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1.
Exp Clin Transplant ; 22(3): 229-238, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38695592

RESUMO

OBJECTIVES: The eradication of leukemia cells while sparing hematopoietic stem cells in the graft before autologous hematopoietic stem cell transplant is critical to prevention of leukemia relapse. Proliferating cells have been shown to be more prone to apoptosis than differentiated cells in response to ultraviolet radiation; however, whether leukemia cells are more sensitive to ultraviolet LED radiation than hematopoietic stem cells remains unclear. MATERIALS AND METHODS: We compared the in vitro responses between murine leukemia L1210 cells and murine hematopoietic stem cells to 280-nm ultraviolet LED radiation. We also investigated the effects of ultraviolet LED radiation on the tumorigenic and metastatic capacity of L1210 cells and hematopoietic stem cell hematopoiesis in a mouse model of hematopoietic stem cell transplant. RESULTS: L1210 cells were more sensitive to ultraviolet LED radiation than hematopoietic stem cells in vitro, as evidenced by significantly reduced colony formation rates and cell proliferation rates, along with remarkably increased apoptosis rates in L1210 cells. Compared with corresponding unirradiated cells, ultraviolet LED-irradiated L1210 cells failed to generate palpable tumors in mice, whereas ultraviolet LED-irradiated bone marrow cells restored hematopoiesis in vivo. Furthermore, transplant with an irradiated mixture of L1210 cells and bone marrow cells showed later onset of leukemia, milder leukemic infiltration, and prolonged survival in mice, compared with unirradiated cell transplant. CONCLUSIONS: Our results suggest that ultraviolet LED radiation can suppress the proliferative and tumorigenic abilities of leukemia cells without reducing the hematopoietic reconstitution capacity of hematopoietic stem cells, serving as a promising approach to kill leukemia cells in autograft before autologous hematopoietic stem cell transplant.


Assuntos
Apoptose , Proliferação de Células , Hematopoese , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Animais , Células-Tronco Hematopoéticas/efeitos da radiação , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/metabolismo , Apoptose/efeitos da radiação , Hematopoese/efeitos da radiação , Proliferação de Células/efeitos da radiação , Linhagem Celular Tumoral , Raios Ultravioleta/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Tempo , Terapia Ultravioleta
2.
PLoS One ; 19(5): e0302936, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38713716

RESUMO

Long-term evolution (LTE) radiofrequency electromagnetic field (RF-EMF) is widely used in communication technologies. Thus, the influence of RF-EMF on biological systems is a major public concern and its physiological effects remain controversial. In our previous study, we showed that continuous exposure of various human cell types to 1.7 GHz LTE RF-EMF at a specific absorption rate (SAR) of 2 W/Kg for 72 h can induce cellular senescence. To understand the precise cellular effects of LTE RF-EMF, we elaborated the 1.7 GHz RF-EMF cell exposure system used in the previous study by replacing the RF signal generator and developing a software-based feedback system to improve the exposure power stability. This refinement of the 1.7 GHz LTE RF-EMF generator facilitated the automatic regulation of RF-EMF exposure, maintaining target power levels within a 3% range and a constant temperature even during the 72-h-exposure period. With the improved experimental setup, we examined the effect of continuous exposure to 1.7 GHz LTE RF-EMF at up to SAR of 8 W/Kg in human adipose tissue-derived stem cells (ASCs), Huh7, HeLa, and rat B103 cells. Surprisingly, the proliferation of all cell types, which displayed different growth rates, did not change significantly compared with that of the unexposed controls. Also, neither DNA damage nor cell cycle perturbation was observed in the 1.7 GHz LTE RF-EMF-exposed cells. However, when the thermal control system was turned off and the subsequent temperature increase induced by the RF-EMF was not controlled during continuous exposure to SAR of 8 W/Kg LTE RF-EMF, cellular proliferation increased by 35.2% at the maximum. These observations strongly suggest that the cellular effects attributed to 1.7 GHz LTE RF-EMF exposure are primarily due to the induced thermal changes rather than the RF-EMF exposure itself.


Assuntos
Proliferação de Células , Campos Eletromagnéticos , Ondas de Rádio , Humanos , Proliferação de Células/efeitos da radiação , Ratos , Animais , Células HeLa , Temperatura
3.
PLoS One ; 19(5): e0299017, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38758777

RESUMO

A growing threat to male infertility has become a major concern for the human population due to the advent of modern technologies as a source of radiofrequency radiation (RFR). Since these technologies have become an integral part of our daily lives, thus, it becomes necessary to know the impression of such radiations on human health. In view of this, the current study aims to focus on the biological effects of radiofrequency electromagnetic radiations on mouse Leydig cell line (TM3) in a time-dependent manner. TM3 cells were exposed to RFR emitted from 4G cell phone and also exposed to a particular frequency of 1800 MHz and 2450 MHz from RFR exposure system. The cells were then evaluated for different parameters such as cell viability, cell proliferation, testosterone production, and ROS generation. A considerable reduction in the testosterone levels and proliferation rate of TM3 cells were observed at 120 min of exposure as compared to the control group in all exposure settings. Conversely, the intracellular ROS levels showed a significant rise at 60, 90 and 120 min of exposure in both mobile phone and 2450 MHz exposure groups. However, RFR treatment for different time durations (15, 30, 45, 60, 90, and 120 min) did not have significant effect on cell viability at any of the exposure condition (2450 MHz, 1800 MHz, and mobile phone radiation). Therefore, our findings concluded with the negative impact of radiofrequency electromagnetic radiations on Leydig cell's physiological functions, which could be a serious concern for male infertility. However, additional studies are required to determine the specific mechanism of RFR action as well as its long-term consequences.


Assuntos
Proliferação de Células , Sobrevivência Celular , Células Intersticiais do Testículo , Ondas de Rádio , Espécies Reativas de Oxigênio , Testosterona , Masculino , Células Intersticiais do Testículo/efeitos da radiação , Células Intersticiais do Testículo/metabolismo , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Ondas de Rádio/efeitos adversos , Proliferação de Células/efeitos da radiação , Testosterona/metabolismo , Sobrevivência Celular/efeitos da radiação , Linhagem Celular , Telefone Celular , Radiação Eletromagnética
4.
Int J Mol Sci ; 25(10)2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38791113

RESUMO

Since the establishment of regulations for exposure to extremely low-frequency (0-300) Hz electromagnetic fields, scientific opinion has prioritised the hypothesis that the most important parameter determining cellular behaviour has been intensity, ignoring the other exposure parameters (frequency, time, mode, waveform). This has been reflected in the methodologies of the in vitro articles published and the reviews in which they are included. A scope review was carried out, grouping a total of 79 articles that met the proposed inclusion criteria and studying the effects of the different experiments on viability, proliferation, apoptosis, oxidative stress and the cell cycle. These results have been divided and classified by frequency, intensity, exposure time and exposure mode (continuous/intermittent). The results obtained for each of the processes according to the exposure parameter used are shown graphically to highlight the importance of a good methodology in experimental development and the search for mechanisms of action that explain the experimental results, considering not only the criterion of intensity. The consequence of this is a more than necessary revision of current exposure protection regulations for the general population based on the reductionist criterion of intensity.


Assuntos
Apoptose , Campos Eletromagnéticos , Estresse Oxidativo , Humanos , Campos Eletromagnéticos/efeitos adversos , Estresse Oxidativo/efeitos da radiação , Animais , Apoptose/efeitos da radiação , Ciclo Celular/efeitos da radiação , Sobrevivência Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação
5.
Am J Physiol Gastrointest Liver Physiol ; 326(6): G631-G642, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38593468

RESUMO

Lysophosphatidic acid (LPA) is a bioactive lipid molecule that regulates a wide array of cellular functions, including proliferation, differentiation, and survival, via activation of cognate receptors. The LPA5 receptor is highly expressed in the intestinal epithelium, but its function in restoring intestinal epithelial integrity following injury has not been examined. Here, we use a radiation-induced injury model to study the role of LPA5 in regulating intestinal epithelial regeneration. Control mice (Lpar5f/f) and mice with an inducible, epithelial cell-specific deletion of Lpar5 in the small intestine (Lpar5IECKO) were subjected to 10 Gy total body X-ray irradiation and analyzed during recovery. Repair of the intestinal mucosa was delayed in Lpar5IECKO mice with reduced epithelial proliferation and increased crypt cell apoptosis. These effects were accompanied by reduced numbers of OLFM4+ intestinal stem cells (ISCs). The effects of LPA5 on ISCs were corroborated by studies using organoids derived from Lgr5-lineage tracking reporter mice with deletion of Lpar5 in Lgr5+-stem cells (Lgr5Cont or Lgr5ΔLpar5). Irradiation of organoids resulted in fewer numbers of Lgr5ΔLpar5 organoids retaining Lgr5+-derived progenitor cells compared with Lgr5Cont organoids. Finally, we observed that impaired regeneration in Lpar5IECKO mice was associated with reduced numbers of Paneth cells and decreased expression of Yes-associated protein (YAP), a critical factor for intestinal epithelial repair. Our study highlights a novel role for LPA5 in regeneration of the intestinal epithelium following irradiation and its effect on the maintenance of Paneth cells that support the stem cell niche.NEW & NOTEWORTHY We used mice lacking expression of the lysophosphatidic acid receptor 5 (LPA5) in intestinal epithelial cells and intestinal organoids to show that the LPA5 receptor protects intestinal stem cells and progenitors from radiation-induced injury. We show that LPA5 induces YAP signaling and regulates Paneth cells.


Assuntos
Proliferação de Células , Mucosa Intestinal , Receptores de Ácidos Lisofosfatídicos , Regeneração , Transdução de Sinais , Proteínas de Sinalização YAP , Animais , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos da radiação , Camundongos , Regeneração/efeitos da radiação , Proteínas de Sinalização YAP/metabolismo , Proliferação de Células/efeitos da radiação , Células-Tronco/efeitos da radiação , Células-Tronco/metabolismo , Organoides/metabolismo , Organoides/efeitos da radiação , Camundongos Knockout , Apoptose/efeitos da radiação , Lisofosfolipídeos/metabolismo , Intestino Delgado/efeitos da radiação , Intestino Delgado/metabolismo , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia
6.
Pathol Res Pract ; 257: 155293, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38615508

RESUMO

Lysophosphatidic acid (LPA) binds to its specific G protein-coupled LPA receptors (LPA1 to LPA6), resulting in the activation of various cellular functions. LPA receptor-mediated signaling facilitates tumor progression in human malignancies. In the present study, we investigated whether LPA receptor-mediated signaling contributes to cellular responses to X-ray irradiation in osteosarcoma MG-63 cells. After X-ray irradiation (2, 4 and 8 Gy), LPAR2 and LPAR3 expression levels in MG-63 cells were significantly elevated in a dose-dependent manner, but no change of LPAR1 expression level was observed. The cell growth activities of MG-63 cells irradiated with X-rays (2, 4 and 8 Gy) were reduced by LPA. Conversely, LPA3 agonist (2 S)-OMPT enhanced the cell growth activities of X-ray irradiated MG-63 cells. The cell movement of MG-63 cells exposed to X-ray irradiation (8 Gy) was inhibited by (2 S)OMPT. In cell survival assay, (2 S)-OMPT suppressed the cell survival to cisplatin (CDDP) of MG-63 cells irradiated with X-rays (8 Gy). The cell survival to CDDP of X-ray irradiated cells was elevated by LPA3 knockdown. Moreover, we evaluated the effects of LPA2 on the cell survival to CDDP of MG-63 cells exposed to X-ray irradiation (8 Gy). The cell survival to CDDP of X-ray irradiated cells was increased by LPA2 agonist GRI-977143 and reduced by LPA2 knockdown. These results suggest that LPA receptor-signaling participates in the modulation of cellular functions induced by X-ray irradiation in osteosarcoma cells.


Assuntos
Neoplasias Ósseas , Osteossarcoma , Receptores de Ácidos Lisofosfatídicos , Humanos , Receptores de Ácidos Lisofosfatídicos/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Osteossarcoma/radioterapia , Linhagem Celular Tumoral , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Raios X , Lisofosfolipídeos/farmacologia , Lisofosfolipídeos/metabolismo
7.
J Photochem Photobiol B ; 255: 112907, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38677259

RESUMO

OBJECTIVE: The objective of this study is to investigate the variances in transcriptome gene expression of normal oral mucosa-derived mesenchymal stem cell (OM-MSC), oral leukoplakia-derived MSC (OLK-MSC) and oral squamous cell carcinoma-derived MSC(OSCC-MSC). as Additionally, the study aims to compare the in vitro proliferation, migration, invasion ability, and response to photodynamic therapy (PDT) of these three MSC, HOK, DOK, leuk1, and Cal27 cell lines. METHODS: HOK, DOK, leuk1, Cal27 cells were cultured in vitro. 3 MSC cells were obtained from OM, OLK, OSCC tissue (n = 3) and identified through flow cytometry. They were also cultured in vitro for osteogenic and lipogenic-induced differentiation. Based on the Illumina HiSeq high-throughput sequencing platform, OM-MSC, OLK-MSC, OSCC-MSC (n = 3) were subjected to transcriptome sequencing, functional annotation, and enrichment analysis of differentially expressed genes and related genes. CCK8 assay, wound healing assay, and transwell assay were performed to compare the proliferation, migration, and invasion of the seven types of cells. The 7 cells were incubated with 0, 0.125 mM, 0.25 mM, 0.5 mM, 1 mM, and 2 mM of the photosensitizer (5-aminolevulinic acid, 5-ALA) in vitro. Subsequently, they were irradiated with a 150 mM, 635 nm laser for 1 min, and the cell activity was detected using the CCK8 assay after 24 h. The mitochondrial changes in the 7 cells before and after the treatment of PDT were detected using the JC-10 probe, and the changes in ATP content were measured before and after the PDT treatment. RESULTS: OM-MSC, OLK-MSC, and OSCC-MSC expressed positive MSC surface markers. After osteogenic and lipogenic-induced differentiation culture, stained calcium nodules and lipid droplets were visible, meeting the identification criteria of MSC. Pathway enrichment analysis revealed that the differentially expressed genes (DEGs) of OSCC-MSC compared to OLK-MSC were primarily associated with the PI3K-Akt signaling pathway and tumor-related pathways. OSCC-MSC exhibited stronger migratory and invasive abilities compared to Cal27. The IC50 values required for OM, OLK, and OSCC-derived MSC were lower than those required for epithelial cells treated with PDT, which were 1.396 mM, 0.9063 mM, and 2.924 mM, respectively. Cell membrane and mitochondrial disruption were observed in seven types of cells after 24 h of PDT treatment. However, HOK, DOK, leuk1, and Cal27 cells had an ATP content increased. CONCLUSIONS: OLK, OSCC epithelial cells require higher concentrations of 5-ALA for PDT treatment than MSC of the same tissue origin. The concentration of 5-ALA required increases with increasing cell malignancy. Differences in the response of epithelial cells and MSC to PDT treatment may have varying impacts on OLK recurrence and malignancy.


Assuntos
Carcinoma de Células Escamosas , Movimento Celular , Proliferação de Células , Células Epiteliais , Leucoplasia Oral , Células-Tronco Mesenquimais , Mucosa Bucal , Neoplasias Bucais , Fotoquimioterapia , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Mucosa Bucal/patologia , Mucosa Bucal/citologia , Leucoplasia Oral/patologia , Leucoplasia Oral/terapia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/metabolismo , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/terapia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Linhagem Celular Tumoral , Ácido Aminolevulínico/farmacologia , Diferenciação Celular/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos
8.
Aging (Albany NY) ; 16(8): 6673-6693, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38683123

RESUMO

PURPOSE: The objective of this study was to investigate the senescent phenotypes of human corneal endothelial cells (hCEnCs) upon treatment with ultraviolet (UV)-A. METHODS: We assessed cell morphology, senescence-associated ß-galactosidase (SA-ß-gal) activity, cell proliferation and expression of senescence markers (p16 and p21) in hCEnCs exposed to UV-A radiation, and senescent hCEnCs induced by ionizing radiation (IR) were used as positive controls. We performed RNA sequencing and proteomics analyses to compare gene and protein expression profiles between UV-A- and IR-induced senescent hCEnCs, and we also compared the results to non-senescent hCEnCs. RESULTS: Cells exposed to 5 J/cm2 of UV-A or to IR exhibited typical senescent phenotypes, including enlargement, increased SA-ß-gal activity, decreased cell proliferation and elevated expression of p16 and p21. RNA-Seq analysis revealed that 83.9% of the genes significantly upregulated and 82.6% of the genes significantly downregulated in UV-A-induced senescent hCEnCs overlapped with the genes regulated in IR-induced senescent hCEnCs. Proteomics also revealed that 93.8% of the proteins significantly upregulated in UV-A-induced senescent hCEnCs overlapped with those induced by IR. In proteomics analyses, senescent hCEnCs induced by UV-A exhibited elevated expression levels of several factors part of the senescence-associated secretory phenotype. CONCLUSIONS: In this study, where senescence was induced by UV-A, a more physiological stress for hCEnCs compared to IR, we determined that UV-A modulated the expression of many genes and proteins typically altered upon IR treatment, a more conventional method of senescence induction, even though UV-A also modulated specific pathways unrelated to IR.


Assuntos
Proliferação de Células , Senescência Celular , Células Endoteliais , Raios Ultravioleta , Humanos , Senescência Celular/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Proliferação de Células/efeitos da radiação , Células Endoteliais/efeitos da radiação , Células Endoteliais/metabolismo , Endotélio Corneano/efeitos da radiação , Endotélio Corneano/metabolismo , Células Cultivadas , Proteômica , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , beta-Galactosidase/metabolismo , beta-Galactosidase/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética
9.
In Vivo ; 38(3): 1079-1093, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38688627

RESUMO

BACKGROUND/AIM: In hepatocellular carcinoma (HCC) treatment, radiotherapy (RT) stands as a pivotal approach, yet the emergence of radioresistance poses a formidable challenge. This study aimed to explore the potential synergy between quetiapine and RT for HCC treatment. MATERIALS AND METHODS: A Hep3B xenograft mouse model was used, the investigation tracked tumor progression, safety parameters, and molecular mechanisms. RESULTS: The findings revealed a synergistic anti-HCC effect when quetiapine was coupled with RT that prolonged tumor growth time and a significantly higher growth inhibition rate compared to the control group. Safety assessments indicated minimal pathological changes, suggesting potential of quetiapine in mitigating RT-induced alterations in liver and kidney functions. Mechanistically, the combination suppressed metastasis and angiogenesis-related proteins, while triggering the activation of apoptosis-related proteins via targeting Epidermal growth factor receptor (EGFR)-mediated signaling. CONCLUSION: The potential of the quetiapine and RT combination is emphasized, offering enhanced anti-HCC efficacy, a safety profile, and positioning quetiapine as a radiosensitizer for HCC treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Fumarato de Quetiapina , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/tratamento farmacológico , Camundongos , Humanos , Fumarato de Quetiapina/farmacologia , Fumarato de Quetiapina/uso terapêutico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Apoptose/efeitos dos fármacos , Progressão da Doença , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Masculino
10.
J Radiat Res ; 65(3): 303-314, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38637316

RESUMO

Angiosarcoma is a rare refractory soft-tissue tumor with a poor prognosis and is treated by radiotherapy. The fibroblast growth factor 1 (FGF1) mutant, with enhanced thermostability due to several substituted amino acids, inhibits angiosarcoma cell metastasis, yet the mechanism of action is unclear. This study aims to clarify the FGF1 mutant mechanism of action using ISOS-1 mouse angiosarcoma cells. The wild-type FGF1 or FGF1 mutant was added to ISOS-1 cells and cultured, evaluating cell numbers over time. The invasive and migratory capacity of ISOS-1 cells was assessed by transwell analysis. ISOS-1 cell radiosensitivity was assessed by colony formation assay after X-ray irradiation. To examine whether mitogen-activated protein kinase (MEK) inhibitor counteracts the FGF1 mutant effects, a combination of MEK inhibitor and FGF1 mutant was added to ISOS-1 cells and cultured. The FGF1 mutant was observed to inhibit ISOS-1 cell proliferation, invasion and migration by sustained FGF1 signaling activation. A MEK inhibitor suppressed the FGF1 mutant-induced inhibition of proliferation, invasion and migration of ISOS-1 cells. Furthermore, the FGF1 mutant enhanced radiosensitivity of ISOS-1 cells, but MEK inhibition suppressed the increased radiosensitivity. In addition, we found that the FGF1 mutant strongly inhibits actin polymerization, suggesting that actin cytoskeletal dynamics are closely related to ISOS-1 cell radiosensitivity. Overall, this study demonstrated that in ISOS-1 cells, the FGF1 mutant inhibits proliferation, invasion and migration while enhancing radiosensitivity through sustained activation of the MEK-mediated signaling pathway.


Assuntos
Movimento Celular , Proliferação de Células , Fator 1 de Crescimento de Fibroblastos , Hemangiossarcoma , Sistema de Sinalização das MAP Quinases , Invasividade Neoplásica , Tolerância a Radiação , Animais , Camundongos , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Fator 1 de Crescimento de Fibroblastos/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Linhagem Celular Tumoral , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos da radiação , Hemangiossarcoma/patologia , Hemangiossarcoma/metabolismo , Hemangiossarcoma/radioterapia
11.
Biomaterials ; 308: 122531, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38531198

RESUMO

Radiation therapy (RT) is essential for triple negative breast cancer (TNBC) treatment. However, patients with TNBC continue to experience recurrence after RT. The role of the extracellular matrix (ECM) of irradiated breast tissue in tumor recurrence is still unknown. In this study, we evaluated the structure, molecular composition, and mechanical properties of irradiated murine mammary fat pads (MFPs) and developed ECM hydrogels from decellularized tissues (dECM) to assess the effects of RT-induced ECM changes on breast cancer cell behavior. Irradiated MFPs were characterized by increased ECM deposition and fiber density compared to unirradiated controls, which may provide a platform for cell invasion and proliferation. ECM component changes in collagens I, IV, and VI, and fibronectin were observed following irradiation in both MFPs and dECM hydrogels. Encapsulated TNBC cell proliferation and invasive capacity was enhanced in irradiated dECM hydrogels. In addition, TNBC cells co-cultured with macrophages in irradiated dECM hydrogels induced M2 macrophage polarization and exhibited further increases in proliferation. Our study establishes that the ECM in radiation-damaged sites promotes TNBC invasion and proliferation as well as an immunosuppressive microenvironment. This work represents an important step toward elucidating how changes in the ECM after RT contribute to breast cancer recurrence.


Assuntos
Proliferação de Células , Matriz Extracelular , Hidrogéis , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral , Animais , Matriz Extracelular/metabolismo , Microambiente Tumoral/efeitos da radiação , Hidrogéis/química , Feminino , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Linhagem Celular Tumoral , Camundongos , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/radioterapia , Macrófagos/metabolismo , Glândulas Mamárias Animais/efeitos da radiação
12.
J Dermatol Sci ; 114(1): 24-33, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38448340

RESUMO

BACKGROUND: The unfolded protein response (UPR) is one of the cytoprotective mechanisms against various stresses and essential for the normal function of skin. Skin injury caused by ionizing radiation (IR) is a common side effect of radiotherapy and it is unclear how UPR affects IR-induced skin injury. OBJECTIVES: To verify the effect of UPR on IR-induced DNA damage in keratinocytes and the relation between an endoplasmic reticulum (ER) protein KTN1 and UPR. METHODS: All experiments were performed on keratinocytes models: HaCaT and HEK-A. ER lumen and the expression levels of KTN1 and UPR pathway proteins (PERK, IRE1α and ATF6) were examined by transmission electron microscopy and immunoblotting, respectively. 4-PBA, an UPR inhibitor, was used to detected its effects on DNA damage and cell proliferation. Subsequently, the effects of KTN1 deletion on UPR, DNA damage and cell proliferation after IR were detected. Tunicamycin was used to reactivate UPR and then we examined its effects on DNA damage. RESULTS: UPR was activated by IR in keratinocytes. Inhibition of UPR aggravated DNA damage and suppressed cell proliferation after IR. KTN1 expression was upregulated by IR and KTN1 depletion reduced ER expansion and the expression of UPR-related proteins. Moreover, KTN1 depletion aggravated DNA damage and suppressed cell proliferation after IR could reversed by reactivation of UPR. CONCLUSION: KTN1 deletion aggravates IR-induced keratinocyte DNA damage via inhibiting UPR. Our findings provide new insights into the mechanisms of keratinocytes in response to IR-induced damage.


Assuntos
Proliferação de Células , Dano ao DNA , Células HaCaT , Queratinócitos , Radiação Ionizante , Resposta a Proteínas não Dobradas , Humanos , Linhagem Celular , Proliferação de Células/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/efeitos da radiação , Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos da radiação , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Queratinócitos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Pele/efeitos da radiação , Pele/patologia , Pele/citologia , Pele/efeitos dos fármacos , Pele/metabolismo , Resposta a Proteínas não Dobradas/efeitos da radiação , Resposta a Proteínas não Dobradas/efeitos dos fármacos
13.
Cell Prolif ; 57(6): e13606, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38454614

RESUMO

Glioblastoma (GBM), a WHO grade IV glioma, is a malignant primary brain tumour for which combination of surgery, chemotherapy and radiotherapy is the first-line approach despite adverse effects. Tumour microenvironment (TME) is characterized by an interplay of cells and soluble factors holding a critical role in neoplastic development. Significant pathophysiological changes have been found in GBM TME, such as glia activation and oxidative stress. Microglia play a crucial role in favouring GBM growth, representing target cells of immune escape mechanisms. Our study aims at analysing radiation-induced effects in modulating intercellular communication and identifying the basis of protective mechanisms in radiation-naïve GBM cells. Tumour cells were treated with conditioned media (CM) derived from 0, 2 or 15 Gy irradiated GBM cells or 0, 2 or 15 Gy irradiated human microglia. We demonstrated that irradiated microglia promote an increase of GBM cell lines proliferation through paracrine signalling. On the contrary, irradiated GBM-derived CM affect viability, triggering cell death mechanisms. In addition, we investigated whether these processes involve mitochondrial mass, fitness and oxidative phosphorylation and how GBM cells respond at these induced alterations. Our study suggests that off-target radiotherapy modulates microglia to support GBM proliferation and induce metabolic modifications.


Assuntos
Neoplasias Encefálicas , Proliferação de Células , Glioblastoma , Microglia , Microambiente Tumoral , Humanos , Glioblastoma/radioterapia , Glioblastoma/patologia , Glioblastoma/metabolismo , Microglia/metabolismo , Microglia/patologia , Microglia/efeitos da radiação , Proliferação de Células/efeitos da radiação , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Microambiente Tumoral/efeitos da radiação , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/metabolismo , Sobrevivência Celular/efeitos da radiação , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação
14.
J Biophotonics ; 17(5): e202300448, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38348528

RESUMO

Photobiomodulation (PBM) has attracted widespread attention in suppressing various pain and inflammation. Primary dysmenorrhea (PD) primarily occurs in adolescents and adult females, and the limited effectiveness and side effects of conventional treatments have highlighted the urgent need to develop and identify new adjunct therapeutic strategies. In this work, the results of pain and PGs demonstrated that 850 nm, 630 nm, and 460 nm all exhibited pain inhibition, decreased PGF2α and upregulated PGE2, while 630 nm PBM has better effectiveness. Then to explore the underlying biological mechanisms of red light PBM on PD, we irradiated prostaglandin-F2α induced HUSM cells and found that low-level irradiance can restore intracellular calcium ion, ROS, ATP, and MMP levels to normal levels. And, red light enhanced cell viability and promoted cell proliferation for normal HUSM cells. Therefore, this study proposes that red light PBM may be a promising approach for the future clinical treatment of PD.


Assuntos
Dinoprosta , Dismenorreia , Terapia com Luz de Baixa Intensidade , Dismenorreia/radioterapia , Feminino , Dinoprosta/análogos & derivados , Dinoprosta/metabolismo , Humanos , Sobrevivência Celular/efeitos da radiação , Proliferação de Células/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Cálcio/metabolismo , Linhagem Celular , Trifosfato de Adenosina/metabolismo
15.
Radiat Res ; 201(5): 429-439, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38253061

RESUMO

The current geopolitical context has brought the radiological nuclear risk to the forefront of concerns. High-dose localized radiation exposure leads to the development of a musculocutaneous radiation syndrome affecting the skin and subcutaneous muscles. Despite the implementation of a gold standard treatment based on an invasive surgical procedure coupled with autologous cell therapy, a muscular defect frequently persists. Targeting the modulation of the Hedgehog (Hh) signaling pathway appears to be a promising therapeutic approach. Activation of this pathway enhances cell survival and promotes proliferation after irradiation, while inhibition by Cyclopamine facilitates differentiation. In this study, we compared the effects of three antagonists of Hh, Cyclopamine (CA), Vismodegib (VDG) and Sonidegib (SDG) on differentiation. A stable cell line of murine myoblasts, C2C12, was exposed to X-ray radiation (5 Gy) and treated with CA, VDG or SDG. Analysis of proliferation, survival (apoptosis), morphology, myogenesis genes expression and proteins production were performed. According to the results, VDG does not have a significant impact on C2C12 cells. SDG increases the expression/production of differentiation markers to a similar extent as CA, while morphologically, SDG proves to be more effective than CA. To conclude, SDG can be used in the same way as CA but already has a marketing authorization with an indication against basal cell cancers, facilitating their use in vivo. This proof of concept demonstrates that SDG represents a promising alternative to CA to promotes differentiation of murine myoblasts. Future studies on isolated and cultured satellite cells and in vivo will test this proof of concept.


Assuntos
Proteínas Hedgehog , Músculo Esquelético , Regeneração , Transdução de Sinais , Animais , Camundongos , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/antagonistas & inibidores , Músculo Esquelético/efeitos da radiação , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/citologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Linhagem Celular , Regeneração/efeitos dos fármacos , Regeneração/efeitos da radiação , Piridinas/farmacologia , Alcaloides de Veratrum/farmacologia , Anilidas/farmacologia , Compostos de Bifenilo/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Desenvolvimento Muscular/efeitos dos fármacos , Desenvolvimento Muscular/efeitos da radiação
16.
Photochem Photobiol ; 100(1): 225-232, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37254280

RESUMO

There are limited data on comparison of pulsed and continuous wave in photobiomodulation therapy (PBM). This study aimed to investigate the effect of PBM with 980 nm laser in pulsed and continuous wave on the proliferation and migration of human gingival fibroblasts (HGF) cells. Cultured HGF were divided into three main groups: (1) irradiated in pulsed mode (frequencies of 50 and 25 KHz; energy densities of 3 and 5 J/cm2 ), (2) irradiated in continuous mode (energy densities of 3.2 and 5.2 J/cm2 ), and (3) no irradiation as control group. HGF proliferation rate was measured by MTT assay at 24, 48, and 72 h post irradiation. In addition, HGF migration rate was measured by scratch test at 24 h post PBM. At 24 h, the group received continuous irradiation at 5.2 J/cm2 showed significantly higher proliferation compared with the control group (p = 0.012). At 48 and 72 h, the groups received continuous, and 50 Hz pulsed irradiation at energy densities of 5.2 and 5 J/cm2 respectively, had significantly higher HGF proliferation rates compared to the control (p < 0.05). Only the continuous irradiations were effective in significant increase of the cell migration. In conclusion, continuous PBM at energy density of 5.2 J/cm2 showed promising effect on HGF proliferation and migration.


Assuntos
Terapia com Luz de Baixa Intensidade , Humanos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular , Lasers , Fibroblastos/efeitos da radiação
17.
J Biophotonics ; 17(2): e202300166, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37975254

RESUMO

We investigated the effects of low-level Er:YAG laser irradiation on proliferation and alternations in early gene expression of gingival fibroblasts. Mice primary gingival fibroblasts were irradiated with an Er:YAG laser (1.8, 3.9, and 5.8 J/cm2 ). Irradiation at 3.9 J/cm2 promoted cell proliferation without significant changes in lactate dehydrogenase or Hspa1a expression. Three hours after irradiation at 3.9 J/cm2 , the Fn1 expression level was significantly increased. RNA-seq identified 15 differentially expressed genes between irradiated and non-irradiated cells, some of which belonged to immediate early genes (IEGs). Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated MAPK pathway enhancement, and gene set enrichment analysis showed enrichment in the TGF-ß signaling gene set. Enhanced proliferation via laser irradiation disappeared upon inhibition of Dusp4, Dusp5, and Tgfr1 expression. Low-level Er:YAG laser irradiation, especially at 3.9 J/cm2 without a major temperature elevation, enhanced fibroblast proliferation, via TGF-ß and the MAPK signaling pathway following IEG expression.


Assuntos
Lasers de Estado Sólido , Camundongos , Animais , Maxila , Proliferação de Células/efeitos da radiação , Fator de Crescimento Transformador beta , Fibroblastos/efeitos da radiação , Expressão Gênica
18.
Eur J Nucl Med Mol Imaging ; 51(2): 395-404, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37796306

RESUMO

PURPOSE: A reliable method for regional in vivo imaging of radiation-induced cellular damage would be of great importance for the detection of therapy-induced injury to healthy tissue and the choice of adequate treatment of radiation emergency patients in both civilian and military events. This study aimed to investigate in a mouse model if positron emission tomography (PET) imaging with proliferation and apoptosis markers is potentially suitable for this purpose. METHODS: Four groups, including twenty mice (wild-type C57BL/6) each, were whole-body irradiated with 0 Gy, 0.5 Gy, 1 Gy, and 3 Gy and examined by PET over a six-month period at defined time points. 3'-[18F]fluoro-3'-deoxythymidine ([18F]FLT) and 2-(5-[18F]fluoropentyl)-2-methyl malonic acid ([18F]ML-10) were used to visualise proliferation and apoptosis. Regional standard uptake values were compared with respect to irradiation dose over time. Histologic data and peripheral blood cell values were correlated with the PET results. RESULTS: The hematopoietic bone marrow showed a significantly increased [18F]FLT signal at early time points after radiation exposure (day 3 and day 7). This correlated with blood parameters, especially leukocytes, and histological data. A significantly increased [18F]FLT signal also occurred in the gastrointestinal tract and thymus at early time points. An increased [18F]ML-10 signal related to irradiation doses was observed in the bone marrow on day 8, but there was a high variability of standard uptake values and no correlation with histological data. CONCLUSION: [18F]FLT showed potential to visualise the extent, regional distribution and recovery from radiation-induced cellular damage in the bone marrow, gastrointestinal tract and thymus. The potential of [18F]FLT imaging to assess the extent of bone marrow affected by irradiation might be especially useful to predict the subsequent severity of hematopoietic impairment and to adapt the therapy of the bone marrow reserve. [18F]ML-10 PET proved to be not sensitive enough for the reliable detection of radiation induced apoptosis.


Assuntos
Tomografia por Emissão de Pósitrons , Irradiação Corporal Total , Humanos , Camundongos , Animais , Irradiação Corporal Total/efeitos adversos , Camundongos Endogâmicos C57BL , Tomografia por Emissão de Pósitrons/métodos , Modelos Animais de Doenças , Proliferação de Células/efeitos da radiação , Apoptose , Didesoxinucleosídeos
19.
Arch Oral Biol ; 159: 105874, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38147800

RESUMO

OBJECTIVE: Photobiomodulation therapy (PBMT) has proven to reduce inflammation and pain and increase wound healing. Thus, the aim of this study was to analyze the effects of PBMT parameters on migration, proliferation, and gene expression after ionizing radiation and bacterial-induced stress in an in vitro study. DESIGN: Keratinocytes (HaCaT) and Fibroblasts (HGFs) were grown in DMEM with 10 % fetal bovine serum until stressful condition induction with lipopolysaccharide (LPS) of Escherichia coli (1 µg/mL), Porphyromonas gingivalis protein extract (5 µg/mL) and ionizing radiation (8 Gy). Low-laser irradiation (660 nm, 30 mW) was carried out in four sessions, with 6 h intervals, and energy density of 2, 3, 4, and 5 J/cm². Scratch assays, immunofluorescence, and RT-qPCR were performed. RESULTS: Treated fibroblasts and keratinocytes showed significant response in proliferation and migration after scratch assays (p < 0.05). Higher expressions of α-SMA in fibroblasts and F-actin in keratinocytes were observed in cells subjected to 3 J/cm². PI3K-pathway genes expression tended to enhance in fibroblasts, presenting a higher relative expression when compared to keratinocytes. In keratinocytes, PBMT groups demonstrated deregulated expression for all inflammatory cytokines' genes tested while fibroblasts presented a tendency to enhance those genes expression in a dose dependent way. CONCLUSIONS: The present study showed that delivering 660 nm, 30 mW was effective to stimulate cell migration, proliferation and to accelerate wound healing. PBMT can modulate cytokines and pathways involved in wound repair. The different energy densities delivering distinct responses in vitro highlights that understanding laser parameters is fundamental to improve treatment strategies.


Assuntos
Terapia com Luz de Baixa Intensidade , Fosfatidilinositol 3-Quinases , Queratinócitos , Fibroblastos/efeitos da radiação , Proliferação de Células/efeitos da radiação , Radiação Ionizante
20.
J Transl Med ; 21(1): 792, 2023 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-37940975

RESUMO

OBJECTIVE: Investigating the impact of centromere protein N (CENP-N) on radiosensitivity of nasopharyngeal carcinoma (NPC) cells. METHODS: Using immunohistochemistry and immunofluorescence to detect CENP-N expression in tissues from 35 patients with radiosensitive or radioresistant NPC. Assessing the effect of combined CENP-N knockdown and radiotherapy on various cellular processes by CCK-8, colony formation, flow cytometry, and Western blotting. Establishing a NPC xenograft model. When the tumor volume reached 100 mm3, a irradiation dose of 6 Gy was given, and the effects of the combined treatment were evaluated in vivo using immunofluorescence and Western blotting techniques. RESULTS: The level of CENP-N was significantly reduced in radiosensitive tissues of NPC (p < 0.05). Knockdown of CENP-N enhanced NPC radiosensitivity, resulting in sensitizing enhancement ratios (SER) of 1.44 (5-8 F) and 1.16 (CNE-2Z). The combined treatment showed significantly higher levels of proliferation suppression, apoptosis, and G2/M phase arrest (p < 0.01) compared to either CENP-N knockdown alone or radiotherapy alone. The combined treatment group showed the highest increase in Bax and γH2AX protein levels, whereas the protein Cyclin D1 exhibited the greatest decrease (p < 0.01). However, the above changes were reversed after treatment with AKT activator SC79. In vivo, the mean volume and weight of tumors in the radiotherapy group were 182 ± 54 mm3 and 0.16 ± 0.03 g. The mean tumor volume and weight in the combined treatment group were 84 ± 42 mm3 and 0.04 ± 0.01 g. CONCLUSION: Knockdown of CENP-N can enhance NPC radiosensitivity by inhibiting AKT/mTOR.


Assuntos
Neoplasias Nasofaríngeas , Proteínas Proto-Oncogênicas c-akt , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/radioterapia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/radioterapia , Linhagem Celular Tumoral , Tolerância a Radiação/genética , Serina-Treonina Quinases TOR , Proliferação de Células/efeitos da radiação , Apoptose/genética
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