Background Cardiovascular risk burden is associated with dementia risk and neurodegeneration-related brain structure,while the role of genetics and incident cardiovascular disease(CVD)remains unclear.Aims To examine t...Background Cardiovascular risk burden is associated with dementia risk and neurodegeneration-related brain structure,while the role of genetics and incident cardiovascular disease(CVD)remains unclear.Aims To examine the association of overall cardiovascular risk burden with the risk of major dementia subtypes and volumes of related brain regions in a large sample,and to explore the role of genetics and CVD onset.Methods A prospective study among 354 654 participants free of CVD and dementia(2006-2010,mean age 56.4 years)was conducted within the UK Biobank,with brain magnetic resonance imaging(MRl)measurement availablefor 15104participants since 2014.CVD risk burden was evaluated by the Framingham General Cardiovascular Risk Score(FGCRS).Dementia diagnosis was ascertained from inpatient and death register data.Results Overamedian 12.0-yearfollow-up,3998 all-cause dementia cases were identified.Higher FGCRS was associated with increasedall-cause dementia risk after adjusting for demographic,major lifestyle,clinical factors and the polygenic risk score(PRS)of Alzheimer's disease.Comparing the high versus low tertile of FGCRS,the odds ratios(ORs)and 95%confidence intervals(Cls)were 1.26(1.12 to 1.41)for all-cause dementia,1.67(1.33 to 2.09)for Alzheimer's disease and 1.53(1.07 to 2.16)for vascular dementia(all p_(treng)<0.05).Incident stroke and coronary heart disease accounted for 14%(95%Cl:9% to 21%)of the association between FGCRS and all-cause dementia.Interactions were not detected for FGCRS and PRS on the risk of any dementia subtype.We observed an 83%(95%Cl:47%to 128%)higher all-cause dementia risk comparing the high-high versus low-low FGCRS-PRS category.For brain volumes,higher FGCRS was associated with greater log-transformed white matter hyperintensities,smaller cortical volume and smaller grey matter volume.Conclusions Our findings suggest that the positive association of cardiovascular risk burden with dementia risk also applies to major dementia subtypes.The association of cardiovascular risk burden with all-cause dementia is largely independent of CVD onset and genetic predisposition to dementia.展开更多
Human hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) promise a valuable source of cells with human genetic background, physiologically relevant liver functions, and unlimited supply. Wi...Human hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) promise a valuable source of cells with human genetic background, physiologically relevant liver functions, and unlimited supply. With over 10 years’ efforts in this field, great achievements have been made. HLCs have been successfully derived and applied in disease modeling, toxicity testing and drug discovery. Large cohorts of induced pluripotent stem cells-derived HLCs have been recently applied in studying population genetics and functional outputs of common genetic variants in vitro. This has offered a new paradigm for genomewide association studies and possibly in vitro pharmacogenomics in the nearly future. However, HLCs have not yet been successfully applied in bioartificial liver devices and have only displayed limited success in cell transplantation. HLCs still have an immature hepatocyte phenotype and exist as a population with great heterogeneity, and HLCs derived from different hPSC lines display variable differentiation efficiency. Therefore, continuous improvement to the quality of HLCs, deeper investigation of relevant biological processes, and proper adaptation of recent advances in cell culture platforms, genome editing technology, and bioengineering systems are required before HLCs can fulfill the needs in basic and translational research. In this review, we summarize the discoveries, achievements, and challenges in the derivation and applications of HLCs.展开更多
Mycotoxins can cause body poisoning and induce carcinogenesis,often with a high mortality rate.Therefore,it is of great significance to seek new targets that indicate mycotoxin activity and to diagnose and intervene i...Mycotoxins can cause body poisoning and induce carcinogenesis,often with a high mortality rate.Therefore,it is of great significance to seek new targets that indicate mycotoxin activity and to diagnose and intervene in mycotoxin-induced diseases in their early stages.MicroRNAs(miRNAs)are physiological regulators whose dysregulation is closely related to the development of diseases.They are thus important markers for the occurrence and development of diseases.In this review,consideration is given to the toxicological mechanisms associated with four major mycotoxins(ochratoxin A,aflatoxin B1,deoxynivalenol,and zearalenone).The roles that miRNAs play in these mechanisms and the interactions between them and their target genes are explained,and summarize the important role of histone modifications in their toxicity.As a result,the ways that miRNAs are regulated in the pathogenicity signaling pathways are revealed which highlights the roles played by miRNAs in preventing and controlling the harmful effects of the mycotoxins.It is hoped that this review will provide a theoretical basis for the prevention and control of the damage caused by these mycotoxins.展开更多
The monocarboxylate transporter 1(MCT1),encoded by gene Slc16a1,is a proton-coupled transporter for lactate and other monocarboxylates.MCT1-mediated lactate transport was recently found to regulate various biological ...The monocarboxylate transporter 1(MCT1),encoded by gene Slc16a1,is a proton-coupled transporter for lactate and other monocarboxylates.MCT1-mediated lactate transport was recently found to regulate various biological functions.However,how MCT1 and lactate in the intestine modulate the physiology and pathophysiology of the body is unclear.In this study,we generated a mouse model with specific deletion of Slc16a1 in the intestinal epithelium(Slc16a1IKO mice)and investigated the functions of MCT1 in the gut.When fed a high-fat diet,Slc16a1IKO male mice had improvement in glucose tolerance and insulin sensitivity,while Slc16a1IKO female mice only had increased adiposity.Deficiency of intestinal MCT1 in male mice was associated with downregulation of pro-inflammatory pathways,together with decreased circulating levels of inflammatory cytokines including tumor necrosis factor alpha(TNFα)and C-C motif chemokine ligand 2(CCL2).Lactate had a stimulatory effect on pro-inflammatory macrophages in vitro.The number of intestinal macrophages was reduced in Slc16a1IKO male mice in vivo.Intestinal deletion of Slc16a1 in male mice reduced interstitial lactate level in the intestine.In addition,treatment of male mice with estrogen lowered interstitial lactate level in the intestine and abolished the difference in glucose homeostasis between Slc16a1IKO and wild-type mice.Deficiency of intestinal MCT1 also blocked the transport of lactate and short-chain fatty acids from the intestine to the portal vein.The effect of Slc16a1 deletion on glucose homeostasis in male mice was partly mediated by alterations in gut microbiota.In conclusion,our work reveals that intestinal MCT1 regulates glucose homeostasis in a sex-dependent manner.展开更多
BACKGROUND Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown. AIM To determine the effect of TMAO on the p...BACKGROUND Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown. AIM To determine the effect of TMAO on the progression of NASH. METHODS A rat model was induced by 16-wk high-fat high-cholesterol (HFHC) diet feeding and TMAO was administrated by daily oral gavage for 8 wk. RESULTS Oral TMAO intervention attenuated HFHC diet-induced steatohepatitis in rats. Histological evaluation showed that TMAO treatment significantly alleviated lobular inflammation and hepatocyte ballooning in the livers of rats fed a HFHC diet. Serum levels of alanine aminotransferase and aspartate aminotransferase were also decreased by TMAO treatment. Moreover, hepatic endoplasmic reticulum (ER) stress and cell death were mitigated in HFHC diet-fed TMAOtreated rats. Hepatic and serum levels of cholesterol were both decreased by TMAO treatment in rats fed a HFHC diet. Furthermore, the expression levels of intestinal cholesterol transporters were detected. Interestingly, cholesterol influxrelated Niemann-Pick C1-like 1 was downregulated and cholesterol efflux-related ABCG5/8 were upregulated by TMAO treatment in the small intestine. Gut microbiota analysis showed that TMAO could alter the gut microbial profile and restore the diversity of gut flora. CONCLUSION These data suggest that TMAO may modulate the gut microbiota, inhibit intestinal cholesterol absorption, and ameliorate hepatic ER stress and cell death under cholesterol overload, thereby attenuating HFHC diet-induced steatohepatitis in rats. Further studies are needed to evaluate the influence on CVD and define the safe does of TMAO treatment.展开更多
Modern diets,which often feature high levels of fat and charcoal-grilled meat,contribute to the pathogenesis of obesity and non-alcoholic fatty liver disease(NAFLD),resulting in liver cancer progression.Benzo(a)pyrene...Modern diets,which often feature high levels of fat and charcoal-grilled meat,contribute to the pathogenesis of obesity and non-alcoholic fatty liver disease(NAFLD),resulting in liver cancer progression.Benzo(a)pyrene(B[a]P)is a common environ-mental and foodborne pollutant found in smoke and fire-grilled foods,which can have an adverse effect on human health.Hepatocellular carcinoma(HCC)is the fifth leading cause of cancer and the second leading cause of cancer-related deaths worldwide.The epidemiological studies suggest that both environmental risk factors and chronic liver injury including NAFL are important for HCC development,but the precise mechanisms linking eating habits to hepato-carcinogenesis remain unclear.In the present study,we demonstrated that various miRNAs in B[a]P-exposed tumor cells contribute to tumor metastasis,among which miR-650 could be the most potent inducer.Furthermore,we found that the suppressor of cytokine signaling 3(SOCS3)is directly regulated by miR-650 and its suppression regulates the activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3)cascade.Our findings reveal a possible adverse outcome pathway of SOCS3/JAK/STAT3 regulation in B[a]P-induced HCC progress.These results provide a better understanding of the adverse effects of chronic exposure to B[a]P on human health.展开更多
Objective: Heat shock factor 1(HSF1), a transcriptional regulator of heat shock proteins(HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far.Methods: ...Objective: Heat shock factor 1(HSF1), a transcriptional regulator of heat shock proteins(HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far.Methods: The mRNA and protein levels of HSF1, HSPs, cleaved PARP, and phosphorylated HSF1 were examined by real-time PCR and Western blot. Forced expression, RNA interference, and immunofluorescence assay were used for mechanistic studies.Cell viability and apoptosis were measured by WST-8 assay and flow cytometry, respectively. Xenograft studies were performed in nude mice to evaluate the effect of dorsomorphin and an HSP90 inhibitor on tumor growth.Results: Dorsomorphin suppressed multiple stimuli-induced and constitutive HSPs expression in cancer cells. Mechanistic studies revealed that dorsomorphin reduced heat-induced HSP expression independent of adenosine monophosphate activated protein kinase. Dorsomorphin reduced heat-stimulated HSF1 Ser320 phosphorylation and nuclear translocation, as well as resting nuclear HSF1 levels in cancer cells. Dorsomorphin induced cancer cell apoptosis by inhibiting HSF1 expression. A structure-activity study revealed that the 4-pyridyl at the 3-site of the pyrazolo [1, 5-a]pyrimidine ring is critical for the anti-HSF1 activities of dorsomorphin. Dorsomorphin sensitized cancer cells to HSP90 and proteasome inhibitors and inhibited HSP70 expression induced by these inhibitors in vitro. In tumor-bearing nude mice, dorsomorphin enhanced HSP90 inhibitor-induced cancer cell apoptosis, tumor growth inhibition, and HSP70 expression.Conclusions: Dorsomorphin is an HSF1 inhibitor. It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance.Hence, dorsomorphin and its derivates may serve as potential precursors for developing drugs against cancer.展开更多
Phenylketonuria(PKU),a disease resulting in the disability to degrade phenylalanine(Phe)is an inborn error with a 1 in 10,000 morbidity rate on average around the world which leads to neurotoxicity.As an potential alt...Phenylketonuria(PKU),a disease resulting in the disability to degrade phenylalanine(Phe)is an inborn error with a 1 in 10,000 morbidity rate on average around the world which leads to neurotoxicity.As an potential alternative to a protein-restricted diet,oral intake of engineered probiotics degrading Phe inside the body is a promising treatment,currently at clinical stage II(Isabella,et al.,2018).However,limited transmembrane transport of Phe is a bottleneck to further improvement of the probiotic’s activity.Here,we achieved simultaneous degradation of Phe both intracellularly and extracellularly by expressing genes encoding the Phe-metabolizing enzyme phenylalanine ammonia lyase(PAL)as an intracellularly free and a cell surface-immobilized enzyme in Escherichia coli Nissle 1917(EcN)which overcomes the transportation problem.The metabolic engineering strategy was also combined with strengthening of Phe transportation,transportation of PAL-catalyzed trans-cinnamic acid and fixation of released ammonia.Administration of our final synthetic strain TYS8500 with PAL both displayed on the cell surface and expressed inside the cell to the Pah^(F263S)PKU mouse model reduced blood Phe concentration by 44.4%compared to the control Ec N,independent of dietary protein intake.TYS8500 shows great potential in future applications for PKU therapy.展开更多
Rapid metastasis to vital organs such as the lung,liver,and brain is responsible for the vast majority of pancreatic cancer deaths.Liver metastasis of pancreatic cancer accounts for the high mortality rate in patients...Rapid metastasis to vital organs such as the lung,liver,and brain is responsible for the vast majority of pancreatic cancer deaths.Liver metastasis of pancreatic cancer accounts for the high mortality rate in patients.Exosomes derived from pancreatic cancer cells tend to be enriched in proteins that are anchored to the cell membrane,supporting the reprogramming of the tumor microenvironment and the progression of distant metastatic lesions.For the first time,our study has demonstrated that cluster of differentiation 44(CD44),a transmembrane glycoprotein delivered by exosomes,is involved in the metastatic process of pancreatic cancer.Moreover,CD44 was found to interact with integrin a6b4 to form a complex,thereby remodeling intracellular skeleton proteins,and to promote tumor cell motility through the activation of the Src and Ras signaling cascades.Notably,we also demonstrated that the CD44–a6b4 complex can be delivered to the target region via the paracrine effects of exosomes.The selective uptake of CD44-competent tumor exosomes by liver cells activated fibrotic pathways and generated a pre-metastatic niche by stimulating the cytokines,proinflammatory factors,and growth factors that ultimately support tumor metastasis.Our results suggest the potential application of exosomal CD44 as a biomarker for the clinical diagnosis of and therapy for pancreatic cancer.展开更多
Clustered regularly interspaced short palindromic repeats(CRISPR)/Cas9-based screening using various guide RNA(g RNA)libraries has been executed to identify functional components for a wide range of phenotypes with re...Clustered regularly interspaced short palindromic repeats(CRISPR)/Cas9-based screening using various guide RNA(g RNA)libraries has been executed to identify functional components for a wide range of phenotypes with regard to numerous cell types and organisms.Using data from public CRISPR/Cas9-based screening experiments,we found that the sequences of g RNAs in the library influence CRISPR/Cas9-based screening.As building a standard strategy for correcting results of all g RNA libraries is impractical,we developed Seq Cor,an open-source programming bundle that enables researchers to address the result bias potentially triggered by the composition of g RNA sequences via the organization of g RNA in the library used in CRISPR/Cas9-based screening.Furthermore,Seq Cor completely computerizes the extraction of sequence features that may influence single-guide RNA knockout efficiency using a machine learning approach.Taken together,we have developed a software program bundle that ought to be beneficial to the CRISPR/Cas9-based screening platform.展开更多
Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum...Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.展开更多
Regulatory T(T_(reg))cells play an essential role in maintaining immune balance across various physiological and pathological conditions.However,the mechanisms underlying T_(reg)homeostasis remain incompletely underst...Regulatory T(T_(reg))cells play an essential role in maintaining immune balance across various physiological and pathological conditions.However,the mechanisms underlying T_(reg)homeostasis remain incompletely understood.Here,we report that RIPK1 is crucial for T_(reg) cell survival and homeostasis.We generated mice with T_(reg) cell-specific ablation of Ripk1 and found that these mice developed fatal systemic autoimmunity due to a dramatic reduction in the Treg cell compartment caused by excessive cell death.Unlike conventional T cells,Treg cells with Ripk1 deficiency were only partially rescued from cell death by blocking FADD-dependent apoptosis.However,simultaneous removal of both Fadd and Ripk3 completely restored the homeostasis of Ripk1-deficient Treg cells by blocking two cell death pathways.Thus,our study highlights the critical role of RIPK1 in regulating Treg cell homeostasis by controlling both apoptosis and necroptosis,thereby providing novel insights into the mechanisms of Treg cell homeostasis.展开更多
Precision medicine emerges as a new approach that takes into account individual variability. Successful realization of precision medicine requires disease models that are able to incorporate personalized dis- ease inf...Precision medicine emerges as a new approach that takes into account individual variability. Successful realization of precision medicine requires disease models that are able to incorporate personalized dis- ease information and recapitulate disease development processes at the molecular, cellular and organ levels. With recent development in stem cell field, a variety of tissue organoids can be derived from patient specific pluripotent stem cells and adult stem cells. In combi- nation with the state-of-the-art genome editing tools, organoids can be further engineered to mimic disease- relevant genetic and epigenetic status of a patient. This has therefore enabled a rapid expansion of sophisticated in vitro disease models, offering a unique system for fundamental and biomedical research as well as the development of personalized medicine. Here we summarize some of the latest advances and future perspectives in engineering stem cell organoids for human disease modeling.展开更多
Obesity is a worldwide epidemic and results from excessive energy intake or inefficient energy expenditure.It is promising to utilize the thermogenic function of brown adipose tissue for obesity intervention.However,t...Obesity is a worldwide epidemic and results from excessive energy intake or inefficient energy expenditure.It is promising to utilize the thermogenic function of brown adipose tissue for obesity intervention.However,the mechanisms controlling the efficacy of norepinephrine-induced thermogenesis in brown adipocytes remain elusive.Here we demonstrate that norepinephrine(NE)induces low-efficacy thermogenesis,evoking both heterogeneous changes(ΔΨm andΔpH)and homogenous responses,one of which is that NE stimulation causes large amounts of ATP consumption in brown adipocytes.We reveal that the proton-ATPase activity of mitochondrial complex V is a key factor that antagonizes proton leakage by UCP1 and determines the efficacy of NE-induced thermogenesis in brown adipocytes.Furthermore,to avoid unnecessary and undesired heat production,we reveal that ATP is a necessary sympathetic cotransmitter for the high efficacy and specificity of NE-induced thermogenesis in brown adipocytes as it increases intracellular calcium concentrations and upregulates the ATP synthase activity of complex V.Thus,we demonstrate the modulation mechanism of thermogenic efficacy in brown adipocytes.These findings imply new strategies to partially or fully utilize the thermogenic capacity of brown adipocytes to identify therapeutic targets for the treatment of obesity and diabetes.展开更多
The title compound phenyl(6-phenyl-3-p-tolyl-6,7-dihydro-5 H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl)methanone(PTM),designed using 4-amino-3-p-tolyl-1H-1,2,4-triazole-5(4 H)-thione as the starting material,was su...The title compound phenyl(6-phenyl-3-p-tolyl-6,7-dihydro-5 H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl)methanone(PTM),designed using 4-amino-3-p-tolyl-1H-1,2,4-triazole-5(4 H)-thione as the starting material,was successfully synthesized via a two-step synthesis route and finally characterized by NMR,FT-IR,single-crystal X-ray diffraction and mass spectrometry techniques.The crystal structure of trans-PTM was obtained from X-ray diffraction:C24H20N4OS,Mr=412.52,monoclinic system,space group P21/c,a=16.650(3),b=13.876(3),c=8.812(2)A,β=100.340(3)°,V=2002.8(7)A^3,F(000)=865,Z=4,Dc=1.3680 g/cm^3,λ=0.71073A,μ=0.186 mm^-1 and the final R=0.0786 for 3514 unique reflections with 2044 observed ones(Ⅰ>2σ(Ⅰ)).The biological activities of antimicrobial and regulation of plant growth of PTM were investigated.The results indicated that PTM showed weak antimicrobial activity on Bacillus pumilus,while promoted the growth of radish and inhibited that of wheat in a dose-dependent manner.Therefore,PTM may be developed as a potential drug to promote the growth of dicotyledonous plants or as an herbicide to inhibit that of monocotyledonous plants in the future.展开更多
Previous studies have indicated an association of fat mass and obesity-associated(FTO)with nonalcoholic fatty liver disease(NAFLD),the most common chronic liver disease worldwide.This study aimed to decipher the compl...Previous studies have indicated an association of fat mass and obesity-associated(FTO)with nonalcoholic fatty liver disease(NAFLD),the most common chronic liver disease worldwide.This study aimed to decipher the complex role of FTO in hepatic lipid metabolism.We found that a decrease in N^(6)-methyladenosine(m^(6)A)RNA methylation in the liver of mice fed with a high-fat diet(HFD)was accompanied by an increase in FTO expression.Overexpression of FTO in the liver promoted triglyceride accumulation by upregulating the expression of lipogenic genes.Mechanistical studies revealed that FTO could stabilize the mRNAs of sterol regulatory element binding transcription factor 1(SREBF1)and carbohydrate responsive element binding protein(ChREBP),two master lipogenic transcription factors,by demethylating m^(6)A sites.Knockdown ofeither SREBF1 or ChREBP attenuated the lipogenic effect of FTO,suggesting that they are bona fide effectors for FTO in regulating lipogenesis.Insulin could stimulate FTO transcription through a mechanism involving the action of intranuclear insulin receptor beta,while knockdown of FTO abrogated the lipogenic effect of insulin.Inhibition ofFTo by entacapone decreased the expression of SREBF1,ChREBP,and downstream lipogenic genes,ameliorating liver steatosis in HFD-fed mice.Thus,our study established a critical role of FTO in both the insulin-regulated hepatic lipogenesis and the pathogenesis of NAFLD and provided a potential strategyfor treating NAFLD.展开更多
Dear Editor,Iron deficiency,documented by World Health Organization(WHO),is the most common nutritional deficiency,and accounts for-50%of anemia globally.Iron-deficiency anemia is notably and frequently associated wit...Dear Editor,Iron deficiency,documented by World Health Organization(WHO),is the most common nutritional deficiency,and accounts for-50%of anemia globally.Iron-deficiency anemia is notably and frequently associated with chronic heart failure,chronic kidney disease,cancer and inflammatory bowel disease.According to WHO Global Health Estimates 2014 Summary,iron-deficiency anemia is a major and prevalent public health problem worldwide,which contributes to 0.2% mortality,especially maternal and child mortality.展开更多
Background:Pancreatic neuroendocrine tumor is a rare and heterogeneous entity,and approximately half of the patients harbored liver metastasis when initially diagnosed,whose prognosis is dismal.High-throughput sequenc...Background:Pancreatic neuroendocrine tumor is a rare and heterogeneous entity,and approximately half of the patients harbored liver metastasis when initially diagnosed,whose prognosis is dismal.High-throughput sequencing has largely uncovered the genomic features of pancreatic neuroendocrine tumor,but the genetic alterations in the metastatic cases remain relatively unclear,which we aimed to study.Methods:Pathologically confirmed well-differentiated pancreatic neuroendocrine tumor samples resected in our hospital from 2000 to 2019 were collected.We performed deep sequencing on the exome of 341 tumor-related genes,and compared the differences of genetic alterations between the metastatic and the non-metastatic cases,as well as between the primary and the paired liver metastatic tumors.Results:Sequencing data of 79 samples from 29 pancreatic neuroendocrine tumor patients were included into analysis.A total of 2,471 somatic variants were identified,75.5%of which were considered as low-abundance.NOTCH1 was the most frequently mutated gene,altered in 26(53.1%)pancreatic neuroendocrine tumor samples from 18(62.1%)patients.Compared with the non-metastatic pancreatic neuroendocrine tumors,the metastatic cases were discovered with more single nucleotide variants and copy number variations,indicating the increased genomic instability.In addition,among the paired metastatic cases,the primary and the metastatic lesions shared limited mutated genes.Conclusions:Through the targeted deep sequencing,we identified the intratumor,intraindividual,and interindividual heterogeneity in the pancreatic neuroendocrine tumor patients,particularly in the metastatic cases,bringing potential challenges for the current biopsy strategies in guiding clinical treatments.展开更多
Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that...Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that although deprivation of the EAA leucine has no effect in unstressed mice,it remarkably reverses the depression-like behaviors induced by chronic restraint stress(CRS).This beneficial effect is independent of feeding and is applicable to the dietary deficiency of other EAAs.Furthermore,the effect of leucine deprivation is suppressed by central injection of leucine or mimicked by central injection of leucinol.Moreover,hypothalamic agouti-related peptide(AgRP)neural activity changes during CRS and leucine deprivation,and chemogenetically inhibiting AgRP neurons eliminates the antidepressant effects of leucine deprivation.Finally,the leucine deprivation-regulated behavioral effects are mediated by amino acid sensor general control non-derepressible 2(GCN2)in AgRP neurons.Taken together,our results suggest a new drug target and/or dietary intervention for the reduction of depressive symptoms.展开更多
基金grants from the National Key R&D Program of China(2023YFF1104301)(by Geng Zong)National Natural Science Foundation of China(82373576)(by Geng Zong)+2 种基金National Science Fund for Excellent Young Scholars(81922060)(by Geng Zong)Strategic Priority CAS Project(XDB38010300)(by Geng Zong)the Zhejiang University Education Foundation Global Partnership Fund(by Changzheng Yuan).
文摘Background Cardiovascular risk burden is associated with dementia risk and neurodegeneration-related brain structure,while the role of genetics and incident cardiovascular disease(CVD)remains unclear.Aims To examine the association of overall cardiovascular risk burden with the risk of major dementia subtypes and volumes of related brain regions in a large sample,and to explore the role of genetics and CVD onset.Methods A prospective study among 354 654 participants free of CVD and dementia(2006-2010,mean age 56.4 years)was conducted within the UK Biobank,with brain magnetic resonance imaging(MRl)measurement availablefor 15104participants since 2014.CVD risk burden was evaluated by the Framingham General Cardiovascular Risk Score(FGCRS).Dementia diagnosis was ascertained from inpatient and death register data.Results Overamedian 12.0-yearfollow-up,3998 all-cause dementia cases were identified.Higher FGCRS was associated with increasedall-cause dementia risk after adjusting for demographic,major lifestyle,clinical factors and the polygenic risk score(PRS)of Alzheimer's disease.Comparing the high versus low tertile of FGCRS,the odds ratios(ORs)and 95%confidence intervals(Cls)were 1.26(1.12 to 1.41)for all-cause dementia,1.67(1.33 to 2.09)for Alzheimer's disease and 1.53(1.07 to 2.16)for vascular dementia(all p_(treng)<0.05).Incident stroke and coronary heart disease accounted for 14%(95%Cl:9% to 21%)of the association between FGCRS and all-cause dementia.Interactions were not detected for FGCRS and PRS on the risk of any dementia subtype.We observed an 83%(95%Cl:47%to 128%)higher all-cause dementia risk comparing the high-high versus low-low FGCRS-PRS category.For brain volumes,higher FGCRS was associated with greater log-transformed white matter hyperintensities,smaller cortical volume and smaller grey matter volume.Conclusions Our findings suggest that the positive association of cardiovascular risk burden with dementia risk also applies to major dementia subtypes.The association of cardiovascular risk burden with all-cause dementia is largely independent of CVD onset and genetic predisposition to dementia.
基金Supported by National Key RD Program of China,No.017YFA0102800,and No.2017YFA0103700the National Natural Science Foundation of China,No.31670829
文摘Human hepatocyte-like cells (HLCs) derived from human pluripotent stem cells (hPSCs) promise a valuable source of cells with human genetic background, physiologically relevant liver functions, and unlimited supply. With over 10 years’ efforts in this field, great achievements have been made. HLCs have been successfully derived and applied in disease modeling, toxicity testing and drug discovery. Large cohorts of induced pluripotent stem cells-derived HLCs have been recently applied in studying population genetics and functional outputs of common genetic variants in vitro. This has offered a new paradigm for genomewide association studies and possibly in vitro pharmacogenomics in the nearly future. However, HLCs have not yet been successfully applied in bioartificial liver devices and have only displayed limited success in cell transplantation. HLCs still have an immature hepatocyte phenotype and exist as a population with great heterogeneity, and HLCs derived from different hPSC lines display variable differentiation efficiency. Therefore, continuous improvement to the quality of HLCs, deeper investigation of relevant biological processes, and proper adaptation of recent advances in cell culture platforms, genome editing technology, and bioengineering systems are required before HLCs can fulfill the needs in basic and translational research. In this review, we summarize the discoveries, achievements, and challenges in the derivation and applications of HLCs.
基金funded by the National Key Research and Development Program of China (2017YFC1600304)the National Natural Science Foundation of China (grants No. 31872538+4 种基金grants No. 31972746grants No.31772809)Liaoning Provincial Natural Fund Guidance Program Project(2019-ZD-0708)China Postdoctoral Science Foundation (2016 T90477)PAPD,Project UHK VT2019–2021 and and MH CZ–DRO (UHHK, 00179906)
文摘Mycotoxins can cause body poisoning and induce carcinogenesis,often with a high mortality rate.Therefore,it is of great significance to seek new targets that indicate mycotoxin activity and to diagnose and intervene in mycotoxin-induced diseases in their early stages.MicroRNAs(miRNAs)are physiological regulators whose dysregulation is closely related to the development of diseases.They are thus important markers for the occurrence and development of diseases.In this review,consideration is given to the toxicological mechanisms associated with four major mycotoxins(ochratoxin A,aflatoxin B1,deoxynivalenol,and zearalenone).The roles that miRNAs play in these mechanisms and the interactions between them and their target genes are explained,and summarize the important role of histone modifications in their toxicity.As a result,the ways that miRNAs are regulated in the pathogenicity signaling pathways are revealed which highlights the roles played by miRNAs in preventing and controlling the harmful effects of the mycotoxins.It is hoped that this review will provide a theoretical basis for the prevention and control of the damage caused by these mycotoxins.
基金funded by the National Natural Science Foundation of China(32230047 to Y.C.)the Shanghai Municipal Science and Technology Major Project(to Y.C.).
文摘The monocarboxylate transporter 1(MCT1),encoded by gene Slc16a1,is a proton-coupled transporter for lactate and other monocarboxylates.MCT1-mediated lactate transport was recently found to regulate various biological functions.However,how MCT1 and lactate in the intestine modulate the physiology and pathophysiology of the body is unclear.In this study,we generated a mouse model with specific deletion of Slc16a1 in the intestinal epithelium(Slc16a1IKO mice)and investigated the functions of MCT1 in the gut.When fed a high-fat diet,Slc16a1IKO male mice had improvement in glucose tolerance and insulin sensitivity,while Slc16a1IKO female mice only had increased adiposity.Deficiency of intestinal MCT1 in male mice was associated with downregulation of pro-inflammatory pathways,together with decreased circulating levels of inflammatory cytokines including tumor necrosis factor alpha(TNFα)and C-C motif chemokine ligand 2(CCL2).Lactate had a stimulatory effect on pro-inflammatory macrophages in vitro.The number of intestinal macrophages was reduced in Slc16a1IKO male mice in vivo.Intestinal deletion of Slc16a1 in male mice reduced interstitial lactate level in the intestine.In addition,treatment of male mice with estrogen lowered interstitial lactate level in the intestine and abolished the difference in glucose homeostasis between Slc16a1IKO and wild-type mice.Deficiency of intestinal MCT1 also blocked the transport of lactate and short-chain fatty acids from the intestine to the portal vein.The effect of Slc16a1 deletion on glucose homeostasis in male mice was partly mediated by alterations in gut microbiota.In conclusion,our work reveals that intestinal MCT1 regulates glucose homeostasis in a sex-dependent manner.
基金Supported by National Key R and D Program of China,No.2017YFC0908903National Natural Science Foundation of China,No.81873565,No.81470840,and No.81800510Shanghai Sailing Program,No.18YF1415900
文摘BACKGROUND Trimethylamine N-oxide (TMAO) has been shown to be involved in cardiovascular disease (CVD). However, its role in nonalcoholic steatohepatitis (NASH) is unknown. AIM To determine the effect of TMAO on the progression of NASH. METHODS A rat model was induced by 16-wk high-fat high-cholesterol (HFHC) diet feeding and TMAO was administrated by daily oral gavage for 8 wk. RESULTS Oral TMAO intervention attenuated HFHC diet-induced steatohepatitis in rats. Histological evaluation showed that TMAO treatment significantly alleviated lobular inflammation and hepatocyte ballooning in the livers of rats fed a HFHC diet. Serum levels of alanine aminotransferase and aspartate aminotransferase were also decreased by TMAO treatment. Moreover, hepatic endoplasmic reticulum (ER) stress and cell death were mitigated in HFHC diet-fed TMAOtreated rats. Hepatic and serum levels of cholesterol were both decreased by TMAO treatment in rats fed a HFHC diet. Furthermore, the expression levels of intestinal cholesterol transporters were detected. Interestingly, cholesterol influxrelated Niemann-Pick C1-like 1 was downregulated and cholesterol efflux-related ABCG5/8 were upregulated by TMAO treatment in the small intestine. Gut microbiota analysis showed that TMAO could alter the gut microbial profile and restore the diversity of gut flora. CONCLUSION These data suggest that TMAO may modulate the gut microbiota, inhibit intestinal cholesterol absorption, and ameliorate hepatic ER stress and cell death under cholesterol overload, thereby attenuating HFHC diet-induced steatohepatitis in rats. Further studies are needed to evaluate the influence on CVD and define the safe does of TMAO treatment.
基金This work was supported by grants from the National Natural Science Foundation of China(82173543,81803269,and 81902939)Shanghai Municipality Health Commission(GWV-10.2-YQ17 and 2019Y0150)+1 种基金Innovative Research Team of High-level Local Universities in Shanghai(YG2017QN68)the Major Science and Technology Innovation Program of Shanghai Municipal Education Commission(2019-01-07-00-01-E00059).
文摘Modern diets,which often feature high levels of fat and charcoal-grilled meat,contribute to the pathogenesis of obesity and non-alcoholic fatty liver disease(NAFLD),resulting in liver cancer progression.Benzo(a)pyrene(B[a]P)is a common environ-mental and foodborne pollutant found in smoke and fire-grilled foods,which can have an adverse effect on human health.Hepatocellular carcinoma(HCC)is the fifth leading cause of cancer and the second leading cause of cancer-related deaths worldwide.The epidemiological studies suggest that both environmental risk factors and chronic liver injury including NAFL are important for HCC development,but the precise mechanisms linking eating habits to hepato-carcinogenesis remain unclear.In the present study,we demonstrated that various miRNAs in B[a]P-exposed tumor cells contribute to tumor metastasis,among which miR-650 could be the most potent inducer.Furthermore,we found that the suppressor of cytokine signaling 3(SOCS3)is directly regulated by miR-650 and its suppression regulates the activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3)cascade.Our findings reveal a possible adverse outcome pathway of SOCS3/JAK/STAT3 regulation in B[a]P-induced HCC progress.These results provide a better understanding of the adverse effects of chronic exposure to B[a]P on human health.
基金supported by grants from the National Key Research and Development Program of China (Grant No.2017YFC1601702)China Postdoctoral Science Foundation (Grant No.2011M500825)
文摘Objective: Heat shock factor 1(HSF1), a transcriptional regulator of heat shock proteins(HSPs), is an attractive therapeutic target for cancer. However, only a few HSF1 inhibitors have been identified so far.Methods: The mRNA and protein levels of HSF1, HSPs, cleaved PARP, and phosphorylated HSF1 were examined by real-time PCR and Western blot. Forced expression, RNA interference, and immunofluorescence assay were used for mechanistic studies.Cell viability and apoptosis were measured by WST-8 assay and flow cytometry, respectively. Xenograft studies were performed in nude mice to evaluate the effect of dorsomorphin and an HSP90 inhibitor on tumor growth.Results: Dorsomorphin suppressed multiple stimuli-induced and constitutive HSPs expression in cancer cells. Mechanistic studies revealed that dorsomorphin reduced heat-induced HSP expression independent of adenosine monophosphate activated protein kinase. Dorsomorphin reduced heat-stimulated HSF1 Ser320 phosphorylation and nuclear translocation, as well as resting nuclear HSF1 levels in cancer cells. Dorsomorphin induced cancer cell apoptosis by inhibiting HSF1 expression. A structure-activity study revealed that the 4-pyridyl at the 3-site of the pyrazolo [1, 5-a]pyrimidine ring is critical for the anti-HSF1 activities of dorsomorphin. Dorsomorphin sensitized cancer cells to HSP90 and proteasome inhibitors and inhibited HSP70 expression induced by these inhibitors in vitro. In tumor-bearing nude mice, dorsomorphin enhanced HSP90 inhibitor-induced cancer cell apoptosis, tumor growth inhibition, and HSP70 expression.Conclusions: Dorsomorphin is an HSF1 inhibitor. It induces cancer cell apoptosis, sensitizes cancer cells to both HSP90 and proteasome inhibitors, and suppresses HSP upregulation by these drugs, which may prevent the development of drug resistance.Hence, dorsomorphin and its derivates may serve as potential precursors for developing drugs against cancer.
基金supported by the National Natural Science Foundation of China(21825804,31921006)the National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”,China(2018ZX09711002-019)the Shanghai Municipal Science and Technology Major Project and the National Key Research and Development Program of China(2018YFA0800603)。
文摘Phenylketonuria(PKU),a disease resulting in the disability to degrade phenylalanine(Phe)is an inborn error with a 1 in 10,000 morbidity rate on average around the world which leads to neurotoxicity.As an potential alternative to a protein-restricted diet,oral intake of engineered probiotics degrading Phe inside the body is a promising treatment,currently at clinical stage II(Isabella,et al.,2018).However,limited transmembrane transport of Phe is a bottleneck to further improvement of the probiotic’s activity.Here,we achieved simultaneous degradation of Phe both intracellularly and extracellularly by expressing genes encoding the Phe-metabolizing enzyme phenylalanine ammonia lyase(PAL)as an intracellularly free and a cell surface-immobilized enzyme in Escherichia coli Nissle 1917(EcN)which overcomes the transportation problem.The metabolic engineering strategy was also combined with strengthening of Phe transportation,transportation of PAL-catalyzed trans-cinnamic acid and fixation of released ammonia.Administration of our final synthetic strain TYS8500 with PAL both displayed on the cell surface and expressed inside the cell to the Pah^(F263S)PKU mouse model reduced blood Phe concentration by 44.4%compared to the control Ec N,independent of dietary protein intake.TYS8500 shows great potential in future applications for PKU therapy.
基金This work was sponsored by grants from the National Natural Science Foundation of China(81803269 and 81427805)the Science and Technology Commission of Shanghai Municipality(18YF1412100 and 2019Y0150)+2 种基金the National Key Research and Development Program of China(2018YFC2000700)the Key Research Program of the Chinese Academy of Sciences(ZDRW-ZS-2017-1)Shanghai Municipality Health Commission(GWV-10.2-YQ17 and 2019Y0150).
文摘Rapid metastasis to vital organs such as the lung,liver,and brain is responsible for the vast majority of pancreatic cancer deaths.Liver metastasis of pancreatic cancer accounts for the high mortality rate in patients.Exosomes derived from pancreatic cancer cells tend to be enriched in proteins that are anchored to the cell membrane,supporting the reprogramming of the tumor microenvironment and the progression of distant metastatic lesions.For the first time,our study has demonstrated that cluster of differentiation 44(CD44),a transmembrane glycoprotein delivered by exosomes,is involved in the metastatic process of pancreatic cancer.Moreover,CD44 was found to interact with integrin a6b4 to form a complex,thereby remodeling intracellular skeleton proteins,and to promote tumor cell motility through the activation of the Src and Ras signaling cascades.Notably,we also demonstrated that the CD44–a6b4 complex can be delivered to the target region via the paracrine effects of exosomes.The selective uptake of CD44-competent tumor exosomes by liver cells activated fibrotic pathways and generated a pre-metastatic niche by stimulating the cytokines,proinflammatory factors,and growth factors that ultimately support tumor metastasis.Our results suggest the potential application of exosomal CD44 as a biomarker for the clinical diagnosis of and therapy for pancreatic cancer.
基金supported by grants from the National Key R&D Program of China(2017YFA0102800 and 2017YFA0103700)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030402)the National Natural Science Foundation of China(31501067,31670829,and 31971063)
文摘Clustered regularly interspaced short palindromic repeats(CRISPR)/Cas9-based screening using various guide RNA(g RNA)libraries has been executed to identify functional components for a wide range of phenotypes with regard to numerous cell types and organisms.Using data from public CRISPR/Cas9-based screening experiments,we found that the sequences of g RNAs in the library influence CRISPR/Cas9-based screening.As building a standard strategy for correcting results of all g RNA libraries is impractical,we developed Seq Cor,an open-source programming bundle that enables researchers to address the result bias potentially triggered by the composition of g RNA sequences via the organization of g RNA in the library used in CRISPR/Cas9-based screening.Furthermore,Seq Cor completely computerizes the extraction of sequence features that may influence single-guide RNA knockout efficiency using a machine learning approach.Taken together,we have developed a software program bundle that ought to be beneficial to the CRISPR/Cas9-based screening platform.
基金supported by the National Natural Science Foundation of China(31730036,31871380,31871382,31930055,31930058,32000500,32022034,32030033,32070730,32130046,3217050247,32150005,32200595,32222024,81730019,81730022,81830014,81921006,81925005,81970426,81971301,81971312,82030041,82061160495,82070805,82071595,82090020,82100841,82120108009,82122024,82125002,82125011,82125012,82130045,82171284,82173061,82173398,82225007,82225015,82225017,82225018,82230047,82230088,82271600,91949106,91949201,92049116,92049302,92049304,92149303,92149306,92157202,92168201,92169102,92249301,92268201)the National Key Research and Development Program of China(2018YFA0800700,2018YFC2000100,2018YFC2000102,2018YFC2002003,2019YFA0110900,2019YFA0801703,2019YFA0801903,2019YFA0802202,2019YFA0904800,2020YFA0113400,2020YFA0803401,2020YFA0804000,2020YFC2002900,2020YFC2008000,2020YFE0202200,2021YFA0804900,2021YFA1100103,2021YFA1100900,2021YFE0114200,2021ZD0202400,2022YFA0806001,2022YFA0806002,2022YFA0806600,2022YFA1103200,2022YFA1103601,2022YFA1103701,2022YFA1103800,2022YFA1103801,2022YFA1104100,2022YFA1104904,2022YFA1303000,2022YFC2009900,2022YFC2502401,2022YFC3602400,2022YFE0118000,2022ZD0213200)+14 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030302,XDB39000000,XDB39030600)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2020085,2021080)CAS Project for Young Scientists in Basic Research(YSBR-076)the Program of the Beijing Natural Science Foundation(JQ20031)Clinical Research Operating Fund of Central High level hospitals(2022-PUMCHE-001)CAMS Innovation Fund for Medical Sciences(CIFMS)(2022-I2M1-004)Talent Program of the Chinese Academy of Medical Science(2022RC310-10)Research Funds from Health@Inno HK Program launched by Innovation Technology Commission of the Hong Kong Special Administrative Region,Guangdong Basic and Applied Basic Research Foundation(2020B1515020044)Guangzhou Planned Project of Science and Technology(202002020039)the Major Technology Innovation of Hubei Province(2019ACA141)the Science and Technology Major Project of Hunan Provincial Science and Technology Department(2021SK1010)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01)the Natural Science Foundation of Sichuan Province(2023NSFSC0003)Yunnan Fundamental Research Project(202201AS070080)the State Key Laboratory of Membrane Biology。
文摘Aging biomarkers are a combination of biological parameters to(i)assess age-related changes,(ii)track the physiological aging process,and(iii)predict the transition into a pathological status.Although a broad spectrum of aging biomarkers has been developed,their potential uses and limitations remain poorly characterized.An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research:How old are we?Why do we get old?And how can we age slower?This review aims to address this need.Here,we summarize our current knowledge of biomarkers developed for cellular,organ,and organismal levels of aging,comprising six pillars:physiological characteristics,medical imaging,histological features,cellular alterations,molecular changes,and secretory factors.To fulfill all these requisites,we propose that aging biomarkers should qualify for being specific,systemic,and clinically relevant.
基金supported by the following grants:National Key Research and Development Program of China(2021YFA1301402)Shanghai Municipal Science and Technology Major Project(ZD2021CY001)+4 种基金National Key Research and Development Program of China(2021YFE0200900,2022YFA0807300)National Natural Science Foundation of China(82101833,82073901)Three-year Action Plan for Shanghai TCM Development and Inheritance Program[ZY(2021-2023)-0103]Top-level Clinical Discipline Project of Shanghai Pudong District(grant/award number:PWYgf 2021-01)Training Plan for Discipline Leaders of Shanghai Pudong New Area Health Commission(grant/award number:PWRd2020-09).
文摘Regulatory T(T_(reg))cells play an essential role in maintaining immune balance across various physiological and pathological conditions.However,the mechanisms underlying T_(reg)homeostasis remain incompletely understood.Here,we report that RIPK1 is crucial for T_(reg) cell survival and homeostasis.We generated mice with T_(reg) cell-specific ablation of Ripk1 and found that these mice developed fatal systemic autoimmunity due to a dramatic reduction in the Treg cell compartment caused by excessive cell death.Unlike conventional T cells,Treg cells with Ripk1 deficiency were only partially rescued from cell death by blocking FADD-dependent apoptosis.However,simultaneous removal of both Fadd and Ripk3 completely restored the homeostasis of Ripk1-deficient Treg cells by blocking two cell death pathways.Thus,our study highlights the critical role of RIPK1 in regulating Treg cell homeostasis by controlling both apoptosis and necroptosis,thereby providing novel insights into the mechanisms of Treg cell homeostasis.
文摘Precision medicine emerges as a new approach that takes into account individual variability. Successful realization of precision medicine requires disease models that are able to incorporate personalized dis- ease information and recapitulate disease development processes at the molecular, cellular and organ levels. With recent development in stem cell field, a variety of tissue organoids can be derived from patient specific pluripotent stem cells and adult stem cells. In combi- nation with the state-of-the-art genome editing tools, organoids can be further engineered to mimic disease- relevant genetic and epigenetic status of a patient. This has therefore enabled a rapid expansion of sophisticated in vitro disease models, offering a unique system for fundamental and biomedical research as well as the development of personalized medicine. Here we summarize some of the latest advances and future perspectives in engineering stem cell organoids for human disease modeling.
文摘Obesity is a worldwide epidemic and results from excessive energy intake or inefficient energy expenditure.It is promising to utilize the thermogenic function of brown adipose tissue for obesity intervention.However,the mechanisms controlling the efficacy of norepinephrine-induced thermogenesis in brown adipocytes remain elusive.Here we demonstrate that norepinephrine(NE)induces low-efficacy thermogenesis,evoking both heterogeneous changes(ΔΨm andΔpH)and homogenous responses,one of which is that NE stimulation causes large amounts of ATP consumption in brown adipocytes.We reveal that the proton-ATPase activity of mitochondrial complex V is a key factor that antagonizes proton leakage by UCP1 and determines the efficacy of NE-induced thermogenesis in brown adipocytes.Furthermore,to avoid unnecessary and undesired heat production,we reveal that ATP is a necessary sympathetic cotransmitter for the high efficacy and specificity of NE-induced thermogenesis in brown adipocytes as it increases intracellular calcium concentrations and upregulates the ATP synthase activity of complex V.Thus,we demonstrate the modulation mechanism of thermogenic efficacy in brown adipocytes.These findings imply new strategies to partially or fully utilize the thermogenic capacity of brown adipocytes to identify therapeutic targets for the treatment of obesity and diabetes.
基金supported by the grants from Zhangzhou Natural Science Foundation of China(No.ZZ2018J39)The work reported in this manuscript has been granted a Chinese Patent(No.ZL201710632570.6)。
文摘The title compound phenyl(6-phenyl-3-p-tolyl-6,7-dihydro-5 H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl)methanone(PTM),designed using 4-amino-3-p-tolyl-1H-1,2,4-triazole-5(4 H)-thione as the starting material,was successfully synthesized via a two-step synthesis route and finally characterized by NMR,FT-IR,single-crystal X-ray diffraction and mass spectrometry techniques.The crystal structure of trans-PTM was obtained from X-ray diffraction:C24H20N4OS,Mr=412.52,monoclinic system,space group P21/c,a=16.650(3),b=13.876(3),c=8.812(2)A,β=100.340(3)°,V=2002.8(7)A^3,F(000)=865,Z=4,Dc=1.3680 g/cm^3,λ=0.71073A,μ=0.186 mm^-1 and the final R=0.0786 for 3514 unique reflections with 2044 observed ones(Ⅰ>2σ(Ⅰ)).The biological activities of antimicrobial and regulation of plant growth of PTM were investigated.The results indicated that PTM showed weak antimicrobial activity on Bacillus pumilus,while promoted the growth of radish and inhibited that of wheat in a dose-dependent manner.Therefore,PTM may be developed as a potential drug to promote the growth of dicotyledonous plants or as an herbicide to inhibit that of monocotyledonous plants in the future.
基金This work was supported by the Chinese Ministry of Science and Technology(2021YFA1100500)the National Natural Science Foundation of China(NSFC,91957205,82070821,and 82000805)+4 种基金Youth Innovation Promotion Association,Chinese Academy of Sciences(2021261)Pujiang Talent Program from the Science and Technology Commission of Shanghai Municipality(21PJ1416100)Young Elite Scientists Sponsorship Program by China Association for Science and Technology(2020QNRC001)the Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province,Jiangnan University(2022-3-1)NHC Key Laboratory of Food Safety Risk Assessment(2020K02).
文摘Previous studies have indicated an association of fat mass and obesity-associated(FTO)with nonalcoholic fatty liver disease(NAFLD),the most common chronic liver disease worldwide.This study aimed to decipher the complex role of FTO in hepatic lipid metabolism.We found that a decrease in N^(6)-methyladenosine(m^(6)A)RNA methylation in the liver of mice fed with a high-fat diet(HFD)was accompanied by an increase in FTO expression.Overexpression of FTO in the liver promoted triglyceride accumulation by upregulating the expression of lipogenic genes.Mechanistical studies revealed that FTO could stabilize the mRNAs of sterol regulatory element binding transcription factor 1(SREBF1)and carbohydrate responsive element binding protein(ChREBP),two master lipogenic transcription factors,by demethylating m^(6)A sites.Knockdown ofeither SREBF1 or ChREBP attenuated the lipogenic effect of FTO,suggesting that they are bona fide effectors for FTO in regulating lipogenesis.Insulin could stimulate FTO transcription through a mechanism involving the action of intranuclear insulin receptor beta,while knockdown of FTO abrogated the lipogenic effect of insulin.Inhibition ofFTo by entacapone decreased the expression of SREBF1,ChREBP,and downstream lipogenic genes,ameliorating liver steatosis in HFD-fed mice.Thus,our study established a critical role of FTO in both the insulin-regulated hepatic lipogenesis and the pathogenesis of NAFLD and provided a potential strategyfor treating NAFLD.
文摘Dear Editor,Iron deficiency,documented by World Health Organization(WHO),is the most common nutritional deficiency,and accounts for-50%of anemia globally.Iron-deficiency anemia is notably and frequently associated with chronic heart failure,chronic kidney disease,cancer and inflammatory bowel disease.According to WHO Global Health Estimates 2014 Summary,iron-deficiency anemia is a major and prevalent public health problem worldwide,which contributes to 0.2% mortality,especially maternal and child mortality.
基金supported by the Science and Technology Commission of Shanghai Municipality(No.19140901700).
文摘Background:Pancreatic neuroendocrine tumor is a rare and heterogeneous entity,and approximately half of the patients harbored liver metastasis when initially diagnosed,whose prognosis is dismal.High-throughput sequencing has largely uncovered the genomic features of pancreatic neuroendocrine tumor,but the genetic alterations in the metastatic cases remain relatively unclear,which we aimed to study.Methods:Pathologically confirmed well-differentiated pancreatic neuroendocrine tumor samples resected in our hospital from 2000 to 2019 were collected.We performed deep sequencing on the exome of 341 tumor-related genes,and compared the differences of genetic alterations between the metastatic and the non-metastatic cases,as well as between the primary and the paired liver metastatic tumors.Results:Sequencing data of 79 samples from 29 pancreatic neuroendocrine tumor patients were included into analysis.A total of 2,471 somatic variants were identified,75.5%of which were considered as low-abundance.NOTCH1 was the most frequently mutated gene,altered in 26(53.1%)pancreatic neuroendocrine tumor samples from 18(62.1%)patients.Compared with the non-metastatic pancreatic neuroendocrine tumors,the metastatic cases were discovered with more single nucleotide variants and copy number variations,indicating the increased genomic instability.In addition,among the paired metastatic cases,the primary and the metastatic lesions shared limited mutated genes.Conclusions:Through the targeted deep sequencing,we identified the intratumor,intraindividual,and interindividual heterogeneity in the pancreatic neuroendocrine tumor patients,particularly in the metastatic cases,bringing potential challenges for the current biopsy strategies in guiding clinical treatments.
基金This work was supported by the National Natural Science Foundation of China(31830044,91957207,81870592,82270905,81970742,82000764,82170868,and 81970731)The National Key R&D Program of China(grant 2018YFA0800600).
文摘Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that although deprivation of the EAA leucine has no effect in unstressed mice,it remarkably reverses the depression-like behaviors induced by chronic restraint stress(CRS).This beneficial effect is independent of feeding and is applicable to the dietary deficiency of other EAAs.Furthermore,the effect of leucine deprivation is suppressed by central injection of leucine or mimicked by central injection of leucinol.Moreover,hypothalamic agouti-related peptide(AgRP)neural activity changes during CRS and leucine deprivation,and chemogenetically inhibiting AgRP neurons eliminates the antidepressant effects of leucine deprivation.Finally,the leucine deprivation-regulated behavioral effects are mediated by amino acid sensor general control non-derepressible 2(GCN2)in AgRP neurons.Taken together,our results suggest a new drug target and/or dietary intervention for the reduction of depressive symptoms.