Background: Human organic cationic transporter1 (Hoct1) is a plasma membrane transporter responsible for the main influx of Imatinib into chronic myeloid leukemia (CML) cells. Single nucleotide polymorphisms (SNPs) in...Background: Human organic cationic transporter1 (Hoct1) is a plasma membrane transporter responsible for the main influx of Imatinib into chronic myeloid leukemia (CML) cells. Single nucleotide polymorphisms (SNPs) in the gene coding for hOCT1 are important factors causing Imatinib resistance. We investigated the frequency of hOCT1 SNP C480G among Egyptian CML patients and its relation to early molecular response as an indicator of treatment outcome. Materials and Methods: Two groups of CML patients were included in this study. Group I consisted of 25 patients responding to Imatinib treatment (Imatinib responsive) and group II consisted of 25 patients resistant to Imatinib (Imatinib resistant). Response criteria were assessed according to the NCCN (National Comprehensive Cancer Network) guidelines 2017. Twenty healthy controls of matched age and sex were also included (group III). For all patients, we studied hOCT1 C480G at initial presentation using Taqman drug metabolism genotyping as well as BCR-ABL percent at diagnosis and after 3 months interval. Results: hOCT1 C480G was present in 32% of studied CML patients. CC (wild) was detected in 68% of group I and 64% of group II. CG (mutant heterozygous) was present in 28% of group I and 36% of group II while GG (mutant homozygous) was detected in only one case in group I. CG was also detected in 15% of control subjects There was no significant difference between hOCT1 C480G polymorphism and Early Molecular Response (χ2 = 0.089, p = 0.765). Conclusions: hOCT1 C480G polymorphism has no association with Imatinib resistance in Egyptian population. However, further studies on a larger number of patients are still needed to confirm this finding.展开更多
Under the background of‘the Belt and Road’and‘China-Mongolia-Russia Economic Corridor’initiatives,this paper studied the urban accessibility level,regional accessibility pattern and regional spatial effects along ...Under the background of‘the Belt and Road’and‘China-Mongolia-Russia Economic Corridor’initiatives,this paper studied the urban accessibility level,regional accessibility pattern and regional spatial effects along the Primorsky No.1 and No.2 transportation corridors.First,the evaluation of urban accessibility level with and without Primorsky No.1 and No.2 high-speed rails(HSRs)opening was conducted with two indicators,i.e.,the weighted average travel time,and the economic potential.After the evaluation,the spatial differentiation pattern of the accessibility changes with and without Primorsky No.1 and No.2 HSRs opening was performed respectively using ArcGIS.On these bases,the regional spatial effects brought by Primorsky No.1 and No.2 HSRs opening were studied.The results are as following.First,the urban accessibility level will be greatly improved by the opening of Primorsky No.1 and No.2 HSRs.All adjacent cities will be integrated into‘1 h HSR communication circle’and the whole journey will be integrated into‘4 h HSR communication circle’along Primorsky No.1 and No.2 corridors,respectively.The HSR accessibility of Primorsky No.1 corridor is stronger than that of Primorsky No.2 corridor.But the HSR accessibility improvement degree of Primorsky No.1 corridor is weaker than that of Primorsky No.2 corridor.Second,spatially,along Primorsky No.1 and No.2 corridors,the HSR accessibility level of the cities which are located in China is stronger than those cities located in Russia,showing the‘High West,Low East’patterns.The HSR accessibility improvement degree of the cities which are located in Russia and Sino-Russian border is stronger than those cities located in China,showing the‘High East,Low West’patterns.Third,Primorsky No.1 and No.2 corridors could connect the China’s‘Heilongjiang Land Sea Silk Road Economic Belt’and‘Changchun-Jilin-Tumen Development Pilot Zone’respectively,gradually involving into the development of China’s Harbin-Changchun Megalopolis.Relying on Harbin(China)and Changchun(China),Primorsky No.1 and No.2 HSRs could connect Northeast China-Beijing HSR,accelerating the diffusion of population,economy and other flows from China’s Beijing-Tianjin-Hebei Urban Agglomeration to Northeast China,and then to Russia’s Far East Federal District.Relying on Suifenhe(China)and Hunchun(China),Primorsky No.1 and No.2 HSRs could be conducive to the development of the second largest sea channels for Northeast China,creating the Northeast Asian Urban Belt,and new sea-rail intermodal pattern among China,Russia,Democratic People’s Republic of Korea,Japan and Republic of Korea.Relying on Vladivostok(Russia)and Zarubino(Russia),Primorsky No.1 and No.2 corridors could connect the‘Ice Silk Road’,building the‘Sino-Russian Northern Maritime Corridor’and‘Sino-Russian Arctic Blue Economic Areas’.展开更多
Background:Hepatocellular carcinoma(HCC)typically begins inconspicuously and progresses swiftly,leading to most patients being diagnosed at an advanced stage.Accordingly,a pressing priority is to clarify the developme...Background:Hepatocellular carcinoma(HCC)typically begins inconspicuously and progresses swiftly,leading to most patients being diagnosed at an advanced stage.Accordingly,a pressing priority is to clarify the development mechanisms of HCC and devise efficient intervention and treatment protocols.Methods:An upstream miRNA of solute carrier transporter family 1 member 5(SLC1A5)was predicted to bemiR-122-5p by various databases,and a dual-luciferase reporter gene assay was used to verify the SLC1A5-and miR-122-5p-targeting relationship.SLC1A5 and miR-122-5p expression in HCC cells was quantitatively assessed using quantitative reverse transcription polymerase chain reaction(qRT–PCR).Western blotting was used to evaluate SLC1A5 expression in HCC cells.To determine the effects of the ferroptosis inducers erastin and L-g-glutamyl-p-nitroanilide(GPNA)on Huh-7 and HepG2 cell viability,a Cell Counting Kit-8 assay was performed.Additionally,various assay kits were used to assess malondialdehyde(MDA),Fe^(2+),and reactive oxygen species(ROS)levels inHCC cells.Moreover,anHCC tumor model was established in nude mice to investigate the growth of HCC tumors overexpressing miR-122-5p.Results:miR-122-5p downregulated SLC1A5 levels.MiR-122-5p knockdown inhibited erastin-promoted ferroptosis,whereas miR-122-5p overexpression promoted ferroptosis.After knocking down miR-122-5p,the MDA,Fe^(2+),and ROS levels in Huh-7 and HepG2 cells decreased,whereas overexpressing miR-122-5p increased the MDA,Fe^(2+),and ROS levels.Following the addition of GPNA,the cells experienced decreased viability and increased MDA levels,which in turn inhibited ferroptosis.Knockdown of SLC1A5 partially reversed the ferroptosis-inhibiting effect induced by knocking downmiR-122-5p.Additionally,the overexpression of miR-122-5p hindered HCC development in vivo.Conclusion:miR-122-5p downregulates SLC1A5,which promotes lipid peroxidation and iron accumulation and inhibits glutamine transport,ultimately causing ferroptosis in HCC cells.展开更多
BACKGROUND Chronic enteropathy associated with solute carrier organic anion transporter family member 2A1(SLCO2A1)(CEAS)is a rare autosomal recessive hereditary disease characterized by anemia,hypoproteinemia,abdomina...BACKGROUND Chronic enteropathy associated with solute carrier organic anion transporter family member 2A1(SLCO2A1)(CEAS)is a rare autosomal recessive hereditary disease characterized by anemia,hypoproteinemia,abdominal pain,diarrhea,and multiple shallow ulcers in the small intestine.Genetic analysis for SLCO2A1 mutations has identified more than 10 variant types,including the mostly reported c.940+1G>A splice site mutation.CASE SUMMARY Herein,we described a 33-year-old female patient who was admitted for anemia,edema,and a positive fecal occult blood test,unaccompanied by abdominal pain and diarrhea.She was diagnosed with CEAS due to compound heterozygous variants,c.940+1G>cA(splice-5)and c.1658T>A(p.Ile553Asn)in SLCO2A1,which had not been previously reported.Importantly,we reviewed 132 reported CEAS patients,which showed that anemia(87.3%)and hypoproteinemia(81%)were the most common symptoms.Nearly 25.8%of patients only had a positive result of fecal occult blood,without any symptoms of gastrointestinal bleeding.CONCLUSION In conclusion,fecal tests should be repeated in patients with anemia and edema to find clues for chronic enteropathy,including the rare cause-CEAS.展开更多
Accumulation of lactate in tumor has been linked to poor prognosis of oral squamous cell carcinoma (OSCC), but the underlying mechanism remained largely uncertain. Previous studies have suggested that presence of canc...Accumulation of lactate in tumor has been linked to poor prognosis of oral squamous cell carcinoma (OSCC), but the underlying mechanism remained largely uncertain. Previous studies have suggested that presence of cancer stem cells (CSCs) closely correlated with cellular malignancy of OSCC. Here, using 3D organoid culture model, we investigated whether lactate promoted CSCs phenotype in primary OSCC cells. We generated organoids using fresh OSCC specimens and verified that organoids recapitulated histopathology and cellular heterogeneity of parental tumor;Organoids were then transfected with a Wnt reporter to visualize Wnt activity. The sphere forming assay demonstrated that high Wnt activity functionally designated CSCs population in OSCC cells. Further investigations indicated that lactate treatment promoted Wnt activity and increased the expression of CSCs (i.e. CD133^+ cells) in organoids. Moreover, silencing monocarboxylate transporter 1 (MCT1), the prominent path for lactate uptake in human tumor with siRNA significantly impaired organoid forming capacity of OSCC cells. Together, our study demonstrated that lactate can promote CSCs phenotype of OSCC,and MCT1 may be a therapeutic target against OSCC growth.展开更多
Iron plays a key role in Parkinson＇s disease （PD）. Increased iron content of the substantia nigra （SN） has been found in PD patients, and divalent metal transporter 1 （DMT1） has been shown to be up-regulated in...Iron plays a key role in Parkinson＇s disease （PD）. Increased iron content of the substantia nigra （SN） has been found in PD patients, and divalent metal transporter 1 （DMT1） has been shown to be up-regulated in the SN of both MPTP-induced PD models and PD patients. However, the mechanisms underlying DMT1 up-regulation are largely unknown. In the present study, we observed that in the SN of 6-hydroxydopamine （6-OHDA）-induced PD rats, DMT1 with the iron responsive element （IRE, DMTI＋IRE）, but not DMT1 without IRE （DMTI-IRE）, was up- regulated, suggesting that increased DMTI＋IRE expression might account for nigral iron accumulation in PD rats. This possibility was further assessed in an in vitro study using 6-OHDA-treated and DMTl＋IRE-over-expressing MES23.5 cells. In 6-OHDA-treated MES23.5 cells, increased iron regulatory protein （IRP） 1 and IRP2 expression was observed, while silencing of IRPs dramatically diminished 6-OHDA-indueed DMTI＋IRE up-regulation. Pre- treatment with N-acetyl-L-cysteine fully suppressed IRPs up-regulation by inhibition of 6-OHDA-indueed oxidative stress. Increased DMTI＋IRE expression resulted in increased iron influx by MES23.5 cells. Our data provide direct evidence that DMTI＋IRE up-regulation can account for IRE/IRP-dependent 6-OHDA-induced iron accumulation initiated by 6-OHDA-induced intracellular oxidative stress and that increased levels of intracellular iron result in ag- gravated oxidative stress. The results of this study provide novel evidence supporting the use of anti-oxidants in the treatment of PD, with the goal of inhibiting iron accumulation by regulation of DMT1 expression.展开更多
Abnormally increased levels of iron in the brain trigger cascade amplification in Alzheimer＇s dis- ease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese her...Abnormally increased levels of iron in the brain trigger cascade amplification in Alzheimer＇s dis- ease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese herbs epimedium herb, milkvetch root and kudzuvine root could relieve the abnormal expression of iron metabolism-related protein in Alzheimer＇s disease patients. An APPs,~JPSI^E9 double transgenic mouse model of Alzheimer＇s disease was used. The intragas- tric administration of compounds from epimedium herb, milkvetch root and kudzuvine root improved pathological alterations such as neuronal edema, increased the number of neurons, downregulated divalent metal transporter 1 expression, upregulated ferroportin 1 expression, and inhibited iron overload in the cerebral cortex of mice with Alzheimer＇s disease. These com- pounds reduced iron overload-induced impairment of the central nervous system, indicating a new strategy for developing novel drugs for the treatment of Alzheimer＇s disease.展开更多
Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate...Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate alcohol consumption has been shown to increase the prevalence of iron overload. Moreover, increased hepatic iron content is associated with greater mortality from alcoholic cirrhosis, suggesting a pathogenic role for iron in alcoholic liver disease. Alcohol increases the severity of disease in patients with genetic hemochromatosis, an iron overload disorder common in the Caucasian population. Both iron and alcohol individually cause oxidative stress and lipid peroxidation, which culminates in liver injury. Despite these observations, the underlying mechanisms of iron accumulation and the source of the excess iron observed in alcoholic liver disease remain unclear. Over the last decade, several novel iron-regulatory proteins have been identified and these have greatly enhanced our understanding of iron metabolism. For example, hepcidin, a circulatory antimicrobial peptide synthesized by the hepatocytes of the liver is now known to play a central role in the regulation of iron homeostasis. This review attempts to describe the interaction of alcohol and iron-regulatory molecules. Understanding these molecular mechanisms is of considerable clinical importance because both alcoholic liver disease and genetic hemochromatosis are common diseases, in which alcohol and iron appear to act synergistically to cause liver injury.展开更多
Extensive iron deposition has been observed in the midbrain substantia nigra （SN） of Parkinson＇s disease （PD） patients, but the mechanisms of iron deposition in the SN remain poorly understood. The present study ...Extensive iron deposition has been observed in the midbrain substantia nigra （SN） of Parkinson＇s disease （PD） patients, but the mechanisms of iron deposition in the SN remain poorly understood. The present study investigated the relationship between dopaminergic neuronal damage, iron content changes, and divalent metal transporter 1 （DMT1） in the midbrain SN of PD rats to explore the relationship between time of iron deposition and DMT1 expression. Frozen midbrain SN sections from model rats were stained with Perls＇ iron. Results showed massive loss of tyrosine hydroxylase （TH）-positive cells in the SN and increased DMT1 expression in model group rats. No obvious iron deposition was observed in the SN during early stages after damage, but significant iron deposition was detected at 8 weeks post-injury. Results demonstrate that the loss of TH-positive cells in the SN appeared simultaneously with increased DMT1 expression. Extensive iron deposition occurred at 8 weeks post injury, which could be regarded as an early time window of iron deposition.展开更多
BACKGROUND Hepatic stellate cells(HSCs)are the key effector cells mediating the occurrence and development of liver fibrosis,while aerobic glycolysis is an important metabolic characteristic of HSC activation.Transfor...BACKGROUND Hepatic stellate cells(HSCs)are the key effector cells mediating the occurrence and development of liver fibrosis,while aerobic glycolysis is an important metabolic characteristic of HSC activation.Transforming growth factor-β1(TGF-β1)induces aerobic glycolysis and is a driving factor for metabolic reprogramming.The occurrence of glycolysis depends on a high glucose uptake level.Glucose transporter 1(GLUT1)is the most widely distributed glucose transporter in the body and mainly participates in the regulation of carbohydrate metabolism,thus affecting cell proliferation and growth.However,little is known about the relationship between TGF-β1 and GLUT1 in the process of liver fibrosis and the molecular mechanism underlying the promotion of aerobic glycolysis in HSCs.AIM To investigate the mechanisms of action of GLUT1,TGF-β1 and aerobic glycolysis in the process of HSC activation during liver fibrosis.METHODS Immunohistochemical staining and immunofluorescence assays were used to examine GLUT1 expression in fibrotic liver tissue.A Seahorse extracellular flux(XF)analyzer was used to examine changes in aerobic glycolytic flux,lactate production levels and glucose consumption levels in HSCs upon TGF-β1 stimulation.The mechanism by which TGF-β1 induces GLUT1 protein expression in HSCs was further explored by inhibiting/promoting the TGF-β1/mothersagainst-decapentaplegic-homolog 2/3(Smad2/3)signaling pathway and inhibiting the p38 and phosphoinositide 3-kinase(PI3K)/AKT signaling pathways.In addition,GLUT1 expression was silenced to observe changes in the growth and proliferation of HSCs.Finally,a GLUT1 inhibitor was used to verify the in vivo effects of GLUT1 on a mouse model of liver fibrosis.RESULTS GLUT1 protein expression was increased in both mouse and human fibrotic liver tissues.In addition,immunofluorescence staining revealed colocalization of GLUT1 and alpha-smooth muscle actin proteins,indicating that GLUT1 expression was related to the development of liver fibrosis.TGF-β1 caused an increase in aerobic glycolysis in HSCs and induced GLUT1 expression in HSCs by activating the Smad,p38 MAPK and P13K/AKT signaling pathways.The p38 MAPK and Smad pathways synergistically affected the induction of GLUT1 expression.GLUT1 inhibition eliminated the effect of TGF-β1 on HSC proliferation and migration.A GLUT1 inhibitor was administered in a mouse model of liver fibrosis,and GLUT1 inhibition reduced the degree of liver inflammation and liver fibrosis.CONCLUSION TGF-β1 induces GLUT1 expression in HSCs,a process related to liver fibrosis progression.In vitro experiments revealed that TGF-β1-induced GLUT1 expression might be one of the mechanisms mediating the metabolic reprogramming of HSCs.In addition,in vivo experiments also indicated that the GLUT1 protein promotes the occurrence and development of liver fibrosis.展开更多
文摘Background: Human organic cationic transporter1 (Hoct1) is a plasma membrane transporter responsible for the main influx of Imatinib into chronic myeloid leukemia (CML) cells. Single nucleotide polymorphisms (SNPs) in the gene coding for hOCT1 are important factors causing Imatinib resistance. We investigated the frequency of hOCT1 SNP C480G among Egyptian CML patients and its relation to early molecular response as an indicator of treatment outcome. Materials and Methods: Two groups of CML patients were included in this study. Group I consisted of 25 patients responding to Imatinib treatment (Imatinib responsive) and group II consisted of 25 patients resistant to Imatinib (Imatinib resistant). Response criteria were assessed according to the NCCN (National Comprehensive Cancer Network) guidelines 2017. Twenty healthy controls of matched age and sex were also included (group III). For all patients, we studied hOCT1 C480G at initial presentation using Taqman drug metabolism genotyping as well as BCR-ABL percent at diagnosis and after 3 months interval. Results: hOCT1 C480G was present in 32% of studied CML patients. CC (wild) was detected in 68% of group I and 64% of group II. CG (mutant heterozygous) was present in 28% of group I and 36% of group II while GG (mutant homozygous) was detected in only one case in group I. CG was also detected in 15% of control subjects There was no significant difference between hOCT1 C480G polymorphism and Early Molecular Response (χ2 = 0.089, p = 0.765). Conclusions: hOCT1 C480G polymorphism has no association with Imatinib resistance in Egyptian population. However, further studies on a larger number of patients are still needed to confirm this finding.
基金Under the auspices of Heilongjiang Provincial Natural Science Foundation of China(No.YQ2024D012),National Natural Science Foundation of China(No.42071162,42101165,42501220)。
文摘Under the background of‘the Belt and Road’and‘China-Mongolia-Russia Economic Corridor’initiatives,this paper studied the urban accessibility level,regional accessibility pattern and regional spatial effects along the Primorsky No.1 and No.2 transportation corridors.First,the evaluation of urban accessibility level with and without Primorsky No.1 and No.2 high-speed rails(HSRs)opening was conducted with two indicators,i.e.,the weighted average travel time,and the economic potential.After the evaluation,the spatial differentiation pattern of the accessibility changes with and without Primorsky No.1 and No.2 HSRs opening was performed respectively using ArcGIS.On these bases,the regional spatial effects brought by Primorsky No.1 and No.2 HSRs opening were studied.The results are as following.First,the urban accessibility level will be greatly improved by the opening of Primorsky No.1 and No.2 HSRs.All adjacent cities will be integrated into‘1 h HSR communication circle’and the whole journey will be integrated into‘4 h HSR communication circle’along Primorsky No.1 and No.2 corridors,respectively.The HSR accessibility of Primorsky No.1 corridor is stronger than that of Primorsky No.2 corridor.But the HSR accessibility improvement degree of Primorsky No.1 corridor is weaker than that of Primorsky No.2 corridor.Second,spatially,along Primorsky No.1 and No.2 corridors,the HSR accessibility level of the cities which are located in China is stronger than those cities located in Russia,showing the‘High West,Low East’patterns.The HSR accessibility improvement degree of the cities which are located in Russia and Sino-Russian border is stronger than those cities located in China,showing the‘High East,Low West’patterns.Third,Primorsky No.1 and No.2 corridors could connect the China’s‘Heilongjiang Land Sea Silk Road Economic Belt’and‘Changchun-Jilin-Tumen Development Pilot Zone’respectively,gradually involving into the development of China’s Harbin-Changchun Megalopolis.Relying on Harbin(China)and Changchun(China),Primorsky No.1 and No.2 HSRs could connect Northeast China-Beijing HSR,accelerating the diffusion of population,economy and other flows from China’s Beijing-Tianjin-Hebei Urban Agglomeration to Northeast China,and then to Russia’s Far East Federal District.Relying on Suifenhe(China)and Hunchun(China),Primorsky No.1 and No.2 HSRs could be conducive to the development of the second largest sea channels for Northeast China,creating the Northeast Asian Urban Belt,and new sea-rail intermodal pattern among China,Russia,Democratic People’s Republic of Korea,Japan and Republic of Korea.Relying on Vladivostok(Russia)and Zarubino(Russia),Primorsky No.1 and No.2 corridors could connect the‘Ice Silk Road’,building the‘Sino-Russian Northern Maritime Corridor’and‘Sino-Russian Arctic Blue Economic Areas’.
基金Hubei Provincial Key Research and Development Program(2023BCB126)Hubei University of ChineseMedicine“14th Five-Year Plan”Outstanding Discipline TeamConstruction Project(HBUCM[2022]No.90).
文摘Background:Hepatocellular carcinoma(HCC)typically begins inconspicuously and progresses swiftly,leading to most patients being diagnosed at an advanced stage.Accordingly,a pressing priority is to clarify the development mechanisms of HCC and devise efficient intervention and treatment protocols.Methods:An upstream miRNA of solute carrier transporter family 1 member 5(SLC1A5)was predicted to bemiR-122-5p by various databases,and a dual-luciferase reporter gene assay was used to verify the SLC1A5-and miR-122-5p-targeting relationship.SLC1A5 and miR-122-5p expression in HCC cells was quantitatively assessed using quantitative reverse transcription polymerase chain reaction(qRT–PCR).Western blotting was used to evaluate SLC1A5 expression in HCC cells.To determine the effects of the ferroptosis inducers erastin and L-g-glutamyl-p-nitroanilide(GPNA)on Huh-7 and HepG2 cell viability,a Cell Counting Kit-8 assay was performed.Additionally,various assay kits were used to assess malondialdehyde(MDA),Fe^(2+),and reactive oxygen species(ROS)levels inHCC cells.Moreover,anHCC tumor model was established in nude mice to investigate the growth of HCC tumors overexpressing miR-122-5p.Results:miR-122-5p downregulated SLC1A5 levels.MiR-122-5p knockdown inhibited erastin-promoted ferroptosis,whereas miR-122-5p overexpression promoted ferroptosis.After knocking down miR-122-5p,the MDA,Fe^(2+),and ROS levels in Huh-7 and HepG2 cells decreased,whereas overexpressing miR-122-5p increased the MDA,Fe^(2+),and ROS levels.Following the addition of GPNA,the cells experienced decreased viability and increased MDA levels,which in turn inhibited ferroptosis.Knockdown of SLC1A5 partially reversed the ferroptosis-inhibiting effect induced by knocking downmiR-122-5p.Additionally,the overexpression of miR-122-5p hindered HCC development in vivo.Conclusion:miR-122-5p downregulates SLC1A5,which promotes lipid peroxidation and iron accumulation and inhibits glutamine transport,ultimately causing ferroptosis in HCC cells.
基金Supported by the National Natural Science Foundation of China(General Program),No.82000493Peking University People’s Hospital Scientific Research Development Funds,No.RDJP2023-09.
文摘BACKGROUND Chronic enteropathy associated with solute carrier organic anion transporter family member 2A1(SLCO2A1)(CEAS)is a rare autosomal recessive hereditary disease characterized by anemia,hypoproteinemia,abdominal pain,diarrhea,and multiple shallow ulcers in the small intestine.Genetic analysis for SLCO2A1 mutations has identified more than 10 variant types,including the mostly reported c.940+1G>A splice site mutation.CASE SUMMARY Herein,we described a 33-year-old female patient who was admitted for anemia,edema,and a positive fecal occult blood test,unaccompanied by abdominal pain and diarrhea.She was diagnosed with CEAS due to compound heterozygous variants,c.940+1G>cA(splice-5)and c.1658T>A(p.Ile553Asn)in SLCO2A1,which had not been previously reported.Importantly,we reviewed 132 reported CEAS patients,which showed that anemia(87.3%)and hypoproteinemia(81%)were the most common symptoms.Nearly 25.8%of patients only had a positive result of fecal occult blood,without any symptoms of gastrointestinal bleeding.CONCLUSION In conclusion,fecal tests should be repeated in patients with anemia and edema to find clues for chronic enteropathy,including the rare cause-CEAS.
基金This project was supported by the National Natural Science Foundation of China (No.81602742).
文摘Accumulation of lactate in tumor has been linked to poor prognosis of oral squamous cell carcinoma (OSCC), but the underlying mechanism remained largely uncertain. Previous studies have suggested that presence of cancer stem cells (CSCs) closely correlated with cellular malignancy of OSCC. Here, using 3D organoid culture model, we investigated whether lactate promoted CSCs phenotype in primary OSCC cells. We generated organoids using fresh OSCC specimens and verified that organoids recapitulated histopathology and cellular heterogeneity of parental tumor;Organoids were then transfected with a Wnt reporter to visualize Wnt activity. The sphere forming assay demonstrated that high Wnt activity functionally designated CSCs population in OSCC cells. Further investigations indicated that lactate treatment promoted Wnt activity and increased the expression of CSCs (i.e. CD133^+ cells) in organoids. Moreover, silencing monocarboxylate transporter 1 (MCT1), the prominent path for lactate uptake in human tumor with siRNA significantly impaired organoid forming capacity of OSCC cells. Together, our study demonstrated that lactate can promote CSCs phenotype of OSCC,and MCT1 may be a therapeutic target against OSCC growth.
基金We thank Dr Wei-dong Le for providing the MES23.5 cell line. This work was supported by grants from the National Program of Basic Research sponsored by the Ministry of Science and Tech- nology of China （2006CB500704）, the National Natural Science Foundation of China （30930036, 30770757, 30870858） and the Natural Science Fund of Shandong Province for Distinguished Young Scholars （JQ200807）.
文摘Iron plays a key role in Parkinson＇s disease （PD）. Increased iron content of the substantia nigra （SN） has been found in PD patients, and divalent metal transporter 1 （DMT1） has been shown to be up-regulated in the SN of both MPTP-induced PD models and PD patients. However, the mechanisms underlying DMT1 up-regulation are largely unknown. In the present study, we observed that in the SN of 6-hydroxydopamine （6-OHDA）-induced PD rats, DMT1 with the iron responsive element （IRE, DMTI＋IRE）, but not DMT1 without IRE （DMTI-IRE）, was up- regulated, suggesting that increased DMTI＋IRE expression might account for nigral iron accumulation in PD rats. This possibility was further assessed in an in vitro study using 6-OHDA-treated and DMTl＋IRE-over-expressing MES23.5 cells. In 6-OHDA-treated MES23.5 cells, increased iron regulatory protein （IRP） 1 and IRP2 expression was observed, while silencing of IRPs dramatically diminished 6-OHDA-indueed DMTI＋IRE up-regulation. Pre- treatment with N-acetyl-L-cysteine fully suppressed IRPs up-regulation by inhibition of 6-OHDA-indueed oxidative stress. Increased DMTI＋IRE expression resulted in increased iron influx by MES23.5 cells. Our data provide direct evidence that DMTI＋IRE up-regulation can account for IRE/IRP-dependent 6-OHDA-induced iron accumulation initiated by 6-OHDA-induced intracellular oxidative stress and that increased levels of intracellular iron result in ag- gravated oxidative stress. The results of this study provide novel evidence supporting the use of anti-oxidants in the treatment of PD, with the goal of inhibiting iron accumulation by regulation of DMT1 expression.
基金supported by the National Natural Science Foundation of China,No.81273983the Natural Science Foundation of Hebei Province in China,No.C2010001471+1 种基金the Scientific and Technological Research Youth Foundation of Colleges and Universities in Hebei Province of China,No.Q2012036the Hebei Provincial Food and Drug Administration in China,No.PT2014053
文摘Abnormally increased levels of iron in the brain trigger cascade amplification in Alzheimer＇s dis- ease patients, resulting in neuronal death. This study investigated whether components extracted from the Chinese herbs epimedium herb, milkvetch root and kudzuvine root could relieve the abnormal expression of iron metabolism-related protein in Alzheimer＇s disease patients. An APPs,~JPSI^E9 double transgenic mouse model of Alzheimer＇s disease was used. The intragas- tric administration of compounds from epimedium herb, milkvetch root and kudzuvine root improved pathological alterations such as neuronal edema, increased the number of neurons, downregulated divalent metal transporter 1 expression, upregulated ferroportin 1 expression, and inhibited iron overload in the cerebral cortex of mice with Alzheimer＇s disease. These com- pounds reduced iron overload-induced impairment of the central nervous system, indicating a new strategy for developing novel drugs for the treatment of Alzheimer＇s disease.
基金Supported by University of Nebraska Medical Center and the Alcoholic Beverage Medical Research Foundation
文摘Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate alcohol consumption has been shown to increase the prevalence of iron overload. Moreover, increased hepatic iron content is associated with greater mortality from alcoholic cirrhosis, suggesting a pathogenic role for iron in alcoholic liver disease. Alcohol increases the severity of disease in patients with genetic hemochromatosis, an iron overload disorder common in the Caucasian population. Both iron and alcohol individually cause oxidative stress and lipid peroxidation, which culminates in liver injury. Despite these observations, the underlying mechanisms of iron accumulation and the source of the excess iron observed in alcoholic liver disease remain unclear. Over the last decade, several novel iron-regulatory proteins have been identified and these have greatly enhanced our understanding of iron metabolism. For example, hepcidin, a circulatory antimicrobial peptide synthesized by the hepatocytes of the liver is now known to play a central role in the regulation of iron homeostasis. This review attempts to describe the interaction of alcohol and iron-regulatory molecules. Understanding these molecular mechanisms is of considerable clinical importance because both alcoholic liver disease and genetic hemochromatosis are common diseases, in which alcohol and iron appear to act synergistically to cause liver injury.
基金the Scientific Research Common Program of Beijing Municipal Commission of Education,No.KM200610025008
文摘Extensive iron deposition has been observed in the midbrain substantia nigra （SN） of Parkinson＇s disease （PD） patients, but the mechanisms of iron deposition in the SN remain poorly understood. The present study investigated the relationship between dopaminergic neuronal damage, iron content changes, and divalent metal transporter 1 （DMT1） in the midbrain SN of PD rats to explore the relationship between time of iron deposition and DMT1 expression. Frozen midbrain SN sections from model rats were stained with Perls＇ iron. Results showed massive loss of tyrosine hydroxylase （TH）-positive cells in the SN and increased DMT1 expression in model group rats. No obvious iron deposition was observed in the SN during early stages after damage, but significant iron deposition was detected at 8 weeks post-injury. Results demonstrate that the loss of TH-positive cells in the SN appeared simultaneously with increased DMT1 expression. Extensive iron deposition occurred at 8 weeks post injury, which could be regarded as an early time window of iron deposition.
基金by National Natural Science Foundation of China,No.82060116,No.81860115 and No.81960118Guizhou Science and Technology Support Project Fund,No.[2021]058.
文摘BACKGROUND Hepatic stellate cells(HSCs)are the key effector cells mediating the occurrence and development of liver fibrosis,while aerobic glycolysis is an important metabolic characteristic of HSC activation.Transforming growth factor-β1(TGF-β1)induces aerobic glycolysis and is a driving factor for metabolic reprogramming.The occurrence of glycolysis depends on a high glucose uptake level.Glucose transporter 1(GLUT1)is the most widely distributed glucose transporter in the body and mainly participates in the regulation of carbohydrate metabolism,thus affecting cell proliferation and growth.However,little is known about the relationship between TGF-β1 and GLUT1 in the process of liver fibrosis and the molecular mechanism underlying the promotion of aerobic glycolysis in HSCs.AIM To investigate the mechanisms of action of GLUT1,TGF-β1 and aerobic glycolysis in the process of HSC activation during liver fibrosis.METHODS Immunohistochemical staining and immunofluorescence assays were used to examine GLUT1 expression in fibrotic liver tissue.A Seahorse extracellular flux(XF)analyzer was used to examine changes in aerobic glycolytic flux,lactate production levels and glucose consumption levels in HSCs upon TGF-β1 stimulation.The mechanism by which TGF-β1 induces GLUT1 protein expression in HSCs was further explored by inhibiting/promoting the TGF-β1/mothersagainst-decapentaplegic-homolog 2/3(Smad2/3)signaling pathway and inhibiting the p38 and phosphoinositide 3-kinase(PI3K)/AKT signaling pathways.In addition,GLUT1 expression was silenced to observe changes in the growth and proliferation of HSCs.Finally,a GLUT1 inhibitor was used to verify the in vivo effects of GLUT1 on a mouse model of liver fibrosis.RESULTS GLUT1 protein expression was increased in both mouse and human fibrotic liver tissues.In addition,immunofluorescence staining revealed colocalization of GLUT1 and alpha-smooth muscle actin proteins,indicating that GLUT1 expression was related to the development of liver fibrosis.TGF-β1 caused an increase in aerobic glycolysis in HSCs and induced GLUT1 expression in HSCs by activating the Smad,p38 MAPK and P13K/AKT signaling pathways.The p38 MAPK and Smad pathways synergistically affected the induction of GLUT1 expression.GLUT1 inhibition eliminated the effect of TGF-β1 on HSC proliferation and migration.A GLUT1 inhibitor was administered in a mouse model of liver fibrosis,and GLUT1 inhibition reduced the degree of liver inflammation and liver fibrosis.CONCLUSION TGF-β1 induces GLUT1 expression in HSCs,a process related to liver fibrosis progression.In vitro experiments revealed that TGF-β1-induced GLUT1 expression might be one of the mechanisms mediating the metabolic reprogramming of HSCs.In addition,in vivo experiments also indicated that the GLUT1 protein promotes the occurrence and development of liver fibrosis.
