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Senescent cells are typically characterized by a stable proliferation arrested in dividing cells accompanied with a senescence-associated secretory phenotype (SASP). Skin cellular senescence is the primary cause of skin aging, whereas the lack of identified skin senescence markers limits our understanding of the mechanisms involved in skin aging. Recent studies have revealed that intracellular calcium signaling has emerged as a key player in regulating cellular senescence and aging. However, the implication and roles of calcium signaling in skin keratinocyte senescence remain only partially understood. In this study, we developed a model for skin keratinocyte senescence using ionizing radiation (I/R) stimulation and found that the calcium-associated gene transglutaminase 2 (TGM2) was significantly induced compared with normal control. Interestingly, inhibition of TGM2 was found to delay skin keratinocyte senescence by suppressing I/R-promoted intracellular calcium signaling, accumulation of reactive oxygen species (ROS), DNA damage, as well as NF-κB-mediated SASP secretion. Taken together, our findings demonstrate that inhibition of TGM2 contributes to bypassing I/R-induced skin keratinocyte senescence and sheds light on novel strategies against skin stresses caused by I/R.
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Cellular senescence is broadly known as a stable cell cycle arrest accompanied by a senescence-associated secretory phenotype (SASP). In the past decades, calcium signaling has emerged as a key mediator of cellular senescence. However, the transcriptional regulation of calcium signaling during cellular senescence remains partially understood. We have previously identified the nuclear receptor RXRA as a key senescence repressor through inhibiting the endoplasmic reticulum (ER) calcium release channel inositol 1,4,5-trisphosphate receptor, type 2 (ITPR2) mediated intracellular calcium signaling. Nevertheless, as a transcriptional recruiter, the mechanism by which RXRA inhibits ITPR2 during cellular senescence remains unclear. Here we identified the zinc finger protein ZBTB17 can interact with RXRA. Interestingly, knockdown of ZBTB17 induces a cascade of RXRA-dependent intracellular calcium signaling, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) accumulation, DNA damages, and ultimately cellular senescence. Moreover, the signaling and senescence phenotype induced by knocking down of ZBTB17 can also be abolished after silencing ITPR2. Altogether, our work provides a new mechanism controlling intracellular calcium signaling and cellular senescence and unveils novel insight toward the role of zinc finger proteins.
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Señalización del Calcio , Receptores Citoplasmáticos y Nucleares , Senescencia Celular , Canales de Calcio , Dedos de ZincRESUMEN
The EP300-ZNF384 fusion gene is an oncogenic driver in B-cell acute lymphoblastic leukemia (B-ALL). In the present study, we demonstrated that EP300-ZNF384 substantially induces the transcription of IL3RA and the expression of IL3Rα (CD123) on B-ALL cell membranes. Interleukin 3 (IL-3) supplementation promotes the proliferation of EP300-ZNF348-positive B-ALL cells by activating STAT5. Conditional knockdown of IL3RA in EP300-ZF384-positive cells inhibited the proliferation in vitro, and induced a significant increase in overall survival of mice, which is attributed to impaired propagation ability of leukemia cells. Mechanistically, the EP300-ZNF384 fusion protein transactivates the promoter activity of IL3RA by binding to an A-rich sequence localized at -222/-234 of IL3RA. Furthermore, forced EP300-ZNF384 expression induces the expression of IL3Rα on cell membranes and the secretion of IL-3 in CD19-positive B precursor cells derived from healthy individuals. Doxorubicin displayed a selective killing of EP300-ZNF384-positive B-ALL cells in vitro and in vivo. Collectively, we identify IL3RA as a direct downstream target of EP300-ZNF384, suggesting CD123 is a potent biomarker for EP300-ZNF384-driven B-ALL. Targeting CD123 may be a novel therapeutic approach to EP300-ZNF384-positive patients, alternative or, more likely, complementary to standard chemotherapy regimen in clinical setting.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Transactivadores , Animales , Humanos , Ratones , Doxorrubicina , Proteína p300 Asociada a E1A , Interleucina-3 , Subunidad alfa del Receptor de Interleucina-3 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transactivadores/metabolismoRESUMEN
Integration of hydrogen evolution with the oxidation of organic substances in one electrochemical system is highly desirable. However, achieving selective oxidation of organic substances in the integrated system is still highly challenging. In this study, a phosphorylated NiMoO4 nanoneedle-like array was designed as the catalytic active electrode for the integration of highly selective electrochemical dehydrogenation of tetrahydroisoquinolines (THIQs) with hydrogen production. The leaching of anions, including MoO42- and PO43-, facilitates the reconstruction of the catalyst. As a result, nickel oxyhydroxides with the doping of PO43- and richness of defects are in situ formed. In situ Raman and density functional theory calculations have shown that the high catalytic activity is attributed to the in situ formed PO43- involved NiOOH substance. In the dehydrogenation process, the involved C-H bond but not the N-H bond is first destroyed. A two-electrode system was then fabricated with the optimized electrode that shows a benchmark current density of 10 mA cm-2 at 1.783 V, providing a yield of 70% for dihydroisoquinolines. A robust stability was also shown for this integrated electrochemical system. The understanding of the reconstruction behavior and the achievement of selective dehydrogenation will provide some hints for electrochemical synthesis.
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The Yang cycle is involved in many essential metabolic pathways in plant growth and development. As extended products of the Yang cycle, the function and regulation network of ethylene and polyamines are well characterized. Nicotianamine (NA) is also a product of this cycle and works as a key metal chelator for iron (Fe) homeostasis in plants. However, interactions between the Yang cycle and NA biosynthesis remain unclear. Here, we cloned maize interveinal chlorosis 1 (mic1), encoding a 5'-methylthioadenosine nucleosidase (MTN), that is essential for 5'-methylthioadenosine (MTA) salvage and NA biosynthesis in maize (Zea mays). A single base G-A transition in the fourth exon of mic1 causes a Gly to Asp change, resulting in increased MTA, reduced Fe distribution, and growth retardation of seedlings. Knockout of ZmMIC1 but not its paralog ZmMTN2 by CRISPR/Cas9 causes interveinal chlorosis, indicating ZmMIC1 is mainly responsible for MTN activity in maize. Transcriptome analysis showed a typical response of Fe deficiency. However, metabolic analysis revealed dramatically reduced NA content in mic1, suggesting NA biosynthesis was impaired in the mutant. Exogenous application of NA transiently reversed the interveinal chlorosis phenotype of mic1 seedlings. Moreover, the mic1 mutant overexpressing a NA synthase gene not only recovered from interveinal chlorosis and growth retardation but was also fertile. These findings provide a link between the Yang cycle and NA biosynthesis, which highlights an aspect of Fe homeostasis regulation in maize.
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Anemia Hipocrómica , Zea mays , Ácido Azetidinocarboxílico/análogos & derivados , Ácido Azetidinocarboxílico/metabolismo , Regulación de la Expresión Génica de las Plantas , Homeostasis , Zea mays/genética , Zea mays/metabolismoRESUMEN
Three new compounds (1-2, 14), as well as 22 known compounds (3-13, 15-25), were extracted for the first time from the Selaginella effusa Alston (S. effusa). For the unknown compounds, the planar configurations were determined via NMR and by high-resolution mass spectrometry, while their absolute configurations were determined by calculated electronic circular dichroism (ECD), and the configuration of the stereogenic center of biflavones 4-5 were established for the first time. The pure compounds (1-25) were tested inâ vitro to determine the inhibitory activity of the enzyme-catalyzed reactions. Compounds 1-9 inhibited α-glucosidase with IC50 values ranging from 0.30±0.02 to 4.65±0.04â µM and kinetic analysis of enzyme inhibition indicated that biflavones 1-3 were mixed-type α-glucosidase inhibitors. Compounds 12-13 showed excellent inhibitory activity against urease, with compound 12 (IC50 =4.38±0.31â µM) showing better inhibitory activity than the positive control drug AHA (IC50 13.52±0.61â µM). In addition, molecular docking techniques were used to simulate inhibitor-enzyme binding and to estimate the binding posture of the α-glucosidase and urease catalytic sites.
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Selaginellaceae , alfa-Glucosidasas , Simulación del Acoplamiento Molecular , alfa-Glucosidasas/metabolismo , Selaginellaceae/metabolismo , Ureasa/metabolismo , Cinética , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Estructura MolecularRESUMEN
Plant flavonoids are secondary metabolites containing a benzo-γ-pyrone structure, which are widely present in plants and have a variety of physiological and pharmacological activities. However, current flavonoid production from plant extraction or chemical synthesis does not meet the requirements of green and sustainable development. Fortunately, microbial synthesis of flavonoids has shown the potential for large-scale production with the advantages of being controllable and environmentally friendly, and a variety of microorganisms have been developed as microbial cell factories (MCFs) to synthesize plant flavonoids owing to the feasibility of genetic manipulations. However, most of MCFs have not yet been commercialized and industrialized because of the challenges posed by unbalanced metabolic flux among various pathways and conflict between cell growth and production. Here, strategies for coping with the challenges are summarized in terms of enzymes, pathways, metabolic networks, host cells. And combined with protein structure prediction, de novo protein design, artificial intelligence (AI), biocatalytic retrosynthesis, and intelligent stress resistance, it provides new insights for the high efficient production of plant flavonoids and other plant natural products in MCFs.
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Flavonoides , Ingeniería Metabólica , Inteligencia Artificial , Redes y Vías Metabólicas , Plantas/genética , Plantas/metabolismoRESUMEN
Objectives: Endoplasmic reticulum (ER) stress and soluble epoxide hydrolase (sEH) upregulation/activation have been implicated in myocardial ischemia/reperfusion (I/R) injury. We previously reported that ER stress mediates angiotensin II-induced sEH upregulation in coronary endothelium, whether and how ER stress regulates sEH expression to affect postischemic cardiac function remain unexplored. This study aimed to unravel the signaling linkage between ER stress and sEH in an ex vivo model of myocardial I/R injury. Methods: Hearts from male Wistar-Kyoto rats were mounted on a Langendorff apparatus and randomly allocated to 7 groups, including control, I/R (30-min ischemia and 60-min reperfusion), and I/R groups pretreated with one of the following inhibitors: 4-PBA (targeting: ER stress), GSK2850163 (IRE1α), SP600125 (JNK), SR11302 (AP-1), and DCU (sEH). The inhibitor was administered for 15 min before ischemia with a peristaltic pump. Hemodynamic parameters including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximal velocity of contraction (+dp/dtmax) and relaxation (-dp/dtmax) of the left ventricle were continuously recorded using an intraventricular balloon. Endothelial dilator function of the left anterior descending artery was studied in a wire myograph upon completion of reperfusion. The expression of ER stress molecules, JNK, c-Jun, and sEH was determined by western-blot. Results: I/R decreased LVSP (105.5±6.4 vs. 146.9±13.4 mmHg), and increased LVEDP (71.4±3.0 vs. 6.0±2.7 mmHg), with a resultant decreased LVDP (34.1±9.2 vs. 140.9±13.1 mmHg). I/R attenuated +dp/dtmax (651.7±142.1 vs. 2806.6±480.6 mmHg/s) and -dp/dtmax (-580.0±109.6 vs. -2118.0±244.9 mmHg/s) (all ps<0.001). The I/R-induced cardiac dysfunction could be alleviated by 4-PBA (LVSP 119.5±15.6 mmHg, p<0.01; LVEDP 21.2±4.2 mmHg, LVDP 98.3±12.0 mmHg, +dp/dtmax 2166.7±208.4 mmHg/s, and -dp/dtmax -1350.9±99.8 mmHg/s, all ps<0.001), GSK2850163 (LVSP 113.4±10.9 mmHg, p<0.01; LVEDP 37.1±3.1 mmHg, LVDP 76.3±13.9 mmHg, +dp/dtmax 1586.5±263.3 mmHg/s, -dp/dtmax -1127.7±159.9 mmHg/s, all ps<0.001), SP600125 (LVSP 113.9±5.6 mmHg, LVDP 40.5±3.3 mmHg, +dp/dtmax 970.1±89.8 mmHg/s, all ps<0.01), SR11302 (LVSP 97.9±7.5 mmHg, p<0.01; LVEDP 52.7±8.6mmHg, p<0.001; LVDP 45.2±9.8mmHg, p<0.05; +dp/dtmax 1231.5±196.6 mmHg/s, p<0.01; -dp/dtmax -658.3±68.9 mmHg/s, p<0.05), or DCU (LVSP 109.9±4.1 mmHg, p<0.01; LVEDP 11.7±1.8 mmHg, LVDP 98.2±4.9 mmHg, +dp/dtmax 1869.8±121.9 mmHg/s, and -dp/dtmax -1492.3±30.8 mmHg/s, all ps<0.001). The relaxant response of the coronary artery to acetylcholine was decreased after I/R in terms of both magnitude and sensitivity (p<0.001). All inhibitors improved acetylcholine-induced relaxation. Global I/R increased sEH expression and induced ER stress in both myocardium and coronary artery. Inhibition of ER stress or IRE1α downregulated I/R-induced sEH expression and inhibited JNK and c-Jun phosphorylation. Both JNK and AP-1 inhibitors lowered sEH level in myocardium and coronary artery in I/R-injured hearts. Conclusions: This study deciphered the molecular linkage between ER stress and sEH regulation in global I/R insult by uncovering a novel signaling axis of IRE1α-JNK-c-Jun/AP-1-sEH, which provided basis for future research on the therapeutic potential of targeting the IRE1α-JNK-c-Jun/AP-1-sEH axis for ischemic myocardial injury.
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Enfermedad de la Arteria Coronaria , Isquemia Miocárdica , Daño por Reperfusión Miocárdica , Acetilcolina , Animales , Endorribonucleasas , Endotelio , Isquemia , Masculino , Miocardio , Proteínas Serina-Treonina Quinasas , Ratas , Ratas Endogámicas WKY , Reperfusión , Transducción de Señal , Factor de Transcripción AP-1RESUMEN
Although the association of elevated homocysteine level with cardiac hypertrophy has been reported, the molecular mechanisms by which homocysteine induces cardiac hypertrophy remain inadequately understood. In this study we aim to uncover the roles of cyclic nucleotide phosphodiesterase 1 (PDE1) and endoplasmic reticulum (ER) stress and their relationship to advance the mechanistic understanding of homocysteine-induced cardiac cell hypertrophy. H9c2 cells and primary neonatal rat cardiomyocytes are exposed to homocysteine with or without ER stress inhibitor TUDCA or PDE1-specific inhibitor Lu AF58027, or transfected with siRNAs targeting PDE1 isoforms prior to homocysteine-exposure. Cell surface area is measured and ultrastructure is examined by transmission electron microscopy. Hypertrophic markers, PDE1 isoforms, and ER stress molecules are detected by q-PCR and western blot analysis. Intracellular cGMP and cAMP are measured by ELISA. The results show that homocysteine causes the enlargement of H9c2 cells, increases the expressions of hypertrophic markers ß-MHC and ANP, upregulates PDE1A and PDE1C, promotes the expressions of ER stress molecules, and causes ER dilatation and degranulation. TUDCA and Lu AF58027 downregulate ß-MHC and ANP, and alleviate cell enlargement. TUDCA decreases PDE1A and PDE1C levels. Silencing of PDE1C inhibits homocysteine-induced hypertrophy, whereas PDE1A knockdown has minor effect. Both cAMP and cGMP are decreased after homocysteine-exposure, while only cAMP is restored by Lu AF58027 and TUDCA. TUDCA and Lu AF58027 also inhibit cell enlargement, downregulate ANP, ß-MHC and PDE1C, and enhance cAMP level in homocysteine-exposed primary cardiomyocytes. ER stress mediates homocysteine-induced hypertrophy of cardiac cells via upregulating PDE1C expression Cyclic nucleotide, especially cAMP, is the downstream mediator of the ER stress-PDE1C signaling axis in homocysteine-induced cell hypertrophy.
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1 , Estrés del Retículo Endoplásmico , Homocisteína , Animales , Factor Natriurético Atrial/genética , Factor Natriurético Atrial/metabolismo , Cardiomegalia/metabolismo , GMP Cíclico/metabolismo , GMP Cíclico/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 1/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Homocisteína/farmacología , Miocitos Cardíacos/metabolismo , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Ratas , Ácido Tauroquenodesoxicólico/farmacologíaRESUMEN
In pancreatic cancer, KRAS G12D can trigger pancreatic cancer initiation and development. Rapid tumor growth is often accompanied by excess intracellular reactive oxygen species (ROS) production, which is unfavorable to tumor. However, the regulation of intracellular ROS levels in KRAS mutant pancreatic cancer remains unclear. In this study, we establish BxPC3 stable cell strains expressing KRAS wild type (WT) and G12D mutation and find unchanged ROS levels despite higher glycolysis and proliferation viability in KRAS mutant cells than KRAS WT cells. The key hydrogen sulfide (H 2S)-generating enzyme cystathionine-γ-lyase (CSE) is upregulated in KRAS mutant BxPC3 cells, and its knockdown significantly increases intracellular ROS levels and decreases cell glycolysis and proliferation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is activated by KRAS mutation to promote CSE transcription. An Nrf2 binding site (â47/â39 bp) in the CSE promoter is verified. CSE overexpression and the addition of NaHS after Nrf2 knockdown or inhibition by brusatol decreases ROS levels and rescues cell proliferation. Our study reveals the regulatory mechanism of intracellular ROS levels in KRAS mutant pancreatic cancer cells, which provides a potential target for pancreatic cancer therapy.
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Factor 2 Relacionado con NF-E2 , Neoplasias Pancreáticas , Humanos , Mutación , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Cistationina gamma-Liasa , Neoplasias PancreáticasRESUMEN
BACKGROUND: In this study, we aimed at elucidating the postoperative survival and prognostic factors in patients with biliary neuroendocrine neoplasm (NEN). METHODS: Cases of biliary system NEN and adenocarcinoma from 1975 to 2016 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. A propensity score matching (PSM) method was used to adjust baseline differences in clinicopathological characteristics in our analysis. The Kaplan-Meier analysis was carried out for survival analysis. RESULTS: A total of 233 patients with biliary system NEN were enrolled in this study, of which 119 patients' lesions located in gallbladder, while the others' located in bile duct. The postoperative overall survival of bile duct NEN is significantly longer than that of gallbladder NEN (P < 0.001). For gallbladder NENs, surgery method (P = 0.020) and lymph node metastasis (P = 0.018) were identified as independent prognostic factors. In terms of ampulla of vater (AOV) NENs, age (P = 0.017) and lymph node metastasis (P = 0.006) were identified as independent prognostic factors, while grade (P = 0.002) and lymph node metastasis (P = 0.036) were identified as independent prognostic factors for extrahepatic bile duct (EBD) NENs. PSM analysis indicated that patients with biliary duct NENs have a better postoperative prognosis than biliary duct adenocarcinoma. CONCLUSIONS: Patients with NEN have better overall survival than patients with adenocarcinoma. Gallbladder NEN has an adverse prognosis than that of biliary tract NEN. The pathological subtype, differentiation, lymph node metastasis, surgery method, and lymph node resection could affect the postoperative prognosis of the gallbladder and biliary tract NEN.
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Adenocarcinoma , Neoplasias de los Conductos Biliares , Conductos Biliares Extrahepáticos , Neoplasias de la Vesícula Biliar , Neoplasias Gastrointestinales , Tumores Neuroendocrinos , Adenocarcinoma/patología , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares Extrahepáticos/patología , Conductos Biliares Intrahepáticos/patología , Neoplasias de la Vesícula Biliar/diagnóstico , Neoplasias de la Vesícula Biliar/patología , Neoplasias de la Vesícula Biliar/cirugía , Neoplasias Gastrointestinales/patología , Humanos , Metástasis Linfática , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/cirugía , Pronóstico , Estudios RetrospectivosRESUMEN
Chronic inflammation is commonly accompanied by the stimulation of matrix metalloproteinases (MMPs) production and the degradation of the extracellular matrix. The overexpression of MMP-9 (Gelatinase B) highly participates in the progression of pathetic cardiac remodeling and liver cancer metastasis. Panax notoginseng (Burkill) F. H. Chen (Sanqi), a widely used traditional Chinese medicinal herb, shows myocardial protective and anti-tumor effects. In this study, we examined the inhibitory effect of different PNG extracts on tumor necrosis factor (TNF)-α-induced MMP-9 expression in cardiac myoblast H9c2 cells. Using a bioassay-guided fractionation scheme, the most active extract was fractionated by silica gel column chromatography and high-performance liquid chromatography until an active compound was obtained. The compound was identified as Ginsenoside Rb1 by nuclear magnetic resonance. Ginsenoside Rb1 inhibited TNF-α-induced MMP-9 production in both H9c2 and liver carcinoma HepG-2 cells. Interestingly, it did not affect the MMP-2 (Gelatinase A) level and the cell proliferation of the two cell lines. The inhibitory effects of Ginsenoside Rb1 may be due to its modulation of double-strand RNA-dependent protein kinase and nuclear factor kappa B signaling pathways. The results reveal the potential use of Ginsenoside Rb1 for the treatment of inflammatory and MMP-9-related cardiac remodeling and metastasis of hepatocellular carcinomas.
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Panax notoginseng , Panax notoginseng/química , FN-kappa B/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , eIF-2 Quinasa , Remodelación VentricularRESUMEN
OBJECTIVES: To investigate the effect and clinical value of the application of vacuum assisted closure (VAC) combined with multiple flaps in the treatment of severe hand trauma. METHODS: A total of 100 patients with severe hand trauma admitted to Harrison International Peace Hospital from September 2015 to September 2020 were selected and randomly divided into two groups according to the randomized block method: the single flap repair group and the combined repair group, with 50 patients in each group. Patients in the single flap repair group underwent flap repair according to their condition, while those in the combined repair group were treated with VAC prior to flap repair. The range of motion and hand sensation scores were compared between the two groups, and their levels of interleukin-8 (IL-8), tumor necrosis factor (TNF) and lipopolysaccharide (LPS) were tested by enzyme-linked immunosorbent assay (ELIS). Moreover, the flap survival rate and the incidence of adverse events were recorded and compared between the two groups. RESULTS: Compared with the single flap repair group, the combined repair group had higher range of motion and hand sensation score (p<0.05), lower levels of IL-8, TNF and LPS (p<0.05), higher flap survival rate (p<0.05), and lower incidence of adverse events (p<0.05). CONCLUSION: VAC combined with multiple flaps boasts significant trauma repair effect and preferable clinical application value in the treatment of patients with severe hand trauma, which is principally reflected in significantly improving the hand function of patients and remarkably alleviating the inflammatory response of patients.
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BACKGROUND AND OBJECTIVES: In this retrospective study, we examined the CA17 tissue expression and analyzed its clinical significance in cholangiocarcinoma (CCA). MATERIALS AND METHODS: Immunohistochemistry was performed to assess CA17 expression on tissue microarrays in a training cohort enrolling 120 CCA patients and a validation cohort comprising 60 CCA patients. Image pro plus was applied to score the staining intensity and expression level of CA17 marker. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of CA17. RESULTS: CA17 cancer biomarker over-expression was significantly observed in CCA compared to their non-tumor counterparts, and positively correlated with aggressive tumor phenotypes, like lymph node metastasis. Meanwhile, patients with high expression of CA17 correlated with worse postoperative overall survival (OS) and recurrence-free survival. Besides, multivariate analysis identified that CA17 expression was an independent prognostic factor for cholangiocarcinoma patients, which indicated that the CA17 could be more efficient than serum CA19-9 in predicting the OS of CCA patients. Notably, the nomogram integrating CA17 expression had better prognostic performance as compared with current TNM staging systems. CONCLUSION: CA17 was an independent adverse prognostic factor for CCA patients' survival, which may serve as a promising prognostic biomarker for CCA patients.
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Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Colangiocarcinoma/patología , Recurrencia Local de Neoplasia/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/cirugía , Colangiocarcinoma/metabolismo , Colangiocarcinoma/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The MUC16 C-terminal (MUC16c) level is associated with tumor serum CA-125 levels, however, the roles remain unclear in gallbladder carcinoma (GBC). In this study, we found that MUC16c promoted glucose uptake and glycolysis for GBC cell proliferation. Mass spectrometry analysis suggested that MUC16c could combine with aldolase. The ALDOC mRNA and protein are overexpressed in GBC tumors. The IHC results also showed the consistent up-regulation of. ALDOC and MUC16c level in GBC tumor tissues than in peritumor tissues. We determined that MUC16c combining with ALDOC promoted ALDOC protein stability and disrupted the ability of ALDOC sensing glucose deficiency, which activated AMPK pathway and increased GBC cell proliferation. ALDOC knockdown significantly inhibited the glucose uptake and glycolysis induced by MUC16c. Our study established important roles of MUC16c promoting GBC cell glycolysis and proliferation and revealed the underlying mechanism of CA-125-related heavy tumor metabolic burden in GBC.
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Antígeno Ca-125/metabolismo , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Fructosa-Bifosfato Aldolasa/metabolismo , Neoplasias de la Vesícula Biliar/metabolismo , Proteínas de la Membrana/metabolismo , Antígeno Ca-125/genética , Fructosa-Bifosfato Aldolasa/genética , Neoplasias de la Vesícula Biliar/genética , Regulación Neoplásica de la Expresión Génica/genética , Glucólisis/genética , Humanos , Proteínas de la Membrana/genéticaRESUMEN
The application of nitrogen fertilizers in the rice-crab co-culture system may expose juvenile Eriocheir sinensis to high ammonia concentrations within a short period of time, potentially causing death. Currently, the molecular mechanism underlying ammonia toxicity in juvenile Eriocheir sinensis remains poorly understood. This study compared the effects of 24 h exposure to different total ammonia-N concentrations (0, 10.47, and 41.87 mg/L) on antioxidant enzyme activities and tandem mass tag (TMT)-based proteomics in the hepatopancreas of juvenile Eriocheir sinensis. During the experiment, water temperature and pH were maintained at 20.4 ± 1.4 °C and 7.69 ± 0.46, respectively. Proteomic data demonstrated that Eriocheir sinensis used different metabolic regulatory mechanisms to adapt to varying ammonia conditions. The tricarboxylic acid (TCA) cycle, glycogen degradation, and oxidative phosphorylation showed marginally upregulated trends under low ammonia exposure. High ammonia stress caused downregulation of the TCA cycle and provided energy by enhancing oxidative phosphorylation, fatty acid beta oxidation, gluconeogenesis, and glycogen degradation. The detoxification of ammonia into urea and glutamine was suppressed under high ammonia stress. Finally, ammonia exposure induced oxidative stress and caused protein damage. Antioxidant enzyme activity analysis further revealed that exposure to high concentrations of ammonia may induce more severe oxidative stress. This study provides a global perspective on the mechanisms underlying ammonia exposure-induced metabolic changes and stress damage in juvenile Eriocheir sinensis.
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Braquiuros , Amoníaco/toxicidad , Animales , Antioxidantes , Hepatopáncreas , ProteómicaRESUMEN
Plastic pollution is a global concern given its prevalence in aquatic and terrestrial ecosystems. Studies have been conducted on the distribution and impact of plastic pollution in marine ecosystems, but little is known on terrestrial ecosystems. Plastic mulch has been widely used to increase crop yields worldwide, yet the impact of plastic residues in cropland soils to soil health and crop production in the long term remained unclear. In this paper, using a global meta-analysis, we found that the use of plastic mulch can indeed increase crop yields on average by 25%-42% in the immediate season due to the increase of soil temperature (+8%) and moisture (+17%). However, the unabated accumulation of film residues in the field negatively impacts its physicochemical properties linked to healthy soil and threatens food production in the long term. It has multiple negative impacts on plant growth including crop yield (at the mean rate of -3% for every additional 100 kg/ha of film residue), plant height (-2%) and root weight (-5%), and soil properties including soil water evaporation capacity (-2%), soil water infiltration rate (-8%), soil organic matter (-0.8%) and soil available phosphorus (-5%) based on meta-regression. Using a nationwide field survey of China, the largest user of plastic mulch worldwide, we found that plastic residue accumulation in cropland soils has reached 550,800 tonnes, with an estimated 6%-10% reduction in cotton yield in some polluted sites based on current level of plastic residue content. Immediate actions should be taken to ensure the recovery of plastic film mulch and limit further increase in film residue loading to maintain the sustainability of these croplands.
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Agricultura , Plásticos , China , Productos Agrícolas , Ecosistema , Abastecimiento de Alimentos , SueloRESUMEN
The naturally persistent flow of hundreds of dust particles is experimentally achieved in a dusty plasma system with the asymmetric sawteeth of gears on the electrode. It is also demonstrated that the direction of the dust particle flow can be controlled by changing the plasma conditions of the gas pressure or the plasma power. Numerical simulations of dust particles with the ion drag inside the asymmetric sawteeth verify the experimental observations of the flow rectification of dust particles. Both experiments and simulations suggest that the asymmetric potential and the collective effect are the two keys in this dusty plasma ratchet. With the nonequilibrium ion drag, the dust flow along the asymmetric orientation of this electric potential of the ratchet can be reversed by changing the balance height of dust particles using different plasma conditions.
RESUMEN
Pentacyclic triterpenoids have wide applications in the pharmaceutical industry. The precise glucosylation at C-3 OH of pentacyclic triterpenoids mediated by uridine 5'-diphospho-glucosyltransferase (UDP-glucosyltransferase [UGT]) is an important way to produce valuable derivatives with various improved functions. However, most reported UGTs suffer from low regiospecificity toward the OH and COOH groups of pentacyclic triterpenoids, which significantly decreases the reaction efficiency. Here, two new UGTs (UGT73C33 and UGT73F24) were discovered in Glycyrrhiza uralensis. UGT73C33 showed high activity but poor regioselectivity toward the C-3 OH and C-30 COOH of pentacyclic triterpenoid, producing three glucosides. UGT73F24 showed rigid regioselectivity toward C-3 OH of typical pentacyclic triterpenoids producing only C-3 O-glucosylated derivatives. In addition, UGT73C33 and UGT73F24 showed a broad substrate scope toward typical flavonoids with various sugar donors. Next, the substrate recognition mechanism of UGT73F24 toward glycyrrhetinic acid (GA) and UDP-glucose was investigated. Two key residues, I23 and L84, were identified to determine activity, and site-directed mutagenesis of UGT73F24-I23G/L84N increased the activity by 4.1-fold. Furthermore, three in vitro GA glycosylation systems with UDP-recycling were constructed, and high yields of GA-3-O-Glc (1.25 mM), GA-30-O-Glc (0.61 mM), and GA-di-Glc (0.26 mM) were obtained. The de novo biosynthesis of GA-3-O-glucose (26.31 mg/L) was also obtained in engineered yeast.
Asunto(s)
Glicosiltransferasas , Glycyrrhiza uralensis , Proteínas de Plantas , Triterpenos/metabolismo , Glicosilación , Glicosiltransferasas/química , Glicosiltransferasas/genética , Glicosiltransferasas/metabolismo , Glycyrrhiza uralensis/enzimología , Glycyrrhiza uralensis/genética , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
In China, the government and the cigarette industry yearly lose millions in sales and tax revenue because of imitation cigarettes. Usually, visual observation is not enough to identify counterfeiting. An auxiliary analytical method is needed for cigarette brands identification. To this end, we developed a portable, low-cost electronic nose (e-nose) system for brand recognition of cigarettes. A gas sampling device was designed to reduce the influence caused by humidity fluctuation and the volatile organic compounds (VOCs) in the environment. To ensure the uniformity of airflow distribution, the structure of the sensing chamber was optimized by computational fluid dynamics (CFD) simulations. The e-nose system is compact, portable, and lightweight with only 15 cm in side length and the cost of the whole device is less than $100. Results from the machine learning algorithm showed that there were significant differences between 5 kinds of cigarettes we tested. Random Forest (RF) has the best performance with accuracy of 91.67% and K Nearest Neighbor (KNN) has the accuracy of 86.98%, which indicated that the e-nose was able to discriminate samples. We believe this portable, cheap, reliable e-nose system could be used as an auxiliary screen technique for counterfeit cigarettes.