Hydrogen exerts neuroprotective effects after subarachnoid hemorrhage by attenuating neuronal ferroptosis and inhibiting neuroinflammation.

OBJECTIVE: Spontaneous subarachnoid hemorrhage (SAH), the third most common stroke subtype, is associated with high mortality and disability rates. Therefore, finding effective therapies to improve neurological function after SAH is critical. The objective of this study was to investigate the potential neuroprotective effects of hydrogen in the context of SAH, specifically, by examining its role in attenuating neuronal ferroptosis and inhibiting neuroinflammation, which are exacerbated by excess iron ions after SAH. METHODS: Mice were exposed to chambers containing 3% hydrogen, and cells were cultured in incubators containing 60% hydrogen. Neurological function in mice was assessed using behavioral scores. Protein changes were detected using western blotting. Inflammatory factors were detected using enzyme linked immunosorbent assay. Probes, electron microscopy, and related kits were employed to detect oxidative stress and ferroptosis. RESULTS: Hydrogen improved the motor function, sensory function, and cognitive ability of mice after SAH. Additionally, hydrogen facilitated Nuclear factor erythroid 2 -related factor 2 activation, upregulated Glutathione peroxidase 4, and inhibited Toll-like receptor 4, resulting in downregulation of inflammatory responses, attenuation of oxidative stress after SAH, and inhibition of neuronal ferroptosis. CONCLUSION: Hydrogen exerts neuroprotective effects by inhibiting neuronal ferroptosis and attenuating neuroinflammation after SAH.

Hydrogen inhalation therapy regulates lactic acid metabolism following subarachnoid hemorrhage through the HIF-1α pathway.

The neuroprotective effects of hydrogen have been demonstrated, but the mechanism is still poorly understood. In a clinical trial of inhaled hydrogen in patients with subarachnoid hemorrhage (SAH), we found that hydrogen reduced the accumulation of lactic acid in the nervous system. There are no studies demonstrating the regulatory effect of hydrogen on lactate and in this study we hope to further clarify the mechanism by which hydrogen regulates lactate metabolism. In cell experiments, PCR and Western Blot showed that HIF-1α was the target related to lactic acid metabolism that changed the most before and after hydrogen intervention. HIF-1α levels were suppressed by hydrogen intervention treatment. Activation of HIF-1α inhibited the lactic acid-lowering effect of hydrogen. We have also demonstrated the lactic acid-lowering effect of hydrogen in animal studies. Our work clarifies that hydrogen can regulate lactate metabolism via the HIF-1αpathway, providing new insights into the neuroprotective mechanisms of hydrogen.

Peroxiredoxin 2 Is a Potential Objective Indicator for Severity and the Clinical Status of Subarachnoid Hemorrhage Patients.

Purpose: We have demonstrated that peroxiredoxin 2 (Prx2) released from lytic erythrocytes and damaged neurons into the subarachnoid space could activate microglia and then result in neuronal apoptosis. In this study, we tested the possibility of using Prx2 as an objective indicator for severity of the subarachnoid hemorrhage (SAH) and the clinical status of the patient. Materials and Methods: SAH patients were prospectively enrolled and followed up for 3 months. Cerebrospinal fluid (CSF) and blood samples were collected 0-3 and 5-7 days after SAH onset. The levels of Prx2 in the CSF and the blood were measured by an enzyme-linked immunosorbent assay (ELISA). We used Spearman's rank coefficient to assess the correlation between Prx2 and the clinical scores. Receiver operating characteristic (ROC) curves were used for Prx2 levels to predict the outcome of SAH by calculating the area under the curve (AUC). Unpaired Student's t-test was used to analyze the differences in continuous variables across cohorts. Results: Prx2 levels in the CSF increased after onset while those in the blood decreased. Existing data showed that Prx2 levels within 3 days in the CSF after SAH were positively correlated with the Hunt-Hess score (R = 0.761, P < 0.001). Patients with CVS had higher levels of Prx2 in their CSF within 5-7 days after onset. Prx2 levels in the CSF within 5-7 days can be used as a predictor of prognosis. The ratio of Prx2 in the CSF and the blood within 3 days of onset was positively correlated with the Hunt-Hess score and negatively correlated with Glasgow Outcome Scale (GOS; R = -0.605, P < 0.05). Conclusion: We found that the levels of Prx2 in the CSF and the ratio of Prx2 in the CSF and the blood within 3 days of onset can be used as a biomarker to detect the severity of the disease and the clinical status of the patient.

A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer.

Many cancers have developed resistance to 5-FU, due to removal by the enzyme uracil-DNA glycosylase (UDG), a type of base excision repair enzyme (BER) that can excise uracil and 5-fluorouracil (5-FU) from DNA. However, the development of UDG inhibitor screening methods, especially for the rapid and efficient screening of natural product/natural product-like compounds, is still limited so far. We developed herein a robust time-resolved photoluminescence method for screening UDG inhibitors, which could significantly improve sensitivity over the screening method based on the conventional steady-state spectroscopy, reducing the substantial fluorescence background interference. As a proof-of-concept, two potential UDG inhibitors were identified from a database of natural products and approved drugs. Co-treatment of these two compounds with 5-FU showed synergistic cytotoxicity, providing the basis for treating drug-resistant cancers. Overall, this method provides an avenue for the rapid screening of small molecule regulators of other BER enzyme activities that can avoid false negatives arising from the background fluorescence.

Emerging Screening Approaches in the Development of Nrf2-Keap1 Protein-Protein Interaction Inhibitors.

Due to role of the Keap1-Nrf2 protein-protein interaction (PPI) in protecting cells from oxidative stress, the development of small molecule inhibitors that inhibit this interaction has arisen as a viable approach to combat maladies caused by oxidative stress, such as cancers, neurodegenerative disease and diabetes. To obtain specific and genuine Keap1-Nrf2 inhibitors, many efforts have been made towards developing new screening approaches. However, there is no inhibitor for this target entering the clinic for the treatment of human diseases. New strategies to identify novel bioactive compounds from large molecular databases and accelerate the developmental process of the clinical application of Keap1-Nrf2 protein-protein interaction inhibitors are greatly needed. In this review, we have summarized virtual screening and other methods for discovering new lead compounds against the Keap1-Nrf2 protein-protein interaction. We also discuss the advantages and limitations of different strategies, and the potential of this PPI as a drug target in disease therapy.

An iridium(III) complex/G-quadruplex ensemble for detection of ochratoxin A based on long-lifetime luminescent.

A G-quadruplex-based platform has been developed for the time-resolved monitoring of ochratoxin A (OTA). The simple platform displays good sensitivity for OTA with a detection limit of 40 nM via steady-state emission spectroscopy. Notably, the platform showed a detection limit of 10.8 nM via time-resolved emission spectroscopy (TRES), which is about 4 times more sensitive than steady-state mode. Moreover, the probe showed excellent selectivity for OTA over other mycotoxins. Furthermore, OTA was successfully detected in actual herbal plant extracts samples. Our platform is the first to detect OTA using TRES to distinguish between the target signals versus the auto-fluorescence of real samples. This platform shows improved detection speed, accuracy and sensitivity with simple operation, low cost, and no requirement for complicated pre-processing.

Rhodium(III)-Based Inhibitor of the JMJD3-H3K27me3 Interaction and Modulator of the Inflammatory Response.

We describe in this study a rhodium(III) complex 1 as a new JMJD3 inhibitor and proinflammatory mediator. Complex 1 selectively inhibited the demethylation of H3K27me3 over other similar substrates, indicating its selectivity for JMJD3 over other histone demethylases, including JMJD2D and KDM5A. In terms of mechanism, complex 1 inhibited the JMJD3-H3K27me3 interaction in mouse macrophage cells and down-regulated the expression of TNF-α. To our knowledge, complex 1 is the first metal-based inhibitor of JMJD3 activity and only the second class of JMJD3 inhibitor reported overall.

Recent progress and developments of iridium-based compounds as probes for environmental analytes.

Metal complexes based on iridium metal centers have attracted attention as probes due to their tunable biological and chemical characteristics. This review highlights recent examples of iridium-based compounds that have been developed as probes for various environmental analytes. We also discuss the further challenges to be overcome for this class of probes in the future.

Iodine-enhanced ultrasound degradation of sulfamethazine in water.

This study investigated sulfamethazine (SMT) ultrasound degradation, enhanced by iodine radicals, generated by potassium iodide (KI) and hydrogen peroxide (H2O2) in situ. The results showed that the ultrasound/H2O2/KI (US/H2O2/KI) combination treatment achieved an 85.10 ±â€¯0.45% SMT removal (%) in 60 min under the following conditions: pH = 3.2, ultrasound power of 195 W, initial SMT concentration of 0.04 mmol·L-1, H2O2 concentration of 120 mmol·L-1, and KI concentration of 2.4 mmol·L-1. UV-Vis spectrophotometric monitoring of molecular iodine (I2) and triiodide (I3-) revealed a correlation between the SMT degradation and the iodine change in the solution. Quenching experiments using methanol, t-butanol and thiamazole as radical scavengers indicated that iodine radicals, such as I and I2-, were more important than hydroxyl radicals (HO) for SMT degradation. SMT degradation under the US/H2O2/KI treatment followed pseudo-first order reaction kinetics. The activation energy (Ea) of SMT degradation was 7.75 ±â€¯0.61 kJ·mol-1, which suggested the reaction was controlled by the diffusion step. Moreover, TOC removal was monitored, and the obtained results revealed that it was not as effective as SMT degradation under the US/H2O2/KI system.

Comparison of direct sequencing and amplification refractory mutation system for detecting epidermal growth factor receptor mutation in non-small-cell lung cancer patients: a systematic review and meta-analysis.

BACKGROUND: Direct sequencing and amplification refractory mutation system (ARMS) are commonly used to detect epidermal growth factor receptor (EGFR) mutation status in patients with non-small-cell lung cancer to inform the decision-making on tyrosine kinase inhibitors treatment. This study aimed to systematically compare the two methods in terms of the rate of detected mutations and the association of detected mutations with clinical outcomes. MATERIAL AND METHODS: PubMed, EMBASE, China National Knowledge Infrastructure (in Chinese) and Wanfang database (in Chinese) were searched to identify relevant studies. Meta-analyses of EGFR mutation rates, rate differences, and the associations of EGFR mutations with clinical outcomes of tyrosine kinase inhibitors treatment were conducted. RESULTS: Eight hundred and sixty-six records were retrieved and 26 studies with 3282 patients were included. The pooled rate of mutations detected by ARMS (41%, 95% confidence interval (CI) 35% to 47%) was significantly higher than that by direct sequencing (28%, 95%CI 22% to 34%), with a weighted rate difference of 11% (95%CI 8% to 13%). There was a consistent trend that the associations between ARMS-detected mutations and clinical outcomes were stronger than those between direct-sequencing-detected mutations and clinical outcomes (pooled risk ratio for objective response: 5.18 vs. 2.25; hazard ratio for progression-free survival: 0.30 vs. 0.42; hazard ratio for overall survival: 0.46 vs. 0.54). CONCLUSIONS: More patients with EGFR mutations can be identified by ARMS than by direct sequencing, and those identified by ARMS seems to be able to benefit more from tyrosine kinase inhibitors than those identified by direct sequencing.