Enterogenic metabolomics signatures of depression: what are the possibilities for the future.

INTRODUCTION: An increasing number of studies indicate that the microbiota-gut-brain axis is an important pathway involved in the onset and progression of depression. The responses of the organism (or its microorganisms) to external cues cannot be separated from a key intermediate element: their metabolites. AREAS COVERED: In recent years, with the rapid development of metabolomics, an increasing amount of metabolites has been detected and studied, especially the gut metabolites. Nevertheless, the increasing amount of metabolites described has not been reflected in a better understanding of their functions and metabolic pathways. Moreover, our knowledge of the biological interactions among metabolites is also incomplete, which limits further studies on the connections between the microbial-entero-brain axis and depression. EXPERT OPINION: This paper summarizes the current knowledge on depression-related metabolites and their involvement in the onset and progression of this disease. More importantly, this paper summarized metabolites from the intestine, and defined them as enterogenic metabolites, to further clarify the function of intestinal metabolites and their biochemical cross-talk, providing theoretical support and new research directions for the prevention and treatment of depression.

Age-related SUMOylation of PLK1 is essential to meiosis progression in mouse oocytes.

Polo like kinase 1 (PLK1) is a protein kinase involved in regulating the spindle assembly and cell cycle control in mammalian oocytes. SUMOylation, one way of post-translational modification, regulates oocyte meiosis by controlling several substrates. However, the relation between PLK1 and SUMOylation in oocytes is still unknown. In this study, we investigated that whether PLK1 was modified by SUMOylation in oocytes and its potential relationship with age-related meiotic abnormalities. We showed that PLK1 had colocalization and protein interaction with Small Ubiquitin-Like Modifier (SUMO)-1 and SUMO-2/3 in mouse oocytes, indicating that PLK1 could be modified by SUMO-1 and SUMO-2/3. Overexpression of PLK1 SUMOylation site mutants PLK1K178R and PLK1K191R caused the increase of the abnormal spindle rate of oocytes and the decline of the first polar body extrusion rate with the abnormal localization of PLK1, suggesting that the SUMOylation modification of PLK1 is essential for normal meiosis in oocytes. Compared with young mice, the expression of PLK1 protein increased and the expression of SUMO-1 and SUMO-2/3 protein decreased in the oocytes of aged mice, indicating that the SUMOylation of PLK1 might be related to the mouse aging. Therefore, our data suggested that PLK1 could be SUMOylated by SUMO-1 and SUMO-2/3 in mouse oocytes and SUMOylation of PLK1 regulated the meiosis progression of oocytes which was related with aging.

Shugoshin Regulates Cohesin, Kinetochore-Microtubule Attachments, and Chromosomal Instability.

Correct regulation of cohesin at chromosome arms and centromeres and accurate kinetochore-microtubule connections are significant for proper chromosome segregation. At anaphase of meiosis I, cohesin at chromosome arms is cleaved by separase, leading to the separation of homologous chromosomes. However, at anaphase of meiosis II, cohesin at centromeres is cleaved by separase, leading to the separation of sister chromatids. Shugoshin-2 (SGO2) is a member of the shugoshin/MEI-S332 protein family in mammalian cells, a crucial protein that protects centromeric cohesin from cleavage by separase and corrects wrong kinetochore-microtubule connections before anaphase of meiosis I. Shugoshin-1 (SGO1) plays a similar role in mitosis. Moreover, shugoshin can inhibit the occurrence of chromosomal instability (CIN), and its abnormal expression in several tumors, such as triple-negative breast cancer, hepatocellular carcinoma, lung cancer, colon cancer, glioma, and acute myeloid leukemia, can be used as biomarker for disease progression and potential therapeutic targets for cancers. Thus, this review discusses the specific mechanisms of shugoshin which regulates cohesin, kinetochore-microtubule connections, and CIN.

[Molecular Mechanism of Aurora Kinase A Regulating the Meiosis of Oocyte].

Aurora kinase A (AURKA),a family member of aurora kinases,is involved in mitotic entry,maturation and separation of centrosome,assembly and stabilization of bipolar spindle,and condensation and separation of chromosome.Studies have demonstrated that AURKA plays a similar role in meiosis,while the specific mechanism and the similarities and differences in its role between meiosis and mitosis remain unclear.Therefore,we reviewed the studies about the localization and activation of AURKA in oocyte meiosis,and compared the role of AURKA in regulating spindle formation,activating spindle assembly checkpoint,and correcting the kinetochore-microtubule attachment between the meiosis of oocytes and the mitosis of somatic cells.This review will lay a theoretical foundation for revealing the mechanism of AURKA in the regulation of cell division and for the clinical research related to cancer and reproduction.

An experimental study of deep brain stimulation lead fracture: possible fatigue mechanisms and prevention approach.

OBJECTIVES: Lead fracture is a common and troublesome hardware-related complication in deep brain stimulation therapy. Frequent cervical movements are suspected as the main cause, but the underlying mechanisms are still unclear. We propose the integrity of the helical structure of the lead wires is important and conduct systematic experiments to demonstrate this. We aim to provide a new view on how lead fracture takes place. MATERIALS AND METHODS: Flexural fatigue tests were conducted on intact and stretched lead wires with a custom-made testing machine. Number of cycles until failure was recorded as the fatigue life, and the fracture morphology was observed under optical and scanning electron microscopes. RESULTS: The fatigue life of the lead wires showed dramatic decline with the severity of deformation, from 434,112 ± 10,277 cycles for an intact specimen down to 19,435 ± 2,622 cycles for a specimen elongated by approximately 20%. The morphology of the fractures revealed characteristic beach marks and striations indicating a fatigue failure. CONCLUSION: We demonstrate that integrity of the helical structure of the wires is crucial to the fatigue performance of the lead. Although the results cannot be directly extrapolated to human subjects, they suggest a possible lead fracture mechanism. The implanted lead may undergo deformation due to large-amplitude motions (e.g., falls) and develop fracture due to the deterioration in fatigue resistance, especially when it is placed at or migrates to the neck. It may be possible to effectively protect the lead by using certain surgical techniques during implantation, such as placing the connector on the calvaria or in a drilled trough at the retroauricular region with reliable fixation.

A comprehensive analysis of the differential expression in the hippocampus of depression induced by gut microbiota compared to traditional stress.

Depression, which is a disease of heterogeneous etiology, is characterized by high disability and mortality rates. Gut microbiota are associated with the development of depression. To further explore any differences in the mechanisms of depression induced by gut microbiota and traditional stresses, as well as facilitate the development of microbiota-based interventions, a fecal microbiota transplantation (FMT) depression model was made. This was achieved by transplanting feces from major depressive disorder (MDD) patients into germ-free mice. Second, the mechanisms of the depression induced by gut microbiota were analyzed in comparison with those of the depression caused by different forms of stress. It turned out that mice exhibited depressive-like behavior after FMT. Then, PCR array analysis was performed on the hippocampus of the depressed mice to identify differentially expressed genes (DEGs). The KEGG analysis revealed that the pathways of depression induced by gut microbes are closely associated with immuno-inflammation. To determine the pathogenic pathways of physiological stress and psychological stress-induced depression, raw data was extracted from several databases and KEGG analysis was performed. The results from the analysis revealed that the mechanisms of depression induced by physiological and psychological stress are closely related to the regulation of neurotransmitters and energy metabolism. Interestingly, the immunoinflammatory response was distinct across different etiologies that induced depression. The findings showed that gut microbiota dysbiosis-induced depression was mainly associated with adaptive immunity, while physiological stress-induced depression was more linked to innate immunity. This study compared the pathogenesis of depression caused by gut microbiota dysbiosis, and physiological and psychological stress. We explored new intervention methods for depression and laid the foundation for precise treatment.

Maternal separation regulates sensitivity of stress-induced depression in mice by affecting hippocampal metabolism.

Depression is a serious mental illness. Previous studies found that early life stress (ELS) plays a vital role in the onset and progression of depression. However, relevant studies have not yet been able to explain the specific effects of early stress on stress-induced depression sensitivity and individual behavior during growth. Therefore, we constructed a maternal separation (MS) model and administered chronic social frustration stress at different stages of their growth while conducting metabolomics analysis on the hippocampus of mice. Our results showed that the immobility time of mice in the forced swimming test was significantly reduced at the end of MS. Meanwhile, mice with MS experience significantly decreased total movement distance in the open field test and sucrose preference ratio in the sucrose preference test when subjected to chronic social defeat stress (CSDS) during adolescence. In adulthood, the results were the opposite. In addition, we found that level changes in metabolites such as Beta-alanine, l-aspartic acid, 2-aminoadipic acid, and Glycine are closely related to behavioral changes. These metabolites are mainly enriched in Pantothenate, CoA biosynthesis, and Beta Alanine metabolism pathways. Our experiment revealed that the effects of ELS vary across different age groups. It will increase an individual's sensitivity to depression when facing CSDS in adolescence, but it will reduce their sensitivity to depression when facing CSDS in adulthood. This may be achieved by regulating the hippocampus's Pantothenate and CoA biosynthesis and Beta Alanine metabolism pathways represented by Beta-alanine, l-Aspartic acid, 2-aminoadipic acid, and Glycine metabolites.

Comprehensive analysis of the gut microbiome and post-translational modifications elucidates the route involved in microbiota-host interactions.

The gut microbiome interacts with the host to maintain body homeostasis, with gut microbial dysbiosis implicated in many diseases. However, the underlying mechanisms of gut microbe regulation of host behavior and brain functions remain unclear. This study aimed to elucidate the influence of gut microbiota on brain functions via post-translational modification mechanisms in the presence or absence of bacteria without any stimulation. We conducted succinylome analysis of hippocampal proteins in germ-free (GF) and specific pathogen-free (SPF) mice and metagenomic analysis of feces from SPF mice. These results were integrated with previously reported hippocampal acetylome and phosphorylome data from the same batch of mice. Subsequent bioinformatics analyses revealed 584 succinylation sites on 455 proteins, including 54 up-regulated succinylation sites on 91 proteins and 99 down-regulated sites on 51 proteins in the GF mice compared to the SPF mice. We constructed a panoramic map of gut microbiota-regulated succinylation, acetylation, and phosphorylation, and identified cross-talk and relative independence between the different types of post-translational modifications in modulating complicated intracellular pathways. Pearson correlation analysis indicated that 13 taxa, predominantly belonging to the Bacteroidetes phylum, were correlated with the biological functions of post-translational modifications. Positive correlations between these taxa and succinylation and negative correlations between these taxa and acetylation were identified in the modulation of intracellular pathways. This study highlights the hippocampal physiological changes induced by the absence of gut microbiota, and proteomic quantification of succinylation, phosphorylation, and acetylation, contributing to our understanding of the role of the gut microbiome in brain function and behavioral phenotypes.

A filtration medium replacement method that increases the efficiency of immunofluorescence staining of oocytes.

Immunofluorescence staining is used to investigate proteins and protein interactions in oocytes. In typical protocols, the medium that suspends the oocytes requires replacement more than ten times during the staining procedure; this is time-consuming, technically challenging and not amenable to automation. We developed a filtration method using negative pressure to replace manual replacement of medium. We investigated oocyte loss, time required and staining results using our filtration method compared to traditional procedure. We found that our filtration method reduced oocyte loss by at least 60% and decreased the time required to obtain comparable staining outcomes. It provides an efficient and fast way to replace culture medium for oocytes.

Fatigue test of helical nervous electrodes and weak point analysis of helical nervous electrodes design.

Due to the increasing number of both implantation and removal of the helical nervous electrodes, the safety and the reliability of the electrode becomes an important issue in its clinical application-particularly its fatigue failure caused by body movement. Utilizing fatigue testing, we evaluated the weak points of the helical electrode. Our data analysis for fatigue cycles recorded by the fatigue test equipment showed that the adhesive strength between the silicone and suture, and the load of the electrode were essential for the mechanical durability of the electrode. The locations of the weak points and improvements for helical electrode design were given. The suggestions of decreasing damages to the nerves in clinical use will be helpful to the surgeons.