BackgroundMitochondrial Lon is a chaperone and DNA-binding protein that functions in protein quality control and stress response pathways. The level of Lon regulates mitochondrial DNA (mtDNA) metabolism and the production of mitochondrial reactive oxygen species (ROS). However, there is little information in detail on how mitochondrial Lon regulates ROS-dependent cancer immunoescape through mtDNA metabolism in the tumor microenvironment (TME).MethodsWe explored the understanding of the intricate interplay between mitochondria and the innate immune response in the inflammatory TME.ResultsWe found that oxidized mtDNA is released into the cytosol when Lon is overexpressed and then it induces interferon (IFN) signaling via cGAS-STING-TBK1, which upregulates PD-L1 and IDO-1 expression to inhibit T-cell activation. Unexpectedly, upregulation of Lon also induces the secretion of extracellular vehicles (EVs), which carry mtDNA and PD-L1. Lon-induced EVs further induce the production of IFN and IL-6 from macrophages, which attenuates T-cell immunity in the TME.ConclusionsThe levels of mtDNA and PD-L1 in EVs in patients with oral cancer function as a potential diagnostic biomarker for anti-PD-L1 immunotherapy. Our studies provide an insight into the immunosuppression on mitochondrial stress and suggest a therapeutic synergy between anti-inflammation therapy and immunotherapy in cancer.

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Clone library of bacterial 16S rRNA gene was constructed to evaluate the bacterial diversity and community structure of uterus samples obtained from three postpartum healthy cows and three metritic cows on days 10 and 40. Sequences were assigned to five major groups (Bacteroidetes, Firmicutes, Fusobacteria, Proteobacteria, and Tenericutes) and to an uncultured group. On day 10, Bacteroidetes, Firmicutes, and Fusobacteria were the dominant group both in healthy and metritic cows. On day 40, the major sequences were affiliated with Bacteroidetes, Firmicutes, Tenericutes, and Proteobacteria. Tenericutes (Ureaplasma diversum) were revealed only from healthy cows, while Proteobacteria (Histophilus somni) were found only from metritic cows. Quantitative PCR revealed that metritic cows on day 10 showed higher value of total bacteria, Bacteroidetes, Peptostreptococcus, and Fusobacterium compared with healthy cows, while only a higher value of Fusobacterium spp. was observed from the metritic cows on day 40 compared with that from healthy cows (P < 0.05). Our data indicates that great difference in the uterine bacterial community in both phyla level and species level exists between healthy and metritic postpartum cows, and dynamic changes in bacterial community occur over time.

The developed acetylated LysargiNase (Ac-LysargiNase), with superior activity and stability, provides complementary ion types compared with trypsin for MS/MS analysis. Based on the two mirror proteases, we developed a novel de novo sequencing algorithm, pNovoM, which performed with higher efficiency and accuracy compared with other software tools.

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A multi-weighted coupled neural networks (MWCNNs) model with event-triggered communication is studied in this paper. On the one hand, the passivity of the presented network model is studied by utilizing Lyapunov stability theory and some inequality techniques, and a synchronization criterion based on the obtained output-strict passivity condition of MWCNNs with event-triggered communication is derived. On the other hand, some robust passivity and robust synchronization criteria based on output-strict passivity of the proposed network with uncertain parameters are presented. At last, two numerical examples are provided to testify the effectiveness of the output-strict passivity and robust synchronization results.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and the most common subtype of non-Hodgkin lymphoma in China. However, many cases still remain biologically and clinically heterogeneous, indicating that the DLBCL mechanism remains unclear. MicroRNAs (miRNAs) are critically responsible for lymphomagenesis. We found that plasma miR-21 level was significantly higher in B-cell lymphoma. However, the exact contribution of miR-21 in DLBCL remains unknown.To determine the function and mechanism of miR-21 in DLBCL, miR-21 and phosphatase and tensin homolog (PTEN) expressions were examined through real-time PCR and immunohistochemical methods. Moreover, the effects of antisense oligonucleotide (ASO) targeting miR-21 (ASO-21) were observed in DLCBL cell line.MiR-21 expressions in cell line and tissues of patients were significantly higher than those in normal controls, which were inversely correlated with PTEN expression. MiR-21 expression was significantly higher in stage III/IV patients than in stage I/II patients. PTEN protein was expressed positively in only 6 patients with DLBCL (6/26). MiR-21 expression level in the PTEN-negative group was 11.73 (2.13–64.29), which was significantly higher than that in the PTEN-positive group (1.04, 0.67–15.15; P = .038). After down-regulating the miR-21 expression, apoptosis of DLBCL cells increased and PTEN protein was up-regulated in ASO-21-treated cells compared with SCO-21-treated cells by western blot.These results suggested that miR-21 affects apoptosis of lymphoma cells by regulating the expression of PTEN in DLBCL, which may be associated with increased poor prognosis for DLBCL patients and represents a useful approach for DLBCL treatment.

Background: The exposure of the nucleus pulposus (NP) causes an immune and inflammatory response, which is intrinsically linked to the pathogenesis of radicular pain. As a newly discovered pro-resolving lipid mediator, maresin 1 (MaR1) could exert powerful inflammatory resolution, neuroprotection, and analgesic activities. In the present research, the analgesic effect of MaR1 was observed. Then, the potential mechanism by which MaR1 attenuated radicular pain was also analyzed in a rat model. Methods: Intrathecal administration of MaR1 (10 or 100 ng) was successively performed in a rat with non-compressive lumbar disk herniation for three postoperative days. Mechanical and thermal thresholds were determined to assess pain-related behavior from days 1 to 7 (n = 8/group). On day 7, the tissues of spinal dorsal horns from different groups were gathered to evaluate expression levels of inflammatory cytokines (IL-1β, IL-18, and TNF-α), the NLRP3 inflammasome and pyroptosis indicators (GSDMD, ASC, NLRP3, and Caspase-1), together with NF-κB/p65 activation (n = 6/group). TUNEL and PI staining were performed to further examine the process of pyroptosis. Results: After intrathecal administration in the rat model, MaR1 exhibited potent analgesic effect dose-dependently. MaR1 significantly prompted the resolution of the increased inflammatory cytokine levels, reversed the up-regulated expression of the inflammasome and pyroptosis indicators, and reduced the cell death and the positive activation of NF-κB/p65 resulting from the NP application on the L5 dorsal root ganglion. Conclusion: This study indicated that the activation of NLRP3 inflammasome and pyroptosis played a significant role in the inflammatory reaction of radicular pain. Also, MaR1 could effectively down-regulate the inflammatory response and attenuate pain by inhibiting NLRP3 inflammasome-induced pyroptosis via NF-κB signaling.