Sarm1 is Essential for Anesthesia-Induced Neuroinflammation and Cognitive Impairment in Aged Mice.

Postoperative cognitive dysfunction (POCD) is a common phenomenon among elderly patients with unclear etiology. Sterile alpha and TIR motif-containing 1 (Sarm1) plays important roles in neuroinflammation and cognitive function, and activates Calpain which has been shown to promote POCD through TrkB cleavage. This study aims to test the hypothesis that Sarm1 is involved in POCD through regulating Calpain activity. Wild type and Sarm1 knock out mice were exposed to isoflurane. Mouse cognitive function was determined by Morris water maze test. Neuroinflammation was determined by Iba1 and GFAP protein levels and mRNA expression of proinflammatory cytokines. Calpain activation was determined by αII-spectrin degradation and TrkB cleavage. Mitogen-activated protein kinase (MAPK) signaling was determined by c-Jun N-terminal kinase and cJun phosphorylation both in vivo and in vitro by Western blot and immunofluorescence staining. We found that Sarm1 deletion suppressed isoflurane induced cognitive impairment and neuroinflammation. Deletion of Sarm1 inhibited isoflurane induced αII-spectrin degradation and TrkB cleavage, which indicates suppression of Calpain activation. Finally, deletion of Sarm1 suppressed isoflurane induced MAPK signaling both in vivo and in vitro. Our findings suggest that isoflurane anesthesia induced cognitive impairment is prevented by Sarm1 deletion in mice, making Sarm1 a potent therapeutic target for treating or preventing POCD.

Nodakenetin Alleviates Inflammatory Pain Hypersensitivity by Suppressing NF-κB Signal Pathway.

BACKGROUND: Inflammatory pain mediated by nuclear factor kappa-B (NF-κB) signal pathway has become an increasingly important clinical issue in the last decade. As a potent antioxidant, Nodakenetin has been shown to have a prominent inhibitory effect on inflammation. However, the therapeutic effects and underlying pharmacological mechanisms of Nodakenetin for inflammatory pain remain unclear. METHODS: Intraplanar injection of complete Freund's adjuvant (CFA) was used to establish a model of chronic inflammation pain in C57BL/6 mice. The chronic neuropathic pain model was conducted by the sciatic nerve ligation surgery. QRT-PCR was performed to estimate the RNA levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). Western blot was used to demonstrated the protein levels of phospho-IkappaBα (IκBα), p50, and p65 in HEK293T cells. RESULTS: The bioactive components of the traditional Chinese medicine Notopterygium forbesii boiss mainly include Nodakenetin, isoimperatorin, and pregnenolone. Nodakenetin significantly alleviated CFA-induced inflammatory pain but showed no significant therapeutic effect on surgically induced neuralgia in a mouse model. In contrast, isoimperatorin and pregnenolone did not relieve CFA-induced inflammatory pain. Mechanistically, Nodakenetin inhibited IL-1ß-induced activation of the NF-κB pathway and phosphorylation of IκBα in HEK293T cells. Furthermore, Nodakenetin treatment suppressed the expression of IL-6, TNF-α, and IL-1ß in mouse bone marrow-derived macrophages. CONCLUSION: Nodakenetin alleviates inflammatory pain induced by CFA injection in vivo and modulates NF-κB signal pathway in vitro.

MiR-503-5p alleviates peripheral neuropathy-induced neuropathic pain in T2DM mice by regulating SEPT9 to inhibit astrocyte activation.

Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM) that causes peripheral and autonomic nervous system dysfunction. Dysregulation of miRNAs plays a crucial role in DPN development. However, the role of miR-503-5p in DPN remains unknown. Herein, T2DM mice (db/db) were used as a DPN model in vivo, and astrocytes isolated from db/db mice were induced with high glucose levels as a DPN model in vitro. MiR-503-5p expression was analyzed using qRT-PCR. GFAP, MCP-1, and SEPT9 protein levels were analyzed using western blotting and immunofluorescence. Luciferase assays were performed to investigate the interaction between miR-503-5p and SEPT9. We found that miR-503-5p expression decreased in the spinal cord of DPN model mice and astrocytes treated with high glucose (HG). The db/db mice displayed higher body weight and blood glucose, lower mechanical withdrawal threshold and thermal withdrawal latency, and higher GFAP and MCP-1 protein levels than db/m mice. However, tail vein injection of agomiR-503-5p remarkably reversed these parameters, whereas antigomiR-503-5p enhanced them. HG markedly facilitated GFAP and MCP-1 protein expression in astrocytes, whereas miR-503-5p mimic or inhibitor transfection markedly blocked or elevated GFAP and MCP-1 protein expression, respectively, in astrocytes with HG. SEPT9 was a target of miR-503-5p. In addition, SEPT9 protein levels were found to be elevated in db/db mice and astrocytes treated with HG. Treatment with agomiR-503-5p and miR-503-5p mimic was able to reduce SEPT9 protein levels, whereas treatment with antigomiR-503-5p and miR-503-5p inhibitor led to inhibition of the protein. Furthermore, SEPT9 overexpression suppressed the depressing effect of miR-503-5p overexpression in astrocytes subjected to HG doses. In conclusion, miR-503-5p was found to alleviate peripheral neuropathy-induced neuropathic pain in T2DM mice by regulating SEPT9 expression.

[Hemodynamic variations during tracheal intubation with intubating laryngeal mask airway versus direct laryngoscope in hypertensive patients].

OBJECTIVE: To compare the variations of cardiovascular responses and vascular angiotensin II (AngII) in hypertensive patients during tracheal intubation with intubating laryngeal mask airway (ILMA) versus direct laryngoscope (DLS). METHODS: A total of 120 hypertensive patients undergoing abdominal surgery were randomly divided into 2 groups, i.e.intubating laryngeal mask airway (Group I) and direct laryngoscope (Group D).Variations of invasive arterial blood pressure and angiotensin II were compared between two groups before and after intubation. RESULTS: The variations of cardiovascular responses and vascular angiotensin II (AngII) during tracheal intubation used of ILMA (T4) and DLS (T4) in an instant, tracheal intubation were immediately accomplished in two groups (T5). The variations of group I were significantly lower than those of group D (P < 0.05). And statistical significance existed between two groups. CONCLUSION: Tracheal intubation with intubating laryngeal mask airway (ILMA) can significantly reduce violent cardiovascular reactions and avoid cardiovascular accidents.

Chrysin Attenuates Oxidative Stress to Alleviate Sevoflurane-Induced Cognitive Impairments in Aged Rats.

OBJECTIVE: Anesthesia-induced cognitive impairments are common for elder patients after surgery. Oxidative stress is the predominant factor contributing to the impairments. This study was to assess the therapeutic potential of an anti-oxidative naturally occurring flavonoid, chrysin, in attenuating sevoflurane-induced cognitive impairments in rat models. METHODS: Rat models of cognitive impairments were constructed by exposing aged rats (18 months old) to sevoflurane for 2 h. Chrysin was administered via oral gavage at the dose of 25, 50, and 100 mg/kg/day for seven days. The elevated plus maze test was used to assess anxiety and explorative behaviors. Spatial memory tests were performed using novel object recognition test, object location memory task, and water maze experiments. Oxidative stress was evaluated by measuring levels of malondialdehyde, nicotinamide adenine dinucleotide phosphate, 4-hydroxynonenal, and glutathione using colorimetric assays. Quantitative real-time polymerase chain reaction and Western blot were used to analyze how chrysin affects nuclear factor E2-related factor (Nrf) signaling. RESULTS: While sevoflurane anesthesia led to significant decline in cognitive performance in object recognition test, object location memory task, and water maze test, chrysin exerted significant effects in alleviating the impairments. Oxidative stress was also reduced in the hippocampus tissue of rats after chrysin intake. Nrf signaling was activated by chrysin treatment in sevoflurane-induced cognitive impairment models. CONCLUSION: Chrysin was effective in alleviating cognitive impairments induced by sevoflurane anesthesia, which was at least in part facilitated by its effects in reducing oxidative stress via activating Nrf signaling.

Effects of transfusion load and suction pressure on renal function in intraoperative salvage autotransfusion.

Although some investigations have been performed to determine the effects of transfusion load and suction pressure on renal function during intraoperative salvage autotransfusion, the precise threshold is still undetermined. A total of 625 patients undergoing surgery with the Continuous AutoTransfusion System (CATSplus) were enrolled and divided into groups according to the utilized suction pressure and transfusion volume. Plasma free hemoglobin (FHB) and creatinine clearance (CCr) were assayed to indicate the renal function. Both 0.03 MPa suction (≥4-unit load) and >5 units transfusion changed the levels of FHB and CCr significantly when measured 24 h post-operation compared to pre-operation. Under 0.02 MPa suction (≥4-unit load), the alteration of FHB and CCr returned to normal after 24 h. Under 3 units transfusion, the levels of FHB and CCr at 6 and 12 h post-operation changed significantly compared to pre-operation (P<0.05 or P<0.01, respectively), and this alteration could be restored to normal at 72 h post-operation. After an exhaustive investigation, less than 4 units transfusion and less than 0.03 MPa suction pressure are recommended for intraoperative salvage autotransfusion.

Ultrasound-guided stellate ganglion block alleviates stress responses and promotes recovery of gastrointestinal function in patients.

BACKGROUND: This study aimed to investigate the effect of preoperative ultrasound-guided stellate ganglion block (SGB) on the perioperative stress responses and gastrointestinal functions of patients undergoing laparoscopic colorectal cancer surgery. METHODS: A total of 60 colorectal cancer patients were enrolled in study and were randomized to be treated with or without SGB therapy. In the SGB group, patients were injected with 7 mL 0.5% ropivacaine in stellate ganglion under ultrasound guidance before anesthesia. Mean artery pressure (MAP), heart rate (HR), recovery of bowel sound and first exhaust, as well as levels of motilin, gastrin, norepinephrine, cortisol, interleukin-6 (IL-6) and C-reactive protein (CRP) were recorded at various time points. RESULTS: 26 patients in the SGB group and 27 patients in the control group were analyzed. No significant differences in MAP or HR were observed between the two groups before, during and after the surgery. SGB promoted recovery of gastrointestinal functions, as evidenced by earlier recovery of bowel sound and first exhaust, as well as increased motilin and gastrin levels. SGB also attenuated stress responses, as shown in reduced norepinephrine, cortisol, IL-6 and CRP levels. CONCLUSIONS: SGB promotes the recovery of gastrointestinal functions and reduces stress responses of colorectal patients undergoing laparoscopic colorectal cancer surgery.

The expression level of COX7C associates with venous thromboembolism in colon cancer patients.

Venous thromboembolism (VTE) is a common complication of colon cancer. In the present study, we aimed to explore the association of the oncogene COX7C to VTE in colon cancer patients. Samples from 580 patients were examined histologically for VTE and pathological characteristic of cancer. Gene mutation and expression analysis were performed using polymerase chain reaction-based assays to evaluate genes related to VTE, including COX7C. Univariate analysis between clinical pathological factors and VTE was conducted. Logistic regression analysis was performed for the prediction of VTE by pathological factors and gene expressions. Among patients investigated, a total of 56 patients had VTE. COX7C had a significant correlation with VTE (p < 0.001). Despite a correlation between tumor size, invasion depth of tumor, lymph node metastasis, lymph node metastasis, distant metastasis, lymphovascular invasion, histologic type and pathology type, Ki-67, and some other genes, to VTE (p > 0.05), only COX7C expression demonstrated significance in its ability to predict VTE. Here, we show that COX7C upregulation strongly correlates with VTE in colon cancer, which implicates its role as a biomarker and therapeutic target of VTE in colon cancer.

Effects of transfusion load and suction pressure on renal function in intraoperative salvage autotransfusion

Although some investigations have been performed to determine the effects of transfusion load and suction pressure on renal function during intraoperative salvage autotransfusion, the precise threshold is still undetermined. A total of 625 patients undergoing surgery with the Continuous AutoTransfusion System (CATSplus) were enrolled and divided into groups according to the utilized suction pressure and transfusion volume. Plasma free hemoglobin (FHB) and creatinine clearance (CCr) were assayed to indicate the renal function. Both 0.03 MPa suction (≥4-unit load) and >5 units transfusion changed the levels of FHB and CCr significantly when measured 24 h post-operation compared to pre-operation. Under 0.02 MPa suction (≥4-unit load), the alteration of FHB and CCr returned to normal after 24 h. Under 3 units transfusion, the levels of FHB and CCr at 6 and 12 h post-operation changed significantly compared to pre-operation (P<0.05 or P<0.01, respectively), and this alteration could be restored to normal at 72 h post-operation. After an exhaustive investigation, less than 4 units transfusion and less than 0.03 MPa suction pressure are recommended for intraoperative salvage autotransfusion.

Melanocortin-4 receptor expression in autonomic circuitry involved in gastric function.

Several studies have shown that CNS provides the regulation of gastric functions. Recent evidence indicated that the activation of melanocortin 4 receptors (MC4R) in brain nuclei played an important role in modulating gastric activity. This study was designed to assess whether MC4R signaling existed in autonomic circuitry modulated the activity of stomach by a virally mediated transsynaptic tracing study. Pseudorabies virus (PRV)-614 was injected into the ventral stomach wall in adult male MC4R-green fluorescent protein (GFP) transgenic mice (n = 5). After a survival time of 5 days, the mice were assigned to humanely sacrifice, and spinal cords and caudal brainstem were removed and sectioned, and processed for PRV-614 visualization. Neurons involved in the efferent control of the stomach were identified following visualization of PRV-614 retrograde tracing. The neurochemical phenotype of MC4R-GFP-positive neurons was identified using fluorescence immunocytochemical labeling. PRV-614/MC4R-GFP dual labeled neurons were detected in spinal IML and the dorsal motor nucleus of the vagus nerve (DMV). Our findings support the hypothesis that MC4R signaling in autonomic circuitry may participate in the modulation of gastric activity by the melanocortinergic-sympathetic pathway or melanocortinergic-parasympathetic pathway.

Inhibition of nuclear factor-kappaB activation is essential for membrane-associated TNF-alpha-induced apoptosis in HL-60 cells.

The killing of tumour cells that are resistant to soluble TNF-alpha (sTNF-alpha) by the membrane-bound form of TNF-alpha (mTNF-alpha) suggests that different intracellular signalling pathways are involved. We found that mTNF-alpha induced apoptosis in HL-60 cells and failed to cause degradation of inhibitor of kappa B alpha (IkappaB-alpha) and translocation and activation of nuclear factor kappa B (NF-kappaB), whereas sTNF-alpha failed to induce apoptosis, but lowered cytoplasmic inhibitor of kappa B alpha, induced translocation of NF-kappaB to the nucleus and experimentally increased activity of the regulated luciferase. Furthermore, mTNF-alpha upregulated the expression of TNF receptor associated factor (TRAF) 1 and failed to induce TRAF1 and TRAF2 membrane translocation, but led to cytoplasmic colocalization. In contrast, sTNF-alpha stimulated the expression of TRAF1 and TRAF2, recruiting both molecules onto the cell membrane poststimulation. These results suggest that the increased susceptibility of HL-60 cells to mTNF-alpha may be due to the failure of TRAF2 membrane translocation caused by the upregulation of TRAF1 expression and formation of a TRAF1/TRAF2 complex in the cytoplasm, thereby inhibiting NF-kappaB activation and inducing apoptosis.