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Cholangiocarcinoma (CCA) is a primary malignant tumor of the liver, typically diagnosed in advanced stages. Surgical resection remains the principal treatment method in clinical practice. Regrettably, the majority of patients receive their diagnosis at an advanced stage, making surgical intervention unfeasible. While chemotherapy serves as the main palliative treatment for advanced CCA, its effectiveness is significantly limited due to the rapid development of chemoresistance. Studying the pathogenesis of CCA and new resistance targets is crucial for improving clinical outcomes. In our current study, we first identified the expression of SLC16A1 in the transcriptome and proteome of human tumors and found abnormal expression of SLC16A1 in various human cancers. Subsequently, we focused our attention on the role of SLC16A1 in CCA. Utilizing bioinformatics analysis, we pioneered the identification of the clinical significance of SLC16A1 in this type of cancer. Specifically, higher expression levels of SLC16A1 were observed in CCA patients with venous invasion and higher T and M stages. Additionally, patients with higher SLC16A1 expression had poorer prognoses. These results suggest the oncogenic role of SLC16A1 in CCA. Further immune infiltration analysis revealed a significant correlation between SLC16A1 and the infiltration levels of cells like neutrophils and macrophages in the tumor microenvironment, indicating SLC16A1's potential involvement in regulating the tumor immune microenvironment of CCA. Moreover, results from functional and pathway enrichment analyses revealed that SLC16A1 might affect clinical outcomes in CCA patients by participating in drug metabolism processes. Finally, through further in vitro and in vivo experiments, we confirmed that SLC16A1, as an oncogene in CCA, promotes the growth of CCA cells and chemoresistance. Knocking down SLC16A1 inhibited the growth of CCA cells and enhanced their sensitivity to 5-Fluorouracil (5-FU). Overall, this study reveals the key role of SLC16A1 in the development of CCA and highlights its significance as a potential target for improving treatment efficacy and chemotherapy sensitivity.
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We previously demonstrated a positive relation of secretory phospholipase A2 group IIA (sPLA2-IIA) with circulating high-density lipoprotein cholesterol (HDL-C) in patients with coronary artery disease, and sPLA2-IIA increased cholesterol efflux in THP-1 cells through peroxisome proliferator-activated receptor-γ (PPAR-γ)/liver X receptor α/ATP-binding cassette transporter A1 (ABCA1) signaling pathway. The aim of the present study was to examine the role of sPLA2-IIA over-expression on lipid profile in a transgenic mouse model. Fifteen apoE-/- and C57BL/7 female mice received bone marrow transplantation from transgenic SPLA2-IIA mice, and treated with specific PPAR-γ inhibitor GW9662. High fat diet was given after one week of bone marrow transplantation, and animals were sacrificed after twelve weeks. Immunohistochemical staining showed over-expression of sPLA2-IIA protein in the lung and spleen. The circulating level of HDL-C, but not that of low-density lipoprotein cholesterol (LDL-C), total cholesterol, or total triglyceride, was increased by sPLA2-IIA over-expression, and was subsequently reversed by GW9662 treatment. Over-expression of sPLA2-IIA resulted in augmented expression of cholesterol transporter ABCA1 at mRNA level in the aortas, and at protein level in macrophages, co-localized with macrophage specific antigen CD68. GW9662 exerted potent inhibitory effects on sPLA2-IIA-induced ABCA1 expression. Conclusively, we demonstrated the effects of sPLA2-IIA on circulating HDL-C level and the expression of ABCA1, possibly through regulation of PPAR-γ signaling in transgenic mouse model, that is in concert with the conditions in patients with coronary artery disease.
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Transportador 1 de Casete de Unión a ATP , Molécula CD68 , Ratones Endogámicos C57BL , Ratones Transgénicos , Animales , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador 1 de Casete de Unión a ATP/genética , Femenino , Ratones , Fosfolipasas A2 Grupo II/metabolismo , Fosfolipasas A2 Grupo II/genética , PPAR gamma/metabolismo , HDL-Colesterol/sangre , HDL-Colesterol/metabolismo , Pulmón/metabolismo , Pulmón/patología , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígenos CD/metabolismo , Antígenos CD/genética , Bazo/metabolismo , Trasplante de Médula Ósea , Humanos , Lípidos/sangreRESUMEN
Background: Human tumors pose significant challenges, with targeted therapy against specific molecular targets or signaling pathways being a mainstay alongside surgical resection. Previous studies have implicated KHDRBS1 in the oncogenesis of certain human tumors such as colorectal and prostate cancers, underscoring its potential as a therapeutic target. However, the comprehensive expression pattern of KHDRBS1 in hepatocellular carcinoma (HCC) warrants further exploration. Methods: Integrating and analyzing multi-omics, multi-cohort data from public databases, coupled with clinical samples and molecular biology validation, we elucidate the oncogenic role of KHDRBS1 in HCC progression. Additionally, leveraging HCC single-cell sequencing data, we segregate malignant cells into KHDRBS1-positive and negative subsets, uncovering significant differences in their expression profiles and functional roles. Results: Our study identifies KHDRBS1 as a tumor-promoting factor in HCC, with its positivity correlating with tumor progression. Furthermore, we highlight the clinical significance of KHDRBS1-positive malignant cells, aiming to further propel its clinical utility. Conclusion: KHDRBS1 plays a key role in HCC development. This study provides crucial insights for further investigation into KHDRBS1 as a therapeutic target in HCC.
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Proteínas Adaptadoras Transductoras de Señales , Biomarcadores de Tumor , Carcinoma Hepatocelular , Neoplasias Hepáticas , Microambiente Tumoral , Humanos , Masculino , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Pronóstico , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Transducción de Señal , Microambiente Tumoral/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismoRESUMEN
Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner. Furthermore, trilobolide-6-O-isobutyrate stimulates the production of reactive oxygen species, leading to oxidative stress and initiation of apoptosis via the activation of the mitochondrial pathway. Data from xenograft tumor assays in nude mice confirms that TBB inhibits tumor growth, and that there are no obvious toxic effects or side effects in vivo. Mechanistically, trilobolide-6-O-isobutyrate exerts antitumor effects by inhibiting STAT3 transcriptional activation, reducing PCNA and Bcl-2 expression, and increasing P21 expression. These findings emphasizes the potential of trilobolide-6-O-isobutyrate as a promising therapeutic candidate for the treatment of CCA.
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Colorectal Carcinoma (CRC) is one of the most common malignant tumors of the digestive tract, with a high mortality rate. DPY30 is one of the core subunits of the histone methyltransferase complex, which was involved in many cancer processes. However, the role of DPY30 in the occurrence and progression of CRC remains unclear. In this study, we sought to evaluate the role and mechanism of DPY30 in CRC cells apoptosis. Here, we identified that knockdown of DPY30 significantly inhibited the HT29 and HCT116 cells proliferation in vitro. Moreover, the knockdown of DPY30 significantly increased the apoptosis rate and promoted the expression of apoptosis-related proteins in CRC cells. Meanwhile, DPY30 knockdown promoted CRC cells apoptosis through endogenous programmed death and in a caspase activation-dependent manner. Furthermore, RNA-seq analysis revealed that the action of DPY30 is closely related to the apoptosis biological processes, and screened its potential effectors Raf1. Mechanistically, DPY30 downregulation promotes MST2-induced apoptosis by inhibiting Raf1 transcriptional activity through histone H3 lysine 4 trimethylation (H3K4me3). In vivo experiments showed that DPY30 was correlated with Raf1 in nude mouse subcutaneous xenografts tissues significantly. Clinical colorectal specimens further confirmed that overexpression of DPY30 in malignant tissues was significantly correlated with Raf1 level. The vital role of the DPY30/Raf1/MST2 signaling axis in the cell death and survival rate of CRC cells was disclosed, which provides potential new targets for early diagnosis and clinical treatment of CRC.
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OBJECTIVE: The tumor microenvironment (TME) in cholangiocarcinoma (CHOL) is typically characterized by a low level of immune infiltration, which accounts for the dismal prognosis of this patient population. This study sought to investigate the mechanisms underlying the reduced infiltration of immune cells into the CHOL TME. METHODS: We constructed a Least Absolute Shrinkage and Selection Operator (LASSO) regression model to identify prognosis-related differentially expressed genes (DEGs). The 'Corrplot' package was employed to analyze the correlation between dermatopontin (DPT) and immune infiltration in CHOL. The Tumor and Immune System Interaction Database (TISIDB) was used to evaluate the association between DPT and immunology. Single-cell analysis was conducted to localize CCL19 secretions. Western blot and qPCR were utilized to detect DPT expression, while immunofluorescence was performed to investigate the cellular localization of DPT. Additionally, ELISA analysis was employed to assess the alteration in CCL19 secretion in cancer-associated fibroblasts (CAFs) and macrophages. RESULTS: Our findings revealed that CHOL patients with low DPT expression had a poorer prognosis. Enrichment analysis demonstrated a positive correlation between DPT levels and the infiltration of immunomodulators and immune cells. Moreover, high DPT levels were associated with enhanced anti-PD-1/PD-L1 immunotherapeutic responses. Furthermore, DPT expression impacted the landscape of gene mutations, showing a negative association with tumor grade, stage, and lymph node metastasis. Based on the results of protein peptides analysis and cell experiments, it was inferred that the downregulation of DPT in CHOL cells effectively suppressed the secretion of CCL19 in macrophages. CONCLUSIONS: DPT is a novel prognosis-related biomarker for CHOL patients, and this study provides preliminary insights into the mechanism by which DPT promotes the infiltration of immune cells into the CHOL TME.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Humanos , Conductos Biliares Intrahepáticos , Quimiocina CCL19 , Colangiocarcinoma/genética , Regulación hacia Abajo , Macrófagos , Microambiente TumoralRESUMEN
DPY30 belongs to the core subunit of components of the histone lysine methyltransferase complex, which is implicated in tumorigenesis, cell senescence, and other biological events. However, its contribution to colorectal carcinoma (CRC) progression and metastasis has yet to be elucidated. Therefore, this study aimed to investigate the biological function of DPY30 in CRC metastasis both in vitro and in vivo. Herein, our results revealed that DPY30 overexpression is significantly positively correlated with positive lymph nodes, epithelial-mesenchymal transition (EMT), and CRC metastasis. Moreover, DPY30 knockdown in HT29 and SW480 cells markedly decreased EMT progression, as well as the migratory and invasive abilities of CRC cells in vitro and lung tumor metastasis in vivo. Mechanistically, DPY30 increased histone H3K4me3 level and promoted EMT and CRC metastasis by upregulating the transcriptional expression of ZEB1. Taken together, our findings indicate that DPY30 may serve as a therapeutic target and prognostic marker for CRC.
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The nuclear receptor superfamily RAR is generally considered to play a crucial role in the development of tumors by regulating the transcription of target genes. Nevertheless, whether RARγ performs tumor-promoting or tumor-suppressing functions and its specific mechanism in thyroid carcinoma (TC) remain unknown. Here, our study demonstrated that RARγ was abnormally overexpressed in TC tissues compared with normal thyroid tissues. Moreover, RARγ expression was remarkably correlated with cell phenotypes such as cell proliferation, migration and invasion. Mechanistically, RARγ knockdown effectively decreased the phosphorylation levels of JAK1 and STAT3, leading to decreased expression of the membrane protein CD24. In a coculture system, TC cells with high levels of CD24 in the membrane were more likely to escape phagocytosis by macrophages via the combination of CD24 with the inhibitory receptor Siglec-10 in the membrane of macrophages. In contrast, the ability of macrophages to engulf TC cells was notably elevated through exogenous addition of CD24 antibody. Collectively, our study revealed a previously undiscovered molecular mechanism of RARγ in promoting the development of TC, shedding light on RARγ as a promising therapeutic target for TC.
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Neoplasias de la Tiroides , Humanos , Antígeno CD24 , Línea Celular Tumoral , Proliferación Celular , Janus Quinasa 1 , Factor de Transcripción STAT3 , Neoplasias de la Tiroides/genética , Receptor de Ácido Retinoico gammaRESUMEN
Curcumin is a polyphenolic compound that has been widely investigated for its health benefits. However, the clinical relevance of curcumin is limited due to its low water solubility and inefficient absorption. Therefore, curcumin is often encapsulated in nanocarriers to improve its delivery and function. In this study, composite nanoparticles composed of stearic acid-modified chitosan (SA-CS) and sodium caseinate (NaCas) were formed using sodium periodate-oxidized dextran with different molecular weights as a crosslinking agent. The effects of oxidized dextran (Odex) with different molecular weights on the composite nanoparticles were compared. The optimal SA-CS/NaCas/Odex composite nanoparticle (NPO) was obtained using an Odex (150 kDa)-to-SA-CS mass ratio of 2:1. Its size, polydispersity index (PDI), and zeta potential (ZP) were 130.2 nm, 0.149, and 25.4 mV, respectively. The particles were highly stable in simulated gastric fluid (SGF) in vitro, and their size and PDI were 172.3 nm and 0.263, respectively. The encapsulation rate of NPO loaded with curcumin (Cur-NPO) was 93% under optimal ultrasonic conditions. Compared with free curcumin, the sustained release of Cur-NPO significantly reduced to 17.9%, and free-radical-scavenging ability improved to 78.7%. In general, the optimal prepared NPO exhibited good GI stability and has potential applications in the formulation of orally bioactive hydrophobic drugs.
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DPY30, a core subunit of the SET1/MLL histone H3K4 methyltransferase complexes, plays an important role in diverse biological functions through the epigenetic regulation of gene transcription, especially in cancer development. However, its involvement in human colorectal carcinoma (CRC) has not been elucidated yet. Here we demonstrated that DPY30 was overexpressed in CRC tissues, and significantly associated with pathological grading, tumor size, TNM stage, and tumor location. Furthermore, DPY30 knockdown remarkably suppressed the CRC cell proliferation through downregulation of PCNA and Ki67 in vitro and in vivo, simultaneously induced cell cycle arrest at S phase by downregulating Cyclin A2. In the mechanistic study, RNA-Seq analysis revealed that enriched gene ontology of cell proliferation and cell growth was significantly affected. And ChIP result indicated that DPY30 knockdown inhibited H3 lysine 4 trimethylation (H3K4me3) and attenuated interactions between H3K4me3 with PCNA, Ki67 and cyclin A2 respectively, which led to the decrease of H3K4me3 establishment on their promoter regions. Taken together, our results demonstrate overexpression of DPY30 promotes CRC cell proliferation and cell cycle progression by facilitating the transcription of PCNA, Ki67 and cyclin A2 via mediating H3K4me3. It suggests that DPY30 may serve as a potential therapeutic molecular target for CRC.
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Neoplasias Colorrectales , Ciclina A2 , Humanos , Ciclina A2/genética , Factores de Transcripción , Epigénesis Genética , Antígeno Ki-67 , Antígeno Nuclear de Célula en Proliferación , Proliferación Celular/genética , Ciclo Celular/genética , Neoplasias Colorrectales/genéticaRESUMEN
Preadipocyte determination expanding the pool of preadipocytes is a vital process in adipocyte hyperplasia, but the molecular mechanisms underlying this process are yet to be elucidated. Herein, SRY-related HMG box transcription factor 4 (SOX4) was identified as a critical target in response to BMP4- and TGFß-regulated preadipocyte determination. SOX4 deficiency is sufficient to promote preadipocyte determination in mesenchymal stem cells (MSCs) and acquisition of preadipocyte properties in nonadipogenic lineages, while its overexpression impairs the adipogenic capacity of preadipocytes and converts them into nonadipogenic lineages. Mechanism studies indicated that SOX4 activates and cooperates with LEF1 to retain the nuclear localization of ß-catenin, thus mediating the crosstalk between TGFß/BMP4 signaling pathway and Wnt signaling pathway to regulate the preadipocyte determination. In vivo studies demonstrated that SOX4 promotes the adipogenic-nonadipogenic conversion and suppresses the adipocyte hyperplasia. Together, our findings highlight the importance of SOX4 in regulating the adipocyte hyperplasia in obesity.
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BACKGROUND: Critically ill patients in intensive care often struggle with disrupted sleep, a prevalent issue in this population. However, the question of which non-pharmacological intervention is most effective in enhancing sleep quality remains unanswered. This study was conducted to comprehensively evaluate and compare the efficacy of various non-pharmacological interventions aimed at improving sleep quality among critically ill individuals. METHODS: We conducted a search of PubMed, Embase, and the Cochrane Library (Cochrane Central Register of Controlled Trials) without language restrictions to identify articles published until July 15, 2023. Randomized controlled trials (RCTs) that investigated various nursing interventions designed to improve sleep quality in critically ill patients were included in this network meta-analysis. All analyses were performed using R software (version 3.4.3) with the "gemtc" package. RESULTS: A total of 2036 patients from 31 RCTs were included in the network meta-analysis, involving 11 different nursing interventions (routine care, relaxation combined with imagery (RI), nursel, musicâ +â earplugsâ +â eye masks, music, eye masks, earplugsâ +â eye masks, earplugs, aromatherapy, Warm footbath combined with acupoint exercise (WFA), Virtual reality meditation (VR)). Eye masks and earplugsâ +â eye masks were associated with improved sleep quality compared to routine care intervention (Pâ <â .05). CONCLUSIONS: In summary, eye masks and earplugsâ +â eye masks stand out as the most effective interventions for enhancing sleep quality in critically ill patients. Therefore, critical care nurses should consider incorporating the use of eye masks alone or combining music with eye masks into the sleep care regimen for critically ill patients.
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Enfermedad Crítica , Calidad del Sueño , Humanos , Cuidados Críticos , Enfermedad Crítica/enfermería , Unidades de Cuidados Intensivos , Metaanálisis en Red , Ensayos Clínicos Controlados Aleatorios como Asunto , SueñoRESUMEN
Osteoarthritis (OA) is a severe inflammation-related disease which leads to cartilage destruction. The retinoic acid receptor gamma (RARγ) has been indicated to be involved in many inflammation processes. However, the role and mechanism of RARγ in cartilage destruction caused by inflammation in OA are still unknown. Here, we demonstrated that the RARγ was highly expressed in chondrocytes of OA patients compared with healthy people and was positively correlated with the damage degree of cartilage in OA. Cytokine TNF-α promoted the transcription and expression of RARγ through activating the NF-κB pathway in OA cartilage. In addition, the overexpression of RARγ resulted in the upregulation of matrix degradation and inflammation associated genes and downregulation of differentiation and collagen production genes in human normal chondrocyte C28/I2 cells. Mechanistically, overexpression of RARγ could increase the level of p-IκBα and p-P65 to regulate the expression of downstream genes. RARγ and IκBα also could interact with each other and had the same localization in C28/I2 cells. Moreover, the SD rats OA model induced by monosodium iodoacetate indicated that CD437 (RARγ agonist) and TNF-α accelerated the OA progression, including more severe cartilage layer destruction, larger knee joint diameter, and higher serum ALP levels, while LY2955303 (RARγ inhibitor) showed the opposite result. RARγ was also highly expressed in OA group and even higher in TNF-α group. In conclusion, RARγ/NF-κB positive feedback loop was activated by TNF-α in chondrocyte to promote cartilage destruction. Our data not only propose a novel and precise molecular mechanism for OA disease but also provide a prospective strategy for the treatment.
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FN-kappa B , Osteoartritis , Humanos , Ratas , Animales , FN-kappa B/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Retroalimentación , Ratas Sprague-Dawley , Osteoartritis/genética , Osteoartritis/metabolismo , Cartílago/metabolismo , Inflamación/metabolismo , Receptor de Ácido Retinoico gammaRESUMEN
We incorporated oxidized dextran (Odex) into nanoparticles composed of gallic acid-modified chitosan (GA-CS) and sodium caseinate (NaCas). The mass ratio of GA-CS to NaCas and the pH of the reaction solution were optimized to obtain nanoparticles with excellent performance and stability. The interactions among various nanomaterials were confirmed by Fourier-transform infrared spectroscopy (FT-IR) and fluorescence spectrometer. The optimized complex nanoparticles had a diameter of approximately 131.2 nm with a polydispersity index (PDI) of 0.14, and a zeta potential of 26.2 mV. Our results showed that Odex enhanced the stability and function of GA-CS/NaCas nanoparticles (NP). At a curcumin loading of 10%, the encapsulation efficiency of Odex-crosslinked GA-CS/NaCas (NP (Odex)) was 96.2%, whereas that for uncrosslinked nanoparticles was 66.9%. Compared to the burst release profile of free curcumin in simulated GI fluids, the sustained release profile of encapsulated curcumin was observed. Radical-scavenging assays confirmed that the nanoparticles had excellent antioxidant activity themselves due to the grafting of phenolic acid on chitosan backbone. Overall, NP (Odex) with good GI stability and antioxidant activity hold promising for the oral delivery of hydrophobic bioactives.
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Caseínas/química , Quitosano/química , Dextranos/química , Ácido Gálico/química , Nanopartículas/química , Curcumina/administración & dosificación , Curcumina/farmacocinética , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Concentración de Iones de Hidrógeno , Cinética , Tamaño de la Partícula , Análisis EspectralRESUMEN
Currently available therapies for hepatocellular carcinoma (HCC), with a high morbidity and high mortality, are only marginally effective and with sharp adverse side effects, which makes it compulsory to explore novel and more effective anticancer molecules. Chinese medicinal herbs exhibited prominent anticancer effects and were applied to supplement clinical cancer treatment. Here, we reported a compound, trilobolide-6-O-isobutyrate (TBB), isolated from the flowers of Wedelia trilobata with a markedly cytotoxic effect on HCC cells. We found that TBB time- and dose-dependently inhibited HCC cells' growth and colony formation in vitro. Moreover, TBB induced cell cycle arrest at the G2/M phase, mitochondrial caspase-dependent apoptosis, and suppressed migration and invasion, as well as the glycolysis of HCC cells. Mechanistically, our data indicated that TBB inhibited the STAT3 pathway activation by directly interacting with the TYR 640/657 sites of the STAT3 protein and decreasing the level of p-STAT3. TBB also regulated the expression of PCNA, Ki67, Cyclin B1, Cyclin E, Bax, Bcl2, MMP2/9, and PGK1 through the inhibition of the IL-6/STAT3 signaling pathway. Lastly, we confirmed that TBB effectively eliminated tumor growth without causing overt toxicity to healthy tissues in the xenograft tumor model. The exploration of anticancer activity and the underlying mechanism of TBB suggested its usage as a promising chemotherapeutic agent for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Apoptosis , Butiratos , Carcinogénesis , Carcinoma Hepatocelular/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Furanos , Humanos , Interleucina-6/metabolismo , Isobutiratos , Neoplasias Hepáticas/tratamiento farmacológico , Factor de Transcripción STAT3/metabolismo , Transducción de SeñalRESUMEN
Colorectal cancer (CRC) is the most fatal gastrointestinal tumor and it is urge to explore powerful drugs for the treatment. Diosgenin (DSG) as a new steroidal had been reported exerts anti-tumor activity in multiple cancers, including CRC. However, the potential mechanism of DSG suppresses CRC remains further to be revealed. Here, we reported that DSG inhibited proliferation of CRC cells in dose- and time-dependent manner, induced apoptosis by modulating p53 and Bcl-2 family proteins expression to mediate mitochondrial apoptosis pathway, suppressed migration and invasion by reducing MMP-9 (matrix metalloproteinase) and decreased aerobic glycolysis by mediating glucose transporter (GLUT) like GLUT3 and GLUT4, and pyruvate carboxylase PC downregulation. Intriguingly, mechanistic study suggests those phenotypes involved DSG inhibited cAMP/PKA/CREB pathway in CRC cells, and result to inhibit the phosphorylation of CREB to regulate the transcription of genes above-mentioned. Finally, nude mice xenograft tumor model further indicated that DSG could be a great agent to suppress the growth of CRC cells in vivo and have no obvious side effects. Taken together, we revealed a unique mechanism that DSG suppresses CRC cells through cAMP/PKA/CREB pathway and DSG is a promising candidate drug for CRC treatment.
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Diosgenina , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Ratones , Transducción de SeñalRESUMEN
RATIONALE: Intraductal papillary neoplasm of the bile ducts (IPNB) is a relatively rare tumor that is clinically characterized by digestive symptoms. The concurrent occurrence of chronic disseminated intravascular coagulation (DIC) with thrombosis is an extremely rare combination, reported in patients with IPNB. The clinical features of chronic DIC include microangiopathic hemolytic anemia, thrombocytopenia, and hypofibrinogenemia. Here, we report the case of a mucin-producing IPNB patient with hematological abnormalities. PATIENT CONCERNS: A 58-year-old male patient suffered from abdominal distension for more than 2âmonths with obstructive jaundice appearance. Abdominal contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography showed a neoplasm in the right hepatic lobe. Multiple intravascular fillings were found in the inferior vena cava, pulmonary artery, and right atrium. Anemia and hypofibrinogenemia were discovered through routine laboratory tests. The count of platelets began to decline 25âdays after admission, while 1âmonth after hospitalization, the patient developed abdominal pain, fever, and shock. DIAGNOSIS: Pathological examination demonstrated IPNB with a part of high-grade intraepithelial neoplasia. Cardiac and inferior vena cava emboli were diagnosed as thrombi without neoplastic cells. Immunohistochemically, tumor cells were positive for Vimentin (mesenchyme), CK7, CK19, MUC-1, MUC-5AC, MUC-6, S-100p (focal), Ki-67 (12%), and negative for Inhibin-α, ER, CK20, CEA, and MUC-2. Additionally, immunohistochemistry indicated that IPNB was a mucus-secretion gastric type. The laboratory tests confirmed the presence of chronic DIC. INTERVENTIONS: The patient was given anticoagulant therapy before hepatectomy and right atrium thrombectomy was performed under cardiopulmonary bypass. OUTCOMES: After anticoagulant therapy, the levels of hemoglobin, platelet, and fibrinogen of the patient returned to normal. Hepatectomy and thrombus removal was successfully performed. Then, the patient was discharged 12âdays after the operation. After 12âmonths of follow-up, the patient recovered well without any hematologic abnormalities and no signs of tumor recurrence were observed. LESSONS: IPNB may cause hematological complications, which can be easily misdiagnosed. It is essential to pay particular attention to the hematological abnormalities of patients with IPNB. Early detection and differential diagnosis of chronic DIC and thrombosis are necessary. We note that anticoagulant therapy coupled with surgery is an effective strategy to treat these complications.
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Neoplasias de los Conductos Biliares/complicaciones , Neoplasias de los Conductos Biliares/patología , Carcinoma Papilar/complicaciones , Carcinoma Papilar/patología , Coagulación Intravascular Diseminada/complicaciones , Trombosis/complicaciones , Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares Intrahepáticos/patología , Conductos Biliares Intrahepáticos/cirugía , Carcinoma Papilar/cirugía , Hepatectomía/métodos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The anti-inflammatory effects of shark compound peptides (SCP) from Chiloscyllium plagiosum were investigated. Results showed that SCP enhanced the viability of RAW 264.7 macrophages in vitro in a dose-dependent manner. Orally administered SCP exhibited potent anti-inflammatory activity in lipopolysaccharide (LPS)-challenged mice by suppressing serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), as well as nitric oxide (NO). Moreover, SCP significantly inhibited the inflammatory rise of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and creatinine (CRE), while blocking the decline of cholinesterase (CHE), with an efficacy close to aspirin. This research showed that orally administered SCP from C. plagiosum notably downregulated uncontrolled inflammatory responses, and conferred substantial protection from endotoxin-induced acute hepatic damage and renal functional impairment. Therefore, oral supplementation of SCP can be used as a preventive approach to reduce the risk of inflammatory-related diseases.
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Tiburones , Animales , Aspartato Aminotransferasas , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Lipopolisacáridos/toxicidad , Ratones , PéptidosRESUMEN
BACKGROUND: Depression is associated with inflammation and Alzheimer's disease (AD). However, detailed molecular mechanisms linking mood, neuroinflammation and AD remain unclear. Although changes in peripheral inflammatory factors such as Interleukin 18 (IL18), and AD-associated amyloid-ß (Aß) peptides have been linked to depression, a solid relationship between these factors in depressive disorder has yet to be established. This study aims to further determine whether plasma IL18, Aß40, Aß42, and the AD-associated tangle component Tau, as well as IL18 single nucleotide polymorphisms (SNPs) may be biomarkers for depression. METHODS: We measured plasma IL18, Aß40, Aß42, and Tau in 64 depressive patients and 75 healthy controls, and characterized genotypes of three IL18 SNPs (rs187238, rs1946518 and rs1946519) in these subjects. Comparisons between depressive patients and controls were carried out in males, in females or in combination. Regression analyses were conducted to examine the correlation between these parameters. RESULTS: We found that none of the plasma levels of IL18, Aß40, Aß42, and Tau, the ratio of Aß42/Aß40, and the genotypes of IL18 SNPs were significantly different between combined depressive patients and combined healthy controls, or between male depressive patients and male controls. However, IL18 levels were less in females than in males in healthy people and were significantly increased in female depressive patients compared to female controls. Moreover, IL18 and standardized IL18 were correlated with standardized Aß42/Aß40 ratio and standardized Tau in depressive patients. CONCLUSIONS: Plasma IL18 may be a potential biomarker for depression in women.
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Péptidos beta-Amiloides/sangre , Depresión/sangre , Interleucina-18/sangre , Proteínas tau/sangre , Anciano , Apolipoproteínas E , Biomarcadores/sangre , Estudios de Casos y Controles , Depresión/diagnóstico , Depresión/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Polimorfismo de Nucleótido SimpleRESUMEN
Purpose: The present study aimed to explore the predictive ability of an ultrasound linear regression equation in patients undergoing endovascular stent placement (ESP) to treat carotid artery stenosis-induced ischemic stroke. Methods: Pearson's correlation coefficient of actual improvement rate (IR) and 10 preoperative ultrasound indices in the carotid arteries of 64 patients who underwent ESP were retrospectively analyzed. A predictive ultrasound model for the fitted IR after ESP was established. Results: Of the 10 preoperative ultrasound indices, peak systolic velocity (PSV) at stenosis was strongly correlated with postoperative actual IR (r = 0.622; P < 0.01). The unstable plaque index (UPI; r = 0.447), peak eccentricity ratio (r = 0.431), and plaque stiffness index (ß; r = 0.512) moderately correlated with actual IR (P < 0.01). Furthermore, the resistance index (r = 0.325) and the dilation coefficient (r = 0.311) weakly correlated with actual IR (P < 0.05). There was no significant correlation between actual IR and the number of unstable plaques, area narrowing, pulsatility index, and compliance coefficient. In combination, morphological, hemodynamic, and physiological ultrasound indices can predict 62.39% of neurological deficits after ESP: fitted IR = 0.9816 - 0.1293ß + 0.0504UPI - 0.1137PSV. Conclusion: Certain carotid ultrasound indices correlate with ESP outcomes. The multi-index predictive model can be used to evaluate the effects of ESP before surgery.