Serum iron status is associated with all-cause mortality in metabolic dysfunction-associated steatotic liver disease: a prospective, observational study.

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading chronic liver disease worldwide. Emerging evidence suggests a close crosstalk between iron status and metabolic syndrome. Therefore, this cohort study aimed to investigate the relationship between serum iron status and all-cause mortality in individuals with MASLD. Methods: A total of 3393 subjects with MASLD identified by ultrasound from the Third National Health and Nutrition Examination Survey (NHANES III) were included in the analysis. Iron status indicators included serum iron, ferritin, transferrin saturation, total iron binding capacity, hemoglobin concentration, mean corpuscular hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin concentration. Cox proportional hazards models and restricted cubic spline models with adjustment for multiple confounders were applied. Stratified analyses were performed by sex and age. Results: During a median of 26.08 years of follow-up, high serum iron and transferrin saturation were significantly associated with reduced all-cause mortality in a linear pattern (P overall<0.001). Compared with the lowest quartile, individuals with serum iron and transferrin saturation in the third or fourth quartile intervals had a 20-40% reduction in long-term mortality. However, there was no independent association of serum ferritin, total iron binding capacity, and red blood cell indices with all-cause mortality in MASLD. Conclusion: This study suggests that serum iron and transferrin saturation have the potential to serve as independent biomarkers of all-cause mortality in patients with MASLD and implies the therapeutic potential of modifying iron status.

Insufficient FUNDC1-dependent mitophagy due to early environmental cadmium exposure triggers mitochondrial redox imbalance to aggravate diet-induced lipotoxicity.

Cadmium (Cd) is a toxic contaminant widely spread in natural and industrial environments. Adolescent exposure to Cd increases risk for obesity-related morbidity in young adults including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Despite this recognition, the direct impact of adolescent Cd exposure on the progression of MASLD later in life, and the mechanisms underlying these effects, remain unclear. Here, adolescent rats received control diet or diets containing 2 mg Cd2+/kg feed for 4 weeks, and then HFD containing 15% lard or control diet in young adult rats was selected for 6 weeks to clarify this issue. Data firstly showed that HFD-fed rats in young adulthood due to adolescent Cd exposure exhibited more severe MASLD, evidenced by increased liver damage, disordered serum and hepatic lipid levels, and activated NLRP3 inflammasome. Hepatic transcriptome analysis revealed the potential effects of mitochondrial dysfunction in aggravated MASLD due to Cd exposure. Verification data further confirmed that mitochondrial structure and function were targeted and disrupted during this process, shown by broken mitochondrial ridges, decreased mitochondrial membrane potential, imbalanced mitochondrial dynamic, insufficient ATP concentration, and enhanced mitochondrial ROS generation. However, mitophagy is inactively involved in clearance of damaged mitochondria induced by early Cd in HFD condition due to inhibited mitophagy receptor FUNDC1. In contrast, FUNDC1-dependent mitophagy activation prevents lipotoxicity aggravated by early Cd via suppressing mitochondrial ROS generation. Collectively, our data show that insufficient FUNDC1-dependent mitophagy can drive the transition from HFD-induced MASLD to MASH, and accordingly, these findings will provide a better understanding of potential mechanism of diet-induced metabolic diseases in the context of early environmental Cd exposure.

Diastereomers of Coibamide A Show Altered Sec61 Client Selectivity and Ligand-Dependent Activity against Patient-Derived Glioma Stem-like Cells.

Coibamide A (CbA) is a cyanobacterial lariat depsipeptide that selectively inhibits multiple secreted and integral membrane proteins from entering the endoplasmic reticulum secretory pathway through binding the alpha subunit of the Sec61 translocon. As a complex peptide-based macrocycle with 13 stereogenic centers, CbA is presumed to adopt a conformationally restricted orientation in the ligand-bound state, resulting in potent antitumor and antiangiogenic bioactivity. A stereochemical structure-activity relationship for CbA was previously defined based on cytotoxicity against established cancer cell lines. However, the ability of synthetic isomers to inhibit the biosynthesis of specific Sec61 substrates was unknown. Here, we report that two less toxic diastereomers of CbA, [L-Hiv2]-CbA and [L-Hiv2, L-MeAla11]-CbA, are pharmacologically active Sec61 inhibitors. Both compounds inhibited the expression of a secreted reporter (Gaussia luciferase), VEGF-A, and a Type 1 membrane protein (VCAM1), while [L-Hiv2]-CbA also decreased the expression of ICAM1 and BiP/GRP78. Analysis of 43 different chemokines in the secretome of SF-268 glioblastoma cells revealed different inhibitory profiles for the two diastereomers. When the cytotoxic potential of CbA compounds was compared against a panel of patient-derived glioblastoma stem-like cells (GSCs), Sec61 inhibitors were remarkably toxic to five of the six GSCs tested. Each ligand showed a distinct cytotoxic potency and selectivity pattern for CbA-sensitive GSCs, with IC50 values ranging from subnanomolar to low micromolar concentrations. Together, these findings highlight the extreme sensitivity of GSCs to Sec61 modulation and the importance of ligand stereochemistry in determining the spectrum of inhibited Sec61 client proteins.

Nighttime color constancy using robust gray pixels.

Color constancy is a basic step for achieving stable color perception in both biological visual systems and the image signal processing (ISP) pipeline of cameras. So far, there have been numerous computational models of color constancy that focus on scenes under normal light conditions but are less concerned with nighttime scenes. Compared with daytime scenes, nighttime scenes usually suffer from relatively higher-level noise and insufficient lighting, which usually degrade the performance of color constancy methods designed for scenes under normal light. In addition, there is a lack of nighttime color constancy datasets, limiting the development of relevant methods. In this paper, based on the gray-pixel-based color constancy methods, we propose a robust gray pixel (RGP) detection method by carefully designing the computation of illuminant-invariant measures (IIMs) from a given color-biased nighttime image. In addition, to evaluate the proposed method, a new dataset that contains 513 nighttime images and corresponding ground-truth illuminants was collected. We believe this dataset is a useful supplement to the field of color constancy. Finally, experimental results show that the proposed method achieves superior performance to statistics-based methods. In addition, the proposed method was also compared with recent deep-learning methods for nighttime color constancy, and the results show the method's advantages in cross-validation among different datasets.

Identification of Down-Expressed CRNN Associated with Cancer Progression and Poor Prognosis in Laryngeal Squamous Cell Carcinoma.

BACKGROUND: The prevalence of laryngeal squamous cell carcinoma (LSCC) is increasing, and it poses a significant threat to human health; therefore, identifying specific targets for LSCC remains crucial. METHODS: Bioinformatics analysis was used to compare the different expression genes expressed in LSCC. Immunohistochemical assay and western blotting were used to analysis protein expression. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide)((4,5 Dimethyl thiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide)4,5 Dimethyl thiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) and 5-ethynyl 2'-deoxyuridine (Edu) assay. Flow cytometry was used to measure the cell cycle. Cell migration was measured by wound healing assay and transwell assay. RESULTS: Our analysis revealed 36 upregulated and 65 downregulated differentially expressed genes (DEGs) when comparing LSCC tumors to adjacent tissues, with cornulin (CRNN) identified as a key hub gene connecting these DEGs. We observed a consistent downregulation of CRNN expression in LSCC cell lines and tissues and was associated with poor patient survival and the tumor microenvironment. CRNN overexpression was found to significantly inhibit cell growth, cell cycle progression, migration and invasion, while CRNN knockdown had the opposite effects. Additionally, in vivo experiments demonstrated that CRNN overexpression suppressed tumor growth in nude mice. CONCLUSIONS: CRNN functions as a potential tumor suppressor and regulates important aspects of LSCC, providing valuable insights into the role of CRNN in LSCC pathogenesis and potential for targeted therapeutic interventions.

Hippocampal circAnk3 Deficiency Causes Anxiety-like Behaviors and Social Deficits by Regulating the miR-7080-3p/IQGAP1 Pathway in Mice.

BACKGROUND: Circular RNAs are highly enriched in the synapses of the mammalian brain and play important roles in neurological function by acting as molecular sponges of microRNAs. circAnk3 is derived from the 11th intron of the ankyrin-3 gene, Ank3, a strong genetic risk factor for neuropsychiatric disorders; however, the function of circAnk3 remains elusive. In this study, we investigated the function of circAnk3 and its downstream regulatory network for target genes in the hippocampus of mice. METHODS: The DNA sequence from which circAnk3 is generated was modified using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9) technology, and neurobehavioral tests (anxiety and depression-like behaviors, social behaviors) were performed in circAnk3+/- mice. A series of molecular and biochemical assays were used to investigate the function of circAnk3 as a microRNA sponge and its downstream regulatory network for target genes. RESULTS: circAnk3+/- mice exhibited both anxiety-like behaviors and social deficits. circAnk3 was predominantly located in the cytoplasm of neuronal cells and functioned as a miR-7080-3p sponge to regulate the expression of Iqgap1. Inhibition of miR-7080-3p or restoration of Iqgap1 in the hippocampus ameliorated the behavioral deficits of circAnk3+/- mice. Furthermore, circAnk3 deficiency decreased the expression of the NMDA receptor subunit GluN2a and impaired the structural plasticity of dendritic synapses in the hippocampus. CONCLUSIONS: Our results reveal an important role of the circAnk3/miR-7080-3p/IQGAP1 axis in maintaining the structural plasticity of hippocampal synapses. circAnk3 might offer new insights into the involvement of circular RNAs in neuropsychiatric disorders.

Integrated lipidomic and transcriptomic analysis reveals clarithromycin-induced alteration of glycerophospholipid metabolism in the cerebral cortex of mice.

Clarithromycin (CLA) has been widely used in the treatment of bacterial infection. Research reveals the adverse effects on the central nervous system among patients receiving CLA treatment; whereas, a relevant underlying mechanism remains considerably unclear. According to our research, an integrated lipidomic and transcriptomic analysis was applied to explore the effect of CLA on neurobehavior. CLA treatment caused anxiety-like behaviors dose-dependently during open field as well as elevated plus maze trials on mice. Transcriptomes and LC/MS-MS-based metabolomes were adopted for investigating how CLA affected lipidomic profiling as well as metabolic pathway of the cerebral cortex. CLA exposure greatly disturbed glycerophospholipid metabolism and the carbon chain length of fatty acids. By using whole transcriptome sequencing, we found that CLA significantly downregulated the mRNA expression of CEPT1 and CHPT1, two key enzymes involved in the synthesis of glycerophospholipids, supporting the findings from the lipidomic profiling. Also, CLA causes changes in neuronal morphology and function in vitro, which support the existing findings concerning neurobehavior in vivo. We speculate that altered glycerophospholipid metabolism may be involved in the neurobehavioral effect of CLA. Our findings contribute to understanding the mechanisms of CLA-induced adverse effects on the central nervous system. 1. Clarithromycin treatment caused anxiety-like behavior with dose-dependent response both in the open field and elevated plus maze test in mice; 2. Clarithromycin exposing predominately disturbed the metabolism of glycerophospholipids in the cerebral cortex of mice; 3. Clarithromycin application remarkably attenuated CEPT1 and CHPT1 gene expression, which participate in the last step in the synthesis of glycerophospholipids; 4. The altered glycerophospholipid metabolomics may be involved in the abnormal neurobehavior caused by clarithromycin.

Puerarin prevents cadmium-induced mitochondrial fission in AML-12 cells via Sirt1-dependent pathway.

Recent investigations have revealed that puerarin (PU) alleviates cadmium (Cd)-caused hepatic damage via inhibiting oxidative stress. Mitochondria are dynamic organelles and play a critical part in regulating the occurrence of oxidative stress, but the role of mitochondria in the protection of PU against hepatocellular damage caused by Cd exposure remains unknown. Thus, this study was aimed to clarify this issue using mouse hepatocyte AML-12 cell line. Transmission electron microscopy analysis firstly showed that PU prevents Cd-induced mitochondrial ultrastructure damage. Mitochondrial network image analysis by confocal microscopy revealed that PU exerts the protection against Cd-induced cytotoxicity via restoring mitochondrial network fragmentation. Also, mitochondrial dynamic protein expression profiles showed that enhanced fission protein levels and inhibited fusion protein levels in Cd-treated cells were significantly reversed by PU, suggesting the protective effect of PU against Cd-induced mitochondrial fission. Moreover, changes of intracellular ATP level and protein levels of key regulators involving in mitochondrial biogenesis indicated that Sirtuin-1(Sirt1) pathway may be involved in the protection of Cd-impaired mitochondrial function by PU. Next, Sirt1 protein levels in treated cells were effectively regulated by genetic knockdown or chemical agonist SRT1720. Accordingly, alleviation of Cd-induced mitochondrial fission assays and cell viability by PU was markedly regulated by SRT1720 or Sirt1 knockdown, suggesting the indispensable role of Sirt1 in this process. Collectively, these findings highlight that PU prevents Cd-induced mitochondrial fission to alleviate cytotoxicity via Sirt1-dependent pathway, which provide novel evidences to fully understand the hepatoprotective action of PU against heavy metal toxicity.

ß-hydroxybutyrate reduces reinstatement of cocaine conditioned place preference through hippocampal CaMKII-α ß-hydroxybutyrylation.

Studies have shown the therapeutic effects of a ketogenic diet (KD) on epilepsy, but the effect of a KD on drug reinstatement is largely unclear. This study aims to investigate whether KD consumption possesses therapeutic potential for cocaine reinstatement and the molecular mechanism. We find that a KD significantly reduces cocaine-induced reinstatement in mice, which is accompanied by a markedly elevated level of ß-hydroxybutyrate (ß-OHB), the most abundant ketone body, in the hippocampus. The underlying mechanism is that ß-OHB posttranslationally modifies CaMKII-α with ß-hydroxybutyrylation, resulting in significant inhibition of T286 autophosphorylation and downregulation of CaMKII activity. Collectively, our results reveal that ß-hydroxybutyrylation is a posttranslational modification of CaMKII-α that plays a critical role in mediating the effect of KD consumption in reducing cocaine reinstatement.

Assessment of reporting completeness in acupuncture studies on patients with functional constipation using the STRICTA guidelines.

OBJECTIVE: To evaluate the completeness of reporting of acupuncture interventions in trials for functional constipation (FC) following the STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) guidelines. METHODS: We searched eight databases for all published trials, including clinical trials, pilot/feasibility studies, observational studies, and case studies, for acupuncture in patients with FC up to June 31, 2021. The completeness of reporting was evaluated using the STRICTA guidelines. RESULTS: Finally, 99 studies were included and analysed based on the latest STRICTA guidelines. Out of the 17 analysed STRICTA sub-items, only five were found to be appropriately reported in more than 90% of the trials, while five were completely reported in less than 30%. CONCLUSIONS: The reporting completeness of acupuncture trials for FC in accordance with STRICTA guidelines is moderate, with poor guideline adherence for several items. Clinical trial reports should be further improved in accordance with STRICTA guidelines to enhance the completeness of evidence. There is also a need to explore the underlying reasons as to why the authors did not report these items and to develop strategies for improving guideline compliance.

The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK.

The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells with an oxidative metabolic phenotype. To provide further insight into the pharmacology of the mandelalides, we studied the AMP-activated protein kinase (AMPK) energy stress pathway and report that mandelalide A is an indirect activator of AMPK. Wild-type mouse embryonic fibroblasts (MEFs) and representative human non-small cell lung cancer (NSCLC) cells showed statistically significant increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in response to mandelalide A. Mandelalide L, which also harbors an A-type macrocycle, induced similar increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in U87-MG glioblastoma cells. In contrast, MEFs co-treated with an AMPK inhibitor (dorsomorphin), AMPKα-null MEFs, or NSCLC cells lacking liver kinase B1 (LKB1) lacked this activity. Mandelalide A was significantly more cytotoxic to AMPKα-null MEFs than wild-type cells, suggesting that AMPK activation serves as a protective response to mandelalide-induced depletion of cellular ATP. However, LKB1 status alone was not predictive of the antiproliferative effects of mandelalide A against NSCLC cells. When EGFR status was considered, erlotinib and mandelalide A showed strong cytotoxic synergy in combination against erlotinib-resistant 11-18 NSCLC cells but not against erlotinib-sensitive PC-9 cells. Finally, prolonged exposures rendered mandelalide A, a potent and efficacious cytotoxin, against a panel of human glioblastoma cell types regardless of the underlying metabolic phenotype of the cell. These results add biological relevance to the mandelalide series and provide the basis for their further pre-clinical evaluation as ATP synthase inhibitors and secondary activators of AMPK.

Cantharidin Inhibits Proliferation of Liver Cancer by Inducing DNA Damage via KDM4A-Dependent Histone H3K36 Demethylation.

Objective: To investigate the effect of cantharidin on DNA damage in hepatocellular carcinoma cells and its possible mechanism. Methods: Cell proliferation assay and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were used to analyze the effects of cantharidin on cell proliferation and apoptosis of hepatocellular carcinoma cells. The expression levels of DNA damage markers H2AX and P21 were analyzed by qRT-PCR. The expression of KDM4A and H3K36me3 was observed by western blot. The expression of KDM4A was regulated by siRNA or plasmid transfection. The effect of KDM4A on DNA damage induced by cantharidin in liver cancer was observed after overexpression and addiction of KDM4A. Results: Cantharidin can significantly inhibit the growth of hepatocellular carcinoma cells and induce apoptosis of hepatocellular carcinoma cells. Cantharidin enhances the chemotherapy sensitivity of liver cancer by targeting the upregulation of KDM4A and the regulation of DNA damage induced by H3K36me3. Overexpression of KDM4A enhances DNA damage induced by cantharidin in HCC. KDM4A silencing attenuated the damage of cantharidin to the DNA of HCC cells. Conclusion: Cantharidin can inhibit the growth and promote apoptosis of hepatocellular carcinoma cells. Meanwhile, cantharidin can induce DNA damage in HCC cells. Mechanism studies have shown that cantharidin induces DNA damage through the demethylation of KDM4A-dependent histone H3K36.

Synapse differentiation-induced gene 1 regulates stress-induced depression through interaction with the AMPA receptor GluA2 subunit of nucleus accumbens in male mice.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are key regulators during the process of synaptic plasticity in major depression disorder (MDD). Synapse differentiation-induced gene 1 (SynDIG1) functions as an atypical AMPAR auxiliary subunit and regulates synaptic AMPAR content; however, the role of SynDIG1 in MDD remains elusive. In this study, we found that the SynDIG1 expression was significantly increased in the neurons of the nucleus accumbens (NAc) of male mice after chronic social defeat stress (CSDS). CSDS enhanced SynDIG1-GluA2 binding and promoted the surface expression of AMPAR subunit GluA2 in the NAc. Knockdown of SynDIG1 decreased the surface expression of GluA2 and reversed the alteration of dendrite spines in the neurons, eventually alleviating the depressive-like behaviors of the stressed mice. Moreover, intra-NAc injection of IP12, a specific peptide to disrupt the interaction of SynDIG1 with GluA2, rescued depressive-like behaviors. Collectively, SynDIG1 regulates the surface expression of GluA2 and dendritic remodeling in the NAc of male mice under CSDS, thus mediating the depressive-like behaviors.

Canine osteosarcoma cells exhibit basal accumulation of multiple chaperone proteins and are sensitive to small molecule inhibitors of GRP78 and heat shock protein function.

Osteosarcoma is the most common type of bone cancer in dogs and humans, with significant numbers of patients experiencing treatment failure and disease progression. In our search for new approaches to treat osteosarcoma, we previously detected multiple chaperone proteins in the surface-exposed proteome of canine osteosarcoma cells. In the present study, we characterized expression of representative chaperones and find evidence for stress adaptation in canine osteosarcoma cells relative to osteogenic progenitors from normal bone. We compared the cytotoxic potential of direct (HA15) and putative (OSU-03012) inhibitors of Grp78 function and found canine POS and HMPOS osteosarcoma cells to be more sensitive to both compounds than normal cells. HA15 and OSU-03012 increased the thermal stability of Grp78 in intact POS cells at low micromolar concentrations, but each induced distinct patterns in Grp78 expression without significant change in Grp94. Both inhibitors were as effective alone as carboplatin and showed little evidence of synergy in combination treatment. However, HMPOS cells with acquired resistance to carboplatin were sensitive to inhibition of Grp78 (by HA15; OSU-03012), Hsp70 (by VER-155008), and Hsp90 (by 17-AAG) function. These results suggest that multiple nodes within the osteosarcoma chaperome may be relevant chemotherapeutic targets against platinum resistance.

mTOR regulates cocaine-induced behavioural sensitization through the SynDIG1-GluA2 interaction in the nucleus accumbens.

Behavioral sensitization is a progressive increase in locomotor or stereotypic behaviours in response to drugs. It is believed to contribute to the reinforcing properties of drugs and to play an important role in relapse after cessation of drug abuse. However, the mechanism underlying this behaviour remains poorly understood. In this study, we showed that mTOR signaling was activated during the expression of behavioral sensitization to cocaine and that intraperitoneal or intra-nucleus accumbens (NAc) treatment with rapamycin, a specific mTOR inhibitor, attenuated cocaine-induced behavioural sensitization. Cocaine significantly modified brain lipid profiles in the NAc of cocaine-sensitized mice and markedly elevated the levels of phosphatidylinositol-4-monophosphates (PIPs), including PIP, PIP2, and PIP3. The behavioural effect of cocaine was attenuated by intra-NAc administration of LY294002, an AKT-specific inhibitor, suggesting that PIPs may contribute to mTOR activation in response to cocaine. An RNA-sequencing analysis of the downstream effectors of mTOR signalling revealed that cocaine significantly decreased the expression of SynDIG1, a known substrate of mTOR signalling, and decreased the surface expression of GluA2. In contrast, AAV-mediated SynDIG1 overexpression in NAc attenuated intracellular GluA2 internalization by promoting the SynDIG1-GluA2 interaction, thus maintaining GluA2 surface expression and repressing cocaine-induced behaviours. In conclusion, NAc SynDIG1 may play a negative regulatory role in cocaine-induced behavioural sensitization by regulating synaptic surface expression of GluA2.

Lipidomics Reveals Dysregulated Glycerophospholipid Metabolism in the Corpus Striatum of Mice Treated with Cefepime.

Cefepime exhibits a broad spectrum of antimicrobial activity and thus is a widely used treatment for severe bacterial infections. Adverse effects on the central nervous system (CNS) have been reported in patients treated with cefepime. Current explanation for the adverse neurobehavioral effect of cefepime is mainly attributed to its ability to cross the blood-brain barrier and competitively bind to the GABAergic receptor; however, the underlying mechanism is largely unknown. In this study, mice were intraperitoneally administered 80 mg/kg cefepime for different periods, followed by neurobehavioral tests and a brain lipidomic analysis. LC/MS-MS-based metabolomics was used to investigate the effect of cefepime on the brain lipidomic profile and metabolic pathways. Repeated cefepime treatment time-dependently caused anxiety-like behaviors, which were accompanied by reduced locomotor activity in the open field test. Cefepime profoundly altered the lipid profile, acyl chain length, and unsaturation of fatty acids in the corpus striatum, and glycerophospholipids accounted for a large proportion of those significantly modified lipids. In addition, cefepime treatment caused obvious alteration in the lipid-enriched membrane structure, neurites, mitochondria, and synaptic vesicles of primary cultured striatal neurons; moreover, the spontaneous electrical activity of striatal neurons was significantly reduced. Collectively, cefepime reprograms glycerophospholipid metabolism in the corpus striatum, which may interfere with neuronal structure and activity, eventually leading to aberrant neurobehaviors in mice.

Simvastatin Blocks Reinstatement of Cocaine-induced Conditioned Place Preference in Male Mice with Brain Lipidome Remodeling.

Drug-associated reward memories are conducive to intense craving and often trigger relapse. Simvastatin has been shown to regulate lipids that are involved in memory formation but its influence on other cognitive processes is elusive. Here, we used a mass spectrometry-based lipidomic method to evaluate the impact of simvastatin on the mouse brain in a cocaine-induced reinstatement paradigm. We found that simvastatin blocked the reinstatement of cocaine-induced conditioned place preference (CPP) without affecting CPP acquisition. Specifically, only simvastatin administered during extinction prevented cocaine-primed reinstatement. Global lipidome analysis showed that the nucleus accumbens was the region with the greatest degree of change caused by simvastatin. The metabolism of fatty-acids, phospholipids, and triacylglycerol was profoundly affected. Simvastatin reversed most of the effects on phospholipids induced by cocaine. The correlation matrix showed that cocaine and simvastatin significantly reshaped the lipid metabolic pathways in specific brain regions. Furthermore, simvastatin almost reversed all changes in the fatty acyl profile and unsaturation caused by cocaine. In summary, pre-extinction treatment with simvastatin facilitates cocaine extinction and prevents cocaine relapse with brain lipidome remodeling.

Puerarin attenuates cadmium-induced hepatic lipid metabolism disorder by inhibiting oxidative stress and inflammation in mice.

Cadmium (Cd) is a common environmental pollutant with known toxic effects on the liver. Puerarin (PU), a natural flavonoid, has been shown to exert protective effect in numerous pathological processes. However, whether PU affords protection in Cd-induced liver damage is still equivocal. Therefore, 40 mice were treated with Cd and/or PU by gavage for 9 weeks, then the serum and liver samples were collected to verify this issue. In this study, Cd exposure triggered hepatic lipid metabolism disorders and resultant liver damage as evidenced by Oil Red O staining and total cholesterol (TC) and triglyceride (TG) levels in serum and liver, aspartate transaminase (AST) and alanine transaminase (ALT) levels in serum, and histopathology, which were significantly improved by PU. Moreover, PU also normalized the expression of Cd-disturbed lipid metabolism-related proteins to improve lipid accumulation, contributing to the alleviation of liver injury. Moreover, Cd-decreased antioxidative indices superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) as well as glutathione (GSH) in hepatic tissues were significantly attenuated by PU administration, while Cd-elevated hepatic malondialdehyde (MDA) and reactive oxygen species (ROS) levels were markedly down-regulated by PU treatment, demonstrating the antioxidant effect of PU against Cd exposure. In addition, PU supplementation increased the anti-inflammatory potential, and normalized the levels of proinflammatory cytokines during Cd exposure. In conclusion, these observations demonstrate that PU treatment decreases oxidative stress and inflammation response, which may contribute to prevent Cd-induced lipid metabolism disorder and consequent liver damage.

4R Tau Modulates Cocaine-Associated Memory through Adult Dorsal Hippocampal Neurogenesis.

The development, persistence and relapse of drug addiction require drug memory that generally develops with drug administration-paired contextual stimuli. Adult hippocampal neurogenesis (AHN) contributes to cocaine memory formation; however, the underlying mechanism remains unclear. Male mice hippocampal expression of Tau was significantly decreased during the cocaine-associated memory formation. Genetic overexpression of four microtubule-binding repeats Tau (4R Tau) in the mice hippocampus disrupted cocaine memory by suppressing AHN. Furthermore, 4R Tau directly interacted with phosphoinositide 3-kinase (PI3K)-p85 and impaired its nuclear translocation and PI3K-AKT signaling, processes required for hippocampal neuron proliferation. Collectively, 4R Tau modulates cocaine memory formation by disrupting AHN, suggesting a novel mechanism underlying cocaine memory formation and provide a new strategy for the treatment of cocaine addiction.SIGNIFICANCE STATEMENT Drug memory that generally develops with drug-paired contextual stimuli and drug administration is critical for the development, persistence and relapse of drug addiction. Previous studies have suggested that adult hippocampal neurogenesis (AHN) plays a role in cocaine memory formation. Here, we showed that Tau was significantly downregulated in the hippocampus in the cocaine memory formation. Tau knock-out (KO) promoted AHN in the hippocampal dentate gyrus (DG), resulting in the enhanced memory formation evoked by cocaine-cue stimuli. In contrast, genetically overexpressed 4R Tau in the hippocampus disrupted cocaine-cue memory by suppressing AHN. In addition, 4R Tau interacted directly with phosphoinositide 3-kinase (PI3K)-p85 and hindered its nuclear translocation, eventually repressing PI3K-AKT signaling, which is essential for hippocampal neuronal proliferation.

TASP1 Promotes Proliferation and Migration in Gastric Cancer via EMT and AKT/P-AKT Pathway.

Threonine aspartase 1 (TASP1) was reported to function in the development of cancer. However, the regulatory mechanism of TASP1 in gastric cancer (GC) remains unclear. In this study, we determined the expression of TASP1 in tissues of GC patients, GC cells by qRT-PCR, and western blot and assessed the relationship between TASP1 and GC cell proliferation and migration via CCK-8 and transwell assay. It was found that the expression of TASP1 in GC tissues or GC cell lines was significantly higher than that in normal adjacent tissues or normal cells. The proliferation and migration of GC cells were inhibited upon TASP1 knockdown. Mechanism investigation revealed that TASP1 promoted GC cell proliferation and migration through upregulating the p-AKT/AKT expression. TASP1 induced GC cell migration via the epithelial -mesenchymal transition (EMT) pathway. In conclusion, TASP1 promotes GC progression through the EMT and AKT/p-AKT pathway, and it may serve as a new potential biomarker and therapeutic target for GC.