scholarly journals 1,25(OH)2D3 Alleviates Aβ(25-35)-Induced Tau Hyperphosphorylation, Excessive Reactive Oxygen Species, and Apoptosis Through Interplay with Glial Cell Line-Derived Neurotrophic Factor Signaling in SH-SY5Y Cells

2020 ◽  
Vol 21 (12) ◽  
pp. 4215 ◽  
Author(s):  
Ching-I Lin ◽  
Yi-Chen Chang ◽  
Ning-Jo Kao ◽  
Wei-Ju Lee ◽  
Tzu-Wen Cross ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Vitamin D ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Molecular Mechanisms ◽  
Active Form ◽  
Reactive Oxygen ◽  
Nuclear Hormone Receptor ◽  
Oxygen Species

Amyloid beta (Aβ) accumulation in the brain is one of the major pathological features of Alzheimer’s disease. The active form of vitamin D (1,25(OH)2D3), which acts via its nuclear hormone receptor, vitamin D receptor (VDR), has been implicated in the treatment of Aβ pathology, and is thus considered as a neuroprotective agent. However, its underlying molecular mechanisms of action are not yet fully understood. Here, we aim to investigate whether the molecular mechanisms of 1,25(OH)2D3 in ameliorating Aβ toxicity involve an interplay of glial cell line-derived neurotrophic factor (GDNF)-signaling in SH-SY5Y cells. Cells were treated with Aβ(25-35) as the source of toxicity, followed by the addition of 1,25(OH)2D3 with or without the GDNF inhibitor, heparinase III. The results show that 1,25(OH)2D3 modulated Aβ-induced reactive oxygen species, apoptosis, and tau protein hyperphosphorylation in SH-SY5Y cells. Additionally, 1,25(OH)2D3 restored the decreasing GDNF and the inhibited phosphorylation of the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) protein expressions. In the presence of heparinase III, these damaging effects evoked by Aβ were not abolished by 1,25(OH)2D3. It appears 1,25(OH)2D3 is beneficial for the alleviation of Aβ neurotoxicity, and it might elicit its neuroprotection against Aβ neurotoxicity through an interplay with GDNF-signaling.

Reactive Oxygen Species-Mediated Apoptosis and Cytotoxicity of Newly Synthesized Pyridazin-3-Ones In P815 (Murin Mastocytoma) Cell Line

Drug Research ◽  
2019 ◽  
Vol 69 (10) ◽  
pp. 528-536
Author(s):  
Najat Bouchmaa ◽  
Reda Ben Mrid ◽  
Youness Boukharsa ◽  
Youssef Bouargalne ◽  
Mohamed Nhiri ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Anticancer Activity ◽  
Cell Line ◽  
Cytotoxic Effect ◽  
Redox Homeostasis ◽  
Reactive Oxygen ◽  
Cytotoxic Activities ◽  
Oxygen Species ◽  
P815 Cell

Abstract Background In cancer cells, the intracellular antioxidant capacity and the redox homeostasis are mainly maintained by the glutathione- and thioredoxin-dependent systems which are considered as promising targets for anticancer drugs. Pyridazinones constitute an interesting source of heterocyclic compounds for drug discovery. The present investigation focused on studying the in-vitro antitumor activity of newly synthesized Pyridazin-3(2h)-ones derivatives against P815 (Murin mastocytoma) cell line. Methods The in-vitro cytotoxic activities were investigated toward the P815 cell line using tetrazolium-based MTT assay. Lipid peroxidation and the specific activities of antioxidant enzymes were also determined. Results The newly compounds had a selective dose-dependent cytotoxic effect without affecting normal cells (PBMCs). Apoptosis was further confirmed through the characteristic apoptotic morphological changes and DNA fragmentation. Two compounds (6f and 7h) were highly cytotoxic and were submitted to extend biological testing to determine the likely mechanisms of their cytotoxicity. Results showed that these molecules may induce cytotoxicity via disturbing the redox homeostasis. Importantly, the anticancer activity of 6f and 7h could be due to the intracellular reactive oxygen species hypergeneration through significant loss of glutathione reductase and thioredoxin reductase activities. This eventually leads to oxidative stress-mediated P815 cell apoptosis. Furthermore, the co-administration of 6f or 7h with Methotrexate exhibited a synergistic cytotoxic effect. Conclusions considering their significant anticancer activity and chemosensitivity, 6f and 7h may improve the therapeutic efficacy of the current treatment for cancer.

scholarly journals Metformin Protects H9C2 Cardiomyocytes from High-Glucose and Hypoxia/Reoxygenation Injury via Inhibition of Reactive Oxygen Species Generation and Inflammatory Responses: Role of AMPK and JNK

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Mingyan Hu ◽  
Ping Ye ◽  
Hua Liao ◽  
Manhua Chen ◽  
Feiyan Yang
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Viability ◽  
High Glucose ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen Species Generation ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Compound C ◽  
Hypoxia Reoxygenation

Metformin is a first-line drug for the management of type 2 diabetes. Recent studies suggested cardioprotective effects of metformin against ischemia/reperfusion injury. However, it remains elusive whether metformin provides direct protection against hypoxia/reoxygenation (H/R) injury in cardiomyocytes under normal or hyperglycemic conditions. This study in H9C2 rat cardiomyoblasts was designed to determine cell viability under H/R and high-glucose (HG, 33 mM) conditions and the effects of cotreatment with various concentrations of metformin (0, 1, 5, and 10 mM). We further elucidated molecular mechanisms underlying metformin-induced cytoprotection, especially the possible involvement of AMP-activated protein kinase (AMPK) and Jun NH(2)-terminal kinase (JNK). Results indicated that 5 mM metformin improved cell viability, mitochondrial integrity, and respiratory chain activity under HG and/or H/R (P<0.05). The beneficial effects were associated with reduced levels of reactive oxygen species generation and proinflammatory cytokines (TNF-α, IL-1α, and IL-6) (P<0.05). Metformin enhanced phosphorylation level of AMPK and suppressed HG + H/R induced JNK activation. Inhibitor of AMPK (compound C) or activator of JNK (anisomycin) abolished the cytoprotective effects of metformin. In conclusion, our study demonstrated for the first time that metformin possessed direct cytoprotective effects against HG and H/R injury in cardiac cells via signaling mechanisms involving activation of AMPK and concomitant inhibition of JNK.

scholarly journals Intraperitoneal Triamcinolone Reduces Postoperative Adhesions, Possibly through Alteration of Mitochondrial Function

2022 ◽  
Vol 11 (2) ◽  
pp. 301
Author(s):  
Neeraja Purandare ◽  
Katherine J. Kramer ◽  
Paige Minchella ◽  
Sarah Ottum ◽  
Christopher Walker ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Function ◽  
Molecular Mechanisms ◽  
Human Fibroblasts ◽  
Reactive Oxygen ◽  
Retrospective Chart Review ◽  
Oxygen Species ◽  
Abdominal Myomectomy ◽  
Hypoxic Conditions

Adhesions frequently occur postoperatively, causing morbidity. In this noninterventional observational cohort study, we enrolled patients who presented for repeat abdominal surgery, after a history of previous abdominal myomectomy, from March 1998 to June 20210 at St. Vincent’s Catholic Medical Centers. The primary outcome of this pilot study was to compare adhesion rates, extent, and severity in patients who were treated with intraperitoneal triamcinolone acetonide during the initial abdominal myomectomy (n = 31) with those who did not receive any antiadhesion interventions (n = 21), as documented on retrospective chart review. Adhesions were blindly scored using a standard scoring system. About 32% of patients were found to have adhesions in the triamcinolone group compared to 71% in the untreated group (p < 0.01). Compared to controls, adhesions were significantly less in number (0.71 vs. 2.09, p < 0.005), severity (0.54 vs. 1.38, p < 0.004), and extent (0.45 vs. 1.28, p < 0.003). To understand the molecular mechanisms, human fibroblasts were incubated in hypoxic conditions and treated with triamcinolone or vehicle. In vitro studies showed that triamcinolone directly prevents the surge of reactive oxygen species triggered by 2% hypoxia and prevents the increase in TGF-β1 that leads to the irreversible conversion of fibroblasts to an adhesion phenotype. Triamcinolone prevents the increase in reactive oxygen species through alterations in mitochondrial function that are HIF-1α-independent. Controlling mitochondrial function may thus allow for adhesion-free surgery and reduced postoperative complications.

The molecular mechanisms of Phytophthora infestans in response to reactive oxygen species (ROS) stress

2021 ◽  
Author(s):  
Xiumei Luo ◽  
Tingting Tian ◽  
Maxime Bonnave ◽  
Xue Tan ◽  
Xiaoqing Huang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Late Blight ◽  
Phytophthora Infestans ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Microbial Pathogens ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Tor Signaling ◽  
Potato Resistance

Reactive oxygen species (ROS) are critical for the growth, development, proliferation, and pathogenicity of microbial pathogens; however, excessive levels of ROS are toxic. Little is known regarding the signaling cascades in response to ROS stress in oomycetes such as Phytophthora infestans, the causal agent of potato late blight. Here, P. infestans was used as a model system to investigate the mechanism underlying the response to ROS stress in oomycete pathogens. Results showed severe defects in sporangium germination, mycelial growth, appressorium formation, and virulence of P. infestans in response to H2O2 stress. Importantly, these phenotypes mimic those of P. infestans treated with rapamycin, the inhibitor of target of rapamycin (TOR, 1-phosphatidylinositol-3-kinase). Strong synergism occurred when P. infestans was treated with a combination of H2O2 and rapamycin, suggesting that a crosstalk exists between ROS stress and the TOR signaling pathway. Comprehensive analysis of transcriptome, proteome and phosphorylation omics showed that H2O2 stress significantly induced the operation of the TOR-mediated autophagy pathway. Monodansylcadaverine (MDC) staining showed that in the presence of H2O2 and rapamycin, the autophagosome level increased in a dosage-dependent manner. Furthermore, transgenic potatoes containing double-stranded RNA of PiTOR (TOR in P. infestans) displayed high resistance to P. infestans. Taken together, TOR is involved in the ROS response and is a potential target for control of oomycete diseases, as host-mediated silencing of PiTOR enhances potato resistance to late blight.

scholarly journals Role of Reactive Oxygen Species in Cancer Progression: Molecular Mechanisms and Recent Advancements

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 735 ◽  
Author(s):  
Vaishali Aggarwal ◽  
Hardeep Tuli ◽  
Ayşegül Varol ◽  
Falak Thakral ◽  
Mukerrem Yerer ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Protein Kinase ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Mitogen Activated Protein Kinase ◽  
Oxygen Species ◽  
Mitogen Activated Protein ◽  
High Concentrations

Reactive oxygen species (ROS) play a pivotal role in biological processes and continuous ROS production in normal cells is controlled by the appropriate regulation between the silver lining of low and high ROS concentration mediated effects. Interestingly, ROS also dynamically influences the tumor microenvironment and is known to initiate cancer angiogenesis, metastasis, and survival at different concentrations. At moderate concentration, ROS activates the cancer cell survival signaling cascade involving mitogen-activated protein kinase/extracellular signal-regulated protein kinases 1/2 (MAPK/ERK1/2), p38, c-Jun N-terminal kinase (JNK), and phosphoinositide-3-kinase/ protein kinase B (PI3K/Akt), which in turn activate the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF). At high concentrations, ROS can cause cancer cell apoptosis. Hence, it critically depends upon the ROS levels, to either augment tumorigenesis or lead to apoptosis. The major issue is targeting the dual actions of ROS effectively with respect to the concentration bias, which needs to be monitored carefully to impede tumor angiogenesis and metastasis for ROS to serve as potential therapeutic targets exogenously/endogenously. Overall, additional research is required to comprehend the potential of ROS as an effective anti-tumor modality and therapeutic target for treating malignancies.

scholarly journals Ascorbate-Dependent Peroxidase (APX) from Leishmania amazonensis Is a Reactive Oxygen Species-Induced Essential Enzyme That Regulates Virulence

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Lucia Xiang ◽  
Maria Fernanda Laranjeira-Silva ◽  
Fernando Y. Maeda ◽  
Jason Hauzel ◽  
Norma W. Andrews ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Macrophage Infection ◽  
Cutaneous Lesions ◽  
Signaling Mechanism ◽  
Content Type ◽  
Temporal Regulation ◽  
Metacyclic Promastigotes

ABSTRACT The molecular mechanisms underlying biological differences between two Leishmania species that cause cutaneous disease, L. major and L. amazonensis, are poorly understood. In L. amazonensis, reactive oxygen species (ROS) signaling drives differentiation of nonvirulent promastigotes into forms capable of infecting host macrophages. Tight spatial and temporal regulation of H2O2 is key to this signaling mechanism, suggesting a role for ascorbate-dependent peroxidase (APX), which degrades mitochondrial H2O2. Earlier studies showed that APX-null L. major parasites are viable, accumulate higher levels of H2O2, generate a greater yield of infective metacyclic promastigotes, and have increased virulence. In contrast, we found that in L. amazonensis, the ROS-inducible APX is essential for survival of all life cycle stages. APX-null promastigotes could not be generated, and parasites carrying a single APX allele were impaired in their ability to infect macrophages and induce cutaneous lesions in mice. Similar to what was reported for L. major, APX depletion in L. amazonensis enhanced differentiation of metacyclic promastigotes and amastigotes, but the parasites failed to replicate after infecting macrophages. APX expression restored APX single-knockout infectivity, while expression of catalytically inactive APX drastically reduced virulence. APX overexpression in wild-type promastigotes reduced metacyclogenesis, but enhanced intracellular survival following macrophage infection or inoculation into mice. Collectively, our data support a role for APX-regulated mitochondrial H2O2 in promoting differentiation of virulent forms in both L. major and L. amazonensis. Our results also uncover a unique requirement for APX-mediated control of ROS levels for survival and successful intracellular replication of L. amazonensis.

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