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Inositol Polyphosphate-Based Compounds as Inhibitors of Phosphoinositide 3-Kinase-Dependent Signaling.
Maffucci, T, Falasca, M
International journal of molecular sciences. 2020;(19)
Abstract
Signaling pathways regulated by the phosphoinositide 3-kinase (PI3K) enzymes have a well-established role in cancer development and progression. Over the past 30 years, the therapeutic potential of targeting this pathway has been well recognized, and this has led to the development of a multitude of drugs, some of which have progressed into clinical trials, with few of them currently approved for use in specific cancer settings. While many inhibitors compete with ATP, hence preventing the catalytic activity of the kinases directly, a deep understanding of the mechanisms of PI3K-dependent activation of its downstream effectors led to the development of additional strategies to prevent the initiation of this signaling pathway. This review summarizes previously published studies that led to the identification of inositol polyphosphates as promising parent molecules to design novel inhibitors of PI3K-dependent signals. We focus our attention on the inhibition of protein-membrane interactions mediated by binding of pleckstrin homology domains and phosphoinositides that we proposed 20 years ago as a novel therapeutic strategy.
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2.
Decoding ABA and osmostress signalling in plants from an evolutionary point of view.
Komatsu, K, Takezawa, D, Sakata, Y
Plant, cell & environment. 2020;(12):2894-2911
Abstract
The plant hormone abscisic acid (ABA) is fundamental for land plant adaptation to water-limited conditions. Osmostress, such as drought, induces ABA accumulation in angiosperms, triggering physiological responses such as stomata closure. The core components of angiosperm ABA signalling are soluble ABA receptors, group A protein phosphatase type 2C and SNF1-related protein kinase2 (SnRK2). ABA also has various functions in non-angiosperms, however, suggesting that its role in adaptation to land may not have been angiosperm-specific. Indeed, among land plants, the core ABA signalling components are evolutionarily conserved, implying their presence in a common ancestor. Results of ongoing functional genomics studies of ABA signalling components in bryophytes and algae have expanded our understanding of the evolutionary role of ABA signalling, with genome sequencing uncovering the ABA core module even in algae. In this review, we describe recent discoveries involving the ABA core module in non-angiosperms, tracing the footprints of how ABA evolved as a phytohormone. We also cover the latest findings on Raf-like kinases as upstream regulators of the core ABA module component SnRK2. Finally, we discuss the origin of ABA signalling from an evolutionary perspective.
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3.
Jasmonates: biosynthesis, perception and signal transduction.
Griffiths, G
Essays in biochemistry. 2020;(3):501-512
Abstract
Jasmonates (JAs) are physiologically important molecules involved in a wide range of plant responses from growth, flowering, senescence to defence against abiotic and biotic stress. They are rapidly synthesised from α-linolenic acid (ALA; C18:3 ∆9,12,15) by a process of oxidation, cyclisation and acyl chain shortening involving co-operation between the chloroplast and peroxisome. The active form of JA is the isoleucine conjugate, JA-isoleucine (JA-Ile), which is synthesised in the cytoplasm. Other active metabolites of JA include the airborne signalling molecules, methyl JA (Me-JA) and cis-jasmone (CJ), which act as inter-plant signalling molecules activating defensive genes encoding proteins and secondary compounds such as anthocyanins and alkaloids. One of the key defensive metabolites in many plants is a protease inhibitor that inactivates the protein digestive capabilities of insects, thereby, reducing their growth. The receptor for JA-Ile is a ubiquitin ligase termed as SCFCoi1 that targets the repressor protein JA Zim domain (JAZ) for degradation in the 26S proteasome. Removal of JAZ allows other transcription factors (TFs) to activate the JA response. The levels of JA-Ile are controlled through catabolism by hydroxylating enzymes of the cytochrome P450 (CYP) family. The JAZ proteins act as metabolic hubs and play key roles in cross-talk with other phytohormone signalling pathways in co-ordinating genome-wide responses. Specific subsets of JAZ proteins are involved in regulating different response outcomes such as growth inhibition versus biotic stress responses. Understanding the molecular circuits that control plant responses to pests and pathogens is a necessary pre-requisite to engineering plants with enhanced resilience to biotic challenges for improved agricultural yields.
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4.
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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5.
Natural products and their derivatives as multifunctional ligands against Alzheimer's disease.
Patil, P, Thakur, A, Sharma, A, Flora, SJS
Drug development research. 2020;(2):165-183
Abstract
Alzheimer's disease (AD), a complex neurodegenerative disorder causing multiple cellular changes including impaired cholinergic system, beta-amyloid (βA) aggregation, tau hyperphosphorylation, metal dyshomeostasis, neuroinflammation, and many other pathways are involved in the pathogenesis of the disease. However, the exact cause of the disease is not known. Natural products such as flavonoids, alkaloids, resveratrol, and curcumin have multifunctional properties, and have drawn the attention of the researchers because these molecules are capable of interacting concurrently with the multiple targets of AD. Therefore, natural products and their derivatives with proven efficacy could be used in the management of the neurodegenerative disorders. This review focuses on the natural product based multitarget directed ligands like tacrine-coumarin, tacrine-huperzine A, harmine-isoxazoline, berberine-thiophenyl, galantamine-indole, pyridoxine-resveratrol, donepezil-curcumin and their mode of action.
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6.
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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7.
Diabetes and Parkinson's Disease: Debating the Link Through Ca2+/cAMP Signalling.
Bergantin, LB
Current diabetes reviews. 2020;(3):238-241
Abstract
BACKGROUND A link between diabetes and Parkinson´s disease (PD) has been established by several reports. Consistent data report that people diagnosed with diabetes have demonstrated an enhanced risk of manifesting PD in their lifetime. The working principles involved in this link have been extensively discussed. Over the last decade, diabetes has been reported to be correlated with an increased risk of dementia, suggesting a potential role of diabetes, or insulin signalling dysregulations, in neurodegeneration. In addition, it is nowadays highly debated that dysregulations related to Ca2+ signalling may be an upstream issue which could also link diabetes and PD. Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling) control both the neurotransmitters/hormones release and neuronal death. CONCLUSION Considering our previous reports about Ca2+/cAMP signalling, the putative contribution of Ca2+/cAMP signalling in this link (between diabetes and PD) is discussed in this paper.
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8.
Nutritional Therapy to Modulate Tryptophan Metabolism and Aryl Hydrocarbon-Receptor Signaling Activation in Human Diseases.
Ghiboub, M, Verburgt, CM, Sovran, B, Benninga, MA, de Jonge, WJ, Van Limbergen, JE
Nutrients. 2020;(9)
Abstract
The aryl hydrocarbon receptor (AhR) is a nuclear protein which, upon association with certain endogenous and exogenous ligands, translocates into the nucleus, binds DNA and regulates gene expression. Tryptophan (Trp) metabolites are one of the most important endogenous AhR ligands. The intestinal microbiota is a critical player in human intestinal homeostasis. Many of its effects are mediated by an assembly of metabolites, including Trp metabolites. In the intestine, Trp is metabolized by three main routes, leading to kynurenine, serotonin, and indole derivative synthesis under the direct or indirect involvement of the microbiota. Disturbance in Trp metabolism and/or AhR activation is strongly associated with multiple gastrointestinal, neurological and metabolic disorders, suggesting Trp metabolites/AhR signaling modulation as an interesting therapeutic perspective. In this review, we describe the most recent advances concerning Trp metabolism and AhR signaling in human health and disease, with a focus on nutrition as a potential therapy to modulate Trp metabolites acting on AhR. A better understanding of the complex balance between these pathways in human health and disease will yield therapeutic opportunities.
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9.
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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10.
Dual Character of Reactive Oxygen, Nitrogen, and Halogen Species: Endogenous Sources, Interconversions and Neutralization.
Moldogazieva, NT, Mokhosoev, IM, Mel'nikova, TI, Zavadskiy, SP, Kuz'menko, AN, Terentiev, AA
Biochemistry. Biokhimiia. 2020;(Suppl 1):S56-S78
Abstract
Oxidative stress resulting from accumulation of reactive oxygen, nitrogen, and halogen species (ROS, RNS, and RHS, respectively) causes the damage of cells and biomolecules. However, over the long evolutionary time, living organisms have developed the mechanisms for adaptation to oxidative stress conditions including the activity of the antioxidant system (AOS), which maintains low intracellular levels of RONS (ROS and RNS) and RHS. Moreover, living organisms have adapted to use low concentrations of these electrophiles for the regulation of cell functions through the reversible post-translational chemical modifications of redox-sensitive amino acid residues in intracellular effectors of signal transduction pathways (protein kinases and protein phosphatases), transcription factors, etc. An important fine-tuning mechanism that ensures involvement of RONS and RHS in the regulation of physiological processes is interconversion between different reactive species. This review focuses on the complex networks of interacting RONS and RHS types and their endogenous sources, such as NOX family of NADPH oxidases, complexes I and III of the mitochondrial electron transport chain, NO synthases, cytochrome P450-containing monooxygenase system, xanthine oxidoreductase, and myeloperoxidases. We highlight that kinetic parameters of reactions involving RONS and RHS determine the effects of these reactive species on cell functions. We also describe the functioning of enzymatic and non-enzymatic AOS components and the mechanisms of RONS and RHS scavenging under physiological conditions. We believe that analysis of interactions between RONS and relationships between different endogenous sources of these compounds will contribute to better understanding of their role in the maintenance of cell redox homeostasis as well as initiation and progression of diseases.