Effects of aluminum (Al) stress on the isoprenoid metabolism of two Citrus species differing in Al-tolerance.

Isoprenoid metabolism and its derivatives took part in photosynthesis, growth regulation, signal transduction, and plant defense to biotic and abiotic stresses. However, how aluminum (Al) stress affects the isoprenoid metabolism and whether isoprenoid metabolism plays a vital role in the Citrus plants in coping with Al stress remain unclear. In this study, we reported that Al-treatment-induced alternation in the volatilization rate of monoterpenes (α-pinene, ß-pinene, limonene, α-terpinene, γ-terpinene and 3-carene) and isoprene were different between Citrus sinensis (Al-tolerant) and C. grandis (Al-sensitive) leaves. The Al-induced decrease of CO2 assimilation, maximum quantum yield of primary PSII photochemistry (Fv/Fm), the lower contents of glucose and starch, and the lowered activities of enzymes involved in the mevalonic acid (MVA) pathway and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway might account for the different volatilization rate of isoprenoids. Furthermore, the altered transcript levels of genes related to isoprenoid precursors and/or derivatives metabolism, such as geranyl diphosphate (GPP) synthase (GPPS) in GPP biosynthesis, geranylgeranyl diphosphate synthase (GGPPS), chlorophyll synthase (CHS) and GGPP reductase (GGPPR) in chlorophyll biosynthesis, limonene synthase (LS) and α-pinene synthase (APS) in limonene and α-pinene synthesis, respectively, might be responsible for the different contents of corresponding products in C. grandis and C. sinensis. Our data suggested that isoprenoid metabolism was involved in Al tolerance response in Citrus, and the alternation of some branches of isoprenoid metabolism could confer different Al-tolerance to Citrus species.

A targetable PRR11-DHODH axis drives ferroptosis- and temozolomide-resistance in glioblastoma.

Temozolomide (TMZ) is a widely utilized chemotherapy treatment for patients with glioblastoma (GBM), although drug resistance constitutes a major therapeutic hurdle. Emerging evidence suggests that ferroptosis-mediated therapy could offer an appropriate alternative treatment option against cancer cells that are resistant to certain drugs. However, recurrent gliomas display robust ferroptosis resistance, although the precise mechanism of resistance remains elusive. In the present work, we report that proline rich protein 11 (PRR11) depletion significantly sensitizes GBM cells to TMZ by inducing ferroptosis. Mechanistically, PRR11 directly binds to and stabilizes dihydroorotate dehydrogenase (DHODH), which leads to glioma ferroptosis-resistant in a DHODH-dependent manner in vivo and in vitro. Furthermore, PRR11 inhibits HERC4 and DHODH binding, by suppressing the recruitment of E3 ubiquitin ligase HERC4 and polyubiquitination degradation of DHODH at the K306 site, which maintains DHODH protein stability. Importantly, downregulated PRR11 increases lipid peroxidation and alters DHODH-mediated mitochondrial morphology, thereby promoting ferroptosis and increasing TMZ chemotherapy sensitivity. In conclusion, our results reveal a mechanism via which PRR11 drives ferroptosis resistance and identifies ferroptosis induction and TMZ as an attractive combined therapeutic strategy for GBM.

The diagnostic value of image-enhanced endoscopy system in sinonasal inverted papilloma.

PURPOSE: This study aimed to evaluate the diagnostic value of image-enhanced endoscopy (IEE) in detecting sinonasal inverted papilloma (SNIP). METHODS: Overall, 86 patients with unilateral nasal papillary or lobulated neoplasms were included between July 2018 and June 2019. All patients underwent IEE examinations, and the diagnosis of all neoplasms was confirmed through postoperative pathology. Logistic regression analysis was conducted to screen for independent predictors of various types of vascular patterns of SNIP. Furthermore, a prognostic nomogram was constructed using the independent predictors screened by logistic regression analysis to evaluate its usefulness in distinguishing SNIP from nasal polyp (NP) and papillary mucosa folds (PMF). RESULTS: In total, 86 consecutive cases were observed, including 37 with SNIP, 40 with NP, and 9 with PMF. Logistic regression analysis showed that spot, corkscrew, and multilayered vascular patterns were independent predictors of SNIP diagnosis. Furthermore, a nomogram comprising the three independent risk factors was constructed with scores of 5, 2, and 3. The area under the receiver operating characteristic curve for predicting SNIP was 0.954, 0.66, 0.71, and 0.76 for the nomogram model, spot vascular pattern, corkscrew vascular pattern, and multilayered vascular pattern, respectively. CONCLUSION: The nomogram model based on spot, corkscrew, and multilayered vascular patterns in SNIP observed using IEE can be a useful diagnostic tool for predicting and distinguishing between NP and PMF.

Induction of a type 2 inflammatory chronic rhinosinusitis in C57BL/6 mice.

Background: Eosinophilic chronic rhinosinusitis (CRS) has been widely studied for its intractability and high recurrence rate. It can be divided into pure and mixed type 2 CRS subtypes. Mouse models that reflect pure type 2 inflammation of CRS are lacking. Objective: This study aims to establish a relatively pure type 2 CRS mouse model and compare it with 2 mixed type 2 CRS models. Methods: Three mouse CRS models were constructed: (1) aerosol ovalbumin (OVA) + aspergillus oryzae-derived protease (AP); (2) intranasal OVA + AP; (3) Intraperitoneal then intranasal OVA + AP (n = 10 per group). Nasal, lung symptoms, IgE, inflammatory cells, cytokines, and remodeling factors were evaluated. Results: Histological and micro-computed tomography showed inflammation, polyps, and opacification in all 3 experimental groups. The aerosol group had significantly increased local eosinophils and type 2 cytokines, while other types of cytokines showed no noticeable change. The nasal instillation groups also showed elevated other inflammatory factors and tissue polypoid changes were more pronounced. More severe pulmonary inflammation was observed with aerosol delivery. Conclusion: Aerosol inhalation mouse model is superior for studying nasal relatively pure type 2 inflammation and lower airway comorbidities.

MYC-induced cytidine metabolism regulates survival and drug resistance via cGas-STING pathway in mantle cell lymphoma.

Lymphocyte proliferation and tumourigenesis are dependent on nucleotide synthesis to support DNA, RNA and phospholipid synthesis. Here, we identified that reprogramming of nucleotide metabolism as an important factor divides mantle cell lymphoma (MCL) into two groups with different transcriptional signalling pathways and varying prognoses. We establish a nucleotide metabolism-related prognostic model that includes six genes with different regression coefficients, which significantly predicts prognosis for MCL patients (p < 0.0001). Of these six genes, de novo CTP synthesis pathway enzyme CTPS1 whose inhibitor (STP938) is already in clinical trials for relapsed/refractory lymphomas (NCT05463263) has the highest regression coefficient. An increase in CTPS1 expression predicts adverse overall survival and progression-free survival with independent prognostic significance in 105 primary MCL samples and GEO database (GSE93291). CRISPR CTPS1 knockout causes DNA damage and proliferation defects in MCL. Additionally, MYC positively regulates CTPS1 expression, and TP53-aberrant and ibrutinib-resistant MCL cells also rely on cytidine metabolism. Furthermore, besides the obvious decreased CTP pool caused by CTPS1 deficiency, CTPS1 inhibition may also induce immune-related responses via activating dsDNA-cGAS-STING pathway, which plays a crucial role in impeding tumour growth in MCL patients.

Cystatin SN in type 2 inflammatory airway diseases.

Cystatin SN, encoded by CST1, belongs to the type 2 (T2) cystatin protein superfamily. In the past decade, several publications have highlighted the association between cystatin SN and inflammatory airway diseases including chronic rhinosinusitis, rhinitis, asthma, chronic obstructive pulmonary disease, and chronic hypersensitivity pneumonitis. It is, therefore, crucial to understand the role of cystatin SN in the wider context of T2 inflammatory diseases. Here, we review the expression of cystatin SN in airway-related diseases with different endotypes. We also emphasize the physiological and pathological roles of cystatin SN. Physiologically, cystatin SN protects host tissues from destructive proteolysis by cysteine proteases present in the external environment or produced via internal dysregulated expression. Pathologically, the secretion of cystatin SN from airway epithelial cells initiates and amplifies T2 immunity and subsequently leads to disease. We further discuss the development of cystatin SN as a T2 immunity marker that can be monitored noninvasively and assist in airway disease management. The discovery, biology, and inhibition capability are also introduced to better understand the role of cystatin SN in airway diseases.

Prognostic significance of absolute monocyte count and lymphocyte to monocyte ratio in mucosa-associated lymphoid tissue (MALT) lymphoma.

To investigate the prognostic significance of peripheral blood absolute monocyte count (AMC) and lymphocyte to monocyte ratio (LMR) in mucosa-associated lymphoid tissue (MALT) lymphoma, we retrospectively analyzed 316 newly diagnosed patients with MALT lymphoma. The best cut-off value of AMC was 0.6 × 109/L and LMR was 1.8 by x-tile according to progression-free survival (PFS). Multivariate analysis showed that MALT-IPI (p < 0.001), Eastern Cooperative Oncology Group performance status (ECOG PS) (p = 0.010), and LMR (p = 0.003) have independent prognostic significance for PFS, MALT-International Prognostic Index (MALT-IPI) (p = 0.018), ß2-microglobulin (ß2-MG) (p = 0.015), and LMR (p = 0.029) predicted poor overall survival (OS). Receiver-operator characteristic (ROC) curves were used to compare the prognostic prediction capability of MALT-IPI and MALT-IPI-M (MALT-IPI combined with LMR); area under the curves (AUCs) for MALT-IPI-M were larger than that for MALT-IPI both PFS (0.682 vs 0.654) and OS (0.804 vs 0.788). Our results indicated that that low level LMR at diagnosis was associated with inferior prognosis. The new prognostic index, MALT-IPI-M, enabled the risk stratification capability for MALT lymphoma survival.

A qualitative analysis method for multi-component gas mixtures via terahertz rotational spectroscopy.

Terahertz rotational spectroscopy is one of the most effective methods of gas sensing. However, the rich and dense spectral peaks of multi-component gas mixtures in the terahertz band increase the difficulty of gas identification. A novel qualitative analysis method is proposed based on the collision broadening mechanism coupled with terahertz spectroscopy technology. First of all, a broadening coefficients database of acetonitrile, formic acid, and formaldehyde colliding with nitrogen was established by experimental measurements and a spectral peak fitting technique. Then the broadening coefficients of the isolated peaks in binary and ternary mixtures perturbed by nitrogen were derived. Finally, the components were identified by matching the broadening coefficients of these isolated peaks with the established database. The proposed qualitative analysis method based on the collision broadening mechanism would be a new approach for identifying multi-component gas mixtures in analytical chemistry.

A quantitative analysis method based on collision broadening for trace gas using terahertz heterodyne spectrometer.

Quantitative analysis of trace gases is an important research field in analytical chemistry. The terahertz electronic spectrometer is one of the most powerful tools for detecting trace gas. Here, a terahertz spectrometer based on frequency multiplier chain and heterodyne detection was presented. The rotational spectra of acetonitrile (CH3CN) gas were measured in the 290-370 GHz frequency band with 100 kHz spectral resolution. The spectrometer demonstrated excellent spectral specificity and the extrapolated limit of detection for CH3CN gas of 1.4 ppm. Furthermore, a novel quantification method of trace gas was proposed based on broadening mechanisms. The CH3CN self- and nitrogen (N2)- collisional broadening coefficients were obtained experimentally for verifying the method. The CH3CN concentration of the validation group was calculated, and the relative error was 0.1%. The error analysis of the different number of measurements of the method was carried out. The method could provide a new perspective for trace gas quantitative analysis.

Inhibiting Hv1 channel in peripheral sensory neurons attenuates chronic inflammatory pain and opioid side effects.

Both opioids and nonsteroidal anti-inflammatory drugs (NSAIDS) produce deleterious side effects and fail to provide sustained relief in patients with chronic inflammatory pain. Peripheral neuroinflammation (PN) is critical for initiation and development of inflammatory pain. A better understanding of molecular mechanisms underlying PN would facilitate the discovery of new analgesic targets and the development of new therapeutics. Emerging evidence suggests that peripheral sensory neurons are not only responders to painful stimuli, but are also actively engaged in inflammation and immunity, whereas the intrinsic regulatory mechanism is poorly understood. Here we report the expression of proton-selective ion channel Hv1 in peripheral sensory neurons in rodents and humans, which was previously shown as selectively expressed in microglia in mammalian central nervous system. Neuronal Hv1 was up-regulated by PN or depolarizing stimulation, which in turn aggravates inflammation and nociception. Inhibiting neuronal Hv1 genetically or by a newly discovered selective inhibitor YHV98-4 reduced intracellular alkalization and ROS production in inflammatory pain, mitigated the imbalance in downstream SHP-1-pAKT signaling, and also diminished pro-inflammatory chemokine release to alleviate nociception and morphine-induced hyperalgesia and tolerance. Thus, our data reveal neuronal Hv1 as a novel target in analgesia strategy and managing opioids-related side effects.

Prognostic significance of serum immunoglobulin paraprotein in mucosa-associated lymphoid tissue (MALT) lymphoma.

To assess the prognostic significance of immunoglobulin (Ig) paraproteinaemia in mucosa-associated lymphoid tissue (MALT) lymphoma, 218 patients diagnosed with MALT lymphoma were enrolled in this study. Serum Ig paraprotein was detected in 42 of 218 patients (19.3%), mostly IgM-K (15, 35.7%), followed by IgM-L and IgG-L. Advanced age (p = 0.025), poor Eastern Cooperative Oncology Group performance status (p = 0.014), bone marrow involvement (p = 0.019), B symptoms (p = 0.039), advanced disease stage (III-IV) (p < 0.0001), elevated serum ß2-microglobulin level (p < 0.0001), multiple extranodal sites of involvement (p < 0.0001), nodal involvement (p < 0.0001), systemic therapy (p < 0.0001) and higher MALT-lymphoma International Prognostic Index (MALT-IPI) scores (p = 0.001) were significantly associated with the presence of serum Ig paraprotein. Multivariate Cox regression analysis showed that Ig paraproteinaemia was an independent prognostic predictor for inferior progression-free survival (PFS) and overall survival. A new prognostic index based on MALT-IPI and Ig paraproteinaemia, as assessed using receiver operating characteristic curves and the area under the curve statistics, showed better discriminative ability than MALT-IPI in predicting PFS. In conclusion, Ig paraproteinaemia was a promising prognostic predictor for MALT lymphoma. Ig paraproteinaemia together with MALT-IPI might contribute to optimising therapeutic management in clinical practice.

Dexmedetomidine and Netrin-1 Combination Therapy Inhibits Endoplasmic Reticulum Stress by Regulating the ERK5/MEF2A Pathway to Attenuate Cerebral Ischemia Injury.

The complexity of hard-to-treat diseases such as ischemic stroke strongly undermines the therapeutic potential of available treatment options. Therefore, current developments have gently shifted from a focus on monotherapy to combined or multiple therapies. Both dexmedetomidine and Netrin-1 have anti-neuronal apoptosis effects, but the mechanism is still unclear. The study aimed to estimate the efficacy of dexmedetomidine and Netrin-1 combination therapy against ERS-induced apoptosis after cerebral ischemia injury in vivo and in vitro, and whether the mechanism is related to the ERK5/MEF2A pathway. Adult male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) in vivo, 90 min ischemia and 24 h reperfusion. The hippocampus slices used to establish oxygen-glucose deprivation (OGD) injury model in vitro. Neterin-1 and Dexmedetomidine were pretreated and post-treated, respectively, before and after the model establishment. MEF2A knockdown was performed by microinjection of AAV9-MEF2A RNAi vector. Orthodromic population spike (OPS) at the end of reoxygenation were recorded. Neurobehavioral tests, TTC staining, Nissl staining, TUNEL staining were performed to assess the effect of the drugs. The expression of CHOP, GRP78, MEF2A, ERK5, and p-ERK5 were investigated by Western blot and immunofluorescence staining. Neurological deficit score, infarct volume, the expression of GRP78, CHOP, and neural apoptotic rate of MCAO group increased markedly. Combination of dexmedetomidine and Netrin-1 resulted in lower infarct volumes and fewer neurological impairments, higher OPS recovery rate, and less damaged and apoptotic cells after cerebral ischemia injury. Furthermore, expression levels of GRP78 and CHOP decreased in the combination therapy group, and it was more effective than the single drug group. Meanwhile, Combination of dexmedetomidine and Netrin-1 increased MEF2A expression and promoted ERK5 phosphorylation. However, the protective effect of dexmedetomidine combined with Netrin-1 in improving neurological function was significantly eliminated by pre-knockdown MEF2A. The neuroprotective effects of dexmedetomidine combined with Netrin on cerebral ischemia-reperfusion injury and hippocampal hypoxia injury in terms of ERS. The synergistic effect of combination therapy is related to the activation of ERK5/MEF2A signaling pathway.

Clinical study of a 125I particle-integrated esophageal covered stent and hyperbaric oxygen in the treatment of advanced esophageal cancer.

OBJECTIVE: this study aimed to investigate the clinical efficacy and feasibility of the treatment of advanced esophageal cancer with a combination of a 125I particle-integrated esophageal covered stent and hyperbaric oxygen. METHODS: forty-five patients with advanced esophageal cancer were enrolled and were randomly divided into two groups: a treatment group and a control group. Patients in the treatment group were treated with a 125I particle-integrated esophageal covered stent and hyperbaric oxygen, while patients in the control group were treated with a 125I particle-integrated esophageal covered stent. The clinical effects and long-term survival time of the two groups were observed. RESULTS: in the treatment group, the complete remission (CR) rate and partial remission (PR) rate of local lesions were 19.2 % and 61.5 %, respectively, and the total effective rate was 80.7 %. In the control group, the CR rate and PR rate of local lesions were 10.5 % and 52.6 %, respectively, and the total effective rate was 63.1 %. The total effective rate was higher in the treatment group than in the control group, which was statistically significant (p < 0.05). CONCLUSION: the combination of a 125I particle-integrated esophageal covered stent and hyperbaric oxygen shows a good short- and long-term efficacy in the treatment of advanced esophageal cancer.

[Effect of transcutaneous electrical acupoint stimulation on postoperative olfactory memory disorder and plasma melatonin in patients with general anesthesia of sevoflurane].

OBJECTIVE: To observe the effect of transcutaneous electrical acupoint stimulation (TEAS) on postoperative olfactory memory disorder in patients with general anesthesia of sevoflurane and to explore its possible mechanism. METHODS: Forty patients who were scheduled to have gynecological and urological procedures under general anesthesia were randomly divided into an observation group and a control group, 20 cases in each group. The patients in the observation group were treated with TEAS (dilatational wave, 2 Hz/100 Hz) at Yingxiang (LI 20) and Yintang (GV 29) 10 min before anesthesia induction until the end of operation; the patients in the control group received general anesthesia directly. The changes of mean arterial pressure (MAP), heart rate (HR) and blood oxygen saturation (SpO2) were recorded before treatment, 30 min after operation and at the end of operation; smell identification score was measured by Connecticut Chemosensory Clinical Research Center (CCCRC) olfactory test before treatment (T0) and when Aldrete recovery score reached 10 points at the end of anesthesia (T1); the concentration of melatonin in plasma was measured by ELISA method in the two groups. RESULTS: The between-group differences and within-group differences of MAP, HR and SpO2 were not significant at each time point (P>0.05). Compared with T0, the score of smell identification and plasma concentration of melatonin were not significantly different at T1 in the observation group (P>0.05), however, the score of smell identification and plasma concentration of melatonin were reduced in the control group (P<0.05). At T1, the score of smell identification and plasma concentration of melatonin in the observation group were higher than those in the control group (P<0.05). CONCLUSION: TEAS could improve the postoperative olfactory memory disorder in patients with general anesthesia of sevoflurane, and its mechanism may be related to the increase of plasma concentration of melatonin.

Effects of different concentrations of desflurane on the index of cardiac electrophysiological balance in gynecologic surgery patients.

The objectives were to observe the effects of different concentrations of desflurane on QT, QTc, Tp-e, Tp-e/QT, and the index of cardiac electrophysiological balance (iCEB). Sixty patients were randomly divided into group D1, group D2, and group D3 by using a random number table, 20 in each group. After entering the operating room, patients received 10 mL/kg hydroxyethyl starch, 0.1 mg/kg midazolam, 0.1 mg/kg vecuronium, 3 µg/kg fentanyl, and 0.3 mg/kg etomidate intravenously and then accepted intubation and mechanical ventilation. The desflurane evaporator was opened. The concentrations of desflurane in the D1, D2, and D3 groups were maintained at 0.6, 1.3, and 2.0 minimum alveolar concentration (MAC), respectively. Twelve-lead ECGs were recorded at time before induction (T1) and at 20 min after desflurane reached the required concentration (T2). HR and MAP were recorded measure and the QT interval, QTc interval, Tp-e interval, Tp-e/QT ratio, and iCEB were calculated. Compared with before inhalation (T1), the QTc interval was prolonged in the D1, D2, and D3 groups after inhalation of different concentrations of desflurane for 20 min (T2) (P < 0.05) and the Tp-e/QT ratio decreased in the D1 and D2 groups at T2 (P < 0.05). Compared with the D1 and D2 groups, the Tp-e/QT ratio of the D3 group increased at T2 (P < 0.05). There was no significant difference in Tp-e interval and iCEB at any time (P > 0.05). The study suggested that inhalation of desflurane at a normal concentration cannot cause arrhythmogenic characteristics and affect the cardiac electrophysiological stability.

Characterization of Calibrated Gelatin Sponge Particles in a Rabbit Renal Embolization Model.

PURPOSE: To evaluate the level of artery occlusion, degradation periods, tissue response and vessel recanalization of calibrated gelatin sponge particles after segmental renal artery embolization. MATERIALS AND METHODS: Superselective embolization of 14 adult rabbits was performed with calibrated gelatin sponge particles (150-350 µm). Two rabbits were killed immediately after the procedure (day 0). One pair of rabbits was killed on each of the following days: 1, 3, 7, 14, 28 and 56. One rabbit from each pair underwent CT angiography before embolization and killing. The pathologic changes of the embolized renal parenchyma and embolic characteristics of calibrated gelatin sponge particles were evaluated histologically and angiographically. RESULTS: Calibrated gelatin sponge particles were distally located in interlobular artery with a dense packing on day 0. The level of occlusion paralleled the size of the particles. Partial degradation of the particles was observed on day 3, and complete degradation was observed on day 14. Vessel recanalization was observed through both CTA and histological analysis starting on day 3. Vascular inflammation responding to gelatin sponge particles was mild and subsided with the degradation of the particles. On day 28 and day 56, attenuation of embolized vessels occurred due to marked intimal proliferation, and vascular occlusion developed. CONCLUSIONS: Gelatin sponge particles of 150-350 µm produced dense and distal embolization, and were resorbed before day 14 with a mild tissue reaction. Vessel recanalization occurred secondary to the resorption of gelatin sponge particles, but permanent vascular occlusion developed due to marked intimal hyperplasia after day 28.

Analysis of curative effect of I125 implantation combined with radiofrequency ablation in treating bone metastases.

The aims of this study were to investigate the clinical effects of I125 implantation combined with radiofrequency ablation in treating bone metastases (BM) and analyze its clinical application so as to provide better treatment protocols for the treatment of BM. A total of 63 BM patients were randomly divided into the I125 implantation group (CON, treated with I125 seeds alone, 33 patients) and the combination group (I125-MA, 30 patients) to compare the clinical efficacy and adverse effects. After treatment, the clinical efficacy of Group I125-MA was significantly better than Group CON, and the quality of life was improved significantly (P< 0.05). I125-MA has relatively better clinical efficacy in treating BM, which can not only significantly improve patients' life quality but also cause no serious adverse reaction. The therapy of I125 implantation combined with radiofrequency ablation provides a new idea for treating bone metastases. Compare Group I125-MA and Group CON, remission rates of bone pain were 76.7% vs 42.4% (P< 0.05); movement ability: 73.3% vs 39.4% (P< 0.05); quality of life: improvement rates: 70% vs 42.4% (P< 0.05), the median initial time of relieve pain: 3.5 days vs 7.6 days (P< 0.05).

Presenilin1/γ-secretase protects neurons from glucose deprivation-induced death by regulating miR-212 and PEA15.

Reduced cerebral glucose utilization is found in aged individuals and often is an early sign of neurodegeneration. Here, we show that under glucose deprivation (GD) conditions, decreased expression of presenilin 1 (PS1) results in decreased neuronal survival, whereas increased PS1 increases neuronal survival. Inhibition of γ-secretase also decreases neuronal survival under GD conditions, which suggests the PS1/γ-secretase system protects neurons from GD-induced death. We also show that neuronal levels of the survival protein, phosphoprotein enriched in astrocytes at ∼15 kDa (PEA15), and its mRNA are regulated by PS1/γ-secretase. Furthermore, down-regulation of PEA15 decreases neuronal survival under reduced glucose conditions, whereas exogenous PEA15 increases neuronal survival even in the absence of PS1, which indicates that PEA15 promotes neuronal survival under GD conditions. The absence or reduction of PS1, as well as γ-secretase inhibitors, increases neuronal miR-212, which targets PEA15 mRNA. PS1/γ-secretase activates the transcription factor, cAMP response element-binding protein, regulating miR-212, which targets PEA15 mRNA. Taken together, our data show that under conditions of reduced glucose, the PS1/γ-secretase system decreases neuronal losses by suppressing miR-212 and increasing its target survival factor, PEA15. These observations have implications for mechanisms of neuronal death under conditions of reduced glucose and may provide targets for intervention in neurodegenerative disorders.-Huang, Q., Voloudakis, G., Ren, Y., Yoon, Y., Zhang, E., Kajiwara, Y., Shao, Z., Xuan, Z., Lebedev, D., Georgakopoulos, A., Robakis, N. K. Presenilin1/γ-secretase protects neurons from glucose deprivation-induced death by regulating miR-212 and PEA15.

Blood lipid abnormality changes the rate of alveolar-capillary uptake of sevoflurane: a prospective, non-interventional, clinical study
.

OBJECTIVE: This research studied the influence of different blood lipid components on the rate of alveolar-capillary uptake of sevoflurane. Method: 104 patients aged 20 - 50 years undergoing elective operations under general anesthesia were mechanically ventilated through endotracheal intubation after intravenous injections of midazolam, vecuronium, fentanyl, and etomidate. They inhaled 2% sevoflurane at an oxygen flow of 2 L/min, then the inspired concentrations (FI) and expired concentrations (FA of sevoflurane were recorded at 1, 3, 5, 7, 10, 15, 20, and 30 minutes. These cases were divided into a normal group and an abnormal group according to the lipid levels. Then, based on the lipid criteria, those cases with abnormal lipid levels were classified into a high-triglyceride (TG) and total-cholesterol (TC) group (group TG+TC) and a group with decreased high-density lipoprotein cholesterol (group HDL-C).The values of FA/FI and the times required to reach the titration value FA/FI = 0.8 were calculated were calculated for each group. RESULTS: Compared with the normal group, FA/FI decreased within 7 - 10 minutes (p < 0.05) and the time taken to reach the titration value was prolonged in the abnormal group (p < 0.05). The value of FA/FI decreased during 7 - 10 minutes (p < 0.05) and the time taken to reach the titration value was longer (p < 0.05) in the group TG+TC. CONCLUSIONS: The increased value of blood/gas partition coefficients (B/G) was caused by the increase in the concentrations of TG and TC in blood lipids.
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Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors.

Activation of EphB receptors by ephrinB (efnB) ligands on neuronal cell surface regulates important functions, including neurite outgrowth, axonal guidance, and synaptic plasticity. Here, we show that efnB rescues primary cortical neuronal cultures from necrotic cell death induced by glutamate excitotoxicity and that this function depends on EphB receptors. Importantly, the neuroprotective function of the efnB/EphB system depends on presenilin 1 (PS1), a protein that plays crucial roles in Alzheimer's disease (AD) neurodegeneration. Furthermore, absence of one PS1 allele results in significantly decreased neuroprotection, indicating that both PS1 alleles are necessary for full expression of the neuroprotective activity of the efnB/EphB system. We also show that the ability of brain-derived neurotrophic factor (BDNF) to protect neuronal cultures from glutamate-induced cell death depends on PS1. Neuroprotective functions of both efnB and BDNF, however, were independent of γ-secretase activity. Absence of PS1 decreases cell surface expression of neuronal TrkB and EphB2 without affecting total cellular levels of the receptors. Furthermore, PS1-knockout neurons show defective ligand-dependent internalization and decreased ligand-induced degradation of TrkB and Eph receptors. Our data show that PS1 mediates the neuroprotective activities of efnB and BDNF against excitotoxicity and regulates surface expression and ligand-induced metabolism of their cognate receptors. Together, our observations indicate that PS1 promotes neuronal survival by regulating neuroprotective functions of ligand-receptor systems.