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Search Results (1,051)

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Keywords = calcium homeostasis

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16 pages, 721 KiB  
Review
Mechanisms and Countermeasures for Muscle Atrophy in Microgravity
by Yizhou Liu, Xiaojian Cao, Qiuzhi Zhou, Chunchu Deng, Yujie Yang, Danxia Huang, Hongmei Luo, Song Zhang, Yajie Li, Jia Xu and Hong Chen
Cells 2024, 13(24), 2120; https://doi.org/10.3390/cells13242120 (registering DOI) - 20 Dec 2024
Viewed by 228
Abstract
Previous studies have revealed that muscle atrophy emerges as a significant challenge faced by astronauts during prolonged missions in space. A loss in muscle mass results in a weakening of skeletal muscle strength and function, which will not only contribute to a decline [...] Read more.
Previous studies have revealed that muscle atrophy emerges as a significant challenge faced by astronauts during prolonged missions in space. A loss in muscle mass results in a weakening of skeletal muscle strength and function, which will not only contribute to a decline in overall physical performance but also elevate the risk of various age-related diseases. Skeletal muscle atrophy in the microgravity environment is thought to be associated with changes in energy metabolism, protein metabolism, calcium ion homeostasis, myostatin levels, and apoptosis. Modulating some pathways could be a promising approach to mitigating muscle atrophy in the microgravity environment. This review serves as a comprehensive summary of research on the impact of microgravity on skeletal muscle, with the aim of providing insights into its pathogenesis and the development of effective treatments. Full article
13 pages, 724 KiB  
Article
Uric Acid Correlates with Serum Levels of Mineral Bone Metabolism and Inflammation Biomarkers in Patients with Stage 3a–5 Chronic Kidney Disease
by Francisco Mendoza Carrera, Gloria Elizabeth Vázquez Rivera, Caridad A. Leal Cortés, Lourdes del Carmen Rizo De la Torre, Renato Parra Michel, Rosalba Orozco Sandoval and Mariana Pérez Coria
Medicina 2024, 60(12), 2081; https://doi.org/10.3390/medicina60122081 - 19 Dec 2024
Viewed by 323
Abstract
Background and Objectives: Uric acid (UA) and the markers of mineral bone metabolism and inflammation are commonly altered in patients with chronic kidney disease (CKD) and are associated with the risk of cardiovascular complications and death. Studies point to a link between [...] Read more.
Background and Objectives: Uric acid (UA) and the markers of mineral bone metabolism and inflammation are commonly altered in patients with chronic kidney disease (CKD) and are associated with the risk of cardiovascular complications and death. Studies point to a link between high serum UA and mineral bone homeostasis and inflammation, but controversy remains. The aim of this study was to evaluate the relationship between UA levels and mineral bone metabolism and inflammation biomarkers in a sample of Mexican patients with CKD 3a–5. Materials and Methods: This cross-sectional study included 146 Mexican patients with CKD 3a–5. In addition, 25 healthy subjects were included in the study with the aim of generating reference data for comparisons. Metabolic parameters including UA serum concentrations, mineral bone metabolism (parathormone (PTH), fibroblast growth factor 23 (FGF23), calcium, and phosphate), and inflammation (interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α)) biomarkers were measured in all of the samples and compared as a function of the estimated glomerular function rate (eGFR) or UA levels. Results: Intact PTH, FGF23, and cytokines were higher in advanced CKD stages. Patients with hyperuricemia had significantly higher values of FGF23 and TNF-α compared with those without hyperuricemia. The eGFR was found to be significantly and negatively correlated with all markers. Uric acid was significantly correlated with phosphate, iPTH, FGF23, and TNF-α, whereas iPTH was significantly correlated with FGF23, TNF-α, and FGF23. Finally, a multivariate analysis confirmed the relationship of eGFR with all the tested biomarkers, as well as other relationships of iPTH with UA and TNF-α and of FGF23 with UA and TNF-α. Conclusions: This study supports the relationship between uric acid and levels of mineral bone metabolism and inflammation biomarkers in patients with CKD at middle to advanced stages. In the follow-up of patients with CKD, monitoring and controlling UA levels through nutritional or pharmacological interventions could help in the prevention of alterations related to mineral bone metabolism. Full article
(This article belongs to the Section Urology & Nephrology)
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<p>Serum concentrations of uric acid, mineral bone metabolism, and inflammation biomarkers according to the CKD stage. The <span class="html-italic">p-</span>values are obtained from ANOVA or Kruskal–Wallis tests, as appropriate. Abbreviations: HS: healthy subjects; iPTH, intact parathyroid hormone; FGF23, fibroblast growth factor 23; IL, interleukin; TNF, tumor necrosis factor.</p>
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15 pages, 1300 KiB  
Review
Endoplasmic Reticulum Calcium Signaling in Hippocampal Neurons
by Vyacheslav M. Shkryl
Biomolecules 2024, 14(12), 1617; https://doi.org/10.3390/biom14121617 - 18 Dec 2024
Viewed by 331
Abstract
The endoplasmic reticulum (ER) is a key organelle in cellular homeostasis, regulating calcium levels and coordinating protein synthesis and folding. In neurons, the ER forms interconnected sheets and tubules that facilitate the propagation of calcium-based signals. Calcium plays a central role in the [...] Read more.
The endoplasmic reticulum (ER) is a key organelle in cellular homeostasis, regulating calcium levels and coordinating protein synthesis and folding. In neurons, the ER forms interconnected sheets and tubules that facilitate the propagation of calcium-based signals. Calcium plays a central role in the modulation and regulation of numerous functions in excitable cells. It is a versatile signaling molecule that influences neurotransmitter release, muscle contraction, gene expression, and cell survival. This review focuses on the intricate dynamics of calcium signaling in hippocampal neurons, with particular emphasis on the activation of voltage-gated and ionotropic glutamate receptors in the plasma membrane and ryanodine and inositol 1,4,5-trisphosphate receptors in the ER. These channels and receptors are involved in the generation and transmission of electrical signals and the modulation of calcium concentrations within the neuronal network. By analyzing calcium fluctuations in neurons and the associated calcium handling mechanisms at the ER, mitochondria, endo-lysosome and cytosol, we can gain a deeper understanding of the mechanistic pathways underlying neuronal interactions and information transfer. Full article
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<p>Key channels and receptors involved in Ca<sup>2+</sup> signaling in hippocampal neurons. The plasma membrane contains voltage-gated Ca<sup>2+</sup> calcium channels (VGCC) and ionotropic glutamate receptors (N-methyl-D-aspartate, NMDA, or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA receptors), and loss of Ca<sup>2+</sup> from the ER also activates STIM1, which then binds to Orai1 at ER-PM junctions to initiate store-operated Ca<sup>2+</sup> entry (SOCE), which allow Ca<sup>2+</sup> entry into neuronal cells. The plasma membrane Na<sup>+</sup>/Ca<sup>2+</sup> exchanger (NCX) and Ca<sup>2+</sup> ATPase (PMCA) regulate the free calcium concentration inside the neurons. The Ca<sup>2+</sup> signal is amplified by Ca<sup>2+</sup> release from the endoplasmic reticulum (ER) via ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP<sub>3</sub>Rs) or removal by sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup>-ATPase (SERCA). In addition, calcium buffers and mitochondria are involved in signal filtering. Mitochondria include NCX, calcium uniporter, and permeability transition pore (PTP) involved in mitochondrial calcium signaling. Nicotinic acid adenine dinucleotide phosphate (NAADP) is produced in response to agonist stimulation that activates Ca<sup>2+</sup> release from endo-lysosomes.</p>
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<p>Schematic representation of a pyramidal neuron. Endoplasmic reticulum network through the entire neuron at the axon, soma, dendritic tree, and spines. Focused ion beam–scanning electron microscopy revealed numerous ER-PM contacts in the cell body, with fewer links in dendrites, axons, and spines (see [<a href="#B20-biomolecules-14-01617" class="html-bibr">20</a>] for details). Insets from the top right represent changes in calcium concentration under train pulse electrical stimulation obtained in different regions (dendritic tree, pre-membrane, inside out of the membrane, and nuclear) of hippocampal pyramidal neuron (modified from [<a href="#B14-biomolecules-14-01617" class="html-bibr">14</a>]).</p>
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14 pages, 2440 KiB  
Review
Effects of Calcium Ion Dyshomeostasis and Calcium Ion-Induced Excitotoxicity in Parkinson’s Disease
by Daleum Nam, Hyejung Kim, Sun Jung Han, Ilhong Son and Dong Hwan Ho
J. Mol. Pathol. 2024, 5(4), 544-557; https://doi.org/10.3390/jmp5040037 - 14 Dec 2024
Viewed by 312
Abstract
Calcium ions (Ca2+) are vital intracellular messengers that regulate a multitude of neuronal functions, including synaptic transmission, plasticity, exocytosis, and cell survival. Neuronal cell death can occur through a variety of mechanisms, including excitotoxicity, apoptosis, and autophagy. In the context of [...] Read more.
Calcium ions (Ca2+) are vital intracellular messengers that regulate a multitude of neuronal functions, including synaptic transmission, plasticity, exocytosis, and cell survival. Neuronal cell death can occur through a variety of mechanisms, including excitotoxicity, apoptosis, and autophagy. In the context of excitotoxicity, the excessive release of glutamate in the synapses can trigger the activation of postsynaptic receptors. Upon activation, Ca2+ influx into the cell from the extracellular space via their associated ion channels, most notably L-type Ca2+ channels. Previous studies have indicated that α-synuclein (α-syn), a typical cytosolic protein, plays a significant role in the pathogenesis of Parkinson’s disease (PD). It is also worth noting that the aggregated form of α-syn has the capacity to affect Ca2+ homeostasis by altering the function of Ca2+ regulation. The upregulation of leucine-rich repeat kinase 2 (LRRK2) is closely associated with PD pathogenesis. LRRK2 mutants exhibit a dysregulation of calcium signaling, resulting in dopaminergic neuronal degeneration. It could therefore be proposed that α-syn and LRRK2 play important roles in the mechanisms underlying Ca2+ dyshomeostasis and excitotoxicity in PD. Full article
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<p>The protein machinery involved in the regulation of Ca<sup>2+</sup> via the plasma membrane. It schematically summarizes the uptake and release of Ca<sup>2+</sup> through components in the plasma membrane.</p>
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<p>Schematic illustration of cellular mechanisms involved in Ca<sup>2+</sup> signals and restoration, including the following 3 compartments: (<b>i</b>) the cellular responses to Ca<sup>2+</sup> in neurons via Ca<sup>2+</sup>-binding and -sensing molecules, (<b>ii</b>) the ER-mediated modulation of Ca<sup>2+</sup> homeostasis, and (<b>iii</b>) the restoration of Ca<sup>2+</sup> by the mitochondria.</p>
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<p>The structure and calcium-mediated PD pathomechanism involving α-syn (<b>A</b>). Monomeric α-syn is related to (i) Ca<sup>2+</sup>-ATPase activities and (ii) the presynaptic docking of synaptic vesicles. (iii) α-syn can form oligomers through calcium binding and is anchored to the intact plasma membrane through the calcium bridge effect. (iv) Moreover, aggregates of α-syn can disrupt Ca<sup>2+</sup> restoration in the ER via binding to SERCA (<b>B</b>).</p>
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<p>The structure of LRRK2 and its role in calcium dyshomeostasis (<b>A</b>). Enhanced LRRK2 kinase activity can alter (i) the activity of CaV2.1 channels, (ii) L- or P-type VGCCs, and (iii) Ca<sup>2+</sup> restoration in the mitochondria (<b>B</b>).</p>
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15 pages, 2014 KiB  
Review
The Unique Roles of Ion Channels in Pluripotent Stem Cells in Response to Biological Stimuli
by Taku Kaitsuka
Biology 2024, 13(12), 1043; https://doi.org/10.3390/biology13121043 - 13 Dec 2024
Viewed by 494
Abstract
Ion channels are essential for mineral ion homeostasis in mammalian cells, and these are activated or inhibited by environmental stimuli such as heat, cold, mechanical, acidic, or basic stresses. These expressions and functions are quite diverse between cell types. The function and importance [...] Read more.
Ion channels are essential for mineral ion homeostasis in mammalian cells, and these are activated or inhibited by environmental stimuli such as heat, cold, mechanical, acidic, or basic stresses. These expressions and functions are quite diverse between cell types. The function and importance of ion channels are well-studied in neurons and cardiac cells, while those functions in pluripotent stem cells (PSCs) were not fully understood. Some sodium, potassium, chloride, calcium, transient receptor potential channels and mechanosensitive Piezo channels are found to be expressed and implicated in pluripotency and self-renewal capacity in PSCs. This review summarizes present and previous reports about ion channels and their response to environmental stimuli in PSCs. Furthermore, we compare the expressions and roles between PSCs and their differentiated embryoid bodies. We then discuss those contributions to pluripotency and differentiation. Full article
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<p>Heatmap of expression levels of pluripotency and differentiation markers in undifferentiated and differentiated human ESCs. The data of mRNA levels in undifferentiated H1 and H9 human ESCs and their differentiated EBs were obtained from the dataset GDS5408 of the NCBI website. Then, a heatmap of pluripotency and differentiation marker levels was created using the Heatmapper website accessed on 7 December 2024 (<a href="http://www.heatmapper.ca" target="_blank">http://www.heatmapper.ca</a>) [<a href="#B13-biology-13-01043" class="html-bibr">13</a>]. The blue shows downregulation, and the yellow shows upregulation. The asterisk refers to a downregulated gene with a ratio of differentiated EBs to undifferentiated ESCs of less than 0.8-fold in both human ESC lines. UD, undifferentiated.</p>
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<p>Heatmap of expression levels of ion channel genes in undifferentiated and differentiated human ESCs. The data of mRNA levels in undifferentiated H1 and H9 human ESCs and their differentiated EBs were obtained from the dataset GDS5408 of the NCBI website. Then, heatmaps of <span class="html-italic">ASICs</span> (<b>A</b>), <span class="html-italic">CACNAs</span>, <span class="html-italic">CACNB</span>, <span class="html-italic">ORAIs</span> (<b>B</b>), <span class="html-italic">CFTR</span>, <span class="html-italic">CLCAs</span>, <span class="html-italic">CLCNs</span>, <span class="html-italic">CLICs</span> (<b>C</b>), <span class="html-italic">CNGA</span>, <span class="html-italic">CNGBs</span>, <span class="html-italic">HCN</span> and <span class="html-italic">HVCN</span> (<b>D</b>) gene levels were created using the Heatmapper website accessed on 7 December 2024 (<a href="http://www.heatmapper.ca" target="_blank">http://www.heatmapper.ca</a>) [<a href="#B13-biology-13-01043" class="html-bibr">13</a>]. The blue shows downregulation, and the yellow shows upregulation. Asterisks refer to downregulated genes with a ratio of differentiated EBs to undifferentiated ESCs of less than 0.8-fold in both human ESC lines. UD, undifferentiated.</p>
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<p>Heatmap of expression levels of ion channel genes in undifferentiated and differentiated human ESCs. The data of mRNA levels in undifferentiated H1 and H9 human ESCs and their differentiated EBs were obtained from the dataset GDS5408 of the NCBI website. Then, heatmaps of <span class="html-italic">KCNAs</span>, <span class="html-italic">KCNBs</span>, <span class="html-italic">KCNCs</span>, <span class="html-italic">KCNDs</span>, <span class="html-italic">KCNEs</span>, <span class="html-italic">KCNGs</span>, <span class="html-italic">KCNHs</span>, <span class="html-italic">KCNJs</span> (<b>A</b>), <span class="html-italic">KCNKs</span>, <span class="html-italic">KCNMs</span>, <span class="html-italic">KCNNs</span>, <span class="html-italic">KCNQs</span>, <span class="html-italic">KCNSs</span>, <span class="html-italic">KCNTs</span>, <span class="html-italic">KCNU</span>, <span class="html-italic">KCNV</span> and <span class="html-italic">KCTD</span> (<b>B</b>) gene levels were created using the Heatmapper website accessed on 7 December 2024 (<a href="http://www.heatmapper.ca" target="_blank">http://www.heatmapper.ca</a>) [<a href="#B13-biology-13-01043" class="html-bibr">13</a>]. The blue shows downregulation, and the yellow shows upregulation. Asterisks refer to downregulated genes with a ratio of differentiated EBs to undifferentiated ESCs of less than 0.8-fold in both human ESC lines. UD, undifferentiated.</p>
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<p>Heatmap of expression levels of ion channel genes in undifferentiated and differentiated human ESCs. The data of mRNA levels in undifferentiated H1 and H9 human ESCs and their differentiated EBs were obtained from the dataset GDS5408 of the NCBI website. Then, heatmaps of <span class="html-italic">NALCN</span>, <span class="html-italic">PIEZOs</span>, <span class="html-italic">PIRT</span> (<b>A</b>), <span class="html-italic">SCNs</span>, <span class="html-italic">SCNNs</span> (<b>B</b>) <span class="html-italic">TMCs</span> and <span class="html-italic">TPCNs</span> (<b>C</b>) gene levels were created using the Heatmapper website accessed on 7 December 2024 (<a href="http://www.heatmapper.ca" target="_blank">http://www.heatmapper.ca</a>) [<a href="#B13-biology-13-01043" class="html-bibr">13</a>]. The blue shows downregulation, and the yellow shows upregulation. Asterisks refer to downregulated genes with a ratio of differentiated EBs to undifferentiated ESCs of less than 0.8-fold in both human ESC lines. UD, undifferentiated.</p>
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<p>Heatmap of expression levels of ion channel genes in undifferentiated and differentiated human ESCs. The data of mRNA levels in undifferentiated H1 and H9 human ESCs and their differentiated EBs were obtained from the dataset GDS5408 of the NCBI website. Then, heatmaps of <span class="html-italic">TRPA</span>, <span class="html-italic">TRPCs</span>, <span class="html-italic">TRPMs</span>, <span class="html-italic">TRPMLs</span>, <span class="html-italic">TRPVs</span> and <span class="html-italic">TRPPs</span> gene levels were created using the Heatmapper website accessed on 7 December 2024 (<a href="http://www.heatmapper.ca" target="_blank">http://www.heatmapper.ca</a>) [<a href="#B13-biology-13-01043" class="html-bibr">13</a>]. The blue shows downregulation, and the yellow shows upregulation. Asterisks refer to downregulated genes with a ratio of differentiated EBs to undifferentiated ESCs of less than 0.8-fold in both human ESC lines. UD, undifferentiated.</p>
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21 pages, 1768 KiB  
Review
Vitamin D and Calcium—An Overview, Review of Metabolism, and the Importance of Co-Supplementation
by Bonny Burns-Whitmore, Erik B. Froyen and Kellene A. Isom
Dietetics 2024, 3(4), 588-608; https://doi.org/10.3390/dietetics3040040 - 12 Dec 2024
Viewed by 361
Abstract
Vitamin D is a conditionally essential fat-soluble vitamin found in foods such as fish; fish oil; egg yolks; animal fats; some mushroom varieties; and fortified foods such as cheese, margarine, milk, infant formula, and some ready-to-eat cereals. Calcium (Ca) is found in milk, [...] Read more.
Vitamin D is a conditionally essential fat-soluble vitamin found in foods such as fish; fish oil; egg yolks; animal fats; some mushroom varieties; and fortified foods such as cheese, margarine, milk, infant formula, and some ready-to-eat cereals. Calcium (Ca) is found in milk, cheese, canned fish, ready-to-eat cereals, milk substitutes, dark green leafy vegetables, and sports drinks. There are more than fifty metabolites of vitamin D. Vitamin D participates in immune regulation, apoptosis induction, insulin secretion, inflammation, cell differentiation, calcium balance and regulation, bone mineralization, and phosphorus homeostasis. Ca is an essential macro-mineral involved in bone and teeth matrices, strength, and hardness; muscle and cardiovascular movement; neurological messaging; and in the release of hormones. Peer-reviewed journal articles were accessed from the search engine PubMed. The authors reviewed the references in the peer-reviewed journal articles, websites, and review articles if the authors proposed a new theory or mechanism. Vitamin D and Ca have important relationships; therefore, many factors may impede or interfere with the body’s ability to absorb or utilize vitamin D and or Ca and may result in low or excessive levels of each. Additionally, genetic/medically related absorption issues and low intake may also result in deficiencies. This review discusses the introduction of each, their functions, absorption, somatic transportation, the relationship between vitamin D and Ca, and recommendations and supplementation strategies if available. Full article
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<p>Selected structures of vitamin D. Structural differences are highlighted in blue. Vitamin D3 (Cholecalciferol), vitamin D2 (Ergocalciferol and nonspecifically, calciferol), 25(OH)D (Calcifediol, also known as calcidiol, 25-hydroxycholecalciferol, or 25-hydroxyvitamin D<sub>3</sub>), 1,25(OH)2D (calcitriol, 1,25-dihydroxycholecalciferol, or 1,25 dihydroxy vitamin D) [<a href="#B4-dietetics-03-00040" class="html-bibr">4</a>].</p>
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<p>Overview of vitamin D in the body [<a href="#B7-dietetics-03-00040" class="html-bibr">7</a>]. Vitamin D2 and vitamin D3 from the diet are absorbed in the intestine and then carried by vitamin D binding protein (DBP) and or chylomicron remnants to the liver. Vitamin D3 produced in the skin is also transported by DBP to the liver. Products of 25(OH)D-DBP may be excreted in the urine or transported to the kidney, and through the actions of calcium, PTH, phosphate, and FGF23, produce 1,25(OH)2D, which is utilized in immune cells, bone tissues, and within the intestine for calcium absorption.</p>
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<p>Vitamin D and its functions in the human body [<a href="#B23-dietetics-03-00040" class="html-bibr">23</a>]. Vitamin D is required for regulation of immune function, phosphorus and calcium homeostasis, insulin secretion, muscle calcium transport, control of cell proliferation and differentiation, growth and bone mineralization, and apoptosis induction.</p>
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<p>Calcium homeostasis, PTH [<a href="#B33-dietetics-03-00040" class="html-bibr">33</a>]. Calcium homeostasis involves the regulation of PTH and calcitonin; formation of calcitrol; Ca regulation levels in the kidney, small intestine, bone; dermal production of vitamin D; and excretion (fecal).</p>
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21 pages, 797 KiB  
Review
Association Between Serum Concentrations of (Certain) Metals and Type 2 Diabetes Mellitus
by Magdalena Tyczyńska, Gabriela Hunek, Weronika Kawecka, Adam Brachet, Marta Gędek, Kinga Kulczycka, Katarzyna Czarnek, Jolanta Flieger and Jacek Baj
J. Clin. Med. 2024, 13(23), 7443; https://doi.org/10.3390/jcm13237443 - 6 Dec 2024
Viewed by 607
Abstract
The findings regarding trace element concentrations in patients diagnosed with type 2 diabetes and healthy controls are inconsistent, and therefore, we determined to gather them in the form of a review to further indicate the need for more advanced knowledge development. In our [...] Read more.
The findings regarding trace element concentrations in patients diagnosed with type 2 diabetes and healthy controls are inconsistent, and therefore, we determined to gather them in the form of a review to further indicate the need for more advanced knowledge development. In our study, we reviewed articles and studies that involved the topics of micronutrient and metal associations with the occurrence and development of type 2 diabetes. We mainly included works regarding human-based studies, but with limited research results, animal-based research was also taken into account. With some newer studies, we reached for initial assumptions of previous statements. The results indicated that higher serum levels of lead, cadmium, arsenic, bromine, barium, strontium, nickel, aluminum, calcium, copper, and ferritin are positively associated with diabetic prevalence. Both too-low and too-high levels of zinc, selenium, and magnesium may be connected to the development of diabetes. Chromium has the capability of insulin response modulation, with enhanced insulin-cell binding, and thus, lower serum levels of chromium can be found in diabetic patients. There are contradictory discoveries regarding manganese. Its supplementation can possibly cease the development of insulin resistance and type 2 diabetes. On the contrary, other studies reported that there is no such connection. Our work indicates that, as micronutrients play a significant role in the pathogenesis of metabolic disorders, more research regarding their bodily homeostasis and type 2 diabetes should be conducted. Full article
(This article belongs to the Special Issue Type 2 Diabetes and Complications: From Diagnosis to Treatment)
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<p>The description of known associations between the pathogenesis of metabolic disturbance in type 2 diabetes mellitus and selected metals, with the inclusion of the most affected organs and metabolic values.</p>
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19 pages, 7637 KiB  
Article
A Genome-Wide Characterization of Receptor-like Cytoplasmic Kinase IV Subfamily Members in Populus deltoides Identifies the Potential Role of PdeCRCK6 in Plant Osmotic Stress Responses
by Huanhuan Pan, Zhengquan He, Linxiu Liu, Renyue Cai, Hu Huang, Xinru Xie, Xun Cao, Yanan Li, Wenmin Qiu, Zhuchou Lu, Xiaojiao Han, Guirong Qiao, Renying Zhuo, Jianjun Hu and Jing Xu
Plants 2024, 13(23), 3371; https://doi.org/10.3390/plants13233371 - 30 Nov 2024
Viewed by 528
Abstract
The IV subfamily of receptor-like cytoplasmic kinase (RLCK-IV), known as calcium-binding receptor-like cytoplasmic kinases (CRCKs), plays a vital role in plant signal transduction, particularly in coordinating growth and responses to abiotic stresses. However, our comprehension of CRCK genes in Populus deltoides, a [...] Read more.
The IV subfamily of receptor-like cytoplasmic kinase (RLCK-IV), known as calcium-binding receptor-like cytoplasmic kinases (CRCKs), plays a vital role in plant signal transduction, particularly in coordinating growth and responses to abiotic stresses. However, our comprehension of CRCK genes in Populus deltoides, a species characterized as fast-growing and pest-resistant but with drought intolerance, is limited. Here, we identify 6 members of the CRCK subfamily on a genome-wide scale in P. deltoides, denoted as PdeCRCK1PdeCRCK6. An evolutionary and structural analysis revealed highly conserved kinase catalytic domains across all PdeCRCKs, characterized by calmodulin (CaM)-binding sites and serine (Ser)/threonine (Thr) phosphorylation sites. The cis-acting elements of promoters indicated the presence of responsive elements for plant hormones, abiotic stresses, and transcription factor binding sites, which is supported by the distinct transcriptional expression patterns of PdeCRCKs under abscisic acid (ABA), polyethylene glycol (PEG), and mannitol treatments. A transient overexpression of PdeCRCK3/5/6 in tobacco (Nicotiana benthamiana) leaves indicated their involvement in reactive oxygen species (ROS) scavenging, polyamine gene synthesis, and ABA signaling pathway modulation. Immunoprecipitation–Mass Spectrometry (IP–MS) and a yeast two-hybrid (Y2H) assay showed that PdeCRCK6 interacted with AAA-type ATPase proteins and ubiquitin, suggesting its potential function in being involved in chloroplast homeostasis and the 26S ubiquitin protease system. Taken together, these findings offer a comprehensive analysis of the RLCK-IV subfamily members in P. deltoides, especially laying a foundation for revealing the potential mechanism of PdeCRCK6 in response to osmotic stresses and accelerating the molecular design breeding of drought tolerance in poplar. Full article
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<p>Sequence alignment of the conserved domain of RLCK-IV/CRCK subfamily proteins between <span class="html-italic">Populus deltoides</span> and <span class="html-italic">Arabidopsis thaliana</span>. The conserved kinase catalytic domain was analyzed in all PdeCRCKs. The black boxes indicate the conserved CaM-binding domain and Ser/Thr phosphorylation site. The blue line indicates the N-terminal variable domains among PdeCRCKs. The important residue Lysine (K) of the CaM-binding domain is highlighted by a blue star.</p>
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<p>Phylogenetic analysis of green-plant RLCK-IV/CRCK subfamily members. A total of 41 RLCK-IVs were identified in <span class="html-italic">A. thaliana</span>, rice, wheat, maize, and <span class="html-italic">P. deltoides</span>. The phylogenetic relationship between <span class="html-italic">P. deltoides</span> and the aforementioned species was analyzed using the maximum likelihood method (ML) with JTT+G and a bootstrap analysis with 1000 replicates in MEGA 11.0.13. The 41 RLCK-IVs were divided into six groups and designated as RLCK-IV-1 to RLCK-IV-6. The different colors in the circle indicate the different species. The red star represents the dicot plants, while the blue star represents the monocot plants. The rectangles of different colors outside the circle represent different structural domains.</p>
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<p>Structural organization of PdeCRCKs. (<b>a</b>) A phylogenetic tree that was generated using MEGA 11.0.13. (<b>b</b>) The conserved motifs of PdeCRCKs, with different motifs represented by different colors. (<b>c</b>) The exon/intron structure of the putative PdeCRCKs, with the yellow boxes indicating exons and green boxes indicating the 3′ or 5′ UTRs (untranslated regions). (<b>d</b>) Visualization of conserved motifs by WebLogo, with the red box representing the Ser/Thr phosphorylation site; the blue box representing the CaM-binding site; and the important residue, Lysine (K), of the CaM-binding site is highlighted by a red star.</p>
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<p>Synteny relationships of gene pairs. The relationships of RLCK-IV duplicated genes between <span class="html-italic">P. deltoides</span> and <span class="html-italic">A. thaliana</span> are indicated by green lines, between <span class="html-italic">P. deltoides</span> and rice by blue lines, and between <span class="html-italic">P. deltoides</span> and <span class="html-italic">P. deltoides</span> by red lines.</p>
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<p><span class="html-italic">Cis</span>-element analysis associated with abiotic stress and phytohormone responsiveness in the promoter regions of <span class="html-italic">PdeCRCKs</span>. The 2000 bp region upstream of the transcriptional start site in <span class="html-italic">PdeCRCKs</span> was obtained and used to analyze the responsive <span class="html-italic">cis</span>-elements. (<b>a</b>) The types and distribution of <span class="html-italic">cis</span>-elements in the promoters. (<b>b</b>) This heatmap shows the number of <span class="html-italic">cis</span>-elements, with higher numbers represented in red and lower numbers in white. (<b>c</b>) All <span class="html-italic">cis</span>-elements were categorized into four groups, and their numbers were counted. Orange represents transcription factor binding sites, blue represents stress-responsive elements, pink represents physiological-responsive elements, and green represents hormone-responsive elements.</p>
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<p>Expression patterns of <span class="html-italic">PdeCRCKs</span> responding to various stresses. (<b>a</b>) The relative expression levels of <span class="html-italic">PdeCRCKs</span> were analyzed based on the leaves of <span class="html-italic">P. deltoides</span> under treatments within 72 h. (<b>b</b>) The relative expression level of <span class="html-italic">PdeCRCK</span> genes were analyzed based on the leaves of <span class="html-italic">P. deltoides</span> treated with 10% PEG-6000 within 24 h. For each time point, the expression of <span class="html-italic">PdeCRCKs</span> in seedlings without any stress was regarded as a reference. Quantitative analyses of all the measurements were conducted using GraphPad Prism 8. Data are presented as a mean ± standard deviation of three biological replicates. Statistical significance was assessed using Student’s <span class="html-italic">t</span>-test and Duncan’s multiple range test: <sup>ns</sup> <span class="html-italic">p</span> &gt; 0.05, * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01.</p>
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<p>Subcellular localization and potential functions of PdeCRCK3, PdeCRCK5, and PdeCRCK6 in tobacco. (<b>a</b>) Subcellular localization of green fluorescent protein (GFP)-PdeCRCK3/5/6 fusion proteins in tobacco cells. Scale bar = 20 μm. D53 (DWARF 53) acts as a nuclear localization marker, and pm-rb CD3-1008 acts as a membrane-localization marker. (<b>b</b>) The relative expression levels of <span class="html-italic">PdeCRCK3/5/6</span> and some stress-responsive genes (<span class="html-italic">NtSOD</span>, <span class="html-italic">NtPOD</span>, <span class="html-italic">NtSAMDC</span>, and <span class="html-italic">NtNCED1</span>) when <span class="html-italic">PdeCRCK3/5/6</span> were overexpressed in tobacco at 0 h, 24 h and 48 h. Quantitative analyses of all measurements were conducted using GraphPad Prism 8. Data are presented as a mean ± standard deviation of three biological replicates. A 1.5-fold and 2-fold increase or decrease are denoted as * and **, respectively to indicate a statistically significant difference between the two conditions. The significance of differences was examined by Student’s <span class="html-italic">t</span>-test and Duncan’s multiple range test.</p>
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<p>Proteins that interact with PdeCRCK6. (<b>a</b>) Co-immunoprecipitation of PdeCRCK6-GFP. The antibody is the ProteinFind Anti-GFP Mouse Monoclonal Antibody from TransGen Biotech. (<b>b</b>) PdeCRCK6 interacted with both AAA-type ATPase family proteins (Podel.05G065100.1) and ubiquitin 6 (Podel.14G119200.1), as determined by a yeast two-hybrid analysis.</p>
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13 pages, 3327 KiB  
Article
Effects of mscM Gene on Desiccation Resistance in Cronobacter sakazakii
by Dongdong Zhu, Zhengyang Zhang, Ping Li and Xinjun Du
Microorganisms 2024, 12(12), 2464; https://doi.org/10.3390/microorganisms12122464 - 30 Nov 2024
Viewed by 596
Abstract
Cronobacter sakazakii, an opportunistic foodborne pathogen, has a strong resistance to osmotic stress and desiccation stress, but the current studies cannot elucidate this resistance mechanism absolutely. A mechanosensitive channel MscM was suspected of involving to desiccation resistance mechanism of C. sakazakii. To [...] Read more.
Cronobacter sakazakii, an opportunistic foodborne pathogen, has a strong resistance to osmotic stress and desiccation stress, but the current studies cannot elucidate this resistance mechanism absolutely. A mechanosensitive channel MscM was suspected of involving to desiccation resistance mechanism of C. sakazakii. To investigate the specific molecular mechanism, the mscM mutant strain (ΔmscM) was constructed using the homologous recombination method, and the cpmscM complementary strain was obtained by gene complementation, followed by the analysis of the difference between the wild-type (WT), mutant, and complementary strains. Compared to the wild-type bacteria (WT), the inactivation rate of the ΔmscM strain decreased by 15.83% (p < 0.01) after desiccation stress. The absence of the mscM gene led to an increase in the membrane permeability of mutant strains. Through turbidity assay, it was found that the intracellular content of potassium ion (K+) of the ΔmscM strain increased by 2.2-fold (p < 0.05) compared to the WT strain, while other metal ion contents, including sodium ion (Na+), calcium ion (Ca2+), and magnesium ion (Mg2+), decreased by 48.45% (p < 0.001), 24.29% (p < 0.001), and 26.11% (p < 0.0001), respectively. These findings indicate that the MscM channel primarily regulates cell membrane permeability by controlling K+ efflux to maintain the homeostasis of intracellular osmotic pressure and affect the desiccation tolerance of bacteria. Additionally, the deletion of the mscM gene did not affect bacterial growth and motility but impaired surface hydrophobicity (reduced 20.52% compared to the WT strain, p < 0.001), adhesion/invasion capability (reduced 26.03% compared to the WT strain, p < 0.001), and biofilm formation ability (reduced 30.19% compared to the WT strain, p < 0.05) of the bacteria. This study provides a reference for the role of the mscM gene in the desiccation resistance and biofilm formation of C. sakazakii. Full article
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<p>Locations of specific primers and PCR amplification: (<b>A</b>) Locations of specific primers used for PCR validation; (<b>B</b>) PCR amplification result from different bacterial strains using different primers pairs, M. Maker; <span class="html-italic">msccM</span> 1 F/R, the WT strain; <span class="html-italic">msccM</span> 2 F/R, the Δ<span class="html-italic">mscM</span> strain; <span class="html-italic">msccM</span> 3 F/R, the <span class="html-italic">cpmscM</span> strain.</p>
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<p>The growth curves of WT, Δ<span class="html-italic">mscM</span>, and <span class="html-italic">cpmscM</span> strains.</p>
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<p>The drying inactivation rate of WT, Δ<span class="html-italic">mscM</span>, and <span class="html-italic">cpmscM</span> strains. ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001.</p>
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<p>The different ion contents in WT, Δ<span class="html-italic">mscM</span>, and <span class="html-italic">cpmscM</span> strains: (<b>A</b>) intracellular potassium ion concentration; (<b>B</b>–<b>D</b>) total Na<sup>+</sup>, Ca<sup>2+</sup>, and Mg<sup>2+</sup> ion contents. * <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001, **** <span class="html-italic">p</span> &lt; 0.0001.</p>
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<p>Outer membrane permeability. **** <span class="html-italic">p</span> &lt; 0.0001.</p>
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<p>Relative adhesion/infestation rate of the different strains.*** <span class="html-italic">p</span> &lt; 0.001, **** <span class="html-italic">p</span> &lt; 0.0001.</p>
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<p>The surface hydrophobicity of bacteria. *** <span class="html-italic">p</span> &lt; 0.001.</p>
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<p>Biofilm formation. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01.</p>
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<p>The illustration of the effects of MscM proteins on <span class="html-italic">C. sakazakii</span>.</p>
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15 pages, 2850 KiB  
Article
Gold Kiwi-Derived Nanovesicles Mitigate Ultraviolet-Induced Photoaging and Enhance Osteogenic Differentiation in Bone Marrow Mesenchymal Stem Cells
by Doyeon Kim, Chanho Lee, Manho Kim and Ju Hyun Park
Antioxidants 2024, 13(12), 1474; https://doi.org/10.3390/antiox13121474 - 29 Nov 2024
Viewed by 506
Abstract
Bone marrow mesenchymal stem cells (BM-MSCs) play a crucial role in bone formation through their ability to differentiate into osteoblasts. Aging, however, detrimentally affects the differentiation and proliferation capacities of BM-MSCs, consequently impairing bone regeneration. Thus, mitigating the aging effects on BM-MSCs is [...] Read more.
Bone marrow mesenchymal stem cells (BM-MSCs) play a crucial role in bone formation through their ability to differentiate into osteoblasts. Aging, however, detrimentally affects the differentiation and proliferation capacities of BM-MSCs, consequently impairing bone regeneration. Thus, mitigating the aging effects on BM-MSCs is vital for addressing bone-related pathologies. In this study, we demonstrate that extracellular nanovesicles isolated from gold kiwi (GK-NVs) protect human BM-MSCs from ultraviolet (UV)-induced photoaging, thereby alleviating aging-related impairments in cellular functions that are crucial for bone homeostasis. Notably, GK-NVs were efficiently taken up by BM-MSCs without causing cytotoxicity. GK-NVs reduced intracellular reactive oxygen species (ROS) levels upon UV irradiation, restoring impaired proliferation and migration capabilities. Furthermore, GK-NVs corrected the skewed differentiation capacities of UV-irradiated BM-MSCs by enhancing osteoblast differentiation, as evidenced by the increased expression in osteoblast-specific genes and the calcium deposition, and by reducing adipocyte differentiation, as indicated by the decreased lipid droplet formation. These findings position GK-NVs as a promising biomaterial for the treatment of bone-related diseases such as osteoporosis. Full article
(This article belongs to the Special Issue Antioxidants as Anti-Aging Interventions)
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<p>Isolation and characterization of the GK-NVs. (<b>A</b>) Schematic diagram illustrating the isolation process of the EVs from the gold kiwi. (<b>B</b>) Size distribution and mean size of the GK-NVs as determined by the NTA. (<b>C</b>) Quantification of the production yield and purity of the GK-NVs. The yield was calculated by dividing the total number of isolated GK-NV particles by the mass of gold kiwi used. The purity was determined by the number of particles per microgram of protein. (<b>D</b>) Zeta potential and PDI of the GK-NVs as measured by the DLS. (<b>E</b>) Morphology of the isolated GK-NVs as observed via TEM (created with BioRender.com).</p>
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<p>Cytotoxicity and cellular uptake of the GK-NVs. (<b>A</b>) Cytotoxicity assessment of the GK-NVs in the BM-MSCs using the trypan blue exclusion assay (ns: not significant; <span class="html-italic">n</span> = 3). (<b>B</b>) Cellular uptake of the GK-NVs by the BM-MSCs. BM-MSCs treated with PKH67-labeled GK-NVs were observed under a fluorescence microscope (scale bar = 100 µm).</p>
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<p>Effect of GK-NVs on the intracellular ROS level, proliferation, and migration of UVB-irradiated BM-MSCs. Following treatment with GK-NVs, the BM-MSCs were exposed to UVB irradiation (80 mJ/cm<sup>2</sup>) (scale bar = 200 µm). (<b>A</b>) Intracellular ROS levels assessed by the H2DCFDA assay. (<b>B</b>) Viable cell populations measured by the WST-8 assay (** <span class="html-italic">p</span> &lt; 0.01 and *** <span class="html-italic">p</span> &lt; 0.005; ns: not significant; <span class="html-italic">n</span> = 3). (<b>C</b>) Scratch closure assay demonstrating the migratory potential of BM-MSCs. The initial scratched area is indicated by the dashed line (scale bar = 200 µm). (<b>D</b>) Transwell migration assay showing the migration of the BM-MSCs treated with the GK-NVs, with migrated cells visualized by crystal violet staining (scale bar = 200 µm). (<b>E</b>) Quantification of the transwell migration assay. Statistical significance was determined by comparison to the UVB-irradiated, GK-NV-untreated control, unless otherwise noted (** <span class="html-italic">p</span> &lt; 0.01 and *** <span class="html-italic">p</span> &lt; 0.005; ns: not significant; <span class="html-italic">n</span> = 3).</p>
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<p>Effects of GK-NVs on the osteoblast differentiation BM-MSCs exposed to UVB irradiation. UVB-irradiated BM-MSCs were treated with GK-NVs twice during the first week of osteogenesis. (<b>A</b>) Representative images of the ALP staining on day 9 of the osteogenic culture (scale bar = 200 µm). (<b>B</b>) Representative image of the ARS staining demonstrating calcium deposition on day 21 of the osteogenic culture (scale bar = 200 µm). (<b>C</b>) Quantification of the ARS staining (** <span class="html-italic">p</span> &lt; 0.01 and *** <span class="html-italic">p</span> &lt; 0.005; ns: not significant; <span class="html-italic">n</span> = 3). (<b>D</b>) Representative image of the Von Kossa staining on day 21 of the osteogenic culture (scale bar = 200 µm). (<b>E</b>) The mRNA expression levels of osteoblast-specific genes, including ALP, Runx2, OPN, and OCN. A qPCR analysis was conducted using the total RNA extracted from the BM-MSCs on day 14 of the osteogenic culture. Statistical significance was determined by comparison to the UVB-irradiated, GK-NV-untreated control, unless otherwise noted (* <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.005; ns: not significant; <span class="html-italic">n</span> = 3).</p>
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<p>Effects of GK-NVs on the adipocyte differentiation BM-MSCs exposed to UVB irradiation. UVB-irradiated BM-MSCs were treated with GK-NVs twice during the first week of adipogenesis. (<b>A</b>) Representative image of the ORO staining demonstrating the formation of lipid droplets on day 14 of the adipogenic culture (scale bar = 200 µm). (<b>B</b>) Quantification of the ORO staining. Statistical significance was determined with a comparison to the UVB-irradiated, GK-NV-untreated control, unless otherwise noted (** <span class="html-italic">p</span> &lt; 0.01 and *** <span class="html-italic">p</span> &lt; 0.005; ns: not significant; <span class="html-italic">n</span> = 3).</p>
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18 pages, 2224 KiB  
Communication
Distribution of the p66Shc Adaptor Protein Among Mitochondrial and Mitochondria—Associated Membranes Fractions in Normal and Oxidative Stress Conditions
by Magdalena Lebiedzinska-Arciszewska, Barbara Pakula, Massimo Bonora, Sonia Missiroli, Yaiza Potes, Patrycja Jakubek-Olszewska, Ines C. M. Simoes, Paolo Pinton and Mariusz R. Wieckowski
Int. J. Mol. Sci. 2024, 25(23), 12835; https://doi.org/10.3390/ijms252312835 - 29 Nov 2024
Viewed by 498
Abstract
p66Shc is an adaptor protein and one of the cellular fate regulators since it modulates mitogenic signaling pathways, mitochondrial function, and reactive oxygen species (ROS) production. p66Shc is localized mostly in the cytosol and endoplasmic reticulum (ER); however, under oxidative stress, p66Shc is [...] Read more.
p66Shc is an adaptor protein and one of the cellular fate regulators since it modulates mitogenic signaling pathways, mitochondrial function, and reactive oxygen species (ROS) production. p66Shc is localized mostly in the cytosol and endoplasmic reticulum (ER); however, under oxidative stress, p66Shc is post-translationally modified and relocates to mitochondria. p66Shc was found in the intermembrane space, where it interacts with cytochrome c, contributing to the hydrogen peroxide generation by the mitochondrial respiratory chain. Our previous studies suggested that p66Shc is localized also in mitochondria-associated membranes (MAM). MAM fraction consists of mitochondria and mostly ER membranes. Contact sites between ER and mitochondria host proteins involved in multiple processes including calcium homeostasis, apoptosis, and autophagy regulation. Thus, p66Shc in MAM could participate in processes related to cell fate determination. Due to reports on various and conditional p66Shc intracellular localization, in the present paper, we describe the allocation of p66Shc pools in different subcellular compartments in mouse liver tissue and HepG2 cell culture. We provide additional evidence for p66Shc localization in MAM. In the present study, we use precisely purified subcellular fraction isolated by differential centrifugation-based protocol from control mouse liver tissue and HepG2 cells and from cells treated with hydrogen peroxide to promote mitochondrial p66Shc translocation. We performed controlled digestion of crude mitochondrial fraction, in which the degradation patterns of p66Shc and MAM fraction marker proteins were comparable. Moreover, we assessed the distribution of the individual ShcA isoforms (p46Shc, p52Shc, and p66Shc) in the subcellular fractions and their contribution to the total ShcA in control mice livers and HepG2 cells. In conclusion, we showed that a substantial pool of p66Shc protein resides in MAM in control conditions and after oxidative stress induction. Full article
(This article belongs to the Special Issue Mitochondrial Biology and Reactive Oxygen Species)
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<p>p66Shc distribution in cellular fractions isolated from mouse liver. (<b>A</b>) The levels of marker proteins in the fractions: for mitochondria (including crude mitochondria (MC) and pure mitochondria (MP))—mitochondrial superoxide dismutase (SOD2), voltage-dependent anion channel (VDAC), mitochondrial import inner membrane translocase (Tim23), and cytochrome c (Cyt c), for ER—calreticulin (Clrt), for mitochondria-associated membranes (MAM) - sigma non-opioid intracellular receptor 1 (Sigma R1), and for cytosol (including crude cytosol (CC) and pure cytosol (CP))—glyceraldehyde-3-phosphate dehydrogenase (GAPDH); (<b>B</b>) the level of ShcA proteins: p66Shc, p52Shc, and p46Shc in fractions isolated from mice livers shown in the representative Western blot picture; (<b>C</b>) quantification of p66Shc in each fraction compared to the p66Shc signal in total homogenate (H); box plots show the medians (lines), means are indicated with (+); <span class="html-italic">n</span> = 6; statistical significance evaluated with ordinary one-way ANOVA with Tukey’s method based multiple comparisons (**** <span class="html-italic">p</span> &lt; 0.0001, * <span class="html-italic">p</span> &lt; 0.05, ns—no significance); (<b>D</b>) heat map showing an enrichment of p66Shc in each fraction in reference to the fraction of origin: homogenate for crude cytosol and crude mitochondria, crude mitochondria for MAM, and purified mitochondria and crude cytosol for purified cytosol and ER; (<b>E</b>) graphs show the percentage contribution of p66Shc in each fraction in the total (100%) of p66Shc content calculated as a sum of p66Shc signals from MP, MAM, CP, and ER fractions (pie chart shows mean percentage representation of p66Shc in each fraction and box plot shows the medians (lines) and means indicated with (+) with SD); <span class="html-italic">n</span> = 6; Statistical significance evaluated with ordinary one-way ANOVA with Tukey’s method based multiple comparisons (**** <span class="html-italic">p</span> &lt; 0.0001, ** <span class="html-italic">p</span> &lt; 0.005, * <span class="html-italic">p</span> &lt; 0.05, ns—no significance); (<b>F</b>) Western blot showing the levels of p66Shc in 25 µg of the total homogenate (H), pure mitochondria (MP), and MAM fractions samples as references and after immunoprecipitation (IP) with anti—ShcA antibodies in MP and MAM fractions from mice livers (IgG, heavy chain of the IP antibodies is visible together with p52Shc at approximately 52 kDa), <span class="html-italic">n</span> = 2; and (<b>G</b>) diagram illustrating the concept of the distribution of the investigated proteins across the intracellular fractions mentioned in the study, described in detail in the text.</p>
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<p>p66Shc distribution in cellular fractions isolated from HepG2 cell cultures. (<b>A</b>) A comparison of the p66Shc protein levels in crude fractions: homogenate (H), post-mitochondrial supernatant—crude cytosolic fraction (CC), and crude mitochondrial fraction (MC) in HepG2 cells untreated and treated with the H<sub>2</sub>O<sub>2</sub> followed by the quantification of p66Shc ratios between MC from H<sub>2</sub>O<sub>2</sub> treated HepG2 to untreated cells after normalization to the level in the total homogenate (input) samples; <span class="html-italic">t</span>-test ** <span class="html-italic">p</span> &lt; 0.005; (<b>B</b>,<b>C</b>) the levels of ShcA proteins: p66Shc, p52Shc, and p46Shc in fractions isolated from untreated HepG2 cells (<b>B</b>) and in fractions isolated from HepG2 cells treated with 1 mM H<sub>2</sub>O<sub>2</sub> for 24 h (<b>C</b>) followed by p66Shc fraction shares quantification showed as the percentage contribution of p66Shc in each fraction in the total (100%) of p66Shc content calculated as a sum of p66Shc signals from MP, MAM, CP, and ER fractions; pie charts show mean percentage representation of p66Shc in each fraction and respective box plots show the mean with (SD); plots show the median with SD, means are indicated with (+); statistical significance evaluated with ordinary one-way ANOVA with Tukey’s method based multiple comparisons (*** <span class="html-italic">p</span> &lt; 0.0005, ** <span class="html-italic">p</span> &lt; 0.005, and * <span class="html-italic">p</span> &lt; 0.05, ns—no significance); levels of marker proteins: for mitochondria—mitochondrial superoxide dismutase (SOD2) and cytochrome c (Cyt c), ER—calreticulin (Clrt), MAM: long-chain-fatty-acid-CoA ligase 4 (ACSL4), cytosol (CC and CP)—GAPDH; (<b>D</b>) heat map presenting quantification of a p66Shc ratio in each fraction to p66Shc in homogenate; and (<b>E</b>) heat map presenting quantification of a p66Shc ratio in each fraction to p66Shc in the respective fraction of origin: homogenate for MC and CC, CC for ER and cytosol, and MC for MAM and MP.</p>
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<p>p66Shc digestion with trypsin in crude mitochondrial fraction isolated from the HepG2 cell line. p66Shc protein and fractions markers: SigmaR1 for MAM, VDAC for outer mitochondrial membrane (OMM), Cyt c for intermembrane space (IMS), and SOD2 for mitochondrial matrix (MM) detected by Western blot in the residual samples after trypsin digestion of 100 µg of MC isolated from (<b>A</b>) control untreated HepG2, and (<b>B</b>) HepG2 cells treated with 1 mM H<sub>2</sub>O<sub>2</sub> for 24 h. Quantification presented below the representative Western blots shows the mean ratio of p66Shc (<b>A</b>,<b>B</b>) and fractions markers (<b>C</b>) in trypsinized samples to the level of p66Shc (<b>A</b>,<b>B</b>) or each fraction marker (<b>C</b>) in the input untreated MC sample (value is assigned as 1) with SD. Statistical significance was calculated with one sample <span class="html-italic">t</span>-test (where value = 1 refers to the input—undigested MC sample), <span class="html-italic">p</span>-value (**** <span class="html-italic">p</span> &lt; 0.0001, *** <span class="html-italic">p</span> &lt; 0.0005, and ** <span class="html-italic">p</span> &lt; 0.005, * <span class="html-italic">p</span> &lt; 0.05, ns—no significance).</p>
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12 pages, 1340 KiB  
Article
The Effect of Ferric Carboxymaltose on Fibroblast Growth Factor 23 (FGF23) in Children with Iron Deficiency Anemia Due to Gastrointestinal Diseases
by Maria Ntoumpara, Elpis Mantadakis, Lemonia Skoura, Paraskevi Panagopoulou, Elpida Emmanouilidou-Fotoulaki, Eleftheria Parasidou, Paraskevoula Koutra and Maria Fotoulaki
Hemato 2024, 5(4), 448-458; https://doi.org/10.3390/hemato5040034 - 28 Nov 2024
Viewed by 472
Abstract
Background: Hypophosphatemia is a known side-effect of parenteral iron administration, especially after intravenous ferric carboxymaltose (FCM). Fibroblast growth factor 23 (FGF23) is thought to play an important role in the pathophysiology of serum phosphate homeostasis. This study aimed to investigate the effects of [...] Read more.
Background: Hypophosphatemia is a known side-effect of parenteral iron administration, especially after intravenous ferric carboxymaltose (FCM). Fibroblast growth factor 23 (FGF23) is thought to play an important role in the pathophysiology of serum phosphate homeostasis. This study aimed to investigate the effects of FCM on FGF23 serum levels in FCM-treated pediatric patients with iron deficiency (ID)/iron deficiency anemia (IDA) caused by gastrointestinal diseases. Methods: Over 30 months, FGF23 serum levels were assessed prospectively in children with ID/IDA due to gastrointestinal diseases and treated with FCM infusion. Serum levels of intact FGF23 (iFGF23) were assessed and correlated to phosphate serum levels and factors of bone metabolism. Blood sampling was performed in three phases: before FCM infusion, 7–10 days after FCM infusion, and 6–8 weeks after FCM infusion. Results: A total of 42 FCM infusions were given to 35 children (20 girls) with a mean age (±SD) of 12.2 (±4.03) years (range: 2–16 years). The median levels of iFGF23 did not show a significant difference across the three phases (p = 0.56). No significant correlation was found between iFGF23 levels and 25-hydroxyvitamin D/parathyroid hormone/serum phosphate/serum calcium/alkaline phosphatase. No significant change was noted between pre- and post-treatment serum phosphate levels. However, four children (11.42%) developed asymptomatic and transient hypophosphatemia. Conclusions: No significant difference was found between pre-and post-FCM infusion serum iFGF23 levels and bone metabolism parameters. An increase of iFGF23 serum levels 7–10 days after FCM infusion was noted in patients with hypophosphatemia. Full article
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<p>Distribution of serum iFGF23 levels in three phases using R software. Median serum iFGF23 levels did not significantly differ across the three phases (<span class="html-italic">p</span> = 0.56).</p>
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<p>Violin plots for serum iFGF23 levels of patients with hypophosphatemia (N = 4) after FCM infusion. A graphically different trend is noted, with an iFGF23 increase 7–10 days after infusion.</p>
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<p>Violin plots for serum iFGF23 levels of patients with normal serum phosphate after FCM infusion. No similar trend is observed in patients with hypophosphatemia. Serum iFGF23 levels remain stable before, 7–10 days after, and 6–8 weeks after FCM infusion.</p>
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<p>A schematic diagram of the method and materials used in the study. Sample collection was performed in three phases as displayed in the vertical flowchart [phosphate (Phos), calcium (Ca), alkaline phosphatase (ALP), urea, creatinine, alanine transaminase (ALT), aspartate aminotransferase (AST), ferritin, total iron-binding capacity (TIBC), 25-hydroxyvitamin D (25(OH)D), intact parathyroid hormone (PTH), C-reactive protein (CRP), and soluble Transferrin Receptor (sTfR)].</p>
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17 pages, 3382 KiB  
Communication
Progressive Cachexia: Tuberculosis, Cancer, or Thyrotoxicosis? Disease-Directed Therapy and Atypical Courses of Autoimmune and Malignant Thyroid Diseases in a High Specialization Era: Case-Control Study with a Critical Literature Review
by Przemyslaw Zdziarski and Zbigniew Sroka
Biomedicines 2024, 12(12), 2722; https://doi.org/10.3390/biomedicines12122722 - 28 Nov 2024
Viewed by 858
Abstract
Background. Critical and progressive cachexia may be observed in numerous medical disciplines, but in patients with various diseases, several pathways overlap (endocrine, inflammatory and kidney diseases, heart failure, cancer). Methods. Unlike numerous cohort studies that examine thyroid cancer and risk factors, a different [...] Read more.
Background. Critical and progressive cachexia may be observed in numerous medical disciplines, but in patients with various diseases, several pathways overlap (endocrine, inflammatory and kidney diseases, heart failure, cancer). Methods. Unlike numerous cohort studies that examine thyroid cancer and risk factors, a different method was used to avoid bias and analyze the sequence of events, i.e., the pathway. A case-control analysis is presented on patients with initial immune-mediated thyroiditis complicated by cachexia, presenting pulmonary pathology coexisting with opportunistic infection, and ultimately diagnosed with cancer (TC—thyroid cancer, misdiagnosed as lung cancer). Results. Contrary to other patients with lung cancer, the presented patients were not active smokers and exclusively women who developed cachexia with existing autoimmune processes in the first phase. Furthermore, the coexistence of short overall survival without cancer progression in the most seriously ill patients, as well as correlation with sex (contrary to history of smoking) and predisposition to mycobacterial disease, are very suggestive. Although we describe three different autoimmune conditions (de Quervain’s, Graves’, and atrophic thyroiditis), disturbances in calcium and metabolic homeostasis, under the influence of hormonal and inflammatory changes, are crucial factors of cachexia and prognosis. Conclusions. The unique sequence sheds light on immune-mediated thyroid disease as a subclinical paraneoplastic process modified by various therapeutic regimens. However, it is also associated with cachexia, systemic consequences, and atypical sequelae, which require a holistic approach. The differential diagnosis of severe cachexia, adenocarcinoma with pulmonary localization, and tuberculosis reactivation requires an analysis of immunological and genetic backgrounds. Contrary to highly specialized teams (e.g., lung cancer units), immunotherapy and general medicine in aging populations require a multidisciplinary, holistic, and inquiring approach. The lack of differentiation, confusing biases, and discrepancies in the literature are the main obstacles to statistical research, limiting findings to correlations of common factors only. Time-lapse case studies such as this one may be among the first to build evidence of a pathway and an association between inflammatory and endocrine imbalances in cancer cachexia. Full article
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<p>Initial patient selection. After initial selection, a small amount of patients was qualified, but contrary to most retrospective analyses of patients with thyroid cancer, in our clinical model, AITD preceded oncogenesis and may be with different types of AITD (i.e., de Quervain thyroiditis, Graves’ disease, Hashimoto/atrophic thyroiditis).</p>
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<p>Flowchart of clinical data collection and time-lapse analysis. Patients with autoimmune thyroid disease (AITD) were the starting point. The case-control study includes patient histories with well-characterized and differentiated autoimmune thyroid disease (AITD) complicated with infectious and neoplastic processes. TC was the sixth cancer in women; it was not observed in men. However, this could be apparent because the initial group consisted of patients with autoimmunity, which is more common in women with no difference between multiparous and childless. Comparing our AITDs where hyperthyroidism, hypothyroidism, or both occurred at different times, no clear effect of hypothyroidism and elevated TSH can be seen. AITD—autoimmune thyroid disease, PFS—progression-free survival, OS—overall survival, TSH—thyroid-stimulating hormone, FT3—free triiodothyronine, FT4—free thyroxine, CT—computer tomography.</p>
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<p>Modification of unique balance between pro- and anticancerous factors (i.e., hormonal and inflammatory signal, respectively) by microbiota (mycobacteria) and steroids. BRAF-BRAFV600E mutation; PTC—papillary thyroid cancer oncogene (RET/PTC), gks—glucocorticoids, MHC—Major Histocompatibility Complex, CTLA4—Cytotoxic T Lymphocyte Antigen-4; TG—thyreoglobulin, TSHR—thyreotropin receptor, TNF—cachectin, PFS—progression-free survival, OS—overall survival. The red symbol indicates the inhibitory effect; the green symbol indicates the stimulating effect.</p>
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20 pages, 1011 KiB  
Review
Shedding Light on Calcium Dynamics in the Budding Yeast: A Review on Calcium Monitoring with Recombinant Aequorin
by Larisa Ioana Gogianu, Lavinia Liliana Ruta and Ileana Cornelia Farcasanu
Molecules 2024, 29(23), 5627; https://doi.org/10.3390/molecules29235627 - 28 Nov 2024
Viewed by 396
Abstract
Recombinant aequorin has been extensively used in mammalian and plant systems as a powerful tool for calcium monitoring. While aequorin has also been widely applied in yeast research, a notable gap exists in the literature regarding comprehensive reviews of these applications. This review [...] Read more.
Recombinant aequorin has been extensively used in mammalian and plant systems as a powerful tool for calcium monitoring. While aequorin has also been widely applied in yeast research, a notable gap exists in the literature regarding comprehensive reviews of these applications. This review aims to address that gap by providing an overview of how aequorin has been used to explore calcium homeostasis, signaling pathways, and responses to stressors, heavy metals, and toxic compounds in Saccharomyces cerevisiae. We also discuss strategies for further developing the aequorin system in yeast, with particular emphasis on its use as a model for human calcium signaling studies, such as the reproduction of the mitochondrial calcium uniporter. By highlighting previous research and pinpointing potential future applications, we discuss the untapped potential of aequorin in yeast for drug screening, environmental toxicity testing, and disease-related studies. Full article
(This article belongs to the Special Issue Bioactive Compounds in Food and Their Applications)
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<p>(<b>a</b>) Crystal structure of aequorin containing the coelenterazine moiety (RCSB PDB ID: 1EJ3); (<b>b</b>) Simulation of Ca<sup>2+</sup> binding to apo-aequorin using AlphaFold3 [<a href="#B31-molecules-29-05627" class="html-bibr">31</a>]. Structures visualization with Chimera X [<a href="#B32-molecules-29-05627" class="html-bibr">32</a>] and labeled based on [<a href="#B33-molecules-29-05627" class="html-bibr">33</a>]. Roman numerals I–IV indicate the position of the EF-hand loops; CTZ = coelenterazine moiety; green spheres represent Ca<sup>2+</sup>.</p>
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<p>Aequorin light emission upon Ca<sup>2+</sup> binding. (Created in BioRender. ruta, l. (2024) <a href="http://BioRender.com/v42t872" target="_blank">BioRender.com/v42t872</a>).</p>
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16 pages, 7466 KiB  
Article
Urolithin A Protects Hepatocytes from Palmitic Acid-Induced ER Stress by Regulating Calcium Homeostasis in the MAM
by Gayoung Ryu, Minjeong Ko, Sooyeon Lee, Se In Park, Jin-Woong Choi, Ju Yeon Lee, Jin Young Kim and Ho Jeong Kwon
Biomolecules 2024, 14(12), 1505; https://doi.org/10.3390/biom14121505 - 26 Nov 2024
Viewed by 537
Abstract
An ellagitannin-derived metabolite, Urolithin A (UA), has emerged as a potential therapeutic agent for metabolic disorders due to its antioxidant, anti-inflammatory, and mitochondrial function-improving properties, but its efficacy in protecting against ER stress remains underexplored. The endoplasmic reticulum (ER) is a cellular organelle [...] Read more.
An ellagitannin-derived metabolite, Urolithin A (UA), has emerged as a potential therapeutic agent for metabolic disorders due to its antioxidant, anti-inflammatory, and mitochondrial function-improving properties, but its efficacy in protecting against ER stress remains underexplored. The endoplasmic reticulum (ER) is a cellular organelle involved in protein folding, lipid synthesis, and calcium regulation. Perturbations in these functions can lead to ER stress, which contributes to the development and progression of metabolic disorders such as metabolic-associated fatty liver disease (MAFLD). In this study, we identified a novel target protein of UA and elucidated its mechanism for alleviating palmitic acid (PA)-induced ER stress. Cellular thermal shift assay (CETSA)-LC-MS/MS analysis revealed that UA binds directly to the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA), an important regulator of calcium homeostasis in mitochondria-associated ER membranes (MAMs). As an agonist of SERCA, UA attenuates abnormal calcium fluctuations and ER stress in PA-treated liver cells, thereby contributing to cell survival. The lack of UA activity in SERCA knockdown cells suggests that UA regulates cellular homeostasis through its interaction with SERCA. Collectively, our results demonstrate that UA protects against PA-induced ER stress and enhances cell survival by regulating calcium homeostasis in MAMs through SERCA. This study highlights the potential of UA as a therapeutic agent for metabolic disorders associated with ER stress. Full article
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<p>Effects of UA on cellular response, ER stress, and lipid accumulation in PA-treated hepatocytes. (<b>A</b>) The MTT assay was performed on HepG2 cells treated with various concentrations of UA (1–100 μM) for 24, 48, and 72 h to evaluate cell proliferation. (<b>B</b>) The MTT assay was used to measure the cell proliferation of HepG2 cells treated with PA (0.5 mM) and UA (20, 40 μM) for 24 h. (<b>C</b>) The Trypan blue exclusion assay was performed to evaluate the cell viability of HepG2 cells treated with PA (0.5 mM) and UA (20, 40 μM) for 24 h. (<b>D</b>) mCherry-CHOP stable HEK293 cells were treated with PA (0.5 mM) and UA (20, 40 μM) for 24 h, and mCherry fluorescence signals were measured. The expression of CHOP was visualized as a fluorescence signal and observed using confocal microscopy (scale bar: 10 μM). (<b>E</b>) HepG2 cells were treated with PA (0.5 mM) and UA (20, 40 μM) for 24 h, followed by staining of intracellular lipid droplets with BODIPY and observation via confocal microscopy (scale bar: 20 μM) (* <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001, **** <span class="html-italic">p</span> &lt; 0.0001).</p>
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<p>CETSA-LC-MS/MS for the identification of the target protein of UA. (<b>A</b>) Overview of the CETSA-LC-MS/MS method. HEK293 cells were treated with DMSO (control) or UA (20 μM) and subjected to thermal treatment (55 °C or 60 °C). Proteins were then extracted, digested with trypsin, and labeled with TMT reagents. The labeled peptides were analyzed by HPLC and LC-MS/MS. (<b>B</b>) Schematic diagram of the target selection identification criteria of the UA process. (<b>C</b>) Heatmap of target candidates of UA localized in the ER and mitochondria. Proteins are clustered by their functions, as indicated on the left side of the heatmap.</p>
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<p>Validation of UA binding to SERCA. (<b>A</b>) Western blot analysis to evaluate the thermal stability of SERCA in HepG2 cells treated with UA (40 μM). (<b>B</b>) Comparison of the binding affinity between UA and two calcium-regulating target proteins: SERCA and CCDC47. HepG2 cells were treated with various concentrations of UA (1–100 μM), followed by isothermal CETSA at 52 °C. (<b>C</b>) The 2D diagram represents amino acids involved in UA binding to SERCA. (<b>D</b>) Predicted binding of UA to the actuator domain of SERCA, as visualized using Discovery Studio software 2018 (CDOCKER energy: −20.57 kcal/mol). (<b>E</b>) The 3D structure of the full-length SERCA protein (PDB: 7E7S), highlighting its four domains. (<b>F</b>) HEK293 cells were transfected with FLAG-SERCA(WT), FLAG-SERCA(R198A), or FLAG-SERCA(K234A) for 48 h and then treated with UA (40 μM). After heat treatment at 52 °C for 3 min, proteins were extracted and analyzed using a Western blot. (<b>G</b>) Measurement of ATPase activity of ER proteins extracted from LX2 cells. UA (20, 40 μM) and thapsigargin (0.1 μM) were each treated for 30 min before ATPase activity was assessed.</p>
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<p>Intracellular calcium levels in PA-treated HepG2 cells with UA. (<b>A</b>) HepG2 cells were transfected with the ER calcium indicator ER-LAR-GECO vector for 48 h, followed by treatment with UA (40 μM), CDN1163 (10 μM), or TG (0.1 μM) for 6 h (scale bar: 20 μm). (<b>B</b>) ER calcium levels were measured in HepG2 cells treated with PA (500 μM) for 6 h, either alone or co-treated with UA (40 μM) and CDN1163 (10 μM) (scale bar: 10 μm). (<b>C</b>) Cytosolic calcium levels were assessed using the Fluo-4-AM after 6 h of treatment with PA, either alone or co-treated with UA (40 μM) and CDN1163 (10 μM) (scale bar: 20 μm). (<b>D</b>) Mitochondrial calcium levels were determined using the Rhod-2-AM after 24 h of treatment with PA, either alone or co-treated with UA (40 μM) and CDN1163 (10 μM) (scale bar: 20 μm) (* <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001, **** <span class="html-italic">p</span> &lt; 0.0001).</p>
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<p>ER stress markers in PA-treated HepG2 cells with UA. (<b>A</b>) Western blot results showing changes in ER stress markers in HepG2 cells treated with PA. (<b>B</b>) HepG2 cells were treated with PA for 6 h in the absence or presence of UA (40 μM), CDN1163 (10 μM), and thapsigargin (0.1 μM). UA down-regulated the level of ER stress-related proteins. (<b>C</b>) HepG2 cells were treated with PA for 24 h in the absence or presence of UA (40μM), CDN1163 (10 μM), and thapsigargin (0.1 μM). UA down-regulated the level of CHOP (* <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, ns: not significant).</p>
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<p>Impact of <span class="html-italic">SERCA</span> knockdown on UA activity in PA-treated cells. (<b>A</b>–<b>C</b>) Following <span class="html-italic">SERCA</span> knockdown with si-SERCA for 24 h, cells were co-treated with PA and UA (40 μM) for 6 h. ER, cytosolic, and mitochondrial calcium levels were then measured using Mag-Fluo-4 AM, Fluo-4 AM, and Rhod-2 AM, respectively (scale bar: 40 μm). (<b>D</b>) <span class="html-italic">SERCA</span> knockdown using si-<span class="html-italic">SERCA</span> for 24 h confirmed the effect of UA (40 μM) on PA-induced ER stress protein levels, as shown by Western blot (* <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001, **** <span class="html-italic">p</span> &lt; 0.0001, ns: not significant).</p>
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<p>Schematic summary of the target proteins and mechanisms of action of UA. HepG2 cells stimulated with PA release ER calcium through IP<sub>3</sub>R, leading to ER stress. UA binds to SERCA, the ER calcium pump, replenishing ER calcium levels and maintaining calcium homeostasis. This mechanism helps protect the cells from stress-induced damage.</p>
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