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1.
Anal Chem ; 95(38): 14261-14270, 2023 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-37712902

RESUMEN

Bioluminescence imaging has changed the daily practice of preclinical research on cancer and other diseases over the last few decades; however, it has rarely been applied in preclinical research on Alzheimer's disease (AD). In this Article, we demonstrated that bioluminescence imaging could be used to report the levels of amyloid beta (Aß) species in vivo. We hypothesized that AkaLumine, a newly discovered substrate for luciferase, could bind to Aß aggregates and plaques. We further speculated that the Aß aggregates/fibrils/plaques could be considered as "functional amyloids", which have a reservoir function to sequester and release AkaLumine to control the bioluminescence intensity, which could be used to report the levels of Aßs. Our hypotheses have been validated via in vitro solution tests, mimic studies with brain tissues and mice, two-photon imaging with AD mice, and in vivo bioluminescence imaging using transgenic AD mice that were virally transduced with AkaLuciferase (AkaLuc), a new luciferase that generates bioluminescence in the near-infrared window. As expected, compared to the control group, we observed that the Aß group showed lower bioluminescence intensity due to AkaLumine sequestering at early time points, while higher intensity was due to AkaLumine releasing at later time points. Lastly, we demonstrated that this method could be used to monitor AD progression and the therapeutic effectiveness of avagacestat, a well-studied gamma-secretase inhibitor. Importantly, a good correlation (R2 = 0.81) was established between in vivo bioluminescence signals and Aß burdens of the tested AD mice. We believe that our approach can be easily implemented into daily imaging experiments and has tremendous potential to change the daily practice of preclinical AD research.


Asunto(s)
Enfermedad de Alzheimer , Animales , Ratones , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides , Proteínas Amiloidogénicas , Secretasas de la Proteína Precursora del Amiloide , Citoesqueleto , Ratones Transgénicos , Placa Amiloide
2.
Zhongguo Zhong Yao Za Zhi ; 48(24): 6702-6710, 2023 Dec.
Artículo en Zh | MEDLINE | ID: mdl-38212030

RESUMEN

This study aims to explore the influence of Polygonati Rhizoma on the pyroptosis in the rat model of diabetic macroangiopathy via the NOD-like receptor thermal protein domain associated protein 3(NLRP3)/cysteinyl aspartate specific proteinase-1(caspase-1)/gasdermin D(GSDMD) pathway. The rat model of diabetes was established by intraperitoneal injection of streptozotocin(STZ) combined with a high-fat, high-sugar diet. The blood glucose meter, fully automated biochemical analyzer, hematoxylin-eosin(HE) staining, enzyme-linked immunosorbent assay, immunofluorescence, immunohistochemistry, and Western blot were employed to measure blood glucose levels, lipid levels, vascular thickness, inflammatory cytokine levels, and expression levels of pyroptosis-related proteins. The mechanism of pharmacological interventions against the injury in the context of diabetes was thus explored. The results demonstrated the successful establishment of the model of diabetes. Compared with the control group, the model group showed elevated levels of fasting blood glucose, total cholesterol(TC), triglycerides(TG) and low-density lipoprotein cholesterol(LDL-c), lowered level of high-density lipoprotein cholesterol(HDL-c), thickened vascular intima, and elevated serum and aorta levels of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß) and interleukin-18(IL-18). Moreover, the model group showed increased NLRP3 inflammasomes and up-regulated levels of caspase-1 and GSDMD in aortic vascular cells. Polygonati Rhizoma intervention reduced blood glucose and lipid levels, inhibited vascular thickening, lowered the levels of TNF-α, IL-1ß, IL-18 in the serum and aorta, attenuated NLRP3 inflammasome expression, and down-regulated the expression levels of caspase-1 and GSDMD, compared with the model group. In summary, Polygonati Rhizoma can slow down the progression of diabetic macroangiopathy by inhibiting pyroptosis and alleviating local vascular inflammation.


Asunto(s)
Complicaciones de la Diabetes , Diabetes Mellitus , Enfermedades Vasculares , Animales , Ratas , Caspasa 1/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Interleucina-18 , Glucemia , Piroptosis , Factor de Necrosis Tumoral alfa , Inflamasomas , Colesterol , Lípidos
3.
Angew Chem Int Ed Engl ; 62(45): e202312519, 2023 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-37721455

RESUMEN

The development of Alzheimer's disease (AD) drugs has recently witnessed substantial achievement. To further enhance the pool of drug candidates, it is crucial to explore non-traditional therapeutic avenues. In this study, we present the use of a photolabile curcumin-diazirine analogue, CRANAD-147, to induce changes in properties, structures (sequences), and neurotoxicity of amyloid beta (Aß) species both in cells and in vivo. This manipulation was achieved through irradiation with LED light or molecularly generated light, dubbed as "molecular light", emitted by the chemiluminescence probe ADLumin-4. Next, aided by molecular chemiluminescence imaging, we demonstrated that the combination of CRANAD-147/LED or CRANAD-147/ADLumin-4 (molecular light) could effectively slow down the accumulation of Aßs in transgenic 5xFAD mice in vivo. Leveraging the remarkable tissue penetration capacity of molecular light, phototherapy employing the synergistic effect of a photolabile Aß ligand and molecular light emerges as a promising alternative to conventional AD treatment interventions.


Asunto(s)
Enfermedad de Alzheimer , Curcumina , Ratones , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/química , Curcumina/farmacología , Curcumina/uso terapéutico , Diazometano , Ratones Transgénicos , Fototerapia , Modelos Animales de Enfermedad
4.
J Am Chem Soc ; 144(9): 4091-4101, 2022 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-35171598

RESUMEN

Despite the clinical success of photodynamic therapy (PDT), the application of this medical technique is intrinsically limited by the low oxygen concentrations found in cancer tumors, hampering the production of therapeutically necessary singlet oxygen (1O2). To overcome this limitation, we report on a novel mitochondria-localized iridium(III) endoperoxide prodrug (2-O-IrAn), which, upon two-photon irradiation in NIR, synergistically releases a highly cytotoxic iridium(III) complex (2-IrAn), singlet oxygen, and an alkoxy radical. 2-O-IrAn was found to be highly (photo-)toxic in hypoxic tumor cells and multicellular tumor spheroids (MCTS) in the nanomolar range. To provide cancer selectivity and improve the pharmacological properties of 2-O-IrAn, it was encapsulated into a biotin-functionalized polymer. The generated nanoparticles were found to nearly fully eradicate the tumor inside a mouse model within a single treatment. This study presents, to the best of our knowledge, the first example of an iridium(III)-based endoperoxide prodrug for synergistic photodynamic therapy/photoactivated chemotherapy, opening up new avenues for the treatment of hypoxic tumors.


Asunto(s)
Neoplasias , Fotoquimioterapia , Profármacos , Animales , Línea Celular Tumoral , Hipoxia/tratamiento farmacológico , Iridio/farmacología , Ratones , Mitocondrias , Neoplasias/tratamiento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Profármacos/farmacología , Profármacos/uso terapéutico , Oxígeno Singlete/uso terapéutico
5.
Anal Chem ; 94(28): 10283-10290, 2022 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-35776781

RESUMEN

G-quadruplex (G4) is a noncanonical nucleic acid secondary structure that has implications for various physiological and pathological processes and is thus essential to exploring new approaches to G4 detection in live cells. However, the deficiency of molecular imaging tools makes it challenging to visualize the G4 in ex vivo tissue samples. In this study, we established a G4 probe design strategy and presented a red fluorescent benzothiazole derivative, ThT-NA, to detect and image G4 structures in living cells and tissue samples. By enhancing the electron-donating group of thioflavin T (ThT) and optimizing molecular structure, ThT-NA shows excellent photophysical properties, including red emission (610 nm), a large Stokes shift (>100 nm), high sensitivity selectivity toward G4s (1600-fold fluorescence turn-on ratio) and robust two-photon fluorescence emission. Therefore, these features enable ThT-NA to reveal the endogenous RNA G4 distribution in living cells and differentiate the cell cycle by monitoring the changes of RNA G4 folding. Significantly, to the best of our knowledge, ThT-NA is the first benzothiazole-derived G4 probe that has been developed for imaging G4s in ex vivo cancer tissue samples by two-photon microscopy techniques.


Asunto(s)
G-Cuádruplex , Benzotiazoles/química , Colorantes Fluorescentes/química , ARN , Espectrometría de Fluorescencia
6.
Biopolymers ; 113(12): e23528, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36444749

RESUMEN

G-quadruplexes (G4s), the noncanonical nucleic acid secondary structure, form within guanine-rich DNA or RNA sequences. G4s formation can affect chromatin architecture and gene regulation and has been associated with various cellular functions, including DNA replication, transcription, and genome maintenance. Visualizing and detecting G4s precisely in such processes is essential to increasing our understanding of G4s biology. Considerable attention has focused on the G4s targeting molecular imaging studies. Besides, fluorescent light-up aptamers (FLAPs, also referred to as fluorogenic aptamers) have gained momentum, which commonly have a G4 scaffolding for imaging intracellular RNAs and metabolites. In this review, we first introduce several representative fluorescent imaging approaches for tracking G4s in cells and in vivo. We also discuss the potential of G4-containing FLAPs in bioimaging and summarize current developments in this field from the standpoint of fluorescent molecules. Finally, we discuss the present challenges and future potential of G4 imaging and G4-containing FLAPs development.


Asunto(s)
G-Cuádruplex , ADN/química , ARN/química , Oligonucleótidos , Regulación de la Expresión Génica
7.
Anal Chem ; 93(28): 9887-9896, 2021 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-34235921

RESUMEN

Molecular switching plays a critical role in biological and displaying systems. Donor-acceptor Stenhouse adducts (DASAs) is a newly re-discovered series of switchable photochromes, and light is the most used approach to control its switching behavior. In this report, we speculated that hydrophobic binding pockets of biologically relevant peptides/proteins could be harnessed to alter its switching behavior without the assistance of light. We designed and synthesized a DASA compound SHA-2, and we demonstrated that the Aß40 species could stabilize SHA-2 in the linear conformation and decrease the rate of molecular switching via fluorescence spectral studies. Moreover, molecular dynamics simulation revealed that SHA-2 could bind to the hydrophobic fragment of the peptide and resulted in substantial changes in the tertiary structure of Aß40 monomer. This structural change is likely to impede the aggregation of Aß40, as evidenced by the results from thioflavin T fluorescence and ProteoStat aggregation detection experiments. We believe that our study opens a new window to alter the switching behavior of DASA via DASA-peptide/protein interactions.


Asunto(s)
Péptidos beta-Amiloides , Simulación de Dinámica Molecular , Interacciones Hidrofóbicas e Hidrofílicas , Fragmentos de Péptidos
8.
Chemistry ; 27(1): 362-370, 2021 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-32716591

RESUMEN

During the last decades, photodynamic therapy (PDT), an approved medical technique, has received increasing attention to treat certain types of cancer. Despite recent improvements, the treatment of large tumors remains a major clinical challenge due to the low ability of the photosensitizer (PS) to penetrate a 3D cellular architecture and the low oxygen concentrations present in the tumor center. To mimic the conditions found in clinical tumors, exceptionally large 3D multicellular tumor spheroids (MCTSs) with a diameter of 800 µm were used in this work to test a series of new RuII polypyridine complexes as one-photon and two-photon PSs. These metal complexes were found to fully penetrate the 3D cellular architecture and to generate singlet oxygen in the hypoxic center upon light irradiation. While having no observed dark toxicity, the lead compound of this study showed an impressive phototoxicity upon clinically relevant one-photon (595 nm) or two-photon (800 nm) excitation with a full eradication of the hypoxic center of the MCTSs. Importantly, this efficacy was also demonstrated on mice bearing an adenocarcinomic human alveolar basal epithelial tumor.


Asunto(s)
Compuestos Organometálicos , Fotoquimioterapia , Fármacos Fotosensibilizantes , Rutenio , Adenocarcinoma Bronquioloalveolar/tratamiento farmacológico , Adenocarcinoma Bronquioloalveolar/metabolismo , Animales , Células HeLa , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Ratones , Neoplasias Basocelulares/tratamiento farmacológico , Neoplasias Basocelulares/metabolismo , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacología , Fotones/uso terapéutico , Fármacos Fotosensibilizantes/farmacología , Piridinas/química , Piridinas/farmacología , Rutenio/química , Rutenio/farmacología , Oxígeno Singlete/metabolismo , Esferoides Celulares , Hipoxia Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Pharmacol Res ; 173: 105886, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34536549

RESUMEN

OBJECTIVES: To enable non-invasive real-time quantification of vasopressin 1A (V1A) receptors in peripheral organs, we sought to develop a suitable PET probe that would allow specific and selective V1A receptor imaging in vitro and in vivo. METHODS: We synthesized a high-affinity and -selectivity ligand, designated compound 17. The target structure was labeled with carbon-11 and tested for its utility as a V1A-targeted PET tracer by cell uptake studies, autoradiography, in vivo PET imaging and ex vivo biodistribution experiments. RESULTS: Compound 17 (PF-184563) and the respective precursor for radiolabeling were synthesized in an overall yield of 49% (over 7 steps) and 40% (over 8 steps), respectively. An inhibitory constant of 0.9 nM towards the V1A receptors was measured, while excellent selectivity over the related V1B, V2 and OT receptor (IC50 >10,000 nM) were obtained. Cell uptake studies revealed considerable V1A binding, which was significantly reduced in the presence of V1A antagonists. Conversely, there was no significant blockade in the presence of V1B and V2 antagonists. In vitro autoradiography and PET imaging studies in rodents indicated specific tracer binding mainly in the liver. Further, the pancreas, spleen and the heart exhibited specific binding of [11C]17 ([11C]PF-184563) by ex vivo biodistribution experiments. CONCLUSION: We have developed the first V1A-targeted PET ligand that is suitable for subtype-selective receptor imaging in peripheral organs including the liver, heart, pancreas and spleen. Our findings suggest that [11C]PF-184563 can be a valuable tool to study the role of V1A receptors in liver diseases, as well as in cardiovascular pathologies.


Asunto(s)
Benzodiazepinas/farmacología , Radiofármacos/farmacología , Receptores de Vasopresinas/metabolismo , Triazoles/farmacología , Animales , Autorradiografía , Benzodiazepinas/farmacocinética , Células CHO , Radioisótopos de Carbono , Cricetulus , Femenino , Ligandos , Hígado/metabolismo , Masculino , Ratones , Miocardio/metabolismo , Páncreas/metabolismo , Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Ratas Wistar , Bazo/metabolismo , Triazoles/farmacocinética
10.
BMC Musculoskelet Disord ; 22(1): 28, 2021 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-33407335

RESUMEN

BACKGROUND: To evaluate the clinical outcomes of arthroscopic tight fibrous band release in the treatment of adult moderate-to-severe gluteal fibrosis using anterior and posterior portals during mid-term follow-up. METHODS: The data of 138 patients (58 males, 80 females) aged between 18 and 42 years (mean, 28.6 years), presenting with bilateral moderate-to-severe gluteal fibrosis (GF) from October 2013 to August 2019, was retrospectively analyzed. All patients underwent arthroscopic tight fibrous band release using anterior and posterior portals with radiofrequency energy. Under arthroscopic guidance through the posterior portal, we debrided the fatty tissue overlying the contracted band of the gluteal muscle and excised the contracted bands using a radiofrequency device introduced through the anterior portal. The pre- and post-operative gluteal muscle contracture disability (GD) scale and the patient satisfaction rate were compared to evaluate the curative effect of the operation. RESULTS: The average operation time was 18 min (range, 10-30 min) and the average blood loss was 4 ml (range, 2-10 ml) for unilateral arthroscopic release. Two cases of post-operative minimal hematomas, 2 cases of bruising and 2 cases of local subcutaneous edema were observed as early complications and were cured by conservative treatment. After surgery, all incisions healed in stage I, and no other complications such as wound infection, nerve and blood vessel injury were detected. One hundred eighteen patients were followed up for 6 to 72 months (mean, 36 months). No lateral instability of the hip was observed and all patients returned to normal gait. The degree of adduction of the hip joint in all these 118 patients was significantly improved relative to their pre-operative conditions. One hundred fifteen patients (97.5%) were able to crouch with knees close to each other after surgery. One hundred fourteen patients (96.6%) were able to cross the affected leg completely without any support. The GD scale was improved from 55.5 ± 10.6 before operation to 90.1 ± 5.2 at the last follow-up (p < 0.05). The patient satisfaction rate was 95.8%. CONCLUSION: Arthroscopic tight fibrous band release using anterior and posterior portals is minimally invasive for adult moderate-to-severe gluteal fibrosis, with a high success rate, quick recovery after surgery and reliable medium-term effect.


Asunto(s)
Artroscopía , Contractura , Adolescente , Adulto , Nalgas , Femenino , Fibrosis , Humanos , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
11.
Ann Noninvasive Electrocardiol ; 25(3): e12714, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31674726

RESUMEN

PURPOSE: The aim is to measure and analyze the wave amplitudes and time intervals of differential graphs of reconstructed impedance cardiography (RICG). METHODS: 180 adults with normal cardiac function between the ages of 18-78 were included in the study. Six mingled impedance changes on chest surface were simultaneously detected for each subject. The differential graphs of five impedance change components of RICG were obtained through waveform separation and software differentiation. The amplitudes of C, X, O, b waves and time intervals of Q-b and Q-C were measured and statistically analyzed. RESULTS: The amplitudes of C and X waves in PL, PR, AO, and that of C, O, b waves in LV and RV, all decrease as age increases. Wave amplitudes of the female group were bigger than those of the male group (p < .01), while the Q-C intervals of the female group were shorter than that of the male group (p < .01). Among five impedance change components, the wave amplitude of AO was larger than those of PL and PR (p < .01), and wave amplitudes of PL and PR were bigger than those of LV and RV (p < .01). Q-C intervals of LV and RV were longer than those of AO, PL and PR (p < .01), while the Q-b intervals of LV and RV were shorter than the Q-C intervals of AO, PL, and PR. CONCLUSIONS: The differential graphs of RICG could reflect indirectly the physiological activities and pathological changes of the heart and of the large blood vessels in thorax.


Asunto(s)
Cardiografía de Impedancia/métodos , Cardiografía de Impedancia/estadística & datos numéricos , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Adulto Joven
12.
BMC Musculoskelet Disord ; 21(1): 440, 2020 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-32631287

RESUMEN

BACKGROUND: This study aimed to compare the arthroscopic internal drainage of popliteal cysts alone or in combination with cyst wall resection in terms of clinical outcomes. METHODS: Forty-two consecutive patients with symptomatic popliteal cysts received arthroscopic treatment. Specifically, 20 of them received arthroscopic internal drainage (AI group) alone and 22 received arthroscopic internal drainage combined with cyst wall resection (AICR group) through double posteromedial portals. Magnetic resonance imaging (MRI) was performed to identify recurrence of popliteal cysts. The Lysholm score and Rauschning-Lindgren grade were used to assess the clinical outcomes. The median of the follow-up period was 24 months (12-48 months). RESULTS: The two groups (AI group and AICR group) were similar in age, gender, cyst diameter, associated joint disorder, preoperative Lysholm score, preoperative Rauschning-Lindgren grade and follow-up period (P > 0.05). Relative to the AI group, the AICR group had a significantly prolonged operation time (P < 0.05) and a higher incidence of complications (P < 0.05). In both groups, the Rauschning-Lindgren grade at the last follow-up significantly differed from the preoperative grade (P < 0.05) and the Lysholm knee score remarkably increased compared to the preoperative score (P < 0.05); however, there were no differences between the two groups at the last follow-up (P > 0.05). According to the MRI results, the cyst disappeared in 11 (55%), shrank in size in 6 (30%) and existed in 3 (15%) patients in the AI group, and was absent in 18 (81.8%) and shrank in size in 4 (18.2%) patients in the AICR group, suggesting a significant difference between the two (P < 0.05). CONCLUSION: Additional resection of cyst wall can result in a lower recurrence rate of cysts but extend the operation time and increase the incidence of perioperative complications compared with arthroscopic internal drainage of popliteal cysts alone.


Asunto(s)
Artroscopía/métodos , Drenaje/métodos , Recurrencia Local de Neoplasia/prevención & control , Quiste Poplíteo/cirugía , Adulto , China , Femenino , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/cirugía , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tempo Operativo , Quiste Poplíteo/diagnóstico por imagen , Complicaciones Posoperatorias , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
13.
Psychol Health Med ; 25(6): 666-674, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31259609

RESUMEN

The purpose of this study was to explore levels of organizational commitment, job satisfaction and work engagement among community health-care workers in China, and to examine spatial relationships of variables. Data were collected by Organizational Commitment Scale, Job Satisfaction Scale and Utrecht Work Engagement Scale from 1404 community health-care workers in Guangzhou and Shenzhen cities. Structural equation model was used to analyze relationships among three variables. Medium levels of organizational commitment, job satisfaction and work engagement were found among community health-care workers. Organizational commitment was positively correlated to work engagement (r = 0.564) and job satisfaction (r = 0.550). The path analysis indicated that total effect (ß = 0.598) of organizational commitment on job satisfaction (R2 = 0.52) consisted of a direct effect (ß = 0.264) and an indirect effect (ß = 0.334), which was mediated positively by work engagement. Improvement in work engagement may lead to higher level of job satisfaction and organizational commitment.


Asunto(s)
Personal de Salud , Satisfacción en el Trabajo , Lealtad del Personal , Compromiso Laboral , Adulto , China , Estudios Transversales , Femenino , Médicos Generales , Humanos , Masculino , Persona de Mediana Edad , Enfermeras y Enfermeros , Encuestas y Cuestionarios , Adulto Joven
14.
Angew Chem Int Ed Engl ; 59(46): 20697-20703, 2020 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-32735748

RESUMEN

The efficacy of photodynamic therapy is typically reliant on the local concentration and diffusion of oxygen. Due to the hypoxic microenvironment found in solid tumors, oxygen-independent photosensitizers are in great demand for cancer therapy. We herein report an iridium(III) anthraquinone complex as a mitochondrion-localized carbon-radical initiator. Its emission is turned on under hypoxic conditions after reduction by reductase. Furthermore, its two-photon excitation properties (λex =730 nm) are highly desirable for imaging. Upon irradiation, the reduced form of the complex generates carbon radicals, leading to a loss of mitochondrial membrane potential and cell death (IC50light =2.1 µm, IC50dark =58.2 µm, PI=27.7). The efficacy of the complex as a PDT agent was also demonstrated under hypoxic conditions in vivo. To the best of our knowledge, it is the first metal-complex-based theranostic agent which can generate carbon radicals for oxygen-independent two-photon photodynamic therapy.


Asunto(s)
Carbono/química , Hipoxia de la Célula , Mitocondrias/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/farmacología , Humanos , Mitocondrias/metabolismo , NADP/metabolismo , Neoplasias/patología , Fotoquimioterapia/métodos , Fotones , Análisis Espectral/métodos , Microambiente Tumoral
15.
Angew Chem Int Ed Engl ; 59(8): 3315-3321, 2020 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-31828932

RESUMEN

Reported is the FeIII -activated lysosome-targeting prodrug FerriIridium for gastric cancer theranostics. It contains a meta-imino catechol group that can selectively bond to, and be oxidized by, free FeIII inside the cell. Subsequent oxidative rearrangement releases FeII and hydrolyses the amine bond under acidic conditions, forming an aminobipyridyl Ir complex and 2-hydroxybenzoquinone. Thus, FeII catalyzes the Fenton reaction, transforming hydrogen peroxide into hydroxyl radicals, the benzoquinone compounds interfere with the respiratory chain, and conversion of the prodrug into the Ir complex leads to an increase in phosphorescence and toxicity. These properties, combined with the high FeIII content and acidity of cancer cells, make FerriIridium a selective and efficient theranostic agent (IC50 =9.22 µm for AGS cells vs. >200 µm for LO2 cells). FerriIridium is the first metal-based compound that has been developed for chemotherapy using FeIII to enhance both selectivity and potency.


Asunto(s)
Iridio/química , Hierro/química , Profármacos/química , Neoplasias Gástricas/tratamiento farmacológico , Animales , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares
16.
Appl Opt ; 56(3): 721-730, 2017 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-28157936

RESUMEN

The Langley mobile ozone lidar (LMOL) is a mobile ground-based ozone lidar system that consists of a pulsed UV laser producing two UV wavelengths of 286 and 291 nm with energy of approximately 0.2 mJ/pulse and repetition rate of 1 kHz. The 527 nm pump laser is also transmitted for aerosol measurements. The receiver consists of a 40 cm parabolic telescope, which is used for both backscattered analog and photon counting. The lidar is very compact and highly mobile. This demonstrates the utility of very small lidar systems eventually leading to space-based ozone lidars. The lidar has been validated by numerous ozonesonde launches and has provided ozone curtain profiles from ground to approximately 4 km in support of air quality field missions.

17.
Chemistry ; 22(26): 8955-65, 2016 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-27145442

RESUMEN

In the present study, four mitochondria-specific and two-photon phosphorescence iridium(III) complexes, Ir1-Ir4, were developed for mitochondria imaging in hypoxic tumor cells. The iridium(III) complex has two anthraquinone groups that are hypoxia-sensitive moieties. The phosphorescence of the iridium(III) complex was quenched by the functions of the intramolecular quinone unit, and it was restored through two-electron bioreduction under hypoxia. When the probes were reduced by reductase to hydroquinone derivative products under hypoxia, a significant enhancement in phosphorescence intensity was observed under one- (λ=405 nm) and two-photon (λ=720 nm) excitation, with a two-photon absorption cross section of 76-153 GM at λ=720 nm. More importantly, these probes possessed excellent specificity for mitochondria, which allowed imaging and tracking of the mitochondrial morphological changes in a hypoxic environment over a long period of time. Moreover, the probes can visualize hypoxic mitochondria in 3D multicellular spheroids and living zebrafish through two-photon phosphorescence imaging.


Asunto(s)
Antraquinonas/química , Hipoxia de la Célula , Complejos de Coordinación/química , Iridio/química , Mitocondrias/patología , Células A549 , Animales , Encéfalo/metabolismo , Encéfalo/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Complejos de Coordinación/metabolismo , Complejos de Coordinación/toxicidad , Humanos , Concentración de Iones de Hidrógeno , Imagenología Tridimensional , Espectrometría de Masas , Microscopía Confocal , Microscopía de Fluorescencia por Excitación Multifotónica , Microsomas Hepáticos/metabolismo , Mitocondrias/metabolismo , Ratas , Espectrometría de Fluorescencia , Esferoides Celulares/citología , Esferoides Celulares/metabolismo , Pez Cebra/metabolismo
18.
Cell Mol Neurobiol ; 36(8): 1377-1387, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26858154

RESUMEN

Our present aim was to investigate whether changes in the expression of α4ß2 nicotinic acetylcholine receptor (nAChR) in patients with vascular dementia (VaD) and ischemic rats are related to cognitive scores. Blood leukocytes for 59 Chinese patients with VaD (diagnosed on the basis of clinical guidelines) and 31 cases as age-matched controls were examined, and the animal model established employing Pulsinelli's four-vessel occlusion. The levels of α4 and ß2 subunit mRNA in leukocytes and the hippocampus were analyzed by real-time PCR, and the protein level in the hippocampus by Western blotting. The mini-mental state examination was utilized to characterize the intellectual capacity of the patients with reference to the DSM IV diagnosis and Hachinski Ischemic Scale score, and the Morris Water Maze test to assess the ability of learning and memory of the rats. In patients, the level of α4 mRNA, but not ß2, in blood leukocytes was clearly lowered, which was significantly correlated to their clinical cognitive test scores. Smoking exerted no impact on the level of α4 mRNA in the present study. In the blood leukocytes and the hippocampus of the brains of the ischemic rats, the levels of both α4 and ß2 mRNA were lowered, and the proteins of these subunits in the hippocampus were decreased. The changes of α4 and ß2 mRNA in blood leukocytes, and their protein levels in the hippocampus were significantly correlated with impaired learning and memory. These findings indicate that alterations in expression of the α4ß2 subtype of nAChR may be involved in the molecular mechanism(s) underlying the cognitive deficit associated with VaD.


Asunto(s)
Isquemia Encefálica/metabolismo , Demencia Vascular/metabolismo , Hipocampo/metabolismo , Leucocitos/metabolismo , Receptores Nicotínicos/metabolismo , Anciano , Anciano de 80 o más Años , Animales , Pueblo Asiatico , Western Blotting , Femenino , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Aprendizaje Espacial
19.
Yi Chuan ; 38(11): 1004-1011, 2016 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-27867150

RESUMEN

MeCP2 mutations are associated with the Rett syndrome (RTT). Currently, there is an urgent need for new animal models for RTT as the existing MeCP2 knockout mouse models fail to fully mimic the pathogenesis and symptoms of RTT patients. In order to investigate the role of MeCP2 in brain development and RTT pathogenesis, we aimed to set up the MeCP2-null rat model using the CRISPR/Cas9 technology. Firstly we constructed the MeCP2 targeting vector and then microinjected Cas9 mRNA and sgRNA mixtures into fertilized ova of SD rats. The sgRNA was designed to target the exon 2 of MeCP2. Next, knockout rats were confirmed using DNA sequencing and Western blotting. Lastly, phenotypes including growth and behaviors of MeCP2 knockout rats were analyzed. The results indicated that the MeCP2 knockout rats showed body weight loss, anxiety tendency and cognitive deficits. The MeCP2-null rat model established in this study recapitulates the major symptoms of RTT patients and provides an alternative tool for future studies of MeCP2 functions.


Asunto(s)
Modelos Animales de Enfermedad , Proteína 2 de Unión a Metil-CpG/genética , Síndrome de Rett/genética , Animales , Secuencia de Bases , Técnicas de Inactivación de Genes , Humanos , Masculino , Proteína 2 de Unión a Metil-CpG/metabolismo , Datos de Secuencia Molecular , Ratas , Ratas Sprague-Dawley , Síndrome de Rett/metabolismo
20.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 36(3): 294-9, 2016 Mar.
Artículo en Zh | MEDLINE | ID: mdl-27236885

RESUMEN

OBJECTIVE: To study features of brain gray matter injury in cerebral infarction patients and intervention of scalp acupuncture by using voxel-based morphology. METHODS: A total of 16 cerebral infarction patients were recruited in this study, and assigned to the scalp acupuncture group and the control group, 8 in each group. Another 16 healthy volunteers were recruited as a normal group. All patients received scanning of T1 structure. Images were managed using VBM8 Software package. Difference of the gray matter structure was compared among the scalp acupuncture group, the control group, and the healthy volunteers. RESULTS: Compared with healthy volunteers, gray matter injury of cerebral infarction patients mainly occurred in 14 brain regions such as cingulate gyrus, precuneus, cuneus, anterior central gyrus, insular lobe, and so on. They were mainly distributed in affected side. Two weeks after treatment when compared with healthy volunteers, gray matter injury of cerebral infarction patients in the scalp acupuncture group still existed in 8 brain regions such as bilateral lingual gyrus, posterior cingulate gyrus, left cuneus, right precuneus, and so on. New gray matter injury occurred in lingual gyrus and posterior cingulate gyrus. Two weeks after treatment when compared with healthy volunteers, gray matter injury of cerebral infarction patients in the control group existed in 23 brain regions: bilateral anterior cingulum, caudate nucleus, cuneate lobe, insular lobe, inferior frontal gyrus, medial frontal gyrus, precuneus, paracentral lobule, superior temporal gyrus, middle temporal gyrus, lingual gyrus, right postcentral gyrus, posterior cingulate gyrus, precentral gyrus, middle frontal gyrus, and so on. New gray matter injury still existed in 9 cerebral regions such as lingual gyrus, posterior cingulate gyrus, postcentral gyrus, and so on. CONCLUSIONS: Brain gray matter structure is widely injured after cerebral infarction. Brain gray matter volume gradually decreased as time went by. Combined use of scalp acupuncture might inhibit the progression of gray matter injury more effectively.


Asunto(s)
Terapia por Acupuntura , Lesiones Encefálicas/terapia , Infarto Cerebral/terapia , Sustancia Gris/patología , Accidente Cerebrovascular/terapia , Encéfalo/fisiopatología , Humanos , Imagen por Resonancia Magnética , Cuero Cabelludo
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