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1
MATHIAS, Shalini, Louis A. PEÑA, and Richard N. KOLESNICK. "Signal transduction of stress via ceramide." Biochemical Journal 335, no. 3 (November 1, 1998): 465–80. http://dx.doi.org/10.1042/bj3350465.
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The sphingomyelin (SM) pathway is a ubiquitous, evolutionarily conserved signalling system analogous to conventional systems such as the cAMP and phosphoinositide pathways. Ceramide, which serves as second messenger in this pathway, is generated from SM by the action of a neutral or acidic SMase, or by de novosynthesis co-ordinated through the enzyme ceramide synthase. A number of direct targets for ceramide action have now been identified, including ceramide-activated protein kinase, ceramide-activated protein phosphatase and protein kinase Cζ, which couple the SM pathway to well defined intracellular signalling cascades. The SM pathway induces differentiation, proliferation or growth arrest, depending on the cell type. Very often, however, the outcome of signalling through this pathway is apoptosis. Mammalian systems respond to diverse stresses with ceramide generation, and recent studies show that yeast manifest a form of this response. Thus ceramide signalling is an older stress response system than the caspase/apoptotic death pathway, and hence these two pathways must have become linked later in evolution. Signalling of the stress response through ceramide appears to play a role in the development of human diseases, including ischaemia/reperfusion injury, insulin resistance and diabetes, atherogenesis, septic shock and ovarian failure. Further, ceramide signalling mediates the therapeutic effects of chemotherapy and radiation in some cells. An understanding of the mechanisms by which ceramide regulates physiological and pathological events in specific cells may provide new targets for pharmacological intervention.
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Šrámek, Jan, Vlasta Němcová-Fürstová, and Jan Kovář. "Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells." International Journal of Molecular Sciences 22, no. 8 (April 20, 2021): 4285. http://dx.doi.org/10.3390/ijms22084285.
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Pancreatic β-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for β-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic β-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in β-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced β-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in β-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in β-cells. This inhibitory intervention may be due to an increase of membrane fluidity.
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Zhang, Shengrui, Klaus Apel, and Chanhong Kim. "Singlet oxygen-mediated and EXECUTER-dependent signalling and acclimation of Arabidopsis thaliana exposed to light stress." Philosophical Transactions of the Royal Society B: Biological Sciences 369, no. 1640 (April 19, 2014): 20130227. http://dx.doi.org/10.1098/rstb.2013.0227.
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Plants respond to environmental changes by acclimation that activates defence mechanisms and enhances the plant's resistance against a subsequent more severe stress. Chloroplasts play an important role as a sensor of environmental stress factors that interfere with the photosynthetic electron transport and enhance the production of reactive oxygen species (ROS). One of these ROS, singlet oxygen ( 1 O 2 ), activates a signalling pathway within chloroplasts that depends on the two plastid-localized proteins EXECUTER 1 and 2. Moderate light stress induces acclimation protecting photosynthetic membranes against a subsequent more severe high light stress and at the same time activates 1 O 2 -mediated and EXECUTER-dependent signalling. Pre-treatment of Arabidopsis seedlings with moderate light stress confers cross-protection against a virulent Pseudomonas syringae strain. While non-pre-acclimated seedlings are highly susceptible to the pathogen regardless of whether 1 O 2 - and EXECUTER-dependent signalling is active or not, pre-stressed acclimated seedlings without this signalling pathway lose part of their pathogen resistance. These results implicate 1 O 2 - and EXECUTER-dependent signalling in inducing acclimation but suggest also a contribution by other yet unknown signalling pathways during this response of plants to light stress.
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Desideri, Enrico, and L. Miguel Martins. "Mitochondrial Stress Signalling: HTRA2 and Parkinson's Disease." International Journal of Cell Biology 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/607929.
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Mitochondria are cellular energy generators whose activity requires a continuous supply of oxygen. Recent genetic analysis has suggested that defects in mitochondrial quality control may be key factors in the development of Parkinson’s disease (PD). Mitochondria have a crucial role in supplying energy to the brain, and their deterioration can affect the function and viability of neurons, contributing to neurodegeneration. These organelles can sow the seeds of their own demise because they generate damaging oxygen-free radicals as a byproduct of their intrinsic physiological functions. Mitochondria have therefore evolved specific molecular quality control mechanisms to compensate for the action of damaging agents such as oxygen-free radicals. PTEN-induced putative kinase 1 (PINK1) and high-temperature-regulated A2 (HTRA2), a mitochondrial protease, have recently been proposed to be key modulators of mitochondrial molecular quality control. Here, we review some of the most recent advances in our understanding of mitochondria stress-control pathways, focusing on how signalling by the p38 stress kinase pathway may regulate mitochondrial stress by modulating the activity of HTRA2 via PINK1 and cyclin-dependent kinase 5 (CDK5). We also propose how defects in this pathway may contribute to PD.
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Ma, Chen-Yu, Yu-Qian Ma, and Min Deng. "Mechanism of Zhen Wu Decoction in the Treatment of Heart Failure Based on Network Pharmacology and Molecular Docking." Evidence-Based Complementary and Alternative Medicine 2022 (March 15, 2022): 1–10. http://dx.doi.org/10.1155/2022/4877920.
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Heart failure (HF) is a serious manifestation or advanced stage of various cardiovascular diseases, and its mortality and rehospitalization rate are still on the rise in China. Based on the network pharmacology method, 59 components of Zhen Wu decoction (ZWD) and 83 target genes related to HF were obtained. Through the PPI network, four potential therapeutic targets were identified: AKT1, IL6, JUN, and MAPK8. The beneficial components of ZWD might intervene HF through the AGE-RAGE signalling pathway in the diabetes component, fluid shear stress and atherosclerosis, the TNF signalling pathway, TB, and Kaposi sarcoma related herpesvirus infection, according to a KEGG enrichment study. The protein interaction network of candidate targets was constructed by the STRING database, and the protein interaction network was clustered by MEODE software. GO and KEGG enrichment analyses were performed on the core modules obtained by clustering. Finally, AutoDock Vina software was used for molecular docking verification of key targets and active ingredients. The result was that 75 active ingredients and 109 genes were screened as potential active ingredients and potential targets of Shengjie Tongyu decoction for CHF treatment. The main active components were quercetin, luteolin, kaempferol, dehydrated icariin, isorhamnetin, formononetin, and other flavonoids. Il-6, MAPK1, MAPK8, AKT1, VEGFA, and JUN were selected as the core targets. Molecular docking showed that the key components were well connected with the target. GO enrichment analysis showed that Shengjie Tongyu decoction could play a role through multiple biological pathways including angiogenesis, regulation of endothelial cell proliferation, binding of cytokine receptors, negative regulation of apoptotic signalling pathways, regulation of nitric oxide synthase activity, and reactive oxygen metabolism. Key pathways mainly focus on the toll-like receptor signalling pathway, nod-like receptor signalling pathway, MAPK signalling pathway, mTOR signalling pathway, JAK-STAT signalling pathway, VEGF signalling pathway, and other pathways. Through molecular docking technology, it was found that a variety of effective components in ZWD, such as kaempferol. Molecular docking technology has preliminatively verified the network pharmacology and laid a foundation for the follow-up pharmacological research.
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Whitmarsh, A. J. "The JIP family of MAPK scaffold proteins." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 828–32. http://dx.doi.org/10.1042/bst0340828.
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The components of MAPK (mitogen-activated protein kinase) signalling pathways can assemble into complexes that are co-ordinated by regulatory proteins including scaffold proteins. There is increasing evidence that scaffold proteins (i) maintain signalling specificity and facilitate the activation of pathway components, (ii) localize pathway components to particular subcellular sites or to specific targets, and (iii) serve as a point of signal integration to allow regulation of MAPK pathways by other signalling events in the cell. One family of scaffold proteins that regulate signalling by stress-activated MAPKs are the JIPs [JNK (c-Jun N-terminal kinase)-interacting proteins]. JIP proteins have been demonstrated to form complexes with specific JNK and p38 MAPK signalling modules and to play important roles in brain development, neuronal trafficking, apoptosis, β-cell function and insulin responses. Here, I briefly review our current understanding of the biochemical properties and physiological roles of JIP proteins.
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Verma, Poonam, Amit Ghosh, Manisha Ray, and Saurav Sarkar. "Lauric Acid Modulates Cancer-Associated microRNA Expression and Inhibits the Growth of the Cancer Cell." Anti-Cancer Agents in Medicinal Chemistry 20, no. 7 (July 3, 2020): 834–44. http://dx.doi.org/10.2174/1871520620666200310091719.
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Background: microRNAs are known to regulate various protein-coding gene expression posttranscriptionally. Fatty acids are cell membrane constituents and are also known to influence the biological activities of the cells like signal transduction, growth and differentiation of the cells, apoptosis induction, and other physiological functions. In our experiments, we used lauric acid to analyse its effects on human cancerous cell lines. Objective: Our objective was to speculate the miRNA expression profile in lauric acid treated and untreated cancerous cell lines and further study the metabolic pathways of the targeted tumour suppressor and oncogenes. Methods: The KB cells and HepG2 cells were treated with lauric acid and miRNA was isolated and the expression of tumour suppressor and oncogenic miRNA was measured by quantitative PCR. The untreated cells were used as control. The metabolic pathways of the target tumour suppressor and oncogenes were examined by GeneMANIA software. Results: Interestingly, the lauric acid treatment suppresses the expression of oncogenic miRNA and significantly upregulated the expression of some tumour suppressor miRNAs. GeneMANIA metabolic pathway revealed that the upregulated tumour suppressor miRNAs regulate several cancer-associated pathways such as DNA damage, signal transduction p53 class mediator, stem cell differentiation, cell growth, cell cycle phase transition, apoptotic signalling pathway, cellular response to stress and radiation, etc. whereas oncogenic miRNAs regulate the cancer-associated pathway like cell cycle phase transition, apoptotic signalling pathway, cell growth, response to oxidative stress, immune response activating cell surface protein signalling pathway, cyclin-dependent protein kinase activity, epidermal growth factor receptor signalling pathways, etc. Conclusion: In our study, we found that lauric acid works as an anticancer agent by altering the expression of miRNAs.
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Tiong, Yee Lian, Khuen Yen Ng, Rhun Yian Koh, Gnanajothy Ponnudurai, and Soi Moi Chye. "Melatonin Prevents Oxidative Stress-Induced Mitochondrial Dysfunction and Apoptosis in High Glucose-Treated Schwann Cells via Upregulation of Bcl2, NF-κB, mTOR, Wnt Signalling Pathways." Antioxidants 8, no. 7 (June 26, 2019): 198. http://dx.doi.org/10.3390/antiox8070198.
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Neuropathy is a complication that affects more than 50% of long-standing diabetic patients. One of the causes of diabetes neuropathy (DN) is the apoptosis of Schwann cells due to prolonged exposure to high glucose and build-up of oxidative stress. Melatonin is a hormone that has a known antioxidant property. In this study, we investigated the protective effect of melatonin on high glucose-induced Schwann cells’ apoptosis. Our results revealed that high glucose promoted apoptosis via mitochondrial-related oxidative stress and downregulated Bcl-2 family proteins in Schwann cells. In this signalling pathway, Bcl-2, Bcl-XL and Mcl-1 proteins were down-regulated while p-BAD and Puma proteins were up-regulated by high glucose treatment. Besides, we also proved that high glucose promoted apoptosis in Schwann cells through decreasing the p-NF-κB in the NF-κB signalling pathway. Key regulators of mTOR signalling pathway such as p-mTOR, Rictor and Raptor were also down-regulated after high glucose treatment. Additionally, high glucose treatment also decreased the Wnt signalling pathway downstream proteins (Wnt 5a/b, p-Lrp6 and Axin). Our results showed that melatonin treatment significantly inhibited high glucose-induced ROS generation, restored mitochondrial membrane potential and inhibited high glucose-induced apoptosis in Schwann cells. Furthermore, melatonin reversed the alterations of protein expression caused by high glucose treatment. Our results concluded that melatonin alleviates high glucose-induced apoptosis in Schwann cells through mitigating mitochondrial-related oxidative stress and the alterations of Bcl-2, NF-κB, mTOR and Wnt signalling pathways.
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Zhou, Xiang, Guoyin An, and Xiang Lu. "Hydrogen sulfide attenuates the development of diabetic cardiomyopathy." Clinical Science 128, no. 5 (November 13, 2014): 325–35. http://dx.doi.org/10.1042/cs20140460.
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H2S alleviates diabetic cardiomyopathy via attenuation of inflammation, oxidative stress and apoptosis. H2S may reduce high glucose-induced oxidative stress by activating the Nrf2/ARE pathway and exert anti-apoptotic effects by inhibiting JNK and p38 MAPK pathways and activating PI3K/Akt signalling.
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Thoms, Hazel C., and Lesley A. Stark. "The NF-κB Nucleolar Stress Response Pathway." Biomedicines 9, no. 9 (August 25, 2021): 1082. http://dx.doi.org/10.3390/biomedicines9091082.
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The nuclear organelle, the nucleolus, plays a critical role in stress response and the regulation of cellular homeostasis. P53 as a downstream effector of nucleolar stress is well defined. However, new data suggests that NF-κB also acts downstream of nucleolar stress to regulate cell growth and death. In this review, we will provide insight into the NF-κB nucleolar stress response pathway. We will discuss apoptosis mediated by nucleolar sequestration of RelA and new data demonstrating a role for p62 (sequestosome (SQSTM1)) in this process. We will also discuss activation of NF-κB signalling by degradation of the RNA polymerase I (PolI) complex component, transcription initiation factor-IA (TIF-IA (RRN3)), and contexts where TIF-IA-NF-κB signalling may be important. Finally, we will discuss how this pathway is targeted by aspirin to mediate apoptosis of colon cancer cells.
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Ouyang, Conghao. "Exploring disease therapeutic strategies by modulating the TNF-/NF-KB signalling pathway." Theoretical and Natural Science 44, no. 1 (July 26, 2024): 235–44. http://dx.doi.org/10.54254/2753-8818/44/20240868.
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In recent years, the number of patients with rheumatic diseases such as ankylosing spondylitis has been increasing, with over 3 million young people suffering from the disease. One main causal factor for these diseases is tumour necrosis factor-a (TNF-a), a pro-inflammatory cytokine that triggers mutations and apoptosis of various cell types by activating multiple signalling pathways. NF-KB is an essential intracellular nuclear transcription factor that participates in the inflammatory and immune responses of the organism and regulates apoptosis and stress responses. Excessive activation of NF-KB has been linked to inflammatory changes in various human diseases, such as rheumatoid arthritis, cardiovascular diseases, etc. Therefore, inhibition of the NF-KB signalling pathway by drugs may become a therapeutic approach. Among multiple signalling pathways that induce inflammation, the TNF-/NF-KB signalling pathway is considered the most important. This review will discuss the relevant diseases for which modulation of the TNF-/NF-KB signalling pathway is the main therapeutic strategy. These strategies include targeted inhibition by blocking the TNF-a/NF-KB signalling pathway, modulation of inflammatory factor transmission at the nanoscale by ribonucleotides, and Oncolytic virus therapy. Some of these strategies are effective and have been applied to treat multiple diseases; others are still in the exploratory phase, but the potential of these exploratory therapies is enormous and promises to overcome the limitations of traditional therapeutic strategies.
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Wojda, Iwona, Rebeca Alonso-Monge, Jan-Paul Bebelman, Willem H. Mager, and Marco Siderius. "Response to high osmotic conditions and elevated temperature in Saccharomyces cerevisiae is controlled by intracellular glycerol and involves coordinate activity of MAP kinase pathways." Microbiology 149, no. 5 (May 1, 2003): 1193–204. http://dx.doi.org/10.1099/mic.0.26110-0.
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In the yeast Saccharomyces cerevisiae, response to an increase in external osmolarity is mediated by the HOG (high osmolarity glycerol) MAP kinase pathway. HOG pathway mutant strains display osmosensitive phenotypes. Recently evidence has been obtained that the osmosensitivity of HOG pathway mutants is reduced during growth at elevated temperature (37 °C). A notable exception is the ste11ssk2ssk22 mutant, which displays hypersensitivity to osmotic stress at 37 °C. This paper reports that overexpression of FPS1 or GPD1 (encoding the glycerol transport facilitator and glycerol-3-phosphate dehydrogenase, respectively, and both affecting intracellular glycerol levels) reduces the hypersensitivity to osmotic stress of ste11ssk2ssk22 at 37 °C. Although in this particular HOG pathway mutant a correlation between suppression of the phenotype and glycerol content could be demonstrated, the absolute level of intracellular glycerol per se does not determine whether a strain is osmosensitive or not. Rather, evidence was obtained that the glycerol level may have an indirect effect, viz. by influencing signalling through the PKC (protein kinase C) MAP kinase pathway, which plays an important role in maintenance of cellular integrity. In order to validate the data obtained with a HOG pathway mutant strain for wild-type yeast cells, MAP kinase signalling under different growth conditions was examined in wild-type strains. PKC pathway signalling, which is manifest at elevated growth temperature by phosphorylation of MAP kinase Mpk1p, is rapidly lost when cells are shifted to high external osmolarity conditions. Expression of bck1-20 or overexpression of WSC3 in wild-type cells resulted in restoration of PKC signalling. Both PKC and HOG signalling, cell wall phenotypes and high osmotic stress responses in wild-type cells were found to be influenced by the growth temperature. The data taken together indicate the intricate interdependence of growth temperature, intracellular glycerol, cell wall structure and MAP kinase signalling in the hyperosmotic stress response of yeast.
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Yin, Fei, Tianyi Jiang, and Enrique Cadenas. "Metabolic triad in brain aging: mitochondria, insulin/IGF-1 signalling and JNK signalling." Biochemical Society Transactions 41, no. 1 (January 29, 2013): 101–5. http://dx.doi.org/10.1042/bst20120260.
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Mitochondria generate second messengers, such as H2O2, that are involved in the redox regulation of cell signalling and their function is regulated by several cytosolic signalling pathways. IIS [insulin/IGF1 (insulin-like growth factor 1) signalling] in the brain proceeds mainly through the PI3K (phosphatidylinositol 3-kinase)–Akt (protein kinase B) pathway, which is involved in the regulation of synaptic plasticity and neuronal survival via the maintenance of the bioenergetic and metabolic capacities of mitochondria. Conversely, the JNK (c-Jun N-terminal kinase) pathway is induced by increased oxidative stress and JNK translocation to the mitochondrion results in impairment of energy metabolism. Moreover, IIS and JNK signalling interact with and antagonize each other. This review focuses on functional outcomes of a metabolic triad that entails the co-ordination of mitochondrial function (energy transducing and redox regulation), IIS and JNK signalling, in the aging brain and in neurodegenerative disorders, such as Alzheimer's disease.
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Sun, Zhan-Bin, Shu-Fan Yu, Chu-Lun Wang, and Ling Wang. "cAMP Signalling Pathway in Biocontrol Fungi." Current Issues in Molecular Biology 44, no. 6 (June 4, 2022): 2622–34. http://dx.doi.org/10.3390/cimb44060179.
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Biocontrol is a complex process, in which a variety of physiological and biochemical characteristics are altered. The cAMP signalling pathway is an important signal transduction pathway in biocontrol fungi and consists of several key components. The G-protein system contains G-protein coupled receptors (GPCRs), heterotrimeric G-proteins, adenylate cyclase (AC), cAMP-dependent protein kinase (PKA), and downstream transcription factors (TFs). The cAMP signalling pathway can regulate fungal growth, development, differentiation, sporulation, morphology, secondary metabolite production, environmental stress tolerance, and the biocontrol of pathogens. However, few reviews of the cAMP signalling pathway in comprehensive biocontrol processes have been reported. This work reviews and discusses the functions and applications of genes encoding each component in the cAMP signalling pathway from biocontrol fungi, including the G-protein system components, AC, PKA, and TFs, in biocontrol behaviour. Finally, future suggestions are provided for constructing a complete cAMP signalling pathway in biocontrol fungi containing all the components and downstream effectors involved in biocontrol behavior. This review provides useful information for the understanding the biocontrol mechanism of biocontrol fungi by utilising the cAMP signalling pathway.
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Lu, Dan, Jingchun Chen, and Tsonwin Hai. "The regulation of ATF3 gene expression by mitogen-activated protein kinases." Biochemical Journal 401, no. 2 (December 21, 2006): 559–67. http://dx.doi.org/10.1042/bj20061081.
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ATF3 (activating transcription factor 3) gene encodes a member of the ATF/CREB (cAMP-response-element-binding protein) family of transcription factors. Its expression is induced by a wide range of signals, including stress signals and signals that promote cell proliferation and motility. Thus the ATF3 gene can be characterized as an ‘adaptive response’ gene for the cells to cope with extra- and/or intra-cellular changes. In the present study, we demonstrate that the p38 signalling pathway is involved in the induction of ATF3 by stress signals. Ectopic expression of CA (constitutively active) MKK6 [MAPK (mitogen-activated protein kinase) kinase 6], a kinase upstream of p38, indicated that activation of the p38 pathway is sufficient to induce the expression of the ATF3 gene. Inhibition of the pathway indicated that the p38 pathway is necessary for various signals to induce ATF3, including anisomycin, IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and H2O2. Analysis of the endogenous ATF3 gene indicates that the regulation is at least in part at the transcription level. Specifically, CREB, a transcription factor known to be phosphorylated by p38, plays a role in this induction. Interestingly, the ERK (extracellular-signal-regulated kinase) and JNK (c-Jun N-terminal kinase)/SAPK (stress-activated protein kinase) signalling pathways are neither necessary nor sufficient to induce ATF3 in the anisomycin stress paradigm. Furthermore, analysis of caspase 3 activation indicated that knocking down ATF3 reduced the ability of MKK6(CA) to exert its pro-apoptotic effect. Taken together, our results indicate that a major signalling pathway, the p38 pathway, plays a critical role in the induction of ATF3 by stress signals, and that ATF3 is functionally important to mediate the pro-apoptotic effects of p38.
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Verma, Nikhil, Harpreet Singh, Divya Khanna, Prashant Singh Rana, and Sanjay Kumar Bhadada. "Classification of drug molecules for oxidative stress signalling pathway." IET Systems Biology 13, no. 5 (October 1, 2019): 243–50. http://dx.doi.org/10.1049/iet-syb.2018.5078.
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Araki, T. "A STAT-regulated, stress-induced signalling pathway in Dictyostelium." Journal of Cell Science 116, no. 14 (July 15, 2003): 2907–15. http://dx.doi.org/10.1242/jcs.00501.
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Feng, Yuchao, Shu Zhang, Decheng Suo, Tianxin Fu, Ying Li, Zetong Li, Changyuan Wang, and Xia Fan. "Integrating Metabolomics and Transcriptomics to Analyse and Reveal the Regulatory Mechanisms of Mung Bean Polyphenols on Intestinal Cell Damage Under Different Heat Stress Temperatures." Nutrients 17, no. 1 (December 29, 2024): 88. https://doi.org/10.3390/nu17010088.
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Background/Objectives: Polyphenols represent a new strategy of dietary intervention for heat stress regulation. Methods: The metabolic and genetic effects of three heat stress-regulated mung bean polyphenols on mouse small intestinal epithelial Mode-k cells were investigated by metabolomics–transcriptomics correlation analysis at different heat stress levels. Results: Lipid metabolism, energy metabolism, and nervous system pathways were the key metabolic regulatory pathways. Under the heat stresses of 39 °C, 41 °C, and 43 °C, the key pathways regulated by mung bean polyphenols on intestinal epithelial Mode-k cells were choline metabolism, pyrimidine metabolism, and the retrograde endorphin signalling pathway in cancer, respectively. FoxO, Rap1, and PI3K-Akt signalling pathways were the key environmental regulatory signalling pathways. Mung bean polyphenols can alleviate heat stress-induced cells at 39 °C by inhibiting cell apoptosis and promoting lipid and amino acid accumulation. Mung bean polyphenols can alleviate the threat of cell death caused by heat stress at 41 °C by regulating heat shock proteins, inhibiting mitochondrial function and some nerve disease-related genes. The threat of cell death by heat stress at 43 °C can be alleviated by regulating nerve-related genes. Conclusions: This study confirmed that mung bean polyphenols can regulate heat stress. The results provide a reference for analysing the mechanism of dietary polyphenol regulating heat stress.
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Dodson, Matthew, Matthew Redmann, Namakkal S. Rajasekaran, Victor Darley-Usmar, and Jianhua Zhang. "KEAP1–NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity." Biochemical Journal 469, no. 3 (July 23, 2015): 347–55. http://dx.doi.org/10.1042/bj20150568.
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Maintaining cellular redox status to allow cell signalling to occur requires modulation of both the controlled production of oxidants and the thiol-reducing networks to allow specific regulatory post-translational modification of protein thiols. The oxidative stress hypothesis captured the concept that overproduction of oxidants can be proteotoxic, but failed to predict the recent finding that hyperactivation of the KEAP1–NRF2 system also leads to proteotoxicity. Furthermore, sustained activation of thiol redox networks by KEAP1–NRF2 induces a reductive stress, by decreasing the lifetime of necessary oxidative post-translational modifications required for normal metabolism or cell signalling. In this context, it is now becoming clear why antioxidants or hyperactivation of antioxidant pathways with electrophilic therapeutics can be deleterious. Furthermore, it suggests that the autophagy–lysosomal pathway is particularly important in protecting the cell against redox-stress-induced proteotoxicity, since it can degrade redox-damaged proteins without causing aberrant changes to the redox network needed for metabolism or signalling. In this context, it is important to understand: (i) how NRF2-mediated redox signalling, or (ii) the autophagy-mediated antioxidant/reductant pathways sense cellular damage in the context of cellular pathogenesis. Recent studies indicate that the modification of protein thiols plays an important role in the regulation of both the KEAP1–NRF2 and autophagy pathways. In the present review, we discuss evidence demonstrating that the KEAP1–NRF2 pathway and autophagy act in concert to combat the deleterious effects of proteotoxicity. These findings are discussed with a special emphasis on their impact on cardiovascular disease and neurodegeneration.
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Coppola, S., and L. Ghibelli. "GSH extrusion and the mitochondrial pathway of apoptotic signalling." Biochemical Society Transactions 28, no. 2 (February 1, 2000): 56–61. http://dx.doi.org/10.1042/bst0280056.
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New evidence suggests that physiological and damaging agents activate two different pathways of apoptotic signalling, which are mediated by protein-protein interactions and mitochondrial alterations respectively. The two pathways converge at the activation of caspase 3, the key effector of the execution phase of apoptosis, thus giving similar final results. The knowledge that different biochemical routes exist allows us to re-evaluate previous apparently contradictory results concerning the events occurring during apoptosis, and their respective roles. In particular, this applies to the role of oxidative stress and redox imbalance in the signal transduction events of apoptosis. It now appears that oxidative alterations are absent, or at least unnecessary, for the development of the physiological pathway. Instead, clear indications are emerging showing that redox imbalance is required for the damage-induced mitochondrial pathway. This is suggested by the finding that the depletion of glutathione, a common event in damage-induced apoptosis, is necessary and sufficient to induce cytochrome c release, the key event of this pathway. A model is proposed with GSH efflux as the backbone of the damage-induced apoptotic pathway.
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Guerrero-Alba, Raquel, Eduardo E. Valdez-Morales, Nestor N. Jimenez-Vargas, Cintya Lopez-Lopez, Josue Jaramillo-Polanco, Takanobu Okamoto, Yasmin Nasser, Nigel W. Bunnett, Alan E. Lomax, and Stephen J. Vanner. "Stress activates pronociceptive endogenous opioid signalling in DRG neurons during chronic colitis." Gut 66, no. 12 (September 2, 2016): 2121–31. http://dx.doi.org/10.1136/gutjnl-2016-311456.
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Aims and backgroundPsychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways.MethodsMouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca2+imaging techniques.ResultsSupernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca2+responses. Stress hormones decreased signalling induced by human and mouse supernatants. This effect resulted from stress hormones signalling directly to DRG neurons and indirectly through signalling to the immune system, leading to decreased opioid levels and increased acute inflammation. The net effect of stress was a change endogenous opioid signalling in DRG neurons from an inhibitory to an excitatory effect. This switch was associated with a change in G protein-coupled receptor excitatory signalling to a pathway sensitive to inhibitors of protein kinase A-protein, phospholipase C-protein and G protein βϒ subunits.ConclusionsStress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD.
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Rexin, Daniel, Christian Meyer, Christophe Robaglia, and Bruce Veit. "TOR signalling in plants." Biochemical Journal 470, no. 1 (August 6, 2015): 1–14. http://dx.doi.org/10.1042/bj20150505.
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Although the eukaryotic TOR (target of rapamycin) kinase signalling pathway has emerged as a key player for integrating nutrient-, energy- and stress-related cues with growth and metabolic outputs, relatively little is known of how this ancient regulatory mechanism has been adapted in higher plants. Drawing comparisons with the substantial knowledge base around TOR kinase signalling in fungal and animal systems, functional aspects of this pathway in plants are reviewed. Both conserved and divergent elements are discussed in relation to unique aspects associated with an autotrophic mode of nutrition and adaptive strategies for multicellular development exhibited by plants.
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Pavlovic, Dusica, Vidosava Djordjevic, and Gordana Kocic. "Signal transduction-free radical modulation." Jugoslovenska medicinska biohemija 21, no. 2 (2002): 69–84. http://dx.doi.org/10.2298/jmh0202069p.
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Signal transduction is the process of signal transmission from cell surface to cell interior. This ubiquitous mechanism enables functioning of general but also specific cell-tissue processes, involved in maintaining of cell homeostasis. Normal transduction processes disturbance represents the most frequent molecular basis in pathogenesis and complications of many diseases. Understanding of all sequences involved in signalling pathway cascades offers a possibility of different modulators application in therapeutic purposes. The activation of phagocyte NADPH oxidase is one of the best studied pathways of signal transduction. Meanwhile, reactive oxygen species generated in the process could modulate numerous cell transduction pathways. Diabetes mellitus may be associated with increase in oxidative stress, which may contribute to a long-term tissue damage. In addition to damage, oxidative stress can initiate cell signalling cascades that modulate cell function and finally could lead to the cell death. Hyperglicemia-induced activation of PKC-MAP kinase pathway has been now recognised as the key biochemical event in the pathogenesis of diabetic complications and insulin resistance.
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Hiew, Lih-Fhung, Chi-Him Poon, Heng-Ze You, and Lee-Wei Lim. "TGF-β/Smad Signalling in Neurogenesis: Implications for Neuropsychiatric Diseases." Cells 10, no. 6 (June 3, 2021): 1382. http://dx.doi.org/10.3390/cells10061382.
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TGF-β/Smad signalling has been the subject of extensive research due to its role in the cell cycle and carcinogenesis. Modifications to the TGF-β/Smad signalling pathway have been found to produce disparate effects on neurogenesis. We review the current research on canonical and non-canonical TGF-β/Smad signalling pathways and their functions in neurogenesis. We also examine the observed role of neurogenesis in neuropsychiatric disorders and the relationship between TGF-β/Smad signalling and neurogenesis in response to stressors. Overlapping mechanisms of cell proliferation, neurogenesis, and the development of mood disorders in response to stressors suggest that TGF-β/Smad signalling is an important regulator of stress response and is implicated in the behavioural outcomes of mood disorders.
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Navarro-García, Federico, Blanca Eisman, Sonia M. Fiuza, César Nombela, and Jesús Pla. "The MAP kinase Mkc1p is activated under different stress conditions in Candida albicans." Microbiology 151, no. 8 (August 1, 2005): 2737–49. http://dx.doi.org/10.1099/mic.0.28038-0.
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Candida albicans is an opportunistic pathogen that has adapted to live and grow in the human body as its natural environment. Under these conditions, this fungus faces numerous challenges, including oxidative, osmotic and enzymic processes that may damage external and internal structures. In view of the key role of MAP kinase signalling pathways in the physiology of C. albicans, the effect of agents mimicking in vivo environmental conditions on the activation of the p42-44 MAP kinases has been analysed. It has been found that Mkc1p is phosphorylated in the presence of oxidative stress, changes in osmotic pressure, cell wall damage and a decrease in the growth temperature. This phosphorylation is dependent on Pkc1p, indicating that both proteins operate in the same signalling pathway in C. albicans. Under some stimuli, the phosphorylation of Mkc1p required the presence of Hog1p, the MAP kinase of the high osmolarity glycerol (HOG) pathway. This suggests the existence of a new regulatory role, at least under some conditions, for these MAP kinase pathways in yeast.
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Halford, Nigel G., and Sandra J. Hey. "Snf1-related protein kinases (SnRKs) act within an intricate network that links metabolic and stress signalling in plants." Biochemical Journal 419, no. 2 (March 27, 2009): 247–59. http://dx.doi.org/10.1042/bj20082408.
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The phosphorylation and dephosphorylation of proteins, catalysed by protein kinases and phosphatases, is the major mechanism for the transduction of intracellular signals in eukaryotic organisms. Signalling pathways often comprise multiple phosphorylation/dephosphorylation steps and a long-standing hypothesis to explain this phenomenon is that of the protein kinase cascade, in which a signal is amplified as it is passed from one step in a pathway to the next. This review represents a re-evaluation of this hypothesis, using the signalling network in which the SnRKs [Snf1 (sucrose non-fermenting-1)-related protein kinases] function as an example, but drawing also on the related signalling systems involving Snf1 itself in fungi and AMPK (AMP-activated protein kinase) in animals. In plants, the SnRK family comprises not only SnRK1, but also two other subfamilies, SnRK2 and SnRK3, with a total of 38 members in the model plant Arabidopsis. This may have occurred to enable linking of metabolic and stress signalling. It is concluded that signalling pathways comprise multiple levels not to allow for signal amplification, but to enable linking between pathways to form networks in which key protein kinases, phosphatases and target transcription factors represent hubs on/from which multiple pathways converge and emerge.
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PARRA-PALAU, Josep L., Gert C. SCHEPER, Daniel E. HARPER, and Christopher G. PROUD. "The Drosophila protein kinase LK6 is regulated by ERK and phosphorylates the eukaryotic initiation factor eIF4E in vivo." Biochemical Journal 385, no. 3 (January 24, 2005): 695–702. http://dx.doi.org/10.1042/bj20040769.
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In Drosophila cells, phosphorylation of eIF4E (eukaryotic initiation factor 4E) is required for growth and development. In Drosophila melanogaster, LK6 is the closest homologue of mammalian Mnk1 and Mnk2 [MAPK (mitogen-activated protein kinase) signal-integrating kinases 1 and 2 respectively] that phosphorylate mammalian eIF4E. Mnk1 is activated by both mitogen- and stress-activated signalling pathways [ERK (extracellular-signal-regulated kinase) and p38 MAPK], whereas Mnk2 contains a MAPK-binding motif that is selective for ERKs. LK6 possesses a binding motif similar to that in Mnk2. In the present study, we show that LK6 can phosphorylate eIF4E at the physiological site. LK6 activity is increased by the ERK signalling pathway and not by the stress-activated p38 MAPK signalling pathway. Consistent with this, LK6 binds ERK in mammalian cells, and this requires an intact binding motif. LK6 can bind to eIF4G in mammalian cells, and expression of LK6 increases the phosphorylation of the endogenous eIF4E. In Drosophila S2 Schneider cells, LK6 binds the ERK homologue Rolled, but not the p38 MAPK homologue. LK6 phosphorylates Drosophila eIF4E in vitro. The phosphorylation of endogenous eIF4E in Drosophila cells is increased by activation of the ERK pathway but not by arsenite, an activator of p38 MAPK. RNA interference directed against LK6 significantly decreases eIF4E phosphorylation in Drosophila cells. These results show that LK6 binds to ERK and is activated by ERK signalling and it is responsible for phosphorylating eIF4E in Drosophila.
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Rao, Xingyu, Zicheng Lei, Huifang Zhu, Kaiyuan Luo, and Chaohua Hu. "Knockdown of KIF23 alleviates the progression of asthma by inhibiting pyroptosis." BMJ Open Respiratory Research 11, no. 1 (April 2024): e002089. http://dx.doi.org/10.1136/bmjresp-2023-002089.
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BackgroundAsthma is a chronic disease affecting the lower respiratory tract, which can lead to death in severe cases. The cause of asthma is not fully known, so exploring its potential mechanism is necessary for the targeted therapy of asthma.MethodAsthma mouse model was established with ovalbumin (OVA). H&E staining, immunohistochemistry and ELISA were used to detect the inflammatory response in asthma. Transcriptome sequencing was performed to screen differentially expressed genes (DEGs). The role of KIF23 silencing in cell viability, proliferation and apoptosis was explored by cell counting kit-8, EdU assay and flow cytometry. Effects of KIF23 knockdown on inflammation, oxidative stress and pyroptosis were detected by ELISA and western blot. After screening KIF23-related signalling pathways, the effect of KIF23 on p53 signalling pathway was explored by western blot.ResultsIn the asthma model, the levels of caspase-3, IgG in serum and inflammatory factors (interleukin (IL)-1β, KC and tumour necrosis factor (TNF)-α) in serum and bronchoalveolar lavage fluid were increased. Transcriptome sequencing showed that there were 352 DEGs in the asthma model, and 7 hub genes includingKIF23were identified. Knockdown of KIF23 increased cell proliferation and inhibited apoptosis, inflammation and pyroptosis of BEAS-2B cells induced by IL-13 in vitro. In vivo experiments verified that knockdown ofKIF23inhibited oxidative stress, inflammation and pyroptosis to alleviate OVA-induced asthma mice. In addition, p53 signalling pathway was suppressed by KIF23 knockdown.ConclusionKnockdown of KIF23 alleviated the progression of asthma by suppressing pyroptosis and inhibited p53 signalling pathway.
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Larcombe, Daniel E., Iryna M. Bohovych, Arnab Pradhan, Qinxi Ma, Emer Hickey, Ian Leaves, Gary Cameron, et al. "Glucose-enhanced oxidative stress resistance—A protective anticipatory response that enhances the fitness of Candida albicans during systemic infection." PLOS Pathogens 19, no. 7 (July 10, 2023): e1011505. http://dx.doi.org/10.1371/journal.ppat.1011505.
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Most microbes have developed responses that protect them against stresses relevant to their niches. Some that inhabit reasonably predictable environments have evolved anticipatory responses that protect against impending stresses that are likely to be encountered in their niches–termed “adaptive prediction”. Unlike yeasts such as Saccharomyces cerevisiae, Kluyveromyces lactis and Yarrowia lipolytica and other pathogenic Candida species we examined, the major fungal pathogen of humans, Candida albicans, activates an oxidative stress response following exposure to physiological glucose levels before an oxidative stress is even encountered. Why? Using competition assays with isogenic barcoded strains, we show that “glucose-enhanced oxidative stress resistance” phenotype enhances the fitness of C. albicans during neutrophil attack and during systemic infection in mice. This anticipatory response is dependent on glucose signalling rather than glucose metabolism. Our analysis of C. albicans signalling mutants reveals that the phenotype is not dependent on the sugar receptor repressor pathway, but is modulated by the glucose repression pathway and down-regulated by the cyclic AMP-protein kinase A pathway. Changes in catalase or glutathione levels do not correlate with the phenotype, but resistance to hydrogen peroxide is dependent on glucose-enhanced trehalose accumulation. The data suggest that the evolution of this anticipatory response has involved the recruitment of conserved signalling pathways and downstream cellular responses, and that this phenotype protects C. albicans from innate immune killing, thereby promoting the fitness of C. albicans in host niches.
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Dóczi, R. "Mitogen-activated protein (MAP) kinase signalling in plant environmental stress responses." Acta Agronomica Hungarica 59, no. 3 (September 1, 2011): 285–90. http://dx.doi.org/10.1556/aagr.59.2011.3.13.
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Due to their sessile life style plants have to cope with a variety of unfavourable environmental conditions. Extracellular stimuli are perceived by specific sensors and receptors and are transmitted within the cell by various signal transduction pathways to trigger appropriate responses. The mitogen-activated protein (MAP) kinase cascades are well-conserved signalling pathway modules found in all eukaryotes. Activated MAP kinases phosphorylate an array of substrate proteins. Phosphorylation results in altered substrate activities that mediate a wide range of responses, including changes in gene expression. The genome of the model plant Arabidopsis thaliana contains genes encoding 20 mitogen-activated protein kinases and 10 MAPK kinases. In plants MAP kinases play a central role in environmental stress signalling; however, our knowledge mainly comes from results on three MAP kinases and their immediate upstream activators. Further studies on additional members of the plant MAP kinase repertoire together with the identification of downstream substrates and connections to specific upstream signal receptors are required to elucidate their specific functions within environmental stress signalling networks. Understanding the mechanisms of specificity in signal flow is indispensable for engineering improved crops with modified MAP kinase signalling for agricultural purposes.
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Chen, Hui, Lianqi Yan, Jingcheng Wang, Yu Sun, Xiaolei Li, Shuai Zhao, Daxin Wang, Gengyao Zhu, and Yuan Liang. "Methotrexate prevents epidural fibrosis through endoplasmic reticulum stress signalling pathway." European Journal of Pharmacology 796 (February 2017): 131–38. http://dx.doi.org/10.1016/j.ejphar.2016.12.032.
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Wang, Xiao-meng, Ying-cui Wang, Xiang-juan Liu, Qi Wang, Chun-mei Zhang, Li-ping Zhang, Hui Liu, Xin-yu Zhang, Yang Mao, and Zhi-ming Ge. "BRD7 mediates hyperglycaemia-induced myocardial apoptosisviaendoplasmic reticulum stress signalling pathway." Journal of Cellular and Molecular Medicine 21, no. 6 (December 13, 2016): 1094–105. http://dx.doi.org/10.1111/jcmm.13041.
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Higdon, Ashlee, Anne R. Diers, Joo Yeun Oh, Aimee Landar, and Victor M. Darley-Usmar. "Cell signalling by reactive lipid species: new concepts and molecular mechanisms." Biochemical Journal 442, no. 3 (February 24, 2012): 453–64. http://dx.doi.org/10.1042/bj20111752.
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The process of lipid peroxidation is widespread in biology and is mediated through both enzymatic and non-enzymatic pathways. A significant proportion of the oxidized lipid products are electrophilic in nature, the RLS (reactive lipid species), and react with cellular nucleophiles such as the amino acids cysteine, lysine and histidine. Cell signalling by electrophiles appears to be limited to the modification of cysteine residues in proteins, whereas non-specific toxic effects involve modification of other nucleophiles. RLS have been found to participate in several physiological pathways including resolution of inflammation, cell death and induction of cellular antioxidants through the modification of specific signalling proteins. The covalent modification of proteins endows some unique features to this signalling mechanism which we have termed the ‘covalent advantage’. For example, covalent modification of signalling proteins allows for the accumulation of a signal over time. The activation of cell signalling pathways by electrophiles is hierarchical and depends on a complex interaction of factors such as the intrinsic chemical reactivity of the electrophile, the intracellular domain to which it is exposed and steric factors. This introduces the concept of electrophilic signalling domains in which the production of the lipid electrophile is in close proximity to the thiol-containing signalling protein. In addition, we propose that the role of glutathione and associated enzymes is to insulate the signalling domain from uncontrolled electrophilic stress. The persistence of the signal is in turn regulated by the proteasomal pathway which may itself be subject to redox regulation by RLS. Cell death mediated by RLS is associated with bioenergetic dysfunction, and the damaged proteins are probably removed by the lysosome-autophagy pathway.
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Guo, Chang, Rachel Smith, Timothy W. Gant, and Martin O. Leonard. "Cerium dioxide nanoparticles protect against oxidative stress induced injury through modulation of TGF-β signalling." Toxicology Research 4, no. 2 (2015): 464–75. http://dx.doi.org/10.1039/c4tx00210e.
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DENHARDT, David T. "Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling." Biochemical Journal 318, no. 3 (September 15, 1996): 729–47. http://dx.doi.org/10.1042/bj3180729.
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The features of three distinct protein phosphorylation cascades in mammalian cells are becoming clear. These signalling pathways link receptor-mediated events at the cell surface or intracellular perturbations such as DNA damage to changes in cytoskeletal structure, vesicle transport and altered transcription factor activity. The best known pathway, the Ras → Raf → MEK → ERK cascade [where ERK is extracellular-signal-regulated kinase and MEK is mitogen-activated protein (MAP) kinase/ERK kinase], is typically stimulated strongly by mitogens and growth factors. The other two pathways, stimulated primarily by assorted cytokines, hormones and various forms of stress, predominantly utilize p21 proteins of the Rho family (Rho, Rac and CDC42), although Ras can also participate. Diagnostic of each pathway is the MAP kinase component, which is phosphorylated by a unique dual-specificity kinase on both tyrosine and threonine in one of three motifs (Thr-Glu-Tyr, Thr-Phe-Tyr or Thr-Gly-Tyr), depending upon the pathway. In addition to activating one or more protein phosphorylation cascades, the initiating stimulus may also mobilize a variety of other signalling molecules (e.g. protein kinase C isoforms, phospholipid kinases, G-protein α and βγ subunits, phospholipases, intracellular Ca2+). These various signals impact to a greater or lesser extent on multiple downstream effectors. Important concepts are that signal transmission often entails the targeted relocation of specific proteins in the cell, and the reversible formation of protein complexes by means of regulated protein phosphorylation. The signalling circuits may be completed by the phosphorylation of upstream effectors by downstream kinases, resulting in a modulation of the signal. Signalling is terminated and the components returned to the ground state largely by dephosphorylation. There is an indeterminant amount of cross-talk among the pathways, and many of the proteins in the pathways belong to families of closely related proteins. The potential for more than one signal to be conveyed down a pathway simultaneously (multiplex signalling) is discussed. The net effect of a given stimulus on the cell is the result of a complex intracellular integration of the intensity and duration of activation of the individual pathways. The specific outcome depends on the particular signalling molecules expressed by the target cells and on the dynamic balance among the pathways.
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Chen, Huanjie, Zhoufan Li, Jingchao Xu, Ning Zhang, Junzhu Chen, Guangzhi Wang, and Yongfu Zhao. "Curcumin Induces Ferroptosis in Follicular Thyroid Cancer by Upregulating HO-1 Expression." Oxidative Medicine and Cellular Longevity 2023 (January 14, 2023): 1–17. http://dx.doi.org/10.1155/2023/6896790.
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Follicular thyroid cancer (FTC) is a highly aggressive type of endocrine malignancy. It is necessary to investigate the mechanisms of tumorigenesis and therapeutic pathways in patients with FTC. Haem oxygenase-1 (HO-1) can regulate oxidative stress and the occurrence of tumors and diseases. In this study, we discovered that HO-1 was abnormally overexpressed in FTC compared with adjacent tissues. However, the HO-1 overexpression was demonstrated to decrease cell viability and to potentially activate the ferroptosis signalling pathway. Ferroptosis is a newly identified form of oxidative cell death and is currently being targeted as a new cancer treatment. Tumorigenesis is significantly inhibited by curcumin. The present study shows that curcumin inhibits the growth of FTC by increasing the HO-1 expression, further activating the ferroptosis pathway. This study demonstrates that the HO-1-ferroptosis signalling pathway might play an important role in FTC tumorigenesis, and that curcumin inhibits the growth of FTC cells by affecting this pathway.
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Byrne, E., A. Wingler, N. Muttucumaru, and N. Halford. "The wheat GCN2 signalling pathway: Does this kinase play an important role in stress signalling?" Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology 150, no. 3 (July 2008): S158. http://dx.doi.org/10.1016/j.cbpa.2008.04.410.
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Byrne, E., N. Muttucumaru, A. Wingler, and N. Halford. "The wheat GCN2 signalling pathway: Does this kinase play an important role in stress signalling?" Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology 150, no. 3 (July 2008): S191. http://dx.doi.org/10.1016/j.cbpa.2008.04.521.
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Gjymishka, Altin, Nan Su, and Michael S. Kilberg. "Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the ATF6 and IRE1/XBP1 arms of the pathway." Biochemical Journal 417, no. 3 (January 16, 2009): 695–703. http://dx.doi.org/10.1042/bj20081706.
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The UPR (unfolded protein response) pathway comprises three signalling cascades mediated by the ER (endoplasmic reticulum) stress-sensor proteins PERK [PKR (double-stranded RNA-activated protein kinase)-like ER kinase], IRE1 (inositol-requiring kinase 1) and ATF6 (activating transcription factor 6). The present study shows that ASNS (asparagine synthetase) transcription activity was up-regulated in HepG2 cells treated with the UPR activators thapsigargin and tunicamycin. ChIP (chromatin immunoprecipitation) analysis demonstrated that during ER stress, ATF4, ATF3 and C/EBPβ (CCAAT/enhancer-binding protein β) bind to the ASNS proximal promoter region that includes the genomic sequences NSRE (nutrient-sensing response element)-1 and NSRE-2, previously implicated by mutagenesis in UPR activation. Consistent with increased ASNS transcription, ChIP analysis also demonstrated that UPR signalling resulted in enhanced recruitment of general transcription factors, including RNA Pol II (polymerase II), to the ASNS promoter. The ASNS gene is also activated by the AAR (amino acid response) pathway following amino acid deprivation of tissue or cells. Immunoblot analysis of HepG2 cells demonstrated that simultaneous activation of the AAR and UPR pathways did not further increase the ASNS or ATF4 protein abundance when compared with triggering either pathway alone. In addition, siRNA (small interfering RNA)-mediated knockdown of XBP1 (X-box-binding protein 1), ATF6α or ATF6β expression did not affect ASNS transcription, whereas siRNA against ATF4 suppressed ASNS transcription during UPR activation. Collectively, these results indicate that the PERK/p-eIF2α (phosphorylated eukaryotic initiation factor 2α)/ATF4 signalling cascade is the only arm of the UPR that is responsible for ASNS transcriptional induction during ER stress. Consequently, ASNS NSRE-1 and NSRE-2, in addition to ERSE (ER stress response element)-I, ERSE-II and the mUPRE (mammalian UPR element), function as mammalian ER-stress-responsive sequences.
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Rahman, Mohammad Bozlur, Leen Vandaele, Tom Rijsselaere, Mohamed Shehab El-Deen, Dominiek Maes, Mohammed Shamsuddin, and Ann Van Soom. "Bovine spermatozoa react to in vitro heat stress by activating the mitogen-activated protein kinase 14 signalling pathway." Reproduction, Fertility and Development 26, no. 2 (2014): 245. http://dx.doi.org/10.1071/rd12198.
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Heat stress has long been recognised as a cause of subfertility in farm animals. The objectives of the present study were to elucidate the effect of heat stress on sperm function and involvement of the mitogen-activated protein kinase (MAPK) 14 signalling pathway. Spermatozoa incubated for 4 h at a physiological temperature (38.5°C) exhibited significantly (P < 0.05) reduced motility, plasma membrane integrity and mitochondrial potential compared with non-incubated spermatozoa; the reductions in these parameters were more severe following incubation at a hyperthermic (41°C) temperature (P < 0.01). Percentages of fertilisation and embryo development were highly affected in spermatozoa incubated at 41°C compared with non-incubated spermatozoa (P < 0.01). Similarly, embryo quality was adversely affected by sperm incubation at 41°C, as indicated by a higher apoptotic cell ratio in Day 7 blastocysts compared with that in the non-incubated control group (14.6% vs 6.7%, respectively; P < 0.01). Using SB203580 (10 µg mL–1), a specific inhibitor of the p38 MAPK pathway, during sperm hyperthermia reduced MAPK14 activation (24.9% vs 35.6%), increased sperm motility (45.8% vs 26.5%) and reduced DNA fragmentation (16.9% vs 23.4%) compared with the untreated control group, but did not improve subsequent fertilisation and embryo development. In conclusion, heat stress significantly affects the potential of spermatozoa to penetrate oocytes, as well as subsequent embryo development and quality. Notably, the data show that the MAPK14 signalling pathway is largely involved in heat-induced sperm damage. However, further research is needed to elucidate other signalling pathways possibly involved in heat-induced sperm damage.
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Coffey, Kelly. "Targeting the Hippo Pathway in Prostate Cancer: What’s New?" Cancers 13, no. 4 (February 4, 2021): 611. http://dx.doi.org/10.3390/cancers13040611.
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Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC.
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Galello, Fiorella, Mariana Bermúdez-Moretti, María Clara Ortolá Martínez, Silvia Rossi, and Paula Portela. "The cAMP-PKA signalling crosstalks with CWI and HOG-MAPK pathways in yeast cell response to osmotic and thermal stress." Microbial Cell 11 (2024): 90–105. http://dx.doi.org/10.15698/mic2024.03.818.
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The yeast Saccharomyces cerevisiae is widely used in food and non-food industries. During industrial fermentation yeast strains are exposed to fluctuations in oxygen concentration, osmot-ic pressure, pH, ethanol concentration, nutrient availability and temperature. Fermentation performance depends on the ability of the yeast strains to adapt to these changes. Suboptimal conditions trigger responses to the external stimuli to allow homeostasis to be maintained. Stress-specific signalling pathways are activated to co-ordinate changes in transcription, translation, protein function, and metabolic fluxes while a transient arrest of growth and cell cycle progression occur. cAMP-PKA, HOG-MAPK and CWI signalling path-ways are turned on during stress response. Comprehension of the mechanisms involved in the responses and in the adaptation to these stresses during fermentation is key to improving this industri-al process. The scope of this review is to outline the advancement of knowledge about the cAMP-PKA signalling and the crosstalk of this pathway with the CWI and HOG-MAPK cascades in response to the environmental challenges heat and hyperosmotic stress.
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Kennedy, Ruth, and Ulf Klein. "Aberrant Activation of NF-κB Signalling in Aggressive Lymphoid Malignancies." Cells 7, no. 11 (October 30, 2018): 189. http://dx.doi.org/10.3390/cells7110189.
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Lymphoid malignancies frequently harbor genetic mutations leading to aberrant activation of nuclear factor-κB (NF-κB) signaling; in normal cells, this pathway has important roles in the control of cell growth, survival, stress responses, and inflammation. Malignancies with mutations in NF-κB pathway components can derive from all cell stages of mature B-cell development; however, aberrant NF-κB activity is particularly prevalent in aggressive subtypes of non-Hodgkin lymphoma and myeloma. NF-κB activation is mediated by two separate pathways, the canonical and alternative pathway, and five downstream transcription factor subunits. Recent findings implicate a predominant role for distinct NF-κB pathways and subunits in certain lymphoma subtypes and myeloma; findings which are complemented by the realization that individual NF-κB subunits can have unique, non-redundant biological roles in the putative tumor precursor cells, including activated B cells, germinal center B cells and plasma cells. The knowledge gained from these studies may be exploited for the development of therapeutic strategies to inhibit aberrant NF-κB activity at the level of the transcription-factor subunits and their target genes, as global inhibition of the pathway is toxic. Here, we provide an overview on the role of aberrant NF-κB activation in aggressive lymphoid malignancies and discuss the potential importance of individual NF-κB subunits in the pathogenesis of tumor subtypes.
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Lee, Ah Young, Ji Won Choi, Takako Yokozawa, and Eun Ju Cho. "Preventive effect of oligonol on nitric oxide and reactive oxygen species production through regulation of nuclear factor kappa B signaling pathway in RAW 264.7 macrophage cells against sodium nitroprusside." RSC Advances 9, no. 7 (2019): 3987–93. http://dx.doi.org/10.1039/c8ra08867e.
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Dai, XiaoXia, YuanYuan Li, RongQiang Zhang, Yan Kou, XiaoYan Mo, JunLing Cao, and YongMin Xiong. "Effects of sodium selenite on c-Jun N-terminal kinase signalling pathway induced by oxidative stress in human chondrocytes and c-Jun N-terminal kinase expression in patients with Kashin–Beck disease, an endemic osteoarthritis." British Journal of Nutrition 115, no. 9 (March 7, 2016): 1547–55. http://dx.doi.org/10.1017/s0007114516000362.
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AbstractThe c-Jun N-terminal kinases (JNK) are members of the mitogen-activated protein kinase family and are activated by environmental stress. Se plays an important role in the biological pathways by forming selenoprotein. Selenoproteins have been shown to exhibit a variety of biological functions including antioxidant functions and maintaining cellular redox balance, and compromise of such important proteins would lead to oxidative stress and apoptosis. We examined the expression levels of JNK in Kashin–Beck disease (KBD) patients, tested the potential protective effects of sodium selenite on tert-butyl hydroperoxide (tBHP)-induced oxidative injury and apoptosis in human chondrocytes as well as its underlying mechanism in this study. We produced an oxidative damage model induced by tBHP in C28/I2 human chondrocytes to test the essential anti-apoptosis effects of Se in vitro. The results indicated that the expression level of phosphorylated JNK was significantly increased in KBD patients. Cell apoptosis was increased and molecule expressions of the JNK signalling pathway were activated in the tBHP-injured chondrocytes. Na2SeO3 protected against tBHP-induced oxidative stress and apoptosis in cells by increasing cell viability, reducing reactive oxygen species generation, increasing Glutathione peroxidase (GPx) activity and down-regulating the JNK pathway. These results demonstrate that apoptosis induced by tBHP in chondrocytes might be mediated via up-regulation of the JNK pathway; Na2SeO3 has an effect of anti-apoptosis by down-regulating the JNK signalling pathway.
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Wiegman, Coen H., Feng Li, Colin J. Clarke, Elen Jazrawi, Paul Kirkham, Peter J. Barnes, Ian M. Adcock, and Kian F. Chung. "A comprehensive analysis of oxidative stress in the ozone-induced lung inflammation mouse model." Clinical Science 126, no. 6 (November 25, 2013): 425–40. http://dx.doi.org/10.1042/cs20130039.
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Oxidative stress-induced lung inflammation is associated with a loss of antioxidant stress response and the activation of the HIF-lα signalling pathway, which may contribute to chronic inflammation and emphysema pathophysiology observed in COPD patients.
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Parga, Juan A., Ana I. Rodriguez-Perez, Maria Garcia-Garrote, Jannette Rodriguez-Pallares, and Jose L. Labandeira-Garcia. "NRF2 Activation and Downstream Effects: Focus on Parkinson’s Disease and Brain Angiotensin." Antioxidants 10, no. 11 (October 20, 2021): 1649. http://dx.doi.org/10.3390/antiox10111649.
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Reactive oxygen species (ROS) are signalling molecules used to regulate cellular metabolism and homeostasis. However, excessive ROS production causes oxidative stress, one of the main mechanisms associated with the origin and progression of neurodegenerative disorders such as Parkinson’s disease. NRF2 (Nuclear Factor-Erythroid 2 Like 2) is a transcription factor that orchestrates the cellular response to oxidative stress. The regulation of NRF2 signalling has been shown to be a promising strategy to modulate the progression of the neurodegeneration associated to Parkinson’s disease. The NRF2 pathway has been shown to be affected in patients with this disease, and activation of NRF2 has neuroprotective effects in preclinical models, demonstrating the therapeutic potential of this pathway. In this review, we highlight recent advances regarding the regulation of NRF2, including the effect of Angiotensin II as an endogenous signalling molecule able to regulate ROS production and oxidative stress in dopaminergic neurons. The genes regulated and the downstream effects of activation, with special focus on Kruppel Like Factor 9 (KLF9) transcription factor, provide clues about the mechanisms involved in the neurodegenerative process as well as future therapeutic approaches.
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Tsai, Nien-Pei, Ping-Chih Ho, and Li-Na Wei. "Regulation of stress granule dynamics by Grb7 and FAK signalling pathway." EMBO Journal 27, no. 5 (February 14, 2008): 715–26. http://dx.doi.org/10.1038/emboj.2008.19.
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Choi, S. J. N., H. S. You, H. K. Lee, and S. Y. Chung. "TACROLIMUS(FK506) INDUCED APOPTOTIC SIGNALLING WITH ENDOPLASMIC RETICULUM STRESS PATHWAY PROTEINS." Transplantation 86, Supplement (July 2008): 634. http://dx.doi.org/10.1097/01.tp.0000330941.16613.65.
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Sanchez-Perez, I., C. Manguan-Garcia, M. Menacho-Marquez, J. R. Murguia, and R. Perona. "hCCR4/CNOT complex targets DNA damage signalling pathway after genotoxic stress." European Journal of Cancer Supplements 6, no. 9 (July 2008): 48. http://dx.doi.org/10.1016/s1359-6349(08)71359-4.
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