MicroRNA-194-5p/Heparin-binding EGF-like growth factor signaling mediates dexamethasone-induced activation of pseudorabies virus in rat pheochromocytoma cells.

Pseudorabies virus (PRV) is a neurotropic virus, which infects a wide range of mammals. The activity of PRV is gradually suppressed in hosts that have tolerated the primary infection. Increased glucocorticoid levels resulting from stressful stimuli overcome repression of PRV activity. However, the host cell mechanism involved in the activation processes under stressful conditions remains unclear. In this study, infection of rat PC-12 pheochromocytoma cells with neuronal properties using PRV at a multiplicity of infection (MOI) = 1 for 24 h made the activity of PRV be the relatively repressed state, and then incubation with 0.5 µM of the corticosteroid dexamethasone (DEX) for 4 h overcomes the relative repression of PRV activity. RNA-seq deep sequencing and bioinformatics analyses revealed different microRNA and mRNA profiles of PC-12 cells with/without PRV and/or DEX treatment. qRT-PCR and western blot analyses confirmed the negative regulatory relationship of miRNA-194-5p and its target heparin-binding EGF-like growth factor (Hbegf); a dual-luciferase reporter assay revealed that Hbegf is directly targeted by miRNA-194-5p. Further, miRNA-194-5p mock transfection contributed to PRV activation, Hbegf was downregulated in DEX-treated PRV infection cells, and Hbegf overexpression contributed to returning activated PRV to the repression state. Moreover, miRNA-194-5p overexpression resulted in reduced levels of HBEGF, c-JUN, and p-EGFR, whereas Hbegf overexpression suppressed the reduction caused by miRNA-194-5p overexpression. Overall, this study is the first to report that changes in the miR-194-5p-HBEGF/EGFR pathway in neurons are involved in DEX-induced activation of PRV, laying a foundation for the clinical prevention of stress-induced PRV activation.

Neutrophil extracellular traps contribute to immunothrombosis formation via the STING pathway in sepsis-associated lung injury.

Neutrophil extracellular traps (NETs) are involved in the activation and dysfunction of multiple overlapping and interacting pathways, including the immune response to injury, inflammation, and coagulation, which contribute to the pathogenesis of sepsis-induced acute lung injury (SI-ALI). However, how NETs mediate the relationship between inflammation and coagulation has not been fully clarified. Here, we found that NETs, through stimulator of interferon genes (STING) activation, induced endothelial cell damage with abundant production of tissue factor (TF), which magnified the dysregulation between inflammatory and coagulant responses and resulted in poor prognosis of SI-ALI model mice. Disruption of NETs and inhibition of STING improved the outcomes of septic mice and reduced the inflammatory response and coagulation. Furthermore, Toll-like receptor 2 (TLR2) on the surface of endothelial cells was involved in the interaction between NETs and the STING pathway. Collectively, these findings demonstrate that NETs activate the coagulant cascade in endothelial cells in a STING-dependent manner in the development of SI-ALI.

Jasmonic acid negatively regulates branch growth in pear.

The quality of seedlings is an important factor for development of the pear industry. A strong seedling with few branches and suitable internodes is ideal material as a rootstock for grafting and breeding. Several branching mutants of pear rootstocks were identified previously. In the present study, 'QAU-D03' (Pyrus communis L.) and it's mutants were used to explore the mechanism that affects branch formation by conducting phenotypic trait assessment, hormone content analysis, and transcriptome analysis. The mutant plant (MP) showed fewer branches, shorter 1-year-old shoots, and longer petiole length, compared to original plants (OP), i.e., wild type. Endogenous hormone analysis revealed that auxin, cytokinin, and jasmonic acid contents in the stem tips of MP were significantly higher than those of the original plants. In particular, the jasmonic acid content of the MP was 1.8 times higher than that of the original plants. Transcriptome analysis revealed that PcCOI1, which is a transcriptional regulatory gene downstream of the jasmonic acid signaling pathway, was expressed more highly in the MP than in the original plants, whereas the expression levels of PcJAZ and PcMYC were reduced in the MP compared with that of the original plants. In response to treatment with exogenous methyl jasmonate, the original plants phenotype was consistent with that of the MP in developing less branches. These results indicate that jasmonic acid negatively regulates branch growth of pear trees and that jasmonic acid downstream regulatory genes play a crucial role in regulating branching.

Consecutive Injection of High-Dose Lipopolysaccharide Modulates Microglia Polarization via TREM2 to Alter Status of Septic Mice.

BACKGROUND: The neuroinflammation of the central nervous system (CNS) is a prevalent syndrome of brain dysfunction secondary to severe sepsis and is regulated by microglia. Triggering the receptor expressed on myeloid cells 2 (TREM2) is known to have protective functions that modulate the microglial polarization of M2 type to reduce inflammatory responses, thereby improving cognition. METHODS: We examined the effect of TREM2 on the polarization state of microglia during the progression of neuroinflammation. After consecutive intraperitoneal injections of lipopolysaccharide for 7 days, we evaluated the inflammation of a septic mice model by hematoxylin-eosin (H&E) and electron microscopy, and we used immunofluorescence (IF) assays and Western blotting to visualize hippocampal sections in C57BL/6 mice to assess TREM2 expression. In addition, we analyzed the state of microglia polarization with quantitative RT-PCR. RESULT: The consecutive injection of LPS for 4 days elevated systemic inflammation and caused behavioral cognitive dysfunction in the septic model. However, on Day 7, the neuroinflammation was considerably attenuated. Meanwhile, TREM2 decreased on Day 4 and increased on Day 7 in vivo. Consistently, LPS could reduce the expression of TREM2 while IFN-ß enhanced TREM2 expression in vitro. TREM2 regulated the microglial M1 phenotype's conversion to the M2 phenotype. CONCLUSION: Our aim in this study was to investigate the interconnection between microglia polarization and TREM2 in neuroinflammation. Our results suggested that IFN-ß could modulate TREM2 expression to alter the polarization state of microglia, thereby reducing LPS-induced neuroinflammation. Therefore, TREM2 is a novel potential therapeutic target for neuroinflammation.

Neutrophil extracellular traps-triggered impaired autophagic flux via METTL3 underlies sepsis-associated acute lung injury.

Neutrophil extracellular traps (NETs) assist pathogen clearance, while excessive NETs formation is associated with exacerbated inflammatory responses and tissue injury in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Autophagy is generally considered to be a protective process, but autophagy dysfunction is harmful. Whether and how NETs affect autophagic flux during sepsis-induced ALI are currently unknown. Here, we confirmed that the level of NETs was increased in ARDS patients and mice models, which led to impairment of autophagic flux and deterioration of the disease. Mechanistically, NETs activated METTL3 mediated m6A methylation of Sirt1 mRNA in alveolar epithelial cells, resulting in abnormal autophagy. These findings provide new insights into how NETs contribute to the development of sepsis-associated ALI/ARDS.

Necroptosis, Pyroptosis, Ferroptosis in Sepsis and Treatment.

ABSTRACT: As a global major health problem and a leading cause of death, sepsis is defined as a failure of homeostasis, which is mainly initiated by an infection and followed by sustained excessive inflammation until immune suppression. Despite advances in the identification and management of clinical sepsis, morbidity, and mortality remain high. In addition, clinical trials have failed to yield promising results. In recent years, the mechanism of regulated cell death (RCD) in sepsis has attracted more and more attention, because these dying cells could release a large number of danger signals which contribute to inflammatory responses and exacerbation of sepsis, providing a new direction for us to make treatment strategy. Here we summarize mechanisms of several forms of RCD in sepsis including necroptosis, pyroptosis, ferroptosis. In conclusion, targeting RCD is considered a promising approach to treat sepsis.

Surgical Stress and Cancer Progression: New Findings and Future Perspectives.

PURPOSE OF REVIEW: The stress response to surgery is essential for maintaining homeostasis and exhibits anti-tumor effects; however, an ongoing and exaggerated stress response may have adverse clinical consequences and even promote cancer progression. This review will discuss the complex relationship between surgical stress and cancer progression. RECENT FINDINGS: Surgical stress exhibits both anti-tumor and cancer-promoting effects by causing changes in the neuroendocrine, circulatory, and immune systems. Many studies have found that many mechanisms are involved in the process, and the corresponding targets could be applied for cancer therapy. Although surgical stress may have anti-tumor effects, it is necessary to inhibit an excessive stress response, mostly showing cancer-promoting effects.

Comparisons of Anatomical Characteristics and Transcriptomic Differences between Heterografts and Homografts in Pyrus L.

Pear (Pyrus L.) is an important temperate fruit worldwide, and grafting is widely used in pear vegetative propagation. However, the mechanisms of graft healing or incompatibility remain poorly understood in Pyrus. To study the differences in graft healing in Pyrus, the homograft "Qingzhen D1/Qingzhen D1" and the heterograft "QAUP-1/Qingzhen D1" as compatibility and incompatibility combinations were compared. Anatomical differences indicated the healing process was faster in homografts than in heterografts. During the healing process, four critical stages in graft union formation were identified in the two types of grafts. The expression of the genes associated with hormone signaling (auxin and cytokinins), and lignin biosynthesis was delayed in the healing process of heterografts. In addition, the PbBglu13 gene, encoded ß-glucosidase, was more highly up-regulated in heterografts than in homografts to promote healing. Meanwhile, the most of DEGs related starch and sucrose metabolism were found to be up-regulated in heterografts; those results indicated that cellulose and sugar signals were also involved in graft healing. The results of this study improved the understanding of the differences in the mechanisms of graft healing between homografts and heterografts.

Walnut intake may increase circulating adiponectin and leptin levels but does not improve glycemic biomarkers: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND & OBJECTIVE: Walnut intake is considered a healthy dietary approach worldwide, particularly as a nutritional tool for the management of obesity and cardiometabolic disorders. Among these lines, leptin and adiponectin, as well as glycemic biomarkers, deserve further attention. We aimed to examine the impact of walnut intake on circulation levels of leptin and adiponectin through a systematic review and meta-analysis of randomized clinical trials (RCTs); secondarily, assessing the glycemic profile as well. METHODS: The literature search was implemented in four following databases: Web of Science, Scopus, PubMed/Medline, and Google Scholar, thus, determining studies that measured the effects of walnut consumption on adiponectin, leptin, and glycemic biomarkers levels from 2004 up to December 2019. RESULTS: Fourteen trials were include in the meta-analysis, with an intervention period ranging from 5 weeks to 12 months.Walnut intake increased leptin (weighted mean difference (WMD): 2.502 ng/mL; 95 % CI: 2.147-2.856, p < 0.001) and adiponectin (WMD: 0.440 ng/mL; 95 % CI: 0.323 to 0.557, p < 0.001) levels. Pertaining to glycemic biomarkers, neither overall analyses nor sub-analyses corroborated with changes in fasting blood glucose (WMD: 0.500 mg/dL, 95 % CI: -0.596, 1.596, p = 0.371), insulin (WMD: -0.21 mg/dL, 95 % CI: -0.67, 0.24, p = 0.367), and glycated hemoglobin (WMD: 0.004 mg/dL, 95 % CI: -0.041, 0.049, p = 0.870) concentrations. CONCLUSION: Walnut intake may increase leptin and adiponectin levels but does not improve glycemic biomarkers.