Rhein (4, 5-dihydroxyanthraquinone-2-carboxylic acid) is a lipophilic anthraquinone extensively found in medicinal herbs, such as Rheum palmatum L., Cassia tora L., Polygonum multiflorum Thunb., and Aloe barbadensis Miller, which have been used medicinally in China for more than 1,000 years. Its biological activities related to human health are being explored actively. Emerging evidence suggests that rhein has many pharmacological effects, including hepatoprotective, nephroprotective, anti-inflammatory, antioxidant, anticancer, and antimicrobial activities. The present review provides a comprehensive summary and analysis of the pharmacological properties of rhein, supporting the potential uses of rhein as a medicinal agent.
In hepatitis B virus-transgenic mice with nonalcoholic steatohepatitis induced by a high-fat (HF) diet, rhein was found to attenuate the serum levels of total cholesterol, triglyceride, and fasting plasma glucose, ameliorating glucose and lipid metabolism [11]. Oral administration of rhein significantly accelerated energy expenditure and decreased the levels of cholesterol and liver triglyceride. It lowered body weight, the expression of the lipogenic enzyme sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes in liver, and the transcriptional activity of SREBP-1c through its upstream regulator, liver X receptor (LXR). Rhein also improved insulin resistance and hepatic steatosis and normalized alanine aminotransferase (ALT) levels in HF diet-induced obese mice. Moreover, rhein regulated the T helpers Th1/Th2 responses by inhibition of T-box expressed in T-cells (T-bet) expression and enhancement of GATA-binding protein-3 expression through increased signal transducer and activator of transcription 6 phosphorylation [12].
rhein
Fibrosis, characterized by extracellular matrix accumulation and disruption of normal tissue structure, is a common cause of chronic failure of many organs [13]. The recent evidence supports rhein as an antifibrotic agent in hepatic disorders. In carbon tetrachloride/ethanol-induced liver fibrosis rats, rhein downregulated the levels of serum ALT, hyalauronic acid, procollagen type III, and liver malondialdehyde (MDA), upregulated the liver superoxide dismutase (SOD) level, and inhibited the expression of transforming growth factor beta 1 (TGF-β1) and alpha-smooth muscle actin (α-SMA), the collagen staining positive area and the grade of fibrosis in the liver [2]. Furthermore, rhein markedly improved histological changes of fibrosis and attenuated the expression of α-SMA and TGF-β1 in the liver, suggesting its protective effect from hepatocyte injury and hepatic fibrosis [14].
Rhein markedly ameliorated the glomerular hypertrophy, mesangial expansion, excessive extracellular matrix, and renal capsule dilation in IgAN rats. Additionally, rhein administration evidently decreased IgA deposition in glomerulus, the volume of urinary red blood cells, 24-h urinary protein excretion, and the expression of upregulated FN and α-SMA in renal tissue [17]. In chronic allograft nephropathy rat models, rhein improved renal function through reductions of renal fibrosis and interstitial inflammation and increases of bone morphogenetic protein 7 and hepatic growth factor levels. Furthermore, both FN and collagen IV were reduced in the extracellular matrix [18].
Cancer invasion is believed to be dependent on extracellular matrix remodeling elicited by tumor cells. Rhein inhibited invasion and migration in human nasopharyngeal carcinoma (NPC) cells through downregulation of the expression of MMP-9, vascular endothelial growth factor (VEGF), growth factor receptor bound protein 2, son of sevenless-1 and Ras, inhibition of the phosphorylation of ERK, p38 MAPK, and activation of transcription factor NF-κB [6]. Rhein prevented HUVEC tube formation, proliferation, and migration stimulated by vascular endothelial growth factor (VEGF165) under normoxic and hypoxic conditions. Moreover, rhein inhibited the activation of phosphatidylinositol 3-kinase (PI3K), phosphorylated-AKT (p-AKT), and phosphorylated ERK, suppressing in vitro angiogenesis. Rhein restrained cell cycle and viability of hormone-dependent breast cancer cells (MCF-7) and hormone-independent breast cancer cells (MDA-MB-435s) under normoxic or hypoxic conditions. In addition, rhein decreased the expression of hypoxia-inducible factor (HIF)-1α, VEGF165, epidermal growth factor (EGF), the phosphorylation of NF-κB inhibitor, and the activity of heat shock protein 90α (Hsp90α) under normoxic or hypoxic conditions [44].
Rhein prevented the mRNA expression of MMP-9, which plays an important role and is the most associated with tumor invasion and metastasis in various human cancers, decreased the levels of MMP-2 and urokinase u-PA, and inhibited the migration and invasion in human tongue cancer SCC-4 cells [7]. A further study demonstrated that rhein dose-dependently induced DNA damage in SCC-4 cells, followed by the inhibition of the mRNA expression of DNA repair-associated O (6)-methylguanine-DNA methyltransferase (MGMT) [45]. The mitosis was inhibited in Allium cepa root tips incubated with rhein in a dose-dependent manner [71].
Rhein induced apoptosis in human promyelocytic leukemia cells (HL-60) through facilitating the loss of mitochondrial membrane potential, cytochrome c release from mitochondrion to cytosol, and cleavage of Bid protein. Rhein also increased the generation of ROS and the phosphorylation of c-Jun N-terminal kinase and p38 kinase [47]. Rhein elevated nuclear condensation and DNA fragmentation, resulting in apoptosis of human NPC cells. Furthermore, rhein increased the activation of caspase-3, -8, -9, and -12 as well as the levels of glucose-regulated protein 78 (GRP 78), PKR-like ER kinase, ATF6, and CCAAT, induced the rapid accumulation of calcium (Ca2+), and lessened the mitochondrial membrane potential. Then Cytochrome c and apoptosis-inducing factor were released [48].
Rhein decreased urinary albumin excretion, extracellular matrix level, and TGF- and FN expression in renal tissue and also reduced the plasma levels of cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), and ApoE in db/db mice with diabetic nephropathy (DN) [72]. In rat mesangial cells transfected with human glucose transporter 1 (GLUT 1) gene, rhein dose-dependently decreased 2-deoxyglucose uptake, reversed cell hypertrophy, and lowered the enhanced glutamine: fructose-6-phosphate aminotransferase activity of the human GLUT 1 gene, suggesting an inhibitory effect on the GLUT 1 overexpression in diabetic nephropathy [56].
It was observed that rhein significantly lowered the secretion of FN and inhibited the proliferation of human mesangial cells in mimic hyperglycemic environment of diabetic nephropathy, the possible mechanism of which might be related to suppression of the bioactivities of TGF-β1 and p38MAPK [57]. TGF- stimulates the glucose uptake by enhancing the GLUT 1 mRNA expression in both human and rat glomerular mesangial cells, which could be antagonized by rhein [58, 59].
Rhein strongly inhibited the uptake of both 2-deoxyglucose and 3-O-methylglucose in Ehrlich ascites tumor cells by alteration of membrane-associated functions [60]. In addition, rhein greatly decreased the induction of ROS in both the NIT-1 cells and isolated islets. Rhein enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes, while it decreased triglyceride accumulation in streptozotocin-induced diabetic mice [61]. Rhein markedly attenuated the increased glucose uptake and GLUT1 mRNA expression stimulated by TGF- in a dose-dependent manner in human glomerular mesangial cells [62]. Rhein reversed the abnormal changes of MMP-9/TIMP-1 ratio and impeded overexpression of integrin-linked kinase in high glucose-induced epithelial-mesenchymal transition of HK-2 cells [73].
Like many herbal monomer, rhein has a potential antibacterial property. For example, rhein inhibited Arylamine N-acetyltransferase activity and growth in the bacterium Helicobacter pylori from peptic ulcer patients [63]. In the other in vitro study, rhein showed a good antibacterial activity against all 21 tested staphylococcus aureus (S. aureus) strains. 28 transporter genes of S. aureus ATCC25923 were differentially regulated by rhein. In particular, rhein increased the transcription of genes (srtB and isdABCDEFGI) encoding iron-regulated surface determinants system and genes (nrdIEF and nrdDG) involved in ribonucleotide reductase systems, while it prevented the transcription of genes (pflAB, nirBDR, narGH, Idh1, COL-SA0660, COL-SA2363, and COL-SA2386) responsible for anaerobic respiration and fermentation [64].
LXRs play important roles in regulating cholesterol homeostasis and lipid and energy metabolism. After bounding directly to LXRs in C57BL/6J mice fed a HF diet, rhein suppressed the expression levels of LXR target genes in both 3T3-L1 and HepG2 cells in vitro. In white adipose tissue, muscle, and liver, rhein reprogrammed the expression of LXR target genes related to adipogenesis and cholesterol metabolism. Rhein activated uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) in wild-type mice, suggesting that rhein may protect against obesity and related metabolic disorders through LXR antagonism and regulation of UCP1 expression in BAT [67]. Rhein downregulated the mRNA levels of adipogenesis-specific transcription factors PPARγ and C/EBPα and their downstream target genes involved in adipocyte differentiation, such as CD36, AP-2, and acyl CoA oxidase in both 3T3-L1 preadipocytes and C57BL/6 mice. Furthermore, the expression of C/EBPβ was reduced by rhein in 3T3-L1 preadipocytes. HF diet-induced weight gain and adiposity were reversed by rhein in C57BL/6 mice [68]. 2ff7e9595c
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