Boosting the synergism between cancer ferroptosis and immunotherapy via targeted stimuli-responsive liposomes.

Both ferroptotic therapy and immunotherapy have been widely employed in cancer treatment. However, ferroptotic cell death fails to induce dendritic cells maturation, which limits the therapeutic outcome of ferroptotic cancer therapy. To address this, the current work reports a tailored liposome to establish a positive loop between ferroptotic therapy and immunotherapy. As the key component of liposome, a unique phospholipid is designed to bear two arachidonic acid tails. The liposome is further surface-engineered with fucose ligand and physically encapsulates immunostimulatory CpG oligodeoxynucleotides (ODNs). The tailored liposome shows enhanced cellular uptake in a model 4T1 cell line. Meanwhile, the high level of reactive oxygen species in cancer cells can induce ferroptosis-specific peroxidation of DAPC and trigger the release CpG ODNs. The CpG ODNs further enable the maturation of dendritic cells and enhance the effector function of CD8+ T cells. IFN-γ released from CD8+ T cells promotes cancer cell ferroptosis via inhibiting SLC7A11 and suppressing the biosynthesis of glutathione. The tailored liposome can also act in synergism with PD-L1 antibody, resulting in enhanced anti-cancer efficacy in a 4T1 tumor-bearing mice model. This work provides a promising strategy for cancer treatment through orchestrating ferroptotic therapy and immunotherapy.

0.1% Nano-silver mediates PD-1/PD-L1 pathway and alleviates chronic apical periodontitis in rats.

This study was to investigate whether the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) and T-helper 17 (Th17)/regulatory T (Treg) balance are associated with chronic apical periodontitis (CAP) relived by 0.1% nano-silver. CAP rat models were established by opening the first molars of the right and left mandible and exposing the pulp cavity to the oral cavity. CAP model was verified by cone-beam computed tomography, X-ray digital radiovisiography, and hematoxylin-eosin (H and E) staining. The rats were randomly divided into the sham, Ca(OH)2, and 0.1% nano-silver groups (n = 12 in each group) 2 weeks after surgery. The pathological changes in the apical area were detected by H and E staining. PD-1, PD-L1, RORγT, IL-17, and Foxp3 in periapical tissues were detected by qRT-PCR and immunohistochemistry. Th17/Treg and PD-1/PD-L1 were analyzed by flow cytometry. After 7, 14, and 21 days of 0.1% nano-silver treatment, inflammatory cells in the apical region were slightly reduced and inflammatory infiltration was relieved compared with the sham group. RORγT, IL-17, PD-1, and PD-L1 decreased and Foxp3 increased after 7, 14, and 21 days of 0.1% nano-silver treatment compared with the sham group (p < 0.05); however, there were no significant differences with Ca(OH)2 group (p > 0.05). Flow cytometry revealed that 0.1% nano-silver solution decreased Th17/Treg and PD-1/PD-L1 ratio. 0.1% Nano-silver significantly reduced the inflammation of CAP in rats. PD-1/PD-L1 was included in Th17/Treg balance restored by 0.1% nano-silver.

Growth of T-cell lymphoma cells is inhibited by mPGES-1/PGE2 suppression via JAK/STAT, TGF-ß/Smad3 and PI3K/AKT signal pathways.

Background: T-cell lymphoma (TCL) has a very poor prognosis with limited treatment options and novel therapeutic target is urgently needed. Our previous studies have found that suppression of membrane-bound prostaglandin E2 synthase l/prostaglandin E2 (mPGES-1/PGE2) exerted anti-neoplastic effects in leukemia cells by suppressing AKT signal pathway. Here, we aim at evaluating the role and mechanism of mPGES-1/PGE2 signaling in TCL. Methods: Expression of mPGES-1 in TCL cell line Hut78 was analyzed by Western blot and immunofluorescence. CAY10526, a selective mPGES-1 inhibitor, was used to treat Hut 78 cells. Cell viability assays was performed by using cell counting kit-8 (CCK-8). Cell apoptosis rate was examined by flow cytometer. PGE2 synthesis was detected by enzyme immunoassay (EIA). The expression of mPGES-1, cleaved caspase-3, Janus kinase/signal transduction and transcription (JAK/STAT), transforming growth factor-ß (TGF-ß)/Smad3 and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway of Hut 78 cells after exposed to CAY10526 was analyzed by Western blot. Results: mPGES-1 was highly expressed in Hut78 cell compared to normal peripheral blood mono-nuclear cells. CAY10526 inhibited cell proliferation and induced apoptosis in Hut78 cells. These effects may be partially attributed to the activation of the Caspase family and the inhibition of JAK/STAT, TGF-ß/Smad3 and PI3K/AKT signal pathways. Conclusions: Our results suggested that mPGES-1/PGE2 could be a potential therapeutic target for TCL.

Comparative efficacy and safety of eleven induction chemotherapy regimens for young adult patients with newly diagnosed acute myeloid leukemia: a network meta-analysis.

The optimal induction chemotherapy regimens for young adult patients with newly diagnosed acute myeloid leukemia (AML) are not well-defined since the lack of direct comparisons between emerging treatments. Network meta-analysis (NMA) is a statistical tool to integrate direct and indirect evidence to evaluate the effect of multiple interventions. Thus, we conducted an NMA to systematically assess the efficacy and safety of different inductions for these patients. PubMed, Embase, Cochrane Library, and Web of Science were searched from establishment to 2020-03-11. Randomized controlled trials (RCTs) using different inductions were included. We deemed 11 trials eligible, including 11 inductions with 5052 participants. Relative risk (RR) and 95% confidence intervals (CIs) were calculated. In terms of complete remission (CR) rate, DAC ranked highest and was significantly higher than IA (RR = 1.27, 95% CI (1.09-1.48)) and DA (RR = 1.28, 95% CI (1.13-1.46)) (p < 0.05). The ranking of DA + Pioglitazone was second only to that of DAC, followed by HAA. For early mortality, HAD, HAA, and DA + GO were significantly higher than DA/IA (p < 0.05). DAC and DA + Pioglitazone showed similar early mortality compared to DA/IA (p > 0.05). Regarding incidence of early grade 3-4 infection, no significant differences between interventions were observed. To conclude, among the included 11 induction regimens, DAC was potentially the top choice for young adult patients with newly diagnosed AML, with highest CR rate, low early mortality, and incidence of early infection. DA + Pioglitazone and HAA also showed a superiority over the others to achieve higher CR rate, while caution should be kept in mind due to the higher early mortality of HAA.

Clinical analysis of 11 cases of nocardiosis.

Nocardiosis is a rare, life-threatening, opportunistic, and suppurative infection. Its clinical manifestation lacks specificity, which makes early diagnosis difficult. A retrospective analysis of the clinical records of 11 patients with nocardiosis admitted to our hospital from January 2013 to November 2018 was conducted. All patients had at least one underlying disorder, such as an autoimmune disease (6/11), a blood malignancy (2/11), avascular necrosis of the femoral head (1/11), bronchiectasis (1/11), or pneumonia (1/11). The first-line treatment was trimethoprim-sulfamethoxazole (TMP-SMX); one or two additional antibiotics were given according to the drug-sensitive test. The median time from onset to treatment was 3 weeks (ranging from 1 to 9 weeks). The median duration of treatment after diagnosis was 20.5 weeks (ranging from 7 to 47 weeks). Eight patients were discharged and survived, and three patients died. This indicates that early use of TMP-SMX combined with sensitive antibiotics could improve the condition of patients and improve the cure rate (8/11). Clinically, it is necessary to consider the possibility of nocardiosis in patients with long-term use of immunosuppressants and poor response to treatment of common bacterial infections. Early diagnosis, timely treatment, and combination drug therapy are keys to improving the outcomes of patients with nocardiosis.

Roles of SP600125 in expression of JNK, RANKL and OPG in cultured dental follicle cells.

OBJECTIVE: To investigate the expression of C-JNK, RANKL and OPG after SP600125 administration in cultured dental follicle cells (DFCs). METHODS: TRAP staining and electron microscope were carried out on day 7 and 9 after coculture of BMMs and DFCs with a ratio of 5:1 in different groups. To determine the effects of SP600125 on the expression of C-JNK, RANKL and OPG mRNA and protein, cultured DFCs were divided into control group, DMSO group and SP600125 groups. Real-time PCR and Western blot analysis were performed to investigate the expression of the mRNA and protein, respectively. RESULTS: TRAP assay indicated that the number of multinucleated osteoclasts in the SP600125 group showed significant decrease compared with that of control (P < 0.05). The expression of JNK protein in the SP600125 groups showed significant decline compared with that of the control group and blank control (P < 0.05). Significant decrease was noticed in the RANKL protein expression with the elevation of SP600125. CONCLUSIONS: SP600125 could inhibit the formation of osteoclast in the coculture system of DFCs and BMMs. After SP600125 treatment, the expression of RANKL and JNK showed a trend of decrease, and the expression of OPG showed gradual increase followed by gradual decrease.

[Odontogenic differentiation of bone marrow-derived mesenchymal stem cells induced by periodontal ligament stem cells].

OBJECTIVE: To investigate the mechanism underlying the mechanism of odontogenic differentiation of bone marrow-derived mesenchymal stem cells (BMMSCs) induced by periodontal ligament stem cells (PDLSCs), and offer an experimental evidence for the combination of the two types of stem cells to make regenerative periodontal complex. METHODS: By means of Transwell(R); chamber, PDLSCs and BMMSCs from miniature pigs were co-cultured indirectly at different mixing ratios of PDLSCs to BMMSCs, 10:1 (group A), 1:1 (group B), 1:10 (group C). On the other hand, PDLSCs and BMMSCs were respectively cultured alone as positive and negative control group. Fourteen days later, the expressions of scleraxis, matrix extracellular phosphoglycoprotein (MEPE), osteocalcin (OCN), osterix (OSX) were detected by immunofluorescence and real-time quantitative PCR (qRT-PCR) to determine the optimal ratio of PDLSCs to BMMSCs for odontogenic differentiation. RESULTS: Immunofluorescence and qRT-PCR showed that the expression levels of sceleraxi, OCN and OSX protein and relative mRNA had no statistically significant difference in the A, B, C groups (P>0.05), but as for MEPE, its relative mRNA expression level in group A was significantly higher than that in group B or C (P<0.01). CONCLUSION: In the indirect co-culture of PDLSCs and BMMSCs, BMMSCs can obtain PDLSCs' biological characteristics to different extent, and meanwhile, a small number of PDLSCs can also induce the odontogenic differentiation of BMMSCs.