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1.
Aquaporins and cation transporters are differentially regulated by two arbuscular mycorrhizal fungi strains in lettuce cultivars growing under salinity conditions.
Santander, C, Aroca, R, Cartes, P, Vidal, G, Cornejo, P
Plant physiology and biochemistry : PPB. 2021;:396-409
Abstract
The aim was to identify the effects of AM symbiosis on the expression patterns of genes associated with K+ and Na+ compartmentalization and translocation and on K+/Na+ homeostasis in some lettuce (Lactuca sativa) cultivars as well as the effects of the relative abundance of plant AQPs on plant water status. Two AM fungi species (Funneliformis mosseae and Claroideoglomus lamellosum) isolated from the hyper-arid Atacama Desert (northern Chile) were inoculated to two lettuce cultivars (Grand Rapids and Lollo Bionda), and watered with 0 and 60 mM NaCl. At 60 days of plant growth, the AM symbiotic development, biomass production, nutrient content (Pi, Na+, K+), physiological parameters, gene expressions of ion channels and transporters (NHX and HKT1), and aquaporins proteins abundance (phosphorylated and non-phosphorylated) were evaluated. Salinity increased the AM root colonization by both inocula. AM lettuce plants showed an improved growth, increased relative water content and improved of K/Na ratio in root. In Grand Rapids cultivar, the high efficiency of photosystem II was higher than Lollo Bionda cultivar; on the contrary, stomatal conductance was higher in Lollo Bionda. Nevertheless, both parameters were increased by AM colonization. In the same way, LsaHKT1;1, LsaHKT1;6, LsaNHX2, LsaNHX4, LsaNHX6 and LsaNHX8 genes and aquaporins PIP2 were up-regulated differentially by both AM fungi. The improved plant growth was closely related to a higher water status due to increased PIP2 abundance, as well as to the upregulation of LsaNHX gene expression, which concomitantly improved plant nutrition and K+/Na+ homeostasis maintenance.
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2.
Formation of the Metal-Binding Core of the ZRT/IRT-like Protein (ZIP) Family Zinc Transporter.
Sharma, G, Merz, KM
Biochemistry. 2021;(36):2727-2738
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Abstract
Zinc homeostasis in mammals is constantly and precisely maintained by sophisticated regulatory proteins. Among them, the Zrt/Irt-like protein (ZIP) regulates the influx of zinc into the cytoplasm. In this work, we have employed all-atom molecular dynamics simulations to investigate the Zn2+ transport mechanism in prokaryotic ZIP obtained from Bordetella bronchiseptica (BbZIP) in a membrane bilayer. Additionally, the structural and dynamical transformations of BbZIP during this process have been analyzed. This study allowed us to develop a hypothesis for the zinc influx mechanism and formation of the metal-binding site. We have created a model for the outward-facing form of BbZIP (experimentally only the inward-facing form has been characterized) that has allowed us, for the first time, to observe the Zn2+ ion entering the channel and binding to the negatively charged M2 site. It is thought that the M2 site is less favored than the M1 site, which then leads to metal ion egress; however, we have not observed the M1 site being occupied in our simulations. Furthermore, removing both Zn2+ ions from this complex resulted in the collapse of the metal-binding site, illustrating the "structural role" of metal ions in maintaining the binding site and holding the proteins together. Finally, due to the long Cd2+-residue bond distances observed in the X-ray structures, we have proposed the existence of an H3O+ ion at the M2 site that plays an important role in protein stability in the absence of the metal ion.
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Alcohol Consumption Is Associated with Poor Prognosis in Obese Patients with COVID-19: A Mendelian Randomization Study Using UK Biobank.
Fan, X, Liu, Z, Poulsen, KL, Wu, X, Miyata, T, Dasarathy, S, Rotroff, DM, Nagy, LE
Nutrients. 2021;(5)
Abstract
BACKGROUND Acute and chronic alcohol abuse has adverse impacts on both the innate and adaptive immune response, which may result in reduced resistance to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and promote the progression of coronavirus disease 2019 (COVID-19). However, there are no large population-based data evaluating potential causal associations between alcohol consumption and COVID-19. METHODS We conducted a Mendelian randomization study using data from UK Biobank to explore the association between alcohol consumption and risk of SARS-CoV-2 infection and serious clinical outcomes in patients with COVID-19. A total of 12,937 participants aged 50-83 who tested for SARS-CoV-2 between 16 March to 27 July 2020 (12.1% tested positive) were included in the analysis. The exposure factor was alcohol consumption. Main outcomes were SARS-CoV-2 positivity and death in COVID-19 patients. We generated allele scores using three genetic variants (rs1229984 (Alcohol Dehydrogenase 1B, ADH1B), rs1260326 (Glucokinase Regulator, GCKR), and rs13107325 (Solute Carrier Family 39 Member 8, SLC39A8)) and applied the allele scores as the instrumental variables to assess the effect of alcohol consumption on outcomes. Analyses were conducted separately for white participants with and without obesity. RESULTS Of the 12,937 participants, 4496 were never or infrequent drinkers and 8441 were frequent drinkers. Both logistic regression and Mendelian randomization analyses found no evidence that alcohol consumption was associated with risk of SARS-CoV-2 infection in participants either with or without obesity (All q > 0.10). However, frequent drinking, especially heavy drinking (HR = 2.07, 95%CI 1.24-3.47; q = 0.054), was associated with higher risk of death in patients with obesity and COVID-19, but not in patients without obesity. Notably, the risk of death in frequent drinkers with obesity increased slightly with the average amount of alcohol consumed weekly (All q < 0.10). CONCLUSIONS Our findings suggest that alcohol consumption has adverse effects on the progression of COVID-19 in white participants with obesity, but was not associated with susceptibility to SARS-CoV-2 infection.
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4.
Biology of the iron efflux transporter, ferroportin.
Rishi, G, Subramaniam, VN
Advances in protein chemistry and structural biology. 2021;:1-16
Abstract
Iron, the most common metal in the earth, is also an essential component for almost all living organisms. While these organisms require iron for many biological processes, too much or too little iron itself poses many issues; this is most easily recognized in human beings. The control of body iron levels is thus an important metabolic process which is regulated essentially by controlling the expression, activity and levels of the iron transporter ferroportin. Ferroportin is the only known iron exporter. The function and activity of ferroportin is influenced by its interaction with the iron-regulatory peptide hepcidin, which itself is regulated by many factors. Here we review the current state of understanding of the mechanisms that regulate ferroportin and its function.
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Analysis of the relationship between the mutation site of the SLC39A4 gene and acrodermatitis enteropathica by reporting a rare Chinese twin: a case report and review of the literature.
Zhong, W, Yang, C, Zhu, L, Huang, YQ, Chen, YF
BMC pediatrics. 2020;(1):34
Abstract
BACKGROUND Acrodermatitis enteropathica (AE) is a rare autosomal recessive hereditary skin disease caused by mutations in the SLC39A4 gene and is characterized by periorificial dermatitis, alopecia and diarrhoea due to insufficient zinc absorption. Only one of the three known sets of twins with AE has genetic information. This case reports the discovery of new mutation sites in rare twin patients and draws some interesting conclusions by analysing the relationship between genetic information and clinical manifestations. CASE PRESENTATION Here, we report a pair of 16-month-old twin boys with AE exhibiting periorificial and acral erythema, scales and blisters, while subsequent laboratory examination showed normal plasma zinc and alkaline phosphatase levels. Further Sanger sequencing demonstrated that the patients were compound heterozygous for two unreported SLC39A4 mutations: a missense mutation in exon 5 (c.926G > T), which led to a substitution of the 309th amino acid residue cysteine with phenylalanine, a splice site mutation occurring in the consensus donor site of intron 5 (c.976 + 2 T > A). A family study revealed that the boys' parents were heterozygous carriers of these two mutations. CONCLUSION We identified a new compound heterozygous mutation in Chinese twins with AE, which consisted of two previous unreported variants in exon 5 and intron 5 of SLC39A4. We propose an up-to-date review that different mutations in SLC39A4 may exhibit different AE manifestations. In conjunction with future research, our work may shed light on genotype-phenotype correlations in AE patients and provide knowledge for genetic counselling and treatment for AE patients.
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Na+ transporter HKT1;2 reduces flower Na+ content and considerably mitigates the decline in tomato fruit yields under saline conditions.
Romero-Aranda, MR, González-Fernández, P, Pérez-Tienda, JR, López-Diaz, MR, Espinosa, J, Granum, E, Traverso, JÁ, Pineda, B, Garcia-Sogo, B, Moreno, V, et al
Plant physiology and biochemistry : PPB. 2020;:341-352
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Abstract
Genes encoding HKT1-like Na+ transporters play a key role in the salinity tolerance mechanism in Arabidopsis and other plant species by retrieving Na+ from the xylem of different organs and tissues. In this study, we investigated the role of two HKT1;2 allelic variants in tomato salt tolerance in relation to vegetative growth and fruit yield in plants subjected to salt treatment in a commercial greenhouse under real production conditions. We used two near-isogenic lines (NILs), homozygous for either the Solanum lycopersicum (NIL17) or S. cheesmaniae (NIL14) allele, at HKT1;2 loci and their respective RNAi-Sl/ScHKT1;2 lines. The results obtained show that both ScHKT1;2- and SlHKT1;2-silenced lines display hypersensitivity to salinity associated with an altered leaf Na+/K+ ratio, thus confirming that HKT1;2 plays an important role in Na+ homeostasis and salinity tolerance in tomato. Both silenced lines also showed Na+ over-accumulation and a slight, but significant, reduction in K+ content in the flower tissues of salt-treated plants and consequently a higher Na+/K+ ratio as compared to the respective unsilenced lines. This altered Na+/K+ ratio in flower tissues is associated with a sharp reduction in fruit yield, measured as total fresh weight and number of fruits, in both silenced lines under salinity conditions. Our findings demonstrate that Na+ transporter HKT1;2 protects the flower against Na+ toxicity and mitigates the reduction in tomato fruit yield under salinity conditions.
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Targeting the Zinc Transporter ZIP7 in the Treatment of Insulin Resistance and Type 2 Diabetes.
Adulcikas, J, Sonda, S, Norouzi, S, Sohal, SS, Myers, S
Nutrients. 2019;(2)
Abstract
Type 2 diabetes mellitus (T2DM) is a disease associated with dysfunctional metabolic processes that lead to abnormally high levels of blood glucose. Preceding the development of T2DM is insulin resistance (IR), a disorder associated with suppressed or delayed responses to insulin. The effects of this response are predominately mediated through aberrant cell signalling processes and compromised glucose uptake into peripheral tissue including adipose, liver and skeletal muscle. Moreover, a major factor considered to be the cause of IR is endoplasmic reticulum (ER) stress. This subcellular organelle plays a pivotal role in protein folding and processes that increase ER stress, leads to maladaptive responses that result in cell death. Recently, zinc and the proteins that transport this metal ion have been implicated in the ER stress response. Specifically, the ER-specific zinc transporter ZIP7, coined the "gate-keeper" of zinc release from the ER into the cytosol, was shown to be essential for maintaining ER homeostasis in intestinal epithelium and myeloid leukaemia cells. Moreover, ZIP7 controls essential cell signalling pathways similar to insulin and activates glucose uptake in skeletal muscle. Accordingly, ZIP7 may be essential for the control of ER localized zinc and mechanisms that disrupt this process may lead to ER-stress and contribute to IR. Accordingly, understanding the mechanisms of ZIP7 action in the context of IR may provide opportunities to develop novel therapeutic options to target this transporter in the treatment of IR and subsequent T2DM.
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New Insights into the Hepcidin-Ferroportin Axis and Iron Homeostasis in iPSC-Derived Cardiomyocytes from Friedreich's Ataxia Patient.
Bolotta, A, Abruzzo, PM, Baldassarro, VA, Ghezzo, A, Scotlandi, K, Marini, M, Zucchini, C
Oxidative medicine and cellular longevity. 2019;:7623023
Abstract
Iron homeostasis in the cardiac tissue as well as the involvement of the hepcidin-ferroportin (HAMP-FPN) axis in this process and in cardiac functionality are not fully understood. Imbalance of iron homeostasis occurs in several cardiac diseases, including iron-overload cardiomyopathies such as Friedreich's ataxia (FRDA, OMIM no. 229300), a hereditary neurodegenerative disorder. Exploiting the induced pluripotent stem cells (iPSCs) technology and the iPSC capacity to differentiate into specific cell types, we derived cardiomyocytes of a FRDA patient and of a healthy control subject in order to study the cardiac iron homeostasis and the HAMP-FPN axis. Both CTR and FRDA iPSCs-derived cardiomyocytes express cardiac differentiation markers; in addition, FRDA cardiomyocytes maintain the FRDA-like phenotype. We found that FRDA cardiomyocytes show an increase in the protein expression of HAMP and FPN. Moreover, immunofluorescence analysis revealed for the first time an unexpected nuclear localization of FPN in both CTR and FRDA cardiomyocytes. However, the amount of the nuclear FPN was less in FRDA cardiomyocytes than in controls. These and other data suggest that iron handling and the HAMP-FPN axis regulation in FRDA cardiac cells are hampered and that FPN may have new, still not fully understood, functions. These findings underline the complexity of the cardiac iron homeostasis.
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9.
Genetic Disorders of Manganese Metabolism.
Anagianni, S, Tuschl, K
Current neurology and neuroscience reports. 2019;(6):33
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Abstract
PURPOSE OF REVIEW This article provides an overview of the pathogenesis, clinical presentation and treatment of inherited manganese transporter defects. RECENT FINDINGS Identification of a new group of manganese transportopathies has greatly advanced our understanding of how manganese homeostasis is regulated in vivo. While the manganese efflux transporter SLC30A10 and the uptake transporter SLC39A14 work synergistically to reduce the manganese load, SLC39A8 has an opposing function facilitating manganese uptake into the organism. Bi-allelic mutations in any of these transporter proteins disrupt the manganese equilibrium and lead to neurological disease: Hypermanganesaemia with dystonia 1 (SLC30A10 deficiency) and hypermanganesaemia with dystonia 2 (SLC39A14 deficiency) are characterised by manganese neurotoxicity while SLC39A8 mutations cause a congenital disorder of glycosylation type IIn due to Mn deficiency. Inherited manganese transporter defects are an important differential diagnosis of paediatric movement disorders. Manganese blood levels and MRI brain are diagnostic and allow early diagnosis to avoid treatment delay.
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10.
Molecular identification of the magnesium transport gene family in Brassica napus.
Zhang, L, Wen, A, Wu, X, Pan, X, Wu, N, Chen, X, Chen, Y, Mao, D, Chen, L, Luan, S
Plant physiology and biochemistry : PPB. 2019;:204-214
Abstract
Magnesium (Mg2+) is an essential element for plant growth. Its transport and homeostasis in plants is mainly maintained by the MRS2/MGT of Mg2+ transporters. Little is known about the MRS2/MGT gene family in Brassica napus L. (B. napus), one of the most important oil grains. In our present study, we identified 36 putative MRS2/MGT genes (BnMGTs) from B. napus and investigated their phylogeny, expression pattern and function. These BnMGT genes were sorted into five distinguished groups by the phylogenetic analysis, and they were clearly homologous with the MRS2/MGT genes in Arabidopsis and rice. Complementation assays using the Salmonella typhimurium mutant MM281 demonstrated that the BnMGT genes were capable of mediating Mg2+ uptake and transport, with varied affinities to Mg2+. The expression pattern analysis showed that the expression of BnMGTs were tissue-specific and varied in different tissues. This work provides the molecular basis to discover the function of BnMGT gene family in plant growth and development.