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1.
Eur J Pharmacol ; 972: 176553, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38574838

RESUMO

Stroke poses a significant risk of mortality, particularly among the elderly population. The pathophysiological process of ischemic stroke is complex, and it is crucial to elucidate its molecular mechanisms and explore potential protective drugs. Ferroptosis, a newly recognized form of programmed cell death distinct from necrosis, apoptosis, and autophagy, is closely associated with the pathophysiology of ischemic stroke. N6022, a selective inhibitor of S-nitrosoglutathione reductase (GSNOR), is a "first-in-class" drug for asthma with potential therapeutic applications. However, it remains unclear whether N6022 exerts protective effects in ischemic stroke, and the precise mechanisms of its action are unknown. This study aimed to investigate whether N6022 mitigates cerebral ischemia/reperfusion (I/R) injury by reducing ferroptosis and to elucidate the underlying mechanisms. Accordingly, we established an oxygen-glucose deprivation/reperfusion (OGD/R) cell model and a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to mimic cerebral I/R injury. Our data, both in vitro and in vivo, demonstrated that N6022 effectively protected against I/R-induced brain damage and neurological deficits in mice, as well as OGD/R-induced BV2 cell damage. Mechanistically, N6022 promoted Nrf2 nuclear translocation, enhancing intracellular antioxidant capacity of SLC7A11-GPX4 system. Furthermore, N6022 interfered with the interaction of GSNOR with GSTP1, thereby boosting the antioxidant capacity of GSTP1 and attenuating ferroptosis. These findings provide novel insights, showing that N6022 attenuates microglial ferroptosis induced by cerebral I/R injury through the promotion of Nrf2 nuclear translocation and inhibition of the GSNOR/GSTP1 axis.


Assuntos
Benzamidas , Ferroptose , Microglia , Fator 2 Relacionado a NF-E2 , Pirróis , Traumatismo por Reperfusão , Animais , Ferroptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/efeitos dos fármacos , Modelos Animais de Doenças , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/patologia , Linhagem Celular , Transporte Ativo do Núcleo Celular/efeitos dos fármacos
3.
Phytomedicine ; 125: 155290, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38308918

RESUMO

BACKGROUND: In our previous study, we provided evidence that Astragalus mongholicus Bunge(AM) and its extracts possess a protective capability against radiation-induced damage, potentially mediated through the reduction of reactive oxygen species (ROS) and nitric oxide (NO). However, we were pleasantly surprised to discover during our experimentation that AM not only offers protection against radiation damage but also exhibits a radiation sensitization effect. This effect may be attributed to a specific small molecule present in AM known as ononin. Currently, radiation sensitizers are predominantly found in nitrazole drugs and nanomaterials, with no existing reports on the radiation sensitization properties of ononin, nor its underlying mechanism. PURPOSE: This study aims to investigate the sensitization effect of the small molecule ononin derived from AM on lung cancer radiotherapy, elucidating its specific molecular mechanism of action. Additionally, the safety profile of combining astragalus small molecule ononin with radiation therapy will be evaluated. METHODS: The effective concentration of ononin was determined through cell survival experiments, and the impact of ononin combined with varying doses of radiation on lung cancer cells was observed using CCK-8 and cell cloning experiments. The apoptotic effect of ononin combined with radiation on lung cancer cells was assessed using Hochester staining, flow cytometry, and WB assay. Additionally, WB and immunofluorescence analysis were conducted to investigate the influence of ononin on HIF-1α/VEGF pathway. Furthermore, Molecular Dynamics Simulation was employed to validate the targeted binding ability of ononin and HIF-1α. A lung cancer cell line was established to investigate the effects of knockdown and overexpression of HIF-1α. Subsequently, the experiment was repeated using tumor bearing nude mice and C57BL/6 mouse models in an in vivo study. Tumor volume was measured using a vernier caliper, while HE, immunohistochemistry, and immunofluorescence techniques were employed to observe the effects of ononin combined with radiation on tumor morphology, proliferation, and apoptosis. Additionally, Immunofluorescence was employed to examine the impact of ononin on HIF-1α/VEGF pathway in vivo, and its effect on liver function in mice was assessed through biochemistry analysis. RESULTS: At a concentration of 25 µM, ononin did not affect the proliferation of lung epithelial cells but inhibited the survival of lung cancer cells. In vitro experiments demonstrated that the combination of ononin and radiation could effectively inhibit the growth of lung cancer cells, induce apoptosis, and suppress the excessive activation of the Hypoxia inducible factor 1 alpha/Vascular endothelial growth factor pathway. In vivo experiments showed that the combination of ononin and radiation reduced the size and proliferation of lung cancer tumors, promoted cancer cell apoptosis, mitigated abnormal activation of the Hypoxia inducible factor 1 alpha pathway, and protected against liver function damage. CONCLUSION: This study provides evidence that the combination of AM and its small molecule ononin can enhance the sensitivity of lung cancer to radiation. Additionally, it has been observed that this combination can specifically target HIF-1α and exert its effects. Notably, ononin exhibits the unique ability to protect liver function from damage while simultaneously enhancing the tumor-killing effects of radiation, thereby demonstrating a synergistic and detoxifying role in tumor radiotherapy. These findings contribute to the establishment of a solid basis for the development of novel radiation sensitizers derived from traditional Chinese medicine.


Assuntos
Glucosídeos , Isoflavonas , Neoplasias Pulmonares , Radiossensibilizantes , Camundongos , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Camundongos Nus , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Fatores de Crescimento do Endotélio Vascular/metabolismo , Tolerância a Radiação , Radiossensibilizantes/farmacologia , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia
4.
Mol Med Rep ; 29(3)2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38275110

RESUMO

Ischemic stroke poses a major threat to human health. Therefore, the molecular mechanisms of cerebral ischemia/reperfusion injury (CIRI) need to be further clarified, and the associated treatment approaches require exploration. The NOD­like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome serves an important role in causing CIRI, and its activation exacerbates the underlying injury. Activation of the NLRP3 inflammasome triggers the maturation and production of the inflammatory molecules IL­1ß and IL­18, as well as gasdermin­D­mediated pyroptosis and CIRI damage. Thus, the NLRP3 inflammasome may be a viable target for the treatment of CIRI. In the present review, the mechanisms of the NLRP3 inflammasome in the intense inflammatory response and pyroptosis induced by CIRI are discussed, and the therapeutic strategies that target the NLRP3­mediated inflammatory response and pyroptosis in CIRI are summarized. At present, certain drugs have already been studied, highlighting future therapeutic perspectives.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Piroptose , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo
5.
BMC Chem ; 17(1): 147, 2023 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-37891641

RESUMO

As an essential marker of cancer treatment, PARP-1 inhibitors could effectively kill tumor cells through a mechanism known as synthetic lethality and are used to treat a variety of cancers. In order to explore novel PARP-1 inhibitors, a series of 22 novel erythrina derivatives were reported and preliminarily explored their mechanism of action. The antitumor activities against four human cancer cell lines including A549, OVCAR-3, HCT-116, and MCF-7 were evaluated, and the preliminary SARs were summarized. Among them, compound 11b exhibited better anti-proliferative effects against A549 cells (IC50 = 1.95 µM). The SI results showed that compound 11b had low toxicity. Moreover, compound 11b displayed excellent PARP-1 inhibitory activities with IC50 values of 19.24 nM. In addition, molecular docking studies provided the rational binding modes of compound 11b in complexes with PARP-1. The flow cytometry assays revealed that compound 11b could induce apoptosis of A549 cells (P < 0.001). Simultaneously, compound 11b could effectively reduce the formation of PAR (P < 0.001). The ADMET prediction results indicated compound 11b had similar properties to rucaparib. Collectively, compound 11b has potential research value for further investigation.

6.
World J Clin Cases ; 11(26): 6040-6050, 2023 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-37731551

RESUMO

BACKGROUND: At present, understanding of the most effective ventilation methods for treating chronic obstructive pulmonary disease (COPD) patients experiencing acute worsening symptoms and respiratory failure remains relatively limited. This report analyzed the efficiency and side effects of various ventilation techniques used for individuals experiencing an acute COPD exacerbation. AIM: To determine whether pressure-controlled ventilation (PCV) can lower peak airway pressures (PAPs) and reduce the incidence of barotrauma compared to volume-controlled ventilation (VCV), without compromising clinical outcomes and oxygenation parameters. METHODS: We have evaluated 600 patients who were hospitalized due to a severe COPD exacerbation, with 400 receiving mechanical ventilation for the respiratory failure. The participants were divided into two different groups, who were administered either VCV or PCV, along with appropriate management. We thereafter observed patients' attributes, clinical factors, and laboratory, radiographic, and arterial blood gas evaluations at the start and during their stay in the intensive care unit (ICU). We have also employed appropriate statistical methods for the data analysis. RESULTS: Both the VCV and PCV groups experienced significant enhancements in the respiratory rate, tidal volume, and arterial blood gas values during their time in the ICU. However, no significant distinctions were detected between the groups in terms of oxygenation indices (partial pressures of oxygen/raction of inspired oxygen ratio) and partial pressures of carbon dioxide improvements. There was no considerable disparity observed between the VCV and PCV groups in the hospital mortality (32% vs 28%, P = 0.53), the number of days of ICU stay [median interquartile range (IQR): 9 (6-14) d vs 8 (5-13) d, P = 0.41], or the duration of the mechanical ventilation [median (IQR): 6 (4-10) d vs 5 (3-9) d, P = 0.47]. The PCV group displayed lower PAPs compared to the VCV group (P < 0.05) from the beginning of mechanical ventilation until extubation or ICU departure. The occurrence of barotrauma was considerably lower in the PCV group in comparison to the VCV group (6% vs 16%, P = 0.03). CONCLUSION: Both VCV and PCV were found to be effective in treating patients with acute COPD exacerbation. However, PCV was associated with lower PAPs and a significant decrease in barotrauma, thus indicating that it might be a safer ventilation method for this group of patients. However, further large-scale study is necessary to confirm these findings and to identify the best ventilation approach for patients experiencing an acute COPD exacerbation.

8.
Front Neurol ; 14: 1196446, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37332994

RESUMO

Introduction: Research on acupuncture for Parkinson's Disease is growing rapidly. A scoping review examines emerging evidence and is important to guide policy and practice. The purpose of this scoping review was to examine the breadth and methodological quality of systematic reviews and meta-analyses, and to map the quality of evidence of these studies to evaluate the efficacy of acupuncture for treatment of PD. Methods: Seven literature databases were searched. Two researchers independently screened the literature and extracted relevant information (such as general characteristics, inclusion criteria, study results, and report quality).The inclusion criteria include publicly published systematic reviews/meta-analyses/systematic reviews of acupuncture treatment for Parkinson's disease. The research subjects are any patients who meet the diagnostic criteria for Parkinson's disease, and intervention measures include acupuncture treatment including electro acupuncture, scalp acupuncture, or combination with other treatment methods. The outcome indicators are all types of results related to PD and the effective measurement tools used. Results: A total of 23 systematic reviews and/or meta-analyses of studies were included. Most of the articles were published between 2019 and 2023 (47.8%). A total of 14 articles (60.9%) were evaluated and classified, and 89 (36.8.1%) of the 242 included articles were of medium and high quality. Discussion: This study comprehensively evaluates the quality and research methods of incorporating SRs/MAs, and concludes that acupuncture treatment for Parkinson's disease may be significant. Considering the shortcomings in research design and methodology, it is not possible to draw conclusions on the evidence of acupuncture treatment for PD at this stage, but it does not mean that acupuncture treatment is ineffective. We hope to focus on improving research design and methods in the study of acupuncture treatment for Parkinson's disease, an increase the credibility of research results.

9.
Sci Rep ; 13(1): 8628, 2023 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-37244970

RESUMO

Accurate and reliable foot measurements at different stances offer comprehensive geometrical information on foot, thus enabling a more comfortable insole/footwear for practical use and daily activities. However, there lacks investigations on continuous deformation of foot shape during the roll-over process. This study analyses the foot deformation of 19 female diabetic patients during half weight bearing standing and self-selected walking speed by using a novel 4D foot scanning system. The scanning system has good repeatability and accuracy in both static and dynamic scanning situations. Point cloud registration for scanned image reorientation and algorithms to automatically extract foot measurements is developed. During the foot roll-over process, maximum deformation of length and girth dimensions are found at first toe contact. Width dimensions have maximum deformation at heel take off. The findings provide a new understanding of foot shape changes in dynamic situations, thus providing an optimal solution for foot comfort, function and protection.


Assuntos
, Calcanhar , Humanos , Feminino , Pé/diagnóstico por imagem , Suporte de Carga , Sapatos , Algoritmos , Caminhada
10.
World J Clin Cases ; 11(13): 3045-3051, 2023 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-37215412

RESUMO

BACKGROUND: The fractional flow reserve (FFR) has made the treatment of coronary heart disease more precise. However, there are few reports on the measurement of FFR via the left internal mammary artery (LIMA). Herein, we described the determination of further treatments by measuring FFR via the LIMA in 2 cases after coronary artery bypass grafting (CABG). CASE SUMMARY: Case 1 was a 66-year-old male who was admitted due to "chest tightness after CABG." The patient underwent CABG 7 years prior due to coronary heart disease. Coronary artery angiography showed complete occlusion of the left anterior descending artery (LAD), and subtotal occlusion of the third segment of the right coronary artery. On arterial angiography, there was 85% stenosis at the distal end of the anastomosis of the LIMA-LAD graft. FFR via LIMA was determined at 0.75. Thus, balloon dilation was performed in Case 1. FFR after balloon dilation was 0.94. Case 2 was a 60-year-old male who was admitted due to "chest tightness after CABG." The patient underwent CABG 6 years prior due to coronary heart disease. There was 60% segmental stenosis in the middle segment of LAD and 75% anastomotic stenosis. FFR measured via LIMA was 0.83 (negative); thus the intervention was not performed. Case 2 was given drug treatments. At the 3-mo follow-up, there was no recurrence of chest tightness or shortness of breath in both cases. They are currently under continual follow-up. CONCLUSION: We provided evidence that FFR measurement via grafted blood vessels, especially LIMA, after CABG is a good method to determine the intervention course.

11.
Front Immunol ; 14: 1133899, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36865554

RESUMO

Radiotherapy is the major treatment of non-small cell lung cancer (NSCLC). The radioresistance and toxicity are the main obstacles that leading to therapeutic failure and poor prognosis. Oncogenic mutation, cancer stem cells (CSCs), tumor hypoxia, DNA damage repair, epithelial-mesenchymal transition (EMT), and tumor microenvironment (TME) may dominate the occurrence of radioresistance at different stages of radiotherapy. Chemotherapy drugs, targeted drugs, and immune checkpoint inhibitors are combined with radiotherapy to treat NSCLC to improve the efficacy. This article reviews the potential mechanism of radioresistance in NSCLC, and discusses the current drug research to overcome radioresistance and the advantages of Traditional Chinese medicine (TCM) in improving the efficacy and reducing the toxicity of radiotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Reparo do DNA , Sistemas de Liberação de Medicamentos , Transição Epitelial-Mesenquimal , Microambiente Tumoral
12.
Artigo em Inglês | MEDLINE | ID: mdl-36834384

RESUMO

Official guidelines state that suitable physical activity is recommended for patients with diabetes mellitus. However, since walking at a rapid pace could be associated with increased plantar pressure and potential foot pain, the footwear condition is particularly important for optimal foot protection in order to reduce the risk of tissue injury and ulceration of diabetic patients. This study aims to analyze foot deformation and plantar pressure distribution at three different walking speeds (slow, normal, and fast walking) in dynamic situations. The dynamic foot shape of 19 female diabetic patients at three walking speeds is obtained by using a novel 4D foot scanning system. Their plantar pressure distributions at the three walking speeds are also measured by using the Pedar in-shoe system. The pressure changes in the toes, metatarsal heads, medial and lateral midfoot, and heel areas are systematically investigated. Although a faster walking speed shows slightly larger foot measurements than the two other walking speeds, the difference is insignificant. The foot measurement changes at the forefoot and heel areas, such as the toe angles and heel width, are found to increase more readily than the measurements at the midfoot. The mean peak plantar pressure shows a significant increase at a faster walking speed with the exception of the midfoot, especially at the forefoot and heel areas. However, the pressure time integral decreases for all of the foot regions with an increase in walking speed. Suitable offloading devices are essential for diabetic patients, particularly during brisk walking. Design features such as medial arch support, wide toe box, and suitable insole material for specific area of the foot (such as polyurethane for forefoot area and ethylene-vinyl acetate for heel area) are essential for diabetic insole/footwear to provide optimal fit and offloading. The findings contribute to enhancing the understanding of foot shape deformation and plantar pressure changes during dynamic situations, thus facilitating the design of footwear/insoles with optimal fit, wear comfort, and foot protection for diabetic patients.


Assuntos
Diabetes Mellitus , Pé Diabético , Humanos , Feminino , Velocidade de Caminhada , , Caminhada , Calcanhar
13.
Eur J Neurol ; 30(11): 3462-3470, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36694359

RESUMO

BACKGROUND AND PURPOSE: Intestinal inflammation and gut microbiota dysbiosis contribute to Parkinson disease (PD) pathogenesis, and growing evidence suggests associations between inflammatory bowel diseases (IBD) and PD. Considered as markers of chronic gastrointestinal inflammation, elevated serum anti-Saccharomyces cerevisiae antibody (ASCA) levels, against certain gut fungal components, are related to IBD, but their effect on PD is yet to be investigated. METHODS: Serum ASCA IgG and IgA levels were measured using an enzyme-linked immunosorbent assay, and the gut mycobiota communities were investigated using ITS2 sequencing and analyzed using the Qiime pipeline. RESULTS: The study included 393 subjects (148 healthy controls [HCs], 140 with PD, and 105 with essential tremor [ET]). Both serum ASCA IgG and IgA levels were significantly higher in the PD group than in the ET and HC groups. Combining serum ASCA levels and the occurrence of constipation could discriminate patients with PD from controls (area under the curve [AUC] = 0.81, 95% confidence interval [CI] = 0.76-0.86) and from patients with ET (AUC = 0.85, 95% CI = 0.79-0.89). Furthermore, the composition of the gut fungal community differed between the PD and HC groups. The relative abundances of Saccharomyces cerevisiae, Aspergillus, Candida solani, Aspergillus flavus, ASV601_Fungi, ASV866_Fungi, and ASV755_Fungi were significantly higher in the PD group, and enriched Malassezia restricta was found in the HC group. CONCLUSIONS: Our study identified elevated serum ASCA levels and enriched gut Saccharomyces cerevisiae in de novo PD.

14.
Small ; 19(9): e2205246, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36581560

RESUMO

Boosting charge separation and transfer of photoanodes is crucial for providing high viability of photoelectrochemical hydrogen (H2 ) generation. Here, a structural engineering strategy is designed and synthesized for uniformly coating an ultrathin CoFe bimetal-organic framework (CoFe MOF) layer over a BiVO4 photoanode for boosted charge separation and transfer. The photocurrent density of the optimized BiVO4 /CoFe MOF(NA) photoanode reaches a value of 3.92 mA cm-2 at 1.23 V versus reversible hydrogen electrode (RHE), up to 6.03 times that of pristine BiVO4 , due to the greatly increased efficiency of charge transfer and separation. In addition, this photoanode records one onset potential that is considerably shifted negatively when compared to BiVO4 . Transient absorption spectroscopy reveals that the CoFe MOF(NA) prolongs charge recombination lifetime by blocking the hole-transfer pathway from the BiVO4 to its surface trap states. This work sheds light on boosting charge separation and transfer through structural engineering to enhance the photocurrent of photoanodes for solar H2 production.

15.
Antioxid Redox Signal ; 38(10-12): 747-767, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36242096

RESUMO

Aims: Radiation by-radiation effect (RIBE) can induce the genomic instability of bone marrow mesenchymal stem cells (BMSCs) adjacent to lung cancer, and this effect not only exists in the short-term, but also accompanies it in the long-term, but its specific mechanism is not clear. Our goal is to explore the similarities and differences in the mechanism of genomic damage in tumor-associated BMSCs induced by short-term and long-term RIBE, and to provide a theoretical basis for adjuvant drugs for protection against RIBE at different clinical time periods. Results: We found that both short- and long-term RIBE induced genomic instability. We could show a high expression of TGF-ß1, TNF-α, and HIF-1α in tumor-associated BMSCs after short-term RIBE whereas only TNF-α and HIF-1α expression was increased in long-term RIBE. We further confirmed that genomic instability is associated with the activation of the HIF-1α pathway and that this is mediated by TNF-α and TGF-ß1. In addition, we found differences in the mechanisms of genomic instability in the considered RIBE windows of analysis. In short-term RIBE, both TNF-α and TGF-ß1 play a role, whereas only TNF-α plays a decisive role in long-term RIBE. In addition, there were differences in BMSC recruitment and genomic instability of different tissues with a more pronounced expression in tumor and bone marrow than compared to lung. Innovation and Conclusion: We could show dynamic changes in the expression of the cytokines TGF-ß1 and TNF-α during short- and long-term RIBE. The differential expression of the two is the key to causing the genomic damage of tumor-associated BMSCs in the considered windows of analysis. Therefore, these results may serve as a guideline for the administration of radiation protection adjuvant drugs at different clinical stages. Antioxid. Redox Signal. 38, 747-767.


Assuntos
Efeito Espectador , Instabilidade Genômica , Células-Tronco Mesenquimais , Fator de Crescimento Transformador beta1 , Fator de Necrose Tumoral alfa , Efeito Espectador/efeitos da radiação , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Células-Tronco Mesenquimais/efeitos da radiação , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Células A549 , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Apoptose/genética , Animais , Camundongos , Camundongos Endogâmicos C57BL
18.
Cancer Gene Ther ; 29(6): 770-783, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34145425

RESUMO

Primary cytoreductive surgery with platinum-taxane-based chemotherapy is the standard treatment for ovarian cancer (OC) patients; however, resistance to chemotherapy is a contributing factor to OC mortality. Paclitaxel (PTX), the most widely used taxane, has become the first-line drug against OC. The molecular mechanism of PTX resistance is different from that of platinum-based agents and is still not completely elucidated. Our previous study showed that glucose-regulated protein 78 (GRP78) is involved in the resistance of OC cells to PTX. However, little is known regarding endogenous inhibitors of this gene. MicroRNAs (miRNAs) play critical roles in the regulation of gene expression; therefore, we sought to identify miRNA(s) with potential to target GRP78 under the hypothesis that miRNA(s) could serve as potential therapeutic targets. Here, we show that miR-181c, predicted to target GRP78, was downregulated in PTX-resistant OC cells and tissues. MiR-181c downregulated GRP78 expression and induced apoptosis by directly targeting its 3'-untranslated region (UTR). Overexpression of miR-181c sensitized resistant OC to PTX by inhibiting the PI3K/Akt pathway in vitro and in vivo. Taken together, our findings indicate that the delivery of miR-181c can efficiently suppress GRP78 expression and GRP78-mediated PTX resistance in OC and suggest that this strategy has therapeutic potential.


Assuntos
MicroRNAs , Neoplasias Ovarianas , Regiões 3' não Traduzidas , Carcinoma Epitelial do Ovário/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Chaperona BiP do Retículo Endoplasmático/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
19.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(6): 1812-1818, 2021 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-34893116

RESUMO

OBJECTIVE: To investigate the effect of gap junction intercellular communication (GJIC) combined by connexin43 (Cx43) and its signal to the biobehavior of multiple myeloma (MM) cells, and its possible mechanism. METHODS: The mesenchymal stem cell (MSC) cells were isolated and cultured from patients with MM and normal donors. The expression of connexin43 (Cx43) in MSC cells from different sources was detected by RT-PCR and Western blot. The side population (SP) cells were sorted by flow cytometry (FCM). The effect of MSC cells from different sources to the cell cycle, Cx43 expression, colony formation in vitro, stem cell related genes expression, cytokines secretion and chemoresistance in MM SP cells as well as with or without Cx43 inhibitor 18α-glycyrrhetinic acid (18α-GA) was observed. RESULTS: There was no significantly difference between the MSC isolated from normal donor and MM patients. Western blot showed that Cx43 expression in SP cells was up-regulated when the cells were incubated with MSC, and medium containing 18α-GA could partially inhibit it, moreover, it was more significant in MSC cells of MM patients. The ability of colony formation of SP cells in vitro was higher than those of MM cells and MM-MSC could promote the colony formation in a co-culture manner. The effect of MM-MSC to SP cells was down-regulated after 18α-GA was added. RT-PCR showed that there was several important stem cell-related genes including c-myc, Oct-4 Klf-4, and Sox-2 were found in RPMI 8226 cells, but those cells were up-regulated in SP cells (P<0.001). Meanwhile, MM-MSC could up-regulate the expression of c-myc, Klf-4 and Sox-2 (P<0.001), but down-regulate Oct-4 gene in the SP cells. The expression of those genes decreased after 18α-GA was added, but showed no significant difference (P>0.05). Cytometry bead array assays showed that MM-MSCs could secrete high level of IL-6, but the levels of IL-6, IL-10 and TGF-ß increased significantly when the MM-MSCs were co-cultured with SP cells (P<0.05), especially the levels of IL-6 and IL-10 were significantly higher than cultured alone. There was no significant change in the levels of bFGF and IL-17 before and after co-cultured. The levels of IL-6, IL-10 and TGF-ß in supernatant decreased significantly after GJ inhibitor 18α-GA was added. PI/Annexin V assay showed that MM cells were sensitive to bortezomib (BTZ)-induced apoptosis, but the sensitivity for SP cells was weaker. The ratio of cell apoptosis was 75.2%±0.77% and 8.12%±0.86% (P<0.001), respectively. MM-MSC could down-regulate the cell apoptosis induced by BTZ, while the sensitivity of MM cells to BTZ could be partially recovered after GJ inhibitor was added. CONCLUSION: MSC derived from MM patients can enhance GJIC to maintain its "hematopoiesis" by up-regulating the expression of Cx43 in MM cells, and at the same time promote cell proliferation and drug recistance by secreting multiple cytokines, which finally contributes to the relapse of MM.


Assuntos
Células-Tronco Mesenquimais , Mieloma Múltiplo , Comunicação Celular , Técnicas de Cocultura , Conexina 43 , Humanos
20.
Langmuir ; 37(49): 14275-14283, 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34846900

RESUMO

Herein, a 1D zinc coordination polymer [Zn(bibp)Cl2]∞ (CP-2-ZX) was assembled from the reaction of 4,4'-bis(imidazol-1-yl)-biphenyl (bibp) with ZnCl2. Through a calcination-thermolysis strategy, sponge-like highly porous carbon AC-Zn-CP was prepared by employing the coralloid sample of CP-2-ZX as the precursor. For comparisons, a series of activated carbon (AC-n) was obtained by the similar heating process on the mixture of bibp with ZnCl2 at different mass ratios. The results illustrate that the atomically dispersed ZnCl2 dot in the 1D chain of CP-2-ZX has an in situ activation effect on the generation of AC-Zn-CP, which can greatly promote the porosity and achieve high-efficiency utilization of ZnCl2. Therefore, the atomically dispersed activating agent provides a new method for environmentally friendly production of porous carbon materials. Significantly, the AC-Zn-CP electrode displays specific capacitance of 215 F g-1 in 3 M KOH solution, which will be largely promoted to 1419 F g-1 in the redox active electrolyte of K3[Fe(CN)6]/KOH. AC-Zn-CP also shows remarkable cycling stability (the capacity retention is 89.0% after 5000 cycles). Moreover, the fabricated symmetric supercapacitor owns a high energy density of 34.8 Wh kg-1 at 785.5 W kg-1. So, the AC-Zn-CP∩K3[Fe(CN)6] system has wide application prospects in supercapacitors.

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