A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative...A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative diseases such as PD and Alzheimer’s disease(AD)and is thought to reflect lysosome dysfunction,lipid accumulation may also contribute to and be indicative of severe lysosomal dysfunction.Much is known about the detrimental effects of glucosylceramide accumulation in PD lysosomes.展开更多
Utilizing transporter-mediated drug delivery to achieve effective oral absorption emerges as a promising strategy.Researchers have been concentrated on discovering solutions to the issues of low solubility and poor pe...Utilizing transporter-mediated drug delivery to achieve effective oral absorption emerges as a promising strategy.Researchers have been concentrated on discovering solutions to the issues of low solubility and poor permeability of insoluble drugs,whereas,current reports have revealed that drug transporter proteins are abundantly expressed in the mucosa of intestinal epithelial cells,and that their mediated drug absorption effectively improved the bioavailability of orally administered drugs.There are two main categories based on the transporter mechanism,which include the family of ATP-binding cassette(ABC)transporters with efflux effects that reduce drug bioavailability and the family of solute carriers(SLC)transporters with uptake effects that promote drug absorption,respectively.Thus,we review studies of intestinal transporter-mediated delivery of drugs to enhance oral absorption,including the types of intestinal transporters,distribution characteristics,and strategies for enhancing oral absorption using transporter-mediated drug delivery systems are summarized,with the aim of providing important theoretical references for the development of intestinal-targeted delivery system.展开更多
Sulfate transporters(SULTRs)facilitate sulfate uptake and transport in plants.In plants,SULTRs can be classified into four distinct functional groups,among which SULTR3 members are the least characterized,and their fu...Sulfate transporters(SULTRs)facilitate sulfate uptake and transport in plants.In plants,SULTRs can be classified into four distinct functional groups,among which SULTR3 members are the least characterized,and their functions have not yet been confirmed,especially for SULTR3 in rice.In this study,we analyzed the expression patterns,subcellular localization,and inorganic phosphate(Pi)transporter activity of SULTR3 proteins in yeast.Except for OsSULTR3.4,which localized to the plasma membrane,other OsSULTR3 members were localized to the endoplasmic reticulum(ER)membrane in rice protoplast cells.展开更多
The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain functio...The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions.Specifically, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice.After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.展开更多
Sucrose transporters(SUTs)contain multiple transmembrane domains that mediate sucrose transport and provide energy for plant growth and development.However,the role of OsSUTs in regulating rice quality and grain yield...Sucrose transporters(SUTs)contain multiple transmembrane domains that mediate sucrose transport and provide energy for plant growth and development.However,the role of OsSUTs in regulating rice quality and grain yield remains unclear.In this study,we identified five rice SUT genes(OsSUT1-OsSUT5)and examined their molecular characteristics and biological functions.OsSUT1,OsSUT2,and OsSUT4 were predominantly expressed in stems,while OsSUT3 and OsSUT5 showed higher expression in panicles.OsSUT1 and OsSUT4 are located on the plasma membrane,whereas OsSUT2,OsSUT3,and OsSUT5 are localized to the tonoplast.展开更多
Glutamate is a regulated molecule in the mammalian testis. Extracellular regulation of glutamate in the body is determined largely by the expression of plasmalemmal glutamate transporters. We have examined by PCR, wes...Glutamate is a regulated molecule in the mammalian testis. Extracellular regulation of glutamate in the body is determined largely by the expression of plasmalemmal glutamate transporters. We have examined by PCR, western blotting and immunocytochemistry the expression of a panel of sodium-dependent plasmalemmal glutamate transporters in the rat testis. Proteins examined included： glutamate aspartate transporter （GLAST）, glutamate transporter 1 （GLT1）, excitatory amino acid carrier 1 （EAAC1）, excitatory amino acid transporter 4 （EAAT4） and EAAT5. We demonstrate that many of the glutamate transporters in the testis are alternately spliced. GLAST is present as exon-3- and exon-9-skipping forms. GLT1 was similarly present as the alternately spliced forms GLT1 b and GLTlc, whereas the abundant brain form （GLTla） was detectable only at the mRNA level. EAAT5 was also strongly expressed, whereas EAAC1 and EAAT4 were absent. These patterns of expression were compared with the patterns of endogenous glutamate localization and with patterns of D-aspartate accumulation, as assessed by immunocytochemistry. The presence of multiple glutamate transporters in the testis, including unusually spliced forms, suggests that glutamate homeostasis may be critical in this organ. The apparent presence of many of these transporters in the testis and sperm may indicate a need for glutamate transport by such cells.展开更多
Sucrose transporters(SUTs)play a crucial role in carbon allocation from the source leaf to the sink end,and the function of SUTs varies among family members.However,the genome-wide identifcation of the SUT superfamily...Sucrose transporters(SUTs)play a crucial role in carbon allocation from the source leaf to the sink end,and the function of SUTs varies among family members.However,the genome-wide identifcation of the SUT superfamily in Camellia oleifera is lacking,and their biological function remains elusive.In this study,four SUT genes-designated Co SUT1-4-were identifed in C.oleifera through a genome-wide analysis and classifed into three subfamilies.We used a combination of cis-acting elements analysis,mRNA quantifcation,histochemical analysis,and heterologous transformation to evaluate the expression profiles and functions of these SUTs.A key finding is that CoSUT4,localized on the plasma membrane,is highly expressed in mature leaves and the early stage of seed development in C.oleifera.In vitro culture of C.oleifera seed revealed the responsiveness of CoSUT4 to various exogenous hormones such as ABA and GA.CoSUT4 was able to restore the growth of the yeast strain SUSY7/ura3(a sucrose transport-defcient mutant)on sucrose-containing media and specifcally contributed to sucrose translocation and tissue growth in CoSUT4-overexpressed apple calli.In situ hybridization identifed chalazal nucellus and transfer cells as the action sites of CoSUT4 at the maternal-flial interface mediating sucrose transportation in oil tea seeds.CoSUT4 overexpression in Arabidopsis thaliana atsuc4 mutant restored the growth and seed yield defciencies of the mutant,leading to an increase in flled seeds and oil content.Additionally,CoSUT4 overexpression enhanced the drought and salt stress tolerance by augmenting sugar content.Overall,these fndings provide valuable insights into the function of SUTs and present promising candidates for the genetic enhancement of seed production in C.oleifera.展开更多
Adenosine triphosphate(ATP)-binding cassette(ABC)transporter systems are divided into importers and exporters that facilitate the movement of diverse substrate molecules across the lipid bilayer,against the concentrat...Adenosine triphosphate(ATP)-binding cassette(ABC)transporter systems are divided into importers and exporters that facilitate the movement of diverse substrate molecules across the lipid bilayer,against the concentration gradient.These transporters comprise two highly conserved nucleotide-binding domains(NBDs)and two transmembrane domains(TMDs).Unlike ABC exporters,prokaryotic ABC importers require an additional substrate-binding protein(SBP)as a recognition site for specific substrate translocation.The discovery of a large number of ABC systems in bacterial pathogens revealed that these transporters are crucial for the establishment of bacterial infections.The existing literature has highlighted the roles of ABC transporters in bacterial growth,pathogenesis,and virulence.These roles include importing essential nutrients required for a variety of cellular processes and exporting outer membrane-associated virulence factors and antimicrobial substances.This review outlines the general structures and classification of ABC systems to provide a comprehensive view of the activities and roles of ABC transporters associated with bacterial virulence and pathogenesis during infection.展开更多
In addition to the loss of motor function,~60% of patients develop pain after spinal cord injury.The cellular-molecular mechanisms are not well understood,but the data suggests that plasticity within the rostral,epice...In addition to the loss of motor function,~60% of patients develop pain after spinal cord injury.The cellular-molecular mechanisms are not well understood,but the data suggests that plasticity within the rostral,epicenter,and caudal penumbra of the injury site initiates a cellularmolecular interplay that acts as a rewiring mechanism leading to central neuropathic pain.Sprouting can lead to the formation of new connections triggering abnormal sensory transmission.The excitatory glutamate transporters are responsible for the reuptake of extracellular glutamate which makes them a critical target to prevent neuronal hyperexcitability and excitotoxicity.Our previous studies showed a sexually dimorphic therapeutic window for spinal cord injury after treatment with the selective estrogen receptor modulator tamoxifen.In this study,we investigated the anti-allodynic effects of tamoxifen in male and female rats with spinal cord injury.We hypothesized that tamoxifen exerts anti-allodynic effects by increasing the expression of glutamate transporters,leading to reduced hyperexcitability of the secondary neuron or by decreasing aberrant sprouting.Male and female rats received a moderate contusion to the thoracic spinal cord followed by subcutaneous slow-release treatment of tamoxifen or matrix pellets as a control(placebo).We used von Frey monofilaments and the“up-down method”to evaluate mechanical allodynia.Tamoxifen treatment decreased allodynia only in female rats with spinal cord injury revealing a sexdependent effect.The expression profile of glutamatergic transporters(excitatory amino acid transporter 1/glutamate aspartate transporter and excitatory amino acid transporter 2/glutamate transporter-1)revealed a sexual dimorphism in the rostral,epicenter,and caudal areas of the spinal cord with a pattern of expression primarily on astrocytes.Female rodents showed a significantly higher level of excitatory amino acid transporter-1 expression while male rodents showed increased excitatory amino acid transporter-2 expression compared with female rodents.Analyses of peptidergic(calcitonin gene-related peptide-α)and non-peptidergic(isolectin B4)fibers outgrowth in the dorsal horn after spinal cord injury showed an increased calcitonin gene-related peptide-α/isolectin B4 ratio in comparison with sham,suggesting increased receptive fields in the dorsal horn.Although the behavioral assay shows decreased allodynia in tamoxifen-treated female rats,this was not associated with overexpression of glutamate transporters or alterations in the dorsal horn laminae fibers at 28 days post-injury.Our findings provide new evidence of the sexually dimorphic expression of glutamate transporters in the spinal cord.The dimorphic expression revealed in this study provides a therapeutic opportunity for treating chronic pain,an area with a critical need for treatment.展开更多
The early responsive to dehydration-like(ERDL or ERD)subfamily,subclade within the monosaccharide transporter(MST)superfamily,is crucial in the regulation of growth and seed yield in Arabidopsis.Here,we identified Os ...The early responsive to dehydration-like(ERDL or ERD)subfamily,subclade within the monosaccharide transporter(MST)superfamily,is crucial in the regulation of growth and seed yield in Arabidopsis.Here,we identified Os ERD5 as an At ERDL6 homologue and explored the function of Os ERD5.We found that Os ERD5 overexpression significantly enhanced the tiller number and grain yield of rice.Os ERD5 was widely expressed in aboveground tissues,encoded a tonoplast-localized protein,and exhibited transport activities for fructose,glucose and mannose when expressed in yeast.Expression character assay revealed that Os ERD5 mediated hexose efflux across tonoplasts and participated in maintaining the diurnal rhythm-regulated intracellular hexose homeostasis.Additional physiological and molecular evidence showed that Os ERD5 overexpression promoted vacuolar glucose efflux,enhanced sucrose synthesis and transport,increased sugar content in the shoot base,and promoted rice tillering by activating the synthesis of cytokinin simultaneously repressing strigolactone and gibberellin signaling.This study elucidates the function of Os ERD5 and the mechanism underlying the overexpression of Os ERD5 increasing rice tillering and yield.展开更多
Rice is the world's largest food crop,but it often encounters flowering asynchronization problems during hybrid rice seed production.In addition,the slow closure of female florets leads to seed mildew and affects ...Rice is the world's largest food crop,but it often encounters flowering asynchronization problems during hybrid rice seed production.In addition,the slow closure of female florets leads to seed mildew and affects the quality.The hormone abscisic acid(ABA)plays a crucial role in plant responses to abiotic stresses.Previous studies showed that exogenous ABA promotes floret closure,although the molecular mechanisms and effects of endogenous ABA on floret closure remain unknown.In this study,the effect of endogenous ABA on floret closure and the molecular mechanism by which ABA promotes floret closure through sugar transporters were investigated by changing the expression levels of OsNCED3 and OsPYL1 in rice.The results showed that overexpression(OE)-OsNCED3increased the endogenous ABA level of florets.Florets closed 5.91 min earlier and OsNCED3 gene knockout line delayed the closure of florets by 5.08 min compared with the wild type.In addition,OsPYL1 regulated the endogenous ABA content and changed the sensitivity to ABA such that the floret closure times for OE and CRISPR-Cas9(CR)were 9.84 min earlier and 12.78 min later,respectively,resulting in an increase in the split husk rate to 15.4%.The gene expression levels of some sugar transporters(STs)changed.The OsPYL1 and OsSWEET4proteins could interact on the cell membrane.These results indicate that ABA promotes the closure of rice florets and the enhanced sensitivity to ABA promotes this effect even more.The molecular mechanism is mainly related to downstream sugar transporters that respond to the ABA signaling pathway,especially OsSWEET4.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),Fe2+,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,Fe2+,and ROS levels in Huh-7 and HepG2 cells decreased,whereas overexpressing miR-122-5p increased the MDA,Fe2+,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
Urea is a major end product of nitrogen catabolism,serving as an osmolyte to regulate osmotic stress in fish exposed to varying water environments.It has been well known that urea transporters(UTs)facilitate the rapid...Urea is a major end product of nitrogen catabolism,serving as an osmolyte to regulate osmotic stress in fish exposed to varying water environments.It has been well known that urea transporters(UTs)facilitate the rapid movement of urea across cell membranes.However,researches on ut genes were predominantly focused on elasmobranchs and early developmental stages of fish.In this investigation,a total of three ut genes were identified in spotted sea bass.Phylogenetic,homology,and syntenic analyses were conducted to validate the annotation and assess the evolutionary relationships among ut genes.Both ut-a and ut-b genes have retained their evolutionary stability,demonstrating a significant level of homology between them.To gain deeper insights into the evolution of ut genes in spotted sea bass,we performed selective pressure analysis using site,branch,and branch-site models.The results suggested that positive selection likely played a significant role in shaping the evolution of the ut gene family.Furthermore,tissue-specific expression analyses revealed high expression levels of ut genes in osmoregulatory tissues such as the gill and kidney.Additionally,all three ut genes exhibited salinity-related expression patterns in gill and kidney tissues during both seawater-to-freshwater(SF)and freshwater-to-seawater(FS)adaptation.In situ hybridization results demonstrated the localization of both ut-a and ut-c mRNAs on the gill lamellae and adjacent gill filament epithelium.In summary,our study establishes a solid foundation for future research elucidating the evolutionary relationships and functional significance of ut genes during salinity acclimation in spotted sea bass and other teleost species.展开更多
Hepatocellular carcinoma(HCC)is a malignant tumour with high prevalence and mortality rate worldwide.Metabolic reprogramming of cancer cells may be a major factor in the process of this disease.Glucose transporter pro...Hepatocellular carcinoma(HCC)is a malignant tumour with high prevalence and mortality rate worldwide.Metabolic reprogramming of cancer cells may be a major factor in the process of this disease.Glucose transporter proteins(GLUTs)are members of the major facilitator superfamily of membrane transporters,playing a pivotal role in the metabolic reprogramming and tumour progression in HCC.This review discusses the advances in the study of GLUTs in HCC,in-cluding the expression patterns,functions and possibilities of GLUTs.In HCC,the expression levels of GLUTs are closely associated with tumour aggressiveness,metabolic reprogramming and prognosis.A series of inhibitors have been de-monstrated efficacy in inhibiting HCC cell growth and glucose uptake in in vitro and in vivo models.These inhibitors offer a novel approach to HCC treatment by reducing the glucose metabolism of tumour cells,thereby impeding tumour growth,and concurrently enhancing the sensitivity to chemotherapeutic agents.This reminds us of the urgent need to elucidate GLUTs’roles in HCC and to determine the most effective ways to translate these findings into clinical practice.展开更多
BACKGROUND Pancreatic cancer,characterized by aggressive proliferation and metastasis,is a lethal malignancy.The nightly hormone melatonin serves as a rhythm-regulating hormone,and is used to treat different cancers i...BACKGROUND Pancreatic cancer,characterized by aggressive proliferation and metastasis,is a lethal malignancy.The nightly hormone melatonin serves as a rhythm-regulating hormone,and is used to treat different cancers including pancreatic cancer.AIM To investigate how melatonin acts against human pancreatic cancer cell lines and analyze the biological processes that cause the observed effects.METHODS Panc-1 and AsPC-1 cells were treated with melatonin.Cell viability was measured using the cell counting kit-8 assay.Western blotting and immunofluorescence were used to analyze protein expression levels.Ferroptosis was measured by analyzing lipid reactive oxygen species and malondialdehyde levels;apoptosis was assessed using flow cytometry.RESULTS Melatonin significantly inhibited the viability,colony formation,migration,and invasion of Panc-1 and AsPC-1 cells.Additionally,melatonin activated the endoplasmic reticulum(ER)stress pathway(protein kinase R-like ER kinase eukaryotic initiation factor 2α-activating transcription factor 4),inhibited glutamine metabolism(alanine-serinecysteine transporter 2-glutaminase 1-glutathione peroxidase 4,alanine-serine-cysteine transporter 2-glutathione peroxidase 4),and promoted ferroptosis in pancreatic cancer cells.Co-treatment with a high melatonin concentration and protein kinase R-like ER kinase agonist(CCT020312)enhanced melatonin-induced ferroptosis in pancreatic cancer cells.Melatonin demonstrated a variety of anticancer effects by inhibiting autophagy.This was achieved through the increased expression of sequestosome-1 and decreased expression of light chain 3.Additionally,melatonin facilitated the promotion of apoptosis.CONCLUSION Melatonin induces ferroptosis in pancreatic cancer cells by activating transcription factor 4-dependent ER stress and inhibiting glutamine metabolism,promotes apoptosis in pancreatic cancer cells,and inhibits autophagy,leading to synergistic anticancer effects.展开更多
The tolerance of rice to drought and saline stress is crucial for maintaining yields and promoting widespread cultivation.From an ethyl methanesulfonate(EMS)-mutagenized mutant library,we identified a mutant that is s...The tolerance of rice to drought and saline stress is crucial for maintaining yields and promoting widespread cultivation.From an ethyl methanesulfonate(EMS)-mutagenized mutant library,we identified a mutant that is susceptible to osmotic stress,named Osmotic Stress Sensitivity 1(Oss1).Using MutMap sequencing,we characterized the role of a choline transporter-related family gene,CTR4(Choline Transporter-Related 4),in rice’s tolerance to drought and salt stress.CTR4 plays a critical role in regulating membrane lipid synthesis.In knockout mutants,the total membrane lipid content,especially unsaturated fatty acids,was significantly reduced.Compared with the wild type,knockout mutants exhibited decreased membrane lipid stability under drought and salt stress,faster water loss,higher relative electrolyte leakage,and lower levels of proline and soluble sugars,leading to impaired tolerance to drought and salt stress.In contrast,the overexpression of CTR4 enhanced seedling tolerance to drought and saline stress.The overexpression lines displayed lower malondialdehyde levels,reduced relative electrolyte leakage,and slower rates of leaf water loss under stress conditions,thereby improving seedling survival rates during stress.Moreover,lipid synthesis gene expression was down-regulated in CTR4 mutants,potentially exacerbating membrane permeability defects and further compromising stress resistance.These findings suggest that CTR4 mediates choline transport and influences cell membrane formation,thereby enhancing rice defenses against drought and salt stress by maintaining lipid homeostasis.展开更多
Pesticides play a pivotal role in modern agriculture. However, the pesticide industry faces significant challenges closely linked to major global concerns such as pesticide resistance, environmental pollution, food sa...Pesticides play a pivotal role in modern agriculture. However, the pesticide industry faces significant challenges closely linked to major global concerns such as pesticide resistance, environmental pollution, food safety, and crop yields. Developing safe, efficient, and environmentally friendly pesticides has become a key challenge for the industry. Recently, Qing Yang and colleagues unveiled the mode of action of a dual-functional protein, the ABCH transporter, which plays essential roles in lipid transport to construct the lipid barrier of insect cuticles and in pesticide detoxification within insects. Since ABCH transporters are critical for all insects but absent in mammals and plants, this elegant and exciting work provides a highly promising target for developing safe, low-resistance pesticides. Here, we highlight the groundbreaking discoveries made by Qing Yang's team in unraveling the intricate mechanisms of the ABCH transporter.展开更多
BACKGROUND The beneficial effects of sodium-glucose co-transporter-2 inhibitors(SGLT2i)on adverse cardiac outcomes in diabetic patients are well-established.However,the effects of SGLT2i against cancer therapy-related...BACKGROUND The beneficial effects of sodium-glucose co-transporter-2 inhibitors(SGLT2i)on adverse cardiac outcomes in diabetic patients are well-established.However,the effects of SGLT2i against cancer therapy-related cardiotoxicity remain understudied.We investigated the association between SGLT2i and cardiac outcomes in cancer patients.METHODS PubMed,Embase,and the Cochrane Library were searched from their inception until September 30,2024 for studies evaluating the effects of SGLT2i in patients with cancer.The primary outcomes included incident heart failure(HF),HF exacerbation,HF hospitalization,atrial fibrillation/atrial flutter(AF/AFL),myocardial infarction,and all-cause mortality.The secondary outcomes included acute kidney injury and sepsis.Odds ratio(OR)with 95%CI was pooled.RESULTS Thirteen studies with 85,596 patients were included.Compared to non-SGLT2i use,SGLT2i treatment was associated with lower risks of incident HF(OR=0.51,95%CI:0.32-0.79,P=0.003),HF exacerbation(OR=0.74,95%CI:0.63-0.87,P<0.001),AF/AFL(OR=0.67,95%CI:0.55-0.82,P<0.001),myocardial infarction(OR=0.61,95%CI:0.41-0.90,P=0.01),and all-cause mortality(OR=0.44,95%CI:0.28-0.69,P<0.001),but not for HF hospitalization(OR=0.58,95%CI:0.22-1.55,P=0.28).As for safety outcomes,SGLT2i use was associated with lower risks of acute kidney injury(OR=0.68,95%CI:0.57-0.81,P<0.001)and sepsis(OR=0.32,95%CI:0.23-0.44,P<0.001).CONCLUSIONS SGLT2i were associated with lower risks of incident HF,HF exacerbation,AF/AFL,myocardial infarction,allcause mortality,acute kidney injury,and sepsis in cancer patients.展开更多
Background Verticillium dahliae,a soil-borne fungi,can cause Verticillium wilt,and seriously diminish the yield and quality of cotton.However,the pathogenic mechanism of V.dahliae is complex and not clearly understood...Background Verticillium dahliae,a soil-borne fungi,can cause Verticillium wilt,and seriously diminish the yield and quality of cotton.However,the pathogenic mechanism of V.dahliae is complex and not clearly understood at the moment.This study aimed to identify the high-affinity nicotinic acid transporter genes in V.dahliae.The gene expression profiles in V.dahliae following sensing of root exudates from susceptible and resistant cotton varieties were analyzed.The function of VdNAT1 in the pathogenic process of V.dahliae was studied using the tobacco rattle virus(TRV)-based host-induced gene silencing(HIGS)technique.Results Eight high-affinity nicotinic acid transporter genes were identified from V.dahliae through the bioinformatics method.Each protein contains a conserved major facilitator superfamily(MFS)domain,which belongs to the MFS superfamily.Evolutionary relationship analysis revealed that all 8 genes belong to the anion:cation symporter(ACS)subfamily.All proteins have transmembrane domains,ranging from 7 to 12.The expression levels of most VdNAT genes were significantly increased after induction by root exudates from susceptible cotton varieties.Silencing VdNAT1 gene by HIGS significantly inhibited the accumulation of fungal biomass in cotton plants,and alleviated the disease symptoms of cotton.Conclusions Eight VdNAT genes were identified from V.dahliae,and most VdNAT genes was up-regulated after induced by root exudates from susceptible cotton variety.In addition,VdNAT1 is required for the pathogenicity of V.dahliae.Overall,these findings will facilitate the pathogenic molecular mechanism of V.dahliae and provide candidate genes.展开更多
Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters poten...Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters potentiate them as targets for developing drugs with ideal pharmacokinetics profiles,including targeted distribution,improved clinical efficacy and low adverse reaction.In this review,we summarize the tissue-specific expression,transport functions and substrates profiles of the major influx and efflux transporters,including solute carrier（SLC） superfamily and adenosine triphosphate（ATP）-binding cassette（ABC） superfamily.Moreover,we describe examples of successful drug or prodrug design based on the function of transporters that yielded drugs with excellent ADME properties.Lastly,we discuss the in vitro and in vivo methods that are broadly applied in the drug designing process to study the interactions between the drugs and the transporters.展开更多
文摘A key pathological feature of Parkinson’s disease(PD)is that lysosomes are overwhelmed with cellular materials that need to be degraded and cleared.While the build-up of protein is characteristic of neurodegenerative diseases such as PD and Alzheimer’s disease(AD)and is thought to reflect lysosome dysfunction,lipid accumulation may also contribute to and be indicative of severe lysosomal dysfunction.Much is known about the detrimental effects of glucosylceramide accumulation in PD lysosomes.
基金funded by the National Natural Science Foundation of China(No.82304730)the Project of Academic and Technical Leaders in Major Disciplines in Jiangxi Province(No.20212BCJL23060)+3 种基金the Natural Science Foundation of Jiangxi Province(No.20232BAB216128)the Project of Jiangxi Provincial Department of Education(No.GJJ2200977)the Jiangxi University of Chinese Medicine Science and Technology Innovation Team Development Program(Nos.CXTD-22004,CXTD-22008)the PhD Startup Foundation of Affiliated Hospital of Jiangxi University of Chinese Medicine(No.23KYQDZJ02).
文摘Utilizing transporter-mediated drug delivery to achieve effective oral absorption emerges as a promising strategy.Researchers have been concentrated on discovering solutions to the issues of low solubility and poor permeability of insoluble drugs,whereas,current reports have revealed that drug transporter proteins are abundantly expressed in the mucosa of intestinal epithelial cells,and that their mediated drug absorption effectively improved the bioavailability of orally administered drugs.There are two main categories based on the transporter mechanism,which include the family of ATP-binding cassette(ABC)transporters with efflux effects that reduce drug bioavailability and the family of solute carriers(SLC)transporters with uptake effects that promote drug absorption,respectively.Thus,we review studies of intestinal transporter-mediated delivery of drugs to enhance oral absorption,including the types of intestinal transporters,distribution characteristics,and strategies for enhancing oral absorption using transporter-mediated drug delivery systems are summarized,with the aim of providing important theoretical references for the development of intestinal-targeted delivery system.
基金supported by the National Natural Science Foundation of China(Grant Nos.32130096 and 32172667)the Central Public-Interest Scientific Institution Basal Research Fund,China(Grant No.Y2022QC14).
文摘Sulfate transporters(SULTRs)facilitate sulfate uptake and transport in plants.In plants,SULTRs can be classified into four distinct functional groups,among which SULTR3 members are the least characterized,and their functions have not yet been confirmed,especially for SULTR3 in rice.In this study,we analyzed the expression patterns,subcellular localization,and inorganic phosphate(Pi)transporter activity of SULTR3 proteins in yeast.Except for OsSULTR3.4,which localized to the plasma membrane,other OsSULTR3 members were localized to the endoplasmic reticulum(ER)membrane in rice protoplast cells.
基金supported by the National Natural Science Foundation of China,Nos.32371070 (to JT),31761163005 (to JT),32100824 (to QX)the Shenzhen Science and Technology Program,Nos.RCBS20210609104606024 (to QX),JCY20210324101813035 (to DL)+4 种基金the Guangdong Provincial Key S&T Program,No.2018B030336001 (to JT)the Key Basic Research Program of Shenzhen Science and Technology Innovation Commission,Nos.JCYJ20200109115405930 (to JT),JCYJ20220818101615033 (to DL),JCYJ20210324115811031 (to QX),JCYJ20200109150717745 (to QX)Shenzhen Key Laboratory of Neuroimmunomodulation for Neurological Diseases,No.ZDSYS20220304163558001 (to JT)Guangdong Provincial Key Laboratory of Brain Connectome and Behavior,No.2023B1212060055 (to JT)the China Postdoctoral Science Foundation,No.2021M693298 (to QX)。
文摘The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions.Specifically, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress–induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice.After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.
基金supported by the National Key Research and Development Program of China(Grant No.2023YFF1000500)the National Natural Science Foundation of China(Grant Nos.32372099,32172080,and 32188102)the Innovation Program of the Chinese Academy of Agricultural Sciences,China(Grant No.CAAS-CSCB-202402).
文摘Sucrose transporters(SUTs)contain multiple transmembrane domains that mediate sucrose transport and provide energy for plant growth and development.However,the role of OsSUTs in regulating rice quality and grain yield remains unclear.In this study,we identified five rice SUT genes(OsSUT1-OsSUT5)and examined their molecular characteristics and biological functions.OsSUT1,OsSUT2,and OsSUT4 were predominantly expressed in stems,while OsSUT3 and OsSUT5 showed higher expression in panicles.OsSUT1 and OsSUT4 are located on the plasma membrane,whereas OsSUT2,OsSUT3,and OsSUT5 are localized to the tonoplast.
文摘Glutamate is a regulated molecule in the mammalian testis. Extracellular regulation of glutamate in the body is determined largely by the expression of plasmalemmal glutamate transporters. We have examined by PCR, western blotting and immunocytochemistry the expression of a panel of sodium-dependent plasmalemmal glutamate transporters in the rat testis. Proteins examined included： glutamate aspartate transporter （GLAST）, glutamate transporter 1 （GLT1）, excitatory amino acid carrier 1 （EAAC1）, excitatory amino acid transporter 4 （EAAT4） and EAAT5. We demonstrate that many of the glutamate transporters in the testis are alternately spliced. GLAST is present as exon-3- and exon-9-skipping forms. GLT1 was similarly present as the alternately spliced forms GLT1 b and GLTlc, whereas the abundant brain form （GLTla） was detectable only at the mRNA level. EAAT5 was also strongly expressed, whereas EAAC1 and EAAT4 were absent. These patterns of expression were compared with the patterns of endogenous glutamate localization and with patterns of D-aspartate accumulation, as assessed by immunocytochemistry. The presence of multiple glutamate transporters in the testis, including unusually spliced forms, suggests that glutamate homeostasis may be critical in this organ. The apparent presence of many of these transporters in the testis and sperm may indicate a need for glutamate transport by such cells.
基金supported by the National Natural Science Foundation of China(32071798)5·5 Engineering Research&Innovation Team Project of Beijing Forestry University,China(BLRC2023B08)。
文摘Sucrose transporters(SUTs)play a crucial role in carbon allocation from the source leaf to the sink end,and the function of SUTs varies among family members.However,the genome-wide identifcation of the SUT superfamily in Camellia oleifera is lacking,and their biological function remains elusive.In this study,four SUT genes-designated Co SUT1-4-were identifed in C.oleifera through a genome-wide analysis and classifed into three subfamilies.We used a combination of cis-acting elements analysis,mRNA quantifcation,histochemical analysis,and heterologous transformation to evaluate the expression profiles and functions of these SUTs.A key finding is that CoSUT4,localized on the plasma membrane,is highly expressed in mature leaves and the early stage of seed development in C.oleifera.In vitro culture of C.oleifera seed revealed the responsiveness of CoSUT4 to various exogenous hormones such as ABA and GA.CoSUT4 was able to restore the growth of the yeast strain SUSY7/ura3(a sucrose transport-defcient mutant)on sucrose-containing media and specifcally contributed to sucrose translocation and tissue growth in CoSUT4-overexpressed apple calli.In situ hybridization identifed chalazal nucellus and transfer cells as the action sites of CoSUT4 at the maternal-flial interface mediating sucrose transportation in oil tea seeds.CoSUT4 overexpression in Arabidopsis thaliana atsuc4 mutant restored the growth and seed yield defciencies of the mutant,leading to an increase in flled seeds and oil content.Additionally,CoSUT4 overexpression enhanced the drought and salt stress tolerance by augmenting sugar content.Overall,these fndings provide valuable insights into the function of SUTs and present promising candidates for the genetic enhancement of seed production in C.oleifera.
基金supported by the Universiti Kebangsaan Malaysia under the Research University Grant(No.GUP-2020-030)awarded to Sylvia CHIENG.
文摘Adenosine triphosphate(ATP)-binding cassette(ABC)transporter systems are divided into importers and exporters that facilitate the movement of diverse substrate molecules across the lipid bilayer,against the concentration gradient.These transporters comprise two highly conserved nucleotide-binding domains(NBDs)and two transmembrane domains(TMDs).Unlike ABC exporters,prokaryotic ABC importers require an additional substrate-binding protein(SBP)as a recognition site for specific substrate translocation.The discovery of a large number of ABC systems in bacterial pathogens revealed that these transporters are crucial for the establishment of bacterial infections.The existing literature has highlighted the roles of ABC transporters in bacterial growth,pathogenesis,and virulence.These roles include importing essential nutrients required for a variety of cellular processes and exporting outer membrane-associated virulence factors and antimicrobial substances.This review outlines the general structures and classification of ABC systems to provide a comprehensive view of the activities and roles of ABC transporters associated with bacterial virulence and pathogenesis during infection.
基金supported by COBRE(P30GM149367)the Puerto Rico Science&Technology Trust(2022-00125)+1 种基金MBRS-RISE Program(R25 GM061838)SC1GM144032 program(all to JDM)。
文摘In addition to the loss of motor function,~60% of patients develop pain after spinal cord injury.The cellular-molecular mechanisms are not well understood,but the data suggests that plasticity within the rostral,epicenter,and caudal penumbra of the injury site initiates a cellularmolecular interplay that acts as a rewiring mechanism leading to central neuropathic pain.Sprouting can lead to the formation of new connections triggering abnormal sensory transmission.The excitatory glutamate transporters are responsible for the reuptake of extracellular glutamate which makes them a critical target to prevent neuronal hyperexcitability and excitotoxicity.Our previous studies showed a sexually dimorphic therapeutic window for spinal cord injury after treatment with the selective estrogen receptor modulator tamoxifen.In this study,we investigated the anti-allodynic effects of tamoxifen in male and female rats with spinal cord injury.We hypothesized that tamoxifen exerts anti-allodynic effects by increasing the expression of glutamate transporters,leading to reduced hyperexcitability of the secondary neuron or by decreasing aberrant sprouting.Male and female rats received a moderate contusion to the thoracic spinal cord followed by subcutaneous slow-release treatment of tamoxifen or matrix pellets as a control(placebo).We used von Frey monofilaments and the“up-down method”to evaluate mechanical allodynia.Tamoxifen treatment decreased allodynia only in female rats with spinal cord injury revealing a sexdependent effect.The expression profile of glutamatergic transporters(excitatory amino acid transporter 1/glutamate aspartate transporter and excitatory amino acid transporter 2/glutamate transporter-1)revealed a sexual dimorphism in the rostral,epicenter,and caudal areas of the spinal cord with a pattern of expression primarily on astrocytes.Female rodents showed a significantly higher level of excitatory amino acid transporter-1 expression while male rodents showed increased excitatory amino acid transporter-2 expression compared with female rodents.Analyses of peptidergic(calcitonin gene-related peptide-α)and non-peptidergic(isolectin B4)fibers outgrowth in the dorsal horn after spinal cord injury showed an increased calcitonin gene-related peptide-α/isolectin B4 ratio in comparison with sham,suggesting increased receptive fields in the dorsal horn.Although the behavioral assay shows decreased allodynia in tamoxifen-treated female rats,this was not associated with overexpression of glutamate transporters or alterations in the dorsal horn laminae fibers at 28 days post-injury.Our findings provide new evidence of the sexually dimorphic expression of glutamate transporters in the spinal cord.The dimorphic expression revealed in this study provides a therapeutic opportunity for treating chronic pain,an area with a critical need for treatment.
基金supported by the National Natural Science Foundation of China(32401743)the Earmarked Fund for the China Agriculture Research System(CARS-01)+1 种基金the Hunan Natural Science Foundation Project(2021JJ40235)the Science and Technology Innovation Program of Hunan Province(2022RC3053)。
文摘The early responsive to dehydration-like(ERDL or ERD)subfamily,subclade within the monosaccharide transporter(MST)superfamily,is crucial in the regulation of growth and seed yield in Arabidopsis.Here,we identified Os ERD5 as an At ERDL6 homologue and explored the function of Os ERD5.We found that Os ERD5 overexpression significantly enhanced the tiller number and grain yield of rice.Os ERD5 was widely expressed in aboveground tissues,encoded a tonoplast-localized protein,and exhibited transport activities for fructose,glucose and mannose when expressed in yeast.Expression character assay revealed that Os ERD5 mediated hexose efflux across tonoplasts and participated in maintaining the diurnal rhythm-regulated intracellular hexose homeostasis.Additional physiological and molecular evidence showed that Os ERD5 overexpression promoted vacuolar glucose efflux,enhanced sucrose synthesis and transport,increased sugar content in the shoot base,and promoted rice tillering by activating the synthesis of cytokinin simultaneously repressing strigolactone and gibberellin signaling.This study elucidates the function of Os ERD5 and the mechanism underlying the overexpression of Os ERD5 increasing rice tillering and yield.
基金supported by the National Natural Science Foundation of China(32260780 and 31360297)the China Postdoctoral Science Foundation(2021M701513)+1 种基金the Jiangxi 2011 Collaborative Innovation Centre of Postharvest Key Technology and Quality Safety of Fruits and Vegetables,China(JXGS-05)the Gan Po 555 Engineering Excel ence Talents Project in Jiangxi Province,China。
文摘Rice is the world's largest food crop,but it often encounters flowering asynchronization problems during hybrid rice seed production.In addition,the slow closure of female florets leads to seed mildew and affects the quality.The hormone abscisic acid(ABA)plays a crucial role in plant responses to abiotic stresses.Previous studies showed that exogenous ABA promotes floret closure,although the molecular mechanisms and effects of endogenous ABA on floret closure remain unknown.In this study,the effect of endogenous ABA on floret closure and the molecular mechanism by which ABA promotes floret closure through sugar transporters were investigated by changing the expression levels of OsNCED3 and OsPYL1 in rice.The results showed that overexpression(OE)-OsNCED3increased the endogenous ABA level of florets.Florets closed 5.91 min earlier and OsNCED3 gene knockout line delayed the closure of florets by 5.08 min compared with the wild type.In addition,OsPYL1 regulated the endogenous ABA content and changed the sensitivity to ABA such that the floret closure times for OE and CRISPR-Cas9(CR)were 9.84 min earlier and 12.78 min later,respectively,resulting in an increase in the split husk rate to 15.4%.The gene expression levels of some sugar transporters(STs)changed.The OsPYL1 and OsSWEET4proteins could interact on the cell membrane.These results indicate that ABA promotes the closure of rice florets and the enhanced sensitivity to ABA promotes this effect even more.The molecular mechanism is mainly related to downstream sugar transporters that respond to the ABA signaling pathway,especially OsSWEET4.
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),Fe2+,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,Fe2+,and ROS levels in Huh-7 and HepG2 cells decreased,whereas overexpressing miR-122-5p increased the MDA,Fe2+,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(No.32072947)the China Agriculture Research System(No.CARS-47)。
文摘Urea is a major end product of nitrogen catabolism,serving as an osmolyte to regulate osmotic stress in fish exposed to varying water environments.It has been well known that urea transporters(UTs)facilitate the rapid movement of urea across cell membranes.However,researches on ut genes were predominantly focused on elasmobranchs and early developmental stages of fish.In this investigation,a total of three ut genes were identified in spotted sea bass.Phylogenetic,homology,and syntenic analyses were conducted to validate the annotation and assess the evolutionary relationships among ut genes.Both ut-a and ut-b genes have retained their evolutionary stability,demonstrating a significant level of homology between them.To gain deeper insights into the evolution of ut genes in spotted sea bass,we performed selective pressure analysis using site,branch,and branch-site models.The results suggested that positive selection likely played a significant role in shaping the evolution of the ut gene family.Furthermore,tissue-specific expression analyses revealed high expression levels of ut genes in osmoregulatory tissues such as the gill and kidney.Additionally,all three ut genes exhibited salinity-related expression patterns in gill and kidney tissues during both seawater-to-freshwater(SF)and freshwater-to-seawater(FS)adaptation.In situ hybridization results demonstrated the localization of both ut-a and ut-c mRNAs on the gill lamellae and adjacent gill filament epithelium.In summary,our study establishes a solid foundation for future research elucidating the evolutionary relationships and functional significance of ut genes during salinity acclimation in spotted sea bass and other teleost species.
文摘Hepatocellular carcinoma(HCC)is a malignant tumour with high prevalence and mortality rate worldwide.Metabolic reprogramming of cancer cells may be a major factor in the process of this disease.Glucose transporter proteins(GLUTs)are members of the major facilitator superfamily of membrane transporters,playing a pivotal role in the metabolic reprogramming and tumour progression in HCC.This review discusses the advances in the study of GLUTs in HCC,in-cluding the expression patterns,functions and possibilities of GLUTs.In HCC,the expression levels of GLUTs are closely associated with tumour aggressiveness,metabolic reprogramming and prognosis.A series of inhibitors have been de-monstrated efficacy in inhibiting HCC cell growth and glucose uptake in in vitro and in vivo models.These inhibitors offer a novel approach to HCC treatment by reducing the glucose metabolism of tumour cells,thereby impeding tumour growth,and concurrently enhancing the sensitivity to chemotherapeutic agents.This reminds us of the urgent need to elucidate GLUTs’roles in HCC and to determine the most effective ways to translate these findings into clinical practice.
基金Supported by Jinhua Municipal Science and Technology Bureau,No.2022-4-254.
文摘BACKGROUND Pancreatic cancer,characterized by aggressive proliferation and metastasis,is a lethal malignancy.The nightly hormone melatonin serves as a rhythm-regulating hormone,and is used to treat different cancers including pancreatic cancer.AIM To investigate how melatonin acts against human pancreatic cancer cell lines and analyze the biological processes that cause the observed effects.METHODS Panc-1 and AsPC-1 cells were treated with melatonin.Cell viability was measured using the cell counting kit-8 assay.Western blotting and immunofluorescence were used to analyze protein expression levels.Ferroptosis was measured by analyzing lipid reactive oxygen species and malondialdehyde levels;apoptosis was assessed using flow cytometry.RESULTS Melatonin significantly inhibited the viability,colony formation,migration,and invasion of Panc-1 and AsPC-1 cells.Additionally,melatonin activated the endoplasmic reticulum(ER)stress pathway(protein kinase R-like ER kinase eukaryotic initiation factor 2α-activating transcription factor 4),inhibited glutamine metabolism(alanine-serinecysteine transporter 2-glutaminase 1-glutathione peroxidase 4,alanine-serine-cysteine transporter 2-glutathione peroxidase 4),and promoted ferroptosis in pancreatic cancer cells.Co-treatment with a high melatonin concentration and protein kinase R-like ER kinase agonist(CCT020312)enhanced melatonin-induced ferroptosis in pancreatic cancer cells.Melatonin demonstrated a variety of anticancer effects by inhibiting autophagy.This was achieved through the increased expression of sequestosome-1 and decreased expression of light chain 3.Additionally,melatonin facilitated the promotion of apoptosis.CONCLUSION Melatonin induces ferroptosis in pancreatic cancer cells by activating transcription factor 4-dependent ER stress and inhibiting glutamine metabolism,promotes apoptosis in pancreatic cancer cells,and inhibits autophagy,leading to synergistic anticancer effects.
基金supported by the National Key Research and Development Program of China(Grant No.2021YFD1200500)STI 2030-Major Projects,China(Grant No.2022ZD04017)Sichuan Department of Science and Technology,China(Grant No.2022JDRC0111).
文摘The tolerance of rice to drought and saline stress is crucial for maintaining yields and promoting widespread cultivation.From an ethyl methanesulfonate(EMS)-mutagenized mutant library,we identified a mutant that is susceptible to osmotic stress,named Osmotic Stress Sensitivity 1(Oss1).Using MutMap sequencing,we characterized the role of a choline transporter-related family gene,CTR4(Choline Transporter-Related 4),in rice’s tolerance to drought and salt stress.CTR4 plays a critical role in regulating membrane lipid synthesis.In knockout mutants,the total membrane lipid content,especially unsaturated fatty acids,was significantly reduced.Compared with the wild type,knockout mutants exhibited decreased membrane lipid stability under drought and salt stress,faster water loss,higher relative electrolyte leakage,and lower levels of proline and soluble sugars,leading to impaired tolerance to drought and salt stress.In contrast,the overexpression of CTR4 enhanced seedling tolerance to drought and saline stress.The overexpression lines displayed lower malondialdehyde levels,reduced relative electrolyte leakage,and slower rates of leaf water loss under stress conditions,thereby improving seedling survival rates during stress.Moreover,lipid synthesis gene expression was down-regulated in CTR4 mutants,potentially exacerbating membrane permeability defects and further compromising stress resistance.These findings suggest that CTR4 mediates choline transport and influences cell membrane formation,thereby enhancing rice defenses against drought and salt stress by maintaining lipid homeostasis.
基金National Natural Science Foundation of China(32471265).
文摘Pesticides play a pivotal role in modern agriculture. However, the pesticide industry faces significant challenges closely linked to major global concerns such as pesticide resistance, environmental pollution, food safety, and crop yields. Developing safe, efficient, and environmentally friendly pesticides has become a key challenge for the industry. Recently, Qing Yang and colleagues unveiled the mode of action of a dual-functional protein, the ABCH transporter, which plays essential roles in lipid transport to construct the lipid barrier of insect cuticles and in pesticide detoxification within insects. Since ABCH transporters are critical for all insects but absent in mammals and plants, this elegant and exciting work provides a highly promising target for developing safe, low-resistance pesticides. Here, we highlight the groundbreaking discoveries made by Qing Yang's team in unraveling the intricate mechanisms of the ABCH transporter.
基金supported by the National Natural Science Foundation of China(No.82170327&No.82370332)the Tianjin Key Medical Discipline(Specialty)Construction Project(TJYXZDXK-029A).
文摘BACKGROUND The beneficial effects of sodium-glucose co-transporter-2 inhibitors(SGLT2i)on adverse cardiac outcomes in diabetic patients are well-established.However,the effects of SGLT2i against cancer therapy-related cardiotoxicity remain understudied.We investigated the association between SGLT2i and cardiac outcomes in cancer patients.METHODS PubMed,Embase,and the Cochrane Library were searched from their inception until September 30,2024 for studies evaluating the effects of SGLT2i in patients with cancer.The primary outcomes included incident heart failure(HF),HF exacerbation,HF hospitalization,atrial fibrillation/atrial flutter(AF/AFL),myocardial infarction,and all-cause mortality.The secondary outcomes included acute kidney injury and sepsis.Odds ratio(OR)with 95%CI was pooled.RESULTS Thirteen studies with 85,596 patients were included.Compared to non-SGLT2i use,SGLT2i treatment was associated with lower risks of incident HF(OR=0.51,95%CI:0.32-0.79,P=0.003),HF exacerbation(OR=0.74,95%CI:0.63-0.87,P<0.001),AF/AFL(OR=0.67,95%CI:0.55-0.82,P<0.001),myocardial infarction(OR=0.61,95%CI:0.41-0.90,P=0.01),and all-cause mortality(OR=0.44,95%CI:0.28-0.69,P<0.001),but not for HF hospitalization(OR=0.58,95%CI:0.22-1.55,P=0.28).As for safety outcomes,SGLT2i use was associated with lower risks of acute kidney injury(OR=0.68,95%CI:0.57-0.81,P<0.001)and sepsis(OR=0.32,95%CI:0.23-0.44,P<0.001).CONCLUSIONS SGLT2i were associated with lower risks of incident HF,HF exacerbation,AF/AFL,myocardial infarction,allcause mortality,acute kidney injury,and sepsis in cancer patients.
基金supported by National Natural Science Foundation of China(No.32160615).
文摘Background Verticillium dahliae,a soil-borne fungi,can cause Verticillium wilt,and seriously diminish the yield and quality of cotton.However,the pathogenic mechanism of V.dahliae is complex and not clearly understood at the moment.This study aimed to identify the high-affinity nicotinic acid transporter genes in V.dahliae.The gene expression profiles in V.dahliae following sensing of root exudates from susceptible and resistant cotton varieties were analyzed.The function of VdNAT1 in the pathogenic process of V.dahliae was studied using the tobacco rattle virus(TRV)-based host-induced gene silencing(HIGS)technique.Results Eight high-affinity nicotinic acid transporter genes were identified from V.dahliae through the bioinformatics method.Each protein contains a conserved major facilitator superfamily(MFS)domain,which belongs to the MFS superfamily.Evolutionary relationship analysis revealed that all 8 genes belong to the anion:cation symporter(ACS)subfamily.All proteins have transmembrane domains,ranging from 7 to 12.The expression levels of most VdNAT genes were significantly increased after induction by root exudates from susceptible cotton varieties.Silencing VdNAT1 gene by HIGS significantly inhibited the accumulation of fungal biomass in cotton plants,and alleviated the disease symptoms of cotton.Conclusions Eight VdNAT genes were identified from V.dahliae,and most VdNAT genes was up-regulated after induced by root exudates from susceptible cotton variety.In addition,VdNAT1 is required for the pathogenicity of V.dahliae.Overall,these findings will facilitate the pathogenic molecular mechanism of V.dahliae and provide candidate genes.
基金National Science and Technology Major Project(Grant No. 2012ZX09506001-004)
文摘Membrane transporters mediate the influx and efflux of various drugs,and play essential roles in drug absorption,distribution,metabolism and excretion（ADME）.The unique characteristics of membranes transporters potentiate them as targets for developing drugs with ideal pharmacokinetics profiles,including targeted distribution,improved clinical efficacy and low adverse reaction.In this review,we summarize the tissue-specific expression,transport functions and substrates profiles of the major influx and efflux transporters,including solute carrier（SLC） superfamily and adenosine triphosphate（ATP）-binding cassette（ABC） superfamily.Moreover,we describe examples of successful drug or prodrug design based on the function of transporters that yielded drugs with excellent ADME properties.Lastly,we discuss the in vitro and in vivo methods that are broadly applied in the drug designing process to study the interactions between the drugs and the transporters.
