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1.
Int J Drug Policy ; 130: 104508, 2024 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-38972146

RESUMEN

BACKGROUND: Public health scholars informed by a dominant biomedical paradigm have in their 'rush to risk' emphasised the problematic aspects of chemsex. Meanwhile, critical chemsex scholars have attemped to destigmatise such sexual-chemical practices and foreground how they can be transformative. Taking these two perspectives as points of departure, we make a case for understanding chemsex vis-à-vis Deleuzean lines of flight. METHODS: Semi-structured in-depth interviews were conducted with 33 purposively sampled sexual minority men seeking therapy for chemsex dependency in Singapore. Interview topics included participants' experiences and histories of chemsex, substance use, and their ongoing recovery. Interviews were audio-recorded, transcribed and then analysed according to key themes. RESULTS: We illustrate how chemically inflected sexual encounters can offer deterritorialising flights of fantasy and freedom from a heteronormative social structure that pathologises gay sex. At the same time, we argue that these flight lines are not static, neither do they extend indefinitely in space-time. Rather, we show how flights of freedom can evolve into lines of fright (or non-flight) when chemsex practitioners are met with critical thresholds that reveal the less-than-desirable aspects of being intoxicated. Consequently, they may eventually consider the reterritorialisation of their lives (i.e. abstinence and recovery) as a more constructive option. Regardless of their decisions to ride on chemically-induced flight lines or to take a step back from such deterritorialising pathways, they have troubled stereotypical perspectives of drug users as passive automatons. CONCLUSIONS: This paper enriches the chemsex scholarship by presenting a Deleuzean conceptualisation of chemical-sexual intimacies without romantacising and/or overstating the 'escape'/'freedom' that chemsex can facilitate. Future research in this arena could explore the complicated intimate relationships that users may have with their drug(s) of choice, and their varied lines of (non-)flight over a longitudinal study.

2.
Int J Mol Sci ; 25(13)2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-39000118

RESUMEN

Multidrug-resistant P. aeruginosa infections pose a serious public health threat due to the rise in antimicrobial resistance. Phage therapy has emerged as a promising alternative. However, P. aeruginosa has evolved various mechanisms to thwart phage attacks, making it crucial to decipher these resistance mechanisms to develop effective therapeutic strategies. In this study, we conducted a forward-genetic screen of the P. aeruginosa PA14 non-redundant transposon library (PA14NR) to identify dominant-negative mutants displaying phage-resistant phenotypes. Our screening process revealed 78 mutants capable of thriving in the presence of phages, with 23 of them carrying insertions in genes associated with membrane composition. Six mutants exhibited total resistance to phage infection. Transposon insertions were found in genes known to be linked to phage-resistance such as galU and a glycosyl transferase gene, as well as novel genes such as mexB, lasB, and two hypothetical proteins. Functional experiments demonstrated that these genes played pivotal roles in phage adsorption and biofilm formation, indicating that altering the bacterial membrane composition commonly leads to phage resistance in P. aeruginosa. Importantly, these mutants displayed phenotypic trade-offs, as their resistance to phages inversely affected antibiotic resistance and hindered biofilm formation, shedding light on the complex interplay between phage susceptibility and bacterial fitness. This study highlights the potential of transposon mutant libraries and forward-genetic screens in identifying key genes involved in phage-host interactions and resistance mechanisms. These findings support the development of innovative strategies for combating antibiotic-resistant pathogens.


Asunto(s)
Elementos Transponibles de ADN , Biblioteca de Genes , Mutación , Pseudomonas aeruginosa , Pseudomonas aeruginosa/virología , Pseudomonas aeruginosa/genética , Elementos Transponibles de ADN/genética , Biopelículas/crecimiento & desarrollo , Bacteriófagos/genética , Bacteriófagos/fisiología
3.
Autophagy ; : 1-23, 2024 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-38963021

RESUMEN

The commonality between various muscle diseases is the loss of muscle mass, function, and regeneration, which severely restricts mobility and impairs the quality of life. With muscle stem cells (MuSCs) playing a key role in facilitating muscle repair, targeting regulators of muscle regeneration has been shown to be a promising therapeutic approach to repair muscles. However, the underlying molecular mechanisms driving muscle regeneration are complex and poorly understood. Here, we identified a new regulator of muscle regeneration, Deaf1 (Deformed epidermal autoregulatory factor-1) - a transcriptional factor downstream of foxo signaling. We showed that Deaf1 is transcriptionally repressed by FOXOs and that DEAF1 targets to Pik3c3 and Atg16l1 promoter regions and suppresses their expression. Deaf1 depletion therefore induces macroautophagy/autophagy, which in turn blocks MuSC survival and differentiation. In contrast, Deaf1 overexpression inactivates autophagy in MuSCs, leading to increased protein aggregation and cell death. The fact that Deaf1 depletion and its overexpression both lead to defects in muscle regeneration highlights the importance of fine tuning DEAF1-regulated autophagy during muscle regeneration. We further showed that Deaf1 expression is altered in aging and cachectic MuSCs. Manipulation of Deaf1 expression can attenuate muscle atrophy and restore muscle regeneration in aged mice or mice with cachectic cancers. Together, our findings unveil an evolutionarily conserved role for DEAF1 in muscle regeneration, providing insights into the development of new therapeutic strategies against muscle atrophy.Abbreviations: DEAF1: Deformed epidermal autoregulatory factor-1; FOXO: Forkhead box O; MuSC: Muscle Stem Cell; PAX7: Paired box 7; PIK3C3: Phosphatidylinositol 3-kinase catalytic subunit type 3.

4.
STAR Protoc ; 5(3): 103197, 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39028618

RESUMEN

Small extracellular vesicles (sEVs) are lipid bilayer-enclosed particles secreted by living cells. Here, we present a protocol for the collection and isolation of sEVs derived from human umbilical cord mesenchymal stem cells (hucMSCs). We describe steps for characterizing their morphology and integrity by transmission electron microscopy (TEM) and size distribution using nanoparticle tracking analysis (NTA) and an atomic force microscope (AFM). We then detail procedures for assessing nanoparticle size analysis and molecular markers by western blotting and Flow NanoAnalyzer.

5.
Ecotoxicol Environ Saf ; 281: 116667, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38964068

RESUMEN

Elucidating the absorption and translocation of heavy metal(loid)s by common vegetables across different growth environments and stages is crucial for conducting accurate environmental risk assessments and for associated control. This study investigated temporal variations in the absorption and translocation capacities of pak choi (Brassica rapa L.) for As, Cd, Cr, Cu, Pb, and Zn in polluted soils during the plant growth cycle under greenhouse and open-field cultivation modes. Results showed high root metal(loid) bioconcentration factors and root-to-shoot translocation factors for Cd (0.25 and 1.44, respectively) and Zn (0.26 and 1.01), but low values for As (0.06 and 0.88) and Pb (0.06 and 0.87). The Cd concentration in the aerial edible parts peaked during the early slow growth period, whereas other heavy metal(loid)s peaked during the later stable maturity period. Root bioconcentration and root-to-shoot translocation factors did not significantly differ between cultivation modes. However, greenhouse cultivation exhibited lower average Cd and Zn concentrations in the edible parts and cumulative uptake amounts of most metal(loid)s than open-field cultivation during the typical harvest period spanning days 60 and 90. Short-term transitioning from open-field to greenhouse cultivation may reduce health risks associated with heavy metal(loid) intake via pak choi consumption. These findings facilitate sustainable agricultural practices and food safety management.


Asunto(s)
Brassica rapa , Metales Pesados , Raíces de Plantas , Contaminantes del Suelo , Contaminantes del Suelo/metabolismo , Metales Pesados/metabolismo , Brassica rapa/crecimiento & desarrollo , Brassica rapa/metabolismo , Raíces de Plantas/metabolismo , Monitoreo del Ambiente/métodos , Brotes de la Planta/metabolismo , Brotes de la Planta/crecimiento & desarrollo , Suelo/química , Agricultura/métodos
6.
Org Lett ; 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-39023295

RESUMEN

2(3H)-Furanones are tremendously important not only because of their wide occurrence in bioactive compounds but also due to their versatility in organic synthesis. Here, a straightforward approach to 2(3H)-furanones from readily available tertiary propargylic alcohols with arylboronic acids in the presence of CO using rhodium as a catalyst has been established. The method exhibits a broad substrate scope tolerating useful functional groups with a moderate to high stereoselectivity.

7.
Chemistry ; : e202401815, 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38925594

RESUMEN

The first aerobic protocol of direct transformation of p-methoxybenzyl (PMB) ethers to carboxylic acids efficiently with Fe(NO3)3•9H2O and TEMPO as catalysts at room temperature has been developed. The reaction accommodates C-Br bond, terminal/non-terminal C-C triple bond, amide, cyano, nitro, ester, and trifluoromethyl groups, etc. Even highly selective oxidative deprotection of different benzylic PMB ethers has been realized. The reaction has been successfully applied to the total synthesis of natural product, (R)-6-hydroxy-7,9-octadecadiynoic acid, demonstrating the practicality of the method. Based on experimental studies, a possible mechanism involving oxygen-stabilized benzylic cation has been proposed.

8.
J Nanobiotechnology ; 22(1): 339, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38890734

RESUMEN

Diabetic kidney disease (DKD), a chronic kidney disease, is characterized by progressive fibrosis caused due to persistent hyperglycemia. The development of fibrosis in DKD determines the patient prognosis, but no particularly effective treatment. Here, small extracellular vesicles derived from mesenchymal stem cells (MSC-sEV) have been used to treat DKD fibrosis. Single-cell RNA sequencing was used to analyze 27,424 cells of the kidney, we have found that a novel fibrosis-associated TGF-ß1+Arg1+ macrophage subpopulation, which expanded and polarized in DKD and was noted to be profibrogenic. Additionally, Actin+Col4a5+ mesangial cells in DKD differentiated into myofibroblasts. Multilineage ligand-receptor and cell-communication analysis showed that fibrosis-associated macrophages activated the TGF-ß1/Smad2/3/YAP signal axis, which promotes mesangial fibrosis-like change and accelerates renal fibrosis niche. Subsequently, the transcriptome sequencing and LC-MS/MS analysis indicated that MSC-sEV intervention could restore the levels of the kinase ubiquitin system in DKD and attenuate renal interstitial fibrosis via delivering CK1δ/ß-TRCP to mediate YAP ubiquitination degradation in mesangial cells. Our findings demonstrate the unique cellular and molecular mechanisms of MSC-sEV in treating the DKD fibrosis niche at a single-cell level and provide a novel therapeutic strategy for renal fibrosis.


Asunto(s)
Nefropatías Diabéticas , Vesículas Extracelulares , Fibrosis , Células Madre Mesenquimatosas , Análisis de la Célula Individual , Transcriptoma , Vesículas Extracelulares/metabolismo , Células Madre Mesenquimatosas/metabolismo , Animales , Ratones , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/terapia , Masculino , Ratones Endogámicos C57BL , Humanos , Macrófagos/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismo , Células Mesangiales/metabolismo , Riñón/patología , Riñón/metabolismo
9.
Sci Total Environ ; 945: 173959, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-38879038

RESUMEN

Quantifying the source contributions of sediments in large fluvial systems with active wind erosion problems has crucial implications for understanding morphological evolution and ecological progression in the Earth system. Much effort have been focused on characterizing sediments of the Yellow River, but quantitation of the sediment source proportions at the basin-wide scale is lacking. To this end, the research aims to quantitatively elucidate the potential source contributions of sediments in the Yellow River based on geochemical characteristics and sediment fingerprinting technique, in order to identify sedimentary mixing effect and propose sustainable development strategies. In total, samples of four source groups (n = 107) and target floodplain sediments (n = 61) were collected and tested for elemental composition, grain size, magnetic susceptibility, and quartz grain microtextures. The results indicated that the optimal tracer combination was determined as P, Zn, and Ca. The average contributions of the "Tibetan Plateau", "Sandy deserts-Loess Plateau", "Loess Plateau", and "Loess Plateau-Qinling Mountains" source groups to the target sediments were 23.0 %, 21.5 %, 31.6 %, and 23.9 %, respectively. The accuracy of source apportionments was supported by the goodness of fit (GOF) and virtual mixtures tests. Meanwhile, large amounts of debris from surrounding mountains was transported to the Loess Plateau through fluvial processes and ultimately mixed with aeolian deposits, leading to sedimentary mixing effect. To maintain water balance and minimize erosion risk, the drought-resistant perennial planting and moderate grazing were recommended. The findings are instrumental in promoting soil and water conservation and disclosing fluvial and aeolian interaction on a global scale.

10.
J Dig Dis ; 25(4): 255-265, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38837552

RESUMEN

OBJECTIVES: In this study we aimed to assess the impact of acetylation of hepatocyte nuclear factor 4α (HNF4α) on lysine 458 on the differentiation therapy of hepatocellular carcinoma (HCC). METHODS: Periodic acid-Schiff (PAS) staining, Dil-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake, and senescence-associated ß-galactosidase (SA-ß-gal) activity analysis were performed to assess the differentiation of HCC cells. HNF4α protein was detected by western blot and immunohistochemistry (IHC). The effects of HNF4α-K458 acetylation on HCC malignancy were evaluated in HCC cell lines, a Huh-7 xenograft mouse model, and an orthotopic model. The differential expression genes in Huh-7 xenograft tumors were screened by RNA-sequencing analysis. RESULTS: K458R significantly enhanced the inhibitory effect of HNF4α on the malignancy of HCC cells, whereas K458Q reduced the inhibitory effects of HNF4α. Moreover, K458R promoted, while K458Q decreased, HNF4α-induced HCC cell differentiation. K458R stabilized HNF4α, while K458Q accelerated the degradation of HNF4α via the ubiquitin proteasome system. K458R also enhanced the ability of HNF4α to inhibit cell growth of HCC in the Huh-7 xenograft mouse model and the orthotopic model. RNA-sequencing analysis revealed that inhibiting K458 acetylation enhanced the transcriptional activity of HNF4α without altering the transcriptome induced by HNF4α in HCC. CONCLUSION: Our data revealed that inhibiting K458 acetylation of HNF4α might provide a more promising candidate for differential therapy of HCC.


Asunto(s)
Carcinoma Hepatocelular , Diferenciación Celular , Factor Nuclear 4 del Hepatocito , Neoplasias Hepáticas , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Acetilación , Animales , Humanos , Ratones , Línea Celular Tumoral , Lisina/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Cell Death Dis ; 15(6): 416, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38879600

RESUMEN

Tripartite motif 8 (TRIM8) is an E3 ligase that plays dual roles in various tumor types. The biological effects and underlying mechanism of TRIM8 in hepatocellular carcinoma (HCC) remain unknown. Hepatocyte nuclear factor 1α (HNF1α) is a key transcriptional factor that plays a significant role in regulating hepatocyte differentiation and liver function. The reduced expression of HNF1α is a critical event in the development of HCC, but the underlying mechanism for its degradation remains elusive. In this study, we discovered that the expression of TRIM8 was upregulated in HCC tissues, and was positively correlated with aggressive tumor behavior of HCC and shorter survival of HCC patients. Overexpression of TRIM8 promoted the proliferation, colony formation, invasion, and migration of HCC cells, while TRIM8 knockdown or knockout exerted the opposite effects. RNA sequencing revealed that TRIM8 knockout suppresses several cancer-related pathways, including Wnt/ß-catenin and TGF-ß signaling in HepG2 cells. TRIM8 directly interacts with HNF1α, promoting its degradation by catalyzing polyubiquitination on lysine 197 in HCC cells. Moreover, the cancer-promoting effects of TRIM8 in HCC were abolished by the HNF1α-K197R mutant in vitro and in vivo. These data demonstrated that TRIM8 plays an oncogenic role in HCC progression through mediating the ubiquitination of HNF1α and promoting its protein degradation, and suggests targeting TRIM8-HNF1α may provide a promising therapeutic strategy of HCC.


Asunto(s)
Carcinoma Hepatocelular , Progresión de la Enfermedad , Factor Nuclear 1-alfa del Hepatocito , Neoplasias Hepáticas , Ubiquitinación , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Ratones Endogámicos BALB C , Ratones Desnudos , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética
12.
Biosens Bioelectron ; 261: 116522, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-38924815

RESUMEN

Molecular detection of nucleic acid plays an important role in early diagnosis and therapy of disease. Herein, a novel and enhanced electrochemical biosensor was exploited based on target-activated CRISPR/Cas12a system coupling with nanoparticle-labeled covalent organic frameworks (COFs) as signal reporters. Hollow spherical COFs (HCOFs) not only served as the nanocarriers of silver nanoparticles (AgNPs)-DNA conjugates for enhanced signal output but also acted as three-dimensional tracks of CRISPR/Cas12a system to improve the cleavage accessibility and efficiency. The presence of target DNA triggered the trans-cleavage activity of the CRISPR/Cas12a system, which rapidly cleaved the AgNPs-DNA conjugates on HCOFs, resulting in a remarkable decrease of the electrochemical signal. As a proof of concept, the fabricated biosensing platform realized highly sensitive and selective detection of human papillomavirus type 16 (HPV-16) DNA ranging from 100 fM to 1 nM with the detection limit of 57.2 fM. Furthermore, the proposed strategy provided a versatile and high-performance biosensor for the detection of different targets by simple modification of the crRNA protospacer, holding promising applications in disease diagnosis.


Asunto(s)
Técnicas Biosensibles , Sistemas CRISPR-Cas , ADN Viral , Técnicas Electroquímicas , Papillomavirus Humano 16 , Nanopartículas del Metal , Estructuras Metalorgánicas , Plata , Técnicas Biosensibles/métodos , Humanos , Nanopartículas del Metal/química , Técnicas Electroquímicas/métodos , Plata/química , Estructuras Metalorgánicas/química , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/aislamiento & purificación , ADN Viral/análisis , ADN Viral/genética , Límite de Detección
13.
Eur J Pharmacol ; 978: 176720, 2024 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-38880217

RESUMEN

Extracellular vesicles (EVs) are minute sacs released by cells into the extracellular milieu, harboring an array of biomolecules including proteins, nucleic acids, and lipids. Notably, a large number of studies have demonstrated the important involvement of EVs in both physiological and pathological aspects of renal function. EVs can facilitate communication between different renal cells, but it is important to recognize their dual role: they can either transmit beneficial information or lead to renal damage and worsening of existing conditions. The composition of EVs in the context of the kidneys offers valuable insights into the intricate mechanisms underlying specific renal functions or disease states. In addition, mesenchymal stem cell-derived EVs have the potential to alleviate acute and chronic kidney diseases. More importantly, the innate nanoparticle properties of EVs, coupled with their engineering potential, make them effective tools for drug delivery and therapeutic intervention. In this review, we focus on the intricate biological functions of EVs in the kidney. In addition, we explore the emerging role of EVs as diagnostic tools and innovative therapeutic agents in a range of renal diseases.

15.
Huan Jing Ke Xue ; 45(6): 3329-3340, 2024 Jun 08.
Artículo en Chino | MEDLINE | ID: mdl-38897755

RESUMEN

With rapid urbanization and human activities exacerbating threats to the degradation of various ecosystem services in modern urban agglomerations, the exploration of the state of ecological security at the scale of urban agglomerations is of great significance. This study considered the Lanzhou-Xining Urban Agglomeration as the research area, based on the land use data in 2000, 2005, 2010, 2015, and 2020. At the same time, the landscape ecological risk index was introduced. The land use change characteristics of the Lanzhou-Xining Urban Agglomeration were analyzed by using the land use transfer matrix, the value per unit area equivalent factor method, and the bivariate spatial autocorrelation analysis method to elucidate the impacts of the changes in the ecological risk index induced by the land use transition on the value of ecosystem services. This study analyzed the land use change characteristics of the Lanzhou-Xining Urban Agglomeration and elucidated the impacts of changes in the ecological risk index on the value of ecosystem services caused by land use transformation. The results showed that:① During the period from 2000 to 2020, the land use types of the Lanzhou-Xining Urban Agglomeration were mainly dominated by grassland, cropland, and forest land. The construction land area had expanded significantly mainly from cropland and grassland, and the six land use types had strong cross-transformation. The total area of land use change was 6 646.05 km2. ② In terms of spatial changes, the spatial pattern of ecosystem service value in the Lanzhou-Xining Urban Agglomeration had not undergone obvious transformation. However, the regional variability was significant, generally showing the distribution characteristics of high in the northwest and low in the southeast. ③From the perspective of temporal change, the value of ecosystem services in the Lanzhou-Xining Urban Agglomeration showed an upward trend, with the total flow of value increasing from 186.459 billion yuan to 192.156 billion yuan, with a total value-added of 5.697 billion yuan. ④ There was a rising trend in the overall ecological risk index of the Lanzhou-Xining Urban Agglomeration over the past 20 years. Low ecological risk areas and lower ecological risk areas dominated the ecological risk areas. There was a significant positive correlation between the value of ecosystem services and the ecological risk index. This study aimed to reveal the understanding of the impacts of land-use practices on ecosystem service values and ecological risks, to provide important references for regional ecological risk management and land-use policy formulation, and thus to promote the high-quality development of the ecological environment in the Yellow River Basin.

16.
Int J Biol Sci ; 20(7): 2640-2657, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38725843

RESUMEN

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.


Asunto(s)
Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Proteína HMGA1a , Inhibidores mTOR , Proteína Proto-Oncogénica c-ets-1 , Proteína 1A de Unión a Tacrolimus , Animales , Humanos , Ratones , Línea Celular Tumoral , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Proteína HMGA1a/metabolismo , Proteína HMGA1a/genética , Ratones Desnudos , Inhibidores mTOR/farmacología , Inhibidores mTOR/uso terapéutico , Proteína Proto-Oncogénica c-ets-1/metabolismo , Proteína Proto-Oncogénica c-ets-1/genética , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Sirolimus/uso terapéutico , Proteína 1A de Unión a Tacrolimus/metabolismo , Proteína 1A de Unión a Tacrolimus/genética , Serina-Treonina Quinasas TOR/metabolismo
17.
Anal Chim Acta ; 1311: 342743, 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38816160

RESUMEN

BACKGROUND: MicroRNA (miRNA) emerges as important cancer biomarker, accurate detection of miRNA plays an essential role in clinical sample analysis and disease diagnosis. However, it remains challenging to realize highly sensitive detection of low-abundance miRNA. Traditional detection methods including northern blot and real-time PCR have realized quantitative miRNA detection. However, these detection methods are involved in sophisticated operation and expensive instruments. Therefore, the development of novel sensing platform with high sensitivity and specificity for miRNA detection is urgently demanded for disease diagnosis. RESULTS: In this work, a novel electrochemical biosensor was constructed for miRNA detection based on target-driven cascade amplified assembly of electroactive covalent organic frameworks (COFs) on tetrahedral DNA nanostructure with multiplex recognition domains (m-TDN). COFs were employed as nanocarriers of electroactive prussian blue (PB) molecules by the "freeze-drying-reduction" method without the use of DNA as gatekeeper, which was simple, mild and efficient. The target-triggered catalytic hairpin assembly (CHA) and glutathione reduction could convert low-abundance miRNA into a large amount of Mn2+. Without the addition of exogenous Mn2+, the dynamically-generated Mn2+-powered DNAzyme cleavage process induced abundant PB-COFs probe assembled on the four recognition domains of m-TDN, resulting in significantly signal output. Using miRNA-182-5p as the model target, the proposed electrochemical biosensor achieved ultrasensitive detection of miRNA-182-5p in the range of 10 fM-100 nM with a detection limit of 2.5 fM. SIGNIFICANCE AND NOVELTY: Taking advantages of PB-COFs probe as the enhanced signal labels, the integration of CHA, Mn2+-powered DNAzyme and m-TDN amplification strategy significantly improved the sensitivity and specificity of the biosensor. The designed sensing platform was capable of miRNA detection in complex samples, which provided a new idea for biomarker detection, holding promising potential in clinical diagnosis and disease screening.


Asunto(s)
Técnicas Biosensibles , ADN Catalítico , ADN , Técnicas Electroquímicas , Estructuras Metalorgánicas , MicroARNs , Nanoestructuras , MicroARNs/análisis , Estructuras Metalorgánicas/química , Técnicas Biosensibles/métodos , Nanoestructuras/química , ADN/química , Humanos , ADN Catalítico/química , ADN Catalítico/metabolismo , Límite de Detección , Ferrocianuros/química
18.
Mol Plant Pathol ; 25(6): e13468, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38808392

RESUMEN

Phytophthora pathogens possess hundreds of effector genes that exhibit diverse expression patterns during infection, yet how the expression of effector genes is precisely regulated remains largely elusive. Previous studies have identified a few potential conserved transcription factor binding sites (TFBSs) in the promoters of Phytophthora effector genes. Here, we report a MYB-related protein, PsMyb37, in Phytophthora sojae, the major causal agent of root and stem rot in soybean. Yeast one-hybrid and electrophoretic mobility shift assays showed that PsMyb37 binds to the TACATGTA motif, the most prevalent TFBS in effector gene promoters. The knockout mutant of PsMyb37 exhibited significantly reduced virulence on soybean and was more sensitive to oxidative stress. Consistently, transcriptome analysis showed that numerous effector genes associated with suppressing plant immunity or scavenging reactive oxygen species were down-regulated in the PsMyb37 knockout mutant during infection compared to the wild-type P. sojae. Several promoters of effector genes were confirmed to drive the expression of luciferase in a reporter assay. These results demonstrate that a MYB-related transcription factor contributes to the expression of effector genes in P. sojae.


Asunto(s)
Phytophthora , Enfermedades de las Plantas , Regiones Promotoras Genéticas , Factores de Transcripción , Phytophthora/patogenicidad , Phytophthora/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Regiones Promotoras Genéticas/genética , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/genética , Glycine max/microbiología , Glycine max/genética , Virulencia/genética
19.
J Nanobiotechnology ; 22(1): 215, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38693585

RESUMEN

Stem cells (SCs) have been used therapeutically for decades, yet their applications are limited by factors such as the risk of immune rejection and potential tumorigenicity. Extracellular vesicles (EVs), a key paracrine component of stem cell potency, overcome the drawbacks of stem cell applications as a cell-free therapeutic agent and play an important role in treating various diseases. However, EVs derived from two-dimensional (2D) planar culture of SCs have low yield and face challenges in large-scale production, which hinders the clinical translation of EVs. Three-dimensional (3D) culture, given its ability to more realistically simulate the in vivo environment, can not only expand SCs in large quantities, but also improve the yield and activity of EVs, changing the content of EVs and improving their therapeutic effects. In this review, we briefly describe the advantages of EVs and EV-related clinical applications, provide an overview of 3D cell culture, and finally focus on specific applications and future perspectives of EVs derived from 3D culture of different SCs.


Asunto(s)
Técnicas de Cultivo Tridimensional de Células , Vesículas Extracelulares , Células Madre , Vesículas Extracelulares/metabolismo , Humanos , Células Madre/citología , Células Madre/metabolismo , Animales , Técnicas de Cultivo Tridimensional de Células/métodos , Técnicas de Cultivo de Célula/métodos
20.
World J Stem Cells ; 16(4): 353-374, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38690515

RESUMEN

Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection typically presents with fever and respiratory symptoms, which can progress to severe respiratory distress syndrome and multiple organ failure. In severe cases, these complications may even lead to death. One of the causes of COVID-19 deaths is the cytokine storm caused by an overactive immune response. Therefore, suppressing the overactive immune response may be an effective strategy for treating COVID-19. Mesenchymal stem cells (MSCs) and their derived exosomes (MSCs-Exo) have potent homing abilities, immunomodulatory functions, regenerative repair, and antifibrotic effects, promising an effective tool in treating COVID-19. In this paper, we review the main mechanisms and potential roles of MSCs and MSCs-Exo in treating COVID-19. We also summarize relevant recent clinical trials, including the source of cells, the dosage and the efficacy, and the clinical value and problems in this field, providing more theoretical references for the clinical use of MSCs and MSCs-Exo in the treatment of COVID-19.

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