PARN Maintains RNA Stability to Regulate Insulin Maturation and GSIS in Pancreatic ß Cells.

Diabetes, a metabolic disorder characterized by hyperglycemia, underscores the importance of normal pancreatic ß-cell development and function in maintaining glucose homeostasis. Poly(A)-specific ribonuclease (PARN) serves as the principal regulator of messenger RNA (mRNA) stability, yet its specific role in pancreatic ß cells remains unclear. This study utilizes mice with targeted PARN deficiency in ß cells to elucidate this role. Notably, Parn conditional knockout mice present unaltered ß-cell development and insulin sensitivity but reduced glucose-stimulated insulin secretion (GSIS). The observed outcomes are corroborated in NIT-1 cells. Furthermore, transcriptomic analyses reveal aberrant mRNA expression of genes crucial for insulin secretion in PARN-deficient ß cells. Insights from linear amplification of complementary DNA ends and sequencing and coimmunoprecipitation experiments reveal an interaction between PARN and polypyrimidine tract-binding protein 1 (PTBP1), regulating the RNA stability of solute carrier family 30, member 8 (Slc30a8) and carbohydrate sulfotransferase 3 (Chst3). Interference with either PARN or PTBP1 disrupts this stability. These data indicate that PARN deficiency hampers GSIS and insulin maturation by destabilizing Slc30a8 and Chst3 RNAs. These findings provide compelling evidence indicating that PARN is a potential therapeutic target for enhancing insulin maturation and secretion.

TSPAN4 influences glioblastoma progression through regulating EGFR stability.

Glioblastoma (GBM) is characterized by high morbidity, mortality, and low cure rates. Recent studies suggest that TSPAN4 is recognized as a marker protein for migrasomes, a vesicular organelle associated with cell migration. However, the intrinsic role of TSPAN4 in cancers has not been clarified, especially in GBM. Here, we report that TSPAN4 promotes GBM progression by interacting with epidermal growth factor receptor (EGFR) and regulating its stability. Clinically, TSPAN4 is highly expressed in GBM and is significantly correlated with poor prognosis. Functionally, TSPAN4 knockdown dramatically inhibits GBM cell proliferation and invasion in vitro, as well as tumorigenicity in vivo. Conversely, overexpression of TSPAN4 facilitates GBM progression. Mechanistically, TSPAN4 knockdown disrupts interaction with EGFR, destabilizing its expression and inactivating EGFR and downstream signaling pathways, such as MEK/ERK, STAT3, and AKT. Our study reveals that TSPAN4 drives GBM progression through regulating EGFR stability and could be a potential target for cancer therapy.

B Cells Dynamic in Aging and the Implications of Nutritional Regulation.

Aging negatively affects B cell production, resulting in a decrease in B-1 and B-2 cells and impaired antibody responses. Age-related B cell subsets contribute to inflammation. Investigating age-related alterations in the B-cell pool and developing targeted therapies are crucial for combating autoimmune diseases in the elderly. Additionally, optimal nutrition, including carbohydrates, amino acids, vitamins, and especially lipids, play a vital role in supporting immune function and mitigating the age-related decline in B cell activity. Research on the influence of lipids on B cells shows promise for improving autoimmune diseases. Understanding the aging B-cell pool and considering nutritional interventions can inform strategies for promoting healthy aging and reducing the age-related disease burden.

Chiral Vanadyl(V) Complexes Enable Efficient Asymmetric Reduction of ß-Ketoamides: Application toward (S)-Duloxetine.

High-valent chiral oxidovanadium(V) complexes derived from 3,5-substituted-N-salicylidene-l-tert-leucine were used as catalysts in asymmetric reduction of N-benzyl-ß-ketoamides. Among six different solvents, three different alcohol additives, and two different boranes examined, the use of pinacolborane in tetrahydrofuran (THF) with a t-BuOH additive led to the best results at -20 °C. The corresponding ß-hydroxyamides can be furnished with yields up to 92% and an enantiomeric excess (ee) up to 99%. We have successfully extended this catalytic protocol for the synthesis of an (S)-duloxetine precursor.