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Background The incidence of diabetic osteoporosis is increasing. This article evaluates the effect of combination treatment with the hypoglycemic drug exendin-4 (Ex-4) and the vitamin D analog eldecalcitol (ED-71) on improving diabetic osteoporosis and explores the relevant mechanism of action. Method Micro-CT, HE staining, immunohistochemistry, qPCR and ELISA were used to evaluate the impact of Ex-4 and ED-71 on bone formation and macrophage polarization in a mouse model of diabetic osteoporosis in vivo. Immunofluorescence, flow cytometry and qPCR were used to characterize the polarization type of macrophages treated with Ex-4 and ED-71 in vitro. A co-culture system of BMSCs and macrophages was established. Subsequently, crystal violet staining, alkaline phosphatase staining and alizarin red staining were used to evaluate the migration and osteogenesis differentiation of BMSCs. Results Ex-4 combined with ED-71 significantly reduced blood glucose levels and enhanced bone formation in mice with diabetic osteoporosis. In addition, Ex-4 synergized with ED-71 to induce the polarization of macrophages into M2 through the PI3K/AKT pathway. Macrophages treated with the combination of Ex-4 and ED-71 can significantly induce the osteogenic differentiation of BMSCs. Conclusion Ex-4 synergized with ED-71 to reduce blood glucose levels significantly. And this combination therapy can synergistically induce osteogenic differentiation of BMSCs by promoting M2 macrophages polarization, thereby improving diabetic osteoporosis. Therefore, the combination of Ex-4 and ED-71 may be a new strategy for the treatment of diabetic osteoporosis.

Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors worldwide, and its prognosis is still not optimistic. Oxaliplatin is a type of platinum chemotherapeutic agent, but its treatment effects on OSCC and molecular mechanisms have not been fully elucidated. Parthanatos, a unique form of cell death, plays an important role in a variety of physiological and pathological processes. This study aims to investigate whether oxaliplatin inhibits OSCC by inducing parthanatos. Our results showed that oxaliplatin inhibited the proliferation and migration of OSCC cells in vitro , and also inhibited the tumorigenesis in vivo . Further experiments proved that oxaliplatin induced parthanatos in OSCC cells, characterized by depolarization of the mitochondrial membrane potential, up-regulation of PARP1, AIF and MIF in the nucleus, as well as the nuclear translocation of AIF. Meanwhile, PARP1 inhibitor rucaparib and siRNA against PARP1 attenuated oxaliplatin-induced parthanatos in OSCC cells. In addition, we found that oxaliplatin caused oxidative stress in OSCC cells, and antioxidant NAC not only relieved oxaliplatin-induced overproduction of reactive oxygen species (ROS) but also reversed parthanatos caused by oxaliplatin. In conclusion, our results indicate that oxaliplatin inhibits OSCC by activating PARP1-mediated parthanatos through increasing the production of ROS.

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