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Disassembling a cancer puzzle: Cell junctions and plasma membrane as targets for anticancer therapy. J Control Release 2018; 286:125-136. [PMID: 30030181 DOI: 10.1016/j.jconrel.2018.07.030] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Revised: 07/13/2018] [Accepted: 07/16/2018] [Indexed: 02/07/2023]
Abstract
Despite an enhanced permeability and retention effect typical of many solid tumors, drug penetration is not always sufficient. Possible strategies for the drug delivery improvement are a modification of the tumor cell-to-cell junctions and usage of cell membrane permeabilization proteins. In this review we discuss epithelial cell junctions as targets for a combined anticancer therapy and propose new possible sources of such agents. We suggest considering viral and bacterial pathogens disrupting epithelial layers as plentiful sources of new therapeutic agents for increasing tumor permeability for other effector agents. We also observe the application of pore forming proteins and peptides of different origin for cytoplasmic delivery of anti-cancer agents and consider the main obstacles of their use in vivo.
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Li ZM, Xu SW, Liu PQ. Salvia miltiorrhizaBurge (Danshen): a golden herbal medicine in cardiovascular therapeutics. Acta Pharmacol Sin 2018; 39:802-824. [PMID: 29698387 PMCID: PMC5943903 DOI: 10.1038/aps.2017.193] [Citation(s) in RCA: 340] [Impact Index Per Article: 48.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 12/31/2017] [Indexed: 02/07/2023]
Abstract
Salvia miltiorrhiza Burge (Danshen) is an eminent medicinal herb that possesses broad cardiovascular and cerebrovascular protective actions and has been used in Asian countries for many centuries. Accumulating evidence suggests that Danshen and its components prevent vascular diseases, in particular, atherosclerosis and cardiac diseases, including myocardial infarction, myocardial ischemia/reperfusion injury, arrhythmia, cardiac hypertrophy and cardiac fibrosis. The published literature indicates that lipophilic constituents (tanshinone I, tanshinone IIa, tanshinone IIb, cryptotanshinone, dihydrotanshinone, etc) as well as hydrophilic constituents (danshensu, salvianolic acid A and B, protocatechuic aldehyde, etc) contribute to the cardiovascular protective actions of Danshen, suggesting a potential synergism among these constituents. Herein, we provide a systematic up-to-date review on the cardiovascular actions and therapeutic potential of major pharmacologically active constituents of Danshen. These bioactive compounds will serve as excellent drug candidates in small-molecule cardiovascular drug discovery. This article also provides a scientific rationale for understanding the traditional use of Danshen in cardiovascular therapeutics.
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Affiliation(s)
- Zhuo-ming Li
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou 510006, China
| | - Suo-wen Xu
- Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York, 14642, USA
| | - Pei-qing Liu
- Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences; National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou 510006, China
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Liu C, Huang Y. Chinese Herbal Medicine on Cardiovascular Diseases and the Mechanisms of Action. Front Pharmacol 2016; 7:469. [PMID: 27990122 PMCID: PMC5130975 DOI: 10.3389/fphar.2016.00469] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 11/18/2016] [Indexed: 12/21/2022] Open
Abstract
Cardiovascular diseases are the principal cause of death worldwide. The potentially serious adverse effects of therapeutic drugs lead to growing awareness of the role of Chinese herbal medicine in the treatment of cardiovascular diseases. Chinese herbal medicine has been widely used in many countries especially in China from antiquity; however, the mechanisms by which herbal medicine acts in the prevention and treatment of cardiovascular diseases are far from clear. In this review, we briefly describe the characteristics of Chinese herbal medicine by comparing with western medicine. Then we summarize the formulae and herbs/natural products applied in the clinic and animal studies being sorted according to the specific cardiovascular diseases. Most importantly, we elaborate the existing investigations into mechanisms by which herbal compounds act at the cellular levels, including vascular smooth muscle cells, endothelial cells, cardiomyocytes and immune cells. Future research should focus on well-designed clinic trial, in-depth mechanic study, investigations on side effects of herbs and drug interactions. Studies on developing new agents with effectiveness and safety from traditional Chinese medicine is a promising way for prevention and treatment of patients with cardiovascular diseases.
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Affiliation(s)
- Cuiqing Liu
- Department of Preventive Medicine, Basic Medical College, Zhejiang Chinese Medical University Hangzhou, China
| | - Yu Huang
- School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong Hong Kong, China
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Li D, Wang J, Hou J, Fu J, Liu J, Lin R. Salvianolic acid B induced upregulation of miR-30a protects cardiac myocytes from ischemia/reperfusion injury. Altern Ther Health Med 2016; 16:336. [PMID: 27586425 PMCID: PMC5009695 DOI: 10.1186/s12906-016-1275-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Accepted: 08/09/2016] [Indexed: 11/10/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs) are a novel class of powerful, endogenous regulators of gene expression. This study was designed to ascertain if miR-30a is involved in the cardioprotective actions of salvianolic acid B (Sal B) against myocardial ischemia-reperfusion (I-R) injury through suppression of autophagy. METHODS Murine myocardial cells that had undergone primary culture were induced by I-R and incubated with Sal B (25, 50, 100 μM) in the presence of a miR-30a mimic or miR-30a inhibitor. Expression of miR-30a, beclin-1, LC3-II and p-Akt protein, cell viability, and lactic acid dehydrogenase (LDH) release were assessed. RESULTS miR-30a expression was down-regulated remarkably in I-R cells, and this suppression could be reversed by Sal B in a dose-dependent manner. Sal B repressed autophagy in I-R myocardial cells. Sal B improved cell viability and reduced the rate of LDH leakage, which suggested that autophagy suppression was beneficial for cell survival. Knockdown of miR-30a with a miR-30a inhibitor could reverse the anti-autophagy effect of Sal B against I-R injury. Furthermore, we confirmed that Sal B has a protective role in miR-30a-mediated autophagy through the PI3K/Akt signaling pathway, which was abrogated by the PI3K inhibitor LY294002. CONCLUSIONS These data suggest that miR-30a is involved in Sal B-mediated cardioprotection against I-R injury through the PI3K/Akt signaling pathway.
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Dong Z, Ma D, Gong Y, Yu T, Yao G. Salvianolic acid B ameliorates CNS autoimmunity by suppressing Th1 responses. Neurosci Lett 2016; 619:92-9. [DOI: 10.1016/j.neulet.2016.01.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 11/02/2015] [Accepted: 01/05/2016] [Indexed: 10/22/2022]
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Son B, Jun SY, Seo H, Youn H, Yang HJ, Kim W, Kim HK, Kang C, Youn B. Inhibitory effect of traditional oriental medicine-derived monoamine oxidase B inhibitor on radioresistance of non-small cell lung cancer. Sci Rep 2016; 6:21986. [PMID: 26906215 PMCID: PMC4764943 DOI: 10.1038/srep21986] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 02/03/2016] [Indexed: 02/07/2023] Open
Abstract
Increased survival of cancer cells mediated by high levels of ionizing radiation (IR) reduces the effectiveness of radiation therapy for non-small cell lung cancer (NSCLC). In the present study, danshensu which is a selected component of traditional oriental medicine (TOM) compound was found to reduce the radioresistance of NSCLC by inhibiting the nuclear factor-κB (NF-κB) pathway. Of the various TOM compounds reported to inhibit the IR activation of NF-κB, danshensu was chosen as a final candidate based on the results of structural comparisons with human metabolites and monoamine oxidase B (MAOB) was identified as the putative target enzyme. Danshensu decreased the activation of NF-κB by inhibiting MAOB activity in A549 and NCI-H1299 NSCLC cells. Moreover, it suppressed IR-induced epithelial-to-mesenchymal transition, expressions of NF-κB-regulated prosurvival and proinflammatory genes, and in vivo radioresistance of mouse xenograft models. Taken together, this study shows that danshensu significantly reduces MAOB activity and attenuates NF-κB signaling to elicit the radiosensitization of NSCLC.
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Affiliation(s)
- Beomseok Son
- Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea
| | - Se Young Jun
- Department of Chemistry, Washington State University, Pullman, Washington, USA
| | - HyunJeong Seo
- Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea
| | - HyeSook Youn
- Nuclear Science Research Institute, Pusan National University, Busan, Republic of Korea
| | - Hee Jung Yang
- Department of Biological Sciences, Pusan National University, Busan, Republic of Korea
| | - Wanyeon Kim
- Nuclear Science Research Institute, Pusan National University, Busan, Republic of Korea.,Department of Biological Sciences, Pusan National University, Busan, Republic of Korea
| | - Hyung Kook Kim
- Department of Nanomaterial Engineering and Nanoconvergence Technology, Pusan National University, Miryang, Republic of Korea
| | - ChulHee Kang
- Department of Chemistry, Washington State University, Pullman, Washington, USA
| | - BuHyun Youn
- Department of Integrated Biological Science, Pusan National University, Busan, Republic of Korea.,Department of Chemistry, Washington State University, Pullman, Washington, USA.,Nuclear Science Research Institute, Pusan National University, Busan, Republic of Korea.,Department of Biological Sciences, Pusan National University, Busan, Republic of Korea
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3, 4-dihydroxyl-phenyl lactic acid restores NADH dehydrogenase 1 α subunit 10 to ameliorate cardiac reperfusion injury. Sci Rep 2015; 5:10739. [PMID: 26030156 PMCID: PMC5377067 DOI: 10.1038/srep10739] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 04/27/2015] [Indexed: 01/16/2023] Open
Abstract
The present study aimed to detect the role of 3, 4-dihydroxyl-phenyl lactic acid (DLA) during ischemia/reperfusion (I/R) induced myocardial injury with emphasis on the underlying mechanism of DLA antioxidant. Male Spragu-Dawley (SD) rats were subjected to left descending artery occlusion followed by reperfusion. Treatment with DLA ameliorated myocardial structure and function disorder, blunted the impairment of Complex I activity and mitochondrial function after I/R. The results of 2-D fluorescence difference gel electrophoresis revealed that DLA prevented the decrease in NDUFA10 expression, one of the subunits of Complex I. To find the target of DLA, the binding affinity of Sirtuin 1 (SIRT1) to DLA and DLA derivatives with replaced two phenolic hydroxyls was detected using surface plasmon resonance and bilayer interferometry. The results showed that DLA could activate SIRT1 after I/R probably by binding to this protein, depending on phenolic hydroxyl. Moreover, the importance of SIRT1 to DLA effectiveness was confirmed through siRNA transfection in vitro. These results demonstrated that DLA was able to prevent I/R induced decrease in NDUFA10 expression, improve Complex I activity and mitochondrial function, eventually attenuate cardiac structure and function injury after I/R, which was possibly related to its ability of binding to and activating SIRT1.
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Pan CS, Liu YH, Liu YY, Zhang Y, He K, Yang XY, Hu BH, Chang X, Wang MX, Wei XH, Fan JY, Wu XM, Han JY. Salvianolic Acid B Ameliorates Lipopolysaccharide-Induced Albumin Leakage from Rat Mesenteric Venules through Src-Regulated Transcelluar Pathway and Paracellular Pathway. PLoS One 2015; 10:e0126640. [PMID: 25992563 PMCID: PMC4438061 DOI: 10.1371/journal.pone.0126640] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Accepted: 04/05/2015] [Indexed: 12/15/2022] Open
Abstract
Lipopolysaccharide (LPS) causes microvascular barrier disruption, leading to albumin leakage from microvessels resulting in a range of disastrous sequels. Salvianolic acid B (SalB) is a major water-soluble component derived from Salvia miltiorrhiza. Previous studies showed its potential to attenuate microvascular barrier dysfunction, but the underlying mechanism is not fully understood. The present study was intended to investigate the impact of SalB on endothelial cell barrier in vivo in rat mesenteric venules as well as in vitro in human umbilical vein endothelial cells (HUVECs), aiming at disclosing the mechanism thereof, particularly the role of Src in its action. Male Wistar rats were challenged by infusion of LPS (2 mg/kg/h) through left femoral vein for 90 min. SalB (5 mg/kg/h) was administrated either simultaneously with LPS or 30 min after LPS infusion through the left jugular vein. Vesicles in venular walls were observed by electron microscopy. HUVECs were incubated with LPS with or without SalB. The expression of Zonula occluden-1 (ZO-1), VE-cadherin, caveolin-1 and Src in HUVECs was assessed by Western blot and confocal microscopy, binding of SalB to Src was measured using Surface Plasmon Resonance and BioLayer Interferometry. Treatment with SalB inhibited albumin leakage from rat mesenteric venules and inhibited the increase of vesicle number in venular endothelial cells induced by LPS. In addition, SalB inhibited the degradation of ZO-1, the phosphorylation and redistribution of VE-cadherin, the expression and phosphorylation of caveolin-1, and phosphoirylation of Src in HUVECs exposed to LPS. Furthermore, SalB was found able to bind to Src. This study demonstrates that protection of SalB against microvascular barrier disruption is a process involving both para- and trans-endothelial cell pathway, and highly suggests Src as the key enzyme for SalB to work.
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Affiliation(s)
- Chun-Shui Pan
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
- Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
- Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
| | - Ying-Hua Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital& Institute, Beijing, China
| | - Yu-Ying Liu
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
- Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
- Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
| | - Yu Zhang
- Department of Integration of Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
- Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
| | - Ke He
- Department of Integration of Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
- Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
| | - Xiao-Yuan Yang
- Department of Integration of Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
- Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
| | - Bai-He Hu
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
- Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
- Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
| | - Xin Chang
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
- Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
- Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
| | - Ming-Xia Wang
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
- Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
- Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
| | - Xiao-Hong Wei
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
| | - Jing-Yu Fan
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
| | - Xin-Min Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital& Institute, Beijing, China
| | - Jing-Yan Han
- Tasly Microcirculation Research Center, Peking University Health Science Center, Beijing, China
- Department of Integration of Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Microcirculation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
- Key Laboratory of Stasis and Phlegm, State Administration of Traditional Chinese Medicine of the People's Republic of China, Beijing, China
- * E-mail:
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Ou JM, Zhang XP, Wu CJ, Wu DJ, Yan P. Effects of dexamethasone and Salvia miltiorrhiza on multiple organs in rats with severe acute pancreatitis. J Zhejiang Univ Sci B 2013; 13:919-31. [PMID: 23125085 DOI: 10.1631/jzus.b1100351] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVE To investigate the protective effects and mechanisms of action of dexamethasone and Salvia miltiorrhiza on multiple organs in rats with severe acute pancreatitis (SAP). METHODS The rats were divided into sham-operated, model control, dexamethasone treated, and Salvia miltiorrhiza treated groups. At 3, 6, and 12 h after operation, the mortality rate of different groups, pathological changes, Bcl-2-associated X protein (Bax) and nuclear factor-κB (NF-κB) protein expression levels in multiple organs (the pancreas, liver, kidneys, and lungs), toll-like receptor 4 (TLR-4) protein levels (only in the liver), intercellular adhesion molecule 1 (ICAM-1) protein levels (only in the lung), and terminal deoxynucleotidy transferase mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) staining expression levels, as well as the serum contents of amylase, glutamate-pyruvate transaminase (GPT), glutamic-oxaloacetic transaminase (GOT), blood urea nitrogen (BUN), and creatinine (CREA) were observed. RESULTS The mortality rate of the dexamethasone treated group was significantly lower than that of the model control group (P<0.05). The pathological changes in multiple organs in the two treated groups were relieved to different degrees (P<0.05 and P<0.01, respectively), the expression levels of Bax and NF-κB proteins, and apoptotic indexes of multiple organs were reduced (P<0.05 and P<0.01, respectively). The contents of amylase, GPT, GOT, BUN, and CREA in the two treated groups were significantly lower than those in model control groups (P<0.05 and P<0.01, respectively). The expression level of ICAM-1 protein in the lungs (at 3 and 12 h) in the dexamethasone treated group was significantly lower than that in the Salvia miltiorrhiza treated group (P<0.05). The serum contents of CREA (at 12 h) and BUN (at 6 h) of the Salvia miltiorrhiza treated group were significantly lower than those in the dexamethasone treated group (P<0.05). CONCLUSIONS Both dexamethasone and Salvia miltiorrhiza can reduce the inflammatory reaction, regulate apoptosis, and thus protect multiple organs of rats with SAP.
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Affiliation(s)
- Jing-min Ou
- Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China
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Salvianolic Acid B Protects From Pulmonary Microcirculation Disturbance Induced by Lipopolysaccharide in Rat. Shock 2013; 39:317-25. [DOI: 10.1097/shk.0b013e318283773e] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Yang DH, Ye ZY, Xie YJ, He XJ, Xu WJ, Zhou WM. Effect of salvianolate on intestinal epithelium tight junction protein zonula occludens protein 1 in cirrhotic rats. World J Gastroenterol 2012; 18:7040-7. [PMID: 23323006 PMCID: PMC3531692 DOI: 10.3748/wjg.v18.i47.7040] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 09/18/2012] [Accepted: 09/22/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the effect of salvianolate on tight junctions (TJs) and zonula occludens protein 1 (ZO-1) in small intestinal mucosa of cirrhotic rats.
METHODS: Cirrhosis was induced using carbon tetrachloride. Rats were randomly divided into the untreated group, low-dose salvianolate (12 mg/kg) treatment group, medium-dose salvianolate (24 mg/kg) treatment group, and high-dose salvianolate (48 mg/kg) treatment group, and were treated for 2 wk. Another 10 healthy rats served as the normal control group. Histological changes in liver tissue samples were observed under a light microscope. We evaluated morphologic indices of ileal mucosa including intestinal villi width and thickness of mucosa and intestinal wall using a pathological image analysis system. Ultrastructural changes in small intestinal mucosa were investigated in the five groups using transmission electron microscopy. The changes in ZO-1 expression, a tight junction protein, were analyzed by immunocytochemistry. The staining index was calculated as the product of the staining intensity score and the proportion of positive cells.
RESULTS: In the untreated group, hepatocytes showed a disordered arrangement, fatty degeneration was extensive, swelling was obvious, and disorganized lobules were divided by collagen fibers in hepatic tissue, which were partly improved in the salvianolate treated groups. In the untreated group, abundant lymphocytes infiltrated the fibrous tissue with proliferation of bile ducts, and collagen fibers gradually decreased and damaged hepatic lobules were partly repaired following salvianolate treatment. Compared with the untreated group, no differences in intestinal villi width between the five groups were observed. The villi height as well as mucosa and intestinal wall thickness gradually thickened with salvianolate treatment and were significantly shorter in the untreated group compared with those in the salvianolate treatment groups and normal group (P < 0.01). The number of microvilli decreased and showed irregular lengths and arrangements in the untreated group. The intercellular space between epithelial cells was wider. The TJs were discontinuous, which indicated disruption in TJ morphology in the untreated group. In the treated groups, the microvilli in the intestinal epithelium were regular and the TJs were gradually integrated and distinct. The expression of ZO-1 decreased in the small intestine of the untreated cirrhotic rats. The high expression rate of ZO-1 in ileal mucosa in the untreated group was significantly lower than that in the medium-dose salvianolate group (21.43% vs 64.29%, χ2 = 5.25, P < 0.05), high-dose salvianolate group (21.43% vs 76.92%, χ2 = 8.315, P < 0.01) and normal group (21.43% vs 90%, χ2 = 10.98, P < 0.01).
CONCLUSION: Salvianolate improves liver histopathological changes, repairs intestinal mucosa and TJ structure, and enhances ZO-1 expression in the small intestinal mucosa in cirrhotic rats.
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Wu WY, Wang YP. Pharmacological actions and therapeutic applications of Salvia miltiorrhiza depside salt and its active components. Acta Pharmacol Sin 2012; 33:1119-30. [PMID: 22941285 DOI: 10.1038/aps.2012.126] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Salvia miltiorrhiza, a traditional medical herb known as danshen, has been widely used in China to improve blood circulation, relieve blood stasis, and treat coronary heart disease. S miltiorrhiza depside salt is a novel drug recently developed at the Shanghai Institute of Materia Medica; it contains magnesium lithospermate B (MLB) and its analogs, rosmarinic acid (RA) and lithospermic acid (LA), as active components. The drug has been used in the clinic to improve blood circulation and treat coronary heart disease. The pharmacological effects of the depside salt from S miltiorrhiza and its components have been extensively investigated. Experimental studies have demonstrated that magnesium lithospermate B possesses a variety of biological activities, especially protective effects in the cardiovascular system such as attenuation of atherosclerosis and protection against myocardial ischemia-reperfusion injury. Rosmarinic acid and lithospermic acid also show beneficial effects on the cardiovascular system. This paper reviews the recent findings regarding the mechanisms underlying the pharmacological actions of the active components of S miltiorrhiza depside salt, based on published works and our own observations.
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Cardoso FL, Kittel Á, Veszelka S, Palmela I, Tóth A, Brites D, Deli MA, Brito MA. Exposure to lipopolysaccharide and/or unconjugated bilirubin impair the integrity and function of brain microvascular endothelial cells. PLoS One 2012; 7:e35919. [PMID: 22586454 PMCID: PMC3346740 DOI: 10.1371/journal.pone.0035919] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2011] [Accepted: 03/27/2012] [Indexed: 11/21/2022] Open
Abstract
Background Sepsis and jaundice are common conditions in newborns that can lead to brain damage. Though lipopolysaccharide (LPS) is known to alter the integrity of the blood-brain barrier (BBB), little is known on the effects of unconjugated bilirubin (UCB) and even less on the joint effects of UCB and LPS on brain microvascular endothelial cells (BMEC). Methodology/Principal Findings Monolayers of primary rat BMEC were treated with 1 µg/ml LPS and/or 50 µM UCB, in the presence of 100 µM human serum albumin, for 4 or 24 h. Co-cultures of BMEC with astroglial cells, a more complex BBB model, were used in selected experiments. LPS led to apoptosis and UCB induced both apoptotic and necrotic-like cell death. LPS and UCB led to inhibition of P-glycoprotein and activation of matrix metalloproteinases-2 and -9 in mono-cultures. Transmission electron microscopy evidenced apoptotic bodies, as well as damaged mitochondria and rough endoplasmic reticulum in BMEC by either insult. Shorter cell contacts and increased caveolae-like invaginations were noticeable in LPS-treated cells and loss of intercellular junctions was observed upon treatment with UCB. Both compounds triggered impairment of endothelial permeability and transendothelial electrical resistance both in mono- and co-cultures. The functional changes were confirmed by alterations in immunostaining for junctional proteins β-catenin, ZO-1 and claudin-5. Enlargement of intercellular spaces, and redistribution of junctional proteins were found in BMEC after exposure to LPS and UCB. Conclusions LPS and/or UCB exert direct toxic effects on BMEC, with distinct temporal profiles and mechanisms of action. Therefore, the impairment of brain endothelial integrity upon exposure to these neurotoxins may favor their access to the brain, thus increasing the risk of injury and requiring adequate clinical management of sepsis and jaundice in the neonatal period.
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Affiliation(s)
- Filipa L. Cardoso
- Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
| | - Ágnes Kittel
- Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
| | - Szilvia Veszelka
- Laboratory of Molecular Neurobiology, Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary
| | - Inês Palmela
- Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
| | - Andrea Tóth
- Laboratory of Molecular Neurobiology, Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary
| | - Dora Brites
- Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
- Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
| | - Mária A. Deli
- Laboratory of Molecular Neurobiology, Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary
| | - Maria A. Brito
- Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
- Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal
- * E-mail:
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Xie X, Wang S, Xiao L, Zhang J, Wang J, Liu J, Shen X, He D, Zheng X, Zhai Y. DBZ blocks LPS-induced monocyte activation and foam cell formation via inhibiting nuclear factor-ĸB. Cell Physiol Biochem 2011; 28:649-62. [PMID: 22178877 DOI: 10.1159/000335760] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2011] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS It has been widely accepted that chronic inflammation plays important roles in the atherogenesis. Danshensu Bingpian Zhi (DBZ) is a novel synthetic compound derived from the traditional Chinese medicine (TCM) formula Fu Fang Dan Shen (FFDS), which is effective on atherosclerosis clinically. We hypothesized that DBZ possessed the anti-atherosclerosis potentials. Here, we examined the inhibitory effects of DBZ on LPS-induced monocyte activation and foam cell formation. METHODS The effects of DBZ were assessed on LPS-induced inflammatory factors expression in monocyte/macrophage. Activation of NF-κB and AP-1 was analyzed by luciferase reporter assay and signaling pathway of NF-κB was investigated to elucidate mechanisms underlying DBZ mediated anti-inflammatory activity. Effects of DBZ on macrophage lipid accumulation were evaluated in native LDL and LPS co-incubated macrophages. RESULTS DBZ inhibited LPS-induced inflammatory factors expression dose dependently in monocytes. DBZ inhibited NF-κB activation strongly and AP-1 slightly. DBZ suppressed the LPS-induced degradation of IκBα, thereby decreasing the translocation of p65 to nucleus. Furthermore, DBZ suppressed LPS-activated macrophages lipid accumulation, partly due to inhibiting the expression of LPS-induced aP2 and ADRP in macrophges. CONCLUSION These results demonstrate that DBZ has potentials on anti-atherosclerosis by suppressing monocyte activation and foam cell formation.
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Affiliation(s)
- Xinni Xie
- Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry and College of Life Sciences, Beijing Normal University, Beijing, P.R. China
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Ho JHC, Hong CY. Salvianolic acids: small compounds with multiple mechanisms for cardiovascular protection. J Biomed Sci 2011; 18:30. [PMID: 21569331 PMCID: PMC3113734 DOI: 10.1186/1423-0127-18-30] [Citation(s) in RCA: 194] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2011] [Accepted: 05/11/2011] [Indexed: 12/14/2022] Open
Abstract
Salvianolic acids are the most abundant water-soluble compounds extracted from Radix Salvia miltiorrhiza (Danshen). In China, Danshen has been wildly used to treat cardiovascular diseases for hundreds of years. Salvianolic acids, especially salvianolic acid A (Sal A) and salvianolic acid B (Sal B), have been found to have potent anti-oxidative capabilities due to their polyphenolic structure. Recently, intracellular signaling pathways regulated by salvianolic acids in vascular endothelial cells, aortic smooth muscle cells, as well as cardiomyocytes, have been investigated both in vitro and in vivo upon various cardiovascular insults. It is discovered that the cardiovascular protection of salvianolic acids is not only because salvianolic acids act as reactive oxygen species scavengers, but also due to the reduction of leukocyte-endothelial adherence, inhibition of inflammation and metalloproteinases expression from aortic smooth muscle cells, and indirect regulation of immune function. Competitive binding of salvianolic acids to target proteins to interrupt protein-protein interactions has also been found to be a mechanism of cardiovascular protection by salvianolic acids. In this article, we review a variety of studies focusing on the above mentioned mechanisms. Besides, the target proteins of salvianolic acids are also described. These results of recent advances have shed new light to the development of novel therapeutic strategies for salvianolic acids to treat cardiovascular diseases.
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Affiliation(s)
- Jennifer Hui-Chun Ho
- Graduate Institute of Clinical Medicine, Taipei Medical University, and Department of Ophthalmology, Wang Fang Hospital, Taipei, Taiwan
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Yang J, Yang S, Gao X, Yuan YJ. Integrative investigation of lipidome and signal pathways in human endothelial cells under oxidative stress. MOLECULAR BIOSYSTEMS 2011; 7:2428-40. [DOI: 10.1039/c1mb00002k] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Shen Y, Hu Y, Zhang Y. Favorable maternal and fetal effects of danshensu in an experimental mice model of preeclampsia. Hypertens Pregnancy 2010; 30:465-80. [PMID: 20964615 DOI: 10.3109/10641955.2010.507842] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Preeclampsia is a serious pregnancy-specific complication that results in high maternal and neonatal mortality and morbidity worldwide. Till date, there is no satisfactory pharmacotherapeutic treatment, except for aspirin and heparin, to stop the preeclampsia progression. Although the mechanism of preeclampsia is poorly understood, it has proved to be associated with coagulation activation. Researches on prophylactic and remedial application of anticoagulants maybe benefit the clinical aspects of preeclampsia individuals. METHODS Sixty-six preeclampsia-like pregnant mice, induced by phosphatidyleserine/phosphatidylcholine (PS/PC) microvesicle administration, were randomly divided into six groups as follows: control group (group C), preeclampsia model group (group PE), group treated with heparin (group H), group treated with aspirin (group A), group treated with low-dose danshensu (group LD), and group treated with high-dose danshensu (group HD). Systolic blood pressure (SBP), proteinuria, mean platelet counts, plasma antithrombin III activity (AT III), D-dimmer levels, thrombin time (TT), fibrin deposition with phosphotungstic acid hematoxylin (PTAH) staining, and thrombomodulin (TM) expression with immunohistochemistry staining in placentas were examined as indices for maternal syndrome. Meanwhile, the number of potentially viable fetuses, weight of fetuses and placentas, weight of fetal brains, nose-breech length, ponderal index (PI), and neurons with hematoxylin-eosin (H/E) and toluidine blue-eosin (Nissl's) staining were all evaluated as indices for fetal syndrome. RESULTS Heparin presents significant effects on maternal syndrome of preeclampsia such as hypertension and proteinuria, and different dose danshensu also presents the certain effects. High-dose danshensu and aspirin all process better effects than low-dose danshensu on decreasing blood pressure to normal level, whereas high-dose danshensu process better effects than aspirin and low-dose danshensu on decreasing proteinuria to normal level. As to danshensu's effects on hemostatic function, high- and low-dose danshensu's marked effects on increasing the plasma AT III activity are same as that of aspirin and inferior to heparin. High-dose danshensu's better effect on elevating the platelet counts is superior to low-dose danshensu and aspirin. Low-dose danshensu's obvious effect on decreasing D-dimmer levels is close to heparin and superior to high-dose danshensu and aspirin. High- and low-dose danshensu's significant effects on reduced TT level are same to that of heparin. Different anticoagulants all have the improvement roles on placental fibrin depositions, but heparin and high-dose danshensu's roles on lowering thrombomodulin expression in placentas are superior to low-dose danshensu and aspirin. But anticoagulant function of high-dose danshensu is still inferior to heparin. Furthermore, we found the following changes: increasing fetal body weight and length in every group, obvious overall improvement in group H, greater amelioration equaling to that in heparin group on maternal body weight, fetal nose-breech length and fetal brain weight in group HD, better changes on survival fetal number in group LD than in other groups, and more corrected brain development in group HD than in group A. We found long-term use of heparin and aspirin, in spite of low-dose administration, can raise the risk of bleeding such as placental abruption and intestinal hemorrhage. But no side effect was observed in mice treated with different dose of danshensu in our study. CONCLUSIONS Danshensu has proven effective in ameliorating the prognosis of maternal syndrome and fetal syndrome in the PE mouse model. We suggest long-term provision of low-dose danshensu in pregnancy, leading to an improvement of preeclampsia syndrome with considerable maternal safety.
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Affiliation(s)
- Yang Shen
- Obstetrics and Gynecology Department, Southeast University Affiliated Zhongda Hospital, Nanjing, China
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Wang SX, Hu LM, Gao XM, Guo H, Fan GW. Anti-inflammatory activity of salvianolic acid B in microglia contributes to its neuroprotective effect. Neurochem Res 2010; 35:1029-37. [PMID: 20238162 DOI: 10.1007/s11064-010-0151-1] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2009] [Accepted: 03/06/2010] [Indexed: 01/04/2023]
Abstract
This study examined whether Salvianolic acid B (Sal B), a major active component of Chinese herb Radix Salviae Miltiorrhizae, may exert an anti-inflammatory effect in microglia and may be neuroprotective by regulating microglial activation. Our results showed that Sal B significantly reduced the production of nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and reactive oxygen species (ROS) induced by lipopolysaccharide (LPS) treatment in rat primary microglia in a dose-dependent manner. Sal B had no effects on ATP-dependent IL-1beta release and interferon (IFN)-gamma-induced NO production. Sal B also suppressed LPS-induced inducible nitric oxide synthase (iNOS), TNF-alpha, and IL-1beta mRNA expression, which was accompanied by inhibiting transcription factor NF-kappaB activation. Sal B could protect neurons through inhibition of microglial activation in a microglia-neuron coculture system. In conclusion, these data demonstrate that anti-inflammatory activity of Sal B in microglia contributes to its neuroprotective effect and suggest that it may be useful for preventing microglia-mediated neuroinflammation.
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Affiliation(s)
- Shao-Xia Wang
- Tianjin Key Laboratory of Traditional Chinese Medicine Pharmacology, Tianjin University of Traditional Chinese Medicine, 312 Anshanxi Road, 300193, Nankai District, Tianjin, China
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Wang G, Sun B, Zhu H, Gao Y, Li X, Xue D, Jiang H. Protective effects of emodin combined with danshensu on experimental severe acute pancreatitis. Inflamm Res 2009; 59:479-88. [PMID: 20043232 DOI: 10.1007/s00011-009-0152-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2009] [Revised: 11/10/2009] [Accepted: 12/06/2009] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE AND DESIGN In the present experiment, we aimed to determine the feasibility and curative effects of emodin combined with danshensu on experimental severe acute pancreatitis (SAP) and the mutual benefit of this synergistic strategy by a prospective animal study. MATERIAL Eighty Wistar rats were randomly divided into four groups (n = 20). TREATMENT SAP was elicited by a retrograde infusion of 5.0% sodium taurocholate into the pancreatic main duct. SAP rats in each group received no further intervention, emodin alone, danshensu (DSS) alone, and emodin combined with DSS (EDSS), respectively. METHODS 48 h after SAP induction, all surviving animals were sacrificed to collect blood and tissue samples for the following measurements: serum levels of amylase, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), endotoxin and D-lactate. Pancreatic levels of TNF-alpha, IL-1beta, maleic dialdehyde (MDA), myeloperoxidase (MPO) activity, nuclear factor-kappaappaB (NF-kappaB) activation as well as wet-dry weight ratio were also evaluated. Ascitic fluid was quantified and the severity of pancreatic damage was analyzed by pathological grading and scoring. RESULTS Compared with the SAP group, the emodin, DSS and EDSS groups had significant differences in every index. Furthermore, EDSS obviously improved all the parameters mentioned above so as to counteract inflammatory response and oxidative stress, as well as most effectively abating pancreatic and intestinal barrier injury. CONCLUSIONS EDSS exerted protective effects on SAP rats and remarkably alleviated the severity of experimental SAP. Mechanisms that might account for the beneficial effects include protecting the intestinal barrier, inhibiting over-inflammatory reaction and abating oxidative stress. The combined strategy proved to be more effective than either emodin or DSS alone and may cause synergistic effects in combination in the early stage of SAP. Broad potential for future clinical practice is foreseeable.
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Affiliation(s)
- Gang Wang
- Department of Hepatobiliary Pancreatic Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng St, Nangang Dist 150001, Harbin, Heilongjiang, People's Republic of China.
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Zhang X, Liu D, Wu D, Zhu C, Ye J, Wang K, Peng L, Zhuo G. Effect of salvia miltiorrhizae on the expressions of TLR4 protein in the liver of rats with SAP or OJ. Inflammation 2009; 32:151-62. [PMID: 19370406 DOI: 10.1007/s10753-009-9114-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
To investigate the effect of salvia miltiorrhizae on the expressions of TLR4 protein in the liver of rats with severe acute pancreatitis (SAP) and obstructive jaundice (OJ), and explore the protective mechanism of salvia miltiorrhizae on the liver of rats. A total of 288 mice was used in SAP- (n = 108) and OJ-associated experiments (n = 180). The rats were randomly divided into sham-operated, model control and treated group. Based on the different time points after operation, these groups were subdivided into 3, 6 and 12 h subgroups (SAP rats, n = 12) or 7, 14, 21 and 28 days subgroups (OJ rats, n = 15). At the corresponding time points after operation, blood and liver specimens were collected to determine the contents of endotoxin and TNF-alpha in the blood as well as the expression levels of TLR4 protein in the liver. Compared with the corresponding model control group, though the number of dead SAP or OJ rats in the treated group declined, no statistical difference was noted; The levels of plasma endotoxin in SAP (at 6 and 12 h) or OJ rats in the treated group decreased significantly (P < 0.001 and P < 0.01, respectively); The levels of serum TNF-alpha in SAP (at 12 h) or OJ rats (on 14 days) declined (P < 0.001 and P < 0.01, respectively); The staining intensity as well as the product of staining intensity and positive rate of TRL4 protein only significantly declined on 7 and 28 days in OJ rats (P < 0.01). On 7 days, treated group in positive rate of TLR4 protein were significantly lower than that in model control group (P < 0.01). The pathological changes in different treated groups of SAP and OJ rats were improved. Salvia miltiorrhizae is able to reduce the levels of plasma endotoxin and inhibit effectively the expressions of TLR4 protein in the liver of SAP or OJ rats, thereby decreasing inflammatory reaction and exerting protective effect on liver function.
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Affiliation(s)
- Xiping Zhang
- Department of General Surgery, Hangzhou First People's Hospital, Hangzhou, Zhejiang Province, China.
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Effects of Salvia miltiorrhiza on intercellular adhesion molecule 1 protein expression in the lungs of rats with severe acute pancreatitis or obstructive jaundice. Pancreas 2009; 38:309-17. [PMID: 19034056 DOI: 10.1097/mpa.0b013e31818f6bea] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The objective of the study was to observe the effects of Salvia miltiorrhiza on intercellular adhesion molecule 1 (ICAM-1) protein expression in the lungs of rats with severe acute pancreatitis (SAP) or obstructive jaundice (OJ). METHODS A total of 288 rats were used for SAP- and OJ-associated experiments. The rats were randomly divided into sham-operated, model control, and treated group. According to the difference of time points after operation, the SAP rats of each group were subdivided into 3-, 6-, and 12-hour groups, whereas the OJ rats were divided into 7-, 14-, 21-, and 28-day groups. The contents of interleukin (IL) 6, IL-18, nitric oxide, malondialdehyde, and superoxide dismutase in serum were determined, and pathological changes and ICAM-1 protein expression in the lungs were observed. RESULTS Compared with the respective model control groups, in treated groups of SAP and OJ rats, the numbers of dead rats declined; serum superoxide dismutase content significantly increased, and serum IL-18, IL-6, and malondialdehyde contents were significantly decreased; the positive staining intensity of ICAM-1 protein in the lungs decreased significantly (P < 0.05, P < 0.01, or P < 0.001); and pathological changes in the lungs were relieved. CONCLUSIONS Salvia miltiorrhiza plays a positive role in the protection of the lungs of SAP and OJ rats.
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Ling S, Luo R, Dai A, Guo Z, Guo R, Komesaroff PA. A pharmaceutical preparation of Salvia miltiorrhiza protects cardiac myocytes from tumor necrosis factor-induced apoptosis and reduces angiotensin II-stimulated collagen synthesis in fibroblasts. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2009; 16:56-64. [PMID: 19010649 DOI: 10.1016/j.phymed.2008.09.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2008] [Revised: 08/06/2008] [Accepted: 09/08/2008] [Indexed: 05/27/2023]
Abstract
Salvia miltiorrhiza is a medicinal herb commonly used in traditional Chinese medicine for the prevention and treatment of cardiovascular disease. This study investigated the effects of Cardiotonic Pill (CP), a pharmaceutical preparation of Salvia miltiorrhiza, on cardiac myocytes and fibroblasts with respect to the viability, proliferation, and collagen synthesis in these cells under various conditions. A cardiac myocyte line, H9c2, and primarily cultured fibroblasts from rat hearts were incubated with CP over a broad concentration range (50-800 microg/ml) under normal cultures, conditions of ischemia (serum-free culture), and stimulation by angiotensin II (AII, 100 nM), hydrogen peroxide (H(2)O(2), 50-200 microM), or tumor necrosis factor alpha (TNFalpha, 40 ng/ml) for 24-48 h. Cell growth, apoptosis, DNA and collagen synthesis, and expression of relevant genes were assessed via cell number study, morphological examination, Annexin-V staining, flow-cytometry, [(3)H]-thymidine or [(3)H]-proline incorporation assay, and Western blotting analysis. It was found that (1) at therapeutic (50 microg/ml) and double therapeutic (100 microg/ml) concentrations, CP did not significantly affect normal DNA synthesis and cell growth in these cardiac cells, while at higher (over 4-fold therapeutic) concentrations (200-800 microg/ml), CP decreased DNA synthesis and cell growth and increased cell death; (2) CP treatment (50 microg/ml) significantly inhibited TNFalpha-induced apoptosis in myocytes, with 12.3+/-1.46% cells being apoptosis in CP treatment group and 37.0+/-7.34% in the control (p<0.01), and simultaneously, expression of activated (phosphorylated) Akt protein was increased by about 2 folds in the CP-treated cells; and (3) in cultured fibroblasts, CP significantly reduced AII-induced collagen synthesis in a concentration-dependent manner (by approximately 50% and approximately 90% reduction of AII-induced collagen synthesis at 50 and 100 microg/ml, respectively). Thus, Salvia miltiorrhiza preparation CP is physiologically active on cardiac cells. The actions by CP to reduce apoptotic damage in myocytes and collagen synthesis in fibroblasts may help to preserve the heart function and reduce heart failure risk. The actions by CP to inhibit DNA synthesis and cell growth, which occurred at over therapeutic doses, may weaken the ability of heart repair. Further studies are needed to identify the chemical compounds in this herbal product that are responsible for these observed physiological effects.
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Affiliation(s)
- Shanhong Ling
- Department of Medicine, Monash University Central and Eastern Clinical School, Alfred Hospital, Melbourne, Victoria, Australia.
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