Publications by authors named "Zhen-Zhou Jiang"

59 Publications

Altered integrity of hepatocyte tight junctions in rats with triptolide-induced cholestasis.

Chin J Nat Med 2021 Mar;19(3):188-194

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Triptolide (TP), an active component of Tripterygium wilfordiiHook. f. (TWHF), has been widely used for centuries as a traditional Chinese medicine. However, the clinical application of TP has been restricted due to multitarget toxicity, such as hepatotoxicity. In this study, 28 days of oral TP administration (100, 200, or 400 μg·kg·d) induced the occurrence of cholestasis in female Wistar rats, as evidenced by increased serum levels of γ-glutamyl transpeptidase (γ-GGT), alkaline phosphatase (ALP) and hepatic total bile acids (TBAs). In addition, the heptocyte polarity associated with the strcture of tight junctions (TJs) was disrupted in both rats and sandwich-cultured primary hepatocytes. Immunoblotting revealed decreased expression of the TJ-associated proteins occludin, claudin-1, and zonula occludens protein (ZO-1), and downregulated mRNA levels of these TJs was also detected by real-time PCR. An immunofluorescence analysis showed abnormal subcellular localization of occludin, claudin-1 and ZO-1, which was also confirmed by transmission electron microscopy. Moreover, the concentration of FITC-dextran, a marker of paracellular penetration, was found to increase rapidly in bile increased rapidly (within 6 minutes) after treatment with TP, which indicated the functional impairment of TJs. Taken together, these results suggest that the administration of TP for 28 consecutive days to rats could induce cholestatic injury in the liver, and the increased paracellular permeability might play an important role in these pathological changes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1875-5364(21)60020-1DOI Listing
March 2021

[2,3,5,4'-Tetrahydroxystibane-2-O-β-D-glucoside induces liver injury by disrupting bile acid homeostasis and phospholipids efflux].

Zhongguo Zhong Yao Za Zhi 2021 Jan;46(1):139-145

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University Nanjing 210009, China Center for Drug Research and Development, Guangdong Pharmaceutical University Guangzhou 510006, China.

Polygonum multiflorum is a traditional Chinese herbal medicine and has many biological activities such as hair-blacking, anti-atherosclerosis, anti-inflammatory and anti-aging. However, the liver injury induced by P. multiflorum has aroused wide attention in recent years. 2,3,5,4'-tetrahydroxystibane-2-O-β-D-glucoside(TSG) is a main component of P. multiflorum, but the role of TSG in inducing liver injury is unclear. The aim of present study was to evaluate TSG's potential liver injury and effects on bile acid homeostasis and phospholipids efflux. C57 BL/6 J mice received intraperitoneal administration of 400 mg·kg~(-1) of TSG daily for 15 days, and then biochemical indexes of liver injury and changes of phospholipid content were detected. The changes of bile acid compositions were detected by LC-MS/MS. The results showed TSG 400 mg·kg~(-1) significantly increased the content of serum total bile acid(TBA) and alkaline phosphatase(ALP). Elevated free bile acid levels were observed in TSG-treated groups, including β-muricholic acid(β-MCA), ursodeoxycholic acid(UDCA), hyodeoxycholic acid(HDCA), chenodeoxycholic acid(CDCA), deoxcholic acid(DCA) in serum and β-MCA, CDCA in liver. TSG inhibited the protein expression of farnesoid X receptor(FXR) and down stream bile salt export pump(BSEP), which may result in the accumulation of bile acid. TSG also inhibited the expression of 25-hydroxycholesterol-7 alpha-hydroxylase(CYP7 B1), which may disturb the alternative pathway for bile acid synthesis. In addition, intraperitoneal injection of TSG 400 mg·kg~(-1) significantly decreased the content of phospholipids in bile. The research showed that TSG significantly inhibited the expression of multidrug resistance protein 2(MDR2) and destroyed the regular distribution of MDR2 on the bile duct membrane of liver. In vitro results showed that the IC_(50) of TSG on HepG2 cells was about 1 500 μmol·L~(-1) and TSG at 500 μmol·L~(-1)(for 24 h) could destroy the distribution of MDR2 on the bile duct membrane of liver. In conclusion, TSG induced liver injury by disrupting bile acid homeostasis and phospholipids efflux.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.19540/j.cnki.cjcmm.20200818.401DOI Listing
January 2021

Catalpol counteracts the pathology in a mouse model of Duchenne muscular dystrophy by inhibiting the TGF-β1/TAK1 signaling pathway.

Acta Pharmacol Sin 2020 Sep 16. Epub 2020 Sep 16.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by a mutation in the gene encoding the dystrophin protein. Catalpol is an iridoid glycoside found in Chinese herbs with anti-inflammatory, anti-oxidant, anti-apoptotic, and hypoglycemic activities that can protect against muscle wasting. In the present study we investigated the effects of catalpol on DMD. Aged Dystrophin-deficient (mdx) mice (12 months old) were treated with catalpol (100, 200 mg·kg·d, ig) for 6 weeks. At the end of the experiment, the mice were sacrificed, and gastrocnemius (GAS), tibialis anterior (TA), extensor digitorum longus (EDL), soleus (SOL) muscles were collected. We found that catalpol administration dose-dependently increased stride length and decreased stride width in Gait test. Wire grip test showed that the time of wire grip and grip strength were increased. We found that catalpol administration dose-dependently alleviated skeletal muscle damage, evidenced by reduced plasma CK and LDH activity as well as increased the weight of skeletal muscles. Catalpol administration had no effect on dystrophin expression, but exerted anti-inflammatory effects. Furthermore, catalpol administration dose-dependently decreased tibialis anterior (TA) muscle fibrosis, and inhibited the expression of TGF-β1, TAK1 and α-SMA. In primary myoblasts from mdx mice, knockdown of TAK1 abolished the inhibitory effects of catalpol on the expression levels of TGF-β1 and α-SMA. In conclusion, catalpol can restore skeletal muscle strength and alleviate skeletal muscle damage in aged mdx mice, thus may provide a novel therapy for DMD. Catalpol attenuates muscle fibrosis by inhibiting the TGF-β1/TAK1 signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41401-020-00515-1DOI Listing
September 2020

Synthesis and Biological Evaluation of Celastrol Derivatives as Potential Immunosuppressive Agents.

J Nat Prod 2020 09 21;83(9):2578-2586. Epub 2020 Aug 21.

State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.

Celastrol, a friedelane-type triterpenoid isolated from the genus , possesses antitumor, anti-inflammatory, and immunosuppressive activities. A total of 42 celastrol derivatives (-, -, and -) were synthesized and evaluated for their immunosuppressive activities. Compounds - showed immunosuppressive effects, with IC values ranging from 25 to 83 nM, and weak cytotoxicity (CC > 1 μM). Compound , with a selectivity index value 31 times higher than that of celastrol, was selected as a lead compound. Further research showed that exerted its immunosuppressive effects by inducing apoptosis and inhibiting cytokine secretion via Lck- and ZAP-70-mediated signaling pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jnatprod.0c00067DOI Listing
September 2020

[Mechanism of psoralen in aggravating hepatotoxicity induced by CCl_4 by delaying liver regeneration].

Zhongguo Zhong Yao Za Zhi 2020 Jun;45(12):2916-2923

School of Traditional Chinese Medicine, Guangdong Pharmaceutical University Guangdong 510006, China Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University Nanjing 210009, China.

This study aimed to investigate whether psoralen can aggravate hepatotoxicity induced by carbon tetrachloride(CCl_4) by inducing hepatocyte cycle arrest and delaying liver regeneration. Female C57 BL/6 mice aged 6-8 weeks were randomly divided into control group, model group(CCl_4 group), combined group(CCl_4+PSO group) and psoralen group(PSO group). CCl_4 group and CCl_4+PSO group were given CCl_4 intraperitoneally at a dose of 100 μL·kg~(-1) once; olive oil of the same volume was given to control group and PSO group intraperitoneally; 12 h, 36 h and 60 h after CCl_4 injection, PSO group and CCl_4+PSO group were administrated with PSO intragastrically at a dose of 200 mg·kg~(-1); 0.5% CMC-Na of the same volume was administrated to control group and PSO group intragastrically. The weight of mice was recorded every day. Serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were measured at 36 h, 60 h and 84 h after CCl_4 injection. Mice were sacrificed after collection of the last serum samples. Liver samples were collected, and liver weight was recorded. Histopathological and morphological changes of liver were observed by haematoxylin and eosin staining. The mRNA levels of HGF, TGF-β, TNF-α, p53 and p21 in liver were detected by RT-qPCR. Western blot was used to detect the levels of cell cycle-related proteins. According to the results, significant increase of serum ALT and AST and centrilobular necrosis with massive inflammatory cell infiltration were observed in CCl_4+PSO group. After PSO administration in CCl_4 model, the mRNA levels of HGF(hepatocyte growth factor) and TNF-α were reduced, while the mRNA expressions of TGF-β, p53 and p21 was up-regulated. The expression of PCNA(proliferating cell nuclear antigen) was significantly increased in CCl_4 and CCl_4+PSO group, while the relative protein level in CCl_4+PSO group was slightly lower than that in CCl_4 group. Compared with control and CCl_4 group, the expression of p27(cyclic dependent kinase inhibitor protein p27) was prominently increased in CCl_4+PSO group. These results indicated that hepatotoxicity induced by CCl_4 could be aggravated by intraperitoneal administration with PSO, and the repair process of liver could be delayed. The preliminary mechanism may be related to the inhibition of PCNA and regulation of some cell cycle-associated protein by psoralen, in which the significant up-regulation of p27, p53 and p21 may play important roles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.19540/j.cnki.cjcmm.20200115.401DOI Listing
June 2020

Organic anion transporter 1 and 3 contribute to traditional Chinese medicine-induced nephrotoxicity.

Chin J Nat Med 2020 Mar;18(3):196-205

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

With the internationally growing popularity of traditional Chinese medicine (TCM), TCM-induced nephropathy has attracted public attention. Minimizing this toxicity is an important issue for future research. Typical nephrotoxic TCM drugs such as Aristolochic acid, Tripterygium wilfordii Hook. f, Rheum officinale Baill, and cinnabar mainly damage renal proximal tubules or cause interstitial nephritis. Transporters in renal proximal tubule are believed to be critical in the disposition of xenobiotics. In this review, we provide information on the alteration of renal transporters by nephrotoxic TCMs, which may be helpful for understanding the nephrotoxic mechanism of TCMs and reducing adverse effects. Studies have proven that when administering nephrotoxic TCMs, the expression or function of renal transporters is altered, especially organic anion transporter 1 and 3. The alteration of these transporters may enhance the accumulation of toxic drugs or the dysfunction of endogenous toxins and subsequently sensitize the kidney to injury. Transporters-related drug combination and clinical biomarkers supervision to avoid the risk of future toxicity are proposed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1875-5364(20)30021-2DOI Listing
March 2020

Quantitative proteomics analysis of Fructus Psoraleae-induced hepatotoxicity in rats.

Chin J Nat Med 2020 Feb;18(2):123-137

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Center for Drug Screening and Pharmacodynamics Evaluation, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Fructus Psoraleae, which is commonly consumed for the treatment of osteoporosis, bone fracture, and leucoderma, induces liver injury. This study investigated the pathogenesis of the ethanol extract of Fructus Psoraleae (EEFP)-induced liver injury in rats. EEFP (1.35, 1.80, and 2.25 g·kg) was administrated to Sprague Dawley (SD) rats for 30 d. We measured liver chemistries, histopathology, and quantitative isobaric tags for relative and absolute quantitation (iTRAQ)-based protein profiling. EEFP demonstrated parameters suggestive of liver injury with changes in bile secretion, bile flow rate, and liver histopathology. iTRAQ analysis showed that a total of 4042 proteins were expressed in liver tissues of EEFP-treated and untreated rats. Among these proteins, 81 were upregulated and 32 were downregulated in the treatment group. KEGG pathway analysis showed that the drug metabolic pathways of cytochrome P450, glutathione metabolism, glycerolipid metabolism, and bile secretion were enriched with differentially expressed proteins. The expression of key proteins related to the farnesoid X receptor (FXR), i.e., the peroxisome proliferators-activated receptor alpha (PPAR-α), were downregulated, and multidrug resistance-associated protein 3 (MRP3) was upregulated in the EEFP-treated rats. Our results provide evidence that EEFP may induce hepatotoxicity through various pathways. Furthermore, our study demonstrates changes in protein regulation using iTRAQ quantitative proteomics analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1875-5364(20)30013-3DOI Listing
February 2020

The hypoglycemic mechanism of catalpol involves increased AMPK-mediated mitochondrial biogenesis.

Acta Pharmacol Sin 2020 Jun 14;41(6):791-799. Epub 2020 Jan 14.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, 210009, China.

Mitochondria serve as sensors of energy regulation and glucose levels, which are impaired by diabetes progression. Catalpol is an iridoid glycoside that exerts a hypoglycemic effect by improving mitochondrial function, but the underlying mechanism has not been fully elucidated. In the current study we explored the effects of catalpol on mitochondrial function in db/db mice and C2C12 myotubes in vitro. After oral administration of catalpol (200 mg·kg·d) for 8 weeks, db/db mice exhibited a decreased fasting blood glucose level and restored mitochondrial function in skeletal muscle. Catalpol increased mitochondrial biogenesis, evidenced by significant elevations in the number of mitochondria, mitochondrial DNA levels, and the expression of three genes associated with mitochondrial biogenesis: peroxisome proliferator-activated receptor gammaco-activator 1 (PGC-1α), mitochondrial transcription factor A (TFAM) and nuclear respiratory factor 1 (NRF1). In C2C12 myotubes, catalpol significantly increased glucose uptake and ATP production. These effects depended on activation of AMP-activated protein kinase (AMPK)-mediated mitochondrial biogenesis. Thus, catalpol improves skeletal muscle mitochondrial function by activating AMPK-mediated mitochondrial biogenesis. These findings may guide the development of a new therapeutic approach for type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41401-019-0345-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470840PMC
June 2020

[Study on difference of liver toxicity and its molecular mechanisms caused by Tripterygium wilfordii multiglycoside and equivalent amount of triptolid in rats].

Zhongguo Zhong Yao Za Zhi 2019 Aug;44(16):3468-3477

Jiangsu Key Laboratory of Drug Screening,China Pharmaceutical University Nanjing 210009,China Center for Drug Research and Development,Guangdong Pharmaceutical University Guangzhou 510006,China.

Tripterygium wilfordii multiglycoside( GTW),an extract derived from T. wilfordii,has been used for rheumatoid arthritis and other immune diseases in China. However its potential hepatotoxicity has not been investigated completely. Firstly,the content of triptolid( TP) in GTW was 0. 008% confirmed by a LC method. Then after oral administration of GTW( 100,150 mg·kg-1) and TP( 12 μg·kg-1) in female Wistar rats for 24 h,it was found that 150 mg·kg-1 GTW showed more serious acute liver injury than 12 μg·kg-1 TP,with the significantly increased lever of serum ALT,AST,TBA,TBi L,TG and bile duct hyperplasia even hepatocyte apoptosis. The expression of mRNA and proteins of liver bile acid transporters such as BSEP,MRP2,NTCP and OATP were down-regulated significantly by GTW to inhibit bile acid excretion and absorption,resulting in cholestatic liver injury. Moreover,GTW was considered to be involved in hepatic oxidative stress injury,although it down-regulated SOD1 and GPX-1 mRNA expression without significant difference in MDA and GSH levels. In vitro,we found that TP was the main toxic component in GTW,which could inhibit cell viability up to 80% in Hep G2 and LO2 cells at the dose of 0. 1 μmol·L-1. Next a LC-MS/MS method was used to detect the concentration of triptolid in plasma from rats,interestingly,we found that the content of TP in GTW was always higher than in the same amount of TP,suggesting the other components in GTW may affect the TP metabolism. Finally,we screened the substrate of p-glycoprotein( p-gp) in Caco-2 cells treated with components except TP extrated from GTW,finding that wilforgine,wilforine and wilfordine was the substrate of p-gp. Thus,we speculated that wilforgine,wilforine and wilfordine may competitively inhibit the excretion of TP to bile through p-gp,leading to the enhanced hepatotoxity caused by GTW than the same amount of TP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.19540/j.cnki.cjcmm.20190301.002DOI Listing
August 2019

[Progress of effect and mechanisms of Tripterygium wilfordii on immune system].

Zhongguo Zhong Yao Za Zhi 2019 Aug;44(16):3374-3383

Jiangsu Key Laboratory of Drug Screening,China Pharmaceutical University Nanjing 210009,China Center for Drug Research and Development,Guangdong Pharmaceutical University Guangzhou 510006,China.

Traditional Chinese medicine Tripterygium wilfordii Hook.f( TWHF) is a natural botanical drug in China. It has complex chemical compositions and has been used for a long history. TWHF was used as an insecticide to protect crops at early stage,and it was later found to have significant effects in the treatment of rheumatoid arthritis,attaining great concerns. With further researches,it was found that TWHF can treat various diseases in the medical field due to a variety of pharmacological activities such as anti-cancer,neuroprotection,anti-inflammatory and immune-suppressing,particularly. Multiple extracts of TWHF have unique immunosuppressive function,playing an immune role through multi-target and multi-channel,with significant effect in the treatment of autoimmune diseases. As an immune-suppressing drug,TWHF is worthy of in-depth research due to its broad application prospects. While achieving good clinical efficacy,reports about its toxic effects to multiple systems of the body are also increasing,greatly hindering its clinical application. In order to fully understand the immune-suppressing function of TWHF and reduce or avoid the occurrence of toxic and side effects,we summarized recent progress of TWHF on the immune organs,cells and factors in recent years,as well as the pharmacology and toxic effects,hoping to provide a scientific and reasonable reference for its wider use in clinical treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.19540/j.cnki.cjcmm.20190419.401DOI Listing
August 2019

[Effect of triptolide on Th17/Treg cells in spleen].

Zhongguo Zhong Yao Za Zhi 2019 Aug;44(15):3330-3334

Jiangsu Key Laboratory of Drug Screening,China Pharmaceutical University Nanjing 210009,China Center for Drug Screening and Pharmacodynamics Evaluation,School of Pharmacy,Guangdong Pharmaceutical University Guangzhou 510006,China.

Triptolide( TP) is isolated from the traditional Chinese medicine Tripterygium wilfordii,which exhibits notable immuneregulative effect. Th17 cells involve in inflammatory response and Treg cells contribute to immune tolerance. They both play an important role in immune response. Previous studies have investigated that TP induced hepatic Th17/Treg imbalance. However,the effect of TP on spleen Th17/Treg cells remains unclear. Therefore,the aim of present study was to investigate the effect of TP on Th17/Treg cells in spleen. In this study,the effect of TP on the proliferation of splenic lymphocyte was detected by cytotoxicity test in vitro. After different concentrations of TP( 2. 5,5,20,40 nmol·L~(-1)) were given to splenic lymphocyte,cytokines secreted from the supernatant of splenic lymphocyte were detected by cytometric bead array,and the expression of suppressor of cytokine signaling( SOCS) mRNA was detected by qRT-PCR. Female C57 BL/6 mice were continuously observed for 24 h after treatment of 500 μg·kg-1 TP. The effects of TP on the splenic tissue structure and the percentage of Th17/Treg cells were examined. The results showed that the IC50 of TP was19. 6 nmol·L~(-1) in spleen lymphocytes. TP inhibited the secretion of IL-2 and IL-10 and induced the expression of SOCS-1/3 mRNA in spleen lymphocytes at the dosage of 2. 5 and 5 nmol·L~(-1) after 24 h in vitro. Administration of TP at dosage of 500 μg·kg-1 had no significant spleen toxicity in vivo. TP treatment increased the percentage of Th17 cells after 12 h and inhibited the proportion of Treg cells after 12 and 24 h. In conclusion,TP reduced the secretion of IL-2 and IL-10 through SOCS-1/3 signaling pathway,thereby induced the percentage of Th17 cells and inhibited the percentage of Treg cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.19540/j.cnki.cjcmm.20181011.001DOI Listing
August 2019

Toxic effects of triptolide on adrenal steroidogenesis in H295R cells and female rats.

J Biochem Mol Toxicol 2019 Nov 26;33(11):e22394. Epub 2019 Sep 26.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.

Triptolide (TP), a major active ingredient of Tripterygium wilfordii, exerts potent immunosuppressive effects in the treatment of rheumatoid arthritis but is not widely used in clinical practice due to its multiorgan toxicity, particularly hepatotoxicity, nephrotoxicity, and reproductive toxicity. An LC-MS/MS approach was employed to explore the endocrine-disrupting effects of TP. The endocrine-disrupting effects of various concentrations (0-100 nM) of TP for 48 hour were firstly investigated using an in vitro model (H295R cell line). It was found that TP did not decrease cell viability. The transcriptional levels of steroidogenic enzymes in H295R cells were assessed by quantificational real-time polymerase chain reaction. The possible adrenal and endocrine effects of oral administration of TP (0, 50, and 500 μg/kg) for 28 days on both normal and collagen-induced arthritis (CIA) rats were also explored. The serum and adrenal tissue hormone levels (corticosterone and progesterone) and adrenal histopathology were analyzed, with the results that TP significantly decreased the level of cortisol in H295R cells and the level of plasma corticosterone in both normal and CIA rats. Histological alterations in adrenal cortex were observed at the dose of 500 μg/kg. Exposure to TP for 48 hour had an obvious inhibitory effect on the messenger RNA transcript levels of HSD3B2, CYP21A2, CYP17A1, and CYP11B1, which is essential for the synthesis of corticosteroids. In a word, TP leads to the disorder of corticosteroid synthesis and secretion, and corticosteroid may be a potential biomarker for the treatment of multiorgan toxicity of TP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbt.22394DOI Listing
November 2019

Preventive Effects of Total Flavonoid C-Glycosides from Abrus mollis on Nonalcoholic Fatty Liver Disease through Activating the PPARα Signaling Pathway.

Planta Med 2019 May 26;85(8):678-688. Epub 2019 Apr 26.

State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.

subsp (Hance) Verdc. (Leguminosae) is a well-known edible plant usually added to soups and beverages. In this study, vicenin-2 (1: ), isoschaftoside (2: ), schaftoside (3: ), and their enrichment fraction, total flavonoid -glycosides, derived from the extracts of , were firstly found to prevent nonalcoholic fatty liver disease both and . In the study, total flavonoid -glycosides decreased the lipid accumulation in oleic acid-treated HepG2 cells. The mechanisms of total flavonoid -glycosides are involved in the regulation of peroxisome proliferator-activated receptor and its downstream, and the reduction of proinflammatory cytokines. In high-fat diet-induced fatty liver rats, total flavonoid -glycosides decreased the levels of glutamic-oxalacetic transaminease and glutamic-pyruvic transaminase, and decreased the lipid accumulation both in the liver and blood without affecting food intake. In addition, total flavonoid -glycosides also increased the activities of the antioxidant enzyme system . In conclusion, total flavonoid -glycosides are active components of on nonalcoholic fatty liver disease, and can be used in functional food and supplements for nonalcoholic fatty liver disease prevention and treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-0895-5838DOI Listing
May 2019

The role of neutrophils in triptolide-induced liver injury.

Chin J Nat Med 2018 Sep;16(9):653-664

Jiangsu Key Laboratory of Drug Screening, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of Traditional Chinese Medicine Evaluation and Translational Research, Nanjing 210009, China. Electronic address:

Triptolide (TP) induces severe liver injury, but its hepatotoxicity mechanisms are still unclear. Inflammatory responses may be involved in the pathophysiology. Neutrophils are the first-line immune effectors for sterile and non-sterile inflammatory responses. Thus, the aim of the present study was to investigate the neutrophilic inflammatory response in TP-induced liver injury in C57BL/6 mice. Our results showed that neutrophils were recruited and accumulated in the liver, which was parallel to or slightly after the development of liver injury. Neutrophils induced release of myeloperoxidase and up-regulation of CD11b, which caused cytotoxicity and hepatocyte death. Hepatic expressions of CXL1, TNF-α, IL-6, and MCP1 were increased significantly to regulate neutrophils recruitment and activation. Up-regulation of toll like receptors 4 and 9 also facilitated neutrophils infiltration. Moreover, neutrophils depletion using an anti-Gr1 antibody showed mild protection against TP overdose. These results indicated that neutrophils accumulation might be the secondary response, not the cause of TP-induced liver injury. In conclusion, the inflammatory response including neutrophil infiltration may play a role in TP-induced hepatotoxicity, but may not be severe enough to cause additional liver injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1875-5364(18)30105-5DOI Listing
September 2018

Activation of natural killer T cells contributes to triptolide-induced liver injury in mice.

Acta Pharmacol Sin 2018 Dec 16;39(12):1847-1854. Epub 2018 Jul 16.

Jiangsu Key Laboratory of Drug Screening, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, 210009, China.

Triptolide (TP) is the main active ingredient of Tripterygium wilfordii Hook.f, which has attracted great interest due to its promising efficacy for autoimmune diseases and tumors. However, severe adverse reactions, especially hepatotoxicity, have restricted its approval in the market. In the present study we explored the role of hepatic natural killer T (NKT) cells in the pathogenesis of TP-induced liver injury in mice. TP (600 μg/kg/day, i.g.) was administered to female mice for 1, 3, or 5 days. We found that administration of TP dose-dependently induced hepatotoxicity, evidenced by the body weight reduction, elevated serum ALT and AST levels, as well as significant histopathological changes in the livers. However, the mice were resistant to the development of TP-induced liver injury when their NKT cells were depleted by injection of anti-NK1.1 mAb (200 μg, i.p.) on days -2 and -1 before TP administration. We further revealed that TP administration activated NKT cells, dominantly releasing Th1 cytokine IFN-γ, recruiting neutrophils and macrophages, and leading to liver damage. After anti-NK1.1 injection, however, the mice mainly secreted Th2 cytokine IL-4 in the livers and exhibited a significantly lower percentage of hepatic infiltrating neutrophils and macrophages upon TP challenge. The activation of NKT cells was associated with the upregulation of Toll-like receptor (TLR) signaling pathway. Collectively, these results demonstrate a novel role of NKT cells contributing to the mechanisms of TP-induced liver injury. More importantly, the regulation of NKT cells may promote effective measures that control drug-induced liver injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41401-018-0084-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289391PMC
December 2018

Biochemical and computational evaluation of Triptolide-induced cytotoxicity against NSCLC.

Biomed Pharmacother 2018 Jul 7;103:1557-1566. Epub 2018 May 7.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China; Center for Drug Screening and Pharmacodynamics Evaluation, School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. Electronic address:

Triptolide is the major bioactive component isolated from the Chinese Medicinal plant Tripterygium wilfordii. Despite the growing interest and the plethora of reports discussing the pharmacological activity of this diterpenoid, no clear consensus regarding its cellular targets and full mechanism of action has been reached. In the present work, a combined in vitro and in silico approach was used to evaluate the biological activity of Triptolide on Non-small cell lung cancer (NSCLC). In vitro, Triptolide treatment induced apoptosis in NSCLC cell lines and down-regulated the phosphorylation of AKT, mTOR, and p70S6K. Triptolide also impacted cellular glycolysis as well as the antioxidant response through the impairment of glucose utilization, HKII, glutathione, and NRF2 levels. Molecular docking results examined the possible interactions between Triptolide and AKT and predicted an allosteric binding to AKT-1 structure. Molecular dynamics simulations were further used to evaluate the stability of the complex formed by Triptolide's best conformer and AKT. These findings provide an insightful approach to the anticancer effect of Triptolide against NSCLC and highlight a possible new role for AKT/mTOR HKII inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2018.04.198DOI Listing
July 2018

Pristimerin exhibits in vitro and in vivo anticancer activities through inhibition of nuclear factor-кB signaling pathway in colorectal cancer cells.

Phytomedicine 2018 Feb 31;40:140-147. Epub 2018 Jan 31.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Jiangsu Province, Nanjing 210009, PR China; Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing 210009, PR China. Electronic address:

Background: Colorectal cancer (CRC) is one of the most common malignancies associated with high mortality rate worldwide. We previously reported that pristimerin inhibits cell growth and induces apoptosis in CRC cells.

Hypothesis/purpose: To further understand the molecular mechanism by which pristimerin elicits its anticancer activities on colon cancer cells, we investigated its effect on nuclear factor-κB (NF-κB) signaling pathway.

Study Design: This study consisted of both in vitro and in vivo experiments involving HCT-116 cell line and xenograft mouse model. Molecular techniques such as qRT-PCR, western blotting and immunofluorescence were used to demonstrate pristimerin in vitro effect on NF-κB signaling pathway; whereas it's in vivo activity was analyzed by western blot and immunohistochemistry on tumor tissues.

Results: Our in vitro results on HCT-116 cells showed that pristimerin inhibited IKK phosphorylation, IкB-α degradations and IкB-α phosphorylation in both dose- and time- dependent manners, which caused suppression of NF-кB p65 phosphorylation, nuclear translocation and accumulation of NF-кB. Moreover, pristimerin was found to inhibit both constitutive activated-NF-кB and tumor necrosis factor-α (TNF-α)- and lipopolysaccharide (LPS)-induced activation of NF-кB signaling pathway. Furthermore, our in vivo results on xenograft animal model revealed that pristimerin inhibited tumor growth mainly through suppressing NF-кB activity in tumor tissues.

Conclusion: Pristimerin antitumor activities were mainly mediated through inhibition of NF-кB signaling pathway in colon tumor cells. These findings further explain that pristimerin has the therapeutic potential for targeting colon cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phymed.2018.01.008DOI Listing
February 2018

Bakuchiol Contributes to the Hepatotoxicity of Psoralea corylifolia in Rats.

Phytother Res 2017 Aug 22;31(8):1265-1272. Epub 2017 Jun 22.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.

Psoralea corylifolia L. (Fructus Psoraleae) is widely used in Asia, but there are concerns about hepatotoxicity caused by constituents such as psoralens and bakukiol. Bakuchiol (BAK) has antiinflammatory, antipyretic, antibacterial antiviral, anticancer, and estrogenic activity but appears to be hepatotoxic in in vitro tests. This study investigated the hepatotoxicity in vivo in rats. Using intragastrically administered bakuchiol at doses of 52.5 and 262.5 mg/kg for 6 weeks. Bodyweight, relative liver weight, biochemical indicators, histopathology, mRNA expression of CYP7A1, HMG-CoA reductase, BSEP, PPARα, SREBP-2, and MRP3 were measured. Many abnormalities were observed in the bakuchiol-treated groups including suppression of weight gain and food intake, change of some parameters in serum biochemistry, and increased weight of liver. The mRNA expression of CYP7A1, HMG-CoA reductase, PPARα, and SREBP-2 decreased in bakuchiol-treated group, the expression of BSEP increased in bakuchiol-treated low dosage, and the expression of BSEP decreased in bakuchiol-treated high dosage. In conclusion, we provide evidence for the first time that bakuchiol can induce cholestatic hepatotoxicity, suggesting potential hepatotoxicity. The mechanism may be related to effects on liver lipid metabolism, but further investigation is necessary. Copyright © 2017 John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ptr.5851DOI Listing
August 2017

Suppression of Baeckea frutescens L. and its components on MyD88-dependent NF-κB pathway in MALP-2-stimulated RAW264.7 cells.

J Ethnopharmacol 2017 Jul 31;207:92-99. Epub 2017 May 31.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Ethnopharmacological Relevance: Baeckea frutescens L. is commonly used as a folk medicinal material. There are nineteen components in its volatile oil, including Pcymol which has effects of eliminating phlegm, relieving asthma and antiviral. This study was aimed to investigate the anti-infectious inflammatory activities of Baeckea frutescens L. and its conponents and analyzing the mechanisms.

Materials And Methods: The anti-infectious inflammation of Baeckea frutescens L. were studied by using macrophage activating lipopeptide-2 (MALP-2)-stimulated RAW264.7 cell model in vitro. Secretion of nitric oxide (NO), expression of inducible NO synthase (iNOS) and cytokines were detected as classic inflammatory index. Expression of Myeloid differentiation factor 88 (MyD88), degradation of inhibitory κBα (IκBα) and nuclear translocation of NF-κB p65 were further investigated.

Results: The results suggested that Baeckea frutescens L. has effect on suppression of MALP-2-mediated inflammation in RAW264.7 cells. The secretion of NO and the expression of iNOS could be inhibited. The secretion of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were also declined. Baeckea frutescens L. significantly decreased the expression of MyD88, therefore, inhibited the degradation of IκBα, reduced the level of nuclear translocation of p65.

Conclusion: The results of this study indicated that Baeckea frutescens L. and its components could inhibit the anti-infectious inflammatory events and iNOS expression in MALP-2 stimulated RAW264.7 cells. Among them, BF-2 might play a role through the inhibition of the MyD88 and NF-κB pathway. Our study might provide a new strategy to design and develop this kind of drug towards mycoplasma-infected inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jep.2017.05.034DOI Listing
July 2017

Triptolide reduces prostate size and androgen level on testosterone-induced benign prostatic hyperplasia in Sprague Dawley rats.

Chin J Nat Med 2017 May;15(5):341-346

Jiangsu Key Laboratory of Drug Screening and Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Benign prostatic hyperplasia (BPH) is an age-related disease of unknown etiology, characterized by prostatic enlargement coincident with distinct alterations in tissue histology. In the present study, we investigated whether triptolide can prevent testosterone-induced prostatic hyperplasia in rats. Castration was performed via the scrotal route after urethane aesthesia. BPH was induced in experimental groups by daily subcutaneous injections of testosterone propionate (TP) for two weeks. Triptolide was administered daily by oral gavage at a dose of 100 and 50 μg·kg for 2 weeks, along with the TP injections. On day 14, the animals were humanely killed by cervical dislocation after aesthesia. Prostates were excised, weighed, and used for histological studies. Testosterone and dihydrotestosterone (DHT) levels in serum and prostate were measured. The results showed that triptolide significantly reduced the prostate weight, and the testosterone and DHT levels in both the serum and prostate. Histopathological examination also showed that triptolide treatment suppressed TP-induced prostatic hyperplasia. In conclusion, triptolide effectively inhibits the development of BPH induced by testosterone in a rat model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1875-5364(17)30054-7DOI Listing
May 2017

Pyrazinamide-induced hepatotoxicity is alleviated by 4-PBA via inhibition of the PERK-eIF2α-ATF4-CHOP pathway.

Toxicology 2017 03 4;378:65-75. Epub 2017 Jan 4.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, China. Electronic address:

Pyrazinamide (PZA)-induced serious liver injury, but the exact mechanism of PZA-induces hepatotoxicity remains controversial. Endoplasmic reticulum (ER) stress-caused cell apoptosis plays a critical role in the development of drug-induced liver injury (DILI). However, the direct connection between PZA toxicity and ER stress is unknown. In this study, we describe the role of ER stress in PZA induced hepatotoxicity in vivo and in vitro. We found that PZA induces apoptosis in HepG2 cells, and causes liver damage in rats, characterized by increased serum ALT, AST and TBA levels. PZA impairs antioxidant defenses, although this effect did not play an important role in resulting liver injury. The ER stress related proteins GRP78, p-PERK, p-eIF2α, ATF4, CHOP and caspase12 were activated after PZA exposure both in vivo and in vitro. Furthermore, as an ER stress inhibitor, sodium 4-phenylbutyrate (4-PBA) could ameliorate PZA toxicity in HepG2 cells and rat liver. These results have potential implications for the pathogenesis of PZA-induced hepatotoxicity in which ER stress especially PERK-eIF2α-ATF4-CHOP pathway participates in hepatocellular injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tox.2017.01.002DOI Listing
March 2017

G-protein coupled receptors as therapeutic targets for neurodegenerative and cerebrovascular diseases.

Neurochem Int 2016 12 9;101:1-14. Epub 2016 Sep 9.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Neurodegenerative and cerebrovascular diseases are frequent in elderly populations and comprise primarily of dementia (mainly Alzheimer's disease) Parkinson's disease and stroke. These neurological disorders (NDs) occur as a result of neurodegenerative processes and represent one of the most frequent causes of death and disability worldwide with a significant clinical and socio-economic impact. Although NDs have been characterized for many years, the exact molecular mechanisms that govern these pathologies or why they target specific individuals and specific neuronal populations remain unclear. As research progresses, many similarities appear which relate these diseases to one another on a subcellular level. Discovering these similarities offers hope for therapeutic advances that could ameliorate the conditions of many diseases simultaneously. G-protein coupled receptors (GPCRs) are the most abundant receptor type in the central nervous system and are linked to complex downstream pathways, manipulation of which may have therapeutic application in many NDs. This review will highlight the potential use of neurotransmitter GPCRs as emerging therapeutic targets for neurodegenerative and cerebrovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuint.2016.09.005DOI Listing
December 2016

Antitumor effect of Deoxypodophyllotoxin on human breast cancer xenograft transplanted in BALB/c nude mice model.

J Infect Chemother 2016 Oct 28;22(10):692-6. Epub 2016 Aug 28.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address:

Recently, biologically active compounds isolated from plants used in herbal medicine have been the center of interest. Deoxypodophyllotoxin (DPT), structurally closely related to the lignan podophyllotoxin, was found to be a potent antitumor and antiproliferative agent, in several tumor cells, in vitro. However, DPT has not been used clinically yet because of the lack of in vivo studies. This study is the first report demonstrating the antitumor effect of DPT on MDA-MB-231 human breast cancer xenografts in nude mice. DPT, significantly, inhibited the growth of MDA-MB-231 xenograft in BALB/c nude mice. The T/C value (the value of the relative tumor volume of treatment group compared to the control group) of groups treated with 5, 10, and 20 mg/kg of intravenous DPT-HP-β-CD was 42.87%, 34.04% and 9.63%, respectively, suggesting the positive antitumor activity of DPT. In addition, the antitumor effect of DPT-HP-β-CD (20 mg/kg) in human breast cancer MDA-MB-231 xenograft was more effective than etoposide (VP-16) (20 mg/kg) and docetaxel (20 mg/kg). These findings suggest that this drug is a promising chemotherapy candidate against human breast carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jiac.2016.07.017DOI Listing
October 2016

Pyrazinamide Induced Rat Cholestatic Liver Injury through Inhibition of FXR Regulatory Effect on Bile Acid Synthesis and Transport.

Toxicol Sci 2016 08 2;152(2):417-28. Epub 2016 Jun 2.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 210009, China

Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of tuberculosis which may cause serious hepatotoxicity; however, the mechanisms underlying these toxicities are poorly understood. Cholestasis plays an important role in drug-induced liver injury. Since there were no previous published works reported cholestasis and PZA hepatotoxicity relationship, this study aimed to identify whether PZA can induce liver injury with characterized evidences of cholestasis and to clarify expression changes of proteins related to both bile acid synthesis and transport in PZA-induced liver injury. PZA (2 g/kg) was administered for 7 consecutive days by oral gavage. Results showed there were 2-fold elevation in both ALT and AST serum levels in PZA-treated rats. In addition, a 10-fold increment in serum total bile acid was observed after PZA administration. The mRNA and protein expressions of bile acid synthesis and transport parameters were markedly altered, in which FXR, Bsep, Mrp2, Mdr2, Ostα/β, Oatp1a1, Oatp1b2, and Cyp8b1 were decreased (P < .05), while Mrp3, Ntcp, Oatp1a4, and Cyp7a1 were increased (P < .05). Moreover, treatment with the FXR agonist obeticholic acid (OCA) generated obvious reductions in serum ALT, AST, and TBA levels in PZA-treated rats. Those effects were due to transcriptional regulation of pre-mentioned target genes by OCA. Taken together, these results suggested that PZA-induced cholestatic liver injury was related to FXR inhibition, leading to the dysfunction in bile acid synthesis and transport.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/toxsci/kfw098DOI Listing
August 2016

Evaluating antithrombotic activity of HY023016 on rat hypercoagulable model.

Eur J Pharmacol 2016 Jun 13;781:190-7. Epub 2016 Apr 13.

Department of Pharmacology, China Pharmaceutical University, Nanjing, Jiangsu, China. Electronic address:

The generation of thrombus is not considered as an isolated progression without other pathologic processes, which may also enhance procoagulant state. The purpose of this study was to assess whether HY023016, a novel dabigatran prodrug and an oral direct thrombin inhibitor, or dabigatran etexilate, another thrombin inhibitor can improve the state of whole blood hypercoagulability in vitro/vivo. By using whole blood flow cytometry we explored the effects of HY023016 and dabigatran etexilate on thrombin and ADP-induced human platelet-leukocyte aggregation generated in vitro. With the method of continuous infusion of thrombin intravenous, we successfully established a rat hypercoagulable model and evaluated the effect of HY023016 or dabigatran etexilate in vivo. HY023016 was able to inhibit thrombin- or ADP-induced platelet P-selectin or CD40L expression, leukocyte CD11b expression and formation of platelet-leukocyte aggregates in dose-dependent manner. Dabigatran etexilate was unable to affect ADP-induced platelet P-selectin or CD40L expression, leukocyte CD11b expression and formation of platelet-leukocyte aggregates. Based on rat hypercoagulable model, dabigatran etexilate could reverse thrombin-induced circulatory system hypercoagulable state in a concentration-dependent manner. Dabigatran etexilate also inhibited electrical stimulation induced formation of arterial thrombus in rat under hypercoagulable state, and extracorporal circulation-induced formation of thrombus in dose-dependent manner. Compared with dabigatran etexilate, HY023016 showed nearly equal or even better antithrombotic activity, regardless of reversing the cycle of rat hypercoagulable state or inhibiting platelet-leukocyte aggregation. In surrmary, HY023016 could effectively improve hypercoagulable state of circulatory system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2016.04.023DOI Listing
June 2016

Pristimerin inhibits proliferation, migration and invasion, and induces apoptosis in HCT-116 colorectal cancer cells.

Biomed Pharmacother 2016 Apr 18;79:112-9. Epub 2016 Feb 18.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address:

Colorectal cancer (CRC) is one of the world's most common cancers with a high mortality rate mainly due to metastasis. Our previous study showed that pristimerin had potent antitumor activities against human CRC cells. In the present study, we further evaluated pristimerin anti-tumor and anti-metastatic properties. MTT assay, Hoechst staining, Annexin V/PI double staining, reactive oxygen species (ROS) measurements were used to assess pristimerin cytotoxicity and apoptotic-inducing effects on HCT-116 cells. Wound healing assay and Transwell assay were used to estimate pristimerin anti-migration and anti-invasion activities on CRC cells. Meanwhile, HCT-116 xenograft model applied for investigating in vivo antitumor activities. Our results showed that pristimerin mediated in vitro HCT-116 cell death, through generation of intracellular ROS and apoptosis induction. Tumor volumes and weights measurements, pathological analysis and Tunnel assay proved that pristimerin inhibited in vivo HCT-116 xenografts growth. Pristimerin was also able to limit CRC invasion and metastasis. It caused downregulation of PI3K/AKT/mTOR pathway and its subsequent downstream p70S6K and E4-BP1 proteins. Collectively, pristimerin exerted both in vitro and in vivo cytotoxic and anti-metastatic effects on HCT-116 cells, suggesting that pristimerin has potential as a new anticancer drug for treatment of colon cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2016.02.003DOI Listing
April 2016

Anticancer Potential and Molecular Targets of Pristimerin: A Mini- Review.

Curr Cancer Drug Targets 2017 ;17(2):100-108

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Jiangsu Province, Nanjing 210009, PR. China.

Pristimerin, a natural triterpenoid isolated form Celastrus and Maytenus spp, has been shown to possess a variety of biological and pharmacological effects. Recently, pristimerin has attracted more attention, especially for its potential anticancer activities. The anticancer activities of pristimerin have been illustrated in various cancer cell lines and animal models. It has been found to inhibit in vitro and in vivo proliferation, survival, angiogenesis and metastasis of tumor cells. These activities have been attributed to its modulation of various molecular targets such as cyclins, apoptosis- related proteins, proteasome activity, reactive oxygen species, as well as NF-kB, AKT/mTOR and MAPK/ERK pathways. This mini-review discussed the cellular impact and animal studies of pristimerin treatment, with more attention on the various molecular targets of pristimerin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1568009616666160112105824DOI Listing
October 2017

Pristimerin demonstrates anticancer potential in colorectal cancer cells by inducing G1 phase arrest and apoptosis and suppressing various pro-survival signaling proteins.

Oncol Rep 2016 Feb 26;35(2):1091-100. Epub 2015 Nov 26.

Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Jiangsu 210009, P.R. China.

Pristimerin is a naturally occurring triterpenoid that has a cytotoxic effect on several cancer cell lines. However, the cytotoxic effects of pristimerin as well as its molecular mechanisms of action against colorectal cancer have never been explored. In the present study, we investigated the anticancer potential of pristimerin, and examined the different signaling pathways affected by its action in three colon cancer cell lines namely HCT-116, COLO-205 and SW-620. Pristimerin was found to possess potent cytotoxic and proliferation inhibitory effects against these cell lines. Cell cycle analysis revealed G1 phase arrest, which was strongly associated with decreased expression of cyclin D1 and cyclin-dependent kinases (cdk4 and cdk6) with concomitant induction of p21. Pristimerin also induced apoptosis in a dose-dependent manner. Cell plasma membrane alterations studied by Annexin V/PI double staining, loss of mitochondrial membrane potential (ΔΨm), measurements of caspase activities and the inhibitory effect of Z-VAD-FMK (a caspase inhibitor) confirmed the apoptotic effect of pristimerin. Moreover, western blot data showed that apoptotic induction was associated with activated caspase-3 and -8, PARP-1 cleavage and modulation of the expression levels of Bcl-2 family proteins. Additionally, pristimerin treatment downregulated the phosphorylated forms of EGFR and HER2 proteins, and subsequently caused a decrease in the phosphorylated forms of Erk1/2, Akt, mTOR and NF-κB proteins. Taken together, these results suggest that pristimerin may have potential as a new targeting therapeutic strategy for the treatment of colon cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/or.2015.4457DOI Listing
February 2016

[Study on hepatotoxicity of aqueous extracts of Polygonum multiflorum in rats after 28-day oral administration: cholestasis-related mechanism].

Zhongguo Zhong Yao Za Zhi 2015 Jun;40(11):2163-7

Objective: To study the effect of aqueous extracts of Polygonum multiflorum (AEPM) on bile acid synthesis, metabolism and transfer-related molecules in rat liver and the hepatotoxicity-related mechanism of P. multiflorum.

Method: Sprague-Dawley rats were orally administered with 30, 60 g x kg(-1) APEM once everyday for consecutively 28 days. At the end of the experiment, mRNA and protein expressions of hepatic MRP3, MRP2, BSEP, FXR and CYP7A1 were detected by Real-time PCR and Western blot

Result: Compared with the normal group, the AEPM high dose group showed significant increases in mRNA expressions of hepatic MRP3 and BSEP of male rats (P < 0.05); AEPM high and low dose groups revealed a notable decrease in mRNA expressions of hepatic FXR (P < 0.05) and remarkable rises in mRNA expressions of hepatic MRP3, MRP2, BSEP, CYP7A1 among female rats (P < 0.05). According to the test results of western blot assay, AEPM high and low dose groups showed consistent changes in protein and mRNA expressions hepatic MRP3, MRP2, BSEP, FXR, CYP7A1.

Conclusion: The 28 oral administration with AEPM in rats showed a certain effect on expressions of bile acid synthesis, metabolism and transfer-related proteins, as well as cholestatic or choleretic effects in the mRNA expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
June 2015

Inhibitory effects of Tripterygium wilfordii multiglycoside on benign prostatic hyperplasia in rats.

Chin J Nat Med 2015 Jun;13(6):421-7

Jiangsu Center of Drug Screening, China Pharmaceutical University, Nanjing 210009, China; Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

The present study was designed to evaluate the inhibitory effects of Tripterygium wilfordii multiglycoside (GTW) against testosterone-induced benign prostatic hyperplasia (BPH) in rats. A total of 45 rats were randomly divided into five groups: Group I, vehicle control group (sham-operated and treated with vehicle); Group II, BPH group; Group III, BPH rats treated with finasteride at a dose of 5 mg·kg(-1); and Groups IV and V, BPH rats treated with GTW at dose levels of 10 and 20 mg·kg(-1), respectively. The drugs were administered orally once a day for 14 days. Prostate weight, prostatic index, and the testosterone and dihydrotestosterone (DHT) levels in serum and prostate, and the serum prostate specific antigen (PSA) levels were measured; prostate tissues were taken for histopathological examination; and serum biochemical analysis was also performed. The BPH rats displayed an increase in prostate weight, prostatic index with increased testosterone and DHT levels in both the serum and prostate, and increased serum PSA levels. GTW treatment at both doses resulted in significant reductions in prostate weight, prostatic index, testosterone and DHT levels in both the serum and prostate, and serum PSA levels, compared with BPH group. Histopathological examination also indicated that GTW treatment at both doses inhibited testosterone-induced prostatic hyperplasia. Serum biochemical analysis showed that the liver and renal functions were normal. In conclusion, GTW inhibited testosterone-induced prostatic hyperplasia in rats, without host toxicity, providing a basis for the development of GTW as a novel therapy for BPH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1875-5364(15)30035-2DOI Listing
June 2015