KCTD proteins regulate morphine dependence via heterologous sensitization of adenylyl cyclase 1 in mice.

Heterologous sensitization of adenylyl cyclase (AC) results in elevated cAMP signaling transduction that contributes to drug dependence. Inhibiting cullin3-RING ligases by blocking the neddylation of cullin3 abolishes heterologous sensitization, however, the modulating mechanism remains uncharted. Here, we report an essential role of the potassium channel tetramerization domain (KCTD) protein 2, 5, and 17, especially the dominant isoform KCTD5 in regulating heterologous sensitization of AC1 and morphine dependence via working with cullin3 and the cullin-associated and neddylation-dissociated 1 (CAND1) protein.

Hypoxia-inducible factor upregulation by roxadustat attenuates drug reward by altering brain iron homoeostasis.

Substance use disorder remains a major challenge, with an enduring need to identify and evaluate new, translational targets for effective treatment. Here, we report the upregulation of Hypoxia-inducible factor-1α (HIF-1α) expression by roxadustat (Rox), a drug developed for renal anemia that inhibits HIF prolyl hydroxylase to prevent degradation of HIF-1α, administered either systemically or locally into selected brain regions, suppressed morphine (Mor)-induced conditioned place preference (CPP). A similar effect was observed with methamphetamine (METH).

Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke.

Efferocytosis of apoptotic neurons by macrophages is essential for the resolution of inflammation and for neuronal protection from secondary damage. It is known that alteration of the Sigma-1 receptor (Sig-1R) is involved in the pathological development of some neurological diseases, including ischemic stroke. The present study aimed to investigate whether and how Sig-1R regulates the phagocytic activity of macrophages/microglia and its significance in neuroprotection and neurological function in stroke.

Structural optimizations and bioevaluation of N-H aporphine analogues as G-biased and selective serotonin 5-HT receptor agonists.

The concept of subtype selectivity and functional bias has recently reshaped current GPCR drug discovery for G protein-coupled receptors. A series of new N-H aporphines with A-ring modifications have been synthesized, and their efficacy on 5-HT receptor activation was evaluated. SAR analysis led to the discovery of several more potent and selective 5-HT receptor agonists (e.

Dopamine D1 receptors mediate methamphetamine-induced dopaminergic damage: involvement of autophagy regulation via the AMPK/FOXO3A pathway.

Rationale: Clinical studies have revealed that methamphetamine abuse increases risk for developing Parkinson's diseases. It is thus important to elucidate the mechanisms by which methamphetamine damages dopaminergic neurons.

Objectives: The present study was designed to elucidate the role of the dopamine D1 receptor in methamphetamine-mediated dopaminergic neuronal damage and its underlying mechanisms.

Early glycolytic reprogramming controls microglial inflammatory activation.

Background: Microglial activation-mediated neuroinflammation plays an important role in the progression of neurodegenerative diseases. Inflammatory activation of microglial cells is often accompanied by a metabolic switch from oxidative phosphorylation to aerobic glycolysis. However, the roles and molecular mechanisms of glycolysis in microglial activation and neuroinflammation are not yet fully understood.

Knockdown of milk-fat globule EGF factor-8 suppresses glioma progression in GL261 glioma cells by repressing microglial M2 polarization.

Tumor-associated microglial cells promote glioma growth, invasion, and chemoresistance by releasing inflammatory factors. Milk fat globule EGF factor 8 protein (MFG-E8), a secreted glycoprotein, is closely related to tissue homeostasis and anti-inflammation. In the present study, we investigated the role of MFG-E8 in microglial polarization and glioma progression in vitro and in vivo.

The oncometabolite 2-hydroxyglutarate inhibits microglial activation via the AMPK/mTOR/NF-κB pathway.

Microglia, the brain-resident macrophage, is known as the innate immune cell type in the central nervous system. Microglia is also the major cellular component of tumor mass of gliomas that plays a key role in glioma development. Mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) frequently occur in gliomas, which leads to accumulation of oncometabolic product 2-hydroxyglutarate (2HG).

Macrophage migration inhibitory factor (MIF) inhibitor, Z-590 suppresses cartilage destruction in adjuvant-induced arthritis via inhibition of macrophage inflammatory activation.

Background: Macrophage migration inhibitory factor (MIF) is a pleiotropic pro-inflammatory mediator that is involved in the progression of rheumatoid arthritis (RA). Previously, we demonstrated a small molecule compound 3-[(biphenyl-4-ylcarbonyl) carbamothioyl] amino benzoic acid (Z-590) could inhibit MIF activity with docking-based virtual screening and experimental evaluation.

Methods: The LPS activated RAW264.

Dihydromyricetin exerts a rapid antidepressant-like effect in association with enhancement of BDNF expression and inhibition of neuroinflammation.

Rationale: Major depressive disorder (MDD) is a highly prevalent illness that affects large populations across the world, and increasing evidence suggests that neuroinflammation and levels of brain-derived neurotrophic factor (BDNF) are closely related to depression. Dihydromyricetin (DHM) is a kind of flavonoid natural product that has been reported to display multiple pharmacological effects, including anti-inflammatory and anti-oxidative properties, and these may contribute to ameliorate MDD.

Objective: This study investigated the effect of DHM on depression-related phenotypes in various experimental animal models.

Clk1-regulated aerobic glycolysis is involved in glioma chemoresistance.

Chemoresistance remains a major challenge for the treatment of glioma. In this study, we investigated the role of Clock 1 (Clk1), which encodes an enzyme that is necessary for ubiquinone biosynthesis in glioma chemoresistance in vitro. The results showed that Clk1 was highly expressed in GL261 mouse glioma cells which were most sensitive to 1,3Bis (2-chloroethyl) 1 nitrosourea (BCNU) while was low expressed in BCNU resistant cells such as glioma cancer stem cells, T98G, U87MG and U251 glioma cells.

Elevated NO emission by the rice roots: based on the abundances of narG and bacterial amoA genes.

Rice fields are an important source of nitrous oxide (NO), where rice plants could act as a key factor controlling NO fluxes during the flooding-drying process; however, the microbial driving mechanisms are unclear. In this study, specially designed equipment was used to grow rice plants and collect emitted NO from the root-growing zone (zone A), root-free zones (zones B, C, and D) independently, at tillering and booting stages under flooding and drying conditions. Soil samples from the four zones were also taken separately.

Sensitive and selective detection of Ag+ in aqueous solutions using Fe3O4@Au nanoparticles as smart electrochemical nanosensors.

Owing to the selective deposition reaction on the surface of magnetic nanoparticles, we reported a simple and selective magnetic electrochemical method for the detection of Ag(+) ions in aqueous solutions. The analyte deposited on the nanoparticles was brought to the surface of a homemade magnetic electrode and detected electrochemically in 0.1 mol/L KCl solution based on the reaction of Ag0 transferred to AgCl.

Asymmetric total synthesis and identification of tetrahydroprotoberberine derivatives as new antipsychotic agents possessing a dopamine D(1), D(2) and serotonin 5-HT(1A) multi-action profile.

An effective and rapid method for the microwave-assisted preparation of the key intermediate for the total synthesis of tetrahydroprotoberberines (THPBs) including l-stepholidine (l-SPD) was developed. Thirty-one THPB derivatives with diverse substituents on A and D ring were synthesized, and their binding affinity to dopamine D(1), D(2) and serotonin 5-HT(1A) and 5-HT(2A) receptors were determined. Compounds 18k and 18m were identified as partial agonists at the D(1) receptor with K(i) values of 50 and 6.

Magnetic beads-based enzymatic spectrofluorometric assay for rapid and sensitive detection of antibody against ApxIVA of Actinobacillus pleuropneumoniae.

In this paper, a simple, easily-operated and enzyme-amplified fluorescence immunoassay method using magnetic particles for the detection of antibody against Actinobacillus pleuropneumoniae (APP) has been presented. The A protein of APP Repeats-in-Toxin IV (ApxIVA) with high specificity to the APP species was immobilized onto the magnetic bead surfaces. Horseradish peroxidase (HRP), which can catalyze the substrate 4-hydroxyphenylacetic acid (p-HPA), generating fluorescent bi-p, p'-hydroxyphenylacetic acid (DBDA), was selected as an enzymatic-amplified tracer.

RPB5-mediating protein is required for the proliferation of hepatocellular carcinoma cells.

RPB5-mediating protein (RMP) is associated with the RNA polymerase II subunit RPB5. RMP functionally counteracts the transcriptional activation of hepatitis B virus X protein that has been shown to play a role in the development of hepatocellular carcinoma (HCC). However, the effect of RMP on the growth of HCC remains unclear.

[Growth inhibition and mechanisms of human bladder cancer T24 cells by adenovirus-mediated ING4 gene in vitro].

Objective: To explore the inhibitory effect and anti-cancer mechanisms of adenovirus-mediated ING4 gene on the human bladder cancer T24 cells in vitro.

Methods: The methods of reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect the expression of ING4 in human bladder urothelial carcinoma T24 line. The influence of Ad-ING4 transfection on cell proliferation was evaluated by MTT assay and cell apoptosis by Hochest33258 staining and flow cytometry.

[In vitro and in vivo inhibitory effect of Ad-ING4 gene on proliferation of human prostate cancer PC-3 cells].

Background And Objective: Adenovirus vector has been widely used in tumor gene therapy. ING4 is a member of growth inhibiting factors and a potent anti-tumor gene which could induce apoptosis of many tumor cells. This study was to investigate the inhibitory effects of adenovirus-mediated ING4 (Ad-ING4) gene on the proliferation of human prostate cancer PC-3 cells in vitro and in vivo, and to explore its mechanisms.

Human Elongator complex is involved in cell cycle and suppresses cell growth in 293T human embryonic kidney cells.

Elongator complex has been associated with hyperphosphorylated RNA polymerase II and is known to play critical roles in transcriptional elongation, as well as in tRNA modification and exocytosis. However, the specific mechanism of how human Elongator complex regulates cell growth and cell cycle remains unclear. To investigate the composition of human Elongator complex and its effects on cell growth, 293T cells were established that stably overexpressed Flag-Elp3 and Flag-Elp4.