Increased excitatory amino acid transporter 2 levels in basolateral amygdala astrocytes mediate chronic stress–induced anxiety-like behavior

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.

The sexually dimorphic expression of glutamate transporters and their implication in pain after spinal cord injury

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.

Host-induced gene silencing of the Verticillium dahliae thiamine transporter protein gene(VdThit)confers resistance to Verticillium wilt in cotton

Verticillium wilt(VW),induced by the soil-borne fungus Verticillium dahliae(Vd),poses a substantial threat to a diverse array of plant species.Employing molecular breeding technology for the development of cotton varieties with heightened resistance to VW stands out as one of the most efficacious protective measures.In this study,we successfully generated two stable transgenic lines of cotton(Gossypium hirsutum L.),VdThitRNAi-1 and VdThit-RNAi-2,using host-induced gene silencing(HIGS)technology to introduce double-stranded RNA(dsRNA)targeting the thiamine transporter protein gene(VdThit).Southern blot analysis confirmed the presence of a single-copy insertion in each line.Microscopic examination showed marked reductions in the colonization and spread of Vd-mCherry in the roots of VdThit-RNAi cotton compared to wild type(WT).The corresponding disease index and fungal biomass of VdThit-RNAi-1/2 also exhibited significant reductions.Real-time quantitative PCR(qRT-PCR)analysis demonstrated a substantial inhibition of VdThit expression following prolonged inoculation of VdThit-RNAi cotton.Small RNA sequencing(sRNA-Seq)analysis revealed the generation of a substantial number of VdThit-specific siRNAs in the VdThit-RNAi transgenic lines.Additionally,the silencing of VdThit by the siVdThit produced by VdThit-RNAi-1/2 resulted in the elevated expression of multiple genes involved in the thiamine biosynthesis pathway in Vd.Under field conditions,VdThit-RNAi transgenic cotton exhibited significantly enhanced disease resistance and yield compared with WT.In summary,our findings underscore the efficacy of HIGS targeting VdThit in restraining the infection and spread of Vd in cotton,thereby potentially enabling the development of cotton breeding as a promising strategy for managing VW.

Identification of the lysine and histidine transporter family in Camellia sinensis and the characterizations in nitrogen utilization

In plants,the lysine and histidine transporter(LHT)family represent a class of proteins that mediate the uptake,translocation,and utilization of amino acids.The tea plant(Camellia sinensis)is a perennial evergreen with a relatively high level of amino acids.However,systematic identification and molecular characterization of the LHT gene family has rarely been reported in tea plants.In this study,22 CsLHTs were identified from the‘Shuchazao’genome and classified into two groups.The modeled three-dimensional structure and the conserved domains presented a high similarity among the LHTs proteins.Moreover,it was predicted that a few genes were conserved through the analysis of the physiochemical characters,structures and cis-elements in promoters.The expression patterns in tea plants revealed that CsLHT7 was mainly expressed in the roots,and CsLHT4 and CsLHT11 exhibited relatively high expression in both the roots and leaves.Moreover,the expression of all three genes could be induced by organic nitrogen.Additionally,heterogeneous expression of CsLHT4,CsLHT7 and CsLHT11 in Arabidopsis thaliana decreased the aerial parts biomass compared with that in WT plants while significantly increased the rosette biomass only for CsLHT11transgenic plants versus WT plants.Overall,our results provide fundamental information about CsLHTs and potential genes in N utilization for further analysis in tea plants.

Global characterization of OsPIP aquaporins reveals that the H_(2)O_(2)transporter OsPIP2;6 increases resistance to rice blast

Plasma membrane intrinsic proteins(PIPs)are conserved plant aquaporins that transport small molecules across the plasma membrane to trigger instant stress responses and maintain cellular homeostasis under biotic and abiotic stress.To elucidate their roles in plant immunity to pathogen attack,we characterized the expression patterns,subcellular localizations,and H_(2)O_(2)-transport ability of 11 OsPIPs in rice(Oryza sativa),and identified OsPIP2;6 as necessary for rice disease resistance.OsPIP2;6 resides on the plasma membrane and facilitates cytoplasmic import of the immune signaling molecule H_(2)O_(2).Knockout of OsPIP2;6 increases rice susceptibility to Magnaporthe oryzae,indicating a positive function in plant immunity.OsPIP2;6 interacts with OsPIP2;2,which has been reported to increase rice resistance to pathogens via H_(2)O_(2)transport.Our findings suggest that OsPIP2;6 cooperates with OsPIP2;2 as a defense signal transporter complex during plant–pathogen interaction.

Sodium-dependent glucose transporter 2 inhibitors effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure

BACKGROUND Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have shown efficacy in reducing heart failure(HF)burden in a very heterogeneous groups of patients,raising doubts about some contemporary assumptions of their mechanism of action.We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy.Two groups of patients were included in the study:the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control.AIM To evaluate the outcomes regarding natriuretic peptide,oxidative stress,inflammation,blood pressure,heart rate,cardiac function,and body weight.METHODS The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain(GLS),N-terminal pro-brain natriuretic peptide,myeloperoxidase(MPO),high-sensitivity C-reactive protein(hsCRP),and systolic and diastolic blood pressure.To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up,a rise in stroke volume index,body mass index(BMI)decrease,and lack of heart rate increase,linear regression analysis was performed.RESULTS There was a greater reduction of MPO,hsCRP,GLS,and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up.Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI,while the predictor of stroke volume index increase was SGLT2i therapy itself.CONCLUSION SGLT2i affect body composition,reduce cardiac load,improve diastolic/systolic function,and attenuate the sympathetic response.Glycemic control contributes to the improvement of heart function,blood pressure control,oxidative stress,and reduction in inflammation.

Glutamine transporters as effective targets in digestive system malignant tumor treatment

Glutamine is one of the most abundant non-essential amino acids in human plasma and plays a crucial role in many biological processes of the human body.Tumor cells take up a large amount of glutamine to meet their rapid proliferation requirements,which is supported by the upregulation of glutamine transporters.Targeted inhibition of glutamine transporters effectively inhibits cell growth and proliferation in tumors.Among all cancers,digestive system malignant tumors(DSMTs)have the highest incidence and mortality rates,and the current therapeutic strategies for DSMTs are mainly surgical resection and chemotherapy.Due to the relatively low survival rate and severe side effects associated with DSMTs treatment,new treatment strategies are urgently required.This article summarizes the glutamine transporters involved in DSMTs and describes their role in DSMTs.Additionally,glutamine transportertarget drugs are discussed,providing theoretical guidance for the further development of drugs DSMTs treatment.

A mutation in the promoter of the yellow stripe-like transporter gene in cucumber results in a yellow cotyledon phenotype

Leaf color mutants in higher plants are considered to be ideal materials for studying the chlorophyll biosynthesis,photosynthesis mechanism and chloroplast development.Herein,we identified a spontaneous mutant,yc412,in cultivated cucumber that exhibited yellow cotyledons.The yellow-lethal mutant was diagnosed with an abnormal chloroplast ultrastructure,and reduced photosynthetic capacity and pigment content.Through bulked segregant analysis-based whole-genome sequencing and fine genetic mapping,we narrowed the yellow cotyledons (yc) locus to a 96.8 kb interval on chromosome 3.By resequencing and molecular cloning,we showed that Csyc is a potential candidate gene,which encodes a yellow stripe-like (YSL) transporter.The T to C mutation in the promoter region of Csyc caused the yellow cotyledon phenotype in yc412.Compared to YZU027A (WT),the expression of Csyc was significantly downregulated in the cotyledons of yc412.Silencing of Csyc in cucumber via virus-induced gene silencing resulted in chlorotic leaves,mainly by suppressing the chlorophyll content.Furthermore,a comparative transcriptome analysis revealed that chloroplast-related genes and chlorophyll biosynthesis genes were significantly downregulated in yc412 cotyledons.Our results provide new insights into the molecular function of the YSL transporter in plant chloroplast development and chlorophyll synthesis.

Effects of the kinetic pattern of dietary glucose release on nitrogen utilization, the portal amino acid profile, and nutrient transporter expression in intestinal enterocytes in piglets

Background Promoting the synchronization of glucose and amino acid release in the digestive tract of pigs could effectively improve dietary nitrogen utilization.The rational allocation of dietary starch sources and the exploration of appropriate dietary glucose release kinetics may promote the dynamic balance of dietary glucose and amino acid supplies.However,research on the effects of diets with different glucose release kinetic profiles on amino acid absorption and portal amino acid appearance in piglets is limited.This study aimed to investigate the effects of the kinetic pattern of dietary glucose release on nitrogen utilization,the portal amino acid profile,and nutrient transporter expression in intestinal enterocytes in piglets.Methods Sixty-four barrows(15.00±1.12 kg)were randomly allotted to 4 groups and fed diets formulated with starch from corn,corn/barley,corn/sorghum,or corn/cassava combinations(diets were coded A,B,C,or D respectively).Protein retention,the concentrations of portal amino acid and glucose,and the relative expression of amino acid and glucose transporter m RNAs were investigated.In vitro digestion was used to compare the dietary glucose release profiles.Results Four piglet diets with different glucose release kinetics were constructed by adjusting starch sources.The in vivo appearance dynamics of portal glucose were consistent with those of in vitro dietary glucose release kinetics.Total nitrogen excretion was reduced in the piglets in group B,while apparent nitrogen digestibility and nitrogen retention increased(P<0.05).Regardless of the time(2 h or 4 h after morning feeding),the portal total free amino acids content and contents of some individual amino acids(Thr,Glu,Gly,Ala,and Ile)of the piglets in group B were significantly higher than those in groups A,C,and D(P<0.05).Cluster analysis showed that different glucose release kinetic patterns resulted in different portal amino acid patterns in piglets,which decreased gradually with the extension of feeding time.The portal His/Phe,Pro/Glu,Leu/Val,Lys/Met,Tyr/Ile and Ala/Gly appeared higher similarity among the diet treatments.In the anterior jejunum,the glucose transporter SGLT1 was significantly positively correlated with the amino acid transporters B0AT1,EAAC1,and CAT1.Conclusions Rational allocation of starch resources could regulate dietary glucose release kinetics.In the present study,group B(corn/barley)diet exhibited a better glucose release kinetic pattern than the other groups,which could affect the portal amino acid contents and patterns by regulating the expression of amino acid transporters in the small intestine,thereby promoting nitrogen deposition in the body,and improving the utilization efficiency of dietary nitrogen.

OsNPF3.1,a nitrate,abscisic acid and gibberellin transporter gene,is essential for rice tillering and nitrogen utilization efficiency

Low-affinity nitrate transporter genes have been identified in subfamilies 4-8 of the rice nitrate transporter 1(NRT1)/peptide transporter family(NPF),but the OsNPF3 subfamily responsible for nitrate and phytohormone transport and rice growth and development remains unknown.In this study,we described OsNPF3.1 as an essential nitrate and phytohormone transporter gene for rice tillering and nitrogen utilization efficiency(NUtE).OsNPF3.1 possesses four major haplotypes of its promoter sequence in 517 cultivars,and its expression is positively associated with tiller number.Its expression was higher in the basal part,culm,and leaf blade than in other parts of the plant,and was strongly induced by nitrate,abscisic acid(ABA)and gibberellin 3(GA_3)in the root and shoot of rice.Electrophysiological experiments demonstrated that OsNPF3.1 is a pH-dependent low-affinity nitrate transporter,with rice protoplast uptake assays showing it to be an ABA and GA_3 transporter.OsNPF3.1 overexpression significantly promoted ABA accumulation in the roots and GA accumulation in the basal part of the plant which inhibited axillary bud outgrowth and rice tillering,especially at high nitrate concentrations.The NUtE of OsNPF3.1-overexpressing plants was enhanced under low and medium nitrate concentrations,whereas the NUtE of OsNPF3.1 clustered regularly interspaced short palindromic repeats(CRISPR)plants was increased under high nitrate concentrations.The results indicate that OsNPF3.1 transports nitrate and phytohormones in different rice tissues under different nitrate concentrations.The altered OsNPF3.1 expression improves NUtE in the OsNPF3.1-overexpressing and CRISPR lines at low and high nitrate concentrations,respectively.

Genome-Wide Discovery and Expression Profiling of the SWEET Sugar Transporter Gene Family in Woodland Strawberry (Fragaria vesca) under Developmental and Stress Conditions: Structural and Evolutionary Analysis

The SWEET(sugar will eventually be exported transporter)family proteins are a recently identified class of sugar transporters that are essential for various physiological processes.Although the functions of the SWEET proteins have been identified in a number of species,to date,there have been no reports of the functions of the SWEET genes in woodland strawberries(Fragaria vesca).In this study,we identified 15 genes that were highly homolo-gous to the A.thaliana AtSWEET genes and designated them as FvSWEET1–FvSWEET15.We then conducted a structural and evolutionary analysis of these 15 FvSWEET genes.The phylogenetic analysis enabled us to categor-ize the predicted 15 SWEET proteins into four distinct groups.We observed slight variations in the exon‒intron structures of these genes,while the motifs and domain structures remained highly conserved.Additionally,the developmental and biological stress expression profiles of the 15 FvSWEET genes were extracted and analyzed.Finally,WGCNA coexpression network analysis was run to search for possible interacting genes of FvSWEET genes.The results showed that the FvSWEET10 genes interacted with 20 other genes,playing roles in response to bacterial and fungal infections.The outcomes of this study provide insights into the further study of FvSWEET genes and may also aid in the functional characterization of the FvSWEET genes in woodland strawberries.

Effects of sodium-dependent glucose transporter 2 inhibitors in patients with type 2 diabetes mellitus and asymptomatic heart failure

Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)have been increa-singly used with proven efficacy in patients with heart failure(HF),regardless of diabetes status.GrubićRotkvićet al recently published an observational study on SGLT2i therapy in patients with type 2 diabetes mellitus and asymptomatic HF.They found that the use of SGLT2i led to reduced cardiac load and improved cardiovascular performance,reinforcing the evolving paradigm that SGLT2i are not merely glucose-lowering agents but are integral to the broader management of cardiovascular risk in patients with type 2 diabetes mellitus.The study by GrubićRotkvićet al contributes to the growing body of literature supporting the early use of SGLT2i in patients with diabetic cardiomyopathy,offering a potential strategy to mitigate the progression of HF.Future larger studies should be con-ducted to confirm these findings,and explore the long-term cardiovascular bene-fits of SGLT2i,particularly in asymptomatic patients at risk of developing HF.

Effectiveness and mechanisms of sodium-dependent glucose transporter 2 inhibitors in type 2 diabetes and heart failure patients

We comment on an article by GrubićRotkvićet al published in the recent issue of the World Journal of Cardiology.We specifically focused on possible factors affecting the therapeutic effectiveness of sodium-dependent glucose transporter inhibitors(SGLT2i)in patients with type 2 diabetes mellitus(T2DM)and their impact on comorbidities.SGLT2i inhibits SGLT2 in the proximal tubules of the kidneys,lowering blood glucose levels by inhibiting glucose reabsorption by the kidneys and causing excess glucose to be excreted in the urine.Previous studies have demonstrated a role of SGLT2i in cardiovascular function in patients with diabetes who take metformin but still have poor glycemic control.In addition,SGLT2i has been shown to be effective in anti-apoptosis,weight loss,and cardiovascular protection.Accordingly,it is feasible to treat patients with T2DM with cardiovascular or renal diseases using SGLT2i.

Smart Cellulose‑Based Janus Fabrics with Switchable Liquid Transportation for Personal Moisture and Thermal Management

The Janus fabrics designed for personal moisture/thermal regulation have garnered significant attention for their potential to enhance human comfort.However,the development of smart and dynamic fabrics capable of managing personal moisture/thermal comfort in response to changing external environments remains a challenge.Herein,a smart cellulose-based Janus fabric was designed to dynamically manage personal moisture/heat.The cotton fabric was grafted with N-isopropylacrylamide to construct a temperature-stimulated transport channel.Subsequently,hydrophobic ethyl cellulose and hydrophilic cellulose nanofiber were sprayed on the bottom and top sides of the fabric to obtain wettability gradient.The fabric exhibits anti-gravity directional liquid transportation from hydrophobic side to hydrophilic side,and can dynamically and continuously control the transportation time in a wide range of 3–66 s as the temperature increases from 10 to 40℃.This smart fabric can quickly dissipate heat at high temperatures,while at low temperatures,it can slow down the heat dissipation rate and prevent the human from becoming too cold.In addition,the fabric has UV shielding and photodynamic antibacterial properties through depositing graphitic carbon nitride nanosheets on the hydrophilic side.This smart fabric offers an innovative approach to maximizing personal comfort in environments with significant temperature variations.

Overexpression of Proline Transporter Gene Isolated from Halophyte Confers Salt Tolerance in Arabidopsis

Proline is one of the most important and widespread osmolyte which functions in adaptation to adverse environmental stresses in many organisms. Also it is an important carbon and nitrogen resource in higher plants. Metabolism of proline has been elucidated in many plant species. However, transport of proline was poorly characterized although transport system plays an important role in proline distribution in different tissues. We isolated one full_length cDNA encoding proline transporter from the typical halophyte: Atriplex hortensis L. through cDNA library screening and 5′_RACE. The deduced amino acid sequence had eleven transmembrane domains, showed 60%-69% similarities to other ProTs and the gene was designated AhProT1. In the phylogenetic tree, higher plants' ProTs, e.g. AhProT1, showed more similar to ProP from microorganisms than ProT from mammalians. AhProT1 gene was transformed into Arabidopsis thaliana under 35S promoter. In MS medium containing [U_ 14 C] proline, AhProT1 + plants were able to accumulate much more radiolabeled proline in the roots than control plants. In MS medium containing different concentrations of NaCl, AhProT1 + plants could endure 200 mmol/L NaCl and keep development and biomass increase with proline supply, whereas control plants died back at 150 mmol/L NaCl.

The Effect of Thoracic Operation on Glucose Transporter-4 mRNA Expression by Preoperative Infusion of Glucose

Objective: To investigate the changes in glucose transporter-4(Glut-4) mRNA expression in skeletal muscle before and after the thoracic operation and to observe the changes in Glut-4 mRNA expression by preoperative infusion of glucose. Methods: Twelve cases of elective thoracic operation were randomly divided into two groups, namely ordinary group Ⅰ and glucose infusion group Ⅱ. One gram of intercostal muscle was taken while thorax being opened and closed from patients under general anesthesia. Total RNA of the muscle cells was extracted by TRIzol one-step assay. Reverse transcription-competitive polymerase chain reaction (RT-PCR) was used to determine the Glut-4 mRNA amplification products with β-actin mRNA as an internal control. The Glut-4 mRNA expression was expressed by targeted gene /β-actin ×100%. The plasma glucose and insulin levels were determined at the same time.Results: Glut-4 mRNA expression was significantly reduced(P<0.05) and plasma glucose level increased (P<0.05), while thorax was being closed as compared with those while being opened. However, Glut-4 mRNA expression in glucose infusion group Ⅱ was significantly higher than ordinary group Ⅰ (P<0.01) and plasma glucose level in group Ⅱ was lower than group Ⅰ(P<0.05) when thorax was being closed. Conclusion: The results indicate that the synthesis of Glut-4 is suppressed by the surgical stress of thoracic operation under general anesthesia. We found that preoperative infusion glucose can increase Glut-4 mRNA expression at the same surgical stress and relieve postoperative insulin resistance.

Bioinformatics Analysis of Zinc Transporter from Baoding Alfalfa

[Objective] This study aimed to perform the bioinformatics analysis of Zinc transporter （ZnT） from Baoding Alfalfa. [Method] Based on the amino acid sequence, the physical and chemical properties, hydrophilicity/hydrophobicity, secondary structure of ZnT from Baoding alfalfa were predicted by a series of bioinformatics software. And the transmembrane domains were predicted by using different online tools. [Result] ZnT is a hydrophobic protein containing 408 amino acids with the theoretical pl of 5.94, and it has 7 potential transmembrane hydrophobic regions. In the sec- ondary structure, co-helix （Hh） accounted for 48.04%, extended strand （Ee） for 9.56%, random coil （Cc） for 42.40%, which was accored with the characteristic of transmembrane protein. [Conclusion] mZnT is a member of CDF family, responsible for transporting Zn^2＋ out of the cell membrane to reduce the concentration and toxicity of Zn^2＋.

Novel understanding of ABC transporters ABCB1/MDR/P-glycoprotein, ABCC2/MRP2, and ABCG2/BCRP in colorectal pathophysiology

AIM: To evaluate ATP-binding cassette(ABC) transporters in colonic pathophysiology as they had recently been related to colorectal cancer(CRC) development. METHODS: Literature search was conducted on Pub Med using combinations of the following terms: ABC transporters, ATP binding cassette transporter proteins, inflammatory bowel disease, ulcerative, colitis, Crohns disease, colorectal cancer, colitis, intestinal inflammation, intestinal carcinogenesis, ABCB1/P-glycoprotein(P-gp/CD243/MDR1), ABCC2/multidrug resistance protein 2(MRP2) and ABCG2/breast cancer resistance protein(BCRP), Abcb1/Mdr1 a, abcc2/Mrp2, abcg2/Bcrp, knock-out mice, tight junction, membrane lipid function. RESULTS: Recently, human studies reported thatchanges in the levels of ABC transporters were early events in the adenoma-carcinoma sequence leading to CRC. A link between ABCB1, high fat diet and gut microbes in relation to colitis was suggested by the animal studies. The finding that colitis was preceded by altered gut bacterial composition suggests that deletion of Abcb1 leads to fundamental changes of hostmicrobiota interaction. Also, high fat diet increases the frequency and severity of colitis in specific pathogenfree Abcb1 KO mice. The Abcb1 KO mice might thus serve as a model in which diet/environmental factors and microbes may be controlled and investigated in relation to intestinal inflammation. Potential molecular mechanisms include defective transport of inflammatory mediators and/or phospholipid translocation from one side to the other of the cell membrane lipid bilayer by ABC transporters affecting inflammatory response and/or function of tight junctions, phagocytosis and vesicle trafficking. Also, diet and microbes give rise to molecules which are potential substrates for the ABC transporters and which may additionally affect ABC transporter function through nuclear receptors and transcriptional regulation. Another critical role of ABCB1 was suggested by the finding that ABCB1 expression identifies a subpopulation of pro-inflammatory Th17 cells which were resistant to treatment with glucocorticoids. The evidence for the involvement of ABCC2 and ABCG2 in colonic pathophysiology was weak. CONCLUSION: ABCB1, diet, and gut microbes mutually interact in colonic inflammation, a well-known risk factor for CRC. Further insight may be translated into preventive and treatment strategies.

Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders

Glutamate is the predominant excitatory neurotransmitter in the human brain and it has been shown that prolonged activation of the glutamatergic system leads to nerve damage and cell death. Following release from the pre-synaptic neuron and synaptic transmission, glutamate is either taken up into the presynaptic neuron or neighbouring glia by transmembrane glutamate transporters. Excitatory amino acid transporter(EAAT) 1 and EAAT2 are Na+-dependant glutamate transporters expressed predominantly in glia cells of the central nervous system. As the most abundant glutamate transporters, their primary role is to modulate levels of glutamatergic excitability and prevent spill over of glutamate beyond the synapse. This role is facilitated through the binding and transportation of glutamate into astrocytes and microglia. The function of EAAT1 and EAAT2 is heavily regulated at the levels of gene expression, post-transcriptional splicing, glycosylation states and cell-surface trafficking of the protein. Both glutamatergic dysfunction and glial dysfunction have been proposed to be involved in psychiatric disorder. This review will present an overview of the roles that EAAT1 and EAAT2 play in modulating glutamatergic activity in the human brain, and mount an argument that these two transporters could be involved in the aetiologies of schizophrenia and affective disorders as well as represent potential drug targets for novel therapies for those disorders.

Role of copper transporters in platinum resistance

Platinum(Pt)-based antitumor agents are effective in the treatment of many solid malignancies. However, their efficacy is limited by toxicity and drug resistance. Reduced intracellular Pt accumulation has been consistently shown to correlate with resistance in tumors. Proteins involved in copper homeostasis have been identified as Pt transporters. In particular, copper transporter receptor 1(CTR1), the major copper influx transporter, has been shown to play a significant role in Pt resistance. Clinical studies demonstrated that expression of CTR1 correlated with intratumoral Pt concentration and outcomes following Pt-based therapy. Other CTRs such as CTR2, ATP7 A and ATP7 B, may also play a role in Pt resistance. Recent clinical studies attempting to modulate CTR1 to overcome Pt resistance may provide novel strategies. This review discusses the role of CTR1 as a potential predictive biomarker of Pt sensitivity and a therapeutic target for overcoming Pt resistance.