A main feature of aged organisms is the accumulation of senescent cells. Accumulated senescent cells, especially stress-induced premature senescent cells, in aged organisms lead to the decline of the regenerative potential and function of tissues. We recently reported that the over-expression of NAMPT, which is the rate-limiting enzyme in mammalian NAD+ salvage pathway, delays replicative senescence in vitro. However, whether Nampt-overexpressing cells are tolerant of stress-induced premature senescence remains unknown. Here, we show that primary mouse embryonic fibroblasts derived from Nampt-overexpressing transgenic mice (Nampt Tg-MEF cells) possess resistance against stress-induced premature senescence in vitro. We found that higher oxidative or endoplasmic reticulum (ER) stress is required to induce premature senescence in Nampt Tg-MEF cells compared to wild-type cells. Moreover, we found that Nampt Tg-MEF cells show acute expression of unfolded protein response (UPR)-related genes, which in turn would have helped to restore proteostasis and avoid cellular senescence. Our results demonstrate that NAMPT/NAD+ axis functions to protect cells not only from replicative senescence, but also from stress-induced premature senescence in vitro. We anticipate that in vivo activation of NAMPT activity or increment of NAD+ would protect tissues from the accumulation of premature senescent cells, thereby maintaining healthy aging.
Snakebite-induced local tissue damage remains a challenge in snakebite envenoming management because venom toxins rapidly disrupt vascular and extracellular matrix integrity at the bite site. This study evaluated the inhibitory effect of marimastat, an inhibitor of zinc-dependent metalloproteinases, against local tissue damage induced by Indonesian Trimeresurus insularis and Calloselasma rhodostoma venoms in a mouse skin model. The minimum hemorrhagic dose (MHD) of C. rhodostoma venom was determined in BALB/c mice and estimated to be 7.07 µg, while the MHD of T. insularis was adopted from a previous study. Mice received intradermal injections of venom at 2× MHD, either alone or pre-incubated with marimastat at venom:marimastat ratios of 1:1, 1:5, and 1:10 based on MHD equivalents. Macroscopic hemorrhage and histopathological changes, including erythrocyte extravasation, inflammatory cell infiltration, and collagen degradation, were assessed three hours after injection. Both venoms induced marked hemorrhagic lesions and tissue damage. Marimastat reduced venom-induced hemorrhage in both models, with near-complete inhibition in the T. insularis 1:10 group and complete inhibition in the C. rhodostoma 1:10 group. Marimastat also decreased erythrocyte extravasation, inflammatory infiltration, and collagen degradation, indicating preservation of microvascular and dermal matrix integrity. These findings support the central role of snake venom metalloproteinases in local viperid tissue damage and highlight marimastat as a promising adjunctive treatment for reducing venom-induced skin injury.