Artesunate suppresses oxidative and inflammatory processes by activating Nrf2 and ROS‑dependent p38 MAPK and protects against cerebral ischemia‑reperfusion injury

Lu, Hui; Wang, Bincheng; Cui, Ningning; Zhang, Yanchun

doi:10.3892/mmr.2018.8666

Cited by 35 publications

(29 citation statements)

References 28 publications

(34 reference statements)

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“…2C). On the other hand, previous studies demonstrated oxidative stress was related to p38 activation 45, 46. Therefore, we considered the H 2 O 2 levels increased might be association with p38 activation on MDA-MB-231 cells with SSZ plus VES treatment.…”

Section: Discussionmentioning

confidence: 86%

Anti-Cancer Effects of Sulfasalazine and Vitamin E Succinate in MDA-MB 231 Triple-Negative Breast Cancer Cells

Wei

et al. 2019

Int. J. Med. Sci.

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Aim: Sulfasalazine (SSZ) displayed anti-cancer activities. Vitamin E succinate (VES) could inhibit cell growth in various cancer cells. However, chemical therapies were often not useful for triple-negative breast cancer cells (TNBCs) treatment. Here, this study investigated the anti-cancer effects and the mechanisms on TNBCs under combination treatment with SSZ and VES. Methods: Cell viability was analyzed by using the MTT assay. The H 2 O 2 levels were determined by using lucigenin-amplified chemiluminescence method. In addition, caspase and MAPs signals were studied by using western blotting. Results: Low-dose VES antagonized the SSZ-induced cytotoxicity effects while high-dose VES promoted the SSZ-induced cytotoxicity effects on TNBCs. In addition, SSZ alone treatment activated both caspase-3 and ERK signals, however, VES alone treatment only activated JNK signals. On the other hand, activation of caspase-3, JNK, and ERK were found in SSZ plus VES-treated cells. Conclusion: Combined SSZ and VES has synergistic or antagonistic cytotoxic effects depending on VES concentration. In addition, different cytotoxic signals are induced on SSZ-treated, VES-treated and SSZ plus VES-treated cells.

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Section: Discussionmentioning

confidence: 86%

Anti-Cancer Effects of Sulfasalazine and Vitamin E Succinate in MDA-MB 231 Triple-Negative Breast Cancer Cells

Wei

et al. 2019

Int. J. Med. Sci.

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“…Moreover, several studies indicated that artemisinin and its derivatives may be beneficial in other clinical applications by conferring different activities such as anti-inflammatory [16–20], anti-viral [21], anti-microbial [22–24], anti-cancer [25–29], immunomodulatory [17, 30], anti-fungal [31], and anti-diabetic [32, 33]. Also, there are in vitro evidences indicating the protective activity of artemisinin towards oxidative stress damage [34–38]. Thus, the main goals of the present study were to examine whether artemisinin confers cytoprotection via its antioxidant properties and to clarify whether the c-Raf/Erk1/2/p90 rsk /CREB pathway is critical in mediating artemisinin protection towards H 2 O 2 oxidative stress-induced apoptosis in BMSCs.…”

Section: Introductionmentioning

confidence: 99%

Protective mechanism of artemisinin on rat bone marrow-derived mesenchymal stem cells against apoptosis induced by hydrogen peroxide via activation of c-Raf-Erk1/2-p90rsk-CREB pathway

Fang¹,

Zhao²,

Li³

et al. 2019

Stem Cell Res Ther

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BackgroundBone marrow-derived mesenchymal stem cell (BMSC) transplantation is one of the new therapeutic strategies for treating ischemic brain and heart tissues. However, the poor survival rate of transplanted BMSCs in ischemic tissue, due to high levels of reactive oxygen species (ROS), limits the therapeutic efficacy of this approach. Considering that BMSC survival may greatly enhance the effectiveness of transplantation therapy, development of effective therapeutics capable of mitigating oxidative stress-induced BMSC apoptosis is an important unmet clinical need.MethodsBMSCs were isolated from the 4-week-old male Sprague Dawley rats by whole bone marrow adherent culturing, and the characteristics were verified by morphology, immunophenotype, adipogenic, and osteogenic differentiation potential. BMSCs were pretreated with artemisinin, and H2O2 was used to induce apoptosis. Cell viability was detected by MTT, FACS, LDH, and Hoechst 33342 staining assays. Mitochondrial membrane potential (ΔΨm) was measured by JC-1 assay. The apoptosis was analyzed by Annexin V-FITC/PI and Caspase 3 Activity Assay kits. ROS level was evaluated by using CellROX® Deep Red Reagent. SOD, CAT, and GPx enzymatic activities were assessed separately using Cu/Zn-SOD and Mn-SOD Assay Kit with WST-8, Catalase Assay Kit, and Total Glutathione Peroxidase Assay Kit. The effects of artemisinin on protein expression of BMSCs including p-Erk1/2, t-Erk1/2, p-c-Raf, p-p90rsk, p-CREB, BCL-2, Bax, p-Akt, t-Akt, β-actin, and GAPDH were measured by western blotting.ResultsWe characterized for the first time the protective effect of artemisinin, an anti-malaria drug, using oxidative stress-induced apoptosis in vitro, in rat BMSC cultures. We found that artemisinin, at clinically relevant concentrations, improved BMSC survival by reduction of ROS production, increase of antioxidant enzyme activities including SOD, CAT, and GPx, in correlation with decreased Caspase 3 activation, lactate dehydrogenase (LDH) release and apoptosis, all induced by H2O2. Artemisinin significantly increased extracellular-signal-regulated kinase 1/2 (Erk1/2) phosphorylation, in a concentration- and time-dependent manner. PD98059, the specific inhibitor of the Erk1/2 pathway, blocked Erk1/2 phosphorylation and artemisinin protection. Similarly, decreased expression of Erk1/2 by siRNA attenuated the protective effect of artemisinin. Additionally, when the upstream activator KRAS was knocked down by siRNA, the protective effect of artemisinin was also blocked. These data strongly indicated the involvement of the Erk1/2 pathway. Consistent with this hypothesis, artemisinin increased the phosphorylation of Erk1/2 upstream kinases proto-oncogene c-RAF serine/threonine-protein kinase (c-Raf) and of Erk1/2 downstream targets p90 ribosomal s6 kinase (p90rsk) and cAMP response element binding protein (CREB). In addition, we found that the expression of anti-apoptotic protein B cell lymphoma 2 protein (BcL-2) was also upregulated by artemisinin.ConclusionThese studies demonstrate the proof...

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“…Artemether, a peroxide sesquiterpenoid lipid-soluble derivative of artemisinin has also been intensively used as an antimalarial and antifever drug [12–14] and in preclinical models was reported to cross the blood-brain barrier [18]. Artemether is also characterized by potent anticancer [15, 16], antiallergic, anti-inflammatory [17, 18], antiviral [19], and antiparasitic pharmacological activities [20, 21]. Cumulative evidences indicate that artemisinin and its derivatives can decrease oxidative stress [19–22].…”

Section: Introductionmentioning

confidence: 99%

“…Artemether is also characterized by potent anticancer [15, 16], antiallergic, anti-inflammatory [17, 18], antiviral [19], and antiparasitic pharmacological activities [20, 21]. Cumulative evidences indicate that artemisinin and its derivatives can decrease oxidative stress [19–22]. For example, we reported that artemisinin conferred neuroprotection to PC12 and cortical neuronal cultures from aponecrotic cell death induced by either hydrogen peroxide (H 2 O 2 ) or sodium nitroprusside (SNP) oxidative stress insults [21, 22].…”

Section: Introductionmentioning

confidence: 99%

Artemether Activation of AMPK/GSK3β(ser9)/Nrf2 Signaling Confers Neuroprotection towards β-Amyloid-Induced Neurotoxicity in 3xTg Alzheimer’s Mouse Model

Zhao

Lazarovici

et al. 2019

Oxidative Medicine and Cellular Longevity

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Alzheimer's disease is a severe neurodegenerative disease. Multiple factors involving neurofibrillary tangles and amyloid-β plaques lead to the progression of the AD, generated by aggregated hyperphosphorylated Tau protein. Inflammation, mitochondrial dysfunction, and oxidative stress play a significant role in the progression of AD. It has been therefore suggested that the multifactorial nature of AD pathogenesis requires the design of antioxidant drugs with a broad spectrum of neuroprotective activities. For this reason, the use of natural products, characterized by multiple pharmacological properties is advantageous as AD-modifying drugs over the single-targeted chemicals. Artemether, a peroxide sesquiterpenoid lipid-soluble compound, has been used in the clinic as an antimalarial drug. Also, it exhibits potent anti-inflammatory and antioxidant activities. Here, we report the neuroprotective effects of Artemether towards Aβ-induced neurotoxicity in neuronal cell cultures. A temporal correlation was found between Artemether neuroprotection towards Aβ-induced neurotoxicity and AMPK/GSK3β phosphorylation activity and increased expression of the activated Nrf2 signaling pathway. In 3xTg-AD mice, Artemether attenuated learning and memory deficits, inhibited cortical neuronal apoptosis and glial activation, inhibited oxidative stress through decrease of lipid peroxidation and increased expression of SOD, and reduced Aβ deposition and tau protein phosphorylation. Moreover, in 3xTg-AD mice, Artemether induced phosphorylation of the AMPK/GSK3β pathway which activated Nrf2, increasing the level of antioxidant protein HO-1. These activities probably produced the antioxidant and anti-inflammatory effects responsible for the neuroprotective effects of Artemether in the 3xTg-AD mouse model. These findings propose Artemether as a new drug for the treatment of AD disease.

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Artesunate suppresses oxidative and inflammatory processes by activating Nrf2 and ROS‑dependent p38 MAPK and protects against cerebral ischemia‑reperfusion injury

Cited by 35 publications

References 28 publications

Anti-Cancer Effects of Sulfasalazine and Vitamin E Succinate in MDA-MB 231 Triple-Negative Breast Cancer Cells

Anti-Cancer Effects of Sulfasalazine and Vitamin E Succinate in MDA-MB 231 Triple-Negative Breast Cancer Cells

Protective mechanism of artemisinin on rat bone marrow-derived mesenchymal stem cells against apoptosis induced by hydrogen peroxide via activation of c-Raf-Erk1/2-p90rsk-CREB pathway

Artemether Activation of AMPK/GSK3β(ser9)/Nrf2 Signaling Confers Neuroprotection towards β-Amyloid-Induced Neurotoxicity in 3xTg Alzheimer’s Mouse Model

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