Lysine 63 ubiquitination is involved in the progression of tubular damage in diabetic nephropathy

The purpose of our study was to evaluate how hyperglycemia (HG)influences Lys63 protein ubiquitination and its involvement in tubular damage and fibrosis in diabetic nephropathy (DN). Gene and protein expression of UBE2v1, a ubiquitin-conjugating E2-enzyme variant that mediates Lys63-linked ubiquitination, and Lys63-ubiquitinated proteins increased in HK2 tubular cells under HG. Matrix-assisted laser desorption/ionization-time of flight/tandemmass spectrometry identified 30 Lys63-ubiquitinated proteins, mainly involved in cellular organization, such as \u3b2-actin, whose Lys63 ubiquitination increased under HG, leading to cytoskeleton disorganization. This effect was reversed by the inhibitor of the Ubc13/UBE2v1 complexNSC697923. Western blot analysis confirmed that UBE2v1 silencing in HK2 under HG, restored Lys63-\u3b2-actin ubiquitination levels tothebasal condition. Immunohistochemistry on patients with type 2diabetic (T2D) revealed an increase in UBE2v1-and Lys63-ubiquitinatedproteins, particularly in kidneys of patients with DN compared with control kidneys and other non diabetic renal diseases, such as membranous nephropathy. Increased Lys63 ubiquitination both in vivo in patients with DN and in vitro, correlated with a-SMA expression, whereas UBE2v1 silencing reduced HG-induced a-SMA protein levels, returning them to basal expression. In conclusion, UBE2v1- and Lys63-ubiquitinated proteins increase in vitro under HG, as well as in vivo in T2D, is augmented in patients with DN, and may affect cytoskeleton organization and influence epithelial-to-mesenchymal transition. This process may drive the progression of tubular damage and interstitial fibrosis in patients with DN

Recent Advances in Synthesis of P-BH3 Compounds

International audienceThis chapter is dedicated to the main achievements since 2007 regarding the synthesis of BH3-phosphorus complexes. Among this class of compounds, phosphine-boranes are the most studied derivatives, mainly as valuable surrogates of phosphines, enabling easy handling and purification. Contrarily, metal phosphido-boranes were so far only considered as in situ intermediates in the P-functionalization of secondary phosphine-boranes. Thorough investigations of their structures as well as their chemical properties have been recently reported. Besides, phosphine-boranes and their phosphides, new families of phosphorus-BH3 complexes, have emerged as useful precursors of new structures in the asymmetric series. New routes toward optically active phosphinous-acid boranes and their esters were developed and applied to the synthesis of enantiopure P-stereogenic secondary and tertiary phosphine-boranes. The stereoselective synthesis of P-stereogenic aminophosphine-boranes, precursors of a new class of chiral ligands has been shortly reported. Studies dealing with the synthesis and reactivity of phosphonite-boranes were successfully applied to the development of efficient syntheses of functionalized H-phosphinates, compounds difficult to access by other routes

The Association between Early Childhood and Later Childhood Sugar-Containing Beverage Intake: A Prospective Cohort Study

Sugar-containing beverages (SCBs) are a major source of sugar intake in children. Early life intake of SCBs may be a strong predictor of SCB intake later in life. The primary objective of this study was to evaluate if SCB intake (defined as 100% fruit juice, soda, and sweetened drinks) in early childhood (≤2.5 years of age) was associated with SCB intake in later childhood (5-9 years of age). A prospective cohort study was conducted using data from the TARGet Kids! primary care practice network (n = 999). Typical daily SCB intake was measured by parent-completed questionnaires. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. A total of 43% of children consumed ≥0.5 cups/day of SCBs at ≤2.5 years and this increased to 64% by 5-9 years. Daily SCB intake, compared to no daily intake, at ≤2.5 years was significantly associated with SCB intake at 5-9 years (adjusted OR: 4.03; 95% CI: 2.92-5.55) and this association was much stronger for soda/sweetened drinks (adjusted OR: 12.83; 95% CI: 4.98, 33.0) than 100% fruit juice (OR: 3.61; 95% CI: 2.63-4.95). Other early life risk factors for SCB intake at 5-9 years were presence of older siblings, low household income, and shorter breastfeeding duration. Daily intake of SCBs in early childhood was strongly associated with greater SCB intake in later childhood. Early life may be an important period to target for population prevention strategies. </p