Trichostatin A Promotes Cytotoxicity of Cisplatin, as Evidenced by Enhanced Apoptosis/Cell Death Markers.

Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the cytotoxicity of the genotoxic anticancer drug cisplatin, yet the underlying mechanism remains poorly understood. Herein, we revealed that TSA at a low concentration (1 µM) promoted the cisplatin-induced activation of caspase-3/6, which, in turn, increased the level of cleaved PARP1 and degraded lamin A&C, leading to more cisplatin-induced apoptosis and G2/M phase arrest of A549 cancer cells. Both ICP-MS and ToF-SIMS measurements demonstrated a significant increase in DNA-bound platinum in A549 cells in the presence of TSA, which was attributable to TSA-induced increase in the accessibility of genomic DNA to cisplatin attacking. The global quantitative proteomics results further showed that in the presence of TSA, cisplatin activated INF signaling to upregulate STAT1 and SAMHD1 to increase cisplatin sensitivity and downregulated ICAM1 and CD44 to reduce cell migration, synergistically promoting cisplatin cytotoxicity. Furthermore, in the presence of TSA, cisplatin downregulated TFAM and SLC3A2 to enhance cisplatin-induced ferroptosis, also contributing to the promotion of cisplatin cytotoxicity. Importantly, our posttranslational modification data indicated that acetylation at H4K8 played a dominant role in promoting cisplatin cytotoxicity. These findings provide novel insights into better understanding the principle of combining chemotherapy of genotoxic drugs and HDAC inhibitors for the treatment of cancers.

Strophanthidin Induces Apoptosis of Human Lung Adenocarcinoma Cells by Promoting TRAIL-DR5 Signaling.

Strophanthidin (SPTD), one of the cardiac glycosides, is refined from traditional Chinese medicines such as Semen Lepidii and Antiaris toxicaria, and was initially used for the treatment of heart failure disease in clinic. Recently, SPTD has been shown to be a potential anticancer agent, but the underlying mechanism of action is poorly understood. Herein, we explored the molecular mechanism by which SPTD exerts anticancer effects in A549 human lung adenocarcinoma cells by means of mass spectrometry-based quantitative proteomics in combination with bioinformatics analysis. We revealed that SPTD promoted the expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2, or DR5) in A549 cells to activate caspase 3/6/8, in particular caspase 3. Consequently, the activated caspases elevated the expression level of apoptotic chromatin condensation inducer in the nucleus (ACIN1) and prelamin-A/C (LMNA), ultimately inducing apoptosis via cooperation with the SPTD-induced overexpressed barrier-to-autointegration factor 1 (Banf1). Moreover, the SPTD-induced DEPs interacted with each other to downregulate the p38 MAPK/ERK signaling, contributing to the SPTD inhibition of the growth of A549 cells. Additionally, the downregulation of collagen COL1A5 by SPTD was another anticancer benefit of SPTD through the modulation of the cell microenvironment.

Audiometric Validation of a Smart Watch Decibel Meter.

This diagnostic study assesses the performance of the Apple Watch Noise application in comparison with a class 1 sound level meter.

Ligand Evolution in the Photoactivatable Platinum(IV) Anticancer Prodrugs.

Photoactivatable Pt(IV) anticancer prodrugs with the structure of [PtIV(N1)(N2)(L1)(L2)(A1)(A2)], where N1 and N2 are non-leaving nitrogen donor ligands, L1 and L2 are leaving ligands, and A1 and A2 are axial ligands, have attracted increasing attention due to their promising photo-cytotoxicity even to cisplatin-resistant cancer cells. These photochemotherapeutic prodrugs have high dark-stability under physiological conditions, while they can be activated by visible light restrained at the disease areas, as a consequence showing higher spatial and temporal controllability and much more safety than conventional chemotherapy. The coordinated ligands to the Pt center have been proved to be pivotal in determining the function and activity of the photoactivatable Pt(IV) prodrugs. In this review, we will focus on the development of the coordinated ligands in such Pt(IV) prodrugs and discuss the effects of diverse ligands on their photochemistry and photoactivity as well as the future evolution directions of the ligands. We hope this review can help to facilitate the design and development of novel photoactivatable Pt(IV) anticancer prodrugs.

Atorvastatin Enhances Inhibitory Effects of Irradiation on Tumor Growth by Reducing MSH2 Expression Both in Prostate Cancer Cells and Xenograft Tumor Models.

BACKGROUND: Prostate cancer (PCa) is the fourth most common tumor in males. OBJECTIVE: This study aimed to investigate effects of atorvastatin (AS) on PCa cells proliferation and clarify the associated mechanisms. METHODS: PCa cell lines were cultured and treated with irradiation (IR) (4 Gy), AS (6 µg/ml), transfected with Bcl-2 siRNA, and then divided into different groups. Xenograft tumor mouse model was established. Bcl-2 and MSH2 gene transcription and protein expression were evaluated using RT-PCR assay and western blot assay. Plate clone formation assay was employed to examine colony formation. MTT assay was used to detect cell viabilities. Flow cytometry analysis was utilized to verify apoptosis. Co-immunoprecipitation and immuno-fluorescence assay were used to identify interaction between Bcl-2 and MSH2. RESULTS: IR significantly reduced colony formation, enhanced Bcl-2 and reduced MSH2 gene transcription in PCa cells compared to un-treated cells (p<0.05). AS significantly strengthened radio-therapeutic effects of IR on colony formation, decreased cell apoptosis and increased Bcl-2 gene transcription/protein expression in PCa cells compared to single IR treatment cells (p<0.05). AS combining IR down-regulated MSH2 gene transcription/protein expression in PCa cells compared to single IR treatment cells (p<0.05). Bcl-2 interacted with MSH2 both in PCa cells and tumor tissues administrating with AS. AS enhanced reductive effects of IR on tumor size of Xenograft tumor mice. CONCLUSION: Atorvastatin administration enhanced inhibitory effects of IR either on PCa cells or tumor size of Xenograft tumor mice. The inhibitory effects of atorvastatin were mediated by reducing MSH2 expression and triggering interaction between Bcl-2 and MSH2, both in vitro and in vivo levels.

Task-dependent effects of nicotine treatment on auditory performance in young-adult and elderly human nonsmokers.

Electrophysiological studies show that nicotine enhances neural responses to characteristic frequency stimuli. Previous behavioral studies partially corroborate these findings in young adults, showing that nicotine selectively enhances auditory processing in difficult listening conditions. The present work extended previous work to include both young and older adults and assessed the nicotine effect on sound frequency and intensity discrimination. Hypotheses were that nicotine improves auditory performance and that the degree of improvement is inversely proportional to baseline performance. Young (19-23 years old) normal-hearing nonsmokers and elderly (61-80) nonsmokers with normal hearing between 500 and 2000 Hz received nicotine gum (6 mg) or placebo gum in a single-blind, randomized crossover design. Participants performed three experiments (frequency discrimination, frequency modulation identification, and intensity discrimination) before and after treatment. The perceptual differences were analyzed between pre- and post-treatment, as well as between post-treatment nicotine and placebo conditions as a function of pre-treatment baseline performance. Compared to pre-treatment performance, nicotine significantly improved frequency discrimination. Compared to placebo, nicotine significantly improved performance for intensity discrimination, and the improvement was more pronounced in the elderly with lower baseline performance. Nicotine had no effect on frequency modulation identification. Nicotine effects are task-dependent, reflecting possible interplays of subjects, tasks and neural mechanisms.

Atorvastatin Enhances Effects of Radiotherapy on Prostate Cancer Cells and Xenograft Tumor Mice Through Triggering Interaction Between Bcl-2 and MSH2.

BACKGROUND Prostate cancer (PCa) is considered to be the 4th most common cancer in males in the world. This study aimed to explore effects of atorvastatin on colony formation of PCa cells and radio-resistance of xenograft tumor models. MATERIAL AND METHODS PCa cell lines, including PC3, DU145, and Lncap, were treated with irradiation (4 Gy) and/or atorvastatin (6 µg/mL). Cells were divided into tumor cell group, irradiation treatment group (IR group) and irradiation+atorvastatin treatment group (IR-AS group). Xenograft tumor mouse model was established. Plate clone formation assay (multi-target/single-hit model) was conducted to evaluate colony formation. Flow cytometry analysis was employed to detect apoptosis. Interaction between Bcl-2 and MSH2 was evaluated with immuno-fluorescence assay. RESULTS According to the plate colony formation assay and multi-target/single-hit model, IR-treatment significantly suppressed colony formation in PCa cells (including PC3, DU145, and Lncap cells) compared to no-IR treated cells (P<0.05). Atorvastatin remarkably enhanced inhibitive effects of irradiation on colony formation of PCa cells (P<0.05), however, the IR+AS group demonstrated no effects on apoptosis, comparing to IR group (P>0.05). Atorvastatin administration (IR+AS group) significantly reduced tumor size of IR-treated PCa cells-induced xenograft tumor mice (P<0.05). Bcl-2 interacted with MSH2 both in tumor tissues of xenograft tumor mice. CONCLUSIONS Atorvastatin administration inhibited colony formation in PCa cells and enhanced effects of radiotherapy on tumor growth of xenograft tumor mice, which might be associated with interaction between Bcl-2 and MSH2 molecule.

Nicotine enhances auditory processing in healthy and normal-hearing young adult nonsmokers.

RATIONALE: Electrophysiological studies show that systemic nicotine narrows frequency receptive fields and increases gain in neural responses to characteristic frequency stimuli. We postulated that nicotine enhances related auditory processing in humans. OBJECTIVES: The main hypothesis was that nicotine improves auditory performance. A secondary hypothesis was that the degree of nicotine-induced improvement depends on the individual's baseline performance. METHODS: Young (18-27 years old), normal-hearing nonsmokers received nicotine (Nicorette gum, 6mg) or placebo gum in a single-blind, randomized, crossover design. Subjects performed four experiments involving tone-in-noise detection, temporal gap detection, spectral ripple discrimination, and selective auditory attention before and after treatment. The perceptual differences between posttreatment nicotine and placebo conditions were measured and analyzed as a function of the pre-treatment baseline performance. RESULTS: Nicotine significantly improved performance in the more difficult tasks of tone-in-noise detection and selective attention (effect size = - 0.3) but had no effect on relatively easier tasks of temporal gap detection and spectral ripple discrimination. The two tasks showing significant nicotine effects further showed no baseline-dependent improvement. CONCLUSIONS: Nicotine improves auditory performance in difficult listening situations. The present results support future investigation of nicotine effects in clinical populations with auditory processing deficits or reduced cholinergic activation.

Electro-tactile stimulation (ETS) enhances cochlear-implant Mandarin tone recognition.

OBJECTIVE: Electro-acoustic stimulation (EAS) is an effective method to enhance cochlear-implant performance in individuals who have residual low-frequency acoustic hearing. To help the majority of cochlear implant users who do not have any functional residual acoustic hearing, electro-tactile stimulation (ETS) may be used because tactile sensation has a frequency range and perceptual capabilities similar to that produced by acoustic stimulation in the EAS users. METHODS: Following up the first ETS study showing enhanced English sentence recognition in noise,1 the present study evaluated the effect of ETS on Mandarin tone recognition in noise in two groups of adult Mandarin-speaking individuals. The first group included 11 normal-hearing individuals who listened to a 4-channel, noise-vocoded, cochlear-implant simulation. The second group included 1 unilateral cochlear-implant user and 2 bilateral users with each of their devices being tested independently. Both groups participated in a 4-alternative, forced-choice task, in which they had to identify a tone that was presented in noise at a 0-dB signal-to-noise ratio via electric stimulation (actual or simulated cochlear implants), tactile stimulation or the combined ETS. RESULTS: While electric or tactile stimulation alone produced similar tone recognition (∼40% correct), the ETS enhanced the cochlear-implant tone recognition by 17-18 percentage points. The size of the present ETS enhancement effect was similar to that of the previously reported EAS effect on Mandarin tone recognition. Psychophysical analysis on tactile sensation showed an important role of frequency discrimination in the ETS enhancement. CONCLUSION: Tactile stimulation can potentially enhance Mandarin tone recognition in cochlear-implant users who do not have usable residual acoustic hearing. To optimize this potential, high fundamental frequencies need to be transposed to a 100-200 Hz range.

Tinnitus treatment with precise and optimal electric stimulation: opportunities and challenges.

PURPOSE OF REVIEW: Electric stimulation is a potent means of neuromodulation that has been used to restore hearing and minimize tremor, but its application on tinnitus symptoms has been limited. We examine recent evidence to identify the knowledge gaps in the use of electric stimulation for tinnitus treatment. RECENT FINDINGS: Recent studies using electric stimulation to suppress tinnitus in humans are categorized according to their points of attacks. First, noninvasive, direct current stimulation uses an active electrode in the ear canal, tympanic membrane, or temporal scalp. Second, inner ear stimulation uses charge-balanced biphasic stimulation by placing an active electrode on the promontory or round window, or a cochlear implant array in the cochlea. Third, intraneural implants can provide targeted stimulation of specific sites along the auditory pathway. Although these studies demonstrated some success in tinnitus suppression, none established a link between tinnitus suppression efficacy and tinnitus-generating mechanisms. SUMMARY: Electric stimulation provides a unique opportunity to suppress tinnitus. Challenges include matching electric stimulation sites and patterns to tinnitus locus and type, meeting the oftentimes-contradictory demands between tinnitus suppression and other indications, such as speech understanding, and justifying the costs and risks of electric stimulation for tinnitus symptoms.

Loudness adaptation accompanying ribbon synapse and auditory nerve disorders.

Abnormal auditory adaptation is a standard clinical tool for diagnosing auditory nerve disorders due to acoustic neuromas. In the present study we investigated auditory adaptation in auditory neuropathy owing to disordered function of inner hair cell ribbon synapses (temperature-sensitive auditory neuropathy) or auditory nerve fibres. Subjects were tested when afebrile for (i) psychophysical loudness adaptation to comfortably-loud sustained tones; and (ii) physiological adaptation of auditory brainstem responses to clicks as a function of their position in brief 20-click stimulus trains (#1, 2, 3 … 20). Results were compared with normal hearing listeners and other forms of hearing impairment. Subjects with ribbon synapse disorder had abnormally increased magnitude of loudness adaptation to both low (250 Hz) and high (8000 Hz) frequency tones. Subjects with auditory nerve disorders had normal loudness adaptation to low frequency tones; all but one had abnormal adaptation to high frequency tones. Adaptation was both more rapid and of greater magnitude in ribbon synapse than in auditory nerve disorders. Auditory brainstem response measures of adaptation in ribbon synapse disorder showed Wave V to the first click in the train to be abnormal both in latency and amplitude, and these abnormalities increased in magnitude or Wave V was absent to subsequent clicks. In contrast, auditory brainstem responses in four of the five subjects with neural disorders were absent to every click in the train. The fifth subject had normal latency and abnormally reduced amplitude of Wave V to the first click and abnormal or absent responses to subsequent clicks. Thus, dysfunction of both synaptic transmission and auditory neural function can be associated with abnormal loudness adaptation and the magnitude of the adaptation is significantly greater with ribbon synapse than neural disorders.

Determination of 49 organophosphorus pesticide residues and their metabolites in fish, egg, and milk by dual gas chromatography-dual pulse flame photometric detection with gel permeation chromatography cleanup.

A new method for the quantitative determination of 49 kinds of organophosphorus pesticide residues and their metabolites in fish, egg, and milk by dual gas chromatography-dual pulse flame photometric detection was developed. Homogenized samples were extracted with acetone and methylene chloride (1 + 1, v/v), and then the extracts were cleaned up by gel permeation chromatography (GPC). The response of each organophosphorus pesticide showed a good linearity with its concentration; the linearity correlation was not less than 0.99. The detection limits (S/N = 3) of pesticides were in the range of 0.001-0.025 mg kg⁻¹. The recovery experiments were performed by blank sample spiked at low, medium, and high fortification levels. The recoveries for fish, egg, and milk were 50.9-142.2, 53.3-137.2, and 50.3-139.4% with relative standard deviations (RSD, n = 6) of 2.3-24.9, 4.3-26.7, and 2.8-32.2%, respectively. The method was applied to detect organophosphorus pesticides in samples collected from the market, and satisfactory results were obtained. This quantitative method was highly sensitive and exact and could be applied to the accurate determination of organophosphorus contaminants in fish, egg, and milk.

[High throuput analysis of organophosphorus pesticide residues and their metabolites in animal original foods by dual gas chromatography-dual pulse flame photometric detection].

A method was established for the quantitative determination of 54 organophosphorus pesticide residues and their metabolites in foods of animal origin by dual gas chromatography-dual pulse flame photometric detection. Homogenized samples were extracted with acetone and methylene chloride, and cleaned-up by gel permeation chromatography (GPC). The response of each analyte showed a good linearity with a correlation coefficient not less than 0. 99. The recovery experiments were performed by a blank sample spiked at low, medium and high fortification levels. The recoveries for beef, mutton, pork, chicken were in the range of 50. 5% -128. 1% with the relative standard deviations (n = 6) of 1. 1% -25. 5%, which demonstrated the good precision and accuracy of the present method. The limits of detection for the analytes were in the range of 0. 001 -0. 170 mg/kg, and the limits of quantification were in the range of 0. 002 -0. 455 mg/kg. Animal food samples collected from markets such as meat, liver and kidney were analyzed, and the residues of dichlorovos and disulfoton-sulfoxide were found in the some samples. The established method is sensitive and selective enough to detect organophosphorus pesticide residues in animal foods.