Chrysin inhibits ferroptosis of cerebral ischemia/reperfusion injury via regulating HIF-1α/CP loop.

Chrysin is a natural flavonoid with powerful neuroprotective capacity. Cerebral ischemia/reperfusion injury (CIRI) is associated with oxidative stress and ferroptosis. Hypoxia-inducible factor 1α (HIF-1α) and ceruloplasmin (CP) are the critical targets for oxidation reactions and iron transport. But the regulatory mechanism between them is still unclear. Transient middle cerebral artery occlusion (tMCAO) model in rats and oxygen and glucose deprivation/re-oxygenation (OGD/R) model in PC12 cells were applied. Pathological tissue staining and biochemical kit were used to evaluate the effect of chrysin. The relationship between HIF-1α and CP was verified by transcriptomics, qRT-PCR and Western blot. In CIRI, HIF-1α/CP loop was discovered to be the regulatory pathway of ferroptosis. CIRI led to activation and nuclear translocation of HIF-1α, which promoted CP transcription and translation, and downstream ferroptosis. Inhibition of HIF-1α had opposite effect on CP and ferroptosis regulation. Overexpression of CP increased the expression of HIF-1α, nevertheless, inhibited the nuclear translocation of HIF-1α and alleviated CIRI. Silencing CP promoted HIF-1α elevation in nucleus and aggravated CIRI. Mechanistically, chrysin restrained HIF-1α nuclear translocation, thereby inhibiting CP transcription and translation, which in turn reduced downstream HIF-1α expression and mitigated ferroptosis in CIRI. Our results highlight chrysin restrains ferroptosis in CIRI through HIF-1α/CP loop.

Discovery of Potent, Selective, and Orally Bioavailable DYRK2 Inhibitors for the Treatment of Prostate Cancer.

Prostate cancer (PCa) seriously threatens male health, and targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) has been verified to reduce PCa burden, while the research progress on the DYRK2 inhibitors was relatively slow. In this work, we discovered DYRK2 inhibitor 12 (IC50 = 9681 nM) through virtual screening. Subsequently, we performed systematic structural optimization to obtain 54 (IC50 = 14 nM). Compound 54 exhibited high selectivity among 215 kinases and significantly suppressed the proliferation and metastasis of PCa cells in vitro. Moreover, compound 54 displayed high safety, favorable bioavailability, and potent tumor growth inhibitory activity in vivo, which could be used as a potential candidate in the discovery of novel anti-PCa drugs.

Pharmacokinetic differences in nicotine and nicotine salts mediate reinforcement-related behavior: an animal model study.

Since their introduction in the United States and Europe in 2007, electronic cigarettes (E-Cigs) have become increasingly popular among smokers. Nicotine, a key component in both tobacco and e-cigarettes, can exist in two forms: nicotine-freebase (FBN) and nicotine salts (NS). While nicotine salt is becoming more popular in e-cigarettes, the effect of nicotine salts on reinforcement-related behaviors remains poorly understood. This study aimed to compare the reinforcing effects of nicotine and nicotine salts in animal models of drug self-administration and explore potential mechanisms that may contribute to these differences. The results demonstrated that three nicotine salts (nicotine benzoate, nicotine lactate, and nicotine tartrate) resulted in greater reinforcement-related behaviors in rats compared to nicotine-freebase. Moreover, withdrawal-induced anxiety symptoms were lower in the three nicotine salt groups than in the nicotine-freebase group. The study suggested that differences in the pharmacokinetics of nicotine-freebase and nicotine salts in vivo may explain the observed behavioral differences. Overall, this study provides valuable insights into the reinforcing effects of nicotine as well as potential differences between nicotine-freebase and nicotine salts.

Discovery of Potent DYRK2 Inhibitors with High Selectivity, Great Solubility, and Excellent Safety Properties for the Treatment of Prostate Cancer.

Prostate cancer (PCa) is a common male cancer with high incidence and mortality, and hormonal therapy as the major treatment for PCa patients is troubled by the inevitable resistance that makes us identify novel targets for PCa. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) was found to be an effective target for the treatment of PCa, but the research on its inhibitors is rather little. In this work, a potent DYRK2 inhibitor 43 (IC50 = 0.6 nM) was acquired through virtual screening and structural optimization, which displayed high selectivity among 205 kinases; meanwhile, detailed interactions of 43 with DYRK2 were illustrated by the cocrystal. Furthermore, 43 possessed great water solubility (29.5 mg/mL), favorable safety properties (LD50 > 10,000 mg/kg), and potent anti-PCa activities, which could be used as a potential candidate in further preclinical studies.

Gut Bacterial Indole-3-acetic Acid Induced Immune Promotion Mediates Preventive Effects of Fu Brick Tea Polyphenols on Experimental Colitis.

Ulcerative colitis has been consistently associated with gut microbiota imbalance and disturbed immune system. Emerging research suggests a protective function of polyphenols on prevention and treatment of ulcerative colitis, yet underlying mechanisms remain unclear. Fu brick tea, a postfermented tea, contains abundant polyphenols with anti-inflammatory and antioxidant properties. In the present study, we found that prophylactic supplementation of polyphenols extracted from Fu brick tea (FBTP) dose-dependently alleviated colitis symptoms, immune cells infiltration, and pro-inflammatory cytokines secretion in mice suffering dextran sulfate sodium induced murine colitis. FBTP substantially reshaped gut microbiota and promoted microbial transformation of tryptophan into indole-3-acetic acid (I3A), thereafter leading to aryl hydrocarbon receptor (AHR)-mediated protection from colitis through enhanced expressions of IL-22 and tight junction proteins (i.e., ZO-1, occluding and claudin-1) in colon. Multiomics integration analyses revealed strong connections between I3A, tryptophan-metabolizing bacteria, AHR activity, and pathological phenotypes of colitis. Notably, FBTP failed to significantly alleviate colitis symptoms in the absence of gut microbiota, while intragastric administration of I3A could imitate benefits of FBTP on colitis alleviation and intestinal epithelial homeostasis through a direct enhancement in AHR activity in microbiota-depleted mice. These findings further determine the key role of gut microbiota controlled I3A-AHR signaling in mediating the FBTP on colitis alleviation. This study provides the first data proposing the FBTP as a natural prebiotic for colitis alleviation through the gut microbiota-dependent modulation of the AHR pathway. Most importantly, we also identified I3A as a key microbial metabolite targeted by FBTP for exhibiting health-promoting effects.

Complete genome sequence analysis of a new potyvirus isolated from Paris polyphylla var. yunnanensis.

The complete genome sequence of a new potyvirus from Paris polyphylla var. yunnanensis was determined. Its genomic RNA consists of 9571 nucleotides (nt), excluding the 3'-terminal poly(A) tail, containing the typical open reading frame (ORF) of potyviruses and encoding a putative large polyprotein of 3061 amino acids. The virus shares 54.20%-59.60% nt sequence identity and 51.80%-57.90% amino acid sequence identity with other potyviruses. Proteolytic cleavage sites and conserved motifs of potyviruses were identified in the polyprotein and within individual proteins. Phylogenetic analysis indicated that the virus was most closely related to lily yellow mosaic virus. The results suggest that the virus should be classified as a member of a novel species within the genus Potyvirus, and we have tentatively named this virus "Paris yunnanensis mosaic chlorotic virus" (PyMCV).

Complete genome sequence of polygonatum mosaic-associated virus 1, a novel member of the genus Potyvirus in China.

The complete genome sequence of a putative novel potyvirus, tentatively named "polygonatum mosaic-associated virus 1" (PMaV1), was sequenced from naturally infected Polygonatum cyrtonema Hua in China. PMaV1 has a typical genome organization of potyviruses with a single large open reading frame (nt 119-9448) that encodes a 3109-aa polyprotein that is predicted to be cleaved into 10 mature proteins by virus-encoded proteases. Pairwise comparisons revealed that PMaV1 shares 71.50% complete genome sequence identity with Polygonatum kingianum virus 4 and 80.00% amino acid sequence identity with Polygonatum kingianum virus 3 of the genus Potyvirus. Phylogenetic analysis indicated that PMaV1 clustered with other potyviruses and that it was most closely related to Polygonatum kingianum virus 3 and Polygonatum kingianum virus 4. These results suggest that PMaV1 is a new member of the genus Potyvirus of the family Potyviridae (Nucleotide sequence data reported are available in the GenBank databases under the accession number OP380926).

Simultaneous stabilization of Pb, Cd, and As in soil by rhamnolipid coated sulfidated nano zero-valent iron: Effects and mechanisms.

Sulfidation effectively improves the electron transfer efficiency of nanoscale zero-valent iron (nZVI), but decreases the specific surface area of nZVI. In this study, sulfidated nZVI (S-nZVI) coated with rhamnolipid (RL-S-nZVI) was synthesized and used to stabilize Pb, Cd, and As in combined polluted soil. The stabilization efficiency of 0.3% (wt) RL-S-nZVI to water soluble Pb, Cd, and As in soil reached 88.76%, 72%, and 63%, respectively. Rhamnolipid coating inhibited the reduction of specific surface area and successfully encapsulated nZVI, thus reducing the oxidation of Fe0. The types of iron oxides in RL-S-nZVI were reduced compared to S-nZVI, but the content and strength of Fe0 iron were obviously enhanced. Furthermore, rhamnolipid functional groups (-COOH and -COO-) were also involved in the stabilization process. In addition, the stabilization efficiency of RL-S-nZVI to the bioavailable Pb, Cd, and As in soil increased by 41%, 41%, and 50%, respectively, compared with nZVI. The presence of organic acids, especially citric acid, improved the stabilization efficiency of RL-S-nZVI to the three metals. The result of BCR sequential extraction indicated that RL-S-nZVI increased the residual state of Pb, Cd, and As and reduced the acid-soluble and reducible state after 28 days of soil incubation. XRD and XPS analyses showed that the stabilization mechanisms of RL-S-nZVI on heavy metals involved in ion exchange, surface complexation, adsorption, co-precipitation, chemisorption, and redox.

Simultaneous immobilization of arsenic, lead, and cadmium in soil by magnesium-aluminum modified biochar: Influences of organic acids, aging, and rainfall.

Magnesium-aluminum modified biochar (MABs) has an outstanding effect on the simultaneous immobilization of arsenic (As), lead (Pb), and cadmium (Cd) in soil, but the stability of remediation effect of MAB under various natural conditions is still unknown. In this study, we investigated the effects of organic acids, dry-wet cycles (DW), freeze-thaw cycles (FT), and rainfall (pH 4, 7, and 8) on the immobilization of As, Pb, and Cd by MAB. The results showed that oxalic acid decreased the immobilization efficiencies of As, Pb, and Cd by 15.5%-38.5%; meanwhile, humic acid reduced the immobilization efficiency of Pb by 89.7%, but elevated that of Cd by 19.5%. The immobilization mechanisms of MAB-5 on three metals were mainly involved in ion exchange and surface-complexation. Compared with the 7th round, the immobilization efficiencies of As, Pb, and Cd by MAB in the 28th round was decreased by 17%-28% in DW, but was increased by 11%-18% in FT. In addition, MAB was transformed into hydrotalcite after FT and DW. After experiencing simulated rainfall, MAB caused more As, Pb, and Cd to be retained in the upper soil layer, and the immobilization effect of MBA was more significant under the stimulated rainfall with higher pH. The study provides a more theoretical basis for the application of MAB in the actual site remediation.

SRSF10 is essential for progenitor spermatogonia expansion by regulating alternative splicing.

Alternative splicing expands the transcriptome and proteome complexity and plays essential roles in tissue development and human diseases. However, how alternative splicing regulates spermatogenesis remains largely unknown. Here, using a germ cell-specific knockout mouse model, we demonstrated that the splicing factor Srsf10 is essential for spermatogenesis and male fertility. In the absence of SRSF10, spermatogonial stem cells can be formed, but the expansion of Promyelocytic Leukemia Zinc Finger (PLZF)-positive undifferentiated progenitors was impaired, followed by the failure of spermatogonia differentiation (marked by KIT expression) and meiosis initiation. This was further evidenced by the decreased expression of progenitor cell markers in bulk RNA-seq, and much less progenitor and differentiating spermatogonia in single-cell RNA-seq data. Notably, SRSF10 directly binds thousands of genes in isolated THY+ spermatogonia, and Srsf10 depletion disturbed the alternative splicing of genes that are preferentially associated with germ cell development, cell cycle, and chromosome segregation, including Nasp, Bclaf1, Rif1, Dazl, Kit, Ret, and Sycp1. These data suggest that SRSF10 is critical for the expansion of undifferentiated progenitors by regulating alternative splicing, expanding our understanding of the mechanism underlying spermatogenesis.

[Exploration of mechanism of "simultaneous treatment of brain and heart" of Naoxintong Capsules based on Toll-like receptor signaling pathway].

This study aims to explore the mechanism of "simultaneous treatment of the brain and the heart" of Naoxintong Capsules(NXT) under cerebral ischemia based on Toll-like receptor(TLR) signaling pathway.Male SD rats were randomized into sham operation group, model group, NXT group, and positive drug group.Middle cerebral artery occlusion(MCAO) model rats were used in model group, NXT group, and positive drug group, respectively.Neurological function was scored with the Bederson scale, and brain infarct rate was measured by 2,3,5-triphenyltetrazolium chloride(TTC) staining.Brain edema was detected with wet-dry weight method.Hematoxylin-eosin(HE) staining and TdT-mediated dUTP nick-end labeling(TUNEL) staining were used to observe and count apoptotic cardiocytes.In addition, serum myocardial enzymes were measured.The expression of 8 TLR signaling pathway-related proteins interferon-α(IFN-α), interferon regulatory factor-3(IRF3), interferon regulatory factor-7(IRF7), TLR2, TLR4, TLR7, TLR9, and tumor necrosis factor-α(TNF-α) in the cerebral cortex and heart of rats was detected by Western blot. Brain infarct rate, neurological function score, and brain water content in NXT group decreased significantly compared with those in the model group. At the same time, the reduction in apoptosis rate of cardiocytes and the content of serum aspartate aminotransferase(AST), alanine aminotransferase(ALT), creatine kinase(CK), and lactate dehydrogenase(LDH) were decreased in the NXT group.Systems pharmacological results and previous research showed that TLR signaling pathway played an important role in immune inflammatory response.The study of TLR signaling pathway and related proteins is helpful to elucidate the mechanism of "simultaneous treatment of the brain and the heart". Western blot results showed that NXT significantly inhibited the expression of IRF3, IRF7, TLR2, TLR7, and TNF-α in cerebral cortex and heart under cerebral ischemia.Cerebral ischemia influences cardiac functions, and TLR signaling pathway is one of the pathways for "simultaneous treatment of the brain and the heart" of NXT.

mTOR contributes to endothelium-dependent vasorelaxation by promoting eNOS expression and preventing eNOS uncoupling.

Clinically used inhibitors of mammalian target of rapamycin (mTOR) negatively impacts endothelial-dependent vasodilatation (EDD) through unidentified mechanisms. Here we show that either the endothelium-specific deletion of Mtor to inhibit both mTOR complexes, or depletion of Raptor or Rictor to disrupt mTORC1 or mTORC2, causes impaired EDD, accompanied by reduced NO in the serum of mice. Consistently, inhibition of mTOR decreases NO production by human and mouse EC. Specifically, inhibition of mTORC1 suppresses eNOS gene expression, due to impairment in p70S6K-mediated posttranscriptional regulation of the transcription factor KLF2 expression. In contrast to mTORC1 inhibition, a positive-feedback between MAPK (p38 and JNK) activation and Nox2 upregulation contributes to the excessive generation of reactive oxygen species (ROS), which causes eNOS uncoupling and decreased NO bioavailability in mTORC2-inhibited EC. Adeno-associated virus-mediated EC-specific overexpression of KLF2 or suppression of Nox2 restores EDD function in endothelial mTORC1- or mTORC2-inhibited mice.

Tissue chondrification and ossification in keloids with primary report of five cases.

Keloid is commonly regarded as a benign skin tumour. Some keloids clinically exhibit hard tissue texture similar to that of cartilage or bone. We hypothesized that the keloid pathological niche environment is likely to induce keloid MSCs towards chondrogenic or osteogenic differentiation and leads to cartilage or bone-like tissue formation. The differences in tissue ossification, histology, mechanical properties, abnormal extracellular matrices and chondrogenic/osteogenic gene expression among sclerous keloids (SKs), regular keloids (RKs) and normal skins (NKs) were carefully examined. The sporadic ossified islets existed in SK group whereas no ossified/chondrified islet was found in other groups by micro-CT reconstruction. H&E, Masson trichrome and safranin O staining revealed lacuna-like structures in SKs, which were featured as bone/cartilage histology. Immunohistochemical staining showed overproduction of osteoprotegerin, type I and III collagen in SK group but similar production level of aggrecan among three groups. The biomechanical analysis demonstrated the weakest compliance of SK tissues. In addition, SK fibroblasts exhibited a relatively slower proliferation rate but higher expression levels of osteogenic and chondrogenic genes among all three groups. These cell populations also showed the strongest potential for lineage transformation. In conclusion, we first reported the presence of ossified and chondrified matrices in some extremely hard keloids in the present study.

Effect of Temperature on the Corrosion Behavior and Corrosion Resistance of Copper-Aluminum Laminated Composite Plate.

In this paper, the effect of temperature on the corrosion behavior and corrosion resistance of the copper-aluminum laminated composite plates were investigated by salt-spray corrosion, potential polarization curve and electrochemical impedance spectroscopy. Moreover, the microstructure of the copper-aluminum laminated composite plate after salt-spray corrosion was observed by scanning electron microscope, and X-ray photoelectron spectroscopy was used to study the composition of corrosion product. The results revealed that the corrosion products of the copper-aluminum laminated composite plate were Al2O3 and AlOOH. Due to the galvanic corrosion of the copper-aluminum laminated composite plate, the cathode underwent oxygen absorption corrosion during the corrosion process; therefore, the presence of moisture and the amount of dissolved oxygen in the corrosive environment had a great influence on the corrosion process. The increasing temperature would evaporate a large amount of moisture, resulting in the corrosion product-aluminum oxide dehydrated and covered the surface of the material in the process of salt-spray corrosion, which played a role in protecting the material. Therefore, the corrosion resistance of the copper-aluminum laminated composite plate first decreased and then increased. In the salt-spray corrosion environment, the corrosion resistance of the copper-aluminum laminated composite plate reached the lowest at 45 °C, and its corrosion rate was the fastest, at 0.728 g/m2·h. The electrochemical corrosion occurred in the solution, and the impact was small; however, in addition to the protective corrosion products, the ion mobility in the solution also had a certain influence on the corrosion rate, and the ionic activity increased with the increase of temperature. Therefore, the corrosion resistance of the copper-aluminum laminated composite plate gradually decreased as the temperature increased, and its corrosion resistance was the worst at 50 °C.

l-Lysine-Based Gelators for the Formation of Oleogels in Four Vegetable Oils.

Supramolecular oleogel is a soft material with a three-dimensional structure, formed by the self-assembly of low-molecular-weight gelators in oils; it shows broad application prospects in the food industry, environmental protection, medicine, and other fields. Among all the gelators reported, amino-acid-based compounds have been widely used to form organogels and hydrogels because of their biocompatibility, biodegradation, and non-toxicity. In this study, four Nα, Nε-diacyl-l-lysine gelators (i.e., Nα, Nε-dioctanoyl-l-lysine; Nα, Nε-didecanoyl-l-lysine; Nα, Nε-dilauroyl-l-lysine; and Nα, Nε-dimyristoyl-l-lysine) were synthesized and applied to prepare oleogels in four kinds of vegetable oils. Gelation ability is affected not only by the structure of the gelators but also by the composition of the oils. The minimum gel concentration (MGC) increased with the increase in the acyl carbon-chain length of the gelators. The strongest gelation ability was displayed in olive oil for the same gelator. Rheological properties showed that the mechanical strength and thermal stability of the oleogels varied with the carbon-chain length of the gelators and the type of vegetable oil. The microstructure of oleogels is closely related to the carbon-chain length of gelators, regardless of oil type. The highest oil-binding capacity (OBC) was obtained in soybean oil for all four gelators, and Nα, Nε-dimyristoyl-l-lysine showed the best performance for entrapping oils.

Multivalent self-assembled nano string lights for tumor-targeted delivery and accelerated biomarker imaging in living cells and in vivo.

Highly efficient monitoring of microRNA is of great significance for cancer research. By attaching aptamers to DNA nanowires through base pairing, here we designed a multivalent self-assembled DNA nanowire for fast quantification of intracellular target miRNAs in special cancer cells. In this work, an aptamer AS1411 and a microRNA-21 anti-sequence labeled with Cy5 were fixed on DNA nanowires, and then a short DNA strand with black hole quencher 2 (BHQ2) hybridizes with the microRNA-21 anti-sequence to quench Cy5. With the aid of AS1411, the probe can recognize and enter the target special cells efficiently. In addition, because of the banding between microRNA-21 and microRNA-21 anti-sequence, short DNA strands with BHQ2 are detached from the DNA nanowire and result in the recovery of Cy5 fluorescence signals. Ultimately, the fluorescence of Cy5 was activated quickly due to the high local concentration of recognition units on the nanowire, resulting in a large number of activated Cy5 dyes in a short time just like DNA nano string lights. Experimental results revealed that the designed DNA nanowire probe shows great performance for specifically and quickly monitoring microRNA-21 in living cells and in vivo. This developed strategy may become a general platform for detecting targets in living cells and possess great potential for biological and diagnostic research.

Simultaneous immobilization of arsenic, lead and cadmium by magnesium-aluminum modified biochar in mining soil.

Owing to the human activities such as smelting and mining, arsenic (As), lead (Pb) and cadmium (Cd) seriously polluted the soil of non-ferrous metal mining areas, thus efficient methods for the simultaneous immobilization of the three heavy metals are urgently needed. In the present study, Mg-Al modified biochars (MABs) were synthesized through a simple one-pot pyrolysis method to immobilize the three heavy metals. According to the BET (Brunauer-Emmett-Teller) test method, MABs had larger specific surface areas than biochar. Compared to the materials obtained at 300 °C and 700 °C, MAB with a pyrolysis temperature of 500 °C (MAB 500) had a significant immobilization effect on As, Pb and Cd in the Gansu mining area. Compared with BC, the removal efficiencies of As, Pb and Cd increased from -62%, 17% and 5% to 52%, 100% and 66%, respectively. And the toxicity characteristic leaching procedure (TCLP) test showed that the leaching concentrations of the three heavy metals in the treated soil were all lower than the standard value. X-ray photoelectron spectroscopy and kinetic experiments showed that there were various mechanisms in the immobilization process of the three heavy metals, and the large specific surface area and the multi-Mg/Al-OH of MABs play an important role in this process. More charges were provided by larger specific surface for ion exchange with heavy metals. In addition, larger specific surface area also provided more adsorption sites. More complex sites were provided by Mg/Al-OH to form Mg/Al-O-M then immobilize the heavy metals. In summary, the immobilization mechanism may involve electrostatic attraction, precipitation/co-precipitation, and surface complexation.

Recent advances of carbon-based nano zero valent iron for heavy metals remediation in soil and water: A critical review.

Heavy metal pollution in soil and water has presented a new challenge for the environmental remediation technology. Nano zero valent iron (nZVI) has excellent adsorbent properties for heavy metals, and thus, exhibits great potential in environmental remediation. Used as supporting materials for nZVI, carbon-based materials, such as activated carbon (AC), biochar (BC), carbon nanotubes (CNTs), and graphene (GNs) with aromatic rings formed by carbon atoms as the skeleton, have a large specific surface area and porous structure. This paper provides a comprehensive review on the advancement of carbon-based nano zero valent iron (C-nZVI) particles for heavy metal remediation in soil and water. First, different types of carbon-based materials and their combination with nZVI, as well as the synthesis methods and common characterization techniques of C-nZVI, are reviewed. Second, the mechanisms for the interactions between contaminants and C-nZVI, including adsorption, reduction, and oxidation reactions are detailed. Third, the environmental factors affecting the remediation efficiency, such as pH, coexisting constituents, oxygen, contact time, and temperature, are highlighted. Finally, perspectives on the challenges for utilization of C-nZVI in the actual contaminated soil and water and on the long-term efficacy and safety evaluation of C-nZVI have been proposed for further development.

Bidirectional role of reactive oxygen species during inflammasome activation in acrolein-induced human EAhy926 cells pyroptosis.

Acrolein, a known toxin in tobacco smoke, has been demonstrated to be associated with inflammatory cardiovascular diseases, such as atherosclerosis. However, the definite mechanism of acrolein-induced inflammation remains unclear. Here, we report that acrolein induces reactive oxygen species (ROS) production in EAhy926 cells. Additionally, acrolein induces EAhy926 cells' inflammatory response and pyroptosis by activating NOD-like receptor protein 3 (NLRP3) inflammasome. Also, acrolein-induced cytotoxicity could be attenuated by N-acetyl-L-cysteine (NAC). Furthermore, acrolein upregulates the level of autophagy which can be reversed by NAC. Notably, the present study also indicates that autophagy inhibited by inhibitor 3-methyladenine (3MA) and siAtg7 exacerbate acrolein-induced NLRP3 inflammasome activation and pyroptosis. In summary, acrolein induced cytotoxicity by ROS-mediated NLRP3 inflammasome activation, and ROS upregulates the level of autophagy to inhibit the NLRP3 inflammasome excessive activation, indicating the bidirectional role of ROS in acrolein-induced cellular inflammation. Our results may provide novel mechanistic insights into acrolein-induced cardiovascular toxicity.

Deletion of BAF250a affects oocyte epigenetic modifications and embryonic development.

BRG1-associated factor 250a (BAF250a) is a component of the SWI/SNF adenosine triphosphate-dependent chromatin remodeling complex, which has been shown to control chromatin structure and transcription. BAF250a was reported to be a key component of the gene regulatory machinery in embryonic stem cells controlling self-renewal, differentiation, and cell lineage decisions. Here we constructed Baf250aF/F ;Gdf9-cre (Baf250aCKO ) mice to specifically delete BAF250a in oocytes to investigate the role of maternal BAF250a in female germ cells and embryo development. Our results showed that BAF250a deletion did not affect folliculogenesis, ovulation, and fertilization, but it caused late embryonic death. RNA sequencing analysis showed that the expression of genes involved in cell proliferation and differentiation, tissue morphogenesis, histone modification, and nucleosome remodeling were perturbed in Baf250aCKO MII oocytes. We showed that covalent histone modifications such as H3K27me3 and H3K27ac were also significantly affected in oocytes, which may reduce oocyte quality and lead to birth defects. In addition, the DNA methylation level of Igf2r, Snrpn, and Peg3 differentially methylated regions was decreased in Baf250aCKO oocytes. Quantitative real-time polymerase chain reaction analysis showed that the relative messenger RNA (mRNA) expression levels of Igf2r and Snrpn were significantly increased. The mRNA expression level of Dnmt1, Dnmt3a, Dnmt3l, and Uhrf1 was decreased, and the protein expression in these genes was also reduced, which might be the cause for impaired imprinting establishment. In conclusion, our results demonstrate that BAF250a plays an important role in oocyte transcription regulation, epigenetic modifications, and embryo development.