Abstract Background Bone marrow-derived mesenchymal stem cells (BMSCs) have the functions of self-renew and differentiating into osteoblasts, adipocytes and chondrocytes, which are regarded as one of the greatest bioscientific achievements in the regenerative medicine field. Tescalcin (TESC), an EF-hand Ca2+binding protein, plays a vital role in cell proliferation and differentiation. However, what the role of TESC in BMSCs still is unknown. The purpose of this study was to explore the functions. Methods Adenovirus was constructed to decrease the expression of TESC. BML-284 was used to active Wnt/β-catenin signaling pathway. qRT-PCR and western blot was used to detect the expression of mRNA and protein levels. ALP staining and activity were used to detect the change of ALP. ARS staining and quantitative analysis were used to determine the mineralization capacity. Immunofluorescence was used to show the expression of protein. Results Firstly, we found that the mRNA and protein levels of TESC was increased during the osteogenic differentiation. Next, we determined that TESC knockdown inhibited the expression of osteogenic-related genes and decreased the capacity of mineralization. Then, we found that Wnt/β-catenin signaling was inhibited after TESC Knockdown by detecting the Wnt/β-catenin signaling pathway-related protein expression. Afterwards, BML-284 was demonstrated to active Wnt/β-catenin signaling successfully and utilized to rescue the negative osteogenic differentiation of TESC knockdown. Conclusion In summary, our study indicated that TESC knockdown inhibited osteogenic differentiation of BMSCs by Wnt/β-catenin signaling pathway. We supposed that TESC acted in the progress of osteogenic differentiation as a key regulator. We provided a new target for the application of BMSCs in regenerative medicine.
Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells in the adrenal gland. However, the cellular molecular characteristics and immune microenvironment of PCCs are incompletely understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 16 tissues from 4 sporadic unclassified PCC patients and 1 hereditary PCC patient with Von Hippel-Lindau (VHL) syndrome. We found that intra-tumoral heterogeneity was less extensive than the inter-individual heterogeneity of PCCs. Further, the unclassified PCC patients were divided into two types, metabolism-type (marked by NDUFA4L2 and COX4I2) and kinase-type (marked by RET and PNMT), validated by immunohistochemical staining. Trajectory analysis of tumor evolution revealed that metabolism-type PCC cells display phenotype of consistently active metabolism and increased metastasis potential, while kinase-type PCC cells showed decreased epinephrine synthesis and neuron-like phenotypes. Cell-cell communication analysis showed activation of the annexin pathway and a strong inflammation reaction in metabolism-type PCCs and activation of FGF signaling in the kinase-type PCC. Although multispectral immunofluorescence staining showed a lack of CD8 + T cell infiltration in both metabolism-type and kinase-type PCCs, only the kinase-type PCC exhibited downregulation of HLA-I molecules that possibly regulated by RET , suggesting the potential of combined therapy with kinase inhibitors and immunotherapy for kinase-type PCCs; in contrast, the application of immunotherapy to metabolism-type PCCs (with antigen presentation ability) is likely unsuitable. Our study presents a single-cell transcriptomics-based molecular classification and microenvironment characterization of PCCs, providing clues for potential therapeutic strategies to treat PCCs.
Clear cell renal cell carcinoma (ccRCC) is the most common solid renal tumor. Therefore, it is necessary to explore the related tumor markers. LGALS3BP (galectin 3 binding protein) is a multifunctional glycoprotein implicated in immunity and cancer. Some studies have shown that LGALS3BP promotes the occurrence and development of tumors. However, their exact role in renal tumorigenesis remains unclear. Our study used a webserver to explore the mRNA expression and clinical features of LGALS3BP in ccRCC. Survival analysis showed that patients with high LGALS3BP expression had significantly worse OS and DFS than those with low LGALS3BP expression. LGALS3BP expression is significantly related to B cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Furthermore, we determined that LGALS3BP is significantly associated with angiogenesis, stemness and proliferation in renal cancer. Three phenotypes may be associated with a poor prognosis. Genes related to proliferation, angiogenesis and stemness were derived from a Venn diagram of FGF2. FGF2 is negatively correlated with proliferation and positively correlated with angiogenesis. Finally, we screened for drugs that may have potential therapeutic value for ccRCC. The PCR results showed that the expression of LGALS3BP in the normal cell line was lower than that in the tumor cell lines. After LGALS3BP knockdown, the proliferation of 769-P and 786-O cells decreased. The present findings show that LGALS3BP is critical for ccRCC cell proliferation and may be a potential target and biomarker for ccRCC.
Abstract Bone marrow mesenchymal stem cells play an important role in osteogenic differentiation, and they complete this important biological process through the coordination of various transcription factors and signal pathways. In recent years, studies have clearly confirmed that long non-coding RNAs (lncRNAs) are involved in osteogenic differentiation, which plays an important biological role in the occurrence and development of osteogenesis-related bone disease. This article reviews the roles and related mechanisms of lncRNAs in osteogenic differentiation, as well as their potential effects on a variety of bone diseases. This understanding may help researchers identify potential therapeutic targets and biological markers in the future.
<p>Supplementary Figure S5. BCMA CAR-T Therapy Enhances the Proportion and Cytotoxic Activity of CD8+ Effector T Cells, Positively Correlating with Therapeutic Responsivity.</p>
Pheochromocytomas (PCCs) are rare neuroendocrine tumors that originate from chromaffin cells in the adrenal gland. However, the cellular molecular characteristics and immune microenvironment of PCCs are incompletely understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 16 tissues from 4 sporadic unclassified PCC patients and 1 hereditary PCC patient with Von Hippel-Lindau (VHL) syndrome. We found that intra-tumoral heterogeneity was less extensive than the inter-individual heterogeneity of PCCs. Further, the unclassified PCC patients were divided into two types, metabolism-type (marked by NDUFA4L2 and COX4I2) and kinase-type (marked by RET and PNMT), validated by immunohistochemical staining. Trajectory analysis of tumor evolution revealed that metabolism-type PCC cells display phenotype of consistently active metabolism and increased metastasis potential, while kinase-type PCC cells showed decreased epinephrine synthesis and neuron-like phenotypes. Cell-cell communication analysis showed activation of the annexin pathway and a strong inflammation reaction in metabolism-type PCCs and activation of FGF signaling in the kinase-type PCC. Although multispectral immunofluorescence staining showed a lack of CD8+ T cell infiltration in both metabolism-type and kinase-type PCCs, only the kinase-type PCC exhibited downregulation of HLA-I molecules that possibly regulated by RET, suggesting the potential of combined therapy with kinase inhibitors and immunotherapy for kinase-type PCCs; in contrast, the application of immunotherapy to metabolism-type PCCs (with antigen presentation ability) is likely unsuitable. Our study presents a single-cell transcriptomics-based molecular classification and microenvironment characterization of PCCs, providing clues for potential therapeutic strategies to treat PCCs.
Abstract Background Osteoporosis is a widespread and serious metabolic bone disease. At present, revealing the molecular mechanisms of osteoporosis and developing effective prevention and treatment methods are of great significance to health worldwide. LncRNA is a non-coding RNA peptide chain with more than 200 nucleotides. Researchers have identified many lncRNAs implicated in the development of diseases and lncRNA H19 is an example. Results A large amount of evidence supports the fact that long non-coding RNA (lncRNA) genes, such as H19 , have multiple, far-reaching effects on various biological functions. It has been found that lncRNA H19 has a role in the regulation of different types of cells in the body including the osteoblasts, osteocytes, and osteoclasts found in bones. Therefore, it can be postulated that lncRNA H19 affects the incidence and development of osteoporosis. Conclusion The prospect of targeting lncRNA H19 in the treatment of osteoporosis is promising because of the effects that lncRNA H19 has on the process of osteogenic differentiation. In this review, we summarize the molecular pathways and mechanisms of lncRNA H19 in the pathogenesis of osteoporosis and summarize the research progress of targeting H19 as a treatment option. Research is emerging that explores more effective treatment possibilities for bone metabolism diseases using molecular targets.
Mastitis is an inflammation of the mammary gland tissue that can lead to decreased milk production and altered milk composition, carrying serious implications for the safety of dairy products. Although both caffeic acid (CA) and umbilical cord-mesenchymal stem cells (UC-MSCs) showed potential anti-inflammatory and immunomodulatory properties, little is known about their combined roles in treating mastitis. Here, we report the combined effects and mechanisms of CA and UC-MSCs on lipopolysaccharide (LPS)-induced mastitis. Based on the network pharmacological analysis, the potential relevant genes involved in the alleviating effects of CA on LPS-induced mastitis were inferred. In LPS-treated mammary epithelial cells, CA or/and UC-MSC conditioned medium (UC-MSC-CM) inhibited the phosphorylation of p65, p50, p38, IκB, and MKK3/6 proteins and the expression of downstream inflammatory factors TNF-α, IL-1β, IL-6, IL-8, and COX-2. Additionally, CA or/and hydrogel-loaded UC-MSCs also suppressed the activation of the above inflammatory pathway, leading to the alleviation of pathological damages in the LPS-induced mouse mastitis model. UC-MSCs exhibited more significant effects than CA, and the combined treatment of both was more effective. Our study sheds light on the synergistic and complementary effects of CA and UC-MSCs in alleviating mastitis, offering clues for understanding the regulation of the p38-MAPK/NF-κB↔TNF-α signal transduction loop in the tumor necrosis factor (TNF) pathway as a potential mechanism. This study provides a theoretical basis for developing a novel antibiotic alternative treatment of mastitis that may contribute to reducing economic losses in animal husbandry and protecting public health safety.
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