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1.
Asian J Androl ; 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35665693

RESUMO

Many therapies are effective in treating varicoceles, including dilation of the pampiniform plexus in males. The most common method of treatment is varicocelectomy. We aimed to assess an alternative technique (microsurgical spermatic [distal end]-superficial or inferior epigastric vein anastomosis) that preserves the normal blood flow pattern for varicocele treatment. We retrospectively analyzed 27 men with varicocele between October 2019 and July 2020. All patients underwent microsurgical spermatic (distal end)-superficial or inferior epigastric vein anastomosis. The prognosis was reviewed retrospectively with an additional survey conducted 3 months after surgery. The mean ± standard deviation of the age was 26.1 ± 7.3 years in patients with microsurgical spermatic (distal end)-superficial or inferior epigastric vein anastomosis. The maximum diameter of the varicocele vein, perineal pain score, sperm density, and forward movement of sperm improved over 3 months after surgery. Microsurgical spermatic (distal end)-superficial or inferior epigastric vein anastomosis is a safe and efficient surgical treatment for varicoceles.

2.
Blood Adv ; 2022 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-35667090

RESUMO

Chromosomal aberrations and gene mutations have been considered to be the major reasons for high recurrence rates and poor survival among AML patients. However, the underlying molecular mechanism of AML gene mutation remains largely unclear. Here, we show that sperm-associated antigen 6 (SPAG6), one of the most markedly increased SPAG genes in AML, significantly contributed to the proliferation and migration of leukemic cells. SPAG6 was highly expressed in AML and its upregulation was negatively correlated with the prognosis of the disease. In vitro, SPAG6 promoted the proliferation and migration of leukemia cells and promoted cell cycle progression from G1 phase to S phase. In vivo, low expression of SPAG6 reduced the proliferation and infiltration of leukemia cells and prolonged the survival of xenograft tumor mice. Furthermore, immunoprecipitation and mass spectrometry analysis showed that SPAG6 interacts with MYO1D. Specifically, overexpression of SPAG6 promoted the translocation of MYO1D into the cell membrane, thus upgrading the expression level of the EGFR family and thereby promoting the progression of AML. Overall, our study found that SPAG6 combined with MYO1D and translocated MYO1D from the cytosol to the cytomembrane, which induced the PI3K/AKT signaling and ERK signaling pathway to regulate the growth and prognosis of AML. SPAG6 may become a new target gene for the treatment of AML.

3.
Cell Death Discov ; 8(1): 274, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35668081

RESUMO

SMYD2, as an oncogene, has been involved in multiple types of cancer, but the potential role of SMYD2 in gastrointestinal stromal tumors (GIST) remains enigmatic and requires further investigation. Hence, this study was conducted with the main objective of analyzing the effect of SMYD2 on GIST. GIST and adjacent normal tissues were collected from 46 patients with GIST where the expression of EZH2, SMYD2, and TET1 was determined, followed by the analysis of their interactions. The functional role of SMYD2 in cell biological functions was determined using a loss-of-function assay in GIST-T1 cells. Nude mouse xenograft experiments were performed to verify the role of the SMYD2/EZH2/TET1 axis in GIST in vivo. EZH2 was upregulated in GIST tissues and cell lines, which was positively correlated with SMYD2 expression and inversely correlated with TET1 expression in GIST tissues. EZH2 silencing due to SMYD2 inhibition reduced GIST-T1 cell proliferation and accelerated cell senescence. EZH2 repressed TET1 expression by promoting H3K27me3 methylation in the TET1 promoter region. TET1 inhibition reversed the effect of EZH2 silencing on the biological functions of GIST-T1 cells. In vivo data further revealed the promoting effect of SMYD2 on the progression of GIST by regulating the EZH2/TET1 axis. Overall, this study demonstrates that SMYD2 can increase EZH2 expression while suppressing TET1 expression, thus accelerating GIST, and creating new treatment opportunities for GIST.

4.
Circ Res ; : 101161CIRCRESAHA121320470, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35652349

RESUMO

BACKGROUND: The ADRB3 (ß3-adrenergic receptors), which is predominantly expressed in brown adipose tissue (BAT), can activate BAT and improve metabolic health. Previous studies indicate that the endocrine function of BAT is associated with cardiac homeostasis and diseases. Here, we investigate the role of ADRB3 activation-mediated BAT function in cardiac remodeling. METHODS: BKO (brown adipocyte-specific ADRB3 knockout) and littermate control mice were subjected to Ang II (angiotensin II) for 28 days. Exosomes from ADRB3 antagonist SR59230A (SR-exo) or agonist mirabegron (MR-exo) treated brown adipocytes were intravenously injected to Ang II-infused mice. RESULTS: BKO markedly accelerated cardiac hypertrophy and fibrosis compared with control mice after Ang II infusion. In vitro, ADRB3 KO rather than control brown adipocytes aggravated expression of fibrotic genes in cardiac fibroblasts, and this difference was not detected after exosome inhibitor treatment. Consistently, BKO brown adipocyte-derived exosomes accelerated Ang II-induced cardiac fibroblast dysfunction compared with control exosomes. Furthermore, SR-exo significantly aggravated Ang II-induced cardiac remodeling, whereas MR-exo attenuated cardiac dysfunction. Mechanistically, ADRB3 KO or SR59230A treatment in brown adipocytes resulted an increase of iNOS (inducible nitric oxide synthase) in exosomes. Knockdown of iNOS in brown adipocytes reversed SR-exo-aggravated cardiac remodeling. CONCLUSIONS: Our data illustrated a new endocrine pattern of BAT in regulating cardiac remodeling, suggesting that activation of ADRB3 in brown adipocytes offers cardiac protection through suppressing exosomal iNOS.

5.
Stem Cell Res Ther ; 13(1): 241, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35672836

RESUMO

BACKGROUND: Repairing radiation-induced bone injuries remains a significant challenge in the clinic, and few effective medicines are currently available. Psoralen is a principal bioactive component of Cullen corylifolium (L.) Medik and has been reported to have antitumor, anti-inflammatory, and pro-osteogenesis activities. However, less information is available regarding the role of psoralen in the treatment of radiation-induced bone injury. In this study, we explored the modulatory effects of psoralen on skeletal stem cells and their protective effects on radiation-induced bone injuries. METHODS: The protective effects of psoralen on radiation-induced osteoporosis and irradiated bone defects were evaluated by microCT and pathological analysis. In addition, the cell proliferation, osteogenesis, and self-renewal of SSCs were explored. Further, the underlying mechanisms of the protective of psoralen were investigated by using RNA sequencing and functional gain and loss experiments in vitro and in vivo. Statistical significance was analyzed using Student's t test. The one-way ANOVA was used in multiple group data analysis. RESULTS: Here, we demonstrated that psoralen, a natural herbal extract, mitigated radiation-induced bone injury (irradiation-induced osteoporosis and irradiated bone defects) in mice partially by rescuing the stemness of irradiated skeletal stem cells. Mechanistically, psoralen restored the stemness of skeletal stem cells by alleviating the radiation-induced suppression of AKT/GSK-3ß and elevating NRF2 expression in skeletal stem cells. Furthermore, the expression of KEAP1 in skeletal stem cells did not significantly change in the presence of psoralen. Moreover, blockade of NRF2 in vivo partially abolished the promising effects of psoralen in a murine model of irradiation-induced osteoporosis and irradiated bone regeneration. CONCLUSIONS: In summary, our findings identified psoralen as a potential medicine to mitigate bone radiation injury. In addition, skeletal stem cells and AKT-GSK-3ß and NRF2 may thus represent therapeutic targets for treating radiation-induced bone injury.


Assuntos
Osteoporose , Lesões por Radiação , Animais , Ficusina/farmacologia , Ficusina/uso terapêutico , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Osteoporose/etiologia , Osteoporose/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células-Tronco/metabolismo , Regulação para Cima
6.
ACS Appl Mater Interfaces ; 14(24): 28221-28229, 2022 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-35679528

RESUMO

Two-dimensional (2D) halide perovskite material is characterized by a mixed conducting behavior that possesses both electronic and ionic conductivity. The study on the influence of the light on ion migration in the 2D perovskite is helpful to improve the performance of perovskite-based optoelectronic devices. Here, we constructed an exfoliated 2D perovskite/carbon nanotubes (CNTs) heterostructure optical synapse, in which CNTs can be used as nanoprobes to qualitatively observe the ion aggregation or dissipation process in 2D perovskite, and found that light significantly changes the memory curve of the reconfigurable optical synapses. Through the molecular dynamic simulation, the dynamic process of ion migration in the heterostructure was simulated and the electrostatic interaction effect of nonequilibrium charge distribution of CNTs on iodide ion was demonstrated. Finally, an effective light-controlled process was realized through the synapses, which in situ regulated the performance of the weight-value discretized BP (WD-BP) neural network. This work lays a foundation for the future development of intelligent nano-optoelectronic devices.

7.
Ann Hematol ; 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35726105

RESUMO

Donor-specific anti-human leukocyte antigen (HLA) antibody (DSA) is associated with a higher incidence of graft failure and mortality in HLA-mismatched allograft settings. However, the optimal protocol of desensitization for patients with positive DSA remains uncertain. We investigated the effectiveness of a desensitization protocol, including rituximab, high-dose intravenous immunoglobulin (IVIG), and a single session of plasma exchange (PE), for haploidentical allograft recipients with a high mean fluorescence intensity (MFI) level of DSA (≥ 5,000). Eleven patients with hematological disease who had positive DSA (median, 11,676, range 5387-20,435) were desensitized by the protocol. All of the patients achieved hematopoietic recovery. The median times for neutrophil and platelet engraftment were 13 (range, 11-26) days and 19 (range, 11-90) days, respectively. Grade II-IV acute graft-versus-host disease (GVHD) was seen in one patient and was controlled completely. Chronic cutaneous GVHD was seen in eight patients. Nine patients are alive with good performance so far. One patient suffered extramedullary relapse, and one patient died of transplantation-associated thrombotic microangiopathy. The 1-year probability of overall survival was 81.8%. These results suggest that successful desensitization could be obtained by a combination of rituximab, high-dose IVIG, and PE for haploidentical allograft recipients with high MFI levels of DSA.

8.
Anal Methods ; 2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35708023

RESUMO

In this study, a core-shell-structured magnetic metal-organic framework (MMOF) composite material (Fe3O4@UiO-66-NH2) was synthesized by the solvothermal method. It was employed as a new absorbent in combination with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for the simultaneous detection of four aflatoxins (AFs) in rice. This method could shorten the pre-processing time by exploiting the advantageous characteristics of magnetic cores. The impurity was removed quickly. The effects of extraction solution, extraction time, adsorbent types, and amount of adsorbent on the extraction rate of target compounds were optimized. Under optimized conditions, AFs were validated and showed a good linear relationship within the 0.375-20 µg kg-1 concentration range (r2 > 0.9992). The limit of detection (LOD) was 0.0188-0.1250 µg kg-1 and the limit of quantification (LOQ) was 0.0375-0.3750 µg kg-1. At three spiking levels (0.375, 2, and 10 µg kg-1), the average recovery values for the four AFs ranged from 85.1% to 111.0%. The relative standard deviation ranged from 3.4% to 7.7%. The new method proved to be simple, fast, efficient, and suitable for the determination of AFs in rice samples.

9.
Front Public Health ; 10: 870920, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35719613

RESUMO

Objective: We aimed to establish nomograms to predict the overall survival (OS) and cancer-specific survival (CSS) of patients with primary urachal carcinoma (UrC). Methods: Information on patients diagnosed with UrC from 1975 to 2018 was collected from the Surveillance, Epidemiology, and End Results (SEER) Program Research Data. The independent prognostic factors were determined using univariate and multivariate Cox regression. Backward variable elimination according to the Akaike information criterion (AIC) identified the most accurate and parsimonious model. Nomograms were built based on regression coefficients. The C-index, calibration plot, Brier score, integrated discrimination improvement (IDI), area under the receiver operating curve (AUC), and decision curve analysis (DCA) curve were used to evaluate the efficiency of models. Results: In total, 236 patients obtained from SEER were divided randomly into training and validation cohorts in a 70:30 ratio (166 and 70 patients, respectively). In the training cohort, multivariate Cox regression analysis indicated that pTNM/Sheldon/Mayo staging systems (included respectively), age, and tumor grade were independent prognostic factors for OS. A similar result was also found in CSS. While other variables, such as radiotherapy and chemotherapy, did not identify significant correlations. In predicting OS and CSS at 3- and 5- years, the nomograms based on pTNM showed superior discriminative and calibration capabilities in comparison to multiple statistical tools. The C-index values for the training cohort were 0.770 for OS and 0.806 for CSS, and similar outcomes were shown in further internal validation (C-index 0.693 for OS and 0.719 for CSS). We also discovered that the link between age at diagnosis and survival follows a U-shaped curve, indicating that the risk of poor prognosis decreases first and then increases with age. Conclusion: The efficacy of pTNM in predicting the prognosis of patients with UrC was greater than that of the Sheldon and Mayo staging system. Therefore, we recommend pTNM as the preferred system to stage UrC. The novel constructed nomograms based on pTNM, age, and tumor grade showed high accuracy and specificity and could be applied clinically to predict the prognosis of patients with UrC.


Assuntos
Neoplasias , Humanos , Internet , Estadiamento de Neoplasias , Curva ROC , Programa de SEER , Neoplasias da Bexiga Urinária
10.
Front Cell Dev Biol ; 10: 853003, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35646902

RESUMO

Glycogen synthase kinase-3ß (GSK-3ß) is a downstream target of oncogenic KRas and can accumulate in the nucleus in pancreatic ductal adenocarcinoma (PDA). To determine the interplay between oncogenic KRas and nuclear GSK-3ß in PDA development, we generated Lox-STOP-Lox (LSL) nuclear-targeted GSK-3ß animals and crossed them with LSL-KRasG12D mice under the control of the Pdx1-cre transgene-referred to as KNGC. Interestingly, 4-week-old KNGC animals show a profound loss of acinar cells, the expansion of ductal cells, and the rapid development of cystic-like lesions reminiscent of intraductal papillary mucinous neoplasm (IPMN). RNA-sequencing identified the expression of several ductal cell lineage genes including AQP5. Significantly, the Aqp5+ ductal cell pool was proliferative, phenotypically distinct from quiescent pancreatic ductal cells, and deletion of AQP5 limited expansion of the ductal pool. Aqp5 is also highly expressed in human IPMN along with GSK-3ß highlighting the putative role of Aqp5+ ductal cells in human preneoplastic lesion development. Altogether, these data identify nGSK-3ß and KRasG12D as an important signaling node promoting the retention of pancreatic ductal progenitor cells, which could be used to further characterize pancreatic ductal development as well as lineage biomarkers related to IPMN and PDA.

11.
Adv Mater ; : e2201600, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35545992

RESUMO

Designing ultrastrong near-infrared (NIR) absorbing organic semiconductors is a critical prerequisite for sensitive NIR thin film organic photodetectors (OPDs), especially in the region of beyond 900 nm, where the absorption coefficient of commercial single crystalline silicon (c-Si) is below 103 cm-1 . Herein, a pyrrolo[3,2-b]thieno[2,3-d]pyrrole heterocyclic core (named as BPPT) with strong electron-donating property and stretched geometry is developed. Relative to their analogue Y6, BPPT-contained molecules, BPPT-4F and BPPT-4Cl, show substantially upshifted and more delocalized highest occupied molecular orbitals, and larger transition dipole moments, leading to bathochromic and hyperchromic absorption spectra extending beyond 1000 nm with very large absorption coefficients (up to 3.7-4.3 × 105 cm-1 ) as thin films. These values are much higher than those (104 to 1 × 105 cm-1 ) of typical organic semiconductors, and 1-2 orders higher than those of commercial inorganic materials, such as c-Si, Ge, and InGaAs. The OPDs based on BPPT-4F or BPPT-4Cl blending polymer PBDB-T show high detectivity of above 1012 Jones in a wide wavelength range of 310-1010 nm with excellent peak values of 1.3-2.2 × 1013 Jones, respectively, which are comparable with and even better than those commercial inorganic photodetectors.

12.
Int J Gynecol Pathol ; 2022 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-35639370

RESUMO

The fetal gut-like phenotype can be found in yolk sac tumors and adenocarcinomas with enteroblastic differentiation (AEBDs). We report a cervical yolk sac tumor in a 44-yr-old woman. The tumor has similar morphology, immunophenotype, and molecular features to the AEBD of the digestive system. The tumor showed a glandular-predominant growth pattern, composed of columnar cells with clear glycogen-rich cytoplasm. The microcystic/reticular architecture or Schiller-Duval bodies were not found in the tumor. Immunohistochemically, the tumor cells were positive for p16, glypican-3 (GPC3), spalt-like transcription factor 4 (SALL4), Cdx-2, and p53. TP53 mutation was identified by next-generation sequencing, and human papillomavirus (HPV) 35 was detected by HPV DNA polymerase chain reaction. In the present case, the adenocarcinoma cells in the superficial cervical glandular epithelium and the nonclear glandular components proved the existence of somatic components. The positivity of p16 and HPV also supports that the present case originates from an HPV-associated adenocarcinoma. The yolk sac tumor should be thought of as "germ cell differentiation" from a somatic carcinoma. This kind of yolk sac tumor arising from somatic-type adenocarcinoma in the female genital tract may be the counterpart of AEBD in the digestive tracts and adenocarcinomas with fetal gut-like morphology in other organs. The tumor might be more aggressive than conventional adenocarcinoma, pathologists should highlight the existence of the enteroblastic component in the pathologic report.

13.
Nano Lett ; 22(11): 4482-4490, 2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35580197

RESUMO

Comfort and mechanical stability are vital for epidermal electronics in daily use. In situ deposition of circuitry without the protection of substrates or encapsulation can produce imperceptible, conformal, and permeable epidermal electronics. However, they are easily destroyed by daily wear because the binding force between deposited materials and skin is usually weak. Here, we in situ deposited skin-adhesive liquid metal particles (ALMP) to fabricate epidermal electronics with robust wear resistance. It represents the most wear-resistant in situ deposited epidermal electronic materials. It can withstand ∼1600 cm, 175 g loaded paper tape wearing by a standard abrasion wear tester. Stretchability, conformality, permeability, and thinness of the ALMP coating provide an imperceptible and comfortable wearing experience. Without degradation of electrical property caused by solvent evaporation, the dry ALMP coating possesses natural advantages over gel electrodes. In situ deposited ALMP is an ideal material for fabricating comfortable epidermal electronics.


Assuntos
Adesivos , Eletrônica , Eletrodos , Metais , Pele
14.
J Sep Sci ; 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35593582

RESUMO

Pivmecillinam, the ester of biologically active antibiotic mecillinam, is an effective oral preparation to treat urinary tract infections. To study pharmacokinetics in humans, LC-MS/MS methods were developed to quantify pivmecillinam and mecillinam in human plasma, respectively. Considering cephalexin as internal standard, analytes were separated on UltimateXB-C18 columns after protein precipitation by acetonitrile. The mobile phase was composed of water containing 0.1% formic acid and methanol. The multiple reactions monitoring transitions of m/z 440.2→167.1, 326.1→167.1, and 348.1→158.1 were selected to inspect pivmecillinam, mecillinam, and the internal standard in positive ion mode. No apparent matrix effect was perceived. Linearities were obtained over calibration ranges of 0.0500-12.0 and 10.0-15,000 ng/ml, respectively. The intraday precisions were below 5.5%, the interday precisions were below 6.1%, and accuracies were within -8.1% to 13.0%. Stability tests were conducted and an acidification step was explored to enhance the stability of pivmecillinam and mecillinam. Further stability was validated under various storage and processing conditions. Both methods were applied to a pharmacokinetic study of pivmecillinam and mecillinam after oral administration of 400 mg pivmecillinam hydrochloride tablets in healthy Chinese subjects.

15.
Artigo em Inglês | MEDLINE | ID: mdl-35580348

RESUMO

In this paper, a new hollow fiber liquid-phase microextraction method was developed to improve the extraction of five fluorescent whitening agents that migrated from plastics food contact materials. Influencing factors, such as the types of membrane, the extraction solvent, the stirring speed, the addition of salt ion, and extraction time, were investigated in detail. Under the optimal conditions, high enrichment factors (71-205) can be obtained with 15 µL extraction solvent. The new method is advantageous; the polypropylene hollow fiber membrane modified by sepiolite nanoparticles had excellent solvent binding force and mass transfer effect compared with the conventional extraction technique. The extracts were analyzed by high performance liquid chromatography-tandem mass spectrometry, the limits of detection were 0.3 or 0.9 ng kg-1 with good correlation coefficients (r2 ≥ 0.9940) for the five fluorescent whitening agents. The intra-day and inter-day recoveries ranged between 82.6% and 112%, with a relative standard deviation of less than 12%. The established method was successfully applied to the analysis of fluorescent whitening agent migration from four types of plastic food contact materials immersed in three food simulants.

16.
Microbiol Spectr ; : e0171421, 2022 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-35588280

RESUMO

As the first-line antimicrobial agent for the infection caused by carbapenem-resistant Enterobacterales, ceftazidime-avibactam develops drug resistance during its ever-growing clinical use. In this study, we report multiple novel variants in blaKPC-2-positive Klebsiella pneumoniae from two separate patients during their exposure to ceftazidime-avibactam. For one patient, the blaKPC-2 gene carried by K. pneumoniae mutated into blaKPC-35, blaKPC-78, and blaKPC-33 over the same period, while that for the other patient mutated into blaKPC-79 and further evolved into blaKPC-76 to enhance resistance level, among which blaKPC-76 and blaKPC-79 were reported for the first time. In contrast with blaKPC-2, the emergent mutations within the Ω-loop conferred high-level resistance to ceftazidime-avibactam with a sharp reduction of carbapenemase activity. These blaKPC-positive K. pneumoniae isolated from sputum (both patients) and cerebrospinal fluid (patient 2) belonged to ST11 and ST859, respectively. All strains located blaKPC alleles on IncFII/IncR plasmids, except one on an IncFII plasmid. Such blaKPC-2 variants first appeared after 9 to 18 days of ceftazidime-avibactam usage, but the lack of its feasible detection method often led to the assumption of ceftazidime-avibactam sensitivity resulting in clinical incorrect usage. Subsequent substitution of ceftazidime-avibactam with carbapenems also failed, because the blaKPC-2-containing K. pneumoniae dominated again. Ultimately, treatment failed even with the therapeutic regimen of ceftazidime-avibactam combined with carbapenems, because of the inadequate concentration of avibactam in infection sites and decreased drug sensitivity of strains caused by increased expression of blaKPC and point mutation of ompK35 and ompK36. As novel KPC variants conferring resistance to ceftazidime-avibactam are constantly emerging worldwide, quick and efficient laboratory detection and surveillance are urgently needed for infection control. IMPORTANCE Carbapenem-resistant K. pneumoniae which was classified as the most urgent threat by World Health Organization, is the most critical public health concern due to its high mortality rate. Recently, the rapid mutation of blaKPC has occurred during anti-infective therapy, which posed an unexpected challenge for both the diagnostic laboratory and clinical practice.

17.
Exp Cell Res ; 417(1): 113211, 2022 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-35597299

RESUMO

Different from the nucleolus-specific localization in some types of cancer cells, ribosomal L1 domain-containing protein 1 (RSL1D1) distributes throughout the nucleus in human colorectal cancer (CRC) cells. RSL1D1 directly interacts with DNA binding domain (aa 93-292) of wild-type p53 (p53-WT) and thereby recruits p53 to HDM2. The ensuing formation of RSL1D1/HDM2/p53 complex enhances p53 ubiquitination and decreases the protein level of p53 in CRC cells. In this study, we investigated the interaction between RSL1D1 and mutant p53 proteins. We first corroborated that aa 93-224 of p53 is a more precise domain for RSL1D1 binding and mutation in either aa 93-224 or aa 225-292 domain of p53 affects RSL1D1-p53 interaction. R175H mutated p53 does not interact with RSL1D1, whereas R273H mutated p53 still can bind to RSL1D1 but showing a remarkably decreased affinity than p53-WT. Although p53-R273H retains a weakened binding affinity with RSL1D1, it can hardly be recruited to HDM2 by RSL1D1 in HCT116 CRC cells. Accordingly, RSL1D1 loses its capacity to negatively regulate either R175H or R273H p53 mutant via directly interaction in HCT116 cells, thereby facilitating p53 mutants to accumulate and gain oncogenic function. Our findings help explain why mutant p53 proteins are more stable than p53-WT in CRC cells.


Assuntos
Neoplasias Colorretais , Proteínas da Gravidez , Proteínas Ribossômicas , Proteína Supressora de Tumor p53 , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , DNA , Células HCT116 , Humanos , Proteínas Mutantes/metabolismo , Mutação/genética , Proteínas da Gravidez/química , Proteínas da Gravidez/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
Eur J Pharm Sci ; 175: 106213, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35605912

RESUMO

Youkenafil is a novel selective phosphodiesterase type 5 inhibitor to treat erectile dysfunction. In order to study the drug-drug interactions of youkenafil, in vitro experiments were conducted with human liver microsomes and recombinant isoenzymes to identify the effect of cytochrome P450 (CYP) enzymes on the metabolism of youkenafil. Then two clinical studies were performed to investigate the effects of itraconazole and rifampicin (potent CYP3A4/5 inhibitor and inducer, respectively) on the pharmacokinetics of youkenafil and its main metabolite, N-desethyl youkenafil (M1). Each study enrolled thirty healthy male subjects. In study 1, subjects were given a single dose of youkenafil (50 mg on Days 1 and 13) and multiple doses of itraconazole (200 mg once daily from Days 6 to 14). In study 2, subjects were given a single dose of youkenafil (100 mg on Days 1 and 20) and multiple doses of rifampicin (600 mg once daily from Days 6 to 20). The results showed that youkenafil was mainly metabolized through CYP3A4/5 in vitro. Itraconazole increased youkenafil AUC and Cmax by about 12- and 6-fold, respectively, and increased M1 AUC and Cmax by 5- and 1.3-fold, respectively. Conversely, rifampicin reduced youkenafil AUC and Cmax both by about 98%. It did not change the AUC of M1 significantly, but increased the Cmax by 30%. All treatments were well tolerated by subjects in both studies. Therefore, co-administration of youkenafil with potent inhibitors or inducers of CYP3A4/5 should be avoided or carefully monitored.

19.
Antibiotics (Basel) ; 11(5)2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35625247

RESUMO

A 22-year-old man, after a hematopoietic stem cell transplant, suffered long-term pneumonia caused by blaKPC-2-positive K. pneumoniae and blaKPC-33-positive K. pneumoniae alternately and finally achieved pathogenic clearance and improvement of clinical infectious conditions after using ceftazidime-avibactam in combination with imipenem as salvage therapy. This case provides a reference for treating infection caused by K. pneumoniae with a KPC variant in countries lacking new antimicrobial agents.

20.
Anal Chem ; 94(21): 7492-7499, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35586900

RESUMO

Recently we have demonstrated that the surface plasmon of noble metal nanoparticles can effectively enhance the ECL intensity of Ru(bpy)32+, and we named this detection principle as surface-enhanced electrochemiluminescence (SEECL-I). However, SEECL based on photomultiplier tube (PMT) detection can only detect one target at a time, which is not suitable for multiple targets detection. In this work, we combined our previous developed SEECL with a bioimaging device to develop a novel multiplexed immunassay for simultaneous and fast analysis of cancer markers. A core-shell nanocomposite consisted of gold-silicon dioxide nanoparticles doped with Ru(bpy)32+(Au@SiO2-Ru) with strong ECL emission was employed as ECL label due to the localized surface plasmon resonance (LSPR) of AuNPs, which can significantly enhance the ECL emission of Ru(bpy)32+. The ECL signals from the 4 × 4 electrode arrays were collected using the constant potential method (current-time curve method) imaging with a sCOMS camera. As a proof-of-concept application, we demonstrated the use of the proposed SEECL-I for simultaneous detection of carcinoembryonic antigen (CEA), neuron specific enolase (NSE), and squamous cell carcinoma antigen (SCC) in exhaled breath condensates (EBCs) with low detection limit (LOD) of 0.17, 0.33, and 0.33 pg/mL (S/N = 3), respectively. The results demonstrated that the proposed SEECL-I strategy can provide a high sensitivity, fast analysis, and high-throughput platform for clinical diagnosis of cancer markers in EBCs.


Assuntos
Técnicas Biossensoriais , Nanopartículas Metálicas , Neoplasias , Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Ouro , Humanos , Imunoensaio/métodos , Medições Luminescentes , Dióxido de Silício
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