RESUMO
SIRT5 has been implicated in various physiological processes and human diseases, including cancer. Development of new highly potent, selective SIRT5 inhibitors is still needed to investigate disease-related mechanisms and therapeutic potentials. We here report new ε-N-thioglutaryllysine derivatives, which were designed according to SIRT5-catalysed deacylation reactions. These ε-N-thioglutaryllysine derivatives displayed potent SIRT5 inhibition, of which the potential photo-crosslinking derivative 8 manifested most potent inhibition with an IC50 value of 120 nM to SIRT5, and low inhibition to SIRT1-3 and SIRT6. The enzyme kinetic assays revealed that the ε-N-thioglutaryllysine derivatives inhibit SIRT5 by lysine-substrate competitive manner. Co-crystallographic analyses demonstrated that 8 binds to occupy the lysine-substate binding site by making hydrogen-bonding and electrostatic interactions with SIRT5-specific residues, and is likely positioned to react with NAD+ and form stable thio-intermediates. Compound 8 was observed to have low photo-crosslinking probability to SIRT5, possibly due to inappropriate position of the diazirine group as observed in SIRT5:8 crystal structure. This study provides useful information for developing drug-like inhibitors and cross-linking chemical probes for SIRT5-related studies.
Assuntos
Sirtuínas , Humanos , Sirtuínas/metabolismo , Lisina/química , Sítios de LigaçãoRESUMO
Hydrogen sulfide (H2S), a well-known poisonous gas, has been recognized as a critical endogenous gas transmitter in the past decade. To provide a quick and efficient detection method for hydrogen sulfide, a novel fluorescent probe DCI-NCN was designed based on an isophoronitrile scaffold featured with the cyanoxy group as the detection group. DCI-NCN shows promising results including high selectivity, high sensitivity, good linear relationship and pH stability in vitro. In addition, good biosystem imaging performance of DCI-NCN is observed in Kunming mice.
Assuntos
Corantes Fluorescentes/química , Sulfeto de Hidrogênio/análise , Nitrilas/química , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Microscopia de Fluorescência , Modelos Moleculares , Imagem ÓpticaRESUMO
Hearing is one of the most important human perception forms, and humans can capture the movement of sound in complex environments. On the basis of this phenomenon, this study explored the possibility of eliciting a steady-state brain response in an intermittent periodic motion sound source. In this study, a novel discrete continuous and orderly change of sound source positions stimulation paradigm was designed based on virtual sound using head-related transfer functions (HRTFs). And then the auditory motion stimulation paradigms with different noise levels were designed by changing the signal-to-noise ratio (SNR). The characteristics of brain response and the effects of different noises on brain response were studied by analyzing electroencephalogram (EEG) signals evoked by the proposed stimulation. Experimental results showed that the proposed paradigm could elicit a novel steady-state auditory evoked potential (AEP), i.e., steady-state motion auditory evoked potential (SSMAEP). And moderate noise could enhance SSMAEP amplitude and corresponding brain connectivity. This study enriches the types of AEPs and provides insights into the mechanism of brain processing of motion sound sources and the impact of noise on brain processing.
Assuntos
Audição , Ruído , Humanos , Estimulação Acústica/métodos , Ruído/efeitos adversos , Audição/fisiologia , Potenciais Evocados Auditivos/fisiologia , EletroencefalografiaRESUMO
The ability of humans to perceive motion sound sources is important for accurate response to the living environment. Periodic motion sound sources can elicit steady-state motion auditory evoked potential (SSMAEP). The purpose of this study was to investigate the effects of different motion frequencies and different frequencies of sound source on SSMAEP. The stimulation paradigms for simulating periodic motion of sound sources were designed utilizing head-related transfer function (HRTF) techniques in this study. The motion frequencies of the paradigm are set respectively to 1-10 Hz, 15 Hz, 20 Hz, 30 Hz, 40 Hz, 60 Hz, and 80 Hz. In addition, the frequencies of sound source of the paradigms were set to 500 Hz, 1000 Hz, 2000 Hz, 3000 Hz, and 4000 Hz at motion frequencies of 6 Hz and 40 Hz. Fourteen subjects with normal hearing were recruited for the study. SSMAEP was elicited by 500 Hz pure tone at motion frequencies of 1-10 Hz, 15 Hz, 20 Hz, 30 Hz, 40 Hz, 60 Hz, and 80 Hz. SSMAEP was strongest at motion frequencies of 6 Hz. Moreover, at 6 Hz motion frequency, the SSMAEP amplitude was largest at the tone frequency of 500 Hz and smallest at 4000 Hz. Whilst SSMAEP elicited by 4000 Hz pure tone was significantly the strongest at motion frequency of 40 Hz. SSMAEP can be elicited by periodic motion sound sources at motion frequencies up to 80 Hz. SSMAEP also has a strong response at lower frequency. Low-frequency pure tones are beneficial to enhance SSMAEP at low-frequency sound source motion, whilst high-frequency pure tones help to enhance SSMAEP at high-frequency sound source motion. The study provides new insight into the brain's perception of rhythmic auditory motion.
Assuntos
Potenciais Evocados Auditivos , Som , Humanos , Estimulação Acústica/métodos , Potenciais Evocados Auditivos/fisiologia , Movimento (Física) , Limiar AuditivoRESUMO
Sulfur dioxide, an air pollutant, is easily hydrated to sulfites and bisulfites and extremely harmful to human health. On the other hand, endogenous sulfur dioxide is the fourth gasotransmitter. In view of the above, it is worth developing an effective method for the detection of these compounds. In this paper, a novel colorimetric fluorescent probe (Hcy-Mo), based on hemi-cyanine, for bisulfites is reported. Hcy-Mo shows excellent selectivity for bisulfites over various other species including cysteine, glutathione, CN-, and HS-, and undergoes 1,4-addition reactions at the C-4 atom of the ethylene group. The reaction can be completed in 30 s in a PBS buffer solution and displays high sensitivity (limit of detection is 80 nM) for bisulfites. Test paper experiments show that the probe can be used for bisulfite detection in aqueous solutions. In addition, Hcy-Mo exhibits excellent cell permeability and low cytotoxicity for the successful detection of bisulfites in living MDA-MB-231 cells and in living mice, implying that this probe would be of great benefit to biological researchers for investigating the detailed biological and pharmacological functions of bisulfites in biological systems.
RESUMO
Noise has been proven to have a beneficial role in non-linear systems, including the human brain, based on the stochastic resonance (SR) theory. Several studies have been implemented on single-modal SR. Cross-modal SR phenomenon has been confirmed in different human sensory systems. In our study, a cross-modal SR enhanced brain-computer interface (BCI) was proposed by applying auditory noise to visual stimuli. Fast Fourier transform and canonical correlation analysis methods were used to evaluate the influence of noise, results of which indicated that a moderate amount of auditory noise could enhance periodic components in visual responses. Directed transfer function was applied to investigate the functional connectivity patterns, and the flow gain value was used to measure the degree of activation of specific brain regions in the information transmission process. The results of flow gain maps showed that moderate intensity of auditory noise activated the brain area to a greater extent. Further analysis by weighted phase-lag index (wPLI) revealed that the phase synchronization between visual and auditory regions under auditory noise was significantly enhanced. Our study confirms the existence of cross-modal SR between visual and auditory regions and achieves a higher accuracy for recognition, along with shorter time window length. Such findings can be used to improve the performance of visual BCIs to a certain extent.