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AIMS: This study aimed to explore the correlation between homeostasis model assessment of insulin resistance(HOMA-IR)and cardiometabolic risk index(CMRI) among different metabolic adults to evaluate the value of HOMA-IR in predicting cardiometabolic risk. METHODS: This cross-sectional study was conducted over 18 months (from August 1, 2020 to February 18, 2022) and included 1550 participants divided into non-metabolic syndrome (non-MetS) group (n = 628) and metabolic syndrome (MetS) group (n = 922) in three centers of China. Logistic regression analysis was employed to investigate the correlation between HOMA-IR, body fat percentage, BMI (body mass index), visceral fat index, waist-to-hip ratio, vitamin D, and CMRI. Further analysis was conducted to evaluate the ability of HOMA-IR in diagnosing high CMRI within different metabolic, gender, and age groups to predict the risk of cardiovascular disease (CVD). RESULTS: HOMA-IR was significantly higher in the MetS group compared with the non-MetS group (P < 0.05). CMRI was significantly higher in the MetS group compared to the non-MetS group (P < 0.05). According to ROC curve analysis, HOMA-IR can predict cardiovascular risk (CVR) in the general population, non-MetS individuals, and MetS people. Logistic regression analysis revealed that BMI, visceral fat index, waist-to-hip ratio, and HOMA-IR are independent risk indicators of high CVR, whereas vitamin D may exert a protective role. CONCLUSIONS: HOMA-IR was an independent risk factor for increased CVR in MetS patients. Moreover, HOMA-IR elevates the risk of CVD regardless of MetS and thus can be used for screening the general population. TRIAL REGISTRATION: The study was registered at the Chinese Clinical Trial Registry (Registration Number: ChiCTR2100054654).
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Fenamates as classical nonsteroidal anti-inflammatory agents are widely used for relieving pain. Preclinical studies and epidemiological data highlight their chemo-preventive and chemotherapeutic potential for cancer. However, comprehensive reviews of fenamates in cancer are limited. To accelerate the repurposing of fenamates, this review summarizes the results of fenamates alone or in combination with existing chemotherapeutic agents. This paper also explores targets of fenamates in cancer therapy, including COX, AKR family, AR, gap junction, FTO, TEAD, DHODH, TAS2R14, ion channels, and DNA. Besides, this paper discusses other mechanisms, such as regulating Wnt/ß-catenin, TGF-ß, p38 MAPK, and NF-κB pathway, and the regulation of the expressions of Sp, EGR-1, NAG-1, ATF-3, ErbB2, AR, as well as the modulation of the tumor immune microenvironment. Furthermore, this paper outlined the structural modifications of fenamates, highlighting their potential as promising leads for anticancer drugs.
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STUDY QUESTION: Do singleton children conceived by ART have a higher asthma risk than naturally conceived (NC) singletons? SUMMARY ANSWER: The asthma risk was similar for ART-conceived singletons and NC singletons, and there were no clear differences between the various types of ART. WHAT IS KNOWN ALREADY: Whether ART increases asthma risk in offspring is questionable. The evidence is inconsistent and limited by ethnicity, geographic distribution, inadequate confounder adjustment, unsatisfactory control groups, and specific methods of ART. Furthermore, the mediating effects of obstetric and neonatal outcomes on the association between ART and asthma remain unclear. STUDY DESIGN SIZE DURATION: This observational, single-centre study was conducted at a reproductive centre of an affiliated university hospital between September 2009 and April 2023. A total of 3227 singletons aged 3-6 years conceived by IVF versus ICSI or fresh versus frozen embryo transfer were retrospectively enrolled, and a total of 1206 NC singletons of the same age were subsequently recruited. PARTICIPANTS/MATERIALS SETTING METHODS: Asthma was defined as a self-reported physician diagnosis or wheezing in the past 12 months. We performed multivariable logistic regression analyses to examine associations between asthma in offspring and ART use, adjusting for parental characteristics (age, education level, occupation type, BMI, asthma), smoking exposure, residence type, child sex, child age, and year of follow-up. Mediating effects were explored using longitudinal mediation structural equation modelling. MAIN RESULTS AND THE ROLE OF CHANCE: Asthma was reported for 51 (4.2%) of the 1206 NC singletons (median [interquartile range] age 5 [4-5] years; 48.1% females) and 169 (5.2%) of the 3227 ART-conceived singletons (5 [5-5] years; 47.6% females). We found that risks of childhood asthma in singletons conceived by ART were, overall, similar to those of NC singletons before (odds ratio [OR], 1.25 [95% CI, 0.92-1.74]; P = 0.170) and after adjustment (adjusted OR [aOR], 0.66 [95% CI, 0.44-1.03]; P = 0.126). The results were similar in multiple sensitivity analyses, and there were no clear differences in asthma risks according to the method of ART. Mediation analysis revealed a significant positive indirect effect of neonatal intensive care unit (NICU) admission (standard path coefficient, b = 0.025, P < 0.05) and a negative indirect effect of breastfeeding (b = -0.012, P < 0.05) on the association between ART and asthma in singleton offspring. LIMITATIONS REASONS FOR CAUTION: This study is limited to singletons only and cannot be generalized. The study is also limited by its retrospective observational single-centre nature and sample size. Mediation analyses were exploratory. Therefore, the findings need to be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: These findings can help infertile couples undergoing ART be reassured about the risk of childhood asthma in singleton offspring. Breastfeeding is recommended as a potentially feasible intervention to reduce the asthma risks in ART-conceived children who are at increased potential risk of asthma, such as those with NICU admissions. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Key Research and Development Program of Zhejiang Province (2021C03100), the National Key Research and Development Program of China (2021YFC2700603), and the Program for Key Subjects of Zhejiang Province in Medicine and Hygiene to Y. Z., the Zhejiang Province Natural Science Foundation (No. LQ22H040006) and the National Natural Science Foundation of China (No.82101759) to M.T., and the National Natural Science Foundation of China (No. 82201860) to J.Y. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: ChiCTR2300069906.
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Traditional animal pose estimation techniques based on images face significant hurdles, including scarce training data, costly data annotation, and challenges posed by non-rigid deformation. Addressing these issues, we proposed dynamic conditional prompts for the prior knowledge of animal poses in language modalities. Then, we utilized a multimodal (language-image) collaborative training and contrastive learning model to estimate animal poses. Our method leverages text prompt templates and image feature conditional tokens to construct dynamic conditional prompts that integrate rich linguistic prior knowledge in depth. The text prompts highlight key points and relevant descriptions of animal poses, enhancing their representation in the learning process. Meanwhile, transformed via a fully connected non-linear network, image feature conditional tokens efficiently embed the image features into these prompts. The resultant context vector, derived from the fusion of the text prompt template and the image feature conditional token, generates a dynamic conditional prompt for each input sample. By utilizing a contrastive language-image pre-training model, our approach effectively synchronizes and strengthens the training interactions between image and text features, resulting in an improvement to the precision of key-point localization and overall animal pose estimation accuracy. The experimental results show that language-image contrastive learning based on dynamic conditional prompts enhances the average accuracy of animal pose estimation on the AP-10K and Animal Pose datasets.
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FAM83B, as one of the FAM83 family members, has been closely involved in cell transformation, and a growing number of scholars have been studied its role in tumours over the years. Whereas the effect and potential mechanism of FAM83B in laryngeal squamous cell carcinoma (LSCC) have not been investigated. In this research, we discovered that the expression quantity of FAM83B was remarkably higher in LSCC tissues (79.65 ± 35.98) than in matched adjacent tissues (59.34 ± 32.59) by tissue microarrays and immunohistochemistry. Furthermore, expression of FAM83B was knocked down in HEP-2 and TU177 cell lines via lentivirus, and in the course of intracorporal and extracorporeal experiments, FAM83B knockdown showed the inhibition of tumour growth, migration, and invasion ability. Moreover, cell cycle assay showed that FAM83B knockdown leads to an apparent accumulation of cells in the G1 phase, indicating that FAM83B knockdown can inhibit cell proliferation. Meanwhile, western blotting (WB) demonstrated that FAM83B knockdown led to a significant reduction in CDK4/CDK6/CCND1 protein expression, which may have decelerated cell cycle progression. Collectively, this study demonstrates that FAM83B serves as an oncogene in LSCC, promoting cell proliferation by controlling the protein expression of CDK4, CDK6, and CCND1, thus inducing a transference of the G1 stage to S stage in cell-cycle of LSCC cells. These results provide an academic foundation for elucidating the mechanism of LSCC occurrence and evolution and for developing treatment strategies for LSCC.
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Introduction: Despite the global prevalence of coronavirus disease 2019 (COVID-19), limited research has been conducted on the effects of SARS-CoV-2 infection on human reproduction. The aims of this study were to investigate the impact of SARS-CoV-2 infection during controlled ovarian stimulation (COS) on the outcomes of assisted reproductive treatment (ART) and the cytokine status of patients. Methods: This retrospective cohort study included 202 couples who received ART treatment, 101 couples infected with SARS-CoV-2 during COS and 101 matched uninfected couples. The parameters of ovarian stimulation and pregnancy outcomes were compared between the two groups. The All-Human Inflammation Array Q3 kit was utilized to measure cytokine levels in both blood and follicular fluid. Results: No difference was found in the number of good-quality embryos (3.3 ± 3.1 vs. 3.0 ± 2.2, P = 0.553) between the infected and uninfected groups. Among couples who received fresh embryo transfers, no difference was observed in clinical pregnancy rate (53.3% vs. 51.5%, P = 0.907). The rates of fertilization, implantation, miscarriage, ectopic pregnancy and live birth were also comparable between the two groups. After adjustments were made for confounders, regression models indicated that the quality of embryos (B = 0.16, P = 0.605) and clinical pregnancy rate (P = 0.206) remained unaffected by SARS-CoV-2 infection. The serum levels of MCP-1, TIMP-1, I-309, TNF-RI and TNF-RII were increased, while that of eotaxin-2 was decreased in COVID-19 patients. No significant difference was found in the levels of cytokines in follicular fluid between the two groups. Conclusion: Asymptomatic or mild COVID-19 during COS had no adverse effects on ART outcomes. Although mild inflammation was present in the serum, it was not detected in the follicular fluid of these patients. The subsequent immune response needs further investigation.
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COVID-19 , Inducción de la Ovulación , Resultado del Embarazo , Técnicas Reproductivas Asistidas , Humanos , COVID-19/inmunología , COVID-19/terapia , Femenino , Embarazo , Inducción de la Ovulación/métodos , Adulto , Estudios Retrospectivos , Masculino , SARS-CoV-2 , Índice de Embarazo , Líquido Folicular/metabolismo , Citocinas/sangre , Citocinas/metabolismo , Inflamación , Transferencia de Embrión , Resultado del TratamientoRESUMEN
Amyloid aggregation is implicated in the pathogenesis of various neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). It is critical to develop high-performance drugs to combat amyloid-related diseases. Most identified nanomaterials exhibit limited biocompatibility and therapeutic efficacy. In this work, we used a solvent-free carbonization process to prepare new photo-responsive carbon nanodots (CNDs). The surface of the CNDs is densely packed with chemical groups. CNDs with large, conjugated domains can interact with proteins through π-π stacking and hydrophobic interactions. Furthermore, CNDs possess the ability to generate singlet oxygen species (1O2) and can be used to oxidize amyloid. The hydrophobic interaction and photo-oxidation can both influence amyloid aggregation and disaggregation. Thioflavin T (ThT) fluorescence analysis and circular dichroism (CD) spectroscopy indicate that CNDs can block the transition of amyloid from an α-helix structure to a ß-sheet structure. CNDs demonstrate efficacy in alleviating cytotoxicity induced by Aß42 and exhibit promising blood-brain barrier (BBB) permeability. CNDs have small size, low biotoxicity, good fluorescence and photocatalytic properties, and provide new ideas for the diagnosis and treatment of amyloid-related diseases.
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Péptidos beta-Amiloides , Carbono , Carbono/química , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/química , Humanos , Catálisis , Oxígeno Singlete/metabolismo , Oxígeno Singlete/química , Barrera Hematoencefálica/metabolismo , Animales , Agregado de Proteínas/efectos de los fármacos , Puntos Cuánticos/química , Amiloide/química , Amiloide/metabolismo , Supervivencia Celular/efectos de los fármacos , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
2,4-dichlorophenol (2,4-DCP), 2,5-DCP, 2,4,5-trichlorophenol (2,4,5-TCP), 2,4,6-TCP, and ortho-phenylphenol (OPP) are widely present in the environment. However, their associations with risk and prognosis of diabetes and prediabetes remains unclear. We investigated the associations of these five phenols with the risk of diabetes and prediabetes, and with all-cause and cardiovascular disease (CVD) mortality, in adults with diabetes or prediabetes (n=6419). Information on diabetes and prediabetes indicators, and mortality data was collected from the National Health and Nutrition Examination Survey. Logistic and Cox regression models were used to explore the associations of the five phenols with risk and prognosis of diabetes and prediabetes. Participants in the highest urinary 2,4-DCP and 2,5-DCP tertiles had higher odds of diabetes [adjusted odds ratio (aOR), 1.34, 95â¯% confidence interval (CI): 1.10, 1.62; aOR, 1.29, 95â¯% CI: 1.07, 1.56, respectively] than those in the lowest tertiles. Participants with urinary OPP concentrations above the limit of detection (LOD), but below median had an aOR of 1.25 (95â¯% CI: 1.08, 1.46) for prediabetes compared to those with concentrations below the LOD. In adults with diabetes, the highest 2,4-DCP and 2,5-DCP tertiles were associated with all-cause mortality [adjusted hazard ratio (aHR), 1.49; 95â¯% CI: 1.08, 2.06; aHR, 1.49; 95â¯% CI: 1.08, 2.05, respectively] and CVD mortality (aHR, 2.58; 95 % CI: 1.33, 4.97; aHR, 1.96; 95â¯% CI: 1.06, 3.60, respectively) compared with the lowest tertiles. Compared with 2,4,5-TCP concentrations below the LOD, those above median were associated with all-cause mortality (aHR: 1.75; 95â¯% CI: 1.24, 2.48) and CVD mortality (aHR: 2.34; 95â¯% CI: 1.19, 4.63) in adults with prediabetes. Furthermore, the associations between these phenols and mortality were strengthened in some subgroups. Environmental exposure to 2,4-DCP, 2,5-DCP, 2,4,5-TCP, and OPP increases the risk or adverse prognosis of diabetes or prediabetes in adults in the US. Further studies are required to confirm these findings.
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Clorofenoles , Diabetes Mellitus , Contaminantes Ambientales , Estado Prediabético , Humanos , Clorofenoles/orina , Masculino , Estado Prediabético/orina , Estado Prediabético/epidemiología , Estado Prediabético/inducido químicamente , Femenino , Persona de Mediana Edad , Diabetes Mellitus/epidemiología , Adulto , Contaminantes Ambientales/orina , Fenoles/orina , Pronóstico , Encuestas Nutricionales , Anciano , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/epidemiología , Exposición a Riesgos Ambientales/estadística & datos numéricos , Exposición a Riesgos Ambientales/efectos adversosRESUMEN
Background: Trans-spinal electrical stimulation (tsES) to the intact spinal cord poststroke may modulate the cortico-muscular control in stroke survivors with diverse lesions in the brain. This work aimed to investigate the immediate effects of tsES on the cortico-muscular descending patterns during voluntary upper extremity (UE) muscle contractions by analyzing cortico-muscular coherence (CMCoh) and electromyography (EMG) in people with chronic stroke. Methods: Twelve chronic stroke participants were recruited to perform wrist-hand extension and flexion tasks at submaximal levels of voluntary contraction for the corresponding agonist flexors and extensors. During the tasks, the tsES was delivered to the cervical spinal cord with rectangular biphasic pulses. Electroencephalography (EEG) data were collected from the sensorimotor cortex, and the EMG data were recorded from both distal and proximal UE muscles. The CMCoh, laterality index (LI) of the peak CMCoh, and EMG activation level parameters under both non-tsES and tsES conditions were compared to evaluate the immediate effects of tsES on the cortico-muscular descending pathway. Results: The CMCoh and LI of peak CMCoh in the agonist distal muscles showed significant increases (p < 0.05) during the wrist-hand extension and flexion tasks with the application of tsES. The EMG activation levels of the antagonist distal muscle during wrist-hand extension were significantly decreased (p < 0.05) with tsES. Additionally, the proximal UE muscles exhibited significant decreases (p < 0.05) in peak CMCoh and EMG activation levels by applying tsES. There was a significant increase (p < 0.05) in LI of peak CMCoh of proximal UE muscles during tsES. Conclusion: The cervical spinal cord neuromodulation via tsES enhanced the residual descending excitatory control, activated the local inhibitory circuits within the spinal cord, and reduced the cortical and proximal muscular compensatory effects. These results suggested the potential of tsES as a supplementary input for improving UE motor functions in stroke rehabilitation.
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The availability of big data can transform the studies in biomedical research to generate greater scientific insights if expert labeling is available to facilitate supervised learning. However, data annotation can be labor-intensive and cost-prohibitive if pixel-level precision is required. Weakly supervised semantic segmentation (WSSS) with image-level labeling has emerged as a promising solution in medical imaging. However, most existing WSSS methods in the medical domain are designed for single-class segmentation per image, overlooking the complexities arising from the co-existence of multiple classes in a single image. Additionally, the multi-class WSSS methods from the natural image domain cannot produce comparable accuracy for medical images, given the challenge of substantial variation in lesion scales and occurrences. To address this issue, we propose a novel anomaly-guided mechanism (AGM) for multi-class segmentation in a single image on retinal optical coherence tomography (OCT) using only image-level labels. AGM leverages the anomaly detection and self-attention approach to integrate weak abnormal signals with global contextual information into the training process. Furthermore, we include an iterative refinement stage to guide the model to focus more on the potential lesions while suppressing less relevant regions. We validate the performance of our model with two public datasets and one challenging private dataset. Experimental results show that our approach achieves a new state-of-the-art performance in WSSS for lesion segmentation on OCT images.
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Investigación Biomédica , Tomografía de Coherencia Óptica , Humanos , Retina/diagnóstico por imagen , Semántica , Procesamiento de Imagen Asistido por Computador , Aprendizaje Automático SupervisadoRESUMEN
Focal vibratory stimulation (FVS) and neuromuscular electrical stimulation (NMES) are promising technologies for sensory rehabilitation after stroke. However, the differences between these techniques in immediate neuromodulatory effects on the poststroke cortex are not yet fully understood. In this research, cortical responses in persons with chronic stroke (n = 15) and unimpaired controls (n = 15) were measured by whole-brain electroencephalography (EEG) when FVS and NMES at different intensities were applied transcutaneously to the forearm muscles. Both FVS and sensory-level NMES induced alpha and beta oscillations in the sensorimotor cortex after stroke, significantly exceeding baseline levels (p < 0.05). These oscillations exhibited bilateral sensory deficiency, early adaptation, and contralesional compensation compared to the control group. FVS resulted in a significantly faster P300 response (p < 0.05) and higher theta oscillation (p < 0.05) compared to NMES. The beta desynchronization over the contralesional frontal-parietal area remained during NMES (p > 0.05), but it was significantly weakened during FVS (p < 0.05) after stroke. The results indicated that both FVS and NMES effectively activated the sensorimotor cortex after stroke. However, FVS was particularly effective in eliciting transient involuntary attention, while NMES primarily fostered the cortical responses of the targeted muscles in the contralesional motor cortex.
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Investigation on long-term effects of robot-assisted poststroke rehabilitation is challenging because of the difficulties in administration and follow-up of individuals throughout the process. A mobile hybrid neuromuscular electrical stimulation (NMES)-robot, i.e., exoneuromusculoskeleton (ENSM) was adopted for a single-group trial to investigate the long-term effects of the robot-assisted self-help telerehabilitation on upper limb motor function after stroke. Twenty-two patients with chronic stroke were recruited to attend a 20-session telerehabilitation program assisted by the wrist/hand module of the ENMS (WH-ENMS). Participants were evaluated before, after, as well as at 3 months and 6 months after the training. The primary outcome measure was the Fugl-Meyer Assessment-Upper Extremity (FMA-UE), supplemented by secondary outcome measures of the FMA-UE of the shoulder and elbow (FMA shoulder/elbow), the FMA-UE of the wrist and hand (FMA wrist/hand), the Modified Ashworth Scale (MAS), the Action Research Arm Test (ARAT), the Wolf Motor Function Test (WMFT), the Functional Independence Measure (FIM), as well as electromyography (EMG) and kinematic measurements. Twenty participants completed the telerehabilitation program, with 19 returning for a 3-month follow-up, and 18 for a 6-month follow-up. Significantly improved clinical scores were observed after the training (p ≤ 0.05). These improvements were maintained after 6 months in the FMA-UE, FMA shoulder/elbow, MAS at the wrist flexor, WMFT score, WMFT time, and FIM (p ≤ 0.05). The maintained improvements in motor function were attributed to reduced muscular compensation, as indicated by EMG and kinematic parameters. The WH-ENMS-assisted self-help telerehabilitation could achieve long-lasting rehabilitative effects in chronic stroke.
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Studying the non-Arrhenius behavior of rubber is crucial to ensure appropriate lifetime prediction and reduce ineffective acceleration experiments. In this paper, accelerated thermal aging from 70 °C to 130 °C is conducted on an ethylene propylene diene monomer (EPDM) rubber and the tensile characteristics of the rubber are tested. Further, the popular Mooney-Rivlin equation is employed to analyze the influence of aging temperature and time on the effective crosslink densities. The enormous increase in the physical crosslinking density when the aging temperature reaches 115 °C demonstrates that the activation energy varied during the degradation process. By combining the Arrhenius extrapolation with the time-temperature superposition (TTS) extrapolation, a novel method to prove the non-Arrhenius behavior of EPDM rubber is provided. Based on the method proposed in this study, the activation energies for the high- and low-temperature processing of rubber can be determined.
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The rapid enrichment of anammox bacteria and its fragile resistance to adverse environment are the critical problems facing of anammox processes. As an abundant component in anammox bacteria, iron has been proved to promote the activity and growth of anammox bacteria in the mature anammox systems, but the functional and metabolic profiles in Fe(III) enhanced emerging anammox systems have not been evaluated. Results indicated that the relative abundance of functional genes involved in oxidative phosphorylation, nitrogen metabolism, cofactors synthesis, and extracellular polymers synthesis pathways was significantly promoted in the system added with 5 mg/L Fe(III) (R5). These enhanced pathways were crucial to energy generation, nitrogen removal, cell activity and proliferation, and microbial self-defense, thereby accelerating the enrichment of anammox bacteria Ca. Brocadia and facilitating their resistance to adverse environments. Microbial community analysis showed that the proportion of Ca. Brocadia in R5 also increased to 64.42 %. Hence, R5 could adapt rapidly to the increased nitrogen loading rate and increase the nitrogen removal rate by 108 % compared to the system without Fe(III) addition. However, the addition of 10 and 20 mg/L Fe(III) showed inhibitory effects on the growth and activity of anammox bacteria, which exhibited the lower relative abundance of Ca. Brocadia and unstable or even collapsed nitrogen removal performance. This study not only clarified the concentration range of Fe(III) that promoted and inhibited the enrichment of anammox bacteria, but also deepened our understanding of the functional and metabolic mechanisms underlying enhanced enrichment of anammox bacteria by Fe(III), providing a potential strategy to hasten the start-up of anammox from conventional activated sludge.
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Reactores Biológicos , Compuestos Férricos , Compuestos Férricos/metabolismo , Anaerobiosis , Oxidación-Reducción , Reactores Biológicos/microbiología , Bacterias/metabolismo , Aguas del Alcantarillado , Nitrógeno/metabolismo , DesnitrificaciónRESUMEN
Mitoxantrone (MX) is an effective treatment for breast cancer; however, high efflux of MX that is accomplished by breast cancer resistance protein (BCRP) leads to acquired multidrug resistance (MDR), reducing MX's therapeutic efficacy in breast cancer. Non-muscle myosin IIA (NMIIA) and its heavy phosphorylation at S1943 have been revealed to play key roles in tumor metastasis and progression, including in breast cancer; however, their molecular function in BCRP-mediated MDR in breast cancer remains unknown. In this study, we revealed that the expression of NMIIA heavy chain phosphorylation at S1943 was downregulated in BCRP-overexpressing breast cancer MCF-7/MX cells, and stable expression of NMIIA-S1943A mutant increased BCRP expression and promoted the resistance of MCF-7/MX cells to MX. Meanwhile, NMIIA S1943 phosphorylation induced by epidermal growth factor (EGF) was accompanied by the downregulation of BCRP in MCF-7/MX cells. Furthermore, stable expression of NMIIA-S1943A in MCF-7/MX cells resulted in upregulation of N-cadherin and the accumulation of ß-catenin on the cell surface, which inhibited the nucleus translocation of ß-catenin and Wnt/ß-catenin-based proliferative signaling. EGF stimulation of MCF-7/MX cells showed the downregulation of N-cadherin and ß-catenin. Our results suggest that decreased NMIIA heavy phosphorylation at S1943 increases BCRP expression and promotes MX resistance in breast cancer cells via upregulating N-cadherin expression.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Neoplasias de la Mama , Cadherinas , Resistencia a Antineoplásicos , Mitoxantrona , Proteínas de Neoplasias , Regulación hacia Arriba , Humanos , Mitoxantrona/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Fosforilación , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Regulación hacia Arriba/efectos de los fármacos , Cadherinas/metabolismo , Cadherinas/genética , Células MCF-7 , Antineoplásicos/farmacología , Cadenas Pesadas de Miosina/metabolismo , Cadenas Pesadas de Miosina/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
Ischemic stroke (IS) is a well-known acute cerebrovascular disease characterized by high disability, morbidity, and recurrence rates with no effective treatments. Dexmedetomidine (DEX), a selective a2-adrenoceptor agonist used in anaesthesiology and pain management, has been found to exhibit neuroprotective effects in various diseases. However, its role in IS and the underlying mechanisms remains to be determined. Hence, the aim of the present study was to investigate the neuroprotective role of DEX in the recovery of mice following middle cerebral artery occlusion (MCAO). Mice were used to establish the animal model, and then DEX was injected. Behavioural tests (neurological function assessments, grip test, and rotarod test), brain water content measurement, ELISA, and measurement of oxidative stress were performed. DEX activated a2-adrenoceptor and resulted in reduced brain injury, as indicated by the decreased brain water content, S100 Calcium Binding Protein B (S100B) content, and neuron-specific enolase (NSE) content, whilst also inhibiting oxidative stress, as indicated by the increased total antioxidant capacity, catalase, glutathione, and superoxide dismutase levels, and decreased malondialdehyde and glutathione oxidized levels. Neuroinflammation was also reduced as indicated by the decrease in IFN-g, IL-1a, IL-1b, IL-6, TNF-a, and MMP levels, improved the recovery of neurological function, as indicated by the decreased neurological function score and mNSS, and increased grip strength and rotarod performance in MCAO mice. These combined results suggest that DEX may be a novel strategy for the treatment of IS.
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Dexmedetomidina , Accidente Cerebrovascular Isquémico , Fármacos Neuroprotectores , Estrés Oxidativo , Recuperación de la Función , Animales , Dexmedetomidina/farmacología , Ratones , Recuperación de la Función/efectos de los fármacos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/efectos de los fármacos , Masculino , Modelos Animales de Enfermedad , Agonistas de Receptores Adrenérgicos alfa 2/farmacología , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismoRESUMEN
γδ T cells play a critical role in homeostasis and diseases such as infectious diseases and tumors in both mice and humans. They can be categorized into two main functional subsets: IFN-γ-producing γδT1 cells and IL-17-producing γδT17 cells. While CD27 expression segregates these two subsets in mice, little is known about human γδT17 cell differentiation and expansion. Previous studies have identified γδT17 cells in human skin and mucosal tissues, including the oral cavity and colon. However, human γδ T cells from peripheral blood mononuclear cells (PBMCs) primarily produce IFN-γ. In this protocol, we describe a method for in vitro expansion and polarization of human γδT17 cells from PBMCs. Key Features ⢠Expansion of γδ T cells from peripheral blood mononuclear cells. ⢠Human IL-17A-producing γδ T-cell differentiation and expansion using IL-7 and anti-γδTCR. ⢠Analysis of IL-17A production post γδ T-cell expansion. This protocol is used in: Science Advances (2022), DOI: 10.1126/sciadv.abm9120.
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An embedded obstacle-type micromixer-concentration gradient generator based on capillary self-driven is proposed and studied. Herringbone structure (HS) for mixing and palisade-shape small channels at the outlet are designed in the device (named HS). Simulation and experimentation are done to study the liquid mixing efficiency in the small channels and concentration gradient at the outlet, and the experimental results agree with the simulation results. For three cases of liquid dripping (sequential, reverse, and delayed drippings), mixing analysis shows that the mixing efficiency increases along both mixing channel and palisade length, and is high in the middle small channel of the palisade-shape area and low on both sides. An obvious concentration gradient at the outlet can form compared with the device without the palisade-shape area. Finally, water pH value detection is done as one of the applications of HS. This study can provide guidance for the application of HS in biochemical detection, cell research, drug screening, etc. based on the capillary-driven effect.
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Simulación por ComputadorRESUMEN
Herein, for the first time, we have successfully constructed a novel near-infrared (NIR) emission fluorescent probe Dpyt for ultrafast detecting (within 5 s) bisulfate and organic amines based on a 1,2-dihydrocyclopenta[b]chromene-barbiturate conjugation system. Upon addition of bisulfate or organic amines, Dpyt displayed a distinct color change from blue to colorless or from purple to blue, respectively, suggesting that the Dpyt can be used to detect two analytes by the naked eye. Based on quantum chemistry calculations, the fluorescence quenching of Dpyt after the addition of HSO3- is caused by the photoinduced electron transfer (PET) process of the adduct Dpyt-HSO3-. The fluorescence enhancement of Dpyt caused by most organic amines is due to the enhanced intramolecular charge transfer (ICT) process of deprotonated Dpyt. Notably, Dpyt can be applied for detecting HSO3- in actual food samples such as red wine and sugar, as well as for imaging of HSO3- and representative propylamine in living cells. And more importantly, indicator labels constructed by filter paper loaded with Dpyt can visually monitor the freshness of salmon in real-time by daylight and fluorescence dual-mode. The comparison with national standard method of China manifests that indicator labels are a valid tool to assess the freshness of seafood.