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Photoperiod has been well-documented to be involved in regulating many activities of animals. However, whether photoperiod takes part in mood control, such as fear response in fish and the underlying mode(s) of action remain unclear. In this study, adult zebrafish males and females (Danio rerio) were exposed to different photoperiods, Blank (12 h light: 12 h dark), Control (12 h light: 12 h dark), Short daylight (SD, 6 h light: 18 h dark) and Long daylight (LD, 18 h light: 6 h dark) for 28 days. After exposure, fear response of the fish was investigated using a novel tank diving test. After alarm substance administration, the onset to higher half, total duration in lower half and duration of freezing in SD-fish were significantly decreased, suggesting that short daylight photoperiod is capable of alleviating fear response in zebrafish. In contrast, comparing with the Control, LD didn't show significant effect on fear response of the fish. Further investigation revealed that SD increased the levels of melatonin (MT), serotonin (5-HT) and dopamine (DA) in the brain while decreased the plasma level of cortisol comparing to the Control. Moreover, the expressions of genes in MT, 5-HT and DA pathways and HPI axis were also altered consistently. Our data indicated that short daylight photoperiod might alleviate fear response of zebrafish probably through interfering with MT/5-HT/DA pathways and HPI axis.
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Melatonina , Fotoperiodo , Animales , Femenino , Masculino , Pez Cebra/metabolismo , Serotonina , Miedo , Melatonina/metabolismo , Dopamina/metabolismoRESUMEN
Tributyltin (TBT), a widely and persistently distributed organontin, has been well documented to disrupt reproduction and behaviors in animals due to its anti-aromatase activity. TBT has been also reported to enhance anxiety in several fish species, whereas the mechanism underlying remains largely unknown. To investigate the disruption of TBT on fish anxiety and the mechanisms possibly involved, adult male zebrafish (Danio rerio) were treated with TBT (100 and 500 ng/L) for 28 days and anxiety behavior was further investigated using a novel tank dive test. Result showed that TBT treatment significantly enhanced the total time of the fish spent in the lower half, delayed the onset time to the higher half of the tank and increased the total duration of freezing of the fish, indicating an enhanced anxiety in TBT-treated fish. Accordingly, TBT sharply elevated the cortisol levels in plasma in a concentration-dependent manner, suggesting that the elevated cortisol level might be involved in the enhanced anxiety. Although the expression of crha was significantly increased and crhbp was significantly decreased in the brain of TBT-treated fish which is consistent to the elevated cortisol level, the expressions of actha and acthb were sharply down-regulated. In contrast, the expressions of genes responsible for the synthesis and action of serotonin (5-HT) (pet1, thp2 and htr1aa), dopamine (DA) (th1, slc6a3, drd2a and drd2b) and gamma-aminobutyric acid (GABA) (gad2 and gabrg2) were all significantly inhibited. The down-regulation of these pivotal genes acting in 5-HT, DA and GABA neurotransmitter systems in response to TBT corresponded well with the TBT-enhanced anxiety in fish. It was thus strongly suggested that these neurotransmitters might be also involved in TBT-enhanced anxiety in adult male zebrafish. The present study extended our understanding of the neurotoxicity of TBT on the anxiety control and behavioral modulation in fish.
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Ansiedad/inducido químicamente , Hidrocortisona/metabolismo , Neurotransmisores/metabolismo , Compuestos de Trialquiltina/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , Dopamina/metabolismo , Masculino , Serotonina/metabolismo , Transducción de Señal/efectos de los fármacos , Pez Cebra/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Objective To explore the molecular mechanism of human papillomavirus subtype 16(HPV-16)E7 oncogene-induced DNA re-replication in response to DNA damage. Methods Flow cytometry was performed to examine the cell cycle changes in RPE1 E7 cells stably expressing HPV-16 E7 and its control cell RPE1 Vector after DNA damage.Immunoblotting assay was used to evaluate the early mitotic inhibitor 1(Emi1)expression in RPE1 E7 and RPE1 Vector cells with or without DNA damage.The changes of the proportion of polyploidy was detected by flow cytometry in DNA-damaged RPE1 E7 cells interfered by Emi1 small interfering RNA. Results Compared with the control cells,the proportion of polyploids in RPE1 E7 cells was significantly increased in response to DNA damage(t=6.397,P=0.0031).Emi1 protein expression was significantly increased in DNA damaged RPE1 E7 cells(t=8.241,P=0.0012).The polyploid ratio of RPE1 E7 cells was significantly reduced after Emi1 was interfered by two independent small interfering RNAs(t=2.916,P=0.0434;t=3.452,P=0.0260). Conclusion In response to DNA damage,Emi1 promoted DNA re-replication caused by HPV-16 E7.
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Replicación del ADN , Daño del ADN , Papillomavirus Humano 16 , Mitosis , Proteínas Oncogénicas ViralesRESUMEN
Recently, we reported that Ilexgenin A exhibits anti-cancer activities and induces cell arrest. Here, we investigated the effect of Ilexgenin A on the inflammation, angiogenesis and tumor growth of hepatocellular carcinoma (HCC). Our current study revealed that Ilexgenin A significantly inhibited the inflammatory cytokines TNF-α and IL-6 levels and downregulated pro-angiogenic factor VEGF production and transcription in HepG2 cells. The underlying mechanism for Ilexgenin A effects appears to be through inhibiting STAT3 and PI3K pathways. Furthermore, we found that not only Ilexgenin A inhibited STAT3 and PI3K pathways in HepG2 cells but also blocked these signaling pathways in HUVECs. Most importantly, by employing two HCC xenografts models - HepG2 and H22, we showed that Ilexgenin A reduced tumor growth and exhibited synergy effect with Sorafenib. ELISA assay, histological analysis and immunohistochemistry examination revealed that the expression of VEGF and MVD was significantly decreased after the treatment with Ilexgenin A and the combination. Moreover, Ilexgenin A could enhance caspase-3/7 activity in vitro and transmission electron microscope indicated that the combination induced evident apoptosis of tumor cells and caused the structural changes of mitochondria in vivo. Although no apparent adverse effects occurred during the treatment period, Sorafenib monotherapy elicited hepatotoxicity for specific expression in the increased level of AST and the ratio of AST/ALT. However, the combination could remedy this adverse effect. In conclusion, the results described in the present study identifies Ilexgenin A as a promising therapeutic candidate that modulates inflammation, angiogenesis, and HCC growth.
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Inhibidores de la Angiogénesis/farmacología , Antiinflamatorios/farmacología , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Factor de Transcripción STAT3/metabolismo , Triterpenos/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Sinergismo Farmacológico , Células Hep G2 , Humanos , Ratones , Ratones Endogámicos BALB C , Niacinamida/farmacología , Fosforilación , SorafenibRESUMEN
Chronic stress causes a variety of psychiatric disorders such as anxiety and depression, but its mechanism is not well understood. Tripartite motif-containing protein 32 (TRIM32) was strongly associated with autism spectrum disorder, attention deficit hyperactivity disorder, anxiety and obsessive compulsive disorder based on a study of copy number variation, and deletion of TRIM32 increased neural proliferation and reduced apoptosis. Here, we propose that TRIM32 is involved in chronic stress-induced affective behaviors. Using a chronic unpredictable mild stress mouse depression model, we studied expression of TRIM32 in brain tissue samples and observed behavioral changes in Trim32 knockout mice. The results showed that TRIM32 protein but not its mRNA was significantly reduced in hippocampus in a time-dependent manner within 8 weeks of chronic stress. These stress-induced affective behaviors and reduction of TRIM32 protein expression were significantly reversed by antidepressant fluoxetine treatment. In addition, Trim32 knockout mice showed reduced anxiety and depressive behaviors and hyperactivities compared with Trim32 wild-type mice under normal and mild stress conditions. We conclude that TRIM32 plays important roles in regulation of hyperactivities and positively regulates the development of anxiety and depression disorders induced by chronic stress.
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Ansiedad/metabolismo , Depresión/metabolismo , Hipocampo/metabolismo , Estrés Psicológico/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Corteza Cerebral/metabolismo , Modelos Animales de Enfermedad , Eliminación de Gen , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Environmental estrogens (EEs) are found extensively in natural waters and negatively affect fish reproduction. Research on the reproductive toxicity of EEs mixtures in fish at environmentally relevant concentrations is scarce. In this study, adult male zebrafish were exposed for 60 days to EES (a mixture of EEs), EE2-low (5.55 ng/L, with an estrogenic potency equal to EES), and EE2-high (11.1 ng/L). After exposure, the expression levels of vtg1, vtg3, and esr1 in the livers in EES-treated fish remained unaltered, whereas they were significantly increased in EE2-treated fish. Both EE2-high and EES exposures notably reduced the gonad somatic index and sperm count. A disrupted spermatogenesis was also observed in the testes of EE2-high- and EES-exposed fish, along with an alteration in the expression of genes associated with spermatogonial proliferation (pcna, nanog), cell cycle transition (cyclinb1, cyclind1), and meiosis (aldh1a2, cyp26a1, sycp3). Both EE2 and EES significantly lowered plasma 11-ketotestosterone levels in males, likely by inhibiting the expression level of genes for its synthesis (scc, cyp17a1 and cyp11b2), and increased 17ß-estradiol (E2) levels, possibly through upregulating the expression of cyp19a1a. A significant increase in tnfrsf1a expression and the tnfrsf1a/tnfrsf1b ratio in EE2-high and EES-treated males also suggests increased apoptosis via the extrinsic pathway. Further investigation showed that both EE2-high and EES diminished the sexual behavior of male fish, accompanied with reduced E2 levels in the brain and the expression of genes in the kisspeptin/gonadotropin-releasing hormone system. Interestingly, the sexual behavior of unexposed females paired with treated males was also reduced, indicating a synergistic effect. This study suggests that EES have a more severe impact on reproduction than EE2-low, and EEs could interfere not only with spermatogenesis in fish, but also with the sexual behaviors of both exposed males and their female partners, thereby leading to a more significant disruption in fish reproduction.
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Estrógenos , Espermatogénesis , Contaminantes Químicos del Agua , Pez Cebra , Animales , Masculino , Pez Cebra/fisiología , Espermatogénesis/efectos de los fármacos , Femenino , Contaminantes Químicos del Agua/toxicidad , Estrógenos/toxicidad , Conducta Sexual Animal/efectos de los fármacos , Testículo/efectos de los fármacos , Testosterona/sangre , Testosterona/análogos & derivadosAsunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Receptor ErbB-2/genética , Trastuzumab/uso terapéutico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Neoplasias de los Conductos Biliares/genética , China , Colangiocarcinoma/genética , Femenino , Humanos , Lapatinib/uso terapéutico , Masculino , Retratamiento , Insuficiencia del TratamientoRESUMEN
Many groundwater construction projects such as South-to-North Water Diversion Project (SNWDP) were conducted for controlling groundwater overexploitation in the North China Plain (NCP). However, more insight is required into the magnitude and distribution of water table depth (WTD) in time and space over the NCP. This study evaluated the variability and the hotspots of WTD based on 83 unconfined monitoring wells and took trend, breakpoint, and time stability into consideration. We found the average WTD of unconfined aquifer for the Southern Hebei Plain generally increased continuously from 1998 to 2020 in spite of the operation of the SNWDP since 2014. However, the rise rate of WTD slows down in recent years and the WTD has decreased in certain subregions. We further divided these groundwater wells into five groups: climb accelerating (Group 1), increase decelerating (Group 2), first rise then descend (Group 3), first descend then rise (Group 4), decrease decelerating (Group 5), and reduce accelerating (Group 6). Moreover, we found that the number of wells that divided into Group1 to Group 5 account for 15 %, 41 %, 25 %, 18 %, and 1 % of the total number of observation wells. The breakpoints of all the wells are from 2001 to 2017 and most of the breakpoints were found before 2014, which demonstrates that other groundwater management strategies implemented in the Southern Hebei Plain prior to the operation of the SNWDP plays a crucial part. The hotspots area for group 1 is mainly distributed in the north region of Shijiazhuang City, group 2 is in southern region of piedmont plain, group 3 is in northern region of Baoding and south-west region of Xingtai City, and group 4 is in Cangzhou City and eastern region of Xingtai City. The method and framework of this study can be applied in other regions suffering from groundwater depletion.
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Surface runoff has dropped sharply in the mountainous area of the Hutuo River, posing a huge challenge to the sustainable use of groundwater in the North China Plain (NCP). The Taihang Mountain area is the main recharge source area of groundwater in the NCP. An in-depth study of spatial variation characteristics, influencing factors, and sources of hydrogeochemical characteristics of surface water and groundwater in the mountainous area of the Hutuo River can facilitate a comprehensive understanding of regional water resource status and sustainable utilization of water resources. Based on isotopic, hydrogeochemical, and mathematical statistics methods, this study analyzed spatial variation of hydrochemical characteristics in surface water and groundwater and its sources and main controlling factors. The results showed that the river water, well water, and spring water were all recharged by atmospheric precipitation in the mountainous areas of the Hutuo River. Under the combined influence of natural factors and human factors, the hydrogeochemical characteristics of river, well, and spring water showed large spatial differences. On the whole, the hydrochemical types of mainstreams were relatively concentrated. In the upper and lower mining reach areas, the mainstream water chemical type was dominated by Ca·Mg-SO4·HCO3, whereas that in the natural vegetation area (middle reach:between Qingshui River and Longhua River) was dominated by Ca·Mg-HCO3·SO4. In the upper stream, the main hydrochemical type of the Yukou River and Ehe River tributaries was Ca·Mg-SO4·HCO3, which was consistent with that of the main stream. The main hydrochemical types of the Muma River and Qingshui River tributaries were Ca-HCO3, Ca·Mg-HCO3, and Ca·Mg-HCO3·SO4 in the midstream. The main hydrochemical types of the Mianhe River and Yehe River tributaries were Ca-SO4, Ca·Mg-SO4, and Ca·Mg-SO4·HCO3. Mineral dissolution was still the main controlling factor for the hydrochemical characteristics of surface water and groundwater in the mountainous area of the Hutuo River. The contribution rates were 69.86% and 18.84% for mineral dissolution and human activities, respectively. Therefore, in the future, water resource utilization in the upper reaches of the Hutuo River should not only consider the issue of water quantity but also a series of water environment problems such as nitrate pollution and mining pollution caused by human activities.
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Understanding climate change and extreme climate is of great significance for ensuring food security and socio-economic development of the Songhua River Basin. Based on the daily precipitation, maximum temperature and minimum temperature data during 1961-2020 from 69 meteorological stations in and around the Songhua River Basin, we analyzed the temporal and spatial variations of extreme temperature and precipitation in the Songhua River Basin using 27 extreme climate indices recommended by the World Meteorological Organization, and linear trend method, Mann-Kendall trend test and ordinary Kriging interpolation methodology. The results showed that, from 1961 to 2020, except for cold speel duration, the extreme cold index in the study area showed a downward trend, while the extreme warm index, extreme value index and other temperature indices showed an upward trend. The increasing trend of the minimum temperature was greater than that of the maximum temperature. Icing days, cold speel duration and warm speel duration showed an increasing trend from south to north, while the minimum value of maximum temperature and that of minimum temperature showed opposite spatial characteristics. The high value areas of summer days and tropical nights were mainly distributed in the southwestern region, while there was no obvious spatial variations of cool days, warm nights, and warm days. Overall, except for cold speel duration, other extreme cold indices had a rapid decreasing trend in the north and west of the Songhua River Basin. In the warm index, summer days, warm nights, warm days, and warm speel duration had a rapid upward trend in the north and west, and tropical nights had the fastest rise in the southwest. In the extreme value index, the maximum of temperature rose fastest in the northwest, while the minimum rose fastest in the northeast. Except for consecutive dry days, the rest of precipitation indices showed an increasing trend, and the fastest rising areas were mainly in the north-central part of the Nenjiang River Basin, while some areas in the south of the Nenjiang River Basin became dry. Heavy precipitation days, very heavy precipitation days, heaviest precipitation days, consecutive wet days, very wet day precipitation, extremely wet day precipitation, and annual precipitation showed a gradual decreasing pattern from southeast to northwest. Overall, the Songhua River Basin was warming and wetting, but there were some differences among different regions, especially the northern and southern parts of the Nenjiang River Basin.
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Cambio Climático , Ríos , Temperatura , Estaciones del Año , Frío , ChinaRESUMEN
Carbamazepine (CBZ) is one of the widely distributed pharmaceutical residues in aquatic environments, yet few researches have addressed its chronic effect on the anxiety of fish, and the mechanisms possibly involved remained elusive. In this study, adult female zebrafish (Danio rerio) were exposed to environmental relevant concentrations of CBZ (CBZ-low, 10 µg/L; CBZ-high, 100 µg/L) for 28 days. After exposure, CBZ-high didn't affect the anxiety of fish. However, the onset time to the higher half of the tank was delayed and the total duration in the lower half of the tank was increased in CBZ-low fish, suggesting an increased anxiety. Further investigation indicated that CBZ-low significantly decreased the gamma-aminobutyric acid (GABA) level in the brain, while increased the serotonin (5-HT) level in the brain and cortisol level in plasma. Accordingly, the mRNA levels of genes in GABA (gad2, abat, gabrb2, gabrg2, gria1a and slc12a2) pathway and HPI (crha, actha, pc1 and pc2) axis were also altered. Despite the upregulation of tph2 was consistent with increased 5-HT level in the brain, significantly downregulated htr1aa and htr1b may indicate attenuated 5-HT potency. Although CBZ-high significantly reduced GABA level in the brain and increased cortisol level in plasma, the effects were dramatically alleviated than that of CBZ-low. Consistently, the expression of genes in HPI (crha, actha, pc1 and pc2) axis and GABA (gad2 and abat) pathway were also altered by CBZ-high, probably due to inconspicuous anxiety response of CBZ-high. Briefly, our data suggested that low concentration of CBZ disrupted zebrafish anxiety by interfering with neurotransmission and endocrine system, thereby bringing about adverse ecological consequences.
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Contaminantes Químicos del Agua , Pez Cebra , Animales , Femenino , Pez Cebra/metabolismo , Serotonina/metabolismo , Hidrocortisona/metabolismo , Carbamazepina/toxicidad , Ansiedad/inducido químicamente , Ácido gamma-Aminobutírico , Contaminantes Químicos del Agua/toxicidad , Contaminantes Químicos del Agua/metabolismoRESUMEN
The three provinces of Northeast China are crucial to national commodity grain production. Soils in those areas have begun to severely degrade after long-term high-intensity use, with wind erosion as one of the main reasons. Based on meteorological and soil data from 1981 to 2019, we evaluated the spatial-temporal characteristics of wind erosion on bare land in the three provinces of Northeast China by using the revised wind erosion equation (RWEQ), and analyzed the contributions of meteorological factors to wind erosion on bare land. The results showed that, the meteorological factors of wind erosion were overall high in southwestern part and low in northeastern part of the region. In general, wind erosion in the region was substantial, especially in Liaoning. During the 39 years, wind erosion significantly increased throughout the whole year and during the growing season, at a rate of 129 and 105 t·km-2 per decade, respectively. The obvious increase in wind erosion was observed in the northwest Liaoning, Liaohe Plain, and Changbai Mountain area. Wind speed and air temperature were the main factors affecting wind erosion during the year and non-growing season, which contributed less during the growing season when precipitation contributed the most. We concluded that climate change has aggravated soil wind erosion in the three provinces of Northeast China.
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Cambio Climático , Viento , Suelo , China , TemperaturaRESUMEN
OBJECTIVE: To study the expression of gene associated with retinoid-interferon-induced mortality-19(GRIM-19) in preimplantation embryo of mice and explore its role in embryonic development. METHODS: The protein and mRNA expressions of GRIM-19 in 2-cell, 4-cell, 8-cell, morula, and blastocyst phases of mice preimplantation embryo were detected by Western blot analysis and Real-time polymerase chain reaction (PCR). RESULTS: GRIM-19 was continuously expressed in every stage of preimplantation embryo of mice. Western blot analysis and Real-time PCR demonstrated a gradual increase of GRIM-19 expression from 2-cell, which reached a peak in 8-cell phase and then decreased progressively. CONCLUSIONS: The expression of GRIM-19 in mouse preimplantation embryos changes as at different developmental phases. GRIM-19 may play an important role during embryonic development.
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Blastocisto/metabolismo , Interferones/farmacología , NADH NADPH Oxidorreductasas/metabolismo , Tretinoina/farmacología , Animales , Blastocisto/efectos de los fármacos , Femenino , Ratones , NADH NADPH Oxidorreductasas/genética , Embarazo , ARN Mensajero/genéticaRESUMEN
To retrospectively compare the clinical efficacy and safety of CT-guided percutaneous injection of lobaplatin vs. ethanol for chemical ablation combined with radiofrequency ablation (RFA) in patients with hepatocellular carcinomas (HCCs) in high-risk locations. From January 2017 to June 2018, a total of 41 patients with HCCs in high-risk locations were enrolled and divided into two groups: percutaneous lobaplatin injection (PLI+RFA) group and percutaneous ethanol injection (PEI+RFA) group. The mixture of lobaplatin or ethanol was accurately injected into the high-risk part of the tumors, while RFA ablated the non-high-risk part. The efficacy and safety were compared between the two groups. 41 patients had 51 lesions in high-risk locations, including 24 cases with 30 lesions in PLI+RFA group and 17 cases with 21 lesions in PEI+RFA group. The complete ablation rate was 93.3% (28/30) in PLI+RFA group and 90.5% (19/21) in PEI+RFA group (P=1.000). The 2-year local tumor progression rate of PLI+RFA group and PEI+RFA group was 20.0% (6/30) and 19.0% (4/21), respectively (P=1.000). No significant differences were found in time to progression and overall survival between the two groups (P=0.501 and P=0.424, respectively). The incidence and severity of adverse events between the two groups were similar (P > 0.05). No severe complications were observed in both groups. Percutaneous lobaplatin injection combined with RFA in the treatment of HCC in high-risk locations may achieve the complete ablation rate similar to percutaneous ethanol injection combined with RFA, but further research is needed to confirm.
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The Yongding River basin is an important water conservation and ecological barrier area in the Northwest of Hebei Province. Reduced runoff and deterioration of the water environment in this area have become increasingly prominent under the effects of climate change and intensive human activities. Clarifying the chemical characteristics and factors of surface water and groundwater in the upper Yongding River basin can provide data and support for the sustainable use of water resources. Stable isotopes of hydrogen and oxygen (δ2H and δ18O) were used to study the sources of surface water and groundwater. Mathematical statistics and hydrogeochemical methods were then used to analyze the regional hydrogeochemical processes and factors of surface water and groundwater. The results showed that precipitation was the main source of surface water and groundwater. Under the effects of natural factors and human activities, the Yang River and Sanggan River basins exhibited significant differences in surface water chemistry. The sub-basins were ranked by ion concentration as follows: Sanggan River>Yang River. The main cation and anions of the Sanggan River basin were Na+, Cl-, and SO42-, while in the Yang River basin, Ca2+ and HCO3- were the most common. The water chemistry of the Sanggan River exhibited greater variation than that of the Yang River. Surface water chemistry were mainly controlled by mineral dissolution and evaporation, but human activities were reflected in different sub-basins. Surface water in the Sanggan River basin was affected by industrial wastewater discharge, while that of the Yang River basin was affected by agricultural production and cities. However, the continuous increase of Cl- and SO42- concentrations, caused by industrial wastewater discharge and acid rain, was the limiting factor for sustainable use of surface water resources. In future, surface water in Sanggan River basin should be used with consideration to the effects of both total salinity and chemical composition of the water, while in Yang River, a focus should be placed on total salinity. The use of surface water resources in accordance with local conditions is an effective measure for the sustainable use of water resources and the restoration of groundwater levels in this region.
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Agua Subterránea , Ríos , Monitoreo del Ambiente , Actividades Humanas , Humanos , AguaRESUMEN
Tributyltin (TBT), an aromatase inhibitor, has been found to disrupt gametogenesis and reproductive behavior in several fish species. However, whether TBT is capable of affecting other behaviors such as aggressive behavior and fear response in fish and the underlying mode(s) of action remain unclear. To study aggressive behavior, adult zebrafish (Danio rerio) males were continuously exposed to two nominal concentrations of TBT (TBT-low, 100â¯ng/L and TBT-high, 500â¯ng/L) for 28 days. To study the fear response, the fish were divided into four groups (Blank and Control, 0â¯ng/L TBT; TBT-low, 100â¯ng/L; and TBT-high, 500â¯ng/L). The fish were then treated with DW (Blank) or with alarm substance (AS) (Control, TBT-low and TBT-high). After exposure, the aggressive behavior of the fish was tested using the mirror test (mirror-biting frequency, approaches to the mirror and duration in approach zone).and fighting test (fish-biting frequency) The mirror-biting frequency, approaches to the mirror, duration in approach zone and fish-biting frequency of the TBT-exposed fish increased significantly compared to those of the control fish, indicating enhanced aggressive behavior. The fear response parameters tested using the novel tank dive test (onset time to the higher half, total duration in the lower half and the frequency of turning) of the TBT-exposed fish were also significantly increased after AS administration, suggesting an enhanced fear response. Further investigation revealed that TBT treatment elevated the plasma level of 11-ketotestosterone (11-KT) and decreased the plasma level of estradiol (E2) in a concentration-dependent manner. Moreover, TBT up-regulated the mRNA levels of ar, c-fos and bdnf1, and suppressed the expression of btg-2 in fish. In addition, exposure to AS increased the plasma level of cortisol and down-regulated the mRNA expression levels of genes involved in 5-HT synthesis (such as tph1b and pet1) in both control and TBT-treated fish. AS significantly suppressed the mRNA level of tph1b, tph2, pet1 and npy in the TBT-high group compared to the control fish. The present study demonstrates that TBT enhances aggressive behavior and fear responses in male zebrafish probably through altering plasma levels of 11-KT, E2 and cortisol and altering the expression of genes involved in the regulation of aggressive behavior (ar, c-fos, bdnf1 and btg-2) and fear responses (tph1b, tph2, pet1 and npy). The present study greatly extends our understanding of the behavioral toxicity of TBT to fish.
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Agresión/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Miedo/efectos de los fármacos , Compuestos de Trialquiltina/toxicidad , Pez Cebra/fisiología , Animales , Masculino , Contaminantes Químicos del Agua/toxicidadRESUMEN
The multidrug resistance protein MRP1 is an ATP binding cassette (ABC) transporter that confers resistance to many anticancer drugs and regulates redox homeostasis, inflammation, and hormone secretion. MRP1 actively transports compounds across cell membranes, and the presence of glutathione (GSH) is required in many cases. However, the process of MRP1-mediated substrate transportation has been poorly understood. With extensive molecular dynamics simulations, we have found a sandwich-like structure which is generated by GSH, a transmembrane α-helices 11 (TM11)-TM17 axis, and anticancer drugs. This structure is crucial in MRP1 transportation. It triggers the motion of TM11 and TM17, followed by the movement of nucleotide-binding domains 1 (NBD1) and 2 (NBD2), and finally an occluded structure is formed. Trp1246, Lys332, and Phe594 were identified as the main contributors in the formation of the sandwich-like structure. Our findings clearly explain the synergy of GSH with an anticancer drug in MRP1 transportation and have significant meanings for the rational design of novel inhibitors against MRP1.
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Antineoplásicos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Transporte Biológico , Glutatión/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismoRESUMEN
Tributyltin (TBT) was reported to affect sexual behavior and gametogenesis in ï¬sh. However, the modes of action involved are largely unclear. In order to elucidate the toxicological mechanisms of TBT in reproduction, zebrafish (Danio rerio) males were exposed to TBT at concentrations of 100 and 500 ng/L for 28 days. After exposure, the sperm count of the treated fish was sharply decreased though the testis weight and gonadosomatic index remained unchanged. Moreover, reduced number of spermatogonia and spermatozoa and increased spermatocytes were observed in TBT-treated fish by histological observation and PCNA-immunostaining. Increased number of apoptotic-positive spermatocytes was also present in TBT-treated fish, indicating an enhanced apoptosis in these cells. Consistent to decreased number of spermatogonia, down-regulated expressions of genes responsible for germ cell proliferation (cyclind1 and pcna) were observed in TBT-treated fish. In contrast, TBT elevated the expressions of genes involved in meiotic entry and maintenance (aldhla2, sycp3 and dmc1) while suppressed the mRNA level of gene responsible for terminus of meiotic entry (cyp26a1), in agreement with arrested meiosis and reduced sperm count. Furthermore, TBT significantly elevated the ratios of bax/bcl-2 and tnfrsf1a/tnfrsf1b in testis, which are markers for intrinsic- and extrinsic-apoptotic pathways, consistent with the enhanced TUNEL positive signals in spermatocytes. Moreover, TBT also significantly affected the parameter of reproductive behaviors in treated fish (reflected by decreased frequency of meeting, visits and time spent in spawning area). Consistently, the expressions of genes responsible for the modulation of reproductive behaviors in brain (such as cyp19a1b, kiss2, gnrh3 and ompb) were significantly down-regulated in treated-fish. Interestingly, disrupted reproductive behaviors of untreated female fish were also observed in the present study. The present study indicated that TBT might affect the reproduction of zebrafish male by disrupting the spermatogenesis and reproductive behavior of the fish.
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Conducta Sexual Animal/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Compuestos de Trialquiltina/toxicidad , Contaminantes Químicos del Agua/toxicidad , Pez Cebra/fisiología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Femenino , Expresión Génica/efectos de los fármacos , Masculino , Meiosis/efectos de los fármacos , Meiosis/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Reproducción/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Espermatozoides/metabolismo , Testículo/efectos de los fármacos , Testículo/metabolismoRESUMEN
In this paper, based on ( α , m ) -convexity, we establish different type inequalities via quantum integrals. These inequalities generalize some results given in the literature.
RESUMEN
The authors discover a general k-fractional integral identity with multi-parameters for twice differentiable functions. By using this integral equation, the authors derive some new bounds on Hermite-Hadamard's and Simpson's inequalities for generalized [Formula: see text]-preinvex functions through k-fractional integrals. By taking the special parameter values for various suitable choices of function h, some interesting results are also obtained.