scholarly journals The Functions of ZIP8, ZIP14, and ZnT10 in the Regulation of Systemic Manganese Homeostasis

2020 ◽  
Vol 21 (9) ◽  
pp. 3304
Author(s):  
James W.W. Winslow ◽  
Kirsten H. Limesand ◽  
Ningning Zhao
Keyword(s):  
Antioxidant Defense ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
The Body ◽  
Metal Transporters ◽  
Cellular Processes ◽  
The Past ◽  
Genes Encoding ◽  
Essential Nutrient

As an essential nutrient, manganese is required for the regulation of numerous cellular processes, including cell growth, neuronal health, immune cell function, and antioxidant defense. However, excess manganese in the body is toxic and produces symptoms of neurological and behavioral defects, clinically known as manganism. Therefore, manganese balance needs to be tightly controlled. In the past eight years, mutations of genes encoding metal transporters ZIP8 (SLC39A8), ZIP14 (SLC39A14), and ZnT10 (SLC30A10) have been identified to cause dysregulated manganese homeostasis in humans, highlighting the critical roles of these genes in manganese metabolism. This review focuses on the most recent advances in the understanding of physiological functions of these three identified manganese transporters and summarizes the molecular mechanisms underlying how the loss of functions in these genes leads to impaired manganese homeostasis and human diseases.

scholarly journals NF-κB and Human Cancer: What Have We Learned over the Past 35 Years?

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 889
Author(s):  
Thomas D. Gilmore
Keyword(s):  
Cell Cycle Progression ◽  
Cell Function ◽  
Immune Cell ◽  
Human Cancer ◽  
Cancer Prognosis ◽  
Cycle Progression ◽  
The Past ◽  
Human Cancers ◽  
Limited Success ◽  
Upstream Regulators

Transcription factor NF-κB has been extensively studied for its varied roles in cancer development since its initial characterization as a potent retroviral oncogene. It is now clear that NF-κB also plays a major role in a large variety of human cancers, including especially ones of immune cell origin. NF-κB is generally constitutively or aberrantly activated in human cancers where it is involved. These activations can occur due to mutations in the NF-κB transcription factors themselves, in upstream regulators of NF-κB, or in pathways that impact NF-κB. In addition, NF-κB can be activated by tumor-assisting processes such as inflammation, stromal effects, and genetic or epigenetic changes in chromatin. Aberrant NF-κB activity can affect many tumor-associated processes, including cell survival, cell cycle progression, inflammation, metastasis, angiogenesis, and regulatory T cell function. As such, inhibition of NF-κB has often been investigated as an anticancer strategy. Nevertheless, with a few exceptions, NF-κB inhibition has had limited success in human cancer treatment. This review covers general themes that have emerged regarding the biological roles and mechanisms by which NF-κB contributes to human cancers and new thoughts on how NF-κB may be targeted for cancer prognosis or therapy.

scholarly journals A bi-directional dialog between vascular cells and monocytes/macrophages regulates tumor progression

2021 ◽  
Author(s):  
Victor Delprat ◽  
Carine Michiels
Keyword(s):  
Tumor Progression ◽  
Cancer Progression ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
The Body ◽  
Vascular Cells ◽  
Tumor Associated Macrophage ◽  
Immune Cell Activation ◽  
The Impact

AbstractCancer progression largely depends on tumor blood vessels as well on immune cell infiltration. In various tumors, vascular cells, namely endothelial cells (ECs) and pericytes, strongly regulate leukocyte infiltration into tumors and immune cell activation, hence the immune response to cancers. Recently, a lot of compelling studies unraveled the molecular mechanisms by which tumor vascular cells regulate monocyte and tumor-associated macrophage (TAM) recruitment and phenotype, and consequently tumor progression. Reciprocally, TAMs and monocytes strongly modulate tumor blood vessel and tumor lymphatic vessel formation by exerting pro-angiogenic and lymphangiogenic effects, respectively. Finally, the interaction between monocytes/TAMs and vascular cells is also impacting several steps of the spread of cancer cells throughout the body, a process called metastasis. In this review, the impact of the bi-directional dialog between blood vascular cells and monocytes/TAMs in the regulation of tumor progression is discussed. All together, these data led to the design of combinations of anti-angiogenic and immunotherapy targeting TAMs/monocyte whose effects are briefly discussed in the last part of this review.

scholarly journals Neuro–Immune Cell Units: A New Paradigm in Physiology

2019 ◽  
Vol 37 (1) ◽  
pp. 19-46 ◽  
Author(s):  
Cristina Godinho-Silva ◽  
Filipa Cardoso ◽  
Henrique Veiga-Fernandes
Keyword(s):  
Adipose Tissue ◽  
Paradigm Shift ◽  
Tissue Repair ◽  
Immune Cell ◽  
The Body ◽  
New Paradigm ◽  
Environmental Signals ◽  
The Past ◽  
Physiological Processes ◽  
The Impact

The interplay between the immune and nervous systems has been acknowledged in the past, but only more recent studies have started to unravel the cellular and molecular players of such interactions. Mounting evidence indicates that environmental signals are sensed by discrete neuro–immune cell units (NICUs), which represent defined anatomical locations in which immune and neuronal cells colocalize and functionally interact to steer tissue physiology and protection. These units have now been described in multiple tissues throughout the body, including lymphoid organs, adipose tissue, and mucosal barriers. As such, NICUs are emerging as important orchestrators of multiple physiological processes, including hematopoiesis, organogenesis, inflammation, tissue repair, and thermogenesis. In this review we focus on the impact of NICUs in tissue physiology and how this fast-evolving field is driving a paradigm shift in our understanding of immunoregulation and organismal physiology.

scholarly journals Pyruvate dehydrogenase kinase is a negative regulator of interleukin-10 production in macrophages

2020 ◽  
Vol 12 (7) ◽  
pp. 543-555
Author(s):  
Yi Rang Na ◽  
Daun Jung ◽  
Juha Song ◽  
Jong-Wan Park ◽  
Jung Joo Hong ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Pyruvate Dehydrogenase ◽  
Cell Function ◽  
Immune Cell ◽  
Interleukin 10 ◽  
The Body ◽  
Pyruvate Dehydrogenase Kinase ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Phase

Abstract Interleukin-10 (IL-10) is the most potent anti-inflammatory cytokine in the body and plays an essential role in determining outcomes of many inflammatory diseases. Cellular metabolism is a critical determinant of immune cell function; however, it is currently unclear whether metabolic processes are specifically involved in IL-10 production. In this study, we aimed to find the central metabolic molecule regulating IL-10 production of macrophages, which are the main producers of IL-10. Transcriptomic analysis identified that metabolic changes were predominantly enriched in Kupffer cells at the early inflammatory phase of a mouse endotoxemia model. Among them, pyruvate dehydrogenase kinase (PDK)-dependent acute glycolysis was negatively involved in IL-10 production. Inhibition or knockdown of PDK selectively increased macrophage IL-10 expression. Mechanistically, PDK inhibition increased IL-10 production via profound phosphorylation of adenosine monophosphate (AMP)-activated protein kinase alpha 1 (AMPKα1) by restricting glucose uptake in lipopolysaccharide-stimulated macrophages. AMPKα1 consequently activated p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and cyclic AMP-responsive element-binding protein to regulate IL-10 production. Our study uncovers a previously unknown regulatory mechanism of IL-10 in activated macrophages involving an immunometabolic function of PDK.

scholarly journals Molecular Mechanisms of Leukocyte Migration and Its Potential Targeting—Lessons Learned From MKL1/SRF-Related Primary Immunodeficiency Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Evelien G. G. Sprenkeler ◽  
Carla Guenther ◽  
Imrul Faisal ◽  
Taco W. Kuijpers ◽  
Susanna C. Fagerholm
Keyword(s):  
Immune System ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Serum Response Factor ◽  
Cell Function ◽  
Immune Cell ◽  
Leukocyte Adhesion ◽  
Adaptive Immune System ◽  
Lessons Learned ◽  
Megakaryoblastic Leukemia

Megakaryoblastic leukemia 1 (MKL1) deficiency is one of the most recently discovered primary immunodeficiencies (PIDs) caused by cytoskeletal abnormalities. These immunological “actinopathies” primarily affect hematopoietic cells, resulting in defects in both the innate immune system (phagocyte defects) and adaptive immune system (T-cell and B-cell defects). MKL1 is a transcriptional coactivator that operates together with serum response factor (SRF) to regulate gene transcription. The MKL/SRF pathway has been originally described to have important functions in actin regulation in cells. Recent results indicate that MKL1 also has very important roles in immune cells, and that MKL1 deficiency results in an immunodeficiency affecting the migration and function of primarily myeloid cells such as neutrophils. Interestingly, several actinopathies are caused by mutations in genes which are recognized MKL(1/2)-dependent SRF-target genes, namely ACTB, WIPF1, WDR1, and MSN. Here we summarize these and related (ARPC1B) actinopathies and their effects on immune cell function, especially focusing on their effects on leukocyte adhesion and migration. Furthermore, we summarize recent therapeutic efforts targeting the MKL/SRF pathway in disease.

scholarly journals T-cell dysfunction in chronic lymphocytic leukemia from an epigenetic perspective

Haematologica ◽  
2021 ◽  
Author(s):  
Fleur S. Peters ◽  
Jonathan C. Strefford ◽  
Eric Eldering ◽  
Arnon P. Kater
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Lymphocytic Leukemia ◽  
T Cell Therapy ◽  
High Expectations ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

Cellular immunotherapeutic approaches such as chimeric antigen receptor (CAR) T-cell therapy in chronic lymphocytic leukemia (CLL) thus far have not met the high expectations. Therefore it is essential to better understand the molecular mechanisms of CLLinduced T-cell dysfunction. Even though a significant number of studies are available on T-cell function and dysfunction in CLL patients, none examine dysfunction at the epigenomic level. In non-malignant T-cell research, epigenomics is widely employed to define the differentiation pathway into T-cell exhaustion. Additionally, metabolic restrictions in the tumor microenvironment that cause T-cell dysfunction are often mediated by epigenetic changes. With this review paper we argue that understanding the epigenetic (dys)regulation in T cells of CLL patients should be leveled to the knowledge we currently have of the neoplastic B cells themselves. This will permit a complete understanding of how these immune cell interactions regulate T- and B-cell function. Here we relate the cellular and phenotypic characteristics of CLL-induced T-cell dysfunction to epigenetic studies of T-cell regulation emerging from chronic viral infection and tumor models. This paper proposes a framework for future studies into the epigenetic regulation of CLL-induced Tcell dysfunction, knowledge that will help to guide improvements in the utility of autologous T-cell based therapies in CLL.

scholarly journals Inflammatory pathways in female reproductive health and disease

Reproduction ◽  
2009 ◽  
Vol 138 (6) ◽  
pp. 903-919 ◽  
Author(s):  
Henry N Jabbour ◽  
Kurt J Sales ◽  
Rob D Catalano ◽  
Jane E Norman
Keyword(s):  
Reproductive Tract ◽  
Cell Function ◽  
Immune Cell ◽  
Reproductive Function ◽  
The Body ◽  
Inflammatory Pathways ◽  
Female Reproductive Health ◽  
Affected Tissue ◽  
Proper Resolution ◽  
Reproductive Events

Inflammation involves alterations to vascular and immune cell function. It is well recognised that many physiological reproductive events such as ovulation, menstruation, implantation and onset of labour display hallmark signs of inflammation. These are orchestrated by specific molecular pathways involving a host of growth factors, cytokines, chemokines and lipid mediators. Resumption of normal reproductive function involves prompt and proper resolution of these inflammatory pathways. Recent literature confirms that resolution of inflammatory pathways involves specific biochemical events that are activated to re-establish homeostasis in the affected tissue. Moreover, initiation and maintenance of inflammatory pathways are the key components of many pathologies of the reproductive tract and elsewhere in the body. The onset of reproductive disorders or disease may be the result of exacerbated activation and maintenance of inflammatory pathways or their dysregulated resolution. This review will address the role of inflammatory events in normal reproductive function and its pathologies.

scholarly journals A Functional Interplay between 5-Lipoxygenase andμ-Calpain Affects Survival and Cytokine Profile of Human Jurkat T Lymphocyte Exposed to Simulated Microgravity

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Valeria Gasperi ◽  
Cinzia Rapino ◽  
Natalia Battista ◽  
Monica Bari ◽  
Nicolina Mastrangelo ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Molecular Mechanisms ◽  
Simulated Microgravity ◽  
Cell Function ◽  
Immune Cell ◽  
Apoptotic Cell ◽  
Immune Cell Function ◽  
Space Flights ◽  
Apoptotic Death ◽  
Mammalian Tissues

A growing body of evidence strongly indicates that both simulated and authentic weightlessness exert a broad range of effects on mammalian tissues and cells, including impairment of immune cell function and increased apoptotic death. We previously reported that microgravity-dependent activation of 5-lipoxygenase (5-LOX) might play a central role in the initiation of apoptosis in human T lymphocytes, suggesting that the upregulation of this enzyme might be (at least in part) responsible for immunodepression observed in astronauts during space flights. Herein, we supplement novel information about the molecular mechanisms underlying microgravity-triggered apoptotic cell death and immune system deregulation, demonstrating that under simulated microgravity human Jurkat T cells increase the content of cytosolic DNA fragments and cytochrome c (typical hallmarks of apoptosis) and have an upregulated expression and activity ofµ-calpain. These events were paralleled by the unbalance of interleukin- (IL-) 2 and interferon- (INF-)γ, anti- and proapoptotic cytokines, respectively, that seemed to be dependent on the functional interplay between 5-LOX andµ-calpain. Indeed, we report unprecedented evidence that 5-LOX inhibition reduced apoptotic death, restored the initial IL-2/INF-γratio, and more importantly revertedµ-calpain activation induced by simulated microgravity.

Ca2+-Operated Transcriptional Networks: Molecular Mechanisms and In Vivo Models

2008 ◽  
Vol 88 (2) ◽  
pp. 421-449 ◽  
Author(s):  
Britt Mellström ◽  
Magali Savignac ◽  
Rosa Gomez-Villafuertes ◽  
Jose R. Naranjo
Keyword(s):  
Molecular Mechanisms ◽  
Critical Role ◽  
Transcriptional Networks ◽  
Calcium Signal ◽  
In Vivo Models ◽  
Cellular Processes ◽  
Calcium Sensors ◽  
Genes Encoding ◽  
Living Organisms

Calcium is the most universal signal used by living organisms to convey information to many different cellular processes. In this review we present well-known and recently identified proteins that sense and decode the calcium signal and are key elements in the nucleus to regulate the activity of various transcriptional networks. When possible, the review also presents in vivo models in which the genes encoding these calcium sensors-transducers have been modified, to emphasize the critical role of these Ca2+-operated mechanisms in many physiological functions.

scholarly journals Inflammatory Modulation Effect of Glycopeptide fromGanoderma capense(Lloyd) Teng

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Yan Zhou ◽  
Song Chen ◽  
Ran Ding ◽  
Wenbing Yao ◽  
Xiangdong Gao
Keyword(s):  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Underlying Mechanism ◽  
Immunomodulatory Effect ◽  
No Production ◽  
Macrophage Cells ◽  
Competition Study ◽  
Dependent Signaling Pathway ◽  
Inflammatory Modulation

Glycopeptide from Ganoderma capense (Lloyd) Teng (GCGP) injection is widely used in kinds of immune disorders, but little is known about the molecular mechanisms of how GCGP could interfere with immune cell function. In the present study, we have found that GCGP had inflammatory modulation effects on macrophage cells to maintain NO production and iNOS expression at the normal level. Furthermore, western blot analysis showed that the underlying mechanism of immunomodulatory effect of GCGP involved NF-κB p65 translation, IκB phosphorylation, and degradation; NF-κB inhibitor assays also confirmed the results. In addition, competition study showed that GCGP could inhibit LPS from binding to macrophage cells. Our data indicates that GCGP, which may share the same receptor(s) expressed by macrophage cells with LPS, exerted immunomodulatory effect in a NF-κB-dependent signaling pathway in macrophages.

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