GroEL triggers NLRP3 inflammasome activation through the TLR/NF-κB p-p65 axis in human periodontal ligament stem cells.

The interaction between bacteria and the host plays a vital role in the initiation and progression of systemic diseases, including gastrointestinal and oral diseases, due to the secretion of various virulence factors from these pathogens. GroEL, a potent virulence factor secreted by multiple oral pathogenic bacteria, is implicated in the damage of gingival epithelium, periodontal ligament, alveolar bone and other peripheral tissues. However, the underlying biomechanism is still largely unknown. In the present study, we verify that GroEL can trigger the activation of NLRP3 inflammasome and its downstream effector molecules, IL-1ß and IL-18, in human periodontal ligament stem cells (hPDLSCs) and resultantly induce high activation of gelatinases (MMP-2 and MMP-9) to promote the degradation of extracellular matrix (ECM). GroEL-mediated activation of the NLRP3 inflammasome requires the participation of Toll-like receptors (TLR2 and TLR4). High upregulation of TLR2 and TLR4 induces the enhancement of NF-κB (p-p65) signaling and promotes its nuclear accumulation, thus activating the NLRP3 inflammasome. These results are verified in a rat model with direct injection of GroEL. Collectively, this study provides insight into the role of virulence factors in bacteria-induced host immune response and may also provide a new clue for the prevention of periodontitis.

Ferroptosis and Preeclampsia: Genetic Analysis of Potential Biomarkers and Therapeutic Targets.

Ferroptosis is the oxidative death of cells attributed to an imbalance in intracellular lipid reactive oxygen species metabolism, a reduction in cell antioxidant capacity, and an accumulation of membrane lipid peroxides. Trophoblast cells are a group of cells susceptible to ferroptosis. The ferroptosis of trophoblast cells has a major effect on the development of preeclampsia (PE), although the impact of ferroptosis-related genes (FRGs) on PE has not been well characterized. This study obtained PE-related information from the Gene Expression Omnibus database and FRGs from the FerrDb ferroptosis database. Seventeen PE-related differentially expressed ferroptosis-related genes (DE-FRGs) that were closely associated with cellular regulation and immune response were obtained. According to the results of a subsequent functional enrichment analysis, it was found that the above marker genes may impact PE by regulating immune response, amino acid metabolism, the cell cycle, and multiple pathways correlated with PE pathogenesis. Subsequently, we used LASSO and support vector machine recursive feature elimination algorithms to help identify GOT1, CFL1, FZD7, VDR, PARP6, TMSB4X, VCP, and ENO3 as marker genes from the 17 obtained genes. According to the results of single-sample gene set enrichment analysis (ssGSEA), the immune microenvironment of PE changed, possibly due to the GOT1 and TMSB4X genes. Furthermore, 23 drugs targeting one marker gene were determined. A constructed ceRNA network revealed a complicated regulatory link based on the eight marker genes. In this study, diagnostic potency was developed, and insight into the mechanism of PE was provided. In-depth research should be conducted before clinical application to evaluate the diagnostic value of DE-FRGs in PE.

Assessment of Wound-Related Pain Experiences of Patients With Chronic Wounds: A Multicenter Cross-Sectional Study in Eastern China.

PURPOSE: The primary aims of this study were to evaluate the prevalence of wound-related pain (WRP) in patients with chronic wounds and assess the use of pain relief measures. DESIGN: A cross-sectional study. SUBJECTS AND SETTING: A convenience sample of patients with chronic wounds was recruited from outpatient clinics of 12 hospitals covering 7 of 13 cities in the Jiangsu province located in eastern China from July 10 to August 25, 2020. The sample comprised 451 respondents, and their mean age was 54.85 (SD 19.16) years; 56.1% (253/451) patients were male. METHODS: An investigator-designed questionnaire was used to collect pain-related information from patients. The questionnaire consisted of 4 parts: (1) basic demographic and clinical information (patient and wound characteristics); (2) wound baseline pain; (3) wound-related procedural pain and pain relief method; and (4) the effect of WRP on the patient. Pain was assessed using the Numerical Rating Scale (NRS) scored from 0 (no pain) to 10 (worst pain). Severity of pain was based on NRS scores' classification as mild (1-3), moderate (4-6), and severe (7-10). The survey was conducted from July 10 to August 25, 2020. Participants were instructed on use of the NRS and then completed the questionnaire following dressing change independently. RESULTS: The 3 most common types of chronic wounds were traumatic ulcers, surgical wounds, and venous leg ulcers. The 3 most prevalent locations were lower limbs, feet, and thorax/abdomen. Of all patients, 62.5% (282/451) and 93.8% (423/451) patients experienced wound baseline pain and wound-related procedural pain, respectively. The mean score of wound baseline pain was 3.76 (SD 1.60) indicating moderate pain. During wound management, the highest pain score was 6.45 (SD 2.75) indicating severe pain; the most severe pain scores were associated with debridement. The use of drugs to relieve wound pain was low, while the use of nondrug-based analgesia was relatively high. Because of WRP, patients with chronic wounds feared dressing changes, hesitated to move, and showed a decline in sleep quality. CONCLUSIONS: Wound baseline pain and wound-related procedural pain were very common in patients with chronic wounds. In the future, targeted intervention plans should be developed by combining drug-based and nondrug-based analgesia according to pain severity.

In vitro transdifferentiated signatures of goat preadipocytes into mammary epithelial cells revealed by DNA methylation and transcriptome profiling.

During mammary development, the transdifferentiation of mammary preadipocytes is one of the important sources for lactating mammary epithelial cells (MECs). However, there is limited knowledge about the mechanisms of dynamic regulation of transcriptome and genome-wide DNA methylation in the preadipocyte transdifferentiation process. Here, to gain more insight into these mechanisms, preadipocytes were isolated from adipose tissues from around the goat mammary gland (GM-preadipocytes). The GM-preadipocytes were cultured on Matrigel in conditioned media made from goat MECs to induce GM-preadipocyte-to-MEC transdifferentiation. The transdifferentiated GM-preadipocytes showed high abundance of keratin 18, which is a marker protein of MECs, and formed mammary acinar-like structures after 8 days of induction. Then, we performed transcriptome and DNA methylome profiling of the GM-preadipocytes and transdifferentiated GM-preadipocytes, respectively, and the differentially expressed genes and differentially methylated genes that play underlying roles in the process of transdifferentiation were obtained. Subsequently, we identified the candidate transcription factors in regulating the GM-preadipocyte-to-MEC transdifferentiation by transcription factor-binding motif enrichment analysis of differentially expressed genes and differentially methylated genes. Meanwhile, the secretory proteome of GM-preadipocytes cultured in conditioned media was also detected. By integrating the transcriptome, DNA methylome, and proteome, three candidate genes, four proteins, and several epigenetic regulatory axes were further identified, which are involved in regulation of the cell cycle, cell polarity establishment, cell adhesion, cell reprogramming, and adipocyte plasticity. These findings provide novel insights into the molecular mechanism of preadipocyte transdifferentiation and mammary development.

The A1762T/G1764A mutations enhance HBV replication by alternating viral transcriptome.

The A1762T/G1764A mutations, one of the most common mutations in the hepatitis B virus basal core promoter, are associated with the progression of chronic HBV infection. However, effects of these mutations on HBV replication remains controversial. This study aimed to systematically investigate the effect of the mutations on HBV replication and its underlying mechanisms. Using the prcccDNA/pCMV-Cre recombinant plasmid system, a prcccDNA-A1762T/G1764A mutant plasmid was constructed. Compared with wild-type HBV, A1762T/G1764A mutant HBV showed enhanced replication ability with higher secreted HBV DNA and RNA levels, while Southern and Northern blot indicated higher intracellular levels of relaxed circular DNA, single-stranded DNA, and 3.5 kb RNA. Meanwhile, the mutations increased expression of intracellular core protein and decreased the production of HBeAg and HBsAg. In vitro infection based on HepG2-NTCP cells and mice hydrodynamic injection experiment also proved that these mutations promote HBV replication. 5'-RACE assays showed that these mutations upregulated transcription of pregenomic RNA (pgRNA) while downregulating that of preC RNA, which was further confirmed by full-length transcriptome sequencing. Moreover, a proportion of sub-pgRNAs with the potential to express polymerase were also upregulated by these mutations. The ChIP-qPCR assay showed that A1762T/G1764A mutations created a functional HNF1α binding site in the BCP region, and its overexpression enhanced the effect of A1762T/G1764A mutations on HBV. Our findings revealed the mechanism and importance of A1762T/G1764A mutations as an indicator for management of CHB patients, and provided HNF1α as a new target for curing HBV-infected patients.

CircRNA_0088196 Regulates Trophoblast Proliferation and Apoptosis in Preeclampsia Through the miR-379-5p/HSPA5 Axis.

Existing research has confirmed the dysregulation of circular RNA (circRNA) in a wide variety of human diseases. Thus, in this study, we explored the potential mechanism of circRNA_0088196 in preeclampsia (PE). We performed quantitative real-time PCR to examine circRNA_0088196 expression and verified the function of circRNA_0088196 in vitro using CCK-8, TUNEL, flow cytometry, and Western blotting analyses. Additionally, we studied the mechanism using dual-luciferase reporter gene experiments. The results of our research revealed the up-regulation of circRNA_0088196 in PE patients' placentas and Heat Shock 70 kDa Protein 5 (HSPA5)-stimulated trophoblast (HTR-8/SVneo) cells. An investigation of the mechanism also showed that there was a binding between miR-379-5p and circRNA_0088196. Additionally, circRNA_0088196 inhibited HTR-8/SVneo cell proliferation and promoted cell apoptosis via the miR-337-3p/HSPA5 axis, thereby facilitating PE. In vivo experiments indicated that circRNA_0088196 regulated HTR-8/SVneo cell production through miR-379-5p. Overall, the findings of this study illustrate that circRNA_0088196 interference promotes cell apoptosis and inhibits HTR-8/SVneo proliferation via the miR-379-5p/HSPA5 axis, thereby accelerating the development of PE.

Association of Neutrophil and Albumin With Mortality Risk in Patients Receiving Peritoneal Dialysis.

OBJECTIVE: Inflammation and nutrition have been recognized as predicting mortality in patients receiving peritoneal dialysis (PD). Serum neutrophil and albumin are crucial factors in inflammation and nutrition status. Up until now, the synergistic effect of neutrophil and albumin on mortality prediction in PD patients is still being determined. Our study sought to assess the effect of the interaction between neutrophils and albumin on the risk of all-cause mortality and cardiovascular disease (CVD) mortality patients receiving PD. METHODS: A total of 1229 PD patients were recruited and divided into three categories in this cohort study. Their relationships with all-cause mortality and CVD mortality were analyzed in multivariable COX regression models adjusted for confounding factors. RESULTS: During the median follow-up of 34.2 months, 222 (18.1%) patients died, and 115 (51.8%) suffered from cardiovascular events. Patients with high neutrophil percentage-to-albumin ratio (NPAR) showed increased all-cause mortality and CVD mortality, with adjusted hazard ratios of 1.490 (95% confidence interval, 1.070-2.074, P = .018) and 1.633 (95% confidence interval, 1.041-2.561, P = .033), respectively, compared with those with low NPAR. Competitive risk models and sensitivity analyses further confirmed this association. In the receiver operating characteristic curve analysis, however, there was little evidence that NPAR is a better indicator than albumin and neutrophil count. CONCLUSIONS: Having a high NPAR is linked to a higher risk of mortality, especially when both high neutrophil and low albumin are present.

E2F1-mediated AUF1 upregulation promotes HCC development and enhances drug resistance via stabilization of AKR1B10.

The AU-rich binding factor 1 (AUF1) is one of the well known adenylate-uridylate-rich element (ARE)-specific RNA-binding proteins (ARE-BPs) for which dysregulation has been reported in various human cancers. However, the involvement of AUF1 in the initiation and progression of hepatocellular carcinoma (HCC) is still elusive. In this study, we aimed at exploring the clinical significance, function, and mechanism of the abnormal expression of AUF1 in HCC. Using a bioinformatics analysis of The Cancer Genome Atlas (TCGA) and Liver Cancer Institute (LCI) database, we identified that AUF1 was abnormally highly expressed in HCC tissues and that the high expression of AUF1 was correlated with poor prognosis in patients with HCC. We also confirmed the increased AUF1 expression and its prognostic value in our HBV-related HCC cohorts. AUF1 overexpression in hepatoma cells promoted cell proliferation and increased the resistance of hepatoma cells toward doxorubicin, whereas knockdown of AUF1 exerted the opposite effects. Mechanistically, we demonstrated that AKR1B10 was a critical target of AUF1 and was essential for sustaining the AUF1-induced proliferation and drug resistance of hepatoma cells. AUF1 increased AKR1B10 expression by binding to the 3'UTR region of AKR1B10 mRNA and stabilizing AKR1B10 mRNA. Additionally, we demonstrated that E2F1 enhanced AUF1 expression in HCC at the transcription level. Our study revealed a novel role of AUF1 in promoting the development and drug resistance of HCC via the post-transcriptional regulation of AKR1B10 expression. The E2F1/AUF1/AKR1B10 axis can serve as a potential therapeutic target in HCC.

Circular RNA circRNF169 functions as a miR-30c-5p sponge to promote cellular senescence.

Circular RNAs (circRNAs), characterized as single-stranded closed circular RNA molecules, have been established to exert pivotal functions in various biological or pathological processes. Nonetheless, the effects and underlying mechanisms concerning circRNAs on the aging and aging-related diseases remain elusive. We herein compared the expression patterns of circRNAs in young and senescent mouse embryonic fibroblasts (MEFs), and uncovered that circRNF169 was dramatically up-regulated in senescent MEFs compared with that in young MEFs. Therefore, we further digged into the role and potential mechanisms of circRNF169 in the senescence of MEFs. The results of senescence-associate-ß-galactosidase staining and BrdU incorporation assay showed that silencing of circRNF169 significantly delayed MEFs senescence and promoted cell proliferation, while ectopic expression of circRNF169 exhibited the opposite effects. Moreover, the dual-luciferase reporter assay confirmed that circRNF169 acted as an endogenous miR-30c-5p sponge, which accelerated cellular senescence by sequestering and inhibiting miR-30c-5p activity. Taken together, our results suggested that circRNF169 exerted a crucial role in cellular senescence through sponging miR-30c-5p and represented a promising target for aging intervention.

Intermetallic Nanocrystals: Seed-Mediated Synthesis and Applications in Electrocatalytic Reduction Reactions.

In recent years, intermetallic nanocrystals (IMNCs) have attracted extensive attention in the field of electrocatalysis. However, precise control over the size, shape, composition, structure, and exposed crystal facet of IMNCs seems to be a challenge to the traditional method of high-temperature annealing although these parameters have a significant effect on the electrocatalytic performance. Controllable synthesis of IMNCs by the wet chemistry method in the liquid phase shows great potential compared with the traditional high-temperature annealing method. In this Review, we attempt to summarize the preparation of IMNCs by the seed-mediated synthesis in the liquid phase, as well as their applications in electrocatalytic reduction reactions. Several representative examples are purposely selected for highlighting the huge potential of the seed-mediated synthesis approach in chemical synthesis. Specifically, we personally perceive the seed-mediated synthesis approach as a promising tool in the future for precise control over the size, shape, composition, structure, and exposed crystal facet of IMNCs.

Influence of Helicobacter pylori infection on PD-1/PD-L1 blockade therapy needs more attention.

BACKGROUND AND OBJECTIVE: The tumor microenvironment and tumor immunity are crucially involved in tumor therapy. Immune checkpoint inhibitors targeting PD-1/PD-L1 signal transduction have been widely used in tumor therapy and have shown ideal clinical efficacy. However, some kinds of cancers still do not respond to PD-1/PD-L1 blockade therapy effectively, including gastric cancer. The related factors should be explored. METHODS AND RESULTS: This review summarizes the recent progression of understanding the influence of Helicobacter pylori infection on PD-1/PD-L1 blockade therapy. Current pieces of evidence have indicated that H. pylori infection might affect the curative effect of tumor therapy associating with the induced immunomodulation. CONCLUSION: It is necessary to understand the overall integration of PD-1/PD-L1 blockade therapy, the tumor microenvironment, and H. pylori infection. Much attention on the influence of H. pylori infection on the efficacy of tumor immunotherapy should be paid.

Effect of Helicobacter pylori on immunotherapy is gaining more attention.

BACKGROUND: Immunotherapy, especially immune checkpoint inhibitors, has been widely used in tumor therapy and have shown ideal clinical efficacy. However, some cancers still do not respond to PD-1/PD-L1 blockade therapy effectively. Helicobacter pylori infection might affect the curative effect of immunotherapy while it is rarely reported. We aimed to visualize the research hotspots and trends of H. pylori and immunotherapy using a bibliometric analysis to help understand the future development of basic and clinical research. METHODS: The relevant publications on H. pylori and immunotherapy were searched on April 20, 2022, in the Web of Science Core Collection Database (WOSCC). The document types were limited to articles and reviews. The VOSviewer 1.6.16 software was used to assess the co-authorship, co-occurrence, citation of countries, institutions, authors, journals, and hotspot keywords. The research status and trend change of H. pylori and immunotherapy were analyzed by bibliometric analysis. RESULTS: A total of 95 studies authored by 561 researchers were eventually included in this study. The majority of the retrieved studies were 55 (58%) original research articles. China conducted the greatest number of studies, followed by USA and Italy. The related topics included the following three aspects: the relationship between microorganisms and cancer, the relationship between gastric cancer and immunity, and the relationship between H. pylori and immunotherapy, including purified/cloned components of H. pylori acting as efficient adjuvant to boost tumor responses and H. pylori infection which modulate host immune responses and impact on the efficacy of antitumor immunity initiated by immune checkpoint inhibitors. The timing diagram revealed that the current research hotspots focused on effects of microorganisms on immunotherapy. CONCLUSION: The effect of H. pylori on cancer immunotherapy is getting more and more attention in these years. It still remains uncertain, and more studies are needed in the future.

Ultrasensitive Pressure-Induced Optical Materials: Europium-Doped Hafnium Silicates with a Khibinskite Structure for Optical Pressure Sensors and WLEDs.

Ultrasensitive pressure-induced optical materials are of great importance owing to their potential applications in optical pressure sensors. However, the lack of outstanding pressure sensitivity, observable color evolution, and structure reliability limits their further development in both practical applications and luminescence theory. To overcome the above problems, an enlightening methodology is proposed to explore the high sensitivity and phase stability of hafnium silicate K2HfSi2O7 (KHSO) phosphor with a Khibinskite structure. By employing X-ray diffraction (XRD) Rietveld refinement, cryogenic spectroscopy, and ancillary calculations, information on Eu2+ ion occupation is completely obtained at atmospheric pressure. The remarkable pressure sensitivity (dλ/dP = 3.25 nm/GPa-1) and excellent phase stability up to 20 GPa, along with the reproducible color hue variation, exhibit unprecedented superiority when used in optical pressure sensors. These advantages can be assigned to the pressure-induced Eu2+-selective occupation and the unique properties of 5d-4f transition (Stokes shift, nephelauxetic effect, and intense crystal field strength), which are clearly proved by measuring the XRD patterns, Raman spectra, and Gaussian fitting spectra under compression and decompression processes. The excellent luminescence property manifests that KHSO/Eu2+ can be considered as a potential luminescent material for solid-state lighting and optical pressure sensors.

Factors that influence hydrogen binding at metal-atop sites.

The d-band model has proven to be effective for understanding trends in the chemisorption of various adsorbates on transition metal surfaces. However, hydrogen adsorption at the atop site of transition metals and their bimetallic alloy surfaces do not always correlate well with the d-band center of the adsorption site. Additionally, the d-band model cannot explain the disappearance of the local minima for H adsorption at the hollow site on the potential energy surface of 5d single-atom element doped Au and Ag(111) surfaces. Here, we use a simple model with factors, including the d-band center, filling of the d-band, renormalized adsorbate states, coupling matrix elements, and surface-adsorbate bond lengths, to correlate with the density functional theory calculated H binding energies on both mono- and bimetallic (111) surfaces. Our results suggest that H adsorption at metal-atop sites is determined by all these factors, not only by the d-band center. The strong adsorption of H at the atop sites of 5d metal surfaces can be explained by their lower repulsive contribution.

Structural decomposition analysis of global carbon emissions: The contributions of domestic and international input changes.

Finding the essential factors driving carbon emissions is vital for the carbon reduction policy-making. Different from the existing research, this paper studied the separate influence of internal and external input structural changes on global carbon emissions. We applied structural decomposition analysis (SDA) to decompose the global carbon emission change into six factors: namely, the carbon emission intensity, the domestic input structure, the international input structure, consumption pattern, consumption volume and population. The results firstly showed that the contributions of different factors to global carbon emissions changed over time. In recent five years, structural changes of domestic inputs became the principle driver of decrease in global carbon emissions. Secondly, the results showed that there were significant differences for countries in their factors for carbon emissions. In India and Russia, domestic input structural change was the major contributor to the decrease in carbon emissions. In Japan and Germany, the most important factor for the increase in carbon emissions was the international input structure. Finally, the results showed the factors for carbon emission changes were correlated to economic development. The international input structural changes significantly increased carbon emissions in high-income countries. Our findings suggested that some countries such as India and Russia, improving the usage efficiency of domestic carbon-intensive products would help reducing carbon emissions. For most high-income countries such as Japan and Germany, they should reduce the dependence on the imported carbon-intensive products by turning the external input sources to countries with technology advantages. In addition, technology exportation of high-income countries would also be beneficial for the global carbon reduction.

Intrinsic Activity of Metal Centers in Metal-Nitrogen-Carbon Single-Atom Catalysts for Hydrogen Peroxide Synthesis.

Metal-nitrogen-carbon (M-N-C) single-atom catalysts (SACs) show high catalytic activity for many important chemical reactions. However, an understanding of their intrinsic catalytic activity remains ambiguous because of the lack of well-defined atomic structure control in current M-N-C SACs. Here, we use covalent organic framework SACs with an identical metal coordination environment as model catalysts to elucidate the intrinsic catalytic activity of various metal centers in M-N-C SACs. A pH-universal activity trend is discovered among six 3d transition metals for hydrogen peroxide (H2O2) synthesis, with Co having the highest catalytic activity. Using density functional calculations to access a total of 18 metal species, we demonstrate that the difference in the binding energy of O2* and HOOH* intermediates (EO2* - EHOOH*) on single metal centers is a reliable thermodynamic descriptor to predict the catalytic activity of the metal centers. The predicted high activity of Ir centers from the descriptor is further validated experimentally. This work suggests a class of structurally defined model catalysts and clear mechanistic principles for metal centers of M-N-C SACs in H2O2 synthesis, which may be further extendable to other reactions.

Enhanced magnetic anisotropy and Curie temperature of the NiI2 monolayer by applying strain: a first-principles study.

Two-dimensional (2D) intrinsic ferromagnetic semiconductors with high magnetic anisotropy (MA) and Curie temperature (TC) are desirable for low-dimensional spintronic applications. We present here the structural stability, MA and TC of the semiconducting NiI2 monolayer under strain from -4% to 4% using first-principles calculations. The unstrained NiI2 monolayer exhibits an in-plane magnetic anisotropy energy of -0.11 meV per unit cell and a TC of 79 K. Most noteworthily, the in-plane MA and TC of the NiI2 monolayer are simultaneously enhanced under compressive strain; meanwhile, the NiI2 monolayer is still stable. In particular, when the compressive strain reaches -4%, the in-plane MA is more than three times higher than that in the unstrained system. Based on the second-order perturbation theory of spin-orbit coupling, the density of states and the orbital magnetic anisotropy contributions are analyzed, indicating that the compressive strain effect originates from the increase of the negative contribution from the spin-orbit coupling interaction between the opposite spin py and px orbitals of the I atom. This study provides a promising route for exploring new 2D ferromagnetic semiconductors with higher MA and TC.

miR-214-3p Targets ß-Catenin to Regulate Depressive-like Behaviors Induced by Chronic Social Defeat Stress in Mice.

ß-Catenin has been implicated in major depressive disorder (MDD), which is associated with synaptic plasticity and dendritic arborization. MicroRNAs (miRNA) are small noncoding RNAs containing about 22 nucleotides and involved in a variety of physiological and pathophysiological process, but their roles in MDD remain largely unknown. Here, we investigated the expression and function of miRNAs in the mouse model of chronic social defeat stress (CSDS). The regulation of ß-catenin by selected miRNA was validated by silico prediction, target gene luciferase reporter assay, and transfection experiment in neurons. We demonstrated that the levels of miR-214-3p, which targets ß-catenin transcripts were significantly increased in the medial prefrontal cortex (mPFC) of CSDS mice. Antagomir-214-3p, a neutralizing inhibitor of miR-214-3p, increased the levels of ß-catenin and reversed the depressive-like behavior in CSDS mice. Meanwhile, antagomir-214-3p increased the amplitude of miniature excitatory postsynaptic current (mEPSC) and the number of dendritic spines in mPFC of CSDS mice, which may be related to the elevated expression of cldn1. Furthermore, intranasal administered antagomir-214-3p also significantly increased the level of ß-catenin and reversed the depressive-like behaviors in CSDS mice. These results may represent a new therapeutic target for MDD.

Activation of AMPK-dependent autophagy in the nucleus accumbens opposes cocaine-induced behaviors of mice.

Cocaine is a strong central nervous system stimulant, which can induce drug addiction. Previous studies have reported that cocaine-induced autophagy is involved in neuroinflammation and cell death. However, the role of autophagy in psychomotor sensitivity to cocaine has not been explored. Here, we reported that D1 receptor -CaMKII-AMPK-FoxO3a signaling pathway was involved in acute cocaine application-induced autophagy in the nucleus accumbens (NAc) both in vitro and in vivo. Furthermore, we found that knockdown of the ATG5 gene in the NAc augmented behavioral response to cocaine, and induction of autophagy in the NAc with rapamycin attenuated cocaine-induced behavioral response, which was coincident with the alterations of dendritic spine density in neurons of NAc. These results suggest that cocaine exposure leads to the induction of autophagy, which is a protective mechanism against behavioral response to cocaine of male mice.

Neuronal HMGB1 in nucleus accumbens regulates cocaine reward memory.

Cocaine is a common abused drug that can induce abnormal synaptic and immune responses in the central nervous system (CNS). High mobility group box 1 (HMGB1) is one kind of inflammatory molecules that is expressed both on neurons and immune cells. Previous studies of HMGB1 in the CNS have largely focused on immune function, and the role of HMGB1 in neurons and cocaine addiction remains unknown. Here, we show that cocaine exposure induced the translocation and release of HMGB1 in the nucleus accumbens (NAc) neurons. Gain and loss of HMGB1 in the NAc bidirectionally regulate cocaine-induced conditioned place preference. From the nucleus to the cytosol, HMGB1 binds to glutamate receptor subunits (GluA2/GluN2B) on the membrane, which regulates cocaine-induced synaptic adaptation and the formation of cocaine-related memory. These data unveil the role of HMGB1 in neurons and provide the evidence for the HMGB1 involvement in drug addiction.