The target compounds were prepared from 5-aminobenzimidazolone by two steps reaction, and their AChE inhibitory activities were measured by Ellman method in vitro. The AChE inhibitory activity of compound 4d is the best of them, and its IC50 value is equal to 7.2 μmol·L(-1), which is better than that of rivastigmine; moreover the 4d had no inhibitory activities to BuChE. Therefore, the inhibitory activities of 5-aminobenzimidazolone derivatives to acetylcholinesterase are worth further researching.
Acetylcholinesterase ; metabolism ; Benzimidazoles ; chemical synthesis ; chemistry ; Cholinesterase Inhibitors ; chemical synthesis ; chemistry ; Drug Design ; Phenylcarbamates ; chemistry ; Rivastigmine ; Structure-Activity Relationship

OBJECTIVETo observe the inhibitory effect of mizolastine on substance P(SP)-induced production of leukotriene B(4) (LTB(4)) and interleukin 5 (IL-5) in mouse skin.

METHODSMice were fed with different doses of mizolastine or other control drugs, 30 min after administration animals were injected intradermally with SP on the back. The treated skin samples were taken and competitive enzyme-link immunoassay (ELISA) method was applied to detect LTB (4) and IL-5 in the skin samples.

RESULTThe LTB(4) and IL-5 levels in 10 mg/kg mizolastine group were (1.23 +/-0.29)pg/ml and (34.28 +/-11.00)pg/ml, respectively, which were lower than those in saline control group [(5.52+/-1.88)pg/ml and (179.62 +/-46.25)pg/ml respectively] or loratadine group [(3.89+/-1.27)pg/ml and (127.74 +/-43.27)pg/ml respectively]. No significant difference was found between 10 mg/kg mizolastine group and dexamethasone group (P=0.161 and P=0.508).

CONCLUSIONMizolastine might inhibit the production of LTB(4) and IL-5 induced by substance P in mouse skin, suggesting that anti-inflammatory effect and the blockade of histamine H1 receptors might be involved in its anti-pruritic mechanisms.

Animals ; Benzimidazoles ; pharmacology ; Female ; Histamine H1 Antagonists ; pharmacology ; Interleukin-5 ; biosynthesis ; Leukotriene B4 ; biosynthesis ; Male ; Mice ; Mice, Inbred BALB C ; Skin ; metabolism ; Substance P ; antagonists & inhibitors

OBJECTIVETo explore the effects of carbendazim on the testicular development and spermatogenic function of male rats and its action mechanism.

METHODSForty clean-grade impubic male Wistar rats were equally randomized into a low-dose, a medium-dose, a high-dose and a control group, treated respectively with carbendazim at 20, 100 and 200 mg/kg (bw) and Tween-80 solution, all by oral gavage once a day for 80 days. After treatment, the rats were weighed, their testes and epididymides immediately excised, their morphological changes observed and the weights of the right testis and epididymis obtained. Sperm motility and counts in the left cauda epididymis were determined. Histopathological changes, cell apoptosis and the expression of Bcl-2/Bax in the testis were detected by HE staining, TUNEL and immunohistochemical SABC method.

RESULTSThe medium- and high-dose groups showed obviously atrophic testes and epididymides, marked histopathological abnormality of the testis, reduced weight of the right testis and epididymis, and decreased sperm motility and counts in the left cauda epididymis (P < 0.01). With the increasing dose of carbendazim, the apoptosis rate and Bax expression were significantly raised, while the expression of Bcl-2 significantly decreased (P < 0.05, P < 0.01).

CONCLUSIONCarbendazim affects the testicular development and spermatogenic function of male rats, and the mechanism may involve cell apoptosis induced by down-regulation of Bcl-2 and up-regulation of Bax.

Animals ; Apoptosis ; drug effects ; Benzimidazoles ; pharmacology ; Carbamates ; pharmacology ; Down-Regulation ; Male ; Rats ; Rats, Wistar ; Spermatogenesis ; drug effects ; Testis ; drug effects ; growth & development ; bcl-2-Associated X Protein ; metabolism

OBJECTIVETo study the effect of peroxisome proliferator activated receptor γ (PPAR-γ) agonist on the angiotensin converting enzyme 2 (ACE2) mRNA expression in monocyte-derived macrophages of essential hypertensive patients.

METHODSTotally 57 essential hypertensive patients were randomly divided into three groups: conventional treatment group (n=18), telmisartan group (n=19), and benazepril group (n=20); 20 patients with normal blood pressure were also selected as the control group. Monocyte-derived macrophages were isolated from blood samples of patients in all four groups. The expression of ACE2 mRNA in monocyte-derived macrophages was detected by RT-PCR before treatment and 4 and 12 weeks after treatment.

RESULTSFour and 12 weeks after treatment, the systolic pressure and diastolic pressure of telmisartan group and benazepril group were significantly lower than that of the conventional treatment group (all P<0.01), and the systolic pressure and diastolic pressure of telmisartan group were significantly lower than that of the benazepril group(both P<0.01) .The expression of ACE2 mRNA in monocyte-derived macrophages were significantly lower in essential hypertensive patients than that in control group (P<0.01). After having been treated for 4 weeks and 12 weeks, the expression of ACE2 mRNA in monocyte-derived macrophages of hypertensive patients in telmisartan and benazepril groups were significantly higher than that in conventional treatment group (all P<0.01), and the expression of ACE2 mRNA in telmisartan group was significantly higher than that in benazepril group (both P<0.01).

CONCLUSIONPPAR-γ agonist could increase the ACE2 mRNA expression in monocyte-derived macrophages of essential hypertensive patients.

Aged ; Benzazepines ; pharmacology ; Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; Female ; Humans ; Hypertension ; drug therapy ; enzymology ; Macrophages ; enzymology ; Male ; Middle Aged ; PPAR gamma ; agonists ; Peptidyl-Dipeptidase A ; genetics ; metabolism ; RNA, Messenger ; genetics

AIMTo clarify whether the activation of mitochondrial ATP sensitive potassium channel and calcium activated potassium channel can influence the permeability transition of normal and ischemic brain mitochondria.

METHODSspectrophotometry was used to determine the effect of the two mitochondrial potassium channel agonists on the swelling of normal and ischemic brain mitochondria respectively.

RESULTSIn normal mitochondria, diazoxide and NS1619 could inhibit the decrease of calcium induced mitochondrial absorbance at 520 nm (A520), which were blocked by atractyloside. When compared with the normal mitochondria, mitochondrial A520 decrease in ischemic brain was even more rapid. Diazoxide and NS1619 could still inhibit the calcium induced mitochondrial A520 decrease, which were blocked by atractyloside.

CONCLUSIONActivation of mitochondrial ATP sensitive potassium channel and calcium activated potassium channel can protect brain mitochondria in vitro probably via influencing the mitochondrial permeability transition.

Animals ; Benzimidazoles ; pharmacology ; Brain ; drug effects ; metabolism ; Brain Ischemia ; metabolism ; Cell Membrane Permeability ; Diazoxide ; pharmacology ; KATP Channels ; metabolism ; Male ; Mitochondria ; drug effects ; metabolism ; Mitochondrial Membrane Transport Proteins ; drug effects ; Potassium Channels, Calcium-Activated ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo explore the effect of telmisartan and pyridoxamine on oxidative stress in brain tissue of spontaneously hypertensive rats.

METHODSTwenty-four spontaneously hypertensive rats were randomly divided into four groups (n = 6): hypertensive control group (HC group), telmisartan group (T group ), pyridoxamine group (P group ), telmisartan and pyridoxamine group (TP group). Wistar-Kyoto (WKY) rats of the same age were served as a normal control group (NC group). Drug treatment lasted for 16 weeks the level of hyde (MDA) in rat brain tissue, as well as superoxide dismutase (SOD) activity and nicotinamide adenine dinucleotide phosphate(NADHP) oxidase p47phox mRNA expression were observed in this study.

RESULTSThe MDA level in brain in HC group were higher than that in NC group and the SOD activity were lower (P < 0.05). T group, P group and TP group had lower MDA level and higher SOD activity than HC group (P < 0.05). The NADPH mRNA in brain in HC group were significantly higher than that in NC group (P < 0.01). T group and TP group had decreased levels of NADPH mRNA (P < 0.01), there was no significant difference between HC group and P group (P > 0.05).

CONCLUSIONThe brain tissue of spontaneous hypertensive rats had been under the status of oxidative stress. Single application of either telmisartan or pyridoxamine could inhibit oxidative stress of brain tissue. However, compare with single treatment of telmisartan, no beneficial effects were observed in combined use of telmisartan and pyridoxamine.

Animals ; Benzimidazoles ; pharmacology ; therapeutic use ; Benzoates ; pharmacology ; therapeutic use ; Brain ; drug effects ; metabolism ; Hypertension ; drug therapy ; metabolism ; Male ; NADPH Oxidases ; metabolism ; Oxidative Stress ; drug effects ; Pyridoxamine ; pharmacology ; therapeutic use ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Superoxide Dismutase ; metabolism

BACKGROUNDVascular smooth muscle cell proliferation is an important process in the development of atherosclerosis and is associated with other cellular processes in atherogenesis. Telmisartan is reported to have partial peroxisome proliferator-activated receptor (PPAR)-γ activating properties and has been referred to as selective PPAR modulators, but valsartan just blocks angiotensin II (AngII) type 1 (AT1) receptors. This study aimed to compare the different effects of telmisartan and valsartan on human aortic smooth muscle cells (HASMCs) proliferation.

METHODSAbility of telmisartan and valsartan to inhibit proliferation of HASMCs was evaluated by the Cell Counting Kit-8 (CCK-8) in continuous cell culture. Whether the antiproliferative effects of telmisartan and valsartan depend on their effects on AngII receptors or activating the peroxisome PPAR-γ was also investigated in this study.

RESULTSTelmisartan inhibited proliferation of HASMCs by 52.4% (P < 0.01) at the concentration of 25 µmol/L and the effect depended on the dose of telmisartan, but valsartan had little effect on HASMCs proliferation (P > 0.05) and no dose response. When tested in cells stimulated with AngII, telmisartan had the same inhibition of HASMCs by 59.2% (P < 0.05) and valsartan also inhibited it by 41.6% (P < 0.05). Telmisartan and valsartan had the same effect on down-regulating AT1 receptor expression and telmisartan was superior to valsartan up-regulating AngII type 2 (AT2) receptor expression. Antiproliferative effects of telmisartan were observed when HASMCs were treated with the PPAR-γ antagonist GW9662 but antiproliferative effects of the PPAR-γ activator pioglitazone were not observed.

CONCLUSIONSTelmisartan, but not valsartan, inhibits HASMCs proliferation and has dose-dependent response without stimulation of AngII. AT2 receptor up-regulation of telmisartan contributes to its greater antiproliferative effects than valsartan. Its PPAR-γ activation does not play a critical role in inhibiting HASMCs proliferation.

Benzimidazoles ; pharmacology ; Benzoates ; pharmacology ; Cell Proliferation ; drug effects ; Humans ; Muscle, Smooth, Vascular ; cytology ; metabolism ; Myocytes, Smooth Muscle ; cytology ; drug effects ; PPAR gamma ; metabolism ; Receptor, Angiotensin, Type 1 ; metabolism ; Receptor, Angiotensin, Type 2 ; metabolism ; Tetrazoles ; pharmacology ; Valine ; analogs & derivatives ; pharmacology ; Valsartan

OBJECTIVETo investigate the effect of poly(ADP-ribose)polymerase(PARP)inhibitor ABT888 combined with carbo on apoptosis of human breast cancer cells.

METHODSMTT was used to detect the cell viability of MDA-MB-435s cells after treatment of carbo and ABT888 with different concentration. FACS and Western-blotting were used to detect the cell apoptosis rate and apoptosis-related protein expression, respectively.

RESULTSCombined application of carbo and ABT888 significantly inhibited the proliferation of MDA-MB-435s cells, and the inhibition rates were significantly higher than that of carbo or ABT888 alone. The combination of carbo and ABT888 markedly induced cell apoptosis(26.3%±1.5%) more than carbo(18.6%±1.6%, P<0.01) and ABT888(14.7%±2.3%, P<0.01) alone. Combination of carbo and ABT888 significantly down-regulated the expression of anti-apoptosis factors Bcl-2 and up-regulated the pro-apoptosis proteins Bax and cleaved caspase-3.

CONCLUSIONThe combination of carbo and ABT888 can suppress the proliferation and induce apoptosis of human breast cancer DA-MB-435s cells.

Apoptosis ; Benzimidazoles ; pharmacology ; Breast Neoplasms ; pathology ; Carboplatin ; pharmacology ; Caspase 3 ; metabolism ; Cell Line, Tumor ; drug effects ; Cell Survival ; Humans ; Poly(ADP-ribose) Polymerase Inhibitors ; pharmacology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; bcl-2-Associated X Protein ; metabolism

OBJECTIVETo investigate the effects of Pyrroloquinoline quinine (PQQ) on hydrogen peroxide-induced apoptosis of Schwann cells (SCs) and its mechanism.

METHODSSCs were isolated and cultured in vitro, and identified by S-100 immunofluorescence staining. The cultured SCs were divided into control group, hydrogen peroxide-treated group, hydrogen peroxide and PQQ treated groups. The intracellular superoxide dismutase (SOD) and malondialdehyde (MDA) content was detected; the apoptotic rate of SCs induced by hydrogen peroxide was determined by flow cytometry assay. The Hoechst33342 staining was used to detect the nuclear fragmentation and apoptotic nuclear condensation of SCs; the Rhodamine123 staining was used to detect the changes of mitochondrial membrane potential in SCs, the Western blot analysis was used to detect the expression of Bcl-2 in hydrogen peroxide induced SCs.

RESULTSThe SOD activity was significantly decreased and MDA level was increased in H2O2 induced SCs (P < 0.05), after addition of PQQ, the SOD content increased and MDA content decreased (P < 0.05). Flow cytometry results showed that the early apoptotic rate was 58.8% in H2O2 induced SCs, which has significant difference compared with the control group (P < 0.05), after addition of 10, 50, 100 nmol/L PQQ, the apoptotic rates were reduced to 33.7%, 18.7%, 3.9% respectively, showing significantly different with injured group (P < 0.05). Hoechst 33342 staining showed that H2O2 induced SCs had typical morphological characteristics, such as uptake of nuclear chromatin, nuclear shrinkage, nuclear fragmentation phenomenon. The proportion of apoptotic cells after PQQ treatment reduced. Rhodamine staining results showed that the H2O2 induced mitochondrial membrane potential reduction in SCs, which was reversed by addition of PQQ. Western blot analysis showed that the expression of Bcl-2 was decreased in H2O2 induced SCs, while it increased significantly after addition of PQQ (P < 0.05).

CONCLUSIONPQQ has a protective effect on oxidative stress-induced apoptosis of SCs.

Apoptosis ; drug effects ; Benzimidazoles ; Cell Nucleus ; drug effects ; DNA Fragmentation ; Fluorescent Dyes ; Humans ; Hydrogen Peroxide ; pharmacology ; Malondialdehyde ; metabolism ; Oxidants ; pharmacology ; Oxidative Stress ; Pyrroles ; pharmacology ; Quinine ; pharmacology ; Quinolines ; pharmacology ; Schwann Cells ; cytology ; drug effects ; Superoxide Dismutase ; metabolism

OBJECTIVETo explore the effects of Candesartan cilexetil on the rats exposed to silica.

METHODNinety-six wistar rats were randomly divided into model-group, intervention-group and control-group (32 rats a group). The intervention-group, model-group and control group were orally exposed to Candesartan cilexetil (10 mg/kg) and normal solution for a week, respectively. Then the model and intervention groups were exposed to silica by intratracheal infusion of silica dust suspension (50 mg/ml), the control group was exposed to 0.5 ml normal solution for 2 days. On the 3rd, 7th, 14th and 28th days after exposure to silica, 8 rats of each group were sacrificed, respectively. The samples of lung tissues were collected. The lung/body coefficients were detected. The pathological examinations were performed by HE and Masson staining. The levels of ACE in the lung tissues were observed by immunochemistry staining. The levels of TGF-β1 and Ang II in the BALF were examined by ELISA.

RESULTSOn the 3rd, 7th, 14th and 28th days after exposure, the levels of alveolitis and pulmonary fibrosis in the intervention group were significantly alleviated as compared with model group, and the lung/body coefficients in the intervention group, which were significantly lower than those in model group respectively (P < 0.01). As compared with control group, the levels of TGF-β1 and Ang II of the BALF in the model and intervention groups significantly enhanced (P < 0.01). As compared with model group, the levels of TGF-β1 and Ang II of the BALF in the intervention group significantly decreased (P < 0.01). As compared with control group, the levels of ACE of the lung tissues in the model and intervention groups significantly increased (P < 0.01). But the level of ACE of the lung tissues in the intervention group was significantly lower than that in the model group (P < 0.01).

CONCLUSIONThe early Candesartan cilexetil intervention could significantly decrease the levels of alveolitis and lung fibrosis, declined the levels of TGF-β(1) and Ang II of BALF and downregulated the expression level of ACE in lung tissues in rats exposed to silica.

Angiotensin II ; metabolism ; Animals ; Benzimidazoles ; pharmacology ; therapeutic use ; Bronchoalveolar Lavage Fluid ; Female ; Lung ; drug effects ; pathology ; Male ; Pulmonary Fibrosis ; chemically induced ; drug therapy ; Rats ; Rats, Wistar ; Silicon Dioxide ; toxicity ; Tetrazoles ; pharmacology ; therapeutic use ; Transforming Growth Factor beta1 ; metabolism