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Ovarian cancer stands as a formidable clinical challenge, with limited therapeutic options. This investigation delves into the intricate molecular mechanisms governing ovarian cancer progression and uncovers Centromere Protein K (CENPK) as a central figure in disease pathogenesis. Elevated CENPK levels within ovarian cancer tissues conspicuously align with adverse clinical outcomes, positioning CENPK as a promising prognostic biomarker. Deeper exploration reveals a direct transcriptional connection between CENPK and the E2F1 transcription factor and clearly establishes E2F1's role as the master regulator of CENPK expression in ovarian cancer. Our inquiry revealing a suppression of tumor-promoting signaling pathways, most notably the mTOR pathway, upon CENPK silencing. Intriguingly, CENPK renders ovarian cancer cells more responsive to the mTOR inhibitor rapamycin, introducing a promising avenue for therapeutic intervention. In summation, our study unravels the multifaceted role of CENPK in ovarian cancer progression. It emerges as a prognostic indicator, a pivotal mediator of cell proliferation and tumorigenicity, and a regulator of the mTOR pathway, shedding light on potential therapeutic avenues for this formidable disease.
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Proliferación Celular , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Proteínas de la Membrana , Neoplasias Ováricas , Transducción de Señal , Serina-Treonina Quinasas TOR , Femenino , Humanos , Línea Celular Tumoral , Factor de Transcripción E2F1 , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Pronóstico , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Dysregulation of cholesterol homeostasis is implicated in the development and progression of hepatocellular carcinoma (HCC) that is characterized by intrahepatic and early extrahepatic metastases. A better understanding of the underlying mechanisms regulating cholesterol metabolism in HCC could help identify strategies to circumvent the aggressive phenotype. Here, we found that high expression of intracellular SPARC (secreted protein acidic and rich in cysteine) was significantly associated with elevated cholesterol levels and an enhanced invasive phenotype in HCC. SPARC potentiated cholesterol accumulation in HCC cells during tumor progression by stabilizing the ApoE protein. Mechanistically, SPARC competitively bound to ApoE, impairing its interaction with the E3 ligase tripartite motif containing 21 (TRIM21) and preventing its ubiquitylation and subsequent degradation. ApoE accumulation led to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing epithelial-mesenchymal transition (EMT). Importantly, sorafenib-resistant HCC cells were characterized by increased expression of intracellular SPARC, elevated cholesterol levels, and enhanced invasive capacity. Inhibiting SPARC expression or reducing cholesterol levels enhanced the sensitivity of HCC cells to sorafenib treatment. Together, these findings unveil interplay between SPARC and cholesterol homeostasis. Targeting SPARC-triggered cholesterol-dependent oncogenic signaling is a potential therapeutic strategy for advanced HCC. SIGNIFICANCE: Intracellular SPARC boosts cholesterol availability to fuel invasion and drug resistance in hepatocellular carcinoma, providing a rational approach to improve the treatment of advanced liver cancer.
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Apolipoproteínas E , Carcinoma Hepatocelular , Colesterol , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Neoplasias Hepáticas , Invasividad Neoplásica , Osteonectina , Sorafenib , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Osteonectina/metabolismo , Osteonectina/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Humanos , Sorafenib/farmacología , Colesterol/metabolismo , Animales , Ratones , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Línea Celular Tumoral , Ratones Desnudos , Masculino , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.
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Neoplasias Colorrectales , Interleucina-6 , Humanos , Carcinogénesis/metabolismo , Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/patología , Histonas/metabolismo , Interleucina-6/metabolismo , Lactatos/metabolismo , Macrófagos/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Microambiente TumoralRESUMEN
Salt stress adversely affects the growth, development, and yield of tomato (Solanum lycopersicum). SAM Synthetase (SAMS), which is responsible for the biosynthesis of S-adenosylmethionine (SAM, a precursor of polyamine biosynthesis), participates in plant response to abiotic stress. However, the regulatory mechanism of SAMS-mediated salt stress tolerance remains elusive. In this study, we characterized a SAMS homologue SlSAMS1 in tomato. We found that SlSAMS1 is highly expressed in tomato roots, and its expression can be induced by salt stress. Crucially, overexpression of SlSAMS1 in tomato enhances salt stress tolerance. Through metabolomic profiling, we identified some differentially accumulated metabolites, especially, a secondary messenger guanosine 3',5'-cyclic monophosphate (cGMP) which may play a key role in SlSAMS1-regulated salt tolerance. A series of physiological and biochemical data suggest that cGMP alleviates salt stress-induced growth inhibition, and potentially acts downstream of the polyamine-nitric oxide (PA-NO) signaling pathway to trigger H2O2 signaling in response to salt stress. Taken together, the study reveals that SlSAMS1 regulates tomato salt tolerance via the PA-NO-cGMP-H2O2 signal module. Our findings elucidate the regulatory pathway of SlSAMS1-induced plant response to salt stress and indicate a pivotal role of cGMP in salt tolerance.
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Solanum lycopersicum , Solanum lycopersicum/genética , Tolerancia a la Sal/genética , Peróxido de Hidrógeno/metabolismo , Estrés Fisiológico , S-Adenosilmetionina/metabolismo , Poliaminas/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
Rotor-stator axial clearance is a crucial design parameter affecting rotating machines' efficiency and safety. To accurately measure the dynamic axial clearance in high-speed machinery, a precise method based on time division multiplexing with frequency domain interferometry has been proposed. This method has proven robust and accurate through simulations and experiments. The inclusion of an optical switch enables the utilization of dispersive interferometry(DPI) and time division multiplexing for multiple channels of the light source. It achieves a static accuracy of 1.5â µm for a 15 mm range and a dynamic accuracy of 9â µm at 3000â rpm.
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PURPOSE: The exact phenoconversion time from isolated rapid eye movement (REM) sleep behavior disorder (iRBD) to synucleinopathies remains unpredictable. This study investigated whole-brain dopaminergic damage pattern (DDP) with disease progression and predicted phenoconversion time in individual patients. METHODS: Age-matched 33 iRBD patients and 20 healthy controls with 11C-CFT-PET scans were enrolled. The patients were followed up 2-10 (6.7 ± 2.0) years. The phenoconversion year was defined as the base year, and every 2 years before conversion was defined as a stage. Support vector machine with leave-one-out cross-validation strategy was used to perform prediction. RESULTS: Dopaminergic degeneration of iRBD was found to occur about 6 years before conversion and then abnormal brain regions gradually expanded. Using DDP, area under curve (AUC) was 0.879 (90% sensitivity and 88.3% specificity) for predicting conversion in 0-2 years, 0.807 (72.7% sensitivity and 83.3% specificity) in 2-4 years, 0.940 (100% sensitivity and 84.6% specificity) in 4-6 years, and 0.879 (100% sensitivity and 80.7% specificity) over 6 years. In individual patients, predicted stages correlated with whole-brain dopaminergic levels (r = - 0.740, p < 0.001). CONCLUSION: Our findings suggest that DDP could accurately predict phenoconversion time of individual iRBD patients, which may help to screen patients for early intervention.
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Trastorno de la Conducta del Sueño REM , Humanos , Trastorno de la Conducta del Sueño REM/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Dopamina , Progresión de la EnfermedadRESUMEN
Flow stimulation before release into the wild may contribute to improved survivability of farmed fish. However, the effects of flow stimulation on the survival rate of fish depend on the fish species and exercise regime, such as exercise type, duration, and intensity. In this study, juvenile Percocypris pingi swam for 18 h per day for 8 weeks under different water speeds, 3 cm s-1 (control) and 1, 2, and 4 body lengths (bl) s-1 , at 20°C. Then, parameters related to the growth rate, swimming capacity, spontaneous activity, and immune function were measured. We found that (1) continuous flow stimulation had no significant influence on the growth but was conducive to the increase in the relative carcass mass; (2) continuous flow stimulation at 2 or 4 bl s-1 enhanced the aerobic swimming capacity (Ucrit ), which may be due to an increase in anaerobic exercise capacity (endurance time) rather than to changes in maximum metabolic rate and aerobic scope; (3) continuous flow stimulation at 4 bl s-1 led to a significant increase in spontaneous activity, which was mainly due to the higher percent time spent moving as compared with the controls; and (4) continuous flow stimulation at 2 bl s-1 may contribute to improving the nonspecific immune parameter (lysozyme activity) in juvenile P. pingi. Our findings suggest that continuous flow stimulation at 2 or 4 bl s-1 for 18 h per day for 56 days at 20°C before release in wild may be a suitable training regime for improving the survival rate of cultured juvenile P. pingi.
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Cyprinidae , Natación , Animales , Natación/fisiologíaRESUMEN
Dysfunction of mesangial cells plays a significant role in the glomerular lesions and is implicated in the pathophysiology of diabetic nephropathy (DN). Macrophages infiltration is the main pathological feature of DN, which can ultimately lead to renal inflammation. Recent studies suggest that the crosstalk between kidney resident cells and inflammatory cells influences the development of DN, and that controlling this crosstalk may help treat DN. Here, we found that DN mice appeared renal pathological damage, including dilation of mesangial matrix and significant infiltration of macrophages, accompanied by increased inflammatory response, NLRP3 inflammasome activation and autophagy deficiency. Additionally, mesangial cells internalized exosomes from high glucose (HG) treated macrophage, resulting the activation of inflammatory cytokines and NLRP3 inflammasome and deficiency of autophagy in vitro and in vivo. Moreover, C57BL/6 mice injected HG-stimulated macrophages-derived exosomes exhibited renal dysfunction and mesangial matrix expansion. Taken together, the present study demonstrated that mesangial cells responded to HG treated macrophage-derived exosomes by promoting the activation of NLRP3 inflammasome and autophagy deficiency, thereby participating in the development of DN.
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Diabetes Mellitus , Nefropatías Diabéticas , Exosomas , Ratones , Animales , Inflamasomas , Nefropatías Diabéticas/patología , Proteína con Dominio Pirina 3 de la Familia NLR , Células Mesangiales , Exosomas/patología , Ratones Endogámicos C57BL , Autofagia , Macrófagos/patologíaRESUMEN
Epidemiological data have shown a positive correlation between lipid levels and tumor occurrence, such as the correlation between tumor frequency and aggressiveness, and cardiovascular disease, obesity, type 2 diabetes mellitus, and hyperinsulinemia. Therefore, reducing fat accumulation or weakening lipid metabolism may affect the carcinogenic processes of cells. Many studies have shown that traditional Chinese Medicine (TCM) has obvious advantages over traditional therapies in terms of fewer side effects, lower toxicity, and lower economic burden. This paper reviews the mechanism by which TCM regulates lipid metabolism and its antitumor effect through this regulation, with the aim of elucidating the bioactive compounds in TCM with good efficacy and few side effects that can provide promising therapeutic drugs for targeting lipid metabolism reprogramming in cancer.
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BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant solid tumor that lacks early diagnostic methods. Recently, targeted immunotherapy and radiotherapy have been integrated with radionuclide-antibody conjugate drugs, which can be used for targeted diagnosis and dynamic imaging of tumors. CEACAM6 is overexpressed in pancreatic tumors and is a potential theranostic target for PDAC. We aimed to develop a novel targeted carrier for theranostics of PDAC and other solid tumors. METHODS: Based on camelid heavy-chain-only antibodies, we developed a CEACAM6-targeting recombinant antibody NY004, and evaluated it as a novel antibody-carrier for imaging and therapy of cancer in tumor models. We labeled NY004 with theranostic nuclides and applied this self-developed antibody platform in diagnostic imaging and antitumor assessment in PDAC models. RESULTS: Through microPET, IHC, and biodistribution assays, targeting and biodistribution of [89Zr]-NY004 in solid tumors including PDAC was examined, and the investigated tumors were all CEACAM6-positive malignancies. We found that NY004 was suitable for use as a drug carrier for radioimmunotheranostics. Our study showed that NY004 was characterized by high targeted uptake and a long retention time in PANC-1 tumors (up to 6 days post-injection), with good specificity and high imaging efficiency. Therapeutic evaluation of the radionuclide-labeled antibody drug [177Lu]-NY004 in PDAC tumor-bearing model revealed that NY004 had high and prolonged uptake in tumors, relatively low non-target organ uptake, and good anti-tumor efficacy. CONCLUSION: As a drug platform for radiotheranostics, CEACAM6-specific antibody NY004 met the requirements of easy-labeling, targeting specificity, and effective persistence in pancreatic adenocarcinoma tissues. KEY POINTS: ⢠[89Zr]-NY004 has good specificity and high imaging efficiency, and is characterized by high tumor-targeting uptake and a long tumor retention time as a PET molecular imaging tracer. ⢠Therapeutic radionuclide-conjugated antibody drug [177Lu]-NY004 has high uptake and prolonged uptake duration in tumors, low non-target organ uptake, and significant tumor-inhibiting efficacy in PDAC model. ⢠The self-developed antibody structure NY004 is a promising drug platform for radioimmunotheranostics of CEACAM6-positive tumors including pancreatic ductal adenocarcinoma.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patología , Adenocarcinoma/patología , Distribución Tisular , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/terapia , Tomografía de Emisión de Positrones/métodos , Radioisótopos/uso terapéutico , Línea Celular Tumoral , Neoplasias PancreáticasRESUMEN
We examined the antifungal characteristics of linalool against Botrytis cinerea using plate inhibition assay and spore germination assay, and assessed the capacity of linalool in controlling tomato gray mold disease via tomato pot inoculation assay. The results showed that linalool exhibited strong inhibitive effects on mycelial growth of B. cinerea, with an EC50 value of 0.581 mL·L-1. In the spore germination test, linalool treatment inhibited spore germination in a dose-dependent manner. The electric conductivity and the malondialdehyde (MDA) contents were significantly increased in linalool-treated B. cinerea than that of the control, indicating that linalool induced oxidative damage and destroyed the cell membrane integrity in B. cinerea. The activities of the superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) in the linalool-treated B. cinerea were decreased significantly by 27.4%, 68.9% and 26.0%, respectively, suggesting that linalool inhibited the antioxidant activity of B. cinerea. In the pot experiment, the diameter of lesions in linalool-treated tomatoes was significantly smaller than that of the control. The activities of SOD, POD, CAT, polyphenol oxidase, and phenylalnine ammonialyase in the linalool-treated tomatoes increased, while the MDA content decreased, suggesting that linalool could alleviate the oxidative damage caused by B. cinerea and promote plant disease resistance. In summary, linalool had inhibitory effect on the growth of B. cinerea and could control gray mold disease in tomatoes. These findings could lay the foundation for developing bota-nical antifungal agents for management of tomato gray mold disease.
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Solanum lycopersicum , Botrytis , Superóxido Dismutasa , Enfermedades de las Plantas/prevención & control , Enfermedades de las Plantas/microbiologíaRESUMEN
Bone metastasis is the most happened metastatic event in prostate cancer (PCa) and needs a large effort in treatment. When PCa metastasizes to the bone, the new microenvironment can induce the epigenome reprogramming and stemness remodeling of cancer cells, thereby increasing the adaptability of cancer cells to the bone microenvironment, and this even leads to the occurrence of secondary tumor metastasis. Our group has previously found that RNA binding motif 3 (RBM3) affects the stem cell-like properties of PCa by interfering with alternative splicing of CD44. However, whether RBM3, as a stress-response protein, can resist microenvironmental remodeling of PCa particularly in bone metastasis remains unknown. By co-culturing PCa cells with osteoblasts to mimic PCa bone metastases, we found that RBM3 upregulates the N6-methyladenosine (m6A) methylation on the mRNA of catenin beta 1 (CTNNB1) in a manner dependent on methyltransferase 3 (METTL3), an N6-adenosine-methyltransferase complex catalytic subunit. Consequently, this modification results in a decreased stability of CTNNB1 mRNA and a followed inactivation of Wnt signaling, which ultimately inhibits the stemness remodeling of PCa cells by osteoblasts. Thus, the present study may extend our understanding of the inhibitory role of RBM3 on particularly bone metastasis of PCa.
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Metiltransferasas , Neoplasias de la Próstata , Masculino , Humanos , ARN Mensajero/genética , Metiltransferasas/metabolismo , Neoplasias de la Próstata/patología , Adenosina/metabolismo , Microambiente Tumoral , Proteínas de Unión al ARN/metabolismo , beta Catenina/metabolismoRESUMEN
Alzheimer's is the most common cause of dementia in the elderly. In this disease, genetic and environmental factors are involved. In Alzheimer's, changes of nucleotide 196 (G> A) or valine polymorphism of 66-methionine in the BDNF gene is a risk factor for brain-derived neurogenic factors. In China, this polymorphism has not been studied in Alzheimer's patients and perhaps this study could provide appropriate information on the prognosis and susceptibility of the disease. Therefore, in this case-control study, 73 patients with Alzheimer's disease and 100 patients as a healthy control group were studied. Blood samples were taken from the mentioned individuals and DNA was extracted. After quantitative and qualitative DNA analysis, a PCR-RFLP test was performed and the results of both groups were compared. The results showed that 14 patients and 7 people in the control group had BDNF gene polymorphism. In the patient group, the number of people with normal allele was 59. Heterozygous people were 8 and people with methionine/methionine alleles were 6. In the control group, 93 normal individuals, 5 heterozygous individuals, and 2 people had methionine/methionine alleles. In general, increasing the accumulation of valine/methionine polymorphism of the BDNF gene in Alzheimer's patients compared to control can indicate the role of this polymorphism. Clinically, patients with this polymorphism had a more unfavorable clinical condition compared to patients without it. Therefore, evaluation of the presence of this polymorphism can provide appropriate information about the disease status.
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Enfermedad de Alzheimer , Factor Neurotrófico Derivado del Encéfalo , Anciano , Enfermedad de Alzheimer/genética , Pueblo Asiatico/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Estudios de Casos y Controles , Genotipo , Humanos , Metionina/genética , Polimorfismo Genético , Polimorfismo de Nucleótido Simple/genética , Valina/genéticaRESUMEN
Paclobutrazol Resistance (PRE) genes encode atypical basic helix-loop-helix (bHLH) transcription factor family. Typical bHLH proteins contain a bifunctional structure with a basic region involved in DNA binding and an adjacent helix-loop-helix domain involved in protein-protein interaction. PRE members lack the basic region but retain the HLH domain, which interacts with other typical bHLH proteins to suppress or enhance their DNA-binding activity. PRE proteins are involved in phytohormone responses, light signal transduction, and fruit pigment accumulation. However, apple (Malus domestica) PRE protein functions have not been studied. In this study, nine MdPRE genes were identified from the apple GDDH13 v1.1 reference genome and were mapped to seven chromosomes. The cis-acting element analysis revealed that MdPRE promoters possessed various elements related to hormones, light, and stress responses. Expression pattern analysis showed that MdPRE genes have different tissue expression profiles. Hormonal and abiotic stress treatments can induce the expression of several MdPRE genes. Moreover, we provide molecular and genetic evidence showing that MdPRE4.3 increases the apple's sensitivity to NaCl, abscisic acid (ABA), and indoleacetic acid (IAA) and improves tolerance to brassinosteroids (BR); however, it does not affect the apple's response to gibberellin (GA). Finally, the protein interaction network among the MdPRES proteins was predicted, which could help us elucidate the molecular and biological functions of atypical bHLH transcription factors in the apple.
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Gynostemma pentaphyllum (Thunb.) Makino (G. pentaphyllum) is a natural herbal drug that has been widely used to treat many diseases. The antitumor effects of G. pentaphyllum were first described in the illustrated catalog of plants. Gypenosides are the major active components of G. pentaphyllum, and they have been widely reported to possess antitumor effects in prostate cancer, gastric cancer, hepatocellular carcinoma, colon cancer, lung cancer, and breast cancer. However, research on the use of gypenoside in the treatment of bladder cancer has not been conducted. In this study, we explored the potential molecular mechanisms of gypenosides in the treatment of bladder cancer using network pharmacology and experimental validation. First, we used a network pharmacology-based method to identify both the effective components of gypenosides and the molecular mechanism underlying their antibladder cancer effects. The results were further confirmed by molecular docking, CCK8 and colony formation assays, and cell cycle and cell apoptosis analyses. Additionally, a mouse xenograft model of bladder cancer was used to investigate the antitumor effect of gypenosides in vivo. We identified 10 bioactive ingredients and 163 gene targets of gypenosides. Network exploration suggested that VEGFA, STAT3, and PI3KCA may be candidate agents for the antibladder cancer effect of gypenosides. In addition, analysis of the Kyoto Encyclopedia of Genes and Genomes pathway revealed that the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway may play a crucial role in the mechanism of action of gypenosides against bladder cancer. Molecular docking revealed that gypenosides combine well with PI3K, AKT, and mTOR. As expected, gypenosides displayed apoptosis-inducing properties in bladder cancer cells by inactivating the PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, gypenosides significantly (P < 0.05) inhibited the growth of bladder cancer cells in vivo. Mechanistically, gypenosides induced the apoptosis of bladder cancer cells via inactivation of the PI3K/AKT/mTOR signaling pathway.
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Fosfatidilinositol 3-Quinasa , Neoplasias de la Vejiga Urinaria , Animales , Apoptosis , Proliferación Celular , Gynostemma , Humanos , Masculino , Mamíferos , Ratones , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Extractos Vegetales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Renal cell carcinoma (RCC) has the highest mortality rate of all urological malignancies. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of all RCC cases and is often accompanied by the accumulation of lipid droplets. Growing evidence indicates that ccRCC is a metabolism-related disease. Gypenosides are commonly used for the clinical treatment of hyperlipidemia, and their antitumor activity has also been recognized. However, the potential inhibitory effects and mechanisms of action of gypenoside L (Gyp L) and gypenoside LI (Gyp LI) in ccRCC remain unclear. In this study, we confirmed that Gyp L and Gyp LI significantly inhibited proliferation and induced apoptosis in ccRCC cells in vitro. We performed network pharmacology and RNA-seq, and verified the results by Western blotting, RT-qPCR, and immunofluorescence experiments. Our results demonstrated that Gyp L and Gyp LI upregulate the expression of COX2 and downregulate the expression levels of cPLA2 and CYP1A1, resulting in reduced arachidonic acid and apoptosis. Gyp L and Gyp LI upregulated the protein levels of DUSP1, p-JUN, and p-JNK, and downregulated p-MEK1/2, p-ERK, and p-P38 levels. Moreover, gypenosides significantly inhibited tumor growth in vivo, and gypenosides significantly reduced cPLA2 and CYP1A1 expression. Furthermore, we performed absolute quantification of arachidonic acid (AA) content in ccRCC cells and tumor tissues by HPLC-MS, and found that the arachidonic acid content was significantly reduced after Gyp L, Gyp LI, and gypenoside intervention. In conclusion, our data suggest that Gyp L, Gyp LI, and gypenosides decrease the content of arachidonic acid in ccRCC cells and tumor tissues, but do not have cytotoxic effects on nude mice. Thus, Gyp L, Gyp LI, and total gypenosides extracted from Gynostemma pentaphyllum exhibited antitumor activities against ccRCC.
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Frequency scanning interferometry using state-of-the-art high-speed frequency-swept laser source can be utilized to measure absolute distance on the order of micrometers to centimeters. Current distance demodulation methods based on fast Fourier transform (FFT) or fringe counting cannot achieve satisfactory accuracy when the number of sampling points within a frequency-sweeping period is small; the conventional Hilbert transform is more accurate, but it needs arctangent calculation and phase unwrapping, which is time consuming. So we propose a fast algorithm based on the conventional Hilbert transform to recover the distance from the interference signal. The algorithm is implemented by first performing a Hilbert transform and then solving the phase and the distance from the Hilbert signal with a novel, to the best of our knowledge, method that eliminates the need for arctangent calculation and phase unwrapping. The whole process took only 40 µs, and it is almost 2 times faster than the conventional Hilbert algorithm with little accuracy lost. Simulation results demonstrate that the proposed algorithm is more accurate than the FFT algorithm, and it achieved a standard deviation of 0.062 µm, which was less than that of the FFT, in our experiment at a distance of approximately 16 mm and measurement speed of 1 kHz.
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The Chinese giant salamander (Andrias davidianus), one of the largest extant amphibian species, has dramatically declined in the wild. As an ectotherm, it may be further threatened by climate change. Therefore, understanding the thermal physiology of this species should be the priority to formulate related conservation strategies. In this study, the plasticity in metabolic rate and thermal tolerance limits of A. davidianus larvae were studied. Specifically, the larvae were acclimated to three temperature levels (7 °C, cold stress; 15 °C, optimum; and 25 °C, heat stress) and two diet items (red worm or fish fray) for 20 days. Our results indicated that cold-acclimated larvae showed increased metabolic capacity, while warm-acclimated larvae showed a decrease in metabolic capacity. These results suggested the existence of thermal compensation. Moreover, the thermal tolerance windows of cold-acclimated and warm-acclimated larvae shifted to cooler and hotter ranges, respectively. Metabolic capacity is not affected by diet but fish-fed larvae showed superiority in both cold and heat tolerance, potentially due to the input of greater nutrient loads. Overall, our results suggested a plastic thermal tolerance of A. davidianus in response to temperature and diet variations. These results are meaningful in guiding the conservation of this species.
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Many studies have found that aerobic exercise training at a moderate water velocity can improve the growth, swimming performance and survival rate of fish. To investigate the effects of aerobic exercise training on the growth, swimming performance, antipredation ability and immune parameters of rock carp, juveniles were placed in training channels with different water velocities (i.e., 3 cm s-1, 1 (body length s-1) bl s-1, 2 bl s-1 and 4 bl s-1) for 6 weeks. Then, the specific growth rate, critical swimming speed (Ucrit) and its metabolism, constant acceleration speed (Ucat), survival rate under predation, spleen index, lysozyme (LZM) activity and immunoglobulin (IgM) level were measured. Training showed no significant effect on the length-specific growth rate, weight-specific growth rate, Ucrit, maximum metabolic rate (MMR), metabolic scope (MS), Ucat or spleen index. The resting metabolic rates (RMRs) of the 2 bl s-1 and 4 bl s-1 training groups were significantly higher than those of the control group and 1 bl s-1 training group. The survival rate of the 1 bl s-1 training group in the presence of predators was significantly higher than that of the control group but significantly lower than those of the 2 bl s-1 and 4 bl s-1 training groups. The LZM activity of the 4 bl s-1 training group was significantly higher than that of the control group. The IgM level of the 2 bl s-1 training group was significantly higher than that of the control group. These data indicate that aerobic exercise training does not improve the growth and swimming performance of juvenile rock carp but can improve their antipredation ability and immunologic function.
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Fleshy fruits undergo a complex ripening process, developing organoleptic fruit traits that attract herbivores and maximize seed dispersal. Ripening is the terminal stage of fruit development and involves a series of physiological and biochemical changes. In fleshy fruits, ripening always involves a drastic color change triggered by the accumulation of pigments and degradation of chlorophyll, softening caused by cell wall remodeling, and flavor formation as acids and sugars accumulate alongside volatile compounds. The mechanisms underlying fruit ripening rely on the orchestration of ripening-related transcription factors, plant hormones, and epigenetic modifications. In this review, we discuss current knowledge of the transcription factors that regulate ripening in conjunction with ethylene and environmental signals (light and temperature) in the model plant tomato (Solanum lycopersicum) and other fleshy fruits. We emphasize the critical roles of epigenetic regulation, including DNA methylation and histone modification as well as RNA m6A modification, which has been studied intensively. This detailed review was compiled to provide a comprehensive description of the regulatory mechanisms of fruit ripening and guide new strategies for its effective manipulation.