Publications by authors named "Chuanrui Ma"

26 Publications

  • Page 1 of 1

Tectorigenin alleviates intrahepatic cholestasis by inhibiting hepatic inflammation and bile accumulation via activation of PPARγ.

Br J Pharmacol 2021 Mar 4. Epub 2021 Mar 4.

Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, 518020, China.

Background And Purpose: Increasing evidence suggests that human cholestasis is closely associated with the accumulation and activation of hepatic macrophages. Research indicates that activation of peroxisome proliferator-activated receptor-γ (PPARγ) exerts liver protective effects in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, the existing PPARγ agonists, such as troglitazone and rosiglitazone, have significant side effects that impede their clinical application in the treatment of CLD. In this study, we found that tectorigenin (TEC) alleviates intrahepatic cholestasis in mice by activating PPARγ.

Experimental Approach: Wild-type mice were intragastrically administered α-naphthylisothiocyanate (ANIT) or fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to simultaneously establish an experimental model of intrahepatic cholestasis and TEC intervention, followed by determination of intrahepatic cholestasis and the mechanisms involved. In addition, PPARγ-deficient mice were administered ANIT and/or TEC to determine whether TEC exerts its liver protective effect by activating PPARγ.

Key Results: We demonstrated that TEC intervention alleviated intrahepatic cholestasis by inhibiting the recruitment and activation of hepatic macrophages as well as by promoting the expression of bile transporters via activation of PPARγ. Furthermore, our results show that TEC increased bile salt export pump (BSEP) expression through enhanced PPARγ binding to the BSEP promoter. We also demonstrated that PPARγ deficiency blocked the hepatoprotective effect of TEC during cholestasis.

Conclusions And Implications: In conclusion, TEC reduced the recruitment and activation of hepatic macrophages, and enhanced the export of bile acids by activating PPARγ. Taken together, our results suggest that TEC is a candidate compound for cholestasis treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.15429DOI Listing
March 2021

Danthron ameliorates obesity and MAFLD through activating the interplay between PPARα/RXRα heterodimer and adiponectin receptor 2.

Biomed Pharmacother 2021 May 12;137:111344. Epub 2021 Feb 12.

Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China; Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China. Electronic address:

Obesity and associated metabolic associated fatty liver diseases (MAFLD) are strongly associated with dysfunction of glucose and lipid metabolism. AMPKα and PPARα are key regulators in the lipid and glucose homeostasis, indicating that novel agents to activate them are promising therapeutic approaches for metabolic syndrome. Noticeably, as a natural anthraquinone derivative extracted from rhubarb, danthron can activate AMPKα in vitro. However, the protective effect of danthron on obesity and associated MAFLD in vivo, as well as the underlying mechanism remains unknown. In this study, obesity and associated MAFLD was induced in C57BL/6J mice by high fat diet (HFD), which were subjected to evaluations on the parameters of systematic metabolism. Simultaneously, the molecular mechanism of danthron on lipid metabolism was investigated in 3T3-L1-derived adipocytes and HepG2 cells in vitro. In vivo, danthron significantly attenuated the obesity and MAFLD by enhancing hepatic fatty acid oxidation, decreasing lipid synthesis, and promoting mitochondrial homeostasis. Mechanistically, danthron significantly promoted combination of RXRα and PPARα, enhanced the binding of RXRα/PPARα heterodimer to the promoter of adiponectin receptor 2 (AdipoR2), by which activating the AMPKα and PPARα pathway. Moreover, PPARα and AdipoR2 can interplay in a loop style. Collectively, this study demonstrates that danthron can substantially ameliorate obesity and associated hepatic steatosis via AdipoR2-mediated dual PPARα/AMPKα activation, which suggests that danthron might be a novel therapeutic approach for inhibition of obesity and hepatic steatosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2021.111344DOI Listing
May 2021

Targeting macrophage liver X receptors by hydrogel-encapsulated T0901317 reduces atherosclerosis without effect on hepatic lipogenesis.

Br J Pharmacol 2021 Apr 23;178(7):1620-1638. Epub 2021 Feb 23.

Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.

Background And Purpose: Targeting macrophage but not hepatocyte liver X receptors (LXRs) can reduce atherosclerosis without effect on hepatic lipogenesis. In this study, we encapsulated LXR ligands with D-Nap-GFFY to form a nanofibre hydrogel (D-Nap-GFFY-T0901317 or GFFY-T0901317) and determined its effect on atherosclerosis, hepatic lipogenesis and the underlying mechanisms involved.

Experimental Approach: D-Nap-GFFY-T0901317 was subcutaneously injected to proatherogenic diet-fed apoE-deficient (Apoe ) mice, followed by determination of the development of atherosclerosis, liver steatosis and the involved mechanisms, with comparison of T0901317 oral administration.

Key Results: Subcutaneous injection of D-Nap-GFFY-T0901317 to Apoe mice inhibited atherosclerosis at a comparable level as T0901317 oral administration without effect on hepatic lipogenesis. More importantly, D-Nap-GFFY-T0901317 regressed the advanced lesions. In arterial wall, D-Nap-GFFY-T0901317 reduced macrophage/foam cells, necrotic cores and calcification and increased collagen content. It activated expression of ABCA1/G1 and smooth muscle α-actin, while inhibiting expression of intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). D-Nap-GFFY-T0901317 also reduced serum pro-inflammatory cytokines and facilitated Kupffer cell M2 polarization. Mechanistically, D-Nap-GFFY-T0901317 was selectively taken up by macrophages but not hepatocytes, resulting in activation of macrophage ABCA1/G1 expression, while having no effect on lipogenic genes in hepatocytes. Moreover, the selective uptake of D-Nap-GFFY-T0901317 by macrophages was mainly completed in a scavenger receptor class A-dependent manner.

Conclusion And Implications: Our study demonstrates that D-Nap-GFFY-T0901317 reduces atherosclerosis without effect on hepatic lipogenesis by targeting macrophage LXRs selectively, indicating its potential application for atherosclerosis treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.15387DOI Listing
April 2021

Encapsulation of LXR ligand by D-Nap-GFFY hydrogel enhances anti-tumorigenic actions of LXR and removes LXR-induced lipogenesis.

Theranostics 2021 1;11(6):2634-2654. Epub 2021 Jan 1.

Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.

Activation of liver X receptor (LXR) by its ligand T0901317 (T317) enhances interferon-γ (IFNγ) production to inhibit tumor growth. However, induction of severe hypertriglyceridemia and fatty liver by T317 limits its application. The naphthylacetic acid modified D-enantiomeric-glycine-phenylalanine-phenylalanine-tyrosine (D-Nap-GFFY) can form a nanofiber hydrogel which is selectively taken up by antigen-presenting cells (APCs). In this study, we determined if D-Nap-GFFY-encapsulated T317 (D-Nap-GFFY-T317) can potently inhibit tumor growth while having no adverse lipogenic effects on the liver. We prepared D-Nap-GFFY-T317 nanofiber hydrogel and subcutaneously injected it into IFNγ deficient (IFNγ) and wild-type (WT) mice with lung carcinoma, either inoculated LLC1 cells or urethane-induced carcinoma. Mice received oral T317 administration were used for comparison. Effects of treatment on tumor growth, lipogenesis and involved mechanisms were investigated. Compared with T317 oral administration, injection of D-Nap-GFFY-T317 more potently inhibited LLC1 tumor growth in mice. The inhibition was dependent on LXR-activated IFNγ expression in APCs. D-Nap-GFFY-T317 increased M1 while reducing M2 type macrophages in tumors. Associated with activation of IFNγ expression, D-Nap-GFFY-T317 enhanced dendritic cell maturation and infiltration into tumors, increased CD3/CD8 cells in tumors, and inhibited tumor angiogenesis. Similarly, D-Nap-GFFY-T317 more potently inhibited growth of urethane-induced lung carcinomas than T317 oral administration. In these two tumor models, T317 oral administration, but not D-Nap-GFFY-T317 injection, activated hepatic lipogenesis and induced fatty liver. Our study demonstrates that D-Nap-GFFY-T317 inhibits lung tumor growth without adverse effects on the liver, indicating the hydrogel-encapsulated LXR ligand might be a novel therapy for tumor treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.53139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806465PMC
January 2021

ERK1/2 inhibition reduces vascular calcification by activating miR-126-3p-DKK1/LRP6 pathway.

Theranostics 2021 1;11(3):1129-1146. Epub 2021 Jan 1.

Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, China.

: Vascular microcalcification increases the risk of rupture of vulnerable atherosclerotic lesions. Inhibition of ERK1/2 reduces atherosclerosis in animal models while its role in vascular calcification and the underlying mechanisms remains incompletely understood. Levels of activated ERK1/2, DKK1, LRP6 and BMP2 in human calcific aortic valves were determined. ApoE deficient mice received ERK1/2 inhibitor (U0126) treatment, followed by determination of atherosclerosis, calcification and miR-126-3p production. C57BL/6J mice were used to determine the effect of U0126 on Vitamin D (VD)-induced medial arterial calcification. HUVECs, HAECs and HASMCs were used to determine the effects of ERK1/2 inhibitor or siRNA on SMC calcification and the involved mechanisms. : We observed the calcification in human aortic valves was positively correlated to ERK1/2 activity. At cellular and animal levels, U0126 reduced intimal calcification in atherosclerotic lesions of high-fat diet-fed apoE deficient mice, medial arterial calcification in VD-treated C57BL/6J mice, and calcification in cultured SMCs and arterial rings. The reduction of calcification was attributed to ERK1/2 inhibition-reduced expression of ALP, BMP2 and RUNX2 by activating DKK1 and LRP6 expression, and consequently inactivating both canonical and non-canonical Wnt signaling pathways in SMCs. Furthermore, we determined ERK1/2 inhibition activated miR-126-3p production by facilitating its maturation through activation of AMPKα-mediated p53 phosphorylation, and the activated miR-126-3p from ECs and SMCs played a key role in anti-vascular calcification actions of ERK1/2 inhibition. : Our study demonstrates that activation of miR-126-3p production in ECs/SMCs and interactions between ECs and SMCs play an important role in reduction of vascular calcification by ERK1/2 inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.49771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738895PMC
January 2021

Astragalus Flavone Ameliorates Atherosclerosis and Hepatic Steatosis Via Inhibiting Lipid-Disorder and Inflammation in apoE Mice.

Front Pharmacol 2020 14;11:610550. Epub 2020 Dec 14.

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.

Atherosclerosis is a major pathogenic driver of cardiovascular diseases. Foam cell formation plays a key role in atherogenesis, which is affected by lipid disorder and inflammation. Therefore, inhibition of foam cell formation is a therapeutic approach for atherosclerosis treatment. Total flavone of (TFA) is extracted from that has protective effect on cardiovascular disease. However, the effect of TFA on atherosclerosis and the underlying mechanism remains unknown. In this study, we determined whether TFA could inhibit atherosclerosis and uncovered the underlying mechanism. , ApoE deficient mice were treated with TFA and high-fat diet for 16 weeks. Subsequently, atherosclerotic lesions, hepatic steatosis and associated genes expression and were determined. We found that TFA reduced atherosclerotic lesion size and enhanced plaque stability, which might be attributed to improved lipid disorder, reduced inflammation and decreased monocyte adhesion. Mechanistically, TFA inhibited hepatic steatosis via regulating the genes responsible for lipid metabolism, by which ameliorating the lipid disorder. Moreover, in macrophage, TFA reduced the expression of scavenger receptors such as CD36 and SRA; and promoted the expression of ATP-binding cassette transporter A1 and G1 (ABCA1/G1). More importantly, TFA reduced miR-33 expression and dampened NFκB activity, by which de-repressing ABCA1/G1 activity and inhibiting the inflammation. Collectively, TFA can attenuate atherosclerosis via dual suppression of miR-33 and NFκB pathway, and partially through inhibition of scavenger receptors in macrophage. In addition, TFA ameliorates the hepatic steatosis and lipid disorder, which in turn contributes to the amelioration of atherosclerosis, suggesting that TFA might be a novel therapeutic approach for inhibition of atherosclerosis and hepatic steatosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.610550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768082PMC
December 2020

Bifunctional supramolecular nanofiber inhibits atherosclerosis by enhancing plaque stability and anti-inflammation in apoE mice.

Theranostics 2020 13;10(22):10231-10244. Epub 2020 Aug 13.

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin 300381, P. R. China.

Atherosclerosis is vascular disease of chronic inflammation and lipid disorder, which is a major cause of coronary heart disease. Foam cell formation is key progress during the atherosclerosis development. Insulin-like growth factor (IGF)-1 is a growth hormone that plays a crucial role in growth, metabolism, and homeostasis. Previous studies have demonstrated that increase in circulating IGF-1 can reduce atherosclerotic burden. However, active IGF-1 is characterized with poor tissue retention and is at a very low level in circulation system. Therefore, supplementation of exogenous IGF-1 to restore the physiological level is a promising approach to inhibit atherosclerosis. In this study, we develop a self-assembling, anti-inflammatory drug-modified peptide derived from IGF-1 to mimic IGF-1 bioactivity and simultaneously with an anti-inflammatory property for the treatment of atherosclerosis. ApoE mice were subcutaneously (s.c.) injected with the different hydrogels or natural IGF-1 protein solution per week and simultaneously fed a high-fat diet for 16 weeks. Atherosclerotic lesion formation and stability were assessed after treatment. Moreover, peritoneal macrophage and serum samples were collected to determine lipid profile and inflammatory cytokines. Concurrently, we determined the effect of bifunctional supramolecular nanofibers/hydrogel on cholesterol efflux, foam cell formation, phenotypic transformation of VSMC to macrophage-like cells, and macrophage polarization or . Bifunctional supramolecular nanofibers/hydrogel for the treatment of atherosclerosis was formed by a short peptide consisting of a tetrapeptide SSSR from C-region of growth factor IGF-1, an anti-inflammatory drug naproxen (Npx), and a powerful self-assembling D-peptide FF. The resulting hydrogel of Npx-FFGSSSR (Hydrogel 1, H1) possessed both the anti-inflammatory and IGF-1 mimicking properties, and it efficiently promoted the expression of ABCA1 and ABCG1, thereby significantly reducing cholesterol accumulation in macrophages and preventing foam cell formation. Moreover, H1 markedly inhibited the transformation of vascular smooth muscle cells (VSMCs) into macrophage-like cells which also contributed to foam cell formation. In addition, H1 significantly reduced the inflammatory response and . Most importantly, the IGF-1 mimetic peptide showed comparable performance to IGF-1 i and inhibited atherosclerosis by markedly reducing lesion area and enhancing plaque stability. Our study provides a novel supramolecular nanomaterial to inhibit pathological progress of atherosclerosis through regulating cholesterol efflux and inflammation, which may contribute to the development of a promising nanomedicine for the treatment of atherosclerosis in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.48410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481406PMC
August 2020

Simultaneous co-assembly of fenofibrate and ketoprofen peptide for the dual-targeted treatment of nonalcoholic fatty liver disease (NAFLD).

Chem Commun (Camb) 2020 May 2;56(36):4922-4925. Epub 2020 Apr 2.

Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, P. R. China.

We have developed a co-assembled nanosystem based on fenofibrate and ketoprofen by tactfully utilizing their simultaneous benzophenone interaction, which greatly enhances the bioavailability of fenofibrate and plays a role in the dual-targeted treatment of NAFLD by reducing hepatic lipid accumulation and inflammatory responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0cc00513dDOI Listing
May 2020

Tectorigenin attenuates diabetic nephropathy by improving vascular endothelium dysfunction through activating AdipoR1/2 pathway.

Pharmacol Res 2020 03 31;153:104678. Epub 2020 Jan 31.

Department of Endocrinology, The 2nd Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, China. Electronic address:

Diabetic nephropathy (DN), a kind of microvascular complication, is a primary cause of end-stage renal disease worldwide. However, therapeutic drugs for DN treatment are still in lack. The glomerular endothelium is essential to maintain selective permeability of glomerular filtration barrier and glomerular vasculature function. Growing evidences show that endothelial dysfunction or injury is the initial stage of vascular damage in DN, which can be induced by hyperglycemia, lipotoxicity, and inflammation. Therefore, to improve the function of vascular endothelium in kidney is a key point for treatment of DN. As a plant isoflavone, tectorigenin (TEC) has attracted considerable attention due to its anti-proliferative and anti-inflammatory functions. However, whether TEC could inhibit the DN development remains unknown. In this study, we examined the effects of TEC on DN development in db/db mice, a type of genetic defect diabetic mice that can spontaneously develop into severe renal dysfunction. Intriguingly, TEC treatment restored diabetes-induced glucose and lipid metabolic disorder; and improved the deterioration of renal function, particularly the renal endothelium function in db/db mice. Additionally, TEC inhibited the renal inflammation via reducing macrophages infiltration and M1 polarization. Moreover, TEC inhibited lipopolysaccharide (LPS)-induced endothelial injury and M1 polarization in vitro. Mechanistically, TEC partially restored the reduction in expression of adiponectin receptor 1/2 (AdipoR1/2), pi-LKB1, pi-AMPKα, and PPARα in vitro and in vivo. Noteworthy, these beneficial pharmacological activities mediated by TEC were significantly attenuated after AdipoR1/2 knockdown by siRNA, indicating that AdipoR1/2 plays a critical role in protection against DN. Collectively, these results suggested that TEC have a potently effect for retarding type 2 diabetes-associated DN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2020.104678DOI Listing
March 2020

Formononetin attenuates atherosclerosis via regulating interaction between KLF4 and SRA in apoE mice.

Theranostics 2020 1;10(3):1090-1106. Epub 2020 Jan 1.

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.

: Atherosclerosis is an underlying cause of coronary heart disease. Foam cell, a hallmark of atherosclerosis, is prominently derived from monocyte-differentiated macrophage, and vascular smooth muscle cells (VSMCs) through unlimitedly phagocytizing oxidized low-density lipoprotein (oxLDL). Therefore, the inhibition of monocyte adhesion to endothelium and uptake of oxLDL might be a breakthrough point for retarding atherosclerosis. Formononetin, an isoflavone extracted from , has exhibited multiple inhibitory effects on proatherogenic factors, such as obesity, dyslipidemia, and inflammation in different animal models. However, its effect on atherosclerosis remains unknown. In this study, we determined if formononetin can inhibit atherosclerosis and elucidated the underlying molecular mechanisms. : ApoE deficient mice were treated with formononetin contained in high-fat diet for 16 weeks. After treatment, mouse aorta, macrophage and serum samples were collected to determine lesions, immune cell profile, lipid profile and expression of related molecules. Concurrently, we investigated the effect of formononetin on monocyte adhesion, foam cell formation, endothelial activation, and macrophage polarization and . : Formononetin reduced and aortic root sinus lesions size. Formononetin enhanced lesion stability by changing the composition of plaque. VSMC- and macrophage-derived foam cell formation and its accumulation in arterial wall were attenuated by formononetin, which might be attributed to decreased SRA expression and reduced monocyte adhesion. Formononetin inhibited atherogenic monocyte adhesion and inflammation. KLF4 negatively regulated the expression of SRA at transcriptional and translational level. : Our study demonstrate that formononetin can substantially attenuate the development of atherosclerosis via regulation of interplay between KLF4 and SRA, which suggests the formononetin might be a novel therapeutic approach for inhibition of atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.38115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956811PMC
April 2021

Combination of MEK1/2 inhibitor and LXR ligand synergistically inhibit atherosclerosis in LDLR deficient mice.

Biochem Biophys Res Commun 2020 02 26;522(2):512-517. Epub 2019 Nov 26.

Key Laboratory of Major Metabolic Diseases and Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. Electronic address:

Combined LXR ligand (T0901317) and MEK1/2 inhibitor (U0126) not only reduces atherosclerosis in apoE deficient mice, but also blocks LXR ligand-induced fatty liver and hypertriglyceridemia. However, the atheroprotective function of combined T0901317 and U0126 should be further investigated in LDLR deficient (LDLR) mice since deficiency of LDLR not apoE can occur to humans with a high frequency. Herein, we validated the effectiveness of this combinational therapy on the development of atherosclerosis in LDLR mice to demonstrate its potential application in clinic. We found although T0901317 or U0126 alone reduced atherosclerotic plaques in en face and aortic root areas in HFD-fed LDLR mice, their combination inhibited lesions in a synergistic manner. Combined U0126 and T0901317 had no effect on serum total cholesterol levels. T0901317 deceased HDL-cholesterol levels, which was restored by combined U0126. Meanwhile, U0126 alleviated T0901317-induced triglyceride accumulation, the major adverse effect of T0901317 which limits its clinical utility. Mechanistically, U0126 reduced fatty acid de novo synthesis by inhibiting hepatic fatty acid synthase (FASN) expression, thereby correcting T0901317-induced triglyceride overproduction. In conclusion, our study demonstrates that combination of MEK1/2 inhibitor and LXR ligand can synergistically reduce atherosclerosis in LDLR deficient mice without lipogenic side effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2019.11.115DOI Listing
February 2020

Rosiglitazone alleviates intrahepatic cholestasis induced by α-naphthylisothiocyanate in mice: The role of circulating 15-deoxy-Δ -PGJ and Nogo.

Br J Pharmacol 2020 03 3;177(5):1041-1060. Epub 2020 Feb 3.

Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.

Background And Purpose: Intrahepatic cholestasis is mainly caused by dysfunction of bile secretion and has limited effective treatment. Rosiglitazone is a synthetic agonist of PPARγ, whose endogenous agonist is 15-deoxy-Δ -PGJ (15d-PGJ ). Reticulon 4B (Nogo-B) is the detectable Nogo protein family member in the liver and secreted into circulation. Here, we determined if rosiglitazone can alleviate intrahepatic cholestasis in mice.

Experimental Approach: Wild-type, hepatocyte-specific PPARγ or Nogo-B knockout mice received intragastric administration of α-naphthylisothiocyanate (ANIT) and/or rosiglitazone, followed by determination of intrahepatic cholestasis and the involved mechanisms. Serum samples from primary biliary cholangitis (PBC) patients and non-PBC controls were analysed for cholestasis-related parameters.

Key Results: Rosiglitazone prevented wild type, but not hepatocyte-specific PPARγ deficient mice from developing ANIT-induced intrahepatic cholestasis by increasing expression of bile homeostatic proteins, reducing hepatic necrosis, and correcting abnormal serum parameters and enterohepatic circulation of bile. Nogo-B knockout provided protection similar to that of rosiglitazone treatment. ANIT-induced intrahepatic cholestasis decreased 15d-PGJ but increased Nogo-B in serum, and both were corrected by rosiglitazone. Nogo-B deficiency in the liver increased 15d-PGJ production, thereby activating expression of PPARγ and bile homeostatic proteins. Rosiglitazone and Nogo-B deficiency also alleviated cholestasis-associated dyslipidemia. In addition, rosiglitazone reduced symptoms of established intrahepatic cholestasis in mice. In serum from PBC patients, the decreased 15d-PGJ and increased Nogo-B levels were significantly correlated with classical cholestatic markers.

Conclusions And Implications: Levels of 15d-PGJ and Nogo are important biomarkers for intrahepatic cholestasis. Synthetic agonists of PPARγ could be used for treatment of intrahepatic cholestasis and cholestasis-associated dyslipidemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.14886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042110PMC
March 2020

Therapeutic potential of NaoXinTong Capsule on the developed diabetic nephropathy in db/db mice.

Biomed Pharmacother 2019 Oct 31;118:109389. Epub 2019 Aug 31.

Department of Biochemistry and Molecular Biology, College of Life Science, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China; Department of Pharmacological Sciences, Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. Electronic address:

The current treatment for diabetic nephropathy (DN) is still limited. NaoXinTong Capsule (NXT) is a Chinese Medicine prescribed to patients with cardiovascular disease. It can also ameliorate metabolic syndromes in patients indicating its anti-diabetic properties. Herein we report the therapeutic effects of NXT on the developed DN. The db/db diabetic mice at ˜12 weeks old, the age with DN at middle/advanced stages, were treated with NXT for 12 weeks. We found NXT treatment reduced diabetes-induced hyperglycemia and dyslipidemia, thereby substantially reduced DN progress. In the kidney, NXT reduced mesangial matrix expansion and glomerulosclerosis by inhibiting extracellular matrix accumulation through activation of matrix metalloproteinase 2/9 and inactivating transforming growth factor β1 expression. NXT reduced podocyte injury by reducing renal inflammation and expression of adhesion molecules. Mechanically, NXT potently activated AMPKα in multiple tissues thereby enhancing energy metabolism. In the liver, NXT increased glucokinase expression and insulin sensitivity by increasing insulin receptor substrate 1/2 and protein kinase B (AKT) 1/2 expression/phosphorylation. In skeletal muscle, NXT activated expression of glucose transporter type 4, AKT, glycogen synthase and peroxisome proliferator activated receptor α/γ. In adipose tissue, NXT reduced fatty acid synthase while activating hormone-sensitive lipase expression. Taken together, our study demonstrates that NXT reduced progress of the developed DN by ameliorating glucose, lipid and energy metabolism, maintaining renal structural and functional integrity. Our study also indicates the potential application of NXT for DN treatment in clinics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2019.109389DOI Listing
October 2019

Formononetin ameliorates cholestasis by regulating hepatic SIRT1 and PPARα.

Biochem Biophys Res Commun 2019 05 27;512(4):770-778. Epub 2019 Mar 27.

First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China; Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China. Electronic address:

Cholestasis, which is characterized by bile acid (BA) overload within the hepatocytes, is a major contributor to liver injury. The dysregulation of bile acid homeostasis, such as excessive bile acid synthesis and defected secretion, leads to intracellular retention of hydrophobic bile acid which undermines the physiological function of hepatocytes. Cholestasis can further develop into hepatic fibrosis and cirrhosis, and eventually life-threating liver failure. In the liver, BA-activated FXR can reduce hepatic BA concentration by negative feedback regulation. Clinically, FXR and PPARα are the pharmacological targets of obeticholic acid and fenofibrate for the treatment of primary biliary cirrhosis, respectively. Formononetin, a natural isoflavone compound, exerts beneficial effects in various biological processes, such as anti-inflammation, anti-tumor. However, the role of formononetin in bile acid metabolism remains unclear. Herein, we show that formononetin improves hepatic/systemic bile acid metabolism and protects against ANIT-induced liver injury. Mechanistically, formononetin improves the genes profile orchestrating bile acid homeostasis through modulating SIRT1-FXR signaling pathway. Moreover, formononetin attenuated ANIT-induced inflammatory response by inactivating JNK inflammation pathway in PPARα dependent manner. Taken together, our study demonstrates that formononetin ameliorates hepatic cholestasis by upregulating expression of SIRT1 and activating PPARα, which is an important anti-cholestatic mechanism of formononetin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2019.03.131DOI Listing
May 2019

CD36 plays a critical role in proliferation, migration and tamoxifen-inhibited growth of ER-positive breast cancer cells.

Oncogenesis 2018 Dec 21;7(12):98. Epub 2018 Dec 21.

School of Food and Biological Engineering, Hefei University of Technology, Hefei, China.

Tamoxifen inhibits estrogen receptor (ER)-positive breast cancer growth while CD36 potentiates cancer metastasis. The effects of CD36 on proliferation/migration of breast cancer cells and tamoxifen-inhibited ER-positive cell growth are unknown. In this study, we correlated the mortality of breast cancer patients to tumor CD36 expression levels. We also found CD36 was higher in ER-rich (MCF-7>T-47D~ZR-75-30) than ER-negative (MDA-MB-231) cells. CD36 siRNA decreased viability and migration of MCF-7 and MDA-MB-231 cells with more potent effects on MCF-7 cells. Inversely, high expressing CD36 enhanced cell growth/migration. Mechanistically, CD36 increased expression of genes responsible for cell proliferation, migration and anti-apoptosis. CD36 also activated ERα and ER-targeted genes for cell cycles, and phosphorylated ERK1/2 (p-ERK1/2). Tamoxifen inhibited CD36 and p-ERK1/2 in ERα-positive but not ERα-negative cells. Reciprocally, inhibition of MCF-7 cell growth by tamoxifen was attenuated by high expressing CD36. CD36, ERα and p-ERK1/2 expression was higher in tamoxifen-resistant MCF-7 (MCF-7/TAMR) cells than normal MCF-7 cells. However, CD36 siRNA restored the capacity of tamoxifen inhibiting MCF-7/TAMR cell growth. CD36 antibody inhibited cell growth and expression of ERα, p-ERK1/2 and CCND1. Therefore, our study unveils a pro-tumorigenic role of CD36 in breast cancer by enhancing proliferation/migration of breast cancer cells while attenuating tamoxifen-inhibited ER-positive cell growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41389-018-0107-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302092PMC
December 2018

LongShengZhi Capsule Reduces Established Atherosclerotic Lesions in apoE-Deficient Mice by Ameliorating Hepatic Lipid Metabolism and Inhibiting Inflammation.

J Cardiovasc Pharmacol 2019 02;73(2):105-117

College of Biomedical Engineering, Hefei University of Technology, Hefei, China.

Disorders of lipid metabolism and inflammation play an important role in atherosclerosis. LongShengZhi (LSZ) capsule, a Chinese herbal medicine, has been used for treatment of patients with vascular diseases for many years. In this article, we determined the effect of LSZ on the progression of established atherosclerotic lesions in apoE-deficient (apoE) mice. ApoE mice were prefed high-fat diet (HFD) for 8 weeks to induce atherosclerosis, then started with LSZ treatment contained in HFD for 10 weeks. Although LSZ had little effect on HFD-induced hypercholesterolemia, it substantially reduced en face and sinus aortic lesions. The reduction of lesions was associated with reduced macrophage/foam cell accumulation by activating ABCA1/ABCG1 expression. LSZ maintained the integrity of arterial wall by increasing collagen or smooth muscle cell content and inhibiting cell apoptosis. LSZ also attenuated HFD-induced fatty liver by down-regulating expression of lipogenic and cholesterol synthetic genes while activating expression of triglyceride catabolism genes. Moreover, LSZ demonstrated potent anti-inflammatory effects. In vivo, LSZ reduced serum TNF-α levels, infiltration of neutrophils, Kupffer cells, and expression of inflammatory cytokines in the liver. In vitro, it inhibited lipopolysaccharide or palmitate-induced expression of inflammatory cytokines in macrophages. Therefore, LSZ reduces atherosclerosis by ameliorating hepatic lipid metabolism and inhibiting inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FJC.0000000000000642DOI Listing
February 2019

Inhibition of Vascular Calcification.

Arterioscler Thromb Vasc Biol 2018 10;38(10):2382-2395

the Department of Biomedical Sciences, College of Biomedical Engineering, Hefei University of Technology, Hefei, China (X.Y., Y.D., Y.L., H.H., Y.C., J.H.).

Objective- Vascular calcification is a major risk factor for rupture of atherosclerotic plaques. High expression of BMP2 (bone morphogenetic protein 2) in lesions suggests its importance in vascular calcification during atherosclerosis. Teniposide is a Topo II (DNA topoisomerase II) inhibitor and is used for cancer treatment. Previously, we reported that teniposide activated macrophage ABCA1 (ATP-binding cassette transporter A1) expression and free cholesterol efflux indicating Topo II inhibitors may demonstrate antiatherogenic properties. Herein, we investigated the effects of teniposide on the development of atherosclerosis and vascular calcification in apoE (apoE deficient) mice. Approach and Results- apoE mice were fed high-fat diet containing teniposide for 16 weeks, or prefed high-fat diet for 12 weeks followed by high-fat diet containing teniposide for 4 weeks. Atherosclerosis and vascular calcification were determined. Human aortic smooth muscle cells were used to determine the mechanisms for teniposide-inhibited vascular calcification. Teniposide reduced atherosclerotic lesions. It also substantially reduced vascular calcification without affecting bone structure. Mechanistically, teniposide reduced vascular calcification by inactivating BMP2/(pi-Smad1/5/8 [mothers against decapentaplegic homolog 1, 5, and 8])/RUNX2 (runt-related transcription factor 2) axis in a p53-dependent manner. Furthermore, activated miR-203-3p by teniposide functioned as a link between activated p53 expression and inhibited BMP2 expression in inhibition of calcification. Conclusions- Our study demonstrates that teniposide reduces vascular calcification by regulating p53-(miR-203-3p)-BMP2 signaling pathway, which contributes to the antiatherogenic properties of Topo II inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.118.311546DOI Listing
October 2018

Activation of liver X receptor plays a central role in antiviral actions of 25-hydroxycholesterol.

J Lipid Res 2018 12 11;59(12):2287-2296. Epub 2018 Oct 11.

School of Food and Biological Engineering, Hefei University of Technology, Hefei, China

Production of 25-hydroxycholesterol (25HC), a potent inhibitor of viral infection, is catalyzed by cholesterol 25-hydroxylase (CH25H). We previously reported that 25HC induced CH25H expression in a liver X receptor (LXR)-dependent manner, implying that LXR can play an important role in antiviral infection. In this study, we determined that activation of LXR by 25HC or synthetic ligands [T0901317 (T317) or GW3965] inhibited infection of herpes simplex virus type 1 (HSV-1) or MLV-(VSV)-GFP in HepG2 cells or RAW 264.7 macrophages. Genetic deletion of LXRα, LXRβ, or CH25H expression in HepG2 cells by CRISPR/Cas9 method increased cell susceptibility to HSV-1 infection and attenuated the inhibition of LXR on viral infection. Lack of interferon (IFN)-γ expression also increased cell susceptibility to viral infection. However, it attenuated, but did not block, the inhibition of LXR on HSV-1 infection. In addition, expression of CH25H, but not IFN-γ, was inversely correlated to cell susceptibility to viral infection and the antiviral actions of LXR. Metabolism of 25HC into 25HC-3-sulfate (25HC3S) by cholesterol sulfotransferase-2B1b moderately reduced the antiviral actions of 25HC because 25HC3S is a weaker inhibitor of HSV-1 infection than 25HC. Furthermore, administration of T317 to BALB/c mice reduced HSV-1 growth in mouse tissues. Taken together, we demonstrate an antiviral system of 25HC with involvement of LXR activation, interaction between CH25H and IFN-γ, and 25HC metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1194/jlr.M084558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277154PMC
December 2018

NaoXinTong Capsules inhibit the development of diabetic nephropathy in db/db mice.

Sci Rep 2018 06 14;8(1):9158. Epub 2018 Jun 14.

College of Biomedical Engineering, Hefei University of Technology, Hefei, China.

NaoXinTong Capsule (NXT), a Chinese medicine, is currently used to treat patients with cardiovascular and cerebrovascular diseases. Clinical observations indicate its anti-diabetic functions with unclear mechanisms. Herein, we report the effect of NXT on diabetic nephropathy (DN). Type 2 diabetic db/db mice were treated with NXT for 14 weeks. In the course of treatment, NXT reduced diabetes-increased glucose levels and improved renal functions. At the end of treatment, we found that NXT ameliorated serum lipid profiles and other biochemical parameters. In the kidney, NXT inhibited mesangial matrix expansion, expression of vascular endothelial growth factor A, fibronectin, advanced glycation end product and its receptor. Meanwhile, it reduced the diabetes-induced podocyte injury by increasing WT1 and nephrin expression. In addition, NXT inhibited accumulation of extracellular matrix proteins by increasing MMP2/9 expression through inactivation of TGFβ/Smad pathway and CTGF expression. Mechanically, NXT activated insulin signaling pathway by increasing expression of INSR, IRS and FGF21, phosphorylation of Akt and AMPKα in the liver, INSR phosphorylation in the kidney, and FGF21 and GLUT4 expression in adipose tissue and skeletal muscle. Taken together, our study demonstrates that NXT inhibits DN by ameliorating glucose/lipid metabolism, maintaining tissue structure integrity, and correcting diabetes-induced renal dysfunctions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-26746-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002396PMC
June 2018

Functional interplay between liver X receptor and AMP-activated protein kinase α inhibits atherosclerosis in apolipoprotein E-deficient mice - a new anti-atherogenic strategy.

Br J Pharmacol 2018 05 23;175(9):1486-1503. Epub 2018 Mar 23.

College of Biomedical Engineering, Hefei University of Technology, Hefei, China.

Background And Purpose: The liver X receptor (LXR) agonist T317 reduces atherosclerosis but induces fatty liver. Metformin activates energy metabolism by activating AMPKα. In this study, we determined if interactions between metformin and T317 could inhibit atherosclerosis without activation of hepatic lipogenesis.

Experimental Approach: Apolipoprotein E-deficient mice were treated with T317, metformin or both agents, in a high-fat diet for 16 weeks. Then, samples of aorta, liver, macrophage and serum were collected to determine atherosclerotic lesions, fatty liver, lipid profiles and expression of related proteins. Techniques used included immunohistochemistry, histology, qRT-PCR and Western blot.

Key Results: T317 inhibited en face and aortic root sinus lesions, and the inhibition was further enhanced by addition of metformin. Co-treatment with metformin and T317 increased lesion stability, by increasing collagen content, and reducing necrotic cores and calcification. Formation of macrophages/foam cells and their accumulation in arterial wall were inhibited by the co-treatment, which was accompanied by increased ABCA1/ABCG1 expression, reduced monocyte adhesion and apparent local proliferation of macrophages. Metformin blocked T317-induced fatty liver by inhibiting T317-induced hepatic LXRα nuclear translocation and expression of lipogenic genes and by activating AMPKα. Moreover, co-treatment with T317 and metformin improved triglyceride metabolism by inducing expression of adipose triglyceride lipase, hormone-sensitive lipase, PPARα and carnitine acetyltransferase and by inhibiting acyl-CoA:diacylglycerol acyltransferase 1 expression.

Conclusions And Implications: Co-treatment with T317 and metformin inhibited the development of atherosclerosis without activation of lipogenesis, suggesting that combined treatment with T317 and metformin may be a novel approach to inhibition of atherosclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.14156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901167PMC
May 2018

25-Hydroxycholesterol activates the expression of cholesterol 25-hydroxylase in an LXR-dependent mechanism.

J Lipid Res 2018 03 3;59(3):439-451. Epub 2018 Jan 3.

Department of Biomedical Sciences, College of Biomedical Engineering, Hefei University of Technology, Hefei, China

Cholesterol 25-hydroxylase (CH25H) catalyzes the production of 25-hydroxycholesterol (25-HC), an oxysterol that can play an important role in different biological processes. However, the mechanisms regulating CH25H expression have not been fully elucidated. In this study, we determined that CH25H is highly expressed in mouse liver and peritoneal macrophages. We identified several liver X receptor (LXR) response elements (LXREs) in the human CH25H promoter. In HepG2 cells, activation of LXR by 25-HC or other oxysterols and synthetic ligands [T0901317 (T317) and GW3965] induced CH25H protein expression, which was associated with increased CH25H mRNA expression. 25-HC or T317 activated CH25H transcription in an LXRE-dependent manner. Thus, high-expressing LXRα or LXRβ activated CH25H expression, and the activation was further enhanced by LXR ligands. In contrast, inhibition of LXRα/β expression attenuated 25-HC or T317-induced CH25H expression. Deficiency of interferon γ expression reduced, but did not block, LXR ligand-induced hepatic CH25H expression. Activation of LXR also substantially induced macrophage CH25H expression. In vivo, administration of GW3965 to mice increased CH25H expression in both liver and peritoneal macrophages. Taken together, our study demonstrates that 25-HC can activate CH25H expression in an LXR-dependent manner, which may be an important mechanism to exert the biological actions of 25-HC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1194/jlr.M080440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832929PMC
March 2018

Activation of Adiponectin Receptor Regulates Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Inhibits Lesions in ApoE-Deficient Mice.

Arterioscler Thromb Vasc Biol 2017 07 25;37(7):1290-1300. Epub 2017 May 25.

From the Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin, China (L.S., Q.L., P.Z., Y. Liu, L.L., M.Y., C.M., X.L., Y. Li); Department of Biomedical Sciences, College of Biomedical Engineering, Hefei University of Technology, China (X.Y., Y.C., J.H., Y.D.); Department of Physiology, Tianjin Medical University, China (R.Z.); Department of Pharmacology, Tianjin University of Traditional Chinese Medicine, China (Y.Z.); Departments of Surgery and Pathology, Medical College of Wisconsin, Milwaukee, WI (Q.R.M.); and Department of Biochemistry and Molecular Biology, College of Life Sciences, The State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H., Y.D.).

Objective: The reduced adiponectin levels are associated with atherosclerosis. Adiponectin exerts its functions by activating adiponectin receptor (AdipoR). Proprotein convertase subtilisin kexin type 9 (PCSK9) degrades LDLR protein (low-density lipoprotein receptor) to increase serum LDL-cholesterol levels. PCSK9 expression can be regulated by PPARγ (peroxisome proliferator-activated receptor γ) or SREBP2 (sterol regulatory element-binding protein 2). The effects of AdipoR agonists on PCSK9 and LDLR expression, serum lipid profiles, and atherosclerosis remain unknown.

Approach And Results: At cellular levels, AdipoR agonists (ADP355 and AdipoRon) induced PCSK9 transcription/expression that solely depended on activation of PPAR-responsive element in the PCSK9 promoter. AdipoR agonists induced PPARγ expression; thus, the AdipoR agonist-activated PCSK9 expression/production was impaired in PPARγ deficient hepatocytes. Meanwhile, AdipoR agonists transcriptionally activated LDLR expression by activating SRE in the LDLR promoter. Moreover, AMP-activated protein kinase α (AMPKα) was involved in AdipoR agonist-activated PCSK9 expression. In wild-type mice, ADP355 increased PCSK9 and LDLR expression and serum PCSK9 levels, which was associated with activation of PPARγ, AMPKα and SREBP2 and reduction of LDL-cholesterol levels. In contrast, ADP355 reduced PCSK9 expression/secretion in apoE-deficient (apoE) mice, but it still activated hepatic LDLR, PPARγ, AMPKα, and SREBP2. More importantly, ADP355 inhibited lesions in en face aortas and sinus lesions in aortic root in apoE mice with amelioration of lipid profiles.

Conclusions: Our study demonstrates that AdipoR activation by agonists regulated PCSK9 expression differently in wild-type and apoE mice. However, ADP355 activated hepatic LDLR expression and ameliorated lipid metabolism in both types of mice and inhibited atherosclerosis in apoE mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.117.309630DOI Listing
July 2017

NaoXinTong Enhances Atorvastatin-induced Plaque Stability While Ameliorating Atorvastatin-induced Hepatic Inflammation.

J Cardiovasc Pharmacol 2017 Jan;69(1):55-64

*College of Life Sciences, Nankai University, Tianjin, China; †College of Biomedical Engineering, Hefei University of Technology, Hefei, China; ‡School of Medicine, Nankai University, Tianjin, China; and §Buchang Pharmaceutical Co Ltd, Xi'an, China.

Buchang NaoXinTong (NXT) is a Chinese medicine that has been used for many years for treatment of patients with coronary heart disease (CHD) in China. Statins substantially reduce hypercholesterolemia and CHD mortality and morbidity. However, there is still a lot of CHD patients who do not respond well to statin therapy. Herein, we report the effects of NXT on atorvastatin-inhibited atherosclerosis and atorvastatin-induced hepatic side effects. After 10 weeks of high-fat diet (HFD) feeding, apoE-deficient mice were randomly divided into 4 groups and received the following treatment for another 8 weeks: group 1, HFD; group 2, HFD containing NXT; group 3, HFD containing atorvastatin; and group 4, HFD containing both NXT and atorvastatin. After treatment, serum lipid profiles, atherosclerotic lesions, and hepatic lipid content and inflammation were determined. NXT moderately increased high-density lipoprotein cholesterol levels, although had little effect on atorvastatin-induced reduction of low-density lipoprotein cholesterol levels. Both NXT and atorvastatin reduced en face lesions and sinus lesions of aortic root. In addition, NXT enhanced atorvastatin-induced lesion plaque stability by increasing smooth muscle cell/collagen content and reducing macrophage accumulation and calcification in lesion areas. The co-treatment of NXT and atorvastatin further reduced hepatic triglyceride levels by downregulating acyl-CoA:diacylglycerol acyltransferase 1 while activating hormone-sensitive lipase, adipose triglyceride lipase, and comparative gene identification-58 expression. The AMPKα pathway was also further activated by the co-treatment. More importantly, the liver injuries caused by atorvastatin, such as hepatic inflammation and elevated serum aminotransferase activities, were substantially attenuated by NXT. Therefore, our study demonstrates that NXT enhances atorvastatin-induced plaque stability and ameliorates atorvastatin-induced hepatic side effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FJC.0000000000000441DOI Listing
January 2017

MEK1/2 inhibitors induce interleukin-5 expression in mouse macrophages and lymphocytes.

Biochem Biophys Res Commun 2016 05 1;473(4):939-946. Epub 2016 Apr 1.

College of Medical Engineering, Hefei University of Technology, Hefei, China; School of Medicine, Nankai University, Tianjin, China. Electronic address:

Uptake of oxidized low-density lipoprotein (oxLDL) by macrophages facilitates the formation of foam cells, the prominent part of atherosclerotic lesions. Interleukin-5 (IL-5) is a cytokine regulating interactions between immune cells. It also activates the production of T15/EO6 IgM antibodies in B-1 cells, which can bind oxLDL thereby demonstrating anti-atherogenic properties. We previously reported that inhibition of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by mitogen-activated protein kinase kinases 1/2 (MEK1/2) inhibitors can reduce atherosclerosis. In this study, we determined the effects of MEK1/2 inhibitors on IL-5 production both in vitro and in vivo. In vitro, MEK1/2 inhibitors (PD98059 and U0126) substantially inhibited phosphorylation of MEK1/2 and ERK1/2. Associated with inhibition of ERK1/2 phosphorylation both in vitro and in vivo, MEK1/2 inhibitors induced IL-5 protein expression in macrophages (RAW macrophages and peritoneal macrophages) and lymphocytes (EL-4 cells). In vivo, administration of mice with MEK1/2 inhibitors increased serum IL-5 levels, and IL-5 protein expression in mouse spleen and liver. At the mechanistic level, we determined that MEK1/2 inhibitors activated IL-5 mRNA expression and IL-5 promoter activity in the liver X receptor (LXR) dependent manner indicating the induction of IL-5 transcription. In addition, we determined that MEK1/2 inhibitors enhanced IL-5 protein stability. Taken together, our study demonstrates that MEK1/2 inhibitors induce IL-5 production which suggests another anti-atherogenic mechanism of MEK1/2 inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2016.03.156DOI Listing
May 2016

NaoXinTong Inhibits the Advanced Atherosclerosis and Enhances the Plaque Stability in Apolipoprotein E Deficient Mice.

J Cardiovasc Pharmacol 2016 Mar;67(3):203-11

*College of Life Sciences, Nankai University, Tianjin, China; †Buchang Pharmaceutical Co, Ltd, Xi'an, China; ‡College of Medical Engineering, Hefei University of Technology, Hefei, China; §Collaborative Innovation Center for Biotherapy, School of Medicine, Nankai University, Tianjin, China.

Buchang NaoXinTong (NXT), a Chinese medicine, has been widely used to treat patients with coronary heart disease in China. However, the underlying mechanisms need more elucidations. In this study, we investigated if NXT can inhibit the progression of the established lesions while stabilizing plaques. Apolipoprotein E deficient (apoE(-/-)) mice in 3 groups received following treatment: group 1 was fed a high-fat diet (HFD) for 18 weeks; group 2 was prefed HFD for 12 weeks followed by HFD containing NXT for additional 6 weeks; group 3 was prefed HFD for 8 weeks followed by HFD containing NXT for additional 10 weeks. After treatment, serum and aorta samples were collected and determined lipid profiles, lesions, collagen content, mineralization, and macrophage accumulation in aortic root, respectively. NXT had slight effect on serum lipid profiles but significantly reduced progression of the advanced lesions. In aortic wall, NXT increased smooth muscle cell/collagen content in lesion cap while reducing buried fibrous caps, mineralization, and macrophage accumulation within lesions, which suggests that NXT can stabilize plaques. In addition, NXT increased expression of smooth muscle 22α mRNA while inhibiting expression of matrix metalloproteinase-2 and tumor necrosis factor α mRNA in aortas. Our study demonstrates that NXT can reduce advanced atherosclerosis and enhance the plaque stability in apoE(-/-) mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FJC.0000000000000334DOI Listing
March 2016

[Quality of life and related factors among family members of tuberculosis patients].

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2013 Oct;38(10):1075-9

Department of Cardiothoracic Surgery, Third Xiangya Hospital, Central South University, Changsha 410013,China.

Objective: To understand the quality of life and related factors among family members of tuberculosis patients and provide a reference for the improvement of their quality of life.

Methods: A total of 222 family members of tuberculosis patients at 4 tuberculosis hospitals in Changsha and 327 healthy controls were surveyed with structured questionnaire, the short version of the WHO quality of life scale (WHOQOL-BREF).

Results: The mean score of the family members of tuberculosis patients in the psychological domain, physical domain and environmental domains was lower than that of the control group (P<0.01). Multiple linear regression showed that gender, age, monthly income, educational level, patient condition and knowledge of tuberculosis prevention and treatment were the factors affecting their quality of life.

Conclusion: The quality of life of the family members of tuberculosis patients is lower than that of the control group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3969/j.issn.1672-7347.2013.10.016DOI Listing
October 2013