PBX1-SIRT1 positive feedback loop attenuates ROS-mediated HF- MSC senescence and apoptosis

Abstract

Background: Stem cell senescence and depletion are major causes of organismal aging and aging-related diseases. The NAD–SIRT1–PARP1 axis has garnered remarkable interest owing to its significant role in regulating stem cell senescence and organismal aging. Event though our recent study showes that PBX1 overexpression attenuates hair follicle-derived mesenchymal stem cell (HF-MSC) senescence and apoptosis by regulating ROS-mediated DNA damage via downregulation of PARP1 expression, suggesting PARP1 downregulation is a common manifestation of the roles of both PBX1 and SIRT1 in the attenuation of HF-MSC senescence, and implying a potential link between PBX1 and SIRT1 via PARP1. Methods: HF-MSCs overexpressing PBX1, overexpressing both PBX1 and PARP1, downregulating SIRT1, and overexpressing PBX1 and downregulating SIRT1 were generated, and biomarkers related to cell senescence, apoptosis, DNA damage, and repair were detected at the cellular and protein levels. Results: (1) PBX1 overexpression alleviated HF-MSC senescence and apoptosis accompanied by upregulation of SIRT1 expression, downregulation of PARP1 expression, and increased intracellular NAD and ATP levels. (2) SIRT1 knockdown or PARP1 overexpression enhanced cellular senescence and apoptosis, accompanied by increased ROS accumulation and DNA damage aggravation and decreased intracellular NAD and ATP levels. (3) PBX1 overexpression rescued HF-MSC senescence and apoptosis induced by SIRT1 knockdown or PARP1 overexpression. (4) Dual luciferase reporter showed PBX1 enhanced SIRT1 expression by activating SIRT1 promoter. Conclusions: Our results reveal that a positive interaction feedback loop exists between PBX1 and SIRT1, that PBX1 is the upstream of SIRT1. To the best of our knowledge we are the first to report that there is a PBX1-SIRT1-PARP1 axis and this axis plays a critical role in alleviation of HF-MSC senescence and apoptosis. The results provide a new perspective on the mechanism of stem cell senescence and age-related disease prevention and treatment.

A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence

“…This test had the capacity for high power to detect even subtle contributions from transcription factors if they had deep binding-site coverage in the input data; five factors attained genome-wide significance (Figure 3B). Among them, PBX1 (Wang et al 2021) and CREBBP (Bandyopadhyay et al 2002;Yang et al 2021) were previously implicated in cellular senescence, providing a first line of evidence for the strength of our approach to identify signatures of condition-dependent transcription factor function. The top-scoring transcription factor in our screen, a basic-helix-loop-helix leucine-zipper protein called upstream stimulatory factor 2 (USF2; Figure 3B-C), had not been experimentally characterized in stress response or senescence.…”

Inhibitory effects of Moringa oleifera leaves extract on xanthine oxidase activity from bovine milk

“…In general, two compounds were reported to have antioxidant activity among the three main compounds, and no activity was reported for 2-dimethyl(trimethylsilylmethyl)silyloxymethyltetrahydrofuran from the samples (Pero 2009;Verma et al 2019). Besides being an antioxidant, quinic acid has anti-inflammatory (Nam et al 2019), anti-hepatitis B virus (Wang et al 2009), and hepatoprotective activities (Kim et al 2007). The biological activity Tabel 1.…”