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Converting solar energy into storable hydrogen energy by employing green photocatalytic technology offers a reliable alternative for meeting the energy crisis. The polyoxometalates are a promising candidate for hydrogen production photocatalysts because of their unique electronic and structural properties and controllable design at the molecular level. Introducing noble metals was proven to be an effective method to greatly enhance the photocatalytic efficiency of polyoxometalates. Herein, two unprecedented compounds of hexameric Ru-POMs, Na4H10[As2RuIV2W11O18(OH)4(H2O)6{AsW8RuIVO31(OH)Cl}2(B-ß-AsW9O33)4]·93H2O (1) and Na2H19[AsRuIII2W11O20(OH)2(H2O)6(RuIIICl3)(B-ß-AsW9O33)6]·90H2O (2), were successfully self-assembled. The H2 evolution rates of 1 and 2 under optimal conditions were 3578.75 and 3027.69 µmol h-1 g-1 with TONs of 255 and 205, respectively. The stability of 1 was demonstrated by a series of characterizations. Besides, a possible photocatalytic mechanism was proposed.
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Autophagy is a lysosomal degradation pathway that degrades cytoplasmic proteins and organelles. Absence of autophagy in hepatocytes has been linked to promoting liver injury and tumorigenesis; however, the mechanisms behind why a lack of autophagy induces these complications are not fully understood. The role of mammalian target of rapamycin (mTOR) in impaired autophagy-induced liver pathogenesis and tumorigenesis was investigated by using liver-specific autophagy related 5 knockout (L-ATG5 KO) mice, L-ATG5/mTOR, and L-ATG5/Raptor double knockout (DKO) mice. We found that deletion of mTOR or Raptor in L-ATG5 KO mice at 2 months of age attenuated hepatomegaly, cell death, and inflammation but not fibrosis. Surprisingly, at 6 months of age, L-ATG5/mTOR DKO and L-ATG5/Raptor DKO mice also had increased hepatic inflammation, fibrosis, and liver injury, similar to the L-ATG5 KO mice. Moreover, more than 50% of L-ATG5/mTOR DKO and L-ATG5/Raptor DKO mice already developed spontaneous tumors, but none of the L-ATG5 KO mice had developed any tumors at 6 months of age. At 9 months of age, all L-ATG5/mTOR DKO and L-ATG5/Raptor DKO had developed liver tumors. Mechanistically, L-ATG5/mTOR DKO and L-ATG5/Raptor DKO mice had decreased levels of hepatic ubiquitinated proteins and persistent nuclear erythroid 2 p45-related factor 2 activation but had increased Akt activation compared with L-ATG5 KO mice. Conclusion: Loss of mTOR signaling attenuates the liver pathogenesis in mice with impaired hepatic autophagy but paradoxically promotes tumorigenesis in mice at a relatively young age. Therefore, the balance of mTOR is critical in regulating the liver pathogenesis and tumorigenesis in mice with impaired hepatic autophagy.
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Proteína 5 Relacionada à Autofagia/fisiologia , Autofagia/fisiologia , Neoplasias Hepáticas/etiologia , Serina-Treonina Quinases TOR/fisiologia , Animais , Carcinogênese , Hepatomegalia/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Proteína Regulatória Associada a mTOR/fisiologiaRESUMO
Scutellariae Radix is a kind of traditional Chinese medicine, which has the functions of heat-clearing and damp-drying, purging fire and detoxifying, hemostasis and miscarriage prevention. Modern pharmacological studies show that Scutellariae Radix has various effects, such as anti-oxidation, anti-inflammatory, liver protection and antiviral microorganisms. By searching the documents in the past ten years, the author has found that Scutellariae Radix and its active components play an important role in protecting the liver. It can prevent and cure liver injuries caused by different reasons, including acute or chronic hepatitis, liver fibrosis and liver cancer. Among all kinds(chemical, immunological, alcoholic, nonalcoholic, viral, ischemia-reperfusion, etc.) of acute or chronic hepatitis, most studies are on CCl_4 induced chemical liver injury. Scutellariae Radix and its active components can significantly reduce the serum transaminase level in hepatitis animals, and reduce the degree of liver pathological damage. The mechanisms include antioxidant stress, anti-inflammatory, anti-apoptosis, inhibition of immunity, anti-virus and regulation of lipid metabolism, etc. Scutellariae Radix and its active components can significantly inhibit the activation of hepatic stellate cells and reduce extracellular matrix, and its anti-fibrosis mechanism involves antioxidation, anti-inflammatory, inducing apoptosis of hepatic stellate cells and so on. Whether in vivo or in vitro, Scutellariae Radix and its active components show a good anti-hepatocarcinoma effect, especially on hepatocarcinoma. Its prevention and treatment mechanisms for hepatocarcinoma mainly include blocking cancer cell cycle, inhibiting cancer cell metastasis, promoting cancer cell apoptosis and inducing autophagy. It can be seen that Scutellariae Radix has multiple functions and mechanisms in liver protection, and has a great development potential. Therefore, this paper reviews the prevention and treatment effects and mechanism of Scutellariae Radix and its components on different liver diseases, in order to provide reference for in-depth study, development and clinical application in the prevention and treatment of liver disease.
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Medicamentos de Ervas Chinesas , Scutellaria baicalensis , Animais , Anti-Inflamatórios , Flavonoides , Medicina Tradicional ChinesaRESUMO
STUDY QUESTION: Does melatonin restore the benzo(a)pyrene (BaP)-induced meiotic failure in porcine oocytes? SUMMARY ANSWER: Melatonin effectively inhibits the increased reactive oxygen species (ROS) level and apoptotic rate in BaP-exposed porcine oocytes to recover the meiotic failure. WHAT IS KNOWN ALREADY: BaP, a widespread environmental carcinogen found in particulate matter, 2.5 µm or less (PM2.5), has been shown to have toxicity at the level of the reproductive systems. BaP exposure disrupts the steroid balance, alters the expression of ovarian estrogen receptor and causes premature ovarian failure through the rapid depletion of the primordial follicle pool. In addition, acute exposure to BaP has transient adverse effects on the follicle growth, ovulation and formation of corpora lutea, which results in transient infertility. STUDY DESIGN, SIZE, DURATION: Porcine oocytes were randomly assigned to control, BaP-exposed and melatonin-supplemented groups. BaP was dissolved in dimethylsulphoxide and diluted to a final concentration of 50, 100 or 250 µM with maturation medium, respectively. Melatonin was dissolved in the absolute ethanol and diluted with maturation medium to a final concentration of 1 nM, 100 nM, 10 µM and 1 mM, respectively. The in vitro cultured oocytes from each group after treatment were applied to the subsequent analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Acquisition of oocyte meiotic competence was assessed using immunostaining, fluorescent intensity quantification and/or immunoblotting to analyse the cytoskeleton assembly, mitochondrial integrity, cortical granule dynamics, ovastacin distribution, ROS level and apoptotic rate. Fertilization ability of oocytes was examined by sperm binding assay and IVF. MAIN RESULTS AND THE ROLE OF CHANCE: BaP exposure resulted in the oocyte meiotic failure (P = 0.001) via impairing the meiotic apparatus, showing a prominently defective spindle assembly (P = 0.003), actin dynamics (P < 0.001) and mitochondrion integrity (P < 0.001). In addition, BaP exposure caused the abnormal distribution of cortical granules (P < 0.001) and ovastacin (P = 0.003), which were consistent with the observation that fewer sperm bound to the zona pellucida surrounding the unfertilized BaP-exposed eggs (P < 0.001), contributing to the fertilization failure (P < 0.001). Conversely, melatonin supplementation recovered, at least partially, all the meiotic defects caused by BaP exposure through inhibiting the rise in ROS level (P = 0.015) and apoptotic rate (P = 0.001). LIMITATIONS, REASONS FOR CAUTION: We investigated the negative impact of BaP on the oocyte meiotic maturation in vitro, but not in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Our findings not only deeply clarify the potential mechanisms of BaP-induced oocyte meiotic failure, but also extend the understanding about how environmental pollutants influence the reproductive systems in humans. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the National Natural Science Foundation of China (31571545) and the Natural Science Foundation of Jiangsu Province (BK20150677). The authors have no conflict of interest to disclose.
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Benzo(a)pireno/toxicidade , Meiose/efeitos dos fármacos , Melatonina/farmacologia , Oócitos/citologia , Oócitos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Carcinógenos Ambientais/toxicidade , China , Feminino , Fertilização/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Mitocôndrias/efeitos dos fármacos , Oócitos/metabolismo , Oogênese/efeitos dos fármacos , Material Particulado/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Interações Espermatozoide-Óvulo/efeitos dos fármacos , Sus scrofaRESUMO
Narrowing the income gap between urban and rural areas is the key to achieving common prosperity in China. On the basis of analyzing the mechanism of climate change's impact on urban-rural income gap, this article empirically analyzes the impact of climate change on urban-rural income gap using provincial-level panel data of 30 provinces in China from 2011 to 2020. Research indicates that climate change significantly impacts the urban-rural income gap at the 1% significance level, implying that climate change exacerbates the urban-rural income gap. This widening effect varies significantly across different regions, particularly in the western regions and areas with lower fiscal support for agriculture. Further analysis reveals that there is a mediating role between the total agricultural output value and resource mismatch in the impact of climate change on urban-rural income inequality; the digital rural construction plays a regulatory role in the impact of climate change on the urban-rural income gap. On this basis, policy recommendations are proposed to promote the development of climate-resilient agriculture, improve the meteorological forecast and early warning system, increase financial support, and optimize the allocation of agricultural resources.
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Mudança Climática , Renda , População Rural , China , Agricultura , População Urbana , HumanosRESUMO
As a regulator in renin-angiotensin-aldosterone system, angiotensin-converting enzyme 2 (ACE2) closely correlated with tumor progression of pancreatic cancer, meantime, was easily affected by a variety of factors. [99mTc]Tc-cyc-DX600 SPECT was established as an ACE2-specific imaging protocol to figure out the ACE2 status in pancreatic tumor. BALB/C-NU mice were used to prepare the subcutaneous cell derived xenograft (CDX) models with HEK-293T or HEK-293T/hACE2 cells to validate ACE2 specificity of [99mTc]Tc-cyc-DX600 SPECT and establish SPECT imaging protocol. On the basis of [99mTc]Tc-cyc-DX600 SPECT and [18F]F-FDG PET/CT, ACE2-dependence on tumor size and tumor metabolism were further verified on orthotopic pancreatic cancer model with KPC cells. Immunohistochemical analysis was used to demonstrate the findings on ACE2 SPECT. [99mTc]Tc-cyc-DX600 was of superior tumor uptake in HEK-293T/hACE2 CDX than wild type (6.74 ± 0.31 %ID/mL vs 1.83 ± 0.26 %ID/mL at 1.5 h post injection (p.i.); 3.14 ± 0.31 %ID/mL vs 1.16 ± 0.15 %ID/mL at 4.5 h p.i.). For the CDX models with PANC-1 cells, a significant negative correlation between the slope of tumor volume and tumor uptake was observed (r = -0.382 for the 1-4th day; r = -0.146 for the 1-5th day; r = -0.114 for the 1-6th day; r = -0.152 for the 1-7th day; but P > 0.05 for all). For orthotopic pancreatic cancer model, the linear correlation between FDG PET and ACE2 SPECT of the pancreatic lesions was negative (r = -0.878), the quantitative values of ACE2 SPCET was positively correlated with the volume of primary lesions (r = 0.752) and also positively correlated with the quantitative values of ACE2 immunohistochemical analysis (r = 0.991). Conclusively, [99mTc]Tc-cyc-DX600 SPECT is an ACE2-specific imaging protocol with clinical translational potential, adding multidimensional information on the disease progression of pancreatic cancer.
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Radium-223 dichloride is the first approved alpha particle-emitting radiopharmaceutical for patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. A large percentage of intestinal enrichment and a slow clearance rate were the main causes of gastrointestinal adverse events after 223RaCl2 administration. The molecular weight of sodium alginate in aqueous solution was determined to be 656 kDa. Sodium alginate exhibits a higher affinity for adsorbing Ra2+ compared to other metal ions belonging to the second main group. Sodium alginate as low as 0.5 g/rat reduced intestinal damage by remodeling 223RaCl2 distribution without affecting bone resorption. Intestinal villi were preserved and enterocyte activity was maintained after sodium alginate intervention. Sodium alginate reduced DNA oxidative damage and lipid peroxidation and maintained endogenous antioxidant status by increasing superoxide dismutase levels and total antioxidant capacity. Furthermore, sodium alginate treatment mitigated DNA damage and apoptosis. The administration of sodium alginate effectively maintained the integrity of the intestinal microbiota, which had undergone perturbations due to radiation exposure. This study demonstrated that sodium alginate could be applied to reduce the adverse effects caused by radiation exposure to the intestine during 223RaCl2-treated and reduced intestinal damage resulted from 223RaCl2 accumulation without affecting bone uptake.
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Neoplasias Ósseas , Neoplasias da Próstata , Masculino , Humanos , Ratos , Animais , Neoplasias Ósseas/tratamento farmacológico , Compostos Radiofarmacêuticos , Neoplasias da Próstata/patologia , Intestinos/patologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêuticoRESUMO
Farmers' entrepreneurship is an important engine to comprehensively help promote rural revitalization. Based on data from the China Household Finance Survey (CHFS2019), this paper empirically examines the effect of digital literacy on farmers' entrepreneurial behavior using the Probit model and instrumental variable method; and examines the mediating role of health status in this effect using the mediation effect model, combined with the Sobel and Bootstrap tests. The results of the study showed that (1) digital literacy positively influenced farmers' entrepreneurial behavior at the 1% significant level, and this positive influence showed some differences across gender and age; (2) health status played a mediating effect in the positive influence of digital literacy on farmers' entrepreneurial behavior. Accordingly, policy recommendations are made to foster farmers' digital literacy, encourage farmers' entrepreneurship, and ensure farmers' "digital health" services.
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Agricultura , Fazendeiros , Humanos , Agricultura/métodos , Alfabetização , China , População RuralRESUMO
As persistent organic pollutants, short-chain chlorinated paraffins (SCCPs) have attracted wide attention in the field of environmental health risk and hazardous waste management. Efficient dechlorination of high content of SCCPs in plastic waste is the committed step for its detoxification and safety treatment. In this study, a high-efficiency and low-temperature process for dechlorination and hydrocarbons recovery from typical SCCPs (52#SCCPs) by subcritical water (SubCW) with alkali enhancer was developed. The introduction of alkali enhancer in the SubCW process had significantly enhanced effect on the dechlorination of 52#SCCPs, and the order of the enhanced effect of alkali enhancer for the dechlorination was NaOH > Na2CO3 > NaHCO3 > NH3·H2O > KOH. The dechlorination behaviors of 52#SCCPs in the NaOH-enhanced SubCW process were studied systematically under different conditions including temperature, residence time, alkali concentration, and volume ratio. The results showed that high-efficiency dechlorination (100 %) of 52#SCCPs could be achieved by the NaOH-enhanced SubCW process at low temperature for a short time (250 °C, 5 min). All of the chlorine released from the molecular chain of 52#SCCPs was transferred to the aqueous phase in the form of inorganic chlorine. The continuous HCl elimination reaction was the primary dechlorination mechanism for 52#SCCPs in the NaOH-enhanced SubCW process. After the dechlorination of 52#SCCPs, high value-added hydrocarbons such as 2,4-hexadiyne (31.74 %) could be obtained. The alkali-enhanced SubCW process proposed in this study is believed to be an environmentally friendly and high-efficiency method for dechlorination/detoxification and resource recovery of SCCPs.
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BACKGROUND AND PURPOSE: The paper observes regulation of the expression levels of NLRP3 and TLR4 in hippocampal CA1 neurons in CUMS mice by aerobic exercise with constructing CUMS depression mouse model, in order to explore the neuroprotective mechanism of aerobic exercise on the hippocampus of depressed mice. STUDY DESIGN AND METHOD: 24 healthy male 8-week-old C57BL/6 mice were randomly divided into CG, MG and ME. Thirteen stress-stimulating factors were randomly formulated into a CUMS stress-stimulating program. The mice were underwent 28 days of CUMS depression model, referenced clinical means for experimental research. The study was approved by the Ethics Committee of Yichun University (YCUEC IRB number LSK NO.2022.18). After model preparation, ME mice were subjected to moderate-intensity treadmill exercise training for 8 weeks. TST, FST and SPT were used to detect the depression-like behaviors of the mice in each group. Nissl staining was used to compare the cell morphology in the CA1 region of the mouse hippocampus. Immunohistochemical staining and western blot were used to detect the changes in the expression levels of NLRP3, TLR4 and other proteins in the CA1 region of the mouse hippocampus. RESULTS: The results of neurobehavioral assessment showed that, the immobility time of TST and FST were significantly increased, and SPT index was significantly decreased of MG mice. Compared with MG, ME mice significantly improved depression-like behaviors such as TST, FST and SPT index. Nissl staining showed that the morphology of neurons in CA1 region of hippocampus of MG mice were mostly vacuolar-like, with severe nuclear pyknosis. Abnormal morphological changes such as vacuolar-like and pyknotic pyknosis of neurons in the hippocampal CA1 region of ME mice were significantly reduced. Protein expression test showed that the number of NLRP3, TLR4, IL-1ß and IL-10 positive neurons in hippocampal CA1 region of MG mice increased significantly compared with CG, and the proportion of positive cells increased significantly, while NLRP3 and TLR4 positive neurons in the hippocampal CA1 region of ME mice were significantly reduced, the proportion of TLR4 positive cells was significantly reduced. CONCLUSION: Systematic moderate-intensity exercise can effectively improve the depression-like behavior of CUMS depressed mice through the expression of TLR4/NLRP3 inflammatory signaling pathway, and provide an effective experimental basis for the clinical rehabilitation treatment of depression.
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Região CA1 Hipocampal , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Masculino , Animais , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Receptor 4 Toll-Like/genética , Depressão/terapia , HipocampoRESUMO
Transarterial embolization (TAE) is a personalized technology that offers precise delivery of chemotherapeutic drugs or selective internal radiation therapy for hepatocellular carcinoma (HCC). Beta-emitting radionuclide embolisms for TAE (ß-based TARE) are commonly used in the clinic via inducing biochemical lethality on tumor cells, while alpha-emitting radionuclides-based embolisms for TAE (α-based TARE) are still under study. The feeding artery plays a key role in tumor growth, metastasis, and recurrence. In this research, the auricular central arteries (ACAs) of rabbits were embolized with silk fibroin-based microspheres (SFMs) or SFMs integrated with α (Ra-223) or ß (I-131) radionuclides to investigate the influence on vessels. TARE-induced tissue necrosis and the following neovascularization were measured by pathological analysis and 68Ga-DOTA-RGD PET/CT. The results showed that, compared to I-131, Ra-223 enhanced the growth inhibition of human hepatoma cells Huh-7 and induced more DNA double-strand breaks in vascular smooth muscle cells. Unlike ß-based TARE, which mainly led to extensive necrosis of surrounding tissues, α-based TARE induced irreversible necrosis of a limited area adjacent to the embolized vessels. RGD PET revealed the inhibition on neovascularization in α-based TARE (SUVmax = 0.053 ± 0.004) when compared with normal group (SUVmax = 0.099 ± 0.036), the SFMs-lipiodol group (SUVmax = 0.240 ± 0.040), and ß-based TARE (SUVmax = 0.141 ± 0.026), owing to the avoidance of the embolism-induced neovascularization. In conclusion, α-based TARE provided a promising strategy for HCC treatments via destroying the embolized vessels and inhibiting neovascularization.
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Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.
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BACKGROUND: High levels of gamma-aminobutyric acid (GABA) accumulate in plant tissues under various stresses. GABA accumulation is also influenced by cultivar. This aim of this study was to select the most promising cultivar of fava bean for GABA accumulation and to optimise the culture conditions for GABA production in germinated fava beans by response surface methodology based on central composite design (CCD). RESULTS: GABA content and glutamate decarboxylase activity in germinated seeds of cultivar S2 were significantly higher than those in other cultivars (P < 0.05). A significant negative correlation (r = -0.765, P < 0.05) between germination percentage and 1000-kernel weight was observed. There was a linear relationship between GABA content and sprout length (R(2) = 0.816). The regression model fitted to the experimental data of CCD was valid in predicting GABA production in germinated fava beans. Temperature and pH value of the culture solution had significant effects on GABA content in germinated fava beans. Under optimal culture conditions (33.6 degrees C, pH 3.19 and an air flow rate of 1.19 L min(-1)), GABA content reached up to 2.41 g kg(-1) dry weight, about 48 times that in raw seeds. CONCLUSION: Germinated fava bean is a good resource of GABA-rich food. Both cultivar and culture conditions have significant effects on GABA production.
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Meio Ambiente , Genótipo , Glutamato Descarboxilase/metabolismo , Plântula/metabolismo , Sementes/metabolismo , Vicia faba/metabolismo , Ácido gama-Aminobutírico/metabolismo , Germinação/fisiologia , Glutamato Descarboxilase/genética , Concentração de Íons de Hidrogênio , Modelos Lineares , Plântula/genética , Sementes/genética , Temperatura , Vicia faba/genética , Ácido gama-Aminobutírico/genéticaRESUMO
Efficient and green strategy for the chemical conversion and fixation of CO2 is an attractive topic. In this work, we reported an efficient catalytic system of organic base coupled ionic liquids that could catalyse the synthesis of quinazolinones via cyclization of 2-aminobenzonitriles with CO2 under mild conditions (e.g., 60 °C, 0.1 MPa). It was found that 1,8-diazabicyclo[5.4.0]undec-7-ene coupled 1-butyl-3-methylimidazole acetate ionic liquids (DBU/[Bmim][OAc]) displayed excellent performance in catalysing the reactions of CO2 with 2-aminobenzonitriles, and a series of quinazolinones were obtained in high yields at atmospheric pressure. Moreover, the ILs had high stability and reusability, and can be reused at least five times without considerable decrease in catalytic activity. This protocol could also be conducted on a gram scale, and may have promising and practical applications in the production of quinazolinones.
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Liver regeneration has become a new hotspot in the study of drug-induced liver injury (DILI). Baicalin has already been reported to alleviate acetaminophen (APAP)-induced acute liver injury in our previous study. This study aims to observe whether baicalin also promotes liver regeneration after APAP-induced liver injury and to elucidate its engaged mechanism. Baicalin alleviated APAP-induced hepatic parenchymal cells injury and enhanced the number of mitotic and proliferating cell nuclear antigen (PCNA)-positive hepatocytes in APAP-intoxicated mice. Baicalin increased hepatic PCNA and cyclinD1 expression in APAP-intoxicated mice. Baicalin induced the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, leading to the increased hepatic expression of interleukin-18 (IL-18) and IL-1ß in APAP-intoxicated mice. The results in vitro demonstrated that IL-18 promoted the proliferation of human normal liver L-02 cells. Moreover, the baicalin-provided promotion on liver regeneration in APAP-intoxicated mice was diminished after the application of NLRP3 inhibitor MCC950 and the recombinant mouse IL-18 binding protein (rmIL-18BP). Baicalin induced the cytosolic accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), and increased the interaction between Nrf2 with Nlrp3, ASC and pro-caspase-1 in livers from APAP-intoxicated mice. Furthermore, the baicalin-provided NLRP3 inflammasome activation and promotion on liver regeneration after APAP-induced liver injury in wild-type mice were diminished in Nrf2 knockout mice. In conclusion, baicalin promoted liver regeneration after APAP-induced acute liver injury in mice via inducing Nrf2 accumulation in cytoplasm that led to NLRP3 inflammasome activation, and then caused the increased expression of IL-18, which induced hepatocytes proliferation.
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Acetaminofen , Doença Hepática Crônica Induzida por Substâncias e Drogas , Doença Hepática Induzida por Substâncias e Drogas , Flavonoides , Regeneração Hepática , Acetaminofen/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Flavonoides/farmacologia , Inflamassomos , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genéticaRESUMO
As a well-known analgesic drug, acetaminophen (APAP) is commonly used to relieve pain for patients with chronic painful diseases. Our previous study has shown that long-term ingestion of APAP caused liver fibrosis in mice. This study further investigated the critical role of nuclear factor erythroid 2-related factor 2 (Nrf2) in regulating APAP-induced liver fibrosis in mice and the anti-fibrotic effect of natural compound andrographolide (Andro). Our results showed that hepatic collagen deposition and hepatic stellate cells (HSCs) activation induced by APAP were more serious in Nrf2 knock-out mice than in normal wild-type mice. Andro reduced HSCs activation in vitro, and also decreased hepatic collagen deposition and HSCs activation induced by APAP in mice. Andro alleviated liver oxidative stress injury induced by APAP in mice and reduced cellular formation of reactive oxygen species (ROS) in HSCs. Andro enhanced Nrf2 nuclear translocation and increased the expression of Nrf2 downstream antioxidant genes both in vitro and in vivo. Furthermore, the Andro-provided protection against APAP-induced liver fibrosis was diminished in Nrf2 knock-out mice. In summary, Nrf2 is critically involved in preventing liver fibrosis induced by long-term administration of APAP in mice, and Andro alleviates APAP-induced liver fibrosis by attenuating liver oxidative stress injury via inducing Nrf2 activation. This study points out the potential application of Andro in the treatment of liver fibrosis in clinic.
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Acetaminofen/toxicidade , Diterpenos/uso terapêutico , Cirrose Hepática/prevenção & controle , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Animais , Antioxidantes/metabolismo , Colágeno/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Hidroxiprolina/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Transporte Proteico/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Before fertilization, mammalian oocyte undergoes an asymmetric division which depends on eccentric positioning of the spindle at the oocyte cortex to form a polar body and an egg. Since the centriole is absent and, as a result, the polar array microtubules are not fully developed in oocytes, microtubules have seldom been considered as required for eccentric positioning of the spindle, while actin-related forces have instead been proposed to be primarily responsible for this process. However, the existing models are largely conflicting and the underlying mechanism of asymmetric division is still elusive. Here we show that poly(ADP-ribose) (PAR) is enriched at mouse oocyte cortical area throughout meiosis. Specific removal of cortical PAR results in an ectopic spindle and a failure of asymmetric division. During spindle migration, when the spindle deviates from the center of oocyte by a pushing force of cytoplasmic actin, the short polar array microtubules emanating from the juxtacortical spindle pole extend to the cortex and penetrate into cortical PAR, docking and stabilizing the spindle at the cortex which facilitates the asymmetric division. This process depends on the affinity between PAR and microtubule-associated proteins such as Spindly, which contributes to a physical link for cortical PAR and the spindle. Notably, fusing a PAR-binding domain to end-binding protein 3, a plus-end tracking protein at the polar array microtubules, restores the asymmetric division of oocytes with Spindly knockdown. Thus, our work demonstrates a comprehensive mechanism for oocyte spindle positioning and asymmetric division.
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Meiose , Oócitos/citologia , Poli Adenosina Difosfato Ribose/metabolismo , Actinas/metabolismo , Actinas/ultraestrutura , Animais , Células Cultivadas , Feminino , Camundongos , Camundongos Endogâmicos ICR , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Oócitos/metabolismo , Oócitos/ultraestrutura , Fuso Acromático/metabolismo , Fuso Acromático/ultraestruturaRESUMO
MicroRNA (miRNA) has been reported to play important roles in regulating drug-induced liver injury. Ethyl acetate extract isolated from rhizoma Dioscoreae bulbifera (EF) has been reported to induce hepatotoxicity in our previous studies. This study aims to observe the altered liver miRNA profile and its related signalling pathway involved in EF-induced hepatotoxicity. Serum alanine/aspartate aminotransferase assay showed that EF (450 mg/kg)-induced hepatotoxicity in mice. Results of miRNA chip analysis showed that the expression of eight miRNAs was up-regulated and of other nine miRNAs was down-regulated in livers from EF-treated mice. Further, the altered expression of miR-200a-3p, miR-5132-5p and miR-5130 was validated using real-time polymerase chain reaction (PCR) assay. There were total seven predicted target genes of miR-200a-3p, miR-5132-5p and miR-5130. Only one kyoto encyclopedia genes and genomes pathway was annotated using those target genes, which is protein processing in endoplasmic reticulum (ER). Furthermore, liver expression of DnaJ subfamily A member 1, a key gene involved in protein processing in ER based on the altered miRNAs, was increased in EF-treated mice. In conclusion, the results demonstrated that EF altered the expression of liver miRNA profile and its related signalling pathway, which may be involved in EF-induced hepatotoxicity.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Dioscorea/química , MicroRNAs/metabolismo , Extratos Vegetais/toxicidade , Rizoma/química , Transcriptoma/efeitos dos fármacos , Animais , Biomarcadores/sangue , Regulação para Baixo , Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Extratos Vegetais/química , Distribuição Aleatória , Organismos Livres de Patógenos EspecíficosRESUMO
Acetaminophen (APAP)-induced acute liver injury has already been well studied. However, whether long-term administration of APAP will cause liver fibrosis is still not very clear. This study aims to investigate the liver fibrosis in mice induced by long-term APAP treatment and the involvement of early growth response 1 (Egr-1). C57BL/6 mice were orally given with APAP (200, 300mg/kg) for 2, 6 or 10 weeks, respectively. Liver hydroxyproline content, collagen deposition and inflammatory cells infiltration were increased in mice treated with APAP (200, 300mg/kg) for 6 or 10 weeks. Liver mRNA expression of collagen (COL)1a1, Col3a1, transforming growth factor-ß (TGF-ß) and serum contents of COL1, COL3, TGF-ß were all increased in APAP-treated mice. Liver expression of α-smooth muscle actin (α-SMA) and phosphorylated ERK1/2 and Smad2/3 were all increased in APAP-treated mice. Furthermore, increased liver mRNA expression of Egr-1 and its subsequent nuclear translocation were found in APAP-treated mice. Egr-1 knock-out mice were further applied. APAP-induced liver fibrosis was found to be more serious in Egr-1 knock-out mice. N-acetyl-p-benzoquinoneimine (NAPQI), the APAP hepatotoxic metabolite, increased cellular mRNA expression of α-SMA, Col1a1, Col3a1, TGF-ß, induced ERK1/2 and Smad2/3 phosphorylation and Egr-1 nuclear translocation in hepatic stellate LX2 cells. In conclusion, long-term administration of APAP induced liver fibrosis in mice, and Egr-1 was critically involved in this process. This study points out a warning and reference for patients with long-term APAP ingestion in clinic.
Assuntos
Acetaminofen/toxicidade , Analgésicos/toxicidade , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Actinas/genética , Actinas/metabolismo , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Linhagem Celular , Colágeno/sangue , Colágeno/genética , Colágeno/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/efeitos dos fármacos , RNA Mensageiro/metabolismo , Proteína Smad2/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Diosbulbin B (DB) is the main hepatotoxic compound distributed in Dioscorea bulbifera L., which is widely used for the treatment of cancer and thyroid disorders in Asia. Scutellarin (SC) is the main compound in medicinal herb Scutellaria barbata D. Don, which is usually combined with Dioscorea bulbifera used for cancer therapy in clinic. AIM OF THE STUDY: This study aims to investigate the protection of SC against the liver injury induced by DB and its engaged mechanism. In addition, the anti-tumor effect of DB and SC is further observed in vivo. MATERIALS AND METHODS: The protection of SC against DB-induced liver injury was evaluated by detecting serum alanine/aspartate aminotransferases (ALT/AST) and alkaline phosphatase (ALP) activities, and further liver histological observation. The inflammatory response was assessed by detecting liver myeloperoxidase (MPO) activity, and serum levels of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interferon-γ (IFN-γ). Western-blot analysis was used to detect the protein expression. The oxidative liver injury was evaluated by detecting liver malondialdehyde (MDA) and glutathione (GSH) contents, and glutathione peroxidase (GPx) enzymatic activity. In vivo anti-tumor activity was analyzed in S180 tumor-bearing mice. RESULTS: SC significantly decreased the increased serum ALT/AST, and ALP activities induced by DB. Liver histological observation evidenced the protection of SC against DB-induced liver injury. SC obviously reduced the increased liver MPO activity and the number of MPO-positive staining cells induced by DB. SC also reversed the decreased expression of inhibitor of κB (IκB) and the translocation of nuclear factor κB (NF-κB) p65 from cytoplasm to nucleus induced by DB. In addition, SC significantly abrogated the increased serum levels of TNF-α, IL-6, and IFN-γ induced by DB. SC decreased the increased liver MDA content induced by DB significantly, and it also increased liver GSH level. The decreased GPx protein expression and its enzymatic activity induced by DB were both obviously reversed after SC treatment. The results in S180 tumor-bearing mice showed that SC combined with DB significantly inhibited tumor growth in vivo. CONCLUSIONS: Our results demonstrate that SC prevents DB-induced liver injury by attenuating NF-κB-mediated hepatic inflammation and ameliorating liver oxidative stress injury. Meanwhile, DB plus SC has significant anti-tumor activity in vivo. This study indicates the potential combination of DB with SC for the treatment of cancer in clinic.