Treatment of manganese and lead poisoning with sodium para-aminosalicylic acid: A contemporary update.

Sodium para-aminosalicylic acid (PAS-Na) treatment for manganese (Mn) intoxication has shown efficacy in experimental and clinical studies, giving rise to additional studies on its efficacy for lead (Pb) neurotoxicity and its associated mechanisms of neuroprotection. The difference between PAS-Na and other metal complexing agents, such as edetate calcium sodium (CaNa2-EDTA), is firstly that PAS-Na can readily pass through the blood-brain barrier (BBB), and complex and facilitate the excretion of manganese and lead. Secondly, PAS-Na has anti-inflammatory effects. Recent studies have broadened the understanding on the mechanisms associated with efficacy of PAS-Na. The latter has been shown to modulate multifarious manganese- and lead- induced neurotoxicity, via its anti-apoptotic and anti-inflammatory effects, as well as its ability to inhibit pyroptosis, and regulate abnormal autophagic processes. These observations provide novel scientific bases and new concepts for the treatment of lead, mercury, copper, thallium, as well as other toxic encephalopathies, and implicate PAS-Na as a compound with greater prospects for clinical medical application.

Attenuated neural activity in processing decision-making feedback in uncertain conditions in patients with mild cognitive impairment.

The present study aimed to explore the potential neural correlates during feedback evaluation during decision-making under risk and ambiguity in MCI. Nineteen individuals with MCI and twenty age-matched HCs were enrolled. Decision-making performance under risk and ambiguity was examined with the modified game of dice task (GDT) and an Iowa gambling task (IGT). Using task-related EEG data, reward positivity (RewP) and feedback P3 (fb-P3) were used to characterize participants' motivation and allocation of cognitive resources. Also, response time and event-related oscillation (ERO) were used to evaluate information processing speed, and the potent of post-feedback information integration and behavioral modulation. MCI patients had lower RewP (p = 0.022) and fb-P3 (p = 0.045) amplitudes in the GDT than HCs. Moreover, the amount and valence of feedback modulated the RewP (p = 0.008; p = 0.017) and fb-P3 (p < 0.001; p < 0.001). In the IGT, in addition to the significantly reduced fb-P3 observed in MCI patients (p = 0.010), the amount and valence of feedback modulated the RewP (p = 0.002; p = 0.020). Furthermore, MCI patients took longer to make decisions (t = 2.15, p = 0.041). The ERO analysis revealed that delta power was reduced in MCI (GDT: p = 0.045; p = 0.011). The findings suggest that, during feedback evaluation when making risky and ambiguous decisions, motivation, allocation of cognitive resources, information processing and neuronal excitability were attenuated in MCI. It implies that neural activity related to decision making was compromised in MCI.

Music training influences online temporal order processing during reading comprehension.

Numerous studies have demonstrated the influence of musical expertise on spoken language processing; however, its effects on reading comprehension remain largely unexplored. This study aims to investigate the role of musical expertise in sentence comprehension, particularly concerning the processing of temporal order. Using two self-paced reading experiments, we examined individuals' responses to two-clause sentences connected by the temporal connectives "before" or "after". "After" sentences consistently presented events in their actual order of temporal occurrence, while "before" sentences described events in reverse temporal order. In both experiments, our analyses of reading times consistently uncovered a significant temporal order effect, with words immediately following the temporal connectives being processed slower in "before" sentences compared to "after" sentences. This suggests the presence of immediate online processing costs associated with "before" sentences. Notably, these processing costs were found to be attenuated in individuals with musical expertise compared to those without. However, analyses of comprehension accuracy showed no advantage of musicians over non-musicians. Specifically, in Experiment 1, the two groups showed no difference in comprehension accuracy, while in Experiment 2, musicians exhibited lower accuracy rates compared to non-musicians in both "before" and "after" sentences. These results suggest that musical expertise may attenuate online processing costs associated with complex linguistic constructs, but could not promote reading accuracy. We concluded that music training is associated with a restricted effect on written sentence comprehension.

Sodium para-aminosalicylic acid attenuates combined manganese/iron-induced cortical synaptic damage in rats.

We established experimental models of manganese (Mn) and iron (Fe) exposure in vitro and in vivo, and addressed the effects of manganese and iron combined exposure on the synaptic function of pheochromocytoma derived cell line 12 (PC12) cells and rat cortex, respectively. We investigated the protective effect of sodium para-aminosalicylate (PAS-Na) on manganese and iron combined neurotoxicity, providing a scientific basis for the prevention and treatment of ferromanganese combined neurotoxicity. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to detect the expression levels of protein and mRNA related to synaptic damage. Y-maze novelty test and balance beam test were used to evaluate the motor and cognitive function of rats. Haematoxylin and eosin (H&E) and Nissl staining were performed to observe the cortical damage of rats. The results showed that the combined exposure of Mn and Fe in rats led to a synergistic effect, attenuating growth and development, and altering learning and memory as well as motor function. The combination of Mn and Fe also caused damage to the synaptic structure of PC12 cells, which is manifested as swelling of dendrites and axon terminals, and even lead to cell death. PAS-Na displayed some antagonistic effects against the Mn- and Fe-induced synaptic structural damage, growth, learning and memory impairment.

Veliparib exerts protective effects in intracerebral hemorrhage mice by inhibiting the inflammatory response and accelerating hematoma resolution.

Poly (ADP-ribose) polymerase (PARP) inhibitors have potent anti-inflammatory effects, including the suppression of brain microglial activation. Veliparib, a well-known PARP1/2 inhibitor, exhibits particularly high brain penetration, but its effects on stroke outcome is unknown. Here, the effects of veliparib on the short-term outcome of intracerebral hemorrhage (ICH), the most lethal type of stroke, were investigated. Collagenase-induced mice ICH model was applied, and the T2-weighted magnetic resonance imaging was performed to evaluate lesion volume. Motor function and hematoma volume were also measured. We further performed immunofluorescence, enzyme linked immunosorbent assay, flow cytometry, and blood-brain barrier assessment to explore the potential mechanisms. Our results demonstrated veliparib reduced the ICH lesion volume dose-dependently and at a dosage of 5 mg/kg, veliparib significantly improved mouse motor function and promoted hematoma resolution at days 3 and 7 post-ICH. Veliparib inhibited glial activation and downregulated the production of pro-inflammatory cytokines. Veliparib significantly decreased microglia counts and inhibited peripheral immune cell infiltration into the brain on day 3 after ICH. Veliparib improved blood-brain barrier integrity at day 3 after ICH. These findings demonstrate that veliparib improves ICH outcome by inhibiting inflammatory responses and may represent a promising novel therapy for ICH.

Determination of 90Sr and 210Pb in food samples by liquid scintillation counting after sequential separation with an extraction chromatographic column.

90Sr and 210Pb are considered to be key radionuclides in internal exposure resulting from dietary intake, however, the established methods employed for their detection are time-comsuming. A method for the sequential separation of 90Sr and 210Pb using a Sr·spec resin by LSC measurement is developed, which is highly suitable for food safety monitoring as its minimal sample requirements. The sequential separation of Sr and Pb from the sample was using 0.05 mol/L HNO3 and 0.05 mol/L C6H5O7(NH4)3. The chemical recoveries of Sr and Pb measured using ICP-OES were 72-83% and 80-88%, respectively. The minimum detectable activities of 90Sr and 210Pb in the food sample were 36.2 mBq/kg and 28.6 mBq/kg, respectively, obtained from a 0.1 kg fresh sample and 300 min counting time. The method was validated using reference materials and compared with other methods. The feasibility of the developed method for other highly complex food matrices needs further investigation.

Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.

Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

PGC-1α in the hippocampus mediates depressive-like and stress-coping behaviours and regulates excitatory synapses in the dentate gyrus in mice.

Decreased hippocampal synaptic plasticity is an important pathological change in stress-related mood disorders, including major depressive disorder. However, the underlying mechanism is unclear. PGC-1α, a transcriptional coactivator, is a key factor in synaptic plasticity. We investigated the relationships between changes in hippocampal PGC-1α expression and depressive-like and stress-coping behaviours, and whether they are related to hippocampal synapses. Adeno-associated virus was used to alter hippocampal PGC-1α expression in male C57BL/6 mice. The sucrose preference test and forced swimming test were used to assess their depressive-like and stress-coping behaviours, respectively. Immunohistochemistry and stereology were used to calculate the total number of excitatory synapses in each hippocampal subregion (the cornu ammonis (CA) 1, CA3, and dentate gyrus). Immunofluorescence was used to visualize the changes in dendritic structure. Western blotting was used to detect the expression of hippocampal PGC-1α and mitochondrial-associated proteins, such as UCP2, NRF1 and mtTFAs. Our results showed that mice with downregulated PGC-1α expression in the hippocampus exhibited depressive-like and passive stress-coping behaviours, while mice with upregulated PGC-1α in the hippocampus exhibited increased stress-coping behaviours. Moreover, the downregulation of hippocampal PGC-1α expression resulted in a decrease in the number of excitatory synapses in the DG and in the protein expression of UCP2 in the hippocampus. Alternatively, upregulation of hippocampal PGC-1α yielded the opposite results. This suggests that hippocampal PGC-1α is involved in regulating depressive-like and stress-coping behaviours and modulating the number of excitatory synapses in the DG. This provides new insight for the development of antidepressants.

P2X7 receptor antagonists modulate experimental autoimmune neuritis via regulation of NLRP3 inflammasome activation and Th17 and Th1 cell differentiation.

BACKGROUND: Guillain-Barré syndrome (GBS), a post-infectious, immune-mediated, acute demyelinating disease of the peripheral nerves and nerve roots, represents the most prevalent and severe acute paralyzing neuropathy. Purinergic P2X7 receptors (P2X7R) play a crucial role in central nervous system inflammation. However, little is known about their role in the immune-inflammatory response within the peripheral nervous system. METHODS: Initially, we assessed the expression of purinergic P2X7R in the peripheral blood of patients with GBS using flow cytometry and qRT-PCR. Next, we explored the expression of P2 X7R in CD4+ T cells, CD8+ T cells, and macrophages within the sciatic nerves and spleens of rats using immunofluorescence labeling and flow cytometry. The P2X7R antagonist brilliant blue G (BBG) was employed to examine its therapeutic impact on rats with experimental autoimmune neuritis (EAN) induced by immunization with the P0180 - 199 peptide. We analyzed CD4+ T cell differentiation in splenic mononuclear cells using flow cytometry, assessed Th17 cell differentiation in the sciatic nerve through immunofluorescence staining, and examined the expression of pro-inflammatory cytokine mRNA using RT-PCR. Additionally, we performed protein blotting to assess the expression of P2X7R and NLRP3-related inflammatory proteins within the sciatic nerve. Lastly, we utilized flow cytometry and immunofluorescence labeling to examine the expression of NLRP3 on CD4+ T cells in rats with EAN. RESULTS: P2X7R expression was elevated not only in the peripheral blood of patients with GBS but also in rats with EAN. In rats with EAN, inhibiting P2X7R with BBG alleviated neurological symptoms, reduced demyelination, decreased inflammatory cell infiltration of the peripheral nerves, and improved nerve conduction. BBG also limited the production of pro-inflammatory molecules, down-regulated the expression of P2X7R and NLRP3, and suppressed the differentiation of Th1 and Th17 cells, thus protecting against EAN. These effects collectively contribute to modifying the inflammatory environment and enhancing outcomes in EAN rats. CONCLUSIONS: Suppression of P2X7R relieved EAN manifestation by regulating CD4+ T cell differentiation and NLRP3 inflammasome activation. This finding underscores the potential significance of P2X7R as a target for anti-inflammatory treatments, advancing research and management of GBS.

Statistical methods for assessing the effects of de novo variants on birth defects.

With the development of next-generation sequencing technology, de novo variants (DNVs) with deleterious effects can be identified and investigated for their effects on birth defects such as congenital heart disease (CHD). However, statistical power is still limited for such studies because of the small sample size due to the high cost of recruiting and sequencing samples and the low occurrence of DNVs. DNV analysis is further complicated by genetic heterogeneity across diseased individuals. Therefore, it is critical to jointly analyze DNVs with other types of genomic/biological information to improve statistical power to identify genes associated with birth defects. In this review, we discuss the general workflow, recent developments in statistical methods, and future directions for DNV analysis.

Systematic characterization of protein structural features of alternative splicing isoforms using AlphaFold 2.

Alternative splicing is an important cellular process in eukaryotes, altering pre-mRNA to yield multiple protein isoforms from a single gene. However, our understanding of the impact of alternative splicing events on protein structures is currently constrained by a lack of sufficient protein structural data. To address this limitation, we employed AlphaFold 2, a cutting-edge protein structure prediction tool, to conduct a comprehensive analysis of alternative splicing for approximately 3,000 human genes, providing valuable insights into its impact on the protein structural. Our investigation employed state of the art high-performance computing infrastructure to systematically characterize structural features in alternatively spliced regions and identified changes in protein structure following alternative splicing events. Notably, we found that alternative splicing tends to alter the structure of residues primarily located in coils and beta-sheets. Our research highlighted a significant enrichment of loops and highly exposed residues within human alternatively spliced regions. Specifically, our examination of the Septin-9 protein revealed potential associations between loops and alternative splicing, providing insights into its evolutionary role. Furthermore, our analysis uncovered two missense mutations in the Tau protein that could influence alternative splicing, potentially contributing to the pathogenesis of Alzheimer's disease. In summary, our work, through a thorough statistical analysis of extensive protein structural data, sheds new light on the intricate relationship between alternative splicing, evolution, and human disease.

Construction of core-shell CoSe2/ZnIn2S4 heterostructures for efficient visible-light-driven photocatalytic hydrogen evolution.

The use of photocatalysts based on semiconductor heterostructures for hydrogen evolution is a prospective tactic for converting solar energy. Herein, visible-light-responsive three-dimensional core-shell CoSe2/ZnIn2S4 heterostructures were successfully fabricated via in situ growth of ZnIn2S4 ultrathin nanosheets on spherical CoSe2. Without any noble metal co-catalysts, the as-prepared CoSe2/ZnIn2S4 composite achieved attractive photocatalytic hydrogen evolution activity under visible light illumination. Optimal CoSe2/ZnIn2S4 achieved a hydrogen evolution rate of 2199 µmol g-1 h-1, which was 7 times higher than that of pristine ZnIn2S4 and even exceeded that of ZnIn2S4 loaded with platinum. In this distinctive core-shell heterostructure, the presence of CoSe2 could considerably improve the ability to harvest light, quicken the charge transfer kinetics, and avoid the agglomeration of ZnIn2S4 nanosheets. Meanwhile, the experimental results demonstrated that the strong interaction between CoSe2 and ZnIn2S4 at the compact interface could appropriately boost the photogenerated electron-hole pair migration and relieve charge recombination, thus improving photocatalytic hydrogen evolution activity. This work has bright prospects in constructing noble-metal-free core-shell heterostructures for solar energy conversion.

Effects of Manganese and Iron, Alone or in Combination, on Apoptosis in BV2 Cells.

The aim of study was to address the effects of manganese and iron, alone and in combination, on apoptosis of BV2 microglia cells, and to determine if combined exposure to these metals augments their individual toxicity. We used a murine microglial BV2 cell line. Cell cytotoxicity was analyzed by propidium iodide (PI) exclusion assay. Cell ROS production was analyzed by 2', 7'-dichlorofluorescin diacetate (DCFH-DA) probe staining. Pro-inflammatory cytokine production was monitored by ELISA. Cell apoptosis was analyzed by PE Annexin V/7-AAD staining. Mitochondrial membrane integrity was analyzed by flow cytometry. We used immunoblotting to analyze the effect of manganese, iron alone, or their combined exposure on the activation of caspase9, P53, Bax, and Bcl2 apoptosis signaling pathways. Caspase3 activity was determined using a Colorimetric. Manganese, iron, and their combined exposure for 24 h induced the activation of BV2 microglia cells and increased ROS production and the expression of the inflammatory cytokines, IL-1ß and TNF-α. And we also found that the apoptosis rate increased, mitochondrial membrane potential decreased, apoptosis-related proteins caspase9, P53, Bax, and Bcl2 expression increased, and caspase3 activity increased. Furthermore, we found that combined manganese-iron cytotoxicity was lower than that induced by manganese exposure alone. Manganese, iron alone, or their combination exposure can induce apoptosis in glial cells. Iron can reduce the toxicity of manganese, and there is an antagonistic effect between manganese and iron.

Antagonizing LINGO-1 reduces activated microglia and alleviates dendritic spine loss in the hippocampus of APP/PS1 transgenic mice.

In Alzheimer's disease (AD), microglia are involved in synaptic pruning and mediate synapse loss. LINGO-1 is a negative regulator of nerve growth, and whether antagonizing LINGO-1 can attenuate synaptic pruning by microglia and rescue dendritic spines in the hippocampus in AD is still unclear. On this basis, the anti-LINGO-1 antibody, which binds to LINGO-1 protein and antagonizes the effects of LINGO-1, was administered to 10-month-old APP/PS1 transgenic mice for 2 months. The Morris water maze test, immunohistochemical and stereological methods, immunofluorescence and 3D reconstruction were used. Compared to wild-type mice, APP/PS1 transgenic mice had worse performance on behavioral tests, fewer dendritic spines but more microglia in the hippocampus. Meanwhile, the microglia in APP/PS1 transgenic mice had more branches of medium length (4-6 µm) and a cell body area with greater variability. Moreover, APP/PS1 transgenic mice had more postsynaptic termini colocalized with microglia in the hippocampus than wild-type mice. The anti-LINGO-1 antibody significantly reversed these changes in AD, indicating that the anti-LINGO-1 antibody can improve hippocampus-dependent learning and memory abilities and effectively rescue dendritic spines in the hippocampus of AD mice and that microglia might participate in this progression in AD. These results provide a scientific basis for further studying the mechanism of the anti-LINGO-1 antibody in AD and help to elucidate the role of LINGO-1 in the treatment of AD.

In vitro and in vivo antimicrobial effects of domiphen combined with itraconazole against Aspergillus fumigatus.

Aspergillus fumigatus, a prevalent saprophytic fungus in the atmosphere, is known to rapidly induce severe invasive aspergillosis (IA) upon inhalation of its conidia by humans or animals. The mortality rate associated with IA exceeds 50%. The misuse of antifungal agents has contributed to the emergence of numerous highly pathogenic drug-resistant strains of A. fumigatus. Our study found that the combination of domiphen and itraconazole had sound synergistic antimicrobial effects against wild-type and itraconazole-resistant A. fumigatus in vivo and in vitro through MIC, FIC, plate inoculation, growth curve experiments, and Galleria mellonella infection model. Drug cytotoxicity and pharmacological tests for acute toxicity assays demonstrated that both itraconazole and domiphen showed minimal cytotoxicity and good biocompatibility. The transcriptome sequencing experiment demonstrated that domiphen exerted a suppressive effect on the expression of various genes, including those involved in drug efflux, redox regulation, and cellular membrane and cell wall remodeling. The present investigation explores the synergistic antimicrobial mechanisms of domiphen and itraconazole, encompassing three key aspects: (i) domiphen inhibited the efflux of itraconazole by reducing the expression of drug efflux-related genes, (ii) the combination has good ability to disrupt the cell membrane and cell wall, (iii) the combination also can remove biofilm more effectively. In summary, the utilization of domiphen as a synergist of itraconazole exhibited disruptive effects on the biofilm, cell wall, and cell membrane of A. fumigatus. This subsequently led to a modified distribution of itraconazole within the fungal organism, ultimately resulting in enhanced antifungal efficacy. The results of this study may provide a new therapeutic strategy for the treatment of IA caused by drug-resistant A. fumigatus.

MnOxHy-modified CoMoP/NF nanosheet arrays as hydrogen evolution reaction and oxygen evolution reaction bifunctional catalysts under alkaline conditions.

It is widely acknowledged that interface engineering strategies can significantly enhance the activity of catalysts. In this study, we developed a CoMoP nanoarray directly grown in situ on a nickel foam (NF) substrate, with the interface structure formed through the electrodeposition of MnOxHy. The resulting heterostructure MnOxHy/CoMoP/NF exhibited remarkable hydrogen evolution reaction (HER) activity, achieving overpotentials as low as 61 and 138 mV at 10 and 100 mA cm-2, respectively. Moreover, MnOxHy/CoMoP/NF demonstrated efficient oxygen evolution reaction (OER) activity with an overpotential of 330 mV at 100 mA cm-2. Remarkably, MnOxHy/CoMoP/NF maintained its catalytic properties and structural integrity even after working continuously for 20 h facilitating the HER at 10 mA cm-2 and the OER at 100 mA cm-2. The Tafel slopes of the HER and OER were determined to be as small as 14 and 55 mV dec-1, respectively, confirming that the coupled interface conferred fast reaction kinetics on the catalyst. When applied in overall water splitting, MnOxHy/CoMoP/NF delivered a voltage of 1.91 V at 100 mA cm-2 with excellent stability. This study demonstrated the feasibility of utilizing a simple electrodeposition technique to fabricate a heterogeneous structure with bifunctional catalytic activity, establishing a solid foundation for diverse industrial applications.

Green Synthesis of MOF-Mediated pH-Sensitive Nanomaterial AgNPs@ZIF-8 and Its Application in Improving the Antibacterial Performance of AgNPs.

Purpose: Herein, an emerging drug delivery system was constructed based on zeolite imidazole backbone (ZIF-8) to improve antibacterial defects of nanosilver (AgNPs), such as easily precipitated and highly cytotoxic. Methods: The homogeneous dispersion of AgNPs on ZIF-8 was confirmed by UV-Vis spectroscopy, FTIR spectroscopy, particle size analysis, zeta potential analysis, and SEM. The appropriate AgNPs loading ratio on ZIF-8 was screened through the cell and antibacterial experiments based on biosafety and antibacterial performance. The optimal environment for AgNPs@ZIF-8 to exert antibacterial performance was probed in the context of bacterial communities under different acid-base conditions. The potential mechanism of AgNPs@ZIF-8 to inhibit the common clinical strains was investigated by observing the biofilm metabolic activity and the level of reactive oxygen species (ROS) in bacteria. Results: The successful piggybacking of AgNPs by ZIF-8 was confirmed using UV-Vis spectroscopy, FTIR spectroscopy, particle size analysis, zeta potential analysis, and SEM characterization methods. Based on the bacterial growth curve (0-24 hours), the antibacterial ability of AgNPs@ZIF-8 was found to be superior to AgNPs. When the mass ratio of ZIF-8 and AgNPs was 1:0.25, the selection of AgNPs@ZIF-8 was based on its superior antimicrobial efficacy and enhanced biocompatibility. Notably, under weakly acidic bacterial microenvironments (pH=6.4), AgNPs@ZIF-8 demonstrated a more satisfactory antibacterial effect. In addition, experiments on biofilms showed that concentrations of AgNPs@ZIF-8 exceeding 1×MIC resulted in more than 50% biofilm removal. The nanomedicine was found to increase ROS levels upon detecting the ROS concentration in bacteria. Conclusion: Novel nanocomposites consisting of low cytotoxicity drug carrier ZIF-8 loaded with AgNPs exhibited enhanced antimicrobial effects compared to AgNPs alone. The pH-responsive nano drug delivery system, AgNPs@ZIF-8, exhibited superior antimicrobial activity in a mildly acidic environment. Moreover, AgNPs@ZIF-8 effectively eradicated pathogenic bacterial biofilms and elevated the intracellular level of ROS.

Dexmedetomidine abates myocardial ischemia reperfusion injury through inhibition of pyroptosis via regulation of miR-665/MEF2D/Nrf2 axis.

The current study intended to delve into the mechanisms of dexmedetomidine (Dex) in regulating myocardial pyroptosis against myocardial ischemia/reperfusion injury (MIRI). The rat MIRI models were induced by ligation/release of the coronary artery in vivo and Langendorff perfusion ex vivo. Hemodynamic parameters, infarction sizes, and histopathological changes were assessed to understand the effects of Dex on MIRI. We explored the mechanisms through functional experiments on an H9c2 cell hypoxia/reoxygenation (H/R) model. Cell viability and apoptosis were evaluated using cell counting kit 8 (CCK-8) and AV/PI dual staining respectively. The expressions of miR-665 and MEF2D mRNA were detected by qRT-PCR. Western blot was employed to determine the expression levels of pyroptosis- and signaling pathway- related proteins. The interplays between miR-665 and MEF2D were validated by Dual-luciferase reporter assays. Our findings indicated that Dex preconditioning dramatically attenuated hemodynamic derangements, infarct size, and histopathological damage in rats undergoing MIRI. Dex markedly augmented cell viability, while suppressing cell apoptosis and expressions of NLRP3, cleaved-caspase-1, ASC, GSDMD, IL-1ß, and IL-18 in H9c2 cells subjected to H/R injury. MiR-665 was significantly upregulated, MEF2D and Nrf2 downregulated following H/R, whereas Dex preconditioning reversed these changes. MEF2D was validated to be a target gene of miR-665. Overexpression of miR-665 decreased the expression of MEF2D and blunted the protective effects of Dex in H9c2 cells. Moreover, the functional rescue experiment further verified that Dex regulated MEF2D/Nrf2 pathway via miR-665. In conclusion, Dex mitigates MIRI through inhibiting pyroptosis via regulating miR-665/MEF2D/Nrf2 axis.

Characteristics and Potential Neural Substrates of Encoding and Retrieval During Memory Binding in Amnestic Mild Cognitive Impairment.

BACKGROUND: Whether encoding or retrieval failure contributes to memory binding deficit in amnestic mild cognitive impairment (aMCI) has not been elucidated. Also, the potential brain structural substrates of memory binding remained undiscovered. OBJECTIVE: To investigate the characteristics and brain atrophy pattern of encoding and retrieval performance during memory binding in aMCI. METHODS: Forty-three individuals with aMCI and 37 cognitively normal controls were recruited. The Memory Binding Test (MBT) was used to measure memory binding performance. The immediate and delayed memory binding indices were computed by using the free and cued paired recall scores. Partial correlation analysis was performed to map the relationship between regional gray matter volume and memory binding performance. RESULTS: The memory binding performance in the learning and retrieval phases was worse in the aMCI group than in the control group (F = 22.33 to 52.16, all p < 0.001). The immediate and delayed memory binding index in the aMCI group was lower than that in the control group (p < 0.05). The gray matter volume of the left inferior temporal gyrus was positively correlated with memory binding test scores (r = 0.49 to 0.61, p < 0.05) as well as the immediate (r = 0.39, p < 0.05) and delayed memory binding index (r = 0.42, p < 0.05) in the aMCI group. CONCLUSION: aMCI may be primarily characterized by a deficit in encoding phase during the controlled learning process. Volumetric losses in the left inferior temporal gyrus may contribute to encoding failure.