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1.
Food Chem ; 366: 130605, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34311239

RESUMO

The Citrus genus is a good source of dietary flavonoids, which have many health benefits. As a representative citrus fruit, the flavonoids composition in Shatianyu (Citrus grandis L. Osbeck) pulp remains to be investigated. In the present study, 11 flavonoids were isolated and identified from Shatianyu pulp flavonoid extracts (SPFEs). Among them, 4 flavonoids were previously undescribed and 2 flavonoids were firstly isolated from pummelo. The cellular antioxidant activity (CAA) and oxygen radical absorbance capacity (ORAC) of isolated compounds were evaluated. Naringin and rhoifolin showed the highest ORAC activity, and the presence of a 3-hydroxy-3-methylglutaryl or a 4'-glucose decreased the ORAC activity of flavonoids. The contribution of isolated flavonoids to the holistic antioxidant activity of SPFEs was determined by an online knockout method. Melitidin, bergamjuicin and naringin contributed most to ORAC activity, while bergamjuicin, melitidin and apigenin-4'-O-ß-d-glucopyranosyl-7-O-α-l-rhamnopyranosyl-(1 â†’ 2)-[6″-O-(3- hydroxy-3-methylgltaryl)]-ß-d-glucopyranoside contributed most to CAA activity.

3.
J Cell Mol Med ; 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523782

RESUMO

Ovarian cancer (OC) is the most lethal gynaecological cancer with genomic complexity and extensive heterogeneity. This study aimed to characterize the molecular features of OC based on the gene expression profile of 2752 previously characterized metabolism-relevant genes and provide new strategies to improve the clinical status of patients with OC. Finally, three molecular subtypes (C1, C2 and C3) were identified. The C2 subtype displayed the worst prognosis, upregulated immune-cell infiltration status and expression level of immune checkpoint genes, lower burden of copy number gains and losses and suboptimal response to targeted drug bevacizumab. The C1 subtype showed downregulated immune-cell infiltration status and expression level of immune checkpoint genes, the lowest incidence of BRCA mutation and optimal response to targeted drug bevacizumab. The C3 subtype had an intermediate immune status, the highest incidence of BRCA mutation and a secondary optimal response to bevacizumab. Gene signatures of C1 and C2 subtypes with an opposite expression level were mainly enriched in proteolysis and immune-related biological process. The C3 subtype was mainly enriched in the T cell-related biological process. The prognostic and immune status of subtypes were validated in the Gene Expression Omnibus (GEO) dataset, which was predicted with a 45-gene classifier. These findings might improve the understanding of the diversity and therapeutic strategies for OC.

4.
J Exp Bot ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34490889

RESUMO

The formation of locule gel is an important process in tomato and a typical characteristic of berry fruit. In this study, we collected a tomato natural mutant that produces all-flesh fruits (AFF) in which the locule tissue remains in a solid state during fruit development. We built genetic populations to fine-map the causal gene of the AFF trait and identified the gene AFF (SlMBP3) as the locus conferring the locule gel formation. We determined the causal mutation as a 416-bp deletion that occurred in the promoter region of AFF and reduced its expression dosage. The 416-bp sequence is highly conserved among Solanaceae species, as well as within the tomato germplasm. Furthermore, with the BC6 NIL materials, we revealed that the reduced expression dosage of AFF did not impact the normal development of seeds but produced unique non-liquefied locule tissue, which was distinct from that of normal tomatoes in terms of metabolic components. We further revealed the importance of AFF gene in locule tissue liquefaction through combined analysis using mRNA-seq and metabolomics. Our findings provide clues to investigate fruit type differentiation in Solanaceae crops and also contribute to the application of the AFF gene in tomato breeding programs.

5.
J Hazard Mater ; 416: 125713, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492773

RESUMO

Hydrogen can be prepared by oil sludge (OS) gasification with steam, which is of great significance for industrial hazardous waste treatment and resource conservation. The gasification performance was studied by a tube furnace reactor. The OS gasification was carried out at different temperatures (600, 700, 800 and 900 °C) and with different steam to OS ratio (SOS) (0.1:1, 0.3:1, 0.5:1). During the gasification process, hydrogen production first increased and then decreased, and hydrogen production was faster in 5-15 min. The yield of hydrogen of OS gasification reached the maximum when the SOS was 0.3:1 at 800 °C. The highest hydrogen yield per unit mass OS was 48.50 mL min-1 g-1. After gasification, the char yield was high, generally more than 50%. It was necessary to treat the char and incineration was an effective solution for low carbon fuels. Thus particle size distribution, incineration thermogravimetric analysis and heavy metal leaching concentrations analysis were carried out. The results showed that the average particle size of char ranged from 85 to 120 µm. The char incineration process could be divided into three stages: water evaporation, the precipitation and combustion of volatiles, and the combustion of fixed carbon and heavy components. After OS gasification at 800 °C, the leaching concentrations of typical heavy metals (As, Cr, Cu, Ni, Pb and Zn) were all up to the standard. Therefore, OS gasification combined with char incineration was an effective approach for the utilization of solid waste, which can recover hydrogen energy and reduce environmental risks.


Assuntos
Esgotos , Vapor , Hidrogênio , Incineração , Água
6.
Nanoscale ; 13(35): 14785-14794, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34533172

RESUMO

Photothermal therapy (PTT) is considered as an efficient therapeutic strategy for wound disinfection. However, there is a dilemma that on the one hand, the high PTT temperature for killing bacteria (>58 °C) could cause serious injury to normal tissue, however, low-temperature results in unsatisfactory treatment efficiency. To settle the issue, we have proposed a novel approach to gently kill bacteria in an apoptosis-like mode via PTT, in which the bacteria can maintain intact membranes but cannot proliferate. This is different from the typical necrosis-like mode of bacterial cell death requiring higher temperatures. We found that PTT prefers to trigger the gradual efflux of Ca2+/Mg2+ ions from the bacterial intracellular content rather than directly destroy the outer membranes, but can cause the dynamic variation of the membrane surface micromorphology. Hence, the microbial viability of E. coli can be dynamically changed from the live state to an apoptosis-like state (45-55 °C), then to apoptosis/necrosis (ca. 58 °C), and finally to necrosis (>61 °C). Based on this strategy, we can kill bacteria through an apoptosis-like mode. Better healing efficacy of mice wounds was achieved at a PTT temperature of 50 °C as compared to that at 58 °C, which sheds light on the wound disinfection and healing applications in clinics with a mild PTT strategy.


Assuntos
Hipertermia Induzida , Nanoestruturas , Animais , Apoptose , Desinfecção , Escherichia coli , Hipertermia , Camundongos , Fototerapia
7.
Front Immunol ; 12: 644350, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34489925

RESUMO

Tumor-infiltrating immune cells shape the tumor microenvironment and are closely related to clinical outcomes. Several transcription factors (TFs) have also been reported to regulate the antitumor activity and immune cell infiltration. This study aimed to quantify the populations of different immune cells infiltrated in tumor samples based on the bulk RNA sequencing data obtained from 50 cancer patients using the CIBERSORT and the EPIC algorithm. Weighted gene coexpression network analysis (WGCNA) identified eigengene modules strongly associated with tumorigenesis and the activation of CD4+ memory T cells, dendritic cells, and macrophages. TF genes FOXM1, MYBL2, TAL1, and ERG are central in the subnetworks of the eigengene modules associated with immune-related genes. The analysis of The Cancer Genome Atlas (TCGA) cancer data confirmed these findings and further showed that the expression of these potential TF genes regulating immune infiltration, and the immune-related genes that they regulated, was associated with the survival of patients within multiple cancers. Exome-seq was performed on 24 paired samples that also had RNA-seq data. The expression quantitative trait loci (eQTL) analysis showed that mutations were significantly more frequent in the regions flanking the TF genes compared with those of non-TF genes, suggesting a driver role of these TF genes regulating immune infiltration. Taken together, this study presented a practical method for identifying genes that regulate immune infiltration. These genes could be potential biomarkers for cancer prognosis and possible therapeutic targets.

8.
J Med Internet Res ; 23(9): e26231, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34505837

RESUMO

BACKGROUND: Day-of-surgery cancellation (DoSC) represents a substantial wastage of hospital resources and can cause significant inconvenience to patients and families. Cancellation is reported to impact between 2% and 20% of the 50 million procedures performed annually in American hospitals. Up to 85% of cancellations may be amenable to the modification of patients' and families' behaviors. However, the factors underlying DoSC and the barriers experienced by families are not well understood. OBJECTIVE: This study aims to conduct a geospatial analysis of patient-specific variables from electronic health records (EHRs) of Cincinnati Children's Hospital Medical Center (CCHMC) and of Texas Children's Hospital (TCH), as well as linked socioeconomic factors measured at the census tract level, to understand potential underlying contributors to disparities in DoSC rates across neighborhoods. METHODS: The study population included pediatric patients who underwent scheduled surgeries at CCHMC and TCH. A 5-year data set was extracted from the CCHMC EHR, and addresses were geocoded. An equivalent set of data >5.7 years was extracted from the TCH EHR. Case-based data related to patients' health care use were aggregated at the census tract level. Community-level variables were extracted from the American Community Survey as surrogates for patients' socioeconomic and minority status as well as markers of the surrounding context. Leveraging the selected variables, we built spatial models to understand the variation in DoSC rates across census tracts. The findings were compared to those of the nonspatial regression and deep learning models. Model performance was evaluated from the root mean squared error (RMSE) using nested 10-fold cross-validation. Feature importance was evaluated by computing the increment of the RMSE when a single variable was shuffled within the data set. RESULTS: Data collection yielded sets of 463 census tracts at CCHMC (DoSC rates 1.2%-12.5%) and 1024 census tracts at TCH (DoSC rates 3%-12.2%). For CCHMC, an L2-normalized generalized linear regression model achieved the best performance in predicting all-cause DoSC rate (RMSE 1.299%, 95% CI 1.21%-1.387%); however, its improvement over others was marginal. For TCH, an L2-normalized generalized linear regression model also performed best (RMSE 1.305%, 95% CI 1.257%-1.352%). All-cause DoSC rate at CCHMC was predicted most strongly by previous no show. As for community-level data, the proportion of African American inhabitants per census tract was consistently an important predictor. In the Texas area, the proportion of overcrowded households was salient to DoSC rate. CONCLUSIONS: Our findings suggest that geospatial analysis offers potential for use in targeting interventions for census tracts at a higher risk of cancellation. Our study also demonstrates the importance of home location, socioeconomic disadvantage, and racial minority status on the DoSC of children's surgery. The success of future efforts to reduce cancellation may benefit from taking social, economic, and cultural issues into account.

9.
Dis Markers ; 2021: 2792884, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34504627

RESUMO

Objective: Neural cell adhesion molecule (NCAM), a glycoprotein widely distributed in the brain, has recently been shown to regulate neuroplasticity. However, the role of NCAM in vascular dementia (VaD) is still unclear. The purpose of this study is to determine whether NCAM is involved in the course of VaD. Methods: Continuous recruitment of VaD patients and control population to join this study. Doctors or nurses are responsible for collecting their clinical characteristics including age, gender, formal education, heart rate, supine systolic blood pressure, supine diastolic blood pressure, fasting glucose, high-density lipoprotein, and low-density lipoprotein. Each participant received the Montreal Cognitive Assessment (MoCA) scale after being enrolled in the group. At the same time, their peripheral blood was collected, and their serum NCAM levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: 98 VaD patients and 83 age- and sex-matched controls were enrolled. There was no significant statistical difference between the VaD group and the control group in terms of the comparison of clinical characteristics (p > 0.05). The MoCA score of VaD patients was significantly lower than that of the controls (27.9 ± 1.4 vs. 23.0 ± 2.1 points, p < 0.001). In addition, the circulating NCAM level of VaD patients was also significantly lower than that of controls (21.7 ± 3.8 vs. 17.6 ± 4.2 ng/mL, p < 0.001). The circulating NCAM level of VaD patients was significantly positively correlated with MoCA score (r = 0.285, p = 0.026). After adjusting for clinical characteristics, circulating NCAM levels are still an independent pathogenic factor of VaD (regression coefficient = 0.223, p = 0.034). Conclusions: VaD patients have low circulating NCAM levels, which can be used as a potential predictor of VaD.

10.
Nat Nanotechnol ; 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504324

RESUMO

Two-dimensional materials are promising candidates for future electronics due to unmatched device performance at atomic limit and low-temperature heterogeneous integration. To adopt these emerging materials in computing and optoelectronic systems, back end of line (BEOL) integration with mainstream technologies is needed. Here, we show the integration of large-area MoS2 thin-film transistors (TFTs) with nitride micro light-emitting diodes (LEDs) through a BEOL process and demonstrate high-resolution displays. The MoS2 transistors exhibit median mobility of 54 cm2 V-1s -1, 210 µA µm-1 drive current and excellent uniformity. The TFTs can drive micrometre-sized LEDs to 7.1 × 107 cd m-2 luminance under low voltage. Comprehensive analysis on driving capability, response time, power consumption and modulation scheme indicates that MoS2 TFTs are suitable for a range of display applications up to the high resolution and brightness limit. We further demonstrate prototypical 32 × 32 active-matrix displays at 1,270 pixels-per-inch resolution. Moreover, our process is fully monolithic, low-temperature, scalable and compatible with microelectronic processing.

11.
J Pept Sci ; : e3365, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34467600

RESUMO

Long-chain scorpion toxin AaH-II isolated from Androctonus australis Hector can selectively inhibit mammalian voltage-gated sodium ion channel Nav 1.7 responsible for pain sensation. Efficient chemical synthesis of AaH-II and its derivatives is beneficial to the study of the function and mechanism of Nav 1.7 and the development of potential peptide inhibitors. Herein, we compared three different strategies, namely, direct solid-phase peptide synthesis, hydrazide-based two-segment native chemical ligation, and hydrazide-based three-segment native chemical ligation for the synthesis of AaH-II. The hydrazide-based two-segment native chemical ligation affords the target toxin with the optimal efficiency, which provides a practically robust procedure for the preparation of tool molecules derived from AaH-II to study the biological functions and modulation of Nav 1.7. Our work highlights the importance of selecting suitable segment condensation approach in the chemical synthesis of protein toxins.

12.
Eur J Neurosci ; 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34494695

RESUMO

Detection of transient changes in interaural correlation is based on the temporal precision of the central representations of acoustic signals. Whether schizophrenia impairs the temporal precision in the interaural correlation process is not clear. In both participants with schizophrenia and matched healthy-control participants, this study examined the detection of a break in interaural correlation (BIC, a change in interaural correlation from 1 to 0 and back to 1), including the longest interaural delay at which a BIC was just audible, representing the temporal extent of the primitive auditory memory (PAM). Moreover, BIC-induced electroencephalograms (EEGs) and the relationships between the early binaural psychoacoustic processing and higher cognitive functions, which were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), were examined. The results showed that compared to healthy controls, participants with schizophrenia exhibited poorer BIC detection, PAM and RBANS score. Both the BIC-detection accuracy and the PAM extent were correlated with the RBANS score. Moreover, participants with schizophrenia showed weaker BIC-induced N1-P2 amplitude which was correlated with both theta-band power and inter-trial phase coherence. These results suggested that schizophrenia impairs the temporal precision of the central representations of acoustic signals, affecting both interaural correlation processing and higher-order cognitions.

13.
Artigo em Inglês | MEDLINE | ID: mdl-34490739

RESUMO

OBJECTIVE: A Mendelian randomization (MR) framework was applied to disentangle the causal effect of branched-chain amino acids (BCAAs) and overweight/obesity in Chinese adolescents. METHODS: Circulating BCAA levels were measured by liquid chromatography coupled with mass spectrometry. A total of 7 BCAAs and 12 BMI-associated common variants identified from released genome-wide association study results were genotyped. Furthermore, a bidirectional MR approach was undertaken to disentangle the causal effect of BCAAs and overweight/obesity, using two-stage regression. RESULTS: Using the inverse variance-weighted strategy and the weighted genetic scoring instruments, the estimated odds ratio per 1-arbitrary-unit increase in the total BCAA level on overweight and obesity odds after adjusting for age and sex was 2.40 (95% CI: 1.38 to 3.42, p < 0.001) and 2.55 (95% CI: 1.35 to 4.82, p = 0.004), respectively. Furthermore, additional MR tests were undertaken using a reversed model, testing the causal effect of increasing BMI variants on total BCAA level. By contrast, no evidence that increased BMI was causally associated with the total BCAA level (estimated ß associated with 1-kg/m2 increase in BMI = 0.05, 95% CI: -0.17 to 0.28, p = 0.642) was observed. CONCLUSIONS: In summary, BCAAs may be causally associated with overweight/obesity or, rather, a congenital dysmetabolism of BCAAs could be a cause of overweight/obesity in adolescents.

14.
Commun Biol ; 4(1): 1034, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465887

RESUMO

COVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10-10, allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10-9, AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10-8, AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19.


Assuntos
COVID-19/etnologia , COVID-19/genética , Grupos Étnicos/genética , Estudo de Associação Genômica Ampla , Predisposição Genética para Doença/genética , Humanos , Íntrons/genética , Polimorfismo de Nucleotídeo Único
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 829-832, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487523

RESUMO

OBJECTIVE: To detect variants of NF1 gene among thirteen patients with neurofibromatosis type 1. METHODS: Genomic DNA was extracted from peripheral blood samples of the patients. High-throughput sequencing was employed to detect potential variants of the NF1 and NF2 genes. RESULTS: Thirteen pathogenic variants were identified among the patients, which included one NF1 deletion, three missense variants, three nonsense variants and six frameshifting variants. Among these, 10 variants have been associated with neurofibromatosis type 1. c.4180A>T (p.Asn1394Tyr), c.4217dupT (p.Leu1406fs) and c.1753dupT(p.Leu585Phefs*3) were unreported previously. Based on the guidelines of the American College of Medical Genetics and Genomics, c.4180A>T (p.Asn1394Tyr) was predicted to be likely pathogenic (PS2+PM1+PM2+PP2), while c.4217dupT (p.Leu1406fs) and c.1753dupT (p.Leu585Phefs*3) were predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION: Variants of the NF1 gene probably underlay the disease among these children. Above findings have enriched the the spectrum of NF1 gene variants.


Assuntos
Genes da Neurofibromatose 1 , Neurofibromatose 1 , Criança , Genômica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Neurofibromatose 1/genética
16.
Nat Nanotechnol ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34475559

RESUMO

Two-dimensional (2D) semiconductors, in particular transition metal dichalcogenides (TMDCs), have attracted great interest in extending Moore's law beyond silicon1-3. However, despite extensive efforts4-25, the growth of wafer-scale TMDC single crystals on scalable and industry-compatible substrates has not been well demonstrated. Here we demonstrate the epitaxial growth of 2 inch (~50 mm) monolayer molybdenum disulfide (MoS2) single crystals on a C-plane sapphire. We designed the miscut orientation towards the A axis (C/A) of sapphire, which is perpendicular to the standard substrates. Although the change of miscut orientation does not affect the epitaxial relationship, the resulting step edges break the degeneracy of nucleation energy for the antiparallel MoS2 domains and lead to more than a 99% unidirectional alignment. A set of microscopies, spectroscopies and electrical measurements consistently showed that the MoS2 is single crystalline and has an excellent wafer-scale uniformity. We fabricated field-effect transistors and obtained a mobility of 102.6 cm2 V-1 s-1 and a saturation current of 450 µA µm-1, which are among the highest for monolayer MoS2. A statistical analysis of 160 field-effect transistors over a centimetre scale showed a >94% device yield and a 15% variation in mobility. We further demonstrated the single-crystalline MoSe2 on C/A sapphire. Our method offers a general and scalable route to produce TMDC single crystals towards future electronics.

17.
Artigo em Inglês | MEDLINE | ID: mdl-34520366

RESUMO

In this article, the problem of tracking control for a class of nonlinear time-varying full state constrained systems is investigated. By constructing the time-varying asymmetric barrier Lyapunov function (BLF) and combining it with the backstepping algorithm, the intelligent controller and adaptive law are developed. Neural networks (NNs) are utilized to approximate the uncertain function. It is well known that in the past research of nonlinear systems with state constraints, the state constraint boundary is either a constant or a time-varying function. In this article, the constraint boundaries both related to state and time are investigated, which makes the design of control algorithm more complex and difficult. Furthermore, by employing the Lyapunov stability analysis, it is proven that all signals in the closed-loop system are bounded and the time-varying full state constraints are not violated. In the end, the effectiveness of the control algorithm is verified by numerical simulation.

18.
Mikrochim Acta ; 188(10): 344, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34528141

RESUMO

A dual signal-amplified sandwich electrochemiluminescence (ECL) immunosensor was fabricated for trace detection of procalcitonin (PCT). CeO2-Au@Pt composed of sea urchin-like Au@Pt nanoparticles coated on CeO2 hollow nanospheres was immobilized on electrode surface to electrochemically catalyze H2O2 to produce a large number of superoxide anion (O2•-). The immunosensor was prepared by linking the capture antibody on immobilized CeO2-Au@Pt with heptapeptide (HWRGWVC), which could maintain the activity of the antibody. The prepared Au star@BSA was used to bind abundant luminol for labeling the secondary antibody (Ab2). Upon the sandwich-typed immunoreactions, the O2•- could react with the introduced luminol on the immunosensor surface to produce strong ECL intensity. With an outstanding linear detection range and a low detection limit of 17 fg/mL, the ECL immunosensor permitted ultrasensitive detection of PCT at a low H2O2 concentration and demonstrated its high application potential in the clinical assay.

19.
J Pharm Biomed Anal ; 205: 114343, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500236

RESUMO

Cabozantinib is a potent inhibitor of tyrosine kinase receptor that plays key role in tumor pathogenesis. Cabozantinib has been approved by U. S. Food and Drug Administration for the treatment of cancer. The present work was aimed to explore the in vitro metabolism of cabozantinib using liver microsomes and hepatocytes from animal species and humans through ultra-high performance liquid chromatography coupled to quadrupole/orbitrap high resolution mass spectrometer. The metabolites were characterized by their elemental compositions, MS and MS/MS spectra. As a result, a total of 26 metabolites were identified, and 15 metabolites were newly reported. Among these metabolites, M12 (oxidative defluorination), M19 and M22 (demethylation), M21 (hydroxylation) and M26 (N-oxygenation) were the major metabolites in all species. Our data revealed that cabozantinib was metabolized via the following pathways: oxidative defluorination, hydroxylation, amide hydrolysis, O-dealkylation, N-oxygenation, demethylation and glucuronidation. Human recombinant cytochrome P450 (CYP) enzyme analysis revealed that metabolism of cabozantinib was mainly catalyzed by CYP3A4, while other CYP enzymes played negligible role. The current study provided valuable metabolic data of cabozantinib from different animal species and humans, which would aid in safety and efficacy assessment.

20.
Int J Biol Sci ; 17(13): 3493-3507, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512161

RESUMO

Histone deacetylases (HDACs) exhibit increased expression in cancer and promote oncogenesis via the acetylation of or interactions with key transcriptional regulators. HDAC inhibitors (HDACis) decrease HDAC activity to selectively inhibit the occurrence and development of tumors. Our study screened and obtained a new HDACi structure. In vitro experiments have showed that among the leads, Z31216525 significantly inhibited the proliferation and induced the apoptosis of epithelial ovarian cancer (EOC) cells. In vivo experiments demonstrated that compared to the control, Z31216525 significantly inhibited tumor growth and showed very low toxicity. Further mechanistic studies revealed that Z31216525 may exert an antitumor effect by inhibiting the expression of the c-Myc gene. Collectively, our studies identified a novel HDACi that is expected to become a new potential therapeutic drug for EOC and has important value for the design of new HDACi structures.

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