Melatonin Increases Bone Mass around the Prostheses of OVX Rats by Ameliorating Mitochondrial Oxidative Stress via the SIRT3/SOD2 Signaling Pathway

Zhou, Wei; Liu, Yu; Shen, Junqi; Yu, Binqing; Lin, Jiayi; Guo, Xiaobin; Sun, Houyi; Chen, Zhanghuan; Yang, Huilin; Xu, Yaozeng

doi:10.1155/2019/4019619

Cited by 64 publications

(49 citation statements)

References 59 publications

(51 reference statements)

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“…4 D and E). In contrast, in normal cells, melatonin is known to upregulate the expression of SIRT3-SOD2 to reduce the oxidative damage [ [30] , [31] , [32] ]. To confirm that the responses of cancer cells to Mel treatment is the opposite of its effects in normal cells, we examined the effect of Mel treatment in normal cells (BHK, Vero, NIH3T3, and HaCaT) under oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

“…All these effects were reversed by treatment with a ROS scavenger, suggesting that excessive oxidative stress plays a key role in Mel-SHK-induced cytotoxicity in cancer cells. Several studies have reported that Mel treatment induces cell death in cancer cells but has beneficial effects on normal cells [ [30] , [31] , [32] , 43 , 44 ]. This is probably because Mel induces the release of mitochondrial cytochrome C, leading to apoptosis in cancer cells [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

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Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway

Wu²,

Muhammad

et al. 2020

Redox Biology

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Recent research suggests that melatonin (Mel), an endogenous hormone and natural supplement, possesses anti-proliferative effects and can sensitise cells to anti-cancer therapies. Although shikonin (SHK) also possesses potential anti-cancer properties, the poor solubility and severe systemic toxicity of this compound hinders its clinical usage. In this study, we combined Mel and SHK, a potentially promising chemotherapeutic drug combination, with the aim of reducing the toxicity of SHK and enhancing the overall anti-cancer effects. We demonstrate for the first time that Mel potentiates the cytotoxic effects of SHK on cancer cells by inducing oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway. Particularly, Mel-SHK treatment induced oxidative stress, increased mitochondrial calcium accumulation and reduced the mitochondrial membrane potential in various cancer cells, leading to apoptosis. This drug combination also promoted endoplasmic reticulum (ER) stress, leading to AKT dephosphorylation. In HeLa cells, Mel-SHK treatment reduced SIRT3/SOD2 expression and SOD2 activity, while SIRT3 overexpression dramatically reduced Mel-SHK-induced oxidative stress, ER stress, mitochondrial dysfunction and apoptosis. Hence, we propose the combination of Mel and SHK as a novel candidate chemotherapeutic regimen that targets the SIRT3/SOD2-AKT pathway in cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway

Wu²,

Muhammad

et al. 2020

Redox Biology

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“…Nrf2, known as GA-binding protein, binds with PGC-1α to regulate the expression of oxidative genes including Sirt3 [12]. Sirt3 in turn regulates the expression of SOD2 and mediates its protective effects against ROS and mitochondrial oxidative stress [8,32,33] by transforming Ac-SOD2 into SOD2 [34]. Further, the Nrf-2a subunit was shown to directly bind to the Sirt3 promoter, and therefore, knockdown or overexpression of Nrf-2 could modulate Sirt3 levels in vitro system [12].…”

Section: Discussionmentioning

confidence: 99%

tert-Butylhydroquinone Treatment Alleviates Contrast-Induced Nephropathy in Rats by Activating the Nrf2/Sirt3/SOD2 Signaling Pathway

Zhou

Wang

Shao

et al. 2019

Oxidative Medicine and Cellular Longevity

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Oxidative stress plays a critical role in the pathophysiology of contrast-induced nephropathy (CIN). Since the specific treatment of CIN remains an unmet medical need, it is imperative to find an effective strategy against the clinical management of CIN. The transcription factor Nrf2 is known to regulate antioxidative stress response. The aim of the present study was to assess the effects of tert-butylhydroquinone (t-BHQ), an activator of Nrf2, in the prevention of CIN and elucidate the underlying mechanism of its action in vitro and in vivo. We established a rat model of CIN and treated the animals with t-BHQ (25 mg/kg). The effects of t-BHQ treatment on CIN rats were elucidated by assessing renal function, HE staining, immunohistochemistry, and western blotting. We also studied the activity of oxidative stress-related markers, such as intracellular ROS level, MDA level, SOD2 activity, and GSH/GSSG ratio. We validated our results by siRNA-mediated silencing of Nrf2 in HK-2 cells exposed to the radiocontrast agent. Treatment with t-BHQ significantly ameliorated the renal function and the histopathological lesions in CIN rats. Further, pretreatment with t-BHQ significantly increased the SOD2 activity and GSH/GSSG ratio and decreased the levels of ROS and MDA in animals subjected to ioversol exposure. In addition, t-BHQ treatment increased the expression of Nrf2, Sirt3, and SOD2 and concomitantly decreased the expression of acetylated-SOD2. When Nrf2-silenced HK-2 cells were exposed to radiocontrast agent, they suffered severe cell oxidative stress, exhibited lower expression of Sirt3 and SOD2, and expressed higher levels of acetylated-SOD2; however, t-BHQ treatment did not affect the protein expression of these indicators in si-Nrf2 HK-2 cells. Our findings suggested that Nrf2 plays an important role in the regulation of the Sirt3/SOD2 antioxidative pathway, and t-BHQ may be a potential agent to ameliorate radiocontrast-induced nephropathy via activating the Nrf2/Sirt3/SOD2 signaling pathway in vitro and in vivo.

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“…Takechi et al [54] reported that MT promoted osseointegration around tibial titanium implants in Wistar rats. Zhou et al [55] showed that MT can accelerate bone formation around dental titanium implants. Therefore, the systemic administration of MT is a potential treatment for diseases such as osteoporosis that involve low bone density throughout the skeletal system.…”

mentioning

confidence: 99%

Sustained Release of Melatonin from GelMA Liposomes Reduced Osteoblast Apoptosis and Improved Implant Osseointegration in Osteoporosis

Xiao

Lin

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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A reduction in bone mass around an implant is the main cause of implant loosening, especially in postmenopausal osteoporosis patients. In osteoporosis, excessive oxidative stress, resulting in osteoblast apoptosis, largely contributes to abnormal bone remodeling. Melatonin (MT) synthesized by the pineal gland promotes osteoblast differentiation and bone formation and has been effectively used to combat oxidative stress. Therefore, we hypothesized that MT attenuates osteoblast apoptosis induced by oxidative stress, promotes osteogenesis in osteoporosis, and improves bone mass around prostheses. Moreover, considering the distribution and metabolism of MT, its systemic administration would require a large amount of MT, increasing the probability of drug side effects, so the local administration of MT is more effective than its systemic administration. In this study, we constructed a composite adhesive hydrogel system (GelMA-DOPA@MT) to bring about sustained MT release in a local area. Additionally, MT-reduced apoptosis caused by hydrogen peroxide- (H2O2-) induced oxidative stress and restored the osteogenic potential of MC3T3-E1 cells. Furthermore, apoptosis in osteoblasts around the implant was significantly attenuated, and increased bone mass around the implant was observed in ovariectomized (OVX) rats treated with this composite system. In conclusion, our results show that GelMA-DOPA@MT can inhibit osteoblast apoptosis caused by oxidative stress, thereby promoting osteogenesis and improving bone quality around a prosthesis. Therefore, this system of local, sustained MT release is a suitable candidate to address implant loosening in patients with osteoporosis.

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Melatonin Increases Bone Mass around the Prostheses of OVX Rats by Ameliorating Mitochondrial Oxidative Stress via the SIRT3/SOD2 Signaling Pathway

Cited by 64 publications

References 59 publications

Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway

Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway

tert-Butylhydroquinone Treatment Alleviates Contrast-Induced Nephropathy in Rats by Activating the Nrf2/Sirt3/SOD2 Signaling Pathway

Sustained Release of Melatonin from GelMA Liposomes Reduced Osteoblast Apoptosis and Improved Implant Osseointegration in Osteoporosis

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