Dopamine D3 receptor regulates basal but not amphetamine-induced changes in pain sensitivity in mice

Pain is a complex and subjective experience that involves not only the transduction of noxious stimuli by nociceptive fibers, but also the cognitive and emotional processing by the brain. Previous studies on the transmission of nociception suggest that the activation of mesolimbic dopamine (DA) system plays an important role in mediating the suppression of tonic pain. The aim of the current study was to examine the role of DA D3 receptor in modulating basal and amphetamine-induced changes in pain sensitivity in mice. We used wild-type and D3 receptor mutant mice and determined allodynia induced by both noxious heat (radiant heat) and mechanical (von Frey hair) stimuli. We show that D3 receptor mutant mice exhibit hypoalgesia in both the tail-flick test and von Frey hair test compared to wild-type mice. Amphetamine-induced hyperalgesia in both D3 receptor mutant and wild-type mice in the tail-flick test and von Frey hair test. There was no significantly difference in the relative change in pain sensitivity between wild-type and D3 receptor mutant mice in both the tail-flick test and von Frey hair test following amphetamine administration. These results suggest that the D3 receptor regulates the transmission of nociception. Moreover, amphetamine can lower pain threshold in mice.     

Diagnosis of pulmonary tuberculosis in HIV-positive patients by microscopic observation drug susceptibility assay

The microscopic observation drug susceptibility assay (MODS) is a novel and promising test for the early diagnosis of tuberculosis (TB). We evaluated the MODS assay for the early diagnosis of TB in HIV-positive patients presenting to Pham Ngoc Thach Hospital for Tuberculosis and Lung Diseases in southern Vietnam. A total of 738 consecutive sputum samples collected from 307 HIV-positive individuals suspected of TB were tested by smear, MODS, and the mycobacteria growth indicator tube method (MGIT). The diagnostic sensitivity and specificity of MODS compared to the microbiological gold standard (either smear or MGIT) were 87 and 93%, respectively. The sensitivities of smear, MODS, and MGIT were 57, 71, and 75%, respectively, against clinical gold standard (MODS versus smear, P<0.001; MODS versus MGIT, P=0.03). The clinical gold standard was defined as patients who had a clinical examination and treatment consistent with TB, with or without microbiological confirmation. For the diagnosis of smear-negative patients, the sensitivities of MODS and MGIT were 38 and 45%, respectively (P=0.08). The median times to detection using MODS and MGIT were 8 and 11 days, respectively, and they were 11 and 17 days, respectively, for smear-negative samples. The original bacterial/fungal contamination rate of MODS was 1.1%, while it was 2.6% for MGIT. The cross-contamination rate of MODS was 4.7%. In conclusion, MODS is a sensitive, specific, and rapid test that is appropriate for the detection of HIV-associated TB; its cost and ease of use make it particularly useful in resource-limited settings.     

Peptide-based inhibitors of the phagocyte NADPH oxidase

Phagocytes such as neutrophils, monocytes and macrophages play an essential role in host defenses against pathogens. To kill these pathogens, phagocytes produce and release large quantities of antimicrobial molecules such as reactive oxygen species (ROS), microbicidal peptides, and proteases. The enzyme responsible for ROS generation is called NADPH oxidase, or respiratory burst oxidase, and is composed of six proteins: gp91phox, p22phox, p47phox, p67phox, p40phox and Rac1/2. The vital importance of this enzyme in host defenses is illustrated by a genetic disorder called chronic granulomatous disease (CGD), in which the phagocyte NADPH oxidase is dysfunctional, leading to life-threatening recurrent bacterial and fungal infections. However, excessive NADPH oxidase activation and ROS over-production can damage surrounding tissues and participate in exaggerated inflammatory processes. As ROS production is believed to be involved in several inflammatory diseases, specific phagocyte NADPH oxidase inhibitors might have therapeutic value. In this commentary, we summarize the structure and activation of the phagocyte NADPH oxidase, and describe pharmacological inhibitors of this enzyme, with particular emphasis on peptide-based inhibitors derived from gp91phox, p22phox and p47phox.     

Suppression of tumor invasion and migration in breast cancer cells following delivery of siRNA against Stat3 with the antimicrobial peptide PR39

PR39, a porcine cathelicidin rich in the amino acids proline and arginine can interact with the negatively charged component of the cell surface, and rapidly penetrate cell membranes. Therefore, we hypothesized that PR39, as a membrane penetrating peptide (MPP), could be exploited as a novel carrier to deliver siRNA into the cell cytoplasm in order to knockdown target gene expression. Firstly, a complex formation of PR39 with siRNA and its cellular colocalization were investigated in our studies. Further, we optimized the ratio of the PR39/siRNA complex, cell/complex incubation period and the concentration of siRNA. The results suggest that PR39 could form a complex with siRNA, and mediate translocation of the siRNA into 4T1 cells. The optimal ratio of siRNA with PR39 was 1:90 which was found to have a maximum Stat3 gene silencing effect after 48?h treatment. Moreover, 4T1 cell proliferation, cell cycle, invasion and migration were investigated. The results suggested that Stat3 knockdown could not result in 4T1 cell proliferation inhibition and cell cycle arrest, while invasion and migration of 4T1 cells were strongly inhibited. Notably, the data also showed that in addition to inhibition of carcinogenesis, single PR39 may play a role in cell invasion and migration. PR39 and Stat3 siRNA displayed synergistic biological effects in inhibiting cell invasion and migration of 4T1 cells, which was more prominent compared with the popular Lipofectamine delivery system.     

从医患的角度看人们对鹿茸的消费心理

本文根据个人多年工作经验,从医生和消费者两个层面归纳分析人们对鹿茸的消费需求和消费心理,希望能对鹿产品开发和培育消费市场有益,从而让更多的人正确认识并应用鹿产品造福百姓。     

A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis

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γ-Secretase inhibitor enhances antitumour effect of radiation in Notch-expressing lung cancer

Background:

Notch receptor has an important role in both development and cancer. We previously reported that inhibition of the Notch3 by γ-secretase inhibitor (GSI) induces apoptosis and suppresses tumour proliferation in non-small-cell lung cancer. Although radiation is reported to induce Notch activation, little is known about the relationship between radiation and Notch pathway.

Methods:

We examined the effect of combining GSI and radiation at different dosing in three Notch expressing lung cancer cell lines. The cytotoxic effect of GSI and radiation was evaluated using MTT assay and clonogenic assay in vitro and xenograft models. Expressions of Notch pathway, mitogen-activated protein kinase (MAPK) pathway and Bcl-2 family proteins were investigated using western blot analysis.

Results:

We discovered that the antitumour effect of combining GSI and radiation was dependent on treatment schedule. γ-Secretase inhibitor administration after radiation had the greatest growth inhibition of lung cancer in vitro and in vivo. We showed that the combination induced apoptosis of lung cancer cell lines through the regulation of MAPK and Bcl-2 family proteins. Furthermore, activation of Notch after radiation was ameliorated by GSI administration, suggesting that treatment with GSI prevents Notch-induced radiation resistance.

Conclusion:

Notch has an important role in lung cancer. Treatment with GSI after radiation can significantly enhance radiation-mediated tumour cytotoxicity.