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The feasibility and performance of using calcined coal gangue (CCG) to substitute metakaolin (MK) as the precursor to prepare alkali-activated materials (AAMs) were thoroughly evaluated by conducting combined experiments of flowability test, mechanical measurement, calorimetry and microstructure analysis, etc. It was found that the increased substitution ratio of CCG to MK can increase the flowability of the prepared paste by up to 28.1% and decrease its viscosity by up to 55.8%. In addition, a prolonged setting time of up to 31.8% was found with the increased substitution amount of CCG to MK, which can be attributed to the low reactivity of CCG compared to that of MK. Lastly, even though the presence of CCG can lead to a decrease in the early compressive strength of the hardened paste, a highly recovered long-term mechanical property can be found due to the continuous reaction of CCG. All of these results prove the feasibility of using CCG as one co-blended precursor with MK to prepare alkali-activated materials.
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Double fertilization in many flowering plants (angiosperms) often occurs during the hot summer season, but the mechanisms that enable angiosperms to adapt specifically to high temperatures are largely unknown. The actin cytoskeleton is essential for pollen germination and the polarized growth of pollen tubes, yet how this process responds to high temperatures remains unclear. Here, we reveal that the high thermal stability of 11 Arabidopsis (Arabidopsis thaliana) actin-depolymerizing factors (ADFs) is significantly different: ADFs that specifically accumulate in tip-growing cells (pollen and root hairs) exhibit high thermal stability. Through ancestral protein reconstruction, we found that subclass II ADFs (expressed specifically in pollen) have undergone a dynamic wave-like evolution of the retention, loss, and regeneration of thermostable sites. Additionally, the sites of AtADF7 with high thermal stability are conserved in ADFs specific to angiosperm pollen. Moreover, the high thermal stability of ADFs is required to regulate actin dynamics and turnover at high temperatures to promote pollen germination. Collectively, these findings suggest strategies for the adaptation of sexual reproduction to high temperature in angiosperms at the cell biology level.
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Proteínas de Arabidopsis , Arabidopsis , Factores Despolimerizantes de la Actina/metabolismo , Actinas/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Temperatura , Germinación/genética , Arabidopsis/metabolismo , Polen/metabolismo , Tubo PolínicoRESUMEN
All living organisms are subjected to mechanical forces at all times. It has been reported that mechanics regulate many key cellular processes, including cell polarity establishment, cell division and gene expression, as a physical signal in both animal and plant development. Plant cells are exposed to several types of mechanical stresses, ranging from turgor-driven tensile stresses, mechanical force modified by heterogeneous growth directions and rates between neighbouring cells, to forces from the environment such as wind and rain, for which they have developed adaptive mechanisms. Increasing evidence has revealed that mechanical stresses markedly influence the alignment of cortical microtubules (CMTs) in plant cells, among other effects. CMTs are able to reorient in response to mechanical stresses at both the single-cell and tissue levels and always align with the maximal tensile stress direction. In this review, we discussed the known and potential molecules and pathways involved in the regulation of CMTs by mechanical stresses. We also summarized the available techniques that have allowed for mechanical perturbation. Finally, we highlighted several key questions remaining to be addressed in this emerging field.
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Microtúbulos , Células Vegetales , Animales , Células Vegetales/fisiología , Microtúbulos/metabolismo , Estrés Mecánico , Desarrollo de la PlantaRESUMEN
Boron-doped carbon materials (BCs), low-cost and environmentally friendly carbocatalysts, were prepared for the activation of persulfate (PS) for the removal of bisphenol A (BPA). Compared with B-free carbon materials (Cs), the adsorption and catalytic activity were significantly enhanced by the boron modification. Fast and efficient removal of BPA was achieved using the BCs/PS system. The BPA removal rate constant increased linearly with the adsorption capacity of BCs. Electron paramagnetic resonance (EPR) spectroscopy and radical quenching experiments indicated that the degradation mechanisms in the BCs/PS system were different from conventional radical-based oxidation pathways. On the contrary, nonradical pathways were demonstrated to dominate the oxidation processes in the removal of BPA using the BCs/PS system. Herein, a mechanism is proposed where PS is activated by the carbon material to form a reactive electron-deficient carbocatalyst ([BCs]*) complex with a high redox potential, driving a nonradical oxidation pathway to achieve BPA removal. Through experimental investigation and the use of electrochemical techniques (cyclic voltammetry, Tafel corrosion analysis and open circuit voltages), B-doped carbon materials for the activation of PS elevate the potential of the derived nonradical [BCs]* complexes, and then accelerate the BPA removal efficiency via an electron transfer process. Utilizing adsorption and nonradical oxidation processes, the BCs/PS system possesses great potential for the removal of BPA in practical applications such as wastewater treatment.
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PURPOSE: The etiology and pathology of granulomatous mastitis (GLM) are still unknown. Expert consensus on the treatment of GLM has not been developed. The objective of this study is to study the effectiveness of traditional Chinese medicine (TCM) combined with surgery in treating GLM. MATERIALS AND METHODS: A retrospective cohort study was implemented at Longhua Hospital of Shanghai University of Traditional Chinese Medicine in China between September 2019 and August 2021. Female patients were included according to the propensity-score matching (PSM) method and balanced according to age and BMI. Patients with GLM diagnosed by pathology and a course of disease ≥ 6 months were included in this trial. Patients were divided into the TCM alone group or TCM + surgery group. RESULTS: In total, 168 female patients were assessed and 102 patients were included in the study after PSM (51 in the TCM group and 51 in the TCM + surgery group). The average age of the patients was 32 years (21-47 years). There was no significant baseline characteristics difference between two groups after PSM. The suppuration rate in the TCM + surgery group was less than that in the TCM group (64.7% vs. 83.35%, P < 0.05), and the TCM + surgery group had a higher 9-month cure rate than the TCM group (86.3% vs. 52.9%, P < 0.05). The full course of disease in the TCM + surgery group was shorter than that in the TCM group (253.9 ± 117.3 days vs. 332.5 ± 111.6 days, P < 0.05). CONCLUSIONS: TCM combined with surgery can improve the cure rate and shorten the full course of GLM treatment, indicating surgery should be integrated in the clinical management of GLM.
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Dehydrins, also known as Group II late embryogenesis abundant (LEA) proteins, are classic intrinsically disordered proteins, which have high hydrophilicity. A wide range of hostile environmental conditions including low temperature, drought, and high salinity stimulate dehydrin expression. Numerous studies have furnished evidence for the protective role played by dehydrins in plants exposed to abiotic stress. Furthermore, dehydrins play important roles in seed maturation and plant stress tolerance. Hence, dehydrins might also protect plasma membranes and proteins and stabilize DNA conformations. In the present review, we discuss the regulatory networks of dehydrin gene expression including the abscisic acid (ABA), mitogen-activated protein (MAP) kinase cascade, and Ca2+ signaling pathways. Crosstalk among these molecules and pathways may form a complex, diverse regulatory network, which may be implicated in regulating the same dehydrin.
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Fenómenos Fisiológicos de las Plantas , Proteínas de Plantas/metabolismo , Plantas/metabolismo , Ácido Abscísico/metabolismo , Señalización del Calcio , Regulación de la Expresión Génica de las Plantas , Sistema de Señalización de MAP Quinasas , Estrés FisiológicoRESUMEN
1H spin-lattice relaxometry (T1, longitudinal) of cement pastes with 0 to 0.18 wt % polycarboxylate superplasticizers (PCEs) at intervals of 0.06 wt % from 10 min to 1210 min was investigated. Results showed that the main peak in T1 relaxometry of cement pastes was shorter and lower along with the hydration times. PCEs delayed and lowered this main peak in T1 relaxometry of cement pastes at 10 min, 605 min and 1210 min, which was highly correlated to its dosages. In contrast, PCEs increased the total signal intensity of T1 of cement pastes at these three times, which still correlated to its dosages. Both changes of the main peak in T1 relaxometry and the total signal intensity of T1 revealed interferences on evaporable water during cement hydration by dispersion mechanisms of PCEs. The time-dependent evolution of weighted average T1 of cement pastes with different PCEs between 10 min and 1210 min was found regular to the four-stage hydration mechanism of tricalcium silicate.
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One new flue gas desulfurization (FGD) gypsum-based binder is attempted in this article, which is made up of FGD gypsum, ground granulated blast furnace slag (GGBS) and ordinary Portland cement (OPC). Influences of raw materials, chemical activators, and curing conditions on the compressive strength of this new binder-based mortar, as well as its durability performances and microscopic characteristics, are investigated in consideration of utilizing FGD gypsum as much as possible. Results show that the compressive strength of this new binder-based mortar under normal curing conditions could increase along with GGBS dosages from three days to 90 days. The compressive strength of one selected mix proportion (FG-4550), which contains the highest dosage of FGD gypsum (45 wt.%), is much the same as those containing the highest dosage of GGBS. A better compressive strength of FG-4550 under normal curing conditions could be gained if the fineness of GGBS is improved. The activated effect of CaCl2 on the compressive strength of FG-4550 is superior to that of Ca(OH)2 under steam curing conditions. FG-4550 shows a good capacity for resistance to water, a low shrinkage ratio, but poor compressive strength after 30 freeze-thaw cycles. Based on the mineralogy of X-ray diffraction, the morphology of scanning electron microscopy and the pore diameter distributions of 1H nuclear magnetic resonance, the compressive strength of this FGD gypsum-based mortar mainly depends on clusters of ettringite.
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Influences of phosphorus slag from 10% to 50% (by mass) on the setting time and the water requirement of the normal consistency of cement pastes, flowability, resistance to carbonation, and the compressive strength of cement mortars were investigated. The physical activation by improving fineness and the chemical activation by adding the chemical activator were evaluated by the compressive strength of cement mortars with 30% by mass of phosphorus slag. Hydration heat, X-ray diffraction, and scanning electron microscopy were used to study the microstructure of cement pastes and mortars with 30% by mass of phosphorus slag and the chemical activator. Results showed that the setting time of cement pastes was delayed by phosphorus slag from 10% to 50%. Phosphorus slag had nearly no effects on the water requirement of the normal consistency of cement pastes and the flowability of cement mortars. The resistance to carbonation of cement mortars was decreased by phosphorus slag from 10% to 50% according to the acceleration carbonation. The compressive strength of cement mortars was also decreased by phosphorus slag from 10% to 50% and the low activity of phosphorus slag was concluded based on compressive strength of cement mortars. The effect of the chemical activator on the compressive strength of cement mortars with 30% by mass of phosphorus slag was better than improving fineness of phosphorus slag from 300 m2/kg to 450 m2/kg. Both hydration heat and cement hydrates were inhibited by phosphorus slag and could be partly compensated by the chemical activator. Loose morphology and propagations of microcracks were found in cement pastes and mortars with 30% by mass of phosphorus slag.
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Bone metastasis of breast cancer causes severe skeletal-related events and poor prognosis. Wensheng Zhuanggu Formula (WSZG), a traditional Chinese prescription, is used to adjunctively treat breast cancer bone metastases in clinical practice. This study was undertaken to investigate the antibone-metastatic activities and mechanisms of WSZG extract by evaluating the effect of this formula on the cross-talk between bone marrow-derived mesenchymal stem cells (BMSCs) and breast cancer cells in triggering epithelial-mesenchymal transition (EMT) in vivo and in vitro. The results demonstrated that BMSCs might enhance the invasive and metastatic potentials of breast cancer cells as a consequence of EMT induction through direct cell-to-cell contact. WSZG treatment remarkably suppressed motility, invasion, EMT-related gene, and protein markers in BMSC-conditioned breast cancer cells and ameliorated bone metastases and damages in nude mice following co-injection of BMSCs and MDA-MB-231BO breast cancer cells. Further investigation showed that the transforming growth factor-ß1 (TGF-ß1)/Smads pathway was an important mechanism enabling BMSCs to induce EMT occurrence of breast cancer cells. WSZG treatment reversed BMSC-induced EMT by downregulating TGF-ß1/Smads signaling. Thus, WSZG extracts may be regarded as a potential antibone-metastatic agent for breast cancer therapy.
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Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Medicamentos Herbarios Chinos/uso terapéutico , Transición Epitelial-Mesenquimal , Células Madre Mesenquimatosas/metabolismo , Transducción de Señal , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Apoptosis/efectos de los fármacos , Neoplasias Óseas/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Regulación hacia Abajo/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Extractos Vegetales/uso terapéutico , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
It is challenging to achieve robust lane detection based on a single frame, particularly when complicated driving scenarios are present. A novel approach based on multiple frames is proposed in this paper by taking advantage of the fusion of vision and Inertial Measurement Units (IMU). Hough space is employed as a storage medium where lane markings can be stored and visited conveniently. The detection of lane markings is achieved by the following steps. Firstly, primary line segments are extracted from a basic Hough space, which is calculated by Hough Transform. Secondly, a CNN-based classifier is introduced to measure the confidence probability of each line segment, and transforms the basic Hough space into a probabilistic Hough space. In the third step, pose information provided by the IMU is applied to align previous probabilistic Hough spaces to the current one and a filtered probabilistic Hough space is acquired by smoothing the primary probabilistic Hough space across frames. Finally, valid line segments with probability higher than 0.7 are extracted from the filtered probabilistic Hough space. The proposed approach is applied experimentally, and the results demonstrate a satisfying performance compared to various existing methods.
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Influence of polycarboxylate superplasticizers (PCs) with different functional units on the hydration heat and hydration products of C3A-gypsum was investigated. Three kinds of PCs with different monomers were discussed. It was seen that PCs mainly shortened the induction stage of C3A-gypsum hydration, and the amount of remaining gypsum was related to the duration of the induction stage. The second heat flow peak of the sample with PCs was higher than that of the blank. Moreover, PC intercalation occurred during the hydration.
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In this study, the setting property and mechanical strength of cement pastes containing accelerators (CPCA) with or without superabsorbent polymers (SAPs) were first studied. The early microstructure evolution and water distribution at 7 and 28 days were probed by 1D (T2) and 2D (T1-T2 maps) H¹ nuclear magnetic resonance (NMR) relaxometry, and the microstructure was systematically investigated by using mercury intrusion porosimetry (MIP), back-scattered electron (BSE) image and energy-dispersive X-ray spectroscopy (EDX) analysis. Results showed that the SAPs in the cement paste containing accelerators had various influences on setting time and compressive strength depending on the type of accelerators. The presence of SAPs in the cement paste containing alkaline free accelerators could alleviate the decrease of internal relative humidity, promote hydration and help to modify the pore structure. Moreover, it was observed that the SAP cavities could be nicely filled with calcium hydroxide (CH) in the cement paste with alkaline free accelerators.
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ETHNOPHARMACOLOGICAL RELEVANCE: Advanced breast cancer frequently metastasizes to the bone, resulting in patient morbidity and mortality. The interaction of tumor cells with osteoclasts and osteoblasts seriously affects the occurrence and development of bone metastasis in breast cancer. The signaling crosstalk among the Jagged1/Notch, TGF-ß and IL-6 signaling pathways plays a significant role in the context of bone metastasis. AIM OF THE STUDY: Although Wenshen Zhuanggu (WSZG) formula efficiently decreased the risk of bone metastases in tumor-bearing mice, it remains unclear how WSZG formula regulates the interaction of cancer cells with osteoclasts and osteoblasts in bone metastasis of breast cancer. MATERIALS AND METHODS: In this study, we investigated the role of WSZG formula in the progress of bone metastasis in breast cancer and focused on the cell-cell interactions of tumor cells with osteoclasts and osteoblasts. Western blotting and quantitative real-time PCR were utilized to evaluate the inhibitory activities of WSZG formula on Jagged1 expression both in vivo and in vitro. Osteoblast co-culture and osteoclastogenesis co-culture were applied to analyze the effects of WSZG formula on the interaction of tumor cells with osteoclasts and osteoblasts. A breast cancer xenograft model was also used to test the inhibitory effects of WSZG formula on bone metastasis in breast cancer. RESULTS: WSZG formula decreased Jagged1 expression in osteolytic lesions in the breast cancer xenograft model. Additionally, WSZG formula decreased Jagged1 expression in tumor cell culture alone or co-culture with pre-osteoclasts and osteoblasts. In addition, WSZG formula decreased Jagged1 expression in Jagged1-overexpressing tumor cells. CONCLUSION: The results of this study suggest that WSZG formula mitigates breast cancer bone metastasis through the Jagged1/Notch signaling pathway mediated by TGF-ß and IL-6.
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Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Animales , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular , Técnicas de Cocultivo , Femenino , Humanos , Interleucina-6/metabolismo , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos , Ratas Sprague-Dawley , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Wenshen Zhuanggu Formula (WSZG) is a traditional Chinese medicine (TCM) prescription used in clinics for adjuvant treatment of breast cancer bone metastases in Longhua Hospital in China. WSZG has been reported to decrease the risk of bone metastases and alleviate the severity of bone lesions in a breast cancer xenograft model. AIM OF THE STUDY: The present study aimed at investigating the pharmacokinetic behaviors of six coumarins in normal and breast cancer bone-metastatic mice following oral administration of WSZG extract. MATERIALS AND METHODS: A bone-metastatic mouse model was established by intracardiac injection of MDA-MB-231BO breast cancer cells, and WSZG extract (1.60â¯g/kg) was given orally to the model and normal mice for 4 weeks. Then, the blood pharmacokinetic parameters of six bioactive components from WSZG (psoralen, isopsoralen, bergapten, xanthotoxin, osthole, and imperatorin) were analyzed by liquid chromatography tandem mass spectrometry. RESULTS: There were significant differences in pharmacokinetic behaviors between normal and pathological states. Compared with normal mice, the model mice showed significantly increased AUC0-t and AUC0-∞ of the bioactive compounds (Pâ¯<â¯0.05) and significantly decreased total blood clearance (CLZ/F) (Pâ¯<â¯0.05). CONCLUSIONS: The different pharmacokinetic behaviors might be partly ascribed to intestinal functional disorders and imbalance of gastrointestinal microbiota under the morbid state. The findings provide some valuable information to evaluate the clinical efficacy and safety of this TCM formula.
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Antineoplásicos/farmacocinética , Neoplasias Óseas/metabolismo , Cumarinas/farmacocinética , Neoplasias Mamarias Experimentales/metabolismo , Extractos Vegetales/farmacocinética , Administración Oral , Animales , Antineoplásicos/sangre , Antineoplásicos/uso terapéutico , Neoplasias Óseas/sangre , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Línea Celular Tumoral , Cumarinas/sangre , Cumarinas/uso terapéutico , Femenino , Humanos , Neoplasias Mamarias Experimentales/sangre , Neoplasias Mamarias Experimentales/tratamiento farmacológico , Neoplasias Mamarias Experimentales/patología , Ratones Endogámicos BALB C , Ratones Desnudos , Extractos Vegetales/sangre , Extractos Vegetales/uso terapéuticoRESUMEN
Triple negative breast cancer (TNBC) has the lowest survival rate of the breast cancer subtypes owing to its aggressive and metastatic behavior. It has been reported that peritumoral adipose tissue contributes to the cell invasiveness and dissemination of TNBC. Emodin is an active anthraquinone derivative isolated from Rheum palmatum, with anticancer properties that have been reported to inhibit lung metastasis in a nude mouse xenograft model. In the present study, the effects of emodin on human TNBC cells and adipocytes were investigated in vivo and in vitro. The TNBC cell lines MDAMB231 and MDAMB453 were cocultured with human adipocytes and treated with either emodin or epirubicin. Cell proliferation was assessed by MTT assay and migration and invasion were examined using a wound healing assay and a Transwell assay. interleukin8, CCchemokine ligand 5 (CCL5) and insulinlike growth factor1 levels in the culture supernatants were detected by ELISA. The epithelialmesenchymal transition (EMT) or metastasis associated markers were determined by western blot analysis. Nude mice fed with a high fat and sugar diet were used investigate the in vivo effect of emodin. The results showed that emodin inhibited TNBC proliferation and invasion more efficiently than epirubicin when cocultured with adipocytes by downregulating the level of CCL5 in adipocyte supernatants; inhibiting the expression level of protein kinase B (AKT); and activating glycogen synthase kinase3i (GSK3) and ßcatenin. This led to the suppressed expression of EMT and invasionassociated markers, including vimentin, snail, matrix metalloproteinase (MMP)2 and MMP9, and upregulation of Ecadherin, contributing to the inhibition of invasion. The in vivo assay showed that emodin inhibited tumor growth, and suppressed the lung and liver metastasis of TNBC cells by decreasing the secretion of CCL5 in mice fed a high fat and sugar diet more efficiently when compared with epirubicin. In conclusion, emodin inhibited the secretion of CCL5 from adipocytes, inhibited the EMT of TNBC cells, and inhibited tumor growth and lung and liver metastasis, which indicated a novel role of emodin in preventing the metastasis of TNBC.
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Adipocitos/metabolismo , Quimiocina CCL5/antagonistas & inhibidores , Quimiocina CCL5/metabolismo , Emodina/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/patología , Adipocitos/efectos de los fármacos , Adulto , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Epirrubicina/farmacología , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Transducción de Señal/efectos de los fármacosRESUMEN
Bone is one of the most common sites for breast cancer metastasis, which greatly contributes to patient morbidity and mortality. Osthole, a major extract from Cnidium monnieri (L.), exhibits many biological and pharmacological activities, however, its potential as a therapeutic agent in the treatment of breast cancer bone metastases remain poorly understood. In this study, we set out to investigate whether osthole could inhibit breast cancer metastasis to bone in mice and clarified the potential mechanism of this inhibition. In the murine model of breast cancer osseous metastasis, mice that received osthole developed significantly less bone metastases and displayed decreased tumor burden when compared with mice in the control group. Osthole inhibited breast cancer cell growth, migration, and invasion, and induced apoptosis of breast cancer cells. Additionally, it also regulated OPG/RANKL signals in the interactions between bone cells (osteoblasts and osteoclasts) and cancer cells. Besides, it also inhibited TGF-ß/Smads signaling in breast cancer metastasis to bone in MDA-231BO cells. The results of this study suggest that osthole has real potential as a therapeutic candidate in the treatment of breast cancer patients with bone metastases.
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Wenshen Zhuanggu formula (WSZG) is a traditional Chinese medicine used as an adjuvant for the prevention of bone metastases in breast cancer patients. In this study we investigated the efficacy of WSZG in preventing bone metastases and the potential mechanisms in a mouse xenograft model of breast cancer bone metastases. This model was established by injection of human MDA-MB-231BO-Luc breast cancer cells alone or a mixture of the cancer cells with bone marrow-derived mesenchymal stem cells (BMSCs) into left ventricle of the heart in female nude mice. Then the mice were treated with WSZG (3.25, 6.5 or 13.0 mg·kg-1·d-1, ig) for four weeks, whereas zoledronic acid (100 µg/kg per week, ig) was used as a positive control. The occurrence and development of bone metastases were monitored via bioluminescent imaging, and bone lesions were assessed using micro-CT. Intracardiac injection of the mixture of MDA-MB-231BO-Luc breast cancer cells with BMSCs significantly facilitated the bone metastatic capacity of the breast cancer cells, and aggravated bone lesions in the mouse xenograft model of breast cancer bone metastases. Administration of WSZG dose-dependently inhibited the incidence and intensity of bone metastases and protected against bone lesions by suppressing osteoclast formation and tumor cell infiltration. Furthermore, administration of WSZG caused a marked reduction in the expression of CCL5/CCR5 and IL-17B/IL-17BR in bone metastatic tissues. The results demonstrate that WSZG exerts potential therapeutic effects in a mouse xenograft model of breast cancer bone metastases, which are partially mediated by weakening the interaction between BMSCs and breast cancer cells in the tumor microenvironment.
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Antineoplásicos/farmacología , Neoplasias Óseas/prevención & control , Neoplasias de la Mama/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Antineoplásicos/administración & dosificación , Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Difosfonatos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Imidazoles/farmacología , Células Madre Mesenquimatosas/citología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Osteoclastos/metabolismo , Extractos Vegetales/administración & dosificación , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Ácido ZoledrónicoRESUMEN
The formation of tumor-promoting premetastatic microenvironment plays a pivotal role on metastatic progression. Understanding how the primary tumor can promote the formation of premetastatic microenvironment in the lung will aid discovery of a final cure for metastatic breast cancer. The murine 4T1 mammary carcinoma cells were injected into the mammary fat pads of the BALB/c mice. Days 0-14 were considered the premetastatic phase. Lung tissues were examined using hematoxylin-eosin staining and transmission electron microscopy. After intravenous injection of TGFß1 pretreated 4T1 cells, the relative pulmonary vascular permeability was quantified, the extravasation, survival, and proliferation of tumor cells in premetastatic lungs were evaluated, and the levels of S100A8, S100A9, VEGF, and Angpt2 were detected in tumor-bearing mice. The results showed that during the premetastatic phase, an inflammatory response and inflammation-induced vascular hyperpermeability were established, leading to an abnormal pulmonary microenvironment, which facilitated extravasation of circulating tumor cells, and subsequent survival and proliferation of metastatic tumor cells in a TGFß-dependent manner. Moreover, the expressions of S100A8, S100A9, VEGF, and Angpt2 were increased, and an induction of these genes by TGFß was further observed in premetastatic lungs. Thus, this study demonstrated that TGFß promoted the creation of premetastatic microenvironment by modulating certain crucial inflammatory cytokines and growth factors, and finally enhanced the ability of circulating cells to seed the lung.
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Citocinas/metabolismo , Mediadores de Inflamación/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Factor de Crecimiento Transformador beta/metabolismo , Microambiente Tumoral , Angiopoyetina 2/genética , Angiopoyetina 2/metabolismo , Animales , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Permeabilidad Capilar , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Modelos Animales de Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/ultraestructura , Ratones , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Metastatic breast cancer often metastasizes to bone. The purposes of the study were (1) to evaluate the use of (99m)Tc-MDP bone scintigraphy for detection of metastatic bone lesions, and (2) to determine the efficacy of zoledronic acid in mice with breast cancer bone metastasis. All tumor-bearing mice were analyzed with radionuclide bone scintigraphy, X-ray, and histological analysis. The metastatic bone tissue was also harvested and analyzed by western blotting and real-time qPCR. Interestingly, zoledronic acid significantly decreased both the tumor burden and the incidence of bone metastasis in mice. In addition, histomorphometric, stereological, and molecular biology analyses demonstrated that zoledronic acid may function to inhibit breast cancer cell growth in the bone microenvironment and regulate the function of osteoblasts and osteoclasts in tumor-bearing mice. Finally, the attenuation of breast cancer bone metastasis using zoledronic acid can be accurately characterized by (99m)Tc bone scintigraphy in mice.