Background: Sjögren's syndrome (SS), an autoimmune disease, was characterized by sicca syndrome and systemic manifestations, presenting significant treatment challenges. Exosomes, naturally derived nanoparticles containing bioactive molecules, have garnered interest in regenerative medicine. The present study aimed to elucidate the immunoregulatory properties and mechanism of exosomes obtained from the stem cells derived from human exfoliated deciduous teeth (SHED-exos) in SS-induced sialadenitis. Methods: SHED-exo nanoparticles were injected into submandibular glands (SMGs) of 14-week-old nonobese diabetic (NOD) mice, a classic animal model of SS. At 21 weeks, the saliva flow rate (SFR) was measured. Lymphocyte proportions were examined via flow cytometry. Inflammatory cytokine levels were examined by the Quantibody mouse Th1/Th2/Th17 array and ELISA. miR-29a-3p expression and its regulatory effect on T-bet was detected using FISH and luciferase reporter gene assay, respectively. Results: SHED-exos injected into SMGs increased SFR, reduced lymphocytic infiltration, and decreased inflammatory cytokine levels in serum, SMG tissues, and saliva. Mechanistically, SHED-exos suppressed the Th1 proportion in spleen lymphocytes in NOD mice. Exosomal miR-29a-3p targeted and suppressed T-bet expression, which is a Th1-specific transcription factor. In vitro, SHED-exos (but not miR-29a-3p-inhibited exosomes) decreased the level of Th1 differentiation and IFN-γ and TNF-α production. Furthermore, SHED-exos (but not miR-29a-3p-inhibited exosomes) blocked the increase in IFN-γ and TNF-α production induced by T-bet overexpression. In vivo, miR-29a-3p-inhibited exosomes neither increase saliva secretion in NOD mice nor decrease lymphocytic infiltration, T-bet expression, and IFN-γ and TNF-α levels in SMGs. Conclusion: SHED-exos suppress Th1 cell differentiation and response through the miR-29a-3p/T-bet axis, contributing to amelioration of SS-induced hyposalivation.

P53 deficiency plays a crucial role in chemotherapy resistance through various biological events, including posttranslational modifications (PTMs). Recently, lysine crotonylation (Kcr) has been shown to play a vital role in cancer progression. However, the global p53-regulated crotonylome and the function of these altered Kcr proteins after p53 deficiency remain unclear. In this study, we used a SILAC-based quantitative crotonylome to identify 3,520 Kcr in 1924 crotonylated proteins in response to p53 knockout. We found that increased crotonylation of RRM2 at K283 (RRM2^K283Cr) in the presence of p53 deficiency promoted HCT116 cell resistance to cisplatin. We discovered that SIRT7 could be the decrotonylase of RRM2 and was downregulated after p53 knockout, resulting in increased RRM2^K283Cr. Mechanistically, p53 deficiency inhibited cell apoptosis by upregulating RRM2 protein expression and RRM2^K283Cr-mediated cleaved-PARP1 and cleaved-caspase3 expression, and SIRT7 was downregulated to upregulate crotonylation of RRM2 upon p53 deficiency. In conclusion, our results indicated that p53 deficiency plays a malignant role in colon cancer resistance to cisplatin therapy by regulating RRM2 protein and RRM2^K283Cr expression. Our findings provide a novel therapeutic target against p53-deficient cancer.

Background: Sjögren’s syndrome (SS) is an autoimmune disorder characterized by sicca syndrome and/or systemic manifestations. In this study, non-obese diabetic (NOD) mice were used as an animal model for studying SS, to evaluate the optimal administration route and dose range of dental pulp stem cells (DPSCs) in the treatment of sialadenitis caused by SS. Methods: Different doses of DPSCs were transplanted into the submandibular glands (SMGs) of 14-week-old NOD mice through two different methods: injection or retrograde perfusion through the catheter orifice into the SMG. At 21 weeks of age, the saliva flow rate (SFR), ectopic lymphocytes, and CD4⁺ T-cell infiltration were measured. Tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) in the glandular tissues were also quantitatively detected. Results: Compared with untreated and PBS-injected controls, different-dose groups of the two administration methods showed an increased saliva flow rate of NOD mice to varying degrees, reduced infiltration of lymphocytes and CD4⁺ T cells in the SMG, and decreased IFN-γ/TNF-α levels. Finally, we compared these two administration routes and found that the perfusion of 2 × 10⁵ DPSCs presents good therapeutic effects. Conclusions: DPSC perfusion through the catheter orifice is a simple and effective treatment method, which is worthy of further investigation through clinical trials.