Second Affiliated Hospital of Wenzhou Medical University

CXCR7, an alternative receptor for the inflammatory chemokine SDF-1, is involved in cell proliferation and migration. Recent studies have reported that CXCR7 also plays a role in adipose tissue. However, evidence regarding the role of CXCR7 and its ligands in adipocyte differentiation is limited. In this study, we aimed to elucidate changes in CXCR7 expression during adipocyte differentiation and the role of the SDF-1/CXCR7/CXCR4 axis in adipogenesis using recombinant SDF-1, the CXCR7 ligand CCX771, and small interfering RNAs. The results indicated that the levels of SDF-1 and its receptors, CXCR7 and CXCR4, decreased during the early stages of adipogenesis. Treatment with recombinant SDF-1 and CCX771 inhibited adipogenesis and lipid accumulation by inducing β-arrestin2, Wnt expression, and AKT phosphorylation and downregulating C/EBPα, PPARγ, and FABP4 expression. In contrast, knockdown of SDF-1 and CXCR7 in preadipocytes downregulated the β-arrestin2/Wnt and AKT pathway, leading to the induction of adipogenesis. Meanwhile, knockdown of CXCR4 had no significant effect. In mice, basal gene expression levels of SDF-1 and CXCR7 were higher in the stromal vascular fraction compared to mature adipocytes and were significantly upregulated by a high-fat diet. Our results provide new insights into the local role of the SDF-1-CXCR7 axis in adipocytes and offer additional benefits for the prevention of obesity-related metabolic disorders.

Currently, certain lung cancer patients exhibit resistance to radiotherapy due to reduced DNA damage under hypoxic conditions and the cytoprotective and immune-resistance effect caused by increased programmed death ligand-1 (PD-L1) and Cyclooxygenase 2 (COX-2) expression after radiotherapy. At present, existing nanoparticles or drugs could hardly effectively, and easily address these obstacles faced by highly effective radiotherapy simultaneously, especially the simultaneous depression of PD-L1 and COX-2. In this study, it is newly proved that some typical nitric oxide (NO) gas donors could co-inhibit PD-L1 and COX-2 expression, revealing the possible not fully proven role of NO in reversing tumor immunotherapy resistance. Then, to realize selective NO generation in tumors, a simple tumor glutathione (GSH) responsive NO gas nanogenerator named SAB-NO nanoparticles was designed and prepared, which was composed of the NO donor Isoamyl Nitrite conjugated with serum albumin (SAB). By doing this, SAB-NO nanoparticles more effectively sensitized radiotherapy through breaking the cytoprotective effects faced by radiotherapy in vitro by generating more DNA damage through reversing tumor hypoxia and impairing the DNA damage repair process through decreasing PD-L1 expression. Then, the combination therapy of SAB-NO nanoparticles and radiotherapy effectively transformed cold tumors into hot ones through avoiding some potential immune-resistance effects induced by radiotherapy treatment alone through PD-L1 and COX-2 co-inhibition. In conclusion, the combined treatment of radiotherapy and SAB-NO nanoparticles finally almost completely suppressed the growth of lung tumors, revealing the novel role of NO donors in sensitizing tumor immunotherapy by avoiding the potential cytoprotective and immune-resistance effects.

Propofol is widely used to induce and maintain anesthesia during gynecological surgery and assisted reproduction. However, few studies have investigated the influence of propofol on ovarian function and the related mechanism. In this study, propofol was administered to female mice, and ovarian function was evaluated by measuring serum AMH levels, follicle counts, and expression of related proteins. IOSE-80 and KGN cells were treated with propofol to assess mitochondrial function and mitophagy using fluorescence staining, ROS and mitochondrial membrane potential assays, and Western blotting. Recombinant TGF-β1 was applied both in vivo and in vitro to investigate the involvement of the TGF-β/SMAD2/3 signaling pathway. These results showed that propofol reduced the serum AMH level and the number of follicles in the mice ovaries, downregulated the protein expressions of FSHR and CYP19A1, and facilitated ovarian cell apoptosis both in vivo and in vitro. Treatment with propofol significantly decreased the mitochondrial fluorescence intensity and increased mitophagy fluorescence in IOSE-80 and KGN cells. Additionally, propofol enhanced ROS generation, decreased mitochondrial membrane potential and increased the levels of proteins associated with mitophagy (LC3B, PINK1, PARKIN). Propofol lessened the abundance of TGF-β1, SMAD2/3 and phosphorylated-SMAD2/3. Co-treatment with recombinant TGF-β1 significantly increased cell survival, reduced apoptosis, and upregulated the protein expression levels of FSHR, CYP19A1, PINK1, and PARKIN in IOSE-80 and KGN cells. These results demonstrated that propofol over-activates mitophagy through the TGF-β/SMAD2/3 pathway, and thus affects ovarian function. This finding provides some guidance for women with fertility needs when choosing anesthesia drugs for surgery.