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1.
Nature ; 623(7989): 956-963, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38030784

RESUMEN

Monolayer graphene with nanometre-scale pores, atomically thin thickness and remarkable mechanical properties provides wide-ranging opportunities for applications in ion and molecular separations1, energy storage2 and electronics3. Because the performance of these applications relies heavily on the size of the nanopores, it is desirable to design and engineer with precision a suitable nanopore size with narrow size distributions. However, conventional top-down processes often yield log-normal distributions with long tails, particularly at the sub-nanometre scale4. Moreover, the size distribution and density of the nanopores are often intrinsically intercorrelated, leading to a trade-off between the two that substantially limits their applications5-9. Here we report a cascaded compression approach to narrowing the size distribution of nanopores with left skewness and ultrasmall tail deviation, while keeping the density of nanopores increasing at each compression cycle. The formation of nanopores is split into many small steps, in each of which the size distribution of all the existing nanopores is compressed by a combination of shrinkage and expansion and, at the same time as expansion, a new batch of nanopores is created, leading to increased nanopore density by each cycle. As a result, high-density nanopores in monolayer graphene with a left-skewed, short-tail size distribution are obtained that show ultrafast and ångström-size-tunable selective transport of ions and molecules, breaking the limitation of the conventional log-normal size distribution9,10. This method allows for independent control of several metrics of the generated nanopores, including the density, mean diameter, standard deviation and skewness of the size distribution, which will lead to the next leap in nanotechnology.

2.
Anal Chem ; 96(2): 910-916, 2024 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-38171356

RESUMEN

Early tumor diagnosis is crucial to successful treatment. Earlier studies have shown that microRNA is a biomarker for early tumor diagnosis. The development of highly sensitive miRNA detection methods, especially in living cells, plays an indispensable role for early diagnosis and treatment of tumor. Although the catalytic hairpin assembly (CHA)-based miRNA analysis strategy is commonly used for disease diagnosis, further application of CHA is hindered due to its low amplification efficiency and low tumor recognition contrast. To address these limitations, we propose a dual-signal amplification strategy based on CHA and APE1-assisted amplification, enabling highly sensitive and high-contrast miRNA imaging. The miR-221 was selected as a target model. This dual-signal amplification strategy has exhibited high amplification efficiency, which could analyze miRNA as low as 21 fM. This strategy also exhibited high specificity, which could distinguish target miRNA and nontarget with single-base differences. Moreover, this method showed significant potential for practical application, as it could successfully distinguish the expression difference of miR-221 in the plasma samples of normal people and patients. Most importantly, the expression level of the APE1 enzyme in tumor cells is higher than that in normal cells, allowing this strategy to sensitively and specifically image miRNA within tumor cells. This proposed method has also been successfully used to indicate fluctuations of intracellular miRNA and to distinguish miRNA expression between normal cells and cancer cells with high contrast. We anticipate that this method will provide fresh insights and can be a powerful tool for tumor diagnosis and treatment based on miRNA analysis.


Asunto(s)
Técnicas Biosensibles , MicroARNs , Humanos , MicroARNs/análisis , Técnicas Biosensibles/métodos , Catálisis , Diagnóstico por Imagen , Límite de Detección
3.
Anal Chem ; 96(22): 9078-9087, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38770734

RESUMEN

As an important disease biomarker, the development of sensitive detection strategies for miRNA, especially intracellular miRNA imaging strategies, is helpful for early diagnosis of diseases, pathological research, and drug development. Hybridization chain reaction (HCR) is widely used for miRNA imaging analysis because of its high specificity and lack of biological enzymes. However, the classic HCR reaction exhibits linear amplification with low efficiency, limiting its use for the rapid analysis of trace miRNA in living cells. To address this problem, we proposed a toehold-mediated exponential HCR (TEHCR) to achieve highly sensitive and efficient imaging of miRNA in living cells using ß-FeOOH nanoparticles as transfection vectors. The detection limit of TEHCR was as low as 92.7 fM, which was 8.8 × 103 times lower compared to traditional HCR, and it can effectively distinguish single-base mismatch with high specificity. The TEHCR can also effectively distinguish the different expression levels of miRNA in cancer cells and normal cells. Furthermore, TEHCR can be used to construct OR logic gates for dual miRNA analysis without the need for additional probes, demonstrating high flexibility. This method is expected to play an important role in clinical miRNA-related disease diagnosis and drug development as well as to promote the development of logic gates.


Asunto(s)
MicroARNs , Hibridación de Ácido Nucleico , MicroARNs/análisis , MicroARNs/metabolismo , Humanos , Límite de Detección , Técnicas de Amplificación de Ácido Nucleico/métodos , Compuestos Férricos/química
4.
Anal Chem ; 96(17): 6774-6783, 2024 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-38634427

RESUMEN

The identification of a specific tumor cell is crucial for the early diagnosis and treatment of cancer. However, it remains a challenge due to the limited sensitivity and accuracy, long response time, and low contrast of the recent approaches. In this study, we develop a dual miRNA-triggered DNA walker (DMTDW) assisted by APE1 for the specific recognition of tumor cells. miR-10b and miR-155 were selected as the research models. Without miR-10b and miR-155 presence, the DNA walker remains inactive as its walking strand of W is locked by L1 and L2. After miR-10b and miR-155 are input, the DNA walker is triggered as miR-10b and miR-155 bind to L1 and L2 of W-L1-L2, respectively, unlocking W. The DNA walker is driven by endogenous APE1 that is highly catalytic and is highly expressed in the cytoplasm of tumor cells but barely expressed in normal cells, ensuring high contrast and reaction efficiency for specific recognition of tumor cells. Dual miRNA input is required to trigger the DNA walker, making this strategy with a high accuracy. The DMTDW strategy exhibited high sensitivity for miRNA analysis with a detection limit of 44.05 pM. Living cell-imaging experiments confirmed that the DMTDW could effectively respond to the fluctuation of miRNA and specifically identified MDA-MB-231 cells from different cell lines. The proposed DMTDW is sensitive, rapid, and accurate for specific tumor cell recognition. We believe that the DMTDW strategy can become a powerful diagnostic tool for the specific recognition of tumor cells.


Asunto(s)
ADN-(Sitio Apurínico o Apirimidínico) Liasa , MicroARNs , MicroARNs/análisis , MicroARNs/metabolismo , MicroARNs/genética , Humanos , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , ADN/química , Línea Celular Tumoral
5.
Small ; 20(10): e2306095, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37903361

RESUMEN

Seasonal influenza still greatly threatens public health worldwide, leading to significant morbidity and mortality. Antiviral medications for influenza treatment are limited and accompanied by increased drug resistance. In severe influenza virus infection, hyperinflammation and hypoxia may be the significant threats associated with mortality, so the development of effective therapeutic methods to alleviate excessive inflammation while reducing viral damage is highly pursued. Here, a multifunctional MOF-based nanohybrid of Cu─TCPP@Mn3 O4 as a novel drug against influenza A virus infection (MOF = metal-organic framework; TCPP = tetrakis (4-carboxyphenyl) porphyrin) is designed. Cu─TCPP@Mn3 O4 exhibits potent inhibitory capability against influenza A virus infection in vitro and in vivo. The mechanism study reveals that Cu─TCPP@Mn3 O4 inhibits the virus entry by binding to the HA2 subunit of influenza A virus hemagglutinin. In addition, the nanoparticles of Mn3 O4 in Cu─TCPP@Mn3 O4 can scavenge intracellular ROS with O2 generation to downregulate inflammatory factors and effectively inhibit cytokines production. By reconstructing the antioxidant microenvironment, Cu─TCPP@Mn3 O4 features as a promising nanomedicine with anti-inflammatory and anti-viral synergistic effects.


Asunto(s)
Gripe Humana , Nanopartículas , Humanos , Especies Reactivas de Oxígeno , Inflamación/tratamiento farmacológico , Antivirales/farmacología , Antivirales/uso terapéutico
6.
Chembiochem ; 25(13): e202400229, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38700379

RESUMEN

Photodynamic therapy (PDT) is a newly emerged strategy for disease treatment. One challenge of the application of PDT drugs is the side-effect caused by the non-specificity of the photosensitive molecules. Most of the photosensitizers may invade not only the pathogenic cells but also the normal cells. In recent, people tried to use special cargoes to deliver the drugs into target cells. DNA nanoflowers (NFs) are a kind of newly-emerged nanomaterial which constructed through DNA rolling cycle amplification (RCA) reaction. It is reported that the DNA NFs were suitable materials which have been widely applied as nanocargos for drug delivery in cancer chemotherapeutic treatment. In this paper, we have introduced a new multifunctional DNA NF which could be prepared through an one-pot RCA reaction. This proposed DNA NF contained a versatile AS1411 G-quadruplex moiety, which plays key roles not only for specific recognition of cancer cells but also for near-infrared ray based photodynamic therapy when conjugating with a special porphyrin molecule. We demonstrated that the DNA NF showed good selectivity toward cancer cells, leading to highly efficient photo-induced cytotoxicity. Moreover, the in vivo experiment results suggested this DNA NF is a promising nanomaterial for clinical PDT.


Asunto(s)
ADN , Nanoestructuras , Fotoquimioterapia , Fármacos Fotosensibilizantes , Humanos , ADN/química , Animales , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/síntesis química , Nanoestructuras/química , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos/farmacología , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Línea Celular Tumoral
7.
Int J Neuropsychopharmacol ; 27(1)2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-38038373

RESUMEN

BACKGROUND: Depression is a neuropsychiatric disease with a high disability rate and mainly caused by the chronic stress or genetic factors. There is increasing evidence that microRNAs (miRNAs) play a critical role in the pathogenesis of depression. However, the underlying molecular mechanism for the pathophysiology of depression of miRNA remains entirely unclear so far. METHODS: We first established a chronic social defeat stress (CSDS) mice model of depression, and depression-like behaviors of mice were evaluated by a series of behavioral tests. Next, we detected several abundantly expressive miRNAs suggested in previous reports to be involved in depression and found miR-182-5p was selected as a candidate for analysis in the hippocampus. Then western blotting and immunofluorescence were used together to examine whether adeno-associated virus (AAV)-siR-182-5p treatment alleviated chronic stress-induced decrease in hippocampal Akt/GSK3ß/cAMP-response element binding protein (CREB) signaling pathway and increase in neurogenesis impairment and neuroinflammation. Furthermore, CREB inhibitor was adopted to examine if blockade of Akt/GSK3ß/CREB signaling pathway abolished the antidepressant actions of AAV-siR-182-5p in mice. RESULTS: Knockdown of miR-182-5p alleviated depression-like behaviors and impaired neurogenesis of CSDS-induced mice. Intriguingly, the usage of agomiR-182-5p produced significant increases in immobility times and aggravated neuronal neurogenesis damage of mice. More importantly, it suggested that 666-15 blocked the reversal effects of AAV-siR-182-5p on the CSDS-induced depressive-like behaviors in behavioral testing and neuronal neurogenesis within hippocampus of mice. CONCLUSIONS: These findings indicated that hippocampal miR-182-5p/Akt/GSK3ß/CREB signaling pathway participated in the pathogenesis of depression, and it might give more opportunities for new drug developments based on the miRNA target in the clinic.


Asunto(s)
Conducta Animal , MicroARNs , Animales , Ratones , Derrota Social , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Hipocampo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Estrés Psicológico/metabolismo
8.
Inorg Chem ; 2024 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-38943593

RESUMEN

Zwitterionic thiolate ligands have the potential to introduce novel assembly modes and functions for noble metal clusters. However, their utilization in the synthesis of silver clusters remains understudied, particularly for the clusters containing reductive Ag(0) species. In this article, we report the first synthesis of a mixed-valence silver(0/I) cluster protected by zwitterionic Tab as thiolate ligands (Tab = 4-(trimethylammonio)benzenethiolate), denoted as [Ag22(Tab)24](PF6)20·16CH3OH·6Et2O (Ag22·16CH3OH·6Et2O), alongside an Ag(I) cluster [Ag20(Tab)12(PhCOO)10(MeCN)2(H2O)](PF6)10·11MeCN (Ag20·11MeCN). Ag22 has a distinct hierarchical supratetrahedral structure with a central {Ag6} kernel surrounded by four [Ag4(Tab)6]4+ units. High-resolution electrospray ionization mass spectra demonstrate that Ag22 has two free electrons, indicating a superatomic core. Ag20 has a drum-like [Ag12(Tab)6(PhCOO)6(H2O)]6+ inner core capped by two tetrahedral-like [Ag4(Tab)3(PhCOO)2(MeCN)]2+ units. Ag20 can be transformed into Ag22 after its reaction with NaBH4 in solution. Antibacterial measurements reveal that Ag22 has a significantly lower minimum inhibitory concentration than that of the Ag20 cluster. This work not only extends the stabilization of silver(0/I) clusters to neutral thiol ligands but also offers new materials for the development of novel antibacterial materials.

9.
BMC Cardiovasc Disord ; 24(1): 147, 2024 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-38448835

RESUMEN

OBJECTIVE: Postoperative delirium is a common and debilitating complication that significantly affects patients and their families. The purpose of this study is to investigate whether there is an effective sedative that can prevent postoperative delirium while also examining the safety of using sedatives during the perioperative period. METHODS: The net-meta analysis was used to compare the incidence of postoperative delirium among four sedatives: sevoflurane, propofol, dexmedetomidine, and midazolam. Interventions were ranked according to their surface under the cumulative ranking curve (SUCRA). RESULTS: A total of 41 RCT studies involving 6679 patients were analyzed. Dexmedetomidine can effectively reduce the incidence of postoperative delirium than propofol (OR 0.47 95% CI 0.25-0.90), midazolam (OR 0.42 95% CI 0.17-1.00), normal saline (OR 0.42 95% CI 0.33-0.54) and sevoflurane (OR 0.39 95% CI 0.18-0.82). The saline group showed a significantly lower incidence of bradycardia compared to the group receiving dexmedetomidine (OR 0.55 95% CI 0.37-0.80). In cardiac surgery, midazolam (OR 3.34 95%CI 2.04-5.48) and normal saline (OR 2.27 95%CI 1.17-4.39) had a higher rate of postoperative delirium than dexmedetomidine, while in non-cardiac surgery, normal saline (OR 1.98 95%CI 1.44-2.71) was more susceptible to postoperative delirium than dexmedetomidine. CONCLUSION: Our analysis suggests that dexmedetomidine is an effective sedative in preventing postoperative delirium whether in cardiac surgery or non-cardiac surgery. The preventive effect of dexmedetomidine on postoperative delirium becomes more apparent with longer surgical and extubation times. However, it should be administered with caution as it was found to be associated with bradycardia.


Asunto(s)
Anestésicos , Delirio del Despertar , Hipnóticos y Sedantes , Humanos , Anestésicos/uso terapéutico , Bradicardia , Dexmedetomidina , Delirio del Despertar/prevención & control , Hipnóticos y Sedantes/uso terapéutico , Midazolam , Propofol , Solución Salina , Sevoflurano , Metaanálisis en Red
10.
J Nanobiotechnology ; 22(1): 275, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38778401

RESUMEN

BACKGROUND: Acute gouty is caused by the excessive accumulation of Monosodium Urate (MSU) crystals within various parts of the body, which leads to a deterioration of the local microenvironment. This degradation is marked by elevated levels of uric acid (UA), increased reactive oxygen species (ROS) production, hypoxic conditions, an upsurge in pro-inflammatory mediators, and mitochondrial dysfunction. RESULTS: In this study, we developed a multifunctional nanoparticle of polydopamine-platinum (PDA@Pt) to combat acute gout by leveraging mild hyperthermia to synergistically enhance UA degradation and anti-inflammatory effect. Herein, PDA acts as a foundational template that facilitates the growth of a Pt shell on the surface of its nanospheres, leading to the formation of the PDA@Pt nanomedicine. Within this therapeutic agent, the Pt nanoparticle catalyzes the decomposition of UA and actively breaks down endogenous hydrogen peroxide (H2O2) to produce O2, which helps to alleviate hypoxic conditions. Concurrently, the PDA component possesses exceptional capacity for ROS scavenging. Most significantly, Both PDA and Pt shell exhibit absorption in the Near-Infrared-II (NIR-II) region, which not only endow PDA@Pt with superior photothermal conversion efficiency for effective photothermal therapy (PTT) but also substantially enhances the nanomedicine's capacity for UA degradation, O2 production and ROS scavenging enzymatic activities. This photothermally-enhanced approach effectively facilitates the repair of mitochondrial damage and downregulates the NF-κB signaling pathway to inhibit the expression of pro-inflammatory cytokines. CONCLUSIONS: The multifunctional nanomedicine PDA@Pt exhibits exceptional efficacy in UA reduction and anti-inflammatory effects, presenting a promising potential therapeutic strategy for the management of acute gout.


Asunto(s)
Gota , Indoles , Polímeros , Especies Reactivas de Oxígeno , Ácido Úrico , Gota/tratamiento farmacológico , Gota/metabolismo , Gota/terapia , Especies Reactivas de Oxígeno/metabolismo , Animales , Ratones , Polímeros/química , Indoles/química , Indoles/farmacología , Nanopartículas/química , Platino (Metal)/química , Platino (Metal)/farmacología , Platino (Metal)/uso terapéutico , Humanos , Peróxido de Hidrógeno/metabolismo , Hipertermia Inducida/métodos , Células RAW 264.7 , Terapia Fototérmica/métodos , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Masculino
11.
Gynecol Endocrinol ; 40(1): 2360085, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38813955

RESUMEN

Premature ovarian insufficiency (POI) is a common gynecological endocrine disease, which seriously affects women's physical and mental health and fertility, and its incidence is increasing year by year. With the development of social economy and technology, psychological stressors such as anxiety and depression caused by social, life and environmental factors may be one of the risk factors for POI. We used PubMed to search peer-reviewed original English manuscripts published over the last 10 years to identify established and experimental studies on the relationship between various types of stress and decreased ovarian function. Oxidative stress, follicular atresia, and excessive activation of oocytes, caused by Stress-associated factors may be the main causes of ovarian function damage. This article reviews the relationship between psychological stressors and hypoovarian function and the possible early intervention measures in order to provide new ideas for future clinical treatment and intervention.


Asunto(s)
Insuficiencia Ovárica Primaria , Estrés Psicológico , Humanos , Insuficiencia Ovárica Primaria/psicología , Insuficiencia Ovárica Primaria/etiología , Insuficiencia Ovárica Primaria/terapia , Femenino , Estrés Psicológico/complicaciones , Estrés Oxidativo/fisiología , Factores de Riesgo , Depresión/etiología
12.
Molecules ; 29(11)2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38893373

RESUMEN

Developing clinically meaningful nanomedicines for cancer therapy requires the drugs to be effective, safe, simple, cheap, and easy to store. In the present work, we report that a simple cationic Fe(III)-rich salt of [FeIIICl(TMPPH2)][FeIIICl4]2 (Fe-TMPP) exhibits a superior anticancer performance on a broad spectrum of cancer cell lines, including breast, colorectal cancer, liver, pancreatic, prostate, and gastric cancers, with half maximal inhibitory concentration (IC50) values in the range of 0.098-3.97 µM (0.066-2.68 µg mL-1), comparable to the best-reported medicines. Fe-TMPP can form stand-alone nanoparticles in water without the need for extra surface modification or organic-solvent-assisted antisolvent precipitation. Critically, Fe-TMPP is TME-responsive (TME = tumor microenvironment), and can only elicit its function in the TME with overexpressed H2O2, converting H2O2 to the cytotoxic •OH to oxidize the phospholipid of the cancer cell membrane, causing ferroptosis, a programmed cell death process of cancer cells.


Asunto(s)
Antineoplásicos , Ferroptosis , Nanomedicina , Humanos , Ferroptosis/efectos de los fármacos , Línea Celular Tumoral , Nanomedicina/métodos , Antineoplásicos/farmacología , Antineoplásicos/química , Nanopartículas/química , Compuestos Férricos/química , Microambiente Tumoral/efectos de los fármacos , Peróxido de Hidrógeno/química , Peróxido de Hidrógeno/farmacología , Supervivencia Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología
13.
Anal Chem ; 95(40): 15025-15032, 2023 10 10.
Artículo en Inglés | MEDLINE | ID: mdl-37769140

RESUMEN

Accurate and specific imaging of low-abundance microRNA (miRNA) in living cells is extremely important for disease diagnosis and monitoring of disease progression. DNA nanomotors have shown great potential for imaging molecules of interest in living cells. However, inappropriate driving forces and complex design and operation procedures have hindered their further application. Here, we proposed an endogenous enzyme-powered DNA nanomotor (EEPDN), which employs an endogenous APE1 enzyme as fuel to execute repetitive cycles of motion for miRNA imaging in living cells. The whole motor system is constructed based on gold nanoparticles without other auxiliary additives. Due to the high efficiency of APE1, this EEPDN system has achieved highly sensitive miRNA imaging in living cells within 1.5 h. This strategy was also successfully used to differentiate the expression of specific miRNA between tumor cells and normal cells, demonstrating a high tumor cell selectivity. This strategy can promote the development of novel nanomotors and is expected to be a perfect intracellular molecular imaging tool for biological and medical applications.


Asunto(s)
Nanopartículas del Metal , MicroARNs , MicroARNs/genética , Oro , ADN/genética , Diagnóstico por Imagen
14.
Int Arch Allergy Immunol ; 184(6): 529-538, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37231897

RESUMEN

Since the global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a symptom of the onset of SARS-CoV-2, olfactory dysfunction (OD), has attracted tremendous attention. OD is not only a negative factor for quality of life but also an independent hazard and early biomarker for various diseases, such as Parkinson's and Huntington's diseases. Therefore, early identification and treatment of OD in patients are critical. Many etiological factors are responsible for OD based on current opinions. Sniffin'Sticks are recommended to identify the initial position (central or peripheral) for OD when treating patients clinically. It is worth emphasizing that the olfactory region in nasal cavity is recognized as the primary and critical olfactory receptor. Many nasal diseases, such as those with traumatic, obstructive and inflammatory causes, can lead to OD. The key question is no refined diagnosis or treatment strategy for nasogenic OD currently. This study summarizes the differences in medical history, symptoms, auxiliary examination, treatment and prognosis of different types of nasogenic OD by analyzing the current studies. We propose using olfactory training after 4-6 weeks of initial treatment for nasogenic OD patients with no significant improvement in olfaction. We hope that our research can provide valuable clinical guidance by systematically summarizing the clinical characteristics of nasogenic OD.


Asunto(s)
Trastornos del Olfato , Trastornos del Olfato/diagnóstico , Trastornos del Olfato/terapia , Humanos , Cavidad Nasal , Pronóstico , Inflamación
15.
Acta Pharmacol Sin ; 44(12): 2537-2548, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37528233

RESUMEN

5-Fluorouracil (5-FU) is the first-line treatment for colorectal cancer (CRC) patients, but the development of acquired resistance to 5-FU remains a big challenge. Deubiquitinases play a key role in the protein degradation pathway, which is involved in cancer development and chemotherapy resistance. In this study, we investigated the effects of targeted inhibition of the proteasomal deubiquitinases USP14 and UCHL5 on the development of CRC and resistance to 5-FU. By analyzing GEO datasets, we found that the mRNA expression levels of USP14 and UCHL5 in CRC tissues were significantly increased, and negatively correlated with the survival of CRC patients. Knockdown of both USP14 and UCHL5 led to increased 5-FU sensitivity in 5-FU-resistant CRC cell lines (RKO-R and HCT-15R), whereas overexpression of USP14 and UCHL5 in 5-FU-sensitive CRC cells decreased 5-FU sensitivity. B-AP15, a specific inhibitor of USP14 and UCHL5, (1-5 µM) dose-dependently inhibited the viability of RKO, RKO-R, HCT-15, and HCT-15R cells. Furthermore, treatment with b-AP15 reduced the malignant phenotype of CRC cells including cell proliferation and migration, and induced cell death in both 5-FU-sensitive and 5-FU-resistant CRC cells by impairing proteasome function and increasing reactive oxygen species (ROS) production. In addition, b-AP15 inhibited the activation of NF-κB pathway, suppressing cell proliferation. In 5-FU-sensitive and 5-FU-resistant CRC xenografts nude mice, administration of b-AP15 (8 mg·kg-1·d-1, intraperitoneal injection) effectively suppressed the growth of both types of tumors. These results demonstrate that USP14 and UCHL5 play an important role in the development of CRC and resistance to 5-FU. Targeting USP14 and UCHL5 with b-AP15 may represent a promising therapeutic strategy for the treatment of CRC.


Asunto(s)
Neoplasias Colorrectales , Complejo de la Endopetidasa Proteasomal , Animales , Ratones , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismo , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Ratones Desnudos , Apoptosis , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos , Ubiquitina Tiolesterasa
16.
J Chem Phys ; 158(8): 084701, 2023 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-36859091

RESUMEN

Unraveling the origin of Helmholtz capacitance is of paramount importance for understanding the interfacial structure and electrostatic potential distribution of electric double layers (EDL). In this work, we combined the methods of ab initio molecular dynamics and classical molecular dynamics and modeled electrified Cu(100)/electrolyte and graphene/electrolyte interfaces for comparison. It was proposed that the Helmholtz capacitance is composed of three parts connected in series: the usual solvent capacitance, water chemisorption induced capacitance, and Pauling repulsion caused gap capacitance. We found the Helmholtz capacitance of graphene is significantly lower than that of Cu(100), which was attributed to two intrinsic factors. One is that graphene has a wider gap layer at interface, and the other is that graphene is less active for water chemisorption. Finally, based on our findings, we provide suggestions for how to increase the EDL capacitance of graphene-based materials in future work, and we also suggest that the new understanding of the potential distribution across the Helmholtz layer may help explain some experimental phenomena of electrocatalysis.

17.
J Nanobiotechnology ; 21(1): 18, 2023 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-36650517

RESUMEN

The occurrence of osteoarthritis (OA) is highly correlated with the reduction of joint lubrication performance, in which persistent excessive inflammation and irreversible destruction of cartilage dominate the mechanism. The inadequate response to monotherapy methods, suboptimal efficacy caused by undesirable bioavailability, short retention, and lack of stimulus-responsiveness, are few unresolved issues. Herein, we report a pH-responsive metal-organic framework (MOF), namely, MIL-101-NH2, for the co-delivery of anti-inflammatory drug curcumin (CCM) and small interfering RNA (siRNA) for hypoxia inducible factor (HIF-2α). CCM and siRNA were loaded via encapsulation and surface coordination ability of MIL-101-NH2. Our vitro tests showed that MIL-101-NH2 protected siRNA from nuclease degradation by lysosomal escape. The pH-responsive MIL-101-NH2 gradually collapsed in an acidic OA microenvironment to release the CCM payloads to down-regulate the level of pro-inflammatory cytokines, and to release the siRNA payloads to cleave the target HIF-2α mRNA for gene-silencing therapy, ultimately exhibiting the synergetic therapeutic efficacy by silencing HIF-2α genes accompanied by inhibiting the inflammation response and cartilage degeneration of OA. The hybrid material reported herein exhibited promising potential performance for OA therapy as supported by both in vitro and in vivo studies and may offer an efficacious therapeutic strategy for OA utilizing MOFs as host materials.


Asunto(s)
Curcumina , Estructuras Metalorgánicas , Osteoartritis , Humanos , Curcumina/farmacología , Condrocitos/metabolismo , ARN Interferente Pequeño/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Inflamación/metabolismo , Concentración de Iones de Hidrógeno
18.
J Nanobiotechnology ; 21(1): 138, 2023 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-37106405

RESUMEN

Since the successful clinical trial of AuroShell for photothermal therapy, there is currently intense interest in developing gold-based core-shell structures with near-infrared (NIR) absorption ranging from NIR-I (650-900 nm) to NIR-II (900-1700 nm). Here, we propose a seed-mediated successive growth approach to produce gold nanoshells on the surface of the nanoscale metal-organic framework (NMOF) of UiO-66-NH2 (UiO = the University of Oslo) in one pot. The key to this strategy is to modulate the proportion of the formaldehyde (reductant) and its regulator / oxidative product of formic acid to harness the particle nucleation and growth rate within the same system. The gold nanoshells propagate through a well-oriented and controllable diffusion growth pattern (points → facets → octahedron), which has not been identified. Most strikingly, the gold nanoshells prepared hereby exhibit an exceedingly broad and strong absorption in NIR-II with a peak beyond 1300 nm and outstanding photothermal conversion efficiency of 74.0%. Owing to such superior performance, these gold nanoshells show promising outcomes in photoacoustic (PA), computed tomography (CT), and photothermal imaging-guided photothermal therapy (PTT) for breast cancer, as demonstrated both in vitro and in vivo.


Asunto(s)
Nanocáscaras , Nanocáscaras/química , Terapia Fototérmica , Oro/química , Imagen Multimodal , Fototerapia
19.
Molecules ; 28(5)2023 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-36903368

RESUMEN

The delivery of biocompatible reagents into cancer cells can elicit an anticancer effect by taking advantage of the unique characteristics of the tumor microenvironment (TME). In this work, we report that nanoscale two-dimensional FeII- and CoII-based metal-organic frameworks (NMOFs) of porphyrin ligand meso-tetrakis (6-(hydroxymethyl) pyridin-3-yl) porphyrin (THPP) can catalyze the generation of hydroxyl radicals (•OH) and O2 in the presence of H2O2 that is overexpressed in the TME. Photodynamic therapy consumes the generated O2 to produce a singlet oxygen (1O2). Both •OH and 1O2 are reactive oxygen species (ROS) that inhibit cancer cell proliferation. The FeII- and CoII-based NMOFs were non-toxic in the dark but cytotoxic when irradiated with 660 nm light. This preliminary work points to the potential of porphyrin-based ligands of transition metals as anticancer drugs by synergizing different therapeutic modalities.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Estructuras Metalorgánicas , Neoplasias , Fotoquimioterapia , Porfirinas , Humanos , Femenino , Estructuras Metalorgánicas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Porfirinas/farmacología , Peróxido de Hidrógeno/farmacología , Ligandos , Fotoquimioterapia/métodos , Neoplasias/tratamiento farmacológico , Antineoplásicos/farmacología , Compuestos Ferrosos/farmacología , Fármacos Fotosensibilizantes/farmacología , Microambiente Tumoral
20.
BMC Oral Health ; 23(1): 312, 2023 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-37217888

RESUMEN

OBJECTIVES: This study was conducted to detect the overall performance of both static and dynamic occlusion in post-orthodontic patients using quantified methods, and to ascertain the correlation between the two states of occlusion. MATERIALS AND METHODS: A total of 112 consecutive patients evaluated by ABO-OGS were included in this study. Based on the pre-treatment Angle's classification of the malocclusion, samples were divided into four groups. After removing orthodontic appliances, each patients underwent the American Board of Orthodontic objective grading system (ABO-OGS) and T-Scan evaluations. All the scores were compared within these groups. Statistical evaluation included reliability tests, multivariate ANOVA, and correlation analyses (p < 0.05 was considered significant). RESULTS: The mean ABO-OGS score was satisfactory and did not differ by Angle classifications. The indices making substantial contributions to ABO-OGS were occlusal contacts, occlusal relationships, overjet, and alignment. Disocclusion time in post-orthodontic patients was longer than normal. Occlusion time, disocclusion time, and force distribution during dynamic motions were considerably influenced by static ABO-OGS measurements, especially occlusal contacts, buccolingual inclination, and alignment. CONCLUSION: Post-orthodontic cases that passed the static evaluation of clinicians and ABO-OGS may nevertheless be left with dental casts interference in dynamic motions. Both static and dynamic occlusion should be extensively evaluated before ending orthodontic treatment. Further research is needed on dynamic occlusal guidelines and standards.


Asunto(s)
Maloclusión , Ortodoncia , Humanos , Estados Unidos , Consejos de Especialidades , Reproducibilidad de los Resultados , Maloclusión/terapia , Oclusión Dental
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