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1.
Artigo em Inglês | MEDLINE | ID: mdl-36662267

RESUMO

BACKGROUND: Ionocytes are rare cells in airway epithelium characterized by a high expression of CFTR. OBJECTIVES: To investigate the morphology and distribution of ionocytes and the function of CFTR in the nasal mucosal epithelium of children. METHODS: The exfoliated cells of nasal mucosa from 101 children were detected using flow cytometry to analyze the number of ionocytes and CFTR and the difference of CFTR function. Nasal mucosa and polyps were collected from 10 children with CRSwNP. The RNAscope of FOXI1 and CFTR was detected in pathological paraffin sections. The expression and distribution of ionocytes and CFTR in nasal mucosa and polyp epithelium were observed. RESULTS: In CRS patients, the number of ionocytes in the nasal epithelium was lower and the number of ionocytes that did not express CFTR was higher, and the function of CFTR was also decreased. The expression of CFTR in the nasal mucosa of CRS showed the characteristics of local dense distribution and increased as the inflammation expanded. The ionocytes were "tadpole-shaped" in the epithelium and gathered in the area of high CFTR expression, the intracellular CFTR was expanded in clusters. Ionocytes that did not express CFTR was more common in the nasal polyps. CONCLUSIONS: The number of ionocytes and the function of CFTR in nasal mucosa of CRS patients decreased. With the expansion of inflammation, CFTR and ionocytes showed more obvious dense distribution. Some ionocytes lost the expression of CFTR and did not show the "tadpole" shape, which may be related to the occurrence of polyps.

2.
Sci Total Environ ; 867: 161431, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36626998

RESUMO

The activity changes of Cd and Cu in paddy field were strongly influenced by the transformation of S, Fe and Mn species. However, in the process of soil redox, how S cooperates with Fe/Mn to regulate the law and mechanism of Cd and Cu speciation transformation still needs to be studied. In this study, we used DGT technology based on layer double hydroxides (LDHs) combined with pore water sampling to investigate soil redox changes, rice growth, and the effects of different forms of sulfur (S0, SO42-) on soil Cd and Cu activities. The results showed that the concentrations of CDGT-Cd and Cu in the soil decreased rapidly in the anaerobic stage, but increased slowly in the oxidative stage. Multiple regression analysis showed that the changes of Cu and Cd concentrations mainly depended on the changes of Fe/Mn morphology. Sulfur treatment promoted the dissolution of Fe/Mn oxides in the short term (<48 h), and the activities of CDGT-Fe, Mn, and Cd increased simultaneously, but CDGT-Cu was not affected. However, after long-term anaerobic conditions (>10 d), sulfur addition reduced the activities of CDGT-Cd and Cu, and decreased the uptake of Cd and Cu by rice. During sulfate reduction, the sulfur addition treatment group resulted in a 24.5-50.2 % decrease in CDGT-Fe, indicating that sulfur addition may delay the release of Cd and Cu after rice planting by promoting the formation of FeS/FeS2. In addition, in the anaerobic stage, Cu formed sulfide before Cd and was fixed, and the higher thermodynamic stability of CuS would promote the dissolution of CdS in the oxidation stage. Overall, soil flooding with sulfur to enhance the generation of metal sulfides and secondary iron ores provides an opportunity to use sulfur as an environmentally friendly modifier to coordinate Fe, Mn to improve heavy metal-contaminated soils.

3.
Chin Med ; 18(1): 6, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635742

RESUMO

BACKGROUND: Chemical profile provides the pronounced evidence for herbal medicine (HM) authentication; however, the chemome is extremely sophisticated. Fortunately, two-dimensional (2D) code, as a quick response means, is conceptually able to store abundant information, exactly fulfilling the chemical information storage demands of HMs. METHODS: We here attempted to denote both MS[Formula: see text] and MS[Formula: see text] dataset of HM with a single 2D-code chart. Measurement of Ganoderma lucidum that is one of the most famous HMs with LC-MS/MS was employed to illustrate the "coding-decoding" workflow for the conversion amongst MS/MS dataset, 2D-code, and chemical profile, and to evaluate the applicability as well. After data acquisition, and m/z value of each deprotonated molecular signal was divided into integer and decimal portions, corresponding to x and y coordinates of 2D-plot, respectively. On the other side, m/z values of all its fragment ions were exactly assigned to serial x values sharing an identical y value being equal to the precursor ion. 2D-code was thereafter produced by plotting these defined dots at a 2D-chart. Regarding a given 2D-code map, the entire chart (x coordinate: 0-600; y coordinate: 0-600) was fragmented into two regions by the line of y=x. MS[Formula: see text] spectral signals always located below the line, whereas all fragment ions lay at the left zone. After extracting information from the edges of each square frame, m/z values of both precursor ion and fragment ions could be harvested and putatively deciphered to a compound through applying some empirical mass fragmentation rules. RESULTS: The entire code of Ganoderma lucidum fruit bodies therefore corresponded exactly to a compound set. The elution program, even the employment of direct infusion, couldn't significantly impact the code, and dramatical differences occurred between different species and amongst different parts of Ganoderma lucidum as well. Not only ganoderic acid cluster but also certain primary metabolites served as the diagnostic compounds towards species differentiation. CONCLUSION: 2D-code might be a meaningful, practical visual way for rapid HM recognition because it is convenient to achieve the conversion amongst MS/MS dataset, 2D-barcode plot, and the chemome.

4.
Surg Endosc ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36690891

RESUMO

BACKGROUND: Few studies have evaluated the preoperative factors predicting the surgical difficulty of robotic distal pancreatectomy (RDP). This study aims to explore such factors and provide guidance on the selection of suitable patients to aid surgeons lacking extensive experience in RDP. METHODS: A retrospective study was conducted on consecutive patients who underwent RDP to identify preoperative factors predicting surgical difficulty. High surgical difficulty was defined by both operation time and intraoperative estimated blood loss exceeding their median, or by conversion to laparotomy. RESULTS: A total of 161 patients were ultimately enrolled, including 51 patients with high levels of surgical difficulty. Multivariate analysis revealed that male sex [OR (95% CI): 4.07 (1.77,9.40), p = 0.001], body mass index (BMI) ≥ 25 kg/m2 OR (95% CI): 2.27 (1.03,5.00), p = 0.042], tumors located at the neck of the pancreas [OR (95% CI): 4.15 (1.49,11.56), p = 0.006] and splenic artery type B [OR (95% CI): 3.28 (1.09,9.91), p = 0.035] were independent risk factors for surgical difficulty. Regarding postoperative complications, high surgical difficulty was associated with the risk of overall complications and pancreatic fistula (grade B/C) (49.0% vs. 22.7%, p < 0.001; 39.2% vs. 19.1%, p = 0.006). CONCLUSION: Male sex, body mass index ≥ 25 kg/m2, tumor located at the neck of the pancreas and splenic artery type B are associated with a high RDP difficulty level. These factors can be used preoperatively to assess the difficulty level of surgery, to help surgeons choose patients suitable for them and ensure surgical safety.

5.
Cancer Lett ; 555: 216049, 2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36608865

RESUMO

Triple-negative breast cancer (TNBC) is one of the most malignant tumors with poor prognosis. Methuosis is a new type of nonapoptotic cell death characterized by the accumulation of cytoplasmic vacuoles. In this study, we synthesized and screened a series of N-phenyl-4-pyrimidinediamine derivatives in TNBC cells, finding that DZ-514 was the best compound with high toxicity independent of the inhibition of BCL6. DZ-514 decreased cell viability, inhibited cell cycle progression, and induced caspase-independent cell death in TNBC cells. Interestingly, DZ-514 induced cytoplasm vacuolation, which could be blocked by Baf A1, the V-ATPase inhibitor. Furthermore, we found that DZ-514-induced vacuoles were derived from macropinosomes rather than autophagosomes. Most importantly, methuosis induced by DZ-514 was partially mediated by activating the ROS-MKK4-p38 axis. Finally, we demonstrated that DZ-514 significantly inhibited tumor growth in an HCC1806 xenograft mouse model. These findings revealed that the novel methuosis inducer DZ-514 could be developed for TNBC treatment.


Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/patologia , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Morte Celular , Apoptose , Endossomos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células
6.
Artigo em Inglês | MEDLINE | ID: mdl-36695823

RESUMO

PURPOSE: Our aim was to assess the prognostic value of [68 Ga]Ga-FAPI-04 positron emission tomography (PET) uptake in PDAC and to evaluate the correlation between in vivo lesional radioactivity with pathological characteristics of pancreatic ductal adenocarcinoma (PDAC). METHODS: We retrospectively analyzed treatment-naïve PDAC patients who underwent preoperative [68 Ga]Ga-FAPI-04 PET/CT followed by pancreatectomy. The tracer uptake was determined as maximum tumor standardized uptake value (SUVmax), FAPI-avid tumor volume (FTV), total lesion FAP expression (TLF) as well total pancreatic uptake (TSUVmax), total FAPI-avid pancreatic volume (FPV), and total pancreatic FAP expression (TPF). Spearman's correlation analysis was performed to evaluate the association between [68 Ga]Ga-FAPI-04 PET/CT imaging and ex vivo immunohistological FAP expression and pathological characteristics of surgical specimens (differentiation, size, vascularity, perineural invasion, and lymph node metastases). Kaplan-Meier and hazard ratio (HR, log-rank) methods were used to evaluate the prognostic value of [68 Ga]Ga-FAPI-04 PET/CT and clinicopathological factors. RESULTS: Thirty-seven surgical PDAC patients were included. The ex vivo expression of FAP was significantly associated with the tumor SUVmax and TLF. FAP expression was more abundant in poorly differentiated PDAC than in well- to moderately differentiated neoplasms. Tumor SUVmax or TLF and pancreatic TSUVmax or TPF were significantly correlated with tumor size, differentiation, and perineural invasion, respectively. SUVmax had a significant independent prognostic value for recurrence-free survival (HR = 2.46, P < 0.05), while [68 Ga]Ga-FAPI-04 TPF predicted overall survival (HR = 12.82, P < 0.05). CONCLUSION: The in vivo [68 Ga]Ga-FAPI-04 uptake in localized PDAC showed a significant correlation with ex vivo FAP expression and aggressive pathological characteristics. [68 Ga]Ga-FAPI-04 PET/CT also presented a potential for postoperative prognostication of PDAC. Elevated fibroblast activity induced by obstructive pancreatitis might be associated with the patient's survival.

7.
Chem Commun (Camb) ; 59(8): 1058-1061, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36606583

RESUMO

We demonstrate that target-activated cascade transcription amplification lights up RNA aptamers for label-free detection of metalloproteinase-2 (MMP-2) activity with zero background. This assay exhibits good specificity and high sensitivity with a limit of detection (LOD) of 0.6 fM. Moreover, it can analyze enzyme kinetic parameters, screen inhibitors, and accurately quantify MMP-2 in cancer cells and clinical serums.


Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Metaloproteinase 2 da Matriz , Aptâmeros de Nucleotídeos/genética , Limite de Detecção , Técnicas de Amplificação de Ácido Nucleico
8.
Adv Sci (Weinh) ; : e2203884, 2022 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-36563124

RESUMO

Triple-negative breast cancer (TNBC) has higher molecular heterogeneity and metastatic potential and the poorest prognosis. Because of limited therapeutics against TNBC, irradiation (IR) therapy is still a common treatment option for patients with lymph nodes or brain metastasis. Thus, it is urgent to develop strategies to enhance the sensitivity of TNBC tumors to low-dose IR. Here, the authors report that E3 ubiquitin ligase Ring finger protein 126 (RNF126) is important for IR-induced ATR-CHK1 pathway activation to enhance DNA damage repair (DDR). Mechanistically, RNF126 physically associates with the MRE11-RAD50-NBS1 (MRN) complex and ubiquitinates MRE11 at K339 and K480 to increase its DNA exonuclease activity, subsequent RPA binding, and ATR phosphorylation, promoting sustained DDR in a homologous recombination repair-prone manner. Accordingly, depletion of RNF126 leads to increased genomic instability and radiation sensitivity in both TNBC cells and mice. Furthermore, it is found that RNF126 expression is induced by IR activating the HER2-AKT-NF-κB pathway and targeting RNF126 expression with dihydroartemisinin significantly improves the sensitivity of TNBC tumors in the brain to IR treatment in vivo. Together, these results reveal that RNF126-mediated MRE11 ubiquitination is a critical regulator of the DDR, which provides a promising target for improving the sensitivity of TNBC to radiotherapy.

10.
J Transl Med ; 20(1): 605, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36527141

RESUMO

BACKGROUND: N6-methyladenosine (m6A) is the most prevalent epigenetic modification in eukaryotic messenger RNAs and plays a critical role in cell fate transition. However, it remains to be elucidated how m6A marks functionally impact the transcriptional cascades that orchestrate stem cell differentiation. The present study focuses on the biological function and mechanism of m6A methylation in dental pulp stem cell (DPSC) differentiation. METHODS: m6A RNA immunoprecipitation sequencing was utilized to assess the m6A-mRNA landscape during DPSC differentiation. Ectopic transplantation of DPSCs in immunodeficient mice was conducted to verify the in vitro findings. RNA sequencing and m6A RNA immunoprecipitation sequencing were combined to identify the candidate targets. RNA immunoprecipitation and RNA/protein stability of Noggin (NOG) were evaluated. The alteration in poly(A) tail was measured by 3'-RACE and poly(A) tail length assays. RESULTS: We characterized a dynamic m6A-mRNA landscape during DPSC mineralization with increasing enrichment in the 3' untranslated region (UTR). Methyltransferase-like 3 (METTL3) was identified as the key m6A player, and METTL3 knockdown disrupted functional DPSC differentiation. Moreover, METTL3 overexpression enhanced DPSC mineralization. Increasing m6A deposition in the 3' UTR restricted NOG expression, which is required for DPSC mineralization. This stage-specific m6A methylation and destabilization of NOG was suppressed by METTL3 knockdown only in differentiated DPSCs. Furthermore, METTL3 promotes the degradation of m6A-tagged NOG by shortening the poly(A) tail length in the differentiated stage. CONCLUSIONS: Our results address an essential role of dynamic m6A signaling in the temporal control of DPSC differentiation and provide new insight into epitranscriptomic mechanisms in stem cell-based therapy.


Assuntos
Adenosina , Metiltransferases , Camundongos , Animais , Metiltransferases/genética , Metiltransferases/metabolismo , Adenosina/metabolismo , Polpa Dentária , Diferenciação Celular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
11.
Front Bioeng Biotechnol ; 10: 1066651, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36532595

RESUMO

With growing concerns about environmental issues and sustainable economy, bioproduction of chemicals utilizing microbial cell factories provides an eco-friendly alternative to current petro-based processes. Creating high-performance strains (with high titer, yield, and productivity) through metabolic engineering strategies is critical for cost-competitive production. Commonly, it is inevitable to fine-tuning or rewire the endogenous or heterologous pathways in such processes. As an important pathway involved in the synthesis of many kinds of chemicals, the potential of the glyoxylate cycle in metabolic engineering has been studied extensively these years. Here, we review the metabolic regulation of the glyoxylate cycle and summarize recent achievements in microbial production of chemicals through tuning of the glyoxylate cycle, with a focus on studies implemented in model microorganisms. Also, future prospects for bioproduction of glyoxylate cycle-related chemicals are discussed.

12.
Artigo em Inglês | MEDLINE | ID: mdl-36542201

RESUMO

Subcortical brain regions play essential roles in the pathology of social anxiety disorder (SAD). While adolescence is the peak period of SAD, the relationships between altered development of the subcortical regions during this period and SAD are still unclear. This study investigated the age-dependent alterations in structural co-variance among subcortical regions and between subcortical and cortical regions, aiming to reflect aberrant coordination during development in the adolescent with SAD. High-resolution T1-weighted images were obtained from 76 adolescents with SAD and 67 healthy controls (HC), ranging from 11 to 17.9 years. Symptom severity was evaluated with the Social Anxiety Scale for Children (SASC) and the Depression Self Rating Scale for Children (DSRS-C). Structural co-variance and sliding age-window analyses were used to detect age-dependent group differences in inter-regional coordination patterns among subcortical regions and between subcortical and cortical regions. The volume of the striatum significantly correlated with SAD symptom severity. The SAD group exhibited significantly enhanced structural co-variance among key regions of the striatum (putamen and caudate). While the co-variance decreased with age in healthy adolescents, the co-variance in SAD adolescents stayed high, leading to more apparent group differences in middle adolescence. Moreover, the striatum's mean structural co-variance with cortical regions decreased with age in HC but increased with age in SAD. Adolescents with SAD suffer aberrant developmental coordination among the key regions of the striatum and between the striatum and cortical regions. The degree of incoordination is age-dependent, which may represent a neurodevelopmental trait of SAD.

13.
PeerJ ; 10: e14423, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36518298

RESUMO

Background: Soil erosion is a severe problem in the karst watershed, and analysis of soil erosion at the watershed scale is urgently needed. Methods: This study tried to estimate the soil erodibility factor (K-factor) using the Erosion Productivity Impact Calculator (EPIC) nomograph and evaluate the spatial distribution of the predicted K-factor in a karst watershed. Soil properties and K-factors of five land use types (NF: natural mixed forest, CF: cypress forest, EF: economic forest, ST: stone dike terrace, VF: vegetable land) in the Xialaoxi small watershed were compared and key factors affecting erodibility were analyzed. Results: Results showed that (1) The erodibility K-factor was unevenly distributed within different site types and strongly influenced by anthropogenic activities. The soil K-factors of sample sites subjected to frequent human disturbance (ST, VF) were high, ranging from 0.0480-0.0520 t hm2 h/(MJ mm hm2), while the soil K-factors of natural site types (NF, CF, and EF) were low, ranging from 0.0436-0.0448 t hm2 h/(MJ mm hm2). (2) The soil texture in the Xialaoxi watershed was mostly loamy, and that of the agricultural areas frequently disturbed by agricultural practices (ST, VF) was silty loam. (3) Soil carbon fractions were affected by land use types. Soil organic carbon storage of NF and CF had strong spatial heterogeneity. The soil organic carbon (SOC) and labile organic carbon (LOC) of the two were significantly higher than those of the disturbed EF and cultivated land soil. (4) There was a synergistic effect between the soil properties and the K-factor. K was significantly negatively related to sand fractions (2-0.05 mm) and non-capillary porosity, while positively related to silt content (0.05-0.002 mm). Overall, changes in bulk density (BD), total porosity (TP), non-capillary porosity (NCP), texture, and organic matter content caused by natural restoration or anthropogenic disturbance were the main reasons for soil erodibility. Natural care (sealing) and construction of stone dike planting practices were effective ways to reduce soil erosion in small karst watershed areas of western Hubei.


Assuntos
Carbono , Solo , Humanos , Solo/química , Carbono/análise , Agricultura , Florestas , Erosão do Solo
14.
Front Chem ; 10: 1052000, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36426103

RESUMO

Carotenoids from Lyciu m barbarum fruits have possessed pharmacological efficacy against eye diseases, cardiovascular disorders, cancer, and benign prostatic hyperplasia. However, the efficient extraction, rapid characterization and activities evaluation of Lycium carotenoids remains a challenge. To concentrate and characterize Lycium carotenoids, we have developed ultrasound-assisted extraction methods with different deep eutectic solvents (DESs) and analyzed carotenoids by ultra-performance convergence chromatography coupled with photo diode array detector and quadrupole time-of-flight mass spectrometry (UPC2-PDA-Q-TOF-MSE). DESs containing choline chloride and malonic acid presented better extraction efficiency and were more environmentally friendly than other extraction methods. Carotenoids were more quickly profiled (in 11 min) by UPC2 compared to by UPLC (in 35 min), with seventeen main peaks were characterized in the MS fragmentation patterns. The in vitro 5α-reductase inhibitory activity of DESs extracts, fractions and components were subsequently assessed, and the predominant component zeaxanthin dipalmitate (ZD) exhibited potent inhibitory activity. Our study provides a chemical and pharmacological basis for the further development of potential new drugs based on Lycium carotenoids.

15.
Plant Mol Biol ; 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36414883

RESUMO

Zinc (Zn) deficiency, caused by inadequate Zn intake in the human diet, has serious health implications. Rice (Oryza sativa) is the staple food in regions with a high incidence of Zn deficiency, so raising Zn levels in rice grain could help alleviate Zn deficiency. The wild relatives of cultivated rice vary widely in grain Zn content and thus are suitable resources for improving this trait. However, few loci underlying grain Zn content have been identified in wild rice relatives. Here, we identified a major quantitative trait locus for grain Zn content, Grain Zn Content 1 (qGZnC1), from Yuanjiang common wild rice (Oryza rufipogon Griff.) using map-based cloning. Down-regulating GZnC1 expression reduced the grain Zn content, whereas the presence of GZnC1 had the opposite effect, indicating that GZnC1 is involved in grain Zn content in rice. Notably, GZnC1 is identical to a previously reported gene, EMBRYO SAC ABORTION 1 (ESA1), involved in seed setting rate. The mutation in GZnC1/ESA1 at position 1819 (T1819C) causes delayed termination of protein translation. In addition, GZnC1 is specifically expressed in developing panicles. Several genes related to Zn-transporter genes were up-regulated in the presence of GZnC1. Our results suggest that GZnC1 activates Zn transporters to promote Zn distribution in panicles. Our work thus sheds light on the genetic mechanism of Zn accumulation in rice grain and provides a new genetic resource for improving Zn content in rice.

16.
Nurs Open ; 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36319594

RESUMO

AIM: The aim of the study was to develop an evidence-based care bundle protocol for preventing falls in hospitalized children. DESIGN: Delphi method. METHODS: Based on the four basic concepts of nursing, the theoretical dimension and item pool of the care bundle first draft were constructed by searching evidence and referring to the care bundle for preventing inpatient fall issues by the China Nursing Quality Promotion Alliance. The Delphi method and trial tests were used to select and adjust items of the care bundle to form the care bundle protocol for preventing falls in hospitalized children. RESULTS: The first draft care bundle for preventing falls in hospitalized children included 4 dimensions and 21 items. In the 2-round Delphi study, one item was removed, and three items were adjusted. One item was adjusted by trial test. Finally, the care bundle protocol for preventing falls in hospitalized children consisted of 4 dimensions and 20 items.

17.
Front Chem ; 10: 1040333, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36385996

RESUMO

Combretastatin A-4 (CA-4) is a potent inhibitor of tubulin polymerization and a colchicine binding site inhibitor (CBSI). The structure-activity relationship study of CA-4 showed that the cis double bond configuration and the 3,4,5-trimethoxy group on the A ring were important factors to maintain the activity of CA-4. Therefore, starting from this condition, chemists modified the double bond and also substituted 3,4,5-trimethoxyphenyl with various heterocycles, resulting in a new generation of CA-4 analogs such as chalcone, Flavonoid derivatives, indole, imidazole, etc. Quinoline derivatives have strong biological activity and have been sought after by major researchers for their antitumor activity in recent years. This article reviews the research progress of novel CA-4 containing quinoline analogs in anti-tumor from 1992 to 2022 and expounds on the pharmacological mechanisms of these effective compounds, including but not limited to apoptosis, cell cycle, tubulin polymerization inhibition, immune Fluorescence experiments, etc., which lay the foundation for the subsequent development of CA-4 containing quinoline analogs for clinical use.

18.
Molecules ; 27(21)2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36364321

RESUMO

Isoliquiritigenin (ISL) is a flavonoid with a chalcone structure extracted from the natural herb Glycyrrhiza glabra. Its anti-inflammatory, antibacterial, antioxidant, and anticancer activities have been extensively studied. Moreover, ISL also possess hypolipidemic and atherosclerosis-reducing effects. However, its cholesterol-lowering mechanisms have not been reported yet. Niemann Pick C1 Like 1 (NPC1L1) is a specific transporter of cholesterol uptake. In this study, we found for the first time that ISL downregulates NPC1L1 expression and competitively inhibits cellular cholesterol uptake by binding to NPC1L1 in a concentration-dependent manner in vitro. This study provides a theoretical basis for further investigation of the molecular mechanisms of its cholesterol-lowering effect in vivo and inspired emerging drug research for cholesterol-lowering purposes through NPC1L1 inhibition.


Assuntos
Anticolesterolemiantes , Chalconas , Chalconas/farmacologia , Transporte Biológico , Proteínas de Membrana Transportadoras/metabolismo , Colesterol/metabolismo , Anticolesterolemiantes/farmacologia
19.
Chem Commun (Camb) ; 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36448567

RESUMO

AIE-active phenyl- and [2.2]paracyclophanyl-based aurones (2-Ph and 2-PCP) were synthesized and investigated with different structures and photophysical properties. The results illustrated that the PCP ring can provide chirality, electron-donating ability and steric hindrance. Accordingly, (Rp)/(Sp)-2-PCP exhibit high sensitivity in trace water detection and aggregation-induced CPL with enhanced quantum yields and luminescence dissymmetry factors.

20.
J Mater Chem B ; 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36449302

RESUMO

Protein kinases play important roles in regulating various cellular processes and may function as potential diagnostic and therapeutic targets for various diseases including cancers. Herein, we construct a phos-tag-directed self-assembled fluorescent magnetobiosensor to simultaneously detect multiple protein kinases with good selectivity and high sensitivity. In the presence of protein kinases (i.e., PKA and Akt1), their substrate peptides (i.e., a FITC-labeled substrate peptide and a Cy5-labeled substrate peptide) are phosphorylated, and are then specifically recognized and captured by a biotinylated phos-tag to generate biotinylated substrate peptides for the assembly of magnetic bead (MB)-peptides-FITC/Cy5 nanostructures. After magnetic separation, the phosphorylated substrate peptides are disassembled from the MB-peptides-FITC/Cy5 nanostructures using deionized water at 80 °C, releasing FITC and Cy5 molecules. The released FITC and Cy5 molecules are detected by steady-state fluorescence measurements, with FITC indicating PKA and Cy5 indicating Akt1. This magnetobiosensor only involves one phos-tag without the requirement of radiolabeling, antibody screening, carboxypeptidase Y (CPY) cleavage, and cumbersome chemical/enzyme reactions. The introduction of magnetic separation can effectively eliminate the interference from complex real samples, generating an extremely low background signal. Moreover, this magnetobiosensor can accurately measure cellular protein kinase activities and screen inhibitors, with great potential for kinase-related biomedical research and therapeutic applications.

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