Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling.

Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here, we show that synaptic and cognitive impairments following repeated exposure to Δ(9)-tetrahydrocannabinol (Δ(9)-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids in the brain. COX-2 induction by Δ(9)-THC is mediated via CB1 receptor-coupled G protein ßγ subunits. Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ(9)-THC exposures. Ablation of COX-2 also eliminates Δ(9)-THC-impaired hippocampal long-term synaptic plasticity, working, and fear memories. Importantly, the beneficial effects of decreasing ß-amyloid plaques and neurodegeneration by Δ(9)-THC in Alzheimer's disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2.

Modulation of external and internal aluminum resistance by ALS3-dependent STAR1-mediated promotion of STOP1 degradation.

The ALMT1 transporter aids malate secretion, chelating Al3+ ions to form nontoxic Al-malate complexes, believed to exclude Al from the roots. However, the extent to which malate secreted by ALMT1 is solely used for the exclusion of Al3+ or can be reutilized by plant roots for internal Al tolerance remains uncertain. In our investigation, we explored the impact of malate secretion on both external and internal Al resistance in Arabidopsis thaliana. Additionally, we delved into the mechanism by which the tonoplast-localized bacterial-type ATP-binding cassette (ABC) transporter complex STAR1/ALS3 promotes the degradation of the Al resistance transcription factor STOP1 to regulate ALMT1 expression. Our study demonstrates that the level of secreted malate influences whether the Al-malate complex is excluded from the roots or transported into root cells. The nodulin 26-like intrinsic protein (NIP) subfamily members NIP1;1 and NIP1;2, located in the plasma membrane, coordinate with STAR1/ALS3 to facilitate Al-malate transport from root apoplasm to the symplasm and eventually to the vacuoles for the internal Al detoxification. ALS3-dependent STAR1 interacts with and promotes the degradation of STOP1, regulating malate exudation. Our findings demonstrate the dual roles of malate exudation in external Al exclusion and Al absorption for internal Al detoxification.

Characteristics of gut microbiota and serum metabolism in patients with atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects 15%-30% of children and 10% of adults globally, with its incidence being influenced by genetic, environmental, and various other factors. While the immune plays a crucial role in the development, the composition of gut microbiota and serum metabolites also contribute to its pathogenesis. SUBJECT: Study the characteristics of gut microbiota and serum metabolites in patients with atopic dermatitis METHOD: In this study, we collected stool and serum samples from 28 AD patients and 23 healthy individuals (NC) for metagenomic sequencing of gut microbiota and non-targeted metabolomic sequencing of serum. RESULT: Our results revealed a lower diversity of gut microbiota in the AD group compared to the NC group. The predominant Phylum in AD patients were Bacteroidetes, Pseudomonas, and Verrucomicrobia, with the most dominant bacterial genus being Faecalibacterium. At the species level, Prevotella copri and Faecalibacterium prausnitzii were found to be the most abundant bacteria. Significant differences in serum metabolite profiles were observed between NC and AD patients, with noticeable variations in metabolite expression levels. The majority of metabolites in the serum of AD patients exhibited low expression, while a few showed high expression levels. Notably, metabolites such as Cholesterol glucuronide, Styrene, Lutein, Betaine, Phosphorylcholine, Taurine, and Creatinine displayed the most pronounced alterations. CONCLUSION: These findings contribute to a further understanding of the complexities underlying this disease.

NRAMP6 and NRAMP1 cooperatively regulate root growth and manganese translocation under manganese deficiency in Arabidopsis.

The essential micronutrient manganese (Mn) in plants regulates multiple biological processes including photosynthesis and oxidative stress. Some Natural Resistance-Associated Macrophage Proteins (NRAMPs) have been reported to play critical roles in Mn uptake and reutilization in low Mn conditions. NRAMP6 was demonstrated to regulate cadmium tolerance and iron utilization in Arabidopsis. Nevertheless, it is unclear whether NRAMP6 plays a role in Mn nutrition. Here, we report that NRAMP6 cooperates with NRAMP1 in Mn utilization. Mutation of NRAMP6 in nramp1 but not in a wild-type background reduces root growth and Mn translocation from the roots to shoots under Mn deficient conditions. Grafting experiments revealed that NRAMP6 expression in both the roots and shoots is required for root growth and Mn translocation under Mn deficiency. We also showed that NRAMP1 could replace NRAMP6 to sustain root growth under Mn deficiency, but not vice versa. Mn deficiency does not affect the transcript level of NRAMP6, but is able to increase and decrease the protein accumulation of NRAMP6 in roots and shoots, respectively. Furthermore, NRAMP6 can be localized to both the plasma membrane and endomembranes including the endoplasmic reticulum, and Mn deficiency enhances the localization of NRAMP6 to the plasma membrane in Arabidopsis plants. NRAMP6 could rescue the defective growth of the yeast mutant Δsmf2, which is deficient in endomembrane Mn transport. Our results reveal the important role of NRAMP6 in Mn nutrition and in the long-distance signaling between the roots and shoots under Mn deficient conditions.

Aberrant KAT2A accumulations render TRIM22-low melanoma sensitive to Notch1 inhibitors via epigenetic reprogramming.

BACKGROUND: Aberrant ubiquitin-proteasome system (UPS) triggers various disorders of biological events and contributes to progression of tumorigenesis. The tripartite motif containing 22 (TRIM22) was demonstrated to participate in the progression of multiple malignancies. Nevertheless, the role of TRIM22 in melanoma is still indefinite. This project aims to investigate the biological function of TRIM22 in melanoma and provide novel therapeutical targets. METHODS: Bioinformatic algorithms were used to investigate prognostic significance of TRIM22. The in vitro or in vivo assays were used to explore the functions of TRIM22 in melanoma. The Co-Immunoprecipitation (Co-IP) and in vivo ubiquitination assays were used to assess regulations of TRIM22 on lysine acetyltransferase 2 A (KAT2A). The Chromatin immunoprecipitation (ChIP) assays and luciferase reporter assay were utilized to explore epigenetic regulations of KAT2A on Notch1. RESULTS: Here, we utilized the bioinformatic methods to confirm that TRIM22 is decreased in melanoma than normal tissues. Patients with low TRIM22 levels had shorter survival months than those with high TRIM22 levels. Targeting TRIM22 favors melanoma cell migration, proliferation, and tumor development in vitro and in vivo. Mechanistically, TRIM22 interacts with KAT2A and promotes its degradation in a ubiquitination-dependent manner. Melanoma cells with TRIM22 deficiency depended on KAT2A to enhance malignant progression, including proliferation, migration, and in vivo growth. KEGG analysis determined the positive correlation between KAT2A and Notch signaling. Chromatin Immunoprecipitation (ChIP) assays implicated that KAT2A directly binds to the promoter region of Notch1 and mediates the enrichment of H3K9ac modification. KAT2A activates Notch1 transcriptional levels and sustains the stemness feature of melanoma cells. Nocth1 inhibitor (IMR-1) effectively suppresses the growth of TRIM22low melanoma in vitro and in vivo but fails to inhibit TRIM22high melanoma. CONCLUSION: Together, our study illustrates the mechanism by which the TRIM22-KAT2A-Notch1 axis promotes melanoma progression, and demonstrates that KAT2A/Nocth1 confers an epigenetic vulnerability in TRIM22low melanoma.

Regulation of Aluminum Resistance in Arabidopsis Involves the SUMOylation of the Zinc Finger Transcription Factor STOP1.

Aluminum (Al) is a primary constraint for crop production on acid soils, which make up more than 30% of the arable land in the world. Al resistance in Arabidopsis (Arabidopsis thaliana) is achieved by malate secretion mediated by the Al-ACTIVATED MALATE TRANSPORTER1 (AtALMT1) transporter. The C2H2-type transcription factor SENSITIVE TO PROTON RHIZOTOXICITY1 (STOP1) is essential and required for Al resistance, where it acts by inducing the expression of Al-resistance genes, including AtALMT1 In this study, we report that STOP1 protein function is modified by SUMOylation. The SMALL UBIQUITIN-LIKE MODIFIER (SUMO) protease ESD4, but not other SUMO proteases, specifically interacts with and deSUMOylates STOP1. Mutation of ESD4 increases the level of STOP1 SUMOylation and the expression of the STOP1-regulated gene AtALMT1, which contributes to the increased Al resistance in esd4 The esd4 mutation does not influence STOP1 protein abundance but increases the association of STOP1 with the AtALMT1 promoter, which might explain the elevated expression of AtALMT1 in esd4 We demonstrate that STOP1 is mono-SUMOylated at K40, K212, or K395 sites, and blocking STOP1 SUMOylation reduces STOP1 stability and the expression of STOP1-regulated genes, leading to the reduced Al resistance. Our results thus reveal the involvement of SUMOylation in the regulation of STOP1 and Al resistance in Arabidopsis.

Chronic administration of ketamine induces cognitive deterioration by restraining synaptic signaling.

The discovery of the rapid antidepressant effects of ketamine has arguably been the most important advance in depression treatment. Recently, it was reported that repeated long-term ketamine administration is effective in preventing relapse of depression, which may broaden the clinical use of ketamine. However, long-term treatment with ketamine produces cognitive impairments, and the underlying molecular mechanisms for these impairments are largely unknown. Here, we found that chronic in vivo exposure to ketamine for 28 days led to decreased expression of the glutamate receptor subunits GluA1, GluA2, GluN2A, and GluN2B; decreased expression of the synaptic proteins Syn and PSD-95; decreased dendrite spine density; impairments in long-term potentiation (LTP) and synaptic transmission in the hippocampal CA1 area; and deterioration of learning and memory in mice. Furthermore, the reduced glutamate receptor subunit and synaptic protein expression and the LTP deficits were still observed on day 28 after the last injection of ketamine. We found that the expression and phosphorylation of CaMKIIß, ERK1/2, CREB, and NF-κB were inhibited by ketamine. The reductions in glutamate receptor subunit expression and dendritic spine density and the deficits in LTP, synaptic transmission, and cognition were alleviated by overexpression of CaMKIIß. Our study indicates that inhibition of CaMKIIß-ERK1/2-CREB/NF-κB signaling may mediate chronic ketamine use-associated cognitive impairments by restraining synaptic signaling. Hypofunction of the glutamatergic system might be the underlying mechanism accounting for chronic ketamine use-associated cognitive impairments. Our findings may suggest possible strategies to alleviate ketamine use-associated cognitive deficits and broaden the clinical use of ketamine in depression treatment.

Safety and efficacy of daratumumab in Chinese patients with relapsed or refractory multiple myeloma: a phase 1, dose-escalation study (MMY1003).

Daratumumab monotherapy demonstrated favorable safety and efficacy in relapsed/refractory multiple myeloma (RRMM) patients in the global phase 1/2 GEN501 and phase 2 SIRIUS studies. MMY1003 evaluated daratumumab monotherapy specifically in Chinese patients with RRMM. This 3-part, open-label, phase 1, dose-escalation study included patients with ≥ 2 prior lines of therapy. Part 3 included patients who had received a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) and experienced disease progression on their last regimen. Patients received intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 and 16 mg/kg in parts 2 + 3. Primary endpoints were dose-limiting toxicity (DLT; part 1), pharmacokinetics (parts 1 + 2), and adverse events (AEs). Fifty patients enrolled. The first 3 patients in part 1 received daratumumab 8 mg/kg; remaining patients in parts 1-3 received daratumumab 16 mg/kg. In the daratumumab 16 mg/kg group (n = 47), patients received a median of 4 prior lines of therapy; 32% were refractory to a PI and IMiD, and 79% were refractory to their last prior therapy. No DLTs occurred. Thirty-six (77%) patients reported grade 3/4 treatment-emergent AEs. Thirteen (28%) patients experienced infusion-related reactions. At an 18.5-month median follow-up, overall response rate was 43%. Median progression-free survival (PFS) and overall survival (OS) were 6.7 months and not reached, respectively; 12-month PFS and OS rates were 35% and 70%. Pharmacokinetic results (n = 22) were consistent with other studies. Safety, pharmacokinetics, and efficacy of daratumumab monotherapy were confirmed in Chinese patients with RRMM. This trial is registered on ClinicalTrials.gov (NCT02852837).

Elevated serum levels of TNF-α, IL-6, and IL-18 in chronic methamphetamine users.

OBJECTIVE: Chronic methamphetamine use causes aberrant changes in cytokines. Our aim was to analyze the serum levels of tumor necrosis factor α (TNF-α), interleukin (IL)-6, and IL-18 in chronic methamphetamine users. Associations between cytokines levels with the demographic properties, methamphetamine use properties, and psychiatric symptoms in chronic methamphetamine users were also evaluated. METHODS: Seventy-eight chronic methamphetamine users who did not continue methamphetamine exposure since hospitalization and 64 healthy controls were enrolled. Serum levels of TNF-α, IL-6, and IL-18 were detected using an enzyme-linked immunosorbent assay. Psychopathological symptoms of chronic methamphetamine users were evaluated by the Positive and Negative Syndrome Scale, Beck Depression Inventory (BDI), and Beck Anxiety Inventory. RESULTS: Serum levels of TNF-α, IL-6, and IL-18 were significantly increased in methamphetamine users who did not continue methamphetamine exposure since hospital admission (average days since last methamphetamine use = 39.06 ± 7.48) when compared to those in controls. Serum IL-6 levels showed significant positive associations with BDI score and current frequency of methamphetamine use in chronic methamphetamine users. CONCLUSIONS: Our results suggest that increased TNF-α, IL-6, and IL-18 levels may have an important role in chronic methamphetamine use-associated psychopathological symptoms.

Golgi-localised manganese transporter PML3 regulates Arabidopsis growth through modulating Golgi glycosylation and cell wall biosynthesis.

Golgi is a critical compartment for both the reutilisation of the essential micronutrient manganese (Mn) and its detoxification. However, whether Mn plays a role in the Golgi remains to be demonstrated in plants. We characterised the function of PML3, a member of the Unknown Protein Family UPF0016, in Mn transport and the regulation of plant growth, Golgi glycosylation and cell wall biosynthesis in Arabidopsis. We also investigated the relationship of PML3 with NRAMP2, a trans-Golgi network localised Mn transporter. PML3-GFP is preferentially localised in the cis-Golgi. PML3 can transport Mn to rescue the hypersensitivity of yeast mutant Δpmr1 to excess Mn. Two mutant alleles of PML3 displayed reduced plant growth and impaired seed development under Mn-deficient conditions. The pml3 mutants also showed impaired Golgi glycosylation and cell wall biosynthesis under Mn deficiency. Double mutations of PML3 and NRAMP2 showed improved plant growth compared with that of single mutants under Mn deficiency, implying that PML3 and NRAMP2 play opposite roles in the regulation of Golgi Mn levels. Our results suggest that PML3 mediates Mn uptake into the Golgi compartments, which is required for proper protein glycosylation and cell wall biosynthesis under Mn-deficient conditions.

Preliminary comparative analysis of kynurenine pathway metabolites in chronic ketamine users, schizophrenic patients, and healthy controls.

OBJECTIVE: The serum kynurenine pathway metabolites kynurenic acid (KYNA), kynurenine (KYN), and tryptophan (TRP) were examined in chronic ketamine users and in schizophrenic patients. The correlations of the metabolites with sociodemographic data, clinical characteristics, and drug use status were analyzed. METHODS: Seventy-nine healthy controls, 78 ketamine users, and 80 schizophrenic patients were recruited. Serum TRP, KYN, and KYNA levels were measured by high-performance liquid chromatography following tandem mass spectrometry (MS/MS). Psychotic symptoms were evaluated using the positive and negative syndrome scale (PANSS), the Beck Depression Inventory (BDI), and the Beck Anxiety Inventory (BAI). RESULTS: Serum levels of TRP, KYNA, and KYN (in ketamine users only) were lower in ketamine users and schizophrenic patients than in controls (p < .05). TRP and KYN were lower in ketamine users than in schizophrenic patients (p < .01). KYNA levels were positively correlated with the current frequency of ketamine use in ketamine users (p = .031), and serum KYNA levels were negatively correlated with the duration of schizophrenia (p = .015). CONCLUSION: TRP, KYNA, and KYN were lower in chronic ketamine users than in controls, and the alterations were in the same direction as those observed in schizophrenic patients.

Basolateral amygdala is required for reconsolidation updating of heroin-associated memory after prolonged withdrawal.

Postretrieval extinction procedures are effective nonpharmacological interventions for disrupting drug-associated memories. Nonetheless, the conditioned stimulus (CS) memory retrieval-extinction procedure is ineffective in inhibiting drug craving and relapse after prolonged withdrawal, which significantly undermines its therapeutic potential. In the present study, we showed that, unlike the CS memory retrieval-extinction procedure, noncontingent heroin injections (unconditioned stimulus [UCS]) 1 hour before the extinction sessions decreased the heroin-priming-induced reinstatement, renewal, and spontaneous recovery of heroin seeking after 28 days of withdrawal (ie, remote heroin-associated memories) in rats. The UCS retrieval manipulation induced reactivation of the basolateral amygdala (BLA) after prolonged withdrawal, and this reactivation was absent with the CS retrieval manipulation. Chemogenetic inactivation of the BLA abolished the inhibitory effect of the UCS memory retrieval-extinction procedure on heroin-priming-induced reinstatement after prolonged withdrawal. Furthermore, the combination of chemogenetic reactivation of BLA and CS retrieval-extinction procedure resembled the inhibitory effect of UCS retrieval-extinction procedure on heroin seeking after prolonged withdrawal. We also observed that the inhibitory effect of the UCS retrieval-extinction procedure is mediated by regulation of AMPA receptor endocytosis in the BLA. Our results demonstrate critical engagement of the BLA in reconsolidation updating of heroin-associated memory after prolonged withdrawal, extending our knowledge of the boundary conditions of the reconsolidation of drug-associated memories.

GRIN2B Gene Polymorphism in Chronic Ketamine Users.

BACKGROUND AND OBJECTIVES: We examined the allelic variants of N-methyl- d-aspartate receptor 2B (GRIN2B) and analyzed the associations between GRIN2B gene polymorphism with ketamine use conditions and psychopathological symptoms in chronic ketamine users. METHODS: A total of 231 subjects were recruited. Four single nucleotide polymorphisms of GRIN2B, rs1805502, rs7301328, rs890, and rs1806201 were examined in 151 male chronic ketamine users and 80 controls. Psychopathological symptoms in chronic ketamine users were evaluated using the Positive and Negative Syndrome Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory. RESULTS: The genotype CC of rs1806201 had a lower frequency in ketamine users than that in control subjects (χ2 = 8.167, P = .004) and the T allele frequency of rs1806201 in ketamine users was higher than that in the control subjects (P = .009, odds ratio = 2.019 [1.196-3.410]). Ketamine users of genotype TT and CC of rs1806201 had an earlier onset of ketamine use than subjects of genotype TC (P = .038, P = .049, respectively). The dose of ketamine consumption per day of use was higher in genotype GG of rs7301328 than that in those with CG in ketamine users (P = .026). There were no significant differences of the severity of psychopathologic symptoms among different genotypes tested. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: GRIN2B gene polymorphism may play a role in ketamine abuse. (Am J Addict 2020;29:105-110).

Changes in serum TNF-α, IL-18, and IL-6 concentrations in patients with chronic schizophrenia at admission and at discharge.

OBJECTIVE: Schizophrenia is correlated with aberrant cytokine concentrations. The goal of our study was to detect the serum concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-18, and IL-6 concentrations in patients with chronic schizophrenia in the acute relapse state at admission and at discharge and to analyze the correlations between the three cytokine concentrations with psychosis symptoms. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to analyze serum concentrations of TNF-α, IL-18, and IL-6 in 68 patients with chronic schizophrenia at admission and at discharge and in 80 controls. The Positive and Negative Syndrome Scale (PANSS) was used to analyze psychosis symptoms of the patients. RESULTS: Serum concentrations of TNF-α, IL-18, and IL-6 in patients at admission were significantly elevated compared to those in controls. After treatment, IL-6 concentrations in patients at discharge were significantly reduced compared to those in patients at admission, and IL-6 concentrations showed no significant difference between patients at discharge and controls. In contrast, TNF-α and IL-18 concentrations showed no significant difference between patients at discharge and patients at admission, and TNF-α and IL-18 concentrations in patients at discharge were still significantly elevated compared to those in controls. IL-6 concentrations in patients at admission showed a positive correlation with negative scores, and IL-6 concentrations in patients at discharge showed positive correlations with positive, negative, and total scores. Reduction in IL-6 concentrations showed positive correlations with reduction in positive, negative, and total scores in patients at discharge. CONCLUSION: Serum concentrations of TNF-α, IL-18, and IL-6 were significantly elevated in patients with chronic schizophrenia in the acute relapse state. After treatment, IL-6 concentrations in patients at discharge were significantly reduced compared to these in patients at admission.

Rates and Patient Characteristics of Electroconvulsive Therapy in China and Comparisons With the United States.

OBJECTIVE: Recent studies have expressed concern about the infrequent and declining use of electroconvulsive therapy (ECT) in the United States. However, it is not known whether the US experience reflects changing global practice or one that varies between countries. This observational study examined use of ECT in the largest psychiatric hospital in China's third largest city over a 4-year period, 2014 to 2017. METHODS: Unduplicated electronic medical records concerning all inpatients with psychiatric diagnoses were examined. Electroconvulsive therapy utilization rates, correlates of ECT use, and its association with readmission within the 6 months following discharge were evaluated using bivariate and multivariate logistic regression analyses. RESULTS: Of 13,831 hospitalized patients, 2460 (17.8%) received ECT. Logistic regression analysis showed ECT utilization was independently associated with being female, younger age, being employed, nonlocal residence, involuntary admission, having no health insurance, longer length of stay, and the diagnoses of bipolar disorder and major depressive disorder. Use of ECT has increased since 2014 but was not significantly related to readmission 6 months after discharge. CONCLUSIONS: Electroconvulsive therapy use appears to be substantially higher in China than in the United States and is associated with indicators of higher rather than lower functioning as reflected by independent associations with youth, employment, and fewer past hospitalizations, but also with behavioral noncompliance as reflected by involuntary admission, and has increased in recent years. Understanding United States-China discrepancies may further international understanding of the diverse roles of ECT in psychiatric practice.

Elevated expression of the EZH2 gene in CALR-mutated patients with primary myelofibrosis.

Primary myelofibrosis (PMF) is one of the BCR/ABL-negative myeloproliferative neoplasms (MPNs), characterized by the diffuse fibrous hyperproliferation, bone marrow osteosclerosis, extramedullary hematopoiesis, and marked splenomegaly. The patients with PMF have an insidious onset, a long duration of clinical course, and the deteriorated quality of life. It has been reported that the CALR gene 9 exon mutations were detected in 25-30% PMF patients, particularly as high as 80% in the JAK2/MPL-negative ones. As the second most common mutation in BCR/ABL-negative MPNs, CALR mutation has been included in the latest World Health Organization (WHO) classification criteria as one of the main diagnostic criteria for both essential thrombocythemia (ET) and PMF. Moreover, the CALR mutations indicated a favorable prognosis, which the mechanism is still under investigation. It was demonstrated that a characterized high expression of EZH2 and SUZ12 in CALR-mutated patients. Taking EZH2 as the research entry point, we initially discussed the mechanism that the CALR-positive patients with PMF exhibited a better prognosis in the current study.

Low serum level of epidermal growth factor in chronic ketamine users.

BACKGROUND: Growth factors play an important role in brain development. Whether epidermal growth factor (EGF) plays a role in the pathophysiology of ketamine related disorders is unexplored. In this study, we examined the serum levels of EGF in chronic ketamine users as compared with healthy controls. The possible correlation between serum EGF levels with the demographic, ketamine use characteristics and psychopathological symptoms were analyzed. METHODS: Sixty-seven chronic ketamine users and 40 healthy subjects were recruited. Serum EGF levels were measured by enzyme-linked immunosorbent assay. Psychopathological symptoms were assessed using Positive and Negative Syndrome Scale, Beck Depression Inventory and Beck Anxiety Inventory. RESULTS: The serum level of EGF in the chronic ketamine users was significantly lower than that of healthy subjects (22.34 ± 4.81 pg/ml vs. 87.10 ± 2.96 pg/ml, F = 15.169, p < 0.01). The serum EGF level was negatively correlated with the current average dose of ketamine consumption per day of use (p = 0.015), and positively associated with the Positive and Negative Syndrome Scale positive symptom score (p = .022). CONCLUSIONS: Serum level of EGF decreased in chronic ketamine users compared with healthy subjects, which may play a role in the pathophysiology of ketamine related disorders.

Altered serum levels of TNF-α, IL-6, and IL-18 in depressive disorder patients.

OBJECTIVE: Depressive disorder is associated with abnormal changes in cytokines levels. This study aimed to assess serum concentrations of tumor necrosis factor (TNF) α, interleukin (IL) 6, and IL-18 in depressive patients. The correlations between these three cytokine concentrations and the patients' clinical characteristics were also assessed. METHODS: Serum TNF-α, IL-6, and IL-18 concentrations were assessed using enzyme-linked immunosorbent assay from 64 depressive patients and 80 healthy control subjects. Depressive symptoms of patients were assessed using Hamilton Depression Scale-17. RESULTS: Depressive patients had increased serum TNF-α and IL-6 concentrations but decreased IL-18 concentrations than controls. TNF-α and IL-6 concentrations were significantly positively associated with Hamilton Depression Scale-17 scores in depressive patients. CONCLUSION: These findings provided additional evidence that altered TNF-α, IL-6, and IL-18 activities may contribute to the pathophysiology of depressive disorder.

A Moldable Nanocomposite Hydrogel Composed of a Mussel-Inspired Polymer and a Nanosilicate as a Fit-to-Shape Tissue Sealant.

The engineering of bioadhesives to bind and conform to the complex contour of tissue surfaces remains a challenge. We have developed a novel moldable nanocomposite hydrogel by combining dopamine-modified poly(ethylene glycol) and the nanosilicate Laponite, without the use of cytotoxic oxidants. The hydrogel transitioned from a reversibly cross-linked network formed by dopamine-Laponite interfacial interactions to a covalently cross-linked network through the slow autoxidation and cross-linking of catechol moieties. Initially, the hydrogel could be remolded to different shapes, could recover from large strain deformation, and could be injected through a syringe to adhere to the convex contour of a tissue surface. With time, the hydrogel solidified to adopt the new shape and sealed defects on the tissue. This fit-to-shape sealant has potential in sealing tissues with non-flat geometries, such as a sutured anastomosis.

Multitasking Human Lectin Galectin-3 Interacts with Sulfated Glycosaminoglycans and Chondroitin Sulfate Proteoglycans.

Glycosaminoglycan (GAG) binding proteins (GAGBPs), including growth factors, cytokines, morphogens, and extracellular matrix proteins, interact with both free GAGs and those covalently linked to proteoglycans. Such interactions modulate a variety of cellular and extracellular events, such as cell growth, metastasis, morphogenesis, neural development, and inflammation. GAGBPs are structurally and evolutionarily unrelated proteins that typically recognize internal sequences of sulfated GAGs. GAGBPs are distinct from the other major group of glycan binding proteins, lectins. The multifunctional human galectin-3 (Gal-3) is a ß-galactoside binding lectin that preferentially binds to N-acetyllactosamine moieties on glycoconjugates. Here, we demonstrate through microcalorimetric and spectroscopic data that Gal-3 possesses the characteristics of a GAGBP. Gal-3 interacts with unmodified heparin, chondroitin sulfate-A (CSA), -B (CSB), and -C (CSC) as well as chondroitin sulfate proteoglycans (CSPGs). While heparin, CSA, and CSC bind with micromolar affinity, the affinity of CSPGs is nanomolar. Significantly, CSA, CSC, and a bovine CSPG were engaged in multivalent binding with Gal-3 and formed noncovalent cross-linked complexes with the lectin. Binding of sulfated GAGs was completely abolished when Gal-3 was preincubated with ß-lactose. Cross-linking of Gal-3 by CSA, CSC, and the bovine CSPG was reversed by ß-lactose. Both observations strongly suggest that GAGs primarily occupy the lactose/LacNAc binding site of Gal-3. Hill plot analysis of calorimetric data reveals that the binding of CSA, CSC, and a bovine CSPG to Gal-3 is associated with progressive negative cooperativity effects. Identification of Gal-3 as a GAGBP should help to reveal new functions of Gal-3 mediated by GAGs and proteoglycans.