Fatty infiltration in the musculoskeletal system: pathological mechanisms and clinical implications

Fatty infiltration denotes the anomalous accrual of adipocytes in non-adipose tissue, thereby generating toxic substances with the capacity to impede the ordinary physiological functions of various organs. With aging, the musculoskeletal system undergoes pronounced degenerative alterations, prompting heightened scrutiny regarding the contributory role of fatty infiltration in its pathophysiology. Several studies have demonstrated that fatty infiltration affects the normal metabolism of the musculoskeletal system, leading to substantial tissue damage. Nevertheless, a definitive and universally accepted generalization concerning the comprehensive effects of fatty infiltration on the musculoskeletal system remains elusive. As a result, this review summarizes the characteristics of different types of adipose tissue, the pathological mechanisms associated with fatty infiltration in bone, muscle, and the entirety of the musculoskeletal system, examines relevant clinical diseases, and explores potential therapeutic modalities. This review is intended to give researchers a better understanding of fatty infiltration and to contribute new ideas to the prevention and treatment of clinical musculoskeletal diseases

Hexokinase 2 promoted cell motility and proliferation by activating Akt1/p-Akt1 in human ovarian cancer cells

Abstract Background Recently, increasing evidence has indicated that elevation of Hexokinase 2 (HK2) plays an important role in several cancers on regulating cell motility and growth. However, its role on regulating cell EMT in human ovarian cancer still less to known. Methods The transwell and wound-healing assay were used to detect the effective of HK2 on regulating motility of ovarian cancer cells. Real Time PCR and Western Blotting were used to explore the changing of EMT-related proteins in HK2-modified cells. The clonogenic formation, cell growth curves and MTT assays were used to evaluate the effective of HK2 on regulating cell proliferation in HK2-modified cells. The flow cytometry was used to detect the differences in the distribution of cells in the cell cycle between the HK2-modified cells and their control cells. The correlation of HK2 and Akt1/p-Akt1 was explored by using Western Blotting, Akt1 inhibitor (MK2206) and transient transfection of an Akt1 recombinant plasmid. The potential correlation between HK2 and EMT-related proteins in human ovarian cancer tissues and OV (ovarian serous cystadenocarcinoma) was confirmed by using Pearson correlation analysis and TIMER 2.0. Results In ovarian cancer cells, overexpressing of HK2 enhanced cell motility by inducing of EMT-related proteins, such as CDH2, fibronectin, MMP9, ZEB1, ZEB2 and vimentin. Moreover, overexpressing of HK2 promoted cell growth by reducing p21 and p27 expression in ovarian cancer cells. Further studies demonstrated that this promotion of cell motility and growth by HK2 was probably a result of it activating of Akt1 (p-Akt1) in ovarian cancer cells. Additionally, the positive correlation between HK2 and p-Akt1, fibronectin, MMP9 expression in human ovarian cancer samples was verified by using Pearson correlation analysis. The positive correlation between HK2 and CDH2, fibronectin, MMP9, ZEB1, ZEB2 and vimentin in OV (ovarian serous cystadenocarcinoma) was confirmed by using TIMER 2.0. Conclusion This study demonstrated that HK2 could induce EMT-related proteins and reduce cell cycle inhibitor by activating Akt1 in human ovarian cancer cells, subsequently enhancing cell motility and growth, suggesting that HK2 participate in the malignant process of ovarian cancer by interacting with Akt1

Characterization of genetic humanized mice with transgenic HLA DP401 or DRA but deficient in endogenous murine MHC class II genes upon Staphylococcus aureus pneumonia

Abstract Background Staphylococcus aureus can cause serious infections by secreting many superantigen exotoxins in “carrier” or “pathogenic” states. HLA DQ and HLA DR humanized mice have been used as a small animal model to study the role of two molecules during S. aureus infection. However, the contribution of HLA DP to S. aureus infection is unknown yet. Methods In this study, we have produced HLA DP401 and HLA DRA0101 humanized mice by microinjection of C57BL/6J zygotes. Neo‐floxed IAβ+/− mice were crossbred with Ella‐Cre and further crossbred with HLA DP401 or HLA‐DRA0101 humanized mice. After several rounds of traditional crossbreeding, we finally obtained HLA DP401‐IAβ−/− and HLA DRA‐IAβ−/− humanized mice, in which human DP401 or DRA0101 molecule was introduced into IAβ−/− mice deficient in endogenous murine MHC class II molecules. A transnasal infection murine model of S. aureus pneumonia was induced in the humanized mice by administering 2 × 108 CFU of S. aureus Newman dropwise into the nasal cavity. The immune responses and histopathology changes were further assessed in lungs in these infected mice. Results We evaluated the local and systemic effects of S. aureus delivered intranasally in HLA DP401‐IAβ−/− and HLA DRA‐IAβ−/− transgenic mice. S. aureus Newman infection significantly increased the mRNA level of IL 12p40 in lungs in humanized mice. An increase in IFN‐γ and IL‐6 protein was observed in HLA DRA‐IAβ−/− mice. We observed a declining trend in the percentage of F4/80+ macrophages in lungs in HLA DP401‐IAβ−/− mice and a decreasing ratio of CD4+ to CD8+ T cells in lungs in IAβ−/− mice and HLA DP401‐IAβ−/− mice. A decreasing ratio of Vβ3+ to Vβ8+ T cells was also found in the lymph node of IAβ−/− mice and HLA DP401‐IAβ−/− mice. S. aureus Newman infection resulted in a weaker pathological injury in lungs in IAβ−/− genetic background mice. Conclusion These humanized mice will be an invaluable mouse model to resolve the pathological mechanism of S. aureus pneumonia and study what role DP molecule plays in S. aureus infection

Current status and development trend of miRNAs in osteoporosis-related research: A bibliometric analysis

Introduction. The occurrence of osteoporosis (OP) has drawn considerable attention from scholars around the world due to the significant impacts thereof on the social economy and the quality of human life. OP research has been rapidly expanding since the inclusion of microRNAs (miRNAs) as critical regulators of gene-expression. However, despite the ability to evaluate miRNA gene therapy in OP being enhanced, there has been a scarcity of updated citation analyses that reflect such developments. In the present study, through bibliometric analysis, the global research activity and trends in regard to the relationship between OP and miRNAs were reviewed. Methods. Publications related to miRNA and OP from 2000 to 2021 were retrieved via Web of Science (WoS). The data included publication years, countries, journals, institutions, authors and keywords, and were sorted and summarized by bibliometrics, before being visually analyzed through VOS Viewer. Results. In the past five years, 599 articles have been published, with said studies accounting for 79.11% of all relevant documents, indicating the increased interest in the present research topic. The country with the highest contribution rate was China, and the publication rate of Journal of Bone and Mineral Research was the highest, followed by Bone. The institutions with the highest contribution rate were Nanjing Medical University. The most frequently occurring keywords were clustered into five groups. The research area of the first group described that circulating miRNA would be a potential biomarker for postmenopausal osteoporosis (PMOP). The remaining four groups involved the influences of miRNAs and exosomes on the osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs), and the interactions of lncRNA and miRNA with OP. Conclusions. The results of the present study will expand the research on miRNAs and OP. The research direction with the highest frequency was the miRNAs acting on osteoblasts and osteoclasts. The influence of miRNAs carried by exosomes on the differentiation of MSCs might become an effective method for OP cell-free treatment

Iron induces B cell pyroptosis through Tom20–Bax–caspase–gasdermin E signaling to promote inflammation post-spinal cord injury

Abstract Background Immune inflammatory responses play an important role in spinal cord injury (SCI); however, the beneficial and detrimental effects remain controversial. Many studies have described the role of neutrophils, macrophages, and T lymphocytes in immune inflammatory responses after SCI, although little is known about the role of B lymphocytes, and immunosuppression can easily occur after SCI. Methods A mouse model of SCI was established, and HE staining and Nissl staining were performed to observe the pathological changes. The size and morphology of the spleen were examined, and the effects of SCI on spleen function and B cell levels were detected by flow cytometry and ELISA. To explore the specific mechanism of immunosuppression after SCI, B cells from the spleens of SCI model mice were isolated using magnetic beads and analyzed by 4D label-free quantitative proteomics. The level of inflammatory cytokines and iron ions were measured, and the expression of proteins related to the Tom20 pathway was quantified by western blotting. To clarify the relationship between iron ions and B cell pyroptosis after SCI, we used FeSO4 and CCCP, which induce oxidative stress to stimulate SCI, to interfere with B cell processes. siRNA transfection to knock down Tom20 (Tom20-KD) in B cells and human B lymphocytoma cell was used to verify the key role of Tom20. To further explore the effect of iron ions on SCI, we used deferoxamine (DFO) and iron dextran (ID) to interfere with SCI processes in mice. The level of iron ions in splenic B cells and the expression of proteins related to the Tom20–Bax–caspase–gasdermin E (GSDME) pathway were analyzed. Results SCI could damage spleen function and lead to a decrease in B cell levels; SCI upregulated the expression of Tom20 protein in the mitochondria of B cells; SCI could regulate the concentration of iron ions and activate the Tom20–Bax–caspase–GSDME pathway to induce B cell pyroptosis. Iron ions aggravated CCCP-induced B cell pyroptosis and human B lymphocytoma pyroptosis by activating the Tom20–Bax–caspase–GSDME pathway. DFO could reduce inflammation and promote repair after SCI by inhibiting Tom20–Bax–caspase–GSDME-induced B cell pyroptosis. Conclusions Iron overload activates the Tom20–Bax–caspase–GSDME pathway after SCI, induces B cell pyroptosis, promotes inflammation, and aggravates the changes caused by SCI. This may represent a novel mechanism through which the immune inflammatory response is induced after SCI and may provide a new key target for the treatment of SCI