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OBJECTIVE: To explore the neuroimage change in Parkinson's disease (PD) patients with cognitive impairments, this study investigated the correlation between plasma biomarkers and morphological brain changes in patients with normal cognition and mild cognitive impairment. The objective was to identify the potential target deposition regions of the plasma biomarkers and to search for the relevant early neuroimaging biomarkers on the basis of different cognitive domains. METHODS: Structural brain MRI and diffusion weighted images were analyzed from 49 eligible PD participants (male/female: 27/22; mean age: 73.4 ± 8.5 years) from a retrospective analysis. Plasma levels of α-synuclein, amyloid beta peptide, and total tau were collected. A comprehensive neuropsychological assessment of the general and specific cognitive domains was performed. Difference between PD patients with normal cognition and impairment was examined. Regression analysis was performed to evaluate the correlation between image-derived index and plasma biomarkers or neuropsychological assessments. RESULTS: Significant correlation was found between plasma Aß-42 level and fractional anisotropy of the middle occipital, angular, and middle temporal gyri of the left brain, as well as plasma T-tau level and the surface area of the isthmus or the average thickness of the posterior part of right cingulate gyrus. Visuospatial and executive function is positively correlated with axial diffusivity in bilateral cingulate gyri. CONCLUSION: In nondemented PD patients, the target regions for plasma deposition might be located in the cingulate, middle occipital, angular, and middle temporal gyri. Changes from multiple brain regions can be correlated to the performance of different cognitive domains. CLINICAL RELEVANCE STATEMENT: Cognitive impairment in Parkinson's disease is primarily linked to biomarkers associated with Alzheimer's disease rather than those related to Parkinson's disease and resembles the frontal variant of Alzheimer's disease, which may guide management strategies for cognitive impairment in Parkinson's disease. KEY POINTS: ⢠Fractional anisotropy, surface area, and thickness in the cingulate, middle occipital, angular, and middle temporal gyri can be significantly correlated with plasma Aß-42 and T-tau level. ⢠Axial diffusivity in the cingulate gyri was correlated with visuospatial and executive function. ⢠The pattern of cognitive impairment in Parkinson's disease can be similar to the frontal variant than typical Alzheimer's disease.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Parkinson , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides , Estudios Retrospectivos , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Pruebas Neuropsicológicas , BiomarcadoresRESUMEN
BACKGROUND: Although radiotherapy is common for head/neck and chest cancers (HNCC), it can result in post-irradiation stenosis of the subclavian artery (PISSA). The efficacy of percutaneous transluminal angioplasty and stenting (PTAS) to treat severe PISSA is not well-clarified. AIMS: To compare the technical safety and outcomes of PTAS between patients with severe PISSA (RT group) and radiation-naïve counterparts (non-RT group). METHODS: During 2000 and 2021, we retrospectively enrolled patients with severe symptomatic stenosis (>60%) of the subclavian artery who underwent PTAS. The rate of new recent vertebrobasilar ischaemic lesions (NRVBIL), diagnosed on diffusion-weight imaging (DWI) within 24 h of postprocedural brain MRI; symptom relief; and long-term stent patency were compared between the two groups. RESULTS: Technical success was achieved in all 61 patients in the two groups. Compared with the non-RT group (44 cases, 44 lesions), the RT group (17 cases, 18 lesions) had longer stenoses (22.1 vs 11.1 mm, P = 0.003), more ulcerative plaques (38.9% vs 9.1%, P = 0.010), and more medial- or distal-segment stenoses (44.4% vs 9.1%, P<0.001). The technical safety and outcome between the non-RT group and the RT group were NRVBIL on DWI of periprocedural brain MRI 30.0% vs 23.1%, P = 0.727; symptom recurrence rate (mean follow-up 67.1 ± 50.0 months) 2.3% vs 11.8%, P = 0.185; and significant in-stent restenosis rate (>50%) 2.3% vs 11.1%, P = 0.200. CONCLUSION: The technical safety and outcome of PTAS for PISSA were not inferior to those of radiation-naïve counterparts. PTAS for PISSA is an effective treatment for medically refractory ischaemic symptoms of HNCC patients with PISSA.
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Angioplastia de Balón , Arteria Subclavia , Humanos , Constricción Patológica , Arteria Subclavia/diagnóstico por imagen , Estudios de Casos y Controles , Estudios Retrospectivos , Angioplastia/métodos , Resultado del Tratamiento , StentsRESUMEN
Salvinal is a natural lignan isolated from the roots of Salvia mitorrhiza Bunge (Danshen). Previous studies have demonstrated its anti-proliferative activity in both drug-sensitive and -resistant cancer cell lines, with IC50 values ranging from 4-17 µM. In this study, a series of salvinal derivatives was synthesized and evaluated for the structure-activity relationship. Among the twenty-four salvinal derivatives, six compounds showed better anticancer activity than salvinal. Compound 25 displayed excellent anticancer activity, with IC50 values of 0.13-0.14 µM against KB, KB-Vin10 (overexpress MDR/Pgp), and KB-7D (overexpress MRP) human carcinoma cell lines. Based on our in vitro microtubule depolymerization assay, compound 25 showed depolymerization activity in a dose-dependent manner. Our findings indicate that compound 25 is a promising anticancer agent with depolymerization activity that has potential for the management of malignance.
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Antineoplásicos , Humanos , Ensayos de Selección de Medicamentos Antitumorales , Relación Estructura-Actividad , Antineoplásicos/farmacología , Moduladores de Tubulina/farmacología , Microtúbulos , Proliferación Celular , Relación Dosis-Respuesta a Droga , Estructura Molecular , Línea Celular Tumoral , Simulación del Acoplamiento MolecularRESUMEN
BACKGROUND: The outcomes of percutaneous transluminal angioplasty and stenting (PTAS) in patients with medically refractory post-irradiation stenosis of the vertebral artery (PISVA) have not been clarified. AIM: This retrospective study evaluated the safety and outcomes of PTAS in patients with severe PISVA compared with their radiation-naïve counterparts (non-RT group). METHODS: Patients with medically refractory severe symptomatic vertebral artery stenosis and undergoing PTAS between 2000 and 2021 were classified as the PISVA group or the non-RT group. The periprocedural neurological complications, periprocedural brain magnetic resonance imaging, the extent of symptom relief, and long-term stent patency were compared. RESULTS: As compared with the non-RT group (22 cases, 24 lesions), the PISVA group (10 cases, 10 lesions) was younger (62.0 ± 8.6 vs 72.4 ± 9.7 years, P = 0.006) and less frequently had hypertension (40.0% vs 86.4%, P = 0.013) and diabetes mellitus (10.0% vs 54.6%, P = 0.024). Periprocedural embolic infarction was not significantly different between the non-RT group and the PISVA group (37.5% vs 35.7%, P = 1.000). At a mean follow-up of 72.1 ± 58.7 (3-244) months, there was no significant between-group differences in the symptom recurrence rate (0.00% vs 4.55%, P = 1.000) and in-stent restenosis rate (10.0% vs 12.5%, P = 1.000). CONCLUSION: PTAS of severe medically refractory PISVA is effective in the management of vertebrobasilar ischemic symptoms in head and neck cancer patients. Technical safety and outcome of the procedure were like those features in radiation-naïve patients.
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Angioplastia de Balón , Insuficiencia Vertebrobasilar , Humanos , Arteria Vertebral , Estudios Retrospectivos , Constricción Patológica , Resultado del Tratamiento , Angioplastia/métodos , Insuficiencia Vertebrobasilar/diagnóstico por imagen , Insuficiencia Vertebrobasilar/terapia , Stents/efectos adversos , Angioplastia de Balón/efectos adversosRESUMEN
MYC has a short half-life that is tightly regulated through phosphorylation and proteasomal degradation. Many studies have claimed that treatment with disulfiram (DSF) with or without copper ions can cause cancer cell death in a reactive oxygen species (ROS)-dependent manner in cancer cells. Our previous study showed that the levels of c-Myc protein and the phosphorylation of threonine 58 (T58) and serine 62 (S62) increased in DSF-Cu-complex-treated oral epidermoid carcinoma Meng-1 (OECM-1) cells. These abovementioned patterns were suppressed by pretreatment with an ROS scavenger, N-acetyl cysteine. The overexpression of c-Myc failed to induce hypoxia-inducible factor 1α protein expression, which was stabilized by the DSF-Cu complex. In this study, we further examined the regulatory mechanism behind the induction of the c-Myc of the DSF-Cu complex in an OECM-1 cell compared with a Smulow-Glickman (SG) human normal gingival epithelial cell. Our data showed that the downregulation of c-Myc truncated nick and p62 and the induction of the ratio of H3P/H3 and p-ERK/ERK might not be involved in the increase in the amount of c-Myc via the DSF/copper complexes in OECM-1 cells. Combined with the inhibitors for various signaling pathways and cycloheximde treatment, the increase in the amount of c-Myc with the DSF/copper complexes might be mediated through the increase in the stabilities of c-Myc (T58) and c-Myc (S62) proteins in OECM-1 cells. In SG cells, only the c-Myc (T58) protein was stabilized by the DSF-Cu (I and II) complexes. Hence, our findings could provide novel regulatory insights into the phosphorylation-dependent stability of c-Myc in DSF/copper-complex-treated oral squamous cell carcinoma.
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Carcinoma de Células Escamosas , Neoplasias de la Boca , Carcinoma de Células Escamosas/tratamiento farmacológico , Línea Celular Tumoral , Cobre/metabolismo , Cobre/farmacología , Disulfiram/farmacología , Humanos , Neoplasias de la Boca/tratamiento farmacológico , Fosforilación , Proteínas Proto-Oncogénicas c-myc/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Serina/metabolismo , Treonina/metabolismoRESUMEN
BACKGROUND: Enhancement profiles of the pulmonary artery (PA) and aorta differ when using computed tomography (CT) angiography. Our aim was to determine the optimal CT protocol for a one-time CT scan that assesses both blood vessels. METHODS: We prospectively enrolled 101 cases of CT angiography in patients with suspected pulmonary embolism or aortic dissection from our center between 2018 and 2020. We also retrospectively collected the data of 40 patients who underwent traditional two-time CT scans between 2015 and 2018. Patients were divided into four groups: test bolus (TB) I, TB II, bolus-tracking (BT) I, and BT II. The enhancement of the PA and aorta, and the radiation doses used in the four groups were collected. Those who underwent two-time scans were classified into the traditional PA or aorta scan groups. Data were compared between the BT and traditional groups. RESULTS: The aortic enhancement was highest in BT II (294.78 ± 64.48 HU) followed BT I (285.18 ± 64.99 HU), TB II (186.58 ± 57.53 HU), and TB I (173.62 ± 69.70 HU). The radiation dose used was lowest in BT I (11.85 ± 5.55 mSv) and BT II (9.07 ± 3.44 mSv) compared with that used in the traditional groups (20.07 ± 7.78 mSv) and accounted for half of the traditional group (45.17-59.02%). The aortic enhancement was also highest in BT II (294.78 ± 64.48 HU) followed by BT I (285.18 ± 64.99 HU) when compared with that in the traditional aorta scan group (234.95 ± 94.18 HU). CONCLUSION: Our CT protocol with a BT technique allows for a lower radiation dose and better image quality of the PA and aorta than those obtained using traditional CT scans. TRIAL REGISTRATION: NCT04832633, retrospectively registered in April 2021 to the clinical trial registry.
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Aneurisma de la Aorta/diagnóstico por imagen , Disección Aórtica/diagnóstico por imagen , Angiografía por Tomografía Computarizada/métodos , Medios de Contraste/administración & dosificación , Yohexol/administración & dosificación , Embolia Pulmonar/diagnóstico por imagen , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dosis de Radiación , Estudios RetrospectivosRESUMEN
BACKGROUND: Danshen is a common traditional Chinese medicine used to treat neoplastic and chronic inflammatory diseases in China. However, the effects of Danshen on human oral cancer cells remain relatively unknown. This study investigated the antiproliferative effects of a Danshen extract on human oral cancer SAS, SCC25, OEC-M1, and KB drug-resistant cell lines and elucidated the possible underlying mechanism. METHODS: We investigated the anticancer potential of the Danshen extract in human oral cancer cell lines and an in vivo oral cancer xenograft mouse model. The expression of apoptosis-related molecules was evaluated through Western blotting, and the concentration of in vivo apoptotic markers was measured using immunohistochemical staining. The antitumor effects of 5-fluorouracil and the Danshen extract were compared. RESULTS: Cell proliferation assays revealed that the Danshen extract strongly inhibited oral cancer cell proliferation. Cell morphology studies revealed that the Danshen extract inhibited the growth of SAS, SCC25, and OEC-M1 cells by inducing apoptosis. The Flow cytometric analysis indicated that the Danshen extract induced cell cycle G0/G1 arrest. Immunoblotting analysis for the expression of active caspase-3 and X-linked inhibitor of apoptosis protein indicated that Danshen extract-induced apoptosis in human oral cancer SAS cells was mediated through the caspase pathway. Moreover, the Danshen extract significantly inhibited growth in the SAS xenograft mouse model. Furthermore, the Danshen extract circumvented drug resistance in KB drug-resistant oral cancer cells. CONCLUSION: The study results suggest that the Danshen extract could be a potential anticancer agent in oral cancer treatment.
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Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Neoplasias de la Boca/metabolismo , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Ratones , Ratones SCID , Salvia miltiorrhiza , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVES: Advanced oral cancer is a major public health concern because of a lack of effective prevention and treatment. Triptolide (TPL), a diterpenoid triepoxide derived from the Chinese herb Tripterygium wilfordii, has been demonstrated to possess strong anticancer properties. In this study, we investigated whether TPL exerts anticancer effects on the tumor microenvironment of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Human macrophage-like U937 cells were co-inoculated with oral cancer SAS cells in a noncontact transwell coculture system. Cytokine expression was detected using ELISA, and cell proliferation was detected using methylene blue. RNA levels were detected using qPCR. Protein levels were detected using Western blot analysis. In vivo experiments involved using xenografted NOD/SCID mice. RESULTS: Our results demonstrated that TPL inhibited the growth of SAS cells co-inoculated with U937 cells in vitro and in vivo. TPL inhibited the invasion, migration ability, and angiogenesis of SAS cells co-inoculated with U937 cells. Expression of cytokines IL-6, IL-8, and TNF-α was induced by co-inoculation, but TPL repressed their expression. CONCLUSION: TPL suppressed the expression of cytokines IL-6, IL-8, and TNF-α, as well as tumor growth, invasion, migration, and angiogenesis in the co-inoculation of human tongue cancer cells with macrophage-like U937 cells. CLINICAL RELEVANCE: TPL is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating tumor-associated macrophages in a tumor microenvironment of HNSCC.
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Antineoplásicos Alquilantes/farmacología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Diterpenos/farmacología , Neovascularización Patológica/tratamiento farmacológico , Fenantrenos/farmacología , Células U937 , Animales , Western Blotting , Carcinoma de Células Escamosas/tratamiento farmacológico , Técnicas de Cocultivo , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática , Compuestos Epoxi/farmacología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Reacción en Cadena de la Polimerasa , Microambiente TumoralRESUMEN
BACKGROUND: Collateral status is an important predictor for the outcome of acute ischemic stroke with large vessel occlusion. Multiphase computed-tomography angiography (mCTA) is useful to evaluate the collateral status, but visual evaluation of this examination is time-consuming. This study aims to use an artificial intelligence (AI) technique to develop an automatic AI prediction model for the collateral status of mCTA. METHODS: This retrospective study enrolled subjects with acute ischemic stroke receiving endovascular thrombectomy between January 2015 and June 2020 in a tertiary referral hospital. The demographic data and images of mCTA were collected. The collateral status of all mCTA was visually evaluated. Images at the basal ganglion and supraganglion levels of mCTA were selected to produce AI models using the convolutional neural network (CNN) technique to automatically predict the collateral status of mCTA. RESULTS: A total of 82 subjects were enrolled. There were 57 cases randomly selected for the training group and 25 cases for the validation group. In the training group, there were 40 cases with a positive collateral result (good or intermediate) and 17 cases with a negative collateral result (poor). In the validation group, there were 21 cases with a positive collateral result and 4 cases with a negative collateral result. During training for the CNN prediction model, the accuracy of the training group could reach 0.999 ± 0.015, whereas the prediction model had a performance of 0.746 ± 0.008 accuracy on the validation group. The area under the ROC curve was 0.7. CONCLUSIONS: This study suggests that the application of the AI model derived from mCTA images to automatically evaluate the collateral status is feasible.
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Isquemia Encefálica , Aprendizaje Profundo , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular/diagnóstico por imagen , Isquemia Encefálica/diagnóstico por imagen , Inteligencia Artificial , Estudios Retrospectivos , AngiografíaRESUMEN
The dysregulated expression of cyclin genes can lead to the uncontrolled proliferation of cancer cells. Histone demethylase Jumonji-C domain-containing protein 5 (KDM8, JMJD5) and cyclin A1 (CCNA1) are pivotal in cell cycle progression. A promising candidate for augmenting cancer treatment is Allyl isothiocyanate (AITC), a natural dietary chemotherapeutic and epigenetic modulator. This study aimed to investigate AITC's impact on the KDM8/CCNA1 axis to elucidate its role in oral squamous cell carcinoma (OSCC) tumorigenesis. The expression of KDM8 and CCNA1 was assessed using a tissue microarray (TMA) immunohistochemistry (IHC) assay. In vitro experiments with OSCC cell lines and in vivo experiments with patient-derived tumor xenograft (PDTX) and SAS subcutaneous xenograft tumor models were conducted to explore AITC's effects on their expression and cell proliferation. The results showed elevated KDM8 and CCNA1 levels in the OSCC patient samples. AITC exhibited inhibitory effects on OSCC tumor growth in vitro and in vivo. Additionally, AITC downregulated KDM8 and CCNA1 expression while inducing histone H3K36me2 expression in oral cancer cells. These findings underscore AITC's remarkable anticancer properties against oral cancer, highlighting its potential as a therapeutic option for oral cancer treatment by disrupting the cell cycle by targeting the KDM8/CCNA1 axis.
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A series of 2-pyridyl-pyrazole derivatives 1-4 possessing five-membered ring hydrogen bonding configuration are synthesized, the structural flexibility of which is strategically tuned to be in the order of 1 > 2 > 3 > 4. This system then serves as an ideal chemical model to investigate the correlation between excited-state intramolecular proton transfer (ESIPT) reaction and molecular skeleton motion associated with hydrogen bonds. The resulting luminescence data reveal that the rate of ESIPT decreases upon increasing the structural constraint. At sufficiently low concentration where negligible dimerization is observed, ESIPT takes place in 1 and 2 but is prohibited in 3 and 4, for which high geometry constraint is imposed. The results imply that certain structural bending motions associated with hydrogen bonding angle/distance play a key role in ESIPT. This trend is also well supported by the DFT computational approach, in which the barrier associated with ESIPT is in the order of 1 < 2 < 3 < 4. Upon increasing the concentration in cyclohexane, except for 2, the rest of the title compounds undergo ground-state dimerization, from which the double proton transfer takes place in the excited state, resulting in a relatively blue shifted dimeric tautomer emission (cf. the monomer tautomer emission). The lack of dimerization in 2 is rationalized by substantial energy required to adjust the angle of hydrogen bond via twisting the propylene bridge prior to dimerization.
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Protones , Pirazoles/química , Piridinas/química , Enlace de Hidrógeno , Modelos Moleculares , Teoría Cuántica , Espectrometría de Fluorescencia , EspectrofotometríaRESUMEN
Colorectal cancer (CRC) ranks third in the United States for incidence or mortality. Surgical resection is the primary treatment for patients at an early stage, while patients with advanced and metastatic CRC receive combined treatment with chemotherapy, radiotherapy, or targeted therapy. C-RAF plays a key role in maintaining clonogenic and tumorigenic capacity in CRC cells and it might be a potential therapeutic target for CRC. Sorafenib is a popular oral multi-kinase inhibitor, including a B-RAF inhibitor that targets the RAF-MEK-ERK pathway. Sorafenib, as a single agent, has tumor-suppressing efficacy, but its clinical application is limited due to many complex drug resistance mechanisms and side effects. GW5074 is one of the C-RAF inhibitors and has the potential to enhance the efficacy of existing cancer chemotherapies. In this study, we investigated whether the combination of sorafenib with GW5074 could reduce the dosage of sorafenib and enhance its tumor-suppressive effect in two CRC cell lines, HCT116 and LoVo cells. Our findings demonstrate that GW5074 can potentiate the cytotoxicity of sorafenib and dramatically reduce the half-maximal inhibitory concentration (IC50) dose of sorafenib from 17 and 31 µM to 0.14 and 0.01 µM in HCT116 and LoVo cells, respectively. GW5074, similar to sorafenib, suppressed the cellular proliferation and induced cellular apoptosis and cytosolic ROS, but had no further enhancement on the above-mentioned effects when combined with sorafenib. The synergistic effects of GW5074 and sorafenib were mainly found in mitochondrial functions, including ROS generation, membrane potential disruption, and fission-fusion dynamics, which were examined by using the flow cytometry analysis. In summary, the C-RAF inhibitor GW5074 might potentiate the cytotoxicity of the B-RAF inhibitor sorafenib mediated through mitochondrial dysfunctions, suggesting that GW5074 potentially serves as a sensitizer for sorafenib application to reduce the risk of drug resistance of CRC treatment. Our findings also provide novel insights on using C-RAF inhibitors combined with sorafenib, the current CRC therapeutic drug choice, in CRC treatment.
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Initiated by excited-state intramolecular proton transfer (ESIPT) reaction, an overall reaction cycle of 4-(2-hydroxybenzylidene)-1,2-dimethyl-1H-imidazol-5(4H)-one (o-HBDI), an analogue of the core chromophore of the green fluorescent protein (GFP), has been investigated. In contrast to the native GFP core, 4-(4-hydroxybenzylidene)-1,2-dimethyl-1H-imidazol-5(4H)-one (p-HBDI), which requires hydrogen-bonding relay to accomplish proton transfer in vivo, o-HBDI possesses a seven-membered-ring intramolecular hydrogen bond and thus provides an ideal system for mimicking an intrinsic proton-transfer reaction. Upon excitation, ESIPT takes place in o-HBDI, resulting in a â¼600 nm proton-transfer tautomer emission. The o-HBDI tautomer emission, resolved by fluorescence upconversion, is comprised of an instantaneous rise to a few hundred femtosecond oscillation in the early relaxation stage. Frequency analysis derived from ultrashort pulse gives two low-frequency vibrations at 115 and 236 cm(-1), corresponding to skeletal deformation motions associated with the hydrogen bond. The results further conclude that ESIPT in o-HBDI is essentially triggered by low-frequency motions and may be barrierless along the reaction coordinate. Femtosecond UV/vis transient absorption spectra also provide supplementary evidence for the structural evolution during the reaction. In CH(3)CN, an instant rise of a 530 nm transient is resolved, which then undergoes 7.8 ps decay, accompanied by the growth of a rather long-lived 580 nm transient species. It is thus concluded that following ESIPT the cis-proton transfer isomer undergoes cis-trans-isomerization. The results of viscosity-dependent dynamics are in favor of the one-bond-flip mechanism, which is in contrast to the volume-conserving isomerization behavior for cis-stilbene and p-HBDI. Further confirmation is given by the picosecond-femtosecond transient IR absorption spectra, where several new and long-lived IR bands in the range of 1400-1500 cm(-1) are assigned to the phenyl in-plane breathing motions of the trans-proton transfer tautomer. Monitored by the nanosecond transient absorption, the 580 nm transient undergoes a â¼7.7 µs decay constant, accompanied by the growth of a new â¼500 nm band. The latter is assigned to a deprotonated tautomer species, which then undergoes the ground-state reverse proton recombination to the original o-HBDI in â¼50 µs, achieving an overall, reversible proton transfer cycle. This assignment is unambiguously supported by pump-probe laser induced fluorescence studies. On these standpoints, a comparison of photophysical properties among o-HBDI, p-HBDI, and wild-type GFP is discussed in detail.
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Materiales Biomiméticos/química , Proteínas Fluorescentes Verdes/química , Imidazoles/química , Protones , Enlace de Hidrógeno , Cinética , Espectrometría de Fluorescencia , EspectrofotometríaRESUMEN
Proton-coupled electron transfer reactions form the basis of many important chemical processes including much of the energy conversion that occurs within living cells. However, much of the physical chemistry that underlies these reaction mechanisms remains poorly understood. In this Account, we report on recent progress in the understanding of excited-state intramolecular proton-coupled electron transfer (PCET) reactions. The strategic design and synthesis of various types of PCET molecules, along with steady-state and femtosecond time-resolved spectroscopy, have uncovered the mechanisms of several excited-state PCET reactions in solution. These experimental advancements correlate well with current theoretical models, in which the proton has quantum motion with a high probability of tunneling. In addition, the rate of proton transfer is commonly incorporated within the rate of rearrangement of solvent molecules. As a result, the reaction activation free energy is essentially governed by the solvent reorganization because the charge redistribution is considered based on a solvent polarity-induced barrier instead of the height of the proton migration barrier. In accord with this theoretical basis, we can rationalize the observation that the proton transfer for many excited-state PCET systems occurs during the solvent relaxation time scale of 1-10 ps: the highly exergonic reaction takes place before the system reaches its equilibrium polarization. Also, we have used various derivatives of proton transfer molecules, especially those of 3-hydroxyflavone to clearly demonstrate how researchers can tune the dynamics of excited-state PCET through changes in the magnitude or direction of the dipole vector within the reaction. Subsequently, using 2-(2'-hydroxyphenyl)benzoxazole as the parent model, we then report on methods for the development of an ideal system for probing PCET reaction. Because future biomedical applications of such systems will likely occur in aqueous environments, we discuss various 7-azaindole analogues, for which proton transfer requires the assistance of protic solvent molecules. These results provide a unique contrast to the ubiquitous studies on the dynamic solvent effects of PCET molecules that undergo intrinsic intramolecular proton motion.
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o-Hydroxy analogues, 1a-g, of the green fluorescent protein chromophore have been synthesized. Their structures and electronic properties were investigated by X-ray single-crystal analyses, electrochemistry, and luminescence properties. In solid and nonpolar solvents 1a-g exist mainly as Z conformers that possess a seven-membered-ring hydrogen bond and undergo excited-state intramolecular proton transfer (ESIPT) reactions, resulting in a proton-transfer tautomer emission. Fluorescence upconversion dynamics have revealed a coherent type of ESIPT, followed by a fast vibrational/solvent relaxation (<1 ps) to a twisted (regarding exo-C(5)-C(4)-C(3) bonds) conformation, from which a fast population decay of a few to several tens of picoseconds was resolved in cyclohexane. Accordingly, the proton-transfer tautomer emission intensity is moderate (0.08 in 1e) to weak (â¼10(-4) in 1a) in cyclohexane. The stronger intramolecular hydrogen bonding in 1g suppresses the rotation of the aryl-alkene bond, resulting in a high yield of tautomer emission (Φ(f) ≈ 0.2). In the solid state, due to the inhibition of exo-C(5)-C(4)-C(3) rotation, intense tautomer emission with a quantum yield of 0.1-0.9 was obtained for 1a-g. Depending on the electronic donor or acceptor strength of the substituent in either the HOMO or LUMO site, a broad tuning range of the emission from 560 (1g) to 670 nm (1a) has been achieved.
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Colorantes Fluorescentes/síntesis química , Proteínas Fluorescentes Verdes/síntesis química , Imagen Molecular/métodos , Cristalografía por Rayos X , Electroquímica , Colorantes Fluorescentes/análisis , Proteínas Fluorescentes Verdes/análisis , Enlace de Hidrógeno , Hidroxilación , Iones , Luminiscencia , Modelos Químicos , Conformación Molecular , Protones , Solventes/química , Espectrometría de FluorescenciaRESUMEN
Two new urethane-based acrylates (UAA and PEG-UAA) were synthesized as polymer blocks. The chemical composition of the two monomers was confirmed by IR and NMR. After cross-linking these blockers by radical polymerization, "hexamethylene PU" [poly(hexamethylene-urethane)] and "PEG-hexamethylene PU" [PEG-poly(hexa-methylene-urethane)] were obtained. The platelet adhesion and platelet activation of these polymers were evaluated in the presence of Platelet Rich Plasma (PRP) blood. The relative blood clotting indexes of the polymers were determined to measure their capability of reducing thrombogenicity. The hemolysis of red blood cells was also assessed to examine the haemocompatibility of the polymers. The hexamethylene PU and PEG-hexamethylene PU showed less platelet adhesion, platelet activation, blood clotting and hemolysis than a commercial PU (Tecoflex). The liquid crystal molecule, cholesteryl oleyl carbonate (COC), showed further improved biocompatibility to human blood, after COC was embedded in the PU polymers. PEG-hexamethylene PU + 10% COC demonstrated the best activity in reducing thrombogenicity and the best haemocompatibility. The inclusion of PEG segments into the PEG-UAA structure increased its hydrophilicity. The methylene bis(cyclohexyl) segments in Tecoflex PU decreased haemocompatibility. These observations are in good agreement with performed contact angle measurements. The PEG-hexamethylene PU loaded with COC might be a promising material for applications in bioengineering.
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Materiales Biocompatibles/síntesis química , Ensayo de Materiales , Poliuretanos/síntesis química , Materiales Biocompatibles/química , Bioingeniería , Coagulación Sanguínea , Plaquetas/fisiología , Hemólisis , Humanos , Activación Plaquetaria , Adhesividad Plaquetaria , Poliuretanos/química , Propiedades de SuperficieRESUMEN
A series of 2-aroyl and 2-aryl-5,6,7-trimethoxyquinoline and 4-aroyl-6,7,8-trimethoxyquinoline combretastatin analogs were synthesized and evaluated for their potential anticancer activity. The 4-aroylquinoline 11 inhibited the growth of the human cancer cells lines KB, HT-29, and MKN45, as well as the three human resistant cancer cell lines KB-vin10, KB-S15, and KB-7D, with IC50 values of 217, 327, 239, 246, 213, and 252 nM, respectively.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Línea Celular Tumoral , HumanosRESUMEN
A series of charge-neutral mononuclear Pt(II) complexes Pt(fpbpy)(pz) (3a), Pt(fpbpy)(dmpz) (4a), Pt(fpbpy)(dbpz) (5a), and Pt(fpbpy)(dtfpz) (6a), fpbpyH = 6-(5-trifluoromethyl-pyrazol-3-yl)-2,2'-bipyridine, pzH = pyrazole, dmpzH = 3,5-dimethylpyrazole, dbpzH = 3,5-di-tert-butylpyrazole, and dtfpzH = 3,5-bis(trifluoromethyl)pyrazole, and the cationic Pt(II) dimer [{Pt(fpbpy)}(2)(mu-pz)](+) (3b), [{Pt(fpbpy)}(2)(mu-dmpz)](+) (4b), and [{Pt(fpbpy)}(2)(mu-dbpz)](+) (5b) were synthesized. Series a mononuclear complexes reveal two distinctive ligand arrangements. As unveiled by X-ray crystallography, 3a exhibits a nearly perfect planar geometry, while structural determination on 6a shows a perpendicular arrangement of dbpz ligand due to steric congestion. In sharp contrast, the dinuclear complexes, exemplified by 4b and 5b, display an intramolecular Pt...Pt separation of 3.601 and 3.403 A, respectively. As for photophysical properties, the structural variation leads to a salient difference in emission features between 3a (580 nm) and 6a (510 nm). The results are rationalized by the contribution of ligand-to-ligand charge transfer and intraligand pi-pi* transition for 3a and 6a in the lowest-lying excited state, respectively. On the other hand, dinuclear complexes 3b and 4b reveal dual phosphorescence (denoted as P(1) and P(2) bands), for which the short wavelength emission (the P(1) band) is akin to that observed for the intraligand pi-pi* transition of 6a, while the much red-shifted, broad emission (the P(2) band) is attributed to the formation of intramolecular ligand-metal-to-metal charge transfer excimer transition. Further studies of relaxation dynamics on both 3b and 4b showed fast excited-state equilibrium between the P(1) and P(2) bands. In contrast, only the P(2) emission band was resolved for 5b, indicating its exergonic excimer formation. Supplementary support of the excited-state thermodynamics is also provided by time-dependent density functional theory calculations, incorporating both geometry optimized S(0) and T(1) states.
RESUMEN
A series of quinoline/isoquinoline-pyrazole isomers (I-III), in which the pyrazole moiety is in a different substitution position, was strategically designed and synthesized, showing a system with five-membered intramolecular hydrogen bonding. Despite the similarity in molecular structure, however, only I undergoes excited-state intramolecular proton transfer, as evidenced by the distinct 560 nm proton-transfer emission and its associated relaxation dynamics. The experimental results support a recent theoretical approach regarding the conjugation effect on a proton (or hydrogen atom) transfer reaction (J. Phys. Chem. A 2009, 113, 4862-4867). The concept simply predicts that more extended pi conjugation, i.e., resonance, for proton-transfer tautomer species could allow for efficient delocalization of excess charge in the reaction center, resulting in a larger thermodynamic driving force for proton transfer.
Asunto(s)
Simulación por Computador , Protones , Pirazoles/química , Quinolinas/química , Ciclohexanos/química , Isomerismo , Estructura MolecularRESUMEN
Dysregulation of histone demethylase Jumonji-C domain-containing protein 5 (JMJD5) has been identified as a great effect on tumorigenesis. Silibinin is a commonly used anti-hepatotoxic drug and exhibits anticancer effect in various cancers. However, the antitumor mechanism between silibinin and JMJD5 in oral squamous cell carcinoma (OSCC) remains unclear. In this study, the clinical significance of JMJD5 on OSCC patients was assessed through tissue microarray. Furthermore, mice bearing patient-derived tumor xenografts (PDTXs) and tongue cancer cell lines were treated with silibinin and evaluated for tumor growth and JMJD5 expression. High expression of JMJD5 in oral cancer was significantly associated with tumor size (P = 0.0241), cervical node metastasis (P = 0.0001) and clinical stage (P = 0.0002), was associated with worse survival rate compared with that of the total cohort (P = 0.0002). Collectively the data indicate that JMJD5 expression may be suitable for detection of unfavorable prognosis in OSCC patients, based in part on its apparent role as a marker of metastasis. In addition, silibinin inhibits cancer growth in vitro and in PDTX models. Furthermore, metastasis-associated protein 1 (MTA1) could regulate the expression for JMJD5 and had a positive correlation with JMJD5. Moreover, silibinin could downregulate JMJD5 and MTA1 in oral cancer. Present study thus identifies that JMJD5 might be an essential prognostic indicator and therapeutic target against OSCC progression. In addition, silibinin is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating JMJD5 in OSCC, through a mechanism likely involving MTA1/JMJD5 axis.