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1.
Insight of the mitochondrial genomes of the Orang Asli and Malays: The heterogeneity and the disease-associated variants.
Sukri, A, Noorizhab, MNF, Teh, LK, Salleh, MZ
Mitochondrion. 2022;:74-84
Abstract
Orang Asli are the oldest inhabitants in Peninsular Malaysia that forms as a national minority while the Malays are the majority. The study aimed to screen the mitochondrial genomes of the Orang Asli and the Malays to discover the disease-associated variants. A total of 99 Orang Asli from six tribes (Bateq, Cheq Wong, Orang Kanaq, Kensiu, Lanoh, and Semai) were recruited. Mitochondrial genome sequencing was conducted using a next-generation sequencing platform. Furthermore, we retrieved mitochondrial DNA sequences from the Malays for comparison. The clinical significance, pathogenicity prediction and frequency of variants were determined using online tools. Variants associated with mitochondrial diseases were detected in the 2 populations. A high frequency of variants associated with mitochondrial diseases, breast cancer, prostate cancer, and cervical cancer were detected in the Orang Asli and modern Malays. As medicine evolves to adopt prediction and prevention of diseases, this study highlights the need for intervention to adopt genomics medicine to strategise better healthcare management as a way forward for Precision Health.
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2.
Platelet calcium signaling by G-protein coupled and ITAM-linked receptors regulating anoctamin-6 and procoagulant activity.
Fernández, DI, Kuijpers, MJE, Heemskerk, JWM
Platelets. 2021;(7):863-871
Abstract
Most agonists stimulate platelet Ca2+ rises via G-protein coupled receptors (GPCRs) or ITAM-linked receptors (ILRs). Well studied are the GPCRs stimulated by the soluble agonists thrombin (PAR1, PAR4), ADP (P2Y1, P2Y12), and thromboxane A2 (TP), signaling via phospholipase (PLC)β isoforms. The platelet ILRs glycoprotein VI (GPVI), C-type lectin-like receptor 2 (CLEC2), and FcγRIIa are stimulated by adhesive ligands or antibody complexes and signal via tyrosine protein kinases and PLCγ isoforms. Marked differences exist between the GPCR- and ILR-induced Ca2+ signaling in: (i) dependency of tyrosine phosphorylation; (ii) oscillatory versus continued Ca2+ rises by mobilization from the endoplasmic reticulum; and (iii) smaller or larger role of extracellular Ca2+ entry via STIM1/ORAI1. Co-stimulation of both types of receptors, especially by thrombin (PAR1/4) and collagen (GPVI), leads to a highly enforced Ca2+ rise, involving mitochondrial Ca2+ release, which activates the ion and phospholipid channel, anoctamin-6. This highly Ca2+-dependent process causes swelling, ballooning, and phosphatidylserine expression, establishing a unique platelet population swinging between vital and necrotic (procoagulant 'zombie' platelets). Additionally, the high Ca2+ status of procoagulant platelets induces a set of additional events: (i) Ca2+ dependent cleavage of signaling proteins and receptors via calpain and ADAM isoforms; (ii) microvesiculation; (iii) enhanced coagulation factor binding; and (iv) fibrin-coat formation involving transglutaminases. Given the additive roles of GPCR and ILR in Ca2+ signal generation, high-throughput screening of biomolecules or small molecules based on Ca2+ flux measurements provides a promising way to find new inhibitors interfering with prolonged high Ca2+, phosphatidylserine expression, and hence platelet procoagulant activity.
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3.
In Vitro Non-Genomic Effects of Calcifediol on Human Preosteoblastic Cells.
Donati, S, Palmini, G, Romagnoli, C, Aurilia, C, Miglietta, F, Falsetti, I, Marini, F, Zonefrati, R, Galli, G, Marcucci, G, et al
Nutrients. 2021;(12)
Abstract
Several recent studies have demonstrated that the direct precursor of vitamin D3, the calcifediol [25(OH)D3], through the binding to the nuclear vitamin D receptor (VDR), is able to regulate the expression of many genes involved in several cellular processes. Considering that itself may function as a VDR ligand, although with a lower affinity, respect than the active form of vitamin D, we have assumed that 25(OH)D3 by binding the VDR could have a vitamin's D3 activity such as activating non-genomic pathways, and in particular we selected mesenchymal stem cells derived from human adipose tissue (hADMSCs) for the in vitro assessment of the intracellular Ca2+ mobilization in response to 25(OH)D3. Our result reveals the ability of 25(OH)D3 to activate rapid, non-genomic pathways, such as an increase of intracellular Ca2+ levels, similar to what observed with the biologically active form of vitamin D3. hADMSCs loaded with Fluo-4 AM exhibited a rapid and sustained increase in intracellular Ca2+ concentration as a result of exposure to 10-5 M of 25(OH)D3. In this work, we show for the first time the in vitro ability of 25(OH)D3 to induce a rapid increase of intracellular Ca2+ levels in hADMSCs. These findings represent an important step to better understand the non-genomic effects of vitamin D3 and its role in endocrine system.
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4.
Calcium signaling in hepatitis B virus infection and its potential as a therapeutic target.
Kong, F, Zhang, F, Liu, X, Qin, S, Yang, X, Kong, D, Pan, X, You, H, Zheng, K, Tang, R
Cell communication and signaling : CCS. 2021;(1):82
Abstract
As a ubiquitous second messenger, calcium (Ca2+) can interact with numerous cellular proteins to regulate multiple physiological processes and participate in a variety of diseases, including hepatitis B virus (HBV) infection, which is a major cause of hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. In recent years, several studies have demonstrated that depends on the distinct Ca2+ channels on the plasma membrane, endoplasmic reticulum, as well as mitochondria, HBV can elevate cytosolic Ca2+ levels. Moreover, within HBV-infected cells, the activation of intracellular Ca2+ signaling contributes to viral replication via multiple molecular mechanisms. Besides, the available evidence indicates that targeting Ca2+ signaling by suitable pharmaceuticals is a potent approach for the treatment of HBV infection. In the present review, we summarized the molecular mechanisms related to the elevation of Ca2+ signaling induced by HBV to modulate viral propagation and the recent advances in Ca2+ signaling as a potential therapeutic target for HBV infection. Video Abstract.
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5.
Emerging roles of the CBL-CIPK calcium signaling network as key regulatory hub in plant nutrition.
Dong, Q, Bai, B, Almutairi, BO, Kudla, J
Journal of plant physiology. 2021;:153335
Abstract
Plant physiology and development essentially depend on sufficient uptake of various essential nutritive ions via their roots and their appropriate transport and distribution within the organism. Many of these essential nutrients are heterogeneously distributed in the soil or are available in fluctuating concentrations. This natural situation requires constant regulatory adjustment and balancing of nutrient uptake and homeostasis. Here, we review recent findings on the role of Ca2+ signals and Ca2+-dependent regulation via the CBL-CIPK Ca2+ sensor-protein kinase network in these processes. We put special emphasis on Ca2+ controlled processes that contribute to establishing the homeostasis of macro-nutrients like potassium (K+), nitrogen (N), and magnesium (Mg2+) and on the micro-nutrient iron (Fe). Increasing experimental evidence indicates the occurrence of nutrient-specific, spatially and temporally defined cytoplasmic Ca2+ elevations as early responses to nutrient fluctuations. Specific CBL-CIPK complexes translate these signals into phosphorylation regulation of important channels and transporters like AKT1, NPF6.3/NRT1.1, AMT1, SLAC1, TPK1 and IRT1. We discuss a crucial and coordinating role for these Ca2+ signaling mechanisms in regulating the sensing, uptake, distribution and storage of various ions. Finally, we reflect on the emerging multifaceted and potentially integrating role of the "nutrient" kinase CIPK23 in regulating multiple nutrient responses. From this inventory, we finally deduce potential mechanisms that can convey the coordinated regulation of distinct steps in the transport of one individual ion and mechanisms that can bring about the integration of adaptive responses to fluctuations of different ions to establish a faithfully balanced plant nutrient homeostasis.
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6.
The Orai Pore Opening Mechanism.
Tiffner, A, Maltan, L, Weiß, S, Derler, I
International journal of molecular sciences. 2021;(2)
Abstract
Cell survival and normal cell function require a highly coordinated and precise regulation of basal cytosolic Ca2+ concentrations. The primary source of Ca2+ entry into the cell is mediated by the Ca2+ release-activated Ca2+ (CRAC) channel. Its action is stimulated in response to internal Ca2+ store depletion. The fundamental constituents of CRAC channels are the Ca2+ sensor, stromal interaction molecule 1 (STIM1) anchored in the endoplasmic reticulum, and a highly Ca2+-selective pore-forming subunit Orai1 in the plasma membrane. The precise nature of the Orai1 pore opening is currently a topic of intensive research. This review describes how Orai1 gating checkpoints in the middle and cytosolic extended transmembrane regions act together in a concerted manner to ensure an opening-permissive Orai1 channel conformation. In this context, we highlight the effects of the currently known multitude of Orai1 mutations, which led to the identification of a series of gating checkpoints and the determination of their role in diverse steps of the Orai1 activation cascade. The synergistic action of these gating checkpoints maintains an intact pore geometry, settles STIM1 coupling, and governs pore opening. We describe the current knowledge on Orai1 channel gating mechanisms and summarize still open questions of the STIM1-Orai1 machinery.
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7.
Molecular Evolution of Calcium Signaling and Transport in Plant Adaptation to Abiotic Stress.
Tong, T, Li, Q, Jiang, W, Chen, G, Xue, D, Deng, F, Zeng, F, Chen, ZH
International journal of molecular sciences. 2021;(22)
Abstract
Adaptation to unfavorable abiotic stresses is one of the key processes in the evolution of plants. Calcium (Ca2+) signaling is characterized by the spatiotemporal pattern of Ca2+ distribution and the activities of multi-domain proteins in integrating environmental stimuli and cellular responses, which are crucial early events in abiotic stress responses in plants. However, a comprehensive summary and explanation for evolutionary and functional synergies in Ca2+ signaling remains elusive in green plants. We review mechanisms of Ca2+ membrane transporters and intracellular Ca2+ sensors with evolutionary imprinting and structural clues. These may provide molecular and bioinformatics insights for the functional analysis of some non-model species in the evolutionarily important green plant lineages. We summarize the chronological order, spatial location, and characteristics of Ca2+ functional proteins. Furthermore, we highlight the integral functions of calcium-signaling components in various nodes of the Ca2+ signaling pathway through conserved or variant evolutionary processes. These ultimately bridge the Ca2+ cascade reactions into regulatory networks, particularly in the hormonal signaling pathways. In summary, this review provides new perspectives towards a better understanding of the evolution, interaction and integration of Ca2+ signaling components in green plants, which is likely to benefit future research in agriculture, evolutionary biology, ecology and the environment.
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8.
The signatures of organellar calcium.
Resentini, F, Ruberti, C, Grenzi, M, Bonza, MC, Costa, A
Plant physiology. 2021;(4):1985-2004
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Free full text
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Abstract
Recent insights about the transport mechanisms involved in the in and out of calcium ions in plant organelles, and their role in the regulation of cytosolic calcium homeostasis in different signaling pathways.
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9.
Insight into susceptibility genes associated with bipolar disorder: a systematic review.
Kalcev, G, Preti, A, Scano, A, Orrù, G, Carta, MG
European review for medical and pharmacological sciences. 2021;(18):5701-5724
Abstract
OBJECTIVE Bipolar disorder (BD) is a severe disorder, and it is associated with an increased risk of mortality. About 25% of patients with BD have attempted and 11% have died by suicide. All these characteristics suggest that the disorders within the bipolar spectrum are a crucial public health problem. With the development of molecular genetics in recent decades, it was possible to more easily detect risk genes associated with this disorder. This study aimed at summarizing the findings of systematic reviews and meta-analyses on the topic and assessing the quality of the available evidence. MATERIALS AND METHODS PubMed/Medline and Web of Science were searched to identify systematic reviews and meta-analyses published during 2013-2019. Standard methodology was applied to synthesize and assess the retrieved literature. RESULTS This systematic review identifies a number of potential risk genes associated with bipolar disorder whose mechanism of action has yet to be confirmed. They are divided into several groups: 1) a list of the most significant susceptibility genetic factors associated with BD; 2) the implication of the ZNF804A gene in BD; 3) the role of genes involved in calcium signaling in BD; 4) DNA methylation in BD; 5) BD and risk suicide genes; 6) susceptibility genes for early-onset BD; 7) candidate genes common to both BD and schizophrenia; 8) genes involved in cognitive status in BD cases; 9) genes involved in structural alteration in BD brain tissue; 10) genes involved in lithium response in BD. CONCLUSIONS Future research should concentrate on molecular mechanisms by which genetic variants play a major role in BD. Supplemental research is needed to replicate the applicable results.
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10.
Genes Associated with Calcium Signaling are Involved in Alcohol-Induced Breast Cancer Growth.
Ho, C, Lin, CY
Alcoholism, clinical and experimental research. 2021;(1):79-91
Abstract
BACKGROUND Alcohol consumption is a risk factor for breast cancer, contributing to up to nearly 23,000 new cases each year. Mechanistic studies show that alcohol increases tumor aggressiveness and metastatic potential, promotes angiogenesis, induces chronic inflammation, and dysregulates RNA polymerase III-related genes. Alcohol has also been shown to affect estrogen signaling in breast cancer, including in our study of the transcriptomic effects of alcohol in breast cancer cells. METHODS To elucidate mechanisms of action of alcohol in breast cancer, we carried out secondary analyses of our alcohol-responsive transcriptome data using gene ontology and pathway databases and analysis tools and cistromic data analysis of candidate transcription factors which may mediate the transcriptomic alterations. Predicted alcohol-responsive pathways and mechanisms were perturbed and examined experimentally in breast cancer cells. The clinical relevance of identified genes was determined by expression profiles in patient samples and correlation with disease outcomes and alcohol consumption in previously published study cohorts. RESULTS Gene ontology analysis showed that alcohol alters the expression of many metabolism-related genes, and cistromic data of differentially expressed genes revealed the potential involvement of nuclear factor of activated T cells 3 (NFATC3) in mediating the transcriptomic effects of alcohol. Pathway analysis also predicted regulation of calcium signaling by alcohol in breast cancer cells. Chemical perturbation of this pathway reversed the effect of alcohol on breast cancer cell growth and reduced the elevated cytosolic Ca2+ levels induced by alcohol. Expression levels of alcohol-responsive genes in tumor samples from breast cancer patients are associated with poor disease outcomes. Moreover, expression of some of these genes was altered in breast cancer patients who consumed alcohol previously as compared to those who did not drink. CONCLUSION Alcohol alters expression of genes that regulate intracellular calcium levels and downstream signaling pathways which drive breast cancer cell proliferation and disease progression.