Sulforaphene suppresses RANKL-induced osteoclastogenesis and LPS-induced bone erosion by activating Nrf2 signaling pathway.

BACKGROUND AND PURPOSE: Inflammatory disorders have been found to induce bone loss through sustained and persistent activation of osteoclast differentiation, leading to heightened bone resorption. The current pharmacological interventions for combating bone loss to harbor adverse effects or contraindications. There is a pressing need to identify drugs with fewer side effects. EXPERIMENTAL APPROACH: The effect and underlying mechanism of sulforaphene (LFS) on osteoclast differentiation were illustrated in vitro and in vivo with RANKL-induced Raw264.7 cell line osteoclastogenesis and lipopolysaccharide (LPS)-induced bone erosion model. KEY RESULTS: In this study, LFS has been shown to effectively impede the formation of mature osteoclasts induced from both Raw264.7 cell line and bone marrow macrophages (BMMs), mainly at the early stage. Further mechanistic investigations uncovered that LFS suppressed AKT phosphorylation. SC-79, a potent AKT activator, was found to reverse the inhibitory impact of LFS on osteoclast differentiation. Moreover, transcriptome sequencing analysis revealed that treatment with LFS led to a significant upregulation in the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant-related genes. Then it's validated that LFS could promote NRF2 expression and nuclear translocation, as well as effectively resist oxidative stress. NRF2 knockdown reversed the suppression effect of LFS on osteoclast differentiation. In vivo experiments provide convincing evidence that LFS is protective against LPS-induced inflammatory osteolysis. CONCLUSION AND IMPLICATIONS: These well-grounded and promising findings suggest LFS as a promising agent to addressing oxidative-stress related diseases and bone loss disorders.

Cytochrome P450 BsCYP99A44 and BsCYP704A177 Confer Metabolic Resistance to ALS Herbicides in Beckmannia syzigachne.

Beckmannia syzigachne is a noxious grassy weed that infests wheat fields in China. Previously, we identified that mesosulfuron-methyl resistance in a B. syzigachne population (R, SD04) was conferred by non-target resistance, such as cytochrome P450 mixed-function oxidases (P450s)-based metabolism. RNA sequencing and real-time PCR (qRT-PCR) were used to discover potential P450s-resistant-related genes. Five cytochrome P450s (CYP704A177, CYP96B84, CYP71D7, CYP93A1, and CYP99A44) were found to be highly expressed in R plants. In this study, CYP99A44 and CYP704A177 were cloned from B. syzigachne and transferred into Arabidopsis thaliana to test the sensitivity of Arabidopsis with and without P450s genes to mesosulfuron-methyl and other acetolactate synthase (ALS)-inhibiting herbicides. Transgenic Arabidopsis overexpressing CYP99A44 became resistant to the sulfonylurea herbicide mesosulfuron-methyl, but showed no resistance to pyroxsulam, imazethapyr, flucarbazone, and bispyribac-sodium. Notably, those overexpressing CYP704A177 showed resistance to pyroxsulam and bispyribac-sodium, but not to mesosulfuron-methyl, imazethapyr, and flucarbazone. These results indicated that B. syzigachne and transgenic Arabidopsis displayed different cross-resistance patterns to ALS-inhibiting herbicides. Subcellular localization revealed that CYP99A44 and CYP704A177 protein were located in the endoplasmic reticulum. Furthermore, these results clearly indicated that CYP99A44-mediated mesosulfuron-methyl resistance in B. syzigachne and CYP704A177 may be involved in B. syzigachne cross-resistance to pyroxsulam and bispyribac-sodium.

Research and application advances in rehabilitation assessment of stroke.

Stroke has a high incidence and disability rate, and rehabilitation is an effective means to reduce the disability rate of patients. To systematize rehabilitation assessment, which is the foundation for rehabilitation therapy, we summarize the assessment methods commonly used in research and clinical applications, including the various types of stroke rehabilitation scales and their applicability, and related biomedical detection technologies, including surface electromyography (sEMG), motion analysis systems, transcranial magnetic stimulation (TMS), magnetic resonance imaging (MRI), and combinations of different techniques. We also introduce some assessment techniques that are still in the experimental phase, such as the prospective application of artificial intelligence (AI) with optical correlation tomography (OCT) in stroke rehabilitation. This review provides a useful bibliography for the assessment of not only the severity of stroke injury, but also the therapeutic effects of stroke rehabilitation, and establishes a solid base for the future development of stroke rehabilitation skills.

Determination of significant parameters in remote ischemic postconditioning for ischemic stroke in experimental models: A systematic review and meta-analysis study.

OBJECTIVES: To systematically review studies using remote ischemia postconditioning (RIPostC) for ischemic stroke in experimental models and obtain factors that significantly influence treatment outcomes. MATERIALS AND METHODS: Peer-reviewed studies were identified and selected based on the eligibility criteria, followed by extraction of data on potentially influential factors related to model preparation, postconditioning, and measure time based on outcome measures including infarct size, neurological scales, and cell tests with autophagy, apoptosis, normal-neuron, and damaged-neuron counting. Then, all data were preprocessed, grouped, and meta-analyzed with the indicator of the standardized mean difference. RESULTS: Fifty-seven studies with 224 experiments (91 for infarct size, 92 for neurological scales, and 41 for cell-level tests) were included. There was little statistical difference between different model preparations, treated body parts, number of treatments, and sides. And treatment effect was generally a positive correlation with the duration of conditioning time to stroke onset with exceptions at some time points. Based on infarct size, the number of cycles per treatment, duration of occlusion, and release per cycle showed significant differences. Combined with the effect sizes by other measures, the occlusion/release duration of 8-10 min per cycle is better than 5 min, and three cycles per treatment were most frequently used with good effects. Effect also varied when measuring at different times, showing statistical differences in infarct size and most neurological scales. RIPostC is confirmed as an effective therapeutic intervention for ischemic stroke, while the RIPostC-mediated autophagy level being activated or inhibited remained conflicting. CONCLUSIONS: Conditioning time, number of cycles per treatment, duration of occlusion, and release per cycle were found to influence the treatment effects of RIPostC significantly. More studies on the relevant influential factors and autophagy mechanisms are warranted.

Overexpression of macrophage-colony stimulating factor-1 receptor as a prognostic factor for survival in cancer: A systematic review and meta-analysis.

BACKGROUND: The relation between the expression of macrophage-colony stimulating factor-1 receptor (CSF-1R) and prognosis of cancer patients has been evaluated in multiple studies, but the results remain controversial. We, therefore, performed a meta-analysis and systematic review to figure out the role of CSF-1R in the prognosis of patients with cancer. METHODS: Several databases were searched, including Web of Science, PubMed, and EMBASE. All human studies were published as full text. The Newcastle-Ottawa risk of bias scale was applied to evaluate the research. We extracted hazard ratios (HRs) with 95% confidence interval (95% CI) which assessed progression-free survival (PFS) and overall survival (OS) in order to assess the impacts of CSF-1R on the prognosis of cancer patients. RESULTS: A total of 12 citations were identified, with studies including 2260 patients in different cancer types that met the eligibility criteria. It was suggested in a pooled analysis that the over-expression of CSF-1R was significantly related to worse PFS (HR: 1.68; P < .001, 1.25-2.10, 95% CI) and also poorer OS (HR=1.28; P < .001, 1.03-1.54, 95% CI). Analysis in subgroups indicated over-expressed CSF-1R was significantly associated with worse OS in hematological malignancy (HR = 2.29; P < .001, 1.49-3.09, 95% CI; model of fixed-effects; I2 = 0.0%, P < .001). Sensitivity analysis suggested that there was no study influencing the stability of the results. CONCLUSIONS: The overexpression of CSF-1R was significantly predictive of worse prognosis in those who suffer from different kinds of malignancies, particularly in hematological malignancy, which indicates that it might be a potential biomarker of prognosis in cancer survival and a potential molecular target in the treatment of malignant tumors.

The Ras/ERK signaling pathway couples antimicrobial peptides to mediate resistance to dengue virus in Aedes mosquitoes.

Aedes mosquitoes can transmit dengue and several other severe vector-borne viral diseases, thereby influencing millions of people worldwide. Insects primarily control and clear the viral infections via their innate immune systems. Mitogen-Activated Protein Kinases (MAPKs) and antimicrobial peptides (AMPs) are both evolutionarily conserved components of the innate immune systems. In this study, we investigated the role of MAPKs in Aedes mosquitoes following DENV infection by using genetic and pharmacological approaches. We demonstrated that knockdown of ERK, but not of JNK or p38, significantly enhances the viral replication in Aedes mosquito cells. The Ras/ERK signaling is activated in both the cells and midguts of Aedes mosquitoes following DENV infection, and thus plays a role in restricting the viral infection, as both genetic and pharmacological activation of the Ras/ERK pathway significantly decreases the viral titers. In contrast, inhibition of the Ras/ERK pathway enhances DENV infection. In addition, we identified a signaling crosstalk between the Ras/ERK pathway and DENV-induced AMPs in which defensin C participates in restricting DENV infection in Aedes mosquitoes. Our results reveal that the Ras/ERK signaling pathway couples AMPs to mediate the resistance of Aedes mosquitoes to DENV infection, which provides a new insight into understanding the crosstalk between MAPKs and AMPs in the innate immunity of mosquito vectors during the viral infection.