Stretchable and conformable variable stiffness device through an electrorheological fluid.

Stiffness variations extend creatures' functions and capabilities to deal with complex environments. In this study, we proposed an electrorheological fluid-based variable stiffness device, named VSERF, made up of soft materials. Our device is soft, thin, and stretchable so that it can conform to surfaces with complex morphologies. The stiffness of the VSERF device can be continuously, independently, and reversibly adjusted by applying an electric field. It achieves 14.8-times compressive stiffness variation and 3.5-times tangential stiffness variation when the electric field intensity increases from 0 V mm-1 to 750 V mm-1. The VSERF device is able to return to its initial shape after removing the external force and electric field, allowing it to be reused. The effects of stretching and bending on the device's capability of stiffness variations are investigated experimentally and the results show that the stiffness variation is unaffected by a stretching strain of up to 20% and a bending curvature of up to 50 m-1. Finally, we show that the VSERF device is capable of conforming to complex surfaces (coral stones, pencils, and 3D printed cubes) in its inactive state, hanging on them with a weight of up to 80 g (19 times of its own weight) in its active state, and detaching when the electric field is removed. The device's short-term and long-term stabilities are experimentally investigated as well. The demonstration of the VSERF's attaching and detaching ability shows that the stiffness-variation device's adaptability to complex environments can be improved.

Effects of leaf colorness, pigment contents and allelochemicals on the orientation of the Asian citrus psyllid among four Rutaceae host plants.

BACKGROUND: Asian citrus psyllid (ACP) is the primary vector responsible for the transmission of the phloem-limited bacteria Candidatus Liberibacter spp., associated with huanglongbing (HLB), which causes great loss to the citrus industry. Although the roles of leaf color and volatile compounds in the orientation of ACP have been proven, the quantification of color and allelochemicals in the host plant are kept unclear, especially in wild citrus germplasms. RESULTS: Chongyi wild mandarin significantly attracted more ACP than wild Hong Kong kumquat, 'Gannan zao' navel orange and orange jasmine did in the four-choice and olfactometer assays. The color parameters of the tender leaves from Chongyi wild mandarin and 'Gannan zao' were similar. The yellow color in both of them was less saturated than that of the other two plants species, but Chongyi wild mandarin had significant lower carotenoid content (P < 0.05). Notably metabolic profiling differences were observed among the healthy tender shoots from the four tested plants via UPLC-QQQ-MS and GC-MS analyses. Comparing with the other three plant species, 66 and 50 metabolites with significantly different contents in Chongyi wild mandarin were selected as UPLC-identified and GC-identified metabolites of interest (P < 0.05), respectively. Flavonoids accounted for a large group of secondary metabolites of interest, which may function as stimulants or repellents of ACP. Higher content of salicylic acid o-hexoside and lower content of (+)-jasmonic acid in Chongyi wild mandarin may lead to higher amount of methyl salicylate (an ACP attractant) and lower amount of trans-ocimene (an attractant to herbivores' natural enemies) as well as the suppression of JA-mediated wounding response. This kind of synergistic or antagonistic effect among the metabolites differentially accumulated in Chongyi wild mandarin made it a more attractive host plant to ACP. CONCLUSIONS: Less saturated yellow color, high amount of attractants, low amount of repellents and insensitivity of JA-mediated wounding response are the four possible reasons why Chongyi wild mandarin attracted more ACP. This work may shed light on the olfactory and visual response of ACP to wild citrus germplasm hosts, and suggest the feasibility of developing ACP attractants or repellents patterned on potential metabolites.

Design and control of a multi-mobile-robot cooperative transport system based on a novel six degree-of-freedom connector.

Multi-robot cooperative object transport on uneven roads is challenging. The key barrier is dealing with nonholonomic and rigid-formation motion constraints. In this study, to alleviate the influence of these constraints on a multi-robot cooperative transport system (MRCTS), a six degree-of-freedom connector capable of sensing three-axial displacements, three-axial forces, and three-axial angular displacements is designed and employed. Based on the local displacements derived from each connector, we develop a position calibration method to calculate the relative position of each robot and achieve a centralized control strategy. Based on the forces sensed by each connector, we design a decentralized control strategy to accomplish cooperative transport in which a leader robot guides the follower robots toward a destination by applying forces, instead of centralized information broadcasting. The experimental results show that the MRCTS works well on an uneven surface, and the tracking errors are within the design stroke of the connectors, demonstrating the effectiveness of the design and control methods of the MRCTS.

Robotic mobile and mirror milling of large-scale complex structures.

Robotization, miniaturization and portability have become the new development trend of milling equipment for large-scale complex structures, and the robotic mobile and mirror milling technology has reached remarkable progress in practical production.

PneuNet: deep learning for COVID-19 pneumonia diagnosis on chest X-ray image analysis using Vision Transformer.

A long-standing challenge in pneumonia diagnosis is recognizing the pathological lung texture, especially the ground-glass appearance pathological texture. One main difficulty lies in precisely extracting and recognizing the pathological features. The patients, especially those with mild symptoms, show very little difference in lung texture, neither conventional computer vision methods nor convolutional neural networks perform well on pneumonia diagnosis based on chest X-ray (CXR) images. In the meanwhile, the Coronavirus Disease 2019 (COVID-19) pandemic continues wreaking havoc around the world, where quick and accurate diagnosis backed by CXR images is in high demand. Rather than simply recognizing the patterns, extracting feature maps from the original CXR image is what we need in the classification process. Thus, we propose a Vision Transformer (VIT)-based model called PneuNet to make an accurate diagnosis backed by channel-based attention through X-ray images of the lung, where multi-head attention is applied on channel patches rather than feature patches. The techniques presented in this paper are oriented toward the medical application of deep neural networks and VIT. Extensive experiment results show that our method can reach 94.96% accuracy in the three-categories classification problem on the test set, which outperforms previous deep learning models.

A pipeline inspection robot for navigating tubular environments in the sub-centimeter scale.

In complex systems like aircraft engines and oil refinery machines, pipeline inspection is an essential task for ensuring safety. Here, we proposed a type of smart material-driven pipeline inspection robot (weight, 2.2 grams; length, 47 millimeters; diameter, <10 millimeters) that could fit into pipes with sub-centimeter diameters and different curvatures. We adopted high-power density, long-life dielectric elastomer actuators as artificial muscles and smart composite microstructure-based, high-efficiency anchoring units as transmissions. Fast assembling of components using magnets with an adjustable number of units was used to fit varying pipeline geometries. We analyzed the dynamic characteristics of the robots by considering soft material's unique properties like viscoelasticity and dynamic vibrations and tuned the activation voltage's frequency and phase accordingly. Powered by tethered cables from outside the pipe, our peristaltic pipeline robot achieved rapid motions horizontally and vertically (horizontal: 1.19 body lengths per second, vertical: 1.08 body lengths per second) in a subcentimeter-sized pipe (diameter, 9.8 millimeters). Besides, it was capable of moving in pipes with varying geometries (diameter-changing pipe, L-shaped pipe, S-shaped pipe, or spiral-shaped pipe), filled media (air or oil), and materials (glass, metal, or carbon fiber). To demonstrate its capability for pipeline inspection, we installed a miniature camera on its front and controlled the robot manually from outside. The robot successfully finished an inspection task at different speeds.

[Characteristics, Ozone Formation Potential, and Source Apportionment of VOCs During the COVID-19 Epidemic in Xiong'an].

Many restrictive measures were implemented in China from January-February 2020 to control the rapid spread of COVID-19. Many studies reported that the COVID-19 lockdown impacted PM2.5, SO2, volatile organic compounds (VOCs), etc. VOCs play important roles in the production of ozone and PM2.5. Ambient VOCs in Xiong'an were measured from December 25, 2019 to January 24, 2020 (prior to epidemic prevention, P1) and from January 25, 2020 to February 24, 2020 (during epidemic prevention, P2) through a VOCs online instrument. In the study, VOCs characteristics and ozone generation potential (OFP) of ambient VOCs were analyzed, and source apportionment of VOCs were analyzed by using Positive Matrix Factorization (PMF). The results showed that φ(TVOCs) during epidemic prevention and control was 45.1×10-9, which was approximately half of that before epidemic prevention and control (90.5×10-9). The chemical composition of VOCs showed significant changes after epidemic prevention and control, the contribution rate of alkanes increased from 37.6% to 53.8%, and the contribution rate of aromatic hydrocarbons and halogenated hydrocarbons decreased from 13.3% and 12.0% to 7.5% and 7.8%, respectively. Aromatic hydrocarbons, halogenated hydrocarbons, and OVOCs decreased by more than 60%. Seven types of the top ten species were the same before and during the epidemic prevention and control, mainly low-carbon alkanes, olefins, aldehydes, and ketones. Dichloromethane, trichloromethane, and BTEXs decreased significantly. The OPP was 566 µg·m-3 and 231 µg·m-3 in P1 and P2, respectively. The OPP of VOCs decreased by more than 30%. The proportion of OFP contribution of aromatic hydrocarbons decreased significantly after the epidemic prevention and control, and the proportion of OFP contribution of alkanes and alkynes increased significantly. Positive matrix factorization (PMF) was then applied for VOCs sources apportionment. Six sources were identified, including background sources, oil-gas volatile sources, combustion sources, industrial sources, solvent use sources, and vehicle exhaust sources. The results showed that after the epidemic prevention and control, the contribution rate of solvent use sources to TVOCs decreased from 24% to 9%. The contribution rates of background sources, oil-gas volatile sources, and combustion sources increased from 13%, 34%, and 24% to 6%, 14%, and 13%, respectively. The relative contributions of vehicle exhaust sources before and after epidemic prevention and control were 21% and 18%, respectively. The observation points were affected by the emission of VOCs from paroxysmal industrial sources before the epidemic prevention and control. The emission was stopped after the epidemic prevention and control, and its contribution rate was reduced from 22% before the epidemic prevention and control to 1%. The concentrations of industrial sources, solvent sources, motor vehicle tail gas sources, and combustion sources decreased by 97%, 82%, 61%, and 15%, respectively, after the epidemic prevention and control. The concentration of background sources remained stable, and the concentration of oil and gas volatile sources increased by 7%. The control of production and traffic activities cannot reduce the emission of VOCs from oil and gas volatile sources, which is the focus of VOCs control in Xiong'an.

Attenuated Actinobacillus pleuropneumoniae as a bacterial vector for expression of Mycoplasma hyopneumoniae P36 gene.

BACKGROUND: Actinobacillus pleuropneumoniae and Mycoplasma hyopneumoniae are causative agents of porcine pneumonia. Over the last few years, attenuated A. pleuropneumoniae live vaccines have been shown to provide protection against A. pleuropneumoniae infection. We postulated that attenuated A. pleuropneumoniae could additionally be used as a vaccine vector for protection against M. hyopneumoniae. METHODS: A mutant strain of A. pleuropneumoniae, SLW36, was constructed by replacing the urease structural gene of mutant strain SLW03 of A. pleuropneumoniae with the L-lactate dehydrogenase gene (p36) of M. hyopneumoniae by transconjugation and counter selection. The urease function and the growth kinetics of SLW36 were measured. Protein expression of P36 was analyzed by sodium dodecylsulfate-polyacrylamide gel electrophoresis and western blotting. The attenuated virulence and immunity of SLW36 were analyzed in a mouse model. RESULTS: The mutant strain SLW36 was urease negative and four-fold less virulent than the parental strain SLW03. There were no differences in expression levels of p36 at different culture time-points and the foreign gene was stable after in vitro passage. Immunoglobulin G responses against p36 antigen and M. hyopneumoniae whole-cell antigen were detected. CONCLUSIONS: The mutant strain SLW36 can induce antibody against p36 and M. hyopneumoniae. The mutant strain SLW36 has the potential to be used as a live vaccine for protection against A. pleuropneumoniae and M. hyopneumoniae. Studies in pigs are needed to confirm protective levels of antibodies and to check for rare side-effects of the vaccine.

Curcumin enhanced antiproliferative effect of mitomycin C in human breast cancer MCF-7 cells in vitro and in vivo.

AIM: To investigate the efficacy of mitomycin C (MMC) in combination with curcumin in suppressing human breast cancer in vitro and in vivo. METHODS: Human breast cancer MCF-7 cells were used. Cell viability was measured using MTT assay. The cell cycle phase was detected with flow cytometric analysis. Cell cycle-associated proteins were examined using Western blot analysis. MCF-7 breast cancer xenografts were established to monitor tumor growth and cell cycle-associated protein expression. RESULTS: Curcumin inhibited MCF-7 breast cancer cell viability in a concentration-dependent manner (IC(50) value=40 µmol/L). Similarly, MMC inhibited the cell viability with an IC(50) value of 5 µmol/L. Combined treatment of MMC and curcumin showed a synergistic antiproliferative effect. In the presence of curcumin (40 µmol/L), the IC(50) value of MMC was reduced to 5 µmol/L. In MCF-7 xenografts, combined administration of curcumin (100 mg/kg) and MMC (1-2 mg/kg) for 4 weeks produced significantly greater inhibition on tumor growth than either treatment alone. The combined treatment resulted in significantly greater G(1) arrest than MMC or curcumin alone. Moreover, the cell cycle arrest was associated with inhibition of cyclin D1, cyclin E, cyclin A, cyclin-dependent kinase 2 (CDK2) and CDK4, along with the induction of the cell cycle inhibitor p21 and p27 both in MCF-7 cells and in MCF-7 xenografts. These proteins were regulated through p38 MAPK pathway. CONCLUSION: The results suggest that the combination of MMC and curcumin inhibits MCF-7 cell proliferation and cell cycle progression in vitro and in vivo via the p38 MAPK pathway.

[Pathologic observation on animal model of silicosis].

OBJECTIVE: To explore the pathological changes of pulmonary fibrosis induced by SiO2 in rats and pigs. METHODS: The silicosis models in rats and pigs were established by non-exposure method. The pathologic changes in lung tissues of rats and pigs were observed with HE staining under a light microscopy and under a transmission electron microscopy (TEM), the expression of cytokines was detected by immunohistochemistry. RESULTS: (1) The main pathologic changes of silicosis models in rats and pigs included: in 7 ∼ 15 days after treatment, silica dusts, dust cells, a lot of macrophages, lung epithelial cells, a few neutrophils, macrophage alveolar inflammation and nodules of stage I were found in alveolar space; in 30 ∼ 90 days after treatment, many nodules of stage I-III or IV with lymphocytes infiltration were observed in respiratory bronchioles, alveoli, interlobular septa, the subpleural and around blood vessels and bronchi. (2) The expression levels of CK protein, SP-A protein, CD68, b-FGF, TNF-α, IL-6, TGF-ß1, NFKappa/P50, Kappa/P65 and VEGF reduced with exposure time, but still were higher than those of the control. (3) The shed alveolar type I cells, proliferation of alveolar type II cells or macrophages and activated cellular function induced by silica were observed under TEM. CONCLUSION: The development of pulmonary fibrosis in silicosis models corresponded with the process from macrophages alveolar inflammation to pulmonary fibrosis.

[Study of combination methods for formula composition of Chinese herbal medicines and their components].

Chinese prescription is composed of Chinese herbal medicines according to "seven compatible relations" and "sovereign, minister, assistant and courier" principles. There are many methods in the research on combination and composition of Chinese herbal medicines. These methods are classified into traditional model and modern model. For the time being, compatibility study of traditional Chinese herbal medicines has developed from traditional model to modern model. The traditional model mainly studies the effects and mechanisms of the whole and split formulae in medical crude drug level, while the modern model mainly studies the effects and mechanisms of Chinese herbal medicine compositions in components combination level. Moreover, quantitative analysis becomes probable by modern model method. Now, setting up of new components combination model and optimal composition methods will not only develop the combination and the composition of Chinese herbal medicines from medicinal crude drug level to components composition level, but also get new formulae which have clear components and effects, and action targets and mechanisms. It will effectively promote the development of Chinese medicine formula.

Pharmacological characterization of a novel nonpeptide antagonist of the human gonadotropin-releasing hormone receptor, NBI-42902.

Suppression of the hypothalamic-pituitary-gonadal axis by peptides that act at the GnRH receptor has found widespread use in clinical practice for the management of sex-steroid-dependent diseases (such as prostate cancer and endometriosis) and reproductive disorders. Efforts to develop orally available GnRH receptor antagonists have led to the discovery of a novel, potent nonpeptide antagonist, NBI-42902, that suppresses serum LH concentrations in postmenopausal women after oral administration. Here we report the in vitro and in vivo pharmacological characterization of this compound. NBI-42902 is a potent inhibitor of peptide radioligand binding to the human GnRH receptor (K(i) = 0.56 nm). Tritiated NBI-42902 binds with high affinity (K(d) = 0.19 nm) to a single class of binding sites and can be displaced by a range of peptide and nonpeptide GnRH receptor ligands. In vitro experiments demonstrate that NBI-42902 is a potent functional, competitive antagonist of GnRH stimulated IP accumulation, Ca(2+) flux, and ERK1/2 activation. It did not stimulate histamine release from rat peritoneal mast cells. Finally, it is effective in lowering serum LH in castrated male macaques after oral administration. Overall, these data provide a benchmark of pharmacological characteristics required for a nonpeptide GnRH antagonist to effectively suppress gonadotropins in humans and suggest that NBI-42902 may have clinical utility as an oral agent for suppression of the hypothalamic-pituitary-gonadal axis.

Modulation of AßPP and GSK3ß by Endoplasmic Reticulum Stress and Involvement in Alzheimer's Disease.

Alzheimer's disease (AD) is a dementia disease with neuronal loss and synaptic impairment. This impairment is caused, at least partly, by the generation of two main AD hallmarks, namely the hyperphosphorylated tau protein comprising neurofibrillary tangles and senile plaques containing amyloid-ß (Aß) peptides. The amyloid-ß protein precursor (AßPP) and glycogen synthase kinase-3ß (GSK3ß) are two main proteins associated with AD and are closely correlated with these hallmarks. Recently, both of the proteins were reported to be modulated by endoplasmic reticulum stress (ERS) and are involved in the pathogenesis of AD. The mechanism of ERS plus the modulation of AßPP processing and GSK3ß activity by ERS in AD are summarized and explored in this review.

[The changes and clinical significance of serum tumor necrosis factor-alpha and endothelin level in bee sting poisoning].

OBJECTIVE: To investigate the change of serum tumor necrosis factor-alpha (TNFalpha) and endothelin (ET) levels and their clinical significance in patients with bee sting poisoning. METHODS: TNFalpha and ET were measured in 97 patients with bee sting poisoning and the results were compared with those in 35 healthy controls. The 97 patients were divided into three groups i.e. mild poisoning group, moderate poisoning group and severe poisoning group and they were also divided according to prognosis into death group and survival group. RESULTS: The levels of serum TNFalpha (1.36 +/- 0.37) microg/L and ET (55.20 +/- 12.60) ng/L in the slight poisoning group increased a little, but they were not significantly different from those in the controls (1.09 +/- 0.25) microg/L and (50.90 +/- 8.80) ng/L (P > 0.05). In the moderate and severe poisoning groups the levels of serum TNFalpha (2.82 +/- 0.79) microg/L, (4.02 +/- 0.93) microg/L and plasma ET (139.30 +/- 58.80) ng/L, (210.50 +/- 86.30) ng/L were significantly higher than those in the controls (P < 0.01). The levels in the severe poisoning group were much higher than those in the moderate poisoning group and the latter much higher than those in the controls. The levels of serum TNFalpha (4.53 +/- 0.89) microg/L and plasma ET (267.50 +/- 98.70) ng/L in the death group were much higher than those in the survival group (2.40 +/- 0.82) microg/L, (107.60 +/- 57.90) ng/L (P < 0.01). The levels of serum TNFalpha were positively correlated with those of plasma ET (P < 0.01). CONCLUSIONS: TNFalpha and ET may be involved in the pathogenesis of bee sting poisoning. It is shown that the higher the levels of serum TNFalpha and plasma ET, the severer degree of the poisoning and the higher fatality rate. Serum TNFalpha and plasma ET levels may be important clinical index in judging the patients, condition and their prognosis in bee sting poisoning. It was an important clinical significance, that may be useful for medicating with antagonist and inhibitor against TNFalpha and ET to prevention and depress death rate in the patients with bee sting poisoning.

3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)- 6-methylpyrimidin-2,4-dione (NBI 42902) as a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor. Design, synthesis, and in vitro and in vivo characterization.

Further structure-activity relationship studies of a series of substituted uracils at the 1, 3, and 5 positions resulted in the discovery of several potent antagonists of the human gonadotropin-releasing hormone receptor. Uracils bearing a side chain derived from phenylglycinol at the 3-position were shown to be orally bioavailable in monkeys. 3-[(2R)-Amino-2-phenylethyl]-1-(2,6-difluorobenzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidin-2,4-dione (R-13b, NBI 42902) displayed subnanomolar binding affinity (K(i) = 0.56 nM) and was a potent functional antagonist (IC(50) = 3.0 nM in Ca(2+) flux assay) at the human GnRH receptor. It also bound to the monkey GnRH receptor with high affinity (K(i) = 3.9 nM). In addition, R-13bhad good plasma exposure in cynomolgus monkeys after oral administration, with a C(max) of 737 ng/mL and an AUC of 2392 ng/mL.h at a 10 mg/kg dose. Moreover, oral administration of R-13b to castrated male cynomolgus monkeys resulted in a significant decrease in serum levels of luteinizing hormone. These results demonstrate that compounds from this series of uracils are potent GnRH antagonists with good oral bioavailability and efficacy in nonhuman primates.

Design of 2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7-dipropylaminopyrazolo[1,5-a]pyrimidine (NBI 30775/R121919) and structure--activity relationships of a series of potent and orally active corticotropin-releasing factor receptor antagonists.

We have previously shown that 3-phenylpyrazolo[1,5-a]pyrimidines exemplified by 8 were potent antagonists of the human corticotropin-releasing factor-1 receptor. A series of 3-pyridylpyrazolo[1,5-a]pyrimidines 15, 25-30, 34, and 35 containing a weakly basic pyridine ring at the 3-position of the bicyclic nucleus was designed to reduce lipophilicity from the initial leads such as 7. Here, we showed that these 3-pyridyl compounds exhibited potent antagonists at the human CRF(1) receptor. Moreover, the hydrophilic and weakly basic pyridine moiety increased the water solubility of some analogues. Compound 26 h exhibited good binding affinity at the human CRF(1) receptor with a K(i) value of 3.5 nM. As a functional antagonist, it dose-dependently inhibited CRF-stimulated cAMP production in cells expressing the CRF(1) receptor (IC(50) = 50 nM), and CRF-stimulated ACTH release from cultured rat pituitary cells (IC(50) = 20 nM). 26 h had a log P value of 4.9 and water solubility of greater than 10 mg/mL. Pharmacokinetic studies in rats showed that 26 h was orally bioavailable and able to penetrate into the brain. 26 h has been demonstrated in vivo efficacy in animal behavioral models that measure anxiolytic activity. These results suggest that analogues from this series were potent CRF(1) receptor antagonists with proper physicochemical properties and good pharmacokinetic profiles. 26 h was developed into a clinical compound and exhibited efficacy in patients with major depression.

[Application of T grain technique to the diagnosis of lung disease and analysis of its image quality].

OBJECTIVE: To compare the image quality of T grain green sensitive film (TML-1) and Lanex Gd(2)O(2)S rare earth intensifying screen with that of XK-1 blue sensitive film and calcium tungstate (CaWO(4)) intensifying screen, and to study the application of T grain technic to the diagnosis of lung diseases. METHODS: 160 coal miners were randomly selected to take both TML-1 and XK-1 chest film of high kV radiographs at the same time. Silver halide granule, fluorescence of intensifying screen, radiographic parameters, the density at different points in the lung and chest radiographs were observed. RESULTS: Silver grains in TML-1 film were more homogeneous in distribution than in XK-1 film. Luminous intensity of Lanex Gd(2)O(2)S rare earth intensifying screen was brighter than CaWO(4) intensifying screen in the same exposure. The exposure doses of TML-1 film was reduced to one third of XK-1 film. The density of chest radiographs was 0.24 to 2.74 in TML-1 film, and 0.30 to 2.60 in XK-1 film. There were greater exposure latitude and more informations in TML-1 film. By apertured-disc observation, the fine structure of lung in TML-1 film was clearer than in XK-1 film, the shape was more concrete and reliable, visualizability was stronger. CONCLUSION: T grain technique may obviously improve the clearness and resolution of image, and enhance the transmission of information, as well as increase the diagnostic informations.

Ginsenoside rb1 reduces isoproterenol-induced cardiomyocytes apoptosis in vitro and in vivo.

Cardiomyocytes apoptosis can lead to heart failure. Conventional and alternative drugs, such as Chinese herbal remedies, have been developed to target cardiomyoblast cells apoptosis. In this study, we investigated the effects of ginsenoside Rb1 (Rb1), an active compound, which is isolated from Notoginseng and Ginseng on isoproterenol-(ISO-) induced apoptosis in rat cardiomyocytes and its mechanism in vivo and in vitro. Rb1 reduced the ISO-induced apoptosis in rat cardiomyocytes and H9c2 cells. The effect of Rb1 was significantly suppressed by H89 (inhibitor for PKA), but not by C-1 (inhibitor for PKC). Based on in-cell blot analysis, the ISO-induced PKA and PKC expressions were decreased by Rb1, which was inhibited by H89, but not by C-1. The expressions of caspase-3 and caspase-9 were decreased after treatment with both ISO and Rb1, but with no change for caspase-8. Our results indicated that Rb1 reducing ISO-induced rat cardiomyocytes apoptosis may be involved in PKA and caspase-9 pathways.

Curcumin improves MMC-based chemotherapy by simultaneously sensitising cancer cells to MMC and reducing MMC-associated side-effects.

Mitomycin C (MMC) potently suppresses tumour growth. However, its use is limited by its severe toxicity to the kidney and bone marrow. The purpose of this study is to investigate whether the chemoprevention agent curcumin can reduce MMC-associated side-effects and improve MMC efficacy in a breast cancer xenograft model. We first determined the effectiveness of combined MMC and curcumin to inhibit in vitro cell growth and to regress in vivo tumour outgrowth. We then investigated the mechanisms associated with MMC/curcumin-induced cell death by examining the effect of MMC/curcumin treatment on apoptosis, the activation of caspase-3, 8 and 9 and the expression of bcl-2 and bax. We also evaluated the ability of curcumin to alleviate MMC-associated side-effects by comparing the levels of creatinine/blood urea nitrogen (Cr/BUN) and glutamic oxalacetic transaminase/glutamic pyruvic transaminase (GPT/GOT) in serum between animals receiving MMC alone and MMC/curcumin. Curcumin significantly sensitised MCF-7 and MDA-MB-231 cells to MMC-induced cell death and improved MMC's ability to regress MCF-7 xenograft. MMC and curcumin together synergistically enhanced apoptosis in MCF-7 cells and the apoptosis most likely resulted from both the activation of caspases and modulation of bcl-2/bax expression. Most importantly, the inclusion of curcumin in MMC treatment decreased MMC-caused severe side-effects evidenced by significant improvement in the kidney function. Enhancing the tumoricidal effect of MMC, curcumin greatly reduces MMC-associated severe side-effects. Therefore, the combination treatment of MMC and curcumin may be of significant therapeutic benefit in treating breast cancer.

Identification of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives as novel GnRH receptor antagonists.

A novel series of 2-(4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-3-yl)-ethylamine derivatives were designed and synthesized as GnRH receptor antagonists. SAR studies led to a series of highly active molecules against both the rat and human receptors. Furthermore, one potent compound, 17j, demonstrated dose-dependent LH suppression in castrated rats.