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Small cell lung cancer (SCLC) is characterized by rapid development of chemoresistance and poor outcomes. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are widely used in breast cancer and other cancer types. However, the molecular mechanisms of CDK4/6 in SCLC chemoresistance remain poorly understood. Here, Rb1flox/flox, Trp53flox/flox, Ptenflox/flox (RTP) and Rb1flox/flox, Trp53flox/flox, MycLSL/LSL (RPM) spontaneous SCLC mouse models, SCLC cell line-derived xenograft (CDX) models, and SCLC patient-derived xenograft (PDX) models are established to reveal the potential effects of CDK4/6is on SCLC chemoresistance. In this study, it is found that CDK4/6is palbociclib (PD) or ribociclib (LEE) combined with chemotherapeutic drugs significantly inhibit SCLC tumor growth. Mechanistically, CDK4/6is do not function through the classic Retionblastoma1 (RB) dependent axis in SCLC. CDK4/6is induce impair autophagy through the AMBRA1-lysosome signaling pathway. The upregulated AMBRA1 protein expression leads to CDK6 degradation via autophagy, and the following TFEB and TFE3 nuclear translocation inhibition leading to the lysosome-related genes levels downregulation. Moreover, it is found that the expression of CDK6 is higher in SCLC tumors than in normal tissue and it is associated with the survival and prognosis of SCLC patients. Finally, these findings demonstrate that combining CDK4/6is with chemotherapy treatment may serve as a potential therapeutic option for SCLC patients.
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Cronobacter species are potential pathogens that can contaminate powdered infant formula. C. sakazakii and C. malonaticus are the most common species of Cronobacter associated with infections. This study mined new molecular targets for the detection of C. sakazakii and C. malonaticus by using comparative genome approaches. Specific target genes mngB and ompR were obtained and used to detect C. sakazakii and C. malonaticus, respectively. A novel detection method, termed ladder-shape melting temperature isothermal amplification (LMTIA), was developed and evaluated. The detection limit for pure C. sakazakii DNA was 1 pg per reaction and 1 fg per reaction for C. malonaticus. The C. sakazakii, C. malonaticus, and the reference stains were all correctly identified. The amplicons can be successfully visualized and identified by naked eyes when hydroxy naphthol blue dye (HNB dye) was used in the reaction. Therefore, the LMTIA assays developed in this study showed potential application for microorganism identification and detection.
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Aqueous zinc-ion batteries (ZIBs) have attracted burgeoning attention and emerged as prospective alternatives for scalable energy storage applications due to their unique merits such as high volumetric capacity, low cost, environmentally friendly, and reliable safety. Nevertheless, current ZIBs still suffer from some thorny issues, including low intrinsic electron conductivity, poor reversibility, zinc anode dendrites, and side reactions. Herein, conductive polyaniline (PANI) is intercalated as a pillar into the hydrated V2O5 (PAVO) to stabilize the structure of the cathode material. Meanwhile, graphene oxide (GO) was modified onto the glass fiber (GF) membrane through simple electrospinning and laser reduction methods to inhibit dendrite growth. As a result, the prepared cells present excellent electrochemical performance with enhanced specific capacity (362 mAh g-1 at 0.1 A g-1), significant rate capability (280 mAh g-1 at 10 A g-1), and admirable cycling stability (74% capacity retention after 4800 cycles at 5 A g-1). These findings provide key insights into the development of high-performance zinc-ion batteries.
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Cerebral ischemia/reperfusion (CIRI) is a leading cause of death worldwide. A small GTPase known as ADP-ribosylation factor-like protein 13B (ARL13B) is essential in several illnesses. The role of ARL13B in CIRI remains unknown, though. A middle cerebral artery occlusion/reperfusion (MCAO/R) in rats as well as an oxygen-glucose deprivation/reoxygenation (OGD/R) models in PC12 cells were constructed. The neuroprotective effects of ARL13B against MCAO/R were evaluated using neurological scores, TTC staining, rotarod testing, H&E staining, and Nissl staining. To detect the expression of proteins associated with the SHH pathway and apoptosis, western blotting and immunofluorescence were employed. Apoptosis was detected using TUNEL assays and flow cytometry. There was increased expression of ARL13B in cerebral ischemia/reperfusion models. However, ARL13B knockdown aggravated CIRI nerve injury by inhibiting the sonic hedgehog (SHH) pathway. In addition, the use of SHH pathway agonist (SAG) can increased ARL13B expression, reverse the effects of ARL13B knockdown exacerbating CIRI nerve injury. ARL13B alleviated cerebral infarction and pathological injury and played a protective role against MCAO/R. Furthermore, ARL13B significantly increased the expression of SHH pathway-related proteins and the anti-apoptotic protein BCL-2, while decreased the expression of pro-apoptotic protein BAX, thus reducing apoptosis. The results from the OGD/R model in PC12 cells were consistent with those obtained in vivo. Surprisingly, we demonstrated that ARL13B regulates the cell cycle to protect against CIRI nerve injury. Our findings indicate that ARL13B protects against CIRI by reducing apoptosis through SHH-dependent pathway activation, and suggest that ARL13B plays a crucial role in CIRI pathogenesis.
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Factores de Ribosilacion-ADP , Proteínas Hedgehog , Ratas Sprague-Dawley , Daño por Reperfusión , Transducción de Señal , Animales , Ratas , Proteínas Hedgehog/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Daño por Reperfusión/patología , Transducción de Señal/fisiología , Células PC12 , Masculino , Factores de Ribosilacion-ADP/metabolismo , Factores de Ribosilacion-ADP/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Apoptosis/fisiología , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/patología , Fármacos Neuroprotectores/farmacologíaRESUMEN
Post-stroke emotional disorders such as post-stroke anxiety and post-stroke depression are typical symptoms in patients with stroke. They are closely associated with poor prognosis and low quality of life. The State Food and Drug Administration of China has approved DL-3-n-butylphthalide (NBP) as a treatment for ischemic stroke (IS). Clinical research has shown that NBP alleviates anxiety and depressive symptoms in patients with IS. Therefore, this study explored the role and molecular mechanisms of NBP in cases of post-stroke emotional disorders using network pharmacology and experimental validation. The results showed that NBP treatment significantly increased the percentage of time spent in the center of the middle cerebral artery occlusion (MCAO) rats in the open field test and the percentage of sucrose consumption in the sucrose preference test. Network pharmacology results suggest that NBP may regulate neuroinflammation and cell death. Further experiments revealed that NBP inhibited the toll-like receptor 4/nuclear factor kappa B signaling pathway, decreased the level of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, and interleukin-6, and M1-type microglia markers (CD68, inducible nitric oxide synthase), and reduced the expression of PANoptosis-related molecules including caspase-1, caspase-3, caspase-8, gasdermin D, and mixed lineage kinase domain-like protein in the hippocampus of the MACO rats. These findings demonstrate that the mechanisms through which NBP ameliorates post-stroke emotional disorders in rats are associated with inhibiting neuroinflammation and PANoptosis, providing a new strategy and experimental basis for treating post-stroke emotional disorders.
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Benzofuranos , Infarto de la Arteria Cerebral Media , Enfermedades Neuroinflamatorias , Ratas Sprague-Dawley , Animales , Benzofuranos/uso terapéutico , Benzofuranos/farmacología , Masculino , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Ratas , Microglía/efectos de los fármacos , Microglía/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/complicaciones , Farmacología en Red , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , Citocinas/metabolismo , FN-kappa B/metabolismoRESUMEN
Avian pathogenic Escherichia coli (APEC) is the causative agent of chicken colibacillosis. Paeoniflorin, a natural ingredient extracted from Paeonia lactiflora, has a variety of pharmacological effects including anti-inflammatory and immunomodulatory. However, its effects and mechanism in APEC-induced acute lung injury (ALI) in chicken is not clear. The aim of this study was to investigate the protective effect of paeoniflorin on APEC-induced ALI and its possible mechanism. Paeoniflorin (25, 50, and 100 mg/kg) was administered by gavage for 5 d starting at 9 d of age and the chicken were infected with APEC by intraperitoneal injection at 12 d of age. The tissues were collected after APEC infection for 36 h for analysis. The results showed that paeoniflorin significantly alleviated the symptoms, increased the survival rate and body weight gain of APEC-infected chicken, and improved the histopathological damages, and reduced APEC loads in lung tissues. In addition, paeoniflorin restored the gene expression of ZO-1, Occludin and Claudin-3 during APEC infection. Moreover, paeoniflorin pretreatment significantly affected the endocannabinoid system (ECs) by increasing DAGL, decreasing MAGL, increasing secretion of 2-AG. Then, paeoniflorin significantly decreased the secretion of IL-1ß, IL-6 and TNF-α in lung tissues, and decreased the mRNA expression of CXCL8, CXCL12, CCL1, CCL5, and CCL17. In addition, paeoniflorin significantly reduced the phosphorylation levels of PI3K, AKT, P65, and IκB. In summary, we found that paeoniflorin inhibited APEC-induced ALI, and its mechanism may be through affecting ECs and inhibiting the activation of PI3K/AKT and NF-κB signaling pathways, which provides a new idea for the prevention and treatment of chicken colibacillosis.
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Lesión Pulmonar Aguda , Pollos , Infecciones por Escherichia coli , Glucósidos , Monoterpenos , FN-kappa B , Fosfatidilinositol 3-Quinasas , Enfermedades de las Aves de Corral , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Lesión Pulmonar Aguda/prevención & control , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/veterinaria , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Glucósidos/farmacología , Glucósidos/administración & dosificación , Monoterpenos/farmacología , Monoterpenos/administración & dosificación , Enfermedades de las Aves de Corral/prevención & control , Enfermedades de las Aves de Corral/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , FN-kappa B/metabolismo , FN-kappa B/genética , Infecciones por Escherichia coli/veterinaria , Infecciones por Escherichia coli/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Proteínas Aviares/metabolismo , Proteínas Aviares/genética , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacosRESUMEN
INTRODUCTION: Mangiferin is a Chinese herbal extract with multiple biological activities. Mangiferin can penetrate the bloodâbrain barrier and has potential in the treatment of nervous system diseases. These findings suggest that mangiferin protects the neurological function in ischemic stroke rats by targeting multiple signaling pathways. However, little is known about the effect and mechanism of mangiferin in alleviating poststroke cognitive impairment. METHODS: Cerebral ischemia/reperfusion (I/R) rats were generated via middle cerebral artery occlusion. Laser speckle imaging was used to monitor the cerebral blood flow. The I/R rats were intraperitoneally (i.p.) injected with 40 mg/kg mangiferin for 7 consecutive days. Neurological scoring, and TTC staining were performed to evaluate neurological function. Behavioral experiments, including the open field test, elevated plus maze, sucrose preference test, and novel object recognition test, were performed to evaluate cognitive function. Metabolomic data from brain tissue with multivariate statistics were analyzed by gas chromatographyâmass spectrometry and liquid chromatographyâmass spectrometry. RESULTS: Mangiferin markedly decreased neurological scores, and reduced infarct areas. Mangiferin significantly attenuated anxiety-like and depression-like behaviors and enhanced learning and memory in I/R rats. According to the metabolomics results, 13 metabolites were identified to be potentially regulated by mangiferin, and the differentially abundant metabolites were mainly involved in lipid metabolism. CONCLUSIONS: Mangiferin protected neurological function and relieved poststroke cognitive impairment by improving lipid metabolism abnormalities in I/R rats.
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Disfunción Cognitiva , Metabolismo de los Lípidos , Ratas Sprague-Dawley , Daño por Reperfusión , Xantonas , Animales , Xantonas/farmacología , Xantonas/uso terapéutico , Masculino , Metabolismo de los Lípidos/efectos de los fármacos , Ratas , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/complicaciones , Daño por Reperfusión/metabolismo , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/metabolismo , Conducta Animal/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Modelos Animales de Enfermedad , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/complicaciones , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacosRESUMEN
Recent studies showed that patients with iron overload had increased risk of insulin resistance or diabetes. Ferroptosis is a new type of cell death mainly caused by iron-dependent oxidative damage. In the present study, we investigated potential mechanisms of iron overload induced hepatic ferroptosis and insulin resistance through in vivo and in vitro experiments. In vivo, the mice models of iron overload were established by intraperitoneal injection of iron dextran. The changes of body weight, serum ferritin and blood glucose were measured. Hematoxylin-eosin (HE) and Perl's stainings were used to observe the pathological changes and iron deposition in the liver of mice. In vitro, HepG2 cells were treated with ferric ammonium citrate (FAC, 9 mmol/L, 24 h) to establish the cell models of iron overload. The labile iron pool, cell viability, glucose consumption and glycogen contents were measured. The ultrastructure of mitochondria was observed by transmission electron microscope (TEM). The malondialdehyde (MDA) and glutathione (GSH) kits were used to detect lipid peroxidation in liver tissues of mice and HepG2 cells. RT-PCR and Western blot were used to detect the mRNA and protein expression levels of ferroptosis factors and JAK2/STAT3 signaling pathway. In this study, we used the iron chelator deferasirox in mice and HepG2 cells. Iron overload caused weight loss, elevated serum ferritin, fasting blood glucose, fasting insulin, HOMA-IR, impaired glucose tolerance, and decreased insulin sensitivity in mice. HE staining and Perls staining showed clumps of iron deposition in the liver of iron overload mice. Iron overload could reduce the glucose consumption, increase MDA contents of HepG2 cells, while reduce glycogen and GSH contents in liver tissues of mice and HepG2 cells. TEM showed deletion of mitochondrial ridge and rupture of outer membrane in HepG2 cells with iron overload. Iron chelator deferasirox could significantly improve the above indicators, which might be related to the activation of JAK2/STAT3/SLC7A11 signaling pathway and hepatic ferroptosis. Iron overload could induce hepatic ferroptosis and insulin resistance by inhibiting the JAK2/STAT3/SLC7A11 signaling pathway, and the iron chelator deferasirox might improve hepatic insulin resistance induced by iron overload.
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This study aimed to assess the diagnostic accuracy of radiomics for predicting osteoporosis and the quality of radiomic studies. The study protocol was prospectively registered on PROSPERO (CRD42023425058). We searched PubMed, EMBASE, Web of Science, and Cochrane Library databases from inception to June 1, 2023, for eligible articles that applied radiomic techniques to diagnosing osteoporosis or abnormal bone mass. Quality and risk of bias of the included studies were evaluated with radiomics quality score (RQS), METhodological RadiomICs Score (METRICS), and Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tools. The data analysis utilized the R program with mada, metafor, and meta packages. Ten retrospective studies with 5926 participants were included in the systematic review and meta-analysis. The overall risk of bias and applicability concerns for each domain of the studies were rated as low, except for one study which was considered to have a high risk of flow and time bias. The mean METRICS score was 70.1% (range 49.6-83.2%). There was moderate heterogeneity across studies and meta-regression identified sources of heterogeneity in the data, including imaging modality, feature selection method, and classifier. The pooled diagnostic odds ratio (DOR) under the bivariate random effects model across the studies was 57.22 (95% CI 27.62-118.52). The pooled sensitivity and specificity were 87% (95% CI 81-92%) and 87% (95% CI 77-93%), respectively. The area under the summary receiver operating characteristic curve (AUC) of the radiomic models was 0.94 (range 0.8 to 0.98). The results supported that the radiomic techniques had good accuracy in diagnosing osteoporosis or abnormal bone mass. The application of radiomics in osteoporosis diagnosis needs to be further confirmed by more prospective studies with rigorous adherence to existing guidelines and multicenter validation.
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INTRODUCTION: Polycystic ovary syndrome (PCOS) is associated with a wide range of unfavorable cardiometabolic risk factors, including obesity, hypertension, insulin resistance, impaired glucose metabolism, dyslipidemia, and metabolic syndrome. Compared with women with regular menstrual cycles, women with a history of irregular menstrual periods have an increased unfavorable cardiometabolic risk. Recently, the association between the severity of oligomenorrhea and hyperinsulinemia and insulin resistance has been demonstrated. However, evidence linking the severity of menstrual cyclicity with cardiometabolic risk in PCOS women is scarce. MATERIAL AND METHODS: This work was a prospective cross-sectional study. A total of 154 women diagnosed with PCOS by the Rotterdam criteria were recruited from July 2021 to September 2022. PCOS women with eumenorrheic (eumeno group), oligomenorrhea (oligo group), and amenorrhea (ameno group) underwent history and physical examination, gonadal steroid hormone measurement, lipid profile, oral glucose tolerance test, and homeostasis model assessment of insulin resistance. RESULTS: A trend toward an increase in unfavorable cardiometabolic risk markers including obesity, hypertension, prevalence of insulin resistance, prediabetes, dyslipidemia, and metabolic syndrome was observed in the ameno group (n = 57) as compared with the eumeno (n = 24) or oligo group (n = 73). A higher prevalence of insulin resistance (odds ratio [OR]: 3.02; 95% confidence interval [CI]: 1.03-8.81) and prediabetes (OR: 3.94; 95% CI: 1.01-15.40) was observed in the ameno group than in the eumeno group, and a higher proportion of dyslipidemia (OR: 2.44; 95% CI: 1.16-5.15) was observed in the ameno group than in the oligo group in the binary logistic regression analysis after adjusting for confounding factors. CONCLUSIONS: PCOS women with amenorrhea show a higher prevalence of insulin resistance, prediabetes, and dyslipidemia compared with those with oligomenorrhea or eumenorrhea. The severity of menstrual dysfunction could be used as a readily obtainable marker for the identification of PCOS women at greatest risk of cardiometabolic diseases.
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Factores de Riesgo Cardiometabólico , Trastornos de la Menstruación , Síndrome del Ovario Poliquístico , Humanos , Femenino , Síndrome del Ovario Poliquístico/complicaciones , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/epidemiología , Adulto , Estudios Transversales , Estudios Prospectivos , Trastornos de la Menstruación/epidemiología , Resistencia a la Insulina , Síndrome Metabólico/epidemiología , Oligomenorrea/epidemiología , Índice de Severidad de la Enfermedad , Dislipidemias/epidemiología , Biomarcadores/sangre , Adulto Joven , Factores de RiesgoRESUMEN
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Transcriptional dysregulation is a hallmark of cancer, and several transcriptional regulators have been demonstrated to contribute to cancer progression. In this study, we identified an upregulation of the transcriptional corepressor downregulator of transcription 1-associated protein 1 (DRAP1) in TNBC, which was closely associated with poor recurrence-free survival in patients with TNBC. DRAP1 promoted TNBC proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. Mechanistically, the downregulator of transcription 1 (DR1)/DRAP1 heterodimer complex inhibited expression of the cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1) and thereby increased activation of mTOR, which sensitized TNBC to treatment with the mTOR inhibitor everolimus. DRAP1 and DR1 also formed a positive feedback loop. DRAP1 enhanced the stability of DR1 by recruiting the deubiquitinase USP7 to inhibit its proteasomal degradation; in turn, DR1 directly promoted DRAP1 transcription. Collectively, this study uncovered a DRAP1-DR1 bidirectional regulatory pathway that promotes TNBC progression, suggesting that targeting the DRAP1/DR1 complex might be a potential therapeutic strategy to treat TNBC. Significance: DR1 and DRAP1 form a positive feedback loop and a repressor complex to cooperatively inhibit cytosolic arginine sensor for mTORC1 subunit 1 transcription and stimulate mTOR signaling, leading to progression and increased everolimus sensitivity in triple-negative breast cancer.
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Progresión de la Enfermedad , Everolimus , Serina-Treonina Quinasas TOR , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Humanos , Femenino , Serina-Treonina Quinasas TOR/metabolismo , Everolimus/farmacología , Animales , Ratones , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Movimiento Celular/efectos de los fármacos , Ratones Endogámicos BALB CRESUMEN
Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer owing to the lack of effective therapeutic targets. Splicing factor 3a subunit 2 (SF3A2), a poorly defined splicing factor, was notably elevated in TNBC tissues and promoted TNBC progression, as confirmed by cell proliferation, colony formation, transwell migration, and invasion assays. Mechanistic investigations revealed that E3 ubiquitin-protein ligase UBR5 promoted the ubiquitination-dependent degradation of SF3A2, which in turn regulated UBR5, thus forming a feedback loop to balance these two oncoproteins. Moreover, SF3A2 accelerated TNBC progression by, at least in part, specifically regulating the alternative splicing of makorin ring finger protein 1 (MKRN1) and promoting the expression of the dominant and oncogenic isoform, MKRN1-T1. Furthermore, SF3A2 participated in the regulation of both extrinsic and intrinsic apoptosis, leading to cisplatin resistance in TNBC cells. Collectively, these findings reveal a previously unknown role of SF3A2 in TNBC progression and cisplatin resistance, highlighting SF3A2 as a potential therapeutic target for patients with TNBC.
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Cisplatino , Neoplasias de la Mama Triple Negativas , Humanos , Cisplatino/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Empalme Alternativo , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismoRESUMEN
Background and Objectives: Recent studies have shown that the imbalance of intestinal flora is related to the occurrence and progression of diabetic nephropathy (DN) and can affect lipid metabolism. Sodium-dependent glucose transporters 2 (SGLT2) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist are commonly used hypoglycemic drugs and have excellent renal safety. The purpose of this study was to compare the protective effects of empagliflozin and liraglutide on kidneys, lipid metabolism, and intestinal microbiota in diabetic mice. Methods: We established a mouse model of type two diabetes by feeding rats a high-fat diet (HFD) followed by an intraperitoneal injection of STZ. The mice were randomly divided into groups: normal control (NC), diabetic model (DM), liraglutide treatment (LirT), empagliflozin treatment (EmpT), and liraglutide combined with empagliflozin treatment (Emp&LirT) groups. Blood glucose, lipids, creatinine, and uric acid, as well as urinary nitrogen and albumin levels were measured. The renal tissues were subjected to HE, PAS and Masson's staining. These parameters were used to evaluate renal function and histopathological changes in mice. Mice feces were also collected for 16sRNA sequencing to analyze the composition of the intestinal flora. Results: All the indexes related to renal function were significantly improved after treatment with drugs. With respect to lipid metabolism, both drugs significantly decreased the serum triglyceride levels in diabetic mice, but the effect of liraglutide on reducing serum cholesterol was better than that of empagliflozin. However, empagliflozin had a better effect on the reduction of low-density lipoproteins (LDL). The two drugs had different effects on intestinal flora. At the phylum level, empagliflozin significantly reduced the ratio of Firmicutes to Bacteroidota, but no effect was seen with liraglutide. At the genus level, both of them decreased the number of Helicobacter and increased the number of Lactobacillus. Empagliflozin also significantly increased the abundance of Muribaculaceae, Muribaculum, Olsenella, and Odoribacter, while liraglutide significantly increased that of Ruminococcus. Conclusion: Liraglutide and empagliflozin were both able to improve diabetes-related renal injury. However, the ability of empagliflozin to reduce LDL was better compared to liraglutide. In addition, their effects on the intestine bacterial flora were significantly different.
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Compuestos de Bencidrilo , Diabetes Mellitus Experimental , Microbioma Gastrointestinal , Glucósidos , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Ratones , Ratas , Animales , Liraglutida/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Metabolismo de los Lípidos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacologíaRESUMEN
CRISPR-Cas systems are defense mechanisms against phages and other nucleic acids that invade bacteria and archaea. In Escherichia coli, it is generally accepted that CRISPR-Cas systems are inactive in laboratory conditions due to a transcriptional repressor. In natural isolates, it has been shown that CRISPR arrays remain stable over the years and that most spacer targets (protospacers) remain unknown. Here, we re-examine CRISPR arrays in natural E. coli isolates and investigate viral and bacterial genomes for spacer targets using a bioinformatics approach coupled to a unique biological dataset. We first sequenced the CRISPR1 array of 1769 E. coli isolates from the fecal samples of 639 children obtained during their first year of life. We built a network with edges between isolates that reflect the number of shared spacers. The isolates grouped into 34 modules. A search for matching spacers in bacterial genomes showed that E. coli spacers almost exclusively target prophages. While we found instances of self-targeting spacers, those involving a prophage and a spacer within the same bacterial genome were rare. The extensive search for matching spacers also expanded the library of known E. coli protospacers to 60%. Altogether, these results favor the concept that E. coli's CRISPR-Cas is an antiprophage system and highlight the importance of reconsidering the criteria use to deem CRISPR-Cas systems active.
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Bacteriófagos , Profagos , Niño , Humanos , Profagos/genética , Escherichia coli/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Bacteriófagos/genética , Genoma Bacteriano , Sistemas CRISPR-CasRESUMEN
BACKGROUND: MiRNAs are closely related to tumor radiosensitivity. MiR-378a-5p level is down-regulated in colorectal cancer (CRC). Therefore, this study intends to explore the role of miR-378a-5p in CRC, especially radiosensitivity. METHODS: The expression of miR-378a-5p was analyzed in CRC samples. CRC cell lines were treated with different doses of X-rays. Bioinformatics analysis, dual-luciferase reporter assay and RT-qPCR were used to detect the expressions and binding relationship of miR-378a-5p and low-density lipoprotein receptor-related protein 8 (LRP8). MiR-378a-5p inhibitor or/and siLRP8 were transfected into CRC cells with or without irradiation. Subsequently, clonogenic assay, flow cytometry and in vivo experiments including tumorigenesis assay, immunohistochemistry, RT-qPCR and Western blot were performed to clarify the role of miR-378a-5p/LRP8 axis in the radiosensitivity of CRC. RESULTS: The down-regulated expression of miR-378a-5p in CRC is related to histological differentiation and tumor-node-metastasis (TNM) stage. After irradiation, the survival fraction of CRC cells was decreased, while the apoptotic rate and the level of miR-378a-5p were increased. Restrained miR-378a-5p repressed apoptosis and apoptosis-related protein expressions, yet promoted the proliferation and the radioresistance of cells by regulating ß-catenin in CRC cells. LRP8 was highly expressed in CRC, and targeted by miR-378a-5p. SiLRP8 improved radiosensitivity and reversed the effect of miR-378a-5p down-regulation on CRC cells. Overexpressed miR-378a-5p and irradiation enhanced the level of miR-378a-5p, yet suppressed the expressions of Ki67 and LRP8 as well as tumorigenesis. CONCLUSION: MiR-378a-5p may exert a radiosensitizing effect on CRC through the LRP8/ß-catenin axis, which may be a new therapeutic target for CRC radioresistance.
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Neoplasias Colorrectales , MicroARNs , Neoplasias , Fármacos Sensibilizantes a Radiaciones , Humanos , beta Catenina/genética , Carcinogénesis , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/radioterapia , Neoplasias Colorrectales/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacologíaRESUMEN
PURPOSE: This study aimed to investigate the prognostic value of alpha-fetoprotein (AFP) ratio in patients with AFP-negative hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively analyzed 600 AFP-negative HCC patients who underwent hepatectomy. The AFP ratio was calculated as the ratio of AFP level 1 week before surgery to the level 20-40 days after hepatectomy. Immunohistochemistry assay was used to assess protein expression in HCC tissue. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). RESULTS: The study found that a cutoff value of 1.6 ng/ml for AFP ratio, determined using X-tile software, was optimal for predicting prognosis. Patients with a high AFP ratio had a worse prognosis compare to those with a low AFP ratio (DFS, P = .026; OS, P = .034). Patients with a high AFP ratio had a worse prognosis compared to those with a low AFP ratio. Multivariate analysis revealed that AFP ratio >1.6, negative HepPar-1 expression, and vascular invasion were independent predictors of both DFS and OS. Vascular invasion had a higher area under the curve (AUC) than AFP ratio and HepPar-1 expression in predicting recurrence and death. The combination of AFP ratio, HepPar-1 expression, and vascular invasion provided better predictive accuracy for DFS and OS. CONCLUSION: The AFP ratio is a potential prognostic marker for AFP-negative HCC patients after hepatectomy. Combining the analysis of AFP ratio with HepPar-1 expression and vascular invasion can enhance the accuracy of predicting prognosis in these patients.
Asunto(s)
Carcinoma Hepatocelular , Hepatectomía , Neoplasias Hepáticas , alfa-Fetoproteínas , Humanos , alfa-Fetoproteínas/metabolismo , alfa-Fetoproteínas/análisis , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Pronóstico , Anciano , Adulto , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Supervivencia sin Enfermedad , Valor Predictivo de las Pruebas , InmunohistoquímicaRESUMEN
Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer with no targeted therapy. Spermatid perinuclear RNA binding protein (STRBP), a poorly characterized RNA-binding protein (RBP), has an essential role in normal spermatogenesis and sperm function, but whether and how its dysregulation contributing to cancer progression has not yet been explored. Here, we report that STRBP functions as a novel oncogene to drive TNBC progression. STRBP expression was upregulated in TNBC tissues and correlated with poor disease prognosis. Functionally, STRBP promoted TNBC cell proliferation, migration, and invasion in vitro, and enhanced xenograft tumor growth and lung colonization in mice. Mechanistically, STRBP interacted with Dicer, a core component of the microRNA biogenesis machinery, and promoted its proteasomal degradation through enhancing its interaction with E3 ubiquitin ligase UBR5. MicroRNA-sequencing analysis identified miR-200a-3p as a downstream effector of STRBP, which was regulated by Dicer and affected epithelial-mesenchymal transition. Importantly, the impaired malignant phenotypes of TNBC cells caused by STRBP depletion were largely rescued by knockdown of Dicer, and these effects were compromised by transfection of miR-200a-3p mimics. Collectively, these findings revealed a previously unrecognized oncogenic role of STRBP in TNBC progression and identified STRBP as a promising target against TNBC.
Asunto(s)
MicroARNs , Neoplasias de la Mama Triple Negativas , Animales , Humanos , Masculino , Ratones , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , Proteolisis , Semen/metabolismo , Espermátides/metabolismo , Espermátides/patología , Neoplasias de la Mama Triple Negativas/patología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Analysis of T-cell receptor (TCR) repertoires in different stages of hepatocellular carcinoma (HCC) might help to elucidate its pathogenesis and progression. This study aimed to investigate TCR profiles in liver biopsies and peripheral blood mononuclear cells (PBMCs) in different Barcelona Clinic liver cancer (BCLC) stages of HCC. Ten patients in early stage (BCLC_A), 10 patients in middle stage (BCLC_B), and 10 patients in late stage (BCLC_C) cancer were prospectively enrolled. The liver tumor tissues, adjacent tissues, and PBMCs of each patient were collected and examined by TCR ß sequencing. Based on the ImMunoGeneTics (IMGT) database, we aligned the V, D, J, and C gene segments and identified the frequency of CDR3 sequences and amino acids sequence. Diversity of TCR in PBMCs was higher than in both tumor tissues and adjacent tissues, regardless of BCLC stage and postoperative recurrence. TCR clonality was increased in T cells from peripheral blood in advanced HCC, compared with the early and middle stages. No statistical differences were observed between different BCLC stages, either in tumors or adjacent tissues. TCR clonality revealed no significant difference between recurrent tumor and non-recurrent tumor, therefore PBMCs was better to be representative of TCR characteristics in different stages of HCC compared to tumor tissues. Clonal expansion of T cells was associated with low risk of recurrence in HCC patients.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Leucocitos Mononucleares/patología , Resultado del Tratamiento , Estadificación de Neoplasias , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Receptores de Antígenos de Linfocitos T/genética , Estudios RetrospectivosRESUMEN
Colorectal cancer (CRC) is the third most prevalent cancer in the world. The PD-1/PD-L1 pathway plays a crucial role in modulating immune response to cancer, and PD-L1 expression has been observed in tumor and immune cells within the tumor microenvironment of CRC. Thus, immunotherapy drugs, specifically checkpoint inhibitors, have been developed to target the PD-1/PD-L1 signaling pathway, thereby inhibiting the interaction between PD-1 and PD-L1 and restoring T-cell function in cancer cells. However, the emergence of resistance mechanisms can reduce the efficacy of these treatments. To counter this, monoclonal antibodies (mAbs) have been used to improve the efficacy of CRC treatments. mAbs such as nivolumab and pembrolizumab are currently approved for CRC treatment. These antibodies impede immune checkpoint receptors, including PD-1/PD-L1, and their combination therapy shows promise in the treatment of advanced CRC. This review presents a concise overview of the use of the PD-1/PD-L1 blockade as a therapeutic strategy for CRC using monoclonal antibodies and combination therapies. Additionally, this article outlines the function of PD-1/PD-L1 as an immune response suppressor in the CRC microenvironment as well as the potential advantages of administering inflammatory agents for CRC treatment. Finally, this review analyzes the outcomes of clinical trials to examine the challenges of anti-PD-1/PD-L1 therapeutic resistance.