Synergistic effects of Rapamycin and Fluorouracil to treat a gastric tumor in a PTEN conditional deletion mouse model.

The tumor suppressor gene phosphatase and tensin homolog (PTEN) in PI3K/Akt/mTOR pathway is essential in inhibiting tumor growth and metastasis. However, whether the mutation of PTEN gene could induce tumorigenesis and impact the treatment of gastric cancer is still unclear. The purpose of the study was to investigate the combined treatment of gastric tumorigenesis using Rapamycin and Fluorouracil (5-Fu) through interfering with the Akt/mTOR pathway in a mouse model with PTEN conditional deletion. Three groups of mice were exposed for 5 days to Rapamycin and 5-Fu separately and together. The gene expression of the Akt/mTOR pathway, the protein expression of caspase-3 and p-Akt, p-S6K and p-4EBP1, and the pathological changes in stomachs were analyzed. Our study demonstrates that the conditional PTEN deletion in the cells of glandular stomach induces hyperplastic gastric tumors in mice. The combined Rapamycin administration with 5-Fu resulted in better outcomes than their separate administration for the treatment of gastric cancer by inhibiting the mTOR signal pathway. Our study indicates that Rapamycin has a synergistic interaction with chemotherapeutic 5-Fu, and demonstrates a potential therapeutic combination treatment on glandular stomach tumor with PTEN functional absence or aberrantly activated Akt/mTOR pathway. It provides important insights into the inhibition of the Akt/mTOR pathway in gastric cancer clinical therapy.

Occupational burnout analysis of border guards in the background of COVID-19 / 中国职业医学

@#Objective To analyze the occupational burnout status and its influencing factors of border guards in the prevention （ - ）Methods and control of coronavirus disease COVID 19 . A total of 1 313 border guards who participate in the prevention and control of epidemic diseases were selected as research subjects using the random cluster sampling method. Military Occupational Burnout Scale and Military Occupational Stress Scale were used to investigate the occupational burnout status and Results occupational stress in the research subjects. The median and 25th and 75th percentiles of military occupational （ ， ） （ ， ）， burnout and occupational stress total scores were 9.0 3.0 15.0 and 76.0 70.0 86.0 respectively. About 73.1% of the subjects were suffered from high occupational stress. The results of multiple linear regression analysis indicated that the higher the scores of interpersonal relationship, military special life, work pressure, unclear role and leadership ability factor in P occupational stress, and the lower the score of personal development, the more serious the occupational burnout (all <0.05 ) ， after excluding the influence of confounding factors; subjects with panic psychology inconvenience caused by closed ， management fear on accountability for poor prevention and no personal hobbies had more serious occupational burnout than （ P ） Conclusion - ， subjects without those factors all <0.05 . In the period of COVID 19 prevention the level of occupational burnout and occupational stress of border guards were generally low. The occupational burnout was mainly affected by occupational stress and fear of the epidemic.

A highly-sensitive "turn on" probe based on coumarin ß-diketone for hydrazine detection in PBS and living cells.

Herein, a new "turn on" fluorescent probe C-1 is developed to specifically detect hydrazine using coumarin nucleus as the fluorophore and ß-diketone as the recognition group. The probe shows high selectivity towards hydrazine over other common ions and amine-containing species, as well as good water solubility and quantitative detectability of hydrazine in concentration range of 1-200 µM. The detection limit is as low as 1.89 ppb, which is lower than the threshold set by EPA (10 ppb). Probe-coated filter papers are confirmed to detect gaseous hydrazine successfully through obvious fluorescence color changes. In addition, the probe has been verified to detect hydrazine in actual water environment and living cells.

Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway.

Atorvastatin (ATO) is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor widely used to treat hypercholesterolemia. However, clinical application is limited by potential hepatotoxicity. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidants, and oxidative stress is implicated in statin-induced liver injury. This study investigated mechanisms of ATO-induced hepatotoxicity and potential mitigation by Nrf2 signaling. ATO reduced Nrf2 and antioxidant enzyme superoxide dismutase-2 (SOD2) expression in human hepatocarcinoma HepG2 cells. ATO also induced concentration-dependent HepG2 cell toxicity, reactive oxygen species (ROS) accumulation, and mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential (MMP) and cellular adenosine triphosphate (ATP). Further, ATO induced mitochondria-dependent apoptosis as indicated by increased Bax/Bcl-2 ratio, cleaved caspase-3, mitochondrial cytochrome c release and Annexin V-fluorescein isothiocyanate/propidium iodide staining. Tert-butylhydroquinone enhanced Nrf2 and SOD2 expression, and partially reversed ATO-induced cytotoxicity, ROS accumulation, MMP reduction, ATP depletion and mitochondria-dependent apoptosis. In conclusion, the present study demonstrates that ATO induces mitochondrial dysfunction and cell apoptosis in HepG2 cells, at least in part, via inhibition of the Nrf2 pathway. Nrf2 pathway activation is a potential prevention for ATO-induced liver injury.

PM2.5 obtained from urban areas in Beijing induces apoptosis by activating nuclear factor-kappa B.

BACKGROUND: Particulate matter (PM), which has adverse effects on citizen health, is a major air pollutant in Beijing city. PM2.5 is an indicator of PM in urban areas and can cause serious damage to human health. Many epidemiological studies have shown that nuclear factor-kappa B (NF-κB) is involved in PM2.5-induced cell injury, but the exact mechanisms are not well understood. METHODS: The cytotoxic effects of PM2.5 at 25-1600 µg/ml for 24 h were determined by MTT assay in Chinese hamster ovary cells (CHO) cells. Flow cytometry was used to determine the apoptosis rate induced by PM2.5. The destabilized enhanced green fluorescent protein (d2EGFP) green fluorescent protein reporter system was used to determine the NF-κB activity induced by PM2.5. The expression of pro-apoptotic Bcl-2-associated death promoter (BAD) proteins induced by PM2.5 was determined by western blotting to explore the relationship between PM2.5 and the NF-κB signaling pathway and to determine the toxicological mechanisms of PM2.5. RESULTS: PM2.5 collected in Beijing urban districts induces cytotoxic effects in CHO cells according to MTT assay with 72.28% cell viability rates even at 200 µg/ml PM2.5 and flow cytometry assays with 26.97% apoptosis rates at 200 µg/ml PM2.5. PM2.5 increases the activation levels of NF-κB, which have maintained for 24 h. 200 µg/ml PM2.5 cause activation of NF-κB after exposure for 4 h, the activation peak appears after 13.5 h with a peak value of 25.41%. The average percentage of NF-κB activation in whole 24 h is up to 12.9% by 200 µg/ml PM2.5. In addition, PM2.5 decreases the expression level of the pro-apoptotic protein BAD in a concentration-dependent manner. CONCLUSIONS: PM2.5 induces NF-κB activation, which persists for 24 h. The expression of pro-apoptotic protein BAD decreased with increased concentrations of PM2.5. These findings suggest that PM2.5 plays a major role in apoptosis by activating the NF-κB signaling pathway and reducing BAD protein expression.

Complexation of triptycene-derived macrotricyclic polyether with paraquat derivatives, diquat, and a 2,7-diazapyrenium salt: guest-induced conformational changes of the host.

Complexation between a triptycene-derived macrotricyclic polyether containing two dibenzo-[30]-crown-10 cavities and different functionalized paraquat derivatives, diquat, and a 2,7-diazapyrenium salt in both solution and solid state was investigated in detail. It was found that depending on the guests with different terminal functional groups and structures, the macrotricyclic polyether could form 1:1 or 1:2 complexes with the guests in different complexation modes in solution and also in the solid state. Especially, the conformation of the macrotricyclic polyether was efficiently adjusted by the encapsulated guests, which was to some extent similar to substrate-induced fit of enzymes. Moreover, the binding and releasing of the guests in the complexes could be controlled by potassium ions.

Synthesis of triptycene-derived macrotricyclic host containing two dibenzo-[18]-crown-6 moieties and its complexation with paraquat derivatives: Li(+)-ion-controlled binding and release of the guests in the complexes.

A new triptycene-derived macrotricyclic host containing two dibenzo-[18]-crown-6 moieties was synthesized and shown to form 1:1 complexes with paraquat derivatives in solution, in which the guests all thread the central cavity of the host. However, it was interestingly found that, depending on the paraquat derivatives with different functional groups, the host can form stable 1:1 or 1:2 complexes in different complexation modes in the solid state, which is significantly different from those of the macrotricyclic host containing two dibenzo-[24]-crown-8 moieties. The formation of the complexes was also proved by the ESI MS and electrochemical experiments. Moreover, it was found that the binding and release of the guests in the complexes could be easily controlled by the addition and removal of lithium ions.

Formation of 1:2 host-guest complexes based on triptycene-derived macrotricycle and paraquat derivatives: anion-π interactions between PF6(-) and bipyridinium rings in the solid state.

A triptycene-derived macrotricyclic host containing two dibenzo-[30]-crown-10 moieties forms stable 1:2 host-guest complexes with paraquat derivatives in both solution and the solid state, in which anion-π interactions between PF(6)(-) and the bipyridinium rings play an important role. Moreover, it was found that binding and release of the guest molecules in the complexes could be easily controlled by the addition and removal of potassium ions.

Complexation between pentiptycene derived bis(crown ether)s and CBPQT4+ salt: ion-controlled switchable processes and changeable role of the CBPQT4+ in host-guest systems.

The pentiptycene derived bis(crown ether)s with two 24-crown-8 moieties in the cis position could include the CBPQT(4+) ring inside their cavities to form 1:1 complexes, and the naphthalene groups connected in the crown ether moieties showed less effective complexation ability toward the CBPQT(4+) ring than the host containing two terminal benzene rings. This result was probably due to the stereohindrance effect of the naphthalene groups, and it was obviously different from that of the pentiptycene derived mono(crown ether)s. For the pentiptycene derived bis(crown ether) with two 24-crown-8 moieties in the trans position, it formed a 1:2 stable complex with the CBPQT(4+) salt in solution and in the solid state, in which the pentiptycene moiety played an important role in stabilizing the complex. Moreover, binding and release of the CBPQT(4+) ring in the complexes based on the pentiptycene-derived crown ethers could be chemically controlled by adding and removing potassium ions, in which the complexation modes played the key role. Interestingly, it was further found that switching the role of the CBPQT(4+) ring in host and guest systems based on the pentiptycene derived bis(crown ether)s was easily achieved, which represents a new kind of supramolecular system.

Self-assembled interwoven cages from triptycene-derived bis-macrotricyclic polyether and multiple branched paraquat-derived subunits.

On the basis of formation of a 1:2 complex between the triptycene-derived bis-macrotricyclic polyether and the paraquat derivative, two novel well-defined interwoven supramolecular cages were constructed by the [3 + 2] and [4 + 2] self-assembly of the polyether and trifurcated and cross paraquat-derived subunits under millimolar concentrations, respectively.

A new [3]rotaxane molecular machine based on a dibenzylammonium ion and a triazolium station.

A novel two-station [3]rotaxane molecular machine based on triptycene-derived macrotricyclic host was conveniently synthesized by the click reaction and methylation of the subsequent 1,2,3-tiazole group. The shuttle process of the [3]rotaxane molecular machine can be reversibly achieved by acid-base control.

A bifunctionalized [3]rotaxane and its incorporation into a mechanically interlocked polymer.

A novel bifunctionalized [3]rotaxane based on a triptycene-derived macrotricyclic host was conveniently synthesized. On the basis of the [3]rotaxane, a linear main-chain poly[3]rotaxane was further obtained by the highly efficient Huisgen 1,3-dipolar cycloaddition.

[Mechanism of estrogen-mediated neuroprotection: regulation of mitochondrial function].

Numerous studies show the neuroprotective effects of estrogen, but the underlying mechanism still remains unclear. Recent studies indicate that mitochondria are critically involved in estrogen-mediated neuroprotection. Mitochondria are the main sources of cellular energy and reactive oxygen species (ROS), they play an important role in signaling transduction and cellular life-death decisions. Estrogen exerts multiple effects on mitochondria under physiological and/or pathological conditions, these effects may include modulating ATP and ROS production, preserving mitochondria membrane potential, maintaining calcium homeostasis, and regulating mitochondrial gene and protein expression, etc. In this paper, we discussed the neuroprotective effects of estrogen, particularly focused on the underlying mechanisms related to mitochondria.

The antidepressant effects of curcumin in the forced swimming test involve 5-HT1 and 5-HT2 receptors.

Curcuma longa is a main constituent of many traditional Chinese medicines, such as Xiaoyao-san, used to manage mental disorders effectively. Curcumin is a major active component of C. longa and its antidepressant-like effect has been previously demonstrated in the forced swimming test. The purpose of this study was to explore the possible contribution of serotonin (5-HT) receptors in the behavioral effects induced by curcumin in this animal model of depression. 5-HT was depleted by the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p.) prior to the administration of curcumin, and the consequent results showed that PCPA blocked the anti-immobility effect of curcumin in forced swimming test, suggesting the involvement of the serotonergic system. Moreover, pre-treatment of pindolol (10 mg/kg, i.p., a beta-adrenoceptors blocker/5-HT(1A/1B) receptor antagonist), 4-(2'-methoxy-phenyl)-1-[2'-(n-2''-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (p-MPPI, 1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (isamoltane, 2.5 mg/kg, i.p., a 5-HT(1B) receptor antagonist) was found to prevent the effect of curcumin (10 mg/kg) in forced swimming test. On the other hand, a sub-effective dose of curcumin (2.5 mg/kg, p.o.) produced a synergistic effect when given jointly with (+)-8-hydroxy-2-(di-n-propylamino)tetralin, (8-OH-DPAT, 1 mg/kg, i.p., a 5-HT(1A) receptor agonist), anpirtoline (0.25 mg/kg, i.p., a 5-HT(1B) receptor agonist) or ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), but not with ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist with higher affinity to 5-HT(2A) receptor) or R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg, i.p., a 5-HT(2A) receptor agonist). Taken together, these results indicate that the antidepressant-like effect of curcumin in the forced swimming test is related to serotonergic system and may be mediated by, at least in part, an interaction with 5-HT(1A/1B) and 5-HT(2C) receptors.

[Impacts of modern biology on drug discovery].

Drug discovery has been improved greatly by series of new ideas and new technologies as well as new approaches emerging in the postgenomic era. On the one hand, the theoretics of drug discovery become more comprehensive and more profound as the development of numerous new disciplines such as genomics, proteomics, transcriptomics, metabonomics, bioinformatics and system biology; on the other hand, the pathways for new drug discovery are broadened by the continuous improvement of technological platforms including computer-aided drug design, high throughput screening, high content screening, biochip, transgenic and RNAi technology. Based on the recent advances on the modern biology, in this article, we specially reviewed the impacts of modern biology on the process of drug discovery.

Metallothionein protects against doxorubicin-induced cardiomyopathy through inhibition of superoxide generation and related nitrosative impairment.

Metallothionein (MT) has been shown to be an effective protector against DOX-induced cardiomyopathy, however the involved precise mechanisms are still unknown. The present study was undertaken to clarify whether the inhibition of superoxide generation and related nitrosative damage were involved in the metallothionein attenuation of DOX-induced cardiac injury. MT-I/II null (MT-/-) mice and corresponding wild-type mice (MT+/+) were pretreated with either saline or zinc (300 micromol/kg, s.c., once a day for 2 days) prior to a single dose of DOX (15 mg/kg, i.p.) or equal volume of saline. Animals were sacrificed on the 4th day after DOX administration and samples were collected for further analyses. DOX caused remarkable cardiac damage in both MT+/+ and MT-/- mice as demonstrated by biochemical and histopathological alterations. Zinc pretreatment significantly increased the cardiac MT levels and therefore inhibited the cardiac toxic effects of DOX only in MT+/+ mice, but not in MT-/- mice. Furthermore, elevated formation of superoxide and peroxynitrite were obviously observed after DOX treatment, while these elevation were prevented by MT induction by zinc in MT+/+ mice, but not in MT-/- mice. These findings suggest that metallothionein induction by zinc exhibits protective effects on the cardiac toxicology of DOX, which might be mediated through the prevention of superoxide generation and related nitrosative impairment.