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Effects of chitosan and oligochitosans on the phosphatidylinositol 3-kinase-AKT pathway in cancer therapy.
Amirani, E, Hallajzadeh, J, Asemi, Z, Mansournia, MA, Yousefi, B
International journal of biological macromolecules. 2020;:456-467
Abstract
Phosphatidylinositol 3-kinase (PI3K)-AKT pathway is one of the most important kinase signaling networks in the context of cancer development and treatment. Aberrant activation of AKT, the central mediator of this pathway, has been implicated in numerous malignancies including endometrial, hepatocellular, breast, colorectal, prostate, and, cervical cancer. Thus regulation and blockage of this kinase and its key target nodes is an attractive approach in cancer therapy and diverse efforts have been done to achieve this aim. Chitosan is a carbohydrate with multiple interesting applications in cancer diagnosis and treatment strategies. This bioactive polymer and its derivative oligomers commonly used in drug/DNA delivery methods due to their functional properties which improve efficiency of delivery systems. Further, these compounds exert anti-tumor roles through the stimulation of apoptosis, immune enhancing potency, anti-oxidative features and anti-angiogenic roles. Due to the importance of PI3K-AKT signaling in cancer targeting and treatment resistance, this review discusses the involvement of chitosan, oligochitosaccharides and carriers based on these chemicals in the regulation of this pathway in different tumors.
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Microenvironment Remodeling and Subsequent Clinical Implications in Diffuse Large B-Cell Histologic Variant of Richter Syndrome.
Augé, H, Notarantonio, AB, Morizot, R, Quinquenel, A, Fornecker, LM, Hergalant, S, Feugier, P, Broséus, J
Frontiers in immunology. 2020;:594841
Abstract
INTRODUCTION Richter Syndrome (RS) is defined as the development of an aggressive lymphoma in the context of Chronic Lymphocytic Leukemia (CLL), with a Diffuse Large B-Cell Lymphoma (DLBCL) histology in 95% cases. RS genomic landscape shares only a few features with de novo DLBCLs and is marked by a wide spectrum of cytogenetic abnormalities. Little is known about RS microenvironment. Therapeutic options and efficacy are limited, leading to a 12 months median overall survival. The new targeted treatments usually effective in CLL fail to obtain long-term remissions in RS. METHODS We reviewed available PubMed literature about RS genomics, PD-1/PD-L1 (Programmed Death 1/Programmed Death Ligand 1) pathway triggering and subsequent new therapeutic options. RESULTS Data from about 207 patients from four landmark papers were compiled to build an overview of RS genomic lesions and point mutations. A number of these abnormalities may be involved in tumor microenvironment reshaping. T lymphocyte exhaustion through PD-L1 overexpression by tumor cells and subsequent PD-1/PD-L1 pathway triggering is frequently reported in solid cancers. This immune checkpoint inhibitor is also described in B lymphoid malignancies, particularly CLL: PD-1 expression is reported in a subset of prolymphocytes from the CLL lymph node proliferation centers. However, there is only few data about PD-1/PD-L1 pathway in RS. In RS, PD-1 expression is a hallmark of recently described « Regulatory B-cells », which interact with tumor microenvironment by producing inhibiting cytokines such as TGF-β and IL-10, impairing T lymphocytes anti-tumoral function. Based upon the discovery of high PD-1 expression on tumoral B lymphocyte from RS, immune checkpoint blockade therapies such as anti-PD-1 antibodies have been tested on small RS cohorts and provided heterogeneous but encouraging results. CONCLUSION RS genetic landscape and immune evasion mechanisms are being progressively unraveled. New protocols using targeted treatments such as checkpoint inhibitors as single agents or in combination with immunochemotherapy are currently being evaluated.
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Redox Signaling from Mitochondria: Signal Propagation and Its Targets.
Ježek, P, Holendová, B, Plecitá-Hlavatá, L
Biomolecules. 2020;(1)
Abstract
Progress in mass spectroscopy of posttranslational oxidative modifications has enabled researchers to experimentally verify the concept of redox signaling. We focus here on redox signaling originating from mitochondria under physiological situations, discussing mechanisms of transient redox burst in mitochondria, as well as the possible ways to transfer such redox signals to specific extramitochondrial targets. A role of peroxiredoxins is described which enables redox relay to other targets. Examples of mitochondrial redox signaling are discussed: initiation of hypoxia-inducible factor (HIF) responses; retrograde redox signaling to PGC1α during exercise in skeletal muscle; redox signaling in innate immune cells; redox stimulation of insulin secretion, and other physiological situations.
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4.
TGR5 Signaling in Hepatic Metabolic Health.
Holter, MM, Chirikjian, MK, Govani, VN, Cummings, BP
Nutrients. 2020;(9)
Abstract
TGR5 is a G protein-coupled bile acid receptor that is increasingly recognized as a key regulator of glucose homeostasis. While the role of TGR5 signaling in immune cells, adipocytes and enteroendocrine L cells in metabolic regulation has been well described and extensively reviewed, the impact of TGR5-mediated effects on hepatic physiology and pathophysiology in metabolic regulation has received less attention. Recent studies suggest that TGR5 signaling contributes to improvements in hepatic insulin signaling and decreased hepatic inflammation, as well as metabolically beneficial improvements in bile acid profile. Additionally, TGR5 signaling has been associated with reduced hepatic steatosis and liver fibrosis, and improved liver function. Despite the beneficial effects of TGR5 signaling on metabolic health, TGR5-mediated gallstone formation and gallbladder filling complicate therapeutic targeting of TGR5 signaling. To this end, there is a growing need to identify cell type-specific effects of hepatic TGR5 signaling to begin to identify and target the downstream effectors of TGR5 signaling. Herein, we describe and integrate recent advances in our understanding of the impact of TGR5 signaling on liver physiology and how its effects on the liver integrate more broadly with whole body glucose regulation.
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5.
Curcumin attenuates proangiogenic and proinflammatory factors in human eutopic endometrial stromal cells through the NF-κB signaling pathway.
Chowdhury, I, Banerjee, S, Driss, A, Xu, W, Mehrabi, S, Nezhat, C, Sidell, N, Taylor, RN, Thompson, WE
Journal of cellular physiology. 2019;(5):6298-6312
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Abstract
Endometriosis is a chronic gynecological inflammatory disorder in which immune system dysregulation is thought to play a role in its initiation and progression. Due to altered sex steroid receptor concentrations and other signaling defects, eutopic endometriotic tissues have an attenuated response to progesterone. This progesterone-resistance contributes to lesion survival, proliferation, pain, and infertility. The current agency-approved hormonal therapies, including synthetic progestins, GnRH agonists, and danazol are often of limited efficacy and counterproductive to fertility and cause systemic side effects due to suppression of endogenous steroid hormone levels. In the current study, we examined the effects of curcumin (CUR, diferuloylmethane), which has long been used as an anti-inflammatory folk medicine in Asian countries for this condition. The basal levels of proinflammatory and proangiogenic chemokines and cytokines expression were higher in primary cultures of stromal cells derived from eutopic endometrium of endometriosis (EESC) subjects compared with normal endometrial stromal cells (NESC). The treatment of EESC and NESC with CUR significantly and dose-dependently reduced chemokine and cytokine secretion over the time course. Notably, CUR treatment significantly decreased phosphorylation of the IKKα/β, NF-κB, STAT3, and JNK signaling pathways under these experimental conditions. Taken together, our findings suggest that CUR has therapeutic potential to abrogate aberrant activation of chemokines and cytokines, and IKKα/β, NF-κB, STAT3, and JNK signaling pathways to reduce inflammation associated with endometriosis.
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Identification of key genes and pathways associated with different immune statuses of hepatitis B virus infection.
Jin, J, Xu, H, Wu, R, Gao, N, Wu, N, Li, S, Niu, J
Journal of cellular and molecular medicine. 2019;(11):7474-7489
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Abstract
We aimed to identify key genes and pathways associated with different immune statuses of hepatitis B virus (HBV) infection. The gene expression and DNA methylation profiles were analysed in different immune statuses of HBV infection. Differentially expressed genes (DEGs) and differentially methylated genes (DMGs) were identified, followed by their functional and integrative analyses. The differential expression of IgG Fc receptors (FcγRs) in chronic HBV-infected patients and immune cells during different stages of HBV infection was investigated. Toll-like receptor (TLR) signalling pathway (including TLR6) and leucocyte transendothelial migration pathway (including integrin subunit beta 1) were enriched during acute infection. Key DEGs, such as FcγR Ib and FcγR Ia, and interferon-alpha inducible protein 27 showed correlation with alanine aminotransferase levels, and they were differentially expressed between acute and immune-tolerant phases and between immune-tolerant and immune-clearance phases. The integrative analysis of DNA methylation profile showed that lowly methylated and highly expressed genes, including cytotoxic T lymphocyte-associated protein 4 and mitogen-activated protein kinase 3 were enriched in T cell receptor signalling pathway during acute infection. Highly methylated and lowly expressed genes, such as Ras association domain family member 1 and cyclin-dependent kinase inhibitor 2A were identified in chronic infection. Furthermore, differentially expressed FcγR Ia, FcγR IIa and FcγR IIb, CD3- CD56+ CD16+ natural killer cells and CD14high CD16+ monocytes were identified between immune-tolerant and immune-clearance phases by experimental validation. The above genes and pathways may be used to distinguish different immune statuses of HBV infection.
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Protein kinase-mediated signalling in priming: Immune signal initiation, propagation, and establishment of long-term pathogen resistance in plants.
Hake, K, Romeis, T
Plant, cell & environment. 2019;(3):904-917
Abstract
"Priming" in plant phytopathology describes a phenomenon where the "experience" of primary infection by microbial pathogens leads to enhanced and beneficial protection of the plant against secondary infection. The plant is able to establish an immune memory, a state of systemic acquired resistance (SAR), in which the information of "having been attacked" is integrated with the action of "being prepared to defend when it happens again." Accordingly, primed plants are often characterized by faster and stronger activation of immune reactions that ultimately result in a reduction of pathogen spread and growth. Prerequisites for SAR are (a) the initiation of immune signalling subsequent to pathogen recognition, (b) a rapid defence signal propagation from a primary infected local site to uninfected distal parts of the plant, and (c) a switch into an immune signal-dependent establishment and subsequent long-lasting maintenance of phytohormone salicylic acid-based systemic immunity. Here, we provide a summary on protein kinases that contribute to these three conceptual aspects of "priming" in plant phytopathology, complemented by data addressing the role of protein kinases crucial for immune signal initiation also for signal propagation and SAR.
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Vitamin D as a Principal Factor in Mediating Rheumatoid Arthritis-Derived Immune Response.
Aslam, MM, John, P, Bhatti, A, Jahangir, S, Kamboh, MI
BioMed research international. 2019;:3494937
Abstract
Rheumatoid arthritis (RA) is a systemic multifactorial autoimmune disorder. The interactions between diverse environmental and genetic factors lead to the onset of this complex autoimmune disorder. Serum levels of vitamin D (VD) are involved in the regulation of various immune responses. Vitamin D is a key signaling molecule in the human body that maintains calcium as well as phosphate homeostasis. It also regulates the functions of the immune system and, thus, can play a substantial role in the etiology of various autoimmune disorders, including RA. Low serum VD levels have been found to be associated with a higher risk of RA, although this finding has not been replicated consistently. The molecular mechanisms by which VD influences autoimmunity need to be further explored to understand how variation in plasma VD levels could affect the pathogenesis of RA. This mini-review focuses on the influence of VD and its serum levels on RA susceptibility, RA-associated complexities, treatment, and transcriptome products of key proinflammatory cytokines, along with other cytokines that are key regulators of inflammation in rheumatoid joints.
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The role of gut microbiota and IL-23/IL-17 pathway in ankylosing spondylitis immunopathogenesis: New insights and updates.
Babaie, F, Hasankhani, M, Mohammadi, H, Safarzadeh, E, Rezaiemanesh, A, Salimi, R, Baradaran, B, Babaloo, Z
Immunology letters. 2018;:52-62
Abstract
Ankylosing spondylitis (AS) is a type of arthritis that is referred to a group of chronic immune-mediated inflammatory diseases termed as seronegative spondyloarthropathies or spondyloarthritides. It typically affects the joints of the spinal and axial skeleton and exhibits common clinical features and genetic factors such as human leukocyte antigen class I allele HLA-B27, the Endoplasmic Reticulum Aminopeptidase 1 (ERAP1), and environmental factors such as microbial triggers. Although the precise etiopathogenic mechanisms that implicate the pathogenesis of AS have still remained to be clarified, the IL-23/IL-17 immune axis has been detected as an important factor in the immunopathogenesis of AS. Moreover, therapeutic options targeting this signaling pathway have been demonstrated to be effective in various other inflammatory diseases that share similar genetic etiology and pathogenetic pathways. In mammalian intestinal, there are trillions of commensal microbes that create the intricate symbiotic relationship with host well-known as the microbiota and play the major role in human health and disease. Several publications have appeared in recent years documenting the pivotal role of the gut microbiota and the IL-23/IL-17 pathway in the pathogenesis of spondyloarthritides. In this review, several points are discussed and summarized including recent advances on the role of the IL-17/IL-23 immune pathway in the pathogenesis of AS, HLA-B27, and ERAP 1 and 2 mediated pathogenesis, AS-related microbiota compositions, and new potential therapies for AS.
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Understanding Cytoskeletal Dynamics During the Plant Immune Response.
Li, J, Staiger, CJ
Annual review of phytopathology. 2018;:513-533
Abstract
The plant cytoskeleton is a dynamic framework of cytoplasmic filaments that rearranges as the needs of the cell change during growth and development. Incessant turnover mechanisms allow these networks to be rapidly redeployed in defense of host cytoplasm against microbial invaders. Both chemical and mechanical stimuli are recognized as danger signals to the plant, and these are perceived and transduced into cytoskeletal dynamics and architecture changes through a collection of well-recognized, previously characterized players. Recent advances in quantitative cell biology approaches, along with the powerful molecular genetics techniques associated with Arabidopsis, have uncovered two actin-binding proteins as key intermediaries in the immune response to phytopathogens and defense signaling. Certain bacterial phytopathogens have adapted to the cytoskeletal-based defense mechanism during the basal immune response and have evolved effector proteins that target actin filaments and microtubules to subvert transcriptional reprogramming, secretion of defense-related proteins, and cell wall-based defenses. In this review, we describe current knowledge about host cytoskeletal dynamics operating at the crossroads of the molecular and cellular arms race between microbes and plants.