The role of the zinc transporter SLC30A2/ZnT2 in transient neonatal zinc deficiency

Metallomics ◽  
2017 ◽  
Vol 9 (10) ◽  
pp. 1352-1366 ◽  
Author(s):  
Yarden Golan ◽  
Taiho Kambe ◽  
Yehuda G. Assaraf
Keyword(s):  
Zinc Deficiency ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Gene Mutations ◽  
Zinc Transporter ◽  
Loss Of Function ◽  
Breastfed Infants ◽  
Nursing Mothers ◽  
Novel Approaches

Transient neonatal zinc deficiency (TNZD) results from loss of function mutations in theSLC30A2/ZnT2gene. Nursing mothers harboring this defective zinc transporter produce zinc-deficient milk. Consequently, their exclusively breastfed infants develop severe zinc deficiency. The present review summarizes our current knowledge onSLC30A2/ZnT2gene mutations and highlights the molecular mechanisms underlying this zinc deficiency. We further propose novel approaches for the early diagnosis and prevention of TNZD.

Mesophyll conductance: the leaf corridors for photosynthesis

2020 ◽  
Vol 48 (2) ◽  
pp. 429-439 ◽  
Author(s):  
Jorge Gago ◽  
Danilo M. Daloso ◽  
Marc Carriquí ◽  
Miquel Nadal ◽  
Melanie Morales ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Main Role ◽  
Mesophyll Conductance ◽  
Future Studies ◽  
Cell Structures ◽  
Leaf Tissues ◽  
Change Framework ◽  
Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

scholarly journals Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 629
Author(s):  
Jorge Gutiérrez-Cuevas ◽  
Ana Sandoval-Rodriguez ◽  
Alejandra Meza-Rios ◽  
Hugo Christian Monroy-Ramírez ◽  
Marina Galicia-Moreno ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Dysfunction ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Peroxisome Proliferator ◽  
White Adipocyte ◽  
Peroxisome Proliferator Activated Receptors ◽  
And Oxidative Stress

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

scholarly journals The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1887 ◽  
Author(s):  
Francesco Bonollo ◽  
George N. Thalmann ◽  
Marianna Kruithof-de Julio ◽  
Sofia Karkampouna
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Therapy Resistance ◽  
Cancer Associated Fibroblasts ◽  
Metastatic Progression ◽  
Normal Prostate ◽  
Prostate Tumorigenesis

Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.

scholarly journals Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

2020 ◽  
Vol 9 (4) ◽  
pp. 1096
Author(s):  
Jessica Gambardella ◽  
Angela Lombardi ◽  
Marco Bruno Morelli ◽  
John Ferrara ◽  
Gaetano Santulli
Keyword(s):  
Human Disease ◽  
Calcium Release ◽  
Current Knowledge ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Genome Wide ◽  
Inositol 1,4,5 Trisphosphate ◽  
Human Disorders

Inositol 1,4,5-trisphosphate receptors (ITPRs) are intracellular calcium release channels located on the endoplasmic reticulum of virtually every cell. Herein, we are reporting an updated systematic summary of the current knowledge on the functional role of ITPRs in human disorders. Specifically, we are describing the involvement of its loss-of-function and gain-of-function mutations in the pathogenesis of neurological, immunological, cardiovascular, and neoplastic human disease. Recent results from genome-wide association studies are also discussed.

scholarly journals Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1648
Author(s):  
Daniel Liedtke ◽  
Christine Hofmann ◽  
Franz Jakob ◽  
Eva Klopocki ◽  
Stephanie Graser
Keyword(s):  
Alkaline Phosphatase ◽  
Clinical Symptoms ◽  
Current Knowledge ◽  
Systemic Disease ◽  
Loss Of Function ◽  
Inorganic Pyrophosphate ◽  
Wide Range ◽  
Mineralization Processes ◽  
Tissue Nonspecific Alkaline Phosphatase

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

scholarly journals Regulation of ST6GAL1 sialyltransferase expression in cancer cells

Glycobiology ◽  
2020 ◽  
Author(s):  
Kaitlyn A Dorsett ◽  
Michael P Marciel ◽  
Jihye Hwang ◽  
Katherine E Ankenbauer ◽  
Nikita Bhalerao ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Translational Regulation ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Sialic Acids ◽  
Invasion Resistance ◽  
Cell Behaviors ◽  
Molecular Events ◽  
Wide Range

Abstract The ST6GAL1 sialyltransferase, which adds α2–6 linked sialic acids to N-glycosylated proteins, is overexpressed in a wide range of human malignancies. Recent studies have established the importance of ST6GAL1 in promoting tumor cell behaviors such as invasion, resistance to cell stress, and chemoresistance. Furthermore, ST6GAL1 activity has been implicated in imparting cancer stem cell characteristics. However, despite the burgeoning interest in the role of ST6GAL1 in the phenotypic features of tumor cells, insufficient attention has been paid to the molecular mechanisms responsible for ST6GAL1 upregulation during neoplastic transformation. Evidence suggests that these mechanisms are multifactorial, encompassing genetic, epigenetic, transcriptional, and post-translational regulation. The purpose of this review is to summarize current knowledge regarding the molecular events that drive enriched ST6GAL1 expression in cancer cells.

scholarly journals USB1 Is a miRNA Deadenylase That Regulates Hematopoietic Development

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2191-2191
Author(s):  
Ho-Chang Jeong ◽  
Siddharth Shukla ◽  
Roy Parker ◽  
Luis Batista
Keyword(s):  
Molecular Mechanisms ◽  
Bone Marrow Failure ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Cyclic Neutropenia ◽  
Hematopoietic Development ◽  
U6 Snrna ◽  
Conditional Expression ◽  
Mutant Cells

Abstract Poikiloderma with neutropenia (PN)is an autosomal-recessive bone marrow failure (BMF) syndrome in which patients harbor homozygous or compound heterozygous mutations in the human gene C16orf57, which encodes the evolutionarily conserved RNA 3' to 5' exonuclease U6 biogenesis 1 (USB1). USB1 is required for the proper maturation of U6 and U6atac snRNAs, core components of the spliceosome, and consequently, splicing defects have been observed in yeast and zebrafish models with USB1 deficiency. However, lymphoblastoid cells from PN patients do not exhibit reduced U6 snRNA levels and have normal pre-mRNA splicing, establishing PN as a singular BMF syndrome, where the underlying genetic cause has been identified but the molecular mechanisms leading to tissue failure remain obscure. To investigate the role of USB1 in a physiological context, we utilized CRISPR/Cas9 to create human embryonic stem cells (hESCs) containing a frequently occurring c.531_del_A loss-of-function mutation in the USB1 gene (USB1_c.531_del_A hESCs). USB1_c.531_del_A hESCs have normal karyotype, normal growth rate, and retain pluripotency, indicating that clinically-relevant mutations in USB1 are not deleterious in undifferentiated hESCs. To elucidate the role of USB1 during hematopoiesis, we performed serum-free hematopoietic differentiations to derive hematopoietic progenitor cells from WT and USB1_c.531_del_A hESCs. The formation of definitive hematopoietic progenitors (CD45+) was decreased in USB1 mutant cells compared to WT cells, and definitive colony potential analysis showed compromised colony formation in USB1 mutants. These observations indicate that loss-of-function mutations in USB1 negatively influence hematopoiesis. Additionally, as PN is associated with severe non-cyclic neutropenia, we analyzed the potential of neutrophil formation in WT and USB1 mutant cells. USB1 mutants have reduced formation of CD15+/CD66b+ lineages, indicating abnormal neutrophil development. Conditional expression of WT USB1 in USB1_c.531_del_A mutant cells rescued these phenotypes, leading to normal hematopoietic development. Interestingly, USB1 mutants showed no reduction in the overall levels of U6 and U6atac snRNAs, similar to what was observed in patient cells. To identify other possible targets of USB1, we sequenced the transcriptome and miRome of WT and USB1 mutant cells in different stages of hematopoietic development. Through these analyses, we demonstrate that hematopoietic failure in USB1 mutants is caused by dysregulated miRNA levels during blood development, due to a failure to remove destabilizing 3' end oligo(A) tails added by PAPD5/7. Moreover, we demonstrate that modulation of oligoadenylation through genetic or chemical inhibition of PAPD5/7 rescues the defective hematopoiesis observed in USB1 mutants. This work indicates USB1 acts as a miRNA deadenylase and suggests PAPD5/7 inhibition as a potential therapy for PN. Disclosures Parker: Faze Therapeutics: Other: Co-founder.

scholarly journals Silencing of SPARC represses heterotopic ossification via inhibition of the MAPK signaling pathway

2019 ◽  
Vol 39 (11) ◽  
Author(s):  
Qianjun Wang ◽  
Qianqian Yang ◽  
Ali Zhang ◽  
Zhiqiang Kang ◽  
Yingsheng Wang ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Loss Of Function ◽  
Alp Activity ◽  
Mechanistic Investigation

Abstract Heterotopic ossification (HO), the pathologic formation of extraskeletal bone, can be disabling and lethal. However, the underlying molecular mechanisms were largely unknown. The present study aimed to clarify the involvement of secreted protein acidic and rich in cysteine (SPARC) and the underlying mechanism in rat model of HO. The mechanistic investigation on roles of SPARC in HO was examined through gain- and loss-of-function approaches of SPARC, with alkaline-phosphatase (ALP) activity, mineralized nodules, and osteocalcin (OCN) content measured. To further confirm the regulatory role of SPARC, levels of mitogen-activated protein kinase (MAPK) signaling pathways-related proteins (extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), p38, nuclear factor κ-B (NF-κB), and IkB kinase β (IKKβ)) were determined. Bone marrow mesenchymal stem cells were treated with pathway inhibitor to investigate the relationship among SPARC, MAPK signaling pathway, and HO. The results suggested that SPARC expression was up-regulated in Achilles tendon tissues of HO rats. Silencing of SPARC could decrease phosphorylation of ERK, JNK, p38, NF-κB, and IKKβ. Additionally, silencing of SPARC or inhibition of MAPK signaling pathway could reduce the ALP activity, the number of mineralized nodules, and OCN content, thus impeding HO. To sum up, our study identifies the inhibitory role of SPARC gene silencing in HO via the MAPK signaling pathway, suggesting SPARC presents a potential target for HO therapy.

scholarly journals L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Marco Giordano ◽  
Alessandra Decio ◽  
Chiara Battistini ◽  
Micol Baronio ◽  
Fabrizio Bianchi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Genetic Manipulation ◽  
Tumor Formation ◽  
In Vitro Assays ◽  
Tumor Initiation ◽  
Loss Of Function ◽  
Stat3 Signaling

Abstract Background Cancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive. Methods The expression of L1CAM was investigated in patient-derived OCSC. The genetic manipulation of L1CAM in OC cells provided gain and loss-of-function models that were then employed in cell biological assays as well as in vivo tumorigenesis experiments to assess the role of L1CAM in OC cell stemness and in OCSC-driven tumor initiation. We applied antibody-mediated neutralization to investigate L1CAM druggability. Biochemical approaches were then combined with functional in vitro assays to study the molecular mechanisms underlying the functional role of L1CAM in OCSC. Results We report that L1CAM is upregulated in patient-derived OCSC. Functional studies showed that L1CAM promotes several stemness-related properties in OC cells, including sphere formation, tumor initiation and chemoresistance. These activities were repressed by an L1CAM-neutralizing antibody, pointing to L1CAM as a druggable target. Mechanistically, L1CAM interacted with and activated fibroblast growth factor receptor-1 (FGFR1), which in turn induced the SRC-mediated activation of STAT3. The inhibition of STAT3 prevented L1CAM-dependent OC stemness and tumor initiation. Conclusions Our study implicate L1CAM in the tumorigenic function of OCSC and point to the L1CAM/FGFR1/SRC/STAT3 signaling pathway as a novel driver of OC stemness. We also provide evidence that targeting this pathway can contribute to OC eradication.

scholarly journals An auxin signaling network translates low-sugar-state input into compensated cell enlargement in the fugu5 cotyledon

PLoS Genetics ◽  
2021 ◽  
Vol 17 (8) ◽  
pp. e1009674
Author(s):  
Hiromitsu Tabeta ◽  
Shunsuke Watanabe ◽  
Keita Fukuda ◽  
Shizuka Gunji ◽  
Mariko Asaoka ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Molecular Mechanisms ◽  
Genetic Interaction ◽  
Mitotic Cell ◽  
Fine Tuning ◽  
Auxin Signaling ◽  
Cell Enlargement ◽  
Loss Of Function ◽  
Nutrient Reserves

In plants, the effective mobilization of seed nutrient reserves is crucial during germination and for seedling establishment. The Arabidopsis H+-PPase-loss-of-function fugu5 mutants exhibit a reduced number of cells in the cotyledons. This leads to enhanced post-mitotic cell expansion, also known as compensated cell enlargement (CCE). While decreased cell numbers have been ascribed to reduced gluconeogenesis from triacylglycerol, the molecular mechanisms underlying CCE remain ill-known. Given the role of indole 3-butyric acid (IBA) in cotyledon development, and because CCE in fugu5 is specifically and completely cancelled by ech2, which shows defective IBA-to-indoleacetic acid (IAA) conversion, IBA has emerged as a potential regulator of CCE. Here, to further illuminate the regulatory role of IBA in CCE, we used a series of high-order mutants that harbored a specific defect in IBA-to-IAA conversion, IBA efflux, IAA signaling, or vacuolar type H+-ATPase (V-ATPase) activity and analyzed the genetic interaction with fugu5–1. We found that while CCE in fugu5 was promoted by IBA, defects in IBA-to-IAA conversion, IAA response, or the V-ATPase activity alone cancelled CCE. Consistently, endogenous IAA in fugu5 reached a level 2.2-fold higher than the WT in 1-week-old seedlings. Finally, the above findings were validated in icl–2, mls–2, pck1–2 and ibr10 mutants, in which CCE was triggered by low sugar contents. This provides a scenario in which following seed germination, the low-sugar-state triggers IAA synthesis, leading to CCE through the activation of the V-ATPase. These findings illustrate how fine-tuning cell and organ size regulation depend on interplays between metabolism and IAA levels in plants.

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