Experimental Biology and Medicine最新文献

{"title":"Collagen II enrichment through scAAV6-RNAi-mediated inhibition of matrix-metalloproteinases 3 and 13 in degenerative nucleus-pulposus cells degenerative disc disease and biological treatment strategies.","authors":"Demissew Shenegelegn Mern,Claudius Thomé","doi":"10.3389/ebm.2024.10048","DOIUrl":"https://doi.org/10.3389/ebm.2024.10048","url":null,"abstract":"Intervertebral disc (IVD) degeneration damaging the extracellular matrix (ECM) of IVDs is the main cause of spine-associated disorders. Degenerative disc disease (DDD) is a multifaceted disorder, where environmental factors, inflammatory cytokines and catabolic enzymes act together. DDD starts typically due to imbalance between ECM biosynthesis and degradation within IVDs, especially through unbalanced degradation of aggrecan and collagen II in nucleus pulposus (NP). Current treatment approaches are primarily based on conservative or surgical therapies, which are insufficient for biological regeneration. The disintegrins and metalloproteinases with thrombospondin motifs (ADAMTSs) and matrix metalloproteinases (MMPs) are the key proteolytic enzymes for degradation of aggrecan and collagens. Previously, high expression levels of ADAMTS4, ADAMTS5, MMP3 and MMP13, which are accompanied with low levels of aggrecan and collagen II, were demonstrated in degenerative human NP cells. Moreover, self-complementary adeno-associated virus type 6 (scAAV6) mediated inhibitions of ADAMTS4 and ADAMTS5 by RNA-interference (RNAi) could specifically enhance aggrecan level. Thus, MMPs are apparently the main degrading enzymes of collagen II in NP. Furthermore, scAAV6-mediated inhibitions of MMP3 and MMP13 have not yet been investigated. Therefore, we attempted to enhance the level of collagen II in degenerative NP cells by scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13. MRI was used to determine preoperative grading of IVD degeneration in patients. After isolation and culturing of NP cells, cells were transduced with scAAV6-shRNAs targeting MMP3 or MMP13; and analysed by fluorescence microscopy, FACS, MTT assay, RT-qPCR, ELISA and western blotting. scAAV6-shRNRs have no impact on cell viability and proliferation, despite high transduction efficiencies (98.6%) and transduction units (1383 TU/Cell). Combined knockdown of MMP3 (92.8%) and MMP13 (90.9%) resulted in highest enhancement of collagen II (143.2%), whereby treatment effects were significant over 56 days (p < 0.001). Conclusively, scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13 help to progress less immunogenic and enduring biological treatments in DDD.","PeriodicalId":12163,"journal":{"name":"Experimental Biology and Medicine","volume":"35 1","pages":"10048"},"PeriodicalIF":3.2,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142248337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrasound-assisted laser therapy for selective removal of melanoma cells.","authors":"Madhumithra Subramanian Karthikesh, Noraida Martinez-Rivera, Eduardo Rosa-Molinar, Xueding Wang, Xinmai Yang","doi":"10.3389/ebm.2024.10096","DOIUrl":"10.3389/ebm.2024.10096","url":null,"abstract":"<p><p>The current study explores the potential of ultrasound-assisted laser therapy (USaLT) to selectively destroy melanoma cells. The technology was tested on an <i>ex vivo</i> melanoma model, which was established by growing melanoma cells in chicken breast tissue. Ultrasound-only and laser-only treatments were used as control groups. USaLT was able to effectively destroy melanoma cells and selectively remove 66.41% of melanoma cells in the <i>ex vivo</i> tumor model when an ultrasound peak negative pressure of 2 MPa was concurrently applied with a laser fluence of 28 mJ/cm² at 532 nm optical wavelength for 5 min. The therapeutic efficiency was further improved with the use of a higher laser fluence, and the treatment depth was improved to 3.5 mm with the use of 1,064 nm laser light at a fluence of 150 mJ/cm². None of the laser-only and ultrasound-only treatments were able to remove any melanoma cells. The treatment outcome was validated with histological analyses and photoacoustic imaging. This study opens the possibility of USaLT for melanoma that is currently treated by laser therapy, but at a much lower laser fluence level, hence improving the safety potential of laser therapy.</p>","PeriodicalId":12163,"journal":{"name":"Experimental Biology and Medicine","volume":"249 ","pages":"10096"},"PeriodicalIF":2.8,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of arterial intima stiffness by disturbed blood flow.","authors":"Briana C Bywaters, Andreea Trache, Gonzalo M Rivera","doi":"10.3389/ebm.2024.10090","DOIUrl":"10.3389/ebm.2024.10090","url":null,"abstract":"<p><p>The intima, comprising the endothelium and the subendothelial matrix, plays a crucial role in atherosclerosis pathogenesis. The mechanical stress arising from disturbed blood flow (d-flow) and the stiffening of the arterial wall contributes to endothelial dysfunction. However, the specific impacts of these physical forces on the mechanical environment of the intima remain undetermined. Here, we investigated whether inhibiting collagen crosslinking could ameliorate the detrimental effects of persistent d-flow on the mechanical properties of the intima. Partial ligation of the left carotid artery (LCA) was performed in C57BL/6J mice, inducing d-flow. The right carotid artery (RCA) served as an internal control. Carotids were collected 2 days and 2 weeks after surgery to study acute and chronic effects of d-flow on the mechanical phenotype of the intima. The chronic effects of d-flow were decoupled from the ensuing arterial wall stiffening by administration of β-aminopropionitrile (BAPN), an inhibitor of collagen crosslinking by lysyl oxidase (LOX) enzymes. Atomic force microscopy (AFM) was used to determine stiffness of the endothelium and the denuded subendothelial matrix in <i>en face</i> carotid preparations. The stiffness of human aortic endothelial cells (HAEC) cultured on soft and stiff hydrogels was also determined. Acute exposure to d-flow caused a slight decrease in endothelial stiffness in male mice but had no effect on the stiffness of the subendothelial matrix in either sex. Regardless of sex, the intact endothelium was softer than the subendothelial matrix. In contrast, exposure to chronic d-flow led to a substantial increase in the endothelial and subendothelial stiffness in both sexes. The effects of chronic d-flow were largely prevented by concurrent BAPN administration. In addition, HAEC displayed reduced stiffness when cultured on soft vs. stiff hydrogels. We conclude that chronic d-flow results in marked stiffening of the arterial intima, which can be effectively prevented by inhibition of collagen crosslinking.</p>","PeriodicalId":12163,"journal":{"name":"Experimental Biology and Medicine","volume":"249 ","pages":"10090"},"PeriodicalIF":2.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of potential biomarkers for cerebral palsy and the development of prediction models.","authors":"Haoyang Zheng, Duo Zhang, Yong Gan, Zesheng Peng, Yuyi Wu, Wei Xiang","doi":"10.3389/ebm.2024.10101","DOIUrl":"10.3389/ebm.2024.10101","url":null,"abstract":"<p><p>Cerebral palsy (CP) is a prevalent motor disorder originating from early brain injury or malformation, with significant variability in its clinical presentation and etiology. Early diagnosis and personalized therapeutic interventions are hindered by the lack of reliable biomarkers. This study aims to identify potential biomarkers for cerebral palsy and develop predictive models to enhance early diagnosis and prognosis. We conducted a comprehensive bioinformatics analysis of gene expression profiles in muscle samples from CP patients to identify candidate biomarkers. Six key genes (CKMT2, TNNT2, MYH4, MYH1, GOT1, and LPL) were validated in an independent cohort, and potential biological pathways and molecular networks involved in CP pathogenesis were analyzed. The importance of processes such as functional regulation, energy metabolism, and cell signaling pathways in the muscles of CP patients was emphasized. Predictive models of muscle sample biomarkers related to CP were developed and visualized. Calibration curves and receiver operating characteristic analysis demonstrated that the predictive models exhibit high sensitivity and specificity in distinguishing individuals at risk of CP. The identified biomarkers and developed prediction models offer significant potential for early diagnosis and personalized management of CP. Future research should focus on validating these biomarkers in larger cohorts and integrating them into clinical practice to improve outcomes for individuals with CP.</p>","PeriodicalId":12163,"journal":{"name":"Experimental Biology and Medicine","volume":"249 ","pages":"10101"},"PeriodicalIF":2.8,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDKL3 is a promising biomarker for diagnosis and prognosis prediction in patients with hepatocellular carcinoma.","authors":"Qingsi Wu, Mengran Lu, Huijuan Ouyang, Tingting Zhou, Jingyuan Lei, Panpan Wang, Wei Wang","doi":"10.3389/ebm.2024.10106","DOIUrl":"10.3389/ebm.2024.10106","url":null,"abstract":"<p><p>Cyclin-dependent kinase-like 3 (CDKL3) has been identified as an oncogene in certain types of tumors. Nonetheless, its function in hepatocellular carcinoma (HCC) is poorly understood. In this study, we conducted a comprehensive analysis of CDKL3 based on data from the HCC cohort of The Cancer Genome Atlas (TCGA). Our analysis included gene expression, diagnosis, prognosis, functional enrichment, tumor microenvironment and metabolic characteristics, tumor burden, mRNA expression-based stemness, alternative splicing, and prediction of therapy response. Additionally, we performed a cell counting kit-8 assay, TdT-mediated dUTP nick-end Labeling staining, migration assay, wound healing assay, colony formation assay, and nude mouse experiments to confirm the functional relevance of CDKL3 in HCC. Our findings showed that CDKL3 was significantly upregulated in HCC patients compared to controls. Various bioinformatic analyses suggested that CDKL3 could serve as a potential marker for HCC diagnosis and prognosis. Furthermore, CDKL3 was found to be involved in various mechanisms linked to the development of HCC, including copy number variation, tumor burden, genomic heterogeneity, cancer stemness, and alternative splicing of CDKL3. Notably, CDKL3 was also closely correlated with tumor immune cell infiltration and the expression of immune checkpoint markers. Additionally, CDKL3 was shown to independently function as a risk predictor for overall survival in HCC patients by multivariate Cox regression analysis. Furthermore, the knockdown of CDKL3 significantly inhibited cell proliferation <i>in vitro</i> and <i>in vivo</i>, indicating its role as an oncogene in HCC. Taken together, our findings suggest that CDKL3 shows promise as a biomarker for the detection and treatment outcome prediction of HCC patients.</p>","PeriodicalId":12163,"journal":{"name":"Experimental Biology and Medicine","volume":"249 ","pages":"10106"},"PeriodicalIF":2.8,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11237920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential therapeutic effects of peroxisome proliferator-activated receptors on corneal diseases.","authors":"Bing Jie Chow, Isabelle Xin Yu Lee, Chang Liu, Yu-Chi Liu","doi":"10.3389/ebm.2024.10142","DOIUrl":"10.3389/ebm.2024.10142","url":null,"abstract":"<p><p>The cornea is an avascular tissue in the eye that has multiple functions in the eye to maintain clear vision which can significantly impair one's vision when subjected to damage. Peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptor proteins comprising three different peroxisome proliferator-activated receptor (PPAR) isoforms, namely, PPAR alpha (α), PPAR gamma (γ), and PPAR delta (δ), have emerged as potential therapeutic targets for treating corneal diseases. In this review, we summarised the current literature on the therapeutic effects of PPAR agents on corneal diseases. We discussed the role of PPARs in the modulation of corneal wound healing, suppression of corneal inflammation, neovascularisation, fibrosis, stimulation of corneal nerve regeneration, and amelioration of dry eye by inhibiting oxidative stress within the cornea. We also discussed the underlying mechanisms of these therapeutic effects. Future clinical trials are warranted to further attest to the clinical therapeutic efficacy.</p>","PeriodicalId":12163,"journal":{"name":"Experimental Biology and Medicine","volume":"249 ","pages":"10142"},"PeriodicalIF":2.8,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11238193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioinformatics and systems biology approach to identify the pathogenetic link of neurological pain and major depressive disorder.","authors":"Jinjing Hu, Jia Fu, Yuxin Cai, Shuping Chen, Mengjian Qu, Lisha Zhang, Weichao Fan, Ziyi Wang, Qing Zeng, Jihua Zou","doi":"10.3389/ebm.2024.10129","DOIUrl":"10.3389/ebm.2024.10129","url":null,"abstract":"<p><p>Neurological pain (NP) is always accompanied by symptoms of depression, which seriously affects physical and mental health. In this study, we identified the common hub genes (Co-hub genes) and related immune cells of NP and major depressive disorder (MDD) to determine whether they have common pathological and molecular mechanisms. NP and MDD expression data was downloaded from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (Co-DEGs) for NP and MDD were extracted and the hub genes and hub nodes were mined. Co-DEGs, hub genes, and hub nodes were analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Finally, the hub nodes, and genes were analyzed to obtain Co-hub genes. We plotted Receiver operating characteristic (ROC) curves to evaluate the diagnostic impact of the Co-hub genes on MDD and NP. We also identified the immune-infiltrating cell component by ssGSEA and analyzed the relationship. For the GO and KEGG enrichment analyses, 93 Co-DEGs were associated with biological processes (BP), such as fibrinolysis, cell composition (CC), such as tertiary granules, and pathways, such as complement, and coagulation cascades. A differential gene expression analysis revealed significant differences between the Co-hub genes ANGPT2, MMP9, PLAU, and TIMP2. There was some accuracy in the diagnosis of NP based on the expression of ANGPT2 and MMP9. Analysis of differences in the immune cell components indicated an abundance of activated dendritic cells, effector memory CD8⁺ T cells, memory B cells, and regulatory T cells in both groups, which were statistically significant. In summary, we identified 6 Co-hub genes and 4 immune cell types related to NP and MDD. Further studies are needed to determine the role of these genes and immune cells as potential diagnostic markers or therapeutic targets in NP and MDD.</p>","PeriodicalId":12163,"journal":{"name":"Experimental Biology and Medicine","volume":"249 ","pages":"10129"},"PeriodicalIF":2.8,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11236560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction: MicroRNA-34a alleviates steroid-induced avascular necrosis of femoral head by targeting Tgif2 through OPG/RANK/RANKL signaling pathway.","authors":"","doi":"10.3389/ebm.2024.10275","DOIUrl":"https://doi.org/10.3389/ebm.2024.10275","url":null,"abstract":"<p><p>[This retracts the article DOI: 10.1177/1535370217703975.].</p>","PeriodicalId":12163,"journal":{"name":"Experimental Biology and Medicine","volume":"249 ","pages":"10275"},"PeriodicalIF":2.8,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reversal of atherosclerosis by restoration of vascular copper homeostasis.","authors":"Xiao Zuo, Xueqin Ding, Yaya Zhang, Y James Kang","doi":"10.3389/ebm.2024.10185","DOIUrl":"10.3389/ebm.2024.10185","url":null,"abstract":"<p><p>Atherosclerosis has traditionally been considered as a disorder characterized by the accumulation of cholesterol and thrombotic materials within the arterial wall. However, it is now understood to be a complex inflammatory disease involving multiple factors. Central to the pathogenesis of atherosclerosis are the interactions among monocytes, macrophages, and neutrophils, which play pivotal roles in the initiation, progression, and destabilization of atherosclerotic lesions. Recent advances in our understanding of atherosclerosis pathogenesis, coupled with results obtained from experimental interventions, lead us to propose the hypothesis that atherosclerosis may be reversible. This paper outlines the evolution of this hypothesis and presents corroborating evidence that supports the potential for atherosclerosis regression through the restoration of vascular copper homeostasis. We posit that these insights may pave the way for innovative therapeutic approaches aimed at the reversal of atherosclerosis.</p>","PeriodicalId":12163,"journal":{"name":"Experimental Biology and Medicine","volume":"249 ","pages":"10185"},"PeriodicalIF":2.8,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141558436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Attenuated mutants of <i>Salmonella enterica</i> Typhimurium mediate melanoma regression via an immune response.","authors":"Genesy Pérez Jorge, Marco Gontijo, Marina Flóro E Silva, Isabella Carolina Rodrigues Dos Santos Goes, Yessica Paola Jaimes-Florez, Lilian de Oliveira Coser, Francisca Janaína Soares Rocha, Selma Giorgio, Marcelo Brocchi","doi":"10.3389/ebm.2024.10081","DOIUrl":"10.3389/ebm.2024.10081","url":null,"abstract":"<p><p>The lack of effective treatment options for an increasing number of cancer cases highlights the need for new anticancer therapeutic strategies. Immunotherapy mediated by <i>Salmonella enterica</i> Typhimurium is a promising anticancer treatment. Candidate strains for anticancer therapy must be attenuated while retaining their antitumor activity. Here, we investigated the attenuation and antitumor efficacy of two <i>S. enterica</i> Typhimurium mutants, Δ<i>tolRA</i> and Δ<i>ihfABpmi</i>, in a murine melanoma model. Results showed high attenuation of Δ<i>tolRA</i> in the <i>Galleria mellonella</i> model, and invasion and survival in tumor cells. However, it showed weak antitumor effects <i>in vitro</i> and <i>in vivo</i>. Contrastingly, lower attenuation of the attenuated Δ<i>ihfABpmi</i> strain resulted in regression of tumor mass in all mice, approximately 6 days after the first treatment. The therapeutic response induced by Δ<i>ihfABpmi</i> was accompanied with macrophage accumulation of antitumor phenotype (M1) and significant increase in the mRNAs of proinflammatory mediators (TNF-α, IL-6, and iNOS) and an apoptosis inducer (Bax). Our findings indicate that the attenuated Δ<i>ihfABpmi</i> exerts its antitumor activity by inducing macrophage infiltration or reprogramming the immunosuppressed tumor microenvironment to an activated state, suggesting that attenuated <i>S. enterica</i> Typhimurium strains based on nucleoid-associated protein genes deletion could be immunotherapeutic against cancer.</p>","PeriodicalId":12163,"journal":{"name":"Experimental Biology and Medicine","volume":"249 ","pages":"10081"},"PeriodicalIF":2.8,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11224151/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}