Synergy of human neutrophils with fluconazole in killing Candida species

The killing of Candida species by human neutrophils in a long-term 24-h assay and possible synergy with fluconazole (FCZ) for killing was investigated. The test medium (TM) consisted of RPMI-1640, penicillin and streptomycin (P/S), and 10% fresh autologous serum. TM alone was highly fungistatic for Candida species compared to TM without serum. When neutrophils were cocultured in TM with Candida species for 24 h the inoculum colony-forming units (CFU) were always significantly reduced (killing) by 58 to 99%. FCZ was tested over a range of 1–500 g/ml, and though almost always fungistatic itself, it synergized with neutrophils for significantly increased killing of C. albicans (isolate Sh27) (P<0.01) and C. albicans (isolate 94-20) (P<0.05). Killing of non-albicans Candida species was so efficient in the absence of FCZ that demonstration of synergy with FCZ was difficult.     

Study of quercetin and fisetin synergistic effect on breast cancer and potentially involved signaling pathways

Naturally-derived drugs have drawn much attention in recent decades. Efficiency, lower toxicity, and economic reasons are some of their advantages that justify this broad range of administration for different diseases, including cancer. If we can find a specific combination that boosts the effects of their single therapy, leading to synergism effect, increased efficiency, and decreased toxicity, they can act even better. Quercetin and fisetin, two well-known flavonoids, have been used to fight against various cancers. In this study, we investigated their possible synergism quercetin and fisetin on MCF7, MDA-MB-231, BT549, T47D, and 4T1 breast cancer cell lines. Then the optimum combined dose was used to study their impacts on wound healing abilities and clonogenic properties. The real-time qPCR was used to study the expression of their validated downstream effectors in predicted pathways. A significant synergism effect (p < .01, combination index: <1) was observed for all cell lines. Combination therapy was significantly more effective in colony formation (p < .0001) and wound healing assays (p < .001) compared to single therapies. The expression level of potential effectors was also showed a greater change. In vivo study confirmed the in vitro results and showed how significantly (p < .001) their synergism promotes their singular function in inhibiting cancer progression. The breast cancer mouse models receiving combined therapy lived longer with higher average body weight and smaller tumor sizes. These results exhibit that quercetin and fisetin inhibit cancer cell proliferation, migration and colony formation synergistically, and matrix metalloproteinase signaling and apoptotic pathways are relatively responsible for inhibitory activities.     

Quantifying the evidence for ecological synergies

There is increasing concern that multiple drivers of ecological change will interact synergistically to accelerate biodiversity loss. However, the prevalence and magnitude of these interactions remain one of the largest uncertainties in projections of future ecological change. We address this uncertainty by performing a meta-analysis of 112 published factorial experiments that evaluated the impacts of multiple stressors on animal mortality in freshwater, marine and terrestrial communities. We found that, on average, mortalities from the combined action of two stressors were not synergistic and this result was consistent across studies investigating different stressors, study organisms and life-history stages. Furthermore, only one-third of relevant experiments displayed truly synergistic effects, which does not support the prevailing ecological paradigm that synergies are rampant. However, in more than three-quarters of relevant experiments, the outcome of multiple stressor interactions was non-additive (i.e. synergies or antagonisms), suggesting that ecological surprises may be more common than simple additive effects.     

Gossypol and an HMT G9a inhibitor act in synergy to induce cell death in pancreatic cancer cells

The histone methyltransferase G9a is overexpressed in a variety of cancer types, including pancreatic adenocarcinoma, and promotes tumor invasiveness and metastasis. We recently reported the discovery of BRD4770, a small-molecule inhibitor of G9a that induces senescence in PANC-1 cells. We observed that the cytotoxic effects of BRD4770 were dependent on genetic background, with cell lines lacking functional p53 being relatively resistant to compound treatment. To understand the mechanism of genetic selectivity, we used two complementary screening approaches to identify enhancers of BRD4770. The natural product and putative BH3 mimetic gossypol enhanced the cytotoxicity of BRD4770 in a synergistic manner in p53-mutant PANC-1 cells but not in immortalized non-tumorigenic pancreatic cells. The combination of gossypol and BRD4770 increased LC3-II levels and the autophagosome number in PANC-1 cells, and the compound combination appears to act in a BNIP3 (B-cell lymphoma 2 19-kDa interacting protein)-dependent manner, suggesting that these compounds act together to induce autophagy-related cell death in pancreatic cancer cells.     

Ultrasonication-ionic liquid synergy for the synthesis of new potent anti-tuberculosis 1,2,4-triazol-1-yl-pyrazole based spirooxindolopyrrolizidines

The aim of the study is to design and synthesis of a new series of potent anti-TB 1,2,4-triazol-1-yl-pyrazole based spirooxindolopyrrolizidines with their safety profile. A synergetic effect of ultrasonication and ionic liquid was shown successfully as a green methodology for the synthesis of title compounds 6a–t. These derivatives were obtained in shorter reaction time with good yields and well characterized by various spectroscopic methods, single-crystal X-ray diffraction (6f). The in vitro anti-tuberculosis activity for newly-synthesized derivatives has been screened against Mycobacterium tuberculosis. Among all, six compounds 6e, 6k, 6l, 6n, 6q and 6r exhibited equal potent activity compared to standard drug ethambutol (MIC: 1.56 µg/mL) and another compound 6h exhibited outstanding activity (MIC: 0.78 µg/mL) than the standard drug ethambutol. Cytotoxic nature of the anti-TB active compounds was evaluated against RAW 264.7 cells. The 6h, 6e, 6k, 6l, 6n, 6q and 6r exhibited lower toxicity which could be promising hits for anti-tuberculosis.     

Mechanism of substrate hydrolysis by a thermophilic endoglucanase from Thermotoga maritima†

A cellulase from the thermophile, Thermotoga maritima, hydrolyzed oligosaccharide substrates by an exoglucanase mode of action but acted as an endoglucanase to rapidly reduce the viscosity of the soluble polysaccharides carboxymethylcellulose and barley -glucan. The V _max for hydrolysis of the substrate, p-nitrophenyl -d-cellobioside, was 42 mol min^–1 (mg protein)^–1, while that for barley -glucan was 637. The enzyme had little activity on crystalline cellulose.     

青弋江流域生态系统服务评估与权衡研究

研究生态系统服务价值变化特征及多种服务之间的权衡协同关系,对平衡经济发展与环境保护具有重要意义。基于修订的当量因子表,结合2000、2009、2018年3个时期遥感解译获取的土地利用数据,运用生态系统服务权衡协同度模型、敏感性分析、空间自相关、土地利用程度综合指数模型等分析了青弋江流域生态系统服务价值（Ecosystem Services Value,ESV）的时空演变特征及9种生态服务之间的权衡协同关系。结果表明：（1）2000、2009及2018年的生态系统服务价值分别为285.19、351.26和294.68亿元,价值总量呈先增后减的变化趋势,其中2009-2018年间总ESV下降了16.1%,生态服务趋于退化。整个研究时段内,林地对ESV的贡献量最大,其次是耕地和水域。（2）2000-2009年,单项生态系统服务间以协同关系为主导,协同率为77.8%,食物生产服务与本研究中的其他服务之间均为权衡关系;2009-2018年间生态系统服务间的关系与前9年基本一致,但食物生产服务与其他服务功能之间的权衡度呈增强的趋势。（3）敏感性分析表明,各时期的敏感性指数（CS）值均小于1,表明基于修订的当量因子表计算获得的生态系统服务价值系数符合青弋江流域的实际情况,计算结果可靠。（4）生态系统服务价值存在较强的正向空间自相关,但集聚程度有下降的趋势。双变量空间自相关分析表明当土地利用程度增强时,生态系统提供的总服务价值或单项服务价值均会降低。研究结果可为青弋江流域土地利用结构的优化调整及生态环境保护提供参考信息。     

Quantifying ecosystem service trade‐offs for plantation forest management to benefit provisioning and regulating services

There is increasing interest worldwide regarding managing plantation forests in a manner that maintains or improves timber production, enhances ecosystem services, and promotes long‐term sustainability of forest resources. We selected the Gan River Basin, the largest catchment of Poyang Lake and a region with a typical plantation distribution in South China, as the study region. We evaluated and mapped four important forest ecosystem services, including wood volume, carbon storage, water yield, and soil retention at a 30 × 30 m resolution, then quantified their trade‐offs and synergies at the county and subwatershed scales. We found that the wood volume and carbon storage services, as well as the soil retention and water yield, exhibited synergistic relationships. However, the carbon storage displayed a trade‐off relationship with the water yield. Additionally, we compared the beneficial spatial characteristics among dominant species in the study region. The results showed that the Chinese fir forest and the pine forest exhibited lower overall benefits than natural forests including the broad‐leaved forest and the bamboo forest. To propose a suitable management strategy for the study region, method of spatial cluster analysis was used based on the four eco‐services at the subwatershed scale. The basin was divided into four management groups instead of treating the region as a homogenous management region. Finally, we proposed more specific and diverse management strategies to optimize forest benefits throughout the entire region.     

Identification of a potent small-molecule inhibitor of bacterial DNA repair that potentiates quinolone antibiotic activity in methicillin-resistant Staphylococcus aureus

The global emergence of antibiotic resistance is one of the most serious challenges facing modern medicine. There is an urgent need for validation of new drug targets and the development of small molecules with novel mechanisms of action. We therefore sought to inhibit bacterial DNA repair mediated by the AddAB/RecBCD protein complexes as a means to sensitize bacteria to DNA damage caused by the host immune system or quinolone antibiotics. A rational, hypothesis-driven compound optimization identified IMP-1700 as a cell-active, nanomolar potency compound. IMP-1700 sensitized multidrug-resistant Staphylococcus aureus to the fluoroquinolone antibiotic ciprofloxacin, where resistance results from a point mutation in the fluoroquinolone target, DNA gyrase. Cellular reporter assays indicated IMP-1700 inhibited the bacterial SOS-response to DNA damage, and compound-functionalized Sepharose successfully pulled-down the AddAB repair complex. This work provides validation of bacterial DNA repair as a novel therapeutic target and delivers IMP-1700 as a tool molecule and starting point for therapeutic development to address the pressing challenge of antibiotic resistance.