BioRN: Treatment Effects (Topic)最新文献

{"title":"Treatment Of Inflammatory Bone Loss in Periodontitis By Stem Cell-Derived Exosomes","authors":"Fengzhen Lei, Mujia Li, Tingting Lin, Hong Zhou, Fei Wang, X. Su","doi":"10.2139/ssrn.3883351","DOIUrl":"https://doi.org/10.2139/ssrn.3883351","url":null,"abstract":"Periodontitis is the primary cause of tooth loss, but there is no effective treatment to repair inflammatory bone loss in periodontitis. Exosomes emerge as essential paracrine factors of mesenchymal stem cells (MSCs) that mediated tissue regeneration. Here, we investigated the potential of exosomes secreted by periodontal ligament stem cells (PDLSCs) as therapeutics for the bone defect in periodontitis. Exosomes secreted from PDLSCs derived from healthy periodontal ligaments (h-PDLSCs) and their function were evaluated on PDLSCs isolated from the inflammatory periodontal ligament of periodontitis patients (i-PDLSCs). Treatment of exosomes of h-PDLSCs led to an increase in the formation of mineralized nodules and the expressions of osteogenic genes and proteins in i-PDLSCs. Mechanistically, h-PDLSCs-exosomes suppressed the over-activation of canonical Wnt signaling to recover the osteogenic differentiation capacity of i-PDLSCs. To evaluate the therapeutic of exosomes on inflammatory bone loss, h-PDLSCs-exosomes loaded with Matrigel or β-TCP were employed to repair bone defects in rat models of periodontitis. Compared to the vehicle-treated control group, h-PDLSCs-exosomes-treated rats resulted in more bone formation in the defect of alveolar bone. In conclusion, these results demonstrated that exosomes derived from healthy PDLSCs could rescue the osteogenesis capacity of endogenous stem cells under an inflammatory environment and promote regeneration of alveolar bone. Our findings suggest that MSCs-derived exosome is an effective and practical cell-free MSC therapeutic for the treatment of periodontitis. STATEMENT OF SIGNIFICANCE: : There is no effective treatment to repair inflammatory bone loss in periodontitis. As essential paracrine factors of PDLSCs, exosomes might mediate tissue regeneration during stem cell therapy. Here, we reported that exosomes secreted from healthy PDLSCs promoted the osteogenic differentiation of PDLSCs derived from periodontitis tissue. Healthy PDLSCs-exosomes treatment resulted in accelerated bone formation in the defect of alveolar bone in rat models of periodontitis. Mechanistically, h-PDLSCs-exosomes suppressed the over-activation of canonical Wnt signaling to recover the osteogenic differentiation capacity of inflammatory PDLSCs. These findings suggest that MSCs-derived exosome is an effective and practical cell-free MSC therapeutic for the treatment of periodontitis.","PeriodicalId":189293,"journal":{"name":"BioRN: Treatment Effects (Topic)","volume":"122 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2021-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126911084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomes from TNF-Α-Treated Human Gingiva-Derived MSCs Inhibit Periodontal Bone Loss Via CD73 and MiR-1260b-Mediated Attenuation of Inflammation","authors":"Yukihiro Nakao, T. Fukuda, Qunzhou Zhang, T. Sanui, T. Shinjo, X. Kou, Chider Chen, Dawei Liu, Yukari Watanabe, Chikako Hayashi, Hiroaki Yamato, Karen Yotsumoto, Urara Tanaka, Takaharu Taketomi, T. Uchiumi, A. Le, S. Shi, F. Nishimura","doi":"10.2139/ssrn.3692013","DOIUrl":"https://doi.org/10.2139/ssrn.3692013","url":null,"abstract":"Mesenchymal stem cell (MSC)–derived exosome plays a central role in the cell-free therapeutics involving MSCs and the contents can be customized under disease-associated microenvironments. However, optimal MSC-preconditioning to enhance its therapeutic potential is largely unknown. Here, we show that preconditioning of gingival tissue-derived MSC (GMSC) with tumor necrosis factor-alpha (TNF-α) is ideal for the treatment of periodontitis. TNF-α stimulation not only increased the amount of exosome secreted from GMSC, but also enhanced the exosomal expression of CD73, thereby inducing anti-inflammatory M2 macrophage polarization. The effect of GMSC-derived exosomes on inflammatory bone loss were examined by ligature-induced periodontitis model in mice. Local injection of GMSCs-derived exosomes significantly reduced periodontal bone resorption and the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, and these effects were further enhanced by preconditioning of GMSCs with TNF-α. Thus, GMSCs-derived exosomes also exhibited anti-osteoclastogenic activity. Receptor activator of NF-κB ligand (RANKL) expression was regulated by Wnt5a in periodontal ligament cells (PDLCs), and exosomal miR-1260b was found to target Wnt5a-mediated RANKL pathway and inhibit its osteoclastogenic activity. These results indicate that significant ability of the TNF-α-preconditioned GMSC-derived exosomes to regulate inflammation and osteoclastogenesis paves the way for establishment of a new therapeutic approach for periodontitis.","PeriodicalId":189293,"journal":{"name":"BioRN: Treatment Effects (Topic)","volume":"28 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2020-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125787630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Instrumental Variables Estimation of Average Treatment Effects in Econometrics and Epidemiology","authors":"J. Angrist","doi":"10.3386/T0115","DOIUrl":"https://doi.org/10.3386/T0115","url":null,"abstract":"The average effect of intervention or treatment is a parameter of interest in both epidemiology and econometrics. A key difference between applications in the two fields is that epidemiologic research is more likely to involve qualitative outcomes and nonlinear models. An example is the recent use of the Vietnam era draft lottery to construct estimates of the effect of Vietnam era military service on civilian mortality. In this paper. I present necessary and sufficient conditions for linear instrumental variables. techniques to consistently estimate average treatment effects in qualitative or other nonlinear models. Most latent index models commonly applied to qualitative outcomes in econometrics fail to satisfy these conditions, and monte carlo evidence on the bias of instrumental estimates of the average treatment effect in a bivariate probit model is presented. The evidence suggests that linear instrumental variables estimators perform nearly as well as the correctly specified maximum likelihood estimator. especially in large samples. Linear instrumental variables and the normal maximum likelihood estimator are also remarkably robust to non-normality.","PeriodicalId":189293,"journal":{"name":"BioRN: Treatment Effects (Topic)","volume":"31 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1991-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122444615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-Delivery of IL-12 Cytokine Gene and Cisplatin Prodrug by Polymetformin-Conjugated Nanosystem for Chemo-Gene Cancer Treatment Through Chemotherapy Sensitization and Tumor Microenvironment Modulation","authors":"Yue Sun, Tong Yang, Yifan Li, Jiayu Yang, Rongyue Zhu, Yanhui Hou, Yanhua Liu","doi":"10.2139/ssrn.3762196","DOIUrl":"https://doi.org/10.2139/ssrn.3762196","url":null,"abstract":"The dose-related toxicity has been one of the major limiting factors in cisplatin (CDDP)-based cancer therapy. Based on it, a novel strategy of combination of CDDP and interleukin-12 (IL-12) gene is an effective treatment, which resulted in synergistic antitumor effects while avoiding dose-limiting toxicity in a cancer mice model. However, efficient encapsulation and co-delivery of CDDP and IL-12 gene while retaining their active remains a significant challenge. In this study, a tumor-targeted micelleplexes (HC/pIL-12/polyMET) were developed for the co-delivery of the chemotherapeutic drug CDDP and plasmid encoding IL-12 gene (pIL-12). The polymetformin (polyMET) were synthesized as the cationic polymer for condensation of pIL-12 to form a cationic pIL-12/polyMET micelleplexes, and the anionic HC prodrug was then collaboratively assembled to pIL-12/polyMET to stabilize the micelleplexes and co-delivery of CDDP. The HC/pIL-12/polyMET micelleplexes exhibited desirable particle size, excellent stability and high pIL-12 loading capacity. More importantly, <i>in vitro</i> cell experiments verified that HC/pIL-12/polyMET micelleplexes could significantly improve the uptake by LLC tumor cells and promote the endosomal escape of CDDP and pIL-12, resulting in enhanced cytotoxicity and apoptosis induction. Besides, this strategy significantly enhanced the pIL-12 transfection efficiency in LLC cells. <i>In vivo</i> studies further revealed that HC/pIL-12/polyMET micelleplexes possessed the highest drug accumulation and excellent pIL-12 transfection efficiency in tumors of LLC tumor-bearing mice. Consequently, the HC/pIL-12/polyMET micelleplexes exhibit significantly tumor growth inhibition, and prolong the overall survival of lung cancer mice model. The underlying immune mechanism demonstrated that the combination of CDDP and pIL-12 activated immune effector cells to release IFN-γ and induced M1-type differentiation of tumor-related macrophages, thereby generating synergistic chemoimmunotherapy effect. Taken together, this study may provide an effective strategy for drug/gene co-delivery and cancer chemoimmunotherapy.","PeriodicalId":189293,"journal":{"name":"BioRN: Treatment Effects (Topic)","volume":"53 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115894614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}