Interactions between CNS and immune cells in tuberculous meningitis

The central nervous system (CNS) harbors its own special immune system composed of microglia in the parenchyma, CNS-associated macrophages (CAMs), dendritic cells, monocytes, and the barrier systems within the brain. Recently, advances in the immune cells in the CNS provided new insights to understand the development of tuberculous meningitis (TBM), which is the predominant form of Mycobacterium tuberculosis (M.tb) infection in the CNS and accompanied with high mortality and disability. The development of the CNS requires the protection of immune cells, including macrophages and microglia, during embryogenesis to ensure the accurate development of the CNS and immune response following pathogenic invasion. In this review, we summarize the current understanding on the CNS immune cells during the initiation and development of the TBM. We also explore the interactions of immune cells with the CNS in TBM. In the future, the combination of modern techniques should be applied to explore the role of immune cells of CNS in TBM

Sirtuin 3, a New Target of PGC-1α, Plays an Important Role in the Suppression of ROS and Mitochondrial Biogenesis

Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuins, which are homologs of the yeast Sir2 gene. SIRT3 is the only sirtuin with a reported association with the human life span. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. PGC-1alpha induces several key reactive oxygen species (ROS)-detoxifying enzymes, but the molecular mechanism underlying this is not well understood.Here we show that PGC-1alpha strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. Knockdown of PGC-1alpha led to decreased Sirt3 gene expression. PGC-1alpha activated the mouse SIRT3 promoter, which was mediated by an estrogen-related receptor (ERR) binding element (ERRE) (-407/-399) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that ERRalpha bound to the identified ERRE and PGC-1alpha co-localized with ERRalpha in the mSirt3 promoter. Knockdown of ERRalpha reduced the induction of Sirt3 by PGC-1alpha in C(2)C(12) myotubes. Furthermore, Sirt3 was essential for PGC-1alpha-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. Overexpression of SIRT3 or PGC-1alpha in C(2)C(12) myotubes decreased basal ROS level. In contrast, knockdown of mSIRT3 increased basal ROS level and blocked the inhibitory effect of PGC-1alpha on cellular ROS production. Finally, SIRT3 stimulated mitochondrial biogenesis, and SIRT3 knockdown decreased the stimulatory effect of PGC-1alpha on mitochondrial biogenesis in C(2)C(12) myotubes.Our results indicate that Sirt3 functions as a downstream target gene of PGC-1alpha and mediates the PGC-1alpha effects on cellular ROS production and mitochondrial biogenesis. Thus, SIRT3 integrates cellular energy metabolism and ROS generation. The elucidation of the molecular mechanisms of SIRT3 regulation and its physiological functions may provide a novel target for treating ROS-related disease

Role of Tissue and Systemic Hypoxia in Obesity and Type 2 Diabetes

Human lifestyle in most modern and developing societies has dramatically changed over past decades. Physical inactivity along with unrestricted access to calorie dense foods has established an “obesogenic” environment and contributed to a serious epidemic of obesity and type 2 diabetes (T2D), associated with increased morbidity and mortality. In 2005 a population-based study conducted by Reichmuth et al. of University of Wisconsin with a cross-sectional and longitudinal analysis identified that among 1387 participants the odds ratio for T2D with an apnea-hypopnea index (AHI) \u3e 15 versus an AHI \u3c 5 was 2.30 (1.28–4.11; p \u3c 0.01) after adjustment for age, sex, and body habitus. Therefore it has been assumed that intermittent hypoxic periods associated with obstructive sleep apnea (OSA) may play a pathogenic role in inducing insulin resistance and T2D. At organ/tissue levels, in 2007–2009 Ye and colleagues first proposed a central role played by adipose tissue hypoxia resulting from adipocyte expansion in promoting chronic inflammation, adiponectin reduction, adipocyte dysfunction, and death in obese individuals. This group of researchers later identified the mediator roles played by hypoxia inducible factor 1α (HIF-1α) and other hypoxia-triggered signaling mechanisms that may promote free fatty acid release and inhibit glucose uptake in adipocytes by inhibition of the insulin-signaling pathway and induction of cell death

Discovery, Antitumor Activity, and Fermentation Optimization of Roquefortines from <i>Penicillium</i> sp. OUCMDZ-1435

Meleagrin and oxaline, which belong to the roquefortine alkaloids with a unique dihydroindole spiroamide framework, have significant bioactivities, especially tumor cell inhibitory activity. In order to discover the requefortine alkaloids, Penicillium sp. OUCMDZ-1435 was fished and identified from marine fungi using molecular probe technology. Meleagrin (1) and oxaline (2) were isolated from it. In addition, we first reported that compounds 1 and 2 could effectively inhibit the proliferation and metastasis of the human HepG2 cell and induce HepG2 cell apoptosis and cell cycle arrest in the G2/M phase. Additionally, the fermentation of Meleagrin (1) was optimized to increase its yield to 335 mg/L. These results provided bioactive inspiration and fungus resources for roquefortine alkaloid development

Biosynthetic Characterization, Heterologous Production, and Genomics-Guided Discovery of GABA-Containing Fungal Heptapeptides

The biosynthetic gene cluster of γ-aminobutyric acid (GABA)-containing fungal cyclic heptapeptides unguisins A (1) and B (2) was identified in the fungus Aspergillus violaceofuscus CBS 115571. In vitro enzymatic reactions and gene deletion experiments revealed that the unguisin pathway involves the alanine racemase UngC to provide d-alanine, which is then accepted by the first adenylation domain of the nonribosomal peptide synthetase (NRPS) UngA. Intriguingly, the hydrolase UngD was found to transform unguisins into previously undescribed linear peptides. Subsequently, heterologous production of these peptides in Aspergillus oryzae was achieved, in which we established a methodology to readily introduce a large NRPS gene into the fungal host. Finally, genome mining revealed new unguisin congeners, each containing a (2R,3R)-β-methylphenylalanine residue