Objectives:Podocytes undergo epithelial-mesenchymal transition(EMT)and ferroptosis in response to hyperglycemic stimulation.This is considered an important early event in the development and progression of diabetic ne...Objectives:Podocytes undergo epithelial-mesenchymal transition(EMT)and ferroptosis in response to hyperglycemic stimulation.This is considered an important early event in the development and progression of diabetic nephropathy(DN).Rhein is the main active anthraquinone derivative in several common traditional herbal medicines.This study aimed to investigate the protective effects of Rhein on podocyte ferroptosis and EMT.Methods:The mouse glomerular podocyte cell line MPC5 was stimulated with high glucose(HG),Rhein,and the ferroptosis inhibitor ferrostatin-1(Fer-1).Mechanistic investigations employed plasmids to overexpress and knockdown Sirtuin-1(SIRT1),solute carrier family 7 member 11(SLC7A11),or p53 and measure ferroptosis-or EMT-related indicators.Results:In the HG-injured podocytes,Rhein enhanced cell viability,reduced malondialdehyde(MDA),ferrous iron(Fe2+),and reactive oxygen species(ROS)levels,increased glutathione(GSH)production,accompanied by the restoration of ferroptosis-and EMT-associated indicator expressions.Mechanistically,Rhein induced SIRT1 and SLC7A11 expression and attenuated p53 expression.SIRT1 knockdown upregulated p53 and downregulated SLC7A11,thereby abolishing the protective effects of Rhein against podocyte ferroptosis and EMT.However,the effects of SIRT1 overexpression were reversed by SLC7A11 knockdown.Conclusion:Rhein activated the SIRT1/p53/SLC7A11 axis to protect podocytes against ferroptosis and EMT.This suggests that Rhein has a potential therapeutic effect on DN patients associated with podocyte injury,and targeting SIRT1/p53/SLC7A11 may represent an innovative therapeutic strategy for DN patients.展开更多
Aim To establish a reversed phase liquid chromatographic method forsimultaneous determination of three main medicinal constituents, baicalin, berberine and rhein, inSanhuang tablets. Methods The separation was perform...Aim To establish a reversed phase liquid chromatographic method forsimultaneous determination of three main medicinal constituents, baicalin, berberine and rhein, inSanhuang tablets. Methods The separation was performed on a Kromasil C_(18) column with TEA-adjusted0.02 mol·L^(-1) H_3PO_4 (pH 6.78)-acetonitrile-methanol (40 : 9 : 7) as mobile phase at aflow-rate of 1.0 mL·min^(-1), with detection at 254 ran. Considering interaction between acidic andalkaline compounds, three standard markers were added respectively and the volume of samplesolution was doubled in recovery experiments. Results Three regression equations revealed excellentlinear relationship between the peak areas and concentrations and the correlation coefficients allsurpassed 0.999 8. The average recovery was 96.1% (RSD = 2.1%) baicalin, 98.5% (RSD = 2.4%) forberberine, and 101.5% (RSD =1.3%) for rhein. Conclusion The method developed can be used to controlthe quality of Sanhuang tablets comprehensively.展开更多
Rhein （4,5-dihydroxyanthraquinone-2-carboxylic acid） is an anthraquinone compound enriched in the rhizome of rhubarb （Rheum palmatum or Rheum tanguticum Maxim）, a traditional Chinese medicine herb. Natural product...Rhein （4,5-dihydroxyanthraquinone-2-carboxylic acid） is an anthraquinone compound enriched in the rhizome of rhubarb （Rheum palmatum or Rheum tanguticum Maxim）, a traditional Chinese medicine herb. Natural product compounds are a source of novel therapeutic agents. Rhein has been initially identified as an anti-inflammatory and anti-oxidant agent. Recent studies indicate that rhein may also have an antitumor effect. However, the molecular mechanisms are still unclear. This review aims to summarize the research of rhein to better understand the anti-tumor activities by targeting cell cycle arrest, apoptosis, invasion, and metastasis of cancer cells. Meanwhile, we also intend to give an overview of the mechanisms identified so far. The breakthrough findings may shed light on using rhein as a targeted-cancer therapy.展开更多
AIM: To investigate the effects of rhein on intestinal epithelial tight junction proteins in rats with IgA nephropathy (IgAN). METHODS: Twenty-eight female Sprague-Dawley rats were randomly divided into four groups (7...AIM: To investigate the effects of rhein on intestinal epithelial tight junction proteins in rats with IgA nephropathy (IgAN). METHODS: Twenty-eight female Sprague-Dawley rats were randomly divided into four groups (7 per group): Control, IgAN, Rhein-treated, and Rheinprevented. Bovine serum albumin, lipopolysaccharide and CCl4 were used to establish the rat model of IgA nephropathy. The Rhein-treated group was given rhein from week 7 until the rats were sacrificed. The Rheinprevented group was given rhein from week 1. Animals were sacrificed at the end of week 10. We observed the changes in the intestinal epithelial tight junctions using transmission electron microscopy, and expression of intestinal epithelial tight junction proteins zona occludens protein (ZO)-1 and occludin by immunofluorescence using laser confocal microscopy. Changes in mRNA and protein expression of ZO-1 and occludin were measured by reverse transcriptase polymerase chain reaction and Western blotting. The ratio of urinary lactulose/mannitol was measured by high performance liquid chromatography (HPLC) for assessing the intestinal permeability. RESULTS: In the control group, the tight junctions lied between epithelial cells on the top of the outer side of the cell membrane, and appeared in dense dotted crystal structures, the neighboring cells were binded tightly with no significant gap, and the tight junction protein ZO-1 and occludin were evenly distributed in the intestinal epithelial cells at the top of the junction. Compared with the control group, in the IgAN group, the structure of the tight junction became obscured and the dotted crystal structures had disappeared; the fluorescence of ZO-1 and occludin was uneven and weaker (5.37 ± 1.27 vs 10.03 ± 1.96, P < 0.01; 4.23 ± 0.85 vs 12.35 ± 4.17, P < 0.01); the mRNA expression of ZO-1 and occludin decreased (0.42 ± 0.19 vs 0.92 ± 0.24, P < 0.01; 0.40 ± 0.15 vs 0.97 ± 0.25, P < 0.01); protein expression of ZO-1 and occludin was decreased (0.85 ± 0.12 vs 1.98 ± 0.43, P < 0.01; 0.72 ± 0.15 vs 1.38 ± 0.31, P < 0.01); and the ratio of urinary lactulose/mannitol increased (3.55 ± 0.68 vs 2.72 ± 0.21, P < 0.01). In the Rheinprevented and Rhein-treated groups, compared with the IgAN group, the intestinal epithelial tight junctions were repaired; fluorescence of ZO-1 and occludin was stronger (11.16 ± 3.52 and 8.81 ± 2.30 vs 5.37 ± 1.27, P < 0.01; 10.97 ± 3.40 and 9.46 ± 2.40 vs 4.23 ± 0.85, P < 0.01); mRNA of ZO-1 and occludin increased (0.81 ± 0.17 and 0.64 ± 0.16 vs 0.42 ± 0.19, P < 0.01; 0.82± 0.22 and 0.76 ± 0.31 vs 0.40 ± 0.15, P < 0.01); protein expression of ZO-1 and occludin was increased (2.07 ± 0.41 and 1.57 ± 0.23 vs 0.85 ± 0.12, P < 0.01; 1.34 ± 0.21 and 1.15 ± 0.17 vs 0.72 ± 0.15, P < 0.01); and the ratio of urinary lactulose/mannitol decreased (2.83 ± 0.43 and 2.87 ± 0.18 vs 3.55 ± 0.68, P < 0.01). CONCLUSION: Rhein can enhance the expression of ZO-1 and occludin, repair damaged tight junctions, and protect the intestinal barrier.展开更多
OBJECTIVE:To examine the effects of catalpol and rhein on pro-and anti-inflammatory responses in C57 BL/6 mice with experimental autoimmune encephalomyelitis(EAE),a model of multiple sclerosis.METHODS:Female C57 BL/6 ...OBJECTIVE:To examine the effects of catalpol and rhein on pro-and anti-inflammatory responses in C57 BL/6 mice with experimental autoimmune encephalomyelitis(EAE),a model of multiple sclerosis.METHODS:Female C57 BL/6 mice were randomly divided into four groups(n=30):(a)normal salinecontrol,(b)EAE control,(c)EAE+prednisone acetate(PA,6 mg/kg),and(d)EAE+catalpol(40 mg/kg)and rhein(5 mg/kg).EAE was induced by injection of myelin oligodendrocyte glycoprotein 35-55 plus pertussis toxin.Treatments were orally administered daily for 40 d.Disease progression and neurological function were assessed using a semi-quantitative scale of tail and limb paralysis.Brains and spinal cords were collected on Days 6,20,and 40 and assessed for histopathological changes by hematoxylin and eosin staining.Production of interleukin(IL)-2,IL-4,IL-10,and IL-17 A protein was measured by enzyme-linked immunosorbent assay.Expression of the T helper(Th)1-,Th2-,Th17-,and regulatory T cell(Treg)-specific transcription factors T-bet,GATA3,ROR-γt,and Foxp3,respectively,were analyzed by quantitative reverse-transcription polymerase chain reaction and western blot analysis.RESULTS:Combination treatment with catalpol and rhein significantly alleviated the clinical disability and neurological dysfunction of mice with EAE.Catalpol and rhein treatment also reduced the infiltration of pro-inflammatory T cells into pathological lesions;significantly increased the expression of the anti-inflammatory factors GATA3,Foxp3,IL-4,and IL-10;and significantly decreased the expression of the pro-inflammatory factors T-bet,ROR-γt,IL-2,and IL-17 A.CONCLUSION:Catalpol and rhein reduced the neurological disabilities of mice with EAE,at least in part by rebalancing the pro-and anti-inflammatory environment in the brains and spinal cords.展开更多
Inflammation is a defensive response of living tissues to damaging agents,which exists in two forms,acute inflammation and chronic inflammation,and chronic inflammation is closely related to arthritis.Currently,the co...Inflammation is a defensive response of living tissues to damaging agents,which exists in two forms,acute inflammation and chronic inflammation,and chronic inflammation is closely related to arthritis.Currently,the commonly prescribed anti-inflammatory medications are greatly limited by high incidence of gastrointestinal erosions in the clinical applications.Rhein,a bioactive constituent of anthraquinone,exhibits excellent anti-inflammatory activities and therapeutic effects on arthritis with less gastrointestinal damages.Although there are numbers of studies on anti-inflammatory effects and mechanisms of rhein in the last few decades,to the best of our knowledge,only a few review articles pay attention to the interactive relationships of rhein on multiple inflammatory signaling pathways and cellular processes from a comprehensive perspective.Herein,we summarized anti-inflammatory effects and mechanisms of rhein and its practical applications in the treatment of arthritis,thereby providing a reference for its basic researches and clinical applications.展开更多
Rhein(Rhe), an anthraquinone derivative, exhibits excellent anti-inflammatory effects and other pharmacological activities, but its clinical application remains limited due to poor solubility. The present work aims at...Rhein(Rhe), an anthraquinone derivative, exhibits excellent anti-inflammatory effects and other pharmacological activities, but its clinical application remains limited due to poor solubility. The present work aims at the improvement of solubility and oral bioavailability of Rhe through cocrystal formation. For this purpose, Rhe and matrine(Mat) were selected as pharmaceutical ingredient(API) and cocrystal former(CCF), respectively, and the Rhe-Mat cocrystal was synthesized and characterized by single crystal X-ray diffraction(SXRD), powder X-ray diffraction(PXRD), thermogravimetric analysis(TGA), differential scanning calorimetry(DSC). The formation mechanism of Rhe-Mat cocrystal was elucidated by molecular surface electrostatic potential(MSEP). It is worth mentioning that the 50-fold increment of dissolution in vitro was observed in pure water in the form of Rhe-Mat cocrystal. Furthermore, the in vivo studies revealed that Rhe-Mat cocrystal indicated the faster absorption rate and the higher peak blood concentration than the pure Rhe. Hence, it can be concluded that current study successfully improved the solubility and oral bioavailability of Rhe.展开更多
The specific crystalline form of a compound remarkably affects its physicochemical properties.Therefore,a detailed analysis of the structural features and intermolecular interactions of a multi-component crystal is fe...The specific crystalline form of a compound remarkably affects its physicochemical properties.Therefore,a detailed analysis of the structural features and intermolecular interactions of a multi-component crystal is feasible to understand the relationships among the structure,physicochemical properties and the formation mechanism.In the present study,three novel cocrystal salt solvates of rhein and berberine were reported for the first time.Various solid characterizations and theoretical computations based on density functional theory(DFT)were carried out to demonstrate the intermolecular interactions.The theoretical computation shows that the strongest interaction existed between berberine cation and rhein anion,and the electrostatic interaction play a dominant role.However,no salt bond was observed between them.Further intrinsic dissolution rate analysis in water shows that the monohydrate exhibits 17 times enhancement in comparison with rhein.The rhein and berberine combined in ionic state in cocrystal salt is the main reason for the solubility improvement.This paper suggests that the interactions between the different components can be visualized and qualitatively and quantitatively analyzed by theoretical computation,which is helpful to understand the relationship between stereochemical structure and physicochemical properties of multi-component complex.展开更多
Glutaraldehyde(GA),the most widely used crosslinking agent for biomaterials,is cytotoxic.CaCl_(2) is of particular interest due to its non-toxic nature.Rhein can chelate Ca^(2+)and promote bone growth.Here we reported...Glutaraldehyde(GA),the most widely used crosslinking agent for biomaterials,is cytotoxic.CaCl_(2) is of particular interest due to its non-toxic nature.Rhein can chelate Ca^(2+)and promote bone growth.Here we reported a novel nano calcium-deficient hydroxyapatite/O-carboxymethyl chitosan-CaCl_(2) microspheres loaded with rhein(RH-nCDHA/OCMC-CaCl_(2) microspheres)using CaCl_(2) as crosslinking agent for bone defect repair.The obtained microspheres were characterized by X-ray diffraction(XRD),scanning electron microscopy(SEM),thermogravimetric analysis(TG)and Fourier transform infrared spectroscopy(FT-IR).The surface of the obtained microspheres is rough with quite a few voids.The nano calcium-deficient hydroxyapatite(nCDHA)accounts for about 70% of the total weight of the microspheres,which is equivalent to the proportion of inorganic substances in human bones.A high encapsulation efficiency(EE)and loading capacity(LC)of the microspheres loaded with rhein was 90.20±0.60% and 11.03±0.30%,respectively.For microspheres using CaCl_(2) in simulated body fluid(SBF)after 14 days,the drug released continuously and bone-like apatite formed like layer.The cells on the surface of the RH-nCDHA/OCMC-CaCl_(2) microspheres grew better comparing with nCDHA/OCMC-GA microspheres and the skull defects of rats after landfill can be almost repaired after 8 weeks,which revealed the potential of the microspheres for bone repair.展开更多
OBJECTIVE:To predict the anti-inflammatory targets and related pathways of rhein in the treatment of asthma by using network pharmacology,and to further explore its potential mechanism in asthma.METHODS:The correspond...OBJECTIVE:To predict the anti-inflammatory targets and related pathways of rhein in the treatment of asthma by using network pharmacology,and to further explore its potential mechanism in asthma.METHODS:The corresponding targets of rhein were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),and the rhein-target network was constructed with Cytoscape 3.7.1 software.The Genbank and Drugbank databases were used to collect and screen asthma targets,and the rhein-target-disease interaction network was constructed.A target protein-protein interaction(PPI)network was constructed using the STRING database to screen key targets.Finally,Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis was used to identify biological processes and signaling pathways.The anti-asthmatic effects of rhein were tested in vitro,and the expression levels of proteins in the mitogen-activated protein kinase/nuclear factor kappa-B(MAPK/NF-κB)signaling pathway were assessed by western blot analysis.RESULTS:Altogether,83 targets of rhein were screened in the relevant databases,989 targets of asthma were obtained in the National Center for Biotechnology Information(NCBI)GENE Database.PPI network analysis and KEGG pathway enrichment analysis predicted that rhein could regulate the epidermal active growth factor receptor(EGFR),mitogen-activated protein kinase 14(MAPK14),tumour necrosis factor receptor superfamily member 1A(TNFRSF1A),receptor tyrosineprotein kinase erb B-2(ERBB2),and other signaling pathways.Furthermore,we selected the MAPK signaling pathway to determine the anti-inflammatory effects of rhein.Consistently,further in vitro experiments demonstrated that rhein was shown to inhibit HBE cells inflammation.CONCLUSION:The anti-inflammatory mechanism of rhein in the treatment of asthma may be related to EGFR,MAPK14,TNFRSF1A and ERBB2 as well as their signaling pathways.To prevent the exacerbation of asthma,instead of targeting a single pathway or a single target,all these targets and their signaling pathways should be controlled holistically.Rhein may alleviate the inflammation of asthma by inhibiting the MAPK/NF-κB pathway.展开更多
Objective:To explore the protective effects of rhein on cardiomyocyte injury in DCM and its possible mecha-nism.Methods:The diabetic model was induced by intraperitoneal injection with streptozotocin and high-fat diet...Objective:To explore the protective effects of rhein on cardiomyocyte injury in DCM and its possible mecha-nism.Methods:The diabetic model was induced by intraperitoneal injection with streptozotocin and high-fat diet.The mice were randomly divided into control group,DM group,and DM+RH group.After 12 weeks treatment with rhein,the change of fast blood glucose,body weight,and heart weight/body weigh(t HW/BW)were observed.HE and Masson staining were used to evalu-ate myocardial structural damage.Transmission electron microscope was used to observe the myocardial mitochondrial structure.The mRNA levels of Sirt1,PGC-1α,TFAM,ANP,BNP andβ-MHC were quantified by RT-PCR.Sirt1,PGC-1α and TFAM protein levels were estimated by Western blot and IHC.Results:Compared with control group,the blood glucose,HW/BW,ANP,BNP andβ-MHC mRNA of DM group were significantly increased(P<0.05).The structures of myocardium and mitochondria were obviously destroyed in DM group.Sirt1,PGC-1α and TFAM expression were significantly decreased(P<0.05).Compared with DM group,the blood glucose,HW/BW,ANP,BNP and β-MHC mRNA of DM+RH group were decreased(P<0.05).The myocardial and mitochondrial injury were improved.Sirt1,PGC-1α and TFAM expression were significantly increased(P<0.05).Conclusion:Rhein exhibits protective effects on diabetic cardiomyopathy which may be achieved by activating Sirt1/PGC-1α pathway.展开更多
To study the effect ofrhein on embryo development of rats and fetuscs,the SD rats were divided into rhein(87.5,175 and 350 mg/kg)group and negative control group treated with 0.5%CMC(carboxyl methyl cellulose).The rat...To study the effect ofrhein on embryo development of rats and fetuscs,the SD rats were divided into rhein(87.5,175 and 350 mg/kg)group and negative control group treated with 0.5%CMC(carboxyl methyl cellulose).The rats were administrated with rhein daily for 10 days from 6th to 15th day after pregnancy.The pregnancy rats were dissected at 20th day after pregnancy.The total weight of the fetuses,the number of corpus luteum,plant gland,absorbed fetus,live fetus,dead futus,monsters,body weight,body height and tail length were recorded.Compared with the control group,rhein group occurred with the administration of toxicity-related clinical symptoms.The changes in weight increase related with the amount ofrhein(P〈0.05)and the increased number of absorbed fetuses in each rhein group(P〈0.05)were presented.Obvious differences occurred in the rhein groups in terms of the incidence of visceral abnormalities,each organ abnormalities and fossa malformations,etc.(P〈0.05).Compared with the control group,there was no significant difference in the low-dose group by fetal rat bone examination(P〉0.05),while the remaining dose groups manifested various bone deformities such as sternum sections missing,incomplete ossification of the skull and thoracic vertebrae separation or deformation,which was obviously different from the control group(P〈0.01).Rhein had a significant effect on the reproductive function of pregnant rats.It can even result in the bones'and internal organs'dysplasia of fetal rats.Rhein has a significant teratogenic effect in rats.展开更多
Several three-liquid-phase extraction systems comprised of organic extractant,polymer and salt aqueous solution were applied to isolate and purify simulated herbal extract containing emodin and rhein.Some influential ...Several three-liquid-phase extraction systems comprised of organic extractant,polymer and salt aqueous solution were applied to isolate and purify simulated herbal extract containing emodin and rhein.Some influential factors on the partitioning behaviors were studied.The results revealed that extractant type and solution pH value were crucial factors for improving the separation performance.The optimal separation results were obtained at pH 8.00 with methyl isobutyl ketone as the extractant,10%(ω) polyethylene glycol with the molecular weight 4000 Da,and 10%(ω) ammonium sulphate.Under the optimized conditions,95%emodin and 97%rhein were simultaneously extracted into the organic phase and polymer-rich phase from simulated herbal solution with the initial concentration of 100×l0^(-6)(ω),respectively,and their separation factor of over 10000 was achieved.By adjusting pH value,back extraction rate of both emodin and rhein could be up to about 99%.With the assistance of molecular simulation program XLOGP3 and molecular orbital package,the possible mechanism of extraction was analyzed,and hydrophobic interaction and hydrogen-bonding interaction might be the major driving forces affecting the partitioning behaviors of emodin and rhein.展开更多
Objective:The anthraquinone compound rhein(1,8-dihydroxy-3-carboxyanthraquinone),derived from Rhei Radix et Rhizoma(rhubarb,Dahuang in Chinese),exhibits notable anti-fibrotic effects.However,the mechanisms underlying ...Objective:The anthraquinone compound rhein(1,8-dihydroxy-3-carboxyanthraquinone),derived from Rhei Radix et Rhizoma(rhubarb,Dahuang in Chinese),exhibits notable anti-fibrotic effects.However,the mechanisms underlying these effects have not been fully elucidated.Suppressor of mothers against decapentaplegic 3(Smad3)phosphorylation plays a crucial role in the canonical transforming growth factor-β(TGF-β)/Smad signalling pathway.In this study,we investigated the effect of rhein on the TGF-β/Smad signalling pathway in renal interstitial fibrosis(RIF).Methods:A unilateral ischaemia-reperfusion injury(UIRI)rat model was employed to simulate renal injury and assess the therapeutic effect of rhein in vivo.In vitro,TGF-β1-stimulated NRK-52E rat renal epithelial cells and HK-2 human proximal tubular epithelial cells were used to mimic fibrotic conditions.Rhein's interaction with Smad3 was further explored using molecular docking and bio-layer interferometry assays.Additionally,Smad3 knockdown and overexpression studies were performed in HK-2 cells to elucidate the functional role of Smad3 in rhein-mediated anti-fibrotic activity.Results:Rhein treatment significantly improved renal function and reduced fibrosis in UIRI rats,primarily by inhibiting Smad3 phosphorylation.Rhein treatment mitigated aberrant remodelling and extracellular matrix accumulation in both NRK-52E and HK-2 cells and in the UIRI rat model.The anti-fibrotic effects of rhein were attenuated by Smad3 deficiency but enhanced by Smad3 overexpression in HK-2 cells.Conclusion:Rhein exerts its anti-fibrotic effects in renal interstitial fibrosis by targeting the TGF-β/Smad3signaling pathway.Acting as a natural antagonist of Smad3,rhein offers promising potential for therapeutic development in renal fibrosis.These findings provide a new mechanistic insight for further clinical research and drug development.展开更多
Diabetic kidney disease(DKD)is the primary cause of mortality among diabetic patients.With the increasing prevalence of diabetes,it has become a major concern around the world.The therapeutic effect of clinical use of...Diabetic kidney disease(DKD)is the primary cause of mortality among diabetic patients.With the increasing prevalence of diabetes,it has become a major concern around the world.The therapeutic effect of clinical use of drugs is far from expected,and therapy choices to slow the progression of DKD remain restricted.Therefore,research on new drugs and treatments for DKD has been a hot topic in the medical field.It has been found that rhein has the potential to target the pathogenesis of DKD and has a wide range of pharmacological effects on DKD,such as anti-nephritis,decreasing blood glucose,controlling blood lipids and renal protection.In recent years,the medical value of rhein in the treatment of diabetes,DKD and renal disease has gradually attracted worldwide attention,especially its potential in the treatment of DKD.Currently,DKD can only be treated with medications from a single symptom and are accompanied by adverse effects,while rhein improves DKD with a multi-pathway and multi-target approach.Therefore,this paper reviews the therapeutic effects of rhein on DKD,and proposes solutions to the limitations of rhein itself,in order to provide valuable references for the clinical application of rhein in DKD and the development of new drugs.展开更多
基金supported by the Hunan Province Natural Science Foundation Medical Industry Joint Fund(No.2024JJ9421)Clinical Medical Technology Innovation Guide Project of Hunan Province(No.2021SK51418).
文摘Objectives:Podocytes undergo epithelial-mesenchymal transition(EMT)and ferroptosis in response to hyperglycemic stimulation.This is considered an important early event in the development and progression of diabetic nephropathy(DN).Rhein is the main active anthraquinone derivative in several common traditional herbal medicines.This study aimed to investigate the protective effects of Rhein on podocyte ferroptosis and EMT.Methods:The mouse glomerular podocyte cell line MPC5 was stimulated with high glucose(HG),Rhein,and the ferroptosis inhibitor ferrostatin-1(Fer-1).Mechanistic investigations employed plasmids to overexpress and knockdown Sirtuin-1(SIRT1),solute carrier family 7 member 11(SLC7A11),or p53 and measure ferroptosis-or EMT-related indicators.Results:In the HG-injured podocytes,Rhein enhanced cell viability,reduced malondialdehyde(MDA),ferrous iron(Fe2+),and reactive oxygen species(ROS)levels,increased glutathione(GSH)production,accompanied by the restoration of ferroptosis-and EMT-associated indicator expressions.Mechanistically,Rhein induced SIRT1 and SLC7A11 expression and attenuated p53 expression.SIRT1 knockdown upregulated p53 and downregulated SLC7A11,thereby abolishing the protective effects of Rhein against podocyte ferroptosis and EMT.However,the effects of SIRT1 overexpression were reversed by SLC7A11 knockdown.Conclusion:Rhein activated the SIRT1/p53/SLC7A11 axis to protect podocytes against ferroptosis and EMT.This suggests that Rhein has a potential therapeutic effect on DN patients associated with podocyte injury,and targeting SIRT1/p53/SLC7A11 may represent an innovative therapeutic strategy for DN patients.
基金Innovation Fund of Chinese Academy of Sciences(KGCX2 SW 213 05)
文摘Aim To establish a reversed phase liquid chromatographic method forsimultaneous determination of three main medicinal constituents, baicalin, berberine and rhein, inSanhuang tablets. Methods The separation was performed on a Kromasil C_(18) column with TEA-adjusted0.02 mol·L^(-1) H_3PO_4 (pH 6.78)-acetonitrile-methanol (40 : 9 : 7) as mobile phase at aflow-rate of 1.0 mL·min^(-1), with detection at 254 ran. Considering interaction between acidic andalkaline compounds, three standard markers were added respectively and the volume of samplesolution was doubled in recovery experiments. Results Three regression equations revealed excellentlinear relationship between the peak areas and concentrations and the correlation coefficients allsurpassed 0.999 8. The average recovery was 96.1% (RSD = 2.1%) baicalin, 98.5% (RSD = 2.4%) forberberine, and 101.5% (RSD =1.3%) for rhein. Conclusion The method developed can be used to controlthe quality of Sanhuang tablets comprehensively.
文摘Rhein （4,5-dihydroxyanthraquinone-2-carboxylic acid） is an anthraquinone compound enriched in the rhizome of rhubarb （Rheum palmatum or Rheum tanguticum Maxim）, a traditional Chinese medicine herb. Natural product compounds are a source of novel therapeutic agents. Rhein has been initially identified as an anti-inflammatory and anti-oxidant agent. Recent studies indicate that rhein may also have an antitumor effect. However, the molecular mechanisms are still unclear. This review aims to summarize the research of rhein to better understand the anti-tumor activities by targeting cell cycle arrest, apoptosis, invasion, and metastasis of cancer cells. Meanwhile, we also intend to give an overview of the mechanisms identified so far. The breakthrough findings may shed light on using rhein as a targeted-cancer therapy.
基金Supported by National Natural Science Foundation of China,No. 81160050Science and Technology Support Program of China, No. 2008BAI68B01+1 种基金Science and Technology Support Program of Jiangxi Province, No. 20111BBG70015-3Natural Science Foundation of Jiangxi Province, No. 2007GQY0997
文摘AIM: To investigate the effects of rhein on intestinal epithelial tight junction proteins in rats with IgA nephropathy (IgAN). METHODS: Twenty-eight female Sprague-Dawley rats were randomly divided into four groups (7 per group): Control, IgAN, Rhein-treated, and Rheinprevented. Bovine serum albumin, lipopolysaccharide and CCl4 were used to establish the rat model of IgA nephropathy. The Rhein-treated group was given rhein from week 7 until the rats were sacrificed. The Rheinprevented group was given rhein from week 1. Animals were sacrificed at the end of week 10. We observed the changes in the intestinal epithelial tight junctions using transmission electron microscopy, and expression of intestinal epithelial tight junction proteins zona occludens protein (ZO)-1 and occludin by immunofluorescence using laser confocal microscopy. Changes in mRNA and protein expression of ZO-1 and occludin were measured by reverse transcriptase polymerase chain reaction and Western blotting. The ratio of urinary lactulose/mannitol was measured by high performance liquid chromatography (HPLC) for assessing the intestinal permeability. RESULTS: In the control group, the tight junctions lied between epithelial cells on the top of the outer side of the cell membrane, and appeared in dense dotted crystal structures, the neighboring cells were binded tightly with no significant gap, and the tight junction protein ZO-1 and occludin were evenly distributed in the intestinal epithelial cells at the top of the junction. Compared with the control group, in the IgAN group, the structure of the tight junction became obscured and the dotted crystal structures had disappeared; the fluorescence of ZO-1 and occludin was uneven and weaker (5.37 ± 1.27 vs 10.03 ± 1.96, P < 0.01; 4.23 ± 0.85 vs 12.35 ± 4.17, P < 0.01); the mRNA expression of ZO-1 and occludin decreased (0.42 ± 0.19 vs 0.92 ± 0.24, P < 0.01; 0.40 ± 0.15 vs 0.97 ± 0.25, P < 0.01); protein expression of ZO-1 and occludin was decreased (0.85 ± 0.12 vs 1.98 ± 0.43, P < 0.01; 0.72 ± 0.15 vs 1.38 ± 0.31, P < 0.01); and the ratio of urinary lactulose/mannitol increased (3.55 ± 0.68 vs 2.72 ± 0.21, P < 0.01). In the Rheinprevented and Rhein-treated groups, compared with the IgAN group, the intestinal epithelial tight junctions were repaired; fluorescence of ZO-1 and occludin was stronger (11.16 ± 3.52 and 8.81 ± 2.30 vs 5.37 ± 1.27, P < 0.01; 10.97 ± 3.40 and 9.46 ± 2.40 vs 4.23 ± 0.85, P < 0.01); mRNA of ZO-1 and occludin increased (0.81 ± 0.17 and 0.64 ± 0.16 vs 0.42 ± 0.19, P < 0.01; 0.82± 0.22 and 0.76 ± 0.31 vs 0.40 ± 0.15, P < 0.01); protein expression of ZO-1 and occludin was increased (2.07 ± 0.41 and 1.57 ± 0.23 vs 0.85 ± 0.12, P < 0.01; 1.34 ± 0.21 and 1.15 ± 0.17 vs 0.72 ± 0.15, P < 0.01); and the ratio of urinary lactulose/mannitol decreased (2.83 ± 0.43 and 2.87 ± 0.18 vs 3.55 ± 0.68, P < 0.01). CONCLUSION: Rhein can enhance the expression of ZO-1 and occludin, repair damaged tight junctions, and protect the intestinal barrier.
基金Supported by the National Natural Science Foundation(No.81973599)Beijing Natural Science Foundation-Key Project of Science and Technology Plan of Beijing Education Commission(KZ/KM/SZ/SM201910025035)The Fund for Beijing Science&Technology Development of Traditional Chinese Medicine(No.QN2018-30)
文摘OBJECTIVE:To examine the effects of catalpol and rhein on pro-and anti-inflammatory responses in C57 BL/6 mice with experimental autoimmune encephalomyelitis(EAE),a model of multiple sclerosis.METHODS:Female C57 BL/6 mice were randomly divided into four groups(n=30):(a)normal salinecontrol,(b)EAE control,(c)EAE+prednisone acetate(PA,6 mg/kg),and(d)EAE+catalpol(40 mg/kg)and rhein(5 mg/kg).EAE was induced by injection of myelin oligodendrocyte glycoprotein 35-55 plus pertussis toxin.Treatments were orally administered daily for 40 d.Disease progression and neurological function were assessed using a semi-quantitative scale of tail and limb paralysis.Brains and spinal cords were collected on Days 6,20,and 40 and assessed for histopathological changes by hematoxylin and eosin staining.Production of interleukin(IL)-2,IL-4,IL-10,and IL-17 A protein was measured by enzyme-linked immunosorbent assay.Expression of the T helper(Th)1-,Th2-,Th17-,and regulatory T cell(Treg)-specific transcription factors T-bet,GATA3,ROR-γt,and Foxp3,respectively,were analyzed by quantitative reverse-transcription polymerase chain reaction and western blot analysis.RESULTS:Combination treatment with catalpol and rhein significantly alleviated the clinical disability and neurological dysfunction of mice with EAE.Catalpol and rhein treatment also reduced the infiltration of pro-inflammatory T cells into pathological lesions;significantly increased the expression of the anti-inflammatory factors GATA3,Foxp3,IL-4,and IL-10;and significantly decreased the expression of the pro-inflammatory factors T-bet,ROR-γt,IL-2,and IL-17 A.CONCLUSION:Catalpol and rhein reduced the neurological disabilities of mice with EAE,at least in part by rebalancing the pro-and anti-inflammatory environment in the brains and spinal cords.
基金supported by Drug Innovation Major Project(Grant Nos.2018ZX09711001-001-015,2018ZX09711001-003-022)CAMS Innovation Fund for Medical Sciences(Grant No.2016-I2M-3-007).
文摘Inflammation is a defensive response of living tissues to damaging agents,which exists in two forms,acute inflammation and chronic inflammation,and chronic inflammation is closely related to arthritis.Currently,the commonly prescribed anti-inflammatory medications are greatly limited by high incidence of gastrointestinal erosions in the clinical applications.Rhein,a bioactive constituent of anthraquinone,exhibits excellent anti-inflammatory activities and therapeutic effects on arthritis with less gastrointestinal damages.Although there are numbers of studies on anti-inflammatory effects and mechanisms of rhein in the last few decades,to the best of our knowledge,only a few review articles pay attention to the interactive relationships of rhein on multiple inflammatory signaling pathways and cellular processes from a comprehensive perspective.Herein,we summarized anti-inflammatory effects and mechanisms of rhein and its practical applications in the treatment of arthritis,thereby providing a reference for its basic researches and clinical applications.
基金supported by Drug Innovation Major Project (Nos. 2018ZX09711001–001–015, 2018ZX09711001–003– 022)CAMS Innovation Fund for Medical Sciences (No. 2016I2M-3–007)。
文摘Rhein(Rhe), an anthraquinone derivative, exhibits excellent anti-inflammatory effects and other pharmacological activities, but its clinical application remains limited due to poor solubility. The present work aims at the improvement of solubility and oral bioavailability of Rhe through cocrystal formation. For this purpose, Rhe and matrine(Mat) were selected as pharmaceutical ingredient(API) and cocrystal former(CCF), respectively, and the Rhe-Mat cocrystal was synthesized and characterized by single crystal X-ray diffraction(SXRD), powder X-ray diffraction(PXRD), thermogravimetric analysis(TGA), differential scanning calorimetry(DSC). The formation mechanism of Rhe-Mat cocrystal was elucidated by molecular surface electrostatic potential(MSEP). It is worth mentioning that the 50-fold increment of dissolution in vitro was observed in pure water in the form of Rhe-Mat cocrystal. Furthermore, the in vivo studies revealed that Rhe-Mat cocrystal indicated the faster absorption rate and the higher peak blood concentration than the pure Rhe. Hence, it can be concluded that current study successfully improved the solubility and oral bioavailability of Rhe.
基金the Drug Innovation Major Project(No.2018ZX09711001-001-015)the CAMS Innovation Fund for Medical Sciences(No.2020-I2M-1-003)。
文摘The specific crystalline form of a compound remarkably affects its physicochemical properties.Therefore,a detailed analysis of the structural features and intermolecular interactions of a multi-component crystal is feasible to understand the relationships among the structure,physicochemical properties and the formation mechanism.In the present study,three novel cocrystal salt solvates of rhein and berberine were reported for the first time.Various solid characterizations and theoretical computations based on density functional theory(DFT)were carried out to demonstrate the intermolecular interactions.The theoretical computation shows that the strongest interaction existed between berberine cation and rhein anion,and the electrostatic interaction play a dominant role.However,no salt bond was observed between them.Further intrinsic dissolution rate analysis in water shows that the monohydrate exhibits 17 times enhancement in comparison with rhein.The rhein and berberine combined in ionic state in cocrystal salt is the main reason for the solubility improvement.This paper suggests that the interactions between the different components can be visualized and qualitatively and quantitatively analyzed by theoretical computation,which is helpful to understand the relationship between stereochemical structure and physicochemical properties of multi-component complex.
文摘Glutaraldehyde(GA),the most widely used crosslinking agent for biomaterials,is cytotoxic.CaCl_(2) is of particular interest due to its non-toxic nature.Rhein can chelate Ca^(2+)and promote bone growth.Here we reported a novel nano calcium-deficient hydroxyapatite/O-carboxymethyl chitosan-CaCl_(2) microspheres loaded with rhein(RH-nCDHA/OCMC-CaCl_(2) microspheres)using CaCl_(2) as crosslinking agent for bone defect repair.The obtained microspheres were characterized by X-ray diffraction(XRD),scanning electron microscopy(SEM),thermogravimetric analysis(TG)and Fourier transform infrared spectroscopy(FT-IR).The surface of the obtained microspheres is rough with quite a few voids.The nano calcium-deficient hydroxyapatite(nCDHA)accounts for about 70% of the total weight of the microspheres,which is equivalent to the proportion of inorganic substances in human bones.A high encapsulation efficiency(EE)and loading capacity(LC)of the microspheres loaded with rhein was 90.20±0.60% and 11.03±0.30%,respectively.For microspheres using CaCl_(2) in simulated body fluid(SBF)after 14 days,the drug released continuously and bone-like apatite formed like layer.The cells on the surface of the RH-nCDHA/OCMC-CaCl_(2) microspheres grew better comparing with nCDHA/OCMC-GA microspheres and the skull defects of rats after landfill can be almost repaired after 8 weeks,which revealed the potential of the microspheres for bone repair.
文摘OBJECTIVE:To predict the anti-inflammatory targets and related pathways of rhein in the treatment of asthma by using network pharmacology,and to further explore its potential mechanism in asthma.METHODS:The corresponding targets of rhein were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),and the rhein-target network was constructed with Cytoscape 3.7.1 software.The Genbank and Drugbank databases were used to collect and screen asthma targets,and the rhein-target-disease interaction network was constructed.A target protein-protein interaction(PPI)network was constructed using the STRING database to screen key targets.Finally,Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis was used to identify biological processes and signaling pathways.The anti-asthmatic effects of rhein were tested in vitro,and the expression levels of proteins in the mitogen-activated protein kinase/nuclear factor kappa-B(MAPK/NF-κB)signaling pathway were assessed by western blot analysis.RESULTS:Altogether,83 targets of rhein were screened in the relevant databases,989 targets of asthma were obtained in the National Center for Biotechnology Information(NCBI)GENE Database.PPI network analysis and KEGG pathway enrichment analysis predicted that rhein could regulate the epidermal active growth factor receptor(EGFR),mitogen-activated protein kinase 14(MAPK14),tumour necrosis factor receptor superfamily member 1A(TNFRSF1A),receptor tyrosineprotein kinase erb B-2(ERBB2),and other signaling pathways.Furthermore,we selected the MAPK signaling pathway to determine the anti-inflammatory effects of rhein.Consistently,further in vitro experiments demonstrated that rhein was shown to inhibit HBE cells inflammation.CONCLUSION:The anti-inflammatory mechanism of rhein in the treatment of asthma may be related to EGFR,MAPK14,TNFRSF1A and ERBB2 as well as their signaling pathways.To prevent the exacerbation of asthma,instead of targeting a single pathway or a single target,all these targets and their signaling pathways should be controlled holistically.Rhein may alleviate the inflammation of asthma by inhibiting the MAPK/NF-κB pathway.
基金National Natural Science Foundation Project (No.81873174)。
文摘Objective:To explore the protective effects of rhein on cardiomyocyte injury in DCM and its possible mecha-nism.Methods:The diabetic model was induced by intraperitoneal injection with streptozotocin and high-fat diet.The mice were randomly divided into control group,DM group,and DM+RH group.After 12 weeks treatment with rhein,the change of fast blood glucose,body weight,and heart weight/body weigh(t HW/BW)were observed.HE and Masson staining were used to evalu-ate myocardial structural damage.Transmission electron microscope was used to observe the myocardial mitochondrial structure.The mRNA levels of Sirt1,PGC-1α,TFAM,ANP,BNP andβ-MHC were quantified by RT-PCR.Sirt1,PGC-1α and TFAM protein levels were estimated by Western blot and IHC.Results:Compared with control group,the blood glucose,HW/BW,ANP,BNP andβ-MHC mRNA of DM group were significantly increased(P<0.05).The structures of myocardium and mitochondria were obviously destroyed in DM group.Sirt1,PGC-1α and TFAM expression were significantly decreased(P<0.05).Compared with DM group,the blood glucose,HW/BW,ANP,BNP and β-MHC mRNA of DM+RH group were decreased(P<0.05).The myocardial and mitochondrial injury were improved.Sirt1,PGC-1α and TFAM expression were significantly increased(P<0.05).Conclusion:Rhein exhibits protective effects on diabetic cardiomyopathy which may be achieved by activating Sirt1/PGC-1α pathway.
文摘To study the effect ofrhein on embryo development of rats and fetuscs,the SD rats were divided into rhein(87.5,175 and 350 mg/kg)group and negative control group treated with 0.5%CMC(carboxyl methyl cellulose).The rats were administrated with rhein daily for 10 days from 6th to 15th day after pregnancy.The pregnancy rats were dissected at 20th day after pregnancy.The total weight of the fetuses,the number of corpus luteum,plant gland,absorbed fetus,live fetus,dead futus,monsters,body weight,body height and tail length were recorded.Compared with the control group,rhein group occurred with the administration of toxicity-related clinical symptoms.The changes in weight increase related with the amount ofrhein(P〈0.05)and the increased number of absorbed fetuses in each rhein group(P〈0.05)were presented.Obvious differences occurred in the rhein groups in terms of the incidence of visceral abnormalities,each organ abnormalities and fossa malformations,etc.(P〈0.05).Compared with the control group,there was no significant difference in the low-dose group by fetal rat bone examination(P〉0.05),while the remaining dose groups manifested various bone deformities such as sternum sections missing,incomplete ossification of the skull and thoracic vertebrae separation or deformation,which was obviously different from the control group(P〈0.01).Rhein had a significant effect on the reproductive function of pregnant rats.It can even result in the bones'and internal organs'dysplasia of fetal rats.Rhein has a significant teratogenic effect in rats.
基金Supported by the National Natural Science Foundation of China(No.2113600921106162+2 种基金21106152)Supported by the National Key Laboratory of Chemical Engineering(No.SKL-ChE-11A04)Supported by the Ministry of Human Resources and Social Security of China
文摘Several three-liquid-phase extraction systems comprised of organic extractant,polymer and salt aqueous solution were applied to isolate and purify simulated herbal extract containing emodin and rhein.Some influential factors on the partitioning behaviors were studied.The results revealed that extractant type and solution pH value were crucial factors for improving the separation performance.The optimal separation results were obtained at pH 8.00 with methyl isobutyl ketone as the extractant,10%(ω) polyethylene glycol with the molecular weight 4000 Da,and 10%(ω) ammonium sulphate.Under the optimized conditions,95%emodin and 97%rhein were simultaneously extracted into the organic phase and polymer-rich phase from simulated herbal solution with the initial concentration of 100×l0^(-6)(ω),respectively,and their separation factor of over 10000 was achieved.By adjusting pH value,back extraction rate of both emodin and rhein could be up to about 99%.With the assistance of molecular simulation program XLOGP3 and molecular orbital package,the possible mechanism of extraction was analyzed,and hydrophobic interaction and hydrogen-bonding interaction might be the major driving forces affecting the partitioning behaviors of emodin and rhein.
基金supported by the National Natural Science Foundation of China(No.81973696)。
文摘Objective:The anthraquinone compound rhein(1,8-dihydroxy-3-carboxyanthraquinone),derived from Rhei Radix et Rhizoma(rhubarb,Dahuang in Chinese),exhibits notable anti-fibrotic effects.However,the mechanisms underlying these effects have not been fully elucidated.Suppressor of mothers against decapentaplegic 3(Smad3)phosphorylation plays a crucial role in the canonical transforming growth factor-β(TGF-β)/Smad signalling pathway.In this study,we investigated the effect of rhein on the TGF-β/Smad signalling pathway in renal interstitial fibrosis(RIF).Methods:A unilateral ischaemia-reperfusion injury(UIRI)rat model was employed to simulate renal injury and assess the therapeutic effect of rhein in vivo.In vitro,TGF-β1-stimulated NRK-52E rat renal epithelial cells and HK-2 human proximal tubular epithelial cells were used to mimic fibrotic conditions.Rhein's interaction with Smad3 was further explored using molecular docking and bio-layer interferometry assays.Additionally,Smad3 knockdown and overexpression studies were performed in HK-2 cells to elucidate the functional role of Smad3 in rhein-mediated anti-fibrotic activity.Results:Rhein treatment significantly improved renal function and reduced fibrosis in UIRI rats,primarily by inhibiting Smad3 phosphorylation.Rhein treatment mitigated aberrant remodelling and extracellular matrix accumulation in both NRK-52E and HK-2 cells and in the UIRI rat model.The anti-fibrotic effects of rhein were attenuated by Smad3 deficiency but enhanced by Smad3 overexpression in HK-2 cells.Conclusion:Rhein exerts its anti-fibrotic effects in renal interstitial fibrosis by targeting the TGF-β/Smad3signaling pathway.Acting as a natural antagonist of Smad3,rhein offers promising potential for therapeutic development in renal fibrosis.These findings provide a new mechanistic insight for further clinical research and drug development.
基金the National Key R&D Program of China(No.2019YFC1711000)Subject Innovation Team of Shaanxi University of Chinese Medicine(No.2019-YL10)。
文摘Diabetic kidney disease(DKD)is the primary cause of mortality among diabetic patients.With the increasing prevalence of diabetes,it has become a major concern around the world.The therapeutic effect of clinical use of drugs is far from expected,and therapy choices to slow the progression of DKD remain restricted.Therefore,research on new drugs and treatments for DKD has been a hot topic in the medical field.It has been found that rhein has the potential to target the pathogenesis of DKD and has a wide range of pharmacological effects on DKD,such as anti-nephritis,decreasing blood glucose,controlling blood lipids and renal protection.In recent years,the medical value of rhein in the treatment of diabetes,DKD and renal disease has gradually attracted worldwide attention,especially its potential in the treatment of DKD.Currently,DKD can only be treated with medications from a single symptom and are accompanied by adverse effects,while rhein improves DKD with a multi-pathway and multi-target approach.Therefore,this paper reviews the therapeutic effects of rhein on DKD,and proposes solutions to the limitations of rhein itself,in order to provide valuable references for the clinical application of rhein in DKD and the development of new drugs.
