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Osteoarthritis is non-inflammatory degenerative joint arthritis, which exacerbates disability in elder persons. The molecular mechanisms of osteoarthritis are elusive. Ubiquitination, one type of post-translational modifications, has been demonstrated to accelerate or ameliorate the development and progression of osteoarthritis via targeting specific proteins for ubiquitination and determining protein stability and localization. Ubiquitination process can be reversed by a class of deubiquitinases via deubiquitination. In this review, we summarize the current knowledge regarding the multifaceted role of E3 ubiquitin ligases in the pathogenesis of osteoarthritis. We also describe the molecular insight of deubiquitinases into osteoarthritis processes. Moreover, we highlight the multiple compounds that target E3 ubiquitin ligases or deubiquitinases to influence osteoarthritis progression. We discuss the challenge and future perspectives via modulation of E3 ubiquitin ligases and deubiquitinases expression for enhancement of the therapeutic efficacy in osteoarthritis patients. We conclude that modulating ubiquitination and deubiquitination could alleviate the osteoarthritis pathogenesis to achieve the better treatment outcomes in osteoarthritis patients.

Background: Spinal cord injury (SCI) is a common disorder of the central nervous system with considerable socio-economic burden. Andrographolide (Andro), the main active component of Andrographis paniculata, has exhibited neuroprotective effects in different models of neurological diseases. The aim of this study was to evaluate the neuroprotective effects of Andro against SCI and explore the related mechanisms.Methods: SCI was induced in rats by the Allen method, and the modeled animals were randomly divided into sham-operated, SCI, SCI + normal saline (NS) and SCI + Andro groups. The rats were injected intraperitoneally with Andro (1 mg/kg) or the same volume of NS starting day one after the establishment of the SCI model for 28 consecutive days. Post-SCI tissue repair and functional recovery were evaluated by measuring the spinal cord water content, footprint tests, Basso-Beattie-Bresnahan (BBB) scores, hematoxylin-eosin (HE) staining and Nissl staining. Apoptosis, oxidative stress and inflammation, as well as axonal regeneration and remyelination were analyzed using suitable markers. The in vitro model of SCI was established by treating cortical neurons with H2O2. The effects of Andro on apoptosis, oxidative stress and inflammation were evaluated as indicated.Results: Andro treatment significantly improved tissue repair and functional recovery after SCI by reducing apoptosis, oxidative stress and inflammation through the nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf-2/HO-1) and nuclear factor-kappa B (NF-κB) signaling pathways. Furthermore, Andro treatment promoted M2 polarization of the microglial cells and contributed to axonal regeneration and remyelination to improve functional recovery after SCI. In addition, Andro also attenuated apoptosis, oxidative stress and inflammation in H2O2-stimulated cortical neurons in vitro.Conclusion: Andro treatment alleviated SCI by reducing apoptosis, oxidative stress and inflammation in the injured tissues and cortical neurons, and promoted axonal regeneration and remyelination for functional recovery.

BackgroundC5AR2 (GPR77, C5L2) is the second receptor for C5a that is a potent protein generated by complement activation. C5AR2 can mediate its own signaling events and exert significant immunomodulatory effects through those events. However, research of C5AR2 in cancer is limited, and its function remains unclear in breast cancer.MethodsThe expression of C5AR2 and its correlations with prognosis, immune infiltration, tumor mutation burden (TMB), and microsatellite instability (MSI) in more than thirty types of cancers were described through GTEx, TCGA, PrognoScan, TIMER2.0, CCLE, HPA, and TISIDB database. C5AR2 showed strong relationships to those immune marker sets in breast cancer. Otherwise, CCK8 assay and Transwell assay were conducted to illustrate the role of C5AR2 in migration, invasion, and proliferation of breast cancer cells.ResultsGenerally, C5AR2 expression differed across most cancerous and noncancerous tissues, and high C5AR2 expression significantly related to poor prognosis in BRCA, GBM, KICH, LAML, LGG, LIHC, PAAD, and STAD. Moreover, C5AR2 expression levels were dramatically correlated with recognized immune infiltration, especially the polarization of macrophages in breast cancer. Gene set enrichment analysis confirmed that C5AR2 participates in regulating multiple signaling pathways involved in tumorigenesis as well as tumor immunity. C5AR2 overexpression facilitated the functions such as migration, invasion, and proliferation in breast cancer cells, which is consistent with bioinformatics analysis.ConclusionsC5AR2 is involved in immune infiltration and malignant characteristics of breast cancer, which may be a prospective biomarker for breast cancer.