The molecular mechanism of MiR-26a-5p regulates autophagy and activates NLRP3 inflammasome to mediate cardiomyocyte hypertrophy.

OBJECTIVE: Many studies have found that miR-26a-5p plays an essential role in the progression of pathological cardiac hypertrophy, however, there is still no evidence on whether miR-26a-5p is related to the activation of autophagy and NLRP3 inflammasome. And the mechanism of miR-26a-5p and NLRP3 inflammasome aggravating pathological cardiac hypertrophy remain unclear. METHODS: Cardiomyocytes were treated with 200µM PE to induce cardiac hypertrophy and intervened with 10mM NLRP3 inhibitor INF39. In addition, we also used the MiR-26a-5p mimic and inhibitor to transfect PE-induced cardiac hypertrophy. RT-qPCR and western blotting were used to detect the expressions of miR-26a-5p, NLRP3, ASC and Caspase-1 in each group, and we used α-SMA immunofluorescence to detect the change of cardiomyocyte area. The expression levels of autophagy proteins LC3, beclin-1 and p62 were detected by western blotting. Finally, we induced the SD rat cardiac hypertrophy model through aortic constriction (TAC) surgery. In the experimental group, rats were intervened with MiR-26a-5p mimic, MiR-26a-5p inhibitor, autophagy inhibitor 3-MA, and autophagy activator Rapamycin. RESULTS: In cell experiments, we observed that the expression of miR-26a-5p was associated with cardiomyocyte hypertrophy and increased surface area. Furthermore, miR-26a-5p facilitated autophagy and activated the NLRP3 inflammasome pathway, which caused changes in the expression of genes and proteins including LC3, beclin-1, p62, ACS, NLRP3, and Caspase-1. We discovered similar outcomes in the TAC rat model, where miR-26a-5p expression corresponded with cardiomyocyte enlargement and fibrosis in the cardiac interstitial and perivascular regions. In conclusion, miR-26a-5p has the potential to regulate autophagy and activate the NLRP3 inflammasome, contributing to the development of cardiomyocyte hypertrophy. CONCLUSION: Our study found a relationship between the expression of miR-26a-5p and cardiomyocyte hypertrophy. The mechanism behind this relationship appears to involve the activation of the NLRP3 inflammasome pathway, which is caused by miR-26a-5p promoting autophagy. Targeting the expression of miR-26a-5p, as well as inhibiting the activation of autophagy and the NLRP3 inflammasome pathway, could offer additional treatments for pathological cardiac hypertrophy.

The protective effect and mechanism of sevoflurane on LPS-induced acute lung injury in mice.

Acute lung injury (ALI) is a disturbance caused by infectious or non-infectious inflammation and lipopolysaccharide (LPS) could induce an artificial pathological ALI process. Sevoflurane has been demonstrated to be an inhaled anesthetic having anti-inflammatory and protective effects on inflammatory injury. To study the protective effects and mechanisms of sevoflurane on LPS-induced acute lung injury in mice. By assessing W/D ratio, sevofluranecan counteract the edema induced by LPS. The ELISA results showed that sevoflurane reduced IFN-γ production and increased IL-10 level. Elevation of PGE2 induced by sevofluraneand LPS in peritoneal macrophages was inhibited by NS-398, an inhibitor of the PGE2 regulator COX-2, indicating that NS-398 blocked COX-2 mediated PGE2 synthesis. NS-398 itself did not cause lung inflammation and mitigated the protective effect of sevoflurane on LPS-induced ALI in mice. LPS changes immune homeostasis, resulting in acute lung inflammatory injury. Inhaled sevoflurane regulates immune homeostasis, thereby playing a protective role in alleviating LPS-induced ALI.

Effects of sericin on the testicular growth hormone/insulin-like growth factor-1 axis in a rat model of type 2 diabetes.

This study investigated the effects of sericin on the testicular growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in rats with type 2 diabetes mellitus. Forty rats were randomly assigned to normal control, type 2 diabetes mellitus, sericin and metformin treated groups. Type 2 diabetes was established by repeated intraperitoneal injection of streptozotocin, and identified by blood glucose ≥16.7 mmol/L at 1 week. The diabetic rats were given no other treatment, these rats in the sericin group were intragastrically perfused with 2.4 g/kg sericin and the metformin treated rats were intragastrically perfused with 55.33 mg/kg Metformin daily for 35 consecutive days. Enzyme-linked immunosorbent assays were used to determine serum testosterone, growth hormone and IGF-1 levels. Immunohistochemical staining, western blotting and reverse transcription-PCR were used to determine testicular growth hormone, growth hormone receptor and IGF-1 expression. The sericin significantly reduced serum growth hormone levels, downregulated growth hormone expression, increased serum testosterone and IGF-1 levels, and upregulated testicular growth hormone receptor and IGF-1 expression. Moreover, there were no significant differences in any of the parameters between the sericin and metformin treated groups. These findings indicated that sericin improved spermatogenic function through regulating the growth hormone/IGF-1 axis, thereby protecting reproductive function against diabetes-induced damage.

The changes of von willebrand factor/a disintegrin-like and metalloprotease with thrombospondin type I repeats-13 balance in aneurysmal subarachnoid hemorrhage.

The aim of this study was to investigate the role of Von Willebrand Factor/thrombospondin type I repeats-13 (VWF/ADAMTS13) balance in aSAH. Fifty eight patients with aSAH at the First Affiliated hospital of Soochow University, Suzhou, China, between January 2012 and January 2014 were eligible for the study. They were divided into delayed cerebral ischemia group (DCI group) and non-delayed cerebral ischemia group (no DCI group), or cerebral vasospasm group (CVS group) and no spasm group (no CVS group), or good outcome group and poor outcome group. The control group consisted of twenty healthy people. All patients underwent CT, DSA, or (and) CTA diagnosed with intracranial subarachnoid hemorrhage which is caused by aneurysm rupture. Venous blood was drawn in tubes at 3 time points: 1 day after SAH (T1), (4±1) days after SAH (T2), and (9±1) days after SAH (T3) to determine plasma concentrations of ADAMTS13, VWF, P-selectin and IL-6 via enzyme-linked immunosorbent assay (ELISA). Transcranial doppler sonography (TCD) was used to measure mean blood flow velocity of the middle cerebral artery (VMCA). Glasgow Outcome Scale (GOS) was measured before discharge. Among 58 patients, 12 (20.7%) had DCI, 40 (68.9%) had TCD evidence of CVS, and 20 (34.5%) had poor outcome. The concentrations of VWF, P-selectin and IL-6 on T1, T2 and T3 after SAH were significantly higher in DCI, CVS and poor outcome groups compared with those of the control group (P < 0.05). The concentrations of VWF, P-selectin and IL-6 were significantly higher in DCI, CVS and poor outcome groups compared with those of the no DCI, no CVS and good outcome groups. The activity of ADAMTS13 was lower in DCI and poor outcome groups compared with those of the no DCI and good outcome groups (P < 0.05). The activity of ADAMTS13 showed no difference in CVS group and no CVS group (P > 0.05). The results of our study suggest that the increased VWF and decreased ADAMTS13 activity were associated with DCI and poor outcome. The balance of VWF/ADAMTS13 could be used to predict the clinical outcome. The deficiency of ADAMTS13 can not only induce DCI but also accelerate inflammatory reaction. Our results reported in this paper may provide new insights into the possible use of ADAMTS13 as a therapeutic agent in aneurysmal subarachnoid hemorrhage.

Intrathecal L-arginine reduces the antinociception of sevoflurane in formalin-induced pain in rats.

The purpose of this study was to investigate the contribution of spinal nitric oxide (NO) to the antinociceptive effects of emulsified sevoflurane in rats. Formalin tests were used to assess the nociceptive response. Immunohistochemistry was performed to determine the effects of emulsified sevoflurane on formalin-induced changes of Fos-like immunoreactive (Fos-LI)-positive neurons in the spinal cord. We found that emulsified sevoflurane administered intraperitoneally at a dosage of 2.5 ml/kg did not impair motor performance in rats, but it significantly decreased the formalin-induced paw licking time. Furthermore, Fos-LI-positive neurons were mainly found in the ipsilateral dorsal horn after the injection of formalin. The administration of emulsified sevoflurane significantly decreased Fos-LI-labeled neurons. Finally, intrathecal L-arginine alone did not affect the basal pain threshold, but it significantly decreased the antinociceptive response of emulsified sevoflurane against formalin injection and the suppressive effects of sevoflurane on formalin-induced Fos protein expression (P<0.05). These data suggest that spinal cord NO is involved in the antinociception of sevoflurane in rats.

Effects of epidural anesthesia and postoperative epidural analgesia on immune function in esophageal carcinoma patients undergoing thoracic surgery.

Thoracic epidural anesthesia (TEA) has been demonstrated to significantly reduce stress and immune dysfunction in trauma patients. In esophageal carcinoma patients undergoing thoracic surgery, TEA combined with general anesthesia during surgery and subsequent postoperative patient-controlled epidural analgesia (PCEA) may improve plasma cortisol (Cor), interleukin (IL)-6 and IL-17 levels and helper T-cell differentiation. A total of 60 esophageal carcinoma patients undergoing thoracic surgery were randomly allocated into groups I, II, III and I (n=15 per group). During surgery, groups I and II received total intravenous general anesthesia (TIVA), whereas groups III and IV received combined TEA and TIVA. Postoperatively, groups I and III received postoperative patient-controlled intravenous analgesia (PCIA), while groups II and IV received PCEA. The Cor, IL-6, IFN-γ, IL-4 and IL-17 levels were measured in peripheral blood samples collected prior to anesthesia (T0), at 2 h after incision (T1), at 4 h postoperatively (T2), at 24 h postoperatively (T3) and at 48 h postoperatively (T4). The plasma Cor, IL-17 and IL-6 levels increased significantly at the beginning of the operation in groups I, II and III, while in group IV there were no significant differences during the entire period, concurrent with enhanced Th0 to Th2 shift, contributing to a Th2-dominant Th1/Th2 ratio. General anesthesia with TEA more efficiently inhibited the onset of the Th2-dominant status and decreased the plasma levels of Cor and IL-6 compared to general anesthesia alone and PCEA inhibited the Th2-dominant status more efficiently compared to PCIA. Therefore, general anesthesia combined with TEA and sole administration of PCEA were demonstrated to inhibit the stress response and minimize immune dysfunction, generating most pronounced results upon combination TEA/PCEA treatment.

An in vitro study of the neuroprotective effect of propofol on hypoxic hippocampal slice.

PRIMARY OBJECTIVE: To determine whether propofol has a neuroprotective effect on hypoxic brain injury. RESEARCH DESIGN: A hippocampal slice, in artificial cerebrospinal fluid (ASCF) with glucose and oxygen deprivation (OGD), was used as an in vitro model for brain hypoxia. METHODS AND PROCEDURES: The orthodromic population spike (OPS) and hypoxic injury potentia1 (HIP) were recorded in the CA1 region when Schaffer collateral was stimulated in the CA3 region of the hippocampal slices during hypoxia. The concentrations of amino acid neurotransmitters in perfusion solution of hippocampal slices were directly measured using high performance liquid chromatography (HPLC). Morphological changes of neurons, astrocytes and mitochondria in CA1 region were observed using histology and electron microscopy. Neuronal apoptosis was evaluated with TUNEL assay. MAIN OUTCOME AND RESULTS: Propofol treatment delayed the elimination of OPS and improved the recovery of OPS; decreased frequency of HIP, postponed the onset of HIP and increased the duration of HIP. Propofol treatment also decreased the release of amino acid neurotransmitters such as aspartate, glutamate and glycine induced by hypoxia, but elevated the release of γ-aminobutyric acid (GABA). Morphological studies showed that propofol treatment attenuated oedema of pyramid neurons in the CA1 region and reduced apoptosis. CONCLUSIONS: Propofol has a neuro-protective effect on hippocampal neuron injury induced by hypoxia.

Effect of ondansetron in preventing postoperative nausea and vomiting under different conditions of general anesthesia: a preliminary, randomized, controlled study.

METHODS: Two hundred and forty patients were randomly allocated into six groups: Group I, anesthesia was maintained with sevoflurane; Group II, anesthesia was maintained with sevoflurane and 8 mg of ondansetron; Group III, anesthesia was maintained with propofol; Group IV, anesthesia was maintained with propofol and 8 mg of ondansetron; Group V, anesthesia was maintained with sevoflurane and propofol; Group VI, anesthesia was maintained with sevoflurane combined with propofol and 8 mg of ondansetron. RESULTS: We found that the incidence of vomiting was lower in group II (17.5%), group IV (7.5%), and group VI (10%) compared with group I (55%), group III (27.5%), and group V (30%), respectively (P < 0.05). The incidence of vomiting was also lower in group III (27.5%) and group V (30%) when compared with group I (55%) (P < 0.05). The incidence of nausea was 55% in group I, 42.5% in group II, 30% in group III, 27.5% in group IV, 30% in group V, and 30% in group VI. Groups III and V had a lower incidence of nausea than group I (P < 0.05). CONCLUSIONS: We conclude that compared with sevoflurane anesthesia alone, anesthesia with either propofol alone or propofol combined with sevoflurane resulted in a reduced incidence of vomiting and nausea during the first 24 h after surgery. Administration of ondansetron effectively reduced the incidence of vomiting but not that of nausea for all three types of general anesthesia.

Effects of preemptive intravenous lornoxicam on the analgesic efficacy of epidural morphine and expression of chemokines in women undergoing hysterectomy.

BACKGROUND: It is believed that preemptive IV lornoxicam treatment can reduce the consumption of other analgesics, improve analgesic efficacy, and ameliorate immune function during patient-controlled IV analgesia. However, the effects of preemptive IV lornoxicam treatment on the analgesic efficacy of patient-controlled epidural analgesia (PCEA) with morphine and on chemokine expression remain unknown. OBJECTIVE: The aim of this prospective, randomized, controlled study was to observe the effects of preemptive IV lornoxicam treatment on the analgesic efficacy of PCEA with morphine and on the expression of monocyte chemotactic protein-1 (MCP-1) and stromal cell-derived factor-1α (SDF-1α) in women undergoing hysterectomy. METHODS: Patients undergoing elective hysterectomy with combined spinal and epidural anesthesia were randomized to 1 of 3 groups to receive IV lornoxicam 8 mg before anesthesia (group 1), lornoxicam 16-mg injection before anesthesia (group 2), or isotonic saline (control) before anesthesia. PCEA was used to treat postoperative pain, and a visual analog scale (VAS) and the Bruggemann Comfort Scale (BCS) were used to evaluate analgesic efficacy. Morphine consumption was recorded. To measure plasma concentrations of MCP-1 and SDF-1α via enzyme-linked immunosorbent assay, venous blood samples were obtained from patients at 4 separate times: before anesthesia (baseline); 0 (immediately after anesthesia administration); and 24 and 48 hours after surgery. RESULTS: Forty-five patients (mean [SD] age, 41 [5] years; mean [SD] weight, 54 [6] kg) undergoing elective hysterectomy were included in the study. There were no significant differences in VAS scores, BCS scores, or morphine consumption between the 3 groups. Compared with baseline values, MCP-1 and SDF-1α concentrations were increased significantly immediately after surgery in all 3 groups (all, P < 0.01) and returned to near-baseline values at 24 hours postsurgery in groups 1 and 2, and by 48 hours postsurgery in the control group. MCP-1 and SDF-1α concentrations in groups 1 and 2 were significantly lower than those in the control group immediately (all, P < 0.01) and 24 hours postsurgery (all, P < 0.05). CONCLUSION: Preemptive IV lornoxicam treatment was associated with attenuation of the plasma concentrations of MCP-1 and SDF-1α immediately after and 24 hours after hysterectomy and was associated with more rapid resolution to near-baseline concentrations of both cytokines in these patients compared with controls; however, it was not associated with significantly reducing epidural morphine consumption.