RESUMEN
BACKGROUND: The novel coronavirus disease 2019 (COVID-19) spreads rapidly among people and causes a pandemic. It is of great clinical significance to identify COVID-19 patients with high risk of death. METHODS: A total of 2169 adult COVID-19 patients were enrolled from Wuhan, China, from February 10th to April 15th, 2020. Difference analyses of medical records were performed between severe and non-severe groups, as well as between survivors and non-survivors. In addition, we developed a decision tree model to predict death outcome in severe patients. RESULTS: Of the 2169 COVID-19 patients, the median age was 61 years and male patients accounted for 48%. A total of 646 patients were diagnosed as severe illness, and 75 patients died. An older median age and a higher proportion of male patients were found in severe group or non-survivors compared to their counterparts. Significant differences in clinical characteristics and laboratory examinations were found between severe and non-severe groups, as well as between survivors and non-survivors. A decision tree, including three biomarkers, neutrophil-to-lymphocyte ratio, C-reactive protein and lactic dehydrogenase, was developed to predict death outcome in severe patients. This model performed well both in training and test datasets. The accuracy of this model were 0.98 in both datasets. CONCLUSION: We performed a comprehensive analysis of COVID-19 patients from the outbreak in Wuhan, China, and proposed a simple and clinically operable decision tree to help clinicians rapidly identify COVID-19 patients at high risk of death, to whom priority treatment and intensive care should be given.
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COVID-19 , Adulto , China/epidemiología , Árboles de Decisión , Humanos , Recién Nacido , Masculino , Estudios Retrospectivos , Factores de Riesgo , SARS-CoV-2RESUMEN
CONTEXT: Previous studies indicate that compound Danshen Dripping Pill (CDDP) improves the adaptation to high-altitude exposure. However, its mechanism of action is not clear. OBJECTIVE: To explore the protective effect of CDDP on hypobaric hypoxia (HH) and its possible mechanism. MATERIALS AND METHODS: A meta-analysis of 1051 human volunteers was performed to evaluate the effectiveness of CDDP at high altitudes. Male Sprague-Dawley rats were randomized into 5 groups (n = 6): control at normal pressure, model, CDDP-170 mg/kg, CDDP-340 mg/kg and acetazolamide groups. HH was simulated at an altitude of 5500 m for 24 h. Animal blood was collected for arterial blood-gas analysis and cytokines detection and their organs were harvested for pathological examination. Expression levels of AQP1, NF-κB and Nrf2 were determined by immunohistochemical staining. RESULTS: The meta-analysis data indicated that the ratio between the combined RR of the total effective rate and the 95% CI was 0.23 (0.06, 0.91), the SMD and 95% CI of SO2 was 0.37 (0.12, 0.62). Pre-treatment of CDDP protected rats from HH-induced pulmonary edoema and heart injury, left-shifted oxygen-dissociation curve and decreased P50 (30.25 ± 3.72 vs. 37.23 ± 4.30). Mechanistically, CDDP alleviated HH-reinforced ROS by improving SOD and GPX1 while inhibiting pro-inflammatory cytokines and NF-κB expression. CDDP also decreased HH-evoked D-dimer, erythrocyte aggregation and blood hemorheology, promoting AQP1 and Nrf2 expression. DISCUSSION AND CONCLUSIONS: Pre-treatment with CDDP could prevent HH-induced tissue damage, oxidative stress and inflammatory response. Suppressed NF-κB and up-regulated Nrf2 might play significant roles in the mechanism of CDDP.
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Mal de Altura/tratamiento farmacológico , Canfanos/farmacología , Medicamentos Herbarios Chinos/farmacología , Inflamación/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Acetazolamida/farmacología , Animales , Análisis de los Gases de la Sangre , Canfanos/administración & dosificación , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Humanos , Inflamación/etiología , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Panax notoginseng , Ensayos Clínicos Controlados Aleatorios como Asunto , Ratas , Ratas Sprague-Dawley , Salvia miltiorrhizaRESUMEN
Mitsugumin 53 (MG53) is a tripartite motif family protein that has been reported to attenuate injury via membrane repair in different organs. Contrast-induced acute kidney injury (CI-AKI) is a common complication caused by the administration of iodinated contrast media (CM). While the cytotoxicity induced by CM leading to tubular cell death may be initiated by cell membrane damage, we wondered whether MG53 alleviates CI-AKI. This study was designed to investigate the effect of MG53 on CI-AKI and the underlying mechanism. A rat model of CI-AKI was established, and CI-AKI induced the translocation of MG53 from serum to injury sites on the renal proximal tubular (RPT) epithelia, as illustrated by immunoblot analysis and immunohistochemical staining. Moreover, pretreatment of rats with recombinant human MG53 protein (rhMG53, 2 mg/mL) alleviated iopromide-induced injury in the kidney, which was determined by measuring serum creatinine, blood urea nitrogen and renal histological changes. In vitro studies demonstrated that exposure of RPT cells to iopromide (20, 40, and 80 mg/mL) caused cell membrane injury and cell death, which were attenuated by rhMG53 (10 and 50 µg/mL). Mechanistically, MG53 translocated to the injury site on RPT cells and bound to phosphatidylserine to protect RPT cells from iopromide-induced injury. In conclusion, MG53 protects against CI-AKI through cell membrane repair and reducing cell apoptosis; therefore, rhMG53 might be a potential effective means to treat or prevent CI-AKI.
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Lesión Renal Aguda/prevención & control , Apoptosis/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Sustancias Protectoras/uso terapéutico , Proteínas de Motivos Tripartitos/uso terapéutico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Animales , Membrana Celular/metabolismo , Células Epiteliales , Femenino , Humanos , Yohexol/análogos & derivados , Riñón/patología , Túbulos Renales Proximales/citología , Masculino , Fosfatidilserinas/metabolismo , Sustancias Protectoras/metabolismo , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapéutico , Proteínas de Motivos Tripartitos/metabolismoRESUMEN
BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, lacking effective targeted therapies, and whose underlying mechanisms are still unclear. The gene coding for Gametogenetin-binding protein (GGNBP2), also known as Zinc Finger Protein 403 (ZNF403), is located on chromosome 17q12-q23, a region known as a breast cancer susceptibility locus. We have previously reported that GGNBP2 functions as a tumor suppressor in estrogen receptor-positive breast cancer. The aim of this study was to evaluate the role and mechanisms of GGNBP2 in TNBC. METHODS: The effect of GGNBP2 on TNBC aggressiveness was investigated both in vitro and in vivo. The protein and mRNA expression levels were analyzed by western blotting and reverse transcription quantitative polymerase chain reaction, respectively. Fluorescence-activated cell sorting analysis was used to evaluate the cell cycle distribution and cell apoptosis. Immunohistochemistry was used to determine the expression of GGNBP2 in breast cancer tissues. RESULTS: We find that GGNBP2 expression decreases in TNBC tissues and is associated with the outcome of breast cancer patients. Furthermore, experimental overexpression of GGNBP2 in MDA-MB-231 and Cal51 cells suppresses cell proliferation, migration and invasion, reduces the cancer stem cell subpopulation, and promotes cell apoptosis in vitro as well as inhibits tumor growth in vivo. In these cell models, overexpression of GGNBP2 decreases the activation of IL-6/STAT3 signaling. CONCLUSION: Our data demonstrate that GGNBP2 suppresses cancer aggressiveness by inhibition of IL-6/STAT3 activation in TNBC.
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Regulación Neoplásica de la Expresión Génica/fisiología , Interleucina-6/metabolismo , Factor de Transcripción STAT3/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Biomarcadores de Tumor/análisis , Femenino , Xenoinjertos , Humanos , Estimación de Kaplan-Meier , Ratones , Ratones Desnudos , Pronóstico , Transducción de Señal/fisiología , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
In the original publication, Fig. 1 depicting the blot for EP300 in CAL51 cells (Fig. 1c) was unintentionally duplicated with that from MDA-MB-231 cells (Fig. 1d). The new figure given in this erratum depicts the correct EP300 blot in Fig. 1c.
RESUMEN
Hormone therapy has become one of the main strategies for breast cancer, however, many estrogen receptor (ER) positive patients end in tumor collapse due to initial or acquired resistance to hormone treatment, which includes Fulvestrant. Here we report that ErbB receptors and downstream PI3K/AKT and ERK pathway have been reactivated after treatment of Fulvestrant in ER positive MCF-7 and T47D cells, which are related to Fulvestrant resistance. HSP90 is a universally expressed chaperone protein and plays a vital role in both normal and cancer cells, HSP90 inhibitor AUY922 can reverse this feedback reactivation effect of Fulvestrant by targeting multiple proteins related in ErbB receptors, PI3K/AKT and ERK pathway, which is much better than single targeting inhibitors. We also consolidate these effects in human fresh breast tumors. Combination of AUY922 and Fulvestrant may become a promising therapy strategy in breast cancer treatment.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Estradiol/análogos & derivados , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Isoxazoles/farmacología , Resorcinoles/farmacología , Antineoplásicos Hormonales/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Estradiol/farmacología , Femenino , Fulvestrant , Humanos , Células MCF-7 , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Estrógenos/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
PURPOSE: We have previously described a novel pathway controlling drug resistance, epithelial-to-mesenchymal transition (EMT) and stemness in breast cancer cells. Upstream in the pathway, three miRs (miR-106b, miR-93 and miR-25) target EP300, a transcriptional activator of E-cadherin. Upregulation of these miRs leads to the downregulation of EP300 and E-cadherin with initiation of an EMT. However, miRs regulate the expression of many genes, and the contribution to EMT by miR targets other than EP300 cannot be ruled out. METHODS: We used lentiviruses expressing EP300-targeting shRNA to downregulate its expression in MCF-7 cells as well as an EP300-knocked-out colon carcinoma cell line. An EP300-expression plasmid was used to upregulate its expression in basal-like CAL51 and MDA-MB-231 breast cancer cells. Drug resistance was determined by short-term proliferation and long-term colony formation assays. Stemness was determined by tumour sphere formation in both soft agar and liquid cultures as well as by the expression of CD44/CD24/ALDH markers. Gene expression microarray analysis was performed in MCF-7 cells lacking EP300. EP300 expression was analysed by immunohistochemistry in 17 samples of metaplastic breast cancer. RESULTS: Cells lacking EP300 became more resistant to paclitaxel whereas EP300 overexpression increased their sensitivity to the drug. Expression of cancer stem cell markers, as well as tumour sphere formation, was also increased in EP300-depleted cells, and was diminished in EP300-overexpressing cells. The EP300-regulated gene signature highlighted genes associated with adhesion (CEACAM5), cytoskeletal remodelling (CAPN9), stemness (ABCG2), apoptosis (BCL2) and metastasis (TGFB2). Some genes in this signature were also validated in a previously generated EP300-depleted model of breast cancer using minimally transformed mammary epithelial cells. Importantly, two key genes in apoptosis and stemness, BCL2 and ABCG2, were also upregulated in EP300-knockout colon carcinoma cells and their paclitaxel-resistant derivatives. Immunohistochemical analysis demonstrated that EP300 expression was low in metaplastic breast cancer, a rare, but aggressive form of the disease with poor prognosis that is characterized by morphological and physiological features of EMT. CONCLUSIONS: EP300 plays a major role in the reprogramming events, leading to a more malignant phenotype with the acquisition of drug resistance and cell plasticity, a characteristic of metaplastic breast cancer.
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Neoplasias de la Mama/genética , Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Proteína p300 Asociada a E1A/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Calpaína/genética , Antígeno Carcinoembrionario/genética , Plasticidad de la Célula/genética , Femenino , Proteínas Ligadas a GPI/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lentivirus/genética , Células MCF-7 , Metástasis de la Neoplasia , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Paclitaxel/administración & dosificación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Factor de Crecimiento Transformador beta2/genéticaRESUMEN
Gametogenetin-binding protein 2 (GGNBP2) is encoded in human chromosome 17q12-q23, a region known as a breast and ovarian cancer susceptibility locus. GGNBP2, also referred to ZFP403, has a single C2H2 zinc finger and a consensus LxxLL nuclear receptor-binding motif. Here, we demonstrate that GGNBP2 expression is reduced in primary human breast tumors and in breast cancer cell lines, including T47D, MCF-7, LCC9, LY2, and MDA-MB-231 compared with normal, immortalized estrogen receptor α (ERα) negative MCF-10A and MCF10F breast epithelial cells. Overexpression of GGNBP2 inhibits the proliferation of T47D and MCF-7 ERα positive breast cancer cells without affecting MCF-10A and MCF10F. Stable GGNBP2 overexpression in T47D cells inhibits 17ß-estradiol (E2)-stimulated proliferation as well as migration, invasion, anchorage-independent growth in vitro, and xenograft tumor growth in mice. We further demonstrate that GGNBP2 protein physically interacts with ERα, inhibits E2-induced activation of estrogen response element-driven reporter activity, and attenuates ER target gene expression in T47D cells. In summary, our in vitro and in vivo findings suggest that GGNBP2 is a novel breast cancer tumor suppressor functioning as a nuclear receptor corepressor to inhibit ERα activity and tumorigenesis.
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Neoplasias de la Mama/metabolismo , Regulación hacia Abajo , Receptor alfa de Estrógeno/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Estradiol/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Ratones , Trasplante de Neoplasias , Elementos de Respuesta/efectos de los fármacosRESUMEN
The epidermal growth factor receptor (EGFR)/PI3K/AKT signaling pathway aberrations play significant roles in breast cancer occurrence and development. However, the status of EGFR and AKT1 gene copy numbers remains unclear. In this study, we showed that the rates of EGFR and AKT1 gene copy number alterations were associated with the prognosis of breast cancer. Among 205 patients, high EGFR and AKT1 gene copy numbers were observed in 34.6% and 27.8% of cases by multi-gene fluorescence in situ hybridization, respectively. Co-heightened EGFR/AKT1 gene copy numbers were identified in 11.7% cases. No changes were found in 49.3% of patients. Although changes in EGFR and AKT1 gene copy numbers had no correlation with patients' age, tumor stage, histological grade and the expression status of other molecular makers, high EGFR (P = 0.0002) but not AKT1 (P = 0.1177) gene copy numbers correlated with poor 5-year overall survival. The patients with co-heightened EGFR/AKT1 gene copy numbers displayed a poorer prognosis than those with tumors with only high EGFR gene copy numbers (P = 0.0383). Both Univariate (U) and COX multivariate (C) analyses revealed that high EGFR and AKT1 gene copy numbers (P = 0.000 [U], P = 0.0001 [C]), similar to histological grade (P = 0.001 [U], P = 0.012 [C]) and lymph node metastasis (P = 0.046 [U], P = 0.158 [C]), were independent prognostic indicators of 5-year overall survival. These results indicate that high EGFR and AKT1 gene copy numbers were relatively frequent in breast cancer. Co-heightened EGFR/AKT1 gene copy numbers had a worse outcome than those with only high EGFR gene copy numbers, suggesting that evaluation of these two genes together may be useful for selecting patients for anti-EGFR-targeted therapy or anti-EGFR/AKT1-targeted therapy and for predicting outcomes.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Receptores ErbB/genética , Dosificación de Gen , Proteínas Proto-Oncogénicas c-akt/genética , Anciano , Biomarcadores de Tumor/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Hibridación Fluorescente in Situ/métodos , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
Multidrug resistance (MDR) remains one of the most significant obstacles in breast cancer treatment, and this process often involves dysregulation of a great number of microRNAs (miRNAs). Some miRNAs are indicators of drug resistance and confer resistance to chemotherapeutic drugs, although our understanding of this complex process is still incomplete. We have used a combination of miRNA profiling and real-time PCR in two drug-resistant derivatives of MCF-7 and Cal51 cells. Experimental modulation of miR expression has been obtained by retroviral transfection. Taxol and doxorubicin IC50 values were obtained by short-term drug sensitivity assays. Apoptosis was determined by flow cytometry after annexin V staining, by caspase 3/7 and caspase 9 activity assays and the levels of apoptosis-related proteins bcl-2 and bax by real-time PCR and Western blot. miR target was studied using transient transfection of luciferase constructs with the 3' untranslated regions (UTR) of target mRNAs. Small interfering RNA-mediated genetic knock-down was performed in MDR cells and its modulatory effect on apoptosis examined. The effect of miRNA on tumorigenicity and tumor drug response was studied in mouse xenografts. miRNA profiling of two drug-resistant breast cancer cell models indicated that miR-218 was down-regulated in both MCF-7/A02 and CALDOX cells. Ectopic expression of miR-218 resensitized both drug-resistant cell lines to doxorubicin and taxol due to an increase in apoptosis. miR-218 binds survivin (BIRC5) mRNA 3'-UTR and down-regulated reporter luciferase activity. Experimental down-regulation of survivin by RNA interference in drug-resistant cells did mimic the sensitization observed when miRNA-218 was up-regulated. In addition, resensitization to taxol was also observed in mouse tumor xenografts from cells over-expressing miR-218. miR-218 is involved in the development of MDR in breast cancer cells via targeting survivin and leading to evasion of apoptosis. Targeting miR-218 and survivin may thus provide a potential strategy for reversing drug resistance in breast cancer.
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Antineoplásicos/farmacología , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Inhibidoras de la Apoptosis/genética , MicroARNs/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Secuencia de Bases , Sitios de Unión , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Caspasas/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Ratones , Paclitaxel/farmacología , ARN Mensajero/genética , Survivin , Transcriptoma , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Nicastrin (NCT) is a crucial component of the γ-secretase (GS) enzyme, which prompted investigations into its biological role in cancer. We have previously shown that nicastrin is overexpressed in breast cancer (BC), conferring worse overall survival in invasive, ERα negative patients. Here, we used 2D and 3D Matrigel, anchorage-independent growth conditions and a breast cancer xenograft mouse model to assess the impact of nicastrin on breast cancer stem cell (BCSC) propagation and invasion in vitro and tumor growth in vivo. Stable knockdown of nicastrin in HCC1806 breast cancer cells reduced cell invasion by 51.4 ± 1.7%, accompanied by a morphological change to a rounded cell phenotype and down-regulation of vimentin, Snail, Twist, MMP2, and MMP9. We observed a reduction of the pool of CD44(+)/CD24(-) and ALDH1 high breast cancer stem cells by threefold and twofold, respectively, and a reduction by 2.6-fold of the mammospheres formation. Nicastrin overexpression in nontransformed MCF10A cells caused an induction of epithelial to mesenchymal regulators, as well as a fivefold increased ALDH1 activity, a threefold enrichment for CD44(+)/CD24(-) stem cells, and a 3.2-fold enhanced mammosphere-forming capacity. Using the γ-sescretase inhibiton, Notch1/4 siRNA, and Akt inhibition, we show that nicastrin regulates breast cancer stem cells partly through Notch1 and the Akt pathway. Exploiting serial dilution transplantation of the HCC1806 cells expressing nicastrin and HCC1806 stably depleted of nicastrin, in vivo, we demonstrate that nicastrin inhibition may be relevant for the reduced tumorigenicity of breast cancer cells. These data could serve as a benchmark for development of nicastrin-targeted therapies in breast cancer.
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Secretasas de la Proteína Precursora del Amiloide/genética , Neoplasias de la Mama/genética , Transformación Celular Neoplásica/genética , Glicoproteínas de Membrana/genética , Células Madre Neoplásicas/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Western Blotting , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Técnicas de Cultivo de Célula , Línea Celular , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Transformación Celular Neoplásica/metabolismo , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Madre Neoplásicas/patología , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , Receptores Notch/genética , Receptores Notch/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Trasplante Heterólogo , Carga Tumoral/genéticaRESUMEN
OBJECTIVE: To investigatethe effect of NVP-BKM120 on the triple-negative breast cancer cell lines. METHODS: Breast cancer cell line MDA-MB-231 and Cal51 were divided into control group and experimental group. The inhibitory effects of BKM120 were evaluated by MTT assays. The drug effects on CSC population and characteristics were investigated through mammosphere formation assay and colony formation assay. Western blot was used to observe the expressionof related protein. The BALB/c mice were injected with stem cells (SCs) and different treatments were administered subsequently. RESULTS: In MDA-MB-231 cell lines, IC50 of BKM120 was (20.01±3.46) µmol/L for SCs and (3.07±0.14) µmol/L for total cells. BKM120 significantly inhibit the cell growth, in vitrocloning and microspheres formed of triple-negative breast cancer cells. BKM120 can inhibit tumor growth in nude mice without significant adverse reactions. CONCLUSION: BKM120 can significantly inhibit the proliferation of the triple-negative breast cancer cell lines.
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Neoplasias de la Mama Triple Negativas , Aminopiridinas , Animales , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MorfolinasRESUMEN
Sorcin, a 22-kDa calcium-binding protein, renders cancer cells resistant to chemotherapeutic agents, thus playing an important role in multidrug resistance. As there is a clear association between drug resistance and an aggressive phenotype, we asked whether sorcin affects also the motility, invasion, and stem cell characteristics of cancer cells. We have used both RNA interference (transient and stable expression of hairpins) and a lentiviral expression vector to experimentally modulate sorcin expression in a variety of cells. We demonstrate that sorcin depletion in MDA-MB-231 breast cancer cells reduces the pool of CD44(+)/CD24(-) and ALDH1(high) cancer stem cells (CSCs) as well as mammosphere-forming capacity. We also observe that sorcin regulates epithelial-mesenchymal transition and CSCs partly through E-cadherin and vascular endothelial growth factor expression. This leads to the acquisition of an epithelial-like phenotype, attenuating epithelial-mesenchymal transition and suppression of metastases in nude mice. The sorcin-depleted phenotype can also be reproduced in lung adenocarcinoma A549 cells and lung fibrosarcoma HT1080 cells. In addition, overexpression of sorcin in MCF7 cells, which have low endogenous sorcin expression levels, increases their migration and invasion in vitro. This offers the rationale for the development of therapeutic strategies down-regulating sorcin expression for the treatment of cancer.
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Adenocarcinoma/secundario , Neoplasias de la Mama/genética , Proteínas de Unión al Calcio/genética , Transición Epitelial-Mesenquimal/genética , Fibrosarcoma/secundario , Neoplasias Pulmonares/secundario , Adenocarcinoma/genética , Adenocarcinoma del Pulmón , Familia de Aldehído Deshidrogenasa 1 , Animales , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Fitogénicos/uso terapéutico , Antígeno CD24/biosíntesis , Movimiento Celular/genética , Proliferación Celular , Doxorrubicina/uso terapéutico , Resistencia a Antineoplásicos/genética , Etopósido/uso terapéutico , Femenino , Fibrosarcoma/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Receptores de Hialuranos/biosíntesis , Isoenzimas/biosíntesis , Neoplasias Pulmonares/genética , Células MCF-7 , Ratones , Ratones Desnudos , Invasividad Neoplásica/genética , Neovascularización Patológica/genética , Interferencia de ARN , ARN Interferente Pequeño , Retinal-Deshidrogenasa/biosíntesis , Esferoides Celulares/citología , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
BACKGROUND: Vascular calcification refers to the abnormal accumulation of calcium in the walls of blood vessels and is a risk factor often overlooked in cardiovascular disease. However, there is currently no specific drug for treating vascular calcification. Compound Danshen Dripping Pill (CDDP) is widely used to treat cardiovascular diseases, but its effect on vascular calcification has not been reported. PURPOSE: We investigated the effects of CDDP on vascular calcification in ApoE-/- mice and in vitro and elucidated its mechanism of action. STUDY DESIGN: Firstly, we found that CDDP has the potential to improve calcification based on network pharmacology analysis. Then, we performed the following experiments: in vivo, ApoE-/- mice were fed a high-fat diet randomly supplemented with CDDP for 16 weeks. Atherosclerosis and vascular calcification were determined. In vitro, human aortic smooth muscle cells (HASMCs), human umbilical vein endothelial cells (HUVECs), and human aortic endothelial cells (HAECs) were used to determine the mechanisms for CDDP-inhibited vascular calcification. RESULTS: In this study, we observed that CDDP reduced intimal calcification in atherosclerotic lesions of ApoE-deficient mice fed a high-fat diet, as well as the calcification in cultured SMCs and ECs. Mechanistically, CDDP inhibited the Wnt/ß-catenin pathway by up-regulating the expression of DKK1 and LRP6, which are upstream inhibitors of Wnt, leading to a reduction in the expression of osteoblastic transition markers (ALP, OPN, BMP2, and RUNX2). Furthermore, CDDP enhanced the secretion of DKK1, which plays a role in mediating EC-SMC crosstalk in calcification. Additionally, VC contributes to vascular aging by inhibiting Sirt1 and increasing senescence parameters (SA-ß-gal, p21, and p16). However, CDDP reversed these changes by activating Sirt1. CDDP also reduced the levels of pro-inflammatory cytokines and the senescence-associated secretory phenotype in vivo and in vitro. CONCLUSIONS: Our study suggests that CDDP reduces vascular calcification by regulating the DKK1/LRP6/ß-catenin signaling pathway in ECs/SMCs and interactions with the crosstalk of ECs and SMCs. It also reduces the senescence of ECs/SMCs, contributing to the Sirt1 activation, indicating CDDP's novel role in ameliorating vascular calcification.
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Aterosclerosis , Dieta Alta en Grasa , Medicamentos Herbarios Chinos , Células Endoteliales de la Vena Umbilical Humana , Salvia miltiorrhiza , Calcificación Vascular , Animales , Calcificación Vascular/tratamiento farmacológico , Humanos , Medicamentos Herbarios Chinos/farmacología , Salvia miltiorrhiza/química , Masculino , Dieta Alta en Grasa/efectos adversos , Aterosclerosis/tratamiento farmacológico , Ratones , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Sirtuina 1/metabolismo , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/efectos de los fármacos , Apolipoproteínas E/genética , Farmacología en Red , Vía de Señalización Wnt/efectos de los fármacos , Aorta/efectos de los fármacos , Canfanos , Péptidos y Proteínas de Señalización Intercelular , Panax notoginsengRESUMEN
Alzheimer's disease is a neurodegenerative disease that leads to dementia and poses a serious threat to the health of the elderly. Traditional Chinese medicine (TCM) presents as a promising novel therapeutic therapy for preventing and treating dementia. Studies have shown that natural products derived from kidney-tonifying herbs can effectively inhibit AD. Furthermore, endoplasmic reticulum (ER) stress is a critical factor in the pathology of AD. Regulation of ER stress is a crucial approach to prevent and treat AD. Thus, in this study, we first collected kidney-tonifying herbs, integrated chemical ingredients from multiple TCM databases, and constructed a comprehensive drug-target network. Subsequently, we employed the endophenotype network (network proximity) method to identify potential active ingredients in kidney-tonifying herbs that prevented AD via regulating ER stress. By combining the predicted outcomes, we discovered that 32 natural products could ameliorate AD pathology via regulating ER stress. After a comprehensive evaluation of the multi-network model and systematic pharmacological analyses, we further selected several promising compounds for in vitro testing in the APP-SH-SY5Y cell model. Experimental results showed that echinacoside and danthron were able to effectively reduce ER stress-mediated neuronal apoptosis by inhibiting the expression levels of BIP, p-PERK, ATF6, and CHOP in APP-SH-SY5Y cells. Overall, this study utilized the endophenotype network to preliminarily decipher the effective material basis and potential molecular mechanism of kidney-tonifying Chinese medicine for prevention and treatment of AD.
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BACKGROUND: Tourette syndrome (TS) represents a neurodevelopmental disorder characterized by an uncertain etiology and influencing factors. Frequently, it co-occurs with conditions such as attention deficit hyperactivity disorder, obsessive-compulsive disorder, and sleep disturbances, which have garnered substantial attention from the research community in recent years. Clinical trials have demonstrated that Shaoma Zhijing Granules (SMZJG, 5-ling granule, also known as TSupport or T92 under U.S. development), a traditional Chinese medicine compound, is an effective treatment for TS. PURPOSE: To conduct scientometric analysis on developing trends, research countries and institutions, current status, hot spots of TS and discuss the underlying mechanisms of SMZJG and its main components on TS. The aim is to provide valuable reference for ongoing clinical and basic research on TS and SMZJG. STUDY DESIGN & METHODS: Using Tourette syndrome, SMZJG and its main components along with their synonyms as keywords, we conducted a comprehensive search across major scientific databases including the Web of Science Core Collection, PubMed and China National Knowledge Infrastructure (CNKI) databases. A total of 5952 references and 99 patents were obtained. Among these, 5039 articles and reviews, as well as 54 patents were analyzed by Citespace and VOSviewer software. RESULTS: The available evidence indicates that the SMZJG's components likely exert their mechanisms in treating TS by regulating the dopaminergic pathway system, neurotransmitter imbalances, reducing neuroinflammation, promoting the repair of nerve damage and improving sleep disorders. CONCLUSION: This comprehensive analysis lays the foundation for an extensive exploration of the feasibility and clinical applications of SMZJG in TS treatment.
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Medicamentos Herbarios Chinos , Síndrome de Tourette , Síndrome de Tourette/tratamiento farmacológico , Humanos , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Medicina Tradicional China/métodos , AnimalesRESUMEN
OBJECTIVE: The recent surge in large language models (LLMs) across various fields has yet to be fully realized in traditional Chinese medicine (TCM). This study aims to bridge this gap by developing a large language model tailored to TCM knowledge, enhancing its performance and accuracy in clinical reasoning tasks such as diagnosis, treatment, and prescription recommendations. MATERIALS AND METHODS: This study harnessed a wide array of TCM data resources, including TCM ancient books, textbooks, and clinical data, to create 3 key datasets: the TCM Pre-trained Dataset, the Traditional Chinese Patent Medicine (TCPM) Question Answering Dataset, and the Spleen and Stomach Herbal Prescription Recommendation Dataset. These datasets underpinned the development of the Lingdan Pre-trained LLM and 2 specialized models: the Lingdan-TCPM-Chat Model, which uses a Chain-of-Thought process for symptom analysis and TCPM recommendation, and a Lingdan Prescription Recommendation model (Lingdan-PR) that proposes herbal prescriptions based on electronic medical records. RESULTS: The Lingdan-TCPM-Chat and the Lingdan-PR Model, fine-tuned on the Lingdan Pre-trained LLM, demonstrated state-of-the art performances for the tasks of TCM clinical knowledge answering and herbal prescription recommendation. Notably, Lingdan-PR outperformed all state-of-the-art baseline models, achieving an improvement of 18.39% in the Top@20 F1-score compared with the best baseline. CONCLUSION: This study marks a pivotal step in merging advanced LLMs with TCM, showcasing the potential of artificial intelligence to help improve clinical decision-making of medical diagnostics and treatment strategies. The success of the Lingdan Pre-trained LLM and its derivative models, Lingdan-TCPM-Chat and Lingdan-PR, not only revolutionizes TCM practices but also opens new avenues for the application of artificial intelligence in other specialized medical fields. Our project is available at https://github.com/TCMAI-BJTU/LingdanLLM.
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Razonamiento Clínico , Medicina Tradicional China , Humanos , Medicamentos Herbarios Chinos/uso terapéutico , Registros Electrónicos de Salud , Procesamiento de Lenguaje Natural , Conjuntos de Datos como AsuntoRESUMEN
Background: Long-term use of nitrates for treating stable angina pectoris (SAP) may lead to patients' tolerance to nitrates. As a traditional Chinese medicine, Compound danshen dropping pills (CDDP) is beneficial for patients with SAP. This study aimed to critically assess the efficacy and safety of CDDP vs. nitrates for SAP. Methods: PubMed, Embase, Web of Science, Cochrane library, CNKI, Wanfang Digital Periodicals, and Chinese Science and Technology Periodicals database were searched from inception to April 2023. Randomized controlled trials (RCTs) comparing CDDP with nitrates for SAP were included. The meta-analysis was conducted to estimate the pooled effect. Results: Twenty-nine studies were included for the statistical analysis. The meta-analyses with the random-effect model indicated that CDDP could significantly increase the effective rate in symptom improvement compared with nitrates (Pooled 9 RCTs, OR = 1.95, 95% CI: 1.25-3.05, P = 0.003, duration of 4 weeks; Pooled 4 RCTs, OR = 3.45, 95% CI: 1.84-6.48, P = 0.0001, duration of 6 weeks; Pooled 13 RCTs, OR = 4.02, 95% CI: 2.14-7.57, P < 0.0001, duration of 8 weeks). The meta-analyses with the random-effect model indicated that CDDP could significantly increase the effective rate in electrocardiogram improvement compared with nitrates (Pooled 5 RCTs, OR = 1.60, 95% CI: 1.02-2.52, P = 0.04, duration of 4 weeks; Pooled 3 RCTs, OR = 2.47, 95% CI: 1.60-3.82, P < 0.0001, duration of 6 weeks; Pooled 11 RCTs, OR = 3.43, 95% CI: 2.68-4.38, P < 0.00001, duration of 8 weeks). The incidence of adverse drug reactions in the CDDP group was lower than that in the nitrates group (Pooled 23 RCTs, OR = 0.15, 95% CI: 0.1-0.21, P < 0.00001). The results of the meta-analyses with fixed-effect model were similar with above results. The levels of the evidence ranged from very low to low. Conclusion: The present study suggests that CDDP with the duration of at least 4 weeks can be considered as an alternative to nitrates for treating SAP. However, more high-quality RCTs are still needed to confirm these findings. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022352888, identifier [CRD42022352888].
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Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE-/-LDLR-/-) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.
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BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with no effective cure. Targeting endoplasmic reticulum (ER) stress pathway may offer a novel approach to ameliorate cognitive deficits in AD. Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine (TCM) prescription, has shown potential benefits for AD. To facilitate the development of new therapeutic agents for AD, it is important to identify the active components and the underlying mechanisms of BSYZ against AD. PURPOSE: The aim of this study was to systematically screen the active components of BSYZ that could improve learning and memory impairment in AD by modulating ER stress pathway. METHODS: A drug-target (D-T) network was constructed to analyze the herbal components of BSYZ. Network proximity method was used to identify the potential anti-AD components that targeted ER stress and evaluate their synergistic effects. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and the literature evidence were considered to select promising candidates for further validation. The selected components were tested in vitro using an AD cell model (APPswe-SH-SY5Y). In vivo anti-AD effects of the components were assessed in APP/PS1 double-transgenic mice. RESULTS: 58 potential anti-AD components targeting ER stress were detected by network proximity analysis, and 13 out of them were selected based on ADMET properties and literature evidence. In vitro experiments confirmed that 5 components, namely gomisin B, ß-Carotene, imperatorin, chrysophanol, and osthole (OST), exhibited anti-AD effects on the APPswe-SH-SY5Y model. Moreover, network proximity analysis suggested that OST and Gomisin B might have synergistic effects on modulating ER stress. In vivo experiments demonstrated that OST, Gomisin B, OST+Gomisin B, and BSYZ all improved learning and memory function in APP/PS1 mice. Gomisin B and OST also restored cellular morphology and tissue structure in APP/PS1 mice. Thioflavine-S (Th-S) staining revealed that they reduced amyloid plaque deposition in the brain tissue of AD model mice. The qPCR results indicated that BSYZ, OST, and Gomisin B differentially regulated IRE1α, PERK, EIF2α, DDIT3, and Caspase 12 expression levels, while the OST and Gomisin B co-administration group showed better efficacy. This trend was further confirmed by immunofluorescence experiments. CONCLUSION: This study identified the active components of BSYZ that could ameliorate learning and memory impairment in AD by targeting ER stress pathway. OST and Gomisin B exhibited synergistic effects on modulating ER stress and reducing amyloid plaque deposition in vivo. Overall, our study elucidated the molecular mechanisms of BSYZ and its active components in attenuating AD symptoms which suggested the therapeutic potential of TCM for AD.