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
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
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
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
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
Background:As accelerators and products of the progression of chronic kidney disease(CKD),advanced oxidation protein products(AOPPs)affect the function of the liver.Huang Gan granules(HGGs)are commonly used to prevent...Background:As accelerators and products of the progression of chronic kidney disease(CKD),advanced oxidation protein products(AOPPs)affect the function of the liver.Huang Gan granules(HGGs)are commonly used to prevent the progression of CKD,but the pharmacokinetics of aloe-emodin,emodin,rhein,and chrysophanol in HGGs in CKD remain unknown.Objective:To investigate the influence and its molecular mechanism of AOPPs on the in vivo pharmacokinetics of aloe-emodin,emodin,rhein,and chrysophanol in HGGs.Methods:We constructed 5/6 nephrectomised(5/6 nx),adenine-induced(adenine)and AOPP-treated rat models.After oral administration of HGG,the concentrations of aloe-emodin,emodin,rhein,and chrysophanol in the plasma samples were detected by high-performance liquid chromatography(HPLC),and their pharmacokinetics were analysed with the PKSolver software.The plasma concentrations of IL-6 and TNF-αare detected by enzyme linked immunosorbent assay(ELISA).The RT-PCR was performed in the HepG2 cells to explore the effect of TNF-αand IL-6 on the mRNA expression of CYP1A2 and CYP3A4.Result:The results showed that the method was suitable for the quantification of four anthraquinones in plasma and excreta samples with satisfactory linear(R R^(2)>0.9931),precision(<9.4%)and accuracy(±10%).In 5/6 nx,adenine and AOPPs-treated rats,the concentrations of TNF-αand IL-6 were increased.In 5/6 nx and adenine rats,the pharmacokinetic parameters(t_(1/2),MRT_(0-∞)and AUC_(0-∞))of aloe-emodin,emodin,rhein,and chryso-phanol were,respectively,significantly increased and correlated with the concentration of AOPPs.In AOPPs-treated rats,the concentration of AOPPs was significantly increased and the pharmacokinetic parameters of four anthraquinones were also increased.Conclusion:In summary,inflammatory cytokine production may be one of the important causes in AOPPs’regulat-ing the pharmacokinetic of aloe-emodin,emodin,rhein,and chrysophanol in the CKD rats.Studies of aloe-emodin,emodin,rhein,and chrysophanol in CKD facilitate the appropriate prescription of HGGs in the clinical.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
Objectives To investigate the effect of rhein on endothelial plasminogen activator inhibitor-1 (PAI-1) mRNA expression and protein production induced by transforming growth factor β1 (TGFβ1), and to explore the mech...Objectives To investigate the effect of rhein on endothelial plasminogen activator inhibitor-1 (PAI-1) mRNA expression and protein production induced by transforming growth factor β1 (TGFβ1), and to explore the mechanism of the protective action of rhein on endothelial cells. Methods A human umbilical endothelium derived cell line (ECV-304) from ATCC was used in this study. The PAI-1 mRNA expression and protein synthesis in the endothelial cells were detected by Northern blot and flow cytometry analysis, respectively. The activity of phospho-p44/p42 MAP kinase induced by TGFβ1 was determined by immunoprecipitation analysis and western blot. Results TGFβ1 rapidly increased PAI-1 mRNA expression in the endothelial cells, and this effect lasted at least 24 hours. The upregulation of PAI-1 mRNA expression induced by TGFβ1 in endothelial cells was inhibited by rhein in a dose-dependent manner. In addition, rhein inhibited endothelial PAI-1 protein production. Further study revealed that rhein had a significant inhibitory effect on the activity of phospho-p44/p42 MAP kinase induced by TGFβ1 in human endothelial cells. Conclusions Our results showed that rhein may have a protective effect on the endothelial dysfunction by inhibiting overexpression of PAI-1, indicating a way for the treatment of vascular diseases.展开更多
Background 5-dihydroxyanthraquinone-2-carboxylic acid (rhein) inhibits oxidoreduction induced by reducing nicotingamide adenine dinucleotide in the mitochondria and reducing reactive oxygen species, it also suppresses...Background 5-dihydroxyanthraquinone-2-carboxylic acid (rhein) inhibits oxidoreduction induced by reducing nicotingamide adenine dinucleotide in the mitochondria and reducing reactive oxygen species, it also suppresses lipid peroxidation in rat brain homogenates. This study was to assess the effects of anthraquinone derivatives, rhein on synaptic transmission in the rat hippocampal CA_1 pyramidal cell layer by intracellular recording.Methods The excitatory postsynaptic potential (EPSP) evoked by stimulation of the Schaffer collaterals in the presence of bicuculline (15 μmol/L) was depressed by application of rhein (0.3-30 μmol/L). The amplitude of the EPSP was restored within 20 minutes after removal of rhein from the supernatant. At a concentration of 30 μmol/L, rhein reduced the amplitude of the EPSP to 42%±3.7% (n=24) of the control. Subsequently, wavelet spectral entropy was used to analyze the EPSP. Results A strong positive correlation was observed between the wavelet spectral entropy and other parameters such as amplitude, slope of rising phase and slope of descending phase of the EPSP. The paired-pulse facilitation (PPF) of the EPSP was significantly increased by rhein (30 μmol/L). The inhibitory postsynaptic potential (IPSP) recorded in the presence of CNQX (20 μmol/L) and APV (40 μmol/L) is not altered by rhein (30 μmol/L). Conclusions Rhein (30 μmol/L) can decrease the frequency but not the amplitude of the miniature EPSP (mEPSP). It is suggested that rhein inhibits excitatory synaptic transmission by decreasing the release of glutamate in rat hippocampal CA_1 pyramidal neurons.展开更多
Objective To explore the effect of rhein on the regulation of glucose transporter 1 (GLUT1) overexpression and the possible molecular mechanism that rhein antagonize the effect of transforming growth factor β1 (TGF ...Objective To explore the effect of rhein on the regulation of glucose transporter 1 (GLUT1) overexpression and the possible molecular mechanism that rhein antagonize the effect of transforming growth factor β1 (TGF β1) in glomerular mesangial cells Methods Cultured mouse mesangial cells were used The expression of GLUT1 mRNA was detected by Northern blotting; the ability of glucose uptake was determined by 2 deoxy [ 3H] D glucose uptake assay Results Rhein had no effect on glucose uptake in mesangial cells cultured in normal glucose concentration TGF β1 could upregulate the expression of GLUT1 mRNA and glucose uptake in mesangial cells This effect was markedly attenuated by the addition of rhein in a dose dependent manner Conclusions TGF β1 could upregulate the expression of GLUT1 mRNA and glucose uptake in mesangial cells, resulting in excessive glucose consumption and extracellular matrix production in diabetic nephropathy Rhein antagonized the effect of TGF β1 in mesangial cells, so it might be a hopeful remedy for the treatment of patients with diabetic展开更多
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.
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 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.
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supported by Guangdong Science and Technology Program(No.2015B020211006)the Technology Project of Guangzhou City in China(No.201604020137)+2 种基金Shenzhen Foundation of Science and Technology(No.JCYJ20190814112205770)Research Foundation of Shenzhen Hospital of Southern Medical University(No.PY2021YM03)the Project of Traditional Chinese Medicine Bureau of Guangdong Province(No.20221273).
文摘Background:As accelerators and products of the progression of chronic kidney disease(CKD),advanced oxidation protein products(AOPPs)affect the function of the liver.Huang Gan granules(HGGs)are commonly used to prevent the progression of CKD,but the pharmacokinetics of aloe-emodin,emodin,rhein,and chrysophanol in HGGs in CKD remain unknown.Objective:To investigate the influence and its molecular mechanism of AOPPs on the in vivo pharmacokinetics of aloe-emodin,emodin,rhein,and chrysophanol in HGGs.Methods:We constructed 5/6 nephrectomised(5/6 nx),adenine-induced(adenine)and AOPP-treated rat models.After oral administration of HGG,the concentrations of aloe-emodin,emodin,rhein,and chrysophanol in the plasma samples were detected by high-performance liquid chromatography(HPLC),and their pharmacokinetics were analysed with the PKSolver software.The plasma concentrations of IL-6 and TNF-αare detected by enzyme linked immunosorbent assay(ELISA).The RT-PCR was performed in the HepG2 cells to explore the effect of TNF-αand IL-6 on the mRNA expression of CYP1A2 and CYP3A4.Result:The results showed that the method was suitable for the quantification of four anthraquinones in plasma and excreta samples with satisfactory linear(R R^(2)>0.9931),precision(<9.4%)and accuracy(±10%).In 5/6 nx,adenine and AOPPs-treated rats,the concentrations of TNF-αand IL-6 were increased.In 5/6 nx and adenine rats,the pharmacokinetic parameters(t_(1/2),MRT_(0-∞)and AUC_(0-∞))of aloe-emodin,emodin,rhein,and chryso-phanol were,respectively,significantly increased and correlated with the concentration of AOPPs.In AOPPs-treated rats,the concentration of AOPPs was significantly increased and the pharmacokinetic parameters of four anthraquinones were also increased.Conclusion:In summary,inflammatory cytokine production may be one of the important causes in AOPPs’regulat-ing the pharmacokinetic of aloe-emodin,emodin,rhein,and chrysophanol in the CKD rats.Studies of aloe-emodin,emodin,rhein,and chrysophanol in CKD facilitate the appropriate prescription of HGGs in the clinical.
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ThisstudywaspartlysupportedbyagrantfromtheNationalNaturalScienceFoundationofChina (No 3 0 171191)
文摘Objectives To investigate the effect of rhein on endothelial plasminogen activator inhibitor-1 (PAI-1) mRNA expression and protein production induced by transforming growth factor β1 (TGFβ1), and to explore the mechanism of the protective action of rhein on endothelial cells. Methods A human umbilical endothelium derived cell line (ECV-304) from ATCC was used in this study. The PAI-1 mRNA expression and protein synthesis in the endothelial cells were detected by Northern blot and flow cytometry analysis, respectively. The activity of phospho-p44/p42 MAP kinase induced by TGFβ1 was determined by immunoprecipitation analysis and western blot. Results TGFβ1 rapidly increased PAI-1 mRNA expression in the endothelial cells, and this effect lasted at least 24 hours. The upregulation of PAI-1 mRNA expression induced by TGFβ1 in endothelial cells was inhibited by rhein in a dose-dependent manner. In addition, rhein inhibited endothelial PAI-1 protein production. Further study revealed that rhein had a significant inhibitory effect on the activity of phospho-p44/p42 MAP kinase induced by TGFβ1 in human endothelial cells. Conclusions Our results showed that rhein may have a protective effect on the endothelial dysfunction by inhibiting overexpression of PAI-1, indicating a way for the treatment of vascular diseases.
文摘Background 5-dihydroxyanthraquinone-2-carboxylic acid (rhein) inhibits oxidoreduction induced by reducing nicotingamide adenine dinucleotide in the mitochondria and reducing reactive oxygen species, it also suppresses lipid peroxidation in rat brain homogenates. This study was to assess the effects of anthraquinone derivatives, rhein on synaptic transmission in the rat hippocampal CA_1 pyramidal cell layer by intracellular recording.Methods The excitatory postsynaptic potential (EPSP) evoked by stimulation of the Schaffer collaterals in the presence of bicuculline (15 μmol/L) was depressed by application of rhein (0.3-30 μmol/L). The amplitude of the EPSP was restored within 20 minutes after removal of rhein from the supernatant. At a concentration of 30 μmol/L, rhein reduced the amplitude of the EPSP to 42%±3.7% (n=24) of the control. Subsequently, wavelet spectral entropy was used to analyze the EPSP. Results A strong positive correlation was observed between the wavelet spectral entropy and other parameters such as amplitude, slope of rising phase and slope of descending phase of the EPSP. The paired-pulse facilitation (PPF) of the EPSP was significantly increased by rhein (30 μmol/L). The inhibitory postsynaptic potential (IPSP) recorded in the presence of CNQX (20 μmol/L) and APV (40 μmol/L) is not altered by rhein (30 μmol/L). Conclusions Rhein (30 μmol/L) can decrease the frequency but not the amplitude of the miniature EPSP (mEPSP). It is suggested that rhein inhibits excitatory synaptic transmission by decreasing the release of glutamate in rat hippocampal CA_1 pyramidal neurons.
文摘Objective To explore the effect of rhein on the regulation of glucose transporter 1 (GLUT1) overexpression and the possible molecular mechanism that rhein antagonize the effect of transforming growth factor β1 (TGF β1) in glomerular mesangial cells Methods Cultured mouse mesangial cells were used The expression of GLUT1 mRNA was detected by Northern blotting; the ability of glucose uptake was determined by 2 deoxy [ 3H] D glucose uptake assay Results Rhein had no effect on glucose uptake in mesangial cells cultured in normal glucose concentration TGF β1 could upregulate the expression of GLUT1 mRNA and glucose uptake in mesangial cells This effect was markedly attenuated by the addition of rhein in a dose dependent manner Conclusions TGF β1 could upregulate the expression of GLUT1 mRNA and glucose uptake in mesangial cells, resulting in excessive glucose consumption and extracellular matrix production in diabetic nephropathy Rhein antagonized the effect of TGF β1 in mesangial cells, so it might be a hopeful remedy for the treatment of patients with diabetic