As an emerging three-dimensional (3D) cell culture model, synovial organoids can highly mimic the structure and function of synovial tissue in vivo, providing a new and powerful tool for the research of synovial-related diseases. This article elaborated in detail on the construction of synovial organoids from the cell sources, culture systems, and construction techniques. Meanwhile, it comprehensively reviewed the application progress of synovial organoids in arthritic diseases including rheumatoid arthritis and osteoarthritis such as disease pathogenesis, drug development, and personalized therapy. Additionally, it explores current challenges and future directions for synovial organoids, providing a reference for further research and applications in related-diseases.

The SARS-CoV-2 pandemic had unprecedented impacts on public health and the economy. Many studies have focused on the mechanisms of SARS-CoV-2 entry into host cells, particularly the spike (S) protein mediated receptor engagement and subsequent virus-host membrane fusion dynamics. However, the mechanistic contribution of cholesterol within spike-incorporated viral envelopes to infectivity has not been well characterized. Herein, we show that targeted cholesterol depletion from the viral envelopes of SARS-CoV-2, SARS-CoV, and MERS-CoV directly impaired viral infectivity in a dose-dependent manner. Although modulation of host cell membrane cholesterol exerted relatively minor effects on viral entry, host cellular cholesterol homeostasis critically governs progeny virion infectivity by determining cholesterol content within nascent viral envelopes. Virions derived from cells with reduced plasma membrane cholesterol demonstrate significantly attenuated infectivity in SARS-CoV-2 and related coronaviruses. In addition, we detected that exogenous cholesterol replenishment restored SARS-CoV-2 entry efficiency by augmenting virus attachment. Collectively, our data demonstrate that biophysical properties of human coronavirus envelopes, particularly cholesterol stoichiometry, function as a key molecular determinant regulating host cell susceptibility. These findings position viral lipidome remodeling as a viable therapeutic target for developing host-directed broad-spectrum antivirals.

The signal transducer and activator of transcription 3 (STAT3), which regulates multiple oncogenic processes, has been found to be constitutively activated in lymphoma, suggesting its potential as a therapeutic target. Here, we constructed an anti-CD19-N-(4-carboxycyclohexylmethyl) maleimide N-hydroxysuccinimide ester (SMCC)-protamine (CSP)-STAT3 small interfering RNA (siRNA) conjugate and demonstrated that the CSP-STAT3 siRNA conjugate could specifically bind to normal B cells and A20 lymphoma cells in vitro. It decreased the STAT3 expression in B cell lymphoma cell lines (A20, SU-DHL-2 and OCI-Ly3), resulting in reduced proliferation of lymphoma cells featured with lower S-phase and higher apoptosis. Using an A20 transplantable lymphoma model, we found that the CSP-STAT3 siRNA conjugate significantly inhibited tumor growth and weight. Ki-67, p-STAT3, STAT3, and serum IL-6 levels were all significantly reduced in A20-bearing mice treated with CSP-STAT3 siRNA. These findings indicate that specifically targeting STAT3 siRNA to B cell lymphoma cell lines can significantly decrease STAT3 activity and inhibit tumor progression in vitro and in vivo, suggesting its potential utilization for cancer treatment.

Neddylation is an important post-translational modification involved in various physiological and pathological processes, but its regulatory role in B cell-mediated immune responses remains unclear. B cells exhibit different response to thymus dependent antigens and thymus independent antigens, making it significant to explore the role of neddylation in this process. B cell-specific Ube2m knockout mice CD19^cre/+Ube2m^fl/fl were constructed using the Cre-LoxP system, with littermate Ube2m^fl/fl (Ctrl) mice as controls. Mice were immunized with 4 antigens (thymus dependent antigens: NP-CGG and DNP-KLH, thymus independent antigens: NP-LPS and DNP-Ficoll), respectively. Serum levels of NP/DNP specific antibodies (IgM, IgG1, IgG2a, IgG2b, IgG2c, IgG3) were detected by ELISA, and the proportions of germinal center B cells and plasma cells in the spleen and bone marrow were analyzed by flow cytometry. Statistical analysis was used to evaluate the differences in immune responses. Compared with the Ctrl mice, CD19^cre/+Ube2m^fl/fl mice showed significantly reduced levels of NP/DNP specific IgG1、IgG2a、IgG2b、IgG2c、IgG3 after thymus independent antigens (NP-LPS, DNP-Ficoll) immunization, while IgM levels were mostly unchanged, and the reduced proportions of plasma cells and germinal center B cells in the bone marrow or spleen were observed. In thymus dependent antigens (NP-CGG, DNP-KLH) immunization models, CD19^cre/+Ube2m^fl/fl mice exhibited significantly decreased levels of IgM, IgG1, IgG2a, IgG2b, IgG2c, IgG3, with differences in the timing and magnitude of antibody reduction induced by different antigens. A significant reduction in the proportions of plasma cells and NP specific germinal center B cells in the spleen were also observed. Deficiency of B cell-intrinsic neddylation extensively impairs immune responses to both thymus independent antigens and thymus dependent antigens in mice, including early primary immune responses, Th1-type cellular immune responses, and Th2-type humoral immune responses, with antigen-dependent regulatory effects. This study provides experimental evidence for understanding the role of neddylation in B cell mediated immune responses.