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1.
Colloids Surf B Biointerfaces ; 217: 112651, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35759892

RESUMO

Gene therapy holds great promise for treatment of gene-associated diseases. However, safe and successful clinical application urgently requires further advancement of constructing efficient delivery systems. Herein, three amphiphilic peptide dendrimers (TTC-L-KRR/KKK/KHH), containing the natural amino acid residues (lysine K, arginine R, and histidine H) and AIE-based photosensitizer (tetraphenylethenethiophene modified cyanoacrylate, TTC) modified with alkyl chain (L), have been designed and prepared for improving therapeutic potency via the combination of gene therapy (GT) and photodynamic therapy (PDT). All three compounds possessed typical aggregation-induced emission (AIE) characteristics and ultralow critical micelle concentrations (CMCs). The liposomes consisting of amphiphilic peptide dendrimers and dioleoylphosphatidylethanolamine (DOPE) can effectively bind DNA into nanoparticles with appropriate sizes, regular morphology and good biocompatibility. Among them, liposomes TTC-L-KKK/DOPE exhibited the highest transfection efficiency up to 5.7-fold as compared with Lipo2000 in HeLa cells. Meanwhile, rapid endocytosis, successful endo/lysosomal escape, gene release and rapid nuclear delivery of DNA revealed the superiority of liposomes TTC-L-KKK/DOPE during gene delivery process. More importantly, efficient reactive oxygen species (ROS) generation by TTC-L-KKK/DOPE led to effective PDT, thus improving therapeutic potency via combining with p53 mediated-gene therapy. Our work brought novel insight and direction for the construction of bio-safe and bio-imaging liposome as the multifunctional nonviral gene vectors for the effective combined gene/photodynamic therapies.

2.
Artigo em Inglês | MEDLINE | ID: mdl-35733628

RESUMO

Pulmonary fibrosis is a serious disease for which effective drugs are unavailable. Here, we treated rat models of bleomycin (BLM)-induced pulmonary fibrosis with Astragali Radix extract injection (AI) combined with or without bone marrow mesenchymal stem cells (BMSCs). We injected rats intratracheally with BLM and transplanted BMSCs via tail vein injection 15 days later. We also intraperitoneally injected AI daily from days 15 to 28. Changes in lung pathology and function, as well as the levels of matrix metalloproteinases, collagen, C-X-C motif chemokine ligand 12 (CXCL12), and cluster of differentiation 90 (CD90) were assessed. The results revealed that compared with the BLM group, groups treated with ARE and BMSCs (alone or combined) reduced the expression levels of TGF-ß1 and collagens I and III, ameliorated pathological lung fibrotic damage, and improved lung function. The expression levels of MMP-1, MMP-3, and MMP-9 were reduced by either AI or BMSCs alone, whereas those of MMP-3, MMP-9, TIMP-1, CXCL12, and CD90 were elevated by combined AI and BMSCs compared with the BLM group. Overall, these findings demonstrated that AI and BMSCs both can reduce damage caused by PF in rats and that AI altered the expression of chemokines and surface markers in BMSCs.

3.
Heart Rhythm O2 ; 3(3): 269-278, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35734294

RESUMO

Background: Catheter ablation is a current therapeutic approach for atrial fibrillation (AF). However, its efficacy for long-standing persistent AF remains suboptimal. Objective: The purpose of this study was to test the hypothesis that a panoramic mapping system (CARTOFINDER, Biosense Webster) can guide pulmonary vein (PV) isolation and additional potential AF drivers. Methods: A total of 76 patients with nonparoxysmal AF referred for ablation guided by a novel high-density panoramic mapping system with CARTOFINDER were prospectively enrolled. Of this cohort, 40 patients (52.6%) had long-standing persistent AF (CARTOFINDER group). We then retrospectively screened the patients with long-standing persistent AF undergoing conventional PV isolation and elimination of non-PV triggers during the contemporary period (conventional group). They were matched at a 1:2 ratio (40 patients in group 1 received ablation guided by CARTOFINDER; 80 patients in group 2 receiving conventional PV isolation and elimination of non-PV triggers). Results: During follow-up, patients in group 1 had a lower recurrence AF rate than those in group 2 (P = .040). There was no difference in recurrence of atrial flutter (P = .996) and atrial tachycardia (P = .525). In Cox proportional hazards regression analysis, AF duration and PV isolation along with AF driver ablation using a panoramic mapping system with CARTOFINDER both were independent predictors of recurrent AF after catheter ablation of long-standing persistent AF. Conclusion: Identification of the potential drivers in long-standing AF is crucial. Compared with conventional PV isolation and elimination of non-PV triggers, ablation guided by a high-density panoramic mapping system (CARTOFINDER) might have a better outcome in patients with long-standing persistent AF.

4.
Microbiol Spectr ; : e0032122, 2022 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-35658602

RESUMO

The hemin acquisition system of Stenotrophomonas maltophilia was elucidated in this study. To identify the TonB-dependent outer membrane receptor for hemin in S. maltophilia, the hemin acquisition systems of Pseudomonas aeruginosa were referenced. PhuR, HasA, and HxuA are three known TonB-dependent outer membrane receptors involved in hemin acquisition by P. aeruginosa. Thus, HemA (Smlt0795) and Smlt2937, the orthologs of PhuR and HasA/HxuA in S. maltophilia, were first considered. KJΔEnt, a stenobactin-null strain, was used as the parental strain for the hemin utilization assay. Deletion of hemA, but not Smlt2937, of KJΔEnt impaired hemin acquisition under iron-depleted conditions, indicating that HemA is the TonB-dependent receptor for hemin uptake. The hemA gene is a member of the hemP-hemA-smlt0796-smlt0797 operon, whose expression was upregulated in a fur mutant and under iron-depleted conditions. The contribution of the hemP-hemA-smlt0796-smlt0797 operon to hemin acquisition was investigated by in-frame deletion mutant construction and hemin utilization assays. Inactivation of hemP, smlt0796, and smlt0797 of KJΔEnt insignificantly affected hemin acquisition under iron-depleted conditions. However, hemP deletion in a fur mutant increased hemin acquisition under iron-depleted conditions. Collectively, we revealed that (i) HemA likely functions as the outer membrane receptor for hemin uptake; (ii) HemP, a predicted transcriptional factor, apparently functions as a repressor of the expression of the hemA transcript; and (iii) in a fur mutant, HemP has a negative impact on hemin acquisition under iron-depleted conditions. IMPORTANCE Stenotrophomonas maltophilia is an emerging multidrug-resistant opportunistic pathogen, increasing the difficulty of treatment of this infection. Iron is a critical element for bacterial viability. Heme is the most abundant iron source in the human host; thus, heme is the major iron source for a pathogen in the infection niche. Blocking iron acquisition from heme can be an alternative strategy to control S. maltophilia infection. Although several hemin acquisition systems have been reported in various pathogens, very little is known about the hemin acquisition systems of S. maltophilia. By in-frame deletion mutant construction and hemin utilization assays, we demonstrated that HemA (Smlt0795) is the TonB-dependent outer membrane receptor for hemin uptake and that HemP (Smlt0794), a predicted transcriptional factor, had a negative impact on hemin acquisition in a fur mutant. The negative regulatory role of HemP in hemin acquisition is first reported.

5.
Chem Commun (Camb) ; 58(52): 7245-7248, 2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35647676

RESUMO

Carbon monoxide (CO) plays an important role in signaling in cells, making its use as a therapeutic tool highly intriguing. Reduced burst emissions are important to avoid the cytotoxicity and tissue damage caused by CO. Here, we developed a stable diiron carbonyl [FeFe] hydrogenase agent that enables prolonged CO release activity (half-life of over 9 h) in cells. The integrated analysis allowed the identification of the key intermediate sites and CO accumulations with subcellular resolution. We observed that the [FeFe]A complex was enriched in neurons with S-methyl bond rupture. Furthermore, the [FeFe]A complex efficiently reduced the aggregation of tau proteins (49.3% reduction) and showed superior biocompatibility in nerve cells (∼ 95% survival).

6.
Front Endocrinol (Lausanne) ; 13: 858267, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35721762

RESUMO

A urine albumin/creatinine ratio (UACR) <30 mg/g is considered to be normal, while increased risk of incident hypertension and cardiovascular disease mortality in subjects with high normal UACR level had been observed. However, a mild elevated but normal UACR level was associated with the risk of initiating chronic kidney disease (CKD) is uncertain. We investigated whether higher normal UACR is associated with the risk of developing CKD. A total of 4821 subjects with type 2 diabetes mellitus (T2DM), an estimated glomerular filtration rate >60 ml/min/1.73 m2 and UACR <30 mg/g enrolled in a diabetes disease management program between 2006 and 2020 were studied. The optimal cutoff point for baseline UACR as a predictor for progression to CKD according to the 2012 KDIGO definition was calculated using receiving operating characteristic curve analysis. After a mean of 4.9 years follow-up, the CKD risk progression increased in parallel with the quartiles of baseline UACR <30 mg/g (p for trend <0.0001). UACR cutoff points of 8.44 mg/g overall, 10.59 mg/g in males and 8.15 mg/g in females were associated with the risk of CKD progression. In multivariate Cox regression analysis, the hazard ratios for the association between UACR (>8.44 mg/g, >10.9 mg/g, >8.15 mg/g in overall, male, and female patients, respectively) and the risk of CKD progression were significant. This study demonstrated that a cutoff UACR value of >10 mg/g could significantly predict the cumulative incidence and progression of CKD in patients with T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Albuminas , Albuminúria/complicações , Albuminúria/epidemiologia , Creatinina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Masculino , Insuficiência Renal Crônica/complicações
7.
J Pharm Biomed Anal ; 218: 114869, 2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-35688008

RESUMO

In present study, an integrating UPLC-QTOF-MS/MS chemical profiling and UPLC-TQ-MS/MS quantification strategy was developed for the holistic quality evaluation of Hibisci Mutabilis Folium (HMF), a traditional Chinese medicinal herb. Using UPLC-QTOF-MS/MS, a total of 58 components were characterized in HMF sample, of which 36 flavonoids, 3 coumarins, 7 organic acids and 4 triterpene acids were unambiguously identified by comparing the chromatographic behavior and mass spectrum with that of reference compounds, or tentatively assigned by comparing the fragmentation pathways and characteristic fragment ions with that of reference substances and/or published literatures together with mass defect filtering (MDF) screening. Meanwhile, 29 representative major components, including 16 flavonoids, 3 coumarins, 7 organic acids and 3 triterpene acids, were quantified by a newly established UPLC-TQ-MS/MS method that was validated in terms of linearity, sensitivity, precision, repeatability, accuracy and stability. The integrated strategy was applied to simultaneously qualifying and quantifying HMF commercial samples and self-prepared samples harvested in difference periods and dried with different methods. It was found that the contents of 29 major components were obviously different in commercial samples or self-prepared samples, suggesting that the holistic quality of HMF commercial samples was inconsistent, and harvesting period and drying method might be the main factors that affect the holistic quality consistency of commercial HMF samples. Standardized harvesting period and drying method should be established for ensuring the holistic quality consistency of HMF.


Assuntos
Medicamentos de Ervas Chinesas , Triterpenos , Cromatografia Líquida de Alta Pressão/métodos , Cumarínicos/análise , Medicamentos de Ervas Chinesas/química , Flavonoides/análise , Espectrometria de Massas em Tandem/métodos , Triterpenos/análise
8.
Anal Chem ; 94(23): 8547-8553, 2022 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-35653437

RESUMO

Laser ablation inductively coupled plasma mass spectrometry imaging of biologically significant targets largely relies on maintaining the original structures of samples. The temperature regulation capability of the ablation cell is crucial. Herein, a rapid cooling cryogenic sample cell (RCCSC) was developed. In the RCCSC chamber, the temperature reduces to -20 °C in 4 min with a minimum 10 h variation of ±0.1 °C at -26 °C. Improvements on the precision were achieved for the elements of interest in NIST 612 and spiked agarose gel under cryogenic conditions. The limits of detection improved by up to 1.57, 1.70, 3.26, and 1.33 fold for 63Cu, 66Zn, 57Fe, and 140Ce in agarose gel, respectively, were obtained under cryogenic conditions compared with those at room temperature. In a time period of testing (10 h), the cryogenic ablation maintains the native state of biological tissues with a high water content to ensure better elemental imaging by reducing thermal effects in ablation and suppressing evaporation of water. The rapid cooling cryogenic ablation significantly improves elemental imaging, as demonstrated by the imaging of various elements in coriander leaves. The present study may provide further insights into elemental distributions in fresh biological samples.


Assuntos
Terapia a Laser , Diagnóstico por Imagem , Espectrometria de Massas/métodos , Sefarose , Água
10.
Materials (Basel) ; 15(12)2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35744157

RESUMO

In wire electrical discharge machining, due to the random distribution of the insulating SiC particles, frequent wire rupture, low machining efficiency and surface quality when the common brass wire electrode (BWE) is used to process high-volume content SiCp/Al composite often appears. To address this issue, this paper proposes a new preparation method of zinc coating and surface microstructure on wire electrodes (ZCSMWE). The preparation process of ZCSMWE includes casting, coating, annealing and plastic processing. The experimental results show that, compared with BWE, ZCSMWE can increase material removal rate (MRR) by 16.67%, reduce surface roughness (Ra) by 21.18% and reduce wire rupture under the same discharge parameters. The analysis of workpiece surface topography shows that ZCSMWE can significantly decrease the recast layer and microcrack on the machined surface. The improvement mechanism of ZCSMWE main includes: The low work function zinc can promote the forming of the discharge channel. The vaporization of low boiling temperature zinc can reduce the temperature of the discharge gap and promote the ejecting of workpiece material. In addition, the surface microstructure on ZCSMWE can make the discharge spark more uniformly distributed and increase the proportion of the effective discharge, which contributes to making the discharge crater on the workpiece and wire electrode shallower and more uniform. The surface microstructure on ZCSMWE can also effectively improve the dielectric circulation, which can promote discharge debris to be expelled out and reduce the temperature in the discharge gap. Then, the wire rupture and microcracks on the workpiece surface can be reduced.

11.
Int J Mol Sci ; 23(12)2022 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-35742970

RESUMO

In the present study, molecularly imprinted polymers (MIPs) were used as a tool to grasp a targeted α-helix or ß-sheet of protein. During the fabrication of the hinge-mediated MIPs, elegant cavities took shape in a special solvent on quartz crystal microbalance (QCM) chips. The cavities, which were complementary to the protein secondary structure, acted as a peptide conformational imprint (PCI) for adenylate kinase 1 (AK1). We established a promising strategy to examine the binding affinities of human AK1 in conformational dynamics using the peptide-imprinting method. Moreover, when bound to AK1, PCIs are able to gain stability and tend to maintain higher catalytic activities than free AK1. Such designed fixations not only act on hinges as accelerators; some are also inhibitors. One example of PCI inhibition of AK1 catalytic activity takes place when PCI integrates with an AK19-23 ß-sheet. In addition, conformation ties, a general MIP method derived from random-coil AK1133-144 in buffer/acetonitrile, are also inhibitors. The inhibition may be due to the need for this peptide to execute conformational transition during catalysis.


Assuntos
Impressão Molecular , Adenilato Quinase/química , Humanos , Impressão Molecular/métodos , Peptídeos/química , Proteínas , Técnicas de Microbalança de Cristal de Quartzo/métodos
12.
Resuscitation ; 2022 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-35750286

RESUMO

BACKGROUND: We aimed to identify distinct trajectories of end-tidal carbon dioxide (EtCO2) during cardiopulmonary resuscitation in patients with out-of-hospital cardiac arrest (OHCA) and to investigate the association between EtCO2 trajectories and OHCA outcomes. METHODS: This was a secondary analysis of a prospectively collected database on adult patients with OHCA who had been resuscitated in the emergency department of a tertiary medical center between 2015 and 2020. The primary outcome was the return of spontaneous circulation (ROSC). Group-based trajectory modelling was used to identify the EtCO2 trajectories. Multivariable logistic regression analysis was performed to evaluate the association between EtCO2 trajectories and ROSC. The predictive performance of the EtCO2 trajectories was assessed using the area under the receiver operating characteristic curve (AUC). RESULTS: The study comprised 655 patients with OHCA. In the primary analysis, three distinct EtCO2 trajectories, including 10-mmHg, 30-mmHg, and 50-mmHg trajectories, were identified. Compared with the 10-mmHg trajectory, both 30-mmHg (odds ratio [OR]: 4.66, 95% confidence interval [CI]: 3.15-6.90) and 50-mmHg (OR: 7.58, 95% CI: 4.30-13.35) trajectories were associated with a higher likelihood of ROSC. In a sensitivity analysis of excluding EtCO2 measured before tracheal intubation or after sodium bicarbonate administration, the predictive ability of the identified EtCO2 trajectories remained. As a single predictor of ROSC, EtCO2 trajectories had an acceptable discriminative performance (AUC: 0.69, 95% CI: 0.66-0.73). CONCLUSION: Three distinct EtCO2 trajectories during cardiopulmonary resuscitation were identified and significantly associated with outcomes. Early identification of these EtCO2 trajectories could potentially guide the ongoing resuscitation efforts.

13.
J Clin Med ; 11(11)2022 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-35683600

RESUMO

Identification of sinus node dysfunction (SND) before termination of persistent AFL by catheter ablation (CA) is challenging. This study aimed to investigate the characteristics and predictors of acute and delayed SND after AFL ablation. We retrospectively enrolled 221 patients undergoing CA of persistent AFL in a tertiary referral center. Patients with SND who required a temporary pacemaker (TPM) after termination of AFL or a permanent pacemaker (PPM) during follow-up were identified. Acute SND requiring a TPM was found in 14 of 221 (6.3%) patients following successful termination of AFL. A total of 10 of the 14 patients (71.4%) recovered from acute SND. An additional 11 (5%) patients presenting with delayed SND required a PPM during follow-up, including 4 patients recovering from acute SND. Of these, 9 of these 11 patients (81.8%) underwent PPM implantation within 1 year after the ablation. In multivariable analysis, female gender and a history of hypothyroidism were associated with the requirement for a TPM following termination of persistent AFL, while older age and a history of hypothyroidism predicted PPM implantation. This study concluded that the majority of patients with acute SND still require a PPM implantation despite the initial improvement. Therefore, it is reasonable to monitor the patients closely for at least one year after AFL ablation.

14.
Cell Biosci ; 12(1): 78, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35642004

RESUMO

BACKGROUND: Mental retardation is a complex neurodevelopmental disorder. NPAT, a component of the histone locus body (HLB), has been implicated as a candidate gene for mental retardation, with a mechanism yet to be elucidated. RESULTS: We identified that mxc, the Drosophila ortholog of NPAT, is required for the development of nervous system. Knockdown of mxc resulted in a massive loss of neurons and locomotion dysfunction in adult flies. In the mxc mutant or RNAi knockdown larval brains, the neuroblast (NB, also known as neural stem cell) cell fate is prematurely terminated and its proliferation potential is impeded concurrent with the blocking of the differentiation process of ganglion mother cells (GMCs). A reduction of transcription levels of histone genes was shown in mxc knockdown larval brains, accompanied by DNA double-strand breaks (DSBs). The subsidence of histone transcription levels leads to prematurely termination of NB cell fate and blockage of the GMC differentiation process. Our data also show that the increase in autophagy induced by mxc knockdown in NBs could be a defense mechanism in response to abnormal HLB assembly and premature termination of NB cell fate. CONCLUSIONS: Our study demonstrate that Mxc plays a critical role in maintaining neural stem cell fate and GMC differentiation in the Drosophila larval brain. This discovery may shed light on the understanding of the pathogenesis of NPAT-related mental retardation in humans.

15.
Microbiol Spectr ; : e0244821, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35647692

RESUMO

Stenotrophomonas maltophilia, a nonfermenting Gram-negative rod, is frequently isolated from the environment and is emerging as a multidrug-resistant global opportunistic pathogen. S. maltophilia harbors eight RND-type efflux pumps that contribute to multidrug resistance and physiological functions. Among the eight efflux pumps, SmeYZ pump is constitutively highly expressed. In our previous study, we demonstrated that loss-of-function of the SmeYZ pump results in pleiotropic phenotypes, including abolished swimming motility, decreased secreted protease activity, and compromised tolerance to oxidative stress and antibiotics. In this study, we attempted to elucidate the underlying mechanisms responsible for ΔsmeYZ-mediated pleiotropic phenotypes. RNA-seq transcriptome analysis and subsequent confirmation with qRT-PCR revealed that smeYZ mutant experienced an iron starvation response because the genes involved in the synthesis and uptake of stenobactin, the sole siderophore of S. maltophilia, were significantly upregulated. We further verified that smeYZ mutant had low intracellular iron levels via inductively coupled plasma mass spectrometry (ICP-MS). Also, KJΔYZ was more sensitive to 2,2'-dipyridyl (DIP), a ferrous iron chelator, in comparison with the wild type. The contribution of SmeYZ, SmeDEF, and SbiAB pumps to stenobactin secretion was suggested by qRT-PCR and further verified by Chrome Azurol S (CAS) activity, iron source utilization, and cell viability assays. We also demonstrated that loss-of-function of SmeYZ led to the compensatory upregulation of SbiAB and SmeDEF pumps for stenobactin secretion. The overexpression of the SbiAB pump resulted in a reduction in intracellular iron levels, which may be the key factor responsible for the ΔsmeYZ-mediated pleiotropic phenotypes, except for antibiotic extrusion. IMPORTANCE Efflux pumps display high efficiency of drug extrusion, which underlies their roles in multidrug resistance. In addition, efflux pumps have physiological functions, and their expression is tightly regulated by various environmental and physiological signals. Functional redundancy of efflux pumps is commonly observed, and mutual regulation occurs among these functionally redundant pumps in a bacterium. Stenotrophomonas maltophilia is an opportunistic pathogen that shows intrinsic multi-drug resistance. In this study, we demonstrated that SmeYZ, SbiAB, and SmeDEF efflux pumps of S. maltophilia display functional redundancy in siderophore secretion. Inactivation of smeYZ led to the upregulation of smeDEF and sbiAB. Unexpectedly, sbiAB overexpression resulted in the reduction of intracellular iron levels, which led to pleiotropic defects in smeYZ mutant. This study demonstrates a previously unidentified connection between efflux pumps, siderophore secretion, and intracellular iron levels in S. maltophilia.

16.
Front Cell Infect Microbiol ; 12: 915099, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35719361

RESUMO

Sepsis, a life-threatening organ dysfunction, is not caused by direct damage of pathogens and their toxins but by the host's severe immune and metabolic dysfunction caused by the damage when the host confronts infection. Previous views focused on the damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), including metabolic proinflammatory factors in sepsis. Recently, new concepts have been proposed to group free fatty acids (FFAs), glucose, advanced glycation end products (AGEs), cholesterol, mitochondrial DNA (mtDNA), oxidized phospholipids (OxPLs), ceramides, and uric acid into metabolism-associated molecular patterns (MAMPs). The concept of MAMPs will bring new guidance to the research and potential treatments of sepsis. Nowadays, sepsis is regarded as closely related to metabolic disorders, and MAMPs play an important role in the pathogenesis and development of sepsis. According to this view, we have explained MAMPs and their possible roles in the pathogenesis of sepsis. Next, we have further explained the specific functions of different types of MAMPs in the metabolic process and their interactional relationship with sepsis. Finally, the therapeutic prospects of MAMPs in sepsis have been summarized.


Assuntos
Sepse , Alarminas , Humanos , Mitocôndrias/metabolismo , Padrões Moleculares Associados a Patógenos
17.
J Cancer ; 13(7): 2061-2073, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35517429

RESUMO

Egl-9 Family Hypoxia Inducible Factor 1 (EGLN1) is a proline hydroxylase mediating degradation of hypoxia-inducible factor α (HIFα) through the ubiquitination system. Studies have indicated an essential role for EGLN1 in angiogenesis and tumorigenesis. However, there is no consensus on the regulation of EGLN1 and its mechanism of action on nasopharyngeal carcinoma (NPC). This study explored the association of the expression of EGLN1 with characteristics of NPC tumors and its underlying mechanism. We found that the expression of EGLN1 showed a positive correlation with tumor T classification and clinical staging of patients with NPC. EGLN1 could promote cell proliferation, invasion and migration, and even enhance the cancer stem cells (CSCs) prosperity and radioresistance of NPC cells. Mechanistically, EGLN1 facilitated degradation of tumor protein p53 through the ubiquitination system. This effect could be weakened in the presence of dimethyloxalylglycine (DMOG), suggesting that EGLN1 down-regulated p53 based on its hydroxylase activity. In conclusion, overexpression of EGLN1 promoted oncogenesis and induced a CSC-like phenotype in NPC cells, then enhancing the ability for radioresistance by interacting with p53 in a hydroxylase-dependent manner. Thus, EGLN1 might serve as a potential therapeutic target for NPC.

18.
Front Mol Neurosci ; 15: 844668, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35600071

RESUMO

Cingulin, a cytoplasmic element of tight junctions (TJs), is involved in maintenance of the integrity of epithelial and endothelial cells. However, the role of cingulin in the development of auditory organs remains unclear. Zebrafish is popular as a model organism for hearing research. Using the whole mount in situ hybridization (WISH) experiment, we detected the expression of cingulin b in the posterior lateral line system (PLLs) of zebrafish. We traced the early development progress of zebrafish PLLs from 36 hpf to 72 hpf, and found that inhibition of cingulin b by target morpholinos resulted in severe developmental obstruction, including decreased number of neuromasts, reduced proliferative cells in the primordium, and repressed hair cell differentiation in the neuromasts. To examine the potential mechanism of cingulin b in the development of zebrafish PLL neuromasts, we performed RNA-seq analysis to compare the differently expressed genes (DEGs) between cingulin b knockdown samples and the controls. The KEGG enrichment analysis revealed that MAPK signaling pathway and cellular senescence were the key pathways with most DEGs in cingulin b-MO morphants compared to the Control-MO embryos. Furthermore, quantitative RT-PCR analysis confirmed the findings by RNA-seq that the transcript levels of cell cycle negative regulators such as tp53 and cdkn1a, were remarkably upregulated after inhibition of cingulin b. Our results therefore indicated an important role of cingulin b in the development of auditory organs, and MAPK signaling pathway was inhibited while cellular senescence pathway was activated after downregulation of cingulin b. We bring forward new insights of cingulin by exploring its function in auditory system.

20.
Drug Deliv ; 29(1): 1370-1383, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35532094

RESUMO

Brain cancer is the most aggressive one among various cancers. It has a drastic impact on people's lives because of the failure in treatment efficacy of the currently employed strategies. Various strategies used to relieve pain in brain cancer patients and to prolong survival time include radiotherapy, chemotherapy, and surgery. Nevertheless, several inevitable limitations are accompanied by such treatments due to unsatisfactory curative effects. Generally, the treatment of cancers is very challenging due to many reasons including drugs' intrinsic factors and physiological barriers. Blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) are the two additional hurdles in the way of therapeutic agents to brain tumors delivery. Combinatorial and targeted therapies specifically in cancer show a very promising role where nanocarriers' based formulations are designed primarily to achieve tumor-specific drug release. A dual-targeting strategy is a versatile way of chemotherapeutics delivery to brain tumors that gets the aid of combined ligands and mediators that cross the BBB and reaches the target site efficiently. In contrast to single targeting where one receptor or mediator is targeted, the dual-targeting strategy is expected to produce a multiple-fold increase in therapeutic efficacy for cancer therapy, especially in brain tumors. In a nutshell, a dual-targeting strategy for brain tumors enhances the delivery efficiency of chemotherapeutic agents via penetration across the blood-brain barrier and enhances the targeting of tumor cells. This review article highlights the ongoing status of the brain tumor therapy enhanced by nanoparticle based delivery with the aid of dual-targeting strategies. The future perspectives in this regard have also been highlighted.


Assuntos
Neoplasias Encefálicas , Nanopartículas , Barreira Hematoencefálica , Encéfalo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Sistemas de Liberação de Medicamentos , Humanos
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