Biochimie最新文献

The translocator protein (TSPO) has been widely investigated as a PET-imaging biomarker of neuroinflammation and, more recently, as a therapeutic target for the treatment of neurodegenerative disease. TSPO ligands have been shown to exert neuroprotective effects in vivo and in vitro models of Alzheimer's disease (AD), by reducing toxic beta amyloid peptides, and attenuating brain atrophy. Recent transcriptomic and proteomic analyses, and the generation of TSPO-KO mice, have enabled new insights into the mechanistic function of TSPO in AD. Using a multi-omics approach in both TSPO-KO- and TSPO ligand-treated mice, we have demonstrated a key role for TSPO in microglial respiratory metabolism and phagocytosis in AD. In this review, we discuss emerging evidence for therapeutic and immunomodulatory functions of TSPO in AD, and new tools for studying TSPO in the brain.

Amyloidosis forms a large family of pathologies associated with amyloid deposit generated by the formation of amyloid fibrils or plaques. The amyloidogenic proteins and peptides involved in these processes are targeted against almost all organs. In brain they are associated with neurodegenerative disease, and the Translocator Protein (TSPO), overexpressed in these inflammatory conditions, is one of the target for the diagnostic. Moreover, TSPO ligands have been described as promising therapeutic drugs for neurodegenerative diseases. Type 2 diabetes, another amyloidosis, is due to a beta cell mass decrease that has been linked to hIAPP (human islet amyloid polypeptide) fibril formation, leading to the reduction of insulin production. In the present study, in a first approach, we link overexpression of TSPO and inflammation in potentially prediabetic patients. In a second approach, we observed that TSPO deficient rats have higher level of insulin secretion in basal conditions and more IAPP fibrils formation compared with wild type animals. In a third approach, we show that diabetogenic conditions also increase TSPO overexpression and IAPP fibril formation in rat beta pancreatic cell line (INS-1E). These data open the way for further studies in the field of type 2 diabetes treatment or prevention.

The central nervous system continuously detects circulating concentrations of lipids such as fatty acids and troglycerides. Once information has been detected, the central nervous system can in turn participate in the control of energy balance and blood sugar levels and in particular regulate the secretion and action of insulin. Neurons capable of detecting circulating lipid variations are located in the hypothalamus and in other regions such as the nucleus accumbens, the striatum or the hippocampus. An excess of lipids will have deleterious effects and may induce central lipotoxicity, in particular following local production of ceramides and the appearance of neuroinflammation which may lead to metabolic diseases such as obesity and type 2 diabetes.

Growth and proliferation of normal and cancerous cells necessitate a finely-tuned regulation of lipid metabolic pathways to ensure the timely supply of structural, energetic, and signaling lipid molecules. The synthesis and remodeling of lipids containing fatty acids with an appropriate carbon length and insaturation level are required for supporting each phase of the mechanisms of cell replication and survival. Mammalian Stearoyl-CoA desaturases (SCD), particularly SCD1, play a crucial role in modulating the fatty acid composition of cellular lipids, converting saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA) in the endoplasmic reticulum (ER). Extensive research has elucidated in great detail the participation of SCD1 in the molecular mechanisms that govern cell replication in normal and cancer cells. More recently, investigations have shed new light on the functional and regulatory role of the Δ9-desaturase in the processes of cell stress and cell death. This review will examine the latest findings on the involvement of SCD1 in the molecular pathways of cell survival, particularly on the mechanisms of ER stress and autophagy, as well in apoptotic and non-apoptotic cell death.

Listeria monocytogenes is a human opportunistic foodborne pathogen that produces life-threatening infections with a high mortality rate. The control of Listeria in the food production environment and effective clinical management of human listeriosis are challenging due to the emergence of antibiotic resistance. Hence we evaluate the in vitro anti-Listeria activity of two synthetic cruzioseptins reproducing their natural sequences CZS-9, and CZS-12, and one engineered sequence based on CZS-1, named [K4K15]CZS-1. The assessment of the in vitro potential of cruzioseptins, highlighted the promising antibacterial effect of [K4K15]CZS-1 in very low concentrations (0.91 μM) and its thermal stability at high-temperature conditions, is compatible with the food industry. Microscopic and metabolomic analyses suggest cruzioseptin induces anti-Listeria bioactivity through membrane disruption and changes in the intracellular metabolome. We also report that [K4K15]CZS-1 is not resistant to peptidases/proteases emphasizing a key advantage for their use as a food preservative. However, there is a need for further structural and functional optimisations for the potential clinical application as an antibiotic. In conclusion, [K4K15]CZS-1 stand out as membrane-active peptides with the ability to induce shifts in the bacteria metabolome and inspire the development of strategies for the prevention of L. monocytogenes emergence and dissemination.

The industrial world exposes living organisms to a variety of metal pollutants. Here we investigated whether such elements affect G-rich sequences susceptible to fold into G-quadruplex (GQ) structures. Thermal stability and conformation of these oligoncleotides was studied at various molar ratios of a variety of heavy metal salts using thermal FRET, transition-FRET (t-FRET) and circular dichroism. Metal ions affected the thermal stability of the GQs to different extents; some metals had no effect on T_m while other metals caused small to moderate changes in T_m at 1:1 or 1:10 molar ratio. While most of the metals had no major effect, Al³⁺, Cd²⁺, Pb²⁺, Hg²⁺ and Zn²⁺ altered the thermal stability and structural features of the GQs. Some metals such as Pb²⁺ and Hg²⁺ exhibit differential interactions with telomere, c-myc and c-kit GQs. Overall, toxic heavy metals affect G-quadruplex stability in a sequence and topology dependent manner. This study provides new insight into how heavy metal exposure may affect gene expression and cellular responses.