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Science China. Life Sciences Jun 2024Cancer stem cells (CSCs) play an important role in metastasis development, tumor recurrence, and treatment resistance, and are essential for the eradication of cancer....
Cancer stem cells (CSCs) play an important role in metastasis development, tumor recurrence, and treatment resistance, and are essential for the eradication of cancer. Currently, therapies fail to eradicate CSCs due to their therapeutic stress-induced cellular escape, which leads to enhanced aggressive behaviors compared with CSCs that have never been treated. However, the underlying mechanisms regulating the therapeutic escape remain unknown. To this end, we established a model to isolate the therapeutic escaped CSCs (TSCSCs) from breast CSCs and performed the transcription profile to reveal the mechanism. Mechanistically, we demonstrated that the behavior of therapeutic escape was regulated through the p38/MAPK signaling pathway, resulting in TSCSCs exhibiting enhanced motility and metastasis. Notably, blocking the p38/MAPK signaling pathway effectively reduced motility and metastasis ability both in vitro and in vivo, which were further supported by downregulated motility-related genes and epithelial-mesenchymal transition (EMT)-related proteins vimentin and N-cadherin. The obtained findings reveal the p38/MAPK pathway as a potential therapeutic target for TSCSCs and would provide profound implications for cancer therapy.
PubMed: 38951428
DOI: 10.1007/s11427-023-2585-5 -
Naunyn-Schmiedeberg's Archives of... Jun 2024A previous study has confirmed the upregulation of circ_0007142 expression in CC. Here, we aimed to investigate the effect and mechanism of circ_0007142 in CC...
A previous study has confirmed the upregulation of circ_0007142 expression in CC. Here, we aimed to investigate the effect and mechanism of circ_0007142 in CC progression. The expression of circ_0007142, microRNA-128-3p (miR-128-3p), S100 calcium-binding protein A14 (S100A14), and epithelial mesenchymal transition (EMT)-related markers was measured by qRT-PCR and Western blot. Cell proliferative, migratory, and invasion abilities were evaluated using cell counting Kit-8, cell colony formation, 5-ethynyl-2'-deoxyuridine, and transwell assays, respectively. The interaction among circ_0007142, miR-128-3p and S100A14 was identified by dual-luciferase reporter and RNA immunoprecipitation assays. In vivo experiment was implemented to investigate the effect of circ_0007142 on tumor growth. CC tissues and cells displayed high expression of circ_0007142 and S100A14, and low expression of miR-128-3p in comparison to the controls. Knockdown of circ_0007142 resulted in the inhibition of cell proliferation, migration invasion, and EMT in vitro. In support, circ_0007142 deficiency hindered tumor growth and EMT in vivo. In rescue experiments, downregulation of miR-128-3p relieved circ_0007142 absence-mediated anticancer impacts. MiR-128-3p overexpression-induced inhibitory effects on cell growth and metastasis were attenuated by S100A14 overexpression. Importantly, circ_0007142 regulated S100A14 expression by sponging miR-128-3p. Circ_0007142 knockdown suppressed CC cell malignant behaviors by miR-128-3p/S100A14 pathway, providing a possible circRNA-targeted therapy for CC.
PubMed: 38951152
DOI: 10.1007/s00210-024-03250-0 -
Zhonghua Yi Xue Za Zhi Jul 2024To investigate the role and underlying mechanisms of intercellular adhesion molecule-1 (ICAM-1) in the adhesion and migration of mesenchymal stem cells (MSCs) in...
To investigate the role and underlying mechanisms of intercellular adhesion molecule-1 (ICAM-1) in the adhesion and migration of mesenchymal stem cells (MSCs) in patients with ankylosing spondylitis (AS). Bone marrow and ligament tissues were collected during surgery from patients with AS and thoracolumbar fractures (as controls, HC) treated from October 2021 to October 2022 at Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital. MSCs were isolated and cultured from the bone marrow using the Ficoll separation method. Cell morphology was observed under high-resolution microscopy, and differences in the cytoskeletal features between AS-and HC-MSCs were analyzed through immunofluorescence staining. The expression of ICAM-1 was quantified in both groups using real-time quantitative polymerase chain reaction (RT-qPCR) and flow cytometry. Transwell migration assays and wound healing experiments were conducted to evaluate the differences in migration rates between the two groups of MSCs. The interspinous ligament and bone marrow was acquired in AS (2 males and 1 female; 33, 37, 32 years old, respectively) and no-AS patients (2 males and 1 female; 35, 32, 38 years old, respectively). AS-MSCs exhibited broader cell morphology compared to HC-MSCs under bright field and fluorescence microscopy. Immunofluorescence staining of the interspinous ligament showed higher expression of ICAM-1 (68.38±3.42 vs 48.31±2.43) and CD105 (37.97±2.16 vs 23.36±2.06) in AS patients (both <0.001). Western blot and RT-qPCR analysis revealed significantly stronger protein expression and transcription levels of ICAM-1 in AS-MSCs when compared to those in HC-MSCs (both <0.001). Flow cytometry confirmed greater mean fluorescence intensity of ICAM-1 in AS-MSCs than in that in HC-MSCs (924.30±54.99 vs 636.47±40.03, =0.002). Regarding cell adhesion efficiency, it showed no significant difference between AS-MSCs and HC-MSCs in the early stage of adhesion (0.5 h: 1 496±213 vs 1 205±163, =0.133), but they were all significantly higher in AS-MSCs in the later stage (1 h: 2 894±172 vs 1 908±155, =0.002; 2 h: 4 540±286 vs 3 334±188, =0.004; 3 h: 5 212±281 vs 4 208±303, =0.014). Finally, cell migration experiments demonstrated a stronger migration capability of AS-MSCs compared to HC-MSCs (5 449±172 vs 4 016±155, <0.001), and the inhibition efficiency of A-205804 on the migration rate of AS-MSCs was stronger than that on HC-MSCs (2 145±239 vs 3 539±316, =0.004). The aberrant expression of ICAM-1 markedly influences the adhesion and migration dynamics of MSCs. Elevated ICAM-1 levels in MSCs derives from patients with AS significantly enhance their migratory capabilities.
Topics: Humans; Intercellular Adhesion Molecule-1; Spondylitis, Ankylosing; Mesenchymal Stem Cells; Cell Movement; Adult; Cell Adhesion; Female; Male; Bone Marrow Cells; Retrospective Studies; Cells, Cultured
PubMed: 38951108
DOI: 10.3760/cma.j.cn112137-20231115-01101 -
Zhonghua Fu Chan Ke Za Zhi Jun 2024To investigate the effect of DNA methylation of laminin α3 (LAMA3) on the prognosis of platinum-resistant epithelial ovarian cancer (EOC) and its possible mechanism....
To investigate the effect of DNA methylation of laminin α3 (LAMA3) on the prognosis of platinum-resistant epithelial ovarian cancer (EOC) and its possible mechanism. (1) The relationship between DNA methylation of LAMA3 and platinum resistance in EOC was evaluated by bioinformatics. (2) A total of 67 EOC patients treated at Guangxi Medical University Cancer Hospital from January 2000 to December 2012 were selected to detect the levels of LAMA3 DNA methylation in EOC tissues using pyrophosphate sequencing technology to explore its diagnostic efficacy for platinum resistance and prognosis in EOC patients. Furthermore, its impact on chemotherapy efficacy and prognosis of platinum resistant EOC patients were also analyzed. (1) Ten proteins highly interacting with LAMA3 were screened from the Gene Interaction Retrieval Platform (STRING) database, including laminin β (LAMB) 3, laminin γ (LAMC) 3, integrin α (ITGA) 6, intestine protein β4 (ITGB4), ITGA3, LAMC1,LAMB2, dystrophin associated glycoprotein 1 (DAG1), LAMB1 and cytochrome P450c17α (COL17A1) protein; kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that LAMA3 and its related interacting proteins participate in the regulation of malignant tumor occurrence and development through signaling pathways such as apoptosis, cell cycle, DNA damage response, epithelial mesenchymal transition (EMT), androgen receptor (AR), estrogen receptor (ER), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt), RAS/mitogen activated protein kinase (MAPK), receptor tyrosine kinase (RTK), tuberous sclerosis protein complex (TSC)/mammalian target of rapamycin (mTOR), and their expression levels were related to the sensitivity of chemotherapy drugs such as cisplatin in EOC. (2) Our clinical data analysis found that the LAMA3 DNA methylation level in EOC tissue of the platinum-sensitive group (35 cases) was 71% (25/35), which was higher than 69% (22/32) in the platinum-resistant group (32 cases), with statistically insignificant difference (=0.057, =0.811). The area under the curve (AUC) of LAMA3 DNA methylation level for assessing platinum resistance in EOC was 0.601, and the AUC for predicting EOC patient prognosis was 0.686. The chemotherapy efficacy of EOC patients with high methylation of LAMA3 DNA was worse than that of patients with low methylation, 50% (12/24) vs 15/15, with statistically significant difference (=10.833, =0.001). The level of LAMA3 DNA methylation had a significant impact on the progression free survival and overall survival of EOC patients (both <0.05). The level of LAMA3 DNA methylation has certain diagnostic and predictive value for platinum resistance and prognosis in EOC patients, which may be closely related to the regulatory mechanism, platinum resistance and prognosis of EOC.
Topics: Humans; Female; Laminin; DNA Methylation; Drug Resistance, Neoplasm; Computational Biology; Carcinoma, Ovarian Epithelial; Prognosis; Ovarian Neoplasms; Gene Expression Regulation, Neoplastic; Antineoplastic Agents; Platinum; Signal Transduction
PubMed: 38951081
DOI: 10.3760/cma.j.cn112141-20240201-00069 -
Acta Biomaterialia Jun 2024The precise mechanisms underlying the cellular response to static electric cues remain unclear, limiting the design and development of biomaterials that utilize this...
The precise mechanisms underlying the cellular response to static electric cues remain unclear, limiting the design and development of biomaterials that utilize this parameter to enhance specific biological behaviours. To gather information on this matter we have explored the interaction of collagen type-I, the most abundant mammalian extracellular protein, with polyvinylidene fluoride (PVDF), an electroactive polymer with great potential for tissue engineering applications. Our results reveal significant differences in collagen affinity, conformation, and interaction strength depending on the electric charge of the PVDF surface, which subsequently affects the behaviour of mesenchymal stem cells seeded on them. These findings highlight the importance of surface charge in the establishment of the material-protein interface and ultimately in the biological response to the material. STATEMENT OF SIGNIFICANCE: The development of new tissue engineering strategies relies heavily on the understanding of how biomaterials interact with biological tissues. Although several factors drive this process and their driving principles have been identified, the relevance and mechanism by which the surface potential influences cell behaviour is still unknown. In our study, we investigate the interaction between collagen, the most abundant component of the extracellular matrix, and poly(vinylidenefluoride) with varying surface charges. Our findings reveal substantial variations in the binding forces, structure and adhesion of collagen on the different surfaces, which collectively explain the differential cellular responses. By exposing these differences, our research fills a critical knowledge gap and paves the way for innovations in material design for advanced tissue regeneration strategies.
PubMed: 38950807
DOI: 10.1016/j.actbio.2024.06.039 -
International Immunopharmacology Jun 2024The mechanism of early tumor recurrence after incomplete microwave ablation (iMWA) is poorly understood. The anti-programmed cell death protein 1 (anti-PD-1) monotherapy...
The mechanism of early tumor recurrence after incomplete microwave ablation (iMWA) is poorly understood. The anti-programmed cell death protein 1 (anti-PD-1) monotherapy is reported to be ineffective to prevent the progression of residual tumor resulted from iMWA. Transforming growth factor-β (TGFβ) signaling pathway plays an important role in tumorigenesis and development. We assume blocking transforming growth factor-β receptor (TGFβR) after incomplete iMWA may synergistically enhance the effect of anti-PD-1 antibody to prevent the progression of residual tumor. We construct an iMWA model with mice harboring Hepa1-6 derived xenograft. The Tgfb1 expression and phosphorylated-Smad3 protein expression is upregulated in the residual tumor after iMWA. With the application of TGFβR inhibitor SB431542, the cell proliferation potential, the tumor growth, the mRNA expression of epithelial mesenchymal transition (EMT) markers including Cdh2, and Vim, and cancer stem cell marker Epcam, and the infiltrating Treg cells are reduced in the residual tumor tissue. In addition, iMWA combined with TGFβR blocker and anti-PD-1 antibody further decreases the cell proliferation, tumor growth, expression of EMT markers and cancer stem cell marker, and the infiltrating Treg cells in the residual tumor tissue. Blocking TGFβR may alleviate the pro-tumoral effect of tumor microenvironment thereby significantly prevents the progression of residual tumor tissue. Our study indicates that blocking TGFβR may be a novel therapeutic strategy to enhance the effect of anti-PD-1 antibody to prevent residual hepatocellular carcinoma (HCC) progression after iMWA.
PubMed: 38950456
DOI: 10.1016/j.intimp.2024.112585 -
Translational Vision Science &... Jul 2024We sought to evaluate the efficacy of growth differentiation factor (GDF)-15 treatment for suppressing epithelial-mesenchymal transition (EMT) and alleviating...
PURPOSE
We sought to evaluate the efficacy of growth differentiation factor (GDF)-15 treatment for suppressing epithelial-mesenchymal transition (EMT) and alleviating transforming growth factor β2 (TGFβ2)-induced lens opacity.
METHODS
To test whether GDF-15 is a molecule that prevents EMT, we pretreated the culture with GDF-15 in neural progenitor cells, retinal pigment epithelial cells, and lens epithelial cells and then treated with factors that promote EMT, GDF-11, and TGFβ2, respectively. To further investigate the efficacy of GDF-15 on alleviating lens opacity, we used mouse lens explant culture to mimic secondary cataracts. We pretreated the lens culture with GDF-15 and then added TGFβ2 to develop lens opacity (n = 3 for each group). Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to measure EMT protein and gene expression, respectively.
RESULTS
In cell culture, GDF-15 pretreatment significantly attenuated EMT marker expression in cultured cells induced by treatment with GDF-11 or TGFβ2. In the lens explant culture, GDF-15 pretreatment also reduced mouse lens opacity induced by exposure to TGFβ2.
CONCLUSIONS
Our results indicate that GDF-15 could alleviate TGFβ2-induced EMT and is a potential therapeutic agent to slow or prevent posterior capsular opacification (PCO) progression after cataract surgery.
TRANSLATIONAL RELEVANCE
Cataracts are the leading cause of blindness worldwide, with the only current treatment involving surgical removal of the lens and replacement with an artificial lens. However, PCO, also known as secondary cataract, is a common complication after cataract surgery. The development of an adjuvant that slows the progression of PCO will be beneficial to the field of anterior complications.
Topics: Animals; Epithelial-Mesenchymal Transition; Transforming Growth Factor beta2; Growth Differentiation Factor 15; Cataract; Mice; Lens, Crystalline; Mice, Inbred C57BL; Cells, Cultured; Disease Models, Animal; Epithelial Cells; Blotting, Western; Retinal Pigment Epithelium
PubMed: 38949633
DOI: 10.1167/tvst.13.7.2 -
Advanced Materials (Deerfield Beach,... Jun 2024Heart transplantation offers life-saving treatment for patients with end-stage heart failure; however, ischemia-reperfusion injury (IRI) and subsequent immune responses...
Heart transplantation offers life-saving treatment for patients with end-stage heart failure; however, ischemia-reperfusion injury (IRI) and subsequent immune responses remain significant challenges. Current therapies primarily target adaptive immunity, with limited options available for addressing IRI and innate immune activation. Although plant-derived vesicle-like nanoparticles show promise in managing diseases, their application in organ transplantation complications is unexplored. Here, this work develops a novel reactive oxygen species (ROS)-responsive multifunctional fusion extracellular nanovesicles carrying rapamycin (FNVs@RAPA) to address early IRI and Ly6CLy6G inflammatory macrophage-mediated rejection in heart transplantation. The FNVs comprise Exocarpium Citri grandis-derived extracellular nanovesicles with anti-inflammatory and antioxidant properties, and mesenchymal stem cell membrane-derived nanovesicles expressing calreticulin with macrophage-targeting ability. A novel ROS-responsive bio-orthogonal chemistry approach facilitates the active targeting delivery of FNVs@RAPA to the heart graft site, effectively alleviating IRI and promoting the polarization of Ly6CLy6G inflammatory macrophages toward an anti-inflammatory phenotype. Hence, FNVs@RAPA represents a promising therapeutic approach for mitigating early transplantation complications and immune rejection. The fusion-targeted delivery strategy offers superior heart graft site enrichment and macrophage-specific targeting, promising improved transplant outcomes.
PubMed: 38949397
DOI: 10.1002/adma.202406758 -
EFORT Open Reviews Jul 2024The combination of pharmacological and non-pharmacological interventions is strongly recommended by current guidelines for knee osteoarthritis. However, few systematic...
PURPOSE
The combination of pharmacological and non-pharmacological interventions is strongly recommended by current guidelines for knee osteoarthritis. However, few systematic reviews have validated their combined efficacy. In this study, we investigated the effects of the combination of pharmacological agents and exercise on knee osteoarthritis.
METHODS
Randomized controlled trials that investigated the efficacy of pharmacological agents combined with exercise for knee osteoarthritis were searched in PubMed, Embase, and Cochrane Library up to February 2024. The network meta-analysis was performed within the frequentist framework. Standardized mean difference (SMD) with 95% CI was estimated for pain and function. Grading of recommendations, assessment, development, and evaluations were used to evaluate the certainty of evidence.
RESULTS
In total, 71 studies were included. The combination therapy outperformed pharmacological or exercise therapy alone. Among the various pharmacological agents combined with exercise, mesenchymal stem cell injection was ranked the best for short-term pain reduction (SMD: -1.53, 95% CI: -1.92 to -1.13, high certainty), followed by botulinum toxin A, dextrose, and platelet-rich plasma. For long-term pain relief, dextrose prolotherapy was the optimal (SMD: -1.76, 95% CI: -2.65 to -0.88, moderate certainty), followed by mesenchymal stem cells, platelet rich in growth factor, and platelet-rich plasma.
CONCLUSION
Exercise programs should be incorporated into clinical practice and trial design. For patients undergoing exercise therapies, mesenchymal stem cell, dextrose, platelet-rich plasma, platelet rich in growth factor, and botulinum toxin A may be the optimal agents.
PubMed: 38949167
DOI: 10.1530/EOR-23-0136 -
Zhonghua Kou Qiang Yi Xue Za Zhi =... Jul 2024Temporomandibular joint osteoarthritis (TMJOA) is a kind of organic disease with synovial inflammation, cartilage degeneration and subchondral bone remodeling as the...
Temporomandibular joint osteoarthritis (TMJOA) is a kind of organic disease with synovial inflammation, cartilage degeneration and subchondral bone remodeling as the main pathological changes. The current treatment is mainly to relieve symptoms, but cannot completely stop the progression of the disease. Mesenchymal stem cells (MSC) have multi-lineage differentiation potential and have good prospects in the repair therapy of TMJOA. Intra-articular injection of MSC from bone marrow, adipose, umbilical cord, dental pulp, etc. has been shown to be effective in numerous animal studies. The above exogenous MSCs can also be used as seed cells to participate in tissue engineering and repair more severe defects. Recent studies have shown that exosomes are important mediators of MSC action and have some potential in the treatment of TMJOA. As the mechanisms of TMJOA are further investigated, there is some prospect that endogenous repair capacity can be activated by local injection of relevant drugs targeting the resident stem cells in the joint.
PubMed: 38949143
DOI: 10.3760/cma.j.cn112144-20230817-00097