Circular RNAs(circRNAs)are a class of regulatory non-coding RNAs characterized by the presence of covalently closed ends.A growing body of evidence suggests that circRNAs play important roles in physiology and patholo...Circular RNAs(circRNAs)are a class of regulatory non-coding RNAs characterized by the presence of covalently closed ends.A growing body of evidence suggests that circRNAs play important roles in physiology and pathology.In particular,accumulating data on circRNA functions in various central nervous system(CNS)diseases and their correlations indicate that circRNAs are critical contributors to the onset and development of brain disorders.In this review,we focus on the regulatory and functional roles of circRNAs in CNS diseases,highlighting their diagnostic and therapeutic potential,with the aim of providing new insights into CNS diseases.展开更多
Screening humanized antibodies from a human Fab phage display library is an effective and quick method to obtain beta-amyloid oligomers. Thus, the present study prepared amyloid-beta 42 oli- gomers and constructed a h...Screening humanized antibodies from a human Fab phage display library is an effective and quick method to obtain beta-amyloid oligomers. Thus, the present study prepared amyloid-beta 42 oli- gomers and constructed a have human Fab phage display library based on blood samples from six healthy people. After three rounds of biopanning in vitro, a human single-domain antibody that spe- cifically recognized amyloid-beta 42 oligomers was identified. Western blot and enzyme-linked im- munosorbent assay demonstrated this antibody bound specifically to human amyloid-beta 42 tetramer and nonamer, but not the monomer or high molecular weight oligomers. This study suc- cessfully constructed a human phage display library and screened a single-domain antibody that specifically recognized amyloid-beta 42 oligomers.展开更多
N^6-methyladenosine(m6A)is identified as the most widespread and abundant internal chemical modification of RNA in eukaryotes.A series of proteins including methyltransferases(also known as“writers”),demethylases(al...N^6-methyladenosine(m6A)is identified as the most widespread and abundant internal chemical modification of RNA in eukaryotes.A series of proteins including methyltransferases(also known as“writers”),demethylases(also known as“erasers”),and m6A-binding proteins(also known as“readers”)were indicated to participate in the m6A methylation.m6A has emerged as a regulator of various cellular,developmental,and disease processes.Notably,there is highest abundance of m^6A methylation in brain than in other organs,which indicates that m^6A plays an essential role in brain functions.Here,we describe the general features,mechanisms,and functions of m^6A in the brain,and discuss the emerging roles of m6A in brain physiology and diseases.展开更多
AIM:To explore the relationship between DNA methyltransferase 1 (DNMT1) and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and its biological significance in primary HCC.METHODS: We carried out an immu...AIM:To explore the relationship between DNA methyltransferase 1 (DNMT1) and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and its biological significance in primary HCC.METHODS: We carried out an immunohistochemical examination of DNMT1 in both HCC and paired non-neoplastic liver tissues from Chinese subjects. DNMT1 mRNA was further examined in HCC cell lines by real-time PCR. We inhibited DNMT1 using siRNA and detected the effect of depletion of DNMT1 on cell proliferation ability and cell apoptosis in the HCC cell line SMMC-7721.RESULTS: DNMT1 protein expression was increased in HCCs compared to histologically normal non-neoplastic liver tissues and the incidence of DNMT1 immunoreactivity in HCCs correlated signifi cantly with poor tumor differentiation (P=0.014). There were more cases with DNMT1 overexpression in HCC with HBV (42.85%) than in HCC without HBV (28.57%). However, no signif icant difference in DNMT1 expression was found in HBV-positive and HBV-negative cases in the Chinese HCC group. There was a trend that DNMT1 RNA expression increased more in HCC cell lines than in pericarcinoma cell lines and normal liver cell lines. In addition, we inhibited DNMT1 using siRNA in the SMMC-7721 HCC cell line and found depletion of DNMT1 suppressed cells growth independent of expression of proliferating cell nuclear antigen (PCNA), even in HCC cell lines where DNMT1 was stably decreased.CONCLUSION: The f indings implied that DNMT1 plays a key role in HBV-related hepatocellular tumorigenesis. Depletion of DNMT1 mediates growth suppression in SMMC-7721 cells.展开更多
Apart from the liver disruption, embryotoxicity and genotoxicity, microcystin (MC)-LR also could cause neurotoxicity. Nematode Caenorhabditis elegans was explored as a model to study the neurotoxicity. In the presen...Apart from the liver disruption, embryotoxicity and genotoxicity, microcystin (MC)-LR also could cause neurotoxicity. Nematode Caenorhabditis elegans was explored as a model to study the neurotoxicity. In the present study, we provided evidence to indicate the neurotoxicity on chemotaxis to NaCl and diacetyl, and thermotaxis from MC-LR exposure to C. elegans. As a result, higher concentrations of MC-LR caused significantly severe defects of chemotaxis to NaCl and diacetyl, and thermotaxis. The neurotoxicity on chemotaxis to NaCl and diacetyl, and thermotaxis from MC-LR exposure might be largely mediated by the damage on the corresponding sensory neurons (ASE, AWA, and AFD) and interneuron AIY. The expression levels ofche-1 and odr-7 were significantly decreased (P 〈 0.01) in animals exposed to MC-LR at concentrations lower than 10 μg/L, whereas the expression levels of ttx-1 and ttx-3 could be significantly (P 〈 0.01) lowered in animals even exposed to 1 μg/L of MC-LR. Moreover, both the chemotaxis to NaCl and diacetyl and the thermotaxis were more significantly reduced in MC-LR exposed mutants of che-1(p674), odr-7(ky4), ttx-1(p767), and ttx-3(ks5) than those in exposed wild-type N2 animals at the same concentrations.展开更多
AIM:To investigate the relationship between 579 G>T polymorphisms in the DNMT3B gene, which is involved in de novo methylation and associated with the risk of esophagus cancer (EC) in Chinese. METHODS:DNMT3B 579 G&...AIM:To investigate the relationship between 579 G>T polymorphisms in the DNMT3B gene, which is involved in de novo methylation and associated with the risk of esophagus cancer (EC) in Chinese. METHODS:DNMT3B 579 G>T genotypes were determined by PCR-RFLP in 194 EC patients and 210 healthy controls matched for age and sex, who did not receive radiotherapy or chemotherapy for newly diagnosed and histopathologically confirmed EC. RESULTS:In control subjects, the frequency of T/T and G/T genotypes, and T and G alleles was 81.4%, 18.1%, 90.05% and 9.55%, respectively. The distribution of genotypes and allelotypes in the EC patients was not significantly different from that in the controls. When stratified by sex and age, there was still no significant association between the risks of EC and GT and GG genotypes. This study also showed a distinct difference in the distribution of DNMT3B and single nucleotide polymorphism (SNP) between Chinese and Koreans.CONCLUSION:DNMT3B 579 G>T polymorphism may not be a stratification marker to predict the susceptibility to EC, at least in Chinese. DNMT3B promoter SNP is diverse in ethnic populations.展开更多
Brain vascular dysfunction in Alzheimer s disease(AD) pathogenesis has become increasingly clea r.Accumulating evidence shows that damaged vascular,including large or small vessels and even neurovascular unit,may acce...Brain vascular dysfunction in Alzheimer s disease(AD) pathogenesis has become increasingly clea r.Accumulating evidence shows that damaged vascular,including large or small vessels and even neurovascular unit,may accelerate the neuropathological process of AD via disrupting brain hypoperfusion,aberrant angiogenesis,and neuroinflammatory response,etc.Thus,vascular dysfunction makes a substantially contribution to the cognitive decline of AD patients.展开更多
Liver diseases constitute a major healthcare burden globally,including acute hepatic injury resulted from acetaminophen overdose,ischemia-reperfusion or hepatotropic viral infection and chronic hepatitis,alcoholic liv...Liver diseases constitute a major healthcare burden globally,including acute hepatic injury resulted from acetaminophen overdose,ischemia-reperfusion or hepatotropic viral infection and chronic hepatitis,alcoholic liver disease(ALD),non-alcoholic fatty liver disease(NAFLD)and hepatocellular carcinoma(HCC).Attainable treatment strategies for most liver diseases remain inadequate,highlighting the importance of substantial pathogenesis.The transient receptor potential(TRP)channels represent a versatile signalling mechanism regulating fundamental physiological processes in the liver.It is not surprising that liver diseases become a newly explored field to enrich our knowledge of TRP channels.Here,we discuss recent findings revealing TRP functions across the fundamental pathological course from early hepatocellular injury caused by various insults,to inflammation,subsequent fibrosis and hepatoma.We also explore expression levels of TRPs in liver tissues of ALD,NAFLD and HCC patients from Gene Expression Omnibus(GEO)or The Cancer Genome Atlas(TCGA)database and survival analysis estimated by Kaplan-Meier Plotter.At last,we address the therapeutical potential and challenges by pharmacologically targeting TRPs to treat liver diseases.The aim is to provide a better understanding of the implications of TRP channels in liver diseases,contributing to the discovery of novel therapeutic targets and efficient drugs.展开更多
We examined the possible multiple defects induced by acute and prolonged exposure to high levels of manganese(Mn) solution by monitoring the endpoints of lifespan,development,reproduction,and stress response.Our dat...We examined the possible multiple defects induced by acute and prolonged exposure to high levels of manganese(Mn) solution by monitoring the endpoints of lifespan,development,reproduction,and stress response.Our data suggest that acute exposure(6 h) to Mn did not cause severe defects of life span,development,and reproduction,similarly,no significant defect could be found in animals exposed to a low concentration of Mn(2.5 μmol/L) for 48 h.In contrast,prolonged exposure(48 h) to high Mn concentrations(75 and 200 μmol/L) resulted in significant defects of life span,development,and reproduction,as well as the increase of the percentage of population with hsp-16.2::gfp expression indicating the obvious induction of stress responses in exposed animals.Moreover,prolonged exposure(48 h) to high concentrations(75 and 200 μmol/L) of Mn decreased the expression levels of antioxidant genes of sod-1,sod-2,sod-3,and sod-4 compared to control.Therefore,prolonged exposure to high concentrations of Mn will induce the severe defects of life span,development,and reproduction in nematodes possibly by affecting the stress response and expression of antioxidant genes in Caenorhabditis elegans.展开更多
The long-term enhancement in glutamate receptor mediated excitatory responses has been observed in stroke model. This pathological form of plasticity, termed post-ischemic long-term potentiation (i-LTP), points to f...The long-term enhancement in glutamate receptor mediated excitatory responses has been observed in stroke model. This pathological form of plasticity, termed post-ischemic long-term potentiation (i-LTP), points to functional reorganization after stroke. Little is known, however, about whether and how this i-LTP would affect subsequent induction of synaptic plasticity. Here, we first directly confirmed that i-LTP was induced in the endothelin-l-induced ischemia model as in other in vitro models. We also demonstrated increased expression of NR2B, CaMKII and p-CaMKII, which are reminiscent of i-LTP. We further induced LTP of field excitatory post- synaptic potentials (fEPSPs) on CA1 hippocampal neurons in peri-infarct regions of the endothelin-l-induced mini-stroke model. We found that LTP of fEPSPs, induced by high-frequency stimulation, displayed a progressive impairment at 12 and 24 hours after ischemia. Moreover, using in vivo multi-channel recording, we found that the local field potential, which represents electrical property of cell ensembles in more restricted regions, was also dam- pened at these two time points. These results suggest that i-LTP elevates the induction threshold of subsequent synap- tic plasticity. Our data helps to deepen the knowledge of meta-synaptic regulation of plasticity after focal ischemia.展开更多
Objective Previous work has showed that excess iron accumulation is harrnftd to reproduction and even promotes death; however, whether the multiple biological toxicity of iron (Fe) exposure could be transferred to p...Objective Previous work has showed that excess iron accumulation is harrnftd to reproduction and even promotes death; however, whether the multiple biological toxicity of iron (Fe) exposure could be transferred to progeny remains unknown. The present study used Caenorhabditis elegans to analyze the multiple toxicities of iron exposure and their possible transferable properties. Methods Three concentrations of iron sulfate solution (2.5μmol/L, 75μmol/L, and 200 μmol/L) were used. The endpoints of lifespan, body size, generation time, brood size, head thrash and body bend frequencies, and chemotaxis plasticity were selected to investigate Fe toxicity and its effect on progeny in Caenorhabditis elegans. Results The Fe toxicity could cause multiple biological defects in a dose-dependent manner by affecting different endpoints in nematodes. Most of the multiple biological defects and behavior toxicities could be transferred from Fe-exposed Caenorhabditis elegans to their progeny. Compared to the parents, no recovery phenotypes were observed for some of the defects in the progeny, such as body bend frequency and life span. We further summarized the defects caused by Fe exposure into 2 groups according to their transferable properties. Conclusion Our results suggest that Fe exposure could cause multiple biological defects, and most of these severe defects could be transferred from Fe exposed nematodes to their progeny.展开更多
Objective To evaluate whether the thermotaxis tracking model is suitable for assessing long-term memory (LTM) in the nematode Caenorhabditis elegans. Methods Animals were trained at 20℃ overnight in presence of foo...Objective To evaluate whether the thermotaxis tracking model is suitable for assessing long-term memory (LTM) in the nematode Caenorhabditis elegans. Methods Animals were trained at 20℃ overnight in presence of food. The percentage of animals performing isothermal tracking (IT) behavior was measured at different time intervals after the training. Results The percentage of animals performing IT behavior, the numbers of body bends inside and outside the training temperature, and the expression patterns of AFD and AIY neurons were similar to those in control animals at 36 and 48 h after training; whereas when extending to 60, 72, and 84 h, locomotory behavior defects were observed in the assayed animals, suggesting that this thermal tracking model is feasible for analyzing LTM at 36 and 48 h after training. Moreover, the percent-age of animals performing IT behavior was reduced at 18, 36, and 48 h after training in neuronal calcium sensor-1 gene (nsc-1) mutant animals compared with that in wild-type N2 animals. In addition, exposure to plumbum (Pb) significantly repressed the LTM at 18, 36, and 48 h after training in both wild-type N2 and ncs-1 mutant animals. Conclusion The thermotaxis tracking model is suitable for evaluating the LTM regulated by NCS-1, and can be employed for elucidating regulatory functions of specific genes or effects of stimuli on memory in C. elegans.展开更多
Functional and structural alterations in brain connectivity associated with brain ischemia have been extensively studied. However, the mechanism whereby local ischemia in deep brain region affect brain functions is st...Functional and structural alterations in brain connectivity associated with brain ischemia have been extensively studied. However, the mechanism whereby local ischemia in deep brain region affect brain functions is still unknown. Here, we first established a mini-stroke model by infusion of endothelin-1 (ET-1) into the dorsal hippo- campus or the lateral amygdala, and then investigated how these mini-infarcts affected brain functions associated with these regions. We found that rats with ET-1 infusion showed deficit in recall of contextual fear memory, but not in learning process and recall of tone fear memory. In novel object task, ET-1 in the hippocampus also elimi- nated object identity memory. ET-1 in the lateral amygdale affected acquisition of fear conditioning and disrupted retention of tone-conditioned fear, but did not impair retention of contextual fear. These findings suggest that ET-1- induced mini-infarct in deep brain area leads to functional deficits in learning and memory associated with these regions.展开更多
Generation of magnetic micrbubbles and their basic magnetic and acoustic mechanism are reviewed. The ultrasound (US) and magnetic resonance (MR) dual imaging, the controlled therapeutic delivery, as well as theran...Generation of magnetic micrbubbles and their basic magnetic and acoustic mechanism are reviewed. The ultrasound (US) and magnetic resonance (MR) dual imaging, the controlled therapeutic delivery, as well as theranostic multifunctions are all introduced based on recent research results. Some on-going research is also discussed.展开更多
Major depressive disorder(MDD)is a highly heterogeneous mental disorder,and its complex etiology and unclear mechanism are great obstacles to the diagnosis and treatment of the disease.Studies have shown that abnormal...Major depressive disorder(MDD)is a highly heterogeneous mental disorder,and its complex etiology and unclear mechanism are great obstacles to the diagnosis and treatment of the disease.Studies have shown that abnormal functions of the visual cortex have been reported in MDD patients,and the actions of several antidepressants coincide with improvements in the structure and synaptic functions of the visual cortex.In this review,we critically evaluate current evidence showing the involvement of the malfunctioning visual cortex in the pathophysiology and therapeutic process of depression.In addition,we discuss the molecular mechanisms of visual cortex dysfunction that may underlie the pathogenesis of MDD.Although the precise roles of visual cortex abnormalities in MDD remain uncertain,this undervalued brain region may become a novel area for the treatment of depressed patients.展开更多
Destruction of the blood-brain barrier is a critical component of epilepsy pathology.Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity.Howeve...Destruction of the blood-brain barrier is a critical component of epilepsy pathology.Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity.However,its effect on blood-brain barrier permeability in epileptic mice remains unclear.In this study,we prepared pilocarpine-induced status epilepticus models and pentylenetetrazol-induced epilepsy models in C57BL/6 mice.S1P1 expression was increased in the hippocampus after status epilepticus,whereas tight junction protein expression was decreased in epileptic mice compared with controls.Intraperitoneal injection of SEW2871,a specific agonist of sphingosine-1-phosphate receptor 1,decreased the level of tight junction protein in the hippocampus of epileptic mice,increased blood-brain barrier leakage,and aggravated the severity of seizures compared with the control.W146,a specific antagonist of sphingosine-1-phosphate receptor 1,increased the level of tight junction protein,attenuated blood-brain barrier disruption,and reduced seizure severity compared with the control.Furthermore,sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1βand tumor necrosis factor-αand caused astrocytosis.Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline,a neuroinflammation inhibitor.Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy-associated depression-like behaviors.Additionally,specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage,seizure severity,and epilepsy-associated depression-like behaviors.Taken together,our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation.展开更多
Accurate and efficient methods for identifying and tracking each animal in a group are needed to study complex behaviors and social interactions.Traditional tracking methods(e.g.,marking each animal with dye or surgic...Accurate and efficient methods for identifying and tracking each animal in a group are needed to study complex behaviors and social interactions.Traditional tracking methods(e.g.,marking each animal with dye or surgically implanting microchips)can be invasive and may have an impact on the social behavior being measured.To overcome these shortcomings,video-based methods for tracking unmarked animals,such as fruit flies and zebrafish,have been developed.However,tracking individual mice in a group remains a challenging problem because of their flexible body and complicated interaction patterns.In this study,we report the development of a multi-object tracker for mice that uses the Faster region-based convolutional neural network(R-CNN)deep learning algorithm with geometric transformations in combination with multi-camera/multi-image fusion technology.The system successfully tracked every individual in groups of unmarked mice and was applied to investigate chasing behavior.The proposed system constitutes a step forward in the noninvasive tracking of individual mice engaged in social behavior.展开更多
G2 pea exhibits an apical senescence delaying phenotype under short-day (SD) conditions; however, the structural basis for its apical development is still largely unknown. In the present study, the apical meristem o...G2 pea exhibits an apical senescence delaying phenotype under short-day (SD) conditions; however, the structural basis for its apical development is still largely unknown. In the present study, the apical meristem of SD-grown G2 pea plants underwent a transition from vegetative to indeterminate inflorescence meristem, but the apical meristem of long-day (LD)-grown G2 pea plants would be further converted to determinate floral meristem. Both SD signal and GA3 treatment enhanced expression of the putative calcium transporter PPF1, and pea homologs of TFL1 (LF and DET), whereas LD signal suppressed their expression at 60 d post-flowering compared with those at 40 d post-flowering. Both PPF1 and LF expressed at the vegetative and reproductive phases in SD-grown apical buds, but floral initiation obviously increased the expression level of PPF1 compared with the unchanged expression level of LF from 40 to 60 d post-flowering. In addition, although the floral initiation significantly enhanced the expression levels of PPF1 and DET, DET was mainly expressed after floral initiation in SD-grown apil buds. Therefore, the main structural difference between LD- and SD-grown apical meristem in G2 pea lies in whether their apical indeterminate inflorescence meristem could be converted to the determinate structure.展开更多
Precise regulation of gene transcription is of great importance to development and diseases.Promoter-proximal transcriptional pause is a key and general mechanism to precisely control transcription in metazoans.Subseq...Precise regulation of gene transcription is of great importance to development and diseases.Promoter-proximal transcriptional pause is a key and general mechanism to precisely control transcription in metazoans.Subsequent to transcription initiation and synthesis of a short RNA,RNA polymerase Ⅱ(Pol Ⅱ)usually pauses at the promoter-proximal regions,standing by for further signals to be released into the productive elongation stage.Fine regulation of Pol Ⅱ pausing and release is achieved by the concerted action of many negative and positive elongation factors,including the super elongation complex(SEC).Recent studies suggested that phase-separated assemblies of transcription regulatory complexes could provide a general biophysical basis for the dynamic regulation of transcription in response to various cellular needs,though direct evidence at endogenous level in living cells is still largely lacking.Here,we summarize and discuss latest advances in understanding how phase separation contributes to RNA polymerase ll-mediated transcription,with a focus on transcriptional pause and release.展开更多
基金supported by grants from the Science and Technology Innovation 2030-Major Project of the Ministry of Science and Technology of China(No.2021ZD0202904 and No.2021ZD0202900)the National Natural Science Foundation of China(No.82230115 and No.82273914)+1 种基金the National Science Fund for Distinguished Young Scholars(No.82025033)the Jiangsu Provincial Key Laboratory of Critical Care Medicine(No.JSKLCCM-2022-02-008).
文摘Circular RNAs(circRNAs)are a class of regulatory non-coding RNAs characterized by the presence of covalently closed ends.A growing body of evidence suggests that circRNAs play important roles in physiology and pathology.In particular,accumulating data on circRNA functions in various central nervous system(CNS)diseases and their correlations indicate that circRNAs are critical contributors to the onset and development of brain disorders.In this review,we focus on the regulatory and functional roles of circRNAs in CNS diseases,highlighting their diagnostic and therapeutic potential,with the aim of providing new insights into CNS diseases.
基金supported by the National Natural Science Foundation of China,No.30600099(FD)
文摘Screening humanized antibodies from a human Fab phage display library is an effective and quick method to obtain beta-amyloid oligomers. Thus, the present study prepared amyloid-beta 42 oli- gomers and constructed a have human Fab phage display library based on blood samples from six healthy people. After three rounds of biopanning in vitro, a human single-domain antibody that spe- cifically recognized amyloid-beta 42 oligomers was identified. Western blot and enzyme-linked im- munosorbent assay demonstrated this antibody bound specifically to human amyloid-beta 42 tetramer and nonamer, but not the monomer or high molecular weight oligomers. This study suc- cessfully constructed a human phage display library and screened a single-domain antibody that specifically recognized amyloid-beta 42 oligomers.
基金This work was supported by the National Key Research and Development Program of China(No.2017YFA0104303)the National Natural Science Foundation of China(No.81673410 and No.81761138048)+1 种基金the Jiangsu Innovation&Entrepreneurship Team Program,the Major Project of National Science and Technology(No.2020 ZX09201015)and the Fundamental Research Funds for the Central Universities(No.2242020K40134).
文摘N^6-methyladenosine(m6A)is identified as the most widespread and abundant internal chemical modification of RNA in eukaryotes.A series of proteins including methyltransferases(also known as“writers”),demethylases(also known as“erasers”),and m6A-binding proteins(also known as“readers”)were indicated to participate in the m6A methylation.m6A has emerged as a regulator of various cellular,developmental,and disease processes.Notably,there is highest abundance of m^6A methylation in brain than in other organs,which indicates that m^6A plays an essential role in brain functions.Here,we describe the general features,mechanisms,and functions of m^6A in the brain,and discuss the emerging roles of m6A in brain physiology and diseases.
基金Supported by National Natural Science Foundation of China,No.30470950
文摘AIM:To explore the relationship between DNA methyltransferase 1 (DNMT1) and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and its biological significance in primary HCC.METHODS: We carried out an immunohistochemical examination of DNMT1 in both HCC and paired non-neoplastic liver tissues from Chinese subjects. DNMT1 mRNA was further examined in HCC cell lines by real-time PCR. We inhibited DNMT1 using siRNA and detected the effect of depletion of DNMT1 on cell proliferation ability and cell apoptosis in the HCC cell line SMMC-7721.RESULTS: DNMT1 protein expression was increased in HCCs compared to histologically normal non-neoplastic liver tissues and the incidence of DNMT1 immunoreactivity in HCCs correlated signifi cantly with poor tumor differentiation (P=0.014). There were more cases with DNMT1 overexpression in HCC with HBV (42.85%) than in HCC without HBV (28.57%). However, no signif icant difference in DNMT1 expression was found in HBV-positive and HBV-negative cases in the Chinese HCC group. There was a trend that DNMT1 RNA expression increased more in HCC cell lines than in pericarcinoma cell lines and normal liver cell lines. In addition, we inhibited DNMT1 using siRNA in the SMMC-7721 HCC cell line and found depletion of DNMT1 suppressed cells growth independent of expression of proliferating cell nuclear antigen (PCNA), even in HCC cell lines where DNMT1 was stably decreased.CONCLUSION: The f indings implied that DNMT1 plays a key role in HBV-related hepatocellular tumorigenesis. Depletion of DNMT1 mediates growth suppression in SMMC-7721 cells.
基金supported by the National Natural Sci- ence Foundation of China (No. 30771113, 30870810)and the Program for New Century Excellent Talents in Universityprovided by the Caenorhabditis Genetics Center (funded by the NIH, National Center for Foundation from Research Resource)
文摘Apart from the liver disruption, embryotoxicity and genotoxicity, microcystin (MC)-LR also could cause neurotoxicity. Nematode Caenorhabditis elegans was explored as a model to study the neurotoxicity. In the present study, we provided evidence to indicate the neurotoxicity on chemotaxis to NaCl and diacetyl, and thermotaxis from MC-LR exposure to C. elegans. As a result, higher concentrations of MC-LR caused significantly severe defects of chemotaxis to NaCl and diacetyl, and thermotaxis. The neurotoxicity on chemotaxis to NaCl and diacetyl, and thermotaxis from MC-LR exposure might be largely mediated by the damage on the corresponding sensory neurons (ASE, AWA, and AFD) and interneuron AIY. The expression levels ofche-1 and odr-7 were significantly decreased (P 〈 0.01) in animals exposed to MC-LR at concentrations lower than 10 μg/L, whereas the expression levels of ttx-1 and ttx-3 could be significantly (P 〈 0.01) lowered in animals even exposed to 1 μg/L of MC-LR. Moreover, both the chemotaxis to NaCl and diacetyl and the thermotaxis were more significantly reduced in MC-LR exposed mutants of che-1(p674), odr-7(ky4), ttx-1(p767), and ttx-3(ks5) than those in exposed wild-type N2 animals at the same concentrations.
基金The National Natural Science Foundation of China, No. 30470950 Qinglan Project of Jiangsu Province of China, 2006
文摘AIM:To investigate the relationship between 579 G>T polymorphisms in the DNMT3B gene, which is involved in de novo methylation and associated with the risk of esophagus cancer (EC) in Chinese. METHODS:DNMT3B 579 G>T genotypes were determined by PCR-RFLP in 194 EC patients and 210 healthy controls matched for age and sex, who did not receive radiotherapy or chemotherapy for newly diagnosed and histopathologically confirmed EC. RESULTS:In control subjects, the frequency of T/T and G/T genotypes, and T and G alleles was 81.4%, 18.1%, 90.05% and 9.55%, respectively. The distribution of genotypes and allelotypes in the EC patients was not significantly different from that in the controls. When stratified by sex and age, there was still no significant association between the risks of EC and GT and GG genotypes. This study also showed a distinct difference in the distribution of DNMT3B and single nucleotide polymorphism (SNP) between Chinese and Koreans.CONCLUSION:DNMT3B 579 G>T polymorphism may not be a stratification marker to predict the susceptibility to EC, at least in Chinese. DNMT3B promoter SNP is diverse in ethnic populations.
基金supported by the Science and Technology Innovation 2030-Major Projects,No.2022ZD021 1 600the National Natural Science Foundation of China,Nos.82271574 and82071204 (all to CX)。
文摘Brain vascular dysfunction in Alzheimer s disease(AD) pathogenesis has become increasingly clea r.Accumulating evidence shows that damaged vascular,including large or small vessels and even neurovascular unit,may accelerate the neuropathological process of AD via disrupting brain hypoperfusion,aberrant angiogenesis,and neuroinflammatory response,etc.Thus,vascular dysfunction makes a substantially contribution to the cognitive decline of AD patients.
基金supported by National Natural Science Foundation of China(81902480)the Fundamental Research Funds for the Central Universities(2632019PY04,China)+9 种基金the Jiangsu Provincial Double-Innovation Doctor ProgramNanjing Science and Technology Innovation Project to Wenhui WangNatural Science Foundation of Jiangsu Province(BK20202002,China)National Natural Science Foundation of China(31971146)Innovation and Entrepreneurship Talent Program of Jiangsu ProvinceGuangxi Funds for Distinguished Experts“Xing Yao”Leading Scholars of China Pharmaceutical University(2021)to Ye Yu(China)China Postdoctoral Science Foundation(2020T130279 and 2020M682812,China)Basic and Applied Basic Research Foundation of Guangdong Province of China(2021A1515011085)to Pengyu LiuNational Natural Science Foundation of China(32000869)to Jin Wang。
文摘Liver diseases constitute a major healthcare burden globally,including acute hepatic injury resulted from acetaminophen overdose,ischemia-reperfusion or hepatotropic viral infection and chronic hepatitis,alcoholic liver disease(ALD),non-alcoholic fatty liver disease(NAFLD)and hepatocellular carcinoma(HCC).Attainable treatment strategies for most liver diseases remain inadequate,highlighting the importance of substantial pathogenesis.The transient receptor potential(TRP)channels represent a versatile signalling mechanism regulating fundamental physiological processes in the liver.It is not surprising that liver diseases become a newly explored field to enrich our knowledge of TRP channels.Here,we discuss recent findings revealing TRP functions across the fundamental pathological course from early hepatocellular injury caused by various insults,to inflammation,subsequent fibrosis and hepatoma.We also explore expression levels of TRPs in liver tissues of ALD,NAFLD and HCC patients from Gene Expression Omnibus(GEO)or The Cancer Genome Atlas(TCGA)database and survival analysis estimated by Kaplan-Meier Plotter.At last,we address the therapeutical potential and challenges by pharmacologically targeting TRPs to treat liver diseases.The aim is to provide a better understanding of the implications of TRP channels in liver diseases,contributing to the discovery of novel therapeutic targets and efficient drugs.
基金supported by the National Natural Science Foundation of China (No. 30771113, 30870810)the Program for New Century Excellent Talents in University
文摘We examined the possible multiple defects induced by acute and prolonged exposure to high levels of manganese(Mn) solution by monitoring the endpoints of lifespan,development,reproduction,and stress response.Our data suggest that acute exposure(6 h) to Mn did not cause severe defects of life span,development,and reproduction,similarly,no significant defect could be found in animals exposed to a low concentration of Mn(2.5 μmol/L) for 48 h.In contrast,prolonged exposure(48 h) to high Mn concentrations(75 and 200 μmol/L) resulted in significant defects of life span,development,and reproduction,as well as the increase of the percentage of population with hsp-16.2::gfp expression indicating the obvious induction of stress responses in exposed animals.Moreover,prolonged exposure(48 h) to high concentrations(75 and 200 μmol/L) of Mn decreased the expression levels of antioxidant genes of sod-1,sod-2,sod-3,and sod-4 compared to control.Therefore,prolonged exposure to high concentrations of Mn will induce the severe defects of life span,development,and reproduction in nematodes possibly by affecting the stress response and expression of antioxidant genes in Caenorhabditis elegans.
基金supported by Major State Basic Research Program of China(Grant No.2013CB733801)
文摘The long-term enhancement in glutamate receptor mediated excitatory responses has been observed in stroke model. This pathological form of plasticity, termed post-ischemic long-term potentiation (i-LTP), points to functional reorganization after stroke. Little is known, however, about whether and how this i-LTP would affect subsequent induction of synaptic plasticity. Here, we first directly confirmed that i-LTP was induced in the endothelin-l-induced ischemia model as in other in vitro models. We also demonstrated increased expression of NR2B, CaMKII and p-CaMKII, which are reminiscent of i-LTP. We further induced LTP of field excitatory post- synaptic potentials (fEPSPs) on CA1 hippocampal neurons in peri-infarct regions of the endothelin-l-induced mini-stroke model. We found that LTP of fEPSPs, induced by high-frequency stimulation, displayed a progressive impairment at 12 and 24 hours after ischemia. Moreover, using in vivo multi-channel recording, we found that the local field potential, which represents electrical property of cell ensembles in more restricted regions, was also dam- pened at these two time points. These results suggest that i-LTP elevates the induction threshold of subsequent synap- tic plasticity. Our data helps to deepen the knowledge of meta-synaptic regulation of plasticity after focal ischemia.
基金supported by the Southeast University Foundation for Excellent Young Scholars (No. 4023001013).
文摘Objective Previous work has showed that excess iron accumulation is harrnftd to reproduction and even promotes death; however, whether the multiple biological toxicity of iron (Fe) exposure could be transferred to progeny remains unknown. The present study used Caenorhabditis elegans to analyze the multiple toxicities of iron exposure and their possible transferable properties. Methods Three concentrations of iron sulfate solution (2.5μmol/L, 75μmol/L, and 200 μmol/L) were used. The endpoints of lifespan, body size, generation time, brood size, head thrash and body bend frequencies, and chemotaxis plasticity were selected to investigate Fe toxicity and its effect on progeny in Caenorhabditis elegans. Results The Fe toxicity could cause multiple biological defects in a dose-dependent manner by affecting different endpoints in nematodes. Most of the multiple biological defects and behavior toxicities could be transferred from Fe-exposed Caenorhabditis elegans to their progeny. Compared to the parents, no recovery phenotypes were observed for some of the defects in the progeny, such as body bend frequency and life span. We further summarized the defects caused by Fe exposure into 2 groups according to their transferable properties. Conclusion Our results suggest that Fe exposure could cause multiple biological defects, and most of these severe defects could be transferred from Fe exposed nematodes to their progeny.
文摘Objective To evaluate whether the thermotaxis tracking model is suitable for assessing long-term memory (LTM) in the nematode Caenorhabditis elegans. Methods Animals were trained at 20℃ overnight in presence of food. The percentage of animals performing isothermal tracking (IT) behavior was measured at different time intervals after the training. Results The percentage of animals performing IT behavior, the numbers of body bends inside and outside the training temperature, and the expression patterns of AFD and AIY neurons were similar to those in control animals at 36 and 48 h after training; whereas when extending to 60, 72, and 84 h, locomotory behavior defects were observed in the assayed animals, suggesting that this thermal tracking model is feasible for analyzing LTM at 36 and 48 h after training. Moreover, the percent-age of animals performing IT behavior was reduced at 18, 36, and 48 h after training in neuronal calcium sensor-1 gene (nsc-1) mutant animals compared with that in wild-type N2 animals. In addition, exposure to plumbum (Pb) significantly repressed the LTM at 18, 36, and 48 h after training in both wild-type N2 and ncs-1 mutant animals. Conclusion The thermotaxis tracking model is suitable for evaluating the LTM regulated by NCS-1, and can be employed for elucidating regulatory functions of specific genes or effects of stimuli on memory in C. elegans.
基金supported by Major State Basic Research Program of China(Grant No.2013CB733801)
文摘Functional and structural alterations in brain connectivity associated with brain ischemia have been extensively studied. However, the mechanism whereby local ischemia in deep brain region affect brain functions is still unknown. Here, we first established a mini-stroke model by infusion of endothelin-1 (ET-1) into the dorsal hippo- campus or the lateral amygdala, and then investigated how these mini-infarcts affected brain functions associated with these regions. We found that rats with ET-1 infusion showed deficit in recall of contextual fear memory, but not in learning process and recall of tone fear memory. In novel object task, ET-1 in the hippocampus also elimi- nated object identity memory. ET-1 in the lateral amygdale affected acquisition of fear conditioning and disrupted retention of tone-conditioned fear, but did not impair retention of contextual fear. These findings suggest that ET-1- induced mini-infarct in deep brain area leads to functional deficits in learning and memory associated with these regions.
基金Project supported by the National Basic Research Program of China (Grant Nos.2011CB933503 and 2013CB733804)the National Natural Science Foundation of China (Grant No.31000453)the Fundamental Research Funds for Central Universities (Grant No.2013CB733804)
文摘Generation of magnetic micrbubbles and their basic magnetic and acoustic mechanism are reviewed. The ultrasound (US) and magnetic resonance (MR) dual imaging, the controlled therapeutic delivery, as well as theranostic multifunctions are all introduced based on recent research results. Some on-going research is also discussed.
基金This review was supported by grants from the National Natural Science Key Foundation of China(81830040 and 82130042)the China Science and Technology Innovation 2030-Major Project(2022ZD0211701 and 2021ZD0200700)+1 种基金the Science and Technology Program of Guangdong(2018B030334001)the Science and Technology Program of Shenzhen(GJHZ20210705141400002,KCXFZ20211020164543006,JCYJ20220818101615033,and 202206063000055).
文摘Major depressive disorder(MDD)is a highly heterogeneous mental disorder,and its complex etiology and unclear mechanism are great obstacles to the diagnosis and treatment of the disease.Studies have shown that abnormal functions of the visual cortex have been reported in MDD patients,and the actions of several antidepressants coincide with improvements in the structure and synaptic functions of the visual cortex.In this review,we critically evaluate current evidence showing the involvement of the malfunctioning visual cortex in the pathophysiology and therapeutic process of depression.In addition,we discuss the molecular mechanisms of visual cortex dysfunction that may underlie the pathogenesis of MDD.Although the precise roles of visual cortex abnormalities in MDD remain uncertain,this undervalued brain region may become a novel area for the treatment of depressed patients.
基金supported by the National Natural Science Foundation of China,Nos.82071393(to HLC),81830040(to ZJZ),82130042(to ZJZ)Science and Technology Program of Guangdong Province,No.2018B030334001(to ZJZ)the Program of Excellent Talents in Medical Science of Jiangsu Province,No.JCRCA2016006(to ZJZ)。
文摘Destruction of the blood-brain barrier is a critical component of epilepsy pathology.Several studies have demonstrated that sphingosine 1-phosphate receptor 1 contributes to the modulation of vascular integrity.However,its effect on blood-brain barrier permeability in epileptic mice remains unclear.In this study,we prepared pilocarpine-induced status epilepticus models and pentylenetetrazol-induced epilepsy models in C57BL/6 mice.S1P1 expression was increased in the hippocampus after status epilepticus,whereas tight junction protein expression was decreased in epileptic mice compared with controls.Intraperitoneal injection of SEW2871,a specific agonist of sphingosine-1-phosphate receptor 1,decreased the level of tight junction protein in the hippocampus of epileptic mice,increased blood-brain barrier leakage,and aggravated the severity of seizures compared with the control.W146,a specific antagonist of sphingosine-1-phosphate receptor 1,increased the level of tight junction protein,attenuated blood-brain barrier disruption,and reduced seizure severity compared with the control.Furthermore,sphingosine 1-phosphate receptor 1 promoted the generation of interleukin-1βand tumor necrosis factor-αand caused astrocytosis.Disruption of tight junction protein and blood-brain barrier integrity by sphingosine 1-phosphate receptor 1 was reversed by minocycline,a neuroinflammation inhibitor.Behavioral tests revealed that sphingosine 1-phosphate receptor 1 exacerbated epilepsy-associated depression-like behaviors.Additionally,specific knockdown of astrocytic S1P1 inhibited neuroinflammatory responses and attenuated blood-brain barrier leakage,seizure severity,and epilepsy-associated depression-like behaviors.Taken together,our results suggest that astrocytic sphingosine 1-phosphate receptor 1 exacerbates blood-brain barrier disruption in the epileptic brain by promoting neuroinflammation.
基金supported by grants from the National Key R&D Program of China(2017YFA0105201)the National Natural Science Foundation of China(81925011,92149304,31900698,32170954,and 32100763+2 种基金the Key-Area Research and Development Program of Guangdong Province(2019B030335001)The Youth Beijing Scholars Program(015),Support Project of High-level Teachers in Beijing Municipal Universities(CIT&TCD20190334)Beijing Advanced Innovation Center for Big Data-based Precision Medicine,Capital Medical University,Beijing,China(PXM2021_014226_000026).
文摘Accurate and efficient methods for identifying and tracking each animal in a group are needed to study complex behaviors and social interactions.Traditional tracking methods(e.g.,marking each animal with dye or surgically implanting microchips)can be invasive and may have an impact on the social behavior being measured.To overcome these shortcomings,video-based methods for tracking unmarked animals,such as fruit flies and zebrafish,have been developed.However,tracking individual mice in a group remains a challenging problem because of their flexible body and complicated interaction patterns.In this study,we report the development of a multi-object tracker for mice that uses the Faster region-based convolutional neural network(R-CNN)deep learning algorithm with geometric transformations in combination with multi-camera/multi-image fusion technology.The system successfully tracked every individual in groups of unmarked mice and was applied to investigate chasing behavior.The proposed system constitutes a step forward in the noninvasive tracking of individual mice engaged in social behavior.
基金Supported by the Southeast University Foundation for Excellent YoungScholars (4023001013)the Program for New Century Excellent Talentsin University.
文摘G2 pea exhibits an apical senescence delaying phenotype under short-day (SD) conditions; however, the structural basis for its apical development is still largely unknown. In the present study, the apical meristem of SD-grown G2 pea plants underwent a transition from vegetative to indeterminate inflorescence meristem, but the apical meristem of long-day (LD)-grown G2 pea plants would be further converted to determinate floral meristem. Both SD signal and GA3 treatment enhanced expression of the putative calcium transporter PPF1, and pea homologs of TFL1 (LF and DET), whereas LD signal suppressed their expression at 60 d post-flowering compared with those at 40 d post-flowering. Both PPF1 and LF expressed at the vegetative and reproductive phases in SD-grown apical buds, but floral initiation obviously increased the expression level of PPF1 compared with the unchanged expression level of LF from 40 to 60 d post-flowering. In addition, although the floral initiation significantly enhanced the expression levels of PPF1 and DET, DET was mainly expressed after floral initiation in SD-grown apil buds. Therefore, the main structural difference between LD- and SD-grown apical meristem in G2 pea lies in whether their apical indeterminate inflorescence meristem could be converted to the determinate structure.
基金supported by grants from the National Key R&D Program of China (2018YFA0800100 and 2018YFA0800101 to CL2018YFA0800103 to Z.L.)+1 种基金the National Natural Science Foundation of China (32030017 and 31970626 to C.L31970617 to Z.L.)。
文摘Precise regulation of gene transcription is of great importance to development and diseases.Promoter-proximal transcriptional pause is a key and general mechanism to precisely control transcription in metazoans.Subsequent to transcription initiation and synthesis of a short RNA,RNA polymerase Ⅱ(Pol Ⅱ)usually pauses at the promoter-proximal regions,standing by for further signals to be released into the productive elongation stage.Fine regulation of Pol Ⅱ pausing and release is achieved by the concerted action of many negative and positive elongation factors,including the super elongation complex(SEC).Recent studies suggested that phase-separated assemblies of transcription regulatory complexes could provide a general biophysical basis for the dynamic regulation of transcription in response to various cellular needs,though direct evidence at endogenous level in living cells is still largely lacking.Here,we summarize and discuss latest advances in understanding how phase separation contributes to RNA polymerase ll-mediated transcription,with a focus on transcriptional pause and release.