ATF4 inhibits TRPV4 function and controls itch perception in rodents and nonhuman primates.

ABSTRACT: Acute and chronic itch are prevalent and incapacitating, yet the neural mechanisms underlying both acute and chronic itch are just starting to be unraveled. Activated transcription factor 4 (ATF4) belongs to the ATF/CREB transcription factor family and primarily participates in the regulation of gene transcription. Our previous study has demonstrated that ATF4 is expressed in sensory neurons. Nevertheless, the role of ATF4 in itch sensation remains poorly understood. Here, we demonstrate that ATF4 plays a significant role in regulating itch sensation. The absence of ATF4 in dorsal root ganglion (DRG) neurons enhances the itch sensitivity of mice. Overexpression of ATF4 in sensory neurons significantly alleviates the acute and chronic pruritus in mice. Furthermore, ATF4 interacts with the transient receptor potential cation channel subfamily V member 4 (TRPV4) and inhibits its function without altering the expression or membrane trafficking of TRPV4 in sensory neurons. In addition, interference with ATF4 increases the itch sensitivity in nonhuman primates and enhances TRPV4 currents in nonhuman primates DRG neurons; ATF4 and TRPV4 also co-expresses in human sensory neurons. Our data demonstrate that ATF4 controls pruritus by regulating TRPV4 signaling through a nontranscriptional mechanism and identifies a potential new strategy for the treatment of pathological pruritus.

Alcohol consumption and gastric cancer risk: a meta-analysis of prospective cohort studies.

We performed this meta-analysis to explore the precise quantification relationship between alcohol consumption and gastric cancer and to provide evidence for preventing gastric cancer. We searched PubMed, Embase, and Web of Science for articles published up to December 2016, and identified 23 cohort studies that included a total population of 5,886,792 subjects. We derived meta-analytic estimates using random-effects models, taking into account correlations between estimates. We also investigated the dose-response relationship between gastric cancer risk and alcohol consumption. We found that alcohol consumption increased gastric cancer risk, where the summary risk ratio was 1.17 (95% confidence interval (CI): 1.00-1.34; I2 = 79.6%, p < 0.05. The dose-response analysis showed that every 10 g/d increment in alcohol consumption was associated with 7% increased gastric cancer risk (95% CI 1.02-1.12; I2 = 28.9%, p = 0.002). This meta-analysis provides evidence that alcohol consumption is an important risk factor of the incidence of gastric cancer.

Effect of Parecoxib as an Adjunct to Patient-Controlled Epidural Analgesia after Abdominal Hysterectomy: A Multicenter, Randomized, Placebo-Controlled Trial.

OBJECTIVE: This multicenter, randomized, placebo-controlled study evaluated the efficacy and side effects of parecoxib during patient-controlled epidural analgesia (PCEA) after abdominal hysterectomy. METHODS: A total of 240 patients who were scheduled for elective abdominal hysterectomy under combined spinal-epidural anesthesia received PCEA plus postoperative intravenous parecoxib 40 mg or saline every 12 h for 48 h after an initial preoperative dose of parecoxib 40 mg or saline. An epidural loading dose of a mixture of 6 mL of 0.25% ropivacaine and 2 mg morphine was administered 30 min before the end of surgery, and PCEA was initiated using 1.25 mg/mL ropivacaine and 0.05 mg/mL morphine with a 2-mL/h background infusion and 2-mL bolus with a 15-min lockout. The primary end point of this study was the quantification of the PCEA-sparing effect of parecoxib. RESULTS: Demographic data were similar between the two groups. Patients in the parecoxib group received significantly fewer self-administrated boluses (0 (0, 3) vs. 7 (2, 15), P < 0.001) and less epidural morphine (5.01 ± 0.44 vs. 5.95 ± 1.29 mg, P < 0.001) but experienced greater pain relief compared with the control group (P < 0.001). Patient global satisfaction was higher in the parecoxib group than the control group (P < 0.001). Length of hospitalization (9.50 ± 2.1, 95% CI 9.12~9.88 vs. 10.41 ± 2.6, 95% CI 9.95~10.87, P = 0.003) and postoperative vomiting (17% vs. 29%, P < 0.05) were also reduced in the parecoxib group. There were no serious adverse effects in either group. CONCLUSION: Our data suggest that adjunctive parecoxib during PCEA following abdominal hysterectomy is safe and efficacious in reducing pain, requirements of epidural analgesics, and side effects. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01566669).

Resolvin D1 protects against hepatic ischemia/reperfusion injury in rats.

OBJECTIVE: Inflammatory responses play an important role in the tissue damage during hepatic ischemia/reperfusion (I/R). Some resolvins have been shown to have protective properties in reducing I/R injury in the heart and kidney. The aim of the study was to investigate the effects of resolvin D1 (RvD1) on hepatic I/R. METHODS: Partial warm ischemia was produced in the left and middle hepatic lobes of Sprague-Dawley rats for 60 min, followed by 6h of reperfusion. Rats received either RvD1 (5 µg/kg) or vehicle by intravenous injection prior to ischemia. On the basis of treatment with RvD1, some rats further received the PI3K inhibitor LY294002. Blood and tissue samples from the groups were collected after 6-h reperfusion. RESULTS: Our results indicate that the RvD1 receptor ALX/FPR2 is present in liver, and that pretreatment with RvD1 prior to I/R insult significantly blunted I/R-induced elevations of alanine aminotransferase (AST) and aspartate aminotransferase (ALT), and significantly improved the histological status of the liver. Moreover, RvD1 significantly inhibited inflammatory cascades, as demonstrated by attenuations of IL-6, TNF-α and myeloperoxidase levels. Reduced apoptosis, and increased phosphorylation of Akt, were observed in the RvD1 group compared with the control I/R group. These effects of RvD1 on hepatic I/R injury were diminished by the PI3K inhibitor. CONCLUSIONS: Administration of RvD1 prior to hepatic I/R attenuates hepatic injury, at least in part through inhibition of inflammatory response and enhancement of phosphorylation of Akt.

Midazolam inhibits the proliferation of human head and neck squamous carcinoma cells by downregulating p300 expression.

The objective of this study was to investigate the mechanism of midazolam in inhibiting the proliferation of hypopharyngeal squamous carcinoma cells. Cultured FaDu cancer cells were treated with different concentrations of midazolam. MTT and BrdU incorporation assays were then used to evaluate cancer cell proliferation. The mRNA and protein levels of p300, a key factor involved in the tumorigenesis of numerous cancers, were measured with RT-PCR and Western blotting, respectively. Midazolam inhibited the expression of p300 and the proliferation of FaDu cells. Additionally, knockdown of p300 resulted in increased expression of p21 and p27 and decreased expression of p-Rb while inhibiting the proliferation of FaDu cells. Midazolam inhibits the proliferation of human head and neck squamous carcinoma cells by downregulating p300. Midazolam may be useful for the treatment of hypopharyngeal squamous cancers.

Does intraoperative ulinastatin improve postoperative clinical outcomes in patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials.

INTRODUCTION: The systematic meta-analysis of randomized controlled trials (RCTs) evaluated the effects of intraoperative ulinastatin on early-postoperative recovery in patients undergoing cardiac surgery. METHODS: RCTs comparing intraoperative ulinastatin with placebo in cardiac surgery were searched through PubMed, Cochrane databases, Medline, SinoMed, and the China National Knowledge Infrastructure (1966 to May 20th, 2013). The primary endpoints included hospital mortality, postoperative complication rate, length of stay in intensive care unit, and extubation time. The physiological and biochemical parameters illustrating postoperative cardiac and pulmonary function as well as inflammation response were considered as secondary endpoints. RESULTS: Fifteen RCTs (509 patients) met the inclusion criteria. Ulinastatin did not affect hospital mortality, postoperative complication rate, or ICU length of stay but reduced extubation time. Ulinastatin also increased the oxygenation index on postoperative day 1 and reduced the plasma level of cardiac troponin-I. Additionally, ulinastatin inhibited the increased level of tumor necrosis factor-alpha, polymorphonuclear neutrophil elastase, interleukin-6, and interleukin-8 associated with cardiac surgery. CONCLUSION: Ulinastatin may be of value for the inhibition of postoperative increased inflammatory agents and most likely provided pulmonary protective effects in cardiac surgery. However, larger adequately powered RCTs are required to define the clinical effect of ulinastatin on postoperative outcomes in cardiac surgery.

[Evaluation of the role of combined TES-MEP and CSEP monitoring during the spinal surgery].

OBJECTIVE: To evaluate of the role of transcranial electrical stimulation motor evoked potential (TES-MEP) in combination with cortical somatosensory evoked potential (CSEP) monitoring during the spinal surgery. METHODS: TES-MEP on bilateral anterior tibial muscle and flexor hallucal brevis and CSEP on bilateral posterior tibial nerve were observed simultaneously on 293 patients during spinal surgery from July 2006 to April 2009. Intravenous anesthesia was employed in all the patients, a part of which were added low dose of sevoflurane or muscle relaxant. The results of TES-MEP, CSEP and combined monitoring were analyzed statistically. Pre-operative and post-operative motor and sensory functions of spinal cord were compared. RESULTS: Success rate of TES-MEP, CSEP and combined monitoring was 90.8%, 96.9% and 100% respectively. For the judgment of motor function of spinal cord, the sensitivity of TES-MEP and CSEP was 100% and 89.3% respectively and the specificity of 98.4% and 96.9%. The Youden index of the two methods was 0.984 and 0.862. For sensory function, the sensitivity of them was 76.7% and 93.3% respectively and the specificity of 98.7% and 98.0%. The Youden index was 0.754 and 0.913. The sensitivity of combined monitoring was 100%, with the specificity of 96.9%. The Youden index was 0.969. CONCLUSIONS: The precision of monitoring motor function of spinal cord with TES-MEP is higher than that with CSEP, however, for sensory function, CSEP is more precise. The sensitivity and precision of combined monitoring for spinal cord function were apparently better than that of unitary TES-MEP or CSEP. The combined TES-MEP and CSEP monitoring is a relatively ideal method.

Subarachnoid transplantation of immortalized galanin-overexpressing astrocytes attenuates chronic neuropathic pain.

Treatment of chronic neuropathic pain resulted from peripheral nerve injury is one of the most difficult problems in modern clinical practice. The use of cell lines as biologic "minipumps" to chronically deliver anti-nociceptive molecules into the pain-processing centers of spinal cord is a newly developing technique for the treatment of pain. Moreover, spinal administration of exogenous galanin (GAL) is a useful target for the treatment of chronic pain after nerve injury. Because of better histocompatibility, lower immunogenicity and reproducibility, immortalized astrocytes (IAST) have been served as a promising cellular vehicle to deliver therapeutic molecules into CNS. In this study, the rat IAST was transfected with rat preprogalanin cDNA and the galanin-synthesizing and secreting cell line, IAST/GAL, was isolated. After cells were transplanted into the subarachnoid space of rats with chronic neuropathic pain induced by spared nerve injury (SNI) of sciatic nerve, their analgesic potential was evaluated by behavioral tests. The results showed that IAST/GAL transfected with preprogalanin gene could express and secrete significantly higher level of GAL protein in vitro and in vivo as compared with control cells. In addition, the pain-related behaviors, thermal hyperalgesia and mechanical allodynia were significantly alleviated during the 1-7 weeks after grafts of IAST/GAL cells, which could be reversed by galanin receptor antagonist M35 temporarily. Taken together, these data suggest that subarachnoid transplant of immortalized galanin-overexpressing astrocytes near the pain-processing centers was able to reverse the development of chronic neuropathic pain, which offers an adjunct approach to currently used therapies for the pain management.