Background and aims: Diabetic kidney is more sensitive to ischemia/reperfusion (I/R) injury, which is associated with increased oxidative stress and impaired nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling. Melatonin, a hormone that is secreted with the rhythm of the light/dark cycle, has antioxidative effects in reducing acute kidney injury (AKI). However, the molecular mechanism of melatonin protection against kidney I/R injury in the state of diabetes is still unknown. In the present study, we hypothesized that melatonin attenuates renal I/R injury in diabetes by activating silent information regulator 2 associated protein 1 (SIRT1) expression and Nrf2/HO-1 signaling. Methods: Control or streptozotocin (STZ)-induced Type 1 diabetic rats were treated with or without melatonin for 4 weeks. Renal I/R injury was achieved by clamping both left and right renal pedicles for 30 min followed by reperfusion for 48 h. Results: Diabetic rats that were treated with melatonin undergoing I/R injury prevented renal injury from I/R, in aspects of the histopathological score, cell apoptosis, and oxidative stress in kidney, accompanied with decreased expressions of SIRT1, Nrf2, and HO-1 as compared with those in control rats. All these alterations were attenuated or prevented by melatonin treatment; but these beneficial effects of melatonin were abolished by selective inhibition of SIRT1 with EX527. Conclusion: These findings suggest melatonin could attenuate renal I/R injury in diabetes, possibly through improving SIRT1/Nrf2/HO-1 signaling.

Ischemic stroke is a devastating disease that causes long-term disability. However, its pathogenesis is unclear, and treatments for ischemic stroke are limited. Recent studies indicate that oxidative stress is involved in the pathological progression of ischemic stroke and that angiogenesis participates in recovery from ischemic stroke. Furthermore, previous studies have shown that Coicis Semen has antioxidative and anti-inflammatory effects in a variety of diseases. In the present study, we investigated whether Coicis Semen has a protective effect against ischemic stroke and the mechanism of this protective effect. Coicis Semen administration significantly decreased the infarct volume and mortality and alleviated neurological deficits at 3, 7 and 14 days after MCAO. In addition, cerebral edema at 3 days poststroke was ameliorated by Coicis Semen treatment. DHE staining showed that ROS levels in the vehicle group were increased at 3 days after reperfusion and then gradually declined, but Coicis Semen treatment reduced ROS levels. The levels of GSH and SOD in the brain were increased by Coicis Semen treatment, while MDA levels were reduced. Furthermore, Coicis Semen treatment decreased the extravasation of EB dye in MCAO mouse brains and elevated expression of the tight junction proteins ZO-1 and Occludin. Double immunofluorescence staining and western blot analysis showed that the expression of angiogenesis markers and TGFβ pathway-related proteins was increased by Coicis Semen administration. Consistent with the in vivo results, cytotoxicity assays showed that Coicis Semen substantially promoted HUVEC survival following OGD/RX in vitro. Additionally, though LY2109761 inhibited the activation of TGFβ signaling in OGD/RX model animals, Coicis Semen cotreatment markedly reversed the downregulation of TGFβ pathway-related proteins and increased VEGF levels. Adult male wild-type C57BL/6J mice were used to develop a middle cerebral artery occlusion (MCAO) stroke model. Infarct size, neurological deficits and behavior were evaluated on days 3, 7 and 14 after staining. In addition, changes in superoxide dismutase (SOD), GSH and malondialdehyde (MDA) levels were detected with a commercial kit. Blood-brain barrier (BBB) permeability was assessed with Evans blue (EB) dye. Western blotting was also performed to measure the levels of tight junction proteins of the BBB. Additionally, ELISA was performed to measure the level of VEGF in the brain. The colocalization of CD31, angiogenesis markers, and Smad1/5 was assessed by double immunofluorescent staining. TGFβ pathway-related proteins were measured by western blotting. Furthermore, the cell viability of human umbilical vein endothelial cells (HUVECs) following oxygen-glucose deprivation/reoxygenation (OGD/RX) was measured by Cell Counting Kit (CCK)-8 assay. Coicis Semen treatment alleviates brain damage induced by ischemic stroke through inhibiting oxidative stress and promoting angiogenesis by activating the TGFβ/ALK1 signaling pathway.

Background and aims: Postoperative pain can cause serious adverse reactions that severely affect postoperative outcome. This study evaluated the effect of dexmedetomidine (DEX) added to sufentanil in intravenous patient-controlled analgesia (PCA) on the relief of pain and inflammatory responses during postoperative recovery of patients undergoing a combined thoracoscopic-laparoscopic esophagectomy (TLE). Methods: Sixty patients undergoing TLE were randomly allocated to receive 1 μg/ml of sufentanil alone (Group S) or 1 μg/ml of sufentanil plus 2.5 μg/ml of DEX (Group D) for postoperative intravenous (IV) PCA. Postoperative pain relief, cumulative PCA requirements, inflammatory marker levels, delirium, and recovery were assessed. Results: A joint DEX and sufentanil regimen significantly reduced the area under the curve of numerical rating scores for pain at rest (NRSR) and coughing (NRSC) at 1-48 h postoperatively (P = 0.000) that were associated with lower PCA-delivered cumulative sufentanil consumption and less PCA frequency until 48 h postoperatively (P < 0.05 and P < 0.0001, respectively). The simultaneous administration of DEX and sufentanil significantly reduced plasma IL-6 and TNF-α concentrations and increased IL-10 level (P < 0.0001, P = 0.0003, and P = 0.0345, respectively), accompanied by better postoperative delirium categories and health statuses of patients (P = 0.024 and P < 0.05, respectively). There was no hypotension, bradycardia, respiratory depression, or oversedation in Group D. Conclusion: Patients receiving DEX in addition to IV PCA sufentanil for TLE exhibited better postoperative analgesia, fewer inflammatory responses, and lower postoperative delirium categories and better health statuses.

Background: Pro-resolving mediators (PRMs) are considered as emerging analgesics for chronic pain. Maresin 1 (MaR1) is a newly identified member of PRMs, and recent studies implicate its potential role in some pain conditions. As the function of MaR1 in neuropathic pain remains unclear, we investigated the effects of MaR1 on pain hypersensitivity and the underlying mechanism using a rat spinal nerve ligation (SNL) model of neuropathic pain. Materials and methods: MaR1 (100 ng/10 μL) or commensurable artificial cerebrospinal fluid was delivered via intrathecal catheter from days 3 to 5 post-SNL followed by assessment of mechanical allodynia and thermal hyperalgesia. Ipsilateral L4–L5 spinal cord tissue was collected on day 7 post-SNL and assessed by Western blotting, enzyme-linked immunosorbent assay or immunohistochemistry. Results: Intrathecal MaR1 significantly attenuated mechanical allodynia and thermal hyperalgesia from day 5 to day 7 post-SNL, which was associated with decreased spinal levels of glial markers, GFAP and IBA1. It was also found that intrathecal MaR1 downregulated phosphorylation levels of NF-κB p65 and its nuclear translocation, as well as decreased protein levels of pro-inflammatory cytokines, TNF-α, IL-1β and IL-6. Further, MaR1 treatment restored PSD95 and synapsin II levels, suggesting that MarR1 also protected synaptic integrity. Conclusion: Our results indicate that MaR1 ameliorates the SNL-induced neuropathic pain by regulating glial activities and pro-inflammatory cytokines release. The present study offers insight into the potential of MaR1 as a novel intervention to ameliorate neuropathic pain.

Background. Previous research has shown that peroxiredoxin 1 (Prdx1) is an important modulator of physiological and pathophysiological cardiovascular events. This study is aimed at investigating the role and underlying mechanism of Prdx1 in doxorubicin- (DOX-) induced cardiotoxicity. Cardiac-specific expression of Prdx1 was induced in mice, and the mice received a single dose of DOX (15 mg/kg) to generate cardiotoxicity. First, our study demonstrated that Prdx1 expression was upregulated in the heart and in cardiomyocytes after DOX treatment. Second, we provided direct evidence that Prdx1 overexpression ameliorated DOX-induced cardiotoxicity by attenuating oxidative stress and cardiomyocyte apoptosis. Mechanistically, we found that DOX treatment increased the phosphorylation level of apoptosis signal-regulating kinase-1 (ASK1) and the downstream protein p38 in the heart and in cardiomyocytes, and these effects were decreased by Prdx1 overexpression. In contrast, inhibiting Prdx1 promoted DOX-induced cardiac injury via the ASK1/p38 pathway. These results suggest that Prdx1 may be an effective therapeutic option to prevent DOX-induced cardiotoxicity.