Paraventricular thalamus to nucleus accumbens circuit activation decreases long-term relapse of alcohol-seeking behaviour in male mice.

BACKGROUND: Some studies have highlighted the crucial role of aversion in addiction treatment. The pathway from the anterior paraventricular thalamus (PVT) to the shell of the nucleus accumbens (NAc) has been reported as an essential regulatory pathway for processing aversion and is also closely associated with substance addiction. However, its impact on alcohol addiction has been relatively underexplored. Therefore, this study focused on the role of the PVT-NAc pathway in the formation and relapse of alcohol addiction-like behaviour, offering a new perspective on the mechanisms of alcohol addiction. RESULTS: The chemogenetic inhibition of the PVT-NAc pathway in male mice resulted in a notable decrease in the establishment of ethanol-induced conditioned place aversion (CPA), and NAc-projecting PVT neurons were recruited due to aversive effects. Conversely, activation of the PVT-NAc pathway considerably impeded the formation of ethanol-induced conditioned place preference (CPP). Furthermore, during the memory reconsolidation phase, activation of this pathway effectively disrupted the animals' preference for alcohol-associated contexts. Whether it was administered urgently 24 h later or after a long-term withdrawal of 10 days, a low dose of alcohol could still not induce the reinstatement of ethanol-induced CPP. CONCLUSIONS: Our results demonstrated PVT-NAc circuit processing aversion, which may be one of the neurobiological mechanisms underlying aversive counterconditioning, and highlighted potential targets for inhibiting the development of alcohol addiction-like behaviour and relapse after long-term withdrawal.

Phosphodiesterase 4 Inhibitor Roflupram Suppresses Inflammatory Responses Using Reducing Inflammasome in Microglia After Spinal Cord Injury.

Context: Neuroinflammation after spinal cord injury (SCI) can lead to long-term damage in neural tissue, which can cause the destruction and dysfunction of the neurological system. Roflupram (ROF), a selective phosphodiesterase 4 inhibitor, may play a protective role against neuropathological diseases, but the specific role of ROF in SCI treatment is unknown. Objective: The study intended to investigate the anti-inflammatory mechanism and therapeutic effects of ROF to determine if it can attenuate lipopolysaccharide (LPS)-induced microglia that induces neuroinflammation and decrease neural-tissue damage following an SCI. Design: The research team performed an animal study. Setting: The study took place at the Fourth Affiliated Hospital of Harbin Medical University in Harbin, China. Animals: The animals were female C57BL/6 mice, aged 8 weeks and weighing approximately 20 g. Intervention: For the in-vitro study, the research team divided BV2 microglial cells into three groups: (1) the control group, which received no LPS stimuli and no ROF treatment, (2) the LPS group, which received LPS stimuli but no ROF treatment, and (3) LPS+ROF group, which received both LPS stimuli and ROF treatment. For the in-vivo study, the research team randomly divided the mice into three groups: (1) the sham group, for which the team didn't induce SCI and which received no ROF treatment (2) the SCI group, for which the team induced SCI but which received no ROF treatment, and (3) the SCI+ROF group, for which the team induced SCI and which received the ROF treatment. Outcome Measures: The research team evaluated: (1) the cell viability of the BV2 microglia cells after five doses of ROF and the RNA levels of inflammatory-activation-related factors, the inflammatory pathway; (2) in-vitro inhibition of inflammation in LPS-activated microglia; (3) the anti-neuroinflammatory role of ROF after SCI induction in vitro; and (4) the role of ROF in neural-structure protection and locomotor-function recovery in vitro. Results: In the in-vitro study, the ROF attenuated microglial inflammation through the inhibition of the NLRP3 inflammasome in vitro, reduced neuroinflammation, and protected against neuronal loss. In the in-vivo study with mice, the ROF: (1) improved the functional recovery of locomotor skills after induction of SCI; (2) acted in an anti-inflammatory role in SCI, restraining microglial inflammation by inhibition of the "nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3" (NLRP3) inflammasome and reduction of caspase-1-dependent, interleukin-1 beta (IL)-1ß; and (3) reduced neuronal death and protected against tissue loss, improving functional recovery after an SCI. Conclusions: The current study demonstrated that ROF can reduce the levels of inflammation in the tissue after spinal cord injury by modulating the AMPK/NLRP3 signaling pathway, thereby promoting the recovery of motor function in mice. ROF is a promising drug for prevention of neural-tissue damage following neural injury.

Zileuton Ameliorates Neuronal Ferroptosis and Functional Recovery After Spinal Cord Injury.

Context: Ferroptosis is a novel type of cell-death pattern characterized by iron-dependent, oxidative stress, and lipid peroxidation. Neurological pathology, especially in spinal cord injury (SCI), may involve a trace amount of ferroptosis. However, it's uncertain whether zileuton (ZIL), a selective 5-lipoxygenase (5-LO) inhibitor, can inhibit ferroptosis in SCI. Objective: The study intended to investigate the etiology of neuronal ferroptosis and the ameliorative effects of ZIL against it for SCI mice. Design: The research team performed an animal study. Setting: The study took place at the Fourth Affiliated Hospital of Harbin Medical University in Harbin, China. Animals: The animals were adult, male, C57BL/6 mice, about 20 to 25 g in weight. Intervention: The research team: (1) stimulated HT22 cells, an immortalized mouse hippocampal neuronal cell line treated with erastin, and mice induced spinal cord trauma using a moderate hit, and (2) treated the cells and mice with ZIL. Outcome measures: The research team measured: (1) motor function, (2) neurological damage, (3) iron content, (4) lipid oxidation, and (5) neuroinflammation and glial response. Results: ZIL administration attenuated ferroptosis and lipid peroxidation in the HT22 cells. Moreover, ZIL mitigated the ferroptosis and inflammation in the injured spinal cords. Hence, ZIL can decrease neurological damage and improve recovery of motor function, indicating an ameliorative role for ZIL in SCI. Conclusions: ZIL has anti-ferroptosis and anti-oxidative effects in neurons, which can contribute to recovery of motor function after induction of SCI. ZIL is a promising drug for inhibiting ferroptosis and protecting neurological functions after induction of SCI.

Indocyanine green derived carbon dots with significantly enhanced properties for efficient photothermal therapy.

A simple yet effective strategy to enhance the properties of traditional dye indocyanine green (ICG) in all aspects was proposed and demonstrated. Specifically, indocyanine green-derived carbon dots (ICGCDs) were synthesized from ICG via a simple hydrothermal treatment. The ICGCDs exhibited significantly enhanced thermal stability and anti-photobleaching compared to ICG. Furthermore, their photothermal properties were also notably strengthened, in which a wider functional pH range, 50% improvement in photothermal conversion efficiency and superior photothermal cyclability were achieved. Thanks to these superior properties, ICGCDs were demonstrated as efficient NIR bioimaging and photothermal agents in both in vitro and in vivo experiments. Most excitingly, the strategy demonstrated in this study is likely to have broad applications in other systems.

Green tea derivative (-)-epigallocatechin-3-gallate (EGCG) confers protection against ionizing radiation-induced intestinal epithelial cell death both in vitro and in vivo.

Radiation-induced intestinal injury (RIII) occurs during instances of intentional or accidental radiation exposure. However, there are few effective treatments available for the prevention or mitigation of RIII currently. (-)-Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, possesses potent antioxidant activity and has been shown to be effective in ameliorating many oxidative stress-related diseases. The therapeutic effects and mechanism of EGCG on RIII have not yet been determined. In the present study, we investigated whether EGCG confers radioprotection against RIII. Our data demonstrated that administration of EGCG not only prolonged the survival time of lethally irradiated mice, but also reduced radiation-induced intestinal mucosal injury. Treatment with EGCG significantly increased the number of Lgr5+ intestinal stem cells (ISCs) and their progeny Ki67+ cells, and reduced radiation-induced DNA damage and apoptosis. Besides, EGCG displayed the same radioprotective effects in human intestinal epithelial HIEC cells as in mice, characterized by a decrease in the number of γH2AX foci and ferroptosis. Moreover, EGCG decreased the level of reactive oxygen species (ROS) and activated the transcription factor Nrf2 and its downstream targets comprising antioxidant proteins Slc7A11, HO-1 and GPX4. Treatment with the Nrf2 inhibitor ML385 abolished the protective effects of EGCG, indicating that Nrf2 activation is essential for EGCG activity. Taken together, our findings demonstrated that EGCG protects against RIII by scavenging ROS and inhibiting apoptosis and ferroptosis through the Nrf2 signal pathway, which could be a promising medical countermeasure for the alleviation of RIII.