Thermosensitive SUMOylation of TaHsfA1 defines a dynamic ON/OFF molecular switch for the heat stress response in wheat.

Dissecting genetic components in crop plants associated with heat stress (HS) sensing and adaptation will facilitate the design of modern crop varieties with improved thermotolerance. However, the molecular mechanisms underlying the ON/OFF switch controlling HS responses (HSRs) in wheat (Triticum aestivum) remain largely unknown. In this study, we focused on the molecular action of TaHsfA1, a class A heat shock transcription factor, in sensing dynamically changing HS signals and regulating HSRs. We show that the TaHsfA1 protein is modified by small ubiquitin-related modifier (SUMO) and that this modification is essential for the full transcriptional activation activity of TaHsfA1 in triggering downstream gene expression. During sustained heat exposure, the SUMOylation of TaHsfA1 is suppressed, which partially reduces TaHsfA1 protein activity, thereby reducing the intensity of downstream HSRs. In addition, we demonstrate that TaHsfA1 interacts with the histone acetyltransferase TaHAG1 in a thermosensitive manner. Together, our findings emphasize the importance of TaHsfA1 in thermotolerance in wheat. In addition, they define a highly dynamic SUMOylation-dependent "ON/OFF" molecular switch that senses temperature signals and contributes to thermotolerance in crops.

Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors.

Objective: Primary resistance to trastuzumab frequently occurs in human epidermal growth factor receptor 2 (HER2)-positive (+) breast cancer patients and remains a clinical challenge. Pyrotinib is a novel tyrosine kinase inhibitor that has shown efficacy in the treatment of HER2+ breast cancer. However, the efficacy of pyrotinib in HER2+ breast cancer with primary trastuzumab resistance is unknown. Methods: HER2+ breast cancer cells sensitive or primarily resistant to trastuzumab were treated with trastuzumab, pyrotinib, or the combination. Cell proliferation, migration, invasion, and HER2 downstream signal pathways were analyzed. The effects of pyrotinib plus trastuzumab and pertuzumab plus trastuzumab were compared in breast cancer cells in vitro and a xenograft mouse model with primary resistance to trastuzumab. Results: Pyrotinib had a therapeutic effect on trastuzumab-sensitive HER2+ breast cancer cells by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and rat sarcoma virus (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) pathways. In primary trastuzumab-resistant cells, pyrotinib inhibited cell growth, migration, invasion, and HER2 downstream pathways, whereas trastuzumab had no effects. The combination with trastuzumab did not show increased effects compared with pyrotinib alone. Compared with pertuzumab plus trastuzumab, pyrotinib plus trastuzumab was more effective in inhibiting cell proliferation and HER2 downstream pathways in breast cancer cells and tumor growth in a trastuzumab-resistant HER2+ breast cancer xenograft model. Conclusions: Pyrotinib-containing treatments exhibited anti-cancer effects in HER2+ breast cancer cells sensitive and with primary resistance to trastuzumab. Notably, pyrotinib plus trastuzumab was more effective than trastuzumab plus pertuzumab in inhibiting tumor growth and HER2 downstream pathways in HER2+ breast cancer with primary resistance to trastuzumab. These findings support clinical testing of the therapeutic efficacy of dual anti-HER2 treatment combining an intracellular small molecule with an extracellular antibody.

Paternally imprinted LATE-FLOWERING2 transcription factor contributes to paternal-excess interploidy hybridization barriers in wheat.

Interploidy hybridization between hexaploid and tetraploid genotypes occurred repeatedly during genomic introgression events throughout wheat evolution, and is commonly employed in wheat breeding programs. Hexaploid wheat usually serves as maternal parent because the reciprocal cross generates progeny with severe defects and poor seed germination, but the underlying mechanism is poorly understood. Here, we performed detailed analysis of phenotypic variation in endosperm between two interploidy reciprocal crosses arising from tetraploid (Triticum durum, AABB) and hexaploid wheat (Triticum aestivum, AABBDD). In the paternal- versus the maternal-excess cross, the timing of endosperm cellularization was delayed and starch granule accumulation in the endosperm was repressed, causing reduced germination percentage. The expression profiles of genes involved in nutrient metabolism differed strongly between these endosperm types. Furthermore, expression patterns of parental alleles were dramatically disturbed in interploidy versus intraploidy crosses, leading to increased number of imprinted genes. The endosperm-specific TaLFL2 showed a paternally imprinted expression pattern in interploidy crosses partially due to allele-specific DNA methylation. Paternal TaLFL2 binds to and represses a nutrient accumulation regulator TaNAC019, leading to reduced storage protein and starch accumulation during endosperm development in paternal-excess cross, as confirmed by interploidy crosses between tetraploid wild-type and clustered regularly interspaced palindromic repeats (CRISPR) - CRISPR-associated protein 9 generated hexaploid mutants. These findings reveal a contribution of genomic imprinting to paternal-excess interploidy hybridization barriers during wheat evolution history and explains why experienced breeders preferentially exploit maternal-excess interploidy crosses in wheat breeding programs.

Prognostic value of gamma-interferon-inducible lysosomal thiol reductase expression in female patients diagnosed with breast cancer.

Because of the high heterogeneity of breast cancer outcome, identification of novel prognostic biomarkers is critical to improve patient stratification and guide precise treatment. We examined the prognostic value of gamma-interferon-inducible lysosomal thiol reductase (GILT) expression in a training set of 416 breast cancer patients and a validation set of 210 patients, and performed functional studies to investigate the functions and underlying mechanisms of GILT on breast cancer prognosis. Our results indicated that high GILT expression in breast cancer cells was associated with improved disease-free survival (DFS; hazard ratio [HR] = 0.189, 95% confidence interval [CI]: 0.099-0.361) and breast cancer-specific survival (BCSS; HR = 0.187, 95% CI: 0.080-0.437) of breast cancer patients both in the training set and the external validation set (HR = 0.453, 95% CI: 0.235-0.873 for DFS, HR = 0.488, 95% CI: 0.245-0.970 for BCSS). In vitro and in vivo studies showed that GILT overexpression inhibited breast cancer cells proliferation, invasion, migration and tumor formation in nude mice and increased sensitivity of breast cancer cells to standard treatment. Proteomics analysis indicated that GILT inhibited reactive oxygen species (ROS) and autophagy activation in breast cancer cells, and GILT overexpression-mediated tumor growth was further enhanced in the presence of autophagy or ROS inhibitors. Our results demonstrate that GILT expression can be effectively used to predict the prognosis and guide treatment strategies of breast cancer patients.

Taurine Prevents Liver Injury by Reducing Oxidative Stress and Cytochrome C-Mediated Apoptosis in Broilers Under Low Temperature.

Hypoxia caused by low ambient temperature leads to hypoxemia in broilers, which aggravates the metabolic burden of the liver. Liver damage is closely related to oxidative stress and apoptosis. It has been proved that taurine can reduce oxygen free radicals, exert antioxidant properties, and inhibit mitochondria-dependent apoptosis. This experiment aimed to determine whether taurine could prevent liver damage by inhibiting oxidative stress and the cytochrome c-mediated apoptotic pathway in broilers under low ambient temperature. Broilers were given 1% taurine in drinking water, and the temperature was raised at 10 °C ~ 12 °C from 21 to 42 days. At 28 and 42 days, the hepatic tissues were collected. The antioxidant capacity of liver tissues and mRNA expression levels of the factors related with cytochrome c-medicated apoptosis pathway were measured. The results showed taurine significantly increased the total antioxidant capacity (T-AOC) at 28 days. Furthermore, taurine also increased the activities of glutathione peroxidase (GSH-PX) while reducing malondialdehyde (MDA) concentration at 28 days and 42 days. Our results also revealed that taurine significantly increased the mRNA expression levels of Hsp 27 and Hsp 90 while decreasing caspase-3 mRNA expression in broiler hepatocytes at 28 days. In addition, taurine also upregulated the expression level of Bcl-2 at 42 days. In summary, the present study found that taurine enhances the antioxidant ability and alleviates cytochrome c-mediated apoptosis in hepatic tissue of broilers under low temperature.

Implementation of evidence in preventing medical device-related pressure injury in ICU patients using the i-PARIHS framework.

AIM: To examine the effectiveness of implementing the evidence in preventing medical device-related pressure injury (MDRPI) in intensive care patients. BACKGROUND: MDRPI is a common problem that significantly complicates patients' medical condition. However, evidence in preventing MDRPI is not properly implemented in clinical practice. METHODS: A pre- and post-implementation study was conducted using the Integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework. A baseline survey was implemented; barriers and enablers of evidence implementation were analysed to inform facilitation support strategies, such as training nursing staff and developing resources and tools. Changes in nurses, patients and the system were assessed after evidence implementation. RESULTS: Nurses' knowledge scores and evidence compliance significantly improved. The incidence of MDRPI in patients decreased from 24.39% to 4.26%. Standardized care and workflows to prevent MDRPI were established. CONCLUSION: The i-PARIHS framework supported effective implementation of the evidence in preventing MDRPI, narrowing the gap between evidence and clinical practice. IMPLICATIONS FOR NURSING MANAGEMENT: We provide an effective case of transforming evidence into practice based on the i-PARIHS framework. It can be used as a reference for colleagues in intensive care unit (ICU) or other settings to implement MDRPI prevention.

FRIZZY PANICLE defines a regulatory hub for simultaneously controlling spikelet formation and awn elongation in bread wheat.

Grain yield in bread wheat (Triticum aestivum L.) is largely determined by inflorescence architecture. Zang734 is an endemic Tibetan wheat variety that exhibits a rare triple spikelet (TRS) phenotype with significantly increased spikelet/floret number per spike. However, the molecular basis underlying this specific spike morphology is completely unknown. Through map-based cloning, the causal genes for TRS trait in Zang734 were isolated. Furthermore, using CRISPR/Cas9-based gene mutation, transcriptome sequencing and protein-protein interaction, the downstream signalling networks related to spikelet formation and awn elongation were defined. Results showed that the null mutation in WFZP-A together with deletion of WFZP-D led to the TRS trait in Zang734. More interestingly, WFZP plays a dual role in simultaneously repressing spikelet formation gene TaBA1 and activating awn development genes, basically through the recruitments of chromatin remodelling elements and the Mediator complex. Our findings provide insights into the molecular bases by which WFZP suppresses spikelet formation but promotes awn elongation and, more importantly, define WFZP-D as a favourable gene for high-yield crop breeding.

Changes in Alternative Splicing in Response to Domestication and Polyploidization in Wheat.

Alternative splicing (AS) occurs extensively in eukaryotes as an important mechanism for regulating transcriptome complexity and proteome diversity, but variation in the AS landscape in response to domestication and polyploidization in crops is unclear. Hexaploid wheat (AABBDD, Triticum aestivum) has undergone two separate allopolyploidization events, providing an ideal model for studying AS changes during domestication and polyploidization events. In this study, we performed high-throughput transcriptome sequencing of roots and leaves from wheat species with varied ploidies, including wild diploids (AbAb, Triticum boeoticum) and tetraploids (AABB, Triticum dicoccoides), domesticated diploids (AmAm, Triticum monococcum) and tetraploids (AABB, Triticum dicoccum), hexaploid wheat (AABBDD, T aestivum), as well as newly synthesized hexaploids together with their parents. Approximately 22.1% of genes exhibited AS, with the major AS type being intron retention. The number of AS events decreased after domestication in both diploids and tetraploids. Moreover, the frequency of AS occurrence tended to decrease after polyploidization, consistent with the functional sharing model that proposes AS and duplicated genes are complementary in regulating transcriptome plasticity in polyploid crops. In addition, the subgenomes exhibited biased AS responses to polyploidization, and ∼87.1% of homeologs showed AS partitioning in hexaploid wheat. Interestingly, substitution of the D-subgenome modified 42.8% of AS patterns of the A- and B-subgenomes, indicating subgenome interplay reprograms AS profiles at a genome-wide level, although the causal-consequence relationship requires further study. Conclusively, our study shows that AS variation occurs extensively after polyploidization and domestication in wheat species.

Genomic Imprinting Was Evolutionarily Conserved during Wheat Polyploidization.

Genomic imprinting is an epigenetic phenomenon that causes genes to be differentially expressed depending on their parent of origin. To evaluate the evolutionary conservation of genomic imprinting and the effects of ploidy on this process, we investigated parent-of-origin-specific gene expression patterns in the endosperm of diploid (Aegilops spp), tetraploid, and hexaploid wheat (Triticum spp) at various stages of development via high-throughput transcriptome sequencing. We identified 91, 135, and 146 maternally or paternally expressed genes (MEGs or PEGs, respectively) in diploid, tetraploid, and hexaploid wheat, respectively, 52.7% of which exhibited dynamic expression patterns at different developmental stages. Gene Ontology enrichment analysis suggested that MEGs and PEGs were involved in metabolic processes and DNA-dependent transcription, respectively. Nearly half of the imprinted genes exhibited conserved expression patterns during wheat hexaploidization. In addition, 40% of the homoeolog pairs originating from whole-genome duplication were consistently maternally or paternally biased in the different subgenomes of hexaploid wheat. Furthermore, imprinted expression was found for 41.2% and 50.0% of homolog pairs that evolved by tandem duplication after genome duplication in tetraploid and hexaploid wheat, respectively. These results suggest that genomic imprinting was evolutionarily conserved between closely related Triticum and Aegilops species and in the face of polyploid hybridization between species in these genera.

Exophiala pseudooligosperma sp. nov., a novel black yeast from soil in southern China.

Exophiala is an important genus, with several species associated with infections in humans and animals. In a survey of soil fungal diversity in Yunnan province, PR China, a novel taxon, Exophiala pseudooligosperma sp. nov., was identified based on combined morphological and molecular phylogenetic features. Morphologically, this species is characterized by having torulose, septate hyphae and swollen, terminal or intercalary conidiogenous cells arising at acute angles from aerial hyphae. Phylogenetic analysis of the combined sequences of the internal transcribed spacer, the small and large nuclear subunit of the rRNA gene and part of the ß-tubulin gene confirmed the phylogenetic position of the new species within the genus Exophiala.

Taurine Prevents the Electrical Remodeling in Ach-CaCl2 Induced Atrial Fibrillation in Rats.

OBJECTIVE: To study the preventive actions and mechanism of taurine on the electrical remodeling in atrial fibrillation (AF) rats. METHODS: Male Wistar rats were injected with the mixture of acetylcholine (Ach) (66 µg/mL)-CaCl2 (10 mg/mL) (i.v.) for 7 days to establish AF model. Taurine was administered in drinking water 1 week before or at the same time of AF model establishment. The duration of AF was monitored by recording ECG of rats during the model establishment. At the end of the experiment, left atrial appendages were cut down to measure the effective refractory period (ERP) by S1-S2 double stimulation method; atrial tissues were collected in order to detect the concentration of K+ and taurine by flame atomic absorption spectrometry and ELISA respectively; total RNA were extracted from the atrium, gene expressions of Kv1.5, Kv4.3, Kir2.1, Kir3.4 were detected by semi-quantitative RT-PCR. RESULTS: Taurine administration effectively shortened the AF duration of rats and prolonged atrial ERP than the model and taurine depleted rats. In addition, atrial K+ level in taurine treated groups was significantly reduced nearly to the normal level. Moreover, the mRNA expression levels of Kir3.4 and Kv1.5 were significantly increased in the taurine preventive treated groups. CONCLUSIONS: Taurine can prevent the atrial electrical remodeling and decrease the duration of AF in rats by reducing the atrial K+ concentration and up-regulating mRNA expression levels of Kir3.4 and Kv1.5.

Cell surface nucleolin is crucial in the activation of the CXCL12/CXCR4 signaling pathway.

Recently, CXCL12-CXCR4 has been focused on therapeutic strategies for papillary thyroid carcinoma (PTC) and other cancers. At the same time, cell surface nucleolin is also over-expressed in PTC and others. Interestingly, a few reports suggest that either CXCR4 or cell surface nucleolin is a co-receptor for HIV-1 entry into CD4+ T cells, which indicates that there is a relationship between CXCR4 and nucleolin. In this study, antibody and siRNA were used to identify effects of cell surface nucleolin and CXCR4 on cell signaling; soft-agar colony formation assay and Transwell assay were used to determine roles of nucleolin and CXCR4 in cell proliferation and migration. Importantly, co-immunoprecipitation was used to demonstrate the relationship between CXCR4 and nucleolin. Results showed CXCR4 and nucleolin were co-expressed in PTC cell line K1, B-CPAP, and TPC-1. Either cell surface nucleolin or CXCR4 was necessary to prompt extracellular signal-regulated kinase phosphorylation. When blocked, CXCR4 or nucleolin can significantly affect TPC-1 proliferation and migration (p < 0.01). Co-immunoprecipitation analysis identified that nucleolin can bind and interact with CXCR4 to activate CXCR4 signaling. This study suggests that nucleolin is crucial in the activation of CXCR4 signaling, which affects cell growth, migration, and invasiveness. Further, nucleolin may interact with other receptors. Our study also offers new ideas for cancer therapy.

Novel [99mTcN]2+ labeled EGFR inhibitors as potential radiotracers for single photon emission computed tomography (SPECT) tumor imaging.

The epidermal growth factor receptor (EGFR) is overexpressed in many cancers, including breast, ovarian, endometrial and non-small cell lung cancer. An EGFR-specific imaging agent could facilitate clinical evaluation of primary tumors or metastases. To achieve this goal, 4-(2-aminoethylamino)-6,7-dimethoxyquinazoline (ADMQ) was synthesized based on a 4-aminoquinazoline core and then conjugated with N-mercapto- acetylglycine (MAG) and N-mercaptoacetyltriglycine (MAG3), respectively, to give compounds 1 and 2. The final complexes [99mTcN]-1 and [99mTcN]-2 were successfully obtained with radiochemical purities of >99% and >98% as measured by radio-HPLC. No decomposition of the two complexes at room temperature was observed over a period of 2 h. Their partition coefficients indicated they were hydrophilic and the electrophoresis results showed they were negatively charged. Biodistribution in tumor-bearing mice demonstrated that the two new complexes showed tumor accumulation, high tumor-tomuscle (T/M) ratios and fast clearance from blood and muscle. Between the two compounds, the 99mTcN-MAG3-ADMQ ([99mTcN]-2) showed the better characteristics, with the tumor/muscle and tumor/blood ratios reached 2.11 and 1.90 at 60 min post-injection, 4.20 and 1.10 at 120 min post-injection, suggesting it could be a promising radiotracer for SPECT tumor imaging.

Label-free Raman spectroscopy reveals tumor microenvironmental changes induced by intermittent fasting for the prevention of breast cancer in animal model.

The development of tools that can provide a holistic picture of the evolution of the tumor microenvironment in response to intermittent fasting on the prevention of breast cancer is highly desirable. Here, we show, for the first time, the use of label-free Raman spectroscopy to reveal biomolecular alterations induced by intermittent fasting in the tumor microenvironment of breast cancer using a dimethyl-benzanthracene induced rat model. To quantify biomolecular alterations in the tumor microenvironment, chemometric analysis of Raman spectra obtained from untreated and treated tumors was performed using multivariate curve resolution-alternative least squares and support vector machines. Raman measurements revealed remarkable and robust differences in lipid, protein, and glycogen content prior to morphological manifestations in a dynamically changing tumor microenvironment, consistent with the proteomic changes observed by quantitative mass spectrometry. Taken together with its non-invasive nature, this research provides prospective evidence for the clinical translation of Raman spectroscopy to identify biomolecular variations in the microenvironment induced by intermittent fasting for the prevention of breast cancer, providing new perspectives on the specific molecular effects in the tumorigenesis of breast cancer.

Conservation tillage facilitates the accumulation of soil organic carbon fractions by affecting the microbial community in an eolian sandy soil.

Conservation tillage (CT) is an important agronomic measure that facilitates soil organic carbon (SOC) accumulation by reducing soil disturbance and plant residue mulching, thus increasing crop yields, improving soil fertility and achieving C neutrality. However, our understanding of the microbial mechanism underlying SOC fraction accumulation under different tillage practices is still lacking. Here, a 6-year in situ field experiment was carried out to explore the effects of CT and traditional tillage (CK) practices on SOC fractions in an eolian sandy soil. Compared with CK, CT increased the particulate OC (POC) content in the 0-30 cm soil layer and the mineral-associated OC (MAOC) content in the 0-20 cm soil layer. Moreover, tillage type and soil depth had significant influences on the bacterial, fungal and protistan community compositions and structures. The co-occurrence network was divided into 4 ecological modules, and module 1 exhibited significant correlations with the POC and MOC contents. After determining their topological roles, we identified the keystone taxa in the network. The results indicated that the most common bacterial taxa may result in SOC loss due to low C use efficiency, while specific fungal (Cephalotrichum) and protistan (Cercozoa) species could facilitate SOC fraction accumulation by promoting macroaggregate formation and predation. Therefore, the increase in keystone fungi and protists, as well as the reduction in bacteria, drove module 1 community function, which in turn promoted SOC sequestration under CT. These results strengthen our understanding of microbial functions in the accrual of SOC fractions, which contributes to the development of conservation agriculture on the Northeast China Plain.

Genomic and transcriptomic analysis of breast cancer identifies novel signatures associated with response to neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has become a standard treatment strategy for breast cancer (BC). However, owing to the high heterogeneity of these tumors, it is unclear which patient population most likely benefit from NAC. Multi-omics offer an improved approach to uncovering genomic and transcriptomic changes before and after NAC in BC and to identifying molecular features associated with NAC sensitivity. METHODS: We performed whole-exome and RNA sequencing on 233 samples (including matched pre- and post-treatment tumors) from 50 BC patients with rigorously defined responses to NAC and analyzed changes in the multi-omics landscape. Molecular features associated with NAC response were identified and validated in a larger internal, and two external validation cohorts, as well as in vitro experiments. RESULTS: The most frequently altered genes were TP53, TTN, and MUC16 in both pre- and post-treatment tumors. In comparison with pre-treatment tumors, there was a significant decrease in C > A transversion mutations in post-treatment tumors (P = 0.020). NAC significantly decreased the mutation rate (P = 0.006) of the DNA repair pathway and gene expression levels (FDR = 0.007) in this pathway. NAC also significantly changed the expression level of immune checkpoint genes and the abundance of tumor-infiltrating immune and stroma cells, including B cells, activated dendritic cells, γδT cells, M2 macrophages and endothelial cells. Furthermore, there was a higher rate of C > T substitutions in NAC nonresponsive tumors than responsive ones, especially when the substitution site was flanked by C and G. Importantly, there was a unique amplified region at 8p11.23 (containing ADGRA2 and ADRB3) and a deleted region at 3p13 (harboring FOXP1) in NAC nonresponsive and responsive tumors, respectively. Particularly, the CDKAL1 missense variant P409L (p.Pro409Leu, c.1226C > T) decreased BC cell sensitivity to docetaxel, and ADGRA2 or ADRB3 gene amplifications were associated with worse NAC response and poor prognosis in BC patients. CONCLUSIONS: Our study has revealed genomic and transcriptomic landscape changes following NAC in BC, and identified novel biomarkers (CDKAL1P409L, ADGRA2 and ADRB3) underlying chemotherapy resistance and poor prognosis, which could guide the development of personalized treatments for BC.

Modified minimum principal stress estimation formula based on Hoek-Brown criterion and equivalent Mohr-Coulomb strength parameters.

The most critical parameter for determining equivalent values for the Mohr-Coulomb friction angle and cohesion from the nonlinear Hoek-Brown criterion is the upper limit of confining stress. For rock slopes, this value is the maximum value of the minimum principal stress ([Formula: see text]) on the potential failure surface. The existing problems in the existing research are analyzed and summarized. Using the finite element method (FEM), the location of potential failure surfaces for a wide range of slope geometries and rock mass properties are calculated using the strength reduction method, and a corresponding finite element elastic stress analysis was carried in order to determine [Formula: see text] of the failure surface. Through a systematic analysis of 425 different slopes, it is found that slope angle (ß) and geological strength index (GSI) have the most significant influence on [Formula: see text] while the influence of intact rock strength and the material constant [Formula: see text] are relatively small. According to the variation of [Formula: see text] with different factors, two new formulas for estimating [Formula: see text] are proposed. Finally, the proposed two equations were applied to 31 real case studies to illustrate the applicability and validity.

H2S Alleviates Propofol-Induced Impaired Learning and Memory by Promoting Nuclear Translocation of Nrf2 and Inhibiting Apoptosis and Pyroptosis in Hippocampal Neurons.

BACKGROUND: Repeated exposure to propofol can affect their learning and memory functions, but the mechanism remains unclear. The current study aimed to investigate the mechanism underlying the effect of hydrogen sulfide (H2S) on the alleviation of propofol-induced learning and memory impairment, mediated by promoting nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and inhibiting apoptosis and pyroptosis in hippocampal neurons. METHODS: Rats used in this study were successively exposed to 200 mg/kg propofol for 8 consecutive weeks, followed by inhalation of 10, 40 or 80 ppm H2S. Subsequently, the effects of different concentrations of H2S on learning and memory were assessed using the water maze assay. Additionally, the effects of H2S on cell apoptosis and pyroptosis and nuclear translocation of Nrf2 in hippocampal neurons were also determined. Furthermore, NaHS (200 µmol/L) was used as an in vitro donor for H2S, and rescue experiments were carried out following Nrf2 knockdown in H19-7 cells. Moreover, Nrf2 function was inhibited following treatment with an intraperitoneal injection of ML385 (30 mg/kg) in the rats. The effects of H2S on reactive oxygen species (ROS) generation, cell apoptosis, and pyroptosis in propofol-treated and Nrf2-deficient H19-7 cells were also investigated. RESULTS: Exposure to propofol for 8 weeks affected the ability of the rats to find underwater platforms (p < 0.01). Further, the exposure induced cell apoptosis and NLR family pyrin domain containing 3 (NLRP3)-related pyroptosis (p < 0.01). Although inhalation of 10 ppm H2S did not attenuate the aforementioned effects (p > 0.05), exposure to 40 and 80 ppm H2S significantly alleviated propofol-induced injury in the hippocampal neurons (p < 0.01). However, the protective effect of 80 ppm H2S was more obvious as compared to that of the other two doses (p < 0.01). In addition, Nrf2 knockdown aggravated the propofol-induced cell pyroptosis and apoptosis as well as reversed the protective effect of H2S against these processes (p < 0.01). In vivo experiments in this study demonstrated that Nrf2 inhibition abrogated the protective effects of H2S inhalation against learning and memory impairment as well as propofol-induced cell apoptosis and pyroptosis in rats (p < 0.01). CONCLUSIONS: H2S could attenuate propofol-induced damage in hippocampal neurons by promoting the nuclear translocation of Nrf2 and inhibiting cell apoptosis and pyroptosis.

Combining Hydrodefluorination and Defluorophosphorylation for Chemo- and Stereoselective Synthesis of gem-Fluorophosphine Alkenes.

A chemo-, regio-, and stereoselective reaction of trifluoromethyl enones, phenylsilane, and phosphine oxides through a sequential hydrodefluorination and defluorophosphorylation relay is developed for the synthesis of distinctive gem-fluorophosphine alkenes. This multicomponent reaction occurred under transition-metal-free conditions with good functional group tolerance. Moreover, the preinstalled carbonyl auxiliary is important for tuning the reactivity of ß-trifluoromethyl enones, thereby enabling controllable and selective functionalization of two fluorine atoms in trifluoromethylated enones.

Na2S·9H2O Enabled Defluorodisulfuration and Hydrodefluorination of Perfluorobutyl Tetralones: Synthesis of Trifluoromethyl 1,2-Dithioles.

An unprecedented defluorocyclization of perfluorobutyl tetralones with Na2S·9H2O was developed for the synthesis of trifluoromethyl 1,2-dithioles, which provided chemists novel access to biologically and pharmaceutically relevant organofluorides. Successive C(sp3)-F bond functionalization at the perfluoroalkyl chain is vital for the formation of four C-H/C-S/S-S bonds and a five-membered S-heterocycle assembly. Cheap, weakly toxic, and odorless inorganic sulfide Na2S·9H2O acts as both a disulfurating precursor and a hydrodefluorinating reagent in this tandem multi-bond-interconverting reaction.