The hallmarks of systemic sclerosis (SSc) are autoimmunity, microangiopathy and fibrosis. Skin fibrosis is accompanied by attrition of the dermal white adipose tissue layer, and alterations in the levels and function of adiponectin. Since these findings potentially implicate adiponectin in the pathogenesis of SSc, we employed a novel pharmacological approach to augment adiponectin signaling using AdipoRon, an orally active adiponectin receptor agonist. Chronic treatment with AdipoRon significantly ameliorated bleomycin-induced dermal fibrosis in mice. AdipoRon attenuated fibroblast activation, adipocyte-to-myofibroblast transdifferentiation, Th2/Th17-skewed polarization of the immune response, vascular injury and endothelial-to-mesenchymal transition within the lesional skin. In vitro, AdipoRon abrogated profibrotic responses elicited by TGF-β in normal fibroblasts, and reversed the inherently-activated profibrotic phenotype of SSc fibroblasts. In view of these broadly beneficial effects on all three cardinal pathomechanisms underlying the clinical manifestations of SSc, pharmacological augmentation of adiponectin signaling might represent a novel strategy for the treatment of SSc.

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Chronic stimulations of ANE or ANE 30-100 K may increase tolerance of oral cancer and leukemia T cells to anticancer drugs, as well as to glucose deprivation and hypoxia conditions, and cause an elevation of autophagy activity responsible for increased drug resistance.

This study aimed to investigate the effect of EBI3 on radiation-induced immunosuppression of cervical cancer HeLa cells by regulating Treg cells through PD-1/PD-L1 signaling pathway. A total of 43 adult female Wistar rats were selected and injected with HeLa cells in the caudal vein to construct a rat model of cervical cancer. All model rats were randomly divided into the radiotherapy group ( n = 31) and the control group ( n = 12). The immunophenotype of Treg cells was detected by the flow cytometry. The protein expressions of EBI3, PD-1, and PD-L1 in cervical cancer tissues were tested by the streptavidin-peroxidase method. HeLa cells in the logarithmic growth phase were divided into four groups: the blank, the negative control group, the EBI3 mimics group, and the EBI3 inhibitors group. Western blotting was used to detect PD-1 and PD-L1 protein expressions. MTT assay was performed to measure the proliferation of Treg cells. Flow cytometry was used to detect cell cycle and apoptosis, and CD4/CD8 T cell ratio in each group. Compared with before and 1 week after radiotherapy, the percentages of CD4T cells and CD8T cells were significantly decreased in the radiotherapy group at 1 month after radiotherapy. Furthermore, down-regulation of EBI3 and up-regulation of PD-1 and PD-L1 were observed in cervical cancer tissues at 1 month after radiotherapy. In comparison to the blank and negative control groups, increased expression of EBI3 and decreased expressions of PD-1 and PD-L1 were found in the EBI3 mimics group. However, the EBI3 inhibitors group had a lower expression of EBI3 and higher expressions of PD-1 and PD-L1 than those in the blank and negative control groups. The EBI3 mimics group showed an increase in the optical density value (0.43 ± 0.05), while a decrease in the optical density value (0.31 ± 0.02) was found in the EBI3 inhibitors group. Moreover, compared with the blank and negative control groups, the apoptosis rates of Treg/CD4T/CD8T cells were decreased in the EBI3 mimics group, but the EBI3 inhibitors group exhibited an increase in apoptosis rate. In conclusion, over-expression of EBI3 could reduce the apoptosis of Treg/CD4T/CD8T cells and prevent radiation-induced immunosuppression of cervical cancer HeLa cells by inhibiting the activation of PD-1/PD-L1 signaling pathway.