The disinfection of drinking water is an important public health service that generates high quality, safe and palatable tap water. The disinfection of drinking water to reduce waterborne disease was an outstanding pu...The disinfection of drinking water is an important public health service that generates high quality, safe and palatable tap water. The disinfection of drinking water to reduce waterborne disease was an outstanding public health achievement of the 20 th century.An unintended consequence is the reaction of disinfectants with natural organic matter,anthropogenic contaminants and bromide/iodide to form disinfection by-products（DBPs）.A large number of DBPs are cytotoxic, neurotoxic, mutagenic, genotoxic, carcinogenic and teratogenic. Epidemiological studies demonstrated low but significant associations between disinfected drinking water and adverse health effects. The distribution of DBPs in disinfected waters has been well defined by advances in high precision analytical chemistry. Progress in the analytical biology and toxicology of DBPs has been forthcoming.The objective of this review was to provide a detailed presentation of the methodology for the quantitative, comparative analyses on the induction of cytotoxicity and genotoxicity of103 DBPs using an identical analytical biological platform and endpoints. A single Chinese hamster ovary cell line was employed in the assays. The data presented are derived from papers published in the literature as well as additional new data and represent the largest direct quantitative comparison on the toxic potency of both regulated and emerging DBPs.These data may form the foundation of novel research to define the major forcing agents of DBP-mediated toxicity in disinfected water and may play an important role in achieving the goal of making safe drinking water better.展开更多
AIM: To determine the therapeutic efficacy of resveratrol on ulcerative colitis (UC) and its underlying mechanisms. METHODS: The mouse UC model was developed using 5% dextran sulfate sodium. Mice were randomly divided...AIM: To determine the therapeutic efficacy of resveratrol on ulcerative colitis (UC) and its underlying mechanisms. METHODS: The mouse UC model was developed using 5% dextran sulfate sodium. Mice were randomly divided into four groups: normal control, UC model group, resveratrol low-dose group (RLD; 50 mg/kg per day), and resveratrol high-dose group (RHD; 100 mg/kg per day). RESULTS: The results showed that RLD regulates Treg/Th17 balance mainly through reducing the number of Th17 cells, whereas RHD regulates Treg/Th17 balance through both downregulating the number of Th17 cells and upregulating the number of Treg cells. Resveratrol can also regulate the level of plasma and intestinal mucosal cytokines including interleukin (IL)-10, transforming growth factor-beta 1, IL-6, and IL-17. The expressions of hypoxia inducible factor (HIF)-1 alpha, mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 were significantly decreased in the intestinal tissues of mice treated with resveratrol. CONCLUSION: The therapeutic efficacy of resveratrol in UC is dose dependent and closely associated with the regulation of Treg/Th17 balance and the HIF-1 alpha/mTOR signaling pathway.展开更多
Objective The aim of this review was to assess RNA interference (RNAi) and its possibility as a potential and powerful tool to develop highly specific double-stranded RNA ( dsRNA) or small interfering RNA (siRNA) base...Objective The aim of this review was to assess RNA interference (RNAi) and its possibility as a potential and powerful tool to develop highly specific double-stranded RNA ( dsRNA) or small interfering RNA (siRNA) based gene-silencing therapeutics. Data sources The data used in this review were obtained from the current RNAi-related research reports. Study selection dsRNA-mediated RNAi has recently emerged as a powerful reverse genetic tool to silence, gene expression in multiple organisms. The discovery that synthetic duplexes of 21 nucleotides siRNAs trigger gene-specific silencing in mammalian cells has further expanded the utility of RNAi in to the mammalian system. Data extraction The currently published papers reporting the discovery and mechanism of RNAi phenomena and application of RNAi on gene function in mammalian cells were included. Data synthesis Since the recent development of RNAi technology in the mammalian system, investigators have used RNAi to elucidate gene function, and to develop gene-based therapeutics by delivery exogenous siRNA or siRNA expressing vector. The general and sequence-specific inhibitory effects of RNAi that will be selective, long-term, and systemic to modulate gene targets mentioned in similar reports have caused much concern about its effectiveness in mammals and its eventual use as a therapeutic mordality. Conclusions It is certain that the ability of RNAi in mammals to silence specific genes, either when transfected directly as siRNAs or when generated from DNA vectors, will undoubtedly accelerate the study of gene function and might also be used as a potentially useful method to develop highly gene-specific therapeutic methods. It is also expected that RNAi might one day be used to treat human diseases.展开更多
Defects in autophagy-mediated clearance of α-synuclein may be one of the key factors leading to progressive loss of dopaminergic neurons in the substantia nigra. Moxibustion therapy for Parkinson’s disease has been ...Defects in autophagy-mediated clearance of α-synuclein may be one of the key factors leading to progressive loss of dopaminergic neurons in the substantia nigra. Moxibustion therapy for Parkinson’s disease has been shown to have a positive effect, but the underlying mechanism remains unknown. Based on this, we explored whether moxibustion could protect dopaminergic neurons by promoting autophagy mediated by mammalian target of rapamycin （mTOR）, with subsequent elimination of α-syn. A Parkinson’s disease model was induced in rats by subcutaneous injection of rotenone at the back of their necks, and they received moxibustion at Zusanli （ST36）, Guanyuan （CV4）and Fengfu （GV16）, for 10 minutes at every point, once per day, for 14 consecutive days. Model rats without any treatment were used as a sham control. Compared with the Parkinson’s disease group, the moxibustion group showed significantly greater tyrosine hydroxylase immunoreactivity and expression of light chain 3-II protein in the substantia nigra, and their behavioral score, α-synuclein immunoreactivity,the expression of phosphorylated mTOR and phosphorylated ribosomal protein S6 kinase （p-p70S6K） in the substantia nigra were significantly lower. These results suggest that moxibustion can promote the autophagic clearance of α-syn and improve behavioral performance in Parkinson’s disease model rats. The protective mechanism may be associated with suppression of the mTOR/p70S6K pathway.展开更多
Activation of the phosphoinositide 3 kinase(PI3K)/Akt/mammalian target of rapamycin(mTOR) pathway is common in breast cancer. There is preclinical data to support inhibition of the pathway, and phase Ⅰ to Ⅲ trials i...Activation of the phosphoinositide 3 kinase(PI3K)/Akt/mammalian target of rapamycin(mTOR) pathway is common in breast cancer. There is preclinical data to support inhibition of the pathway, and phase Ⅰ to Ⅲ trials involving inhibitors of the pathway have been or are being conducted in solid tumors and breast cancer. Everolimus, an mTOR inhibitor, is currently approved for the treatment of hormone receptor(HR)-positive, human epidermal growth factor receptor 2(HER2)-negative breast cancer. In this review, we summarise the efficacy and toxicity findings from the randomised clinical trials, with simplified guidelines on the management of potential adverse effects. Education of healthcare professionals and patients is critical for safety and compliance. While there is some clinical evidence of activity of mTOR inhibition in HR-positive and HER2-positive breast cancers, the benefits may be more pronounced in selected subsets rather than in the overall population. Further development of predictive biomarkers will be useful in the selection of patients who will benefit from inhibition of the PI3K/Akt/mTOR(PAM) pathway.展开更多
In the Linxia Basin on the northeast margin of the Tibetan Plateau, the Cenozoic strata are very thick and well exposed. Abundant mammalian fossils are discovered in the deposits from the Late Oligocene to the Early P...In the Linxia Basin on the northeast margin of the Tibetan Plateau, the Cenozoic strata are very thick and well exposed. Abundant mammalian fossils are discovered in the deposits from the Late Oligocene to the Early Pleistocene. The Dzungariotherium fauna comes from the sandstones of the Jiaozigou Formation, including many representative Late Oligocene taxa. The Platybelodon fauna comes from the sandstones of the Dongxiang Formation and the conglomerates of the Laogou Formation, and its fossils are typical Middle Miocene forms, such as Hemicyon, Amphicyon, Platybelodon, Choerolophodon, Anchitherium, and Hispanotherium. The Hipparion fauna comes from the red clay of the Liushu and Hewangjia Formations, and its fossils can be distinctly divided into four levels, including three Late Miocene levels and one Early Pliocene level. In the Linxia Basin, the Hipparion fauna has the richest mammalian fossils. The Equus fauna comes from the Wucheng Loess, and it is slightly older than that of the classical Early Pleistocene Nihewan Fauna. The mammalian faunas from the Linxia Basin provide the reliable evidence to divide the Cenozoic strata of this basin and correlate them with European mammalian sequence.展开更多
Rapamycin treatment has been shown to increase autophagy activity and activate Akt phosphorylation, suppressing apoptosis in several models of ischemia reperfusion injury. However, little has been studied on the neuro...Rapamycin treatment has been shown to increase autophagy activity and activate Akt phosphorylation, suppressing apoptosis in several models of ischemia reperfusion injury. However, little has been studied on the neuroprotective effects on spinal cord injury by activating Akt phosphorylation. We hypothesized that both effects of rapamycin, the increased autophagy activity and Akt signaling, would contribute to its neuroprotective properties. In this study, a compressive spinal cord injury model of rat was created by an aneurysm clip with a 30 g closing force. Rat models were intraperitoneally injected with rapamycin 1 mg/kg, followed by autophagy inhibitor 3-methyladenine 2.5 mg/kg and Akt inhibitor IV 1 μg/kg. Western blot assay, immunofluorescence staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay were used to observe the expression of neuronal autophagy molecule Beclin 1, apoptosis-related molecules Bcl-2, Bax, cytochrome c, casp ase-3 and Akt signaling. Our results demonstrated that rapamycin inhibited the expression of mTOR in injured spinal cord tissue and up-regulated the expression of Beclin 1 and phosphorylated-Akt. Rapamycin prevented the decrease of bcl-2 expression in injured spinal cord tissue, reduced Bax, cytochrome c and caspase-3 expression levels and reduced the number of apoptotic neurons in injured spinal cord tissue 24 hours after spinal cord injury. 3-Methyladenine and Akt inhibitor IV intervention suppressed the expression of Beclin-1 and phosphorylated-Akt in injured spinal cord tissue and reduced the protective effect of rapamycin on apoptotic neurons. The above results indicate that the neuroprotective effect of rapamycin on spinal cord injury rats can be achieved by activating autophagy and the Akt signaling pathway.展开更多
About 75% of all breast cancers are estrogen receptor(ER)-positive. They generally have a more favorable clinical behavior, prognosis, and pattern of recurrence, and endocrine therapy forms the backbone of treatment. ...About 75% of all breast cancers are estrogen receptor(ER)-positive. They generally have a more favorable clinical behavior, prognosis, and pattern of recurrence, and endocrine therapy forms the backbone of treatment. Anti-estrogens(such as tamoxifen and fulvestrant) and aromatase inhibitors(such as anastrozole, letrozole, and exemestane) can effectively control the disease and induce tumor responses in a large proportion of patients. However, the majority of patients progress during endocrine therapy(acquired resistance) and a proportion of patients may fail to respond to initial therapy(de novo resistance). Endocrine resistance is therefore of clinical concern and there is great interest in strategies that delay or circumvent it. A deeper knowledge of the molecular mechanisms that drive endocrine resistance has recently led to development of new strategies that have the promise to effectivelyovercome it. Many resistance mechanisms have been described, and the crosstalk between ER and growth factor receptor signaling pathways seems to represent one of the most relevant. Compounds that are able to inhibit key elements of these pathways and restore endocrine sensitivity have been studied and more are currently under development. The aim of this review is to summarize the molecular pathophysiology of endocrine resistance in breast cancer and its impact on current clinical management.展开更多
Background:Cervical cancer has the fourth highest incidence and mortality rate of all cancers in women worldwide;让seriously harms their physical and mental health.The aim of this study was to observe the roles and pr...Background:Cervical cancer has the fourth highest incidence and mortality rate of all cancers in women worldwide;让seriously harms their physical and mental health.The aim of this study was to observe the roles and preliminary mechanism of Taurine(Tau)-induced apoptosis in cervical cancer cells.Methods:Cells from the human cervical cancer cell line SiHa were transfected with the recombinant plasmid pEGFP-N1-MST1(mammalian sterile 20-like kinase 1);then,the cell proliferation activity was analyzed by the MTT assay,cell apoptosis by flow cytometry,and the related protein levels by Western blotting.Results:Tau inhibited the proliferation of SiHa cells and induced apoptosis in these cells(the apoptotic rate was 21.95%in the Tau 160 mmol/L group and 30%in the Tau 320 mmol/L group),upregulated the expression of the MST1(control,0.53;Tau 40-320 mmol/L groups,0.84-1.45)and Bax(control,0.45;Tau 40-320 mmol/L groups,0.64-1.51)proteins(P<0.01),and downregulated the expression of Bcl-2(control,1.28,Tau 40-320 mmol/L groups,0.93-0.47)(P<0.01).The overexpression of MST1 promoted the apoptosis of SiHa cells,enhanced the apoptosis-inductive effects of Tau(P<0.01),upregulated the expression of the proapoptotic proteins p73,p53,PUMA(p53 upregulated modulator of apoptosis),and caspase-3,and promoted the phosphorylation of YAP(Yes-associated protein).Conclusions:Tau inhibited the proliferation and induced the apoptosis of cervical cancer SiHa cells.The MST1 protein plays an important role in the Tau-induced apoptosis of cervical cancer cells.展开更多
Information from eleven profiles of eolian earthy red silty clay and loess of the middle of the Late Miocene to Holocene age have been studied and correlated. A complete summary profile with projected isotopic ages an...Information from eleven profiles of eolian earthy red silty clay and loess of the middle of the Late Miocene to Holocene age have been studied and correlated. A complete summary profile with projected isotopic ages and fossil-bearing beds has been assembled. The profile is subdivided into 12 stratigraphic units proceeding from the lower (older) to the upper (younger) one. The character of mammalian assemblages contained in each unit was analyzed and the corresponding pa- leo-climatic environments were deduced. The environmental character of each period and the change from the middle of the Late Miocene at about 8.0 Ma B.P. up to the Holocene progressed from the hot semiarid and semi-moist, warmer-moist, warm-moister of the Late Miocene. To slightly less warm moist, cool-dry, slight-warmer-moister of the Pliocene; later the cool to cold dry periods alternated frequently with the mild semiarid and semi-moist periods of the Quaternary. Vegetation progressed from the grasslands with sparse woods, wooded shrub-grasslands and subtropical forest-grasslands of the Late Miocene age to sparse grasslands and dry grasslands of the Pliocene; and to sparse grasslands, dry grasslands and tundras of the Quaternary. The climate changes in the Neogene were of low-amplitute in a generally warm-humid background. Those of the Quaternary were of higher am- plitude with a longer phase. Cool or cold dry and slightly warm semiarid and semi-moist climates al- ternated on a generally cool-dry background. The tendency since the start of the Quaternary was the change to more northern and western shift in the Loess Plateau, with progressively cooler and dryer conditions. The dramatic uplift of the Qinghai-Xizang (Tibet) Plateau and the forming and expansion of the Arctic ice sheet might be the main reasons of the more pronounced changes in the Quaternary.展开更多
Background The mammalian target of rapamycin （mTOR） pathway, a key cellular signaling pathway associated with various cellular functions, has distinct roles in the inflammatory process. In this study, the mTOR inhib...Background The mammalian target of rapamycin （mTOR） pathway, a key cellular signaling pathway associated with various cellular functions, has distinct roles in the inflammatory process. In this study, the mTOR inhibitor rapamycin （Rapa） was used to test whether inhibition of mTOR activation attenuates lipopolysaccharide （LPS）-induced acute lung injury （ALl） in a murine model.Methods Mice pretreated with Rapa or vehicle were given LPS intratracheally. Local cell numbers and inflammatory cytokines present in the bronchoalveolar lavage fluid （BAL）, wet-to-dry weight ratio, histopathology of the lungs, and survival were evaluated.Results The phosphorylation of S6, a major downstream target of mTOR, had a 3-fold increase in lung tissue after LPS stimulation, but the increase was blocked by Rapa. Rapa reduced the levels of TNF-α （LPS vs. LPS ＋ Rapa,（1672.74±193.73） vs. （539.17±140.48） pg/ml, respectively; P 〈0.01） and IL-6 （LPS vs. LPS ＋ Rapa： （7790.88±1170.54）vs. （1968.57±474.62） pg/ml, respectively; P 〈0.01） in the BAL fluid. However, Rapa had limited effects on the overall severity of ALI, as determined by the wet-to-dry weight ratio of the lungs, number of neutrophils in the BAL fluid, and changes in histopathology. In addition, Rapa failed to reduce mortality in the LPS-induced ALI model.Conclusions We confirmed that mTOR was activated during LPS-induced ALI and strongly inhibited by Rapa.Although Rapa reduced the levels of the mediators of inflammation, the overall severity and survival of the ALI murine model were unchanged.展开更多
Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma(HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase Ⅲ st...Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma(HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase Ⅲ studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/m TOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.展开更多
文摘The disinfection of drinking water is an important public health service that generates high quality, safe and palatable tap water. The disinfection of drinking water to reduce waterborne disease was an outstanding public health achievement of the 20 th century.An unintended consequence is the reaction of disinfectants with natural organic matter,anthropogenic contaminants and bromide/iodide to form disinfection by-products（DBPs）.A large number of DBPs are cytotoxic, neurotoxic, mutagenic, genotoxic, carcinogenic and teratogenic. Epidemiological studies demonstrated low but significant associations between disinfected drinking water and adverse health effects. The distribution of DBPs in disinfected waters has been well defined by advances in high precision analytical chemistry. Progress in the analytical biology and toxicology of DBPs has been forthcoming.The objective of this review was to provide a detailed presentation of the methodology for the quantitative, comparative analyses on the induction of cytotoxicity and genotoxicity of103 DBPs using an identical analytical biological platform and endpoints. A single Chinese hamster ovary cell line was employed in the assays. The data presented are derived from papers published in the literature as well as additional new data and represent the largest direct quantitative comparison on the toxic potency of both regulated and emerging DBPs.These data may form the foundation of novel research to define the major forcing agents of DBP-mediated toxicity in disinfected water and may play an important role in achieving the goal of making safe drinking water better.
基金Supported by Outstanding Doctoral Thesis Support Project of Guangdong Province,No.85514045the Technical Research and Development Project of Shenzhen,No.JCYJ20130402092657774the Medical Research Foundation of Guangdong Province,No.B2013347
文摘AIM: To determine the therapeutic efficacy of resveratrol on ulcerative colitis (UC) and its underlying mechanisms. METHODS: The mouse UC model was developed using 5% dextran sulfate sodium. Mice were randomly divided into four groups: normal control, UC model group, resveratrol low-dose group (RLD; 50 mg/kg per day), and resveratrol high-dose group (RHD; 100 mg/kg per day). RESULTS: The results showed that RLD regulates Treg/Th17 balance mainly through reducing the number of Th17 cells, whereas RHD regulates Treg/Th17 balance through both downregulating the number of Th17 cells and upregulating the number of Treg cells. Resveratrol can also regulate the level of plasma and intestinal mucosal cytokines including interleukin (IL)-10, transforming growth factor-beta 1, IL-6, and IL-17. The expressions of hypoxia inducible factor (HIF)-1 alpha, mammalian target of rapamycin (mTOR), and signal transducer and activator of transcription 3 were significantly decreased in the intestinal tissues of mice treated with resveratrol. CONCLUSION: The therapeutic efficacy of resveratrol in UC is dose dependent and closely associated with the regulation of Treg/Th17 balance and the HIF-1 alpha/mTOR signaling pathway.
文摘Objective The aim of this review was to assess RNA interference (RNAi) and its possibility as a potential and powerful tool to develop highly specific double-stranded RNA ( dsRNA) or small interfering RNA (siRNA) based gene-silencing therapeutics. Data sources The data used in this review were obtained from the current RNAi-related research reports. Study selection dsRNA-mediated RNAi has recently emerged as a powerful reverse genetic tool to silence, gene expression in multiple organisms. The discovery that synthetic duplexes of 21 nucleotides siRNAs trigger gene-specific silencing in mammalian cells has further expanded the utility of RNAi in to the mammalian system. Data extraction The currently published papers reporting the discovery and mechanism of RNAi phenomena and application of RNAi on gene function in mammalian cells were included. Data synthesis Since the recent development of RNAi technology in the mammalian system, investigators have used RNAi to elucidate gene function, and to develop gene-based therapeutics by delivery exogenous siRNA or siRNA expressing vector. The general and sequence-specific inhibitory effects of RNAi that will be selective, long-term, and systemic to modulate gene targets mentioned in similar reports have caused much concern about its effectiveness in mammals and its eventual use as a therapeutic mordality. Conclusions It is certain that the ability of RNAi in mammals to silence specific genes, either when transfected directly as siRNAs or when generated from DNA vectors, will undoubtedly accelerate the study of gene function and might also be used as a potentially useful method to develop highly gene-specific therapeutic methods. It is also expected that RNAi might one day be used to treat human diseases.
基金supported by the National Natural Science Foundation of China,No.81403456,81473788a grant from the Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion,No.HBPCIC-2016-003
文摘Defects in autophagy-mediated clearance of α-synuclein may be one of the key factors leading to progressive loss of dopaminergic neurons in the substantia nigra. Moxibustion therapy for Parkinson’s disease has been shown to have a positive effect, but the underlying mechanism remains unknown. Based on this, we explored whether moxibustion could protect dopaminergic neurons by promoting autophagy mediated by mammalian target of rapamycin （mTOR）, with subsequent elimination of α-syn. A Parkinson’s disease model was induced in rats by subcutaneous injection of rotenone at the back of their necks, and they received moxibustion at Zusanli （ST36）, Guanyuan （CV4）and Fengfu （GV16）, for 10 minutes at every point, once per day, for 14 consecutive days. Model rats without any treatment were used as a sham control. Compared with the Parkinson’s disease group, the moxibustion group showed significantly greater tyrosine hydroxylase immunoreactivity and expression of light chain 3-II protein in the substantia nigra, and their behavioral score, α-synuclein immunoreactivity,the expression of phosphorylated mTOR and phosphorylated ribosomal protein S6 kinase （p-p70S6K） in the substantia nigra were significantly lower. These results suggest that moxibustion can promote the autophagic clearance of α-syn and improve behavioral performance in Parkinson’s disease model rats. The protective mechanism may be associated with suppression of the mTOR/p70S6K pathway.
文摘Activation of the phosphoinositide 3 kinase(PI3K)/Akt/mammalian target of rapamycin(mTOR) pathway is common in breast cancer. There is preclinical data to support inhibition of the pathway, and phase Ⅰ to Ⅲ trials involving inhibitors of the pathway have been or are being conducted in solid tumors and breast cancer. Everolimus, an mTOR inhibitor, is currently approved for the treatment of hormone receptor(HR)-positive, human epidermal growth factor receptor 2(HER2)-negative breast cancer. In this review, we summarise the efficacy and toxicity findings from the randomised clinical trials, with simplified guidelines on the management of potential adverse effects. Education of healthcare professionals and patients is critical for safety and compliance. While there is some clinical evidence of activity of mTOR inhibition in HR-positive and HER2-positive breast cancers, the benefits may be more pronounced in selected subsets rather than in the overall population. Further development of predictive biomarkers will be useful in the selection of patients who will benefit from inhibition of the PI3K/Akt/mTOR(PAM) pathway.
基金the National Natural Science Foundation of China(No.40232023)Chinese Academy of Sciences(No.KZCX2-103,RJZ2001-105)Ministry of Science and Technology of China(No.G2000077700).
文摘In the Linxia Basin on the northeast margin of the Tibetan Plateau, the Cenozoic strata are very thick and well exposed. Abundant mammalian fossils are discovered in the deposits from the Late Oligocene to the Early Pleistocene. The Dzungariotherium fauna comes from the sandstones of the Jiaozigou Formation, including many representative Late Oligocene taxa. The Platybelodon fauna comes from the sandstones of the Dongxiang Formation and the conglomerates of the Laogou Formation, and its fossils are typical Middle Miocene forms, such as Hemicyon, Amphicyon, Platybelodon, Choerolophodon, Anchitherium, and Hispanotherium. The Hipparion fauna comes from the red clay of the Liushu and Hewangjia Formations, and its fossils can be distinctly divided into four levels, including three Late Miocene levels and one Early Pliocene level. In the Linxia Basin, the Hipparion fauna has the richest mammalian fossils. The Equus fauna comes from the Wucheng Loess, and it is slightly older than that of the classical Early Pleistocene Nihewan Fauna. The mammalian faunas from the Linxia Basin provide the reliable evidence to divide the Cenozoic strata of this basin and correlate them with European mammalian sequence.
基金supported by the National Natural Science Foundation of China,No.81401004(to XGL)Medical and Health Technology Development Program of Zhejiang Province of China,No.2015-KY1001-036(to XGL)
文摘Rapamycin treatment has been shown to increase autophagy activity and activate Akt phosphorylation, suppressing apoptosis in several models of ischemia reperfusion injury. However, little has been studied on the neuroprotective effects on spinal cord injury by activating Akt phosphorylation. We hypothesized that both effects of rapamycin, the increased autophagy activity and Akt signaling, would contribute to its neuroprotective properties. In this study, a compressive spinal cord injury model of rat was created by an aneurysm clip with a 30 g closing force. Rat models were intraperitoneally injected with rapamycin 1 mg/kg, followed by autophagy inhibitor 3-methyladenine 2.5 mg/kg and Akt inhibitor IV 1 μg/kg. Western blot assay, immunofluorescence staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay were used to observe the expression of neuronal autophagy molecule Beclin 1, apoptosis-related molecules Bcl-2, Bax, cytochrome c, casp ase-3 and Akt signaling. Our results demonstrated that rapamycin inhibited the expression of mTOR in injured spinal cord tissue and up-regulated the expression of Beclin 1 and phosphorylated-Akt. Rapamycin prevented the decrease of bcl-2 expression in injured spinal cord tissue, reduced Bax, cytochrome c and caspase-3 expression levels and reduced the number of apoptotic neurons in injured spinal cord tissue 24 hours after spinal cord injury. 3-Methyladenine and Akt inhibitor IV intervention suppressed the expression of Beclin-1 and phosphorylated-Akt in injured spinal cord tissue and reduced the protective effect of rapamycin on apoptotic neurons. The above results indicate that the neuroprotective effect of rapamycin on spinal cord injury rats can be achieved by activating autophagy and the Akt signaling pathway.
文摘About 75% of all breast cancers are estrogen receptor(ER)-positive. They generally have a more favorable clinical behavior, prognosis, and pattern of recurrence, and endocrine therapy forms the backbone of treatment. Anti-estrogens(such as tamoxifen and fulvestrant) and aromatase inhibitors(such as anastrozole, letrozole, and exemestane) can effectively control the disease and induce tumor responses in a large proportion of patients. However, the majority of patients progress during endocrine therapy(acquired resistance) and a proportion of patients may fail to respond to initial therapy(de novo resistance). Endocrine resistance is therefore of clinical concern and there is great interest in strategies that delay or circumvent it. A deeper knowledge of the molecular mechanisms that drive endocrine resistance has recently led to development of new strategies that have the promise to effectivelyovercome it. Many resistance mechanisms have been described, and the crosstalk between ER and growth factor receptor signaling pathways seems to represent one of the most relevant. Compounds that are able to inhibit key elements of these pathways and restore endocrine sensitivity have been studied and more are currently under development. The aim of this review is to summarize the molecular pathophysiology of endocrine resistance in breast cancer and its impact on current clinical management.
基金the National Natural Science Foundation(No.81360032)Jiangxi Provincial Natural Science Foundation(No.20171BAB215059).
文摘Background:Cervical cancer has the fourth highest incidence and mortality rate of all cancers in women worldwide;让seriously harms their physical and mental health.The aim of this study was to observe the roles and preliminary mechanism of Taurine(Tau)-induced apoptosis in cervical cancer cells.Methods:Cells from the human cervical cancer cell line SiHa were transfected with the recombinant plasmid pEGFP-N1-MST1(mammalian sterile 20-like kinase 1);then,the cell proliferation activity was analyzed by the MTT assay,cell apoptosis by flow cytometry,and the related protein levels by Western blotting.Results:Tau inhibited the proliferation of SiHa cells and induced apoptosis in these cells(the apoptotic rate was 21.95%in the Tau 160 mmol/L group and 30%in the Tau 320 mmol/L group),upregulated the expression of the MST1(control,0.53;Tau 40-320 mmol/L groups,0.84-1.45)and Bax(control,0.45;Tau 40-320 mmol/L groups,0.64-1.51)proteins(P<0.01),and downregulated the expression of Bcl-2(control,1.28,Tau 40-320 mmol/L groups,0.93-0.47)(P<0.01).The overexpression of MST1 promoted the apoptosis of SiHa cells,enhanced the apoptosis-inductive effects of Tau(P<0.01),upregulated the expression of the proapoptotic proteins p73,p53,PUMA(p53 upregulated modulator of apoptosis),and caspase-3,and promoted the phosphorylation of YAP(Yes-associated protein).Conclusions:Tau inhibited the proliferation and induced the apoptosis of cervical cancer SiHa cells.The MST1 protein plays an important role in the Tau-induced apoptosis of cervical cancer cells.
文摘Information from eleven profiles of eolian earthy red silty clay and loess of the middle of the Late Miocene to Holocene age have been studied and correlated. A complete summary profile with projected isotopic ages and fossil-bearing beds has been assembled. The profile is subdivided into 12 stratigraphic units proceeding from the lower (older) to the upper (younger) one. The character of mammalian assemblages contained in each unit was analyzed and the corresponding pa- leo-climatic environments were deduced. The environmental character of each period and the change from the middle of the Late Miocene at about 8.0 Ma B.P. up to the Holocene progressed from the hot semiarid and semi-moist, warmer-moist, warm-moister of the Late Miocene. To slightly less warm moist, cool-dry, slight-warmer-moister of the Pliocene; later the cool to cold dry periods alternated frequently with the mild semiarid and semi-moist periods of the Quaternary. Vegetation progressed from the grasslands with sparse woods, wooded shrub-grasslands and subtropical forest-grasslands of the Late Miocene age to sparse grasslands and dry grasslands of the Pliocene; and to sparse grasslands, dry grasslands and tundras of the Quaternary. The climate changes in the Neogene were of low-amplitute in a generally warm-humid background. Those of the Quaternary were of higher am- plitude with a longer phase. Cool or cold dry and slightly warm semiarid and semi-moist climates al- ternated on a generally cool-dry background. The tendency since the start of the Quaternary was the change to more northern and western shift in the Loess Plateau, with progressively cooler and dryer conditions. The dramatic uplift of the Qinghai-Xizang (Tibet) Plateau and the forming and expansion of the Arctic ice sheet might be the main reasons of the more pronounced changes in the Quaternary.
文摘Background The mammalian target of rapamycin （mTOR） pathway, a key cellular signaling pathway associated with various cellular functions, has distinct roles in the inflammatory process. In this study, the mTOR inhibitor rapamycin （Rapa） was used to test whether inhibition of mTOR activation attenuates lipopolysaccharide （LPS）-induced acute lung injury （ALl） in a murine model.Methods Mice pretreated with Rapa or vehicle were given LPS intratracheally. Local cell numbers and inflammatory cytokines present in the bronchoalveolar lavage fluid （BAL）, wet-to-dry weight ratio, histopathology of the lungs, and survival were evaluated.Results The phosphorylation of S6, a major downstream target of mTOR, had a 3-fold increase in lung tissue after LPS stimulation, but the increase was blocked by Rapa. Rapa reduced the levels of TNF-α （LPS vs. LPS ＋ Rapa,（1672.74±193.73） vs. （539.17±140.48） pg/ml, respectively; P 〈0.01） and IL-6 （LPS vs. LPS ＋ Rapa： （7790.88±1170.54）vs. （1968.57±474.62） pg/ml, respectively; P 〈0.01） in the BAL fluid. However, Rapa had limited effects on the overall severity of ALI, as determined by the wet-to-dry weight ratio of the lungs, number of neutrophils in the BAL fluid, and changes in histopathology. In addition, Rapa failed to reduce mortality in the LPS-induced ALI model.Conclusions We confirmed that mTOR was activated during LPS-induced ALI and strongly inhibited by Rapa.Although Rapa reduced the levels of the mediators of inflammation, the overall severity and survival of the ALI murine model were unchanged.
文摘Sorafenib is the only and standard systematic chemotherapy drug for treatment of advanced hepatocellular carcinoma(HCC) at the current stage. Although sorafenib showed survival benefits in large randomized phase Ⅲ studies, its clinical benefits remain modest and most often consist of temporary tumor stabilization, indicating that more effective first-line treatment regimens or second-line salvage therapies are required. The molecular pathogenesis of HCC is very complex, involving hyperactivated signal transduction pathways such as RAS/RAF/MEK/ERK and PI3K/AKT/m TOR and aberrant expression of molecules such as receptor tyrosine kinases and histone deacetylases. Simultaneous or sequential abrogation of these critical pathways or the functions of these key molecules involved in angiogenesis, proliferation, and apoptosis may yield major improvements in the management of HCC. In this review, we summarize the emerging sorafenib-based combined molecule targeting for HCC treatment and analyze the rationales of these combinations.
