AZD1390, an ataxia telangiectasia mutated inhibitor, attenuates microglia-mediated neuroinflammation and ischemic brain injury.

AIMS: Excessive neuroinflammation mediated mainly by microglia plays a crucial role in ischemic stroke. AZD1390, an ataxia telangiectasia mutated (ATM) specific inhibitor, has been shown to promote radio-sensitization and survival in central nervous system malignancies, while the role of AZD1390 in ischemic stroke remains unknown. METHODS: Real-time PCR, western blot, immunofluorescence staining, flow cytometry and enzyme-linked immunosorbent assays were used to assess the activation of microglia and the release of inflammatory cytokines. Behavioral tests were performed to measure neurological deficits. 2,3,5-Triphenyltetrazolium chloride staining was conducted to assess the infarct volume. The activation of NF-κB signaling pathway was explored through immunofluorescence staining, western blot, co-immunoprecipitation and proximity ligation assay. RESULTS: The level of pro-inflammation cytokines and activation of NF-κB signaling pathway was suppressed by AZD1390 in vitro and in vivo. The behavior deficits and infarct size were partially restored with AZD1390 treatment in experimental stroke. AZD1390 restrict ubiquitylation and sumoylation of the essential regulatory subunit of NF-κB (NEMO) in an ATM-dependent and ATM-independent way respectively, which reduced the activation of the NF-κB pathway. CONCLUSION: AZD1390 suppressed NF-κB signaling pathway to alleviate ischemic brain injury in experimental stroke, and attenuated microglia activation and neuroinflammation, which indicated that AZD1390 might be an attractive agent for the treatment of ischemic stroke.

An NF-κB/OVOL2 circuit regulates glucose import and cell survival in non-small cell lung cancer.

BACKGROUND: Tumor cells tend to utilize glycolysis rather than aerobic respiration even under aerobic conditions. OVOL2, an inhibitory C2H2 zinc finger transcription factor, is a potential tumor suppressor in cancers. However, the association between OVOL2 and tumor energy metabolism is unknown. METHODS: Western blotting was used to determine the expression of OVOL2 in different non-small cell lung cancer (NSCLC) cell lines and mouse models. The metabolic parameters in NSCLC cells following overexpression or knockdown OVOL2 were examined. To define the mechanism by which OVOL2 regulates aerobic glycolysis, interacting protein of OVOl2 and downstream molecular events were identified by luciferase assay and co-immunoprecipitation. We documented the regulatory mechanism in mouse xenograft models. Finally, clinical relevance of OVOL2, NF-κB signaling and GLUT1 was measured by immunostaining. RESULTS: OVOL2 is downregulated in NSCLC and overexpression of OVOL2 inhibits the survival of cancer cells. Moreover, OVOL2 directly binds to P65 and inhibits the recruitment of P300 but facilitates the binding of HDAC1 to P65, which in turn negatively regulates NF-κB signaling to suppress GLUT1 translocation and glucose import. In contrast, OVOL2 expression is negatively regulated by NF-κB signaling in NSCLC cells via the ubiquitin-proteasome pathway. Re-expression of OVOL2 significantly compromise NF-κB signaling-induced GLUT1 translocation, aerobic glycolysis in NSCLC cells and mouse models. Immunostaining revealed inverse correlations between the OVOL2 and phosphorylated P65 levels and between the OVOL2 and membrane GLUT1 levels, and a strong correlation between the phosphorylated P65 and membrane GLUT1 levels. CONCLUSIONS: These results suggest a regulatory circuit linking NF-κB and OVOL2, which highlights the role of NF-κB signaling and OVOL2 in the modulation of glucose metabolism in NSCLC. Video Abstract.

Structure-activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy.

As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives were designed, synthesized, and evaluated for their biological activities. The preliminary SARs studies indicate that the quinazoline scaffold was also acceptable for the block A of class II MET inhibitors. The further pharmacokinetic studies led to the identification of the most promising compound 22a with favorable in vitro potency (MET, IC50 = 9.0 nM), human microsomal metabolic stability (t1/2 = 621.2 min) and oral bioavailability (F = 42%). Moreover, 22a displayed good in vivo antitumor efficacy (IR of 81% in 75 mg/kg) in MET-positive human glioblastoma U-87 MG xenograft model. These positive results indicated that 22a is a potential new MET-targeted antitumor drug lead, which is worthy of further development.

Diaryl Ether: A Privileged Scaffold for Drug and Agrochemical Discovery.

Diaryl ether (DE) is a functional scaffold existing widely both in natural products (NPs) and synthetic organic compounds. Statistically, DE is the second most popular and enduring scaffold within the numerous medicinal chemistry and agrochemical reports. Given its unique physicochemical properties and potential biological activities, DE nucleus is recognized as a fundamental element of medicinal and agrochemical agents aimed at different biological targets. Its drug-like derivatives have been extensively synthesized with interesting biological features including anticancer, anti-inflammatory, antiviral, antibacterial, antimalarial, herbicidal, fungicidal, insecticidal, and so on. In this review, we highlight the medicinal and agrochemical versatility of the DE motif according to the published information in the past decade and comprehensively give a summary of the target recognition, structure-activity relationship (SAR), and mechanism of action of its analogues. It is expected that this profile may provide valuable guidance for the discovery of new active ingredients both in drug and pesticide research.

Neuroprotective effects of ZL006 in Aß1-42-treated neuronal cells.

Amyloid beta (Aß)-induced neurotoxicity and oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). ZL006 is shown to reduce over-produced nitric oxide and oxidative stress in ischemic stroke by interrupting the interaction of neuronal nitric oxide synthase and postsynaptic density protein 95. However, few studies are reported on the role of ZL006 in AD. To investigate whether ZL006 exerted neuroprotective effects in AD, we used Aß1-42 to treat primary cortical neurons and N2a neuroblastoma cells as an in vitro model of AD. Cortical neurons were incubated with ZL006 or dimethyl sulfoxide for 2 hours and treated with Aß1-42 or NH3•H2O for another 24 hours. The results of cell counting Kit-8 (CCK-8) assay and calcein-acetoxymethylester/propidium iodide staining showed that ZL006 pretreatment rescued the neuronal death induced by Aß1-42. Fluorescence and western blot assay were used to detect oxidative stress and apoptosis-related proteins in each group of cells. Results showed that ZL006 pretreatment decreased neuronal apoptosis and oxidative stress induced by Aß1-42. The results of CCK8 assay showed that inhibition of Akt or NF-E2-related factor 2 (Nrf2) in cortical neurons abolished the protective effects of ZL006. Moreover, similar results were also observed in N2a neuroblastoma cells. ZL006 inhibited N2a cell death and oxidative stress induced by Aß1-42, while inhibition of Akt or Nrf2 abolished the protective effect of ZL006. These results demonstrated that ZL006 reduced Aß1-42-induced neuronal damage and oxidative stress, and the mechanisms might be associated with the activation of Akt/Nrf2/heme oxygenase-1 signaling pathways.

Genetic, epigenetic and biochemical regulation of succinate dehydrogenase function.

Succinate dehydrogenase (SDH), complex II or succinate:quinone oxidoreductase (SQR) is a crucial enzyme involved in both the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), the two primary metabolic pathways for generating ATP. Impaired function of SDH results in deleterious disorders from cancer to neurodegeneration. SDH function is tailored to meet the energy demands in different cell types. Thus, understanding how SDH function is regulated and how it operates in distinct cell types can support the development of therapeutic approaches against the diseases. In this article we discuss the molecular pathways which regulate SDH function and describe extra roles played by SDH in specific cell types.

The anti-cancer compound Schweinfurthin A targets Osh2 and disrupts lipid metabolism in the yeast model.

Schweinfurthin A (Sch A) is a natural product with a selective and strong anti-cancer effect. Although it is known to target oxysterol binding proteins, the detailed mode of action is not well understood. Here, we provide strong evidence that yeast cells can be used as a eukaryotic model system to decipher the molecular modes of Sch A. We show that Sch A (100 µM) targets Osh2 (a yeast oxysterol binding protein homolog) genetically and taking advantage of computational chemistry indicate that the tetrahydro-2H-xanthene portion of Sch A forms H-bonds with residues Ser105, Val113, and Lys201, while its isoprenoid side chain is placed in a hydrophobic pocket lined by the side chains of Leu41, Leu45, Leu58, Met56, and Phe174 in Osh2. This model suggests that Sch A occupies the same binding pocket in Osh2 which is occupied by its natural substrate, ergosterol. Osh proteins transport sterol and PI(4)P in a cyclic manner between two membranes. Therefore, we suggest that Sch A interferes with this function of Osh2. In support of this hypothesis, we show that Sch A toxicity rate changes upon manipulating the enzymes that modify the levels of sterol and PI(4)P. This approach also informs how Sch A exerts its toxic effect in yeast cells. These enzymes include Coq1, Sac1, Plc1, Stt4, Pik1, and Mss4. We demonstrate that Coq1 an enzyme required for coenzyme Q synthesis (also involved in sterol metabolism indirectly), Sac1, and Stt4 the enzymes governing PI(4)P level modify Sch A toxicity and finally propose Sch A disrupts sterol/PI(4)P exchange between membranes by occupying the sterol/PI(4)P binding pocket in Osh2.

Molecular pathogenesis of tumorigenesis caused by succinate dehydrogenase defect.

Succinate dehydrogenase (SDH), also named as complex II or succinate:quinone oxidoreductases (SQR) is a critical enzyme in bioenergetics and metabolism. This is because the enzyme is located at the intersection of oxidative phosphorylation and tricarboxylic acid cycle (TCA); the two major pathways involved in generating energy within cells. SDH is composed of 4 subunits and is assembled through a multi-step process with the aid of assembly factors. Not surprisingly malfunction of this enzyme has marked repercussions in metabolism leading to devastating tumors such as paraganglioma and pheochromocytoma. It is already known that mutations in the genes encoding subunits lead to tumorigenesis, but recent discoveries have indicated that mutations in the genes encoding the assembly factors also contribute to tumorigenesis. The mechanisms of pathogenesis of tumorigenesis have not been fully understood. However, a multitude of signaling pathways including succinate signaling was determined. We, here discuss how defective SDH may lead to tumor development at the molecular level and describe how yeast, as a model system, has contributed to understanding the molecular pathogenesis of tumorigenesis resulting from defective SDH.

The assembly of succinate dehydrogenase: a key enzyme in bioenergetics.

Succinate dehydrogenase (SDH) also known as complex II or succinate:quinone oxidoreductase is an enzyme involved in both oxidative phosphorylation and tricarboxylic acid cycle; the processes that generate energy. SDH is a multi-subunit enzyme which requires a series of proteins for its proper assembly at several steps. This enzyme has medical significance as there is a broad range of human diseases from cancers to neurodegeneration related to SDH malfunction. Some of these disorders have recently been linked to defective assembly factors, reinvigorating further research in this area. Apart from that this enzyme has agricultural importance as many fungicides have been/will be designed targeting specifically this enzyme in plant fungal pathogens. In addition, we speculate it might be possible to design novel fungicides specifically targeting fungal assembly factors. Considering the medical and agricultural implications of SDH, the aim of this review is an overview of the SDH assembly factors and critical analysis of controversial issues around them.

2,7-naphthyridinone-based MET kinase inhibitors: A promising novel scaffold for antitumor drug development.

As part of our effort to develop new molecular targeted antitumor drug, a novel 2,7-naphthyridone-based MET kinase inhibitor, 8-((4-((2-amino-3-chloropyridin-4-yl)oxy)- 3-fluorophenyl)amino)-2-(4-fluorophenyl)-2,7-naphthyridin-1(2H)-one (13f), was identified. Knowledge of the binding mode of BMS-777607 in MET led to the design of new inhibitors that utilize novel 2,7-naphthyridone scaffold to conformationally restrain the key pharmacophoric groups (block C). Detailed SAR studies resulted in the discovery of a new MET inhibitor 13f, displaying favorable in vitro potency and oral bioavailability. More importantly, 13f exhibited excellent in vivo efficacy (tumor growth inhibition/TGI of 114% and 95% in 50 mg/kg, respectively) both in the U-87 MG and HT-29 xenograft models. The favorable drug-likeness of 13f indicated that 2,7-naphthyridinone may be used a promising novel scaffold for antitumor drug development. The preclinical studies of 13f are under way.

LncRNA-1810034E14Rik reduces microglia activation in experimental ischemic stroke.

BACKGROUND: Activation of microglial cells plays an important role in neuroinflammation after ischemic stroke. Inhibiting the activation of microglial cells has been suggested as a potential therapeutic approach in the treatment of ischemic stroke. METHODS: Oxygen-glucose deprivation in primary microglial cells and transient middle cerebral artery occlusion (MCAO) in C57BL/6 mice were used as the in vitro and in vivo ischemic stroke models. Microarray analysis was performed to investigate the overall impact of long non-coding RNAs (lncRNAs) on the inflammation status of microglial cells. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers. ELISA was taken to measure the level of cytokines. Immunofluorescence was used to observe the activation of microglial cells. Western blotting was performed to test the p65 phosphorylation. RESULTS: In this study, we showed that LncRNA-1810034E14Rik was significantly decreased in LPS-treated or oxygen-glucose deprivation-induced microglial cells. Overexpression of 1810034E14Rik decreased the infarct volume and alleviated brain damage in MCAO mice. 1810034E14Rik overexpression reduced the expression of inflammatory cytokines not only in ischemic stroke mice but also in oxygen-glucose deprivation-induced microglial cells. Moreover, 1810034E14Rik overexpression could suppress the activation of microglial cells and inhibit the phosphorylation of p65. CONCLUSIONS: LncRNA-1810034E14Rik plays an anti-inflammatory role in ischemic stroke and regulates p65 phosphorylation, making it a potential target for stroke treatment.

In Vivo Imaging Markers for Prediction of Radiotherapy Response in Patients with Nasopharyngeal Carcinoma: RESOLVE DWI versus DKI.

In this prospective study, we compared the performance of readout segmentation of long variable echo trains of diffusion-weighted imaging (RESOLVE DWI) and diffusion kurtosis imaging (DKI) for the prediction of radiotherapy response in patients with nasopharyngeal carcinoma (NPC). Forty-one patients with NPC were evaluated. All patients underwent conventional MRI, RESOLVE DWI and DKI, before and after radiotherapy. All patients underwent conventional MRI every 3 months until 1 year after radiotherapy. The patients were divided into response group (RG; 36/41 patients) and no-response group (NRG; 5/41 patients) based on follow-up results. DKI (the mean of kurtosis coefficient, Kmean and the mean of diffusion coefficient, Dmean) and RESOLVE DWI (the minimum apparent diffusion coefficient, ADCmin) parameters were calculated. Parameter values at the pre-treatment period, post-treatment period, and the percentage change between these 2 periods were obtained. All parameters differed between the RG and NRG groups except for the pretreatment Dmean and ADCmin. Kmean-post was considered as an independent predictor of local control, with 87.5% sensitivity and 91.3% specificity (optimal threshold = 0.30, AUC: 0.924; 95% CI, 0.83-1.00). Kmean-post values of DKI have the potential to be used as imaging biomarkers for the early evaluation of treatment effects of radiotherapy on NPC.

Gadolinium-chelate functionalized bismuth nanotheranostic agent for in vivo MRI/CT/PAI imaging-guided photothermal cancer therapy.

Multifunctional nanomaterials with simple structure and good biosafety, integrating multimodal imaging and therapeutic functions, can facilitate the development of clinical cancer treatments. Here, a simple but powerful pure bismuth based nanoparticle (Gd-PEG-Bi NPs) was developed from pure Bi NPs and gadolinium-diethylenetriaminepentaacetic acid-bis-tetradecylamide, which not only shows high quality MRI/CT/PAI triple-modal imaging, but can also be a potent photothermal therapy agent under the guidance of the triple-modal imaging. The Gd-PEG-Bi NPs showed good stability and excellent biocompatibility. In vitro and in vivo study demonstrated that Gd-PEG-Bi NPs have ultrahigh X-ray attenuation coefficient, short T1 relaxation time in MRI, and strong PAI signal. Following the imaging diagnosis, the excellent light-to-heat conversion efficiency of Gd-PEG-Bi NPs was capable of suppressing the tumor growth effectively under near-infrared laser radiation in vivo. Such multifunctional nanoparticles were ideal candidates for cancer diagnosis and treatment.

Retrospective analysis of the utility of multiparametric MRI for differentiating between benign and malignant breast lesions in women in China.

We explored the utility of time-resolved angiography with interleaved stochastic trajectories dynamic contrast-enhanced magnetic resonance imaging (TWIST DCE-MRI), readout segmentation of long variable echo-trains diffusion-weighted magnetic resonance imaging- diffusion-weighted magnetic resonance imaging (RESOLVE-DWI), and echo-planar imaging- diffusion-weighted magnetic resonance imaging (EPI-DWI) for distinguishing between malignant and benign breast lesions.This retrospective analysis included female patients with breast lesions seen at a single center in China between January 2016 and April 2016. Patients were allocated to a benign or malignant group based on pathologic diagnosis. All patients received routine MRI, RESOLVE-DWI, EPI-DWI, and TWIST DCE-T1WI. Variables measured included quantitative parameters (K, Kep, and Ve), semiquantitative parameters (rate of contrast enhancement for contrast agent inflow [W-in], rate of contrast decay for contrast agent outflow [W-out], and time-to-peak enhancement after contrast agent injection [TTP]) and apparent diffusion coefficient (ADC) values for RESOLVE-DWI (ADCr) and EPI-DWI (ADCe). Receiver-operating characteristic (ROC) curve analysis was used to evaluate the diagnostic utility of each parameter for differentiating malignant from benign breast lesions.A total of 87 patients were included (benign, n = 20; malignant, n = 67). Compared with the benign group, the malignant group had significantly higher K, Kep and W-in and significantly lower W-out, TTP, ADCe, and ADCr (all P < .05); Ve was not significantly different between groups. RESOLVE-DWI was superior to conventional EPI-DWI at illustrating lesion boundary and morphology, while ADCr was significantly lower than ADCe in all patients. Kep, W-out, ADCr, and ADCe showed the highest diagnostic efficiency (based on AUC value) for differentiating between benign and malignant lesions. Combining 3 parameters (Kep, W-out, and ADCr) had a higher diagnostic efficiency (AUC, 0.965) than any individual parameter and distinguished between benign and malignant lesions with high sensitivity (91.0%), specificity (95.0%), and accuracy (91.9%).An index combining Kep, W-out, and ADCr could potentially be used for the differential diagnosis of breast lesions.

China's Efforts on Management, Surveillance, and Research of Noncommunicable Diseases: NCD Scorecard Project.

BACKGROUND: The incidence of noncommunicable diseases (NCDs) is rising dramatically throughout the world. Aspects of researches concerned with the improvement and development of prevention and control of NCDs have been conducted. Furthermore, the influence of most determinants of the major NCDs has showed that a broad and deep response involving stakeholders in different sectors is required in the prevention and control of NCDs. OBJECTIVE: China has experienced an increase in NCDs in a short period compared with many countries. To address the burden of NCDs in China, it is important to learn about the progress that has been made in prevention and control of NCDs in China and worldwide, informed by opinions of stakeholders in different areas. METHODS: In 2014, GRAND South developed the NCD Scorecard instrument to evaluate progress of NCD prevention and control in 23 countries through a 2-round Delphi process. The scorecard included 51 indicators in 4 domains: governance, surveillance and research, prevention and risk factors, and health system response. Stakeholders were then selected in the areas of government, nongovernmental organizations, private sectors, and academia to join the NCD Scorecard survey. Indicators of progress were scored by stakeholders from 0 (no activity), 1 (present but not adequate), and 2 (adequate) to 3 (highly adequate) and then the percentage of progress in each domain was calculated, representing the current situation in each country. FINDINGS: There were 14 indicators in the domains of governance and surveillance and research. Of 429 stakeholders worldwide, 41 in China participated in the survey. China scored in the top 5 out of all participating countries in those 2 domains, scoring 67% in governance and 64% in surveillance and research. Indicators on which China scored particularly well included having a well-resourced unit or department responsible for NCDs, having a strong national system for recording the cause of all deaths, and having a system of NCD surveillance. Areas where China had the greatest need for improvement included increasing taxes on tobacco and addressing the needs of the population older than age 70 dying from major NCDs. CONCLUSION: In China the burden of disease of NCDs and disabilities remains serious, although China has put significant efforts into its governance and surveillance and research. To improve, further action is needed on reducing tobacco consumption, increasing investment in the national health budget, and increasing the focus on system construction.

Diffusion-kurtosis imaging predicts early radiotherapy response in nasopharyngeal carcinoma patients.

In this prospective study, we analyzed diffusion kurtosis imaging (DKI) parameters to predict the early response to radiotherapy in 23 nasopharyngeal carcinoma (NPC) patients. All patients underwent conventional magnetic resonance imaging (MRI) and DKI before and after radiotherapy. The patients were divided into response (RG; no residual tumors; 16/23 patients) and no-response (NRG; residual tumors; 7/23 patients) groups, based on MRI and biopsy results 3 months after radiotherapy. The maximum diameter of tumors in RG and NRG patients were similar prior to radiotherapy (p=0.103). The pretreatment diffusion coefficient (D) parameters (Daxis, Dmean and Drad) were higher in RG than NRG patients (p=0.022, p=0.027 and p=0.027). Conversely, the pre-treatment fractional anisotropy (FA) and kurtosis coefficient (K) parameters (Kaxis, Kfa, Kmean, Krad and Mkt) were lower in RG than NRG patients (p=0.015, p=0.022, p=0.008, p=0.004, p=0.001, p=0.002). The Krad coefficient (0.76) was the best parameter to predict the radiotherapy response. Based on receiver operating characteristic curve analysis Krad showed 71.4% sensitivity and 93.7% specificity (AUC: 0.897, 95% CI, 0.756-1). Multivariate analysis indicated DKI parameters were independent prognostic factors for the short-term effect in NPC. Thus, DKI predicts the early response to radiotherapy in NPC patients.

Diammonium glycyrrhizinate attenuates Aß(1-42) -induced neuroinflammation and regulates MAPK and NF-κB pathways in vitro and in vivo.

BACKGROUND AND PURPOSE: Beta-amyloid (Aß)-mediated inflammation contributes to the progression and chronicity of Alzheimer's disease (AD), although the exact mechanism remains unclear. This study aimed to investigate whether diammonium glycyrrhizinate (DG) could inhibit Aß-induced inflammation in vitro and in vivo and to explore the underlying mechanisms. METHODS: Aß(1-42) was injected to bilateral hippocampus of mice to make the AD models in vivo. The levels of mRNA and protein of inflammatory cytokines were measured by real-time PCR and Western blotting, respectively. The viability of SH-SY5Y and HT-22 cells was determined by MTT. NF-κB p65 translocation was analyzed by Western blotting and immunostaining. Phosphorylation of ERK, p38, and JNK was tested by Western blotting. RESULTS: DG suppressed Aß(1-42) -induced activation of microglia and inflammation in vitro and in vivo. The media from Aß(1-42) -activated microglia decreased the viability of SH-SY5Y and HT-22 cells, but it was rescued when pretreated with DG. DG could inhibit the activation of MAPK and NF-κB signaling pathways and attenuate the memory deficits in Aß(1-42) -induced AD mice. CONCLUSIONS: DG protects Aß(1-42) -induced AD models in vitro and in vivo through reducing activation of microglia and inflammation, which may be involved in MAPK and NF-κB pathways.

[Surgical treatment of sternal tumors: resection of the tumors and reconstruction of the chest wall defects].

OBJECTIVE: To investigate the efficacy of surgical treatment of sternal tumors and repairing methods of the chest wall defects. METHODS: Fifteen patients with sternal tumors were diagnosed and underwent resection of the sternal tumors according to the en-bolck principle and repair of the chest wall defects using various materials from January 1968 to December 2010 in our hospital. RESULTS: Of 6 patients with sternal manubrim tumors, one patient had reconstruction only with steel wire, other 5 patients healed completely after repair with soft materials. Of 7 patients with sternal body tumors, one patient recovered quickly without reconstruction because he had only partial resection; four patients had chest wall repair with soft materials, but they breathed hardly; and two patients had chest wall reconstruction with rigid materials. One patient had ventilatory support, another patient recovered quickly. Ventilatory support was needed in two patients treated by subtotal sternectomy because they had chest wall repair with soft materials. CONCLUSIONS: In surgical treatment of sternal tumors by manubrim sternetomy, the chest wall defects can be constructed with soft materials. After resection of sternal body tumors and subtotal sternectomy, the thoracic wall defects need to be reconstructed with rigid materials.

Rieske iron-sulfur protein of the cytochrome bc(1) complex: a potential target for fungicide discovery.

The cytochrome bc(1) complex (complex III, cyt bc(1)) is an essential component of cellular respiration. Cyt bc(1) has three core subunits that are required for its catalytic activity: cytochrome b, cytochrome c(1), and the Rieske iron-sulfur protein (ISP). Although most fungicides inhibit this enzyme by binding to the cytochrome b subunit, resistance to these fungicides has developed rapidly due to their widespread application. Resistance is mainly associated with mutations in cytochrome b, the only subunit encoded by mitochondrial DNA. Recently, the flexibility and motion of the ISP and its essential role in electron transfer have received intense attention; this leads us to propose a new classification of cyt bc(1) inhibitors (three types of Q(o) inhibitors) that mobilize, restrict, or fix the rotation of the ISP. Importantly, the strengths of the ISP-inhibitor interactions correlate with inhibitor activity and the development of resistance to Q(o) inhibitors, thereby offering clues for designing novel cyt bc(1) inhibitors with high potency and a low risk of resistance.

Ameliorative effects of diammonium glycyrrhizinate on inflammation in focal cerebral ischemic-reperfusion injury.

The present study investigated the neuroprotective potential of Diammonium Glycyrrhizinate (DG) in focal cerebral ischemic-reperfusion (IR) injury in mice. The middle cerebral artery occlusion (MCAO) model of the mouse was used. Mice were treated with DG (20mg/kg per day, intraperitoneal injection) or saline as control, from the beginning of the reperfusion to 7 days. The focal cerebral IR injury resulted in significant neurological deficits, infarct size, and brain water content (BWC) at 1 day, 3 days and 7 days after MCAO. A significant increase in various inflammatory mediators like interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB) and astrocytic glial fibrillary acidic protein (GFAP) was also observed in the IR challenged brains. The DG treatment significantly improved neurofunction, decreased infarct size, and suppressed edema in the focal cerebral IR injury. The neuroprotective effect of DG was found to be associated with significant reduction in the IL-1, TNF-α, COX-2, iNOS, NF-κB and GFAP levels. In summary, this study suggested that DG has a neuroprotective effect on cerebral IR injury and this effect is likely related to DG's anti-inflammatory function.