Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD + metabolism influences both tissue ageing and cancer. However, the role of NAD + metabolism in regulating the SASP is poorly understood. Here we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD + salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT is regulated by HMGAs during senescence. The HMGAs/NAMPT/NAD + signaling axis promotes the proinflammatory SASP through enhancing glycolysis and mitochondrial respiration. HMGAs/NAMPT promotes the proinflammatory SASP through NAD + -mediated suppression of AMPK kinase, which suppresses p53-mediated inhibition of p38MAPK to enhance NFκb activity. We conclude that NAD + metabolism governs the proinflammatory SASP. Given the tumor-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD + augmentation should be administered with precision.

Fuzeon (also known as T-20 or enfuvirtide), one of the C-peptides derived from the HIV-1 envelope glycoprotein transmembrane subunit gp41 C-terminal heptad repeat (CHR) region, is the first member of a new class of anti-HIV drugs known as HIV fusion inhibitors. It has been widely believed that T-20 shares the same mechanism of action with C34, another C-peptide. The C34 is known to compete with the CHR of gp41 to form a stable 6-helix bundle (6-HB) with the gp41 N-terminal heptad repeat (NHR) and prevent the formation of the fusogenic gp41 core between viral gp41 NHR and CHR, thereby inhibiting fusion between viral and target cell membranes. Here we present data to demonstrate that, contrary to this belief, T-20 cannot form stable 6-HB with N-peptides derived from the NHR region, nor can it inhibit the 6-HB formation of the fusogenic core. Instead, it may interact with N-peptides to form unstable or insoluble complexes. Our data suggest that T-20 has a different mechanism of action from C34. The interaction of T-20 with viral NHR region alone may not prevent the formation of the fusion active gp41 core. We also demonstrate that the T-20-mediated anti-HIV activity can be significantly abrogated by peptides derived from the membrane-spanning domain in gp41 and coreceptor binding site in gp120. These new findings imply that T-20 inhibits HIV-1 entry by targeting multiple sites in gp41 and gp120. Further elucidation of the mechanism of action of T-20 will provide new target(s) for development of novel HIV entry inhibitors.

Three-dimensional (3D) hierarchically porous nanostructures with controlled morphology and dimensionality represent one kind of important material and have received enormous attention for a series of applications. In this work, 3D hierarchically porous ZnO architectures were synthesized via an amino acid-assisted biomimetic hydrothermal method combined with subsequent calcination. First a basic zinc carbonate (BZC) precursor with a lamellar spherical morphology assembled by interconnected nanosheets was synthesized. By subsequent calcination, the as-obtained BZC precursor can be facilely transformed into porous ZnO with a large surface area of 193.7 m 2 /g, while maintaining its 3D hierarchical morphology. The 3D hierarchically porous ZnO superstructures are further employed as a support to load Au nanoparticles (AuNPs) to construct hybrid nanomaterials for chemical gas sensors. The AuNP-functionalized 3D hierarchically porous ZnO nanomaterials, combining the high surface accessibility of porous materials and catalytic activity of small AuNPs, demonstrated excellent sensor properties in terms of higher sensitivity and very fast response. Furthermore, it is expected this AuNP-functionalized 3D hierarchically porous nanostructure may provide a new pathway to develop advanced nanomaterials for applications like gas sensors, low temperature CO oxidation and photocatalysis.

Hierarchically three-dimensional (3D) porous ZnO architectures were synthesized by a template-free, economical hydrothermal method combined with subsequent calcination. First, a precursor of hierarchical basic zinc carbonate (BZC) nanostructures self-assembled by sheet-like blocks was prepared. Then calcination of the precursor produced hierarchically 3D porous ZnO architectures composed of interconnected ZnO nanosheets with high porosity resulting from the thermal decomposition of the precursor. The products were characterized by X-ray diffraction, Fourier tranform infrared spectroscopy, thermogravimetric-differential thermalgravimetric analysis, scanning electron microscopy, transmission electron microscopy, and Brunauer-Emmett-Teller N 2 adsorption-desorption analyses. Control experiments with variations in solvent and reaction time respectively revealed that ethanol was responsible for the formation of the BZC precursor, and the self-assembly of BZC nanosheets into hierarchically 3D architectures was highly dependent on the reaction time. Gas sensing tests showed that these hierarchically porous ZnO architectures were highly promising for gas sensor applications, as the gas diffusion and mass transportation in sensing materials were significantly enhanced by their unique structures. Moreover, it is believed that this solution-based approach can be extended to fabricate other porous metal oxide materials with a unique morphology or shape.

ARID1A , encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wildtype, tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylates Lys-120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates p53’s apoptosis-promoting function by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.