JAK2/STAT3 inhibition attenuates intestinal ischemia-reperfusion injury via promoting autophagy: in vitro and in vivo study.

BACKGROUND: Intestinal ischemia-reperfusion (I/R) causes severe injury to the intestine, leading to systemic inflammation and multiple organ failure. Autophagy is a stress-response mechanism that can protect against I/R injury by removing damaged organelles and toxic protein aggregates. Recent evidence has identified JAK-STAT signaling pathway as a new regulator of autophagy process, however, their regulatory relationship in intestinal I/R remains unknown. METHODS AND RESULTS: We systematically analyzed intestinal transcriptome data and found that JAK-STAT pathway was largely activated in response to I/R with most significant upregulation observed for JAK2 and STAT3. ChIP-Seq and luciferase assays in an in vitro oxygen-glucose deprivation and reoxygenation model revealed that activated JAK2/STAT3 signaling directly inhibited the transcription of autophagy regulator Beclin-1, leading to the suppression of autophagy and the activation of intestinal cell death. These findings were further confirmed in an in vivo mouse model, in which, intestinal I/R injury was associated with the activation of JAK2/STAT3 pathway and the deactivation of Beclin-1-mediated autophagy, while inhibiting JAK2/STAT3 with AG490 reactivated autophagy and improved survival after intestinal I/R injury. CONCLUSIONS: JAK2/STAT3 signaling suppresses autophagy process during intestinal I/R, while inhibiting JAK-STAT can be protective against intestinal I/R injury by activating autophagy. These findings expand our knowledge on intestinal I/R injury and provide therapeutic targets for clinical treatment.

Dexmedetomidine inhibits mitochondria damage and apoptosis of enteric glial cells in experimental intestinal ischemia/reperfusion injury via SIRT3-dependent PINK1/HDAC3/p53 pathway.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) injury commonly occurs during perioperative periods, resulting in high morbidity and mortality on a global scale. Dexmedetomidine (Dex) is a selective α2-agonist that is frequently applied during perioperative periods for its analgesia effect; however, its ability to provide protection against intestinal I/R injury and underlying molecular mechanisms remain unclear. METHODS: To fill this gap, the protection of Dex against I/R injury was examined in a rat model of intestinal I/R injury and in an inflammation cell model, which was induced by tumor necrosis factor-alpha (TNF-α) plus interferon-gamma (IFN-γ) stimulation. RESULTS: Our data demonstrated that Dex had protective effects against intestinal I/R injury in rats. Dex was also found to promote mitophagy and inhibit apoptosis of enteric glial cells (EGCs) in the inflammation cell model. PINK1 downregulated p53 expression by promoting the phosphorylation of HDAC3. Further studies revealed that Dex provided protection against experimentally induced intestinal I/R injury in rats, while enhancing mitophagy, and suppressing apoptosis of EGCs through SIRT3-mediated PINK1/HDAC3/p53 pathway in the inflammation cell model. CONCLUSION: Hence, these findings provide evidence supporting the protective effect of Dex against intestinal I/R injury and its underlying mechanism involving the SIRT3/PINK1/HDAC3/p53 axis.

Dexmedetomidine protects intestinal ischemia-reperfusion injury via inhibiting p38 MAPK cascades.

Intestinal ischemia-reperfusion (I/R) is a life-threatening condition associated with high morbidity and mortality. Dexmedetomidine (DEX), an agonist of α2-adrenoceptor with sedation and analgesia effect, has recently been identified with protective function against I/R injury in multiple organs. However, the mechanism underlying the beneficial effect of DEX on intestine after I/R injury remained poorly understood. In the present study, using in both in vitro and in vivo models, we found that intestinal I/R injury was associated with the activation of p38 MAPK cascade, while DEX was capable of deactivating p38 MAPK and thus protect intestinal cells from apoptosis by inhibiting p38 MAPK-mediated mitochondrial depolarization and cytochrome c (Cyto C) release. Moreover, through inhibiting p38 MAPK activity, the downstream production of pro-inflammatory cytokines-regulated by NF-κB was also suppressed by DEX treatment, leading to the resolution of I/R-induced inflammation in intestine. In general, our study provided evidence that DEX protected intestine from I/R injury by inhibiting p38 MAPK-mediated mitochondrial apoptosis and inflammatory response.

KDM4B promotes DNA damage response via STAT3 signaling and is a target of CREB in colorectal cancer cells.

Resistance to radiotherapy is a major limitation for the successful treatment of colorectal cancer (CRC). Recently, accumulating evidence supports a critical role of epigenetic regulation in tumor cell survival upon irradiation. Lysine Demethylase 4B (KDM4B) is a histone demethylase involved in the oncogenesis of multiple human cancers but the underlying mechanisms have not been fully elucidated. Here we show that KDM4B is overexpressed in human colorectal cancer (CRC) tumors and cell lines. In CRC cells, KDM4B silencing induces spontaneous double-strand breaks (DSBs) formation and potently sensitizes tumor cells to irradiation. A putative mechanism involved suppression of Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway, which is essential for efficient repair of damaged DNA. Overexpression of STAT3 in KMD4B knockdown cells largely attenuates DNA damage triggered by KDM4B silencing and increases cell survival upon irradiation. Moreover, we find evidence that transcription factor CAMP Responsive Element Binding Protein (CREB) is a key regulator of KMD4B expression by directly binding to a conserved region in KMD4B promoter. Together, our findings illustrate the significance of CREB-KDM4B-STAT3 signaling cascade in DNA damage response, and highlight that KDM4B may potentially be a novel oncotarget for CRC radiotherapy.

Stellate ganglion block alleviates postoperative cognitive dysfunction via inhibiting TLR4/NF-κB signaling pathway.

Postoperative cognitive dysfunction (POCD) is common in aged patients after major surgery and is associated with increased risk of long-term morbidity and mortality. However, the underlying mechanism remains largely unknown and the clinical management of POCD is still controversial. Stellate ganglion block (SGB) is a clinical treatment for nerve injuries and circulatory issues. Recent evidence has identified the benefits of SGB in promoting learning and memory. We thus hypothesize that SGB could be effective in improving cognitive function after surgery. In present study, we established POCD model in aged rats via partial liver resection surgery. We found that the development of POCD was associated with the activation of toll-like receptor 4/nuclear factor kapa-B (TLR4/NF-κB) signaling pathway in the microglia in dorsal hippocampus, which induced the production of pro-inflammatory mediators (TNF-α, IL-1ß, IL-6) and promoted neuroinflammation. More importantly, we showed evidence that preoperative treatment with SGB could inhibit microglial activation, suppress TLR4/NF-κB-mediated neuroinflammation and effectively attenuate cognitive decline after the surgery. Our study suggested that SGB may serve as a novel treatment to prevent POCD in elderly patients. As SGB is safe procedure widely used in clinic, our findings can be easily translated into clinical practice and benefit more patients.

Dexmedetomidine promotes the recovery of neurogenesis in aged mouse with postoperative cognitive dysfunction.

Recently, growing evidence has demonstrated Dexmedetomidine (Dex) a promising intervene preventing postoperative cognitive decline (POCD) following surgery, which is associated with neuroinflammation leading to neuronal apoptosis and deregulated neurogenesis. Previous studies suggested the anti-inflammation and anti-neuroapoptosis action of Dex. Therefore we hypothesize the promoting neurogenesis of Dex linked to stimulating BDNF and subsequent p-MPAK production in a rat model of POCD. In the present study, the POCD animal model was established by performing an exploratory laparotomy under isoflurane anaesthesia in old rats, utilizing which Dex response is confirmed by behavioural tests. Inflammatory biomarkers as IL-1ß and TNF-α, mature neuron percentage measured by doublecortin staining (DCX), promoting factors as brain derived growth factor (BDNF), phosphorylated cAMP response element binding protein (CREB) and proteins of kinase A (PKA), MAPK production as p-P38-MAPK protein express were measured. Herein, we showed that surgery reduced DCX-positive neurons and expression of BDNF representing neurogenesis profoundly. As expected, Dex rescued the associated cognitive impairment and inflammatory changes, as well as up-regulated expression of BDNF, PKA, p-CREB/CREB and following p-P38-MAPK regulation. Our results confirmed the protective Dex response and indicated the proneurogenesis role of it as well, suggesting the mechanism of beneficial effects of Dex to prevent POCD.

Evaluation of dexmedetomidine in combination with sufentanil or butorphanol for postoperative analgesia in patients undergoing laparoscopic resection of gastrointestinal tumors: A quasi-experimental trial.

The aim of this study was to evaluate the efficacy of dexmedetomidine in combination with sufentanil or butorphanol for postoperative analgesia in patients undergoing laparoscopic resection of a gastrointestinal tumor.This quasi-experimental trial was conducted in Nanchang, China, from January 2014 to December 2015. Eighty patients (age 27-70 years, American Society of Anesthesiologists physical status I-II) undergoing laparoscopic resection of a gastrointestinal tumor were randomized into 4 groups and offered intravenous patient-controlled analgesia for pain control after surgery. The patients received sufentanil 2.0 µg/kg in combination with dexmedetomidine 1.5 µg/kg (group S1) or 2.0 µg/kg (group S2), or butorphanol 0.15 mg/kg in combination with dexmedetomidine 1.5 0 µg/kg (group N1) or 2.0 µg/kg (group N2). Oxygen saturation, mean arterial pressure (MAP), heart rate, visual analog scale score, and Ramsay sedation score were recorded at enrollment (T0), at extubation (T1), and 4 (T2), 8 (T3), 12 (T4), 24 (T5), and 48 (T6) hours thereafter. Side effects and satisfaction scores were evaluated after surgery.MAP increased in all groups at T1 but not significantly so when compared with T0. Heart rate decreased significantly in group S2 when compared with the other groups at T1-T5 (P < 0.05). MAP decreased significantly in group S2 when compared with group S1 at T4-T6 (P < 0.05). MAP increased significantly in group N1 when compared with group N2 at T4-T5 (P < 0.05). There was a statistically significant decrease in mean visual analog scale score in group S2 when compared with group S1 at T2 (P < 0.05) and group N2 at T1-T2 (P < 0.05). Two patients in group S1 had vomiting. There were no reports of drowsiness, respiratory depression, or other complications. The satisfaction score was higher in group S2 than in the other groups.Dexmedetomidine in combination with sufentanil or butorphanol can be used safely and effectively for postoperative analgesia in patients undergoing laparoscopic resection of a gastrointestinal tumor. The combination of dexmedetomidine 2.0 µg/kg and sufentanil is particularly beneficial in these patients.

The preventive effects of dexmedetomidine against intestinal ischemia-reperfusion injury in Wistar rats.

OBJECTIVES: Intestinal ischemia-reperfusion is a major problem, which may lead to multiorgan failure and death. The aim of this study was to evaluate the protective effects of dexmedetomidine on cell proliferation, antioxidant system, cell death, and structural integrity in intestinal injury induced by ischemia-reperfusion in rats. MATERIALS AND METHODS: Animals were randomized into three groups: group A, sham-operated or control; group B, intestinal ischemia/reperfusion (IR); and group C, intestinal IR pretreated with 50 µg of dexmedetomidine. Intestine tissue was collected from all rats 30 min after desufflation, and fresh frozen for histological and biochemical evaluation. RESULTS: The intestinal tissue of group B rats showed a significant decrease in the antioxidant enzyme activities. However, these enzyme activities were improved by the administration of dexmedetomidine. Inhibiting the protein expression of MCP7, PAR2, P-JAK, P-STAT1, and P-STAT3 proved the protective effect of dexmedetomidine. The immunohistochemical staining revealed its protective effect by maintaining the normal structural integrity, less caspase-3 immuno reactivity, and increased cell proliferation count in the intestinal tissues. CONCLUSIONS: Intraperitoneal injection of dexmedetomidine significantly protected intestine IR injury in rats by inhibiting the inflammatory response, intestinal epithelial apoptosis, and maintaining structural integrity of intestinal cells.