Calcium Signaling in Vertebrate Development and Its Role in Disease

Accumulating evidence over the past three decades suggests that altered calcium signaling during development may be a major driving force for adult pathophysiological events. Well over a hundred human genes encode proteins that are specifically dedicated to calcium homeostasis and calcium signaling, and the majority of these are expressed during embryonic development. Recent advances in molecular techniques have identified impaired calcium signaling during development due to either mutations or dysregulation of these proteins. This impaired signaling has been implicated in various human diseases ranging from cardiac malformations to epilepsy. Although the molecular basis of these and other diseases have been well studied in adult systems, the potential developmental origins of such diseases are less well characterized. In this review, we will discuss the recent evidence that examines different patterns of calcium activity during early development, as well as potential medical conditions associated with its dysregulation. Studies performed using various model organisms, including zebrafish, Xenopus, and mouse, have underscored the critical role of calcium activity in infertility, abortive pregnancy, developmental defects, and a range of diseases which manifest later in life. Understanding the underlying mechanisms by which calcium regulates these diverse developmental processes remains a challenge; however, this knowledge will potentially enable calcium signaling to be used as a therapeutic target in regenerative and personalized medicine.

Download Full-text

Autophagy Modulators and Neuroinflammation

Current Medicinal Chemistry ◽

10.2174/0929867325666181031144605 ◽

2020 ◽

Vol 27 (6) ◽

pp. 955-982 ◽

Cited By ~ 4

Author(s):

Kyoung Sang Cho ◽

Jang Ho Lee ◽

Jeiwon Cho ◽

Guang-Ho Cha ◽

Gyun Jee Song

Keyword(s):

Neurodegenerative Disorders ◽

Neurological Disorders ◽

Mammalian Cells ◽

Critical Role ◽

Therapeutic Agents ◽

Mechanisms Of Action ◽

Scientific Interest ◽

Therapeutic Tools ◽

Underlying Mechanisms

Background: Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders. Objective: The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation. Methods: We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions. Results: Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders. Conclusion: Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.

Download Full-text

Role of Vascular Endothelial Growth Factor (VEGF) in Human Embryo Implantation: Clinical Implications

Biomolecules ◽

10.3390/biom11020253 ◽

2021 ◽

Vol 11 (2) ◽

pp. 253

Author(s):

Xi Guo ◽

Hong Yi ◽

Tin Chiu Li ◽

Yu Wang ◽

Huilin Wang ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Recurrent Miscarriage ◽

Embryo Implantation ◽

Critical Role ◽

Angiogenic Factor ◽

Vascular Endothelial ◽

Underlying Mechanisms ◽

Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a well-known angiogenic factor that plays a critical role in various physiological and pathological processes. VEGF also contributes to the process of embryo implantation by enhancing embryo development, improving endometrial receptivity, and facilitating the interactions between the developing embryo and the endometrium. There is a correlation between the alteration of VEGF expression and reproductive failure, including recurrent implantation failure (RIF) and recurrent miscarriage (RM). In order to clarify the role of VEGF in embryo implantation, we reviewed recent literature concerning the expression and function of VEGF in the reproductive system around the time of embryo implantation and we provide a summary of the findings reported so far. We also explored the effects and the possible underlying mechanisms of action of VEGF in embryo implantation.

Download Full-text

The Emerging Role of GC-MSCs in the Gastric Cancer Microenvironment: From Tumor to Tumor Immunity

Stem Cells International ◽

10.1155/2019/8071842 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Zhaoji Pan ◽

Yiqing Tian ◽

Guoping Niu ◽

Chengsong Cao

Keyword(s):

Gastric Cancer ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Wound Repair ◽

Critical Role ◽

The Novel ◽

Potential Biomarker ◽

Underlying Mechanisms ◽

Gastric Cancer Progression

Mesenchymal stem cells (MSCs) have been declared to not only participate in wound repair but also affect tumor progression. Tumor-associated MSCs, directly existing in the tumor microenvironment, play a critical role in tumor initiation, progression, and development. And different tumor-derived MSCs have their own unique characteristics. In this review, we mainly describe and discuss recent advances in our understanding of the emerging role of gastric cancer-derived MSC-like cells (GC-MSCs) in regulating gastric cancer progression and development, as well as the bidirectional influence between GC-MSCs and immune cells of the tumor microenvironment. Moreover, we also discuss the potential biomarker and therapeutic role of GC-MSCs. It is anticipated that new and deep insights into the functionality of GC-MSCs and the underlying mechanisms will promote the novel and promising therapeutic strategies against gastric cancer.

Download Full-text

Preexisting Virus-Specific T Lymphocytes-Mediated Enhancement of Adenovirus Infections to Human Blood CD14+ Cells

Viruses ◽

10.3390/v11020154 ◽

2019 ◽

Vol 11 (2) ◽

pp. 154

Author(s):

Fengling Feng ◽

Jin Zhao ◽

Pingchao Li ◽

Ruiting Li ◽

Ling Chen ◽

...

Keyword(s):

T Lymphocytes ◽

Viral Infection ◽

Viral Infections ◽

Critical Role ◽

Scavenger Receptor ◽

Activation Markers ◽

Gm Csf ◽

Cell Responses ◽

Underlying Mechanisms

Antigen-specific T lymphocytes play a critical role in controlling viral infections. However, we report here that preexisting virus-specific T cell responses also contribute to promoting adenovirus (Ad) infection. Previously, we found that CD14+ monocytes from Ad-seropositive individuals exhibited an increased susceptibility to Ad infection, when compared with that of Ad-seronegative individuals. But the underlying mechanisms for this enhancement of viral infection are not completely clarified. In this study, we found that the efficacy of Ad infection into CD14+ monocytes was significantly decreased after CD3+ T lymphocytes depletion from PBMC samples of Ad-seropositive individuals. In contrast, adding virus-specific CD3+ T lymphocytes into PBMC samples of Ad-seronegative individuals resulted in a significant increase of infection efficacy. CD3+ T lymphocytes in PBMC samples from Ad-seropositive individuals were more sensitive to be activated by adenovirus stimulus, characterized by upregulation of multiple cytokines and activation markers and also enhancement of cell proliferation. Further studies demonstrated that GM-CSF and IL-4 can promote Ad infection by up-regulating the expression of scavenger receptor 1 (SR-A) and integrins αVβ5 receptor of CD14+ cells. And taken together, these results suggest a novel role of virus-specific T cells in mediating enhancement of viral infection, and provide insights to understand the pathogenesis and complicated interactions between viruses and host immune cells.

Download Full-text

The glutathione degrading enzyme, Chac1, is required for calcium signaling in developing zebrafish: redox as an upstream activator of calcium

Biochemical Journal ◽

10.1042/bcj20190077 ◽

2019 ◽

Vol 476 (13) ◽

pp. 1857-1873 ◽

Cited By ~ 1

Author(s):

Shambhu Yadav ◽

Bindia Chawla ◽

Mohammad Anwar Khursheed ◽

Rajesh Ramachandran ◽

Anand Kumar Bachhawat

Keyword(s):

Redox Potential ◽

Calcium Signaling ◽

Reduced Glutathione ◽

Developmental Defects ◽

Degrading Enzyme ◽

Embryonic Lethal ◽

Intracellular Glutathione ◽

Cellular Oxidation ◽

Glutathione Redox

Abstract Calcium signaling is essential for embryonic development but the signals upstream of calcium are only partially understood. Here, we investigate the role of the intracellular glutathione redox potential in calcium signaling using the Chac1 protein of zebrafish. A member of the γ-glutamylcyclotransferase family of enzymes, the zebrafish Chac1 is a glutathione-degrading enzyme that acts only on reduced glutathione. The zebrafish chac1 expression was seen early in development, and in the latter stages, in the developing muscles, brain and heart. The chac1 knockdown was embryonic lethal, and the developmental defects were seen primarily in the myotome, brain and heart where chac1 was maximally expressed. The phenotypes could be rescued by the WT Chac1 but not by the catalytically inactive Chac1 that was incapable of degrading glutathione. The ability of chac1 to alter the intracellular glutathione redox potential in the live animals was examined using Grx1-roGFP2. The chac1 morphants lacked the increased degree of cellular oxidation seen in the WT zebrafish. As calcium is also known to be critical for the developing myotomes, brain and heart, we further investigated if the chac1 knockdown phenotypes were a consequence of the lack of calcium signals. We observed using GCaMP6s, that calcium transients normally seen in the developing embryos were strongly attenuated in these knockdowns. The study thus identifies Chac1 and the consequent change in intracellular glutathione redox potential as important upstream activators of calcium signaling during development.

Download Full-text

Punicalagin protects H9c2 cardiomyocytes from doxorubicin-induced toxicity through activation of Nrf2/HO-1 signaling

Bioscience Reports ◽

10.1042/bsr20190229 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 2

Author(s):

Mingfang Ye ◽

Linlin Zhang ◽

Yuanming Yan ◽

Huizhong Lin

Keyword(s):

Wide Spectrum ◽

Critical Role ◽

Antitumor Agent ◽

Cytochrome C Release ◽

Beneficial Effects ◽

H9c2 Cardiomyocytes ◽

Underlying Mechanisms ◽

Interfering Rna

Abstract Doxorubicin (DOX) is a wide-spectrum antitumor agent, but its clinical application is largely limited by its cardiotoxicity. Therefore, identification of effective agents against DOX-induced cardiotoxicity is of critical importance. The present study aimed to determine the beneficial role of punicalagin (PUN), a polyphenol isolated from pomegranate, in DOX-induced cardiotoxicity in vitro and explored the underlying mechanisms. H9c2 cardiomyocytes were pretreated with different concentrations (50, 100 and 200 μM) of PUN prior to DOX exposure. The results showed that PUN pretreatment significantly increased cell viability, inhibited lactate dehydrogenase (LDH) release and suppressed cell apoptosis induced by DOX. Additionally, PUN pretreatment attenuated the loss of mitochondrial membrane potential and cytochrome c release. Besides, PUN further enhanced the expression of nuclear Nrf2 and HO-1 in DOX-treated H9c2 cells, and the aforementioned beneficial effects of PUN were partially abolished by small interfering RNA (siRNA)-mediated Nrf2 knockdown. Hence, our findings clearly revealed that PUN might be a promising agent for alleviating the cardiotoxicity of DOX, and Nrf2/HO-1 signaling might serve a critical role during this process.

Download Full-text

Reduced Expression of Glutathione S-Transferase α4 Promotes Vascular Neointimal Hyperplasia in CKD

Journal of the American Society of Nephrology ◽

10.1681/asn.2017030290 ◽

2017 ◽

Vol 29 (2) ◽

pp. 505-517 ◽

Cited By ~ 2

Author(s):

Jinlong Luo ◽

Guang Chen ◽

Ming Liang ◽

Aini Xie ◽

Qingtian Li ◽

...

Keyword(s):

Glutathione Transferase ◽

Neointimal Hyperplasia ◽

Critical Role ◽

Mapk Signaling ◽

Neointima Formation ◽

Glutathione S Transferase ◽

Protein Levels ◽

Underlying Mechanisms ◽

Arteries And Veins

Neointima formation is the leading cause of arteriovenous fistula (AVF) failure. We have shown that CKD accelerates this process by transforming the vascular smooth muscle cells (SMCs) lining the AVF from a contractile to the synthetic phenotype. However, the underlying mechanisms affecting this transformation are not clear. Previous studies have shown that the α-class glutathione transferase isozymes have an important role in regulating 4-hydroxynonenal (4-HNE)–mediated proliferative signaling of cells. Here, using both the loss- and gain-of-function approaches, we investigated the role of glutathione S-transferase α4 (GSTA4) in modulating cellular 4-HNE levels for the transformation and proliferation of SMCs. Compared with non-CKD controls, mice with CKD had downregulated expression of GSTA4 at the mRNA and protein levels, with concomitant increase in 4-HNE in arteries and veins. This effect was associated with upregulated phosphorylation of MAPK signaling pathway proteins in proliferating SMCs. Overexpressing GSTA4 blocked 4-HNE–induced SMC proliferation. Additionally, inhibitors of MAPK signaling inhibited the 4-HNE–induced responses. Compared with wild-type mice, mice lacking GSTA4 exhibited increased CKD-induced neointima formation in AVF. Transient expression of an activated form of GSTA4, achieved using a combined Tet-On/Cre induction system in mice, lowered levels of 4-HNE and reduced the proliferation of SMCs. Together, these results demonstrate the critical role of GSTA4 in blocking CKD-induced neointima formation and AVF failure.

Download Full-text

RNA-Sequencing-Based Transcriptomic Analysis Reveals a Role for Annexin-A1 in Classical and Influenza A Virus-Induced Autophagy

Cells ◽

10.3390/cells9061399 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1399 ◽

Cited By ~ 1

Author(s):

Jianzhou Cui ◽

Dhakshayini Morgan ◽

Dao Han Cheng ◽

Sok Lin Foo ◽

Gracemary L. R. Yap ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A Virus ◽

Influenza A ◽

Influenza Infection ◽

Critical Role ◽

Mtor Inhibitors ◽

Influenza Viruses ◽

Annexin A1 ◽

Underlying Mechanisms

Influenza viruses have been shown to use autophagy for their survival. However, the proteins and mechanisms involved in the autophagic process triggered by the influenza virus are unclear. Annexin-A1 (ANXA1) is an immunomodulatory protein involved in the regulation of the immune response and Influenza A virus (IAV) replication. In this study, using clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 (CRISPR associated protein 9) deletion of ANXA1, combined with the next-generation sequencing, we systematically analyzed the critical role of ANXA1 in IAV infection as well as the detailed processes governing IAV infection, such as macroautophagy. A number of differentially expressed genes were uniquely expressed in influenza A virus-infected A549 parental cells and A549 ∆ANXA1 cells, which were enriched in the immune system and infection-related pathways. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway revealed the role of ANXA1 in autophagy. To validate this, the effect of mechanistic target of rapamycin (mTOR) inhibitors, starvation and influenza infection on autophagy was determined, and our results demonstrate that ANXA1 enhances autophagy induced by conventional autophagy inducers and influenza virus. These results will help us to understand the underlying mechanisms of IAV infection and provide a potential therapeutic target for restricting influenza viral replication and infection.

Download Full-text

Role of EGFR/ErbB2 and PI3K/AKT/e-NOS in Lycium barbarum polysaccharides Ameliorating Endothelial Dysfunction Induced by Oxidative Stress

The American Journal of Chinese Medicine ◽

10.1142/s0192415x19500782 ◽

2019 ◽

Vol 47 (07) ◽

pp. 1523-1539 ◽

Cited By ~ 2

Author(s):

Wenjuan Zhang ◽

Huifang Yang ◽

Lingqin Zhu ◽

Yan Luo ◽

Lihong Nie ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Cell Viability ◽

Therapeutic Option ◽

Critical Role ◽

Ang Ii ◽

Lycium Barbarum ◽

Underlying Mechanisms ◽

Lycium Barbarum Polysaccharides

Lycium barbarum polysaccharides (LBP) are the major ingredients of wolfberry. In this study, we investigated the role of LBP in endothelial dysfunction induced by oxidative stress and the underlying mechanisms using thoracic aortic endothelial cells of rat (RAECs) as a model. We found that Ang II inhibits cell viability of RAECs with 10[Formula: see text][Formula: see text]mol/L of Ang II treatment for 24[Formula: see text]h most potential ([Formula: see text]), the level of reactive oxygen species (ROS) is increased by Ang II treatment ([Formula: see text]), and the expression of Occludin and Zonula occludens-1 (ZO-1) is decreased by Ang II treatment ([Formula: see text]). However, preincubation of cells with LBP could inhibit the changes caused by Ang II, LBP increased cell viability ([Formula: see text]), decreased the level of ROS ([Formula: see text]), and up-regulated the expression of Occludin ([Formula: see text]) and ZO-1. In addition, Ang II treatment increased the expression of EGFR and p-EGFR (Try1172) and which can be inhibited by LBP. On the contrary, expression of ErbB2, p-ErbB2 (Try1248), PI3K, p-e-NOS (Ser1177) ([Formula: see text]), and p-AKT (Ser473) ([Formula: see text]) was inhibited by Ang II treatment and which can be increased by LBP. Treatment of the cells with inhibitors showed that the regulation of p-e-NOS and p-AKT expression by Ang II and LBP can be blocked by PI3K inhibitor wortmannin but not EGFR and ErbB2 inhibitor AC480. Taken together, our results suggested that LBP plays a critical role in maintaining the integrality of blood vessel endothelium through reduced production of ROS via regulating the activity of EGFR, ErbB2, PI3K/AKT/e-NOS, and which may offer a novel therapeutic option in the management of endothelial dysfunction.

Download Full-text

Snapin deficiency is associated with developmental defects of the central nervous system

Bioscience Reports ◽

10.1042/bsr20100110 ◽

2010 ◽

Vol 31 (2) ◽

pp. 151-158 ◽

Cited By ~ 8

Author(s):

Bing Zhou ◽

Yi-Bing Zhu ◽

Lin Lin ◽

Qian Cai ◽

Zu-Hang Sheng

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Protein Quality ◽

Third Ventricle ◽

Critical Role ◽

Developmental Defects ◽

Lysosomal Function ◽

Quality Control Process ◽

The Central Nervous System

The autophagy–lysosomal pathway is an intracellular degradation process essential for maintaining neuronal homoeostasis. Defects in this pathway have been directly linked to a growing number of neurodegenerative disorders. We recently revealed that Snapin plays a critical role in co-ordinating dynein-driven retrograde transport and late endosomal–lysosomal trafficking, thus maintaining efficient autophagy–lysosomal function. Deleting snapin in neurons impairs lysosomal proteolysis and reduces the clearance of autolysosomes. The role of the autophagy–lysosomal system in neuronal development is, however, largely uncharacterized. Here, we report that snapin deficiency leads to developmental defects in the central nervous system. Embryonic snapin−/− mouse brain showed reduced cortical plates and intermediate zone cell density, increased apoptotic death in the cortex and third ventricle, enhanced membrane-bound LC3-II staining associated with autophagic vacuoles and an accumulation of polyubiquitinated proteins in the cortex and hippocampus. Thus our results provide in vivo evidence for the essential role of late endocytic transport and autophagy–lysosomal function in maintaining neuronal survival and development of the mammalian central nervous system. In addition, our study supports the existence of a functional interplay between the autophagy–lysosome and ubiquitin–proteasome systems in the protein quality-control process.

Download Full-text