Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.312
Filtrar
Más filtros

Tipo del documento
Intervalo de año de publicación
1.
Nature ; 611(7935): 289-294, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36352136

RESUMEN

The discovery of a method to separate isotopologues, molecular entities that differ in only isotopic composition1, is fundamentally and technologically essential but remains challenging2,3. Water isotopologues, which are very important in biological processes, industry, medical care, etc. are among the most difficult isotopologue pairs to separate because of their very similar physicochemical properties and chemical exchange equilibrium. Herein, we report efficient separation of water isotopologues at room temperature by constructing two porous coordination polymers (PCPs, or metal-organic frameworks) in which flip-flop molecular motions within the frameworks provide diffusion-regulatory functionality. Guest traffic is regulated by the local motions of dynamic gates on contracted pore apertures, thereby amplifying the slight differences in the diffusion rates of water isotopologues. Significant temperature-responsive adsorption occurs on both PCPs: H2O vapour is preferentially adsorbed into the PCPs, with substantially increased uptake compared to that of D2O vapour, facilitating kinetics-based vapour separation of H2O/HDO/D2O ternary mixtures with high H2O separation factors of around 210 at room temperature.

2.
J Biol Chem ; 300(4): 107123, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38417796

RESUMEN

Thiram is a toxic fungicide extensively used for the management of pathogens in fruits. Although it is known that thiram degrades in plant tissues, the key enzymes involved in this process remain unexplored. In this study, we report that a tau class glutathione S-transferase (GST) from Carica papaya can degrade thiram. This enzyme was easily obtained by heterologous expression in Escherichia coli, showed low promiscuity toward other thiuram disulfides, and catalyzed thiram degradation under physiological reaction conditions. Site-directed mutagenesis indicated that G-site residue S67 shows a key influence for the enzymatic activity toward thiram, while mutation of residue S13, which reduced the GSH oxidase activity, did not significantly affect the thiram-degrading activity. The formation of dimethyl dithiocarbamate, which was subsequently converted into carbon disulfide, and dimethyl dithiocarbamoylsulfenic acid as the thiram degradation products suggested that thiram undergoes an alkaline hydrolysis that involves the rupture of the disulfide bond. Application of the GST selective inhibitor 4-chloro-7-nitro-2,1,3-benzoxadiazole reduced papaya peel thiram-degrading activity by 95%, indicating that this is the main degradation route of thiram in papaya. GST from Carica papaya also catalyzed the degradation of the fungicides chlorothalonil and thiabendazole, with residue S67 showing again a key influence for the enzymatic activity. These results fill an important knowledge gap in understanding the catalytic promiscuity of plant GSTs and reveal new insights into the fate and degradation products of thiram in fruits.


Asunto(s)
Carica , Glutatión Transferasa , Tiram , Carica/enzimología , Carica/genética , Fungicidas Industriales/metabolismo , Glutatión Transferasa/metabolismo , Glutatión Transferasa/genética , Glutatión Transferasa/química , Mutagénesis Sitio-Dirigida , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Tiram/metabolismo , Escherichia coli/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
3.
Plant J ; 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39139125

RESUMEN

Soil salinity significantly limits rice productivity, but it is poorly understood how excess sodium (Na+) is delivered to the grains at the reproductive stage. Here, we functionally characterized OsHAK4, a member of the clade IV HAK/KUP/KT transporter subfamily in rice. OsHAK4 was localized to the plasma membrane and exhibited influx transport activity for Na+, but not for K+. Analysis of organ- and growth stage-dependent expression patterns showed that very low expression levels of OsHAK4 were detected at the vegetative growth stage, but its high expression in uppermost node I, peduncle, and rachis was found at the reproductive stage. Immunostaining indicated OsHAK4 localization in the phloem region of node I, peduncle, and rachis. Knockout of OsHAK4 did not affect the growth and Na+ accumulation at the vegetative stage. However, at the reproductive stage, the hak4 mutants accumulated higher Na+ in the peduncle, rachis, husk, and brown rice compared to the wild-type rice. Element imaging revealed higher Na+ accumulation at the phloem region of the peduncle in the mutants. These results indicate that OsHAK4 plays a crucial role in retrieving Na+ from the phloem in the upper nodes, peduncle, and rachis, thereby preventing Na+ distribution to the grains at the reproductive stage of rice.

4.
Brief Bioinform ; 24(1)2023 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-36592058

RESUMEN

The progress of single-cell RNA sequencing (scRNA-seq) has led to a large number of scRNA-seq data, which are widely used in biomedical research. The noise in the raw data and tens of thousands of genes pose a challenge to capture the real structure and effective information of scRNA-seq data. Most of the existing single-cell analysis methods assume that the low-dimensional embedding of the raw data belongs to a Gaussian distribution or a low-dimensional nonlinear space without any prior information, which limits the flexibility and controllability of the model to a great extent. In addition, many existing methods need high computational cost, which makes them difficult to be used to deal with large-scale datasets. Here, we design and develop a depth generation model named Gaussian mixture adversarial autoencoders (scGMAAE), assuming that the low-dimensional embedding of different types of cells follows different Gaussian distributions, integrating Bayesian variational inference and adversarial training, as to give the interpretable latent representation of complex data and discover the statistical distribution of different types of cells. The scGMAAE is provided with good controllability, interpretability and scalability. Therefore, it can process large-scale datasets in a short time and give competitive results. scGMAAE outperforms existing methods in several ways, including dimensionality reduction visualization, cell clustering, differential expression analysis and batch effect removal. Importantly, compared with most deep learning methods, scGMAAE requires less iterations to generate the best results.


Asunto(s)
Perfilación de la Expresión Génica , Análisis de Expresión Génica de una Sola Célula , Perfilación de la Expresión Génica/métodos , Análisis de Secuencia de ARN/métodos , Distribución Normal , Teorema de Bayes , Análisis de la Célula Individual/métodos , Análisis por Conglomerados
5.
FASEB J ; 38(5): e23553, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38470398

RESUMEN

Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder in reproductive-aged women that frequently leads to infertility due to poor oocyte quality. In this study, we identified a new active peptide (advanced glycation end products receptors RAGE344-355 ) from PCOS follicular fluid using mass spectrometry. We found that supplementing PCOS-like mouse oocytes with RAGE344-355 attenuated both meiotic defects and oxidative stress levels, ultimately preventing developmental defects. Additionally, our results suggest that RAGE344-355 may interact with eEF1a1 to mitigate oxidative meiotic defects in PCOS-like mouse oocytes. These findings highlight the potential for further clinical development of RAGE344-355 as a potent supplement and therapeutic option for women with PCOS. This research addresses an important clinical problem and offers promising opportunities for improving oocyte quality in PCOS patients.


Asunto(s)
Síndrome del Ovario Poliquístico , Humanos , Femenino , Animales , Ratones , Adulto , Oocitos , Suplementos Dietéticos , Estrés Oxidativo , Péptidos
6.
Circ Res ; 133(11): 885-898, 2023 11 10.
Artículo en Inglés | MEDLINE | ID: mdl-37929582

RESUMEN

BACKGROUND: Pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) is a common and highly morbid syndrome, but mechanisms driving PH-HFpEF are poorly understood. We sought to determine whether a well-accepted murine model of HFpEF also displays features of PH, and we sought to identify pathways that might drive early remodeling of the pulmonary vasculature in HFpEF. METHODS: Eight-week-old male and female C57BL/6J mice received either Nγ-nitro-L-arginine methyl ester and high-fat diet or control water and diet for 2, 5, and 12 weeks. The db/db mice were studied as a second model of HFpEF. Early pathways regulating PH were identified by bulk and single-cell RNA sequencing. Findings were confirmed by immunostain in lungs of mice or lung slides from clinically performed autopsies of patients with PH-HFpEF. ELISA was used to verify IL-1ß (interleukin-1 beta) in mouse lung, mouse plasma, and also human plasma from patients with PH-HFpEF obtained at the time of right heart catheterization. Clodronate liposomes and an anti-IL-1ß antibody were utilized to deplete macrophages and IL-1ß, respectively, to assess their impact on pulmonary vascular remodeling in HFpEF in mouse models. RESULTS: Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice developed PH, small vessel muscularization, and right heart dysfunction. Inflammation-related gene ontologies were overrepresented in bulk RNA sequencing analysis of whole lungs, with an increase in CD68+ cells in both murine and human PH-HFpEF lungs. Cytokine profiling showed an increase in IL-1ß in mouse and human plasma. Finally, clodronate liposome treatment in mice prevented PH in Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice, and IL-1ß depletion also attenuated PH in Nγ-nitro-L-arginine methyl ester/high-fat diet-treated mice. CONCLUSIONS: We report a novel model for the study of PH and right heart remodeling in HFpEF, and we identify myeloid cell-derived IL-1ß as an important contributor to PH in HFpEF.


Asunto(s)
Insuficiencia Cardíaca , Hipertensión Pulmonar , Animales , Femenino , Humanos , Masculino , Ratones , Ácido Clodrónico , Insuficiencia Cardíaca/metabolismo , Hipertensión Pulmonar/etiología , Interleucina-1beta , Ratones Endogámicos C57BL , Células Mieloides/metabolismo , Volumen Sistólico/fisiología
7.
Nature ; 569(7756): 378-382, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-31092939

RESUMEN

Over 60 years of spacecraft exploration has revealed that the Earth's Moon is characterized by a lunar crust1 dominated by the mineral plagioclase, overlying a more mafic (richer in iron and magnesium) mantle of uncertain composition. Both crust and mantle formed during the earliest stages of lunar evolution when late-stage accretional energy caused a molten rock (magma) ocean, flotation of the light plagioclase, sinking of the denser iron-rich minerals, such as olivine and pyroxene, and eventually solidification2. Very large impact craters can potentially penetrate through the crust and sample the lunar mantle. The largest of these craters is the approximately 2,500-kilometre-diameter South Pole-Aitken (SPA) basin3 on the lunar far side. Evidence obtained from orbiting spacecraft shows that the floor of the SPA basin is rich in mafic minerals4, but their mantle origin is controversial and their in situ geologic settings are poorly known. China's Chang'E-4 lunar far-side lander recently touched down in the Von Kármán crater5,6 to explore the floor of the huge SPA basin and deployed its rover, Yutu-2. Here we report on the initial spectral observations of the Visible and Near Infrared Spectrometer (VNIS)7 onboard Yutu-2, which we interpret to represent the presence of low-calcium (ortho)pyroxene and olivine, materials that may originate from the lunar mantle. Geological context6 suggests that these materials were excavated from below the SPA floor by the nearby 72-km-diameter Finsen impact crater event, and transported to the landing site. Continued exploration by Yutu-2 will target these materials on the floor of the Von Kármán crater to understand their geologic context, origin and abundance, and to assess the possibility of sample-return scenarios.

8.
Circulation ; 147(17): 1291-1303, 2023 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-36970983

RESUMEN

BACKGROUND: During cardiomyocyte maturation, the centrosome, which functions as a microtubule organizing center in cardiomyocytes, undergoes dramatic structural reorganization where its components reorganize from being localized at the centriole to the nuclear envelope. This developmentally programmed process, referred to as centrosome reduction, has been previously associated with cell cycle exit. However, understanding of how this process influences cardiomyocyte cell biology, and whether its disruption results in human cardiac disease, remains unknown. We studied this phenomenon in an infant with a rare case of infantile dilated cardiomyopathy (iDCM) who presented with left ventricular ejection fraction of 18% and disrupted sarcomere and mitochondria structure. METHODS: We performed an analysis beginning with an infant who presented with a rare case of iDCM. We derived induced pluripotent stem cells from the patient to model iDCM in vitro. We performed whole exome sequencing on the patient and his parents for causal gene analysis. CRISPR/Cas9-mediated gene knockout and correction in vitro were used to confirm whole exome sequencing results. Zebrafish and Drosophila models were used for in vivo validation of the causal gene. Matrigel mattress technology and single-cell RNA sequencing were used to characterize iDCM cardiomyocytes further. RESULTS: Whole exome sequencing and CRISPR/Cas9 gene knockout/correction identified RTTN, the gene encoding the centrosomal protein RTTN (rotatin), as the causal gene underlying the patient's condition, representing the first time a centrosome defect has been implicated in a nonsyndromic dilated cardiomyopathy. Genetic knockdowns in zebrafish and Drosophila confirmed an evolutionarily conserved requirement of RTTN for cardiac structure and function. Single-cell RNA sequencing of iDCM cardiomyocytes showed impaired maturation of iDCM cardiomyocytes, which underlie the observed cardiomyocyte structural and functional deficits. We also observed persistent localization of the centrosome at the centriole, contrasting with expected programmed perinuclear reorganization, which led to subsequent global microtubule network defects. In addition, we identified a small molecule that restored centrosome reorganization and improved the structure and contractility of iDCM cardiomyocytes. CONCLUSIONS: This study is the first to demonstrate a case of human disease caused by a defect in centrosome reduction. We also uncovered a novel role for RTTN in perinatal cardiac development and identified a potential therapeutic strategy for centrosome-related iDCM. Future study aimed at identifying variants in centrosome components may uncover additional contributors to human cardiac disease.


Asunto(s)
Cardiomiopatía Dilatada , Femenino , Embarazo , Animales , Humanos , Cardiomiopatía Dilatada/genética , Pez Cebra , Volumen Sistólico , Función Ventricular Izquierda , Centrosoma/metabolismo , Miocitos Cardíacos
9.
J Am Chem Soc ; 146(22): 15479-15487, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38780095

RESUMEN

The development of efficient and low-cost catalysts is essential for photocatalysis; however, the intrinsically low photocatalytic efficiency as well as the difficulty in using and recycling photocatalysts in powder morphology greatly limit their practical performance. Herein, we describe quasi-homogeneous photocatalysis to overcome these two limitations by constructing ultrastiff, hierarchically porous, and photoactive aerogels of conjugated microporous polymers (CMPs). The CMP aerogels exhibit low density but high stiffness beyond 105 m2 s-2, outperforming most low-density materials. Extraordinary stiffness ensures their use as robust scaffolds for scaled photocatalysis and recycling without damage at the macroscopic level. A challenging but desirable reaction for direct deaminative borylation is demonstrated using CMP aerogel-based quasi-homogeneous photocatalysis with gram-scale productivity and record-high efficiency under ambient conditions. Combined terahertz and transient absorption spectroscopic studies unveil the generation of high-mobility free carriers and long-lived excitonic species in the CMP aerogels, underlying the observed superior catalytic performance.

10.
Artículo en Inglés | MEDLINE | ID: mdl-38447814

RESUMEN

BACKGROUND & AIMS: In phase 2 studies, efruxifermin, an Fc-FGF21 analog, significantly reduced steatohepatitis and fibrosis in patients with non-alcoholic steatohepatitis, now called metabolic dysfunction-associated steatohepatitis (MASH), for which there is no approved treatment. Type 2 diabetes (T2D) and obesity are prevalent among patients with MASH and increasingly treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This study evaluated the safety and efficacy of efruxifermin in patients with MASH, fibrosis, and T2D taking a GLP-1RA. METHODS: Cohort D was a double-blind, placebo-controlled, phase 2b study in adults with T2D and MASH with fibrosis (F1-F3) on stable GLP-1RA therapy randomized (2:1) to receive efruxifermin 50 mg or placebo, once weekly for 12 weeks. The primary endpoint was safety and tolerability of efruxifermin added to a stable dose of GLP-1RA. Secondary endpoints included changes in hepatic fat fraction (HFF), markers of liver injury and fibrosis, and metabolic parameters. RESULTS: Adults (N = 31) with T2D and MASH fibrosis (F1-F3) on a stable GLP-1RA (semaglutide, 48.4%; dulaglutide, 45.2%; liraglutide, 6.5%) received efruxifermin 50 mg (n = 21) or placebo (n = 10) for 12 weeks. The addition of efruxifermin to a GLP-1RA appeared safe and well-tolerated. The most frequent efruxifermin-related adverse events were mild to moderate gastrointestinal events. One patient receiving efruxifermin discontinued due to nausea, and another withdrew consent. There were no treatment-related serious adverse events. After 12 weeks, efruxifermin reduced HFF by 65% (P < .0001 vs placebo) compared with a 10% reduction for placebo (GLP-1RA alone). Efruxifermin also improved noninvasive markers of liver injury, fibrosis, glucose, and lipid metabolism while maintaining GLP-1RA-mediated weight loss. CONCLUSIONS: The tolerability profile of efruxifermin added to GLP-1RA appeared comparable to that of either drug alone, while also significantly reducing HFF and noninvasive markers of fibrosis in patients with MASH and T2D. Liver health in patients already on a GLP-1RA may be further improved by addition of efruxifermin. CLINICALTRIALS: gov, Number: NCT05039450.

11.
Small ; 20(15): e2306821, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38009496

RESUMEN

Low-dimensional perovskites afford improved stability against moisture, heat, and ionic migration. However, the low dimensionality typically results in a wide bandgap and strong electron-phonon coupling, which is undesirable for optoelectronic applications. Herein, semiconducting A-site organic cation engineering by electron-acceptor bipyridine (bpy) cations (2,2'-bpy2+ and 4,4'-bpy2+) is employed to optimize band structure in low-dimensional perovskites. Benefiting from the merits of lower lowest unoccupied molecular orbital (LUMO) energy for 4,4'-bpy2+ cation, the corresponding (4,4'-bpy)PbI4 is endowed with a smaller bandgap (1.44 eV) than the (CH3NH3)PbI3 (1.57 eV) benchmark. Encouragingly, an intramolecular type II band alignment formation between inorganic Pb-I octahedron anions and bpy2+ cations favors photogenerated electron-hole pairs separation. In addition, a shortening distance between inorganic Pb-I octahedral chains in (4,4'-bpy)PbI4 single crystal (SC) can effectively promote carrier transfer. As a result, a self-powered photodetector based on (4,4'-bpy)PbI4 SC exhibits 131 folds higher on/off ratio (3807) than the counterpart of (2,2'-bpy)2Pb3I10 SC (29). The presented result provides an effective strategy for exporting novel organic cation-based low-dimensional perovskite SC for high-performance optoelectronic devices.

12.
J Transl Med ; 22(1): 384, 2024 Apr 24.
Artículo en Inglés | MEDLINE | ID: mdl-38659083

RESUMEN

BACKGROUND: Chimeric antigen receptor (CAR) T-cells have demonstrated significant efficacy in targeting hematological malignancies, and their use continues to expand. Despite substantial efforts spent on the optimization of protocols for CAR T-cell manufacturing, critical parameters of cell culture such as pH or oxygenation are rarely actively monitored during cGMP CAR T-cell generation. A comprehensive understanding of the role that these factors play in manufacturing may help in optimizing patient-specific CAR T-cell therapy with maximum benefits and minimal toxicity. METHODS: This retrospective study examined cell culture supernatants from the manufacture of CAR T-cells for 20 patients with B-cell malignancies enrolled in a phase 1/2 clinical trial of anti-CD22 CAR T-cells. MetaFLEX was used to measure supernatant pH, oxygenation, and metabolites, and a Bio-Plex assay was used to assess protein levels. Correlations were assessed between the pH of cell culture media throughout manufacturing and cell proliferation as well as clinical outcomes. Next-generation sequencing was conducted to examine gene expression profiles of the final CAR T-cell products. RESULTS: A pH level at the lower range of normal at the beginning of the manufacturing process significantly correlated with measures of T-cell expansion and metabolism. Stable or rising pH during the manufacturing process was associated with clinical response, whereas a drop in pH was associated with non-response. CONCLUSIONS: pH has potential to serve as an informative factor in predicting CAR T-cell quality and clinical outcomes. Thus, its active monitoring during manufacturing may ensure a more effective CAR T-cell product.


Asunto(s)
Lectina 2 Similar a Ig de Unión al Ácido Siálico , Linfocitos T , Humanos , Concentración de Iones de Hidrógeno , Linfocitos T/inmunología , Lectina 2 Similar a Ig de Unión al Ácido Siálico/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Proliferación Celular , Técnicas de Cultivo de Célula
13.
BMC Cancer ; 24(1): 1013, 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39148050

RESUMEN

BACKGROUND: The chemotherapy regimens recommended for both rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) patients are myelosuppressive and can reduce the absolute neutrophil count (ANC) and subsequently increase the risk of febrile neutropenia (FN). However, only a few studies have focused on the efficacy and safety of granulocyte-colony stimulating factor (G-CSF) drugs in pediatric and adolescent patients with RMS and ES. Our objective was to investigate the efficacy and safety of mecapegfilgrastim, a biosimilar of pegfilgrastim, in prophylaxis of FN for pediatric and adolescent patients with RMS or ES. METHODS: In this single-arm, single-center, prospective study, pediatric and adolescent patients with RMS or ES were enrolled to receive either VAC (vincristine, cyclophosphamide, dactinomycin) regimen or VDC (vincristine, cyclophosphamide, doxorubicin) regimen in a 3-week cycle, followed by treatment with mecapegfilgrastim (100 µg/kg, maximum 6 mg) given at 24 h after completing chemotherapy. The primary endpoint was the incidence rate of FN. Secondary endpoints included the incidence rate of grade 4 neutropenia, duration of ANC ≤ 0.5 × 109/L, incidence rate of chemotherapy delay or reduction, use of antibiotics, and safety profile. RESULTS: In total, 2 of the 30 (6.7%, 95% CI: 0.82-22.07) patients experienced FN after the first cycle of chemotherapy. Eight (26.7%, 95% CI: 12.28-45.89) patients experienced grade 4 neutropenia after receiving prophylactic mecapegfilgrastim. Eight patients experienced ANC ≤ 0.5 × 109/L with a median duration of 4.5 days; among them, 6 patients reached the lowest point of their ANC level on day 7, and 5 of them recovered by day 10. No dose reductions, delays, or discontinuation of chemotherapy was reported. Twenty-one (70.0%) patients received antibiotics during the treatment period. No patient experienced FN in the 0-5 years and the 13-18 years groups, and 2 patients experienced FN in the 6-12 years group. Two patients, 6 patients, and no patient experienced grade 4 neutropenia in the 0-5 years, 6-12 years, and 13-18 years groups, respectively. CONCLUSION: Mecapegfilgrastim showed acceptable efficacy and safety profile in pediatric and adolescent patients with RMS or ES. Further randomized studies with large sample size are warranted. TRIAL REGISTRATION: This clinical trial was registered at Chictr.org.cn (No.ChiCTR1900022249). Registered on March 31, 2019.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neutropenia Febril , Filgrastim , Rabdomiosarcoma , Sarcoma de Ewing , Humanos , Masculino , Femenino , Adolescente , Sarcoma de Ewing/tratamiento farmacológico , Niño , Proyectos Piloto , Estudios Prospectivos , Preescolar , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Rabdomiosarcoma/tratamiento farmacológico , Neutropenia Febril/prevención & control , Neutropenia Febril/inducido químicamente , Neutropenia Febril/etiología , Filgrastim/uso terapéutico , Filgrastim/administración & dosificación , Filgrastim/efectos adversos , Ciclofosfamida/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Dactinomicina/administración & dosificación , Dactinomicina/efectos adversos , Dactinomicina/uso terapéutico , Doxorrubicina/efectos adversos , Doxorrubicina/administración & dosificación , Lactante
14.
Protein Expr Purif ; 224: 106564, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-39111349

RESUMEN

Pectin lyases are important in various industries, including tobacco leaves processing. In this paper, a novel pectin lyase Pel04 from Bacillus velezensis was characterized. Pel04 molecular weight (Mw) and isoelectric point (pI) of the protein sequence after removing the signal peptide are 43.0 kDa. The optimal temperature and pH of Pel04 is 50 °C and 9.0, respectively. Pel04 was stable in the range of 30-50 °C, and pH 9.5-11. Ca2+ can significantly stimulate the enzyme activity, while Cu2+, Co2+, Fe3+, and Mn2+ have inhibitory effects on Pel04. By Pel04 treatment, the overall content of acids, alcohols, esters and other aromas in tobacco leaves increased, while the contents of phenolic and heterocyclic substances decreased. Pel04 has important potential for industrial application particularly in improving quality of tobacco leaves.


Asunto(s)
Bacillus , Estabilidad de Enzimas , Nicotiana , Polisacárido Liasas , Concentración de Iones de Hidrógeno , Polisacárido Liasas/química , Polisacárido Liasas/metabolismo , Polisacárido Liasas/genética , Bacillus/enzimología , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Temperatura , Hojas de la Planta/química , Hojas de la Planta/enzimología
15.
J Surg Oncol ; 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39082465

RESUMEN

Malignant peritoneal mesothelioma (MPM) is a rare and invasive tumor, and some patients will develop paraneoplastic syndrome (PS) during the course of the disease. This review summarizes PS associated with MPM, focusing on the clinical characteristics and treatment progress in hematological, endocrine, rheumatic, neurological, urinary, and other systems to decrease missed diagnosis and misdiagnosis, help early diagnosis and prompt treatment, and provide guidance for the clinical decision-making of this kind of patients.

16.
J Surg Oncol ; 2024 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-39183488

RESUMEN

BACKGROUND: To explore the most effective adjuvant chemotherapy regimen for malignant peritoneal mesothelioma (MPM) through patient derived tumor-like cell clusters (PTC) drug sensitivity test. METHODS: PTC were cultured in vitro with intraoperative specimens, and drug sensitivity test was performed to calculate the most effective chemotherapy regimen for MPM. The patients were divided into conventional and individualized chemotherapy group according to whether they received PTC drug testing. Univariate and multivariate analyses were conducted to identify independent prognostic factors. RESULTS: Among 186 MPM patients included, 63 underwent PTC culture and drug sensitivity test. The results showed that the most effective chemotherapy regimen was oxaliplatin + gemcitabine. After propensity score matching, a total of 64 patients were enrolled in the following study, including 32 patients receiving individualized chemotherapy guided by PTC drug results as group 1 and 32 patients receiving conventional chemotherapy as group 2. Survival analysis showed that the median OS of group 1 was not reached, significantly longer than that of group 2 (23.5 months) (p < 0.05). CONCLUSIONS: Compared with conventional chemotherapy, individualized chemotherapy guided by PTC drug sensitivity tests can prolong patient survival, and oxaliplatin + gemcitabine + apatinib could be the optimal adjuvant treatment regimen for MPM.

17.
Inorg Chem ; 63(10): 4758-4769, 2024 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-38408314

RESUMEN

The efficiency of nitrogen mustards (NMs), among the first chemotherapeutic agents against cancer, is limited by their monotonous mechanism of action (MoA). And tumor hypoxia is a significant obstacle in the attenuation of the chemotherapeutic efficacy. To repurpose the drug and combat hypoxia, herein, we constructed an organo-Ir(III) prodrug, IrCpNM, with the composition of a reactive oxygen species (ROS)-inducing moiety (Ir-arene fragment)-a hypoxic responsive moiety (azo linker)-a DNA-alkylating moiety (nitrogen mustard), and realized DNA damage response (DDR)-mediated autophagy for hypoxic lung cancer therapy for the first time. Prodrug IrCpNM could upregulate the level of catalase (CAT) to catalyze the decomposition of excessive H2O2 to O2 and downregulate the expression of the hypoxia-inducible factor (HIF-1α) to relieve hypoxia. Subsequently, IrCpNM initiates the quadruple synergetic actions under hypoxia, as simultaneous ROS promotion and glutathione (GSH) depletion to enhance the redox disbalance and severe oxidative and cross-linking DNA damages to trigger the occurrence of DDR-mediated autophagy via the ATM/Chk2 cascade and the PIK3CA/PI3K-AKT1-mTOR-RPS6KB1 signaling pathway. In vitro and in vivo experiments have confirmed the greatly antiproliferative capacity of IrCpNM against the hypoxic solid tumor. This work demonstrated the effectiveness of the DNA damage-responsive organometallic prodrug strategy with the microenvironment targeting system and the rebirth of traditional chemotherapeutic agents with a new anticancer mechanism.


Asunto(s)
Neoplasias Pulmonares , Profármacos , Humanos , Especies Reactivas de Oxígeno/metabolismo , Profármacos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Peróxido de Hidrógeno , Hipoxia , Autofagia , Daño del ADN , ADN , Línea Celular Tumoral , Microambiente Tumoral
18.
Inorg Chem ; 63(11): 5235-5245, 2024 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-38452249

RESUMEN

Cancer treatment has faced severe obstacles due to the smart biological system of cancer cells. Herein, we report a three-in-one agent Ir-CA via attenuation of cancer cell stemness with the down-regulated biomarker CD133 expression from the mitochondria-directed chemotherapy. Over 80% of Ir-CA could accumulate in mitochondria, result in severe mitochondrial dysfunctions, and subsequently initiate mitophagy and cell cycle arrest to kill cisplatin-resistant A549R cells. In vitro and in vivo antimetastatic experiments demonstrated that Ir-CA can effectively inhibit metastasis with down-regulated MMP-2/MMP-9. RNA seq analysis and Western blotting indicated that Ir-CA also suppresses the GSTP1 expression to decrease the intracellular Pt-GS adducts, resulting in the detoxification and resensitization to cisplatin of A549R cells. In vivo evaluation indicated that Ir-CA restrains the tumor growth and has minimal side effects and superior biocompatibility. This work not only provides the first three-in-one agent to attenuate cancer cell stemness and simultaneously realize anticancer, antimetastasis, and conquer metallodrug resistance but also demonstrates the effectiveness of the mitochondria-directed strategy in cancer treatment.


Asunto(s)
Antineoplásicos , Neoplasias , Cisplatino/farmacología , Línea Celular Tumoral , Ciclo Celular , Mitocondrias , Apoptosis , Antineoplásicos/farmacología , Antineoplásicos/metabolismo , Neoplasias/metabolismo
19.
Environ Sci Technol ; 2024 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-39288224

RESUMEN

The nonradical oxidation pathway for pollutant degradation in Fenton-like catalysis is favorable for water treatment due to the high reaction rate and superior environmental robustness. However, precise regulation of such reactions is still restricted by our poor knowledge of underlying mechanisms, especially the correlation between metal site conformation of metal atom clusters and pollutant degradation behaviors. Herein, we investigated the electron transfer and pollutant oxidation mechanisms of atomic-level exposed Ag atom clusters (AgAC) loaded on specifically crafted nitrogen-doped porous carbon (NPC). The AgAC triggered a direct electron transfer (DET) between the terminal oxygen (Oα) of surface-activated peroxodisulfate and the electron-donating substituents-containing contaminants (EDTO-DET), rendering it 11-38 times higher degradation rate than the reported carbon-supported metal catalysts system with various single-atom active centers. Heterocyclic substituents and electron-donating groups were more conducive to degradation via the EDTO-DET system, while contaminants with high electron-absorbing capacity preferred the radical pathway. Notably, the system achieved 79.5% chemical oxygen demand (COD) removal for the treatment of actual pharmaceutical wastewater containing 1053 mg/L COD within 30 min. Our study provides valuable new insights into the Fenton-like reactions of metal atom cluster catalysts and lays an important basis for revolutionizing advanced oxidation water purification technologies.

20.
Mol Biol Rep ; 51(1): 220, 2024 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-38281218

RESUMEN

D-ribose, an ubiquitous pentose compound found in all living cells, serves as a vital constituent of numerous essential biomolecules, including RNA, nucleotides, and riboflavin. It plays a crucial role in various fundamental life processes. Within the cellular milieu, exogenously supplied D-ribose can undergo phosphorylation to yield ribose-5-phosphate (R-5-P). This R-5-P compound serves a dual purpose: it not only contributes to adenosine triphosphate (ATP) production through the nonoxidative phase of the pentose phosphate pathway (PPP) but also participates in nucleotide synthesis. Consequently, D-ribose is employed both as a therapeutic agent for enhancing cardiac function in heart failure patients and as a remedy for post-exercise fatigue. Nevertheless, recent clinical studies have suggested a potential link between D-ribose metabolic disturbances and type 2 diabetes mellitus (T2DM) along with its associated complications. Additionally, certain in vitro experiments have indicated that exogenous D-ribose exposure could trigger apoptosis in specific cell lines. This article comprehensively reviews the current advancements in D-ribose's digestion, absorption, transmembrane transport, intracellular metabolic pathways, impact on cellular behaviour, and elevated levels in diabetes mellitus. It also identifies areas requiring further investigation.


Asunto(s)
Diabetes Mellitus Tipo 2 , Insuficiencia Cardíaca , Enfermedades Metabólicas , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ribosa/metabolismo , Adenosina Trifosfato
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA