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1.
Proc Natl Acad Sci U S A ; 121(1): e2307395120, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38157451

RESUMEN

Oxidative stress, which can be activated by a variety of environmental risk factors, has been implicated as an important pathogenic factor for inflammatory bowel disease (IBD). However, how oxidative stress drives IBD onset remains elusive. Here, we found that oxidative stress was strongly activated in inflamed tissues from both ulcerative colitis patients and Crohn's disease patients, and it caused nuclear-to-cytosolic TDP-43 transport and a reduction in the TDP-43 protein level. To investigate the function of TDP-43 in IBD, we inducibly deleted exons 2 to 3 of Tardbp (encoding Tdp-43) in mouse intestinal epithelium, which disrupted its nuclear localization and RNA-processing function. The deletion gave rise to spontaneous intestinal inflammation by inducing epithelial cell necroptosis. Suppression of the necroptotic pathway with deletion of Mlkl or the RIP1 inhibitor Nec-1 rescued colitis phenotypes. Mechanistically, disruption of nuclear TDP-43 caused excessive R-loop accumulation, which triggered DNA damage and genome instability and thereby induced PARP1 hyperactivation, leading to subsequent NAD+ depletion and ATP loss, consequently activating mitochondrion-dependent necroptosis in intestinal epithelial cells. Importantly, restoration of cellular NAD+ levels with NAD+ or NMN supplementation, as well as suppression of ALKBH7, an α-ketoglutarate dioxygenase in mitochondria, rescued TDP-43 deficiency-induced cell death and intestinal inflammation. Furthermore, TDP-43 protein levels were significantly inversely correlated with γ-H2A.X and p-MLKL levels in clinical IBD samples, suggesting the clinical relevance of TDP-43 deficiency-induced mitochondrion-dependent necroptosis. Taken together, these findings identify a unique pathogenic mechanism that links oxidative stress to intestinal inflammation and provide a potent and valid strategy for IBD intervention.


Asunto(s)
Enfermedades Inflamatorias del Intestino , Necroptosis , Humanos , Animales , Ratones , NAD/metabolismo , Estructuras R-Loop , Enfermedades Inflamatorias del Intestino/metabolismo , Células Epiteliales/metabolismo , Mucosa Intestinal/metabolismo , Inflamación/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Mitocondrias/metabolismo
2.
FASEB J ; 38(5): e23532, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38451470

RESUMEN

Although elevated glycolysis has been widely recognized as a hallmark for highly proliferating cells like stem cells and cancer, its regulatory mechanisms are still being updated. Here, we found a previously unappreciated mechanism of mammalian target of rapamycin complex 2 (mTORC2) in regulating glycolysis in intestinal stem cell maintenance and cancer progression. mTORC2 key subunits expression levels and its kinase activity were specifically upregulated in intestinal stem cells, mouse intestinal tumors, and human colorectal cancer (CRC) tissues. Genetic ablation of its key scaffolding protein Rictor in both mouse models and cell lines revealed that mTORC2 played an important role in promoting intestinal stem cell proliferation and self-renewal. Moreover, utilizing mouse models and organoid culture, mTORC2 loss of function was shown to impair growth of gut adenoma and tumor organoids. Based on these findings, we performed RNA-seq and noticed significant metabolic reprogramming in Rictor conditional knockout mice. Among all the pathways, carbohydrate metabolism was most profoundly altered, and further studies demonstrated that mTORC2 promoted glycolysis in intestinal epithelial cells. Most importantly, we showed that a rate-limiting enzyme in regulating glycolysis, 6-phosphofructo-2-kinase (PFKFB2), was a direct target for the mTORC2-AKT signaling. PFKFB2 was phosphorylated upon mTORC2 activation, but not mTORC1, and this process was AKT-dependent. Together, this study has identified a novel mechanism underlying mTORC2 activated glycolysis, offering potential therapeutic targets for treating CRC.


Asunto(s)
Neoplasias , Proteínas Proto-Oncogénicas c-akt , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Células Epiteliales , Glucólisis , Mamíferos , Diana Mecanicista del Complejo 2 de la Rapamicina , Ratones Noqueados , Fosfofructoquinasa-2 , Sirolimus
3.
EMBO J ; 39(7): e103255, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-32128839

RESUMEN

The Hippo-YAP signaling pathway plays an essential role in epithelial cells during intestinal regeneration and tumorigenesis. However, the molecular mechanism linking stromal signals to YAP-mediated intestinal regeneration and tumorigenesis is poorly defined. Here, we report a stroma-epithelium ISLR-YAP signaling axis essential for stromal cells to modulate epithelial cell growth during intestinal regeneration and tumorigenesis. Specifically, upon inflammation and in cancer, an oncogenic transcription factor ETS1 in stromal cells induces expression of a secreted protein ISLR that can inhibit Hippo signaling and activate YAP in epithelial cells. Deletion of Islr in stromal cells in mice markedly impaired intestinal regeneration and suppressed tumorigenesis in the colon. Moreover, the expression of stromal cell-specific ISLR and ETS1 significantly increased in inflamed mucosa of human IBD patients and in human colorectal adenocarcinoma, accounting for the epithelial YAP hyperactivation. Collectively, our findings provide new insights into the signaling crosstalk between stroma and epithelium during tissue regeneration and tumorigenesis.


Asunto(s)
Neoplasias Colorrectales/metabolismo , Inmunoglobulinas/genética , Inmunoglobulinas/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Proteína Proto-Oncogénica c-ets-1/metabolismo , Animales , Neoplasias Colorrectales/genética , Modelos Animales de Enfermedad , Técnicas de Inactivación de Genes , Células HCT116 , Células HEK293 , Células HT29 , Vía de Señalización Hippo , Humanos , Enfermedades Inflamatorias del Intestino/genética , Mucosa Intestinal/metabolismo , Masculino , Ratones , Mutación , Regiones Promotoras Genéticas , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal
4.
Environ Res ; 247: 118173, 2024 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-38224935

RESUMEN

The rapid development of the phosphorus chemical industry has caused serious pollution problems in the regional eco-environment. However, understanding of their ecotoxic effects remains limited. This study aimed to investigate the developmental toxicity of a stream polluted by a phosphorus chemical plant (PCP) on zebrafish embryos. For this, zebrafish embryos were exposed to stream water (0, 25, 50, and 100% v/v) for 96 h, and developmental toxicity, oxidative stress, apoptosis, and DNA damage were assessed. Stream water-treated embryos exhibited decreased hatching rates, heart rates, and body lengths, as well as increased mortality and malformation rates. The general morphology score system indicated that the swim bladder and pigmentation were the main abnormal morphological endpoints. Stream water promoted antioxidant enzymes (superoxide dismutase (SOD), peroxidase (POD), and glutathione peroxidase (GPx)), lipid peroxidation, and DNA damage. It also triggered apoptosis in the embryos' heads, hearts, and spines by activating apoptotic enzymes (Caspase-3 and Caspase-9). Additionally, stream water influenced growth, oxidative stress, and apoptosis-related 19 gene expression. Notably, tyr, sod (Mn), and caspase9 were the most sensitive indicators of growth, oxidative stress, and apoptosis, respectively. The current trial concluded that PCP-polluted stream water exhibited significant developmental toxicity to zebrafish embryos, which was regulated by the oxidative stress-mediated activation of endogenous apoptotic signaling pathways.


Asunto(s)
Contaminantes Químicos del Agua , Pez Cebra , Animales , Pez Cebra/metabolismo , Ríos , Embrión no Mamífero , Contaminantes Químicos del Agua/metabolismo , Estrés Oxidativo , Superóxido Dismutasa/metabolismo
5.
Angew Chem Int Ed Engl ; 63(21): e202316991, 2024 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-38520357

RESUMEN

Conventional strategies for highly efficient and selective CO2 photoreduction focus on the design of catalysts and cocatalysts. In this study, we discover that hydrogen bond network breakdown in reaction system can suppress H2 evolution, thereby improving CO2 photoreduction performance. Photosensitive poly(ionic liquid)s are designed as photocatalysts owing to their strong hydrogen bonding with solvents. The hydrogen bond strength is tuned by solvent composition, thereby effectively regulating H2 evolution (from 0 to 12.6 mmol g-1 h-1). No H2 is detected after hydrogen bond network breakdown with trichloromethane or tetrachloromethane as additives. CO production rate and selectivity increase to 35.4 mmol g-1 h-1 and 98.9 % with trichloromethane, compared with 0.6 mmol g-1 h-1 and 26.2 %, respectively, without trichloromethane. Raman spectroscopy and theoretical calculations confirm that trichloromethane broke the systemic hydrogen bond network and subsequently suppressed H2 evolution. This hydrogen bond network breakdown strategy may be extended to other catalytic reactions involving H2 evolution.

6.
Int J Hyperthermia ; 39(1): 1026-1035, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35914867

RESUMEN

OBJECTIVE: Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. Poor prognosis and low survival rates have driven the development of novel therapeutic strategies. Nanosecond pulsed electric field has emerged as a novel, minimal invasive and non-thermal treatment for solid tumors. It is of great significance to study the combination therapy of nsPEF and other treatment strategies for pancreatic cancer. METHODS: We developed neutrophil membrane-wrapped liposomal nanoparticles loaded with gemcitabine (NE/Lip-GEM) and investigated their use as a complementary agent for nsPEF treatment. RESULTS: Our results showed that neutrophil-mediated delivery of liposomal-gemcitabine (NE/Lip-GEM) efficiently inhibited the growth of pancreatic tumors in mice whose has been treated with incomplete nsPEF ablation. CONCLUSIONS: The combination of nsPEF and NE/Lip-GEM may be a promising synergistic strategy for pancreatic cancer therapy.


Asunto(s)
Nanopartículas , Neoplasias Pancreáticas , Animales , Línea Celular Tumoral , Ratones , Nanopartículas/uso terapéutico , Neutrófilos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas
7.
BMC Public Health ; 22(1): 1863, 2022 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-36199057

RESUMEN

BACKGROUND: Despite the widespread use of the single item self-rated health (SRH) question, its reliability has never been evaluated in Chinese population. METHODS: We used data from the China Health and Retirement Longitudinal Study, waves 1-4 (2011-2019). In wave 1, the same SRH question was asked twice, separated by other questions, on a subset of 4533 subjects, allowing us to examine the test-retest reliability of SRH. In addition, two versions of SRH questions (the WHO and US versions) were asked (n = 11,429). Kappa (κ), weighted kappa ([Formula: see text]), and polychoric correlation coefficient (ρ) were used for reliability assessment. Cox proportional-hazards models were estimated to assess the predictive validity of SRH measurement for mortality over 7 years of follow up. To do so, relative index of inequality (RII) and slope index of inequality (SII) were estimated for each SRH scale. RESULTS: There was moderate to substantial test-retest reliability (κ = 0.54, [Formula: see text]=0.63) of SRH; 31% of respondents who used the same scale twice changed their ratings after answering other questions. There was strong positive association between the two SRH measured by the two scales (ρ > 0.8). Compared with excellent/very good SRH, adjusted hazard ratios (HR) of death are 2.30 (95% CI, 1.70-3.13) for the US version and 1.86 (95% CI, 1.33-2.60) for the WHO version. Using slope indices of inequality, the WHO version estimated slightly larger mortality differences (RII = 3.50, SII = 15.53) than the US version (RII = 3.25, SII = 14.80). CONCLUSIONS: In Chinese middle-aged and older population, the reliability of SRH is generally good, although the two commonly used versions of SRH scales could not be compared directly. Both indices predict mortality, with similar predictive validity.


Asunto(s)
Estado de Salud , Jubilación , Anciano , China/epidemiología , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Reproducibilidad de los Resultados
8.
Phytother Res ; 36(6): 2572-2582, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35499270

RESUMEN

Therapeutic drugs of chronic neuralgia have a high risk of addiction, making it crucial to identify novel drugs for chronic neuralgia. This study aimed to explore the therapeutic effect of paeoniflorin on chronic sciatica via inhibiting Schwann cell apoptosis. 28 SD rats were randomly divided into four groups, including the sham operation group, chronic constriction injury (CCI) group, mecobalamin group, and paeoniflorin group. The therapeutic effect and mechanism of paeoniflorin were evaluated via rat and cell experiments. Mechanical, hot, or cold hyperalgesia was induced in the rats after CCI operation, while paeoniflorin relieved chronic neuralgia. Besides, paeoniflorin decreased the levels of IL1, IL6, TNF-α, CRP, and LPS and increased the level of IL10 in serum. As for the sciatic nerve, the number of inflammatory cells was decreased, and Schwann cells were present after paeoniflorin treatment, and paeoniflorin promoted the recovery of nerve structure. In cell experiments, LPS induced Schwann cell apoptosis via the TLR4/NF-kB pathway. And paeoniflorin attenuated LPS-induced Schwann cell apoptosis by decreasing the levels of TLR4, p-NF-kB, caspase3, cleaved-caspase3, and cleaved-caspase7. Overall, these results suggest that paeoniflorin alleviates chronic sciatica by decreasing inflammatory factor levels and promotes the repair of damaged nerves by reducing Schwann cell apoptosis.


Asunto(s)
Neuralgia , Ciática , Animales , Apoptosis , Constricción , Glucósidos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Lipopolisacáridos/farmacología , Monoterpenos , FN-kappa B/metabolismo , Neuralgia/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Células de Schwann , Nervio Ciático , Ciática/tratamiento farmacológico , Ciática/metabolismo , Receptor Toll-Like 4/metabolismo
9.
J Environ Manage ; 321: 115855, 2022 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-35994962

RESUMEN

Nutrients and heavy metals (HM) in the sediment have an impact on microbial diversity and community structure. In this study, the distribution characteristics of nutrients, HM, and microbial community in the sediments along the Longsha River, a tributary of the Pearl River (or Zhu Jiang), China were investigated by analyzing samples from 11 sites. On the basis of the HM-contamination level, the 11 sampling sites were divided into three groups to explore the changes in microbial communities at different ecological risk levels. Results indicated that nutrient concentrations were higher near farmlands and residential lands, while the ecological risk of HM at the 11 sampling sites was from high to low as S10 > S2 > S9 > S6 > S11 > S7 > S5 > S8 > S3 > S4 > S1. Among these HM, Cu, Cr, and Ni had intense ecological risks. In addition, the results of Variance Partitioning Analysis (VPA) revealed a higher contribution of HM (35.93%) to microbial community variation than nutrients (12.08%) and pH (4.08%). Furthermore, the HM-tolerant microbial taxa (Clostridium_sensu_stricto_1, Romboutsia, norank_o__Gaiellales, and etc.) were the dominant genera, and they were more dynamic around industrial lands, while microbes involved in the C, N, and S cycles (e.g., Smithella, Thiobacillus, Dechloromonas, Bacter oidetes_vadinHA17, and Syntrophorhabdus) were inhibited by HM, while their abundance was lower near industrial lands and highway but higher around residential lands. A three-unit monitoring program of land-use types, pollutants, and microbial communities was proposed. These results provide a new perspective on the control of riparian land-use types based on contaminants and microbes, and different microbial community response patterns may provide a reference for contaminant control in sediments with intensive industrial activities.


Asunto(s)
Metales Pesados , Microbiota , China , Monitoreo del Ambiente/métodos , Sedimentos Geológicos/química , Metales Pesados/análisis , Nutrientes , Medición de Riesgo , Ríos/química
10.
Molecules ; 27(13)2022 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-35807564

RESUMEN

Spider silk is one of the hottest biomaterials researched currently, due to its excellent mechanical properties. This work reports a novel humidity sensing platform based on a spider silk-modified quartz tuning fork (SSM-QTF). Since spider silk is a kind of natural moisture-sensitive material, it does not demand additional sensitization. Quartz-enhanced conductance spectroscopy (QECS) was combined with the SSM-QTF to access humidity sensing sensitively. The results indicate that the resonance frequency of the SSM-QTF decreased monotonously with the ambient humidity. The detection sensitivity of the proposed SSM-QTF sensor was 12.7 ppm at 1 min. The SSM-QTF sensor showed good linearity of ~0.99. Using this sensor, we successfully measured the humidity of disposable medical masks for different periods of wearing time. The results showed that even a 20 min wearing time can lead to a >70% humidity in the mask enclosed space. It is suggested that a disposable medical mask should be changed <2 h.


Asunto(s)
Cuarzo , Seda , Humedad , Cuarzo/química , Análisis Espectral/métodos
11.
Trends Analyt Chem ; 130: 115975, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32834242

RESUMEN

The abuse of illicit drugs usually associated with dramatic crimes may cause significant problems for the whole society. Wastewater-based epidemiology (WBE) has been demonstrated to be a novel and cost-effective way to evaluate the abuse of illicit drugs at the community level, and has been used as a routine method for monitoring and played a significant role for combating the crimes in some countries, e.g. China. The method can also provide temporal and spatial variation of drugs of abuse. The detection methods mainly remain on the conventional liquid chromatography coupled with mass spectrometry, which is extremely sensitive and selective, however needs advanced facility and well-trained personals, thus limit it in the lab. As an alternative, sensors have emerged to be a powerful analytical tool for a wide spectrum of analytes, in particular aptamer sensors (aptasensors) have attracted increasing attention and could act as an efficient tool in this field due to the excellent characteristics of selectivity, sensitivity, low cost, miniaturization, easy-to-use, and automation. In this review, we will briefly introduce the context, specific assessment process and applications of WBE and the recent progress of illicit drug aptasensors, in particular focusing on optical and electrochemical sensors. We then highlight several recent aptasensors for illicit drugs in new technology integration and discuss the feasibility of these aptasensor for WBE. We will summarize the challenges and propose our insights and opportunity on aptasensor for WBE to evaluate community-wide drug use trends and public health.

12.
Water Res ; 257: 121649, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-38718655

RESUMEN

In this study, the distribution and toxicity of nanoscale zero valent iron (nZVI) and nZVIs coated with citric acid and sodium tripolyphosphate (CA-nZVI and STPP-nZVI) in mice were investigated. nZVIs were primarily found in the livers and spleens, followed by the lungs, hearts, and kidneys. Histologic analysis revealed no significant histopathologic abnormalities or lesions in all organs except the liver at 14th d gavage. nZVIs did not have a noticeable impact on the body weight of the mice or the weight of their organs. Compared with the control group, there were no significant changes in hematology indexes in the nZVIs groups. However, the nZVIs groups exhibited varying levels of elevation in alanine aminotransferase, aspartate aminotransferase, and creatinine, suggesting liver and kidney inflammation in mice. The up-regulation of Nuclear Factor erythroid 2-Related Factor 2 and Heme oxygenase 1 in the nZVIs groups may be a response to nZVIs-induced oxidative stress. Immunohistochemical analysis confirmed the inflammatory response induced by the three nZVI groups. Chelating agents did not have a significant impact on the distribution or toxicity of nZVIs in mice. This study contributes to a comprehensive and detailed insight into nZVI toxicity in the environmental field.


Asunto(s)
Hierro , Animales , Ratones , Hierro/química , Distribución Tisular , Hígado/efectos de los fármacos , Quelantes/química , Riñón/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Nanopartículas del Metal/química , Masculino , Hemo-Oxigenasa 1/metabolismo , Bazo/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo
13.
Sci Total Environ ; 912: 168855, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38029993

RESUMEN

The reactivity and mechanism of the Fe-doped biochar (FeBC) Fenton reaction are typically influenced by the amount and type of Fe species in materials. This study investigated the effects of different Fe precursors (FeSO4, Fe(NO)3, FeCl2, and FeCl3) used to prepare Fenton catalyst FeBCs (FeSBC, FeNBC, FeC2BC, and FeC3BC) on the physicochemical characteristics, pH resistance, and reactivity for bisphenol A (BPA) removal. In addition to the FeSBC/H2O2 (0.007 min-1) system, FeNBC/H2O2 (1.143 min-1), FeC2BC/H2O2 (0.278 min-1), and FeC3BC/H2O2 (0.556 min-1) completely removed BPA within 20 min under the optimal conditions (FeBCs: 0.1 g/L; H2O2: 1 mM; BPA: 20 mg/L; pH 3). FeBCs/H2O2 systems demonstrated good stability and resistance to inorganic anions and natural organic matter under appropriate initial pH conditions. However, FeC2BC and FeC3BC exhibited better pH applicability than FeNBC. Characterization results indicated that the physicochemical properties of FeBCs were dependent on the Fe precursor, which correlated with the degree of Fe corrosion and the production of distinct reactive oxygen species (ROS). Quenching experiments and electron spin resonance detection results indicated that OH, 1O2, and O2- species were all engaged in BPA removal; the ROS concentrations were significantly influenced by the initial pH and Fe precursor. The results indicate that Fe precursors significantly impact the performance and characteristics of Fe-based biochar materials, which are tailorable to specific applications.

14.
ACS Omega ; 9(5): 5854-5861, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38343987

RESUMEN

Hydrogels have drawn intensive attention as fascinating materials for biomedicine. However, fabricating hydrogels with injectable and self-healing properties remains a challenge. Herein, we reported a biocompatible poly(N-vinylpyrrolidone)/carboxymethyl cellulose (PVP/CMC) hydrogel with excellent injectable and self-healing properties. The PVP/CMC hydrogel exhibits good biocompatible, injectable, and self-healing properties. The sol-gel transition of PVP/CMC hydrogels demonstrates an outstanding self-healing behavior, and the bisected hydrogels can self-heal within 30 s. The hydrogels have a good swelling ratio, and the swelling ratio increases with increasing amount of CMC in PVP and reaches a maximum of 2850% at a 1.0:1.5 PVP and CMC ratio. In addition, the hydrogel possesses excellent drug release capacity, and its drug release rate reaches 70%. Moreover, the release of 4-aminosalicylic acid (4-ASA) in the hydrogel can be controlled by adjusting the proportion of the hydrogel. The PVP/CMC hydrogel with excellent biocompatible, injectable, and self-healing properties has great potential for applications in drug release.

15.
Nat Chem ; 16(8): 1320-1329, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38528101

RESUMEN

Recent efforts in genome mining of ribosomally synthesized and post-translationally modified peptides (RiPPs) have expanded the diversity of post-translational modification chemistries. However, RiPPs are rarely reported as hybrid molecules incorporating biosynthetic machinery from other natural product families. Here we report lipoavitides, a class of RiPP/fatty-acid hybrid lipopeptides that display a unique, putatively membrane-targeting 4-hydroxy-2,4-dimethylpentanoyl (HMP)-modified N terminus. The HMP is formed via condensation of isobutyryl-coenzyme A (isobutyryl-CoA) and methylmalonyl-CoA catalysed by a 3-ketoacyl-(acyl carrier protein) synthase III enzyme, followed by successive tailoring reactions in the fatty acid biosynthetic pathway. The HMP and RiPP substructures are then connected by an acyltransferase exhibiting promiscuous activity towards the fatty acyl and RiPP substrates. Overall, the discovery of lipoavitides contributes a prototype of RiPP/fatty-acid hybrids and provides possible enzymatic tools for lipopeptide bioengineering.


Asunto(s)
Ribosomas , Acilación , Ribosomas/metabolismo , Ácido Graso Sintasas/metabolismo , Ácido Graso Sintasas/química , Ácido Graso Sintasas/genética , Procesamiento Proteico-Postraduccional , Péptidos/química , Péptidos/metabolismo , Lipopéptidos/química , Lipopéptidos/metabolismo , Lipopéptidos/biosíntesis , Ácidos Grasos/química , Ácidos Grasos/metabolismo
16.
Adv Sci (Weinh) ; : e2402327, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38981014

RESUMEN

Dysregulation of the transforming growth factor-ß (TGF-ß) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug-resistant CSCs. Through a genome-wide CRISPR activation screen utilizing stem-like drug-resistant properties as a readout, the TGF-ß receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-ß-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-ß receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-ß signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly-ubiquitination and proteasomal degradation. Moreover, hyperactive TGF-ß signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-ß signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-ß signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1-mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF-ß signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.

17.
Front Oncol ; 13: 1198941, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37293591

RESUMEN

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor of the digestive tract. The most effective method of reducing the disease burden in areas with a high incidence of esophageal cancer is to prevent the disease from developing into invasive cancer through screening. Endoscopic screening is key for the early diagnosis and treatment of ESCC. However, due to the uneven professional level of endoscopists, there are still many missed cases because of failure to recognize lesions. In recent years, along with remarkable progress in medical imaging and video evaluation technology based on deep machine learning, the development of artificial intelligence (AI) is expected to provide new auxiliary methods of endoscopic diagnosis and the treatment of early ESCC. The convolution neural network (CNN) in the deep learning model extracts the key features of the input image data using continuous convolution layers and then classifies images through full-layer connections. The CNN is widely used in medical image classification, and greatly improves the accuracy of endoscopic image classification. This review focuses on the AI-assisted diagnosis of early ESCC and prediction of early ESCC invasion depth under multiple imaging modalities. The excellent image recognition ability of AI is suitable for the detection and diagnosis of ESCC and can reduce missed diagnoses and help endoscopists better complete endoscopic examinations. However, the selective bias used in the training dataset of the AI system affects its general utility.

18.
Artículo en Inglés | MEDLINE | ID: mdl-36981656

RESUMEN

In the face of labour-force ageing, understanding labour-market characteristics and the health status of middle-aged and older workers is important for sustainable social and economic development. Self-rated health (SRH) is a widely-used instrument to detect health problems and predict mortality. This study investigated labour-market characteristics that may have an impact on the SRH among Chinese middle-aged and older workers, using data from the national baseline wave of the China Health and Retirement Longitudinal Study. The analytical sample included 3864 individuals who at the time held at least one non-agricultural job. Fourteen labour-market characteristics were clearly defined and investigated. Multiple logistic regression models of the associations of each labour-market characteristic with SRH were estimated. Seven labour-market characteristics were associated with higher odds of poor SRH when controlled for age and sex. Employment status and earned income remained significantly associated with poor SRH, when controlling for all the sociodemographic factors and health behaviours. Doing unpaid work in family businesses is associated with 2.07 (95% CI, 1.51-2.84) times probability of poor SRH, compared with employed individuals. Compared with more affluent individuals (highest quintile of earned income), people in the fourth and fifth quintiles had 1.92 (95% CI, 1.29-2.86) times and 2.72 (95% CI, 1.83-4.02) times higher chance, respectively, of poor SRH. In addition, residence type and region were important confounders. Measures improving adverse working conditions should be taken to prevent future risk of impaired health among the Chinese middle-aged and older workforce.


Asunto(s)
Empleo , Jubilación , Persona de Mediana Edad , Humanos , Anciano , Estudios Longitudinales , Estado de Salud , Envejecimiento
19.
Sci Total Environ ; 878: 163141, 2023 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-36990234

RESUMEN

There are increasing concerns about microplastic (MP) pollution in the natural environment. Consequently, numerous physicochemical and toxicological studies have been conducted on the effects of MPs. However, few studies have concerned the potential impact of MPs on contaminated site remediation. We herein investigated the influence of MPs on the temporary and post heavy metal removal by iron nanoparticles, including pristine and sulfurized nano zero-valent irons (nZVI and S-nZVI). MPs inhibited adsorption of most heavy metals during the treatment of iron nanoparticles, and facilitated their desorption, such as Pb (II) from nZVI and Zn (II) from S-nZVI. However, such effects presented by MPs was usually less than those by dissolved oxygen (DO). Most desorption cases are irrelevant to the reduced formats of heavy metals involving redox reactions, such as Cu (I) or Cr (III), suggesting that the influence of MPs on metals are limited to those binding with iron nanoparticles through surface complexation or electrostatic interaction. As another common factor, natural organic matter (NOM) had almost no influence on the heavy metal desorption. These insights shed lights for enhanced remediation of heavy metals by nZVI/S-NZVI in the presence of MPs.

20.
J Hazard Mater ; 457: 131821, 2023 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-37315414

RESUMEN

The effects of tripolyphosphate (TPP) on organic pollutant degradation in saline wastewater using Fe0/H2O2 were systematically investigated to elucidate its mechanism and the main reactive oxygen species (ROS). Organic pollutant degradation was dependent on the Fe0 and H2O2 concentration, Fe0/TPP molar ratio, and pH value. The apparent rate constant (kobs) of TPP-Fe0/H2O2 was 5.35 times higher than that of Fe0/H2O2 when orange II (OGII) and NaCl were used as the target pollutant and model salt, respectively. The electron paramagnetic resonance (EPR) and quenching test results showed that •OH, O2•-, and 1O2 participated in OGII removal, and the dominant ROS were influenced by the Fe0/TPP molar ratio. The presence of TPP accelerates Fe3+/Fe2+ recycling and forms Fe-TPP complexes, which ensures sufficient soluble Fe for H2O2 activation, prevents excessive Fe0 corrosion, and thereby inhibits Fe sludge formation. Additionally, TPP-Fe0/H2O2/NaCl maintained a performance similar to those of other saline systems and effectively removed various organic pollutants. The OGII degradation intermediates were identified using high-performance liquid chromatography-mass spectrometry (HPLC-MS) and density functional theory (DFT), and possible degradation pathways for OGII were proposed. These findings provide a facile and cost-effective Fe-based AOP method for removing organic pollutants from saline wastewater.

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