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BACKGROUND: Interstitial lung disease (ILD) treatment is a critical unmet need. Selenium is an essential trace element for human life and an antioxidant that activates glutathione, but the gap between its necessity and its toxicity is small and requires special attention. Whether selenium can be used in the treatment of ILD remains unclear. METHODS: We investigated the prophylactic and therapeutic effects of selenite, a selenium derivative, in ILD using a murine model of bleomycin-induced idiopathic pulmonary fibrosis (IPF). We further elucidated the underlying mechanism using in vitro cell models and examined their relevance in human tissue specimens. The therapeutic effect of selenite in bleomycin-administered mice was assessed by respiratory function and histochemical changes. Selenite-induced apoptosis and reactive oxygen species (ROS) production in murine lung fibroblasts were measured. RESULTS: Selenite, administered 1 day (inflammation phase) or 8 days (fibrotic phase) after bleomycin, prevented and treated deterioration of lung function and pulmonary fibrosis in mice. Mechanistically, selenite inhibited the proliferation and induced apoptosis of murine lung fibroblasts after bleomycin treatment both in vitro and in vivo. In addition, selenite upregulated glutathione reductase (GR) and thioredoxin reductase (TrxR) in murine lung fibroblasts, but not in lung epithelial cells, upon bleomycin treatment. GR and TrxR inhibition eliminates the therapeutic effects of selenite. Furthermore, we found that GR and TrxR were upregulated in the human lung fibroblasts of IPF patient samples. CONCLUSIONS: Selenite induces ROS production and apoptosis in murine lung fibroblasts through GR and TrxR upregulation, thereby providing a therapeutic effect in bleomycin-induced IPF.
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Apoptose , Bleomicina , Fibroblastos , Espécies Reativas de Oxigênio , Ácido Selenioso , Bleomicina/efeitos adversos , Animais , Camundongos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Ácido Selenioso/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Modelos Animais de Doenças , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Masculino , Proliferação de Células/efeitos dos fármacosRESUMO
Objectives: The study objectives were to test an innovative T-tube procedure involving ablative bronchoscopy for the treatment of total airway occlusion and to orchestrate a safe and nontraumatic maneuver to treat intricate subglottic stenosis amenable for substituting the conventional surgical intervention. Methods: This was an uncontrolled single-center cohort study on 1254 patients from January 2001 to June 2021. Patients underwent the modified T-tube procedure treatment for tracheal stenosis. Only 42 patients were included in the study because they had full records for subglottic total occlusion sitting tracheostomy. The ablative bronchoscopy, aided by a fixed suspending laryngoscope, was applied to retunnel their total airway occlusion. T-tube revision and removal were conducted under general anesthesia with laryngeal mask airway aid during follow-up. Results: The primary outcome was 90-day mortality. The secondary outcome was 90-day morbidity. The 42 patients included in the study had a mean age of 52.29 years (range, 9-84 years) with 22 men (52.38%). Their mean length of hospital stay was 13.67 days (range, 2-45 days). Their mean operation time was 73 minutes (range, 43-256 minutes). Their mean length of the tracheal stenosis was 2.8 cm (range, 0.8-6.3 cm). Outcomes were good in 29 patients (69.05%), satisfactory in 10 patients (23.81%), and considered failures in 3 patients (7.14%). A total of 16 patients (38.10%) underwent decannulation, and 3 patients (7.14%) were shifted to a Shiley tracheostomy. All 42 patients had a median follow-up of 6.2 years (range, 1.5-16.3 years). Conclusions: The modified T-tube procedure, which offered both resilience and versatility, improved the conventional technique in treating those patients experiencing total tracheal stenosis and who were unqualified for conventional open surgery.
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Polyphyllin G, a pennogenyl saponin extracted from Paris polyphylla, has been shown to possess antitumor effects. In this study, we demonstrated that doxycycline, an antibiotic medicine, could significantly enhance the sensitivities of osteosarcoma cell lines to polyphyllin G. As the cells were pretreated with doxycycline at non-toxic concentrations and then co-exposed to polyphyllin G, this combination could induce a rapid cell death distinct from apoptosis. The non-apoptotic cell death was characterized by a loss of integrity of plasma membrane without externalization of phosphatidyl serine. Furthermore, this combined treatment resulted in suppression of cell viability and colony-forming ability, and increased the level of γ-H2A.X, a critical marker for DNA damage, in osteosarcoma cell lines. When examining the underlying mechanism, it was revealed combination of polyphyllin G and doxycycline triggered an enhanced generation of reactive oxygen species (ROS), and up-regulated mitochondrial oxidative stress within 0.5 h. Co-administration of the ROS inhibitor NAC reversed the suppressed cell viability and colony-forming ability, and abolished the increased level of γ-H2A.X in the cells with the combined treatment, indicating that the enhanced ROS was involved in the anti-proliferative effect of the combined treatment. Overall, the results demonstrated that doxycycline may function as chemosensitizers by inducing an acute and lethal ROS production to enhance cytotoxic of polyphyllin G in osteosarcoma cell lines, and the combined use of drugs may provide an alternative thinking for the development of new therapeutic agents.
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Doxiciclina , Osteossarcoma , Espécies Reativas de Oxigênio , Saponinas , Humanos , Apoptose , Morte Celular , Linhagem Celular Tumoral , Doxiciclina/farmacologia , Doxiciclina/uso terapêutico , Osteossarcoma/patologia , Espécies Reativas de Oxigênio/metabolismo , Saponinas/farmacologia , Saponinas/uso terapêuticoRESUMO
Systemic sclerosis associated with lung interstitial lung disease (SSc-ILD) is the most common cause of death among patients with SSc. Mesenchymal stem cell (MSCs) transplantations had been treated by SSc patients that showed in the previous case report. The therapeutic mechanisms and effects of MSCs on SSc-ILD are still obscure. In this study, we investigated the therapeutic effects and mechanisms of treatment of BM-MSC derived from C57BL/6 on the topoisomerase I (TOPO I) induced SSc-ILD-like mice model. The mice were immunized with a mixture of recombinant human TOPO I in PBS solution (500 U/mL) and completed Freund's adjuvant [CFA; 1:1 (volume/volume)] twice per week for 9 weeks. On week 10, the mice were sacrificed to analyze the related pathological parameters. Lung and skin pathologies were analyzed using histochemical staining. CD4 T-helper (TH) cell differentiation in lung and skin-draining lymph nodes was detected using flow cytometry. Our results revealed that allogeneic and syngeneic MSCs exhibited similar repressive effects on TOPO I-induced IgG1 and IgG2a in the SSc group. After intravascular (IV) treatment with syngeneic or allogeneic MSCs, the dermal thickness and fibrosis dramatically condensed and significantly reduced airway hyperresponsiveness. These findings showed that both allogeneic and syngeneic MSCs have therapeutic potential for SSc-ILD.
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Doenças Pulmonares Intersticiais , Células-Tronco Mesenquimais , Pneumonia , Escleroderma Sistêmico , Humanos , Animais , Camundongos , DNA Topoisomerases Tipo I , Camundongos Endogâmicos C57BL , Fibrose , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/terapia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/patologia , Pulmão/patologia , Pneumonia/patologiaRESUMO
This study aimed to evaluate the protein expression of glutathione peroxidase 4 (GPX4) in resected non-small cell lung cancer (NSCLC). The clinical relevance and prognostic significance of GPX4 expression were analyzed. We reviewed patients with resected NSCLCs at Taipei Veterans General Hospital between September 2002 and January 2018. Available paraffin-embedded specimens were retrieved for immunohistochemistry (IHC) staining to detect GPX4 expression. The cutoff value for defining GPX4 positivity was determined according to the percentage of tumor stained in the microscopic field. The correlation between immune expression, clinicopathologic data, overall survival (OS), and disease-free survival (DFS) were analyzed. A total of 265 NSCLC specimens were retrieved for IHC staining. GPX4 expression positive was in 192 (72.5%) according to a cutoff value of 5%. GPX4 was a significant prognostic factor for OS and DFS on multivariate analysis at both 5% and 25% cutoff values. GPX4 expression was associated with poor OS and DFS, especially in lung adenocarcinoma (p = 0.008, and 0.027, respectively). In conclusions, IHC analysis revealed that GPX4 expression was associated with poor survival outcomes in patients with resected lung adenocarcinoma. Further research is needed to understand the role of GPX4 in tumorigenesis and the underlying mechanism responsible for survival outcomes in patients with resected lung adenocarcinoma.
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Adenocarcinoma de Pulmão , Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Neoplasias Pulmonares/cirurgia , Adenocarcinoma de Pulmão/cirurgia , Adenocarcinoma/cirurgiaRESUMO
Treatments for osteoarthritis would benefit from the enhanced visualization of injured articular cartilage and from the targeted delivery of disease-modifying drugs to it. Here, by using ex vivo human osteoarthritic cartilage and live rats and minipigs with induced osteoarthritis, we report the application of collagen-binding peptides, identified via phage display, that are home to osteoarthritic cartilage and that can be detected via magnetic resonance imaging when conjugated with a superparamagnetic iron oxide. Compared with the use of peptides with a scrambled sequence, hyaluronic acid conjugated with the collagen-binding peptides displayed enhanced retention in osteoarthritic cartilage and better lubricated human osteoarthritic tissue ex vivo. Mesenchymal stromal cells encapsulated in the modified hyaluronic acid and injected intra-articularly in rats showed enhanced homing to osteoarthritic tissue and improved its regeneration. Molecular docking revealed WXPXW as the consensus motif that binds to the α1 chain of collagen type XII. Peptides that specifically bind to osteoarthritic tissue may aid the diagnosis and treatment of osteoarthritic joints.
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Cartilagem Articular , Osteoartrite , Animais , Humanos , Ratos , Suínos , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/metabolismo , Ácido Hialurônico/metabolismo , Lubrificação , Colágeno Tipo XII/metabolismo , Simulação de Acoplamento Molecular , Porco Miniatura , Osteoartrite/metabolismo , Regeneração , Peptídeos/metabolismoRESUMO
It has been known that senescence-associated secretory phenotype (SASP) triggers senescence of the surrounding normal cells. However, SASP signaling regarding mesenchymal stromal cell aging remains to be fully elucidated. Therefore, the present study aimed to clarify the molecular mechanism of late (passage) MSC-induced paracrine SASP-mediated senescence of early (passage) MSCs during ex vivo expansion. Here, we conducted an extensive characterization of senescence features in bone-marrow (BM)-derived MSCs from healthy human donors. Late MSCs displayed an enlarged senescent-like morphology, induced SASP-related proinflammatory cytokines (IL-1α and IL-8), and reduced clonogenic capacity and osteogenic differentiation when compared to early MSCs. Of note, paracrine effects of SASP-related IL-1α and IL-8 from late MSCs induced cellular senescence of early MSCs via an NF-κB-dependent manner. Moreover, cellular senescence of early MSCs was promoted by the synergistic action of IL-1α and IL-8. However, inhibition of NF-κB by shRNA transfection or using inhibitors in early MSCs blocked early MSCs cellular senescence caused by paracrine SASP of late MSCs. In conclusion, these findings reveal that late MSCs display features of senescence and that, during ex vivo expansion, SASP-related proinflammatory cytokines contribute to activate a cellular senescence program in early MSCs that may ultimately impair their functionality.
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Células-Tronco Mesenquimais , NF-kappa B , Humanos , NF-kappa B/metabolismo , Osteogênese , RNA Interferente Pequeno/metabolismo , Interleucina-8/metabolismo , Células-Tronco Mesenquimais/metabolismoRESUMO
Breast cancer includes biologically distinct subtypes, and the time between rise in distant metastases and overall survival for the subtypes are different. The mechanisms involved in these differences in tumor metastasis remain to be elucidated. Here, we demonstrated that, luminal type A breast cancer cells, such as MCF7 and T47D, when overexpressed with active mutant form of Snail (6SA-Snail) increased in the expression of EMT markers such as Vimentin, N-cadherin and Fibronectin but decreased in the expression of E-cadherin, compared to control vectors or wild type Snail. Moreover, this mutant increased in migration and invasion ability, while decreased in the capacity to survive and form spheres in tumor spheroid medium. Luciferase reporter assay and chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) analysis revealed that Snail downregulated Src by binding to the E-box of Src promoter. Human luminal type A breast cancer specimens showed an inverse correlation between Vimentin and Src expression. Most importantly, downregulation of Src by Snail was not found in breast cancer cell types other than luminal type A. Therefore, elucidation of the differences in signaling pathways involved in controlling migration, invasion and colonization may have a therapeutically beneficial effect on breast cancer treatment.
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A rotator cuff tear is an age-related common cause of pain and disability. Studies including our previously published ones have demonstrated that mesenchymal stem cells cultured under hypoxic conditions [hypoxic multipotent stromal cells (MSCs)] facilitate the retention of transplanted cells and promote wound healing. However, there are very few, if any, reports targeting the punctured supraspinatus tendons to create more or equally serous wounds as age-related tears of rotator cuff. It remains to be determined whether transplantation of bone-marrow-derived hypoxic MSCs into the punctured supraspinatus tendon improves tendon repair and, when combined with ultrasound-guided delivery, could be used for future clinical applications. In this study, we used a total of 33 Sprague-Dawley rats in different groups for normal no-punched control, hypoxic MSC treatment, nontreated vehicle control, and MSC preparation, and then evaluated treatment outcomes by biomechanical testing and histological analysis. We found that the ultimate failure load of the hypoxic MSC-treated group was close to that of the normal tendon and significantly greater than that of the nontreated vehicle control group. In vivo tracking of cells labeled with superparamagnetic iron oxide (SPIO) nanoparticles revealed an enhanced retention of transplanted cells at the tear site. Our study demonstrates that hypoxic MSCs improve rotator cuff tear repair in a rat model.
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Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Lesões do Manguito Rotador , Animais , Hipóxia/patologia , Hipóxia/terapia , Ratos , Ratos Sprague-Dawley , Manguito Rotador/patologia , Lesões do Manguito Rotador/terapiaRESUMO
Microsatellite-instable (MSI), a predictive biomarker for immune checkpoint blockade (ICB) response, is caused by mismatch repair deficiency (MMRd) that occurs through genetic or epigenetic silencing of MMR genes. Here, we report a mechanism of MMRd and demonstrate that protein phosphatase 2A (PP2A) deletion or inactivation converts cold microsatellite-stable (MSS) into MSI tumours through two orthogonal pathways: (i) by increasing retinoblastoma protein phosphorylation that leads to E2F and DNMT3A/3B expression with subsequent DNA methylation, and (ii) by increasing histone deacetylase (HDAC)2 phosphorylation that subsequently decreases H3K9ac levels and histone acetylation, which induces epigenetic silencing of MLH1. In mouse models of MSS and MSI colorectal cancers, triple-negative breast cancer and pancreatic cancer, PP2A inhibition triggers neoantigen production, cytotoxic T cell infiltration and ICB sensitization. Human cancer cell lines and tissue array effectively confirm these signaling pathways. These data indicate the dual involvement of PP2A inactivation in silencing MLH1 and inducing MSI.
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Neoplasias Colorretais/imunologia , Instabilidade de Microssatélites , Neoplasias Pancreáticas/imunologia , Proteína Fosfatase 2/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Animais , Antígenos/genética , Antígenos/imunologia , Neoplasias Colorretais/genética , Metilação de DNA , Reparo de Erro de Pareamento de DNA , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/genética , Proteína Fosfatase 2/genética , Linfócitos T Citotóxicos/imunologia , Neoplasias de Mama Triplo Negativas/genéticaRESUMO
Although oncolytic viruses are currently being evaluated for cancer treatment in clinical trials, systemic administration is hindered by many factors that prevent them from reaching the tumor cells. When administered systemically, mesenchymal stem cells (MSCs) target tumors, and therefore constitute good cell carriers for oncolytic viruses. MSCs were primed with trichostatin A under hypoxia, which upregulated the expression of CXCR4, a chemokine receptor involved in tumor tropism, and coxsackievirus and adenovirus receptor that plays an important role in adenoviral infection. After priming, MSCs were loaded with conditionally replicative adenovirus that exhibits limited proliferation in cells with a functional p53 pathway and encodes Escherichia coli nitroreductase (NTR) enzymes (CRAdNTR) for targeting tumor cells. Primed MSCs increased tumor tropism and susceptibility to adenoviral infection, and successfully protected CRAdNTR from neutralization by anti-adenovirus antibodies both in vitro and in vivo, and specifically targeted p53-deficient colorectal tumors when infused intravenously. Analyses of deproteinized tissues by UPLC-MS/QTOF revealed that these MSCs converted the co-administered prodrug CB1954 into cytotoxic metabolites, such as 4-hydroxylamine and 2-amine, inducing oncolysis and tumor growth inhibition without being toxic for the host vital organs. This study shows that the combination of oncolytic viruses delivered by MSCs with the activation of prodrugs is a new cancer treatment strategy that provides a new approach for the development of oncolytic viral therapy for various cancers.
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BACKGROUND: Acute kidney injury (AKI) is an emerging global healthcare issue without effective therapy yet. Autophagy recycles damaged organelles and helps maintain tissue homeostasis in acute renal ischemia-reperfusion (I/R) injury. Hypoxic mesenchymal stem cells (HMSCs) represent an innovative cell-based therapy in AKI. Moreover, the conditioned medium of HMSCs (HMSC-CM) rich in beneficial trophic factors may serve as a cell-free alternative therapy. Nonetheless, whether HMSCs or HMSC-CM mitigate renal I/R injury via modulating tubular autophagy remains unclear. METHODS: Renal I/R injury was induced by clamping of the left renal artery with right nephrectomy in male Sprague-Dawley rats. The rats were injected with either PBS, HMSCs, or HMSC-CM immediately after the surgery and sacrificed 48 h later. Renal tubular NRK-52E cells subjected to hypoxia-reoxygenation (H/R) injury were co-cultured with HMSCs or treated with HMSC-CM to assess the regulatory effects of HSMCs on tubular autophagy and apoptosis. The association of tubular autophagy gene expression and renal recovery was also investigated in patients with ischemic AKI. RESULT: HMSCs had a superior anti-oxidative effect in I/R-injured rat kidneys as compared to normoxia-cultured mesenchymal stem cells. HMSCs further attenuated renal macrophage infiltration and inflammation, reduced tubular apoptosis, enhanced tubular proliferation, and improved kidney function decline in rats with renal I/R injury. Moreover, HMSCs suppressed superoxide formation, reduced DNA damage and lipid peroxidation, and increased anti-oxidants expression in renal tubular epithelial cells during I/R injury. Co-culture of HMSCs with H/R-injured NRK-52E cells also lessened tubular cell death. Mechanistically, HMSCs downregulated the expression of pro-inflammatory interleukin-1ß, proapoptotic Bax, and caspase 3. Notably, HMSCs also upregulated the expression of autophagy-related LC3B, Atg5 and Beclin 1 in renal tubular cells both in vivo and in vitro. Addition of 3-methyladenine suppressed the activity of autophagy and abrogated the renoprotective effects of HMSCs. The renoprotective effect of tubular autophagy was further validated in patients with ischemic AKI. AKI patients with higher renal LC3B expression were associated with better renal recovery. CONCLUSION: The present study describes that the enhancing effect of MSCs, and especially of HMCSs, on tissue autophagy can be applied to suppress renal tubular apoptosis and attenuate renal impairment during renal I/R injury in the rat. Our findings provide further mechanistic support to HMSCs therapy and its investigation in clinical trials of ischemic AKI.
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Injúria Renal Aguda , Células-Tronco Mesenquimais , Traumatismo por Reperfusão , Injúria Renal Aguda/terapia , Animais , Apoptose , Autofagia , Humanos , Hipóxia , Isquemia , Rim , Masculino , Ratos , Ratos Sprague-Dawley , Reperfusão , Traumatismo por Reperfusão/terapiaRESUMO
It has not been well studied which cells and related mechanisms contribute to endochondral ossification. Here, we fate mapped the leptin receptor-expressing (LepR+) mesenchymal stem cells (MSCs) in different embryonic and adult extremities using Lepr-cre; tdTomato mice and investigated the underling mechanism using Lepr-cre; Ppp2r1afl/fl mice. Tomato+ cells appear in the primary and secondary ossification centers and express the hypertrophic markers. Ppp2r1a deletion in LepR+ MSCs reduces the expression of Runx2, Osterix, alkaline phosphatase, collagen X, and MMP13, but increases that of the mature adipocyte marker perilipin, thereby reducing trabecular bone density and enhancing fat content. Mechanistically, PP2A dephosphorylates Runx2 and BRD4, thereby playing a major role in positively and negatively regulating osteogenesis and adipogenesis, respectively. Our data identify LepR+ MSC as the cell origin of endochondral ossification during embryonic and postnatal bone growth and suggest that PP2A is a therapeutic target in the treatment of dysregulated bone formation.
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Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Células-Tronco Mesenquimais/metabolismo , Osteogênese/fisiologia , Proteína Fosfatase 2/metabolismo , Receptores para Leptina/metabolismo , Adipogenia , Animais , Densidade Óssea , Osso e Ossos/citologia , Osso e Ossos/embriologia , Osso e Ossos/metabolismo , Diferenciação Celular , Proliferação de Células , Condrogênese , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Fosforilação , Gravidez , Proteína Fosfatase 2/deficiência , Proteína Fosfatase 2/genética , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: There remains a scarcity of both autografts and allografts for tracheal transplantation after long-segmental resection. Subsequently, tissue engineering has become a promising alternative for tracheal transplantation, which requires successful in vitro chondrogenesis. METHODS: To optimize the protocol for in situ chondrogenesis using the pig-derived whole Umbilical Cord (UC) as the starting material, it must be performed without using the UC-multipotent stromal cell (MSCs) isolation procedure. Nevertheless, chondrogenic induction is performed under a variety of conditions; with or without TGF-ß1 at different concentrations, and also in combination with either a rotatory or hollow organ bioreactor. The engineered explant sections were analyzed using various histochemical and immunohistochemical stains to assess the expression of chondrocyte markers. Cell viability was determined through use of the APO-BrdU TUNEL assay kit. RESULTS: The results showed that culture conditions induced heterogeneous chondrogenesis in various compartments of the UC. Moreover, explants cultured with 10 ng/ml TGF-ß1 under hypoxic (1% O2) in combination with a bioreactor, significantly enhanced the expression of aggrecan and type II collagen, but were lacking in the production of Glycosaminoglycans (GAGs), as evidenced by alcian blue staining. We speculated that whole segment UCs allowed for the differentiation into premature chondrocytes in our tissue-engineered environments. CONCLUSION: This study has provided exciting preliminary evidence showing that a stem cell-rich UC wrapped around an anatomical tracheal scaffold and implanted in vivo can induce nodes of new cartilage growth into a structurally functional tissue for the repairing of long-segmental tracheal stenosis.
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BACKGROUND: Air pollution exposure and idiopathic pulmonary fibrosis (IPF) cause a poor prognosis after SARS-CoV-2 infection, but the underlying mechanisms are not well explored. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the keys to the entry of SARS-CoV-2. We therefore hypothesized that air pollution exposure and IPF may increase the expression of ACE2 and TMPRSS2 in the lung alveolar region. We measured their expression levels in lung tissues of control non-IPF and IPF patients, and used murine animal models to study the deterioration of IPF caused by particulate matter (PM) and the molecular pathways involved in the expression of ACE2 and TMPRSS2. RESULTS: In non-IPF patients, cells expressing ACE2 and TMPRSS2 were limited to human alveolar cells. ACE2 and TMPRSS2 were largely upregulated in IPF patients, and were co-expressed by fibroblast specific protein 1 (FSP-1) + lung fibroblasts in human pulmonary fibrotic tissue. In animal models, PM exposure increased the severity of bleomycin-induced pulmonary fibrosis. ACE2 and TMPRSS2 were also expressed in FSP-1+ lung fibroblasts in bleomycin-induced pulmonary fibrosis, and when combined with PM exposure, they were further upregulated. The severity of pulmonary fibrosis and the expression of ACE2 and TMPRSS2 caused by PM exposure were blocked by deletion of KC, a murine homologue of IL-8, or treatment with reparixin, an inhibitor of IL-8 receptors CXCR1/2. CONCLUSIONS: These data suggested that risk of SARS-CoV-2 infection and COVID-19 disease severity increased by air pollution exposure and underlying IPF. It can be mediated through upregulating ACE2 and TMPRSS2 in pulmonary fibroblasts, and prevented by blocking the IL-8/CXCR1/2 pathway.
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Enzima de Conversão de Angiotensina 2/genética , COVID-19/etiologia , Fibrose Pulmonar Idiopática/complicações , Material Particulado/toxicidade , SARS-CoV-2 , Serina Endopeptidases/genética , Enzima de Conversão de Angiotensina 2/fisiologia , Animais , Humanos , Interleucina-8/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/enzimologia , Serina Endopeptidases/fisiologia , Regulação para CimaRESUMO
BACKGROUND: Parkinson's disease (PD) is a neurological disorder characterized by the progressive loss of midbrain dopamine (DA) neurons. Bone marrow mesenchymal stem cells (BMSCs) can differentiate into multiple cell types including neurons and glia. Transplantation of BMSCs is regarded as a potential approach for promoting neural regeneration. Glial cell line-derived neurotrophic factor (GDNF) can induce BMSC differentiation into neuron-like cells. This work evaluated the efficacy of nigral grafts of human BMSCs (hMSCs) and/or adenoviral (Ad) GDNF gene transfer in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats. AIM: To evaluate the efficacy of nigral grafts of hMSCs and/or Ad-GDNF gene transfer in 6-OHDA-lesioned hemiparkinsonian rats. METHODS: We used immortalized hMSCs, which retain their potential for neuronal differentiation. hMSCs, preinduced hMSCs, or Ad-GDNF effectively enhanced neuronal connections in cultured neurons. In vivo, preinduced hMSCs and/or Ad-GDNF were injected into the substantia nigra (SN) after induction of a unilateral 6-OHDA lesion in the nigrostriatal pathway. RESULTS: Hemiparkinsonian rats that received preinduced hMSC graft and/or Ad-GDNF showed significant recovery of apomorphine-induced rotational behavior and the number of nigral DA neurons. However, DA levels in the striatum were not restored by these therapeutic treatments. Grafted hMSCs might reconstitute a niche to support tissue repair rather than contribute to the generation of new neurons in the injured SN. CONCLUSION: The results suggest that preinduced hMSC grafts exert a regenerative effect and may have the potential to improve clinical outcome.
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Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we demonstrate that the CSCs of esophageal squamous carcinoma cells enriched by spheroid culture have increased intracellular iron levels and lipid peroxidation, thereby increasing exposure to several products of lipid peroxidation, such as MDA and 4-HNE. However, CSCs do not reduce cell viability until glutathione is depleted by erastin treatment. Mechanistic studies revealed that damage from elevated lipid peroxidation is avoided through the activation of Hsp27, which upregulates GPX4 and thereby rescues CSCs from ferroptosis-induced cell death. Our results also revealed a correlation between phospho-Hsp27 and GPX4 expression levels and poor prognosis in patients with esophageal cancer. Together, these data indicate that targeting Hsp27 or GPX4 to block this intrinsic protective mechanism against ferroptosis is a potential treatment strategy for eradicating CSC in esophageal squamous cell carcinoma.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Ferroptose , Morte Celular/fisiologia , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Humanos , Peroxidação de Lipídeos/fisiologia , Células-Tronco Neoplásicas/metabolismo , Fosfolipídeo Hidroperóxido Glutationa PeroxidaseRESUMO
A 62-year-old man was referred to our medical centre with productive cough and high fever over the span of one week, as well as the affiliated symptoms of chronic cough and dizziness for more than six months. Computed tomography (CT) of the thorax was performed and analysed revealing lobulated empyema with thick pleura and two foreign body (FB) retentions in the right lower lobe bronchus. The patient proceeded to thoracoscopic decortications and finalized through retrieval of two dark black stained bonelets with ignored aspiration. After surgery, the patient recovered uneventfully and was discharged in stable condition.
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Repairing the peripheral nerves following a segmental defect injury remains surgically challenging. Because of some disadvantages of nerve grafts, nerve regeneration, such as conduits combined with bone marrow-derived mesenchymal stem cells (BMSCs), may serve as an alternative. BMSCs expand under hypoxic conditions, decrease in senescence, and increase in proliferation and differentiation potential into the bone, fat, and cartilage. The purpose of this study was to investigate whether BMSCs increased the neuronal differentiation potential following expansion under hypoxic conditions. Isolated human BMSCs (hBMSCs) expand under hypoxia or normoxia, and neuronal differentiation proceeds under normoxia. in vitro tests revealed hypoxia culture enhanced the RNA and protein expression of neuronal markers. The electrophysiology of hBMSC-differentiated neuron-like cells was also enhanced by the hypoxia culturing. Our animal model indicated that the potential treatment of hypoxic rat BMSCs (rBMSCs) was better than that of normoxic rBMSCs because the conduit with the hypoxic rBMSCs injection demonstrated the highest recovery rate of gastrocnemius muscle weights. There were more toluidine blue-stained myelinated nerve fibers in the hypoxic rBMSCs group than in the normoxic group. To sum up, BMSCs cultured under hypoxia increased the potential of neuronal differentiation both in vivo and in vitro.