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Chemotherapy is an effective approach for cancer therapy when plant-derived sensitizers are combined with chemotherapeutics. Zerumbone, a natural phytochemical, has been documented to have various pharmacological roles. Here, we evaluated the chemosensitization potential of zerumbone in a breast cancer cell line in vitro. Zerumbone-induced cytotoxicity in MCF-7 cells was assessed by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT)-based metabolic analysis. Reactive oxygen species (ROS)-mediated mitochondrial membrane alterations, DNA damage, and apoptotic morphological changes were measured by fluorescence microscopy methods. A biochemical assay was employed to analyze Thiobarbituric acid reactive substances (TBARS) and antioxidant levels. Apoptotic marker expression levels were investigated by immunoblotting. MTT assay revealed that zerumbone significantly enhanced paclitaxel (PTX)-induced cell death in breast cancer cells in a concentration-dependent manner. Furthermore, our study demonstrated that zerumbone (15 µM) significantly enhanced ROS when combined with PTX (1 µM) treatment. Additionally, we observed that zerumbone enhanced the impairment of mitochondrial membrane potential and oxidative DNA damage, thereby inducing apoptosis in combination with PTX. Western blot analysis indicated that zerumbone significantly upregulated BAX, caspase-7, and caspase-9 expression and decreased BCL-2 expression, thereby inducing proapoptotic protein-mediated cell death combined with PTX. The prooxidant properties of zerumbone potentially resensitize breast cancer cells to PTX by enhancing intracellular ROS-mediated oxidative stress.
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Neoplasias da Mama , Paclitaxel , Humanos , Feminino , Paclitaxel/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias da Mama/tratamento farmacológico , Estresse Oxidativo , Apoptose , Linhagem Celular TumoralRESUMO
Imatinib, an inhibitor of tyrosine kinase, shows remarkable efficacy in chronic myeloid leukaemia (CML). Autophagy protects tumour cells against chemotherapeutic stimulation and contributes to imatinib resistance in CML. Kinesin family member 23 (KIF23) is involved in cytokinesis and associated with autophagy. The role of KIF23 in autophagy-induced imatinib resistance in CML was investigated. First, to induce drug resistance, CML cells were exposed to increasing concentrations of imatinib. The concentration of imatinib resistance in CML cells was screened through upregulation of 50% inhibitory concentration (IC50 ) values. KIF23 was elevated in imatinib-resistant tissues and cells of CML. Second, knockdown of KIF23 reduced IC50 values of imatinib-resistant CML cells to imatinib. Moreover, silence of KIF23 also suppressed cell proliferation and promoted apoptosis of imatinib-resistant CML cells. Third, immunofluorescence analysis showed that the number of LC3 bright spots in imatinib-resistant CML cells was reduced by silence of KIF23. Knockdown of KIF23 upregulated p62 expression and downregulated the expression ratio of LC3-II to LC3-I in imatinib-resistant CML cells. Last, silence of KIF23 decreased nuclear ß-catenin and increased cytoplasmic ß-catenin in imatinib-resistant CML cells. Activator of Wnt/ß-catenin attenuated KIF23 silence-induced increase of apoptosis and decrease of autophagy in imatinib-resistant CML cells. In conclusion, loss of KIF23 repressed autophagy-induced imatinib resistance in CML cells through inactivation of Wnt/ß-catenin pathway.
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Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Antineoplásicos/farmacologia , Apoptose , Autofagia , beta Catenina , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Mesilato de Imatinib/farmacologia , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteínas Associadas aos Microtúbulos , Via de Sinalização WntRESUMO
BACKGROUND & PROBLEMS: Parent-infant attachment is affected by parent-infant interaction. The limitations on related visitations during the COVID-19 pandemic suspended the opportunity to engage in kangaroo care (skin-to-skin contact) activities. These changes impacted parent-infant attachment in the neonatal intensive care unit. After investigation, the score of premature infant-parent attachment was found to be only 64.6 points during the period in which visitation limitations were in effect. PURPOSE: To enhance maternal-premature infant attachment during the pandemic period by 10% (from an average score of 64.6 to 71.1). RESOLUTION: This project involved nurses playing audio files provided by mothers to their premature infants, and recording a video and taking pictures of the infants during this process. This project used a cloud platform as bidirectional pipelines. Furthermore, emotional support and caring information were provided to the mothers via expressive arts therapy and phone interviews. RESULTS: After the intervention, the premature infant-parent attachment score rose to 74.4 from the pre-intervention score of 64.6. CONCLUSIONS: During pandemic control periods, traditional modes of care aimed at building infant-parent attachment are not applicable. The intervention project used was found to be an effective alternative approach to increasing maternal-premature infant attachment. Breaking the restrictions of time and place, this project applies family-centered care, and may provide a reference for developing software, hardware, and communication equipment for other care units related to newborns.
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COVID-19 , Unidades de Terapia Intensiva Neonatal , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Mães , Pandemias , SARS-CoV-2RESUMO
Alzheimer's disease (AD) is one of the most common diseases in older populations. Its main clinical features include cognitive dysfunction, affective disorder, and abnormal mental behavior. Due to the lack of therapeutic drugs, professional care has become an important diagnostic and therapeutic strategy for Alzheimer's disease patients. At present, most Alzheimer's disease patients are cared for at home by relatives or caregivers, and less than l0% of city-based patients receive care in old-age institutions. Due to mixed treatment regimens in the hospital, care services do not necessarily match patient care needs and thus Alzheimer's disease patients do not receive adequate treatment. Developed countries have a mature care system for the elderly, but no graded care model for the elderly with Alzheimer's disease currently exists in China. In this paper, the author draws on the experience of developed countries to construct an index system for the graded care of Alzheimer's disease patients that is suited to conditions in China. This article addresses the burden faced by the elderly with Alzheimer's disease and the current standard of care for the elderly at home and abroad. After explaining the necessity of constructing a care model for the elderly with Alzheimer's disease, the author then explains the practicability of the care system proposed in this study in order to provide a whole-course care model for the mentally impaired elderly in China.
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Doença de Alzheimer/enfermagem , Modelos de Enfermagem , Garantia da Qualidade dos Cuidados de Saúde/métodos , Idoso , China , Humanos , Pesquisa em Avaliação de EnfermagemRESUMO
BACKGROUND: China is the country with the largest population of elderly, accounting for more than 17.3% of the total population. The arrival of the so-called "silver wave" has generally reduced the abilities of daily life of the elderly and has continued to increase endowment pressures. Assisting the elderly in China to age successfully is an urgent problem. PURPOSE: To understand the living arrangement intentions of the elderly in Western China and to provide a reference for the reformation of the social endowment service system. METHODS: A self-designed questionnaire and Barthel self-care ability scale were conducted on 2,078 elderly people living in Guangxi and Ningxia Provinces in China. RESULTS: A total of 1,634 participants (78.6%) chose home-based care, 187 (9.0%) chose community care, and 257 (12.3%) chose institutional care. Differences in age, ethnic group, household registration, education level, family monthly income, family income and expenditure situation, and religion all significantly affected living arrangement intention (all p < .05). Logistic regression showed that age, ethnicity, household registration, religion, marital status, family monthly income, and length of hospital stay were all primary factors of influence on the home care intention of the elderly people (all p < .05). CONCLUSIONS: A significant majority of the elderly in this study expressed an intention to choose home-based care. It will be necessary to build a home-based mode of care that incorporates medical-care functions. In addition, the health service functions of community and institutions should be improved and perfected, as the intention to live in these settings is also growing. Appropriate services should be provided to meet the living arrangement intentions of the elderly in order to start a new era of elderly care customization. Finally, the development and expansion of "Internet Plus" should be leveraged to build a social endowment service system that meets the comprehensive range of elderly-care needs.
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Intenção , Características de Residência , Idoso , China , HumanosRESUMO
Both overall survival (OS) and disease-specific survival (DSS) are significant when determining a patient's prognosis for breast cancer (BC). The effect of DSS-related microRNAs on BC susrvival, however, is not well understood. Here, we spotted differentially expressed miRNAs (DEMs) in the TCGA database of BC DSS, identified eight DSS-related miRNAs, and constructed a risk model. AUC values at 1, 3, and 5 years were 0.852, 0.861, and 0.868, respectively, indicating a risk model's excellent prognostic prediction ability. Then, we validated miRNA roles in BC OS and finally defined miR-551b as an independently prognostic miRNA in BC. According to function analysis, miR-551b is strongly linked with the emergence and spread of cancer, including protein ubiquitination, intracellular protein transport, metabolic pathways, and cancer pathways. Moreover, we confirmed the low expression of miR-551b in BC tissue and cells. After miR-551b inhibition or overexpression, cell function was either dramatically increased or diminished, respectively, indicating that miR-551b could regulate BC proliferation, invasion, and migration. In conclusion, we thoroughly clarified BC-related miRNAs on DSS and OS and verified miR-551b as a crucial regulator in the development and prognosis of cancer. These results can offer fresh ideas for BC therapy.
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This study aims to assess the prevalence of geriatric syndromes and identify factors associated with multiple geriatric syndromes in community-dwelling older adults in China. We utilized a convenience sampling method to recruit older adults and from one rural and one urban community in Chengdu, China, from October 2022 to March 2023. A total of 706 older adults aged 60 years or older were included. Ten geriatric syndromes were investigated including two mental disorders: depressive symptoms, cognitive impairment; and eight somatic disorders: pain, falls, sleep disturbance, constipation, polypharmacy, multimorbidity, malnutrition and frailty. Multiple geriatric syndromes were defined as an individual having two or more geriatric syndromes. The data obtained were analysed using descriptive statistics. The independent risk factors for multiple geriatric syndromes were assessed using a logistic regression model. This study found that 90.5% of the participants had at least one geriatric syndrome, with 72.8% experiencing multiple geriatric syndromes. The top four geriatric syndromes in our study were polypharmacy (58.5%), malnutrition/at risk of malnutrition (43.1%), multimorbidity (42.1%), and frailty/prefrailty (34.3%). Of the older adults, 368(52.1%) had only somatic disorders, 18(2.5%) had only mental disorders and 253 (35.8%) had somatic-mental disorders. According to the logistic regression analysis, residence, age, marriage, BMI, and self-related health were significantly associated with multiple geriatric syndromes among older adults. This study highlights that multiple geriatric syndromes are prevalent among community-dwelling older adults in China, and underscores the significance of certain demographic factors in their occurrence. Future longitudinal studies are needed to establish the temporal relationship between multiple geriatric syndromes and these demographic factors, as well as to explore causal relationships and effective prevention strategies for geriatric syndrome.
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Disfunção Cognitiva , Fragilidade , Desnutrição , Humanos , Idoso , Fragilidade/epidemiologia , Fragilidade/diagnóstico , Vida Independente , Disfunção Cognitiva/epidemiologia , Fatores de Risco , Desnutrição/epidemiologia , Síndrome , Avaliação Geriátrica/métodosRESUMO
Objectives: ADL and Sensory and Communication Abilities are important indicators of the quality of life of the elderly which are significant determinants of health, particularly in developing countries. The present cross-sectional study investigated effect of ADL and Sensory and Communication Abilities on depressive symptoms, as well as the the role of gender in these effects. Design: This is a cross-sectional study. Setting: A nationally representative cross-sectional survey among the Chinese population aged 60 years and over. Participants: A total of 163296 females and 148724 males aged 65 and over in 2019 in urban China. Outcome measures: Prevalence, risk factors and gender differences in geriatric depressive symptoms among urban elderly. Results: Approximately 95.69% of the participants had depressive symptoms according to the CESD-10, with no statistically significant gender difference of 52.15% in females and 47.85% in males. Logistic regression findings suggest that geriatric depressive symptoms are significantly associated with the lack of eldercare (OR=2.427, female; OR=1.426, male), living alone(OR= 1.430, female; OR= 1.179, male), ADL dysfunction (OR=1.528, female; OR=1.246, male), and impaired sensory and communication ability (OR=1.338, female; OR=1.185, male) among both female and male participants. Remarkably, geriatric depressive symptoms are only significantly associated with age (≥75, OR = 1.327), marital status (unmarried, OR=1.598), the number of children (no children, OR=2.271), and the living arrangement (living alone, OR= 1.430) among female participants. Conclusion: Significant gender differences in these associations were found for living alone, ADL dysfunction and impaired sensory and communication ability. Moreover, the study emphasized that the gender difference exists in terms of geriatric depression in urban China. Females are more likely to experience depressive than males with the same circumstances.
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BACKGROUND: In 2009, China launched a new round of healthcare reform to provide households with secure, efficient, convenient, equitable and affordable healthcare services. Healthcare reform is underpinned by three critical pillars: the health workforce, funding, and infrastructure, with reform of the health workforce being particularly significant. OBJECTIVE: This study analyses the disparities in regional distribution and the inequity of healthcare workforce allocation across hospitals and primary health centers in China over twelve years. DESIGN: Retrospective longitudinal data from the National Health Statistics Yearbook 2011-2022 and National Statistical Yearbook in China from 2011 to 2022 were collected for analysis. PARTICIPANTS: The focus was on hospitals and primary health centers, explicitly examining their health technician and nursing workforce. METHODS: The research utilized four key indicators of the healthcare workforce to evaluate the distribution of health resources between hospitals and primary health centers. Furthermore, the Gini coefficient and Theil index were employed to assess the inequality in allocating the health workforce. RESULTS: Between 2010 and 2021, there was a nationwide increase in the ratio of health workers per 1000 population in hospitals and primary health centers. It is noted that rural districts had higher ratios than urban districts in terms of the number of health technicians and nurses per 1000 population, whether in hospitals or primary health centers; western districts had higher ratios than eastern and central districts did. In the same year, at different levels of medical institutions, the Theil indices of health technicians and nurses in hospitals were lower than those in primary health centers in terms of both demographic and geographical dimensions. Regarding the allocation of the health workforce by population, the Gini coefficient remained below 0.3, while for geographical allocation, it exceeded 0.4. CONCLUSIONS: This study analyzed the temporal trends and inequality of health-resource allocation at the hospital and primary health center levels in China, noting trends of improvements in the quantity and inequality in health workforce allocation from 2010 to 2021, suggesting the success of the government's efforts to advance healthcare reform since 2009. The allocation of health workforce based on population exhibits greater fairness compared to geographical distribution.
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Mão de Obra em Saúde , Atenção Primária à Saúde , China , Estudos Longitudinais , Atenção Primária à Saúde/estatística & dados numéricos , Mão de Obra em Saúde/estatística & dados numéricos , Humanos , Hospitais/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Estudos RetrospectivosRESUMO
BACKGROUND AND PURPOSE: Parents of preterm infants experience anxiety and stress in the neonatal intensive care unit (NICU). Visitation restrictions due to COVID-19 have increased maternal pressure and limited bonding opportunities. Little research exists in Taiwan on using video conferencing as a solution. This study investigates depression and stress levels in mothers of preterm infants and evaluates the effectiveness of video visitation during NICU restrictions. METHODS: This study adopts a cross-sectional design and a qualitative survey. Mothers of premature infants were recruited and they participated in the study. Interventions for video visits were scheduled on the third day of admission to the NICU (T1) and during the second week of the study (T2). After each video visit, participants completed an online survey. The study's online survey used structured questionnaires including demographics, the Edinburgh Postnatal Depression Scale (EPDS) and the Parental Stress Scale (PSS): Infant Hospitalization (IH). RESULTS: A total of 51 mothers of preterm infants participated in the study. During the T1 and T2 periods, single mothers with lower educational levels and those aged below 30 experienced depression and high levels of stress. Lower birth weight and gestational age were associated with maternal depression. Video visitation intervention led to a significant decrease in depression scores (EPDS, T1: 11.3 ± 5.5 vs. T2: 10.1 ± 5.2, p = 0.039). Positive correlations were observed between EPDS and PSS: IH scores (p < 0 .005). CONCLUSION: Video visitation intervention can reduce maternal depression in mothers with preterm infants. Since it is practical, video visitation may be applied even after the pandemic.
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Intracranial hemorrhage is a cerebral vascular disease with high mortality. Automotive diagnosing and segmentation of intracranial hemorrhage in Computed Tomography (CT) could assist the neurosurgeon in making treatment plans, which improves the survival rate. In this paper, we design a grouped capsule network named GroupCapsNet to segment the hemorrhage region from a Non-contract CT scan. In grouped capsule network, we constrain the prediction capsules for output capsules produced from different groups of input capsules with various types in each layer. This method can reduce the number of intermediate prediction capsules and accelerate the capsule network. In addition, we modify the squashing function to further accelerate the forward procedure without sacrificing its performance. We evaluate our proposed method with a collected dataset containing 210 intracranial hemorrhage CT scan slices. In experiments, our proposed method achieves competitive results in intracranial hemorrhage area segmentation compared to the existing methods.
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Hemorragias Intracranianas , Esportes com Raquete , Tomografia Computadorizada por Raios X , Humanos , Hemorragias Intracranianas/diagnóstico por imagem , Neurocirurgiões , CintilografiaRESUMO
This study aims to describe the activity of daily living (ADL) situation and determine the relationship between health behavior and ADL among older adults in China. A cross-sectional, observational study was conducted in one urban community and one rural community in Chengdu (a city located in Southwest China), China, from October 2022 to March 2023. A total of 706 older adults were included in this study. The associations between health behaviour and ADL were assessed by logistic regression model. Of the 706 older adults, 169 (23.9%) were disabled in ADL. According to the logistic regression analysis, age (60-69 years old: OR = 0.015, 95% CI 0.007 to 0.035, P < 0.001; 70-79 years old: OR = 0.116, 95% CI 0.060 to 0.227, P < 0.001), resident(OR = 0.568, 95% CI 0.330 to 0.976, P = 0.041), chronic disease (0 type: OR = 0.023, 95% CI 0.001 to 0.379, P = 0.008; 1-4 types: OR = 0.357, 95% CI 0.219 to 0.582, P < 0.001), no exercise (OR = 4.562, 95% CI 2.263 to 8.026, P < 0.001), and physical examination (OR = 2.217, 95% CI 1.294 to 3.496, P = 0.003) were significantly associated with ADL among older adults in Southwest China. This study showed that older adults had a higher ADL disability ratio. Age, resident, chronic disease, exercise and physical examination were associated with ADL among older adults. The study indicates that medium/high exercise maybe a protective factor for older adults, and nursing staff can encourage older adults to exercise when carrying out primary prevention measures. The government and public health institutions should give special attention to older adults and help them to acquire the habit of having an annual physical examination.
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Atividades Cotidianas , Pessoas com Deficiência , Humanos , Idoso , Pessoa de Meia-Idade , Estudos Transversais , China/epidemiologia , Comportamentos Relacionados com a Saúde , Doença CrônicaRESUMO
Natural killer (NK) cells actively participate in anti-tumor immunity and are thus regarded as a promising tool in immunotherapy against esophageal cancer (EC). However, the mechanisms regulating NK cell activation and exhaustion have not been completely elucidated. In this study, we characterized the expression and function of MLLT1 super elongation complex subunit (MLLT1) in esophageal NK cells in a mouse EC model. MLLT1 was down-regulated in esophageal NK cells, especially NK cells expressing both T cell immunoglobulin and mucin-domain containing-3 (TIM-3) and lymphocyte activation gene3(LAG-3). In vitro knockdown of MLLT1 in NK cells resulted in significant decreases in the expression of IFN-γ and perforin, as well as impaired NK cell cytotoxicity on tumor cells. Adoptive transfer of MLLT-deficient NK cells into EC-bearing mice showed consistent impairment of NK cell anti-tumor activity, as evidenced by decreases in IFN-γ and perforin but not granzyme B. Furthermore, EC tissue cells, which were enriched from the esophagus of EC-bearing mice, induced down-regulation of MLLT1 in splenic NK cells. This down-regulation was partially restored by a TIM-3 blocking antibody. Therefore, this study indicated that TIM-3 signaling down-regulated MLLT1 in esophageal NK cells, and MLLT1 down-regulation undermined the tumoricidal function of NK cells in EC. Our study unveils a novel mechanism underlying NK cell exhaustion/dysfunction in the EC microenvironment. MLLT1 could be a potential target in future NK cell-mediated immunotherapy against EC.
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Proteínas de Ligação a DNA/metabolismo , Neoplasias Esofágicas , Receptor Celular 2 do Vírus da Hepatite A , Fatores de Transcrição/metabolismo , Animais , Modelos Animais de Doenças , Regulação para Baixo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Células Matadoras Naturais , Camundongos , Perforina/genética , Perforina/metabolismo , Microambiente TumoralRESUMO
BACKGROUND: T helper 17 (Th17) cells actively participate in the tumor immune response in lung cancer. However, the heterogeneity and plasticity of intratumoral Th17 cells in lung cancer remain elusive. In this study, Th17 subpopulations were characterized in a mouse lung cancer model. METHODS: Urethane was administered to induce lung cancer in interleukin (IL)-17-EGFP transgenic mice. Flow cytometry was used to analyze the phenotypes, signaling status, and functions of Th17 subpopulations either in vivo or in vitro. The adoptive transfer assay and real-time polymerase chain reaction were applied to analyze the plasticity of Th17 subpopulations. RESULTS: IL-6Rαhigh CD27- Th17 and IL-6Rαlow CD27+ Th17 were identified in intratumoral Th17 cells. The two subpopulations expressed equivalent RORγt. However, the former expressed higher T-bet but lower Foxp3, more IL-17A and IFN-γ but less IL-10 than the latter. Furthermore, IL-6Rαhigh CD27- Th17 moderately inhibited the proliferation of lung cancer cells while IL-6Rαlow CD27+ Th17 could not. IL-6Rαhigh CD27- Th17 exhibited weaker Jun N-terminal kinases (JNK) signaling but stronger signal transducer and activator of transcription 3 (Stat3) signaling than IL-6Rαlow CD27+ Th17. The adoptive transfer assay indicated that both subpopulations downregulated RORγt in recipients' spleens but maintained RORγt in recipients' lungs. Meanwhile, IL-6Rαhigh CD27- Th17 expressed higher T-bet and IFN-γ than IL-6Rαlow CD27+ Th17 in the recipients. IL-6Rαlow CD27+ Th17 expressed Foxp3 and IL-10 in recipients' spleens but not lungs. CONCLUSIONS: This study reveals intratumoral Th17 subpopulations with distinct functional properties and signaling patterns, thus offering valuable insight into Th17 heterogeneity and plasticity in lung cancer.
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Neoplasias Pulmonares , Receptores de Interleucina-6 , Animais , Interferon gama , Neoplasias Pulmonares/genética , Camundongos , Receptores de Interleucina-6/genética , Células Th17 , Membro 7 da Superfamília de Receptores de Fatores de Necrose TumoralRESUMO
Osteoarthritis (OA) is a major cause of cartilage pain and limited mobility in middle-aged and elderly individuals. The degeneration of cartilage induced by inflammation and cartilage anabolic and catabolic disorder plays a key role in OA. Shikimic acid (SA), a natural ingredient extracted from Illicium verum, has been shown to exert notable anti-inflammatory effects in previous studies, suggesting its potential effects in the treatment of OA. In this study, we revealed that the pretreatment of SW1353 human chondrocytes with SA before interleukin 1ß (IL-1ß) stimulation effectively decreased the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (Cox)-2, matrix metalloproteinases (MMPs; MMP3 and MMP13), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5, type X collagen, and p62; increased the expression of type II collagen, ATG7, Beclin-1, and LC3; and increased the autophagic flux. Mechanistically, we found that SA suppressed the IL-1ß-induced activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) pathways. Furthermore, the results of safranin O staining and toluidine blue staining of primary rat cartilage chondrocytes and a trauma-induced rat model of OA showed that SA alleviated progression of OA in vivo. Collectively, our research enhances understanding of the mechanism of protective effect of SA against the progression of OA, which involves amelioration of cartilage degeneration, thereby providing new evidence for the use of SA as a therapy to prevent the development of OA.
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Multi-drug resistance (MDR) of tumor is a major cause of chemotherapy failure. In this study, a pH-sensitive graft copolymer, poly(ß-amino ester)-g-ß-cyclodextrin (PBAE-g-ß-CD), was synthesized via Michael addition polymerization and was employed to co-deliver doxorubicin (DOX), a chemotherapy agent, and adjudin (ADD), a mitochondrial inhibitor, in the form of dual-drug co-loaded nanoparticles (NPs). Specifically, DOX was conjugated to 1-adamantaneacetic acid (Aa) to generate a prodrug that was subsequently encapsulated in the cavity of cyclodextrin via host-guest interactions. In addition, ADD was encapsulated by poly(ß-aminoester) (PBAE). The introduction of the Aa-d-α-tocopheryl polyethylene glycolsuccinate (TPGS) conjugate enhanced the biocompatibility and serum stability of the resulting NPs. The NPs can realize precise ratiometric control of drugs being loaded, increase cellular uptake of the drugs, induce mitochondrial dysfunction and augment tumor treatment efficiency by inducing apoptosis. Western blot and polymerase chain reaction analyses showed that inhibition of P-glycoprotein and X-linked inhibitor of apoptosis protein expression may underlie inhibition of tumor resistance mediated by NPs. The MCF-7/ADR xenograft tumor model also revealed that in comparison with DOX, the NPs exhibited satisfactory performance in promoting apoptosis of tumor cells and achieved high therapeutic outcomes for MDR tumors. STATEMENT OF SIGNIFICANCE: Combination chemotherapy is an effective way to overcome MDR of tumor. However, one of the major obstacles for successful combination chemotherapy is the co-loading, co-delivery and controlled release of two different drugs, whose chemo-physical properties may be totally different. In this study, a pH-sensitive NP system was designed to realize the co-loading and precise ratiometric control of DOX and ADD, as well as the programmed drug release. That is, ADD release was triggered by low pH in endo/lysosome after endocytosis and then DOX was hydrolyzed to achieve a sustained release in tumor cells. Therefore, the NPs exhibited an effectively growth inhibition against MDR cells both in vitro and in vivo via the synergistic effect of ADD and DOX, which provided a promising strategy for treatment of MDR cancer.
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Doxorrubicina , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Hidrazinas , Indazóis , Nanopartículas , Neoplasias Experimentais , Animais , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Humanos , Hidrazinas/química , Hidrazinas/farmacocinética , Hidrazinas/farmacologia , Concentração de Íons de Hidrogênio , Indazóis/química , Indazóis/farmacocinética , Indazóis/farmacologia , Células MCF-7 , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The volatile compounds of mulberries obtained from three cultivars (M. nigra, Y1, M. Macroura, Y2 and M. Alba, Y3) were investigated by gas chromatography-olfactometry (GC-O), odor activity value (OAV), gas chromatography-mass spectrometry (GC-MS) and flame photometric detection (FPD). The results showed that 41, 37 and 41 compounds were detected in Y1, Y2 and Y3 samples, respectively. In addition, 12, 11, and 12 sulfur compounds were identified in three samples by FPD, respectively. Quantitative analysis showed 2-(methylthio)ethanol, methionol, dimethyl sulfide, methional and 3-ethylthiophene were present in relatively high amounts in each of the three samples. Furthermore, benzaldehyde, ethyl butanoate, (E)-2-nonenal, 1-hexanol, hexanal, methional, 3-mercaptohexyl acetate and 3-mercaptohexanol were present with much higher OAVs than other compounds. Finally, four compounds (pentanal, ethyl acetate, acetic acid, methionol) were selected to investigate possible effects on six descriptors, which indicated that the volatile compounds at sub-threshold concentrations are likely to contribute to overall aroma.
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Frutas/química , Morus/química , Odorantes/análise , Compostos Orgânicos Voláteis/análise , Acetatos/análise , Aldeídos/análise , Cromatografia Gasosa/métodos , Análise de Alimentos , Cromatografia Gasosa-Espectrometria de Massas/métodos , Olfatometria/métodos , Compostos de Enxofre/análise , Compostos Orgânicos Voláteis/químicaRESUMO
Twenty-four kinds of representative aroma compounds in Oolong tea were selected to evaluate the interactions by the variation in the threshold values of these compounds before, and after, they were mixed. Result demonstrated that the ratios of the referenced threshold values of heptanal, ß-damascenone, and methional to their determined thresholds were larger, namely, 5, 3.85, and 2.5, respectively. On the other hand, the mixed compounds with similar structure and aroma mainly presented a synergistic effect and additive action. Moreover, a masking effect was found among compounds with different structures. (E)-2-hexenal was added to tea infusion at a concentration below its threshold level to investigate whether, or not, the sub-threshold compounds affected the overall odour sensation of Oolong tea by sensory analysis and electronic nose (E-nose). The result indicated that the aroma of the tea infusion with added (E)-2-hexenal had changed before, and after, they were mixed.
Assuntos
Camellia sinensis/química , Nariz Eletrônico/estatística & dados numéricos , Chá/química , Compostos Orgânicos Voláteis/química , Sinergismo Farmacológico , OlfatoRESUMO
The volatile compounds of cranberries obtained from four cultivars (Early Black, Y1; Howes, Y2; Searles, Y3; and McFarlin, Y4) were analyzed by gas chromatography-olfactometry (GC-O), gas chromatography-mass spectrometry (GC-MS), and GC-flame photometric detection (FPD). The result presented that a total of thirty-three, thirty-four, thirty-four, and thirty-six odor-active compounds were identified by GC-O in the Y1, Y2, Y3, and Y4, respectively. In addition, twenty-two, twenty-two, thirty, and twenty-seven quantified compounds were demonstrated as important odorants according to odor activity values (OAVs > 1). Among these compounds, hexanal (OAV: 27-60), pentanal (OAV: 31-51), (E)-2-heptenal (OAV: 17-66), (E)-2-hexenal (OAV: 18-63), (E)-2-octenal (OAV: 10-28), (E)-2-nonenal (OAV: 8-77), ethyl 2-methylbutyrate (OAV: 10-33), ß-ionone (OAV: 8-73), 2-methylbutyric acid (OAV: 18-37), and octanal (OAV: 4-24) contributed greatly to the aroma of cranberry. Partial least-squares regression (PLSR) was used to process the mean data accumulated from sensory evaluation by the panelists, odor-active aroma compounds (OAVs > 1), and samples. Sample Y3 was highly correlated with the sensory descriptors "floral" and "fruity". Sample Y4 was greatly related to the sensory descriptors "mellow" and "green and grass". Finally, an aroma reconstitution (Model A) was prepared by mixing the odor-active aroma compounds (OAVs > 1) based on their measured concentrations in the Y1 sample, indicating that the aroma profile of the reconstitution was pretty similar to that of the original sample.