Total glucosides of paeony alleviates experimental Sjögren's syndrome through inhibiting NLRP3 inflammasome activation of submandibular gland cells.

OBJECTIVES: The mechanisms by which total glucosides of paeony (TGP) mitigates Sjögren's syndrome (SS) remains elusive. In the present study, we aim to explore the relationship between the therapeutic effects of TGP in the treatment of SS and NLRP3 inflammasome activation in submandibular gland (SG) cells. METHODS: Female non-obese diabetic (NOD) mice were selected as the model of SS. The mice were divided into PBS and TGP treatment group. For treatment, TGP (400mg·kg-1) was administered intragastrically every day for 4 weeks. The SS-like symptoms and pathological changes of the SG of mice were compared between the PBS and TGP group. The activation of NLRP3 inflammasome in SG was detected by RT-qPCR, immunohistochemistry and western blot. The SG cells stimulated by lipopolysaccharide (LPS) and adenosine triphosphate (ATP) for activation of NLRP3 inflammasome were treated with or without TGP. Then, NLRP3 inflammasome activation was assessed. The IL-1ß and IL-18 in homogenate of SG, serum and supernatant were detected by ELISA. RESULTS: Compared with balb/c mice, NOD mice showed SS-like symptoms and lymphocyte infiltration in SG, and the expression of NLRP3 inflammasome in SG was significantly increased. The SS-like symptoms were alleviated, and lymphocyte infiltration in SG was reduced, and the level of NLRP3 inflammasome in SG mice was decreased after TGP treatment. TGP also significantly inhibit the activation of NLRP3 inflammasome of SG cells in vitro. CONCLUSIONS: Collectively, our results indicated that TGP alleviates SS through inhibition of the activation of NLRP3 inflammasome of SG. These findings clarified the mechanism underlying the therapeutic effects of TGP on SS, and provided new evidence for the further application of TGP in the treatment of SS.

IL-27 regulates NLRP3 inflammasome activation of MDSCs in experimental Sjögren's syndrome.

Excessive NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation has an important function in the pathogenesis of Sjögren's syndrome (SS). Increased and dysfunctional myeloid-derived suppressor cells (MDSCs) promoted SS. However, NLRP3 inflammasome activation of MDSCs in SS and its regulated components are unclear. Splenic MDSCs were purified by immunomagnetic beads and cultured. Western blot was used to assess NLRP3 inflammasomes. Interleukin-1ß (IL-1ß) and IL-18 were measured using enzyme-linked immunosorbent assay. Here we showed that the NLRP3 inflammasome was activated in non-obese diabetic (NOD) mice with SS-like manifestations. We found that NLRP3 inflammasome activation was augmented in MDSCs of SS mice and NLRP3 inflammasome activation was suppressed in IL-27-deficient NOD mice. Consistent with findings of SS mice in vivo, we observed that NLRP3 inflammasome activation by adenosine triphosphate and lipopolysaccharide was remarkably intensified in MDSCs with IL-27 treatment in vitro. Collectively, our data highlighted that IL-27 regulates NLRP3 inflammasome activation of MDSCs in experimental SS.

Predicting Response of Severe Aplastic Anemia to Rabbit-Antithymocyte Immunoglobulin Based Immunosuppressive Therapy Combined With Eltrombopag.

Addition of eltrombopag (E-PAG) to intensive immunosuppressive therapy (IST) contributes to restoring hematopoiesis in patients with severe aplastic anemia (SAA). Used at relatively low doses in the East Asian population, the efficacies of E-PAG and the predictors for efficacy are not clear. We conducted a retrospective, multicenter study to analyze the efficacy and the possible predicting factors at 6 months in 58 adult SAA patients with rabbit ATG-based IST and E-PAG. The response rate and complete response rate at 6 months were 76% and 21%, respectively. The baseline reticulocyte percentage [area under a curve (AUC)=0.798, 95% confidence interval (CI) 0.640-0.956, P=0.006], absolute reticulocyte count (ARC) (AUC =0.808, 95%CI 0.647-0.970, P=0.004), red cell distribution width - coefficient of variation (RDW-CV) (AUC=0.722, 95%CI 0.494-0.950, P=0.040), and absolute lymphocyte count (ALC) (AUC=0.706, 95%CI 0.522-0.890, P=0.057) were highly predictive of response at 6 months. The tipping values of reticulocyte percentage, ARC, RDW-CV, and ALC were 0.45%, 7.36×109/L, 11.75%, and 1.06×109/L, respectively. The sensitivity and specificity of reticulocyte percentages were 81.6% and 66.7%; ARC were 86.8% and 66.7%, RDW-CV were 94.7% and 55.6%; ALC were 55.3% and 88.9%. At a median follow-up of 15.5 months, the 2-year cumulative overall survival was 92%. The baseline reticulocyte percentage, ARC, RDW-CV, and ALC were potential factors in predicting a favorable effect of rabbit-ATG based IST plus E-PAG in SAA patients of East Asia (ChiCTR2100045895). Clinical Trial Registration: http://www.chictr.org.cn/edit.aspx?pid=125480&htm=4, identifier ChiCTR2100045895.

Potential Effects of the FLT3-ITD Mutation on Chemotherapy Response and Prognosis of Acute Promyelocytic Leukemia.

PURPOSE: To evaluate the influence of FLT3-ITD mutations on the treatment response and long-term survival of newly-diagnosed patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid and arsenic trioxide. METHODS: The long-term survival of 90 newly-diagnosed APL patients (age range 12-75 years) was retrospectively analyzed.The FLT3-ITD mutation rate was assayed by polymerase chain reaction (PCR) amplification and sequencing analysis. Its impact on the treatment response, event-free survival(EFS), or overall survival(OS) was investigated in patients with and without the mutations. RESULTS: The FLT3-ITD mutation rate in newly-diagnosed APL patients was 20% (18/90). The white blood cell (WBC) count at diagnosis in patients with mutations was significantly higher than that in patients without mutations while the FLT3-ITD mutation rate was higher in the high-risk group than in the low/intermediate-risk group. Patients with mutations had a significantly higher early death (ED) rate (16.67% vs 1.39%) for those lacking the mutation (P =0.024). However, the complete remission (CR) and differentiation syndrome (DS) rates in the two groups were similar. Kaplan Meier analysis for EFS and OS at five years showed a significant difference between the patients stratified by FLT3-ITD mutation status (log-rank P =0.010 and P =0.009, respectively). CONCLUSION: FLT3-ITD mutations can be related to high peripheral WBC counts in APL patients. APL patients with mutations displayed a higher ED rate compared to those without mutations. Patients carrying mutations had reduced five-year EFS and OS rates. Thus, reducing the overall death rate during induction treatment might be an effective way to improve the prognosis of patients with FLT3-ITD mutations.

Decitabine as a treatment choice for de novo acute basophilic leukemia: transient response-a case report.

Acute basophilic leukemia (ABL), as a rare form of acute myeloid leukaemia (AML) accounts for <1% of cases of AML. ABL has not been detected for encouragingly specific targets. Here we report a de novo fragile ABL case treated with decitabine based regimen with transient response even if overall survival was a 3-month. The case of a 79-year-old male who was complained of fever, rashes and cytopenia is reported in the current study. The diagnosis of ABL was identified due to characteristic cytomorphological features and immunophenotype of myeloid blast cells without the Philadelphia chromosome. The patient initially presented with short-term improvement with decitabine. Combination of decitabine and arsenic trioxide in second chemotherapy regimen didn't reverse the end of death with a 3 months overall survival. In conclusion, our study revealed that decitabine may be an efficient therapeutic option in ABL patients and warranted much more exploration in use.

Fatty acid synthase (FASN) levels in serum of colorectal cancer patients: correlation with clinical outcomes.

Fatty acid synthase (FASN) is a common phenotype to many kinds of human cancers, such as those of the breast, ovary, pancreas, prostate, colon, and so on. Increased FASN levels have been detected in the serum of the patients with breast and pancreatic cancers. The relationship between the FASN level in serum and the clinicopathological characteristics of colorectal cancer is investigated in this study. FASN levels in serum were examined with enzyme-linked immunosorbent assay (ELISA) in 74 patients with colorectal cancer and 40 healthy persons. Pathological and clinical factors associated with FASN concentrations in serum were investigated and analyzed by statistical analysis. The FASN level in colorectal cancer patients' serum is significantly higher than that in healthy persons' serum. FASN levels in the serum of colorectal cancer patients are associated with tumor extent, lymph node metabasis status, distant metastasis, and tumor clinical stage. The 5-year overall survival rate and 5-year disease-free survival rate among patients with low FASN levels in serum are significantly higher than those among patients with high FASN levels in serum (log-rank P = 0.003). The high FASN level in serum is a promising independent predictor of colorectal cancers with advanced phases, late clinical stages, and shorter survival. These results suggest that FASN concentration in serum may be a potential and useful tumor marker.