In Addition to Damaging the Plasma Membrane, Phenolic Monoterpenoid Carvacrol Can Bind to the Minor Groove of DNA of Phytopathogenic Fungi to Potentially Control Tea Leaf Spot Caused by Lasiodiplodia theobromae.

Carvacrol expresses a wide range of biological activities, but the studies of its mechanisms focused on bacteria, mainly involving the destruction of the plasma membrane. In this study, carvacrol exhibited strong activities against several phytopathogenic fungi and demonstrated a novel antifungal mechanism against Lasiodiplodia theobromae. RNA sequencing indicated that many genes of L. theobromae hyphae were predominately induced by carvacrol, particularly those involved in replication and transcription. Hyperchromic, hypsochromic, and bathochromic effects in the UV-visible absorption spectrum were observed following titration of calf thymus DNA (ctDNA) and carvacrol, which indicated the formation of a DNA-carvacrol complex. Circular dichroism (CD) spectroscopy indicated that the response of DNA to carvacrol was similar to that of 4',6-diamidino-2-phenylindole (DAPI) but different from that of ethidium bromide (EB), implying the ionic bonds between carvacrol and ctDNA. Fluorescence spectrum (FS) analysis indicated that carvacrol quenched the fluorescence of double-stranded DNA (dsDNA) more than single-stranded DNA, indicating that carvacrol mainly bound to dsDNA. A displacement assay showed that carvacrol reduced the fluorescence intensity of the DNA-DAPI complex through competition with DAPI, but this did not occur for DNA-EB. The FS assay revealed that carvacrol bound to the AAA sequence on the minor groove of ds-oligonucleotides. The hydroxyl of carvacrol was verified to bind to ctDNA through a comparative test in which structural analogs of carvacrol, including thymol and 4-ethyl-1,2-dimethyl, were analyzed. The current study indicated carvacrol can destruct plasma membranes and bind to the minor groove of DNA, inhibiting fungal proliferation by disturbing the stability of dsDNA.

The DNA Repair-Associated Protein Gadd45γ Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory.

We have identified a member of the growth arrest and DNA damage (Gadd45) protein family, Gadd45γ, which is known to be critically involved in DNA repair, as a key player in the regulation of immediate early gene (IEG) expression underlying the consolidation of associative fear memory in adult male C57BL/6 mice. Gadd45γ temporally influences learning-induced IEG expression in the prelimbic prefrontal cortex (PLPFC) through its interaction with DNA double-strand break (DSB)-mediated changes in DNA methylation. Our findings suggest a two-hit model of experience-dependent IEG activity and learning that comprises (1) a first wave of IEG expression governed by DSBs and followed by a rapid increase in DNA methylation, and (2) a second wave of IEG expression associated with the recruitment of Gadd45γ and active DNA demethylation at the same site, which is necessary for memory consolidation.SIGNIFICANCE STATEMENT How does the pattern of immediate early gene transcription in the brain relate to the storage and accession of information, and what controls these patterns? This paper explores how Gadd45γ, a gene that is known to be involved with DNA modification and repair, regulates the temporal coding of IEGs underlying associative learning and memory. We reveal that, during fear learning, Gadd45γ serves to act as a coordinator of IEG expression and subsequent memory consolidation by directing temporally specific changes in active DNA demethylation at the promoter of plasticity-related IEGs.

MicroRNA regulatory networks in the pathogenesis of sarcopenia.

Sarcopenia is an age-related disease characterized by disturbed homeostasis of skeletal muscle, leading to a decline in muscle mass and function. Loss of muscle mass and strength leads to falls and fracture, and is often accompanied by other geriatric diseases, including osteoporosis, frailty and cachexia, resulting in a general decrease in quality of life and an increase in mortality. Although the underlying mechanisms of sarcopenia are still not completely understood, there has been a marked improvement in the understanding of the pathophysiological changes leading to sarcopenia in recent years. The role of microRNAs (miRNAs), especially, has been clearer in skeletal muscle development and homeostasis. miRNAs form part of a gene regulatory network and have numerous activities in many biological processes. Intervention based on miRNAs may develop into an innovative treatment strategy to conquer sarcopenia. This review is divided into three sections: firstly, the latest understanding of the pathogenesis of sarcopenia is summarized; secondly, increasing evidence for the involvement of miRNAs in the regulation of muscle quantity or quality and muscle homeostasis is highlighted; and thirdly, the possibilities and limitations of miRNAs as a treatment for sarcopenia are explored.

The marine-derived furanone reduces intracellular lipid accumulation in vitro by targeting LXRα and PPARα.

Recent studies have demonstrated that commercially available lipid-lowering drugs cause various side effects; therefore, searching for anti-hyperlipidaemic compounds with lower toxicity is a research hotspot. This study was designed to investigate whether the marine-derived compound, 5-hydroxy-3-methoxy-5-methyl-4-butylfuran-2(5H)-one, has an anti-hyperlipidaemic activity, and the potential underlying mechanism in vitro. Results showed that the furanone had weaker cytotoxicity compared to positive control drugs. In RAW 264.7 cells, the furanone significantly lowered ox-LDL-induced lipid accumulation (~50%), and its triglyceride (TG)-lowering effect was greater than that of liver X receptor (LXR) agonist T0901317. In addition, it significantly elevated the protein levels of peroxisome proliferator-activated receptors (PPARα) and ATP-binding cassette (ABC) transporters, which could be partially inhibited by LXR antagonists, GSK2033 and SR9243. In HepG2 cells, it significantly decreased oleic acid-induced lipid accumulation, enhanced the protein levels of low-density lipoprotein receptor (LDLR), ABCG5, ABCG8 and PPARα, and reduced the expression of sterol regulatory element-binding protein 2 (~32%). PPARα antagonists, GW6471 and MK886, could significantly inhibit the furanone-induced lipid-lowering effect. Furthermore, the furanone showed a significantly lower activity on the activation of the expression of lipogenic genes compared to T0901317. Taken together, the furanone exhibited a weak cytotoxicity but had powerful TC- and TG-lowering effects most likely through targeting LXRα and PPARα, respectively. These findings indicate that the furanone has a potential application for the treatment of dyslipidaemia.

Protective mechanisms of hydrogen sulfide in myocardial ischemia.

Hydrogen sulfide (H2 S), which has been identified as the third gaseous signaling molecule after nitric oxide (NO) and carbon monoxide (CO), plays an important role in maintaining homeostasis in the cardiovascular system. Endogenous H2 S is produced mainly by three endogenous enzymes: cystathionine ß-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfur transferase. Numerous studies have shown that H2 S has a significant protective role in myocardial ischemia. The mechanisms by which H2 S affords cardioprotection include the antifibrotic and antiapoptotic effects, regulation of ion channels, protection of mitochondria, reduction of oxidative stress and inflammatory response, regulation of microRNA expression, and promotion of angiogenesis. Amplification of NO- and CO-mediated signaling through crosstalk between H2 S, NO, and CO may also contribute to the cardioprotective effect. Exogenous H2 S donors are expected to become effective drugs for the treatment of cardiovascular diseases. This review article focuses on the protective mechanisms and potential therapeutic applications of H2 S in myocardial ischemia.

Ezetimibe promotes CYP7A1 and modulates PPARs as a compensatory mechanism in LDL receptor-deficient hamsters.

BACKGROUND: The LDL-C lowering effect of ezetimibe has been attributed primarily to increased catabolism of LDL-C via up-regulation of LDL receptor (LDLR) and decreased cholesterol absorption. Recently, ezetimibe has been demonstrated to have reverse cholesterol transport (RCT) promoting effects in mice, hamsters and humans. However, the underlying mechanisms are still not clear. The aim of this study is to investigate whether ezetimibe improves RCT-related protein expression in LDLR-/- hamsters. METHODS: A high-fat diet was used to induce a human-like hyperlipidemia in LDLR-/- hamsters. Lipid profiles were assayed by commercially available kits, and the effects of ezetimibe on lipid metabolism-related protein expression were carried out via western blot. RESULTS: Our data demonstrated that ezetimibe administration significantly reduced plasma total cholesterol (~ 51.6% reduction, P < 0.01) and triglyceride (from ~ 884.1 mg/dL to ~ 277.3 mg/dL) levels in LDLR-/- hamsters fed a high-fat diet. Ezetimibe administration (25 mg/kg/d) significantly promoted the protein expression of cholesterol 7 alpha-hydroxylase A1 (CYP7A1), LXRß and peroxisome proliferator-activated receptor (PPAR) γ; and down-regulated the protein expression of PPARα and PPARß. However, it showed no significant effect on sterol regulatory element-binding protein (SREBP)-1c, SREBP-2, proprotein convertase subtilisin/kexin type 9 (PCSK9), Niemann-Pick C1-like 1 (NPC1L1), and ATP-biding cassette (ABC) G5/G8. CONCLUSION: Ezetimibe may accelerate the transformation from cholesterol to bile acid via promoting CYP7A1 and thereby enhance RCT. As a compensatory mechanism of TG lowering, ezetimibe promoted the protein expression of PPARγ and decreased PPARα and ß. These results are helpful in explaining the lipid-lowering effects of ezetimibe and the potential compensatory mechanisms.

Optimisation of double-enzymatic extraction of arabinoxylan from fresh corn fibre.

Enzymatic extraction of arabinoxylans (AXs) is an attractive and environmentally friendly extraction option, in which technical considerations (yield and purity) have been coupled with environmental concerns. Amano HC 90 and Cellulase were combined to evaluate their interactive effects on AX extraction from destarched, deproteinised bran (DSDPB). A response surface methodology was used to obtain the optimal extraction conditions. The experimental data fit well with the predicted values and the model adequately represented the actual relationship among the measured parameters. The extraction yield and AX content in the extract under optimal conditions (double-enzyme dose of 920 U/g, pH of 3.0, extraction temperature of 35.0 °C; extraction time of 6 h; and DSDPB to liquid ratio of 1:30) were 40.73 ± 0.09% and 75.88 ± 0.11%, respectively. The double-enzymatic extraction method of AX from fresh corn fibre was more efficient than the chemical method.

The role of intestinal microbiota in cardiovascular disease.

Accumulating evidence has indicated that intestinal microbiota is involved in the development of various human diseases, including cardiovascular diseases (CVDs). In the recent years, both human and animal experiments have revealed that alterations in the composition and function of intestinal flora, recognized as gut microflora dysbiosis, can accelerate the progression of CVDs. Moreover, intestinal flora metabolizes the diet ingested by the host into a series of metabolites, including trimethylamine N-oxide, short chain fatty acids, secondary bile acid and indoxyl sulfate, which affects the host physiological processes by activation of numerous signalling pathways. The aim of this review was to summarize the role of gut microbiota in the pathogenesis of CVDs, including coronary artery disease, hypertension and heart failure, which may provide valuable insights into potential therapeutic strategies for CVD that involve interfering with the composition, function and metabolites of the intestinal flora.

Exogenous supplement of N-acetylneuraminic acid improves macrophage reverse cholesterol transport in apolipoprotein E-deficient mice.

BACKGROUND: N-acetylneuraminic acid (NANA) is the major form of sialic acid in mammals, and the plasma NANA level is increased in patients with cardiovascular diseases. Exogenous supplement of NANA has been demonstrated to reduce hyperlipidaemia and the formation of atherosclerotic lesions; however, the underlying mechanisms have not yet been clarified. The aim of this study is to investigate whether exogenous supplement of NANA improves reverse cholesterol transprot (RCT) in vivo. METHODS: Apolipoprotein E-deficient mice fed a high-fat diet were used to investigate the effect of NANA on RCT by [3H]-cholesterol-loaded macrophages, and the underlying mechanism was further investigated by various molecular techniques using fenofibrate as a positive control. RESULTS: Our novel results demonstrated that exogenous supplement of NANA significantly improved [3H]-cholesterol transfer from [3H]-cholesterol-loaded macrophages to the plasma (an increase of > 42.9%), liver (an increase of 35.8%), and finally to the feces (an increase of 50.4% from 0 to 24 h) for excretion in apolipoprotein E-deficient mice fed a high-fat diet. In addition, NANA up regulated the protein expression of ATP-binding cassette (ABC) G1 and peroxisome proliferator-activated receptor α (PPARα), but not the protein expression of ABCA1and scavenger receptor B type 1 in the liver. Therefore, the underlying mechanism of NANA in improving RCT may be partially due to the elevated protein levels of PPARα and ABCG1. CONCLUSION: Exogenous supplement of NANA improves RCT in apolipoprotein E-deficient mice fed a high-fat diet mainly by improving the protein expression of PPARα and ABCG1. These results are helpful in explaining the lipid-lowering effect of NANA.

Inorganic Salts Induce Thermally Reversible and Anti-Freezing Cellulose Hydrogels.

Inspired by the anti-freezing mechanisms found in nature, ionic compounds (ZnCl2 /CaCl2 ) are integrated into cellulose hydrogel networks to enhance the freezing resistance. In this work, cotton cellulose is dissolved by a specially designed ZnCl2 /CaCl2 system, which endows the cellulose hydrogels specific properties such as excellent freeze-tolerance, good ion conductivity, and superior thermal reversibility. Interestingly, the rate of cellulose coagulation could be promoted by the addition of extra water or glycerol. This new type of cellulose-based hydrogel may be suitable for the construction of flexible devices used at temperature as low as -70 °C.

FGF1 improves functional recovery through inducing PRDX1 to regulate autophagy and anti-ROS after spinal cord injury.

Fibroblast growth factor 1 (FGF1) is thought to exert protective and regenerative effects on neurons following spinal cord injury (SCI), although the mechanism of these effects is not well understood. The use of FGF1 as a therapeutic agent is limited by its lack of physicochemical stability and its limited capacity to cross the blood-spinal cord barrier. Here, we demonstrated that overexpression of FGF1 in spinal cord following SCI significantly reduced tissue loss, protected neurons in the ventricornu, ameliorated pathological morphology of the lesion, dramatically improved tissue recovery via neuroprotection, and promoted axonal regeneration and remyelination both in vivo and in vivo. In addition, the autophagy and the expression levels of PRDX1 (an antioxidant protein) were induced by AAV-FGF1 in PC12 cells after H2 O2 treatment. Furthermore, the autophagy levels were not changed in PRDX1-suppressing cells that were treated by AAV-FGF1. Taken together, these results suggest that FGF1 improves functional recovery mainly through inducing PRDX1 expression to increase autophagy and anti-ROS activity after SCI.

Valproate Attenuates Endoplasmic Reticulum Stress-Induced Apoptosis in SH-SY5Y Cells via the AKT/GSK3ß Signaling Pathway.

Endoplasmic reticulum (ER) stress-induced apoptosis plays an important role in a range of neurological disorders, such as neurodegenerative diseases, spinal cord injury, and diabetic neuropathy. Valproate (VPA), a typical antiepileptic drug, is commonly used in the treatment of bipolar disorder and epilepsy. Recently, VPA has been reported to exert neurotrophic effects and promote neurite outgrowth, but its molecular mechanism is still unclear. In the present study, we investigated whether VPA inhibited ER stress and promoted neuroprotection and neuronal restoration in SH-SY5Y cells and in primary rat cortical neurons, respectively, upon exposure to thapsigargin (TG). In SH-SY5Y cells, cell viability was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and the expression of ER stress-related apoptotic proteins such as glucose­regulated protein (GRP78), C/EBP homologous protein (CHOP), and cleaved caspase-12/-3 were analyzed with Western blot analyses and immunofluorescence assays. To explore the pathway involved in VPA-induced cell proliferation, we also examined p-AKT, GSK3ß, p-JNK and MMP-9. Moreover, to detect the effect of VPA in primary cortical neurons, immunofluorescence staining of ß-III tubulin and Anti-NeuN was analyzed in primary cultured neurons exposed to TG. Our results demonstrated that VPA administration improved cell viability in cells exposed to TG. In addition, VPA increased the levels of GRP78 and p-AKT and decreased the levels of ATF6, XBP-1, GSK3ß, p-JNK and MMP-9. Furthermore, the levels of the ER stress-induced apoptosis response proteins CHOP, cleaved caspase-12 and cleaved caspase-3 were inhibited by VPA treatment. Meanwhile, VPA administration also increased the ratio of Bcl-2/Bax. Moreover, VPA can maintain neurite outgrowth of primary cortical neurons. Collectively, the neurotrophic effect of VPA is related to the inhibition of ER stress-induced apoptosis in SH-SY5Y cells and the maintenance of neuronal growth. Collectively, our results suggested a new approach for the therapeutic function of VPA in neurological disorders and neuroprotection.

High expression of OCT4 is frequent and may cause undesirable treatment outcomes in patients with acute myeloid leukemia.

In recent years, many researches have shown that OCT4 is overexpressed in both germ cell tumors and somatic cancers. Meanwhile, OCT4 has relationship with poor prognosis in a lot of solid tumors, such as hepatocellular carcinoma, gastric cancer, and esophageal cancer. In our study, we investigated the expression status of OCT4 and its clinical significance in patients with acute myeloid leukemia (AML) using real-time quantitative PCR. The receiver operating characteristic (ROC) curve reveals that the level of OCT4 expression could be available for a potential diagnostic biomarker for differentiating AML from controls with an area under the ROC curve (AUC) of 0.915 (95 % confidence interval (CI) 0.837-0.992; P < 0.001). At the cutoff value of 0.56, the sensitivity and the specificity are 75.9 and 81.2 %, respectively. The amount of white blood cell (WBC) of patients with high OCT4 expression is higher than that of patients with low OCT4 expression (18.2 × 10(9) versus 2.7 × 10(9) L(-1), P = 0.001). Among those patients who are less than 70 years old, patients with OCT4 high expression have significantly shorter overall survival (OS) than those without OCT4 high expression (P = 0.048). These findings suggest that OCT4 high expression is a common event and may have an adverse impact on prognosis in AML.

MiR-378 promotes the migration of liver cancer cells by down-regulating Fus expression.

BACKGROUND: miR-378 regulates osteoblast differentiation and participates in tumor cell self-renewal and chemo-resistance. However, the function of miR-378 in liver cancer cell migration has not been reported to date. METHODS: miR-378 expression was examined using real-time quantitative PCR. HepG2 cell migration and liver cell invasion were examined using wound-healing and cell invasion assays. Additionally, HepG2 cell metastasis was analyzed in nude mice. RESULTS: miR-378 over-expression enhances HepG2 cell proliferation, migration and liver cell invasion. Typical metastatic lesions were found in the livers of mice injected with miR-378-transfected cells, and high levels of the CMV promoter were detected in the nodules, indicating that miR-378 promoted the metastasis of the tumor cells to the liver. We also demonstrated that miR-378 down-regulated Fus expression. CONCLUSIONS: Our results suggested that miR-378 enhanced cell migration and metastasis by down-regulating Fus expression.

CT-based radiomics for predicting lymph node metastasis in esophageal cancer: a systematic review and meta-analysis.

Objective: We aimed to evaluate the diagnostic effectiveness of computed tomography (CT)-based radiomics for predicting lymph node metastasis (LNM) in patients diagnosed with esophageal cancer (EC). Methods: The present study conducted a comprehensive search by accessing the following databases: PubMed, Embase, Cochrane Library, and Web of Science, with the aim of identifying relevant studies published until July 10th, 2023. The diagnostic accuracy was summarized using the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC). The researchers utilized Spearman's correlation coefficient for assessing the threshold effect, besides performing meta-regression and subgroup analysis for the exploration of possible heterogeneity sources. The quality assessment was conducted using the Quality Assessment of Diagnostic Accuracy Studies-2 and the Radiomics Quality Score (RQS). Results: The meta-analysis included six studies conducted from 2018 to 2022, with 483 patients enrolled and LNM rates ranging from 27.2% to 59.4%. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC, along with their corresponding 95% CI, were 0.73 (0.67, 0.79), 0.76 (0.69, 0.83), 3.1 (2.3, 4.2), 0.35 (0.28, 0.44), 9 (6, 14), and 0.78 (0.74, 0.81), respectively. The results demonstrated the absence of significant heterogeneity in sensitivity, while significant heterogeneity was observed in specificity; no threshold effect was detected. The observed heterogeneity in the specificity was attributed to the sample size and CT-scan phases (P < 0.05). The included studies exhibited suboptimal quality, with RQS ranging from 14 to 16 out of 36. However, most of the enrolled studies exhibited a low-risk bias and minimal concerns relating to applicability. Conclusion: The present meta-analysis indicated that CT-based radiomics demonstrated a favorable diagnostic performance in predicting LNM in EC. Nevertheless, additional high-quality, large-scale, and multicenter trials are warranted to corroborate these findings. Systematic Review Registration: Open Science Framework platform at https://osf.io/5zcnd.

Mechanism of the Treatment of Irritable Bowel Syndrome with Sini Powder and Tong Xie Yao Fang Decoction Based on Network Pharmacology.

This study used a network pharmacology approach to investigate the potential active ingredients of Sini Powder and Tong xie yao fang decoction and the underlying mechanisms in irritable bowel syndrome (IBS) treatment. The potential active ingredients of Sini Powder and Tong xie yao fang decoction were obtained from TCMSP databases, and the potential targets of the active ingredients were predicted and analyzed by using the Swiss Target Prediction database. T Genecard, DisGeNET, and OMIM databases were processed to screen the potential therapeutic targets in IBS. The interaction of overlapped candidates between the potential biotarget of herb extracts and the potential therapeutic target of IBS were analyzed by STRING website and visualized by the Cytoscape V3.8.0 software. Gene ontology (GO) analysis and Kyoto Genomics and Genomics Encyclopedia (KEGG) pathway were processed to categorize and map the potential biofunctions and effects of these candidates by using David database. Result. There were 139 predicted active components and 248 related biotargets of Sini Powder and Tong xie yao fang decoction which were involved in IBS treatment, and 522 annotations and 101 related pathways are obtained by enrichment analysis (P < 0.01, FDR < 0.05). The underlying mechanisms of Sini Powder and Tong xie yao fang decoction may be related to neuroactive ligand-receptor interaction, calcium, cAMP, and HIF-1 signaling pathways. In conclusion, our results showed that the effect and mechanism of Sini Powder and Tong xie yao fang decoction in IBS treatment were in multi-ingredient, multitargets and multipathways, which would provide several potential and promising strategies for the further research and development of Sini Powder and Tong xie yao fang decoction on IBS treatment.

Biomechanical analysis of lumbar spine with interbody fusion surgery and U-shaped lumbar interspinous spacers.

Previous research indicates whole-body vibration may lead to low back pain. The aim of this study is assessing the dynamic characteristics of a lumbar spine with Coflex and Coflex-F (commercial implants used as lumbar interspinous spacers) and effect of lumbar interbody fusion surgery. A transient dynamic analysis is performed on three numerical lumbar spine models under the loading condition of a vertical sinusoidal force of ±40 N with a compressive follower preload of 400 N. Also, Coflex-F model with and without interbody fusion surgery is analyzed under the same loading condition. The results show that the maximum value and vibration amplitude of von Mises stress in annulus ground substance (AGS) and intradiscal pressure (IDP) at implanted segment decrease from healthy model to Coflex model, and Coflex-F model. By contrast, for adjacent segments the maximum value of implanted models are larger than that of healthy model. The maximum value of endplates with and without cage are 2.44 MPa and 1.73 MPa (L4 inferior endplate), 1.94 MPa and 1.42 MPa (L5 superior endplate), respectively. The vibration amplitude of Coflex-F model with fusion surgery is smaller than that without fusion surgery. Coflex and Coflex-F not only protect implanted segment but also have a negative effect on adjacent segments. Inserting cage for Coflex-F model can absorb vibration energy at adjacent segments.

Setosphapyrone C and D accelerate macrophages cholesterol efflux by promoting LXRα/ABCA1 pathway.

LXRα agonists have attracted significant attention due to their potential biological activities on promoting cholesterol efflux. This study was designed to investigate whether setosphapyrone C and D have potential lipid-lowering capacity and the underlying mechanisms in vitro. Our data showed that setosphapyrone C and D had weak cytotoxicity compared to the liver X receptor α (LXRα) agonist T0901317. In RAW 264.7 macrophages, setosphapyrone C and D significantly enhanced [3H]-cholesterol efflux by ~ 21.3% and 32.4%, respectively; furthermore, setosphapyrone C and D enhanced the protein levels of ATP-binding cassette transporter (ABC) A1 and LXRα by 58% and 69%, and 60% and 70% (8 µM), respectively; however, they had no effect on the protein levels of ABCG1 and scavenger receptor B type 1; additionally, they had minor effect on the mRNA expression of lipogenic genes. Of note, setosphapyrone C and D significantly enhanced LXRα/ABCA1pathway in mice primary macrophages. In BRL cells, setosphapyrone C and D significantly improved the protein levels of ABCA1 and ABCG1; setosphapyrone D significantly enhanced the protein expression of low-density lipoprotein. Collectively, setosphapyrone C and D with weak cytotoxicity exhibited effective lipid-lowering effect via enhancing LXRα/ABC pathways. Setosphapyrones possess potential application for the treatment of hyperlipidemic diseases.

Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction.

DNA forms conformational states beyond the right-handed double helix; however, the functional relevance of these noncanonical structures in the brain remains unknown. Here we show that, in the prefrontal cortex of mice, the formation of one such structure, Z-DNA, is involved in the regulation of extinction memory. Z-DNA is formed during fear learning and reduced during extinction learning, which is mediated, in part, by a direct interaction between Z-DNA and the RNA-editing enzyme Adar1. Adar1 binds to Z-DNA during fear extinction learning, which leads to a reduction in Z-DNA at sites where Adar1 is recruited. Knockdown of Adar1 leads to an inability to modify a previously acquired fear memory and blocks activity-dependent changes in DNA structure and RNA state-effects that are fully rescued by the introduction of full-length Adar1. These findings suggest a new mechanism of learning-induced gene regulation that is dependent on proteins that recognize alternate DNA structure states, which are required for memory flexibility.

Publisher Correction: Dynamic regulation of Z-DNA in the mouse prefrontal cortex by the RNA-editing enzyme Adar1 is required for fear extinction.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.