2, interleukin 27, and galectin 3 as predictors for outcome in patients admitted to intensive care units
  215. Identification of diagnostic immune-related gene biomarkers for predicting heart failure after acute myocardial infarction
  216. Long-term administration of probiotics prevents gastrointestinal mucosal barrier dysfunction in septic mice partly by upregulating the 5-HT degradation pathway
  217. miR-192 inhibits the activation of hepatic stellate cells by targeting Rictor
  218. Diagnostic and prognostic value of MR-pro ADM, procalcitonin, and copeptin in sepsis
  219. Review Articles
  220. Prenatal diagnosis of fetal defects and its implications on the delivery mode
  221. Electromagnetic fields exposure on fetal and childhood abnormalities: Systematic review and meta-analysis
  222. Characteristics of antibiotic resistance mechanisms and genes of Klebsiella pneumoniae
  223. Saddle pulmonary embolism in the setting of COVID-19 infection: A systematic review of case reports and case series
  224. Vitamin C and epigenetics: A short physiological overview
  225. Ebselen: A promising therapy protecting cardiomyocytes from excess iron in iron-overloaded thalassemia patients
  226. Aspirin versus LMWH for VTE prophylaxis after orthopedic surgery
  227. Mechanism of rhubarb in the treatment of hyperlipidemia: A recent review
  228. Surgical management and outcomes of traumatic global brachial plexus injury: A concise review and our center approach
  229. The progress of autoimmune hepatitis research and future challenges
  230. METTL16 in human diseases: What should we do next?
  231. New insights into the prevention of ureteral stents encrustation
  232. VISTA as a prospective immune checkpoint in gynecological malignant tumors: A review of the literature
  233. Case Reports
  234. Mycobacterium xenopi infection of the kidney and lymph nodes: A case report
  235. Genetic mutation of SLC6A20 (c.1072T > C) in a family with nephrolithiasis: A case report
  236. Chronic hepatitis B complicated with secondary hemochromatosis was cured clinically: A case report
  237. Liver abscess complicated with multiple organ invasive infection caused by hematogenous disseminated hypervirulent Klebsiella pneumoniae: A case report
  238. Urokinase-based lock solutions for catheter salvage: A case of an upcoming kidney transplant recipient
  239. Two case reports of maturity-onset diabetes of the young type 3 caused by the hepatocyte nuclear factor 1α gene mutation
  240. Immune checkpoint inhibitor-related pancreatitis: What is known and what is not
  241. Does total hip arthroplasty result in intercostal nerve injury? A case report and literature review
  242. Clinicopathological characteristics and diagnosis of hepatic sinusoidal obstruction syndrome caused by Tusanqi – Case report and literature review
  243. Synchronous triple primary gastrointestinal malignant tumors treated with laparoscopic surgery: A case report
  244. CT-guided percutaneous microwave ablation combined with bone cement injection for the treatment of transverse metastases: A case report
  245. Malignant hyperthermia: Report on a successful rescue of a case with the highest temperature of 44.2°C
  246. Anesthetic management of fetal pulmonary valvuloplasty: A case report
  247. Rapid Communication
  248. Impact of COVID-19 lockdown on glycemic levels during pregnancy: A retrospective analysis
  249. Erratum
  250. Erratum to “Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway”
  251. Erratum to: “Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p”
  252. Retraction
  253. Retraction of “Study to compare the effect of casirivimab and imdevimab, remdesivir, and favipiravir on progression and multi-organ function of hospitalized COVID-19 patients”
  254. Retraction of “circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis”
  255. Retraction of “miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells”
  256. Retraction of “SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis”
  257. Retraction of “circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury”
  258. Retraction of “lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells”
  259. Special issue Linking Pathobiological Mechanisms to Clinical Application for cardiovascular diseases
  260. Effect of cardiac rehabilitation therapy on depressed patients with cardiac insufficiency after cardiac surgery
  261. Special issue The evolving saga of RNAs from bench to bedside - Part I
  262. FBLIM1 mRNA is a novel prognostic biomarker and is associated with immune infiltrates in glioma
  263. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part III
  264. Development of a machine learning-based signature utilizing inflammatory response genes for predicting prognosis and immune microenvironment in ovarian cancer
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