Temporal lobe epilepsy (TLE) is a neurological disorder affecting millions of people worldwide and currently represents the most common form of focal epilepsy. Thus, the search for aetiological and pathophysiological parameters of TLE is ongoing. Preclinical work and post-mortem human studies suggest adult hippocampal neurogenesis as a potentially relevant factor in TLE pathogenesis. Although progress has been made in elucidating the molecular links between TLE and hippocampal neurogenesis, recent evidence suggests that additional peripheral mediators may be involved. The microbiota-gut-brain axis mediates bidirectional communication between the gut and the brain and could comprise a link between neurogenesis and TLE. In this review, we discuss emerging evidence highlighting a potential role for the gut microbiome in connecting TLE pathogenesis and hippocampal neurogenesis. We focus in particular on mechanisms associated with neuronal excitability, neuroinflammation and gut microbial metabolites. As the evidence does not yet support a direct link between gut microbiota-regulated hippocampal neurogenesis and TLE aetiology or pathophysiology, future studies are needed to establish whether current findings comprise circumstantial links or a potentially novel avenue for clinically relevant research.Macrophages undergo extensive metabolic rewiring upon activation which assist the cell in roles beyond energy production and synthesis of anabolic building blocks. So-called immunometabolites that accumulate upon immune activation can serve as co-factors for enzymes and can act as signaling molecules to modulate cellular processes. Selleckchem All trans-Retinal As such, the Krebs-cycle-associated metabolites succinate, itaconate and alpha-ketoglutarate (αKG) have emerged as key regulators of macrophage function. Here, we describe that 2-hydroxyglutarate (2HG), which is structurally similar to αKG and exists as two enantiomers, accumulates during later stages of LPS-induced inflammatory responses in mouse and human macrophages. D-2HG was the most abundant enantiomer in macrophages and its LPS-induced accumulation followed the induction of Hydroxyacid-Oxoacid Transhydrogenase (HOT). HOT interconverts αKG and gamma-hydroxybutyrate into D-2HG and succinic semialdehyde, and we here identified this enzyme as being immune-responsive and regulated during the course of macrophage activation. The buildup of D-2HG may be further explained by reduced expression of D-2HG Dehydrogenase (D2HGDH), which converts D-2HG back into αKG, and showed inverse kinetics with HOT and D-2HG levels. We tested the immunomodulatory effects of D-2HG during LPS-induced inflammatory responses by transcriptomic analyses and functional profiling of D-2HG-pre-treated macrophages in vitro and mice in vivo. Together, these data suggest a role for D-2HG in the negative feedback regulation of inflammatory signaling during late-stage LPS-responses in vitro and as a regulator of local and systemic inflammatory responses in vivo. Finally, we show that D-2HG likely exerts distinct anti-inflammatory effects, which are in part independent of αKG-dependent dioxygenase inhibition. Together, this study reveals an immunometabolic circuit resulting in the accumulation of the immunomodulatory metabolite D-2HG that can inhibit inflammatory macrophage responses.Mangroves are plants that live in tropical and subtropical coastal regions of the world, they are adapted to high salt environments and cyclic tidal flooding. Mangroves play important ecological roles, including acting as breeding grounds for many fish species and to prevent coastal erosion. The genomes of three mangrove species, Bruguiera gymnorhiza, Bruguiera cylindrica, and a hybrid of the two, Bruguiera hainesii were sequenced, assembled and annotated. The two progenitor species, B. gymnorhiza and B. cylindrica, were found to be highly similar to each other and sufficiently similar to B. parviflora to allow it to be used for reference based scaffolding to generate chromosome level scaffolds. The two subgenomes of B. hainesii were independently assembled and scaffolded. Analysis of B. hainesii confirms that it is a hybrid and the hybridisation event was estimated at 2.4 to 3.5 million years ago using a Bayesian Relaxed Molecular Clock approach.Advanced maternal aging has become a worldwide public health issue contributing to female fertility decline. To provide a complete landscape of transcriptome and epigenetic changes during oocyte aging and maturation, we applied a parallel bimodal genomics approach to parallel transcriptome and methylome profiles of mouse oocytes at single-cell and single-base resolution. Age-associated gene expression changes were associated with defective spindle assembly and mitochondrial dysfunction. Parallel sequencing data suggested aged-related defects in mRNA degradation and methylome remodelling during oocyte maturation. Differentially methylated region in aged mature oocyte was associated with trimethylation of Histone H3 at Lysine 4. More importantly, RNA expression-based prediction model for assessing maturation and oocytes age. Taken together, our work provides a better understanding of molecular mechanisms during mouse oocyte aging, points a new direction of oocyte quality assessment and paves the way for developing novel treatments to improve oocyte quality.Phototherapy, particularly photothermal therapy (PTT) and photodynamic therapy (PDT), has been widely investigated for tumor treatment. However, the limited tissue penetration depth of light in the near-infrared I (NIR-I) region and the hypoxic tumor microenvironment (TME) severely constrain their clinical applications. To address these challenges, in the present study, we developed a chlorin e6 (Ce6) and MnO2-coloaded, hyaluronic acid (HA)-coated single-walled carbon nanohorns (SWNHs) nanohybrid (HA-Ce6-MnO2@SWNHs) for PDT and PTT combination therapy of tumor. HA-Ce6-MnO2@SWNHs responded to the mild acidic TME to ameliorate tumor hypoxia, thus enhancing tumor PDT. Moreover, HA-Ce6-MnO2@SWNHs had a high photothermal conversion efficiency at 1064 nm (55.48%), which enabled deep tissue penetration (3.05 cm) and allowed for highly efficient tumor PTT in near-infrared II (NIR-II) window. PDT and PTT combination therapy with HA-Ce6-MnO2@SWNHs achieved a good therapeutic efficacy on 4T1 tumor-bearing mice, eradicating the primary tumors and suppressing cancer recurrence. Our study provides a promising strategy for developing a hypoxia relief and deep tissue penetration phototherapy platform by using SWNHs for highly effective tumor PDT and NIR-II PTT combination therapy. STATEMENT OF SIGNIFICANCE The hypoxic tumor microenvironment (TME) and the limited penetration of the NIR-I light in biological tissues compromise the efficacy of photothermal therapy (PTT) and photodynamic therapy (PDT) on tumors. Here, we developed a chlorin e6 (Ce6) and MnO2-coloaded, hyaluronic acid (HA)-coated single-walled carbon nanohorns (SWNHs) nanohybrid (HA-Ce6-MnO2@SWNHs) for PDT and PTT combination therapy of tumors. The nanohybrid could efficiently accumulate in tumors through CD44-mediated active targeting. The sequential MnO2-enhanced PDT and efficient NIR-II PTT had a remarkable therapeutic effect by eliminating the primary tumor and simultaneously inhibiting tumor recurrence.With the development of redox-related therapy modalities in cancer therapy, photodynamic therapy (PDT) has gradually become the most widely used type in the clinic. However, the hypoxic tumor microenvironment restricted the curative effect of PDT. Here, a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy was designed to alleviate tumor hypoxia on the basis of PDT. Specifically, the oxygen producer MnO2, oxygen consumption inhibitor atovaquone (ATO) and photosensitizer hypericin (HY) were loaded in SHRN. MnO2 reacted with excess H2O2 in the tumor microenvironment to increase oxygen generation, while ATO inhibited electron transfer in the aerobic respiratory chain to decrease oxygen consumption. Then, HY utilized this sufficient oxygen to produce ROS under irradiation to enhance the PDT effect. In vitro and in vivo assays confirmed that SHRN exhibits powerful and overall antitumor PDT effects. This formulation may provide an alternative strategy for the development of PDT effects in hypoxic tumor microenvironments. STATEMENT OF SIGNIFICANCE We constructed a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy to alleviate tumor hypoxia on the basis of photodynamic therapy (PDT). This work uniquely aimed at not only increased O2 generation in hypoxic tumor microenvironment but also reduced O2 consumption. Moreover, we designed a nanodrug delivery system to enhance the tumor permeability of SHRN. In vitro and in vivo assays all confirmed that SHRN exhibited powerful and overall antitumor effects. This formulation may provide an alternative strategy for the development of the PDT effect in hypoxic solid tumor.Abdominal aortic aneurysms (AAAs) are a dangerous cardiovascular disease, the pathogenesis of which is not yet fully understood. In the present work a recent mechanopathological theory, which correlates AAA progression with microstructural and mechanical alterations in the tissue, is investigated using multiscale models. The goal is to combine these changes, within the framework of mechanobiology, with possible mechanical cues that are sensed by vascular cells along the AAA pathogenesis. Particular attention is paid to the formation of a ‘neo-adventitia’ on the abluminal side of the aortic wall, which is characterized by a highly random (isotropic) distribution of collagen fibers. Macro- and micro-scale results suggest that the formation of an AAA, as expected, perturbs the micromechanical state of the aortic tissue and triggers a growth and remodeling (G&R) reaction by mechanosensing cells such as fibroblasts. This G&R then leads to the formation of a thick neo-adventitia that appears to bring the micromechaure experimental studies, with important implications for AAA risk assessment.Diallyl disulfide (DADS) has been suggested to possess hepatoprotection against alcoholic liver disease (ALD) by a couple of pilot studies, while the underlying mechanisms remain largely unknown. This study aimed to investigate the hepatoprotective effects of DADS against ethanol-induced liver steatosis and early inflammation by using the chronic-plus-binge mice model and cultured J774A.1 macrophages and AML12 hepatocytes. We found that DADS significantly attenuated ethanol-induced elevation of serum aminotransferase activities, accumulation of liver triglyceride, hepatocytes apoptosis, oxidative stress, infiltration of macrophages and neutrophils, and proinflammatory polarization of macrophages in mice livers. In addition, chronic-plus-binge drinking induced apparent intestinal mucosa damage and disturbance of gut microbiota, endotoxemia, and activation of hepatic NF-κB signaling and NLRP3 inflammasome, which was inhibited by DADS. In vitro studies using cocultured AML12/J774A.1 cells showed that DADS suppressed ethanol/LPS-induced cell injury and inflammatory activation of macrophages. Furthermore, DADS ameliorated ethanol-induced decline of peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1 (CPT1), and phosphorylated AMP-activated protein kinase (AMPK) protein levels in mice livers and AML12 cells. These results demonstrate that DADS could prevent ethanol-induced liver steatosis and early inflammation by regulating the gut-liver axis and maintaining fatty acid catabolism.