PET Imaging of Neurofibromatosis Type 1 with a Fluorine-18 Labeled Tryptophan Radiotracer.

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder. Plexiform neurofibromas (PNFs) are benign tumors commonly formed in patients with NF1. PNFs have a high incidence of developing into malignant peripheral nerve sheath tumors (MPNSTs) with a 5-year survival rate of only 30%. Therefore, the accurate diagnosis and differentiation of MPNSTs from benign PNFs are critical to patient management. We studied a fluorine-18 labeled tryptophan positron emission tomography (PET) radiotracer, 1-(2-[18F]fluoroethyl)-L-tryptophan (L-[18F]FETrp), to detect NF1-associated tumors in an animal model. An ex vivo biodistribution study of L-[18F]FETrp showed a similar tracer distribution and kinetics between the wild-type and triple mutant mice with the highest uptake in the pancreas. Bone uptake was stable. Brain uptake was low during the 90-min uptake period. Static PET imaging at 60 min post-injection showed L-[18F]FETrp had a comparable tumor uptake with [18F]fluorodeoxyglucose (FDG). However, L-[18F]FETrp showed a significantly higher tumor-to-brain ratio than FDG (n = 4, p < 0.05). Sixty-minute-long dynamic PET scans using the two radiotracers showed similar kidney, liver, and lung kinetics. A dysregulated tryptophan metabolism in NF1 mice was further confirmed using immunohistostaining. L-[18F]FETrp is warranted to further investigate differentiating malignant NF1 tumors from benign PNFs. The study may reveal the tryptophan-kynurenine pathway as a therapeutic target for treating NF1.

Control for multiple risk factors and incident heart failure and mortality in patients with diabetes mellitus: Insights from the Kailuan cohort study.

BACKGROUND: This study evaluated the relationship between controlling multiple risk factors and diabetes-related heart failure and all-cause mortality, and the extent to which the excess risk can be reduced. METHODS: 17,676 patients with diabetes and 69,493 matched non-diabetic control subjects were included in the Kailuan study, with a median follow-up of 11.19 years. The risk factor control was defined by the attainment of target values for systolic blood pressure, body mass index, low-density lipoprotein cholesterol, fasting blood glucose, high-sensitive C-reactive protein and smoking. Fine-Gray and Cox models were used to estimate associations between the degree of risk factor control and risk of heart failure and all-cause mortality respectively. RESULTS: Among diabetes patients, there was a gradual reduction in the risk of outcomes as the degree of risk factor control increased. For each additional risk factor that was controlled, there was an associated 16 % decrease in heart failure risk and a 10 % decrease in all-cause mortality risk. Among diabetes patients with ≥5 well-controlled risk factors, the adjusted hazard ratio compared to controls for heart failure and all-cause mortality was 1.25 (95 %CI: 0.99-1.56) and 1.17(95 %CI: 1.05-1.31) respectively. The protective effect of comprehensive risk factor control on the risk of heart failure was more pronounced in men and those using antihypertensive medications. CONCLUSIONS: Control for multiple risk factors is associated with reduced heart failure and all-cause mortality risks in a cumulative and sex-specific manner. However, despite optimization of risk factor control, diabetes patients still face increased risks compared to the general population.

Changes in Life's Essential 8 and risk of cardiovascular disease in Chinese people.

BACKGROUND: The American Heart Association recently released an updated algorithm for evaluating cardiovascular health-Life's Essential 8 (LE8). However, the associations between changes in LE8 score over time and risk of cardiovascular disease (CVD) remain unclear. METHODS: We investigated associations between 6-year changes (2006-12) in LE8 score and risk of subsequent CVD events (2012-20) among 53 363 Chinese men and women from the Kailuan Study, who were free from CVD in 2012. The LE8 score was calculated based on eight components: diet quality, physical activity, smoking status, sleep health, body mass index, blood lipids, blood glucose and blood pressure. Multivariable-adjusted Cox proportional-hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We documented 4281 incident CVD cases during a median of 7.7 years of follow-up. Compared with participants whose LE8 scores remained stable in a 6-year period, those with the large increases of LE8 score over the 6-year period had a lower risk of CVD, heart disease and stroke in the subsequent 8 years [HRs and 95% CIs: 0.67 (0.64, 0.70) for CVD, 0.65 (0.61, 0.69) for heart disease, 0.71 (0.67, 0.76) for stroke, all Ptrend < 0.001]. Conversely, those with the large decreases of LE8 score had 47%, 51% and 41% higher risk for CVD, heart disease and stroke, respectively. These associations were consistent across the subgroups stratified by risk factors. CONCLUSIONS: Improving LE8 score in a short- and moderate-term was associated with a lower CVD risk, whereas decreased LE8 score over time was associated with a higher risk.

Bridge connection between depression and anxiety symptoms and lifestyles in Chinese residents from a network perspective.

Background: Lifestyle habits are vital components of the culture of mental health treatment settings. We examined the bridge connection between depressive and anxiety symptoms and lifestyles from a network perspective using a population-based study. Methods: Face-to-face interviews were conducted with a provincially representative sample of 13,768 inhabitants from the Guangdong Sleep and Psychosomatic Health Survey based on standardized evaluation techniques. We identified the central symptoms by expected influence. The interconnection between depression and anxiety symptoms, as well as the bridge connectivity linking depression-anxiety symptoms and lifestyle factors, were assessed using the bridge centrality index. Network stability and sensibility analyses were performed using a case-dropping bootstrap procedure. Results: The core symptom that exhibited the highest expected influence was fatigue or little energy, followed by uncontrollable worry, trouble relaxing, and sad mood in the depression-anxiety symptoms network, while guilt was the most interconnected symptom and had the highest bridge strength. Surrounding nodes of each node explained an average variance of 57.63%. Additionally, suicidal thoughts were recognized as collective bridging symptoms connecting lifestyle variables in the network integrating depression-anxiety symptoms with lifestyle factors. Current tobacco and alcohol consumption were positively associated with suicidal thoughts and irritability. Habitual diet rhythm and physical exercise frequency were linked to suicidal thoughts, guilt, and poor appetite or overeating. Suicidal thoughts, irritability, and guilt indicated the greatest connectivity with lifestyle factors. All networks had high stability and accuracy. Conclusion: These highlighted core and bridge symptoms could serve as latent targets for the prevention and intervention of comorbid depression and anxiety. It might be crucial for clinical practitioners to design effective and targeted treatment and prevention strategies aiming at specific lifestyles and behaviors.

3,5,6-Trichloro-2-pyridinol confirms ototoxicity in mouse cochlear organotypic cultures and induces cytotoxicity in HEI-OC1 cells.

The metabolite of organophosphate pesticide chlorpyrifos (CPF), 3,5,6-Trichloro-2-pyridinol (TCP), is persistent and mobile toxic substance in soil and water environments, exhibiting cytotoxic, genotoxic, and neurotoxic properties. However, little is known about its effects on the peripheral auditory system. Herein, we investigated the effects of TCP exposure on mouse postnatal day 3 (P3) cochlear culture and an auditory cell line HEI-OC1 to elucidate the underlying molecular mechanisms of ototoxicity. The damage of TCP to outer hair cells (OHC) and support cells (SC) was observed in a dose and time-dependent manner. OHC and SC were a significant loss from basal to apical turn of the cochlea under exposure over 800 µM TCP for 96 h. As TCP concentrations increased, cell viability was reduced whereas reactive oxygen species (ROS) generation, apoptotic cells, and the extent of DNA damage were increased, accordingly. TCP-induced phosphorylation of the p38 and JNK MAPK are the downstream effectors of ROS. The antioxidant agent, N-acetylcysteine (NAC), could reverse TCP-mediated intracellular ROS generation, inhibit the expressive level of cleaved-caspase 3 and block phosphorylation of p38/JNK. Overall, this is the first demonstration of TCP damaging to peripheral sensory HCs and SC in organotypic cultures from the postnatal cochlea. Data also showed that TCP exposure induced oxidase stress, cell apoptosis and DNA damage in the HEI-OC1 cells. These findings serve as an important reference for assessing the risk of TCP exposure.

Preparation and bioactivity of the rare ginsenosides Rg3 and Rh2: An updated review.

Ginseng, an ancient medicinal herb, is used in oriental medicine for the treatment of various diseases. Saponins are the main bioactive components of ginseng, but the multiple glucosyl side chains on its molecules prevent ginsenosides from entering the blood through the intestinal membrane, thus reducing the efficacy. The preparation of rare ginsenosides, which are easy to be absorbed by human body and have higher drug activity, has been widely practiced by removing the sugar group of natural ginsenosides in vitro. Rare ginsenosides Rg3 and Rh2 have been approved as drugs or health supplements to improve immune function. This review summarizes the preparation methods of ginsenoside Rg3 and Rh2 in recent years. Ginsenoside Rg3 and Rh2 were prepared by biotransformation of protopanaxadiol type ginsenoside, with the highest conversion rate of 98.19% and 95.89% in the laboratory, respectively. At present, improving the conversion rate and reducing the production cost are still the bottleneck of industrial scale production of Rg3 and Rh2 through the deglycosylation directly from Rb1, Rb2, Rb3, Rc and Rd in the crude extract of ginseng. In addition, ginsenosides Rg3 and Rh2 play anti-inflammatory, anticancer, cardiovascular protective, immunomodulatory, neuroprotective, anti-diabetic, anti-fatigue, anti-allergic, anti-aging, antioxidant and other pharmacological effects by activating AMPK, JNK, NF-κB, MAPKs, P13K/AKT/mTOR and other signaling pathways. As potential drugs for prevention and treatment of various diseases, ginsenoside Rg3 and Rh2 need to further clarify other underlying mechanisms of action through in vitro and in vivo experiments.

Subjective cognitive decline symptoms and its association with socio-demographic characteristics and common chronic diseases in the southern Chinese older adults.

BACKGROUND: Subjective cognitive decline (SCD) may be the first symptomatic manifestation of Alzheimer's disease, but information on its health correlates is still sparse in Chinese older adults. This study aimed to estimate SCD symptoms and its association with socio-demographic characteristics, common chronic diseases among southern Chinese older adults. METHODS: Participants aged 60 years and older from 7 communities and 2 nursing homes in Guangzhou were recruited and interviewed with standardized assessment tools. Pittsburgh Sleep Quality Index (PSQI), Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) were used to measure poor sleep quality, depression symptoms and anxiety symptoms. The SCD symptoms were measured by SCD questionnaire 9 (SCD-Q9) which ranged from 0 to 9 points, with a higher score indicating increased severity of the SCD. Participants were divided into low score group (SCD-Q9 score ≤ 3) and higher score group (SCD-Q9 score > 3). Chi-square tests and multivariate logistic regression analysis were used for exploring the influences of different characteristics of socio-demographic and lifestyle factors on SCD symptoms. Univariate and multivariate logistic regression analysis were applied to explore the association between SCD symptoms with common chronic diseases. RESULTS: A total of 688 participants were included in our analysis with a mean age of 73.79 (SD = 8.28, range: 60-101), while 62.4% of the participants were females. The mean score of the SCD-Q9 was 3.81 ± 2.42 in the whole sample. A total of 286 participants (41.6%) were defined as the low score group (≤3 points), while 402 participants (58.4%) were the high score group (> 3 points). Multivariate logistic regression analysis revealed that female (OR = 1.99, 95%CI: 1.35-2.93), primary or lower education level (OR = 2.58, 95%CI: 1.38-4.83), nursing home (OR = 1.90, 95%CI: 1.18-3.05), napping habits (OR = 1.59, 95%CI: 1.06-2.40), urolithiasis (OR = 2.72, 95%CI: 1.15-6.40), gout (OR = 2.12, 95%CI: 1.14-3.93), poor sleep quality (OR = 1.93, 95%CI: 1.38-2.71), depression symptoms (OR = 3.01, 95%CI: 1.70-5.34) and anxiety symptoms (OR = 3.11, 95%CI: 1.29-7.46) were independent positive related to high SCD-Q9 score. On the other hand, tea-drinking habits (OR = 0.64, 95%CI: 0.45-0.92), current smoking (OR = 0.46, 95%CI: 0.24-0.90) were independent negative related to high SCD-Q9 score. CONCLUSIONS: Worse SCD symptoms were closely related to common chronic diseases and socio-demographic characteristics. Disease managers should pay more attention to those factors to early intervention and management for SCD symptoms among southern Chinese older adults.

NMR-Based Metabolomic Analysis on the Protective Effects of Apolipoprotein A-I Mimetic Peptide against Contrast Media-Induced Endothelial Dysfunction.

Endothelial dysfunction plays key roles in the pathological process of contrast media (CM)-induced acute kidney injury (CI-AKI) in patients undergoing vascular angiography or intervention treatment. Previously, we have demonstrated that an apolipoprotein A-I (apoA-I) mimetic peptide, D-4F, inhibits oxidative stress and improves endothelial dysfunction caused by CM through the AMPK/PKC pathway. However, it is unclear whether CM induce metabolic impairments in endothelial cells and whether D-4F ameliorates these metabolic impairments. In this work, we evaluated vitalities of human umbilical vein endothelial cells (HUVECs) treated with iodixanol and D-4F and performed nuclear magnetic resonance (NMR)-based metabolomic analysis to assess iodixanol-induced metabolic impairments in HUVECs, and to address the metabolic mechanisms underlying the protective effects of D-4F for ameliorating these metabolic impairments. Our results showed that iodixanol treatment distinctly impaired the vitality of HUVECs, and greatly disordered the metabolic pathways related to energy production and oxidative stress. Iodixanol activated glucose metabolism and the TCA cycle but inhibited choline metabolism and glutathione metabolism. Significantly, D-4F pretreatment could improve the iodixanol-impaired vitality of HUVECs and ameliorate the iodixanol-induced impairments in several metabolic pathways including glycolysis, TCA cycle and choline metabolism in HUVECs. Moreover, D-4F upregulated the glutathione level and hence enhanced antioxidative capacity and increased the levels of tyrosine and nicotinamide adenine dinucleotide in HUVECs. These results provided the mechanistic understanding of CM-induced endothelial impairments and the protective effects of D-4F for improving endothelial cell dysfunction. This work is beneficial to further exploring D-4F as a potential pharmacological agent for preventing CM-induced endothelial impairment and acute kidney injury.

Phosphoesterase complex modulates microflora and chronic inflammation in rats with alcoholic fatty liver disease.

Phosphoesterase complex (Pho), a major active component of barley malt, has been demonstrated to be clinically effective in relieving alcoholic fatty liver disease (AFLD), and several lines of evidence have suggested that microbial dysbiosis, caused by chronic alcohol overconsumption, plays a key role in the progression of AFLD. The current study aimed to investigate the modulatory effect of Pho on gut microflora. The microbiota diversity, determined via detection of the V4 region of 16S rDNA genes, was analyzed in rats fed the Lieber-Decarli diet. Gut permeability was evaluated via mucus layer staining. Dysbiosis-associated chronic inflammation was investigated by observing the expression of the following inflammatory molecules in the liver: tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1 (MCP-1), chemokine (C-X-C motif) ligand 1 (CXCL-1) and interleukin 1 beta (IL-1ß). Pyrosequencing revealed that the gut microbiota in Pho-treated rats was different from that of AFLD rats at both the phylum and genus levels. In addition, Pho significantly alleviated dysbiosis-associated disruption of gut permeability and inflammation, increased mucus layer thickness and downregulated TNF-α, MCP-1, CXCL-1 and IL-1ß expression. In summary, the current results revealed that the microflora, gut barrier and chronic inflammation in AFLD may be modulated by Pho.

RACK7 recognizes H3.3G34R mutation to suppress expression of MHC class II complex components and their delivery pathway in pediatric glioblastoma.

Histone H3 point mutations have been identified in incurable pediatric brain cancers, but the mechanisms through which these mutations drive tumorigenesis are incompletely understood. Here, we provide evidence that RACK7 (ZMYND8) recognizes the histone H3.3 patient mutation (H3.3G34R) in vitro and in vivo. We show that RACK7 binding to H3.3G34R suppresses transcription of CIITA, which is the master regulator of MHC (major histocompatibility complex) class II molecules and genes involved in vesicular transport of MHC class II molecules to the cell surface, resulting in suppression of MHC class II molecule expression and transport. CRISPR-based knock-in correction of the H3.3G34R mutation in human pediatric glioblastoma (pGBM) cells significantly reduces overall RACK7 chromatin binding and derepresses the same set of genes as does knocking out RACK7 in the H3.3G34R pGBM cells. By demonstrating that H3.3G34R and RACK7 work together, our findings suggest a potential molecular mechanism by which H3.3G34R promotes cancer.

Vascular Endothelial Growth Factor-Transfected Bone Marrow Mesenchymal Stem Cells Improve the Recovery of Motor and Sensory Functions of Rats With Spinal Cord Injury.

STUDY DESIGN: Basic science. OBJECTIVE: The aim of this study was to examine the effect of vascular endothelial growth factor (VEGF)-transfected bone marrow mesenchymal stem cells (BMSCs) on the recovery of motor and sensory functions of rats with spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: There is no effective treatment to protect against SCI. BMSCs have been widely applied to the treatment of nervous system damage due to the function of prompt neurite growth and inhibition of demyelination following injury. METHODS: VEGF-transfected BMSCs were injected to rats with SCI and the recovery of motor and sensory functions was observed. The Basso, Beattie, and Bresnahan, mechanical withdrawal threshold and thermal withdraw latency grading was conducted to assess the recovery status of motor and sensory functions of the SCI rats. The expression of VEGF, CD31, and NF200 was detected by immunofluorescence. RESULTS: The recovery of the rat motor and sensory functions in the VEGF-transfected BMSC (BMSC-VEGF) group was higher than those of the other groups with the exception of the Sham group (P < 0.05). The expression of the CD31 and NF200 proteins in the rat SCI regions was the highest in the BMSC-VEGF group, whereas the survival of BMSC in the BMSC-VEGF group was increased compared with that in the BMSC-Ad group. In addition, the injection of VEGF-transfected BMSCs can improve the angiogenesis of the injured area and retain the survival of injected cells and neurons. CONCLUSION: The injection of BMSC-VEGF improved the recovery of motor function in SCI rats. LEVEL OF EVIDENCE: N/A.

Apple polysaccharide protects ICR mice against colitis associated colorectal cancer through the regulation of microbial dysbiosis.

The study tried to investigate whether apple polysaccharide (AP) could prevent colitis associated colorectal cancer (CACC) through the regulation of intestinal microbiota disorders. 10 % AP (w/v) was administrated to ICR mice by gavage for 15 wk. It was found that AP treatment protected against CACC in mice effectively. The level of Lactobacillus in the intestine of AOM/DSS-treated mice was significantly decreased and that of Fusobacterium increased; while AP could reverse this trend and increase the intestinal microbiota diversity. The number of T cells and macrophages in the colon tissue of mice in AOM/DSS group elevated; while AP could reduce the number of these cells significantly. AP suppressed nuclear aggregation of ß-catenin, inhibited the activation of Wnt pathway in colon tissues. These data suggest that AP prevented ICR mice from CACC at least in part through regulating intestinal flora disorder and Wnt pathway.

Correction to: DNMT3A reads and connects histone H3K36me2 to DNA methylation.

The author would like to add the below information in this correction. A similar study from Chao Lu group was published online on 5 September 2019 in Nature, entitled "The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape" (Weinberg et al., 2019). Although both the studies reported the preferential recognition of H3K36me2 by DNMT3A PWWP, ours in addition uncovered a stimulation function by such interaction on the activity of DNMT3A. On the disease connections, we used a NSD2 gain-of-function model which led to the discovery of potential therapeutic implication of DNA inhibitors in the related cancers, while the other study only used NSD1 and DNMT3A loss-of-function models.

Successful Treatment by Surgery of a Primary Cutaneous Mucormycosis Caused by Mucor irregularis.

We report a case of primary cutaneous mucormycosis caused by Mucor irregularis. A 66-year-old man was presented to our hospital with a history of gradually enlarging plaque on the right leg for about a year. The identification of pathogen based on the fungus morphology and DNA sequencing revealed M. irregularis as the responsible fungus for skin lesion. The lesion was removed incidentally by a surgery procedure, and no recrudescence was seen during a follow-up of 24-month observation.

The apolipoprotein A-I mimetic peptide, D-4F, restrains neointimal formation through heme oxygenase-1 up-regulation.

D-4F, an apolipoprotein A-I (apoA-I) mimetic peptide, possesses distinctly anti-atherogenic effects. However, the biological functions and mechanisms of D-4F on the hyperplasia of vascular smooth muscle cells (VSMCs) remain unclear. This study aimed to determine its roles in the proliferation and migration of VSMCs. In vitro, D-4F inhibited VSMC proliferation and migration induced by ox-LDL in a dose-dependent manner. D-4F up-regulated heme oxygenase-1 (HO-1) expression in VSMCs, and the PI3K/Akt/AMP-activated protein kinase (AMPK) pathway was involved in these processes. HO-1 down-regulation with siRNA or inhibition with zinc protoporphyrin (Znpp) impaired the protective effects of D-4F on the oxidative stress and the proliferation and migration of VSMCs. Moreover, down-regulation of ATP-binding cassette transporter A1 (ABCA1) abolished the activation of Akt and AMPK, the up-regulation of HO-1 and the anti-oxidative effects of D-4F. In vivo, D-4F restrained neointimal formation and oxidative stress of carotid arteries in balloon-injured Sprague Dawley rats. And inhibition of HO-1 with Znpp decreased the inhibitory effects of D-4F on neointimal formation and ROS production in arteries. In conclusion, D-4F inhibited VSMC proliferation and migration in vitro and neointimal formation in vivo through HO-1 up-regulation, which provided a novel prophylactic and therapeutic strategy for anti-restenosis of arteries.

NMR-based metabolomic analysis for the effects of creatine supplementation on mouse myoblast cell line C2C12.

Creatine (Cr) supplementation has drawn much attention from researchers owing to its widespread efficacy in sports, and more recently, in therapeutic fields. However, the underlying molecular mechanisms remain elusive. Here, we performed nuclear magnetic resonance-based metabolomic analysis to address the metabolic profile of aqueous extracts from the mouse myoblast cell line C2C12 exposed to 2 mM Cr for 24 h (the Cr-treated group). Results showed that Cr supplementation facilitated the proliferation of C2C12 myoblasts. Both pattern recognition and hierarchical cluster analyses demonstrated that the metabolic profiles of the Cr-treated and control groups were distinctly different. We identified 13 characteristic metabolites significantly responsible for the discrimination of metabolic profiles between the two groups, through orthogonal projection to latent structures discriminant analysis and independent samples t-test. We further verified the discrimination performances of these metabolites by conducting univariate receiver operating characteristic curve analysis. Compared with the control group, the Cr-treated group exhibited increased levels of Cr, phosphocreatine (PCr), glutathione (GSH), and glucose, but decreased levels of leucine, valine, isoleucine, phenylalanine, methionine, choline, O-phosphocholine, sn-glycero-3-phosphocholine, and glycerol. Our results demonstrated that Cr supplementation upregulated PCr and glucose, promoted trichloroacetic acid cycle anaplerotic flux and GSH-mediated antioxidant capacity, and stabilized lipid membranes through suppressing glycerophospholipid metabolism. Our work provides new clues to the molecular mechanisms underlying the pleiotropic effects of Cr in muscle cells.

The apolipoprotein A-I mimetic peptide, D-4F, alleviates ox-LDL-induced oxidative stress and promotes endothelial repair through the eNOS/HO-1 pathway.

Apolipoprotein A-I (apoA-I) mimetic peptide exerts many anti-atherogenic properties. However, the underlying mechanisms related to the endothelial protective effects remain elusive. In this study, the apoA-I mimetic peptide, D-4F, was used. Proliferation assay, wound healing, and transwell migration experiments showed that D-4F improved the impaired endothelial proliferation and migration resulting from ox-LDL. Endothelial adhesion molecules expression and monocyte adhesion assay demonstrated that D-4F inhibited endothelial inflammation. Caspase-3 activation and TUNEL stain indicated that D-4F reduced endothelial cell apoptosis. A pivotal anti-oxidant enzyme, heme oxygenase-1 (HO-1) was upregulated by D-4F. The Akt/AMPK/eNOS pathways were involved in the expression of HO-1 induced by D-4F. Moreover, the anti-oxidation, pro-proliferation, and pro-migration capacities of D-4F were diminished by the inhibitors of both eNOS (L-NAME) and HO-1 (Znpp). Additionally, downregulation of ATP-binding cassette transporter A1 (ABCA1) by siRNA abolished the activation of Akt, AMPK and eNOS, and reduced the upregulation of HO-1 triggered by D-4F. Furthermore, D-4F promoted the reendothelialization of injured intima in carotid artery injury model of C57BL/6J mice in vivo. In summary, these findings suggested that D-4F might be a powerful candidate in the protection of endothelial cells and the prevention of cardiovascular disease (CVD).

Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex.

Regulation of enhancer activity is important for controlling gene expression programs. Here, we report that a biochemical complex containing a potential chromatin reader, RACK7, and the histone lysine 4 tri-methyl (H3K4me3)-specific demethylase KDM5C occupies many active enhancers, including almost all super-enhancers. Loss of RACK7 or KDM5C results in overactivation of enhancers, characterized by the deposition of H3K4me3 and H3K27Ac, together with increased transcription of eRNAs and nearby genes. Furthermore, loss of RACK7 or KDM5C leads to de-repression of S100A oncogenes and various cancer-related phenotypes. Our findings reveal a RACK7/KDM5C-regulated, dynamic interchange between histone H3K4me1 and H3K4me3 at active enhancers, representing an additional layer of regulation of enhancer activity. We propose that RACK7/KDM5C functions as an enhancer "brake" to ensure appropriate enhancer activity, which, when compromised, could contribute to tumorigenesis.

Overexpression of a Triticum aestivum Calreticulin gene (TaCRT1) Improves Salinity Tolerance in Tobacco.

Calreticulin (CRT) is a highly conserved and abundant multifunctional protein that is encoded by a small gene family and is often associated with abiotic/biotic stress responses in plants. However, the roles played by this protein in salt stress responses in wheat (Triticum aestivum) remain obscure. In this study, three TaCRT genes were identified in wheat and named TaCRT1, TaCRT2 and TaCRT3-1 based on their sequence characteristics and their high homology to other known CRT genes. Quantitative real-time PCR expression data revealed that these three genes exhibit different expression patterns in different tissues and are strongly induced under salt stress in wheat. The calcium-binding properties of the purified recombinant TaCRT1 protein were determined using a PIPES/Arsenazo III analysis. TaCRT1 gene overexpression in Nicotiana tabacum decreased salt stress damage in transgenic tobacco plants. Physiological measurements indicated that transgenic tobacco plants showed higher activities of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) than non-transgenic tobacco under normal growth conditions. Interestingly, overexpression of the entire TaCRT1 gene or of partial TaCRT1 segments resulted in significantly higher tolerance to salt stress in transgenic plants compared with their WT counterparts, thus revealing the essential role of the C-domain of TaCRT1 in countering salt stress in plants.

Effects of culture media on metabolic profiling of the human gastric cancer cell line SGC7901.

Cell culture metabolomics has demonstrated significant advantages in cancer research. However, its applications have been impeded by some influencing factors such as culture media, which could significantly affect cellular metabolic profiles and lead to inaccuracy and unreliability of comparative metabolomic analysis of cells. To evaluate the effects of different culture media on cellular metabolic profiling, we performed NMR-based metabolomic analysis of the human gastric cancer cell line SGC7901 cultured in both RPMI1640 and DMEM. We found that SGC7901 cultured in the two media exhibited distinct metabolic profiles with obviously different levels of discrepant metabolites, even though they showed almost the same cellular morphology and proliferation rates. When SGC7901 originally cultured in RPMI1640 was gradually acclimated in DMEM, both the metabolic profiles and most of the discrepant metabolite levels gradually converged toward those of the cells originally cultured in DMEM without significantly altered cell proliferation rates. However, several metabolite levels did not show the converging trends. Our results indicate that the effects of culture media on metabolic profiling must be carefully taken into account for comparative metabolomic analysis of cell lines. This work may be of benefit to the development of cell culture metabolomics.