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catalpol Prevents Glomerular Angiogenesis Induced by Advanced Glycation End Products via Inhibiting Galectin-3

当代医学科学(英文) 2023年第4期43卷 668-678页

作者： Wei-xiang SUN Yu-yan GAO Ying CAO Jin-fu LU Gao-hong LV Hui-qin XU Jiangsu Key Laboratory for High-Tech Research and Development of Veterinary Biopharmaceuticals Jiangsu Agri-animal Husbandry Vocational CollegeTaizhou 225300China Department of Chinese Pharmaceutical Technology School of Animal PharmacyJiangsu Agri-animal Husbandry Vocational CollegeTaizhou 225300China Department of Pharmacology School of PharmacyNanjing University of Chinese MedicineNanjing 210023China Jiangsu Key laboratory of Pharmacology and Safety Evaluation for Chinese Material Medica Nanjing University of Chinese MedicineNanjing 210023China Department of Pharmacology School of PharmacyNanjing University of Chinese Medicine Hanlin CollegeTaizhou 225300China

Objective:The main characteristics of diabetic nephropathy(DN)at the early stage are abnormal angiogenesis of glomerular endothelial cells(GECs)and macrophage infiltration.Galectin-3 plays a pivotal role in the pathogenesis of DN via binding with its ligand,advanced glycation end products(AGEs).catalpol,an iridoid glucoside extracted from Rehmannia glutinosa,has been found to ameliorate vascular inflammation,reduce endothelial permeability,and protect against endothelial damage in diabetic milieu.However,little is known about whether catalpol could exert an anti-angiogenesis and anti-inflammation effect induced by AGEs.Methods:Mouse GECs(mGECs)and RAW 264.7 macrophages were treated with different concentrations of AGEs(0,50,100,200 and 400μg/mL)for different time(0,6,12,24 and 48 h)to determine the optimal concentration of AGEs and treatment time.Cells were treated with catalpol(10μmol/L),GB1107(1μmol/L,galectin-3 inhibitor),PX-478(50μmol/L,HIF-1αinhibitor),adenovirus-green fluorescent protein(Ad-GFP)[3×10^(7)plaque-forming unit(PFU)/mL]or Ad-galectin-3-GFP(2×10^(8)PFU/mL),which was followed by incubation with 50μg/mL AGEs.The levels of galectin-3,vascular endothelial growth factor A(VEGFA)and pro-angiogenic factors angiopoietin-1(Ang-1),angiopoietin-2(Ang-2),tunica interna endothelial cell kinase-2(Tie-2)were detected by enzyme-linked immunosorbent assay(ELISA).Cell counting kit-8(CCK-8)assay was used to evaluate the proliferation of these cells.The expression levels of galectin-3,vascular endothelial growth factor receptor 1(VEGFR1),VEGFR2,and hypoxia-inducible factor-1α(HIF-1α)in mGECs and those of galectin-3 and HIF-1αin RAW 264.7 macrophages were detected by Western blotting and immunofluorescence(IF)staining.The rat DN model was established.catalpol(100 mg/kg)or GB1107(10 mg/kg)was administered intragastrically once a day for 12 weeks.Ad-galectin-3-GFP(6×10^(7)PFU/mL,0.5 mL)or Ad-GFP(6×10^(6)PFU/mL,0.5 mL)was injected into the tail vein of rats 48 h before the sacrifice of the animals.The expression of gale

关键词： catalpol glomerular angiogenesis advanced glycation end products galectin-3

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Protective effects of catalpol on cardio-cerebrovascular diseases: A comprehensive review

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Journal of Pharmaceutical Analysis 2023年第10期13卷 1089-1101页

作者： Zixi Zhang Yongguo Dai Yichao Xiao Qiming Liu Department of Cardiovascular Medicine The Second Xiangya HospitalCentral South UniversityChangshaHunan410011China Department of Clinical Pharmacology College of PharmacyDalian Medical UniversityDalianLiaoning116044China Department of Pharmacology Wuhan University TaiKang Medical School(School of Basic Medical Sciences)Wuhan430071China

catalpol,an iridoid glucoside isolated from Rehmannia glutinosa,has gained attention due to its potential use in treating cardio-cerebrovascular diseases(CVDs).This extensive review delves into recent studies on catalpol's protective properties in relation to various CVDs,such as atherosclerosis,myocardial ischemia,infarction,cardiac hypertrophy,and heart failure.The review also explores the compound's anti-oxidant,anti-inflammatory,and anti-apoptotic characteristics,emphasizing the role of vital signaling pathways,including PGC-1a/TERT,PI3K/Akt,AMPK,Nrf2/HO-1,estrogen receptor(ER),Nox4/NF-kB,and GRP78/PERK.The article discusses emerging findings on catalpol's ability to alleviate diabetic cardiovascular complications,thrombosis,and other cardiovascular-related conditions.Although clinical studies specifically addressing catalpol's impact on CVDs are scarce,the compound's established safety and well-tolerated nature suggest that it could be a valuable treatment alternative for CVD patients.Further investigation into catalpol and related iridoid derivatives may unveil new opportunities for devising natural and efficacious CVD therapies.

关键词： catalpol Cardio-cerebrovascular diseases Anti-atherosclerosis Cerebrovascular protection Heart protection

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Global gene expression analysis in liver of db/db mice treated with catalpol

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Chinese Journal of Natural Medicines 2018年第8期16卷 590-598页

作者： LIU Jing ZHANG He-Ran HOU Yan-Bao JING Xiao-Long SONG Xin-Yi SHEN Xiu-Ping Tianjin Institute of Pharmaceutical Research Co. Ltd. Tianjin Institute of Pharmaceutical Research Drug Safety Assessment Co. Ltd. Qinghai Yangzong Pharmaceutical Co. Ltd.

catalpol,a major bioactive component from Rehmannia glutinosa,which has been used to treat diabetes.The present study was designed to elucidate the anti-diabetic effect and mechanism of action for catalpol in db/db mice.The db/db mice were randomly divided into six groups(10/group) according to their blood glucose levels:db/db control,metformin(positive control),and four dose levels of catalpol treatment(25,50,100,and 200 mg·kg^(-1)),and 10 db/m mice were used as the normal control.All the groups were administered orally for 8 weeks.The levels of fasting blood glucose(FBG),random blood glucose(RBG),glucose tolerance,insulin tolerance,and glycated serum protein(GSP) and the globe gene expression in liver tissues were analyzed.Our results showed that catalpol treatment obviously reduced water intake and food intake in a dose-dependent manner.catalpol treatment also remarkably reduce fasting blood glucose(FBG) and random blood glucose(RBG) in a dose-dependent manner.The RBG-lowering effect of catalpol was better than that of metformin.Furthermore,catalpol significantly improved glucose tolerance and insulin tolerance via increasing insulin sensitivity.catalpol treatment significantly decreased GSP level.The comparisons of gene expression in liver tissues among normal control mice,db/db mice and catalpol treated mice(200 and 100 mg·kg^(-1)) indicated that there were significant increases in the expressions of 287 genes,whichwere mainly involved in lipid metabolism,response to stress,energy metabolism,and cellular processes,and significant decreases in the expressions of 520 genes,which were mainly involved in cell growth,death,immune system,and response to stress.Four genes expressed differentially were linked to glucose metabolism or insulin signaling pathways,including Irs1(insulin receptor substrate 1),Idh2(isocitrate dehydrogenase 2(NADP+),mitochondrial),G6pd2(glucose-6-phosphate dehydrogenase 2),and SOCS3(suppressor of cytokine signaling 3).In conclusion,catalpol ecerted significant hypoglycemic effect and remar

关键词： catalpol db/db Mice Antidiabetic effect DNA microarray Gene expression SOCS3

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Protective effects of catalpol and rhein in murine experimental autoimmune encephalomyelitis via regulation of T helper (Th)1, Th2,Th17, and regulatory T cell responses

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Journal of Traditional Chinese Medicine 2019年第6期39卷 809-817页

作者： Wei Mingyan Yang Tao Li Qian Zhou Dongdong Du Zongpan Fan Yongping Department of Traditional Chinese Medicine Beijing Tiantan HospitalCapital Medical UniversityBeijing 100050China Beijing Tongrentang Traditional Chinese Medicine Hospital Beijing 100051China Department of Traditional Chinese Medicine Beijing Tiantan HospitalCapital Medical UniversityBeijing 100070China Beijing Integrative Medicine on Encephalopathy Research Institution Beijing 100070China Center for Integrative Medicine Beijing Ditan HospitalCapital Medical UniversityBeijing 100015China Department of Neurology Beijing Daxing District Hospital of Integrated Chinese and Western MedicineBeijing 100076China

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.

关键词： Multiple sclerosis Encephalomyelitis Autoimmunity catalpol Rhein Th1-Th2 balance Th17 cells

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Relationship with spatial memory in diabetic rats and protein kinase Cγ,caveolin-1 in the hippocampus and neuroprotective effect of catalpol

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Chinese Medical Journal 2014年第5期127卷 916-923页

作者： Zhou Haicheng Liu Jing Ren Liyuan Liu Wei Xing Qian Men Lili Song Guirong Du Jianling Department of Endocrinology First Affiliated Hospital of Dalian Medical University Dalian Liaoning 116011 China

Background The mechanisms underlying diabetic encephalopathy are largely unknown,and no effective treatments are available.catalpol has received much attention due to its numerous biological effects,especially in neuroprotective studies.The aim of this study was to investigate the effects of catalpol on cognitive functions in diabetic rats and the underlying mechanisms.Methods A rat model of diabetes was established by streptozotocin injection,followed by intraperitoneal infusion of catalpol after 10 weeks.Two weeks later,the Morris water maze was used to test the spatial learning performance.Nissl staining was performed to evaluate the morphological changes in the hippocampus.Expression of protein kinase Cy （PKCy） and caveolin-1 （Cav-1） in the hippocampus were assessed by reverse transcription PCR and Western blotting.Activities of anti-oxidative enzymes such as glutathione （GSH）,superoxide dismutase （SOD） and catalase （CAT） and levels of malonaldehyde （MDA） were measured using commercial kits.Results Significant hippocampal neuronal injury was observed in rats with streptozotocin-induced diabetes.Moreover,cognitive dysfunction was associated with markedly increased oxidative stress in the brain.catalpol treatment significantly attenuated cognitive deficits,neuronal damage,and oxidative stress in the brain of diabetic rats.Biochemical analyses showed that catalpol reversed the down-regulation of PKCγ and Cav-1 expression in the diabetic rats.Conclusions Spatial memory in diabetic rats is associated with the expression of PKCy and Cav-1.catalpol treatment markedly attenuated oxidative stress,reversed the alteration of PKCy,Cav-1 and spatial memory deficits.

关键词： catalpol diabetic encephalopathy protein kinase Cγ caveolin-1

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Changes in synapse quantity and growth associated protein 43 expression in the motor cortex of focal cerebral ischemic rats following catalpol treatment

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Neural Regeneration Research 2011年第18期6卷 1380-1385页

作者： Dong Wan Huifeng Zhu Yong Luo Peng Xie Department of Emergency First Affiliated Hospital of Chongqing Medical University Chongqing 400016 China College of Pharmaceutical Sciences & College of Chinese Medicine Southwest University Chongqing 400715 China Department of Neurology First Affiliated Hospital of Chongqing Medical University Chongqing 400016 China

The present study investigated the effects of catalpol, the main constituent of the Chinese herb Rehmannia root, on neurons following brain ischemia, A rat model of focal permanent brain ischemia was established using electrocoagulation, The rats were intrapedtoneally injected with catalpol, at a dose of 5 mg/kg, daily for 1 week, Results showed that the number of neuronal synapses in the motor cortex and growth associated protein 43 expression were increased following catalpol treatment, indicating that catalpol might contribute to neuroplasticity and ameliorate functional neurological deficits induced by cerebral ischemia.

关键词： catalpol growth-associated protein 4：3 neurological function permanent middle cerebral artery occlusion behavioral assessment neurological deficit neuroplasticity neural regeneration

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LC/MS/MS and radioisotope method combined for recognizing the affinity between catalpol and OCT2 transporter

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Frontiers of Chemical Science and Engineering 2012年第4期6卷 436-442页

作者： Zhiyu ZHANG Changxiao LIU Duanyun SI Rong LU Xiulin YI School of Chemical Engineering and Technology Tianjin UniversityTianjin 300072China State Key Laboratory of Drug Delivery Technology and Pharmacokinetics Tianjin Institute of Pharmaceutical ResearchTianjin 300193China

More and more herbal medicines are found to be the substrates of drug transporters. In this paper, chromatography/tandem mass spectrometry （LC/MS/MS） combined with radioisotope method was used for the quantification of catalpol, a traditional Chinese medicine, to study the affinity relationship between herbal medicines and transporters. catalpol uptake experiment was carried out by using several transporters （OAT1, OCT2, OAT3, OATP 1B 1 and OATP2B 1）. And samples were precipitated with methanol and quantified with LC/MS/MS. The results show that catalpol has a good affinity with OCT2- transfected $2 cells. After studying drug-drug interaction between catalpol and 14C-tetraethylammonium （TEA）, we found that catalpol is able to facilitate TEA transport mediated by OCT2, suggesting that catalpol could probably be a new promoter of OCT2.

关键词： catalpol LC/MS/MS OCT2

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Synergistic interactions of catalpol and stachyose in STZ-HFD induced diabetic mice: Synergism in regulation of blood glucose, lipids, and hepatic and renal function

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Chinese Herbal Medicines 2019年第1期11卷 70-77页

作者： Xiao-fang Chen Deng-qun Liao Zhen-xian Qin Xian-en Li Institute of Medicinal Plant Development Chinese Academy of Medical Sciences & Peking Union Medical College

Objective: Rehmanniae Radix has been traditionally used to treat diabetes. catalpol(CAT) and stachyose(STA) are two of the main bioactive compounds in Rehmannia Radix and found to have similar therapeutic effects on diabetes and its complications. In this paper, we aimed to investigate whether there were synergistic therapeutic effects of CAT and STA on diabetes.Methods: Streptozotocin(STZ) with the feeding of high-sugar-high-fat diet(HFD) was applied to induce diabetic C57BL/6 mice. STZ-HFD induced diabetic mice were then divided into model and six medicaltreated groups: metformin(MET), STA, CAT, and three combinations of CAT:STA(1:1, 1:2, 2:1). Blood, liver,and kidney samples were isolated after six-week oral administration for biochemical assays of serum lipids, the indicators of kidney and liver functions and HE staining for liver tissues.Results: It turned out that CAT, STA and their three combinations(1:1, 1:2, 2:1) could effectively control body weight, blood glucose, kidney weight and liver weight index, and well regulate levels of TC, HDL-c,TG, ALT, and TBA. In addition, CAT and its combination with STA at the ratio of 2:1 could significantly improve albumin content, compared to that in model group. STA and CAT and their combinations showed the improvements on kidney function in terms of urinary creatinine(Ucr). However, there were no such consistent observations on serum creatinine(Scr) and creatinine clearance rate(Ccr). The combination of CAT and STA at the ratio of 1:1 exhibited the better adjusting effects on kidney weight and liver weight indexes and the levels of ALT, Ucr, Scr, and Ccr. Our results demonstrated that the combinations of CAT and STA especially 1:1 showed similar or better improvements on diabetes-associated complications,compared to the sole CAT or STA treatment.Conclusion: Thus, we concluded that there were synergistic therapeutic effects between CAT and STA on STZ/HFD-induced type 2 diabetes. This project provided insights and technical supports for the innovation of discovering b

关键词： catalpol high-sugar and high-fat diet Rehmannia glutinosa Libosch stachyose STZ-induced diabetes synergism

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catalpol Upregulates Hippocampal GAP-43 Level of Aged Rats with Enhanced Spatial Memory and Behavior Response

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Journal of Behavioral and Brain Science 2012年第4期2卷 495-504页

作者： Jing Liu Yang Liu Wei Zou Lin Song Lijia An Department of Biology Liaoning Normal University Dalian China School of Environmental and Biological Science Dalian University of Technology Dalian China Sino-UK Regenerative Medicine Center the First Affiliated Hospital of Dalian Medical University Dalian China

Rehmannia glutinosa is a traditional Chinese medical herb and has a long history in cognitive deficits therapy. Its ther-apeutic efficacy has been confirmed by clinical studies. In this study, we attempted to investigate the effects of catalpol, an iridoid from Rehmannia glutinosa, on cognitive and behavioral function of aged rats with memory loss. 22 - 24 month Sprague-Dawley spontaneous rats of memory loss with aging were selected by step-down type passive avoidance test and randomly allocated to two groups: the aged rats with memory loss (control group) and the catal- pol-treated (5 mg/kg) group. We performed open-field and Y-maze test to evaluate special performance and behavior response before and after catalpol treatment for 5 and 10 days. Growth-associated protein (GAP-43) in hippocampus and frontal cortex was measured using immunohistochemistry and quantitative Western Blotting. The results showed that catalpol could significantly improve not only spatial learning and memory but also locomotor activity and ex-plora- tory behavior of aged rats with memory loss. GAP-43 protein in hippocampal CA3 region and dentate granule of catal- pol-treated rats was significantly enhanced than that of control group. Western blot analysis demonstrated a catal- pol-associated increase of GAP-43 in hippocampus of catalpol-treated rats and correlated with spatial memory, loco- motor activity and exploratory behavior. However, there was no difference in GAP-43 protein in frontal cortex between two groups. These results indicated that catalpol could enhance spatial performance and behavioral responses in aged rats with memory loss, and the mechanism may involve up-regulation of GAP-43 level of hippocampus in the brain. It also suggested that catalpol may be a useful natural drug for Alzheimer’s disease (AD) treatment by modulating hippo- campal neuroplasticity.

关键词： catalpol GAP-43 Protein Neuroplasticity Behavior Memory Loss with Aging

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Development and Validation of an LC-MS/MS Method for Determination of catalpol and Harpagide in Small Volume Rat Plasma: Application to a Pharmacokinetic Study

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Yangtze Medicine 2018年第2期2卷 95-107页

作者： Shuangmin Chen Yijun Ren Xi Xu Dandan Li Wenlian Li Zhenzhen Liu Department of Medical Function Health Medical Center Yangtze University Jingzhou China Department of Drug Clinical Trails Center Hospital of Jingzhou Jingzhou China

A rapid and sensitive liquid chromatography-tandem mass chromatography (LC-MS/MS) method has been developed and validated for simultaneous determination of catalpol and harpagide in rat plasma. The samples were extracted by one-step protein precipitation and separated on a SunFireTM C18 column (100 mm × 2.1 mm, 3.5 μm;Waters) using acetonitrile-10 mM ammonium formate as mobile phase at a flow rate 0.3 mL/min in gradient mode. The analytes were detected without interference in Multiple Reaction Monitoring (MRM) mode with negative electrospray ionization. Linear responses were obtained for catalpol ranging from 20 to 5000 ng/mL and harpagide ranging from 10 to 2500 ng/mL. Coefficients of correlation (r) for the calibration curves were more than 0.99 for both analytes. Intra- and inter-day accuracy and precision were within the acceptable limits of less than 15.0% at all concentrations. The quantitation method was successfully applied for simultaneous estimation of catalpol and harpagide after oral administration of Zeng Ye Decoction.

关键词： LC-MS/MS Pharmacokinetics catalpol Harpagide Zeng Ye Decoction

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