The kynurenine pathway regulated by intestinal innate lymphoid cells mediates postoperative cognitive dysfunction.

Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that can impair learning and memory for days, months, or even years after anesthesia/surgery. POCD is strongly associated with an altered composition of the gut microbiota (dysbiosis), but the accompanying metabolic changes and their role in gut-brain communication and POCD pathogenesis remain unclear. Here, the present study reports that anesthesia/surgery in aged mice induces elevated intestinal indoleamine 2,3-dioxygenase (IDO) expression and activity, which shifts intestinal tryptophan (TRP) metabolism toward more IDO-catalyzed kynurenine (KYN) and less gut bacteria-catabolized indoleacetic acid (IAA). Both anesthesia/surgery and intraperitoneal KYN administration induce increased KYN levels that correlate with impaired spatial learning and memory, whereas dietary IAA supplementation attenuates the anesthesia/surgery-induced cognitive impairment. Mechanistically, anesthesia/surgery increases interferon-γ (IFN-γ)-producing group 1 innate lymphoid cells (ILC1) in the small intestine lamina propria and elevates intestinal IDO expression and activity, as indicated by the higher ratio of KYN to TRP. The IDO inhibitor 1-MT and antibodies targeting IFN-γ or ILCs mitigate anesthesia/surgery-induced cognitive dysfunction, suggesting that intestinal ILC1 expansion and the ensuing IFN-γ-induced IDO upregulation may be the primary pathway mediating the shift to the KYN pathway in POCD. The ILC1-KYN pathway in the intestine could be a promising therapeutic target for POCD.

Intensity-surged and bandwidth-extended terahertz radiation in two-foci cascading plasmas.

The two-color strong-field mixing in gas medium is a widely used approach to generate bright broadband terahertz (THz) radiation. Here, we present a new, to the best of our knowledge, and counterintuitive method to promote THz performance in the two-color scheme. Beyond our knowledge that the maximum THz generation occurs with two-color foci overlapped, we found that, when the foci of two-color beams are noticeably separated along the propagation axis resulting in cascading plasmas, the THz conversion efficiency is surged by one order of magnitude and the bandwidth is stretched by more than two times, achieving 10-3 conversion efficiency and >100 THz bandwidth under the condition of 800/400 nm, ∼35 fs driving lasers. With the help of the pulse propagation equation and photocurrent model, the observations can be partially understood by the compromise between THz generation and absorption due to the spatial redistribution of laser energy in cascading plasmas. The present method can be extended to a mid-infrared driving laser, and new records of THz peak power and conversion efficiency are expected.

Taurine attenuates AFB1-induced liver injury by alleviating oxidative stress and regulating mitochondria-mediated apoptosis.

Aflatoxin B1 (AFB1), which widely exists in soil and crops, is the most toxic aflatoxin and a carcinogen to humans and animals. The liver is the main organ that processes AFB1 and other mycotoxins and is also the main target of AFB1 toxicity. Taurine is known to exhibit a variety of physiological and pharmacological functions. In the present study, taurine was administered to detect the protective effect and mechanism of taurine in AFB1-induced liver injury in rats. The results showed that taurine inhibited the increase in hepatic injury indices, hepatic apoptosis and hepatic malondialdehyde (MDA) contents while significantly enhanced the hepatic activities of antioxidant enzymes and mitochondrial function-related indices in AFB1-poisoned rats. Meanwhile, the expression levels of key factors in the Nrf2 signalling pathway were upregulated while the expression levels of key proteins in the mitochondria-mediated apoptotic pathway were downregulated after taurine administration. The results showed that taurine can reverse AFB1-induced liver injury and abnormal apoptosis through activation of the Nrf2 signalling pathway and its downstream antioxidant enzymes, which further protects mitochondria from oxidative stress and the subsequent apoptotic pathway.

Electroacupuncture relieves neuropathic pain by inhibiting degradation of the ecto-nucleotidase PAP in the dorsal root ganglions of CCI mice.

BACKGROUND: Although electroacupuncture is widely used in chronic pain management, it is quite controversial due to its unclear mechanism. We hypothesised that EA alleviates pain by inhibiting degradation of the ecto-nucleotidase prostatic acid phosphatase (PAP) and facilitating ATP dephosphorylation in dorsal root ganglions (DRGs). METHODS: We applied EA in male C57 mice subjected to chronic constriction injury (CCI) and assessed extracellular ATP and 5'-nucleotidease expression in DRGs. Specifically, we used a luminescence assay, quantitative reverse transcriptase-polymerase chain reaction, Western blotting, immunohistochemistry and nociceptive-related behavioural changes to gather data, and we tested for effects after PAP expression was inhibited with an adeno-associated virus (AAV). Moreover, membrane PAP degradation was investigated in cultured DRG neurons and the inhibitory effects of EA on this degradation were assessed using immunoprecipitation. RESULTS: EA treatment alleviated CCI surgery-induced mechanical pain hypersensitivity. Furthermore, extracellular ATP decreased significantly in both the DRGs and dorsal horn of EA-treated mice. PAP protein but not mRNA increased in L4-L5 DRGs, and inhibition of PAP expression via AAV microinjection reversed the analgesic effect of EA. Membrane PAP degradation occurred through a clathrin-mediated endocytosis pathway in cultured DRG neurons; EA treatment inhibited the phosphorylation of adaptor protein complex 2, which subsequently reduced the endocytosis of membrane PAP. CONCLUSIONS: EA treatment alleviated peripheral nerve injury-induced mechanical pain hypersensitivity in mice by inhibiting membrane PAP degradation via reduced endocytosis and subsequently promote ATP dephosphorylation in DRGs. SIGNIFICANCE: In a mouse model of chronic pain, electroacupuncture treatment increased levels of prostatic acid phosphatase (PAP: an ecto-nucleotidase known to relieve pain hypersensitivity) by inhibiting PAP degradation in dorsal root ganglions. This promoted extracellular ATP dephosphorylation, inhibited glia activation and eventually alleviated peripheral nerve injury-induced mechanical pain hypersensitivity in mice. Our findings represent an important step forward in clarifying the mechanisms of pain relief afforded by acupuncture treatment.

Identification, Structure-Activity Relationships of Marine-Derived Indolocarbazoles, and a Dual PKCθ/δ Inhibitor with Potent Antipancreatic Cancer Efficacy.

Protein kinases C (PKCs) are a family of serine/threonine kinases involved in various cellular processes, including proliferation, differentiation, cell survival, and apoptosis. Here, we report the identification, structure-activity relationship (SAR), and 3D-QSAR studies of 69 natural indolocarbazoles, including 15 new compounds, from marine streptomyces strains. Interestingly, we found that the chair conformational isomer of 7-oxo-staurosporine (compound 15) inhibited PKCθ more potently than the corresponding boat isomer. An evaluation of kinase selectivity and antitumor efficacy revealed that 15 was a potent dual PKCθ/δ inhibitor and that it could efficiently inhibit tumor growth in pancreatic cancer (PC) by inducing cellular apoptosis and suppressing the NF-κB/p-P65 pathway. In addition, we demonstrated that overexpression of p-PKCδ and p-P65 was associated with poor survival rates in patients with PC, and p-PKCθ expression also showed significant positive correlations with p-PKCδ and p-P65 levels. Finally, the PC patient-derived xenograft model further confirmed the potential anti-PC efficacy of 15.

Multiple Anesthesia/Surgery Cannot Impair Reference Memory in Adult Mice.

Postoperative cognitive dysfunction increases mortality and morbidity in perioperative patients. Numerous studies have demonstrated that multiple surgery/anesthesia during the neurodevelopmental period affects cognitive function, whereas a single anesthesia/surgery rarely causes cognitive dysfunction in adults. However, whether adults who undergo multiple anesthesia/surgery over a short period will experience cognitive dysfunction remains unclear. In this study, central nervous system inflammation and changes in cholinergic markers were investigated in adult mice subjected to multiple laparotomy procedures over a short period of time. The results showed that despite the increased expression of IL-6 and TNF-α in the hippocampus after multiple operations and the activation of microglia, multiple anesthesia/surgery did not cause a decline in cognitive function in adult mice. There were no changes in the cholinergic markers after multiple anesthesia/surgery.

Anti-CXCR4 Single-Chain Variable Fragment Antibodies Have Anti-Tumor Activity.

Monoclonal antibodies (mAbs) are large and have limitations as cancer therapeutics. Human single-chain variable fragment (scFv) is a small antibody as a good alternative. It can easily enter cancer tissues, has no immunogenicity and can be produced in bacteria to decrease the cost. The chemokine receptor CXCR4 is overexpressed in different cancer cells. It plays an important role in tumor growth and metastasis. Its overexpression is associated with poor prognosis in cancer patients and is regarded as an attractive target for cancer treatment. In this study, a peptide on the CXCR4 extracellular loop 2 (ECL2) was used as an antigen for screening a human scFv antibody library by yeast two-hybrid method. Three anti-CXCR4 scFv antibodies were isolated. They could bind to CXCR4 protein and three cancer cell lines (DU145, PC3, and MDA-MB-231) and not to 293T and 3T3 cells as negative controls. These three scFvs could decrease the proliferation, migration, and invasion of these cancer cells and promote their apoptosis. The two scFvs were further examined in a mouse xenograft model, and they inhibited the tumor growth. Tumor immunohistochemistry also demonstrated that the two scFvs decreased cancer cell proliferation and tumor angiogenesis and increased their apoptosis. These results show that these anti-CXCR4 scFvs can decrease cancer cell proliferation and inhibit tumor growth in mice, and may provide therapy for various cancers.

Treatment strategies for Graves' ophthalmopathy: a network meta-analysis.

PURPOSE: Various treatments have been investigated for Graves' ophthalmopathy (GO). We aimed to provide an overall profile of the efficacy and tolerability of various interventions for active and moderate to severe GO. METHODS: PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched on 6 July 2018. Randomised controlled trials (RCT) investigating GO treatments were included. Two researchers independently extracted data according to a predefined form. A random effects network meta-analysis was performed using a frequentist approach. The primary outcome was efficacy, and the secondary outcome was tolerability (side effect discontinuation). RESULTS: Thirty-three studies with 1846 patients with GO were included. Orbital radiotherapy (ORT) plus intravenous glucocorticoids (IVGC) (OR 27.11; 95% CI 4.57 to 160.92), mycophenolate mofetil (MMF) (24.40, 95% CI 5.28 to 112.67), oral glucocorticoids (OGC) plus ciclosporin (20.22, 95% CI 1.60 to 255.20), IVGC plus MMF (12.08, 95% CI 2.96 to 49.35), teprotumumab (8.92, 95% CI 2.51 to 31.77), ORT plus OGC (4.88, 95% CI 1.25 to 19.06), rituximab (RTX) (4.85, 95% CI 1.18 to 19.86), somatostatin analogues (4.23, 95% CI 1.60 to 11.16), OGC plus azathioprine (AzA) (5.77, 95% CI 1.17 to 28.47) and IVGC (4.96, 95% CI 1.96 to 12.55) showed significantly better improvement than no treatment. ORT plus IVGC ranked first, followed by MMF. High heterogeneity and significant local inconsistency were observed in the RTX studies. The results of the sensitivity analyses were similar to those of the main analysis. CONCLUSION: A robust recommendation regarding the best treatment cannot be made, because most evidence was rated as low or very low quality according to the Grading of Recommendations, Assessment, Development and Evaluations framework. Large RCTs and individual participant data meta-analyses are necessary to confirm these results and explore potential moderators. PROPERO TRIAL REGISTRATION NUMBER: CRD42018103029.

Adsorption behavior and mechanism of arsenic on mesoporous silica modified by iron-manganese binary oxide (FeMnOx/SBA-15) from aqueous systems.

Iron-manganese binary oxides (FeMnOx) can remove contaminants from aqueous solutions with high efficiency, and mesoporous silica (SBA-15) is widely used as a supporting material due to its large specific surface area and good stability. In this study, SBA-15 was used to support FeMnOx in the synthesis of a novel arsenic (As) adsorbent (FeMnOx/SBA-15), and its characteristics under different reaction conditions, such as pH, temperature, presence of competing ions, and humic acid, were tested. The results showed that the contaminant adsorption efficiency of the novel adsorbent was better than that of bare FeMnOx, as the addition of SBA-15 decreased the agglomeration effect of FeMnOx. Additionally, FeMnOx/SBA-15 underwent calcination to further enhance its performance. The state of iron and manganese in FeMnOx/SBA-15 and the corresponding arsenic removal efficiency were improved by calcination at 350 °C with an FeMnOx/SBA-15 mass fraction of approximately 45%. Almost 90% of As (50 mL, 5.0 mg L-1) could be removed by 0.2 g L-1 of FeMnOx/SBA-15 (mass ratio of 45% and calcination temperature of 350 °C). The FeMnOx/SBA-15 could regenerate and still be used after four consecutive cycles. The high As sorption capacity, ability to regenerate, and reusability of FeMnOx/SBA-15 confirmed that this adsorbent is promising for treating As-contaminated drinking water.

Sleep deprivation of rats increases postsurgical expression and activity of L-type calcium channel in the dorsal root ganglion and slows recovery from postsurgical pain.

Perioperative sleep disturbance is a risk factor for persistent pain after surgery. Clinical studies have shown that patients with insufficient sleep before and after surgery experience more intense and long-lasting postoperative pain. We hypothesize that sleep deprivation alters L-type calcium channels in the dorsal root ganglia (DRG), thus delaying the recovery from post-surgical pain. To verify this hypothesis, and to identify new predictors and therapeutic targets for persistent postoperative pain, we first established a model of postsurgical pain with perioperative sleep deprivation (SD) by administering hind paw plantar incision to sleep deprivation rats. Then we conducted behavioral tests, including tests with von Frey filaments and a laser heat test, to verify sensory pain, measured the expression of L-type calcium channels using western blotting and immunofluorescence of dorsal root ganglia (an important neural target for peripheral nociception), and examined the activity of L-type calcium channels and neuron excitability using electrophysiological measurements. We validated the findings by performing intraperitoneal injections of calcium channel blockers and microinjections of dorsal root ganglion cells with adeno-associated virus. We found that short-term sleep deprivation before and after surgery increased expression and activity of L-type calcium channels in the lumbar dorsal root ganglia, and delayed recovery from postsurgical pain. Blocking these channels reduced impact of sleep deprivation. We conclude that the increased expression and activity of L-type calcium channels is associated with the sleep deprivation-mediated prolongation of postoperative pain. L-type calcium channels are thus a potential target for management of postoperative pain.

Perioperative acute myocardial infarction in patients after non-cardiac surgery in China: Characteristics and risk factors.

To examine the characteristics and short-term outcome of perioperative myocardial infarction (PMI), a single-center retrospective study was carried out. The electronic medical records of 278,939 patients aged 45 years or older who underwent non-cardiac surgery at Renji Hospital from January 2003 to December 2015 were screened based on diagnostic codes (ICD121, ICD121.0, ICD121.1, ICD121.2, ICD121.3, ICD121.4, or ICD121.9). The incidence and characteristics of PMI and mortality risk factors were analyzed after non-cardiac surgery. PMI was reported in 45 patients, with an incidence rate of 1.61 per 10,000 and a mortality rate of 75.6% (34/45). The PMI incidence rate increased significantly with age. The PMI incidence rate was the highest for vascular surgery (5.82 per 10,000 cases). PMI occurs mainly within 48 h of surgery, with most cases showing an onset in the general wards. Logistic analysis showed that the use of nitrates is the independent protective factor for the outcomes of patients with PMI. The incidence of PMI in non-cardiac surgery is approximately 2 of 10,000 in patients aged 45 years or older, and increased significantly with age. The use of nitrates might be helpful for their survival.

Long non-coding RNA 00312 downregulates cyclin B1 and inhibits hepatocellular carcinoma cell proliferation in vitro and in vivo.

Long non-coding RNAs are dysregulated in human hepatocellular carcinoma (HCC). We tested the potential effect of long non-coding RNA 00312 ("Lnc00312") on human HCC cell behavior in vitro and in vivo. Forced-expression of Lnc00312 by a lentiviral vector induced proliferation inhibition and apoptosis in HepG2 cells and primary human HCC cells. Lnc00312 downregulated cyclin B1 and induced G2-M cell cycle arrest in HCC cells. Restoring cyclin B1 expression by a cyclin B1 cDNA construct inhibited Lnc00312-induced cytotoxicity against HCC cells. Conversely, siRNA-mediated knockdown of Lnc00312 increased cyclin B1 expression and promoted HepG2 cell proliferation. In vivo, the growth of HepG2 xenograft tumors in severe combined immunodeficient (SCID) mice was largely inhibited after expression of Lnc00312. Significantly, Lnc00312 is downregulated in human HCC tissues, which is negatively correlated with the tumor grade. Overall, Lnc00312 inhibits human HCC cell proliferation in vitro and in vivo. Cyclin B1 could be a key target protein of Lnc00312 in human HCC cells.

Cr(VI) induces cytotoxicity in vitro through activation of ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction via the PI3K/Akt signaling pathway.

The occupational and environmental toxicant hexavalent chromium [Cr(VI)] can cause severe damage to the liver; however, the exact mechanisms associated with its toxicity have not been thoroughly demonstrated. In the present study, the underlying mechanisms of Cr(VI)-induced hepatotoxicity were investigated. Our results showed that Cr(VI) inhibited the growth and proliferation of L-02 hepatocytes. Further study revealed that Cr(VI) significantly induced S-phase cell cycle arrest and apoptosis accompanying with the overproduction of reactive oxygen species (ROS). Cr(VI)-induced apoptosis could be prevented by inhibiting ROS with N-acetyl-l-cysteine (NAC). Additionally, our data showed that Cr(VI)-induced endoplasmic reticulum (ER) stress and mitochondrial dysfunction were concentration- and time-dependent. Moreover, inhibition of C/EBA homologous protein (CHOP) expression by siRNA partially prevented Cr(VI)-induced cell apoptosis, mitochondrial dysfunction and ROS generation. We also found that Cr(VI) treatment inhibited the PI3K/Akt pathway in a concentration- and time-dependent manner. After using IGF-1 (50ng/mL), the specific agonist of the PI3K/AKT signaling pathway, the facilitating effects of Cr(VI) were depressed. This finding demonstrated the relationship between the PI3K/Akt pathway, ER stress and mitochondrial dysfunction. Collectively, these findings indicated that Cr(VI) increased ROS production. Increased ROS production may account for inhibition of the PI3K/Akt pathway and lead to ER stress and mitochondrial dysfunction, which consequently induces apoptosis in L-02 hepatocytes. This study provides novel insights into the molecular mechanisms of Cr(VI)-induced cytotoxicity.

The natural logarithm of zinc-α2-glycoprotein/HOMA-IR is a better predictor of insulin sensitivity than the product of triglycerides and glucose and the other lipid ratios.

AIM: The euglycemic-hyperinsulinemic clamp (EHC) is not available in most clinical settings and is costly, time consuming and invasive, and requires trained staff. Therefore, an accessible and inexpensive test to identify insulin resistance (IR) is needed. The aim of this study is to assess whether zinc-α2-glycoprotein (ZAG) index [Ln ZAG/homeostasis model assessment of IR (HOMA-IR)] is a better surrogate index for estimating IR or metabolic syndrome (MetS) compared with other surrogate indices. METHODS: We performed a population-based cross-sectional study. Two hundred healthy subjects, 102 polycystic ovary syndrome (PCOS) patients, 97 newly diagnosed type 2 diabetes mellitus (nT2DM) and 84 impaired glucose tolerance (IGT) subjects were enrolled. The EHC was performed to identify IR. Circulating ZAG and adiponectin levels were determined by ELISA. RESULTS: The ZAG index was significantly lower in participants with IR including IGT, nT2DM and PCOS than in those without IR. In addition, subjects with MetS had lower ZAG indices and higher the product of fasting triglycerides and glucose (TyG) indices than those without MetS. The ZAG index showed a significantly stronger association with M values than the other surrogate indices, whereas the TyG index showed a stronger association with MetS. The optimal cutoff value of the ZAG index for detection of IR was 2.97 with a sensitivity of 88% and a specificity of 91%, whereas the optimal cutoff value of TyG index for detection of MetS was 4.90 with a sensitivity of 82% and a specificity of 86%. CONCLUSION: The ZAG index is a better marker than the other surrogate indices for identifying IR, whereas the TyG index has high sensitivity and specificity for identifying MetS.

Elevated circulating levels of irisin and the effect of metformin treatment in women with polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) is an insulin resistance (IR) state, like obesity and type 2 diabetes mellitus (T2DM). Although previous studies have suggested a correlation between irisin and the metabolic parameters associated with obesity and T2DM, the results have been inconsistent. OBJECTIVE: Our objective was to (1) determine circulating irisin levels in women with PCOS and control subjects, (2) examine the relationship of irisin and conventional markers of insulin resistance, and (3) examine irisin changes with interventions modulating IR in PCOS women. PATIENTS AND DESIGN: This study was comprised of a series of cross-sectional and interventional studies of 178 PCOS and 123 healthy women from the general population and outpatients of the Internal Medicine Department at the Second Affiliated Hospital, Chongqing Medical University, China. Forty seven women with PCOS were randomly assigned to 6 months of oral metformin (850 mg bid). The oral glucose tolerance test (OGTT) and the euglycemic-hyperinsulinemic clamp (EHC) were performed to assess glucose tolerance and insulin sensitivity. Outcome measures were IR (AUC(Insulin) and M values) on an OGTT and EHC, irisin levels, and metabolic markers. RESULTS: Circulating irisin was significantly higher in both overweight/obese (body mass index [BMI] ≥ 25 kg/m(2)) and PCOS women (P < .01). Circulating irisin levels correlated with BMI, WHR, FAT%, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), AUC(Insulin), homeostasis model assessment of insulin resistance (HOMA2-IR), M values, and free androgen index (FAI). During EHC, short-term hyperinsulinemia exhibited an inhibitory effect on irisin levels. After 6 months of metformin treatment, there was a significant decrease in circulating irisin in PCOS women following improved IR. CONCLUSIONS: These data suggest that irisin may be a useful marker of IR in PCOS women.

Immunodominant epitopes in nsp2 of porcine reproductive and respiratory syndrome virus are dispensable for replication, but play an important role in modulation of the host immune response.

Non-structural protein 2 (nsp2) of porcine reproductive and respiratory syndrome virus (PRRSV) is the largest protein of this virus. In addition to its crucial role in virus replication, recent studies have indicated its involvement in modulating host immunity. In this study, each of the six identified immunodominant nsp2 B-cell epitopes (ES2-ES7) was deleted using a type I PRRSV cDNA infectious clone. Deletion of ES3, ES4 or ES7 allowed the generation of viable virus. In comparison with the parental virus, the DeltaES3 mutant showed increased cytolytic activity and more vigorous growth kinetics, whilst the DeltaES4 and DeltaES7 mutants displayed decreased cytolytic activity and slower growth kinetics in MARC-145 cells. These nsp2 mutants were characterized further in a nursery pig disease model. The results showed that the DeltaES4 and DeltaES7 mutants exhibited attenuated phenotypes, whereas the DeltaES3 mutant produced a higher peak viral load in pigs. The antibody response reached similar levels, as measured by IDEXX ELISA at 21 days post-infection, and slightly higher levels of mean virus neutralizing titres were observed from pigs infected by the DeltaES4 and DeltaES7 mutants. The expression of innate and T-helper 1 cytokines was measured in peripheral blood mononuclear cells or virus-infected macrophages. The results consistently showed that interleukin-1beta and tumour necrosis factor alpha expression levels were downregulated in cells that were stimulated (or infected) with the DeltaES3 mutant compared with parental virus and the other nsp2 deletion mutants. These results suggest that certain regions in nsp2 are non-essential for PRRSV replication but may play an important role in modulation of host immunity in vivo.