SPRC protects hypoxia and re-oxygenation injury by improving rat cardiac contractile function and intracellular calcium handling.

S-Propargyl-L-cysteine (SPRC, also named as ZYZ-802) is a new compound synthesized in our lab. We investigated whether SPRC has exerted protective effects against cardiac hypoxia/re-oxygenation (H/R) and also explored its mechanisms. In our study, isolated ventricular myocytes were subject to a simulated hypoxia solution for 30 min to induce cell injury. Intracellular concentration of Ca(2+) ([Ca(2+)]i) was measured using specific dyes and detected by digital imaging apparatus. Apoptotic cells were evaluated by TUNEL assay. Intervention with SPRC (10 µM) 30 min before hypoxia, can significantly attenuate the apoptosis of isolated papillary muscles resulting from the H/R injury and protect morphology of the muscles. In isolated ventricular myocytes, SPRC considerably improved left ventricular functional recovery. SPRC also suppressed the increase of ([Ca(2+)]i) during hypoxia stage. By measuring the calcium transient of the cell we concluded that SPRC can preserve the RyR and SERCA activities and improve Ca(2+) handling during the H/R. Furthermore, the protective effect of SPRC can be partly blocked by CSE inhibitor PAG.

Arsenic trioxide induces the apoptosis in vascular smooth muscle cells via increasing intracellular calcium and ROS formation.

The present study was designed to investigate whether arsenic trioxide induced the apoptosis in rat mesenteric arterial smooth muscle cells (SMCs), which provides new insights into mechanisms of arsenic-related vascular diseases. Here, we found that arsenic trioxide significantly decreased the viability of SMCs in a dose-dependent manner. In addition, higher level of arsenic trioxide directly caused cellular necrosis. The Hoechst and AO/EB staining demonstrated that apoptotic morphological change was presented in SMCs exposed to arsenic trioxide. The TUNEL assay displayed that more positive apoptotic signal appeared in SMCs treated with arsenic trioxide. The following result showed that ROS formation was markedly increased in arsenic trioxide-treated SMCs. Pretreatment with N-acetylcysteine, an anti-oxidant reagent, obviously attenuated the enhancement of ROS production and the reduction of cell viability induced by arsenic trioxide in SMCs. Arsenic trioxide also enhanced free intracellular Ca(2+) level in SMCs. BAPTA also significantly prevented the increased intracellular Ca(2+) and decreased cell viability induced by arsenic trioxide in SMCs. These results suggested that arsenic trioxide obviously induced apoptosis in SMCs, and its mechanism was partially associated with intracellular ROS formation and free Ca(2+) increasing.

Apparent diffusion coefficient-based histogram analysis differentiates histological subtypes of periampullary adenocarcinoma.

BACKGROUND: For periampullary adenocarcinoma, the histological subtype is a better prognostic predictor than the site of tumor origin. Intestinal-type periampullary adenocarcinoma (IPAC) is reported to have a better prognosis than the pan-creatobiliary-type periampullary adenocarcinoma (PPAC). However, the classification of histological subtypes is difficult to determine before surgery. Apparent diffusion coefficient (ADC) histogram analysis is a noninvasive, non-enhanced method with high reproducibility that could help differentiate the two subtypes. AIM: To investigate whether volumetric ADC histogram analysis is helpful for distinguishing IPAC from PPAC. METHODS: Between January 2015 and October 2018, 476 consecutive patients who were suspected of having a periampullary tumor and underwent magnetic resonance imaging (MRI) were reviewed in this retrospective study. Only patients who underwent MRI at 3.0 T with different diffusion-weighted images (b-values = 800 and 1000 s/mm2) and who were confirmed with a periampullary adenocarcinoma were further analyzed. Then, the mean, 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles of ADC values and ADCmin, ADCmax, kurtosis, skewness, and entropy were obtained from the volumetric histogram analysis. Comparisons were made by an independent Student's t-test or Mann-Whitney U test. Multiple-class receiver operating characteristic curve analysis was performed to determine and compare the diagnostic value of each significant parameter. RESULTS: In total, 40 patients with histopathologically confirmed IPAC (n = 17) or PPAC (n = 23) were enrolled. The mean, 5th, 25th, 50th, 75th, 90th, and 95th percentiles and ADCmax derived from ADC1000 were significantly lower in the PPAC group than in the IPAC group (P < 0.05). However, values derived from ADC800 showed no significant difference between the two groups. The 75th percentile of ADC1000 values achieved the highest area under the curve (AUC) for differentiating IPAC from PPAC (AUC = 0.781; sensitivity, 91%; specificity, 59%; cut-off value, 1.50 × 10-3 mm2/s). CONCLUSION: Volumetric ADC histogram analysis at a b-value of 1000 s/mm2 might be helpful for differentiating the histological subtypes of periampullary adenocarcinoma before surgery.

Quantitative diffusion-weighted magnetic resonance enterography in ileal Crohn's disease: A systematic analysis of intra and interobserver reproducibility.

BACKGROUND: Magnetic resonance enterography (MRE) is increasingly attractive as a noninvasive and radiation-free tool for assessing Crohn's disease (CD). Diffusion-weighted imaging (DWI) is recommended as an optional MRE sequence for CD by the European Society of Gastrointestinal and Abdominal Radiology, and has shown a superb potential as a quantitative modality for bowel inflammation evaluation. However, the measurement reproducibility of quantitative DWI analysis in MRE has not been ascertained so far. To facilitate the application of quantitative diffusion-weighted MRE in the clinical routine, systematic investigations of the intra and interobserver reproducibility of DWI quantitative parameters should be performed. AIM: To evaluate the intra and interobserver reproducibility of quantitative analysis for diffusion-weighted MRE (DW-MRE) in ileal CD. METHODS: Forty-four subjects (21 with CD and 23 control subjects) who underwent ileocolonoscopy and DW-MRE (b = 800 s/mm2) within one week were included. Two radiologists independently measured apparent diffusion coefficients (ADC) of the terminal ileum and signal intensity ratio (SR) of the terminal ileum to ipsilateral psoas muscle on DWI images (b = 800 s/mm2). Between- and within-reader agreements were assessed using intraclass correlation coefficients (ICC), coefficients of variation (CoV), and 95% limits of agreement of Bland-Altman plots (BA-LA LoA). Diagnostic performances of ADC and SR for identifying inflamed terminal ileum from the normal were evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: There were no significant differences in ADC or SR values between the two sessions or between the two radiologists either in the CD or control group (paired t-test, P > 0.05). The intra and interobserver reproducibility of ADC (ICC: 0.952-0.984; CoV: 3.73-6.28%; BA-LA LoA: ±11.27% to ±15.88%) and SR (ICC: 0.969-0.989; CoV: 3.51%-4.64%; BA-LA LoA: ±10.62% to ±15.45%) was excellent for CD. Agreement of ADC measurements was slightly less in control subjects (ICC: 0.641-0.736; CoV: 10.47%-11.43%; BA-LA LoA: ± 26.59% to ± 30.83%). SR of normal terminal ileum demonstrated high intra and interobserver reproducibility (ICC: 0.944-0.974; CoV: 3.73%-6.28%; BA-LA LoA: ± 18.58% to ± 24.43%). ADC and SR of two readers had outstanding diagnostic efficiencies (area under the ROC curve: 0.923-0.988). CONCLUSION: Quantitative parameters derived from DW-MRE have good to excellent intra and interobserver agreements with high diagnostic accuracy, and can serve as robust and efficient quantitative biomarkers for CD evaluation.

Assessing the Early Response of Advanced Cervical Cancer to Neoadjuvant Chemotherapy Using Intravoxel Incoherent Motion Diffusion-weighted Magnetic Resonance Imaging: A Pilot Study.

BACKGROUND: Diffusion-weighted imaging (DWI) with the intravoxel incoherent motion (IVIM) model has shown promising results for providing both diffusion and perfusion information in cervical cancer; however, its use to predict and monitor the efficacy of neoadjuvant chemotherapy (NACT) in cervical cancer is relatively rare. The study aimed to evaluate the use of DWI with IVIM and monoexponential models to predict and monitor the efficacy of NACT in cervical cancer. METHODS: Forty-two patients with primary cervical cancer underwent magnetic resonance exams at 3 time points (pre-NACT, 3 weeks after the first NACT cycle, and 3 weeks after the second NACT cycle). The response to treatment was determined according to the response evaluation criteria in solid tumors 3 weeks after the second NACT treatment, and the subjects were classified as two groups: responders and nonresponders groups. The apparent diffusion coefficient (ADC), true diffusion coefficient (D), perfusion-related pseudo-diffusion coefficient (DFNx01), and perfusion fraction (f) values were determined. The differences in IVIM-derived variables and ADC between the different groups at the different time points were calculated using an independent samples t-test. RESULTS: The D and ADC values were all significantly higher for the responders than for the nonresponders at all 3 time points, but no significant differences were observed in the DFNx01 and f values. An analysis of the receiver operating characteristic (ROC) curves indicated that a D value threshold <0.93 × 10-3 mm 2 /s and an ADC threshold <1.11 × 10-3 mm 2 /s could differentiate responders from nonresponders at pre-NACT time point, yielding area under the curve (AUC) of which were 0.771 and 0.806, respectively. The ROC indicated that the AUCs of D and ADC at the 3 weeks after the first NACT cycle and 3 weeks after the second NACT cycle were 0.823, 0.763, and 0.787, 0.794, respectively. The AUC values of D and ADC at these 3 time points were not significantly different (P = 0.641, 0.512, and 0.547, respectively). CONCLUSIONS: D and ADC values may be useful for predicting and monitoring the efficacy of NACT in cervical cancer. An IVIM model may be equal to monoexponential model in predicting and monitoring the efficacy of NACT in cervical cancer.

Inhibition of NADPH oxidase 4-related signaling by sodium hydrosulfide attenuates myocardial fibrotic response.

BACKGROUND: Myocardial fibrosis plays a pivotal role in the development of heart failure. Hydrogen sulfide (H2S) is an endogenous gasotransmitter with potent cardioprotective properties; however, whether H2S is involved in fibrotic process remains unknown. This study aimed to explore the role of H2S in the process of cardiac fibrosis and the underlying mechanisms. METHODS: Myocardial infarction (MI) was established in rats by ligation of coronary artery. Activation of rat neonatal cardiac fibroblasts was induced by angiotensin II (Ang II). Fibrotic responses in ischemic myocardium and in Ang II-stimulated cardiac fibroblasts were examined. The effects of sodium hydrosulfide (NaHS, an exogenous H2S donor) on NADPH oxidase 4 (Nox4), reactive oxygen species (ROS) production, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, heme oxygenase-1 (HO-1), and cystathionine γ-lyase (CSE) were tested to elucidate the protective mechanisms of H2S on fibrotic response. RESULTS: NaHS treatment inhibited Ang II-induced expression of α-smooth muscle actin, connective tissue growth factor (CTGF), and type I collagen and upregulated expression of HO-1 in cardiac fibroblasts. Ang II-induced Nox4 expression in cardiac fibroblasts was quenched by NaHS and this was associated with a decreased ROS production and reduced ERK1/2 phosphorylation and CTGF expression. In vivo studies using MI model indicated that NaHS administration attenuated Nox4 expression and fibrotic response. Moreover, NaHS therapy also prevented cardiac inflammatory response accompanied by increases in HO-1 and CSE expression. CONCLUSIONS: The beneficial effect of H2S, at least in part, was associated with a decrease of Nox4-ROS-ERK1/2 signaling axis and an increase in HO-1 expression.

Hydrogen sulfide as an endogenous modulator in mitochondria and mitochondria dysfunction.

Hydrogen sulfide (H(2)S) has historically been considered to be a toxic gas, an environmental and occupational hazard. However, with the discovery of its presence and enzymatic production through precursors of L-cysteine and homocysteine in mammalian tissues, H(2)S has recently received much interest as a physiological signaling molecule. H(2)S is a gaseous messenger molecule that has been implicated in various physiological and pathological processes in mammals, including vascular relaxation, angiogenesis, and the function of ion channels, ischemia/reperfusion (I/R), and heart injury. H(2)S is an endogenous neuromodulator and present studies show that physiological concentrations of H(2)S enhance NMDA receptor-mediated responses and aid in the induction of hippocampal long-term potentiation. Moreover, in the field of neuronal protection, physiological concentrations of H(2)S in mitochondria have many favorable effects on cytoprotection.