PARP1 inhibition enhances reactive oxygen species on gut microbiota

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) plays a key role in genome stability by modulating DNA-damage responses. Activated by DNA interruptions through ultraviolet (UV) exposure, PARylation is synthesized by PARP1 and serves as a survival mechanism for cancer and metabolic diseases. Several strategies including ROS and antimicrobial peptides (AMPs) function in host defenses, while the targeted tissue and mechanism under DNA damage are unknown. Here, we show that DNA damage induces responses specifically in the gut tissue. The knockdown of PARP1 reduces the activation of PARylation. Parp1 knockdown under DNA damage results in over-accumulated ROS and secretion of AMPs through the regulation of Relish, a subunit of nuclear factor-κB (NF-κB). Double-knockdown of Parp1 and Relish specifically in the gut inhibits AMP secretion. In conclusion, the host defense is achieved through ROS accumulation rather than the AMPs under DNA damage. In contrast, the knockdown of PARP1 exacerbates ROS accumulation to a harmful level. Under this circumstance, NF-κb targeted AMP secretion is provoked for host defense. Microbiome and functional analysis provide evidence for the hazard of DNA damage and show variations in the metabolic pathways following Parp1 inhibition. Our findings suggest the notion that PARP1 inhibition contributes to ROS accumulation under DNA damage and its role in NF-κb activation for host defense.

Specific and shared biological functions of PARP2 – is PARP2 really a lil’ brother of PARP1?

“…Since microbial antigens modulate iNKT activation (Refs 257, 258, 261, 262), gut microbiota composition may have significant effect on iNKT cell function not only in intestine but probably distant tissues, as well (Refs 255, 261, 262, 263). Interestingly, PARP1−/− mice display a more diverse gut microbiota composition compared to their wild-type littermates (Refs 264, 265, 266), although these alterations were not linked to immune modifications in PARP1−/− mice so far. Future studies might determine if a functional association exists between gut microbiota and immune cell homoeostasis in PARP2−/− mice.…”

Molecular Dipole Modulation of Porphyrins to Enhance Photocatalytic Oxidation Activity for Inactivation of Intracellular Bacteria

“…coli), and vancomycin-resistant S. aureus (VRSA), and so on are represented by β -lactamase production. − The antibacterial approach using reactive oxygen species (ROS) is different from carbapenem antibiotics and is not limited by traditional resistance mechanisms, so it can inhibit the growth of drug-resistant microorganisms. − Moreover, the sterilization mechanism of ROS is derived from its oxidative properties, and this effect is not easy to induce mutation to generate new drug-resistant bacteria. − …”

PARP-1 inhibitor alleviates liver lipid accumulation of atherosclerosis via modulating bile acid metabolism and gut microbes

“…In the past, poly(ADP-ribose) polymerase 1(PARP1), the foremost isoform of the PARP enzyme family, a cellular stress sensor, has been used to treat cancers. 6,7 Notably, PARP1 plays a vital role in glucose and lipid metabolism and is widely expressed in almost all tissues and cells of the human body, including metabolic tissues and organs such as the liver, skeletal muscle, hormone glands, and adipose tissue. 8 These findings suggest that activated PARP1 poly(ADP)ribosylated CCAAT enhancer binding protein beta (C/EBPb) and peroxisome proliferator-activated receptor (PPARb, PPARa) restrict adipogenesis and fatty acid metabolism.…”