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Hao Wu, Junduo Wu, Shengzhu Zhou, Wenlin Huang, Ying Li, Huan Zhang, Junnan Wang and Ye Jia

Endothelial dysfunction contributes to diabetic macrovascular complications. Sirtuin 1 (SIRT1) protects against diabetic vasculopathy. SRT2104 is a novel SIRT1 activator and was not previously studied for its effects on diabetes-induced aortic endothelial dysfunction. Additionally, whether or to what extent deacetylation of P53, a substrate of SIRT1, is required for the effects of SIRT1 activation was unclear, given the fact that SIRT1 has multiple targets. Moreover, little was known about the pathogenic role of P53 in diabetes-induced aortic injury. To these ends, diabetes was induced by streptozotocin in C57BL/6 mice. The diabetic mice developed enhanced aortic contractility, oxidative stress, inflammation, P53 hyperacetylation and a remarkable decrease in SIRT1 protein, the effects of which were rescued by SRT2104. In HG-treated endothelial cells (ECs), P53 siRNA and SRT2104 produced similar effects on the induction of SIRT1 and the inhibition of P53 acetylation, oxidative stress and inflammation. Interestingly, SRT2104 failed to further enhance these effects in the presence of P53 siRNA. Moreover, P53 activation by nutlin3a completely abolished SRT2104’s protection against HG-induced oxidative stress and inflammation. Further, forced activation of P53 by nutlin3a increased aortic contractility in the healthy mice and generated endothelial oxidative stress and inflammation in both the normal glucose-cultured ECs and the aortas of the healthy mice. Collectively, the present study demonstrates that P53 deacetylation predominantly mediates SRT2104’s protection against diabetes-induced aortic endothelial dysfunction and highlights the pathogenic role of P53 in aortic endothelial dysfunction.

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Ziping Jiang, Junduo Wu, Fuzhe Ma, Jun Jiang, Linlin Xu, Lei Du, Wenlin Huang, Zhaohui Wang, Ye Jia, Laijin Lu and Hao Wu

Over a half of the diabetic individuals develop macrovascular complications that cause high mortality. Oxidative stress (OS) promotes endothelial dysfunction (ED) which is a critical early step toward diabetic macrovascular complications. Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system and combats diabetes-induced OS. Previously, we found that impaired NRF2 antioxidant signaling contributed to diabetes-induced endothelial OS and dysfunction in mice. The present study has investigated the effect of microRNA-200a (miR-200a) on NRF2 signaling and diabetic ED. In aortic endothelial cells (ECs) isolated from C57BL/6 wild-type (WT) mice, high glucose (HG) reduced miR-200a level and increased the expression of kelch-like ECH-associated protein 1 (Keap1) – a target of miR-200a and a negative regulator of NRF2. This led to inactivation of NRF2 signaling and exacerbation of OS and inflammation. MiR-200a mimic (miR-200a-M) or inhibitor modulated KEAP1/NRF2 antioxidant signaling and manipulated OS and inflammation under HG condition. These effects were completely abolished by knockdown of Keap1, indicating that Keap1 mRNA is a major target of miR-200a. Moreover, the protective effect of miR-200a-M was completely abrogated in aortic ECs isolated from C57BL/6 Nrf2 knockout (KO) mice, demonstrating that NRF2 is required for miR-200a’s actions. In vivo, miR-200a-M inhibited aortic Keap1 expression, activated NRF2 signaling, and attenuated hyperglycemia-induced OS, inflammation and ED in the WT, but not Nrf2 KO, mice. Therefore, the present study has uncovered a miR-200a/KEAP1/NRF2 signaling that controls aortic endothelial antioxidant capacity that protects against diabetic ED.

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Jing Li, Pan-Pan Zhao, Ting Hao, Dan Wang, Yu Wang, Yang-Zi Zhu, Yu-Qing Wu and Cheng-Hua Zhou

Urotensin II (U-II), a cyclic peptide originally isolated from the caudal neurosecretory system of fishes, can produce proinflammatory effects through its specific G protein-coupled receptor, GPR14. Neuropathic pain, a devastating disease, is related to excessive inflammation in the spinal dorsal horn. However, the relationship between U-II and neuropathic pain has not been reported. This study was designed to investigate the effect of U-II antagonist on neuropathic pain and to understand the associated mechanisms. We reported that U-II and its receptor GPR14 were persistently upregulated and activated in the dorsal horn of L4–6 spinal cord segments after chronic constriction injury (CCI) in rats. Intrathecal injection of SB657510, a specific antagonist against U-II, reversed CCI-induced thermal hyperalgesia and mechanical allodynia. Furthermore, we found that SB657510 reduced the expression of phosphorylated c-Jun N-terminal kinase (p-JNK) and nuclear factor-κB (NF-κB) p65 as well as subsequent secretion of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α). It was also showed that both the JNK inhibitor SP600125 and the NF-κB inhibitor PDTC significantly attenuated thermal hyperalgesia and mechanical allodynia in CCI rats. Our present research showed that U-II receptor antagonist alleviated neuropathic pain possibly through the suppression of the JNK/NF-κB pathway in CCI rats, which will contribute to the better understanding of function of U-II and pathogenesis of neuropathic pain.

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Wenpeng Dong, Ye Jia, Xiuxia Liu, Huan Zhang, Tie Li, Wenlin Huang, Xudong Chen, Fuchun Wang, Weixia Sun and Hao Wu

Oxidative stress contributes to the pathogenesis of diabetic nephropathy (DN). Nuclear factor erythroid 2-related factor 2 (NRF2) plays a key role in cellular defense against oxidative stress. NRF2 activators have shown promising preventive effects on DN. Sodium butyrate (NaB) is a known activator of NRF2. However, it is unknown whether NRF2 is required for NaB protection against DN. Therefore, streptozotocin-induced diabetic C57BL/6 Nrf2 knockout and their wild-type mice were treated in the presence or absence of NaB for 20 weeks. Diabetic mice, but not NaB-treated diabetic mice, developed significant renal oxidative damage, inflammation, apoptosis, fibrosis, pathological changes and albuminuria. NaB inhibited histone deacetylase (HDAC) activity and elevated the expression of Nrf2 and its downstream targets heme oxygenase 1 and NAD(P)H dehydrogenase quinone 1. Notably, deletion of the Nrf2 gene completely abolished NaB activation of NRF2 signaling and protection against diabetes-induced renal injury. Interestingly, the expression of Kelch-like ECH-associated protein 1, the negative regulator of NRF2, was not altered by NaB under both diabetic and non-diabetic conditions. Moreover, NRF2 nuclear translocation was not promoted by NaB. Therefore, the present study indicates, for the first time, that NRF2 plays a key role in NaB protection against DN. Other findings suggest that NaB may activate Nrf2 at the transcriptional level, possibly by the inhibition of HDAC activity.

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Shou-Si Lu, Yun-Li Yu, Hao-Jie Zhu, Xiao-Dong Liu, Li Liu, Yao-Wu Liu, Ping Wang, Lin Xie and Guang-Ji Wang

Berberine (BBR), a hypoglycemic agent, has shown beneficial metabolic effects for anti-diabetes, but its precise mechanism was unclear. Glucagon-like peptide-1 (GLP-1) is considered to be an important incretin that can decrease hyperglycemia in the gastrointestinal tract after meals. The aim of this study was to investigate whether BBR exerts its anti-diabetic effects via modulating GCG secretion. Diabetes-like rats induced by streptozotocin received BBR (120 mg/kg per day, i.g) for 5 weeks. Two hours following the last dose, the rats were anaesthetized and received 2.5 g/kg glucose by gavage. At 15-minute and 30-minute after glucose load, blood samples, pancreas, and intestines were obtained to measure insulin and GCG using ELISA kit. The number of L cells in the ileum and β-cells in the pancreas were identified using immunohistology. The expression of proglucagon mRNA in the ileum was measured by RT-PCR. The results indicated that BBR treatment significantly increased GCG levels in plasma and intestine (P<0.05) accompanied with the increase of proglucagon mRNA expression and the number of L-cell compared with the controls (P<0.05). Furthermore, BBR increased insulin levels in plasma and pancreas as well as β-cell number in pancreas. The data support the hypothesis that the anti-diabetic effects of BBR may partly result from enhancing GCG secretion.