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Aim To analyse the effect of systemic application of N-methyl pyrrolidone ( NMP) on the pulp-dentine complex and on the jawbone of ovariectomized rats. Method Female Sprague Dawley rats were randomly divided into a Sham-operated group (Sham n = 6) and an oestrogen depletion by ovariectomy ( OVX n = 12) group. In 6 of the ovariectomized animals, N-methyl pyrrolidone ( NMP) in phosphate-buffered saline ( PBS) was administered systemically weekly by intraperitoneal injection (i.p.); the other 6 were injected with PBS (Veh). After 15 weeks of injections, the jaw bones were collected and pulps extracted from the incisors teeth. Histology was used to determine pre-dentine thickness in teeth and radiography to determine alveolar bone mass. Immunohistological staining and RT- PCR were performed to verify the presence and localization of the odontoblast-specific dentine sialoprotein and to quantify its expression in the dentine-pulp complex. Mandibular cortical width and mandibular height were evaluated by means of X-ray analysis. Statistical analysis was performed with analysis of variance ( anova). Results Both pre-dentine ( P = 0.029) and alveolar bone structures ( P = 0.049) were significantly reduced due to oestrogen deficiency in OVX Veh and OVX. NMP treatment normalized these parameters to the Sham level. DSPP expression in OVX NMP animals was significantly higher ( P = 0.046) than in OVX Veh. X-ray analysis confirmed that ovariectomy significantly reduced the mandibular cortical width in the OVX Veh group compared to the Sham Veh and OVX NMP ( P = 0.020). Conclusion N-methyl pyrrolidone ( NMP) had a remarkable anti-osteoporotic ability preserving activity in the pulp-dentine complex and preventing jawbone loss. These effects make NMP a promising candidate for the preservation of the activity of the pulp-dentine complex and jawbone thickness in post-menopausal females. [ABSTRACT FROM AUTHOR]

Epithelial skin cancers are extremely common, but the mechanisms underlying their malignant progression are still poorly defined. Here, we identify the NRF3 transcription factor as a tumor suppressor in the skin. NRF3 protein expression is strongly downregulated or even absent in invasively growing cancer cells of patients with basal and squamous cell carcinomas (BCC and SCC). NRF3 deficiency promoted malignant conversion of chemically induced skin tumors in immunocompetent mice, clonogenic growth and migration of human SCC cells, their invasiveness in 3D cultures, and xenograft tumor formation. Mechanistically, the tumor-suppressive effect of NRF3 involves HSPA5, a key regulator of the unfolded protein response, which we identified as a potential NRF3 interactor. HSPA5 levels increased in the absence of NRF3, thereby promoting cancer cell survival and migration. Pharmacological inhibition or knock-down of HSPA5 rescued the malignant features of NRF3-deficient SCC cells in vitro and in preclinical mouse models. Together with the strong expression of HSPA5 in NRF3-deficient cancer cells of SCC patients, these results suggest HSPA5 inhibition as a treatment strategy for these malignancies in stratified cancer patients., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)