// Ling Ding 1 , Guikai Liang 1 , Zhangting Yao 1 , Jieqiong Zhang 1 , Ruiyang Liu 1 , Huihui Chen 1 , Yulu Zhou 1 , Honghai Wu 1 , Bo Yang 1 , Qiaojun He 1 1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China Correspondence to: Qiaojun He, e-mail: qiaojunhe@zju.edu.cn Keywords: metformin, macrophage polarization, cancer metastasis, AMPKα1 Received: July 05, 2015 Accepted: October 09, 2015 Published: October 19, 2015 ABSTRACT Accumulated evidence suggests that M2-like polarized tumor associated macrophages (TAMs) plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-like TAMs as an appealing target for therapy intervention. Here we found that metformin significantly suppressed IL-13 induced M2-like polarization of macrophages, as illustrated by reduced expression of CD206, down-regulation of M2 marker mRNAs, and inhibition of M2-like macrophages promoted migration of cancer cells and endothelial cells. Metformin triggered AMPKα1 activation in macrophage and silencing of AMPKα1 partially abrogated the inhibitory effect of metformin in IL-13 induced M2-like polarization. Administration of AICAR, another activator of AMPK, also blocked the M2-like polarization of macrophages. Metformin greatly reduced the number of metastases of Lewis lung cancer without affecting tumor growth. In tumor tissues, the percentage of M2-like macrophage was decreased and the area of pericyte-coated vessels was increased. Further, the anti-metastatic effect of metformin was abolished when the animals were treated with macrophages eliminating agent clodronate liposome. These findings suggest that metformin is able to block the M2-like polarization of macrophages partially through AMPKα1, which plays an important role in metformin inhibited metastasis of Lewis lung cancer.
In monomictic lakes, the potential intensification of hypolimnetic deoxygenation due to human activities and climate change threatens lake ecosystems and water quality. Understanding the trends and mechanisms of hypolimnetic deoxygenation would allow for the adaptive management of monomictic lakes. This study investigated the trends and drivers of hypolimnetic deoxygenation in Lake Fuxian (a monomictic lake in south-western China) over the past 150 years using paleolimnological evidence and historical records. Analysis of enrichment factors for molybdenum (Mo), uranium (U), and vanadium (V), and ratios of U/thorium (Th), pristane (Pr)/phytane (Ph), and total organic carbon (TOC)/total phosphorus (TP) in a dated sediment core indicated that the extent of hypolimnetic deoxygenation was relatively low before 1994 and increased substantially thereafter. Nutrient monitoring records and sediment n-alkane proxies indicated notable eutrophication of the lake since 1986 and a greater degree of human disturbance in the catchment between 1951 and 1967. Due to their asynchronous occurrence, eutrophication and catchment disturbance could not be the major drivers of hypolimnetic deoxygenation. Interestingly, climate records indicated that the local ambient temperature exhibited similar trends to that of hypolimnetic deoxygenation, including markedly higher temperatures after 1994. This implies that prolonged water column stratification due to climate warming could have promoted hypolimnetic deoxygenation by limiting oxygen exchange between the upper and lower water columns. In comparing the results with those of Lake Erhai, another monomictic lake with contrasting morphology and hydrology characteristics, we found that the low surface area/depth ratio and long water residence time in Lake Fuxian enable dissolved oxygen of the lake hypolimnion vulnerable to temperature over the lake.
Green (technical) innovation is expected to be an effective tool for addressing environmental crises. However, the effect of environmental regulations on green innovation may depend on the type of environmental regulation. To that end, this study utilizes panel data covering 30 Chinese provinces to explore the mechanism underlying the relationship between these two variables in light of the heterogeneity in environmental regulations and pollutants. The direct effects of three types of environmental regulations and four pollutants are verified, as are the thresholds in the effects of environmental regulations on green innovation. The results show that 1) both market-incentive and public participation-based environmental regulations have positive effects on green innovation, while command-and-control regulations do not. Unlike the effects of the market-incentive tool, which has a single threshold, the effect of public participation-based environmental regulations has two thresholds, which indicates that there is too little public participation for such regulations to be effective and too much for them to be sensitive to environmental protection. 2) Three of the four pollutants (industrial wastewater, waste gas, and carbon emissions) have a significantly positive impact on green innovation only when they exceed the first threshold value, whereas an increase in industrial solid waste has little effect on green innovation until it exceeds the second threshold value. 3) In the eastern region, all three kinds of environmental regulations play significant roles in promoting green innovation, and their effects are greater than those in the western region. However, the effect of environmental regulations in the central region is not different from that in the western region.
Sertraline (SER) is one of the most frequently detected antidepressant drugs in aquatic environments. However, knowledge regarding SER-induced behavioral alterations in fish is insufficient, as well as the mechanisms underlying SER-induced toxicity. The present study aimed to determine behavioral and molecular responses in larval fish following SER exposure with a focus on its mode of action. Zebrafish embryos (~6 h-post-fertilization, hpf) were exposed to one of three concentrations of SER (1, 10, 100 μg/L) for 6 days, respectively. Evaluated parameters included development, behavior, transcripts related to serotonin signaling, serotonin levels, and acetylcholinesterase activity. Accelerated hatching of zebrafish embryos was observed for those fish exposed to 100 μg/L SER at 54 hpf. Locomotor activity (e.g. distance moved and mobile cumulative duration) was significantly reduced in larval zebrafish following exposure to 10 and 100 μg/L SER. Conversely, larval fish showed increased dark-avoidance after exposure to 1–100 μg/L SER. Of the measured transcripts related to serotonin signaling, only serotonin transporter (serta) and serotonin receptor 2c (5-ht2c) mRNA levels were increased in fish in response to 10 μg/L SER treatment. However, serotonin levels were unaltered in larvae exposed to SER. There were no differences among groups in acetylcholinesterase activity at any concentration tested. Taking together, the results evidenced that exposure to SER alters behavioral responses in early-staged zebrafish, which may be related to the abnormal expression of 5-ht2c. This study elucidates molecular responses to SER and characterizes targets that may be sensitive to antidepressant pharmaceuticals in larval fish.
Psychotropic pharmaceuticalsand their metabolites are a growing concern for aquatic environments and may accumulate in aquatic organisms. In this study, 21 parent psychotropic pharmaceuticals and 8 metabolites from three categories of psychotropic drugs (anxiolytics, antiepileptics, and antidepressants) were evaluated in Gao–Bao–Shaobo lake (GBSL), a shallow lake in China. Among them, 18 psychotropic pharmaceuticals and 8 metabolites were detected in water samples from GBSL (0.2 up to ∼24.5 ng/L), and 13 psychotropic pharmaceuticals and 5 metabolites were identified in fish (1 up to ∼126.2 ng/g dw). In the wet season, concentrations of psychotropic pharmaceuticals and their metabolites showed an increase from the inflow to the discharge subarea. Carbamazepine and sertraline were the dominant pharmaceuticals detected in fish with bioaccumulation factors, exceeding 5000 L/kg. Physicochemical parameters (log Kow and MW) were negatively correlated with the pharmaceutical levels in fish. Carbamazepine posed a moderate risk to aquatic organisms in all subareas. Hazard quotient results showed that the consumption of fish from GBSL is unlikely to exhibit a direct adverse effect on humans. Our results indicated that a comprehensive understanding of psychotropic pharmaceutical contaminations in surface waters should consider not only the parent pharmaceuticals but also the subsequent accumulation of their metabolites in fish.
Carnosic acid (CA) has been reported to exhibit a variety of bioactivities including antioxidation, neuroprotection, and anti-inflammation; however, the impact of CA on subarachnoid hemorrhage (SAH) has never been elucidated. The current study was undertaken to explore the role of CA in early brain injury (EBI) secondary to SAH and the underlying mechanisms. Adult male Sprague-Dawley rats were perforated to mimic a clinical aneurysm with SAH. CA or vehicle was administered intravenously immediately after the SAH occurred. Mortality, SAH grade, neurologic function scores, brain water content, Evans blue extravasation, and the levels of reactive oxygen species (ROS) levels in the ipsilateral cortex were determined 24 h after the SAH occurred. Western blot, immunofluorescence, Fluoro-Jade C (FJC) and TUNEL staining were also performed. Our results showed that CA decreased ROS levels, alleviated brain edema and blood-brain barrier permeability, reduced neuronal cell death, and promoted neurologic function improvement. To probe into the potential mechanisms. We showed that CA increased SIRT1, MnSOD, and Bcl-2 expression, as well as decreased p66shc, Bax, and cleaved caspase-3 expression. Interestingly, sirtinol, a selective inhibitor of SIRT1, abolished the anti-apoptotic effects of CA. Taken together, these data revealed that CA has a neuroprotective role in EBI secondary to SAH. The potential mechanism may involve suppression of neuronal apoptosis through the SIRT1/p66shc signaling pathway. CA may provide a promising therapeutic regimen for management of SAH.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)