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1.
Cell Death Dis ; 14(8): 527, 2023 08 16.
Article in English | MEDLINE | ID: mdl-37587140

ABSTRACT

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with high morbidity and mortality worldwide. Although the dysregulation of BARX1 expression has been shown to be associated with malignant cancers, including NSCLC, the underlying mechanism remains elusive. In this study, we identified BARX1 as a common differentially expressed gene in lung squamous cell carcinoma and adenocarcinoma. Importantly, we uncovered a novel mechanism behind the regulation of BARX1, in which ZFP36 interacted with 3'UTR of BARX1 mRNA to mediate its destabilization. Loss of ZFP36 led to the upregulation of BARX1, which further promoted the proliferation, migration and invasion of NSCLC cells. In addition, the knockdown of BARX1 inhibited tumorigenicity in mouse xenograft. We demonstrated that BARX1 promoted the malignant phenotypes by transactivating a set of master oncogenes involved in the cell cycle, DNA synthesis and metastasis. Overall, our study provides insights into the mechanism of BARX1 actions in NSCLC and aids a better understanding of NSCLC pathogenesis.


Subject(s)
Adenocarcinoma , Carcinoma, Non-Small-Cell Lung , Homeodomain Proteins , Lung Neoplasms , Transcription Factors , Tristetraprolin , Animals , Humans , Mice , Carcinoma, Non-Small-Cell Lung/genetics , Homeodomain Proteins/genetics , Lung Neoplasms/genetics , Oncogenes , Phenotype , Transcription Factors/genetics , Tristetraprolin/genetics
2.
J Appl Toxicol ; 42(3): 529-539, 2022 03.
Article in English | MEDLINE | ID: mdl-34550611

ABSTRACT

The effects of low-dose radiation (LDR, ≤0.1 Gy) on living organisms have been the hot areas of radiation biology but do not reach a definitive conclusion yet. So far, few studies have adequately accounted for the male reproductive system responses to LDR, particularly the regulation of testosterone content. Hence, this study was designed to evaluate the effects of LDR on Leydig cells and testicular tissue, especially the ability to synthesize testosterone. We found that less than 0.2-Gy 60 Co gamma rays did not cause significant changes in the hemogram index and the body weight; also, pathological examination did not find obvious structural alterations in testis, epididymis, and other radiation-sensitive organs. Consistently, the results from in vitro showed that only more than 0.5-Gy gamma rays could induce remarkable DNA damage, cycle arrest, and apoptosis. Notably, LDR disturbed the contents of testosterone in mice serums and culture supernatants of TM3 cells and dose dependently increased the expression of 3ß-HSD. After cotreatment with trilostane (Tril), the inhibitor of 3ß-HSD, increased testosterone could be partially reversed. Besides, DNA damage repair-related enzymes, including DNMT1, DNMT3B, and Sirt1, were increased in irradiated TM3 cells, accompanying by evident demethylation in the gene body of 3ß-HSD. In conclusion, our results strongly suggest that LDR could induce obvious perturbation in the synthesis of testosterone without causing organic damage, during which DNA demethylation modification of 3ß-HSD might play a crucial role and would be a potential target to prevent LDR-induced male reproductive damage.


Subject(s)
Demethylation , Gamma Rays/adverse effects , Mesenchymal Stem Cells/radiation effects , Multienzyme Complexes/metabolism , Progesterone Reductase/metabolism , Steroid Isomerases/metabolism , Testis/radiation effects , Testosterone/metabolism , Animals , Dose-Response Relationship, Radiation , Male , Mice , Mice, Inbred C57BL
3.
Biosens Bioelectron ; 192: 113507, 2021 Nov 15.
Article in English | MEDLINE | ID: mdl-34330037

ABSTRACT

Rolling circle amplification (RCA) had the prospect of assisting clinic diagnosis with advantage in in situ mRNA detection at single cell level. However, for direct mRNA detection, RCA had relatively low detection specificity and efficiency. Here, we introduced 4-(10, 15, 20-Triphenylporphyrin-5-yl)phenylamine (TPP) modified Au nanoparticle (Au-TPP) to improve the specificity of in-situ RCA. Through photothermal effect, Au-TPP acted as the specific heat source upon irradiation of 635 nm laser. The photothermal mediated RCA would be initiated only when the Au-TPP as well as the padlock anchored adjacently on the same target mRNA. Furthermore, we introduced 'C' form target-specific oligonucleotide linker probes to make generic padlock and Au-TPP for different mRNA targets, so that for a new mRNA target one does not have to redesign the padlock and the Au-TPP probe. By these strategies, we successfully developed a specific and photothermal mediated hyperbranched rolling circle amplification for direct in situ mRNA detection, suitable for both formalin-fixed paraffin-embedded (FFPE) tissue section and frozen tissue section.


Subject(s)
Biosensing Techniques , Metal Nanoparticles , Gold , Nucleic Acid Amplification Techniques , Oligonucleotide Probes , RNA, Messenger/genetics
4.
Front Pharmacol ; 12: 646121, 2021.
Article in English | MEDLINE | ID: mdl-34177570

ABSTRACT

Aconitine is attracting increasing attention for its unique positive inotropic effect on the cardiovascular system, but underlying molecular mechanisms are still not fully understood. The cardiotonic effect always requires abundant energy supplement, which is mainly related to mitochondrial function. And OPA1 has been documented to play a critical role in mitochondrial morphology and energy metabolism in cardiomyocytes. Hence, this study was designed to investigate the potential role of OPA1-mediated regulation of energy metabolism in the positive inotropic effect caused by repeated aconitine treatment and the possible mechanism involved. Our results showed that repeated treatment with low-doses (0-10 µM) of aconitine for 7 days did not induce detectable cytotoxicity and enhanced myocardial contraction in Neonatal Rat Ventricular Myocytes (NRVMs). Also, we first identified that no more than 5 µM of aconitine triggered an obvious perturbation of mitochondrial homeostasis in cardiomyocytes by accelerating mitochondrial fusion, biogenesis, and Parkin-mediated mitophagy, followed by the increase in mitochondrial function and the cellular ATP content, both of which were identified to be related to the upregulation of ATP synthase α-subunit (ATP5A1). Besides, with compound C (CC), an inhibitor of AMPK, could reverse aconitine-increased the content of phosphor-AMPK, OPA1, and ATP5A1, and the following mitochondrial function. In conclusion, this study first demonstrated that repeated aconitine treatment could cause the remodeling of mitochondrial function via the AMPK-OPA1-ATP5A1 pathway and provide a possible explanation for the energy metabolism associated with cardiotonic effect induced by medicinal plants containing aconitine.

5.
Oxid Med Cell Longev ; 2021: 8865813, 2021.
Article in English | MEDLINE | ID: mdl-33968299

ABSTRACT

Cassiae Semen is a widely used herbal medicine and a popular edible variety in many dietary or health beverage. Emerging evidence disclosed that improper administration of Cassiae Semen could induce obvious liver injury, which is possibly attributed to emodin, one of the bioactive anthraquinone compounds in Cassiae Semen, which caused hepatotoxicity, but the underlying mechanisms are not completely understood. Hence, the present study firstly explored the possible role of oxidative stress-mediated mitochondrial dysfunction and ER stress in emodin-cause apoptosis of L02 cells, aiming to elaborate possible toxic mechanisms involved in emodin-induced hepatotoxicity. Our results showed that emodin-induced ROS activated ER stress and the UPR via the BiP/IRE1α/CHOP signaling pathway, followed by ER Ca2+ release and cytoplasmic Ca2+ overloading. At the same time, emodin-caused redox imbalance increased mtROS while decreased MMP and mitochondrial function, resulting in the leaks of mitochondrial-related proapoptotic factors. Interestingly, blocking Ca2+ release from ER by 2-APB could inhibit emodin-induced apoptosis of L02, but the restored mitochondrial function did not reduce the apoptosis rates of emodin-treated cells. Besides, tunicamycin (TM) and doxorubicin (DOX) were used to activate ER stress and mitochondrial injury at a dosage where obvious apoptosis was not observed, respectively. We found that cotreatment with TM and DOX significantly induced apoptosis of L02 cells. Thus, all the results indicated that emodin-induced excessive ROS generation and redox imbalance promoted apoptosis, which was mainly associated with BiP/IRE1α/CHOP signaling-mediated ER stress and would be enhanced by oxidative stress-mediated mitochondrial dysfunction. Altogether, this finding has implicated that redox imbalance-mediated ER stress could be an alternative target for the treatment of Cassiae Semen or other medicine-food homologous varieties containing emodin-induced liver injury.


Subject(s)
Emodin/therapeutic use , Endoplasmic Reticulum Stress/drug effects , Mitochondria/metabolism , Protein Kinase Inhibitors/therapeutic use , Animals , Apoptosis , Cell Line, Tumor , Emodin/pharmacology , Humans , Protein Kinase Inhibitors/pharmacology , Signal Transduction , Smegmamorpha
6.
Med Res Rev ; 41(3): 1798-1811, 2021 05.
Article in English | MEDLINE | ID: mdl-33512023

ABSTRACT

Aconitine (AC) is well-known as the main toxic ingredient and active compound of Aconitum species, of which several aconites are essential herbal medicines of Traditional Chinese Medicine (TCM) and widely applied to treat diverse diseases for their excellent anti-inflammatory, analgesic, and cardiotonic effects. However, the cardiotoxicity and neurotoxicity of AC attracted a lot of attention and made it a favorite botanic poison in history. Nowadays, the narrow therapeutic window of AC limits the clinical application of AC-containing herbal medicines; overdosing on AC always induces ventricular tachyarrhythmia and heart arrest, both of which are potentially lethal. But the underlying cardiotoxic mechanisms remained chaos. Recently, beyond its cardiotoxic effects, emerging evidence shows that low doses of AC or its metabolites could generate cardioprotective effects and are necessary to aconite's clinical efficacy. Consistent with TCM's theory that even toxic substances are powerful medicines, AC thus could not be simply identified as a toxicant or a drug. To prevent cardiotoxicity while digging the unique value of AC in cardiac pharmacology, there exists a huge urge to better know the characteristic of AC being a cardiotoxic agent or a potential heart drug. Here, this article reviews the advances of AC metabolism and focuses on the latest mechanistic findings of cardiac efficacy and toxicity of this aconite alkaloid or its metabolites. We also discuss how to prevent AC-related cardiotoxicity, as well as the issues before the development of AC-based medicines that should be solved, to provide new insight into the paradoxical nature of this ancient poison.


Subject(s)
Aconitum , Drugs, Chinese Herbal , Poisons , Aconitine/adverse effects , Aconitine/toxicity , Drugs, Chinese Herbal/adverse effects , Humans , Poisons/toxicity
7.
Oxid Med Cell Longev ; 2020: 8870656, 2020.
Article in English | MEDLINE | ID: mdl-33381274

ABSTRACT

Ophiopogonin D (OPD) and Ophiopogonin D' (OPD') are two bioactive ingredients in Ophiopogon japonicus. Previously published studies have often focused on the therapeutic effects related to OPD's antioxidant capacity but underestimated the cytotoxicity-related side effects of OPD', which may result in unpredictable risks. In this study, we reported another side effect of OPD', hemolysis, and what was unexpected was that this side effect also appeared with OPD. Although hemolysis effects for saponins are familiar to researchers, the hemolytic behavior of OPD or OPD' and the interactions between these two isomers are unique. Therefore, we investigated the effects of OPD and OPD' alone or in combination on the hemolytic behavior in vitro and in vivo and adopted chemical compatibility and proteomics methods to explain the potential mechanism. Meanwhile, to explain the drug-drug interactions (DDIs), molecular modeling was applied to explore the possible common targets. In this study, we reported that OPD' caused hemolysis both in vitro and in vivo, while OPD only caused hemolysis in vivo. We clarified the differences and DDIs in the hemolytic behavior of the two isomers. An analysis of the underlying mechanism governing this phenomenon showed that hemolysis caused by OPD or OPD' was related to the destruction of the redox balance of erythrocytes. In vivo, in addition to the redox imbalance, the proteomics data demonstrated that lipid metabolic disorders and mitochondrial energy metabolism are extensively involved by hemolysis. We provided a comprehensive description of the hemolysis of two isomers in Ophiopogon japonicus, and risk warnings related to hemolysis were presented. Our research also provided a positive reference for the development and further research of such bioactive components.


Subject(s)
Hemolysis/drug effects , Ophiopogon/chemistry , Saponins/pharmacology , Spirostans/pharmacology , Animals , Antioxidants/adverse effects , Antioxidants/chemistry , Antioxidants/isolation & purification , Antioxidants/pharmacology , Blood Cells/drug effects , Blood Cells/metabolism , Drugs, Chinese Herbal/adverse effects , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Isomerism , Male , Mice , Oxidation-Reduction/drug effects , Proteome/drug effects , Proteome/metabolism , Rabbits , Rats , Rats, Wistar , Risk Assessment , Saponins/adverse effects , Saponins/chemistry , Saponins/isolation & purification , Spirostans/adverse effects , Spirostans/chemistry , Spirostans/isolation & purification , Toxicity Tests, Acute
9.
Toxicol Lett ; 327: 19-31, 2020 Jul 01.
Article in English | MEDLINE | ID: mdl-32234357

ABSTRACT

Traditional Chinese Medicines (TCMs)-containing aconitine are popular and indispensable home remedies in Asia for thousands of years due to its excellent pharmaceutical effects. Accumulating evidence has identified that repeated-dose of aconitine could cause polymorphic ventricular arrhythmias. However, underlying molecular mechanisms are still not fully understood. Hence, the present study firstly investigated the potential role of Notch1 signaling in aconitine-induced cardiotoxicity, aiming to elaborate possible molecular mechanisms involved in aconitine triggered ventricular arrhythmias. Our results showed that aconitine increased Notch1 signaling and downstream KDM5A expression in human and rat cardiomyocytes at non-detectable cytotoxic doses. Furthermore, aconitine promoted the formation of a new regulatory complex containing NICD and KDM5A in a CK2αHI regime, which then targeted to HCN4 promoter and induced re-expression of HCN4 in mature cardiomyocytes. Ultimately, HCN4-mediated If current contributed to aconitine-caused alterations in beating rate of rat cardiomyocytes. All changes aforementioned were significantly ameliorated by Notch1 inhibitor, suggesting that Notch1-mediated epigenetic regulation of HCN4 contributes to aconitine-induced ventricular myocardial dysrhythmia. Thus, our findings provide a novel toxic mechanism and position Notch1/NICD/KDM5A/HCN4 toxicity pathway as a potential target for the treatments of repeated-dose of medicine containing aconitine induced ventricular arrhythmias.


Subject(s)
Aconitine/pharmacology , Arrhythmias, Cardiac/chemically induced , Heart Ventricles/drug effects , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism , Potassium Channels/metabolism , Receptor, Notch1/metabolism , Animals , Animals, Newborn , Cell Line , Cell Survival/drug effects , Gene Expression Regulation/drug effects , Histones , Humans , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics , Mitochondria/drug effects , Mitochondria/metabolism , Muscle Proteins/genetics , Muscle Proteins/metabolism , Myocytes, Cardiac/drug effects , Potassium Channels/genetics , Rats , Receptor, Notch1/genetics , Superoxides/metabolism
10.
Front Pharmacol ; 11: 624529, 2020.
Article in English | MEDLINE | ID: mdl-33584308

ABSTRACT

Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. However, the toxic mechanism of action involved is still unclear. Recently, pathogenic ferroptosis mediated lipid peroxidation was demonstrated to cause kidney injury. Therefore, this study explored the role of ferroptosis induced by mitochondrial iron overload in ALI-induced nephrotoxicity, aiming to identify the possible toxic mechanism of ALI-induced chronic nephropathy. Our results showed that ALI inhibited HK-2 cell activity in a dose-dependent manner and significantly suppressed glutathione (GSH) levels, accompanying by significant increases in intracellular 4-hydroxynonenal (4-HNE) and intracellular iron ions. Moreover, the ALI-mediated cytotoxicity could be reversed by deferoxamine mesylate (DFO). Compared with other inhibitors, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, obviously alleviated ALI-induced cytotoxicity. Furthermore, we have shown that ALI could remarkably increase the levels of superoxide anion and ferrous ions in mitochondria, and induce mitochondrial damage and condensed mitochondrial membrane density, the morphological characteristics of ferroptosis, all of which could be reversed by DFO. Interestingly, ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment. In conclusion, our results demonstrated that mitochondrial iron overload-mediated antioxidant system inhibition would assist ALI-induced ferroptosis in renal tubular epithelial cells, and Nrf2-HO-1/GPX4 antioxidative system could be an important intervention target to prevent medicine containing ALI-induced nephropathy.

11.
J Steroid Biochem Mol Biol ; 172: 149-159, 2017 09.
Article in English | MEDLINE | ID: mdl-28711487

ABSTRACT

Aucubin (AU) is an iridoid glycoside that has been shown to display estrogenic properties and has various pharmacological effects. Herein, we described the angiogenic properties of AU. In the study, hindlimb ischemia was induced by ligation of femoral artery on the right leg of ovariectomized mice. AU treatment significantly accelerated perfusion recovery and reduced tissue injury in mice muscle. Quantification of CD31-positive vessels in hindlimb muscles provided evidences that AU promoted angiogenesis in peripheral ischemia. In addition, results from quantitative PCR and western blot suggested AU induced angiogenesis via vascular endothelial cell growth factor (VEGF)/Akt/endothelial nitric oxide synthase (eNOS) signaling pathway. More interestingly, AU's angiogenic effects could be completely abolished in estrogen receptor beta (ERß) knockout mice. In conclusion, the underlying mechanisms were elucidated that AU produced pro-angiogenic effects through ERß-mediated VEGF signaling pathways. These results expand knowledge about the beneficial effects of AU in angiogenesis and blood flow recovery. It might provide insight into the ERß regulating neovascularisation in hindlimb ischemia and identify AU as a potent new compound used for the treatment of peripheral vascular disease.


Subject(s)
Angiogenesis Inducing Agents/pharmacology , Estrogen Receptor beta/genetics , Iridoid Glucosides/pharmacology , Ischemia/drug therapy , Neovascularization, Physiologic/drug effects , Phytoestrogens/pharmacology , Animals , Disease Models, Animal , Estrogen Receptor beta/deficiency , Female , Femoral Artery/surgery , Gene Expression Regulation , Hindlimb , Ischemia/genetics , Ischemia/pathology , Ischemia/surgery , Ligation , Mice , Mice, Inbred C57BL , Mice, Knockout , Nitric Oxide Synthase Type III/genetics , Nitric Oxide Synthase Type III/metabolism , Ovariectomy , Platelet Endothelial Cell Adhesion Molecule-1/genetics , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Recovery of Function/drug effects , Signal Transduction , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
12.
J Ethnopharmacol ; 209: 13-23, 2017 Sep 14.
Article in English | MEDLINE | ID: mdl-28669772

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Naoxintong capsules (NXT), a traditional Chinese Medical preparation, are widely used for treatment of cardiovascular diseases, while the mechanism is still unclear. MATERIALS AND METHODS: Myocardial infarction (MI) was induced by ligation of the left coronary artery in mice. Echocardiographic measurements were performed to do physiological assessments of left ventricle (LV) function. Histological and immunohistochemical staining was used to determine infarct size, capillary density, tissue endothelial nitric oxide synthase (eNOS) expression. Bone Marrow Transplantation (BMT) model and flow cytometric (FCM) analyses were applied to assay endothelial progenitor cells (EPCs) mobilization. Quantitative Real-Time Reverse Transcription Polymerase Chain Reaction (qRT-PCR), Western blotting and enzyme-linked immunosorbent assay (ELISA) were performed to detect the expressions of vascular endothelial growth factor (VEGF), kinase domain region (KDR), phosphorylated-Akt (p-Akt), phosphorylated-eNOS (p-eNOS). RESULTS: NXT administration reduced myocardium fibrosis and increased myocardium capillary density in response to MI. NXT increased circulating Sca1+/ Fetal liver kinase 1 (Flk1)+ mononuclear cells (MNCs) and soluble Kit ligand (sKitL) of bone marrow (BM) in response to MI. In mice transplanted with green fluorescent protein (GFP) BM cells, NXT increased the numbers of GFP-positive cells at the border zone of the ischemic region in MI-induced mice. NXT increased the numbers of eNOS-expressing BM-derived cells in tissues, which was involved in increased the expressions of VEGF, KDR, p-eNOS, p-Akt in the myocardium. CONCLUSION: NXT-mediated recovery in MI-induced mice was involved in mobilization and incorporation of bone marrow-derived EPCs/circulating angiogenic cells (CACs) leading to enhancement of neovascularization via VEGF/eNOS signaling.


Subject(s)
Drugs, Chinese Herbal/pharmacology , Myocardial Infarction/drug therapy , Neovascularization, Physiologic/drug effects , Nitric Oxide Synthase Type III/metabolism , Signal Transduction/drug effects , Vascular Endothelial Growth Factor A/metabolism , Animals , Gene Expression Regulation/drug effects , Green Fluorescent Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myocardial Infarction/pathology , Nitric Oxide Synthase Type III/genetics , Vascular Endothelial Growth Factor A/genetics
13.
Arch Pharm Res ; 39(2): 249-258, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26481132

ABSTRACT

Phytoestrogens were widely used as natural alternatives to estrogen for treating cardiovascular diseases. They have been reported to have cardioprotective and anti-inflammatory response, but the mechanisms remain unclear. In this study, we found cryptotanshinone and wogonin exhibited phytoestrogenic property in an estrogen-responsive reporter assay. In EA.hy926 cells, treatment of cryptotanshinone and wogonin led to significant increase in NO production levels, which were inhibited by co-incubation of estrogen receptor (ER)α antagonist methyl-piperidino-pyrazole (MPP). The expression of endothelial NO synthase (eNOS) and ERα were up-regulated with the same treatment, indicating they stimulate NO and eNOS expression via ERα-dependent pathway in endothelial cells. While in lipopolysaccharide activated vascular smooth muscle cell line A7r5, cryptotanshinone and wogonin exerted anti-inflammatory effects by inhibiting NO and inducible NO synthase expression via ERß-dependent pathway. The reduction of NO synthesis was not affected by MPP, and was abrogated by ERß antagonist R,R-tetrahydrochrysene. Our findings provide the potential molecular mechanism of cryptotanshinone and wogonin as phytoestrogens for their cardioprotective effects, which exerted regulatory effects on NO synthesis through differential regulation of estrogen receptors. It can be employed as a basis for evaluating the beneficial effects of phytoestrogens in the treatment of patients at risk of cardiovascular disease.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Endothelial Cells/drug effects , Estrogen Receptor alpha/agonists , Estrogen Receptor beta/agonists , Flavanones/pharmacology , Lipopolysaccharides/pharmacology , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , Nitric Oxide Synthase Type III/metabolism , Nitric Oxide Synthase Type II/metabolism , Phenanthrenes/pharmacology , Phytoestrogens/pharmacology , Dose-Response Relationship, Drug , Down-Regulation , Endothelial Cells/enzymology , Estrogen Receptor alpha/genetics , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/genetics , Estrogen Receptor beta/metabolism , HeLa Cells , Humans , Muscle, Smooth, Vascular/enzymology , Myocytes, Smooth Muscle/enzymology , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II/genetics , Nitric Oxide Synthase Type III/genetics , Signal Transduction/drug effects , Transfection , Up-Regulation
14.
Zhongguo Zhong Yao Za Zhi ; 41(15): 2864-2871, 2016 Aug.
Article in Chinese | MEDLINE | ID: mdl-28914030

ABSTRACT

Naoxintong capsule has beneficial effects for activating blood circulation, dispersing blood stasis and dredging collateral. It is widely used in the treatment of coronary heart disease, angina pectoris, stroke and cardiovascular disease. However, the pharmacodynamic basis and possible mechanism of its preventive effects are not clear. In this study, 10 male and 10 female C57BL/6 mice were used, and were randomly divided into the control group (saline) and Naoxintong group. Adaptively fed for 7 days in common conditions, mice were given Naoxintong capsule or saline for 3 days via intragastric administration. Serum was collected from 6 mice in each group 1 h after the last administration. Serum proteins were prepared to do two-dimensional gel electrophoresis. Then image analysis and mass spectrometry detection were carried out to screen and identify the differentially expressed proteins and make bioinformatics analysis. It was found that 24 differentially expressed proteins between Naoxintong group and control group. Compared with the control group, 12 proteins were increased, and 12 were decreased. The proteins were involved in apoptosis signal pathway and vascular endothelial growth factor signal transduction pathway, in which vasohibin-1 is a negative feedback regulation factor in angiogenesis. Western blot showed that the expression of vasohibin-1 in Naoxintong group was reduced, which is consistent with the result in two-dimensional electrophoresis. Serum proteins expression is different between Naoxintong and control groups. The targets of these differentially expressed proteins include endothelial cells, inflammatory cells and platelets. The changes on proteins showed that Naoxintong capsule may ameliorate coronary heart disease and ischemic cerebrovascular disease, and provide potential biological markers to prevent ischemic disease.


Subject(s)
Cell Cycle Proteins/metabolism , Cerebrovascular Disorders/prevention & control , Drugs, Chinese Herbal/pharmacology , Proteome/analysis , Animals , Apoptosis , Electrophoresis, Gel, Two-Dimensional , Female , Male , Mice , Mice, Inbred C57BL , Signal Transduction , Vascular Endothelial Growth Factor A/metabolism
15.
Zhongguo Zhong Yao Za Zhi ; 41(23): 4416-4423, 2016 Dec.
Article in Chinese | MEDLINE | ID: mdl-28933121

ABSTRACT

Endothelial progenitor cells (EPCs) are precursor cells of endothelial cells. Signal molecules produced by ischemia and hypoxia can promote mobilization of bone marrow EPCs to peripheral circulation and formation of novel blood vessels in tissues that are damaged during heart attack. Naoxintong capsule (NXT) has the functions of promoting blood circulation, removing blood stasis, promoting the circulation of qi and relieving pain. The various components in NXT have protective effects on blood vessels and can effectively improve the symptoms of ischemia. However, its effect on EPCs is not clear. To study the intervention effect of NXT on mobilization and homing of peripheral blood EPCs, green fluorescent protein (GFP) transgenic mice were used for bone marrow transplantation (BMT) and then unilateral hind limb ischemia model (UHLI) were constructed. For BMT, wild-type ICR mice were irradiated by CS137 and then injected with 4×106 bone marrow cells isolated from GFP mice. The bone marrow reconstitution of recipients was assessed by quantification of GFP bone marrow-derived cells (BMDC) from transplanted mice 4 weeks after BMT. The UHLI model was duplicated by ligating femoral artery and divided into three groups: the model group, the NXT group (model+NXT) and the positive control group (model+simvastatin). Flow cytometry was used to detect the proportion of GFP positive cells and the peripheral blood EPCs levels at 1, 3, 7, 14 days before and after surgery. Ischemic tissue of gastrocnemius muscle was excised at 3 and 7 days after operation for immunofluorescence staining to detect the number of GFP+ cells. The bone marrow chimerism was achieved at day 28 after BMT. There was no significant difference in the percentage of GFP positive cells between BMT mice and GFP transgenic mice. NXT and simvastatin could significantly increase the number of peripheral blood EPCs 1,3 days after surgery. Three and seven days after operation, the number of homing EPCs was significantly higher in NXT group and positive control group than that in model group (P<0.001). In conclusion, NXT can obviously promote the mobilization and homing of EPCs.


Subject(s)
Bone Marrow Transplantation , Drugs, Chinese Herbal/pharmacology , Endothelial Progenitor Cells/drug effects , Hematopoietic Stem Cell Mobilization , Ischemia/drug therapy , Animals , Bone Marrow Cells , Endothelial Progenitor Cells/cytology , Mice , Mice, Inbred ICR , Mice, Transgenic
16.
Biol Pharm Bull ; 38(12): 1873-8, 2015.
Article in English | MEDLINE | ID: mdl-26632179

ABSTRACT

Wogonin, a natural flavonoid, is one of the bioactive compounds of the medicinal herb Eucommia ulmoides OLIV. widely used in southeastern Asia for treating hypertension. However, the molecular mechanisms for the therapeutic benefits remain largely unclear. The present study investigated the vasodilatory effect of wogonin and its possible mechanisms. The flavonoid (0.1-100 µM) caused concentration-dependent relaxations in endothelium-intact aortic rings precontracted with norepinephrine (NE, 1 µM) or potassium chloride (KCl, 60 mM). Preincubation with wogonin (10, 100 µM) for 20 min significantly inhibited the contractile responses to NE (0.1, 1, 10 µM) or KCl (7.5, 15, 30, 60 mM). Relaxant responses to wogonin were not inhibited by N(G)-nitro-L-arginine methylester (100 µM) or endothelial denudation. In a Ca(2+)-free Krebs' solution, wogonin not only blocked Ca(2+) influx-dependent vasoconstriction by either NE (1 µM) or KCl (100 mM), but also inhibited NE (1 µM)-induced tonic contraction, which is dependent on intracellular Ca(2+) release. Wogonin also suppressed the elevation of [Ca(2+)]i induced by KCl (60 mM) after exhausting the calcium store in sarcoplasmic and endoplasmic reticula with thapsigargin (1 µM) or by ATP (100 µM) in primary vascular smooth muscle cells. These findings suggest that wogonin-induced responses are mainly due to the inhibition of both intracellular Ca(2+) release and extracellular Ca(2+) influx.


Subject(s)
Drugs, Chinese Herbal/pharmacology , Eucommiaceae/chemistry , Flavanones/pharmacology , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , Vasoconstriction/drug effects , Vasodilator Agents/pharmacology , Animals , Aorta , Calcium/metabolism , Endothelium, Vascular/metabolism , Hypertension/drug therapy , Hypertension/physiopathology , Male , Muscle, Smooth, Vascular/metabolism , NG-Nitroarginine Methyl Ester/pharmacology , Norepinephrine , Phytotherapy , Potassium Chloride , Rats, Wistar
17.
Zhonghua Yi Xue Za Zhi ; 94(4): 273-5, 2014 Jan 28.
Article in Chinese | MEDLINE | ID: mdl-24731493

ABSTRACT

OBJECTIVE: To evaluate the efficacy, biological behaviors and safety of aromatase inhibitors in early male breast cancer. METHODS: A total of 12 male breast cancer patients of stages I and II took aromatase inhibitors. Their levels of estradiol were measured before and after medication. Another 12 patients received tamoxifen as controls. The recurrence, mortality and side effects were monitored and analyzed. RESULTS: Their 5-year disease-free survival rates were 69.4%, 77.0% and 5-year overall survival rates 75.0%, 83.4% respectively. No drug withdrawal occurred because of side effects. No inter-group statistical significance existed in estrogen receptor (9 vs 10 cases), progesterone receptor (10 vs 9 cases ), human epidermal growth factor receptor 2 (2 vs 3 cases ), stage T, N, M and disease-free survival rate, disease related 5-year overall survival rate (both P > 0.05) . There was statistical difference in the level of estradiol before and after medication. The level of estradiol was initially <5 ng/L in one patient, but rose during disease progression. CONCLUSIONS: The efficacy of aromatase inhibitors and tamoxifen in early male breast cancer patients is comparable. And the activity of aromatase inhibitors is correlated with a significantly reduced level of E(2) level. Some patients may develop secondary resistance.


Subject(s)
Aromatase Inhibitors/therapeutic use , Breast Neoplasms, Male/drug therapy , Aged , Aromatase Inhibitors/adverse effects , Breast Neoplasms, Male/pathology , Disease-Free Survival , Humans , Male , Neoplasm Staging , Prognosis , Survival Rate , Tamoxifen/therapeutic use
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