Resolvin D1 Induces mTOR-independent and ATG5-dependent Autophagy in BV-2 Microglial Cells.

OBJECTIVE: The activation state of microglia is known to occupy a central position in the pathophysiological process of cerebral inflammation. Autophagy is a catabolic process responsible for maintaining cellular homeostasis. In recent years, autophagy has been demonstrated to play an important role in neuroinflammation. Resolvin D1 (RvD1) is a promising therapeutic mediator that has been shown to exert substantial anti-inflammatory and proresolving activities. However, whether RvD1-mediated resolution of inflammation in microglia is related to autophagy regulation needs further investigation. The present study aimed to explore the effect of RvD1 on microglial autophagy and its corresponding pathways. METHODS: Mouse microglial cells (BV-2) were cultured, treated with RvD1, and examined by Western blotting, confocal immunofluorescence microscopy, transmission electron microscopy, and flow cytometry. RESULTS: RvD1 promoted autophagy in both BV-2 cells and mouse primary microglia by favoring the maturation of autophagosomes and their fusion with lysosomes. Importantly, RvD1 had no significant effect on the activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, RvD1-induced mTOR-independent autophagy was confirmed by observing reduced cytoplasmic calcium levels and suppressed calcium/calmodulin-dependent protein kinase II (CaMK II) activation. Moreover, by downregulating ATG5, the increased phagocytic activity induced by RvD1 was demonstrated to be tightly controlled by ATG5-dependent autophagy. CONCLUSION: The present work identified a previously unreported mechanism responsible for the role of RvD1 in microglial autophagy, highlighting its therapeutic potential against neuroinflammation.

OVOL2 inhibits macrophage M2 polarization by regulating IL-10 transcription, and thus inhibits the tumor metastasis by modulating the tumor microenvironment.

Invasion and metastasis of breast cancer cells is an important cause of death in breast cancer patients. In the tumor microenvironment, M2 polarization of macrophages can promote the invasion and metastasis of tumor cells. OVOL2 is an evolutionarily conserved transcription regulator, but its effect in macrophages has not been described previously. The aim of this study was to investigate the effects of OVOL2 on macrophage polarity and the role of these effects in the tumor metastasis. We found that overexpression of OVOL2 in macrophages significantly inhibited M2 polarization and thus inhibits breast cancer metastasis. We propose a novel mechanism in which OVOL2 inhibits M2 polarization of macrophages and thus reduces their ability to induce invasion and metastasis of breast cancer. By shedding new light on the regulation of metastasis in cancers, our study provides a new strategy for the targeted therapy of cancer.

Trimetazidine offers myocardial protection in elderly coronary artery disease patients undergoing non-cardiac surgery: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Trimetazidine (TMZ) pretreatment protects cardiomyocytes during cardiac surgery. TMZ may protect elderly patients with ischaemic heart disease (IHD) undergoing non-cardiac surgery. METHODS: This was a randomized, double-blind, placebo-controlled trial (registration #ChiCTR1900025018) of patients with IHD scheduled to undergo non-cardiac surgery at Shenzhen People's Hospital (Shenzhen, Guangdong Province, China) between June 2014 and September 2015, randomized to 60 mg TMZ or placebo 12 h before surgery. The primary endpoint was the occurrence of in-hospital cardiovascular events. The secondary endpoints were myocardial ischaemia on five-lead electrocardiogram (cECG), cardiac troponin I (cTnI) elevation, cardiac death, acute coronary events, heart failure, and arrhythmia requiring treatments. RESULTS: Compared with the placebo group, the TMZ group showed a lower occurrence of in-hospital cardiovascular events (primary endpoint, 20.0% vs. 37.5%, P = 0.02), myocardial ischaemia (15.0% vs. 32.5%, P < 0.01), cTnI elevation (2.5% vs. 10%, P < 0.01), acute coronary events (10.0% vs. 20.0%, P < 0.05), heart failure (0% vs. 2.5%, P < 0.05), and arrhythmia requiring treatment (17.5% vs. 35.0%, P < 0.05). There was no acute myocardial infarction during the 30-day postoperative period. CONCLUSIONS: In elderly patients with IHD undergoing non-cardiac surgery, TMZ pretreatment was associated with myocardial protective effects. Trial registration The trial was prospectively registered at http://www.chictr.org.cn/showproj.aspx?proj=41909 with registration number [ChiCTR1900025018] (7/8/2019).

Etomidate vs propofol in coronary heart disease patients undergoing major noncardiac surgery: A randomized clinical trial.

BACKGROUND: The ideal depth of general anesthesia should achieve the required levels of hypnosis, analgesia, and muscle relaxation while minimizing physiologic responses to awareness. The choice of anesthetic strategy in patients with coronary heart disease (CHD) undergoing major noncardiac surgery is becoming an increasingly important issue as the population ages. This is because general anesthesia is associated with a risk of perioperative cardiac complications and death, and this risk is much higher in people with CHD. AIM: To compare hemodynamic function and cardiovascular event rate between etomidate- and propofol-based anesthesia in patients with CHD. METHODS: This prospective study enrolled consecutive patients (American Society of Anesthesiologists grade II/III) with stable CHD (New York Heart Association class I/II) undergoing major noncardiac surgery. The patients were randomly allocated to receive either etomidate/remifentanil-based or propofol/remifentanil-based general anesthesia. Randomization was performed using a computer-generated random number table and sequentially numbered, opaque, sealed envelopes. Concealment was maintained until the patient had arrived in the operating theater, at which point the consulting anesthetist opened the envelope. All patients, data collectors, and data analyzers were blinded to the type of anesthesia used. The primary endpoints were the occurrence of cardiovascular events (bradycardia, tachycardia, hypotension, ST-T segment changes, and ventricular premature beats) during anesthesia and cardiac troponin I level at 24 h. The secondary endpoints were hemodynamic parameters, bispectral index, and use of vasopressors during anesthesia. RESULTS: The final analysis included 40 patients in each of the propofol and etomidate groups. The incidences of bradycardia, hypotension, ST-T segment changes, and ventricular premature beats during anesthesia were significantly higher in the propofol group than in the etomidate group (P < 0.05 for all). The incidence of tachycardia was similar between the two groups. Cardiac troponin I levels were comparable between the two groups both before the induction of anesthesia and at 24 h after surgery. When compared with the etomidate group, the propofol group had significantly lower heart rates at 3 min after the anesthetic was injected (T1) and immediately after tracheal intubation (T2), lower systolic blood pressure at T1, and lower diastolic blood pressure and mean arterial pressure at T1, T2, 3 min after tracheal intubation, and 5 min after tracheal intubation (P < 0.05 for all). Vasopressor use was significantly more in the propofol group than in the etomidate group during the induction and maintenance periods (P < 0.001). CONCLUSION: In patients with CHD undergoing noncardiac major surgery, etomidate-based anesthesia is associated with fewer cardiovascular events and smaller hemodynamic changes than propofol-based anesthesia.

Transcriptomic and proteomic analysis reveals mechanisms of low pollen-pistil compatibility during water lily cross breeding.

BACKGROUND: In water lily (Nymphaea) hybrid breeding, breeders often encounter non-viable seeds, which make it difficult to transfer desired or targeted genes of different Nymphaea germplasm. We found that pre-fertilization barriers were the main factor in the failure of the hybridization of Nymphaea. The mechanism of low compatibility between the pollen and stigma remains unclear; therefore, we studied the differences of stigma transcripts and proteomes at 0, 2, and 6 h after pollination (HAP). Moreover, some regulatory genes and functional proteins that may cause low pollen-pistil compatibility in Nymphaea were identified. RESULTS: RNA-seq was performed for three comparisons (2 vs 0 HAP, 6 vs 2 HAP, 6 vs 0 HAP), and the number of differentially expressed genes (DEGs) was 8789 (4680 were up-regulated), 6401 (3020 were up-regulated), and 11,284 (6148 were up-regulated), respectively. Using label-free analysis, 75 (2 vs 0 HAP) proteins (43 increased and 32 decreased), nine (6 vs 2 HAP) proteins (three increased and six decreased), and 90 (6 vs 0 HAP) proteins (52 increased and 38 decreased) were defined as differentially expressed proteins (DEPs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that the DEGs and DEPs were mainly involved in cell wall organization or biogenesis, S-adenosylmethionine (SAM) metabolism, hydrogen peroxide decomposition and metabolism, reactive oxygen species (ROS) metabolism, secondary metabolism, secondary metabolite biosynthesis, and phenylpropanoid biosynthesis. CONCLUSIONS: Our transcriptomic and proteomic analysis highlighted specific genes, incuding those in ROS metabolism, biosynthesis of flavonoids, SAM metabolism, cell wall organization or biogenesis and phenylpropanoid biosynthesis that warrant further study in investigations of the pollen-stigma interaction of water lily. This study strengthens our understanding of the mechanism of low pollen-pistil compatibility in Nymphaea at the molecular level, and provides a theoretical basis for overcoming the pre-fertilization barriers in Nymphaea in the future.

pH-Sensitive Black Phosphorous-Incorporated Hydrogel as Novel Implant for Cancer Treatment.

In this study, black phosphorus nanosheets (BPNSs) were incorporated into a hydrogel formed from dibenzaldehyde-functionalized polymer (DF-PEG) and polyaspartylhydrazide (PAHy) polymer to create an injectable and pH-sensitive DF-PEG-PAHy/BPNSs hydrogel, which can be used as a smart depot for synergistic chemo-photothermal cancer therapy. The DF-PEG-PAHy/BPNSs hydrogel exhibited excellent gelation characteristics, pH sensitivity, and near-infrared responsiveness. The nanocomposite hydrogel provided controlled drug release and near-infrared irradiation speeded up release of drug from the hydrogel because of the photothermal effect of the BPNSs. Cytotoxicity tests confirmed that the hydrogel has good biocompatibility and exerts its photothermal effect in vitro. Antitumor tests in mice demonstrated the capacity of DF-PEG-PAHy/BPNSs hydrogel for synergistic chemo-photothermal therapy in vivo. The hydrogel showed reduced adverse effects because of stable drug release in the tumor area and an efficient photothermal effect. Together, these data demonstrated the potential of DF-PEG-PAHy/BPNSs hydrogel containing a chemotherapy drug to serve as a novel smart delivery system for combined chemo-photothermal cancer therapy.

Target-controlled infusion of propofol and remifentanil combined with dexmedetomidine reduces functional endoscopic sinus surgery bleeding.

The aim of the present study was to investigate the effects of target-controlled infusion (TCI) of propofol and remifentanil combined with dexmedetomidine on functional endoscopic sinus surgery (FESS) bleeding and surgical field. 62 patients scheduled to undergo FESS were randomly divided into experimental group (intravenous 0.5 µg kg-1 h-1 dexmedetomidine after 0.5 µg kg-1 bolus within 15 min until the end of surgery) or control group (intravenous saline administration at the same dose). All patients underwent endotracheal intubation under general anesthesia with TCI of propofol and remifentanil for anesthesia induction and maintenance. During anesthesia, arterial pressure (MAP), heart rate (HR), intraoperative propofol and remifentanil dosage and intraoperative blood loss were recorded. Surgeons rated their satisfaction with the surgical field using the Numeric Rating Scale (NRS). Following surgery, visual analog scale (VAS) was assessed. During tracheal intubation and extubation, HR and MAP in the experimental group were significantly lower compared with the control group (P<0.05); HR was also significantly lower compared with the control group throughout surgery (P<0.05). The mean infusion rate of propofol and remifentanil was significantly lower in the experimental group compared with the control group (P=0.001 and P=0.045, respectively). Blood loss in the experimental group was significantly lower compared with the control group (P=0.007). NRS and VAS scores in the experimental group were significantly improved compared with control group (P<0.01). In conclusion, TCI of propofol and remifentanil for FESS combined with dexmedetomidine reduced intraoperative bleeding and improved the quality of surgical field compared with the same procedure without dexmedetomidine. Dexmedetomidine also reduced the increase in MAP and HR during tracheal intubation and extubation, and improved postoperative analgesia quality.

Dexmedetomidine alleviates pulmonary edema by upregulating AQP1 and AQP5 expression in rats with acute lung injury induced by lipopolysaccharide.

This study aims to elucidate the mechanisms by which dexmedetomidine alleviates pulmonary edema in rats with acute lung injury induced by lipopolysaccharide (LPS). Male Wistar rats were randomly divided into five groups: normal saline control (NS) group, receiving intravenous 0.9% normal saline (5 mL/kg); LPS group, receiving intravenous LPS (10 mg/kg); small-dose dexmedetomidine (S) group, treated with a small dose of dexmedetomidine (0.5 µg · kg(-1) · h(-1)); medium-dose dexmedetomidine (M) group, treated with a medium dose of dexmedetomidine (2.5 µg · kg(-1) · h(-1)); high-dose dexmedetomidine (H) group, treated with a high dose of dexmedetomidine (5 µg · kg(-1) · h(-1)). The rats were sacrificed 6 h after intravenous injection of LPS or NS, and the lungs were removed for evaluating histological characteristics and determining the lung wet/dry weight ratio (W/D). The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1ß (IL-1ß) in the lung tissues were assessed by enzyme- linked immunosorbent assay (ELISA). The mRNA and protein expression levels of aquaporin-1 (AQP1) and aquaporin-5 (AQP5) were detected by RT-PCR, immunohistochemistry, and Western blotting. The lung tissues from the LPS groups were significantly damaged, which were less pronounced in the H group but not in the small-dose dexmedetomidine group or medium-dose dexmedetomidine group. The W/D and the concentrations of TNF-α and IL-1ß in the pulmonary tissues were increased in the LPS group as compared with those in NS group, which were reduced in the H group but not in S group or M group (P<0.01). The expression of AQP1 and AQP5 was lower in the LPS group than in the NS group, and significantly increased in the H group but not in the S group or M group (P<0.01). Our findings suggest that dexmedetomidine may alleviate pulmonary edema by increasing the expression of AQP-1 and AQP-5.

Ringer's malate solution protects against the multiple organ injury and dysfunction caused by hemorrhagic shock in rats.

Malic acid, in the form of its anion malate, is a key intermediate in the major biochemical energy-producing cycle known as the citric acid or Krebs cycle. In this study, the authors investigated the protective effect of a novel crystalloid solution of Ringer's malate following fluid resuscitation of hemorrhagic shock using a rat model. Under general anesthesia, Sprague-Dawley male rats were subjected to 60 min of hemorrhagic shock (40 mmHg for 60 min) followed by crystalloid resuscitation. Groups were as follows: (1) sham shock, (2) normal saline, (3) Ringer's lactate, and (4) Ringer's malate. The experiment was terminated at 4 h after resuscitation. Mean arterial blood pressure (MAP) and blood biophysical parameters were monitored during the experiment. The alanine aminotransferase, aspartate aminotransferase, urea, creatinine, superoxide dismutase, and malondialdehyde levels in plasma were detected. The intestine, liver, lung, and renal histopathology were measured. It was found that Ringer's malate could increase MAP immediately and maintain MAP for a long time. Ringer's malate could reduce the level of alanine aminotransferase, aspartate aminotransferase, urea, and creatinine. At the same time, the activity of superoxide dismutase was increased, and the level of malondialdehyde was decreased. Histopathology indicated that Ringer's malate can protect against the multiple organ injury caused by hemorrhagic shock in rats. Ringer's malate prevented circulatory failure and alleviated multiple organ dysfunction syndrome in animals with hemorrhagic shock. The study suggests that Ringer's malate solution could be a potential novel therapeutic agent for fluid resuscitation.