[Progress in the Treatment of Adult Langerhans Cell Histiocytosis --Review].

Langerhans cell histiocytosis (LCH) is a rare proliferative disease dominated by the proliferation of Langerhans cells, which is inflammatory myeloid neoplasms. Its clinical manifestations are variable, occurring at any age and at any site, and it is rarer in adults than in children. The gold standard for diagnosis is histopathological biopsy. Due to the rarity of adult LCH and the heterogeneity of this disease, treatment of adult LCH should be developed according to the extent of the disease and risk stratification. With the discovery of MAPK, PI3K and c-KIT signaling pathway activation, especially BRAF V600E and MAP2K1 mutations, targeted therapy has become a hot spot for therapeutic research. Meanwhile, the discovery of high expression of M2-polarized macrophages and Foxp3+ regulatory T cells (Treg) in LCH has provided an important basis for the immunotherapy. In this article, we will focus on reviewing the latest research progress in the treatment of adult LCH in recent years, and provide a reference for clinical research on the treatment of adult LCH patients.

ATP6AP2 knockdown in cardiomyocyte deteriorates heart function via compromising autophagic flux and NLRP3 inflammasome activation.

Moderate autophagy can remove damaged proteins and organelles. In some inflammatory diseases, autophagy plays a protective role by inhibiting the NOD-like receptor family pyrin domain containing 3(NLRP3). (Pro)renin receptor (PRR, or ATP6AP2) is a critical component of the V-ATPase required for autophagy. It remains controversial about ATP6AP2 in the pathological process. The impact of ATP6AP2 on NLRP3 inflammasome and autophagic flux remains unknown under pressure overload stress. This research explores the potential link between ATP6AP2, autophagic flux, and NLRP3. There was upregulation of ATP6AP2 from 5-day post-TAC, and this expression remained at a high level until 8-weeks post-TAC in wild mice. Meanwhile, autophagic flux switched from early compensatory activation to blocking in the heart failure phase. NLRP3 activation can be seen at 8-week post-TAC. Adenovirus-mediated knockdown of ATP6AP2(shR-ATP6AP2) accelerated the progress of heart failure. After TAC was induced, shR-ATP6AP2 significantly deteriorated heart function and fibrosis compared with the shR-Scr group. Meanwhile, there was an elevated expression of NLRP3 and autophagic flux blockage. A transgenic mouse(Tg) with cardio-restricted ATP6AP2/(P)RR overexpression was constructed. Although high expression in cardiac tissue, there were no spontaneous functional abnormalities under the basal state. Cardiac function, fibrosis, hypertrophy remained identical to the control TAC group. However, SQSTM1/P62 was reduced, which indicated the relief of autophagic flux blockage. Further, Neonatal rat ventricular myocyte (NRVMs) transfected with shR-ATP6AP2 showed more susceptibility than sh-Scr NRVMs to phenylephrine-induced cell death. More reactive oxygen species (ROS) or mito-ROS accumulated in the shR-ATP6AP2 group when phenylephrine stimulation. Blocking NLRP3 activation in vivo partly rescued cardiac dysfunction and fibrosis. In conclusion, ATP6AP2 upregulation is a compensatory response to pressure overload. If not effectively compensated, it compromises autophagic flux, leads to dysfunctional mitochondria accumulation, further produces ROS to activate NLRP3, eventually accelerates heart failure.

Antioxidant Activity of Novel Casein-Derived Peptides with Microbial Proteases as Characterized via Keap1-Nrf2 Pathway in HepG2 Cells.

Casein-derived antioxidant peptides by using microbial proteases have gained increasing attention. Combination of two microbial proteases, Protin SD-NY10 and Protease A "Amano" 2SD, was employed to hydrolyze casein to obtain potential antioxidant peptides that were identified by LCMS/ MS, chemically synthesized and characterized in a oxidatively damaged HepG2 cell model. Four peptides, YQLD, FSDIPNPIGSEN, FSDIPNPIGSE, YFYP were found to possess high 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging ability. Evaluation with HepG2 cells showed that the 4 peptides at low concentrations (< 1.0 mg/ml) protected the cells against oxidative damage. The 4 peptides exhibited different levels of antioxidant activity by stimulating mRNA and protein expression of the antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), as well as nuclear factor erythroid-2-related factor 2 (Nrf2), but decreasing the mRNA expression of Kelch-like ECH-associated protein 1 (Keap1). Furthermore, these peptides decreased production of reactive oxygen species (ROS) and malondialdehyde (MDA), but increased glutathione (GSH) production in HepG2 cells. Therefore, the 4 casein-derived peptides obtained by using microbial proteases exhibited different antioxidant activity by activating the Keap1-Nrf2 signaling pathway, and they could serve as potential antioxidant agents in functional foods or pharmaceutic preparation.

[Prognostic Value of Corrected Levels of Serum Calcium and Serum Lactate Dehydrogenase for Newly Diagnosed Multiple Myeloma Patients].

OBJECTIVE: To investigate the prognostic value of the serum calcium level corrected by serum albumin (cCA) and corrected serum lactate dehydrogenase (LDH) level for the risk stratification for newly diagnosed multiple myeloma (MM) patients. METHODS: The clinical data and survival of 186 newly diagnosed MM patients admitted to our hospital from June 1, 2015 to November 1, 2017 were collected. The patients's survival time was obtained by telephone and follow-up visits to patients and their families. The value of the prognostic system consisting of cCA levels and LDH levels in the survival time of MM patients was retrospectively analyzed. Moreover, the post-corrected hypercalcemia and high LDH as 2 factors were used for risk stratification, then according to these 2 factors, the MM patients were divided into 3 groups: group 1 (no risk factor), group 2 (1 risk factor) and group 3 (2 risk factors), and the effect of risk factors on the prognosis of MM patients was analyzed. RESULTS: The median follow-up time was 16 months. The cumulative OS rate of the post-corrected hypercalcemia group was lower than that of the non-hypercalcemia group. The 1-year cumulative OS rate in the 2 groups was 79.0%±6.7% and 88.6%±3.0%, the 3-year cumulative OS rate was 53.0%±10.5% and 74.6%±6.6% (P=0.016), respectively. The cumulative OS rate of the high LDH group [LDH ＞upper limit of normal (ULN), ULN=250 U/L] was lower than that in the normal LDH group. The 1-year cumulative OS rate in the 2 groups was 71.6%±8.6% and 90.0%±2.8%, the 2-year cumulative OS rate was 44.9%±12.1% and 83.1%±4.0%, respectively, and the median OS time was 19 months (95%CI: 15.32-23.34) and not reached (P=0.001). The risk stratification analysis showed that the median OS time of the 3 group was not reached (n=103, 57%), not reached (n=70, 39%) and 17 months (n=7, 4%, 95%CI: 5.19-28.41, P＜0.001). Patients with two risk factors had a prognosis worse than patients with 0-1 risk factor. CONCLUSION: The prognostic combination of corrected serum calcium and LDH levels may provide a basis for risk stratification and prognosis in MM patients in clinical practice.