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Genipin protects against H2O2-induced oxidative damage in retinal pigment epithelial cells by promoting Nrf2 signaling.
Zhao, H, Wang, R, Ye, M, Zhang, L
International journal of molecular medicine. 2019;(2):936-944
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Abstract
Oxidative stress serves a vital function in the pathogenesis of age‑related macular degeneration (AMD); genipin (GP) possesses antioxidative properties. The present study aimed to investigate the effects of GP on retinal pigment epithelial (RPE) cells induced by H2O2 and the underlying mechanism. ARPE‑19 cells were subjected to H2O2 treatment to induce oxidative damage. Cell viability was determined via an MTT assay. Reactive oxygen species (ROS) levels and cell apoptosis were detected by flow cytometry. Nuclear factor‑erythroid 2‑related factor‑2 (Nrf2) signaling‑associated and the expression of apoptosis‑associated factors were measured using reverse transcription‑quantitative polymerase chain reaction assay and western blotting. The results revealed that 200 µM H2O2 and 30 µM GP were determined to be the optimal concentrations for subsequent experimentation. GP reversed the inhibitory effects of H2O2 by promoting cell viability, attenuating ROS accumulation and cell apoptosis, and increased the expression of Nrf2, heme oxygenase‑1 (HO‑1) and NAD(P)H: Quinine oxidoreductase 1 (NQO1); Nrf2 silencing inhibited HO‑1 and NQO1 expression. In addition, Nrf2 silencing enhanced the effects of H2O2 by promoting ROS production and cell apoptosis. Compared with H2O2, Nrf2 silencing further decreased the expression levels of B‑cell lymphoma‑2 (Bcl‑2), but increased that of Bcl‑2‑associated X protein and cleaved‑caspase‑3. The results of the present study revealed that Nrf2 silencing attenuated the protective effects of GP on H2O2‑induced injury in ARPE‑19 cells by promoting apoptosis and oxidation. Collectively, GP attenuated oxidative damage induced by H2O2 in ARPE‑19 cells. Furthermore, the molecular mechanism may be associated with the Nrf2 signaling pathway. The findings of the present study nay provide insight into a potential therapeutic agent for the treatment of AMD.
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Polyphenols for diabetes associated neuropathy: Pharmacological targets and clinical perspective.
Naseri, R, Farzaei, F, Fakhri, S, El-Senduny, FF, Altouhamy, M, Bahramsoltani, R, Ebrahimi, F, Rahimi, R, Farzaei, MH
Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences. 2019;(2):781-798
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Abstract
OBJECTIVES Diabetic neuropathy (DNP) is a widespread and debilitating complication with complex pathophysiology that is caused by neuronal dysfunction in diabetic patients. Conventional therapeutics for DNP are quite challenging due to their serious adverse effects. Hence, there is a need to investigate novel effective and safe options. The novelty of the present study was to provide available therapeutic approaches, emerging molecular mechanisms, signaling pathways and future directions of DNP as well as polyphenols' effect, which accordingly, give new insights for paving the way for novel treatments in DNP. EVIDENCE ACQUISITION A comprehensive review was done in electronic databases including Medline, PubMed, Web of Science, Scopus, national database (Irandoc and SID), and related articles regarding metabolic pathways on the pathogenesis of DNP as well as the polyphenols' effect. The keywords "diabetic neuropathy" and "diabetes mellitus" in the title/abstract and "polyphenol" in the whole text were used. Data were collected from inception until May 2019. RESULTS DNP complications is mostly related to a poor glycemic control and metabolic imbalances mainly inflammation and oxidative stress. Several signaling and molecular pathways play key roles in the pathogenesis and progression of DNP. Among natural entities, polyphenols are suggested as multi-target alternatives affecting most of these pathogenesis mechanisms in DNP. CONCLUSION The findings revealed novel pathogenicity signaling pathways of DNP and affirmed the auspicious role of polyphenols to tackle these destructive pathways in order to prevent, manage, and treat various diseases. Graphical Abstract .
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The Use of Nutraceuticals to Counteract Atherosclerosis: The Role of the Notch Pathway.
Aquila, G, Marracino, L, Martino, V, Calabria, D, Campo, G, Caliceti, C, Rizzo, P
Oxidative medicine and cellular longevity. 2019;:5470470
Abstract
Despite the currently available pharmacotherapies, today, thirty percent of worldwide deaths are due to cardiovascular diseases (CVDs), whose primary cause is atherosclerosis, an inflammatory disorder characterized by the buildup of lipid deposits on the inside of arteries. Multiple cellular signaling pathways have been shown to be involved in the processes underlying atherosclerosis, and evidence has been accumulating for the crucial role of Notch receptors in regulating the functions of the diverse cell types involved in atherosclerosis onset and progression. Several classes of nutraceuticals have potential benefits for the prevention and treatment of atherosclerosis and CVDs, some of which could in part be due to their ability to modulate the Notch pathway. In this review, we summarize the current state of knowledge on the role of Notch in vascular health and its modulation by nutraceuticals for the prevention of atherosclerosis and/or treatment of related CVDs.
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Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients.
Bhattacharyya, S, Ahmed, AT, Arnold, M, Liu, D, Luo, C, Zhu, H, Mahmoudiandehkordi, S, Neavin, D, Louie, G, Dunlop, BW, et al
Translational psychiatry. 2019;(1):173
Abstract
Metabolomics provides valuable tools for the study of drug effects, unraveling the mechanism of action and variation in response due to treatment. In this study we used electrochemistry-based targeted metabolomics to gain insights into the mechanisms of action of escitalopram/citalopram focusing on a set of 31 metabolites from neurotransmitter-related pathways. Overall, 290 unipolar patients with major depressive disorder were profiled at baseline, after 4 and 8 weeks of drug treatment. The 17-item Hamilton Depression Rating Scale (HRSD17) scores gauged depressive symptom severity. More significant metabolic changes were found after 8 weeks than 4 weeks post baseline. Within the tryptophan pathway, we noted significant reductions in serotonin (5HT) and increases in indoles that are known to be influenced by human gut microbial cometabolism. 5HT, 5-hydroxyindoleacetate (5HIAA), and the ratio of 5HIAA/5HT showed significant correlations to temporal changes in HRSD17 scores. In the tyrosine pathway, changes were observed in the end products of the catecholamines, 3-methoxy-4-hydroxyphenylethyleneglycol and vinylmandelic acid. Furthermore, two phenolic acids, 4-hydroxyphenylacetic acid and 4-hydroxybenzoic acid, produced through noncanconical pathways, were increased with drug exposure. In the purine pathway, significant reductions in hypoxanthine and xanthine levels were observed. Examination of metabolite interactions through differential partial correlation networks revealed changes in guanosine-homogentisic acid and methionine-tyrosine interactions associated with HRSD17. Genetic association studies using the ratios of these interacting pairs of metabolites highlighted two genetic loci harboring genes previously linked to depression, neurotransmission, or neurodegeneration. Overall, exposure to escitalopram/citalopram results in shifts in metabolism through noncanonical pathways, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.
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Focusing on the nuclear and subnuclear dynamics of light and circadian signalling.
Ronald, J, Davis, SJ
Plant, cell & environment. 2019;(10):2871-2884
Abstract
Circadian clocks provide organisms the ability to synchronize their internal physiological responses with the external environment. This process, termed entrainment, occurs through the perception of internal and external stimuli. As with other organisms, in plants, the perception of light is a critical for the entrainment and sustainment of circadian rhythms. Red, blue, far-red, and UV-B light are perceived by the oscillator through the activity of photoreceptors. Four classes of photoreceptors signal to the oscillator: phytochromes, cryptochromes, UVR8, and LOV-KELCH domain proteins. In most cases, these photoreceptors localize to the nucleus in response to light and can associate to subnuclear structures to initiate downstream signalling. In this review, we will highlight the recent advances made in understanding the mechanisms facilitating the nuclear and subnuclear localization of photoreceptors and the role these subnuclear bodies have in photoreceptor signalling, including to the oscillator. We will also highlight recent progress that has been made in understanding the regulation of the nuclear and subnuclear localization of components of the plant circadian clock.
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Impact of taxanes on androgen receptor signaling.
Bai, S, Zhang, BY, Dong, Y
Asian journal of andrology. 2019;(3):249-252
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Abstract
The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metastatic castration-resistant prostate cancer. Docetaxel and cabazitaxel are the first- and second-line chemotherapy, respectively, for patients with metastatic castration-resistant prostate cancer. These two taxanes, in general, function by (i) inhibiting mitosis and inducing apoptosis and (ii) preventing microtubule-dependent cargo trafficking. In prostate cancer, taxanes have been reported to inhibit the nuclear translocation and activity of the androgen receptor. However, whether this is attainable or not clinically remains controversial. In this review, we will provide a comprehensive view of the effects of taxanes on androgen receptor signaling in prostate cancer.
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The Placental Growth Factor Pathway and Its Potential Role in Macular Degenerative Disease.
Cunningham, F, Van Bergen, T, Canning, P, Lengyel, I, Feyen, JHM, Stitt, AW
Current eye research. 2019;(8):813-822
Abstract
There is growing evidence that placental growth factor (PlGF) is an important player in multiple pathologies, including tumorigenesis, inflammatory disorders and degenerative retinopathies. PlGF is a member of the vascular endothelial growth factor (VEGF) family and in the retina, binding of this growth factor to specific receptors is associated with pathological angiogenesis, vascular leakage, neurodegeneration and inflammation. Although they share some receptor signalling pathways, many of the actions of PlGF are distinct from VEGF and this has revealed the enticing prospect that it could be a useful therapeutic target for treating early and late stages of diabetic retinopathy (DR) and neovascular age-related macular degeneration (AMD). Recent research suggests that modulation of PlGF could also be important in the geographic atrophy (GA) form of late AMD by protecting the outer retina and the retinal pigment epithelium (RPE). This review discusses PlGF and its signalling pathways and highlights the potential of blocking the bioactivity of this growth factor to treat irreversible visual loss due to the two main forms of AMD.
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Through the eyes of a pathogen: light perception and signal transduction in Acinetobacter baumannii.
Pezza, A, Tuttobene, M, Abatedaga, I, Valle, L, Borsarelli, CD, Mussi, MA
Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology. 2019;(10):2363-2373
Abstract
Sunlight is a ubiquitous environmental stimulus for the great majority of living organisms on Earth; therefore it is logical to expect the development of "seeing mechanisms" which lead them to successfully adapt to particular ecological niches. Although these mechanisms were recognized in photosynthetic organisms, it was not until recent years that the scientific community found out about light perception in chemotrophic ones. In this review we summarize the current knowledge about the mechanism of light sensing through the blue light receptor BlsA in Acinetobacter baumannii. We highlight its function as a global regulator that pleiotropically modulates a large number of physiological processes, many of which are linked to the ability of this opportunist pathogen to persist in adverse intrahospital environments. Moreover, we describe with some specific examples the molecular basis of how this photoregulator senses blue light and translates this physical signal by modulating gene expression of target regulons. Finally, we discuss the possible course of these investigations needed to dissect this complex regulatory network, which ultimately will help us better understand the A. baumannii physiology.
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TNFα stimulates NO release in EA.hy926 cells by activating the CaMKKβ-AMPK-eNOS pathway.
Dymkowska, D, Drabarek, B, Michalik, A, Nowak, N, Zabłocki, K
The international journal of biochemistry & cell biology. 2019;:57-67
Abstract
Previously we showed that a mild stimulation of EA.hy926 cells with tumour necrosis factor alpha (TNFα) activated mitochondrial biogenesis, probably as a mechanism preventing cell death. This was accompanied by an increased phosphorylation of eNOS and elevation of NO release. The aim of the present study was to explain the biochemical basis of this effect. Our results indicate that eNOS is the only enzyme catalysing NO generation in EA.hy926 cells, and TNFα stimulates its activity by activating AMP-activated protein kinase (AMPK). Inhibition of AMPK with Compound C prevents the TNFα-induced activatory phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and reduces the NO release. AMPK is activated by phosphorylation catalysed by liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase kinase beta (CaMKKβ), which are phosphorylated and thereby activated in the presence of TNFα. Moreover, CaMKKβ catalyses an activatory phosphorylation of sirtuin 1, which could deacetylate and activate eNOS both directly and indirectly by an elevating the LKB1 activity. TNFα hardly increases the nuclear fraction of sirtuin 1, thus its major activity is probably attributed to the cytosolic pool. This is in line with the elevated activity of eNOS. We conclude that the increased AMPK-dependent phosphorylation of eNOS at least partially explains the stimulation of NO generation by TNFα in EA.hy926 cells.
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Impaired neurodevelopmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk.
Kumar, S, Reynolds, K, Ji, Y, Gu, R, Rai, S, Zhou, CJ
Journal of neurodevelopmental disorders. 2019;(1):10
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Abstract
BACKGROUND The development of an autistic brain is a highly complex process as evident from the involvement of various genetic and non-genetic factors in the etiology of the autism spectrum disorder (ASD). Despite being a multifactorial neurodevelopmental disorder, autistic patients display a few key characteristics, such as the impaired social interactions and elevated repetitive behaviors, suggesting the perturbation of specific neuronal circuits resulted from abnormal signaling pathways during brain development in ASD. A comprehensive review for autistic signaling mechanisms and interactions may provide a better understanding of ASD etiology and treatment. MAIN BODY Recent studies on genetic models and ASD patients with several different mutated genes revealed the dysregulation of several key signaling pathways, such as WNT, BMP, SHH, and retinoic acid (RA) signaling. Although no direct evidence of dysfunctional FGF or TGF-β signaling in ASD has been reported so far, a few examples of indirect evidence can be found. This review article summarizes how various genetic and non-genetic factors which have been reported contributing to ASD interact with WNT, BMP/TGF-β, SHH, FGF, and RA signaling pathways. The autism-associated gene ubiquitin-protein ligase E3A (UBE3A) has been reported to influence WNT, BMP, and RA signaling pathways, suggesting crosstalk between various signaling pathways during autistic brain development. Finally, the article comments on what further studies could be performed to gain deeper insights into the understanding of perturbed signaling pathways in the etiology of ASD. CONCLUSION The understanding of mechanisms behind various signaling pathways in the etiology of ASD may help to facilitate the identification of potential therapeutic targets and design of new treatment methods.