The receptor activator of NF-κB (RANK) and immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptors are essential factors involved in regulating osteoclast formation and bone remodeling. Here, we identify early estrogen-induced gene 1 (EEIG1) as a novel RANK ligand (RANKL)-inducible protein that physically interacts with RANK and further associates with Gab2, PLCγ2 and Tec/Btk kinases upon RANKL stimulation. EEIG1 positively regulates RANKL-induced osteoclast formation, likely due to its ability to facilitate RANKL-stimulated PLCγ2 phosphorylation and NFATc1 induction. In addition, an inhibitory peptide designed to block RANK-EEIG1 interaction inhibited RANKL-induced bone destruction by reducing osteoclast formation. Together, our results identify EEIG1 as a novel RANK signaling component controlling RANK-mediated osteoclast formation, and suggest that targeting EEIG1 might represent a new therapeutic strategy for the treatment of pathological bone resorption.

Prunella vulgaris L, a perennial herb widely used in Asia in the treatment of various diseases including cancer. In vitro studies have demonstrated the therapeutic effect of Prunella vulgaris L. against breast cancer through multiple pathways. However, the nature of the biological mechanisms remains unclear. In this study, a Network pharmacology based approach was used to explore active constituents and potential molecular mechanisms of Prunella vulgaris L. for the treatment of breast cancer. The methods adopted included active constituents prescreening, target prediction, GO and KEGG pathway enrichment analysis. Molecular docking experiments were used to further validate network pharmacology results. The predicted results showed that there were 19 active ingredients in Prunella vulgaris L. and 31 potential gene targets including AKT1, EGFR, MYC, and VEGFA. Further, analysis of the potential biological mechanisms of Prunella vulgaris L. against breast cancer was performed by investigating the relationship between the active constituents, target genes and pathways. Network analysis showed that Prunella vulgaris L. exerted a promising preventive effect on breast cancer by acting on tumor-associated signaling pathways. This provides a basis to understand the mechanism of the anti-breast cancer activity of Prunella vulgaris L.

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The E3 ubiquitin ligase TRAF6 and the associated kinase TAK1 are key components of the signaling pathways that activate nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) in response to various stimuli. The cytokine RANKL (receptor activator of NF-κB ligand) is essential for the differentiation of bone marrow cells into bone-resorbing osteoclasts through the activation of NF-κB and MAPK. We found that the scaffold protein RACK1 (receptor for activated C kinase 1) selectively mediated the RANKL-dependent activation of p38 MAPK through the TRAF6-TAK1 axis by interacting with the MAPK kinase MKK6, which is upstream of p38 MAPK. RACK1 was necessary for the differentiation of bone marrow cells into osteoclasts through the stimulation of p38 MAPK activation. Osteoclast precursors exposed to RANKL exhibited an interaction among RACK1, RANK, TRAF6, TAK1, and the kinase MKK6, thereby leading to the activation of the MKK6–p38 MAPK pathway. Experiments in which RACK1 or TAK1 were knocked down in osteoclast precursors indicated that RACK1 acted as a bridge bringing MKK6 to the TRAF6-TAK1 complex. Furthermore, local administration of RACK1-specific siRNA into mice calvariae reduced the RANKL-induced loss of bone by reducing the numbers of osteoclasts. These findings suggest that RACK1 specifies the RANKL-stimulated activation of p38 MAPK by facilitating the association of MKK6 with TAK1, and may provide a molecular target for a new therapeutic strategy to treat bone diseases.

The WHO has upgraded the status of coronavirus disease 2019 (COVID-19) from epidemic to global pandemic. The psychometric properties aspects of COVID-19 patients without comorbidities in the short term after discharge have not been reported. In this study, the Short Form 36 (SF-36) was used to evaluate the psychometric properties and to find relevant risk factors. Methods: The study was conducted in seven hospitals from January 2020 to April 2020. The SF-36 questionnaire was administered one month after discharge. Univariate analysis and multivariate regression model were used to analyze the risk factors of psychometric properties impairment. Results: In univariate analysis of independent risk factors, according to the comparison of whether the duration of positive nucleic acid was greater than 20 days, the positive nucleic acid duration was independently related to the decreased role-emotional value [100, IQR (66-100) vs 100, IQR (0, 100); p = 0.0156]. In addition, multivariable linear regression model showed that male sex and positive nucleic acid duration were related to decreased role-emotional value (p = 0.03< 0.05; p = 0.01< 0.05, respectively). Mental health was associated with age (p= 0.0435). Subsequently, we divided into three subgroups: less than seven days, 7 to 14 days and more than 14 days according to the positive nucleic acid duration. The results revealed that there were significant differences in the vitality value and mental health value of patients aged 46 to 69 in the subgroup where the positive nucleic acid duration longer than 14 days (p= 0.0472; p= 0.0311< 0.05, respectively). Similarly, there are also significant differences in role-emotional value in different genders (p= 0.0316). Conclusion: The study described the psychometric properties of COVID-19 patients without comorbidities shortly after discharge. Risk factors for psychometric properties damage included age, male sex, and nucleic acid duration.