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Background: Chronic ketamine use leads to cognitive impairments, however, the neural mechanisms underpinning these impairments are still unclear., Aims: Many studies showed Anterior cingulate cortex (ACC)is strongly involved in cognition and drug addiction, as supported by our previous studies. The objective of this study was to assess the variations in resting-state functional connectivity (FC) changes in the right anterior cingulate cortex (ACC) of chronic ketamine users (CKUs) and their relationship with cognitive performance., Methods: The study enrolled 28 chronic ketamine users (CKUs) and 30 healthy controls (HCs). Resting-state functional magnetic resonance imaging (fMRI) data were gathered from both groups. Cognitive functions were evaluated using the MATRICS Consensus Cognitive Battery (MCCB)., Results: CKUs demonstrated significantly poorer cognitive performance than HCs in various cognitive domains, including Visual Learning, Speed of Processing, Working Memory, and the composite score of MCCB. Group-level comparisons revealed that CKUs exhibited enhanced functional connectivity between the right ACC and the right postcentral gyrus (PCG) compared to HCs. There was a positive relationship between the connectivity of right ACC-PCG and reasoning and problem-solving score, but there was no significant association with the characteristics of ketamine use., Conclusion: CKUs showed enhanced connectivity between the right ACC and the right PCG. This enhanced functional connectivity may indicate functional compensation for cognitive deficits in CKUs, especially for reasoning and problem-solving impairments in CKUs., Competing Interests: Declaration of Competing Interest The authors of this paper declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The ALMT1 transporter aids malate secretion, chelating Al 3+ 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 Al 3+ 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., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Activating the cGAS-STING pathway of circulating tumor cell clusters (CTC clusters) represents a promising strategy to mitigate metastases. To fully exploit the potential of cholesterol-regulating agents in activating CTCs' STING levels, we developed a nanoparticle (NP) composed of metal complex lipid (MCL). This design includes MCL-miriplatin to increase NP stiffness and loads lomitapide (lomi) modulating cholesterol levels, resulting in the creation of PLTs@Pt-lipid@lomi NPs. MCL-miriplatin not only enhances lomi's eliciting efficacy on STING pathway but also increases NPs' stiffness, thus a vital factor affecting the penetration into CTC clusters to further boost lomi's ability. Demonstrated by cy5 tracking experiments, PLTs@Pt-lipid@lomi NPs quickly attach to cancer cell via platelet membrane anchorage, penetrate deep into the spheres, and reach the subcellular endoplasmic reticulum where lomi regulates cholesterol. Additionally, these NPs have been shown to track CTCs in the bloodstream, a capability not demonstrated by the free drug. PLTs@Pt-lipid@lomi NPs more efficiently activate the STING pathway and reduce CTC stemness compared to free lomi. Ultimately, PLTs@Pt-lipid@lomi NPs reduce metastasis in a post-surgery animal model. While cholesterol-regulating agents are limited in efficacy when being repositioned as immunomodulatory agents, this MCL-composing NP strategy demonstrates the potential to effectively deliver these agents to target CTC clusters., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Conventional photodynamic therapy (PDT) in cancer treatment needs to utilize oxygen to produce reactive oxygen species to eliminate malignant tissues. However, oxygen consumption in tumor microenvironment exacerbates cancer cell hypoxia and may promote vasculature angiogenesis. Since the mammalian target of rapamycin (mTOR) signaling pathway plays a vital role in endothelial cell proliferation and fibrosis, mTOR inhibitor drugs hold the potential to reverse hypoxia-evoked angiogenesis for improved PDT effect. In this study, a carrier-free nanodrug formulation composed of Torin 1 as mTORC1/C2 dual inhibitor and Verteporfin as a photosensitizer and Yes-associated protein inhibitor is developed. These two drug molecules can self-assemble into stable nanoparticles through π-π stacking and hydrophobic interactions with good long-term stability. The nanodrugs can prompt synergistic apoptosis, combinational anti-angiogenesis, and strong immunogenic cell death effects upon near-infrared light irradiation in vitro. Furthermore, the nanosystem also exhibits improved antitumor effect, anti-cancer immune response, and distant tumor inhibition through tumor microenvironment remodeling in vivo. In this way, the nanodrugs can reverse PDT-elicited angiogenesis and promote cancer immunotherapy to eliminate tumor tissues and prevent metastasis. This nanosystem provides insights into integrating mTOR inhibitors and photosensitizers for safe and effective breast cancer treatment in clinical settings., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

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., (© 2024 The Author(s). Skin Research and Technology published by John Wiley & Sons Ltd.)

Acute ketamine administration results in psychotic symptoms similar to those observed in schizophrenia and is regarded as a pharmacological model of schizophrenia. Accumulating evidence suggests that patients with schizophrenia show increased IL-6 levels in the blood and cerebrospinal fluid and that IL-6 levels are associated with the severity of psychotic symptoms. In the present study, we found that a single ketamine exposure led to increased expression of IL-6 and IL-6Rα, decreased dendritic spine density, increased expression and currents of T-type calcium channels, and increased neuron excitability in the hippocampal CA1 area 12 h after exposure. Acute ketamine administration also led to impaired prepulse inhibition (PPI) 12 h after administration. Additionally, we found that the expression of signaling molecules IKKα/β, NF-κB, JAK2, and STAT3 was upregulated 12 h after a single ketamine injection. The decreases in dendritic spine density, the increases in calcium currents and neuron excitability, and the impairments in PPI were ameliorated by blocking IL-6 or IL-6Rα. Our findings show that blocking IL-6 or its receptor may protect hippocampal neurons from hyperexcitability, thereby ameliorating ketamine-induced psychotic effects. Our study provides additional evidence that targeting IL-6 and its receptor is a potential strategy for treating psychotic symptoms in acute ketamine-induced psychosis and schizophrenia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Aims: To investigate effects of repetitive transcranial magnetic stimulation (rTMS) on the prospective memory (PM) in patients with schizophrenia (SCZ)., Methods: Fifty of 71 patients completed this double-blind placebo-controlled randomized trial and compared with 18 healthy controls' (HCs) PM outcomes. Bilateral 20 Hz rTMS to the dorsolateral prefrontal cortex at 90% RMT administered 5 weekdays for 4 weeks for a total of 20 treatments. The Positive and Negative Symptom Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), and PM test were assessed before and after treatment., Results: Both Event-based PM (EBPM) and Time-based PM (TBPM) scores at baseline were significantly lower in patients with SCZ than that in HCs. After rTMS treatments, the scores of EBPM in patients with SCZ was significantly improved and had no differences from that in HCs, while the scores of TBPM did not improved. The negative symptom scores on PANSS and the scores of almost all subscales and total scores of SANS were significantly improved in both groups., Conclusions: Our findings indicated that bilateral high-frequency rTMS treatment can alleviate EBPM but not TBPM in patients with SCZ, as well as improve the negative symptoms., Significance: Our results provide one therapeutic option for PM in patients with SCZ., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

This study aimed to compare the pharmacokinetics and bioavailability of 2 formulations: a fixed-dose combination tablet containing allisartan isoproxil (AI) and indapamide sustained-release (SR), and a monotherapy combination of AI and indapamide SR, in healthy Chinese subjects. A monocentric, open-label, single-dose, randomized, 2-way crossover study design was implemented. A total of 38 healthy male and female volunteers were equally divided into 2 treatment sequences. The analysis of plasma concentrations was conducted using a nonstereospecific liquid chromatography/tandem mass spectrometric method. The primary pharmacokinetic parameters were calculated using a noncompartmental model. Safety assessments were performed throughout the study. For the fixed-dose combination and monotherapy combination, the mean values of EXP3174 (metabolite of AI) C max , AUC 0-t , and AUC 0-∞ were 987 and 999 ng/mL, 8059 and 7749 ng/mL h, and 8332 and 8007 ng/mL h, respectively. The corresponding values for indapamide were 27 and 32 ng/mL, 1002 and 1105 ng/mL h, and 1080 and 1172 ng/mL h. No serious adverse events were reported during the study. The combination tablet containing 240 mg of AI and 1.5 mg of indapamide SR met the bioequivalence standards. Additionally, both formulations were tolerated and had good safety profiles in the research., (© 2023, The American College of Clinical Pharmacology.)

Prodrug photolysis enables spatiotemporal control of drug release at the desired lesions. For photoactivated therapy, near-infrared (NIR) light is preferable due to its deep tissue penetration and low phototoxicity. However, most of the photocleavable groups cannot be directly activated by NIR light. Here, we report a upconversion-like process via only one step of energy transfer for NIR light-triggered prodrug photolysis. We utilize a photosensitizer (PS) that can be activated via singlet-triplet (S-T) absorption and achieve photolysis of boron-dipyrromethene (BODIPY)-based prodrugs via triplet-triplet energy transfer. Using the strategy, NIR light can achieve green light-responsive photolysis with a single-photon process. A wide range of drugs and bioactive molecules are designed and demonstrated to be released under low-irradiance NIR light (100 mW/cm 2 , 5 min) with high yields (up to 87%). Moreover, a micellar nanosystem encapsulating both PS and prodrug is developed to demonstrate the practicality of our strategy in normoxia aqueous environment for cancer therapy. This study may advance the development of photocleavable prodrugs and photoresponsive drug delivery systems for photo-activated therapy., (© 2023. The Author(s).)

Choroidal neovascularization (CNV) is the key pathological event of wet age-related macular degeneration (wAMD) leading to irreversible vision loss. Currently, anti-angiogenic therapy with anti-vascular endothelial growth factor (VEGF) agents has become the standard treatment for wAMD, while it is still subject to several limitations, including the safety concerns of monthly intravitreal administration and insufficient efficacy for neovascular occlusion. Combined therapy with photodynamic therapy (PDT) and anti-angiogenic agents has emerged as a novel treatment paradigm. Herein, a novel and less-invasive approach is reported to achieve anti-angiogenic and photodynamic combination therapy of wAMD by intravenous administration of a photoactivatable nanosystem (Di-DAS-VER NPs). The nanosystem is self-assembled by reactive oxygen species (ROS)-sensitive dasatinib (DAS) prodrug and photosensitizer verteporfin (VER). After red-light irradiation to the diseased eyes, intraocular release of anti-angiogenic DAS is observed, together with selective neo-vessels occlusion by VER-generated ROS. Notably, Di-DAS-VER NPs demonstrates promising therapeutic efficacy against CNV with minimized systemic toxicity. The study enables an efficient intravenous wAMD therapy by integrating a photoactivation process with combinational therapeutics into one simple nanosystem., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

As one of the new nanomaterials, TiN/Ti 3 C 2 shows excellent optoelectronic characteristics, thus it has been widely used in many applications, such as biomedicine, optical sensors, image processing, and optical switching. With the advancement of communication capabilities and communication networks, optical fiber communication has put a higher demand on signal processing. In order to overcome the limitations of the electronic transfer rate bottleneck, the concept of all-optical signal processing has been proposed. Utilizing the excellent optical nonlinear effect of the TiN/Ti 3 C 2 heterojunction-coated microfiber (THM), a novel THM-based optical Kerr switch has been proposed. Injecting a strong control light and a signal light into the device simultaneously, and controlling the state of turn on or off of the control light, can adjust the intensity of the signal light. Based on this, the amplitude modulation of the signal light can be achieved. With a control light power of 200 mW, the maximum extinction ratio of the signal light reaches 27 dB. We believe that this type of compact device can demonstrate great potential for integration with current high-speed fiber communication networks, providing a possible method for all-optical signal processing through nonlinear effects, and has broad prospects in the field of all-optical signal processing, robots, and high-speed communication., Competing Interests: The authors declare that they have no significant conflict of interest., (This journal is © The Royal Society of Chemistry.)

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 TRIM22 low melanoma in vitro and in vivo but fails to inhibit TRIM22 high 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 TRIM22 low melanoma., (© 2023. The Author(s).)

Myocardial infarction (MI) is a highly prevalent and lethal disease worldwide. Prevention and timely recovery are critical for the control of the recurrence and heart failure in MI survivors. The present study was designed to investigate the cardioprotective activity of the herbal medicine formula Baoyuan Decoction (BYD) and identify the active compounds and molecular targets. The ethanolic BYD extract (BYDE) was prepared by water extraction and ethanol precipitation of four herbal medicines, Astragali Radix, Ginseng Radix et Rhizoma, Cinnamomi Cortex, and Glycyrrhizae Radix et Rhizoma. Initially, BYDE was validated for the cardioprotective effectiveness in a mouse model of ischemia injury and rat cardiomyocyte H9C2 cells. As results, BYDE effectively reduced infarct size from 56% to 37% and preserved cardiac functions in mouse MI model while protected H9C2 cells against oxygen glucose deprivation. Subsequent network pharmacology analysis revealed that 122 bioactive ingredients, including flavonoids and saponins from the UPLC-MS/MS profile of BYDE, might target 37 MI-related proteins, including inflammatory and apoptotic mediators (e.g., TNF, NFKB1, CASPs, TNFRSF1A, CXCL12, BCL2A1). Pathway enrichment analysis suggested that BYDE might control the cardiac inflammation via targeting the tumor necrosis factor-alpha (TNF-α)/nuclear factor-κB (NF-κB) pathway while the selected targets were also implicated in IL-17 signaling pathway, lipid and atherosclerosis. Consequently, adenosine, ginsenoside Rh2, isoliquiritigenin, and licochalcone A were selected to generate the four-compound mixture AGILe and validated for the inhibitory effects on the TNF-α/NF-κB pathway. The results of the present study suggested that the mixture AGILe might be a potential cardioprotective remedy against MI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Chen, Zhao, Zhao, Fan, Wang, Chen and Rong.)

Background: Alcohol use disorder (AUD) has become a significant global factor in various diseases. As a non-pharmacological therapy, certain therapeutic potential has been found in acupuncture; however, in-depth mechanistic studies related to acupuncture for patients with AUD are still insufficient., Methods: Based on a randomized control design and a multi-omics analysis plan, this protocol details the recruitment (42 AUD patients), group allocation (21 in acupuncture group vs. 21 in sham acupuncture group), intervention and follow-up (replacement drugs as a normal treatment, 2 weeks acupuncture duration, and 3 month follow-up), and data collection and analytical processes. For the clinical outcomes, in addition to the time required for alcohol withdrawal symptoms to subside as the primary outcome, changes in the alcohol withdrawal symptoms, alcohol craving, mood dysfunction, sleep disorder, fatigue, self-efficacy, gastrointestinal symptoms, the quality of life, and the relapse outcomes will be compared between the groups to confirm the acupuncture clinical effectiveness on alcohol withdraw. The gut microbiome and the fecal metabolomics will also be assessed to explore the association of the structure and the function of gut microflora and the mediation of acupuncture effect on AUD fully utilizing gut microflora multi-modal data and clinical information, via the combination of multi-omics methods, feature screening algorithms and appropriate models., Discussion: The results of this study may help to strengthen clinical evidence of the mechanism of acupuncture intervention in patients with AUD, through understanding of the regulatory mechanism of acupuncture in the gut microbiome and its metabolism as well as AUD-related clinical manifestations., Trial Registration: Chinese Clinical Trial Registry ChiCTR2200058120. Registered on 24 Mar 2022., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Lan, Fan, Chen, Wei, Li, Fan, Tang and Lu.)

Background: Polymyositis (PM) and dermatomyositis (DM) are non-suppurative and autoimmune inflammatory diseases of striated muscle. Interstitial lung disease (ILD) is a group of heterogeneous diseases that mainly involve the pulmonary interstitium, alveoli, and/or bronchioles, also known as diffuse parenchymal lung disease (DPLD). A significant cause of death in persons with polymyositis (PM) and dermatomyositis (DM) is concurrent interstitial lung disease (ILD). However, research on the clinical characteristics and associated influencing factors of PM/DM combined with ILD (PM/DM-ILD) is currently scarce in China., Objective: The study aimed to probe the clinical features and risk factors of PM/DM-ILD., Methods: The data of 130 patients with PM/DM were gathered. General medical status, clinical symptoms, laboratory parameters, high-resolution CT, therapeutic outcomes, and prognoses were retrospectively reviewed in patients with PM/DM with (ILD group) and without (NILD) ILD., Results: The age of the ILD group (n=65) was more than the NILD group (n=65), and the difference was statistically significant; there were no significant between-group variations in the PM/DM ratio, sex, or duration of the disease. The initial symptoms were arthritis and respiratory symptoms in the ILD group, and myasthenia symptoms in the NILD group. Incidences of Raynaud's phenomenon, dry cough, expectoration, dyspnea on exertion, arthritis, fever, total globulin (GLOB), erythrocyte sedimentation rate (ESR), and anti-Jo-1 antibody rate were higher for ILD; however, albumin (ALB), creatine kinase aspartate aminotransferase activity ratio (CK/AST) and CK levels were significantly lower in the ILD group. Bivariate logistic regression analysis showed age, dry cough, arthritis, dyspnea on exertion, anti-Jo-1 antibody, and elevated GLOB to be independent risk factors for ILD among patients with PM/DM., Conclusion: Advanced age, dry cough, arthritis, dyspnea on exertion, anti-Jo-1 antibody positivity, and elevated GLOB level are risk factors for PM/DM-ILD. This information could be utilized to carefully monitor changing lung function in these patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Accumulating evidence suggests that some patients with schizophrenia have high production of autoantibodies against the N-methyl-d-aspartate receptor (NMDAR) subunit GluN1 and that these antibodies lead to cognitive impairment. However, the molecular mechanisms of the deficits seen in these patients are largely unknown. In the present study, we found that passive infusion of GluN1 antibody into the hippocampus of mice for 7 days led to decreased expression of GluN1, phosphor-Ser897-GluN1, and EphrinB2 receptor (EphB2R); deficits in long-term potentiation (LTP) and synaptic transmission in the hippocampal CA1 area; impairment in prepulse inhibition (PPI); and deterioration of recognition memory in novel object recognition test. We also found decreased expression of CaMKIIβ, ERK1/2, CREB, and NF-κB after 7 days of GluN1 antibody exposure, as was the phosphorylation of these signaling molecules. The decrease in GluN1 and phosphor-Ser897-GluN1 expression and the deficits in LTP, PPI, and recognition memory were ameliorated by CaMKIIβ overexpression. These results suggest that downregulation of CaMKIIβ-ERK1/2-CREB-NF-κB signaling is responsiable for GluN1 antibody-associated impairment in PPI and memory and that GluN1 antibody-induced NMDAR hypofunction is the underlying mechanism of this impairment. Our findings indicate possible strategies to ameliorate NMDAR antibody-associated cognitive impairment in neuropsychiatric disease. They also provide evidence that NMDAR hypofunction is an underlying mechanism for cognitive impairment in schizophrenia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier B.V.)

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)., (© 2022. The Author(s).)

Molecular aggregates with environmental responsive properties are desired for their wide practical applications such as bioprobes. Here, a series of smart near-infrared (NIR) luminogens for hyperlipidemia (HLP) diagnosis is reported. The aggregates of these molecules exhibit a twisted intramolecular charge-transfer effect in aqueous media, but aggregation-induced emission in highly viscous media due to the restriction of the intramolecular motion. These aggregates, which can autonomously respond to different environments via switching the aggregation state without changing their chemical structures are described, as "smart aggregates". Intriguingly, these luminogens demonstrate NIR-II and NIR-III luminescence with ultralarge Stokes shifts (>950 nm). Both in vitro detection and in vivo imaging of HLP can be realized in a mouse model. Linear relationships exist between the emission intensity and multiple pathological parameters in blood samples of HLP patients. Thus, the design of smart aggregate facilitates rapid and accurate detection of HLP and provides a promising attempt in aggregate science., (© 2022 Wiley-VCH GmbH.)

Triple-negative breast cancer (TNBC) has been listed as one of the most fatal diseases, and no effective targeting treatment is clinically available. Although CD44-targeting hyaluronic acid (HA) has been utilized as targeting ligands in many studies, no facile ways have been developed through HA self-assembly at the nanoparticle surface. Herein, we reported N -isopropylacrylamide-grafted chitosan-based nanoparticles self-assembling with HA (HA-NPs) through electrostatic forces and loaded with curcumin (CUR). The HA-NPs displayed pH-responsive properties due to the chemical modification of chitosan, and the preparation process was optimized by central composite design-response surface methodology. HA anchorage confers the vehicle with tumor-targeting capability. HA-NPs displayed more robust effects of inhibiting TNBC primary tumor growth than free CUR and a plain counterpart but without increased systemic cytotoxicity. In addition, in vivo pharmacokinetic studies showed that HA-NPs significantly increased the in vivo residence time of free CUR and improved the bioavailability of CUR. These findings suggested that chitosan-based HA-NPs may provide a feasible and unique strategy to achieve CD44 targeting and enhance its efficacy in vivo for the treatment of advanced TNBC.

Background: Ketamine has become a major substance of abuse worldwide. Nevertheless, The long-term effects of ketamine use on intrinsic spontaneous neural activity remain unknown., Objectives: In the present study, rs-fMRI was used to explore whether chronic ketamine use changes the intrinsic spontaneous neural activity, and whether the intrinsic spontaneous neural activity changes in chronic ketamine users(CKUs) are associated with cognitive impairments observed in chronic ketamine users., Methods: 28 CKUs and 30 healthy controls(HC) were enrolled. The fractional amplitude of low-frequency fluctuations (fALFF) was measured to evaluate the intrinsic spontaneous neural activity in multiple brain regions. Cognitive alterations were assessed using MATRICS Consensus Cognitive Battery (MCCB)., Results: CKUs showed higher fALFF in the right parahippocampal gyrus(PHG), right anterior cingulate cortex(ACC), left cerebellar vermis, left posterior cingulate cortex(PCC), bilateral caudate, and lower fALFF in the right middle occipital gyrus(MOG), left cuneus, right precuneus. The fALFF in the right PHG, left cerebellar vermis, bilateral caudate, right ACC of CKUs presented a negative correlation with the average quantity of ketamine use/day(g) and estimated total ketamine consumption. The fALFF in left PCC had a negative correlation with the average quantity of ketamine use/day(g). Speed of processing on MCCB presented a negative correlation with the fALFF in the right MOG., Conclusion: Our study found abnormal fALFF in multiple brain areas in CKUs, which indicated the changes of intrinsic spontaneous neural activity in multiple brain areas. The changes of fALFF were associated with the severity of ketamine use and cognitive impairment in CKUs., Competing Interests: Declaration of Competing Interest There are no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Compared to normal cells, cancer cells generate ATP mainly through aerobic glycolysis, which promotes tumorigenesis and tumor progression. Long non-coding RNAs (LncRNAs) are a class of transcripts longer than 200 nucleotides with little or without evident protein-encoding function. LncRNAs are involved in the ten hallmarks of cancer, interestingly, they are also closely associated with aerobic glycolysis. However, the mechanism of this process is non-transparent to date. Demonstrating the mechanism of lncRNAs regulating tumorigenesis and tumor progression through aerobic glycolysis is particularly critical for cancer therapy, and may provide novel therapeutic targets or strategies in cancer treatment. In this review, we discuss the role of lncRNAs and aerobic glycolysis in tumorigenesis and tumor progression, and further explore their interaction, in hope to provide a novel therapeutic target for cancer treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fan, Fu, Feng, Chen, Wang, Wu, Bian and Li.)

Warburg effect of aerobic glycolysis in hepatic M1 macrophages is a major cause for metabolic dysfunction and inflammatory stress in non-alcoholic fatty liver disease (NAFLD). Plant-derived triterpene celastrol markedly inhibited macrophage M1 polarization and adipocyte hypertrophy in obesity. The present study was designed to identify the celastrol-bound proteins which reprogrammed metabolic and inflammatory pathways in M1 macrophages. Pyruvate kinase M2 (PKM2) was determined to be a major celastrol-bound protein. Peptide mapping revealed that celastrol bound to the residue Cys 31 while covalent conjugation altered the spatial conformation and inhibited the enzyme activity of PKM2. Mechanistic studies showed that celastrol reduced the expression of glycolytic enzymes (e.g., GLUT1, HK2, LDHA, PKM2) and related signaling proteins (e.g., Akt, HIF-1α, mTOR), shifted aerobic glycolysis to mitochondrial oxidative phosphorylation and skewed macrophage polarization from inflammatory M1 type to anti-inflammatory M2 type. Animal experiments indicated that celastrol promoted weight loss, reduced serum cholesterol level, lipid accumulation and hepatic fibrosis in the mouse model of NAFLD. Collectively, the present study demonstrated that celastrol might alleviate lipid accumulation, inflammation and fibrosis in the liver via covalent modification of PKM2., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Myocardial infarction triggers oxidative DNA damage, apoptosis and adverse cardiac remodeling in the heart. Small ubiquitin-like modifier (SUMO) proteins mediate post-translational SUMOylation of the cardiac proteins in response to oxidative stress signals. Upregulation of isoform SUMO2 could attenuate myocardial injury via increasing protein SUMOylation. The present study aimed to discover the identity and cardioprotective activities of SUMOylated proteins. A plasmid vector for expressing N-Strep-SUMO2 protein was generated and introduced into H9c2 rat cardiomyocytes. The SUMOylated proteins were isolated with Strep-Tactin ® agarose beads and identified by MALDI-TOF-MS technology. As a result, γ-actin was identified from a predominant protein band of ~42 kDa and verified by Western blotting. The roles of SUMO2 and γ-actin SUMOylation were subsequently determined in a mouse model of myocardial infarction induced by ligating left anterior descending coronary artery and H9c2 cells challenged by hypoxia-reoxygenation. In vitro lentiviral-mediated SUMO2 expression in H9c2 cells were used to explore the role of SUMOylation of γ-actin. SUMOylation of γ-actin by SUMO2 was proven to be a new cardioprotective mechanism from the following aspects: 1) SUMO2 overexpression reduced the number of TUNEL positive cells, the levels of 8-OHdG and p-γ-H2ax while promoted the nuclear deposition of γ-actin in mouse model and H9c2 cell model of myocardial infarction; 2) SUMO-2 silencing decreased the levels of nuclear γ-actin and SUMOylation while exacerbated DNA damage; 3) Mutated γ-actin (K 68 R/K 284 R) void of SUMOylation sites failed to protect cardiomyocytes against hypoxia-reoxygenation challenge. The present study suggested that SUMO2 upregulation promoted DNA damage repair and attenuated myocardial injury via increasing SUMOylation of γ-actin in the cell nucleus., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease with several liver-associated pathologic characteristics such as aberrant lipid accumulation, persistent chronic inflammation and hyperactive endoplasmic reticulum (ER) stress. Plant-derived celastrol (CEL) appeared to be a promising anti-inflammatory and anti-obesity drug but the clinical application was delayed by low oral bioavailability. The present study was designed for developing biodegradable albumin-based nanoparticles to deliver CEL to the liver for treating NAFLD. CEL was entrapped into lactosylated bovine serum albumin (Lac-BSA) by high pressure homogenization to generate CEL-loaded Lac-BSA nanoparticles (CEL-Lac-BSA). CEL-Lac-BSA displayed spherical morphology, narrow size distribution at 158.6 ± 3.4 nm and reasonable drug-loading efficiency at 13.62 ± 0.13%. CEL-Lac-BSA not only showed better hepatocyte uptake and hepatic deposition than free CEL, but also outperformed in reducing lipid deposition, ameliorating liver function and enhancing insulin sensitivity in a mouse model of diet-induced NAFLD. Mechanistic studies indicated that CEL-Lac-BSA more effectively downregulated the mRNA levels of genes for lipogenesis and lipid transporter while upregulated the mRNA levels of lipolysis mediators. Western blot analysis confirmed the outperformance of CEL-Lac-BSA in enhancing the activation of AMP-activated protein kinase (AMPK) and silent information regulation 2 homolog (SIRT1) and the protein levels of fatty acid synthase (FASN) and sterol regulatory element-binding protein-1c (SREBP1c) in NAFLD mice. Taken together, CEL-Lac-BSA showed better potential in the treatment of diet-induced NAFLD. Lactose-coating of albumin-based nanoparticles effectively facilitated the liver-targeting release of hydrophobic drug CEL for ameliorating hepatic steatosis. Therefore, CEL-Lac-BSA may be translated into a potential clinical therapy against obesity and NAFLD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., (© 2022 Society for Experimental Biology and John Wiley & Sons Ltd.)

Itraconazole, an effective broad-spectrum antifungal drug, has been well established for its anticancer activity in cancers including melanoma. However, details concerning its underlying mechanism in melanoma are unclear. This work investigated the function of itraconazole-induced 5'-monophosphate (AMP)-activated protein kinase alpha (AMPKα) in melanoma progression through ERK signaling. The AMPKα level in melanoma tissues and cells was assessed by RT-qPCR and western blot. Survival analysis of patients with melanoma based on the AMPKα expression level was performed according to TCGA database. Melanoma cell proliferation, migration, and invasion were examined using CCK-8, colony formation, wound healing, and Transwell assays. A xenograft tumor model was established to examine the effect of itraconazole on tumor growth in vivo. The AMPKα mRNA and protein levels were reduced in melanoma tissues and cells. A low expression of AMPKα indicated a poor prognosis. Functionally, itraconazole restrained melanoma cell proliferation, migration, and invasion by upregulating AMPKα. Itraconazole activated AMPK signaling and inhibited ERK signaling in melanoma cells. Activation of ERK signaling reversed the effect of itraconazole on cellular process in melanoma. Moreover, itraconazole-induced AMPKα inhibited melanoma tumor growth in vivo by inhibiting ERK signaling. Itraconazole-induced AMPKα inhibits the progression of melanoma by inhibition of ERK signaling., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Obesity is hallmarked by endoplasmic reticulum (ER) stress, chronic inflammation and metabolic dysfunctions. The control of obesity is the key to preventing the onset of non-alcoholic fatty liver disease, diabetes, cerebro-cardiovascular diseases and cancers. As a promising anti-obesity drug, plant-derived celastrol is challenged by poor water solubility and low oral bioavailability in clinical applications. The present study was designed to develop a biocompatible albumin-based nanoparticle carrier system for the controlled release of celastrol in diet-induced obese mice. Celastrol was loaded into bovine serum albumin (BSA) nanoparticles to yield celastrol-BSA-NPs by high pressure homogenization. Celastrol-BSA-NPs exhibited spherical morphology, narrow size distribution with a diameter of 125.6 ± 2.2 nm, satisfactory drug-loading efficiency at 13.88 ± 0.12% and a sustained-release profile over a period of 168 h. Compared with free celastrol, celastrol-BSA-NPs effectively improved cellular uptake, intestinal absorption and hepatic deposition. In animal experiments, celastrol-BSA-NPs outperformed free celastrol in lowering lipid accumulation, improving insulin sensitivity, and reducing inflammation in diet-induced obesity. Collectively, celastrol-BSA-NPs exhibited better bioavailability and in vivo efficacy in the treatment of diet-induced obesity. Importantly, such albumin-based nanoparticles may be a general biocompatible drug carrier system for the controlled release of hydrophobic compounds ( e.g. , celastrol) for the treatment of obesity and non-alcoholic fatty liver disease.

Targeting endoplasmic reticulum (ER) stress, inflammation, and metabolic dysfunctions may halt the pathogenesis of obesity and thereby reduce the prevalence of diabetes, cardiovascular disesases, and cancers. The present study was designed to elucidate the mechnaisms by which plant-derived celastrol ameliorated inflammation and lipid accumulation in obesity. The mouse model of diet-induced obesity was induced by feeding high-fat diet for 3 months and subsequently intervented with celastrol for 21 days. Hepatic and adipose tissues were analyzed for lipid accumulation, macrophage activation, and biomarker expression. As result, celastrol effectively reduced body weight, suppressed ER stress, inflammation, and lipogenesis while promoted hepatic lipolysis. RNA-sequencing revealed that celastrol-loaded nanomicelles restored the expression of 49 genes that regulate ER stress, inflammation, and lipid metabolism. On the other hand, celastrol-PEG4-alkyne was synthesized for identifying celastrol-bound proteins in RAW264.7 macrophages. ER chaperone GRP78 (78 kDa glucose-regulated protein) was identified by proteomics approach for celastrol binding to the residue Cys 41 . Upon binding and conjugation, celastrol diminished the chaperone activity of GRP78 by 130-fold and reduced ER stress in palmitate-challenged cells, while celastrol analog lacking quinone methide failed to exhibit antiobesity effects. Thus, covalent GRP78 inhibition may induce the reprograming of ER signaling, inflammation, and metabolism against diet-induced obesity., Competing Interests: DL, NF, XZ, FN, JZ, WZ, MH, DL, YW, JR No competing interests declared, (© 2022, Luo et al.)

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., (© 2021 John Wiley & Sons Ltd.)

Alcohol dependence (AD) is a condition of alcohol use disorder in which the drinkers frequently develop emotional symptoms associated with a continuous alcohol intake. AD characterized by metabolic disturbances can be quantitatively analyzed by metabolomics to identify the alterations in metabolic pathways. This study aimed to: i) compare the plasma metabolic profiling between healthy and AD-diagnosed individuals to reveal the altered metabolic profiles in AD, and ii) identify potential biological correlates of alcohol-dependent inpatients based on metabolomics and interpretable machine learning. Plasma samples were obtained from healthy ( n = 42) and AD-diagnosed individuals ( n = 43). The plasma metabolic differences between them were investigated using liquid chromatography-tandem mass spectrometry (AB SCIEX ® QTRAP 4500 system) in different electrospray ionization modes with scheduled multiple reaction monitoring scans. In total, 59 and 52 compounds were semi-quantitatively measured in positive and negative ionization modes, respectively. In addition, 39 metabolites were identified as important variables to contribute to the classifications using an orthogonal partial least squares-discriminant analysis (OPLS-DA) (VIP > 1) and also significantly different between healthy and AD-diagnosed individuals using univariate analysis ( p -value < 0.05 and false discovery rate < 0.05). Among the identified metabolites, indole-3-carboxylic acid, quinolinic acid, hydroxy-tryptophan, and serotonin were involved in the tryptophan metabolism along the indole, kynurenine, and serotonin pathways. Metabolic pathway analysis revealed significant changes or imbalances in alanine, aspartate, glutamate metabolism, which was possibly the main altered pathway related to AD. Tryptophan metabolism interactively influenced other metabolic pathways, such as nicotinate and nicotinamide metabolism. Furthermore, among the OPLS-DA-identified metabolites, normetanephrine and ascorbic acid were demonstrated as suitable biological correlates of AD inpatients from our model using an interpretable, supervised decision tree classifier algorithm. These findings indicate that the discriminatory metabolic profiles between healthy and AD-diagnosed individuals may benefit researchers in illustrating the underlying molecular mechanisms of AD. This study also highlights the approach of combining metabolomics and interpretable machine learning as a valuable tool to uncover potential biological correlates. Future studies should focus on the global analysis of the possible roles of these differential metabolites and disordered metabolic pathways in the pathophysiology of AD., Competing Interests: CL was employed by the company Guangzhou Rely Medical Diagnostic Technology Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhu, Huang, Huang, Wen, Lan, Wang, Lu, Wang, Fan and Shang.)

Background: Small ubiquitin-like modifier (SUMO) proteins modify proteins through SUMOylation as an essential protein post-translational modification (PTM) for regulating redox status, inflammation, and cardiac fibrosis in myocardial infarction. This study aimed to investigate whether natural product puerarin could alleviate myocardial ischemia/reperfusion injury (MI-RI) by targeting protein SUMOylation. Methods: Mouse MI-RI model was induced by ligating the left anterior descending (LAD) coronary artery and subsequently treated with puerarin at the dose of 100 mg/kg. Rat cardiomyocyte H9c2 cells were challenged by hypoxia/reoxygenation and treated with puerarin at concentrations of 10, 20, and 40 μM. The infarction area of mouse hearts was assessed by 2% TTC staining. Cell damage was analyzed for the release of lactate dehydrogenase (LDH) in serum and cell culture medium. Western blot technique was employed to detect the expression of SUMO2, phospho-ERK, pro-inflammatory biomarker COX2, fibrosis index galectin-3, apoptosis-related protein cleaved PARP-1. The activation of the estrogen receptor (ER) pathway was assayed by the dual-luciferase reporter system. Results: The present study validated that puerarin effectively reduced myocardial infarct size and LDH release in the mouse MI-RI model. In the cell culture system, puerarin effectively decreased the release of LDH and the protein level of COX2, galectin-3, and cleaved PARP-1. Mechanistic studies revealed that puerarin increased the expression of SUMO2, SUMOylation of proteins and the activation of ER/ERK pathway in cardiomyocytes. ER, ERK and SUMO2 inhibitors attenuated the cardioprotective effects of puerarin. Conclusion: Puerarin may alleviate myocardial injury by promoting protein SUMOylation through ER/ERK/SUMO2-dependent mechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao, Zhao, Zhang, Fan and Rong.)

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., (© 2021 The Authors New Phytologist © 2021 New Phytologist Foundation.)

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 CaMKIIβ, 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 CaMKIIβ. Our study indicates that inhibition of CaMKIIβ-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., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Aerosolized Azacitidine has been shown to inhibit orthotopic lung cancer growth and induce re-expression of methylated tumor suppressor genes in murine models. We hypothesized that inhaled Azacitidine is safe and effective in reversing epigenetic changes in the bronchial epithelium secondary to chronic smoking., Patients and Methods: We report the first in human study of inhaled Azacitidine. Azacitidine in aqueous solution was used to generate an aerosol suspension of 0.25-5 μm particle size. Main inclusion criteria: Stage IV or recurrent NSCLC with predominantly lung involvement, ≥1 prior systemic therapy, ECOG PS 0-1, and adequate pulmonary function. Patients received inhaled Azacitidine daily on days 1-5 and 15-19 of 28-day cycles, at 3 escalating doses (15, 30 and 45 mg/m 2 daily). The primary objective was to determine the feasibility and tolerability of this new therapeutic modality. The key secondary objectives included pharmacokinetics, methylation profiles and efficacy., Results: From 3/2015 to 2/2018, eight patients received a median number of 2 (IQR = 1) cycles of inhaled Azacitidine. No clinically significant adverse events were observed, except one patient treated at the highest dose developed an asymptomatic grade 2 decreased DLCO which resolved spontaneously. One patient receiving 12 cycles of therapy had an objective and durable partial response, and two patients had stable disease. Plasma Azacitidine was only briefly detectable in patients treated at the higher doses. Moreover, in 2 of 3 participants who agreed and underwent pre- and post-treatment bronchoscopy, the global DNA methylation in the bronchial epithelium decreased by 24 % and 79 % post-therapy, respectively. The interval between last inhaled treatment and bronchoscopy was 3 days., Conclusions: Inhaled Azacitidine resulted in negligible plasma levels compared to the previously reported subcutaneous administration and was well-tolerated. The results justify the continued development of inhaled Azacitidine at non-cytotoxic doses for patients with lung-confined malignant and/or premalignant lesions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Previous studies have examined the effects of long-term ketamine use on gray matter volume. But it is unclear whether chronic ketamine use alters cortical thickness and whether cortical thickness changes in chronic ketamine users are associated with cognitive deficits observed in chronic ketamine users. Methods: Here, 28 chronic ketamine users and 30 healthy controls (HCs) were recruited. Cortical morphometry based on Computational Anatomy Toolbox (CAT12) was used to measure cortical thickness. Cognitive performance was measured by MATRICS Consensus Cognitive Battery (MCCB). Two-sample t -test was used to assess differences in cortical thickness and cognitive performance between the two groups. Partial correlation analysis was used for assessing correlations between cortical thickness changes and clinical characteristics, cognitive performance in chronic ketamine users. Results: Chronic ketamine users exhibited significantly reduced cortical thickness in frontal, parietal, temporal, and occipital lobes compared to HC [false discovery rate (FDR) corrected at p < 0.05]. In chronic ketamine users, the average quantity (g) of ketamine use/day was negatively correlated with cortical thickness in the left superior frontal gyrus (SFG), right caudal middle frontal gyrus (MFG), and right paracentral lobule. The frequency of ketamine use (days per week) was negatively correlated with cortical thickness in the left isthmus cingulate cortex. Duration of ketamine use (month) was negatively correlated with cortical thickness in the left precentral gyrus. The chronic ketamine users showed significantly poorer cognitive performance on the working memory ( P = 0.009), visual learning ( P = 0.009), speed of processing ( P < 0.000), and Matrics composite ( P = 0.01). There was no correlation between scores of domains of MCCB and reduced cortical thickness. Conclusion: The present study observed reduced cortical thickness in multiple brain areas, especially in the prefrontal cortex (PFC) in chronic ketamine users. Dose, frequency, and duration of ketamine use was negatively correlated with cortical thickness of some brain areas. Our results suggest that chronic ketamine use may lead to a decrease of cortical thickness. But the present study did not observe any correlation between reduced cortical thickness and decreased cognitive performance in chronic ketamine users., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhong, Wu, Wu, He, Zhang, Huang, Cao and Fan.)

The application of 3D printing in planning endoscopic endonasal transsphenoidal surgery is illustrated based on the analysis of patients with intracranial skull base diseases who received treatment in our department. Cranial computed tomography/magnetic resonance imaging data are attained preoperatively, and three-dimensional reconstruction is performed using MIMICS (Materialise, Leuven, Belgium). Models of intracranial skull base diseases are printed using a 3D printer before surgery. The models clearly demonstrate the morphologies of the intracranial skull base diseases and the spatial relationship with adjacent large vessels and bones. The printing time of each model is 12.52-15.32 h, and the cost ranges from 900 to 1500 RMB. The operative approach was planned in vitro, and patients recovered postoperatively well without severe complications or death. In a questionnaire about the application of 3D printing, experienced neurosurgeons achieved scores of 7.8-8.8 out of 10, while unexperienced neurosurgeons achieved scores of 9.2-9.8. Resection of intracranial skull base lesions is demonstrated to be well assisted by 3D printing technique, which has great potential in disclosing adjacent anatomical relationships and providing the required help to clinical doctors in preoperative planning.

Background: Anxiety, an important factor that affects the therapeutic effect and preservation rate of methadone maintenance treatment, has a high prevalence among MMT patients. This study aims to investigate the effects of treatment status and life quality on anxiety in MMT patients., Methods: One hundred and Seventy-seven methadone maintenance treatment users in Guangzhou, China were evaluated. The socio-demographic, duration and MMT-related characteristics were documented. Anxiety level and quality of life were evaluated by Beck Anxiety inventory (BAI) and the Quality of Life-Drug Addiction (QOL-DA) respectively. The correlation between different factors and BAI score was also analyzed., Results: The BAI total score and the QOL-DA score were 7.1±8.2, 163.5±21.4 respectively. 30.5% of the subjects showed mild to severe anxiety. Treatment interruption and QOL-DA score had strong correlations with the score of BAI, with correlation coefficients of 0.17 and - 0.08 respectively., Conclusions: Anxiety symptoms were commonly presented in MMT patients. Treatment interruption and quality of life are two major factors affecting anxiety of MMT patients.

Objective: We previously found that chronic ketamine usages were associated with various psychotic and cognitive symptoms mimicking schizophrenia. The blockade of the NMDA receptor and subsequent nitric oxide synthase 1 (NOS1) dysfunction were found to be closely correlated with schizophrenia including NOS1 gene polymorphisms. We examined the allelic variants of the gene coding neuronal nitric oxide synthase 1 ( NOS1 ) in chronic ketamine users in the Chinese population and analyzed the association between NOS1 gene polymorphism and psychopathological symptoms in chronic ketamine users. The association between the NOS1 polymorphism and ketamine use characteristics was also examined. Methods: One hundred ninety seven male chronic ketamine users and 82 controls were recruited. Four common SNPs of the NOS1 gene, rs6490121, rs41279104, rs3782206, and rs3782219, were examined by real-time PCR with the TaqMan® assay system. Psychopathological symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS), Beck Depression Inventory (BDI), and the Beck Anxiety Inventory (BAI). Results: The genotype distribution of rs6490121 and rs41279104 in chronic ketamine users was significantly different from that in the control ( p = 0.0001 and p = 0.002). The G allele frequency of rs6490121 in ketamine users was higher than that in the control ( p = 2.23 * 10 -6 , OR = 3.07, 95% CI = 1.93-4.90). The T allele frequency of rs41279104 in chronic ketamine users was higher than that in the control ( p = 0.01, OR = 1.76, 95% CI = 1.14-2.72). The BAI score was significantly different among the three genotypic groups of rs6490121 ( F = 6.21, p = 0.002) in ketamine users; subjects of genotype AG and GG had a lower score than subjects of genotype AA. The score of the negative symptom subscale of PANSS was significantly different among the three genotypic groups of rs41279104 ( F = 5.39, p = 0.005); in ketamine users, subjects of genotype CT and TT had a higher score than subjects of genotype CC. There was no difference in drug use characteristics in different genotypes of the four NOS1 gene polymorphisms tested in ketamine users ( p > 0.05)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Chen, Zhang, Zhou, Ding, Fan and He.)

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., (© 2020 American Society of Plant Biologists. All rights reserved.)

Competing Interests: Competing interests: None declared.

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., (© 2020 John Wiley & Sons Ltd.)

Introduction: Electroconvulsive therapy (ECT) is an effective treatment for patients with mood disorders and is most often used for treatment-resistant cases. This study aimed to examine the effectiveness of ECT in a real-world treatment sample in a Chinese psychiatric hospital which included both treatment-resistant and nontreatment-resistant patients., Methods: An observational study of symptom outcomes from admission to the time of discharge was conducted with 37 inpatients diagnosed with unipolar or bipolar depression treated with ECT. Symptom severity was assessed with the 17-item Hamilton Rating Scales for Depression (HRSD-17) and treatment-resistance with the Maudsley Staging Model (MSM). Stratifying at the MSM median admission characteristics and symptom change was compared between patients who were treatment-resistant (n = 18) and who were not (n = 19). The outcome difference between groups was compared using analyses of covariance adjusted for baseline characteristics including symptom severity, followed by linear regression to identify factors associated symptom improvement in the entire sample., Results: The sample (n = 37) showed moderate treatment-resistance (MSM = 7.30 ± 1.13) at admission and both groups received 8.3 ± 2 ECT sessions. The treatment-resistant group had a smaller proportion of bipolar patients and more severe symptoms, but showed no significant difference from the nontreatment-resistant group in HDRS-17 scores at the time of discharge (adjusted means = 6.23 ± 1.00 vs. 5.94 ± 0.97, Partial η 2  = 0.001, p = .845). Baseline symptom severity was the strongest correlate of reduction in HDRS-17 scores (β = 0.891, p < .001)., Conclusions: Symptom change with ECT in depression did not differ by level of treatment-resistance but was greatest among those with more severe baseline symptoms. Correlates of ECT effectiveness should be further evaluated in stratified randomized trials., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

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., (© 2019 Society for the Study of Addiction.)

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 (χ 2  = 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)., (© 2020 American Academy of Addiction Psychiatry.)

Background: Calreticulin (CALR) exon 9 frameshift mutations have recently been identified in 30-40% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) without JAK2 or MPL mutations. We aimed to develop a qPCR assay to screen type I and II mutations of CALR., Methods: Three different fluorescent-labeled hydrolysis probes and one pair of primers in a closed-tube system were developed to detect CALR type I and II mutations and distinguish them from wild-type. The sensitivity and specificity were validated using TA-cloning plasmids containing CALR wild-type and type I and II mutants, respectively. Fifty-nine ET and PMF specimens were screened by TaqMan qPCR and sequenced by Sanger sequencing. For intra-assay validation, 20 replicates of the assay were performed with each sample. For inter-assay validation, four replications of each sample were carried out and repeated continuously for 5 days., Results: We found that triplex probe-based TaqMan qPCR was reliable in detecting CALR type I and II mutants within DNA that was diluted to 1% of total DNA with the wild-type DNA as background. In 59 patient specimens, six of the observed mutations of CALR were type I and five were type II. Genotyping results obtained from TaqMan qPCR were 100% concordant with Sanger sequencing. The intra- and inter-assay CVs of TaqMan qPCR were less than 3%, respectively., Conclusions: Triplex probe-based TaqMan qPCR is an accurate and sensitive method for screening ET or PMF patients with type I and II mutations in CALR.

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.

Botanical triterpene celastrol is a candidate drug for the treatment of obesity, except for concerns over the safety in clinical application. The present study was designed to investigate the anti-obesity, anti-inflammatory and toxic activities of celastrol-loaded nanomicelles (nano-celastrol) in diet-induced obese mice. Celastrol was loaded into PEG-PCL nanoparticles, yielding nano-celastrol with optimal size, spherical morphology, good bioavailability, slower peak time and clearance in mice. Nano-celastrol (5 or 7.5 mg/kg/d of celastrol) was administered into diet-induced obese C57BL/6 N male mice for 3 weeks. As result, higher dose nano-celastrol reduced body weight and body fat mass in an equally effective manner as regular celastrol, although lower dose nano-celastrol showed less activity. Similarly, nano-celastrol improved glucose tolerance in mice equally well as regular celastrol, whereas higher dose nano-celastrol improved the response to insulin. As for macrophage M1/M2 polarization in liver, nano-celastrol reduced the expression of macrophage M1 biomarkers (e.g., IL-6, IL-1β, TNF-α, iNOS) in a dose-dependent manner and marginally increased the expression of macrophage M2 biomarkers (e.g., Arg-1, IL-10). Moreover, celastrol could cause anus irritation and disturb intestinal and colonic integrity, whereas nano-celastrol did not cause any injury to mice. Collectively, nano-celastrol represents a translatable therapeutic opportunity for treating diet-induced obesity in humans., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)