The lateral septum partakes the regulation of propofol-induced anxiety-like behavior.

Repeated exposure to propofol during early brain development is associated with anxiety disorders in adulthood, yet the mechanisms underlying propofol-induced susceptibility to anxiety disorders remain elusive. The lateral septum (LS), primarily composed of γ-aminobutyric acidergic (GABAergic) neurons, serves as a key brain region in the regulation of anxiety. However, it remains unclear whether LS GABAergic neurons are implicated in propofol-induced anxiety. Therefore, we conducted c-Fos immunostaining of whole-brain slices from mice exposed to propofol during early life. Our findings indicate that propofol exposure activates GABAergic neurons in the LS. Selective activation of LS GABAergic neurons resulted in increased anxiety-like behavior, while selective inhibition of these neurons reduced such behaviors. These results suggest that the LS is a critical brain region involved in propofol-induced anxiety. Furthermore, we investigated the molecular mechanism of propofol-induced anxiety in the LS. Microglia activation underlies the development of anxiety. Immunofluorescence staining and Western blot analysis of LS revealed activated microglia and significantly elevated levels of phospho-NF-κB p65 protein. Additionally, a decrease in the number of neuronal spines was observed. Our study highlights the crucial role of the LS in the development of anxiety-like behavior in adulthood following childhood propofol exposure, accompanied by the activation of inflammatory pathways.

Oral administration of RDP58 ameliorated DSS-induced colitis in intestinal microbiota dependent manner.

BACKGROUND: Although the pathogenesis of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), has not been fully elucidated, accumulating researches suggest that intestinal microbiota imbalance contributes to the development of IBD in patients and animal models. RDP58, a peptide-based computer-assisted rational design, has been demonstrated to be effective in protecting against a wide range of autoimmune and inflammatory diseases. However, the underlying mechanism by which RDP58 protects against IBD mediated by intestinal microbiota has yet to be elucidated. METHODS: The colitis model was induced by continuously administering 2.5 % (wt/vol) dextran sodium sulfate (DSS) solution for 7 days. The manifestations of colon inflammation were assessed via daily weight changes, colon length, tumor necrosis factor-alpha (TNF-α) level, disease activity index (DAI) score, pathology score, and intestinal barrier permeability. Intestinal microbiota analysis was carried out by 16S-rRNA sequencing. Colonic short chain fatty acids (SCFAs) and regulatory T cells (Tregs) were also detected. To further confirm the protective effect of RDP58 on intestinal microbiota, broad-spectrum antibiotic cocktail (ABX) treatment and fecal microbial transplantation (FMT) experiment were performed. RESULTS: Oral administration of RDP58 ameliorated DSS-induced mice colitis by altering the diversity and composition of intestinal microbiota. Notably, RDP58 significantly upregulated SCFAs-producing microbiota, thereby promoting the generation of Tregs. ABX and FMT were performed to verify the above mechanism. CONCLUSIONS: RDP58 ameliorated DSS-induced colitis through altering intestinal microbiota and enhancing SCFAs and Tregs production in intestinal microbiota dependent manner, potentially provide a novel therapy for IBD.

Tau Accumulation in the Spinal Cord Contributes to Chronic Inflammatory Pain by Upregulation of IL-1ß and BDNF.

Microtubule-associated protein Tau is responsible for the stabilization of neuronal microtubules under normal physiological conditions. Much attention has been focused on Tau's contribution to cognition, but little research has explored its role in emotions such as pain, anxiety, and depression. In the current study, we found a significant increase in the levels of p-Tau (Thr231), total Tau, IL-1ß, and brain-derived neurotrophic factor (BDNF) on day 7 after complete Freund's adjuvant (CFA) injection; they were present in the vast majority of neurons in the spinal dorsal horn. Microinjection of Mapt-shRNA recombinant adeno-associated virus into the spinal dorsal cord alleviated CFA-induced inflammatory pain and inhibited CFA-induced IL-1ß and BDNF upregulation. Importantly, Tau overexpression was sufficient to induce hyperalgesia by increasing the expression of IL-1ß and BDNF. Furthermore, the activation of glycogen synthase kinase 3 beta partly contributed to Tau accumulation. These findings suggest that Tau in the dorsal horn could be a promising target for chronic inflammatory pain therapy.

Lipocalin 2 in the Paraventricular Thalamic Nucleus Contributes to DSS-Induced Depressive-Like Behaviors.

The incidence rate of anxiety and depression is significantly higher in patients with inflammatory bowel diseases (IBD) than in the general population. The mechanisms underlying dextran sulfate sodium (DSS)-induced depressive-like behaviors are still unclear. We clarified that IBD mice induced by repeated administration of DSS presented depressive-like behaviors. The paraventricular thalamic nucleus (PVT) was regarded as the activated brain region by the number of c-fos-labeled neurons. RNA-sequencing analysis showed that lipocalin 2 (Lcn2) was upregulated in the PVT of mice with DSS-induced depressive behaviors. Upregulating Lcn2 from neuronal activity induced dendritic spine loss and the secreted protein induced chemokine expression and subsequently contributed to microglial activation leading to blood-brain barrier permeability. Moreover, Lcn2 silencing in the PVT alleviated the DSS-induced depressive-like behaviors. The present study demonstrated that elevated Lcn2 in the PVT is a critical factor for DSS-induced depressive behaviors.

Egr2 contributes to age-dependent vulnerability to sevoflurane-induced cognitive deficits in mice.

Sevoflurane inhalation is prone to initiate cognitive deficits in infants. The early growth response-2 (Egr-2) gene is DNA-binding transcription factor, involving in cognitive function. In this study we explored the molecular mechanisms underlying the vulnerability to cognitive deficits after sevoflurane administration. Six-day-old (young) and 6-week-old (early adult) mice received anesthesia with 3% sevoflurane for 2 h daily for 3 days. We showed that multiple exposures of sevoflurane induced significant learning ability impairment in young but not early adult mice, assessed in Morris water maze test on postnatal days 65. The integrated differential expression analysis revealed distinct transcription responses of Egr family members in the hippocampus of the young and early adult mice after sevoflurane administration. Particularly, Egr2 was significantly upregulated after sevoflurane exposure only in young mice. Microinjection of Egr2 shRNA recombinant adeno-associated virus into the dentate gyrus alleviated sevoflurane-induced cognitive deficits, and abolished sevoflurane-induced dendritic spins loss and BDNF downregulation in young mice. On the contrary, microinjection of the Egr2 overexpression virus in the dentate gyrus aggravated learning ability impairment induced by sevoflurane in young mice but not early adult mice. Furthermore, we revealed that sevoflurane markedly upregulated the nuclear factors of activated T-cells NFATC1 and NFATC2 in young mice, which were involved in Egr2 regulation. In conclusion, Egr2 serves as a critical factor for age-dependent vulnerability to sevoflurane-induced cognitive deficits.

Insights Into Translatomics in the Nervous System.

Most neurological disorders are caused by abnormal gene translation. Generally, dysregulation of elements involved in the translational process disrupts homeostasis in neurons and neuroglia. Better understanding of how the gene translation process occurs requires detailed analysis of transcriptomic and proteomic profile data. However, a lack of strictly direct correlations between mRNA and protein levels limits translational investigation by combining transcriptomic and proteomic profiling. The much better correlation between proteins and translated mRNAs than total mRNAs in abundance and insufficiently sensitive proteomics approach promote the requirement of advances in translatomics technology. Translatomics which capture and sequence the mRNAs associated with ribosomes has been effective in identifying translational changes by genetics or projections, ribosome stalling, local translation, and transcript isoforms in the nervous system. Here, we place emphasis on the main three translatomics methods currently used to profile mRNAs attached to ribosome-nascent chain complex (RNC-mRNA). Their prominent applications in neurological diseases including glioma, neuropathic pain, depression, fragile X syndrome (FXS), neurodegenerative disorders are outlined. The content reviewed here expands our understanding on the contributions of aberrant translation to neurological disease development.

The potential mechanism of postoperative cognitive dysfunction in older people.

Postoperative cognitive dysfunction (POCD) is a common disorder following surgery, which seriously threatens the quality of patients' life, especially the older people. Accumulating attention has been paid to POCD worldwide in pace with the popularization of anesthesia/surgery. The development of medical humanities and rehabilitation medicine sets higher demands on accurate diagnosis and safe treatment system of POCD. Although the research on POCD is in full swing, underlying pathogenesis is still inconclusive due to these conflicting results and controversial evidence. Generally, POCD is closely related to neuropsychiatric diseases such as dementia, depression and Alzheimer's disease in molecular pathways. Researchers have come up with various hypotheses to reveal the mechanisms of POCD, including neuroinflammation, oxidative stress, autophagy disorder, impaired synaptic function, lacking neurotrophic support, etc. Recent work focused on molecular mechanism of POCD in older people has been thoroughly reviewed and summed up here, concerning the changes of peripheral circulation, pathological pathways of central nervous system (CNS), the microbiota-gut-brain axis and the related brain regions. Accordingly, this article provides a better perspective to understand the development situation of POCD in older people, which is conductive to uncover the pathological mechanism and exploit reasonable treatment strategy of POCD.

Synthetic Imine Resveratrol Analog 2-Methoxyl-3,6-Dihydroxyl-IRA Ameliorates Colitis by Activating Protective Nrf2 Pathway and Inhibiting NLRP3 Expression.

Resveratrol (RSV) is a naturally occurring polyphenol that exhibits pleiotropic health benefits, including anticolitis and colon cancer-protective activity. Recently, we identified the novel imine RSV analog (IRA), 2-methoxyl-3,6-dihydroxyl-IRA 3,4,5,4-tetramethoxystilbene (C33), as a putative activator of nuclear factor erythroid 2-related factor 2 (Nrf2). The present study was designed to evaluate the ability of C33 to activate the Nrf2 signaling pathway and its anticolitis effect in comparison to RSV. The anticolitis action of C33 was assessed in a mouse model of colitis induced by dextran sulfate sodium (DSS). The effect of C33 on the Nrf2 signaling pathway was examined in vitro and in vivo. Compared to RSV, C33 triggered a more dramatic increase in the expression of genes downstream of Nrf2 in LS174T cells as well as in the small intestine and colon of wild-type (WT) mice. Correlated with its superior ability to activate the cytoprotective Nrf2 pathway, C33 was significantly better in ameliorating DSS-induced colitis by improving the inflammation score, as well as downregulating the markers of inflammation in WT mice. Moreover, induction of the NOD-like receptors family pyrin domain containing 3 (NLRP3) inflammasome by colitis was also significantly inhibited by the IRA. Nrf2 knockout completely abolished the effects of C33, indicating that Nrf2 is the important mechanistic target of C33 in vivo. In conclusion, the novel IRA, C33, has stronger anticolitis effects than RSV. Further studies are warranted to evaluate C33 as a potential therapeutic agent for inflammatory bowel disease and cancer chemoprevention.

Mkp-1 is required for chemopreventive activity of butylated hydroxyanisole and resveratrol against colitis-associated colon tumorigenesis.

Many dietary compounds show promising protective activity against colon cancer by activating nuclear factor-erythroid 2 related factor 2 (Nrf2). Recently, we reported that mitogen-activated protein kinase phosphatase 1 (Mkp-1) exhibits crosstalk with the Nrf2 signaling pathway, protecting against intestinal inflammation. Here, we present evidence that Mkp-1 is required for the chemopreventive action of the Nrf2 activators butylated hydroxyanisole (BHA) and resveratrol (RSV). In an azoxymethane/dextran sulfate sodium model of colitis-associated tumorigenesis, Mkp-1-/- mice exhibited a phenotype similar to Nrf2-/- mice with significantly more tumors than WT mice. Tumors from Mkp-1-/- mice exhibited higher levels of macrophage infiltration than those from WT mice. This was accompanied by increased expression of nitrotyrosine and p53BP1, markers of oxidative stress and DNA damage, respectively. Moreover, dietary suppression of tumorigenesis using BHA (0.5%) or RSV (300 ppm) supplementation was achieved in WT but not in Mkp-1-/- mice. In adenomas from WT mice, the expression of Mkp-1 was markedly lower than in adjacent normal tissue, concomitant with the down-regulation of Nrf2 and its target genes. Our data revealed that Mkp-1 is required in the protective role of Nrf2 signaling against colitis-associated tumorigenesis.

Temporal Changes of Spinal Transcriptomic Profiles in Mice With Spinal Nerve Ligation.

Neuropathic pain (NP) is an intractable disease accompanying with allodynia, hyperalgesia and spontaneous pain. Accumulating evidence suggested that large volume of neurotransmitters, genes, and signaling pathways were implicated with the initiation and development of NP, while the underlying mechanism still remained poorly understood. Therefore, it was extremely important to further elucidate the potential regulatory networks for developing appropriate treatment options. Here, the RNA-Seq high-throughput sequencing was employed to determine the genes expression change in mice undergoing spinal nerve ligation (SNL). Meanwhile, the differentially expressed genes (DEGs) were analyzed by using integrated Differential Expression and Pathway analysis (iDEP) tools and String database. Then, quantitative real-time PCR (qRT-PCR) was employed to detect the expression of hub gens. The results showed that the DEGs mainly comprised 1712 upregulated and 1515 downregulated genes at 7 days, and consisted of 243 upregulated and 357 downregulated genes at 28 days after surgery, respectively. Additionally, 133 genes and two pathways including retrograde endocannabinoid signaling and cardiac muscle contraction collectively participated in biological reactions of 7th and 28th day after operation. Moreover, the results showed that the mRNA and protein expression of Ccl5, Cacna2d1, Cacna2d2, Cacnb2, Gabrb3, GluA1, and GluA2 were significantly upregulated in SNL-7/28d group than that of in Sham-7/28d group (SNL-7d vs. Sham-7d; SNL-28d vs. Sham-28d; P < 0.05). And the level of Glra2, Glra4, Glra3, Grik1, Grik2, NR1, NR2A, and NR2B was obviously increased in SNL-7d group compared to Sham-7d group (P < 0.05), but which was no statistical difference between SNL-28d group and Sham-28d group. Therefore, these results provided new perspectives and strategies for deeply illuminating the underlying mechanism, and identifying the key elements for treating NP.

Resveratrol: An overview of its anti-cancer mechanisms.

Cancer is one of the leading causes of death worldwide. Chemotherapy and radiotherapy are the conventional primary treatments for cancer patients. However, most of cancer cells develop resistance to both chemotherapy and radiotherapy after a period of treatment, besides their lethal side-effects. This motivated investigators to seek more effective alternatives with fewer side-effects. In the last few years, resveratrol, a natural polyphenolic phytoalexin, has attracted much attention due to its wide biological effects. In this concise review, we highlight the role of resveratrol in the prevention and therapy of cancer with particular focus on colorectal and skin cancer. Also, we discuss the molecular mechanisms underlying its chemopreventive and therapeutic activity. Finally, we highlight the problems associated with the clinical application of resveratrol and how attempts have been made to overcome these drawbacks.

Mkp-1 protects mice against toxin-induced liver damage by promoting the Nrf2 cytoprotective response.

The present study was undertaken to investigate the possible protective effect of mitogen-activated protein kinase phosphatase 1 (Mkp-1) on toxin-induced hepatic injury. Here, we uncovered a positive feedback loop between Mkp-1, a dual threonine/tyrosine phosphatase, and nuclear factor erythroid 2-related factor 2 (Nrf2), a crucial regulator of the defense system in the liver. Mkp-1-/- mice exhibited decreased protein levels of Nrf2, phase II gene products, and reduced glutathione (GSH) in the liver. Induction of detoxifying enzymes by the Nrf2 activator butylated hydroxyanisole (BHA) or sulforaphane, was attenuated in the liver and small intestines of Mkp-1-/- mice, indicating that the Nrf2 signaling pathway is impaired as a result of Mkp-1 deficiency. Mkp-1-/- mice suffered more severe liver injury after a single exposure to hepatotoxin carbon tetrachloride (CCl4) than their wild-type (WT) counterparts. BHA partially rescued the CCl4-induced liver damage in WT mice, but not in Mkp-1-/- mice, suggesting the requirement of Mkp-1 in the activation of Nrf2 signaling against the liver injury. Mechanistically, Mkp-1 upregulated Nrf2 through a direct interaction with the Neh2 domain in the transcription factor, while Nrf2 enhanced the expression of Mkp-1 mRNA by binding to the ARE site at -1719 to -1710bp in the Mkp-1 promoter. Our results reveal novel role of Mkp-1 in the maintenance of redox homeostasis in the liver. Thus, strategies aimed at augmenting Mkp-1 expression may be beneficial in protecting the liver and may provide novel therapeutic approaches to toxin-induced liver injury.