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Malic enzyme (ME) genes are key functional metabolic enzymes playing a crucial role in carcinogenesis. However, the detailed effects of ME gene expression on breast cancer progression remain unclear. Here, our results revealed ME1 expression was significantly upregulated in breast cancer, especially in patients with oestrogen receptor/progesterone receptor-negative and human epidermal growth factor receptor 2-positive breast cancer. Furthermore, upregulation of ME1 was significantly associated with more advanced pathological stages (p < 0.001), pT stage (p < 0.001) and tumour grade (p < 0.001). Kaplan-Meier analysis revealed ME1 upregulation was associated with poor disease-specific survival (DSS: p = 0.002) and disease-free survival (DFS: p = 0.003). Multivariate Cox regression analysis revealed ME1 upregulation was significantly correlated with poor DSS (adjusted hazard ratio [AHR] = 1.65; 95% CI: 1.08-2.52; p = 0.021) and DFS (AHR, 1.57; 95% CI: 1.03-2.41; p = 0.038). Stratification analysis indicated ME1 upregulation was significantly associated with poor DSS (p = 0.039) and DFS (p = 0.038) in patients with non-triple-negative breast cancer (TNBC). However, ME1 expression did not affect the DSS of patients with TNBC. Biological function analysis revealed ME1 knockdown could significantly suppress the growth of breast cancer cells and influence its migration ability. Furthermore, the infiltration of immune cells was significantly reduced when they were co-cultured with breast cancer cells with ME1 knockdown. In summary, ME1 plays an oncogenic role in the growth of breast cancer; it may serve as a potential biomarker of progression and constitute a therapeutic target in patients with breast cancer.
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Neoplasias de Mama Triplo Negativas , Humanos , Mama , Carcinogênese , Técnicas de Cocultura , Intervalo Livre de DoençaRESUMO
AIMS AND OBJECTIVES: The main aim of this study is to synthesize the prevalent predictive models for pressure injuries in hospitalized patients, with the goal of identifying common predictive factors linked to pressure injuries in hospitalized patients. This endeavour holds the potential to provide clinical nurses with a valuable reference for providing targeted care to high-risk patients. BACKGROUND: Pressure injuries (PIs) are a frequently occurring health problem throughout the world. There are mounting studies about risk prediction model of PIs reported and published. However, the prediction performance of the models is still unclear. DESIGN: Systematic review and meta-analysis: The Cochrane Library, PubMed, Embase, CINAHL, Web of Science and Chinese databases including CNKI (China National Knowledge Infrastructure), Wanfang Database, Weipu Database and CBM (China Biology Medicine). METHODS: This systematic review was conducted following PRISMA recommendations. The databases of Cochrane Library, PubMed, Embase, CINAHL, Web of Science, and CNKI, Weipu Database, Wanfang Database and CBM were searched for all studies published before September 2023. We included studies with cohort, case-control designs, reporting the development of risk model and have been validated externally and internally among the hospitalized patients. Two researchers selected the retrieved studies according to the inclusion and exclusion criteria, and critically evaluated the quality of studies based on the CHARMS checklist. The PRISMA guideline was used to report the systematic review and meta-analysis. RESULTS: Sixty-two studies were included, which contained 99 pressure injuries risk prediction models. The AUC (area under ROC curve) of modelling in 32 prediction models were reported ranged from .70 to .99, while the AUC of verification in 38 models were reported ranged from .70 to .98. Gender (OR = 1.41, CI: .99 ~ 1.31), age (WMD = 8.81, CI: 8.11 ~ 9.57), diabetes mellitus (OR = 1.64, CI: 1.36 ~ 1.99), mechanical ventilation (OR = 2.71, CI: 2.05 ~ 3.57), length of hospital stay (WMD = 7.65, CI: 7.24 ~ 8.05) were the most common predictors of pressure injuries. CONCLUSION: Studies of PIs risk prediction model in hospitalized patients had high research quality, and the risk prediction models also had good predictive performance. However, some of the included studies lacked of internal or external validation in modelling, which affected the stability and extendibility. The aged, male patient in ICU, albumin, haematocrit, low haemoglobin level, diabetes, mechanical ventilation and length of stay in hospital were high-risk factors for pressure injuries in hospitalized patients. In the future, it is recommended that clinical nurses, in practice, select predictive models with better performance to identify high-risk patients based on the actual situation and provide care targeting the high-risk factors to prevent the occurrence of diseases. RELEVANCE TO CLINICAL PRACTICE: The risk prediction model is an effective tool for identifying patients at the risk of developing PIs. With the help of risk prediction tool, nurses can identify the high-risk patients and common predictive factors, predict the probability of developing PIs, then provide specific preventive measures to improve the outcomes of these patients. REGISTRATION NUMBER (PROSPERO): CRD42023445258.
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BACKGROUND AND PURPOSE: Post-stroke cognitive impairment (PSCI) is a frequent consequence of stroke, which affects the quality of life and prognosis of stroke survivors. Numerous studies have indicated that blood biomarkers may be the key determinants for predicting and diagnosing cognitive impairment, but the results remain varied. Therefore, this meta-analysis aims to summarize potential biomarkers associated with PSCI. METHODS: PubMed, Web of Science, Embase, and Cochrane Library were comprehensively searched for studies exploring blood biomarkers associated with PSCI from inception to 15 April 2022. RESULTS: 63 studies were selected from 4,047 references, which involves 95 blood biomarkers associated with the PSCI. We meta-analyzed 20 potential blood biomarker candidates, the results shown that the homocysteine (Hcy) (SMD = 0.35; 95 %CI: 0.20-0.49; P < 0.00001), c-reactive protein (CRP) (SMD = 0.49; 95 %CI: 0.20-0.78; P = 0.0008), uric acid (UA) (SMD = 0.41; 95 %CI: 0.06-0.76; P = 0.02), interleukin 6 (IL-6) (SMD = 0.92; 95 % CI: 0.27-1.57; P = 0.005), cystatin C (Cys-C) (SMD = 0.58; 95 %CI: 0.28-0.87; P = 0.0001), creatinine (SMD = 0.39; 95 %CI: 0.23-0.55; P < 0.00001) and tumor necrosis factor alpha (TNF-α) (SMD = 0.45; 95 %CI: 0.08-0.82; P = 0.02) levels were significantly higher in patients with PSCI than in the non-PSCI group. CONCLUSION: Based on our findings, we recommend that paramedics focus on the blood biomarkers levels of Hcy, CRP, UA, IL-6, Cys-C, creatinine and TNF-α in conjunction with neuroimaging and neuropsychological assessment to assess the risk of PSCI, which may help with early detection and timely preventive measures. At the same time, other potential blood biomarkers should be further validated in future studies.
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Biomarcadores , Cognição , Disfunção Cognitiva , Valor Preditivo dos Testes , Acidente Vascular Cerebral , Humanos , Biomarcadores/sangue , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/complicações , Idoso , Feminino , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Idoso de 80 Anos ou maisRESUMO
Streptococcus pneumoniae is an opportunistic human pathogen that utilizes the competence regulon, a quorum-sensing circuitry, to acquire antibiotic resistance genes and initiate its attack on the human host. Interception of the competence regulon can therefore be utilized to study S. pneumoniae cell-cell communication and behavioral changes, as well as attenuate S. pneumoniae infectivity. Herein we report the design and synthesis of cyclic dominant negative competence-stimulating peptide (dnCSP) analogs capable of intercepting the competence regulon in both S. pneumoniae specificity groups with activities at the low nanomolar range. Structural analysis of lead analogs provided important insights as to the molecular mechanism that drives CSP receptor binding and revealed that the pan-group cyclic CSPs exhibit a chimeric hydrophobic patch conformation that resembles the hydrophobic patches required for both ComD1 and ComD2 binding. Moreover, the lead cyclic dnCSP, CSP1-E1A-cyc(Dap6E10), was found to possess superior pharmacological properties, including improved resistance to enzymatic degradation, while remaining nontoxic. Lastly, CSP1-E1A-cyc(Dap6E10) was capable of attenuating mouse mortality during acute pneumonia caused by both group 1 and group 2 S. pneumoniae strains. This cyclic pan-group dnCSP is therefore a promising drug lead scaffold against S. pneumoniae infections that could be administered individually or utilized in combination therapy to augment the effects of current antimicrobial agents.
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Proteínas de Bactérias/química , Proteínas de Bactérias/farmacologia , Percepção de Quorum/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Infecções Pneumocócicas/tratamento farmacológico , Ligação Proteica , Regulon/efeitos dos fármacosRESUMO
Head and neck squamous cell carcinoma (HNSCC) is the most common malignancy in Taiwan. Therefore, refining the diagnostic sensitivity of biomarkers for early-stage tumours and identifying therapeutic targets are critical for improving the survival rate of HNSCC patients. Metabolic reprogramming contributes to cancer development and progression. Metabolic pathways, specifically, play a crucial role in these diverse biological and pathological processes, which include cell proliferation, differentiation, apoptosis and carcinogenesis. Here, we investigated the role and potential prognostic value of the ubiquitin-conjugating enzyme E2 (UBE2) family in HNSCC. Gene expression database analysis followed by tumour comparison with non-tumour tissue showed that UBE2C was upregulated in tumours and was associated with lymph node metastasis in HNSCC patients. Knockdown of UBE2C significantly reduced the invasion/migration abilities of SAS and CAL27 cells. UBE2C modulates glycolysis pathway activation and HIF-1α expression in SAS and CAL27 cells. CoCl2 (HIF-1α inducer) treatment restored the expression of glycolytic enzymes and the migration/invasion abilities of UBE2C knockdown cells. Based on our findings, UBE2C expression mediates HIF-1α activation, increasing glycolysis pathway activation and the invasion/migration abilities of cancer cells. UBE2C may be an independent prognostic factor and a therapeutic target in HNSCC.
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Neoplasias de Cabeça e Pescoço , Subunidade alfa do Fator 1 Induzível por Hipóxia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Enzimas de Conjugação de Ubiquitina , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Glicólise/genética , Neoplasias de Cabeça e Pescoço/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Enzimas de Conjugação de Ubiquitina/genéticaRESUMO
Peptididylarginine deiminase type 2 (PADI2) catalyzes the conversion of arginine residues to citrulline residues on proteins. We demonstrate that PADI2 induces T cell activation and investigate how PADI2 promotes activated T cell autonomous death (ACAD). In activated Jurkat T cells, overexpression of PADI2 significantly increases citrullinated proteins and induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling, ultimately resulting in the expression of autophagy-related proteins and autophagy. PADI2 promoted autophagy and resulted in the early degradation of p62 and the light chain 3B (LC3B)-II accumulation. In Jurkat T cells, silencing the autophagy-related gene (Atg) 12 protein inhibits PADI2-mediated autophagy and promotes ER stress and apoptosis, whereas overexpression of Atg12 decreased ER stress and prolonged autophagy to promote cell survival. Additionally, PADI2 regulates T cell activation and the production of Th17 cytokines in Jurkat T cells (interleukins 6, IL-17A, IL-17F, IL-21, and IL-22). In Jurkat T cells, silencing IL-6 promotes autophagy mediated by PADI2 and inhibits PADI2-induced apoptosis, whereas silencing Beclin-1 increases the activation and survival of Th17-like T cells while decreasing autophagy and apoptosis. PADI2 silencing alleviates ER stress caused by PADI2 and decreases cytokine expression associated with Th17-like T cell activation and ACAD. We propose that PADI2 was involved in Th17 lymphocyte ACAD via a mechanism involving ER stress and autophagy that was tightly regulated by PADI2-mediated citrullination. These findings suggest that inhibiting Th17 T cell activation and the development of severe autoimmune diseases may be possible through the use of novel antagonists that specifically target PADI2.
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Estresse do Retículo Endoplasmático , Proteína-Arginina Desiminase do Tipo 2 , Células Th17 , Apoptose , Autofagia , Proteína Beclina-1 , Estresse do Retículo Endoplasmático/imunologia , Proteína-Arginina Desiminase do Tipo 2/imunologia , Células Th17/imunologiaRESUMO
Callicarpa nudiflora, belonging to the family Verbenaceaae, is wildly used as a traditional Chinese herbal medicine (Luo-hua-zi-zhu) for hemostasis, antibiosis and antiphlogosis in clinic. However, the underlying chemical basis of C. nudiflora for the significant effects remains obscure. Hence, an ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry method was established for the characterization of multi-constituents in C. nudiflora. As a result, 57 chemical compounds were identified based on their retention times, accurate masses and MS/MS data, and 20 of them were uncovered for the first time in C. nudiflora. In addition, an optimized UHPLC fingerprint analysis, combined with chemometrics including similarity analysis, principal component analysis and partial least squares-discriminant analysis was developed for quality assessment and origin discrimination of C. nudiflora. Multivariate data analysis revealed the resemblances and differences of C. nudiflora related to regions, while partial least squares-discriminant analysis screened nine characteristic markers including luteoloside, acteoside, luteolin-4'-O-ß-D-glucopyranoside, pachypodol, isoquercitrin, nudifloside, 5,7,3',4'-tetrahydroxy-8-methoxy-6-C-ß-D-glucopyranosylflavone, 7α-acetoxysandaracopimaric acid and sandaracopimaric acid which contributed the most to the classification. This was the first report on the comprehensive profiling of chemical components in C. nudiflora, which helped to uncover the material basis of C. nudiflora and possess potential value for quality evaluation and clinical application purpose.
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Callicarpa , Medicamentos de Ervas Chinesas , Callicarpa/química , Espectrometria de Massas em Tandem , Luteolina , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/químicaRESUMO
Cellular metabolism governs the signaling that supports physiological mechanisms and homeostasis in an individual, including neuronal transmission, wound healing, and circadian clock manipulation. Various factors have been linked to abnormal metabolic reprogramming, including gene mutations, epigenetic modifications, altered protein epitopes, and their involvement in the development of disease, including cancer. The presence of multiple distinct hallmarks and the resulting cellular reprogramming process have gradually revealed that these metabolism-related molecules may be able to be used to track or prevent the progression of cancer. Consequently, translational medicines have been developed using metabolic substrates, precursors, and other products depending on their biochemical mechanism of action. It is important to note that these metabolic analogs can also be used for imaging and therapeutic purposes in addition to competing for metabolic functions. In particular, due to their isotopic labeling, these compounds may also be used to localize and visualize tumor cells after uptake. In this review, the current development status, applicability, and limitations of compounds targeting metabolic reprogramming are described, as well as the imaging platforms that are most suitable for each compound and the types of cancer to which they are most appropriate.
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Relógios Circadianos , Neoplasias , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Relógios Circadianos/genética , Transdução de Sinais/genética , Reprogramação Celular , HomeostaseRESUMO
CONTEXT: Yi-Qi Cong-Ming (YQCM) decoction has been widely used to prevent age-related hearing loss (ARHL), the most prevalent neurodegenerative disease in the elderly. OBJECTIVE: To explore the mechanism of YQCM decoction in the treatment of ARHL. MATERIALS AND METHODS: The chemical constituents of YQCM were screened from the Traditional Chinese Medicine Systems Pharmacology Database. Potential targets of YQCM against ARHL were predicted by DrugBank, GeneCards, and OMIM database. Protein-protein network and enrichment analysis were used for exploring possible molecular mechanisms. Molecular docking and an in vitro model of ARHL by exposing auditory cells with 100 µM H2O2 for 3 h were applied. Cell viability and mitochondrial membrane potential (ΔΨM) were detected by CCK-8 and high-content analysis. γH2AX and cleaved caspase-3 were detected by Western blot. RESULTS: The main compounds have good affinities with hub targets, especially AKT1, PTGS2, and CASP3. GO and KEGG analysis showed that the main biological process and key targets were related to negative regulation of the apoptotic process. H2O2 treatment could reduce the cell viability by 68% and impaired ΔΨM, while 90 µg/mL YQCM pre-treatment could restore the cell viability by 97.45% and increase ΔΨM (2-fold higher). YQCM pre-treatment also reduced γH2AX and cleaved caspase-3 protein levels. CONCLUSIONS: Our study suggested that YQCM prevents ARHL by modulating the apoptosis process in auditory hair cells. Moreover, this study proved that bioinformatics analysis combined with molecular docking and cell model is a promising method to explore other possible pharmacological interventions of ARHL.
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Medicamentos de Ervas Chinesas , Perda Auditiva , Doenças Neurodegenerativas , Idoso , Caspase 3 , Medicamentos de Ervas Chinesas/uso terapêutico , Perda Auditiva/tratamento farmacológico , Humanos , Peróxido de Hidrogênio/toxicidade , Medicina Tradicional Chinesa/métodos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Doenças Neurodegenerativas/tratamento farmacológicoRESUMO
This study reveals an uncovered mechanism for the regulation of polyamine homeostasis through protein arginyl citrullination of antizyme (AZ), a natural inhibitor of ornithine decarboxylase (ODC). ODC is critical for the cellular production of polyamines. AZ binds to ODC dimers and promotes the degradation of ODC via the 26S proteasome. This study demonstrates the protein citrullination of AZ catalyzed by peptidylarginine deiminase type 4 (PAD4) both in vitro and in cells. Upon PAD4 activation, the AZ protein was citrullinated and accumulated, leading to higher levels of ODC proteins in the cell. In the PAD4-overexpressing and activating cells, the levels of ODC enzyme activity and the product putrescine increased with the level of citrullinated AZ proteins and PAD4 activity. Suppressing cellular PAD4 activity reduces the cellular levels of ODC and downregulates cellular polyamines. Furthermore, citrullination of AZ in the C-terminus attenuates AZ function in the inhibition, binding, and degradation of ODC. This paper provides evidence to illustrate that PAD4-mediated AZ citrullination upregulates cellular ODC and polyamines by retarding ODC degradation, thus interfering with the homeostasis of cellular polyamines, which may be an important pathway regulating AZ functions that is relevant to cancer biology.
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Citrulinação/efeitos dos fármacos , Homeostase/fisiologia , Inibidores da Ornitina Descarboxilase/farmacologia , Ornitina Descarboxilase/metabolismo , Poliaminas/metabolismo , Proteínas de Transporte/metabolismo , Citrulinação/fisiologia , Homeostase/efeitos dos fármacos , Humanos , Inibidores da Ornitina Descarboxilase/metabolismo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismoRESUMO
PURPOSE: Extensive clinical evidence suggests that time spent outdoors might reduce the risk of myopia. This study aimed to determine whether increasing sunlight exposure has a protective effect on hyperopic-defocus induced myopia in a non-human primate. METHODS: Twelve 2-month-old rhesus monkeys were treated monocularly with photorefractive keratectomy (PRK) (4.0 D) and divided randomly into two groups: artificial light (AL; n = 6) and natural light (NL; n = 6). Monkeys in the AL group were reared under artificial (indoor) lighting (08:00-20:00 h). Monkeys in the NL group were exposed to natural (outdoor) lighting for 4 h (09:00-11:00 and 15:00-17:00 h). Ocular refraction, corneal power and axial dimensions were measured before sunlight exposure and every 10 days after PRK. At day 180, retinal histology and apoptosis activity were evaluated by hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase biotin (dUTP) nick end labelling (TUNEL) assay. RESULTS: Mean (±SD) PRK induced anisometropia was +3.11 (0.33) D. At the end of the experiment, both eyes of the NL monkeys exhibited significantly more hyperopia and shorter vitreous chamber depths (VCD), compared with AL monkeys (p < 0.05). The NL group exhibited a significantly slower rate of compensation to the induced anisometropia than the AL group (p < 0.05). The retinas of both groups exhibited normal histology and levels of apoptosis. CONCLUSIONS: Moderate sunlight exposure exerts protective effects against the myopic shift resulting from PRK-induced defocus in monkeys. These results are consistent with current clinical findings that increased outdoor exposure protects against myopia development. Sunlight exposure should serve as an independent positive factor in human myopia control.
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Miopia , Ceratectomia Fotorrefrativa , Luz Solar , Animais , Córnea , Lasers de Excimer , Macaca mulatta , Miopia/etiologia , Miopia/prevenção & controle , Ceratectomia Fotorrefrativa/efeitos adversos , Refração OcularRESUMO
Urothelial cancer is a malignant tumor with metastatic ability and high mortality. Malignant tumors of the urinary system include upper tract urothelial cancer and bladder cancer. In addition to typical genetic alterations and epigenetic modifications, metabolism-related events also occur in urothelial cancer. This metabolic reprogramming includes aberrant expression levels of genes, metabolites, and associated networks and pathways. In this review, we summarize the dysfunctions of glycolytic enzymes in urothelial cancer and discuss the relevant phenotype and signal transduction. Moreover, we describe potential prognostic factors and risks to the survival of clinical cancer patients. More importantly, based on several available databases, we explore relationships between glycolytic enzymes and genetic changes or drug responses in urothelial cancer cells. Current advances in glycolysis-based inhibitors and their combinations are also discussed. Combining all of the evidence, we indicate their potential value for further research in basic science and clinical applications.
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Inibidores Enzimáticos/farmacologia , Transdução de Sinais/genética , Neoplasias Urológicas/enzimologia , Neoplasias Urológicas/genética , Efeito Warburg em Oncologia/efeitos dos fármacos , Anaerobiose/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Humanos , Fenótipo , Prognóstico , Regulação para Cima/genéticaRESUMO
BACKGROUND: Chemotherapy is currently one of the most effective treatments for advanced breast cancer. Anti-microtubule agents, including taxanes, eribulin and vinca-alkaloids are one of the primary major anti-breast cancer chemotherapies; however, chemoresistance remains a problem that is difficult to solve. We aimed to discover novel candidate protein targets to combat chemoresistance in breast cancer. METHODS: A lentiviral shRNA-based high-throughput screening platform was designed and developed to screen the global kinome to find new therapeutic targets in paclitaxel-resistant breast cancer cells. The phenotypes were confirmed with alternative expression in vitro and in vivo. Molecular mechanisms were investigated using global phosphoprotein arrays and expression microarrays. Global microarray analysis was performed to determine TAOK3 and genes that induced paclitaxel resistance. RESULTS: A serine/threonine kinase gene, TAOK3, was identified from 724 screened kinase genes. TAOK3 shRNA exhibited the most significant reduction in IC50 values in response to paclitaxel treatment. Ectopic downregulation of TAOK3 resulted in paclitaxel-resistant breast cancer cells sensitize to paclitaxel treatment in vitro and in vivo. The expression of TAOK3 also was correlated to sensitivity to two other anti-microtubule drugs, eribulin and vinorelbine. Our TAOK3-modulated microarray analysis indicated that NF-κB signaling played a major upstream regulation role. TAOK3 inhibitor, CP43, and shRNA of NF-κB both reduced the paclitaxel resistance in TAOK3 overexpressed cells. In clinical microarray databases, high TAOK3 expressed breast cancer patients had poorer prognoses after adjuvant chemotherapy. CONCLUSIONS: Here we identified TAOK3 overexpression increased anti-microtubule drug resistance through upregulation of NF-κB signaling, which reduced cell death in breast cancer. Therefore, inhibition of the interaction between TAOK3 and NF-κB signaling may have therapeutic implications for breast cancer patients treated with anti-microtubule drugs. Video abstract.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Microtúbulos/metabolismo , NF-kappa B/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Camundongos Endogâmicos NOD , Camundongos SCID , Paclitaxel/farmacologia , Prognóstico , Taxoides/farmacologiaRESUMO
The competence stimulating peptide (CSP) plays a key role in the regulation of pneumococcal quorum sensing (QS), a communication system that is critical to the infectivity of pneumococci. CSP functions through binding and activating a transmembrane receptor, ComD. Molecules that can modulate pneumococcal QS through intercepting CSP:ComD interaction may serve as new generation of antibacterial agents to treat pneumococcal infections. In this work, we systematically modified the N-terminus of CSP1, a region that is essential to ComD activation, to identify detailed structural features of the N-terminus that are responsible for its function. Our results revealed structural features that are optimal to achieve receptor activation and structure-activity trends that improve our understanding of CSP:ComD interaction, all of which will contribute to the design of novel pneumococcal QS modulators with higher potency and improved pharmacological properties.
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Proteínas de Bactérias/metabolismo , Peptídeos/química , Percepção de Quorum/efeitos dos fármacos , Streptococcus pneumoniae/metabolismo , Proteínas de Bactérias/química , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Peptídeos/farmacologia , Relação Estrutura-AtividadeRESUMO
Streptococcus pneumoniae is an important pathogen that utilizes quorum sensing (QS) to regulate genetic transformation, virulence, and biofilm formation. The competence-stimulating peptide (CSP) is a 17-amino acid signal peptide that is used by S. pneumoniae to trigger QS. S. pneumoniae strains can be divided into two main specificity groups based on the CSP signal they produce (CSP1 or CSP2) and their compatible receptors (ComD1 or ComD2, respectively). Modulation of QS in S. pneumoniae can be achieved by targeting the CSP:ComD interaction using synthetic CSP analogues. However, to rationally design CSP-based QS modulators with enhanced activities, an in-depth understanding of the structural features that are required for receptor binding is needed. Herein, we report a comprehensive in-solution three-dimensional structural characterization of eight CSP1 and CSP2 analogues with varied biological activities using nuclear magnetic resonance spectroscopy. Analysis of these structures revealed two distinct hydrophobic patches required for effective ComD1 and ComD2 binding.
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Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Percepção de Quorum , Receptores de Superfície Celular/metabolismo , Streptococcus pneumoniae/metabolismo , Modelos Moleculares , Conformação ProteicaRESUMO
A series of tetrandrine derivatives were designed and synthesized using Suzuki coupling reaction. Eleven targeted compounds with over 50% inhibition against HL60 and A549 human cancer cell lines at 10 µM were further evaluated for the in vitro antitumor activities by MTT or SRB assay. The biological results revealed that some compounds exhibited potent antitumor activities. Thiophene derivative 6 and acetylphenyl derivative 5 were the most active ones against HL60 and A549 cell lines, with IC50 values less than 5 µM, which thus could be considered as useful candidate for further development of new antitumor agents.
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Antineoplásicos/síntese química , Benzilisoquinolinas/síntese química , Benzilisoquinolinas/farmacologia , Desenho de Fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzilisoquinolinas/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
This study was aimed to optimize the extraction (CO2 supercritical extraction) process and purification (ethanol washing and decontaminating) process of total fatty acid in Brassica campestris pollen. With the extraction yield of total fatty acid as index, CO2 supercritical extraction of total fatty acid in B. campestris polle was optimized by central composite design-response surface methodology. Ethanol washing and decontaminating was done for the extract through orthogonal design with content of total fatty acid (linolenic acid amide, linolenic acid glyceride, linolenic acid and palmitic acid) as the indexes. The optimum parameters of CO2 supercritical extraction technology were as follows: extraction pressure of 35 MPa, extraction temperature of 60 âand extraction time of 3 h. When extract of supercritical fluid was purified by 50 times of 80% ethanol for 1.5 h, the content of total fatty acid can reach 60%. In addition, this process was stable and steady, provided reliable basis for production.
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Brassica/química , Cromatografia com Fluido Supercrítico/métodos , Ácidos Graxos/isolamento & purificação , Pólen/química , Ácidos Graxos/química , Cromatografia Gasosa-Espectrometria de Massas , Óleos de Plantas/química , Óleos de Plantas/isolamento & purificação , Pressão , TemperaturaRESUMO
Lung cancer is the leading cause of cancer mortality worldwide. Although many biomarkers have been identified for lung cancer, their low specificity and sensitivity present an urgent need for the identification of more candidate biomarkers. In this study, we conducted MRM-based targeted analysis to evaluate the potential utility of a list of candidate proteins for lung cancer diagnosis. A total of 1249 transitions of 420 peptides representing 102 candidate proteins from our previous study and the literature were first screened by MRM analysis in pooled plasma samples, resulting in 78 proteins remaining in the list. Relative quantification of these 78 proteins was further performed in 60 individual plasma samples from lung adenocarcinoma patients in stages I-III and matched healthy control subjects. Ultimately, nine proteins were found to be able to distinguish patients from controls. Further combinations of five, three, and two candidate marker proteins improved the sensitivity to discriminate patients from controls and resulted in a merged AUC value of nearly 1.00 in stages I-III patients versus controls. Our results highlighted several possible markers for lung adenocarcinoma, and the proposed protein panels require further validation in a larger cohort to evaluate their potential use in clinical applications or development of therapeutics.
Assuntos
Adenocarcinoma/sangue , Biomarcadores Tumorais/sangue , Neoplasias Pulmonares/sangue , Espectrometria de Massas/métodos , Peptídeos/sangue , Proteômica/métodos , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Biomarcadores Tumorais/metabolismo , Proteínas Sanguíneas/análise , Proteínas Sanguíneas/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Estadiamento de Neoplasias , Peptídeos/metabolismo , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
RATIONALE: Metabolic alterations contribute to cancer development and progression. However, the molecular mechanisms relating metabolism to cancer metastasis remain largely unknown. OBJECTIVES: To identify a key metabolic enzyme that is aberrantly overexpressed in invasive lung cancer cells and to investigate its functional role and prognostic value in lung cancer. METHODS: The differential expression of metabolic enzymes in noninvasive CL1-0 cells and invasive CL1-5 cells was analyzed by a gene expression microarray. The expression of target genes in clinical specimens from patients with lung cancer was examined by immunohistochemistry. Pharmacologic and gene knockdown/overexpression approaches were used to investigate the function of the target gene during invasion and metastasis in vitro and in vivo. The association between the target gene expression and clinicopathologic parameters was further analyzed. Bioinformatic analyses were used to discover the signaling pathways involved in target gene-regulated invasion and migration. MEASUREMENTS AND MAIN RESULTS: Squalene synthase (SQS) was up-regulated in CL1-5 cells and in the tumor regions of the lung cancer specimens. Loss of function or knockdown of SQS significantly inhibited invasion/migration and metastasis in cell and animal models and vice versa. High expression of SQS was significantly associated with poor prognosis among patients with lung cancer. Mechanistically, SQS contributed to a lipid-raft-localized enrichment of tumor necrosis factor receptor 1 in a cholesterol-dependent manner, which resulted in the enhancement of nuclear factor-κB activation leading to matrix metallopeptidase 1 up-regulation. CONCLUSIONS: Up-regulation of SQS promotes metastasis of lung cancer by enhancing tumor necrosis factor-α receptor 1 and nuclear factor-κB activation and matrix metallopeptidase 1 expression. Targeting SQS may have considerable potential as a novel therapeutic strategy to treat metastatic lung cancer.
Assuntos
Farnesil-Difosfato Farnesiltransferase/metabolismo , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/secundário , Microdomínios da Membrana/metabolismo , Invasividade Neoplásica/fisiopatologia , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Animais , Linhagem Celular Tumoral , Colesterol/biossíntese , Modelos Animais de Doenças , Farnesil-Difosfato Farnesiltransferase/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Metaloproteinase 1 da Matriz/metabolismo , Prognóstico , Regulação para CimaRESUMO
Phytochemical investigation on the EtOH extract from the aerial part of Callicarpa kwangtungensis led to the isolation and characterization of 10 caffeoyl phenylethanoid glycosides, 2'-acetylacteoside (1), tubuloside E (2), acteoside (3), tubuloside B (4), isoacteoside (5), alyssonoside (6), 2'-acetylforsythoside B (7), brandioside (8), forsythoside B (9), and poliumoside (10). Compound 4 was isolated from the plants of Verbenaceae,and 6 was obtained from the Callicarpa genus, for the first time, while compounds 1, 2, 5 and 7 were firstly reported from the plant.