Plasmid DNA-coding p62 as a bone effective anti-inflammatory/anabolic agent

Abstract

We recently reported that a DNA plasmid coding p62-SQSTM1 acts as an effective anti tumor vaccine against both transplantable mouse tumors and canine spontaneous mammary neoplasms. Here we report the unexpected finding that intramuscular delivery of p62 DNA exerts a powerful anti-osteoporotic activity in a mouse model of inflammatory bone loss (i.e, ovariectomy) by combining bone-sparing and osteo-synthetic effects. Notably, the suppression of osteoporosis by p62DNA was associated with a sharp down-regulation of master inflammatory cytokines, and up-regulation of endogenous p62 protein by bone-marrow stromal cells. The present data provide a solid rational to apply p62 DNA vaccine as a safe, new therapeutic for treatment of inflammatory related bone loss diseases.

In vivobiocompatibility of p(HPMAm-lac)-PEG hydrogels hybridized with hyaluronan

“…Notably, after 3 weeks of treatment, tumour necrosis factor alpha (TNF‐α) was also decreased (Figure c). All of these compounds are well known to play important roles in a number of chronic and acute inflammatory diseases (Dinarello, ; Sasaki et al , ; Sabbieti et al , ). In this context, it is assumed that this peculiar anti‐inflammatory effect of the VinylSulfTC_10/HA‐SH_56 hydrogels administered resulted from HA release during the hydrogel degradation.…”

p62/SQSTM1 – steering the cell through health and disease

“…osteosarcoma, oral squamous cell carcinoma, cutaneous malignant melanoma, esophageal adenocarcinoma, ovarian, colon, breast and non-small cell lung cancers, and solid tumors Daniels et al, 2013;Ellis et al, 2014;Giatromanolaki et al, 2014;Inoue et al, 2012;Iwadate et al, 2014;Liu et al, 2014a;Luo et al, 2013;Ma et al, 2018;Niklaus et al, 2017;Park et al, 2013;Ruan et al, 2018;Schläfli et al, 2016), and has attracted attention as a potential therapeutic target (Yan et al, 2017;Zhang et al, 2016). An antitumor SQSTM1 DNA vaccine has already been developed and trialed in humans (Gabai et al, 2014;Ponomarenko et al, 2017;Sabbieti et al, 2015;Venanzi et al, 2013); however, SQSTM1 can have both beneficial and deleterious effects depending on the pathological context, as is the case for autophagy itself (Dikic and Elazar, 2018). Then, any hope to develop successful therapeutic strategies in pathologies with SQSTM1 alterations needs to keep in mind the complexity of the SQSTM1 signaling network and how it is affected in each particular disease situation: its tight posttranslational regulation, its role in autophagy, its function in the Keap1-Nrf2 axis and its role as a signaling hub.…”

p62/SQSTM1 expression in canine mammary tumours: Evolutionary notes

“…Of note p62 DNA treatment of patients partially restored their sensitivity to conventional chemotherapy which they previously failed . However, it remains to be revealed if the anti‐cancer activity of p62‐encoding plasmid in humans is due to a direct adaptive immune response it elicits against the over‐expressed p62 as it was originally hypothesized or if the anti‐cancer effect results from the fact that the plasmid reduces chronic inflammation as observed in animal models for osteoporosis, age‐related macular degeneration and diet‐induced obesity .…”

“…In the supernatant the protein concentration was determined following the Bradford method . Western blotting was performed as previously described . Human recombinant p62 was purchased from Enzo Life Sciences (Vinci‐Biochem s.r.l., Firenze, Italy).…”

“…After washing blots were incubated with horseradish peroxidase (HRP)‐conjugated donkey anti‐rabbit IgG (Cell Signaling, Euroclone Milano, Italy). Immunoreactive bands were visualized using luminol reagents/ECL film as described …”