Structurally novel HDAC inhibitors based on the trans-β-arylacryl tetrahydroisoquinoline scaffold: the design, synthesis, and anti-cancer activity / 药学学报

In this study, a series of 18 histone deacetylases inhibitors (HDACis), derived from our in-house anti-cancer trans-β-arylacryl 1,2,3,4-tetrahydroisoquinoline-based scaffold, were designed, synthesized, and antitumor evaluated. HDAC1 inhibitory activity assay showed that compounds 13d-13f and 13m-13o demonstrated attractive enzymatic activity with IC50 at single-digit nanomolar or subnanomolar level.In addition, 13o exerted superior anti-proliferative activity (A549, IC50 = 0.89 μmol·L-1; HCT116, IC50 = 0.49 μmol·L-1) to that of vorinostat (SAHA).Besides,13e, with the most potent HDAC1 enzymatic activity (IC50 = 3.8 nmol·L-1), also displayed attractive cellular activity (A549, IC50 = 1.74 μmol·L-1; HCT116, IC50 = 2.43 μmol·L-1). The Western blot analysis illustrated that 13e treatment increased the acetylation of H3 and α-tubulin in a dose-dependent manner in A549 cells. In summary, 13e and 13o deserve further functional investigation.

Design, synthesis, and biological evaluation of phenylpropenamides compounds as anti-platelet aggregation / 药学学报

Twenty phenylpropenamide analogs with structural novelty were designed and synthesized upon pharmacophore-combination strategy. The structures of target compounds were elucidated by IR, 1H NMR, 13C NMR and MS, and all the target compounds were biologically evaluated for the inhibitory activities of platelet aggregation induced by adenosine diphoshate (ADP) and (AA) arachidonic acid via Bron method. As a result, compounds 6b, 9b, 9d and 9h demonstrated potent inhibitory activity against platelet aggregation induced by AA. Meanwhile, compounds 6b, 6d, 6j, 9b and 9g exhibited significant suppression of platelet aggregation induced by ADP.

Design, synthesis and biological evaluation of the novel ligustrazine derivatives / 药学学报

Using ligustrazine as the leading compound, we designed and synthesized ten novel ligustrazine derivatives, whose structures were determined by 1H NMR, 13C NMR and MS. Inhibitory effects of the new compounds on the proliferation of A549, A549/DDP and HBE cells were detected by MTT assay. The inhibi-tory activity of the synthesized compounds on migration and invasion of A549 cells were evaluated through scratch assay and transwell assay. Mechanism of the inhibition on migration and invasion was investigated by Western blotting. In addition, the cell cycle was analyzed with flow cytometry. The results showed that, both compounds Z8 and Z10 have an anti-proliferative activity, and the potencies of inhibition of tumor-cell migration and invasion were attributed to the down-regulation of MMP-2 and MMP-9. The compounds Z8 and Z10 could also enhance G2/M arrest in A549 cell as revealed by cell cycle analysis.

The anti-HIV-1 activities of benzophenones non-nucleoside reverse transcriptase inhibitors in vitro / 药学学报

To evaluate the anti-HIV-1 activities of 5 benzophenones non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as DY1203, DY1204, DY1119, DY1208 and DY1209 in vitro, the cytotoxicity of 5 compounds were tested on C8166, MT-4, H9 and PBMC with the MTT assay. The anti-HIV-1 activities of compounds were evaluated on laboratory-adapted strain, drug-resistant strains and primary isolated strains by p24 antigen expression ELISA. The inhibition of HIV-1 recombinant reverse transcriptase activity was assessed by ELISA assay. Among 5 compounds, DY1203 and DY1204 showed low cytotoxicities with CC50 greater than 200 μg·mL-1. DY1119, DY1208 and DY1209 showed strong anti-HIV-1 activities against HIV-1IIIB, HIV-174V, HIV-1RF/V82F/184V, HIV-1NL4-3 gp41(36G) N42S, HIV-1KM018, HIV-1TC-1 and HIV-1Wan. However, NNRTIs drug-resistant strain HIV-1A17 showed different resistance to these compounds. The 5 compounds proved active against HIV-1 recombinant reverse transcriptase. DY1208 is expected to become a new lead compound for its high therapeutic index. The results can provide new information for HIV-1 drug research and promote the development of new HIV-1 drugs.

Phenotypic modulation of vascular smooth muscle cells in diabetes mellitus and intervention of traditional Chinese medicines / 中国中药杂志

Proliferation and migration of vascular smooth muscle cells (VSMC) are common pathological features of diabetic vascular complications,such as atherosclerosis and hypertension. Phenotypic modulation of VSMC is the basis for VSMC proliferation and migration. Therefore, studies on VSMC phenotypic modulation and its mechanisms in diabetes mellitus were of important significance to the prevention and therapy of diabetic vascular complications. This paper introduces VSMC phenotypic modulation and the underlying mechanisms in diabetes mellitus, and summarizes advance of studies on traditional Chinese medicine intervention upon VSMC phenotypic modulation, so as to provide reference for preventing and treating diabetic vascular complications with traditional Chinese medicines.

Flow cytometric analysis for detecting mitochondrial permeability transition pore opening / 南方医科大学学报

<p><b>OBJECTIVE</b>To introduce a new method for detecting mitochondrial permeability transition pore (PTP) opening with flow cytometry using the resveratrol-inducing PTP opening model.</p><p><b>METHODS</b>Mitochondria were isolated from rat livers and selectively labeled with nonyl acridine orange. The mitochondrial membrane potential was detected using flow cytometry with TMRE (tetramethylrhodamine, ethyl ester) labeling. PTP opening induced by resveratrol was represented by the changes of mitochondrial side-scattering (SSC) detected by flow cytometry.</p><p><b>RESULTS</b>Flow cytometry was capable of defining the purity of the mitochondria isolated. The fluorescence intensities and SSC of the mitochondria were decreased after resveratrol treatment, indicating that resveratrol could induce PTP opening. Ciclosporin A inhibited resveratrol-induced PTP opening.</p><p><b>CONCLUSION</b>Flow cytometric analysis allows accurate and convenient detection of mitochondrial membrane potential, mitochondrial swelling and PTP opening.</p>

Diagnosis and surgical treatment of tight carotid stenosis / 中华外科杂志

<p><b>OBJECTIVE</b>To explore the specialty of diagnosis and surgery of tight carotid stenosis.</p><p><b>METHOD</b>From January 2000 to December 2009, 53 patients with tight carotid stenosis (> 95%) were operated on. All 53 patients had tight carotid stenosis more than 95% on one side in whom 28 had contralateral carotid stenosis or occlusion. The clinical and imaging data as well as surgical outcomes of the patients were retrospectively analyzed.</p><p><b>RESULTS</b>Forty-five patients had postoperatively done well without any complications. There were 3 cases of hemodynamic instability and one case of cardiac ischemia which resolved in one to two days. One patient developed mild hoarseness. One complicated with bacteremia due to deep vein catheter insertion. Two patients experienced brain hemorrhage. None of this series occurred perioperative brain ischemia.</p><p><b>CONCLUSIONS</b>Tight carotid stenosis indicates a need for expeditious carotid endarterectomy with very low rates of brain ischemia. Intraoperative shunting is seldom necessary. Postoperative hyperperfusion syndrome and brain hemorrhage should be worried. Micro-endarterectomy can effectively prevent from restenosis.</p>

The strategy of management for bilateral carotid atherosclerotic stenosis / 中华外科杂志

<p><b>OBJECTIVE</b>To evaluate the indication, time and strategy of surgery for patients with bilateral carotid atherosclerotic stenosis.</p><p><b>METHODS</b>Seventy-four patients with bilateral carotid atherosclecrotic stenosis were admitted to our hospital from February 1987 to December 2007. In 34 patients who presented with unilateral symptoms and underwent ipsilateral carotid endarterectomy (CEA), contralateral CEA or carotid artery stenting (CAS) was performed in 8 because of severe stenosis (> 70%) or unstable plaque. Thirty-eight patients presented with bilateral symptoms. Among them, 15 underwent CEA on both sides, 3 were performed CEA on one side and CAS on the other side, while 20 underwent unilateral CEA only. In 2 asymptomatic patients, CEA was also performed.</p><p><b>RESULTS</b>Ninety-three cases of CEA were performed in 74 patients. Sixty-eight patients were uneventful after operation. Neurological deficits deteriorated in 2 patients. Four patients developed cardiac ischemia, cerebral hemorrhage and hoarseness respectively. Sixty-seven patients were followed-up for 4.9 years. No cerebral ischemia relevant to operated carotid artery developed in 63 patients.</p><p><b>CONCLUSIONS</b>If the indication is obvious, CEA should be performed no matter how contralateral carotid artery is. The strategy of therapy is individual. Whether using shunt depends on intra-operative monitoring.</p>

Liangge san effects the expression of CD14 and scaverger receptor in the Kupffer cells of liver of endotoxemia mice / 中国中药杂志

<p><b>OBJECTIVE</b>To study the effects of Liangge San to the expression of CD14 and scaverger receptor(SR) in the kupffer cells of liver and the pathological changes of liver tissue of endotoxemia-mice.</p><p><b>METHOD</b>The model was established with intravenous injection of lipopolysaccharide (LPS) and at the same time different dose Liangge San were given. The expression of CD14 and scaverger receptor were detected with immunohigtochemistry at the 2nd, 4th, 8th hour ofter injury and analyzed with computer image system, and the pathological changes of liver tissue were also observed.</p><p><b>RESULT</b>At the three different hours, the expression of CD14 and scaverger receptor in macrophages of liver of LPS-injury group showed significant increase and significant decrease respectively, compared with that of the blank-control group (P < 0.01). The expression in dexamethasone group and Liangge San different dose groups were intermediate between those in injury group and those in control group. Compared with expression of LPS-injury group, those of dexamethasone group and Liangge San different dose groups showed significant differences (P < 0.01), especially that of Liangge San high dose group. Liver cells showed vacuole change. Changes of CD14 and SR expression were paralleled with the severity of liver damages of the mice.</p><p><b>CONCLUSION</b>Liangge San can inhibite the up-regulation of CD14 expression and down-regulation of scaverger receptor expression in a dosage-dependent manner and also alleviate the damages of liver induced by LPS.</p>

Resveratrol induces HepG2 cell apoptosis by depolarizing mitochondrial membrane / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the effects of resveratrol on the proliferation, apoptosis, mitochondrial membrane potential and cell morphology of human liver cancer cell line HepG2.</p><p><b>METHODS</b>The changes in HepG2 cell growth and proliferation in response to resveratrol treatment were evaluated by MTT assay, and resveratrol-induced apoptosis of HepG2 cells was investigated by flow cytometry. Inverted microscope and electron microscope were employed for observing morphological changes of the treated cells. The whole-cell mitochondrial membrane potential was measured in separate experiments using two fluorimetric probes, rhodamine123 and TMRE, respectively. HepG2 cells treated with rhodamine123 were analyzed by flow cytometry and cells treated with TMRE by confocal microscope.</p><p><b>RESULTS</b>MTT assay showed that low concentrations of resveratrol produced no significant effect on the growth of HepG2 cells, whereas at high concentrations, resveratrol could obviously inhibit the cell growth in a time- and dose-dependent manner. Resveratrol also induced apoptosis of HepG2 cells, and after a 24-hour treatment, resveratrol caused sharp increment of the mitochondria membrane potential.</p><p><b>CONCLUSION</b>Resveratrol is capable of inhibiting the proliferation of HepG2 cells and inducing cell apoptosis by depolarizing mitochondrial membrane potential.</p>

Resveratrol promotes Ca2+-induced Ca2+ release from rat liver cell mitochondria mediated by Ca2+ / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the effects of resveratrol (Res) on mitochondrial opening and Ca(2+)-induced Ca(2+) release (CICR) from rat liver cell mitochondria mediated by Ca(2+).</p><p><b>METHODS</b>Wistar rat liver cell mitochondria was extracted and Res-induced mitochondrial swelling was assessed spectrophotometrically at 540 nm to examine the permeability transition pore (PTP) opening. The membrane potential changes of Res-treated mitochondria were measured with fluorescence spectrophotometery. Ca(2+) uptake and release by the mitochondria was determined by absorbance change of arsenazo III at 685-675 nm monitored by dual wavelength spectrophotometry.</p><p><b>RESULTS</b>Res promoted Ca(2+)-mediated PTP opening, and this effect was completely inhibited by CsA and lowered by trifluoperazine. CICR accelerated by Res treatment was completely blocked by ruthenium red and partly by trifluoperazine.</p><p><b>CONCLUSION</b>Res can promote PTP opening by inducing CICR, which may be one of the pathways that Res induces cell apoptosis.</p>

Effects of resveratrol on growth inhibition and gap-junctional intercellular communication of HepG2 cells / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the effects of the resveratrol on proliferation and gap-junctional intercellular communication (GJIC) in human liver cancer cell line HepG2.</p><p><b>METHODS</b>MTT assay was used to observe the effects of resveratrol on HepG2 cell growth, and the distribution of cell cycles was detected with flow cytometry (FCM). The effects of resveratrol on GJIC of HepG2 cells labeled with 5'-CFDA/AM was examined with fluorescence redistribution after photobleaching (FRAP) and confocal microscope.</p><p><b>RESULTS</b>The results of MTT assay indicated that the proliferation of HepG2 cells was significantly inhibited by resveratrol in a time- and dose-dependent manner. Resveratrol could arrest HepG2 cell growth in S phase, inhibit DNA synthesis and induce cell apoptosis. Furthermore, the levels of GJIC increased sharply after resveratrol treatment of the cells.</p><p><b>CONCLUSION</b>Resveratrol is capable of inhibiting HepG2 cell proliferation, causing cell growth arrest at S phase and inducing cell apoptosis. Increased GJIC level contributes to the effect of resveratrol in HepG2 cell proliferation inhibition and its cancer chemopreventive activity.</p>